CN1476442A - 具有IKB-激酶(IKK-β)抑制活性的吡啶衍生物 - Google Patents
具有IKB-激酶(IKK-β)抑制活性的吡啶衍生物 Download PDFInfo
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- CN1476442A CN1476442A CNA018192203A CN01819220A CN1476442A CN 1476442 A CN1476442 A CN 1476442A CN A018192203 A CNA018192203 A CN A018192203A CN 01819220 A CN01819220 A CN 01819220A CN 1476442 A CN1476442 A CN 1476442A
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- China
- Prior art keywords
- amino
- alkyl
- radical
- piperidinyl
- hydroxyphenyl
- Prior art date
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- 150000003222 pyridines Chemical class 0.000 title claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 title description 9
- 102000001284 I-kappa-B kinase Human genes 0.000 title description 2
- 108060006678 I-kappa-B kinase Proteins 0.000 title description 2
- -1 nitro, amino Chemical group 0.000 claims abstract description 337
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 87
- 239000001257 hydrogen Substances 0.000 claims abstract description 85
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 55
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 47
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 39
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 22
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims abstract description 8
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 7
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 122
- 229920006395 saturated elastomer Polymers 0.000 claims description 62
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 27
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical compound C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 7
- 125000003170 phenylsulfonyl group Chemical class C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 208000003250 Mixed connective tissue disease Diseases 0.000 claims description 5
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 201000001981 dermatomyositis Diseases 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims description 4
- 125000006721 (C5-C10) heteroaryl (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 206010010741 Conjunctivitis Diseases 0.000 claims description 3
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 208000024780 Urticaria Diseases 0.000 claims description 3
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 208000005987 polymyositis Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 201000005539 vernal conjunctivitis Diseases 0.000 claims description 3
- CETGRCDGYVBQML-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-(1,2,3,6-tetrahydropyridin-5-yl)pyridin-2-yl]phenol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CC=2)O)=CC=1C1=CCCNC1 CETGRCDGYVBQML-UHFFFAOYSA-N 0.000 claims description 2
- VRTFOUDCQHOCPY-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]-3-(cyclopropylmethoxy)phenol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CC2)=CC=1C1CCCNC1 VRTFOUDCQHOCPY-UHFFFAOYSA-N 0.000 claims description 2
- HSJJRKNDXMKFKR-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]-3-propoxyphenol Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(CO)C(N)=N1 HSJJRKNDXMKFKR-UHFFFAOYSA-N 0.000 claims description 2
- DMACSHODVXTYON-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]pyridin-3-ol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CN=2)O)=CC=1C1CCCNC1 DMACSHODVXTYON-UHFFFAOYSA-N 0.000 claims description 2
- QZUAQCKUXDWPHT-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-4-ylpyridin-2-yl]-3-(cyclopropylmethoxy)phenol Chemical compound OCC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CC2)=CC=1C1CCNCC1 QZUAQCKUXDWPHT-UHFFFAOYSA-N 0.000 claims description 2
- UZBXYMHLKCOBOS-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-2-(5-piperidin-3-yl-2,4-dihydro-1H-pyrido[2,3-d][1,3]oxazin-7-yl)phenol Chemical compound C=1C(C2CNCCC2)=C2COCNC2=NC=1C=1C(O)=CC=CC=1OCC1CC1 UZBXYMHLKCOBOS-UHFFFAOYSA-N 0.000 claims description 2
- ZORSFUGTMPLBNN-UHFFFAOYSA-N 3-acetyl-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d]pyrimidin-2-one Chemical compound N1C(=O)N(C(=O)C)CC2=C1N=C(C=1C(=CC=CC=1O)OCC1CC1)C=C2C1CCCNC1 ZORSFUGTMPLBNN-UHFFFAOYSA-N 0.000 claims description 2
- VWSSLCXIHNUQTG-UHFFFAOYSA-N 7-(2-hydroxy-6-propoxyphenyl)-5-piperidin-4-yl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CCNCC2)=C(COC(=O)N2)C2=N1 VWSSLCXIHNUQTG-UHFFFAOYSA-N 0.000 claims description 2
- VOUAFWJSZVETCC-UHFFFAOYSA-N 7-(2-hydroxyphenyl)-5-piperidin-3-yl-3,4-dihydro-1H-1,8-naphthyridin-2-one Chemical compound OC1=CC=CC=C1C1=CC(C2CNCCC2)=C(CCC(=O)N2)C2=N1 VOUAFWJSZVETCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- MOMLCJXOIMMUMB-UHFFFAOYSA-N chembl181334 Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(C#N)C(N)=N1 MOMLCJXOIMMUMB-UHFFFAOYSA-N 0.000 claims description 2
- YLQCMQRAHFNHMO-UHFFFAOYSA-N chembl183703 Chemical compound N#CC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CCC2)=CC=1C1CCCNC1 YLQCMQRAHFNHMO-UHFFFAOYSA-N 0.000 claims description 2
- YCBMOJCSUJUUBS-UHFFFAOYSA-N chembl361841 Chemical compound N#CC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CCC2)=CC=1C1CCNCC1 YCBMOJCSUJUUBS-UHFFFAOYSA-N 0.000 claims description 2
- DYVFBWXIOCLHPP-UHFFFAOYSA-N chembl368427 Chemical compound N#CC=1C(N)=NC(C=2C(=CC=CC=2O)OCC2CC2)=CC=1C1CCNCC1 DYVFBWXIOCLHPP-UHFFFAOYSA-N 0.000 claims description 2
- AMSPCSYNFCFPJS-UHFFFAOYSA-N chembl369306 Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CCNCC2)=C(C#N)C(N)=N1 AMSPCSYNFCFPJS-UHFFFAOYSA-N 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
- QGIDQRLFIMJXSS-UHFFFAOYSA-N 2,2-dimethylpropyl N-[[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-3-ylpyridin-3-yl]methyl]carbamate Chemical compound CC(C)(C)COC(=O)NCC1=C(N)N=C(C=2C(=CC=CC=2O)OCC2CC2)C=C1C1CCCNC1 QGIDQRLFIMJXSS-UHFFFAOYSA-N 0.000 claims 1
- ICGXFLJTVZTHPV-UHFFFAOYSA-N 2-[6-amino-5-(hydroxymethyl)-4-piperidin-3-ylpyridin-2-yl]-3-(2,2-dimethylpropoxy)phenol Chemical compound CC(C)(C)COC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(CO)C(N)=N1 ICGXFLJTVZTHPV-UHFFFAOYSA-N 0.000 claims 1
- PMBBEGCHIYEDOE-UHFFFAOYSA-N 2-amino-4-(2-aminoethylamino)-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]pyridine-3-carbonitrile Chemical compound NC1=C(C#N)C(NCCN)=CC(C=2C(=CC=CC=2O)OCC2CC2)=N1 PMBBEGCHIYEDOE-UHFFFAOYSA-N 0.000 claims 1
- MWJZCWXDCPUUKA-UHFFFAOYSA-N 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(1-methylpiperidin-3-yl)pyridine-3-carbonitrile Chemical compound C1N(C)CCCC1C1=CC(C=2C(=CC=CC=2O)OCC2CC2)=NC(N)=C1C#N MWJZCWXDCPUUKA-UHFFFAOYSA-N 0.000 claims 1
- BCAHWVMQDYMSQK-UHFFFAOYSA-N 2-amino-6-[2-hydroxy-6-(4-methylpentoxy)phenyl]-4-piperidin-4-ylpyridine-3-carbonitrile Chemical compound CC(C)CCCOC1=CC=CC(O)=C1C1=CC(C2CCNCC2)=C(C#N)C(N)=N1 BCAHWVMQDYMSQK-UHFFFAOYSA-N 0.000 claims 1
- GSWTYFPALXHXJD-UHFFFAOYSA-N 7-(2-hydroxy-6-propoxyphenyl)-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d][1,3]oxazin-2-one Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(COC(=O)N2)C2=N1 GSWTYFPALXHXJD-UHFFFAOYSA-N 0.000 claims 1
- UXDFQDPPXQQANA-UHFFFAOYSA-N 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-5-piperidin-3-yl-1,4-dihydropyrido[2,3-d]pyrimidine-3-carboxamide Chemical compound N1C(=O)N(C(=O)N)CC2=C1N=C(C=1C(=CC=CC=1O)OCC1CC1)C=C2C1CCCNC1 UXDFQDPPXQQANA-UHFFFAOYSA-N 0.000 claims 1
- 102100021854 Inhibitor of nuclear factor kappa-B kinase subunit beta Human genes 0.000 claims 1
- 101710205525 Inhibitor of nuclear factor kappa-B kinase subunit beta Proteins 0.000 claims 1
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- RCUGCDPYJHBMHI-UHFFFAOYSA-N ethyl 7-(2-hydroxy-6-propoxyphenyl)-2-oxo-5-piperidin-3-yl-3,4-dihydro-1H-1,8-naphthyridine-3-carboxylate Chemical compound CCCOC1=CC=CC(O)=C1C1=CC(C2CNCCC2)=C(CC(C(=O)OCC)C(=O)N2)C2=N1 RCUGCDPYJHBMHI-UHFFFAOYSA-N 0.000 claims 1
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- SURZCVYFPAXNGN-UHFFFAOYSA-N methyl-carbamic acid ethyl ester Chemical compound CCOC(=O)NC SURZCVYFPAXNGN-UHFFFAOYSA-N 0.000 claims 1
- ZLQUUMARLOVRLO-UHFFFAOYSA-N propan-2-yl n-methylcarbamate Chemical compound CNC(=O)OC(C)C ZLQUUMARLOVRLO-UHFFFAOYSA-N 0.000 claims 1
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- 125000005236 alkanoylamino group Chemical group 0.000 abstract description 2
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 abstract 1
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- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 abstract 1
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- BDEYDSLTLJSISR-UHFFFAOYSA-N tert-butyl 3-[3-amino-6-(2-hydroxyphenyl)-2H-pyrazolo[3,4-b]pyridin-4-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=CC(C=2C(=CC=CC=2)O)=NC2=C1C(N)=NN2 BDEYDSLTLJSISR-UHFFFAOYSA-N 0.000 description 1
- FLPQJANYBBMRDX-UHFFFAOYSA-N tert-butyl 3-[3-amino-6-(2-phenylmethoxyphenyl)-2h-pyrazolo[3,4-b]pyridin-4-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=CC(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=NC2=C1C(N)=NN2 FLPQJANYBBMRDX-UHFFFAOYSA-N 0.000 description 1
- ZFBPJMKVHNOJTP-UHFFFAOYSA-N tert-butyl 3-[3-cyano-6-(2-phenylmethoxyphenyl)-2-(propylamino)pyridin-4-yl]piperidine-1-carboxylate Chemical compound N#CC=1C(NCCC)=NC(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=CC=1C1CCCN(C(=O)OC(C)(C)C)C1 ZFBPJMKVHNOJTP-UHFFFAOYSA-N 0.000 description 1
- LZFKJTREMQRXPS-UHFFFAOYSA-N tert-butyl 3-[6-[2-acetamido-6-[(4-methoxyphenyl)methoxy]phenyl]-2-amino-3-cyanopyridin-4-yl]piperidine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC(NC(C)=O)=C1C1=CC(C2CN(CCC2)C(=O)OC(C)(C)C)=C(C#N)C(N)=N1 LZFKJTREMQRXPS-UHFFFAOYSA-N 0.000 description 1
- KXROFCAAFGPQJZ-UHFFFAOYSA-N tert-butyl 3-[7-(2-hydroxyphenyl)-2,4-dioxo-1H-pyrido[2,3-d]pyrimidin-5-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1C1=CC(C=2C(=CC=CC=2)O)=NC2=C1C(=O)NC(=O)N2 KXROFCAAFGPQJZ-UHFFFAOYSA-N 0.000 description 1
- LPCLMIXPTAHPPN-UHFFFAOYSA-N tert-butyl 3-[7-(2-hydroxyphenyl)-3-methyl-2,4-dioxo-1H-pyrido[2,3-d]pyrimidin-5-yl]piperidine-1-carboxylate Chemical compound C=12C(=O)N(C)C(=O)NC2=NC(C=2C(=CC=CC=2)O)=CC=1C1CCCN(C(=O)OC(C)(C)C)C1 LPCLMIXPTAHPPN-UHFFFAOYSA-N 0.000 description 1
- LRVZCCYHEZVHPF-UHFFFAOYSA-N tert-butyl 3-[[2-(2-amino-2-oxoethoxy)-3-cyano-6-(2-phenylmethoxyphenyl)pyridin-4-yl]amino]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1NC1=CC(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=NC(OCC(N)=O)=C1C#N LRVZCCYHEZVHPF-UHFFFAOYSA-N 0.000 description 1
- AKQXKEBCONUWCL-UHFFFAOYSA-N tert-butyl 3-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(N)C1 AKQXKEBCONUWCL-UHFFFAOYSA-N 0.000 description 1
- GFIQXPZTOFYEMI-UHFFFAOYSA-N tert-butyl 3-formyl-3-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C)(C=O)C1 GFIQXPZTOFYEMI-UHFFFAOYSA-N 0.000 description 1
- MJALQPCUZXQHKS-UHFFFAOYSA-N tert-butyl 4-[2-amino-3-cyano-6-[2-(cyclopropylmethoxy)-6-[(4-methoxyphenyl)methoxy]phenyl]pyridin-4-yl]piperidine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC(OCC2CC2)=C1C1=CC(C2CCN(CC2)C(=O)OC(C)(C)C)=C(C#N)C(N)=N1 MJALQPCUZXQHKS-UHFFFAOYSA-N 0.000 description 1
- MCTSLUFMMVLJJK-UHFFFAOYSA-N tert-butyl 4-[2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(hydroxymethyl)pyridin-4-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=CC(C=2C(=CC=CC=2O)OCC2CC2)=NC(N)=C1CO MCTSLUFMMVLJJK-UHFFFAOYSA-N 0.000 description 1
- OQIYIZMEVVEKQR-UHFFFAOYSA-N tert-butyl 4-[6-carbamoyl-2-[2-(cyclopropylmethoxy)-6-[(4-methoxyphenyl)methoxy]phenyl]-7-oxo-6,8-dihydro-5h-1,8-naphthyridin-4-yl]piperidine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC(OCC2CC2)=C1C1=CC(C2CCN(CC2)C(=O)OC(C)(C)C)=C(CC(C(N)=O)C(=O)N2)C2=N1 OQIYIZMEVVEKQR-UHFFFAOYSA-N 0.000 description 1
- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
- GTHBSOYQXIUICB-UHFFFAOYSA-N tert-butyl 5-[2-amino-3-(hydroxymethyl)-6-[2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-4-yl]-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC=C1C1=CC(C=2CN(CCC=2)C(=O)OC(C)(C)C)=C(CO)C(N)=N1 GTHBSOYQXIUICB-UHFFFAOYSA-N 0.000 description 1
- XJFFILNBBDXUHL-UHFFFAOYSA-N tert-butyl 5-[7-[2-[(4-methoxyphenyl)methoxy]phenyl]-2-oxo-1,4-dihydropyrido[2,3-d][1,3]oxazin-5-yl]-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC=C1C1=CC(C=2CN(CCC=2)C(=O)OC(C)(C)C)=C(COC(=O)N2)C2=N1 XJFFILNBBDXUHL-UHFFFAOYSA-N 0.000 description 1
- KUDYDGWGDRZATE-UHFFFAOYSA-N tert-butyl 5-formyl-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=C(C=O)C1 KUDYDGWGDRZATE-UHFFFAOYSA-N 0.000 description 1
- JAXGMBUVQWCKRW-UHFFFAOYSA-N tert-butyl n-(3-formylcyclohexyl)-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1CCCC(C=O)C1 JAXGMBUVQWCKRW-UHFFFAOYSA-N 0.000 description 1
- ZJTYRNPLVNMVPQ-LBPRGKRZSA-N tert-butyl n-[(2s)-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C=O)CC1=CC=CC=C1 ZJTYRNPLVNMVPQ-LBPRGKRZSA-N 0.000 description 1
- UTVUHWFFPOHMFU-UHFFFAOYSA-N tert-butyl n-[1-[2-amino-3-(hydroxymethyl)-6-(2-phenylmethoxyphenyl)pyridin-4-yl]-2-phenylethyl]carbamate Chemical compound C=1C(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=NC(N)=C(CO)C=1C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 UTVUHWFFPOHMFU-UHFFFAOYSA-N 0.000 description 1
- VCBQHUZBBTUJQR-UHFFFAOYSA-N tert-butyl n-[1-[2-oxo-7-(2-phenylmethoxyphenyl)-1,4-dihydropyrido[2,3-d][1,3]oxazin-5-yl]-2-phenylethyl]carbamate Chemical compound C=1C(C=2C(=CC=CC=2)OCC=2C=CC=CC=2)=NC=2NC(=O)OCC=2C=1C(NC(=O)OC(C)(C)C)CC1=CC=CC=C1 VCBQHUZBBTUJQR-UHFFFAOYSA-N 0.000 description 1
- NGMLKQKPJJPTDQ-UHFFFAOYSA-N tert-butyl n-[2-[[2-amino-6-[2-(cyclopropylmethoxy)-6-[(4-methoxyphenyl)methoxy]phenyl]-3-(hydroxymethyl)pyridin-4-yl]amino]ethyl]carbamate Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC(OCC2CC2)=C1C1=CC(NCCNC(=O)OC(C)(C)C)=C(CO)C(N)=N1 NGMLKQKPJJPTDQ-UHFFFAOYSA-N 0.000 description 1
- FFAHNSHILFJJCX-UHFFFAOYSA-N tert-butyl n-[2-[[7-[2-(cyclopropylmethoxy)-6-[(4-methoxyphenyl)methoxy]phenyl]-2-oxo-1,4-dihydropyrido[2,3-d][1,3]oxazin-5-yl]amino]ethyl]carbamate Chemical compound C1=CC(OC)=CC=C1COC1=CC=CC(OCC2CC2)=C1C1=CC(NCCNC(=O)OC(C)(C)C)=C(COC(=O)N2)C2=N1 FFAHNSHILFJJCX-UHFFFAOYSA-N 0.000 description 1
- ISTGQSQWSKCNFJ-UHFFFAOYSA-N tert-butyl n-ethylcarbamate Chemical compound CCNC(=O)OC(C)(C)C ISTGQSQWSKCNFJ-UHFFFAOYSA-N 0.000 description 1
- JHLVEBNWCCKSGY-UHFFFAOYSA-N tert-butyl n-methylcarbamate Chemical compound CNC(=O)OC(C)(C)C JHLVEBNWCCKSGY-UHFFFAOYSA-N 0.000 description 1
- AZAKMLHUDVIDFN-UHFFFAOYSA-N tert-butyl nitrate Chemical compound CC(C)(C)O[N+]([O-])=O AZAKMLHUDVIDFN-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- JYEVUDXCQHLXNG-UHFFFAOYSA-N tert-butyl pyridine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CN=C1 JYEVUDXCQHLXNG-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- CMUTXJXHVDKYAN-UHFFFAOYSA-L tetrabutylazanium difluoride Chemical compound [F-].[F-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC CMUTXJXHVDKYAN-UHFFFAOYSA-L 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
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- 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
- C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
- C07D213/09—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles
- C07D213/10—Preparation by ring-closure involving the use of ammonia, amines, amine salts, or nitriles from acetaldehyde or cyclic polymers thereof
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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
- C07D213/73—Unsubstituted amino or imino radicals
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
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Abstract
通式(I)的吡啶化合物,其中-R1为,其中R11为氢、C1-6烷基、卤素、羟基、C1-12烷氧基、硝基、氨基、C1-6烷基磺酰氨基、C1-6烷氧基羰基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷酰基氨基、苯基C1-6烷基氨基、苯基磺酰基氨基或-O-(CH2)n-R111;R2为氢或卤素;R3为氢、-CR31R32R33或-NR34R35;R4为氢、氨基甲酰基、CN、羧基等;R5为氨基、C1-6烷基氨基、二C1-6烷基氨基等,或它们的盐。所述化合物具有优异的抗炎活性以及其它生物活性。
Description
技术领域
本发明涉及新型吡啶衍生物、它们的制备方法以及包含它们的药用制剂。本发明吡啶衍生物抑制IκB激酶β(IKK-β或IKK-beta)的活性,因此抑制核因子kappa B(NF-κB)的活性,能够用于预防和治疗NF-κB活性相关性疾病,特别是用于治疗炎症性疾病。
背景技术
核因子kappa B(NF-κB)属于密切相关的同型二聚体以及杂型二聚体的转录因子复合物家族,所述复合物因子由各种组合的Rel/NF-κB家族多肽构成。NF-κB以及相关的家族成员参与调节50种以上的涉及免疫反应以及炎症反应的基因((Barnes PJ,Karin M(1997)N EnglJ Med 336,1066-1071)和(Baeuerle PA,Baichwal VR(1997)AdvImmunol 65,111-137))。大多数细胞类型中,NF-κB为包含50 kDa和65 kDa亚基的杂二聚体(p50/RelA)。杂二聚体通常隔离在细胞质中,与NF-B(IκB)-家族蛋白抑制剂缔合以保持非活性状态。IκB家族蛋白屏蔽NF-κB的核转移信号。一旦细胞受到不同细胞因子(例如TNF-α、IL-1)、CD40配体、脂多糖(LPS)、氧化剂、促细胞分裂剂(例如佛波醇酯)、病毒或其它因素的刺激,IκB蛋白在特异的丝氨酸残基磷酸化、多遍在蛋白化,然后通过蛋白酶体依赖性途径降解。从IκB释放后,活性NF-κB能够转移至核,以选择方式结合到优选的基因特异性增强子序列。NF-κB调节的基因中有很多促炎介质、细胞因子、细胞粘连分子以及急性期蛋白的编码基因。若干这样的细胞因子和介质依次表达可能导致通过自分泌和旁分泌机制进一步激活NF-κB。
有大量的证据显示NF-κB在许多包括气道炎症以及哮喘的炎症性疾病中起主要作用((Yang L等,J Exp Med 188(1998),1739-1750)、(Hart LA等,Am J Respir Crit Care Med 158(1998),1585-1592)、(StaceyMA等,Biochem Biophys Res Commun 236(1997),522-526)(Barnes Pand Adcock IM,Trends Pharmacol Sci 18(1997),46-50))。
此外,已经证实糖皮质激素(它是目前为止最有效的治疗哮喘的药物)通过直接与转录因子NF-κB的相互作用并抑制其活性以及激活肽-1(AP-1)而抑制气道炎症((Barnes P(1997)Pulmon PharmacolTherapeut 10,3-19),(Dumont A等,(1998)Trends Biochem Sci 23,233-235))。
通常,对NF-κB激活的抑制获得很强的抗炎作用,类似于或超过甾族化合物抗炎效果。所以,NF-B抑制作用应该可改善典型哮喘炎症症状、变应性鼻炎、特应性皮炎、荨麻疹、结膜炎、春季结膜炎、类风湿性关节炎、全身性红斑狼疮、牛皮癣、溃破性结肠炎、系统性炎症反应综合征、脓毒病、多肌炎、皮肤肌炎、Polyaritis nodoa、混合型结缔组织疾病、Sjoegren’S综合征、痛风等。
此外,几项研究提示NF-κB在肿瘤转化中起关键作用。例如,NF-κB与由于基因过度表达、扩增、重排或易位引起的体外以及体内的细胞转化有关(Mercurio,F.和Manning,A.M.(1999)Oncogene,18:6163-6171)。在某些人类淋巴肿瘤细胞中,NF-κB家族成员基因重排或扩增。Mayo,M.W.,Baldwin A.S.((2000)Biochmica et BiophysicaActa 1470 M55-M62还公开了它可能参与癌症病变。Mayo M.W.等公开了对NF-κB的抑制作用导致阻滞某些癌症、特别是结肠直肠癌的发生和/或发展。
最后,NF-κB还可能参与调节神经元细胞死亡。已经证实在局灶性脑缺血中NF-κB被激活并促进细胞死亡(Nature medicine第5卷第5期,1999年5月)。
过去数年的大量研究鉴定出IκB激酶(IKK)复合物负责信号诱导性IκB磷酸化((Mercurio,F.和Manning,A.M.(1999)Current Opinion inCell Biology,11:226-232)、(Mercurio,F.和Manning,A.M.(1999)Oncogene,18:6163-6171)、(Barnkett,M.和Gilmore T.D.(1999)Oncogene 18,6910-6924)、(Zandi,E.和Karin,M.,(1999)19:4547-4551)、(Israel,A.,(2000)trends in CELL BIOLOGY 10:129-133)以及(Hatada,E.N等,(2000)Current Opinion in Immunology,12:52-58)。这种复合物最有可能是导致NF-κB激活的所有各种刺激的整合点。IKK-复合物(分子量700-900 kDa)由不同蛋白组成,包括两种同源IκB激酶(称为IKK-α和IKK-β)、一种诱导NF-κB的上游激酶NIK、称为IKAP的支架蛋白(它把三种激酶限制一起)以及一种调节亚单位IKK-Y(它优选与IKK-β相互作用)。
