CA2179396C - Tetrahydrofuran antifungals - Google Patents
Tetrahydrofuran antifungals Download PDFInfo
- Publication number
- CA2179396C CA2179396C CA002179396A CA2179396A CA2179396C CA 2179396 C CA2179396 C CA 2179396C CA 002179396 A CA002179396 A CA 002179396A CA 2179396 A CA2179396 A CA 2179396A CA 2179396 C CA2179396 C CA 2179396C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- esters
- formula
- pharmaceutically acceptable
- ester
- 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.)
- Expired - Lifetime
Links
- 229940121375 antifungal agent Drugs 0.000 title claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 title description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 157
- 150000002148 esters Chemical class 0.000 claims abstract description 71
- -1 phosphate ester Chemical class 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 25
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 16
- 239000010452 phosphate Substances 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 206010017533 Fungal infection Diseases 0.000 claims abstract description 8
- 208000031888 Mycoses Diseases 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 53
- 230000000843 anti-fungal effect Effects 0.000 claims description 31
- 239000002253 acid Chemical class 0.000 claims description 30
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 17
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229920000570 polyether Polymers 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- 101100439663 Arabidopsis thaliana CHR7 gene Proteins 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000003429 antifungal agent Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001033 ether group Chemical group 0.000 claims description 3
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 3
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 230000002265 prevention Effects 0.000 claims 4
- 238000003747 Grignard reaction Methods 0.000 claims 2
- AEZSNIWNOPGMOQ-UHFFFAOYSA-N N-(1-aminopropylidene)formamide Chemical compound C(=O)N=C(CC)N AEZSNIWNOPGMOQ-UHFFFAOYSA-N 0.000 claims 2
- 125000004185 ester group Chemical group 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
- 239000000243 solution Substances 0.000 description 62
- 239000000047 product Substances 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 229910000104 sodium hydride Inorganic materials 0.000 description 27
- 239000002585 base Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- PXACTUVBBMDKRW-UHFFFAOYSA-M 4-bromobenzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-M 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000003921 oil Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000000010 aprotic solvent Substances 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 9
- 229960004884 fluconazole Drugs 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- OWBTYPJTUOEWEK-UHFFFAOYSA-N (-)-(2R,3R)--2,3-butanediol Natural products CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 description 8
- 229920000858 Cyclodextrin Polymers 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 150000002170 ethers Chemical class 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 101150041968 CDC13 gene Proteins 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000002421 cell wall Anatomy 0.000 description 6
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000002024 ethyl acetate extract Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- OWBTYPJTUOEWEK-QWWZWVQMSA-N (R,R)-butane-2,3-diol Chemical compound C[C@@H](O)[C@@H](C)O OWBTYPJTUOEWEK-QWWZWVQMSA-N 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- 241000233866 Fungi Species 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 241000228212 Aspergillus Species 0.000 description 4
- 241001527609 Cryptococcus Species 0.000 description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 3
- 241001480043 Arthrodermataceae Species 0.000 description 3
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- 239000007818 Grignard reagent Substances 0.000 description 3
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 3
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- KJTULOVPMGUBJS-UHFFFAOYSA-N tert-butyl-[tert-butyl(diphenyl)silyl]oxy-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 KJTULOVPMGUBJS-UHFFFAOYSA-N 0.000 description 3
- HFGZFHCWKKQGIS-NOZJJQNGSA-N (2r,3r)-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1,2,4-triazol-1-yl)butan-2-ol Chemical compound C([C@@](O)([C@@H](C)S(C)(=O)=O)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 HFGZFHCWKKQGIS-NOZJJQNGSA-N 0.000 description 2
- MDTUWBLTRPRXBX-UHFFFAOYSA-N 1,2,4-triazol-3-one Chemical compound O=C1N=CN=N1 MDTUWBLTRPRXBX-UHFFFAOYSA-N 0.000 description 2
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
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Abstract
A compound represented by formula (I) 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 (C3 to C8) alkyl group substituted by one or two hydroxy moieties, an ether or ester (e.g., a polyestherester or phosphate ester) thereof a pharmaceutically acceptable salt thereof and pharmaceutical compositions thereof useful for treating and/or preventing fungal infections are disclosed.
Description
i 79396 BACKGROUND OF THE INVENTION
This invention relates to tetrahydrofuran antifungals, (2R-cis)-4-[4-[4-(4-([(5-(2,4-dihalophenyl)-tetrahydro-5-(1 H-1,2,4-triazol-t -yimethyl)-tetrahydrofuran-3-yljmethoxyjphenylj-2,4-dihydro-2-[mono- or dihydroxy-substituted (C3-C8) alkyl]-3H-1,2,4-triazol-3-one substituted antifungals, pharmaceutically acceptable esters, ethers and salts thereof, pharmaceutical compositions containing them, and methods of treating and/or preventing antifungal infections in hosts, including warm-blooded animals, espeaally humans with such tetrahydrofuran antifungals.
International Publication Number WO 89/04829, published 1 June 1990 and USP 5,039,676 (A.K. Saksena gt ~L) discloses (~) ~i,~ and (~)_ (traps antifungal compounds represented by the formula ~~ 20 ~ ~ NON-Z
X
O
~2 \N~ ~
N
wherein X= F, Cl; Z=loweralkyl, (C2-C8) alkanoyl or phenyl substituted by 2-loweralkyl-3-oxo-1,2,4-triazol-4-yi,e.g., (~)-dig and (~)-traps-1-(4-[j2-(2,4-difluorophenyl)-2-((1 H-1,2,4-triazol-1-yl)methyljtetrahydro-4-furanyl]methoxy]phenyl]-4-(1-methylethyl)piperazine. However, WO 89/04829 does not disclose the compounds of this invention.
Commonly-owned European Patent Publication No. 0539938, published 5 May 1993 discloses, for example, [(5R)-cis-4-[4-[4-[4-[[5-(2,4-dihalophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-7yl]methoxy]phenyl]-1-piperazinyl]phenyl)-2,4-dihydro-2-(C~ -C~o)alkyl)]-3H-1,2,4-triazol-3-one antifungals but does not disclose the compounds of this invention.
Janssen U. S. Patent 4,791,111 discloses, for example, ~+ cis-io 4[4-[4-[4-[[2-2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-2,4dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazol-3-one useful as an antimicrobial agent and having increased solubility, but does not disclose the compounds of this invention.
There is a need for broad-spectrum antifungal agents having is increased solubility and having favorable activity profile for treating systemic fungal infections, especially Aspergillus, Candida, Cyrptococcus and opportunistic infections.
SUMMARY OF INVENTION
2o The present invention provides compounds represented by formula I
H O N. R~
x R ',,,\ O ~ I NVN ~ ~ NON
O/
~N-N f Il N/
2s wherein X is independently both F or both CI or one X is independently F and the other is independently CI;
This invention relates to tetrahydrofuran antifungals, (2R-cis)-4-[4-[4-(4-([(5-(2,4-dihalophenyl)-tetrahydro-5-(1 H-1,2,4-triazol-t -yimethyl)-tetrahydrofuran-3-yljmethoxyjphenylj-2,4-dihydro-2-[mono- or dihydroxy-substituted (C3-C8) alkyl]-3H-1,2,4-triazol-3-one substituted antifungals, pharmaceutically acceptable esters, ethers and salts thereof, pharmaceutical compositions containing them, and methods of treating and/or preventing antifungal infections in hosts, including warm-blooded animals, espeaally humans with such tetrahydrofuran antifungals.
International Publication Number WO 89/04829, published 1 June 1990 and USP 5,039,676 (A.K. Saksena gt ~L) discloses (~) ~i,~ and (~)_ (traps antifungal compounds represented by the formula ~~ 20 ~ ~ NON-Z
X
O
~2 \N~ ~
N
wherein X= F, Cl; Z=loweralkyl, (C2-C8) alkanoyl or phenyl substituted by 2-loweralkyl-3-oxo-1,2,4-triazol-4-yi,e.g., (~)-dig and (~)-traps-1-(4-[j2-(2,4-difluorophenyl)-2-((1 H-1,2,4-triazol-1-yl)methyljtetrahydro-4-furanyl]methoxy]phenyl]-4-(1-methylethyl)piperazine. However, WO 89/04829 does not disclose the compounds of this invention.
Commonly-owned European Patent Publication No. 0539938, published 5 May 1993 discloses, for example, [(5R)-cis-4-[4-[4-[4-[[5-(2,4-dihalophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-7yl]methoxy]phenyl]-1-piperazinyl]phenyl)-2,4-dihydro-2-(C~ -C~o)alkyl)]-3H-1,2,4-triazol-3-one antifungals but does not disclose the compounds of this invention.
Janssen U. S. Patent 4,791,111 discloses, for example, ~+ cis-io 4[4-[4-[4-[[2-2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-2,4dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazol-3-one useful as an antimicrobial agent and having increased solubility, but does not disclose the compounds of this invention.
There is a need for broad-spectrum antifungal agents having is increased solubility and having favorable activity profile for treating systemic fungal infections, especially Aspergillus, Candida, Cyrptococcus and opportunistic infections.
SUMMARY OF INVENTION
2o The present invention provides compounds represented by formula I
H O N. R~
x R ',,,\ O ~ I NVN ~ ~ NON
O/
~N-N f Il N/
2s wherein X is independently both F or both CI or one X is independently F and the other is independently CI;
s .~l .. ~1~939b R~ is a straight or branched chain (C3 to Cg) alkyl group substituted by one or two hydroxy moieties or stereoisomers thereof or an ester or ether thereof, or a pharmaceutically acceptable salt thereof.
In a preferred aspect of the present invention, there is provided compounds represented by formula II
H ~ *~HR2R3 ''''''~ O ~ N
~N ~ ~ N~ N
~N~ ~ [ II J
N
wherein X is independently both F or both CI or one X is independently F and the other is independently CI;
wherein R2 is H or (C~-C3) alkyl and Rg is (C~-Cg) alkyl substituted by one hydroxy moiety and the carbon with the asterisk (') has the R
or S absolute configuration; an ester or ether thereof or a pharmaceutically acceptable salt thereof.
In another preferred aspect, the present invention provides a compound represented by formula III
_ O
F '''''~~ /
O ~ ~ N N ~ ~ ~N-R5 i O~ U , ~=N
N
N' ~~ III
'N
wherein R5 is ~ S nne nne ~~r~,.. ~u,.
R I OH , ~~ OH , ~-~ OH , S
~
In a preferred aspect of the present invention, there is provided compounds represented by formula II
H ~ *~HR2R3 ''''''~ O ~ N
~N ~ ~ N~ N
~N~ ~ [ II J
N
wherein X is independently both F or both CI or one X is independently F and the other is independently CI;
wherein R2 is H or (C~-C3) alkyl and Rg is (C~-Cg) alkyl substituted by one hydroxy moiety and the carbon with the asterisk (') has the R
or S absolute configuration; an ester or ether thereof or a pharmaceutically acceptable salt thereof.
In another preferred aspect, the present invention provides a compound represented by formula III
_ O
F '''''~~ /
O ~ ~ N N ~ ~ ~N-R5 i O~ U , ~=N
N
N' ~~ III
'N
wherein R5 is ~ S nne nne ~~r~,.. ~u,.
R I OH , ~~ OH , ~-~ OH , S
~
' X179396 _ S Me .'aR Me S Me ~~~~OH
OH ' OH ' R~
iini 1~ nu a OH , ~ OH , ~1 OH , Me R ' Me R ~ S
-~Me ~ Me S
~.OH
' OH' OH' ...~. Me 'Me Or OH ~ OH
an ester or ether thereof or a pharmaceutically acceptable salt thereof.
In another aspect of the present invention there is provided a compound represent by the formula IV
Rg F H
~ /~ j'-N' O ~N~~ NON
~ IV
F ~~N~
~= N
wherein R ~H(C2H5)CH(ORs)CH3 or -CH(CH3)CH(ORs)CH3 9°
wherein R6 is H, a polyether ester, a phosphate ester; a sulfate ester; a heterocyclic ester; an alkanoate ester; an alkenoate ester; an amino acid ester; an acid ester or a pharmaceutically acceptable salt thereof.
OH ' OH ' R~
iini 1~ nu a OH , ~ OH , ~1 OH , Me R ' Me R ~ S
-~Me ~ Me S
~.OH
' OH' OH' ...~. Me 'Me Or OH ~ OH
an ester or ether thereof or a pharmaceutically acceptable salt thereof.
In another aspect of the present invention there is provided a compound represent by the formula IV
Rg F H
~ /~ j'-N' O ~N~~ NON
~ IV
F ~~N~
~= N
wherein R ~H(C2H5)CH(ORs)CH3 or -CH(CH3)CH(ORs)CH3 9°
wherein R6 is H, a polyether ester, a phosphate ester; a sulfate ester; a heterocyclic ester; an alkanoate ester; an alkenoate ester; an amino acid ester; an acid ester or a pharmaceutically acceptable salt thereof.
__-_._._ T _..._-WO 95/17407 217 9 3 9 6 pCT/US94114236 DETAILED DESCRIPTION OF THE INVENTION AND OF THE PREP RRFD
EMBODIMENTS
The term "(C3-Cg) alkyl group substituted by one or two hydroxy moieties", as used herein means straight and branched chain alkyl groups of three to eight carbons including but not Limited to methyl, ethyl, n- and i~,Q-propyl, n-, sec-, i~ and ~r -butyl, n_-, sec -. i~-, ~r and n~-pentyl _n-, ~-, j~-~r - and n~-hexyl, n-, ~-, ~-, ~- and n~-heptyl, _n, ~- ~, ~r -and ngQ
octyl, substituted by one or two hydroxy moieties and includes R and S
stereoisomers of such (C3-C8) alkyl groups.
The term "(Ci-C3) alkyl substituted by one hydroxy moiety" means -CH20H , -CH(OH)CH3 , -CHZCH20H , -CH(OH)C2H$ , -CH2CH(OH)CH3 , and -(CH2)3-OH wherein the carbons with the asterisk(*) have the R or S absolute configuration.
The term "hydroxy-substituted C4 or C~ alkyl grcup" means -CH(C2H5)CH(OH)CH3 ,-CH(C2H5)CHZCH20H , -(CHZ)2 CH(OH)C2H5 , -CH(CH3)CH(OH)CH3 ,-~~~3)~~~ ar. -CH(C2H5)CHZOH
wherein each carbon with the asterisk (*) has the ~R or S absolute configuration.
The term "pharmaceutically acceptable ethers" means (a) straight and branched chain alkyloxy groups of one to twenty carbons, preferably of one to eight carbons, more preferably one to six carbons and (b) aryl(C~-C6) alkyloxy groups of the formula -O -(CHR7)n-Ar wherein R~ ~ H ar (cl-C6) straight and branched chain alkyl and n= 0 to 6 preferably 1 to 3 and Ar is phenyl, phenyl substituted by halo, especially chloro and fluoro, or by vitro, cyano and trihalomethyl especially trifluoromethyl. Most preferred ether groups include methyloxy and benzyloxy.
A
The term "esters" means (a) polyether esters (b) phosphate esters (c) heterocyclic esters (d) alkanoate and alkenoate esters (e) amino-alkanoates and (f) acid esters and (g) sulfate esters.
The term "polyether esters as used herein means those polyether esters O
represented by the formula - C-(CHR~)S-(OCHR~CHR~)t-ORg-, wherein R7 is as defined herein and s is an integer from 1 to 6, preferably s = 1 to 3 and more preferably s = 1; t is an integer from 1 to 6; preferably t is 1 to 3, more preferably t is 2 or 3.
R8 is R7 or (CHR~)5-C02R7 ~ preferably R$ is CH3 or C2H5 or CH2C02H or CHZC02CH3 . Typically suitable polyether esters -CO~H20(CHZCH20)~CH3 , ~-COCH20(CH2CH20y2CH,;
include . , , and -COCH20(CH2CH20)3CH3 . ' The term 'phosphate esters" as used herein means those phosphate acids esters represented by the formula O O
C -(CHR7)rT-~O)m P-(O1N)2 wherein z is 0 or 1; R7 is as defined herein above and preferably is H; n is an integer from 0 to 6, m is 0 or 1 and W
is H, CH2Ar or . OH and wherein Ar is as defined herein above.
O
Typically suitable phosphate acids and esters include P-(OCHZCsH$)2 O
- P- (OH) 2 .._.. , , P- ~ /
II
OH OH -.C-(CH2)n-0- P(OH)2 wherein m= n = 1 to 4; or O
-C-CH(CH3)-O-P(OH)2 and pharmaceutically acceptable salts thereof.
The term "heterocyciic ester" as used herein means heterocyclic esters O
- - ~CHR
(CHR7)w'-N ( 7)q represented by the formula Y''' wherein R~ is as defined herein above, W is an integer of from 1 to 5 preferably W is 1 to 3; q is = 3 or 4 and Y is CHR~, -O-, NH, NR7, S, SO or S02 Typically suitable heterocyclic esters include O O O
CHz- N - ~. CHI N~NH - ~~ CH N S I !-1 - ~- CH N
O
- ~ O _ N~ ~ 3 C CH 2--N O ~ O - CH 2--~V~SO 2 U
O
and - C - CH 2--N
The term "alkanoate and alkenoate esters" as used herein means straight or branched chain alkanoate or alkenoate groups optionally substituted by a hydroxy or ether moiety or mixtures of such alkanoates or alkenoates.
Preferred alkanoate esters include acetate to decanoate, especially acetate to butanoate. Preferred hydroxy substituted alkanoate ester include C~
to C8 alkanoate substituted one hydroxy moiety, especially ~1~9396 CCH20H and -C-CH(OH)CH3 . Preferred alkenoate esters are the C~o-C2o alkenoates and include C~4 to C18 alkenoates, such as ~-7-hexadecenoate.
The term "amino alkanoate" as used herein include the natural and unnatural amino acid residues preferably with amino groups protected by the conventional protecting groups well known to those in art such as phenyl acetate.
The term "acid ester' as used herein means those acid esters O
-C- CR R -~-OH
represented by the formula ( ~ ~)k wherein R7 is as defined herein above and k is an integer of from 1 to 8. Typically suitable acid esters include oxalic, malonic, succinic glutaric and adipic acids as well as O O
branched chain diacids such as CCHCH3-COH
The term "ether" as used herein means (C~-C6) alkyl or aryl (C~-C6) alkyl which are conveniently made by the well known Williamson Synthesis of ethers. Typicaly suitable ethers groups include methyl and benzyl.
The compounds of the present invention as well as the esters and ethers thereof exhibit broad spectrum antifungal activity in various in vi r assays against n i , other yeasts, dematophytes, As~rgillus and opportunistic fungi. The in vi r antifungal activity test were performed via conventional agar dilution methods in Sabouraud dextrose broth ("SDB") medium against a large number of fungi. Minimum Inhibitory Concentrations ("MICs") were measured after 24, 48 and 72 hour tests.
The term "opportunistic fungi" include Crytococcus. HistoQlasma.
Blastomvces Coccidioides Fusarium Mucor Paracoccidioides Fonsecaea . , 2179396 lNanaiella. Soorothrix PneumocvstiS Trichosoorq_n as shown by in viv activity in an appropriate animal species e.g. mouse, rat or rabbit. The compounds of the inventions are expected to exhibit activity against many genera and species of bacteria, protozoa, gram negatives, gram positives, Anaerobes, i n II
r i , L~yCODr ~3Sma, Treoonema, Gardneralla, Trichomononas and ~canosoma The preferred compounds of formula III wherein R5=hydroxy-substituted C4 and C5 alkyl groups, exhibited the following in vi r antifungal activity in SDB against 37 species of As~erq~illus niq~er, flavus, mi and rr ~ geometric mean MICs in the range of <_0.05 to >_1.53 (mcg/ml) and geometric mean MFCs in the range of 0.27 to 24.24 mcg/ml.
The preferred compounds of formula III wherein R5 is a hydroxy-substituted C5 alkyl group exhibited (1 ) superior antifungal activity as measured by geometric mean MICs and MFCs in various in vi r assays against ~
Ricans (N=26), . kr ' (N=26), I r (N=9), C. trooicalis (N=4), ~,, stellatoidea (N=1 ), C. neoformans (N=3), and the dermatophytes, T.T. rubrum.
T.T. manta, and T. tonsurans (N=6) (after 48 or 78 hours) compared to fluconazole as well as (2) superior anti-fungal activity in the following inin vivo models: an A DerQIIhIS- flaVl~S and fumiaa~ (four strains) in a pulmonary immuno-compromised mouse model (PO-1 XDX4D) compared to other azoles e.g.
itraconazole, and in a Candida albi _ans (four species) systemic model with normal and compromised mice (PO-1 XDX4D) compared to other azoles, e.g.
fluconazole.
The in viv oral antifungal activity of the compounds of the present invention were compared to azole antifungals, e.g., fluconazole in an Asoerqillus pulmonary infection model in mice. The procedure of David Loebenberg et al. entitled "Sch 42427, The Active Enantiomer of Antifungal agent Sch 39304; In vitro Activity", Antimicrobial AaentS and Chemotheraov (1992), ~ 498-501 was used. The Asoergillus- flavus pulmonary model is also ~ ~ X9396 ._ WO 95/17407 PCTlUS94114236 described in European Patent Application No. 0 539,938 AI published on 5 May 1993.
The preferred compounds of formula III exhibited superior antifungal in vi r activity in SDB against 37 species of Aspergillus with (a) geometric mean MICs of < 0.05 to s 0.81 compared to fluconazole (geometric mean MIC >_ 32 and (b) with geometric mean MFCs of <_ 0.89 to < 3.78 compared to fluconazole (geometric mean MFC >_ 32).
The Tables Q, R, and S hereinbelow display the superior in vi r antifungal activity of three preferred compounds of formula III compared to fluconazole. Table D displays such antifungal acitivity such as the percentage of strains of various fungi with MICs <_ 1 mcg/ml for the three preferred compounds of formula III compared to fluconazole. Table R displays the antifungai activity as the percentage of the same strains with MFCs < 1 mcglml.
Table S displays the in vi r MIC 90 values for the three preferred compounds of formula III agains the same organisms listed in Tables Q and R.
The most preferred compound of formula III where R5 =
Me S
S
OH
showed consistently higher serum levels in mice, rats, dogs and monkeys following oral dosing with a methyl cellulose formulation compared to azoles of similiar structure and also exhibited very long serum half life following O.D. dosing with good tissue distribution. The above listed most preferred compound of formula III are not inducers of various cytochrome P-450 liver drug metabolizing enzymes after oral administration in an inin vivo rat model io FOR COMPOUNDS
OF
FORMULA I II
PERCENTAGE
OF STRAINS
WITH MICs (MC G/ML) Me s Me Me 85 uu~
~~OH ~S OH ~~R__OH
~ ~
Aspergillus 37 100 100 100 0 Candida Albicans 26 100 100 100 100 Candida Kursei 16 100 100 100 100 Candida Tropicalis & Stellatoidea5 100 100 100 100 Candida Glabrdta 9 22 22 33 0 Cryptococcus 3 100 100 100 0 Neoformans Dermatophytes6 100 100 100 100 1. O
H N, A5 F ''''~O N~ N N~ N
O/
F ~ ~ (~l N
2. FLZ = fiuconazole WO PC'TlUS94/14236 TABLE R
IN VITRO ACTIVITY SELECTEDCOMPOUNDS
ANTIFUNGAL FOR OF
FORMULA IIh PERCENTAGE OF STRAINS l MCGIML
WITH MICs S
IM CG/MU
MB S Me S Me nn.~
/~ OH /~ OH ~/ R OH
~ ~
Aspergillus 50 62 89 0 Candida Albicans 100 100 100 100 Candida Kursei 1-16 88 94 100 0 Candida Tropicalis 8~ Steltatoidea 100 100 100 100 Candida Gtabrata 22 22 22 0 Cryptococcus 100 100 100 0 Neofortnans Dermatophytes 67 83 100 0 1. 0 H ' R' ~N
N _ N
N
~ ~ ~ i O
~N-N I~I
_ N' 2. FLZ = fluconazole m TABLE S
IN VITRO ANTiFUNGAL ACTIVITY FOR SELECTED COMPOUNDS OF
FORMULA IIh PERCENTAGE OF STRAINS WITH MICs Sl MCGIML
n~ncr ~,~~ v g5 ~i~-~
/ g pH ~/ p ' OH
1~etA'c ~/ S OH
s Aspergiilus 37 .122 .096 .112 29.9 Candida Atbicans 26 274 .174 .139 .887 Candida iCursei 16 .058 .014 .12 29.9 Candida Tropicalis 8~ Steilatoidea 5 .11? .117 .354 .917 Candida G~~ g 28.8 17.1 28.8 29.3 Cryptococcus 3 .05 .007 .101 25.9 Neofortnans Dermatophytes 6 .165 .101 '707 29'4 1. 0 H ~N.
F ~O~IN~~IN~%N
R 0, ~N._N I ~ J
N' 2. F11= fiu~nazole 2 ~ 7396 ._ The preferred esters and ethers of the compounds of the present invention of formula IV also exhibited superior in viv antifungal activity against a broad range of fungi. After oral and parenteral e.g. IV administration in mice, rats, dogs and monkeys. The preferred esters and ethers of formula IV listed below wherein Rg is _ _ O
/ N ~ / N~N-Rs LN
IV
Rs Rs Me O
Me 'P~OCH2CgH5 ~~OH
OCHzCBHs ~ O
NIA 961.4 M' 759.3 217939b Rs Rs Me p~O~O~O~OH S
Me O O Me p Me ~ ~5 ~N.Me a AA* 841 ~O~.O~O.~oMe S
Mi' 905 Me a ~O
s Me O ~ O~O~O~OMe S Me ~ 826 Me ~ 905 Me O
S
....0 Me R ~ O~O~O~OMe a O O H2 2NMG
M"891 S
R Me Me 1O~ 'Me Me ~O~O~ ~ 853.2 O a M' 817 S O,P,,O
a Me ~'OH .2NMG
... p OH
O~O~O~Me R a M' 781.7 Me NI~ 861 1~OPO3Hp. 2NMG
Me Me 1 - -O
""' R O M* 881.3 p~OH ~NMG Me Me O S
NI+ 801 ~ OP03H2. 2NMG
Me O
M' 881.3 2 ~ 7939b Rs R9 Me S Me O~ ,~O .... R
Me P~OCHvMe OCH2Celi5 Me 0O
AA+ 7424 Me Me OH
,... R O i ~ S ...H
.2Et3N O~Me Me 10H OH Me O
M* 873.3 ~ X3.1 Me a R .... R
""' O' ~'p O
Me P1~OH ~~ Me O
OH
AA* 781.8 ~ X8.7 CeHn Me Me S S
O~O_ProH ~~ R ~OMe Me O OH Me AA+ 839 AA+ 701. 4 Me S
Me O ~ O
O ~ ~ Me ~ i Me NH.CO.CH2C6H5 +
M 821.5 AA+ 983 The more preferred esters listed hereinabove are readily metabolized in viv to the corresponding alcohols e.g. R5 is Me Me S R
S a mm OH S OH
Me Me The most preferred metabolizable esters include those of compounds of formula IV wherein R9 is Me S
S S
OCOCH20(CH2CH20)3Me S OCCH2~~R~)q M ~,e Me O
~ 2NMG
S
S wherein Y, R~ and q are as defined OP03 H2 herein above Me ~ 2NMG
S
S and Me ~2NMG
S
O _.H
O
~. ~ ~ ~ 9396 WO 95!17407 PCT/US94/14236 The antifungal compounds of this invention represented by formula I have the R absolute stereochemical configuration at the carbon in the tetrahydrofuran ring bearing the di-halophenyl and 1H,1,2,4-tria2ol-1-ylmethyl moieties, and the CH20Y moiety has the "cis" stereochemical configuration relative to the 1 H,1,2,4-triazol-1-ylmethyl moiety. See the formula I
hereinbelow.
