CN1307159C - TNF-α生成抑制剂 - Google Patents
TNF-α生成抑制剂 Download PDFInfo
- Publication number
- CN1307159C CN1307159C CNB2004100546746A CN200410054674A CN1307159C CN 1307159 C CN1307159 C CN 1307159C CN B2004100546746 A CNB2004100546746 A CN B2004100546746A CN 200410054674 A CN200410054674 A CN 200410054674A CN 1307159 C CN1307159 C CN 1307159C
- Authority
- CN
- China
- Prior art keywords
- compound
- adamantyl
- ethyl
- pyridyl
- propyl
- 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
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 title description 16
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 title description 16
- 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 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 371
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 63
- 239000001257 hydrogen Substances 0.000 claims abstract description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 18
- 230000006433 tumor necrosis factor production Effects 0.000 claims abstract description 16
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 10
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- QVHCDIXOASJMAN-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]pentan-1-amine Chemical compound C1C(C2)CC3CC2CC1(CCNCCCCC)C3 QVHCDIXOASJMAN-UHFFFAOYSA-N 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- BXUVXRODAMZIAZ-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-2-(2-pyridin-4-ylethylsulfanyl)acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CSCCC1=CC=NC=C1 BXUVXRODAMZIAZ-UHFFFAOYSA-N 0.000 claims description 5
- RAPHLBWFMHYIDV-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-5-pyridin-4-ylpentanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CCCCC1=CC=NC=C1 RAPHLBWFMHYIDV-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- HVPRNDSHZDOEKF-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-3-(pyridin-4-ylmethylsulfanyl)propanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CCSCC1=CC=NC=C1 HVPRNDSHZDOEKF-UHFFFAOYSA-N 0.000 claims description 4
- JEUZRAOJTMEPSJ-UHFFFAOYSA-N n-pentyl-n-(2-phenylethyl)-5-pyridin-4-ylpentanamide Chemical compound C=1C=NC=CC=1CCCCC(=O)N(CCCCC)CCC1=CC=CC=C1 JEUZRAOJTMEPSJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 2
- GJIMUROXBBUAQJ-UHFFFAOYSA-N 6-pyridin-4-ylhexanoic acid Chemical compound OC(=O)CCCCCC1=CC=NC=C1 GJIMUROXBBUAQJ-UHFFFAOYSA-N 0.000 claims 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 27
- 125000003118 aryl group Chemical group 0.000 abstract description 16
- 125000003342 alkenyl group Chemical group 0.000 abstract description 14
- 125000004450 alkenylene group Chemical group 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 abstract description 8
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 239000001301 oxygen Substances 0.000 abstract description 5
- 229940124597 therapeutic agent Drugs 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 195
- 239000000243 solution Substances 0.000 description 124
- 239000000543 intermediate Substances 0.000 description 121
- 239000000203 mixture Substances 0.000 description 114
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000011541 reaction mixture Substances 0.000 description 81
- 229920006395 saturated elastomer Chemical group 0.000 description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- 239000012044 organic layer Substances 0.000 description 70
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 64
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- -1 amino, hydroxy Chemical group 0.000 description 51
- 238000010898 silica gel chromatography Methods 0.000 description 50
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 238000001816 cooling Methods 0.000 description 39
- 239000002904 solvent Substances 0.000 description 38
- 238000002360 preparation method Methods 0.000 description 36
- 239000011780 sodium chloride Substances 0.000 description 34
- 239000010410 layer Substances 0.000 description 33
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 32