IKK-β为756个氨基酸的丝氨酸-苏氨酸激酶,与IKK-α具有52%的同一性而且具有相同结构域结构((Mercurio F等(1997)Science278,860-866.)、(Woronicz JD等,(1997)Science 278,866-869.)、(ZandiE等,(1997)Cell 91,243-252.)。IKK-β与IKK-α在体外和细胞内分别生成同型二聚体及杂二聚体。IKK-β还与IKK-γ、IKAP、NIK以及IκBα相互作用。重组IKK-β以同等效力使IκBα和IκBβ在特异丝氨酸残基磷酸化(LiJ等,(1998)J Biol Chem 273,30736-30741.)、(ZandiE,Chen Y,Karin M(1998)Science 281,1360-1363.)。IKK-β与IKK-α相比具有更高的组成性激酶活性。与其一致的是,有数据提示,与IKK-α相比,过度表达的IKK-β激活转录NF-κB-依赖性报道基因的作用更强。已经证实不同细胞系或新的人细胞在不同刺激(包括TNF-α、IL-1β、LPS、抗-CD3/抗-CD28共同刺激、蛋白激酶C以及钙调磷酸酶、B-细胞受体/CD40配体刺激以及钒酸盐)作用下激活IKK-β。IKK-β在从患有类风湿性关节炎或骨关节炎患者的滑膜分离出的成纤维细胞样滑膜细胞(FLS)中激活(Zandi E等,(1997)Cell 91,243-252.)、(O’Connell MA等,(1998)J Biol Chem 273,30410-30414.)、(KempiakSJ等,(1999)J Immunol 162,3176-3187.)。此外,IKK-β能够被结构上相关的上游激酶MEKK-1和NIK激活,很可能是通过磷酸化T-环(激活环)内特异性丝氨酸残基以及通过某些蛋白激酶C同工型((Nakano H等,(1998)Proc Natl Acad Sci USA 95,3537-3542.)、(Lee FS等,(1998)Proc Natl Acad Sci USA 95,9319-9324.)、(Nemoto S等,(1998)Mol Cell Biol 18,7336-7343.)、(Lallena MJ等,(1999)Mol CellBiol 19,2180-2188.))。已经证实IKK-β的催化非活性突变体可以抑制由TNF-α、IL-1β、LPS、抗-CD3/抗-CD28刺激引起的NF-κB激活((Mercurio F等,(1997)Science 278,860-866.)、(Woronicz JD等,(1997)Science 278,866-869.))。当MEKK1或MK过度表达时也观测到同样的效果。此外,IKK-β激活环突变抑制IL-1和TNF-α信号转导(DelhaseM等,(1999)Science 284,309-313.)。基于上述试验结果,有非常清晰的证据显示在导致NF-κB激活的各种途径中IKK-β起关键作用。
简言之,对IKK-β的特异性抑制应该可导致体内很强抗炎以及免疫调节效果,能有效改善哮喘和其它疾病的主要病因。此外,可以预期IKK-β抑制剂具有抗肿瘤以及抗局部缺血作用。
Manna等公开了以下通式表示的4,6-二取代的3-氰基-2-氨基吡啶:其中(R’,R”)表示(OCH3,OCH3)、(Cl,Cl)、(H,Cl)、(H,Br)、(H,CH3)、(H,OCH3)、(H,NO2)或(H,N(CH3)2),
Manna等既没有公开在吡啶环的4位上有脂肪族基团的吡啶衍生物,也没有提到上述已知吡啶衍生物对IKK-β激酶或NF-κB的抑制活性。
因此需要开发基于特异性选择性抑制NF-κB活性的具有有效抗炎作用的新型化合物。
发明概述
其中R11为氢、C1-6烷基、卤素、羟基、C1-12烷氧基、硝基、氨基、C1-6烷基磺酰基氨基、C1-6烷氧基羰基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷酰基氨基、苯基C1-6烷基氨基、苯基磺酰基氨基或--O-(CH2)n-R111,
其中n为选自0-6的整数,R111为C2-6链烯基、苯甲酰基、二苯基甲基、二(C1-6烷基)氨基、C1-6烷酰基、C1-6烷氧基羰基、或具有0-3个选自S、O和N的杂原子的3-10元饱和或不饱和环且任选被以下基团取代:C1-6烷基、单或二卤素、卤素取代的C1-6烷基、硝基、氰基、C1-6烷氧基羰基、苯基、羟基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷酰基氨基、C1-6烷氧基或氨基甲酰基;
R2为氢或卤素;
R3为氢或1,2,3,6-四氢-吡啶、-CR31R32R33,
其中R31为氢或C1-6烷基,
R32为氢,α-氨基苄基,任选被一个或两个选自以下的取代基取代的C1-6烷基:羟基、氨基、氨基取代的苯基、苯基、卤素取代的苯基以及C1-6烷氧基取代的苯基,或者为具有0-3个选自S、O和N的杂原子的5-8元饱和环并任选被C1-6烷基取代,
R33为氢、氨基、C1-6烷氧基羰基氨基、C2-6链烯氧基羰基氨基、哌啶子基-C1-6烷基羰基氨基、哌啶基-C1-6烷基羰基氨基,或者
R32和R33可以与相邻碳原子构成具有0-3个选自N、O和S的杂原子的5-8元饱和环,所述环任选被以下基团取代:苯基-C1-6烷基、C1-6烷氧基取代的苯基-C1-6烷基、C1-6烷基、氨基、氰基、羟基、氨基甲酰基、羧基、C1-6烷基氨基、C1-6烷氧基羰基、二(C1-6烷基)氨基、苄基氨基、C1-6烷基磺酰基、哌啶子基C1-6烷基羰基,或者任选与苯稠合;
或者为
-NR34R35,
其中R34为氢或C1-6烷基,
R35为氢、具有0-3个选自N、O和S的杂原子的5-8元饱和环或者-(CH2)m-NR351R352(m表示1-6的任意整数)
其中R351为氢、C1-6烷基,
R352为氢、C1-6烷基、C1-6烷酰基、C1-6烷基取代的苯基、苯甲酰基、C1-6烷酰基、苯基氨基羰基、苯基磺酰基,或者
R34和R35可以与相邻的氮原子一起构成5-8元饱和杂环,除了相邻氮原子外所述杂环还可以任选包含NH、S或O原子,且任选被氨基甲酰基、氨基或C1-6烷基取代;
R4为羟基羰基、C1-6烷酰基、氨基甲酰基、硝基、氰基、羧基、C1-6烷氧基羰基、C1-6烷基氨基甲酰基、C1-6烷基氨基、5-10元杂芳基(羟基)甲基、5-10元杂芳基-C1-6烷基、或者被羟基和5-7元饱和环取代的甲基、任选被一个以下基团取代的C1-6烷基:羟基、C1-6烷氧基、C1-6烷基磺酰基氨基、C1-6烷基羰基氨基、C5-10芳基、C5-10芳基磺酰基、C5-10芳硫基、C5-10芳氧基、咪唑基或二氧代取代的吡咯烷氧基(pyrolidino-oxy),
-(CH2)pNHCOR41、-(CH2)pNHC(=S)R41,
其中p为1-6的任意整数,R41为C1-6烷氧基、氨基、苯基氨基、C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、C3-10环烷基氨基,
R3和R4可以与吡啶环上的碳原子一起构成4-10元单环烷基或双环烷基,任选插入NH并任选被苄基、=NH或=O取代;
R5为NR51R52,
其中R51为氢、C1-6烷基,
R52为氢、C1-6烷基、苯基、苄基、C1-6烷酰基,或者NR51R52可以构成饱和5-6元环,除了相邻氮原子外还任选包含NH或O其它杂原子,
或者
R4和R5可以构成
-R40-CO-NH-、-R40-SO2-NH-、-R40-C(=S)-NH-、-R40-CH2-NH-,
其中所述-R40-为-CHR401-O-、-CH2-NR401-、-CO-NR401-、-CH2-CHR401-、-CH=CR401-(其中R401为C1-6烷酰基、C1-6烷基、苯基、C1-6烷基磺酰基、C3-8环烷基氨基羰基、氢、卤素、硝基、氨基、氰基、苯甲酰基氨基、苯基磺酰基、氨基甲酰基、羟基羰基、C1-6烷氧基羰基、C1-12烷基氨基羰基、卤素取代的C1-6烷基氨基羰基、C1-6烷酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基羰基、二(C1-6烷基)氨基C1-6烷基氨基羰基、氢化茚基氨基羰基、二苯基甲基氨基羰基、吡咯烷基羰基、C1-6烷氧基C1-6烷基氨基羰基、吗啉代羰基、哌嗪基羰基、苯基C1-6烷基氨基羰基、羟基羰基C1-6烷基氨基羰基、C3-8环烷基氨基羰基、C3-8环烷基C1-6烷基氨基羰基、羟基C1-6烷基氨基羰基、羧基乙基氨基羰基、C1-6烷基磺酰基氨基羰基)
-CR41=N-NH-(R41为氢、氨基或C1-6烷酰基氨基)、-CR42=N-C=N-(R42为氢或氨基)。
本发明化合物具有出乎意料的优异IKK-β激酶抑制活性以及细胞因子抑制活性。因此,它们尤其适合用作NF-κB抑制剂以及特别适合用于制备可以用于治疗NF-κB依赖性疾病的药物或医用组合物。
更明确地讲,由于本发明吡啶衍生物抑制IKK-β激酶活性,所以它们可用于治疗和预防以下涉及NF-κB活性的疾病:炎性症状,包括哮喘;变应性鼻炎;特应性皮炎;荨麻疹;结膜炎;春季结膜炎;慢性关节风湿病;全身性红斑狼疮;牛皮癣;溃破性结肠炎;系统炎性反应综合征(SIRS);脓毒病;多肌炎;皮肤肌炎(DM);Polyaritisnodoa(PN);混合型结缔组织疾病(MCTD);Sjoegren’S综合征;痛风等。
本发明化合物还可用于治疗和预防如局部缺血和癌症等疾病,因为所述疾病也涉及IKK-β激酶活性以及NF-κB活性。
式(I)优选化合物为以下这样的化合物或其盐:
-R1为或
其中R11为氢、C1-6烷基、卤素、羟基、C1-12烷氧基、氨基、C1-6烷酰基氨基、苯基C1-6烷基氨基、苯基磺酰基氨基或-O-(CH2)n-R111,其中n为选自1-6的整数,R111为C2-6链烯基、苯甲酰基、二苯基甲基、二(C1-6烷基)氨基、C1-6烷酰基、C1-6烷氧基羰基或具有0-3个选自S、O和N的杂原子的3-10元饱和或不饱和环,任选被以下基团取代:C1-6烷基、单或二卤素、卤素取代的C1-6烷基、硝基、氰基、C1-6烷氧基羰基、苯基;
R2为氢;
R3为氢、1,2,3,6-四氢-吡啶、-CR31R32R33,
其中R31为氢或C1-6烷基,
R32为氢、α-氨基苄基、任选被一个或两个选自以下的取代基取代的C1-6烷基:羟基、氨基、氨基取代的苯基、苯基、卤素取代的苯基以及C1-6烷氧基取代的苯基,或者为具有0-3个选自S、O和N的杂原子的5-8元饱和环并任选被C1-6烷基取代,
R33为氢、氨基、C1-6烷氧基羰基氨基、C2-6链烯氧基羰基氨基、哌啶子基-C1-6烷基羰基氨基,或者
R32和R33可以与相邻碳原子构成具有0-3个选自N、O和S的杂原子的5-8元饱和环,所述环任选被以下基团取代:苯基-C1-6烷基、C1-6烷氧基取代的苯基-C1-6烷基、C1-6烷基、氨基、羧基、C1-6烷基氨基、C1-6烷氧基羰基、二(C1-6烷基)氨基、苄基氨基、C1-6烷基磺酰基、哌啶子基C1-6烷基羰基,或者任选与苯稠合;
或者为
-NR34R35,
其中R34为氢,
R35为氢、具有0-3个选自N、O和S的杂原子的5-8元饱和环或者-(CH2)m-NR351R352(m表示1-6的任意整数)
其中R351为氢、C1-6烷基,
R352为氢、C1-6烷基、C1-6烷酰基、C1-6烷基取代的苯基、苯甲酰基、C1-6烷酰基、苯基氨基羰基、苯基磺酰基,或者
R34和R35可以与相邻的氮原子一起构成5-8元饱和杂环,除了相邻氮原子外所述杂环还可以任选包含NH、S或O原子,任选被氨基甲酰基、氨基或C1-6烷基取代;
R4为羟基羰基、C1-6烷酰基、氨基甲酰基、氰基、羧基、C1-6烷氧基羰基、C1-6烷基氨基甲酰基、C1-6烷基氨基、5-10元杂芳基(羟基)甲基、5-10元杂芳基-C1-6烷基、或者被羟基和5-7元饱和环取代的甲基、任选被一个以下基团取代的C1-6烷基:羟基、C1-6烷氧基、C1-6烷基磺酰基氨基、C1-6烷基羰基氨基、C5-10芳基、C5-10芳硫基、C5-10芳基亚氧硫基、C5-10芳氧基、咪唑基或二氧代取代的吡咯烷氧基,
-(CH2)pNHCOR41、-(CH2)pNHC(=S)R41
其中p为1-6的任意整数,R41为C1-6烷氧基、氨基、苯基氨基、C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、C3-10环烷基氨基,
R3和R4可以与吡啶环上的碳原子一起构成4-10元单环烷基或双环烷基,任选插入NH并任选被苄基、=NH或=O取代;
R5为NR51R52,
其中R51为氢、C1-6烷基,
R52为氢、C1-6烷基、苯基、苄基、C1-6烷酰基,或者NR51R52可以构成哌啶子基,
或者
R4和R5可以构成
-R40-CO-NH-、-R40-SO2-NH-、-R40-C(=S)-NH-或-R40-CH2-NH-、
其中所述-R40-为-CHR401-O-、-CH2-NR401-、-CO-NR401-、(其中R401为氢、C1-6烷酰基、C1-6烷氧基羰基、C1-6烷基、苯基、C1-6烷基磺酰基、C3-8环烷基氨基羰基、C1-6烷基氨基羰基、氨基甲酰基、二(C1-6烷基)氨基羰基)、-CH2-CHR402-、-CH=CR402-、(其中R402为氢、卤素、硝基、氨基、氰基、苯甲酰基氨基、苯基磺酰基、氨基甲酰基、羟基羰基、C1-6烷氧基羰基、C1-12烷基氨基羰基、卤素取代的C1-6烷基氨基羰基、C1-6烷酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基羰基、二(C1-6烷基)氨基C1-6烷基氨基羰基、氢化茚基氨基羰基、二苯基甲基氨基羰基、吡咯烷基羰基、C1-6烷氧基C1-6烷基氨基羰基、吗啉代羰基、哌嗪基羰基、苯基C1-6烷基氨基羰基、C3-8环烷基氨基羰基、羟基羰基C1-6烷基氨基羰基、C3-8环烷基C1-6烷基氨基羰基、羟基C1- 6烷基氨基羰基、羧基乙基氨基羰基、甲基磺酰基氨基羰基),
-CR41=N-NH-(R41为羟基、氨基或C1-6烷酰基氨基)或-CR42=N-C=N-(R42为氨基)。
式(I)化合物更优选的化合物或其盐中:
其中R11为氢、C1-12烷氧基或-O-(CH2)n-R111,
其中n为选自1-6的整数,R111为苯基、C3-8环烷基;
R2为氢;
R3为1,2,3,6-四氢-吡啶、-CR31R32R33,
其中R31为氢,
R32和R33与相邻碳原子一起构成5-8元插入NH的饱和环,所述环任选被以下基团取代:苯基-C1-6烷基、C1-6烷氧基取代的苯基-C1-6烷基、C1-6烷基、氨基、羧基、C1-6烷基氨基、C1-6烷氧基羰基、二(C1-6烷基)氨基、苄基氨基、C1-6烷基磺酰基、哌啶子基C1-6烷基羰基,或者任选与苯稠合;
或者
-NR34R35,
其中R34为氢,
R35为-(CH2)m-NR351R352(m表示1-6的任意整数)
其中R351为氢、C1-6烷基,
R352为氢、C1-6烷基、C1-6烷酰基、C1-6烷基取代的苯基、苯甲酰基、C1-6烷酰基、苯基氨基羰基、苯基磺酰基;
R4为氰基、任选被羟基或C1-6烷氧基取代的C1-6烷基、或者
-(CH2)pNHCOR41、-(CH2)pNHC(=S)R41,
其中p为1-6的任意整数,R41为C1-6烷氧基、氨基、苯基氨基、C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、C3-10环烷基氨基;
R5为氨基,
或者
R4和R5可以构成
-R40-CO-NH-、-R40-SO2-NH-、-R40-C(=S)-NH-或-R40-CH2-NH-,
其中所述-R40-为-CHR401-O-、-CH2-NR401-、-CO-NR401-、(其中R401为氢、C1-6烷酰基、C1-6烷氧基羰基、C1-6烷基、苯基、C1-6烷基磺酰基、C3-8环烷基氨基羰基、C1-6烷基氨基羰基、氨基甲酰基、二(C1-6烷基)氨基羰基)、-CH2-CHR402-、-CH=CR402-、(其中R402为氢、卤素、硝基、氨基、氰基、苯甲酰基氨基、苯基磺酰基、氨基甲酰基、羟基羰基、C1-6烷氧基羰基、C1-2烷基氨基羰基、卤素取代的C1-6烷基氨基羰基、C1-6烷酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基羰基、二(C1-6烷基)氨基C1-6烷基氨基羰基、氢化茚基氨基羰基、二苯基甲基氨基羰基、吡咯烷基羰基、C1-6烷氧基C1-6烷基氨基羰基、吗啉代羰基、哌嗪基羰基、苯基C1-6烷基氨基羰基、C3-8环烷基氨基羰基、羟基羰基C1-6烷基氨基羰基、C3-8环烷基C1-6烷基氨基羰基、羟基C1- 6烷基氨基羰基、羧基乙基氨基羰基、甲基磺酰基氨基羰基)、-CR41=N-NH-(R41为羟基、氨基、C1-6烷酰基氨基)或-CR42=N-C=N-(R42为氨基)。
本发明化合物优选以下化合物或其盐:
1. | 7-(2-羟基苯基)-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]-噁嗪-2-酮; |
2. | 2-氨基-6-[2-(苄氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈; |
3. | 2-氨基-6-(2-羟基-6-丙氧基苯基)-4-(3-哌啶基)烟腈; |
4. | 2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-(苄氧基)苯酚; |
5. | 7-[2-(苄氧基)-6-羟基苯基]-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3d][1,3]噁嗪-2-酮; |
6. | 2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈三氟乙 |
酸盐; | |
7. | 7-(2-羟基苯基)-5-(3-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮; |
8. | 2-氨基-6-[2-(环丁基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈; |
9. | 2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-丙氧基苯酚; |
10 | 7-(2-羟基-6-丙氧基苯基)-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3d][1,3]-噁嗪-2-酮; |
11 | 7-(2-羟基-6-丙氧基苯基)-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯; |
12 | 7-(2-羟基-6-丙氧基苯基)-5-(3-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮; |
13 | 2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚; |
14 | 2-[6-氨基-5-(羟基甲基)-4-(4-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚; |
15 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮; |
16 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯; |
17 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(4-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮; |
18 | 6’-氨基-5’-(羟基甲基)-4’-(3-哌啶基)-2,2’-联吡啶-3-醇; |
19 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(4-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮; |
20 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-3-氟-5-(3-哌啶基)-1,8-萘啶-2(1H)-酮; |
21 | 7-(2-羟基-6-丙氧基苯基)-5-(4-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮; |
22 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,4-二氢-2H-吡啶 |
并[2,3-d][1,3]噁嗪-2-酮; | |
23 | 3-(环丙基甲氧基)-2-[5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-7-基]苯酚; |
24 | 2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-(新戊氧基)苯酚; |
25 | 2-[6’-氨基-5’-(羟基甲基)-1,2,5,6-四氢-3,4’-联吡啶-2’-基]苯酚; |
26 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,8-萘啶-2(1H)-酮; |
27 | N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基}乙酰胺; |
28 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-甲酰胺; |
29 | 3-乙酰基-7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢吡啶并[2,3-d]嘧啶-2(1H)-酮; |
30 | 2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(4-哌啶基)烟腈; |
31 | 2-氨基-4-[(2-氨基乙基)氨基]-6-[2-(环丙基甲氧基)-6-羟基-苯基]烟腈; |
32 | N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基}-N’-丙基脲; |
33 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢-吡啶并[2,3-d]嘧啶-2(1H)-酮; |
34 | [2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基氨基甲酸乙酯; |
35 | 2-氨基-6-{2-羟基-6-[(4-甲基戊基)氧基]苯基}-4-(4-哌啶基)烟腈; |
36 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-甲酰胺; |
37 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-N-异丙基-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-甲酰胺; |
38 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸乙酯; |
39 | N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基}脲; |
40 | 2-氨基-6-(2-羟基-6-丙氧基苯基)-4-(4-哌啶基)烟腈; |
41 | N-环己基-7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺; |
42 | 2-氨基-6-[2-(环丁基甲氧基)-6-羟基苯基]-4-(4-哌啶基)烟腈; |
43 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-N,N-二甲基-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺; |
44 | 2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(1-甲基-3-哌啶基)烟腈; |
45 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢-吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺; |
46 | [2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基氨基甲酸异丙酯; |
47 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸异丙酯; |
48 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸异丁酯; |
49 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸新戊酯; |
50 | [2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基氨基甲酸新戊酯; |
51 | 2-氨基-6-[2-(己氧基)-6-羟基苯基]-4-(4-哌啶基)烟腈; |
52 | 7-[2-(环丙基甲氧基)-6-羟基苯基]-N-乙基-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺。 |
本发明式(I)化合物可以(但不限于)结合各种已知方法制备。在部分实施方案中,用作初始原料或中间体的一个或多个本发明化合物取代基(例如氨基、羧基以及羟基)最好用本领域熟练技术人员已知的保护基团保护。Greene和Wuts的“Protective Groups in OrganicSynthesis(第二版)”介绍了保护基团的实例。
例如通过以下的反应流程A可以制备化合物(I-a)或其盐,
其中X为CH或N,R11、R2和R3定义同上。
式(II)化合物
其中R11和R定义同上,与式R3-CHO(III)醛、式(IV)NCCH2CN腈以及铵盐(例如乙酸铵)反应。R3定义同上。在某些情况下,最好用R3’-CHO(III’)替代R3-CHO(III)。R3’可以为被乙基、叔丁基等酯化的R3或者可以通过常规方法容易地转化为R3的其它酯或取代基。在反应期间式(II)化合物的羟基用适当的保护基团(例如苄基、甲氧基苄基和甲硅烷基)保护,反应后去保护。R3’还可以用酸处理获得R3。
反应流程A
反应流程A中步骤1和步骤1’可以在没有溶剂或在溶剂中进行,溶剂包括:例如醚(例如二氧六环和四氢呋喃);芳族烃(例如苯、甲苯和二甲苯);腈(例如乙腈);酰胺(例如二甲基甲酰胺(DMF)和二甲基乙酰胺);亚砜(例如二甲基亚砜)等。
反应温度可根据反应化合物选择设定。反应温度通常为(但不限于)约50℃~200℃。通常反应可以进行30分钟~48小时、优选1~24小时。
通式(II)、(III)、(III’)化合物可以市售获得或可以用已知工艺制备。
反应流程A的步骤2和步骤2’可以在例如以下条件进行:在氢气氛中,氢化催化剂,例如Pd-C,在溶剂中,溶剂包括例如酯(例如乙酸乙酯)、醚(例如二氧六环和四氢呋喃);芳族烃(例如苯、甲苯和二甲苯);腈(例如乙腈);酰胺(例如二甲基甲酰胺(DMF)和二甲基乙酰胺);亚砜(例如二甲基亚砜)等。
反应温度可以为(但不限于)约50℃~200℃。通常反应可以进行30分钟~48小时、优选1~24小时。
反应流程A的步骤3和步骤3’可以为从酯获得R3的任何类型的常规反应,例如用酸处理、用碱处理、酰胺化以及氢化或其它反应(例如烷基化)等来获得R3。
其中X、R2和R3定义同上,Y为C1-12烷基或R111-(CH2)n-,其中R111和n定义同上。
反应流程B
在反应流程B中,式(II-a)化合物与醛(III)、腈(IV)以及乙酸铵在反应流程A的相同条件下获得式(V’)化合物。通式(II-a)化合物的苄基保护基团可以用任何适当的保护基团替代。反应完后除去保护基团。反应流程B的步骤4中,化合物(V)与L-Y反应,其中L为离去基团,例如卤素原子,例如氯、溴或碘原子;C6-C10芳基磺酰氧基,例如苯磺酰氧基、多磺酰氧基或对甲苯磺酰氧基;C1-C4烷基磺酰氧基,例如甲烷磺酰氧基等。Y为C1-C6烷基或-(CH2)n-R111(其中R111定义同上)。化合物(V)与L-Y的反应可以在溶剂中进行,溶剂包括:例如醇(例如甲醇和乙醇);醚(例如二氧六环和四氢呋喃(THF));腈(例如乙腈);酰胺(例如二甲基甲酰胺(DMF)和二甲基乙酰胺);亚砜(例如二甲基亚砜)等。任选使用两种或多种以上所列溶剂的混合物。
化合物(V)与L-Y的反应温度可以根据反应化合物选择设定。反应温度通常为(但不限于)约-10℃~200℃,优选约10℃-80℃。通常反应可以进行30分钟~48小时、优选1~24小时。反应最好在碱存在下进行。碱的实例包括碱金属氢化物(例如氢化钠或氢化钾);碱金属醇盐(例如甲醇钠或乙醇钠);碱金属氢氧化物(例如氢氧化钠或氢氧化钾);碳酸盐(例如碳酸钠或碳酸钾)以及碳酸氢盐(例如碳酸氢钠和碳酸氢钾);有机胺(例如三乙胺)。
反应流程B步骤3与反应流程A步骤3相同。
其中X、R11、R2、R34和R35定义同上。
首先,式(VI)化合物可以与二硫化碳以及R60-L(其中R60为C1-6烷基,L为以上定义的离去基团)反应获得式(VII)化合物。式(VI)化合物的苄基保护基团可以用任何适当的保护基团替代。在碱(例如氢化钠和二甲基乙酰胺的混合物)存在下反应可有利于本反应。
所得化合物(VII)可以与氰基乙酰胺在溶剂和碱存在下反应。然后,可以氧化化合物(VIII)获得化合物(IX)。再将化合物(IX)与卤代乙酰胺(例如氯代乙酰胺)在碱存在下在溶剂中反应。所得化合物(X)与NHR34R35(R34和R35定义同上)反应。最后,所得产物与碱反应,去保护后获得化合物(I-c)。
反应各个步骤中使用的溶剂包括例如醚(例如二氧六环和四氢呋喃);芳族烃(例如苯、甲苯和二甲苯);腈(例如乙腈);酰胺(例如二甲基甲酰胺(DMF)和二甲基乙酰胺);亚砜(例如二甲基亚砜)等。上述溶剂可以单独或组合使用。
反应中使用的碱的实例包括碱金属氢氧化物(例如氢化钠或氢化钾);碱金属醇盐(例如甲醇钠或乙醇钠);碱金属氢氧化物(例如氢氧化钠或氢氧化钾);碳酸盐(例如碳酸钠或碳酸钾)以及碳酸氢盐(例如碳酸氢钠和碳酸氢钾);有机胺(例如三乙胺)。
反应温度可根据反应化合物选择设定。除非另有说明,反应温度约10℃~200℃。通常各反应步骤可以进行30分钟~48小时、优选1~24小时。
如果需要,吡啶环二位的氨基可按照常规方法修饰以制备其它基团例如烷基氨基、烷酰基氨基等。
当R11为C1-6烷基磺酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷酰基氨基、苯基C1-6烷基氨基或苯基磺酰基氨基时,它在反应流程A中用常规方法从-NH2衍生得到。
式(I-a)、(I-b)和(I-c)的化合物可以进一步反应以修饰吡啶环的2位以及3位取代基,合成所需要的本发明范围的化合物。同样在以上反应流程A、B和C中,可以修饰吡啶环的2位及3位取代基。可以用以下的常规方法修饰2位的氨基:
其中L为离去基团且定义同上,Z为苄基、C1-6烷基或苯基,或者NHZ可以构成5-6元饱和环,所述环除相邻氮原子外,任选包含NH或O其它杂原子。
另一实施方案中,2位的氨基可以利用酰基氯转化为酰胺。
3位的氰基可以用常规的碱水解转化为氨基甲酰基。
利用酯的常规反应,可容易地将3位的叔丁氧基羰基修饰为醇、羧基等。醇或羧基可以进一步用常规方法转化为其它取代基。
而在另一实施方案中,3位和4位的取代基一起构成任选具有取代基的环。任何常规方法或其组合可以用于形成环。形成环的实例如下所示。
当式(I)所示化合物或其盐具有互变异构体和/或立体异构体(例如几何异构体和构象异构体)时,它们的单独的异构体或其混合物也包括在本发明范围。
当式(I)所示化合物或其盐的结构中具有不对称碳原子时,它们的旋光化合物和外消旋混合物也包括在本发明范围。
式(I)所示化合物的典型盐包括由本发明化合物与无机酸或有机酸、或者有机碱或无机碱反应制备的盐。所述盐分别称为酸加成盐和碱加成盐。
形成酸加成盐的酸包括无机酸,例如(但不限于)硫酸、磷酸、盐酸、氢溴酸、氢碘酸等,以及有机酸,例如(但不限于)对甲苯磺酸、甲磺酸、乙二酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸、乙酸等。
碱加成盐包括衍生自无机碱的盐,无机碱,例如(但不限于)氢氧化铵、碱金属氢氧化物、碱土金属氢氧化物、碳酸盐、碳酸氢盐等,以及有机碱,例如(但不限于)乙醇胺、三乙胺、三(羟基甲基)氨基甲烷等。无机碱的实例包括氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钙、碳酸钙等。
根据其取代基,本发明化合物或其盐可以修饰形成低级烷基酯或已知的其它酯;和/或水合物或其它溶剂化物。这些酯、水合物以及溶剂化物都包括在本发明范围。
本发明化合物可以以口服制剂给药,例如(但不限于)常规片剂和肠包衣片剂、胶囊剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、溶液剂、混悬剂、糖浆剂、固体气雾剂和液体气雾剂以及乳剂。它们也可以为药学领域普通技术人员熟知的胃肠外制剂给药,例如(但不限于)静脉内、腹膜内、皮下、肌内等制剂。本发明化合物可以通过局部使用合适的鼻内溶媒以鼻内制剂给药或用本领域普通技术人员熟知的透皮给药系统通过透皮途径给药。
使用本发明化合物的剂量方案可以由本领域普通技术人员根据各种因素选择,包括但不限于年龄、体重、性别以及接受者的健康状况、所治疗病症的严重程度、给药途径、接受者的代谢水平以及排泄功能、使用的剂型、使用的具体化合物及其盐。
本发明化合物优选在给药前与一种或多种药学上可接受的赋形剂配制在一起。赋形剂为惰性物质,例如但不限于载体、稀释剂、调味剂、甜味剂、润滑剂、增溶剂、混悬剂、粘合剂、片剂的崩解剂以及包囊材料。
而本发明的另一实施方案为包含本发明化合物以及一种或多种药学上可接受的赋形剂的药用制剂,所述赋形剂与制剂的其它成分相容而且对接受者无害。通过混合治疗有效量的本发明化合物与一种或多种相容性药学上可接受的赋形剂制备本发明药用制剂。制备本发明组合物过程中,活性成分可以与稀释剂混合,或包封于载体内,载体可以为胶囊、小药囊、纸或其它容器形式。所述载体可以用作稀释剂,它可以为固体、半固体或用作溶媒的液体,或者可以为片剂、丸剂、粉末剂、锭剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂、包含例如最多10%(重量)活性成分的软膏、软明胶胶囊以及硬明胶胶囊、栓剂、无菌注射液以及无菌包装的粉末形式。
对于口服给药,活性成分可以与口服无毒性的药学上可接受载体混合,例如但不限于乳糖、淀粉、蔗糖、葡萄糖、碳酸钠、甘露醇、山梨醇、碳酸钙、磷酸钙、硫酸钙、甲基纤维素等;任选与崩解剂混合一起,例如但不限于玉米、淀粉、甲基纤维素、琼脂皂土、黄原胶、海藻酸等;任选粘合剂,例如但不限于明胶、阿拉伯胶、天然糖、β-乳糖、玉米甜味剂、天然及合成树胶、阿拉伯胶、黄芪胶、藻酸钠、羧甲基纤维素、聚乙二醇、蜡等;任选润滑剂,例如但不限于硬酯酸镁、硬酯酸钠、硬脂酸、油酸钠、苯甲酸钠、乙酸钠、氯化钠、滑石粉等。
对于粉末制剂,载体可以为微细固体,它与微细活性成分混合。活性成分可以与具有粘结性质的的载体以适当比例混合,压制成所需要的形状及尺寸的片剂。所述粉剂和片剂优选包含约1~99%(重量)的活性成分,其为本发明新型组合物。合适的固体载体有羧基甲基纤维素镁、低熔点蜡以及可可油。
无菌液体制剂包括混悬剂、乳剂、糖浆剂和酏剂。活性成分可以溶于或悬浮于药学上可接受的载体,例如无菌水、无菌有机溶剂或无菌水和无菌有机溶剂的混合物。
活性成分也可溶于合适的有机溶剂,例如丙二醇水溶液。可以通过将微细活性成分分散于淀粉水溶液或羧基甲基纤维素钠水溶液或适当的油液制备其它组合物。
制剂可以为适合给予人或其它哺乳动物的单位剂型,它为包含单位剂量的物理分散单位。单位剂型可以为胶囊或片剂、或多个胶囊或片剂。“单位剂量”是预先确定数量的本发明活性化合物(设计产生所需治疗效果)和一种或多种赋形剂。单位剂量中活性成分量可以在约0.1~1000mg范围内变化或调整,或者根据具体的治疗对象可更高。
当用于所指出的作用时,本发明的通常口服剂量为约0.01mg/kg/天~100mg/kg/天、优选0.1mg/kg/天~30mg/kg/天、最优选约0.5mg/kg/天~10mg/kg/天。为胃肠外给药情况下,已证实的通常有利给药量为约0.001~100mg/kg/天,优选0.01mg/kg/天~1mg/kg/天。本发明化合物可以每天以单剂量给药,或者将每天总剂量以分剂量给药,每天2次、3次或更多次。当然如果通过透皮剂型给药,给药是连续的。
本发明化合物的效果通过以下测试和药理试验进行检验。[IKK-β激酶抑制测定](1)制备IKK-β激酶蛋白。
利用公开序列(Woronicz JD等,(1997)Science 278,866-869)设计的一对引物通过PCR产生编码人IKK-β可读框的cDNA片段。用ElongaseTM扩增试剂盒(Life Technologies)由QuickclonecDNA(Clontech)获得模板。凝胶纯化通过PCR产生的所述DNA片段,亚克隆入pBluescript。将Bluescript中克隆的cDNA片段插入到pcDNA3.1/His C KpnI/NotIp,然后转移入pVL1393SmaL/XbaI(Pharmingen)构建杆状病毒转移载体。然后将载体与线性化杆状病毒(BaculoGoldTM,Pharmingen)一起用于转染Sf21细胞(Invitrogen,San Diego,CA)。产生的重组杆状病毒在Sf21细胞中克隆并扩增,在补充10%FCS、50g/ml庆大霉素、0.1%Pluronic F-68(LifeTechnologies,Inc.)的TNM-FH昆虫细胞培养基(Life Technologies,Inc.)的悬浮培养物(200ml于1L锥形烧瓶中;27℃;130rpm)中生长。用该扩增病毒以感染复数5按照标准方案(Crossen R,Gruenwald S(1997)Baculovirus Expression Vector System Instruction Manual,PharmingenCorporation)感染Sf21细胞,48小时后收获。将细胞溶解获得所产生的IKK-β激酶与组氨酸融合的嵌合蛋白(His-标记的IKK-beta)。
(2)制备纯化的GST-IκBα融合蛋白
构建包含编码在IPTG-诱导型启动子控制下的GST与IκBα氨基酸残基1-54融合蛋白的核苷酸序列的表达载体。将表达载体引入大肠杆菌,培养转化株后溶解获得GST-IκBα融合蛋白。然后将所得GST-IκBα融合蛋白纯化并生物素化用于激酶测试。
(3)检测IKK-β激酶活性
用96-孔板进行IKK-β激酶测定测试本发明化合物的抑制活性。首先,将5μl含2.5%二甲基亚砜(DMSO)的受试化合物加入U型底96孔板(Falcon)的所有孔。背景(BG)以及完全磷酸化(TP)的对照孔中加入5μl 2.5%DMSO。将重组IKK-β(最终0.6μg/ml)和生物GST-IκBα(1-54)(最终0.2uM)用25μl 2x激酶缓冲液β(40mM Tris-HCl,pH 7.6,40mM MgCl2、40mM β-甘油磷酸酯、40mM对硝基苯基磷酸、2mMEDTA、40mM磷酸肌酸、2mM DTT、2mM Na3VO4、0.2mg/ml BSA以及0.8mM苯基甲基磺酰氟)稀释,转移到96-孔板。将不含IKK-β的生物-GST-IκBα(1-54)的25μl 2x激酶缓冲液β转移到BG孔。然后加入20μl 12.5μM ATP、62.5μCi/ml[γ-33P]ATP(AmershamPharmacia Biotech),所得混合物在室温下温育2小时。加入150μl终止缓冲液(100mM EDTA、1mg/ml BSA、0.2mg NaN3)终止激酶反应。将150μl样品转移到包被链霉抗生物素蛋白的白色MTP(SteffensBiotechniche Analysen GmbH#08114E14.FWD)以捕获生物素化的底物。温育1小时后,利用MW-96平板洗涤器(BioTec)用300μl包括0.9%NaCl和0.1%(w/v)吐温-20的洗涤缓冲液洗涤各孔5次以消除未结合的放射性。加入170μL MicroScint-PS闪烁混合物(Packard)后用TopCount闪烁计数器检测结合的放射性。[Syk酪氨酸激酶选择性抑制测定]
(1)制备Syk蛋白
利用RT-PCR法,用人Burkitt淋巴瘤B细胞系Raji(American TypeCulture Collection)的全部RNA克隆编码人Syk可读框的cDNA片段。将所述cDNA片段插入到pAcG2T(Pharmingen,San Diego,CA)构建杆状病毒转移载体。然后将载体与线性化杆状病毒(BaculoGoldTM,Pharmingen)一起用于转染Sf21细胞(Invitrogen,San Diego,CA)。
产生的重组杆状病毒在Sf21细胞中克隆并扩增。用该扩增的高滴度病毒感染Sf21细胞,以便产生Syk激酶与谷胱甘肽-S-转移酶(GST)融合的嵌合蛋白。
用谷胱甘肽柱(Amersham Pharmacia Biotech AB,Uppsala,Sweden)按照制造商的用法说明书纯化所得的GST-Syk。SDS-PAGE证实其蛋白纯度为90%以上。
(2)合成肽
然后,包括两个酪氨酸残基的30个残基肽片段(KISDFGLSKALRADENYYKAQTHGKWPVKW)用肽合成仪合成。再将所述片段的N-末端生物素化获得生物素化激活环形肽(AL)。
(3)检测Syk酪氨酸激酶活性