H ''~~~~,.C H20Y
R
Oi "cis"
\N~N
N fIJ
and Y =
C
I
wherein Ri is a straight or branched chain (C3-C8) alkyl group substituted by one or two hydroxy groups, which preferably exists as a single stereoisomer, but mixtures of stereoisomers are also contemplated as within the scope of this invention.
The compounds of formula I are generically but not specifically disclosed as the "cis" series, type ii, at col. 9 lines 59-68 of Saksena gt ~(. USP
5,039.676 and Example 68 at Cot. 5, line 16 to col. 52, line 44.
The compounds of this invention may be prepared by use of the sequence of steps illustrated in the following Schemes I-V. In Scheme I, compound 3 is readily prepared from commercially available compound 1 according to Examples ~, ~ and ~. Compound 4 is prepared by reaction of L(+) -diethyl tartarate ("L-DET") and molecular sieves in the presence of titanium -isopropoxide (i-Pr0)4Ti in an aprotic solvent, such as methylene chloride, at a temperature 0° to -35°C. See for Example, T. Katsuki, K.B.
Sharpless, ,~
Am. Chem. Soc.. 102, 5974 (1980); and 1_Q~, 464 (1981 ). An oxidizing agent, e.g. ~r -butylhydroperoxide ("TBHP') is added to this reaction mixture (step d of Scheme I) . Compound 3 is added and the compound of formula 4 (when L(+)-diethyl tartarate is used) is produced. Reaction of compound 4 with 1 H-1,2,4-triazoie in the presence of strong base, e.g., NaH in an aprotic solvent, such as DMF, at 0°-80°C provides the diol compound of formula 5. The primary hydroxy . .
group in compound 5 is converted into a leaving group, e.g., mesylate or tosylate (compound 6) by reaction of 5 with, for example, mesyl chloride ("MsCI") , in an aprotic solvent, e.g., methylene chloride in the presence of base, e.g., triethylamine ("Et3N"). Compound 6 is treated with strong base, e.g., sodium hydride (NaH) in an aprotic solvent, e.g., DMF at room temperature to give oxirane compound 7. Reaction of 7 with diethyl malonate in the presence of strong base, e.g., sodium hydride in an aprotic solvent, e.g., DMSO at 25°-75°C provides the lactone 8. Reduction of 8 with a metal hydride, e.g., lithium borohydride (LiBH4) in an alcohol, e.g., ethanol (EtOH), provides the triol 9.
Conversion of the two primary alcohols of 9 into leaving groups (mesylates or tosylates) by reaction of 9 with excess tosyl chloride in an aprotic solvent, e.g., THF, in the presence of base, e.g., Et3N, provides ditosylate 10. Compound 10 is contacted with strong base, e.g., NaH, in an aprotic solvent such as toluene at elevated temperatures of 100°-120°C to provide a mixture of two tosylates (~i,~
and traps) which are separated by chromatography to yield to the dig-tosylate 11. Reaction of compound 11 with a~ohols HOY in the presence of strong base, such as NaH in an aprotic solvent, such as DMSO at a temperature of 25°-75°C provides compounds of formula I.
Scheme II provides an alternative reaction sequence to obtain compounds of the present invention.. Reaction of compound 11 with the commercially available compound 12 in the presence of NaH gives compound 13. Hydrolysis of N-acetyl group in 13 is accomplished with a strong base such as NaOH in the presence of n-BuOH to provide compound 14. It should be made clear that instead of N-acetyl group in compound 12, any other base labile groups such as N-formyl, N-benzoyl, etc., can also be used to provide corresponding N-formyl and N-benzoyl derivatives of compound 13. Reaction s of 13 with p-chloronitrobenzene in the presence of a hydrochloric acid scavenger such as K2C03 provides the vitro compound 15. Catalytic reduction of 15 in the presence of a. platinum or palladium catalyst yields the amine 16.
Treatment of 16 with phenylchloroformate in the presence of pyridine gives the urethane intermediate 17. Reaction of 17 with hydrazine yields the to semicarbazide 18 which is cyclized in the presence of formamidine acetate to furnish the key triazolone 19. Alkylation of 19 according to Examples 19 and 24 provides the compounds of structure 20 including compounds of formula 1 wherein r1 is defined as hereinabove.
Scheme III provides a stereospecific access to the cis-alcohol is 26 and cis-tosylate 11 by application of enzyme chemistry. For Example, reaction of the triol 9 with ethyl acetate in the presence of porcine pancreatic lipase gives a single monoacetate 21. The remaining primary hydroxy group in 21 is protected by an acid labile group such as tetrahydropyranyl group to give a compound such as 22. Hydrolysis of the acetoxy group in 22 is 2o accomplished with a base such a KOH which provides 23. The remaining steps are: (i) tosylation of compound 23 to provide 24; (ii) cyclization of 24 in the presence of NaH to provide 25; (iii) deprotection of THP ether in 25 using an acid catalyst such as p-toluene sulfonic acid (to give 26) followed by tosylation of the resulting 26 to furnish the key intermediate 11.
2s A detailed description of a preferred preparation of key intermediate is disclosed in commonly owned Canadian Patent Application Serial No. 2,161,622, filed April 29, 1994.
~ 179°~
x ° x x a i x ~ ~ . -----r x 1 x d x t s x x x L ~
lc,l x ~., .r.ic ,81~1~ (a) NaOA~ (b) Wfttt9 R~a~on; (c) KOH; (~ L-0E1,1'BHP, (I-Ph4Ti; (e) NaH,1,2,4-triazole,DAAF; (~ Ms~Ct, E33N,CHZCIz; (~) 1~.
DAAF; (h) NaH, CH~(COOEi~, DAitSO; m UBH,, ElOH; ~ TsCI, ESN, THF;
(k) Wit. toluene. hoax m chromatography; (m) NaOY, DM.SO
Xs F o~ C~
SUBSTITUTE SHEET (RULE 26) 217939b + Ho ~ ~ V coca ll (Xs CI 0~ ~
SUBSTITUTE SHEET (RULE 26) __ __ ____ T_ . __ ~~ (cont'd.j !, 8: (a) NaH; (b) NaOWn-BuOH; (c) P-a.CsH,,NO~I KzC ~(~ ~ per:
(a) CsHsCCOCII pyridn~/ CHI; (f) NH=.NEhI Hip! dioxana. ~) na ail OMF! hue; (h) aoco~5n~ to Examples 18 and 20 SUBSTITUTE SHEET (RULE 26~
21 ~93~6 x ~-°'n~
b x ~ ~w.r~, a d az .1 It 8~: (a) ~n~ psr~c Ipasd E~o~4~ (b) dhYdr~pyaN ti'; (~ ~:
(d) Toy chloddoJ PYd~nt: (a) NaH; (t) Math~noil H'; (p) Tosyi chbrid~/ pyrid~.
SUBSTITUTE SHEET (RULE 26) SCHEME IV
_ O
Me0 \ ~ NON \ ~ N~NH
~N
(i) Aq. HBr (ii) SEM.CI
H
,, F OTs HO \ ~ N O \O>
N \ ~ ~ +
-SEM
~ N \ I
F
N
(iii)NaH, DMSO
H _ O
F R ~~~~ O \ ~ N~ N \ ~ N~ N-X
~ ~OJ N
F ~~'; ~ 30 X= SEM
N 19X=H
I X= R ~
SCHEME V
H
F ''~~ OTs R _ ~--~ _ O ~ / N~ N ~ / N02 F \ ~N.N
L \~ 30 Na (X=F) H _ ~ _ F ''~~ ~ O ~ / NON ~ / N 02 °°f /
(by crystn.) F ~ ~ N' N> 15 F
'N
H _ _ F '''~~O ~ / N~N ~ / NH2 ~q~8nt.
/ ~ -Ol ~
F ~ ~N-N 16F
'N H O
n F ''~~~0 ~ / NON ~ / N~OPh H
..~90% / = O
F ~ I ~N~N 17F
L
N
_ _ O -~90%
H
F R ',,,\O ~ / N~ ~ / N~ NN
/ ? O~ H NH2 F ' \N~N~ 18F
~N O
H _ _ n F ~~,, w y' N H
R O ~ / NON ~ / ~N
/I
90% ' O
F ~ ~ N~N> 1 9F
N
SCHEME VI
O O
R~x~COOR R~x ~x * NV b R * NV
OH ~ OH ~ OR'x RiX is preferably CH3 R'~X is preferably CH=Ph c N-NHCHO N-NHCHO
~x R~x~CHO
R * * R~ ,~ a R' H
OCH2Ph ~ Ph OCHpPh 40 (Syn isomer > 9:1) 39 38 H - _ O
a~~.0 F ~ I ~ - ~ I N~OPh H
\
N. N
N
fg O
H _ .v...0_ /-1 ~N. R~
F ~ I V ~ I ~N
g O
Me F N~N R = S
N, 20F ' S OH
Me (a) pyrrolidine, r.t., 24 h: (b) R4X-X, NaH, DMF; (c) RED-AL, toluene. -20°: (d) H~NNHCHO, MeOH:
(e) R~MgBr. EtzO. -10°C to r.t., 24 h: (f) jgof Scheme V and procedure of Example 32d; (g) Hy Pd, HCOOH. 8090.
~ 179396 Scheme VII
Preparation of Polyether Esters Re(OCHR~CHR~)tOH ~G-(CHR~)BC02Na(43) Re(OCHR~CHR~)t-O(CHR~)S-C4~H
Base/THF
O Me H S
X ''''~ O N~N N N S
/ ~N OH
I ' O J _ Me X ~ ~ 20F
N
DCCD, DMAPt, 44 H O Me X ,'.~ - .--' - y-R O ~ ~ N N ~ ~ N ~ 'N~, , O (CHR O CHR HR R
O ~ ~ ~ ~ Me ~ ~)s ( ~ ~)c s X \ l N~ 45X p 1 DCCD = Dicyclohexylcarbodiamide DMAP = 4-(N,N-Dimethylamino)Pyridine Table for Scheme VII
Me R' OH
using 20F (X = F) Me M.S.
~S M+
PG = Protecting 759.3 Group, e.
.. CH Ph CH3(OCH2CH2)30HCICH2C02H COCH20(CH2CH20)3Me gp5 Table fog Scheme VII
R Me R = .....
S OH
Me M-S
.
CHg(OCH2CH~OH CICH2C02Na -COCH20(CH2CH20)Me gy CH3(OCH2CH)20H CICH2C02Na -COCH20(CH2CH20)2Me gg~
CH3(OCH2CH2)30H CICH2C02Na ,COCH2(CH2CH20)gMe 905 H02C(OCH2CHv20H CICH2C02Na -COCH20(CH2CH20)2COOH905 20F 46R~
Me S Me ( ~" )2N-P-{OCH2CsH5)2 R~ = O
Me OH Tetrazole, t-Bu00H Me p(OCH H
., 2Cs s)2 O
Pd/C, H2, AcOH, ETOH
H O Me X
\ / ~N ~ / N~N S
/ , ~=N S OP03H2 Me N-N
l N~
47 ~ 2NMG
SCHEME VIIIB
O
Me 20F, R = mmR HO C ~CHR~)nLG (49) R1 -~~~~~~~R Me i Me S OH pCCD, DMAP, CH2CI2 Me O (CHR~)nHal LG = Hal O
1. AgOP(OCH2C6H5 )z 2. AcOH 10%Pd/C. H2 ETOH
O R Me O
H ~,y /~ ~Nmn S II
X R O ~ / NUN ~ / ~NMe O (CHR7)n-O-P(OH)2 IIJz N-N
Table for Scheme VIIIA
X=F
47 R~ M.S. (M+) Me S .2NMG 781,8 / ~ OP03H 2 Me Me 781.7 S .2NMG
~ OP03H 2 Me Me 873.3 SO
/i~ OP (OH)-OC 6H40H
Me/
47 R~ M.S. (M+) Me 961.4 O
S
OP(OCH2CsH5)2 Me Me 961.2 S O
~OP(OCH2CgH~)2 M /
Table for Scheme VIIIB
X2.$1 ~. (M+) HOCOCH2C1 Me 839 S
.2NMG
/~ OCOCH20POgH2 Me HOCO(CH2)40H ~ Me 881.3 ""'R'\ .2NMG
~~
OCO(CH~40P03H2 M
HOCO(CH2)40H ~Me 881.3 /S
.2NMG
~~
OCO(CH~40P03H2 M
Me 853.2 S-HOCOCH(.OH)CH3R
~~~~~
S II
~ OCO - C a,, H
Me ~
.2NMG CH3 F R ,," ~ / V \ /
A R-_ ~ ~ O
F L
N
Me R M a H O CH20Ph 54 A R- ~ ~"" R O CH20Ph A R-N~N~...
O H DCCD, DMAP, CH2C12 N M a Me O
10%Pd/C. H2, EtOH, AcOH
O O
Me Me A R-N~ t~.... R ~ ~ A R-N~ t~.... R
OuC H 20-p~
N I OCHZPh ~(~ C~CHpOH
Me O OCHZPh Me O
I(b) Me (C) ~ Me A R-N ~.... R ,,o --~ A R-N ~.... R ,o O CH20~~OH ~N O CH20-P~OH
Me ~ OH Me ~ OH
58 O O .2NMG Satt 58.2N MG
(a)~~P(OCH2Ph)2 ,Tetrazole, t-Bu00H; (b)10%Pd/C, H2, EtOH, AcOH; (C)2NMG
2~i9396 Scheme IX
Preparation of Hetero~...-iic Esters Me 20i=, R~ = S +
S Hal-(CHR~)wCOHaI
off 62 H3C Base Me x R H ~~~~vO \ / NON N NBC S
\ l vN ,~~O (CHR7)w Hal Me \N_N O
~N~ ss H_ ( HR~)q s0 R H '''~~O \ / N~N N N: S Me ( HR~)q O ~ a \ / vN ~O (CHR7)w Me O
~'N~ s~
6~ Rl M.S~(Mt) Me S
S OCOCH2~ O
Me Me S
/ ~ OCOCH2.. NMe Me Me S
~ OCOCH2~~
Me i 2179396 _ Me /~ OCOCH 2.-~J~
Me Scheme IV provides an additional reaction sequence to obtain the compounds of the present invention. Compound 27 is prepared from the methyl ether of compound 12 in Scheme II by subjecting the methyl ether of 12 to the reactions of steps a to g of Scheme II. Reaction of compound 27 with aqueous HBr or BBr3 gives phenolic compound 28. Reaction of compound 28 with one equivalent of NaH and subsequent treatment with, for example, 2-(trimethyl)-silylethoxymethyl chloride ("SEM-CI")and DMF at ambient temperatures produces SEM-nitrogen-protected compound 29. Deprotonation of compound 29 with NaH followed by reaction of the so-formed anion with tosylate 11 in DMF or DMSO at elevated temperatures produces compound 30. The nitrogen protecting group of 30, e.g., SEM is removed by treatment with, for example, 6NHC1 in methanol at ambient temperatures for 3 hr to produce compound 19.
Compound 19 is treated with NaH and DMSO at 20°C for 3/4 hr. and thereafter alkylated with R~X to produce compound I. In R~X, Ri is a C3-C8 alkyl group having at least one protected hydroxy moiety, e.g., O-SEM and X~ is a leaving group, for example, brosylate. Removal of the hydroxy protecting group from compound 31, e.g., O-SEM is accomplished by, for example, 6NHC1 in methanol to give compounds of this invention of formula I.
Scheme V provides a preferred route for preparation of the compounds of this invention set forth in Scheme II. The sodium salt of compound 31 prepared by reaction of (4-(4-(4-nitrophenyl)-1-piperazinylJphenol with NaH in anhydrous DMSO at 50°-60° C for 30 minutes is reacted with the 2,4-diflurophenyl tosylate 11 F (compound 11 in Scheme II wherein X=F) for 1 h.
at 50°-70° C to provide, after flash silica chromatography or crystallization, compound 15F (compound 15 in Scheme II wherein X=F). Reduction of 15F by hydrogenation in the presence of 5% Pd/C in ethanol containing 1 NHCI
provided. amino compound 16F (compound 16 in Scheme II wherein X=F).
Reaction of 16F with phenylchloroformate in anhydrous pyridine at 0-5°C
for 2h.
provided phenylcarbamate 17F (compound 17 of Scheme II wherein X=F).
Reaction of 17F with hydrazine hydrate in 1,2-dimethoxyethane at 80°C
for 4h.
provided the semicarbazide 18F (compound 18 of Scheme II wherein X=F).
Reaction of 18F with formamidine acetate and Et3N in 2-methoxyethanol under dry argon in stirred reactor at 80°C overnight provided 3H-1,2.4-triazol-3-one 19F (compound 19 in Scheme II wherein X=F). Reaction of compound 19(f) with R~X in accordance with the procedure of Scheme IV produced compounds of formula I.
Scheme VI provides an alternative, stereoselective route for preparation of the preferred compounds of this invention. Compound 35 (e.g.
~-lactic acid methylester) is contacted with excess pyrrolidine in methylene chloride for 24 hours at room temperature to give amide 36. Reaction of 36 and NaH with for example, benzyl halide in DMF gave 37. Selective reduction of amide 37 with a 3.4M solution of sodium bis(2-methoxyethoxy)aluminum hydride ("RED-AI") in toluene at -20°C gave aldehyde 38. Reaction of aldehyde 38 with H2NNHCHO in methanol gave 39 which was reacted with a Grignard reagent e.g. ethylmagnesium bromide in dry ether at a temperature of -10°C to room temperature for 24 hours to give 40 wherein the ratio of the S,S isomer:
S,R isomer was 94:6. When the Grigand reaction was done in the presence of 1.2 equivalents of bis(trimethylsilyl)acetamide the SS to SR ratio was 99:1.
Compound 40 was reacted with compound 17F of Scheme V in toluene in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) for six hours at 80°C.
Cyclization was effected by raising the temperature to 100°-110°C and continuing to maintain this temperature overnight. After purification via TLC, ~i79396 20F was obtained. Treatment of 20F with hydrogen and palladium black in methanol containing formic acid heated to 60°C gave the crude product which was isolated and purified (via TLC) to give compound 20F i.e. the compound of formula III wherein Me S
RS = and X = F, Mt = 701 OH
The reaction of the Grignard reagent on the propanimine 39 produces 40 wherein the absolute stereochemistry induced at the new chiral center in 40 is substantially the same (i.e., S) as that at the chiral carbon in 39.
By the term "substantially the same" as used herein is meant the ratio of S:S
to S:R (in e.g., 40) is greater than 9:1, preferably is greater than 15:1 and most preferably is at least 99:1.
The mass spectral data presented herein as M+ are parent ions which were determined by Fast Atom Bombardonment (FAB) technique and represent the ~M+1 peaks.
Scheme VII provides a general method for preparation of the polyether esters of alcohols of the present invention. The alcoholate of alcohol ether 42 e.g. CH3(OCH2CH2)30H i.e., 42 wherein R~ = H and t = 3, was prepared by reaction, of 42 with excess strong base e.g. NaH in an anhydrous ether e.g. THF at ice bath temperatures. The so-formed reaction mixture was stirred for several hours i.e., 2 or more and the sodium salt of acid 43 e.g.
sodium salt of chloroacetic acid (43 wherein LG=CI, R~=H and s=1 ) was added thereto. The so-formed reaction mixture was stirred at ice-bath temperatures and stirring was continued as temperature was allowed to warm to room temperature. Water was carefully added to the reaction mixture and the polyether acid 44 was separated and purified by conventional techniques.
_._ -.____ _ T. _._.____.__ .._.
To a solution of 44 in CH2C12 was added 1.3-1.5 equivalents of the base 4-(N,N-dimethylamino)pyridine ("DMAP") and 20F wherein Me R~
OH
. The temperature of the so formed reaction mixture was lowered by use of an ice bath and 1.3-1.5 equivalents of dicyclohexylcarbodiimide ("DCCP") was added thereto. The so-formed reaction mixture was continuously stirred as the temperature was allowed to warm to room temperature. The urea precipitate was removed and the crude product isolated by conventional techniques. The so formed residue was purified by chromatography on silica gel to provide the pure compound [M + Hj+ = 906 by FAB. By the appropriate substitution of different starting materials 42 and 43 the compounds 45 listed in Table for Scheme VII were prepared. The MS values for products listed under 45 in the Table for Scheme VII were measured by Fast Atom Bombardment ("FAB").
Schemes VIII A-C illustrate the generalised methods for preparing phosphate esters of the alcohols of this invention. Scheme VIIIA provides a method for preparation of phosphate esters of formula IV wherein R6 is O o - C Z - (CHR~~(Q)m p(QW)2 and z = m=n = 0. Compound 20F of Scheme II in methylene chloride at room temperature was reacted with 1.5 equivalents of N,N-diisopropyls-dibenzylphosphoramide, 1.5 equivalents of tert-butyl peroxide (3M in iso-octane) and a base such as tetrazole for several hours. The progress of the reaction was followed by TLC (5% methanol:EtoAc v:v) on silica gel. The crude product in EtoAc was washed with sodium thiosulfate and purified using standard techniques to provide the dibenzylphosphate ester 46. The dibenzyl ester groups of 46 were removed to . . ~~ 7939b give 47 by treatment of 46 dissolved in equal volumes of ethanol and glacial acetic acid in the presence of excess 10% Pd/C under a hydrogen atmosphere at room temperature in a stirred reactor overnight. The reaction was continued until no starting material was found by TLC (or NMR). The catatyst was removed by filtration and the crude phosphate ester 47 was purified by standard techniques. Treatment of 47 in methanol at room temperature with two equivalents of base e.g. NMG (or Et3N) provided 47 ~ 2NMG. The compounds 46 and 47 prepared in accordance with Scheme VIIIA are listed in the Table for Scheme VIIA.
Scheme VIIIB illustrates preparation of phosphate esters of II
- C Z - (CHR~~-(O)Tn p(OV~2 formula IV wherein R6 = z =m=1 and n = o.
Compound 20F dissolved in methylene chloride was treated with 1.3 equivalents of DMAD 1.3 equivalents of DCCD and 1.3 equivalent of the acid II
HO C (CHR ~)n LG
49 of the formula Z e.g., H02C(CH2)4Br, i.e., z = 1, n = 4, R~ = H and the leaving group LG is Br. The reaction was stirred at room temperature until no starting material was found by TLC purification of the crude Me R1 =
~~ 02C(CH 2)a&
product gave bromide 50, a white solid wherein The bromide 50 in a benzene was heated at 80°C overnight with 1.5 equivalents of silver dibenzylphosphate (available from Sigma Chemical Co., St. Louis). The reaction mixture was cooled and washed with aqueous base, e.g., K2C03. The crude product was separated and purified by silica gel column chromatography to give the dibenzyl phosphate ester 51. Treatment of 51 in ethanol/glacial acetic acid with excess 10% Pd/C under a hydrogen _....y atmosphere overnight at room temperature gave phosphate ester 52.
Treatment of 52 in methanol with two equivalents of base e.g. NMG (or Et3N) gave 52 ~ 2NMG.
Scheme VIIIC provides an alternative procedure for preparation of phosphate esters of formula IV wherein R6 is as defined above for Scheme VIIIB and z = 1 and n = 1. The benzyl ether of methyl acetate 53 in methanol-water and excess base e.g. K2C03 were stirred overnight at room temperature to give the benzyl ether 54. Reaction of a solution of 20F and 54 in methylene chloride with a 1.3 -1.5 equivalents of DCCD and DMAP at room temperature overnight gave ester 55. The benzyl ether group of 55 was removed by treatment with excess 10%
Pd/C in ethanol-glacial acid under a hydrogen atmosphere at room temperature overnight. Purification of the crude product gave 56. Treatment of 56 with 1.5 equivalents of diisopropyldibenzylphosphate and 1.5 equivalents of tent-butyl peroxide and tetrazole in accordance with the procedure of Scheme VIIIB gave dibenzyl ester 57. Removal of the dibenzyl groups with 10% Pd/C in ethanol-glacial acetic acid under hydrogen atmosphere gave (as described hereinabove) phosphate ester 58. Treatment of 58 with two equivalents of base, e.g. NMG, gave 58 ~ 2NMG.
Scheme IX illustrates the preparation of heterocyclic esters of the S
OH
present invention. Compound 20F, wherein ~ dissolved in methylene chloride is reacted with compound 62 in the (Hal=Br or CI, w=1-5, e.g., CI-CH2-COCI) in presence of a base such as pyridine at a temperature of 0°-5°C for four hours. The reaction was placed in a refrigerator overnight.
Additional compound 62 and base could be added, if necessary, and the reaction continued until no 20F is present by TLC. Purification of the crude product by column chromatography on silica gel gave pure 59 (w=1, Hal=CI).
..
__ k Reaction of 59 with excess of the nitrogen heterocyclic compound 60 (e.g., Y=NH, R~=H and q=4) at a temperature of 50°-60°C for 1 hour produced 61.
Substitution of nitrogen heterocyclic compound 60 with a five and six membered compounds, e.g. morphiline, N-methylpiperdine provided the compounds listed in table below Scheme IX.
The alkanoate and alkenoate esters of 20F are conveniently prepared by standard synthetic techniques, (for example, by reaction of the anhydride or acid halide of the alkanoic acid or alkenoic acid in tghe presence of base e.g, pyridine) produced the alkanoate or alkenoates of the compounds of formula I.
The sulfate esters may be prepared by reaction of the alcohol compounds of formulas I to IV with sulfur trioxide in the presence of excess pryridine at temperatures of 70°-90°C for at least 2 hours in accordance with the procedure of R.M. Moriarty et. al. Tetrahedron Letters, Vol. 35, No. 44, p 8103-8106 (1994).
The compounds of formula I may also be prepared by reaction of compound 11 with alcohols of formula HOY in the presence of a strong base, e.g., NaH in an aprotic solvent, such as DMSO.
