HRP20050703A2 - Pyridine derivatives useful for inhibiting sodium/calcium exchange system - Google Patents
Pyridine derivatives useful for inhibiting sodium/calcium exchange system Download PDFInfo
- Publication number
- HRP20050703A2 HRP20050703A2 HR20050703A HRP20050703A HRP20050703A2 HR P20050703 A2 HRP20050703 A2 HR P20050703A2 HR 20050703 A HR20050703 A HR 20050703A HR P20050703 A HRP20050703 A HR P20050703A HR P20050703 A2 HRP20050703 A2 HR P20050703A2
- Authority
- HR
- Croatia
- Prior art keywords
- yloxy
- pyridin
- chroman
- nmr
- mhz
- Prior art date
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- 230000002401 inhibitory effect Effects 0.000 title claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title description 4
- 239000011575 calcium Substances 0.000 title description 4
- 229910052791 calcium Inorganic materials 0.000 title description 4
- 150000003222 pyridines Chemical class 0.000 title description 4
- 239000011734 sodium Substances 0.000 title description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title description 2
- 229910052708 sodium Inorganic materials 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 59
- -1 -OH Chemical group 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 230000007246 mechanism Effects 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 7
- 206010003119 arrhythmia Diseases 0.000 claims description 6
- 230000006793 arrhythmia Effects 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 101100240522 Caenorhabditis elegans nhr-18 gene Proteins 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 101100240526 Caenorhabditis elegans nhr-20 gene Proteins 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 265
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 236
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000000203 mixture Substances 0.000 description 77
- 239000000243 solution Substances 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 37
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 239000002904 solvent Substances 0.000 description 31
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 30
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000003480 eluent Substances 0.000 description 19
- UCPDMDGWCCESMP-UHFFFAOYSA-N 6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-amine Chemical compound N1=CC(N)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 UCPDMDGWCCESMP-UHFFFAOYSA-N 0.000 description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- GZONLGPIHCCJOI-UHFFFAOYSA-N 5-nitro-2-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridine Chemical compound N1=CC([N+](=O)[O-])=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 GZONLGPIHCCJOI-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- HNNVEYLZESPTPQ-UHFFFAOYSA-N 2-chloro-n-[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]acetamide Chemical compound N1=CC(NC(=O)CCl)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 HNNVEYLZESPTPQ-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
- 238000001816 cooling Methods 0.000 description 13
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 12
- NFAWYKUUWDFTHZ-UHFFFAOYSA-N 2-phenyl-3,4-dihydro-2h-chromen-6-ol Chemical class C1CC2=CC(O)=CC=C2OC1C1=CC=CC=C1 NFAWYKUUWDFTHZ-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- XYHWPQUEOOBIOW-UHFFFAOYSA-N 6-hydroxyflavanone Chemical class C1C(=O)C2=CC(O)=CC=C2OC1C1=CC=CC=C1 XYHWPQUEOOBIOW-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 9
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 description 9
- KYSUJMHYJQLLLO-UHFFFAOYSA-N 6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-amine;piperidine-4-carboxylic acid Chemical compound OC(=O)C1CCNCC1.N1=CC(N)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 KYSUJMHYJQLLLO-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- HRVBYTVYJAPLHB-UHFFFAOYSA-N 2-(4-fluorophenyl)-3,4-dihydro-2h-chromen-6-ol Chemical compound C1CC2=CC(O)=CC=C2OC1C1=CC=C(F)C=C1 HRVBYTVYJAPLHB-UHFFFAOYSA-N 0.000 description 8
- KFUMHIDDQQILEL-UHFFFAOYSA-N 2-phenyl-3,4-dihydro-2h-chromen-7-ol Chemical class O1C2=CC(O)=CC=C2CCC1C1=CC=CC=C1 KFUMHIDDQQILEL-UHFFFAOYSA-N 0.000 description 8
- ZJUXJQSYXBYFFO-UHFFFAOYSA-N 4-[(4-methylpiperazin-4-ium-1-yl)methyl]benzoate Chemical compound C1CN(C)CCN1CC1=CC=C(C(O)=O)C=C1 ZJUXJQSYXBYFFO-UHFFFAOYSA-N 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 8
- 150000003927 aminopyridines Chemical class 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- CTNPHHZPAJYPFO-PDXBGNJTSA-N (3s,5s,8r,9s,10s,13r,14s,17r)-3-[(2r,4s,5r,6r)-5-[(2r,3s,4s,5r,6s)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-5,14-dihydroxy-13-methyl-17-(5-oxo-2h-furan Chemical compound C1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C=O)CC[C@@H](C[C@@]5(O)CC[C@H]4[C@@]3(O)CC2)O[C@H]2C[C@@H]([C@@H]([C@@H](C)O2)O[C@@H]2[C@H]([C@H](O)[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)[C@H](CO)O2)O)OC)=CC(=O)OC1 CTNPHHZPAJYPFO-PDXBGNJTSA-N 0.000 description 7
- GCTFDMFLLBCLPF-UHFFFAOYSA-N 2,5-dichloropyridine Chemical compound ClC1=CC=C(Cl)N=C1 GCTFDMFLLBCLPF-UHFFFAOYSA-N 0.000 description 7
- FFEOOGDQASYIMF-UHFFFAOYSA-N 5-chloro-2-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridine Chemical compound N1=CC(Cl)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 FFEOOGDQASYIMF-UHFFFAOYSA-N 0.000 description 7
- 241000700199 Cavia porcellus Species 0.000 description 7
- FHIREUBIEIPPMC-UHFFFAOYSA-N K-Strophanthin-beta Natural products O1C(C)C(OC2C(C(O)C(O)C(CO)O2)O)C(OC)CC1OC(CC1(O)CCC2C3(O)CC4)CCC1(C=O)C2CCC3(C)C4C1=CC(=O)OC1 FHIREUBIEIPPMC-UHFFFAOYSA-N 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 7
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- SUIHNCCYZMUFEH-UHFFFAOYSA-N 2-(3-hydroxyphenyl)-3,4-dihydro-2h-chromen-6-ol Chemical compound OC1=CC=CC(C2OC3=CC=C(O)C=C3CC2)=C1 SUIHNCCYZMUFEH-UHFFFAOYSA-N 0.000 description 6
- CXFCPHACGDFVOB-UHFFFAOYSA-N 2-(4-fluorophenyl)-3,4-dihydro-2h-chromene-4,6-diol Chemical compound O1C2=CC=C(O)C=C2C(O)CC1C1=CC=C(F)C=C1 CXFCPHACGDFVOB-UHFFFAOYSA-N 0.000 description 6
- NTHKEMDHJFZMRT-UHFFFAOYSA-N 2-(4-fluorophenyl)-6-hydroxy-2,3-dihydrochromen-4-one Chemical compound C1C(=O)C2=CC(O)=CC=C2OC1C1=CC=C(F)C=C1 NTHKEMDHJFZMRT-UHFFFAOYSA-N 0.000 description 6
- UHRFABAQBKFMNK-UHFFFAOYSA-N 2-phenyl-2,3-dihydro-1,4-benzodioxin-6-ol Chemical compound C1OC2=CC(O)=CC=C2OC1C1=CC=CC=C1 UHRFABAQBKFMNK-UHFFFAOYSA-N 0.000 description 6
- BHJGJIOVSSSXDF-UHFFFAOYSA-N 2-phenyl-2,3-dihydro-1h-inden-5-ol Chemical compound C1C2=CC(O)=CC=C2CC1C1=CC=CC=C1 BHJGJIOVSSSXDF-UHFFFAOYSA-N 0.000 description 6
- UTVSNCZURCQGEV-UHFFFAOYSA-N 6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol Chemical compound C1CC2=CC(O)=CC=C2CC1C1=CC=CC=C1 UTVSNCZURCQGEV-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 210000003540 papillary muscle Anatomy 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000001384 succinic acid Substances 0.000 description 6
- UPOFPJMROJNPAW-UHFFFAOYSA-N 3-(3-fluorophenyl)-3,4-dihydro-2h-chromen-7-ol Chemical compound C1OC2=CC(O)=CC=C2CC1C1=CC=CC(F)=C1 UPOFPJMROJNPAW-UHFFFAOYSA-N 0.000 description 5
- FJUORDALKHVXDF-UHFFFAOYSA-N 3-(3-fluorophenyl)-7-hydroxychromen-4-one Chemical compound C=1C(O)=CC=C(C2=O)C=1OC=C2C1=CC=CC(F)=C1 FJUORDALKHVXDF-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- OUYPJKIKPBDKMY-UHFFFAOYSA-N 5-nitro-2-[(2-phenyl-2,3-dihydro-1h-inden-5-yl)oxy]pyridine Chemical compound N1=CC([N+](=O)[O-])=CC=C1OC1=CC=C(CC(C2)C=3C=CC=CC=3)C2=C1 OUYPJKIKPBDKMY-UHFFFAOYSA-N 0.000 description 5
- SWAJPHCXKPCPQZ-UHFFFAOYSA-N 7-hydroxyflavanone Chemical class O1C2=CC(O)=CC=C2C(=O)CC1C1=CC=CC=C1 SWAJPHCXKPCPQZ-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 150000003869 acetamides Chemical class 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000002349 favourable effect Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 210000003205 muscle Anatomy 0.000 description 5
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 5
- 150000002989 phenols Chemical class 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- WLDWSGZHNBANIO-UHFFFAOYSA-N 2',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC=C1O WLDWSGZHNBANIO-UHFFFAOYSA-N 0.000 description 4
- XATOFSIUMVTTJN-UHFFFAOYSA-N 2-(3-hydroxyphenyl)-3,4-dihydro-2h-chromene-4,6-diol Chemical compound O1C2=CC=C(O)C=C2C(O)CC1C1=CC=CC(O)=C1 XATOFSIUMVTTJN-UHFFFAOYSA-N 0.000 description 4
- MXJZJVWVHUGNLF-UHFFFAOYSA-N 2-[[3-(3-fluorophenyl)-3,4-dihydro-2h-chromen-7-yl]oxy]-5-nitropyridine Chemical compound N1=CC([N+](=O)[O-])=CC=C1OC1=CC=C(CC(CO2)C=3C=C(F)C=CC=3)C2=C1 MXJZJVWVHUGNLF-UHFFFAOYSA-N 0.000 description 4
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 4
- ASHGTJPOSUFTGB-UHFFFAOYSA-N 3-methoxyphenol Chemical class COC1=CC=CC(O)=C1 ASHGTJPOSUFTGB-UHFFFAOYSA-N 0.000 description 4
- LKMWTIGVJAWQHQ-UHFFFAOYSA-N 3-phenyl-3,4-dihydro-2h-chromen-7-ol Chemical compound C1OC2=CC(O)=CC=C2CC1C1=CC=CC=C1 LKMWTIGVJAWQHQ-UHFFFAOYSA-N 0.000 description 4
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- BEXDBPAEQPELLB-UHFFFAOYSA-N diazonio-[2-[[6-[[2-(4-fluorophenyl)-3,4-dihydro-2h-chromen-6-yl]oxy]pyridin-3-yl]amino]-2-oxoethyl]azanide Chemical compound C1=CC(F)=CC=C1C1OC2=CC=C(OC=3N=CC(NC(=O)CN=[N+]=[N-])=CC=3)C=C2CC1 BEXDBPAEQPELLB-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- OIYITSUJHOCOEC-UHFFFAOYSA-N ethyl 1-[2-oxo-2-[[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]amino]ethyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1CC(=O)NC(C=N1)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 OIYITSUJHOCOEC-UHFFFAOYSA-N 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical class NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005283 haloketone group Chemical group 0.000 description 1
- 150000005748 halopyridines Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical class CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- IETJRGLPKIGOPZ-UHFFFAOYSA-N n',n'-diethyl-n-[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]ethane-1,2-diamine;dihydrochloride Chemical compound Cl.Cl.N1=CC(NCCN(CC)CC)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 IETJRGLPKIGOPZ-UHFFFAOYSA-N 0.000 description 1
- RGNTWPWVGHUURZ-UHFFFAOYSA-N n',n'-dimethyl-n-[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]ethane-1,2-diamine;dihydrochloride Chemical compound Cl.Cl.N1=CC(NCCN(C)C)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 RGNTWPWVGHUURZ-UHFFFAOYSA-N 0.000 description 1
- MZBIYMSQKYTZMN-UHFFFAOYSA-N n-(5-nitropyridin-2-yl)-6-[[2-[3-(5-nitropyridin-2-yl)oxyphenyl]-3,4-dihydro-2h-chromen-6-yl]oxy]pyridin-3-amine Chemical compound N1=CC([N+](=O)[O-])=CC=C1NC(C=N1)=CC=C1OC1=CC=C(OC(CC2)C=3C=C(OC=4N=CC(=CC=4)[N+]([O-])=O)C=CC=3)C2=C1 MZBIYMSQKYTZMN-UHFFFAOYSA-N 0.000 description 1
- DBLXEVDUJLGAIL-UHFFFAOYSA-N n-[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]piperidine-4-carboxamide Chemical compound C1CNCCC1C(=O)NC(C=N1)=CC=C1OC(C=C1CC2)=CC=C1OC2C1=CC=CC=C1 DBLXEVDUJLGAIL-UHFFFAOYSA-N 0.000 description 1
- QPHJFRIWUUGZEZ-UHFFFAOYSA-N n-[6-[[2-(3-phenylmethoxyphenyl)-3,4-dihydro-2h-chromen-6-yl]oxy]pyridin-3-yl]methanesulfonamide Chemical compound N1=CC(NS(=O)(=O)C)=CC=C1OC1=CC=C(OC(CC2)C=3C=C(OCC=4C=CC=CC=4)C=CC=3)C2=C1 QPHJFRIWUUGZEZ-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000005480 nicotinamides Chemical class 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- HHAVHBDPWSUKHZ-UHFFFAOYSA-N propan-2-ol;propan-2-one Chemical compound CC(C)O.CC(C)=O HHAVHBDPWSUKHZ-UHFFFAOYSA-N 0.000 description 1
- VHWJSJBTUWUEAL-UHFFFAOYSA-N propanamide;hydrochloride Chemical compound Cl.CCC(N)=O VHWJSJBTUWUEAL-UHFFFAOYSA-N 0.000 description 1
- AMSCUQGYIGXFOH-UHFFFAOYSA-N pyridin-3-ylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CN=C1 AMSCUQGYIGXFOH-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- HDCNFHUECOEYFB-SKCDSABHSA-N tert-butyl (2s)-2-[[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC(C=N1)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 HDCNFHUECOEYFB-SKCDSABHSA-N 0.000 description 1
- FIVXKYGIRPGCKO-QSAPEBAKSA-N tert-butyl (2s)-2-[[6-[[2-(2-fluorophenyl)-3,4-dihydro-2h-chromen-6-yl]oxy]pyridin-3-yl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC(C=N1)=CC=C1OC1=CC=C(OC(CC2)C=3C(=CC=CC=3)F)C2=C1 FIVXKYGIRPGCKO-QSAPEBAKSA-N 0.000 description 1
- FLRBJAMXBUJFJF-SKCDSABHSA-N tert-butyl (2s)-2-[[6-[[2-(3-fluorophenyl)-3,4-dihydro-2h-chromen-6-yl]oxy]pyridin-3-yl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC(C=N1)=CC=C1OC1=CC=C(OC(CC2)C=3C=C(F)C=CC=3)C2=C1 FLRBJAMXBUJFJF-SKCDSABHSA-N 0.000 description 1
- ULAHAGFHEJCREI-SKCDSABHSA-N tert-butyl (2s)-2-[[6-[[2-(4-fluorophenyl)-3,4-dihydro-2h-chromen-6-yl]oxy]pyridin-3-yl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC(C=N1)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC(F)=CC=3)C2=C1 ULAHAGFHEJCREI-SKCDSABHSA-N 0.000 description 1
- HYQCRDDRMLMTMJ-UHFFFAOYSA-N tert-butyl 4-[[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NC(C=N1)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 HYQCRDDRMLMTMJ-UHFFFAOYSA-N 0.000 description 1
- KAWHULVGZCZFGF-FKSKYRLFSA-N tert-butyl n-[(2r)-1-oxo-1-[[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]amino]propan-2-yl]carbamate Chemical compound N1=CC(NC(=O)[C@H](NC(=O)OC(C)(C)C)C)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 KAWHULVGZCZFGF-FKSKYRLFSA-N 0.000 description 1
- DTNIOAYHINWROM-WKDCXCOVSA-N tert-butyl n-[(2s)-3-methyl-1-oxo-1-[[6-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]pyridin-3-yl]amino]butan-2-yl]carbamate Chemical compound N1=CC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)=CC=C1OC1=CC=C(OC(CC2)C=3C=CC=CC=3)C2=C1 DTNIOAYHINWROM-WKDCXCOVSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/02—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Područje izuma
Prikazani izum se odnosi na nove terapijski aktivne spojeve i njihove farmaceutski prihvatljive soli i estere. Prikazani izum se također odnosi na farmaceutske kompozicije koje sadrže ove spojeve kao aktivne satojke. Spojevi iz ovog izuma su snažni inhibitori mehanizma Na+/Ca2+ izmjene.
Stanje tehnike
Mehanizam Na+/Ca2+ izmjene je jedan od mehanizama za transport iona koji reguliraju koncentraciju natrijev1H i kalcijev1H iona u stanicama. Spojeve koja selektivno inhibiraju mehanizam Na+/Ca2+ izmjene i time sprečavaju nakupljanje Ca2+ u stanicama smatraju se korisnim u sprečavanju mehanizma povređivanja stanica srčanog mišića i slično poslije ishemije i reperfuzije. Takvi spojevi su korisni npr. u liječenju ishemičn1H bolesti kao što su bolest srca, ishemična cerebralna bolest, ishemična renalna bolest i u zaštiti stanica za vrijeme trombolitične terapije, angioplastike, ugradnje premosnica u koronarnu arteriju ili transplantacije organa i aritmije.
Spojevi sposobni inhibirati sustav Na+/Ca2+ izmjene su opisani ranije, npr. u patentnim publikacijama WO 97/09306, EP 0978506, EP 1031556, JP 11049752 i JP 11302235.
Pregled izuma
Sada je pronađeno da su spojevi formule (I) ili (II) izrazito snažni inhibitori mehanizma Na+/Ca2+ izmjene i da su naročito korisni u liječenju aritmija.
Spojevi iz prikazanog izuma imaju strukturu prikazanu formulom (I) ili (II):
[image]
gdje
Xje-O-,-CH2-ili-C(O)-;
Z je -CHR12- ili valentna veza;
Y je -CH2-, -C(O)-, CH(OR13)-, -O-, -S-;
uz uvjete da, ako je Z valentna veza, Y nije C(O);
ako isprekidana linija predstavlja opcionu dvogubu vezu, onda je Z -R12-, a Y je
-CH2-, -C(O)- ili CH(OR10)- (u formuli II) ili
-CH- (u formuli I);
R2 i R3 su nezavisno H, niži alkil, niži alkoksi, -NO2, halogen, -CF3, -OH, benziloksi ili grupa formule (IIIa)
[image]
R1 je H, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, NHC(O)R5, NHCH2R5, NHR20, NR21R22, NHC(NH)NHCH3 ili, u slučaju kad je spoj formule (II) gdje postoji opciona dvoguba veza ili u slučaju kad je R2 ili R3 benziloksi ili grupa formule (IIIa) ili u slučaju kad je piridinski prsten formule (I) ili (II) spojen s atomom kisika na 3-, 4- ili 5-om mjestu, R1 može biti i -NO2 ili NR16R17;
R4 je H, -NO2. CN, halogen, -CONH2, -COOR15, -CH2NR15R18, -NR16R17, -NHC(O)R5 ili -NHC(NH)NHCH3;
R5 je alkil supstituiran s 1 do 3 supstituenta odabranih iz grupe koja sadrži halogen, amino i hidroksi, ili karboksialkil, u kojem je alkilni dio po izboru supstituiran s 1 do 3 supstituenta odabranih iz grupe koja sadrži halogen, amino i hidroksil, -CHR6NR7R8 ili jednom od slijedećih grupa
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W je N ili CH;
Q je CHR14NR9, S ili O;
R6 jeH ili niži alkil;
R7 i R8 su nezavisno H, acil, niži alkil ili niži hidroksialkil;
R9 je H, niži alkil ili fenil;
R10 i R11 su nezavisno H ili niži alkil;
R12 je H ili niži alkil;
R13 je H, alkilsulfonil ili acil;
R14 je H,-OH, -COOR15;
R15 je H ili niži alkil;
R16 i R17 su nezavisno H, acil, alkilsulfonil, -C(S)NHR18 ili -C(O)NHR18;
R18 je H ili niži alkil;
R19 je H ili -OH;
R20 je piridinil grupa po izboru supstituirana -NO2 grupom;
R21 i R22 su niži alkil;
i njihove farmaceutski prihvatljive soli i esteri.
U jednoj skupini povoljnih spojeva i njihovih farmaceutski prihvatljivih soli i estera su spojeve formule (Ib) ili (IIb), gdje su R1, R2, R3, X, Y i Z kao što je definirano ranije.
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U jednoj podskupini povoljnih spojeva i njihovih farmaceutski prihvatljivih soli i estera su spojeve formule (Ic) ili (IIc), gdje su R1, R2, R3, X, Y i Z kao što je definirano ranije.
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U jednoj drugoj skupini povoljnih spojeva i njihovih farmaceutski prihvatljivih soli i estera su spojeve formule (I) ili (II) gdje je R1 -NHC(O)R5, X je O, Y je CH2 i Z je CHR12. U jednoj podskupini povoljnih spojeva i njihovih farmaceutski prihvatljivih soli i estera su spojeve formule (I) ili (II) gdje je R1 -NHC(O)R5, X je O, Y je CH2, Z je CH2 i R5 je alkil supstituiran s 1 do 3 supstituenta odabranih iz grupe koja sadrži halogen, amino i hidroksi, ili karboksialkil, u kojima je alkilni dio po izboru supstituiran s 1 do 3 supstituenta odabranih iz grupe koja sadrži halogen, amino i hidroksil, -CHR3NR7R8 ili jednom od slijedećih grupa:
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U jednoj drugoj skupini povoljnih spojeva i njihovih farmaceutski prihvatljivih soli i estera su spojeve gdje je R2 ili R3 benziloksi ili grupa formule (IIIa)
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U jednoj podskupini povoljnih spojeva i njihovih farmaceutski prihvatljivih soli i estera su spojeve gdje su R4 i R1 NO2.
Prikazani izum također osigurava farmaceutsku kompoziciju koja sadrži spoj formule (I) ili (II) zajedno s farmaceutski prihvatljivim nosačem.
Prikazani izum nadalje osigurava postupak za inhibiranje mehanizma Na+/Ca2+ izmjene u stanici, koji se sastoji od davanja subjektu kojem je to potrebno terapeutski djelotvorne količine spojeve formule (I) ili (II).
Prikazani izum nadalje osigurava postupak sprečavanja nakupljanja Ca2+ iona u stanicama, koji se sastoji od davanja subjektu kojem je to potrebno terapeutski djelotvorne količine spojeve formule (I) ili (II).
Prikazani izum nadalje osigurava postupak za liječenje aritmija, koji se sastoji od davanja subjektu kojem je to potrebno terapeutski djelotvorne količine spojeve formule (I) ili (II).
Kratak opis crteža
Slika 1 prikazuje učinke naslovnih spojeva iz Primjera 13, 33, 14a i 14b na vrijeme početka brzog rasta postkontrakcija u papilarnim mišićima zamorca, induciranih strofantinom.
Slika 2 prikazuje učinke spojeva iz Primjera 13, 33, 14a i 14b na amplitude postkontrakcija u papilarnim mišićima zamorca, induciranih strofantinom.
Slika 3 prikazuje učinke spojeva iz Primjera 13, 33, 14a i 14b na vrijeme do amplituda postkontrakcija u papilarnim mišićima zamorca, induciranih strofantinom.
Detaljan opis izuma
Spojevi iz izuma se dobiju iz odgovarajućih derivata fenola (IV), gdje su R2, R3, X, Z i Y isti kao što su definirano ranije.
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Sinteze su prikazane Shemom 1, gdje je formula (IV) skraćena kao Ar-OH (IV). Piridin-2-iloksi derivati (1) su dobijeni reakcijama s povoljnim halopiridinima (2), gdje R1 je vodik, nitro, cijano, halogen, ili amid, a X1 klor ili brom. Derivati nitropiridina i nikotinamida se reduciraju do odgovarajućih amina (3) i (4), respektivno.
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Reakcija 2-kloro-5-klorometilpiridina (5) s diemetilaminom daje (6-kloropiridin-3-ilmetil)dimetilamin (6), koji zatim reagira s derivatima fenola (IV), kao što je pokazano na Shemi 2.
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Derivati nikotinske kiseline (12) i njihovi esteri (11) dobijaju se kao što je pokazano na Shemi 3. Esterifikacija 6-kloronikotinske kiseline i njena reakcija s derivatima fenola (IV) daje derivate estera nikotinske kiseline (11) (R može biti niži alkil). Derivati nikotinske kiseline (12) se dobijaju hidrolizom.
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Derivati aminopiridina (3) reagiraju s povoljnim amino kiselinama i drugim derivatima karboksilnih kiselina, uz pomoć l-(dimetilaminopropil)-3-etilkarbodiimid hidroklorida kao sredstva za kuplovanje, da se dobiju derivati amida (13), kao što je pokazano na slijedećoj Shemi 4, gdje je R5 kao što je definirano ranije. Po izboru, amidni derivati (13) se dobiju dobro poznatim postupcima aciliranja. Zaštitne grupe se uklone prema želji.
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4-(4-metilpiperazin-1-ilmetil)benzojeva kiselina (17) se dobija kao što je opisano na slijedećoj Shemi 5. 4-klorometilbenzojeva kiselina (14) se prvo esterizira metil estrom da se zaštiti kiselinska grupa u slijedećoj reakciji. Metil ester 4-klorometilbenzojeve kiseline (15) se zatim ostavi reagirati s 1-metilpiperazinom da se dobije metil ester 4-(4-metilpiperazin-1-ilmetil)benzojeve kiseline (16). Metil ester se razgradi grijanjem s kalijevim hidroksidom u metanolu. 4-(4-metilpiperazin-1-ilmetil)benzojeva kiselina reagira kao što je opisano ranije u Shemi 4 s derivatima aminopiridina (3) da dobijemo N-4-(4-metilpiperazin-1-ilmetil)benzamid derivat (13). Na slizan način se dobiju i drugi N-4-(piperazin-1-ilmetil)benzamid derivati (13).
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Derivati 2-kloroacetamida (13'), gdje je R5 CH2Cl, reagiraju s natrijevim azidom da se dobiju derivati azida (18) koji se zatim reduciraju do odgovarajućih 2-aminoacetamidnih derivata (19), kao što je pokazano na slijedećoj Shemi 6, gdje su R7 i R8 kao što je definirano ranije. Derivati acetamida (20) se dobijaju iz derivata 2-kloroacetamida (13') reagiranjem s različitim aminima. Amidna grupa derivata acetamida (20) se reducira da se dobiju odgovarajući amini (21).
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Kao što je pokazano na slijedećoj Shemi 7, gdje su R2 i R3 kao što je definirano ranije, 6- i 7-hidroksiflavanski derivati (23) su dobijeni iz odgovarajućih flavanona (22) Clemmensen-ovom redukcijom. 6- i 7-hidroksiflavanoni (22) su komercijalno dostupni ili se mogu sintetizirati postupcima opisanim u literaturi, npr. J. Org Chem., 1960, 25, 1247-9 i J. Org, Chem., 1958,23,1159-61 ili kao što je opisano kasnije na Shemi 9.
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Slijedeća Shema 8, gdje su R2 i R3 kao što je definirano ranije, opisuje sintezu 2-fenil indan-5-ola (30). Kondenzacija p-anisaldehida (24) sa supstituiranom fenil octenom kiselinom (25) daje smjesu cis i trans izomera odgovarajuće akrilne kiseline (26). Poslije hidriranja i intramolekularne Friedel-Crafts-ove reakcije, karbonima funkcionalna grupa 1-indanona (28) se reducira Clemmensen-ovom redukcijom. Konačno, metoksi indan (29) je refluksiran u koncentriranoj bromovodičnoj kiselini da se dobije 2-fenil indan-5-ol (30).
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Derivati 6-hidroksiflavanona se sitetizira kao što je pokazano na Shemi 9 gdje su R2, R3 i R12 kao što je definirano ranije. 2',5'-dihidroksiacetofenon ili odgovarajući propiofenon (32) je kondenziran odgovarajućim benzaldehidom (31), što daje smjesu povoljnih 6-hidroksiflavanona (34) i odgovarajući halkon (35). Halkon se ciklizira do flavanona.
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Benzaldehidni derivati (31), u kojima R2 i R3 sadrže piridinsku grupu, dobijaju se reakcijom hidroksibenzaldehida (35) s piridinskim derivatima (36) (u kojima X1 je klor ili brom, a R' vodik, nitro ili halogen), kao što je pokazano na Shemi 10.
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2-fenilkroman-4,6-diolni derivati (39) se dobijaju iz odgovarajućih 6-hidroksiflavanona (38) redukcijom kao što je pokazano na Shemi 11, gdje su R2, R3 i R12 kao što je definirano ranije. Ovi diolni derivati se dalje reduciraju u 6-hidroksiflavane (40).
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Slijedeća Shema 12, gdje su R2 i R3 kao što je definirano ranije, opisuje sintezu 7-hidroksiizoflavona (45) i 7-hidroksiizoflavana (46). Acilacija 3-metoksifenola (41) supstituiranim fenil octenim kiselinama (42) daje odgovarajuće 2-hidroksideoksibenzoine (43) koji se cikliziraju trietilortoformijatima da se dobiju izoflavoni (44). Skidanje zaštite bromovodičnom kiselinom i katalitička hidrogenizacija daje 7-hidroksiizoflavane (46).
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Slijedeća Shema 13 opisuje sintezu 2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-ol (50). Reakcija 2-merkaptobenzen-1,4-diola (47) sa stiren epoksidom (48) u prisutnosti baze daje sulfid (49). Zatvaranje prstena kiselim ionoizmjenjivačem daje 2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-ol (50).
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Slijedeća Shema 14 opisuje sintezu 6-fenil-5,6,7,8-tetrahidro-naftalen-2-ola (55) i 6-hidroksi-2-fenil-3,4-dihidro-2H-naftalen-1-ona (54). α-arilacija 6-metoksi-1-tetralona (51) katalizirana paladijem daje 6-metoksi-2-fenil-3,4-dihidro-2H-naftalen-1-on (53) koji, poslije demetilizacije, dovodi do fenolnog spoja (54). Redukcija trietilsilanom daje 6-fenil-5,6,7,8-tetrahidronaftalen-2-ol (55).
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Slijedeća Shema 15, gdje su R2 i R3 kao što je definirano ranije, a R" je odgovarajuća zaštitna grupa, opisuje sintezu 2,3-dihidro-2-fenil-benzo[1,4]dioksin-6-ola (60). Poslije uklanjanja zaštitnih hidroksilnih grupa 2,5-dihidroksiacetofenona, ovaj keton se preuređuje per-kiselinama i daje fenol (56) poslije hidrolize. Fenol (56) se kondenzira haloketonom i poslije redukcije i uklanjanja zaštitnih grupa, hidroksifenol (59) se ciklizira do 2,3-dihidro-2-fenil-benzo[1,4]-dioksin-6-ola(60).
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Derivati dihidroksiflavana (61) reagiraju s derivatima piridina na sličan način kao što je opisano za spoj (1) na Shemi 1. 4-kromanolni derivat (62), gdje je R* OH, se reducira do odgovarajućeg flavana trietilsilanom u kiseloj sredini. 5-nitropiridinski derivati (62) se reduciraju do odgovarajućih 2-aminoderivata (63), koji se zatim aciliraju ili meziliraju ili reagiraju s različitim amino- ili karboksilno kiselinskim derivatima kao što je opisano na Shemi 4 za spoj (13).
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Kad se nitro grupa u benziloksi derivatima (65) reducira hidrogenizacijom uz korištenje paladija kao katalizatora, dobijaju se [6-(5-aminopiridin-2-iloksi)kroman-2-il]fenol derivati (68), koji se zatim aciliraju ili meziliraju. Ovi fenolni derivati (69) zatim reagiraju s piridinskim derivatima (2) da dobijemo derivat kao (70), kao što je pokazano na slijedećoj Shemi 17. Redukcija cinkom dovodi do amina kao (66), koji se zatim acilira, mezilira ili reagira s različitim amino- ili karboksilno kiselinskim derivatima kao što je opisano na Shemi 4 za spoj (13).
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Alkilni derivati aminopiridina (3) se dobiju redukcijskom aminacijom kao što je pokazano na Shemi 18 za dimetilaminske derivate (71). U toku reakcije, dio aminskih grupa se premjesti s 5. na 4. poziciju.
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Slijedeća Shema 19 opisuje sintezu l-metil-3-(piridinil)tiouree (73) i N-metil-N’-(piridinil)gvanidinsk1H (74) derivata. Aminopiridinski derivati (3) su reagirali s metil izotiocijanatom da se dobiju derivati tiouree (73), koji su zatim tretirani prvo metil jodidom, a zatim metanolskom otopinom amonijaka da dobijemo gvanidinski derivat (74).
