TW200424171A - Indole derivatives useful for the treatment of diseases - Google Patents

Info

Publication number

TW200424171A

TW200424171A TW092128121A TW92128121A TW200424171A TW 200424171 A TW200424171 A TW 200424171A TW 092128121 A TW092128121 A TW 092128121A TW 92128121 A TW92128121 A TW 92128121A TW 200424171 A TW200424171 A TW 200424171A

Authority

TW

Taiwan

Prior art keywords

hydroxy

ethyl

propyl

amino

group

Prior art date

2002-10-11

Links

• Espacenet
• Global Dossier
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 27
• 201000010099 disease Diseases 0.000 title claims abstract description 25
• 238000011282 treatment Methods 0.000 title claims description 21
• 150000002475 indoles Chemical class 0.000 title abstract description 48
• 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 17
• 238000002360 preparation method Methods 0.000 claims abstract description 172
• 238000000034 method Methods 0.000 claims abstract description 87
• 239000000203 mixture Substances 0.000 claims abstract description 71
• 230000002757 inflammatory effect Effects 0.000 claims abstract description 10
• 208000023504 respiratory system disease Diseases 0.000 claims abstract description 8
• -1 benzyloxy, hydroxyl Chemical group 0.000 claims description 159
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 131
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 104
• 150000001875 compounds Chemical class 0.000 claims description 74
• 150000003839 salts Chemical class 0.000 claims description 69
• 229910052739 hydrogen Inorganic materials 0.000 claims description 64
• 239000001257 hydrogen Substances 0.000 claims description 64
• 239000000126 substance Substances 0.000 claims description 55
• 239000002253 acid Substances 0.000 claims description 51
• 125000000217 alkyl group Chemical group 0.000 claims description 50
• 208000006673 asthma Diseases 0.000 claims description 44
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
• 150000001412 amines Chemical class 0.000 claims description 38
• 150000002431 hydrogen Chemical class 0.000 claims description 33
• 206010006451 bronchitis Diseases 0.000 claims description 30
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
• 239000003814 drug Substances 0.000 claims description 25
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 239000012453 solvate Substances 0.000 claims description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• 201000009267 bronchiectasis Diseases 0.000 claims description 17
• 238000006243 chemical reaction Methods 0.000 claims description 17
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
• 230000000155 isotopic effect Effects 0.000 claims description 16
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
• 229940079593 drug Drugs 0.000 claims description 12
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
• 230000001105 regulatory effect Effects 0.000 claims description 10
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 9
• 230000004064 dysfunction Effects 0.000 claims description 9
• 238000007792 addition Methods 0.000 claims description 8
• 230000008506 pathogenesis Effects 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 231100000252 nontoxic Toxicity 0.000 claims description 6
• 230000003000 nontoxic effect Effects 0.000 claims description 6
• 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 5
• 206010014561 Emphysema Diseases 0.000 claims description 5
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 4
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 4
• 206010006458 Bronchitis chronic Diseases 0.000 claims description 4
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 4
• 230000001154 acute effect Effects 0.000 claims description 4
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
• 208000007451 chronic bronchitis Diseases 0.000 claims description 4
• 230000008878 coupling Effects 0.000 claims description 4
• 238000010168 coupling process Methods 0.000 claims description 4
• 238000005859 coupling reaction Methods 0.000 claims description 4
• 208000015181 infectious disease Diseases 0.000 claims description 4
• 230000002458 infectious effect Effects 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 230000000414 obstructive effect Effects 0.000 claims description 4
• 125000006239 protecting group Chemical group 0.000 claims description 4
• 206010006482 Bronchospasm Diseases 0.000 claims description 3
• 208000037656 Respiratory Sounds Diseases 0.000 claims description 3
• 206010047924 Wheezing Diseases 0.000 claims description 3
• 239000013566 allergen Substances 0.000 claims description 3
• 150000001409 amidines Chemical class 0.000 claims description 3
• 230000007885 bronchoconstriction Effects 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
• 208000000884 Airway Obstruction Diseases 0.000 claims description 2
• 235000017060 Arachis glabrata Nutrition 0.000 claims description 2
• 235000010777 Arachis hypogaea Nutrition 0.000 claims description 2
• 235000018262 Arachis monticola Nutrition 0.000 claims description 2
• 206010003557 Asthma exercise induced Diseases 0.000 claims description 2
• 208000035143 Bacterial infection Diseases 0.000 claims description 2
• 206010006448 Bronchiolitis Diseases 0.000 claims description 2