H
''''\
R ''''~ OTs / OY
+ -OY ~ X
11 N ( I]
(R)-"Tosylate" Series See Example 15 wherein X = F or CI
Y=
and R~ = a (C3-Cg) alkyl group substituted by one or two hydroxy moieties.
__. ~- ~ . __ . ~ _ _____~-Compounds represented by formula ! exhibit broad spectrum antifungal activity, in conventional antifungal screening tests, against human ' and animal pathogens, such as the following: AspergiJlus, Blastomyces, . Candida, Cryptococcus, CoccidioTdes, Epidermophyton, Fonsecaea, Fusarium, Mucor, Saccharomyces, Torulopsis, Trichophyton , Trichosporon, Sporothrix and Pneumocysitis.
The preferred compounds of formula !V exhibit topical, oral and parenteral antifungal activity in in vivo tests in animals and such activity is unexpectedly better than that of existing antifungal agents e.g. itraconazole and fluconazole as well as that of the azole compounds specifically disclosed by Saksena gt~l. in USP 5,039,676 and International Publication No.
WO 93109114.
The antifungal compounds of formula l and pharmaceutical compositons of this invention are expected to exhibit anti-allergic, anti-inflammatory and immunomodulating activities, broad spectrum antiinfeciive activity, e.g., antibacterial, anti-protozoal and antihelminthic activities.
The present invention also provides a composition for treating or preventing fungal infections comprising an antifungally effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or difuent therefor.
The pharmaceutical compositions of the present invention may also contain a fungicidally effective amount of other antifungal compounds such as cell wall active compound. The term "cell wall active compound", as used herein, means any compound that interteres wifh the fungal cell wall and includes, but is not limited to, compounds such as papufacandins, echinocandins, and aculeacins as well as fungal cell wall inhibitors such as nikkomycins, e.g, nikkomycin K and others which are described in USP
5,006,513 . , a The pharmaceutically acceptable salts of the compounds of the present invention include pharmaceutically acceptable acid and base addition salts.
The preferred pharmaceutically acceptable acid addition salts are nontoxic acid addition salts formed by adding to the compounds of the present invention about a calculated amount of a mineral acid, such as HCI, HBr, H2S04, HN03 or H3P04, or of an organic acid, such as an alkyl or arylsulfonic acid such as methanesulfonic, isithionic, para- toluenesulfonic, naphthylsulfonic and the like.
The pharmaceutically acceptable bases found suitable for use in the present invention are those which form pharmaceutically acceptable salts of the acidic pharmaceutically acceptable esters of the antifungal compounds of formulas I, II, III or IV and include suitable organic and inorganic bases.
Suitable organic bases include primary, secondary and tertiary alkyl amines, alkanolamines, aromatic amines, alkylaromatic amines and cyclic amines.
Exemplary organic amines include the pharmaceutically acceptable bases selected form chloroprocaine, procaine, piperazine, glucamine, N-methylglucamine, N-N-dimethyl glucamine ethylendediamine, diethanolamine, diisopropylamine, diethylamine, N-benzylenediamine, diethanolamine, diisopropylamine, diethylamine, N-benzyl-2-phenylethylamine, N-n'dibenzylethylenediamine, choline, clemizole, triethylamine ("ET3N"), tris(hydroxymethyl)aminomethane, or D-glucosamine. The preferred organic bases include N-methyl glucamine ("NMG"), diethanolamine, and tris(hydroxymethyl) aminomethane ("TRIS"). Use of two equivalents of NMG in this invention is more preferred. The suitable inorganic bases also include alkali metal hydroxides such as sodium hydroxide.
The pharmaceutical compositions of the present invention may be adapted for any mode of administration e.g., for oral, parenteral, e.g., sc, im. IV
and IP, topical or vaginal administration or by inhalation (orally or intranasally) . . :. . :, . 2179396 Such compositions are formulated by combining the compound of formula I or an equivalent amount of a pharmaceutically acceptable salt of compound I with an suitable, inert, pharmaceutically acceptable carrier or diluent.
Examples of suitable compositions include solid or liquid compositions for oral administration such as tablets, capsules, pills, powders, granules, solutions, suppositories, troches, lozenges, suspensions or emulsions. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
Topical dosage forms may be prepared according to procedures well known in the art, and may contain a variety of ingredients, excipients and additives. The formulations for topical use include ointments, creams, lotions, powders, aerosols, pessaries and sprays.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredients are dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution with an appropriate amount of a hydroxypropyl a- (3 or -y-cyclodextrin having 2 to 11 hydroxypropyl groups per molecule of cyclodextrin, polyethylene glycol, e.g., PEG-200 or propylene glycol, which solutions may also contain water. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the active component in finely divided form in water. A particularly preferred aqueous s pharmaceutical composition may be prepared from the compounds of formulas I to IV together with hydroxypropyl-~i-cyclodextrin in water. The use of derivatives of a-,(3- and y-cyclodextrins, for example, hydroxpropyl-(3-cyclodextrin are disclosed by N. Bodor USP 4,983,586, Pitha USP 4,727,064 and Janssen Pharmaceutica International published Patent Application WO
io 85/02767, July 4, 1985.
The pharmaceutical compositions of the present invention may be prepared by admixing the pharmaceutically acceptable carrier, e.g., a hydroxypropyl-~-cyclodextrin in water, and adding thereto an antifungally effective amount of a drug of the present invention. The solution so formed is is filtered, and optionally, the water may be removed by well known methods, e.g., rotatory evaporation or lyophilization. The formation of the solution may take place at a temperature of about 15° to 35°C. The water is normally sterilized water and may also contain pharmaceutically acceptable salts and buffers, e.g., phosphate or citrate as well as preservatives. The molar ratio of 2o the antifungal compound of formula I to hydroxpropyl-~3-cyclodextrin is about 1:1 to 1:80, preferably 1:1 to 1:2. Normally the hydroxypropyl-~i-cyclodextrin is present in molar excess.
Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for either oral or 2s parenteral administration. The solid form preparations intended to be converted to liquid form may contain, in addition, to the active materials, such as compounds of this invention, and optionally a cell wall active compound, especially a fungal cell wall inhibitor, e.g., a nikkomycin, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, 3o solubilizing agents and the like. The solvent utilized for preparing the liquid . ..
WO 95/17407 PCT/~JS94/14236 form preparations may be water, isotonic water, ethanol, glycerin, polyethylene glycols, propylene glycol, and the like, as well as mixtures thereof.
Parenteral forms to be injected intravenously, intramuscularly, or subcutaneously are usually in the form of a sterile solution, and may contain salts or glucose to make the solution isotonic.
The topical dosage for humans for antifungal use in the form of a pharmaceutical formulation comprising a compound of formula I (usually in the concentration in the range from about 0.1 % to about 20% preferably from about 0.5% to about 10% by weight) together with a non-toxic, pharmaceutically acceptable topical carrier, is applied daily to the affected skin until the condition has improved.
In general, the oral dosage for humans for antifungal use ranges from about 1 mg per kilogram of body weight to about 50 mg per kilogram of body weight per day, in single or divided doses, with about 2 mg per kilogram of body weight to about 20 mg per kilogram of body weight per day being preferred and the dose of about 5 mg per kilogram of body weight to about 10 mg per kilogram of body weight per day being most preferred.
In general, the parenteraf dosage for humans for antifungal use ranges from about 0.5 mg per kilogram of body weight per day, to about 20 mg kilogram of body weight per day, in single or divided doses, with about 1 to about 10 mg per kilogram of body weight per day being preferred.
The exact amount, frequency and period of administration of the compounds of the present invention for antifungal use will vary, of course, depending upon the sex, age and medical condition of the patent as well as the severity of the infection as determined by the attending clinician.
z ~ ~93~6 WO 95/17407 PC'T/LTS94/14236 GENERAL EXPERIMENTAL
The compounds of this invention are prepared in accordance with Schemes I-IX hereinabove and the following Examples using commercially available starting materials.
F O F O
CI ~ OAc + NaOAc / /
F F
EXAMPLE 1 a Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20°C for 18 hr. then concentrate it to 1 L.
Pour the residue into 6 L of cold dilute aqueous HCI and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2S04, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluting with CH2C1-2-hexane to obtain 198 g of the title compound.
F O F
OAc ~ OAc F ~ / + MePh3PBr + Na-HMDS T~ F
EXAMPLE 1 b 1-j2-(2.4-Difluorophenylll-2-aropenol acetate Suspend 131 g of MePh3PBr in 270 mL of mechanically-stirred, dry THF at 20°C. Add 393 mL of 1 M NaN(Me3Si)2 in THF, slowly at first, then rapidly over 5 min. while applying just enough ice cooling to maintain the temperature at < 23°C. Stir the so-formed mixture for 1 hr at 20°-24°C, cool it to _ _T_.__ -70°C, and stir it another 1/2 hr. Then add thereto a solution of 65.5 g of the product of Example 1 a in 140 mL of dry THE, at a rate slow enough to keep the temperature below -70°C. Continue to stir the so-formed reaction mixture in the cold bath overnight during which the temperature rises to 20°C. Add 50 mL of EtOAc to the so-formed suspension, and then add 3 L of hexane. Allow the so-formed mixture to stand for ~15 min., and suction-filter to remove Ph3P0.
While the filter cake is still damp, transfer it to a beaker. Triturate the cake thoroughly with 1/2 L of hexane and suction-filter again to remove the remainder of product.
Wash the combined hexane filtrates with 2 x 1 L of a 1:1 (v/v) MeOH-water, and then with brine. Dry the organic layer over MgS04, filter and evaporate the filtrate to leave a red oil. Add 1.5 L of hexane and suction-filter through a Celite pad to leave a clear yellow solution. Chromatograph the yellow oil on silica gel, eluting with 1/2 L of hexane, then 1 L of 15:1 (v/v) hexane-EtOAc. Combine the homogeneous fractions to yield 38.6 g of the title compound as an oil.
F OAC F O H
w v F ~ i + KOH -'~' ~ i F
EXAMPLE 1 c Dissolve 40 g of the product of Example 1 b in 400 mL of dioxane.
Add a solution of 18 g of 85% KOH in 315 mL of water. Stir the so-formed mixture vigorously for 1 hr, and then pour the mixture into 1 L of Et20.
Separate the aqueous layer and extract it with 250 mL of Et20. Combine the organic extracts, and wash them with water and then brine. Dry the organic extract over anhydrous K2C03, and add 10 g of charcoal thereto. Filter, and evaporate the filtrate to leave 31.3 g of the title compound as a straw-colored oil.
21 l X396 -EXAMPLE 1 d j~~~[2-(2.4-Difluoro~henyll]oxiran~lmethanol Add 33g of activated 3A molecular sieve powder to a solution of 13g of L-(+)-diethyl tartarate in 2.3L of CH2C12, and cool the so-formed mixture to -5°C. Add a solution of 15.4 mL of titanium tetra-isopropoxide in 100 mL of CH2C12 over 2-3 minutes and then cool the so-formed mixture to -22°C.
Add 109.5 mL of a 5.5 M solution of ~r -butylhydroperoxide in 2,2,4-trimethyl-pentane over 4-6 minutes, and cool the so-formed mixture to -25°C. Stir the mixture at -25°C for 25 minutes and then add a solution of 40g of 2-(2,4-difluorophenyl)-3-propenol of Example 1c in 100 mL of CH2C12 over 3-4 minutes. Stir the so-formed mixture at -27°C for 4 1/2 hour. Add 102 mL
of 30%
aqueous sodium hydroxide saturated with NaCI and stir the so-formed mixture while warming to +10°C over a 1/2 hour period. Add thereto 100 g of anhydrous MgS04 and 33g of Celite, and stir 1/2 hour at +10°C. Suction-filter the mixture, wash the so-formed filter cake with 1.2 L of diethyl ether (Et20) and then 1.5L of toluene, and dry the combined organic layers over anhydrous MgS04. Filter the organic layer, and evaporate the filtrate in vacuo to form a residue. Dissolve the residue in 1 L of Et20 and suction-filter the mixture to remove insolubles. Suction-filter the filtrate through 100g of silica gel, and wash the pad with 200 mL of fresh Et20. Evaporate the filtrate in vacuo to give a 41 g (94%) of the crude title compound as a yellowish oil, ( ~ - 36.7°
(c=I, MeOH); PMR (CDC13) d 7.40(m,1 H), 6.85(m, 2H), 3.95(m,2H), 3.31 (d,1 H), 2.84 (d,1 H), 1.91 (m,1 H, deuterium exchangeable).
Rl-l+1-f2-f2-12.4-Difluoroohenvl)loxiranvllmethan Follow the procedure of Example 1 d, except substitute an equivalent amount of D-(-) diethyl tartarate in place of L-(+) diethyl tartarate to give the crude title compound, ~a~ + 33.9° (c=I, MeOH).
_ . T _ __._ _- _ T___-_.
L17959~
Purify a portion of the crude compound by silica gel chromatography to obtain a sample homogeneous by TLC, [a~ + 40.0° (c=I, MeOH) (R)-(-)-2-(2.4-Difluorooheny~-3-(1 2 4-triazol-1- I~)-1 2:nrooanediol Dissolve 8.91 g of 1 H-1,2,4-triazole in 150 mL of anhydrous DMF
and cool so-formed mixture to 0-5°C. Add 2.81 g of sodium hydride (60%
oil dispersion) and stir the so-formed mixture 30 minutes at room temperature. Add thereto 10.9 g of the product of Example 1 d. Stir the so-formed reaction mixture for 2 hours at 60-70°C. Cool the mixture to room temperature, add thereto 10 ml of H20 and evaporate it inin vacuo to give a residue. Dissolve the residue in mL of H20 and 900 ml of ethyl acetate (EtOAc). Extract the H20 layer with another 250 mL of EtOAc. Wash the combined EtOAc extracts with 100 mL of brine. Dry the EtOAc extracts over anhydrous MgS04 and evaporate. Triturate the so-formed oily residue with 10 mL of CH2C12 and add 100 mL of Et20. Stir the CH2C12-Et20 mixture for 1 hour at room temperature. Filter to give 11.2g a (75%) of the title compound, [ ~ - 70.7 (c=1.0, MeOH), mass spectrum (FAB):
256 [M+H]+. Recrystallize 1.Og of the filtered product from 5 mL of CH3CN to a give 0.83g of the title compound, m.p. 99-100°C; [ ~ - 71.5°
(c=1.0, MeOH);
elemental analysis: Calculated for C~ ~ Hi i F2N3021 /2CH3CN; 52.27C, 4.57H, 17.78N, 13.78F; Found: 52.26C, 4.58H, 17.54N, 13.78F; PMR(DMSO) d 8.25 (s,1 ), 7.66(s,1 ), 7.33, (m,1 ), 7.09(t,1 ), 6.90(t,1 ), 5.72(s,1 ), 5.05(t,1 ), 4.53(s,2), 3.61 (m,2).
(Sl-(+)-2-(2.4-Difluoroohenyl)-3-(1 2 4-triazol-1-vl)-1 2 ~panediol . .. 2179396 Follow the procedure of Example 3, except substitute an equivalent quantity of the product of Example 2 in place of the product of a Example 1 to give the title compound; MP. 95-101 °C; [ ~ +
70.0° (c=1.0, MeOH). The PMR and Mass spectra were consistent with the structure of the title compound.
LR)-2- 2.4-Difluorophenyl)-3-(1.2.4-triazol-1-~1-1.2~panediol-1 methanesulfonate Suspend 10.9 g of the powdered product of Example 3 in 150 mL
of CH2CI2. Add thereto 8.95 mL of triethylamine and cool to the so-formed mixture 0-5°C. Add 3.64 mL of methanesulfonyl chloride in 20 ml of over 10 min. Stir the so-formed mixture for 1 hour at room temperature. Cool it to 0-5°C, extract with 100 mL of cold (0-5°C) 5% KH2P04, followed by 100 mL
of cold (0-5°C) H20, followed by 50 mL of brine. Dry the separated organic layer over anhydrous MgS04 and evaporate to obtain 13.7 g (96%) of the title [M+H+j+; PMR (CDC13) d 7.95 (s,1 ), 7.82 (s,1 ), 7.53(m,1 ), 6.81 (m,2), 4.84(d,1 ), 4.65(d,1 ), 4.46(m,2), 3.05(s,3).
lSl-2-(2.4-Difluoroohenvll-3-(1.2.4-triazol-1,r1 1.2-oronanediol-1 methanesulfonate Follow the procedure of Example 5, except substitute an equivalent quantity of the product of Example 4 in place of the product of Example 3 to give the title compound . The PMR is consistent with the structure of the title compound.
So T..
IRl-1-f2-f2-f2.4-Difluoroohenyl~loxiranvlmeth~rl] 1 2 4 triazole Dissolve 13.7g of the product of Example 5 in 200 mL of anhydrous DMF and cool the so-formed solution to 10-15°C. Add thereto 1.71 g of sodium hydride (60% oil dispersion) and stir the so-formed reaction mixture at room temperature for 90 minutes. Concentrate in vacuo to 50 mL. Add thereto 200 mL of cold H20 (0-5°C) and extract with 3 x200 mL portions of EtOAc. Wash the combined EtOAc extracts with 100 mL of brine. Dry the EtOAc extracts over anhydrous MgS04 and evaporate it to give 10.8 g of a residue.
Apply the residue in CH2C12 to a column of 400 g of MPLC grade silican gel previously prepared by slurry packing with CH2C12 containing 1 mL of Et3N per liter. Elute with 1 liter, each of 25, 50 and 75% EtOAc; CH2C12 (v/v) followed by 2 liters of EtOAc. Combine the fractions to give 6.92g (68%) of the title compound. Mass spectrum (FAB): 238 [M+H]+; PMR (CDC13) d 7.97(s,1 ), 7.77(s,1 ), 7.07(m,1 ), 6.73(m,2); 4.73(d,1 ), 4.41 (d,1 ), 2.84(d,1 ), 2.78(d,1 ).
(S)-1-f2-f2-l2 4-difluoro heny,~~xiranvimethyl 1 2 4 triazol Follow the procedure of Example 7, except substitute an equivalent amount of the product of Example 6 in place of the product of Example 5 to give the title compound. [PMR is consistent with the structure of the title compound].
Ethvll5R-cisl- and l5R-tran~~-5-r~ 4 Difluoroohenvl) 2 oxo 5 [(1 H 1 2 4 triazol 1-vl)methvlltetrahvdro-3-furancarboxvlate Dissolve 9.35 mL of diethyl malonate in 70 mL of anhydrous DMSO. Add 2.24g of sodium hydride (60% oil dispersion) in 2 portions and stir the so-formed reaction mixture at room temperature for 1 hour. Add 6.65 g of w . . ~ 179396 _ the product of Example 7 and stir 18 hours at 50-55°C. Cool to room temperature and pour the reaction mixture into a well-stirred mixture of 500 mL
of KH2P04, 500 mL of brine, and 1 liter of EtOAc. Separate and extract the H20 layer with another 300 mL of EtOAc. Wash the combined EtOAc extracts with 500 mL of brine, Dry the EtOAc extracts over anhydrous MgS04 and evaporate to give an oil. Apply the oil with CH2C12 to a column of 400 g MPLC grade silica gel prepared with hexane. Elute with 500 mL of hexane, followed by 2 liters of 50% EtOAc: hexane (v/v), followed by 2 liters of EtOAc. Combine fractions to give 8.66g (80%) of the title compound. Mass spectrum (FAB): 352[M+H]+, PMR
(CDC13) d 8.08(s,2), 7.91 (s,1 ), 7.71 (s,1 ), 7.42(m,1 ), 7.13(m,1 ), 7.85(m,2), 4.60(m,4), 4.10(m,4), 3.49(t,1 ), 3.14(t,1 ), 3.89(m,4), 1.18(m,6).
F;h_YL(5S-cisl. and (5S-trans)-5-x,2.4-Difluorophen~l-2-oxo-5- 1 H-1.2.4-triazol-1-yl)methyl]tetrahydro-3-furancarbox I
Follow the procedure of Example 9, except substitute an equivalent amount of the product of Example 8 in place of the product of Example 7 to give the title compound. [PMR and mass spectra are consistent with the structure of the title compound].
~R)-(-)-4-(2.4-Difluorohhenyl)-2-hydrox~methyl-5-j1 H- 1.2.4-triazol-1-yl~]-1.4-pentanediol Dissolve 8.5 g of the product of Example 9 in 125 mL of EtOH and add 2.15 g of LiCI. Cool the stirred mixture to 0°C and add 1.92 g of NaBH4 in portions. Stir the mixture for 18 hr without further cooling. Add 125 mL of MeOH
and 10 mL of H20 to the mixture and stir for 4 hr. Evaporate the mixture to dryness and extract the precipitate with warm EtOH. Evaporate the extract to dryness, add 200 mL of THF to the residue, and sonicate the stirred mixture for ~. 2119396 15 min. Filter the mixture and evaporate the filtrate. Chromatograph the residue on silica gel, eluting with CH2C12-MeOH-NH40H (95:5:1 ) v/v/v) to obtain 3.9 g of the title compound. Mass spectrum (FAB): 314 (M+H+); PMR
(DMSO) d 8.25(s,1 ), 7.69(s,1 ), 7.35(m,1 ), 7.13(m,1 ), 6.94(m,1 ), 6.27(s,1 ), 5.16(t,1 ), 4.44(m,4), 3.39(m,1 ), 3.20(m,1 ), 3.05(t,2), 2.11 (m,1 ), 1.52(m,1 ).
fS)-(+)-4-(2.4-Difluoroohenvl)-2-hydroxvmethyl-5~1 H-(1 2 4 triazolyl~] 1 4 oentanediol Follow the procedure of Example 11, except substitute an equivalent amount of the product of Example 10 in place of the product of Example 9 to give the title compound. Chromatograph a portion of the crude product on silica gel eluting with CH2C12-MeOH-NH40H to give a product homogeneous by TLC. Dissolve the material in H20 and filter, and lyophilize the filtrate to give the title compound. ~a~ + 54.50 (c=1.0, MeOH) (Rl-(-)-4-(2.4-Difluorooh~nvl)-2-fff4-methyl~envl)-sulfonyloxy~methyl]~j1 H
(1-2.4-triazolvlll-1 4-oentanedi I-1-(4-methvlbenzene ~Ifonate Dissolve 4.4g of the product of Example 11 in 50 mL of CH2C12-THF (1:1, v/v). Add 4.7 mL of Et3N and 180 mg of N,N-dimethylaminopyridine, and cool the solution to 0°C. Add thereto 5.9 g of p-toluenesulfonyl chloride in portions and stir the so-formed reaction mixture at 0°C for 1/2 hour, and then stir it at room temperature for 5 hours. Add 100 mL of EtOAc and suction-filter the mixture. Concentrate the filtrate; add thereto 150 mL of EtOAc, and wash with 5% aqueous KH2P04. Wash the organic layer with cold aqueous 5% NaHC03, then with saturated brine, and then dry it over anhydrous MgS04. Filter the mixture, and evaporate the filtrate. Chromatograph the residue on silica gel, eluting with EtOAC-hexane to give 6.4 g (73%) of the title compound, PMR
2 i 7 ~ 3 9 6 pCT/17594/14236 (CDC13) d 7.95(s,1 ), 7.67(m,5), 7.30(m,6) 6.70(t,2), 4.74(d,1 ), 4.53(d,1 ), 4.13(m,1 ), 3.97(m,1 ), 3.8(m,2), 2.43(s,6), 1.95(m,2), 1.77(m,1 ). Mass spectrum (FAB): 622 [M+HJ+.
(Sl-(+)-4-(2.4-Difluoroohenvl)-2-Q 4-methy~henyll-sulfonvlox l~C,meth~l-5-(1 H
(1.2.4-triazolvi)1-1.4-oentanediol-1 (4-methylbenzene)sulfonate . Follow the procedure of Example 13 except substitute an equivalent amount of the product of Example 12 in place of the product of Example 11 to obtain the title compound, [~~ + 14.2° (~1, MeOH).
(-1-l5R-cisl-5-(2.4-Difluo roohe null-5~( 1 H-1.2.4-triazo I-1-vl) methyl-tetrahvdro-3-furanmethanol.4-toluenesy~ h~ ovate Dissolve 6.3g of the product of Example 13 in 150 mL of toluene and heat the so-formed solution to 100°C. Add 2.4g of 60% NaH
dispersion in oil portionwise, and then heat the so-formed reaction mixture at reflux until cyclization is complete (approx. 3-4 hours). Coot the mixture and decant the solution from excess NaH. Wash the solution with cold 5% aqueous KH2P04.
Evaporate the organic layer to form a residue and chromatograph the residue on silica gel, eluting with acetone-hexane to obtain 1.6g (35%) of the title compound as the less polar of the two products, [a~ - 39.4°(c=1, CHC13);
PMR (CDC13) d 8.09 (s,1 ), 7.88 (m,3), 7.31 (m,3), 6.81 (m,2), 4.52(ABq,2), 3.99(m,1 ), 3.85(m,1 ), 3.70(m,1 ), 3.59(m,1 ), 2.49(m,2), 2.47(s,3), 1.90(m,1 ).
Mass spectrum (FAB): 450 [M+H]+.
_T-_._ ~ 179396 L+~-!5S-cisl-5-(2 4-Difl mrnnhonvl ~ [~1 H 1 ~nl 1 W1 2 4 trig methvll-tetrahvdro-3-furanmethanol 4 tonr~nA~~ n..h..n.,.
Follow the procedure of Example 15, except substitute an equivalent amount of the product of Example 14 in place of the product of Example 13 to give the title compound, [a~ + 40.3° (c=0.3, CHCI3), mp 96-98°C.
L1 fl2R)-cisl-4-f4-f4-f4-rt5_!~ a ~~fn ~~..,hen"I~ . . ydro-4 I 1 I ( n- m h I-1- h 4-dihvdro-3H-1.2.4-triazol-~-nna The title compound is prepared starting with the tosylate of Example 15 and 4-[4-(4-nitrophenyl)-1-piperazinyljphenol (Example 3a of USP
4,791,111) and using the synthetic scheme outlined in Scheme V and J.
Heeres, et al., J. Med. Chpm 1984, Vol 27, p894-900 at 898 and 900.
R - i -4- 4- 4- 4- 4- i r h n I -T h r - - 1 H-4- I-1- Im h I - -F r n I n I -1-Pi r 'n I h n I - 4-ih ro-2-fl lSl-Methvl-2lR)-Hvdroxvoroovll ~N ~ ~ a Tri zoo ~ nno a. 2:O-SEM Ether of (2R ~R~-~ z-Q".~.".a:..~
To a stirred solution of 4.95g of (2R, 3R)-2,3-butanediol, (55 mmoles) and 9.3g of SEM-CI (55.7 mmoles) in 55 mi of anhydrous DMF at O°C were added in four portions 2.34g of 60% oil-dispersed NaH (58.5 mmoles) over 10 min.
