HRP980470A2 - 2-aminopyridines containing fused ring substituents - Google Patents
2-aminopyridines containing fused ring substituentsInfo
- Publication number
- HRP980470A2 HRP980470A2 HR60/057,094A HRP980470A HRP980470A2 HR P980470 A2 HRP980470 A2 HR P980470A2 HR P980470 A HRP980470 A HR P980470A HR P980470 A2 HRP980470 A2 HR P980470A2
- Authority
- HR
- Croatia
- Prior art keywords
- nmr
- cdcl
- pyridin
- ylamine
- naphthalen
- Prior art date
Links
- 150000003930 2-aminopyridines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 104
- 229910052799 carbon Inorganic materials 0.000 claims description 48
- -1 chloro, fluoro, bromo, iodo Chemical group 0.000 claims description 43
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 25
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 208000002193 Pain Diseases 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
- 241000124008 Mammalia Species 0.000 claims description 18
- 230000001154 acute effect Effects 0.000 claims description 16
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- 206010061218 Inflammation Diseases 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 13
- 230000004054 inflammatory process Effects 0.000 claims description 13
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 12
- 206010012335 Dependence Diseases 0.000 claims description 12
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 206010040070 Septic Shock Diseases 0.000 claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 230000036303 septic shock Effects 0.000 claims description 9
- 208000030507 AIDS Diseases 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 208000019901 Anxiety disease Diseases 0.000 claims description 8
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 8
- 208000000094 Chronic Pain Diseases 0.000 claims description 8
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 8
- 208000011231 Crohn disease Diseases 0.000 claims description 8
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 8
- 208000010412 Glaucoma Diseases 0.000 claims description 8
- 206010019196 Head injury Diseases 0.000 claims description 8
- 208000023105 Huntington disease Diseases 0.000 claims description 8
- 206010021138 Hypovolaemic shock Diseases 0.000 claims description 8
- 208000019695 Migraine disease Diseases 0.000 claims description 8
- 206010063837 Reperfusion injury Diseases 0.000 claims description 8
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 8
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 8
- 206010047700 Vomiting Diseases 0.000 claims description 8
- 208000005298 acute pain Diseases 0.000 claims description 8
- 230000036506 anxiety Effects 0.000 claims description 8
- 206010015037 epilepsy Diseases 0.000 claims description 8
- 229960005181 morphine Drugs 0.000 claims description 8
- 201000006417 multiple sclerosis Diseases 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 230000004770 neurodegeneration Effects 0.000 claims description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 230000007135 neurotoxicity Effects 0.000 claims description 8
- 201000008482 osteoarthritis Diseases 0.000 claims description 8
- 230000016087 ovulation Effects 0.000 claims description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
- 206010040560 shock Diseases 0.000 claims description 8
- 208000020431 spinal cord injury Diseases 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 208000028017 Psychotic disease Diseases 0.000 claims 4
- 208000006011 Stroke Diseases 0.000 claims 4
- 210000005013 brain tissue Anatomy 0.000 claims 4
- 230000006866 deterioration Effects 0.000 claims 4
- 230000000968 intestinal effect Effects 0.000 claims 4
- 208000002780 macular degeneration Diseases 0.000 claims 4
- 206010027599 migraine Diseases 0.000 claims 4
- 230000000241 respiratory effect Effects 0.000 claims 4
- 208000011580 syndromic disease Diseases 0.000 claims 4
- 230000002265 prevention Effects 0.000 claims 3
- MNUHYQZBNHDABI-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexan-6-amine Chemical class C1NCC2C(N)C21 MNUHYQZBNHDABI-UHFFFAOYSA-N 0.000 claims 1
- 150000003053 piperidines Chemical class 0.000 claims 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 111
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 107
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 239000007787 solid Substances 0.000 description 41
- 239000000243 solution Substances 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 239000003921 oil Substances 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 25
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- 238000010992 reflux Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000012267 brine Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 8
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 8
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000005605 benzo group Chemical group 0.000 description 8
- 206010013663 drug dependence Diseases 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 208000011117 substance-related disease Diseases 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
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- 239000006260 foam Substances 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
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- 230000005764 inhibitory process Effects 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 230000035939 shock Effects 0.000 description 5
- 239000002562 thickening agent Substances 0.000 description 5
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 5
- KRRMRDUDIDIHRZ-UHFFFAOYSA-N 4-[6-(2,5-dimethyl-1H-pyrrol-3-yl)pyridin-2-yl]-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound Cc1cc(c(C)[nH]1)-c1cccc(n1)-c1ccc(O)c2CCCCc12 KRRMRDUDIDIHRZ-UHFFFAOYSA-N 0.000 description 4
- CNRQNFFMXHNVBU-UHFFFAOYSA-N 6-[4-[2-(dimethylamino)ethoxy]-5,6,7,8-tetrahydronaphthalen-1-yl]pyridin-2-amine Chemical compound C1=2CCCCC=2C(OCCN(C)C)=CC=C1C1=CC=CC(N)=N1 CNRQNFFMXHNVBU-UHFFFAOYSA-N 0.000 description 4
- 208000007848 Alcoholism Diseases 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- 206010029350 Neurotoxicity Diseases 0.000 description 4
- 206010057852 Nicotine dependence Diseases 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 208000025569 Tobacco Use disease Diseases 0.000 description 4
- 206010044221 Toxic encephalopathy Diseases 0.000 description 4
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- 208000006673 asthma Diseases 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 4
- 230000007850 degeneration Effects 0.000 description 4
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- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 4
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- 238000006722 reduction reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- HTNWPEUXFDDPFM-UHFFFAOYSA-N (4-phenylmethoxynaphthalen-1-yl)boronic acid Chemical compound C12=CC=CC=C2C(B(O)O)=CC=C1OCC1=CC=CC=C1 HTNWPEUXFDDPFM-UHFFFAOYSA-N 0.000 description 3
- CWLKTJOTWITYSI-UHFFFAOYSA-N 1-fluoronaphthalene Chemical compound C1=CC=C2C(F)=CC=CC2=C1 CWLKTJOTWITYSI-UHFFFAOYSA-N 0.000 description 3
- UQFRAYYPECGRQT-UHFFFAOYSA-N 2-(2,5-dimethyl-1h-pyrrol-3-yl)-6-(4-fluoronaphthalen-1-yl)pyridine Chemical compound N1C(C)=CC(C=2N=C(C=CC=2)C=2C3=CC=CC=C3C(F)=CC=2)=C1C UQFRAYYPECGRQT-UHFFFAOYSA-N 0.000 description 3
- CSGPZVMBYBXUKI-UHFFFAOYSA-N 6-[4-(piperidin-3-ylmethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl]pyridin-2-amine Chemical compound NC1=CC=CC(C=2C=3CCCCC=3C(OCC3CNCCC3)=CC=2)=N1 CSGPZVMBYBXUKI-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
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- 101710090055 Nitric oxide synthase, endothelial Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
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Classifications
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- 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
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Description
Područje izuma
Izum se odnosi na neke 2-aminopiridine koji sadrže supstituente kondenziranog prstena koji pokazuju aktivnost kao inhibitori sintaze dušičnog oksida (NOS); također i na farmaceutske preparate koji iste sadrže kao i na njihovu primjenu za tretman bolesti centralnog živčanog sustava, upala, septičkog šoka i drugih bolesti.
Poznata su tri izooblika NOS - izazvan oblik (I-NOS) i 2 konstitutivna oblika označena kao, respektivno, neuronski NOS (N-NOS) i endotelni NOS (E-NOS). Svaki od tih enzima vrši konverziju arginina u citrulin dok se produkti molekula dušičnog oksida (NO) razvijaju kao odziv na razne stimulacije. Vjeruje se da višak proizvodnje dušičnog oksida (NO) sa NOS igra ulogu u patologiji više bolesti i stanja kod sisavca. Na primjer, smatra se da NO dobiven sa I-NOS igra ulogu u bolestima koja uključuju sustavnu hipotenziju takvu kao toksični šok i kao i terapija sa nekim citokinima. Pokazano je da pacijenti koji imaju rak tretiran sa citokinima kao što su interleukin 1 (IL-1); interleukin 2 (IL-2) ili faktor nekroze tumora (TNF) boluju od šoka izazvanog citokinom i hipotenzije uslijed NO dobivenog od maktofaga, npr., izazvanog sa NOS (I-NOS); vidjeti Chemical & Engineering News, prosinac 20; str. 33; (1993). I-NOS inhibitori mogu isto stanje činiti i obrnutim. Isto tako se vjeruje da I-NOS igra ulogu u patologiji bolesti centralnog živčanog sustava kao što su nedostatak prokrvljenosti istog. Na primjer, inhibicijom I-NOS pokazano je da se poboljšava cerebralno ishemijsko oštećenje kod štakora, vidjeti Am. J. Physiol., 268; str. R286 (1995)). Potiskivanje sporedno izazvanog artritisa sa selektivnim inhibiranjem I-NOS opisano je u Eur. J. Pharmacol., 273; str. 15-24 (1995).
Za NO proizveden sa N-NOS smatra se da igra ulogu u bolestima takvim kao cerebralni nedostatak prokrvljenosti, bol, i tolerancija na opijate. Na primjer, inhibicija N-NOS smanjuje jačinu infarkta poslije okluzije proksimalne srednje cerebralne arterije kod štakora, vidjeti primjerice J. Cerebr. Blood Flow Metab., 14; str. 924-929 (1994). Pokazano je da inhibiranje N-NOS je učinkovito kod antinocicepcije, kao što je evidentirano kod aktivnost u posljednjoj fazi lizanja zadnje šape izazvane formalinom i ispitivanja abdominalnog stezanja izazvanog octenom kiselinom, vidjeti Br. J. Pharmacol., 110; str. 219-224 (1993). Dalje, potkožna injekcija Freund pomoćnog sredstva kod štakora izaziva povećanje u NOS-pozitivnim neuronima u kičmenoj moždini što se manifestira sa povećanom osjetljivošću na bol, koja se može tretirati sa NOS inhibitorima, npr. vidjeti Japanese Journal of Pharmacology, 75; str. 327-335 *1997). Konačno, za opioidno povlačenje kod glodavaca opisano je da je reducirano sa inhibiranjem N-NOS, vidjeti primjerice Neuropschopharmacol., 13; str. 269-293 (1995).
Bit izuma
Isti izum se odnosi na spojeve formule
[image]
gdje je prsten A kondenzirani 5-7 člani zasićen ili nezasićen prsten gdje su od nula do dva člana prstena heteroatomi izabrani, neovisno, od dušika, kisika i sumpora, pod uvjetom da 2 člana prstena koji nisu susjedi mogu oba biti heteroatomi;
X je kisik ili veza;
n je cijeli broj od 2 do 6; i
R1 i R2 su odabrani, neovisno, od (C1-C6) alkila, arila, teterahidronaftalena i aralkila, gdje je spomenuti aril i afril dio spomenutog aralkila je fenil ili naftil i alkil dio je normalan ili razgranat i sadrži od 1 do 6 atoma ugljika, i gdje spomenuti (C1-C6) alkil, spomenuti aril, spomenuti teterahidronaftalen i aril dio spomenutog aralkila mogu po želji biti supstituirani sa 1 do 3 supstituenta, poželjno od 0 do 2 supstituenta, koji su odabrani, neovisno, od halo (npr., kloro, fluoro, bromo, jodo); nitro, hidroksi, cijano, amino, (C1-C4) alkoksi, i (C1-C4) alkilamino;
ili R1 i R2 formiraju, zajedno sa dušikom na koji su vezani, piperazin, azetidin, piperidin ili pirolidin prsten ili azabiciklični prsten koji sadrži prsten od 6 do 14 članova, od 1 do 3 je dušik a ostatak čini ugljik, gdje su primjeri spomenutih azabicikličnih prstena slijedeći
[image]
također R1 ili R2 mogu biti vezani na (CH2)n skupinu zbog formiranja prstena od 4 do 7 članova;
gdje R3 i R4 su odabrani od vodika, (C1-C6) alkila, fenila, naftila, (C1-C6)alkil-C(=O)-, HC(=O)-, (C1-C6)alkoksi-(C=O)-, fenil-C(=O)-, naftil-C(=O)-, i R6R7NC(=O)- gdje R6 i R7 su odabrani, neovisno od vodika i (C1-C6) alkila;
R5 je odabran od vodika, (C1-C6) alkila, fenila, naftila, fenil-(C1-C6)alkil- i naftil(C1-C6)alkil-;
i gdje spomenuti piperazin, azetidin, piperidin i pirolidin prsteni mogu po želji biti supstituirani sa jednim ili više supstituenata, poželjno sa od 0 do 2 supstituenta koji su odabrani, neovisno, od (C1-C6) alkila, amino, (C1-C6) alkilamino, (di-(C1-C6)alkil)amino, fenila supstituiranog sa 5 do 6-članim heterocikličnim prstenima koji sadrže od 1 do 4 atoma dušika u prstenu, benzoila, benzoilmetila, benzilkarbonila, fenilaminokarbonila, feniletila i fenoksikarbonila, i gdje fenilni dijelovi bilo kojeg od gornjih supstituenata mogu po želji biti supstituirani jednim ili više supstituenata, poželjno sa od 0 do 2 supstituenta, koji su odabrani, neovisno, od halo, (C1-C3) alkila, (C1-C3) alkoksi, nitro, amino, cijano, CF3 i OCF3;
i farmaceutski prihvatljive soli takvih spojeva.
Slijedeća spojeva su poželjni spojevi prema izumu:
6-(4-(2-dimetilamino-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-pirolidin-1-il-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-((benzo(1,3)dioksol-5-ilmetil)-amino)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(6,7-dimetoksi-3,4-dihidro-1H-izokinolin-2-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
3-(2-(4-(6-amino-piridin-2-il)-naftalen-1-iloksi-etil)-3-aza-biciklo(3,1,0)heks-6-ilamin;
6-(4-(2-(4-fenetil-piperazin-1-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-pirolidin-1-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-benzil-piperidin-4-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-benzil-pirolidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(piperidin-4-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-pirolidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-izobutil-piperidin-4-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-furan-2-ilmetil-piperidin-4-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-izobutil-pirolidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-furan-2-ilmetil-pirolidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-morfolin-4-il-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-diizopropilamino-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-metil-piperidin-4-iloksi)-naftalen-1-il)-piridin-2-ilamin:
6-(4-(1-metil-pirolidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(3-dimetilamino-propoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-aza-biciklo(2,2,2)okt-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-piperidin-1-il-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(3,4-dihidro-1H-ihokinolin-2-il)-etoksi)-naftalen-1-il)-piridin-1-ilamin;
6-(4-(2-(4-dimetilamino-piperidin-1-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(tert-butil-metil-amino)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6(4-(2-(4-metil-piperazin-1-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(4-fenil-piperidin-1-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(7,8-dihidro-5H-(1,3)dioksolo(4,5-g)izokinolin-6-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(piperidin-2-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-metil-piperidin-2-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-metil-piperidin-3-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-cikloheksiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(piperidin-3-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-izobutil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-furan-2-ilmetil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(8-metil-8-aza-biciklo(3,2,1)okt-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-metil-pirolidin-2-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(azetidin-2-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin;
6-(7-(2-dimetilamino-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-pirolidin-1-il-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-(benzil-metil-amino)-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-(4-feneteil-piperazin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-(4-izobutil-piperazin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-morfolin-4-il-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-diizopropilamino-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-(7,8-dihidro-5H-(1,3)dioksolo(4,5-g)izokinolin-6-il)-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-(4-metil-piperazin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-(tert-butil-metil-amino)-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(7-(2-(4-dimetilamino-piperidin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin;
6-(8-(2-dimetilamino-etoksi)-1,2,3,4-teterahidro-1,4-metano-naftalen-5-il)-piridin-2-ilamin;
6-(8-(2-pirolidin-1-il-etoksi)_1,2,3,4-teterahidro-1,4-metano-naftalen-5-il)-piridin-2-ilamin;
6-(4-(2-dimetilamin-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-pirolidin-1-il-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(tert-butil-metil-amino)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-diizopropilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-dietilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(3,4-dihidro-1H-izokinolin-2-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-piperidin-1-il-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-morfolin-4-il-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(7,8-dihidro-5H-(1,3)dioksolo(4,5-g)izokinolin-6-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(4-metil-piperazin-1-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(4-dimetilamino-piperidin-1-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(7,8-dihidro-5H-(1,3)dioksolo(4,5-g)izokinolin-6-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-izobutil-piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(1-metil-piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-(2-dietilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-cikloheksiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(pirolidin-2-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin; i
6-(4-(2-dimetilamino-etoksi)-6,7,8,9-teterahidro-5H-benzociklohepten-1-il)-piridin-2-ilamin;
i farmaceutski prihvatljive soli gornjih spojeva.
Slijedeći spojevi su dodatni primjeri spojeva prema ovom izumu:
6-(4-(2-amino-ciklopentiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-ciklobutiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-ciklopropiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(3-amin-cikloheksiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(3-amino-ciklopentiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(3-amino-ciklobutiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(4-amino-cikloheksiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-ciklopentiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-ciklobutiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-ciklopropiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(3-amino-cikloheksiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(3-amino-ciklopentiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(3-amino-ciklobutiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(4-amino-cikloheksiloksi)-naftalen-1-il)-piridin-2-ilamin;
6-(4-(2-amino-ciklopentiloksi)-indan-4-il)-piridin-2-ilamin-2-ilamin;
6-(4-(2-amino-ciklobutiloksi)-indan-4-il)-piridin-2-ilamin;
6-(4-(2-amino-ciklopropiloksi)-indan-4-il)-piridin-2-ilamin;
6-(4-(3-amino-cikloheksiloksi)-indan-4-il)-piridin-2-ilamin;
6-(4-(3-amino-ciklopentiloksi)-indan-4-il)-piridin-2-ilamin;
6-(4-(3-amino-ciklobutiloksi)-indan-4-il)-piridin-2-ilamin;
6-(4-(4-amino-cikloheksiloksi)-indan-4-il)-piridin-2-ilamin;
6-(4-piperidin-3-ilmetoksi)-6,7,8-teterahidro-5H-benzociklohepten-1-il)-piridin-2-ilamin;
6-(4-(2-pirolidinil-etoksi)-6,7,8-teterahidro-5H-benzociklohepten-1-il)-piridin-2-ilamin;
6-(4-(2-amino-cikloheksiloksi)-6,7,8,9-teterahidro-5H-benzociklohepten-1-il)-piridin-2-ilamin;
6-(4-(2-(4-dimetilamino-piperidin-1-il)-etoksi))-6,7,8,9-teterahidro-5H-benzociklohepten-1-il)-piridin-2-ilamin; i
6-(4-(2-(4-metil-piperazin-1-il)-etokai))-6,7,8,9-teterahidro-5H-benzociklohepten-1-il)-piridin-2-ilamin.
Isti izum također se odnosi na farmaceutski prihvatljive adicijske soli kiseline spojeva formule I. Kiseline koje se koriste za dobivanje farmaceutski prihvatljivih adicijskih soli gore spomenutih baznih spojeva iz ovog izuma su one koje formiraju netoksične adicijske soli kiseline, npr., soli koje sadrže farmakološki prihvatljive anione, kao što su hidroklorid, hidrobromid, hidrojodid, nitrat, sulfat, bisulfat, fosfat, fosfat kiseline, acetat, laktat, citrat, citrat kiseline, tartrat, bitartrat, sukcinat, maleat, fumarat, glukonat, saharat, benzoat, metansulfonat, etansulfonat, benzensulfonat, p-toluensulfonat i pamoat (npr., 1,1-metilen-bis-(2-hidroksi-3-naftoat))soli.
Termin "alkil", na način kako se ovdje koristi, ako nije drugačije naznačeno, uključuje zasićene monovalentne ugljikovodične radikale koji imaju normalne, razgranate ili ciklične dijelove ili njihove kombinacije.
Termin "jedan ili više supstituenata", na način kako se ovdje koristi, odnosi se na broj supstituenata koji je jednak od jedan do maksimalnog broja supstituenata mogućih baziranih na broju dostupnih mjesta vezanja.
Termin "halo" i "halogen" na način kako se ovdje koristi, ako nije drugačije naznačeno, uključuje kloro, fluoro, bromo i jodo.
Primjeri specifičnijih realizacija iz ovog izuma uključuju:
(a) spojevi formule I gdje A je pirolo;
(b) spojevi formule I gdje prsten A je pirido;
(c) spojevi formule I gdje X je veza;
(d) spojevi formule I gdje prsten A je pirimido;
(e) spojevi formule I gdje n je 2 ili 3;
(f) spojevi formule I gdje X je kisik;
(g) spojevi formule I gdje R1 i R2 su odabrani, neovisno, od (C1-C6) alkila;
(h) spojevi formule I gdje R1 i R2 ne formiraju prsten sa dušikom na koji su oni vezani;
(i) spojevi formule I gdje R1 i R2 formiraju zajedno sa dušikom na koji su oni vezani, piperazin, azetidin, piperidin ili pirolidin prsten;
(j) spojevi formule I gdje R1 je odabran od (C1-C6) alkila a R2 je odabran od arila, teterahidronaftalena i aralkila; i
(k) spojevi formule I gdje prsten A je tieno ili tiazolo.
Isti izum se također odnosi na farmaceutski preparat za tretiranje ili prevenciju stanja odabranog iz skupine koja sadrži upale, migrene (npr., astma); šok, akutni i kronični bol, hipovolemski šok, reperfuzijska povreda, Crohnova bolest, ulcerativni kolitis, septički šok, multipl skleroza, AIDS združen sa ludilom, neurodegenerativne bolesti, neuronska toksičnost, depresiju (npr., glavno bolest depresije i distimije, Prakinsonovu bolest, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti (npr., ovisnosti od droga, alkohola i nikotina); emezis, epilepsiju, zabrinutost, duševne bolesti, traumu na glavi, sindrom respiratornog bola kod odraslih (ARDS); toleranciju izazvanu morfinom i simptome povlačenja u sebe, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, maskularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, uključujući čovjeka, sa djelotvornom količinom spojeva formule I, ili njegove farmaceutski prihvatljive soli koja je djelotvorna u tretiranju ili prevenciji takvog stanja, i farmaceutski prihvatljiv nosač.
Isti izum se također odnosi na farmaceutski preparat za tretiranje ili prevenciju stanja odabranog iz skupine koja sadrži upale, migrene (npr., astma); šok, akutni i kronični bol, hipovolemski šok, reperfuzijska povreda, Crohnova bolest, ulcerativni kolitis, septički šok, multipl skleroza, AIDS združen sa ludilom, neurodegenerativne bolesti, neuronska toksičnost, depresiju (npr., glavno bolest depresije i distimije, Prakinsonovu bolest, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti (npr., ovisnosti od droga, alkohola i nikotina); emezis, epilepsiju, zabrinutost, duševne bolesti, traumu na glavi, sindrom respiratornog bola kod odraslih (ARDS); toleranciju izazvanu morfinom i simptome povlačenja u sebe, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, maskularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, uključujući čovjeka, koji obuhvaća unošenje u spomenutog sisavca djelotvornu količinu spojeva formule I, ili njegove farmaceutski prihvatljive soli koja je djelotvorna u tretiranju ili prevenciji takvog stanja.
Isti izum se također odnosi na farmaceutski preparat za inhibiranje sintaze dušičnog oksida (NOS) kod sisavca, uključujući čovjeka, koji sadrži NOS inhibitornu djelotvornu količinu spojeva formule I, ili njegove farmaceutski prihvatljive soli i farmaceutski prihvatljiv nosač.
Isti izum se također odnosi na postupak inhibiranja NOS kod sisavca, uključujući čovjeka, koji obuhvaća unošenje NOS inhibitorne djelotvorne količine spojeva formule I, ili njegove farmaceutski prihvatljive soli.