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Soli i esteri ovih spojeve se, kad je to izvodljivo, dobiju poznatim postupcima. Fiziološki prihvatljive soli su korisne kao aktivni lijekovi. Primjeri su soli s neorganskim kiselinama kao što su klorovodična, bromovodična ili dušična kiselina, i soli s organskim kiselinama kao što su metansulfonska, limunska ili vinska kiselina. Fiziološki pr1Hvatljivi esteri su također korisni kao aktivni lijekovi. Primjeri su esteri s alifatskim ili aromatskim kiselinama kao što je octena kiselina, ili s alifatskim ili aromatskim alkoholima kao što je etanol.
Termin "alkil", kao što se ovdje koristi samostalno ili kao dio druge grupe, uključuje i linearne i razgranate i prstenaste radikale s do 18 ugljikovih atoma, povoljno 1 do 7 ugljikovih atoma. Termin "niži alkil", kao što se ovjde koristi samostalno ili kao dio druge grupe, uključuje i linearne i razgranate i prstenaste radikale s 1 do 7 ugljikovih atoma. Specifični primjeri alkilnih i niže alkilnih ostataka, respektivno, su metil, etil, propil, izopropil, butil, terc butil, pentil, ciklopentil, heksil, cikloheksil, oktil, decil i dodecil, uključujući njihove različite izomere razgranatih lanaca.
Termin "alkoksi", kao što se ovdje koristi samostalno ili kao dio druge grupe, uključuje alkil grupu kao što je definirana ranije, zakvačenu za atom kisika.
Termin "acil", kao što se ovdje koristi samostalno ili kao dio druge grupe, odnosi se na alkilkarbonil ili alkenilkarbonil grupu, kod čega su alkil i alkenil grupe definirane ranije.
Spojeve iz ovog izuma se daju pacijentu u terapeutski učinkovitim količinama, koje se obično kreću u području od oko 0,05 do 200 mg, povoljno od 0,1 do 100 mg, a još povoljnije od 0,5 do 50 mg na dan, u ovisnosti od starosti, težine, stanja pacijenta, načina davanja i inhibitora Na+/Ca2+ izmjene koji se koristi. Spojeve iz ovog izuma se formuliraju u oblike doza držeći se principa poznatih u struci. Može se davati pacijentu kao takvo ili u kombinaciji s povoljnim farmaceutskim ekscipijentima u obliku tableta, granula, kapsula, supozitorija, emulzija, suspenzija ili otopina. Biranje povoljnih sastojaka za kompoziciju je rutina za uobičajenog stručnjaka. Jasno je da se koriste i povoljni nosači, otapala, sastojci za formiranje gela, sastojci za formiranje disperzije, antioksidanti, boje, sladila, spojeve za vlaženje i drugi sastojci koji se normalno koriste u ovom području tehnologije. Kompozicije koje sadrže aktivno spoj daju se enteralno ili parenteralno, kod čega je povoljan oralni način. Sastojci aktivnog spoja u kompoziciji se kreću od oko 0,5 do 100 %, povoljno od oko 0,5 do oko 20 % ukupne težine kompozicije.
Eksperimenti
Djelotvornost spojeva iz prikazanog izuma su testirani na aritmijama izazvanim strofantinom u papilarnim mišićima zamorca.
Postupci
Papilami mišići zamorca su postavljeni u horizontalnu kivetu za mišiće. Kuka, spojena s prenosnikom sile, je zakvačena za drugi kraj mišića. Mišićni preparati su električno stimulirani frekvencom od 1 Hz preko platinske elektrode. Modificirana Tyrode-ova otopina je korišten za superfuziju mišićnih preparata. Sastav Tyrode-ove otopine je bio slijedeći (mM): NaCl 135, MgCl2 x 6H2O 1, KCl 5, CaCl2 x 2H2O 2, NaHCO3 15, Na2HPO4 x 2H2O 1 i glukoza 10. Tyrode-ova otopina je zasićena smjesom od 95% O2 i 5% CO2 da se pH podesi na 7,4. Eksperimenti su obavljeni na 37 °C. Prikupljanje i analiza naprezanja u trzaju su obavljeni pomoću Action Potential and Force Measurement Svstem (ACFO v 1.0, Fision Ltd, Finland).
Inhibicija aritmija izazvanih strofantinom
Blokiranjem natrij-kalij ATPaze, strofantin povećava unutarstanični natrij koji je zamjenjen kalcijem preko NCX. Povećani unutarstanični kalcij dovodi do preopterećeni a sarkoplazmatskog retikuluma (SR) i spontanog oslobađanja kalcija iz SR inducirajući zakašnjele postpolarizacije (DADs). Ekvivalent za DADs u signalu sile su postkontrakcije (ACs), koje se vide kao spontani trzaji poslije ritmičnog kontroliranog trzaja.
Ispitani su antiaritmični učinci naslovnog spoja iz Primjera 13, 33, 14a i 14b. Rezultati su prikazani na Slikama 1 do 3. Slika 1 prikazuje učinke spojeva na vrijeme početka brzog rasta postkontrakcija izazvanih strofantinom. Slika 2 pokazuje učinke spojeve na amplitude postkontrakcija izazvanih strofantinom u papilarnim mišićima zamorca. Slika 3 pokazuje učinke spojeva na vrijeme do amplitude postkontrakcija izazvanih strofantinom u papilarnim mišićima zamorca.
U općem slučaju, spojevi iz izuma odgađaju pojavljivanje i smanjuju amplitudu postkontrakcija. Naslovni spoj iz Primjera 33, u koncentraciji od 10 μM, je u stanju da potpuno inhibira pojavljivanje druge postkontrakcije izazvane strofantinom.
PRIMJERI:
Primjeri 1 do 11 generalno opisuju dobijanje intermedijera spojeva iz ovog izuma. Dobijanje spojeva iz ovog izuma je generalno opisano od Primjera 12 nadalje.
Primjer 1. Intermedijeri
a) 2-fenilkromanolni intermedijeri
2-fenilkroman-6-ol
Cink (5,4 g, 83,2 mmola), živin (II) klorid (340 mg), koncentrirani klorovodik (0,2 ml) i voda su miješani na sobnoj temperaturi 15 minuta i smjesa je dekantirana. 6-hidroksiflavanon (1,0 g) je dodan kao suspenzija u smjesi octene kiseline (25 ml), koncentriranog klorovodika (5,2 ml) i vode (2 ml). Reakcijska smjesa je refluksirana 11⁄2 sata. Poslije hlađenja do sobne temperature, reakcijska smjesa je profiltrirana i filtrat je ekstrahiran etil acetatom. Kombinirani organski slojevi su oprani zasićenom otopinom NaHCO3, zatim vodom i osušeni pomoću Na2SO4. 2-fenilkroman-6-ol je pročišćen kromatografijom na koloni, uz upotrebu heptan-etil acetata (2:1) kao eluenta.
1H NMR (400 MHz, ds-DMSO) δ: 8.78 (s, 1H), 7.43-7.31 (m, 5H), 6.63 (d, 1H, J 8.6 Hz) 6.51 (dd, 1H, J 8.6, 2.9 Hz), 6.48 (d, 1H, J 2.9 Hz), 4.98 (dd, 1H, J, 9.9, 2.2 Hz), 2.89 (ddd, 1H, J -16.7, 11.3, 6.1 Hz), 2.63 (ddd, 1H, J -16.7, 5.5, 3.3 Hz) 2.10 (m, 1H), 1.94 (m, 1H).
Korištenjem istog postupka kao što je opisano ranije za 2-fenilkroman-6-ol, ali zamjenjujući 6-hidroksiflavanon 7-hidroksifiavanonom, dobijen je:
2-fenilkroman-7-ol
1H NMR (400 MHz, CD3OD) δ: 7.41-7.28 (m, 5H), 6.86 (d, 1H, J 8.2 Hz) 6.32 (dd, 1H, J 8.2, 2.4 Hz), 6.29 (d, 1H, J 2.4 Hz), 5.00 (dd, 1H, J 9.9,2.4 Hz), 2.84 (m, 1H), 2.64 (m, 1H) 2.15 (m, 1H), 1.99 (m, 1H).
b) 5-nitro-2-(2-(nesupstituiran)fenilkromaniloksi)piridinski intermedijeri
5-nitro-2-(2-fenilkroman-6-iloksi)piridin
Kalijev fluorid (225 mg) je dodan u otopinu 2-fenilkroman-6-ola (300 mg) u suhom DMF (3 ml). Poslije miješanja dobijene smjese na 120°C 30 minuta, dodan je 2-kloro-5-nitropiridin (195 mg). Reakcijska smjesa je miješana još 6'/2 sati na 120°C. Poslije hlađenja do sobne temperature, dodan je 1M otopine HCl i smjesa je ekstrahirana etil acetatom. Kombinirani organski slojevi su oprani vodom, zatim zasićenom otopinom NaCl i osušeni pomoću Na2SO4. 5-nitro-2-(2-fenilkroman-6-iloksi)-piridin je rekristaliziran iz aceton-2-propanola(1:5).
1H NMR (400 MHz, d6-DMSO) δ: 9.00 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.47-7.32 (m, 5H), 7.20 (d, 1H, J 9.2 Hz), 7.00-6.89 (m, 3H), 5.15 (dd, 1H, J 10.1, 2.2 Hz), 2.99 (ddd, 1H, J -16.8, 11.3, 6.2 Hz), 2.75 (ddd, 1H, J -16.8, 5.4, 3.3 Hz) 2.18 (m, 1H), 2.02 (m, 1H).
Korištenjem istog postupka kao što je opisano ranije za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin, ali zamjenjujući 2-fenilkroman-6-ol s 2-fenilkroman-7-olom, dobijen je:
5-nitro-2-(2-fenilkroman-7-iloksi)piridin
1H NMR (400 MHz, d6-DMSO) 8: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.46-7.32 (m, 5H), 7.22 (d, 1H, J 9.1 Hz), 7.20 (d, 1H, J 8.9 Hz) 6.72 (dd, 1H, J 8.9, 2.3 Hz), 6.72 (d, 1H, J 2.3 Hz), 5.16 (dd, 1H, J 10.1, 2.1 Hz), 2.97 (ddd, 1H, J -16.7, 11.3, 5.9 Hz), 2.77 (ddd, 1H, J -16.7, 8.1,4.5 Hz) 2.20 (m, 1H), 2.02 (m, 1H).
Primjer 2. Intermedijeri
a) Kroman-4-nonski intermedijeri
6-hidroksi-2-(4-fluorofenil)kroman-4-on
2',5'-dihidroksiacetofenon (3,0 g) je otopljen u toploj glacijalnoj octenoj kiselini (40 ml). Dodani su 4-fluorobenzaldehid (2,4 ml) i amonijev acetat (1,97 g). Reakcijska smjesa je refluksirana 8 sati. Ostavljena je da se ohladi do sobne temperature i sipana na led. Formirani precipitat je profiltriran i dobijeno je 4,23 g smjese 2-(4-fluorofenil)-6-hidrokskroman-4-ona i l-(2,5-dihidroksifenil)-3-(4-fluorofenil)propenona. Dobijena smjesa je otopljena u etanolu (75 ml) i dodan je natrijev acetat (3,4 g). Reakcijska smjesa je refluksirana 5 sati. Zatim je ostavljena da se ohladi do sobne temperature, razrijeđena vodom i profiltrirana. 2-(4-fluorofenil)-6-hidrokskroman-4-on je rekristaliziran iz octene kiseline.
1HNMR (400 MHz, d6-DMSO) δ: 7.59 (m, 2H), 7.27 (m, 2H), 7.14 (d, 1H, J 3.1 Hz), 7.05 (dd, 1H, J 8.9, 3.1 Hz), 6.96 (d, 1H, J 8.9 Hz), 5.56 (dd, 1H, J 13.2, 2.8 Hz), 3.18 (dd, 1H, J -16.9,13.2 Hz), 2.77 (dd, 1H, J -16.9,2.8 Hz).
Korištenjem istog postupka kao što je opisano ranije za 6-hidroksi-2-(4-fluorofenil)kroman-4-on, ali zamjenjujući 4-fluorobenzaldehid odgovarajućim benzaldehidom, dobijen je:
2-(3-fluorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.47 (m, 1H), 7.40-7.37 (m, 2H), 7.22 (m, 1H), 7.12 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.59 (dd, 1H, J 13.0,2.9 Hz), 3.21 (dd, 1H, J -16.9,13.0 Hz), 2.82 (dd, 1H, J -16.9, 2.9 Hz).
2-(2-fluorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.67 (m, 1H), 7.47 (m, 1H), 7.32-7.25 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.04 (dd, 1H, J 8.9, 3.0 Hz), 6.95 (d, 1H, J 8.9 Hz), 5.77 (dd, 1H, J 13.5, 2.8 Hz), 3.26 (dd, 1H, J -16.9,13.5 Hz), 2.76 (dd, 1H, J -16.9, 2.8 Hz).
2-(2,3-difluorofenil)-6-hidrokskroman-4-on
1HNMR(400MHz,d6-DMSO)5: 9.51 (s, 1H), 7.53-7.46 (m,2H), 7.31 (m, 1H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.96 (d, 1H, J 8.8 Hz), 5.82 (dd, 1H, J 13.4, 2.8 Hz), 3.26 (dd, 1H, J -16.9,13.4 Hz), 2.79 (dd, 1H, J -16.9,2.8 Hz).
2-(2,4-difluorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.46 (s, 1H), 7.73 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 7.13 (d, 1H, J 2.9 Hz), 7.04 (dd, 1H, J 8.8,2.9 Hz), 6.95 (d, 1H, J 8.8 Hz), 5.74 (dd, 1H, J 13.5,2.8 Hz), 3.28 (dd, 1H, J -16.9,13.5 Hz), 2.74 (dd, 1H, J -16.9, 2.8 Hz).
2-(2,5-difluorofenil)-6-hidrokskroman-4-on
1H NMR (300 MHz, d6-DMSO) δ: 9.46 (s, 1H), 7.53 (m, 1H), 7.36-7.30 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.76 (dd, 1H, J 13.6,2.7 Hz), 3.26 (dd, 1H, J -16.8,13.6 Hz), 2.76 (dd, 1H, J -16.8,2.7 Hz).
2-(2,6-difluorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 7.55 (m, 1H) 7.22-7.18 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.03 (dd, 1H, J 8.9, 3.0 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.84 (dd, 1H, J 14.0, 3.0 Hz), 3.38 (dd, 1H, J -17.0,14.0 Hz), 2.80 (dd, 1H, J -17.0,3.0 Hz).
2-(3,5-difluorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, 1H), 7.30-7.23 (m, 3H), 7.12 (d, 1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 7.00 (d, 1H, J 8.8 Hz), 5.60 (dd, 1H, J 13.1, 2.8 Hz), 3.15 (dd, 1H, J-16.8, 13.1 Hz), 2.85 (dd, 1H, J-16.8,2.8 Hz).
6-Hidroksi-2-(2-trifluorometilfenil)kroman-4-on
1H NMR (300 MHz, d6-DMSO) δ: 9.48 (s, 1H), 8.07 (m, 1H) 7.86-7.79 (m, 2H), 7.66 (m, 1H), 7.15 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.95 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 13.8,2.4 Hz), 3.38 (dd, 1H, J -16.9,13.8 Hz), 2.66 (dd, 1H, J -16.9, 3.0 Hz).
6-hidroksi-2-(4-trifluorometilfenil)kroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, 1H), 7.82-7.76 (m, 4H), 7.13 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.99 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 12.9, 2.9 Hz), 3.16 (dd, 1H, J -16.9, 12.9 Hz), 2.86 (dd, 1H, J -16.9,2.9 Hz).
2-(3-kloro-4-fluorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.53 (m, 1H), 7.36-7.31 (m, 2H), 7.13 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.9, 3.0 Hz), 6.96 (d, 1H, J 8.9 Hz), 5.76 (dd, 1H, J 13.5, 2.7 Hz), 3.26 (dd, 1H, J -16.9,13.5 Hz), 2.75 (dd, 1H, J -16.9,2.7 Hz).
2-(2-klorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, 1H), 7.77 (dd, 1H, J 7.7,2.0 Hz), 7.53 (dd, 1H, J 7.6,1.8 Hz), 7.49-7.41 (m, 2H), 7.14 (d, 1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 6.93 (d, 1H, J 8.8 Hz), 5.78 (dd, 1H, J 13.6, 2.6 Hz), 3.19 (dd, 1H, J -16.9, 13.6 Hz), 2.78 (dd, 1H, J-16.9,2.6 Hz).
2-(3-klorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, 1H), 7.62 (s, 1H), 7.51-7.45 (m, 3H), 7.12 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8,3.0 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.58 (dd, 1H, J 13.1, 2.9 Hz), 3.18 (dd, 1H, J-16.9,13.1 Hz), 2.81 (dd, 1H, J -16.9,2.9 Hz).
2-(2,4-diklorofenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, 1H), 7.78 (d, 1H, J 8.5 Hz), 7.71 (d, 1H, J 2.0 Hz), 7.57 (dd, 1H, J 8.5,2.0 Hz), 7.14 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.77 (dd, 1H, J 13.5,2.7 Hz), 3.18 (dd, 1H, J -16.9, 13.5 Hz), 2.78 (dd, 1H, J -16.9,2.7 Hz).
2-(3-bromofenil)-6-hidrokskroman-4-on
1H NMR (300 MHz, d6-DMSO) δ: 9.41 (s, 1H), 7.50 (m, 1H), 7.59-7.53 (m, 2H), 7.39 (m, 1H) 7.12 (d, 1H, J 2.9 Hz), 7.05 (dd, 1H, J 8.8, 2.9 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.57 (dd, 1H, J 13.0,2.9 Hz), 3.12 (dd, 1H, J -16.9,13.0 Hz), 2.81 (dd, 1H, J -16.9,2.9 Hz).
2-(4-etilfenil)-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 7.43 (d, 2H, J 8.1 Hz), 7.25 (d, 2H, J 8.1 Hz), 7.11 (d, 1H, J 3.1 Hz), 7.03 (dd, 1H, J 8.9, 3.1 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.51 (dd, 1H, J 13.0,2.9 Hz), 3.15 (dd, 1H, J -16.9, 13.0 Hz), 2.75 (dd, 1H, J -16.9, 2.9 Hz), 2.62 (q, 2H, J 7.5 Hz), 1.18 (t, 3H, J 7.5Hz).
6-hidroksi-2-(2-nitrofenil)kroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, 1H), 8.05-8.06 (m, 1H), 7.96-7.98 (m, 1H), 7.83-7.87 (m, 1H), 7.65-7.69 (m, 1H), 7.14 (d, 1H, J 3.1 Hz), 7.05 (dd, 1H, J 8.8, 3.1 Hz), 6.91 (d, 1H, J 8.8 Hz), 5.69 (dd, 1H, J 13.0,2.6 Hz), 3.22 (dd, 1H, J 16.8, 13.0 Hz), 2.98 (dd, 1H, J 16.8,2.6 Hz).
6-hidroksi-2-(3-nitrofenil)kroman-4-on
1H NMR (300 MHz, d6-DMSO) δ: 8.40 (s, 1H), 8.24 (dd, 1H, J 8.2,2.3 Hz), 8.01 (d, 1H, J 7.9 Hz), 7.74 (t, 1H, J 15.9, 7.9 Hz), 7.13 (d, 1H, J 2.9 Hz), 7.07 (dd, 1H, J 8.8,2.9 Hz), 7.00 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 13.1,2.9 Hz), 3.21 (dd, 1H, J 16.8,13.1 Hz), 2.88 (dd, 1H, J 16.8, 2.9 Hz).
6-hidroksi-2-(4-nitrofenil)kroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.48 (s, 1H), 8.29 (d, 2H, J 6.9 Hz), 7.83 (d, 2H, J 6.9 Hz), 7.13 (d, 1H J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 7.01 (d, 1H, J 8.8 Hz), 5.77 (dd, 1H, J 13.0,3.0 Hz), 3.15 (dd, 1H, J 16.8,13.0 Hz), 2.89 (dd, 1H, J 16.8, 3.0 Hz).
6-hidroksi-2-(3-metoksifenil)kroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.42 (s, 1H), 7.33 (t, 1H, J 15.8, 8.3 Hz), 7.12 (d, 1H, J 3.0 Hz), 7.10 (s, 1H), 7.09 (d, 1H, J 8.3 Hz), 7.04 (dd, 1H, J 8.8, 3.0 Hz), 6.96 (d, 1H, 8.8 Hz), 6.93 (dd, 1H, J 8.0, 2.5 Hz), 5.52 (dd, 1H, J 12.9, 2.9 Hz), 3.77 (s, 3H), 3.17 (dd, 1H, J 16.9,12.9 Hz), 2.77 (dd, 1H, J 16.9,2.9 Hz).
6-hidroksi-3-metil-2-fenilkroman-4-on
1H NMR (300 MHz, d6-DMSO) δ: 9.37 (s, 1H), 7.53 (m, 2H), 7.47-7.39 (m, 3H), 7.13 (d, 1H, J 3.1 Hz), 7.02 (dd, 1H, J 8.9,3.1 Hz), 6.89(d, 1H, J 8.9 Hz), 5.17 (d, 1H, J 12.3), 3.18 (dq, 1H, J 12.3,6.9 Hz), 0.84 (d, 3H, J 6.9 Hz).
b) Kroman-4,6-diolni intermedijeri 2-(4-fluorofenil)kroman-4,6-diol
U suspenziju 2-(4-fluorofenil)-6-hidrokskroman-4-ona (3,4 g) u suhom THF (34 ml) dodana je, kap po kap, otopina boran-THF kompleksa (20 ml, 1,0 M u THF) pod dušikom. Reakcijska smjesa je refluksirana 1 sat. Poslije hlađenja do sobne temperature, sipana je u ledenu 2M otopinu HCl. 2-(4-fluorofenil)kroman-4,6-diol je profiltriran.
1H NMR (400 MHz, d6-DMSO) δ: 8.84 (s, 1H), 7.48 (m, 2H), 7.21 (m, 2H), 6.89 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.7 Hz), 5.42 (bs, 1H), 5.12 (d, 1H, J 10.7 Hz), 4.87 (m, 1H), 2.25 (m, 1H), 1.89 (m, 1H).
Korištenjem istog postupka kao što je opisano ranije za 2-(4-fluorofenil)kroman-4,6-diol, ali zamjenjujući 2-(4-fluorofenil)-6-hidrokskroman-4-on odgovarajućim 2-fenil-6-hidrokskroman-4-onom, dobij en je:
2-(3-fluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.45 (m, 1H), 7.30-7.25 (m, 2H), 7.15 (m, 1H), 6.88 (d, 1H, J 2.8 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.44 (d, 1H, J 7.0 Hz), 5.15 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.29 (m, 1H), 1.86 (m, 1H).
2-(2-fluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.28-7.21 (m, 2H), 6.89 (d, 1H, J 2.9 Hz), 6.60 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.8 Hz), 5.46 (d, 1H, J 6.9 Hz), 5.35 (d, 1H, J 10.6 Hz), 4.89 (m, 1H), 2.26 (m, 1H), 1.98 (m, 1H).
2-(2,3-difluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) 8: 8.88 (s, 1H), 7.45-7.36 (m, 2H), 7.28 (m, 1H), 6.89 (d, 1H, J 2.8 Hz), 6.61 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.49 (bs, 1H), 5.40 (dd, 1H, J 11.8,1.4 Hz), 4.90 (m, 1H), 2.28 (m, 1H), 1.99 (m, 1H).
2-(2,4-difluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.86 (s, 1H), 7.61 (m, 1H), 7.28 (m, 1H), 7.14 (m, 1H), 6.88 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.9 Hz), 6.54 (dd, 1H, J 8.9, 2.7 Hz), 5.46 (s, 1H), 5.32 (dd, 1H, J 11.9,1.4 Hz), 4.88 (m, 1H), 2.24 (m, 1H), 1.99 (m, 1H).
2-(2,5-difluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.39-7.22 (m, 3H), 6.89 (d, 1H, J 2.8 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 8.7,2.8 Hz), 5.50 (d, 1H, J 6.8 Hz), 5.35 (d, 1H, J 11.2 Hz), 4.89 (m, 1H), 2.28 (m, 1H), 1.95 (m, 1H).
2-(2,6-difluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.48 (m, 1H), 7.17-7.13 (m, 2H), 6.90 (d, 1H, J 2.9 Hz), 6.55-6.54 (m, 2H), 5.46 (dd, 1H, J 12.2, 1.8 Hz), 4.87 (tn, 1H), 2.37 (m, 1H), 2.23 (ra, 1H).
2-(3,5-difluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.21-7.17 (m, 3H), 6.88 (d, 1H, J 2.4 Hz), 6.64 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 2.4, 8.7 Hz), 5.47 (d, 1H, J 7.0 Hz), 5.17 (d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.32 (m, 1H), 1.85 (m, 1H).
2-(2-trifluorometilfenil)kroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) δ: 8.89 (s, 1H), 7.83 (m, 1H), 7.79-7.74 (m, 2H), 7.58 (m, 1H), 6.90 (d, 1H, J 2.7 Hz), 6.61 (d, 1H, J 8.9 Hz), 6.56 (dd, 1H, J 8.7, 2.7 Hz), 5.51 (d, 1H, J 6.5 Hz), 5.34 (d, 1H, J 11.6 Hz), 4.88 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H).
2-(4-trifluorometilfenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.86 (s, 1H), 7.77 (d, 2H, J 8.3 Hz), 7.68 (d, 2H, J 8.3 Hz), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 8.7, 2.9 Hz), 5.45 (d, 1H, J 7.0 Hz), 5.26 (d, 1H, J 11.2 Hz), 4.90 (m, 1H), 2.32 (m, 1H), 1.85 (m, 1H).
2-(3-kloro-4-fluorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.88 (s, 1H), 7.39-7.24 (m, 3H), 6.88 (d, 1H, J 2.8 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.49 (d, 1H, J 6.8 Hz), 5.35 (d, 1H, J 11.3 Hz), 4.89 (m, 1H), 2.39 (m, 1H), 1.97 (m, 1H).
2-(2-klorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 7.63 (dd, 1H, J 7.7, 1.8 Hz), 7.49 (dd, 1H, J 7.8, 1.4 Hz), 7.45-7.36 (m, 2H), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.8 Hz), 6.56 (dd, 1H, J 8.9, 2.9 Hz), 5.39 (dd, 1H, J 11.7, 1.5 Hz), 4.90 (m, 1H), 2.33 (m, 1H), 1.82 (m, 1H).
2-(3-klorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6DMSO) δ: 8.85 (s, 1H), 7.50 (d, 1H, J 1.7 Hz), 7.46-7.38 (m, 3H), 6.88 (d, 1H, J 2.5 Hz), 6.62 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6, 2.5 Hz), 5.44 (d, 1H, J 6.6 Hz), 5.15 (dd, 1H, J 11.8,1.4 Hz), 4.87 (m, 1H), 2.29 (m, 1H), 1.85 (m, 1H).
2-(2,4-diklorofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.89 (s, 1H), 7.66 (d, 1H, J 2.1 Hz), 7.64 (d, 1H, J 8.5 Hz), 7.51 (dd, 1H, J 2.1, 8.5 Hz), 6.89 (d, 1H, J 2.7 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 2.7, 8.7 Hz), 5.50 (d, 1H, J 6.8 Hz), 5.37 (d, 1H, J 10.4 Hz), 4.90 (m, 1H), 2.32 (m, 1H), 1.80 (m, 1H).
2-(3-bromofenil)-kroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) δ: 8.83 (s, 1H), 7.63 (m, 1H) 7.53 (m, 1H) 7.46 (m, 1H) 7.37 (m, 1H), 6.88 (d, 1H, J 2.9 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.9 Hz), 5.42 (d, 1H, J 7.0 Hz), 5.14 (d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.29 (m, 1H), 1.84 (m, 1H).
2-(4-etilfenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.81 (s, 1H), 7.34 (d, 2H, J 8.0 Hz) 7.22 (d, 2H, J 8.0 Hz), 6.88 (d, 1H, J 2.8 Hz), 6.57 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6,2.8 Hz), 5.39 (d, 1H, J 7.1 Hz), 5.06 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.61 (q, 2H, J 7.6 Hz), 2.29 (m, 1H), 1.84 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).
2-(2-nitrofenil)kroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.99-8.02 (m, 1H), 7.77-7.86 (m, 2H), 7.59-7.64 (m, 1H), 6.89 (d, 1H, J 2.4 Hz), 6.56-6.57 (tn, 2H), 5.51-5.55 (m, 2H), 4.85-4.92 (m, 1H), 2.42-2.47 (m, 1H), 1.85-1.96 (m, 1H).
2-(3 -nitrofenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.89 (br s, 1H), 8.29 (s, 1H), 8.20 (dd, 1H, J 8.2, 2.3 Hz), 7.93 (d, 1H, J 7.9 Hz), 7.71 (t, 1H, J 15.9, 7.9 Hz), 6.89 (d, 1H, J 2.8 Hz), 6.66 (d, 1H, J 8.7 Hz), 6.57 (dd, 1H, J 8.7, 2.9 Hz), 5.47 (br s, 1H), 5.33 (d, 1H, J 10.7 Hz), 4.88-4.92 (m, 1H), 2.33-2.39 (m, 1H), 1.83-1.92 (m, 1H).
2-(4-nitrofenil)kroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) δ: 8.86 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.74 (d, 2H, J 6.9 Hz), 6.89 (d, 1H J 2.8 Hz), 6.65 (d, 1H, J 8.6 Hz), 6.56 (dd, 1H, J 8.6, 2.8 Hz), 5.46 (d, 1H, J 6.9 Hz), 5.32 (d, 1H, J 10.5 Hz), 4.86-4.94 (m, 1H), 2.31-2.38 (m, 1H), 1.78-1.89 (m, 1H).
2-(3-metoksifenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.31 (t, 1H, J 15.7, 7.9 Hz), 6.99-7.02 (m, 2H), 6.88-6.90 (m, 2H), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7,2.8 Hz), 5.40 (d, 1H, J 7.0 Hz), 5.08 (d, 1H, J 11.5 Hz), 4.83-4.89 (m, 1H), 3.77 (s, 3H), 2.23-2.28 (m, 1H), 1.83-1.92 (m, 1H).
3-metil-2-fenilkroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) δ: 8.79 (s, 1H), 7.42-7.33 (m, 5H), 6.88 (bs, 1H,), 6.53 (m, 2H), 5.37 (d, 1H, J 8.0 Hz), 4.70 (d, 1H, J 10.6 Hz), 1.94 (m, 1H), 0.73 (d, 3H, J 6.7 Hz).
c) Kroman-6-ol intermedijeri 2-(4-fluorofenil)kroman-6-ol
Trietilsilan (14 ml) je polako dodan u otopinu 2-(4-fluorofenil)kroman-4,6-diola (2,9 g) u diklorometanu (58 ml). Trifluorooctena kiselina (27 ml) je zatim dodana kap po kap u reakcijsku smjesu i miješana na sobnoj temperaturi 1 sat. Reakcijska smjesa je sipana na smjesu leda i vode i ekstrahirana diklorometanom. Ostatak je uparen pod smanjenim tlakom uz toluen da se dobije 2-(4-fluorofenil)kroman-6-ol.
1H NMR (400 MHz, CDCl3) δ: 7.38 (m, 2H), 7.06 (m, 2H), 6.77 (d, 1H, J 8.6 Hz), 6.61 (dd, 1H, J 8.6,2.9 Hz) 6.57 (d, 1H, 8.6 Hz), 4.97 (dd, 1H, J 10.2,2.4 Hz), 2.95 (ddd, 1H, J -16.8,11.4,6.2 Hz), 2.74 (ddd, 1H, J -16.8, 5.3,3.1 Hz), 2.15 (m, 1H), 2.05 (m, 1H).
Korištenjem istog postupka kao što je opisano ranije za 2-(4-fluorofenil)kroman-6-ol, ali zamjenjujući 2-(4-fluorofenil)kroman-4,6-diol odgovarajućim 2-fenilkroman-4,6-diolom, dobijenje:
2-(3-fluorofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.78 (s, 1H), 7.43 (m, 1H), 7.28-7.25 (m, 2H), 7.14 (m, 1H), 6.66 (d, 1H, J 8.5 Hz) 6.52 (dd, 1H, J 8.5, 2.7 Hz), 6.49 (d, 1H, J 2.7 Hz), 5.03 (dd, 1H, J 9.9,2.1 Hz), 2.86 (tn, 1H), 2.63 (m, 1H) 2.13 (m, 1H), 1.93 (m, 1H).
2-(2-fluorofenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ 7.50 (m, 1H), 7.39 (m, 1H), 7.26-7.19 (m, 2H), 6.63 (m, 1H) 6.53-6.50 (m, 2H), 5.21 (dd, 1H, J, 10.2, 2.3 Hz), 2.98 (ddd, 1H, J -16.9, 11.2, 6.0 Hz), 2.66 (ddd, 1H, J-16.9,5.0,2.9Hz)2.11 (m, 1H), 1.99 (m, 1H).
2-(2,3-difluorofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.26 (m, 1H), 6.64 (dd, 1H, 9.0, 2.8 Hz), 6.54-6.51 (m, 2H), 5.25 (dd, 1H, J 10.2, 2.2 Hz), 2.93 (m, 1H), 2.66 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).
2-(2,4-difluorofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.83 (s, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 7.13 (m, 1H), 6.63 (m, 1H), 6.53-6.50 (m, 2H), 5.17 (dd, 1H, J 10.3, 2.3 Hz), 2.92 (ddd, 1H, J -17.0, 11.5, 5.8 Hz), 2.66 (ddd, 1H, J -17.0,5.0,2.7 Hz), 2.09 (m, 1H), 1.98 (m, 1H).
