HRP960533A2 - Novel macrocyclic compounds as metalloprotease inhibitors - Google Patents

Info

Publication number

HRP960533A2

HRP960533A2 HR08/743,439A HRP960533A HRP960533A2 HR P960533 A2 HRP960533 A2 HR P960533A2 HR P960533 A HRP960533 A HR P960533A HR P960533 A2 HRP960533 A2 HR P960533A2

Authority

HR

Croatia

Prior art keywords

alkyl

aryl

hydroxycarboxamide

oxa

oxo

Prior art date

1995-11-14

Links

• Espacenet
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• 239000003475 metalloproteinase inhibitor Substances 0.000 title description 4
• 150000002678 macrocyclic compounds Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 266
• -1 branched Chemical group 0.000 claims description 170
• 125000003118 aryl group Chemical group 0.000 claims description 146
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 142
• 125000000217 alkyl group Chemical group 0.000 claims description 140
• 229910052739 hydrogen Inorganic materials 0.000 claims description 120
• 239000001257 hydrogen Substances 0.000 claims description 115
• 125000003545 alkoxy group Chemical group 0.000 claims description 113
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 106
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 102
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 98
• 125000001424 substituent group Chemical group 0.000 claims description 92
• 125000005843 halogen group Chemical group 0.000 claims description 87
• 125000004442 acylamino group Chemical group 0.000 claims description 86
• 238000000034 method Methods 0.000 claims description 83
• 125000005518 carboxamido group Chemical group 0.000 claims description 80
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 68
• 239000000203 mixture Substances 0.000 claims description 60
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 59
• 150000001408 amides Chemical class 0.000 claims description 52
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 50
• KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical group C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 claims description 46
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 46
• 125000004001 thioalkyl group Chemical group 0.000 claims description 46
• 125000004122 cyclic group Chemical group 0.000 claims description 45
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
• 125000001041 indolyl group Chemical group 0.000 claims description 44
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
• 125000004429 atom Chemical group 0.000 claims description 41
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 40
• 125000004414 alkyl thio group Chemical group 0.000 claims description 40
• 125000001769 aryl amino group Chemical group 0.000 claims description 40
• 125000005110 aryl thio group Chemical group 0.000 claims description 40
• 125000004104 aryloxy group Chemical group 0.000 claims description 40
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 40
• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 40
• 125000004432 carbon atom Chemical group C* 0.000 claims description 39
• 229910052736 halogen Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• 150000003839 salts Chemical group 0.000 claims description 34
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 32
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 32
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 32
• 229910052760 oxygen Inorganic materials 0.000 claims description 32
• 239000000651 prodrug Chemical group 0.000 claims description 31
• 229940002612 prodrug Drugs 0.000 claims description 31
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 29
• 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 29
• 229920006395 saturated elastomer Polymers 0.000 claims description 28
• 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 27
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 26
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 25
• 238000011282 treatment Methods 0.000 claims description 25
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 24
• 101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 claims description 24
• 241000124008 Mammalia Species 0.000 claims description 24
• 125000005842 heteroatom Chemical group 0.000 claims description 24
• 125000002883 imidazolyl group Chemical group 0.000 claims description 24
• 125000001072 heteroaryl group Chemical group 0.000 claims description 22
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 20
• 229940124530 sulfonamide Drugs 0.000 claims description 20
• 150000003456 sulfonamides Chemical class 0.000 claims description 20
• 229910052717 sulfur Inorganic materials 0.000 claims description 20
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
• 208000027866 inflammatory disease Diseases 0.000 claims description 18
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 108010003059 aggrecanase Proteins 0.000 claims description 17
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 16
• 125000000623 heterocyclic group Chemical group 0.000 claims description 15
• 239000003112 inhibitor Substances 0.000 claims description 15
• AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 12
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 12
• 229960003104 ornithine Drugs 0.000 claims description 12
• 238000006467 substitution reaction Methods 0.000 claims description 12
• 230000003278 mimic effect Effects 0.000 claims description 11
• 101100240516 Caenorhabditis elegans nhr-10 gene Proteins 0.000 claims description 10
• 125000002252 acyl group Chemical group 0.000 claims description 10
• 125000005257 alkyl acyl group Chemical group 0.000 claims description 10
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 10
• 150000002391 heterocyclic compounds Chemical class 0.000 claims description 10
• 125000003107 substituted aryl group Chemical group 0.000 claims description 10
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 10
• MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 9
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 9
• AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 8
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
• 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 claims description 8
• 125000005197 alkyl carbonyloxy alkyl group Chemical group 0.000 claims description 8
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 8
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 8
• 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 8
• 210000000845 cartilage Anatomy 0.000 claims description 8
• 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims description 8
• KATXJJSCAPBIOB-UHFFFAOYSA-N cyclotetradecane Chemical compound C1CCCCCCCCCCCCC1 KATXJJSCAPBIOB-UHFFFAOYSA-N 0.000 claims description 8
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
• 229960001153 serine Drugs 0.000 claims description 7
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 6
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 5
• 239000004471 Glycine Substances 0.000 claims description 5
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
• 150000004820 halides Chemical class 0.000 claims description 5
• 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 4
• 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 4
• 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 4
• 229910052770 Uranium Inorganic materials 0.000 claims description 4
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 150000002825 nitriles Chemical class 0.000 claims description 4
• 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 4
• 229910052727 yttrium Inorganic materials 0.000 claims description 4