Isti izum se također odnosi na farmaceutski preparat za tretiranje ili prevenciju stanja odabranog iz skupine koja sadrži upale, migrene (npr., astma); šok, akutni i kronični bol, hipovolemski šok, reperfuzijska povreda, Crohnova bolest, ulcerativni kolitis, septički šok, multipl skleroza, AIDS združen sa ludilom, neurodegenerativne bolesti, neuronska toksičnost, depresiju (npr., glavno bolest depresije i distimije, Prakinsonovu bolest, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti (npr., ovisnosti od droga, alkohola i nikotina); emezis, epilepsiju, zabrinutost, duševne bolesti, traumu na glavi, sindrom respiratornog bola kod odraslih (ARDS); toleranciju izazvanu morfinom i simptome povlačenja u sebe, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, maskularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, uključujući čovjeka, koji sadrži NOS inhibitornu djelotvornu količinu spojeva formule I, ili njegove farmaceutski prihvatljive soli i farmaceutski prihvatljiv nosač.
Isti izum se također odnosi na farmaceutski preparat za tretiranje ili prevenciju stanja odabranog iz skupine koja sadrži upale, migrene (npr., astma); šok, akutni i kronični bol, hipovolemski šok, reperfuzijska povreda, Crohnova bolest, ulcerativni kolitis, septički šok, multipl skleroza, AIDS združen sa ludilom, neurodegenerativne bolesti, neuronska toksičnost, depresiju (npr., glavno bolest depresije i distimije, Prakinsonovu bolest, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti (npr., ovisnosti od droga, alkohola i nikotina); emezis, epilepsiju, zabrinutost, duševne bolesti, traumu na glavi, sindrom respiratornog bola kod odraslih (ARDS); toleranciju izazvanu morfinom i simptome povlačenja u sebe, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, maskularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, uključujući čovjeka, koji obuhvaća unošenje u spomenutog sisavca NOS inhibitorne djelotvorne količine spojeva formule I, ili njegove farmaceutski prihvatljive soli.
Spojevi formule I mogu sadržavati kiralne centre i zato mogu postojati u raznim enantiomernim i diastereomernim oblicima. Isti izum se odnosi na sve optičke izomere i sve stereoizomere spojeva formule I i njihovih smjesa, i na sve farmaceutske preparate i postupke gore definirane koje sadrže ih sadrže ili koriste, respektivno.
Formula I gore uključuje spojeve identične onim opisanim ali uz činjenicu da su jedan ili više vodika, ugljika ili drugih atoma zamijenjeni njihovim izotopima. Takvi spojeva mogu biti korisni kao istraživački i dijagnostički alati u metabolizmu farmakokinetičkih studija i u pokusima vezanja.
Detaljni opis izuma
Spojevi formule I mogu se dobiti kao što je opisano u slijedećim reakcijskim shemama i diskusiji. Ako nije drugačije naznačeno, prsten A, X, n, R1; R2; R3; R4; R5; R6 i R7 i strukturna formula I u reakcijskim shemama i diskusiji koje slijede su kao što je gore definirano.
SHEMA 1
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SHEMA 2
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SHEMA 2; nastavak
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SHEMA 3
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Shema 1 ilustrira postupak dobivanja spojeva formule I gdje X je veza a prsten A je benzo. Sheme 2 i 3 prikazuju postupke dobivanja spojeva formule I gdje X je kisik a prsten A je benzo. Početni materijali korišteni u postupcima iz shema 1 i 2 ili su komercijalno dostupni, poznati u stanju tehnike ili se lagano mogu dobiti od poznatih spojeva postupcima koji su jasni stručnjacima područja.
Referiranje na shemu 1; spoj formule II se ohladi na oko -70 °C u suhom teterahidrofuranu (THF); i zatim se dodaje otopina n-butil litija. Rezultantna otopina se zatim tretira trietil boratom i ostavi se grijati do sobne temperature zbog formiranja spojevi formule III.
Spoj formule II reagira sa spojem formule IV zbog formiranja spojeva formule V. Ista reakcija se općenito vrši u otapalu, etanola u vodi, u prisustvu kalcijevog karbonata i teterakistrifenilfosfin paladija, na temperaturi oko refluksne temperature.
Spoj formule VI može se formirati na slijedeći način. Prvo, spoj formule V reagira sa N-bromosukcinimidom (NBS) i bis(1-cijano-1-aza)-cikloheksanom u ugljikovom teterakloridu i refluksira se tijekom oko 8 sati, sa dodatnim dijelovima inicijatora koji se dodaju tijekom 1; 2 i 4 sata. Poslije isparavanja otapala, produkt iste reakcije reagira sa trietilamonijevim cijanidom u metilen kloridu na temperaturi oko sobne zbog formiranja spojeva formule VI.
Zasićene otopine spojeva formule VI u etanolu sa klorovodikom, praćeno sa refluksiranjem smjese i zatim grijanjem u vodenoj otopini klorovodične kiseline, daje spoj formule VII.
Spoj formule VII koji se formira u prethodnoj fazi može se pretvoriti u spoj formule IA na slijedeći način. Prvo, spoj formule VII reagira sa podesnim spojem formule R2R1NH i N-etil-N-dimetilaminopropil karbodiimidom (EDAC) u prisustvu baze. Primjeri podesnih baza su one odabrane od trialkilamina, karbonata alkalnog metala i karbonata zemno alkalnog metala. Ista reakcija se tipično vrši u otapalu takvom kao acetonitril, metilen klorid ili N,N-dimetilformamid (DMF); na temperaturi od oko sobne temperature do oko 100 °C, poželjno oko sobne temperature. Poželjno, reakcija se vrši u prisustvu katalitičkog aditiva takvog kao N-hidroksisukcinimid ili hidroksibenzotriazol.
Produkt gornje reakcije zatim reagira korištenjem postupaka dobro poznatih stručnjacima. Na primjer, redukcija se može vršiti korištenjem litij aluminij hidrida u teterahidrofuranu, sa ili bez aluminij klorida, ili korištenjem bor metil sulfida u teterahidrofuranu, na temperaturi od oko -78 °C do oko 0 °C, poželjno na oko -70 °C, zbog dobivanja željenog spoja formule IA.
Referiranje na shemu 2; spoj formule VIII reagira sa teterabutilamonij tribromidom u 1,2-dikloroetanu na temperaturi oko sobne. Produkt iste reakcije se zatim tretira sa benzil bromidom i kalij karbonatom u otapalu takvom kao acetonitril, na temperaturi oko refluksa reakcijske smjese, zbog formiranja spojevi formule IX.
Spoj formule IX se zatim pretvori u 1-benziloksi-naftalen-4-bornu kiselinu postupkom gore opisanim za dobivanje derivata borne kiseline formule III u shemi 1.
Reakcija 1-benziloksi-naftalen-4-borne kiseline sa spojem formule X u etanolskom otapalu, u prisustvu natrij karbonata i teterakistrifenil paladija, na temperaturi oko refluksa reakcijske smjese, daje spoj formule XI.
Spoj formule XI može se konvertirati u spoj formule XIII korištenjem slijedećeg postupka sa dvije faze. Spoj formule XI reagira sa amonij formatom i 10 % paladija na ugljiku, u etanolskom otapalu, na temperaturi oko refluksa reakcijske smjese, zbog dobivanja spojeva analognog sa onim koje ima formulu XI, gdje je benziloksi skupina formule XI zamijenjena sa hidroksi skupinom. Spoj formule XII se zatim formira reagiranjem gornjeg hidroksi derivata sa 2-bromoetilacetatom i kalij karbonatom u acetonitrilu na temperaturi oko refluksne reakcijske smjese.
Bazna hidroliza spojevi formule XII, praćena reakcijom sa N-etil-N-3-dimetilaminopropilkarbodiimidom (EDAC) i podesnim spojem koje ima formulu R1R2NH daje željeni spoj formule XIII. Bazna hidroliza tipično se vrši korištenjem hidroksida alkalnog metala ili zemnoalkalnog metala u smjesi THF, metanola i vode na temperaturi oko sobne. Reakcija sa R1R2NH i EDAC općenito se vrši korištenjem postupka gore opisanog za dobivanje spojeva formule IA od formule VII u shemi 1.
Spoj formule XIII može se pretvori u željeni spoj formule IB kako slijedi. Spoj formule XIII reducira se zbog formiranja odgovarajućeg spoja gdje je karbonil skupina zamijenjena metilen skupinom, poslije čega je uklonjena 2,5-dimetilpirolil zaštitna skupina. Redukcija se može vršiti korištenjem postupaka dobro poznatih stručnacima, na primjer, korištenjem litij aluminij hidrida u teterahidrofuranu, sa ili bez aluminij klorida, ili korištenjem bor metil sulfida u teterahidrofuranu, na temperaturi od oko -78 °C do oko 0 °C, poželjno oko -70 °C.
Uklanjanje 2,5-dimetilpirolil zaštitne skupine se može vršititi reakcijom sa hidroksilamin hidrokloridom. Ista reakcija se općenito vrši u alkoholnom otapalu ili vodenoj otopini alkohola, na temperaturi oko sobne temperature do oko refluksne temperature, tijekom 8 do oko 72 sata.
Spojevi formule I koji su identični onima formule IB uz činjenicu da je prsten A drugačiji od benzo mogu se dobiti na analogni način, polazeći sa podesnim spojem koje je analogan onom formule VIII, gdje je nesupstituiran benzo prsten formule VIII zamijenjen sa prstenom drugačijim od benzo koji je unutar definicije prstena A.
Referiranje na shemu 3; poznati 1-fluoronaftalen (XIV) se bromira bromom u octenoj kiselini na temperaturi od oko sobne do temperature refluksa reakcijske smjese tijekom 1 do oko 48 sati, i brom je ohlađen na oko -70 °C u suhom teterahidrofuranu (THF); i zatim je dodana otopina n-butil litija. Rezultantna otopina je zatim tretirana trietil boratom i ostavljena je grijati se do sobne temperature zbog formiranja spojeva formule XV. Spoj formule XV reagira sa spojem formule IV zbog formiranja spojeva formule XVI. Ista reakcija se općenito vrši u etanolu otopljenom u vodi, u prisustvu natrij karbonata i teterakistrifenilfosfin paladija, na temperaturi blizu refluksne. Spoj formule XVI se zatim tretira alkoksidom alkalnog metala dobivenim od spojeva formule HO(CH2)nNR1R2 i natrij hidrida u polarnom otapalu takvom kao dimetilformamid, na temperaturi od oko sobne do 140 °C tijekom 1 do oko 48 sati. Ista reakcija daje odgovarajuće spojeve formule XVII, koji se zatim deblokiraju zbog uklanjanja 2,5-dimetilpirolil zaštitne skupine reakcijom sa hidroksilamin hidrokloridom. Ista reakcija se općenito vrši u alkoholnom ili vodom razblaženom alkoholnom otapalu na temperaturi od sobne do temperature refluksa reakcijske smjese, poželjno na temperaturi oko refluksne, tijekom 8 do oko 72 sata.
Spojevi formule I koji su identični sa onima formula IA i IB ali uz činjenicu da je prsten A drugačiji od benzo mogu se dobiti na analogan način, polazeći od podesnih početnih materijala koji su analogni onima iz formula VIII i XIV, na shemi 1; 2 i 3 respektivno, gdje je nesupstituiran benzo prsten takvih početnih materijala zamijenjen sa prstenom drugačijim od benzo koji je unutar definicije prstena A.
Dobivanje drugih spojeva formule I koji nisu specifično opisani u gornjoj eksperimentalnoj sekciji može se izvršiti korištenjem kombinacija reakcija gore opisanih što će biti jasno stručnjacima područja.
U svakoj od reakcija gore diskutiranih i ilustriranih, tlak nije kritičan ako nije drugačije naznačeno. Tlakovi od oko 0,5 atmosfere do oko 5 atmosfera su općenito prihvatljivi, i ambijentni tlak, npr., oko 1 atmosfere je poželjan i podesan.
Spojevi formule I ("aktivni spojevi iz ovog izuma") koja su bazne prirode sposobni su formirati razne soli sa raznim neorganskim i organskim kiselinama. Mada takve soli moraju biti farmaceutski prihvatljive za unošenje u životinje, često je poželjno u praksi da se početno izolira spoj formule I iz reakcijske smjese kao farmaceutski prihvatljiva sol i zatim se jednostavno pretvori natrag u spoj slobodne baze tretmanom sa alkalnim reagensom i daljim konvertiranjem slobodne baze u farmaceutski prihvatljivu adicijsku sol kiseline. Adicijske soli kiseline spojeva aktivne baze iz ovog izuma lagano se dobivaju tretiranjem baznog spoja sa suštinski ekvivalentnom količinom neorganske ili organske kiseline u u vodenom mediju otopljenog otapala ili u podesnom organskom otapalu, kao što je metanol ili etanol. Poslije pažljivog isparavanja otapala dobiva se lagano željena kruta sol.
Aktivni spojevi iz ovog izuma i njihove farmaceutski prihvatljive soli su korisni kao NOS inhibitori npr., oni posjeduju sposobnost da se inhibira NOS enzim kod sisavaca, i zato su sposobni funkcionirati kao terapijski agensi u tretmanu gore spomenutih bolesti od kojih boluju sisavci.
Aktivni spojevi iz ovog izuma i njihove farmaceutski prihvatljive soli mogu se unositi preko oralnih, parenteralnih ili topikalnih puteva. Općenito, ista spoj se najpoželjnije unosi u dozi u opsegu od oko 0,01 do oko 250 mg po danu, u jednoj ili više doza (npr., od 1 do 4 doza po danu); mada će varijacije biti potrebne zavisno od vrste, težine i stanja subjekta koji se tretira i određenog izabranog puta unošenja. Nivo doziranja koji je u opsegu od oko 0,07 mg do oko 21 mg po kg tjelesne težine je najpoželjniji. Mogu se svejedno dešavati varijacije prema vrstama životinja koje se tretiraju i njihovog pojedinačnog odziva, isto kao i od tipa izabrane farmaceutske formulacije i perioda vremena i intervala u kojima se vrši takvo unošenje. U nekim slučajevima, dozni nivoi ispod donje granice gore spomenutog opsega mogu biti više nego adekvatni, dok u drugim slučajevima još se veće doze mogu koristiti bez prouzročavanja bilo kojeg štetnog sporednog efekta, pod uvjetom da se takve veće doze prvo podijele u nekoliko malih doza za unošenje tijekom dana.
Aktivni spojevi iz izuma mogu se unositi sami ili u kombinaciji sa farmaceutski prihvatljivim nosačima ili razrjeđivačima jednim od 3 prije naznačena puta, i takvo unošenje se može vršiti u jednoj ili više doza. Određenije, novi terapijski agensi iz ovog izuma mogu se unositi u velikom mnoštvu razni oblika doziranja, npr., oni se mogu kombinirati sa raznim farmaceutski prihvatljivim inertnim nosačima u obliku tableta, kapsula, pilulica, pastila, tvrdih kandia, prahova, sprejeva, krema, melema, supozitorija, želea, gelova, pasta, losiona, pomasti, vodenih suspenzija, ubrizgavajućih otopine, eliksira, sirupa i slično. Takvi nosači uključuju čvrste razrjeđivače ili punila, sterilne vodene medije i razna netoksična organska otapala, itd. Dalje, oralni farmaceutski preparati mogu se po želji zasladiti i/ili začiniti. Općenito, terapijski djelotvorni spojevi iz ovog izuma prisutni su u takvim oblicima doziranja u nivoima koncentracija u opsegu od oko 5,0 % do oko 70 % masenih.
Za oralno unošenje, tablete koje sadrže razne ekscipijente kao što su mikrokristalna celuloza, natrijev citrat, kalcijev karbonat, dikalcijev fosfat i glicin mogu se koristiti zajedno sa raznim dezintegratorima takvima kao škrob (poželjno škrob žita, krompira ili tapioke); alginska kiselina i neki kompleksni silikati, zajedno sa granulacijskim vezivima slično polivinilpirolidonu, sukrozi, želatini i akaciji. Dodatno, agensi podmazivanja kao magnezij stearat, natrij lauril sulfat i talk često su vrlo korisni za potrebe tabletiranja. Čvrsti preparati sličnog tipa mogu se također koristiti kao punila u želatinskim kapsulama; poželjni materijali u vezi ovog uključuju laktozu ili mliječni šećer isto kao polietilen glikole velike molekularne težine. Kada se vodene suspenzije i/ili eliksiri namjene za oralno unošenje, aktivni sastojak se može kombinirati sa raznim agensima zaslađivanja ili začinima ili bojama, i, ako se želi, emulgatorima i/ili agensima za suspendiranje, isto uz razrjeđivače poput vode, etanola, propilen glikola, glicerina i raznih slične njihovih kombinacija.
Za parenteralno unošenje mogu se koristiti otopine aktivnog spoja iz ovog izuma u ulju sezama ili kikirikija ili u vodenoj otopini propilen glikola. Vodenu otopina treba biti po želji puferirana (poželjno pH veći od 8) ako je potrebno i tekući otapalo se prvo izotonski izlučuje. Isto tako vodene otopine su podesne za potrebe intravenoznih injekcija. Uljne otopine su podesne za upotrebu u intraartikularnim, intramuskulaturnim i potkožnim injekcijama. Dobivanje tih otopina pod sterilnim uvjetima lagano se vrši standardnim farmaceutskim tehnikama dobro poznatim stručnjacima područja.
Dodatno, također je moguće da se unose aktivni spojevi iz ovog izuma topikalno pri tretmanu upala kože i to se čini pomoću krema, želea, pasta, melema, pomasti i slično, u skladu sa standardnom farmaceutskom praksom.
Sposobnost spojeva formule I da inhibiraju NOS može se odrediti korištenjem postupaka opisanih u literaturi. Sposobnost spojeva iz formule I da inhibiraju endotelni NOS može se odrediti korištenjem postupaka koje su opisali Schmidt et al. u Proc. Natl. Acad. Sci. USA, 88; str. 365-369 (1991) i Pollock et al., u Proc. Natl. Acad. Sci. USA, 88; str. 10480-10484 (1991). Sposobnost spojeva formule I da inhibiraju izazvan NOS može se odrediti korištenjem postupaka koje su opisali Schmidt et al., u Proc. Natl. Acad, Sci. USA, 88; str. 365-369 (1991) i Garvey et al., u J. Biol. Chem., 269; str. 26669-26676 (1994). Sposobnost spojeva formule I da inhibiraju neuronski NOS može se odrediti korištenjem postupka koji su opisali Bredt i Snyder u Proc. Natl. Acad. Sci. USA, 87; 682-685 (1990).
Od 16 spojeva formule I koji su testirani, svi pokazuju IC50 < 10 µM za inhibiciju izazvanog ili neuronskog NOS.
Isti izum je ilustriran sa slijedećim primjerima. Razumije se, međutim, da izum nije ograničen specifičnim detaljima primjera. Točke taljenja nisu korigirane. Spektri protonskih neklearnih magnetskih rezonancija (1H NMR) i 13C spektri nuklearne magnetske rezonance mjereni su za otopine u deuterokloroformu (CDCl3) ili u CD3OD ili CD3SOCD3 a vršne pozicije su izražene u dijelovima na milion (ppm) donjeg polja od teterametilsilana (TMS). Vršni oblici su označeni kako slijedi: s, singlet, d, dublet, t, triplet, q, kvartet, m, multiplet, b, širok.
Primjer 1
6-(4-(2-(4-fenetil-piperazin-1-il)-naftalen-1-il)-piridin-2-ilamin
N-t-butilkarbonil-6--bromo-piridil-2-amin
U bocu od 125 ml sa kružnim dnom opremljenu sa N2 ulazom dodani su 0,865 g (5 mmol) 6-bromo-2-aminopiridina, 0,677 ml (5,5 mmol) trimetilacetil klorida, 15 ml suhog acetonitrila, i 1,045 ml (7,5 mmol) trietilamina. Reakcija je miješana na sobnoj temperaturi tijekom 14 sati, sipana u vodu, i miješana dok se ne formira čvrst talog. Krutina je filtrirana, isprana vodom, i osušena zbog dobivanja 1,04 g (81 %); tt 87-90 °C.
1H-NMR (�, CDCl3): 1,28 (s, 9H); 7,17 (d, J=8; 1H); 7,52 (t, J=8; 1H); 8,00 (bs, 1H); 8,19 (d, J=8; 1H).
13C-NMR (�, CDCl3): 27,3; 39,8; 112,2; 123,3; 139,0; 140,5; 151,6; 177,1.
B. 4-metilnaftalen-1-borna kiselina
U bocu od 125 ml sa kružnim dnom opremljenu sa N2 ulazom dodani su 1,78 g (11,4 mmol) 1-bromo-4-metilnaftalen i 20 ml suhog teterahidrofurana. Otopina je ohlađena na -70 °C, i 5,49 ml (13,7 mmol) 2,5 M otopine n-butil litija je dodano tijekom 5 minuta, i reakcija je miješana na -70 °C tijekom 10 minuta. Otopina je zatim tretiran sa 2,34 ml (13,7 mmol) trietil borata, miješan 5 minuta na -70 °C, zatim zagrijana na sobnu temperaturu i miješana 40 sati. Reakcija je ugašena vodenom otopinom amonij klorida, sipana u 0,5 N klorovodične kiseline, i ekstrahirana u etil acetatu. Organski sloj je ispran slanom vodom, osušen preko natrijevog sulfata, i isparen do bijele krutine poslije trituriranja heksanom, tt 224-228 °C, 1,9 g (90 %).
1H-NMR (�, CDCl3): 2,63 (s, 3H); 7,25 (m, 1H); 7,3-7,5 (m, 3H); 7,75 (m, 1H); 7,95 (m, 1H).
13C-NMR (�, CDCl3): 19,4; 124,5; 125,5; 125,7; 126,0; 128,5; 128,9; 129,9; 131,6; 134,9; 135,3.
C. N-t-butilkarbonil-6-(4-metilnaftalen-1-il)-piridin-2-ilamin
U bocu od 100 ml sa kružnim dnom opremljenom zgušnjivačem i N2 ulazom dodani su 975 mg (3,795 mmol) N-t-butilkarbonil-6-bromo-piridil-2-amina, 706 mg (3,795 mmol) 4-metilnaftalen-1-borne kiseline, 1,61 g (15,18 mmol) natrijevog karbonata, 50 mg (0,04 mmol) teterakistrifenilfosfin paladija, 18 ml etanola, i 2 ml vode, i reakcija je grijana na 80 °C tijekom 13 sati. TLC je pokazao veći spot na Rf = 0,2 u 15 % etil acetata u heksanu, a LMC je pokazao veći lokalni izrazit maksimum na P+1 = 319. Reakcija je ohlađena u vodi, i ekstrahirana u etil acetatu. Organski sloj je ispran vodom i slanom vodom, osušen preko natrijevog sulfata, i isparen. Ostatak je kromatografiran na silika gelu korištenjem heksan/etil acetata kao eluanta zbog dobivanja 1,25 g (100 %) pjene.
1H-NMR (�, CDCl3): 1,32 (s, 9H); 2,73 (s, 3H); 7,25 (m, 1H); 7,3-7,5 (m, 4H); 7,81 (t, J=8; 1H); 8,00 (d, J=8; 1H); 8,05 (d, J=8; 1H); 8,145 (bs, 1H); 8,31 (d, J=8; 1H).
13C-NMR (�, CDCl3): 19,7; 27,5; 60,4; 112,1; 121,1; 124,4; 125,8; 126,08; 126,11; 126,16; 126,9; 131,1; 132,9; 135,3; 1338,7; 151,3; 157,8; 177,3.
MS (%): 319 (roditelj+1; 100).
D. N-t-butilkarbonil-6-(4-cijanometilnaftalen-1-il)-piridin-2-ilamin
U bocu od 100 ml sa kružnim dnom opremljenu sa N2 ulazom dodani su 1,21 g (3,795 mmol) N-t-butilkarbonil-6-(4-metilnaftalen-1-il)-piridin-2-ilamina, 810 mg (4,554 mmol) N-bromosukcinimida, 35 ml ugljik teteraklorida, i 10 mg bis-(1-cijano-1-azo)-cikloheksana. Reakcija je grijana na refluksu tijekom ukupno 8 sati dok su dodatni dijelovi inicijatora dodani na 1; 2; i 4 sata. Reakcija je ohlađena, filtrirana sa ugljik teterakloridom, i isparena. Crveno ulje, 2,5 g, je direktno dalje korišteno.
