NZ581610A - Substituted benzoylamino-indan-2-carboxylic acids and related compounds - Google Patents
Substituted benzoylamino-indan-2-carboxylic acids and related compoundsInfo
- Publication number
- NZ581610A NZ581610A NZ581610A NZ58161008A NZ581610A NZ 581610 A NZ581610 A NZ 581610A NZ 581610 A NZ581610 A NZ 581610A NZ 58161008 A NZ58161008 A NZ 58161008A NZ 581610 A NZ581610 A NZ 581610A
- Authority
- NZ
- New Zealand
- Prior art keywords
- indan
- carboxylic acid
- methyl
- benzoylamino
- amino
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 94
- LQKLWIFWSAACJF-UHFFFAOYSA-N 1-benzamido-2,3-dihydro-1h-indene-2-carboxylic acid Chemical class OC(=O)C1CC2=CC=CC=C2C1NC(=O)C1=CC=CC=C1 LQKLWIFWSAACJF-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 83
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 4
- 208000006673 asthma Diseases 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- BGHPCLFHLVTPQG-UHFFFAOYSA-N 2-[(3-methyl-2-prop-2-enoxybenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC=CC(C(=O)NC2(CC3=CC=CC=C3C2)C(O)=O)=C1OCC=C BGHPCLFHLVTPQG-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 230000004962 physiological condition Effects 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- VXGZSCGHSSMMRH-UHFFFAOYSA-N 2-[(3-chloro-2-propan-2-yloxybenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)OC1=C(Cl)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 VXGZSCGHSSMMRH-UHFFFAOYSA-N 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- OGIZPFDDOBNJOF-UHFFFAOYSA-N 2-[(2-cyclobutyloxy-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC=CC(C(=O)NC2(CC3=CC=CC=C3C2)C(O)=O)=C1OC1CCC1 OGIZPFDDOBNJOF-UHFFFAOYSA-N 0.000 claims description 6
- YIJFSXUJEOMRLN-UHFFFAOYSA-N 2-[(3,5-dichloro-2-prop-2-enoxyphenyl)sulfonylamino]-1,3-dihydroindene-2-carboxylic acid Chemical compound C1C2=CC=CC=C2CC1(C(=O)O)NS(=O)(=O)C1=CC(Cl)=CC(Cl)=C1OCC=C YIJFSXUJEOMRLN-UHFFFAOYSA-N 0.000 claims description 6
- LQYWUXJBHFXOOE-UHFFFAOYSA-N 2-[[2-(cyclopropylmethoxy)-3-methylbenzoyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC=CC(C(=O)NC2(CC3=CC=CC=C3C2)C(O)=O)=C1OCC1CC1 LQYWUXJBHFXOOE-UHFFFAOYSA-N 0.000 claims description 6
- ZFNNJCNJQGPLHU-UHFFFAOYSA-N 5-methoxy-2-[(3-methyl-2-propan-2-yloxybenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound C1C2=CC(OC)=CC=C2CC1(C(O)=O)NC(=O)C1=CC=CC(C)=C1OC(C)C ZFNNJCNJQGPLHU-UHFFFAOYSA-N 0.000 claims description 6
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- FDPUDIAMESRREB-UHFFFAOYSA-N 2-[(3-methyl-2-propan-2-yloxybenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)OC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 FDPUDIAMESRREB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- YAJDKGWZDVHDQJ-UHFFFAOYSA-N 2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-1,3-dihydroindene-2-carboxylic acid Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)O)CC2=CC=CC=C2C1 YAJDKGWZDVHDQJ-UHFFFAOYSA-N 0.000 claims description 2
- SOUFZMAJMOXZDL-UHFFFAOYSA-N 2-[(2-cyclobutyloxy-3-methylbenzoyl)amino]-4-fluoro-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC=CC(C(=O)NC2(CC3=C(F)C=CC=C3C2)C(O)=O)=C1OC1CCC1 SOUFZMAJMOXZDL-UHFFFAOYSA-N 0.000 claims description 2
- AXWYMDVKFCTCSX-UHFFFAOYSA-N 2-[(2-propan-2-ylsulfanylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)SC1=CC=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 AXWYMDVKFCTCSX-UHFFFAOYSA-N 0.000 claims description 2
- KXMYCMOTDIYDMS-UHFFFAOYSA-N 2-[(3,5-dichloro-2-cyclobutyloxybenzoyl)amino]-5-fluoro-1,3-dihydroindene-2-carboxylic acid Chemical compound C1C2=CC=C(F)C=C2CC1(C(=O)O)NC(=O)C1=CC(Cl)=CC(Cl)=C1OC1CCC1 KXMYCMOTDIYDMS-UHFFFAOYSA-N 0.000 claims description 2