所有试剂用Syk激酶测试缓冲液(50mM Tris-HCl(pH8.0)、10mMMgCl2、0.1mM Na3VO4、0.1%BSA、1mM DTT)稀释。首先,将包括3.2μg GST-Syk和0.5μg AL的混合物(35μl)加入96孔板的所有孔。然后5μl受试化合物在2.5%二甲基亚砜(DMSO)存在下加入到各孔。该混合物中加入300μM ATP(10μl)引发激酶反应。最终反应混合物(50μl)由0.65nM GST-Syk、3uM AL、30uM ATP、一种受试化合物、0.25%DMSO以及一种Syk激酶测试缓冲液组成。
混合物在室温下(RT)温育1小时,加入120μl终止缓冲液(50mMTris-HCl(pH 8.0)、10mM EDTA、500mM NaCl、0.1%BSA)终止反应。将混合物转移到包被链霉抗生物素蛋白的平板,在室温下温育30分钟使生物素-AL结合到平板。用包含0.05%吐温-20的Tris-缓冲盐水(TBS)(50mM Tris-HCl(pH 8.0)、138mM NaCl、2.7mM KCl)洗涤所述平板3次后,加入由50mM Tris-HCl(pH8.0)、138mM NaCl、2.7mM KCl、1%BSA、60ng/ml抗磷酸酪氨酸单克隆抗体、4G10(Upstate Biotechnology)组成的100μl抗体溶液后在室温下温育60分钟,所述抗体溶液提前用Amersham Pharmacia试剂盒进行铕标记。洗涤后,加入100μl增强溶液(Amersham Pharmacia Biotech),然后用多标记计数器ARVO(Wallac Oy,Finland)检测时间分辨荧光,以400毫秒延迟以及400毫秒窗口在340nm激发,615nm发射。[检测在TNF-α作用下A549细胞的RANTES产量]
(1)制备A549细胞
将人A549肺上皮细胞系(ATCC#CCL-g85)维持于补充了10%FCS(Gibco)、100U/ml青霉素、100μg/ml链霉素以及2mM谷酰胺(培养基)的Dulbecco改良型Eagle培养基(D-MEM,Nikken BiomedicalInstitute)。在96孔平底组织培养板(Falcon#3072)的各孔中接种4万(4×104)细胞(80μl/孔)。所述板静置2小时,因此细胞粘附于各孔底。各孔中加入10μl溶媒(1%DMSO)、受试化合物的1%DMSO系列稀释液或者5nM地塞米松的1%DMSO溶液作为对照。混合物(90μl/孔)在37℃温育1小时。1小时后,将1μg/ml TNF-α(10μl)的培养基加入到混合物获得100μl反应混合物。将反应混合物培养24小时以使100ng/ml TNF-α刺激细胞。同样制备没有TNF-α,仅有溶媒的细胞。
(2)检测RANTES产量
然后,用定量夹层酶免疫测定技术测定各孔上清液中细胞释放的RANTES浓度。首先,在96孔NUNC氟板(Nalge Nunc,New YorkUSA)的各孔中加入2μ/kl 小鼠抗人RANTES mAb(R & D Systems,#mAb678)的PBS缓冲液(pH7.4,100μl)(最终200ng/孔),将所述板在4℃静置过夜以进行抗体包被。然后将板的各孔用350μl洗涤缓冲液(0.05%吐温-20、0.85%NaCl以及25mM Tris/HCl pH7.4)洗涤三次。各孔中加入包含1%BSA(Sigma99%纯度,100g)、5%蔗糖(Nacalaitesque,99%纯度,500g)以及0.02%叠氮化物(Nacalai tesque,100%,500g)的封闭缓冲液(200μl),然后将板静置4小时以稳定包被抗体。其次,在包被抗体的96孔NUNC氟板的各孔中加入以上(1)中制备的细胞培养物上清液50μl。以重组的人RANTES(Pepro Tech,Inc.#300-06)作为标准测定RANTES产量(线性范围1~10ng/ml)。各孔中加入Eu-标记的小鼠抗人RANES mAb(60ng/ml:R & D Systems,#mAb278)的补充了1%BSA和0.05%吐温20的PBS(50μl)。反应混合物在室温下温育4小时。在利用Sera Washer(Sera Washer)(Bio-Tech,#MW-96R)用洗涤缓冲液(0.05%吐温-20、0.85%NaCl以及25mM Tris/HCl pH7.4,350μl/孔)洗涤5次后,将增强溶液(DELFIA,#1244-405,100μl/孔)加入各孔。所述板在室温、适度振摇下温育10分钟。荧光强度用DELFIA荧光计(Wallac)检测。在340nm激发,在615nm检测发射。[检测在LPS作用下外周血单核细胞(PBMC)的TNF-α产量]
(1)制备PBMC
制备人PBMC:首先从健康供血者获得血液,从血液分离细胞。所述分离用Ficoll Pacque(Pharmacia#17-1440-02)通过Ficoll梯度离心法完成。献血后3小时内使用所分离的PBMC。用PBS洗涤3次后,将PBMC重新悬浮于补充了10%FCS(Gibco)、100U/ml青霉素、100μg/ml链霉素以及2mM谷酰胺(培养基)的RPMI 1640(NikkenBioMedical Institute)。将细胞(1×105个,150μl/孔)接种到96孔平底组织培养板(Falcon#3072)的各孔中。各孔中加入20μl溶媒(1%DMSO)、受试化合物的1%DMSO系列稀释液或250nM地塞米松的1%DMSO溶液作为对照。混合物(170μl/孔)在37℃温育1小时。1小时后,将20ng/ml LPS(30μl)的培养基加入到混合物获得200μl反应混合物。将反应混合物培养7小时以使3ng/ml LPS刺激细胞。同样制备没有LPS刺激,仅有溶媒的细胞。然后收集反应混合物的上清液。
(2)检测TNF-α产量
用DuoSetTM ELISA Development Kit(GenzymeTechne,Minneapolis,USA)按照制造商的推荐方法测定所述上清液的TNF-α浓度。首先,在96孔板(NUNC,MaxisorpTM的各孔中加入4μg/ml小鼠的抗人TNF-αAb的PBS缓冲液(100μl),将所述板在4℃静置过夜使抗体进行包被。然后将板的各孔利用Sera Washer(Bio-Tech,#MW-96R)用350μl包含PBS、0.05%吐温20(Nakalai tesque)的洗涤缓冲液洗涤五次。各孔中加入300μl 1%BSA(Sigma)、5%蔗糖的PBS。在室温下温育2小时后,废弃缓冲液,加入50μl培养基。其次,在96孔板的各孔中加入以上(1)中制备的经刺激的细胞培养物上清液50μl。以重组的人TNF-α(Genzyme Techme)作为标准测定TNF-α产量(线性范围30~2,000pg/ml)。反应混合物在室温下温育1小时。洗涤5次后,各孔中加入100μl生物素化山羊抗人TNF-α抗体(GenzymeTechne,300ng/ml)的含0.1%BSA、0.05%吐温的PBS(试剂稀释液),在室温下温育1小时。经过5次洗涤后,各孔中加入100μl结合链霉抗生物素蛋白的辣根过氧化物酶(Genzyme Techne,1/100的试剂稀释液)。20分钟后,将所述板的各孔用洗涤缓冲液(350μl/孔)洗涤5次。将辣根过氧化物酶的底物和H2O2(TMBZ过氧化物酶检测试剂盒,SUMILON#ML-1120T)加入混合物,混合物在室温下静置。10分钟后加入2N H2SO4终止反应。用微量培养板读数器(Labosystems,Multiscan Multisoft)在450nm检测光密度。通过对比各样品与标准曲线的光学密度进行各样品的TNF-α定量分析。[检测在抗体刺激作用下Jurkat T细胞的IL-2产量]
检测Jurkat T细胞(E6-1克隆;ATCC#TIB-152)在抗CD3/抗CD28抗体刺激作用下的IL-2产量
(1)制备固定抗体
首先,将抗-CD3抗体(400ng/孔Nichirei,NU-T3 4μg/ml的100μl Dulbecco’s PBS)加入96-孔板(Falcon#3072)的各孔中,将所述板在室温下静置2小时使抗体包被其上。然后将所述板各孔用250μl PBS洗涤3次。
(2)制备Jurkat细胞培养物
Jurkat T细胞用补充了10%加热灭火的胎牛血清、2mM L-谷酰胺、100U/ml青霉素G以及100μg/ml链霉素(培养基)的RPMI 1640培养基培养。将20万(2×105)细胞(190μl/孔)接种到96-孔U型底组织培养板(Falcon#3077)的各孔。各孔中加入10μl溶媒(0.2%DMSO)、化合物的0.2%DMSO系列稀释液或作为参考的25 nM环孢菌素A的0.2%DMSO溶液。混合物(200μl)在37℃、湿化5%CO2环境中温育1小时。
(3)刺激细胞
将(2)中获得反应混合物(100μl)加入(1)中准备的固定抗体板的各孔。孔中加入抗-CD28抗体(Nichirei,KOLT-2,6μg/ml细胞培养基,50μl/孔)以及2.5μg/ml山羊抗小鼠κ链抗体(Bethyl Laboratories,(Cat#A90-119A)10μg/ml培养基,50μl/孔)。将各孔反应混合物在37℃温育24小时使固定抗-CD3抗体(400ng/well)以及抗-CD28抗体(1.5ug/ml)刺激细胞,然后用抗小鼠κ链抗体(2.5μg/ml)交联细胞受体。
(4)检测IL-2产量
然后收集所述反应混合物的上清液。用DuoSetTM ELISADevelopment Kit(GenzymeTechne,Minneapolis,USA)按照制造商的推荐方法测定所述上清液的IL-2浓度。首先,在96孔板(NUNC,MaxisorpTM)的各孔中加入2μg/ml小鼠抗人IL-2 Ab的PBS缓冲液(100μl),将所述板在4℃静置过夜使抗体包被于板上。然后将板的各孔利用Sera Washer(Bio-Tech,#MW-96R)用350μl包含PBS、0.05%吐温20(Nakalai tesque)的洗涤缓冲液洗涤五次。各孔中加入250μl 1%BSA(Sigma)的PBS、0.05%吐温20(稀释缓冲液)。在室温下温育2小时后,废弃缓冲液,加入50μl培养基。其次,在包被小鼠抗人IL-2抗体的96孔板各孔中加入以上(3)中制备的经刺激的细胞培养物上清液50μl。以重组的人IL-2(Genzyme Techne)作为标准测定IL-2产量(线性范围200~5,400pg/ml)。反应混合物在室温下温育1小时。经过5次洗涤后,各孔中加入100μl生物素化兔抗人IL-2抗体(GenzymeTechne,1.25μg/ml)的稀释缓冲液,在室温下温育1小时。经过5次洗涤后,各孔中加入100μl结合链霉抗生物素蛋白的辣根过氧化物酶(Genzyme Techne,1/1000的稀释缓冲液)。20分钟后,将所述板的各孔用洗涤缓冲液(350μl/孔)洗涤5次。将底物和H2O2(TMBZ过氧化物酶检测试剂盒,SUMILON#ML-1120T)加入混合物,混合物在室温下静置。10分钟后加入2N H2SO4终止反应。用微量培养板读数器(Labosystems,Multiscan Multisoft)在450nm检测光密度。通过对比各样品与标准曲线的光学密度进行各样品IL-2产量的定量分析。[小鼠LPS-诱导的TNF-α产量]
8周龄BALB/C雌性小鼠分成两组,一个对照组和一个处理组。将一种溶液(包含200μg/小鼠LPS的0.9%生理盐水溶液)腹膜注射(ip)给予对照小鼠。处理组小鼠在首先腹膜注射本发明化合物30分钟后注射LPS。在给予戊巴比妥(80mg/kg,i.p.)麻醉下,在LPS注射后90分钟从处理组以及对照组小鼠的后静脉腔收集血液放入包含2%EDTA溶液的96孔板。在4℃以1800rpm离心分离血浆10分钟,然后用4倍体积的包含1%牛血清白蛋白的磷酸盐缓冲盐水(pH7.4)稀释。用酶联免疫吸附测定试剂盒(Pharmingen,San Diego,CA.)测定样品的TNF-α浓度
测定各组5只小鼠TNF-α平均水平,然后计算TNF-α水平减少的百分数。与对照小鼠相比,处理组小鼠TNF-α水平显著降低。所得结果说明本发明化合物能够抑制LPS-诱导的细胞因子活性。
体外测试结果和细胞测定结果(A549)见以下的实施例以及实施例表格。数据对应于固相合成得到的化合物,因此纯度水平约40-90%。由于应用原因,所述化合物活性分为以下四级:
体外:IC50=A(=或<)0.5uM<B(=或<)2-<C(=或<)10μM<D
细胞:IC50=A(=或<)1μM<B(=或<)10μM<C
本发明化合物在其它细胞活性和体外测定中显示了优异的选择性以及很强的活性
实施例
本发明将在以下用实施例详细介绍,但它们绝不应该解释为对本发明界限和范围的限定。
如果没有其它说明,以下实施例中所有涉及百分数的定量数据为重量百分数。质子核磁共振(1H NMR)谱用Bmker DRX-300在300或500 MHz进行记录
500 Bruker UltraShieldTM和化学位移以相对于四甲基硅烷(TMS)的百万分之几表示。质谱用电雾化(ES)电离技术(micromass PlatformLC)获得。[初始化合物1A]
(初始化合物1A)
将2’-羟基苯乙酮(68.1g,0.500mol)、苄基溴(94.1g,0.550mol)以及K2CO3(103g,0.750mol)的丙酮(1.0L)混合物加热回流,然后持续搅拌过夜。在冷却至室温后,减压浓缩混合物。残余物用水稀释,然后用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。减压蒸馏提纯粗产物获得无色油状物1-[2-(苄氧基)苯基]乙酮。(100g产量;88%)[初始化合物1B]
2’-羟基苯乙酮(6.79g,30mmol)的乙醚(200ml)溶液中加入溴(5.00g,31mmol)的乙醚(20mL)溶液。在室温下搅拌30分钟后,混合物用乙醚(100mL)稀释,然后依次用饱和NaHCO3水溶液(100mL)和盐水(100mL)洗涤。合并的有机相用硫酸钠干燥,过滤后减压浓缩。残余物依次用乙醚和己烷洗涤,然后减压干燥获得1-[2-(苄氧基)苯基]-2-溴乙酮。(8.42 g产量;92%)
(初始化合物1B)
1-[2-(苄氧基)苯基]-2-溴乙酮(2.59g,8.5mmol)和吡啶(1.37mL,17mmol)的THF溶液中加入四丁基铵二氟化氢(4.78g,17mmol)。反应混合物在回流下搅拌22小时。混合物用乙醚(250mL)稀释,然后依次用1N盐酸水溶液(100mL)和盐水(100mL)洗涤。有机相用硫酸钠干燥,过滤后减压浓缩。粗产物用硅胶柱色谱法(己烷/乙酸乙酯,4∶1)提纯获得1-[2-(苄氧基)苯基]-2-氟乙酮(688mg产量;33%)。[初始化合物1C]
(初始化合物1C)
在搅拌下的2’-羟基苯乙酮(5.000g,36.724mmol)的乙腈(200mL)溶液中加入碳酸钾(7.613g,55.086mmol)。将混合物在50℃搅拌30分钟。将4-硝基苄基溴(8.727g,40.396mmol)加入混合物,然后继续在50℃搅拌12小时。将碳酸钾(0.508g,3.672mmol)和4-硝基苄基溴(0.793g,3.672mmol)加入到混合物,所得混合物在50℃搅拌12小时。冷却至室温后,减压浓缩反应混合物,用乙酸乙酯稀释。有机相用水洗涤,用硫酸钠干燥,过滤,然后浓缩。所得残余物用己烷洗涤获得白色固体1-{2-[(4-硝基苄基)氧基]苯基}乙酮。(8.900g产量;89%)[初始化合物1D]
(初始化合物1E)
(2’,6’-二羟基)苯乙酮(25.0g,164mmol)、苄基溴(40ml,337mmol)、碳酸钾(136g,986mmol)和碘化钠(2.5g,16mmol)的丙酮(500ml)悬浮液在回流下搅拌过夜。减压浓缩混合物,用乙酸乙酯(500mL)和水(250mL)稀释。分离出的水相用乙酸乙酯(200mL×2)萃取。合并的有机相用盐水(100mL)洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用己烷研磨,过滤收集,用己烷洗涤后减压干燥获得[1-[2,6-双(苄氧基)苯基]乙酮(24.9g产量;46%)。[初始化合物1F]
将3-羟基甲基吡啶腈(3.00g,25.0mmol)(按照“Synthesis”316(1983)和“J.Org.Chem.”48 1375(1983)制备)、碳酸钾(5.40g,39.1mmol)以及苄基溴(5.10g,29.8mmol)的丙酮(150mL)悬浮液在室温下搅拌20小时。过滤反应混合物,蒸发滤液。残余物用硅胶柱色谱法(乙酸乙酯/正己烷=1/3-1/2)提纯,接着用乙酸乙酯/正己烷=1/4重结晶获得无色固体3-苄氧基甲基吡啶腈(4.354g产量;83%)。
(初始化合物1F)
3-苄氧基甲基吡啶腈(2.50g,11.9mmmol)的四氢呋喃(100mL)冷(0℃)溶液中滴加0.92M甲基溴化镁的四氢呋喃(150mL,138mmol)溶液。将混合物在0℃搅拌30分钟,然后在室温下搅拌4小时。将反应混合物倾入水(2000ml)中,用10%硫酸(500mL)酸化。搅拌30分钟后,将反应混合物缓慢地倾入饱和碳酸氢钠水溶液,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,过滤,然后蒸发。残余物用硅胶柱色谱法(乙酸乙酯/正己烷=1/3)提纯获得无色油状物1-(2-苄氧基-苯基)-乙酮(2.49g产量;92%)。[初始化合物1G]
在搅拌下的1-(2,6-二羟基苯基)乙酮(50.0g,328mmol)的丙酮(1000mL)溶液中加入碳酸钾(227g,1643mmol)和(溴代甲基)环丙烷(35.1ml,361mmol)。将混合物在50℃搅拌2天。用Celite_过滤反应混合物,然后减压浓缩滤液。残余物用水稀释,用乙酸乙酯萃取。分离出的有机相用水和盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。将残余物悬浮于己烷。再将悬浮液在80℃搅拌30分钟。过滤溶液,将滤液冷却至室温。过滤收集所得白色固体,用己烷洗涤,然后减压干燥获得浅黄色固体1-{2-[(环丙基甲基)氧基]-6-羟基苯基}乙酮(56.3g产量;83%)。
(初始化合物1G)
在搅拌下的1-{2-[(环丙基甲基)氧基]-6-羟基苯基}乙酮(56.3g,272mmol)的丙酮(1000mL)溶液中加入碳酸钾(188g,1364mmol)、4-甲氧基苄基氯(40.9ml,300mmol)和碘化四丁基铵(20.2g,54.6mmol)。混合物在回流下搅拌过夜。反应混合物冷却至室温,用Celite_过滤,然后减压浓缩滤液。残余物用水稀释,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。再将所得白色固体用乙醇重结晶,过滤收集,用乙醇洗涤,然后减压干燥获得白色固体1-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}乙酮(79.2g产量;89%)。[初始化合物1H]
在搅拌下的5-硝基-4H-1,3-苯并二噁英(10.0g,55.203mmol)的四氯化碳(70ml)溶液中加入N-溴代丁二酰亚胺(10.808g,60.723mmol)和2,2’-偶氮二异丁腈(0.906g,5.520mmol)。将混合物在100℃搅拌2小时。冷却至室温后,将乙醇钠(4.884g,71.764mmol)的乙醇(70mL)溶液加入到混合物,然后继续在室温下搅拌3小时。反应物用水猝灭,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=9/1)提纯获得浅黄色油状物4-乙氧基-5-硝基-4H-1,3-苯并二噁英(10.8 g产量;87%)。
在搅拌下的4-乙氧基-5-硝基-4H-1,3-苯并二噁英(5.80g,25.755mmol)的乙醇(15mL)及THF(10mL)溶液中加入4N HCl的1,4-二氧六环(20mL)溶液。将混合物在60℃搅拌6小时,在90℃搅拌6小时。冷却至室温后,反应混合物用水稀释,用乙酸乙酯萃取。有机相用硫酸镁干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=9/1)提纯获得浅黄色油状物2-羟基-6-硝基苯甲醛(4.450g产量;定量)。
在氩气氛下,向搅拌下的2-羟基-6-硝基苯甲醛(4.5g,26.926mmol)溶液滴加三甲基铝(2M的甲苯溶液,27mL)。将混合物在室温下搅拌1小时。将反应混合物倾入冷(0℃)1N盐酸水溶液,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,过滤后浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=9/1)提纯获得橙色油状物2-(1-羟基乙基)-3-硝基苯酚(4.660g产量;95%)。
在搅拌下的2-(1-羟基乙基)-3-硝基苯酚(0.300g,1.638mmol)的丙酮(5ml)溶液中加入碳酸钾(0.25g,1.802mmol)。混合物在室温下搅拌15分钟,将4-甲氧基苄基氯(0.22mL,1.638mmol)加入到混合物。将混合物在室温下搅拌2小时,在60℃搅拌3小时。反应物用饱和氯化铵水溶液猝灭,用乙酸乙酯萃取。有机相用硫酸钠干燥,过滤后浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=4/1)提纯。纯化的化合物用二异丙醚洗涤获得白色固体1-{2-[(4-甲氧基苄基)氧基]-6-硝基苯基}乙醇(0.201g产量;41%)。
在搅拌下的1-{2-[(4-甲氧基苄基)氧基]-6-硝基-苯基}乙醇(0.20g,0.659mmol)的二氯甲烷(20ml)冷(0℃)溶液中加入分子筛4A(1g)、N-氧化N-甲基吗啉(0.15g,1.319mmol)和过钌酸四正丙基铵(perruthenate)(0.01g)。将混合物在室温下搅拌12小时。反应混合物用Celite_过滤,滤液用乙酸乙酯稀释。有机相用饱和氯化铵水溶液洗涤,用硫酸钠干燥,过滤后减压浓缩获得白色固体1-{2-[(4-甲氧基苄基)氧基]-6-硝基苯基}乙酮(0.159g产量;80%)。残余物在下一步骤直接使用无需再提纯。
(初始化合物1H)
在搅拌下的1-{2-[(4-甲氧基苄基)氧基]-6-硝基苯基}乙酮(0.50g,1.659mmol)的乙醇悬浮液中加入氯化铵(0.10g,1.825mmol)的水(5mL)溶液,接着加入铁粉(0.75g)。将混合物在100℃搅拌1小时。反应混合物用Celite_过滤。滤液用乙酸乙酯稀释,用水洗涤。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩获得黄色固体1-{2-氨基-6-[(4-甲氧基苄基)氧基]苯基}乙酮(0.790g产量;108%)。残余物在下一步骤直接使用无需再提纯。[初始化合物1I]
2-氟-6-羟基苯甲酸(5.00g,32.029mmol)的二甲基甲酰胺(200mL)冷(0℃)溶液中加入N,O-二甲基羟胺盐酸盐(6.25g,64.057mmol)、1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(9.82g,48.043mmol)、1-羟基苯并三唑(5.19g,38.435mmol)以及三乙胺(8.93mL,64.057mmol)。将混合物在室温下搅拌15小时。反应混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。所得残余物用硅胶柱色谱法(乙酸乙酯/己烷=2/1)提纯获得橙色固体2-氟-6-羟基-N-甲氧基-N-甲基苯甲酰胺(4.320g产量;68%)。
在搅拌下的2-氟-6-羟基-N-甲氧基-N-甲基苯甲酰胺(4.320g,21.689mmol)的丙酮(50mL)溶液中加入4-甲氧基苄基氯(3.74g,23.858mmol)、碳酸钾(4.50g,32.534mmol)以及碘化钾(360mg,2.169mmol)。将混合物在回流下搅拌15小时。冷却至室温后,过滤反应混合物,然后减压浓缩滤液。残余物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=2/1)提纯获得浅黄色油状物2-氟-N-甲氧基-6-[(4-甲氧基苄基)氧基]-N-甲基苯甲酰胺(6.926g产量;定量)。
(初始化合物1I)2-氟-N-甲氧基-6-[(4-甲氧基苄基)氧基]-N-甲基苯甲酰胺(6.926g,21.70mmol)的四氢呋喃(10mL)冷(0℃)溶液中加入1N甲基溴化镁的四氢呋喃(43.40ml,43.40mmol)溶液。反应混合物在回流下搅拌4小时。冷却至室温后,反应混合物用饱和碳酸氢钠水溶液猝灭,用乙酸乙酯萃取。分离出的有机相用水和盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(己烷∶乙酸乙酯,3/1)提纯获得浅黄色固体1-{2-氟-64(4-甲氧基苄基)氧基]苯基}乙酮(1.21g产量;20%)。[初始化合物1J]
将3-羟基-2-噻吩羧酸甲酯(5.00g,31.61mmol)、苄基溴(3.76mL,31.61mmol)以及K2CO3(4.81g,34.77g)的丙酮(50mL)混合物在回流下搅拌1.5小时。冷却至室温后,过滤混合物,然后减压浓缩滤液。残余物用硅胶柱色谱法(己烷∶乙酸乙酯=15/1-9/1)提纯获得浅黄色油状物3-(苄氧基)-2-噻吩羧酸甲酯(7.91g产量:定量)。
3-(苄氧基)-2-噻吩羧酸甲酯(7.85g,31.61mmol)的MeOH(32ml)及THF(16mL)溶液中加入2N NaOH(21mL),混合物在回流下搅拌10小时,然后减压浓缩。残余物用水稀释,用乙醚洗涤。分离出的水相用5N HCl酸化。过滤收集析出的固体,用己烷洗涤,然后在60℃减压干燥获得黄色固体3-(苄氧基)-2-噻吩羧酸(6.76g产量;91%)。
3-(苄氧基)-2-噻吩羧酸(3.00g,12.81mmol)的CH2Cl2(30mL)溶液中加入乙二酰氯(1.34ml,15.4mmol)和DMF(0.05mL)。将混合物在室温下搅拌1小时,然后减压浓缩。将残余物溶于乙酸乙酯(10mL)。然后将溶液在0℃加入N,O-二甲基羟胺盐酸盐(1.50g,15.37mmol)和K2CO3(3.54g,25.62mmol)的乙酸乙酯(30mL)及水(30mL)的混合物。在0℃剧烈地搅拌混合物0.5小时,在室温下剧烈搅拌1.5小时。分出有机相,用1N HCl、饱和NaHCO3和盐水洗涤,用硫酸钠干燥,过滤,然后蒸发。残余物用硅胶柱色谱法(正己烷/乙酸乙酯=2/1)提纯获得浅黄色固体3-(苄氧基)-N-甲氧基-N-甲基-2-噻吩甲酰胺(3.473g产量;98%)。
(初始化合物1J)
3-(苄氧基)-N-甲氧基-N-甲基-2-噻吩-甲酰胺(3.47g,12.50mmol)的THF(50ml)冷(0℃)溶液中加入甲基溴化镁的THF(1M,35mL)溶液。在0℃搅拌1小时后,反应混合物用饱和氯化铵水溶液猝灭,用水稀释,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后蒸发。残余物用硅胶柱色谱法(己烷/乙酸乙酯/CH2Cl2=3/1/1)提纯,接着用正己烷/乙酸乙酯重结晶获得白色固体1-[3-(苄氧基)-2-噻吩基]乙酮(2.592g产量;89%)。[初始化合物2A]
氢化锂铝(2.44g,64mmol)的THF(40mL)冷(0℃)悬浮液中加入1-苄基-5-氧代-3-吡咯烷羧酸甲酯(5.00g,21mmol)。将反应混合物在室温下搅拌5小时。反应混合物中依次加入水(2.5mL)、15%氢氧化钠水溶液(2.5mL)以及水(7.5mL)。混合物用Celite_过滤。减压浓缩滤液获得(1-苄基-3-吡咯烷基)甲醇。(4.16g产量;定量)
Pd(OH)2(0.4g)的甲醇(30mL)悬浮液中加入(1-苄基-3-吡咯烷基)甲醇(4.16g,21mmol)。将反应混合物在氢气氛下搅拌24小时。反应混合物用乙酸乙酯(200mL)稀释,然后用Celite_过滤。减压浓缩滤液获得3-吡咯烷基甲醇(2.33g产量;定量)。
(初始化合物2A)
3-吡咯烷基甲醇(2.33g,21mmol)和三乙胺(4.8mL,35mmol)的二氯甲烷(60mL)溶液在0℃加入二碳酸二叔丁酯(5.3g,24mmol)。将反应混合物在室温下搅拌26小时。混合物用乙酸乙酯(200mL)稀释,依次用1N HCl(100mL)、饱和碳酸氢钠水溶液(100ml)以及盐水(100mL)洗涤。将有机相用硫酸钠干燥,过滤,然后减压浓缩获得3-(羟基甲基)-1-吡咯烷羧酸叔丁酯(4.06g产量;96%)。
在氩气氛下向3-(羟基甲基)-1-吡咯烷羧酸叔丁酯(4.0g,20mmol)、二氯甲烷(100mL)、二甲基亚砜(20ml)和三乙胺(16.9mL,121mmol)的冷(0℃)混合物中加入三氧化硫-吡啶复合物(9.63g,60mmol)。将反应混合物温热至室温,然后持续搅拌1小时。混合物用乙醚(200mL)和饱和碳酸氢钠水溶液(100mL)萃取。分离出的水相进一步用乙醚(100mL×2)萃取。合并的有机相依次用1N HCl水溶液(100mL)、饱和NaHCO3水溶液(100mL)以及盐水(100mL)洗涤。有机相用硫酸钠干燥,过滤后减压浓缩(5.32g产量;定量)。[初始化合物2B]
在搅拌下的3-哌啶羧酸(100.000g,774.233mmol)的二氧六环(400ml)冷(0℃)溶液中加入2N NaOH(400ml,800mmol)和二碳酸二叔丁酯(168.978g,774.233mmol)。使混合物温热至室温,然后持续搅拌12小时。减压浓缩混合物。残余物用水稀释,用1N HCl水溶液酸化(pH 3-4)。过滤收集所得固体。将白色固体溶于乙酸乙酯,用水洗涤。分离出的有机相用硫酸钠干燥,过滤,然后浓缩。将所得固体悬浮于己烷,再过滤收集,然后减压干燥获得白色固体1-(叔丁氧基羰基)-3-哌啶羧酸。(156g产量;88%)
包含三乙胺(4.681mL,33.584mmol)的1-(叔丁氧基羰基)-3-哌啶羧酸(7.000g,30.531mmol)的二氯甲烷(200mL)冷(0℃)溶液中依次加入六氟磷酸苯并三唑-1-基-氧基-三吡咯烷基-磷鎓(15.885g,30.531mmol)、N,O-二甲基羟胺(3.276g,33.584mmol)以及三乙胺(4.255ml,30.531mmol)。使混合物温热至室温,然后持续搅拌12小时。反应混合物用二氯甲烷稀释,依次用1N HCl水溶液、饱和碳酸氢钠水溶液以及盐水洗涤。有机相用硫酸钠干燥,过滤,然后浓缩。所得残余物用硅胶柱色谱法(氯仿/乙酸乙酯=10/1-9/1)提纯获得白色固体3-{[甲氧基(甲基)氨基]羰基}-1-哌啶-羧酸叔丁酯。(8.050g产量;96%)
(初始化合物2B)
在30分钟内向搅拌下的氢化锂铝(4.355g,114.743mmol)的乙醚(500mL)冷(-15℃)悬浮液中滴加3-{{甲氧基(甲基)氨基]羰基}-1-哌啶-羧酸叔丁酯(25.000g,91.795mmol)的THF(150mL)溶液。反应混合物用1N硫酸氢钾(300mL)猝灭,再用1∶1乙醚和乙酸乙酯的混合物萃取。有机相用硫酸镁干燥,过滤,然后减压浓缩获得3-甲酰基-哌啶-1-羧酸叔丁酯,它直接用于下一步无需再提纯。(22.56g产量;定量)[初始化合物2C]
在搅拌下的3-哌啶甲酸(nipecotinic acid)(3.0g,23.3mmol)的1,4-二氧六环(12mL)冷(0℃)溶液中加入2N NaOH溶液(24.0ml,48.0mmol),接着加入氯甲酸苄基酯(3.96g,23.2mmol)的1,4-二氧六环(12mL)溶液。将反应混合物温热至室温,然后持续搅拌3小时。减压浓缩混合物。残余物用水稀释,用1H HCl酸化(pH3-4)。混合物用乙酸乙酯萃取,分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后蒸发。将所得白色固体悬浮于己烷,过滤收集,用己烷洗涤,然后减压干燥获得白色固体1-[(苄氧基)羰基]-3-哌啶羧酸(4.4g产量;71%)。
搅拌下向包含甲基吗啉(2mL)的1-[(苄氧基)羰基]-3-哌啶羧酸(4.0g,15.2mmol)的无水THF(50mL)冷(-15℃~-20℃)溶液中滴加氯甲酸异丁酯(2.28g,16.7mmol)的THF(10mL)溶液。将混合物搅拌在同样温度搅拌20分钟后,加入包含甲基吗啉(2ml)的N,O-二甲基羟胺盐酸盐(1.63g,16.7mmol)的THF(20mL)溶液。使反应混合物温热至室温,然后搅拌16小时。减压浓缩反应混合物,在乙酸乙酯和水间分配。分离出的有机相用依次用1N HCl、饱和NaHCO3以及盐水洗涤。有机相用硫酸钠干燥,过滤,然后减压浓缩获得无色油状物3-{[甲氧基(甲基)氨基]羰基}-1-哌啶羧酸苄基酯(4.7g产量;定量)。
(初始化合物2C)
在氩气氛下向氢化锂铝(0.70g,18.4mmol)的无水THF(100mL)冷(-78℃)悬浮液滴加3-{[甲氧基(甲基)氨基]羰基}-1-哌啶羧酸苄基酯(4.5g,14.7mmol)的THF(30mL)溶液,然后在-78℃持续搅拌45分钟。反应混合物用0.5N KHSO4(130ml)猝灭,然后用乙醚萃取。分离出的有机相用硫酸镁干燥,过滤,然后减压浓缩获得无色油状物3-甲酰基-1-哌啶羧酸苄基酯(0.54g产量;82%)。[初始化合物2D]
3-氨基环己烷-羧酸(10.0g,69.8mmol)的1,4-二氧六环(100ml)及2N NaOH(100mL)的冷(0℃)混合物中加入二碳酸二叔丁酯(15.2g,69.8mmol)。混合物在室温下搅拌1.5小时,然后用2N HCl中和。减压浓缩所得混合物。残余物用2N HCl酸化,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后蒸发。残余固体用己烷研磨,过滤收集,然后减压干燥获得白色固体3-[(叔丁氧基羰基)氨基]环己烷羧酸(8.00g产量;47%)。
包含三乙胺(3.1mL,22.2mmol)的3-[(叔丁氧基羰基)氨基]-环己烷羧酸(5.00g,20.6mmol)的二氯甲烷(50ml)冷(0℃)溶液中依次加入六氟磷酸苯并三唑-1-基氧基三(吡咯烷基)磷鎓(10.7g,20.6mmol)、N,O-二甲基羟胺盐酸盐(2.21g,20.6mmol)以及Et3N(3.2ml,23.0mmol)。将所得混合物温热至室温,然后持续搅拌18小时。反应混合物用二氯甲烷稀释,依次用1N HCl、饱和碳酸氢钠水溶液以及盐水洗涤。有机相用硫酸钠干燥,过滤,然后蒸发。残余物用硅胶柱色谱法(己烷/乙酸乙酯=1∶1)提纯获得无色油状物3-{[甲氧基(甲基)氨基]羰基}环己基氨基甲酸叔丁酯(5.39g产量;92%)。
NaH(60%,340mg,8.38mmol)的THF(10ml)悬浮液中滴加3-{[甲氧基(甲基)氨基]羰基}环己基氨基甲酸叔丁基酯(2.00g,6.98mmol)的THF(10ml)溶液,接着加入甲基碘(1.09g,7.68mmol)。混合物在60℃搅拌0.5小时。冷却至室温后,将混合物倾入水中,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,过滤后蒸发。残余物用硅胶柱色谱法(己烷/乙酸乙酯=1/1)提纯获得N-[3-(N-甲氧基-N-甲基-氨基甲酰基)环己基]-N-甲基氨基甲酸叔丁酯无色油状物(1.94g产量;93%)。
(初始化合物2D)
在10分钟内向氢化锂铝(380mg,9.9mmol)的Et2O(40ml)冷(0℃)悬浮液滴加N-[3-(N-甲氧基-N-甲基氨基甲酰基)环己基]-N-甲基氨基甲酸叔丁酯(2.38g,7.92mmol)的Et2O(40mL)溶液。将反应混合物在0℃搅拌0.5小时,再用1N KHSO4(100mL)猝灭。分出有机相,用硫酸镁干燥,蒸发获得无色油状物3-甲酰基环己基(甲基)氨基甲酸叔丁酯,它直接用于下一步骤无需再提纯(1.66g产量;87%)。[初始化合物2E]
3-哌啶甲酸乙酯(7.86g,50mmol)的CH2Cl2(120ml)冷(0℃)溶液中加入二碳酸二叔丁酯(11.46g,52.5mmol)。将所得混合物在室温下搅拌4小时。反应混合物用5%NaHCO3水溶液稀释。分出有机相,用硫酸镁干燥,过滤后减压蒸发获得1-叔丁基3-乙基1,3-哌啶二羧酸酯(12.8g产量;定量)。
在氩气氛下向二异丙基氨基化锂(LDA)(23.3mmol)的THF(10mL)冷(-78℃)溶液滴加1-叔丁基3-乙基1,3-哌啶二羧酸酯(3.0g,11.6mmol)的THF(5mL)溶液,然后在-50℃搅拌2小时。所得混合物在-50℃加入MeI(1.98g,14mmol)的THF溶液。将反应混合物温热至室温,再用饱和氯化铵水溶液猝灭。减压浓缩混合物,残余物在乙酸乙酯和水间分配。分出有机相,用硫酸镁干燥,过滤后减压浓缩。粗产物用硅胶柱色谱法(己烷∶乙酸乙酯,9∶1)提纯获得浅黄色油状物1-叔丁基3-乙基3-甲基-1,3-哌啶二羧酸酯(2.27g产量;72%)。
1-叔丁基3-乙基3-甲基-1,3-哌啶二羧酸酯(2.3g,8.48mmol)的无水THF冷(-20℃)溶液中加入LiBH4(2M的THF溶液,10.6mmol),然后持续搅拌过夜。将反应混合物温热至室温。反应混合物用冰水冷却,用1N HCl水溶液酸化(pH 5-6)。减压浓缩混合物,然后用乙酸乙酯萃取。分出有机相,用硫酸镁干燥,过滤,然后蒸发。粗产物用硅胶柱色谱法(己烷∶乙酸乙酯,4∶1-3∶1)提纯获得无色油状物3-(羟基甲基)-3-甲基-1-哌啶羧酸叔丁酯(1.5g产量;78%)。
(初始化合物2E)
向冰水冷却的3-(羟基甲基)-3-甲基-1-哌啶羧酸叔丁酯(1.5g,6.6mmol)的CH2Cl2溶液中依次加入DMSO(7.1g,91.6mmol)、Et3N(5.5mL,39.8mmol)以及三氧化硫-吡啶复合物(3.1g,19.9mmol)。将混合物在室温下搅拌1小时。反应混合物用乙醚稀释,用硅胶柱色谱法(己烷∶乙酸乙酯,5∶1-4∶1)提纯获得无色油状物3-甲酰基-3-甲基-1-哌啶羧酸叔丁酯(1.3g产量;86%)。[初始化合物2F]
1,3-环己烷二羧酸(10g,58mmol)的MEOH(50mL)溶液中加入浓硫酸(2mL)。然后将混合物在室温下搅拌4小时。减压浓缩混合物,然后在乙酸乙酯和饱和碳酸氢钠水溶液间分配。有机相用盐水洗涤,用硫酸钠干燥,然后蒸发获得无色油状物1,3-环己烷二羧酸二甲酯(11.6g产量;定量)。1,3-环己烷二羧酸二甲酯(11.6g,57.9mmol)的MeOH(58mL)溶液在O℃于1小时内滴加1N NaOH溶液(58mL)。将所得混合物在0℃搅拌0.5小时,在室温下搅拌2小时。减压浓缩混合物,残余溶液在乙酸乙酯和水间分配。分出水相,用浓HCl酸化(15mL),加入NaCl使其饱和,然后用乙酸乙酯萃取。萃取液用硫酸钠干燥,过滤后减压浓缩获得无色油状物3-(甲氧基羰基)环己烷羧酸(6.16g产量;57%)。
(初始化合物2F)
3-(甲氧基羰基)环己烷羧酸(1.25g,6.71mmol)的THF(20mL)冷(-78℃)溶液中加入BH3·Me2S(0.7mL,7.38mmol)。将所得混合物在-78℃至室温搅拌过夜。反应混合物用饱和氯化铵水溶液猝灭,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,然后蒸发。残余物用硅胶柱色谱法(正己烷/乙酸乙酯=2/1)提纯获得无色油状物3-(羟基甲基)环己烷羧酸甲酯(845mg产量;73%)。3-(羟基甲基)环己烷羧酸甲酯(840mg,4.88mmol)的Et3N(4.4mL,32mmol)及DMSO(10ml)溶液中加入三氧化硫-吡啶复合物(2.56g,16.1mmol)。将混合物在室温下搅拌1小时。反应混合物在乙酸乙酯和水间分配。有机相用盐水洗涤,用硫酸钠干燥,过滤后蒸发。残余物用硅胶柱色谱法(正己烷/乙酸乙酯=2/1)提纯获得浅黄色油状物3-甲酰基环己烷羧酸甲酯(795mg产量;96%)。[初始化合物2G]
甲氧基甲基磷鎓氯化物(5.14g,15mmol)的THF(18ml)悬浮液在0℃加入叔丁醇钾(1.98g,15mmol),将混合物在0℃搅拌0.5小时。在-20℃滴加3-甲酰基-1-哌啶羧酸叔丁酯(2.13g,10mmol)的THF(8ml)溶液,将所得混合物在0℃至室温搅拌过夜。混合物在甲苯和水间分配。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后蒸发。用硅胶柱色谱(己烷/乙酸乙酯=5/1)提纯获得无色油状物3-(2-甲氧基乙烯基)-1-哌啶羧酸叔丁酯(1.16g产量;48%)。
(初始化合物2G)
将3-(2-甲氧基乙烯基)-1-哌啶羧酸叔丁酯(1.16g,4.81mmol)溶于90%甲酸(2mL)。将混合物在室温下搅拌40分钟。然后混合物在乙酸乙酯和饱和碳酸氢钠水溶液间分配。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后蒸发。用柱色谱法(己烷/乙酸乙酯=4/1)提纯获得3-(2-氧代乙基)-1-哌啶羧酸叔丁酯无色油状物(652mg产量;60%)。[初始化合物2H]
3-甲氧基羰基4-哌啶酮HCl(10g,51.6mmol)和三乙胺(10.8mL,77.5mmol)的二氯甲烷(100mL)冷(0℃)混合物中加入二碳酸二叔丁酯(11.8g,54.2mmol)的二氯甲烷(100mL)溶液。将混合物在室温下搅拌2小时,然后减压浓缩。残余物用水猝灭,用乙醚萃取,用硫酸镁干燥,过滤,然后蒸发获得1-叔丁基3-甲基4-氧代-1,3-哌啶二羧酸酯,它直接用于下一步反应无需再提纯。(14.9g产量;定量)
1-叔丁基3-甲基4-氧代-1,3-哌啶二羧酸酯(134.0g,520.8mmol)的甲醇(800ml)冷(0℃)溶液中分批加入NaBH4(9.85g,260.4mmol)。将所得混合物搅拌过夜使其温热至室温。减压除去溶剂,将残余物溶于乙酸乙酯,用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩获得1-叔丁基3-甲基4-羟基-1,3-哌啶二羧酸酯,它直接用于下一步反应无需再提纯。(120.8g,产率90%)
