WO2009131246A1 - Dérivés de sordarine pour prévenir ou traiter des maladies infectieuses causées par des micro-organismes pathogènes - Google Patents
Dérivés de sordarine pour prévenir ou traiter des maladies infectieuses causées par des micro-organismes pathogènes Download PDFInfo
- Publication number
- WO2009131246A1 WO2009131246A1 PCT/JP2009/058437 JP2009058437W WO2009131246A1 WO 2009131246 A1 WO2009131246 A1 WO 2009131246A1 JP 2009058437 W JP2009058437 W JP 2009058437W WO 2009131246 A1 WO2009131246 A1 WO 2009131246A1
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- WO
- WIPO (PCT)
- Prior art keywords
- lower alkyl
- optionally substituted
- group
- compound
- substituent
- Prior art date
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- 208000035473 Communicable disease Diseases 0.000 title claims abstract description 17
- 244000000010 microbial pathogen Species 0.000 title claims description 12
- 150000000137 sordarin derivatives Chemical class 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 5
- 241001465754 Metazoa Species 0.000 claims abstract description 4
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 422
- 150000001875 compounds Chemical class 0.000 claims description 369
- 125000001424 substituent group Chemical group 0.000 claims description 131
- -1 4,5-dihydroimidazolyl Chemical group 0.000 claims description 120
- 125000005936 piperidyl group Chemical group 0.000 claims description 84
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
- 125000004076 pyridyl group Chemical group 0.000 claims description 67
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 54
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 42
- 125000003342 alkenyl group Chemical group 0.000 claims description 38
- 125000002757 morpholinyl group Chemical group 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical class 0.000 claims description 37
- 238000004519 manufacturing process Methods 0.000 claims description 34
- 125000005843 halogen group Chemical group 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 23
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 17
- 125000002883 imidazolyl group Chemical group 0.000 claims description 16
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 16
- 125000004193 piperazinyl group Chemical group 0.000 claims description 15
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 12
- 125000000335 thiazolyl group Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000003725 azepanyl group Chemical group 0.000 claims description 5
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 claims description 5
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 claims description 5
- 125000005959 diazepanyl group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims description 5
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000005962 1,4-oxazepanyl group Chemical group 0.000 claims description 4
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 4
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 3
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 claims description 3
- 125000005237 alkyleneamino group Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 325
- 230000000843 anti-fungal effect Effects 0.000 abstract description 7
- 230000000845 anti-microbial effect Effects 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 338
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 202
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 193
- 239000000243 solution Substances 0.000 description 176
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 174
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 168
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 127
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 126
- 239000012267 brine Substances 0.000 description 114
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 108
- 238000006243 chemical reaction Methods 0.000 description 96
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 84
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 84
- 235000019341 magnesium sulphate Nutrition 0.000 description 84
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 80
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 76
- 229920006395 saturated elastomer Polymers 0.000 description 73
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 71
- 239000012044 organic layer Substances 0.000 description 67
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 59
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- 238000010898 silica gel chromatography Methods 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 41
- 239000000741 silica gel Substances 0.000 description 41
- 229910002027 silica gel Inorganic materials 0.000 description 41
- 229960001866 silicon dioxide Drugs 0.000 description 41
- 235000019270 ammonium chloride Nutrition 0.000 description 40
- 239000002904 solvent Substances 0.000 description 39
- 235000017557 sodium bicarbonate Nutrition 0.000 description 37
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 229910052938 sodium sulfate Inorganic materials 0.000 description 35
- 235000011152 sodium sulphate Nutrition 0.000 description 35
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 25
- 239000000725 suspension Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000012746 preparative thin layer chromatography Methods 0.000 description 24
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
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- 125000006239 protecting group Chemical group 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 17
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 238000001816 cooling Methods 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 15
- 230000008020 evaporation Effects 0.000 description 15
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 14
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 14
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 239000012312 sodium hydride Substances 0.000 description 13
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- 150000002170 ethers Chemical class 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
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- 125000004434 sulfur atom Chemical group 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
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- 239000010410 layer Substances 0.000 description 8
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 8
- 235000019345 sodium thiosulphate Nutrition 0.000 description 8
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- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 7
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- 125000003118 aryl group Chemical group 0.000 description 4
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- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000169 tricyclic heterocycle group Chemical group 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- VHKIEYIESYMHPT-UHFFFAOYSA-N triethyl(methoxycarbonylsulfamoyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC VHKIEYIESYMHPT-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- WRTMQOHKMFDUKX-UHFFFAOYSA-N triiodide Chemical compound I[I-]I WRTMQOHKMFDUKX-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- BRDAGCMKJWBIKZ-QLHIUHCYSA-N zofimarin Chemical compound O[C@H]1[C@H](OC(=O)\C=C/C=C/C)[C@H](OC)[C@@H](C)O[C@H]1OC[C@]1([C@@]2(C(C(C)C)=C3)C(O)=O)[C@H]3C[C@]2(C=O)[C@@H]2CC[C@@H](C)[C@H]2C1 BRDAGCMKJWBIKZ-QLHIUHCYSA-N 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07C255/47—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of rings being part of condensed ring systems
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C07C2603/86—Ring systems containing bridged rings containing four rings
Definitions
- the present invention relates to a sordarin derivative and a salt thereof, which are useful as a medicament.
- Sordarin is an antifungal antibiotic discovered in 1971 as a metabolite of Sordaria araneosa [see Helvetica Chimica Acta 54, 1178 (1971)].
- Other compounds having the sordarin skeleton have been reported as antifungal agents: zofimarin (Japanese Kokai).
- JP62040292 JP62040292
- moriniafungin WO2003/051889
- JP2003/261450 discloses the following compounds:
- the present invention relates to a sordarin derivative and/or a pharmaceutically acceptable salt thereof.
- fungi especially antifungal activities, in which the fungi may include Aspergillus, Cryptococcus, Candida, Mucor, Actinomyces, Histoplasma, Dermatophyte, Malassezia, Fusarium, and the like).
- the object sordarin derivative of the present invention is represented by Formula (I):
- R 1 is -CHO, -CO-lower alkyl, cyano, -COOH or lower alkyl substituted with one or more OH(s);
- R 2 is -COOH or protected carboxy
- R 4 , R 6 and R 7 are each H or lower alkyl optionally substituted with one or more suitable substituent(s);
- R 5 is H, lower alkyl optionally substituted with one or more suitable substituent(s), lower alkenyl optionally substituted with one or more suitable substituent(s), lower alkyl optionally substituted with one or more suitable substituent(s), -0-lower alkenyl optionally substituted with one or more suitable substituent(s) or cycloalkyl;
- X is CHR 10 or O,
- n is an integer of O or 1]
- R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a composition
- a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, in association with pharmaceutically acceptable carriers or excipients.
- the present invention further relates to the use of a compound of Formula (I), or its pharmaceutically acceptable salt, for the manufacture of a medicament for preventing and/or treating infectious diseases caused by pathogenic microorganisms.
- the present invention still further relates to a method for the prophylactic and/or therapeutic treatment of infectious diseases caused by pathogenic microorganisms, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a human being or an animal.
- the present invention still further relates to an agent for preventing and/or treating infectious diseases caused by pathogenic microorganisms which comprises the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
- the present invention still further relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for curing infectious diseases caused by pathogenic microorganisms.
- the present invention still further relates to a process for preparing a pharmaceutical composition for preventing or treating infectious diseases caused by pathogenic microorganisms, which comprises mixing a compound of Formula (I) or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable carriers, vehicles or excipients.
- the present invention still further relates to a commercial package comprising the pharmaceutical composition containing a compound of Formula (I) and a written matter associated therewith, wherein the written matter states that the compound of Formula (I) can or should be used for preventing or treating infectious diseases.
- a “lower alkyl” is a linear or branched alkyl having 1 to 8 carbons (hereinafter abbreviated as C 1-8 ).
- Non-limiting examples of a lower alkyl include methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, sec-butyl, tert-butyl, r ⁇ -pentyl, n-hexy ⁇ , n-heptyl, and «-octyl.
- the lower alkyl is a methyl, ethyl, «-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, «-pentyl, 3-methylbutyl, 2,2-dimethylpropyl, «-hexyl, 2-ethylbutyl, rc-heptyl, or r ⁇ -octyl.
- a “lower alkenyl” is a linear or branched C 2-8 alkenyl.
