NZ523462A - 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of glycogen synthase kinase-3beta and method of preparation thereof - Google Patents

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Publication number

NZ523462A

NZ523462A NZ523462A NZ52346201A NZ523462A NZ 523462 A NZ523462 A NZ 523462A NZ 523462 A NZ523462 A NZ 523462A NZ 52346201 A NZ52346201 A NZ 52346201A NZ 523462 A NZ523462 A NZ 523462A

Authority

NZ

New Zealand

Prior art keywords

heteroalkyl

hydrogen

alkyl

compound

formula

Prior art date

2000-07-27

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• 239000003112 inhibitor Substances 0.000 title claims abstract description 22
• 238000000034 method Methods 0.000 title claims description 51
• LKDTVSJUXXGXKE-UHFFFAOYSA-N 3-(1h-indol-2-yl)-4-phenylpyrrole-2,5-dione Chemical class C=1C2=CC=CC=C2NC=1C=1C(=O)NC(=O)C=1C1=CC=CC=C1 LKDTVSJUXXGXKE-UHFFFAOYSA-N 0.000 title abstract description 4
• 238000002360 preparation method Methods 0.000 title description 3
• 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 title description 2
• 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 233
• -1 cyano, nitro, amino Chemical group 0.000 claims abstract description 226
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 96
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 89
• 239000001257 hydrogen Substances 0.000 claims abstract description 85
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 70
• 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 70
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 57
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 54
• 201000010099 disease Diseases 0.000 claims abstract description 42
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 42
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 39
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 38
• 208000006673 asthma Diseases 0.000 claims abstract description 27
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 20
• 150000002367 halogens Chemical class 0.000 claims abstract description 20
• 125000004475 heteroaralkyl group Chemical group 0.000 claims abstract description 19
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 19
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 18
• 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 16
• 230000007815 allergy Effects 0.000 claims abstract description 16
• 125000004442 acylamino group Chemical group 0.000 claims abstract description 15
• 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 15
• 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 14
• 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 12
• 208000026935 allergic disease Diseases 0.000 claims abstract description 12
• 230000001404 mediated effect Effects 0.000 claims abstract description 12
• 150000003839 salts Chemical class 0.000 claims abstract description 12
• 125000001424 substituent group Chemical group 0.000 claims abstract description 12
• 241000124008 Mammalia Species 0.000 claims abstract description 10
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 8
• 208000020925 Bipolar disease Diseases 0.000 claims abstract description 8
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
• 206010061598 Immunodeficiency Diseases 0.000 claims abstract description 7
• 208000029462 Immunodeficiency disease Diseases 0.000 claims abstract description 7
• 208000030886 Traumatic Brain injury Diseases 0.000 claims abstract description 7
• 230000007813 immunodeficiency Effects 0.000 claims abstract description 7
• 208000028867 ischemia Diseases 0.000 claims abstract description 7
• 230000009529 traumatic brain injury Effects 0.000 claims abstract description 7
• 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 6
• 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 6
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
• 208000008589 Obesity Diseases 0.000 claims abstract description 6
• 201000011510 cancer Diseases 0.000 claims abstract description 6
• 235000020824 obesity Nutrition 0.000 claims abstract description 6
• 201000010065 polycystic ovary syndrome Diseases 0.000 claims abstract description 6
• 208000011580 syndromic disease Diseases 0.000 claims abstract description 6
• 239000000203 mixture Substances 0.000 claims description 66
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
• 239000003814 drug Substances 0.000 claims description 25
• 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 claims description 24
• 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 claims description 24
• 125000001153 fluoro group Chemical group F* 0.000 claims description 17
• 102000004127 Cytokines Human genes 0.000 claims description 16
• 108090000695 Cytokines Proteins 0.000 claims description 16
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
• 238000004519 manufacturing process Methods 0.000 claims description 15
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
• 239000002253 acid Substances 0.000 claims description 12
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 11
• 125000002947 alkylene group Chemical group 0.000 claims description 7
• 125000001041 indolyl group Chemical group 0.000 claims description 7
• 239000002585 base Substances 0.000 claims description 5
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
• 201000010105 allergic rhinitis Diseases 0.000 claims description 4
• 239000012458 free base Substances 0.000 claims description 2
• MZUZXNZGBBUAIM-UHFFFAOYSA-N 3-(1h-indol-3-yl)-4-phenylfuran-2,5-dione Chemical compound C=1NC2=CC=CC=C2C=1C=1C(=O)OC(=O)C=1C1=CC=CC=C1 MZUZXNZGBBUAIM-UHFFFAOYSA-N 0.000 claims 1