- SIDVYXCWNASQAI-UHFFFAOYSA-N 2-[(3-bromo-2-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=C(Br)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 SIDVYXCWNASQAI-UHFFFAOYSA-N 0.000 claims description 2
- KBANFOAVVPTUAL-UHFFFAOYSA-N 2-[(3-chloro-2-prop-2-enoxybenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound C1C2=CC=CC=C2CC1(C(=O)O)NC(=O)C1=CC=CC(Cl)=C1OCC=C KBANFOAVVPTUAL-UHFFFAOYSA-N 0.000 claims description 2
- ALMZBDOLVFFLJZ-UHFFFAOYSA-N 2-[(5-chloro-2-cyclobutyloxy-3-methylbenzoyl)amino]-5-fluoro-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC(Cl)=CC(C(=O)NC2(CC3=CC(F)=CC=C3C2)C(O)=O)=C1OC1CCC1 ALMZBDOLVFFLJZ-UHFFFAOYSA-N 0.000 claims description 2
- DYXHQOILPANHKB-UHFFFAOYSA-N 2-[[2-(2-methylprop-1-enyl)-3-(trifluoromethyl)benzoyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound C1=CC=C(C(F)(F)F)C(C=C(C)C)=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 DYXHQOILPANHKB-UHFFFAOYSA-N 0.000 claims description 2
- ZAFOXUZNHBJXET-UHFFFAOYSA-N 2-[[2-[ethyl(methyl)amino]pyridine-3-carbonyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CCN(C)C1=NC=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 ZAFOXUZNHBJXET-UHFFFAOYSA-N 0.000 claims description 2
- VGAHKLJXSCXITG-UHFFFAOYSA-N 2-[[5-chloro-2-[methyl(propan-2-yl)amino]pyridine-3-carbonyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)N(C)C1=NC=C(Cl)C=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 VGAHKLJXSCXITG-UHFFFAOYSA-N 0.000 claims description 2
- FSIHSVMSLLMCQD-UHFFFAOYSA-N 4,7-difluoro-2-[[3-methyl-2-(2-methylpropyl)benzoyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)CC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC(C(F)=CC=C2F)=C2C1 FSIHSVMSLLMCQD-UHFFFAOYSA-N 0.000 claims description 2
- RREJNSHSDBPJIE-UHFFFAOYSA-N 5-chloro-2-[(2-cyclobutyloxy-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC=CC(C(=O)NC2(CC3=CC(Cl)=CC=C3C2)C(O)=O)=C1OC1CCC1 RREJNSHSDBPJIE-UHFFFAOYSA-N 0.000 claims description 2
- JGVKSNVSVQTRCR-UHFFFAOYSA-N 5-fluoro-2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-1,3-dihydroindene-2-carboxylic acid Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)O)CC2=CC(F)=CC=C2C1 JGVKSNVSVQTRCR-UHFFFAOYSA-N 0.000 claims description 2
- JJAGIHLMZAAAQP-UHFFFAOYSA-N 5-fluoro-2-[(3-methyl-2-propan-2-yloxybenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)OC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC(F)=CC=C2C1 JJAGIHLMZAAAQP-UHFFFAOYSA-N 0.000 claims description 2
- ZEZCZUQIVHQJHW-UHFFFAOYSA-N 5-methoxy-2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-1,3-dihydroindene-2-carboxylic acid Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(O)=O)CC2=CC=C(OC)C=C2C1 ZEZCZUQIVHQJHW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 230000001668 ameliorated effect Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- CGVUCVLXGMIVEB-UHFFFAOYSA-N 1,3-dimethyl-5-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-4,6-dihydrocyclopenta[c]thiophene-5-carboxylic acid Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(O)=O)CC2=C(C)SC(C)=C2C1 CGVUCVLXGMIVEB-UHFFFAOYSA-N 0.000 claims 1
- GCFWKDAGJGTYAJ-UHFFFAOYSA-N 2-(5,6,7,8-tetrahydronaphthalen-1-ylcarbamoyl)-1,3-dihydroindene-2-carboxylic acid Chemical compound C1CCCC2=C1C=CC=C2NC(=O)C1(C(=O)O)CC2=CC=CC=C2C1 GCFWKDAGJGTYAJ-UHFFFAOYSA-N 0.000 claims 1
- ZRRSNBBGZBTVMN-UHFFFAOYSA-N 2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-5-(trifluoromethyl)-1,3-dihydroindene-2-carboxylic acid Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)O)CC2=CC(C(F)(F)F)=CC=C2C1 ZRRSNBBGZBTVMN-UHFFFAOYSA-N 0.000 claims 1
