CN1324012C - TNF-α生成抑制剂 - Google Patents
TNF-α生成抑制剂 Download PDFInfo
- Publication number
- CN1324012C CN1324012C CNB200410054677XA CN200410054677A CN1324012C CN 1324012 C CN1324012 C CN 1324012C CN B200410054677X A CNB200410054677X A CN B200410054677XA CN 200410054677 A CN200410054677 A CN 200410054677A CN 1324012 C CN1324012 C CN 1324012C
- Authority
- CN
- China
- Prior art keywords
- compound
- ethyl
- adamantyl
- pyridyl
- urea
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 title description 29
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 title description 29
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 384
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 239000001257 hydrogen Substances 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 28
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 20
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 9
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 8
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 6
- 230000006433 tumor necrosis factor production Effects 0.000 claims abstract description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 483
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 245
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 226
- 239000004202 carbamide Substances 0.000 claims description 184
- -1 N-oxide compound Chemical class 0.000 claims description 155
- LLJRXVHJOJRCSM-UHFFFAOYSA-N 3-pyridin-4-yl-1H-indole Chemical group C=1NC2=CC=CC=C2C=1C1=CC=NC=C1 LLJRXVHJOJRCSM-UHFFFAOYSA-N 0.000 claims description 151
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000001118 alkylidene group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 230000003356 anti-rheumatic effect Effects 0.000 claims 1
- 239000003435 antirheumatic agent Substances 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 38
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 28
- 229910052760 oxygen Inorganic materials 0.000 abstract description 21
- 239000001301 oxygen Substances 0.000 abstract description 18
- 125000003118 aryl group Chemical group 0.000 abstract description 17
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 125000002947 alkylene group Chemical group 0.000 abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 7
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 125000004450 alkenylene group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 222
- 235000013877 carbamide Nutrition 0.000 description 181
- 239000000243 solution Substances 0.000 description 144
- 239000000203 mixture Substances 0.000 description 119
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 91
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 239000011541 reaction mixture Substances 0.000 description 80
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- 239000012044 organic layer Substances 0.000 description 70
- 238000003756 stirring Methods 0.000 description 69
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
- 238000010898 silica gel chromatography Methods 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- 238000001035 drying Methods 0.000 description 47
- 150000001408 amides Chemical class 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 45
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
- 238000005406 washing Methods 0.000 description 43
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 38
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
- 238000002360 preparation method Methods 0.000 description 35
- 239000007864 aqueous solution Substances 0.000 description 29
- 239000012299 nitrogen atmosphere Substances 0.000 description 29
- 238000000034 method Methods 0.000 description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 26
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 21
- DFTPIBFPPYDWEC-UHFFFAOYSA-N 5-pyridin-4-ylpentanoic acid Chemical compound OC(=O)CCCCC1=CC=NC=C1 DFTPIBFPPYDWEC-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 238000002425 crystallisation Methods 0.000 description 19
- 230000008025 crystallization Effects 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000000463 material Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- VYWQTJWGWLKBQA-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;chloride Chemical compound Cl.NC(N)=O VYWQTJWGWLKBQA-UHFFFAOYSA-N 0.000 description 13
- 150000003672 ureas Chemical class 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 235000019260 propionic acid Nutrition 0.000 description 12
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 12
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000002158 endotoxin Substances 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 9
- 239000012280 lithium aluminium hydride Substances 0.000 description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 235000015320 potassium carbonate Nutrition 0.000 description 9
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 9
- 125000004076 pyridyl group Chemical group 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- ZRQJSWOPZOITNN-UHFFFAOYSA-N urea;dihydrochloride Chemical compound Cl.Cl.NC(N)=O ZRQJSWOPZOITNN-UHFFFAOYSA-N 0.000 description 8
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methylthiourea Natural products CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 7
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 150000003335 secondary amines Chemical class 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 6
- 239000004305 biphenyl Substances 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 150000003141 primary amines Chemical class 0.000 description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000009834 vaporization Methods 0.000 description 6
- 230000008016 vaporization Effects 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 5
- 125000004103 aminoalkyl group Chemical group 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- XGEGHDBEHXKFPX-NJFSPNSNSA-N methylurea Chemical compound [14CH3]NC(N)=O XGEGHDBEHXKFPX-NJFSPNSNSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- JURFPUSNTWSSPJ-UHFFFAOYSA-N 3-pyridin-4-ylpropan-1-amine Chemical compound NCCCC1=CC=NC=C1 JURFPUSNTWSSPJ-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- PYNUOAIJIQGACY-UHFFFAOYSA-N propylazanium;chloride Chemical compound Cl.CCCN PYNUOAIJIQGACY-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- DOHBWNHTMAUNTK-UHFFFAOYSA-N 2-methyl-3-pyridin-4-ylpropan-1-amine Chemical compound NCC(C)CC1=CC=NC=C1 DOHBWNHTMAUNTK-UHFFFAOYSA-N 0.000 description 3
- YGULNNXYUJYOSY-UHFFFAOYSA-N 2-methyl-3-pyridin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=C1 YGULNNXYUJYOSY-UHFFFAOYSA-N 0.000 description 3
- WCFJUSRQHZPVKY-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NCCC(O)=O WCFJUSRQHZPVKY-UHFFFAOYSA-N 0.000 description 3
- FVQKGQNSCKJPIJ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCN2C(OCC2)=O)C=CC=1 FVQKGQNSCKJPIJ-UHFFFAOYSA-N 0.000 description 3
- 206010006895 Cachexia Diseases 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- JOSCNYCOYXTLTN-GFCCVEGCSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)CO JOSCNYCOYXTLTN-GFCCVEGCSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 description 3
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical compound OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- HNLXNPWUWRIZRM-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-propyl-5-pyridin-4-ylpentanamide Chemical class C1C(C2)CC(C3)CC2CC13CCN(CCC)C(=O)CCCCC1=CC=NC=C1 HNLXNPWUWRIZRM-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- VJLYHTOSFSGXGH-CQSZACIVSA-N (2R)-1-[3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxybenzoyl]pyrrolidine-2-carboxylic acid Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)N2[C@H](CCC2)C(=O)O)C=CC=1 VJLYHTOSFSGXGH-CQSZACIVSA-N 0.000 description 2
- ZQEBQGAAWMOMAI-SSDOTTSWSA-N (2r)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1C(O)=O ZQEBQGAAWMOMAI-SSDOTTSWSA-N 0.000 description 2
- ZXAQFYZQHPGMMN-BZSJEYESSA-N (3R)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylcyclohexane-1-carboxamide Chemical compound C1C[C@H](CC(C1)C(=O)NC2=CC=CC=C2)OC3=CC(=CC(=N3)C(F)(F)F)CN ZXAQFYZQHPGMMN-BZSJEYESSA-N 0.000 description 2
- SNAKUPLQASYKTC-AWEZNQCLSA-N (3S)-3-[[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxymethyl]-N-phenylpiperidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC[C@@H]1CN(CCC1)C(=O)NC1=CC=CC=C1 SNAKUPLQASYKTC-AWEZNQCLSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- MYKHOEVLMCOTCP-UHFFFAOYSA-N 1-(2-cyclohexylethyl)-1-(2-methoxyethyl)-3-methyl-3-pyridin-4-ylurea Chemical compound C1(CCCCC1)CCN(C(=O)N(C1=CC=NC=C1)C)CCOC MYKHOEVLMCOTCP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ADLPNADGKPULBG-UHFFFAOYSA-N 2,3-dimethoxy-3-oxopropanoic acid Chemical compound COC(C(O)=O)C(=O)OC ADLPNADGKPULBG-UHFFFAOYSA-N 0.000 description 2
- NUUUXJAVFDBNRA-UHFFFAOYSA-N 2-(1-adamantyl)-n-ethylethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCC)C3 NUUUXJAVFDBNRA-UHFFFAOYSA-N 0.000 description 2
- QPHKFMOPPHRCKW-UHFFFAOYSA-N 2-(1-adamantyl)-n-methylethanamine Chemical compound C1C(C2)CC3CC2CC1(CCNC)C3 QPHKFMOPPHRCKW-UHFFFAOYSA-N 0.000 description 2
- AOTQGWFNFTVXNQ-UHFFFAOYSA-N 2-(1-adamantyl)acetic acid Chemical compound C1C(C2)CC3CC2CC1(CC(=O)O)C3 AOTQGWFNFTVXNQ-UHFFFAOYSA-N 0.000 description 2
- GKRPMKRIQVEDAE-UHFFFAOYSA-N 2-(1-adamantyl)ethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCN)C3 GKRPMKRIQVEDAE-UHFFFAOYSA-N 0.000 description 2
- BVKRPQCDGACLPX-UHFFFAOYSA-N 2-[4-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyindol-1-yl]-N-methyl-N-phenylacetamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC1=C2C=CN(C2=CC=C1)CC(=O)N(C1=CC=CC=C1)C BVKRPQCDGACLPX-UHFFFAOYSA-N 0.000 description 2
- ZZZQLDFHIZXCAA-UHFFFAOYSA-N 2-methyl-3-pyridin-4-ylpropanamide Chemical compound NC(=O)C(C)CC1=CC=NC=C1 ZZZQLDFHIZXCAA-UHFFFAOYSA-N 0.000 description 2
- WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 2
- CJYDQTAWSHWBIT-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-hydroxy-2-methylpropyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC(C)(C)O)C=CC=1 CJYDQTAWSHWBIT-UHFFFAOYSA-N 0.000 description 2
- LIDBMZYKSAXTQG-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-sulfamoylethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCS(N)(=O)=O)C=CC=1 LIDBMZYKSAXTQG-UHFFFAOYSA-N 0.000 description 2
- FJPUKTJEFOXMJX-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[1-(hydroxymethyl)cyclopropyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2(CC2)CO)C=CC=1 FJPUKTJEFOXMJX-UHFFFAOYSA-N 0.000 description 2
- ZUNFPBNHELLPPP-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(dimethylamino)ethyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCN(C)C)C=CC=1 ZUNFPBNHELLPPP-UHFFFAOYSA-N 0.000 description 2
- VVPGEFWZAXBZHR-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]sulfanyl-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)SC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 VVPGEFWZAXBZHR-UHFFFAOYSA-N 0.000 description 2
- BURCZJNCKSLVSZ-UHFFFAOYSA-N 3-hydroxy-3-pyridin-4-ylpropanenitrile Chemical compound N#CCC(O)C1=CC=NC=C1 BURCZJNCKSLVSZ-UHFFFAOYSA-N 0.000 description 2
- UAJOHTPJVGVBJV-UHFFFAOYSA-N 3-quinolin-4-ylprop-2-en-1-amine Chemical compound C1=CC=C2C(C=CCN)=CC=NC2=C1 UAJOHTPJVGVBJV-UHFFFAOYSA-N 0.000 description 2
- HOWFLZVASJDZRZ-UHFFFAOYSA-N 4-[[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxymethyl]-N-phenylpiperidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OCC1CCN(CC1)C(=O)NC1=CC=CC=C1 HOWFLZVASJDZRZ-UHFFFAOYSA-N 0.000 description 2
- DDUHZTYCFQRHIY-UHFFFAOYSA-N 7-chloro-3',4,6-trimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione Chemical compound COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- NRLQBVLOUUPAMI-UHFFFAOYSA-N 8-[3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxybenzoyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)N2CCC3(CNC(O3)=O)CC2)C=CC=1 NRLQBVLOUUPAMI-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- NMHBAYVSPWXWKU-UHFFFAOYSA-N CCC(C)NC1(CC(C2)C3)CC3CC2C1.OC(CCCCC1=CC=NC=C1)=O Chemical class CCC(C)NC1(CC(C2)C3)CC3CC2C1.OC(CCCCC1=CC=NC=C1)=O NMHBAYVSPWXWKU-UHFFFAOYSA-N 0.000 description 2
- XMKQLIPOJDSLFJ-UHFFFAOYSA-N CCC(O)=O.NCCCC1=CC=NC=C1 Chemical class CCC(O)=O.NCCCC1=CC=NC=C1 XMKQLIPOJDSLFJ-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- ONHDSOVNHIGQMU-UHFFFAOYSA-N Cl.Cl.C1(CCCCC1)CCN(C(=O)N(C1=CC=NC=C1)C)CCNC Chemical compound Cl.Cl.C1(CCCCC1)CCN(C(=O)N(C1=CC=NC=C1)C)CCNC ONHDSOVNHIGQMU-UHFFFAOYSA-N 0.000 description 2
- WIWLRQWTCYJAOH-UHFFFAOYSA-N Cl.S1C(=CC=C1)N(C(=O)N)C.C1(CCCCC1)CCC1(C(=O)O)C(C(C(=O)O)(CC=C1)C1=CC=NC=C1)C Chemical compound Cl.S1C(=CC=C1)N(C(=O)N)C.C1(CCCCC1)CCC1(C(=O)O)C(C(C(=O)O)(CC=C1)C1=CC=NC=C1)C WIWLRQWTCYJAOH-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000005741 Metalloproteases Human genes 0.000 description 2
- 108010006035 Metalloproteases Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- GXFIJNNOECYQOJ-UHFFFAOYSA-N [2-[1-(1-methylpyrazol-4-yl)indol-4-yl]oxy-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound CN1N=CC(=C1)N1C=CC2=C(C=CC=C12)OC1=NC(=CC(=C1)CN)C(F)(F)F GXFIJNNOECYQOJ-UHFFFAOYSA-N 0.000 description 2
- BYWBCSRCPLBDFU-CYBMUJFWSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-aminopyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)N BYWBCSRCPLBDFU-CYBMUJFWSA-N 0.000 description 2
- LJHFUFVRZNYVMK-CYBMUJFWSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)O LJHFUFVRZNYVMK-CYBMUJFWSA-N 0.000 description 2
- UGKIKJFPXNOHHA-UHFFFAOYSA-N [5-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypyridin-3-yl]-(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=NC=1)C(=O)N1CC(C(C1)O)F UGKIKJFPXNOHHA-UHFFFAOYSA-N 0.000 description 2
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 2
- DZHMRSPXDUUJER-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;dihydrogen phosphate Chemical compound NC(N)=O.OP(O)(O)=O DZHMRSPXDUUJER-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000026500 emaciation Diseases 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000004993 haloalkoxycarbonyl group Chemical group 0.000 description 2
- 150000003840 hydrochlorides Chemical group 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BUCBPAXMXLVROO-UHFFFAOYSA-N n-methyl-3-pyridin-4-ylpropan-1-amine Chemical compound CNCCCC1=CC=NC=C1 BUCBPAXMXLVROO-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920002050 silicone resin Polymers 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RUXFGSULXQGEMZ-LLVKDONJSA-N (2R)-1-(2-pyridin-4-ylethyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCN1CCc1ccncc1 RUXFGSULXQGEMZ-LLVKDONJSA-N 0.000 description 1
- RUXFGSULXQGEMZ-NSHDSACASA-N (2s)-1-(2-pyridin-4-ylethyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1CCC1=CC=NC=C1 RUXFGSULXQGEMZ-NSHDSACASA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ZWHOTPNCEFWATE-CQSZACIVSA-N (3R)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpyrrolidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@H]1CN(CC1)C(=O)NC1=CC=CC=C1 ZWHOTPNCEFWATE-CQSZACIVSA-N 0.000 description 1