1H-NMR (�, CDCl3): 1,33 (s, 9H); 5,00 (s, 2H); 7,26 (d, J=7,5; 1H); 7,49 (m, 2H); 7,63 (m, 2H); 7,84 (t, J=8; 1H); 8,02 (d, J=8; 1H); 8,115 (bs, 1H); 8,22 (d, J=8; 1H); 8,36 (d, J=7,5; 1H).
13C-NMR (�, CDCl3): 27,6; 31,6; 39,9; 112,6; 121,0; 124,1; 126,6; 126,7; 127,3; 131,5; 131,7; 134,1; 138,8; 139,5; 151,4; 157,1; 177,35.
MS (%): 379/399 (roditelj+1; 100).
Gornje ulje je uzeto u 35 ml suhog metilen klorida i tretirano sa 593 mg (3,795 mmol) teteraetilamonij cijanida, i reakcija je miješana na sobnoj temperaturi tijekom 13 sati. LCMS je pokazao veći lokalni izrazit maksimum na P+1 = 344 a TLC je pokazao veći spot na Rf = 0,6 u 10 % etil acetata u metilen kloridu. Reakcija je isparena, i ostatak je kromatografiran na silika gelu korištenjem etil acetata u metilen kloridu kao eluantu zbog dobivanja 1,00 g (77 %) pjene.
1H-NMR (�, CDCl3): 1,3 (s, 9H); 4,18 (s, 3H); 7,26 (d, J=7,5; 1H); 7,53 (m, 2H); 7,63 (m, 2H); 7,84 (t, J=8; 1H); 7,92 (d, J=8; 1H); 8,04 (d, J=8,5; 1H); 8,10 (bs, 1H); 8,34 (d, J=8; 1H).
13C-NMR (�, CDCl3): 22,0; 27,5; 39,9; 112,6; 121,0; 122,75; 126,7; 126,9; 127,2; 131,2; 131,4; 138,9; 139,1; 151,4; 156,9; 177,35.
MS (%): 344 (roditelj+1; 100).
E. 6-(4-karboksimetilnaftalen-1-il)-piridin-2-ilamin
U bocu od 100 ml sa kružnim dnom opremljenu sa N2 ulazom dodani su 1,00 g (2,915 mmol) N-butilkarbonil-6-(4-cijanometilnaftalen-1-il)-piridin-2-ilamina i 35 ml etanola. Otopina je zasićena sa HCl i refluksirana 14 sati, dodavanjem 2 kapi vode odjednom kad je dostignut refluks. Reakcija (LCMS je pokazala P+1 = 391) je ohlađena i isparena, i ostatak je uzet u etil acetatu, ispran sa vodenom otopinom natrij bikarbonata, vodom i slanom vodom, osušen preko natrij sulfata, i isparen u ulje, 1,09 g (96 %); koje je direktno dalje korišteno.
1H-NMR (�, CDCl3): 1,21 (t, J=7; 3H); 1,31 (s, 9H); 4,09 (s, 2H); 4,13 (q, J=7; 2H); 4,13 (q, J=7; 2H); 7,25 (d, J=7,5; 1H); 7,4-7,6 (m, 4H); 7,82 (t, J=7,5; 1H); 7,4-7,6 (m, 4H); 7,82 (t, J=7,5; 1H); 7,99 (d, J=8; 1H); 8,06 (d, J=8; 1H); 8,13 (bs, 1H); 8,31 (d, J=8; 1H).
13C-NMR (�, CDCl3): 14,2; 27,5; 39,5; 60,4; 61,0; 112,3; 121,1; 124,2; 126,3; 126,4; 126,8; 127,5; 131,4; 131,7; 132,5; 137,8; 138,7; 151,3; 157,5; 171,4; 177,3.
MS (%): 391 (roditelj+1; 100).
Gornje ulje je uzeto u 26 ml 6 N klorovodične kiseline, i grijano na 95-100 °C tijekom 12 sati. LCMS je pokazao P+1 = 279. Reakcija je ohlađena, isprana eterom, isparena, i konačno osušena pod vakuumom da se dobije bijela krutina, 0,85 g (93 % ukupno) produkta kao hidrokloridne soli.
MS (%): 279 (roditelj+1; 100).
F. 6-(4-(4-(2-feniletil)piperazinilkarbonil)-metilennaftalen-1-il)-piridin-2-ilamin
U bocu od 100 ml sa kružnim dnom opremljenu sa N2 ulazom dodani su 157 mg (0,50 mmol) 6-(4-karboksimetilnaftalen-1-il)-piridin-2-ilamin, 95 mg (0,50 mmol) N-fenetilpiperazina, 96 mg (0,50 mmol) N-etila, N-3-dimetilaminopropil-karbodiimida, 0,230 ml (1,65 mmol) trietilamina, 10 mg N-hidroksibenzotriazola, i 7 ml suhog acetonitrila. Reakcija je miješana na sobnoj temperaturi 12 sati (LCMS je pokazao P+1 = 451 i TLC je pokazao Rf = 0,3 u 10 % metanol/metilen kloridu); zatim je isparena i ostatak je kromatografiran na silika gelu korištenjem metanol/metilen klorida kao eluanta zbog dobivanja produkta kao pjene, 230 mg ( 100 %).
1H-NMR (�, CDCl3): 2,37 (m, 2H); 2,52 (m, 2H); 2,59 (m, 2H); 2,76 (m, 2H); 3,46 (m, 2H); 3,76 (m, 2H); 4,17 (s, 2H); 4,73 (bs, 2H, NH2); 6,46 (d, J=8; 1H); 6,83 (d, J=7,5; 1H); 7,1-7,6 (m, 10H); 7,98 (d, J=8; 1H); 8,14 (d, J=8,5; 1H).
13C-NMR (�, CDCl3): 33,4; 38,5; 41,8; 46,1; 52,8; 53,2; 60,2; 137,2; 115,2; 123,5; 125,6; 126,1; 126,2; 126,3; 126,5; 127,0; 128,5; 128,7; 131,6; 132,2; 138,1; 138,5; 139,9; 157,4; 158,3; 169,7.
MS (%): 451 (roditelj+1; 100).
G. 6-(4-(2-fenetil-piperazin-1-il)-etil)-naftalen-1-il)-piridin-2-ilamin
U bocu od 100 ml sa kružnim dnom opremljenu sa N2 ulazom dodani su 200 mg aluminij klorida i 5 ml suhog teterahidrofurana. Otopina je ohlađena na 0 °C, i dodano je 3,50 ml (3,50 mmol) 1,0 M otopine litij aluminij anhidrida u teterahidrofuranu. Miješanje je nastavljeno na sobnoj temperaturi tijekom 20 minuta, zatim je otopina ohlađena na -70 °C, i dodan je otopina od 225 mg (0,50 mmol) 6-(4-(4-(2-feniletil)piperazinilkarbonil)-metilnaftalen-1-il)-piridin-2-ilamina u 7 ml suhog teterahidrofurana. Miješanje je nastavljeno 1 sat na -70 °C, zatim 2 sata na sobnoj temperaturi (LCMS je pokazao P+1 = 437); praćeno sa pažljivim gašenjem sa 5 ml 1 N klorovodične kiseline. Poslije miješanja tijekom 20 minuta (min.); reakcija je tretirana sa 6 ml 6 N u vodi otopljenog natrij hidroksida, i ekstrahirana sa nekoliko dijelova metilen klorida. Organska faza je osušena preko natrij sulfata i isparena zbog dobivanja ulja, koje je konvertirano u hidrokloridnu sol korištenjem HCl u eteru, dajući produkt, 175 mg (64 %) kao bijele krutina, tt. 80-105 °C.
1H-NMR (�, CDCl3): 2,65 (m, 6H); 2,76 (m, 4H); 2,84 (m, 4H); 3,33 (m, 2H); 4,68 (bs, 2H, NH2); 6,44 (d, J=8; 1H); 6,85 (d, J=7; 1H); 7,1-7,6 (m, 10H); 8,11 (m, 2H).
13C-NMR (�, CDCl3): 30,9; 33,7; 53,3; 59,7; 60,6; 106,9; 115,2; 123,9; 125,77; 125,83; 126,1; 126,7; 126,9; 128,4; 128,7; 131,4; 132,3; 136,9; 137,8; 138,0; 140,4; 157,9; 158,2.
MS (%): 437 (roditelj+1; 100).
Anal. izrač. za C29H32N4*Cl*3/2H2O*1/2(C4H10O): C 69,32; H 7,69; N 10,43.
Nađeno: C, 69,46; H 7,35; N 10,36.
Primjer 2
3-(2-(4-(6-amino-piridin-2-il)-naftalen-1-il)-etil)-3-aza-biciklo(3,1,0)heks-6-ilamin
Dobiven kao u primjeru 1; sa fazom dodatnog deblokiranja korištenjem trifluorooctene kiseline u metilen kloridu zbog uklanjanja t-butoksikarbonil zaštitne skupine, u 71 % prinosu, tt. 250-260 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,24 (bs, 2H); 1,36 (bs, 1H); 2,43 (m, 2H); 2,72 (m, 2H); 3,1-3,2 (m, 4H); 4,63 (bs, 2H, NH2); 6,45 (d, J=8; 1H); 6,83 (d, J=7; 1H); 7,3-7,6 (m, 5H); 8,07 (m, 2H).
13C-NMR (�, CDCl3): 25,8; 29,7; 32,7; 55,0; 56,7; 106,8; 115,2; 123,9; 125,7; 125,9; 126,6; 126,8; 131,5; 132,2; 137,1; 137,6; 138,0; 157,9; 158,1.
MS (%): 345 (roditelj+1; 100).
Anal. izrač. za C22H24N4*7/4HCl*(C4H10O): C 64,74; H 7,47; N 11,61.
Nađeno: C, 64,34; H 6,94; N 11,20.
Primjer 3
6-(4-(2-(4-benzihidril-piperidin-1-il)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; u 74 % prinosu, tt 225-235 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,32 (m, 1H); 1,64 (m, 1H); 2,07 (m, 2H); 2,17 (m, 1H); 2,70 (m, 2H); 3,06 (m, 2H); 3,31 (m, 2H); 3,55 (d, J=8; 1H); 3,75 (m, 2H); 4,64 (bs, 2H, NH2); 6,45 (d, J=8; 1H); 6,85 (d, J=7; 1H); 7,16-7,6 (m, 14H); 8,10 (m, 2H).
13C-NMR (�, CDCl3): 25,7; 31,0; 31,5; 39,7; 54,0; 60,1; 68,0; 106,8; 115,2; 123,9; 125,7; 125,8; 126,1; 126,2; 126,7; 126,9; 128,1; 128,6; 131,6; 132,3; 137,1; 137,7; 138,0; 143,9; 157,9; 158,2.
MS (%): 498 (roditelj+1; 100).
Anal. izrač. za C35H35N3*2HCl: C 73,67; H 6,54; N 7,36.
Nađeno: C 73,86; H 6,97; N 7,04.
Primjer 4
6-(4-(2-(6,7-dimetoksi-3,4-dihidro-1H-izokinolin-2-il)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; u 56,5 % prinosu, tt 172-176 °C.
1H-NMR (�, CDCl3): 2,87 (m, 6H); 3,41 (m, 2H); 3,71 (m, 2H); 3,826 (s, 3H); 3,831 (s, 3H); 4,60 (bs, 2H, NH2); 6,47 (d, J=8; 1H); 6,56 (s, 1H); 6,60 (s, 1H); 6,84 (d, J=7,5; 1H); 7,4-7,6 (m, 5H); 8,12 (m, 2H).
13C-NMR (�, CDCl3): 28,7; 31,3; 51,1; 55,7; 55,80; 55,83; 59,3; 106,8; 109,4; 111,3; 115,15; 123,8; 125,67; 125,74; 126,0; 126,5; 126,8; 131,5; 132,2; 136,8; 137,7; 138,0; 147,1; 147,4; 157,8; 158,0.
MS (%): 440 (roditelj+1; 100).
Anal. izrač. za C28H29N3O2*1/4H2O: C 75,73; H 6,70; N 9,46.
Nađeno: C, 75,66; H 6,54; N 9,17.
Primjer 5
6-(4-(2-(6-metoksi-1,3,4,9-teterahidro-�-karbolin-2-il)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; u 60 % prinosu, tt 132-138 °C.
1H-NMR (�, CDCl3): 2,81 (m, 2H); 2,91 (m, 4H); 3,31 (m, 2H); 3,51 (bs, 2H); 3,83 (s, 3H); 4,61 (bs, 2H, NH2); 6,46 (d, J=8; 1H); 6,75 (dd, J=2,5,8,7); 6,84 (d, J=7; 1H); 6,92 (d, J=2,5; 1H); 7,08 (d, J=8; 1H); 7,36 (d, J=7; 1H); 7,4-7,6 (m, 3H); 8,08 (d, J=8; 1H); 8,13 (dd, J=1,8; 1H); 8,39 (bs, 1H).
13C-NMR (�, CDCl3): 25,5; 50,2; 51,1; 55,8; 58,7; 67,9; 100,2; 103,9; 107,8; 110,7; 111,3; 115,2; 123,8; 125,7; 125,8; 126,1; 126,8; 127,5; 131,1; 131,6; 132,1; 132,8; 136,8; 137,6; 138,1; 153,7; 157,7; 158,0.
MS (%): 449 (roditelj+1; 100).
Anal. izrač. za C29H28N4O*(C4H10O): C 75,83; H 7,33; N 10,72.
Nađeno: C 75,80; H 7,00; N 11,33.
Primjer 6
6-(4-(2-((benzo(1,3)dioksol-5-ilmetil)-amino)-etil)-naftalen-1-il)-piridin-1-ilamin
Dobiven kao u primjeru 1; u 77 % prinosu, tt 80-110 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 3,00 (t, J=7; 2H); 3,31 (t, J=7; 2H); 3,70 (s, 2H); 4,62 (bs, 2H, NH2); 5,90 (s, 2H); 6,48 (d, J=8; 1H); 6,72 (s, 1H); 6,73 (m, 1H); 6,81 (m, 1H); 6,85 (d, J=7; 1H); 7,4-7,6 (m, 5H); 8,09 (m, 2H).
13C-NMR (�, CDCl3): 33,7; 49,7; 53,7; 100,9; 106,9; 108,1; 108,7; 115,2; 121,2; 123,9; 125,76; 125,80; 126,1; 126,5; 126,8; 131,7; 132,3; 134,2; 136,5; 137,8; 138,1; 146,5; 147,7; 157,8; 158,1.
MS (%): 398 (roditelj+1; 100).
Anal. izrač. za C25H23N3O2*2HCl*H2O*1/2(C4H10O): C 61,72; H 6,14; N 8,00.
Nađeno: C 61,81; H 5,97; N 7,56.
Primjer 7
6-(4-(2-(3,4-difluoro-benzilamino)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; u 91 % prinosu, tt 70-80 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,93 (t, J=7; 2H); 3,315 (t, J=7; 2H); 3,70 (s, 2H); 4,76 (bs, 2H, NH2); 6,47 (d, J=8; 1H); 6,81 (d, J=7; 1H); 7,0-7,2 (m, 3H); 7,4-7,6 (m, 5H); 8,06 (m, 2H).
13C-NMR (�, CDCl3): 32,9; 49,2; 52,2; 107,1; 115,0; 117,1; 123,7; 124,2; 125,9; 126,1; 126,4; 126,7; 131,6; 132,0; 135,8; 137,8; 138,1; 148,1; 148,3; 148,8; 149,0; 150,6; 150,7; 151,3; 151,4; 157,4; 158,1.
MS (%): 390 (roditelj+1; 100).
Anal. izrač. za C24H21N3O2*3/2HCl*1/2H2O*(C4H10O): C 63,78; H 6,40; N 7,97.
Nađeno: C 63,94; H 5,95; N 7,89.
Primjer 8
6-(4-(2-(3,4,5-trimetoksi-benzilamino)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; u 80 % prinosu, tt 79-95 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 3,02 (t, J=7; 2H); 3,34 (t, J=7; 2H); 3,73 (s, 2H); 3,78 (s, 6H); 3,795 (s, 3H); 4,655 (bs, 2H, NH2); 6,46 (d, J=8; 1H); 6,49 (s, 2H); 6,82 (d, J=7,5; 1H); 7,4-7,6 (m, 5H); 8,08 (m, 2H).
13C-NMR (�, CDCl3): 33,5; 49,7; 54,0; 55,9; 60,7; 104,7; 106,9; 115,0; 123,8; 125,4; 125,70; 125,74; 126,1; 126,4; 126,7; 131,6; 132,1; 135,8; 136,3; 136,6; 137,8; 138,0; 153,1; 157,6; 158,1.
MS (%): 444 (roditelj+1; 100).
Anal. izrač. za C27H29N3O3*2HCl*(C4H10O): C 63,05; H 7,00; N 7,11.
Nađeno: C, 63,04; H 6,70; N 6,96.
Primjer 9
6-(4-(2-(3-kloro-benzilamino)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; korištenjem prekursora 3,4-diklorobenzilamina. U ovom slučaju, litij aluminij hidrid/aluminij klorid redukcija je uklonila jedan od atoma klora, dajući 3-klorobenzil spoj. Finalni produkt je dobiven u 73 % prinosu, tt 60-75 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,99 (t, J=7; 2H); 3,30 (t, J=7; 2H); 3,73 (bs, 2H, NH2); 6,46 (d, J=8; 1H); 6,83 (d, J=7; 1H); 7,2-7,6 (m, 9H); 8,07 (m, 2H).
13C-NMR (�, CDCl3): 33,6; 49,7; 68,0; 107,0; 115,1; 123,9; 125,8; 126,1; 126,5; 126,8; 128,5; 129,5; 131,7; 132,2; 136,3; 137,8; 138,1; 157,7; 158,2.
MS (%): 388 (roditelj+1; 100).
Anal. izrač. za C24H22N3Cl*HCl*H2O*1/2(C4H10O): C 65,13; H 6,31; N 8,76.
Nađeno: C 64,84; H 6,25; N 8,35.
Primjer 10
6-(4-(2-((furan-2-ilmetil)-amino)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; u 44 % prinosu, tt 185-205 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 3,00 (t, J=7; 2H); 3,295 (t, J=7; 2H); 3,79 (s, 2H); 4,68 (bs, 2H, NH2); 6,13 (bs, 1H); 6,26 (bs, 1H); 6,45 (d, J=8; 1H); 6,83 (d, J=7,5; 1H); 7,3-7,6 (m, 6H); 8,08 (m, 2H).
13C-NMR (�, CDCl3): 33,4; 46,1; 49,5; 106,9; 107,0; 110,0; 115,05; 123,8; 125,7; 126,0; 126,4; 126,7; 131,6; 132,1; 136,2; 137,7; 138,0; 141,75; 153,5; 157,6; 158,1.
MS (%): 344 (roditelj+1; 100).
Anal. izrač. za C22H21N3O*HCl*3/2H2O: C 64,23; H 6,25; N 10,21.
Nađeno: C 64,42; H 6,04; N 9,86.
Primjer 11
6-(4-(2-(3,4-dikloro-benzilamino)-etil)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 1; korištenjem bor metil sulfida umjesto litijum aluminij hidrid/aluminij klorid redukcije u finalnoj fazi. Finalni produkt je dobiven u 68,5 % prinosu, tt. 145-170 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,98 (t, J=7; 2H); 3,295 (t, J=7; 2H); 3,71 (s, 2H); 4,60 (bs, 2H, NH2); 6,49 (d, J=8; 1H); 6,85 (d, J=7,5; 1H); 7,2-7,6 (m, 7H); 8,09 (m, 2H).
13C-NMR (�, CDCl3): 33,6; 49,7; 52,7; 107,0; 115,3; 123,8; 125,8; 125,9; 126,2; 126,5; 126,9; 127,3; 127,4; 129,9; 130,0; 130,2; 130,7; 131,7; 132,2; 132,3; 136,2; 138,1; 140,7; 157,8; 158,1.
MS (%): 388 (roditelj+1; 100).
Anal. izrač. za C24H21N3Cl2*HCl*2H2O*1/4(C4H10O): C 58,71; H 5,87; N 7,90.
Nađeno: C 58,35; H 5,92; N 6,62.
Primjer 12
6-(4-(2-(dimetilamino-etoksi)-naftalen-1-il)-piridin-2-ilamin
Referiranje na shemu 2
A. 4-bromo-1-benziloksi-naftalen
U bocu od 250 ml sa kružnim dnom opremljenu sa lijevkom za dodavanje i N2 ulazom dodani su 2,88 g (20 mmol) 1-naftola i 50 ml 1,2-dikloroetana, i sa miješanjem otopina 9,64 g (20 mmol) teterabutilamonij tribromida u 30 ml 1,2-dikloroetana ukapavanjem tijekom 10 minuta. Poslije miješanja tijekom dodatnih 10 minuta na sobnoj temperaturi, otopina je isprana razrijeđenim vodenom otopinom natrijeva bisulfitom i vodom, osušena preko natrij sulfata, i isparena. Smjesa produkta i tributilamonijeve soli direktno je korištena.
1H-NMR (�, CDCl3): 7,22 (d, J=8; 1H); 7,43 (m, 2H); 7,50 (dt, J=1,8; 1H); 8,05 (d, J=8; 1H); 8,18 (d, J=8; 1H).
13C-NMR (�, CDCl3): 109,8; 111,4; 122,7; 125,3; 126,25; 126,7; 137,4; 129,9; 132,5; 153,0.
Gornje ulje je otopljeno u 100 ml acetonitrila, i tretirano sa 3,57 ml (30 mmol) benzil bromida i 5,53 g (40 mmol) kalij karbonata, refluksirano 14 sati. TLC je pokazao veći spot na Rf = 0,2 u 5 % metilen klorid/heksanu. Reakcija je ohlađena, sipana u razrijeđenu klorovodičnu kiselinu/etil acetat, i organski sloj je izdvojen, ispran vodom i slanom vodom, osušen preko natrijevog sulfata, i isparen. Ostatak je kromatografiran na silika gelu korištenjem metilen klorid/heksana kao eluanta zbog dobivanja 5,8 g (93 %) ulja.
1H-NMR (�, CDCl3): 5,22 (s, 2H); 6,74 (d, J=8; 1H); 7,4-7,7 (m, 8H); 8,21 (d, J=8; 1H); 8,39 (d, J=8; 1H).
13C-NMR (�, CDCl3): 70,3; 105,9; 113,6; 122,7; 126,1; 126,9; 127,0; 127,4; 127,9; 128,1; 128,7; 129,5; 132,6; 136,7; 154,3.
MS (%): 314 (roditelj+1; 100).
B. 1-benziloksi-naftalen-4-borna kiselina
Korištenjem postupka u primjeru 1A, 5,95 g (19 mmol) 4-bromo-1-benziloksi-naftalena konvertirano je u produkt u 55 % prinosu kao bijelu krutinu, tt. 149-152 °C.
1H-NMR (�, CDCl3): 5,18 (s, 2H); 6,82 (m, 1H); 7,2-7,8 (m, 8H); 8,28 (m, 2H).
13C-NMR (�, CDCl3): 69,9; 104,5; 104,7; 122,2; 124,4; 124,8; 125,0; 126,5; 126,6; 127,6; 127,7; 127,9; 128,0; 128,5; 130,9; 132,9; 136,9.
C. 2-(2,5-dimetilpirolil)-6-(4-benziloksi-1-naftil)-piridin
Dobiven kao u primjeru 1B, u 100 % prinosu kao ulje.
