NZ575410A - 2-(1H-Indazol-3-ylamino)-1H-benzimidazole derivatives - Google Patents

Info

Publication number

NZ575410A

NZ575410A NZ575410A NZ57541007A NZ575410A NZ 575410 A NZ575410 A NZ 575410A NZ 575410 A NZ575410 A NZ 575410A NZ 57541007 A NZ57541007 A NZ 57541007A NZ 575410 A NZ575410 A NZ 575410A

Authority

NZ

New Zealand

Prior art keywords

optionally substituted

carbon

indazol

compound

alkyl

Prior art date

2006-09-07

Links

• Espacenet
• Global Dossier
• Discuss

• FCEUOEMHFKJMLW-UHFFFAOYSA-N N-(1H-benzimidazol-2-yl)-1H-indazol-3-amine Chemical class N1N=C(C2=CC=CC=C12)NC1=NC2=C(N1)C=CC=C2 FCEUOEMHFKJMLW-UHFFFAOYSA-N 0.000 title abstract 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 155
• -1 hydroxy, amino Chemical group 0.000 claims abstract description 122
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 95
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 89
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 41
• 125000003368 amide group Chemical group 0.000 claims abstract description 37
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 29
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 24
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 23
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 22
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 20
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims abstract description 17
• 229940124530 sulfonamide Drugs 0.000 claims abstract description 16
• 150000003456 sulfonamides Chemical class 0.000 claims abstract description 16
• NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims abstract description 15
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 15
• 125000005553 heteroaryloxy group Chemical group 0.000 claims abstract description 14
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims abstract description 14
• 239000004202 carbamide Substances 0.000 claims abstract description 13
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
• 201000011510 cancer Diseases 0.000 claims abstract description 10
• 206010040047 Sepsis Diseases 0.000 claims abstract description 9
• 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 9
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 9
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 8
• 201000004681 Psoriasis Diseases 0.000 claims abstract description 8
• 206010052779 Transplant rejections Diseases 0.000 claims abstract description 8
• 208000026935 allergic disease Diseases 0.000 claims abstract description 8
• 208000006673 asthma Diseases 0.000 claims abstract description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
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• 208000018737 Parkinson disease Diseases 0.000 claims abstract description 5
• 208000006011 Stroke Diseases 0.000 claims abstract description 5
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 5
• 230000000747 cardiac effect Effects 0.000 claims abstract description 5
• 230000009091 contractile dysfunction Effects 0.000 claims abstract description 5
• 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 claims abstract description 5
• 239000003937 drug carrier Substances 0.000 claims abstract description 5
• 206010064570 familial cold autoinflammatory syndrome Diseases 0.000 claims abstract description 5
• 206010028417 myasthenia gravis Diseases 0.000 claims abstract description 5
• 201000008482 osteoarthritis Diseases 0.000 claims abstract description 5
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 5
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims abstract description 4
• VDRMHRQQXLXAAC-UHFFFAOYSA-N [1-(4-hydroxycyclohexyl)-2-[[5-(2-methoxyphenyl)-1h-indazol-3-yl]amino]benzimidazol-5-yl]-pyrrolidin-1-ylmethanone Chemical compound COC1=CC=CC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(C=C4N=3)C(=O)N3CCCC3)C3CCC(O)CC3)C2=C1 VDRMHRQQXLXAAC-UHFFFAOYSA-N 0.000 claims abstract description 3
• AXZVEOQAICRWJY-UHFFFAOYSA-N 1-(4-hydroxycyclohexyl)-2-[[5-(2-methoxyphenyl)-1h-indazol-3-yl]amino]-n-(3-methylbutyl)benzimidazole-5-carboxamide Chemical compound COC1=CC=CC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(C=C4N=3)C(=O)NCCC(C)C)C3CCC(O)CC3)C2=C1 AXZVEOQAICRWJY-UHFFFAOYSA-N 0.000 claims abstract 2
• 125000000217 alkyl group Chemical group 0.000 claims description 69
• 238000006243 chemical reaction Methods 0.000 claims description 33
• 125000005843 halogen group Chemical group 0.000 claims description 32
• 125000001424 substituent group Chemical group 0.000 claims description 32
• 239000000243 solution Substances 0.000 claims description 29
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
• 125000003545 alkoxy group Chemical group 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 21
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
• 229940124597 therapeutic agent Drugs 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 11
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
• 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 7