1-叔丁基3-甲基4-羟基-1,3-哌啶-二羧酸酯(1,64g,6.32mmol)、4-二甲基氨基吡啶(16.0mg,0.13mmol)以及三乙胺(2.64mL,19.0mmol)的二氯甲烷(25ml)冷(0℃)溶液中滴加三氟醋酸酐(1.12ml,7.91mmol)。将反应混合物在室温下搅拌40小时。反应物用10%K2CO3溶液猝灭,用CHCl3萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后减压蒸发。粗产物用硅胶柱色谱法(己烷∶乙酸乙酯=5∶1)提纯获得浅黄色油状物1-叔丁基3-甲基5,6-二氢-1,3(2H)-吡啶二羧酸酯。(707.4mg,产率46%)
在氩气氛下向1-叔丁基3-甲基5,6-二氢-1,3(2H)-吡啶二羧酸酯(700.0mg,2.90mmol)的无水甲苯(40mL)冷(-20℃)溶液滴加二异丁基氢化铝的甲苯(1.5M,4.83mL,7.25mmol)溶液。将反应混合物在0℃搅拌30分钟,然后在室温下搅拌。反应物中加入水猝灭,然后再持续搅拌1小时。滤除铝盐沉淀。滤液用饱和NH4Cl溶液稀释,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后蒸发获得5-(羟基甲基)-3,6-二氢-1(2H)-吡啶羧酸叔丁酯,它直接用于下一步反应无需再提纯。(580.0mg,收率94%)
(初始化合物2H)
5-(羟基甲基)-3,6-二氢-1(2H)-吡啶羧酸叔丁酯(14.65g,68.69mmol)的二氯甲烷溶液中加入二氧化锰(89.58g,1030.36mmol),然后在室温下搅拌过夜。反应混合物用Celite_过滤,减压浓缩滤液获得5-甲酰基-3,6-二氢-1(2H)-吡啶羧酸叔丁酯,其纯度足以在下一步反应直接使用。(13.55g,收率94%)实施例1-1
(1)将2’-苄氧基苯乙酮(初始化合物1A)(10.00g,44.19mmol)、3-甲酰基-1-哌啶羧酸叔丁酯(初始化合物2B)(10.37g,44.61mmol)、丙二腈(3.21g,48.61mmol)以及乙酸铵(17.03g,220.97mmol)的甲苯(50ml)混合物在150℃搅拌2小时。冷却至室温后,反应混合物用乙酸乙酯稀释。有机相用水以及饱和盐水洗涤,用硫酸钠干燥,过滤后浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=2/1)提纯。纯化的化合物(黄色油状物)用乙醇重结晶获得白色固体3-{2-氨基-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯。(5.83g产量;27%)。
(2)将3-{2-氨基-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(2.160g,4.457mmol)和10%Pd-C(0.720g)的乙酸乙酯(30mL)混合物在室温下于氢气氛(3atm)中搅拌2天。混合物用Celite_过滤,然后减压浓缩滤液。残余物用乙醚重结晶获得白色固体3-[2-氨基-3-氰基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.180g产量;10%)
(3)在搅拌下的3-[2-氨基-3-氰基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.170g,0.431mmol)的二氧六环(30mL)溶液中加入4NHCl的二氧六环(3mL)溶液。将混合物在室温下搅拌12小时。过滤收集所得沉淀,滤液用二氧六环洗涤获得2-氨基-6-(2-羟基苯基)-4-(3-哌啶基)-烟腈盐酸盐(0.075g产量;53%)。
分子量:330.82
质谱:295(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A/(Jurkat)-A
1H-NMR(300MHz,DMSO-d6):1.81-1.89(4H,m),2.88-2.92(1H,m),3.31-3.40(4H,m),6.89-6.94(2H,m),7.32-7.38(1H,m),7.43(1H,s),8.05(1H,d,J=7.4Hz),8.83-8.85(1H,brs),9.45-9.47(1H,brs)。实施例1-2
用初始化合物2A代替2B,按照实施例1-1介绍的类似方法制备2-氨基-6-(2-羟基苯基)-4-(3-吡咯烷基)烟腈三氟乙酸盐。
分子量:394.36
质谱:281(M+H)+
体外活性等级:A
细胞活性等级:(A594)-A/(Jurkat)-B
1H-NMR(500MHz,DMSO-d6):2.10(1H,m),3.60-3.70(2H,m),6.91(2H,m),7.36-7.44(4H,m),8.05(1H,d,J=8.2Hz),9.00(2H,br),13.35(1H,s)。实施例1-3
用初始化合物2E代替2B,按照实施例1-1介绍的类似方法制备2-氨基-6-(2-羟基苯基)-4-(3-甲基哌啶-3-基)-烟腈盐酸盐。
分子量:344.85
质谱:309(M+H)+
体外活性等级:B
细胞活性等级:(A594)-B
1H-NMR(500MHz,DMSO-d6):1.52(3H,s),1.78(2H,brd,J=38.1Hz),1.97-2.04(1H,m),2.37-2.44(1H,m),2.99(2H,brd,J=31.7Hz),3.34(1H,dd,J=5.5,12.5Hz),3.75(1H,dd,J=5.5,12.5Hz),6.92-6.96(2H,m),7.22(1H,s),7.33-7.39(2H,m),8.05-8.08(1H,m),9.02(1H,brs),9.42(1H,brs)。实施例1-4
用初始化合物1B替代1A,按照实施例1-1介绍的类似方法制备2-氨基-5-氟-6-(2-羟基苯基)-4-(3-哌啶基)-烟腈三氟乙酸盐。
分子量:426.37
质谱:3 13(M+H)+
体外活性等级:A
细胞活性等级:(A594)-B/(Jurkat)-B
1H-NMR(500MHz,DMSO-d6):1.77(2H,m),1.95(3H,m),2.94(1H,t,J=10.7Hz),3.25-3.37(2H,m),3.50(1H,d,J=12.0Hz),6.90(1H,dt,J=1.0,8.2Hz),6.93(1H,d,J=8.2Hz),7.03(2H,br),7.32(1H,dt,J=1.6,8.5Hz),7.47(1H,dd,J=1.6,7.9Hz),8.73(2H,br),10.72(1H,s)。实施例1-5
用初始化合物2D代替2B,按照实施例1-1介绍的相同方法制备2-氨基-6-(2-羟基苯基)-4-[3-甲基氨基]环己基]烟腈盐酸盐。
分子量:358.87
质谱:323(M+H)+
体外活性等级:A
细胞活性等级:(A594)-B
1H-NMR(300MHz,DMSO-d6):1.34-1.86(5H,m),1.86-2.04(1H,m),2.04-2.30(2H,m),2.50-2.60(3H,m),2.76-2.95(1H,m),3.17(1H,brs),6.85-6.96(2H,m),7.20-7.40(3H,m),7.99(1H,d,J=8.1Hz),9.11(2H,brs)。实施例1-6
用初始化合物1F替代1A,按照实施例1-1介绍的相同方法制备6-氨基-3’-羟基-4-(3-哌啶基)-2,2’-联吡啶-5-腈盐酸盐。
分子量:368.27
质谱:337(M+H)+
体外活性等级:A
细胞活性等级:(A594)-A
1H-NMR(500MHz,DMSO-d6):1.78-1.82(2H,m),1.93-1.95(2H,m),3.03-3.07(1H,m),3.27-3.37(3H,m),3.56(1H,m),7.39(1H,dd,J=1.6,8.5Hz),7.43(1H,dd,J=4.1,8.5Hz),7.56(1H,br),7.76(1H,s),8.23(1H,dd,J=1.6,4.1Hz),8.78(1H,br),9.18(1H,br)。实施例1-7
用初始化合物1J替代1A,按照实施例1-1介绍的相同方法制备2-氨基-6-(3-羟基-2-噻吩基)-4-(3-哌啶基)烟腈氢溴酸盐。
分子量:381.30
质谱:301(M+H)+
体外活性等级:A
细胞活性等级:(A594)-A
1H-NMR(500 MHz,DMSO-d6):1.69-1.84(2H,m),1.84-2.00(2H,m),2.94-3.06(1H,m),3.12-3.28(2H,m),3.28-3.40(2H,m),6.82(2H,d,J=5.4Hz),6.83(1H,s),7.63(2H,d,J=5.4Hz),8.55-8.70(1H,m),8.85-9.00(1H,m)。实施例1-8
将3-[2-氨基-3-氰基-6-(2-羟基苯基)-4-吡啶基]环己烷羧酸甲酯(151mg,0.43mmol)的2N NaOH(1mL)及THF(2mL)悬浮液在60℃搅拌4小时。反应混合物用1N HCl(2ml)中和,然后用水稀释。过滤收集所得沉淀,用EtOH洗涤,干燥(60℃,2小时,减压)获得黄色固体3-[2-氨基-3-氰基-6-(2-羟基苯基)-4-吡啶基]环己烷羧酸(105mg产量;72%)。
分子量:337.38
质谱:338(M+H)+
体外活性等级:B
细胞活性等级:(A594)-C
1H-NMR(300MHz,DMSO-d6):1.30-2.14(8H,m),2.30-2.59(1H,m),2.70-2.89(1H,m),6.83-6.93(2H,m),7.24-7.38(4H,m),8.00-8.10(1H,m),12.41(1H,s),13.47(1H,s)。实施例1-9
用初始化合物1D代替1A,并用初始化合物2H代替2B,按照实施例1-1介绍的相同方法制备2’-氨基-6’-(2-羟基苯基)-1,2,5,6-四氢-3,4’-联吡啶-3’-腈盐酸盐。
分子量:328.80
质谱:293(M+H)+
体外活性等级:A
细胞活性等级:(A594)-A
1H-NMR(500MHz,DMSO-d6):2.52(2H,brs),3.24(2H,brs),4.05(2H,brs),6.45(1H,s),6.90-6.93(2H,m),7.35-7.46(4H,m),8.01-8.02(1H,m),9.37(1H,brs)。实施例1-10
用初始化合物1H替代1A,按照实施例1-1介绍的相同方法制备2-氨基-6-(2-氨基-6-羟基苯基)-4-(3-哌啶基)烟腈盐酸盐。
分子量:345.83
质谱:310(M+H)+
体外活性等级:C
细胞活性等级:(A594)-C
1H-NMR(500 MHz,DMSO-d6):1.81-1.92(3H,m),2.89-2.93(1H,m),3.28-3.32(3H,m),6.97(2H,dd,j=11.7,8.2Hz),7.30(2H,t,J=8.2Hz),9.01(1H,m),9.59(1H,M)。实施例1-11
(1)用初始化合物1H替代1A,按照实施例1-1步骤(1)介绍的相同方法制备3-(2-氨基-6-{2-氨基-6-[(4-甲氧基苄基)氧基]苯基}-3-氰基-4-吡啶基)-1-哌啶羧酸叔丁酯。
(2)在搅拌下的包含乙酸(0.03g,0.566mmol)的3-(2-氨基-6-{2-氨基-6-[(4-甲氧基苄基)氧基]苯基}-3-氰基-4-吡啶基)-1-哌啶羧酸叔丁酯(0.30g,0.566mmol)的甲醇(10mL)冷(0℃)溶液中加入苯甲醛(0.08mL,1.133mmol),接着加入氰基硼氢化钠(0.04g,0.566mmol),然后继续在0℃搅拌3小时。反应物用水猝灭,用乙酸乙酯萃取。有机相用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=4/1)提纯获得黄色无定型物3-(2-氨基-6-{2-(苄基氨基)-6-[(4-甲氧基苄基)氧基]-苯基}-3-氰基-4-吡啶基)-1-哌啶羧酸叔丁酯(0.299g产量;85%)。
分子量:435.96
质谱:400(M+H)+
体外活性等级:B
细胞活性等级:(A594)C
1H-NMR(500 MHz,DMSO-d6):1.69-1.83(2H,m),1.90-1.92(2H,m),2.89-2.92(1H,m),3.15-3.18(1H,m),3.28-3.33(3H.m),4.28(2H,s),6.17(1H,d,J=8.2Hz),6.32(1H,d,J=8.2Hz),7.00(1H,t,J=8.2Hz),7.09(1H,s),7.20-7.23(1H,m),7.28-7.33(4H,m),8.97(1H,m),9.47(1H,m)。实施例1-12
在搅拌下的包含三乙胺(0.02g,0.227mmol)的3-(2-氨基-6-{2-氨基-6-[(4-甲氧基苄基)氧基]苯基}-3-氰基-4-吡啶基)-1-哌啶羧酸叔丁酯(0.10g,0.189mmol)(由实施例1-11步骤(1)获得)的二氯甲烷(10mL)冷(0℃)溶液中加入醋酸酐(0.08g,0.889mmol)。在0℃持续搅拌5小时。使混合物温热至室温,然后持续搅拌30分钟。反应物用水猝灭,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=2/1-1/1-1/2)提纯获得浅黄色油状物3-(6-{2-(乙酰基氨基)-6-[(4-甲氧基苄基)氧基]苯基}-2-氨基-3-氰基-4-吡啶基)-1-哌啶-羧酸叔丁酯(0.102g产量;94.5%)。
然后将黄色油状物按照实施例1-1步骤(2)相同的方法用酸处理获得N-{2-[6-氨基-5-氰基-4-(3-哌啶基)-2-吡啶基]-3-羟基苯基}乙酰胺盐酸盐。
分子量:387.87
质谱:352(M+H)+
体外活性等级:C
细胞活性等级:(A594)C
1H-NMR(500MHz,DMSO-d6):1.60-1.86(4H,m),1.90(3H,s),2.88-2.95(1H,m),3.12-3.26(4H,m),6.78(1H,d,J=8.2Hz),7.02(1H,s),7.23(1H,t,J=8.2Hz),7.28-7.30(1H,m),8.90-8.92(1H,m),9.40-9.42(1H,m),9.90(1H,brs)。实施例1-13至1-44
(1)用初始化合物1E替代1A,按照实施例1-1步骤(1)介绍的类似方法制备3-{2-氨基-6-[2,6-双(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(3.54g产量;30%)。
(2)将包含乙酸(5ml)的3-{2-氨基-6-[2,6-双(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(3.46g,5.9mmol)和Pd/C(10%,600mg)的乙酸乙酯(50mL)悬浮液在室温下于氢气氛中搅拌2天。反应混合物用THF(200ml)稀释,用Celite_过滤。减压浓缩滤液。残余物用乙酸乙酯和己烷洗涤,然后减压干燥获得3-[2-氨基-3-氰基-6-(2,6-二羟基-苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(1.82g产量;76%)。
(3)按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[2-氨基-3-氰基-6-(2,6-二羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(200mg,0.49mmol)。过滤收集所得沉淀,用乙酸乙酯和己烷洗涤,然后减压干燥获得2-氨基-6-(2,6-二羟基苯基)-4-(3-哌啶基)烟腈盐酸盐(123mg产量;73%)。
分子量:346.82
质谱:311(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):1.66-1.99(5H,m),2.91-3.20(2H,m),3.23-3.42(3H,m),6.41(2H,d,J=7.9Hz),7.08(1H,t,J=7.9Hz),7.28(2H,brd),7.65(1H,s),8.82(1H,brd),9.17(1H,brd)。实施例2-2
将3-[2-氨基-3-氰基-6-(2,6-二羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(300mg,0.73mmol)(由实施例2-1步骤(2)获得)、苄基溴(0.1mL,0.80mmol)以及碳酸钾(303mg,2.19mmol)于丙酮(15mL)及THF(15mL)溶液中的悬浮液在室温下搅拌2天。减压浓缩反应混合物,然后溶于乙酸乙酯(100ml)和水(100mL)。分离出的水相用乙酸乙酯萃取(100ml×2)。合并的有机相用盐水(100mL)洗涤,用硫酸钠干燥,过滤,然后减压浓缩。粗产物用硅胶柱色谱法(己烷/乙酸乙酯,4∶1-2∶1-1∶1)提纯获得3-{2-氨基-6-[2-(苄氧基)-6-羟基苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(239mg产量;65%)。
3-{2-氨基-6-[2-(苄氧基)-6-羟基苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(239mg,0.48mmol)的二氧六环(25ml)溶液中加入4N HCl/二氧六环(25mL)。将反应混合物在室温下搅拌过夜。过滤收集所得沉淀,用乙酸乙酯和己烷洗涤,减压干燥获得2-氨基-6-[2-(苄氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈盐酸盐(184mg产量;88%)。
分子量:436.95
质谱:401(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):1.07-1.14(1H,m),1.65-1.74(3H,m),2.57-2.73(2H,m),3.07-3.12(1H,m),3.17-3.23(2H,m),5.07(1H,d,J=11.3Hz),5.12(1H,d,J=11.3Hz),6.57(1H,d,J=8.3Hz),6.73(1H,d,J=8.3Hz),7.24-7.49(8H,m),8.72(1H,brd),9.01(1H,brd),12.54(1H,s)。实施例2-3
用初始化合物1G替代1A,按照制备初始化合物2B的类似方法制备的4-甲酰基-哌啶-1-羧酸叔丁酯,按照实施例1-1步骤(1)的类似方法制备4-(2-氨基-3-氰基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-吡啶基)-1-哌啶羧酸叔丁酯。
在搅拌下的4-(2-氨基-3-氰基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-吡啶基)-1-哌啶羧酸叔丁酯(0.63g,1.077mmol)的1,4-二氧六环(25mL)溶液中加入4N HCl的1,4-二氧六环(25mL)溶液。将混合物在室温下搅拌12小时。过滤收集所得固体,用二异丙醚洗涤获得黄色固体2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈盐酸盐(0.340g产量;79%)。
分子量:400.91
质谱:365(M+H)+
体外活性等级:A
细胞活性等级:(A549)A
1H-NMR(500MHz,DMSO-d6):0.31-0.34(2H,m),0.55-0.59(2H,m),1.03-1.04(1H,m),1.91-1.99(4H,m),3.06-3.14(3H,m),3.37-3.39(2H,m),3.87(2H,d,J=7.3Hz),6.55(2H,dd,J=9.9,8.2Hz),7.23(1H,t,J=8.2Hz),9.19-9.11(1H,m),9.20-9.23(1H,m)。
实施例2-4至2-87
(1)用初始化合物1G、2B以及其它原料,按照实施例2-3介绍的类似方法制备2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈盐酸盐。
(2)在搅拌下的2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈盐酸盐(200.0mg,0.50mmol)的MeOH溶液中加入甲醛(0.5mL)和氰基硼氢化钠(40.8mg,0.65mmol),在室温下搅拌2小时。反应物中加入水猝灭,用乙酸乙酯萃取,用硫酸镁干燥,过滤后蒸发。残余物用己烷研磨,干燥。粗产物用制备型硅胶TLC(含5%MeOH的二氯甲烷)提纯获得黄色固体2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(1-甲基-3-哌啶基)烟腈。(28.5mg,收率15%)
分子量:378.48
质谱:379(M+H)+
体外活性等级:A
细胞活性等级:(A549)A
1H-NMR(300MHz,CDCl3):0.37-0.42(2H,m),0.67-0.73(2H,m),0.82-0.88(1H,m),1.27-1.35(1H,m),1.76-2.09(4H,m),2.31(3H,s),2.91-3.00(2H,m),3.14-3.23(1H,m),3.86(2H,五重峰(pent,J=8.8Hz),5.15(2H,brs),6.39(1H,d,J=8.3Hz),6.62(1H,d,J=8.3Hz),7.20(1H,t,J=8.3Hz),7.95(1H,s)。实施例3-2
在搅拌下的2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈盐酸盐(200.0mg,0.50mmol)(由实施例3-1步骤(1)获得)的MeOH溶液中加入苯甲醛(0.25mL,2.49mmol),接着加入氰基硼氢化钠(40.8mg,0.65mmol),然后在室温下持续搅拌2小时。反应物加入水猝灭,用乙酸乙酯萃取,用硫酸镁干燥,过滤后蒸发。残余物用己烷研磨,干燥。粗产物用制备型硅胶TLC(含5%MeOH的二氯甲烷)提纯获得黄色固体2-氨基-4-(1-苄基-3-哌啶基)-6-[2-(环丙基甲氧基)-6-羟基-苯基]烟腈。(35.7mg,收率16%)
分子量:454.58
质谱:455(M+H)+
体外活性等级:C
细胞活性等级:(A549)C
1H-NMR(300MHz,CDCl3):0.35-0.37(2H,m),0.62-0.64(2H,m),0.83-1.29(2H,m),1.75-2.21(5H,m),2.93-3.24(3H,m),3.50-3.61(2H,m),3.78-3.88(2H,m),5.12(2H,brs),6.39(1H,d,J=8.3Hz),6.60(1H,d,J=8.3Hz),7.16-7.32(6H,m),7.93(1H,s),13.33(1H,brs)。实施例3-3至3-8
(1)将溴化铜(II)(1.106g,4.953mmol)和亚硝酸叔丁酯(0.736ml,6.191mmol)的乙腈(30mL)混合物在65℃搅拌15分钟。将3-{2-氨基-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(2.000g,4.127mmol)(由实施例1-1步骤(1)获得)的乙腈(20ml)溶液滴加到上述混合物。将混合物在65℃搅拌2小时。冷却至室温后,反应混合物用乙酸乙酯稀释。分离出的有机相用1N HCl水溶液和盐水洗涤,用硫酸钠干燥,过滤,然后浓缩。残余物用乙醚重结晶获得白色固体3-{2-溴-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(1.010g产量;45%)。
(2)在搅拌下的3-{6-[2-(苄氧基)苯基]-2-溴-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.300g,0.547mmol)的DMSO溶液中加入三乙胺(0.229ml,1.341mmol)和苄胺(0.147g,1.367mmol)。将混合物在70℃搅拌12小时。冷却至室温后,反应混合物用水猝灭,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=4/1-2/1)提纯获得黄色无定型物3-{6-[2-(苄氧基)苯基]-2-苄基氨基-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯。(0.290g产量;92%)
(3)然后按照实施例1-1步骤(2)介绍的相同方法除去苄基。将残余物悬浮于乙醇,过滤获得白色固体3-[2-(苄基氨基)-3-氰基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.150g产量;61%)
(4)按照实施例1-1步骤(3)介绍的类似方法在酸性体条件下处理3-[2-(苄基氨基)-3-氰基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.145g,0.299mmol)。过滤收集所得固体,然后减压干燥获得2-(苄基氨基)-6-(2-羟基苯基)-4-(3-哌啶基)烟腈盐酸盐。(0.075g产量;60%)
分子量:420.95
质谱:385(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B/Jurkat-B
1H-NMR(300MHz,DMSO-d6):1.80-1.92(4H,m),2.90-2.93(1H,m),3.31-3.40(4H,m),4.59(2H,d,J=5.6Hz),6.84-6.92(2H,m),7.19-7.31(5H,m),7.47(1H,s),8.00(1H,d,J=6.8Hz),8.11-8.15(1H,m),8.91(1H,brs),9.52(1H,brs),12.59(1H,brs),12.90(1H,brs)。实施例4-2
在搅拌下的3-{6-[2-(苄氧基)苯基]-2-溴-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.100g,0.182mmol)(由实施例4-1步骤(1)获得)的DMSO(2ml)溶液中加入丙胺(0.108g,1.823mmol)和三乙胺(0.038mL,0.273mmol)。将混合物在40℃搅拌12小时。反应物用水猝灭,所得反应混合物用乙酸乙酯萃取。有机相用硫酸钠干燥,过滤,然后浓缩。浓缩物用硅胶柱(己烷/乙酸乙酯=4/1)提纯获得无色油状物3-{6-[2-(苄氧基)苯基]-3-氰基-2-丙基氨基-4-吡啶基}-1-哌啶羧酸叔丁酯。(0.104g产量;定量)
然后按照实施例1-1步骤(2)介绍的相同方法除去苄基。残余物用乙醚洗涤获得所需产物白色固体。(0.112g产量;定量)
然后按照实施例1-1步骤(3)介绍的相同方法在酸性条件下处理3-[3-氰基-6-(2-羟基苯基)-2-(丙基氨基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.110g,0.252mmol)。过滤收集所得固体,然后减压干燥获得6-(2-羟基苯基)-4-(3-哌啶基)-2-(丙基氨基)烟腈盐酸盐。(0.062g产量;66%)
分子量:372.90
质谱:337(M+H)+
体外活性等级:C
细胞活性等级:(A549)-C
1H-NMR(300MHz,DMSO-d6):0.92(3H,t,J=7.4Hz),1.62(2H,m),1.80-1.95(4H,m),2.89-2.93(1H,m),3.33-3.46(6H,m),6.91-6.97(2H,m),7.34-7.40(1H,m),7.48(1H,s),7.57(1H,brs),8.08-8.17(1H,m),8.97-9.07(1H,m),9.67-9.71(1H,m)。实施例4-3
按照实施例4-2的类似方法制备6-(2-羟基苯基)-2-(甲基氨基)-4-(3-哌啶基)烟腈盐酸盐。
分子量:344.85
质谱:309(M+H)+
体外活性等级:C
细胞活性等级:(A549)-C
1H-NMR(300MHz,DMSO-d6):1.83-1.96(4H,m),3.31(4H,s),3.30-3.56(4H,m),6.90-6.96(2H,m),7.34-7.37(1H,m),7.39(1H,s),7.55(1H,brs),8.10(1H,d,J=7.9Hz),8.87-8.90(1H,m),9.52-9.54(1H,m),13.80(1H,brs)。实施例4-4
按照实施例4-2的类似方法制备2-苯氨基-6-(2-羟基苯基)-4-(3-哌啶基)烟腈盐酸盐。
分子量:406.92
质谱:371(M+H)+
体外活性等级:D
细胞活性等级:(A549)-B
1H-NMR(300MHz,DMSO-d6):1.87-2.00(4H,m),2.91-2.95(1H,m),3.34(1H,m),6.79(1H,d,J=8.3Hz),6.91(1H,t,J=7.2Hz),7.18-7.44(1H,brs),7.66(1H,s),8.06(1H,d,J=6.8Hz),8.84(1H,m),9.43(2H,m),12.42(1H,brs)。实施例4-5
按照实施例4-2的类似方法制备6-(2-羟基苯基)-2-(1-哌嗪基)-4-(3-哌啶基)烟腈二盐酸盐。
分子量:436.39
质谱:364(M+H)+
体外活性等级:D
1H-NMR(500MHz,DMSO-d6):1.81-1.83(2H,m),1.90-1.95(2H,m),2.93-2.95(1H,m),3.76-3.78(4H,m),6.98(1H,t,J=7.3Hz),7.37-7.40(1H.m),7.84(1H,s),8.03-8.05(1H,m),8.78-8.81(1H,m),9.14(1H,brs),9.24-9.27(1H,m),12.10(1H,s)。实施例5-1
(1)将3-{6-[2-(苄氧基)苯基]-2-溴-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.300g,0.547mmol)(由实施例4-1步骤(1)获得)、肼一水合物(3mL)以及1,4-二氧六环(1mL)的混合物在100℃搅拌1.5小时。反应物用水猝灭,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,过滤,然后浓缩。残余物用乙醇重结晶获得黄色固体{3-[3-氨基-6-(2-苄氧基-苯基)-1H-吡唑并[3,4-b]吡啶-4-基]-1-哌啶羧酸叔丁酯。(0.210g产量;72%)
(2)然后按照实施例1-1步骤(2)介绍的相同方法除去苄基。残余物用硅胶柱(己烷/乙酸乙酯=2/1-1/1)提纯获得橙色固体3-[3-氨基-6-(2-羟基苯基)-1H-吡唑并[3,4-b]吡啶-4-基]-1-哌啶羧酸叔丁酯。(0.080g产量;49%)
3-[3-氨基-6-(2-羟基苯基)-1H-吡唑并[3,4-b]吡啶-4-基]-1-哌啶羧酸叔丁酯(0.075g,0.183mmol)的1,4-二氧六环(3mL)溶液中加入4NHCl的1,4-二氧六环(3mL)溶液。将混合物在室温下搅拌12小时。过滤收集所得固体获得2-[3-氨基-4-(3-哌啶基)-1H-吡唑并[3,4-b]吡啶-6-基]苯酚盐酸盐。(0.062g产量;98%)
分子量:345.83
质谱:310(M+H)+
体外活性等级:C
细胞活性等级:A549-B
1H-NMR(300MHz,DMSO-d6):1.97-2.27(4H,m),2.95-3.11(1H,m),3.12-3.23(1H,m),3.30-3.39(3H,m),6.94-6.99(2H,m),7.32-7.38(1H,m),7.73(1H,s),8.12(1H,d,J=7.2Hz)。实施例5-2
在搅拌下的3-{3-氨基-6-[2-(苄氧基)苯基]-1H-吡唑并[3,4-b]吡啶-4-基}-1-哌啶羧酸叔丁酯(0.200g,0.400mmol)(由实施例5-1步骤(1)获得)的THF(3ml)冷(0℃)溶液中加入吡啶(1ml)和乙酰氯(0.035g,0.440mmol)。将混合物在0℃搅拌1小时。反应物用水猝灭,用乙酸乙酯萃取。有机相用饱和盐水洗涤,用硫酸钠干燥,过滤,然后浓缩。残余物用二异丙醚重结晶获得白色固体。(0.180g产量;83%)
然后按照实施例1-1步骤(2)介绍的相同方法除去苄基。将残余物悬浮于乙醇,过滤获得所需白色固体产物。(0.120g产量;82%)
按照实施例1-1步骤(3)介绍的相同方法在酸性条件下处理3-[3-(乙酰基氨基)-6-(2-羟基苯基)-1H-吡唑并[3,4-b]吡啶-4-基]-1-哌啶羧酸叔丁酯(0.115g,0.260mmol)获得N-[6-(2-羟基苯基)-4-(3-哌啶基)-1H-吡唑并[3,4-b]吡啶-3-基]乙酰胺盐酸盐。(0.097g产量;96%)
分子量:387.87
质谱:352(M+H)+
体外活性等级:D
细胞活性等级:A549-C
1H-NMR(500MHz,DMSO-d6):1.80-1.91(4H,m),1.95(3H,s),2.82-2.92(1H,m),3.34-3.44(4H,m),6.92-6.95(2H,m),7.36-7.39(1H,m),7.66(1H,s),8.12(1H,d,J=8.2Hz),8.83-8.85(1H,m),9.48-9.49(1H,m),9.56(1H,s),10.21(1H,s),13.59(1H,brs)。实施例6-1
在搅拌下的3-{2-氨基-6-[2-(苄基-氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(由实施例1-1步骤(1)获得)(0.500g,1.032mmol)的吡啶(10mL)冷(0℃)溶液中加入乙酰氯(0.477mL,6.70mmol)。将混合物在0℃至室温搅拌3小时,然后继续在室温下搅拌5小时。反应混合物用水猝灭,用乙酸乙酯萃取。有机相用硫酸钠干燥,过滤,然后浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=9/1-4/1-2/1)提纯获得所需产物的混合物,即3-{2-(乙酰基氨基)-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基]-1-哌啶羧酸叔丁酯以及相应的二酰化化合物。将所得混合物溶于THF(5mL),用1N NH3水溶液(1mL)处理,在室温下搅拌1小时。反应混合物用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,过滤后浓缩获得白色无定型物3-{2-(乙酰基氨基)-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯。(0.432g产量;80%)
然后按照实施例1-1步骤(2)介绍的相同方法除去苄基。残余物用乙醇重结晶获得所需黄色固体产物。(0.110g产量;31%)
按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[2-(乙酰基氨基)-3-氰基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.100g,0.229mmol)。过滤收集所得沉淀,用1,4-二氧六环洗涤,然后减压干燥获得N-[3-氰基-6-(2-羟基苯基)-4-(3-哌啶基)-2-吡啶基]乙酰胺盐酸盐。(0.101g产量;定量)
分子量:372.86
质谱:337(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.86-1.97(4H,m),2.19(3H,s),2.91-2.94(1H,m),3.33-3.47(4H,m),6.96-6.99(2H,m),7.38-7.41(1H,m),8.11-8.13(2H,m),8.94-8.96(1H,m),9.62-9.64(1H,m),10.97(1H,s)。实施例6-2
用初始化合物1G和4-甲酰基哌啶-1-羧酸叔丁酯以及其它原料,按照实施例6-1的类似方法制备N-[3-氰基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(4-哌啶基)-2-吡啶基]乙酰胺盐酸盐。
分子量:442.95
质谱:407(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.28-0.31(2H,m),0.55-0.58(2H,m),1.32(1H,m),1.98-2.01(2H,m),2.16(3H,s),3.09-3.13(2H,m),3.24-3.28(1H,m),3.40-3.42(2H,m),3.87(2H,d,J=6.9Hz),6.57(2H,dd,J=8.5,2.8Hz),7.24(1H,t,J=8.5Hz),7.92(1H,s),9.06-9.15(2H,m),10.93(1H,s)。实施例7-1(1)
在搅拌下的3-{2-氨基-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.300g,0.619mmol)(由实施例1-1步骤(1)获得)的乙醇(10mL)悬浮液中加入氢氧化钾(0.695g,12.381mmol)的乙醇(20mL)溶液。将反应混合物在70℃搅拌60小时。冷却至室温后,将反应混合物倾入水中,滤出所得固体,减压干燥获得白色无定型物3-{2-氨基-6-[2-(苄氧基)苯基]-3-氨基甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯。(0.226g产量;73%)
(2)按照实施例1-1步骤(2)介绍的相同方法除去苄基。将残余物悬浮于乙醇,过滤获得白色固体3-[2-氨基-3-(氨基甲酰基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.045g产量;46%)
(3)按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[2-氨基-3-(氨基甲酰基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.040g,0.097mmol)获得黄色固体2-氨基-6-(2-羟基苯基)-4-(3-哌啶基)烟酰胺盐酸盐。(0.008g产量;24%)
分子量:348.84
质谱:313(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(300MHz,DMSO-d6):1.68-1.92(4H,m),2.90-2.93(1H,m),3.17-3.34(4H,m),6.89-6.97(2H,m),7.29-7.34(2H,m),7.80-7.86(2H,m),8.09(1H,brs),8.80-8.82(1H,m),9.34-9.37(1H,m)。实施例7-2在搅拌下的3-{2-氨基-6-[2-(苄氧基)苯基]-3-氨基甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.400g,0.800mmol)(由实施例7-1步骤(1)获得)的THF(10mL)冷(0℃)溶液中加入三乙胺(0.50mL,3.58mmol),接着加入三光气(0.354g,1.19mmol)。将反应混合物在室温下搅拌12小时。反应物用水猝灭,用乙酸乙酯萃取。有机相用盐水洗涤,用硫酸钠干燥,过滤,然后浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=2/1-1/1)提纯,用乙醇重结晶获得白色固体3-{7-[2-(苄氧基)苯基]-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基}-1-哌啶羧酸叔丁酯。(0.406g产量;97%)
然后按照实施例1-1步骤(2)介绍的相同方法除去苄基。残余物用乙醇洗涤获得白色固体3-[7-(2-羟基苯基)-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁酯。(0.036g产量;29%)
按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[7-(2-羟基苯基)-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁酯(0.036g,0.80mmol)的二氧六环(3ml)溶液获得黄色固体7-(2-羟基苯基)-5-(3-哌啶基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮盐酸盐。(0.016g产量;52%)
分子量:374.83
质谱:339(M+H)+
体外活性等级:A
细胞活性等级:(A549)-C
1H-NMR(500MHz,DMSO-d6):1.78-1.83(2H,m),1.94-1.95(2H,m),2.90-2.92(1H,m),4.68-4.69(1H,m),6.97-6.99(2H,m),7.39-7.42(1H,m),7.85(1H,s),8.16(1H,dd,J=8.4,1.4Hz),8.75(1H,brs),9.43(1H,m),11.45(1H,d,J=1.4Hz),12.05(1H,d,J=1.4Hz),12.44(1H,brs)。实施例7-3