1H-NMR (�, CDCl3): 2,25 (s, 6H); 5,29 (s, 2H); 5,92 (s, 2H); 6,95 (d, J=8; 1H); 7,21 (d, J=7,5; 1H); 7,3-7,6 (m, 9H); 7,89 (t, J=8; 1H); 8,14 (m, 1H); 8,45 (m, 1H).
13C-NMR (�, CDCl3): 13,5; 70,1; 104,8; 106,8; 106,8; 119,7; 122,5; 123,4; 125,2; 125,3; 125,9; 126,4; 126,9; 127,3; 127,9; 128,2; 128,6; 130,5; 132,0; 136,9; 138,0; 151,8; 155,0; 159,1.
MS (%): 405 (roditelj+1; 100).
D. 2-(2,5-dimetilpirolil)-6-(4-hidroksi-1-naftil)-piridin
U bocu od 125 ml sa kružnim dnom opremljenu sa N2 ulazom dodani su 1,53 g (3,795 mmol) 2-(2,5-dimetilpirolil)-6-(4-benziloksi-1-naftil)-piridina, 1,20 g (18,975 mmol) amonij formata, 100 mg 10 % paladija na ugljiku, i 30 ml etamola. Reakcija je refluksirana 4 sata, sa dodatnim katalizatorom i format je dodan na 2 i 3 sata, zatim je ohlađena i filtrirana preko celite sa etanolom i metilen kloridom. Filtrat je isparen i ostatak je uzet u otopinu etil acetat/u vodi otopljenog natrij bikarbonata. Organski sloj je ispran slanom vodom, osušen preko natrij sulfata, i isparen u svijetlo smeđu tekućinu, 1,21 g ( 100 %).
1H-NMR (�, CDCl3): 2,105 (s, 6H); 5,775 (s, 2H); 6,66 (d, J=8; 1H); 7,04 (d, J=8; 1H); 7,29 (m, 2H); 7,38 (d, J=8; 1H); 7,72 (t, J=8; 1H); 7,95 (m, 1H); 8,18 (m, 1H).
13C-NMR (�, CDCl3): 13,8; 106,7; 106,8; 107,6; 119,6; 122,55; 124,5; 124,7; 125,0; 126,5; 128,4; 128,5; 128,7; 132,0; 138,2; 151,5; 153,9; 159,3.
MS (%): 315 (roditelj+1; 100).
E. 2-(2,5-dimretilpirolil)-6-(4-(2-karboetoksimetiloksi)-1-naftil)-piridin
U bocu od 125 ml sa kružnim dnom opremljenu sa zgušnjivačem i N2 ulazom dodani su 1,19 g (3,795 mmol) 2-(2,5-dimetilpirolil)-6-(4-hidroksi-1-naftil)-piridina, 0,505 ml (4,554 mmol) etil bromoacetata, 1,05 g (7,59 mmol) kalij karbonata, i 25 ml acetonitrila. Smjesa je refluksirana 12 sati, ohlađena (TLC Rf = 0,6 u 1/1-etil acetat/heksanu); sipana u vodu, i ekstrahirana u etil acetatu. Organski sloj je ispran sa slanom vodom, osušen preko natrij sulfata, i isparen. Ostatak je kromatografiran na silika gelu korištenjem heksan/etil acetata kao eluanta zbog dobivanja 2,05 g ( 100 %) ulja.
1H-NMR (�, CDCl3): 1,31 (t, J=7; 3H); 2,26 (s, 6H); 4,29 (q, J=7; 2H); 4,82 (s, 2H); 5,94 (s, 2H); 6,78 (d, J=8; 1H); 7,20 (d, J=8; 1H); 7,5-7,6 (m, 5H); 7,87 (t, J=8; 1H); 8,15 (m, 1H); 8,50 (m, 1H).
13C-NMR (�, CDCl3): 13,6; 14,2; 61,4; 65,7; 104,6; 107,0; 119,9; 122,6; 123,6; 125,3; 125,6; 125,8; 127,2; 128,0; 128,6; 131,4; 132,1; 138,3; 151,8; 154,3; 158,9; 168,6.
MS (%): 401 (roditelj+1; 100).
F. 2-(2,5-dimetilpirolil)-6-(4-(2-karboksimetiloksi)-1naftil)-piridin
U bocu od 125 ml sa kružnim dnom opremljenu sa zgušnjivačem i N2 ulazom dodani su 1,52 g (3,795 mmol) 2-(2,5-dimetilpirolil)-6-(4-(2-karboetoksimetiloksi)-1-naftil)-piridina, 15 ml teterahidrofurana, i 478 mg (11,385 mmol) litij hidroksid hidrata u 15 ml vode sa dodatnim metanolom zbog održavanja otopine. Reakcija je miješana na sobnoj temperaturi tijekom 12 sati, (LCMS P+1 = 373); sipana u vodenu otopinu klorovodične kiseline, i ekstrahirana u etil acetatu. Organski sloj je ispran slanom vodom, osušen preko natrij sulfata, i isparen u krutinu, 1,27 g (90 %).
1H-NMR (�, CDCl3): 2,20 (s, 6H); 4,74 (s, 2H); 5,89 (s, 2H); 6,765 (d, J=8; 1H); 7,20 (d, J=8 1H); 7,4-7,6 (m, 4H); 7,885 (t, J=8; 1H); 8,04 (m, 1H); 8,44 (m, 1H).
13C-NMR (�, CDCl3): 13,3; 65,3; 104,5; 106,9; 120,3; 122,6; 124,0; 125,0; 125,6; 125,7; 127,2; 128,0; 128,7; 130,0; 132,0; 138,6; 151,7; 154,3; 158,9; 170,9.
MS (%): 373 (roditelj+1; 100).
G. 2-(2,5-dimetilpirolil)-6-(4-(2-dimetilaminokarbonil)metiloksi)-1-naftil)-piridin
Dobiven kao u primjeru 1D u 100 % prinosu kao ulje.
1H-NMR (�, CDCl3): 2,225 (s, 6H); 2,97 (s, 3H); 3,10 (s, 3H); 4,90 (s, 2H); 5,89 (s, 2H); 6,93 (d, J=8; 1H); 7,21 (d, J=8; 1H); 7,4-7,6 (m, 4H); 7,90 (t, J=8; 1H); 8,09 (m, 1H); 8,38 (m, 1H).
13C-NMR (�, CDCl3): 13,5; 35,8; 36,8; 67,9; 104,7; 106,8; 119,9; 122,2; 123,5; 125,4; 125,56; 125,63; 127,1; 128,6; 131,2; 132,1; 138,2; 151,8; 154,1; 159,0; 167,7.
MS (%): 400 (roditelj+1; 100).
H. 2-(2,5-dimetilpirolil)-6-(4-(2-(2-dimetilaminoetil)metiloksi)-1-naftil)-piridin
Dobiven kao u primjeru 1E u 100 % prinosu kao ulje.
1H-NMR (�, CDCl3): 2,24 (s, 6H); 2,42 (s, 6H); 2,915 (t, J=6; 2H); 4,30 (t, J=6; 2H); 5,91 (s, 2H); 6,90 (d, J=8; 1H); 7,20 (d, J=8; 1H); 7,5-7,7 (m, 4H); 7,89 (t, J=8; 1H); 8,13 (m, 1H); 8,37 (m, 1H).
13C-NMR (�, CDCl3): 13,5; 46,2; 58,2; 67,0; 104,3; 106,8; 119,7; 122,5; 123,5; 125,2; 125,3; 123,8; 126,9; 128,3; 138,6; 130,4; 132,0; 138,1; 151,8; 155,3; 159,1.
MS (%): 386 (roditelj+1; 100).
I. 6-(4-(2-dimetilamino-etoksi)-naftalen-1-il)-piridin-2-ilamin
U bocu od 100 ml sa kružnim dnom opremljenu sa zgušnjivačem i N2 ulazom dodani su 155 mg (0,403 mmol) 2-(2,5-dimetilpirolil)-6-(4-(2-(2-dimetilaminoetil)metiloksi)-1-naftil)-piridina, 500 mg hidroksilamin hidroklorida, 9 ml etanola i 1 ml vode. Otopina je refluksirana 40 h (LCMS P+1 = 308); ohlađena, sipana u razrijeđenu vodenu otopinu klorovodične kiseline, i isprana etil acetatom. Sloj vodene otopine je podešen na pH 12 sa 6 N vodenom otopinom natrij hidroksida i ekstrahiran sa nekoliko dijelova metilen klorida. Organski sloj je osušen preko natrij sulfata i isparen u krutinu, 81 mg (65 %); tt. 98-106 °C.
1H-NMR (�, CDCl3): 2,395 (s, 6H); 2,89 (t, J=6; 2H); 4,27 (t, J=6; 2H); 4,65 (bs, 2H, NH2); 6,43 (d, J=8; 1H); 6,84 (m, 2H); 7,4-7,6 (m, 4H); 8,10 (m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 46,2; 58,2; 66,9; 104,2; 106,6; 115,2; 122,2; 125,1; 125,7; 125,8; 126,7; 127,2; 131,4; 132,2; 138,0; 154,7; 157,8; 158,2.
MS (%): 308 (roditelj+1; 100).
Anal. izrač. za C19H21N3O*1/4H2O: C 73,17; H 6,95; N 13,47.
Nađeno: C 73,18; H 7,00; N 13,43.
Primjer 13
6-(4-(2-pirolidin-1-il-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 69 % prinosu, tt 245-255 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,79 (bs, 4H); 2,685 (bs, 2H); 3,035 (t, J=6; 2H); 4,30 (t, J=6; 2H); 4,68 (bs, 2H, NH2); 6,41 (d, J=8; 1H); 6,82 (m, 2H); 7,4-7,6 (m, 4H); 8,10 (m, 1H); 8,31 (m, 1H).
13C-NMR (�, CDCl3): 23,6; 54,9; 55,0; 67,8; 104,2; 106,6; 115,1; 122,2; 125,0; 125,7; 125,8; 126,6; 127,3; 131,4; 132,2; 138,0; 154,7; 157,7; 158,2.
MS (%): 334 (roditelj+1; 100).
Anal. izrač. za C21H23N3O*2HCl*1/2(C4H10O): C 63,30; H 6,82; N 9,48.
Nađeno: C 62,23; H 6,41; N 9,56.
Primjer 14
6-(4-(2-((benzo(1,3)dioksol-5-ilmetil)-amino)-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 75 % prinosu, tt 60-80 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 3,12 (t, J=6; 2H); 3,81 (s, 2H); 4,25 (t, J=6; 2H); 5,91 (s, 2H); 6,41 (d, J=8; 1H); 6,7-6,8 (m, 4H); 6,89 (s, 1H); 7,4-7,5 (m, 4H); 8,10 (m, 1H); 8,28 (m, 1H).
13C-NMR (�, CDCl3): 47,9; 53,5; 67,7; 100,9; 104,4; 106,6; 108,1; 108,7; 115,1; 121,3; 122,0; 125,1; 125,7; 125,8; 126,7; 127,3; 131,5; 132,2; 134,1; 138,0; 146,6; 147,8; 154,6; 157,6; 158,3.
MS (%): 414 (roditelj+1; 100).
Anal. izrač. za C25H23N3O3*HCl*3/2H2O): C 62,96; H 5,71; N 8,81.
Nađeno: C 63,17; H 5,63; N 8,48.
Primjer 15
6-(4-(2-(6,7-dimetoksi-3,4-dihidro-1H-izokinolin-2-il)-etoksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 61 % prinosu, tt 130-150 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,83 (m, 2H); 2,90 (m, 2H); 3,105 (t, J=6; 2H); 3,74 (s, 2H); 3,78 (s, 3H); 3,80 (s, 3H); 4,37 (t, J=6; 2H); 4,69 (bs, 2H, NH2); 6,39 (d, J=8; 1H); 6,49 (s, 1H); 6,57 (s, 1H); 6,84 (m, 2H); 7,4-7,5 (m, 4H); 8,11 (m, 1H); 8,33 (m, 1H).
13C-NMR (�, CDCl3): 28,6; 51,6; 55,9; 56,1; 56,8; 67,0; 104,3; 106,6; 109,5; 111,3; 115,1; 122,2; 125,1; 125,7; 125,8; 125,9; 126,4; 126,7; 127,3; 147,2; 147,5; 154,6; 157,6; 158,2.
MS (%): 456 (roditelj+1; 100).
Anal. izrač. za C28H29N3O3*2HCl*H2O): C 61,54; H 5,71; N 6,09.
Nađeno: C 61,77; H 6,04; N 7,35.
Primjer 16
3-(2-(4-(6-amino-piridin-2-il)-naftalen-1-iloksi)-etil-biciklo(3,1,0)heks-6-2-ilamin
Dobiven kao u primjeru 12; u 63 % prinosu, (praćenjem faze deblokiranja sa trifluorooctenom kiselinom u metilen kloridu zbog uklanjanja t-butoksikarbonil zaštitne skupine); tt 140-155 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,35 (bs, 2H); 1,41 (s, 1H); 2,53 (bs, 2H); 2,93 (t, J=6; 2H); 3,11 (m, 4H); 4,185 (t, J=6; 2H); 4,67 (bs, 2H, NH2); 6,42 (d, J=8; 1H); 6,81 (m, 2H); 7,4-7,5 (m, 4H); 8,10 (m, 1H); 8,29 (m, 1H).
13C-NMR (�, CDCl3): 25,8; 32,6; 54,0; 55,6; 67,7; 104,2; 106,6; 115,2; 122,2; 125,1; 125,7; 125,9; 126,6; 127,3; 132,1; 133,7; 138,0; 154,7; 157,7; 158,2.
MS (%): 361 (roditelj+1; 100).
Anal. izrač. za C22H24N4O*2HCl*1/2(C4H10O): C 61,28; H 6,64; N 11,91.
Nađeno: C 61,89; H 6,44; N 11,83.
Primjer 17
6-(4-(2-(4-fenetil-1-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 78 % prinosu, tt 45-80 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,5-2,9 (m, 12H); 3,00 (t, J=6; 2H); 4,325 (t, J=6; 2H); 4,62 (bs, 2H); 6,47 (d, J=8; 1H); 6,84 (d, J-8 1H); 6,85 (d, J=7; 1H); 7,20 (m, 3H); 7,28 (m, 2H); 7,46 (m, 4H); 8,10 (m, 1H); 8,31 (m, 1H).
13C-NMR (�, CDCl3): 33,53; 53,14; 53,64; 57,135; 60,43; 66,61; 104,26; 106,49; 115,165; 122,10., 125,04; 125,43; 125,61; 125,94; 126,57; 127,15; 128,29; 128,61; 131,41; 132,40; 137,92; 140,23; 154,61; 157,67; 158,03.
MS (%): 453 (roditelj+1; 100).
Anal. izrač. za C29H32N4O*3HCl*3/2H2O)*(C4H10O): C 59,77; H 7,30; N 8,45. Nađeno: C, 59,42; H 7,19; N 8,05.
Primjer 18
6-(4-(2-(3-amino-pirolidin-1-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 59 % prinosu, tt 70-90 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,25 (m, 2H); 2,5 (m, 1H); 2,6 (m, 1H); 2,88 (m, 2H); 3,035 (t, J=6; 2H); 4,30 (t, J=6; 2H); 4,59 (bs, 2H); 6,47 (d, J=8; 1H); 6,85 (m, 2H); 7,4-7,6 (m, 4H); 8,09 (m, 1H); 8,31 (m, 1H).
13C-NMR (�, CDCl3): 35,14; 50,90; 53,95; 54,71; 64,63; 67,60; 104,19; 106,45; 115,21; 122,12; 125,00; 125,60; 126,54; 126,72; 127,16; 137,92; 142,45; 147,38; 154,66; 156,33; 157,92.
MS (%): 349 (roditelj+1; 100).
Anal. izrač. za C21H24N4O*2HCl*2(C4H10O)*1/3(CH2Cl2): C 58,92; H 7,87; N 9,37.
Nađeno: C 58,93; H 7,84; N 7,77.
Primjer 19
6-(4-(2-diizopropilamino-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 97,5 % prinosu, tt 70-90 °C, kao amorfna krutina.
1H-NMR (�, CDCl3): 1,09 (d, J=6,6; 12H); 3,01 (t, J=7; 2H); 3,11 (m, 2H); 4,12 (t, J=7; 2H); 5,62 (d, J=8; 1H); 6,86 (m, 2H); 7,47 (m, 4H); 8,14 (m, 1H); 8,35 (m, 1H).
13C-NMR (�, CDCl3): 20,94; 44,49; 49,61; 69,61; 104,27; 106,50; 115,22; 124,97; 125,70; 125,86; 126,59; 127,34; 131,20; 132,17; 137,98; 154,93; 157,90; 158,14.
MS (%): 364 (roditelj+1; 100).
HRMS izrač. za C23H30N3O: Nađeno: 364,2383.
Primjer 20
6-(4-(2-morfolin-4-il-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 60 % prinosu, kao amorfna krutina.
1H-NMR (�, CDCl3): 2,66 (m, 4H); 3,96 (t, J=6; 2H); 3,74 (m, 4H); 4,32 (t, J=6; 2H); 4,60 (bs, 2H); 6,48 (d, J=8; 1H); 6,86 (m, 2H); 7,46 (m, 4H); 8,11 (m, 1H); 8,30 (m, 1H).
13C-NMR (�, CDCl3): 54,10; 57,55; 66,54; 66,94; 104,32; 106,49; 115,19; 122,02; 125,07; 125,61; 125,78; 126,60; 127,13; 131,42; 132,10; 137,97; 154,56; 157,93.
MS (%): 350 (roditelj+1; 100).
Anal. izrač. za C21H23N3O2*1/4H2O: C 72,18; H 6,63; N 12,03.
Nađeno: C 71,62; H 6,67; N 11,69.
Primjer 21
6-(4-(2-piperidin-1-il-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 60 % prinosu, kao amorfna krutina kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,45 (m, 2H); 1,60 (m, 4H); 2,58 (m, 4H); 2,93 (t, J=6; 2H); 4,30 (t, J=6; 2H); 4,66 (bs, 2H); 6,38 (d, J=8; 1H); 6,82 (m, 2H); 7,45 (m, 4H); 8,11 (m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 24,19; 26,07; 55,05; 57,91; 66,66; 104,33; 106,54; 115,09; 122,2; 125,07; 125,75; 125,86; 126,62; 127,18; 131,46; 132,17; 137,94; 154,71; 157,75; 158,24.
MS (%): 348 (roditelj+1; 100).
Anal. izrač. za C22H25N3O*2HCl*3H2O*1/4(C4H10O): C 56,04; H 7,26; N 8,52.
Nađeno: C 56,20; H 7,11; N 8,27.
Primjer 23
6-(4-(2-(4-dimetilamino-piperidin-1-il-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 73 % prinosu, kao krutina kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,56 (m, 2H); 1,80 (m, 2H); 2,18 (m, 3H); 2,26 (m, 3H); 2,26 (s, 6H); 7,44 (m, 4H); 8,09 (m, 1H); 8,29 (m, 1H).
13C-NMR (�, CDCl3): 28,33; 29,70; 41,61; 53,65; 57,12; 62,11; 66,77; 76,76; 104,33; 106,51; 115,22; 122,15; 125,09; 125,70; 126,64; 127,23; 131,49; 132,15; 137,97; 154,65; 157,80; 158,08.
MS (%): 391 (roditelj+1; 100).
Anal. izrač. za C24H30N4O*3HCl*3H2O*1/2(C4H10O): C 52,84; H 7,50; N 9,48.
Nađeno: C 52,65; H 7,78; N 9,38.
HRMS izrač. za C24H31N4O: 391,2485.
Primjer 24
6-(4-(1-benzil-piperidin-4-iloksi)-naftalen-1-il)-piridin-2-ilamin
A. 4-bromo-1-fluoronaftalen
U bocu od 50 ml sa kružnim dnom opremljenom zgušnjivačem i N2 ulazom dodani su 3,75 ml (5,0 g, 34,25 mmol) 1-fluoronaftalena i 10 ml ugljik teteraklorida, praćeno sa dodavanjem ukapavanjem 1,7 ml (5,5 g., 34,375 mmol) broma tijekom 3 min. Reakcija je grijana na 50-60 °C dok je HBr razvijan tijekom 2 sata. Ostatak je otopljen u metanolu i držan na 0 °C. Poslije filtriranja sa hladnim metanolom, produkt sa tt bliskom sobnoj temperaturi, bio je 4,62 g (60 %) kao žuto ulje.
1H-NMR (�, CDCl3): 7,02 (t, J=8; 1H); 7,67-7,7 (m, 3H); 8,10 (d, J=8,5; 1H); 8,20 (d, J=8,5; 1H).
GCMS (%): 224/226 (roditelj, Br79/Br81 100).
B. 4-fluoronaftalen-1-borna kiselina
U bocu od 250 ml sa kružnim dnom sa 3 grlića opremljenom sa pregradom i N2 ulazom dodani su 4,62 g (20,53 mmol) 4-bromo-1-fluoronaftalena i 100 ml suhog teterahidrofurana. Otopina je ohlađena na -70 °C, i 15,4 ml (24,64 mmol) 1,6 M otopine butil litija u heksanu dodano je ukapavanjem tijekom 5 min. Reakcija je miješana na -70 °C tijekom 10 min, zatim je dodano 4,2 ml (3,59 g, 24,64 mmol) trietil borata, i reakcija je miješana na -70 °C tijekom 20 min i grijana na sobnoj temperaturi. Poslije miješanja preko noći na sobnoj temperaturi, reakcija je ugašena sa zasićenom vodenom otopinom amonij klorida, zakiseljena sa 1 N klorovodičnom kiselinom, i ekstrahirana u etil acetatu (dva puta). Kombiniran organski sloj je ispran sa slanom vodom, osušen preko natrij sulfata, i isparen. Ostatak je trituriran sa heksanom zbog dobivanja sasvim bijelog praha, 1,97 g (51 % - kao smjesa monoaril i diaril bornih kiselina).
1H-NMR (�, CDCl3): 7,2-7,4 (m, 1H); 7,5-7,7 (m, 3H); 8,0-8,5 (m, 1H); 8,5 i 9,2 (m, 1H).
APCI (-) (%): 189 (roditelj-1; 60)
C. 2-(2,5-dimetilpirolil)-6-(4-fluoro-naftil-1-il)piridin
U bocu od 50 ml sa kružnim dnom opremljenom zgušnjivačem i N2 ulazom dodani su 404 mg (2,13 mmol) 4-fluoronaftalen-1-borne kiseline, 534 mg (2,13 mmol) 2-(2,5-dimetilpirolil)-6-bromopiridina, 902 mg (8,51 mmol) natrij karbonata, 150 mg teterakistrifenilfosfina, 10 ml etanola, i 2 ml vode. Reakcija je refluksirana preko noći, ohlađena, sipana u vodu, i ekstrahirana u etil acetatu. Poslije kombiniranja sa drugim prolazom u većem opsegu, kombinirani organski sloj je ispran slanom vodom, osušen preko natrij sulfata, i isparen. Ostatak je kromatografiran na silika gelu korištenjem heksan/etil acetata kao eluanta zbog dobivanja 4,72 g (85 %) ulja.
1H-NMR (�, CDCl3): 2,25 (s, 6H); 5,92 (s, 2H); 7,1-7,2 (m, 2H); 7,4-7,6 (m, 4H); 7,95 (t, J=8; 1H); 8,12 (d, J=8; 1H); 8,19 (d, J=8; 1H).
13C-NMR (�, CDCl3): 13,41; 106,97; 108,82; 109,02; 120,18; 120,78; 120,84; 123,42; 123,81; 123,96; 125,48; 126,20; 127,32; 127,68; 127,76; 128,56; 132,35; 133,90; 138,22; 151,87; 157,82; 158,30; 160,34.
MS (%): 317 (roditelj+1; 100).
HRMS izrač. za C21H18N2F (roditelj+1): 317,1454.
Nađeno: 317,1462.