2-(2,5-Difluorofenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.34-7.22 (m, 3H), 6.71-6.51 (m, 3H), 5.20 (m, 1H), 2.93 (m, 1H,), 2.68 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H).
2-(2,6-difluorofenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ : 8.85 (s, 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.26 (m, 1H), 6.64 (dd, 1H, J 9.0, 2.8 Hz), 6.54-6.51 (m, 2H), 5.25 (dd, 1H, J 10.2, 2.2 Hz), 2.93 (m, 1H,), 2.66 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).
2-(3,5-difluorofenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.20-7.14 (m, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.53 (d, 1H, J 2.9 Hz), 6.50 (dd, 1H, J 8.6, 2.9 Hz), 5.05 (dd, 1H, J 9.8, 2.2 Hz), 2.88 (ddd, 1H, J -16.7, 10.8, 5.9 Hz), 2.62 (ddd, 1H, J -16.7, 8.9, 5.0 Hz), 2.15 (m, 1H), 1.93 (m, 1H).
2-(2-trifluorometilfenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.86 (s, 1H), 7.81-7.75 (m, 3H), 7.57 (m, 1H), 6.674 (dd, 1H, J 7.1, 2.1 Hz), 6.54-6.51 (m, 2H), 5.14 (d, 1H, J 10.5 Hz), 2.95 (m, 1H), 2.72 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H).
2-(4-trifluorometilfenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.75 (d, 2H, J 8.3 Hz), 7.65 (d, 2H, J 8.3 Hz), 6.67 (d, 1H, J 8.6 Hz), 6.53 (d, 1H, J 2.9 Hz) 6.51 (dd, 1H, 8.6,2.9 Hz), 5.12 (d, 1H, J 8.3 Hz), 2.90 (m, 1H), 2.63 (m, 1H), 2.16 (m, 1H), 1.92 (m, 1H).
2-(3-kloro-4-fluorofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.84 (s, 1H), 7.33-7.21 (m, 3H), 6.66 (d, 1H, J 8.3 Hz) 6.54-6.51 (m, 2H), 5.19 (d, 1H, J, 8.8 Hz), 2.92 (m, 1H), 2.66 (m, 1H) 2.12 (m, 1H), 1.96 (m, 1H).
2-(2-klorofenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ: 7.58-7.36 (m, 4H), 6.66 (m, 1H), 6.55-6.51 (m, 2H), 5.23 (dd, 1H, J 10.1,2.1 Hz), 2.92 (m, 1H), 2.68 (m, 1H), 2.17 (m, 1H), 1.87 (m, 1H).
2-(3-klorofenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ: 8.79 (s, 1H), 7.48 (d, 1H, J 0.7 Hz), 7.42-7.37 (m, 3H), 6.71-6.49 (m, 3H), 5.04 (m, 1H), 2.91 (m, 1H), 2.65 (m, 1H), 2.12 (m, 1H), 1.93 (m, 1H).
2-(2,4-diklorofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.65 (d, 1H, J 2.2 Hz), 7.57 (d, 1H, J 8.4 Hz), 7.49 (dd, 1H, J 8.4, 2.2 Hz), 6.67-6.51 (m, 3H), 5.21 (dd, 1H, J 10.3, 2.1 Hz), 2.91 (m, 1H), 2.69 (m, 1H), 2.16 (m, 1H), 1.85 (m, 1H).
2-(3 -bromofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.81 (s, 1H), 7.61 (m, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.35 (m, 1H) 6.67-6.48 (m, 3H), 5.01 (m, 1H), 2.87 (m, 1H,), 2.63 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H).
2-(4-etilfenil)kroman-6-ol
1H NMR (400 MHz, CD3OD) δ: 7.26 (d, 2H, J 8.2 Hz) 7.13 (d, 2H, J 8.2 Hz), 6.65 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6, 2.8 Hz), 6.51 (d, 1H, J 2.8 Hz)„ 4.83 (dd, 1H, J 10.1, 2.3 Hz), 2.84 (m, 1H,), 2.62 (m, 1H), 2.59 (q, 2H, J 7.6 Hz) 2.03 (m, 1H), 1.93 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).
2-(2-nitrofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 8.00 (d, 1H, J 8.0 Hz), 7.79-7.80 (m, 2H), 7.59-7.63 (m, 1H), 6.59-6.62 (m, 1H), 6.50-6.53 (m, 2H), 5.36 (dd, 1H, J 10.2, 2.0 Hz), 2.89-2.93 (m, 1H), 2.67-2.73 (m, 1H), 2.26-2.31 (m, 1H), 1.90-1.95 (m, 1H).
2-(3-nitrofenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ: 8.80 (s, 1H), 8.26 (s, 1H), 8.19 (dd, 1H, J 8.1, 2.3 Hz), 7.90 (d, 1H, J 7.9 Hz), 7.70 (t, 1H, J 15.9, 7.9 Hz), 6.70 (d, 1H, J 8.4 Hz), 6.51-6.55 (m, 2H), 5.19 (dd, 1H, J 10.0, 2.0), 2.86-2.91 (m, 1H), 2.61-2.68 (m, 1H), 2.17-2.23 (m, 1H), 1.91-1.97 (m, 1H).
2-(4-nitrofenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.84 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.71 (d, 2H, J 6.9 Hz), 6.69 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6, 2.8 Hz), 6.50 (d, 1H, J 2.8 Hz), 5.19 (dd, 1H, J 9.9, 2.2 Hz), 2.87-2.91 (m, 1H), 2.61-2.66 (m, 1H), 2.16-2.21 (m, 1H), 1.89-1.93 (m, 1H).
2-(3-Metoksifenil)kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ: 8.75 (s, 1H), 7.28 (t, 1H, J 15.7, 7.9 Hz), 6.96-6.99 (m, 2H), 6.87 (dd, 1H, J 7.9, 2.5 Hz), 6.63 (d, 1H, J 8.3 Hz), 6.52 (d, 1H, J 2.9 Hz), 6.48 (s, 1H), 4.95 (dd, 1H, J 9.8, 2.2 Hz), 3.75 (s, 3H), 2.82-2.89 (m, 1H), 2.57-2.66 (m, 1H), 2.06-2.13 (m, 1H), 1.89-1.97 (m, 1H).
3-Metil-2-fenilkroman-6-ol
1H NMR (400 MHz, CD3OD) δ: 8.77 (s, 1H), 7.41-7.33 (m, 5H), 6.59-6.48 (m, 3H), 4.56 (d, 1H, J 9.2 Hz), 2.73 (dd, 1H, J -16.5, 5.0 Hz), 2.54 (dd, 1H, J -16.5, 5.8 Hz), 2.11 (m, 1H), 0.72 (d, 3H, J 6.6 Hz).
d) 2-[2-fenilkroman-6-iloksi]-5-nitropiridin intermedijeri
2-[2-(4-fluorofenil)kroman-6-iloksi]-5-nitropiridin
2-[2-(4-fluorofenil)kroman-6-iloksi]-5-nitropiridin je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru l(b) polazeći od 160 mg of 2-(4-fluorofenil)kroman-6-ol.
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (dd, 1H, J 2.9, 0.4 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.51 (m, 2H), 7.24 (m, 1H), 7.20 (dd, 1H, J 9.1, 0.4 Hz), 7.01 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7, 2.8 Hz) 6.91 (d, 1H, 8.7 Hz), 5.15 (dd, 1H, J 10.3, 2.2 Hz), 2.94 (m, 1H), 2.76 (m, 1H) 2.17 (m, 1H), 2.01 (m, 1H).
Korištenjem istog postupka kao što je opisano ranije za 2-[2-(4-fluorofenil)kroman-6-iloksi]-5-nitropiridin, ali zamjenjujući 2-(4-fluorofenil)kroman-6-ol odgovarajućim 2-fenilkroman-6-olom, dobijen je:
2-[2-(3-fluorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.46 (dd, 1H, J 9.0, 2.8 Hz), 7.36 (m, 1H), 7.21-7.15 (m, 2H), 7.03 (m, 1H), 7.01 (d, 1H, J 9.0 Hz), 6.98 (d, 1H, J 8.6 Hz) 6.92 (dd, 1H, J 8.6, 2.7 Hz), 6.90 (d, 1H, J 2.7 Hz), 5.09 (dd, 1H, J 10.3, 2.4 Hz), 3.01 (ddd, 1H, J-16.9, 11.4, 6.0Hz),2.82 (ddd, 1H, J-16.9,5.1,3.2 Hz) 2.24 (m, 1H), 2.09 (m, 1H).
2-[2-(2-fluorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) 5: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.56 (m, 1H), 7.43 (m, 1H), 7.30-7.22 (m, 2H), 7.20 (d, 1H, J 9.1 Hz), 7.02 (d, 1H, J 2.8 Hz) 6.98 (dd, 1H, J 8.7, 2.8 Hz), 6.91 (d, 1H, J 8.7 Hz), 5.37 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (ddd, 1H, J-17.0,11.5,6.0 Hz), 2.82 (ddd, 1H, J -17.0,5.1,2.8 Hz) 2.18 (m, 1H), 2.08 (m, 1H).
2-[2-(2,3-difluorofenil)kroman-6-iloksi]-5-nitropiridin
1HNMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 3.0Hz), 8.60 (dd, 1H, J 9.1, 3.0 Hz), 7.45 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.21 (d, 1H, 9.1Hz), 7.03 (d, 1H, J 2.7 Hz), 6.98 (dd, 1H, J 8.8, 2.7 Hz), 6.92 (d, 1H, 8.8 Hz), 5.42 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (m, 1H), 2.79 (m, 1H) 2.21 (m, 1H), 2.08 (m, 1H).
2-[2-(2,4-difluorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, d6 -DMSO) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.0, 3.0 Hz), 7.61 (m, 1H), 7.31 (m, 1H), 7.21 (d, 1H, 9.0Hz), 7.17 (m, 1H) 7.02 (d, 1H, J 2.9 Hz), 6.97 (dd, 1H, J 8.9, 2.9 Hz), 6.91 (d, 1H, 8.9 Hz), 5.34 (dd, 1H, J 9.9, 2.0 Hz), 3.03 (m, 1H), 2.78 (m, 1H) 2.17 (m, 1H), 2.07 (m, 1H).
2-[2-(2,5-difluorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) δ: 9.07 (dd, 1H, J 2.8, 0.4 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.26 (m, 1H), 7.05-6.91 (m, 6H), 5.35 (dd, 1H, J 10.3, 1.5 Hz), 3.04 (ddd, 1H, J -16.9, 11.7,6.0 Hz), 2.82 (ddd, 1H, J-16.9, 5.2, 3.0 Hz) 2.29 (m, 1H), 2.01 (m, 1H).
2-[2-(2,6-difluorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.1, 3.0 Hz), 7.45 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.21 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 2.7 Hz), 6.98 (dd, 1H, J 8.8,2.7 Hz) 6.92 (d, 1H, J 8.8 Hz), 5.42 (dd, 1H, J 10.4,2.3 Hz), 3.04 (m, 1H), 2.79 (m, 1H) 2.21 (m, 1H), 2.08 (m, 1H).
2-[2-(3,5-difluorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.23-7.19 (m, 4H), 7.01-6.95 (m, 3H), 5.18 (dd, 1H, J 10.0, 2.1 Hz), 2.97 (ddd, 1H, J -16.9, 10.9, 5.7 Hz), 2.76 (ddd, 1H, J -16.9, 8.4,4.7 Hz) 2.22 (m, 1H), 1.99 (m, 1H).
2-[2-(2-trifluorometilfenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2,2.9 Hz), 7.86-7.76 (m, 3H), 7.60 (m, 1H), 7.22 (d, 1H, J 9.2 Hz) 7.05 (d, 1H, J 2.7 Hz), 6.99 (dd, 1H, J 8.7, 2.7 Hz), 6.91 (d, 1H, 8.7 Hz), 5.30 (d, 1H, J 10.0, Hz), 3.05 (m, 1H), 2.84 (ra, 1H) 2.16-2.00 (m, 2H).
2-[2-(4-trifluorometilfenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.79 (d, 2H, J 8.2 Hz), 7.70 (d, 1H, J 8.2 Hz), 7.21 (d, 1H, J 9.1 Hz) 7.01 (dd, 1H, J 8.7, 2.7 Hz) 6.98 (d, 1H, J 2.7 Hz), 6.95 (d, 1H, 8.7 Hz), 5.29 (dd, 1H, J 10.1, 2.0 Hz), 3.00 (ddd, 1H, J-16.9, 10.1, 5.8 Hz), 2.4 (ddd, 1H, J-16.9, 8.4,4.5 Hz) 2.24 (m, 1H), 1.99 (m, 1H).
2-[2-(3-kloro-4-fluorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1,2.9 Hz), 7.40-7.27 (m, 3H), 7.21 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 2.7 Hz) 6.98 (dd, 1H, J 8.8, 2.7 Hz), 6.94 (d, 1H, J 8.8 Hz), 5.36 (dd, 1H, J 10.7,2.1 Hz), 3.04 (m, 1H), 2.80 (m, 1H) 2.18 (m, 1H), 1.99 (m, 1H).
2-[2-(2-klorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9, 0.5 Hz), 8.60 (dd, 1H, J 9.1,2.9 Hz), 7.62 (dd, 1H, J 7.5, 1.8 Hz), 7.51 (dd, 1H, J 7.6, 1.7 Hz), 7.45-7.40 (m, 2H), 7.21 (dd, 1H, J 9.1, 0.5 Hz), 7.04 (d, 1H, J 2.7 Hz), 6.99 (dd, 1H, J 8.8, 2.7 Hz), 6.94 (d, 1H, 8.8 Hz), 5.40 (dd, 1H, J 10.4,2.1 Hz), 3.04 (m, 1H), 2.80 (m, 1H) 2.24 (m, 1H), 1.95 (m, 1H).
2-[2-(3-klorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0, 2.9 Hz), 7.53 (s, 1H), 7.46-7.42 (m, 3H), 7.20 (d, 1H, J 9.0 Hz) 7.00 (dd, 1H, J 8.7, 2.7 Hz), 6.97 (d, 1H, J 2.7 Hz), 6.94 (d, 1H, J 8.7 Hz), 5.18 (dd, 1H, J 10.2, 2.2 Hz), 2.97 (ddd, 1H, J -17.0, 11.5, 5.9 Hz), 2.83 (ddd, 1H, J -17.0, 8.1,4.5 Hz) 2.21 (m, 1H), 2.00 (m, 1H).
2-[2-(2,4-diklorofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) δ: 9.06 (d, 1H, J 2.7 Hz), 8.47 (dd, 1H, J 9.0, 2.7 Hz), 7.56 (d, 1H, J 8.4 Hz), 7.41 (d, 1H, J 2.0 Hz), 7.33 (dd, 1H, J 8.4, 2.0 Hz) 7.02 (d, 1H, J 9.0 Hz) 6.99-6.92 (m, 3H), 5.39 (dd, 1H, J 10.4, 2.2 Hz), 3.06 (ddd, 1H, J -16.9, 11.9, 6.0 Hz), 2.83 (ddd, 1H, J -16.9, 5.3,2.7 Hz) 2.34 (m, 1H), 1.89 (m, 1H).
2-[2-(3-bromofenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.66 (bs, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.39 (m, 1H) 7.20 (d, 1H, J 9.2 Hz) 7.01-6.93 (m, 3H), 5.17 (dd, 1H, J 10.1, 2.2 Hz), 2.97 (m, 1H), 2.72 (ra, 1H) 2.20 (m, 1H), 2.00 (m, 1H).
2-[2-(4-etilfenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.36 (d, 2H, J 8.1 Hz) 7.24 (d, 2H, J 8.1 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.00 (d, 1H, J 2.7 Hz) 6.96 (dd, 1H, J 8.8, 2.7 Hz), 6.89 (d, 1H, J 2.7 Hz), 5.11 (dd, 1H, J 10.1, 2.2 Hz), 2.98 (m, 1H), 2.75 (m, 1H), 2.62 (q, 2H, J 7.5 Hz) 2.16 (m, 1H), 2.01 (m, 1H), 1.19 (t, 3H, J 7.5 Hz).
5-nitro-2-[2-(2-nitrofenil)kroman-6-iloksi]piridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 8.03 (d, 1H, J 7.9 Hz), 7.80-7.85 (m, 2H), 7.62-7.66 (m, 1H), 7.22 (d, 1H, J 9.1 Hz), 7.04 (d, 1H, J 2.8 Hz), 6.98 (dd, 1H, J 8.8, 2.8 Hz), 6.88 (d, 1H, J 8.8 Hz), 5.52 (dd, 1H, J 10.3, 2.0 Hz), 2.99-3.31 (m, 1H), 2.80-2.85 (m, 1H), 2.35-2.40 (m, 1H), 1.99-2.04 (m, 1H).
5-nitro-2-[2-(3-nitrofenil)kroman-6-iloksi]piridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0, 2.9 Hz), 8.32 (s, 1H), 8.23 (d, 1H, J 8.3 Hz), 7.95 (d, 1H, J 7.9 Hz), 7.74 (t, 1H, J 15.8, 7.9 Hz), 7.21 (d, 1H, J 9.0 Hz), 6.96-7.03 (m, 3H), 5.35 (d, 1H, J 8.7 Hz), 2.98-3.06 (m, 1H), 2.72-2.79 (m, 1H), 2.26-2.33 (m, 1H), 1.99-2.06 (m, 1H).
5-nitro-2-[2-(4-nitrofenil)kroman-6-iloksi]piridin
1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 8.29 (d, 2H, J 6.9 Hz), 7.76 (d, 2H, J 6.9 Hz), 7.21 (d, 1H, J 9.1 Hz), 6.98-7.02 (m, 3H), 5.35 (dd, 1H, J 9.9, 2.2 Hz), 2.96-3.05 (m, 1H), 2.73-2.78 (m, 1H), 2.24-2.29 (m, 1H), 1.96-2.04 (m, 1H).
2-[2-(3-metoksifenil)kroman-6-iloksi]-5-nitropiridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 7.32 (t, 1H, J 15.7, 7.9 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 8.4 Hz), 7.01 (s, 1H), 7.00 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7, 2.8 Hz), 6.92 (d, 1H, J 8.7 Hz), 6.90 (dd, 1H, J 8.4, 2.6 Hz), 5.12 (dd, 1H, J 10.0, 2.3 Hz), 3.77 (s, 3H), 2.93-2.97 (m, 1H), 2.71-2.77 (m, 1H), 2.15-2.20 (m, 1H), 1.99-2.05 (m, 1H).
2-(3-metil-2-fenilkroman-6-iloksi)-5-nitropiridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.59 (dd, 1H, J 9.1, 2.8 Hz), 7.43-7.36 (m, 5H), 7.19 (d, 1H, J 9.1 Hz), 7.00 (d, 1H, J 2.6 Hz) 6.95 (dd, 1H, J 8.7, 2.6 Hz), 6.86 (d, 1H, J 8.7 Hz), 4.73 (d, 1H, J 9.3 Hz), 2.85 (dd, 1H, J -16.7, 5.0 Hz), 2.64 (dd, 1H, J -16.5, 10.9 Hz), 2.18 (m, 1H), 0.77 (d, 3H, J 6.7 Hz).
Primjer 3. Intermedijeri
(5-nitropiridin-2-iloksi)-2-fenilkroman-4-onskiintennedijeri
6-(5-nitropiridin-2-iloksi)-2-fenilkroman-4-on
6-(5-nitropiridin-2-iloksi)-2-fenilkroman-4-onje dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1(b), korištenjem 200 mg 6-hidroksiflavanona.
1H NMR (400 MHz, d6-DMSO) δ: 9.03 (bs, 1H), 8.64 (d, 1H, J 9.0 Hz), 7.59-7.41 (m, 7H), 7.31 (d, 1H, J 9.0 Hz), 7.23 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 12.3, 2.9 Hz), 3.30 (dd, 1H, -16.3,12.3 Hz), 2.87 (dd, 1H, -16.3,2.9 Hz).
Korištenjem istog postupka kao što je opisano ranije za 6-(5-nitropiridin-2-iloksi)-2-fenilkroman-4-on, ali zamjenjujući 6-hidroksiflavanon odgovarajućim derivatom 2-fenilkromanona, dobijen je:
7-(5-nitropiridin-2-iloksi)-2-fenilkroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.67 (dd, 1H, J 9.0, 2.8 Hz), 7.89 (d, 1H, 8.6 Hz), 7.60-7.35 (m, 6H), 7.04 (d, 1H, 2.1 Hz), 6.97 (dd, 1 H, 8.6, 2.1 Hz), 5.75 (dd, 1H, J 13.0,2.7 Hz), 3.32 (dd, 1H, 16.9,13.0 Hz), 2.85 (d, -16.9, 2.7 Hz).
3-metil-6-(5-nitropiridin-2-iloksi)-2-fenilkroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.03 (d, 1H, J 2.9 Hz), 8.64 (dd, 1H, J 9.1, 2.9 Hz), 7.59-7.56 (m, 3H), 7.50-7.32 (m, 4H) 7.30 (d, 1H, J 9.1 Hz), 7.18 (d, 1H, J 8.9 Hz), 5.38 (d, 1H, J 12.5 Hz), 3.36 (dd, 1H, J 12.5,6.9 Hz), 0.86 (d, 3H, J 6.9 Hz).
Primjer 4. Intermedijeri
2-(2,3-dihidro-2-fenil-benzo[1,4]dioksin-6-iloksi)-5-nitropiridin
a) 1-[2,5-bis(benziloksi)fenil]etanon
Smjesa 1-(2,5-dihidroksifenil)etanona (3,16 g), benzil klorida (7,04 g), kalijevog karbonata (12,4 g) i 18-Crown-6 (30 mg) u 2-butanonu (50 ml) je grijana pod refluksom 5 sati. Poslije hlađenja, precipitat je odfiltriran. Filtrat je uparen do suhog pod sniženim tlakom i dodan mu je eter (50 ml). Otopina je oprana dvaputa razrijeđenom otopinom natrijevog hidroksida, dvaput razrijeđenom klorovodičnom kiselinom, osušena preko natrijevog sulfata i u biti uparena do suhog pod sniženim tlakom. Ostatak je trituriran hladnim n-heptanom (30 ml) i precipitat je odfiltriran na vakuum pumpi te poslije sušenja dobijemo 2,85 g l-[2,5-bis(benziloksi)fenil]etanona.
1H NMR (400 MHz, DMSO- d6) δ: 2.50 (s, 3H), 5.08 (s, 2H), 5.18 (s,2H), 7.20-7.50 (m, 13H).
b) 2,5-bis(benziloksi)fenil ester octene kiseline
Otopina 1-[2,5-bis(benziloksi)fenil]etanona (2,25 g) i 40%-ne peroctene kiseline (1,63 ml) u octenoj kiselini (5,4 ml) je miješana na 60°C 1 sat. Poslije hlađenja do sobne temperature, precipitiran proizvod je sakupljen filtracijom, opran hladnim etrom i osušen pod sniženim tlakom. 2,5-bis(benziloksi)fenil ester octene kiseline je rekristaliziran iz 2-propanola. Prinos je 1,87 g.
1H NMR (DMSO- d6,) δ: 2.23 (s, 1H), 5.03 (s, 2H), 5.05 (s, 2H), 6.84-7.44 (m, 13H).
c) 2,5-bis(benziloksi)fenol
Otopina 2,5-bis(benziloksi)fenil estera octene kiseline (1,85 g) i 5M otopina natrijevog hidroksida (10,6 ml) u etanolu (11 ml) je grijana pod refluksom 6,5 sati. Poslije uparavanja etanola pod sniženim tlakom, bistra otopina je zakiseljena razrijeđenom klorovodičnom kiselinom. Precipitiran proizvod je sakupljen filtracijom, opran hladnom vodom i osušen pod sniženim tlakom. Prinos je 0.56 g.
1H NMR (DMSO- d6) δ: 4.97 (s, 2H), 5.01 (s, 2H), 6.34 (dd, J 3.1, 8.8 Hz, 1H), 6.49(d, J 3.1 Hz, 1H), 6.85 (d, J 8.8 Hz, 1H), 7.28-7.46 (m, 10H), 9.1 (br s, 1H).
d) 2-[2,5-Bis(benziloksi) fenoksi]-1-feniletanone
Smjesa 2,5-bis(benziloksi)fenola (0,28 g), 2-bromoacetofenona (0,22 g), kiselog kalijevog karbonata (0,25 g) i 18-Crown-6 (3 mg) u acetonitrilu (4,2 ml) je miješana na 22°C jedan tjedan. Smjesa je profiltrirana i uparena do suhog pod sniženim tlakom. Ostatak je trituriran smjesom etera (8,2 ml) i vode (1,4 ml) na temperaturi ledene vodene kupke. Proizvod je sakupljen filtracijom, opran hladnim eterom i osušen pod sniženim tlakom. Prinos je 0,14 g.
1H NMR (DMSO- d6) δ: 4.98 (s, 2H), 5.06 (s, 2H), 5.58 (s, 2H), 6.51 (dd, J 8.9,2.3 Hz, 1H), 6.68 (d, J 2.3 Hz, 1H), 6.94 (d, J 8.9 Hz, 1H), 7.28-8.03 (m, 15H).
e)2-[2,5-bis(benziloksi)fenoksi]-1-feniletanol
Otopini 2-[2,5-bis(benziloksi)fenoksi]-1-feniletanona (0,14 g) u metanolu (0,5 ml) i tetrahidrofurana (1,9 ml) dodan je natrijev borohidrid (6,5 mg) na temperaturi od 0°C. Reakcija je miješana 15 minuta na 0°C i 2 sata na temperaturi od 22°C. Poslije dodavanja vode (5 ml), metanol i tetrahidrofuran su otpareni. Poslije miješanja ostatka 0,5 sata na 22°C, proizvod je profiltriran, opran hladnom vodom i osušen pod sniženim tlakom. Prinos je 0,09 g.
1H NMR (DMSO- d6) δ: 4.05 (m, 2H), 4.91 (m, 1H), 4.95 (s, 2H), 5.01 (s, 2H), 5.59 (d, J 4.7 Hz, 1H), 6.47 (dd, J 2.8,8.8 Hz, 1H), 6.68 (d, J 2.8 Hz, 1H), 6.89 (d, J 8.8 Hz, 1H), 7.24-7.45 (m, 15H).
f) 2-(2-hidroksi-2-feniletoksi)benzen-1,4-diol
Otopina 2-[2,5-bis(benziloksi)fenoksi]-1-feniletanol (3,9 g) u etanolu (175 ml) je hidrirana u prisutnosti 10 % paladija na ugljenu (100 mg) na 30 psi. Katalizator je uklonjen filtracijom i otapalo je upareno pod sniženim tlakom. Ostatak je rekristaliziran iz smjese toluen - etil acetat 8:1 (15 ml). Prinos 2-(2-hidroksi-2-feniletoksi)benzen-l,4-diola je 1,2 g.
1H NMR (DMSO- d6) δ: 3.79 (dd, J 9.6, 8.3 Hz, 1H), 4.00 (dd, J 9.6, 3.6 Hz, 1H), 4.94 (ddd, J 3.6, 8.3, 3.9 Hz, 1H), 5.66 (d, J 3.9 Hz, 1H), 6.18 (dd, J 8.5, 2.3 Hz, 1H), 6.34 (d, J 2.3, 1H), 6.57 (d, J 8.5, 1H), 7.26-7'.47 (m, 5H), 7.97 (s, 1H), 8.66 (s, 1H).
g) 2,3-dihidro-2-fenil-benzo[1,4]dioksin-6-ol
Otopina 2-(2-hidroksi-2-feniletoksi)benzen-l,4-diola (1,2 g) u toluenu (75 ml) je grijana s katalizatorom Amberlvst 15 (0,5 g) pod refluksom 7 sati. Poslije filtracije, otapalo je upareno pod sniženim tlakom. Ostatak je pročišćen kromatografijom na koloni silika gela (toluen/etil acetat/sirćetna kiselina, 8:1:1). Prinos 2,3-dihidro-2-fenil-benzo[1,4]dioksin-6-ola je 0.5 g.
1H NMR (DMSO- d6) δ: 4.02 (dd, J 8.5, 11.4 Hz, 1H), 4.35 (dd, J 2.3, 11.4 Hz, 1H), 5.11 (dd, J 8.5, 2.3 Hz, 1H), 6.29 (dd, J 2.8, 8.5 Hz, 1H), 6.32 (d, J 2.8 Hz, 1H), 6.75 (d, J 8.5 Hz, 1H), 7.36-7.47 (m, 5H), 8.99 (s, 1H).
h) 2-(2,3-dihidro-2-fenil-benzo[1,4]dioksin-6-iloksi)-5-nitropiridin
Otopina 2,3-dihidro-2-fenil-benzo[1,4]dioksin-6-ola (80 mg), 2-kloro-5-nitropiridina (56 mg) i kalijevog karbonata (52 mg) u dimetilformamidu (1,0 ml) je miješana na 120 °C 2 sata. Poslije hlađenja smjese, dodana je voda (10 ml) i precipitiran proizvod je profiltriran, opran vodom i 2-propanolom i osušen pod sniženim tlakom. Prinos je 60 mg, a t. t. 163-170°C.
1H NMR (DMSO- d6) δ 4.16 (dd, J 8.5, 11.6 Hz, 1H), 4.47 (dd, J 11.6, 2.6 Hz, 1H), 5.28 (dd, J 2.6, 8.5 Hz, 1H), 6.75 (dd, J 2.6, 8.8 Hz, 1H), 6.88 (d, J 2.6 Hz, 1H), 7.05 (d, J 8.8 Hz, 1H), 7.21 (d, J 9.1 Hz, 1H), 7.39-7.52 (m, 5H), 8.60 (dd, J 2.8, 9.1 Hz, 1H), 9.05 (d, J 2.8 Hz, 1H).
Primjer 5. Intermedijeri
5-nitro-2-(6-fenil-5,6,7,8-tetrahidro-naftalen-2-iloksi)-piridin
a) 6-metoksi-2-fenil-3,4-dihidro-2H-naftalen-1-on
Smjesa paladij (II) acetata (0,57 g), rac-2,2'-bis(difenilfosfino)-1,1'-binaftila (1,91 g) i kalijevog terc-butoksida (4,15 g) u suhom toluenu je miješana pod argonom 10 minuta. Dodani su bromobenzen (5,34 g) i 6-metoksi-1-tetralon (3,0 g) otopljeni u suhom toluenu i smjesa je miješana na 100°C 2 sata. Reakcijska smjesa je ohlađena do sobne temperature i sipana u zasićeni vodeni amonijev klorid i ekstrahirana etil eterom. Organski ekstrakt je opran slanom otopinom, osušen i uparen. Sirov proizvod je pročišćen fleš kromatografijom na silika gelu, uz upotrebu toluena i toluen/etil acetata (9:1) kao eluenata.
1H NMR (400 MHz, d6-DMSO) δ: 7.87 (d, 1H, J 7.8 Hz), 7.16-7.33 (m, 5H), 6.91-6.94 (m, 2H), 3.85 (s, 3H), 3.82-3.88 (m, 1H), 3.06-3.14 (m, 1H), 2.92-2.98 (m, 1H), 2.23-2.38 (m, 2H).
b) 6-hidroksi-2-fenil-3,4-dihidro-2H-naftalen-1 –on
6-metoksi-2-feml-3,4-dihidro-2H-naftalen-1-on (1,0 g) je refluksiran 47%-nom HBr (20 ml) sve dok polazni materijal nije nestao. Smjesa je sipana u vodu i ekstrahirana etil acetatom. Etil acetat je osušen i uparen. Proizvod je rekristaliziran iz toluena.
1H NMR (400 MHz, d6-DMSO) δ: 10.35 (s, 1H), 7.79 (d, 1H, J 8.6 Hz), 7.15-7.33 (m, 5H), 6.75 (dd, 1H, J 8.6, 2.4 Hz), 6.68 (d, 1H, J 2.3 Hz), 3.79-3.85 (m, 1H), 2.99-3.06 (m, 1H), 2.83-2.90 (m, 1H), 2.19-2.33 (m, 2H).
c)6-fenil-5,6,7,8-tetrahidro-naftalen-2-ol
Otopini 6-hidroksi-2-fenil-3,4-dihidro-2H-naftalen-1-ona (50 mg) u trifluorooctenoj kiselini je dodan trietilsilan (98 mg). Smjesa je grijana na 60°C 3 sata. Otapalo je upareno, voda je dodana ostatku i smjesa je ekstrahirana etil acetatom. Organski ekstrakt je osušen i uparen.
1H NMR (400 MHz, d6-DMSO) δ: 9.02 (s, 1H), 7.18-7.32 (m, 5H), 6.87 (d, 1H, J 7.9), 6.50-6.53 (m, 2H), 2.68-2.92 (m, 5H), 1.94-1.99 (m, 1H), 1.81-1.89 (m, 1H).
d) 5-nitro-2-(6-fenil-5,6,7,8-tetrahidro-naftalen-2-iloksi)-piridin
6-fenil-5,6,7,8-tetrahidro-naftalen-2-ol (30 mg), 2-kloro-5-nitropiridin (21 mg) i kalijev fluorid (23 mg) u suhom dimetilformamidu su zagrijani na 120 °C sve dok polazni materijal nije nestao. Voda i 1 N HCl su dodane i smjesa je ekstrahirana etil acetatom. Etil acetat je opran slanom otopinom i vodom, osušen i uparen. Proizvod je rekristaliziran iz toluena.
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.4 Hz), 8.61 (dd, 1H, J 9.0, 2.5), 7.18-7.35 (m, 7H), 6.95-6.99 (m, 2H), 2.83-3.01 (m, 5H), 1.87-2.04 (m, 2H).