• 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 125000005975 2-phenylethyloxy group Chemical group 0.000 claims description 2
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 claims description 2
• UEVXKGPJXXDGCX-UHFFFAOYSA-N cyclotridecane Chemical compound C1CCCCCCCCCCCC1 UEVXKGPJXXDGCX-UHFFFAOYSA-N 0.000 claims description 2
• OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 claims description 2
• 230000002255 enzymatic effect Effects 0.000 claims description 2
• 230000005764 inhibitory process Effects 0.000 claims description 2
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 238000012360 testing method Methods 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 43
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 20
• 239000003937 drug carrier Substances 0.000 claims 10
• XIZCDQOKKYYCRH-UHFFFAOYSA-N 1h-benzimidazole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)N)=NC2=C1 XIZCDQOKKYYCRH-UHFFFAOYSA-N 0.000 claims 1
• 102000016284 Aggrecans Human genes 0.000 claims 1
• 108010067219 Aggrecans Proteins 0.000 claims 1
• 238000001514 detection method Methods 0.000 claims 1
• 239000012634 fragment Substances 0.000 claims 1
• 238000012544 monitoring process Methods 0.000 claims 1
• 230000000638 stimulation Effects 0.000 claims 1
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 217
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 214
• 239000000243 solution Substances 0.000 description 207
• 239000000047 product Substances 0.000 description 146
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 138
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 134
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 117
• 239000002253 acid Substances 0.000 description 98
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
• 238000006243 chemical reaction Methods 0.000 description 92
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 88
• 230000002829 reductive effect Effects 0.000 description 81
• 235000019439 ethyl acetate Nutrition 0.000 description 79
• 238000003756 stirring Methods 0.000 description 76
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 72
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
• 239000000463 material Substances 0.000 description 70
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
• 239000012267 brine Substances 0.000 description 65
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
• TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 64
• 229910001868 water Inorganic materials 0.000 description 61
• KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 54
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
• 150000002431 hydrogen Chemical class 0.000 description 49
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 49
• 239000007787 solid Substances 0.000 description 47
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 45
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 44
• 235000019341 magnesium sulphate Nutrition 0.000 description 44
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 41
• 229910052763 palladium Inorganic materials 0.000 description 37
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 34
• 239000003054 catalyst Substances 0.000 description 31
• 238000007327 hydrogenolysis reaction Methods 0.000 description 31
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
• 238000005984 hydrogenation reaction Methods 0.000 description 30
• 239000000741 silica gel Substances 0.000 description 30
• 229910002027 silica gel Inorganic materials 0.000 description 30
• 238000010511 deprotection reaction Methods 0.000 description 29
• 239000002904 solvent Substances 0.000 description 28
• 229940024606 amino acid Drugs 0.000 description 26
• 235000001014 amino acid Nutrition 0.000 description 26
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 25
• NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 24
• 150000001413 amino acids Chemical class 0.000 description 24
• 238000000746 purification Methods 0.000 description 24
• 238000010898 silica gel chromatography Methods 0.000 description 23
• 239000012317 TBTU Substances 0.000 description 21
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 21
• 125000003396 thiol group Chemical class [H]S* 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• 108060008682 Tumor Necrosis Factor Proteins 0.000 description 18
• 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 18
• 102000005741 Metalloproteases Human genes 0.000 description 17
• 108010006035 Metalloproteases Proteins 0.000 description 17
• 239000006260 foam Substances 0.000 description 17
• 238000005710 macrocyclization reaction Methods 0.000 description 17
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• 239000012298 atmosphere Substances 0.000 description 16
• 239000000543 intermediate Substances 0.000 description 16
• 108090000765 processed proteins & peptides Proteins 0.000 description 16
• 235000017557 sodium bicarbonate Nutrition 0.000 description 16
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 230000008878 coupling Effects 0.000 description 15
• 238000010168 coupling process Methods 0.000 description 15
• 238000005859 coupling reaction Methods 0.000 description 15
• 238000004237 preparative chromatography Methods 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 13
• XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 13
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 12
• 239000007864 aqueous solution Substances 0.000 description 12
• 206010003246 arthritis Diseases 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• 239000011734 sodium Substances 0.000 description 12
• 238000003786 synthesis reaction Methods 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 239000012223 aqueous fraction Substances 0.000 description 11
• 125000002619 bicyclic group Chemical group 0.000 description 11
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• 229940124597 therapeutic agent Drugs 0.000 description 11
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
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• 238000004128 high performance liquid chromatography Methods 0.000 description 9
• 150000003951 lactams Chemical class 0.000 description 9
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
• 238000004007 reversed phase HPLC Methods 0.000 description 9
• 239000012265 solid product Substances 0.000 description 9
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
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• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
• 230000029936 alkylation Effects 0.000 description 8
• 238000005804 alkylation reaction Methods 0.000 description 8
• 150000001412 amines Chemical class 0.000 description 8
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 8
• 239000003480 eluent Substances 0.000 description 8
• 150000002148 esters Chemical class 0.000 description 8
• 229910052757 nitrogen Inorganic materials 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 206010039073 rheumatoid arthritis Diseases 0.000 description 8
• 238000007127 saponification reaction Methods 0.000 description 8
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 8
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
• 239000004472 Lysine Substances 0.000 description 7
• WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 7
• 230000000694 effects Effects 0.000 description 7
• MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 7
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
• 102000004190 Enzymes Human genes 0.000 description 6
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