• 206010011224 Cough Diseases 0.000 claims description 2
• 208000000059 Dyspnea Diseases 0.000 claims description 2
• 206010013975 Dyspnoeas Diseases 0.000 claims description 2
• 208000004657 Exercise-Induced Asthma Diseases 0.000 claims description 2
• 206010017533 Fungal infection Diseases 0.000 claims description 2
• 208000016300 Idiopathic chronic eosinophilic pneumonia Diseases 0.000 claims description 2
• 208000031888 Mycoses Diseases 0.000 claims description 2
• 208000010362 Protozoan Infections Diseases 0.000 claims description 2
• 208000036142 Viral infection Diseases 0.000 claims description 2
• 201000009961 allergic asthma Diseases 0.000 claims description 2
• 229910052786 argon Inorganic materials 0.000 claims description 2
• 230000001580 bacterial effect Effects 0.000 claims description 2
• 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
• 230000001684 chronic effect Effects 0.000 claims description 2
• 201000009323 chronic eosinophilic pneumonia Diseases 0.000 claims description 2
• 230000007613 environmental effect Effects 0.000 claims description 2
• 208000024695 exercise-induced bronchoconstriction Diseases 0.000 claims description 2
• 230000003325 follicular Effects 0.000 claims description 2
• 230000002538 fungal effect Effects 0.000 claims description 2
• 201000010659 intrinsic asthma Diseases 0.000 claims description 2
• 230000002427 irreversible effect Effects 0.000 claims description 2
• 230000001991 pathophysiological effect Effects 0.000 claims description 2
• 235000020232 peanut Nutrition 0.000 claims description 2
• 230000000750 progressive effect Effects 0.000 claims description 2
• 230000009385 viral infection Effects 0.000 claims description 2
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 4
• 125000001475 halogen functional group Chemical group 0.000 claims 2
• 239000013067 intermediate product Substances 0.000 claims 2
• SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 claims 1
• 241001553178 Arachis glabrata Species 0.000 claims 1
• XMLMFKJCOZHNCZ-UHFFFAOYSA-N C(=O)(O)C=1C(=C(C=2CC3=CC=CC=C3C2C1)N)C(=O)O Chemical compound C(=O)(O)C=1C(=C(C=2CC3=CC=CC=C3C2C1)N)C(=O)O XMLMFKJCOZHNCZ-UHFFFAOYSA-N 0.000 claims 1
• 229920000877 Melamine resin Polymers 0.000 claims 1
• 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims 1
• 238000002651 drug therapy Methods 0.000 claims 1
• RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 claims 1
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims 1
• JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 claims 1
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims 1
• 125000004043 oxo group Chemical group O=* 0.000 claims 1
• 230000002685 pulmonary effect Effects 0.000 claims 1
• CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 claims 1
• 125000003944 tolyl group Chemical group 0.000 claims 1
• 230000000172 allergic effect Effects 0.000 abstract description 7
• 239000000543 intermediate Substances 0.000 abstract description 3
• 230000008569 process Effects 0.000 abstract description 3
• 208000035475 disorder Diseases 0.000 abstract 2
• 208000026935 allergic disease Diseases 0.000 abstract 1
• 208000027866 inflammatory disease Diseases 0.000 abstract 1
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 126
• 238000005481 NMR spectroscopy Methods 0.000 description 81
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
• 239000002904 solvent Substances 0.000 description 56
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
• 239000011734 sodium Substances 0.000 description 50
• 230000000694 effects Effects 0.000 description 45
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
• 239000000243 solution Substances 0.000 description 40
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 30
• 229910001868 water Inorganic materials 0.000 description 27
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 26
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
• 229910052757 nitrogen Inorganic materials 0.000 description 23
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
• 229910052799 carbon Inorganic materials 0.000 description 19
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
• 239000003795 chemical substances by application Substances 0.000 description 18
• 239000012044 organic layer Substances 0.000 description 18
• 239000007787 solid Substances 0.000 description 18
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 17
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
• 238000005160 1H NMR spectroscopy Methods 0.000 description 14
• 239000000047 product Substances 0.000 description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
• 229910021529 ammonia Inorganic materials 0.000 description 13
• 239000007789 gas Substances 0.000 description 13
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
• 235000019341 magnesium sulphate Nutrition 0.000 description 13
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
• JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
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• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• 229940124597 therapeutic agent Drugs 0.000 description 9
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• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
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