Primjer 6. Intermedijeri
6-(5-nitro-piridin-2-iloksi)-2-fenil-3,4-dihidro-2H-naftalen-1 -on
6-(5-nitro-piridin-2-iloksi)-2-fenil-3,4-dihidro-2H-naftalen-1-on je dobijen kao što je opisano za 5-nitro-2-(6-fenil-5,6,7,8-tetrahidro-naftalen-2-iloksi)-piridin u Primjeru 5(d), korištenjem 50 mg 6-hidroksi-2-fenil-3,4-dihidro-2H-naftalen-1-ona, 33 mg 2-kloro-5-nitropiridina i 37 mg kalijum fluorida.
1H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.68 (dd, 1H, J 9.0, 2.9), 8.01 (d, 1H, J 8.5), 7.37 (d, 1H, J 9.1 Hz), 7.21-7.38 (m, 7H), 3.96-4.04 (m, 1H), 3.15-3.23 (m, 1H), 2.98-3.04 (m, 1H), 2.39-2.48 (m, 1H), 2.25-2.31 (m, 1H).
Primjer 7. Intermedijeri
2-[3-(fenil)kroman-7-iloksi]-5-nitropiridinintermedijeri
a) 2-(3-fluorofenil)-1-(2-hidroksi-4-metoksifenil)etanon
(3-fluorofenil)octena kiselina (3,7 g) i 3-metoksifenol (3,0 g) su otopljeni u BF3 Et2O (60 ml, 20 ekv) pod argonom. Smjesa je miješana na 60-70°C sve dok polazni materijali nisu nestali (9 sati) i sipana je u veliki volumen ledene vode. Poslije ekstrakcije etil acetatom, kombinirani organski slojevi su oprani vodom, osušeni i upareni. Sirovi proizvod je pročišćen kromatografijom na koloni, uz upotrebu CH2Cl2 kao eluenta.
1H NMR (400 MHz, d6-DMSO) δ: 12.41 (br s, 1H), 8.02 (d, 1H, J 9.0 Hz), 7.34-7.3S (m, 1H), 7.09-7.13 (m, 3H), 6.56 (dd, 1H, J 9.0, 2.5 Hz), 6.49 (d, 1H, J 2.5 Hz), 4.41 (s, 2H), 3.83 (s, 3H).
b)3-(3-fluorofenil)-7-metoksikromen-4-on
2-(3-fluorofenil)-1-(2-hidroksi-4-metoksifenil)etanon (1,76 g) je otopljen u piridinu (88 ml). Piperidin (8,8 ml) i trietilortoformijat (88 ml) su dodani i smjesa je miješana 3,5 sata na 120°C. Poslije sipanja smjese u vodu i zakiseljavanja konc. HCl, sirov proizvod je profiltriran. Prečišćavanje kromatografijom na koloni korištenjem heptan-etil acetata (7:3) kao eluenta daje 3-(3-fluorofenil)-7-metoksikromen-4-on.
1H NMR (400 MHz, d6-DMSO) δ: 8.57 (s, 1H), 8.06 (d, 1H, J 8.9 Hz), 7.45-7.50 (m, 3H), 7.21-7.25 (m, 1H), 7.20 (d, 1H, J 2.4 Hz), 7.12 (dd, 1H, J 8.9,2.4 Hz), 3.92 (s, 3H).
c)3-(3-fluorofenil)-7-hidroksikromen-4-on
3-(3-fluorofenil)-7-metoksikromen-4-on (320 mg) je refluksiran s 47 %-nom HBr (18 ml) sve dok polazni materijal nije nestao. Smjesa je sipana u vodu i precipitat je profiltriran i osušen dajući 3-(3-fluorofenil)-7-hidroksikromen-4-on.
1H NMR (400 MHz, d6-DMSO) δ: 10.87 (s, 1H), 8.49 (s, 1H), 7.99 (d, 1H, J 8.7 Hz), 7.43-7.49 (m, 3H), 7.20-7.24 (m, 1H), 6.97 (dd, 1H, J 8.7,2.2 Hz), 6.90 (d, 1H, J 2.2 Hz).
d) 3-(3-fluorofenil)kroman-7-ol
3-(3-fluorofenil)-7-hidroksikromen-4-on (160 mg) je otopljen u etanolu (40 ml) i dodan je 10 % paladij na ugljenu (400 mg). Reakcijska smjesa je hidrirana 6 sati kod normalnog tlaka i na sobnoj temperaturi. Zatim je profiltrirana kroz Celite i oprana etanolom. Otapalo je upareno pod smanjenim tlakom te se dobio 3-(3-fluorofenil)-krotnan-7-ol.
1H NMR (400 MHz, d6-DMSO) δ: 9.19 (br s, 1H), 7.38 (m, 1H), 7.17-7.21 (m, 2H), 7.08 (m, 1H), 6.88 (d, 1H, J 8.2 Hz), 6.30 (dd, 1H, J 8.2, 2.4 Hz), 6.20 (d, 1H, J 2.4 Hz), 4.22 (dd, 1H, J 10.3,3.6 Hz), 4.02 (t, 1H, 10.3 Hz), 3.20 (m, 1H), 2.90 (m, 2H).
e)2-[3-(3-fluorofenil)kroman-7-iloksi]-5-nitropiridin
2-[3-(3-fluorofenil)kroman-7-iloksi]-5-nitropiridin je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1(b), korištenjem 125 mg 3-(3-fluorofenil)-kroman-7-ola. Proizvod je rekristaliziran iz etanola.
1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.0, 2.8 Hz), 7.33 (m, 1H), 7.16 (d, 1H J 8.9 Hz), 6.95-7.06 (m, 4H), 6.69-6.71 (m, 2H), 4.38 (dd, 1H, J 10.6,4.3 Hz), 4.06 (t, 1H, 10.6 Hz), 3.30 (m, 1H), 3.06 (m, 2H).
Korištenjem istog postupka kao što je opisano ranije za 3-(3-fluorofenil)kroman-7-ol, ali zamjenjujući 3-(3-fluorofenil)-7-hidroksikromen-4-on odgovarajućim 7-hidroksi-3-fenil-kromen-4-onom, dobijen je:
3-fenilkroman-7-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.18 (br s, 1H), 7.31-7.34 (m, 4H), 7.25-7.27 (m, 1H), 6.88 (d, 1H, J 8.2 Hz), 6.30 (dd, 1H, J 8.2, 2.4 Hz), 6.20 (d, 1H, J 2.4 Hz), 4.21 (dd, 1H, J 10.3,3.6 Hz), 4.00 (t, 1H, 10.3 Hz), 3.13 (m, 1H), 2.84-2.87 (m, 2H).
Korištenjem istog postupka kao što je opisano ranije za 2-[3-(3-fluorofenil)kroman-7-iloksi]-5-nitropiridin, ali zamjenjujući 3-(3-fluorofenil)kroman-7-ol s 3-fenilkroman-7-olom, dobijen je:
5-nitro-2-(3-fenilkrornan-7-iloksi)piridin
1H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.34-7.38 (m, 4H), 7.27-7.30 (m, 1H), 7.22 (m, 2H), 6.70-6.74 (m, 2H), 4.31 (dd, 1H, J 10.4, 3.5 Hz), 4.12 (t, 1H, 10.4 Hz), 3.24 (m, 1H), 3.01-3.11 (m, 2H).
7-hidroksi-3-fenilkromen-4-on je komercijalno dostupan ili se sintetizira postupcima opisanim za 3-(3-fluorofenil)-7-hidroksikromen-4-on.
Primjer 8. Intermedijeri
5-nitro-2-(2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin
a) 2-(2-hidroksi-1 -feniletilsulfanil)benzen-1,4-diol
Otopini 2-merkaptobenzen-1,4-diola (0,5 g) i kalijevog karbonata (0,49 g) u vodi (5 ml) koja se miješa, dodan je 2-feniloksiran (0,40 ml) pod argonom. Smjesa je miješana na sobnoj temperaturi 2,5 sata, a zatim tretirana 2 M HCl i ekstrahirana etil acetatom. Kombinirani organski slojevi su oprani vodom i slanom otopinom, osušeni i upareni. Sirovi proizvod je pročišćen kromatografijom na koloni korištenjem heptan-etil acetata (1:1) kao eluenta.
1H NMR (400 MHz, d6-DMSO) δ: 8.94 (br s, 1H), 8.72 (br s, 1H), 7.24-7.37 (m, 5H), 6.62-6.65 (m, 2H), 6.47 (dd, 1H, J 8.6,2.8 Hz), 4.97 (br s, 1H), 4.34 (m, 1H), 3.72 (m, 2H).
b) 2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-ol
Otopina 2-(2-hidroksi-1-feniletilsulfanil)benzen-1,4-diol (0,83 g) u suhom toluenu (60 ml) je miješan s Amberlyst-om 15 (0,5 g) na 60°C sve dok polazni materijal nije nestao. Poslije filtriranja smjese i uparavanja otapala, sirovi proizvod je pročišćen kromatografijom na koloni, korištenjem heptan-etil acetata (1:1) kao eluenta.
1H NMR (400 MHz, CDCl3) δ: 7.41 (m, 4H), 7.33-7.40 (m, 1H), 6.81 (d, 1H, J 8.7 Hz), 6.61 (d, 1H, J 3.0 Hz), 6.51 (dd, 1H, J 8.7,3.0 Hz), 5.10 (dd, 1H, J 9.6, 1.9 Hz), 3.28 (dd, 1H, J 13.0,9.6 Hz), 3.06 (dd, 1H, J 13.0,1.9 Hz).
c)5-nitro-2-(2-feml-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin
5-nitro-2-(2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1(b) korištenjem 269 mg 2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-ola. Proizvod je rekristaliziran iz etanola.
1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.43 (m, 4H), 7.37-7.41 (m, 1H), 7.02 (d, 1H, J 9.1 Hz), 6.99 (d, 1H, J 8.9 Hz), 6.95 (d, 1H, J 2.8 Hz), 6.82 (dd, 1H, J 8.9, 2.8 Hz), 5.21 (dd, 1H, J 9.7, 1.9 Hz), 3.31 (dd, 1H, 13.2, 9.7 Hz), 3.11 (dd, 1H, 13.2,1.9 Hz).
Primjer 9. Intermedijeri
5-nitro-2-(2-fenilindan-5-iloksi)piridin
a) 3-(4-metoksifenil)-2-fenilakrilna kiselina
Trietilamin je dodan otopini p-anisaldehida (10 g) i feniloctene kiseline (10 g) u anhidridu octene kiseline (25 ml). Reakcijska smjesa je miješana na 90°C 8 sati. Reakcijska smjesa je ohlađena i dodana je vodena (600 ml) otopina kalijevog karbonata (81 g). Poslije dodavanja, reakcijska smjesa je zagrijvana na 60°C jedan sat. Prije neutralizacije koncentriranom klorovodičnom kiselinom, reakcijska smjesa je ohlađena ispod 10°C. Precipitat je profiltriran i opran vodom.
1H-NMR (400 MHz, d6-DMSO): 12.6 (bs, 1H), 7.67 (s, 1H), 7.4-7.3 (m, 3H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.8-6.7 (m, 2H), 3.70 (s, 3H). (M)+ = 254 (100%).
b) 3-(4-metoksifenil)-2-fenilpropionska kiselina
13 g 3-(4-metoksifenil)-2-fenilakrilne kiseline je otopljeno u 600 ml etil acetata i 2,6 g 10% paladija na ugljenu je dodato u inertnoj atmosferi. Polazni materijal je hidriran na sobnoj temperaturi te se dobio kvantitativni prinos 3-(4-metoksifenil)-2-fenilpropionske kiseline.
1H-NMR (400 MHz, d6-DMSO): 12.3 (bs, 1H), 7.32-7.20 (m, 5H), 7.1-7.0 (m, 2H), 6.8-6.7 (m, 2H), 3.79 (dd, 1H, J 6.9, 8.7 Hz), 3.70 (s, 3H), 3.22 (dd, 1H, J 8.7, 13.7 Hz), 2.87 (dd, 1H, J 6.9, 13.7 Hz).
c) 6-metoksi-2-fenilindan-1-on
Otopini 3-(4-metoksifenil)-2-fenilpropionske kiseline (4,6 g) u suhom metilen kloridu (26 ml), dodane su dvije kapi suhog DMF. Dodan je tionilklorid (3 ml) i reakcijska smjesa je miješana na 40°C 4 h. Otapalo je upareno pod vakuumom. Precipitat je otopljen u metilen kloridu. Otopina je ohlađena do 0-3°C. Ova otopina i aluminijev klorid (2,5g) su miješani polako više od 4 sata, održavajući temperaturu ispod 4°C. Poslije miješanja na hladnom, reakcijska smjesa je miješana na sobnoj temperaturi 2 sata. Reakcija je ugašena sipanjem u razrijeđenu ledenu klorovodičnu kiselinu. Slojevi su razdvojeni i vodena otopina je ekstrahirana metilen kloridom. Kombinirani organski slojevi su oprani vodom, osušeni i upareni. Sirovi proizvod je trituriran te se dobilo 2,9 g 6-metoksi-2-fenilindan-1-ona.
1H-NMR (400 MHz, d6-DMSO): 7.56 (d, 1H), 7.35-7.23 (m, 4H), 7.18-7.13 (m, 3H), 4.02 (dd, 1H, J 3.9, 8.0 Hz), 3.82 (s, 3H), 3.61 (dd, 1H, J 8.0, 17.2 Hz), 3.11 (dd, 1H, J 3.9, 17.2 Hz).
d) 5-metoksi-2-fenilindan
5-metoksi-2-fenilindan je dobijen kao što je opisano za 2-fenilkroman-6-ol u Primjeru 1(a) korištenjem 600 mg of 6-metoksi-2-fenilindan-1-on.
1H-NMR (400 MHz, d6-DMSO): 7.32-7.27 (m, 4H), 7.21-7.18 (m, 1H), 7.13 (d, 1H, J 8.2 Hz), 6.83 (d, 1H, J 2.4 Hz), 6.72 (dd, 1H, J 2.4, 8.2 Hz), 3.72 (s, 3H), 3.64 (k, 1H, J 8.5 Hz), 3.23 (dt, 2H, J 8.5,15.9 Hz), 2.92 (m, 2H).
e) 2-fenilindan-5-ol
Smjesa 5-metoksi-2-fenilindana (200 mg) i koncentrirane HBr (4 ml) je refluksirana 5,5 sati. Reakcijska smjesa je ostavljena da se ohladi do sobne temperature, dodano je 20 ml ledene vode i ekstrahirana je metilen kloridom. Kombinirani organski slojevi su oprani slanom otopinom i osušeni pomoću Na2SO4. Otapala su uparena te se dobio 2-fenilindan-5-ol.
1H-NMR (400 MHz, d6-DMSO): 9.05 (bs, 1H), 7.3-7.28 (m, 4H), 7.26-7.15 (m, 1H), 7.0 (d, 1H, J 8.1 Hz), 6.64 (d, 1H, J 1.9 Hz), 6.55 (dd, 1H, J 1.9, 8.1 Hz), 3.60 (k, 1H, J 8.6 Hz), 3.18 (m, 2H), 2.86 (dt, 2H, J 8.6, 16 Hz).
f) 5-nitro-2-(2-fenilindan-5-iloksi) piridin
5-nitro-2-(2-fenilindan-5-iloksi) piridin je dobijen kao što je opisano za 2-fenilkroman-6-iloksi)piridin u Primjeru l(b) korištenjem 107 mg 2-fenilindan-5-ola.
1H-NMR (400 MHz d6-DMSO): 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 2.9, 9.1 Hz), 7.38-7.28 (m, 5H), 7.24-7.20 (m, 2H), 7.11 (d, 1H, J 2.2 Hz), 7.00 (dd, 1H, J 2.2, 8.0 Hz), 3.72 (k, 1H, J 8.9 Hz), 3.36-3.28 (m, 2H), 3.01 (dd, 2H, J 8.9,15.3 Hz).
Primjer 10. Intermedijeri
5-aminopiridin intermedijeri
5-amino-2-(2-fenilkroman-6-iloksi)piridin
5-nitro-2-(2-fenilkroman-6-iloksi)piridin (2,26g) je otopljen u 350 ml glacijalne octene kiseline. Cink u prahu (8,48g) je dodan nekoliko puta zbog egzotermne reakcije. Smjesa je miješana na sobnoj temperaturi 2 sata i profiltrirana. Cink je opran glacijalnom octenom kiselinom. Kiselina je uparena, dodan je toluen i opet je uparen. Dobijena smjesa je otopljena u CH2Cl2 i oprana 1M NaOH. Vodena faza je nadalje oprana CH2Cl2-om. Obje organske frakcije su kombinirane i osušene preko Na2SO4. Proizvod je pročišćen kromatografijom na koloni.
1H-NMR (400 MHz; d6-DMSO) δ: 7.52 (d, 1H, 3 2.8 Hz), 7.46-7.30 (m, 5H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.82-6.72 (m, 3H), 6.69 (d, 1H, J 8.6 Hz), 5.08 (dd, 1H, J 10.0, 2.1 Hz), 5.00 (s, 2H), 3.00-2.87 (m, 1H), 2.74-2.64 (m, 1H), 2.19-2.10 (m, 1H), 2.05-1.91 (m, 1H).
Korištenjem istog postupka kao što je opisano ranije za 5-amino-2-(2-fenilkroman-6-iloksi)piridin, ali zamjenjujući 5-nitro-2-(2-fenilkroman-6-iloksi)piridin odgovarajućim nitropiridinskim intermedijerom, dobijen je:
6-[2-(4-fluorofenil)kroman-6-iloksi]piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 1.52-1 Al (m, 3H), 7.24 (m, 2H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.84-6.68 (m, 4H), 5.09 (dd, 1H, J 10.2, 2.1 Hz), 5.00 (bs, 2H), 2.93 (m, 1H), 2.69 (m, 1H), 2.13 (m, 1H), 1.98 (m, 1H).
6-[2-(3-fluorofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 3.0 Hz), 7.44 (m, 1H), 7.30-7.25 (m, 2H), 7.16 (m, 1H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.83-6.73 (m, 3H), 6.69 (d, 1H, J 8.6 Hz), 5.13 (dd, 1H, J 10.0, 3.0 Hz), 5.00 (s, 2H), 2.93 (ddd, 1H, -16.8, 10.5, 5.3 Hz), 2.68 (ddd, 1H, J-16.8, 8.0,4.4 Hz), 2.18 (m, 1H), 1.96 (m, 1H).
6-[2-(2-fluorofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.52 (m, 1H), 7.51 (d, 1H, J 3.0 Hz), 7.41 (m, 1H), 7.28-7.24 (m, 2H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.81-6.73 (m, 3H), 6.70 (d, 1H, J 8.6 Hz), 5.31 (dd, 1H, J 10.3, 2.2 Hz), 5.00 (s, 2H), 2.98 (m, 1H), 2.72 (m, 1H), 2.15 (m, 1H), 2.06 (m, 1H).
6-[2-(2,3-difluorofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.52 (d, 1H, J 3.0 Hz), 7.45-7.27 (m, 3H), 7.06 (dd, 1H, J 8.6, 3.0 Hz), 6.76-6.69 (m, 4H), 5.36 (dd, 1H, J 10.3, 2.2 Hz), 5.01 (bs, 2H), 2.97 (m, 1H), 2.73 (m, 1H), 2.18 (m, 1H), 2.03 (m, 1H).
6-[2-(2,4-difluorofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.58 (m, 1H), 7.51 (d, 1H, J 3.3 Hz), 7.30 (m, 1H), 7.15 (m, 1H), 7.05 (dd, 1H, J 8.3, 3.3 Hz), 6.84-6.73 (m, 3H), 6.70 (d, 1H, J 8.3 Hz), 5.27 (dd, 1H, J 10.3,2.3 Hz), 5.01 (bs, 2H), 2.97 (m, 1H), 2.73 (m, 1H), 2.13 (m, 1H), 2.03 (m, 1H).
6-[2-(2,5-difluorofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (300 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 2.9 Hz), 7.36-7.25 (m, 3H), 7.05 (dd, 1H, J 8.6, 2.9 Hz), 6.84-6.68 (m, 4H), 5.29 (d, 1H, J 8.6), 4.99 (bs, 2H), 2.96 (m, 1H), 2.72 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).
6-[2-(2,6-difluorofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.52-7.47 (m, 2H), 7.24 (m, 1H), 7.19-7.14 (m, 3H), 7.07 (dd, 1H, J 8.6, 2.9 Hz), 6.76-6.51 (m, 3H), 5.37 (dd, 1H, J 11.6, 2.0 Hz), 5.00 (bs, 2H), 3.00 (m, 1H), 2.78 (m, 1H), 2.32 (m, 1H), 2.11 (m, 1H).
6-[2-(3,5-difluorofenil)kroraan-6-iloksi]-piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 2.9 Hz), 7.22-7.17 (m, 3H), 7.05 (dd, 1H, J 8.6,2.9 Hz), 6.84 (dd, 1H, J 7.9,2.0 Hz), 6.76-6.74 (m, 2H), 6.69 (d, 1H, J 8.6 Hz), 5.14 (dd, 1H, J 10.0, 2.2 Hz), 5.01 (bs, 2H), 2.91 (ra, 1H), 2.69 (m, 1H), 2.20 (m, 1H), 1.97 (m, 1H).
6-[2-(4-trifluorometilfenil)kroman-6-iloksi]piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.78 (d, 2H, J 8.4 Hz), 7.68 (d, 2H, J 8.4 Hz), 7.52 (dd, 1H, J 2.9, 0.5 Hz), 7.06 (dd, 1H, 8.6, 2.9 Hz) 6.84 (m, 1H), 6.77-6.75 (m, 2H), 6.70 (dd, 1H, J 8.6, 0.5 Hz), 5.23 (dd, 1H, J 10.0,2.0 Hz), 5.01 (bs, 2H), 2.95 (ddd, 1H, -16.8, 11.1, 5.9 Hz), 2.69 (ddd, 1H, J -16.8, 8.5,4.8 Hz), 2.21 (m, 1H), 1.97 (m, 1H).
6-[2-(2-klorofenil)kroman-6-iloksi]piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.59 (m, 1H), 7.52-7.38 (m, 4H), 7.06 (dd, 1H, J 8.6, 3.0 Hz), 6.87-6.70 (m, 4H), 5.33 (dd, 1H, J 10.3, 2.1 Hz), 5.01 (bs, 2H), 2.97 (m, 1H), 2.74 (m, 1H), 2.20 (m, 1H), 1.93 (m, 1H).
6-[2-(2-aminofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (300 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 2.9 Hz), 7.15-7.18 (m, 1H), 7.05 (dd, 1H, J 8.6,2.9 Hz), 6.98-7.00 (m, 1H), 6.77 (d, 1H, J 8.6 Hz), 6.73-6.75 (m, 2H), 6.66-6.71 (m, 2H), 6.56-6.61 (m, 1H), 5.11 (dd, 1H, J 10.4,2.0 Hz), 5.01 (s, 2H), 4.99 (s, 2H), 2.94-2.99 (m, 1H), 2.66-2.74 (m, 1H), 2.06-2.13 (m, 1H), 1.88-1.95 (m, 1H).
6-[2-(3-aminofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (300 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 2.8 Hz), 7.05 (dd, 1H, J 8.6, 2.8 Hz), 7.01 (t, 1H, J 15.4, 7.7 Hz), 6.70-6.78 (m, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.63 (s, 1H), 6.54 (d, 1H, J 7.7 Hz), 6.50 (d, 1H, J 8.6 Hz), 5.06 (s, 2H), 4.98 (s, 2H), 4.90 (dd, 1H, J 10.0, 2.2 Hz), 2.85-2.96 (m, 1H), 2.62-2.74 (m, 1H), 2.05-2.11 (m, 1H), 1.89-1.95 (m, 1H).
6-[2-(4-aminofenil)kroman-6-iloksi]-piridin-3-ilamin
1H NMR (400 MHz, d6-DMSO) δ: 7.50 (d, 1H, J 2.9 Hz), 7.07 (d, 2H, 8.4 Hz), 7.04 (dd, 1H, J 8.6, 2.9 Hz), 6.71 (s, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.56 (d, 2H, J 8.4 Hz), 5.07 (s, 2H), 4.99 (s, 2H), 4.84 (dd, 1H, J 9.7, 2.3 Hz), 2.86-2.95 (m, 1H), 2.66-2.71 (m, 1H), 1.95-2.05 (m, 2H).
6-[2-(3-metoksifenil)kroman-6-iloksi]piridin-3-ilamin ORM-10684
1H NMR (400 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 3.0 Hz), 7.31 (t, 1H, J 15.8, 7.9 Hz), 7.04 (dd, 1H, J 8.7, 3.0 Hz), 6.99-7.02 (m, 1H), 6.99 (d, 1H, J 2.6 Hz), 6.90 (dd, 1H, J 8.9, 2.6 Hz), 6.79-6.81 (m, 1H), 6.72-6.74 (m, 2H), 6.69 (d, 1H, J 8.9 Hz), 5.06 (dd, 1H, 1 9.9, 2.2 Hz), 4.50 (s, 2H), 3.77 (s, 3H), 2.88-2.95 (m, 1H), 2.66-2.71 (m, 1H), 2.12-2.17 (m, 1H), 1.94-2.00 (m, 1H).
6-(5-aminopiridin-2-iloksi)-2-fenilkroman-4-on
1H NMR (400 MHz, CD3OD) δ: 7.62 (d, 1H, J 3.0 Hz), 7.51-7.49 (m, 2H), 7.42-7.33 (m, 3H), 7.25-7.18 (m, 3H), 7.06 (d, 1H, J 8.8 Hz), 6.76 (d, 1H, J 8.6Hz), 5.50 (dd, 1H, J 13.0, 2.9 Hz), 3.08 (dd, 1H, -17.0,13.0 Hz), 2.82 (dd, 1H, J -17.0, 2.9 Hz).
6-(2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin-3-ilamin hidroklorid
1H NMR (400 MHz, CDCl3) δ: 8.20 (d, 1H, J 2.1 Hz), 7.87 (dd, 1H, J 8.9, 2.1 Hz), 7.41-7.44 (m, 4H), 7.37-7.40 (m, 1H), 6.98 (d, 1H, J 8.9 Hz), 6.97 (d, 1H, J 8.8 Hz), 6.93 (d, 1H, J 2.7 Hz), 6.80 (dd, 1H, J 8.8, 2.7 Hz), 5.20 (dd, 1H, J 9.6, 1.9 Hz), 3.30 (dd, 1H, 13.2, 9.6 Hz), 3.12 (dd, 1H, 13.2,1.9 Hz).
6-(5-aminopiridin-2-iloksi)-2-fenilkromen-4-on
1H-NMR (300 MHz; d6-DMSO) δ: 8.14-8.10 (m, 2H), 7.63-7.51 (m, 5H), 7.42 (d, 1H, J 2.9 Hz) 7.14 (dd, 1H, J 8.6,2.9 Hz), 7.03 (s, 1H), 6.89 (d, 1H, J 8.6 Hz), 5.19 (s, 2H).
6-{2-[3-(Piridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-ilamin
1H NMR (400 MHz, ds-DMSO) δ: 8.16 (dd, 1H, J 4.7, 1.3 Hz), 7.86 (ddd, 1H, H 8.7, 6.9, 2.0 Hz), 7.51 (d, 1H, J 2.8 Hz), 7.44 (t, 1H, J 7.8 Hz), 7.29 (d, 1H, J 7.8 Hz), 7.19 (s, 1H), 7.13 (dd, 1H, J 6.9, 5.2 Hz), 7.09-7.03 (m, 3H), 6.81-6.71 (m, 3H), 6.69 (d, 1H, J 8.7 Hz), 5.11 (d, 1H, J 9.8 Hz), 4.99 (s, 2H), 2.89 (ra, 1H), 2.68 (m, 1H), 2.17 (m, 1H), 1.97 (m, 1H).
Korištenjem istog postupka kao što je opisano za 5-amino-2-(2-fenilkroman-6-iloksi)piridin, ali zamjenjujući 5-nitro-2-(2-fenilkroman-6-iloksi)-piridin sa:
2- [2-(3,4-difluorofenil)kroman-6-iloksi] -5-nitropiridinom,
5-nitro-2-[2-(2-trifluorometilfenil)kroman-6-iloksi]piridinom,
2-[2-(3-kloro-4-fluorofenil)kroman-6-iloksi]-5-nitropiridinom,
2-[2-(3-klorofenil)kroman-6-iloksi]-5-nitropiridinom,
2-[2-(2,4-diklorofenil)kroman-6-iloksi]-5-nitropiridinom,
2-[2-(3-bromofenil)kroman-6-iloksi]-5-nitropiridinom,
2-[2-(4-etilfenil)kroman-6-iloksi]-5-nitropiridinom,
2-(3-metil-2-fenilkroman-6-iloksi)-5-nitropiridinom,
5-nitro-2-(2-fenilkroman-7-iloksi)-piridinom,
7-(5-nitropiridin-2-iloksi)-2-fenilkroman-4-onom,
3-metil-6-(5-nitropiridin-2-iloksi)-2-fenilkroman-4-onom,
2-(2,3-dihidro-2-fenil-benzo[1,4]dioksin-6-iloksi)-5-nitropiridinom,
5-nitro-2-(6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)piridinom,
6-(5-nitropiridin-2-iloksi)-2-fenil-3,4-dihidro-2H-naftalen-1 -onom,
2-[3-(3-fluorofenil)kroman-7-iloksi]-5-nitropiridinom,
2-(3-fenilkroman-7-iloksi)-5-nitropiridinom,
5-nitro-2-(2-fenilindan-5-iloksi)piridinom,
5-Nitro-2-(2-fenilindan-5-iloksi)piridinom
dobije se:
6-[2-(3,4-difluorofenil)kroman-6-iloksi]piridin-3-ilamin,
6-[2-(2-trifluorometilfenil)kroman-6-iloksi]piridin-3-ilamin,
6-[2-(3-kloro-4-fluorofenil)kroman-6-iloksi]piridin-3-ilamin,
6-[2-(3-klorofenil)kroman-6-iloksi]piridin-3-ilamin,
6-[2-(2,4-diklorofenil)kroman-6-iloksi]piridin-3-ilamin,
6-[2-(3-bromofenil)kroman-6-iloksi]piridin-3-ilamin,
6-[2-(4-etilfenil)kroman-6-iloksi]piridin-3-ilamin,
6-(3-metil-2-fenilkroman-6-iloksi)piridin-3-ilamin,
5-amino-2-(2-fenilkroman-7-iloksi)piridin,
7-(5-aminopiridin-2-iloksi)-2-fenilkroman-4-on,
6-(5-aminopiridin-2-iloksi)-3-raetil-2-fenilkroman-4-on,
6-(2-fenil-2,3-dihidrobenzo[1,4]dioksin-6-iloksi)piridin-3-ilamin,
6-(6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)piridin-3-ilamin,
6-(5 -aminopiridin-2-iloksi)-2-fenil-3,4-dihidro-2H-naftalen-1 -on,
6-[3-(3-fluorofenil)kroman-7-iloksi]piridin-3-ilamin,
6-(3-fenilkroman-7-iloksi)-piridin-3-ilamin,
6-(2-fenilindan-5-iloksi)-piridin-3-ilamin, respektivno.
Primier 11. Intermedijeri
3-piridiniloksibenzaldehidni intermedijeri
3-(5-kloropiridin-2-iloksi)benzaldehid
3-hidroksibenzaldehid (3,0 g) je otopljen u suhom DMF (30 ml) u dušiku. Kalijev terc-butoksid (3,0 g) je dodan u otopinu i rezultujuća smjesa je miješana 30 minuta. 2,5-dikloropiridin (3,6 g) je dodan i smjesa je miješana na 120°C 1,5 sat. Reakcijska smjesa je ostavljena da se ohladi do sobne temperature, dodana je 1M otopina HCl i ekstrahirana je etil acetatom. Kombinirane organske faze su oprane vodom i zasićenom otopinom NaCl i osušene. Proizvod je pročišćen kromatografijom na koloni, korištenjem heptan-etil acetata (3:l)kaoeluenta.
1H NMR (400 MHz, d6-DMSO) δ: 10.01 (s, 1H), 8.22 (d, 1H, J 2.6 Hz), 8.01 (dd, 1H, J 8.7,2.6 Hz), 7.79 (d, 1H, J 7.6 Hz), 7.69-7.65 (m, 2H), 7.52 (m, 1H), 7.20 (d, 1H, J 8.7 Hz).
Slično, polazeći od 2-kloropiridina, dobijen je:
3-(piridin-2-iloksi)benzaldehid.
1H NMR (400 MHz, d6-DMSO) δ: 10.01 (s, 1H), 8.17 (dd, 1H, J 5.0, 1.7 Hz), 7.90 (ddd, 1H, J 8.5,6.8,1.9 Hz), 7.77 (d, 1H, J 7.8 Hz), 7.66, (t, 1H, J 7.8 Hz), 7.63 (m, 1H), 7.50 (m, 1H), 7.18 (dd, 1H, J 6.9,5.0 Hz), 7.13 (d, 1H, 8.3 Hz).
Primjer 12.
6-(5-nitropiridin-2-iloksi)-2-fenilkromen-4-on
6-(5-nitropiridin-2-iloksi)-2-fenilkromen-4-on je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1(b) polazeći od 500 mg 6-hidroksiflavona. Proizvod je rekristaliziran iz smjese 2-propanola i acetona.
