CN101759628A - 乙炔基吲哚化合物 - Google Patents
乙炔基吲哚化合物 Download PDFInfo
- Publication number
- CN101759628A CN101759628A CN200910260865A CN200910260865A CN101759628A CN 101759628 A CN101759628 A CN 101759628A CN 200910260865 A CN200910260865 A CN 200910260865A CN 200910260865 A CN200910260865 A CN 200910260865A CN 101759628 A CN101759628 A CN 101759628A
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- CN
- China
- Prior art keywords
- methyl
- phenyl
- compound
- butoxy
- ethynyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- VYWBXQOYASJNLB-UHFFFAOYSA-N 2-ethynyl-1h-indole Chemical class C1=CC=C2NC(C#C)=CC2=C1 VYWBXQOYASJNLB-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 318
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 211
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 135
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 132
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 101
- -1 3-carboxyl propyl group Chemical group 0.000 claims description 89
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 36
- 229940002612 prodrug Drugs 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 21
- 208000006673 asthma Diseases 0.000 abstract description 16
- 201000010099 disease Diseases 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 208000030603 inherited susceptibility to asthma Diseases 0.000 abstract description 10
- 206010011224 Cough Diseases 0.000 abstract description 9
- 230000003042 antagnostic effect Effects 0.000 abstract description 8
- 208000023504 respiratory system disease Diseases 0.000 abstract description 6
- 201000002859 sleep apnea Diseases 0.000 abstract description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 abstract description 4
- 206010039085 Rhinitis allergic Diseases 0.000 abstract description 4
- 201000010105 allergic rhinitis Diseases 0.000 abstract description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 abstract description 4
- 206010006458 Bronchitis chronic Diseases 0.000 abstract description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 3
- 206010014561 Emphysema Diseases 0.000 abstract description 3
- 206010035664 Pneumonia Diseases 0.000 abstract description 3
- 206010006451 bronchitis Diseases 0.000 abstract description 3
- 208000007451 chronic bronchitis Diseases 0.000 abstract description 3
- 201000009890 sinusitis Diseases 0.000 abstract description 3
- 206010001076 Acute sinusitis Diseases 0.000 abstract description 2
- 206010009137 Chronic sinusitis Diseases 0.000 abstract description 2
- 208000029523 Interstitial Lung disease Diseases 0.000 abstract description 2
- 208000027157 chronic rhinosinusitis Diseases 0.000 abstract description 2
