ES2226488T3 - Compuestos utiles en el tratamiento de enfermedades inflamatorias. - Google Patents
Compuestos utiles en el tratamiento de enfermedades inflamatorias.Info
- Publication number
- ES2226488T3 ES2226488T3 ES99964583T ES99964583T ES2226488T3 ES 2226488 T3 ES2226488 T3 ES 2226488T3 ES 99964583 T ES99964583 T ES 99964583T ES 99964583 T ES99964583 T ES 99964583T ES 2226488 T3 ES2226488 T3 ES 2226488T3
- Authority
- ES
- Spain
- Prior art keywords
- amino
- phenyl
- oxy
- acetyl
- alkyl
- 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
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 211
- 238000011282 treatment Methods 0.000 title claims description 17
- 208000027866 inflammatory disease Diseases 0.000 title description 3
- -1 nitro, hydroxy Chemical group 0.000 claims abstract description 188
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 89
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 62
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 17
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 5
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims abstract description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000002785 azepinyl group Chemical group 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- GVONPBONFIJAHJ-UHFFFAOYSA-N imidazolidin-4-one Chemical compound O=C1CNCN1 GVONPBONFIJAHJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims abstract description 3
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims abstract description 3
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims abstract description 3
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims abstract description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 117
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 89
- 239000011347 resin Substances 0.000 claims description 86
- 229920005989 resin Polymers 0.000 claims description 86
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 71
- 235000019260 propionic acid Nutrition 0.000 claims description 70
- 239000001257 hydrogen Substances 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
- 239000002253 acid Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 26
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 24
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims description 22
- 239000012453 solvate Substances 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 10
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 6
- 239000004793 Polystyrene Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229920002223 polystyrene Polymers 0.000 claims description 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 4
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- PPSXZSXHLIIACO-HEVIKAOCSA-N (2s)-2-[[(2s)-2-[[2-(2-tert-butylphenoxy)acetyl]amino]-4-methylpentanoyl]amino]-3-[4-[4-[(2-phenylacetyl)amino]piperidine-1-carbonyl]oxyphenyl]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCC(CC2)NC(=O)CC=2C=CC=CC=2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C(C)(C)C PPSXZSXHLIIACO-HEVIKAOCSA-N 0.000 claims description 3
- FLJPNJMQUJHZIM-ZEQRLZLVSA-N (2s)-2-[[(2s)-4-methyl-2-[[2-(2-methylphenoxy)acetyl]amino]pentanoyl]amino]-3-[4-(morpholine-4-carbonyloxy)phenyl]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCOCC2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C FLJPNJMQUJHZIM-ZEQRLZLVSA-N 0.000 claims description 3
- PGTAKIDUHHSBIG-NSOVKSMOSA-N (2s)-3-[4-(4-acetylpiperazine-1-carbonyl)oxyphenyl]-2-[[(2s)-2-[[2-(2-tert-butylphenoxy)acetyl]amino]-4-methylpentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCN(CC2)C(C)=O)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C(C)(C)C PGTAKIDUHHSBIG-NSOVKSMOSA-N 0.000 claims description 3