1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.67 (dd, 1H, J 9.0, 2.9 Hz), 8.16-8.13 (m, 2H), 7.95 (d, 1H, J 9.0 Hz), 7.82 (d, 1H, J 2.9 Hz), 7.63 (dd, 1H, J 9.1, 2.9 Hz), 7.64-7.61 (m, 3H), 7.38 (d, 1H, J 9.1 Hz), 7.09 (s, 1H).
Primjer 13.
2-[2-(3-(5-nitropiridin-2-iloksi)fenil)kroman-6-iloksi]-5-nitropiridin i njegovi derivati
a) 6-hidroksi-2-(3-hidroksifenil)kroman-4-on (intermedijer)
6-hidroksi-2-(3-hidroksifenil)kroman-4-on je dobijen kao što je opisano za 6-hidroksi-2-(4-fluorofenil)kroman-4-on u Primjeru 2(a), ali polazeći od 3-hidroksibenzaldehida. Proizvod je rekristaliziran iz etanola.
1H NMR (400 MHz, d6-DMSO) δ: 9.50 (bs, 1H), 9.41 (bs, 1H), 7.22-7.17 (m, 1H), 7.11 (d, 1H, J 3.0 Hz), 7.03 (dd, 1H J 3.0, 8.9 Hz), 6.64 (d, 1H, J 8.9 Hz), 6.92-6.90 (m, 2H), 6.76-6.73 (m, 1H), 5.46 (dd, 1H J 2.9, 12.7 Hz), 3.09 (dd, 1H, J 12.7, 16.9 Hz), 2.75 (dd, 1H, J 2.9,16.9 Hz).
Slično su dobijeni:
6-hidroksi-2-(4-hidroksifenil)kroman-4-on
1H NMR (400 MHz, d6-DMSO) 8: 9.54 (bs, 1H), 9.38 (bs, 1H), 7.34-7.31 (m, 2H), 7.10 (d, 1H, J 3.0 Hz), 7.02 (dd, 1H J 3.0, 8.8 Hz), 6.91 (d, 1H, J 8.8 Hz), 6.80-6.77 (m, 2H), 5.40 (dd, 1H J 2.7,13.1 Hz), 3.17 (dd, 1H, J 13.2,16.9 Hz), 2.68 (dd, 1H, J 2.7,16.9 Hz).
6-hidroksi-2-(3-benziloksifenil)kroman-4-on
1H NMR (400 MHz, d6-DMSO) 8: 9.41 (bs, 1H), 7.50-7.30 (m, 6H), 7.20 (s, 1H), 7.12-7.08 (m, 2H), 7.05-7.00 (m, 2H), 6.95 (d, 1H, J 8.9 Hz), 5.52 (dd, 1H J 2.9, 12.9 Hz), 5.12 (s, 2H), 3.16 (dd, 1H, J 12.9,16.9 Hz), 2.78(dd, 1H, J 2.9,16.9 Hz).
2-[3-(5-kloropiridin-2-iloksi)fenil]-6-hidrokskroman-4-on
1H NMR (400 MHz, d6-DMSO) δ: 9.52 (bs, 1H), 8.22 (d, 1H, J 2.6 Hz), 7.97 (dd, 1H, J 8.8, 2.6 Hz), 7.47 (t, 1H, J 7.7 Hz), 7.39 (d, 1H, J 7.7 Hz), 7.32 (s, 1H), 7.16-7.10 (m, 3H), 7.04 (dd, 1H, J 8.8, 3.0 Hz), 6.96 (d, 1H, J 8.8 Hz), 5.57 (dd, 1H, J 13.0, 2.7 Hz), 3.17 (dd, 1H, J -16.8,13.0 Hz), 2.80 (dd, 1H, J -16.8,2.7 Hz).
6-hidroksi-2-[3-(piridin-2-iloksi)fenil]kroman-4-on
1H NMR (300 MHz, d6-DMSO) δ: 8.16 (ddd, 1H, J 5.0, 2.0, 1.8 Hz), 7.86 (m, 1H), 7.46 (t, 1H, J 7.8 Hz), 7.37 (d, 1H, J 7.8 Hz), 7.30 (d, 1H J 2.0 Hz), 7.16-7.10 (m, 3H), 7.06-7.02 (m, 2H), 6.94 (d, 1H, J 8.8 Hz), 5.57 (dd, 1H, J 12.9,2.9 Hz), 3.17 (dd, 1H, J -16.8, 12.9 Hz), 2.80 (dd, 1H, J -16.8,2.9 Hz).
b) 2-(3-hidroksifenil)kroman-4,6-diol (intermedijer)
2-(3-hidroksifenil)kroman-4,6-diol je dobijen kao što je opisano za 2-(4-fluoro-fenil)kroman-4,6-diol u Primjeru 2(b), ali polazeći od 6-hidroksi-2-(3-hidroksifenil)kroman-4-ona.
1H NMR (400 MHz, d6-DMSO) δ: 9.43 (bs, 1H), 8.88 (bs, 1H), 7.19-7.15 (m, 1H), 6.87 (d, 1H, J 2.7 Hz), 6.84-6.82 (m, 2H), 6.72-6.69 (m, 1H), 6.58 (d, 1H, J 8.7 Hz), 6.53 (dd, 1H, J 2.7, 8.7), 5.01 (d, 1H, J 11.3 Hz), 4.86 (dd, 1H, J 6.2,10.8 Hz), 2.25-2.19 (m, 1H), 1.88-1.75 (m, 1H).
Slično su dobijeni:
2-(4-hidroksifenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 9.41 (bs, 1H), 8.79 (bs, 1H), 7.23-7.21 (m, 2H), 6.87 (s, 1H), 6.77-6.74 (m, 2H), 6.53 (m, 2H), 5.37 (d, 1H, J 7.0 Hz), 4.97 (d, 1H, J 11.6 Hz), 4.85-4.82 (m, 1H), 2.20-2.15 (m, 1H), 1.95-1.85 (m, 1H).
2-(3-benziloksifenil)kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.81 (bs, 1H), 7.47-7.28 (m, 6H), 7.09 (s, 1H), 7.02 (d, 1H, J 7.9 Hz), 6.97 (dd, 1H, J 2.4, 7.9 Hz), 6.88 (d, 1H, J 2.8 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 2.8, 8.7 Hz), 5.40 (d, 1H, J 6.2 Hz), 5.12 (s, 2H), 5.08 (d, 1H, J 10.9 Hz), 4.88-4.85 (m, 1H), 2.28-2.23 (m, 1H), 1.92-1.77 (m, 1H).
2-[3-(5-kloropiridin-2-iloksi)fenil]kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.82 (s, 1H), 8.22 (d, 1H, J 2.6 Hz), 7.97 (dd, 1H, J 8.6, 2.6 Hz), 7.45 (t, 1H, J 7.9 Hz), 7.31 (d, 1H, J 7.9 Hz), 7.20 (d, 1H, J 1.7 Hz), 7.12 (d, 1H, J 8.6 Hz), 7.11 (dd, 1H, J 7.9,1.7 Hz), 6.87 (d, 1H, J 2.6 Hz), 6.59 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6,2.6 Hz), 5. 41 (bs, 1H), 5.14 (d, 1H, J 12.9 Hz), 4.86 (m, 1H) 2.29 (m, 1H), 1.87 (m, 1H).
2-[3-(piridin-2-iloksi)fenil]kroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) δ: 8.82 (s, 1H), 8.17 (m, 1H), 7.86 (m, 1H), 7.43 (t, 1H, J 7.8 Hz), 7.29 (d, 1H, J 7.8 Hz), 7.18 (s, 1H), 7.15-7.04 (m, 3H), 6.87 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.53 (dd, 1H, J 8.7,2.7 Hz), 5.40 (d, 1H, J 7.0 Hz), 5.14 (d, 1H, J 11.6 Hz), 4.86 (m, 1H) 2.29 (m, 1H), 1.88 (m, 1H).
c) 2-(3-hidroksifenil)kroman-6-ol (intermedijer)
2-(3-hidroksifenil)kroman-6-ol je dobijen kao što je opisano za 2-(4-fluoro-fenil)kroman-6-ol u Primjeru 2(c) ali polazeći od 2-(3-hidroksifenil)kroman-4,6-diola.
1H NMR (400 MHz, d6-DMSO) δ: 9.38 (s, 1H), 8.77 (s, 1H), 7.17-7.13 (m, 1H), 6.82-6.79 (m, 2H), 6.70-6.67 (m, 1H), 6.62 (d, 1H, J 8.6 Hz), 6.52-6.47 (m, 2H), 4.89 (dd, 1H, J 2.1,9.9 Hz), 2.86-2.82 (ra, 1H), 2.65-2.59 (m, 1H), 2.09-2.04 (m, 1H), 1.91-1.85 (m, 1H).
Slično su dobijeni:
2-(3-benziloksifenil)kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.77 (s, 1H), 7.46-7.26 (m, 6H), 7.06 (s, 1H), 7.00-6.93 (m, 2H), 6.63 (d, 1H, J 8.5 Hz), 6.52-6.47 (m, 2H), 5.10 (s, 2H), 4.96 (dd, 1H, J 1.8, 9.8 Hz), 2.91-2.82 (m, 1H), 2.67-2.59 (m, 1H), 2.12-2.07 (m, 1H), 1.99-1.87 (m, 1H).
2-[3-(5-kloropiridin-2-iloksi)fenil]kroman-6-ol
1H NMR (300 MHz, d6-DMSO) δ: 8.75 (s, 1H), 8.21 (d, 1H, J 2.6 Hz), 7.95 (dd, 1H, J 8.7, 2.6 Hz), 7.43 (t, 1H, J 7.8 Hz), 7.28 (d, 1H, J 7.8 Hz), 7.18 (d, 1H, J 1.9 Hz), 7.11-7.07 (m, 2H), 6.61-6.48 (m, 3H), 5.01 (dd, 1H, J 9.8, 2.0 Hz), 2.87 (m, 1H) 2.62 (ra, 1H), 2.13 (m, 1H), 1.93 (m, 1H).
2-[3-(piridin-2-iloksi)fenil]kroman-6-ol
1H NMR (400 MHz, d6-DMSO) δ: 8.81 (bs, 1H), 8.17 (m, 1H), 7.85 (m, 1H), 7.42 (t, 1H, J 7.9 Hz), 7.26 (d, 1H, J 7.9 Hz), 7.16-7.12 (m, 2H), 7.07-7.02 (m, 2H), 6.63 (d, 1H, J 8.2 Hz), 6.57-6.48 (m, 2H), 5.01 (d, 1H, J 8.5 Hz), 2.88 (m, 1H) 2.63 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).
d) 2-[2-(3-(5-nitropiridin-2-iloksi)fenil)kroman-6-iloksi]-5-nitropiridin
2-[2-(3-(5-nitropiridin-2-iloksi)fenil)kroman-6-iloksi]-5-nitropiridin je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1 (b), ali polazeći od 2-(3-hidroksifenil)kroman-6-ola i korištenjem 210 mol-% 2-kloro-5-nitropiridina.
1H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, 1H, J 2.9 Hz), 9.03 (d, 1H, J 2.9 Hz), 8.64 (dd, 1H, J 2.9, 9.1 Hz), 8.60 (dd, 1H, J 2.9, 9.1 Hz), 7.52 (t, 1H, J 7.8 Hz), 7.41 (d, 1H, J 7.8 Hz), 7.33-7.31 (m, 1H), 7.28 (d, 1H, J 7.8 Hz), 7.23-7.18 (m, 2H) 7.01-6.90 (m, 3H), 5.20 (dd, 1H, J 2.1, 10.1 Hz), 3.07-2.92 (m, 1H), 2.80-2.70 (m, 1H), 2.30-2.18 (m, 1H), 2.10-1.98 (m, 1H).
Korištenjem samo 100 mol-% 2-kloro-5-nitropiridina dobijeni su:
5-nitro-2-[2-(3-benziloksifenil)kroman-6-iloksi]piridin
1H NMR (300 MHz, d6-DMSO) δ: 9.03 (d, 1H, J 2.9 Hz), 8.59 (dd, 1H, J 2.9, 9.1 Hz), 7.47-7.29 (m, 6H), 7.19 (d, 1H, J 9.1 Hz), 7.10 (s, 1H), 7.05-6.92 (m, 5H), 5.14-5.10 (m, 3H), 3.00-2.88 (m, 1H), 2.75-2.69 (m, 1H), 2.20-2.14 (m, 1H), 2.07-1.95 (m, 1H).
5-nitro-2-{2-[3-(5-kloropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin
1H NMR (300 MHz, de-DMSO) δ: 9.02 (d, 1H, J 2.9 Hz), 8.59 (dd, 1H, J 9.1, 2.9 Hz), 8.22 (d, 1H, J 2.8 Hz), 7.97 (dd, 1H, J 8.7, 2.8 Hz), 7.46 (t, 1H, J 7.8 Hz), 7.33 (d, 1H, J 7.8 Hz), 7.23, (s, 1H), 7.19 (d, 1H, J 9.1 Hz), 7.13-7.10 (m, 2H), 6.99-6.89 (m, 3H), 5.18 (d, 1H, J 8.0 Hz), 2.97 (m, 1H), 2.75 (m, 1H), 2.21 (m, 1H), 2.01 (m, 1H).
5-nitro-2-{2-[3-(piridin-2-iloksi)fenil]kroman-6-iloksi}piridin
1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.7 Hz), 8.59 (dd, 1H, J 9.1, 2.7 Hz), 8.17 (m, 1H), 7.86 (m, 1H), 7.45 (t, 1H, J 7.8 Hz), 7.31 (d, 1H, J 7.8 Hz), 7.21, (s, 1H), 7.20 (d, 1H, J 9.1 Hz), 7.13 (m, 1H), 7.09 (m, 1H), 7.06 (8.6 Hz), 7.04 (2.5 Hz), 6.96 (dd, 1H, J 8.6,2.5 Hz), 5.18 (d, 1H, J 8.8 Hz), 2.98 (m, 1H), 2.72 (m, 1H), 2.21 (m, 1H), 2.02 (ra, 1H).
Primjer 14.
6-(5-nitropiridin-2-iloksi)-2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-4-ol i njegovi derivati
a)6-(5-nitropiridin-2-iloksi)-2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-4-ol
6-(5-nitropiridin-2-iloksi)-2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-4-ol je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1 (b), ali polazeći od 2-(3-hidroksifenil)kroman-4,6-diola i korištenjem 210 mol-% 2-kloro-5-nitropiridina.
1H NMR (400 MHz, d6-DMSO) δ: 9.06 (d, 1H, J 2.8 Hz), 9.03 (d, 1H, J 2.8 Hz), 8.64 (dd, 1H, J 2.8, 9.1 Hz), 8.61 (dd, 1H, J 2.8, 9.1 Hz), 7.54 (t, 1H, J 7.9 Hz), 7.43 (d, 1H, J 7.9 Hz), 7.36 (s, 1H), 7.30 (d, 1H, J 9.1 Hz), 7.25-7.21 (m, 3H) 7.01 (dd, 1H, J 2.9, 8.7 Hz), 6.89 (d, 1H, J 8.7 Hz), 5.67 (d, 1H, J 6.4 Hz), 5.36 (d, 1H, J 10.8 Hz), 5.01-4.95 (m, 1H), 2.41-2.36 (m, 1H), 2.02-1.92 (m, 1H).
Slično su dobijem:
b)6-(5-nitropiridin-2-iloksi)-2-[4-(5-nitropiridin-2-iloksi)fenil]kroman-4-ol
1H NMR (400 MHz, d6-DMSO) δ: 9.05-9.04 (m, 2H, glavni i sporedni), 8.66-8.60 (m, 2H, major & minor), 7.61-7.58 (m, 2H, major & minor), 7.31-7.21 (m, 5H, major & minor), 7.10 (dd, 1 H, J 2.9, 8.8 Hz, minor), 7.03 (dd, 1H, J 3, 8.8 Hz, major), 6.97 (d, 1H, J 8.8 Hz, minor) 6.89 (d, 1H, J 8.8 Hz, major), 5.68 (d, 1H, J 6.4 Hz, major), 5.63 (d, 1H, J 4.7 Hz, minor), 5.37-5.30 (m, 1H, major & minor), 5.04-4.97 (m, 1H, major), 4.69-4.65 (m, 1H, minor), 2.41-2.36 (m, 1H, major), 2.21-2.15 (m, 2H, major & minor), 2.07-1.98 (m, 1H, major).
Primjer 15.
2-{2-[4-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}-5-nitropiridin
2-{2-[4-(5-nitropiridin-2-iloksi)-fenil]-kroman-6-iloksi}-5-nitropiridin je dobijen kao što je opisano za 2-(4-fluorofenil)kroman-6-ol u Primjeru 2(c), ali polazeći od 6-(5-nitropiridin-2-iloksi)-2-[4-(5-nitropiridin-2-iloksi)fenil]-kroman-4-ola.
1H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, 2H, J 2.9 Hz), 8.65-8.58 (m, 2H), 7.58-7.55 (m, 2H), 7.30-7.26 (m, 3H), 7.20 (d, 1H, J 9.1 Hz), 7.03-6.91 (m, 3H) 5.20 (dd, 1H, J 2.0,10.1 Hz), 3.06-2.97 (m, 1H), 2.81-2.75 (m, 1H), 2.26-2.21 (m, 1H), 2.11-2.02 (m, 1H).
Primjer 16.
6-[2-(3-(5-aminopiridin-2-iloksi)fenil)kroman-6-iloksi]-piridin-3-ilamin i njegovi derivati
6-[2-(3-(5-aminopiridin-2-iloksi)fenil)kroman-6-iloksi]-piridin-3-ilamin je dobijen kao što je opisano za 5-amino-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 10, ali polazeći od 2-[2-(3-(5-nitropiridin-2-iloksi)fenil)kroman-6-iloksi]-5-nitropiridina. Proizvod je izoliran u obliku njegove dihidrokloridne soli.
1H NMR (300 MHz, d6-DMSO) δ: 8.12 (m, 2H), 7.78 (m, 1H), 7.45 (t, 1H, J 7.8 Hz), 7.31 (d, 1H, J 7.2 Hz), 7.21 (s, 1H), 7.13-7.04 (m, 3H), 6.91-6.87 (m, 3H), 5.15 (d, 1H, J 9.8 Hz), 3.02-2.91 (m, 1H), 2.76-2.70 (m, 1H), 2.23-2.17 (m, 1H), 2.05-1.93 (m, 1H).
Slično su dobijeni:
6-[2-(3-benziloksifenil)kroman-6-iloksi]piridin-3-ilaminhidroklorid
1H NMR (400 MHz, ds-DMSO) δ: 7.85 (s, 1H), 7.47-7.29 (m, 6H), 7.09 (s, 1H), 7.02 (d, 1H, J 7.4 Hz), 6.98 (dd, 1H, J 2.3, 8.2 Hz), 6.91 (d, 1H, J 8.7 Hz), 6.85-6.81 (m, 4H), 5.12 (s, 2H), 5.09 (d, 1H, J 9.5 Hz), 2.96-2.89 (m, 1H), 2.72-2.67 (m, 1H) 2.20-2.14 (m, 1H), 2.03-1.97 (m, 1H).
6-(5-aminopiridin-2-iloksi)-2-[3-(5-aminopiridin-2-iloksi)fenil]kroman-4-ol dihidroklorid
1H NMR (400 MHz, d6-DMSO) δ: 8.15 (d, 2H, J 2.6 Hz), 7.82 (dd, 2H, J 2.6, 8.8 Hz), 7.47 (t, 1H, 7.9 Hz), 7.35 (d, 1H, J 7.9 Hz), 7.24 (s, 1H), 7.19-7.08 (m, 4H), 6.94 (dd, 1H, 2.8, 8.8 Hz), 6.84 (d, 1H, 8.8 Hz), 5.30 (d, 1H, J 10.9 Hz), 4.96 (dd, 1H, J 6.1, 10.7 Hz), 2.38-2.32 (m, 1H), 1.98-1.88 (m, 1H).
Primjer 17.
3-[6-(5-aminopiridin-2-iloksi)kroman-2-il]fenol
2,15 g 5-nitro-2-[2-(3-benziloksifenil)kroman-6-iloksi]piridina je otopljeno u 600 ml etanola i 430 mg/g 10% paladija na ugljenu je dodano u inertnoj atmosferi. Polazni materijal je hidriran na sobnoj temperaturi te se dobio kvantitativni prinos 3-[6-(5-aminopiridin-2-iloksi)kroman-2-il] fenola.
1H NMR (400 MHz, d6-DMSO) δ: 9.50 (bs, 1H), 7.52 (d, 1H, J 3.0 Hz), 7.17 (t, 1H, J 8.1 Hz), 7.05 (dd, 1H, J 3.0, 8.6 Hz), 6.84-6.68 (m, 7H), 5.01-4.99 (m, 3H), 2.91-2.86 (m, 1H), 2.70-2.63 (m, 1H), 2.14-2.08 (m, 1H), 1.96-1.89 (m, 1H).
Primjer 18.
2-acetilamino-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid
5-amino-2-(2-fenilkroman-6-iloksi)-piridina (500 mg) i N-acetilglicina (275 mg) je otopljeno u 35 ml metilen klorida. Dodan je l-(3-dimetilaminopropil)-3-etilkarbodiimid hidroklorida (450 mg). Smjesa je miješana na sobnoj temperaturi 6 sati. Reakcija je ugašena dodatkom vode i formirani precipitat je profiltriran.
1H-NMR (400 MHz; d6-DMSO) δ: 10.1 (s, 1H), 8.30 (d, 1H, J 2.7 Hz), 8.21 (t, 1H, J 5.7 Hz), 8.00 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.30 (m, 5H), 6.95 (d, 1H, J 8.9 Hz), 6.87-6.84 (m, 3H), 5.12 (dd, 1H, J 1.90, 10.0 Hz), 3.86 (d, 2H, J 5.7 Hz), 3.00-2.92 (m, 1H), 2.75-2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.03-1.97 (m, 1H).
Korištenjem istog postupka kao što je opisano ranije za 2-acetilamino-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid, ali zamijenjujući 5-amino-2-(2-fenilkroman-6-iloksi)piridin s:
6-[2-(4-fluorofenil)kroman-6-iloksi]-pmdin-3-ilaminom,
6-[2-(3-fluorofenil)kroman-6-iIoksi] -piridin-3 -ilaminom,
6-[2-(2-fluorofenil)kroman-6-iloksi]-piridin-3-ilaminom,
6-[2-(2,3-difluorofenil)kroman-6-iloksi]-piridin-3-ilaminom)
6-[2-(2,4-difluorofenil)kroman-6-iloksi]-piridin-3-ilaminom,
6-[2-(2,5-difluorofenil)kroman-6-iloksi]-piridin-3-ilaminom,
6-[2-(2,6-difluorofenil)kroman-6-iloksi]-piridin-3-ilaminom,
6-[2-(3,4-difluorofenil)kroman-6-iloksi]piridin-3-ilaminom,
6- [2-(3,5-difluorofenil)kroman-6-iloksi] -piridin-3-ilaminom,
6-[2-(2-trifluorometilfenil)kroman-6-iloksi]piridin-3-ilaminom,
6-[2-(4-trifluorometilfenil)kroman-6-iloksi]piridin-3-ilaminom,
6-[2-(3-kloro-4-fluorofenil)kroman-6-iloksi]piridin-3-ilaminom,
6-[2-(2-klorofenil)kroman-6-iloksi]piridin-3-ilaminom,
6-[2-(3-klorofenil)kroman-6-iloksi]piridin-3-ilaminom,
6-[2-(2,4-diklorofenil)kroman-6-iloksi]piridin-3-ilaminom,
6-t2-(3-bromofenil)kroman-6-iloksi]piridin-3-ilaminom,
6-[2-(4-etilfenil)kroman-6-iloksi]piridin-3-ilaminom,
6-[2-(3-metoksifenil)kroman-6-iloksi]piridin-3-ilaminoni,
6-(3-metil-2-fenilktoman-6-iloksi)piridin-3-ilaminom,
5-amino-2-(2-fenilkroman-7-iloksi)piridinom,
6-(5-aminopiridin-2-iloksi)-2-fenilkroman-4-onom,
7-(5-aminopiridin-2-iloksi)-2-fenilkroman-4-onom,
6-(5-aminopiridin-2-iloksi)-3-raetil-2-fenilkroman-4-onom,
6-(2-fenil-2,3-dihidrobenzo[1,4]dioksin-6-iloksi)piridin-3-ilaminom,
6-(6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)piridin-3-ilaminom,
6-(5 -aminopiridin-2-iloksi)-2-fenil-3,4-dihidro-2H-naftalen-1 -onom,
6-(2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin-3-ilaminom,
6-[3-(3-fluorofenil)kroman-7-iloksi]piridin-3-ilaminom,
6-(3-fenilkroman-7-iloksi)-piridin-3-ilaminom,
6-(5-aminopiridin-2-iloksi)-2-fenilkromen-4-onom,
6-(2-fenilindan-5-iloksi)-piridin-3-ilaminom, dobijeni su:
2-acetilamino-N-{6-[2-(4-fluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(3-fluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(2-fluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(2,3-difluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(2>4-difluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(2,5-difluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(2,6-difluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(3,4-difluorofenil)kroman-6-iloksi]piridin-3-il}acetamid
2-acetilamino-N-{6-[2-(3,5-difluorofenil)kroman-6-iloksi]piridin-3-il}acetamid
2-acetilamino-N-{6-[2-(2-trifluorometilfenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(4-trifluorometilfenil)kronian-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(3-kloro-4-fluorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(2-klorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(3-klorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(2,4-diklorofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(3-bromofenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(4-etilfenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-[2-(3-metoksifenil)kroman-6-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-{6-(3-metil-2-fenilkroman-6-iloksi)piridin-3-il}acetamid,
2-acetilaraino-N-[6-(2-fenilkroman-7-iloksi)-piridin-3-il]-acetamid,
2-acetilamino-N-[6-(4-okso-2-fenilkK>man-6-iloksi)piridin-3-il]acetamid,
2-acetilamino-N-[6-(4-okso-2-fenilktoman-7-iloksi)piridin-3-il]acetamid,
2-acetilamino-N-[6-(3-metil-4-okso-2-fenilkroman-6-iloksi)piridin-3-il]acetamid,
2-acetilamino-N-[6-(2-fenil-2,3-dihidrobenzo[1,4]dioksin-6-iloksi)piridin-3-il]acetamid,
2-acetilamino-N-[6-(6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)-piridin-3-il]acetamid,
2-acetilamino-N-[6-(5-okso-6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)piridin-3-il]acetamid,
2-acetilamino-N-[6-(2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin-3-iljacetamid,
2-acetilamino-N-{6-[3-(3-fluorofenil)kroman-7-iloksi]piridin-3-il}acetamid,
2-acetilamino-N-(3-fenilkroman-7-iloksi)piridin-3-il]acetamid,
2-acetilamino-N-[6-(4-okso-2-fenil-4//-kromen-6-iloksi)piridin-3-il]acetamid,
2-acetilamino-N-[6-(2-fenilindan-5-iloksi)piridin-3-il]acetamid, respektivno.
Primjer 19.
[6-(2-fenilkroman-6-iloksi)piridin-3-il]amidpiperidin-4-karboksilne kiseline
a) tere-butil ester 4-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]piperidin-1-karboksilne kiseline
5-amino-2-(2-fenilkroman-6-iloksi)-piridin (500 mg) i N-(ferc-butoksikarboml)-heksahidroizonikotinska kiselina (541 mg) su otopljeni u 40 ml THF. Dodan je l-(3-dimetil-aminopropil)-3-etilkarbodiimid hidroklorid (451 mg). Smjesa je refluksirana nekoliko sati. Reakcija je ugašena dodatkom vode i ekstrahirana je etil acetatom. Kombinirani organski slojevi su oprani vodom, zasićenom otopinom natrijevog karbonata, osušeni Na2SO4 i upareni.
1H-NMR(300 MHz; d6-DMSO) δ: 10.0 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.92 (d, 1H, J 8.8 Hz), 6.87-6.84 (m, 3H), 5.13 (dd, 1H, J 2.2, 10.1 Hz), 4.04-3.96 (m, 2H), 2.99-2.91 (m, 1H), 2.81-2.69 (m, 3H), 2.20-2.12 (m, 2H), 2.08-1.98 (m, 1H), 1.79-1.74 (m, 3H), 1.50-1.35 (m, UH).
b) [6-(2-fenilkroman-6-iloksi)piridin-3-il]amid piperidin-4-karboksilne kiseline
Smjesa tez-c-butil estra 4-[6-(2-fenil-kroman-6-iloksi)-piridin-3-ilkarbamoil]-piperidin-1-karboksilne kiseline (860 mg) i 1 M HCl u dietil etru (13 ml) je miješana na sobnoj temperaturi 24 sata. Precipitat je profiltriran i opran etrom.
1H-NMR (300 MHz; d6-DMSO) δ: 10.3 (s, 1H), 8.97 (bs, 1H), 8.65 (bs, 1H), 8.34 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.94 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (dd, 1H, J 2.3, 10.0 Hz), 3.35-3.29 (m, 2H), 2.97-2.89 (m, 3H), 2.74-2.66 (m, 2H), 2.19-2.13 (m, 1H), 2.00-1.74 (m, 5H), 1.50-1.35 (m, 11H).
Primjer 20.
2-amino-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]propionamid i njegovi derivati
2-amino-N-[6-(2-fenilkroraan-6-iloksi)-piridin-3-il]propionamid i njegovi derivati su dobijeni kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19(a) i (b), ali zamijenjujući N-(terc-butoksikarbonil) heksahidroizonikotinsku kiselinu s (S), (R) ili (S,R)-2-terc-butoksikarbonilamino-propionskom kiselinom.
a) Terc-butil ester {l-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]etil} karbamin-ske kiseline i njegovi derivati
Terc-butil ester {(S)-1-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]etil} karb-aminske kiseline
1H-NMR (300 MHz; d6-DMSO) δ: 10.0 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.33 (m, 5H), 6.94 (d, 1H, J 8.9 Hz), 6.87-6.84 (m, 3H), 5.11 (dd, 1H, J 2.0, 10.0 Hz), 4.08 (t, 1H, J 7.1 Hz), 3.00-2.91 (m, 1H), 2.75-2.69 (m, 1H), 2.19-2.04 (m, 1H), 2.02-1.97 (m, 1H), 1.38 (s, 9H), 1.26 (d, 3H, J 7.1 Hz).
Terc-butil ester {(R)-1-[6-(2-Fenilkroman-6-iloksi)piridin-3-ilkarbamoil]etil}karb-aminske kiseline
1H NMR (400 MHz, d6-DMSO) δ: 10.05 (br s, 1H), 8.31 (d, 1H, J 2.4 Hz), 8.04 (dd, 1H, 12.4, 8.9 Hz), 7.39-7.46 (m, 3H), 7.32-7.35 (m, 1H), 7.08 (m, 1H), 6.94 (d, 1H, J 8.9 Hz), 6.81-6.86 (m, 3H), 5.12 (d, 1H, J 10.1 Hz), 4.11 (m, 1H), 2.98 (m, 1H), 2.70 (m, 1H), 2.17 (m, 1H), 2.00 (m, 1H), 1.38 (s, 9H), 1.26 (d, 3H, J 7.1 Hz).
b) 2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]propionamid i njegovi derivati
(S)-2-amino-N-[6-(2-fenilkroman-6-iloksi)piridm-3-il]propionamidhidroklorid
1H-NMR (400 MHz; d6-DMSO) δ: 10.9 (s, 1H), 8.39 (d, 1H, J 2.5 Hz), 8.05 (dd, 1H, J 2.5, 8.8 Hz), 7.46-7.31 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (d, 1H, J 8.6 Hz), 4.07 (m, 1H) 3.01-2.92 (m, 1H), 2.75-2.70 (m, 1H), 2.19-2.15 (m, 1H), 2.02-1.97 (m, 1H).
(R)-2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]propionamidhidroklorid
1H NMR (400 MHz, d6-DMSO) δ: 10.78 (br s, 1H), 8.37 (d, 1H, J 2.8 Hz), 8.27 (br s, 2H), 8.03 (dd, 1H, J 2.8, 8.8 Hz), 7.39-7.46 (m, 4H), 7.34-7.35 (m, 1H), 7.00 (d, 1H, J 8.8 Hz), 6.86-6.88 (m, 3H), 5.12 (d, 1H, J 10.5 Hz), 4.04 (m, 1H), 2.96 (m, 1H), 2.72 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H), 1.47 (d, 3H, J 6.9 Hz).
Primjer 21.
2-amino-3-metil-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]butiramid i njegovi derivati
2-amino-3-metil-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]butiramid i njegovi derivati su dobijeni kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19 (a) i (b), ali zamijenjujući N-(terc-butoksikarbonil)-heksahidroizonikotinsku kiselinu s (S), (R) ili (S,R)-2-te/-c-butoksikarbonilamino-3-metilbutemom kiselinom.
a) Terc-butil ester {2-metil-1-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]propil}-karbaminske kiseline i njegovi derivati
Terc-butil ester {(S)-2-metil-1-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]-propiljkarbaminske kiseline
1H-NMR (300 MHz; d6-DMSO) δ : 10.1 (s, 1H), 8.32 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.94 (d, 1H, J 8.8 Hz), 6.89-6.84 (m, 3H), 5.11 (dd, 1H, J 2.2, 10.0 Hz), 3.91 (t, 1H, J 6.7 Hz), 3.04-2.91 (m, 1H), 2.78-2.69 (m, 1H), 2.21-2.12 (m, 1H), 2.07-1.92 (m, 2H), 1.39 (s, 9H), 0.9 (d, 6H, J 6.7 Hz).