在搅拌下的3-{2-氨基-6-[2-(苄氧基)苯基]-3-氨基甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.100g,0.199mmol)(由实施例7-1步骤(1)获得)的苯基醚(1ml)溶液中加入异氰酸苯酯(0.047g,0.398mmol)。混合物在140℃搅拌12小时。冷却至室温后,过滤除去所得固体(脲)。减压浓缩滤液。残余物用硅胶柱色谱法提纯获得白色无定型物3-[7-(2-苄氧基苯基)-2,4-二氧代-3-苯基-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁基酯。(0.090g产量;78%)
按照实施例1-1步骤(2)介绍的相同方法除去苄基。残余物用乙醇洗涤获得所需白色固体产物。(0.060g产量;83%)
按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[7-(2-羟基苯基)-2,4-二氧代-3-苯基-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁酯(0.050g,0.100mmol)获得黄色固体7-(2-羟基苯基)-3-苯基-5-(3-哌啶基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮盐酸盐。(0.016mg产量;37%)
分子量:450.93
质谱:415(M+H)+
体外活性等级:B
细胞活性等级:(A549)-C
1H-NMR(300 MHz,DMSO-d6):1.71-1.96(4H,m),2.71-2.91(1H,m),3.27-3.53(3H,m),4.56(1H,m),6.98-7.03(2H,m),7.34-7.53(6H,m),7.89(1H,s),8.18-8.21(1H,m),8.69-8.70(1H,m),9.24-9.25(1H,m),12.47(1H,s)。实施例8-1
(1)将1-{2-[(4-甲氧基苄基)氧基]苯基}乙酮(14.2g,55.4mmol)(初始化合物1D)、3-甲酰基-1-哌啶羧酸苄基酯(13.7g,55.4mmol)(初始化合物2C)、氰基乙酸叔丁酯(7.8g,55.4mmol)以及乙酸铵(9.8g,166.1mmol)的1,2-二甲氧基乙烷(60mL)溶液在回流下搅拌3.5小时。冷却至室温后,混合物在乙酸乙酯和水间分配。分离出的有机相用水和盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。残余物用硅胶柱色谱法(乙酸乙酯∶己烷,1∶2)提纯获得浅黄色油状物2-氨基-4-{1-[(苄氧基)羰基]-3-哌啶基}-6-{2-[(4-甲氧基苄基)氧基]苯基}烟酸叔丁酯(4.89g产量;14%)。
(2)2-氨基-4-{1-[(苄氧基)羰基]-3-哌啶基}-6-[{2-[(4-甲氧基苄基)氧基]苯基}烟酸叔丁酯(0.95g,1.67mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(10mL),然后继续在室温下搅拌过夜。减压浓缩混合物。残余物用甲苯稀释,然后通过共沸蒸馏减压浓缩除去过量三氟乙酸获得2-氨基-4-{1-[(苄氧基)羰基]-3-哌啶基}-6-(2-羟基苯基)烟酸(1.1g产量;定量)。
(3)在室温下,2-氨基-4-{1-[(苄氧基)羰基]-3-哌啶基}-6-(2-羟基苯基)烟酸(1.1g,2.5mmol)的THF(10mL)及MeOH(5mL)溶液中滴加三甲基甲硅烷基重氮甲烷(diazomatane)(4.0mL)。将反应混合物在室温下搅拌1.5小时,反应物用乙酸猝灭。混合物在乙酸乙酯和水间分配。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,3∶1)提纯,接着用CH2Cl2和己烷的混合物重结晶获得黄色固体2-氨基-4-{1-[(苄氧基)羰基]-3-哌啶基}-6-(2-羟基苯基)烟酸甲酯(0.39g产量;34%)。
(4)2-氨基-4-{1-[(苄氧基)羰基]-3-哌啶基}-6-(2-羟基苯基)烟酸甲酯(60mg,0.130mmol)的甲醇(2.0mL)及THF(1.0mL)溶液中加入10%Pd-C(200mg)。将混合物在室温下氢气氛(1atm)中搅拌6.5小时。混合物用Celite_过滤,用依次MeOH和THF洗涤。减压浓缩滤液。残余物用制备型TLC(己烷∶乙酸乙酯,2∶1)提纯获得黄色固体6-氨基-4-(2-羟基-苯基)-5,9-二氮杂-三环[7.3.1.02,7]十三碳-2(7),3,5-三烯-8-酮(16mg产量;40%)。
分子量:295.34
质谱:296(M+H)+
体外活性等级:B
细胞活性等级:(A549)-B
1H-NMR(300MHz,CDCl3-d):1.42(1H,d,J=14.3Hz),1.84(1H,m),1.92(1H,d,J=13.6Hz),2.17(1H,m),2.85(1H,s),3.16(1H,td,J=3.0,12.7Hz),3.35(1H,dd,J=1.9,12.2Hz),3.63(1H,d,J=13.2Hz),3.92(1H,dd,J=4.5,12.8Hz),6.88(1H,td,J=1.1,8.3Hz),6.99(1H,dd,J=1.1,8.3Hz),7.04(1H,s),7.32(1H,td,J=1.1,8.3Hz),7.75(1H,dd,J=1.5,8.0Hz)。实施例8-2
在0℃氩气氛下,2-氨基-4-{1-[(苄氧基)羰基]-3-哌啶基}-6-(2-羟基-苯基)烟酸(750mg,1.676mmol)(由实施例8-1步骤(2)获得)、甲胺盐酸盐(230mg,3.352mmol)、三乙胺(340mg,3.35mmol)以及1-羟基苯并三唑(360mg,2.68mmol)的溶液中加入1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(390mg,2.0mmol)。将混合物在室温下搅拌过夜。反应混合物用乙酸乙酯萃取,用水和盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,2∶1)提纯获得浅黄色固体3-{2-氨基-6-(2-羟基苯基)-3-(N-甲基氨基甲酰基)-4-吡啶基}-1-哌啶羧酸苄基酯(337mg产量;44%)。
3-{2-氨基-6-(2-羟基苯基)-3-(N-甲基氨基甲酰基)-4-吡啶基}-1-哌啶羧酸苄基酯(130mg,0.274mmol)的MeOH(2mL)及THF(2mL)溶液中加入Pd-C(180mg)。将混合物在室温下氢气氛中搅拌过夜。反应混合物用Celite_过滤,用THF洗涤,然后减压浓缩。残余物用乙酸乙酯稀释,加入4N HCl的1,4-二氧六环溶液。所得黄色沉淀用乙腈洗涤。减压干燥所收集的固体获得2-氨基-6-(2-羟基苯基)-N-甲基-4-(3-哌啶基)烟酰胺盐酸盐(10mg产量;81%)。
分子量:362.86
质谱:327(M+H)+
体外活性等级:B
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.69-1.77(2H,m),1.82-1.86(2H,m),2.80(3H,d,J=4.4Hz),2.88(1H,m),3.03(1H,m),3.19-3.29(3H,m),6.89-6.93(3H,m),7.29-7.32(2H,m),7.85(1H,br),8.50(1H,br),8.85(1H,br),9.16(1H,br)。实施例8-3
用初始化合物1G(替代1D)、2C以及其它原料,按照实施例8-1和8-2类似的方法制备2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-N-甲基-4-(3-哌啶基)-烟酰胺盐酸盐。
分子量:432.95
质谱:397(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(300MHz,DMSO-d6):0.29-0.34(2H,m),0.49-0.55(2H,m),1.21(1H,m),1.74-1.89(5H,m),2.84(3H,d,J=4.5Hz),3.10-3.11(2H,m),3.25-3.28(2H,m),3.78-3.90(2H,m),6.59(1H,d,J=8.3Hz),6.65(1H,d,J=8.3Hz),7.20(1H,s),7.26(1H,t,J=8.3Hz),7.56(1H,brs),8.76(1H,brs),9.08(1H,brs),13.8(1H,brs)。实施例9-1
(1)将初始化合物1A(3.500g,15.47mmol)、初始化合物2B(3.299g,15.47mmol)、氰基乙酸叔丁酯(2.184g,15.47mmol)、乙酸铵(3.577g,46.40mmol)以及1,2-二甲氧基乙烷(17mL)的混合物加热回流3.5小时。冷却至室温后,减压浓缩混合物,残余物在乙酸乙酯和水间分配。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。残余物用硅胶快速色谱法(己烷∶乙酸乙酯,4∶1)提纯获得2-氨基-6-[2-(苄氧基)苯基]-4-[1-(叔丁氧基羰基)-3-哌啶基]烟酸叔丁酯。(1.892g产量;22%)
(2)然后用实施例1-1步骤(2)介绍的类似方法除去苄基。将所得固体悬浮于乙醇,过滤收集,用乙醇洗涤,然后减压干燥获得2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-(2-羟基苯基)烟酸叔丁酯(0.322g产量;38%)
(3)按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-(2-羟基苯基)烟酸叔丁酯(0.050g,0.106mmol)获得2-氨基-6-(2-羟基苯基)-4-(3-哌啶基)烟酸叔丁酯盐酸盐(0.034g产量;79%)。
分子量:405.92
质谱:370(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.60(9H,s),1.76-1.95(4H,m),2.90-2.97(1H,m),3.20-3.46(4H,m),6.89-6.94(2H,m),7.31-7.36(1H,m),7.38(1H,s),8.02(1H,dd,J=1.3,8.2Hz),9.09(1H,br),9.29(1H,br),13.78(1H,br)。实施例9-2
2-氨基-6-(2-羟基苯基)-4-(3-哌啶基)烟酸叔丁酯盐酸盐(0.023g,0.057mmol)(由实施例9-1获得)的二氯甲烷(1.0mL)溶液中加入三氟乙酸(TFA)(1.0mL)。搅拌6小时后,减压浓缩混合物。将残余物溶于1,4-二氧六环(3.0mL),然后用HCl的1,4-二氧六环(4N,0.2mL)溶液处理。在氩气氛下过滤收集所得沉淀,用1,4-二氧六环和乙腈洗涤,然后减压干燥获得2-氨基-6-(2-羟基苯基)-4-(3-哌啶基)-烟酸盐酸盐(0.020g产量;定量)。
分子量:349.82
质谱:314(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.75-1.93(4H,m),2.92(1H,brm),2.92-3.39(3H,m),3.63-3.67(1H,brm),6.91-6.96(2H,m),7.32-7.36(1H,m),7.37(1H,s),7.95(1H,d,J=7.9Hz),8.84(1H,br),9.41(1H,br),13.80(1H,br)。实施例9-3
用按初始化合物1G的类似方法制备的1-(2-苄氧基-6-环丙基甲氧基-苯基)-乙酮、初始化合物2B以及其它原料,按照实施例9-2介绍的类似方法制备2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟酸盐酸盐。
分子量:419.91
质谱:384(M+H)+
体外活性等级:A
细胞活性等级:(A549)-C
1H-NMR(500MHz,DMSO-d6):0.31-0.32(2H,m),0.51-0.53(2H,m),1.20(1H,m),1.70-1.74(2H,m),1.89-1.91(2H,m),2.89(1H,m),3.18(1H,m),3.26-3.28(3H,m),3.83(2H,dd,J=6.9,7.3Hz),6.58(1H,d,J=8.2Hz),6.65(1H,d,J=8.5Hz),7.28(1H,dd,J=8.2,8.5Hz),7.30(1H,s),7.81(1H,brs),8.92(1H,brs),9.37(1H,brs)。实施例10-1
(1)在0℃氩气氛下,2-氨基-6-[2-(苄氧基)苯基]-4-[1-(叔丁氧基羰基)-3-哌啶基]烟酸(0.500g,0.993mmol)(由实施例9-1步骤(1)产物衍生得到)、甲胺盐酸盐(0.134g,1.896mmol)、三乙胺(0.277mL,1.986mmol)以及1-羟基苯并三唑(0.215g,1.589mmol)的二氯甲烷(10.0mL)溶液中加入1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(0.228g,1.191mmol)。将混合物在室温下搅拌过夜。减压浓缩反应混合物,然后用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(二氯甲烷/甲醇=19/1)提纯获得黄色油状物3-{2-氨基-6-[2-(苄氧基)苯基]-3-[(甲基氨基)羰基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.11g,21%)。
(2)在氩气氛下向3-{2-氨基-6-[2-(苄氧基)苯基]-3-[(甲基氨基)羰基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.120g,0.232mmol)和三乙胺(0.213g,2.090mmol)的四氢呋喃(10ml)冷(-20℃)溶液中加入三光气(0.069g,0.232mmol)。继续在0℃至室温下搅拌过夜。反应混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得残余物用制备型TLC(己烷/乙酸乙酯=2/1)提纯获得浅黄色固体3-{7-[2-(苄氧基)苯基]-3-甲基-2,4-二氧代-1,2,3,4-四氢-吡啶并[2,3-d]嘧啶-5-基}-1-哌啶羧酸叔丁酯(0.0655g,52%)。
(3)按照实施例1-1步骤(2)类似方法处理3-{7-[2-(苄氧基)苯基]-3-甲基-2,4-二氧代-1,2,3,4-四氢-吡啶并[2,3-d]嘧啶-5-基}-1-哌啶羧酸叔丁酯(0.065g,0.120mmol)。残余物用制备型TLC(己烷/乙酸乙酯=1/1)提纯获得3-[7-(2-羟基苯基)-3-甲基-2,4-二氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁酯(0.010g,18%),然后将其用实施例1-1步骤(3)介绍的方法处理获得7-(2-羟基-苯基)-3-甲基-5-哌啶-3-基-1H-吡啶并[2,3-d]嘧啶-2,4-二酮盐酸盐。
分子量:388.86
质谱:353(M+H)+
体外活性等级:A
细胞活性等级:A549-B
1H-NMR(500MHz,DMSO-d6):1.81-1.85(2H,m),1.96-1.98(2H,m),2.91(1H,m),3.26(3H,s),3.31-3.40(3H,m),4.70(1H,m),6.97-7.00(2H,m),7.39(1H,m),7.86(1H,s),8.16(1H,m),8.73(1H,br),9.17(1H,br),12.37(1H,s)。实施例10-2
用按照初始化合物1G的类似方法制备的1-(2-苄氧基-6-环丙基甲氧基-苯基)-乙酮、初始化合物2B以及其它原料,按照实施例10-1的类似方法制备7-(2-环丙基甲氧基-6-羟基-苯基)-3-甲基-5-哌啶-3-基-1H-吡啶并[2,3-d]嘧啶-2,4-二酮。
分子量:458.95
体外活性等级:A
1H-NMR(500MHz,DMSO-d6):0.31-0.34(2H,m),0.56-0.60(2H,m),1.27(1H,m),1.67(1H,m),1.79(1H,m),1.91-2.01(2H,m),2.87(1H,m),3.06(1H,m),3.27(3H,s),3.30(1H,m),3.39(1H,m),3.83(1H,dd,J=7.3,9.8Hz),3.91(2H,dd,J=6.9,9.8Hz),4.65(1H,m),6.58(2H,d,J=8.5Hz),7.25(1H,dd,J=8.2,8.5Hz,7.91(1H,s),8.83(1H,brs),9.32(1H,brs),12.2(1H,brs)。实施例11-1
(1)在氩气氛下,2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-(2-羟基苯基)烟酸叔丁酯(由实施例9-1步骤(2)获得)(0.200g,0.426mmol)的THF(3.0mL)冷(0℃)溶液中加入LiBH4(0.019g,0.85mmol)。在室温下搅拌过夜后,混合物用水猝灭,然后用乙酸乙酯和0.5N HCl萃取。分离出的有机相用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,1∶1)提纯获得3-[2-氨基-3-(羟基甲基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶-羧酸叔丁酯。(0.161g产量;95%)
按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[2-氨基-3-(羟基甲基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.160g,0.401mmol)的1,4-二氧六环(3.0ml)溶液获得2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]苯酚盐酸盐。(0.132g产量;98%)
分子量:335.84
质谱:300(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):1.75-1.98(4H,m),2.90(1H,br),3.14-3.33(3H,m),3.56-3.60(1H,br),4.58(2H,dd,J=13.0,20.2Hz),6.96(1H,t,J=7.6Hz),7.06(1H,d,J=7.9Hz),7.19(1H,s),7.37(1H,brt,J=7.3Hz),7.65(1H,brd,J=7.6Hz),9.03(1H,br),9.32(1H,br),13.59(1H,br)。实施例11-2
用初始化合物1I和2B以及其它原料,用实施例11-1的类似方法制备2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-氟苯酚盐酸盐。
分子量:353.83
质谱:318(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):1.03(3H,t,J=7.6Hz),1.83(4H,m),3.00(2H,m),3.31(2H,m),3.71(1H,m),4.56(2H,dd,J=13.1,19.4),5.16(1H,br),6.79(2H,m),7.12(1H,s),7.32(1H,m),8.52(1H,d,J=9.8Hz),8.86(1H,d,J=9.8Hz),14.0(1H,br)。实施例11-3
用初始化合物1F、初始化合物2B以及其它原料,用实施例11-1的类似方法制备6’-氨基-5’-(羟基甲基)-4’-(3-哌啶基)-2,2’-联吡啶-3-醇盐酸盐。
分子量:336.82
质谱:301(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):1.81-1.95(3H,m),2.46-2.64(1H,m),3.00-3.06(2H,m),3.28-3.39(2H,m),3.54-3.60(1H,m),4.56(1H,d,J=13.0Hz),4.59(1H,d,J=13.0Hz),7.41-7.50(2H,m),7.81(1H,s),8.24(1H,d),J=3.8Hz),8.92(1H,br),9.07(1H,br)。实施例11-4
(1)用初始化合物1D代替1A、2H代替2B,按照实施例9-1步骤(1)的类似方法制备2’-氨基-6’-{2-[(4-甲氧基苄基)氧基]苯基}-5,6-二氢-3,4’-联吡啶-1,3’(2H)-二羧酸二叔丁酯。
(2)2’-氨基-6’-{2-[(4-甲氧基-苄基)氧基]苯基}-5,6-二氢-3,4’-联吡啶-1,3’(2H)-二羧酸二叔丁酯(50.0mg,0.09mmol)的THF(4.5mL)冷(0℃)溶液中滴加双(2-甲氧基乙氧基)氢化铝钠(0.10ml),然后在0℃搅拌1小时。加入饱和NH4Cl溶液猝灭反应物,过滤,用乙酸乙酯洗涤。合并的有机相用盐水洗涤,用硫酸镁干燥,过滤后蒸发。粗产物用制备型硅胶TLC(含15%丙酮的氯仿)提纯获得白色泡沫状2’-氨基-3’-(羟基甲基)-6’-{2-[(4-甲氧基苄基)氧基]苯基}-5,6-二氢-3,4’-联吡啶-1(2H)-羧酸叔丁酯(25mg,收率57%)。
(3)2’-氨基-3’-(羟基甲基)-6’-{2-[(4-甲氧基苄基)氧基]苯基}-5,6-二氢-3,4’-联吡啶-1(2H)-羧酸叔丁酯(25.0mg,0.05mmol)在室温下用2N HCl的二氧六环(4.0mL)溶液处理过夜。过滤收集所得固体,用乙醚洗涤,然后减压干燥获得2-[6’-氨基-5’-(羟基甲基)-1,2,5,6-四氢-3,4’-联吡啶-2’-基]苯酚盐酸盐。(14mg,收率87%)
分子量:333.82
质谱:298(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(300MHz,D20):2.51(2H,brs),3.35(2H,brs),3.83(2H,s),4.58(2H,s),6.04(1H,brs),6.93-7.01(3H,m),7.34-7.47(2H,m)。实施例12-1
(1)将1-[2,6-双(苄氧基)苯基]乙酮(8.00g,24.067mmol)(初始化合物1E)、3-甲酰基-1-哌啶羧酸叔丁酯(5.133g,24.067mmol)(初始化合物2B)、氰基乙酸叔丁酯(3.398g,24.067mmol)和乙酸铵(5.432g,72.202mmol)的1,2-二甲氧基乙烷(24ml)混合物在100℃于封闭管中搅拌过夜。冷却至室温后,反应混合物在乙酸乙酯和水间分配。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。残余物用30mL二氯甲烷稀释,将MnO2加入到混合物,然后将混合物在室温下搅拌5小时。混合物用Celite_过滤,然后减压浓缩。所得残余物(液体)用硅胶柱色谱法(己烷/乙酸乙酯=2/1)提纯获得浅黄色油状物2-氨基-6-[2,6-双(苄氧基)苯基]-4-[1-(叔丁氧基羰基)-3-哌啶基]烟酸叔丁酯。(2.5g产量;16%)
(2)将2-氨基-6-[2,6-双(苄氧基)苯基]-4-[1-(叔丁氧基羰基)-3-哌啶基]烟酸叔丁酯(1.00g,1.052mmol)和10%钯(Paradium)-碳(0.500g)的20ml乙酸乙酯悬浮液在室温下于氢气氛(1atm)中搅拌过夜。用Celite_过滤除去钯碳后,减压浓缩滤液获得褐色油状物2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-(2,6-二羟基苯基)-烟酸叔丁酯。(0.710g产量;97%)
(3)2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-(2,6-二羟基苯基)烟酸叔丁酯(1.280g,2.636mmol)和K2CO3(3.643g,26.36mmol)的DMF(100mL)溶液中加入(溴甲基)环丙烷(0.268mL,2.768mmol)。在50℃持续搅拌20小时。蒸发除去溶剂后,残余物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=3/1)提纯获得褐色固体2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-[2-(环丙基甲氧基)-6-羟基苯基]烟酸叔丁酯(0.820g产量;58%)。
按照实施例11-1步骤(1)的类似方法处理2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-[2-(环丙基甲氧基)-6-羟基苯基]烟酸叔丁酯,然后按照实施例1-1步骤(3)的类似方法处理获得2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚盐酸盐。
分子量:405.93
质谱:370(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(300MHz,DMSO-d6):0.26-0.29(2H,m),0.47-0.52(2H,m),1.13(1H,m),1.75-1.83(5H,m),2.90-2.93(2H,m),3.04-3.17(2H,m),3.81-3.86(2H,m),4.60(2H,s),6.55(1H,d,J=8.3Hz),6.60(1H,d,J=8.3Hz),7.06(1H,s),7.27(1H,t,J=8.3Hz),7.59(1H,br),8.96(1H,br),9.25(1H,br),13.58(1H,br)。实施例12-2至12-7
(1)2-氨基-6-[2-(苄氧基)苯基]-4-[1-(叔丁氧基羰基)-3-哌啶基]烟酸叔丁酯(由实施例9-1步骤(1)获得)(2.590g,4.627mmol)的THF(25mL)冷(0℃)溶液中加入LiBH4(0.202g,9.255mmol)。将混合物在室温下搅拌5小时,然后用水猝灭。混合物用乙酸乙酯和水萃取。分离出的有机相用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,2∶3)提纯获得3-[2-氨基-6-[2-(苄氧基)苯基]-3-(羟基甲基)-4-吡啶基]-1-哌啶-羧酸叔丁基酯。(0.904g产量;40%)
(2)3-[2-氨基-6-[2-(苄氧基)苯基]-3-(羟基-甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.900g,1.838mmol)的二氯甲烷(20mL)溶液中加入氧化锰(IV)(3.20g,36.8mmol)。在室温下搅拌40分钟后,过滤混合物除去锰盐。减压浓缩滤液。所得固体用乙酸乙酯和己烷混合物重结晶提纯获得3-[2-氨基-6-[2-(苄氧基)苯基]-3-甲酰基-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.651g产量;73%)
(3)然后按照实施例1-1步骤(2)介绍的类似方法除去苄基。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,2∶1)提纯获得3-[2-氨基-3-甲酰基-6-(2-羟基-苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.536g产量;定量)
(4)在氩气氛下向3-[2-氨基-3-甲酰基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.100g,0.252mmol)的1,4-二氧六环(2.0mL)溶液中加入HCl的1,4-二氧六环(4N,2.0ml)溶液,然后继续在室温下搅拌1小时。混合物用Et2O稀释,倾析出上清液。沉淀用Et2O洗涤两次,然后减压干燥获得浅黄色固体,然后将其溶于甲醇(2.0mL)。混合物用冰-水浴冷却。然后在氩气氛下将氰基硼氢化钠(0.047g,0.76mmol)加入到混合物。使混合物温热至室温,然后持续搅拌过夜。减压浓缩所得混合物。将残余物溶于二氯甲烷(2.0ml)和THF(2.0mL)的混合物。混合物中加入三乙胺(0.140mL,1.006mmol),接着加入二碳酸二叔丁酯(0.110g,0.503mmol),然后持续搅拌2小时。所得混合物在乙酸乙酯和水间分配。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,2∶1)提纯获得3-[2-氨基-6-(2-羟基苯基)-3-(甲氧基-甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.033g产量;47%)
(4)按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[2-氨基-6-(2-羟基苯基)-3-(甲氧基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.025g,0.060mmol)获得2-[6-氨基-5-(甲氧基甲基)-4-(3-哌啶基)-2-吡啶基]苯酚盐酸盐。
分子量:349.86
质谱:314(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):1.40-1.74(4H,m),2.80-2.92(2H,m),4.03-4.13(2H,m),4.42(1H,d,J=11.5Hz),4.50(1H,d,J=11.5Hz),6.22-6.32(2H,m),6.81-6.85(2H,m),7.17(1H,s),7.21(1H,brt,J=7.3Hz),7.93(1H,brd,J=7.6Hz),14.30(1H,br)。实施例14-1
包含三乙胺(0.089mL,0.64mmol)的3-[2-氨基-6-[2-(苄氧基)苯基]-3-(羟基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.104g,0.212mmol)(由实施例13-1步骤(1)获得)的THF(2.0mL)冷(0℃)溶液中加入三光气(0.044g,0.15mmol)。搅拌30分钟后,使混合物温热至室温,然后再持续搅拌1小时。所得混合物用水猝灭,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,5∶3)提纯获得3-{7-[2-苄氧基]苯基}-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]-噁嗪-5-基}-1-哌嗪羧酸叔丁酯。(0.058g产量;53%)
3-{7-[2-苄氧基]苯基}-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基}-1-哌嗪羧酸叔丁酯(0.050g,0.097mmol)的乙酸乙酯(3.0ml)溶液在碳载钯(10%,0.10g)存在下于1atm氢化过夜。所得混合物用Celite_过滤,用乙酸乙酯和THF洗涤。减压浓缩合并的滤液,残余物用硅胶柱色谱法(己烷∶乙酸乙酯,2∶1)提纯获得3-[2-氨基-6-(2-羟基苯基)-3-甲基-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.027g产量;73%)
按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[2-氨基-6-(2-羟基苯基)-3-甲基-4-吡啶基]-1-哌啶-羧酸叔丁酯(0.025g,0.065mmol)获得2-[6-氨基-5-甲基-4-(3-哌啶基)-2-吡啶基]苯酚盐酸盐。(0.017g产量;82%)
分子量:319.84
质谱:284(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A/Jurkat-B
1H-NMR‘(500MHz,DMSO-d6):1.08-1.75(4H,m),2.10(3H,s),2.55-2.98(3H,m),4.12(1H,br),6.19(2H,brd,J=15.1Hz),6.79-6.83(2H,m),7.12(1H,s),7.18(1H,brt,J=7.9Hz),7.88(1H,br)。实施例15-1
(1)3-{2-氨基-6-[2-(苄氧基)苯基]-3-甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯(400mg,0.82mmol)(由实施例13-1步骤(2)获得)的THF(2.0mL)冷(-20℃)溶液中滴加甲基溴化镁的THF(7.38ml,7.38mol)溶液。将混合物在-20℃搅拌2小时,用饱和氯化铵水溶液猝灭,用乙酸乙酯萃取。分离出的有机相用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯,3∶2)提纯获得黄色油状物3-[2-氨基-6-[2-(苄氧基)苯基]-3-(1-羟基乙基)-4-吡啶基]-1-哌啶羧酸叔丁酯。(356mg产量;86%)
(3)按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[2-氨基-3-(1-羟基乙基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(30mg,0.07mmol)获得黄色固体2-[6-氨基-5-(1-羟基乙基)-4-(3-哌啶基)-2-吡啶基]苯酚盐酸盐。(20mg产量;78%)
分子量:349.86
质谱:296(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.83-1.92(7H,m),2.90-2.91(1H,m),3.13-3.15(1H,m),3.57(3H,s),5.29-5.39(1H,m),6.89-6.99(1H,m),7.05-7.10(1H,m),7.17(1H,d,J=3.16Hz),7.27-7.40(2H,m),7.62(1H,d,J=5.0Hz),7.68-7.87(2H,m),13.50(1H,brs)。实施例15-2
按照实施例15-1的类似方法制备2-[6-氨基-5-[羟基(苯基)甲基]-4-(3-哌啶基)-2-吡啶基]苯酚盐酸盐。
分子量:411.94
质谱:376(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.67-1.74(2H,m),1.89-1.99(2H,m),2.88-2.93(1H,m),3.14-3.24(4H,m),6.32(1H,s),6.91(1H,d,J=2.2Hz),6.92-7.01(2H,m),7.24-7.32(3H,m),7.34-7.40(6H,m),7.42-7.44(1H,m),7.75(1H,d,J=7.9Hz)。实施例15-3
在搅拌下的3-[2-氨基-6-[2-(苄氧基)苯基]-3-(1-羟基乙基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.100g,0.199mmol)(由实施例15-1步骤(1)获得)的二氯甲烷(1mL)溶液中加入二氧化锰(0.350g,3.971mmol)。将混合物在室温下搅拌2小时。混合物用Celite_过滤,然后减压浓缩获得3-{3-乙酰基-2-氨基-6-[2-(苄氧基)苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯。
然后按照实施例1-1步骤(2)的类似方法处理3-{3-乙酰基-2-氨基-6-[2-(苄氧基)苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.090g,0.169mmol)。残余物用乙醇重结晶获得浅黄色固体3-[3-乙酰基-2-氨基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶-羧酸叔丁酯。(0.019g,收率27%)
然后按照实施例1-1步骤(3)的类似方法处理3-[3-乙酰基-2-氨基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶-羧酸叔丁酯(0.020g,0.044mmol)。过滤收集所得沉淀,用乙腈洗涤,然后减压干燥获得1-[2-氨基-6-(2-羟基-苯基)-4-(3-哌啶基)-3-吡啶基]乙酮盐酸盐。(0.014g,收率89%)
分子量:347.85
质谱:312(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO):1.17-1.87(4H,m),2.92-2.98(1H,m),2.56(3H,s),3.00-3.29(4H,m),6.98-6.91(4H,m),7.30(1H,dd,J=7.3,7.9Hz),7.37(1H,s),8.73(1H,d,J=7.6Hz),13.73(1H,brs)。实施例16-1
溴化铜(II)(0.82g,3.692mmol)的乙腈(10ml)溶液中加入硝酸叔丁酯(0.550mL,4.614mmol)。将混合物在65℃搅拌15分钟。将3-{2-氨基-6-[2-(苄氧基)苯基]-3-甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯(1.50g,3.076mmol)(由实施例13-1步骤(2)获得)的乙腈(10mL)溶液加入到上述混合物,在65℃搅拌3小时。冷却至室温后,反应混合物用水稀释,用乙酸乙酯萃取。将有机相用硫酸钠干燥,过滤后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=4/1-2/1-1/1)提纯获得白色固体3-{6-[2-(苄氧基)苯基]-2-溴-3-甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.260g产量;15%)。
在搅拌下的3-{6-[2-(苄氧基)苯基]-2-溴-3-甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.150g,0.272mmol)的1,4-二氧六环(1mL)溶液中加入肼一水合物(0.5mL)。将反应混合物在90℃搅拌15小时。冷却至室温后,反应物用水猝灭,用乙酸乙酯萃取。将有机相用硫酸钠干燥,过滤后减压浓缩。残余物用乙醚重结晶获得白色固体3-{6-[2-(苄氧基)苯基]-1H-吡唑并[3,4-b]吡啶-4-基}-1-哌啶羧酸叔丁酯(0.030g,23%)。然后按照实施例1-1步骤(2)的类似方法处理3-{6-[2-(苄氧基)苯基]-1H-吡唑并[3,4-b][吡啶-4-基]-1-哌啶-羧酸叔丁酯,再按照实施例1-1步骤(3)处理获得2-(4-哌啶-3-基-1H-吡唑并[3,4-b]吡啶-6-基)-苯酚盐酸盐。
分子量:330.82
质谱:295(M+H)+
体外活性等级:B
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.91-2.05(4H,m),6.97-7.00(2H,m),7.35-7.87(1H,m),7.87(1H,s),8.16(1H,d,J=7.3Hz),8.42(1H,s),8.96(1H,brs),9.26(1H,brs)。实施例17-1
(1)将初始化合物1G(10.00g,30.638mmol)、2B(13.069g,61.275mmol)、氰基乙酸叔丁酯(8.650g,61.275mmol)和乙酸铵(6.902g,91.913mmol)的二氧六环(10mL)混合物在90℃搅拌过夜。冷却至室温后,反应混合物用乙酸乙酯稀释(100mL)。混合物中加入氯醌(1.507g,6.128mmol),在室温下搅拌。1.5小时后,将抗坏血酸(1.079g,6.128mmol)加入到混合物。搅拌1.5小时后,混合物在乙酸乙酯和水间分配。有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=2/1)提纯获得浅褐色2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-{2-(环丙基-甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}烟酸叔丁酯(4.9g,24%)
(2)在氩气氛下,2-氨基-4-[1-(叔丁氧基羰基)-3-哌啶基]-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}烟酸叔丁酯(4.9g,7.426mmol)的四氢呋喃(60mL)冷溶液中滴加Vitride_(10mL)。在0℃持续搅拌1小时。用饱和氯化铵水溶液猝灭后,将饱和酒石酸钠钾水溶液加入到混合物,然后剧烈搅拌混合物。将混合物用乙酸乙酯萃取,用水和盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩获得3-[2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-(羟基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯,它在下一步骤直接使用无需再提纯(4.38g产量;定量)。
(3)在搅拌下的3-[2-氨基-6-{2-(环丙基甲氧基)-64(4-甲氧基苄基)氧基]苯基}-3-(羟基甲基)-4-吡啶基]-1-哌啶-羧酸叔丁酯(0.501g,0.850mmol)的1,4-二氧六环溶液中加入37%甲醛溶液(5.000mL)和1NHCl(5.000mL)。将混合物在室温下搅拌2小时。反应混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。所得残余物用硅胶柱色谱法(乙酸乙酯/己烷=3/2)提纯获得无色泡沫状1,1-二甲基乙基(叔丁基)-3-{7-[2-[(环丙基甲基)氧基]-6-({[4-(甲氧基)-苯基]甲基}氧基)苯基]-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基}-1-哌啶羧酸酯(0.319g产量;62%)。