The resulting mixture was stirred at 0°C for 4 hours and at ambient temperature overnight. The turbid reaction mixture was poured onto 0.5L of 5% KH2 P04 solution and extracted with 2 x 300 ml of ether; the combined ethereal solut van ~~~~3~6 was washed once with distilled water, saturated brine, dried over MgS04 and evaporated to give a colorless liquid. Flash chromatography over 350g silica gel,with 1 L of 7% ETOAC/Hexane, 2L of 10% ETOAC/Hexane and 1 L of 15%
ETOAC/Hexane gave 1.74g of the title compound (yield 14.4%) MS:(M+H)+=221.
b. Brosvlation A mixture of 0.7g of the 2-0-SEM ether of Example 18(a), (3.18 mmoles) and 0.978 of 4-bromobenzenesulfonyl chloride (3.82 mmoles) in 5ml of anhydrous pyridine was stirred under NZ atmosphere at ambient temperature for 6 hours. The reddish slurry reaction mixture was diluted with 50m1 of ice-cold water, extracted with 2 x 25m1 of ether. The combined ethereal solution was washed with 2 x 25m1 of 1-% CuS04 solution, distilled water, saturated brine, dried over MgS04 and evaporated to give a reddish oily residue. Flash chromatography over 50g silica gel with 1 L of 10% ETOAC/Hexane gave 1.02g of the brosylate as a colorless liquid (yield 72.9%) [a) p = -3.69° (CHC13 ; c=1 ) c. Alkylation Reaction A mixture of 0.98g of the brosylate of Example 18(b) (2.23 mmoles), 0.69g of the 3H-1,2,4-triazol-3-one of Example 17 (1.12 mmoles) and 0.37g of cesium carbonate (1.12 mmoles) in 20 ml of anhydrous DMF was stirred at 80°C under N2 overnight (-20 hours). The reaction mixture was diluted with 100m1 of ice-cold water, extracted with 2 x 50 ml of ethyl acetate. The combined organic solution was washed once with distilled water, saturated brine, dried over MgS04 and evaporated to give a brown solid residue. Flash chromatography of the residue over 125g silica gel with 1.2L of 80%
2~~9396 ,,,..-ETOAC/Hexane gave 0.3278 of the product as a tan solid (yield 35.7%) MS=(M+H)+=81.7.
d. Acidic Hvdrolvsis of 18(c1 to the titiA ~..,.~",.;
A mixture of 0.328 of the SEM-ether of Example 18(c) and 6ml of 6N HCI
solution in 6ml of methanol was stirred at ambient temperature for 4 hours and was evaporated under reduced pressure. The residue was diluted with 5ml of ice water, carefully basified with 10% Na2COg solution until pH=8-9 was obtained. Extraction of the so-formed reaction mixture with 2 x25m1 of CH2 CI2 followed by washing with saturated brine, drying over MgS04 and evaporation gave a tan solid. Filtration of the tan solid through a 508 silica gel column and elution with 0.75L of 4% MeOH/CHZCI2 gave 0.268 of title product as a tan solid, yield 96.6%. MS={M+H)+-_687; «~ - -23.65° {CHCI3 ; c=1 ) Exam a 19 (-)-f12R1-cisl-4-f4-f4-f4-ffl,~-« 4-Difluoro~r y1) Tetrah~,dro 5 (1 H ~ 2_a Triazol-1-vlmethvll-'~-F~rany-()~Il"eih~xerlPhenvl~ 1 PipArazin)r(lphenY~]~,4 Dihvdro-2-lfllR)-Methvl-2~R~-H~~~~..,~r,r,r,QYI~ 3H 1 2 4 Triazol 3 one a. Mitsunobu Reaction To a stirred solution of 0.728 of the 2-O-SEM ether of Example 18(a) (3.27 mmoles), 2.1 g of triphenyl phosphine (8.068) and 1.28 of p-nitrobenzoic acid (7.17 mmoles) in 30m1 of dry benzene at 0°C were added, dropwise, 1.25m1 (8.06 mmoles) of diethyl azodicarboxylate ("DEAD"). The so-formed clear yellow solution became turbid and the mixture was stirred at ambient temperature for 2 hours, and mixture loaded on a 1008 silica gel column.
Elution of the column with 15% ETOAC/Hexane gave 1.58 of the 3-~i-nitrobenzoate having the S absolute configuration (95% yield) MS: 219 1 ?9396 (M+ - 150), 252 (M+ - 117).
b. Basic Hydro_lycis of the o-Nitrobanzoate A solution of 1.12g of of the p-nitrobenzoate of Example 19(a) {3 mmoles) and 3.5m1 of 1 N NaOH solution in 20mi of methanol was stirred at ambient temperature for 3 hours. Solvents were evaporated and the residue was diluted with l0ml of distilled water, and extracted with 2 x 20m1 of ether. The combined ethereal solution was washed once with saturated brine, dried over MgS04 and evaporated to give 0.67g of the corresponding alcohol as a colorless liquid 0100%), which was used directly for the next reaction without further purification.
c. Brosylation. Akyrlation and Acidic Hvdro y~
Following the procedures of Example 18(c) and (d), the title compound was prepared in 32% overall yield in 3 steps from the products of Example 19(b) and of Example 17. MS: (M+H]+=687; ~a~~ - -23.65° (CHCI3 ; c=1 ) f-)-fl2R)-cisl-4-f4-f4-j4-j(f5-(2.4-Difluoroo, h~nyl -TetrahYdro-5-(1H-1 2 4-Triazol-1-vlmethvl)-3-Furanyl)MethoxylPhenyIJ-1-PioerazinyjlPhenyll 2 4 Dihvdro-2-f(S)-1-Methvl-3-HydroxvoroQy~-3H-1 2 4-Triazol-3-one a. Formation of TBDPS Ether To a solution of 0.9g or (R)-(-}-1,3-butanediol (10 mmoles), 1.5g of imidazole (22 mmoles) in 10 ml of anhydrous DMF at 0°C were added 3ml of t-butylchlorodiphenylsilane ("TBDPS") (11 mmoles) over 3 minutes. The reaction mixture was stirred at 0°C for 4 hours, diluted with 50m1 of ice-cold water and extracted with 2 x 30m1 of ether. The aqueous phase was back extracted with 5~
50m1 of ether and the combined ethereal solution was washed once with saturated brine, dried over MgS04 and evaporated to give a colorless residue.
Flash chromatography over 1508 silica gel with 1.5L of 5% EtOAC/Hexane and 1 L of 10% EtOAC/Hexane gave 2.878 of the TBDPS ether (87.5%) (ajp3 = +0.64° (CHCI3 ; c=1 ) MS: (M+H]+: 329;
b. Brosyiation To a solution of 0.9848 of TBDPS ether of Example 20(a) (3 mmoles) in 7ml of anhydrous pyridine were added 0.8458 of 4-bromobenzenesulfonyl chloride (3.3 mmoles). The reaction was run and worked-up and purified in accordance with the procedure of Example 18(b) and 1.028 of the brosylate was obtained in 61.1 % yield; MS: [M+23j+ = 569/571;
Iajp = +2.45° (CHC13 ; c=1 ) c., Alltylation The brosylate of Example 20(b), 0.958 (1.74 mmoles) was reacted with the compound of Example 17 according to the procedure of Example 18(c) to provide 0.498 of corresponding alkylated product, yield 60.3% MS: (M+H)+ 925 Iajp = -32.27° (CHC13 ; c=1 ) d. Acidic vdrol The compound of Example 20(c), 0.328, (0.35 mmoels) was hydrolyzed by 6N HCI solution in accordance with the procedure of Example 18(d) to give 0.228 of the title compound (yield 92.4%); MS: M+ = 686; (M+Na]+ = 709;
(ajo3 = -38.52° (CHCl3 ; c=1 ) Alternatively a solution of 0.198 of the compound of Example 20(c) and 60mg of tetrabutylammonium fluoride (0.23 mmoles) in 5ml of THF was stirred at ambient temperature for 24 hours. The brown solution was concentrated to a 2 ~ 79396 -syrup. Flash chromatography of the syrup over 50g silica gel with 0.5L each of 2% and 4% MeOH/CH2C12. gave 0.11 g of the title compound (yield 88.7%).
Exam to a 21 (-)-ff2R)-cisl-4-f4-f4-f4-ff5-(2 4-Difluoroohenyl)-Tetrahvdro-5-(1 H-1 2 4 Tria2ol-1-Ylmethvl)-3-FuranvIJMethoxy,)Phern,u-1-Pig erazinvllPhenylj-2 4 Dihvdro-2-flRl-1-Methyl-3-Hydrox o~ro,Qyll-3H-1 2 4-Triazol-3-one The procedures of Example 20 were followed except an equivalent amount of S-(+)-1,3-butanediol was substituted for the corresponding R
enantiomer. An overall 31.8% yield of the title compound was obtained in four steps; MS=[M+Hj+ = 687.
Example 22 (-)-f(2R)-cisl-4-f4-f4-f4-[(5-(2 4-Difluoroy~henyll-Tetrahvdro-5 (1 H 1 2 4 Triazol-1-vlmethvl)- -Furan~jMe-yjPhenyl~-j=Pioerazinyl~PhenYlj 2 4 Dihvdro-2-fllS)-Methyl-2-HydroxYp~QYI~-3H-1 2 4-Triazol-3-one.
a. Benzylation To a solution of 10g of (2R, 3R)-(-)-2,3-butanediol (111 mmoles) in 40m1 of anhydrous CH2C12 and 80m1 of cyclohexane at 0°C were added 1 ml of trifluoromethanesulfonic acid (TfOH), followed by dropwise addition of 21 ml of benzyl trichloroacetimidate (113 mmoles). The resulting slurry was stirred at ambient temperature overnight, diluted with 125m1 of hexane and filtered. The combined filtrate was concentrated to a yellow syrup. Flash chromatography of the yellow syrup over 250g silica gel with 1.5L of 7% ETOAC/Hexane, 2L of 15% ETOAC/Hexane and 2L of 25% ETOAC/Hexane, 1.5L of 10%
_.. _~_ __....
-- y ~ r2179396 MeOH/CH2C12 gave 11.888 of the 2-monobenzyl ether of the starting material (74.5% yield) and 2.038 of unreacted starting material MS: [M+H]+: 181.
b. Mitsunob Reaction The 2-monobenzyl ether of Example 22(a), 5.48, was converted into 6.68 of the 3- benzoate ester (yield 66.9%) by Mitsunobu reaction in accordance with the procedure of Example 19(a); MS: [M+H]+_- 330.
c. Alkali rolv i The 5.38 of the product of Example 22(b) was subjected to alkaline hydrolysis according to the procedure of Example 19(b) to give 2.338 of the 2-monobenzyl ether of (2R,3S)-2,3-butanediol (yield 80.3%) (M+H)+ = 181;
[a]p3 = -23.75° (CHC13 ; c=1 ) d. Formation of the ~ ~rho.
To a stirred solution of 3.148 of the product of Example 22(c) (17.44 mmoles) and 3.8m1 of di-isopropylethylamine (2.828, 21.8 mmoles) in 30m1 of anhydrous CH2Cl2 at ambient temperature were added 3.8m1 of SEM-CI
(3.648, 21.8 mmoles) in one portion. Fuming formed and the resulting yellow solution was stirred for 20 hours. The orange-colored reaction mixture was evaporated under reduced pressure and the solid residues were partitioned between ether and water. The ethereal solution was washed once with distilled water, saturated brine, dried over mg 504 and concentrated to give the crude product. Flash chromatography of the crude product over 2008 silica gel with 2L of 3% ETOAC/Hexane gave 5.38 of the 3-O-SEM ether of the product of Example 22(c) (98% yield) as a colorless liquid; MS: [M+H]+ = 311.
217396 _ e. HYdrogenolysis A mixture of 5.25g of the product of Example 22(d) (16.94 mmoles) and 0.5g of 10% Pd/C in 150m1 of methanol was hydrogenated under atmospheric pressure for 6 hours. Catalysts were filtered and washed with additional methanol. The combined filtrate was concentrated to give a colorless liquid.
Flash chromatography of the liquid over 100g silica gel with 2L of 10%
ETOAC/hexane 3.53g of the free alcohol (yield 95%) as a colorless liquid; MS:
174, 103.
f. Bros, lair tion The product of Example 22(e) 1 g was converted into 1.52g of the corresponding brosylate in 76.2%yield in accordance with the procedure of (aj -1.53° (CHC13 ; c=1 ) 18(b);
g. Alkylation Reaciton The brosylate of Example 22(f), 1.48g of was reacted with the product of Example 17 to give 0.75g of the 2-alkylated triazol-3-one (yield 54.3%);
[a]p3 = -32.69° (CHCI3 ; c-1 ) h. Acidic H~olysis Hydrolysis of 0.7g of the product of Example 22(g) in accorcdance with the procedure of Example 18(d) gave 0.51g of the title compound as a cream solid (yield 86.7%); [aj~ - -32.69° (CHC13 ; c=1 ) Example 23 . ~ '-' ~11~3~6 (-)-f(2R)-cisl-4-f4-f4-f4-ff5-f? a mst~~oro'~envll Tetrah~ ro 5 (1 H 1 2 4 Triazol-1-vlmethvl)-~-FuranvllM~pthoxvlPhenvll 1 Pioerai~,~ n~~~~~
ih r - - 1 -M h I- -H r x r I - H-1 4-Tri I- n .
a. blitsunobu React~~n The product of step a of Example 22 (1.99g, 9.05 mmoles) was reacted with p-nitrobenzoic acid in accordance with the procedure Example 19(a) to give 3.3g of product (yield 98.8%); MS = [M+Hj+ = 221.
b. Alkaline Hv rol is The product of step (a) of this Example (2.36g, 6.4 mmoles) was hydrolyzed by 7ml of 1 N NaOAc to give 1.18g of the 3-O-SEM ether of (2S,3S) 2,3-butanediol (yield 83.7%). MS: [M+Hj+ = 221 [°~jo3 - +55.15° (CHCI3 : C=1 ) c. Brosvlate Formation The product of step (b) of this Example (1.15g were converted into the brosylate in accordance with the procedure of Example 18(b) to give 3.47g of the brosylate (yield 97.7%) .
d. Alkvlation and Acidi - Hvdrolva~c The procedures of Example 18(c) and (d) were followed except the product of Example 23(c) was substituted for that of 18(b) to give the title compound.
Example 24 ~ 119396 _ l2R-cis~-4-f4-f4-14-ff-5-12.4-difluoroohen~,l1-tetrahvdro-5-l1 H-1 2 4-triazol-1-vlmethvllfuran-3-vllmethoxvlohenyl]-1-pioerazin~ljhhen~,l2-4-dihydro-2-((Sl-1-ethyl-2lS)-hvdroxvorooylj-3H-1.24-Triazol-3-One a. The methyl ester of (S)-lactic acid was converted into the corresponding benzyloxymethyl ether in accordance with the procedure of W. C. Still, et al.
Tetrahedron Letters, ~1_, 1035-1038 (1980).
b. Reduction to the Aldeh~e DIBAL-H, 37.7m1 of a 1 M solution, was added dropwise to a stirred solution of 7.67g of the ester of step (a) of this Example in toluene at -78°C (dry ice/acetone bath) under an atmosphere of nitrogen. After 6 min. methanol (l0ml) followed by an aqueous aolution of Rochelles salt were added. After warming to room temperature the moisture was partitioned between ETOAc and water. The organic phase was separated, washed with water, dried (MgS04) and concentrated to produce the crude aldehyde which was used in the next step without purification.
b. Grianard Step The THF solution of SOmI of 1 molar solution of the ethyl magnesium bromide Grignard reagent was added dropwise to a stirred THF solution of the crude aldehyde obtained from step (b) of this Example at -78°C (dry iceJacetone bath) under an atmosphere of nitrogen. After the addition was complete, the resulting mixture was allowed to warm slowly to room temperature overnight and stirred for a further period of 48 h. An aqueous solution of Rochelles salt was added and then the resulting mixture was partitioned between acetone and water. The organic phase was separated, washed with water, dried (MgS04) and concentrated. The residue was purified by column chromotography on silica gel using ETOAC/Hexane (1:10) as eluant to give (i) non-polar alcohol (2S,3S) 2.31 g;31 %, as a colorless oil.
(ii) a mixture of both alcohols, 1.23g; 41 and (iii) polar alcohol (2S,3R) 1.23g; 16%, as a colorless oil.
c. Brosvlation of Qol2~ alcohol 4-Bromobenzenesulphonyl chloride (1.0358, 4.1 mmoles) was added to a stirred solution of (0.6058, 2.7 mmoles) the polar (2S, 3R) alcohol of step (b) of this Example and 2.208 (5.9 mmoles) of DMAP in CH2C12 at room temperature under an atmosphere of nitrogen. The resulting mixture was stirred for 12 h. and then partitioned between ETOAC and water. The organic phase was separated, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel using ETOAC/Hexane (1:10) as eluant to give the desired brosylate (85%) as a colorles oil.
d. Alk~ation and acidic hydrolysis The procedures of Example 18(c) and (d) were followed except the (2S, 3R) bosylate of step (c) of this Example was substituted for that used in Example 18(c). The acidic hydrolysis produced the title compound as a white solid, mp 170-172°C.
Example 25 L?R-cis)-4-~4-f4-f4-j(-5-(2.4-difluorohenyll-tetrahYdro-5-(1 H-1.2.4-triazol-1-vlmethvllfuran-3-vllmethoxvj~henvll-1-~i~erazinvfl~henvll-2.4-dihvdro-2-f(R?-1-ethyl-2fS)-hvdroxvoroovl~-3H-1.2.4-triazol-3-one.
The procedures of Example 24 were followed except the non-polar (2S,3S) alcohol from step (b) of Example 24 was converted into the (2S,3S)-3-brosylate. Alkylation of the brosylate followed by acidic hydrolysis of the SEM
6~
~ I ~939~ __ protecting group in accordance with the procedures of Example 24(d) provided the title compound.
R- i -4-f4-f4-f4-ff-5-(2.4-c~ifluorrac_ henyl - trahydro-5-l1 H-1 2 4-triazol 1-vlmethvllfuran-3-vllmethoxvloh~ll-vi erazinyllohenyl]~-4-di~dro-2-jlR) 1 Qthvl-2 ( R )-hvdro xv~ row I]-3 H-1.2.4-triazol-3-On a The procedures of Example 24 were followed except the methyl ester of (R) lactic ester was substituted for the methyl ester of (S)-lactic acid in step (a) of Example 24. The (2R, 3S) alcohol was used in steps (c) and (d) to provide the title compound.
Example 2727 R- i -4-f4-f4~f4-ff-5-(2.4-difluoroohenyl)-tetrahvdro-5-(1 H-1 2 4-triazol-1-vlmethvllfuran-3-vilmethoxvlohenyl]1-oioe_ -razinyljohenyl]2-4-dihvdro 2 ((Sl 1 eLyl-2lR)-hvdroxvorooyl]-3H-1 24-triazol-3-On The procedures of Example 26 were followed except the (2R, 3R) alcohol was used in steps (c) and (d) to provide the title compound.
Exams ((2R'cis)cis)-4-f4-f4-f4-ff-5-12.4-difluoro henyl)-tetrahvdro-5-(1 H 1 2 4 triazol 1-vlmethvllfuran-3-vllmethoxvlohenv111-oiper~yllohenvll -4-dihvdro 2 [(R1 1 ~yl-3-hvdroxvoroovl] ~H-1.2.4-tri~nl-3-One a. Reduction To methyl (3R)-hydroxyvalerate (5.289, 40.0 mmoles) dissolved in 100m1 of anhydrous THF at 0-5°C was added dropwise 60m1 of a 1 M THF solution of LiAIH4 (60 mmoles). The solution was allowed to warm to ambient temperature and to the so-formed mixture was added sequentially, 2.5 mL of water, __. T _ _ dropwise, 2.5mL of 15% NaOH and 7.5mL of water. The so-formed reaction mixture was stirred at ambient temperature for 4 h. The inorganic solids were removed by filtration and the filtrate was evaporated to give 4.31 g of (3R)-1,3-pentanediol.
b. 1O-SEM .thpr formation The procedure of Example 18(a) was followed except an equivalent quantity of the product of step (a) of this Example was substituted for the (2R, 3R)-2,3-butanediol to provde the title compound.
c. Mitsunob Reaction The procedure of Example 19(a) was followed except that an equivalent quantity of the product of step (b) of this Example was substituted for the 2-SEM
ether of (2R,3R)-2,3-butanediol to give 3.34g of the corresponding p-nitrobenzoate.
d. Basyol The procedure of Example 19(b) was followed except that an equivalent quantity of the p-nitrobenzoate ester of step (c) of this Example was used to provide 1.88g of the 1-O-SEM ether of (3S)-1,3-pentanediol.
e. Brosvlation Alkvlation ~nd A id H I ~ i The procedures of Example 18 (b), (c), and (d) were followed except that an equivalent quantity of the product of step (d) of this Example was substituted for the corresponding 1-0-SEM ether of (2R, 3R) 2,3-butanediol used in Example 19(b) to produce 1.04g of the title compound of this Example falp3 = -8.42° (CHC13 ; c=1 ) ~217~.3~6 _.
WO 95/17407 . PCTNS94/14236 Examgle 29 ( R-cisl-4-f4-f4-[4-j[-5-(2.4-difluoroohenyl~-tetrahyrdro-5-l1 H-1 2 4-triazol-1-vlmethvl)furan-3-vl]methoxy]~hgn 1Y11_oioerazinyllohen~l2-4-dih~rdro-2-[(S1-ethyl-3-hvdroxvcroQ~l,~-3H-1.2.4-triazol-3-One.
The procedures (a) and (b) of Example 28 were followed to produce the 1-O-SEM-(3R)-1,3-pentanediol which was converted directly into the 3R
brosylate by following the procedures of Example 18(b). The 3R brosylate was used to alkylate the product of Example 17 in accordance with the procedures of Example 18(c). The so-formed product was subjected to acidic hydrolysis in accordance with the procedures of Example 18(d) to provide 368mg (90%
yield) of the title compound; [a]~3 47' 11 ° (CHC13 ; c-1 ) Example 3030 (2R-ci~,-4-f4-f4-f4-[[-5-(2.4-difluoroohenyl -tetrahydro-5- 1 H-1 2 4-triazol-1-vlmethvl)-3-furanvllmethoxY] hen~,~1 rioerazin~rljohenyll2-4-dihydro-2-f1-h dy rox_y-l2R)-butvlj-3H-1.2.4-triazol-3-One a. Preparation of 1251-1.2.-butanediol A solution of (2S)-3-butene-1,2-diol which was purchased from Eastman Kodak, (3g, 0.034mmoles) in 40mL of ethanol was hydrogenated in the presence of 300mg of 10% Pd/C overnight. The so-formed reaction mixture was filtered through celite. The so-formed filter cake was washed with ethanol and the combined filtrates were evaporated to provide 2.08g (68% yield) of the title compound.
b. 1-O-SEM ether formation. brosvlaton. alkylation and acidic hydroysis The procedures of Example 18(a) - (d) were followed except that an equivalent amount of the product of step (a) of this Example was substituted for _.__ T _ _ _ . ._ ..__ -.T_-. . v ~ ~ 19396 the (2R, 3R) 2,3-butanediol of Example 18 to provide the title compound -24.3° (CHC13 ; c_-1 ) Exam a 31 ,(2R-~'y,-4-f4-f4-f4-ff-5-(2 4-difluoroohenvll tetrahvdro 5 f1 H 1 2 4 tn~ zm hvdroxv-l2~-bstyp-~-H_1.2 4_triazm ~ one The procedures of Example 30 were followed except that an equivalent quantity of (2R)-3-butane-1,2-diol (available from Eastmand Kodak) was substituted for (2S)-3-butane-1,2-diol in step (a) of Example 30. The procedures of Example 30(b) were there after followed to produce the title compound ~~')03 29'4° (CHC13 ; c=1 ) - i -4- 4- 4 - 4- if r n _1 4 _ _1 _ I I f r I h x n I - i i I I- 4- ih Qthvl-2lS)-hvdroxvoroovll-'~H-1 2 4 tria~nl ~ "ne a. n I x r 'v i f benZVl1 lacti _ anir~ nyrrnliriinn ~ ;ide: To a solution of the S-(O-benzyl)lactic acid pyrrolidene amide prepared in accordance with the procedure of Tetrahedron, 1989, vol. ~, pages 57-67 (5g, 0.0214 mol.) dissolved in 20 ml of toluene cooled to in a ice methanol bath was added slowly with stirring 4.25 ml or RED-AL (3.4M solution of sodium bis(2-methoxyethoxy) aluminum hydride) in toluene available from Aldrich Chemical Catalogue #19, 619-3). The solution was stirred fro 5 hrs., quenched with 2.5 ml of acetone and thereafter with 35 ml of 2NHC1. The so-formed mixture was extracted with EtoAc. The organic extracts were washed with water, NaHC03 and brim, ~ over Na2S04 and evaporated to give the titled product.
b. (S1-2-lBen2vloxy)-N;~~mylaminoLgronanimine. The , propionaldehyde of step (a) (1 g, 16.09 mml) was added dropwise to a solution of formic hydrazine (0.738, 12.18 mmol) dissolved in 5 m! of methanol. The so-formed reaction mixture was stirred overnight.r The solvent was removed by evaporation and the so-formed residue was stirred with ethyl ether. The undlssolved excess formic hydrazine was removed by ~Itration and the ether was removed to provide a residue which was chromatograpned on silica gel(I) using 20% EtoAc: hexane (v:v) to give 805 mg of the title product as a light yellow waxy solid having strong UV activity; ms [M + H)+= 207.
c. 2~3-125. 3S1-2-lBensyt~)oentylJformic a~i~ hyd ztde Ethytmagnesium bromide (1.3 ml, 3.9 mmot, 3.0 molar in ethyl ether) was added to a stirred solution of 200 mg, 0.97 mmol of the propanimine of step (b) in 10 m! of ethyl ether at 0°C. The so-formed reaction mixture was stirred overnight at room temperature and quenched with water. The organic layer was separated and the solvent removed to provide a residue which was chromatographed on silica gel using 30 to 50°/° of EtoAc:hexane (v:v) to provide 713 mg; (50 % yield) of the title compound as an oil. The ratio of S,S isomer.