- 102000004155 Cysteinyl leukotriene receptor 2 Human genes 0.000 abstract 2
- 108090000655 Cysteinyl leukotriene receptor 2 Proteins 0.000 abstract 2
- 102000010918 Cysteinyl leukotriene receptors Human genes 0.000 abstract 2
- 108050001116 Cysteinyl leukotriene receptors Proteins 0.000 abstract 2
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 abstract 2
- 230000005923 long-lasting effect Effects 0.000 abstract 2
- 230000003389 potentiating effect Effects 0.000 abstract 2
- 230000001684 chronic effect Effects 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 185
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 183
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 183
- 238000002360 preparation method Methods 0.000 description 150
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- 238000005160 1H NMR spectroscopy Methods 0.000 description 96
- 239000002585 base Substances 0.000 description 86
- 230000000704 physical effect Effects 0.000 description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 239000003814 drug Substances 0.000 description 37
- 239000000203 mixture Substances 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 33
- 238000000034 method Methods 0.000 description 32
- 239000012141 concentrate Substances 0.000 description 30
- 235000008504 concentrate Nutrition 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- 238000005406 washing Methods 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- 238000003810 ethyl acetate extraction Methods 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 239000000370 acceptor Substances 0.000 description 19
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 229940079593 drug Drugs 0.000 description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 17
- 239000003795 chemical substances by application Substances 0.000 description 17
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 235000011121 sodium hydroxide Nutrition 0.000 description 16
- 238000001035 drying Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 13
- 229910000024 caesium carbonate Inorganic materials 0.000 description 13
- 238000000634 powder X-ray diffraction Methods 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000007789 gas Substances 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 10
- 230000032050 esterification Effects 0.000 description 10
- 238000005886 esterification reaction Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 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 10
- 229920002554 vinyl polymer Polymers 0.000 description 10