- YNDIBNHBFJYOFE-ACHIHNKUSA-N (2s)-3-[4-(4-benzoylpiperazine-1-carbonyl)oxyphenyl]-2-[[(2s)-2-[[2-(2-tert-butylphenoxy)acetyl]amino]-4-methylpentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCN(CC2)C(=O)C=2C=CC=CC=2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C(C)(C)C YNDIBNHBFJYOFE-ACHIHNKUSA-N 0.000 claims description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 229920005990 polystyrene resin Polymers 0.000 claims description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- NKNFUWZGJLRHEF-SVBPBHIXSA-N (2s)-2-[[(2s)-2-(dibenzofuran-4-carbonylamino)-4-methylpentanoyl]amino]-3-[4-(morpholine-4-carbonyloxy)phenyl]propanoic acid Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)C=1C=2OC3=CC=CC=C3C=2C=CC=1)CC(C)C)C(O)=O)C(C=C1)=CC=C1OC(=O)N1CCOCC1 NKNFUWZGJLRHEF-SVBPBHIXSA-N 0.000 claims description 2
- ODUJTJVQQFNWEX-PXLJZGITSA-N (2s)-2-[[(2s)-2-(dibenzofuran-4-carbonylamino)-4-methylpentanoyl]amino]-3-[4-[4-[(2-phenylacetyl)amino]piperidine-1-carbonyl]oxyphenyl]propanoic acid Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)C=1C=2OC3=CC=CC=C3C=2C=CC=1)CC(C)C)C(O)=O)C(C=C1)=CC=C1OC(=O)N(CC1)CCC1NC(=O)CC1=CC=CC=C1 ODUJTJVQQFNWEX-PXLJZGITSA-N 0.000 claims description 2
- HUHLSTSVAXPHTF-VMPREFPWSA-N (2s)-2-[[(2s)-2-[[2-(1-bromonaphthalen-2-yl)oxyacetyl]amino]-4-methylpentanoyl]amino]-3-[4-[4-(furan-2-carbonyl)piperazine-1-carbonyl]oxyphenyl]propanoic acid Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)COC=1C(=C2C=CC=CC2=CC=1)Br)CC(C)C)C(O)=O)C(C=C1)=CC=C1OC(=O)N(CC1)CCN1C(=O)C1=CC=CO1 HUHLSTSVAXPHTF-VMPREFPWSA-N 0.000 claims description 2
- SBCVXKWLVINGKC-ZEQRLZLVSA-N (2s)-2-[[(2s)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-[4-(morpholine-4-carbonyloxy)phenyl]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCOCC2)=CC=1)C(O)=O)C(=O)OCC1=CC=CC=C1 SBCVXKWLVINGKC-ZEQRLZLVSA-N 0.000 claims description 2
- VVZPENFOQVEKIV-VMPREFPWSA-N (2s)-2-[[(2s)-4-methyl-2-[[2-[4-(piperidine-1-carbonyl)phenoxy]acetyl]amino]pentanoyl]amino]-3-[4-(morpholine-4-carbonyloxy)phenyl]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCOCC2)=CC=1)C(O)=O)C(=O)COC(C=C1)=CC=C1C(=O)N1CCCCC1 VVZPENFOQVEKIV-VMPREFPWSA-N 0.000 claims description 2
- JPJAYGCKRULCOQ-UIOOFZCWSA-N (2s)-3-[4-(4-acetylpiperazine-1-carbonyl)oxyphenyl]-2-[[(2s)-4-methyl-2-[[2-(2-methylphenoxy)acetyl]amino]pentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCN(CC2)C(C)=O)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C JPJAYGCKRULCOQ-UIOOFZCWSA-N 0.000 claims description 2
- BTPNIOFQMCTNHX-KYJUHHDHSA-N (2s)-3-[4-(4-carbamoylpiperidine-1-carbonyl)oxyphenyl]-2-[[(2s)-4-methyl-2-[[2-[4-(piperidine-1-carbonyl)phenoxy]acetyl]amino]pentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCC(CC2)C(N)=O)=CC=1)C(O)=O)C(=O)COC(C=C1)=CC=C1C(=O)N1CCCCC1 BTPNIOFQMCTNHX-KYJUHHDHSA-N 0.000 claims description 2
- LWTXVGKEFCWSEV-UIOOFZCWSA-N (2s)-3-[4-[4-(furan-2-carbonyl)piperazine-1-carbonyl]oxyphenyl]-2-[[(2s)-2-[[2-(2-iodophenoxy)acetyl]amino]-4-methylpentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCN(CC2)C(=O)C=2OC=CC=2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1I LWTXVGKEFCWSEV-UIOOFZCWSA-N 0.000 claims description 2
- KMSVUEKDRPJQNE-BCRBLDSWSA-N (2s)-3-[4-[4-[(2-cyclohexylacetyl)amino]piperidine-1-carbonyl]oxyphenyl]-2-[[(2s)-2-[[2-(2-cyclohexylphenoxy)acetyl]amino]-4-methylpentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCC(CC2)NC(=O)CC2CCCCC2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C1CCCCC1 KMSVUEKDRPJQNE-BCRBLDSWSA-N 0.000 claims description 2
- AZUVFLGTAWFMHP-CONSDPRKSA-N (2s)-3-[4-[4-[(2-cyclohexylacetyl)amino]piperidine-1-carbonyl]oxyphenyl]-2-[[(2s)-2-[[2-(2-iodophenoxy)acetyl]amino]-4-methylpentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCC(CC2)NC(=O)CC2CCCCC2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1I AZUVFLGTAWFMHP-CONSDPRKSA-N 0.000 claims description 2