- ZWHOTPNCEFWATE-AWEZNQCLSA-N (3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpyrrolidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CC1)C(=O)NC1=CC=CC=C1 ZWHOTPNCEFWATE-AWEZNQCLSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- LDMHOAPGYQKRCB-UHFFFAOYSA-N 1-(2-cyclohexylethyl)-1-[2-(dimethylamino)ethyl]-3-methyl-3-pyridin-4-ylurea Chemical compound C1(CCCCC1)CCN(C(=O)N(C1=CC=NC=C1)C)CCN(C)C LDMHOAPGYQKRCB-UHFFFAOYSA-N 0.000 description 1
- RAVIQFQJZMTUBX-AWEZNQCLSA-N 1-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-2-(3,4-dichlorophenyl)ethanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(CC1=CC(=C(C=C1)Cl)Cl)=O RAVIQFQJZMTUBX-AWEZNQCLSA-N 0.000 description 1
- XAOMFUPJQYNDEG-LBPRGKRZSA-N 1-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-2-methylpropan-1-one Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(C(C)C)=O XAOMFUPJQYNDEG-LBPRGKRZSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- YDTDIWODTJABHQ-UHFFFAOYSA-N 1-butyl-1-(2-cyclohexylethyl)-3-methyl-3-pyridin-4-ylurea Chemical compound C(CCC)N(C(=O)N(C1=CC=NC=C1)C)CCC1CCCCC1 YDTDIWODTJABHQ-UHFFFAOYSA-N 0.000 description 1
- XTIGGAHUZJWQMD-UHFFFAOYSA-N 1-chloro-2-methoxyethane Chemical compound COCCCl XTIGGAHUZJWQMD-UHFFFAOYSA-N 0.000 description 1
- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical group CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 1
- WMQUKDQWMMOHSA-UHFFFAOYSA-N 1-pyridin-4-ylethanone Chemical compound CC(=O)C1=CC=NC=C1 WMQUKDQWMMOHSA-UHFFFAOYSA-N 0.000 description 1
- DFIFVMZOFMQSAG-UHFFFAOYSA-N 1-tert-butyl-3-methylurea Chemical group CNC(=O)NC(C)(C)C DFIFVMZOFMQSAG-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 description 1
- FCWKTYAKHOSQHZ-UHFFFAOYSA-N 2,2-dimethyl-3-pyridin-4-ylpropan-1-amine Chemical compound NCC(C)(C)CC1=CC=NC=C1 FCWKTYAKHOSQHZ-UHFFFAOYSA-N 0.000 description 1
- HDYOQAAFGJNYGF-UHFFFAOYSA-N 2-(1-adamantyl)-n-(2-methoxyethyl)ethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCCOC)C3 HDYOQAAFGJNYGF-UHFFFAOYSA-N 0.000 description 1
- YCDYBBMGDLNZGL-UHFFFAOYSA-N 2-(1-adamantyl)-n-(cyclopentylmethyl)ethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2CC13CCNCC1CCCC1 YCDYBBMGDLNZGL-UHFFFAOYSA-N 0.000 description 1
- KGHHHQGTHLYMHB-UHFFFAOYSA-N 2-(1-adamantyl)-n-(furan-2-ylmethyl)ethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2CC13CCNCC1=CC=CO1 KGHHHQGTHLYMHB-UHFFFAOYSA-N 0.000 description 1
- XCKXWSFNJOQMIH-UHFFFAOYSA-N 2-(1-adamantyl)-n-(thiophen-2-ylmethyl)ethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2CC13CCNCC1=CC=CS1 XCKXWSFNJOQMIH-UHFFFAOYSA-N 0.000 description 1
- UJLORXABZWLMMF-UHFFFAOYSA-N 2-(1-adamantyl)-n-benzylethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2CC13CCNCC1=CC=CC=C1 UJLORXABZWLMMF-UHFFFAOYSA-N 0.000 description 1
- PVMRHHYSMYVGQV-UHFFFAOYSA-N 2-(1-adamantyl)-n-methylethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNC)C3 PVMRHHYSMYVGQV-UHFFFAOYSA-N 0.000 description 1
- XZBAGOKDTBEUAK-UHFFFAOYSA-N 2-(pyridin-4-ylmethyl)butan-1-amine Chemical compound CCC(CN)CC1=CC=NC=C1 XZBAGOKDTBEUAK-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- RNIUHIHTGPHJEN-AWEZNQCLSA-N 2-[(3S)-1-[2-(3,4-dichlorophenyl)acetyl]piperidin-3-yl]oxy-6-(trifluoromethyl)pyridine-4-carbonitrile Chemical compound ClC=1C=C(C=CC=1Cl)CC(=O)N1C[C@H](CCC1)OC=1C=C(C#N)C=C(N=1)C(F)(F)F RNIUHIHTGPHJEN-AWEZNQCLSA-N 0.000 description 1
- DCGQVDFBDSTUML-AWEZNQCLSA-N 2-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidine-1-carbonyl]chromen-4-one Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(=O)C=1OC2=CC=CC=C2C(C=1)=O DCGQVDFBDSTUML-AWEZNQCLSA-N 0.000 description 1
- APDYPEOKIUKUQV-UHFFFAOYSA-N 2-[1-(2-oxo-2-piperidin-1-ylethyl)indol-4-yl]oxy-6-(trifluoromethyl)pyridine-4-carbonitrile Chemical compound O=C(CN1C=CC2=C(C=CC=C12)OC=1C=C(C#N)C=C(N=1)C(F)(F)F)N1CCCCC1 APDYPEOKIUKUQV-UHFFFAOYSA-N 0.000 description 1
- CWSUDZBRNKKURY-UHFFFAOYSA-N 2-benzyl-3-pyridin-4-ylpropan-1-amine Chemical compound C=1C=NC=CC=1CC(CN)CC1=CC=CC=C1 CWSUDZBRNKKURY-UHFFFAOYSA-N 0.000 description 1
- KWNVSNXIXBJJHG-UHFFFAOYSA-N 2-cyclohexyl-n-(2-methoxyethyl)ethanamine;hydrochloride Chemical compound Cl.COCCNCCC1CCCCC1 KWNVSNXIXBJJHG-UHFFFAOYSA-N 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- YQORMSBFOZKIPW-UHFFFAOYSA-N 2-pyridin-1-ium-4-ylbutanoate Chemical compound CCC(C(O)=O)C1=CC=NC=C1 YQORMSBFOZKIPW-UHFFFAOYSA-N 0.000 description 1
- IDLHTECVNDEOIY-UHFFFAOYSA-N 2-pyridin-4-ylethanamine Chemical compound NCCC1=CC=NC=C1 IDLHTECVNDEOIY-UHFFFAOYSA-N 0.000 description 1
- LCVMHCVYIXLDOD-UHFFFAOYSA-N 3-(2-cyclohexylethylamino)propanamide;hydrochloride Chemical compound Cl.NC(=O)CCNCCC1CCCCC1 LCVMHCVYIXLDOD-UHFFFAOYSA-N 0.000 description 1
- QOJIAZGPGSUWMD-UHFFFAOYSA-N 3-(pyridin-4-ylmethylazaniumyl)propanoate Chemical compound OC(=O)CCNCC1=CC=NC=C1 QOJIAZGPGSUWMD-UHFFFAOYSA-N 0.000 description 1
- HCPYTVPYSHNTLF-UHFFFAOYSA-N 3-[2-cyclohexylethyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound CC(C)(C)OC(=O)N(CCC(O)=O)CCC1CCCCC1 HCPYTVPYSHNTLF-UHFFFAOYSA-N 0.000 description 1
- MROVZCRMXJZHCN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-hydroxyethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCO)C=CC=1 MROVZCRMXJZHCN-UHFFFAOYSA-N 0.000 description 1
- SHBHYINHXNTBRP-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-methylsulfonylethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCS(=O)(=O)C)C=CC=1 SHBHYINHXNTBRP-UHFFFAOYSA-N 0.000 description 1
- VTNULXUEOJMRKZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2H-tetrazol-5-ylmethyl)benzamide Chemical compound N=1NN=NC=1CNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O VTNULXUEOJMRKZ-UHFFFAOYSA-N 0.000 description 1
- SONNQRNOTIAJDS-GFCCVEGCSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(2R)-2,3-dihydroxypropyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC[C@H](CO)O)C=CC=1 SONNQRNOTIAJDS-GFCCVEGCSA-N 0.000 description 1
- GDSLUYKCPYECNN-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(4-fluorophenyl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC=C(C=C2)F)C=CC=1 GDSLUYKCPYECNN-UHFFFAOYSA-N 0.000 description 1
- ISXSUKUXUPLGTD-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(5-oxopyrrolidin-2-yl)methyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2NC(CC2)=O)C=CC=1 ISXSUKUXUPLGTD-UHFFFAOYSA-N 0.000 description 1
- ZMCQQCBOZIGNRV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(1,2,4-triazol-1-yl)ethyl]benzamide Chemical compound NCC1=CC(OC2=CC=CC(=C2)C(=O)NCCN2C=NC=N2)=NC(=C1)C(F)(F)F ZMCQQCBOZIGNRV-UHFFFAOYSA-N 0.000 description 1
- AJZDHLHTTJRNQJ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(tetrazol-1-yl)ethyl]benzamide Chemical compound N1(N=NN=C1)CCNC(C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)=O AJZDHLHTTJRNQJ-UHFFFAOYSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- OIBZMMPOWDEASK-UHFFFAOYSA-N 3-[[[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]amino]methyl]-N-(2-methylsulfonylethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)NCC=1C=C(C(=O)NCCS(=O)(=O)C)C=CC=1 OIBZMMPOWDEASK-UHFFFAOYSA-N 0.000 description 1
- XXAFCSLVTWGVEY-UHFFFAOYSA-N 3-[[[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]amino]methyl]-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)NCC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 XXAFCSLVTWGVEY-UHFFFAOYSA-N 0.000 description 1
- UNVITKXYWWBWJQ-UHFFFAOYSA-N 3-[methyl(pyridin-4-ylmethyl)amino]propanoic acid Chemical compound OC(=O)CCN(C)CC1=CC=NC=C1 UNVITKXYWWBWJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- OOOKFECOOJGDKJ-UHFFFAOYSA-N 3-methyl-4-pyridin-4-ylbutan-2-amine Chemical compound CC(N)C(C)CC1=CC=NC=C1 OOOKFECOOJGDKJ-UHFFFAOYSA-N 0.000 description 1
- QXDRXJVROBDWIJ-UHFFFAOYSA-N 3-pyridin-4-ylbutan-1-amine Chemical compound NCCC(C)C1=CC=NC=C1 QXDRXJVROBDWIJ-UHFFFAOYSA-N 0.000 description 1
- NMNFWLIHFSRPKT-UHFFFAOYSA-N 3-pyridin-4-ylbutanamide Chemical compound NC(=O)CC(C)C1=CC=NC=C1 NMNFWLIHFSRPKT-UHFFFAOYSA-N 0.000 description 1
- KYSQGRVBIOODEO-UHFFFAOYSA-N 3-pyridin-4-ylbutanoic acid Chemical compound OC(=O)CC(C)C1=CC=NC=C1 KYSQGRVBIOODEO-UHFFFAOYSA-N 0.000 description 1
- VEONADHCZDIKEW-UHFFFAOYSA-N 3-quinolin-4-ylpropan-1-amine Chemical compound C1=CC=C2C(CCCN)=CC=NC2=C1 VEONADHCZDIKEW-UHFFFAOYSA-N 0.000 description 1
- DWCBGHNGQBPOOR-UHFFFAOYSA-N 4-(2-chloroethyl)pyridine;hydrochloride Chemical compound Cl.ClCCC1=CC=NC=C1 DWCBGHNGQBPOOR-UHFFFAOYSA-N 0.000 description 1
- ZDHKVKPZQKYREU-UHFFFAOYSA-N 4-(chloromethyl)pyridine;hydron;chloride Chemical compound Cl.ClCC1=CC=NC=C1 ZDHKVKPZQKYREU-UHFFFAOYSA-N 0.000 description 1
- QEIVWSRXBYOTAZ-UHFFFAOYSA-N 4-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpiperidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC1CCN(CC1)C(=O)NC1=CC=CC=C1 QEIVWSRXBYOTAZ-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- MPZMVUQGXAOJIK-UHFFFAOYSA-N 4-bromopyridine;hydron;chloride Chemical compound Cl.BrC1=CC=NC=C1 MPZMVUQGXAOJIK-UHFFFAOYSA-N 0.000 description 1
- LTEOZJKVMBWJRT-UHFFFAOYSA-N 4-pyridin-1-ium-4-ylbutanoate Chemical compound OC(=O)CCCC1=CC=NC=C1 LTEOZJKVMBWJRT-UHFFFAOYSA-N 0.000 description 1
- FTFBFLRZEAZBAU-UHFFFAOYSA-N 4-pyridin-4-ylbutan-2-one Chemical compound CC(=O)CCC1=CC=NC=C1 FTFBFLRZEAZBAU-UHFFFAOYSA-N 0.000 description 1
- FOFSNCRMWLKAIM-UHFFFAOYSA-N 5-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-1H-quinolin-2-one Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC1=C2CCC(NC2=CC=C1)=O FOFSNCRMWLKAIM-UHFFFAOYSA-N 0.000 description 1
- ZFYXJIYPIORSQE-UHFFFAOYSA-N 5-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-methylsulfonylethyl)pyridine-3-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=NC=C(C(=O)NCCS(=O)(=O)C)C=1 ZFYXJIYPIORSQE-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- RIMXEJYJXDBLIE-UHFFFAOYSA-N 6-bromohex-1-ene Chemical compound BrCCCCC=C RIMXEJYJXDBLIE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RTESCXBOUIGCED-UHFFFAOYSA-N C(=O)(OCC)Cl.NCCC(=O)O Chemical compound C(=O)(OCC)Cl.NCCC(=O)O RTESCXBOUIGCED-UHFFFAOYSA-N 0.000 description 1
- GJSYEHWZILYZBH-UHFFFAOYSA-N C(C)(=O)NC1(C(C=CC=C1)O)[As](O)(O)=O Chemical compound C(C)(=O)NC1(C(C=CC=C1)O)[As](O)(O)=O GJSYEHWZILYZBH-UHFFFAOYSA-N 0.000 description 1
- VFWCVFXSJJESEC-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N(C)CCN(C(=O)N(C1=CC=NC=C1)C)CCC1CCCCC1 Chemical compound C(C)(C)(C)OC(=O)N(C)CCN(C(=O)N(C1=CC=NC=C1)C)CCC1CCCCC1 VFWCVFXSJJESEC-UHFFFAOYSA-N 0.000 description 1
- MQLCHGVHHBVPBY-UHFFFAOYSA-N C12(CC3CC(CC(C1)C3)C2)C(=CCCC)C Chemical compound C12(CC3CC(CC(C1)C3)C2)C(=CCCC)C MQLCHGVHHBVPBY-UHFFFAOYSA-N 0.000 description 1
- XPPYMHMBNUDRRI-UHFFFAOYSA-N CN(CCNCCC12CC3CC(C1)CC(C3)C2)C(=O)OC(C4=CC=CC=C4)C(=O)OCC5=CC=CC=C5 Chemical compound CN(CCNCCC12CC3CC(C1)CC(C3)C2)C(=O)OC(C4=CC=CC=C4)C(=O)OCC5=CC=CC=C5 XPPYMHMBNUDRRI-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000723347 Cinnamomum Species 0.000 description 1
- SMRSHVSLJBCRGB-UHFFFAOYSA-N Cl.C1(CCCCC1)CCN(C=1SC=CC1)C Chemical compound Cl.C1(CCCCC1)CCN(C=1SC=CC1)C SMRSHVSLJBCRGB-UHFFFAOYSA-N 0.000 description 1
- TUFZGIQUAGOKRK-UHFFFAOYSA-N Cl.C12(CC3CC(CC(C1)C3)C2)CCNCCC Chemical compound Cl.C12(CC3CC(CC(C1)C3)C2)CCNCCC TUFZGIQUAGOKRK-UHFFFAOYSA-N 0.000 description 1
- XWJPSBLIDZMRNK-UHFFFAOYSA-N ClC1=CC(=NC=C1)CCl.ClCC1=CC=NC=C1 Chemical compound ClC1=CC(=NC=C1)CCl.ClCC1=CC=NC=C1 XWJPSBLIDZMRNK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- CJJRFNMXRJJDGT-UHFFFAOYSA-N N1=CC=C(C=C1)CC(CC)=NO Chemical compound N1=CC=C(C=C1)CC(CC)=NO CJJRFNMXRJJDGT-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PWATWSYOIIXYMA-UHFFFAOYSA-N Pentylbenzene Chemical compound CCCCCC1=CC=CC=C1 PWATWSYOIIXYMA-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- QNPVBDZIJXGIEZ-UHFFFAOYSA-N S1C(=CC=C1)N(C(=O)N)C.C1(CCCCC1)CCC1(C(=O)O)C(C(C(=O)O)(CC=C1)C1=CC=NC=C1)C Chemical compound S1C(=CC=C1)N(C(=O)N)C.C1(CCCCC1)CCC1(C(=O)O)C(C(C(=O)O)(CC=C1)C1=CC=NC=C1)C QNPVBDZIJXGIEZ-UHFFFAOYSA-N 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- JDCLUYDBENDDSR-NSHDSACASA-N [(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-(5-methyl-1,3,4-oxadiazol-2-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(=O)C=1OC(=NN=1)C JDCLUYDBENDDSR-NSHDSACASA-N 0.000 description 1
- RWQJLIWMOBYOTI-AWEZNQCLSA-N [(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-pyridin-3-ylmethanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(=O)C=1C=NC=CC=1 RWQJLIWMOBYOTI-AWEZNQCLSA-N 0.000 description 1
- WGCOQYDRMPFAMN-ZDUSSCGKSA-N [(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-pyrimidin-5-ylmethanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(=O)C=1C=NC=NC=1 WGCOQYDRMPFAMN-ZDUSSCGKSA-N 0.000 description 1
- PKZVFOVXYKCBCJ-UHFFFAOYSA-N [2-(1H-indol-4-yloxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1C=CC2=C(C=CC=C12)OC1=NC(=CC(=C1)CN)C(F)(F)F PKZVFOVXYKCBCJ-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- YQYBUJYBXOVWQW-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3,4-dihydro-1H-isoquinolin-2-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1CC2=CC=CC=C2CC1 YQYBUJYBXOVWQW-UHFFFAOYSA-N 0.000 description 1
- YKKPYMXANSSQCA-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3-pyrazol-1-ylazetidin-1-yl)methanone Chemical compound N1(N=CC=C1)C1CN(C1)C(=O)C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F YKKPYMXANSSQCA-UHFFFAOYSA-N 0.000 description 1
- LJHFUFVRZNYVMK-ZDUSSCGKSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3S)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@H](CC1)O LJHFUFVRZNYVMK-ZDUSSCGKSA-N 0.000 description 1
- JWSIZPAOIFLWKM-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]methanone Chemical compound CN(C)C1CN(CC1O)C(=O)c1cccc(Oc2cc(CN)cc(n2)C(F)(F)F)c1 JWSIZPAOIFLWKM-UHFFFAOYSA-N 0.000 description 1
- KDSYNTPPPISIJB-UHFFFAOYSA-N [3-[[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxymethyl]phenyl]-(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone Chemical compound NCc1cc(OCc2cccc(c2)C(=O)N2CC(O)C(F)C2)nc(c1)C(F)(F)F KDSYNTPPPISIJB-UHFFFAOYSA-N 0.000 description 1
- IQUWAPNUQVLWGG-GFCCVEGCSA-N [5-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypyridin-3-yl]-[(3R)-3-aminopyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=NC=1)C(=O)N1C[C@@H](CC1)N IQUWAPNUQVLWGG-GFCCVEGCSA-N 0.000 description 1
- LBTYFJLXOHTXMW-UHFFFAOYSA-M [Br-].C(=O)(OCC1=CC=CC=C1)C(OC(=O)C1=C(C=CC=C1)[P+](C1=CC=CC=C1)(C1=CC=CC=C1)C)C1=CC=CC=C1 Chemical compound [Br-].C(=O)(OCC1=CC=CC=C1)C(OC(=O)C1=C(C=CC=C1)[P+](C1=CC=CC=C1)(C1=CC=CC=C1)C)C1=CC=CC=C1 LBTYFJLXOHTXMW-UHFFFAOYSA-M 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical class 0.000 description 1
- 230000003816 axenic effect Effects 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- RMKNCYHVESPYFD-UHFFFAOYSA-N decan-1-amine;hydrochloride Chemical compound [Cl-].CCCCCCCCCC[NH3+] RMKNCYHVESPYFD-UHFFFAOYSA-N 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HCFPRFJJTHMING-UHFFFAOYSA-N ethane-1,2-diamine;hydron;chloride Chemical compound [Cl-].NCC[NH3+] HCFPRFJJTHMING-UHFFFAOYSA-N 0.000 description 1
- ZVHRTJHLSYKEAK-UHFFFAOYSA-N ethyl 2-[5-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-2-oxo-3,4-dihydroquinolin-1-yl]acetate Chemical compound CCOC(=O)CN1C(=O)CCC2=C1C=CC=C2OC1=NC(=CC(CN)=C1)C(F)(F)F ZVHRTJHLSYKEAK-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 108010025899 gelatin film Proteins 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- FEIQEWJEXNBGIS-UHFFFAOYSA-N methyl 3-[2-cyclohexylethyl-[methyl(pyridin-4-yl)carbamoyl]amino]propanoate Chemical compound C1(CCCCC1)CCN(C(=O)N(C1=CC=NC=C1)C)CCC(=O)OC FEIQEWJEXNBGIS-UHFFFAOYSA-N 0.000 description 1