- PASVIKSOGNJXIL-UHFFFAOYSA-N (2-bromo-5-fluorophenyl)hydrazine Chemical compound NNC1=CC(F)=CC=C1Br PASVIKSOGNJXIL-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 206010006482 Bronchospasm Diseases 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 230000007885 bronchoconstriction Effects 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 235000015320 potassium carbonate Nutrition 0.000 description 9
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000003889 eye drop Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000002464 receptor antagonist Substances 0.000 description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000000151 deposition Methods 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 239000000043 antiallergic agent Substances 0.000 description 6
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 6
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 6
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 6
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- GRJZJFUBQYULKL-UHFFFAOYSA-N 4-bromo-1h-indole Chemical class BrC1=CC=CC2=C1C=CN2 GRJZJFUBQYULKL-UHFFFAOYSA-N 0.000 description 5
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- BNGZNZUNROGDHT-UHFFFAOYSA-N n-[4-oxo-2-(2h-tetrazol-5-yl)chromen-8-yl]-4-(4-phenylbutoxy)benzamide;hydrate Chemical compound O.C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC1=CC=CC(C(C=2)=O)=C1OC=2C=1N=NNN=1 BNGZNZUNROGDHT-UHFFFAOYSA-N 0.000 description 5
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- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
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- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- 229910017488 Cu K Inorganic materials 0.000 description 3
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Abstract
本发明涉及一种乙炔基吲哚化合物,研发了作为具有有效口服活性和长效cysLT1/cysLT2受体拮抗活性的式(I)的化合物:该化合物表现出对cysLT1/cysLT2受体的有效拮抗活性并且甚至在口服给药的情况中也具有长效作用,且因此适用作预防和/或治疗各种疾病的口服活性剂,例如呼吸性疾病(例如哮喘(支气管哮喘等),慢性阻塞性肺疾病(COPD),肺气肿,慢性支气管炎,肺炎(间质性肺炎等),严重急性呼吸器官综合征(SARS),急性呼吸窘迫综合征(ARDS),呼吸暂停综合征,过敏性鼻炎,窦炎(急性窦炎,慢性窦炎等),肺纤维化,咳嗽(慢性咳嗽等)等)。
Description
技术领域
本发明涉及式(1)的化合物:
其中所有符号均与如下文定义的含义相同。
背景技术
支气管哮喘为病理学状况,其中气道因气道收缩或炎症而缩小,导致阵发性咳,喘鸣和呼吸困难。支气管哮喘的治疗剂包括具有有效抗炎作用的吸入性皮质类固醇,为支气管舒张剂的β刺激剂和茶碱以及抑制化学介体活性的活性剂等。
组胺,白三烯,前列腺素等称作从肥大细胞或炎性细胞中释放的涉及支气管哮喘的化学介体。在白三烯(LTs)中,LTC4,LTD4和LTE4表示的半胱氨酰白三烯(下文称作“cysLTs”)具有比组胺强约1,000倍的气道收缩效应。此外,cysLTs一般通过炎性细胞浸润,气道超敏反应和气道中粘液分泌促进诱导气道炎症,由此它们深入涉及支气管哮喘的潜在病理学状况。
CysLTs为体内生理学活性物质,它们为花生四烯酸的5-脂氧合酶代谢物。存在至少两种不同类型的cysLTs受体,且迄今为止已经克隆了cysLT1受体和cysLT2受体(Nature,399,789-793,1999,J.Biol.,Chem.,275,30531-30536,2000)。cysLT1受体主要在气道平滑肌中表达,且深入涉及支气管哮喘发作(Am.J.Respir.Crit.CareMed.,163,226-233,2001)。同时,据报导cysLT2受体采用LTC4,LTD4和LTE4作为配体,与cysLT1受体类似,且在支气管平滑肌中表达(J.Biol.Chem.,275,30531-30536,2000,Am.J.Respir.Crit.CareMed.,164,2098-2101,2001)。