- Non-limiting examples include vinyl, propenyl, butenyl, pentenyl, 1 -methyl vinyl, l-methyl-2-propenyl, 1,3-butadienyl, and 1,3-pentadienyl.
- the lower alkenyl is a C 2-4 alkenyl, in other embodiments 2-propen-l-yl, 2-methyl-2 ⁇ propen-l-yl, or 3-buten-l-yl.
- a “lower alkynyl” is a linear or branched C 2-8 alkynyl. Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, l-methyl-2-propynyl, 1,3-butadiynyl, and 1,3-pentadiynyl. In some embodiments, the lower alkynyl is a 3,3-dimethylbutyn-l-yl.
- a “lower alkylene” is a linear or branched C 1-8 alkylene. Non-limiting examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, and
- a “lower alkenylene” is a linear or branched C 2-8 alkenylene.
- Non-limiting examples include vinylene, ethylidene, propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, and 1,3-pentadienylene.
- a “lower alkynylene” is a linear or branched C 2-8 alkynylene. Non-limiting examples include ethynylene, propynylene, butynylene, pentynylene, hexynylene, 1 ,3 -butadiynylene, and 1 ,3 -pentadiynylene.
- a "halogen” is F, Cl, Br, or I.
- halogeno lower alkyl is a C 1-8 alkyl substituted with one or more halogen atoms.
- the halogeno lower alkyl is a C 1-8 alkyl substituted with 1 to 5 halogen atoms, in other embodiments trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, and 4,4,4-trifluorobutyl, chloromethyl, and iodomethyl.
- a “cycloalkyl” is a C 3-10 saturated cyclic hydrocarbon group, which may be bridged. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl. In some embodiments, the cycloalkyl is a C 3-8 saturated cyclic hydrocarbon group.
- a "cycloalkenyl” is a C 4-15 cycloalkehyl, which may be bridged, and includes a cyclic group fused with a benzene ring at the double bond thereof.
- Non-limiting examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, 1-tetrahydronaphthyl, 1-indenyl, 9-fluorenyl.
- aryl is a C 6-14 mono- to tri-cyclic aromatic hydrocarbon group. In some embodiments, the aryl is a phenyl or naphthyl.
- a "heterocyclic” group is a cyclic group comprising (i) a monocyclic 3- to
- heterocycles may consist spiro compounds.
- a sulfur atom(s) or a nitrogen atom(s) constituting the ring may be oxidized to form oxide or dioxide.
- heterocyclic groups include the groups described below: (1) Monocyclic saturated heterocyclic groups i) containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, etc.; ii) containing 1 to 3 nitrogen atoms, and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, oxazepanyl, etc.; iii) containing 1 to 2 sulfur atoms, such as tetrahydrothiopyranyl, etc.; iv) containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, such
- Monocyclic unsaturated heterocyclic groups i) containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, dihydroimidazolyl, pyrazolyl, pyridyl, dihydropyridinyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl, etc.; ii) containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazinyl, etc.; iii) containing 1 to 2 sulfur atoms, such as
- Fused polycyclic saturated heterocyclic groups i) containing 1 to 5 nitrogen atoms such as decahydroquinolinyl, decahydroisoquinolinyl, quinuclidinyl, octahydro-2H-pyrido[l ,2- ⁇ ]pyrazinyl, octahydropyrrolo[l ,2- ⁇ ]pyrazinyl, 1 ,3,8-triazaspiro[4,5]decanyl, l-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl,
- Fused polycyclic unsaturated heterocyclic groups i) containing 1 to 5 nitrogen atoms such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl, tetrahydrobenzimidazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, tetrahydroisoquinolinyl, indazolyl, imidazopyridinyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinozalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazolyl, benzopyrimidinyl, naphthylidinyl, quinazolinyl, cinnolinyl, 6,7-d
- acyl includes the following acyl groups: (1) Aliphatic acyl groups, specifically -CHO, -CO-Io was alkyl, -CO-lower alkenyl, -CO-lower alkylene-O-lower alkyl, -CO-cycloalkyl, -CO-cycloalkenyl, etc.;
- a "protected carboxy” includes the following groups:
- Esterified carboxyl groups specifically -CO-O-lower alkyl, -CO-O-lower alkenyl, -CO-0-lower alkynyl, -CO-O-lower alkylene-O-lower alkyl, -CO-O-lower alkylene-aryl, -CO-O-lower alkylene-O-aryl, CO-O-CH(aryl) 2 , etc.;
- Optionally substituted means “unsubstituted” or “substituted.” When there are multiple substituents, they may be the same or different.
- suitable substituents include lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, lower alkenylene, lower alkynylene, halogen, halogeno lower alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic group, acyl, amino, oxa, oxo, sulfonyl, etc., and the combination of these substituents.
- Other embodiments of the compound (I) are as follows: (AA) The compound of Formula (I), wherein
- R 1 is -CHO, -CO-lower alkyl, cyano, -COOH or lower alkyl substituted with one or more
- R 2 is -COOH or -COO-lower alkyl
- -OCO-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl
- -OCO-piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a substituent selected from the group consisting of piperidyl and piperazinyl optionally substituted with a lower alkyl
- -OCO-piperazinyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of -OH, -0-lower alkylene-OH, amino optionally substituted with one or two lower alkyl(s), -SO 2 -phenyl, piperidyl optionally substituted with one or more lower alkyl(s), morpholinyl, phenyl, pyridyl and -CO-morpholinyl; phenyl optionally substituted with a morpholinyl optionally substituted with one or more lower alkyl(s), thiazolyl and pyrimidinyl; amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of cycloalkyl, piperidyl and pyridyl; cycloalkyl, 4,5
- -CO-amino optionally substituted with a lower alkyl, phenyl, piperidyl, and pyridyl; imidazolyl optionally substituted with one or more lower alkyl(s), furyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, benzimidazolyl optionally substituted with one or more lower alkyl(s), isoquinolyl, isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-2H-pyrido[l ,2- ⁇ ]pyrazinyl, octahydropyrrolo [ 1 ,2- ⁇ ]pyrazinyl, l,3,8-triazaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of phenyl and oxo; and
- Y is -CH 2 -, NH or O;
- R 12 and R 13 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of
- 1,2-benzisoxazolyl optionally substituted with one or more halogen(s), or
- l,4-dioxa-8-azaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consisting of -COOH, -COO-lower alkyl, and lower alkyl optionally substituted with a piperidyl; l-oxa-8-azaspiro[4,5]decanyl optionally substituted with one or more lower alkyl(s) optionally substituted with a morpholinyl; l-oxa-4,9-diazaspiro[5,5]undecanyl optionally substituted with one or more lower alkyl(s), and
- R 14 Is H, lower alkyl optionally substituted with a substituent selected from the group consisting of -OH, -0-lower alkyl, -O-SO 2 -lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of piperidyl, pyridyl and -0-lower alkyl;
- -OCO-piperazinyl optionally substituted with a lower alkyl, phenyl, heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, piperidyl, piperazinyl, diazepanyl and morpholinyl, each of which is optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl; halogen, methylidene, halogeno lower alkyl, lower alkenyl, -OH, oxo, -0-lower alkyl optionally substituted with a substituent selected from the group consisting of -0-lower alkyl and phenyl; -OCO-piperazinyl optionally substituted with a lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of -0-lower alkyl and pyr
- R 15 is H, lower alkyl, -OH, -O-lower alkyl or halogen;
- R 16 , R 17 , R 18 and R 19 are each lower alkyl;
- R 20 is amino optionally subsituted with one or two lower alkyl(s);
- A is lower alkylene;
- B is CH 2 , NH or O; p is an integer of O to 3; and q is an integer of 0 to 3, provided that p + q is an integer of 0 to 3;
- R 5 is H 3 lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of -CHO, -COOH, -COO-lower alkyl,
- -0-lower alkyl optionally substituted with one or more substiruent(s) selected from the group consisting of cycloalkyl, phenyl, and
- -CO-amino optionally substituted with one or two lower alkyl(s); -0-lower alkenyl, or cycloalkyl;
- R 8 , R 9 and R 11 are each lower alkyl harmaceutically acceptable salt thereof.
- (BB) The compound of Formula (I), wherein R 1 is -CHO;
- R 2 is -COOH
- R 4 is defined as above (AA);
- R 5 is lower alkyl optionally substituted with a cycloalkyl, halogeno lower alkyl, or cycloalkyl;
- R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.