- OJVSEHLMRCLAFY-UHFFFAOYSA-N methyl propanoate;hydrochloride Chemical compound Cl.CCC(=O)OC OJVSEHLMRCLAFY-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- RVAYVIPSSSQCDR-UHFFFAOYSA-N n-(2-cyclohexylethyl)-n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCNCCC1CCCCC1 RVAYVIPSSSQCDR-UHFFFAOYSA-N 0.000 description 1
- SIGIIXYMDHGVLA-UHFFFAOYSA-N n-(2-cyclohexylethyl)butan-1-amine;hydrochloride Chemical compound Cl.CCCCNCCC1CCCCC1 SIGIIXYMDHGVLA-UHFFFAOYSA-N 0.000 description 1
- WZLFSVMIRVBIDX-UHFFFAOYSA-N n-(4-pyridin-4-ylbutan-2-ylidene)hydroxylamine Chemical compound ON=C(C)CCC1=CC=NC=C1 WZLFSVMIRVBIDX-UHFFFAOYSA-N 0.000 description 1
- UETJZLOJRIGDCO-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-2,2,2-trifluoroethanamine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCC(F)(F)F)C3 UETJZLOJRIGDCO-UHFFFAOYSA-N 0.000 description 1
- AEGKZRYAVYNRQF-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-3-pyridin-4-ylpropan-1-amine Chemical compound C1C(C2)CC(C3)CC2CC13CCNCCCC1=CC=NC=C1 AEGKZRYAVYNRQF-UHFFFAOYSA-N 0.000 description 1
- RMGFRMIDJCTQML-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-4,4,4-trifluorobutan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCCCC(F)(F)F)C3 RMGFRMIDJCTQML-UHFFFAOYSA-N 0.000 description 1
- CWVCBWZEFZBYHM-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-5,5,5-trifluoropentan-1-amine Chemical compound C1C(C2)CC3CC2CC1(CCNCCCCC(F)(F)F)C3 CWVCBWZEFZBYHM-UHFFFAOYSA-N 0.000 description 1
- WXGVVOZOHQDFAW-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n',n'-dimethylethane-1,2-diamine;dihydrochloride Chemical compound Cl.Cl.C1C(C2)CC3CC2CC1(CCNCCN(C)C)C3 WXGVVOZOHQDFAW-UHFFFAOYSA-N 0.000 description 1
- CWUKRQPZLBVFRU-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-methylcyclopropanamine Chemical compound C1C(C2)CC(C3)CC2CC13CCN(C)C1CC1 CWUKRQPZLBVFRU-UHFFFAOYSA-N 0.000 description 1
- LDIKGSPWKZGHQK-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]cyclopentanamine;hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2CC13CCNC1CCCC1 LDIKGSPWKZGHQK-UHFFFAOYSA-N 0.000 description 1
- UNTIWBXRPBRLJC-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]hexan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCCCCCC)C3 UNTIWBXRPBRLJC-UHFFFAOYSA-N 0.000 description 1
- AAIFNJQLLMRNDS-UHFFFAOYSA-N n-[2-(1h-imidazol-5-yl)ethyl]-3-methylbutan-1-amine;dihydrochloride Chemical compound Cl.Cl.CC(C)CCNCCC1=CN=CN1 AAIFNJQLLMRNDS-UHFFFAOYSA-N 0.000 description 1
- CDEMNRGJMIWVIH-UHFFFAOYSA-N n-[2-(3,4,5-trimethoxyphenyl)ethyl]cyclopropanamine Chemical compound COC1=C(OC)C(OC)=CC(CCNC2CC2)=C1 CDEMNRGJMIWVIH-UHFFFAOYSA-N 0.000 description 1
- QYUUWFKPJWELGD-UHFFFAOYSA-N n-[2-(3,4-dimethoxyphenyl)ethyl]cyclohexanamine Chemical compound C1=C(OC)C(OC)=CC=C1CCNC1CCCCC1 QYUUWFKPJWELGD-UHFFFAOYSA-N 0.000 description 1
- LIBBCZOPAZDNJW-UHFFFAOYSA-N n-ethyl-2-(3,4,5-trimethoxyphenyl)ethanamine Chemical compound CCNCCC1=CC(OC)=C(OC)C(OC)=C1 LIBBCZOPAZDNJW-UHFFFAOYSA-N 0.000 description 1
- PQLZOJVOVZMIAE-UHFFFAOYSA-N n-ethyl-3-pyridin-4-ylpropan-1-amine Chemical compound CCNCCCC1=CC=NC=C1 PQLZOJVOVZMIAE-UHFFFAOYSA-N 0.000 description 1
- NBUOVUWCFITPSC-UHFFFAOYSA-N n-methyl-n-propyladamantan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(N(C)CCC)C3 NBUOVUWCFITPSC-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- UZNUTPJHIJECKF-UHFFFAOYSA-N n-pyridin-4-ylbutanamide Chemical compound CCCC(=O)NC1=CC=NC=C1 UZNUTPJHIJECKF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- NSTHNVMITOXEJZ-UHFFFAOYSA-N oxalic acid;3-pyridin-4-ylprop-2-enal Chemical compound OC(=O)C(O)=O.O=CC=CC1=CC=NC=C1 NSTHNVMITOXEJZ-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- FZFZFCIODKYFEV-UHFFFAOYSA-N pentan-1-amine;hydrochloride Chemical compound Cl.CCCCCN FZFZFCIODKYFEV-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- SKJJGBRWKOFYAD-UHFFFAOYSA-N piperidin-1-ylurea Chemical compound NC(=O)NN1CCCCC1 SKJJGBRWKOFYAD-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LTUDISCZKZHRMJ-UHFFFAOYSA-N potassium;hydrate Chemical compound O.[K] LTUDISCZKZHRMJ-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UTZZANSZTMOPAI-UHFFFAOYSA-N pyridin-4-ylmethylurea Chemical compound NC(=O)NCC1=CC=NC=C1 UTZZANSZTMOPAI-UHFFFAOYSA-N 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- SWEZTZWTWVKNMF-UHFFFAOYSA-N tert-butyl 3-(2-cyclohexylethylamino)propanoate Chemical compound CC(C)(C)OC(=O)CCNCCC1CCCCC1 SWEZTZWTWVKNMF-UHFFFAOYSA-N 0.000 description 1
- XITRWBCZOGFMAQ-UHFFFAOYSA-N tert-butyl 3-[2-(1-adamantyl)ethylamino]propanoate;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCCC(=O)OC(C)(C)C)C3 XITRWBCZOGFMAQ-UHFFFAOYSA-N 0.000 description 1
- TYILMRSTAZBPAI-UHFFFAOYSA-N tert-butyl 3-[2-cyclohexylethyl-[methyl(pyridin-4-yl)carbamoyl]amino]propanoate Chemical compound C(C)(C)(C)OC(=O)CCN(C(=O)N(C1=CC=NC=C1)C)CCC1CCCCC1 TYILMRSTAZBPAI-UHFFFAOYSA-N 0.000 description 1
- HONNWTDYWUAZJF-UHFFFAOYSA-N tert-butyl 4-[2-[4-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyindol-1-yl]acetyl]piperazine-1-carboxylate Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC1=C2C=CN(C2=CC=C1)CC(=O)N1CCN(CC1)C(=O)OC(C)(C)C HONNWTDYWUAZJF-UHFFFAOYSA-N 0.000 description 1
- QKRKMOWZDWMYTB-UHFFFAOYSA-N tert-butyl n-(3-amino-3-oxopropyl)-n-(2-cyclohexylethyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CCC(N)=O)CCC1CCCCC1 QKRKMOWZDWMYTB-UHFFFAOYSA-N 0.000 description 1
- HFSAXDLSTDMFTC-UHFFFAOYSA-N tert-butyl n-[2-(1-adamantyl)ethylamino]carbamate Chemical compound C1C(C2)CC3CC2CC1(CCNNC(=O)OC(C)(C)C)C3 HFSAXDLSTDMFTC-UHFFFAOYSA-N 0.000 description 1
- GOCKANRSHLSOEC-UHFFFAOYSA-N tert-butyl n-[2-(2-cyclohexylethylamino)ethyl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CCNCCC1CCCCC1 GOCKANRSHLSOEC-UHFFFAOYSA-N 0.000 description 1
- NIPDQJPBXRAJPW-UHFFFAOYSA-N tert-butyl n-[2-[2-(1-adamantyl)ethylamino]ethyl]-n-methylcarbamate Chemical compound C1C(C2)CC3CC2CC1(CCNCCN(C)C(=O)OC(C)(C)C)C3 NIPDQJPBXRAJPW-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 1
- NWBDOLAYNYVVTO-UHFFFAOYSA-N tert-butyl propanoate;hydrochloride Chemical compound Cl.CCC(=O)OC(C)(C)C NWBDOLAYNYVVTO-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- IPSRAFUHLHIWAR-UHFFFAOYSA-N zinc;ethane Chemical group [Zn+2].[CH2-]C.[CH2-]C IPSRAFUHLHIWAR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/32—Sulfur atoms
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Obesity (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Transplantation (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Communicable Diseases (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明的目的是提供TNF-α生成抑制剂,它们可用作治疗剂,用于治疗自身免疫疾病如类风湿性关节炎。本发明的具有通式[1]所示结构的新化合物或其盐具有出色的TNF-α生成抑制活性,其中“A”是-(NR4)-;“B”是亚烷基或亚链烯基;R1、R2和R4是氢、烷基、链烯基、金刚烷基等;R3是芳基或不饱和杂环;并且“X”是氧或硫。
Description
技术领域
本发明涉及用作自身免疫疾病,例如类风湿性关节炎治疗剂的TNF-α生成抑制剂。
背景技术
TNF-α(肿瘤坏死因子-α)被认为是一种细胞因子,其通过炎症广泛地参与生物预防-免疫机制。已知长时间的和过度的生成TNF-α是引发组织损伤和各种疾病的病因。有TNF-α参与的疾病的实例有许多,例如关节风湿病、系统性红斑狼疮(SLE)、恶病质、急性感染性疾病、变态反应、发热、贫血和糖尿病(Yamazaki,ClinicalImmunology,
27,1270,1995)。据报道,TNF-α在类风湿性关节炎和克隆病的发病机理中起重要作用,这两种疾病都是自身免疫疾病(Andreas Eigler等,Immunology Today,
18,487,1997)。
从这些报道可以预期,抑制TNF-α生成的化合物可有效治疗上述疾病,并且已进行了各种研究(上面提及的文献:Yamazaki,ClinicalImmunology,
27,1270,1995;Andreas Eigler等,ImmunologyToday,
18,487,1997)。最近,另据报道,作为蛋白水解酶的金属蛋白酶参与TNF-α的分泌并且金属蛋白酶抑制剂对TNF-α生成等的抑制具有重要影响(已公开的PCT No.508115/1997的日文翻译本)。日本特许公开专利申请44533/2000和119249/2000公开了对TNF-α的生成具有抑制作用的化合物。所有这些化合物都是在侧链具有硫原子的脲衍生物。
研究对TNF-α的生成具有抑制活性的化合物具有重要意义,它们可用作自身免疫疾病,例如类风湿性关节炎、变态反应和糖尿病的治疗剂。
发明内容
本发明者制备了具有各种化学结构的化合物并进行了药理试验。结果,本发明者发现具有下面通式[1]所示结构的新化合物表现出出色的TNF-α生成抑制活性,从而完成了本发明。
本发明涉及下面通式[1]表示的化合物及其盐(若没有限制条件,下文称之为“本发明化合物”),以及包含其作为活性成分的药物组合物,
其中“A”是-(NR4)-、-(CR5R6)或-O-;
“B”是在其链中可以包含-O-、-S-、-(NR7)-、-CO-、-N=或下式基团的亚烷基或亚链烯基,
其中亚烷基和亚链烯基可被羟基、烷氧基、环烷基、芳基、甲硅烷氧基或者饱和或不饱和的杂环取代,并且“B”可以与“A”一起形成饱和的杂环;
R1、R2、R4、R5和R6是相同或不同的,它们是氢、烷基、链烯基、炔基、环烷基、环烯基、羟基、酰基或氨基,其中烷基、链烯基、炔基、环烷基或环烯基可被卤素、羟基、氨基、环烷基、金刚烷基、芳基、羧基、烷氧羰基、芳氧羰基、氨基羰基、氰基或者饱和或不饱和的杂环取代;
R1和R2、R2和R4、R2和R5、以及R2和R6各自可形成饱和或不饱和的杂环;
R3是芳基或者不饱和杂环;
R7是氢或烷基;
“X”是O或S;
“n”是1-5的整数;并且
上述氨基、羟基和氨基羰基的各个氢可被下列基团取代:烷基、环烷基、金刚烷基、金刚烷基烷基、芳基、芳烷基、酰基、烷氧基烷基、烷氧羰基、烷基氨基羰基、环烷氧基羰基、芳基烷氧羰基、烷基磺酰基、芳基磺酰基、卤代烷氧基羰基、咪唑基羰基、吡啶基羰基、饱和或不饱和的杂环、或者被饱和或不饱和的杂环取代的烷基。下文也适用该定义。
上面通式[1]表示的化合物适宜组成药物组合物,是TNF-α生成抑制剂的活性成分,该抑制剂可用作自身免疫疾病,如类风湿性关节炎、变态反应和糖尿病的治疗剂。
下面详细描述通式[1]中定义的各个基团。
亚烷基是具有1-12个碳原子的直链或支链亚烷基,例如亚甲基、亚乙基、1,3-亚丙基、亚丙基、1,4-亚丁基、1,5-亚戊基、1,6-亚己基、1,8-亚辛基、1,10-亚癸基、1,12-亚十二烷基、甲基亚甲基、乙基亚乙基、二甲基亚乙基、丙基亚乙基、异丙基亚乙基或甲基-1,3-亚丙基。
亚链烯基是具有一个或多个双键并且具有2-12个碳原子的直链或支链亚链烯基,例如亚乙烯基、亚丙烯基、亚丁烯基、亚戊烯基、亚己烯基、亚辛烯基、亚丁二烯基或甲基亚丙烯基。
烷基是具有1-12个碳原子的直链或支链烷基,例如甲基、乙基、丙基、丁基、戊基、己基、辛基、癸基、十二烷基、异丙基、异丁基、异戊基、异己基、异辛基、叔丁基或3,3-二甲基丁基。
烷氧基是具有1-12个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、丁氧基、己氧基、辛氧基、癸氧基、十二烷氧基、异丙氧基或叔丁氧基。
链烯基是具有2-12个碳原子的直链或支链链烯基,例如乙烯基、2-丙烯基、3-丁烯基、5-己烯基或异丙烯基。
炔基是具有2-12个碳原子的直链或支链炔基,例如乙炔基、丙炔基或丁炔基。
环烷基是具有3-20个碳原子的环烷基,例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基或环十二烷基。
环烯基是具有5-20个碳原子的环烯基,例如环戊烯基、环己烯基或环庚烯基。
芳基是芳族烃环,例如苯基或萘基,并且该环可具有一定或多个取代基。取代基是实例是烷基、环烷基、羧基、氨基、羟基、氨基烷基、羟基烷基、硝基、氰基、卤素、烷氧基等。
甲硅烷氧基是包含硅的有机基团,例如三烷基甲硅烷氧基、二烷基(芳基)甲硅烷氧基、烷基(二芳基)甲硅烷氧基或三芳基甲硅烷氧基。
卤素是氟、氯、溴或碘。
杂环是,例如饱和或不饱和的包含1-4个氮、氧和/或硫的5-20元单环或双环杂环。杂环可具有一个或多个取代基。取代基的实例是烷基、环烷基、羧基、氨基、羟基、氨基烷基、羟基烷基、硝基、氰基、卤素、烷氧基、芳基、芳基烷基、饱和或不饱和的杂环等。当上述杂环在其环中具有氮或硫原子时,该原子可被氧化为N-氧化物或S-氧化物等形式。
饱和杂环的具体实例是单环杂环,例如其环中具有氮的吡咯烷、哌啶、高哌啶和哌嗪,其环中具有氮和氧的吗啉,和其环中具有氮和硫的硫代吗啉。这些杂环可与苯环等稠合形成双环杂环,例如四氢喹啉和四氢异喹啉。
不饱和杂环的具体实例是,其环中具有氮的单杂环,例如吡咯、吡啶、吡唑、咪唑、吡嗪、哒嗪和嘧啶,以及双环杂环,例如吲哚、喹啉、异喹啉、苯并咪唑、1,5-二氮杂萘、吡咯并吡啶和咪唑并吡啶;其环中具有氧的单环杂环如呋喃和双环杂环如苯并呋喃;其环中具有硫的单环杂环如噻吩和双环杂环如苯并噻吩;其环中具有氮和氧或硫的单环杂环如噁唑、异噁唑、噻唑和异噻唑,和双环杂环如苯并噁唑、苯并噻唑、噻吩并吡啶、噁唑并吡啶、噻唑并吡啶和呋喃并吡啶等。此外,上述不饱和杂环可包含部分饱和键。
发明内容
本发明中的盐是指任何可药用盐,并且可列举与无机酸如盐酸、硝酸、硫酸或磷酸的盐;与有机酸如乙酸、富马酸、马来酸、琥珀酸或酒石酸的盐;与碱金属或碱土金属的盐,例如钠、钾或钙盐等。本发明化合物的季铵盐也包括在本发明的盐内。另外,当本发明化合物存在几何异构体或旋光异构体时,这些异构体也包括在本发明的范围之内。本发明化合物可以是水合物或溶剂化物形式。
本发明的优选实例是下列化合物(1)-(3)。
(1)其中通式[1]定义的各基团选自下列1)-4)或者所述基团由1)-4)中两个或多个组合定义的化合物或其盐。
1)R3:吡啶环。
2)R1、R2、R4、R5和R6中的至少一个:金刚烷基烷基、金刚烷氧基烷基、金刚烷基氨基烷基或金刚烷基氨基羰基烷基。
3)R1和R2中的至少一个:金刚烷基烷基、金刚烷氧基烷基、金刚烷基氨基烷基或金刚烷基氨基羰基烷基。
4)R1和R2中的至少一个:金刚烷基烷基。
(2)其中通式[1]定义的各基团是下列基团的化合物或其盐,
A:-(NR4)-、-(CR5R6)或-O-;
B:在其链中可包含-O-、-S-、-(NR7)-、-CO-、-N=或下式所示基团的亚烷基或亚链烯基,
其中亚烷基可被羟基、烷氧基、芳基、甲硅烷氧基或者饱和或不饱和的杂环取代,并且“B”可以与“A”一起形成饱和的杂环;
R1:氢、烷基、链烯基、炔基、环烷基、环烯基、羟基或氨基,其中烷基、链烯基、炔基、环烷基或环烯基可被下列基团取代:卤素、羟基、氨基、环烷基、芳基、羧基、烷氧羰基、烷基氨基羰基、金刚烷基、芳氧基羰基、氰基或者饱和或不饱和的杂环,R1中的氨基、羟基和氨基羰基的各个氢可被下列基团取代:烷基、环烷基、芳基、芳烷基、酰基、烷氧羰基、环烷氧基羰基、芳基烷氧羰基、卤代烷氧基羰基、咪唑基羰基、不饱和杂环、或者被不饱和杂环取代的烷基,
R2:金刚烷基烷基、金刚烷氧基烷基、金刚烷基氨基烷基或金刚烷基氨基羰基烷基,
R3:不饱和杂环,
R4:氢、烷基、金刚烷基烷基、羧基烷基、烷氧羰基、烷氧羰基烷基、氨基、烷基氨基、酰基氨基或烷氧羰基氨基,
R5和R6:相同或不同,为氢、烷基、氨基或烷氧羰基氨基,
R7:氢或烷基,
X:O或S,
n:1-5的整数。
其中R2是金刚烷基烷基并且R3是吡啶环的化合物或其盐在这些化合物中是更优选的。
此外,其中通式[1]定义的各基团是下列基团的化合物或其盐是尤其优选的。
A:-(NR4)-、-(CR5R6)或-O-;
B:在其链中可包含-S-或者下式所示基团的亚烷基或亚链烯基,
R1:烷基或链烯基,其中烷基可被卤素或氨基取代,并且氨基进一步可被烷基、酰基、芳基烷氧羰基、环烷氧基羰基或烷氧羰基取代,
R2:金刚烷基烷基,
R3:吡啶环,
R4:氢,
R5和R6:氢,
X:O,
n:1-5的整数。
(3)其中通式[1]定义的各基团是下列基团的化合物或其盐,
A:-(NR4)-、-(CR5R6)或-O-;
B:其链中可包含-O-、-S-、-(NR7)-、-N=或下式所示基团的亚烷基或亚链烯基,
其中亚烷基可被羟基、烷氧基、芳基或者饱和或不饱和的杂环取代,并且“B”可以与“A”形成饱和杂环,
R1:氢、烷基、链烯基、炔基、环烷基、环链烯基、羟基或氨基,其中烷基、链烯基、炔基、环烷基或环链烯基可被下列基团取代:卤素、羟基、氨基、环烷基、芳基、羧基、烷氧羰基、芳氧羰基、氨基羰基、氰基或者饱和或不饱和的杂环,R1中的氨基、羟基和氨基羰基的各个氢可被下列基团取代:烷基、环烷基、芳基、芳烷基、酰基、烷氧羰基、环烷氧基羰基、芳基烷氧羰基、不饱和杂环、或者被不饱和杂环取代的烷基,
R2:烷基、链烯基、环烷基、环烷基烷基或芳基烷基,
R3:吡啶环,
R4:氢、烷基、金刚烷基烷基、羧基烷基、烷氧羰基烷基、氨基、烷基氨基、酰基氨基或烷氧羰基氨基,
R5和R6:相同或不同,为氢或烷基,
R7:氢或烷基,
X:O或S,
n:1-5的整数。
其中通式[1]定义的各基团是下列基团的化合物或其盐是这些化合物中更优选的。
A:-(NR4)-或-(CR5R6);
B:亚烷基或亚链烯基,
R1:烷基或链烯基,其中烷基可被卤素、氨基、环烷基、芳基、咪唑基或吡啶环取代,并且氨基进一步可被烷基、酰基、烷氧羰基、环烷氧基羰基或芳基烷氧羰基取代,
R2:烷基、链烯基或芳基烷基,
R3:吡啶环,
R4:氢,
R5和R6:氢,
X:O。
其中R1是具有三个或三个以上碳原子的烷基、R2是烷基或芳烷基的化合物或其盐是这些化合物中特别优选的。
其中通式[1]定义的各基团是下列基团的化合物或其盐是更优选的。
A:-(NR4)-或-(CR5R6);
B:亚烷基或亚链烯基,
R1:烷基、链烯基或环烷基,其中烷基可被下列基团取代:卤素、羟基、氨基、环烷基、芳基、羧基、烷氧羰基、芳氧羰基、氨基羰基、吡啶环或噻吩环,R1中的氨基、羟基和氨基羰基的各个氢可进一步被烷基、芳基、芳烷基、酰基、烷氧羰基、环烷氧基羰基或芳基烷氧羰基取代,
R2:环烷基或环烷基烷基,
R3:吡啶环,
R4:氢,
R5和R6:氢,
X:O。
最优选的本发明化合物的具体实例是下列化合物或其盐。
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]-1-(3,3,3-三氟丙基)脲
·1-[2-(1-金刚烷基)乙基]-1-(2-丁烯基)-3-[3-(4-吡啶基)丙基]脲
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲
·1-[3-(1-金刚烷基)丙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲
·(Z)-1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)-2-丙烯基]脲
·(-)-1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲
·1-[2-(1-金刚烷基)乙基]-3-[1-甲基-3-(4-吡啶基)丙基]-1-戊基脲
·(+)-1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[2-甲基-3-(4-吡啶基)丙基]脲
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺
·3-(4-吡啶基甲硫基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺
·2-[2-(4-吡啶基)乙硫基]乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺
·6-(4-吡啶基)己酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺
·顺-1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(4-吡啶基)环丙基甲基]脲
·1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[2-甲基-3-(4-吡啶基)丙基]脲
·(E)-1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)-2-丙烯基]脲
·(+)-1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲
·1,1-二丁基-3-[3-(4-吡啶基)丙基]脲
·3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基-1-苯乙基脲
·5-(4-吡啶基)戊酸N-戊基-N-苯乙基酰胺
·1-(2-环己基乙基)-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲
本发明化合物可以例如按照下面的反应途径1-3制备。本发明化合物不仅可通过这些途径制备,也可通过不同的反应途径制备。后面的实施例中将描述详细的合成方法。
反应途径1
仲胺(D)可通过还原酰胺(A)或者将伯胺(B)与具有离去基团的化合物(C)反应获得。(该仲胺也可使用上述化学反应式中R1和R2互换的化合物来合成)。类似地,仲胺(G)可通过将具有离去基团的化合物(E)与伯胺(F)反应获得。可按如下获得本发明化合物[2]:在缩合试剂(H)(例如1,1′-羰基二咪唑)的存在下,将伯胺(B)或仲胺(D)与伯胺(F)或仲胺(G)反应。
反应途径2
按如下获得本发明化合物[3]:在缩合试剂(例如,1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐)的存在下,将伯胺(B)或通过反应途径1合成的仲胺(D)与羧酸(I)反应。
反应途径3
按如下获得本发明化合物[4]:在缩合试剂(例如,N,N′-二琥珀酰亚氨基碳酸酯)的存在下,将伯胺(B)或通过反应途径1合成的仲胺(D)与醇(J)反应。
在上述合成方法中,当反应物的分子中具有巯基、羟基或氨基时,如果需要,这些基团可以使用适宜的保护基保护,并且反应后,这些保护基也可通过常规方法除去。当反应物的分子中具有羧基时,如果需要,羧基可被酯化,并且该酯也可通过水解或其它一般方法转化为羧酸。
可采用常规方法将通过上述合成方法获得的化合物转化为上述的盐。
为研究通过上述合成方法获得的本发明化合物的功效,测定对TNF-α生成的抑制作用。下面的“药理学试验”部分将描述细节。对通过脂多糖(LPS)刺激引起的TNF-α释放的体内抑制作用的研究中,本发明化合物表现出出色的TNF-α生成抑制作用。
已知TNF-α的生成与自身免疫疾病如类风湿性关节炎、克隆病和系统性红斑狼疮、恶病质、急性感染性疾病、变态反应、发热、贫血、糖尿病等的发病机理密切相关。预期抑制TNF-α生成的化合物,如本发明化合物,可用于治疗各种这类疾病。
本发明提供抑制TNF-α生成的方法、治疗自身免疫疾病的方法和治疗风湿病的方法,这些方法包括给患者施用包含有效量的本发明化合物或其可药用盐和可药用添加剂的组合物。
本发明化合物可经口服或胃肠外给药。剂型的实例是片剂、胶囊、颗粒剂、粉剂、注射剂等。本发明化合物可通过常规方法配制成制剂。例如,口服制剂如片剂、胶囊、颗粒剂和粉剂可如下制备:可任选地加入稀释剂,如乳糖、结晶纤维素、淀粉或植物油;润滑剂,如硬脂酸镁或滑石;粘合剂,如羟丙基纤维素或聚乙烯吡咯烷酮;崩解剂,如羧甲基纤维素钙或低取代的羟丙基甲基纤维素;包衣试剂如羟丙基甲基纤维素、大粒凝胶或硅氧烷树脂;或者成膜剂如明胶膜。
可根据症状、年龄、剂型等适当选择本发明化合物的剂量。在口服制剂的情况下,本发明化合物可每日服用一次至数次,每日剂量为0.1-5000mg,优选为1-1000mg。
下面是中间体的制备实施例、本发明化合物的制备和制剂实施例及药理学试验结果。这些实施例不是用于限制本发明的范围,而是用于更清楚地理解本发明。
本发明的最佳实施方式
[A]中间体的制备
制备实施例1
·2-(1-金刚烷基)-N-戊基乙胺盐酸盐(中间体1-1)
将戊胺(2.69ml,23.2mmol)、碳酸钾(2.14g,15.5mmol)和碘化钠(2.30g,15.3mmol)加到甲磺酸2-(1-金刚烷基)乙基酯(2.07g,8.01mmol)的乙醇(45.8ml)溶液中,并使该混合物回流17小时。减压下浓缩该反应混合物,并将该浓缩物用氯仿(100ml)稀释。该稀释液用1N氢氧化钠水溶液(100ml)和饱和氯化钠水溶液(100ml)顺序洗涤,有机层用硫酸镁干燥。减压下蒸发溶剂,残余物经硅胶柱色谱纯化。将4N氯化氢的乙酸乙酯溶液(3.1ml)加到所得的游离形式的标题化合物(1.52g,6.10mmol)在乙酸乙酯(0.50ml)中的溶液中。沉淀的固体用乙酸乙酯洗涤并过滤,得到1.33g(60%)标题化合物。
IR(KBr):2924,2850,2519,1456cm-1
mp:263.0-264.5℃
采用类似于制备实施例1的方法,获得下列化合物。标题化合物有时不以盐酸盐形式分离。
·N′-[2-(1-金刚烷基)乙基]-N-(苄氧羰基)-N-甲基乙二胺(中间体1-2)
IR(neat):2901,2844,1704cm-1
·2-(1-金刚烷基)-N-(环戊基甲基)乙胺盐酸盐(中间体1-3)
IR(KBr):2907,2847,1452cm-1
mp:300.0-310.0℃
·N′-[2-(1-金刚烷基)乙基]-N-(叔丁氧羰基)-N-甲基乙二胺(中间体1-4)
IR(neat):3307,2902,2846,1698cm-1
·2,2′-二(1-金刚烷基)二乙基胺盐酸盐(中间体1-5)
IR(KBr):2900,2845,2735,2453cm-1
mp:325℃
·2-(1-金刚烷基)-N-丙基乙胺(中间体1-6)
IR(neat):3276,2903,2846,1450cm-1