普仑司特水合物,孟鲁司特钠和扎鲁司特目前为商购的白三烯受体拮抗剂,且它们用作治疗支气管哮喘的口服药物和/或治疗过敏性鼻炎的口服药物。
普仑司特水合物
孟鲁司特钠
扎鲁司特
然而,已知这些白三烯受体拮抗剂对轻度或中度支气管哮喘比对重度更有效。还已知存在某些无应答者,其药剂对轻度或中度支气管哮喘不具有足够的作用。因此,对具有治疗活性高于现存药剂的药剂存在需求。
实现该目的的手段之一在于提高所述药剂的白三烯受体拮抗活性。目前商购的三种化合物均为cysLT1拮抗剂。作为强化受体拮抗活性的手段,设计了进一步增强cysLT1拮抗活性的方法和促成cysLT1拮抗活性与cysLT2拮抗活性组合的方法。
同时,需要以定期为基础给予抗喘药,且由此优选口服制剂,它们对服药而言是便利的。在口服制剂中,为给药的便利性而优选具有较低给药频率的药物。即优选具有长效活性的口服抗哮喘药。在研发口服制剂方面,极为重要的是改善药物效力的期限。
然而,特别是在口服制剂中,本身关注的化合物可能不稳定;可以表现出难以递送至靶器官;或尽管化合物的拮抗活性有效,但是可能表现出早期代谢和排泄。基于这些原因,不易于获得具有长期有效作用的化合物。
WO2005/021518(专利文件1)中描述了具有cysLT2受体拮抗作用的式(A)的化合物:
其中R1A和R2A各自独立地表示具有可以被保护的酸性基团的基团,DA和EA各自独立地表示键或具有含有1-8个原子的主链的间隔基,R3A表示取代基,环AA表示可以进一步具有取代基的环状基团,环BA表示可以进一步具有取代基的环状基团,YA和ZA各自独立地表示碳原子或氮原子,且表示单键或双键,其中当YA和/或ZA表示氮原子时,键表示单键。
然而,尽管其中披露了各种环稠合的化合物,但是其中未披露或暗示哪个环特别促成药物功效期限。
WO2006/090817(专利文件2)披露了具有有效的白三烯受体拮抗作用与极佳的口服活性的式(B)的化合物:
其中R11B和R12B各自独立地表示取代基,选自R51B,R52B和R53B的两个基团各自独立地表示具有可以被保护的酸性基团的基团,R51B,R52B和R53B中的另一个表示氢原子或取代基,R3B表示
(其中VB和WB各自独立地表示键或具有带有1-8个原子的主链的间隔基,且环AB和环BB各自独立地表示具有带有取代基的环状基团等,mB表示0或1-4的整数,nB表示0或1-2的整数,pB表示0或1,且表示单键或双键,其中mB和pB之和为小于或等于4的整数(对基团的解释选择必要的部分)。为了描述式中的符号,选择了必要的部分。
然而,尽管在上述专利文件中描述了取代基的各种类型,但是未披露或暗示可以基于取代基类型和/或取代位置获得的作用。特别地,专利文件2完全未披露改善药物功效期限与保持有效口服活性的方案。此外,在专利文件2中,实施例化合物(其中VB表示三键)仅为实施例101中所述的4-(1-(羧甲基)-7-{[2-羟基-4-(4-苯氧基丁氧基)苯基]乙炔基)-1H-吲哚-3-基)丁酸。
本发明披露的内容
因此,对发现具有有效口服活性和长效作用的cysLT1/cysLT2受体拮抗剂存在需求。
本发明的这一目的和其它目的通过发现式(I)的化合物适用作呼吸性疾病的治疗药物而实现。即本发明涉及:
(1)式(I)的化合物或其盐,溶剂合物或前体药物:
其中:
R1表示羧甲基或3-羧基丙基,
R2表示氢原子或C1-4烷基,
R3表示[1-(羧甲基)环丙基]甲基或3-羧基丙基,
R4表示氢原子或卤原子,且
环1表示:
其中R5表示C1-4烷基或卤原子,m表示0或1-5的整数,R5在m为2或2以上时可以相同或不同,且箭头结合丁氧基。
(2)上述条款(1)的化合物,其中环1为
其中箭头具有与上述条款(1)相同的含义。
(3)上述条款(2)的化合物,其中R1为3-羧基丙基且R3为3-羧基丙基。
(4)上述条款(1)的化合物,其中该化合物为
(i)4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(ii)4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(iii)4,4’-[2-甲基-7-({4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(iv)4,4’-[7-({4-[4-(2,3-二氟苯氧基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(v)4,4’-[7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(vi)4,4’-[2-甲基-7-({4-[4-(2,3,4,5-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(vii)4,4’-[2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(viii)4,4’-[7-({4-[4-(4-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(ix)4,4’-[7-({4-[4-(4-氟-3-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(x)4,4’-[4-氟-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(xi)4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-4-氟-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(xii)4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(xiii)4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(xiv)[3-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1-基]乙酸,