- UDQBYOINRNOXIK-UHFFFAOYSA-N 2-[(3,5-dichloro-2-propan-2-yloxyphenyl)sulfonylamino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)OC1=C(Cl)C=C(Cl)C=C1S(=O)(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 UDQBYOINRNOXIK-UHFFFAOYSA-N 0.000 claims 1
- PMGMYYQMBLQSCM-UHFFFAOYSA-N 2-[(3-methyl-2-propan-2-yloxybenzoyl)amino]-5-(trifluoromethyl)-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)OC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC(C(F)(F)F)=CC=C2C1 PMGMYYQMBLQSCM-UHFFFAOYSA-N 0.000 claims 1
- SYKKDRADGMMKSP-UHFFFAOYSA-N 2-[[2-[methyl(prop-2-enyl)amino]pyridine-3-carbonyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound C=CCN(C)C1=NC=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 SYKKDRADGMMKSP-UHFFFAOYSA-N 0.000 claims 1
- BGXUVTNSAMGSBX-UHFFFAOYSA-N 2-[[2-[methyl(propan-2-yl)amino]pyridine-3-carbonyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)N(C)C1=NC=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 BGXUVTNSAMGSBX-UHFFFAOYSA-N 0.000 claims 1
- GELSENAULVQSEV-UHFFFAOYSA-N 5-bromo-2-[(2-cyclobutyloxy-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC=CC(C(=O)NC2(CC3=CC(Br)=CC=C3C2)C(O)=O)=C1OC1CCC1 GELSENAULVQSEV-UHFFFAOYSA-N 0.000 claims 1
- GGQUHFALWYXUAB-UHFFFAOYSA-N FC1=C2CC(CC2=C(C=C1)F)(C(=O)O)NC(C1=C(C(=CC=C1)C)C=C(C)C)=O.FC1=C2CC(CC2=CC=C1F)(C(=O)O)NC(C1=C(C(=CC=C1)C)CC(C)C)=O Chemical compound FC1=C2CC(CC2=C(C=C1)F)(C(=O)O)NC(C1=C(C(=CC=C1)C)C=C(C)C)=O.FC1=C2CC(CC2=CC=C1F)(C(=O)O)NC(C1=C(C(=CC=C1)C)CC(C)C)=O GGQUHFALWYXUAB-UHFFFAOYSA-N 0.000 claims 1
- 210000003719 b-lymphocyte Anatomy 0.000 abstract description 12
- 102000005962 receptors Human genes 0.000 abstract description 6
- 108020003175 receptors Proteins 0.000 abstract description 6
- 108010061298 CXCR5 Receptors Proteins 0.000 abstract description 5
- 102000012001 CXCR5 Receptors Human genes 0.000 abstract description 5
- 201000006417 multiple sclerosis Diseases 0.000 abstract description 5
- 208000011231 Crohn disease Diseases 0.000 abstract description 4
- 206010025135 lupus erythematosus Diseases 0.000 abstract description 4
- 230000004913 activation Effects 0.000 abstract description 2
- 230000003915 cell function Effects 0.000 abstract description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 423
- 229910001868 water Inorganic materials 0.000 description 411
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 405
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 376
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 274
- 239000000243 solution Substances 0.000 description 235
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 233
- -1 penten-l-yl Chemical group 0.000 description 209
- 239000007787 solid Substances 0.000 description 201
- 235000019439 ethyl acetate Nutrition 0.000 description 188
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 179
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 170
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 158
- 239000000047 product Substances 0.000 description 157
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 154
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 150
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 146
- 238000006243 chemical reaction Methods 0.000 description 146
- 239000002244 precipitate Substances 0.000 description 107
- 239000012267 brine Substances 0.000 description 98
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 98
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 238000003756 stirring Methods 0.000 description 75