(4)在搅拌下的1,1-二甲基乙基(叔丁基)-3-{7-[2-[(环丙基甲基)氧基]-6-({[4-(甲氧基)苯基]甲基}氧基)苯基]-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基}-1-哌啶羧酸酯(0.050g,0.083mmol)的1,4-二氧六环溶液中加入4N HCl的1,4-二氧六环(2.000mL)溶液。将混合物在室温下搅拌6小时。减压浓缩反应混合物。所得残余物用乙腈洗涤获得无色固体3-(环丙基甲氧基)-2-[5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-7-基]-苯酚盐酸盐(0.033g产量;95%)。
分子量:417.94
质谱:382(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.30(2H,brs),0.51(2H,brs),1.17(1H,m),1.84(4H,m),2.86(1H,m),4.91(2H,br),5.01(2H,br),6.58(1H,d,J=7.9Hz),6.64(1H,br),7.16(1H,br),7.26(1H,t,J=7.9Hz),8.30(1H,br),9.14(1H,br),9.29(1H,br),13.95(1H,br)。实施例18-1
在氩气氛下向3-[2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-(羟基甲基)-4-吡啶基]-1-哌啶-羧酸叔丁酯(5.0g,8.478mmol)(由实施例17-1步骤(2)获得)和二异丙基乙胺(4.12mL,25.435mmol)的四氢呋喃(200ml)冷(0℃)溶液中滴加三光气(1.258g,4.239mmol)的四氢呋喃(100mL)溶液。使混合物温热至室温,然后持续搅拌3小时。用水猝灭后,混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=1/1)提纯获得白色3-(7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基)-1-哌啶羧酸叔丁酯(3.2g,产量;61%)。
在室温下向3-(7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)-氧基]苯基}-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基)-1-哌啶-羧酸叔丁酯(2.0g,3.248mmol)的二氧六环(15mL)溶液加入4N HCl的二氧六环(30ml)溶液。持续搅拌3小时。蒸发除去溶剂后,所得固体用乙腈研磨,过滤收集,用乙腈洗涤。减压干燥固体获得白色固体7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮盐酸盐(0.865g产量;62%)。
分子量:431.92
质谱:396(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.26-0.37(2H,m),0.51-0.63(2H,m),1.20-1.31(1H,m),1.72-1.95(4H,m),2.80-2.96(2H,m),3.17-3.37(3H,m),3.79-3.88(2H,m),5.48(1H,d,J=14.2Hz),5.53(1H,d,J=14.2Hz),6.54(2H,d,J=8.2Hz),7.17(1H,t,J=8.2Hz),7.77(1H,s),9.05(1H,br),9.27(1H,br),10.96(1H,S)。实施例18-2
包含三乙胺(0.226g,2.23mmol)的3-[2-氨基-3-(羟基甲基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.297g,0.74mmol)(由实施例11-1步骤(1)获得)的THF(3.00mL)冷(0℃)溶液中加入三光气(0.221g,0.74mmol)。30分钟后,使混合物温热至室温,然后持续搅拌1小时。反应物用碳酸氢钠水溶液猝灭,用乙酸乙酯萃取。有机相依次用氯化铵水溶液、水和盐水洗涤。有机相用硫酸钠干燥,过滤后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯,3∶2)提纯获得浅黄色固体3-[7-(2-羟基苯基)-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基]-1-哌啶羧酸叔丁酯。(46.2mg产量;14.6%)
3-[7-(2-羟基苯基)-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3][噁嗪-5-基]-1-哌啶羧酸叔丁酯(45mg,0.11mmol)的1,4-二氧六环(1.0ml)溶液中加入4N HCl的1,4-二氧六环(2.0mL)溶液。在室温下将混合物搅拌1小时。过滤收集所得固体,用1,4-二氧六环洗涤,然后减压干燥获得白色固体7-(2-羟基苯基)-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮盐酸盐。(22.8mg产量;60%)
分子量:361.83
质谱:326(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A/Jurkat-B
1H-NMR(500MHz,DNSO-d6):1.80-1.96(5H,m),2.86-2.93(1H,m),3.13-3.26(3H,m),5.46-5.55(2H,m),6.91-6.94(2H,m),7.30-7.33(1H,m),7.77(1H,s),8.03-8.04(1H,m),11.15(1H,s),12.46(1H,brs)。实施例18-3
用3-[2-氨基-3-(1-羟基乙基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(由实施例15-1步骤(2)获得)按照实施例18-2的类似方法制备7-(2-羟基-苯基)-4-甲基-5-哌啶-3-基-1,4-二氢-苯并[d][1,3]-噁嗪-2-酮盐酸盐。
分子量:375.86
质谱:340(M+H)+
体外活性等级:B
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.52-1.53(3H,m),1.80-2.04(5H,m),2.91-2.95(1H,m),3.13-3.21(3H,m),5.83-5.85(1H,m),6.92-6.95(3H,m),7.32(1H,dd,J=7.9,7.3Hz),8.04(1H,d,J=7.6Hz),11.2(1H,s),12.44(1H,brs)。实施例18-4/18-5
将初始化合物1A(3.000g,13.258mmol)、N-叔丁氧基-羰基-苯基丙氨醛(3.305g,13.258mmol)、氰基乙酸叔丁酯(1.872g,13.258mmol)、乙酸铵(3.066g,39.774mmol)和1,2-二甲氧基乙烷(5.0mL)的混合物加热回流6小时。冷却至室温后,混合物用乙酸乙酯和饱和NaHCO3溶液萃取。分离出的有机相依次用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用二异丙醚研磨获得黄色固体2-氨基-6-[2-(苄氧基)苯基]-4-{1-[(叔丁氧基羰基)氨基]-2-苯基乙基}-1,4-二氢-3-吡啶羧酸叔丁酯(1.281g产量;16%)。
在室温下向2-氨基-6-[2-(苄氧基)苯基]-4-{1-[(叔丁氧基-羰基)氨基]-2-苯基乙基}-1,4-二氢-3-吡啶羧酸叔丁酯(1.200g,2.007mmol)的二氯甲烷(20.0mL)溶液加入氯醌(0.543g,2.208mmol),然后持续搅拌1小时。过滤混合物后减压浓缩滤液。残余物用乙酸乙酯和10%NaHCO3水溶液萃取。分离出的有机相依次用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。粗产物用乙醇结晶获得浅黄色固体2-氨基-6-[2-(苄氧基)苯基]-4-{1-[(叔丁氧基-羰基)氨基]-2-苯基乙基}烟酸叔丁酯(0.972g产量;84%)。
向2-氨基-6-[2-(苄氧基)苯基]-4-{1-[(叔丁氧基羰基)氨基]-2-苯基乙基}烟酸叔丁酯(0.100g,0.198mmol)的THF(1.50mL)冷(0℃)溶液滴加Vitride_(0.500mL),然后持续搅拌2小时。在0℃用饱和NH4Cl水溶液猝灭混合物,用乙酸乙酯萃取。分离出的有机相依次用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。粗产物用硅胶柱色谱法(己烷∶乙酸乙酯,1∶1)提纯获得无色油状物1-{2-氨基-6-[2-(苄氧基)苯基]-3-甲酰基-4-吡啶基}-2-苯基乙基氨基甲酸叔丁酯(0.044g产量;51%)。
1-{2-氨基-6-[2-(苄氧基)苯基]-3-甲酰基-4-吡啶基}-2-苯基乙基氨基甲酸叔丁酯(0.040g,0.092mmol)的乙醇(1.0ml)溶液中加入NaBH4(0.010g,0.26mmol),然后持续搅拌3小时。混合物用乙酸乙酯和饱和氯化铵水溶液萃取。分离出的有机相依次用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。粗产物用乙醇结晶获得浅黄色固体1-[2-氨基-6-[2-(苄氧基)苯基]-3-(羟基甲基)-4-吡啶基]-2-苯基乙基氨基甲酸叔丁酯(0.023g产量;57%)。
向包含三乙胺(0.167ml,1.199mmol)的1-[2-氨基-6-[2-(苄氧基)苯基]-3-(羟基甲基)-4-吡啶基]-2-苯基乙基氨基甲酸叔丁酯(0.210g,0.400mmol)的THF(3.0ml)冷(0℃)溶液滴加三光气(0.059g,0.200mmol)的THF(1.0mL)溶液。在0℃搅拌45分钟后,使混合物温热至室温,然后持续搅拌30分钟。在0℃冷却反应混合物,然后用饱和碳酸氢钠水溶液猝灭。所得混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。粗产物用硅胶柱色谱法(己烷∶乙酸乙酯,2∶1)提纯获得无色油状物1-{7-[2-(苄氧基)苯基]-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基}-2-苯基乙基氨基甲酸叔丁酯(0.170g产量;77%)。
然后按照实施例1-1步骤(2)以及实施例1-1步骤(3)的类似方法处理1-{7-[2-(苄氧基)苯基]-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3][噁嗪-5-基]-2-苯基乙基氨基甲酸叔丁酯获得5-(1-氨基-2-苯基-乙基)-7-(2-羟基-苯基)-1,4-二氢-吡啶并[2,3-d][1,3]噁嗪-2-酮盐酸盐。实施例18-4/18-5
分子量:397.86
质谱:362(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):3.11(1H,dd,J=10.1,12.9Hz),3.44(1H,dd,J=5.0,12.9Hz),4.25(1H,d,J=14.5Hz),4.71-4.74(1H,m),5.35(1H,d,J=14.5Hz),6.93-6.99(2H,m),7.08(2H,dd,J=1.9,7.3Hz),7.23-7.28(3H,m),7.33-7.36(1H,m),8.13(1H,dd,J=1.3,7.9Hz),8.37(1H,s),8.98(3H,br),11.18(1H,s),12.32(1H,br)。实施例18-6
2’-氨基-3’-(羟基甲基)-6’-{2-[(4-甲氧基苄基)氧基]苯基}-5,6-二氢-3,4’-联吡啶-1(2H)-羧酸叔丁酯(25.0mg,0.05mmol)(由实施例11-4步骤(2)获得)和三乙胺(0.02mL,0.14mmol)的THF(3.0ml)冷(0℃)溶液中加入三光气(5.7mg,0.02mmol)的THF(3.0mL)溶液,然后持续搅拌30分钟。将反应混合物温热至室温。冷却反应物至0℃,然后加入饱和碳酸氢钠水溶液猝灭,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后蒸发。粗产物用制备型硅胶TLC(含10%丙酮的氯仿)提纯获得白色固体5-(7-{2-[(4-甲氧基苄基)氧基]苯基}-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基)-3,6-二氢-1(2H)-吡啶羧酸叔丁酯。(21.7mg,收率83%)
质谱:324(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,MeOH-d4):2.63-2.65(2H,m),3.44-3.49(2H,m),4.02(2H,brd,J=1.9Hz),5.45(2H,s),6.04(1H,s),6.88-6.95(2H,m),7.29-7.32(1H,m),7.63(1H,s),7.90(1H,dd,J=1.3,7.9Hz)。实施例18-7至18-16
将7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮盐酸盐(0.070g,0.160mmol)(由实施例18-1获得)和2.5N HCl的1,4-二氧六环(4mL)溶液的混合物在80℃搅拌过夜。冷却至室温后,减压浓缩混合物。所得残余物用二氯甲烷(3mL)稀释,加入三乙胺(0.064g,0.497mmol)。在氩气氛下向冷却的(0℃)混合物中加入二碳酸二叔丁酯(0.047g,0.218mmol)。在室温下持续搅拌过夜。用水猝灭后,混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。残余物用制备型TLC(己烷/乙酸乙酯=1/1)提纯获得3-[7-(2,6-二羟基苯基)-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基]-1-哌啶羧酸叔丁酯(0.019g,19%)。在室温下向3-[7-(2,6-二羟基苯基)-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基]-1-哌啶羧酸叔丁酯的二氧六环(1mL)溶液中加入4N HCl的二氧六环(1ml)溶液。持续搅拌3小时。蒸发除去溶剂后,所得残余物用乙腈洗涤,然后减压干燥获得褐色固体7-(2,6-二羟基苯基)-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]-噁嗪-2-酮盐酸盐(0.007g,46%)。
分子量:377.83
质谱:342(M+H)+
体外活性等级:
细胞活性等级:(A549)-
1H-NMR(500MHz,DMSO-d6):1.73-1.89(4H,m),2.89-2.94(2H,m),3.19(1H,m),3.25-3.32(2H,m),5.46(1H,d,J=14.2Hz),5.51(1H,d,J=14.2Hz),6.41(2H,d,J=8.2Hz),7.03(1H,t,J=8.2Hz),7.88(1H,s),8.90(1H,br),9.14(1H,br),11.01(1H,s)。实施例20-1
在搅拌下的3-[2-氨基-6-[2-(苄氧基)-6-羟基苯基]-3-(羟基甲基)-4-吡啶基]-1-哌啶羧酸叔丁基酯(0.100g,0.198mmol)(由实施例13-1的类似步骤获得)的二氯甲烷(3ml)溶液中加入二氧化锰(0.340g,3.956mmol)。将混合物在室温下搅拌2小时。混合物用Celite_过滤,然后减压浓缩。残余物用乙醇重结晶获得黄色固体3-{2-氨基-6-[2-(苄氧基)-6-羟基苯基]-3-甲酰基-4-吡啶基}-1-哌啶-羧酸叔丁酯。(0.092g,收率93%)
在搅拌下的3-{2-氨基-6-[2-(苄氧基)-6-羟基苯基]-3-甲酰基-4-吡啶基}-1-哌啶羧酸叔丁酯(0.090g,0.183mmol)的1,4-二氧六环(2mL)溶液中加入4N HCl的二氧六环(2mL)溶液。将混合物在室温下搅拌2小时。过滤收集所得沉淀,用乙腈洗涤,然后减压干燥获得2-氨基-6-[2-(苄氧基)-6-羟基苯基]-4-(3-哌啶基)烟碱醛盐酸盐。(0.103g,收率定量)
在氩气氛下向2-氨基-6-[2-(苄氧基)-6-羟基苯基]-4-(3-哌啶基)烟碱醛盐酸盐(0.100g,0.227mmol)的甲醇冷(0℃)溶液加入NaBH3CN(0.040mL,0.682mmol)。将混合物在室温下搅拌12小时,然后减压浓缩。残余物用乙酸乙酯和水萃取。分离出的有机相用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=2/1)提纯获得白色固体2-(6-氨基-5,9-二氮杂三环[7.3.1.02,7]十三碳-2,4,6-三烯-4-基)-3-(苄氧基)苯酚。
在搅拌下的2-(6-氨基-5,9-二氮杂三环[7.3.1.02,7]十三碳-2,4,6-三烯-4-基-3-(苄氧基)苯酚的1,4-二氧六环(2ml)溶液中加入4N HCl的二氧六环(2mL)溶液。将混合物在室温下搅拌2小时。过滤收集所得沉淀,用乙腈洗涤,然后减压干燥获得2-(6-氨基-5,9-二氮杂三环[7.3.1.02,7]十三碳-2,4,6-三烯-4-基)-3-(苄氧基)苯酚盐酸盐。(0.018g,收率19%)
分子量:423.95
质谱:388(M+H)+
体外活性等级:B
细胞活性等级:(A549)-C
1H-NMR(500MHz,DMSO-d6):1.10-1.23(2H,m),1.41(1H,d,J=12.3Hz),1.71-1.80(1H,m),2.79(1H,d,J=12.9Hz),2.89-2.91(2H,m),2.97(1H,d,J=12.9Hz),3.44(2H,d,J=18.3Hz),3.81(1H,d,J=18.0Hz),5.09-5.17(2H,m),6.01(1H,s),6.64(1H,d,J=8.5Hz),7.13(1H,t,J=8.2Hz),7.33-7.41(4H,m),7.49(2H,d,J=1.6Hz)。实施例20-2
将5-[(1R)-1-氨基-2-苯基乙基]-7-(2-羟基苯基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮盐酸盐(0.014g,0.035mmol)(由实施例18-4获得)的乙腈(3.0mL)混合物加热回流2小时。减压浓缩所得混合物。将残余物溶于1,4-二氧六环(1.0mL),用4N HCl的1,4-二氧六环(0.5mL)溶液处理,然后减压浓缩。残余物用乙腈研磨,然后减压干燥获得2-[(1R)-4-氨基-1-苄基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-6-基]苯酚盐酸盐白色固体(0.010g产量;80%)。
分子量:353.85
质谱:318(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):3.30(1H,dd,J=9.1,14.1Hz),3.54(1H,dd,J=5.0,14.1Hz),4.26-4.42(2H,brm),5.20(1H,br),6.91(1H,t,J=7.9Hz),6.97(1H,d,J=8.2Hz),7.29-7.39(2H,m),7.41(1H,t,J=7.9Hz),7.62(1H,d,J=7.3Hz),10.14(1H,br),10.31(1H,br),13.90(1H,br)。实施例20-3
分子量:353.85
质谱:318(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):3.30(1H,dd,J=9.1,14.1Hz),3.54(1H,dd,J=5.0,14.1Hz),4.26-4.42(2H,brm),5.20(1H,br),6.91(1H,t,J=7.9Hz),6.97(1H,d,J=8.2Hz),7.29-7.39(2H,m),7.41(1H,t,J=7.9Hz),7.62(1H,d,J=7.3Hz),10.14(1H,br),10.31(1H,br),13.90(1H,br)。实施例21-1
(1)在搅拌下的3-[2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-(羟基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.050g,0.085mmol)(由实施例17-1步骤(2)获得)和二硫二苯(0.055g,0.254mmol)的四氢呋喃(3ml)溶液中加入三丁基膦(0.060mL,0.254mmol)。将混合物在室温下搅拌24小时。混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物(液体)用硅胶柱色谱法(己烷/乙酸乙酯=3/1-1/1)提纯获得泡沫状(form)3-{2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-[(苯硫基)甲基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.021g产量;37%)。
(2)在搅拌下的3-{2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-[(苯硫基)甲基]-4-吡啶基}-1-哌啶-羧酸叔丁酯的1,4-二氧六环(2mL)溶液中加入4 N HCl的二氧六环(2mL)溶液。将混合物在室温下搅拌过夜,用乙酸乙酯稀释。过滤收集所得沉淀,用乙醇洗涤,然后减压干燥获得2-[6-氨基-5-[(苯硫基)甲基]-4-(3-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚盐酸盐。
分子量:498.09
质谱:462(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):0.30(2H,brs),0.51(2H,brs),1.67(2H,m),1.80(1H,br),4.26(1H,d,J=12.6Hz),4.37(1H,br),6.59(2H,br),7.36(2H,t,J=7.6Hz),7.46(2H,d,J=7.6Hz),7.72(1H,br),8.61-8.98(2H,br),10.36(1H,br),13.58(1H,br)。实施例21-2
(1)用初始化合物1G、按照初始化合物2B的类似方法制备的叔丁基4-甲酰基-哌啶-1-羧酸以及其它原料,按照实施例11-1步骤(1)的类似方法制备4-[2-氨基-6-[2-(环丙基甲氧基)-6-羟基-苯基]-3-(羟基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯。
(2)在室温向搅拌下的4-[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-3-(羟基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.250g,0.528mmol)的乙腈(10mL)溶液加入1,1’-羰基二咪唑(0.170g,1.056mmol)。搅拌2小时后,反应混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。过滤收集所得固体,用己烷洗涤,然后减压干燥获得4-[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-3-(1H-咪唑-1-基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯。(0.242g,收率88%)
(3)在搅拌下的4-[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-3-(1H-咪唑-1-基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.260g,0.500mmol)的1,4-二氧六环(10mL)溶液中加入4N HCl的二氧六环(10mL)溶液。将混合物在室温下搅拌2小时。过滤收集所得沉淀,用乙腈洗涤,然后减压干燥获得2-[6-氨基-5-(1H-咪唑-1-基甲基)-4-(4-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚盐酸盐。(0.248g产量;定量)
分子量:455.99
质谱:420(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.32(2H,d,J=4.7Hz),0.52(2H,d,J=4.7Hz),1.27(1H,brs),1.71(2H,d,J=13.6Hz),1.91-1.98(2H,m),3.00-3.31(2H,m),3.32-3.35(3H,m),3.86(2H,d,J=6.9Hz),5.62(2H,s),6.58(1H,d,J=8.5Hz),6.64(1H,d,J=6.9Hz),7.26(1H,dd,J=8.5,7.9Hz),7.66(1H,s),7.71(1H,s),9.31(1H,s)。实施例21-3
用碳酸二苯酯替代1,1’-羰基二咪唑,按照实施例21-2的类似方法制备2-[6-氨基-5-(苯氧基甲基)-4-(4-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚盐酸盐。
分子量:482.03
质谱:446(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.31(2H,d,J=4.7Hz),0.50(2H,d,J=6.9Hz),1.16-1.19(1H,m),1.84(2H,d,J=13.2Hz),1.91-1.99(2H,m),2.96(2H,m),3.57(1H,s),3.76(2H,d,J=6.6Hz),5.20(2H,s),6.61(1H,d,J=8.2Hz),6.66(1H,d,J=6.0Hz),6.75(1,d,J=8.5Hz),7.20(1H,t,J=7.3Hz),7.08(2H,d,J=7.9Hz),7.15(1H,t,J=7.9Hz),7.36(2H,t,J=7.9Hz)。实施例21-4
用碳酸N,N’-二丁二酰亚胺酯替代1,1’-羰基二咪唑,按照实施例21-2的类似方法制备1-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(4-哌啶基)-3-吡啶基]甲氧基}-2,5-吡咯烷二酮盐酸盐。
分子量:503.00
质谱:467(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.19(2H,d,J=5.0Hz),0.52(2H,d,J=7.3Hz),1.21(1H,brs),1.91-1.96(4H,m),2.71(4H,s),3.03(2H,d,J=8.2Hz),3.85(2H,d,J=6.9Hz),5.18(2H,s),6.59(1H,d,J=8.5Hz),6.64(1H,d,J=7.6Hz),7.05(1H,brs),7.27(1H,t,J=7.9Hz),7.60(1H,brs),8.82(1H,brs),8.92(1H,d,J=9.1Hz)。实施例22-1
(1)3-[2-氨基-6-[2-(苄氧基)苯基]-3-(羟基甲基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.050g,0.102mmol)(由实施例13-1步骤(1)获得)的甲苯(1.0mL)冷(0℃)溶液中加入二苯基-磷酰基叠氮化物(0.024mL,0.112mmol),接着加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(0.017mL,0.112mmol)。30分钟后,使混合物温热至室温,然后持续搅拌2小时。减压浓缩混合物,残余物在乙酸乙酯和水间分配。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,2∶1)提纯获得3-{2-氨基-3-(叠氮基甲基)-6-[2-(苄氧基)苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯。(0.038g产量;72%)
(2)3-{2-氨基-3-(叠氮基甲基)-6-[2-(苄氧基)苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.030g,0.058mmol)的乙酸乙酯(1.0mL)溶液在碳载钯(10%,0.015g)存在下于1atm氢化过夜。将所得混合物过滤,用乙酸乙酯洗涤。减压浓缩合并的滤液获得3-[2-氨基-3-(氨基甲基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯,它在下一步骤直接使用无需再提纯。
(3)在氩气氛下,3-[2-氨基-3-(氨基甲基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.020g,0.050mmol)的THF(2.0mL)冷(0℃)溶液中加入1,1’-羰基二咪唑(0.009g,0.055mmol)。搅拌15分钟后,将混合物用饱和碳酸氢钠溶液猝灭。所得混合物在乙酸乙酯和饱和氯化铵溶液间分配。分离出的有机相用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。将残余物溶于乙酸乙酯(2.0mL)。混合物在60℃加热1小时,冷却至室温。过滤收集所得沉淀,用乙酸乙酯洗涤后减压干燥获得3-[7-(2-羟基苯基)-2-氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁酯。(0.007g产量;33%)
(4)按照实施例1-1步骤(3)介绍的类似方法在酸性条件下处理3-[7-(2-羟基苯基)-2-氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁基酯(0.006g,0.014mmol)获得7-(2-羟基苯基)-5-(3-哌啶基)-3,4-二氢吡啶并[2,3-d]嘧啶-2(1H)-酮盐酸盐。(0.005g产量;98%)
分子量:360.85
质谱:325(M+H)+
体外活性等级:A
细胞活性等级:B
1H-NMR(500MHz,DMSO-d6):1.76-1.93(4H,m),2.88-3.37(5H,m),4.47(2H,dd,J=15.4,24.3Hz),6.87-6.92(2H,m),7.26-7.30(2H,m),7.63(1H,s),8.00(1H,d,J=8.2Hz),8.57(1H,br),9.01(1H,br),10.08(1H,s),12.78(1H,br)。实施例22-2
用初始化合物1G、2B以及其它原料,按照实施例22-1的类似方法制备7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢-1H-吡啶并[2,3-d]嘧啶-2-酮盐酸盐。
分子量:430.94
质谱:395(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.34(2H,m),0.57(2H,m),1.27(1H,m),1.73-1.87(4H,m),2.82-2.90(2H,m),3.14(1H,m),3.29-3.33(2H,m),3.80-3.88(2H,m),4.49(2H,s),6.52(2H,d,J=8.2Hz),7.16(1H,t,J=8.2Hz),7.75(1H,s),9.11(1H,br),9.26(1H,br),9.92(1H,s)。实施例22-3
用初始化合物1G和叔丁基4-甲酰基-哌啶-1-羧酸以及其它原料,按照实施例22-1的类似方法制备7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(4-哌啶基)-3,4-二氢-1H-吡啶并[2,3-d]嘧啶-2-酮盐酸盐。
分子量:430.94
质谱:395(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.32(2H,d,J=4.5Hz),0.57(2H,d,J=1.7Hz),1.33-1.38(1H,m),1.80-1.91(4H,m),2.96-3.05(3H,m),3.34-3.39(3H,m),4.47(2H,s),6.51(2H,dd,J=3.8,8.3Hz),7.15(1H,t,J=7.9Hz),7.24(1H,s),7.74(1H,s),9.86(1H,s)。实施例22-4
用由实施例22-1步骤(2)获得的3-[2-氨基-3-(氨基甲基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯,按照实施例22-1或22-2的类似方法制备7-(2-羟基苯基)-5-(3-哌啶基)-3,4-二氢-1H-吡啶并[2,3-d]嘧啶-2-硫酮盐酸盐。
分子量:447.00
质谱:411(M+H)+
体外活性等级:
细胞活性等级:(A549)-
1H-NMR(500mHz,DMSO-d6):0.33-0.36(2H,m),0.57-0.59(2H,m),1.28(1H,m),1.72-1.81(2H,m),1.89-1.90(2H,m),2.82-2.89(2H,m),3.00(1H,m),3.27-3.34(2H,m),3.82-3.85(2H,m),4.54-4.56(2H,m),6.52(2H,d,J=8.2Hz),7.16(1H,t,J=8.2Hz),7.83(1H,s),8.73(1H,br),9.08(2H,br),11.13(1H,s)。实施例22-5
将3-[2-氨基-3-(氨基甲基)-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.060g,0.151mmol)(由实施例22-1步骤(2)获得)、磺酰胺(0.022g,0.226mmol)和吡啶(2.0mL)的混合物在回流下搅拌过夜。冷却至室温后,混合物在乙酸乙酯和水间分配。分离出的有机相依次用0.5N HCl溶液、水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。粗产物用硅胶柱色谱法(己烷∶乙酸乙酯,1∶1)提纯获得浅黄色泡沫状3-[7-(2-羟基苯基)-2,2-二氧代基-3,4-二氢-1H-吡啶并[2,3-c][1,2,6]噻二嗪-5-基]-1-哌啶羧酸叔丁酯(0.059g产量;85%)。
然后按照实施例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得2-[2,2-二氧代基-5-(3-哌啶基)-3,4-二氢-1H-吡啶并[2,3-c][1,2,6]噻二嗪-7-基]苯酚盐酸盐。
分子量:396.90
质谱:361(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR’(500MHz,DMSO-d6):1.82-1.91(4H,m),2.86-2.93(1H,m),3.18-3.36(4H,m),4.52(2H,s),6.90-6.93(2H,m),7.30(1H,dt,J=1.6,8.5Hz),7.65(1H,brs),8.00(1H,d,J=7.6Hz),8.97(1H,br),9.32(1H,br)。实施例23-1
(1)利用初始化合物1G、2B以及实施例22-1步骤(1)和(2)的类似方法制备3-{2-氨基-3-(氨基甲基)-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯。
(2)3-{2-氨基-3-(氨基甲基)-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(1.9g,4.055mmol)和三乙胺(1.13ml,8.109mmol)的四氢呋喃(40.0mL)冷(0℃)溶液中加入醋酸酐(0.457mL,4.865mmol)。将混合物在0℃搅拌4小时。用水猝灭后,混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。所得残余物(黄色固体)用乙酸乙酯/二异丙醚重结晶提纯获得3-{3-(乙酰基氨基-甲基)-2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(1.13g产量;55%)。
(3)按照实施例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基}乙酰胺盐酸盐。
分子量:446.98
质谱:411(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.28-0.30(2H,m),0.47-0.50(2H,m),1.13(1H,m),1.85-1.90(4H,m),1.93(3H,s),2.88(1H,m),3.06(1H,m),3.23(1H,m),3.33(1H,m),3.73(1H,m),3.80(2H,m),4.32-4.39(2H,dd,J=5.6,15.5Hz),6.58(1H,d,J=8.5Hz),6.65(1H,d,J=8.2Hz),7.09(1H,s),7.27(1H,J=8.2Hz),7.80(1H,br),8.98(2H,br),9.29(1H,br),13.63(1H,br)。实施例23-2
(1)在氩气氛下,向3-{2-氨基-3-(氨基甲基)-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.300g,0.640mmol)(由实施例23-1步骤(1)获得)和三乙胺(0.067mL,0.704mmol)的四氢呋喃(30mL)冷(0℃)溶液中加入氯甲酸乙酯(0.134mL,0.960mmol)。使混合物温热至室温,然后持续搅拌4小时。用水猝灭后,混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=1/1)提纯获得浅黄色泡沫状(form)3-(2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-3-{[(乙氧基羰基)氨基]甲基}-4-吡啶基)-1-哌啶羧酸叔丁酯(0.246g产量;71%)。
(2)然后按照实施例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得[2-氨基-6-[2-(环丙基甲氧基)-6-羟基-苯基]-4-(3-哌啶基)-3-吡啶基]甲基氨基甲酸乙酯盐酸盐。
分子量:477.01
质谱:441(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.28-0.30(2H,m),0.48-0.51(2H,m),1.17(3H,t,J=7.1Hz),1.22(1H,m),1.82-1.89(5H,m),2.88(1H,m),3.03(1H,m),3.25(1H,m),3.69(1H,m),3.84(2H,m),4.03(2H,q,J=6.9Hz),4.28(2H,dd,J=5.4,15.1Hz),6.59(1H,d,J=8.2Hz),6.65(1H,d,J=8.2Hz),7.11(1H,s),7.27(1H,t,J=8.2Hz),7.64(1H,s),7.86(1H,s),8.80(1H,s),9.27(1H,s)。实施例23-3
(1)3-{2-氨基-3-氨基甲基}-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.150g,0.320mmol)(由实施例23-1步骤(1)获得)的四氢呋喃(10.0ml)溶液中加入异氰酸环己酯(0.044g,0.352mmol)。将混合物在室温下搅拌1.5小时,然后减压浓缩。所得残余物用制备型TLC(乙酸乙酯)提纯获得黄色泡沫状(form)3-{2-氨基-3[(3-环己基-脲基)-甲基]-6-[2-(环丙基甲氧基)-6-羟基-苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.113g产量;60%)。
(2)然后按照实施例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基-苯基]-4-(3-哌啶基)-3-吡啶基]甲基}-N’-环己基脲盐酸盐。
分子量:530.12
质谱:494(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.27-0.28(2H,m),0.47-0.49(2H,m),1.10-1.14(4H,m),1.22-1.27(3H,m),1.51(1H,m),1.62-1.65(2H,m),1.73-1.74(3H,m),1.83-1.89(5H,m),2.88(1H,m),3.01(1H,m),3.72(1H,m),3.78-3.85(2H,m),4.29-4.32(2H,m),6.59(1H,d,J=8.5Hz),6.66(1H,d,J=8.2Hz),7.05(1H,s),7.27(1H,t,J=8.2Hz),8.98(1H,s),9.25(1H,s),10.3(1H,s),13.5(1H,s)。实施例23-4至23-15