Terc-butil ester {(R)-2-metil-1-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]-propiljkarbaminske kiseline
1H NMR (400 MHz, d6-DMSO) δ: 10.11 (br s, 1H), 8.32 (d, 1H, J 2.3 Hz), 8.04 (dd, 1H, J 2.6, 8.8 Hz), 7.39-7.46 (m, 4H), 7.32-7.35 (m, 1H), 6.95 (d, 1H, J 8.8 Hz), 6.85-6.87(m, 4H), 5.11 (d, 1H, J 8.1 Hz), 3.91 (ra, 1H), 2.94 (m, 1H), 2.72 (m, 1H), 2.16 (m, 1H), 1.96-2.03 (m, 2H), 1.39 (s, 9H), 0.90 (d, 6H, J 6.6 Hz).
b) 2-amino-3-metil-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]butiramid i njegovi derivati
(S)-2-amino-3-metil-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]butiramid
1H-NMR (300 MHz; d6-DMSO) δ: 10.8 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.31 (bs, 3H), 8.05 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.98-6.86 (m, 3H), 5.12 (dd, 1H, J 2.2, 10.0 Hz), 3.82-3.78 (m, 1H), 3.08-2.90 (m, 1H), 2.78-2.68 (m, 1H), 2.30-2.10 (m, 2H), 2.07-1.92 (m, 1H), 1.02-0.98 (m, 6H).
(R)-2-amino-3-metil-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]butiramidhidroklorid
1H NMR (400 MHz, d6-DMSO) δ: 10.97 (br s, 1H), 8.43 (s, 1H), 8.35 (br s, 2H), 8.07 (dd, 1H, J 2.4, 8.7 Hz), 7.39-7.46 (m, 4H), 7.32-7.36 (m, 1H), 7.00 (d, 1H, J 8.7 Hz), 6.86-6.89 (m, 3H), 5.12 (d, 1H, J 10.2 Hz), 3.83 (m, 1H), 2.97 (m, 1H), 2.73 (m, 1H), 2.17-2.23 (m, 2H), 1.99 (m, 1H), 1.00 (d, 6H, J 6.5 Hz).
Primjer 22.
(S)-2-amino-3-metil-N-(6-{2-[3-(5-nitropiridin-2-iloksifenilkroraan-6-iloksi}piridin-3-il)butiramid hidroklorid
a) rerc-butil ester ((S)-1-{6-[2-(3-hidroksifenil)kroman-6-iloksi]piridin-3-ilkarbamoil} -2-metil-propil)karbaminske kiseline
Terc-butil ester ((S)-1-{6-[2-(3-Hidroksifenil)kroman-6-iloksi]piridin-3-ilkarbamoil}-2-metil-propil)karbaminske kiseline je dobijen korištenjem istog postupka kao što je opisano u Primjeru 21(a) za terc-butil ester {(S)-2-metil-1-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]propil}karbaminske kiseline, ali zamijenjujući 5-amino-2-(2-fenilkroman-6-iloksi)piridin s 3-[6-(5-aminopiridin-2-iloksi)kroman-2-il]fenolom (opisanom u Primjeru 17).
1H NMR (400 MHz, d6-DMSO) δ: 10.11 (br s, 1H), 9.42 (br s, 1H), 8.32 (s, 1H); 8.04 (dd, 1H, J 2.2, 8.9 Hz), 7.18 (t, 1H, J 8.2 Hz), 6.95 (d, 1H, J 8.9 Hz), 6.90 (d, 1H, J 8.5 Hz), 6.84-6.86 (m, 6H), 6.71 (d, 1H, J 8.2 Hz), 5.03 (d, 1H, J 9.7 Hz), 3.91 (m, 1H), 2.94 (m, 1H), 2.70 (m, 1H), 2.14 (m, 1H), 1.95 (m, 1H), 1.39 (s, 9H), 0.90 (d, 6H, J 6.6 Hz).
b) Terc-butil ester [(S)-2-metil-1-(6-{2-[3-(5-nitropiridin-2-iloksi) fenil] kroman-6-iloksi} piridin-3-ilkarbamoil)propil] karbaminske kiseline
Terc-butil ester [(S)-2-metil-1-(6-{2-[3-(5-nitropiridin-2-iloksi) fenil] kroman-6-iloksi} -piridin-3-ilkarbamoil)propil] karbaminske kiseline je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1(b).
1H NMR (400 MHz, d6-DMSO) δ: 10.14 (br s, 1H), 9.05 (d, 1H, J 2.8 Hz), 8.63 (dd, 1H, 2.8,9.0 Hz), 8.32 (s, 1H); 8.04 (dd, 1H, J 2.6, 8.7 Hz), 7.52 (t, 1H, J 8.0 Hz), 7.40 (d, 1H, J 7.6 Hz), 7.27-7.31 (m, 2H), 7.21 (dd, 1H, J 0.9, 8.0 Hz), 6.94 (d, 1H, J 8.7 Hz), 6.85-6.91 (m, 4H), 5.17 (d, 1H, J 9.8 Hz), 3.91 (m, 1H), 2.94 (m, 1H), 2.73 (m, 1H), 2.21 (m, 1H), 2.02 (m, 1H), 1.39 (s, 9H), 0.89 (d, 6H, J 6.6 Hz).
c) (S)-2-amino-3-metil-N-(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}-piridin-3-il)butiramid hidroklorid
(S)-2-amino-3-metil-N-(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)butiramid hidroklorid je dobijen na isti način kao što je opisano za (S)-2-amino-3-metil-A46-(2-fenilkroman-6-iloksi)-piridin-3-il]butiramid u Primjeru 21(b).
1H NMR (400 MHz, d6-DMSO) δ: 10.91 (br s, 1H), 9.05 (d, 1H, J 2.7 Hz), 8.64 (dd, 1H, 3.0, 9.1 Hz), 8.38 (d, 1H, J 2.5 Hz), 8.32 (br s, 2H), 8.06 (dd, 1H, 3 2.5, 8.8 Hz), 7.52 (t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.6 Hz), 7.27-7.32 (m, 2H), 7.22 (d, 1H, J 8.1 Hz), 7.00 (d, 1H, J 8.8 Hz), 6.86-6.89 (m, 4H), 5.17 (d, 1H, J 8.8 Hz), 3.81 (m, 1H), 2.96 (m, 1H), 2.73 (m, 1H), 2.20 (ra, 1H), 2.00 (m, 1H), 0.99-1.01 (m, 6H).
Primjer 23.
[6-(2-fenilkroman-6-iloksi)piridin-3-il]amid pirolidin-2-karboksilne kiseline i njegovi derivati
[6-(2-fenilkroman-6-iloksi)piridin-3-il]amid pirolidin-2-karboksilne kiseline i njegovi derivati su dobijeni kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19 (a) i (b), ali zamijenjujući N-(terc-butoksikarbonil)heksahidroizonikotinsku kiselinu s 1-fcvc-butil estrom (S), (R) ili (R,S)-pirolidin-1,2-dikarboksilne kiseline i 5-amino-2-(2-fenilkroman-6-iloksi)-piridin odgovarajućim 5-aminopiridinskim derivatima.
a) Terc-butil ester 2-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil] pirolidin-1-karboksilne kiseline i njegovi derivati
terc-butil ester 2-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]-(S)-pirolidin-1 -karboksilne kiseline.
1H NMR (300 MHz, d6-DMSO) δ: 10.1 (s, 1H), 8.31 (d, 1H, J 2.4 Hz), 8.03 (dd, 1H, J 2.4, 8.8 Hz), 7.47-7.33 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.87-6.85 (m, 3H), 5.12 (dd, 1H, J 2.1, 9.9 Hz), 4.25 (m, 1H), 3.5-3.3 (m, 2H), 2.97 (m, 1H), 2.74 (m, 1H), 2.29-2.11 (m, 2H), 2.09-1.73 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
Terc-butil ester 2-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]-(R)-pirolidin-1-karboksilne kiseline
1H NMR (400 MHz, d6-DMSO) δ: 10.09 (s, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J 8.8 Hz), 7.46-7.33 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (d, 1H, J 10,0 Hz), 4.18 (m, 1H), 3.42-3.31 (m, 2H), 2.97 (m, 1H), 2.75 (m, 1H), 2.22-2.17 (m, 2H), 2.01-1.80 (m, 4H), 1.40 (s,3H) 1.29 (m,6H).
Terc-butil ester 2-[6-(2-(4-fluorofenil)kroman-6-iloksi)piridin-3-ilkarbamoil]-(S)-pirolidin-1-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.09 (s, 1H), 8.31 (d, 1H, 2.5 Hz), 8.03 (dd, 1H, J 8.8, 2.5 Hz), 7.50 (m, 2H), 7.23 (m, 2H), 6.95 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (d, 1H, J 8.6 Hz), 4.26 (m, 1H), 3.41-3.34 (m, 2H), 2.96 (m, 1H), 2.73 (m, 1H), 2.22-2.13 (m, 2H), 1.90-1.80 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
Terc-butil ester 2-[6-(2-(3-fluorofenil)kroman-6-iloksi)piridin-3-ilkarbamoil]-(S)-pirolidin-1-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.09 (s, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J 8.7 Hz), 7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.17 (m, 1H), 6.95 (d, 1H, J 8.7 Hz), 6.87-6.85 (m, 3H), 5.16 (d, 1H, J 8.6 Hz), 4.17 (m, 1H), 3.41-3.34 (m, 2H), 2.95 (m, 1H), 2.72 (m, 1H), 2.22-2.18 (m, 2H), 1.95-1.79 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
Terc-butil ester 2-[6-(2-(2-Fluorofenil)kroman-6-iloksi)piridin-3-ilkarbamoil]-(S)-pirolidin-1-karboksilne kiseline
1H NMR (400 MHz, d6-DMSO) δ: 10.09 (s, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J 8.7 Hz), 7.55 (m, 1H), 7.41 (ra, 1H), 7.29-7.23 (m, 2H), 6.96 (d, 1H, J 8.7 Hz), 6.90-6.85 (m, 3H), 5.34 (d, 1H, J 9.6 Hz), 4.17 (m, 1H), 3.44-3.35 (m, 2H), 3.00 (m, 1H), 2.75 (m, 1H), 2.17 (m, 1H) 2.05 (m, 1H), 1.90-1.77 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
b) [6-(2-fenilkroman-6-iloksi)piridin-3-il]amid pirolidin-2-karboksilne kiseline i njegovi derivati
[6-(2-fenilkroman-6-iloksi)piridin-3-il]amid hidroklorid (S)-pirolidin-2-karboksilne kiseline.
lH NMR (300 MHz, d6-DMSO) δ: 10.9 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.99-6.85 (m, 3H), 5.12 (dd, 1H, 2.2, 10.1 Hz), 3.32-3.20 (m, 2H), 2.97 (m, 1H), 2.74 (m, 1H), 2.42 (m, 1H), 2.15 (m, 1H), 2.08-1.90 (m,4H).
[6-(2-fenilkroman-6-iloksi)piridin-3-il]amid hidroklorid (R)-pirolidin-2-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 11.11 (s, 1H), 10.03 (bs, 1H), 8.71 (bs, 1H), 8.40 (s, 1H), 8.06 (d, 1H, J 8.8 Hz), 7.46-7.32 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.88-6.86 (m, 3H), 5.12 (d, 1H, 9.9 Hz), 4.39 (m, 1H), 3.27-3.20 (m, 2H), 2.98 (m, 1H), 2.73 (m, 1H), 2.44 (m, 1H), 2.17 (m, 1H), 2.04-1.93 (m, 4H).
[6-(2-(4-fluorofenl)kroman-6-iloksi)piridin-3-il]amid hidroklorid (S)-pirolidin-2-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.92 (s, 1H), 9.72 (bs, 1H), 8.70 (bs, 1H), 8.38 (d, 1H, J 2.5 Hz), 8.03 (dd, 1H, J 8.9,2.5 Hz), 7.50 (m, 2H), 7.23 (m, 2H), 7.00 (d, 1H, J 8.9 Hz), 6.89-6.86 (m, 3H), 5.12 (d, 1H, 10.1 Hz), 4.35 (m, 1H), 3.29-3.24 (m, 2H), 2.97 (m, 1H), 2.73 (m, 1H), 2.42 (m, 1H), 2.16 (m, 1H), 2.03-1.91 (m, 4H).
[6-(2-(3-fluoro)fenilkroman-6-iloksi)piridin-3-il]amid hidroklorid (S)-pirolidin-2-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.97 (s, 1H), 9.79 (bs, 1H), 8.70 (bs, 1H), 8.38 (d, 1H, J 2.6 Hz), 8.04 (dd, 1H, J 8.9, 2.6 Hz), 7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.17 (m, 1H), 7.01 (d, 1H, J 8.9 Hz), 6.90-6.85 (m, 3H), 5.16 (d, 1H, 8.4 Hz), 4.37 (m, 1H), 3.29-3.24 (m, 2H), 2.96 (m, 1H), 2.72 (m, 1H), 2.42 (m, 1H), 2.20 (m, 1H), 2.03-1.91 (m, 4H).
[6-(2-(2-fluorofenil)kroman-6-iloksi)piridin-3-il]amid hidroklorid (S)-pirolidin-2-karboksilne kiseline
1H NMR (400 MHz, d6-DMSO) 8: 10.90 (s, 1H), 9.70 (bs, 1H), 8.71 (bs, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 8.9, 2.5 Hz), 7.55 (m, 1H), 7.42 (m, 1H), 1.29-121 (m, 2H), 7.01 (d, 1H, J 8.9 Hz), 6.90-6.86 (m, 3H), 5.34 (d, 1H, 8.6 Hz), 4.37 (m, 1H), 3.29-3.24 (m, 2H), 2.99 (m, 1H), 2.76 (m, 1H), 2.40 (m, 1H), 2.17 (m, 1H), 2.07-1.91 (m, 4H).
Primjer 24.
(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)amid (S)-pirolidin-2- karboksilne kiseline
(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)amid (S)-pirolidin-2- karboksilne kiseline je dobijen kao što je opisano za (S)-2-amino-3-metil-N-(6-{2-[3-(5-nitropiridin-2-iloksi-fenil-kroman-6-iloksi}piridin-3-il)-butiramid u Primjeru 22, koraci (a)-(c), polazeći od 1-terc-butil estra (S)-pirolidin-1,2-dikarboksilne kiseline.
a) Terc-butil ester 2-{6-[2-(3-hidroksifenil)kroman-6-iloksi]piridin-3-ilkarbarnoil}-(S)-pirolidin-1-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.09 (s, 1H), 9.43 (s, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J 8.9 Hz), 7.18 (t, 1H, J 8.0 Hz), 6.95 (d, 1H, J 8.9 Hz), 6.87-6.84 (m, 5H), 6.71, (d, 1H, J 7.2 Hz), 5.03 (d, 1H, J 8.2 Hz), 4.19 (m, 1H), 3.42-3.35 (m, 2H), 2.93 (m, 1H), 2.69 (m, 1H), 2.21-2.12 (m, 2H), 1.95-1.79 (m, 4H), 1.40 (s, 3H) 1.28 (m, 6H).
b) Terc-butil ester 2-(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-ilkarbamoil)-(S)-pirolidin-1-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.09 (s, 1H), 9.05 (d, 1H, J 2.9 Hz), 8.63 (dd, 1H, J 8.9, 2.9 Hz), 8.31 (s, 1H), 8.03 (d, 1H, J 8.8 Hz), 7.52 (t, 1H, J 7.8 Hz), 7.40 (d, 1H, J 7.8 Hz), 7.31-7.27 (m, 2H) 7.21 (dd, 1H, J 7.8,1.7 Hz), 6.95 (d, 1H, J 8.9 Hz), 6.87-6.85 (m, 3H), 5.17 (d, 1H, J 9.3 Hz), 4.18 (m, 1H), 3.42-3.34 (m, 2H), 2.95 (m, 1H), 2.73 (m, 1H), 2.20 (m, 1H), 1.97 (m, 1H), 1.89-1.79 (m, 4H), 1.40 (s, 3H) 1.28 (m, 6H).
c) (6- {2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)amid hidroklorid (S)-pirolidin-2-karboksilne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.89 (s, 1H), 9.69 (bs, 1H), 9.05 (d, 1H, J 2.8 Hz), 8.71 (bs, 1H), 8.64 (dd, 1H, J 9.0,2.8 Hz), 8.37 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 8.8, 2.7 Hz), 7.52 (t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.9 Hz), 7.31-7.27 (m, 2H), 7.21 (d, 1H, J 8.8 Hz), 7.00 (d, 1H, J 9.0 Hz), 6.88-6.83 (m, 3H), 5.17 (d, 1H, 8.4 Hz), 4.35 (m, 1H), 3.29-3.24 (m, 2H), 2.95 (m, 1H), 2.73 (m, 1H), 2.40 (m, 1H), 2.22 (m, 1H), 2.04-1.91 (m, 4H).
Primjer 25.
(S)-2-amino-3-hidroksi-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]propionamid hidro-klorid
(S)-2-amino-3-hidroksi-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]propionamid hidro-klorid je dobijen kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19 (a) i (b), ali zamijenjujući N-{terc-butoksikarbonil)heksahidroizonikotinsku kiselinu s (S)-2-terc-butoksikarbonilamino-3-hidroksipropionskom kiselinom.
a) Terc-butil ester {(S)-2-hidroksi-1-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]-etiljkarbaminske kiseline
1H NMR (400 MHz, d6-DMSO) δ: 10.07 (br s, 1H), 8.33 (d, 1H, J 2.4 Hz), 8.05 (dd, 1H, J 2.4,9.0 Hz), 7.39-7.47 (m, 5H), 7.32-7.36 (m, 1H), 6.94 (d, 1H, J 9.0 Hz), 6.85-6.86 (m, 2H), 6.77 (br d, 1H, J 7.3 Hz), 5.12 (d, 1H, J 10.0 Hz), 4.95 (br s, 1H), 4.14 (m, 1H), 3.63 (br s, 2H), 2.95 (m, 1H), 2.70 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H), 1.39 (s, 9H).
b) (S)-2-amino-3-hidroksi-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]propionamid hidroklorid
1H NMR (400 MHz, CD3OD) δ: 8.63 (d, 1H, J 2.4 Hz), 8.22 (dd, 1H, J 2.4, 9.1 Hz), 7.36-7.45 (m, 4H), 7.29-7.33 (m, 1H), 7.05 (d, 1H, J 9.1 Hz), 6.94-6.97 (m, 3H), 5.11 (d, 1H, J 10.0 Hz), 4.15 (m, 1H), 3.97-4.06 (m, 2H), 3.03 (m, 1H), 2.79 (m, 1H), 2.24 (m, 1H), 2.07 (m, 1H).
Primjer 26.
(S)-2-amino-4-[6-(2-feiulkroman-6-iloksi)piridin-3-ilkarbamoil]maslačna kiselina
(S)-2-amino-4-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]maslačna kiselina je dobijena kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19 (a) i (b), ali zamijenjujući N-(terc-butoksikarbonil)-heksahidroizonikotinsku kiselinu s 1-terc-butil estrom (S)-2-karboksiaminoglutame kiseline.
a) Terc-butil ester (S)-2-terc-butoksikarbonilamino-4-[6-(2-fenilkroman-6-iloksi)-piridin-3-ilkarbamoil]maslačne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.01 (br s, 1H), 8.28 (d, 1H, J 2.4 Hz), 8.01 (dd, 1H, J 2.4, 8.8 Hz), 7.39-7.46 (m, 4H), 7.32-7.35 (m, 1H), 7.14 (br d, 1H, J 7.7 Hz), 6.93 (d, 1H, J 8.8 Hz), 6.84-6.86 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 3.84 (m, 1H), 2.97 (m, 1H), 2.71 (m, 1H), 2.38-2.42 (m, 2H), 2.16 (m, 1H), 1.96-2.04 (m, 2H), 1.81 (m, 1H), 1.40 (s, 9H), 1.38 (s, 9H).
b) Hidroklorid (S)-2-amino-4-[6-(2-fenilkrornan-6-iloksi)piridin-3-ilkarbamoil]maslačne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.28 (br s, 1H), 8.41 (br s, 2H), 8.33 (d, 1H, J 2.4 Hz), 8.03 (dd, 1H, J 2.4, 8.8 Hz), 7.39-7.46 (m, 4H), 7.32-7.36 (m, 1H), 6.94 (d, 1H, J 8.8 Hz), 6.85-6.86 (m, 3H), 5.12 (d, 1H, J 10.1 Hz), 3.96 (m, 1H), 2.97 (m, 1H), 2.72 (m, 1H), 2.50-2.65 (m, 2H), 2.12-2.19 (m, 3H), 2.00 (m, 1H).
Primjer 27.
(S)-4-amino-4-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]maslačna kiselina
(S)-4-amino-4-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]maslačna kiselina je dobijena kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19 (a) i (b), ali zamijenjujući N-(terc-butoksikarbonil)-heksahidroizonikotinsku kiselinu s 5-tere-butil estrom (S)-2-karboksiaminoglutame kiseline.
a) Terc-butil ester (S)-4-terc-butoksikarbonilamino-4-[6-(2-fenilkroman-6-iloksi)-piridin-3-ilkarbamoil]maslačne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 10.09 (br s, 1H), 8.32 (d, 1H, J 2.4 Hz), 8.04 (dd, 1H, J 2.4, 8.8 Hz), 7.39-7.47 (m, 4H), 7.32-7.35 (m, 1H), 7.06 (br d, 1H, J 7.7 Hz), 6.94 (d, 1H, J 8.8 Hz), 6.85-6.86 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 4.07 (m, 1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.26-2.27 (m, 2H), 2.17 (m, 1H), 1.92-2.04 (m, 2H), 1.75 (m, 1H), 1.38 (br s, 18H).
b) Hidroklorid (S)-4-amino-4-[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]maslačne kiseline.
1H NMR (400 MHz, MeOD) δ: 8.54 (d, 1H, J 2.8 Hz), 8.15 (dd, 1H, J 2.8, 9.0 Hz), 7.43-7.45 (m, 2H), 7.36-7.40 (m, 2H), 7.29-7.33 (m, 1H), 7.01 (d, 1H, J 9.0 Hz), 6.93-6.94 (m, 3H), 5.11 (d, 1H, J 10.0 Hz), 4.11 (m, 1H), 3.01 (m, 1H), 2.79 (m, 1H), 2.56 (m, 2H), 2.22-2.30 (m, 3H), 2.03-2.09 (m, 1H).
Primjer 28.
(S)-3-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamidjantarne kiseline
(S)-3-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamid jantarne kiseline je dobijen kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19 (a) i (b), ali zamijenjujući N-(terc-butoksikarbonil)-heksahidroizonikotinsku kiselinu s 4-terc-butil estrom (S)-2-terc-butoksikarbonil-aminojantarne kiseline.
a) rerc-butil ester (S)-3-terc-butoksikarbonilamino-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]monoamida jantame kiseline
1H-NMR (400 MHz; d6-DMSO) δ: 10.12 (s, 1H), 8.31 (d, 1H, J 2.4 Hz), 8.02 (dd, 1H, J 8.9, 2.4 Hz), 7.46-7.39 (m, 5H), 7.34 (d, 1H, J 7.1 Hz), 6.94 (d, 1H, J 8.9 Hz), 6.87-6.84 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 4.44 (m, 1H), 2.97 (m, 1H), 2.74-2.65 (m, 2H), 2.50 (m, 1H), 2.16 (m, 1H), 2.00 (m, 1H), 1.38 (s, 18H).
b) Hidroklorid (S)-3-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamida jantarne kiseline
1H-NMR (400 MHz; d6-DMSO) δ: 10.83 (s, 1H), 8.41 (bs, 3H), 8.36 (d, 1H, J 2.4 Hz), 8.03 (dd, 1H, J 8.9, 2.4 Hz), 7.47-7.32 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.88-6.85 (m, 3H), 5.12 (d, 1H, J 10.1 Hz), 4.25 (m, 1H), 3.03-2.87 (m, 3H), 2.73 (m, 1H), 2.17 (m, 1H), 2.00 (m, 1H).
Primjer 29.
(S)-2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamid jantarne kiseline
Hidroklorid (S)-2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamid jantarne kiseline je dobijen kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il]amin piperidin-4-karboksilne kiseline u Primjeru 19 (a) i (b), ali zamijenjujući N-(terc-butoksikarbonil)heksahidroizonikotinsku kiselinu s terrc-butil estrom (S)-2-terc butoksikarbonilaminojantarne kiseline.
a) Terc-butil ester (S)-2-terc-butoksikarbonilamino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamida jantarne kiseline
lH-NMR (400 MHz; d6-DMSO) δ: 10.10 (s, 1H), 8.29 (s, 1H), 8.15 (d, 1H, J 8.9 Hz), 7.47-7.39 (m, 5H), 7.34 (d, 1H, J 8.4 Hz), 6.94 (d, 1H, J 8.9 Hz), 6.86-6.84 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 4.29 (m, 1H), 2.97 (m, 1H), 2.82-2.76 (m, 2H), 2.61 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H), 1.38 (s, 12H), 1.36 (s, 6H).
b) Hidroklorid (S)-2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamida jantarne kiseline
1H-NMR (400 MHz; d6-DMSO) δ: 13.7 (bs, 1H), 10.52 (s, 1H), 8.36-8.32 (m, 4H), 8.01 (d, 1H, J 8.7Hz), 7.46-7.32 (m, 5H), 6.96 (d, 1H, J 8.7 Hz), 6.87-6.85 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 4.27 (m, 1H), 3.07-2.93 (m, 3H), 2.72 (m, 1H), 2.18 (m, 1H), 2.00 (m, 1H).
Primjer 30.
N-{6-[2-(4-fluorofenil)kroman-6-iloksi]piridin-3-il}-4-(4-metil-piperazin-1-ilmetil)-benzamid
a) Metil ester 4-klorometilbenzoeve kiseline
4-klorometilbenzoeva kiselina (2,0 g) je otopljena u 300 ml metanola i dodano je 0,5 ml koncentrirane sumporne kiseline. Smjesa je miješana na sobnoj temperaturi osam dana. Metanol je uparen i ostatak je otopljen u etil acetatu. Organski sloj je opran zasićenom otopinom NaHCO3, osušen pomoću Na2SO4 i uparen te se dobio metil ester 4-klorometilbenzoeve kiseline.
1H NMR (300 MHz, d6-DMSO) δ: 3.86 (s, 3H), 4.84 (s, 2H), 7.59 (d, 2H, J 8.2 Hz), 7.97 (d, 2H, J 8.2 Hz).
b) Metil ester 4-(4-metilpiperazin-1-ilmetil)benzoeve kiseline
Metil ester 4-klorometilbenzoeve kiseline (1,66 g), 1-metilpiperazin (1,8 g) i natrij jodid (0,67 g) su dodani u aceton (50 ml). Reakcijska smjesa je miješana na 60 °C 9 sati. Dodano je još l-metilpiperazina(0,9 g) i natrij jodida (0,34 g) i poslije miješanja dodatnih 1,5 sat na 60°C, reakcijska smjesa je ostavljena da se ohladi do sobne temperature. Smjesa je profiltrirana i aceton je uparen. Ostatak je otopljen u etil acetatu i opran vodom. Otapalo je osušeno pomoću NaSO4 i upareno te se dobio metil ester 4-(4-metilpiperazin-1-ilmetil)benzoeve kiseline.
1H NMR (300 MHz, d6-DMSO) δ: 2.18 (s, 3H), 2.37 (bs, 8H), 3.53 (s, 2H), 3.84 (s, 3H), 7.44 (d, 2H, J 8.1 Hz), 7.91 (d, 2H, J 8.2 Hz).
Klorid metil estra 4-(4-metilpiperazin-1-ilmetil)benzoeve kiseline
Metil ester 4-(4-metilpiperazin-1-ilmetil)benzoeve kiseline je otopljen u etil acetatu i dodana je otopina 1 M HCl i dietil etra. Smjesa je miješana 1 sat i precipitirana sol HCl je profiltrirana i oprana dietil etrom.
1H NMR (300 MHz, d6-DMSO) 8: 2.78 (s, 3H), 3.10-3.75 (m, 8H), 3.87 (s, 3H), 4.35 (bs, 2H), 7.77 (d, 2H, J 7.5 Hz), 8.00 (d, 2H, J 8.1 Hz).
c) 4-(4-metilpiperazin-1-ilmetil)benzoeva kiselina
Klorid metil estera 4-(4-metilpiperazin-1-ilmetil)benzoeve kiseline (1,25 g) je otopljen u otopini kalijevog hidroksida u metanolu (0,93 g KOH u 15 ml metanola). Dodana je voda (0,75 ml) i smjesa je refluksirana 1 sat. Reakcijska smjesa je ostavljena da se ohladi do sobne temperature i pH je postavljen na 6 pomoću 2M HCl. Otapalo je upareno i ostatak je osušen pod vakuumom. Ostatak je sadržavao 4-(4-metilpiperazin-1-ilmetil)benzoevu kiselinu i neorganske soli. Dalje je korišten bez prečišćavanja i uzeto je da je prinos naslovnog spojeve 100%.
1H NMR (400 MHz, d6-DMSO) δ: 2.27 (s, 3H), 2.44 (bs, 2H), 3.18-3.95 (m, 8H), 7.41 (d, 2H, J 8.0 Hz), 7.89 (d, 2H, J 8.1 Hz).
d) N- {6-[2-(4-fluorofenil)kroman-6-iloksi]piridin-3-il} -4-(4-metilpiperazin-1 -ilmetil)-benzamid
4-(4-metilpiperazin-1-ilmetil)benzoeva kiselina (oko 0,19 g), 6-[2-(4-fluorofenil)-kroman-6-iloksi]piridin-3-ilamin (0,18 g) i l-(3-dimetilaminopropil)-3-etilkarbodiimid hidroklorid (0,12 g) su dodati u diklorometan (12 ml). Smjesa je miješana na sobnoj temperaturi i poslije 4 sata, dodano je još 4-(4-metilpiperazin-1-ilmetil)-benzoeve kiseline (ca 0,11 g) i l-(3-dimetil-aminopropil)-3-etilkarbodiimid hidroklorida (0,046 g). Miješanje je nastavljeno još 3 sata. Dodani su voda i diklorometan, a zatim su razdvojene organska i vodena faza. Vodena faza je ekstrahirana diklorometanom. Proizvod je pročišćen kromatografijom na koloni, korištenjem diklorometana / metanola (9:1) kao eluenta te se dobio N-{6-[2-(4-fiuorofenil)kroman-6-iloksi]piridin-3-il}-4-(4-metilpiperazin-1-ilmetil)benzamid.
1HNMR (300 MHz, d6-DMSO) δ: 1.90-2.08 (m, 1H), 2.11-2.21 (m, 1H), 2.18 (s, 3H), 2.38 (bs, 8H), 2.68-2.79 (m, 1H), 2.91-3.05 (m, 1H), 3.54 (s, 2H), 5.13 (dd, 1H, J 2.0, 10.1 Hz), 6.86 (d, 2H, J 1.2 Hz), 6.90 (s, 1H), 6.98 (d, 1H, J 8.8 Hz), 7.19-7.27 (m, 2H), 7.43-7.54 (m, 4H), 7.92 (d, 2H, J 8.2 Hz), 8.18 (dd, 1H, J 2.7, 8.9 Hz), 8.48 (d, 1H, J 2.7 Hz), 10.31 (s, 1H).
Primjer 31.
N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamid jantarne kiseline
6-(2-fenilkroman-6-iloksi)piridin-3-ilamin (Primjer 35) (270 mg) i jantama kiselina (151 mg) su otopljeni u diklorometanu (16 ml). l-(3-dimetilaminopropil)-3-etilkarbodiimid hidroklorid (245 mg) je dodan u reakcijsku smjesu i ona je miješana na sobnoj temperaturi 3 sata. Dodana je voda i smjesa je profiltrirana. Precipitat je sakupljen, tretiran metanolom i opet profiltriran. Metanolni filtrat je uparen do suhog te se dobio N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]monoamid jantarne kiseline.
1H NMR (400 MHz, d6-DMSO) δ: 12.0 (bs, 1H), 10.08 (s, 1H), 8.29 (d, 1H, J 2.4 Hz), 8.01 (dd, 1H, J 8.8, 2.4 Hz), 7.46-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (d, 1H, J 8.6 Hz), 2.96 (m, 1H), 2.70 (m, 1H), 2.56-2.52 (m, 4H), 2.16 (m, 1H), 2.00 (m, 1H).
Primjer 32.
2-kloro-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
Ohlađenoj otopini 5-amino-2-(2-fenilkroman-6-iloksi)-piridina (500 mg) u 7,5 ml metilen klorida dodan je trietil amin (437 μl) i kloracetil klorid (163 μl). Reakcijska smjesa je miješana na sobnoj temperaturi 3 sata i reakcija je ugašena dodavanjem vode. Vodeni sloj je zakiseljen i ekstrahiran metilen kloridom. Kombinirani organski slojevi su osušeni pomoću Na2SO4 i upareni. 2-kloro-N-[6-(2-fenil-kroman-6-iloksi)-piridin-3-il]-acetamid je pročišćen kromatografijom na koloni, korištenjem 10% metanola u metilen kloridu kao eluenta.
1H-NMR (400 MHz; d6 -DMSO) δ: 10.4 (s, 1H), 8.30 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.32 (m, 5H), 6.97 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J 2.10, 10.1 Hz), 4.27 (s, 2H), 2.97-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.97 (m, 1H).