D. 2-(2,5-dimetilpirolil)-6-(4-((N-benzil)-4-pipridiniloksi)-naft-1-il)piridin
U bocu od 20 ml sa kružnim dnom opremljenom zgušnjivačem i N2 ulazom dodani su 121 mg (0,633 mml) 4-hidroksi-N-benzilpiperidina i 5 ml suhog dimetilformamida, praćeno sa 32 mg (0,791 mmol) natrij hidrida (60 % u ulju). Reakcija je grijana na 70 °C zbog osiguranja formiranja alkoksida, i zatim je dodano 100 mg (0,316 mmol) 2-(2,5-dimetilpirolil)-6-(4-fluoro-naft-1-il)piridina u 2 ml suhog dimetilformamida, i reakcija je grijana na 80°C tijekom 10 min. Reakcija je ohlađena, sipana u vodu, i ekstrahirana u etil acetatu. Poslije kombiniranja sa drugim prolazom u većem opsegu, kombinirani organski sloj je ispran slanom odom, osušen preko natrij sulfata, i isparen. Ostatak je kromatografiran na silika gelu korištenjem metanol/metilen klorida kao eluanta zbog dobivanja 489 mg (54 %) ulja.
1H-NMR (�, CDCl3): 2,04 (m, 2H); 2,10 (m, 2H); 2,25 (s, 6H); 2,44 (m 2H); 2,79 (m, 2H); 3,58 (s, 2H); 4,65 (m, 1H); 5,91 (s, 2H); 6,92 (d, J=8; 1H); 7,2-7,6 (m, 7H); 7,90 (t, J=8; 1H); 8,12 (m, 1H); 8,39 (m, 1H).
13C-NMR (�, CDCl3): 13,55; 30,69; 50,43; 63,19; 72,54; 105,94; 106,84; 119,72; 122,68; 123,50; 125,22; 126,69; 126,90; 127,08; 128,32; 128,67; 129,09; 129,19; 130,12; 132,22; 138,09; 138,40; 151,83; 153,75; 159,16.
MS (%): 488 (roditelj+1; 100).
HRMS izrač. za C33H34N3O (roditelj+1): 488,2702.
Nađeno: 488,2703.
E. 6-(4-(1-benzil-piperidein-4-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 121; u 93 % prinosu, tt 265-285 °C (dec.); kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,9-2,1 (m, 4H); 2,41 (m, 2H); 2,77 (m, 2H); 4,61 (m, 1H); 4,68 (bs, 2H, NH); 6,42 (d, J=8; 1H); 6,86 (m, 2H); 7,2-7,5 (m, 9H); 8,12 (m, 1H); 8,37 (m, 1H).
13C-NMR (�, CDCl3): 30,65; 50,37; 63,10; 72,53; 106,05; 106,49; 115,08; 122,37; 124,97; 125,67; 126,52; 126,70; 126,97; 127,12; 128,12; 129,11; 131,24; 132,38; 137,89; 138,35; 153,16; 157,66; 158,16.
MS (%): 410 (roditelj+1; 100).
Anal. izrač. za C27H27N3O*2HCl*5/3H2O: C 63,28; H 6,36; N 8,20.
Nađeno: C 63,18; H 6,40; N 7,88.
Primjer 25
6-(4-(1-benzil-pirolidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 98 % prinosu, tt 160-170 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,15 (m, 1H); 2,36 (m, 1H); 2,67 (m, 1H); 2,79 (m,1H); 2,87 (m, 1H); 3,12 (m, 1H); 3,69 (ABq, J=13; Dn=20; 2H); 4,74 (bs, 2H); 5,00 (m, 1H); 6,37 (d, J=8; 1H); 6,72 (d, J=8; 1H); 6,83 (d, J=8; 1H); 7,2-7,6 (m, 9H); 8,14 (m, 1H); 8,38 (m, 1H).
13C-NMR (�, CDCl3): 32,37; 52,84; 60,17; 60,35; 77,0; 105,32; 106,52; 114,95; 122,40; 125,02; 125,70; 126,11; 126,62; 127,03; 127,12; 128,28; 128,82; 131,33; 132,28; 137,88; 138,70; 153,59; 157,59; 158,26.
MS (%): 396 (roditelj+1; 100).
Anal. izrač. za C26H25N3O*2HCl*5/3H2O: C 62,65; H 6,13; N 8,43.
Nađeno: C 62,73; H 6,06; N 8,40.
Primjer 26
6-(4-(4-dimetilamino-butoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 71 % prinosu, tt 78-90 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,75 (m, 2H); 1,94 (m, 2H); 2,23 (s, 6H); 2,37 (m, 2H); 4,16 (t, J=6; 2H); 4,63 (bs, 2H); 6,43 (d, J=8; 1H); 6,83 (m, 2H); 7,4-7,6 (m, 4H); 8,08 (m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 24,33; 27,12; 45,31; 59,34; 67,90; 104,06; 106,44; 115,11; 122,09; 124,91; 125,57; 125,83; 126,49; 127,17; 131,12; 132,08; 137,88; 154,86; 157,73; 158,06.
MS (%): 336 (roditelj+1; 100).
Anal. izrač. za C21H25N3O*2HCl*1/2(H2CO3)*5/4H2O: C 55,91; H 6,66; N 9,10.
Nađeno: C 55,89; H 6,89; N 8,80.
Primjer 27
6-(4-(piperidin-4-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 88 % prinosu, tt 65-75 °C kao slobodna baza, i tt 205-220 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,80 (m, 2H); 2,01 (m, 2H); 2,72 (m, 2H); 3,12 (m, 2H); 4,59 (m, 1H); 4,71 (bs, 2H); 6,38 (d, J=8; 1H); 6,82 (m, 2H); 7,4-7,6 (m, 4H); 8,10 (m, 1H); 8,34 (m, 1H).
13C-NMR (�, CDCl3): 32,01; 43,63; 73,20; 106,09; 106,44; 114,95; 122,30; 124,94; 125,66; 126,49; 126,67; 127,05; 131,32; 132,35; 137,84; 153,03; 157,64; 158,19.
MS (%): 320 (roditelj+1; 100).
Anal. izrač. za C20H21N3O*3/4(C4H8O2)*1/2H2O: C 70,03; H 7,15; N 10,65.
Nađeno: C 70,30; H 6,70; N 10,99.
Primjer 28
6-(4-(pirolidin-3-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 75 % prinosu, tt 60-70 °C kao slobodna baza, i tt 180-200 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,05 (m, 2H); 2,87 (m, 1H); 3,05 (m, 1H); 3,14 (m, 1H); 3,25 (m, 1H); 4,73 (bs, 2H); 4,94 (m, 1H); 6,37 (d, J=8; 1H); 6,74 (d, J=8; 1H); 6,79 (d, J=7; 1H); 7,42 (m, 4H); 8,10 (m, 1H); 8,24 (m, 1H).
13C-NMR (�, CDCl3): 33,34; 46,13; 53,62; 76,81; 105,43; 106,43; 106,47; 114,91; 122,06; 124,98; 125,70; 126,13; 126,54; 127,00; 131,35; 132,23; 137,82; 153,29; 157,56; 158,23.
MS (%): 306 (roditelj+1; 100).
HRMS izrač. za C19H20N3O: 306,1606.
Nađeno: 306,1608.
Primjer 29
6-(4-(1-izobutil-piperidin-4-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 38 % prinosu, tt 198-210 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 0,92 (d, J=7; 6H); 1,81 (m, 1H); 2,01 (m, 2H); 2,12 (m, 2H); 2,16 (d, J=7; 2H); 2,39 (m, 2H); 2,75 (m, 2H); 4,59 (m, 3H); 6,46 (d, J=8; 1H); 6,87 (m, 2H); 7,4-7,6 (m, 4H); 8,09 (m, 1H); 8,33 (m, 1H).
13C-NMR (�, CDCl3): 20,92; 25,59; 30,46; 50,83; 66,81; 72,56; 106,06; 8106,42; 115,16; 122,30; 124,92; 125,63; 126,49; 126,70; 127,07; 131,24; 132,24; 132,33; 137,89; 153,14; 157,76; 158,00.
MS (%): 376 (roditelj+1; 100).
Anal. izrač. za C24H29N3O*2HCl*3/2H2O: C 60,63; H 7,21; N 8,84.
Nađeno: C 60,77; H 7,30; N 8,48.
Primjer 30
6-(4-(1-furan-2-ilmetil-piperidin-4-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 38 % prinosu, tt 178-195 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,07 (m, 4H); 2,48 (m, 2H); 2,76 (m, 2H); 3,59 (s, 2H); 4,5 (bs, 2H); 4,62 (m, 1H); 6,21 (m, 1H); 6,31 (m, 1H); 6,45 (d, J=8; 1H); 6,85 (m, 2H); 7,4-7,6 (m, 5H); 8,09 (m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 30,42; 49,93; 54,93; 72,00; 106,08; 106,44; 108,69; 109,98; 115,16; 122,30; 124,95; 125,61; 126,49; 126,70; 127,05; 131,29; 132,23; 137,89; 142,07; 151,74; 153,06; 157,73; 158,02.
MS (%): 400 (roditelj+1; 100).
Anal. izrač. za C25H25N3O2*2HCl*9/4H2O: C 58,54; H 6,19; N 8,19.
Nađeno: C 58,66; H 6,13; N 8,04.
Primjer 31
6-(4-(1-izobutil-pirolidin-3-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 45 % prinosu, tt 78-85 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 0,94 (d, J=7; 6H); 1,76 (m, 1H); 2,14 (m, 1H); 2,2-2,4 (m, 3H); 2,6-2,9 (m, 3H); 3,10 (m, 1H); 4,59 (bs, 2H); 5,03 (m, 1H); 6,45 (d, J=8; 1H); 6,75 (d, J=8; 1H); 6,85 (d, J=8; 1H); 7,4-7,6 (m, 4H); 8,10 (m, 1H); 8,33 (m, 1H).
13C-NMR (�, CDCl3): 20,35; 21,02; 27,31; 32,20; 53,31; 60,50; 64,82; 105,29; 106,42; 115,15; 122,37; 124,92; 125,56; 126,16; 126,56; 127,05; 131,20; 132,21; 137,88; 153,66; 157,73; 158,03.
MS (%): 362 (roditelj+1; 100).
HRMS izrač. za C23H28N3O: 362,2232.
Nađeno: 362,2217.
Primjer 32
6-(4-(1-furan-2-ilmetil-pirolidin-3-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 46 % prinosu, tt 140-160 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,15 (m, 1H); 2,38 (m, 1H); 2,7-2,9 (m, 3H); 3,21 (m, 1H); 3,72 (ABq, J=7; Dn=20; 2H); 4,60 (bs, 2H); 5,03 (m, 1H); 6,21 (m, 1H); 6,31 (m, 1H); 6,44 (d, J=8; 1H); 6,72 (d, J=8; 1H); 6,84 (d, J=7; 1H); 7,37 (m, 1H); 7,44 (m, 4H); 8,10 ((m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 32,34; 51,72; 52,53; 59,80; 76,70; 105,19; 106,47; 107,98; 110,03; 115,12; 122,37; 124,95; 125,57; 126,06; 126,59; 127,02; 131,30; 132,21; 137,89; 141,98; 152,21; 153,53; 157,67; 158,05.
MS (%): 386 (roditelj+1; 100).
Anal. izrač. za C24H23N3O2*2HCl*9/4H2O: C 57,78; H 5,96; N 8,42.
Nađeno: C 57,96; H 5,98; N 8,14.
Primjer 33
6-(4-(1-metil-piperidin-4-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 90 % prinosu, tt 179-187 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,00 (m, 4H); 2,26 (s, 3H); 2,33 (m, 2H); 2,645 (m, 2H); 4,54 (m, 1H); 4,76 (bs, 2H); 6,35 (d, J=8; 1H); 6,78 (d, J=7; 1H); 6,81 (d, J=8; 1H); 7,41 (m, 4H); 8,09 (m, 1H); 8,33 (m, 1H).
13C-NMR (�, CDCl3): 30,46; 46,13; 52,35; 71,64; 105,93; 106,51; 114,88; 122,27; 124,95; 125,66; 126,47; 126,59; 127,07; 131,26; 132,32; 137,84; 153,02; 157,47; 158,26.
MS (%): 334 (roditelj+1; 100).
Anal. izrač. za C21H23N3O*2HCl*H2O*(C4H8O): C 60,48; H 7,11; N 8,46.
Nađeno: C 60,19; H 7,61; N 9,94.
Primjer 34
6-(4-(1-metil-pirolidin-3-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 77 % prinosu, tt 138-145 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,10 (m, 1H); 2,35 (m, 1H); 2,395 (s, 3H); 2,55 (m, 1H); 2,79 (m, 1H); 2,89 (m, 1H); 2,99 (m, 1H); 4,69 (bs, 2H); 5,01 (m, 1H); 6,41 (d, J=8; 1H); 6,70 (d, J=8; 1H); 6,81 (d, J=8; 1H); 7,43 (m, 4H); 8,07 (m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 32,97; 42,10; 55,09; 62,34; 77,39; 105,13; 106,51; 115,04; 122,39; 124,94; 125,54; 126,03; 126,57; 126,99; 131,26; 132,21; 137,88; 153,53; 157,57; 158,15.
MS (%): 320 (roditelj+1; 100).
Anal. izrač. za C20H21N3O*2HCl*3H2O: C 53,82; H 6,55; N 9,41.
Nađeno: C 54,02; H 6,45; N 9,13.
Primjer 35
6-(4-(3-dimetilamino-propoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 91,5 % prinosu, tt 105-120 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 2,08 (m, 2H); 2,26 (s, 6H); 2,54 (t, J=7; 2H); 4,18 (t, J=6; 2H); 4,72 (bs, 2H); 6,40 (d, J=8; 1H); 6,81 (m, 2H); 7,45 (m, 4H); 8,08 (m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 27,47; 45,41; 56,52; 66,39; 104,16; 106,47; 115,01; 122,03; 124,91; 125,63; 125,77; 126,47; 127,20; 131,17; 132,08; 137,85; 154,78; 157,63; 158,17.
MS (%): 322 (roditelj+1; 100).
Anal. izrač. za C20H23N3O*2HCl*7/2H2O: C 52,52; H 7,05; N 9,19.
Nađeno: C 52,62; H 6,77; N 8,73.
Primjer 36
6-(4-(1-aza-biciklo(2,2,2)okt-3-iloksi-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 89 % prinosu, tt 220-228 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,41 (m, 1H); 1,54 (m, 1H); 1,71 (m, 1H); 2,09 (m, 1H); 2,27 (m,1H); 2,78 (m, 3H); 2,96 (m, 2H); 3,30 (m, 1H); 4,56 (m, 1H); 4,71 (bs, 2H); 6,39 (d, J=8; 1H); 6,70 (d, J=8; 1H); 6,81 (d, J=7; 1H); 7,43 (m, 4H); 8,09 (m, 1H); 8,32 (m, 1H).
13C-NMR (�, CDCl3): 19,61; 24,37; 25,15; 46,53; 47,33; 55,73; 73,44; 105,38; 106,47; 114,95; 122,07; 125,01; 125,73; 126,24; 126,54; 127,05; 131,29; 132,33; 137,84; 153,00; 157,56; 158,20.
MS (%): 346 (roditelj+1; 100).
Anal. izrač. za C22H23N3O*2HCl*5/2H2O: C 57,02; H 6,52; N 9,07.
Nađeno: C 57,07; H 6,27; N 8,88.
Primjer 37
6-(4-(2-dimetil-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
A. 4-bromo-5,6,7,8-teterahidro-1-benziloksinaftalen
U bocu od 250 ml sa kružnim dnom opremljenom sa lijevkom za dodavanje i N2 ulazom dodani su 2,96 g (20 mmol) 5,6,7,8-teterahidro-naftalen-1-ola i 50 ml 1,2-dikloroetana, i sa miješanjem otopine 9,64 g (20 mmol) tributilamonij tribromida u 30 ml 1,2-dikloroetana ukapavanjem tijekom 10 min. Poslije miješanja dodatnih 10 min na sobnoj temperaturi, otopina je isprana sa vodom, razrijeđenim vodenom otopinom natrij bisulfitom, i vodom, osušen preko natrij sulfata, i isparen. Smjesa produkta i tributilaminij bromida je korištena direktno.
1H-NMR (�, CDCl3): 1,70 (m, 4H); 2,56 (t, J=6; 2H); 2,61 (t, J=6; 2H); 7,02 (AB, 2H); 8,0 (bs, 1H, OH).
13C-NMR (�, CDCl3): 22,2; 22,9; 23,8; 30,5; 114,7; 126,6; 129,0; 136,7; 154,1.
Gornje ulje je otopljeno u 100 ml acetonitrila, i tretirano sa 3,57 ml (30 mmol) benzil bromida i 5,53 g (40 mmol) kalij karbonata, refluksirano 14 h. TLC je pokazao glavni spot na Rf=0,3 u 10 % metilen klorid/heksanu (sa benzil bromidom na Rf=0,4). Reakcija je ohlađena, sipana u razrijeđenu vodenu otopinu klorovodične kiseline/etil acetatu, i organski sloj je izdvojen, ispran vodom i slanom vodom, osušen preko natrij sulfata, i isparen. Ostatak je kromatografiran na silika gelu korištenjem metilen klorid/heksana kao eluanta zbog dobivanja 4,0 g (63 %) ulja.
1H-NMR (�, CDCl3): 1,77 (m, 4H); 2,75 (m, 4H); 5,045 (s, 2H); 6,62 (d, J=9; 1H); 7,3-7,5 (m, 6H).
13C-NMR (�, CDCl3): 22,2; 22,9; 24,0; 30,7; 69,9; 109,8; 116,7; 127,1; 127,9; 128,6; 129,1; 129,3; 137,2; 137,5; 155,6.
B. 5,6,7,8-teterahidro-1-benziloksinaftalen-4-borna kiselina
Dobiven kao u primjeru 12B kao bijela krutina poslije trituriranja sa heksanom, tt. 199-205 °C, u 72 % prinos.
1H-NMR (�, CDCl3): 1,72 (m, 4H); 2,70 (m, 4H); 5,005 (s, 2H); 6,66 (m, 1H); 7,01 (d, J=8; 1H); 7,2-7,4.
13C-NMR (�, CDCl3): 22,6; 22,9; 23,4; 30,0; 107,8; 125,9; 127,0; 127,6; 128,4; 131,1; 137,5; 140,8; 156,9.
C. 2-(2,5-dimetilpirolil)-6-(4-benziloksi-5,6,7,8-teterahidro-naftalen-1-il)-piridin
Dobiven kao u primjeru 12C u 100 % prinosu kao ulje.
1H-NMR (�, CDCl3): 1,81 (m, 2H); 1,91 (m, 2H); 2,29 (s, 6H); 2,93 (m, 4H); 5,19 (s, 2h); 6,02 (s, 2H); 6,91 (d, J=8; 1H); 7,21 (d, J=8; 1H); 7,32 (d, J=8; 1H); 7,4-7,6 (m, 6H); 7,89 (t, J=8; 1H).
13C-NMR (�, CDCl3): 13,5; 22,5; 23,0; 24,0; 28,9; 69,8; 106,8; 108,2; 119,6; 123,1; 126,8; 127,2; 127,8; 12,9; 128,6; 128,7; 132,8; 136,8; 137,6; 138,0; 151,4; 156,8; 160,4.
MS (%): 409 (roditelj+1; 100).
D. 2-(2,5-dimetilpirolil)-6-(4-hidroksi-5,6,7,8-teterahidro-naftalen-1-il)-piridin
Dobiven kao u primjeru 12D u 100 % prinosu kao krutina niske točke taljenja.
1H-NMR (�, CDCl3): 1,67 (m, 2H); 1,77 (m, 2H); 2,16 (s, 6H); 2,63 (m, 2H); 2,73 (m, 2H); 5,89 (s, 2H); 6,3 (bs, 1H, OH); 6,51 (d, J=8; 1H); 7,02 (d, J=8; 1H); 7,13 (d, J=8; 1H); 7,35 (d, J=8; 1H); 7,83 (t, J=8; 1H).
13C-NMR (�, CDCl3): 13,3; 22,3; 22,8; 23,3; 28,6; 106,6; 112,1; 119,7; 123,3; 124,2; 127,8; 128,7; 131,6; 138,1; 151,2; 154,4; 160,5.
MS (%): 319 (roditelj+1; 100).
E. 2-(2,5-dimetilpirolil)-6-(4-karboetoksimetoksi-5,6,7,8-teterahidro-naftalen-1-il)-piridin
Dobiven kao u primjeru 12E u 83,5 % prinosu kao ulje.
1H-NMR (�, CDCl3): 1,31 (t, J=7; 3H); 1,71 (m, 2H); 1,83 (m, 2H); 2,19 (s, 6H); 4,26 (q, J=7; 2H); 4,66 (s, 2H); 6,64 (d, J=8; 1H); 7,12 (d, J=8; 1H); 7,20 (d, J=8; 1H); 7,35 (d, J=8; 1H); 7,82 (t, J=8; 1H).
13C-NMR (�, CDCl3): 13,4; 14,2; 22,3; 22,9; 23,7; 28,7; 61,2; 65,5; 106,7; 107,8; 119,6; 123,0; 126,9; 127,7; 128,5; 133,4; 137,0; 138,1; 151,3; 156,0; 160,1; 169,0.
MS (%): 405 (roditelj+1; 100).
F. 2-(2,5-dimetilpirolil)-6-(4-karboksimetoksi-5,6,7,8-teterahidro-naftalen-1-il)-piridin
Dobiven kao u primjeru 12F u 100 % prinosu kao krutina, tt 199-206 °C
1H-NMR (�, CDCl3): 1,62 (m, 2H); 1,72 (m, 2H0; 2,08 (s, 6H); 2,66 (m, 2H); 2,75 (m, 2H); 4,56 (s, 2H); 5,81 (s, 2H); 6,58 (d, J=8; 1H); 7,09 (m, 2H); 7,31 (d, J=8; 1H); 7,80 (t, J=8; 1H).
13C-NMR (�, CDCl3): 12,95; 22,1; 22,6; 23,4; 28,4; 65,0; 106,5; 107,7; 119,9 123,3; 126,7; 127,4; 132,8; 136,6; 138,3; 151,1; 155,9; 160,1; 171,2.
MS (%): 377 (roditelj+1; 100).
G. 2-(2,5-dimetilpirolil)-6-(4-(N,N-dimetilkarboksamido)metoksi-5,6,7,8-teterahidro-naftalen-1-il)-piridin
Dobiven kao u primjeru 12G u 100 % prinosu kao ulje.
1H-NMR (�, CDCl3): 1,67 (m, 2H); 1,77 (m, 2H); 2,14 (s, 6H); 2,76 (m, 4H); 2,96 (s, 3H); 3,08 (s, 3H); 4,71 (s, 2H); 5,86 (s, 2H); 6,75 (d, J=8; 1H); 7,11 (d, J=8; 1H); 7,16 (d, J=8; 1H); 7,34 (d, J=8; 1H); 7,82 (t, J=8; 1H).
13C-NMR (�, CDCl3): 13,3; 22,2; 22,8; 23,6; 28,6; 35,7; 36,7; 67,7; 106,5; 107,7; 119,6; 122,9; 126,5; 127,8; 128,6; 133,2; 136,8; 138,0; 151,2; 155,9; 160,2; 168,1.
MS (%): 404 (roditelj+1; 100).
H. 2-(2,5-dimetilpirolil)-6-(4-(4-(N,N-dimetilaminoetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin
Dobiven kao u primjeru 12H u 93 % prinosu kao ulje.
1H-NMR (�, CDCl3): 1,69 (m, 2H); 1,78 (m, 2H); 1,78 (m, 2H); 2,16 (s, 6H); 2,36 (s, 6H); 2,73 (t, J=7; 2H); 2,78 (m, 4H); 4,11 (t, J=7; 2H); 5,88 (s, 2H); 6,74 (d, J=8; 1H); 7,11 (d, J=8; 1H); 7,20 (d, J=8; 1H); 7,36 (d, J=8; 1H); 7,81 (t, J=8; 1H).