在氩气氛下向3-{3-[(乙酰基氨基)甲基]-2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(1.134g,2.220mmol)(由实施例23-1步骤(1)获得)和三乙胺(1.871ml,13.320mmol)的四氢呋喃(150ml)冷(0℃)溶液滴加三光气(0.652g,2.220mmol)的四氢呋喃(150mL)溶液。搅拌过夜后,用水猝灭反应混合物。混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。所得残余物(黄色固体)用硅胶柱色谱法(己烷/乙酸乙酯=1/1)提纯获得白色泡沫状(form)3-{3-乙酰基-7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-1,2,3,4-四氢-吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁酯(0.569g产量;48%)。
然后按照实施例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得3-乙酰基-7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢吡啶并[2,3-d]嘧啶-2(1H)-酮盐酸盐。
分子量:472.98
质谱:437(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.31-0.34(2H,m),0.56-0.59(2H,m),1.26(1H,m),1.74-1.79(2H,m),1.81-1.93(2H,m),2.47(H,s),2.85-2.98(2H,m),3.21-3.34(3H,m),3.81-3.86(2H,m),4.93(2H,s),6.52(2H,d,J=8.2Hz),7.16(1H,t,J=8.2Hz),7.78(1H,s),8.79(1H,br),9.30(1H,br),10.95(1H,s)。实施例24-2
在氩气氛下向3-(2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-3-{[(乙氧基羰基)氨基]甲基}-4-吡啶基)-1-哌啶-羧酸叔丁酯(0.145g,0.268mmol)(由实施例23-2步骤(1)获得)和三乙胺(0.226mL,1.609mmol)的四氢呋喃(30mL)冷(0℃)溶液中加入三光气(0.079g,0.268mmol)的四氢呋喃(10ml)溶液。使混合物温热至室温,然后持续搅拌3小时。用水猝灭后,混合物用乙酸乙酯萃取。分离出的有机相依次用水和盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得残余物用制备型TLC(己烷/乙酸乙酯=1/1)提纯获得白色固体5-[1-(叔丁氧基羰基)-3-哌啶基]-7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸乙酯(0.904g产量;60%)。
然后按照实施例1-1步骤(3)的类似方法处理以上叔丁酯获得7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸乙酯盐酸盐。
分子量:503.00
质谱:467(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.31-0.34(2H,m),0.55-0.59(2H,m),1.26-1.28(1H,brs),1.27(3H,t,J=7.3Hz),1.74-1.85(3H,m),2.85-2.95(2H,m),3.22-3.25(1H,m),3.30-3.32(2H,m),3.79-3.87(1H,m),4.22-4.25(2H,m),4.91(2H,s),6.52(2H,d,J=8.2Hz),7.16(1H,t,J=8.2Hz),7.78(1H,s),8.91(1H,brs),9.29(1H,br),10.86(1H,s)。实施例24-3
在氩气氛下向3-{2-氨基-3-({[(环己基氨基)-羰基]氨基}甲基)-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.039g,0.065mmol)(由实施例23-3步骤(1)获得)和三乙胺(15.0mL,0.389mmol)的四氢呋喃(10.0ml)冷(0℃)溶液滴加三光气(0.019g,0.065mmol)的四氢呋喃(5.0mL)溶液。将混合物在0℃搅拌2小时。用水猝灭后,混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤后减压浓缩。所得残余物(白色固体)用二异丙醚研磨,过滤收集,用二异丙醚洗涤,然后减压干燥获得3-{3-[(环己基氨基)羰基]-7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基}-1-哌啶羧酸叔丁酯(0.021g产量;52%)。
然后按照例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得N-环己基-7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺盐酸盐。
分子量:556.11
质谱:520(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR‘(500MHz,DMSO-d6):0.32-0.34(2H,m),0.55-0.59(2H,m),1.24-1.35(8H,m),1.64(1H,m),1.75-1.78(2H,m),1.82-1.84(4H,m),1.91-1.93(2H,m),2.86(1H,m),2.96(1H,m),3.16(1H,m),3.62(1H,m),3.63-3.88(2H,dd,J=6.9,9.8Hz),4.98(2H,s),6.52(2H,d,J=8.2Hz),7.16(1H,t,J=8.5Hz),7.77(1H,s),9.00(1H,s),10.82(1H,s),11.73(1H,s)。实施例24-4
在氩气氛下向3-{2-氨基-3-(氨基甲基)-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-吡啶基}-1-哌啶羧酸叔丁酯(0.150g,0.320mmol)(由实施例23-1步骤(1)获得)和三乙胺(0.067mL,0.480mmol)的四氢呋喃(9mL)冷(0℃)溶液中加入甲磺酰氯(0.027ml,0.352mmol)。在0℃持续搅拌1小时。用水猝灭后,混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得黄色残余物用二异丙醚/二氯甲烷重结晶获得黄色固体3-(2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-3-{[(甲基磺酰基)氨基]甲基}-4-吡啶基)-1-哌啶羧酸叔丁酯(0.097g产量;56%)。
在氩气氛下向3-(2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-3-{[(甲基磺酰基)氨基]甲基}-4-吡啶基)-1-哌啶-羧酸叔丁酯(0.050g,0.091mmol)和三乙胺(0.077ml,0.549mmol)的四氢呋喃(15ml)冷(0℃)溶液中加入三光气(0.027g,0.091mmol)的四氢呋喃(5mL)溶液。使混合物温热至室温,然后在氩气氛下持续搅拌3小时。用水猝灭后,用乙酸乙酯萃取混合物。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。所得黄色固体用二异丙醚研磨,过滤收集获得黄色固体3-[7-[2-(环丙基甲氧基)-6-羟基苯基]-3-(甲基磺酰基)-2-氧代-1,2,3,4-四氢吡啶并[2,3-d]嘧啶-5-基]-1-哌啶羧酸叔丁酯(0.028g产量;55%)。
然后按照实施例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得7-[2-(环丙基甲氧基)-6-羟基苯基]-3-(甲基-磺酰基)-5-(3-哌啶基)-3,4-二氢吡啶并[2,3-d]嘧啶-2(1H)-酮盐酸盐。
分子量:509.03
质谱:473(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR‘(500MHz,DMSO-d6):0.30-0.33(2H,m),0.54-0.58(2H,m),1.26(1H,m),1.73-1.78(2H,m),1.88-1.93(2H,m),2.88(1H,m),2.99(1H,m),3.13(1H,m),3.30-3.35(2H,m),3.50(3H,s),3.83(2H,dd,J=6.9,7.2Hz),4.97(2H,s),6.53(2H,d,J=8.2Hz),7.17(1H,t,J=8.5Hz),7.75(1H,s),8.67(1H,s),9.11(1H,s),11.02(1H,s)。实施例24-5至24-10
3-[2-氨基-3-甲酰基-6-(2-羟基苯基)-4-吡啶基]-1-哌啶羧酸叔丁酯(0.86g,2.16mmol)的乙醇(25ml)悬浮液中加入丙二酸二乙酯(6.93g,43.27mmol)和哌啶(2.14ml,21.64mmol),将混合物加热回流过夜。混合物冷却至室温,然后用乙醇稀释。过滤收集所得沉淀,用乙醇洗涤后减压干燥获得黄色固体5-[1-(叔丁氧基羰基)-3-哌啶基]-7-(2-羟基苯基)-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸乙酯(0.752g产量;71%)。
然后按照实施例1-1步骤(3)的类似方法处理以上氨基甲酸叔丁酯获得7-(2-羟基苯基)-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-羧酸乙酯盐酸盐。
分子量:429.91
质谱:394(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.34(3H,t,J=7.1Hz),1.89-2.07(4H,m),2.92-3.00(1H,m),3.40-3.44(1H,m,3.77(1H,br),4.32(2H,q,J=7.1Hz),6.97-7.01(2H,m),7.41(1H,t,J=7.25Hz),8.01(1H,s),8.21(1H,d,J=7.25Hz),8.62(1H,s),8.83(1H,br),9.18(1H,br),12.69(1H,s),12.96(1H,brs)。实施例25-2
(1)在搅拌下的3-[2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-(羟基甲基)-4-吡啶基]-1-哌啶-羧酸叔丁酯(1.100g,1.863mmol)(由实施例17-1步骤(2)获得)的二氯甲烷(50ml)溶液中加入二氧化锰(3.240g,37.261mmol)。将混合物在室温下搅拌3小时,用Celite_过滤。减压浓缩滤液获得3-(2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-甲酰基-4-吡啶基)-1-哌啶羧酸叔丁酯(0.978g产量;89%)。
(2)在搅拌下的3-(2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-甲酰基-4-吡啶基)-1-哌啶羧酸叔丁酯(0.500g,0.851mmol)、三乙基-2-氟-2-膦酰基乙酸酯(0.350mL,1.701mmol)和无水氯化锂(0.072g,1.701mmol)的乙腈(20mL)溶液中加入1,8-二氮杂二环[5,4,0]十一碳-7-烯(0.250ml,1.701mmol)。将混合物在室温下搅拌30分钟,减压浓缩。残余物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物(液体)用硅胶柱色谱法(己烷/乙酸乙酯=2/1-1/1)提纯获得泡沫状(form)3-(2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-6-氟-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶羧酸叔丁酯(0.261g,49%)。
然后按照实施例21-1步骤(2)的类似方法处理以上氨基甲酸叔丁酯获得7-[2-(环丙基甲氧基)-6-羟基苯基]-3-氟-5-(3-哌啶基)-1,8-萘啶-2(1H)-酮盐酸盐。
分子量:445.93
质谱:410(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.32(2H,m),0.55(2H,m),1.25(1H,m),1.94(4H,m),2.95(2H,m),3.65(1H,br),6.58(2H,d,J=8.2Hz),7.23(1H,t,J=8.2Hz),7.97(1H,s),8.15(1H,d,J=11.4Hz),8.64(1H,br),9.01(1H,br),11.66(1H,br),13.02(1H,d,J=5.4Hz)。实施例25-3
(1)用初始化合物1G和叔丁基4-甲酰基哌啶-1-羧酸,按照实施例25-2步骤(1)的类似方法制备4-(2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基-苄基)氧基]苯基}-3-甲酰基-4-吡啶基)-1-哌啶羧酸叔丁酯。4-(2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-甲酰基-4-吡啶基)-1-哌啶羧酸叔丁酯(0.400g,0.681mmol)的乙醇(5.0ml)溶液中加入乙基丙二酸一胺(1.780g,13.612mmol)和哌啶(0.580g,6.806mmol)。将混合物回流12小时。反应混合物用乙酸乙酯和水萃取。分离出的有机相用NaHCO3和盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物(液体)用硅胶柱色谱法(己烷/乙酸乙酯=1/1和乙酸乙酯100%)提纯获得黄色泡沫状(form)4-(6-(氨基羰基)-2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶羧酸叔丁酯。(0.455g产量;定量)
(2)然后按照实施例21-1步骤(2)的类似方法处理以上氨基甲酸叔丁酯获得7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(4-哌啶基)-1,2-二氢-1,8-萘啶-3-甲酰胺盐酸盐。
分子量:470.96
质谱:435(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):0.32(2H,d,J=4.7Hz),0.57(2H,d,J=7.9Hz),1.32-1.35(1H,m),1.91-2.01(5H,m),3.23-3.26(3H,m),3.70-3.80(2H,m),3.90(2H,d,J=6.9Hz),6.59(2H,dd,J=1.7,8.3Hz),7.26(1H,t,J=8.2Hz),7.87(1H,d,J=3.5Hz),8.01(1H,s),8.70(1H,d,J=12.3Hz),8.87(1H,d,J=10.7Hz),8.99(1H,d),J=3.4Hz),9.06(1H,s),13.05(1H,s)。实施例25-4
(1)(二苯氧基基磷酰基)乙酸乙酯(1.090g,3.403mmol)的THF(15ml)溶液中加入1,8-二氮杂二环[5,4,0]十一碳-7-烯(0.520g,3.403mmol)和NaI(0.510g,3.403mmol),接着加入3-(2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]-苯基}-3-甲酰基-4-吡啶基)-1-哌啶羧酸叔丁酯(1.000g,1.701mmol)(由实施例25-2步骤(1)获得)的THF(5mL)溶液。将混合物在0℃搅拌1.5小时,用饱和碳酸氢钠水溶液猝灭。混合物用乙酸乙酯萃取,萃取液用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。残余物用硅胶柱色谱法(己烷/乙酸乙酯=3∶2至1∶2)提纯获得无定型固体3-(2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶羧酸叔丁酯(0.276g,27%)。
(2)在搅拌下的3-(2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶-羧酸叔丁酯(0.260g,0.425mmol)的1,4-二氧六环(2ml)溶液中加入4N HCl的二氧六环(2mL)溶液。将混合物在室温下搅拌过夜,用乙酸乙酯稀释。过滤收集所得沉淀,用乙醇洗涤,然后减压干燥获得黄色固体7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,8-萘啶-2(1H)-酮盐酸盐(0.146g,80%)。
分子量:427.93
质谱:392(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.34(2H,m),0.58(2H,m),1.28(1H,m),1.91(4H,m),2.89(1H,brd,J=6.6Hz),3.00(1H,dd,J=10.4,12.3Hz),3.37(2H,dd,J=12.3,12.6Hz),6.57(2H,d,J=8.2Hz),6.67(1H,d,J=9.8Hz),7.23(1H,t,J=8.2Hz),7.99(1H,s),8.21(1H,d,J=9.8Hz),9.02(1H,br),9.14(1H,br),12.45(1H,brs)。实施例25-5至25-8
按照实施例25-1至25-4的类似合成步骤制备表8所示化合物。
(1)在氩气氛下向5-[1-(叔丁氧基羰基)-3-哌啶基]-7-(2-羟基苯基)-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸乙酯(0.050g,0.101mmol)的THF(2.0ml)冷(0℃)溶液中加入LiBH4(0.004g,0.20mmol)。使混合物温热至室温,然后持续搅拌3小时。所得混合物用水猝灭,使其在乙酸乙酯和饱和氯化铵溶液间分配。分离出的有机相用水和盐水洗涤,用硫酸钠干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(己烷∶乙酸乙酯,3∶2)提纯获得5-[1-(叔丁氧基羰基)-3-哌啶基]-7-(2-羟基苯基)-2-氧代-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯。(0.027g产量;54%)
(2)按照实施例1-1中介绍的类似方法在酸性条件下处理5-[1-(叔丁氧基羰基)-3-哌啶基]-7-(2-羟基苯基)-2-氧代-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯(0.024g,0.048mmol)获得7-(2-羟基苯基)-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯。(0.019g产量;91%)
分子量:431.92
质谱:396(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR‘(500MHz,DMSO-d6):1.16-1.21(3H,m),1.83-1.95(4H,m),2.87-2.94(1H,m),3.18-3.37(6H,m),4.12-4.17(2H,m),6.90-6.93(2H,m),7.29(1H,t,J=7.88Hz),7.73(1H,s),8.03(1H,d,J=7.88Hz),8.81-8.90(1H,m),9.23-9.30(1H,m),11.33(1H,s)。实施例26-2
在氩气氛下,4-(6-(氨基羰基)-2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶-羧酸酯(0.200g,0.305mmol)(由实施例25-3步骤(1)获得)的甲醇(5.0mL)冷(0℃)溶液中加入NaBH4(0.010g,0.367mmol)。使混合物温热至室温,然后持续搅拌12小时。反应混合物用水猝灭,用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩获得4-(6-(氨基羰基)-2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)-氧基]苯基}-7-氧代-5,6,7,8-四氢-1,8-萘啶-4-基)-1-哌啶羧酸叔丁酯。(0.133g产量;67%)
在搅拌下的4-(6-(氨基羰基)-2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-7-氧代-5,6,7,8-四氢-1,8-萘啶-4-基)-1哌啶羧酸叔丁酯(0.120g,0.187mmol)的1,4-二氧六环(3mL)溶液中加入4N HCl的二氧六环(1mL)溶液。将混合物在室温下搅拌2小时。过滤收集所得沉淀,用乙腈洗涤,然后减压干燥获得7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(4-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-甲酰胺盐酸盐。(0.080g,收率90%)
分子量:472.98
质谱:437(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.33(2H,d,J=4.4Hz),0.60(2H,d,J=6.3Hz),1.33-1.39(1H,m),1.77-1.91(5H,m),3.06-3.10(2H,m),3.20(3H,d,J=8.2Hz),3.86(2H,dd,J=2.2,7.1Hz),6.53(2H,dd,J=8.2,7.0Hz),7.16(1H,t,J=8.2Hz),7.20(1H,s),7.56(1H,s),7.84(1H,s),11.02(1H,s)。实施例26-3至26-6
按照实施例26-1至26-2的类似合成步骤制备表9所示化合物。
将7-(2-羟基苯基)-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯盐酸盐(0.012g,0.023mmol)(由实施例26-1步骤(2)获得)的2.5N HCl(3.0mL)溶液加热回流4小时。冷却至室温后,减压浓缩混合物。残余物用乙腈洗涤,减压干燥获得7-(2-羟基苯基)-5-(3-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮盐酸盐。(0.007g产量;70%)
分子量:359.86
质谱:324(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):1.83-1.94(4H,m),2.57-2.64(2H,m),2.89-3.01(3H,m),3.19-3.37(4H,m),6.88-6.93(2H,m),7.28(1H,t,J=8.2Hz),7.69(1H,s),8.01(1H,d,J=7.9Hz),8.90(1H,br),9.16(1H,br),10.99(1H,s)。实施例27-2至27-5
按照以上实施例27-1介绍的类似方法合成实施例27-2至27-5的化合物。
在搅拌下的7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶)-3,4-二氢-1,8-萘啶-2(1H)-酮(0.029g,0.074mmol)(由实施例27-3获得)的THF(1.5mL)溶液中滴加Vitride_(70%甲苯溶液,0.500mL)。将混合物在65℃搅拌1小时。冷却至室温后,混合物用饱和酒石酸钠钾水溶液猝灭。混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物用制备型TLC(氯仿/甲醇=4/1)提纯获得3-(环丙基甲氧基)-2-[4-(3-哌啶基)-5,6,7,8-四氢-1,8-萘啶-2-基]苯酚。(0.003g产量;11%)
分子量:379.51
质谱:380(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,CDCl3):0.42(2H,m),0.68(2H,m),1.35(1H,m),1.91(1H,d,J=12.0Hz),1.98(2H,m),2.63(1H,dt,J=2.8,12.Hz),2.77(3H,m),2.86(1H,m),3.11(2H,dd,J=2.3,10.5Hz),3.40(2H,dt,J=2.8,5.4Hz),3.83(2H,d,J=6.9Hz),4.75(1H,brs),6.38(1H,dd,J=1.3,8.2Hz),6.59(1H,dd,J=1.3,8.2Hz),7.09(1H,t,J=8.2Hz),7.78(1H,s),14.69(1H,br)。实施例29-01
(1)在搅拌下的3-(2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-甲酰基-4-吡啶基)-1-哌啶羧酸叔丁酯(0.100g,0.170mmol)(由实施例25-2步骤(1)获得)和硝基乙酸乙酯(0.060mL,0.510mmol)的乙醇(5ml)溶液中加入哌啶(0.050mL,0.510mmol)。将混合物在75℃搅拌18小时,然后减压浓缩。残余物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物(液体)用硅胶柱色谱法(己烷/乙酸乙酯=3/1-3/2)提纯获得3-(2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-6-硝基-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶羧酸叔丁酯(0.105g产量;94%)。
(2)在搅拌下的3-(2-{2-(环丙基甲氧基)-6-[(4-甲氧基-苄基)氧基]苯基}-6-硝基-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶-羧酸叔丁酯(0.085g,0.129mmol)、铁粉(0.300g)、乙醇(4.5ml)和水(0.5mL)的混合物中加入氯化铵(0.100g)。将混合物在85℃搅拌30分钟。冷却至室温后,混合物用Celite_过滤。减压浓缩滤液。残余物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩获得3-(6-氨基-2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]-苯基}-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶羧酸叔丁酯(0.068g产量;84%)。(3)然后按照实施例25-4步骤(2)介绍的类似方法除去苄基以及氨基甲酸叔丁酯获得3-氨基-7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,8-萘啶-2(1H)-酮盐酸盐。
分子量:442.95
质谱:407(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.35(2H,m),0.62(2H,m),1.32(1H,m),1.73(1H,ddd,J=4.1,8.2,8.2Hz),1.93(3H,m),2.90(1H,dd,J=11.7,12.3Hz),3.11(1H,dd,J=11.0,11.7Hz),6.54(2H,d,J=8.2Hz),6.93(1H,s),7.17(1H,t,J=8.2Hz),7.99(1H,s),9.10(1H,br),9.28(1H,br),12.55(1H,s)。实施例29-2
在搅拌下的3-(6-氨基-2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶-羧酸叔丁酯(0.068g,0.109mmol)(由实施例29-1步骤(2)获得)和三乙胺(0.05ml,0.327mmol)的二氯甲烷(3mL)溶液中加入苯甲酰氯(0.01mL,0.109mmol)和4-二甲基氨基吡啶(0.001g,0.011mmol)。将混合物在室温下搅拌19小时,倾入水中。混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=5/1-3/2)提纯获得3-{2-{2-(环丙基甲氧基)-6-[(4-甲氧基)-苄氧基]苯基}-7-氧代-[(1-苯基-甲酰氧基)-氨基]-7,8-二氢-1,8-萘啶-4-基}-1-哌啶羧酸叔丁酯(0.022g产量;28%]。
然后按照实施例25-4步骤(2)介绍的类似方法除去苄基和氨基甲酸叔丁酯获得N-[7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-基]苯甲酰胺盐酸盐。
分子量:547.06
质谱:511(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):0.34(2H,m),0.59(2H,m),1.29(1H,m),1.80-2.08(4H,m),2.96(1H,br),3.18(1H,dd,J=11.4,11.7Hz),6.59(2H,d,J=8.2Hz),7.23(1H,t,J=8.2Hz),7.61(2H,t,J=7.9Hz),7.68(1H,m),8.01(2H,m),8.04(1H,s),8.80(1H,br),9.03(2H,s),9.61(1H,s),13.13(1H,s)。实施例29-3按照实施例29-2的类似方法制备N-[7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-基]乙酰胺盐酸盐。
分子量:484.99
质谱:449(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
(500MHz,DMSO-d6):0.33(2H,m),0.59(2H,m),1.28(1H,m),1.76(1H,m),1.89(1H,m),1.98(1H,m),2.92(1H,dd,J=11.4,12.0Hz),3.17(1H,dd J=11.0,12.0Hz),6.57(2H,d,J=8.5Hz),7.21(1H,t,J=8.5Hz),7.99(1H,s),8.78(1H,br),8.94(1H,s),9.02(1H,br),9.69(1H,s),11.92(1H,br),12.93(1H,s)。实施例30-1
(1)在搅拌下的5-[1-(叔丁氧基羰基)-3-哌啶基]-7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸乙酯(0.276g,0.403mmol)(用丙二酸二乙酯代替硝基乙酸乙酯按照实施例29-1步骤(1)的类似方法获得)的四氢呋喃(4ml)和水(1mL)溶液中加入氢氧化锂一水合物(0.015g,0.605mmol)。将混合物在室温下搅拌18小时,用1N盐酸水溶液酸化(pH3-4)。混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩获得5-[1-(叔丁氧基羰基)-3-哌啶基]-7-{2-(环丙基-甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸(0.259g产量;98%)。
(2)然后按照实施例25-4步骤(2)介绍的类似方法除去苄基和氨基甲酸叔丁酯获得7-(2-环丙基甲氧基-6-羟基-苯基)-2-氧代-5-哌啶-3-基-1,2-二氢-[1,8]萘啶-3-羧酸盐酸盐。
分子量:471.94
质谱:436(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
‘(500MHz,DMSO-d6):0.30-0.33(2H,m),0.54-0.55(2H,m),1.23(1H,m),1.92-1.98(4H,m),2.91(1H,m),3.04(1H,m),3.39-3.41(3H,m),3.86-3.89(3H,m),6.61(2H,d,J=8.5Hz),7.27(1H,t,J=8.2Hz),8.07(1H,s),8.72(1H,s),9.24(1H,s),13.74(1H,s),14.43(1H,s)。实施例31-1
(1)在搅拌下的5-[1-(叔丁氧基羰基)-3-哌啶基]-7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸(0.200g,0.305mmol)(由实施例30-1步骤(1)获得)和1-羟基苯并三唑水合物(0.062g,0.457mmol)的二甲基甲酰胺(4mL)溶液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.070g,0.366mmol)。将混合物在室温下搅拌18小时,然后用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物用硅胶柱色谱法(己烷/乙酸乙酯=1/1)提纯获得3-{2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-7-氧代-6-[(丙基氨基)-羰基]-7,8-二氢-1,8-萘啶-4-基}-1-哌啶羧酸叔丁酯(0.129g产量;61%)。
(2)然后按照实施例25-4步骤(2)介绍的类似方法除去苄基和氨基甲酸叔丁酯获得7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-N-丙基-1,2-二氢-1,8-萘啶-3-甲酰胺。
分子量:513.04
质谱:477(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.33(2H,m),0.57(2H,m),0.94(3H,t,J=7.3Hz),1.27(1H,m),1.58(2H,tq,J=7.3,7.3Hz),1.92(4H,m),2.90(1H,m),3.06(1H,t,J=12.3Hz),6.59(2H,d,J=8.2Hz),7.26(1H,t,J=8.2Hz),8.07(1H,s),9.01(1H,s),9.69(1H,t,J=6.0Hz),11.80(1H,s)。反应31-2
在搅拌下的甲磺酰胺(0.026g,0.268mmol)和三乙胺(0.030mL,0.229mmol)的甲苯(2mL)溶液中加入氯化三甲基甲硅烷(0.020mL,0.152mmol)。将混合物在90℃搅拌1小时,然后减压浓缩。用二氯甲烷(2mL)稀释的残余物中依次加入三乙胺(0.020mL,0.152mmol)、4,4-二甲基氨基吡啶(0.002g,0.015mmol)、苯并三唑-1-基氧基-三(二甲基氨基)磷鎓六氟磷酸盐(0.040g,0.091mmol)以及5-[1-(叔丁氧基羰基)-3-哌啶基]-7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-2-氧代-1,2-二氢-1,8-萘啶-3-羧酸(0.050g,0.076mmol)。将混合物在室温下搅拌6小时。混合物用乙酸乙酯和水萃取。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。所得残余物用制备型TLC(己烷/乙酸乙酯=1/1×2)提纯获得3-(2-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-6-{[(甲基磺酰基)-氨基]羰基}-7-氧代-7,8-二氢-1,8-萘啶-4-基)-1-哌啶羧酸叔丁酯(0.024g产量;43%)。
然后按照实施例25-4步骤(2)介绍的类似方法除去苄基和氨基甲酸叔丁酯获得N-{[7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-基]羰基}甲磺酰胺盐酸盐。
分子量:549.05
质谱:513(M+H)+
体外活性等级:A
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):0.33(2H,m),0.55(2H,m),1.25(1H,m),1.95(4H,m),2.92(1H,br),3.06(1H,t,J=12.0Hz),3.40(2H,t,J=11.7Hz),3.45(3H,s),6.61(2H,d,J=8.2Hz),7.28(1H,t,J=8.2Hz),8.09(1H,s),8.74(1H,br),9.08(1H,s),11.62(1H,br),12.72(1H,br),13.56(1H,br)。实施例31-3至31-27
用初始化合物1G、2B以及其它原料,按照实施例1-1步骤(1)的类似方法制备3-(2-氨基-3-氰基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-吡啶基)-1-哌啶羧酸叔丁酯。
3-(2-氨基-3-氰基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-吡啶基)-1-哌啶羧酸叔丁酯(0.580g,0.999mmol)的原甲酸三乙酯(1.2ml)溶液中加入硫酸铵(0.004g,0.030mmol),将混合物在150℃搅拌2小时。冷却至室温后,依次加入EtOH(1.5ml)和NH3的EtOH(8.6N,0.5mL)溶液。将混合物在室温下搅拌过夜,减压浓缩。残余物用己烷和异丙醚研磨,然后减压干燥获得褐色固体3-(2-{[(1E)-氨基亚甲基]氨基}-3-氰基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基-苄基)氧基]苯基}-4-吡啶基)-1-哌啶羧酸叔丁基酯(0.543g产量;89%)。
3-(2-{[(1E)-氨基亚甲基]氨基}-3-氰基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-吡啶基)-1-哌啶-羧酸叔丁酯(0.180g,0.289mmol)的MeOH(5mL)和甲苯(5ml)溶液中加入三氟乙酸(0.01mL)。将混合物静置20天,减压浓缩。用硅胶柱色谱(CH2Cl2/MeOH 50∶1至20∶1)提纯获得无色油状物3-(4-氨基-7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]-苯基}吡啶并[2,3-d]嘧啶-5-基)-1-哌啶羧酸叔丁酯(0.026g,收率;15%)。
然后按照实施例25-4步骤(2)介绍的类似方法除去苄基和氨基甲酸叔丁酯获得黄色粉末2-[4-氨基-5-(3-哌啶基)吡啶并[2,3-d]嘧啶-7-基]-3-(环丙基甲氧基)苯酚盐酸盐(0.004g,24%)。
分子量:391.48
质谱:392(M+H)+
体外活性等级:C
细胞活性等级:(A549)-B
1H-NMR(500MHz,CDCl3):0.41-0.47(2H,m),0.65-0.77(2H,m),0.77-0.92(1H,m),1.32-1.42(1H,m),1.78-1.84(1H,m),1.84-1.97(2H,m),2.15-2.24(1H,m),2.72(1H,dd,J=2.8,12.0Hz),2.80-2.88(m,1H),3.16-3.26(1H,m),3.34-3.46(2H,m),3.91(2H,d,J=6.9Hz),5.95(2H,brs),6.42(1H,dd,J=1.0,8.2Hz),6.73(1H,dd,J=1.0,8.2Hz),7.23-7.26(1H,m),8.63(1H,s),8.69(1H,s),15.00(1H,br)。实施例33-1
在室温下向乙二酰氯(3.63g,28.6mmol)的乙腈(5.00mL)溶液加入DMF(5.00ml)。10分钟后,加入2-(4-甲氧基苯基甲氧基)苯乙酮(3.33g,13.0mmol)(初始化合物1D)的DMF(50ml)溶液,然后持续搅拌过夜。向反应混合物中依次加入丙二腈(1.03g,15.6mmol)和Et3N(7.25mL,52.0mmol),然后持续搅拌过夜。将反应混合物倾入水中,然后用乙醚萃取。分离出的有机相用盐水洗涤,再用硫酸镁干燥,过滤后减压浓缩。残余物用硅胶柱色谱法(CHCl3)提纯获得2-((2Z)-3-(二甲基氨基)-3-{2-[(4-甲氧基苄基)-氧基]苯基}-2-亚丙烯基)丙二腈(1.27g产量;27%)。
2-((2Z)-3-(二甲基氨基)-3-{2-[(4-甲氧基-苄基)氧基]苯基}-2-亚丙烯基)丙二腈(1.26g,3.51mmol)的MeOH冷(-78℃)溶液中加入液NH3,将混合物于封闭管中在120℃加热过夜。冷却至室温后,将反应混合物倾入水中,所得混合物用乙酸乙酯萃取。分离出的有机相用盐水洗涤,用硫酸镁干燥,过滤,然后减压浓缩。粗产物用硅胶柱色谱法提纯(己烷∶乙酸乙酯,70∶30)获得2-氨基-6-({2-[(4-甲氧基苄基)氧基]苯基}烟腈(0.050g产量;4.3%)。