- 239000000741 silica gel Substances 0.000 description 74
- 229910002027 silica gel Inorganic materials 0.000 description 74
- 239000012044 organic layer Substances 0.000 description 69
- 238000010828 elution Methods 0.000 description 62
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 60
- 239000007821 HATU Substances 0.000 description 59
- 239000011541 reaction mixture Substances 0.000 description 58
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 56
- 238000003818 flash chromatography Methods 0.000 description 55
- 238000005481 NMR spectroscopy Methods 0.000 description 48
- 238000004128 high performance liquid chromatography Methods 0.000 description 45
- 239000000377 silicon dioxide Substances 0.000 description 45
- 101150041968 CDC13 gene Proteins 0.000 description 40
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 229910052757 nitrogen Inorganic materials 0.000 description 40
- 229940024606 amino acid Drugs 0.000 description 38
- 125000003118 aryl group Chemical group 0.000 description 38
- 150000001413 amino acids Chemical class 0.000 description 36
- 235000001014 amino acid Nutrition 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 125000004122 cyclic group Chemical group 0.000 description 34
- 125000001072 heteroaryl group Chemical group 0.000 description 33
- 239000000725 suspension Substances 0.000 description 32
- 229910052763 palladium Inorganic materials 0.000 description 31
- YLLIGHVCTUPGEH-UHFFFAOYSA-M potassium;ethanol;hydroxide Chemical compound [OH-].[K+].CCO YLLIGHVCTUPGEH-UHFFFAOYSA-M 0.000 description 30
- 125000004432 carbon atom Chemical group C* 0.000 description 29
- QDBFVFBOZSMMSV-UHFFFAOYSA-N ethyl 2-amino-1,3-dihydroindene-2-carboxylate Chemical compound C1=CC=C2CC(C(=O)OCC)(N)CC2=C1 QDBFVFBOZSMMSV-UHFFFAOYSA-N 0.000 description 29
- 238000004458 analytical method Methods 0.000 description 28
- 229910052786 argon Inorganic materials 0.000 description 28
- 239000010410 layer Substances 0.000 description 28
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 27
- 125000004494 ethyl ester group Chemical group 0.000 description 26
- 238000001914 filtration Methods 0.000 description 25
- 238000005086 pumping Methods 0.000 description 25
- 125000006413 ring segment Chemical group 0.000 description 24
- 101000922405 Homo sapiens C-X-C chemokine receptor type 5 Proteins 0.000 description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
- 239000003054 catalyst Substances 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 125000000464 thioxo group Chemical group S=* 0.000 description 20
- 239000000463 material Substances 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 102100031658 C-X-C chemokine receptor type 5 Human genes 0.000 description 17
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 17
- 125000000623 heterocyclic group Chemical group 0.000 description 16
- 238000005984 hydrogenation reaction Methods 0.000 description 16
- 125000006239 protecting group Chemical group 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- 229910052717 sulfur Inorganic materials 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 125000004434 sulfur atom Chemical group 0.000 description 15
- 238000004090 dissolution Methods 0.000 description 14
- XIINPLULSMJOGR-UHFFFAOYSA-N ethyl 2-[(2-hydroxy-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1O XIINPLULSMJOGR-UHFFFAOYSA-N 0.000 description 14
- YFDBXEBHBLYSIP-UHFFFAOYSA-N ethyl 2-[(2-iodo-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1I YFDBXEBHBLYSIP-UHFFFAOYSA-N 0.000 description 13