S,R isomer in the product was 94:6. When the reaction was repeated in the presence of 1.2 equivalent of bis(trimethylsiiyi) acetamide the S,S:S,R ratio improved to 99:7 MS: [M + H]+ = 237 d. Cvclizatton Reaction A solution of 156.3 mg, 0.66 mmot of the product of step (c) and 400 mg 0.60 mmol of 17F of Scheme V and 1 mole of DBU (1,8-diaza bicyclo [5.4.OJundec-7-ere) in volume was stirred at 80°C for six hours; the temperature D
..~ 2119396 was raised to 100° to 110°C and stirring was continued at this temperature overnight. The reaction mixture was allowed to coo( to room temperature and ~ the stirring was continued over the weekend. The solvent was removed by evaporation and the crude product was purified on preparative TLC (80%
EtoAc) hexane, v:v) to provide 200 mg of the benzyi ether of the title product of this example as a foamy solid; MS:(M + Nj+ i 792 This cyclization reaction is the invention of Mergelsberg, Gala g~, which is disclosed in commonly-owned U.S. Patent 5, 625, 064.
e. ~Ivdrog~enolysis To the solution of the benzyl ether (190 mgs , 0.24 mmol) of step d dissolved in 10 ml of methanol was added 40 mg of Pd black on carbon and 4 mf of formic acid. The reaction flask was sealed with a bailon and heated at fi0°C for four hours. The catalyst was removed by filtration through a celite cake and the filtrate was poured into c:ofd water. The pH of the so-formed solution was adjusted to a value of 4 to 5 with amonia. The so-fom~ed mixture was extracted with EtoAc. The organic layer was separted and dried over Na2S04.
The solvent was removed to provide a crude product which was purified on preparative TLC (5% methanol: CH2CL2, v:v) to give 95 mg of the title compound of this example. (57% yield) as a tan solid. MS : (M+ H]+ = 701.
[oc] a -28.4 (c, = 1.0, CHCI3)
EMBODIMENTS
The term "(C3-Cg) alkyl group substituted by one or two hydroxy moieties", as used herein means straight and branched chain alkyl groups of three to eight carbons including but not Limited to methyl, ethyl, n- and i~,Q-propyl, n-, sec-, i~ and ~r -butyl, n_-, sec -. i~-, ~r and n~-pentyl _n-, ~-, j~-~r - and n~-hexyl, n-, ~-, ~-, ~- and n~-heptyl, _n, ~- ~, ~r -and ngQ
octyl, substituted by one or two hydroxy moieties and includes R and S
stereoisomers of such (C3-C8) alkyl groups.
The term "(Ci-C3) alkyl substituted by one hydroxy moiety" means -CH20H , -CH(OH)CH3 , -CHZCH20H , -CH(OH)C2H$ , -CH2CH(OH)CH3 , and -(CH2)3-OH wherein the carbons with the asterisk(*) have the R or S absolute configuration.
The term "hydroxy-substituted C4 or C~ alkyl grcup" means -CH(C2H5)CH(OH)CH3 ,-CH(C2H5)CHZCH20H , -(CHZ)2 CH(OH)C2H5 , -CH(CH3)CH(OH)CH3 ,-~~~3)~~~ ar. -CH(C2H5)CHZOH
wherein each carbon with the asterisk (*) has the ~R or S absolute configuration.
The term "pharmaceutically acceptable ethers" means (a) straight and branched chain alkyloxy groups of one to twenty carbons, preferably of one to eight carbons, more preferably one to six carbons and (b) aryl(C~-C6) alkyloxy groups of the formula -O -(CHR7)n-Ar wherein R~ ~ H ar (cl-C6) straight and branched chain alkyl and n= 0 to 6 preferably 1 to 3 and Ar is phenyl, phenyl substituted by halo, especially chloro and fluoro, or by vitro, cyano and trihalomethyl especially trifluoromethyl. Most preferred ether groups include methyloxy and benzyloxy.
A
The term "esters" means (a) polyether esters (b) phosphate esters (c) heterocyclic esters (d) alkanoate and alkenoate esters (e) amino-alkanoates and (f) acid esters and (g) sulfate esters.
The term "polyether esters as used herein means those polyether esters O
represented by the formula - C-(CHR~)S-(OCHR~CHR~)t-ORg-, wherein R7 is as defined herein and s is an integer from 1 to 6, preferably s = 1 to 3 and more preferably s = 1; t is an integer from 1 to 6; preferably t is 1 to 3, more preferably t is 2 or 3.
R8 is R7 or (CHR~)5-C02R7 ~ preferably R$ is CH3 or C2H5 or CH2C02H or CHZC02CH3 . Typically suitable polyether esters -CO~H20(CHZCH20)~CH3 , ~-COCH20(CH2CH20y2CH,;
include . , , and -COCH20(CH2CH20)3CH3 . ' The term 'phosphate esters" as used herein means those phosphate acids esters represented by the formula O O
C -(CHR7)rT-~O)m P-(O1N)2 wherein z is 0 or 1; R7 is as defined herein above and preferably is H; n is an integer from 0 to 6, m is 0 or 1 and W
is H, CH2Ar or . OH and wherein Ar is as defined herein above.
O
Typically suitable phosphate acids and esters include P-(OCHZCsH$)2 O
- P- (OH) 2 .._.. , , P- ~ /
II
OH OH -.C-(CH2)n-0- P(OH)2 wherein m= n = 1 to 4; or O
-C-CH(CH3)-O-P(OH)2 and pharmaceutically acceptable salts thereof.
The term "heterocyciic ester" as used herein means heterocyclic esters O
- - ~CHR
(CHR7)w'-N ( 7)q represented by the formula Y''' wherein R~ is as defined herein above, W is an integer of from 1 to 5 preferably W is 1 to 3; q is = 3 or 4 and Y is CHR~, -O-, NH, NR7, S, SO or S02 Typically suitable heterocyclic esters include O O O
CHz- N - ~. CHI N~NH - ~~ CH N S I !-1 - ~- CH N
O
- ~ O _ N~ ~ 3 C CH 2--N O ~ O - CH 2--~V~SO 2 U
O
and - C - CH 2--N
The term "alkanoate and alkenoate esters" as used herein means straight or branched chain alkanoate or alkenoate groups optionally substituted by a hydroxy or ether moiety or mixtures of such alkanoates or alkenoates.
Preferred alkanoate esters include acetate to decanoate, especially acetate to butanoate. Preferred hydroxy substituted alkanoate ester include C~
to C8 alkanoate substituted one hydroxy moiety, especially ~1~9396 CCH20H and -C-CH(OH)CH3 . Preferred alkenoate esters are the C~o-C2o alkenoates and include C~4 to C18 alkenoates, such as ~-7-hexadecenoate.
The term "amino alkanoate" as used herein include the natural and unnatural amino acid residues preferably with amino groups protected by the conventional protecting groups well known to those in art such as phenyl acetate.
The term "acid ester' as used herein means those acid esters O
-C- CR R -~-OH
represented by the formula ( ~ ~)k wherein R7 is as defined herein above and k is an integer of from 1 to 8. Typically suitable acid esters include oxalic, malonic, succinic glutaric and adipic acids as well as O O
branched chain diacids such as CCHCH3-COH
The term "ether" as used herein means (C~-C6) alkyl or aryl (C~-C6) alkyl which are conveniently made by the well known Williamson Synthesis of ethers. Typicaly suitable ethers groups include methyl and benzyl.
The compounds of the present invention as well as the esters and ethers thereof exhibit broad spectrum antifungal activity in various in vi r assays against n i , other yeasts, dematophytes, As~rgillus and opportunistic fungi. The in vi r antifungal activity test were performed via conventional agar dilution methods in Sabouraud dextrose broth ("SDB") medium against a large number of fungi. Minimum Inhibitory Concentrations ("MICs") were measured after 24, 48 and 72 hour tests.
The term "opportunistic fungi" include Crytococcus. HistoQlasma.
Blastomvces Coccidioides Fusarium Mucor Paracoccidioides Fonsecaea . , 2179396 lNanaiella. Soorothrix PneumocvstiS Trichosoorq_n as shown by in viv activity in an appropriate animal species e.g. mouse, rat or rabbit. The compounds of the inventions are expected to exhibit activity against many genera and species of bacteria, protozoa, gram negatives, gram positives, Anaerobes, i n II
r i , L~yCODr ~3Sma, Treoonema, Gardneralla, Trichomononas and ~canosoma The preferred compounds of formula III wherein R5=hydroxy-substituted C4 and C5 alkyl groups, exhibited the following in vi r antifungal activity in SDB against 37 species of As~erq~illus niq~er, flavus, mi and rr ~ geometric mean MICs in the range of <_0.05 to >_1.53 (mcg/ml) and geometric mean MFCs in the range of 0.27 to 24.24 mcg/ml.
The preferred compounds of formula III wherein R5 is a hydroxy-substituted C5 alkyl group exhibited (1 ) superior antifungal activity as measured by geometric mean MICs and MFCs in various in vi r assays against ~
Ricans (N=26), . kr ' (N=26), I r (N=9), C. trooicalis (N=4), ~,, stellatoidea (N=1 ), C. neoformans (N=3), and the dermatophytes, T.T. rubrum.
T.T. manta, and T. tonsurans (N=6) (after 48 or 78 hours) compared to fluconazole as well as (2) superior anti-fungal activity in the following inin vivo models: an A DerQIIhIS- flaVl~S and fumiaa~ (four strains) in a pulmonary immuno-compromised mouse model (PO-1 XDX4D) compared to other azoles e.g.
itraconazole, and in a Candida albi _ans (four species) systemic model with normal and compromised mice (PO-1 XDX4D) compared to other azoles, e.g.
fluconazole.
The in viv oral antifungal activity of the compounds of the present invention were compared to azole antifungals, e.g., fluconazole in an Asoerqillus pulmonary infection model in mice. The procedure of David Loebenberg et al. entitled "Sch 42427, The Active Enantiomer of Antifungal agent Sch 39304; In vitro Activity", Antimicrobial AaentS and Chemotheraov (1992), ~ 498-501 was used. The Asoergillus- flavus pulmonary model is also ~ ~ X9396 ._ WO 95/17407 PCTlUS94114236 described in European Patent Application No. 0 539,938 AI published on 5 May 1993.
The preferred compounds of formula III exhibited superior antifungal in vi r activity in SDB against 37 species of Aspergillus with (a) geometric mean MICs of < 0.05 to s 0.81 compared to fluconazole (geometric mean MIC >_ 32 and (b) with geometric mean MFCs of <_ 0.89 to < 3.78 compared to fluconazole (geometric mean MFC >_ 32).
The Tables Q, R, and S hereinbelow display the superior in vi r antifungal activity of three preferred compounds of formula III compared to fluconazole. Table D displays such antifungal acitivity such as the percentage of strains of various fungi with MICs <_ 1 mcg/ml for the three preferred compounds of formula III compared to fluconazole. Table R displays the antifungai activity as the percentage of the same strains with MFCs < 1 mcglml.
Table S displays the in vi r MIC 90 values for the three preferred compounds of formula III agains the same organisms listed in Tables Q and R.
The most preferred compound of formula III where R5 =
Me S
S
OH
showed consistently higher serum levels in mice, rats, dogs and monkeys following oral dosing with a methyl cellulose formulation compared to azoles of similiar structure and also exhibited very long serum half life following O.D. dosing with good tissue distribution. The above listed most preferred compound of formula III are not inducers of various cytochrome P-450 liver drug metabolizing enzymes after oral administration in an inin vivo rat model io FOR COMPOUNDS
OF
FORMULA I II
PERCENTAGE
OF STRAINS
WITH MICs (MC G/ML) Me s Me Me 85 uu~
~~OH ~S OH ~~R__OH
~ ~
Aspergillus 37 100 100 100 0 Candida Albicans 26 100 100 100 100 Candida Kursei 16 100 100 100 100 Candida Tropicalis & Stellatoidea5 100 100 100 100 Candida Glabrdta 9 22 22 33 0 Cryptococcus 3 100 100 100 0 Neoformans Dermatophytes6 100 100 100 100 1. O
H N, A5 F ''''~O N~ N N~ N
O/
F ~ ~ (~l N
2. FLZ = fiuconazole WO PC'TlUS94/14236 TABLE R
IN VITRO ACTIVITY SELECTEDCOMPOUNDS
ANTIFUNGAL FOR OF
FORMULA IIh PERCENTAGE OF STRAINS l MCGIML
WITH MICs S
IM CG/MU
MB S Me S Me nn.~
/~ OH /~ OH ~/ R OH
~ ~
Aspergillus 50 62 89 0 Candida Albicans 100 100 100 100 Candida Kursei 1-16 88 94 100 0 Candida Tropicalis 8~ Steltatoidea 100 100 100 100 Candida Gtabrata 22 22 22 0 Cryptococcus 100 100 100 0 Neofortnans Dermatophytes 67 83 100 0 1. 0 H ' R' ~N
N _ N
N
~ ~ ~ i O
~N-N I~I
_ N' 2. FLZ = fluconazole m TABLE S
IN VITRO ANTiFUNGAL ACTIVITY FOR SELECTED COMPOUNDS OF
FORMULA IIh PERCENTAGE OF STRAINS WITH MICs Sl MCGIML
n~ncr ~,~~ v g5 ~i~-~
/ g pH ~/ p ' OH
1~etA'c ~/ S OH
s Aspergiilus 37 .122 .096 .112 29.9 Candida Atbicans 26 274 .174 .139 .887 Candida iCursei 16 .058 .014 .12 29.9 Candida Tropicalis 8~ Steilatoidea 5 .11? .117 .354 .917 Candida G~~ g 28.8 17.1 28.8 29.3 Cryptococcus 3 .05 .007 .101 25.9 Neofortnans Dermatophytes 6 .165 .101 '707 29'4 1. 0 H ~N.
F ~O~IN~~IN~%N
R 0, ~N._N I ~ J
N' 2. F11= fiu~nazole 2 ~ 7396 ._ The preferred esters and ethers of the compounds of the present invention of formula IV also exhibited superior in viv antifungal activity against a broad range of fungi. After oral and parenteral e.g. IV administration in mice, rats, dogs and monkeys. The preferred esters and ethers of formula IV listed below wherein Rg is _ _ O
/ N ~ / N~N-Rs LN
IV
Rs Rs Me O
Me 'P~OCH2CgH5 ~~OH
OCHzCBHs ~ O
NIA 961.4 M' 759.3 217939b Rs Rs Me p~O~O~O~OH S
Me O O Me p Me ~ ~5 ~N.Me a AA* 841 ~O~.O~O.~oMe S
Mi' 905 Me a ~O
s Me O ~ O~O~O~OMe S Me ~ 826 Me ~ 905 Me O
S
....0 Me R ~ O~O~O~OMe a O O H2 2NMG
M"891 S
R Me Me 1O~ 'Me Me ~O~O~ ~ 853.2 O a M' 817 S O,P,,O
a Me ~'OH .2NMG
... p OH
O~O~O~Me R a M' 781.7 Me NI~ 861 1~OPO3Hp. 2NMG
Me Me 1 - -O
""' R O M* 881.3 p~OH ~NMG Me Me O S
NI+ 801 ~ OP03H2. 2NMG
Me O
M' 881.3 2 ~ 7939b Rs R9 Me S Me O~ ,~O .... R
Me P~OCHvMe OCH2Celi5 Me 0O
AA+ 7424 Me Me OH
,... R O i ~ S ...H
.2Et3N O~Me Me 10H OH Me O
M* 873.3 ~ X3.1 Me a R .... R
""' O' ~'p O
Me P1~OH ~~ Me O
OH
AA* 781.8 ~ X8.7 CeHn Me Me S S
O~O_ProH ~~ R ~OMe Me O OH Me AA+ 839 AA+ 701. 4 Me S
Me O ~ O
O ~ ~ Me ~ i Me NH.CO.CH2C6H5 +
M 821.5 AA+ 983 The more preferred esters listed hereinabove are readily metabolized in viv to the corresponding alcohols e.g. R5 is Me Me S R
S a mm OH S OH
Me Me The most preferred metabolizable esters include those of compounds of formula IV wherein R9 is Me S
S S
OCOCH20(CH2CH20)3Me S OCCH2~~R~)q M ~,e Me O
~ 2NMG
S
S wherein Y, R~ and q are as defined OP03 H2 herein above Me ~ 2NMG
S
S and Me ~2NMG
S
O _.H
O
~. ~ ~ ~ 9396 WO 95!17407 PCT/US94/14236 The antifungal compounds of this invention represented by formula I have the R absolute stereochemical configuration at the carbon in the tetrahydrofuran ring bearing the di-halophenyl and 1H,1,2,4-tria2ol-1-ylmethyl moieties, and the CH20Y moiety has the "cis" stereochemical configuration relative to the 1 H,1,2,4-triazol-1-ylmethyl moiety. See the formula I
hereinbelow.
H ''~~~~,.C H20Y
R
Oi "cis"
\N~N
N fIJ
and Y =
C
I
wherein Ri is a straight or branched chain (C3-C8) alkyl group substituted by one or two hydroxy groups, which preferably exists as a single stereoisomer, but mixtures of stereoisomers are also contemplated as within the scope of this invention.
The compounds of formula I are generically but not specifically disclosed as the "cis" series, type ii, at col. 9 lines 59-68 of Saksena gt ~(. USP
5,039.676 and Example 68 at Cot. 5, line 16 to col. 52, line 44.
The compounds of this invention may be prepared by use of the sequence of steps illustrated in the following Schemes I-V. In Scheme I, compound 3 is readily prepared from commercially available compound 1 according to Examples ~, ~ and ~. Compound 4 is prepared by reaction of L(+) -diethyl tartarate ("L-DET") and molecular sieves in the presence of titanium -isopropoxide (i-Pr0)4Ti in an aprotic solvent, such as methylene chloride, at a temperature 0° to -35°C. See for Example, T. Katsuki, K.B.
Sharpless, ,~
Am. Chem. Soc.. 102, 5974 (1980); and 1_Q~, 464 (1981 ). An oxidizing agent, e.g. ~r -butylhydroperoxide ("TBHP') is added to this reaction mixture (step d of Scheme I) . Compound 3 is added and the compound of formula 4 (when L(+)-diethyl tartarate is used) is produced. Reaction of compound 4 with 1 H-1,2,4-triazoie in the presence of strong base, e.g., NaH in an aprotic solvent, such as DMF, at 0°-80°C provides the diol compound of formula 5. The primary hydroxy . .
group in compound 5 is converted into a leaving group, e.g., mesylate or tosylate (compound 6) by reaction of 5 with, for example, mesyl chloride ("MsCI") , in an aprotic solvent, e.g., methylene chloride in the presence of base, e.g., triethylamine ("Et3N"). Compound 6 is treated with strong base, e.g., sodium hydride (NaH) in an aprotic solvent, e.g., DMF at room temperature to give oxirane compound 7. Reaction of 7 with diethyl malonate in the presence of strong base, e.g., sodium hydride in an aprotic solvent, e.g., DMSO at 25°-75°C provides the lactone 8. Reduction of 8 with a metal hydride, e.g., lithium borohydride (LiBH4) in an alcohol, e.g., ethanol (EtOH), provides the triol 9.
Conversion of the two primary alcohols of 9 into leaving groups (mesylates or tosylates) by reaction of 9 with excess tosyl chloride in an aprotic solvent, e.g., THF, in the presence of base, e.g., Et3N, provides ditosylate 10. Compound 10 is contacted with strong base, e.g., NaH, in an aprotic solvent such as toluene at elevated temperatures of 100°-120°C to provide a mixture of two tosylates (~i,~
and traps) which are separated by chromatography to yield to the dig-tosylate 11. Reaction of compound 11 with a~ohols HOY in the presence of strong base, such as NaH in an aprotic solvent, such as DMSO at a temperature of 25°-75°C provides compounds of formula I.
Scheme II provides an alternative reaction sequence to obtain compounds of the present invention.. Reaction of compound 11 with the commercially available compound 12 in the presence of NaH gives compound 13. Hydrolysis of N-acetyl group in 13 is accomplished with a strong base such as NaOH in the presence of n-BuOH to provide compound 14. It should be made clear that instead of N-acetyl group in compound 12, any other base labile groups such as N-formyl, N-benzoyl, etc., can also be used to provide corresponding N-formyl and N-benzoyl derivatives of compound 13. Reaction s of 13 with p-chloronitrobenzene in the presence of a hydrochloric acid scavenger such as K2C03 provides the vitro compound 15. Catalytic reduction of 15 in the presence of a. platinum or palladium catalyst yields the amine 16.
Treatment of 16 with phenylchloroformate in the presence of pyridine gives the urethane intermediate 17. Reaction of 17 with hydrazine yields the to semicarbazide 18 which is cyclized in the presence of formamidine acetate to furnish the key triazolone 19. Alkylation of 19 according to Examples 19 and 24 provides the compounds of structure 20 including compounds of formula 1 wherein r1 is defined as hereinabove.
Scheme III provides a stereospecific access to the cis-alcohol is 26 and cis-tosylate 11 by application of enzyme chemistry. For Example, reaction of the triol 9 with ethyl acetate in the presence of porcine pancreatic lipase gives a single monoacetate 21. The remaining primary hydroxy group in 21 is protected by an acid labile group such as tetrahydropyranyl group to give a compound such as 22. Hydrolysis of the acetoxy group in 22 is 2o accomplished with a base such a KOH which provides 23. The remaining steps are: (i) tosylation of compound 23 to provide 24; (ii) cyclization of 24 in the presence of NaH to provide 25; (iii) deprotection of THP ether in 25 using an acid catalyst such as p-toluene sulfonic acid (to give 26) followed by tosylation of the resulting 26 to furnish the key intermediate 11.
2s A detailed description of a preferred preparation of key intermediate is disclosed in commonly owned Canadian Patent Application Serial No. 2,161,622, filed April 29, 1994.
~ 179°~
x ° x x a i x ~ ~ . -----r x 1 x d x t s x x x L ~
lc,l x ~., .r.ic ,81~1~ (a) NaOA~ (b) Wfttt9 R~a~on; (c) KOH; (~ L-0E1,1'BHP, (I-Ph4Ti; (e) NaH,1,2,4-triazole,DAAF; (~ Ms~Ct, E33N,CHZCIz; (~) 1~.
DAAF; (h) NaH, CH~(COOEi~, DAitSO; m UBH,, ElOH; ~ TsCI, ESN, THF;
(k) Wit. toluene. hoax m chromatography; (m) NaOY, DM.SO
Xs F o~ C~
SUBSTITUTE SHEET (RULE 26) 217939b + Ho ~ ~ V coca ll (Xs CI 0~ ~
SUBSTITUTE SHEET (RULE 26) __ __ ____ T_ . __ ~~ (cont'd.j !, 8: (a) NaH; (b) NaOWn-BuOH; (c) P-a.CsH,,NO~I KzC ~(~ ~ per:
(a) CsHsCCOCII pyridn~/ CHI; (f) NH=.NEhI Hip! dioxana. ~) na ail OMF! hue; (h) aoco~5n~ to Examples 18 and 20 SUBSTITUTE SHEET (RULE 26~
21 ~93~6 x ~-°'n~
b x ~ ~w.r~, a d az .1 It 8~: (a) ~n~ psr~c Ipasd E~o~4~ (b) dhYdr~pyaN ti'; (~ ~:
(d) Toy chloddoJ PYd~nt: (a) NaH; (t) Math~noil H'; (p) Tosyi chbrid~/ pyrid~.
SUBSTITUTE SHEET (RULE 26) SCHEME IV
_ O
Me0 \ ~ NON \ ~ N~NH
~N
(i) Aq. HBr (ii) SEM.CI
H
,, F OTs HO \ ~ N O \O>
N \ ~ ~ +
-SEM
~ N \ I
F
N
(iii)NaH, DMSO
H _ O
F R ~~~~ O \ ~ N~ N \ ~ N~ N-X
~ ~OJ N
F ~~'; ~ 30 X= SEM
N 19X=H
I X= R ~
SCHEME V
H
F ''~~ OTs R _ ~--~ _ O ~ / N~ N ~ / N02 F \ ~N.N
L \~ 30 Na (X=F) H _ ~ _ F ''~~ ~ O ~ / NON ~ / N 02 °°f /
(by crystn.) F ~ ~ N' N> 15 F
'N
H _ _ F '''~~O ~ / N~N ~ / NH2 ~q~8nt.
/ ~ -Ol ~
F ~ ~N-N 16F
'N H O
n F ''~~~0 ~ / NON ~ / N~OPh H
..~90% / = O
F ~ I ~N~N 17F
L
N
_ _ O -~90%
H
F R ',,,\O ~ / N~ ~ / N~ NN
/ ? O~ H NH2 F ' \N~N~ 18F
~N O
H _ _ n F ~~,, w y' N H
R O ~ / NON ~ / ~N
/I
90% ' O
F ~ ~ N~N> 1 9F
N
SCHEME VI
O O
R~x~COOR R~x ~x * NV b R * NV
OH ~ OH ~ OR'x RiX is preferably CH3 R'~X is preferably CH=Ph c N-NHCHO N-NHCHO
~x R~x~CHO
R * * R~ ,~ a R' H
OCH2Ph ~ Ph OCHpPh 40 (Syn isomer > 9:1) 39 38 H - _ O
a~~.0 F ~ I ~ - ~ I N~OPh H
\
N. N
N
fg O
H _ .v...0_ /-1 ~N. R~
F ~ I V ~ I ~N
g O
Me F N~N R = S
N, 20F ' S OH
Me (a) pyrrolidine, r.t., 24 h: (b) R4X-X, NaH, DMF; (c) RED-AL, toluene. -20°: (d) H~NNHCHO, MeOH:
(e) R~MgBr. EtzO. -10°C to r.t., 24 h: (f) jgof Scheme V and procedure of Example 32d; (g) Hy Pd, HCOOH. 8090.
~ 179396 Scheme VII
Preparation of Polyether Esters Re(OCHR~CHR~)tOH ~G-(CHR~)BC02Na(43) Re(OCHR~CHR~)t-O(CHR~)S-C4~H
Base/THF
O Me H S
X ''''~ O N~N N N S
/ ~N OH
I ' O J _ Me X ~ ~ 20F
N
DCCD, DMAPt, 44 H O Me X ,'.~ - .--' - y-R O ~ ~ N N ~ ~ N ~ 'N~, , O (CHR O CHR HR R
O ~ ~ ~ ~ Me ~ ~)s ( ~ ~)c s X \ l N~ 45X p 1 DCCD = Dicyclohexylcarbodiamide DMAP = 4-(N,N-Dimethylamino)Pyridine Table for Scheme VII
Me R' OH
using 20F (X = F) Me M.S.
~S M+
PG = Protecting 759.3 Group, e.
.. CH Ph CH3(OCH2CH2)30HCICH2C02H COCH20(CH2CH20)3Me gp5 Table fog Scheme VII
R Me R = .....
S OH
Me M-S
.