将2-氨基-6-({2-[(4-甲氧基苄基)氧基]苯基}烟腈(0.050g,0.151mmol)、三氟乙酸(3.00mL)、苯甲醚(0.50ml)和水(0.50mL)的混合物在室温下搅拌过夜。反应混合物用甲苯稀释,然后减压浓缩。将残余物溶于THF,然后加入己烷获得沉淀。过滤收集沉淀,用己烷洗涤,然后减压干燥获得2-氨基-6-(2-羟基苯基)烟腈。(0.026g产量;82%)
分子量:211.23
质谱:212(M+H)+
体外活性等级:B
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):6.87-6.92(2H,m),7.31-7.39(4H,m),7.94(1H,d,J=8.3Hz),8.01(1H,d,J=8.3Hz),13.38(1H,brs)。实施例34-1
(1)2-(苄氧基)苯乙酮(5.66g,25mmol)(初始化合物1A)的甲苯(40mL)溶液中加入二硫化碳(6.0ml,99.8mmol)和甲基碘(10mL,245mmol)。将氢化钠(60%悬浮液,2.00g,50mmol)和N,N-二甲基乙酰胺(10mL)加入到混合物。将所得混合物在室温下搅拌1小时,回流2小时。冷却至室温后,反应混合物在CH2Cl2和水间分配。分出有机相,用水洗涤,干燥,然后减压浓缩。残余固体用二异丙醚研磨获得浅黄色固体1-[2-(苄基)苯基]-3,3-双[(甲硫基)-2-丙烯-1-酮(5.17g产量;63%)。
(2)氰基乙酰胺(1.27g,15.1mmol)的2-丙醇(50ml)悬浮液中加入氢化钠(60%悬浮液,0.605g,15.1mmol)。将混合物在室温下搅拌10分钟。向混合物中一次性加入1-[2-(苄基)苯基]-3,3-双(甲硫基)-2-丙烯-1-酮(5.00g,15.1mmol)。将所得混合物回流4小时。冷却至室温后,混合物用1N HCl稀释。过滤收集所得沉淀,用EtOH洗涤获得黄色结晶固体6-[2-(苄氧基)苯基]-4-(甲硫基)-2-氧代-1,2-二氢-烟腈(4.43g,产量;84%)。
(3)6-[2-(苄氧基)苯基]-4-(甲硫基)-2-氧代-1,2-二氢-烟腈(4.00g,11.5mmol)的CH2Cl2冷(0℃)溶液中一次性加入间氯代过苯甲酸(mCPBA)(69%,3.45g,13.8mmol)。将反应混合物在0℃至室温搅拌1小时,用包含Na2S2O3-5H2O(5g)的饱和NaHCO3水溶液(80ml)猝灭,用CH2Cl2稀释。分离出的有机相用饱和NaHCO3溶液洗涤,用硫酸钠干燥,过滤,然后减压浓缩。残余固体用二异丙醚研磨获得黄色固体6-[2-(苄氧基)苯基]-4-(甲基亚硫酰基)-2-氧代-1,2-二氢-烟腈(4.00g产量;96%)。
(4)将6-[2-(苄氧基)苯基]-4-(甲基亚硫酰基)-2-氧代-1,2-二氢-3-吡啶腈(2.97g,8.16mmol)、溴乙酰胺(1.27g,9.21mmol)和K2CO3(1.43g,10.4mmol)的DMF(30mL)混合物在60℃搅拌1.5小时。将反应混合物倾入水中,过滤收集所得沉淀。获得的固体用丙酮洗涤获得固体2-{[6-[2-(苄氧基)苯基]-3-氰基-4-(甲基亚硫酰基)-2-吡啶基]氧基}乙酰胺(2.09g产量;61%)。
(5)将2-{[6-[2-(苄氧基)苯基]-3-氰基-4-(甲基亚硫酰基)-2-吡啶基]氧基}乙酰胺(300mg,0.71mmol)和吗啉(1.0ml)的混合物在130℃搅拌1小时,然后加入水。过滤收集所得沉淀然,减压干燥获得黄色固体2-{[6-[2-(苄氧基)苯基]-3-氰基-4-(4-吗啉基)-2-吡啶基]氧基}乙酰胺(304mg产量;96%)。
(6)2-{[6-[2-(苄氧基)苯基]-3-氰基-4-(4-吗啉基)-2-吡啶基]氧基}乙酰胺(318mg,0.72mmol)的DMF(1mL)溶液中加入K2CO3(198mg,1.43mmol),将混合物在130℃搅拌24小时。混合物在乙酸乙酯和水间分配。有机相用盐水洗涤,用硫酸钠干燥,然后减压浓缩。用硅胶柱色谱(己烷/乙酸乙酯=3/1至2/1)提纯,接着用二异丙醚研磨获得白色固体2-氨基-6-[2-(苄氧基)苯基]-4-(4-吗啉基)烟腈(141mg产量;51%)。
(7)然后按照实施例1-1步骤(2)介绍的相同方法除去苄基。残余物用Et2O研磨,减压干燥获得固体2-氨基-6-(2-羟基苯基)-4-(4-吗啉基)烟腈(68mg产量;76%)。
分子量:296.33
质谱:297(M+H)+
体外活性等级:B
细胞活性等级:(A549)-C
1H-NMR(300MHz,DMSO-d6):3.44-3.54(4H,m),3.68-3.78(4H,m),6.77-6.90(3H,m),7.08(2H,brs),7.25-7.35(1H,m),7.92-8.00(1H,m),13.77(1H,s)。实施例34-2
将2-{[6-[2-(苄氧基)苯基]-3-氰基-4-(甲基亚硫酰基)-2-吡啶基]-氧基}乙酰胺(500mg,1.19mmol)(由实施例34-1步骤(4)获得)和六氢异烟酰胺(228mg,1.78mmol)的DMF(2mL)混合物在130℃搅拌5小时。冷却至室温后,混合物在乙酸乙酯和水间分配。有机相用盐水洗涤,用硫酸钠干燥,减压浓缩获得固体1-{2-(2-氨基-2-氧代乙氧基)-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-4-哌啶甲酰胺(485mg,产量;84%)。
将1-{2-(2-氨基-2-氧代乙氧基)-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-4-哌啶甲酰胺(485mg,1.00mmol)和K2CO3(280mg,2.03mmol)的DMF(2.5ml)混合物在130℃搅拌28小时。冷却至室温后,将混合物用水稀释,过滤收集所得沉淀。沉淀用EtOH和CH2Cl2洗涤获得固体1-{2-氨基-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}-4-哌啶甲酰胺(119mg产量;28%)。
然后按照实施例1-1步骤(2)介绍的类似方法除去苄基获得固体1-[2-氨基-3-氰基-6-(2-羟基苯基)-4-吡啶基]-4-哌啶甲酰胺(19mg产量;36%)。
分子量:337.38
质谱:338(M+H)+
体外活性等级:B
细胞活性等级:(A549)-C
1H-NMR(300MHz,DMSO-d6):1.58-1.77(2H,m),1.77-1.90(2H,m),2.30-2.46(1H,m),2.98-3.15(2H,m),3.97(2H,d,J=12.8Hz),6.73-6.90(4H,m),7.10(2H,s),7.22-7.36(2H,m),7.94(1H,d,J=7.2Hz),13.85(1H,s)。实施例34-3
1-[(苄氧基)羰基]-3-哌啶羧酸(3.00g,11.4mmol)和Et3N(1.56mL,11.4mmol)的t-BuOH(30mL)溶液中加入二苯基磷酰基叠氮化物(DPPA)(2.46mL,11.4mmol),将混合物回流21小时。冷却至室温后,减压浓缩混合物,残余物在乙酸乙酯和饱和碳酸氢钠水溶液间分配。有机相用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸钠干燥,然后减压浓缩。用硅胶柱色谱(己烷/乙酸乙酯=4/1至3/1)提纯获得固体3-[(叔丁氧基羰基)氨基]-1-哌啶羧酸苄基酯(2.22g产量;58%)。
将3-[(叔丁氧基羰基)氨基]-1-哌啶羧酸苄基酯(2.25g,6.73mmol)和10%Pd/C(0.229g)的EtOH(20mL)混合物在室温下氢气氛中(1atm)搅拌14小时。用Celite_过滤除去催化剂,然后减压浓缩滤液获得固体3-哌啶基氨基甲酸叔丁酯(1.22g产量;91%)。
用所得3-哌啶基氨基甲酸叔丁酯和2-{[6-[2-(苄氧基)苯基]-3-氰基-4-(甲基亚硫酰基)-2-吡啶基]氧基}乙酰胺作初始原料,按照实施例34-1介绍的类似方法制备2-氨基-4-(3-氨基-1-哌啶基)-6-(2-羟基苯基)烟腈盐酸盐。
分子量:345.83
质谱:310(M+H)+
体外活性等级:B
细胞活性等级:(A549)-B
1H-NMR(500MHz,DMSO-d6):1.59-1.76(2H,m),1.82-1.95(1H,m),2.02-2.14(1H,m),3.27-3.50(3H,m),3.90-4.05(1H,m),4.08-4.22(1H,m),6.80(1H,s),6.92(1H,t,J=7.6Hz),6.96-7.06(1H,m),7.37(1H,t,J=6.9Hz),7.79(3H,brs),8.39(3H,brs),13.25(1H,brs)。实施例34-4
将2-{[6-[2-(苄氧基)苯基]-3-氰基-4-(甲基亚硫酰基)-2-吡啶基]-氧基}乙酰胺(500mg,1.19mol)(由实施例34-1步骤(4)获得)和3-氨基-1-哌啶羧酸叔丁酯(555mg,2.77mmol)的DMF(0.6ml)混合物在130℃搅拌24小时。冷却至室温后,混合物在乙酸乙酯和水间分配。有机相用水和盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。用硅胶柱色谱法(己烷/乙酸乙酯=1/1)提纯获得泡沫状3-({2-(氨基甲酰基甲氧基)-6-[2-(苄氧基)苯基]-3-氰基-4-吡啶基}氨基)-1-哌啶羧酸叔丁酯(360mg产量;64%)。
用所得化合物,按照实施例34-2介绍的类似方法制备2-氨基-6-(2-羟基苯基)-4-(3-哌啶基氨基)烟腈盐酸盐。
分子量:345.83
质谱:310(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(300MHz,DMSO-d6):1.68-2.06(4H,m),2.66-2.96(2H,m),3.17-3.38(2H,m),4.23(1H,brs),6.73(1H,s),6.92(1H,t,J=7.5Hz),7.01(1H,d,J=7.5Hz),7.37(1H,t,J=7.5Hz),7.55(3H,br),7.78(1H,d,J=7.5Hz),9.20(2H,brs),13.20(1H,br)。实施例34-5至34-19
叔丁醇钾(0.809g,6.128mmol)的THF(5ml)悬浮液中加入1-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]-苯基}乙酮(1.00g,3.064mmol)(初始化合物1G)的THF(5)mL)溶液,接着依次加入二硫化碳(0.23mL,3.83mmol)和甲基碘(0.57ml,9.19mmol)。将所得混合物在室温下搅拌40分钟,然后在乙酸乙酯和水间分配。有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。用硅胶柱色谱(己烷/乙酸乙酯4∶1至3∶1)提纯获得浅黄色油状物1-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3,3-双(甲硫基)-2-丙烯-1-酮(0.825g产量;63%)。
NaH(60%,0.056g,1.39mmol)的THF(3ml)悬浮液中一次性加入氰基乙酸叔丁酯(0.197g,1.392mmol)的THF(1ml)溶液。10分钟后,加入1-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)-氧基]苯基}-3,3-双(甲硫基)-2-丙烯-1-酮(0.500g,1.16mmol)的THF(3ml)溶液,接着加入二苯并-18-冠-6(0.013g,0.035mmol)。将所得混合物回流4小时。冷却至室温后,混合物在0.1N乙酸溶和二氯甲烷间分配。分出有机相,用硫酸钠干燥,过滤,然后减压浓缩。将残余油状物溶于1,2-二氯乙烷(1ml)和乙酸(1mL),加入乙酸铵(1.20g,15.57mmol)。将混合物在120℃搅拌0.5小时。冷却至室温后,混合物在乙酸乙酯和饱和碳酸氢钠水溶液间分配。有机相用饱和碳酸氢钠水溶液和盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。用硅胶柱色谱(己烷/乙酸乙酯4∶1至3∶1)提纯获得浅黄色油状物2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-(甲硫基)烟酸叔丁酯(0.177g产量;29%)。
2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-(甲硫基)烟酸叔丁酯(1.72g,3.30mmol)的CH2Cl2(20mL)冷(0℃)溶液中加入m-CPBA(69%,0.82g,3.30mmol)。将反应混合物在0℃搅拌15分钟,用包含Na2S2O3(1g)的饱和碳酸氢钠水溶液(20mL)猝灭。分出有机相,用硫酸钠干燥,过滤,然后减压浓缩。用硅胶柱色谱(己烷/乙酸乙酯=3∶2至1∶1)提纯获得固体,将其用乙酸乙酯和二异丙醚研磨获得白色粉末2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-4-(甲基亚硫酰基)烟酸叔丁酯(1.112 产量;63%)。
将2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基-苄基)氧基]苯基}-4-(甲基亚硫酰基)烟酸叔丁酯(0.118g,0.219mmol)和乙二胺(0.29mL)的混合物在100℃搅拌8小时。冷却至室温后,混合物在乙酸乙酯和水间分配。分离出的有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。将残余物溶于CH2Cl2(2ml),加入二碳酸二叔丁酯(0.060g,0.275mmol)。将混合物在室温下搅拌2小时,减压浓缩。残余物用柱色谱法提纯获得泡沫状2-氨基-4-({2-[(叔丁氧基羰基)氨基]乙基}氨基)-6-{2-(环丙基甲氧基)-6-[(4-甲氧基-苄基)氧基]苯基}烟酸叔丁酯(0.121g,92%)。
2-氨基-4-({2-[(叔丁氧基羰基)-氨基]乙基}氨基)-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-烟酸叔丁酯(0.113g,0.178mmol)的THF(5mL)冷(0℃)溶液中加入Vitride_(3.4M,1.0mL,3.4mmol)溶液。将混合物在0℃搅拌0.5小时,用饱和酒石酸钠钾水溶液猝灭,然后在乙酸乙酯和水间分配。有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩获得固体,将其用乙酸乙酯和二异丙醚研磨获得粉红色固体2-{[2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]-苯基}-3-(羟基甲基)-4-吡啶基]氨基}乙基氨基甲酸叔丁酯(0.078g产量;78%)。
2-{[2-氨基-6-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)氧基]苯基}-3-(羟基甲基)-4-吡啶基]氨基}乙基氨基甲酸叔丁酯(0.050g,0.089mmol)和Et3N(0.074ml,0.531mmol)的THF(10mL)冷(0℃)溶液中一次性加入三光气(0.013g,0.044mmol)。将混合物在0℃搅拌1小时,然后在乙酸乙酯和水间分配。有机相用盐水洗涤,用硫酸钠干燥,过滤,然后减压浓缩。用硅胶柱色谱(乙酸乙酯)提纯获得无色油状物2-[(7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)-氧基]苯基}-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基)氨基]乙基氨基甲酸叔丁酯(0.036g产量;69%)。
2-[(7-{2-(环丙基甲氧基)-6-[(4-甲氧基苄基)-氧基]苯基}-2-氧代-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-5-基)氨基]乙基氨基甲酸叔丁酯(0.032g,0.054mmol)的1,4-二氧六环(1mL)溶液中加入4N HCl的1,4-二氧六环(1mL)溶液。将混合物在室温下搅拌过夜。过滤收集所得沉淀,用乙酸乙酯洗涤获得固体5-[(2-氨基乙基)氨基]-7-[2-(环丙基甲氧基)-6-羟基苯基]-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮盐酸盐(0.013g产量;59%)。
分子量:406.87
质谱:370(M+H)+
体外活性等级:A
细胞活性等级:(A549)-A
1H-NMR(500MHz,DMSO-d6):0.26-0.36(2H,m),0.47-0.57(2H,m),1.15-1.25(1H,m),2.96-3.07(2H,m),3.50-3.60(2H,m),3.85(2H,d,J=6.9Hz),5.45(2H,brs),6.57(1H,d,J=8.2Hz),6.56-6.68(1H,m),6.96(1H,brs),7.24(1H,t,J=8.2Hz),7.75(1H,br),8.18(3H,brs),10.86(1H,br)。实施例35-2
按照实施例35-1的类似方法制备5-(2-苄基氨基-乙基氨基)-6-(2-环丙基甲氧基-6-羟基-苯基)-1,4-二氢-吡啶并[2,3-d][1,3]噁嗪-2-酮盐酸盐。
分子量:497.00
质谱:461(M+H)+
体外活性等级:A
(500MHz,DMSO-d6):0.26-0.35(2H,m),0.45-0.58(2H,m),1.10-1.28(1H,m),3.16(2H,brs),3.67(2H,br),3.85(2H,d,J=6.8Hz),4.13-4.25(2H,m),5.43(2H,brs),6.50-6.65(2H,m),7.04(1H,brs),7.22(1H,t,J=8.3Hz),7.35-7.50(4H,m),7.50-7.65(3H,m),9.44(2H,br),10.74(1H,br)。
Claims (15)
1.一种式(I)吡啶衍生物或其盐,
其中R11为氢、C1-6烷基、卤素、羟基、C1-12烷氧基、硝基、氨基、C1-6烷基磺酰基氨基、C1-6烷氧基羰基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷酰基氨基、苯基C1-6烷基氨基、苯基磺酰基氨基或-O-(CH2)n-R111,
其中n为选自0-6的整数,R111为C2-6链烯基、苯甲酰基、二苯基甲基、二(C1-6烷基)氨基、C1-6烷酰基、C1-6烷氧基羰基、或具有0-3个选自S、O和N的杂原子的3-10元饱和或不饱和环并任选被以下基团取代:C1-6烷基、单或二卤素、卤素取代的C1-6烷基、硝基、氰基、C1-6烷氧基羰基、苯基、羟基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷酰基氨基、C1-6烷氧基或氨基甲酰基;
R2为氢或卤素;
R3为氢或1,2,3,6-四氢-吡啶、-CR31R32R33,
其中R31为氢或C1-6烷基,
R32为氢,α-氨基苄基,任选被一个或两个选自以下的取代基取代的C1-6烷基:羟基、氨基、氨基取代的苯基、苯基、卤素取代的苯基以及C1-6烷氧基取代的苯基,或者为具有0-3个选自S、O和N的杂原子的5-8元饱和环并任选被C1-6烷基取代,
R33为氢、氨基、C1-6烷氧基羰基氨基、C2-6链烯氧基羰基氨基、哌啶子基-C1-6烷基羰基氨基、哌啶基-C1-6烷基羰基氨基,或者
R32和R33可以与相邻碳原子构成具有0-3个选自N、O和S的杂原子的5-8元饱和环,所述环任选被以下基团取代:苯基-C1-6烷基、C1-6烷氧基取代的苯基-C1-6烷基、C1-6烷基、氨基、氰基、羟基、氨基甲酰基、羧基、C1-6烷基氨基、C1-6烷氧基羰基、二(C1-6烷基)氨基、苄基氨基、C1-6烷基磺酰基、哌啶子基C1-6烷基羰基,或者任选与苯稠合;
或者为
-NR34R35,
其中R34为氢或C1-6烷基,
R35为氢、具有0-3个选自N、O和S的杂原子的5-8元饱和环或者-(CH2)m-NR351R352(m表示1-6的任意整数)
其中R351为氢、C1-6烷基,
R352为氢、C1-6烷基、C1-6烷酰基、C1-6烷基取代的苯基、苯甲酰基、C1-6烷酰基、苯基氨基羰基、苯基磺酰基,或者
R34和R35可以与相邻的氮原子一起构成5-8元饱和杂环,除了相邻氮原子外所述杂环还可以任选包含NH、S或O原子,任选被氨基甲酰基、氨基或C1-6烷基取代;
R4为羟基羰基、C1-6烷酰基、氨基甲酰基、氰基、硝基、羧基、C1-6烷氧基羰基、C1-6烷基氨基甲酰基、C1-6烷基氨基、5-10元杂芳基(羟基)甲基、5-10元杂芳基-C1-6烷基、或者被羟基和5-7元饱和环取代的甲基、任选被一个选自以下的基团取代的C1-6烷基:羟基、C1-6烷氧基、C1-6烷基磺酰基氨基、C1-6烷基羰基氨基、C5-10芳基、C5-10芳基磺酰基、C5-10芳硫基、C5-10芳氧基、咪唑基或二氧代取代的吡咯烷氧基,
-(CH2)pNHCOR41、-(CH2)pNHC(=S)R41,
其中p为1-6的任意整数,R41为C1-6烷氧基、氨基、苯基氨基、C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、C3-10环烷基氨基,
R3和R4可以与吡啶环上的碳原子一起构成4-10元单环烷基或双环烷基,任选插入NH并任选被苄基、=NH或=O取代;
R5为NR51R52,
其中R51为氢、C1-6烷基,
R52为氢、C1-6烷基、苯基、苄基、C1-6烷酰基,或者NR51R52可以构成饱和5-6元环,除了相邻氮原子外还任选包含NH或O作为其它杂原子,
或者
R4和R5可以构成
-R40-CO-NH-、-R40-SO2-NH-、-R40-C(=S)-NH-、-R40-CH2-NH-,
其中所述-R40-为-CH401-O-、-CH2-NR401-、-CO-NR401-、-CH2-CHR401-、-CH=CR401-(其中R401为C1-6烷酰基、C1-6烷基、苯基、C1-6烷基磺酰基、C3-8环烷基氨基羰基、氢、卤素、硝基、氨基、氰基、苯甲酰基氨基、苯基磺酰基、氨基甲酰基、羟基羰基、C1-6烷氧基羰基、C1-12烷基氨基羰基、卤素取代的C1-6烷基氨基羰基、C1-6烷酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基羰基、二(C1-6烷基)氨基C1-6烷基氨基羰基、氢化茚基氨基羰基、二苯基甲基氨基羰基、吡咯烷基羰基、C1-6烷氧基C1-6烷基氨基羰基、吗啉代羰基、哌嗪基羰基、苯基C1-6烷基氨基羰基、羟基羰基C1-6烷基氨基羰基、C3-8环烷基氨基羰基、C3-8环烷基C1-6烷基氨基羰基、羟基C1-6烷基氨基羰基、羧基乙基氨基羰基、C1-6烷基磺酰基氨基羰基),
-CR41=N-NH-(R41为氢、氨基或C1-6烷酰基氨基)、-CR42=N-C=N-(R42为氢或氨基)。
2.权利要求1要求保护的化合物或其盐,其中
其中R11为氢、C1-6烷基、卤素、羟基、C1-12烷氧基、氨基、C1-6烷酰基氨基、苯基C1-6烷基氨基、苯基磺酰基氨基或-O-(CH2)n-R111,其中n为选自1-6的整数,R111为C2-6链烯基、苯甲酰基、二苯基甲基、二(C1-6烷基)氨基、C1-6烷酰基、C1-6烷氧基羰基或具有0-3个选自S、O和N的杂原子的3-10元饱和或不饱和环,而且其任选被以下基团取代:C1-6烷基、单或二卤素、卤素取代的C1-6烷基、硝基、氰基、C1-6烷氧基羰基、苯基;
R2为氢;
R3为氢、1,2,3,6-四氢-吡啶、-CR31R32R33,
其中R31为氢或C1-6烷基,
R32为氢、α-氨基苄基、任选被一个或两个选自以下的取代基取代的C1-6烷基:羟基、氨基、氨基取代的苯基、苯基、卤素取代的苯基以及C1-6烷氧基取代的苯基,或者为具有0-3个选自S、O和N的杂原子的5-8元饱和环并任选被C1-6烷基取代,
R33为氢、氨基、C1-6烷氧基羰基氨基、C2-6链烯氧基羰基氨基、哌啶子基-C1-6烷基羰基氨基,或者
R32和R33可以与相邻碳原子构成具有0-3个选自N、O和S的杂原子的5-8元饱和环,所述环任选被以下基团取代:苯基-C1-6烷基、C1-6烷氧基取代的苯基-C1-6烷基、C1-6烷基、氨基、羧基、C1-6烷基氨基、C1-6烷氧基羰基、二(C1-6烷基)氨基、苄基氨基、C1-6烷基磺酰基、哌啶子基C1-6烷基羰基,或者任选与苯稠合;
或者为
-NR34R35,
其中R34为氢,
R35为氢、具有0-3个选自N、O和S的杂原子的5-8元饱和环或者-(CH2)m-NR351R352(m表示1-6的任意整数)
其中R351为氢、C1-6烷基,
R352为氢、C1-6烷基、C1-6烷酰基、C1-6烷基取代的苯基、苯甲酰基、C1-6烷酰基、苯基氨基羰基、苯基磺酰基,或者
R34和R35可以与相邻的氮原子一起构成5-8元饱和杂环,除了相邻氮原子外所述杂环还可以任选包含NH、S或O原子,任选被氨基甲酰基、氨基或C1-6烷基取代;
R4为羟基羰基、C1-6烷酰基、氨基甲酰基、氰基、羧基、C1-6烷氧基羰基、C1-6烷基氨基甲酰基、C1-6烷基氨基、5-10元杂芳基(羟基)甲基、5-10元杂芳基-C1-6烷基、或者被羟基和5-7元饱和环取代的甲基、任选被一个以下基团取代的C1-6烷基:羟基、C1-6烷氧基、C1-6烷基磺酰基氨基、C1-6烷基羰基氨基、C5-10芳基、C5-10芳硫基、C5-10芳基亚氧硫基、C5-10芳氧基、咪唑基或二氧代取代的吡咯烷氧基,
-(CH2)pNHCOR41、-(CH2)pNHC(=S)R41
其中p为1-6的任意整数,R41为C1-6烷氧基、氨基、苯基氨基、C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、C3-10环烷基氨基,
R3和R4可以与吡啶环上的碳原子一起构成4-10元单环烷基或双环烷基,任选插入NH并任选被苄基、=NH或=O取代;
R5为NR51R52,
其中R51为氢、C1-6烷基,
R52为氢、C1-6烷基、苯基、苄基、C1-6烷酰基,或者NR51R52可以构成哌啶子基,
或者
R4和R5可以构成
-R40-CO-NH-、-R40-SO2-NH-、-R40-C(=S)-NH-或-R40-CH2-NH-、
其中所述-R40-为-CHR401-O-、-CH2-NR401-、-CO-NR401-、(其中R401为氢、C1-6烷酰基、C1-6烷氧基羰基、C1-6烷基、苯基、C1-6烷基磺酰基、C3-8环烷基氨基羰基、C1-6烷基氨基羰基、氨基甲酰基、二(C1-6烷基)氨基羰基)、-CH2-CHR402-、-CH=CR402-、(其中R402为氢、卤素、硝基、氨基、氰基、苯甲酰基氨基、苯基磺酰基、氨基甲酰基、羟基羰基、C1-6烷氧基羰基、C1-12烷基氨基羰基、卤素取代的C1-6烷基氨基羰基、C1-6烷酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基羰基、二(C1-6烷基)氨基C1-6烷基氨基羰基、氢化茚基氨基羰基、二苯基甲基氨基羰基、吡咯烷基羰基、C1-6烷氧基C1-6烷基氨基羰基、吗啉代羰基、哌嗪基羰基、苯基C1-6烷基氨基羰基、C3-8环烷基氨基羰基、羟基羰基C1-6烷基氨基羰基、C3-8环烷基C1-6烷基氨基羰基、羟基C1-6烷基氨基羰基、羧基乙基氨基羰基、甲基磺酰基氨基羰基),
-CR41=N-NH-(R41为羟基、氨基或C1-6烷酰基氨基)或-CR42=N-C=N-(R42为氨基)。
3.权利要求1要求保护的化合物或其盐,其中
其中R11为氢、C1-12烷氧基或-O-(CH2)n-R111,
其中n为选自1-6的整数,R111为苯基、C3-8环烷基;
R2为氢;
R3为1,2,3,6-四氢-吡啶、-CR31R32R33,
其中R31为氢,
R32和R33与相邻碳原子一起构成5-8元插入NH的饱和环,所述环任选被以下基团取代:苯基-C1-6烷基、C1-6烷氧基取代的苯基-C1-6烷基、C1-6烷基、氨基、羧基、C1-6烷基氨基、C1-6烷氧基羰基、二(C1-6烷基)氨基、苄基氨基、C1-6烷基磺酰基、哌啶子基C1-6烷基羰基,或者任选与苯稠合;
或者为
-NR34R35,
其中R34为氢,
R35为-(CH2)m-NR351R352(m表示1-6的任意整数)
其中R351为氢、C1-6烷基,
R352为氢、C1-6烷基、C1-6烷酰基、C1-6烷基取代的苯基、苯甲酰基、C1-6烷酰基、苯基氨基羰基、苯基磺酰基;
R4为氰基、任选被羟基或C1-6烷氧基取代的C1-6烷基、或者
-(CH2)pNHCOR41、-(CH2)pNHC(=S)R41,
其中p为1-6的任意整数,R41为C1-6烷氧基、氨基、苯基氨基、C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、C3-10环烷基氨基;
R5为氨基,
或者
R4和R5可以构成
-R40-CO-NH-、-R40-SO2-NH-、-R40-C(=S)-NH-或-R40-CH2-NH-,
其中所述-R40-为-CHR401-O-、-CH2-NR401-、-CO-NR401-、(其中R401为氢、C1-6烷酰基、C1-6烷氧基羰基、C1-6烷基、苯基、C1-6烷基磺酰基、C3-8环烷基氨基羰基、C1-6烷基氨基羰基、氨基甲酰基、二(C1-6烷基)氨基羰基)、-CH2-CHR402-、-CH=CR402-、(其中R402为氢、卤素、硝基、氨基、氰基、苯甲酰基氨基、苯基磺酰基、氨基甲酰基、羟基羰基、C1-6烷氧基羰基、C1-12烷基氨基羰基、卤素取代的C1-6烷基氨基羰基、C1-6烷酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基羰基、二(C1-6烷基)氨基C1-6烷基氨基羰基、氢化茚基氨基羰基、二苯基甲基氨基羰基、吡咯烷基羰基、C1-6烷氧基C1-6烷基氨基羰基、吗啉代羰基、哌嗪基羰基、苯基C1-6烷基氨基羰基、C3-8环烷基氨基羰基、羟基羰基C1- 6烷基氨基羰基、C3-8环烷基C1-6烷基氨基羰基、羟基C1-6烷基氨基羰基、羧基乙基氨基羰基、甲基磺酰基氨基羰基),
-CR41=N-NH-(R41为羟基、氨基、C1-6烷酰基氨基)或-CR42=N-C=N-(R42为氨基)。
4.权利要求1要求保护的化合物或其盐,其中-R1为或
其中R11为氢、C1-6烷氧基或-O-CH2-R111,
其中R111为苯基、C3-4环烷基;
R2为氢;
R3为1,2,3,6-四氢-吡啶、-CR31R32R33,
其中R31为氢,
R32和R33与相邻碳原子一起构成哌啶或吡咯烷,所述吡啶或吡咯烷任选被C1-6烷基取代;
或者为
-NR34R35,
其中R34为氢,
R35为-(CH2)m-NR351R352(m表示1-6的任意整数)
其中R351为氢、C1-6烷基,
R352为氢、C1-6烷基、C1-6烷酰基、C1-6烷基取代的苯基、苯甲酰基、C1-6烷酰基、苯基氨基羰基、苯基磺酰基;
R4为氰基、羟基甲基或-CH2NHCOR41,
其中R41为C1-6烷氧基、氨基、苯基氨基、C1-6烷基、C1-6烷基氨基、二(C1-6烷基)氨基、C3-10环烷基氨基;
R5为氨基,
或者
R4和R5可以构成
-R40-CO-NH-或-R40-CH2-NH-,
其中所述-R40-为-CHR401-O-、-CH2-NR401-、-CO-NR401-、(其中R401为氢、C1-6烷酰基、C1-6烷氧基羰基、C1-6烷基、苯基、C1-6烷基磺酰基、C3-8环烷基氨基羰基、C1-6烷基氨基羰基、氨基甲酰基、二(C1-6烷基)氨基羰基)、-CH2-CHR402-、-CH=CR402-、(其中R402为氢、卤素、硝基、氨基、氰基、苯甲酰基氨基、苯基磺酰基、氨基甲酰基、羟基羰基、C1-6烷氧基羰基、C1-12烷基氨基羰基、卤素取代的C1-6烷基氨基羰基、C1-6烷酰基氨基、C1-6烷基氨基、二(C1-6烷基)氨基羰基、二(C1-6烷基)氨基C1-6烷基氨基羰基、氢化茚基氨基羰基、二苯基甲基氨基羰基、吡咯烷基羰基、C1-6烷氧基C1-6烷基氨基羰基、吗啉代羰基、哌嗪基羰基、苯基C1-6烷基氨基羰基、C3-8环烷基氨基羰基、羟基羰基C1- 6烷基氨基羰基、C3-8环烷基C1-6烷基氨基羰基、羟基C1-6烷基氨基羰基、羧基乙基氨基羰基、甲基磺酰基氨基羰基)。
5.权利要求1要求保护的化合物,所述化合物选自以下的化合物或其盐:1.7-(2-羟基苯基)-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]-噁嗪-2-酮;2.2-氨基-6-[2-(苄氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈;3.2-氨基-6-(2-羟基-6-丙氧基苯基)-4-(3-哌啶基)烟腈;4.2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-(苄氧基)苯酚;5.7-[2-(苄氧基)-6-羟基苯基]-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3 d][1,3]噁嗪-2-酮;6.7-(2-羟基苯基)-5-(3-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮;7.2-氨基-6-[2-(环丁基甲氧基)-6-羟基苯基]-4-(3-哌啶基)烟腈;8.2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-丙氧基苯酚;9.7-(2-羟基-6-丙氧基苯基)-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]-噁嗪-2-酮;10.7-(2-羟基-6-丙氧基苯基)-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯;11.7-(2-羟基-6-丙氧基苯基)-5-(3-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮;12.2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚;13.2-[6-氨基-5-(羟基甲基)-4-(4-哌啶基)-2-吡啶基]-3-(环丙基甲氧基)苯酚;14.7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢-1,8-萘啶 -2(1H)-酮;15.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-羧酸乙酯;16.7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(4-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮;17.6’-氨基-5’-(羟基甲基)-4’-(3-哌啶基)-2,2’-联吡啶-3-醇;18.7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(4-哌啶基)-3,4-二氢-1,8-萘啶-2(1H)-酮;19.7-[2-(环丙基甲氧基)-6-羟基苯基]-3-氟-5-(3-哌啶基)-1,8-萘啶-2(1H)-酮;20.7-(2-羟基-6-丙氧基苯基)-5-(4-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮;21.7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-2-酮;22.3-(环丙基甲氧基)-2-[5-(3-哌啶基)-1,4-二氢-2H-吡啶并[2,3-d][1,3]噁嗪-7-基]苯酚;23.2-[6-氨基-5-(羟基甲基)-4-(3-哌啶基)-2-吡啶基]-3-(新戊氧基)苯酚;24.2-[6’-氨基-5’-(羟基甲基)-1,2,5,6-四氢-3,4’-联吡啶-2’-基]苯酚;25.7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-1,8-萘啶-2(1H)-酮;26.N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基}乙酰胺;27.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-甲酰胺;28.3-乙酰基-7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢吡啶并[2,3-d]嘧啶-2(1H)-酮;29.2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(4-哌啶基)烟腈;30.2-氨基-4-[(2-氨基乙基)氨基]-6-[2-(环丙基甲氧基)-6-羟基苯基]烟腈;31.N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基}-N’-丙基脲;32.7-[2-(环丙基甲氧基)-6-羟基苯基]-5-(3-哌啶基)-3,4-二氢-吡啶并[2,3-d]嘧啶-2(1H)-酮;33.[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基氨基甲酸乙酯;34.2-氨基-6-{2-羟基-6-[(4-甲基戊基)氧基]苯基}-4-(4-哌啶基)烟腈;35.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,2,3,4-四氢-1,8-萘啶-3-甲酰胺;36.7-[2-(环丙基甲氧基)-6-羟基苯基]-N-异丙基-2-氧代-5-(3-哌啶基)-1,2-二氢-1,8-萘啶-3-甲酰胺;37.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸乙酯;38.N-{[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基}脲;39.2-氨基-6-(2-羟基-6-丙氧基苯基)-4-(4-哌啶基)烟腈;40.N-环己基-7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺;41.2-氨基-6-[2-(环丁基甲氧基)-6-羟基苯基]-4-(4-哌啶基)烟腈;42.7-[2-(环丙基甲氧基)-6-羟基苯基]-N,N-二甲基-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺;43.2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(1-甲基-3-哌啶基)烟腈;44.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺;45.[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基氨基甲酸异丙酯;46.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸异丙酯;47.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸异丁酯;48.7-[2-(环丙基甲氧基)-6-羟基苯基]-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-羧酸新戊酯;49.[2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(3-哌啶基)-3-吡啶基]甲基氨基甲酸新戊酯;50.2-氨基-6-[2-(己氧基)-6-羟基苯基]-4-(4-哌啶基)烟腈;51.7-[2-(环丙基甲氧基)-6-羟基苯基]-N-乙基-2-氧代-5-(3-哌啶基)-1,4-二氢吡啶并[2,3-d]嘧啶-3(2H)-甲酰胺。
6.一种药物,所述药物包含作为活性成分的权利要求1要求保护的化合物或其盐。
7.一种药用组合物,所述组合物包含权利要求1要求保护的化合物或其盐以及一种或多种药学上可接受的赋形剂。
8.一种IκB激酶β抑制剂,所述抑制剂包含作为活性成分的权利要求1要求保护的化合物或其盐。
9.一种抗炎药物,所述抗炎药物包含作为活性成分的权利要求1要求保护的化合物或其盐。
10.权利要求9要求保护的抗炎药物,其中所述药物用于治疗或预防选自以下的疾病:哮喘;变应性鼻炎;特应性皮炎;荨麻疹;结膜炎;春季结膜炎;慢性关节风湿病;全身性红斑狼疮;牛皮癣;溃破性结肠炎;系统炎性反应综合征(SIRS);脓毒病;多肌炎;皮肤肌炎(DM);Polyaritis nodoa(PN);混合型结缔组织疾病(MCTD);Sioegren’S综合征;痛风。
11.一种免疫抑制剂,所述免疫抑制剂包含作为活性成分的权利要求1要求保护的化合物或其盐。
12.一种治疗局部缺血的药物,所述药物包含作为活性成分的权利要求1要求保护的化合物或其盐。
13.一种抗肿瘤药物,所述药物包含作为活性成分的权利要求1要求保护的化合物或其盐。
14.一种治疗疾病的方法,所述方法包括给予其需要患者有效量的权利要求1的化合物。
15.权利要求1的化合物在制备药物中的用途,所述药物用于治疗哮喘。
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CN107417605A (zh) * | 2017-08-02 | 2017-12-01 | 江苏艾立康药业股份有限公司 | 作用于脯氨酰羟化酶的吡啶衍生化合物 |
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