- -OH 5 -0-lower alkyl amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of piperidyl, pyridyl and -O-lower alkyl; -OCO-piperazinyl optionally substituted with a lower alkyl, phenyl, heterocyclic group selected from the group consisting of pyridyl, pyrrolidinyl, piperidyl, piperazinyl, diazepanyl and morpholinyl, each of which is optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl; halogen, methylidene, halogeno lower alkyl, lower alkenyl, -OH, oxo, -O-lower alkyl optionally substituted with a substituent selected from the group consisting of -O-lower alkyl and phen
- R 5 is lower alkyl optionally substituted with a cycloalkyl, halogeno lower alkyl, or cycloalkyl;
- X is CH 2 ; and n is 0
- R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.
- R 1 is -CHO
- R 6 is H, lower alkyl optionally substituted with a substituent selected from the group consisting of
- R 8 , R 9 and R 11 are each lower alkyl, or a pharmaceutically acceptable salt thereof.
- R 7 is lower alkyl optionally substituted with a substituent selected from the group consisting of amino optionally substituted with one or two lower alkyl(s), tetrahydroisoquinolinyl, piperidyl optionally substituted with a piperidyl, and morpholinyl ] and
- R 8 , R 9 and R 11 are each lower alkyl or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention may have tautomers and geometric isomers, depending upon the type of substituents.
- the present invention encompasses these isomers and also includes isolated isomers or a mixture thereof.
- compounds of Formula (I) may have asymmetric carbon atom(s) or axial asymmetry, and thus optical isomers such as (R)- and (5)-isomers may be present.
- optical isomers such as (R)- and (5)-isomers may be present.
- the present invention includes all mixtures of those isomers, as well as each isolated isomer.
- the present invention further includes pharmaceutically acceptable prodrugs of compounds of Formula (I).
- Pharmacologically acceptable prodrugs are compounds having a group that can be converted to an amino group, OH, CHO, COOH, etc. of the present invention by solvo lysis or under a physiological condition. Examples of a group that forms a prodrug are the groups mentioned, for example, in Proc. Med. 5, 2157-2161 (1985) and
- the compound of the present invention may form an acid addition salt or may also form a salt with a base, depending on the type of substituent. These salts are also included in the present invention as long as they are pharmaceutically acceptable ones. Specific examples thereof are acid addition salts such as a salt with an inorganic acid, e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, and a salt with an organic acid, e.g.
- an inorganic base e.g. sodium, potassium, magnesium, calcium or aluminum
- organic base e.g. methylamine, ethylamine, ethanolamine, lysine or ornithine
- ammonium salt e.g. sodium, potassium, magnesium, calcium or aluminum
- the present invention also includes hydrates, solvates, and crystalline polymorphs of a compound of the present invention, as well as pharmaceutically acceptable salts thereof.
- the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
- the compound of the present invention and the pharmaceutically acceptable salt thereof, can be produced by applying various known synthetic methods, utilizing characteristics based on its basic skeleton or its type of substituents.
- an appropriate protective group a group that can be easily converted to said functional group
- Examples of such functional groups are amino group, OH, CHO, and COOH.
- These groups can be protected, for example, by the protective groups cited in "Protective Groups in Organic Synthesis (Third Edition, 1999)" by Greene and Wuts, which can be appropriately selected and used according to the reaction conditions. In this method, the protective group is removed if necessary after it has been introduced and the reaction carried out, in order to produce the desired compound.
- a prodrug of compound (I) may be manufactured by, as with the aforementioned protective group, introducing a specific group in the raw material-to-intermediate stage, or by causing a reaction using the resulting compound (I).
- the reaction may be carried out by applying methods known to persons skilled in the art, such as common esterification, amidation, or dehydration.
- R 1 is -CHO, -CO-lower alkyl, cyano, -COOH or lower alkyl substituted with one or more OH(s);
- R 2 is -COOH or -COO-lower alkyl
- lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of
- -0-lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of cycloalkyl, phenyl, and
- -CO-amino optionally substituted with one or two lower alkyl(s); -0-lower alkenyl, or cycloalkyl;
- R 8 , R 9 and R 11 are each lower alkyl;
- X is CHR 10 or O, wherein R 10 is H, lower alkyl, -COOH or -COO-lower alkyl;
- L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy); and n is an integer of O or 1 ; r is an integer of 1 to 8; R 101 R 102 NH is as follows: 1) R 101 and R 102 are each 1-I) H,
- -CO-piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl, -0-lower alkyl, -OH, -OCO-amino optionally substituted with one or two lower alkyl(s) optionally substituted with a piperidyl,
- -COO-lower alkyl optionally substituted with a phenyl, -CO-amino optionally substituted with a lower alkyl, phenyl, piperidyl, and pyridyl; imidazolyl optionally substituted with one or more lower alkyl(s), furyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, benzimidazolyl optionally substituted with one or more lower alkyl(s), isoquinolyl, isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-2H-pyrido[l,2- ⁇ 2] ⁇ yrazinyl, octahydropyrrolo[l ,2- ⁇ ]pyrazinyl, l,3,8-triazaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the
- Y is -CH 2 -, NH or O;
- R 12 and R 13 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of -OH, -O-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl, lower alkenyl, and phenyl optionally substituted with l one or more halogeno lower alkyl(s);
- -COO-lower alkyl -CO-pyrrolidinyl, -CONH-pyridyl, -SCVphenyl, phenyl, naphthyl, pyrrolidinyl optionally substituted with one or more lower alkyl(s), piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a -OH, morpholinyl, tetrahydrofuranyl, and pyridyl; lower alkenyl, halogeno lower alkyl, -OH, -O-lower alkyl, halogen, -COOH, -COO-lower alkyl,
- cycloalkyl optionally substituted with one or more lower alkyl(s)
- phenyl optionally substituted with one or more -OH(s)
- piperidyl optionally substituted with one or more alkyl(s)
- pyridyl pyrimidinyl
- 1,2-benzisoxazolyl optionally substituted with one or more halogen(s)
- 1,3-dihydrobenzimidazolyl optionally substituted with an oxo; and m is an integer of 0 to 3
- R 101 , R 102 , and NH are taken together to form a heterocyclic group selected from the group consisting of imidazolyl optionally substituted with a lower alkyl, 1,2,3,6-tetrahydropyridinyl optionally substituted with one or more substituent(s) selected from the group consisting of cyano, phenyl optionally substituted with an amino optionally substituted with one or two lower alkyl(s), imidazolyl optionally substituted with a lower alkyl, thiazolyl, thienyl, and pyridyl;
- R 101 R 102 N- is
- R 14 Is H, lower alkyl optionally substituted with a substituent selected from the group consisting of
- -CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl, -CO-morpholinyl, -CO-piperazinyl optionally substituted with a lower alkyl, cycloalkyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl and cycloalkyl; phenyl optionally substituted with one or more substituent(s) selected from the group consisting of halogen and morpholinyl optionally substituted with one or more lower alkyl(s); heterocyclic group selected from the group consisting of pyrrolidinyl, .piperidyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, azepanyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl and l,4-di
- R 15 is H, lower alkyl, -OH, -O-lower alkyl or halogen;
- R 16 , R 17 , R 18 and R 19 are each lower alkyl;
- R is amino optionally subsituted with one or two lower alkyl(s);
- B is CH 2 , NH or O; and p is an integer of 0 to 3, q is an integer of 0 to 3, provided that p + q is an integer of 0 to 3] .]
- Compound (Ia) of the present invention can be obtained by the reaction of compound (1) with amine (2).
- compound (1) and (2) are used in an equimolar amount or in an excessive amount for either of the compounds, and the mixture is stirred in a solvent inert under the reaction conditions, or without solvent, from cooling to reflux conditions, preferably 0°C to 80°C, and generally for 0.1 hours to 5 days.
- Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
- alcohols such as methanol, ethanol, and 2-propanol
- aromatic hydrocarbons such as benzene, toluene, and xylene
- ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane
- halogenated hydrocarbons such as dichlorome
- an organic base such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine
- an inorganic base such as potassium carbonate, sodium carbonate, and potassium hydroxide
- each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ia).
- Compound (Ib) of the present invention can be obtained by the reaction of compound (3) with amine (2) in a reaction condition similar to Method 1.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ib).
- Compound (Ic) of the present invention can be obtained by a cyclization of compound (4).
- compound (4) is stirred in a solvent inert under the reaction conditions, from cooling to reflux conditions, preferably room temperature, and generally for 0.1 hours to 5 days.
- solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxy ethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
- the reaction may be performed in the presence of an organic or inorganic acid (e.g. trifluoroacetic acid).
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ic).
- R 1 , R 2 , R 8 , R 9 , R 11 , X, and n are defined as Method 1;
- R 103 is lower alkyl
- L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy).]
- Compound (Id) of the present invention can be obtained by a cyclization of compound (5) followed by alkylation.
- compound (5) is stirred in the presence of an equimolar or an excessive amount of base in a solvent inert under the reaction conditions from cooling to reflux conditions, preferably 0°C to 8O 0 C, and generally for 0.1 hours to 5 days.
- Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1 ,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, water, and mixtures thereof.
- alcohols such as methanol, ethanol, and 2-propanol
- aromatic hydrocarbons such as benzene, toluene, and xylene
- ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1 ,2-dimethoxyethane
- the base examples include organic bases such as triethylamine, N,N-diisopropylethylamine, 1.8-diazabicyclo[5.4.0]-7-undecene, and n-butyllithium; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, and potassium tert-butoxide. It is sometimes advantageous to perform this reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride.
- organic bases such as triethylamine, N,N-diisopropylethylamine, 1.8-diazabicyclo[5.4.0]-7-undecene, and n-butyllithium
- inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, and potassium tert-butoxide. It is sometimes advantageous to perform this reaction in the presence of a phase transfer catalyst such as tetra-n-but
- the intermediate (6) and compound (7) are used in an equimolar amount or in an excessive amount for either of the compounds, and the mixture is stirred in a reaction condition similar to the first step.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Id).
- R 1 , R 2 , R 8 , R 9 , and R 11 are defined as Method 1;
- L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy).]
- Compound (Ie) of the present invention can be obtained from compound (8) in a reaction condition similar to Method 4.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ie).
- R 1 , R 2 , R 5 , R 8 , R 9 , R 11 , X, and n are defined as Method 1;
- R 104 Is lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of -OH,
- Compound (If) of the present invention can be obtained by the hydrogenation of compound (9).
- compound (9) is stirred in the presence of a metal catalyst under a hydrogen atmosphere in a solvent inert under the reaction conditions, and generally for 1 hour to 5 days.
- This reaction is conducted generally from cooling to heating conditions, preferably room temperature.
- the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, acetic acid, water, ethyl acetate, N,N-dimethylformamide, ,and mixtures thereof.
- the metal catalyst there may be suitably used palladium catalysts such as palladium-carbon, palladium black, palladium hydroxide; platinum catalysts such as platinum plate and platinum oxide; nickel catalysts such as reduced nickel and Raney nickel; rhodium catalysts such as chlorotris(triphenylphosphine)rhodium(I); iron catalysts such as reduced iron; and the like.
- palladium catalysts such as palladium-carbon, palladium black, palladium hydroxide
- platinum catalysts such as platinum plate and platinum oxide
- nickel catalysts such as reduced nickel and Raney nickel
- rhodium catalysts such as chlorotris(triphenylphosphine)rhodium(I)
- iron catalysts such as reduced iron
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (If).
- R 1 , R 2 , R 5 , R 8 , R 9 , R 11 , X, n, and r are defined as Method 1; L 1 is halogen.
- Compound (Ig) of the present invention can be obtained from compound (1) in a reaction condition similar to Method 6.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ig).
- Compound (Ij) of the present invention can be obtained by the reduction of compound (Ih).
- compound (Ih) is treated with an equimolar or excessive amount of a reducing agent in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -2O 0 C to 8O 0 C, and generally for 0.1- hours to 3 days.
- Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1 ,2-dimethoxyethane, alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, N,N-dimethylformarnide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof.
- hydride reducing agents such as sodium borohydride and diisobutylaluminum hydride
- metal reducing agents such as sodium, zinc, and iron.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ij).
- Compound (Ik) of the present invention can be obtained by the oxidation of compound (Ih) .
- compound (Ih) is treated with an equimolar or excessive amount of an oxidizing agent in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -20 0 C to 8O 0 C, and generally for 0.1 hours to 3 days.
- Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, water, and mixtures thereof.
- ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane
- halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform
- aromatic hydrocarbons such as benzene, toluene, and xylene, N,N-dimethylformamide, dimethyl sulfoxide, ethyl
- oxidizing agent there are suitably used, for example, hydrogen peroxide, cumene hydroperoxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, oxone, activated manganese dioxide, chromic acid, potassium permanganate, sodium periodide, sodium chlorite, and Dess-Martin reagent.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ik).
- R 2j is COOH
- R 5 , R 8 , R 9 , R 11 , R 101 , R 102 , X, n, and r are defined as Method 1;
- R 105 is lower alkyl;
- M is a metal which is used in organometallic reaction (e.g. lithium, magnesium, zinc).
- Compound (Im) of the present invention can be obtained by the reaction of compound (Ih) and (10).
- compound (Ih) is treated with an equimolar or excessive amount of compound (10) in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -20°C to 80°C, and generally for 0.1 hours to 3 days.
- a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -20°C to 80°C, and generally for 0.1 hours to 3 days.
- the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and mixtures thereof.
- the compound (10) may be previously prepared or generated in situ.
- each protective group of R may be removed during the reaction, or those on the product can be deprotected to produce the compound (Im).
- R 2k is COOH
- R 5 , R 8 , R 9 , R 11 , R 101 , R 102 , X, n, and r are defined as Method 1;
- R 105 is defined as Method 10.
- Compound (In) of the present invention can be obtained from compound (Im) in a reaction condition similar to Method 9.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (In).
- R 1 , R 2 ,R 5 , R 8 , R 9 , R 11 , X, and n are defined as Method 1;
- R 106 is lower alkyl;
- s is an integer of 1 to 8;
- L 2 is a leaving group (e.g. methanesulfonyloxy, p-toluenesulfonyloxy);
- R i07 R i08 NH is as follows .
- R 107 and R 108 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of cycloalkyl, piperidyl and pyridyl; cycloalkyl, 4,5-dihydroimidazolyl, pyridyl, and quinuclidinyl; or
- R 107 , R 108 , and NH are taken together to form a heterocyclic group selected from the group consisting of piperidin-2-yl optionally substituted with one or more lower alkyl(s), pyrrolidin-2-yl optionally substituted with one or more lower alkyl(s), pyridyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with a substituent selected from the group consisting of
- -OH -0-lower alkyl, amino optionally substituted with one or two lower alkyl(s) optionally substituted with one or two substituent(s) selected from the group consisting of phenyl and pyridyl; piperidyl, and morpholinyl; halogen, -0-lower alkyl, amino optionally substituted with one or two substituent(s) selected from the group consisting of lower alkyl and -CO-lower alkyl; -COOH,
- -COO-lower alkyl optionally substituted with a phenyl, -CO-amino optionally substituted with a lower alkyl, phenyl, piperidyl, and pyridyl; imidazolyl optionally substituted with one or more lower alkyl(s), furyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl, benzimidazolyl optionally substituted with one or more lower alkyl(s), isoquinolyl, isoindolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-2H-pyrido[l,2- ⁇ ]pyrazinyl, octahydropyrrolo[l ,2- ⁇ ]pyrazinyl, l,3,8-triazaspiro[4,5]decanyl optionally substituted with one or more substituent(s) selected from the group consist
- Y is -CH 2 -, NH or O;
- R 12 and R 13 are each H, lower alkyl optionally substituted with a substituent selected from the group consisting of
- -COOH, -COO-lower alkyl, -CO-amino optionally substituted with one or two lower alkyl(s), -S ⁇ 2 -lower alkyl, cycloalkyl optionally substituted with one or more lower alkyl(s), phenyl optionally substituted with one or more -OH(s), piperidyl optionally substituted with one or more alkyl(s), pyridyl, pyrimidinyl,
- 1,2-benzisoxazolyl optionally substituted with one or more halogen(s), or
- Compound (Ir) of the present invention can be obtained by the conversion of hydroxy group in compound (Ip) into a leaving group, followed by a reaction with amine (11).
- compound (Ip) is treated with an equimolar or excessive amount of a sulfonylating reagent under the reaction conditions similar to Method 1.
- a sulfonylating reagent include methanesulfonyl chloride and p-toluenesulfonyl chloride.
- compound (Ir) of the present invention can be obtained by a reaction of compound (Iq) and amine (11) in a reaction condition similar to Method 1.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Ir).