·N′-[2-(1-金刚烷基)乙基]-N,N-二甲基乙二胺二盐酸盐(中间体1-7)
IR(KBr):3424,2901,2846,2445cm-1
mp:254.5-259.0℃
·2-(1-金刚烷基)-N-环戊基乙胺盐酸盐(中间体1-8)
IR(KBr):2910,2846,2771,2450cm-1
mp:300-312℃
·2-(1-金刚烷基)-N-环丙基乙胺(中间体1-9)
IR(neat):3272,2901,2845cm-1
·2-(1-金刚烷基)-N-(2-甲氧基乙基)乙胺盐酸盐(中间体1-10)
IR(KBr):2909,2846,2792,1451cm-1
mp:278.5-281.5℃
·(1-金刚烷基)-N-(2-丙炔基)乙胺(中间体1-11)
IR(neat):2900,2845,1450cm-1
·N-戊基-2-(2-吡啶基)乙胺(中间体1-12)
IR(neat):3305,2927,2857,1591cm-1
·2-(1-金刚烷基)-N-苄基乙胺盐酸盐(中间体1-13)
IR(KBr):2900,2846,2750,2528,2468,2372,1585cm-1
mp:264.0-265.0℃
·2-(1-金刚烷基)-N-呋喃甲基乙胺盐酸盐(中间体1-14)
IR(KBr):3456,2903,2846,2741,2426cm-1
mp:225.0-233.0℃
·2-(1-金刚烷基)-N-丁基乙胺(中间体1-15)
IR(neat):2903,1683,1450cm-1
·2-环己基-N-(2-噻吩基)甲基乙胺盐酸盐(中间体1-16)
·N-戊基苯乙胺盐酸盐(中间体1-17)
IR(KBr):3028,2957,2786,1456cm-1
mp:260.0-285.0℃
·2-环己基-N-丁基乙胺盐酸盐(中间体1-18)
IR(KBr):2921,2853,2794,2739,2442,1590,1484,1451cm-1
mp:250℃或更高
·2-环己基-N-戊基乙胺盐酸盐(中间体1-19)
IR(KBr):2924,2793,1451cm-1
mp:250℃或更高
·N-(叔丁氧羰基)-N′-(2-环己基乙基)-N-甲基乙二胺(中间体1-20)
IR(neat):3350,2923,2850,1697,1481,1449cm-1
·N′-(2-环己基乙基)-N,N-二甲基乙二胺(中间体1-21)
IR(neat):3310,2921,2850,2815,1448cm-1
·N-[2-(1-金刚烷基)乙基]-3-(4-吡啶基)丙胺(中间体1-22)
IR(neat):3291,2902,2845,1602,1450cm-1
·2-(1-金刚烷基)-N-异丙基乙胺盐酸盐(中间体1-23)
IR(KBr):2909,2846,2754,2464,1588,1476,1451cm-1
mp:266.0-269.5℃
·N-(2-哌啶子基乙基)戊胺(中间体1-24)
IR(neat):2932,2854,1466cm-1
·2-(1-金刚烷基)-N-[(2-甲基噻唑-4-基)甲基]乙胺(中间体1-25)
IR(neat):2901,2844,1449cm-1
·N-[2-(1-金刚烷基)乙基]肉桂胺(中间体1-26)
IR(neat):2901,2845,1449cm-1
·N-[2-(1-金刚烷基)乙基]-2-甲基-2-丙烯基胺(中间体1-27)
IR(neat):2902,2845,1450cm-1
·N-[2-(1-金刚烷基)乙基]-3-甲基-2-丁烯基胺(中间体1-28)
IR(neat):2903,2846,1450cm-1
·N-[2-(1-金刚烷基)乙基]癸胺盐酸盐(中间体1-29)
IR(KBr):2926,2849,2778,2469cm-1
mp:204.0-208.5℃
·N-[2-(1-金刚烷基)乙基]己胺盐酸盐(中间体1-30)
IR(KBr):2909,2848,2766,2446cm-1
mp:230.0-243.0℃
·2-(1-金刚烷基)-N-(苄氧基)乙胺(中间体1-31)
IR(neat):2901,2846,1452cm-1
·2-(1-金刚烷基)-N-[(2-噻吩基)甲基]乙胺盐酸盐(中间体1-32)
IR(KBr):2908,2846,2757,2426cm-1
mp:257.0-260.0℃
·N-[2-(1-金刚烷基)乙基]-2-丁烯基胺(中间体1-33)
IR(neat):2901,1450cm-1
·N-[2-(1-金刚烷基)乙基]烯丙基胺(中间体1-34)
IR(neat):2902,1450cm-1
·N-[2-(1-金刚烷基)乙基]环丙基甲胺(中间体1-35)
IR(neat):2901,1450cm-1
·N-[2-(1-金刚烷基)乙基]-3,3,3-三氟丙胺盐酸盐(中间体1-36)
IR(KBr):2910,2849,2767,2598,2457cm-1
mp:300.0-310.0℃
·1-[2-(1-金刚烷基)乙基]-2-(叔丁氧羰基)肼(中间体1-37)
IR(KBr):3288,2899,1705cm-1
mp:73.5-81.0℃
·N-(叔丁氧羰基)-N-甲基-N′-苯乙基乙二胺(中间体1-38)
IR(neat):3326,3025,2975,2930,1694,1454cm-1
·N-(叔丁氧羰基)-N-甲基-N′-戊基乙二胺(中间体1-39)
IR(neat):2958,2929,1694,1457cm-1
·N-(苄氧羰基)-N-甲基-N′-苯乙基乙二胺(中间体1-40)
IR(neat):3309,3027,2936,2824,1698,1454cm-1
·N-(苄氧羰基)-N-甲基-N′-戊基乙二胺(中间体1-41)
IR(neat):2928,2858,1703,1455cm-1
·2-环己基-N-(2-甲氧基乙基)乙胺盐酸盐(中间体1-42)
IR(KBr):2923,2855,2784,2478,2444cm-1
mp:205.0-208.0℃
·N-乙基-3,4,5-三甲氧基苯乙胺(中间体1-43)
IR(neat):3300,2936,2828,1588,1508,1457,1419,1331,1236,1126,1008cm-1
·5-[2-(异戊基氨基)乙基]咪唑二盐酸盐(中间体1-44)
IR(KBr):2806,2467,1619,1604,1446,1347,1089,914,827,735,627,622cm-1
mp:235.2-238.0℃
·N-环己基-3,4-二甲氧基苯乙胺(中间体1-45)
IR(neat):2928,2852,1591,1515,1463,1449,1416,1261,1236,1155,1139,1029,802,761cm-1
bp:170℃/210Pa
·N-环丙基-3,4,5-三甲氧基苯乙胺(中间体1-46)
IR(neat):3304,2932,2832,1588,1505,1459,1418,1332,1236,1126,1009cm-1
·N′-[2-(1-金刚烷基)乙基]-N-(叔丁氧羰基)-N-甲基-1,3-丙二胺(中间体1-47)
IR(neat):3308,2902,2845,1698,1480cm-1
·N-环己基(苯基)甲基-3-(4-甲氧基苯基)丙胺盐酸盐(中间体1-48)
IR(KBr):2928,2857,2765,1592,1510,1455,1230,1064,1033,817cm-1
mp:187.5-189.5℃
·N-二苯基甲基-3-苯基丙胺(中间体1-49)
IR(neat):3024,2931,1601,1493,1452cm-1
·N-戊基-3-苯基丙胺盐酸盐(中间体1-50)
IR(KBr):3027,2955,2870,2780,2492,2413cm-1
mp:230.0-238.0℃
·N-乙酰基-N′-[2-(1-金刚烷基)乙基]乙二胺盐酸盐(中间体1-51)
IR(KBr):2897,2845,2361,1826,1707,1567m-1
mp:245.0-247.0℃
·N-异戊基-3,3,3-三氟丙胺盐酸盐(中间体1-52)
IR(KBr):2961,2800,1253,1173m-1
mp:288℃或更高
·N-[2-(1-金刚烷基)乙基]-2,2,2-三氟乙胺盐酸盐(中间体1-53)
IR(KBr):2904,2849,1273,1233,1176,1145m-1
mp:263.0-265.0℃
·3-环己基-N-丙基丙胺盐酸盐(中间体1-54)
IR(KBr):2924,2854,2779m-1
mp:234.6-235.4℃
·N′-[3-(1-金刚烷基)丙基]-N-(叔丁氧羰基)-N-甲基乙二胺(中间体1-55)
1H-NMR(400MHz,CDCl3)δ0.99-1.10(m,2H),1.32-1.52(m,17H),1.55-1.65(m,4H),1.70(d,J=11.8Hz,3H),1.93(s,3H),2.58(t,J=7.2Hz,2H),2.77(br,2H),2.91(s,3H),3.33(br,2H)
制备实施例2
·4-(3-氨基丙基)吡啶(中间体2-1)
将N-[3-(4-吡啶基)丙基]邻苯二甲酰亚胺(67.1g,252mmol)与甲醇(504ml)和一水合肼(18.3ml,378mmol)混合,并将该混合物回流3小时。将反应混合物放置后,滤除不溶物,减压浓缩滤液。往残余物中加入氯仿(1升)和4N氢氧化钠水溶液(500ml),分层,有机层经硫酸钠干燥。将有机层减压浓缩,然后减压蒸馏,得到20.5g(60%)无色油状的标题化合物。
IR(neat):3362,2933,1603cm-1
bp:76.0-79.0℃/40Pa
采用类似于制备实施例2的方法获得下列化合物。
·3-(4-吡啶基)-2-丙烯基胺(中间体2-2)
IR(neat):3280,3024,1599cm-1
·2-(4-吡啶氧基)乙胺(中间体2-3)
IR(KBr):3298,3102,1610,1216,1049cm-1
mp:108.0-111.5℃
·3-(4-喹啉基)-2-丙烯基胺(中间体2-4)
IR(neat):3270,2944,1585,1568,1508cm-1
制备实施例3
·2-(1-金刚烷基)-N-甲基乙胺(中间体3-1)
在冰冷却5分钟后,将1-金刚烷乙酸N-甲基酰胺(1.54g,7.45mmol)的四氢呋喃(15.0ml)溶液滴加到氢化铝锂(569mg,15.0mmol)的乙醚(34.0ml)溶液中。将该化合物回流6小时后,再在冰冷却下搅拌。往反应混合物中加入乙酸乙酯以处理过量的氢化铝锂,然后该混合物用1N盐酸(50ml)萃取两次。往萃取液中加入4N氢氧化钠水溶液,使其碱化,再用乙醚(80ml)萃取。有机层用饱和氯化钠水溶液(60ml)洗涤并经硫酸镁干燥。减压蒸发溶剂,得到890mg(66%)标题化合物。
IR(neat):2902,2845,1449cm-1
采用类似于制备实施例3的方法获得下列化合物。也可使用4N氯化氢的乙酸乙酯溶液将化合物转化为相应的盐酸盐。
·2-(1-金刚烷基)-N-乙基乙胺盐酸盐(中间体3-2)
IR(KBr):2896,2847,2753,2468,1610cm-1
mp:230-245℃
·N-甲基-3-(4-吡啶基)丙胺(中间体3-3)
IR(neat):3292,2934,1602cm-1
·1-金刚烷基-N-丙基甲胺盐酸盐(中间体3-4)
IR(KBr):2905,1584,1451cm-1
mp:340℃
·2-(1-金刚烷基)-N-甲基乙胺盐酸盐(中间体3-5)
IR(KBr):3422,2900,2846,2676,2450,1630cm-1
mp:200-220℃
·3-(1-金刚烷基)-N-丙基丙胺盐酸盐(中间体3-6)
IR(KBr):2899,2467,1449cm-1
mp:159.5-162.0℃
·1-金刚烷基-N-戊基甲胺盐酸盐(中间体3-7)
IR(KBr):2916,2603,2509,2418,1477cm-1
mp:170-235℃
·N-[3-(1-金刚烷基)丙基]戊胺盐酸盐(中间体3-8)
IR(KBr):2901,2847,1466,1453cm-1
mp:199-224℃
·N-[2-(1-金刚烷基)乙基]-4,4,4-三氟丁胺盐酸盐(中间体3-9)
IR(KBr):3422,2908,2852,2770,2518,1452,1255,1148cm-1
mp:243-274℃
·N-[2-(1-金刚烷基)乙基]-5,5,5-三氟戊胺(中间体3-10)
IR(neat):2903,2846,1450,1255,1142cm-1
·N-[3-(1-金刚烷基)丙基]丁胺盐酸盐(中间体3-11)
IR(KBr):2904,2847,2756,1453cm-1
mp:275.0-276.8℃
·3-(1-金刚烷基)-N-(2,2,2-三氟乙基)丙胺盐酸盐(中间体3-12)
IR(KBr):2902,2850,2739,1274,1258,1176,1139cm-1
mp:262.0-268.0℃
·4-(1-金刚烷基)-N-乙基丁胺盐酸盐(中间体3-13)
IR(KBr):2901,2847,2457,1451cm-1
mp:224-230℃
·4-(1-金刚烷基)-N-丙基丁胺盐酸盐(中间体3-14)
IR(KBr):2899,2848,2751,2410,1451cm-1
mp:234-249℃
·N-(1-金刚烷基)-N′-丙基乙二胺二盐酸盐(中间体3-15)
IR(KBr):2927,2719,2508,2429,1471cm-1
mp:288.5-289.5℃
制备实施例4
·3-[N-[2-(1-金刚烷基)乙基]氨基]丙酸叔丁基酯盐酸盐(中间体4-1)
将2-(1-金刚烷基)乙胺盐酸盐(1.0g,4.6mmol)溶于乙醇(10ml),并在冰冷却下加入三乙胺(0.65ml,4.6mmol)和丙烯酸叔丁基酯(0.75ml,5.1mmol)。然后,使温度升至室温,并将该混合物搅拌过夜。将反应混合物减压浓缩,往残余物中加入1N氢氧化钠水溶液(30ml)和乙酸乙酯(50ml),并分层。乙酸乙酯层顺序用水(50ml)和饱和氯化钠溶液(50ml)洗涤并经无水硫酸镁干燥。将乙酸乙酯层减压浓缩,浓缩物经硅胶柱色谱纯化。将所得油状物(0.50g,1.6mmol)溶于乙醚(20ml),并往其中加入4N氯化氢的乙酸乙酯溶液(1.0ml,4.0mmol),沉淀出固体。滤出该固体,用乙醚洗涤,得到0.33g(23%)标题化合物。
IR(KBr):2902,2846,1733,1166cm-1
mp:210℃
采用类似于制备实施例4的方法获得下列化合物。标题混合物有时不是以盐酸盐的形式分离。
·3-[N-(2-环己基乙基)氨基]丙酸甲酯盐酸盐(中间体4-2)
IR(KBr):2924,2853,2792,1736,1455,1439cm-1
mp:185.0-187.5℃
·3-[N-(2-环己基乙基)氨基]丙酸叔丁基酯(中间体4-3)
IR(neat):2977,2922,2850,1728,1449cm-1
·3-[N-[3-(4-吡啶基)丙基]氨基]丙酸叔丁基酯盐酸盐(中间体4-4)
IR(neat):3322,2977,2933,1724,1602,1367,1153cm-1
制备实施例5
·5-(4-吡啶基)戊酸(中间体5-1)
将N,N-二甲基甲酰胺(17ml)加到(苄氧羰基甲基)三苯基溴化膦鎓(4.60g,9.36mmol)和β-(4-吡啶基)丙烯醛草酸盐(1.90g,8.51mmol)的混合物中,并将该混合物在冰冷却下搅拌。往其中加入碳酸钾(4.70g,34.0mmol),并使温度升至室温。将该混合物搅拌过夜,然后用乙酸乙酯(100ml)稀释并用水(100ml)洗涤两次,再用饱和盐水(50ml)洗涤。有机层经硫酸钠干燥,并减压蒸发乙酸乙酯。残余物经硅胶柱色谱纯化,得到2.29g(定量)浅黄色油状物的5-(4-吡啶基)戊酸-2,4-二烯苄基酯。
然后,将甲醇(42ml)和乙酸(1.0ml,18mmol)加到5-(4-吡啶基)戊酸-2,4-二烯苄基酯(2.25g,8.48mmol)中,并往该混合物中吹入10分钟氮气。将催化量的氢氧化钯碳加到该混合物中,并将其在氢气氛和室温下搅拌过夜。通过硅藻土过滤滤除不溶性物质,并减压浓缩滤液。将乙酸乙酯(50ml)加到固化的残余物中,并将该混合物在室温搅拌3小时。滤出结晶,得到1.00g(66%)浅黄色结晶的标题化合物。
IR(KBr):2943,1719,1636,1605cm-1
mp:155.0-180.0℃。
制备实施例6
·3-[N-(2-环己基乙基)氨基]丙酰胺盐酸盐(中间体6-1)
在冰冷却条件下,将三氟乙酸(6ml)加到3-[N-(2-环己基乙基)氨基]丙酸叔丁酯(中间体4-3,2.0g,7.8mmol)中。将该混合物搅拌过夜,然后减压浓缩。将4N氯化氢的乙酸乙酯溶液加到该残余物中,并将其减压浓缩,然后用乙醚滤出所得结晶,得到1.5g(96%)3-[N-(2-环己基乙基)氨基]丙酸盐酸盐。
然后,将四氢呋喃(8ml)加到3-[N-(2-环己基乙基)氨基]丙酸盐酸盐(1.0g,4.2mmol)中,并在室温下搅拌该混合物。将碳酸二叔丁基酯(1.1g,5.1mmol)和三乙胺(1.3ml,9.3mmol)加到该混合物中,并搅拌过夜,然后将5%柠檬酸水溶液(10ml)加到该反应混合物中。将其用氯仿(60ml)萃取,有机层用饱和盐水(20ml)洗涤。有机层经硫酸镁干燥并减压浓缩。残余物经硅胶柱色谱纯化,得到0.79g(62%)无色油状的3-[N-(叔丁氧羰基)-N-(2-环己基乙基)氨基]丙酸。
然后,将无水四氢呋喃(7ml)加到3-[N-(叔丁氧羰基)-N-(2-环己基乙基)氨基]丙酸(0.59g,2.0mmol)中,并在-78℃下搅拌该混合物。将N-甲基吗啉(0.22ml,2.0mmol),然后将氯代甲酸异丁基酯(0.38ml,2.9mmol)的四氢呋喃(3ml)溶液加到该混合物中。1小时后,往其中加入28%的氨水溶液(6.0ml,9.8mmol),并将其搅拌1.5小时。将氯仿(50ml)加到反应混合物中,使温度升至室温,将该混合物顺序用饱和碳酸氢钠水溶液(20ml)和饱和盐水(20ml)洗涤。有机层经硫酸镁干燥并减压浓缩,残余物经硅胶柱色谱纯化,得到0.34g(58%)无色结晶的3-[N-(叔丁氧羰基)-N-(2-环己基乙基)氨基]丙酰胺。
然后,将4N氯化氢的1,4-二噁烷(3.1ml)溶液加到3-[N-(叔丁氧羰基)-N-(2-环己基乙基)氨基]丙酰胺(0.37g,1.2mmol)中,并将该混合物在室温搅拌过夜。减压浓缩该反应混合物,并往所得固体中加入二异丙基醚,滤出固体,得到0.30g(定量)的无色结晶的标题化合物。
IR(KBr):3386,3196,2921,2852,2808,1705,1656,1452cm-1
mp:165.0℃
制备实施例7
·二-5-己烯基胺(中间体7-1)
将N,N-二甲基甲酰胺(28ml)加到3-氨基丙腈(0.98g,14mmol)中,并在室温下搅拌该混合物。将6-溴-1-己烯(5.0g,31mmol)、碘化钠(11g,73mmol)和碳酸钾(5.8g,42mmol)加到该混合物中,并将其搅拌过夜。该反应混合物用乙醚(100ml)稀释,并将其用水(100ml,两次)和饱和盐水(50ml)顺序洗涤。有机层经硫酸镁干燥并减压浓缩。残余物经硅胶柱色谱纯化,得到2.2g(66%)无色油状的3-(二-5-己烯基)氨基丙腈。
然后,将乙醇(8.6ml)和氢氧化钾(0.85g,13mmol)加到3-(二-5-己烯基)氨基丙腈(2.0g,8.6mmol)中,并使该混合物回流7.5小时。将反应混合物放置,然后往其中加入水(150ml)和氯仿(150ml)。分层,有机层经硫酸钠干燥并减压浓缩,残余物经硅胶柱色谱纯化,得到0.32g(21%)浅黄色油状的标题化合物。
IR(neat):3076,2976,2928,2856,1679,1640cm-1
采用类似于制备实施例7的方法,获得下面的化合物。
·二-7-辛烯基胺(中间体7-2)
IR(neat):3075,2976,2926,2854,1640cm-1
制备实施例8
·N-[2-(1-金刚烷基)乙基]丙胺盐酸盐(中间体8-1)
将2-(丙基氨基)乙醇(2.4g,23mmol)与1-溴金刚烷(0.50g,2.3mmol)和三乙胺(0.32ml,2.3mmol)混合,并在100℃的外部温度下将该混合物搅拌2小时,在130℃的外部温度下搅拌5小时并在150℃的外部温度下搅拌3小时。将该反应混合物放置,然后将乙酸乙酯(50ml)加到该反应混合物中,将其顺序用水(50ml)洗涤两次,用盐水(30ml)洗涤一次。有机层经硫酸钠干燥并减压浓缩。残余物经硅胶柱色谱纯化,将4N氯化氢的乙酸乙酯溶液(2ml)加到分离的物质中,并减压浓缩。用乙酸乙酯滤出所得结晶,得到0.16g(25%)无色结晶的标题化合物。
IR(KBr):3544,2907,2502,1584cm-1
mp:232.0-232.7℃
制备实施例9
·2-丙基氨基乙酸N-(1-金刚烷基)酰胺(中间体9-1)
将乙醇(36ml)加到溴乙酸(5.00g,36.0mmol)中,并在冰冷的水冷却下搅拌该混合物。用1分钟将丙胺(14.8ml,180mmol)加到该混合物中,然后在80℃的外部温度下将其搅拌2.5小时。往其中加入4N氢氧化钠水溶液(27ml),并减压浓缩。然后将水(27ml)和四氢呋喃(30ml)加到该浓缩物中,并在室温搅拌该混合物。将碳酸二叔丁基酯(9.43g,43.2mmol)的四氢呋喃(6ml)溶液加到该混合物中,并在15分钟后,将一水合柠檬酸加到该反应混合物中,使其微弱酸化。将其用乙酸乙酯(150ml)萃取,有机层顺序用水(100ml)和饱和盐水(50ml)洗涤。有机层经硫酸钠干燥并减压浓缩。残余物经硅胶柱色谱纯化,得到5.06g(65%)无色固体的2-[N-(叔丁氧羰基)-N-丙基氨基]乙酸。
然后,将二氯甲烷(208ml)加到2-[N-(叔丁氧羰基)-N-丙基氨基]乙酸(4.52g,20.8mmol)和1-金刚烷胺(3.46g,22.9mmol)的混合物中,并在室温搅拌该混合物。往其中加入N,N-二异丙基乙基胺(7.25ml,41.6mmol),然后加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(8.71g,22.9mmol),并将其搅拌过夜。将反应混合物减压浓缩,残余物经硅胶柱色谱纯化,得到无色油状的7.88g(定量)2-[N′-(叔丁氧羰基)-N′-丙基氨基]乙酸N(1-金刚烷基)酰胺。所得油状物在室温下固化。
然后,将4N氯化氢的乙酸乙酯溶液(55ml,0.22mol)加到2-[N′-(叔丁氧羰基)-N′-丙基氨基]乙酸N-(1-金刚烷基)酰胺(7.68g,21.9mmol)中,并将该混合物在室温搅拌1小时。所得结晶用乙酸乙酯滤出并用乙酸乙酯洗涤,得到5.97g(95%)无色结晶的标题化合物。
IR(KBr):3272,2906,2848,2589,1676,1562cm-1
mp:278.0-279.2℃
制备实施例10
·N-(叔丁氧羰基)-2-(4-吡啶氧基)乙胺(中间体10-1)
在冰冷却下,将二碳酸二叔丁基酯(380mg,1.74mmol)和三乙胺(240μl,1.74mmol)加到中间体2-4(200mg,1.45mmol)的四氢呋喃(5ml)溶液中,使温度升至室温,并将该混合物搅拌25分钟。从反应混合物中减压蒸发溶剂,将残余物分配到乙酸乙酯(50ml)和饱和碳酸氢钠水溶液(50ml)中。水层进一步用氯仿(50ml)萃取,合并的有机层经无水硫酸镁干燥。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到70mg(20.2%)标题化合物。
IR(neat):3230,2976,1706,1596cm-1
制备实施例11
·(RS)-2-甲基-3-(4-吡啶基)丙胺(中间体11-1)
在氮气氛下,将N,N-二甲基甲酰胺(143ml)加到氢化钠(5.36g,134mmol)中,并将该混合物在冰冷却下搅拌。用5分钟时间,将甲基丙二酸二乙酯(11.7g,67.1mmol)的N,N-二甲基甲酰胺(40ml)溶液滴加到该混合物中,10分钟后,在5分钟时间内往其中逐渐加入4-氯甲基吡啶(4-chloropicolyl)盐酸盐(10.0g,61.0mmol),并使温度升至室温。1小时后,往该反应混合物中加入饱和碳酸氢钠水溶液(500ml),将其用乙醚(400ml)萃取。有机层顺序用水(100ml)和饱和盐水(50ml)洗涤并经硫酸镁干燥。将有机层减压浓缩,得到17.2g(定量的,包含氢化钠油)棕色油状的2-甲基-2-(4-吡啶基甲基)丙二酸二乙酯。
然后,将6N盐酸(96.8ml,581mmol)2-甲基-2-(4-吡啶基甲基)丙二酸二乙酯(17.2g,64.6mmol)中并将该混合物回流过夜。将该反应混合物放置,然后用己烷(100ml)洗涤除去2-甲基-2-(4-吡啶基甲基)丙二酸二乙酯中含有的氢化钠油,并减压浓缩。用乙酸乙酯滤出所得结晶,得到10.7g(82%)浅粉色结晶的2-甲基-3-(4-吡啶基)丙酸。
然后,将氯仿(8ml)、亚硫酰氯(2.2ml,30.6mmol)和N,N-二甲基甲酰胺(1滴)加到2-甲基-3-(4-吡啶基)丙酸(1.69g,10.2mmol)中,并将该混合物搅拌回流1小时。减压浓缩反应混合物,将氯仿(8ml)加到该浓缩物中,并在冰冷却下,将该混合物缓慢滴加到搅拌的28%氨水溶液中。10分钟后,使温度升至室温,并将其搅拌过夜。将反应混合物减压浓缩,将乙酸乙酯(100ml)加到该浓缩物中,滤除所得不溶性物质。减压浓缩滤液,残余物经硅胶柱色谱纯化,用乙醚滤出所得结晶,得到0.72g(43%)浅黄色结晶的2-甲基-3-(4-吡啶基)丙酰胺。
然后,在氮气氛下,将无水乙醚(20ml)加到氢化铝锂(0.45g,12mmol)中,并在冰冷却下搅拌该混合物。在5分钟内,将2-甲基-3-(4-吡啶基)丙酰胺(0.68g,4.1mmol)的无水二氯甲烷(20ml)溶液滴加到该混合物中,使温度升至室温,并将其搅拌过夜。将反应混合物再次用冰冷却,往其中缓慢加入乙酸乙酯(5ml),然后加入1N氢氧化钠水溶液(总计100ml),开始时缓慢加入。将其用氯仿(100ml)萃取,有机层经硫酸钠干燥并减压浓缩,得到0.56g(90%)浅黄色油状的标题化合物。
IR(neat):3293,2957,2925,1602cm-1
采用类似于制备实施例11的方法,得到下列化合物。可使用旋光活性酸通过光学拆分获得旋光活性物质。
·2-(4-吡啶基甲基)丁胺(中间体11-2)
IR(neat):3296,3025,2960,2874,1602cm-1
·2-苄基-3-(4-吡啶基)丙胺(中间体11-3)
IR(neat):3296,3062,3025,1602cm-1
·2,2-二(4-吡啶基甲基)乙胺(中间体11-4)
IR(neat):3290,3026,2924,1602,1557cm-1
·(-)-2-甲基-3-(4-吡啶基)丙胺(中间体11-5)
IR(neat):3362,3301,2958,1603cm-1
[α]20 D:-10.6°(MeOH,C 1.0)
·(+)-2-甲基-3-(4-吡啶基)丙胺(中间体11-6)
IR(neat):3362,3296,2958,1603cm-1
[α]20 D:+9.9°(MeOH,C 1.0)
制备实施例12
·3-(4-喹啉基)丙胺(中间体12-1)
在氮气氛下和室温下,将催化量的10%钯碳加到制备实施例2中获得的3-(4-喹啉基)-2-丙烯基胺(中间体2-4)(188mg,1.02mmol)的甲醇(3ml)溶液中,并将该混合物在氢气氛下搅拌过夜。使反应混合物通过硅藻土过滤,减压蒸发溶剂,并将所得残余物分配到乙酸乙酯(30ml)和饱和氯化铵水溶液(30ml)中。将4N氢氧化钠水溶液(30ml)加到水层中,用氯仿(100ml)萃取,所得的有机层经无水硫酸镁干燥。减压蒸发溶剂,得到145mg(76.3%)标题化合物。
IR(neat):3350,2938,1591,1510cm-1
制备实施例13
·3-(4-吡啶基)丁胺(中间体13-1)
将N,N-二甲基甲酰胺(33ml)加到4-乙酰基吡啶(2.00g,16.5mmol)和(苄氧羰基)甲基三苯基溴化膦鎓(8.94g,18.2mmol)中并在冰冷却下搅拌。往其中加入碳酸钾(9.12g,66.0mmol),使外部温度升至70℃,并将其搅拌过夜。该反应化合物用乙醚(100ml)稀释,并顺序用盐水(100ml,两次)和饱和盐水(50ml)洗涤。有机层经硫酸镁干燥并减压浓缩。残余物经硅胶柱色谱纯化,得到1.77g(42%:E和Z形式的混合物)浅黄色油状的3-(4-吡啶基)-2-丁烯酸苄基酯。
然后,将甲醇(31ml)和乙酸(0.71ml,12.4mmol)加到3-(4-吡啶基)-2-丁烯酸苄基酯(1.75g,6.20mmol)中,并在室温下往其中通入10分钟氮气。将催化量的10%钯碳加到该混合物中,并在氢气氛和室温下将其搅拌过夜。滤除不溶性物质,减压浓缩滤液。用丙酮滤出所得结晶,得到0.61g(60%)浅黄色结晶3-(4-吡啶基)丁酸。
然后,将氯仿(5ml)、亚硫酰氯(0.80ml,11mmol)和N,N-二甲基甲酰胺(1滴)加到3-(4-吡啶基)丁酸(0.60g,3.6mmol)中,并将该混合物在搅拌下回流1小时。减压浓缩反应混合物,往该浓缩物中加入氯仿(5ml),并在冰冷却下,将其缓慢地加到搅拌下的饱和氨水/四氢呋喃溶液(5ml)中。2.5小时后,滤除不溶性物质,减压浓缩滤液。残余物经硅胶柱色谱纯化,得到0.34g浅黄色结晶的3-(4-吡啶基)丁酰胺及其烯烃氧化物的混合物。
然后,在氮气氛下,将无水乙醚(8ml)加到氢化铝锂(0.16g,4.2mmol)中,并在冰冷却下搅拌该混合物。在2分钟时间内,将3-(4-吡啶基)丁酰胺(0.22g,1.4mmol)的无水二氯甲烷(8ml)溶液滴加到该混合物中,使温度升至室温,并将其搅拌过夜。将乙酸乙酯(1ml)和1N氢氧化钠水溶液(20ml)加到该反应混合物中,并将其用氯仿(50ml)萃取。有机层经无水硫酸钠干燥,并减压浓缩。残余物经硅胶柱色谱纯化,得到0.15g(75%)浅黄色油状的标题化合物。
IR(neat):3350,2963,2873,1601cm-1
制备实施例14
·N-(4-吡啶基)乙二胺(中间体14-1)
在氮气氛下,将乙二胺(10.4ml,155mmol)加到4-溴吡啶盐酸盐(3.00g,15.5mmol)中,并将该混合物回流1.5小时。使温度冷却到室温,将碳酸钾(8.57g,62.0mmol)加到该反应混合物中,并将其搅拌10分钟。然后,滤除固体并顺序用甲苯和2-丙醇洗涤。减压浓缩滤液,残余物经碱性硅胶柱色谱纯化,用二异丙基醚滤出所得固体,得到1.63g(77%)浅黄色固体的标题化合物。
IR(KBr):3320,3240,3028,2930,1615cm-1
mp:114.0-116.5℃
制备实施例15
·4-(3-氨基丁基)吡啶(中间体15-1)
在氮气氛下,将无水N,N-二甲基甲酰胺(41ml)加到氢化钠(2.81g,70.3mmol)中,并在冰冷的水冷却下搅拌该混合物。用10分钟,将乙酰乙酸叔丁基酯(6.33g,40.0mmol)的N,N-二甲基甲酰胺(20ml)溶液滴加到该混合物中,10分钟后,在氮气氛下,用3分钟往其中逐渐加入4-(氯甲基)吡啶盐酸盐(5.00g,30.5mmol),并使温度升至室温。2小时后,将饱和碳酸氢钠水溶液(150ml)加到该反应混合物中,并用乙酸乙酯(100ml)萃取。有机层顺序用水(100ml)和饱和盐水(50ml)洗涤,并经无水硫酸钠干燥。将有机层减压浓缩,残余物经时间柱色谱纯化,得到浅黄色油状的1.34g(18%)2-乙酰基-3-(4-吡啶基)丙酸乙酯。
然后,将6N盐酸(8ml)2-乙酰基-3-(4-吡啶基)丙酸乙酯(1.20g,4.81mmol)中,并将该混合物回流1.5小时。将反应混合物减压浓缩,将2-丙醇(10ml)加到该浓缩物中,并将其再次减压浓缩。将乙酸乙酯加到所得固体中,滤出固体,得到0.79g(89%)浅黄色固体的4-(4-吡啶基)-2-丁酮。
然后,将水(12ml)和四氢呋喃(1.2ml)加到4-(4-吡啶基)-2-丁酮(736mg,3.96mmol)中,并在室温搅拌该混合物。将碳酸钠(483mg,4.56mmol)和羟胺盐酸盐(358mg,5.15mmol)加到该混合物中,将其搅拌1.5小时后,用乙酸乙酯(50ml)稀释。往其中加入碳酸氢钠,使其分层,有机层用饱和盐水(10ml)洗涤。有机层经无水硫酸钠干燥并减压浓缩。将环己烷加到所得结晶中,并滤出结晶,得到584mg(90%)浅黄色结晶的4-(4-吡啶基)-2-丁酮肟。
然后,在氮气氛下,将无水乙醚(19ml)加到氢化铝锂(257mg,6.77mmol)中并在冰冷却下搅拌该混合物。用7分钟,将4-(4-吡啶基)-2-丁酮肟(556mg,3.38mmol)的乙醚(15ml)溶液滴加到该混合物中,然后使温度升至室温,并回流过夜。再使其回流两天,然后在冰冷却下搅拌。将乙酸乙酯缓慢加到该反应混合物中,然后往其中加入1N氢氧化钠水溶液(开始时缓慢加入,总计20ml)。往其中加入氯仿(80ml),用硅藻土滤除不溶性物质。分层,减压浓缩氯仿层。将残余物与水层合并,往其中加入四氢呋喃(20ml),并将其在室温下搅拌。往其中加入碳酸二叔丁基酯(1.48g,6.78mmol),并将其搅拌过夜。用氯仿萃取(50ml),有机层经无水硫酸镁干燥并减压浓缩。残余物经硅胶柱色谱纯化。往残余物中加入4N氯化氢的乙酸乙酯溶液(3ml)和乙醇(1ml),并在室温搅拌该混合物。3小时后,减压浓缩反应混合物。往残余物中加入氯仿(5ml)、甲醇(5ml)和三乙胺(1ml)。残余物经碱性硅胶柱色谱纯化,得到161mg(32%)棕色油状的标题化合物。
IR(neat):3354,3280,2958,2925,2866,1602cm-1
采用类似于制备实施例15的方法获得下列混合物。
·1,2-二甲基-3-(4-吡啶基)丙胺(中间体15-2)
IR(neat):3360,3287,2963,2930,2876,1602cm-1
·乙基-3-(4-吡啶基)丙胺(中间体15-3)
IR(neat):3357,2963,2934,2875,1605cm-1
制备实施例16
·2,2-二甲基-3-(4-吡啶基)丙胺(中间体16-1)
在氮气氛下,将二异丙基胺(10.0ml,71.5mmol)的四氢呋喃(150ml)溶液冷却到-78℃,并用10分钟往其中滴加1.6N丁基锂的己烷溶液。该混合物用冰冷的水冷却20分钟,然后再次冷却到-78℃,并用5分钟,往该混合物中滴加异丁腈(3.03ml,33.3mmol)。再用5分钟,往其中滴加4-吡啶甲醛(3.18ml,33.3mmol),并将其搅拌1小时20分钟。将水(100ml)加到反应混合物中,并使用连续萃取仪用乙酸乙酯(200ml)连续萃取3天。所得有机层经无水硫酸镁干燥并减压浓缩,得到的固体用乙醚滤出,得到4.20g(71.6%)无色固体的3-羟基-2,2-二甲基-3-(4-吡啶基)丙腈。