CHg(OCH2CH~OH CICH2C02Na -COCH20(CH2CH20)Me gy CH3(OCH2CH)20H CICH2C02Na -COCH20(CH2CH20)2Me gg~
CH3(OCH2CH2)30H CICH2C02Na ,COCH2(CH2CH20)gMe 905 H02C(OCH2CHv20H CICH2C02Na -COCH20(CH2CH20)2COOH905 20F 46R~
Me S Me ( ~" )2N-P-{OCH2CsH5)2 R~ = O
Me OH Tetrazole, t-Bu00H Me p(OCH H
., 2Cs s)2 O
Pd/C, H2, AcOH, ETOH
H O Me X
\ / ~N ~ / N~N S
/ , ~=N S OP03H2 Me N-N
l N~
47 ~ 2NMG
SCHEME VIIIB
O
Me 20F, R = mmR HO C ~CHR~)nLG (49) R1 -~~~~~~~R Me i Me S OH pCCD, DMAP, CH2CI2 Me O (CHR~)nHal LG = Hal O
1. AgOP(OCH2C6H5 )z 2. AcOH 10%Pd/C. H2 ETOH
O R Me O
H ~,y /~ ~Nmn S II
X R O ~ / NUN ~ / ~NMe O (CHR7)n-O-P(OH)2 IIJz N-N
Table for Scheme VIIIA
X=F
47 R~ M.S. (M+) Me S .2NMG 781,8 / ~ OP03H 2 Me Me 781.7 S .2NMG
~ OP03H 2 Me Me 873.3 SO
/i~ OP (OH)-OC 6H40H
Me/
47 R~ M.S. (M+) Me 961.4 O
S
OP(OCH2CsH5)2 Me Me 961.2 S O
~OP(OCH2CgH~)2 M /
Table for Scheme VIIIB
X2.$1 ~. (M+) HOCOCH2C1 Me 839 S
.2NMG
/~ OCOCH20POgH2 Me HOCO(CH2)40H ~ Me 881.3 ""'R'\ .2NMG
~~
OCO(CH~40P03H2 M
HOCO(CH2)40H ~Me 881.3 /S
.2NMG
~~
OCO(CH~40P03H2 M
Me 853.2 S-HOCOCH(.OH)CH3R
~~~~~
S II
~ OCO - C a,, H
Me ~
.2NMG CH3 F R ,," ~ / V \ /
A R-_ ~ ~ O
F L
N
Me R M a H O CH20Ph 54 A R- ~ ~"" R O CH20Ph A R-N~N~...
O H DCCD, DMAP, CH2C12 N M a Me O
10%Pd/C. H2, EtOH, AcOH
O O
Me Me A R-N~ t~.... R ~ ~ A R-N~ t~.... R
OuC H 20-p~
N I OCHZPh ~(~ C~CHpOH
Me O OCHZPh Me O
I(b) Me (C) ~ Me A R-N ~.... R ,,o --~ A R-N ~.... R ,o O CH20~~OH ~N O CH20-P~OH
Me ~ OH Me ~ OH
58 O O .2NMG Satt 58.2N MG
(a)~~P(OCH2Ph)2 ,Tetrazole, t-Bu00H; (b)10%Pd/C, H2, EtOH, AcOH; (C)2NMG
2~i9396 Scheme IX
Preparation of Hetero~...-iic Esters Me 20i=, R~ = S +
S Hal-(CHR~)wCOHaI
off 62 H3C Base Me x R H ~~~~vO \ / NON N NBC S
\ l vN ,~~O (CHR7)w Hal Me \N_N O
~N~ ss H_ ( HR~)q s0 R H '''~~O \ / N~N N N: S Me ( HR~)q O ~ a \ / vN ~O (CHR7)w Me O
~'N~ s~
6~ Rl M.S~(Mt) Me S
S OCOCH2~ O
Me Me S
/ ~ OCOCH2.. NMe Me Me S
~ OCOCH2~~
Me i 2179396 _ Me /~ OCOCH 2.-~J~
Me Scheme IV provides an additional reaction sequence to obtain the compounds of the present invention. Compound 27 is prepared from the methyl ether of compound 12 in Scheme II by subjecting the methyl ether of 12 to the reactions of steps a to g of Scheme II. Reaction of compound 27 with aqueous HBr or BBr3 gives phenolic compound 28. Reaction of compound 28 with one equivalent of NaH and subsequent treatment with, for example, 2-(trimethyl)-silylethoxymethyl chloride ("SEM-CI")and DMF at ambient temperatures produces SEM-nitrogen-protected compound 29. Deprotonation of compound 29 with NaH followed by reaction of the so-formed anion with tosylate 11 in DMF or DMSO at elevated temperatures produces compound 30. The nitrogen protecting group of 30, e.g., SEM is removed by treatment with, for example, 6NHC1 in methanol at ambient temperatures for 3 hr to produce compound 19.
Compound 19 is treated with NaH and DMSO at 20°C for 3/4 hr. and thereafter alkylated with R~X to produce compound I. In R~X, Ri is a C3-C8 alkyl group having at least one protected hydroxy moiety, e.g., O-SEM and X~ is a leaving group, for example, brosylate. Removal of the hydroxy protecting group from compound 31, e.g., O-SEM is accomplished by, for example, 6NHC1 in methanol to give compounds of this invention of formula I.
Scheme V provides a preferred route for preparation of the compounds of this invention set forth in Scheme II. The sodium salt of compound 31 prepared by reaction of (4-(4-(4-nitrophenyl)-1-piperazinylJphenol with NaH in anhydrous DMSO at 50°-60° C for 30 minutes is reacted with the 2,4-diflurophenyl tosylate 11 F (compound 11 in Scheme II wherein X=F) for 1 h.
at 50°-70° C to provide, after flash silica chromatography or crystallization, compound 15F (compound 15 in Scheme II wherein X=F). Reduction of 15F by hydrogenation in the presence of 5% Pd/C in ethanol containing 1 NHCI
provided. amino compound 16F (compound 16 in Scheme II wherein X=F).
Reaction of 16F with phenylchloroformate in anhydrous pyridine at 0-5°C
for 2h.
provided phenylcarbamate 17F (compound 17 of Scheme II wherein X=F).
Reaction of 17F with hydrazine hydrate in 1,2-dimethoxyethane at 80°C
for 4h.
provided the semicarbazide 18F (compound 18 of Scheme II wherein X=F).
Reaction of 18F with formamidine acetate and Et3N in 2-methoxyethanol under dry argon in stirred reactor at 80°C overnight provided 3H-1,2.4-triazol-3-one 19F (compound 19 in Scheme II wherein X=F). Reaction of compound 19(f) with R~X in accordance with the procedure of Scheme IV produced compounds of formula I.
Scheme VI provides an alternative, stereoselective route for preparation of the preferred compounds of this invention. Compound 35 (e.g.
~-lactic acid methylester) is contacted with excess pyrrolidine in methylene chloride for 24 hours at room temperature to give amide 36. Reaction of 36 and NaH with for example, benzyl halide in DMF gave 37. Selective reduction of amide 37 with a 3.4M solution of sodium bis(2-methoxyethoxy)aluminum hydride ("RED-AI") in toluene at -20°C gave aldehyde 38. Reaction of aldehyde 38 with H2NNHCHO in methanol gave 39 which was reacted with a Grignard reagent e.g. ethylmagnesium bromide in dry ether at a temperature of -10°C to room temperature for 24 hours to give 40 wherein the ratio of the S,S isomer:
S,R isomer was 94:6. When the Grigand reaction was done in the presence of 1.2 equivalents of bis(trimethylsilyl)acetamide the SS to SR ratio was 99:1.
Compound 40 was reacted with compound 17F of Scheme V in toluene in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) for six hours at 80°C.
Cyclization was effected by raising the temperature to 100°-110°C and continuing to maintain this temperature overnight. After purification via TLC, ~i79396 20F was obtained. Treatment of 20F with hydrogen and palladium black in methanol containing formic acid heated to 60°C gave the crude product which was isolated and purified (via TLC) to give compound 20F i.e. the compound of formula III wherein Me S
RS = and X = F, Mt = 701 OH
The reaction of the Grignard reagent on the propanimine 39 produces 40 wherein the absolute stereochemistry induced at the new chiral center in 40 is substantially the same (i.e., S) as that at the chiral carbon in 39.
By the term "substantially the same" as used herein is meant the ratio of S:S
to S:R (in e.g., 40) is greater than 9:1, preferably is greater than 15:1 and most preferably is at least 99:1.
The mass spectral data presented herein as M+ are parent ions which were determined by Fast Atom Bombardonment (FAB) technique and represent the ~M+1 peaks.
Scheme VII provides a general method for preparation of the polyether esters of alcohols of the present invention. The alcoholate of alcohol ether 42 e.g. CH3(OCH2CH2)30H i.e., 42 wherein R~ = H and t = 3, was prepared by reaction, of 42 with excess strong base e.g. NaH in an anhydrous ether e.g. THF at ice bath temperatures. The so-formed reaction mixture was stirred for several hours i.e., 2 or more and the sodium salt of acid 43 e.g.
sodium salt of chloroacetic acid (43 wherein LG=CI, R~=H and s=1 ) was added thereto. The so-formed reaction mixture was stirred at ice-bath temperatures and stirring was continued as temperature was allowed to warm to room temperature. Water was carefully added to the reaction mixture and the polyether acid 44 was separated and purified by conventional techniques.
_._ -.____ _ T. _._.____.__ .._.
To a solution of 44 in CH2C12 was added 1.3-1.5 equivalents of the base 4-(N,N-dimethylamino)pyridine ("DMAP") and 20F wherein Me R~
OH
. The temperature of the so formed reaction mixture was lowered by use of an ice bath and 1.3-1.5 equivalents of dicyclohexylcarbodiimide ("DCCP") was added thereto. The so-formed reaction mixture was continuously stirred as the temperature was allowed to warm to room temperature. The urea precipitate was removed and the crude product isolated by conventional techniques. The so formed residue was purified by chromatography on silica gel to provide the pure compound [M + Hj+ = 906 by FAB. By the appropriate substitution of different starting materials 42 and 43 the compounds 45 listed in Table for Scheme VII were prepared. The MS values for products listed under 45 in the Table for Scheme VII were measured by Fast Atom Bombardment ("FAB").
Schemes VIII A-C illustrate the generalised methods for preparing phosphate esters of the alcohols of this invention. Scheme VIIIA provides a method for preparation of phosphate esters of formula IV wherein R6 is O o - C Z - (CHR~~(Q)m p(QW)2 and z = m=n = 0. Compound 20F of Scheme II in methylene chloride at room temperature was reacted with 1.5 equivalents of N,N-diisopropyls-dibenzylphosphoramide, 1.5 equivalents of tert-butyl peroxide (3M in iso-octane) and a base such as tetrazole for several hours. The progress of the reaction was followed by TLC (5% methanol:EtoAc v:v) on silica gel. The crude product in EtoAc was washed with sodium thiosulfate and purified using standard techniques to provide the dibenzylphosphate ester 46. The dibenzyl ester groups of 46 were removed to . . ~~ 7939b give 47 by treatment of 46 dissolved in equal volumes of ethanol and glacial acetic acid in the presence of excess 10% Pd/C under a hydrogen atmosphere at room temperature in a stirred reactor overnight. The reaction was continued until no starting material was found by TLC (or NMR). The catatyst was removed by filtration and the crude phosphate ester 47 was purified by standard techniques. Treatment of 47 in methanol at room temperature with two equivalents of base e.g. NMG (or Et3N) provided 47 ~ 2NMG. The compounds 46 and 47 prepared in accordance with Scheme VIIIA are listed in the Table for Scheme VIIA.
Scheme VIIIB illustrates preparation of phosphate esters of II
- C Z - (CHR~~-(O)Tn p(OV~2 formula IV wherein R6 = z =m=1 and n = o.
Compound 20F dissolved in methylene chloride was treated with 1.3 equivalents of DMAD 1.3 equivalents of DCCD and 1.3 equivalent of the acid II
HO C (CHR ~)n LG
49 of the formula Z e.g., H02C(CH2)4Br, i.e., z = 1, n = 4, R~ = H and the leaving group LG is Br. The reaction was stirred at room temperature until no starting material was found by TLC purification of the crude Me R1 =
~~ 02C(CH 2)a&
product gave bromide 50, a white solid wherein The bromide 50 in a benzene was heated at 80°C overnight with 1.5 equivalents of silver dibenzylphosphate (available from Sigma Chemical Co., St. Louis). The reaction mixture was cooled and washed with aqueous base, e.g., K2C03. The crude product was separated and purified by silica gel column chromatography to give the dibenzyl phosphate ester 51. Treatment of 51 in ethanol/glacial acetic acid with excess 10% Pd/C under a hydrogen _....y atmosphere overnight at room temperature gave phosphate ester 52.
Treatment of 52 in methanol with two equivalents of base e.g. NMG (or Et3N) gave 52 ~ 2NMG.
Scheme VIIIC provides an alternative procedure for preparation of phosphate esters of formula IV wherein R6 is as defined above for Scheme VIIIB and z = 1 and n = 1. The benzyl ether of methyl acetate 53 in methanol-water and excess base e.g. K2C03 were stirred overnight at room temperature to give the benzyl ether 54. Reaction of a solution of 20F and 54 in methylene chloride with a 1.3 -1.5 equivalents of DCCD and DMAP at room temperature overnight gave ester 55. The benzyl ether group of 55 was removed by treatment with excess 10%
Pd/C in ethanol-glacial acid under a hydrogen atmosphere at room temperature overnight. Purification of the crude product gave 56. Treatment of 56 with 1.5 equivalents of diisopropyldibenzylphosphate and 1.5 equivalents of tent-butyl peroxide and tetrazole in accordance with the procedure of Scheme VIIIB gave dibenzyl ester 57. Removal of the dibenzyl groups with 10% Pd/C in ethanol-glacial acetic acid under hydrogen atmosphere gave (as described hereinabove) phosphate ester 58. Treatment of 58 with two equivalents of base, e.g. NMG, gave 58 ~ 2NMG.
Scheme IX illustrates the preparation of heterocyclic esters of the S
OH
present invention. Compound 20F, wherein ~ dissolved in methylene chloride is reacted with compound 62 in the (Hal=Br or CI, w=1-5, e.g., CI-CH2-COCI) in presence of a base such as pyridine at a temperature of 0°-5°C for four hours. The reaction was placed in a refrigerator overnight.
Additional compound 62 and base could be added, if necessary, and the reaction continued until no 20F is present by TLC. Purification of the crude product by column chromatography on silica gel gave pure 59 (w=1, Hal=CI).
..
__ k Reaction of 59 with excess of the nitrogen heterocyclic compound 60 (e.g., Y=NH, R~=H and q=4) at a temperature of 50°-60°C for 1 hour produced 61.
Substitution of nitrogen heterocyclic compound 60 with a five and six membered compounds, e.g. morphiline, N-methylpiperdine provided the compounds listed in table below Scheme IX.
The alkanoate and alkenoate esters of 20F are conveniently prepared by standard synthetic techniques, (for example, by reaction of the anhydride or acid halide of the alkanoic acid or alkenoic acid in tghe presence of base e.g, pyridine) produced the alkanoate or alkenoates of the compounds of formula I.
The sulfate esters may be prepared by reaction of the alcohol compounds of formulas I to IV with sulfur trioxide in the presence of excess pryridine at temperatures of 70°-90°C for at least 2 hours in accordance with the procedure of R.M. Moriarty et. al. Tetrahedron Letters, Vol. 35, No. 44, p 8103-8106 (1994).
The compounds of formula I may also be prepared by reaction of compound 11 with alcohols of formula HOY in the presence of a strong base, e.g., NaH in an aprotic solvent, such as DMSO.
H
''''\
R ''''~ OTs / OY
+ -OY ~ X
11 N ( I]
(R)-"Tosylate" Series See Example 15 wherein X = F or CI
Y=
and R~ = a (C3-Cg) alkyl group substituted by one or two hydroxy moieties.
__. ~- ~ . __ . ~ _ _____~-Compounds represented by formula ! exhibit broad spectrum antifungal activity, in conventional antifungal screening tests, against human ' and animal pathogens, such as the following: AspergiJlus, Blastomyces, . Candida, Cryptococcus, CoccidioTdes, Epidermophyton, Fonsecaea, Fusarium, Mucor, Saccharomyces, Torulopsis, Trichophyton , Trichosporon, Sporothrix and Pneumocysitis.
The preferred compounds of formula !V exhibit topical, oral and parenteral antifungal activity in in vivo tests in animals and such activity is unexpectedly better than that of existing antifungal agents e.g. itraconazole and fluconazole as well as that of the azole compounds specifically disclosed by Saksena gt~l. in USP 5,039,676 and International Publication No.
WO 93109114.
The antifungal compounds of formula l and pharmaceutical compositons of this invention are expected to exhibit anti-allergic, anti-inflammatory and immunomodulating activities, broad spectrum antiinfeciive activity, e.g., antibacterial, anti-protozoal and antihelminthic activities.
The present invention also provides a composition for treating or preventing fungal infections comprising an antifungally effective amount of a compound represented by formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or difuent therefor.
The pharmaceutical compositions of the present invention may also contain a fungicidally effective amount of other antifungal compounds such as cell wall active compound. The term "cell wall active compound", as used herein, means any compound that interteres wifh the fungal cell wall and includes, but is not limited to, compounds such as papufacandins, echinocandins, and aculeacins as well as fungal cell wall inhibitors such as nikkomycins, e.g, nikkomycin K and others which are described in USP
5,006,513 . , a The pharmaceutically acceptable salts of the compounds of the present invention include pharmaceutically acceptable acid and base addition salts.
The preferred pharmaceutically acceptable acid addition salts are nontoxic acid addition salts formed by adding to the compounds of the present invention about a calculated amount of a mineral acid, such as HCI, HBr, H2S04, HN03 or H3P04, or of an organic acid, such as an alkyl or arylsulfonic acid such as methanesulfonic, isithionic, para- toluenesulfonic, naphthylsulfonic and the like.
The pharmaceutically acceptable bases found suitable for use in the present invention are those which form pharmaceutically acceptable salts of the acidic pharmaceutically acceptable esters of the antifungal compounds of formulas I, II, III or IV and include suitable organic and inorganic bases.
Suitable organic bases include primary, secondary and tertiary alkyl amines, alkanolamines, aromatic amines, alkylaromatic amines and cyclic amines.
Exemplary organic amines include the pharmaceutically acceptable bases selected form chloroprocaine, procaine, piperazine, glucamine, N-methylglucamine, N-N-dimethyl glucamine ethylendediamine, diethanolamine, diisopropylamine, diethylamine, N-benzylenediamine, diethanolamine, diisopropylamine, diethylamine, N-benzyl-2-phenylethylamine, N-n'dibenzylethylenediamine, choline, clemizole, triethylamine ("ET3N"), tris(hydroxymethyl)aminomethane, or D-glucosamine. The preferred organic bases include N-methyl glucamine ("NMG"), diethanolamine, and tris(hydroxymethyl) aminomethane ("TRIS"). Use of two equivalents of NMG in this invention is more preferred. The suitable inorganic bases also include alkali metal hydroxides such as sodium hydroxide.
The pharmaceutical compositions of the present invention may be adapted for any mode of administration e.g., for oral, parenteral, e.g., sc, im. IV
and IP, topical or vaginal administration or by inhalation (orally or intranasally) . . :. . :, . 2179396 Such compositions are formulated by combining the compound of formula I or an equivalent amount of a pharmaceutically acceptable salt of compound I with an suitable, inert, pharmaceutically acceptable carrier or diluent.
Examples of suitable compositions include solid or liquid compositions for oral administration such as tablets, capsules, pills, powders, granules, solutions, suppositories, troches, lozenges, suspensions or emulsions. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
Topical dosage forms may be prepared according to procedures well known in the art, and may contain a variety of ingredients, excipients and additives. The formulations for topical use include ointments, creams, lotions, powders, aerosols, pessaries and sprays.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredients are dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution with an appropriate amount of a hydroxypropyl a- (3 or -y-cyclodextrin having 2 to 11 hydroxypropyl groups per molecule of cyclodextrin, polyethylene glycol, e.g., PEG-200 or propylene glycol, which solutions may also contain water. Aqueous solutions suitable for oral use can be prepared by adding the active component in water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the active component in finely divided form in water. A particularly preferred aqueous s pharmaceutical composition may be prepared from the compounds of formulas I to IV together with hydroxypropyl-~i-cyclodextrin in water. The use of derivatives of a-,(3- and y-cyclodextrins, for example, hydroxpropyl-(3-cyclodextrin are disclosed by N. Bodor USP 4,983,586, Pitha USP 4,727,064 and Janssen Pharmaceutica International published Patent Application WO
io 85/02767, July 4, 1985.
The pharmaceutical compositions of the present invention may be prepared by admixing the pharmaceutically acceptable carrier, e.g., a hydroxypropyl-~-cyclodextrin in water, and adding thereto an antifungally effective amount of a drug of the present invention. The solution so formed is is filtered, and optionally, the water may be removed by well known methods, e.g., rotatory evaporation or lyophilization. The formation of the solution may take place at a temperature of about 15° to 35°C. The water is normally sterilized water and may also contain pharmaceutically acceptable salts and buffers, e.g., phosphate or citrate as well as preservatives. The molar ratio of 2o the antifungal compound of formula I to hydroxpropyl-~3-cyclodextrin is about 1:1 to 1:80, preferably 1:1 to 1:2. Normally the hydroxypropyl-~i-cyclodextrin is present in molar excess.
Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for either oral or 2s parenteral administration. The solid form preparations intended to be converted to liquid form may contain, in addition, to the active materials, such as compounds of this invention, and optionally a cell wall active compound, especially a fungal cell wall inhibitor, e.g., a nikkomycin, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, 3o solubilizing agents and the like. The solvent utilized for preparing the liquid . ..
WO 95/17407 PCT/~JS94/14236 form preparations may be water, isotonic water, ethanol, glycerin, polyethylene glycols, propylene glycol, and the like, as well as mixtures thereof.
Parenteral forms to be injected intravenously, intramuscularly, or subcutaneously are usually in the form of a sterile solution, and may contain salts or glucose to make the solution isotonic.
The topical dosage for humans for antifungal use in the form of a pharmaceutical formulation comprising a compound of formula I (usually in the concentration in the range from about 0.1 % to about 20% preferably from about 0.5% to about 10% by weight) together with a non-toxic, pharmaceutically acceptable topical carrier, is applied daily to the affected skin until the condition has improved.
In general, the oral dosage for humans for antifungal use ranges from about 1 mg per kilogram of body weight to about 50 mg per kilogram of body weight per day, in single or divided doses, with about 2 mg per kilogram of body weight to about 20 mg per kilogram of body weight per day being preferred and the dose of about 5 mg per kilogram of body weight to about 10 mg per kilogram of body weight per day being most preferred.
In general, the parenteraf dosage for humans for antifungal use ranges from about 0.5 mg per kilogram of body weight per day, to about 20 mg kilogram of body weight per day, in single or divided doses, with about 1 to about 10 mg per kilogram of body weight per day being preferred.
The exact amount, frequency and period of administration of the compounds of the present invention for antifungal use will vary, of course, depending upon the sex, age and medical condition of the patent as well as the severity of the infection as determined by the attending clinician.
z ~ ~93~6 WO 95/17407 PC'T/LTS94/14236 GENERAL EXPERIMENTAL
The compounds of this invention are prepared in accordance with Schemes I-IX hereinabove and the following Examples using commercially available starting materials.
F O F O
CI ~ OAc + NaOAc / /
F F
EXAMPLE 1 a Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of Nal, and 3 L of DMF. Stir the mixture at 20°C for 18 hr. then concentrate it to 1 L.
Pour the residue into 6 L of cold dilute aqueous HCI and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2S04, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluting with CH2C1-2-hexane to obtain 198 g of the title compound.
F O F
OAc ~ OAc F ~ / + MePh3PBr + Na-HMDS T~ F
EXAMPLE 1 b 1-j2-(2.4-Difluorophenylll-2-aropenol acetate Suspend 131 g of MePh3PBr in 270 mL of mechanically-stirred, dry THF at 20°C. Add 393 mL of 1 M NaN(Me3Si)2 in THF, slowly at first, then rapidly over 5 min. while applying just enough ice cooling to maintain the temperature at < 23°C. Stir the so-formed mixture for 1 hr at 20°-24°C, cool it to _ _T_.__ -70°C, and stir it another 1/2 hr. Then add thereto a solution of 65.5 g of the product of Example 1 a in 140 mL of dry THE, at a rate slow enough to keep the temperature below -70°C. Continue to stir the so-formed reaction mixture in the cold bath overnight during which the temperature rises to 20°C. Add 50 mL of EtOAc to the so-formed suspension, and then add 3 L of hexane. Allow the so-formed mixture to stand for ~15 min., and suction-filter to remove Ph3P0.
While the filter cake is still damp, transfer it to a beaker. Triturate the cake thoroughly with 1/2 L of hexane and suction-filter again to remove the remainder of product.
Wash the combined hexane filtrates with 2 x 1 L of a 1:1 (v/v) MeOH-water, and then with brine. Dry the organic layer over MgS04, filter and evaporate the filtrate to leave a red oil. Add 1.5 L of hexane and suction-filter through a Celite pad to leave a clear yellow solution. Chromatograph the yellow oil on silica gel, eluting with 1/2 L of hexane, then 1 L of 15:1 (v/v) hexane-EtOAc. Combine the homogeneous fractions to yield 38.6 g of the title compound as an oil.
F OAC F O H
w v F ~ i + KOH -'~' ~ i F
EXAMPLE 1 c Dissolve 40 g of the product of Example 1 b in 400 mL of dioxane.
Add a solution of 18 g of 85% KOH in 315 mL of water. Stir the so-formed mixture vigorously for 1 hr, and then pour the mixture into 1 L of Et20.
Separate the aqueous layer and extract it with 250 mL of Et20. Combine the organic extracts, and wash them with water and then brine. Dry the organic extract over anhydrous K2C03, and add 10 g of charcoal thereto. Filter, and evaporate the filtrate to leave 31.3 g of the title compound as a straw-colored oil.
21 l X396 -EXAMPLE 1 d j~~~[2-(2.4-Difluoro~henyll]oxiran~lmethanol Add 33g of activated 3A molecular sieve powder to a solution of 13g of L-(+)-diethyl tartarate in 2.3L of CH2C12, and cool the so-formed mixture to -5°C. Add a solution of 15.4 mL of titanium tetra-isopropoxide in 100 mL of CH2C12 over 2-3 minutes and then cool the so-formed mixture to -22°C.