(xv)(1-{[1-(羧甲基)-7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]甲基}环丙基)乙酸,
(xvi)[3-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1-基]乙酸,或
(xvii)4,4’-[7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸。
(5)药物组合物,包含上述条款(1)的式(I)的化合物或其盐,溶剂合物或前体药物作为活性组分。
(6)上述条款(5)的组合物,为cysLT1/cysLT2受体拮抗剂。
(7)上述条款(6)的组合物,用于预防和/或治疗cysLT1/cysLT2受体-介导的疾病。
(8)上述条款(7)的组合物,其中cysLT1/cysLT2受体-介导的疾病为呼吸性疾病。
(9)上述条款(8)的组合物,其中所述呼吸性疾病为哮喘,慢性阻塞性肺疾病,肺气肿,慢性支气管炎,肺炎,严重急性呼吸器官综合征,急性呼吸窘迫综合征,过敏性鼻炎,窦炎,肺纤维化或咳嗽。
(10)药物,包含上述条款(1)的式(I)的化合物或其盐,溶剂合物或前体药物,和一种或多种选自如下的成员:白三烯受体拮抗剂,类固醇药,抗组胺药,磷酸二酯酶抑制剂,弹性蛋白酶抑制剂,抗胆碱能药,5-脂氧合酶抑制剂,前列腺素,非类固醇类抗炎药,拟交感神经药,血栓烷合酶抑制剂和血栓烷受体拮抗剂。
(11)预防和/或治疗哺乳动物cysLT1/cysLT2受体-介导的疾病的方法,该方法包括对有此需要的哺乳动物给予有效量的上述条款(1)的式(I)的化合物或其盐,溶剂合物或前体药物,和
(12)上述条款(1)的式(I)的化合物或其盐,溶剂合物或前体药物在制备用于预防和/或治疗cysLT1/cysLT2受体-介导的疾病的药剂中的应用。
附图简述
图1表示4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸晶体的粉末X-射线衍射光谱图。
图2表示4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸晶体的差示扫描量热(DSC)图。
图3表示4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸晶体的粉末X-射线衍射光谱图。
图4表示4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸晶体的差示扫描量热(DSC)图。
图5表示4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸晶体的粉末X-射线衍射光谱图。
图6表示4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸晶体的差示扫描量热(DSC)图。
发明详述
作为对解决上述问题的深入研究的结果,本发明的发明人发现式(I)的化合物强力拮抗cysLT1/cysLT2受体并且甚至在口服给药的情况下也表现出长效作用。
在本发明中,R1表示羧甲基或3-羧基丙基。
在本发明中,R2表示氢原子或C1-4烷基。C1-4烷基的实例可以包括甲基,乙基,正-丙基,异丙基,正-丁基,异丁基,仲-丁基,叔丁基等。
在本发明中,R3表示[1-(羧甲基)环丙基]甲基或3-羧基丙基。
在本发明中,R4表示氢原子或卤原子。卤原子的实例可以包括氟原子,氯原子,溴原子,碘原子等。
在本发明中,环1表示其中R5表示C1-4烷基或卤原子,m表示0或1-5的整数,R5在m为2或2以上时可以相同或不同,且箭头结合丁氧基。R5表示的“C1-4烷基”具有与R2表示的C1-4烷基相同的含义。R5表示的卤原子具有与R4表示的卤原子相同的含义。
在本发明中,优选R1为3-羧基丙基。
在本发明中,优选R2为C1-4烷基,且更优选为甲基。
在本发明中,优选R3为3-羧基丙基。
在本发明中,优选R4为氢原子或氟原子。
在本发明中,优选R5为甲基或氟原子。
在本发明中,优选m为2-5的整数。
在本发明中,优选环1为
其中箭头结合丁氧基。
在本发明中,优选式(I)为式(I-1):
其中R2表示氢原子或C1-4烷基,
R4表示氢原子或卤原子,且
环1-1表示:
其中箭头结合丁氧基。
在本发明中,优选化合物的具体实例可以包括:
(1)4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,(2)4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,(3)4,4’-[2-甲基-7-({4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,(4)4,4’-[7-({4-[4-(2,3-二氟苯氧基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,(5)4,4’-[7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,(6)4,4’-[2-甲基-7-({4-[4-(2,3,4,5-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,(7)4,4’-[2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,(8)4,4’-[7-({4-[4-(4-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,(9)4,4’-[7-({4-[4-(4-氟-3-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,(10)4,4’-[4-氟-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