2-kloro-N-{6-[2-(4-fluorofenil)kroman-6-iloksi]piridin-3-il}acetamid je dobijen korištenjem istog postupka kao što je opisano ranije za 2-kloro-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid, ali zamijenjujući 5-amino-2-(2-fenilkroman-6-iloksi)piridin sa 5-amino-2-(2-(4-fluorofenilkroman-6-iloksi)piridinom.
1H-NMR (400 MHz; d6-DMSO) δ: 10.4 (s, 1H), 8.29 (d, 1H, J 2.7 Hz), 8.02 (dd, 1H, J 2.7, 8.8 Hz), 7.52-7.48 (m, 2H), 7.25-7.20 (m, 2H), 6.97 (d, 1H, J 8.8 Hz), 6.88-6.84 (m, 3H), 5.12 (dd, 1H, J 1.90, 10.2 Hz), 4.27 (s, 2H), 2.98-2.92 (m, 1H), 2.76-2.69 (m, 1H), 2.18-2.13 (m, 1H), 2.01-1.96 (m, 1H).
Slično, korištenjem istog postupka kao što je opisano ranije za 2-kloro-N-[6-(2-fenil-kroman-6-iloksi)piridin-3-il]acetamid, ali zamijenjujući 5-amino-2-(2-fenilkroman-6-iloksi)-piridin odgovarajućim piridin-3-ilamin-derivatom navedenim u Primjeru 18, dobiju se:
2-kloro-N-{6-[2-(3-fluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(2-fluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(2,3-difluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(2,4-difluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(2,5-difluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(2,6-difluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(3,4-difluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(3,5-difluorofeml)kroman-6-iloksi]-piridm-3-il}acetamid,
2-kloro-N-{6-[2-(2-trifluorometilfenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(4-trifluorometilfenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(3-kloro-4-fluorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(2-klorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(3-klorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(2,4-diklorofenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N- {6-[2-(3-bromofenil)kroman-6-iloksi]-piridin-3-il} acetamid,
2-kloro-N-{6-[2-(4-etilfenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-{6-[2-(3-metoksifenil)kroman-6-iloksi]-piridin-3-il}acetamid,
2-kloro-N-[6-(3-metil-2-fenilkroman-6-iloksi)-piridin-3-il]acetamid,
2-kloro-N-[6-(2-fenilkroman-7-iloksi)-piridin-3-il]acetamid,
2-kloro-N-[6-(4-okso-2-fenilkroman-6-iloksi)piridin-3-il]acetamid,
2-kloro-N-[6-(4-okso-2-fenilkroman-7-iloksi)piridin-3-il]acetamid,
2-kloro-N-[6-(3-metil-4-okso-2-fenilkroman-6-iloksi)piridin-3-il]acetamid,
2-kloro-N-[6-(2-fenil-2,3-dihidrobenzo[1,4]dioksin-6-iloksi)piriđin-3-il]acetamid,
2-kloro-N-[6-(6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)piridin-3-il]acetamid,
2-kloro-N-[6-(5-okso-6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)piridin-3-il]acetamid
2-kloro-N-[6-(2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin-3-il]acetamid,
2-kloro-N-{6-[3-(3-fluorofenil)kroman-7-iloksi]piridin-3-il}acetaniid,
2-kloro-N-[6-(3-fenilkroman-7-iloksi)piridin-3-il]acetamid,
2-kloro-N-[6-(4-okso-2-feiulkromen-6-iloksi)piridin-3-il]acetamid,
2-kloro-N-[6-(2-fenilmdan-5-iloksi)piridin-3-il]acetamid,
respektivno.
Primjer 33.
2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
a) 2-azido-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
2-kloro-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid (500 mg), natrijev azid (445 mg) i acetonitril su pomiješani. Reakcijska smjesa je refluksirana 3 sata. Poslije hlađenja do sobne temperature, reakcijska smjesa je profiltrirana i filtrat je uparen do suhog.
1H-NMR (400 MHz; d6-DMSO) δ: 10.3 (s, 1H), 8.29 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.96 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J 2.20, 10.1 Hz), 4.07 (s, 2H), 3.00-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Slično je dobijen:
2-azido-N-{6-[2-(4-fluorofenil)kroman-6-iloksi]-piridin-3-il}-acetamid
1H-NMR (400 MHz; ds-DMSO) δ: 10.3 (s, 1H), 8.30 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.53-7.47 (m, 2H), 7.26-7.19 (m, 2H), 6.96 (d, 1H, J 8.8 Hz), 6.88-6.84 (m, 3H), 5.12 (dd, 1H, J 2.1, 10.1 Hz), 4.07 (s, 2H), 3.00-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.97 (m, 1H).
b) 2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il] acetamid
2-azido-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid (500 mg) je otopljen u metanolu (100 ml) i dodan je 10 %-ni paladij na ugljenu (125 mg). Polazni materijal je hidriran 5 sati na sobnoj temperaturi te se dobio 2-amino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid. Proizvod je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-DMSO) δ: 10.7 (s, 1H), 8.35 (d, 1H, J 2.6 Hz), 8.17 (bs, 3H), 8.01 (dd, 1H, J 2.6, 8.9 Hz), 7.47-7.32 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.89-6.86 (m, 3H), 5.12 (dd, 1H, J 1.90, 10.1 Hz), 3.79 (q, 2H, J 5.6 Hz), 3.01-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.20-2.15 (m, 1H), 2.05-1.94 (m, 1H).
Slično je dobijen:
2-amino-N-{6-[2-(4-fluorofenil)kroman-6-iloksi]-piridin-3-il}-acetamid
1H-NMR (400 MHz; d6-DMSO) δ: 10.8 (s, 1H), 8.36 (d, 1H, J 2.7 Hz), 8.21 (bs, 3H), 8.02 (dd, 1H, J 2.7, 8.9 Hz), 7.52-1.47 (m, 2H), 7.26-7.19 (m, 2H), 6.99 (d, 1H, J 8.9 Hz), 6.88-6.85 (m, 3H), 5.14 (dd, 1H, J 1.90, 10.0 Hz), 3.79 (q, 2H, J 5.7 Hz), 2.97-2.91 (m, 1H), 2.74-2.69 (m, 1H), 2.19-2.12 (m, 1H), 2.01-1.91 (m, 1H).
Primjer 34.
N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-2-(4-fenilpiperazin-1-il)acetamid
Otopini 2-kloro-N-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamida (500 mg) u acetonitrilu dodani su kalijev karbonat (333 mg) i 1-fenilpiperazin (213 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano diklorometanom. Organski ekstrakt je osušen i uparen. Proizvod je pročišćen kromatografijom na koloni, korištenjem 10%-nog metanola u dihlometanu kao eluenta. N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-2-(4-fenilpiperazin-1-il)acetamid je izoliran u obliku dihidroklorida.
1H NMR (300 MHz, d6-MeOH) δ: 8.70 (bs, 1H), 8.25 (dd, 1H, J 2.1, 9.1 Hz), 7.46-7.28 (m, 7H), 7.09-6.96 (m, 7H), 5.12 (dd, 1H, J 2.3, 9.8 Hz), 4.32 (s, 2H), 3.73-3.40 (m, 8H), 3.10-2.95 (m, 1H), 2.90-2.76 (m, 1H), 2.33-2.20 (m, 1H), 2.13-2.00 (m, 1H).
Primjer 35.
2-(4-metilpiperazin-1-il)-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-acetamid
Otopini 2-kloro-N-(2-fenilkroman-6-iloksi)piridin-3-il]acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i 1-metilpiperazin (62 ni). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano diklorometanom. Organski ekstrakt je osušen i uparen N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-2-(4-metilpiperazin-1-il)acetamid je izoliran u obliku dihidroklorida.
1H-NMR (300 MHz; d6-DMSO) δ: 10.7 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.31 (m, 5H), 6.99 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J 2.0, 10.0 Hz), 3.95 (s, 2H), 3.68-3.42 (m, 4H), 3.42-3.18 (m, 4H), 2.97-2.91 (m, 1H), 2.81 (s, 3H), 2.80-2.73 (m, 1H), 2.25-2.10 (m, 1H), 2.10-1.96 (m, 1H).
Primjer 36.
N-[6-(2-femlkroman-6-iloksi)piridin-3-il]-2-piperazin-1-ilacetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i 1-metilpiperazin (262 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smesu je dodata voda. Otapalo je ekstrahirano diklorometanom. Organski ekstrakt je osušen i uparen N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-2-(4-piperazin-1-il)acetamid je izoliran u obliku dihidroklorida.
1H-NMR (400 MHz; d6-DMSO) δ: 10.7 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.33 (m, 5H), 6.99 (d, 1H, J 8.9 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J 2.1, 10.1 Hz), 3.5-3.2 (m, 10H), 2.97-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.20-2.15 (m, 1H), 2.03-1.97 (m, 1H).
Primjer 37.
2-morfolin-4-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
Otopini 2-kloro-N-[6-(2-femlkroman-6-iloksi)-piridin-3-il]-acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i morfolin (53 mg). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. 2-morfolin-4-il-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-DMSO) δ: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.23 (s, 2H), 4.02-3.76 (m, 4H), 3.55-3.20 (m, 4H), 3.00-2.92 (m, 1H), 2.75-2.69 (m, 1H), 2.19-2.15 (m, 1H), 2.03-1.98 (m, 1H).
Primjer 38.
N-(2-fenilkroman-6-iloksi)piridin-3-il]-2-tiomorfolta-4-il acetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i tiomorfolin (63 mg). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. N-(2-fenilkroman-6-iloksi)-piridin-3-il]-2-thiomorpholin-4-il-acetamid je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-DMSO) δ: 11.0 (s, 1H), 8.37 (d, 1H, J 2.6 Hz), 8.02 (dd, 1H, J 2.6, 8.9 Hz), 7.46-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.86 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.1 Hz), 4.20 (bs, 2H), 3.85-2.65 (m, 10H), 2.20-2.15 (m, 1H), 2.05-1.95 (m, 1H).
Primjer 39.
N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-2-pyrrolidin-1-il acetamid Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i pirolidin (51 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. N-[6-(2-fenilkroman-6-iloksi) piridin-3-il]-2-pirolidin-1-il acetamid je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-DMSO) δ: 10.8 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.02 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.25 (d, 2H, 5.4 Hz), 3.67-3.55 (m, 2H), 3.20-3.06 (m, 2H), 3.06-2.90 (m, 1H), 2.80-2.65 (m, 1H), 2.23-2.12 (m, 1H), 2.10-1.85 (m, 5H).
Primjer 40.
2-(2,5-dimetilpirolidin-1-il)-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i 2,5-dimetilpirolidin (81 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. Proizvod je pročišćen kromatografijom na koloni, uz eluciju s gradijentom metanola - diklorometana (2 % -> 5 %).
1H-NMR (300 MHz; d6-DMSO) δ: 9.66 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.06 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.88-6.84 (m, 3H), 5.12 (dd, 1H, J 2.1, 9.9 Hz), 3.22 (s, 2H), 3.05-2.88 (m, 1H), 2.78-2.66 (m, 3H), 2.22-2.12 (m, 1H), 2.08-1.92 (m, 1H), 1.90-1.79 (m, 2H), 1.43-1.34 (m, 2H), 1.06 (d, 6H, J 6.1 Hz).
Primjer 41.
N-[6-(2-fenilkroman-6-iloksi)piridin-3 -il]-2-piperidin-1 -il acetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i piperidin (60 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano diklormetanom. Organski ekstrakt je osušen i uparen. N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-2-(4-piperin-1-il)acetamid je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-DMSO) δ: 11.0 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.46-7.32 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.13 (d, 2H, J 4.9 Hz), 3.52-3.41 (m, 2H), 3.15-2.90 (m, 3H), 2.79-2.67 (m, 1H), 2.24-2.12 (m, 1H), 2.07-1.92 (m, 1H), 1.85-1.33 (m, 6H).
Primjer 42.
2-(4-hidroksipiperidin-1-il)-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i 4-hidroksipiperidin (62 mg). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. Proizvod je pročišćen kromatografijom na koloni, korištenjem 10%-nog metanola u metilen kloridu kao eluenta. 2-(4-hidroksipiperidin-1-il)-N-[6-(2-fenil-kroman-6-iloksi)-piridin-3-il]-acetamid je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-MeOH) δ: 8.41 (s, 1H), 8.06 (dd, 1H, J 2.7, 9.0 Hz), 7.45-7.28 (m, 5H), 6.95-6.85 (m, 4H), 5.10 (dd, 1H, J 2.1, 10.0 Hz), 4.13 (s, 2H), 3.72-3.68 (m, 1H), 3.48-3.43 (m, 3H), 3.25-3.10 (m, 1H), 3.02-2.97 (m, 1H), 2.81-2.75 (m, 1H), 2.26-1.76 (m, 6H). (M)+ = 459 (5.8%), 360 (7.4%), 114 (100%).
Primjer 43.
2-(3-hidroksipiperidin-1-il)-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid hidroklorid
2-(3-hidroksipiperidin-1-il)-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid hidroklorid je sintetiziran primjenom istog postupka kao što je opisano za 2-(4-hidroksipiperidin-1-il)-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid u Primjeru 41, ali zamijenjujući 4-hidroksipiperidin s 3-hidroksipiperidinom.
1H-NMR (400 MHz; MeOD) δ: 1.47 (m, 1H), 1.62 (ra, 1H), 1.75 (m, 1H), 1.87 (m, 1H), 2.05 (m, 1H), 2.22 (m, 1H), 2.37-2.57 (m, 3H), 2.68-2.72 (m, 2H), 3.01 (m, 1H), 3.08-3.22 (m, 2H), 3.80-3.88 (m, 1H), 5.08 (dd, 1H, J 1.8, 10.0 Hz), 6.82-6.91 (m, 4H), 7.27-7'.46 (m, 5H), 8.06 (m, 1H), 8.35 (d, 1H, J 2.1 Hz).
Primjer 44.
2-(3-hidroksipirolidin-1-il)-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid hidroklorid
2-(3-hidroksipiperidin-1-il)-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid hidroklorid je sintetiziran primjenom istog postupka kao što je opisano za 2-(4-hidroksipiperidin-1-il)-7y-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamid u Primjeru 41, ali zamijenjujući 4-hidroksipiperidin s pirolidin-3-olom.
1H-NMR (400 MHz; d6-DMSO) δ: 1.81-2.31 (m, 4H), 2.68-2.77 (m, 1H), 2.91-3.02 (m, 1H), 3.05-3.57 (m, 2 H), 3.63-3.78 (m, 2H), 4.17-4.50 (m, 3H), 5.12 (d, 1H, J 8.5 Hz), 6.84-6.90 (m, 3H), 7.00 (dd, 1H, J 2.5, 8.8 Hz), 7.32-7.49 (m, 5H), 8.03 (dd, 1 H, J 2.7, 8.8 Hz), 8.36 (s, 1H), 10.40 (bd, 1H, J 30.3 Hz), 10.93 (d, 1H, J 3.2 Hz).
Primjer 45.
Etil ester 1- {[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]metil}piperidin-4-karboksilne kiseline
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i etil ester piperidin-4-karboksilne kiseline (94 (il). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. Proizvod je pročišćen kromatografijom na koloni, korištenjem 10%-nog metanola u metilenkloridu kao eluenta. Etil ester l-{[6-(2-fenilkroman-6-iloksi)piridin-3-ilkarbamoil]metil}piperidin-4-karboksilne kiseline je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-MeOH) δ: 8.48 (s, 1H), 8.10 (dd, 1H, J 2.2, 9.0 Hz), 7.45-7.29 (m, 5H), 6.99-6.88 (tn, 4H), 5.10 (dd, 1H, J 2.0, 10.0 Hz), 4.23-4.15 (m, 4H), 3.76-3.72 (m, 2H), 3.22-3.15 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.75 (m, 2H), 2.27-1.97 (m, 6H), 1.27 (t, 3H, J 7.2 Hz). (M)+ = 515 (2.9%), 470 (4.3%), 360 (8.5%), 170 (100%).
Primjer 46.
2-Dietilamino-N-[6-(2-feiulkroman-6-iloksi)piridin-3-il]acetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamida (200 mg) u acetonitrilu dodani su kalijev karbonat (133 mg) i dietil amin (63 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. Proizvod je pročišćen kromatografijom na koloni, korištenjem 10%-nog metanola u metilenkloridu kao eluenta. 2-dietilamino-N-[6-(2-fenil-kroman-6-iloksi)piridin-3-il]acetamid je izoliran u obliku hidroklorida.
1H-NMR (400 MHz; d6-DMSO) δ: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 2.0, 10.0 Hz), 4.14 (d, 2H, J 4.9 Hz), 3.24 (k, 4H, J 7.2 Hz), 3.01-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.15 (m, 1H), 2.04-1.94 (m, 1H), 1.24 (t, 6H, J 7.2 Hz).
Primjer 47.
2-Dimetilamino-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]-acetamida (177 mg) u acetonitrilu dodani su kalijev karbonat (118 mg) i 33 %-ni dimetilamin u etanolu (480 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. 2-dimetilamino-N-[6-(2-fenil-kroman-6-iloksi)-piridin-3-il]acetamid je izoliran u obliku hidroklorida.
1H-NMR (300 MHz; d6-DMSO) δ: 11.3 (s, 1H), 8.41 (d, 1H, J 2.3 Hz), 8.07 (dd, 1H, J 2.3, 8.8 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (d, 1H, J 8.5 Hz), 4.20 (s, 2H), 3.01-2.69 (m, 8H), 2.20-1.91 (m, 2H).
Primjer 48.
2-[bis(-2-hidroksietil)amino]-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid
Otopini 2-kloro-N-[6-(2-fenilkroman-6-iloksi)-piridin-3-il]acetamida (177 mg) u acetonitrilu dodani su kalijev karbonat (118 mg) i dietanolamin (65 μl). Smjesa je miješana na sobnoj temperaturi. U reakcijsku smjesu je dodana voda. Otapalo je ekstrahirano etil acetatom. Organski ekstrakt je osušen i uparen. 2-[bis(2-hidroksietil)amino]-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]acetamid je pročišćen kromatografijom na koloni, korištenjem 10%-nog metanola u metilenkloridu kao eluenta.
1H-NMR (400 MHz; d6-DMSO) δ: 10.1 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.07 (dd, 1H, J 2.7, 8.8 Hz), 7.46-7.31 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (dd, 1H, J 2.1, 10.0 Hz), 4.71 (t, 2H, J 5.4 Hz), 3.50 (q, 4H, J 5.4 Hz), 2.97-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.67 (t, 4H, J 5.4 Hz), 2.18-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Primjer 49.
[6-(2-fenilkroman-6-iloksi)piridin-3-il](2-pirolidin-1-iletil)amin
[6-(2-fenilkroman-6-iloksi)piridin-3-il]-2-pirolidin-1-il acetamid (0,20 g) je otopljen u suhom THF (2 ml) i dodana je otopina boran-THF kompleksa (3,3 ml, 1,0 M u THF), kap po kap, u atmosferi dušika. Reakcijska smjesa je refluksirana 2 sata. Otapalo je upareno i precipitat je razrijeđen metanolom. Otopina je zakieljen 6N-nom HCl i miješana na 70°C jedan sat. Poslije hlađenja do sobne temperature, dodana je 5 %-na otopina NaOH i smjesa je ekstrahirana etil acetatom. Otopina je osušenoa preko Na2SO4 i uparena pod sniženim tlakom. [6-(2-fenilkroman-6-iloksi)piridin-3-il](2-pirolidin-1-iletil)amin je izoliran u obliku hidroklorida.
1H NMR (400 MHz, d6-DMSO) δ: 10.24 (br s, 1H), 7.60 (d, 1H, J 2.9 Hz), 7.38-7.45 (m, 4H), 7.34 (m, 1H), 7.19 (dd, 1H, J 2.9, 8.7 Hz), 6.75-6.82 (m, 4H), 5.09 (d, 1H, J 9.9 Hz), 3.57 (m, 2H), 3.38-3.43 (m, 2H), 3.29 (m, 2H), 3.03 (m, 2H); 2.94 (m, 1H), 2.69 (m, 1H), 2.16 (m, 1H), 1.99 (m, 3H), 1.89 (m, 2H).
Slijedeći Primjeri 50-53 su dobijeni kao što je opisano za [6-(2-fenilkroman-6-iloksi)piridin-3-il](2-pirolidin-1-iletil)amin u Primjeru 49, zamijenjujući [6-(2-fenilkroman-6-iloksi)piridin-3-il]-2-pirolidin-1-il acetamid odgovarajućim acetamidnim derivatom.
Primjer 50.
N-etil-N'-[6-(2-fenilkroman-6-iloksi)piridin-3-il]etan-1,2-diamindihidroklorid
1H NMR (400 MHz, d6-DMSO) δ: 8.85 (br s, 2H), 7.60 (d, 1H, J 2.8 Hz), 7.38-7.45 (m, 4H), 7.34 (d, 1H, J 6.8 Hz), 7.21 (dd, 1H, J 3.0,8.8 Hz), 6.76-6.83 (m, 4H), 5.10 (d, 1H, J 8.1 Hz), 3.36 (t, 2H, J 6.3 Hz), 3.06 (m, 2H), 2.92-2.97 (m, 3H), 2.69 (m, 1H), 2.16 (m, 1H), 2.01 (m, 1H), 1.21 (t, 3H, J 7.2 Hz).
Primjer 51.
N*l*-[6-(2-fenilkroman-6-iloksi)piridin-3-il]etan-1,2-diamindihidroklorid
lH NMR (400 MHz, d6-DMSO) δ: 7.99 (br s, 2H), 7.58 (d, 1H, J 2.7 Hz), 7.38-7.45 (m, 4H), 7.34 (d, 1H, J 7.0 Hz), 7.17 (dd, 1H, J 3.0, 8.7 Hz), 6.75-6.82 (m, 4H), 5.10 (d, 1H, J 7.8 Hz), 3.27-3.30 (m, 2H), 2.93-2.97 (m, 3H), 2.69 (m, 1H), 2.16 (m, 1H), 1.99 (m, 1H).
Primjer 52.
N,N-dietil-N'-[6-(2-fenilkroman-6-iloksi)piridin-3-il]etan-1,2-diamin dihidroklorid
1H NMR (400 MHz, d6-DMSO) δ: 7.61 (d, 1H, J 2.8 Hz), 7.38-7.45 (m, 4H), 7.34 (m, 1H), 7.19 (dd, 1H, J 2.8, 8.8 Hz), 6.75-6.83 (m, 4H), 5.10 (d, 1H, J 7.8 Hz), 3.42-3.44 (m, 2H), 3.18-3.22 (m, 6H), 2.92 (ra, 1H), 2.69 (m, 1H), 2.14 (m, 1H), 1.99 (m, 1H), 1.21 (t, 6H, J 7.2 Hz).
Primjer 53.
N,N-dimetil-N'-[6-(2-fenilkroman-6-iloksi)piridin-3-il]etan-1,2-diamin dihidroklorid
1H NMR (400 MHz, d6-DMSO) δ: 7.61 (d, 1H, J 2.8 Hz), 7.38-7.45 (m, 4H), 7.34 (m, 1H), 7.20 (dd, 1H, J 2.9, 8.8 Hz), 6.75-6.83 (m, 4H), 5.10 (d, 1H, J 8.0 Hz), 3.42 (t, 2H, J 6.2 Hz), 3.22 (t, 2H, J 6.2 Hz), 2.93 (m, 1H), 2.80 (s, 6H), 2.69 (m, 1H), 2.16 (m, 1H), 1.98 (m, 1H).
Primjer 54.
Metansulfonamidni derivati
N-{6-[2-(3-(N-metansulfonil(5-aminopiridin-6-iloksi-))fenil)kroman-6-iloksi]-piridin-3 -il} –metansulfonamid
Piridin (620 μl) i metansufonil klorid (260 (il) su dodani u ohlađenu otopinu 6-[2-(3-(5-aminopiridin-2-iloksi)fenil)kroman-6-iloksi]-piridin-3-ilamina (650 mg) u suhom THF (11 ml). Poslije miješanja dobijene smjese na sobnoj temperaturi dodatna 2 sata, dodana je 1 M klorovodična kiselina. Otapalo je ekstrahirano etil acetatom. Kombinirani organski slojevi su oprani vodom, osušeni pomoću Na2SO4 i upareni. N-{6-[2-(3-(N-metansulfonil(5-aminopiridin-6-iloksi-))fenil)-kroman-6-iloksi]-piridin-3-il}metansulfonamidjerekristaliziran iz smjese metanola i dietil etra.
1H NMR (300 MHz, d6-DMSO) δ: 9.74 (s, 1H), 9.67 (s, 1H), 8.02 (d, 1H, 2.7 Hz), 7.98 (d, 1H, J 2.7 Hz), 7.72 (dd, 1H, J 2.7, 8.8 Hz), 7.67 (dd, 1H, J 2.7, 8.8 Hz), 7.44 (t, 1H, J 7.8 Hz), 7.30 (d, 1H, 7.8 Hz), 7.20 (s, 1H), 7.09-7.05 (m, 2H), 6.97 (d, 1H, J 8.8 Hz), 6.89- 6.85 (m, 3H), 5.14 (d, 1H J 8.5 Hz), 3.00 (s, 3H), 2.98 (m, 3H), 2.98-2.91 (m, 1H), 2.75-2.70 (m, 1H), 2.21-2.17 (m, 1H), 2.02-1.97 (m, 1H).
6-[(N-metansulfonil(5-aminopiridin-6-iloksi-)]-2-{3-[Af-metansulfonil-(5-aminopiridin-6-iloksi-)]fenil}kroman-4-ol
1H NMR (300 MHz, d6-DMSO) δ: 9.73 (s, 1H), 9.66 (s, 1H), 8.03 (d, 1H, J 2.6 Hz), 7.99 (d, 1H, J 2.6 Hz), 7.71-7.66 (m, 2H), 7.45 (t, 1H, J 7.8 Hz), 7.32 (d, 1H, J 7.8 Hz), 7.22-6.80 (m, 7H), 5.29 (d, 1H J 11.5 Hz), 4.95 (dd, 1H, J 6.1, 10.5 Hz), 3.00 (s, 3H), 2.99 (s, 3H), 2.38-2.31 (m, 1H), 1.99-1.91 (m, 1H).
N-{6-[2-(3-benziloksifenil)kroman-6-iloksi]piridin-3-il}metansulfonamid
1H NMR (300 MHz, d6-DMSO) δ: 9.64 (s, 1H), 7.98 (d, 1H, J 2.8 Hz), 7.66 (dd, 1H, J 2.8, 8.9 Hz), 7.47-7.28 (m, 6H), 7.09 (s, 1H), 7.04-6.94 (m, 3H), 6.89-6.85 (m, 3H), 5.12 (s, 2H), 5.09 (dd, 1H, J 2.1, 12.0 Hz), 2.98 (s, 3H), 2.98-2.89 (m, 1H), 2.73-2.67 (m, 1H) 2.20-2.14 (m, 1H), 2.02-1.96 (m, 1H).
N-{6-[2-(3-hidroksifenil)kroman-6-iloksi]piridin-3-il}metansulfonamid
1H NMR (400 MHz, d6-DMSO) δ: 9.42 (s, 1H), 7.98 (d, 1H, J 2.8 Hz), 7.66 (dd, 1H, J 2.8, 8.8 Hz), 7.18 (t, 1H, J 8.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 6.88-6.83 (m, 5H), 6.73-6.69 (m, 1H), 5.03 (dd, 1H J 2.1, 9.9 Hz), 2.98 (s, 3H), 2.98-2.90 (m, 1H), 2.72-2.67 (m, 1H), 2.16-2.11 (m, 1H), 1.98-1.91 (m, 1H).
Primjer 55.
N-(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)-metansulfonamid
Kalijev fluorid (42 mg) je dodan otopini N-{6-[2-(3-hidroksi-fenil)kroman-6-iloksi]piridin-3-il}metansulfonamida (100 mg) u suhom DMF (1 ml). Poslije miješanja dobijene smjese na 120°C 30 minuta, dodan je 2-kloro-5-nitropiridin (40 mg). Reakcijska smjesa je miješana još 30 minuta na 120°C. Poslije hlađenja do sobne temperature, dodano je 1M otapala HCl i formirani precipitat je profiltriran. N-(6-{2-[3-(5-Nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il) metansulfonamid je pročišćen kromatografijom na koloni, korištenjem 1:1 smjese etil acetata i heptana kao eluenta.
1H NMR (300 MHz, d6-DMSO) δ: 9.64 (s, 1H), 9.04 (d, 1H, J 2.9 Hz), 8.63 (dd, 1H, J 2.9, 9.1 Hz), 7.98 (d, 1H, J 2.7 Hz), 7.66 (dd, 1H, J 2.7, 8.8 Hz), 7.52 (t, 1H, J 7.7 Hz), 7.39 (d, 1H, J 7.7 Hz), 7.31 (s, 1H), 7.27 (d, 1H, J 9.1 Hz), 7.22-7.19 (m, 1H), 6.96 (d, 1H, J 8.8 Hz), 6.89-6.85 (m, 3H), 5.17 (d, 1H, J 7.8 Hz), 2.97 (s, 3H), 2.98-2.92 (m, 1H), 2.76-2.69 (m, 1H) 2.28-2.19 (m, 1H), 2.02-1.97 (m, 1H).
Primjer 56.
(5-nitropiridin-2-il)(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)amin
5-nitropiridin-2-il)(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)amin je dobijen primjenom istog postupka kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru l(b), polazeći od N-{6-[2-(3-hidroksifenil)kroman-6-iloksi]piridin-3-iljmetansulfonamida.
1H NMR (300 MHz, d6-DMSO) δ: 10.14 (s, 1H), 9.02 (m, 1H), 8.63 (dd, 1H, J 2.8, 8.8 Hz), 8.40 (d, 1H, J 2.8 Hz), 8.30 (dd, 1H, J 2.8, 9.2 Hz), 8.13 (dd, 1H, J 2.6, 8.6 Hz), 7.52 (t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.8 Hz), 7.31 (s, 1H), 7.28 (d, 1H, J 9.2 Hz), 7.21 (dd, 1H, J 2.1, 7.9 Hz), 6.70 (d, 1H, J 8.8 Hz), 6.85-6.90 (m, 5H), 5.18 (d, 1H, J 8.1 Hz), 2.97 (m, 1H), 2.74 (m, 1H), 2.23 (m, 1H), 2.02 (m, 1H).
Primjer 57.
N-{6-[2-(3-(N-acil(5-aminopiridin-6-iloksi-))fenil)kroman-6-iloksi]piridin-3-il}-acetamid
6-[2-(3-(5-aminopiridin-2-iloksi)fenil)kroman-6-iloksi]piridin-3-ilamin iz Primjera 16 (289 mg) je otopljen u 3 ml suhog piridina u atmosferi dušika. Dodan je DMAP (16 mg). Dodan je AcCl (240 μl) na sobnoj temperaturi u reakcijsku otopinu kap po kap, zbog burne i egzotermne reakcije. Reakcija je miješana 4,5 sata na sobnoj temperaturi i ugašena sporim dodavanjem nekoliko kapi H2O. 50 ml toluena je dodato i upareno je do suhog. Uparavanje toluena je ponovljeno dvaput. Dobijena smeđkasta smjesa je pročišćena kromatografijom na koloni (10%-ni metanol u diklorometanu) te se dobio kristalan blago žućkasti proizvod. Proizvod je dalje pročišćen rekristalizacijom iz smjese metanol/dietil etar.
1H-NMR (400 MHz; CDCl3) δ: 8.12-8.03 (m, 4H), 7.42-736 (m, 2H), 7.26-7.21 (m, 2H), 7.15 (s, 1H), 7.06 (dd, 1H, J 1.7, 8.0 Hz), 6.91-6.82 (m, 5H), 5.08 (dd, 1H, J 9.6,2.3 Hz), 3.02-2.90 (m, 1H), 2.80-2.70 (m, 1H), 2.28-2.14 (m, 7H), 2.14-2.01 (m, 1H).
Primjer 58.
N-(6-{2-[3-(5-Nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)acetamid
a) N-{6-[2-(3-hidroksifenil)kroman-6-iloksi]piridin-3-il}acetamid je dobijen kao što je opisano za N-(6-{2-[3-(5-acetilaminopiridin-2-iloksi)-fenil]-kroman-6-iloksi}piridin-3-il)acet-amid u Primjeru 57, polazeći od 3-[6-(5-aminopiridin-2-iloksi)kroman-2-il]fenola, korištenjem 1,2 ekv. AcCl.
1H NMR (400 MHz, d6-DMSO) δ: 10.03 (s, 1H), 9.42 (s, 1H), 8.27 (d, 1H, J 2.6 Hz), 8.01 (dd, 1H, J 8.8,2.6 Hz), 7.18 (t, 1H, J 8.0 Hz), 6.93 (d, 1H, J 8.8 Hz), 6.84-6.85 (m, 5H), 6.72 (d, 1H, J 8.9 Hz), 5.03 (d, 1H, J 8.2 Hz), 2.94 (m, 1H), 2.70 (m, 1H), 2.14 (m, 1H), 2.04 (s,3H), 1.94 (m, 1H).
b) N-(6-{2-[3-(5-nitropiridin-2-iloksi)fenil]kroman-6-iloksi}piridin-3-il)acetamid je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru l(b), polazeći od N-{6-[2-(3-hidroksifenil)kroman-6-iloksi]piridin-3-il}acetamida.
1H NMR (400 MHz, d6-DMSO) δ: 10.03 (s, 1H), 9.05 (d, 1H, J 2.1 Hz), 8.63 (d, 1H, J 8.9 Hz), 8.26 (s, 1H), 8.00 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H), 1.21-1M (m, 2H), 7.20 (m, 1H), 6.92 (d, 1H, J 8.9 Hz), 6.85-6.87 (m, 3H), 5.17 (d, 1H, J 10.4 Hz), 2.96 (m, 1H), 2.71 (m, 1H), 2.20 (m, 1H), 2.04 (s, 3H), 1.99 (m, 1H).