13C-NMR (�, CDCl3): 13,3; 22,3; 22,9; 23,7; 28,7; 46,2; 58,4; 66,6; 106,6; 107,6; 119,5; 122,95; 126,5; 127,7; 128,6; 132,4; 136,6; 137,9; 151,2; 156,9; 160,35.
MS (%): 390 (roditelj+1; 100).
I. 6-(4-(N,N-dimetilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12l u 57 % prinosu kao hidrokloridna sol, tt 239-242 °C od metanol/izopropil etera.
1H-NMR (�, CDCl3): 1,64 (m, 2H); 1,71 (m, 2H); 2,33 (s, 6H); 2,67 (m, 4H); 2,74 (t, J=6; 2H); 4,07 (t, J=6; 2H); 4,55 (bs, 2H); 6,36 (d, J=8; 1H); 6,67 (d, J=8; 1H); 7,07 (d, J=8; 1H); 7,40 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,3; 22,8; 23,6; 28,1; 46,0; 58,2; 66,4; 106,0; 107,4; 114,3; 126,2; 126,8; 133,5; 136,2; 137,6; 156,3; 157,6; 158,8.
MS (%): 312 (roditelj+1; 100).
Anal. izrač. za C19H25N3O*2HCl*1/4H2O: C 58,69; H 7,13; N 10,81.
Nađeno C 58,72; H 7,14; N 10,79.
6-(4-(N,N-dimetilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin može se također dobiti slijedećim postupkom:
J. 4-bromo-1-(N,N-dimetilaminoetpksi)-5,6,7,8-teterahidro-naftalen
U bocu od 1 l sa kružnim dnom opremljenom zgušnjivačem i N2 ulazom dodani su 10,0 g (44 mmol) 4-bromo-5,6,7,8-teterahidro-naftalen-1-ola (primjer 37A); 19 g (130 mmol) 2-dimetilaminoetil klorid hidroklorid, 30,3 g (220 mmol) trituriranog kalij karbonata i 600 ml acetonitrila. Reakcija je refluksirana 60 sati, praćeno sa dodatnim dijelom klorida i nastavljeno je refluksiranje tijekom 24 sata. Reakcija je ohlađena, filtrirana i koncentrirana. Ostatak je kromatografiran na silika gelu korištenjem metanol/metilen klorida kao eluanta zbog dobivanja 8,55 g (65 %) kao svijetlo smeđe ulje.
1H-NMR (�, CDCl3): 1,72 (m, 4H); 2,33 (s, 6H); 2,63 (m, 2H); 2,68 (m, 2H); 2,73 (t, J=6; 2H); 4,01 (t, J=6; 2H); 6,53 (d, J=8; 1H); 7,28 (d, J=8; 1H).
13C-NMR (�, CDCl3): 22,1; 22,8; 23,7; 30,5; 46,0; 538,2; 66,6; 109,2; 116,4; 128,8; 129,2; 137,2; 155,6.
MS (%): 298/300 (roditelj+1).
K. 1-(N,N-dimetilaminoetoksi)-5,6,7,8-teterahidro-naftalen-1-borna kiselina
U bocu od 1 L sa kružnim dnom opremljenom pregradom i N2 ulazom dodani su 8,55 g (28,7 mmol) 4-bromo-1-(2-dimetilaminoetoksi)-5,6,7,8-teterahidro-naftalena i 300 ml suhog teterahidrofurana. Otopina je ohlađena na -70 °C, i dodano je 13,8 ml (34,4 mmol) od 2,5 M otopine butil litija u heksanu. Reakcija je miješana na -70 °C tijekom 1 h, zatim je dodano 5,9 ml (34,4 mmol) trietil borata, i reakcija je miješana na -70 °C tijekom 2 h i zagrijana na sobnu temperaturu tijekom noći. Reakcija je ugašena sa zasićenom vodenom otopinom amonij klorida i ekstrahirana 3 puta etil acetatom. Organski sloj je ispran slanom vodom, osušen preko natrij sulfata, i isparen. Ostatak je trituriran sa heksanom u bijelu krutinu, 6,3 g (83,5 %).
1H-NMR (�, CDCl3): 1,79 (m, 4H); 2,44 (s, 6H); 2,68 (m, 2H); 2,89 (m, 2H); 2,32 (m, 2H); 4,19 (m, 2H); 6,74 (d, J=8; 1H); 8,03 (d, J=8; 1H).
L. 2-(2,5-dimetilpirolil)-6-(4-(N,N-dimetilaminoetoksi)-5,6,7,8-teterahidro-naftalen-1-il-piridin.
U bocu od 500 ml sa kružnim dnom opremljenom zgušnjivačem i N2 ulazom dodani su 6,3 g (23,4 mmol) 1-(N,N-dimetilaminoetoksi)-5,6,7,8-teterahidro-naftalen-4-borne kiseline, 6,0 g (23,4 mmol) 6-bromo-2-(2,5-dimetilpirolil) piridina, 10,1 g (95,6 mmol) natrij karbonata, 552 mg teterakistrifenilfosfin paladija, 200 ml etanola i 20 ml vode. Reakcija je refluksirana tijekom 20 sati i filtrirana. Filtrat je koncentriran, uzet sa otopinom 1N natrij hidroksida, i ekstrahiran 3 puta u etil acetatu. Organski sloj je ispran sa zasićenom vodenom otopinom natrij bikarbonata i slanom vodom, osušen preko natrij sulfata i isparen. Ostatak je kromatografiran na silika gelu korištenjem metanol/metilen klorida kao eluanta zbog dobivanja 7,67 g (82 %) produkta kao ulje.
1H-NMR (�, CDCl3): 1,69 (m, 2H); 1,78 (m, 2H); 2,16 (s, 6H); 2,36 (s, 6H); 2,73 (t, J=7; 2H); 2,78 (m, 4H); 4,11 (t, J=7; 2H); 5,88 (s, 2H); 6,74 (d, J=8; 1H); 7,11 (d, J=8; 1H); 7,20 (d, J=8; 1H); 7,36 (d, J=8; 1H); 7,81 (t, J=8; 1H).
13C-NMR (�, CDCl3): 13,3; 22,3; 22,9; 23,7; 28,7; 46,2; 58,4; 66,6; 106,6; 107,6; 119,5; 122,95; 126,5; 127,7; 128,6; 132,4; 136,6; 137,9; 151,2; 156,9; 160,35.
MS (%): 390 (roditelj+1; 100).
Isti materijal je zatim konvertiran u 6-(4-(N,N-dimetilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin postupkom danim u primjeru 37l u 83 % prinosu.
Primjer 38
6-(4-(2-pirolidin-1-il-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 58 % prinosu, kao higroskopna krutina kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,64 (m, 2H); 1,74 (m, 2H); 1,77 (m, 4H); 2,62 (m, 4H); 2,68 (m, 4H); 2,89 (t, J=6; 2H); 4,10 (t, J=6; 2H); 4,52 (bs, 2H); 6,37 (d, J=8; 1H); 6,63 (d, J=8; 1H); 6,65 (d, J=8; 1H); 7,07 (d, J=8; 1H); 7,40 (t, J=8; 1H).
13C-NMR (�, CDCl3): 24,4; 22,9; 23,5; 23,7; 28,2; 54,9; 55,0; 67,4; 106,1; 107,5; 114,4; 126,3; 126,9; 133,5; 136,3; 137,7; 156,4; 157,7; 158,9.
MS (%): 338 (roditelj+1; 100).
Anal. izrač. za C21H27N3O*2HCl*3H2O: C 54,31; H 7,60; N 9,05.
Nađeno C 54,00; H 7,83; N 9,19.
Primjer 39
6-(4-(2-(tert-butil-metil-amino)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 93 % prinosu, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,08 (s, 9H); 1,64 (m, 2H); 1,74 (m, 2H); 2,325 (s, 3H); 2,68 (m, 4H); 2,79 (t, J=6; 2H); 4,01 (t, J=6; 2H); 6,37 (d, J=8; 1H); 6,64 (d, J=8; 1H); 6,68 (d, J=8; 1H); 7,08 (d, J=8; 1H); 7,41 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,44; 22,89; 23,72; 26,07; 28,24; 36,67; 50,50; 67,89; 106,05; 107,50; 114,52; 126,21; 126,88; 133,32; 136,19; 137,73; 156,56; 157,65; 158,97.
MS (%): 354 (roditelj+1; 100).
Anal. izrač. za C22H31N3O*2HCl*3H2O: C 55,00; H 8,18; N 8,75.
Nađeno C 55,00; H 8,18; N 8,57.
Primjer 40
6-(4-(2-diizopropilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 83 % prinosu, tt 50-60 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,04 (d, J=7; 8H); 1,65 (m, 2H); 1,75 (m, 2H); 2,69 (m, 4H); 2,83 (t, J=7; 2H); 3,05 (septet, J=7; 1H); 3,90 (t, J=7; 2H); 4,55 (bs, 2H); 6,38 (d, J=8; 1J); 6,65 (d, J=8; 1H); 6,70 (d, J=8; 1H); 7,09 (d, J=8; 1H); 7,42 (t, J=8; 1H).
13C-NMR (�, CDCl3): 20,79; 22,37; 22,81; 23,63; 28,16; 44,51; 49,42; 69,26; 105,99; 107,53; 114,39; 126,14; 126,79; 133,18; 136,12; 137,67; 156,51; 157,60; 158,88.
MS (%): 368 (roditelj+1; 100).
Anal. izrač. za C23H33N3O*2HCl*5/2H2O*(C4H10O): C 57,95; H 9,01; N 7,51.
Nađeno: C 57,74; H 8,62; N 7,25.
Primjer 41
6-(4-(2-dietilamino-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 42 % prinosu, kao higroskopna krutina kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,07 (t, J=7; 6H); 1,66 (m, 2H); 1,735 (m, 2H); 2,6-2,8 (m, 8H); 2,91 (t, J=6; 2H); 4,05 (t, J=6; 2H); 4,49 (bs, 2H); 6,39 (d, J=8; 1H); 6,65 (d, J=8; 1H); 6,69 (d, J=8; 1H); 7,09 (d, J=8; 1H); 7,43 (t, J=8; 1H).
13C-NMR (�, CDCl3): 11,92; 22,35; 22,80; 23,60; 25,28; 28,11; 47,78; 51,67; 66,62; 105,96; 107,43; 126,20; 126,77; 133,39; 136,20; 137,64; 156,43; 157,54; 158,91.
MS (%): 340 (roditelj+1; 100).
Primjer 42
6-(4-(2-(3,4-dihidro-1H-izokinolin-2-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 67 % prinosu, kao amorfna krutina kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,67 (m, 2H); 1,79 (m, 2H); 2,73 (m, 4H); 2,94 (m, 4H); 3,03 (t, J=6; 2H); 3,83 (s, 2H); 4,24 (t, J=6; 2H); 4,87 (bs, 2H); 6,37 (d, J=8; 1H); 6,65 (d, J=8; 1H); 6,74 (d, J=8; 1H); 7,0-7,2 (m, 5H); 7,43 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,39; 22,81; 23,73; 28,17; 28,82; 32,46; 51,37; 56,38; 56,86; 66,47; 106,47; 114,47; 125,56; 126,10; 126,14; 126,53; 126,95; 128,61; 133,25; 133,98; 134,47; 136,30; 137,84; 156,31; 157,79; 158,46.
MS (%): 400 (roditelj+1; 100).
HRMS izrač. za C26H30N3O: 400,2383.
Nađeno: 400,2389.
Primjer 43
6-(4-(2-piperidin-1-il--etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 93 % prinosu, kao pjena, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,42 (m, 2H); 1,58 (m, 6H); 1,74 (m, 2H); 2,51 (m, 4H); 2,67 (m, 4H); 2,79 (t, J=6; 2H); 4,10 (t, J=6; 2H); 4,535 (bs, 2H); 6,34 (d, J=8; 1H); 6,63 (d, J=8; 1H); 6,67 (d, J=8; 1H); 7,08 (d, J=8; 1H); 7,39 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,43; 22,87; 23,71; 24,18; 26,04; 28,23; 55,04; 58,01; 66,24; 106,05; 107,56; 114,37; 126,88; 133,55; 136,26; 137,70; 156,38; 157,72; 158,90.
MS (%): 352 (roditelj+1; 100).
Anal. izrač. za C22H23N3O*2HCl*2H2O*1/2(C4H10O): C 57,94; H 8,10; N 8,45.
Nađeno: C 58,25; H 7,78; N 8,69.
Primjer 44
6-(4-(2-morfoli-4-il-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 67 % prinosu, kao bijela amorfna krutina.
1H-NMR (�, CDCl3): 1,64 (m, 2H); 1,74 (m, 2H); 2,58 (m, 4H); 2,68 (m, 4H); 2,81 (t, J=6; 2H); 3,71 (m, 4H); 4,11 (t, J=6; 2H); 4,45 (bs, 2H); 6,39 (d, J=8; 1H); 6,66 (m, 2H); 7,09 (d, J=8; 1H); 7,43 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,39; 22,85; 23,72; 28,21; 54,16; 57,73; 66,26; 67,03; 106,12; 107,61; 114,53; 126,36; 126,88; 136,39; 137,80; 156,30; 157,57; 158,83.
MS (%): 354 (roditelj+1; 100).
Anal. izrač. za C21H27N3O2*1/2H2O: C 69,59; H 7,79; N 11,59.
Nađeno: C 69,61; H 7,51; N 11,56.
Primjer 45
6-(4-(2-7,8-dihidro-5H-(1,3)dioskolo(4,5-g)izokinolin-6-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 82 % prinosu, kao bijela amorfna krutina, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,65 (m, 2H); 1,76 (m, 2H); 2,72 (m, 4H); 2,84 (m, 4H); 2,98 (t, J=6; 2H); 3,69 (s, 2H); 4,20 (t, J=6; 2H); 4,52 (bs, 2H); 5,86 (s, 2H); 6,37 (d, J=8; 1H); 6,47 (s, 1H); 6,55 (s, 1H); 6,65 (d, J=8; 1H); 7,11 (d, J=8; 1H); 7,42 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,44; 22,89; 23,79; 28,25; 29,09; 51,47; 56,57; 56,87; 66,69; 100,59; 106,11; 106,47; 107,57; 108,43; 114,46; 126,31; 126,92; 127,04; 127,51; 133,65; 136,38; 137,76; 145,67; 146,03; 156,35; 157,68; 158,87.
MS (%): 444 (roditelj+1; 100).
Anal. izrač. za C27H29N3O3: C 73,11; H 6,59; N 9,47.
Nađeno: C 73,37; H 7,19; N 8,96.
HRMS izrač. za C27H30N3O3: 444,2287.
Nađeno: 444,2287.
Primjer 46
6-(4-(2-(4-metil-piperazin-1-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 100 % prinosu, kao amorfna krutina, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,62 (m, 2H); 1,72 (m, 2H); 2,26 (s, 3H); 2,4-2,8 (m, 12H); 2,81 (t, J=6; 2H); 4,09 (t, J=6; 2H); 4,50 (bs, 2H); 6,35 (d, J=8; 1H); 6,63 (m, 2H); 7,07 (d, J=8; 1H); 7,39 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,4; 22,9; 23,37; 28,2; 46,1; 53,37; 55,2; 57,3; 66,3; 106,1; 107,6; 114,4; 126,3; 126,9; 133,6; 136,3; 137,7; 156,3; 157,7; 158,9.
MS (%): 367 (roditelj+1; 100).
Anal. izrač. za C22H30N4O*3HCl*H2O*1/2(C4H10O): C 54,29; H 7,59; N 10,55.
Nađeno: C 54,20; H 7,59; N 10,50.
Primjer 47
6-(4-(2-(4-dimetilamino-piperidin-1-il)-etoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 92 % prinosu, kao amorfna krutina, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,54 (m, 2H); 1,64 (m, 2H); 1,64 (m, 2H); 1,77 (m, 4H); 2,12 (m, 3H); 2,26 (s,6H); 2,66 (m, 4H); 2,80 (t, J=6; 2H); 3,03 (m, 2H); 4,09 (t, J=6; 2H); 4,48 (bs, 2H); 6,37 (d, J=8; 1H); 6,64 (d, J=8; 1H); 6,67 (d, J=8; 1H); 7,07 (d, J=8; 1H); 7,41 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,32; 22,78; 23,61; 28,27; 41,56; 53,55; 57,15; 62,04; 66,31; 105,96; 107,51; 114,36; 126,23; 126,79; 133,52; 136,22; 137,62; 149,63; 156,25; 157,56; 158,85.
MS (%): 395 (roditelj+1; 100).
HRMS izrač. za C24H35N4O: C 395,2807.
Nađeno: C 395,2811.
Primjer 48
6-(4-(piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
A. 2-(2,5-dimetilpirolil)-6-(4-N-(4-toluensulfonil)-(pieridin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin
U bocu od 125 ml sa kružnim dnom opremljenu sa zgušnjivačem i N2 ulazom dodani su 2,0 g (6,3 mmol) 2-(2,5-dimetilpirolil)-6-(4-hidroksi-5,6,7,8-teterahidro-naftalen-1-il)-piridina, 4,0 g (9,4 mmol) 3-(hidroksimetil)-piperidina-di-p-tolensulfonata, 3,5 g (25,2 mol) kalij karbonata, i 60 ml suhog dimetilformamida. Reakcija je grijana na 140 °C tijekom 14 sati, ohlađena, i sipana u vodu. Smjesa je ekstrahirana sa etil acetatom, i organski sloj je ispran dobro sa vodom i slanom vodom, osušen preko natrij sulfata, i isparen. Ostatak je kromatografiran na silika gelu korištenjem heksan/etil acetata kao eluanta zbog dobivanja 3,1 g (86 %) bijele krutine.
1H-NMR (�, CDCl3): 1,25 (m, 2H); 1,67 (m, 4H); 1,77 (m, 4H); 2,15 (s, 6H); 2,42 (s, 3H); 2,66 (m, 2H); 2,76 (m, 2H); 3,6-3,9 (m, 5H); 5,87 (s, 2H); 6,66 (d, J=8; 1H); 7,12 (d, J=8; 1H); 7,18 (d, J=8; 1H); 7,3-7,4 (m, 3H); 7,63 (m,2H); 7,82 (t, J=8; 1H).
13C-NMR (�, CDCl3): 21,43; 22,19; 22,74; 23,53; 23,97; 26,44; 28,53; 35,74; 46,60; 49,30; 69,59; 106,48; 107,31; 119,42; 122,83; 126,39; 127,63; 128,55; 129,51; 132,52; 133,17; 136,62; 137,77; 143,34; 151,14; 156,50; 160,11.
MS (%): 570 (roditelj+1; 100).
B. 6-(4-N-(4-toluensulfonil)-(piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
U bocu od 500 ml sa kružnim dnom opremljenu sa zgušnjivačem i N2 ulazom dodani su 3,1 g (5,4 mmol) 2-(2,5-dimetilpirolil)-6-(4-(N-(4-toluensulfonil)-(piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridina, 7,6 g (100 mmol) hidroksilamin hidroklorida, 259 ml etanola, i 25 ml vode. Reakcija je refluksirana 5 dana, ohlađena, i isparena. Ostatak je uzet u etil acetatu i 1 N klorovodičnoj kiselini, i organski sloj je ispran sa dodatnim etil acetatom i podešen na pH 12 sa 6N otopinom natrij hidroksida, zatim ekstrahiran sa etil acetatom. Organski sloj je ispran sa slanom vodom, osušen preko natrij sulfata, i isparen zbog dobivanja 2,87 g (100 %) svijetlo smeđe pjene.
1H-NMR (�, CDCl3): 1,16 (m, 1H); 1,6-1,8 (m, 7H); 2,2-2,4 (m, 3H); 2,41 (s, 3H); 2,7 (m, 4H); 3,7-3,9 (, 4H); 4,51 (bs, 2H); 6,395 (d, J=8; 1H); 6,61 (d, J=8; 1H); 6,64 (d, J=8; 1H); 7,08 (d, J=8; 1H); 7,29 (m, 2H); 7,42 (t, J=8; 1H); 7,62 (m, 2H).
13C-NMR (�, CDCl3): 21,53; 22,39; 22,85; 23,62; 24,09; 26,52; 28,23; 35,84; 46,70; 49,43; 69,70; 106,19; 107,36; 114,43; 126,35; 127,73; 129,61; 133,16; 133,71; 136,44; 137,80; 143,42; 156,18; 157,67; 158,73.
MS (%): 492 (roditelj+1; 100).
C. 6-(4-(piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
U bocu sa 3 grlića sa kružnim dnom opremljenu sa zgušnjivačem, pregradom i N2 ulazom dodani su 4,5 g (33,6 mmol) aluminij klorida i 150 ml suhog 1,2-dimetoksietana. Reakcija je ohlađena na 0 °C, i dodano je 79 ml (79 mmol) 1,0 M otopine litij aluminij hidrida u teterahidrofuranu. Reakcija je miješana na sobnoj temperaturi tijekom 30 min, zatim je ohlađena na -70 °C, i otopina 2,77 g (5,6 mmol) 6-(4-(N-(4-toluensulfonil)-(piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamina u 150 ml suhog 1,2-dimetoksietana je dodana tijekom 10 min. Reakcija je miješana i zagrijana na sobnu temperaturu, zatim je grijana na refluksu tijekom 3 dana. Reakcija je ohlađena, ugašena pažljivo sa 1 N klorovodičnom kiselinom, zatim podešena na pH 12 sa 6 N otopinom natrij hidroksida. Smjesa je ekstrahirana sa nekoliko dijelova metilen klorida, i organski sloj je ispran sa vodenom otopinom natrij bikarbonata, osušen preko natrij sulfata, i isparen. Ostatak je kromatografiran korištenjem metanol/metilen klorid/trietilamina kao eluanta zbog dobivanja 784 mg (41,5 %) sasvim bijele krutine, koja je konvertirana u hidrokloridnu sol.
1H-NMR (�, CDCl3): 1,21 (m, 1H); 1,46 (m, 1H); 1,6-2,0 (m, 8H); 2,4-2,6 (m, 2H); 2,66 (m, 3H); 3,1 (m, 2H); 3,76 (m, 2H); 4,57 (bs, 2H); 6,35 (d, J=8; 1H); 6,60 (d, J=8; 1H); 6,63 (d, J=8; 1H); 7,39 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,4; 22,9; 23,6; 25,3; 27,6; 28,2; 36,6; 46,2; 49,3; 70,7; 106,2; 107,3; 114,4; 126,4; 126,8; 133,5; 137,8; 156,5; 157,8; 158,7.
MS (%): 338 (roditelj+1; 100).
Anal. izrač. za C21H27N3O*1/2H2O: C 72,80; H 8,15; N 12,13.
Nađeno: C 73,11; H 8,29; N 11,89.
Primjer 49
6-(4-(1-metil-piperidin-3-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 48; sa redukcionom aminacijem sa formaldehidom u mravljoj kiselini, u 84,5 % prinosu, kao žuta amorfna krutina, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,12 (m, 2H); 1,6-2,0 (m, 8H); 2,18 (m, 1H); 2,29 (s, 3H); 2,69 (m, 4H); 2,79 (m, 1H); 3,00 (m, 1H); 3,81 (m, 2H); 4,44 (bs, 2H); 6,40 (d, J=8; 1H); 6,65 (m, 2H); 7,08 (d, J=8; 1H); 7,43 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,32; 22,80; 23,54; 24,83; 26,71; 28,16; 36,45; 46,60; 56,13; 59,30; 70,68; 107,24; 114,49; 126,26; 126,74; 127,83; 133,29; 136,16; 137,68; 156,44; 157,49; 158,89.
MS (%): 352 (roditelj+1; 100).
HRMS izrač. za C22H30N3O: 352,2389.
Nađeno: 352,2365.