- R 1 , R 2 ,R 5 , R 8 , R 9 , R 11 , X, n, and r are defined as Method 1 ;
- R 109 R 110 NH is as follows:
- R 109 and R 110 are each H or lower alkyl optionally substituted with a piperidyl; or
- R 109 , R 110 , and NH are taken together to form a heterocyclic group selected from the group consisting of piperidyl optionally substituted with a piperidyl, and piperazinyl optionally substituted with one or more lower alkyl(s) optionally substituted with a piperidyl;
- L 3 is a leaving group comprising halogen, imidazolyl, phenoxy, or 4-nitrophenoxy.
- the first step is performed by reacting compound (Is) with an equimolar or excessive amount of a carbonylating reagent, in a solvent inert under the reaction conditions, in the presence of a base from cooling to heating conditions, preferably -20°C to 80°C, and generally for 0.1 hours to approximately 1 day.
- an equimolar or excessive amount of amine (12) for compound (It) is added to the reaction mixture of first step, and the mixture is allowed to be reacted under cooling to heating conditions, preferably -20°C to 80 0 C, and generally for 0.1 hours to approximately 1 day.
- Non-limiting examples of the solvent used here include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
- halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform
- aromatic hydrocarbons such as benzene, toluene, and xylene
- ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide,
- Examples of the carbonylating reagent include diphosgene, triphosgene, l,l'-carbonyldiimidazole, 4-nitrophenyl chloroformate, and phenyl chloroformate.
- the compound (It) may be isolated for the subsequent reaction after the first step.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Iu).
- R 1 , R 2 ,R 5 , R 8 , R 9 , R 11 , X, and n are defined as Method 1 ;
- R 106 and s are defined as Method 12;
- L 3 is defined as Method 13;
- R 111 R 112 NH is as follows:
- R 111 and R 112 are each H or lower alkyl optionally substituted with a piperidyl; or
- R 111 , R 112 , and NH are taken together to form a heterocyclic group selected from the group consisting of piperidyl optionally substituted with one or more lower alkyl(s) optionally substituted with a substituent selected from the group consisting of piperidyl and piperazinyl optionally substituted with a lower alkyl; piperazinyl optionally substituted with one or more substituent(s) selected from the group consisting of lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of
- Compound (Iv) of the present invention can be obtained from compound (Ip) in a reaction condition similar to Method 13.
- the each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Iv).
- R 1 , R 2 , R 8 , R 9 , and R 11 are defined as Method 1; R 6a is H or lower alkyl.
- Compound (Iw) of the present invention can be obtained by a cyclization of compound (15).
- compound (15) is treated with an equimolar or excessive amount of an acid or a dehydrating agent in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably 0°C to 80°C, and generally for 0.1 hours to 3 days.
- a solvent inert equimolar or excessive amount of an acid or a dehydrating agent in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably 0°C to 80°C, and generally for 0.1 hours to 3 days.
- the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, and mixtures thereof.
- acids such as sulfuric acid, phosphoric acid, p-toluenesulfonic acid.
- dehydrating agent there may be suitably used phosphorus pentoxide, phosphorus pentasulfide.
- each protective group may be removed during the reaction, or those on the product can be deprotected to produce the compound (Iw).
- R 1 , R 2 , R 8 , R 9 , and R 11 are defined as Method 1;
- R 6b is an aminomethyl group optionally substituted with one or two lower alkyl(s),
- Compound (Iy) of the present invention can be obtained by electrophilic substitution reaction of compound (Ix).
- electrophilic substitution reaction examples include the Friedel-Crafts reaction, the Vilsmeier reaction, and aminomethylation described in References below.
- R lq is cyano, or protected aldehyde;
- R 5 is H, lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of
- -CO-amino optionally substituted with one or two lower alkyl(s), -CO-piperidyl, -O-lower alkyl, -O-phenyl, cycloalkyl, phenyl, piperidyl and morpholinyl; lower alkenyl optionally substituted with a -COO-lower alkyl, halogeno lower alkyl,
- -O-lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of cycloalkyl, phenyl, and
- -CO-amino optionally substituted with one or two lower alkyl(s); -O-lower alkenyl, or cycloalkyl;
- R 8 , R 9 and R 11 are each lower alkyl;
- X is CHR 10 , wherein R 10 is H or lower alkyl;
- R 113 is lower alkyl optionally substituted with one or more substituent(s) selected from the group consisting of cycloalkyl, phenyl, and -CO-amino optionally substituted with one or two lower alkyl(s); or
- n is an integer of 0 or 1 ;
- PG 1 and PG 2 are each carboxylic acid protective group (e.g. lower alkyl, benzyl, diphenylmethyl) ;
- PG 3 is hydroxy protective group (e.g. trimethlsilyl, tert-butyldimethylsilyl);
- L is a leaving group (e.g. halogen, methanesulfonyloxy, p-toluenesulfonyloxy);
- L 1 and Z are each halogen
- M is a metal which is used in organometallic reaction (e.g. lithium, magnesium, zinc).
- Reaction Scheme 1 shows the synthesis of intermediate compounds (Ia), (Ib), (Ic), (4), (5), and (8).
- Treatment of known compound (16) with compound (17) can give compound (18) (Method A), which can be subjected to halocyclization to afford compound (Ia) (Method B).
- Epoxidation of compound (18) can give compound (4) (Method C).
- Compound (Ib) can be prepared in a similar manner to by treatment of compound (16) with compound (19) followed by halocyclization (Method D, B). Exocyclic ether bond can be introduced selectively before halocyclization (Method E, B).
- Compound (5) is a starting material for Manufacturing Method 4, whose preparation can be carried out in a similar manner to that of compound (4) (Method A, C).
- Compound (8) is a starting material for Manufacturing Method 5, whose preparation can be carried out in a similar manner by treatment of compound (16) with compound (25) followed by deprotection and conversion to a leaving group (Method A, F).
- the staring compound is treated with an equimolar or excessive amount of a halogenating agent and a base in a solvent inert under the reaction conditions, from cooling to reflux conditions, preferably room temperature, and generally for 0.1 hours to 5 days.
- Non-limiting examples of the solvent used here include alcohols such as methanol, ethanol, and 2-propanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, and chloroform, water, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, and mixtures thereof.
- alcohols such as methanol, ethanol, and 2-propanol
- aromatic hydrocarbons such as benzene, toluene, and xylene
- ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane
- halogenated hydrocarbons such
- halogenating agent there may be suitably used halogens such as iodine, fluorine, chlorine, and bromine, phosphorus trihalides such as phosphorus tribromide and phosphorus trichloride, phosphorus pentahalides such as phosphorus pentachloride and phosphorus pentabromide, phosphoryl chloride, thionyl halides such as thionyl chloride and thionyl bromide, N-halogenosuccinimide such as N-bromosuccinimide, N-chlorosuccinimide and N-iodosuccinimide.
- phosphorus trihalides such as phosphorus tribromide and phosphorus trichloride
- phosphorus pentahalides such as phosphorus pentachloride and phosphorus pentabromide
- phosphoryl chloride thionyl halides such as thionyl chloride and thionyl bromide
- inorganic base such as (sodium or potassium) alkoxide, hydroxide, carbonate, and bicarbonate
- organic base such as triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine.
- R lq , R 8 , R 9 , R 11 , PG 1 , and n are defined as Reaction Scheme 1;
- R 5 and X are defined as Manufacturing Method 1 ;
- R , 104 is defined as Manufacturing Method 6.
- Reaction Scheme 2 illustrates the synthesis of intermediate compound (9aa).
- Compound (Iaa) can be subjected to oxidation (Method G), followed by Wittig-type reaction
- alkyl(triphenyl)phosphonium halide is treated with a strong base such as potassium tert-butoxide, potassium or sodium bis(trimethylsilyl)amide, n-butyllithium, or sodium hydride.
- a strong base such as potassium tert-butoxide, potassium or sodium bis(trimethylsilyl)amide, n-butyllithium, or sodium hydride.
- the aldehyde is added and the reaction mixture is stirred at room temperature for about 4 to 48 hours in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -20 0 C to 80°C, generally for 0.1 hours to 3 days.
- alkylphosphonates are used instead of alkyl(triphenyl)phosphonium halides, preferably alkyl (dialkoxyphosphoryl)acetates.
- Non-limiting examples of the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, dimethyl sulfoxide, acetonitrile, and mixtures thereof.
- ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane
- aromatic hydrocarbons such as benzene, toluene, and xylene
- dimethyl sulfoxide dimethyl sulfoxide
- acetonitrile and mixtures thereof.