- 229910052939 potassium sulfate Inorganic materials 0.000 description 13
- 125000006242 amine protecting group Chemical group 0.000 description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 101000858064 Homo sapiens C-X-C motif chemokine 13 Proteins 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 239000012131 assay buffer Substances 0.000 description 11
- 125000005349 heteroarylcycloalkyl group Chemical group 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- MSOVLVYBZYSIEE-UHFFFAOYSA-N 5-fluoro-2-[[3-methyl-2-(2-methylpropyl)benzoyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)CC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC(F)=CC=C2C1 MSOVLVYBZYSIEE-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 239000002815 homogeneous catalyst Substances 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- FQSVUDYSMORLMZ-UHFFFAOYSA-N 2-[[3-methyl-2-(2-methylprop-1-enyl)benzoyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)=CC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 FQSVUDYSMORLMZ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102100025277 C-X-C motif chemokine 13 Human genes 0.000 description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 9
- 125000003435 aroyl group Chemical group 0.000 description 9
- XBNYAPZYKPRHOU-UHFFFAOYSA-N ethyl 2-[(3,5-dichloro-2-cyclobutyloxybenzoyl)amino]-5-fluoro-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=C(F)C=C2CC1(C(=O)OCC)NC(=O)C1=CC(Cl)=CC(Cl)=C1OC1CCC1 XBNYAPZYKPRHOU-UHFFFAOYSA-N 0.000 description 9
- QKKCRMFZEXRHDU-UHFFFAOYSA-N ethyl 2-[[2-(cyclopropylmethoxy)-3-methylbenzoyl]amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1OCC1CC1 QKKCRMFZEXRHDU-UHFFFAOYSA-N 0.000 description 9
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 9
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- GCFQXKYHWFWGSB-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid Chemical compound C1CCCC2=C1C=CC=C2C(=O)O GCFQXKYHWFWGSB-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 8
- 150000001204 N-oxides Chemical class 0.000 description 8
- 125000001931 aliphatic group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
- 125000004423 acyloxy group Chemical group 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- LUHJGDWXYDGTDX-UHFFFAOYSA-N ethyl 2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)OCC)CC2=CC=CC=C2C1 LUHJGDWXYDGTDX-UHFFFAOYSA-N 0.000 description 7
- ALGUFXXMHCJCRV-UHFFFAOYSA-N ethyl 2-[(3-chloro-2-hydroxybenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(Cl)=C1O ALGUFXXMHCJCRV-UHFFFAOYSA-N 0.000 description 7
- VODNSGUPHOMFQC-UHFFFAOYSA-N ethyl 2-[(3-methyl-2-propan-2-yloxybenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1OC(C)C VODNSGUPHOMFQC-UHFFFAOYSA-N 0.000 description 7
- DACHDWKCTGDKHK-UHFFFAOYSA-N ethyl 5-fluoro-2-[(2-iodo-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=C(F)C=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1I DACHDWKCTGDKHK-UHFFFAOYSA-N 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 125000003831 tetrazolyl group Chemical group 0.000 description 7
- CDBLFEOUDLTXIW-UHFFFAOYSA-N 2-[(2-cyclobutyloxy-3-methylbenzoyl)amino]-5-fluoro-1,3-dihydroindene-2-carboxylic acid Chemical compound CC1=CC=CC(C(=O)NC2(CC3=CC(F)=CC=C3C2)C(O)=O)=C1OC1CCC1 CDBLFEOUDLTXIW-UHFFFAOYSA-N 0.000 description 6
- YTZCQXUJSSFFGC-UHFFFAOYSA-N 2-cyclobutyloxy-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1OC1CCC1 YTZCQXUJSSFFGC-UHFFFAOYSA-N 0.000 description 6
- JWJROCGWYJMKLG-UHFFFAOYSA-N 3-methyl-2-propan-2-yloxybenzoic acid Chemical compound CC(C)OC1=C(C)C=CC=C1C(O)=O JWJROCGWYJMKLG-UHFFFAOYSA-N 0.000 description 6