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 2
- OXRSFHYBIRFJSF-UHFFFAOYSA-N 3-phenyl-1,4-dihydropyrazol-5-one Chemical compound N1C(=O)CC(C=2C=CC=CC=2)=N1 OXRSFHYBIRFJSF-UHFFFAOYSA-N 0.000 claims description 2
- ORSUMIZRRGPJBR-UHFFFAOYSA-N 4,5-dihydro-1h-pyridazin-6-one Chemical compound O=C1CCC=NN1 ORSUMIZRRGPJBR-UHFFFAOYSA-N 0.000 claims description 2
- 101100118680 Caenorhabditis elegans sec-61.G gene Proteins 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
- MNASXWZLHZIIKC-BCRBLDSWSA-N (2s)-2-[[(2s)-2-[[2-(2-benzoylphenoxy)acetyl]amino]-4-methylpentanoyl]amino]-3-[4-[4-[(2-phenylacetyl)amino]piperidine-1-carbonyl]oxyphenyl]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCC(CC2)NC(=O)CC=2C=CC=CC=2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C(=O)C1=CC=CC=C1 MNASXWZLHZIIKC-BCRBLDSWSA-N 0.000 claims 1
- RZMCXMNNXGCFQG-DQEYMECFSA-N (2s)-3-[4-(4-carbamoylpiperidine-1-carbonyl)oxyphenyl]-2-[[(2s)-4-methyl-2-[[2-(2-methylphenoxy)acetyl]amino]pentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCC(CC2)C(N)=O)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C RZMCXMNNXGCFQG-DQEYMECFSA-N 0.000 claims 1
- SHNAAOJNYHBXJK-BCRBLDSWSA-N (2s)-3-[4-[4-[[2-(4-chlorophenyl)acetyl]amino]piperidine-1-carbonyl]oxyphenyl]-2-[[(2s)-2-[[2-(2-cyclohexylphenoxy)acetyl]amino]-4-methylpentanoyl]amino]propanoic acid Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(OC(=O)N2CCC(CC2)NC(=O)CC=2C=CC(Cl)=CC=2)=CC=1)C(O)=O)C(=O)COC1=CC=CC=C1C1CCCCC1 SHNAAOJNYHBXJK-BCRBLDSWSA-N 0.000 claims 1
- 230000001800 adrenalinergic effect Effects 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 239000000018 receptor agonist Substances 0.000 claims 1
- 229940044601 receptor agonist Drugs 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 460
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 297
- 239000000543 intermediate Substances 0.000 description 210
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 179
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 153
- 239000000243 solution Substances 0.000 description 141
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 130
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 129
- 239000000203 mixture Substances 0.000 description 122
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 113
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 110
- 238000003756 stirring Methods 0.000 description 104
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 103
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 101
- 239000007787 solid Substances 0.000 description 101
- 239000010410 layer Substances 0.000 description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 83
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 73
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 68
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 63
- 239000012299 nitrogen atmosphere Substances 0.000 description 59
- 239000000741 silica gel Substances 0.000 description 59
- 229910002027 silica gel Inorganic materials 0.000 description 59
- 238000003818 flash chromatography Methods 0.000 description 57
- 239000012043 crude product Substances 0.000 description 52
- 229920006395 saturated elastomer Polymers 0.000 description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- 239000006260 foam Substances 0.000 description 42
- 239000000284 extract Substances 0.000 description 41
- 235000017557 sodium bicarbonate Nutrition 0.000 description 41
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 41