- 239000003921 oil Substances 0.000 description 30
- 235000019198 oils Nutrition 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- 239000013078 crystal Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 25
- 235000017557 sodium bicarbonate Nutrition 0.000 description 24
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000004202 carbamide Substances 0.000 description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 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 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000002158 endotoxin Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 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
- 239000002585 base Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 239000012280 lithium aluminium hydride Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 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
- 229910052717 sulfur Inorganic materials 0.000 description 9
- DFTPIBFPPYDWEC-UHFFFAOYSA-N 5-pyridin-4-ylpentanoic acid Chemical compound OC(=O)CCCCC1=CC=NC=C1 DFTPIBFPPYDWEC-UHFFFAOYSA-N 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- UOOOCYFGAHYTSG-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]pentan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCNCCCCC)C3 UOOOCYFGAHYTSG-UHFFFAOYSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- 150000003335 secondary amines Chemical class 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000003141 primary amines Chemical class 0.000 description 6
- YWJSTJKZGMYFRH-WAYWQWQTSA-N 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[(z)-3-pyridin-4-ylprop-2-enyl]urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NC\C=C/C1=CC=NC=C1 YWJSTJKZGMYFRH-WAYWQWQTSA-N 0.000 description 5
- HPQYWBQXGAYWHZ-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-3-[3-(1-oxidopyridin-1-ium-4-yl)propyl]-1-pentylurea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NCCCC1=CC=[N+]([O-])C=C1 HPQYWBQXGAYWHZ-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 206010020751 Hypersensitivity Diseases 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
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- OTOGOOXMAOJQSH-UHFFFAOYSA-N n-[2-[2-(1-adamantyl)ethyl-(3-pyridin-4-ylpropylcarbamoyl)amino]ethyl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCNC(=O)C)C(=O)NCCCC1=CC=NC=C1 OTOGOOXMAOJQSH-UHFFFAOYSA-N 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 5
- KVEZXCUOYZFWFT-UHFFFAOYSA-N (2-methyl-3-pyridin-4-ylpropyl) n-[2-(1-adamantyl)ethyl]-n-pentylcarbamate Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)OCC(C)CC1=CC=NC=C1 KVEZXCUOYZFWFT-UHFFFAOYSA-N 0.000 description 4
- RBNPERAXQUZNCT-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-1-amino-3-(3-pyridin-4-ylpropyl)urea;dihydrochloride Chemical compound Cl.Cl.C1C(C2)CC(C3)CC2CC13CCN(N)C(=O)NCCCC1=CC=NC=C1 RBNPERAXQUZNCT-UHFFFAOYSA-N 0.000 description 4
- MHBZVASHZYXXNB-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-(4-pyridin-4-ylbutan-2-yl)urea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NC(C)CCC1=CC=NC=C1 MHBZVASHZYXXNB-UHFFFAOYSA-N 0.000 description 4
- XFOLXQRCHOAHDJ-UHFFFAOYSA-N 1-[2-(1-adamantyl)ethyl]-3-(3-hydroxy-3-pyridin-4-ylpropyl)-1-pentylurea Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)NCCC(O)C1=CC=NC=C1 XFOLXQRCHOAHDJ-UHFFFAOYSA-N 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-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
- 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
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- 241000700159 Rattus Species 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
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- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 4
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 4
- AKQZDJIZNCKJSP-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-3-(pyridin-4-ylmethylideneamino)propanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CCN=CC1=CC=NC=C1 AKQZDJIZNCKJSP-UHFFFAOYSA-N 0.000 description 4