- R lq , R 8 , R 9 , R 11 , PG 1 , L, L 1 , M 5 and Z are defined as Reaction Scheme 1 ;
- R 5s is lower alkyl, lower alkenyl, halogeno lower alkyl, or cycloalkyl, each of which is optionally substituted with one or more substituent(s) selected from the group consisting of
- Reaction Scheme 3 shows a stereoselective synthesis of intermediate compound (Id).
- An optically active monocrotonated binaphthol (27) can be alkylated stereoselective ⁇ to give compound (29).
- Reductive cleavage of the chiral auxiliary can give a chiral alcohol (30) which can be transformed to a halide (31) by conventional methods.
- the halide (31) can be subjected to the reaction with compound (16) (Method A described above), then the halocyclization can afford compound (Id) as a diastereomixture (Method B described above).
- the desired stereoisomer can be obtained by precipitaion.
- the diastereoisomers with opposite stereochemistry at R 5s can be obtained in a similar manner by using chiral auxiliary of opposite absolute stereochemistry.
- the monocrotonated binaphthol is treated with an equimolar or excessive amount of strong base in a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -2O 0 C to 8O 0 C, and generally for 0.1 hours to 3 days followed by addition of compound (28).
- a solvent inert under the reaction conditions, from cooling to heating conditions, preferably -2O 0 C to 8O 0 C, and generally for 0.1 hours to 3 days followed by addition of compound (28).
- the solvent used here include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and mixtures thereof.
- the strong base include lithium diisopropylamide, sodium hexamethyldisilazide, organomagnesium, organolithium, and organozinc.
- Compounds of the present invention are isolated and purified as a free compound or as a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorphorous substance thereof.
- Pharmaceutically acceptable salts of compounds of Formula (I) of the present invention can be produced by subjecting the compound to a general salt-formation reaction.
- Isolation and purification can be carried out by applying general chemical operations such as extraction, fractional crystallization, and various fractional chromatographic techniques.
- isomers can be prepared by selecting an appropriate raw material or can be separated by using the difference in physicochemical properties among the isomers.
- an optical isomer can be isolated by a general optical resolution (for example, fractional crystallization or chromatography using a chiral column). It is also possible to start from an appropriate optically active compound.
- mice serum The MICs in mouse serum were determined by the microdilution method using
- Inoculum suspension of 10 6 cells/mL were prepared by a hemocytometric procedure and diluted to obtain an inoculum size of approximately 1.0 x 10 3 cells/mL.
- Microplates were incubated at 37 0 C for 24 hours in 5% CO 2 . The MICs were defined as the lowest concentrations at which no visible growth was observed. Representative results are shown in Table 1.
- the compounds of the present invention have antimicrobial activity (especially, antifungal activity).
- the antifungal activity particularly against the following fungi, can be confirmed by the method described above and in vivo animal model.
- Absidia e.g. Absidia corymbifera, etc.
- Aspergillus e.g. Aspergillus cl ⁇ vatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, etc.
- Absidia e.g. Absidia corymbifera, etc.
- Aspergillus e.g. Aspergillus cl ⁇ vatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, etc.
- Blastomyces e.g. Blastomyces dermatitidis, etc.
- Candida e.g. Candida albicans, Candida glabrata, Candida guilliermondii, Candida kejyr,
- Cladosporium e.g. Cladosporium trichloides, etc.
- Coccidioides e.g. Coccidioides immitis, etc.
- Cryptococcus e.g. Cryptococcus neoformans, etc.
- Cunninghamella e.g. Cunninghamella elegans, etc.
- Exophiala e.g. Exophiala dermatitidis, Exophiala spinifera, etc.
- Epidermophyton e.g. Epidermophytonfloccosum, etc.
- Fonsecaea e.g. Fonsecaea pedrosoi, etc.
- Fusarium e.g. Fusarium solani, etc.
- Geotrichum e.g. Geotrichum candiddum, etc.
- Histoplasma e.g. Histoplasma capsulatum var. capsulatum, etc.
- Malassezia e.g. Malassezia furfur, etc.
- Microsporum e.g. Microsporum canis, Microsporum gypseum, etc.
- Paracoccidioides e.g. Paracoccidioides brasiliensis, etc.
- Penicillium e.g. Penicillium marneffei, etc.
- Phialophora Pneumocystis (e.g. Pneumocystis jiroveci, etc.);
- Pseudallescheria e.g. Pseudallescheria boydii, etc.
- Rhizopus e.g. Rhizopus microsporus var. rhizopodiformis, Rhizopus oryzae, etc.
- Saccharomyces e.g. Saccharomyces cerevisiae, etc.
- Scopulariopsis e.g. Sporothrix schenckii, etc.
- Trichophyton e.g. Trichophyton mentagrophytes, Trichophyton rubrum, etc.
- Trichosporon e.g. Trichosporon asahii, Trichosporon cutaneum, etc.
- the above fungi are well-known to cause various infection diseases in skin, eye, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung, endocardium, brain, meninges, urinary organ, vaginal portion, oral cavity, ophthalmus, systemic, kidney, heart, external auditory canal, bone, nasal cavity, paranasal cavity, spleen, liver, hypodermal tissue, lymph duct, gastrointestine, articulation, muscle, tendon, interstitial plasma cell in lung, blood, and so on.
- the compounds of the present invention are used for preventing and treating various infectious diseases in a human being or an animal, such as dermatophytosis (e.g. trichophytosis, etc.), pityriasis versicolor, candidiasis, cryptococcosis, geotrichosis, trichosporosis, aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis, chromomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotic keratitis, otomycosis, Pneumocystis pneumonia, fungemia, and so on.
- dermatophytosis e.g. trichophytosis, etc.
- pityriasis versicolor
- the compounds of the present invention can be used in combination with various preventive or therapeutic medicaments such as azoles (e.g. fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, posaconazole, ER 30346), polyenes (e.g. amphotericin B, nystatin), liposomal and lipid forms thereof (e.g. Abelcet, AmBisome,
- azoles e.g. fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, posaconazole, ER 30346
- polyenes e.g. amphotericin B, nystatin
- liposomal and lipid forms thereof e.g. Abelcet, AmBisome
- Amphocil purine or pyrimidine nucleotide inhibitors (e.g. flucytosine), polyoxins (e.g. nikkomycines, in particular nikkomycine Z or nikkomycine X), other chitin inhibitors; mannan inhibitors (e.g. predamycin), bactericidal/permeability-inducing (BPI) protein products (e.g. XMP.97, XMP.127), or complex carbohydrate antifungal agents (e.g. CAN-296).
- nucleotide inhibitors e.g. flucytosine
- polyoxins e.g. nikkomycines, in particular nikkomycine Z or nikkomycine X
- other chitin inhibitors e.g. mannan inhibitors (e.g. predamycin), bactericidal/permeability-inducing (BPI) protein products (e.g. XMP.97, XMP.127),
- the pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular; external (topical); oral administration; parenteral (including subcutaneous, intravenous and intramuscular) administrations; insufflation (including aerosols from metered dose inhalator); nebulizer; or dry powder inhalator.
- a pharmaceutical preparation for example, in solid, semisolid or liquid form, which contains a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular; external (topical); oral administration; parenteral (including subcutaneous, intrave
- the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsules, or suppositories; creams; ointments; aerosols; powders for insufflation; in a liquid form such as solutions, emulsions, or suspensions for injection; ingestion; eye drops; and any other form suitable for use. And, if necessary, there may be included in the above preparation auxiliary substance such as stabilizing, thickening, wetting, emulsifying and coloring agents; perfumes or buffer; or any other commonly may be used as additives.
- auxiliary substance such as stabilizing, thickening, wetting, emulsifying and coloring agents; perfumes or buffer; or any other commonly may be used as additives.
- a compound of Formula (I) or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired antimicrobial effect upon the process or condition of diseases.
- intravenous, intramuscular, pulmonary, oral administration, eye drop administration or insufflation there are intravenous, intramuscular, pulmonary, oral administration, eye drop administration or insufflation.
- a daily dose of 0.01-400 mg of the compound of Formula (I) per kg weight of human being in the case of intramuscular administration, a daily dose of 0.1-20 mg of the compound of Formula (I) per kg weight of human being, in case of oral administration, a daily dose of 0.5-50 mg of the compound of Formula (I) per kg weight of human being is generally given for treating or preventing infectious diseases.