- WHSXTWFYRGOBGO-UHFFFAOYSA-N 3-methylsalicylic acid Chemical compound CC1=CC=CC(C(O)=O)=C1O WHSXTWFYRGOBGO-UHFFFAOYSA-N 0.000 description 6
- UHRGPFIPUHZRNO-UHFFFAOYSA-N 5,6-difluoro-2-[(3-methyl-2-prop-1-enylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC=CC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC(F)=C(F)C=C2C1 UHRGPFIPUHZRNO-UHFFFAOYSA-N 0.000 description 6
- RCKNFKFXUYXQGD-HWKANZROSA-N 5-fluoro-2-[[3-methyl-2-[(e)-prop-1-enyl]benzoyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound C\C=C\C1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC(F)=CC=C2C1 RCKNFKFXUYXQGD-HWKANZROSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 241000534944 Thia Species 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 125000005605 benzo group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 125000002993 cycloalkylene group Chemical group 0.000 description 6
- 238000009510 drug design Methods 0.000 description 6
- JNLWQMLFODWJIQ-UHFFFAOYSA-N ethyl 2-(1h-indole-4-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC2=C1C=CN2 JNLWQMLFODWJIQ-UHFFFAOYSA-N 0.000 description 6
- WQZVXRYEEJQHMN-UHFFFAOYSA-N ethyl 2-(isoquinoline-4-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1=CC=C2C(C(=O)NC3(CC4=CC=CC=C4C3)C(=O)OCC)=CN=CC2=C1 WQZVXRYEEJQHMN-UHFFFAOYSA-N 0.000 description 6
- IRZLNMUMKVHKNI-UHFFFAOYSA-N ethyl 2-[(3-chloro-2-propan-2-yloxybenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(Cl)=C1OC(C)C IRZLNMUMKVHKNI-UHFFFAOYSA-N 0.000 description 6
- HJHFPZIPYYFGIF-UHFFFAOYSA-N ethyl 2-[(3-methyl-2-pent-1-ynylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound CCCC#CC1=C(C)C=CC=C1C(=O)NC1(C(=O)OCC)CC2=CC=CC=C2C1 HJHFPZIPYYFGIF-UHFFFAOYSA-N 0.000 description 6
- HQSPSIKDKVRRKE-UHFFFAOYSA-N ethyl 2-amino-5-fluoro-1,3-dihydroindene-2-carboxylate Chemical compound C1=C(F)C=C2CC(C(=O)OCC)(N)CC2=C1 HQSPSIKDKVRRKE-UHFFFAOYSA-N 0.000 description 6
- WLKLVXIIMGJUAE-UHFFFAOYSA-N ethyl 5,6-difluoro-2-[(2-iodo-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC(F)=C(F)C=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1I WLKLVXIIMGJUAE-UHFFFAOYSA-N 0.000 description 6
- KLKXUECZQALZGZ-UHFFFAOYSA-N ethyl 5-bromo-2-[(2-cyclobutyloxy-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=C(Br)C=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1OC1CCC1 KLKXUECZQALZGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 102000049118 human CXCR5 Human genes 0.000 description 6
- JERBJVMJIKOGMC-UHFFFAOYSA-N methyl 2-[(2-hydroxy-3-methylbenzoyl)amino]-1,3-dihydrophenalene-2-carboxylate Chemical compound C1C(C=23)=CC=CC3=CC=CC=2CC1(C(=O)OC)NC(=O)C1=CC=CC(C)=C1O JERBJVMJIKOGMC-UHFFFAOYSA-N 0.000 description 6
- NSRHPUFZCCKCAM-UHFFFAOYSA-N methyl 4-[(3-methyl-2-propan-2-yloxybenzoyl)amino]thiane-4-carboxylate Chemical compound C=1C=CC(C)=C(OC(C)C)C=1C(=O)NC1(C(=O)OC)CCSCC1 NSRHPUFZCCKCAM-UHFFFAOYSA-N 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- LYUBDNXWDVVZHM-UHFFFAOYSA-N tert-butyl 5-[(2-ethoxycarbonyl-1,3-dihydroinden-2-yl)carbamoyl]-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC2=C1C=CC=C2C(=O)NC1(C(=O)OCC)CC2=CC=CC=C2C1 LYUBDNXWDVVZHM-UHFFFAOYSA-N 0.000 description 6
- XTSVCKSIAZUPIW-UHFFFAOYSA-N 2-[(3-methyl-2-pentylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CCCCCC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 XTSVCKSIAZUPIW-UHFFFAOYSA-N 0.000 description 5
- PFESIXUWYFDMJH-UHFFFAOYSA-N 2-[(3-methyl-2-propylbenzoyl)amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CCCC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC=CC=C2C1 PFESIXUWYFDMJH-UHFFFAOYSA-N 0.000 description 5