Add 109.5 mL of a 5.5 M solution of ~r -butylhydroperoxide in 2,2,4-trimethyl-pentane over 4-6 minutes, and cool the so-formed mixture to -25°C. Stir the mixture at -25°C for 25 minutes and then add a solution of 40g of 2-(2,4-difluorophenyl)-3-propenol of Example 1c in 100 mL of CH2C12 over 3-4 minutes. Stir the so-formed mixture at -27°C for 4 1/2 hour. Add 102 mL
of 30%
aqueous sodium hydroxide saturated with NaCI and stir the so-formed mixture while warming to +10°C over a 1/2 hour period. Add thereto 100 g of anhydrous MgS04 and 33g of Celite, and stir 1/2 hour at +10°C. Suction-filter the mixture, wash the so-formed filter cake with 1.2 L of diethyl ether (Et20) and then 1.5L of toluene, and dry the combined organic layers over anhydrous MgS04. Filter the organic layer, and evaporate the filtrate in vacuo to form a residue. Dissolve the residue in 1 L of Et20 and suction-filter the mixture to remove insolubles. Suction-filter the filtrate through 100g of silica gel, and wash the pad with 200 mL of fresh Et20. Evaporate the filtrate in vacuo to give a 41 g (94%) of the crude title compound as a yellowish oil, ( ~ - 36.7°
(c=I, MeOH); PMR (CDC13) d 7.40(m,1 H), 6.85(m, 2H), 3.95(m,2H), 3.31 (d,1 H), 2.84 (d,1 H), 1.91 (m,1 H, deuterium exchangeable).
Rl-l+1-f2-f2-12.4-Difluoroohenvl)loxiranvllmethan Follow the procedure of Example 1 d, except substitute an equivalent amount of D-(-) diethyl tartarate in place of L-(+) diethyl tartarate to give the crude title compound, ~a~ + 33.9° (c=I, MeOH).
_ . T _ __._ _- _ T___-_.
L17959~
Purify a portion of the crude compound by silica gel chromatography to obtain a sample homogeneous by TLC, [a~ + 40.0° (c=I, MeOH) (R)-(-)-2-(2.4-Difluorooheny~-3-(1 2 4-triazol-1- I~)-1 2:nrooanediol Dissolve 8.91 g of 1 H-1,2,4-triazole in 150 mL of anhydrous DMF
and cool so-formed mixture to 0-5°C. Add 2.81 g of sodium hydride (60%
oil dispersion) and stir the so-formed mixture 30 minutes at room temperature. Add thereto 10.9 g of the product of Example 1 d. Stir the so-formed reaction mixture for 2 hours at 60-70°C. Cool the mixture to room temperature, add thereto 10 ml of H20 and evaporate it inin vacuo to give a residue. Dissolve the residue in mL of H20 and 900 ml of ethyl acetate (EtOAc). Extract the H20 layer with another 250 mL of EtOAc. Wash the combined EtOAc extracts with 100 mL of brine. Dry the EtOAc extracts over anhydrous MgS04 and evaporate. Triturate the so-formed oily residue with 10 mL of CH2C12 and add 100 mL of Et20. Stir the CH2C12-Et20 mixture for 1 hour at room temperature. Filter to give 11.2g a (75%) of the title compound, [ ~ - 70.7 (c=1.0, MeOH), mass spectrum (FAB):
256 [M+H]+. Recrystallize 1.Og of the filtered product from 5 mL of CH3CN to a give 0.83g of the title compound, m.p. 99-100°C; [ ~ - 71.5°
(c=1.0, MeOH);
elemental analysis: Calculated for C~ ~ Hi i F2N3021 /2CH3CN; 52.27C, 4.57H, 17.78N, 13.78F; Found: 52.26C, 4.58H, 17.54N, 13.78F; PMR(DMSO) d 8.25 (s,1 ), 7.66(s,1 ), 7.33, (m,1 ), 7.09(t,1 ), 6.90(t,1 ), 5.72(s,1 ), 5.05(t,1 ), 4.53(s,2), 3.61 (m,2).
(Sl-(+)-2-(2.4-Difluoroohenyl)-3-(1 2 4-triazol-1-vl)-1 2 ~panediol . .. 2179396 Follow the procedure of Example 3, except substitute an equivalent quantity of the product of Example 2 in place of the product of a Example 1 to give the title compound; MP. 95-101 °C; [ ~ +
70.0° (c=1.0, MeOH). The PMR and Mass spectra were consistent with the structure of the title compound.
LR)-2- 2.4-Difluorophenyl)-3-(1.2.4-triazol-1-~1-1.2~panediol-1 methanesulfonate Suspend 10.9 g of the powdered product of Example 3 in 150 mL
of CH2CI2. Add thereto 8.95 mL of triethylamine and cool to the so-formed mixture 0-5°C. Add 3.64 mL of methanesulfonyl chloride in 20 ml of over 10 min. Stir the so-formed mixture for 1 hour at room temperature. Cool it to 0-5°C, extract with 100 mL of cold (0-5°C) 5% KH2P04, followed by 100 mL
of cold (0-5°C) H20, followed by 50 mL of brine. Dry the separated organic layer over anhydrous MgS04 and evaporate to obtain 13.7 g (96%) of the title [M+H+j+; PMR (CDC13) d 7.95 (s,1 ), 7.82 (s,1 ), 7.53(m,1 ), 6.81 (m,2), 4.84(d,1 ), 4.65(d,1 ), 4.46(m,2), 3.05(s,3).
lSl-2-(2.4-Difluoroohenvll-3-(1.2.4-triazol-1,r1 1.2-oronanediol-1 methanesulfonate Follow the procedure of Example 5, except substitute an equivalent quantity of the product of Example 4 in place of the product of Example 3 to give the title compound . The PMR is consistent with the structure of the title compound.
So T..
IRl-1-f2-f2-f2.4-Difluoroohenyl~loxiranvlmeth~rl] 1 2 4 triazole Dissolve 13.7g of the product of Example 5 in 200 mL of anhydrous DMF and cool the so-formed solution to 10-15°C. Add thereto 1.71 g of sodium hydride (60% oil dispersion) and stir the so-formed reaction mixture at room temperature for 90 minutes. Concentrate in vacuo to 50 mL. Add thereto 200 mL of cold H20 (0-5°C) and extract with 3 x200 mL portions of EtOAc. Wash the combined EtOAc extracts with 100 mL of brine. Dry the EtOAc extracts over anhydrous MgS04 and evaporate it to give 10.8 g of a residue.
Apply the residue in CH2C12 to a column of 400 g of MPLC grade silican gel previously prepared by slurry packing with CH2C12 containing 1 mL of Et3N per liter. Elute with 1 liter, each of 25, 50 and 75% EtOAc; CH2C12 (v/v) followed by 2 liters of EtOAc. Combine the fractions to give 6.92g (68%) of the title compound. Mass spectrum (FAB): 238 [M+H]+; PMR (CDC13) d 7.97(s,1 ), 7.77(s,1 ), 7.07(m,1 ), 6.73(m,2); 4.73(d,1 ), 4.41 (d,1 ), 2.84(d,1 ), 2.78(d,1 ).
(S)-1-f2-f2-l2 4-difluoro heny,~~xiranvimethyl 1 2 4 triazol Follow the procedure of Example 7, except substitute an equivalent amount of the product of Example 6 in place of the product of Example 5 to give the title compound. [PMR is consistent with the structure of the title compound].
Ethvll5R-cisl- and l5R-tran~~-5-r~ 4 Difluoroohenvl) 2 oxo 5 [(1 H 1 2 4 triazol 1-vl)methvlltetrahvdro-3-furancarboxvlate Dissolve 9.35 mL of diethyl malonate in 70 mL of anhydrous DMSO. Add 2.24g of sodium hydride (60% oil dispersion) in 2 portions and stir the so-formed reaction mixture at room temperature for 1 hour. Add 6.65 g of w . . ~ 179396 _ the product of Example 7 and stir 18 hours at 50-55°C. Cool to room temperature and pour the reaction mixture into a well-stirred mixture of 500 mL
of KH2P04, 500 mL of brine, and 1 liter of EtOAc. Separate and extract the H20 layer with another 300 mL of EtOAc. Wash the combined EtOAc extracts with 500 mL of brine, Dry the EtOAc extracts over anhydrous MgS04 and evaporate to give an oil. Apply the oil with CH2C12 to a column of 400 g MPLC grade silica gel prepared with hexane. Elute with 500 mL of hexane, followed by 2 liters of 50% EtOAc: hexane (v/v), followed by 2 liters of EtOAc. Combine fractions to give 8.66g (80%) of the title compound. Mass spectrum (FAB): 352[M+H]+, PMR
(CDC13) d 8.08(s,2), 7.91 (s,1 ), 7.71 (s,1 ), 7.42(m,1 ), 7.13(m,1 ), 7.85(m,2), 4.60(m,4), 4.10(m,4), 3.49(t,1 ), 3.14(t,1 ), 3.89(m,4), 1.18(m,6).
F;h_YL(5S-cisl. and (5S-trans)-5-x,2.4-Difluorophen~l-2-oxo-5- 1 H-1.2.4-triazol-1-yl)methyl]tetrahydro-3-furancarbox I
Follow the procedure of Example 9, except substitute an equivalent amount of the product of Example 8 in place of the product of Example 7 to give the title compound. [PMR and mass spectra are consistent with the structure of the title compound].
~R)-(-)-4-(2.4-Difluorohhenyl)-2-hydrox~methyl-5-j1 H- 1.2.4-triazol-1-yl~]-1.4-pentanediol Dissolve 8.5 g of the product of Example 9 in 125 mL of EtOH and add 2.15 g of LiCI. Cool the stirred mixture to 0°C and add 1.92 g of NaBH4 in portions. Stir the mixture for 18 hr without further cooling. Add 125 mL of MeOH
and 10 mL of H20 to the mixture and stir for 4 hr. Evaporate the mixture to dryness and extract the precipitate with warm EtOH. Evaporate the extract to dryness, add 200 mL of THF to the residue, and sonicate the stirred mixture for ~. 2119396 15 min. Filter the mixture and evaporate the filtrate. Chromatograph the residue on silica gel, eluting with CH2C12-MeOH-NH40H (95:5:1 ) v/v/v) to obtain 3.9 g of the title compound. Mass spectrum (FAB): 314 (M+H+); PMR
(DMSO) d 8.25(s,1 ), 7.69(s,1 ), 7.35(m,1 ), 7.13(m,1 ), 6.94(m,1 ), 6.27(s,1 ), 5.16(t,1 ), 4.44(m,4), 3.39(m,1 ), 3.20(m,1 ), 3.05(t,2), 2.11 (m,1 ), 1.52(m,1 ).
fS)-(+)-4-(2.4-Difluoroohenvl)-2-hydroxvmethyl-5~1 H-(1 2 4 triazolyl~] 1 4 oentanediol Follow the procedure of Example 11, except substitute an equivalent amount of the product of Example 10 in place of the product of Example 9 to give the title compound. Chromatograph a portion of the crude product on silica gel eluting with CH2C12-MeOH-NH40H to give a product homogeneous by TLC. Dissolve the material in H20 and filter, and lyophilize the filtrate to give the title compound. ~a~ + 54.50 (c=1.0, MeOH) (Rl-(-)-4-(2.4-Difluorooh~nvl)-2-fff4-methyl~envl)-sulfonyloxy~methyl]~j1 H
(1-2.4-triazolvlll-1 4-oentanedi I-1-(4-methvlbenzene ~Ifonate Dissolve 4.4g of the product of Example 11 in 50 mL of CH2C12-THF (1:1, v/v). Add 4.7 mL of Et3N and 180 mg of N,N-dimethylaminopyridine, and cool the solution to 0°C. Add thereto 5.9 g of p-toluenesulfonyl chloride in portions and stir the so-formed reaction mixture at 0°C for 1/2 hour, and then stir it at room temperature for 5 hours. Add 100 mL of EtOAc and suction-filter the mixture. Concentrate the filtrate; add thereto 150 mL of EtOAc, and wash with 5% aqueous KH2P04. Wash the organic layer with cold aqueous 5% NaHC03, then with saturated brine, and then dry it over anhydrous MgS04. Filter the mixture, and evaporate the filtrate. Chromatograph the residue on silica gel, eluting with EtOAC-hexane to give 6.4 g (73%) of the title compound, PMR
2 i 7 ~ 3 9 6 pCT/17594/14236 (CDC13) d 7.95(s,1 ), 7.67(m,5), 7.30(m,6) 6.70(t,2), 4.74(d,1 ), 4.53(d,1 ), 4.13(m,1 ), 3.97(m,1 ), 3.8(m,2), 2.43(s,6), 1.95(m,2), 1.77(m,1 ). Mass spectrum (FAB): 622 [M+HJ+.
(Sl-(+)-4-(2.4-Difluoroohenvl)-2-Q 4-methy~henyll-sulfonvlox l~C,meth~l-5-(1 H
(1.2.4-triazolvi)1-1.4-oentanediol-1 (4-methylbenzene)sulfonate . Follow the procedure of Example 13 except substitute an equivalent amount of the product of Example 12 in place of the product of Example 11 to obtain the title compound, [~~ + 14.2° (~1, MeOH).
(-1-l5R-cisl-5-(2.4-Difluo roohe null-5~( 1 H-1.2.4-triazo I-1-vl) methyl-tetrahvdro-3-furanmethanol.4-toluenesy~ h~ ovate Dissolve 6.3g of the product of Example 13 in 150 mL of toluene and heat the so-formed solution to 100°C. Add 2.4g of 60% NaH
dispersion in oil portionwise, and then heat the so-formed reaction mixture at reflux until cyclization is complete (approx. 3-4 hours). Coot the mixture and decant the solution from excess NaH. Wash the solution with cold 5% aqueous KH2P04.
Evaporate the organic layer to form a residue and chromatograph the residue on silica gel, eluting with acetone-hexane to obtain 1.6g (35%) of the title compound as the less polar of the two products, [a~ - 39.4°(c=1, CHC13);
PMR (CDC13) d 8.09 (s,1 ), 7.88 (m,3), 7.31 (m,3), 6.81 (m,2), 4.52(ABq,2), 3.99(m,1 ), 3.85(m,1 ), 3.70(m,1 ), 3.59(m,1 ), 2.49(m,2), 2.47(s,3), 1.90(m,1 ).
Mass spectrum (FAB): 450 [M+H]+.
_T-_._ ~ 179396 L+~-!5S-cisl-5-(2 4-Difl mrnnhonvl ~ [~1 H 1 ~nl 1 W1 2 4 trig methvll-tetrahvdro-3-furanmethanol 4 tonr~nA~~ n..h..n.,.
Follow the procedure of Example 15, except substitute an equivalent amount of the product of Example 14 in place of the product of Example 13 to give the title compound, [a~ + 40.3° (c=0.3, CHCI3), mp 96-98°C.
L1 fl2R)-cisl-4-f4-f4-f4-rt5_!~ a ~~fn ~~..,hen"I~ . . ydro-4 I 1 I ( n- m h I-1- h 4-dihvdro-3H-1.2.4-triazol-~-nna The title compound is prepared starting with the tosylate of Example 15 and 4-[4-(4-nitrophenyl)-1-piperazinyljphenol (Example 3a of USP
4,791,111) and using the synthetic scheme outlined in Scheme V and J.
Heeres, et al., J. Med. Chpm 1984, Vol 27, p894-900 at 898 and 900.
R - i -4- 4- 4- 4- 4- i r h n I -T h r - - 1 H-4- I-1- Im h I - -F r n I n I -1-Pi r 'n I h n I - 4-ih ro-2-fl lSl-Methvl-2lR)-Hvdroxvoroovll ~N ~ ~ a Tri zoo ~ nno a. 2:O-SEM Ether of (2R ~R~-~ z-Q".~.".a:..~
To a stirred solution of 4.95g of (2R, 3R)-2,3-butanediol, (55 mmoles) and 9.3g of SEM-CI (55.7 mmoles) in 55 mi of anhydrous DMF at O°C were added in four portions 2.34g of 60% oil-dispersed NaH (58.5 mmoles) over 10 min.
The resulting mixture was stirred at 0°C for 4 hours and at ambient temperature overnight. The turbid reaction mixture was poured onto 0.5L of 5% KH2 P04 solution and extracted with 2 x 300 ml of ether; the combined ethereal solut van ~~~~3~6 was washed once with distilled water, saturated brine, dried over MgS04 and evaporated to give a colorless liquid. Flash chromatography over 350g silica gel,with 1 L of 7% ETOAC/Hexane, 2L of 10% ETOAC/Hexane and 1 L of 15%
ETOAC/Hexane gave 1.74g of the title compound (yield 14.4%) MS:(M+H)+=221.
b. Brosvlation A mixture of 0.7g of the 2-0-SEM ether of Example 18(a), (3.18 mmoles) and 0.978 of 4-bromobenzenesulfonyl chloride (3.82 mmoles) in 5ml of anhydrous pyridine was stirred under NZ atmosphere at ambient temperature for 6 hours. The reddish slurry reaction mixture was diluted with 50m1 of ice-cold water, extracted with 2 x 25m1 of ether. The combined ethereal solution was washed with 2 x 25m1 of 1-% CuS04 solution, distilled water, saturated brine, dried over MgS04 and evaporated to give a reddish oily residue. Flash chromatography over 50g silica gel with 1 L of 10% ETOAC/Hexane gave 1.02g of the brosylate as a colorless liquid (yield 72.9%) [a) p = -3.69° (CHC13 ; c=1 ) c. Alkylation Reaction A mixture of 0.98g of the brosylate of Example 18(b) (2.23 mmoles), 0.69g of the 3H-1,2,4-triazol-3-one of Example 17 (1.12 mmoles) and 0.37g of cesium carbonate (1.12 mmoles) in 20 ml of anhydrous DMF was stirred at 80°C under N2 overnight (-20 hours). The reaction mixture was diluted with 100m1 of ice-cold water, extracted with 2 x 50 ml of ethyl acetate. The combined organic solution was washed once with distilled water, saturated brine, dried over MgS04 and evaporated to give a brown solid residue. Flash chromatography of the residue over 125g silica gel with 1.2L of 80%
2~~9396 ,,,..-ETOAC/Hexane gave 0.3278 of the product as a tan solid (yield 35.7%) MS=(M+H)+=81.7.
d. Acidic Hvdrolvsis of 18(c1 to the titiA ~..,.~",.;
A mixture of 0.328 of the SEM-ether of Example 18(c) and 6ml of 6N HCI
solution in 6ml of methanol was stirred at ambient temperature for 4 hours and was evaporated under reduced pressure. The residue was diluted with 5ml of ice water, carefully basified with 10% Na2COg solution until pH=8-9 was obtained. Extraction of the so-formed reaction mixture with 2 x25m1 of CH2 CI2 followed by washing with saturated brine, drying over MgS04 and evaporation gave a tan solid. Filtration of the tan solid through a 508 silica gel column and elution with 0.75L of 4% MeOH/CHZCI2 gave 0.268 of title product as a tan solid, yield 96.6%. MS={M+H)+-_687; «~ - -23.65° {CHCI3 ; c=1 ) Exam a 19 (-)-f12R1-cisl-4-f4-f4-f4-ffl,~-« 4-Difluoro~r y1) Tetrah~,dro 5 (1 H ~ 2_a Triazol-1-vlmethvll-'~-F~rany-()~Il"eih~xerlPhenvl~ 1 PipArazin)r(lphenY~]~,4 Dihvdro-2-lfllR)-Methvl-2~R~-H~~~~..,~r,r,r,QYI~ 3H 1 2 4 Triazol 3 one a. Mitsunobu Reaction To a stirred solution of 0.728 of the 2-O-SEM ether of Example 18(a) (3.27 mmoles), 2.1 g of triphenyl phosphine (8.068) and 1.28 of p-nitrobenzoic acid (7.17 mmoles) in 30m1 of dry benzene at 0°C were added, dropwise, 1.25m1 (8.06 mmoles) of diethyl azodicarboxylate ("DEAD"). The so-formed clear yellow solution became turbid and the mixture was stirred at ambient temperature for 2 hours, and mixture loaded on a 1008 silica gel column.
Elution of the column with 15% ETOAC/Hexane gave 1.58 of the 3-~i-nitrobenzoate having the S absolute configuration (95% yield) MS: 219 1 ?9396 (M+ - 150), 252 (M+ - 117).
b. Basic Hydro_lycis of the o-Nitrobanzoate A solution of 1.12g of of the p-nitrobenzoate of Example 19(a) {3 mmoles) and 3.5m1 of 1 N NaOH solution in 20mi of methanol was stirred at ambient temperature for 3 hours. Solvents were evaporated and the residue was diluted with l0ml of distilled water, and extracted with 2 x 20m1 of ether. The combined ethereal solution was washed once with saturated brine, dried over MgS04 and evaporated to give 0.67g of the corresponding alcohol as a colorless liquid 0100%), which was used directly for the next reaction without further purification.
c. Brosylation. Akyrlation and Acidic Hvdro y~
Following the procedures of Example 18(c) and (d), the title compound was prepared in 32% overall yield in 3 steps from the products of Example 19(b) and of Example 17. MS: (M+H]+=687; ~a~~ - -23.65° (CHCI3 ; c=1 ) f-)-fl2R)-cisl-4-f4-f4-j4-j(f5-(2.4-Difluoroo, h~nyl -TetrahYdro-5-(1H-1 2 4-Triazol-1-vlmethvl)-3-Furanyl)MethoxylPhenyIJ-1-PioerazinyjlPhenyll 2 4 Dihvdro-2-f(S)-1-Methvl-3-HydroxvoroQy~-3H-1 2 4-Triazol-3-one a. Formation of TBDPS Ether To a solution of 0.9g or (R)-(-}-1,3-butanediol (10 mmoles), 1.5g of imidazole (22 mmoles) in 10 ml of anhydrous DMF at 0°C were added 3ml of t-butylchlorodiphenylsilane ("TBDPS") (11 mmoles) over 3 minutes. The reaction mixture was stirred at 0°C for 4 hours, diluted with 50m1 of ice-cold water and extracted with 2 x 30m1 of ether. The aqueous phase was back extracted with 5~
50m1 of ether and the combined ethereal solution was washed once with saturated brine, dried over MgS04 and evaporated to give a colorless residue.
Flash chromatography over 1508 silica gel with 1.5L of 5% EtOAC/Hexane and 1 L of 10% EtOAC/Hexane gave 2.878 of the TBDPS ether (87.5%) (ajp3 = +0.64° (CHCI3 ; c=1 ) MS: (M+H]+: 329;
b. Brosyiation To a solution of 0.9848 of TBDPS ether of Example 20(a) (3 mmoles) in 7ml of anhydrous pyridine were added 0.8458 of 4-bromobenzenesulfonyl chloride (3.3 mmoles). The reaction was run and worked-up and purified in accordance with the procedure of Example 18(b) and 1.028 of the brosylate was obtained in 61.1 % yield; MS: [M+23j+ = 569/571;
Iajp = +2.45° (CHC13 ; c=1 ) c., Alltylation The brosylate of Example 20(b), 0.958 (1.74 mmoles) was reacted with the compound of Example 17 according to the procedure of Example 18(c) to provide 0.498 of corresponding alkylated product, yield 60.3% MS: (M+H)+ 925 Iajp = -32.27° (CHC13 ; c=1 ) d. Acidic vdrol The compound of Example 20(c), 0.328, (0.35 mmoels) was hydrolyzed by 6N HCI solution in accordance with the procedure of Example 18(d) to give 0.228 of the title compound (yield 92.4%); MS: M+ = 686; (M+Na]+ = 709;
(ajo3 = -38.52° (CHCl3 ; c=1 ) Alternatively a solution of 0.198 of the compound of Example 20(c) and 60mg of tetrabutylammonium fluoride (0.23 mmoles) in 5ml of THF was stirred at ambient temperature for 24 hours. The brown solution was concentrated to a 2 ~ 79396 -syrup. Flash chromatography of the syrup over 50g silica gel with 0.5L each of 2% and 4% MeOH/CH2C12. gave 0.11 g of the title compound (yield 88.7%).
Exam to a 21 (-)-ff2R)-cisl-4-f4-f4-f4-ff5-(2 4-Difluoroohenyl)-Tetrahvdro-5-(1 H-1 2 4 Tria2ol-1-Ylmethvl)-3-FuranvIJMethoxy,)Phern,u-1-Pig erazinvllPhenylj-2 4 Dihvdro-2-flRl-1-Methyl-3-Hydrox o~ro,Qyll-3H-1 2 4-Triazol-3-one The procedures of Example 20 were followed except an equivalent amount of S-(+)-1,3-butanediol was substituted for the corresponding R
enantiomer. An overall 31.8% yield of the title compound was obtained in four steps; MS=[M+Hj+ = 687.
Example 22 (-)-f(2R)-cisl-4-f4-f4-f4-[(5-(2 4-Difluoroy~henyll-Tetrahvdro-5 (1 H 1 2 4 Triazol-1-vlmethvl)- -Furan~jMe-yjPhenyl~-j=Pioerazinyl~PhenYlj 2 4 Dihvdro-2-fllS)-Methyl-2-HydroxYp~QYI~-3H-1 2 4-Triazol-3-one.
a. Benzylation To a solution of 10g of (2R, 3R)-(-)-2,3-butanediol (111 mmoles) in 40m1 of anhydrous CH2C12 and 80m1 of cyclohexane at 0°C were added 1 ml of trifluoromethanesulfonic acid (TfOH), followed by dropwise addition of 21 ml of benzyl trichloroacetimidate (113 mmoles). The resulting slurry was stirred at ambient temperature overnight, diluted with 125m1 of hexane and filtered. The combined filtrate was concentrated to a yellow syrup. Flash chromatography of the yellow syrup over 250g silica gel with 1.5L of 7% ETOAC/Hexane, 2L of 15% ETOAC/Hexane and 2L of 25% ETOAC/Hexane, 1.5L of 10%
_.. _~_ __....
-- y ~ r2179396 MeOH/CH2C12 gave 11.888 of the 2-monobenzyl ether of the starting material (74.5% yield) and 2.038 of unreacted starting material MS: [M+H]+: 181.
b. Mitsunob Reaction The 2-monobenzyl ether of Example 22(a), 5.48, was converted into 6.68 of the 3- benzoate ester (yield 66.9%) by Mitsunobu reaction in accordance with the procedure of Example 19(a); MS: [M+H]+_- 330.
c. Alkali rolv i The 5.38 of the product of Example 22(b) was subjected to alkaline hydrolysis according to the procedure of Example 19(b) to give 2.338 of the 2-monobenzyl ether of (2R,3S)-2,3-butanediol (yield 80.3%) (M+H)+ = 181;
[a]p3 = -23.75° (CHC13 ; c=1 ) d. Formation of the ~ ~rho.