在室温下,将三乙胺(1.57ml,11.3mmol)加到3-羟基-2,2-二甲基-3-(4-吡啶基)丙腈(1.00g,5.67mmol)的二氯甲烷(20ml)溶液中。再将对甲苯磺酰氯(1.30g,6.80mmol)加到该混合物中,将其温热到50℃,搅拌3天。将反应混合物放置,然后减压浓缩,残余物经硅胶柱色谱纯化,得到699mg(37.4%)浅黄色固体的2,2-二甲基-3-(4-吡啶基)-3-(对甲苯磺酰氧基)丙腈。
在氮气氛下和冰冷的水冷却下,将无水乙醚(10ml)滴加到氢化铝锂(345mg,9.10mmol)中,然后往该混合物中加入2,2-二甲基-3-(4-吡啶基)-3-(对甲苯磺酰氧基)丙腈(600mg,1.82mmol)的四氢呋喃(10ml)溶液。将其在室温搅拌过夜,并在冰冷的水冷却和剧烈搅拌下,顺序将水(324μl)、15%氢氧化钠水溶液(324μl)和水(972μl)加到该反应混合物中。有机层经无水硫酸镁干燥并减压浓缩,残余物经硅胶柱色谱纯化,得到浅黄色油状的标题化合物(83.0mg,0.505mmol,28%)。
IR(neat):3290,3074,2960,1652,1602,1417cm-1
制备实施例17
·(RS)-2-甲基-3-(4-吡啶基)丙醇(中间体17-1)
将通过制备实施例11的合成方法获得2-甲基-3-(4-吡啶基)丙酸(136g,0.676mol)溶于四氢呋喃(1500ml)中,并在冰冷的水冷却下,往该溶液中加入硼氢化钠(56.2g,1.49mol)。30分钟后,在冰冷的水冷却下,往该混合物中滴加碘(85.8g,0.338mol)和四氢呋喃(500ml)的混合液,并使温度升至室温。2小时后,该反应混合物用冰冷的水冷却,并将饱和的碳酸氢钠水溶液(100ml)滴加到该反应混合物中。再往其中加入饱和的氯化钠水溶液(900ml)和水(400ml),并将其用氯仿萃取(1升×2)。有机层顺序用0.01%硫代硫酸钠水溶液(1升)和饱和氯化钠水溶液(500ml)洗涤,经无水硫酸镁干燥并减压浓缩,得到127.1g(定量)的黄色油状标题化合物。
IR(neat):3292,2928,1606,1558,1419cm-1
制备实施例18
·3-(叔丁基二苯基甲硅烷氧基)-3-(4-吡啶基)丙胺(中间体18-1)
在-80℃下,用5分钟将二异丙基胺(1.98g,19.6mmol)滴加到丁基锂/己烷溶液(10.5ml,16.8mmol)在无水四氢呋喃(20ml)中的溶液中,使温度升至0℃,并将该混合物搅拌30分钟。将该混合物再次冷却到-80℃,然后用7分钟,将乙腈(573mg,14.0mmol)滴加到该混合物中,20分钟后,用10分钟往其中滴加4-吡啶甲醛(758mg,7.08mmol)。50分钟后,往该反应混合物中加入饱和氯化铵水溶液(20ml),并使温度升至室温。将该混合物连续萃取四天(乙酸乙酯和水)。有机层经无水硫酸镁干燥,减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到3-羟基-3-(4-吡啶基)丙腈(666mg,无色结晶,63.5%)。
然后,将咪唑(4.60g,67.5mmol)和N,N-二甲基甲酰胺(30ml)加到所得到的3-羟基-3-(4-吡啶基)丙腈(1.00g,6.75mmol)中,并在室温搅拌该混合物。将叔丁基二苯基氯硅烷(2.23g,8.10mmol)加到该混合物中,将其搅拌1天并在50℃的外部温度下再搅拌3小时。将乙酸乙酯(50ml)和乙醚(50ml)加到反应混合物中,将其顺序用水(20ml)洗涤三次,和用饱和盐水(30ml)洗涤一次,有机层经无水硫酸镁干燥。将有机层减压浓缩,残余物经硅胶柱色谱纯化,得到2.58g(98.9%)无水油状的3-(叔丁基二苯基甲硅烷氧基)-3-(4-吡啶基)丙腈。
在氮气氛下,将氢化铝锂(299mg,7.87mmol)悬浮在无水乙醚(10ml)中,并在8分钟内、搅拌下,将得到的3-(叔丁基二苯基甲硅烷氧基)-3-(4-吡啶基)丙腈(1.00g,2.59mmol)的无水乙醚(15ml)溶液滴加到该悬浮液中。使温度升至室温,并将该混合物搅拌75分钟。该反应混合物用冰冷却,将乙酸乙酯(15ml)加到该反应混合物中,并顺序往其中加入水(0.28ml)、15%氢氧化钠水溶液(0.28ml)和水(0.85ml)。使温度升至室温并将其搅拌10分钟。该反应混合物经无水硫酸镁干燥,减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到标题化合物(180.0mg,黄色油状物,17.8%)。
IR(neat):3286,3071,2932,2858,1601,1428cm-1
采用类似于制备实施例18的方法,获得下列化合物。
·3-(叔丁基二甲基甲硅烷氧基)-3-(4-吡啶基)丙胺(中间体18-2)
制备实施例19
·N-[2-(1-金刚烷基)乙基]-2-丁炔基胺(中间体19-1)
将二甲基亚砜(60ml)和三乙胺(8.4ml,60mmol)加到2-丁炔-1-醇(3.0ml,40ml)中,并在冰冷的水冷却下搅拌该混合物。将三氧化硫-吡啶复合物(4.2g,26mmol)加到该混合物中,15分钟后,再往其中加入三氧化硫-吡啶复合物(5.1g,32mmol),并将其搅拌1.5小时。往反应混合物中加入水(40ml),并将其用二氯甲烷(40ml)萃取两次。有机层用1N盐酸(30ml)洗涤两次,用水(40ml)洗涤两次并经无水硫酸镁干燥。减压蒸发溶剂,得到1.0g(37%)棕色油状的2-丁炔醛。
然后,将2-(1-金刚烷基)乙胺盐酸盐(2.0g,9.3mmol)分配到氯仿(30ml)和1N氢氧化钠水溶液(40ml)中,有机层经无水硫酸镁干燥并减压浓缩,得到2-(1-金刚烷基)乙胺。将甲醇(15ml)和三乙胺(2.6ml,19mmol)加到2-(1-金刚烷基)乙胺中,并将该混合物在室温搅拌。然后将通过上述反应获得的2-丁炔醛(0.80g,12mmol)的甲醇(10ml)溶液加到该混合物中,3小时后,在冰冷的水冷却下,往其中加入硼氢化钠(1.9g,50mmol)。1小时后,往反应混合物中加入水(40ml),并将其用氯仿(60ml)萃取。有机层用饱和盐水(40ml)洗涤并经无水硫酸镁干燥。减压浓缩有机层,残余物经硅胶柱色谱纯化,得到0.48g(22%)棕色油状的标题化合物。
IR(neat):3302,2902,2846,2279,2244cm-1
[B]本发明化合物的制备
实施例1
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-1)
将1,1′-羰基二咪唑(427mg,2.63mmol)加到4-(3-氨基丙基)吡啶(中间体2-1)(285mg,2.09mmol)的四氢呋喃(10ml)溶液中,并将该混合物在室温搅拌20分钟。往该混合物中加入2-(1-金刚烷基)-N-戊基乙胺盐酸盐(中间体1-1)(571mg,2.00mmol),并将其回流1小时。该反应混合物用乙酸乙酯(50ml)稀释,并顺序用饱和碳酸氢钠水溶液(50ml)和饱和氯化钠水溶液(50ml)洗涤,有机层经硫酸镁干燥。减压蒸发溶剂,沉淀的固体用二异丙基醚洗涤并过滤,得到606mg(73%)标题化合物。
IR(KBr):2900,2845,1618,1534cm-1
mp:124.0-124.7℃
采用类似于实施例1的方法获得下列化合物。
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)-2-丙烯基]脲(化合物1-2)
IR(neat):3339,2902,2846,1626,1530cm-1
·N-[3-(4-吡啶基)丙基]-1-哌啶甲酰胺(化合物1-3)
IR(neat):3339,2934,2854,1621,1538cm-1
·N-[3-(4-吡啶基)丙基]-1,2,3,6-四氢吡啶-1-甲酰胺(化合物1-4)
IR(neat):3337,2922,2858,1624,1537,1414cm-1
·N-[3-(4-吡啶基)丙基]-1,2,3,4-四氢异喹啉-2-甲酰胺(化合物1-5)
IR(KBr):3342,2925,1614,1543,1489cm-1
mp:76.0-79.0℃
·N-[3-(4-吡啶基)丙基]-4-吗啉甲酰胺(化合物1-6)
IR(KBr):3347,2968,1626,1546,1115cm-1
mp:94.0-98.0℃
·N-[3-(4-吡啶基)丙基]-1-高哌啶甲酰胺(化合物1-7)
IR(neat):3343,2927,1625,1537cm-1
·1,1-二烯丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-8)
IR(neat):3350,2928,1628,1603,1535cm-1
·N-[3-(4-吡啶基)丙基]-2-十氢异喹啉甲酰胺(化合物1-9)
IR(neat):3343,2855,2622,1621,1539cm-1
·1,1-二丁基-3-[3-(4-吡啶基)丙基]脲(化合物1-10)
IR(neat):3347,2957,2872,1626,1537cm-1
·1,1-二己基-3-[3-(4-吡啶基)丙基]脲(化合物1-11)
IR(neat):3348,2928,2857,1626,1532cm-1
·1,1-二异戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-12)
IR(neat):3344,2955,2869,1626,1533cm-1
·1,1-二癸基-3-[3-(4-吡啶基)丙基]脲(化合物1-13)
IR(neat):3346,2925,2854,1626,1537cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-(N-苄氧羰基-N-甲基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-14)
IR(neat):3360,2902,2846,1772,1699,1634,1532cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-(二甲基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-15)
IR(KBr):3322,2900,2845,1621,1526cm-1
mp:104.0-106.5℃
·1-[2-(1-金刚烷基)乙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-16)
IR(KBr):3331,2901,2846,1622,1602,1534cm-1
Mp:99.0-103.0℃
·1-[2-(1-金刚烷基)乙基]-1-(2-丙炔基)-3-[3-(4-吡啶基)丙基]脲(化合物1-17)
IR(KBr):3322,3204,2899,2845,2112,1626,1605,1543,1444cm-1
Mp:152.0-154.0℃
·1-[2-(1-金刚烷基)乙基]-1-(2-甲氧基乙基)-3-[3-(4-吡啶基)丙基]脲(化合物1-18)
IR(KBr):3321,2900,2846,1625,1602,1534,1451cm-1
mp:101.5-104.5℃
·1-[2-(1-金刚烷基)乙基]-1-环丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-19)
IR(KBr):3365,2900,1633cm-1
mp:108.0-115.5℃
·1-[2-(1-金刚烷基)乙基]-1-氰基甲基-3-[3-(4-吡啶基)丙基]脲(化合物1-20)
IR(neat):3350,2903,2247,1644cm-1
·1-[2-(1-金刚烷基)乙基]-1-环戊基甲基-3-[3-(4-吡啶基)丙基]脲(化合物1-21)
IR(KBr):3328,2906,2845,1615,1450cm-1
mp:155.0-158.0℃
·1-[2-(1-金刚烷基)乙基]-1-环丙基甲基-3-[3-(4-吡啶基)丙基]脲(化合物1-22)
IR(KBr):3328,2900,2845,1618,1534cm-1
mp:123.0-125.0℃
·1-[2-(1-金刚烷基)乙基]-1-烯丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-23)
IR(KBr):3329 2900,1625,1538cm-1
mp:99.0-102.0℃
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]-1-(3,3,3-三氟丙基)脲(化合物1-24)
IR(KBr):3310,2900,2847,1622,1543cm-1
mp:107.5-109.0℃
·1-[2-(1-金刚烷基)乙基]-1-(2-丁烯基)-3-[3-(4-吡啶基)丙基]脲(化合物1-25)
IR(KBr):3328,2900,1619cm-1
mp:89.5-93.5℃
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-26)
IR(neat):3350,2903,2846,1694,1633,1537cm-1
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]-1-(2-噻吩基)甲基脲(化合物1-27)
IR(KBr):3328,2900,2845,1626,1544cm-1
mp:142.5-144.5℃
·1-[2-(1-金刚烷基)乙基]-1-苄氧基-3-[3-(4-吡啶基)丙基]脲(化合物1-28)
IR(neat):3444,3350,2902,2846,1666,1517cm-1
·1-[2-(1-金刚烷基)乙基]-1-己基-3-[3-(4-吡啶基)丙基]脲(化合物1-29)
IR(KBr):3354,2901,2845,1619,1538cm-1
mp:119.5-121.5℃
·1-(1-金刚烷基)甲基-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-30)
IR(neat):3350,2902,1626cm-1
·1-[2-(1-金刚烷基)乙基]-1-(3-甲基-2-丁烯基)-3-[3-(4-吡啶基)丙基]脲(化合物1-31)
IR(KBr):3358,2900,2845,1622,1526cm-1
mp:93.0-96.0℃
·1-[2-(1-金刚烷基)乙基]-1-癸基-3-[3-(4-吡啶基)丙基]脲(化合物1-32)
IR(KBr):3340,2924,2846,1626,1602,1534cm-1
mp:75.0-76.0℃
·1-2-(1-金刚烷基)乙基]-1-(2-甲基-2-丙烯基)-3-[3-(4-吡啶基)丙基]脲(化合物1-33)
IR(KBr):3336,2905,2846,1624,1544cm-1
mp:108.0-109.0℃
·1-[2-(1-金刚烷基)乙基]-1-肉桂基-3-[3-(4-吡啶基)丙基]脲(化合物1-34)
IR(KBr):3374,2899,2844,1619,1534cm-1
mp:130.0-134.5℃
·1-[3-(1-金刚烷基)丙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-35)
IR(neat):3349,2901,1626,1536cm-1
·1-(1-金刚烷基)甲基-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-36)
IR(neat):3349,2903,1625,1531cm-1
·1-[2-(1-金刚烷基)乙基]-1-(2-甲基噻唑-4-基)甲基-3-[3-(4-吡啶基)丙基]脲(化合物1-37)
IR(neat):3337,2901,1632,1536cm-1
·1,1-二戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-38)
IR(neat):3347,2929,2859,1626,1537cm-1
·1-戊基-1-(2-哌啶子基乙基)-3-[3-(4-吡啶基)丙基]脲(化合物1-39)
IR(neat):3350,2933,2856,1640,1533cm-1
·1-[2-(1-金刚烷基)乙基]-1-甲基-3-[3-(4-吡啶基)丙基]脲(化合物1-40)
IR(KBr):3334,2901,2846,1626,1604,1534cm-1
mp:99.0-109.0℃
·1-[2-(1-金刚烷基)乙基]-1-乙基-3-[3-(4-吡啶基)丙基]脲(化合物1-41)
IR(KBr):3324,2901,2845,1622,1540cm-1
mp:106.0-115.0℃
·1-[2-(1-金刚烷基)乙基]-1-糠基-3-[3-(4-吡啶基)丙基]脲(化合物1-42)
IR(KBr):3331,2900,2846,1618,1538cm-1
mp:128.0-130.0℃
·1-[2-(1-金刚烷基)乙基]-1-苄基-3-[3-(4-吡啶基)丙基]脲(化合物1-43)
IR(KBr):3335,2901,2847,1619,1538cm-1
mp:130.5-135.0℃
·1-(2-环己基乙基)-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-44)
IR(neat):3345,2923,1625,1603,1531cm-1
·1-戊基-1-苯乙基-3-[3-(4-吡啶基)丙基]脲(化合物1-45)
IR(neat):3345,3063,2929,1625,1533cm-1
·1-丁基-1-(2-环己基乙基)-3-(4-吡啶基)甲基脲(化合物1-46)
IR(neat):3342,2922,2851,1629,1602,1563,1530,1448cm-1
·1-(2-环己基乙基)-1,3-二[(4-吡啶基)甲基]脲(化合物1-47)
IR(neat):3337,3029,2922,2850,1633,1602,1534,1445cm-1
·1-(2-环己基乙基)-3-(4-吡啶基)甲基-1-(2-噻吩基)甲基脲(化合物1-48)
IR(neat):3342,2921,2850,1631,1602,1562,1536,1415,1267,1227cm-1
·1-[2-(叔丁氧羰基)乙基]-1-(2-环己基乙基)-3-(4-吡啶基)甲基脲(化合物1-49)
IR(neat):3347,2977,2923,2851,1727,1633,1602,1563,1531,1449cm-1
·1-(2-环己基乙基)-1-[2-(甲氧基羰基)乙基]-3-(4-吡啶基)甲基脲(化合物1-50)
IR(neat):3348,2923,2850,1737,1633,1603,1563,1532,1437cm-1
·1-(2-氨基甲酰基乙基)-1-(2-环己基乙基)-3-(4-吡啶基)甲基脲
(化合物1-51)
IR(neat):3324,2922,2850,1673,1632,1606,1563,1530,1448cm-1
·1-(2-环己基乙基)-1-戊基-3-(4-吡啶基)甲基脲(化合物1-52)
IR(KBr):3313,2925,1627,1602,1527,1410cm-1
mp:64.7-65.8℃
·1-(2-环己基乙基)-1-(2-二甲基氨基乙基)-3-(4-吡啶基)甲基脲(化合物1-53)
IR(KBr):3346,2922,2850,2778,1635,1562,1533,1448cm-1
·1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-1-(2-环己基乙基)-3-(4-吡啶基)甲基脲(化合物1-54)
IR(neat):3338,2976,2924,2851,1694,1633,1602,1563,1531,1484,1450cm-1
·1-戊基-1-[2-(2-吡啶基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-55)
IR(neat):3350,2929,2859,1633,1602,1537cm-1
·1,1-二[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-56)
IR(neat):3358,2901,2845,1625,1530c-1
mp:80℃
·1-[2-(1-金刚烷基)乙基]-1-丁基-3-[3-(4-吡啶基)丙基]脲(化合物1-57)
IR(KBr):3315,2901,1618,1534cm-1
mp:109.5-118.0℃
·1,1-二(2-羟基丙基)-3-[3-(4-吡啶基)丙基]脲盐酸盐(化合物1-58)
IR(neat):3350,1688,1638,1538cm-1
·1-[二(叔丁氧羰基氨基甲基)]甲基-1-异戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-59)
IR(neat):3326,2960,1698,1631,1525cm-1
·1-环己基(苯基)甲基-1-(3-苯基丙基)-3-[3-(4-吡啶基)丙基]脲(化合物1-60)
IR(KBr):3352,2931,1619,1522cm-1
mp:107.0-112.0℃
·1,1-二环己基-3-[3-(4-吡啶基)丙基]脲(化合物1-61)
IR(KBr):3304,2930,2848,1638,1602,1533cm-1
mp:143.0-145.5℃
·1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-1-苯乙基-3-[3-(4-吡啶基)丙基]脲(化合物1-62)
IR(neat):3350,1694,1633,1532,1166cm-1
·1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-63)
IR(neat):3350,1694,1632,1537,1167cm-1
·1-[2-(N-苄氧羰基-N-甲基氨基)乙基]-1-苯乙基-3-[3-(4-吡啶基)丙基]脲(化合物1-64)
IR(neat):3350,1698,1632,1531cm-1
·1-[3-(1-金刚烷基)丙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-65)
IR(KBr):3333,2901,2844,1623,1602,1543cm-1
·1-[2-(1-金刚烷基)乙基]-3-戊基-1-[3-(4-吡啶基)丙基]脲(化合物1-66)
IR(KBr):3370,3322,2903,2846,1618,1534cm-1
mp:47.0-50.0℃
·3-[2-(1-金刚烷基)乙基]-1-[2-(叔丁氧羰基)乙基]-1-[3-(4-吡啶基)丙基]脲(化合物1-67)
IR(neat):3348,2902,2846,1726,1627,1538,1367,1152cm-1
·1-[2-(1-金刚烷基)乙基]-1-异丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-68)
IR(KBr):3330,2903,2845,1614,1533cm-1
mp:132.0-134.0℃
·1-[2-(1-金刚烷基)乙基]-1-[2-(叔丁氧羰基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-69)
IR(KBr):3356,2903,1720,1622,1538,1156cm-1
mp:124.5-127.0℃
·1-[2-(1-金刚烷基)乙基]-1-环戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-70)
IR(KBr):3297,2906,2844,1618,1544cm-1
mp:135.5-137.5℃
·1-[2-(1-金刚烷基)乙基]-1-(叔丁氧羰基氨基)-3-[3-(4-吡啶基)丙基]脲(化合物1-71)
IR(neat):3231,2903,1732,1650cm-1
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-(2-吡啶基)甲基脲(化合物1-72)
IR(KBr):3333,2900,2844,1625,1535cm-1
mp:87.5-92.0℃
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-(3-吡啶基)甲基脲(化合物1-73)
IR(KBr):3328,2901,2846,1622,1530cm-1
mp:88.5-101.5℃
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-(4-吡啶基)甲基脲(化合物1-74)
IR(KBr):3331,2900,2845,1626,1538cm-1
mp:96.5-108.0℃
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(2-吡啶基)乙基]脲(化合物1-75)
IR(KBr):3346,2904,2845,1622,1539cm-1
mp:80.0-100.0℃
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(3-吡啶基)乙基]脲(化合物1-76)
IR(KBr):3334,2900,2845,1618,1541cm-1
mp:112.5-114.5℃
·1-(2-环己基乙基)-1-(2-甲氧基乙基)-3-(4-吡啶基)甲基脲(化合物1-77)
IR(neat):3350,2922,2850,1633,1603,1534cm-1
·1-[2-(N-苄氧羰基-N-甲基氨基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-78)
IR(neat):3358,2930,1701,1633,1534cm-1
·1-乙基-3-[3-(4-吡啶基)丙基]-1-(3,4,5-三甲氧基苯乙基)脲(化合物1-79)
IR(neat):3350,2936,1626,1590,1530,1239cm-1
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(4-吡啶基)乙基]脲(化合物1-80)
IR(KBr):3346,2901,2844,1622,1538cm-1
mp:107-118℃
·1-[2-(1H-5-咪唑基)乙基]-1-异戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-81)
IR(neat):3117,2954,1606,1537cm-1
·1-环己基-1-(3,4-二甲氧基苯乙基)-3-[3-(4-吡啶基)丙基]脲(化合物1-82)
IR(neat):3353,2931,1621,1515,1236,1029cm-1
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(2-吡啶基)丙基]脲(化合物1-83)
IR(KBr):3324,2900,2845,1622,1538cm-1
mp:84.4-85.7℃
·1-2-(1-金刚烷基)乙基]-1-戊基-3-[3-(3-吡啶基)丙基]脲(化合物1-84)
IR(KBr):3355,2902,2845,1615,1526cm-1
mp:99.9-105.2℃
·1-环丙基-3-[3-(4-吡啶基)丙基]-1-(3,4,5-三甲氧基苯乙基)脲(化合物1-85)
IR(neat):3400,2938,1644,1590,1510,1239,1128cm-1
·1-[2-(1-金刚烷基)乙基]-3-(4-二甲基氨基)苯乙基-1-戊基脲(化合物1-86)
IR(KBr):3341,2900,2845,1619,1526cm-1
mp:115.8-118.1℃
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[4-(4-吡啶基)丁基]脲(化合物1-87)
IR(KBr):3354,2900,2844,1618,1538cm-1
mp:74.1-78.1℃
·1-[2-(1-金刚烷基)乙基]-3-(叔丁氧羰基)-1-戊基-3-[2-(4-吡啶基)氧乙基]脲(化合物1-88)
IR(neat):2903,2847,1704,1590cm-1
·1-[2-(1-金刚烷基)乙基]-1-[3-[N-(叔丁氧羰基)-N-甲基氨基]丙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-89)
IR(neat):3350,2903,2847,1694,1632,1531cm-1
·1-环己基(苯基)甲基-1-[3-(4-甲氧基苯氧基)丙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-90)
IR(neat):3369,2930,1626,1510,1231cm-1
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-喹啉基)丙基]脲(化合物1-91)
IR(KBr):3354,2902,2845,1622,1534cm-1
mp:80.2-102.0℃
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(1-咪唑基羰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-92)
IR(neat):3366,2902,2846,1695,1635,1604,1531cm-1
·1-二苯基甲基-1-(3-苯基丙基)-3-[3-(4-吡啶基)丙基]脲(化合物1-93)
IR(KBr):3334,3026,2927,1621,1522cm-1
mp:123.0-124.8℃
·1,1-二(5-己烯基)-3-[3-(4-吡啶基)丙基]脲(化合物1-94)
IR(neat):3350,3074,2930,2859,1621,1538cm-1
·1,1-二(7-辛烯基)-3-[3-(4-吡啶基)丙基]脲(化合物1-95)
IR(neat):3349,3074,2927,2856,1625,1537cm-1
·4-[2-[3-[2-(1-金刚烷基)乙基]-3-戊基]脲基乙基]苯磺酰胺(化合物1-96)
IR(KBr):3423,2906,2847,1598,1540,1161cm-1
mp:85.0-120.7℃
·1-[2-(1-金刚烷基)乙基]-3-(1-咪唑基)丙基-1-戊基脲(化合物1-97)
IR(KBr):3340,2902,2845,1618,1534cm-1
mp:97.0-100.0℃
·1-[2-(1-金刚烷基)乙基]-3-(4-羟基苯乙基)-1-戊基脲(化合物1-98)
IR(KBr):3392,2902,2845,1614,1535,1515cm-1
mp:96.3-99.4℃
·1-[2-(1-金刚烷基)乙基]-1-[2-(3-叔丁基-1-甲基脲基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-99)
IR(neat):3310,2903,1632,1537cm-1
·1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-100)
IR(KBr):3347,2957,2902,2846,1621,1604,1539cm-1
mp:105.3-112.3℃
·1-[2-(1-金刚烷基)乙基]-1-[2-(1-甲基-3-丙基脲基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-101)
IR(neat):3316,2902,1631,1537cm-1
·1-戊基-1-(3-苯基丙基)-3-[3-(4-吡啶基)丙基]脲(化合物1-102)
IR(neat):3348,2929,1625,1537cm-1
·1-[2-(乙酰氨基)乙基]-1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-103)
IR(neat):3291,2902,2846,1632,1556,753cm-1
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丁基]脲(化合物1-104)
IR(KBr):3346,2901,2845,1618,1601,1539cm-1
mp:93.0-98.0℃
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]-1-(4,4,4-三氟丁基)脲(化合物1-105)
IR(KBr):3317,2901,2846,1618,1538,1255,1123cm-1
mp:142.6-145.0℃
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]-1-(5,5,5-三氟戊基)脲(化合物1-106)
IR(KBr):3333,2900,2846,1618,1534,1259,1140cm-1
mp:116.9-118.9℃
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[2-甲基-3-(4-吡啶基)丙基]脲(化合物1-107)
IR(neat):3350,2902,2846,1694,1672,1633,1603,1537cm-1
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(4-吡啶基甲基)丁基]脲(化合物1-108)
IR(KBr):3347,2900,2845,1622,1538cm-1
mp:72.0-77.0℃
·1-[2-(1-金刚烷基)乙基]-3-[2-苄基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-109)
IR(KBr):3329,2902,2846,1622,1544cm-1
mp:111.0-116.0℃
·1-[2-(1-金刚烷基)乙基]-3-[2,2-二(4-吡啶基甲基)乙基]-1-戊基脲(化合物1-110)
IR(KBr):3330,2905,2845,1619,1602,1534cm-1
mp:124.0-136.0℃
·(Z)-1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)-2-丙烯基]脲(化合物1-111)
IR(neat):3338,2901,2846,1625,1596,1530cm-1
·(E)-1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)-2-丙烯基]脲(化合物1-112)
IR(KBr):3315,2900,2845,1623,1526cm-1
mp:90-118℃