- IVNHEZOUYYHHRT-UHFFFAOYSA-N 2-[[2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-5-carbonyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound C1C2=CC=CC=C2CC1(C(O)=O)NC(=O)C1=CC=CC2=C1CCN(C(=O)OC(C)(C)C)C2 IVNHEZOUYYHHRT-UHFFFAOYSA-N 0.000 description 5
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 5
- PZUXUOZSSYKAMX-UHFFFAOYSA-N 2-iodo-3-methylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1I PZUXUOZSSYKAMX-UHFFFAOYSA-N 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- SSNLQKKZPHUPJN-UHFFFAOYSA-N 5,6-difluoro-2-[[3-methyl-2-(2-methylpropyl)benzoyl]amino]-1,3-dihydroindene-2-carboxylic acid Chemical compound CC(C)CC1=C(C)C=CC=C1C(=O)NC1(C(O)=O)CC2=CC(F)=C(F)C=C2C1 SSNLQKKZPHUPJN-UHFFFAOYSA-N 0.000 description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 5
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 5
- 125000000732 arylene group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- CBGJTFVFXNNQQV-UHFFFAOYSA-N ethyl 1H-cyclopenta[c]thiophene-5-carboxylate Chemical compound C(C)OC(=O)C1=CC=2C(CSC=2)=C1 CBGJTFVFXNNQQV-UHFFFAOYSA-N 0.000 description 5
- NWWXIYHYVCSZEY-UHFFFAOYSA-N ethyl 2-(1h-indole-7-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC2=C1NC=C2 NWWXIYHYVCSZEY-UHFFFAOYSA-N 0.000 description 5
- LUQOROIMGGDAJB-UHFFFAOYSA-N ethyl 2-(2,3-dihydro-1-benzofuran-7-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC2=C1OCC2 LUQOROIMGGDAJB-UHFFFAOYSA-N 0.000 description 5
- FHLSPFAQCWDPIU-UHFFFAOYSA-N ethyl 2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-5-(trifluoromethyl)-1,3-dihydroindene-2-carboxylate Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)OCC)CC2=CC(C(F)(F)F)=CC=C2C1 FHLSPFAQCWDPIU-UHFFFAOYSA-N 0.000 description 5
- NVRVMJQFGYMADI-UHFFFAOYSA-N ethyl 2-(naphthalene-1-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1=CC=C2C(C(=O)NC3(CC4=CC=CC=C4C3)C(=O)OCC)=CC=CC2=C1 NVRVMJQFGYMADI-UHFFFAOYSA-N 0.000 description 5
- ADYVZBMJTIANEF-UHFFFAOYSA-N ethyl 2-(quinolin-8-ylsulfonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1=CN=C2C(S(=O)(=O)NC3(CC4=CC=CC=C4C3)C(=O)OCC)=CC=CC2=C1 ADYVZBMJTIANEF-UHFFFAOYSA-N 0.000 description 5
- QOHOAHDVQZJVIM-UHFFFAOYSA-N ethyl 2-(quinoline-4-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1=CC=C2C(C(=O)NC3(CC4=CC=CC=C4C3)C(=O)OCC)=CC=NC2=C1 QOHOAHDVQZJVIM-UHFFFAOYSA-N 0.000 description 5
- JTUKRJFWKWOYEF-UHFFFAOYSA-N ethyl 2-(quinoline-8-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1=CN=C2C(C(=O)NC3(CC4=CC=CC=C4C3)C(=O)OCC)=CC=CC2=C1 JTUKRJFWKWOYEF-UHFFFAOYSA-N 0.000 description 5
- KMGYGUPXSWJVIU-UHFFFAOYSA-N ethyl 2-(quinoxaline-5-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1=CN=C2C(C(=O)NC3(CC4=CC=CC=C4C3)C(=O)OCC)=CC=CC2=N1 KMGYGUPXSWJVIU-UHFFFAOYSA-N 0.000 description 5
- XXYOZXJLLWRRPR-UHFFFAOYSA-N ethyl 2-[(2-butan-2-yloxy-3-methylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1OC(C)CC XXYOZXJLLWRRPR-UHFFFAOYSA-N 0.000 description 5
- VRJUJWFHODXCOU-UHFFFAOYSA-N ethyl 2-[(3-chloro-2-prop-2-enoxybenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(Cl)=C1OCC=C VRJUJWFHODXCOU-UHFFFAOYSA-N 0.000 description 5
- FQHDOCGKZOSDCV-UHFFFAOYSA-N ethyl 2-[(3-methyl-2-prop-1-enylbenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1C=CC FQHDOCGKZOSDCV-UHFFFAOYSA-N 0.000 description 5
- BYRNUKDMSRDJIY-UHFFFAOYSA-N ethyl 2-[(3-methyl-2-prop-2-enoxybenzoyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1OCC=C BYRNUKDMSRDJIY-UHFFFAOYSA-N 0.000 description 5