- the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation form pressurized as powders which may be formulated and the powder compositions may be inhaled with the aid of an insufflation powder inhaler device.
- the preferred delivery system for inhalation is a metered dose inhalation aerosol, which may be formulated as a suspension or solution of compound in suitable propellants such as fluorocarbons or hydrocarbons.
- aerosol administration is a preferred method of administration. Insufflation is also a desirable method, especially where infection may have spread to ears and other body cavities. Alternatively, parenteral administration may be employed using drip intravenous administration.
- the preferred pharmaceutical composition is the lyophilized form containing the compound of Formula (I) or its pharmaceutically acceptable salt.
- the amount of the compound of Formula (I) or its pharmaceutically acceptable salt contained in the composition for a single unit dosage of the present invention is 0.1 to 400 mg, more preferably 1 to 200 mg, still more preferably 5 to 100 mg, specifically 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100 mg.
- Preparation 58 A suspension of the compound of Preparation 57 in Table 3 (130 mg), hydroxylamine hydrochloride (168 mg) and sodium hydrogen carbonate in EtOH (2 mL) was stirred at 60 Deg for 4 hrs and diluted with AcOEt. The mixture was washed with water (3 times), saturated aqueous ammonium chloride, and brine. The organic layer was dried over magnesium sulfate and concentrated to give the compound of Preparation 58 in Table 3 (145 mg).
- the mixture was poured into saturated aqueous ammonium chloride and extracted with DCM.
- Preparation 70 A mixture of palladium(II) chloride (14.9 mg) and copper(I) chloride (99.9 mg) in DMF (5 mL) and water (0.5 mL) was stirred for 1 hr under oxygen. To this mixture was added a solution of the compound of Preparation 69 in Table 3 (500 mg) in DMF (5 mL) and water (0.5 mL), and the mixture was stirred for 3 hrs under oxygen. The reaction mixture was diluted with AcOEt and water, and filtered through celite pad. The filtrate was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 70 in Table 3 (350 mg).
- Preparation 78 A b solution of the compound of Preparation 73 in Table 3 (100 mg) in piperidine (1.0 mL) was stirred at 60 Deg for 5 hrs. The mixture was diluted with AcOEt, washed with water (x 3) and brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 2 plates, acetone) to give the compound of Preparation 78 in Table 3 (56.0 mg).
- Preparation 82 Phosphoryl chloride (0.0116 mL) was added dropwise to DMF (0.2 mL) at 0 Deg, and the mixture was stirred at the temperature for 30 Min. To the mixture was added a solution of the compound of Preparation 81 in Table 3 (25 mg) in DMF (0.3 mL) at 0 Deg, and the mixture was stirred at the temperature for 1 hr. The mixture was diluted with AcOEt, and washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 20% AcOEt in hexane) to give the compound of Preparation 82 in Table 3 (20 mg).
- N-ethylquinuclidin-3 -amine hydrochloride was obtained from 3-quinuclidinone hydrochloride and ethylamine by the platinum dioxide-catalyzed reductive animation.
- N-ethylquinuclidin-3 -amine hydrochloride (2.00 g) in DMF (40 mL) was added triethylamine (1.75 mL) at 55 Deg, and the mixture was allowed to cool to room temperature for 8 hrs. The mixture was extracted with chloroform / MeOH (4 / 1). The extract was washed with brine, dried over magnesium sulfate, and concentrated to give N-ethylquinuclidin-3 -amine (2.00 g).
- 2-(Isobutylamino)ethanol was obtained from 2-methylpropanal and 2-aminoethanol by the platinum dioxide-catalyzed reductive amination.
- Benzyl (2-hydroxyethyl)methylcarbamate was obtained from 2-(methylamino)ethanol and benzyloxycarbonyl chloride.
- : )-2,6-dimethylmorpholin-4-yl]ethyl]ethylcarbamate was obtained from 2-[[(benzyloxy)carbonyl](ethyl)amino]ethyl methanesulfonate and cis-2,6- dimethylmorpholine.
- 2,2-Dimethyl-N-(2-piperidin-l-ylethyl)propan ⁇ l -amine was obtained from pivalaldehyde and 2-(l-piperidinyl)ethylamine by the platinum dioxide-catalyzed reductive amination.
- Benzyl cyclopropyl(2-piperidin-l-ylethyl)carbamate was obtained from N-(2-piperidin- 1 -ylethyl)cyclopropanamine and benzyloxycarbonyl chloride.
- N-methyl-2-piperidin-l-ylethanamine was obtained from benzyl methyl(2-piperidin-l-ylethyl)carbamate by catalytic hydrogenation.
- Benzyl isobutyl[2-(l-methylpiperidin-2-yl)ethyl]carbamate was obtained from 2-methyl-N-[2-(l-methylpiperidin-2-yl)ethyl]propan-l -amine and benzyloxycarbonyl chloride.
- N,N-dimethyl-N'-(2-piperidin-l-ylethyl)ethane-l,2-diamine was obtained by the reduction of N-[2-(dimethylamino)ethyl]-2-piperidin-l-ylacetamide with lithium aluminum hydride.
- 2-Piperidin-l-ylethyl methanesulfonate was obtained from 1-piperidineethanol and methanesulfonyl chloride.
- N-(2-piperidin-l-ylethyl)butanamide was obtained from 2-(l-piperidyl)ethylamine and butanoyl chloride.
- N-(2-piperidin-l-ylethyl)butan-l -amine was obtained by the reduction of N-(2-piperidin-l-ylethyl)butanamide with lithium aluminum hydride.
- N-ethyl-3-piperidin-l-ylpropan-l -amine was obtained from l-(3-chloropropyl)- piperidine and ethylamine hydrochloride.
- Benzyl (3-hydroxypropyl)carbamate was obtained from 3-amino-l-propanol and benzyl chlorocarbonate.
- N-methyl-l-(l-methyl-lH-imidazol-4-yl)methanamine was obtained from 1 -methyl- lH-imidazole-4 ⁇ carboxaldehyde and methylamine by the palladium on carbon-catalyzed reductive animation.
- 2-Piperidin-l-yl-N-(2-piperidin-l-ylethyl)ethanamine was obtained by the reduction of 2-piperidin-l-yl-N-(2-piperidin-l-ylethyl)acetamide with lithium aluminum hydride.
- Benzyl 4-[2-[(methylsulfonyl)oxy]ethyl]piperazine- 1-carboxylate was obtained from benzyl 4-(2-hydroxyethyi)piperazine- 1-carboxylate and methanesulfonyl chloride.
- Benzyl 2-methyl-4-octylpiperazine- 1-carboxylate was obtained from benzyl 2-methylpiperazine- 1-carboxylate and 1-bromooctane.
- Benzyl 3-(hydroxymethyl)piperidine-l-carboxylate was obtained from piperidin-3-ylmethanol and benzyl chlorocarbonate.
- Benzyl 2-(piperidin-l-ylcarbonyl)piperidine-l-carboxylate was obtained from l-(benzyloxycarbonyl)piperidine-2-carboxylic acid and piperidine.
- Preparation 135 l-(Piperidin-2-ylcarbonyl)piperidine was obtained from benzyl 2-(piperidin- l-ylcarbonyl)piperidine-l-carboxylate by catalytic hydrogenation.
- 1,3 '-Bipiperidine was obtained from l'-benzyl- 1,3 '-bipiperidine by catalytic hydrogenation.
- Preparation 140 l-[(3S)-l-benzylpyrrolidin-3-yl]piperidine was obtained from (3i?)-l- benzylpyrrolidin-3 -yl methanesulfonate and piperidine .
- Benzyl (25)-2-(hydroxymethyl)piperidine-l-carboxylate was obtained by the reduction of (25)-l-[(benzyloxy)carbonyl]piperidine-2-carboxylic acid with borane - THF complex.
- Piperidin-4-yl 4-methylpiperazine-l-carboxylate was obtained from l-[(benzyloxy)carbonyl]piperidin-4-yl 4-methylpiperazine-l-carboxylate by catalytic hydrogenation.
- 4-Isobutyl-4-methoxypiperidine trifluoroacetate was obtained by the treatment of tert-butyl 4-isobutyl-4-methoxypiperidine- 1 -carboxylate with trifluoroacetic acid.
- Benzyl 4-[(2i?*,65'*)-2,6-dimethylmorpholin-4-yl]piperidine-l -carboxylate was obtained from benzyl 4-oxopiperidine-l -carboxylate and cis-2,6- dimethylmorpholine by the reductive animation using sodium cyanoborohydride.