• 238000001514 detection method Methods 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 241000283973 Oryctolagus cuniculus Species 0.000 claims description 5
• 238000002866 fluorescence resonance energy transfer Methods 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 4
• 229930105110 Cyclosporin A Natural products 0.000 claims description 4
• 108010036949 Cyclosporine Proteins 0.000 claims description 4
• 102000003996 Interferon-beta Human genes 0.000 claims description 4
• 108090000467 Interferon-beta Proteins 0.000 claims description 4
• UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 claims description 4
• 239000000872 buffer Substances 0.000 claims description 4
• 239000003246 corticosteroid Chemical class 0.000 claims description 4
• 229960000598 infliximab Drugs 0.000 claims description 4
• GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 4
• 229960001940 sulfasalazine Drugs 0.000 claims description 4
• NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 3
• 230000004048 modification Effects 0.000 claims description 3
• 238000012986 modification Methods 0.000 claims description 3
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
• 238000012360 testing method Methods 0.000 claims description 3
• IDFPQEHZYBXIFO-GFCCVEGCSA-N (R)-(4-fluoro-2-propylphenyl)-(1H-imidazol-2-yl)methanol Chemical compound CCCc1cc(F)ccc1[C@@H](O)c1ncc[nH]1 IDFPQEHZYBXIFO-GFCCVEGCSA-N 0.000 claims description 2
• RSFJUAJAYHSBHD-UHFFFAOYSA-N 1-cyclohexyl-n-[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]-5-(morpholin-4-ylmethyl)benzimidazol-2-amine Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CN5CCOCC5)C=C4N=3)C3CCCCC3)C2=C1 RSFJUAJAYHSBHD-UHFFFAOYSA-N 0.000 claims description 2
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 2
• JIDRQSULGLZGQN-UHFFFAOYSA-N 3-[2-[(5-bromo-1h-indazol-3-yl)amino]benzimidazol-1-yl]propan-1-ol Chemical compound C1=CC=C2N(CCCO)C(NC=3C4=CC(Br)=CC=C4NN=3)=NC2=C1 JIDRQSULGLZGQN-UHFFFAOYSA-N 0.000 claims description 2
• XHVAWZZCDCWGBK-WYRLRVFGSA-M Aurothioglucose Chemical compound OC[C@H]1O[C@H](S[Au])[C@H](O)[C@@H](O)[C@@H]1O XHVAWZZCDCWGBK-WYRLRVFGSA-M 0.000 claims description 2
• CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
• VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 2
• 108010008165 Etanercept Proteins 0.000 claims description 2
• 108010072051 Glatiramer Acetate Proteins 0.000 claims description 2
• FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
• FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 claims description 2
• AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 claims description 2
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• 229960002170 azathioprine Drugs 0.000 claims description 2
• LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 claims description 2
• 229960001334 corticosteroids Drugs 0.000 claims description 2
• 229940111134 coxibs Drugs 0.000 claims description 2
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• 239000003862 glucocorticoid Substances 0.000 claims description 2
• XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 2
• 229960004171 hydroxychloroquine Drugs 0.000 claims description 2
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• KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical class NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 2
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• NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 claims 3
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• OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 claims 2
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• VTJFVOQGGHESGO-UHFFFAOYSA-N 1-cyclohexyl-n-[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]-5-(piperidin-1-ylmethyl)benzimidazol-2-amine Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CN5CCCCC5)C=C4N=3)C3CCCCC3)C2=C1 VTJFVOQGGHESGO-UHFFFAOYSA-N 0.000 claims 1
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims 1
• FETDUDQELDASEU-UHFFFAOYSA-N 3-[2-[[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]amino]benzimidazol-1-yl]propan-1-ol Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=CC=C4N=3)CCCO)C2=C1 FETDUDQELDASEU-UHFFFAOYSA-N 0.000 claims 1
• LAUITIJUKVWARK-UHFFFAOYSA-N 4-[2-[[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]amino]-5-[[4-(2-pyridin-4-ylethyl)piperazin-1-yl]methyl]benzimidazol-1-yl]cyclohexan-1-ol Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CN5CCN(CCC=6C=CN=CC=6)CC5)C=C4N=3)C3CCC(O)CC3)C2=C1 LAUITIJUKVWARK-UHFFFAOYSA-N 0.000 claims 1
• FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 1
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• KEUZEVMRSCNJPS-UHFFFAOYSA-N [1-cyclohexyl-2-[[5-[3-(methoxymethyl)phenyl]-1h-indazol-3-yl]amino]benzimidazol-5-yl]methanol Chemical compound COCC1=CC=CC(C=2C=C3C(NC=4N(C5=CC=C(CO)C=C5N=4)C4CCCCC4)=NNC3=CC=2)=C1 KEUZEVMRSCNJPS-UHFFFAOYSA-N 0.000 claims 1
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