- VHSWYAUVJJYAAS-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-n-pentyl-6-pyridin-4-ylhexanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)CCCCCC1=CC=NC=C1 VHSWYAUVJJYAAS-UHFFFAOYSA-N 0.000 description 4
- 238000005192 partition Methods 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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- 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
- CLCGLDBXZNIGSN-UHFFFAOYSA-N n-[2-[2-(1-adamantyl)ethyl-(3-pyridin-4-ylpropylcarbamoyl)amino]ethyl]-n,3,3-trimethylbutanamide Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCN(C)C(=O)CC(C)(C)C)C(=O)NCCCC1=CC=NC=C1 CLCGLDBXZNIGSN-UHFFFAOYSA-N 0.000 description 1
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- QRGMHLNCNMTOOO-UHFFFAOYSA-N n-[3-(1-adamantyl)propyl]butan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCCNCCCC)C3 QRGMHLNCNMTOOO-UHFFFAOYSA-N 0.000 description 1
- FZAADKUAINUUOF-UHFFFAOYSA-N n-[3-(1-adamantyl)propyl]pentan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(CCCNCCCCC)C3 FZAADKUAINUUOF-UHFFFAOYSA-N 0.000 description 1
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- ZHIAZZWWYFQHPQ-UHFFFAOYSA-N n-methyl-n-pentyladamantan-1-amine;hydrochloride Chemical compound Cl.C1C(C2)CC3CC2CC1(N(C)CCCCC)C3 ZHIAZZWWYFQHPQ-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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
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- NSTHNVMITOXEJZ-TYYBGVCCSA-N oxalic acid;(e)-3-pyridin-4-ylprop-2-enal Chemical compound OC(=O)C(O)=O.O=C\C=C\C1=CC=NC=C1 NSTHNVMITOXEJZ-TYYBGVCCSA-N 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N pentanoic acid group Chemical group C(CCCC)(=O)O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
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- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- PYNUOAIJIQGACY-UHFFFAOYSA-N propylazanium;chloride Chemical compound Cl.CCCN PYNUOAIJIQGACY-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 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
- CBMBSAWCELAEFR-UHFFFAOYSA-N tert-butyl 3-[2-(1-adamantyl)ethylcarbamoyl-(3-pyridin-4-ylpropyl)amino]propanoate Chemical compound C1C(C2)CC(C3)CC2CC13CCNC(=O)N(CCC(=O)OC(C)(C)C)CCCC1=CC=NC=C1 CBMBSAWCELAEFR-UHFFFAOYSA-N 0.000 description 1
- JWBHGQPTFKPYLI-UHFFFAOYSA-N tert-butyl 3-[2-cyclohexylethyl(pyridin-4-ylmethylcarbamoyl)amino]propanoate Chemical compound C=1C=NC=CC=1CNC(=O)N(CCC(=O)OC(C)(C)C)CCC1CCCCC1 JWBHGQPTFKPYLI-UHFFFAOYSA-N 0.000 description 1
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-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
- IXHBUBNGCHLSKI-UHFFFAOYSA-N tert-butyl N-methyl-N-[3-phenyl-3-(3-pyridin-4-ylpropylcarbamoylamino)butyl]carbamate Chemical compound C(C)(C)(C)OC(=O)N(C)CCC(C)(C1=CC=CC=C1)NC(=O)NCCCC1=CC=NC=C1 IXHBUBNGCHLSKI-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 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
- CNXYWLPHGMOCQV-UHFFFAOYSA-N tert-butyl n-[1-[2-(1-adamantyl)ethyl-pentylamino]-1-oxo-3-(pyridin-4-ylmethylsulfanyl)propan-2-yl]carbamate Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)C(NC(=O)OC(C)(C)C)CSCC1=CC=NC=C1 CNXYWLPHGMOCQV-UHFFFAOYSA-N 0.000 description 1
- PLZNEQILFLBHON-UHFFFAOYSA-N tert-butyl n-[2-(1-adamantyl)ethyl-pentylcarbamoyl]-n-(2-pyridin-4-yloxyethyl)carbamate Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCCCC)C(=O)N(C(=O)OC(C)(C)C)CCOC1=CC=NC=C1 PLZNEQILFLBHON-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
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- JSJROSBIFNFPRJ-UHFFFAOYSA-N tert-butyl n-[2-[2-(1-adamantyl)ethyl-(3-pyridin-4-ylpropylcarbamoyl)amino]ethyl]carbamate Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCNC(=O)OC(C)(C)C)C(=O)NCCCC1=CC=NC=C1 JSJROSBIFNFPRJ-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
- KIGSVKIVUVBZPA-UHFFFAOYSA-N tert-butyl n-[2-[2-cyclohexylethyl(pyridin-4-ylmethylcarbamoyl)amino]ethyl]-n-methylcarbamate Chemical compound C=1C=NC=CC=1CNC(=O)N(CCN(C)C(=O)OC(C)(C)C)CCC1CCCCC1 KIGSVKIVUVBZPA-UHFFFAOYSA-N 0.000 description 1