- Preparation 150 To 4-isobutyl-4-methoxypiperidine trifluoroacetate (500 mg) were added 1.0 M hydrochloric acid and AcOEt. The layers were separated, and to the aqueous layer were added 1.0 M aqueous sodium hydroxide and diethyl ether. The layers were separated, and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave 4-isobutyl-4-methoxypiperidine (83.6 mg).
- Benzyl 4-morpholin-4-ylpiperidine-l-carboxylate was obtained from benzyl 4-oxopiperidine-l-carboxylate and morpholine by the reductive animation using titanium tetraisopropoxide.
- 4-Piperidin-4-ylmorpholine was obtained from benzyl 4-morpholin-4-ylpiperidine- 1-carboxylate by catalytic hydrogenation.
- Benzyl 2-(chloromethyl)-l ,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate was obtained from benzyl 4-oxopiperidine-l-carboxylate and 3-chloro-l,2-propanediol.
- Benzyl 2-(piperidin-l-ylmethyl)-l ,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate was obtained from benzyl 2-(chloromethyl)-l,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate and piperidine.
- Example 4 To a solution of the compound of Example 322 in Table 5 (7.5 mg) in THF (0.2 mL) and EtOH (0.1 mL) was added IM aqueous sodium hydroxide (0.1 mL). The mixture was stirred at room temperature for 2 hrs. The mixture was diluted with MeOH (2.6 mL) and purified by HPLC (Cl 8, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated and diluted with AcOEt, washed with saturated sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 4 in Table 5 (7.0 mg).
- Example 9 To a solution of the compound of Example 7 in Table 5 (30 mg) in DCM (0.3 mL) was added Dess-Martin periodinane (57 mg) at room temperature, and the mixture was stirred for 1 hr at the temperature. After the mixture was filtered, the filtrate was diluted with AcOEt, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by HPLC (C 18, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, and the residue was diluted with AcOEt. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 8 in Table 5 (7.6 mg).
- Example 9 To a solution of the compound of Example 7 in Table 5 (30 mg) in DCM (0.3 mL) was added Dess-Martin periodinane (57 mg) at room temperature,
- Example 11 To a solution of the compound of Example 501 in Table 5 (10 mg) in MeOH (1 mL) was added palladium hydroxide on carbon (0.25 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs, filtered, and concentrated in vacuo. The residue was purified by HPLC (C 18, 20-100% acetonitrile in water (+0.2% formic acid)). The desired fraction was concentrated, and the residue was redissolved with AcOEt. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 11 in Table 5 (10 mg).
- Example 13 To a solution of the compound of Preparation 244 in Table 3 (50 mg) in MeOH (3 niL) and AcOEt (1 mL) was added palladium hydroxide on carbon (5 mg). The mixture was stirred under hydrogen atmosphere at room temperature for 10 hrs, filtered, and concentrated in vacuo. The residue was purified by TLC (silica gel, 10% AcOEt in hexane). The desired fraction was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated to give the compound of Example 13 in Table 5 (18.1 mg).
- Example 26 To a solution of the compound of Preparation 70 in Table 3 (150 mg) and anisole (0.1 mL) and THF (2 mL) was added phosphorus pentasulfide (109 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added IM aqueous sodium hydroxide, and the mixture was stirred for 1 hr and extracted with AcOEt. The organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate, and brine, dried over magnesium sulfate, and concentrated. The residue was purified with preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 33% EtOAc in hexane) to give the compound of Example 26 in Table 5 (8.9 mg).
- Example 27 To a solution of the compound of Preparation 66 in Table 3 (60 mg) in DMF (1 mL) was added sodium hydride (8 mg), and the mixture was stirred at 60 Deg for 1 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and the residue was redissolved in DMF (1 mL). To the solution was added sodium hydride (8 mg), and the mixture was stirred at 60 Deg for 1 hr and cooled to room temperature. To the mixture was added 1-bromopentane (0.06 mL), and the mixture was stirred at 60 Deg for 1 hr.
- Example 29 To a solution of the compound of Example 36 in Table 5 (10.0 mg) in MeOH (0.2 mL) and acetonitrile (0.2 mL) was added a solution of (trimethylsilyl)diazomethane in diethyl ether (2.0 M, 0.002 mL) at room temperature. The mixture was stirred at the temperature for 1 hr. To the mixture was added acetic acid and the mixture was stirred at room temperature for 10 Min. Evaporation of the solvent followed by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) gave the compound of Example 28 in Table 5 (1.0 mg).
- Example 29 Example 29
- Example 32 A mixture of the compound of Preparation 81 in Table 3 (35 mg), THF (1 mL), water (0.1 mL), and p-toluenesulfonic acid monohydrate (1.3 mg) was stirred at room temperature for 2 hrs. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL), and hydrogenated over 10% palladium on carbon (50% wet, 3 mg) at room temperature for 1 hr. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative-TLC (silica gel, 20 cm x 20 cm x 0.5 mm, 10% MeOH in DCM) to give the compound of Example 32 in Table 5 (4.5 mg).
- the Preparation compounds 162-456 shown in the following tables were produced using respectively corresponding materials.
- the structures and production methods thereof are shown in Table 3, production methods and physicochemical data thereof in Table 4.
- the Example compounds 36-898 shown in the following tables were produced using respectively corresponding materials. Structures of respective Example compounds are shown in Table 5 and 6, production methods and physicochemical data thereof in Table 7.
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Abstract
La présente invention concerne un nouveau dérivé de sordarine ou un sel pharmaceutiquement acceptable de celui-ci, qui a des activités antimicrobiennes (en particulier, des activités antifongiques), un procédé pour la préparation de celui-ci, une composition pharmaceutique comprenant celui-ci, et un procédé pour le traitement prophylactique et/ou thérapeutique de maladies infectieuses chez un être humain ou un animal.
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PCT/JP2009/058437 WO2009131246A1 (fr) | 2008-04-24 | 2009-04-22 | Dérivés de sordarine pour prévenir ou traiter des maladies infectieuses causées par des micro-organismes pathogènes |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9593106B2 (en) | 2013-02-07 | 2017-03-14 | Heptares Therapeutics Limited | Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists |
EP3200792A4 (fr) * | 2014-10-03 | 2018-05-09 | The Institute for Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center | Inhibiteurs de poly(adp-ribose) polymérase 1 structurellement non apparentés à nad |
KR20220101420A (ko) * | 2021-01-11 | 2022-07-19 | 고려대학교 산학협력단 | 모리니아펀진을 유효성분으로 포함하는 식물병 방제용 조성물 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015178A1 (fr) * | 1996-10-07 | 1998-04-16 | Merck & Co., Inc. | Derives de sordarine |
-
2009
- 2009-04-22 WO PCT/JP2009/058437 patent/WO2009131246A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015178A1 (fr) * | 1996-10-07 | 1998-04-16 | Merck & Co., Inc. | Derives de sordarine |
Non-Patent Citations (2)
Title |
---|
HANADATE T ET AL: "FR290581, a novel sordarin derivative: Synthesis and antifungal activity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 19, no. 5, 22 January 2009 (2009-01-22), pages 1465 - 1468, XP025994296, ISSN: 0960-894X * |
SERRANO-WU ET AL: "Oxime derivatives of sordaricin as potent antifungal agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, 2002, pages 943 - 946, XP002535587 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9593106B2 (en) | 2013-02-07 | 2017-03-14 | Heptares Therapeutics Limited | Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists |
US10030012B2 (en) | 2013-02-07 | 2018-07-24 | Heptares Therapeutics Limited | Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists |
EP3200792A4 (fr) * | 2014-10-03 | 2018-05-09 | The Institute for Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center | Inhibiteurs de poly(adp-ribose) polymérase 1 structurellement non apparentés à nad |
US10550108B2 (en) | 2014-10-03 | 2020-02-04 | Institute For Cancer Research | Poly(ADP-ribose) polymerase 1 inhibitors structurally unrelated to NAD |
KR20220101420A (ko) * | 2021-01-11 | 2022-07-19 | 고려대학교 산학협력단 | 모리니아펀진을 유효성분으로 포함하는 식물병 방제용 조성물 |
KR102526812B1 (ko) * | 2021-01-11 | 2023-04-27 | 고려대학교 산학협력단 | 모리니아펀진을 유효성분으로 포함하는 식물병 방제용 조성물 |
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