Primjer 50
6-(4-(1-izobutil-piperidin-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 48 sa redukcionom aminacijem sa izobutiraldehidom, u 5,7 % prinosu, kao svijetlo žuto-smeđa amorfni krutina, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 0,90 (d, J=6; 6H); 1,19 (m, 1H); 1,6-2,0 (m, 10H); 2,15 (m, 3H); 2,68 (m, 4H); 2,83 (m, 1H); 2,98 (m, 1H); 3,83 (m, 2H); 4,54 (bs, 2H); 6,41 (d, J=8; 1H); 6,65 (m, 2H); 7,08 (d, J=8; 1H); 7,435 (t, J=8; 1H).
13C-NMR (�, CDCl3): 20,99; 21,06; 22,42; 22,87; 23,61; 24,44; 25,36; 27,34; 28,22; 35,98; 54,48; 57,44; 67,05; 70,71; 106,19; 107,36; 114,54; 126,33; 126,86; 133,14; 136,24; 137,86; 156,58; 157,59; 158,82.
MS (%): 394 (roditelj+1; 100).
HRMS izrač. za C25H36N3O: C 394,2858.
Nađeno: C 394,2893.
Primjer 51
6-(4-(2-(7,8-dihidro-5H-(1,3)dioksolo(4,5-g)izohonolin-6-il)-etoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 12; u 65 % prinosu, kao amorfna krutina.
1H-NMR (d, CDCl3): 2,85 (m, 2H); 2,93 (m, 2H); 3,15 (t, J=6; 2H); 3,77 (s, 2H); 4,415 (t, J=6; 2H); 4,56 (bs, 2H); 5,87 (s, 2H); 6,48 (s, 1H); 6,51 (d, J=8; 1H); 6,56 (s, 1H); 6,88 (m, 2H); 7,4-7,6 (m, 4H); 8,10 (m, 1H); 8,31 (m, 1H).
13C-NMR (d, CDCl3): 28,9; 51,4; 566,4; 56,6; 66,8; 100,5; 104,3; 106,4; 106,5; 108,3; 115,3; 122,1; 125,1; 125,6; 125,8; 126,8; 127,2; 131,3; 132,1; 138,0; 145,7; 146,0; 154,6; 157,6; 157,8.
MS (%): 440 (roditelj+1; 100).
HRMS izrač. za C27H26N3O: 440,1974.
Nađeno: 440,1971.
Primjer 52
6-(7-(2-dimetilamino-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; polazeći sa 1-indanolom, u 57 % prinosu, tt 215-218 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 2,00 (quin, J=6; 2H); 2,32 (s, 6H); 2,72 (t, J=6; 2H); 2,86 (t, J=7; 2H); 3,06 (t, J=7; 2H); 4,10 (t, J=6; 2H); 4,63 (bs, 2H); 6,32 (d, J=8; 1H); 6,71 (d, J=8; 1H); 6,76 (d, J=8; 1H); 7,39 (m, 2H).
13C-NMR (d, CDCl3): 25,31; 29,56; 33,78; 46,07; 58,24; 66,46; 106,02; 109,34; 112,88; 127,97; 129,99; 132,66; 137,80; 144,30; 155,24; 157,34; 158,08.
MS (%): 298 (roditelj+1; 100).
Anal. izrač. za C18H23N3O*2HCl*1/2H2O: C 56,99; H 6,91; N 11,08.
Nađeno: C 56,59; H 6,93; N 11,01.
Primjer 53
6-(7-(2-diizopropilamino-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 63 % prinosu, kao žutosmeđ amorfni krutina, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 1,06 (d, J=6; 12H); 2,02 (quin, J=7; 2H); 2,875 (m, 4H); 3,10 (m, 4H); 3,98 (m, 2H); 4,52 (bs, 2H); 6,35 (d, J=8; 1H); 6,74 (d, J=8; 1H); 6,80 (d, J=8; 1H); 7,41 (m, 2H).
13C-NMR (d, CDCl3): 20,71; 25,33; 29,56; 33,81; 44,65; 49,86; 68,95; 105,94; 109,31; 112,99; 127,99; 129,76; 132,48; 137,83; 144,27; 155,45; 157,94.
MS (%): 354 (roditelj+1; 100).
Anal. izrač. za C22H31N3O*2HCl*H2O*1/2(C4H10O): C 59,87; H 8,37; N 8,73.
Nađeno: C 59,69; H 8,19; N 8,75.
Primjer 54
6-(7-(2-morfolin-4-il-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 93 % prinosu, žutosmeđa amorfna krutina.
1H-NMR (d, CDCl3): 2,0 (quin, J=7; 2H); 2,58 (m, 4H); 2,79 (t, J=6; 2H); 2,86 (t, J=7; 2H); 3,09 (t, J=7; 2H); 3,71 (m, 4H, 4,14 (t, J=6; 2H); 4,57 (bs, 2H); 6,33 (d, J=8; 1H); 6,72 (d, J=8; 1H); 6,79 (d, J=8; 1H); 7,40 (m, 2H).
13C-NMR (d, CDCl3): 25,20; 29,50; 33,73; 54,10; 57,56; 66,18; 66,92; 105,89; 109,33; 112,81; 127,91; 130,07; 132,59; 137,71; 144,29; 155,04; 157,26; 157,95.
MS (%): 340 (roditelj+1; 100).
Anal. izrač. za C20H25N3O2: C 70,77; H 7,42; N 12,38.
Nađeno: C 70,49; H 7,58; N 12,02.
Primjer 55
6-(7-(2-(7,8-dihidro-5H-(1,3)dioksolo(4,5-g)izokinolin-6-il)-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 81 % prinosu, kao pjena.
1H-NMR (d, CDCl3): 2,04 (quin, J=7; 2H); 2,8-3,0 (m, 8H); 3,11 (t, J=7; 2H); 3,70 (s, 2H); 4,24 (t, J=6; 2H); 4,63 (bs, 2H); 5,86 (bs, 2H); 6,35 (d, J=8; 1H); 6,48 (s, 1H); 6,55 (s, 1H); 6,76 (d, J=8; 1H); 6,81 (d, J=8; 1H); 7,4-7,5 (m, 2H).
13C-NMR (d, CDCl3): 25,25; 28,83; 29,56; 33,75; 51,24; 56,29; 56,46; 66,49; 100,52; 105,99; 106,39; 108,34; 109,30; 112,86; 126,89; 127,28; 127,98; 129,88; 132,59; 137,82; 144,32; 145,63; 145,99; 155,12; 157,13; 157,87.
MS (%): 430 (roditelj+1; 100).
HRMS izrač. za C26H28N3O3: 430,2160.
Nađeno: 430,2131.
Primjer 56
6-(7-(2-(4-metil-piperazin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 81 % prinosu, kao žutosmeđ krutina, tt > 205 °C. kao hidrokloridna sol.
1H-NMR (d, CDCl3): 2,00 (quin, J=7; 2H); 2,26 (s, 3H); 2,4-2,7 (m, 8H); 2,8-2,9 (m, 4H); 3,08 (t, J=7; 2H); 4,13 (t, J=6; 2H); 4,49 (bs, 2H); 6,34 (d, J=8; 1H); 6,71 (d, J=8; 1H); 6,79 (d, J=8; 1H); 7,40 (t, J=8; 1H).
13C-NMR (d, CDCl3): 25,20; 29,46; 33,72; 45,96; 53,55; 55,04; 57,08; 66,24; 105,85; 109,32; 112,86; 127,86; 129,97; 132,61; 137,69; 144,23; 155,08; 157,31; 157,87.
MS (%): 353 (roditelj+1; 100).
HRMS izrač. za C21H29N4O: 353,2345.
Nađeno: 353,2341.
Primjer 57
6-(7-(2-(tert-butil-metil-amino)-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 96 % prinosu, tt pjena na 110 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 1,10 (s, 9H); 2,005 (quin, J-7; 2H); 2,34 (s, 3H); 2,81 (t, J=7; 2H); 2,87 (t, J=7; 2H); 3,07 (t, J=7; 2H); 4,09 (t, J=7; 2H); 4,79 (bs, 2H); 6,34 (d, J=8; 1H); 6,75 (m, 2H); 7,40 (m, 2H).
13C-NMR (d, CDCl3): 14,11; 25,26; 25,89; 29,47; 32,51; 33,65; 36,50; 50,31; 67,47; 106,04; 109,13; 112,84; 128,01; 129,50; 132,33; 137,81; 144,07; 155,34; 156,10; 157,24; 158,05.
MS (%): 340 (roditelj+1; 100).
HRMS izrač. za C21H30N3O: 340,2381.
Nađeno: 340,2389.
Primjer 58
6-(7-(2-dimetilamino-piperidin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 100 % prinosu, kao amorfna krutina, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 1,60 (m, 2H); 1,82 (m, 3H); 2,00 (quin, J=7; 2H); 2,13 (M, 2H); 2,27 (s, 6H); 2,80 (t, J=6; 2H); 2,85 (t, J=7; 2H); 3,06 (t, J=7; 2H); 4,15 (t, J=6; 2H); 4,75 (bs, 2H); 6,35 (d, J=8; 1H); 6,72 (d, J=8; 1H); 6,76 (d, J=8; 1H); 7,405 (m, 2H).
13C-NMR (d, CDCl3):25,22; 27,83; 29,47; 32,47; 33,63; 41,37; 53,51; 56,96; 51,98; 66,14; 106,04; 109,30; 112,86; 127,99; 129,77; 132,49; 137,81; 144,16; 155,09; 155,91; 157,20; 158,00.
MS (%): 381 (roditelj+1; 100).
HRMS izrač. za C23H33N4O: 381,2669.
Nađeno: 381,2654.
Primjer 59
6-(7-(2-pirolidin-1-il-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 72 % prinosu, tt 113-117 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 1,77 (m, 4H); 2,01 (quin, J=7; 2H); 2,62 (m, 4H); 2,89 (m, 4H); 3,08 (t, J=7; 2H); 4,15 (t, J=6; 2H); 4,52 (bs, 2H); 6,34 (d, J=8; 1H); 6,73 (d, J=8; 1H); 6,79 (d, J=8; 1H); 7,40 (m, 4H).
13C-NMR (d, CDCl3): 23,53; 25,30; 29,57; 33,78; 54,88; 54,98; 67,37; 105,94; 109,36; 112,99; 127,97; 129,94; 132,65; 137,80; 144,28; 155,27; 157,45; 157,95.
MS (%): 324 (roditelj+1; 100).
Anal. izrač. za C20H25N3O*2HCl*3/2H2O: C 56,74; H 7,14; N 9,92.
Nađeno: C 56,40; H 7,07; N 9,84.
Primjer 60
6-(7-(2-(N-benzil, N-metil-amino)-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 48 % prinosu, tt 110-130 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 2,045 (quin, J=7; 2H); 2,37 (s, 3H); 2,87 (t, J=6; 2H); 2,92 (t, J=7; 2H); 3,13 (t, J=7; 2H); 3,65 (s, 2H); 4,16 (t, J=6; 2H); 4,65 (bs, 2H); 6,34 (d, J=8; 1H); 6,74 (d, J=8; 1H); 6,82 (d, J=8; 1H); 7,2-7,6 (m, 7H).
13C-NMR (d, CDCl3): 25,37; 29,67; 33,86; 43,04; 55,84; 62,74; 66,54; 106,04; 109,25; 112,94; 127,07; 128,04; 128,32; 129,98; 132,62; 137,84; 139,06; 144,34; 155,34; 157,42; 158,13.
MS (%): 374 (roditelj+1; 100).
Anal. izrač. za C24H27N3O*2HCl: C 64,57; H 6,55; N 9,41.
Nađeno: C 64,52; H 6,88; N 9,38.
Primjer 61
6-(7-((4-fenetilpiperazin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 41 % prinosu, tt 105-130 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 1,995 (quin, J=7; 2H); 2,5-2,9 (m, 16H); 3,08 (t, J=7; 2H); 4,13 (t, J=6; 2H); 4,61 (bs, 2H); 6,30 (d, J=8; 1H); 6,70 (d, J-8; 1H); 6,76 (d, J=8; 1H); 7,2-7,5 (m, 7H).
13C-NMR (d, CDCl3): 25,31; 29,57; 33,60; 33,82; 53,20; 53,69; 57,22; 60,55; 66,27; 105,95; 109,35; 112,82; 126,02; 128,37; 128,66; 128,69; 130,07; 132,62; 137,76; 140,29; 144,30; 155,17; 157,34; 158,10.
MS (%): 443 (roditelj+1; 100).
Anal. izrač. za C28H34N4O*2HCl: C 65,24; H 7,04; N 10,87.
Nađeno: C 65,03; H 7,23; N 10,81.
Primjer 62
6-(7-((4-izobutilpiperazin-1-il)-etoksi)-indan-4-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 92 % prinosu, tt 170-190 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 0,85 (d, J=6; 6H); 1,73 (m, 1H); 2,0 (m, 2H); 2,04 (d, J=7; 2H); 2,40 (m, 4H); 2,60 (m, 4H); 2,79 (t, J=7; 2H); 2,84 (t, J=7; 2H); 3,07 ((t, J=7; 2H); 4,13 (t, J=6; 2H); 4,57 (bs, 2H); 6,32 (d, J=8; 1H); 6,70 (d, J=8; 1H); 6,76 (d, J=8; 1H); 7,38 (m, 2H).
13C-NMR (d, CDCl3): 25,16; 25,28; 29,45; 33,69; 53,47; 53,70; 57,16; 66,22; 66,84; 105,82; 109,32; 112,79; 127,88; 129,96; 132,56; 137,65; 144,20; 155,12; 157,33; 157,92.
MS (%): 395 (roditelj+1; 100).
Anal. izrač. za C24H34N4O*3HCl*H2O: C 55,23; H 7,53; N 10,73.
Nađeno: C 55,51; H 7,72; N 10,46.
Primjer 63
6-(4-(2-amino-cikloheksiloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; u 96 % prinosu, tt 218-230 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 1,36 (m, 4H); 1,76 (m, 2H); 2,0-2,4 (m, 2H); 3,05 (m, 1H); 4,10 (m, 1H); 4,62 (bs, 2H); 6,45 (d, J=8; 1H); 6,93 (d, J=8; 1H); 7,4-7,6 (m, 4H); 8,08 (m, 1H); 8,32 (m, 1H).
13C-NMR (d, CDCl3): 24,30; 24,49; 29,60; 33,36; 54,87; 83,58; 106,14; 106,51; 115,12; 122,07; 125,00; 125,71; 126,50; 126,57; 127,12; 131,32; 132,28; 137,94; 153,86; 157,64; 158,05.
MS (%): 334 (roditelj+1; 100).
Anal. izrač. za C21H23N3O*2HCl*1/4H2O*1/2(C4H8O): C 60,73; H 6,54; N 9,24.
Nađeno: C 60,63; H 6,58; N 9,10.
Primjer 64
6-(4-(piperidin-3-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 38 % prinosu, tt 164-185 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 1,2-1,4 (m, 1H); 1,54 (m, 1H); 1,69 (m, 1H); 1,91 (m, 1H); 2,07 (m, 1H); 2,45 (m, 1H); 2,55 (m, 1H); 2,8-3,0 (m, 1H); 3,04 (m, 1H); 3,25 (m, 1H); 3,92 (m, 2H); 4,71 (bs, 2H); 6,43 (d, J=8; 1H); 6,78 (d, J=8; 1H); 6,82 (d, J=8; 1H); 7,4-7,6 (m, 4H); 8,08 (m, 1H); 8,29 (m, 1H).
13C-NMR (d, CDCl3): 25,72; 27,81; 36,93; 46,67; 49,84; 71,04; 103,97; 106,55; 115,05; 122,04; 125,02; 125,60; 125,73; 126,60; 127,17; 131,17; 132,05; 137,95; 154,79; 157,60; 158,13.
MS (%): 334 (roditelj+1; 100).
Anal. izrač. za C21H23N3O*2HCl*1/2H2O*1/4(C4H8O): C 60,41; H 6,45; N 9,61.
Nađeno: C 60,33; H 6,50; N 9,28.
Primjer 65
6-(4-(1-izobutil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 57 % prinosu, tt 133-148 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 0,91 (d, J=6; 6H); 1,65 (septet, J=6; 1H); 2,37 (d, J=7; 2H); 3,18 (m, 2H); 3,98 (m, 2H); 4,56 (bs, 2H); 5,01 (m, 1H); 6,47 (d, J=8; 1H); 6,59 (d, J=8; 1H); 6,84 (d, J=8; 1H); 7,3-7,5 (m, 4H); 8,09 (m, 1H); 8,30 (m, 1H).
13C-NMR (d, CDCl3): 20,89; 27,19; 62,17; 67,03; 68,54; 104,60; 106,61; 115,26; 122,16; 125,20; 125,73; 126,78; 127,05; 131,87; 132,25; 138,25; 138,04; 152,89; 157,70; 158,04.
MS (%): 348 (roditelj+1; 100).
Anal. izrač. za C22H25N3O*2HCl*1/2H2O*(C4H8O): C 60,35; H 7,01; N 8,12.
Nađeno: C 60,50; H 7,05; N 8,00.
Primjer 66
6-(4-(8-metil-8-aza-biciklo(3,2,1)okt-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 93 % prinosu, tt 260-275 °C, kao hidrokloridna sol.
1H-NMR (d, CDCl3): 2,0-2,3 (m, 8H); 2,305 (s, 3H); 3,15 (m, 2H); 4,59 (bs, 2H); 4,75 (m, 1H); 6,43 (d, J=8; 1H); 6,79 (d, J=8; 1H); 7,4-7,6 (m, 4H); 8,09 (m, 1H); 8,29 (m, 1H).
13C-NMR (d, CDCl3): 25,81; 35,97; 40,52; 59,84; 69,09; 104,46; 106,38; 115,09; 122,16; 125,00; 125,70; 126,31; 126,47; 127,12; 130,74; 132,39; 137,89; 153,06; 157,79; 158,00.
MS (%): 360 (roditelj+1; 100).
Anal. izrač. za C23H25N3O*1/2(CO2) (npr., 1/2 karboksilata): C 73,99; H 6,61; N 11,02.
Nađeno: C 74,00; H 6,65; N 10,85.
Primjer 67
6-(4-(1-furan-2-ilmetil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 50 % prinosu, tt 75-90 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 3,34 (m, 2H); 3,71 (s, 2H); 3,97 (m, 2H); 4,58 (bs, 2H); 5,01 (m, 1H); 6,20 (m, 1H); 6,30 (m, 1H); 6,48 (d, J=8; 1H); 6,57 (d, J=8; 1H); 6,84 (d, J=7; 1H); 7,3-7,5 (m, 5H); 8,09 (m, 1H); 8,30 (m, 1H).
13C-NMR (�, CDCl3): 54,99; 61,12; 66,84; 104,54; 106,57; 107,86; 110,06; 115,18; 122,07; 125,15; 125,63; 126,72; 126,95; 131,79; 132,16; 138,01; 142,28; 151,47; 152,74; 157,49; 157,90.
MS (%): 372 (roditelj+1; 100).
HRMS izrač. za C23H22N4O2: 372,1712.
Nađeno: 372,1690.
Primjer 68
6-(4-(pirolidin-2-ilmetoksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 48 korištenjem R-N-t-BOC-pirolidin-2-metanola, praćeno sa konverzijom u tozilat i alkiliranjem sa 2-(2,5-dimetilpirolil)-6-(4-hidroksi-5,6,7,8-teterahidro-naftalen-1-il)-piridinom, zatim deblokiranjem zbog dobivanja žutosmeđe amorfne krutine, u 95 % prinosu, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 1,63 (m, 3H); 1,74 (m, 4H); 1,90 (m, 1H); 2,68 (m, 4H); 2,96 (AB, 2H); 3,50 (m, 1H); 3,90 (m, 2H); 4,56 (bs, 2H); 6,37 (d, J=8; 1H); 6,63 (d, J=7; 1H); 6,67 (d, J=8; 1H); 7,07 (d, J=8; 1H); 7,40 (t, J=8; 1H).
13C-NMR (�, CDCl3): 22,31; 22,77; 23,57; 25,28; 27,91; 28,13; 46,50; 57,42; 70,65; 106,06; 107,50; 114,32; 126,16; 126,80; 136,22; 137,67; 156,28; 157,63; 158,72.
MS (%): 324 (roditelj+1; 100).
HRMS izrač. za C20H26N3O: 324,2076.
Nađeno: 324,2055.
Primjer 69
6-(4-(1-metil-pirolidin-2-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; korištenjem S-(-)-1-metil-pirolidin metanola zbog dobivanja, poslije deblokiranja u 88 % prinosu, žutosmeđeg krutine, tt 80-95 °C, �D = -36,47 ° (c=1; CH2Cl2).
1H-NMR (�, CDCl3): 1,8 (m, 2H); 1,9 (m, 1H); 2,12 (m, 1H); 2,34 (m, 1H); 2,56 (s, 3H); 2,83 (m, 1H); 3,13 (m, 1H); 4,13 (AB, 2H); 4,63 (bs, 2H); 6,41 (d, J=8; 1H); 6,83 (m, 2H); 7,46 (m, 4H); 8,10 (m, 1H); 8,31 (m, 1H).
13C-NMR (�, CDCl3): 23,00; 28,92; 41,87; 57,79; 64,27; 71,57; 104,06; 106,45; 115,09; 122,07; 124,97; 125,64; 125,73; 126,01; 126,53; 127,20; 131,29; 132,06; 137,89; 154,78; 157,69; 158,07.
MS (%): 334 (roditelj+1; 100).
Anal. izrač. za C21H23N3O*1/3H2O: C 74,31; H 7,03; N 12,38.
Nađeno: C 74,11; H 7,19; N 12,22.
Primjer 70
6-(4-(2-amino-cikloheksiloksi)-5,6,7,8-teterahidro-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 48; preko slijedeće sekvence od 4-faze: 2-(2,5-dimetilpirolil)-6-(4-hidroksi-5,6,7,8-teterahidro-naftalen-1-il)-piridin prvo se alkilira sa 2-klorocikloheksanonom, korištenjem kalij karbonata kao baze i sa katalitičkom količinom natrij jodida, u dimetilformamidu na 80 °C tijekom 24 sata, u 92 % prinosu. Rezultirajući keton je konvertiran u oksim metil eter korištenjem O-metilhidroksilamin hidroklorida i trietilamina u metanolu na refluksu tijekom 16 h u 81 % prinosu. Oksim eter je zatim reduciran u amin korištenjem bor metil sulfida u teterahidrofuranu na refluksu tijekom 2 dana, praćeno sa refluksiranjem u etanolu sa natrij karbonatom i cezij fluoridom tijekom 16 sati, u 12 % prinosu. Amin je zatim deblokiran sa hidroksilamin hidrokloridom u refluksirajućem etanolu otopljenom u vodi zbog dobivanja željenog finalnog produkta u 89 % prinosu kao žuto-smeđe krutine poslije konverzije hidrokloridne soli.
1H-NMR (�, CDCl3): 1,2-1,5 (m, 6H); 1,6-1,9 (m, 6H); 2,70 (m, 4H); 2,94 (m, 1H); 4,49 (m, 1H); 4,55 (bs, 2H); 6,39 (d, J=8; 1H); 6,65 (d, J=8; 1H); 6,72 (d, J=8; 1H); 7,07 (d, J=8; 1H); 7,43 (t, J=8; 1H).
13C-NMR (�, CDCl3): 20,3; 22,4; 22,37; 23,7; 23,9; 27,4; 28,2; 30,9; 52,1; 75,8; 106,1; 108,6; 114,4; 126,8; 127,0; 133,1; 136,5; 137,7; 154,9; 157,6; 158,7.
MS (%): 338 (roditelj+1; 100).
HRMS izrač. za C21H28N3O: 338,2232.
Nađeno: 338,2256.
Primjer 71
6-(4-(azetidin-2-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; korištenjem L-azetidin-2-karboksilne kiseline kao prekursora u N-t-BOC-azetidin-2-metanolu kao reagensu zbog dodavanja 2-(2,5-dimetilpirolil)-6-(4-fluoro-naft-1-il)piridina sa uklanjanjem skupina blokiranja zbog dobivanja 45 % prinosa krutine, tt 135-150 °C.