·1-异戊基-3-[3-(4-吡啶基)丙基]-1-(3,3,3-三氟丙基)脲(化合物1-113)
IR(neat):3342,2956,1628,1604,1539cm-1
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]-1-(2,2,2-三氟乙基)脲(化合物1-114)
IR(KBr):3346,2901,2847,1630,1604,1544,1145,1108cm-1
mp:106.2-107.3℃
·3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基-1-苯乙基脲(化合物1-115)
IR(KBr):3352,2927,2858,1622,1530,1496,1453,1416,1276cm-1
mp:49.0-50.0℃
·1,1-二丁基-3-[2-甲基-3-(4-吡啶基)丙基]脲(化合物1-116)
IR(neat):3347,2957,2929,1624,1534cm-1
·1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-(3,3,3-三氟丙基)脲(化合物1-117)
IR(KBr):3354,2901,2847,1626,1540cm-1
mp:81.1-84.1℃
·1-(2-环己基乙基)-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-118)
IR(neat):3346,2923,2852,1625,1533cm-1
·1-(3-环己基丙基)-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-119)
IR(neat):3346,2922,1626,1537cm-1
·(-)-1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-120)
IR(KBr):3337,2900,1616,1526cm-1
mp:103.0-104.0℃
[α]20 D:-4.6°(MeOH,C 1.0)
·(+)-1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-121)
IR(KBr):3336,2900,1616,1526cm-1
mp:102.9-103.5℃
[α]20 D:+4.2°(MeOH,C 1.0)
·1-[3-(1-金刚烷基)丙基]-1-丁基-3-[3-(4-吡啶基)丙基]脲(化合物1-122)
IR(KBr):3323,2954,2904,2846,1624,1603,1548cm-1
mp:79.8-80.4℃
·1-[3-(1-金刚烷基)丙基]-3-[3-(4-吡啶基)丙基]-1-(2,2,2-三氟乙基)脲(化合物1-123)
IR(KBr):3355,2902,2848,1627,1605,1545,1145,1112cm-1
mp:88.9-90.0℃
·1-[4-(1-金刚烷基)丁基]-1-乙基-3-[3-(4-吡啶基)丙基]脲(化合物1-124)
IR(KBr):3352,2897,2847,1626,1604,1539cm-1
mp:92.7-93.7℃
·1-[4-(1-金刚烷基)丁基]-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-125)
IR(KBr):3343,2900,2847,1625,1604,1544cm-1
mp:110.0-110.5℃
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(4-吡啶基氨基)乙基]脲(化合物1-126)
IR(KBr):3301,2904,2848,1628,1602,1527cm-1
mp:133.9-134.5℃
·(+)-1-[3-(1-金刚烷基)丙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-丙基脲(化合物1-127)
IR(neat):3350,2902,2846,1625,1534cm-1
[α]20 D:+4.2°(MeOH,C 0.51)
·1-[3-(1-金刚烷基)丙基]-1-丙基-3-(4-吡啶基)甲基脲(化合物1-128)
IR(KBr):3319,2902,1630,1604,1537cm-1
mp:96.0-98.0℃
·1-[3-(1-金刚烷基)丙基]-1-丙基-3-[2-(4-吡啶基)乙基]脲(化合物1-129)
IR(neat):3345,2901,1634,1538cm-1
·1-[3-(1-金刚烷基)丙基]-1-乙基-3-[3-(4-吡啶基)丙基]脲(化合物1-130)
IR(KBr):3345,2969,2905,2845,1622,1605,1535cm-1
mp:97.5-98.2℃
·1-[2-(1-金刚烷氧基)乙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-131)
IR(neat):3344,2911,2853,1642,1603,1534cm-1
·1-(1-金刚烷基)氨基羰基甲基-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-132)
IR(KBr):3335,3261,2910,2853,1662,1622,1543cm-1
mp:132.0-132.5℃
·1-[3-(1-金刚烷基)丙基]-1-丙基-3-[4-(4-吡啶基)丁基]脲(化合物1-133)
IR(neat):3350,2901,1623,1532cm-1
·1-[3-(1-金刚烷基)丙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-134)
IR(neat):3347,2902,2846,1696,1632,1603,1534,1167cm-1
·1-[2-(1-金刚烷基)乙基]-3-[2,2-二甲基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-135)
IR(KBr):3338,2905,1620,1600,1541cm-1
mp:82.5-84.9℃
·1-[3-(1-金刚烷基)丙基]-3-[3-(4-吡啶基)丙基]-1-(3,3,3-三氟丙基)脲(化合物1-136)
IR(neat):3349,2902,1628,1538cm-1
·1-[2-(1-金刚烷基)乙基]-3-[1-甲基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-137)
IR(KBr):3338,2902,2847,1615,1533cm-1
mp:128.5-129.0℃
·1-[2-(1-金刚烷基)乙基]-3-[3-(叔丁基二甲基甲硅烷氧基)-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-138)
IR(neat):3355,2904,2849,1628,1600,1532,1099cm-1
·(+)-1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[2-甲基-3-(4-吡啶基)丙基]脲(化合物1-139)
IR(KBr):3345,2910,2848,1693,1622,1602,1538,1248cm-1
mp:122.7-123.7℃
[α]20 D:+2.8°(MeOH,C 1.0)
·1-[2-(1-金刚烷基)氨基乙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲(化合物1-140)
IR(neat):3275,2908,2849,1636,1536cm-1
·1-[2-(1-金刚烷基)乙基]-1-(2-丁炔基)-3-[3-(4-吡啶基)丙基]脲(化合物1-141)
IR(neat):3351,2903,2847,2290,2221,1630,1605,1538cm-1
·1-[2-(1-金刚烷基)乙基]-3-[1,2-二甲基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-142)
IR(neat):3354,2904,2847,1623,1604,1525cm-1
·1-[2-(1-金刚烷基)乙基]-3-[1-乙基-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-143)
IR(neat):3352,2904,2847,1622,1605,1529cm-1
·1-[2-(1-金刚烷基)乙基]-3-[3-(叔丁基二苯基甲硅烷氧基)-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-144)
IR(neat):3360,3072,3050,2903,2849,1634,1602,1532,1428cm-1
实施例2
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-丙基酰胺(化合物2-1)
将N,N-二甲基甲酰胺(8.4ml)加到2-(1-金刚烷基)-N-丙基乙胺(中间体1-6)(0.37g,1.7mmol)和5-(4-吡啶基)戊酸(中间体5-1)(0.30g,1.7mmol)的混合物中,并将其在室温搅拌。往其中加入N-甲基吗啉(0.27ml,2.5mmol),然后加入1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.38g,2.0mmol),并将其搅拌过夜。减压浓缩反应混合物,将乙酸乙酯(20ml)加到残余物中,并用饱和碳酸氢钠水溶液(20ml)和饱和盐水(5ml)顺序洗涤。有机层经硫酸钠干燥,并减压蒸发乙酸乙酯。残余物经碱性硅胶柱色谱纯化,得到0.21g(33%)无色油状标题化合物。
IR(neat):2092,2846,1644,1602cm-1
采用类似于实施例2的方法获得下列化合物。
·5-(4-吡啶基)戊酸N-(1-金刚烷基)甲基-N-丙基酰胺(化合物2-2)
IR(neat):3067,2903,2847,1644,1602cm-1
·5-(4-吡啶基)戊酸N-(1-金刚烷基)甲基-N-戊基酰胺(化合物2-3)
IR(neat):2903,2847,1644,1601,1454cm-1
·5-(4-吡啶基)戊酸N,N-二丁基酰胺(化合物2-4)
IR(neat):2958,2932,1641,1602cm-1
·5-(4-吡啶基)戊酸N,N-二异戊基酰胺(化合物2-5)
IR(neat):2956 2870,1639,1603cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-(2-丁烯基)酰胺(化合物2-6)
IR(neat):2903,2847,1642,1602cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-[2-[N′-(叔丁氧羰基)-N′-甲基氨基]乙基]酰胺(化合物2-7)
IR(neat):2904,2847,1695,1644,1602cm-1
·5-(4-吡啶基)戊酸N-[3-(1-金刚烷基)丙基]-N-丙基酰胺(化合物2-8)
IR(neat):2902,2846,1643,1602cm-1
·5-(4-吡啶基)戊酸N-戊基-N-苯乙基酰胺(化合物2-9)
IR(neat):2930 2860,1642,1602cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-(2-二甲基氨基乙基)酰胺(化合物2-10)
IR(neat):2903,2847,1639,1605cm-1
·5-(4-吡啶基)戊酸N-(2-环己基乙基)-N-戊基酰胺(化合物2-11)
IR(neat):2924,2853,1644,1601cm-1
·5-(4-吡啶基)戊酸N,N-二[2-(1-金刚烷基)乙基]酰胺(化合物2-12)
IR(neat):2901,2846,1643,1602cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-(3,3,3-三氟丙基)酰胺(化合物2-13)
IR(neat):2904,2848,1647,1602cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-14)
IR(neat):2903,2847,1736,1643,1602cm-1
·3-(4-吡啶基甲硫基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-15)
IR(neat):2903,1643,1599cm-1
·2-甲基-3-(4-吡啶基甲硫基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-16)
IR(neat):2903,1639,1600cm-1
·2-(叔丁氧羰基)氨基-3-(4-吡啶基甲硫基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-17)
IR(neat):3284,2903,1705,1644cm-1
·2-[2-(4-吡啶基)乙硫基]乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-18)
IR(neat):2902,1635,1602cm-1
·(2R)-2-(叔丁氧羰基)氨基-3-[2-(4-吡啶基)乙硫基]丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-19)
IR(neat):3287,2903,1705,1644,1602cm-1
[α]20 D:-19.0°(MeOH,C 0.43)
·6-(4-吡啶基)己酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-20)
IR(neat):2903,1644,1602cm-1
·4-(4-吡啶基)丁酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物2-21)
IR(neat):2903,1644,1602cm-1
实施例3
·1-[2-(1-金刚烷基)乙基]-1-(2-甲基氨基乙基)-3-[3-(4-吡啶基)丙基]脲二盐酸盐(化合物3-1)
将甲醇(4.4ml)加到1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-26)(0.30g,0.6mmol)中,将氯化钙管与容器相连,并在室温搅拌该混合物。将10%氯化氢的甲醇溶液(4.4ml)加到该混合物中,将其搅拌一天,减压浓缩反应混合物,得到0.30g(定量)浅黄色非晶粉末的标题化合物。
IR(neat):3351,2904,2846,1634,1538cm-1
采用类似于实施例3的方法获得下列化合物。
·1-(2-环己基乙基)-1-(2-甲基氨基乙基)-3-(4-吡啶基)甲基脲二盐酸盐(化合物3-2)
IR(neat):3323,2923,2850,1638,1529,1449cm-1
·1-[2-(1-金刚烷基)乙基]-1-氨基-3-[3-(4-吡啶基)丙基]脲二盐酸盐(化合物3-3)
IR(KBr):3410,2902,1637cm-1
mp:约100℃
·2-氨基-3-(4-吡啶基甲硫基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺二盐酸盐(化合物3-4)
IR(neat):3402,2901,1638,1608,1503cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-(2-甲基氨基乙基)酰胺(化合物3-5)
IR(neat):3312,2902,2846,1643,1602,1450,1416cm-1
·(2R)-2-氨基-3-[2-(4-吡啶基)乙硫基]丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺二盐酸盐(化合物3-6)
IR(KBr):3423,2902,1638,1609cm-1
[α]20 D:-4.9°(H2O,C 0.52)
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(4-吡啶基)氧乙基]脲(化合物3-7)
IR(neat):3246,2903,2846,1698,1604cm-1
实施例4
·4-[3-[3-[2-(1-金刚烷基)乙基]-3-戊基脲基]丙基]-1-甲基碘化吡啶鎓(化合物4-1)
在室温下,将碘甲烷(90μl,1.5mmol)加到1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-1)(0.30g,0.73mmol)的丙酮(1.5ml)溶液中,并将该混合物搅拌过夜。减压蒸发反应混合物的溶剂,滤出沉淀结晶并用乙酸乙酯洗涤,得到389mg(96%)标题化合物。
IR(KBr):3374,2926,2900,1616,1526cm-1
mp:168.0-171.0℃
采用类似于实施例4的方法获得下列化合物。
·4-[3-[3-[2-(1-金刚烷基)乙基]-3-[2-[N-(叔丁氧羰基)-N-甲基氨基]乙基]脲基]丙基]-1-甲基吡啶鎓碘化物(化合物4-2)
IR(neat):3342,2903,2846,1682,1644,1520,1235,1166cm-1
·4-[3-[3-[2-(1-金刚烷基)乙基]-3-[2-[N-(叔丁氧羰基)氨基]乙基]脲基]丙基]-1-苄基吡啶鎓溴化物(化合物4-3)
IR(KBr):3312,2907,2846,1714,1694,1625,1534,1246,1171cm-1
mp:97℃
实施例5
·N-[2-(1-金刚烷基)乙基]-N-戊基氨基甲酸3-(4-吡啶基)丙基酯(化合物5-1)
在室温下将4-吡啶丙醇(528mg,3.85mmol)溶于乙腈(20ml),并往其中加入三乙胺(1.61ml,11.6mmol)。再将N,N′-琥珀酰亚氨基碳酸酯(1.48g,5.87mmol)加到该混合物中,并将其搅拌2.5小时。减压浓缩反应混合物,并往残余物中加入乙酸乙酯(100ml)和饱和碳酸氢钠水溶液(50ml)。分层,有机层用饱和氯化钠溶液(50ml)洗涤。有机层经无水硫酸钠干燥,并减压蒸发溶剂。将残余物减压干燥并溶于无水二氯甲烷(10ml)。然后,往其中加入2-(1-金刚烷基)-N-戊基乙胺盐酸盐(中间体1-1)(1.32g,4.62mmol)和三乙胺(0.80ml,5.7mmol)的二氯甲烷(90ml)溶液并将其搅拌1.5小时。反应混合物顺序用饱和碳酸氢钠水溶液(50ml)和饱和氯化钠水溶液(50ml)洗涤,有机层经无水硫酸钠干燥。减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到1.54g(97%)油状标题化合物。
IR(neat):2903,2847,1742,1698cm-1
采用类似于实施例5的方法获得下列化合物。
·1-[2-(1-金刚烷基)乙基]-1-[2-(N-环己氧基羰基-N-甲基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物5-2)
IR(neat):3350,2904,2847,1682,1633,1604,1531cm-1
·N-[3-(1-金刚烷基)丙基]-N-丙基氨基甲酸3-(4-吡啶基)丙基酯(化合物5-3)
IR(neat):2901,2846,1740,1695,1645,1602,1451,1423cm-1
·N-[2-(1-金刚烷基)乙基]-N-(3,3,3-三氟丙基)氨基甲酸3-(4-吡啶基)丙基酯(化合物5-4)
IR(neat):2903,2847,1705,1603,1482,1451,1425cm-1
·N-[2-(1-金刚烷基)乙基]-N-[2-[N′-(叔丁氧羰基)-N′-甲基氨基]乙基]氨基甲酸3-(4-吡啶基)丙基酯(化合物5-5)
IR(neat):2903,2847,1699,1603,1480,1424cm-1
·N-[2-(1-金刚烷基)乙基]-N-戊基氨基甲酸2-甲基-3-(4-吡啶基)丙基酯(化合物5-5)
IR(neat):2904,2847,1701,1602,1450,1424,1381cm-1
实施例6
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]六氢-2,4-嘧啶二酮盐酸盐(化合物6-1)
将4N氯化氢的1,4-二噁烷(2.5ml)溶液加到1-[2-(1-金刚烷基)乙基]-1-[2-(叔丁氧羰基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-69)(0.23g,0.49mmol)中,并将该混合物在室温搅拌过夜。减压浓缩反应混合物,往残余物中加入1N氢氧化钠水溶液(20ml)和乙酸乙酯(30ml)并分层。乙酸乙酯层顺序用水(20ml)和饱和氯化钠溶液(20ml)洗涤并经无水硫酸镁干燥。减压浓缩乙酸乙酯层,将所得油状物溶于乙醚(20ml)中。在冰冷却下,往其中加入4N氯化氢的乙酸乙酯溶液(0.50ml,2.00mol),将该混合物减压浓缩,并滤出沉淀的固体,用乙酸乙酯洗涤,得到0.17g(79%)标题化合物。
IR(KBr):2902,2437,1710,1666cm-1
mp:177.0-178.5℃
采用类似于实施例6的方法获得下列化合物。
·1-[2-(环己基)乙基]-3-(4-吡啶基)甲基六氢-2,4-嘧啶二酮盐酸盐(化合物6-2)
IR(KBr):2925,2850,1718,1671,1600,1493,1450cm-1-
mp:64.0-74.5℃
·3-[2-(1-金刚烷基)乙基]-1-[3-(4-吡啶基)丙基]六氢-2,4-嘧啶二酮盐酸盐(化合物6-3)
IR(KBr):2906,2845,1716,1696,1658,1486cm-1
mp:170℃
实施例7
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]硫脲(化合物7-1)
在氮气氛下,将4-(3-氨基丙基)吡啶(中间体2-1)(0.24g,1.8mmol)的无水四氢呋喃溶液(10ml)加到1,1′-硫代羰基二咪唑(0.31g,1.8mmol)中,并将该混合物在室温搅拌。1小时后,往该混合物中加入2-(1-金刚烷基)-N-戊基乙胺盐酸盐(中间体1-1)(0.50g,1.8mmol)的无水四氢呋喃(10ml)溶液,将其回流2.5小时。将反应混合物放置,然后往该反应混合物中加入乙酸乙酯(50ml)和饱和碳酸氢钠水溶液(50ml),并分层。乙酸乙酯层用饱和氯化钠水溶液(50ml)洗涤并经无水硫酸镁干燥,浓缩物经硅胶柱色谱纯化,得到0.18g(24%)标题化合物。
IR(neat):3304,2902,2846,1603,1530,1345cm-1
采用类似于实施例7的方法获得下列化合物。
·1-(2-羟基乙基)-1-苯乙基-3-[3-(4-吡啶基)丙基]硫脲(化合物7-2)
IR(KBr):3022,2920,2876,1606,1585cm-1
mp:105.6-107.1℃
实施例8
·1-苯乙基-3-[3-(4-吡啶基)丙基]-2-咪唑烷硫酮(化合物8-1)
将无水四氢呋喃(2.5ml)加到1-(2-羟基乙基)-1-苯乙基-3-[3-(4-吡啶基)丙基]硫脲(化合物7-2)(601mg,1.75mmol)和三苯膦(913mg,3.49mmol)中,并将其在冰/甲醇冷却下搅拌。往其中滴加偶氮二甲酸二异丙基酯(710mg,3.49mmol)的无水四氢呋喃(100ml)溶液,10分钟后,往反应混合物中加入乙酸乙酯(100ml)。将其顺序用饱和碳酸氢钠水溶液(40ml)和饱和盐水(40ml)洗涤,有机层经硫酸钠干燥并减压浓缩。残余物经硅胶柱色谱纯化,滤出所得固体,用己烷洗涤,得到107mg(19%)结晶的标题化合物。
IR(KBr):3064,3018,2926,2858,1601,1560,1498,1456cm-1
mp:99.5-104.0℃
实施例9
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]六氢嘧啶-2-酮(化合物9-1)
在冰冷却下,往1-金刚烷乙酸(1.50g,7.72mmol)的无水二氯甲烷(30.0ml)溶液中加入1-羟基苯并三唑(1.15g,8.49mmol)、β-丙氨酸乙酯盐酸盐(1.30g,8.49mmol)、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(1.63g,8.49mmol)和N-甲基吗啉(2.05ml,18.7mmol),并将该混合物在室温搅拌过夜。减压浓缩反应混合物,往残余物中加入乙酸乙酯(50ml)。将其顺序用10%柠檬酸水溶液(50ml)、水(50ml)、饱和碳酸氢钠水溶液(50ml)、水(50ml)和饱和氯化钠水溶液(50ml)洗涤,有机层经无水硫酸镁干燥。减压浓缩有机层,得到2.48g(定量)白色固体的3-[(1-金刚烷基)甲基甲酰氨基]丙酸乙酯。
然后,将3-[(1-金刚烷基)甲基甲酰氨基]丙酸乙酯(2.40g,8.18mmol)溶于乙醇(5ml),在冰冷却下往其中加入2N氢氧化钠水溶液(4.50ml,9.00mmol),并将该混合物在室温搅拌2小时。在冰冷却下,往反应混合物中加入2N盐酸(15ml),以使其弱微酸化,并将其用乙酸乙酯(70ml)萃取。有机层顺序用水(50ml)和饱和氯化钠水溶液(50ml)洗涤并经无水硫酸镁干燥。减压浓缩有机层,滤出沉淀的固体,用乙醚洗涤,得到1.43g(70.1%)3-[(1-金刚烷基)甲基甲酰氨基]丙酸。
然后,在冰冷却下,往3-[(1-金刚烷基)甲基甲酰氨基]丙酸(1.4g,5.6mmol)的无水二氯甲烷(10ml)溶液中加入1-羟基苯并三唑(0.83g,6.2mmol)、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(1.2g,6.2mmol)、4-(3-氨基丙基)吡啶(中间体2-1)(0.80g,5.9mmol)和N-甲基吗啉(0.68ml,6.2mmol),并将该混合物在室温搅拌过夜。减压浓缩反应混合物,往残余物中加入乙酸乙酯(50ml)。将其顺序用饱和碳酸氢钠水溶液(30ml)、水(30ml)和饱和氯化钠水溶液(30ml)洗涤,有机层经无水硫酸镁干燥。减压浓缩有机层,滤出沉淀的固体并用乙醚洗涤,得到1.9g(88%)3-[(1-金刚烷基)甲基甲酰氨基]丙酸3-(4-吡啶基)丙基酰胺。
在冰冷却下,将无水乙醚(20ml)加到氢化铝锂(0.45g,12mmol)中。然后,用15分钟往该混合物中滴加所得的3-[(1-金刚烷基)甲基甲酰氨基]丙酸3-(4-吡啶基)丙基酰胺(0.50g,1.3mmol)的无水四氢呋喃(10ml)溶液,并将其在室温搅拌过夜后,再回流4.5小时。然后,在冰冷却下,小心地往反应混合物中加入2N氢氧化钠水溶液(30ml)和乙酸乙酯(30ml)并分层。乙酸乙酯层顺序用水(30ml)和饱和氯化钠水溶液(30ml)洗涤并经无水硫酸镁干燥。减压浓缩乙酸乙酯层,残余物经硅胶柱色谱纯化,得到0.05g(10%)N-[2-(1-金刚烷基)乙基]-N′-[3-(4-吡啶基)丙基]-1,3-丙二胺。
往无水二氯甲烷(50ml)中加入所得的N-[2-(1-金刚烷基)乙基]-N′-[3-(4-吡啶基)丙基]-1,3-丙二胺(80mg,0.23mmol)的无水二氯甲烷(10ml)溶液,并在室温和搅拌下,用20分钟滴加1,1′-羰基二咪唑(40mg,0.26mmol)的无水二氯甲烷(10ml)溶液。将该混合物搅拌过夜,减压浓缩反应混合物,残余物经硅胶柱色谱纯化,得到8.0mg(9.4%)标题化合物。
IR(neat):3400,2902,2846,1625,1531,1451cm-1
实施例10
·1-乙酰氨基-1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-1)
在室温下,将吡啶(2.0ml)和乙酸酐(1.0ml)加到1-[2-(1-金刚烷基)乙基]-1-氨基-3-[3-(4-吡啶基)丙基]脲二盐酸盐(化合物3-3)(0.20g,0.47mmol)中,并将该化合物搅拌15分钟。减压蒸发反应混合物的溶剂,将残余物分配到乙酸乙酯(10ml)和水(10ml)中。有机层用饱和碳酸氢钠水溶液(10ml)和饱和盐水(10ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到0.11g(58%)标题化合物。
IR(KBr):3374,3163,2907,1694,1638cm-1
mp:140.0-146.0℃
采用类似于实施例10的方法,获得下列化合物。可任选地使用酰氯。
·1-[2-(N-乙酰基-N-甲基氨基)乙基]-1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-2)
IR(neat):3337,2902,1632,1535,1492cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-(N-异烟酰基-N-甲基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-3)
IR(neat):3350,2902,2846,1633,1531,1450,1408cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-甲基-N-(甲磺酰基)氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-4)
IR(KBr):3319,2902,2845,1616,1540,1326,1142cm-1
mp:164.9-167.2℃
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-甲基-N-(对甲苯磺酰基)氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-5)
IR(neat):3358,2902,2846,1633,1603,1531,1343,1161cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(3,3-二甲基丁酰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-6)
IR(KBr):3325,2906,2845,1652,1616,1534cm-1
mp:101.4-102.4℃
·1-[2-(1-金刚烷基)乙基]-1-[2-(N-乙氧羰基-N-甲基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-7)
IR(neat):3350,2902,2846,1698,1633,1532cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)氨基]乙基-]3-[3-(4-吡啶基)丙基]脲(化合物10-8)
IR(KBr):3312,2905,2845,1710,1637,1606,1534,1269,1249,1174cm-1
mp:158.0-160.5℃
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(叔丁氧羰基)-N-乙基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-9)
IR(neat):3349,2902,2846,1693,1667,1633,1603,1531,1452,1416cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(1,1-二甲基-2,2,2-三氯乙氧羰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-10)
IR(neat):3359,2903,2846,1707,1636,1603,1534cm-1
mp:47.0-52.0℃
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(1,1-二甲基丙氧羰基)-N-甲基氨基]乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-11)
IR(neat):3349,2972,2902,2846,1695,1631,1603,1534,1226,1159cm-1
·1-[2-(1-金刚烷基)乙基]-1-[2-(N-异丙氧羰基-N-甲基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-12)
IR(neat):3350,2903,2846,1696,1632,1603,1530cm-1
·(-)-1-[2-(1-金刚烷基)乙基]-1-[2-(N-甲氧羰基-N-甲基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物10-13)
IR(neat):3350,2904,2847,1694,1633,1603,1530cm-1
[α]20 D:-27.5°(MeOH,C 1.0)
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(3,3-二甲基丁酰基)-N-甲基氨基]乙基]-3-[2-甲基-3-(4-吡啶基)丙基]脲(化合物10-14)
IR(neat):3324,2902,2846,1633,1537cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-[2-(N′-异丙氧羰基-N′-甲基氨基)乙基]酰胺(化合物10-15)
IR(neat):3553,2978,2903,2847,1697,1646cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-[2-(N′-苄氧羰基-N′-甲基氨基)乙基]酰胺(化合物10-16)
IR(neat):3387,3030,2903,2847,1701,1646,1602,1453,1422cm-1
·5-(4-吡啶基)戊酸N-[2-(1-金刚烷基)乙基]-N-[2-[N′-(3,3-二甲基丁酰基)-N′-甲基氨基]乙基]酰胺(化合物10-17)
IR(neat):3501,2903,2847,1645,1603,1455,1417cm-1
实施例11
·1-[2-(1-金刚烷基)乙基]-1,3-二甲基-3-[3-(4-吡啶基)丙基]脲(化合物11-1)