To a stirred solution of 3.148 of the product of Example 22(c) (17.44 mmoles) and 3.8m1 of di-isopropylethylamine (2.828, 21.8 mmoles) in 30m1 of anhydrous CH2Cl2 at ambient temperature were added 3.8m1 of SEM-CI
(3.648, 21.8 mmoles) in one portion. Fuming formed and the resulting yellow solution was stirred for 20 hours. The orange-colored reaction mixture was evaporated under reduced pressure and the solid residues were partitioned between ether and water. The ethereal solution was washed once with distilled water, saturated brine, dried over mg 504 and concentrated to give the crude product. Flash chromatography of the crude product over 2008 silica gel with 2L of 3% ETOAC/Hexane gave 5.38 of the 3-O-SEM ether of the product of Example 22(c) (98% yield) as a colorless liquid; MS: [M+H]+ = 311.
217396 _ e. HYdrogenolysis A mixture of 5.25g of the product of Example 22(d) (16.94 mmoles) and 0.5g of 10% Pd/C in 150m1 of methanol was hydrogenated under atmospheric pressure for 6 hours. Catalysts were filtered and washed with additional methanol. The combined filtrate was concentrated to give a colorless liquid.
Flash chromatography of the liquid over 100g silica gel with 2L of 10%
ETOAC/hexane 3.53g of the free alcohol (yield 95%) as a colorless liquid; MS:
174, 103.
f. Bros, lair tion The product of Example 22(e) 1 g was converted into 1.52g of the corresponding brosylate in 76.2%yield in accordance with the procedure of (aj -1.53° (CHC13 ; c=1 ) 18(b);
g. Alkylation Reaciton The brosylate of Example 22(f), 1.48g of was reacted with the product of Example 17 to give 0.75g of the 2-alkylated triazol-3-one (yield 54.3%);
[a]p3 = -32.69° (CHCI3 ; c-1 ) h. Acidic H~olysis Hydrolysis of 0.7g of the product of Example 22(g) in accorcdance with the procedure of Example 18(d) gave 0.51g of the title compound as a cream solid (yield 86.7%); [aj~ - -32.69° (CHC13 ; c=1 ) Example 23 . ~ '-' ~11~3~6 (-)-f(2R)-cisl-4-f4-f4-f4-ff5-f? a mst~~oro'~envll Tetrah~ ro 5 (1 H 1 2 4 Triazol-1-vlmethvl)-~-FuranvllM~pthoxvlPhenvll 1 Pioerai~,~ n~~~~~
ih r - - 1 -M h I- -H r x r I - H-1 4-Tri I- n .
a. blitsunobu React~~n The product of step a of Example 22 (1.99g, 9.05 mmoles) was reacted with p-nitrobenzoic acid in accordance with the procedure Example 19(a) to give 3.3g of product (yield 98.8%); MS = [M+Hj+ = 221.
b. Alkaline Hv rol is The product of step (a) of this Example (2.36g, 6.4 mmoles) was hydrolyzed by 7ml of 1 N NaOAc to give 1.18g of the 3-O-SEM ether of (2S,3S) 2,3-butanediol (yield 83.7%). MS: [M+Hj+ = 221 [°~jo3 - +55.15° (CHCI3 : C=1 ) c. Brosvlate Formation The product of step (b) of this Example (1.15g were converted into the brosylate in accordance with the procedure of Example 18(b) to give 3.47g of the brosylate (yield 97.7%) .
d. Alkvlation and Acidi - Hvdrolva~c The procedures of Example 18(c) and (d) were followed except the product of Example 23(c) was substituted for that of 18(b) to give the title compound.
Example 24 ~ 119396 _ l2R-cis~-4-f4-f4-14-ff-5-12.4-difluoroohen~,l1-tetrahvdro-5-l1 H-1 2 4-triazol-1-vlmethvllfuran-3-vllmethoxvlohenyl]-1-pioerazin~ljhhen~,l2-4-dihydro-2-((Sl-1-ethyl-2lS)-hvdroxvorooylj-3H-1.24-Triazol-3-One a. The methyl ester of (S)-lactic acid was converted into the corresponding benzyloxymethyl ether in accordance with the procedure of W. C. Still, et al.
Tetrahedron Letters, ~1_, 1035-1038 (1980).
b. Reduction to the Aldeh~e DIBAL-H, 37.7m1 of a 1 M solution, was added dropwise to a stirred solution of 7.67g of the ester of step (a) of this Example in toluene at -78°C (dry ice/acetone bath) under an atmosphere of nitrogen. After 6 min. methanol (l0ml) followed by an aqueous aolution of Rochelles salt were added. After warming to room temperature the moisture was partitioned between ETOAc and water. The organic phase was separated, washed with water, dried (MgS04) and concentrated to produce the crude aldehyde which was used in the next step without purification.
b. Grianard Step The THF solution of SOmI of 1 molar solution of the ethyl magnesium bromide Grignard reagent was added dropwise to a stirred THF solution of the crude aldehyde obtained from step (b) of this Example at -78°C (dry iceJacetone bath) under an atmosphere of nitrogen. After the addition was complete, the resulting mixture was allowed to warm slowly to room temperature overnight and stirred for a further period of 48 h. An aqueous solution of Rochelles salt was added and then the resulting mixture was partitioned between acetone and water. The organic phase was separated, washed with water, dried (MgS04) and concentrated. The residue was purified by column chromotography on silica gel using ETOAC/Hexane (1:10) as eluant to give (i) non-polar alcohol (2S,3S) 2.31 g;31 %, as a colorless oil.
(ii) a mixture of both alcohols, 1.23g; 41 and (iii) polar alcohol (2S,3R) 1.23g; 16%, as a colorless oil.
c. Brosvlation of Qol2~ alcohol 4-Bromobenzenesulphonyl chloride (1.0358, 4.1 mmoles) was added to a stirred solution of (0.6058, 2.7 mmoles) the polar (2S, 3R) alcohol of step (b) of this Example and 2.208 (5.9 mmoles) of DMAP in CH2C12 at room temperature under an atmosphere of nitrogen. The resulting mixture was stirred for 12 h. and then partitioned between ETOAC and water. The organic phase was separated, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel using ETOAC/Hexane (1:10) as eluant to give the desired brosylate (85%) as a colorles oil.
d. Alk~ation and acidic hydrolysis The procedures of Example 18(c) and (d) were followed except the (2S, 3R) bosylate of step (c) of this Example was substituted for that used in Example 18(c). The acidic hydrolysis produced the title compound as a white solid, mp 170-172°C.
Example 25 L?R-cis)-4-~4-f4-f4-j(-5-(2.4-difluorohenyll-tetrahYdro-5-(1 H-1.2.4-triazol-1-vlmethvllfuran-3-vllmethoxvj~henvll-1-~i~erazinvfl~henvll-2.4-dihvdro-2-f(R?-1-ethyl-2fS)-hvdroxvoroovl~-3H-1.2.4-triazol-3-one.
The procedures of Example 24 were followed except the non-polar (2S,3S) alcohol from step (b) of Example 24 was converted into the (2S,3S)-3-brosylate. Alkylation of the brosylate followed by acidic hydrolysis of the SEM
6~
~ I ~939~ __ protecting group in accordance with the procedures of Example 24(d) provided the title compound.
R- i -4-f4-f4-f4-ff-5-(2.4-c~ifluorrac_ henyl - trahydro-5-l1 H-1 2 4-triazol 1-vlmethvllfuran-3-vllmethoxvloh~ll-vi erazinyllohenyl]~-4-di~dro-2-jlR) 1 Qthvl-2 ( R )-hvdro xv~ row I]-3 H-1.2.4-triazol-3-On a The procedures of Example 24 were followed except the methyl ester of (R) lactic ester was substituted for the methyl ester of (S)-lactic acid in step (a) of Example 24. The (2R, 3S) alcohol was used in steps (c) and (d) to provide the title compound.
Example 2727 R- i -4-f4-f4~f4-ff-5-(2.4-difluoroohenyl)-tetrahvdro-5-(1 H-1 2 4-triazol-1-vlmethvllfuran-3-vilmethoxvlohenyl]1-oioe_ -razinyljohenyl]2-4-dihvdro 2 ((Sl 1 eLyl-2lR)-hvdroxvorooyl]-3H-1 24-triazol-3-On The procedures of Example 26 were followed except the (2R, 3R) alcohol was used in steps (c) and (d) to provide the title compound.
Exams ((2R'cis)cis)-4-f4-f4-f4-ff-5-12.4-difluoro henyl)-tetrahvdro-5-(1 H 1 2 4 triazol 1-vlmethvllfuran-3-vllmethoxvlohenv111-oiper~yllohenvll -4-dihvdro 2 [(R1 1 ~yl-3-hvdroxvoroovl] ~H-1.2.4-tri~nl-3-One a. Reduction To methyl (3R)-hydroxyvalerate (5.289, 40.0 mmoles) dissolved in 100m1 of anhydrous THF at 0-5°C was added dropwise 60m1 of a 1 M THF solution of LiAIH4 (60 mmoles). The solution was allowed to warm to ambient temperature and to the so-formed mixture was added sequentially, 2.5 mL of water, __. T _ _ dropwise, 2.5mL of 15% NaOH and 7.5mL of water. The so-formed reaction mixture was stirred at ambient temperature for 4 h. The inorganic solids were removed by filtration and the filtrate was evaporated to give 4.31 g of (3R)-1,3-pentanediol.
b. 1O-SEM .thpr formation The procedure of Example 18(a) was followed except an equivalent quantity of the product of step (a) of this Example was substituted for the (2R, 3R)-2,3-butanediol to provde the title compound.
c. Mitsunob Reaction The procedure of Example 19(a) was followed except that an equivalent quantity of the product of step (b) of this Example was substituted for the 2-SEM
ether of (2R,3R)-2,3-butanediol to give 3.34g of the corresponding p-nitrobenzoate.
d. Basyol The procedure of Example 19(b) was followed except that an equivalent quantity of the p-nitrobenzoate ester of step (c) of this Example was used to provide 1.88g of the 1-O-SEM ether of (3S)-1,3-pentanediol.
e. Brosvlation Alkvlation ~nd A id H I ~ i The procedures of Example 18 (b), (c), and (d) were followed except that an equivalent quantity of the product of step (d) of this Example was substituted for the corresponding 1-0-SEM ether of (2R, 3R) 2,3-butanediol used in Example 19(b) to produce 1.04g of the title compound of this Example falp3 = -8.42° (CHC13 ; c=1 ) ~217~.3~6 _.
WO 95/17407 . PCTNS94/14236 Examgle 29 ( R-cisl-4-f4-f4-[4-j[-5-(2.4-difluoroohenyl~-tetrahyrdro-5-l1 H-1 2 4-triazol-1-vlmethvl)furan-3-vl]methoxy]~hgn 1Y11_oioerazinyllohen~l2-4-dih~rdro-2-[(S1-ethyl-3-hvdroxvcroQ~l,~-3H-1.2.4-triazol-3-One.
The procedures (a) and (b) of Example 28 were followed to produce the 1-O-SEM-(3R)-1,3-pentanediol which was converted directly into the 3R
brosylate by following the procedures of Example 18(b). The 3R brosylate was used to alkylate the product of Example 17 in accordance with the procedures of Example 18(c). The so-formed product was subjected to acidic hydrolysis in accordance with the procedures of Example 18(d) to provide 368mg (90%
yield) of the title compound; [a]~3 47' 11 ° (CHC13 ; c-1 ) Example 3030 (2R-ci~,-4-f4-f4-f4-[[-5-(2.4-difluoroohenyl -tetrahydro-5- 1 H-1 2 4-triazol-1-vlmethvl)-3-furanvllmethoxY] hen~,~1 rioerazin~rljohenyll2-4-dihydro-2-f1-h dy rox_y-l2R)-butvlj-3H-1.2.4-triazol-3-One a. Preparation of 1251-1.2.-butanediol A solution of (2S)-3-butene-1,2-diol which was purchased from Eastman Kodak, (3g, 0.034mmoles) in 40mL of ethanol was hydrogenated in the presence of 300mg of 10% Pd/C overnight. The so-formed reaction mixture was filtered through celite. The so-formed filter cake was washed with ethanol and the combined filtrates were evaporated to provide 2.08g (68% yield) of the title compound.
b. 1-O-SEM ether formation. brosvlaton. alkylation and acidic hydroysis The procedures of Example 18(a) - (d) were followed except that an equivalent amount of the product of step (a) of this Example was substituted for _.__ T _ _ _ . ._ ..__ -.T_-. . v ~ ~ 19396 the (2R, 3R) 2,3-butanediol of Example 18 to provide the title compound -24.3° (CHC13 ; c_-1 ) Exam a 31 ,(2R-~'y,-4-f4-f4-f4-ff-5-(2 4-difluoroohenvll tetrahvdro 5 f1 H 1 2 4 tn~ zm hvdroxv-l2~-bstyp-~-H_1.2 4_triazm ~ one The procedures of Example 30 were followed except that an equivalent quantity of (2R)-3-butane-1,2-diol (available from Eastmand Kodak) was substituted for (2S)-3-butane-1,2-diol in step (a) of Example 30. The procedures of Example 30(b) were there after followed to produce the title compound ~~')03 29'4° (CHC13 ; c=1 ) - i -4- 4- 4 - 4- if r n _1 4 _ _1 _ I I f r I h x n I - i i I I- 4- ih Qthvl-2lS)-hvdroxvoroovll-'~H-1 2 4 tria~nl ~ "ne a. n I x r 'v i f benZVl1 lacti _ anir~ nyrrnliriinn ~ ;ide: To a solution of the S-(O-benzyl)lactic acid pyrrolidene amide prepared in accordance with the procedure of Tetrahedron, 1989, vol. ~, pages 57-67 (5g, 0.0214 mol.) dissolved in 20 ml of toluene cooled to in a ice methanol bath was added slowly with stirring 4.25 ml or RED-AL (3.4M solution of sodium bis(2-methoxyethoxy) aluminum hydride) in toluene available from Aldrich Chemical Catalogue #19, 619-3). The solution was stirred fro 5 hrs., quenched with 2.5 ml of acetone and thereafter with 35 ml of 2NHC1. The so-formed mixture was extracted with EtoAc. The organic extracts were washed with water, NaHC03 and brim, ~ over Na2S04 and evaporated to give the titled product.
b. (S1-2-lBen2vloxy)-N;~~mylaminoLgronanimine. The , propionaldehyde of step (a) (1 g, 16.09 mml) was added dropwise to a solution of formic hydrazine (0.738, 12.18 mmol) dissolved in 5 m! of methanol. The so-formed reaction mixture was stirred overnight.r The solvent was removed by evaporation and the so-formed residue was stirred with ethyl ether. The undlssolved excess formic hydrazine was removed by ~Itration and the ether was removed to provide a residue which was chromatograpned on silica gel(I) using 20% EtoAc: hexane (v:v) to give 805 mg of the title product as a light yellow waxy solid having strong UV activity; ms [M + H)+= 207.
c. 2~3-125. 3S1-2-lBensyt~)oentylJformic a~i~ hyd ztde Ethytmagnesium bromide (1.3 ml, 3.9 mmot, 3.0 molar in ethyl ether) was added to a stirred solution of 200 mg, 0.97 mmol of the propanimine of step (b) in 10 m! of ethyl ether at 0°C. The so-formed reaction mixture was stirred overnight at room temperature and quenched with water. The organic layer was separated and the solvent removed to provide a residue which was chromatographed on silica gel using 30 to 50°/° of EtoAc:hexane (v:v) to provide 713 mg; (50 % yield) of the title compound as an oil. The ratio of S,S isomer.
S,R isomer in the product was 94:6. When the reaction was repeated in the presence of 1.2 equivalent of bis(trimethylsiiyi) acetamide the S,S:S,R ratio improved to 99:7 MS: [M + H]+ = 237 d. Cvclizatton Reaction A solution of 156.3 mg, 0.66 mmot of the product of step (c) and 400 mg 0.60 mmol of 17F of Scheme V and 1 mole of DBU (1,8-diaza bicyclo [5.4.OJundec-7-ere) in volume was stirred at 80°C for six hours; the temperature D
..~ 2119396 was raised to 100° to 110°C and stirring was continued at this temperature overnight. The reaction mixture was allowed to coo( to room temperature and ~ the stirring was continued over the weekend. The solvent was removed by evaporation and the crude product was purified on preparative TLC (80%
EtoAc) hexane, v:v) to provide 200 mg of the benzyi ether of the title product of this example as a foamy solid; MS:(M + Nj+ i 792 This cyclization reaction is the invention of Mergelsberg, Gala g~, which is disclosed in commonly-owned U.S. Patent 5, 625, 064.
e. ~Ivdrog~enolysis To the solution of the benzyl ether (190 mgs , 0.24 mmol) of step d dissolved in 10 ml of methanol was added 40 mg of Pd black on carbon and 4 mf of formic acid. The reaction flask was sealed with a bailon and heated at fi0°C for four hours. The catalyst was removed by filtration through a celite cake and the filtrate was poured into c:ofd water. The pH of the so-formed solution was adjusted to a value of 4 to 5 with amonia. The so-fom~ed mixture was extracted with EtoAc. The organic layer was separted and dried over Na2S04.
The solvent was removed to provide a crude product which was purified on preparative TLC (5% methanol: CH2CL2, v:v) to give 95 mg of the title compound of this example. (57% yield) as a tan solid. MS : (M+ H]+ = 701.
[oc] a -28.4 (c, = 1.0, CHCI3)
Claims (31)
1. A compound selected from compounds represented by the formula I and pharmaceutically acceptable salts and esters thereof 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 to C5) alkyl group substituted by one hydroxy moiety.
and the other is independently Cl;
R1 is a straight or branched chain (C4 to C5) alkyl group substituted by one hydroxy moiety.
2. A compound of Claim 1 wherein R1 is a hydroxy-substituted C4- or C5-alkyl group selected from:
-~H(C2H5)~H(OR4)CH3, -~H(C2H5)CH2CH2OR4, -(CH2)2-~H(OR4)C2H5, -~H(CH3)~H(OR4)CH3, -~H(C2H5)CH2OR4 and -~H(CH3)CH2CH2OR4 wherein R4 is H or an ester of the hydroxy moiety and the carbons with the asterisk(*) have the R or S absolute configuration or a pharmaceutically acceptable salt thereof.
-~H(C2H5)~H(OR4)CH3, -~H(C2H5)CH2CH2OR4, -(CH2)2-~H(OR4)C2H5, -~H(CH3)~H(OR4)CH3, -~H(C2H5)CH2OR4 and -~H(CH3)CH2CH2OR4 wherein R4 is H or an ester of the hydroxy moiety and the carbons with the asterisk(*) have the R or S absolute configuration or a pharmaceutically acceptable salt thereof.
3. A compound selected from compounds represented by formula III and pharmaceutically acceptable salts and esters thereof wherein R5 is
4. A compound of Claim 3 selected from compounds represented by the formula IV and pharmaceutically acceptable salts and esters thereof wherein R9 = ~H(C2H5)~H(OR6)CH3 or -CH(CH3)CH(OR6)CH3 wherein OR6 represents OH or an esterified hydroxy group.
5. A compound of any one of claims 1 to 4 wherein said pharmaceutically acceptable esters are selected from polyether esters, phosphate esters, sulfate esters, heterocyclic esters, alkanoate esters, alkenoate esters, amino acid esters and acid esters wherein (a) the term "polyether esters" means those polyether esters represented by the formula:
wherein R7 is H or (C1-C6) straight or branched chain alkyl group; and s is an integer from 1 to 6; t is an integer from 1 to 6; R8 is R7 or -(CHR7)S-CO2R7 and (b) the term "phosphate esters" means those phosphate acid esters represented by the formula wherein z is 0 or 1; m is O or 1; R7 is H or a (C1-C6) straight or branched chain alkyl group and preferably is H; n is an integer from 0 to 6 and W is H, CH2Ar or and wherein Ar is phenyl or phenyl substituted by halo, cyano, nitro or trihalomethyl; and (c) the term sulfate esters means the hydrogen of the hydroxy moiety is replaced by SO(OH)2; and (d) the term "heterocyclic esters" means those heterocyclic esters represented by the formula wherein R7 is as defined herein above, W is an integer of from 1 to 5 preferably W is 1 to 3; q is = 3 or 4 and Y is CHR7, -O-, NH, NR7, S, SO or SO2; and (e) the terms "alkanoate esters and alkenoate esters" mean straight or branched chain alkanoate or alkenoate groups optionally substituted by a hydroxy or ether moiety or mixtures of such alkanoates or alkenoates; and (f) the term "amino acid esters" means the natural and unnatural amino acid residues preferably with amino groups protected by the conventional protecting groups; and (g) the term "acid ester" means acid esters represented by the formula wherein R7 is as defined herein above and k is an integer of from 1 to 8.
wherein R7 is H or (C1-C6) straight or branched chain alkyl group; and s is an integer from 1 to 6; t is an integer from 1 to 6; R8 is R7 or -(CHR7)S-CO2R7 and (b) the term "phosphate esters" means those phosphate acid esters represented by the formula wherein z is 0 or 1; m is O or 1; R7 is H or a (C1-C6) straight or branched chain alkyl group and preferably is H; n is an integer from 0 to 6 and W is H, CH2Ar or and wherein Ar is phenyl or phenyl substituted by halo, cyano, nitro or trihalomethyl; and (c) the term sulfate esters means the hydrogen of the hydroxy moiety is replaced by SO(OH)2; and (d) the term "heterocyclic esters" means those heterocyclic esters represented by the formula wherein R7 is as defined herein above, W is an integer of from 1 to 5 preferably W is 1 to 3; q is = 3 or 4 and Y is CHR7, -O-, NH, NR7, S, SO or SO2; and (e) the terms "alkanoate esters and alkenoate esters" mean straight or branched chain alkanoate or alkenoate groups optionally substituted by a hydroxy or ether moiety or mixtures of such alkanoates or alkenoates; and (f) the term "amino acid esters" means the natural and unnatural amino acid residues preferably with amino groups protected by the conventional protecting groups; and (g) the term "acid ester" means acid esters represented by the formula wherein R7 is as defined herein above and k is an integer of from 1 to 8.
6. A compound of Claim 4 wherein R6 is a polyether ester group represented by the formula:
wherein R7 is H or (C1-C6) straight or branched chain alkyl group, R8 is R7 or and s is 1 to 6 and t is 1 to 6.
wherein R7 is H or (C1-C6) straight or branched chain alkyl group, R8 is R7 or and s is 1 to 6 and t is 1 to 6.
7. A compound of Claim 4 wherein R6 is a phosphate acid ester group represented by the formula:
wherein z is 0 or 1, m is 0 or 1 n is 0 to 6, and R, is H or (C1-C6) straight or branched chain alkyl group and W is H or CH2Ar or wherein Ar is phenyl or phenyl substituted by halo, cyano, nitro or trihalomethyl.
wherein z is 0 or 1, m is 0 or 1 n is 0 to 6, and R, is H or (C1-C6) straight or branched chain alkyl group and W is H or CH2Ar or wherein Ar is phenyl or phenyl substituted by halo, cyano, nitro or trihalomethyl.
8. A compound of Claim 5 which is a pharmaceutically acceptable salt thereof.
9. A compound of Claim 3 selected from compounds of formula III set forth wherein R5 is and pharmaceutically acceptable salts and esters thereof.
10. A compound of the formula or a pharmaceutically acceptable salt or ester thereof.
11. The compound of Claim 9 or 10 which is a phosphate acid ester represented by the formula wherein z is 0 or 1; R7 is H; m is 0 or 1, n is an integer from 0 to 6 and W
is H.
is H.
12. The compound of Claim 9 or 10 which is the phosphate acid ester represented by the formula wherein n = 1 to 4; or that is a phosphate ester represented by the formula
13. A pharmaceutical composition for treating or preventing fungal infection comprising an antifungally effective amount of a compound of any one of claims 1 to 12 together with a pharmaceutically acceptable carrier therefor.
14. The pharmaceutical composition of Claim 13 in a form for oral or parenteral administration.
15. A method of making compounds of the formula III of claim 3 wherein R4 is ~H(C2H5)~H(OH)CH3 wherein the absolute stereochemistry at each asterisk carbon (*) is same i.e., S,S or R,R substantially free of S,R or R,S and wherein S- or R-lactic acid ester is converted into the corresponding amide, which is selectively reduced to the corresponding aldehyde and then converted into the corresponding N-formyl amino propanimine which comprises reacting the N-formyl amino propanimine of the formula with ethyl magnesium bromide under Grignard reaction conditions sufficient to produce a compound of the formula wherein the absolute stereochemistry induced at the doubt asterisk carbon (**) is substantially the same as that at the single asterisk carbon and wherein PG is a conventional hydroxy protecting group such as benzyl.
16. A method of Claim 15 wherein S-lactic acid methyl ester is used as the starting material and the Grignard reaction is conducted in the presence of more than one equivalent of bis(trimethylsilyl)acetamide.
17. An antifungal pharmaceutical composition comprising an acceptable antifungally effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 12, in association with a pharmaceutically acceptable carrier.
18. Use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 12, in the manufacture of a medicament for treatment or prevention of antifungal infections.
19. A compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as defined in any one of claims 1 to 12, for use in the treatment or prevention of antifungal infections.
20. (2R-cis)-4-[4-[4-[4-[[-5-(2,4-Difluorophenyl)-tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[(R)-1-ethyl-2 (S)-hydroxypropyl]-3 H-1,2,4-triazol-3-one of the formula:
21. A pharmaceutically acceptable salt of the compound of claim 20.
22. A pharmaceutically acceptable ester of the compound of claim 20.
23. A phosphate acid ester of the compound of claim 20, having the formula:
~
wherein n is an integer of 1 to 4.
~
wherein n is an integer of 1 to 4.
24. An antifungal pharmaceutical composition comprising an anti-fungally effective amount of the compound of claim 20, in association with a pharmaceutically acceptable carrier.
25. An antifungal pharmaceutical composition comprising an anti-fungally effective amount of a phosphate acid ester of claim 23, in association with a pharmaceutically acceptable carrier.
26. Use of the compound of claim 20, in the manufacture of a medicament for treating or preventing fungal infection.
27. Use of a phosphate acid ester of claim 23, in the manufacture of a medicament for treating or preventing fungal infection.
28. The compound of claim 20, for use in the treatment or prevention of fungal infection.
29. A phosphate acid ester of claim 23, for use in the treatment or prevention of fungal infection.
30. Use of the compound of claim 20, as an antifungal agent.
31. Use of a phosphate acid ester of claim 23, as an antifungal agent.
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US17108393A | 1993-12-21 | 1993-12-21 | |
US08/171,083 | 1993-12-21 | ||
PCT/US1994/014236 WO1995017407A1 (en) | 1993-12-21 | 1994-12-20 | Tetrahydrofuran antifungals |
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US5039676A (en) * | 1990-05-11 | 1991-08-13 | Schering Corporation | Tri- and tetra-substituted-oxetanes and tetrahydrofurans and intermediates thereof |
IL103558A0 (en) * | 1991-10-30 | 1993-03-15 | Schering Corp | Tri-substituted tetrahydrofuran antifungals |
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