- QPYBUGNGRZGZAH-UHFFFAOYSA-N tert-butyl n-[2-[3-(1-adamantyl)propylamino]ethyl]-n-methylcarbamate Chemical compound C1C(C2)CC3CC2CC1(CCCNCCN(C)C(=O)OC(C)(C)C)C3 QPYBUGNGRZGZAH-UHFFFAOYSA-N 0.000 description 1
- NPNYVHXUYPXUSI-UHFFFAOYSA-N tert-butyl n-[2-[3-methylbutyl(3-pyridin-4-ylpropylcarbamoyl)amino]-3-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)N(CCC(C)C)C(=O)NCCCC1=CC=NC=C1 NPNYVHXUYPXUSI-UHFFFAOYSA-N 0.000 description 1
- DTCXEAIRKNDNID-UHFFFAOYSA-N tert-butyl n-[3-[2-(1-adamantyl)ethyl-pentylamino]-3-oxopropyl]carbamate Chemical compound C1C(C2)CC3CC2CC1(CCN(CCCCC)C(=O)CCNC(=O)OC(C)(C)C)C3 DTCXEAIRKNDNID-UHFFFAOYSA-N 0.000 description 1
- MEHBFBZIYWSMDC-UHFFFAOYSA-N tert-butyl n-[3-[2-(1-adamantyl)ethylamino]propyl]-n-methylcarbamate Chemical compound C1C(C2)CC3CC2CC1(CCNCCCN(C)C(=O)OC(C)(C)C)C3 MEHBFBZIYWSMDC-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
- 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
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- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 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
- 150000003672 ureas Chemical class 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
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- A61P7/06—Antianaemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Transplantation (AREA)
- Physical Education & Sports Medicine (AREA)
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- Obesity (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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| CNB018102336A Expired - Fee Related CN1284771C (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 |
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| CNB018102336A Expired - Fee Related CN1284771C (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 |
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| EP (4) | EP1302461B1 (enExample) |
| JP (4) | JP3867196B2 (enExample) |
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| CN (3) | CN1307159C (enExample) |
| AT (4) | ATE374186T1 (enExample) |
| AU (3) | AU6067401A (enExample) |
| CA (2) | CA2736344A1 (enExample) |
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| DE (4) | DE60143098D1 (enExample) |
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| PT (1) | PT1302461E (enExample) |
| WO (1) | WO2001092229A1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2284138T3 (es) * | 2000-05-31 | 2007-11-01 | Santen Pharmaceutical Co., Ltd. | Inhibidores de la produccion de tnf-alfa para el tratamiento de enfermedades autoinmunes. |
| US7741346B2 (en) * | 2001-11-30 | 2010-06-22 | Santen Pharmaceutical Co., Ltd. | Angiogenesis inhibitor |
| WO2003077847A2 (en) | 2002-03-12 | 2003-09-25 | Merck & Co., Inc. | Substituted amides |
| 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 |
| US7652039B2 (en) | 2002-05-17 | 2010-01-26 | Sequella, Inc. | Methods of use and compositions for the diagnosis and treatment of infectious disease |
| 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 |
| WO2006035759A1 (ja) * | 2004-09-27 | 2006-04-06 | Santen Pharmaceutical Co., Ltd. | 呼吸器疾患治療剤 |
| WO2006035760A1 (ja) * | 2004-09-27 | 2006-04-06 | Santen Pharmaceutical Co., Ltd. | 皮膚疾患治療剤 |
| 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 |
| US20090192198A1 (en) | 2005-01-05 | 2009-07-30 | Abbott Laboratories | Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme |
| EP1846362A2 (en) * | 2005-01-05 | 2007-10-24 | 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 |
| EP2666767A1 (en) * | 2007-10-16 | 2013-11-27 | 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 |
| RU2404157C1 (ru) * | 2009-02-16 | 2010-11-20 | Государственное образовательное учреждение высшего профессионального образования Волгоградский государственный технический университет (ВолгГТУ) | Способ получения n-(1-адамантилалкил)циклоалкиламинов |
| HRP20090186A2 (hr) | 2009-03-31 | 2010-10-31 | Institut Ruđer Bošković | Adamantanski bisureidni derivati, metoda priprave i primjena u detekciji aniona |