- 239000002904 solvent Substances 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- 229910052938 sodium sulfate Inorganic materials 0.000 description 38
- 235000011152 sodium sulphate Nutrition 0.000 description 38
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 36
- 235000019441 ethanol Nutrition 0.000 description 34
- 239000012267 brine Substances 0.000 description 33
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 32
- 235000019341 magnesium sulphate Nutrition 0.000 description 32
- 239000000706 filtrate Substances 0.000 description 28
- 239000000725 suspension Substances 0.000 description 28
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 27
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 26
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9828074.6A GB9828074D0 (en) | 1998-12-18 | 1998-12-18 | Therapeutically useful compounds |
| GB9828074 | 1998-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2226488T3 true ES2226488T3 (es) | 2005-03-16 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES99964583T Expired - Lifetime ES2226488T3 (es) | 1998-12-18 | 1999-12-16 | Compuestos utiles en el tratamiento de enfermedades inflamatorias. |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US6867192B1 (https=) |
| EP (1) | EP1140837B1 (https=) |
| JP (1) | JP4431282B2 (https=) |
| KR (1) | KR20010101258A (https=) |
| CN (1) | CN1330637A (https=) |
| AR (1) | AR023727A1 (https=) |
| AT (1) | ATE273954T1 (https=) |
| AU (1) | AU760169B2 (https=) |
| BR (1) | BR9916282A (https=) |
| CA (1) | CA2355630A1 (https=) |
| CO (1) | CO5170533A1 (https=) |
| CZ (1) | CZ20012209A3 (https=) |
| DE (1) | DE69919580T2 (https=) |
| ES (1) | ES2226488T3 (https=) |
| GB (1) | GB9828074D0 (https=) |
| GT (1) | GT199900217A (https=) |
| HK (1) | HK1038744A1 (https=) |
| HU (1) | HUP0104867A3 (https=) |
| IL (1) | IL142908A0 (https=) |
| NO (1) | NO20012995L (https=) |
| NZ (1) | NZ511478A (https=) |
| PE (1) | PE20001387A1 (https=) |
| PL (1) | PL348059A1 (https=) |
| TR (1) | TR200101709T2 (https=) |
| WO (1) | WO2000037444A1 (https=) |
| ZA (1) | ZA200103948B (https=) |
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| EP1244656A1 (en) | 1999-12-28 | 2002-10-02 | Pfizer Products Inc. | Non-peptidyl inhibitors of vla-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases |
| GB0014869D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Novel pharmaceutical formulation |
| GB0014849D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Pharmaceutical aerosol formulation |
| GB0014883D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Novel pharmaceutical formulation |
| GB0014881D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Pharmaceutical aerosol formulation |
| GB0014851D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Novel pharmaceutical formulation |
| GB0014947D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Novel pharmaceutical formulation |
| GB0014892D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Novel pharmaceutical formulation |
| GB0127423D0 (en) * | 2001-11-15 | 2002-01-09 | Glaxo Group Ltd | Process |
| GB0218630D0 (en) | 2002-08-10 | 2002-09-18 | Tanabe Seiyaku Co | Novel compounds |
| AU2004240940A1 (en) | 2003-05-20 | 2004-12-02 | Genentech, Inc. | Thiocarbamate inhibitors of alpha-4 integrins |
| TW201422238A (zh) | 2004-06-04 | 2014-06-16 | Genentech Inc | Ｃｄ２０抗體於治療多發性硬化症之用途及用於該用途之物品 |
| US9158106B2 (en) | 2005-02-23 | 2015-10-13 | Pixtronix, Inc. | Display methods and apparatus |
| US8482496B2 (en) | 2006-01-06 | 2013-07-09 | Pixtronix, Inc. | Circuits for controlling MEMS display apparatus on a transparent substrate |
| US9261694B2 (en) | 2005-02-23 | 2016-02-16 | Pixtronix, Inc. | Display apparatus and methods for manufacture thereof |