,(11)4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-4-氟-2-甲基-1H-吲哚-1,3-二基]二丁酸,(12)4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,(13)4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,(14)[3-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1-基]乙酸,(15)(1-{[1-(羧甲基)-7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]甲基}环丙基)乙酸,(16)[3-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1-基]乙酸或(17)4,4’-[7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸及其盐,溶剂合物或前体药物。
更优选的化合物为4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,或4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,其盐,溶剂合物或前体药物。
可以通过公知方法,例如下文所述的方法,与之类似的方法或实施例中所述的方法制备式(1)的本发明化合物。在如下各制备方法中,可以以盐的形式使用原料物质。下述式(I)药学上可接受的盐可以作为盐使用。
可以按照式(II)的化合物的碱水解反应制备式(I)的化合物:
其中R1-1表示甲氧基羰基甲基,乙氧基羰基甲基,3-(甲氧基羰基)丙基或3-(乙氧基羰基)丙基,且R3-1表示[1-(甲氧基羰基甲基)环丙基]甲基,[1-(乙氧基羰基甲基)环丙基]甲基,3-(甲氧基羰基)丙基或3-(乙氧基羰基)丙基。
式(II)化合物的碱水解反应在0-120℃的温度下和例如在有机溶剂(乙二醇,甲醇,乙醇,四氢呋喃,二噁烷,二甲氧基乙烷等)中,使用碱金属氢氧化物(氢氧化钠,氢氧化钾,氢氧化锂等),碱土金属氢氧化物(氢氧化钡,氢氧化钙等)或碳酸盐(碳酸钠,碳酸钾等)或其水溶液或其混合物进行。
可以按照如反应方案1中所示的方法制备式(II)的化合物。在反应方案1中,X表示溴原子,碘原子或三氟甲磺酰氧基,AcO表示乙酰氧基,Z表示卤原子,羟基,甲磺酰氧基或对甲苯磺酰氧基,且其它符号表示与如上所述定义相同的含义。
反应方案1
在反应方案1中,交叉偶联反应,羟基的脱保护反应和醚化反应可以在如下所述条件或本说明书所述实施例中的条件下进行。
式(III)的化合物与式(IV)的化合物之间的交叉偶联反应在如下条件下进行,例如在有机溶剂(乙酸乙酯,乙酸异丙酯,苯,甲苯,二甲苯,庚烷,环己烷,四氢呋喃,二噁烷,二甲氧基乙烷,乙醇,异丙醇,聚乙二醇,二甲亚砜,N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,N-甲基-2-吡咯烷酮,二氯甲烷,氯仿,丙酮,乙腈,水,其混合物等)中,在有或没有单独的碱(二乙胺,三乙胺,丙胺,二异丙基胺,二异丙基乙胺,二丁胺,三丁胺,吡咯烷,哌啶,N-甲基哌啶,1,4-二氮杂双环[2.2.2]辛烷(DABCO),吡啶,氢氧化钠,碳酸氢钠,碳酸钠,碳酸钾,碳酸铯,磷酸钠,磷酸钾,氟化钾等)和催化剂(钯催化剂(例如四(三苯基膦)钯(Pd(PPh3)4),二氯双(三苯基膦)钯(PdCl2(PPh3)2),乙酸钯(Pd(OAc)2),二氯化钯(PdCl2),钯黑,1,1’-双(二苯基膦基二茂铁)二氯钯(PdCl2(dppf)2),二氯二烯丙基钯(PdCl2(烯丙基)2),苯基双(三苯基膦)碘化钯(PhPdI(PPh3)2),三(二亚苄基丙酮)二钯(Pd2(DBA)3),双(三-叔丁基膦)钯(Pd(tBu3P)2)等)或其与配体(例如三苯基膦,三-叔丁基膦等)的混合物或其与铜催化剂(例如碘化亚铜(I))等)的混合物存在下,且在有或没有相转移催化剂(例如氟化四丁基铵,溴化四丁基铵,碘化四丁基铵,乙酸四丁基铵等)存在下,在室温-120℃下。
在交叉偶联反应后,羟基的脱保护反应在,例如有机溶剂(甲醇,乙醇,四氢呋喃,二噁烷,二甲氧基乙烷或其混合物等)中,使用碱金属氢氧化物(氢氧化钠,氢氧化钾,氢氧化锂等),碱土金属氢氧化物(氢氧化钡,氢氧化钙等)或碳酸盐(碳酸钠,碳酸钾,碳酸铯等)或其水溶液或其混合物在0-100℃的温度下进行。
(1)当Z为卤原子,甲磺酰氧基或对-甲苯磺酰氧基时,式(V)的化合物与式(VI)的化合物之间的醚化在如下条件下进行:例如在有机溶剂(诸如二甲基甲酰胺,二甲亚砜,N,N-二甲基乙酰胺,N-甲基-2-吡咯烷酮,1,3-二甲基-2-咪唑烷酮,氯仿,二氯甲烷,乙醚,四氢呋喃,苯或甲苯)中,在有碱金属氢氧化物(诸如氢氧化钠,氢氧化钾或氢氧化锂),碱土金属氢氧化物(诸如氢氧化钡或氢氧化钙)或碳酸盐(诸如碳酸钠,碳酸钾或碳酸铯),碱金属磷酸盐(诸如磷酸钾)或其水溶液或其混合物存在下,和在有或没有相转移催化剂(例如氟化四丁基铵,溴化四丁基铵,碘化四丁基铵,乙酸四丁基铵等)存在下,在0℃-120℃温度下。
(2)当Z是羟基时,醚化反应在如下条件下进行:例如在有机溶剂(诸如二氯甲烷,乙醚,四氢呋喃,乙腈,苯或甲苯)中,在有偶氮化合物(诸如偶氮二甲酸二乙酯,偶氮二甲酸二异丙酯,1,1’-(偶氮二羰基)二哌啶或1,1’-偶氮双(N,N-二甲基甲酰胺))和膦化合物(诸如三苯基膦,三丁膦或三甲膦)存在下,在0-60℃温度下。
例如,可以通过使用本说明书实施例2,10,20或51中所述的方法或常规的公知方法制备式(III)的吲哚化合物。
用作式(III),(IV)和(VI)的原料物质或试剂的化合物本身为公知的或易于通过本说明书实施例中所述的方法或任意常规的公知方法制备,例如“Comprehensive Organic Transformations:A Guideto Functional Group Preparations,第2版(由Richard C.Larock,John Wiley & Sons Inc.编写,1999)”中所述的方法而制备。