在室温和氮气氛下搅拌三光气(190mg,0.640mmol)的二氯甲烷(6.0ml)溶液。用17分钟,往其中滴加2-(1-金刚烷基)-N-甲基乙胺(中间体3-1)(330mg,1.71mmol)和二异丙基乙胺(0.357ml,2.05mmol)的二氯甲烷(6.0ml)溶液。8分钟后,将N-甲基-3-(4-吡啶基)丙胺(中间体3-3)(264mg,1.78mmol)和二异丙基乙胺(0.357ml,2.05mmol)的二氯甲烷(5.1ml)溶液一齐加到该混合物中,并将其搅拌20小时。该反应混合物用乙醚(40ml)稀释,并顺序用饱和碳酸氢钠水溶液(40ml)洗涤两次和用饱和氯化钠水溶液(40ml)洗涤一次,有机层经硫酸镁干燥。减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到335mg(54%)标题化合物。
IR(neat):2903,2846,1638,1602,1492cm-1
实施例12
·1-[2-(1-金刚烷基)乙基]-1-羟基-3-[3-(4-吡啶基)丙基]脲盐酸盐(化合物12-1)
将2N盐酸(4.0ml)加到1-[2-(1-金刚烷基)乙基]-1-苄氧基-3-[3-(4-吡啶基)丙基]脲(化合物1-28)(438mg,0.978mmol)的甲醇(9.78ml)溶液中,并往其中通入氮气。往该混合物中加入10%钯碳(43mg),并将其在1个大气压的氢气氛下搅拌3天。滤除钯碳,减压浓缩滤液,浓缩物用乙醚(30ml)稀释。将其顺序用饱和碳酸氢钠水溶液(30ml)和饱和氯化钠水溶液(30ml)洗涤,有机层经硫酸镁干燥。减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到119mg(34%)标题化合物。
IR(KBr):3438,3152,2903,2847,1650cm-1
mp:101.0-102.5℃
实施例13
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲盐酸盐(化合物13-1)
将4N氯化氢的乙酸乙酯溶液(0.400ml,1.60mmol)加到1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-1)(200mg,0.486mmol)的氯仿(0.3ml)溶液中。减压蒸发溶剂,沉淀的固体用乙酸乙酯洗涤并过滤。所得的结晶粗品在2-丁酮(5.0ml)中重结晶,得到94mg(43%)标题化合物。
IR(KBr):3322,3050,2902,2496,1621,1534,1450cm-1
mp:157.0-158.0℃
采用类似于实施例13的方法,获得下列化合物。
·1-[2-(1-金刚烷基)乙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲盐酸盐(化合物13-2)
IR(neat):3338,2901,2845,1620,1450cm-1
·1-(2-环己基乙基)-3-(4-吡啶基)甲基-1-(2-噻吩基)甲基脲盐酸盐(化合物13-3)
IR(KBr):3296,2923,1635,1599,1518cm-1
mp:161.8-164.4℃
·1-[2-(1-金刚烷基)乙基]-1-丁基-3-[3-(4-吡啶基)丙基]脲盐酸盐(化合物13-4)
IR(neat):3331,2901,2845,1754,1636,1537cm-1
·1,1-二[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]脲盐酸盐(化合物13-5)
IR(KBr):3289,2900,2844,1637,1560cm-1
mp:120.0-122.5℃
·1-[2-(1-金刚烷基)乙基]-1-(2-氨基乙基)-3-[3-(4-吡啶基)丙基]脲二盐酸盐(化合物13-6)
IR(neat):3358,2902,2846,1634,1538,756cm-1
·2-[2-(4-吡啶基)乙基氨基]乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺二盐酸盐(化合物13-7)
IR(KBr):3424,2902,1651cm-1
mp:133.7-137.0℃
·3-[N′-甲基-N′-(4-吡啶基甲基)氨基]丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺二盐酸盐(化合物13-8)
IR(KBr):3424,2901,2846,1641cm-1
·1,1-二异戊基-3-[3-(4-吡啶基)丙基]脲盐酸盐(化合物13-9)
IR(KBr):3082,2956,2869,2614,1626,1526cm-1
mp:120.5-131.7℃
·1-[3-(1-金刚烷基)丙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲磷酸盐(化合物13-10)
IR(KBr):3517,3423,1642,1594,1539,1508cm-1
mp:148.0-149.0℃
实施例14
·1-[2-(1-金刚烷基)乙基]-3-[3-羟基-3-(4-吡啶基)丙基]-1-戊基脲(化合物14-1)
将1-[2-(1-金刚烷基)乙基]-3-[3-(叔丁基二甲基甲硅烷氧基)-3-(4-吡啶基)丙基]-1-戊基脲(化合物1-138)(136mg,0.250mmol)在10%氯化氢-甲醇(2.3ml)中的溶液在室温搅拌3天。减压蒸发溶剂,将残余物分配到乙酸乙酯(50ml)、水(30ml)和1N氢氧化钠水溶液(20ml)中,有机层用饱和氯化钠水溶液(40ml)洗涤。有机层经无水硫酸钠干燥,减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到标题化合物(59.2mg,无色非晶粉末,55.3%)。
IR(neat):3339,2904,2847,1622,1605,1532cm-1
实施例15
·顺-1-[2-(1-金刚烷基)乙基]-1-戊基-3-[2-(4-吡啶基)环丙基甲基]脲(化合物15-1)
在氮气氛和冰冷却下,将1.0M二乙基锌的己烷溶液(3.1ml,3.1mmol)和氯碘甲烷(0.44ml,6.1mol)加到(Z)-1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)-2-丙烯基]脲(化合物1-111)的无水1,2-二氯乙烷(3ml)溶液中,并将该混合物搅拌1小时。在冰冷却下,将饱和氯化铵水溶液(10ml)加到该反应混合物中,将其在室温搅拌20分钟后,分配到乙酸乙酯(20ml)和饱和氯化铵水溶液(10ml)中。有机层用饱和氯化钠水溶液(10ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到9.0mg(3.5%)无色结晶的标题化合物。
IR(KBr):3340,3025,2903,2847,1617,1603,1525cm-1
mp:128.0-130.0℃
实施例16
·4-[3-[3-[2-(1-金刚烷基)乙基]-3-戊基脲基]丙基]吡啶N-氧化物(化合物16-1)
在室温和氮气氛下,将间氯过苯甲酸(2.5g,15mmol)加到1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲(化合物1-1)(3.0g,7.3mmol)的溶液中,并将该混合物搅拌过夜。将反应混合物分配到氯仿(20ml)和1N氢氧化钠水溶液(60ml)中。有机层顺序用水(10ml)和饱和氯化钠水溶液(10ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到2.92g(94.2%)标题化合物。
IR(KBr):3346,2902,2845,1622,1538,1217,1178cm-1
mp:97.8-127.0℃
实施例17
·1-[2-(1-金刚烷基)乙基]-1-[2-[N-(2-甲氧基乙基)-N-甲基氨基]乙基1-3-[3-(4-吡啶基)丙基]脲(化合物17-1)
在室温下,往N,N-二甲基甲酰胺(20ml)中加入1-[2-(1-金刚烷基)乙基]-1-(2-甲基氨基乙基)-3-[3-(4-吡啶基)丙基]脲(1.50g,3.76mmol)(该化合物是化合物3-1的游离碱)、碳酸钾(1.56g,11.3mmol)和碘化钠(1.69g,11.3mmol),然后将2-氯乙基甲基醚(412μl,4.51mmol)加到该混合物中,并将其在80℃加热。将其搅拌过夜,将乙醚(50ml)和水(100ml)加到该反应混合物中,并进行萃取。所得的有机层用水(100ml)和饱和氯化钠水溶液(50ml)洗涤,经无水硫酸镁干燥并减压浓缩。残余物经硅胶柱色谱纯化,得到552mg(32.1%)浅黄色油状的标题化合物。
IR(neat):3350,2901,1643,1602,1531cm-1
实施例18
·2-[2-(4-吡啶基)乙基氨基]乙酸N-[2-(1-金刚烷基)乙基1-N-戊基酰胺(化合物18-1)
将溴代乙酸(0.50g,3.6mmol)溶于无水四氢呋喃(20ml)中,并在-15℃和氮气氛下搅拌该溶液。将N-甲基吗啉(0.40ml,3.6mmol)和氯代碳酸异丁基酯(0.45ml,3.5mmol)加到该溶液中。然后往该混合物中滴加2-(1-金刚烷基)-N-戊基乙胺盐酸盐(中间体1-1)的游离碱的无水四氢呋喃(20ml)溶液。将其在0℃搅拌1.5小时,将饱和碳酸氢钠水溶液(70ml)和乙酸乙酯(70ml)加到该反应混合物中,使其分配。乙酸乙酯层顺序用水(70ml)和饱和氯化钠水溶液(70ml)洗涤并经无水硫酸镁干燥。将乙酸乙酯层减压浓缩,得到1.3g(定量)油状的2-溴代乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺。
然后,将2-溴代乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(1.3g,3.5mmol)溶于无水N,N-二甲基甲酰胺(30ml)中,往其中加入碳酸钾(1.5g,11mmol)、碘甲烷(1.6g,11mmol)和4-(2-氨基乙基)吡啶(0.43,g 3.5mmol),并将该混合物在75℃的外部温度下搅拌过夜。将水(100ml)和乙醚(100ml)加到反应混合物中,使其分配,乙醚层顺序用水(70ml)洗涤两次,用饱和氯化钠水溶液(120ml)洗涤一次并经无水硫酸镁干燥。减压浓缩乙醚层,浓缩物经硅胶柱色谱纯化,得到0.6g(40%)油状的标题化合物。
IR(neat):3312,2902,2846,1651,1602,1454cm-1
采用类似于实施例18的方法,获得下列化合物。
·3-[N′-甲基-N′-(4-吡啶基甲基)]氨基丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物18-2)
IR(neat):2902,2846,1643cm-1
·2-[2-(4-吡啶基)乙氧基]乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物18-3)
IR(neat):2902,2846,1650,1602,1451,1113cm-1
实施例19
·(R)-1-[2-(4-吡啶基)乙基]-2-吡咯烷甲酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺盐酸盐(化合物19-1)
将N-叔丁氧羰基-L-脯氨酸(1.7g,8.0mmol)溶于无水四氢呋喃(20ml)中,并将该溶液在-15℃和氮气氛下搅拌。往该溶液中加入N-甲基吗啉(0.90ml,8.0mmol)和氯代碳酸异丁基酯(1.0ml,8.0mmol)。10分钟后,用5分钟往该混合物中滴加中间体1-1的游离碱(2.0g,8.0mmol)的无水四氢呋喃(20ml)溶液。将其在0℃搅拌45分钟,然后使温度升至室温,并将其搅拌过夜。将饱和碳酸氢钠水溶液(50ml)和乙酸乙酯(50ml)加到该反应混合物中,使其分配。乙酸乙酯层顺序用10%柠檬酸溶液(50ml)、水(50ml)和饱和氯化钠水溶液(50ml)洗涤并经无水硫酸镁干燥。减压浓缩乙酸乙酯层,浓缩物经硅胶柱色谱纯化,得到1.9g(52%)油状的(R)-1-(叔丁氧羰基)-2-吡咯烷甲酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺,该化合物是目标化合物。
然后,在冰冷却下,将4N氯化氢/二噁烷(20ml,81mmol)加到(R)-1-(叔丁氧羰基)-2-吡咯烷甲酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(1.8g,4.0mmol),然后使温度升至室温,并将该混合物搅拌1.5小时。减压浓缩反应混合物,得到1.5g(定量)非晶固体(R)-2-吡咯烷甲酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺盐酸盐。
然后,将(R)-2-吡咯烷甲酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺盐酸盐(1.4g,3.7mmol)溶于无水N,N-二甲基甲酰胺(40ml)中,往该溶液中加入碳酸钾(2.6g,19mmol)、碘甲烷(1.7g,11mmol)和4-(2-氯乙基)吡啶盐酸盐(0.70g,3.7mmol),并将该混合物在80℃的外部温度下搅拌过夜。将2N氢氧化钠水溶液(70ml)和乙醚(70ml)加到该反应混合物中,使其分配,乙醚层顺序用处水(70ml)和饱和氯化钠水溶液(70ml)洗涤并经无水硫酸镁干燥。减压浓缩乙醚层,浓缩物经硅胶柱色谱纯化,得到0.80g(47%)油状的标题化合物。
IR(neat):2902,2846,1644cm-1
[α]20 D:-48.1°(MeOH,C 1.0)
采用类似于实施例19的方法,获得下列化合物。
·(S)-1-[2-(4-吡啶基)乙基]-2-吡咯烷甲酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺盐酸盐(化合物19-2)
IR(neat):2902,2846,1601cm-1
[α]20 D:+41.6°(MeOH,C 1.0)
实施例20
·1-[2-(1-金刚烷基)乙基]-1-[2-(N-乙基氨基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物20-1)
在氮气氛下,将氢化铝锂(890mg,23.5mmol)悬浮于无水乙醚(10ml)中,并在冰冷却和搅拌下,用2小时将1-[2-(乙酰氨基)乙基]-1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-103)(4.86g,11.4mmol)的无水四氢呋喃(60ml)溶液滴加到该悬浮液中。使温度升至室温,并将该混合物搅拌70小时。在冰冷却下,将乙酸乙酯(25ml)加到该反应混合物中,然后往其中加入1N氢氧化钠水溶液(25ml),并将其通过硅藻土过滤,以除去不溶物。滤液分配到乙酸乙酯(25ml)和水(25ml)中,有机层用饱和氯化钠水溶液(20ml)洗涤。有机层经无水硫酸镁干燥,减压蒸发溶剂,残余物经硅胶柱色谱纯化,得到标题化合物(2.33g,49.8%)。
IR(KBr):3309,2901,2845,1615,1534cm-1
mp:96.8-104.9℃
实施例21
·3-(4-吡啶基亚甲基氨基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物21-1)
将3-(叔丁氧羰基氨基)丙酸(1.0g,5.3mmol)溶于无水四氢呋喃(15ml)中,并往其中加入N-甲基吗啉(0.6ml,5.5mmol)。将其在-15℃搅拌,并往其中加入氯代碳酸异丁基酯(0.7ml,5.4mmol)。然后在-18℃下往其中加入2-(1-金刚烷基)-N-戊基乙胺盐酸盐(中间体1-1)的游离碱(1.5g,5.3mmol)的无水四氢呋喃(15ml)溶液。将其在0℃搅拌1.5小时,往该反应混合物中加入乙酸乙酯(100ml)和饱和碳酸氢钠水溶液(100ml),使其分配。有机层顺序用10%柠檬酸水溶液(100ml)、水(100ml)和饱和氯化钠水溶液(100ml)洗涤并经无水硫酸镁干燥。减压浓缩有机层,浓缩物经硅胶柱色谱纯化,得到1.9g(85%)油状的3-(叔丁氧羰基氨基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺。
在冰冷却下,将4.0N氯化氢/1,4-二噁烷(22ml,88mmol)加到3-(叔丁氧羰基氨基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(1.9g,4.4mmol)中。并将该混合物搅拌1小时15分钟。减压浓缩反应混合物,得到1.4g(89%)目标物的盐酸盐。往该盐酸盐中加入1N氢氧化钠水溶液(80ml),并将其用氯仿(80ml)萃取。氯仿层用饱和氯化钠水溶液(80ml)洗涤并经无水硫酸镁干燥。减压浓缩氯仿层,得到油状的3-氨基丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺。
将3-氨基丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺溶于无水四氢呋喃(10ml),并将该溶液在冰冷却下搅拌。将4-吡啶甲醛(0.42ml,4.3mmol)加到该溶液中,并将其在室温搅拌3小时。减压浓缩反应混合物,得到1.7g(定量)油状的标题化合物。
IR(neat):2901,1713,1644,1454cm-1
实施例22
·3-(4-吡啶基甲基氨基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物22-1)
将3-(4-吡啶基亚甲基氨基)丙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物21-1)(1.6g,3.9mmol)溶于甲醇,将10%钯碳(催化量的)加到该溶液中,并将该混合物在1个大气压的氢气和室温下搅拌7小时。滤除10%钯碳,减压浓缩滤液,浓缩液经硅胶柱色谱纯化,得到0.58g(36%)油状的标题化合物。
IR(neat):3313,2902,2846,1636,1451cm-1
实施例23
·1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-氰基)吡啶基]丙基]-1-戊基脲(化合物23-1)
在室温和氮气氛下,将三甲基甲硅烷基氰化物(1.2ml,9.4mmol)和三乙胺(0.65ml,4.7mmol)加到4-[3-[3-[2-(1-金刚烷基)乙基]-3-戊基脲基]丙基]吡啶N-氧化物(化合物16-1)(1.0g,2.3mmol)的无水乙腈(1.5ml)的溶液中,并将该混合物回流过夜。将反应混合物分配到氯仿(40ml)和饱和碳酸氢钠水溶液(40ml)中。有机层用饱和氯化钠水溶液(10ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,滤出所得残余物,并用二异丙基醚洗涤,得到730mg(73.0%)结晶的标题化合物。
IR(KBr):3334,2900,2845,2234,1621,1534cm-1
mp:112.0-123.0℃
实施例24
·1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-氨基甲基)吡啶基]丙基]-1-戊基脲(化合物24-1)
在氮气氛下,将催化量的10%钯碳加到1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-氰基)吡啶基]丙基]-1-戊基脲(化合物23-1)(0.20g,0.46mmol)的甲醇(2.0ml)溶液中,并将该混合物在氢气氛下搅拌过夜。将反应混合物通过硅藻土过滤,减压蒸发溶剂,将所得残余物分配到乙醚(50ml)和水(50ml)中。将2N氢氧化钠水溶液(10ml)加到水层中,将其进一步用乙醚(50ml)萃取。合并的有机层用饱和氯化钠水溶液(10ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,滤出所得残余物,用二异丙基醚洗涤,得到151mg(74.4%)结晶的标题化合物。
IR(KBr):3346,2901,2845,1621,1538cm-1
mp:88.0-95.0℃
实施例25
·1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-羧基)吡啶基]丙基]-1-戊基脲(化合物25-1)
在室温下,将6N盐酸(1.5ml,9.2mmol)加到1-[2-(1-金刚烷基)乙基]-3-[3-[4-[(2-氰基)吡啶基]丙基]-1-戊基脲(化合物23-1)(0.20g,0.46mmol)中,并将该混合物回流过夜。减压蒸发反应混合物的溶剂,滤出所得结晶,用丙酮洗涤。将结晶溶于氯仿(40ml),该溶液顺序用水(40ml)和饱和氯化钠水溶液(10ml)洗涤。有机层经无水硫酸镁干燥,减压蒸发溶剂,得到132mg(63.0%)标题化合物。
IR(KBr):3326,2905,2848,1704,1621,1539cm-1
mp:130℃
实施例26
·1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-羟甲基)吡啶基]丙基]-1-戊基脲(化合物26-1)
在氮气氛和冰冷却下,将1.0M硼烷-四氢呋喃复合物的四氢呋喃溶液(0.66ml,0.66mmol)加到1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-羧基)吡啶基]丙基]-1-戊基脲(化合物25-1)(0.10g,0.22mmol)的无水四氢呋喃(0.7ml)溶液中,并将该混合物在室温搅拌4.5小时。在冰冷却下,将水(3ml)加到反应混合物中,并将其分配到乙酸乙酯(15ml)和0.1%氢氧化钠水溶液(10ml)中。有机层用饱和氯化钠水溶液(10ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到53mg油状的标题化合物的硼烷配盐。
IR(neat):3342,2904,1630,1531cm-1
实施例27
·1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-甲基)吡啶基]丙基]-1-戊基脲(化合物27-1)
在室温下,将对甲苯磺酰氯(23mg,0.12mmol)加到1-[2-(1-金刚烷基)乙基]-3-[3-[4-(2-羟甲基)吡啶基]丙基]-1-戊基脲(化合物26-1)(50mg,0.11mmol)和三乙胺(20μl,0.13mmol)在无水二氯甲烷(1.0ml)中的溶液中,并将该混合物在室温搅拌过夜。将反应混合物分配到氯仿(9ml)和水(10ml)中,有机层经无水硫酸镁干燥。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化。将催化量的10%钯碳加到所得对甲苯磺酰基形式的甲醇(1ml)溶液中,并将该混合物在氢气氛下搅拌7天,得到18mg(38%)油状标题化合物。
IR(neat):3345,2903,2847,1624,1534cm-1
实施例28
·1-[2-(1-金刚烷基)乙基]-1-(2-氨基乙基)-3-[3-(4-吡啶基)丙基]脲(化合物28-1)
在冰冷却下,将6N盐酸(15ml)加到1-[2-(乙酰氨基)乙基]-1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]脲(化合物1-103)(1.02g,2.39mmol)的甲醇(10ml)溶液中,并将该混合物在90℃加热搅拌3天。用1N氢氧化钠水溶液(10ml)中和该反应混合物,往其中加入氯仿(50ml)和水(10ml),并分层。有机层用饱和氯化钠水溶液(50ml)洗涤并经无水硫酸镁干燥,减压蒸发溶剂。残余物经硅胶柱色谱纯化,得到200mg(21.7%)油状的标题化合物。
IR(neat):3306,2902,2846,1629,1605,1537,753cm-1
实施例29
·4-[2-[N-[2-(1-金刚烷基)乙基]-N-戊基羰基甲氧基]乙氧基]吡啶N-氧化物(化合物29-1)
在冰冷却下,将2-(1-金刚烷基)-N-戊基乙胺盐酸盐(中间体1-1)(0.50g,1.7mmol)加到二甘醇酰氯(0.31ml,2.6mmol)和三乙胺(0.70ml,5.1mmol)的无水二氯甲烷(6ml)溶液中,并将该混合物在室温搅拌过夜。将甲醇(5ml)加到该反应混合物中,将其搅拌3小时。减压蒸发溶剂,将残余物分配到乙酸乙酯和水(分别为15ml)中,有机层用饱和氯化钠水溶液(5ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到0.39g(60%)油状的2-甲氧羰基甲氧基乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺。
然后,在冰冷却下,将硼氢化钠(0.18g,4.8mmol)加到2-甲氧羰基甲氧基乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(0.37g,0.96mmol)的甲醇(3ml)溶液中,并将该混合物在室温搅拌过夜。将水(10ml)加到反应混合物中,将其搅拌10分钟。然后往其中加入水(20ml)和乙酸乙酯(30ml),并分层。有机层用饱和氯化钠水溶液(10ml)洗涤并经无水硫酸镁干燥。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到74mg(22%)油状的2-(2-羟基乙氧基)乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺。
然后,在室温下,将4-硝基吡啶N-氧化物(24mg,0.17mmol)和碳酸钾(28mg,0.20mmol)加到2-(2-羟基乙氧基)乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(60mg,0.17mmol)的N,N-二甲基甲酰胺(0.4ml)溶液中,并将该混合物在60℃搅拌2天。减压蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到39mg油状的标题化合物。
1H-NMR(400MHz,CDCl3)δ0.87-0.93(m,3H),1.20-1.40(m,6H),1.47-1.60(m,8H),1.61-1.67(m,3H),1.68-1.76(m,3H),1.97(brs,3H),3.10-3.19(m,2H),3.25-3.36(m,2H),3.94-3.98(m,2H),4.20-4.27(m,4H),6.81-6.86(m,2H),8.10-8.15(m,2H)
实施例30
·2-[2-(4-吡啶基氧)乙氧基]乙酸N-[2-(1-金刚烷基)乙基]-N-戊基酰胺(化合物30-1)
在室温和氮气氛下,将催化量的10%钯碳加到4-[2-[N-[2-(1-金刚烷基)乙基]-N-戊基羰基甲氧基]乙氧基]吡啶N-氧化物(化合物29-1)(39mg,0.088mmol)和乙酸酐(20μl,0.18mmol)在甲醇(0.4m)和乙酸(0.1ml)的混合溶剂中的溶液中,并将该混合物在氢气氛下搅拌4天。用硅藻土过滤该反应混合物,减压蒸发滤液的溶剂,残余物分配到乙酸乙酯(20ml)和饱和碳酸氢钠水溶液(20m)中。有机层用饱和氯化钠水溶液(10ml)洗涤并经无水硫酸镁干燥。蒸发溶剂,所得残余物经硅胶柱色谱纯化,得到16mg(42%)油状标题化合物。
IR(neat):2903,1651,1592cm-1
实施例31
·1-[2-(1-金刚烷基)乙基]-3-[3-氧代-3-(4-吡啶基)丙基]-1-戊基脲(化合物31-1)
在冰冷却下,将1,1,1-三乙酰氧基-1,1-二氢-1,2-苯并碘杂茂(benziodoxol)-3(1H)-酮(221mg,0.520mmol)加到1-[2-(1-金刚烷基)乙基]-3-[3-羟基-3-(4-吡啶基)丙基]-1-戊基脲(100mg,0.234mmol)的无水二氯甲烷(2ml)溶液中,使温度升至室温,并将其搅拌1小时。该反应混合物再次用冰冷却,将乙酸乙酯(10ml)、饱和亚硫酸钠水溶液(5ml)和饱和碳酸氢钠水溶液(5ml)加到反应混合物中,并将其搅拌15分钟。将反应混合物分配到乙酸乙酯(50ml)和水(10ml)中,有机层顺序用饱和亚硫酸钠水溶液(5ml)、饱和碳酸氢钠水溶液(5ml)和饱和氯化钠水溶液(25ml)洗涤。有机层经无水硫酸镁干燥,减压蒸发溶剂,得到87.3mg(87.8%)无色结晶的标题化合物。
IR(KBr):3328,2901,2847,1710,1619,1540cm-1
mp:103.5-104.0℃
[C]制剂
下面显示了使用本发明化合物的口服制剂和注射剂的一般制剂实施例。
1)片剂
配方1(100mg)
本发明化合物 1mg
乳糖 66.4mg
玉米淀粉 20mg
羧甲基纤维素钙 6mg
羟丙基纤维素 4mg
硬脂酸镁 0.6mg
上述配方的片剂用2mg/片的包衣剂(为常规包衣剂,例如羟丙基甲基纤维素、大粒凝胶或硅氧烷树脂),获得所需的包衣片。(包衣剂可同样应用于下面的片剂)。通过适当改变本发明化合物和添加剂的量可获得所需的片剂。
2)胶囊
配方1(150mg)
本发明化合物 5mg
乳糖 145mg
通过适当改变本发明化合物与乳糖的混合比例可获得所需胶囊。
3)注射剂
配方1(10ml)
本发明 10-1000mg
氯化钠 90mg
氢氧化钠 适量
盐酸 适量
无菌纯化水 适量
通过适当改变本发明化合物与添加剂的比例可获得所需的注射剂。
[D]药理学试验
按照Tsuji等的方法(Inflamm.res.46(1997)193-198),通过体内试验研究对由脂多糖(LPS)刺激诱发的TNF-α生成的抑制作用。
使用体重为约200g、约8周龄的雌性大鼠作为试验动物(每组5只)。将得自沙门氏菌的LPS溶于生理盐水,制备LPS溶液(1mg/ml)。将各种试验物质溶于或均匀地悬浮于1%甲基纤维素溶液,得到试验物质-制剂液体。
将上述LPS溶液(0.5ml/kg)施于大鼠的爪垫。LPS给药后,立即经口服给予试验物质-制剂液体(包含10mg/kg或3mg/kg试验物质)。LPS给予后2小时,从腹动脉收集血样并在4℃和3000rpm离心10分钟。用TNF-α特异性ELISA试剂盒测定所得血浆中的TNF-α水平。未施与LPS的组(对照)的血浆中没有观察到TNF-α。
通过下式测定试验物质对TNF-α生成的抑制率。
抑制率(%)=[(A-B)/A]×100
A:未给予试验物质组的血浆TNF-α水平
B:给予了试验物质组的血浆TNF-α水平
(结果)
当经口服给予大鼠试验物质(10mg/kg或3mg/kg)时,计算对TNF-α生成的抑制率(%),许多本发明化含物对TNF-α的生成表现出高抑制率。表1显示了口服给予10mg/kg的试验结果,表2显示了口服给予3mg/kg的试验结果。
表1
试验物质 | 抑制率(%) | 试验物质 | 抑制率(%) |
化合物1-1 | 92.1 | 化合物1-42 | 86.7 |
化合物1-18 | 78.9 | 化合物1-43 | 67.6 |
化合物1-20 | 60.0 | 化合物1-44 | 93.7 |
化合物1-22 | 87.0 | 化合物1-45 | 91.1 |
化合物1-24 | 95.8 | 化合物1-55 | 78.1 |
化合物1-25 | 89.0 | 化合物1-66 | 79.4 |
化合物1-26 | 95.5 | 化合物1-68 | 79.0 |
化合物1-27 | 81.3 | 化合物1-70 | 87.9 |
化合物1-28 | 90.4 | 化合物1-120 | 95.1 |
化合物1-31 | 92.6 | 化合物1-139 | 94.1 |
化合物1-32 | 62.4 | 化合物2-1 | 91.5 |
化合物1-34 | 70.8 | 化合物2-3 | 51.8 |
化合物1-35 | 82.5 | 化合物6-1 | 50.5 |
化合物1-37 | 84.3 | 化合物7-1 | 71.5 |
化合物1-38 | 92.3 | 化合物11-1 | 50.8 |
表2
试验物质 | 抑制率(%) | 试验物质 | 抑制率(%) |
化合物1-10 | 63.0 | 化合物4-1 | 42.8 |
化合物1-78 | 61.5 | 化合物5-3 | 49.4 |
化合物1-84 | 35.5 | 化合物5-4 | 62.6 |
化合物1-95 | 70.8 | 化合物5-5 | 42.8 |
化合物1-111 | 85.1 | 化合物5-6 | 41.7 |
化合物1-137 | 82.1 | 化合物10-16 | 62.8 |
化合物2-7 | 78.7 | 化合物10-17 | 53.8 |
化合物2-9 | 84.5 | 化合物14-1 | 36.3 |
化合物2-11 | 53.5 | 化合物15-1 | 73.8 |
化合物2-14 | 87.3 | 化合物16-1 | 74.3 |
化合物2-15 | 68.1 | 化合物18-1 | 55.7 |
化合物2-18 | 87.3 | 化合物18-3 | 56.6 |
化合物2-20 | 82.1 | 化合物27-1 | 68.6 |
化合物3-4 | 76.1 | 化合物31-1 | 46.8 |
工业实用性
药理学试验的结果清楚地显示出,由于本发明化合物表现出出色的TNF-α生成抑制作用,本发明化合物可用于广泛的医药用途,作为其中有TNF-α参与的疾病的治疗剂,例如自身免疫疾病如类风湿性关节炎、克隆病和系统性红斑狼疮、恶病质、急性感染性疾病、变态反应、发热、贫血、糖尿病等。
Claims (15)
1.通式[1]表示的化合物或其盐,
其中“A”是-(NR4)-;
“B”是C1-6亚烷基;
R1、R2和R4相同或不同,为氢、C1-12烷基或C2-12链烯基,其中C1-12烷基可被卤素、C3-8环烷基、金刚烷基或苯基取代;R1、R2和R4中的至少一个为C3-8环烷基C1-12烷基、金刚烷基C1-12烷基或苯基C1-12烷基;
R3是可以形成N-氧化物的吡啶环,其中,吡啶环可以被卤素、C1-6烷基取代;
“X”是0。
2.权利要求1的化合物或其盐,其中R1和R2中的至少一个是金刚烷基C1-12烷基。
3.权利要求1的化合物或其盐,其中
“A”是-(NR4)-;
“B”是C1-6亚烷基;
R1是C1-12烷基或C2-12链烯基,其中C1-12烷基可被卤素、C3-8环烷基或苯基取代;
R2是金刚烷基C1-12烷基;
R3是吡啶环;
R4是氢、C1-12烷基或金刚烷基C1-12烷基;
“X”是0。
4.权利要求3的化合物或其盐,其中
“A”是-(NR4)-;
“B”是C1-6亚烷基,
R1是C1-12烷基或C2-12链烯基,其中C1-12烷基可被卤素取代;
R2是金刚烷基C1-12烷基;
R3是吡啶环;
R4是氢;