| US20070205969A1 (en) | 2005-02-23 | 2007-09-06 | Pixtronix, Incorporated | Direct-view MEMS display devices and methods for generating images thereon |
| US8310442B2 (en) | 2005-02-23 | 2012-11-13 | Pixtronix, Inc. | Circuits for controlling display apparatus |
| US7742016B2 (en) | 2005-02-23 | 2010-06-22 | Pixtronix, Incorporated | Display methods and apparatus |
| US8159428B2 (en) | 2005-02-23 | 2012-04-17 | Pixtronix, Inc. | Display methods and apparatus |
| US9082353B2 (en) | 2010-01-05 | 2015-07-14 | Pixtronix, Inc. | Circuits for controlling display apparatus |
| US8519945B2 (en) | 2006-01-06 | 2013-08-27 | Pixtronix, Inc. | Circuits for controlling display apparatus |
| US9229222B2 (en) | 2005-02-23 | 2016-01-05 | Pixtronix, Inc. | Alignment methods in fluid-filled MEMS displays |
| US7999994B2 (en) | 2005-02-23 | 2011-08-16 | Pixtronix, Inc. | Display apparatus and methods for manufacture thereof |
| MY149159A (en) | 2005-11-15 | 2013-07-31 | Hoffmann La Roche | Method for treating joint damage |
| US8526096B2 (en) | 2006-02-23 | 2013-09-03 | Pixtronix, Inc. | Mechanical light modulators with stressed beams |
| US9176318B2 (en) * | 2007-05-18 | 2015-11-03 | Pixtronix, Inc. | Methods for manufacturing fluid-filled MEMS displays |
| TW201014605A (en) | 2008-09-16 | 2010-04-16 | Genentech Inc | Methods for treating progressive multiple sclerosis |
| US8169679B2 (en) | 2008-10-27 | 2012-05-01 | Pixtronix, Inc. | MEMS anchors |
| WO2010075249A2 (en) | 2008-12-22 | 2010-07-01 | Genentech, Inc. | A method for treating rheumatoid arthritis with b-cell antagonists |
| WO2011097252A2 (en) | 2010-02-02 | 2011-08-11 | Pixtronix, Inc. | Methods for manufacturing cold seal fluid-filled display apparatus |
| KR20120139854A (ko) | 2010-02-02 | 2012-12-27 | 픽스트로닉스 인코포레이티드 | 디스플레이 장치를 제어하기 위한 회로 |
| WO2013101771A2 (en) | 2011-12-30 | 2013-07-04 | Genentech, Inc. | Compositions and method for treating autoimmune diseases |
| KR20140119777A (ko) | 2012-01-31 | 2014-10-10 | 제넨테크, 인크. | 항-ig-e m1'' 항체 및 그의 사용 방법 |
| US9134552B2 (en) | 2013-03-13 | 2015-09-15 | Pixtronix, Inc. | Display apparatus with narrow gap electrostatic actuators |
| US10100012B2 (en) * | 2014-05-30 | 2018-10-16 | Sphaera Pharma Pvt. Ltd. | Compounds as anti-tubercular agents |
| ES2835274T3 (es) * | 2015-07-08 | 2021-06-22 | Axerovision Inc | Composiciones farmacéuticas que contienen un antagonista de la integrina alfa 4 para el tratamiento de afecciones inflamatorias oculares |
| EP4732904A2 (en) | 2015-10-06 | 2026-04-29 | F. Hoffmann-La Roche AG | Method for treating multiple sclerosis |
| EP4067368A1 (en) | 2016-06-01 | 2022-10-05 | Athira Pharma, Inc. | Compounds |
| CN109722455B (zh) * | 2017-10-31 | 2022-03-11 | 中国科学院天津工业生物技术研究所 | 微生物发酵生产谷内酯的方法、工程菌及应用 |
| US20230033021A1 (en) | 2018-06-20 | 2023-02-02 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with an integrin inhibitor |
| AU2019373242B2 (en) | 2018-10-30 | 2023-07-13 | Gilead Sciences, Inc. | Compounds for inhibition of alpha 4 beta 7 integrin |
| CN112969700B (zh) | 2018-10-30 | 2024-08-20 | 吉利德科学公司 | 作为α4β7整合素抑制剂的咪唑并吡啶衍生物 |
| KR102659859B1 (ko) | 2018-10-30 | 2024-04-25 | 길리애드 사이언시즈, 인코포레이티드 | 알파4β7 인테그린의 억제를 위한 화합물 |
| EP4541422A3 (en) | 2018-10-30 | 2025-06-25 | Gilead Sciences, Inc. | Quinoline derivatives as alpha4beta7 integrin inhibitors |
| KR102908219B1 (ko) | 2019-08-14 | 2026-01-08 | 길리애드 사이언시즈, 인코포레이티드 | 알파 4 베타 7 인테그린의 저해용 화합물 |
| KR20230110514A (ko) * | 2020-10-21 | 2023-07-24 | 아주라 오프탈믹스 엘티디 | 안구 장애의 치료를 위한 화합물 및 방법 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1593858A1 (de) * | 1967-03-02 | 1970-10-29 | Hoechst Ag | Verfahren zur Herstellung tyrosinhaltiger Peptide und deren Derivaten |
