ES2284138T3 - Inhibidores de la produccion de tnf-alfa para el tratamiento de enfermedades autoinmunes. - Google Patents
Inhibidores de la produccion de tnf-alfa para el tratamiento de enfermedades autoinmunes. Download PDFInfo
- Publication number
- ES2284138T3 ES2284138T3 ES05290275T ES05290275T ES2284138T3 ES 2284138 T3 ES2284138 T3 ES 2284138T3 ES 05290275 T ES05290275 T ES 05290275T ES 05290275 T ES05290275 T ES 05290275T ES 2284138 T3 ES2284138 T3 ES 2284138T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- adamantyl
- quad
- aryl
- compound
- 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 - Lifetime
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- 238000004519 manufacturing process Methods 0.000 title claims description 19
- 239000003112 inhibitor Substances 0.000 title claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 123
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 70
- 229920006395 saturated elastomer Chemical group 0.000 claims abstract description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 23
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 14
- 150000002367 halogens Chemical group 0.000 claims abstract description 14
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 10
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 8
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims abstract description 5
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims abstract description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims abstract description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims abstract description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 3
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 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 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- XROGXXDLFGZJEI-UHFFFAOYSA-N 2-[2-[1-[2-(1-adamantyl)ethyl]-2H-pyridin-4-yl]ethylsulfanyl]-N-pentylacetamide Chemical compound C(CCCC)NC(CSCCC1=CCN(C=C1)CCC12CC3CC(CC(C1)C3)C2)=O XROGXXDLFGZJEI-UHFFFAOYSA-N 0.000 claims description 2
- ORLSOMPCXOYQDH-UHFFFAOYSA-N 5-[1-[2-(1-adamantyl)ethyl]-2H-pyridin-4-yl]-N-pentylpentanamide Chemical compound C(CCCC)NC(CCCCC1=CCN(C=C1)CCC12CC3CC(CC(C1)C3)C2)=O ORLSOMPCXOYQDH-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000001363 autoimmune Effects 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- 230000003356 anti-rheumatic effect Effects 0.000 claims 1
- 239000003435 antirheumatic agent Substances 0.000 claims 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 1
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 34
- 239000000203 mixture Substances 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000126 substance Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- 239000007864 aqueous solution Substances 0.000 description 22
- 238000000034 method Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 239000002158 endotoxin Substances 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 208000026935 allergic disease Diseases 0.000 description 5
- 230000007815 allergy Effects 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 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 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- DFTPIBFPPYDWEC-UHFFFAOYSA-N 5-pyridin-4-ylpentanoic acid Chemical compound OC(=O)CCCCC1=CC=NC=C1 DFTPIBFPPYDWEC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-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 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 206010006895 Cachexia Diseases 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 208000011231 Crohn disease Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 3
- 206010037660 Pyrexia Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000027950 fever generation Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
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- 208000015181 infectious disease Diseases 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- QVHCDIXOASJMAN-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]pentan-1-amine Chemical compound C1C(C2)CC3CC2CC1(CCNCCCCC)C3 QVHCDIXOASJMAN-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 238000009519 pharmacological trial Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 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
- 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 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 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JURFPUSNTWSSPJ-UHFFFAOYSA-N 3-pyridin-4-ylpropan-1-amine Chemical compound NCCCC1=CC=NC=C1 JURFPUSNTWSSPJ-UHFFFAOYSA-N 0.000 description 2
- ZHRQMBYNDJPMBN-UHFFFAOYSA-N 5-[1-[3-(1-adamantyl)propyl]-2H-pyridin-4-yl]-N-propylpentanamide Chemical compound C(CC)NC(CCCCC1=CCN(C=C1)CCCC12CC3CC(CC(C1)C3)C2)=O ZHRQMBYNDJPMBN-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
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- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
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- 150000001408 amides Chemical class 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
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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 2
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- VFAAOGWVAACBND-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]-2-bromo-n-pentylacetamide Chemical compound C1C(C2)CC3CC2CC1(CCN(CCCCC)C(=O)CBr)C3 VFAAOGWVAACBND-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UEPYNCNDMALIHK-UHFFFAOYSA-N n-[2-(1-adamantyl)ethyl]propan-1-amine Chemical compound C1C(C2)CC3CC2CC1(CCNCCC)C3 UEPYNCNDMALIHK-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
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- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
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- 150000003335 secondary amines Chemical class 0.000 description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000006433 tumor necrosis factor production Effects 0.000 description 2
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
- 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-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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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- RWMRTGBPXPWRIZ-UHFFFAOYSA-N tert-butyl n-[2-[2-(1-adamantyl)ethyl-(3-pyridin-4-ylpropylcarbamoyl)amino]ethyl]-n-methylcarbamate Chemical compound C1C(C2)CC(C3)CC2CC13CCN(CCN(C)C(=O)OC(C)(C)C)C(=O)NCCCC1=CC=NC=C1 RWMRTGBPXPWRIZ-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
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
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- 125000005389 trialkylsiloxy group Chemical group 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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Classifications
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- 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
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—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
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—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
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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
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- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- 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
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- 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
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- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- 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
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| ES01934447T Expired - Lifetime ES2293993T3 (es) | 2000-05-31 | 2001-05-31 | Inhibidores de produccion de tnf-alfa. |
| ES06076696T Expired - Lifetime ES2339141T3 (es) | 2000-05-31 | 2001-05-31 | Compuestos de 1-((adamantil)alquil)-3-((piridinil)alquil)urea como inhibidores tnf-alfa utiles para enfermedades autoinmunes. |
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| ES06076696T Expired - Lifetime ES2339141T3 (es) | 2000-05-31 | 2001-05-31 | Compuestos de 1-((adamantil)alquil)-3-((piridinil)alquil)urea como inhibidores tnf-alfa utiles para enfermedades autoinmunes. |
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| 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 |
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| 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 |
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- 2001-05-31 WO PCT/JP2001/004586 patent/WO2001092229A1/ja not_active Ceased
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