- RGWNIHNPQAGOMW-UHFFFAOYSA-N ethyl 2-[(3-methyl-2-propan-2-yloxybenzoyl)amino]-5-(trifluoromethyl)-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=C(C(F)(F)F)C=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1OC(C)C RGWNIHNPQAGOMW-UHFFFAOYSA-N 0.000 description 5
- JVSNXQJZEWOICX-UHFFFAOYSA-N ethyl 2-[(4-fluoronaphthalene-1-carbonyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1=CC=C2C(C(=O)NC3(CC4=CC=CC=C4C3)C(=O)OCC)=CC=C(F)C2=C1 JVSNXQJZEWOICX-UHFFFAOYSA-N 0.000 description 5
- NWDHFTLMKZMJFV-UHFFFAOYSA-N ethyl 2-[(5-oxo-7,8-dihydro-6h-naphthalene-1-carbonyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound O=C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)OCC)CC2=CC=CC=C2C1 NWDHFTLMKZMJFV-UHFFFAOYSA-N 0.000 description 5
- OODRVBWIRKYBBD-UHFFFAOYSA-N ethyl 2-[[2-(cyclopenten-1-yl)-3-methylbenzoyl]amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1C2=CC=CC=C2CC1(C(=O)OCC)NC(=O)C1=CC=CC(C)=C1C1=CCCC1 OODRVBWIRKYBBD-UHFFFAOYSA-N 0.000 description 5
- DXJABNCXYJORLD-AUWJEWJLSA-N ethyl 2-[[3-methyl-2-[(z)-pent-1-enyl]benzoyl]amino]-1,3-dihydroindene-2-carboxylate Chemical compound CCC\C=C/C1=C(C)C=CC=C1C(=O)NC1(C(=O)OCC)CC2=CC=CC=C2C1 DXJABNCXYJORLD-AUWJEWJLSA-N 0.000 description 5
- GOMHAXVNEBKHAN-UHFFFAOYSA-N ethyl 2-[methyl(5,6,7,8-tetrahydronaphthalene-1-carbonyl)amino]-1,3-dihydroindene-2-carboxylate Chemical compound C1CCCC2=C1C=CC=C2C(=O)N(C)C1(C(=O)OCC)CC2=CC=CC=C2C1 GOMHAXVNEBKHAN-UHFFFAOYSA-N 0.000 description 5
- QSBHJAJMLPGXPQ-UHFFFAOYSA-N ethyl 3-methyl-6-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-5,7-dihydrocyclopenta[c]pyridine-6-carboxylate Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)OCC)CC2=CC(C)=NC=C2C1 QSBHJAJMLPGXPQ-UHFFFAOYSA-N 0.000 description 5
- BKOAYQMMGGVDAN-UHFFFAOYSA-N ethyl 5,6-dimethyl-2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)OCC)CC2=CC(C)=C(C)C=C2C1 BKOAYQMMGGVDAN-UHFFFAOYSA-N 0.000 description 5
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- BXSKAKTVBYVOJO-UHFFFAOYSA-N ethyl 5-fluoro-2-(5,6,7,8-tetrahydronaphthalene-1-carbonylamino)-1,3-dihydroindene-2-carboxylate Chemical compound C1CCCC2=C1C=CC=C2C(=O)NC1(C(=O)OCC)CC2=CC(F)=CC=C2C1 BXSKAKTVBYVOJO-UHFFFAOYSA-N 0.000 description 5
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
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- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
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- QRDZFPUVLYEQTA-UHFFFAOYSA-N quinoline-8-carboxylic acid Chemical compound C1=CN=C2C(C(=O)O)=CC=CC2=C1 QRDZFPUVLYEQTA-UHFFFAOYSA-N 0.000 description 1
- JUYUYCIJACTHMK-UHFFFAOYSA-N quinoline-8-sulfonyl chloride Chemical compound C1=CN=C2C(S(=O)(=O)Cl)=CC=CC2=C1 JUYUYCIJACTHMK-UHFFFAOYSA-N 0.000 description 1
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- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
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- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000002374 tyrosine Nutrition 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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| CA2656150A1 (en) * | 2006-06-28 | 2008-01-03 | Sanofi-Aventis | New cxcr2 inhibitors |
| WO2008036967A2 (en) * | 2006-09-22 | 2008-03-27 | Reddy Us Therapeutics, Inc. | Novel heterocyclic compounds as lasy activators |
| RU2477279C2 (ru) | 2007-06-05 | 2013-03-10 | Санофи-Авентис | Замещенные бензоиламиноиндан-2-карбоновые кислоты и родственные соединения |
| MX2010011754A (es) * | 2008-05-05 | 2010-12-06 | Sanofi Aventis | Derivados de acido ciclopentanocarboxilico condensados sustituidos con acilamino y su uso como productos farmaceuticos. |
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