Primjer 59.
N-metil-N-[6-(2-fenilkroman-6-iloksi)piridin-3-il]gvanidin
a) 1-metil-3-[6-(2-fenilkroman-6-iloksi)piridin-3-il]tiourea
Otopina 6-(2-fenilkroman-6-iloksi)piridin-3-ilamina (150 mg) i metil izotiocijanata (94 ni) u etanolu je refluksirana 10 sati. Poslije hlađenja, otapala su uparena. Sirovi proizvod 1-metil-3-[6-(2-fenilkroman-6-iloksi)piridin-3-il]tiourea je pročišćen kromatografijom na koloni (5%-ni metanol u diklorometanu).
1H NMR (400 MHz, d6-DMSO) δ: 9.45 (bs, 1H), 8.02 (d, 1H, J 2.7 Hz), 7.81 (dd, 1H, J 2.7, 8.8 Hz), 7.70 (bs, 1H), 7.47-7.38 (m, 4H), 7.36-7.32 (m, 1H), 6.94-6.86 (m, 4H), 5.12 (dd, 1H J 2.3, 10.1 Hz), 2.98-2.93 (m, 1H), 2.90 (d, 3H, J 4.3 Hz), 2.76-2.71 (m, 1H), 2.19-2.15 (m, 1H), 2.15-1.99 (m, 1H).
b) N-metil-N-[6-(2-femlkroman-6-iloksi)piridin-3-il]gvanidin
Otopina 1-metil-3-[6-(2-fenilkroman-6-iloksi)piridin-3-il]tiouree (150 mg), metiljodida (36 ni) i acetona (15 ml) je refluksirana 90 minuta. Otapalo je upareno i ostatak je otopljen u 4 ml metanola zasićenog s NH3. Smjesa je zagrijavana pod tlakom na 100°C 16 sati. Otapalo je upareno i ostatak je pročišćen kromatografijom na koloni, korištenjem 10%-nog metanola u diklorometanu kao eluenta.
1H NMR (400 MHz, d6-DMSO) δ: 9.35 (bs, 1H), 8.04 (d, 1H, J 2.7 Hz), 7.71 (dd, 1H, J 2.7, 8.8 Hz), 7.65 (bs, 1H), 7.47-7.34 (m, 5H), 7.05 (d, 1H, J 8.8 Hz), 6.90-6.88 (m, 3H), 5.13 (d, 1H J 7.9 Hz), 3.01-2.98 (m, 1H), 2.80 (d, 3H, J 4.4 Hz), 2.75-2.71 (m, 1H), 2.19-2.15 (m, 1H), 2.02-1.98 (m, 1H).
Primjer 60.
Dimetil-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-amin i dimetil-[2-(2-fenilkroman-6-iloksi)-piridin-4-il]-amin
5-amino-2-(2-fenilkroman-6-iloksi)piridin (ORM-10543) (0,20 g, 0,63 mmola) i 37% formaldehid (0,73 ml, 0,80 mmola) su otopljeni u acetonitrilu (12 ml). Dodan je natrijcijanoborohidrid (0,16 g, 2,51 mmol) i smjesa je miješana 30 minuta na sobnoj temperaturi. pH je namješten na 6-7 octenom kiselinom i reakcijska smjesa je miješana dodatnih 30 minuta. Otapalo je upareno. Ostatak je otopljen u 10%-noj otopini kalijhidroksida i ekstrahiran metilen kloridom. Organska faza je osušena i uparena. Rekristalizacija iz dietiletra je dala dimetil-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-amin čistoće 92%. Rekristalizacijski filtrat je uparen. Ostatak je otopljen u metilen kloridu i dodan je 1M HCl-dietiletar. Dimetil-[2-(2-fenilkroman-6-iloksi)-piridin-4-il]-amin je precipitiran kao hidroklorid čistoće 95,3%.
Dimetil-[6-(2-fenilkroman-6-iloksi)piridin-3-il]-amin
1H-NMR (400 MHz; d6-DMSO) δ: 2.01 (m, 1H), 2.18 (m, 1H), 2.76 (m, 1H), 2.95 (s, 6H), 2.95-3.04 (m, 1H), 5,14 (d, 1H, J 8.2 Hz), 6.91-6.99 (m, 4H), 7.35-7.48 (m, 5H), 7.63 (d, 1H, J 3.1 Hz), 7.72 (dd, 1H, 3.2, 9.4 Hz).
Dimetil-[2-(2-fenilkroman-6-iloksi)-piridin-4-il]-amin
1H-NMR (400 MHz; d6-DMSO) δ: 1.99 (m, 1H), 2.16 (m, 1H), 2.69 (m, 1H), 2.86 (s, 6H), 2.94 (m, 1H), 5,10 (d, 1H, J 9.2 Hz), 6.75-6.86 (m, 4H), 7.27-7.35 (m, 2H), 7.37-7.48 (m, 4H), 7.65 (d, 1H, 2.9 Hz).
Primjer 61.
5-kloropiridiniloksi derivati
5-kloro-2-(2-fenilkroman-6-iloksi)piridin
2-fenilkroman-6-ol (500 mg) je otopljen u suhom DMF (5 ml) u atmosferi dušika. Kalijev terc-butoksid (270 mg) je dodan u otopinu i rezultirajuća smjesa je miješana 30 minuta. Dodan je 2,5-dikloropiridin i smjesa je miješana na 120°C 2,5 sata. Reakcijska smjesa je ostavljena da se ohladi do sobne temperature, dodana je otopina 1M HCl i ekstrahirana je etil acetatom. Kombinirane organske faze su oprane vodom i zasićenom otopinom NaCl i osušene. Sirovi proizvod je propušten kroz kolonu od silika gela uz korišćenje heptan - etil acetata (3:1) kao eluenta, a zatim je rekristaliziran iz 2-propanola.
1H NMR (300 MHz, d6-DMSO) δ: 8.19 (d, 1H, J 2.6 Hz), 7.92 (dd, 1H, 8.8, 2.6 Hz), 7.47-7.34 (m, 5H), 7.02 (d, 1H, J 8.8 Hz) 6.92-6.87 (m, 3H), 5.12 (dd, 1H, J 10.0, 2.1 Hz), 2.97 (m, 1H), 2.73 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).
2-[2-(3-(5-kloropiridin-2-iloksi)fenil)kroman-6-iloksi]-5-kloropiridin je dobijen na isti način, korištenjem 200 mol-% 2,5-dikloropiridina i polazeći od 2-(3-hidroksifenil)kroman-6-ola.
1H NMR (400 MHz, d6-DMSO) δ: 8.22 (d, 1H, J 2.6 Hz), 8.19 (d, 1H, J 2.9 Hz), 7.97 (dd, 1H, J 8.9, 2.6 Hz), 7.92 (dd, 1H, J 9.0, 2.9 Hz), 7.46 (t, 1H, J 7.9 Hz), 7.32 (d, 1H, J 7.8 Hz), 7.22, (s, 1H), 7.13-7.10 (m, 2H), 7.02 (d, 1H, J 9.2 Hz) 6.91-6.87 (m, 2H), 5.15 (dd, 1H, J 10.0,2.1 Hz), 2.96 (m, 1H), 2.74 (m, 1H), 2.18 (m, 1H), 1.99 (m, 1H)
Korištenjem istog postupka kao što je opisano ranije za 5-kloro-2-(2-fenilkroman-6-iloksi)piridin, ali zamijenjujući 2-fenilkroman-6-ol s:
2-(4-fluorofenil)kroman-6-olom,
2-(3-fluorofenil)kroman-6-olom,
2-(2-fluorofenil)kroman-6-olom,
2-(2,3-difluorofenil)kroman-6-olom,
2-(2,4-difluorofenil)kroman-6-olom,
2-(2,5-difluorofenil)kroman-6-olom,
2-(2,6-difluorofenil)kroman-6-olom,
2-(3,4-difluorofenil)kroman-6-olom,
2-(3,5-difluorofenil)kroman-6-olom,
2-(2-trifluorometilfenil)kroman-6-olom,
2-(4-trifluorometilfenil)kroman-6-olom,
2-(3-kloro-4-fluorofenil)kroman-6-olom,
2-(2-klorofenil)kroman-6-olom,
2-(3-klorofenil)kroman-6-olom,
2-(2,4-diklorofenil)kroman-6-olom,
2-(3-bromofenil)kroman-6-olom,
2-(4-etilfenil)kroman-6-olom,
2-(3-metoksifenil)kroman-6-olom,
3-metil-2-fenilkroman-6-olom,
2-fenilkroman-7-olom,
6-hidroksiflavanonom,
7-hidroksiflavanonom,
6-hidroksi-3-metil-2-fenilkroman-4-onom,
2-fenil-2,3-dihidrobenzo[1,4]dioksin-6-olom,
6-fenil-5,6,7.8-tetrahidronaftalen-2-olom,
6-hidroksi-2-fenil-3,4-dihidro-2H-naftalen-1-onoin,
2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-olom,
3-(3-fluorofenil)kroman-7-olom,
3-fenilkroman-7-olom,
6-hidroksiflavonom,
2-fenilindan-5-olom,
dobiju se:
5-kloro-2-[2-(4-fluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(3-fluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2-fluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2,3-difluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2,4-difluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2,5-difluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2,6-difluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(3,4-difluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(3,5-difluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2-trifluorometilfenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(4-trifluorometilfenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(3-kloro-4-fluorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2-klorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(3-klorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(2,4-diklorofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(3-bromofenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(4-etilfenil)kroman-6-iloksi]piridin,
5-kloro-2-[2-(3-metoksifenil)kroman-6-iloksi]piridin,
5-kloro-2-(3-metil-2-fenilkroman-6-iloksi)piridin,
5-kloro-2-(2-fenilkroman-7-iloksi)piridin,
6-(5-kloropiridin-2-iloksi)-2-fenilkroman-4-on,
7-(5-kloropiridin-2-iloksi)-2-fenilkroman-4-on,
6-(5-kloropiridin-2-iloksi)-3-metil-2-fenilkroman-4-on,
5-kloro-2-(2-fenil-2,3-dihidrobenzo[1,4]dioksin-6-iloksi)piridin,
5-kloro-2-(6-fenil-5,6,7,8-tetrahidronaftalen-2-iloksi)piridin,
6-(5-kloropiridin-2-iloksi)-2-fenil-3,4-dihidro-2/f-naftalen-1-on,
5-kloro-2-(2-fenil-2,3-dihidrobenzo[1,4]oksatiin-6-iloksi)piridin,
5-kloro-2-[3-(3-fluorofenil)kroman-7-iloksi]piridin,
5-kloro-2-(3-fenilkroman-7-iloksi)piridin,
6-(5-kloropiridin-2-iloksi)-2-fenilkromen-4-on,
5-kloro-2-(2-fenilindan-5-iloksi)piridin, respektivno.
Primjer 62.
2-piridinski derivati
2-(2-fenilkroman-6-iloksi)piridin
2-(2-fenilkroman-6-iloksi)piridin je dobijen na isti način kao 5-kloro-2-(2-fenilh-roman-6-iloksi)piridin u Primjeru 61, ali zamijenjujući 2,5-dikloropiridin s 2-kloropiridinom.
1H NMR (400 MHz, d6-DMSO) δ: 8.13 (dd, 1H, J 5.1, 1.9 Hz), 7.81 (ddd, 1H, 8.6, 6.9, 1.9 Hz), 7.47-7.32 (m, 5H), 7.08 (dd, 1H, J 6.9, 5.1 Hz), 6.95 (d, 1H, J 8.6 Hz), 6.90-6.86 (m, 3H), 5.11 (dd, 1H, J 10.2,2.2 Hz), 2.97 (m, 1H), 2.73 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).
2-[2-(3-(piridin-2-iloksi)fenil)kroman-6-iloksi]piridin je dobijen na isti način, korištenjem 200 mol-% 2-kloropiridina i polazeći od 2-(3-hidroksifenil)kroman-6-ola.
1H NMR (400 MHz, d6-DMSO) δ: 8.17 (dd, 1H, J 4.1,1.7 Hz), 8.13 (dd, 1H, J 4.1, 1.0 Hz), 7.86 (ddd, 1H, J 8.6, 7.5, 1.7 Hz), 7.81 (ddd, 1H, 8.5, 7.5,1.0 Hz), 7.45 (t, 1H, J 7.9 Hz) 7.30 (d, 1H, J 7.5 Hz), 7.20 (s, 1H), 7.15-7.06 (m, 3H), 7.04 (d, 1H, J 8.6 Hz), 6.95 (d, 1H, J 8.5 Hz), 6.89-6.86 (m, 3H), 5.15 (d, 1H, J 8.7 Hz), 2.95 (m, 1H), 2.73 (m, 1H), 2.21 (m, 1H), 2.00 (m, 1H).
Primjer 63.
4-(2-fenil-kroman-6-iloksi)-piridin
4-(2-fenil-kroman-6-iloksi)-piridin je dobijen na isti način kao 5-kloro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 61, ali zamijenjujući 2,5-dikloropiridin s 4-kloropiridinom.
1H NMR (400 MHz, d6-DMSO) δ: 8.43 (dd, 2H, J 4.8, 1.5 Hz), 7.47-7.33 (m, 5H), 6.98-6.93 (m, 3H), 6.88 (dd, 2H, J 4.8, 1,5 Hz), 5.14 (dd, 1H, J 10.2, 2.2 Hz), 2.99 (m, 1H), 2.75 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H).
Primjer 64.
6-nikotinamidni derivati
6-(2-fenilkroman-6-iloksi)nikotinamid
6-(2-fenilkroman-6-iloksi) nikotinamid je dobijen na isti način kao 5-kloro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 61, ali zamijenjujući 2,5-dikloropiridin s 6-kloronikotinamidom.
1H NMR (400 MHz, d6-DMSO) δ: 8.61 (d, 1H, J 2.4 Hz), 8.23 (dd, 1H, J 8.7, 2.4 Hz), 8.00 (bs, 1H), 7.47-7.32 (m, 6H), 7.01 (d, 1H, J 8.7 Hz), 6.93-6.86 (m, 3H), 5.13 (dd, 1H, J 8.2,1.9 Hz), 3.00 (m, 1H), 2.73 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H).
6-(2-[3-(5-karbamoilpiridin-2-iloksi)fenil]fenilkroman-6-iloksi) nikotinamid je dobijen na isti način, korištenjem 200 mol-% 6-kloronikotinamida i polazeći od 2-(3-hidroksifenil)kroman-6-ola.
1H NMR (400 MHz, d6-DMSO) δ: 8.63 (d, 1H, J 2.4 Hz), 8.61 (d, 1H, J 2.4 Hz), 8.27 (dd, 1H, J 8.6,2.4 Hz), 8.23 (dd, 1H, J 8.7,2.4 Hz), 8.03 (bs, 1H), 8.00 (bs, 1H), 7.48 (t, 1H, J 7.9 Hz), 7.46 (bs, 1H), 7.44 (bs, 1H), 7.35 (d, 1H, J 7.7 Hz), 7.25, (s, 1H), 7.14 (dd, 1H, 7.9, 7.7 Hz), 7.11 (d, 1H, 8.7 Hz), 7.01 (d, 1H, 8.6 Hz), 6.93-6.89 (m, 3H), 5.17 (d, 1H, J 8.7 Hz), 2.97 (m, 1H), 2.76 (m, 1H), 2.20 (m, 1H), 1.99 (m, 1H).
Primjer 65.
C- [6-(2-fenilkroman-6-iloksi)piridin-3-il]metilamin hidroklorid
U otopinu 6-(2-fenilkroman-6-iloksi) nikotinamida (100 mg) u suhom THF (2,0 ml) dodana je kap po kap otopina boran-THF kompleksa (0,6 ml, 1,0 M THF). Dobijena smjesa je refluksirana 4 sata. Poslije hlađenja do sobne temperature, 3M otopine HCl je dodano i THF je uparen pod vakuumom. Smjesa je zaalkaljena 50 %-nim otopinom NaOH, ekstrahirana etil acetatom i osušena. Hidroklorid C-[6-(2-fenilkroman-6-iloksi)piridin-3-il]metilamina je dobijen obradom pomoću otapala HCL - etar.
1H NMR (400 MHz, d6-DMSO) δ: 8.29 (bs, 3H), 8.21 (s, 1H), 7.95 (d, 1H, J 8.5 Hz), 7.47-7.34 (m, 5H), 7.03 (d, 1H, J 8.5 Hz), 6.89-6.86 (m, 3H), 5.13 (d, 1H, J 8.4 Hz), 4.00 (m, 2H), 2.94 (m, 1H), 2.70 (m, 1H), 2.19 (m, 1H), 2.00 (m, 1H).
Primjer 66.
Dimetil-[6-(2-fenilkroman-6-iloksi)piridin-3-ilmetil]amin
a) (6-kloropiridin-3 -ilmetil)dimetilamin
2-kloro-5-(klorometil)piridin (500 mg) je otopljen u etanolu (7,0 ml). Dodani su dimetilamin (0,83 ml, 33 % u etanolu) i kalijev karbonat (641 mg) i rezultujuća smjesa je refluksirana 1,5 sat. Poslije uparavanja etanola, dodana je voda i vodena smjesa je ekstrahirana etil acetatom.
1H NMR (400 MHz, de-DMSO) δ: 8.31 (d, 1H, J 2.3 Hz), 7.77 (dd, 1H, J 8.2, 2.3 Hz), 7.47 (d, 1H, J 8.2 Hz), 3.41 (s, 2H), 2.14 (s, 6 H).
b)Dimetil-[6-(2-fenilkroman-6-iloksi)piridin-3-ilmetil]amin
Dimetil-[6-(2-fenilkroman-6-iloksi)piridin-3-ilmetil]amin je dobijen kao što je opisano za 5-kloro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 61, ali zamijenjujući 2,5-dikloropiridin s (6-kloropiridin-3-ilmetil)dimetilaminom.
1H NMR (400 MHz, CDCl3) δ: 8.03 (d, 1H, J 2.3 Hz), 7.65 (dd, 1H, J 8.4, 2.3 Hz), 7.44-7.32 (m, 5H), 6.92-6.88 (m, 3H), 6.84 (d, 1H, J 8.4 Hz), 5.05 (dd, 1H, J 10.2, 2.3 Hz), 3.36 (s, 2H), 3.02 (m, 1H), 2.80 (m, 1H), 2.23 (s, 1H), 2.19 (m, 1H), 2.10 (m, 1H).
Primjer 67.
Metil ester 6-(2-fenilkroman-6-iloksi)nikotinske kiseline
a) Metil ester 6-kloronikotinske kiseline
6-kloronikotinska kiselina (2,0 g) je otopljena u metanolu i dodana je koncentrirana klorovodična kiselina (3,0 ml). Reakcijska smjesa je refluksirana 5 sati i metanol je uklonjen u vakuumu. Dodan je etil acetat i dobijena otopina je oprana zasićenom otopinom natrij bikarbonata, vodom i slanom otopinom.
1H NMR (400 MHz,) δ: 8.92 (d, 1H, J 2.1 Hz), 8.32 (dd, 1H, J 8.4, 2.1 Hz), 7.70 (d, 1H, J 8.4 Hz), 3.90 (s, 3H).
b) Metil ester 6-(2-fenilkroman-6-iloksi)nikotinske kiseline
Metil ester 6-(2-fenilkroman-6-iloksi)nikotinske kiseline je dobijen kao što je opisano za 5-kloro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 61, ali zamijenjujući 2,5-dikloropiridin metil estrom 6-kloronikotinske kiseline.
1H NMR (400 MHz, CDCl3) δ: 8.70 (d, 1H, J 2.4 Hz), 8.29 (dd, 1H, J 8.6, 2.4 Hz), 7.47-7.32 (m, 5H), 7.07 (d, 1H, J 8.6 Hz), 6.96-6.88 (m, 3H), 5.14 (d, 1H, J 10.0 Hz), 3.85 (s, 3H), 2.97 (m, 1H), 2.74 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H).
Primjer 68.
6-(2-fenilkroman-6-iloksi)nikotinska kiselina
6-(2-fenilkroman-6-iloksi)nikotinska kiselina (200 mg), voda (10 ml), etanol (2 ml) i kalijum hidroksid su sipani u balon. Rezultujuća smjesa je refluksirana 2,5 sata. Poslije hlađenja do sobne temperature, pH je namješten na 1 koncentriranom klorovodičnom kiselinom i bijeli precipitat je profiltriran.
1H NMR (300 MHz, d6-DMSO) δ: 13.12 (s, 1H), 8.67 (d, 1H, J 2.4 Hz), 8.25 (dd, 1H, J 8.6, 2.4 Hz), 7.48-7.34 (m, 5H), 7.04 (d, 1H, J 8.6 Hz), 6.95-6.86 (m, 3H), 5.14 (dd, 1H, J 10.0,2.2 Hz), 2.99 (m, 1H), 2.74 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).
Primjer 69.
6-nikotinonitrilni derivati
6-(2-fenilkroraan-6-iloksi)nikotinonitril
6-(2-fenilkroman-6-iloksi)nikotinonitril je dobijen kao što je opisano za 5-nitro-2-(2-fenilkroman-6-iloksi)piridin u Primjeru 1 (b), korištenjem 500 mg 2-fenilkroman-6-ola i zamijenjujući 2-kloro-5-nitropiridin s 337 mg 6-kloronikotinonitrila. Proizvod je pročišćen kromatografijom na koloni, korištenjem heptan - etil acetata kao eluenta, a zatim kristaliziran iz 2-propanola.
1H NMR (400 MHz, d6-DMSO) δ: 8.65 (d, 1H, J 2.4 Hz), 8.28 (dd, 1H, 8.8, 2.4 Hz), 7.47-7.34 (m, 5H), 7.17 (d, 1H, J 8.8 Hz) 6.96-6.87 (m, 3H), 5.14 (dd, 1H, J 10.1, 2.2 Hz), 2.99 (m, 1H), 2.73 (m, 1H), 2.18 (m, 1H), 2.00 (m, 1H).
6-{2-[3-(5-cijanopiridin-2-iloksi)-fenil]kroman-6-iloksi}nikotinonitril je dobijen na isti način, korištenjem 200 mol-% 6-kloronikotinonitrila i polazeći od 2-(3-hidroksifenil)-kroman-6-ola.
1H NMR (400 MHz, d6-DMSO) δ: 8.66 (d, 1H, J 2.2 Hz), 8.64 (d, 1H, J 2.3 Hz), 8.33 (dd, 1H, J 8.6, 2.3 Hz), 8.28 (dd, 1H, J 8.7, 2.2 Hz), 7.50 (t, 1H, J 7.8 Hz), 7.38 (d, 1H, J 7.8 Hz), 7.28, (s, 1H), 7.26 (d, 1H, 8.6 Hz), 7.19-7.16 (m, 2H), 6.97-6.88 (m, 2H), 5.18 (d, 1H, J 8.3 Hz), 2.97 (m, 1H), 2.74 (m, 1H), 2.22 (m, 1H), 2.01 (m, 1H).
Primjer 70.
3-(2-fenilkroman-6-iloksi)piridin
2-fenilkroman-6-ol (598 mg), 3-bromopiridin (500 mg), kalijev hidroksid (322 mg) i kalijev jodid su sipani u balon sa suhim DMSO (10 ml). Reakcijska smjesa je miješana na 120°C 3,5 sata. Poslije hlađenja do sobne temperature, dodana je 1M otopina HCl i smjesa je ekstrahirana diklorometanom. Kombinirani organski ekstrakti su oprani 1 M otopinom HCl, zatim vodom i slanom otopinom i osušeni. 3-(2-fenilkroman-6-iloksi)piridin je pročišćen kromatografijom na koloni, korištenjem heptan - etil acetata kao eluenta.
1H NMR (400 MHz, d6-CDCl3 + MeOH) δ: 8.31 (s, 1H), 8.24 (dd, 1H, J 3.8, 1.9 Hz), 7.45-7.25 (m, 7H), 6.87 (d, 1H, J 8.6 Hz), 6.83 (dd, 1H, J 8.6,2.6 Hz), 6.81 (d, 1H, J 2.6 Hz), 5.07 (dd, 1H, J 10.1,2.3 Hz), 2.98 (m, 1H), 2.78 (m, 1H), 2.23 (m, 1H), 2.12 (m, 1H).
Claims (9)
1. Spoj, naznačen time, da je spoj formule (I) ili (II):
[image]
gdje
Xje-O-,-CH2-ili-C(O)-;
Z je -CHR12- ili valentna veza;
Y je -CH2-, -C(O)-, CH(OR13)-, -O-, -S-;
uz uvjet da, ako je Z valentna veza, Y nije C(O);
isprekidana linija predstavlja dvogubu vezu po izboru, u kojem slučaju Z je -CR12-, a Y je
-CH2-, -C(O)- ili CH(OR10)- (u formuli II) ili
-CH- (u formuli I);
R2 i R3 su nezavisno H, niži alkil, niži alkoksi, -NO2, halogen, -CF3, -OH, benziloksi ili grupa formule (IIIa)
[image]
R1 je H, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, NHC(O)R5, NHCH2R5, NHR20, NR21R22, NHC(NH)NHCH3 ili, u slučaju da je spoj formule (II) gdje opciona dvoguba veza postoji, ili u slučaju da je R2 ili R3 benziloksi ili grupa formule (IIIa), ili u slučaju daje piridinski prsten formule (I) ili (II) zakvačen za atom kisika na 3-oj, 4-oj ili 5-oj poziciji, R1 može biti i -NO2 ili NR16R17;
R4 je H, -NO2, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, -NR16R17, -NHC(O)R5 ili -NHC(NH)NHCH3;
R5 je alkil supstituiran 1 do 3 supstituenta odabranih iz grupe koja sadrži halogen, amino i hidroksi, ili karboksialkil, u kojem je alkilni dio po izboru supstituiran 1 do 3 supstituenta odabranim iz grupe koja sadrži halogen, amino i hidroksil, -CHR6NR7R8 ili jedne od slijedećih grupa:
[image]
W je N ili CH;
Q jeCHR14, NR9, S ili O;
R6 je H ili niži alkil;
R7 i R8 su nezavisno H, acil, niži alkil ili niži hidroksialkil;
R9 je H, niži alkil ili fenil;
R10 i R11 su nezavisno H ili niži alkil;
R12 je H ili niži alkil;
R13 je H, alkilsulfonil ili acil;
R14 je H,-OH,-COOR15;
R15 jeH ili niži alkil;
R16 i R17 su nezavisno H, acil, alkilsulfonil, -C(S)NHRl8 ili -C(O)NHR18;
R18 je H ili niži alkil;
R19 je H ili-OH;
R20 je iridinil grupa po izboru supstituirana -NO2 grupom;
R21 i R22 su niži alkil;
i njihove farmaceutski prihvatljive soli i esteri.
2. Spoj prema zahtjevu 1, naznačen time, da je R1-NHC(O)R5 X je O, Y je CH2 i Z je CHR12.
3. Spoj prema zahtjevu 2, naznačen time, da je Z CH2, a R5 je alkil supstituiran 1 do 3 supstituenta odabranih iz grupe koja sadrži halogen, amino i hidroksi, ili karboksialkil, u kojem je alkilni dio po izboru supstituiran 1 do 3 supstituenta odabranim iz grupe koja sadrži halogen, amino i hidroksil, -CHR6NR7R8 ili jedne od slijedećih grupa:
[image]
4. Spoj prema zahtjevu 1, naznačen time, da je R2 ili R3 benziloksi ili grupa formule (IIIa)
[image]
5. Spoj prema zahtjevu 4, naznačen time, daje R4 NO2.
6. Spoj prema zahtjevu 4 ili 5, naznačen time, da je R1 NO2.
7. Farmaceutska kompozicija, naznačena time, da sadrži spoj prema zahtevu 1 zajedno s farmaceutski prihvatljivim nosačem.
8. Postupak za inhibiranje mehanizma Na+/Ca2+ izmjene u stanici, naznačen time, da se sastoji od davanja subjektu koji ima potrebu za tim terapijski efektivne količine spojeve iz zahtjeva 1.
9. Postupak za liječenje aritmija, naznačen time, da se sastoji od davanja subjektu koji ima potrebu za tim terapijski efektivne količine spojeve iz zahtjeva 1.
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EP2524908A1 (en) * | 2011-05-20 | 2012-11-21 | LEK Pharmaceuticals d.d. | Process for the preparation of alfa-substituted ketones and their application in synthesis of pharmaceutically active compounds |
SI2567958T1 (sl) | 2011-09-12 | 2015-01-30 | Sanofi | Substituirani 2-(kroman-6-iloksi)-tiazoli in njihova uporaba kot farmacevtiki |
WO2013037388A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals |
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US8912224B2 (en) | 2011-09-12 | 2014-12-16 | Sanofi | Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals |
WO2013144191A1 (de) * | 2012-03-29 | 2013-10-03 | Bayer Intellectual Property Gmbh | Substituierte 2 -amino - 3 - cyanopyridine als inhibitoren des natrium calcium austausches und ihre verwendung bei kardiovaskulären erkrankungen |
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CN108137807B (zh) * | 2015-08-19 | 2020-09-29 | 日产化学工业株式会社 | 液晶取向剂中使用的酰亚胺系聚合物 |
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KR102587178B1 (ko) | 2016-09-07 | 2023-10-06 | 파마케아, 인크. | 리실 옥시다아제-유사 2 억제제의 결정질 형태 및 제조 방법 |
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CN115850258A (zh) * | 2022-12-27 | 2023-03-28 | 东北林业大学 | 一种马赛替尼的合成方法 |
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US2820817A (en) * | 1954-02-04 | 1958-01-21 | Mcneilab Inc | Oxygenated indan compounds and method of making the same |
BE650081A (hr) | 1963-07-03 | |||
US3862232A (en) * | 1963-07-03 | 1975-01-21 | Upjohn Co | 1-(p-hydroxyphenyl)-2-phenyl-6-(2-diethylaminoethoxy)-3,4-dihydronaphthalene and the salts thereof |
GB1154119A (en) | 1968-05-20 | 1969-06-04 | Merck Ag E | 3-Alkyl-Flavanones |
JPH04113839A (ja) * | 1990-09-05 | 1992-04-15 | Mitsubishi Petrochem Co Ltd | ポリカーボネート樹脂積層物 |
FR2733685B1 (fr) * | 1995-05-05 | 1997-05-30 | Adir | Utilisation des derives du benzopyrane pour l'obtention de compositions pharmaceutiques destinees au traitement des pathologies liees a l'echangeur c1-/hc03-, na+ independant |
JPH0967336A (ja) | 1995-09-04 | 1997-03-11 | Kanebo Ltd | 新規なイソチオウレア誘導体 |
WO1998043943A1 (fr) | 1997-03-27 | 1998-10-08 | Taisho Pharmaceutical Co., Ltd. | Derives de 2-phenoxyaniline |
JPH1149752A (ja) * | 1997-08-05 | 1999-02-23 | Taisho Pharmaceut Co Ltd | フェノキシピリジン誘導体 |
DE19742508A1 (de) * | 1997-09-26 | 1999-04-01 | Hoechst Marion Roussel De Gmbh | Sulfonamid-substituierte Chromane, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltende pharmazeutische Zubereitungen |
DK1031556T3 (da) | 1997-10-20 | 2003-02-24 | Taisho Pharmaceutical Co Ltd | 2-phenoxyanilinderivater |
JPH11302235A (ja) | 1998-04-15 | 1999-11-02 | Taisho Pharmaceut Co Ltd | フェノキシアルキルアミン誘導体 |
AU4360200A (en) | 1999-04-23 | 2000-11-10 | Bristol-Myers Squibb Company | Bicyclic acyl guanidine sodium/proton exchange inhibitors and method |
CZ2002802A3 (cs) * | 1999-09-17 | 2003-02-12 | Nissan Chemical Industries, Ltd. | Benzopyranové deriváty |
FI20011507A0 (fi) | 2001-07-10 | 2001-07-10 | Orion Corp | Uusia yhdisteitä |
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US7482340B2 (en) | 2009-01-27 |
NZ541087A (en) | 2008-04-30 |
CN1745078A (zh) | 2006-03-08 |
CA2512184A1 (en) | 2004-07-29 |
BRPI0406669A (pt) | 2005-12-20 |
NO20053730L (no) | 2005-10-07 |
JP2006516271A (ja) | 2006-06-29 |
FI20030030A0 (fi) | 2003-01-09 |
RS20050528A (en) | 2007-06-04 |
IS7969A (is) | 2005-08-02 |
IL169435A0 (en) | 2007-07-04 |
UA81941C2 (uk) | 2008-02-25 |
ZA200505461B (en) | 2006-03-29 |
AU2004203943B2 (en) | 2009-09-17 |
EP1583759A1 (en) | 2005-10-12 |
EA200501104A1 (ru) | 2005-12-29 |
AU2004203943A1 (en) | 2004-07-29 |
PL378326A1 (pl) | 2006-03-20 |
KR20050095601A (ko) | 2005-09-29 |
US20060241147A1 (en) | 2006-10-26 |
WO2004063191A1 (en) | 2004-07-29 |
MXPA05007435A (es) | 2005-09-12 |
CN100457752C (zh) | 2009-02-04 |
EA008539B1 (ru) | 2007-06-29 |
AR042733A1 (es) | 2005-06-29 |
NO20053730D0 (no) | 2005-08-03 |
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