在本说明书的每一个反应中,正如本领域技术人员显而易见的,使用加热的反应可以使用水浴,油浴,沙浴或微波进行。
在本说明书的每一个反应中,还可以使用适当负载在聚合物(例如聚苯乙烯,聚丙烯酰胺,聚丙烯,聚乙二醇等)上的固相支持试剂。
在本说明书的每一个反应中,可以通过常规纯化方式,例如在常压或减压下蒸馏,使用硅胶或硅酸镁的高效液相色谱法,薄层色谱法,离子交换树脂,清除剂树脂或柱色谱法或洗涤或重结晶。可以对每一反应进行纯化或可以在完成某些反应后进行纯化。
除非另有特别的提及,否则本发明包括所有异构体。例如本发明包括所有的通过色谱分离产生的互变体,极性化合物(高极性化合物和低极性化合物),平衡化合物,旋转异构体及其任意比例的混合物。
可以通过使用本说明书实施例中所述的方法或任意常规的公知方法将式(I)的化合物转化成盐。优选的盐为药学上可接受的盐。
化合物的盐的实例包括碱金属盐,碱土金属盐,铵盐和胺盐。
优选所述盐为水-溶性的。合适的盐的实例包括碱金属(诸如钾和钠)盐,碱土金属(诸如钙和镁)盐,铵盐和药学上可接受的有机胺(诸如四甲基铵,三乙胺,甲胺,二甲胺,环戊胺,苄胺,苯乙胺,哌啶,一乙醇胺,二乙醇胺,三(羟基甲基)氨基甲烷,赖氨酸,精氨酸和N-甲基-D-葡萄糖胺)的盐。
可以通过使用本说明书实施例中所述的方法或任意常规的公知方法将式(I)的化合物及其盐转化成溶剂合物。优选该溶剂合物为无毒性的和水-溶性的。适当的溶剂合物的实例可以包括溶剂合物,例如水合物和醇化物(例如乙醇化物等)。
cysLT1/cysLT2受体-拮抗化合物还可以以式(I)化合物的前体药物的形式使用。
术语式(I)的化合物的“前体药物”意指通过与活体内的酶,胃酸等反应转化成式(I)的化合物的化合物。式(I)的化合物的前体药物的实例包括:化合物,其中R1和/或R3表示的羧基,例如被酯化或酰胺化(例如化合物,其中式(I)的化合物的羧基被乙基酯化,异丙基酯化,苯基酯化,羧甲基酯化,二甲氨基甲基酯化,新戊酰氧基甲基酯化,乙氧基羰基氧基乙基酯化,酞基酯化,(5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基)甲基酯化,环己氧基羰基乙基酯化,1-{[(环己氧基)羰基]氧基}乙基酯化,甲基酰胺化等);或化合物,其中羧基被羟基甲基等代替。可以通过本身公知的方法制备这些化合物。式(I)的化合物的前体药物可以为水合物和非水合物中的任一种。
此外,式(I)的化合物可以用同位素(例如2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,35S,18F,36Cl,123I,125I等)等标记。
[毒性]
式(I)的化合物具有低毒性并且被认为其安全性足以用于药物应用。
[药物应用]
本发明的化合物用于拮抗cysLT1/cysLT2受体。因此,该化合物适用作,例如气道收缩抑制剂,炎性细胞(例如嗜酸细胞,中性白细胞,淋巴细胞,嗜碱粒细胞等)浸润抑制剂,粘液分泌抑制剂或气道超敏反应增加的抑制剂。
此外,本发明的化合物适用作预防和/或治疗cysLT1/cysLT2受体-相关疾病的活性剂,例如呼吸性疾病(例如哮喘(支气管哮喘,阿司匹林诱发的哮喘,锻炼诱发的哮喘等),慢性阻塞性肺疾病(COPD),肺气肿,慢性支气管炎,肺炎(间质性肺炎,嗜酸细胞性肺炎等),严重急性呼吸器官综合征(SARS),急性呼吸窘迫综合征(ARDS),呼吸暂停综合征(睡眠呼吸暂停综合征,伴随扁桃腺样肥大的睡眠障碍性呼吸,腺体样切除术/扁桃体切除术后的睡眠障碍性呼吸等),过敏性鼻炎,窦炎(急性窦炎,慢性窦炎等),肺纤维化,咳嗽(慢性咳嗽等)等),或作为祛痰剂或镇咳药。
此外,本发明的化合物还可以用作改善呼吸功能的活性剂。本文所用的术语“呼吸功能”意指,例如空气进入/离开肺的流入或流出(肺活量),氧气从肺递送至血液而使CO2从血液中释放至体外(氧交换容量),呼吸阻力等。
本文所用的术语“呼吸器官”意指涉及呼吸的身体部分,诸如气道,口腔,鼻腔,鼻窦,气管,支气管,细支气管和肺。
此外,本发明的化合物还用于预防和/或治疗其它涉及cysLT1/cysLT2受体的疾病,诸如心血管疾病(例如心绞痛,心肌梗死,急性冠状动脉综合征,心功能不全,心律失常,心肌病(扩张型心肌病,肥厚性心肌病等),心包炎,瓣膜炎,心肌炎,心脏压塞,低心排出量综合征,二尖瓣狭窄等),囊性纤维化,动脉粥样硬化,肺纤维化,脑梗死,脑水肿,动脉瘤头痛(偏头痛,丛集性头痛,紧张型头痛等),妇科疾病(子宫内膜异位症,痛经等),梅尼埃病,癫痫症,癌症,肾病,胃肠道溃疡,炎性肠病等。
本文所用的术语“cysLT1/cysLT2受体拮抗活性”意指本发明的化合物表现出对cysLT1受体和cysLT2受体的拮抗作用。
本发明的化合物还可以与其它药物组合给药,目的在于:1)补充和/或强化本发明化合物的预防和/或治疗作用等;2)改善本发明化合物的药代动力学特性和吸收和降低剂量等;和/或3)减少本发明化合物的副作用等。
本发明的化合物和其它药物可以以将这些成分配制成一种制剂的组合药物的形式给药,或可以单独的制剂的形式给药。就将这些药物以单独的制剂的形式给药而言,可以同时或在不同时间给予它们。在后面的情况中,可以在其它药物治疗前给予本发明的化合物。可选择地,可以在本发明化合物前给予其它药物。给予它们的方法可以相同或不同。
上述其它药物可以为低分子量化合物或高分子量蛋白质,多肽,多核苷酸(DNAs,RNAs和基因),反义药物,诱杀剂,抗体,疫苗等。可以在考虑临床使用剂量作为标准的情况下适当选择其它药物的剂量。本发明化合物与其它药物之间的配制比例可以适当选择,这取决于所治疗的受试者的年龄和体重,给药方法和时间,靶向的疾病,其症状或病情,组合等。例如相对于1质量份的本发明化合物而言其它药物的使用范围在0.01-100质量份。可以单独给予其它药物或以其任意组合的方式给予,例如任意一种或多种选自下列相同或不同基团的适当比例的化合物。应理解用于补充和/或强化本发明化合物预防和/或治疗作用的其它药物不仅包括已经发现的药物,而且包括基于上述机理的未来研发的药物。