“X”是0。
5.选自下组化合物的化合物:
·1-[2-(1-金刚烷基)乙基]-1-戊基-3-[3-(4-吡啶基)丙基]脲,
·1-[2-(1-金刚烷基)乙基]-3-[3-(4-吡啶基)丙基]-1-(3,3,3-三氟丙基)脲,
·1-[2-(1-金刚烷基)乙基]-1-(2-丁烯基)-3-[3-(4-吡啶基)丙基]脲,
·1-[3-(1-金刚烷基)丙基]-1-丙基-3-[3-(4-吡啶基)丙基]脲,
·(-)-1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲,
·1-[2-(1-金刚烷基)乙基]-3-[1-甲基-3-(4-吡啶基)丙基]-1-戊基脲,
·1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲,和
·(+)-1-[2-(1-金刚烷基)乙基]-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲或其盐。
6.权利要求1的化合物或其盐,其中
“A”是-(NR4)-;
R1是C1-12烷基或C2-12链烯基,其中C1-12烷基可被卤素、C3-8环烷基或苯基取代;
R2是C3-8环烷基C1-12烷基或苯基C1-12烷基;
R3是吡啶环;
R4是氢、C1-12烷基或金刚烷基C1-12烷基;
“X”是0。
7.权利要求6的化合物或其盐,其中
“A”是-(NR4)-;
R1是C1-12烷基或C2-12链烯基,其中C1-12烷基可被卤素、C3-8环烷基或苯基取代;
R2是苯基C1-12烷基;
R3是吡啶环;
R4是氢;并且
“X”是0。
8.权利要求7的化合物或其盐,其中R1是C1-12烷基并且R2是苯基C1-12烷基。
9.选自如下的化合物:
·3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基-1-苯乙基脲。
10.权利要求6的化合物或其盐,其中
“A”是-(NR4)-;
R1是C1-12烷基、C2-12链烯基,其中C1-12烷基可被卤素、C3-8环烷基或苯基取代;
R2是C3-8环烷基C1-12烷基;
R3是吡啶环;
R4是氢;并且
“X”是0。
11.1-(2-环己基乙基)-3-[2-甲基-3-(4-吡啶基)丙基]-1-戊基脲或其盐。
12.一种药物组合物,其含有权利要求1-11任一项的化合物或其盐作为活性成分。
13.一种TNF-α生成抑制剂,其含有权利要求1-11任一项的化合物或其盐作为活性成分。
14.一种自身免疫疾病治疗剂,其含有权利要求1-11任一项的化合物或其盐作为活性成分。
15.一种抗风湿病的药物,其含有权利要求1-11任一项的化合物或其盐作为活性成分。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000162945 | 2000-05-31 | ||
JP162945/2000 | 2000-05-31 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018102336A Division CN1284771C (zh) | 2000-05-31 | 2001-05-31 | TNF-α生成抑制剂 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1590375A CN1590375A (zh) | 2005-03-09 |
CN1324012C true CN1324012C (zh) | 2007-07-04 |
Family
ID=18666780
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004100546746A Expired - Fee Related CN1307159C (zh) | 2000-05-31 | 2001-05-31 | TNF-α生成抑制剂 |
CNB200410054677XA Expired - Fee Related CN1324012C (zh) | 2000-05-31 | 2001-05-31 | TNF-α生成抑制剂 |
CNB018102336A Expired - Fee Related CN1284771C (zh) | 2000-05-31 | 2001-05-31 | TNF-α生成抑制剂 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004100546746A Expired - Fee Related CN1307159C (zh) | 2000-05-31 | 2001-05-31 | TNF-α生成抑制剂 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018102336A Expired - Fee Related CN1284771C (zh) | 2000-05-31 | 2001-05-31 | TNF-α生成抑制剂 |
Country Status (15)
Country | Link |
---|---|
US (5) | US7098226B2 (zh) |
EP (4) | EP1561749B1 (zh) |
JP (4) | JP3867196B2 (zh) |
KR (2) | KR100978304B1 (zh) |
CN (3) | CN1307159C (zh) |
AT (4) | ATE481385T1 (zh) |
AU (3) | AU6067401A (zh) |
CA (2) | CA2409741C (zh) |
CY (1) | CY1107089T1 (zh) |
DE (4) | DE60143098D1 (zh) |
DK (1) | DK1302461T3 (zh) |
ES (4) | ES2293993T3 (zh) |
NO (2) | NO324472B1 (zh) |
PT (1) | PT1302461E (zh) |
WO (1) | WO2001092229A1 (zh) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60143098D1 (de) * | 2000-05-31 | 2010-10-28 | Santen Pharmaceutical Co Ltd | (Pyridinyl)alkyl-Amide oder -Harnstoffe als TNF-alpha Bildung Inhibitoren |
WO2003045367A1 (fr) * | 2001-11-30 | 2003-06-05 | Santen Pharmaceutical Co., Ltd. | Inhibiteur d'angiogenese |
NZ534757A (en) | 2002-03-12 | 2006-07-28 | Merck & Co Inc | Substituted amides |
US7652039B2 (en) | 2002-05-17 | 2010-01-26 | Sequella, Inc. | Methods of use and compositions for the diagnosis and treatment of infectious disease |
US7456222B2 (en) | 2002-05-17 | 2008-11-25 | Sequella, Inc. | Anti tubercular drug: compositions and methods |
US20040033986A1 (en) | 2002-05-17 | 2004-02-19 | Protopopova Marina Nikolaevna | Anti tubercular drug: compositions and methods |
WO2005034857A2 (en) | 2003-09-05 | 2005-04-21 | Sequella, Inc. | Methods and compositions comprising diamines as new anti-tubercular therapeutics |
WO2005102332A1 (ja) * | 2004-04-27 | 2005-11-03 | Santen Pharmaceutical Co., Ltd. | 変形性関節症治療剤 |
WO2005102331A1 (ja) * | 2004-04-27 | 2005-11-03 | Santen Pharmaceutical Co., Ltd. | 骨粗鬆症治療剤 |
UA87854C2 (en) * | 2004-06-07 | 2009-08-25 | Мерк Энд Ко., Инк. | N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators |
WO2006035760A1 (ja) * | 2004-09-27 | 2006-04-06 | Santen Pharmaceutical Co., Ltd. | 皮膚疾患治療剤 |
WO2006035759A1 (ja) * | 2004-09-27 | 2006-04-06 | Santen Pharmaceutical Co., Ltd. | 呼吸器疾患治療剤 |
WO2006043518A1 (ja) * | 2004-10-18 | 2006-04-27 | Santen Pharmaceutical Co., Ltd. | 神経疾患治療剤 |
KR101496206B1 (ko) * | 2005-01-05 | 2015-02-27 | 애브비 인코포레이티드 | 11-베타-하이드록시스테로이드 데하이드로게나제 타입 1 효소의 억제제로서의 아다만틸 유도체 |
WO2006074330A2 (en) * | 2005-01-05 | 2006-07-13 | Abbott Laboratories | Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme |
US20090192198A1 (en) | 2005-01-05 | 2009-07-30 | Abbott Laboratories | Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme |
US8562629B2 (en) * | 2006-10-24 | 2013-10-22 | Arthrocare Corporation | Suture device having selective needle actuation and related method |
EP1935420A1 (en) | 2006-12-21 | 2008-06-25 | Merck Sante | 2-Adamantyl-butyramide derivatives as selective 11beta-HSD1 inhibitors |
WO2009020603A2 (en) * | 2007-08-08 | 2009-02-12 | The Scripps Research Institute | Upp amphiphilic alpha-helix mimetics |
CA2702455A1 (en) * | 2007-10-16 | 2009-04-23 | Santen Pharmaceutical Co., Ltd. | Therapeutic agent for trpv1-mediated disease |
CN102196810B (zh) * | 2008-10-22 | 2013-11-06 | 参天制药株式会社 | 改善肠吸收性的药物组合物 |
HRP20090186A2 (hr) | 2009-03-31 | 2010-10-31 | Institut Ruđer Bošković | Adamantanski bisureidni derivati, metoda priprave i primjena u detekciji aniona |
KR101231412B1 (ko) * | 2009-12-29 | 2013-02-07 | 실트로닉 아게 | 실리콘 웨이퍼 및 그 제조 방법 |
US9856214B2 (en) | 2013-11-15 | 2018-01-02 | The Wistar Institute Of Anatomy And Biology | EBNA1 inhibitors and their method of use |
JP6771491B2 (ja) | 2015-05-14 | 2020-10-21 | ザ ウィスター インスティテュート オブ アナトミー アンド バイオロジー | Ebna1阻害剤およびその使用方法 |
EP3793546A4 (en) | 2018-05-17 | 2021-12-08 | The Wistar Institute | CRYSTALLINE FORMS OF EBNA1-INHIBITOR AND METHOD OF MANUFACTURING AND USING THEREOF |
CN110423216B (zh) * | 2019-08-26 | 2021-01-05 | 浙江工业大学 | 一种2-(1-金刚烷甲酰胺基)乙基甲酸酯类化合物及其制备方法和应用 |
WO2024084056A1 (en) * | 2022-10-21 | 2024-04-25 | Etherna Immunotherapies Nv | Ionizable lipids |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999050238A1 (fr) * | 1998-03-26 | 1999-10-07 | Santen Pharmaceutical Co., Ltd. | Nouveaux derives d'uree |
WO2000007985A1 (fr) * | 1998-08-05 | 2000-02-17 | Santen Pharmaceutical Co., Ltd. | Nouveaux derives d'uree renfermant des heterocycles aromatiques azotes |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2640055A (en) * | 1951-01-06 | 1953-05-26 | Warner Hudnut Inc | Amides |
CH500979A (de) * | 1967-02-16 | 1970-12-31 | Shimamoto Takio | Verfahren zur Herstellung von Pyridinmethylcarbamaten |
US3682922A (en) * | 1969-01-16 | 1972-08-08 | Searle & Co | N-acyl-n-{8 (n{40 ,n{40 -disubstituted amino)-alkyl{9 -1-adamantylmethylamines |
US4597902A (en) | 1981-05-20 | 1986-07-01 | A. H. Robins Company, Incorporated | N-(arylthioalkyl)-N'-(aminoalkyl)ureas |
US4724235A (en) | 1981-05-20 | 1988-02-09 | A. H. Robins Company, Incorporated | N-(arylthioalkyl)-N'-(aminoalkyl)ureas useful in the treatment of arrhythmia |
US4555515A (en) * | 1985-02-25 | 1985-11-26 | Stauffer Chemical Co. | Pyridylpropyl carbamates as insect repellents |
US5599944A (en) * | 1987-03-24 | 1997-02-04 | Bayer Aktiengesellschaft | Intermediates for herbicidal sulphonylaminocarbonyltriazolinones having substituents which are bonded via sulphur |
US5776963A (en) * | 1989-05-19 | 1998-07-07 | Hoechst Marion Roussel, Inc. | 3-(heteroaryl)-1- (2,3-dihydro-1h-isoindol-2-yl)alkyl!pyrrolidines and 3-(heteroaryl)-1- (2,3-dihydro-1h-indol-1-yl)alkyl!pyrrolidines and related compounds and their therapeutic untility |
FR2664269B1 (fr) * | 1990-07-05 | 1992-10-02 | Roussel Uclaf | Nouveaux derives n-substitues d'alpha-mercapto alkylamines, leur procede de preparation, leur application a titre de medicaments et les compositions les renfermant. |
US5173506A (en) | 1990-08-16 | 1992-12-22 | Schering Corporation | N-(mercaptoalkyl)ureas and carbamates |
CA2095429A1 (en) * | 1990-11-06 | 1992-05-07 | Paul E. Bender | Imidazolidinone compounds |
NZ242054A (en) * | 1991-03-22 | 1993-11-25 | British Tech Group | Pyridine derivatives having a bridged alicyclic group; medicaments |
GB9401129D0 (en) | 1994-01-21 | 1994-03-16 | British Bio Technology | Hydroxamic acid derivatives as metalloproteinase inhibitors |
AU1884595A (en) * | 1994-04-29 | 1995-11-29 | Pfizer Inc. | Novel acyclic and cyclic amides as neurotransmitter release enhancers |
DE69634822T2 (de) * | 1995-08-22 | 2006-04-27 | Japan Tobacco Inc. | Amid-verbindungen und ihre anwendung |
GB9526558D0 (en) | 1995-12-27 | 1996-02-28 | Fujisawa Pharmaceutical Co | Heterobicyclic derivatives |
GB9526560D0 (en) | 1995-12-27 | 1996-02-28 | Bayer Ag | Use of 2-Amino-Heterocycles |
EP0880511A4 (en) * | 1996-01-16 | 1999-06-16 | Merck & Co Inc | INTEGRIN RECEPTOR ANTAGONISTS |
IT1283637B1 (it) | 1996-05-14 | 1998-04-23 | Italfarmaco Spa | Composti ad attivita' antinfiammatoria ed immunosoppressiva |
JP2001506257A (ja) * | 1996-12-17 | 2001-05-15 | 藤沢薬品工業株式会社 | Mmpまたはtnf阻害剤としてのピペラジン化合物 |
ATE228590T1 (de) | 1997-09-17 | 2002-12-15 | Chemiefaser Lenzing Ag | Verfahren zur behandlung von cellulosefasern |
EP0903434B1 (de) | 1997-09-17 | 2002-11-27 | Lenzing Aktiengesellschaft | Verfahren zur Behandlung von Cellulosefasern |
JP3603177B2 (ja) | 1998-03-26 | 2004-12-22 | 参天製薬株式会社 | 新規ウレア誘導体 |
JP3472917B2 (ja) | 1998-08-05 | 2003-12-02 | 参天製薬株式会社 | 含窒素芳香族複素環を有する新規ウレア誘導体 |
AU3631500A (en) * | 1999-03-19 | 2000-10-09 | Du Pont Pharmaceuticals Company | N-adamant-1-yl-n'-(4-chlorobenzothiazol-2-yl) urea useful in the treatment of inflammation and as an anticancer radiosensitizing agent |
KR20010112408A (ko) | 1999-04-07 | 2001-12-20 | 모리타 다카카즈 | N-치환되고-N'-치환된 우레아 유도체 및 TNF-α 생성억제제로서의 그의 용도 |
DE29910780U1 (de) * | 1999-06-21 | 1999-09-16 | Hahn Schickard Ges | Halte- und Betätigungsvorrichtung |
DE60143098D1 (de) * | 2000-05-31 | 2010-10-28 | Santen Pharmaceutical Co Ltd | (Pyridinyl)alkyl-Amide oder -Harnstoffe als TNF-alpha Bildung Inhibitoren |
WO2003045367A1 (fr) | 2001-11-30 | 2003-06-05 | Santen Pharmaceutical Co., Ltd. | Inhibiteur d'angiogenese |
-
2001
- 2001-05-31 DE DE60143098T patent/DE60143098D1/de not_active Expired - Lifetime
- 2001-05-31 CN CNB2004100546746A patent/CN1307159C/zh not_active Expired - Fee Related
- 2001-05-31 KR KR1020087023872A patent/KR100978304B1/ko not_active IP Right Cessation
- 2001-05-31 AU AU6067401A patent/AU6067401A/xx active Pending
- 2001-05-31 AT AT05290274T patent/ATE481385T1/de not_active IP Right Cessation
- 2001-05-31 EP EP05290275A patent/EP1561749B1/en not_active Expired - Lifetime
- 2001-05-31 CN CNB200410054677XA patent/CN1324012C/zh not_active Expired - Fee Related
- 2001-05-31 AT AT01934447T patent/ATE374186T1/de active
- 2001-05-31 DE DE60140495T patent/DE60140495D1/de not_active Expired - Lifetime
- 2001-05-31 DK DK01934447T patent/DK1302461T3/da active
- 2001-05-31 KR KR1020027016230A patent/KR100880698B1/ko not_active IP Right Cessation
- 2001-05-31 WO PCT/JP2001/004586 patent/WO2001092229A1/ja active IP Right Grant
- 2001-05-31 CA CA2409741A patent/CA2409741C/en not_active Expired - Fee Related
- 2001-05-31 ES ES01934447T patent/ES2293993T3/es not_active Expired - Lifetime
- 2001-05-31 EP EP05290274A patent/EP1568692B1/en not_active Expired - Lifetime
- 2001-05-31 US US10/168,777 patent/US7098226B2/en not_active Expired - Fee Related
- 2001-05-31 ES ES05290274T patent/ES2353020T3/es not_active Expired - Lifetime
- 2001-05-31 ES ES05290275T patent/ES2284138T3/es not_active Expired - Lifetime
- 2001-05-31 EP EP01934447A patent/EP1302461B1/en not_active Expired - Lifetime
- 2001-05-31 ES ES06076696T patent/ES2339141T3/es not_active Expired - Lifetime
- 2001-05-31 JP JP2001164523A patent/JP3867196B2/ja not_active Expired - Fee Related
- 2001-05-31 CA CA2736344A patent/CA2736344A1/en not_active Abandoned
- 2001-05-31 AT AT06076696T patent/ATE448204T1/de not_active IP Right Cessation
- 2001-05-31 EP EP06076696A patent/EP1743885B1/en not_active Expired - Lifetime
- 2001-05-31 AT AT05290275T patent/ATE358122T1/de not_active IP Right Cessation
- 2001-05-31 CN CNB018102336A patent/CN1284771C/zh not_active Expired - Fee Related
- 2001-05-31 DE DE60130658T patent/DE60130658T2/de not_active Expired - Lifetime
- 2001-05-31 PT PT01934447T patent/PT1302461E/pt unknown
- 2001-05-31 AU AU2001260674A patent/AU2001260674B2/en not_active Ceased
- 2001-05-31 DE DE60127595T patent/DE60127595T2/de not_active Expired - Lifetime
-
2002
- 2002-11-28 NO NO20025718A patent/NO324472B1/no not_active IP Right Cessation
-
2006
- 2006-02-28 AU AU2006200864A patent/AU2006200864B2/en not_active Ceased
- 2006-05-19 JP JP2006140241A patent/JP4482735B2/ja not_active Expired - Fee Related
- 2006-06-07 US US11/448,634 patent/US7491739B2/en not_active Expired - Fee Related
- 2006-06-22 US US11/472,603 patent/US7345064B2/en not_active Expired - Fee Related
-
2007
- 2007-06-29 NO NO20073371A patent/NO20073371L/no not_active Application Discontinuation
- 2007-08-15 US US11/893,238 patent/US20080182881A1/en not_active Abandoned
- 2007-12-14 CY CY20071101588T patent/CY1107089T1/el unknown
-
2009
- 2009-09-23 US US12/586,515 patent/US7923461B2/en not_active Expired - Fee Related
- 2009-12-14 JP JP2009283085A patent/JP2010059205A/ja active Pending
- 2009-12-14 JP JP2009283084A patent/JP2010059204A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999050238A1 (fr) * | 1998-03-26 | 1999-10-07 | Santen Pharmaceutical Co., Ltd. | Nouveaux derives d'uree |
WO2000007985A1 (fr) * | 1998-08-05 | 2000-02-17 | Santen Pharmaceutical Co., Ltd. | Nouveaux derives d'uree renfermant des heterocycles aromatiques azotes |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1324012C (zh) | TNF-α生成抑制剂 | |
CN1078889C (zh) | 非肽类速激肽受体拮抗剂 | |
CN1207289C (zh) | 金属蛋白酶抑制剂,含有它们的药物组合物和其药物用途,其制备方法和中间体 | |
CN1290825C (zh) | 邻位、间位取代的双芳基化合物、它们的制备方法、它们作为药物的用途和含有它们的药物制剂 | |
CN1045595C (zh) | 合成3-氨基哌啶衍生物的中间体的制备方法 | |
CN1179945C (zh) | 吲哚衍生物、其制备方法及用途 | |
CN1537102A (zh) | 用作钾通道抑制剂的邻位取代的含氮双芳基化合物 | |
CN1224614C (zh) | 吲哚满-2-酮衍生物、其制备方法及其作为催产素受体配体的应用 | |
CN1309720C (zh) | 哌嗪化合物 | |
CN1195738C (zh) | 2′-取代的1,1′-联苯-2-甲酰胺、它们的制备方法、作为药物的用途和含有它们的药物制剂 | |
CN1125064C (zh) | 3-吡啶基对映体及其作为镇痛剂的用途 | |
CN1169792C (zh) | 取代的乙烯基吡啶衍生物和含有它们的药物 | |
CN1604776A (zh) | 作为用于治疗神经病综合症的pde-4抑制剂的4-(4-烷氧基-3-羟基苯基)-2-吡咯烷酮衍生物 | |
CN1599724A (zh) | 咪唑-4-羧酰胺衍生物及其制备和用于治疗肥胖症的方法 | |
CN101080226A (zh) | 酰氨基化合物及它们作为药物的用途 | |
CN1910144A (zh) | 用于疾病治疗的磺胺衍生物 | |
CN1703397A (zh) | 磺酰基氨基-乙酸衍生物及其作为阿立新受体拮抗剂的应用 | |
CN1805929A (zh) | 磷酸二酯酶4抑制剂 | |
CN101031541A (zh) | 4-氨基甲基苄脒衍生物及其作为因子Ⅷa抑制剂的用途 | |
CN1444573A (zh) | 甲酰胺化合物及其作为人11cby受体拮抗剂的用途 | |
CN1520402A (zh) | 非对称环二胺化合物 | |
CN101039916A (zh) | 作为大电导钙激活k通道开启剂的咪唑衍生物 | |
CN1894240A (zh) | 阿片受体拮抗剂 | |
CN1217932C (zh) | 抗菌剂 | |
CN1604774A (zh) | 血管生成抑制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C41 | Transfer of patent application or patent right or utility model | ||
TR01 | Transfer of patent right |
Effective date of registration: 20160329 Address after: Tokyo, Japan, Japan Patentee after: Step Pharmaceutical Company Limited Address before: Osaka Japan Patentee before: Santen Pharmaceutical Co., Ltd. |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070704 Termination date: 20170531 |
|
CF01 | Termination of patent right due to non-payment of annual fee |