| US8357939B2 (en) * | 2009-12-29 | 2013-01-22 | Siltronic Ag | Silicon wafer and production method therefor |
| MX2016006325A (es) | 2013-11-15 | 2016-12-02 | Wistar Inst | Inhibidores del antígeno nuclear 1 de epstein-barr, y su método de uso. |
| KR102616818B1 (ko) | 2015-05-14 | 2023-12-22 | 더 위스타 인스티튜트 오브 아나토미 앤드 바이올로지 | Ebna1 억제제 및 그의 사용 방법 |
| CN112543634A (zh) | 2018-05-17 | 2021-03-23 | 威斯达研究所 | Ebna1抑制剂晶体形式及其制备和使用方法 |
| 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 |
| CN120303251A (zh) * | 2022-10-21 | 2025-07-11 | 伊泽阿恩埃免疫疗法股份有限公司 | 可电离脂质 |
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| WO2000007985A1 (en) * | 1998-08-05 | 2000-02-17 | Santen Pharmaceutical Co., Ltd. | Novel urea derivatives bearing nitrogenous aromatic heterocycles |
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| ATE228590T1 (de) | 1997-09-17 | 2002-12-15 | Chemiefaser Lenzing Ag | Verfahren zur behandlung von cellulosefasern |
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| 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 |
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| 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 |
| ES2284138T3 (es) * | 2000-05-31 | 2007-11-01 | Santen Pharmaceutical Co., Ltd. | Inhibidores de la produccion de tnf-alfa para el tratamiento de enfermedades autoinmunes. |
| US7741346B2 (en) | 2001-11-30 | 2010-06-22 | Santen Pharmaceutical Co., Ltd. | Angiogenesis inhibitor |
-
2001
- 2001-05-31 ES ES05290275T patent/ES2284138T3/es not_active Expired - Lifetime
- 2001-05-31 ES ES05290274T patent/ES2353020T3/es not_active Expired - Lifetime
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- 2001-05-31 DE DE60143098T patent/DE60143098D1/de not_active Expired - Lifetime
- 2001-05-31 DE DE60140495T patent/DE60140495D1/de not_active Expired - Lifetime
- 2001-05-31 KR KR1020087023872A patent/KR100978304B1/ko not_active Expired - Fee Related
- 2001-05-31 KR KR1020027016230A patent/KR100880698B1/ko not_active Expired - Fee Related
- 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 CN CNB2004100546746A patent/CN1307159C/zh not_active Expired - Fee Related
- 2001-05-31 CN CNB018102336A patent/CN1284771C/zh not_active Expired - Fee Related
- 2001-05-31 AT AT01934447T patent/ATE374186T1/de active
- 2001-05-31 EP EP01934447A patent/EP1302461B1/en not_active Expired - Lifetime
- 2001-05-31 DE DE60130658T patent/DE60130658T2/de not_active Expired - Lifetime
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- 2001-05-31 EP EP05290274A patent/EP1568692B1/en not_active Expired - Lifetime
- 2001-05-31 AT AT05290274T patent/ATE481385T1/de not_active IP Right Cessation
- 2001-05-31 CN CNB200410054677XA patent/CN1324012C/zh not_active Expired - Fee Related
- 2001-05-31 WO PCT/JP2001/004586 patent/WO2001092229A1/ja not_active Ceased
- 2001-05-31 ES ES01934447T patent/ES2293993T3/es not_active Expired - Lifetime
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- 2001-05-31 DK DK01934447T patent/DK1302461T3/da active
- 2001-05-31 EP EP05290275A patent/EP1561749B1/en not_active Expired - Lifetime
- 2001-05-31 AU AU2001260674A patent/AU2001260674B2/en not_active Ceased
- 2001-05-31 PT PT01934447T patent/PT1302461E/pt unknown
- 2001-05-31 AT AT05290275T patent/ATE358122T1/de not_active IP Right Cessation
-
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 JP2009283084A patent/JP2010059204A/ja active Pending
- 2009-12-14 JP JP2009283085A patent/JP2010059205A/ja active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999050238A1 (en) * | 1998-03-26 | 1999-10-07 | Santen Pharmaceutical Co., Ltd. | Novel urea derivatives |
| WO2000007985A1 (en) * | 1998-08-05 | 2000-02-17 | Santen Pharmaceutical Co., Ltd. | Novel urea derivatives bearing nitrogenous aromatic heterocycles |
Non-Patent Citations (1)
| Title |
|---|
| PYRI DYLALKANOLS W-PYRIDYLALKANAMIDES AND W PYRIDYLALKYLAMINES-JOACHIM M MAYER BERNARD TESTA STRUCT URAL FACTORSAFFECTING THEBASICITYOFW,HELVETICA CHIMICA ACTA,Vol.65 No.183 1982 * |
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