| US4105602A (en) | 1975-02-10 | 1978-08-08 | Armour Pharmaceutical Company | Synthesis of peptides with parathyroid hormone activity |
| US6248713B1 (en) * | 1995-07-11 | 2001-06-19 | Biogen, Inc. | Cell adhesion inhibitors |
| EP1017382B1 (en) | 1997-05-29 | 2006-03-01 | Merck & Co., Inc. (a New Jersey corp.) | Biarylalkanoic acids as cell adhesion inhibitors |
| EP1001764A4 (en) | 1997-05-29 | 2005-08-24 | Merck & Co Inc | HETEROCYCLIC AMIDE COMPOUNDS AS INHIBITORS OF CELL ADHESION |
| CA2291708A1 (en) | 1997-05-29 | 1998-12-03 | Merck & Co., Inc. | Sulfonamides as cell adhesion inhibitors |
| JP2002501518A (ja) | 1997-05-30 | 2002-01-15 | セルテック セラピューティックス リミテッド | 抗炎症性チロシン誘導体 |
-
1998
- 1998-12-18 GB GBGB9828074.6A patent/GB9828074D0/en not_active Ceased
-
1999
- 1999-12-15 AR ARP990106429A patent/AR023727A1/es not_active Application Discontinuation
- 1999-12-15 CO CO99078241A patent/CO5170533A1/es not_active Application Discontinuation
- 1999-12-16 EP EP99964583A patent/EP1140837B1/en not_active Expired - Lifetime
- 1999-12-16 ES ES99964583T patent/ES2226488T3/es not_active Expired - Lifetime
- 1999-12-16 AU AU30391/00A patent/AU760169B2/en not_active Ceased
- 1999-12-16 HU HU0104867A patent/HUP0104867A3/hu unknown
- 1999-12-16 WO PCT/EP1999/010000 patent/WO2000037444A1/en not_active Ceased
- 1999-12-16 US US09/868,395 patent/US6867192B1/en not_active Expired - Lifetime
- 1999-12-16 BR BR9916282-2A patent/BR9916282A/pt not_active IP Right Cessation
- 1999-12-16 DE DE69919580T patent/DE69919580T2/de not_active Expired - Lifetime
- 1999-12-16 JP JP2000589516A patent/JP4431282B2/ja not_active Expired - Lifetime
- 1999-12-16 PL PL99348059A patent/PL348059A1/xx not_active Application Discontinuation
- 1999-12-16 KR KR1020017007579A patent/KR20010101258A/ko not_active Withdrawn
- 1999-12-16 NZ NZ511478A patent/NZ511478A/en unknown
- 1999-12-16 TR TR2001/01709T patent/TR200101709T2/xx unknown
- 1999-12-16 CN CN99814654A patent/CN1330637A/zh active Pending
- 1999-12-16 IL IL14290899A patent/IL142908A0/xx unknown
- 1999-12-16 AT AT99964583T patent/ATE273954T1/de not_active IP Right Cessation
- 1999-12-16 PE PE1999001274A patent/PE20001387A1/es not_active Application Discontinuation
- 1999-12-16 CA CA002355630A patent/CA2355630A1/en not_active Abandoned
- 1999-12-16 CZ CZ20012209A patent/CZ20012209A3/cs unknown
- 1999-12-16 HK HK02100145.2A patent/HK1038744A1/zh unknown
- 1999-12-17 GT GT199900217A patent/GT199900217A/es unknown
-
2001
- 2001-05-15 ZA ZA200103948A patent/ZA200103948B/en unknown
- 2001-06-15 NO NO20012995A patent/NO20012995L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU760169B2 (en) | 2003-05-08 |
| DE69919580D1 (de) | 2004-09-23 |
| BR9916282A (pt) | 2001-10-02 |
| GT199900217A (es) | 2001-06-09 |
| PE20001387A1 (es) | 2000-12-22 |
| AU3039100A (en) | 2000-07-12 |
| GB9828074D0 (en) | 1999-02-17 |
| EP1140837B1 (en) | 2004-08-18 |
| HUP0104867A3 (en) | 2002-06-28 |
| CO5170533A1 (es) | 2002-06-27 |
| AR023727A1 (es) | 2002-09-04 |
| EP1140837A1 (en) | 2001-10-10 |
| US6867192B1 (en) | 2005-03-15 |
| HUP0104867A2 (hu) | 2002-04-29 |
| NZ511478A (en) | 2003-08-29 |
| CA2355630A1 (en) | 2000-06-29 |
| WO2000037444A1 (en) | 2000-06-29 |
| DE69919580T2 (de) | 2005-09-01 |
| JP2002533326A (ja) | 2002-10-08 |
| CZ20012209A3 (cs) | 2001-09-12 |
| ZA200103948B (en) | 2002-11-15 |
| TR200101709T2 (tr) | 2001-12-21 |
| PL348059A1 (en) | 2002-05-06 |
| KR20010101258A (ko) | 2001-11-14 |
| CN1330637A (zh) | 2002-01-09 |
| NO20012995D0 (no) | 2001-06-15 |
| HK1038744A1 (zh) | 2002-03-28 |
| NO20012995L (no) | 2001-08-15 |
| JP4431282B2 (ja) | 2010-03-10 |
| ATE273954T1 (de) | 2004-09-15 |
| IL142908A0 (en) | 2002-04-21 |
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