1H-NMR (�, CDCl3): 2,33 (m, 1H); 2,43 (m, 1H); 3,4 (bs, 1H); 3,54 (m, 1H); 3,67 (m, 1H); 4,20 (m, 2H); 4,37 (m, 1H); 4,625 (bs, 2H); 6,45 (d, J=8; 1H); 6,84 (m, 2H); 7,45 (m, 4H); 8,10 (m, 1H); 8,31 (m, 1H).
13C-NMR (�, CDCl3): 29,93; 44,25; 57,45; 72,10; 104,39; 106,54; 115,15; 122,00; 125,04; 125,63; 125,73; 126,63; 127,15; 131,50; 132,06; 137,95; 154,59; 157,62; 158,03.
MS (%): 306 (roditelj+1; 100).
Anal. izrač. za C19H19N3O*2HCl*3/2H2O*1/2(C4H8O): C 56,13; H 6,28; N 9,35.
Nađeno: C 56,24; H 6,52; N 9,05.
Primjer 72
6-(4-(1-piridin-3-ilmetil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 24 % prinosu, tt 150-180 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 3,29 (m, 2H); 3,71 (s, 2H); 3,92 (m, 2H); 4,57 (bs, 2H); 5,005 (m, 1H); 6,47 (d, J=8; 1H); 6,56 (d, J=8; 1H); 6,83 (d, J=7; 1H); 7,24 (m, 1H); 7,39 (d, J=8; 1H); 7,5-7,6 (m, 4H); 7,63 (m, 1H); 8,09 (m, 1H); 8,29 (m, 1H); 8,50 (m, 1H); 8,54 (s, 1H).
13C-NMR (�, CDCl3): 60,9; 61,4; 66,8; 104,5; 106,6; 115,1; 122,0; 123,4; 125,5; 125,7; 126,7; 126,9; 132,2; 133,3; 136,0; 138,0; 148,7; 149,8; 152,7; 157,5; 158,0.
MS (%): 383 (roditelj+1; 100).
Anal. izrač. za C24H22N4O2*3HCl*3H2O*1/3(C4H8O): C 53,39; H 5,95; N 9,83.
Nađeno: C 53,22; H 6,18; N 9,43.
Primjer 73
6-(4-(azetidin-3-ilmetoksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; gdje je N-BOC azetidin-3-metanol dodan u 2-(2,5-dimetilpirolil)-6-(4-fluoro-naft-1-il)piridin kao u primjeru 24D praćeno sa sekvencijalnim uklanjanjem BOC i pirolil zaštitnih skupina, sa finalnom fazom obrade u 75 % prinosu, tt 88-110 °C, kao hidrokloridna sol.
1H-NMR (�, CDCl3): 3,27 (m, 1H); 3,64 (m, 2H); 3,78 (m, 2H); 4,25 (d, J=6; 2H); 4,63 (bs, 2H); 6,45 (d, J=8; 1H); 6,83 (m, 2H); 7,4-7,6 (m, 4H); 8,09 (m, 1H); 8,29 (m, 1H).
13C-NMR (�, CDCl3): 34,2; 49,8; 69,8; 104,2; 106,5; 115,1; 122,0; 125,0; 125,4; 125,6; 125,7; 126,6; 127,1; 131,4; 132,0; 138,0; 154,7; 157,6; 158,1.
MS (%): 306 (roditelj+1; 100).
Anal. izrač. za C19H19N3O*2HCl*2H2O*3/2(C4H8O): C 57,25; H 7,00; N 8,04.
Nađeno: C 57,47; H 7,14; N 8,21.
Primjer 74
6-(4-(1-piridin-2-ilmetil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; u 24 % prinosu, tt 97-120 °C, kao hidrokloridna sol iz teterahidrofurana.
1H-NMR (�, CDCl3): 3,42 (m, 2H); 3,89 (s, 2H); 4,015 (m, 2H); 4,62 (bs, 2H); 5,045 (m, 1H); 6,47 (d, J=8; 1H); 6,57 (d, J=8; 1H); 6,82 (d, J=7; 1H); 7,16 (m, 1H); 7,3-7,5 (m, 5H); 7,64 ((t, J=8; 1H); 8,07 (m, 1H); 8,30 (m, 1H); 8,55 (m, 1H).
13C-NMR (�, CDCl3): 61,62; 64,89; 67,10; 104,52; 115,64; 122,09; 122,13; 122,42; 125,18; 125,60; 126,73; 126,92; 131,75; 132,16; 136,58; 138,04; 149,30; 152,77; 157,41; 157,76; 157,96.
MS (%): 383 (roditelj+1; 100).
Anal. izrač. za C24H22N4O2*3HCl*7/4H2O: C 55,08; H 5,49; N 10,70.
Nađeno: C 55,44; H 5,61; N 10,31.
Primjer 75
6-(4-(N-metil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; korištenjem formaldehida u metanolu sa natrij cijanoborohidridom na sobnoj temperaturi, u 30 % prinosu, tt 240-255 °C, kao hidrokloridna sol iz teterahidrofurana.
1H-NMR (�, CDCl3): 2,45 (s, 3H); 2,75 (bs, 2H); 3,30 (m, 2H); 3,99 (m, 2H); 4,96 (m, 1H); 6,47 (d, J=8; 1H); 6,55 (d, J=8; 1H); 6,80 (d, J=7; 1H); 7,3-7,5 (m, 4H); 8,03 (m, 1H); 8,28 (m, 1H).
13C-NMR (�, CDCl3): 45,81; 63,07; 66,19; 104,44; 106,84; 115,08; 121,97; 125,23; 125,43; 125,57; 126,87; 131,82; 132,15; 138,14; 152,56; 157,13; 158,05.
MS (%): 306 (roditelj+1; 100).
Anal. izrač. za C19H19N3O*2HCl*2H2O: C 55,08; H 6,08; N 10,14.
Nađeno: C 55,34; H 6,01; N 9,82.
Primjer 76
6-(4-(N-izopropil-azetidin-3-iloksi)-naftalen-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 24; kao sporedni produkt reakcije korištene za dobivanje primjera 75; od acetona u metanolu, u 19 % prinosu, tt 120-135 °C, kao hidrokloridna sol iz teterahidrofurana.
1H-NMR (�, CDCl3): 0,99 (d, J=6; 6H); 2,49 (septet, J=6; 1H); 3,25 (m, 2H); 3,96 (m, 2H); 4,65 (bs, 2H); 4,97 (m, 1H); 6,48 (d, J=8; 1H); 6,60 (d, J=8; 1H); 6,81 (d, J=6; 1H); 7,4-7,5 (m, 4H); 8,03 (m, 1H); 8,27 (m, 1H).
13C-NMR (�, CDCl3): 19,30; 50,44; 58,78; 65,40; 104,52; 106,81; 115,12; 122,00; 125,20; 125,45; 125,56; 126,73; 126,89; 131,78; 132,15; 138,15; 152,66; 157,21; 158,02.
MS (%): 332 (roditelj+1; 100).
Anal. izrač. za C21H23N3O*2HCl*2H2O: C 57,02; H 6,61; N 9,50.
Nađeno: C 57,04; H 6,51; N 9,29.
Primjer 77
6-(4-(2-dimetilamino-etoksi)-6,7,8,9-teterahidro-5H-benzociklohepten-1-il)-piridin-2-ilamin
Dobiven kao u primjeru 37; korištenjem 4-hidroksi-6,7,8,9-5H-benzocikloheptena kao početnog materijala, koji je dobiven kako slijedi: 8 g (71,4 mmol) 2-hidroksipirona (Syn. Commun., 5; 461; (1975)) i 20 ml cikloheptena reagirali su u zabrtvljenoj cijevi na 150 °C tijekom 24 h zbog dobivanja 1-okso-3,4,6,7,8,9-heksahidro-5H-benzocikloheptena u 49,5 % prinosu, praćeno reakcijom sa izopropenil acetatom zbog dobivanja enol acetata i tretmanom sa 2,3-dikloro-5,6-dicijanobenzokinona na 90 °C tijekom 1,5 h (vidjeti J. Med. Chem., 37; 3803 (1994)) zbog dobivanja 4-acetoksi-6,7,8,9-teterahidro-5H-benzocikloheptena u 69 % prinosu kao ulja. Hidroliza sa 3,7 ekvivalenta trituriranog kalijevog hidroksida u etanolu na sobnoj temperaturi tijekom 2 h dala je 44 % prinosa željenog 4-hidroksi-6,7,8,9-teterahidro-5H-benzocikloheptena poslije pročišćavanja kromatografijom na koloni kao bijele krutine. Preostale faze u sekvenci zatim su pratile primjer 48. Finalna faza je obrađena u 89 % prinosu zbog dobivanja produkta kao amorfne krutina kao hidrokloridna soli iz etera.
1H-NMR (�, CDCl3): 1,58 (m, 4H); 1,79 (m, 2H); 2,34 (s, 6H); 2,75 (m, 4H); 2,93 (m, 2H); 4,06 (t, J=6; 2H); 4,48 (bs, 2H); 6,39 (d, J=8; 1H); 6,62 (d, J=8; 1H); 6,74 (d, J=8; 1H); 7,10 (d, J=8; 1H); 7,41 (d, J=8; 1H).
13C-NMR (�, CDCl3): 25,51; 27,36; 27,75; 31,21; 32,46; 46,03; 58,35; 67,43; 105,94; 109,95; 114,72; 127,58; 132,85; 133,74; 142,88; 155,43; 157,74; 159,32.
MS (%): 326 (roditelj+1; 100).
Claims (9)
1. Spoj formule:
[image]
naznačen time, da je prsten A kondenzirani 5-7 člani zasićeni ili nezasićeni prsten gdje su od nula do dva člana prstena heteroatomi izabrani, neovisno, od dušika, kisika i sumpora, pod uvjetom da 2 člana prstena koji nisu susjedi mogu oba biti heteroatomi;
X je kisik ili veza;
n je cijeli broj od 2 do 6; i
R1 i R2 su odabrani, neovisno, od (C1-C6) alkila, arila, teterahidronaftalena i aralkila, gdje spomenuti aril i afril dio spomenutog aralkila je fenil ili naftil i alkil dio je normalan ili razgranat i sadrži od 1 do 6 atoma ugljika, i gdje spomenuti (C1-C6) alkil, spomenuti aril, spomenuti teterahidronaftalen i aril dio spomenutog aralkila mogu po želji biti supstituirani sa 1 do 3 supstituenta, poželjno od 0 do 2 supstituenta, koji su odabrani, neovisno, od halo (npr., kloro, fluoro, bromo, jodo); nitro, hidroksi, cijano, amino, (C1-C4) alkoksi, i (C1-C4) alkilamino;
ili R1 i R2 formiraju, zajedno sa dušikom na koji su oni vezani, piperazin, azetidin, piperidin ili pirolidin prsten ili azabiciklični prsten koji sadrži prsten od 6 do 14 članova, od 1 do 3 dušika a ostatak čini ugljik;
i gdje spomenuti piperazin, azetidin, piperidin i pirolidin prsteni mogu po želji biti supstituirani sa jednim ili više supstituenata, poželjno sa od 0 do 2 supstituenta koji su odabrani, neovisno, od (C1-C6) alkila, amino, (C1-C6) alkilamino, (di-(C1-C6)alkil)amino, fenila supstituiranog sa 5 do 6-članim heterocikličnim prstenima koji sadrže od 1 do 4 atoma dušika prstena, benzoila, benzoilmetila, benzilkarbonila, fenilaminokarbonila, feniletila i fenoksikarbonila, i gdje fenil dijelovi bilo kojeg od gornjih supstituenata može po želji biti supstituiran sa jednim ili više supstituenata, poželjno sa od 0 do 2 supstituenta, koji su odabrani, neovisno, od halo, (C1-C3) alkila, (C1-C3) alkoksi, nitro, amino, cijano, CF3 i OCF3;
također R1 ili R2 mogu biti vezani na (CH2)n skupinu zbog formiranja prstena od 4 do 7 članova;
i farmaceutski prihvatljive soli takvih spojeva.
2. Spoj prema zahtjevu 1; naznačen time, da NR1R2 je po želji supstituiran piperidin, azetidin, piperazin ili pirolidin prsten ili 3-aza-biciklo[3,1,0]heks-6-ilamin prsten;
i gdje spomenuti piperazin, azetidin, piperidin i pirolidin prsteni mogu po želji biti supstituirani sa jednim ili više supstituenata, poželjno sa od 0 do 2 supstituenta koji su odabrani, neovisno, od (C1-C6) alkila, amino, (C1-C6) alkilamino, (di-(C1-C6)alkil)amino, fenila supstituiranog sa 5 do 6-članim heterocikličnim prstenima koji sadrže od 1 do 4 atoma dušika u prstenu, benzoila, benzoilmetila, benzilkarbonila, fenilaminokarbonila, feniletila i fenoksikarbonila, i gdje fenil dijelovi bilo kojeg od gornjih supstituenata može po želji biti supstituiran sa jednim ili više supstituenata, poželjno sa od 0 do 2 supstituenta, koji su odabrani, neovisno, od halo, (C1-C3) alkila, (C1-C3) alkoksi, nitro, amino, cijano, CF3 i OCF3.
3. Spoj prema zahtjevu 1; naznačen time, da NR1R2 formira azabiciklični prsten koji ima formulu:
[image]
gdje R3 i R4 su odabrani od vodika, (C1-C6) alkila, fenila, naftila, (C1-C6)alkil-C(=O)-, HC(=O)-, (C1-C6)alkoksi-(C=O)-, fenil-C(=O)-, naftil-C(=O)-, i R6R7NC(=O)- gdje R6 i R7 su odabrani, neovisno od vodika i (C1-C6) alkila;
R5 je odabran od vodika, (C1-C6) alkila, fenila, naftila, fenil-(C1-C6)alkil- i naftil(C1-C6)alkil-.
4. Farmaceutski preparat za tretiranje ili prevenciju stanja odabranog iz skupine koja sadrži migrenske upale, udare, akutne i kronične bolove, hipovolemički šok, reperfuzijske povrede, Crohnovu bolest, ulcerativni kolitis, septički šok, multipl sklerozu, AIDS združen sa propadanjem moždanog tkiva, neurodegenerativne bolesti, neuronsku toksičnost, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti, emezis, epilepsiju, zabrinutost, psihoze, traume na glavi, sindrom respiratornog bola odraslih (ARDS); induciranu toleranciju morfinom i simptome povlačenja, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, makularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, naznačen time, da sadrži količinu spojeva prema zahtjevu 1; koja je djelotvorna u tretiranju ili prevenciji takvog stanja, i odgovarajući farmaceutski prihvatljiv nosač.
5. Postupak tretiranja ili prevencije stanja odabranog iz skupine koja sadrži migrenske upale, udare, akutne i kronične bolove, hipovolemički šok, reperfuzijske povrede, Crohnovu bolest, ulcerativni kolitis, septički šok, multipl sklerozu, AIDS združen sa propadanjem moždanog tkiva, neurodegenerativne bolesti, neuronsku toksičnost, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti, emezis, epilepsiju, zabrinutost, psihoze, traume na glavi, sindrom respiratornog bola odraslih (ARDS); induciranu toleranciju morfinom i simptome povlačenja, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, makularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, naznačen time, da obuhvaća unošenje u spomenutog sisavca količinu spojeva prema zahtjevu 1; koja je djelotvorna u tretiranju ili prevenciji takvog stanja.
6. Farmaceutski preparat za inhibiranje sintaze dušičnog oksida (NOS) kod sisavca, prema zahtjevu 1; naznačen time, da sadrži NOS inhibitornu djelotvornu količinu spojeva prema zahtjevu 1; i farmaceutski prihvatljiv nosač.
7. Upotreba inhibiranja NOS kod sisavca, naznačen time, da obuhvaća unošenje NOS inhibitorne djelotvorne količine spojeva prema zahtjevu 1.
8. Farmaceutski preparat za tretiranje ili prevenciju stanja odabranog iz skupine koja sadrži migrenske upale, udare, akutne i kronične bolove, hipovolemički šok, reperfuzijske povrede, Crohnovu bolest, ulcerativni kolitis, septički šok, multipl sklerozu, AIDS združen sa propadanjem moždanog tkiva, neurodegenerativne bolesti, neuronsku toksičnost, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti, emezis, epilepsiju, zabrinutost, psihoze, traume na glavi, sindrom respiratornog bola odraslih (ARDS); induciranu toleranciju morfinom i simptome povlačenja, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, makularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, naznačen time, da sadrži NOS inhibitornu djelotvornu količinu spojeva prema zahtjevu 1 i farmaceutski prihvatljiv nosač.
9. Postupak tretiranja ili prevencije stanja odabranog iz skupine koja sadrži migrenske upale, udare, akutne i kronične bolove, hipovolemički šok, reperfuzijske povrede, Crohnovu bolest, ulcerativni kolitis, septički šok, multipl sklerozu, AIDS združen sa propadanjem moždanog tkiva, neurodegenerativne bolesti, neuronsku toksičnost, Alzheimjerovu bolest, kemijske ovisnosti i sklonosti, emezis, epilepsiju, zabrinutost, psihoze, traume na glavi, sindrom respiratornog bola odraslih (ARDS); induciranu toleranciju morfinom i simptome povlačenja, upalu crijeva, osteoartritis, reumatski artritis, ovulaciju, skraćenu kardiomiopatiju, akutnu povredu kičmene moždine, Huntingtonovu bolest, glaukom, makularnu degeneraciju, dijabetsku neuropatiju i rak kod sisavaca, naznačen time, da obuhvaća unošenje u spomenutog sisavca NOS inhibitorne djelotvorne količine spojeva prema zahtjevu 1.
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US20010049379A1 (en) | 1997-08-27 | 2001-12-06 | Lowe John Adams | 2-aminopyridines containing fused ring substituents |
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HUP0102236A3 (en) * | 1998-06-03 | 2003-01-28 | Pfizer Prod Inc | 2-aminopyridines containing fused ring substituents as nitric oxide synthase inhibitors and pharmaceutical compositions containing them and their use |
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ID29892A (id) | 1999-02-25 | 2001-10-18 | Pfizer Prod Inc | 2-aminopiridin yang mengandung substituen-substituen cincin terlebur |
GB0004151D0 (en) * | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel use |
GB0004149D0 (en) * | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel compounds |
GB0004153D0 (en) | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel use |
GB0004152D0 (en) | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel compounds |
FR2805818B1 (fr) * | 2000-03-03 | 2002-04-26 | Aventis Pharma Sa | Derives d'azetidine, leur preparation et les compositions pharmaceutiques les contenant |
BR0112939A (pt) | 2000-08-16 | 2005-11-01 | Upjohn Co | Compostos para o tratamento de distúrbios de dependência |
CN100356917C (zh) | 2001-05-15 | 2007-12-26 | 霍夫曼-拉罗奇有限公司 | 用作糖尿病治疗中的PPAR-α和PPAR-γ激活剂的羧酸取代的噁唑衍生物 |
SE0102640D0 (sv) | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
US20030045449A1 (en) * | 2001-08-15 | 2003-03-06 | Pfizer, Inc. | Pharmaceutical combinations for the treatment of neurodegenerative diseases |
DE10159922A1 (de) * | 2001-12-06 | 2003-06-26 | Gruenenthal Gmbh | Substituierte 2-Pyrrolidin-2-yl-1H-indol-Derivate |
PL374818A1 (en) | 2002-07-03 | 2005-10-31 | F.Hoffmann-La Roche Ag | Oxazole derivatives and their use as insulin sensitizers |
NZ538058A (en) * | 2002-08-14 | 2006-11-30 | Neurosearch As | Quinuclidine derivatives and their use for treating disorders related to CNS and PNS |
JP4533141B2 (ja) | 2002-08-30 | 2010-09-01 | エフ.ホフマン−ラ ロシュ アーゲー | PPARα及びPPARγアゴニストとしての新規2−アリールチアゾール化合物 |
EP1539746B1 (en) | 2002-09-12 | 2006-11-15 | F. Hoffmann-La Roche Ag | N-substituted-1h-indol-5-propionic acid compounds as ppar agonists useful for the treatment of diabetes |
US20040092741A1 (en) * | 2002-11-08 | 2004-05-13 | Pfizer Inc | Substituted pyridines via boronic acid coupling |
ATE405560T1 (de) | 2002-11-25 | 2008-09-15 | Hoffmann La Roche | Indolderivaten |
US7160876B2 (en) | 2003-12-22 | 2007-01-09 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US7655657B2 (en) | 2003-12-22 | 2010-02-02 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
EP1773847A2 (en) * | 2004-07-09 | 2007-04-18 | Glaxo Group Limited | Antibacterial agents |
JP2008523058A (ja) * | 2004-12-10 | 2008-07-03 | アボット・ラボラトリーズ | 縮合ビシクロ複素環置換キヌクリジン誘導体 |
AR068032A1 (es) * | 2007-08-27 | 2009-10-28 | Kalypays Inc | Quinolonas sustituidas con heterociclicos utiles como inhibidores de oxido nitrico sintetasa |
WO2009029617A1 (en) * | 2007-08-27 | 2009-03-05 | Kalypsys, Inc. | Diarylamine-substituted quinolones useful as inducible nitric oxide synthase inhibitors |
UA105182C2 (ru) | 2008-07-03 | 2014-04-25 | Ньюрексон, Інк. | Бензоксазины, бензотиазины и родственные соединения, которые имеют ингибирующую nos активность |
DE102008054141A1 (de) | 2008-10-31 | 2010-05-06 | Merck Patent Gmbh | Neue Materialien für organische Elektrolumineszenzvorrichtungen |
DE102009033371A1 (de) | 2009-07-16 | 2011-05-12 | Merck Patent Gmbh | Materialien für elektronische Vorrichtungen |
WO2014138460A1 (en) | 2013-03-07 | 2014-09-12 | Northwestern University | 2-aminopyridine-based selective neuronal nitric oxide synthase inhibitors |
CN104725249B (zh) * | 2013-12-20 | 2019-02-12 | 广东东阳光药业有限公司 | 苄胺类衍生物及其在药物上的应用 |
WO2016073623A2 (en) | 2014-11-04 | 2016-05-12 | Northwestern University | Mammalian and bacterial nitric oxide synthase inhibitors |
US10759791B2 (en) | 2014-11-04 | 2020-09-01 | Northwestern University | Mammalian and bacterial nitric oxide synthase inhibitors |
CN106478376A (zh) * | 2016-10-08 | 2017-03-08 | 贵州大学 | 一种4‑氟萘‑1‑醇的制备工艺 |
CN114560779A (zh) * | 2022-01-25 | 2022-05-31 | 杭州华东医药集团浙江华义制药有限公司 | 一种米拉贝隆关键中间体的合成方法 |
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AT400845B (de) * | 1993-12-06 | 1996-03-25 | Chem Pharm Forsch Gmbh | Neue thienothiazinderivate, ein verfahren zu ihrer herstellung und ihre verwendung |
AU4515696A (en) * | 1994-12-12 | 1996-07-03 | Merck & Co., Inc. | Substituted 2-aminopyridines as inhibitors of nitric oxide synthase |
JPH08311028A (ja) * | 1995-05-17 | 1996-11-26 | Japan Tobacco Inc | 2−アミノピリジン誘導体及びそれら化合物を含有してなる一酸化窒素合成酵素阻害剤 |
JPH09132529A (ja) * | 1995-11-09 | 1997-05-20 | Ono Pharmaceut Co Ltd | 一酸化窒素合成酵素阻害剤 |
CN1168719C (zh) * | 1996-03-29 | 2004-09-29 | 辉瑞大药厂 | 6-苯基吡啶-2-基胺衍生物以及药物组合物和用途 |
HN1997000027A (es) * | 1996-12-06 | 1997-06-05 | Pfizer Prod Inc | Derivados de 6-fenil piridil - 2 amina |
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