• 229910021529 ammonia Inorganic materials 0.000 claims 1
• 108010001483 Glycogen Synthase Proteins 0.000 abstract description 4
• YAEMHJKFIIIULI-UHFFFAOYSA-N n-(4-methoxybenzyl)-n'-(5-nitro-1,3-thiazol-2-yl)urea Chemical compound C1=CC(OC)=CC=C1CNC(=O)NC1=NC=C([N+]([O-])=O)S1 YAEMHJKFIIIULI-UHFFFAOYSA-N 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 157
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 104
• 239000000243 solution Substances 0.000 description 79
• 235000019439 ethyl acetate Nutrition 0.000 description 72
• 229910001868 water Inorganic materials 0.000 description 71
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 59
• 239000011541 reaction mixture Substances 0.000 description 53
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 44
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
• 238000006243 chemical reaction Methods 0.000 description 34
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
• 150000002431 hydrogen Chemical class 0.000 description 30
• 238000003786 synthesis reaction Methods 0.000 description 30
• 210000004027 cell Anatomy 0.000 description 29
• 239000011780 sodium chloride Substances 0.000 description 29
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
• 230000015572 biosynthetic process Effects 0.000 description 28
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
• 239000000741 silica gel Substances 0.000 description 25
• 229910002027 silica gel Inorganic materials 0.000 description 25
• 229960001866 silicon dioxide Drugs 0.000 description 25
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 24
• 239000003039 volatile agent Substances 0.000 description 22
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 20
• 239000010410 layer Substances 0.000 description 19
• 239000012044 organic layer Substances 0.000 description 18
• 238000003756 stirring Methods 0.000 description 18
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
• 108010058846 Ovalbumin Proteins 0.000 description 17
• 210000001744 T-lymphocyte Anatomy 0.000 description 17
• 229940092253 ovalbumin Drugs 0.000 description 17
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
• 239000012043 crude product Substances 0.000 description 16
• 230000000694 effects Effects 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 102100030627 Transcription factor 7 Human genes 0.000 description 15
• FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 15
• 238000000746 purification Methods 0.000 description 15
• 239000007787 solid Substances 0.000 description 15
• 229910052786 argon Inorganic materials 0.000 description 14
• 230000005764 inhibitory process Effects 0.000 description 14
• WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 14
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
• BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 13
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
• 238000003556 assay Methods 0.000 description 13
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 13
• 230000002829 reductive effect Effects 0.000 description 13
• 229910052938 sodium sulfate Inorganic materials 0.000 description 13
• 235000011152 sodium sulphate Nutrition 0.000 description 13
• 101000653540 Homo sapiens Transcription factor 7 Proteins 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• 238000004809 thin layer chromatography Methods 0.000 description 12
• 239000000047 product Substances 0.000 description 11
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
• 102000003816 Interleukin-13 Human genes 0.000 description 10
• 108090000176 Interleukin-13 Proteins 0.000 description 10
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• 239000000706 filtrate Substances 0.000 description 10
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• 150000003254 radicals Chemical class 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• 102000004388 Interleukin-4 Human genes 0.000 description 9
• 108090000978 Interleukin-4 Proteins 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 235000011054 acetic acid Nutrition 0.000 description 9
• 235000011114 ammonium hydroxide Nutrition 0.000 description 9
• 229910052799 carbon Inorganic materials 0.000 description 9
• 238000001704 evaporation Methods 0.000 description 9
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• 238000009472 formulation Methods 0.000 description 9
• 239000003921 oil Substances 0.000 description 9
• 235000019198 oils Nutrition 0.000 description 9
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
• IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 8
• 239000004615 ingredient Substances 0.000 description 8
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
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• 241001529936 Murinae Species 0.000 description 6
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
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• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
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• 238000006460 hydrolysis reaction Methods 0.000 description 6
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• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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• RGTAEYDIDMGJLX-UHFFFAOYSA-N 3-(3-aminophenyl)-4-(1-methylindol-3-yl)pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C1=CC=CC(N)=C1 RGTAEYDIDMGJLX-UHFFFAOYSA-N 0.000 description 5
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