对上述组合药物有效预防和/或治疗的疾病没有特别限制。其中补充和/或强化所述疾病可以为本发明化合物预防和/或治疗作用得到的那些疾病。
补充和/或强化本发明化合物对哮喘的预防和/或治疗作用的其它药物的实例包括白三烯受体拮抗剂,抗组胺药,磷酸二酯酶抑制剂,弹性蛋白酶抑制剂,抗胆碱能药,抗过敏药(化学介体释放抑制剂,组胺拮抗剂,血栓烷合酶抑制剂,血栓烷受体拮抗剂,Th2细胞因子抑制剂等),类固醇药,支气管扩张药(黄嘌呤衍生物,副交感神经阻滞药,拟交感神经药),疫苗治疗剂,金制剂,中草药,非类固醇抗炎药,5-脂氧合酶抑制剂,5-脂氧合酶激活蛋白拮抗剂,白三烯合成抑制剂,前列腺素,大麻素-2受体刺激剂,镇咳药,祛痰药,来自接种痘苗病毒的家兔皮肤组织的提取物等。
白三烯受体拮抗剂的实例包括普仑司特水合物,孟鲁司特钠,扎鲁司特,MK-571,LY-203647,WY-46016,WY-48422,WY-49353,WY-49451,RG-12553,MDL-43291,CGP-44044A,RG-14524,LY-287192,LY-290324,L-695499,RPR-105735B,WAY-125007,OT-4003,LM-1376,LY-290154,SR-2566,L-740515,LM-1453,CP-195494,LM-1484,CR-3465,阿鲁司特,泊比司特,硫鲁司特,L-648051,RG-12525,RG-7152,SK&F-106203,SR-2640,WY-50295,伊拉司特钠,维鲁司特,MCC-847,BAY-x-7195,利托司特,西那司特,CGP-44826,FK-011,YM-158,MEN-91507,KCA-757,RS-601,RS-635,S-36496,ZD-3523,DS-4574,吡咯司特,AS-35,YM-57158,MCI826,NZ-107,4414-CERM,YM-16638,Wy-48252,Wy-44329,Wy-48090,VUF-4679,托鲁司特,SM-11044,SC-39070,OT-3473,N-2401,LY-243364,L-649923,多夸司特,DP-1934,YM-17551,Wy-47120,VUF-K-8707,SK&F-88046,SK&F-101132,SK&F-102922,LY-137617,LY-163443,LY-302905,L-647438,L-708738,KY-234,FPL-55712,CP-288886,S-36527,CGP-35949,CS-615,MDL-19301D,SCH-40120和ZD-3705等。
优选白三烯受体拮抗剂为普仑司特水合物,孟鲁司特钠,扎鲁司特或MK-571,且更优选白三烯受体拮抗剂为普仑司特水合物,孟鲁司特钠,扎鲁司特。
抗组胺药的实例包括苯海拉明,盐酸二苯拉林,茶氯酸二苯拉林,富马酸氯马斯汀,茶苯海明,马来酸d1-氯苯那敏,马来酸d-氯苯那敏,盐酸曲普利啶,盐酸异丙嗪,酒石酸阿利马嗪,盐酸异西喷地,盐酸高氯环秦,羟嗪,盐酸赛庚啶,盐酸左卡巴斯汀,阿司咪唑,贝他斯汀,地氯雷他定,TAK-427,ZCR-2060,NIP-530,糠酸莫米松,咪唑斯汀,BP-294,安多司特,金诺芬,阿伐斯汀等。
磷酸二酯酶4抑制剂优选为磷酸二酯酶抑制剂。磷酸二酯酶4抑制剂的实例包括咯利普兰,西洛司特(商品名:Ariflo),Bay19-8004,NIK-616,罗氟司特(BY-217),西潘茶碱(BRL-61063),阿替唑兰(atizoram)(CP-80633),SCH-351591,YM-976,V-11294A,PD-168787,D-4396,IC-485等。
弹性蛋白酶抑制剂的实例包括西维来司他钠水合物(ONO-5046),ONO-6818,MR-889,PBI-1101,EPI-HNE-4,R-665,ZD-0892,ZD-8321,GW-311616,AE-3763,DMP-777,L-659286,L-658758,L-680833,L-683845等。
抗胆碱药的实例包括异丙托溴铵,氧托溴铵,氟托溴铵,西托溴铵,替米维林,噻托溴铵,瑞伐托酯(UK-112166)等。
在抗过敏药中,化学介体释放抑制剂的实例包括色甘酸钠,曲尼司特,氨来呫诺,瑞吡司特,异丁司特,吡嘧司特钾,他扎司特,奈多罗米,色甘酸盐,伊拉帕泛等。
在抗过敏药中,血栓烷合酶抑制剂的实例包括盐酸奥扎格雷,咪曲司特钠等。
在抗过敏药中,血栓烷受体拮抗剂的实例包括塞曲司特,雷马曲班,多米曲班钙水合物,KT-2-962等。
在抗过敏药中,Th2细胞因子抑制剂的实例包括甲磺司特等。
作为外用药的类固醇药包括丙酸氯倍他索,醋酸二氟拉松,醋酸氟轻松,糠酸莫米松,倍他米松二丙酸盐,丁酸丙酸倍他米松,倍他米松戊酸酯,二氟泼尼酯,布地奈德,戊酸二氟可龙,安西奈德,哈西奈德,地塞米松,丙酸地塞米松,戊酸地塞米松,醋酸地塞米松,醋酸氢化可的松,丁酸氢化可的松,丁酸丙酸氢化可的松,丙酸地泼罗酮,戊酸醋酸泼尼松龙,丙酮肤轻松,二丙酸倍氯米松,曲安奈德,新戊酸氟米松,二丙酸阿氯米松,丁酸氯倍他松,泼尼松龙,氟氢缩松等。
作为内服药和注射剂的类固醇药包括醋酸可的松,氢化可的松,氢化可的松磷酸钠,氢化可的松琥珀酸钠,醋酸氟氢可的松,泼尼松龙,醋酸泼尼松龙,泼尼松龙琥珀酸钠,泼尼松龙叔丁乙酯,泼尼松龙磷酸钠,醋酸卤泼尼松,甲泼尼龙,醋酸甲泼尼松,琥钠甲泼尼松龙,曲安西龙,醋酸曲安西龙,曲安奈德,地塞米松,醋酸地塞米松,地塞米松磷酸钠,棕榈酸地塞米松,醋酸帕拉米松,倍他米松等。吸入药物包括二丙酸倍氯米松,丙酸氟替卡松,布地奈德,氟尼缩松,曲安西龙,ST-126P,环索奈德,棕榈酸地塞米松,糠酸莫米松,磺酸普拉睾酮,地夫可特,磺庚甲泼尼龙,琥钠甲泼尼松龙等.
在支气管扩张药中,黄嘌呤衍生物的实例包括氨茶碱,茶碱,多索茶碱,西潘茶碱,二羟丙茶碱,丙羟茶碱,胆茶碱等。
在支气管扩张药中,拟交感神经药的实例包括肾上腺素,盐酸麻黄碱,d1-甲麻黄碱盐酸盐,盐酸甲氧那明,硫酸异丙肾上腺素,盐酸异丙肾上腺素,硫酸奥西那林,盐酸氯丙那林,盐酸曲托喹酚,硫酸沙丁胺醇,硫酸特布他林,硫酸海索那林,盐酸妥洛特罗,盐酸丙卡特罗,氢溴酸非诺特罗,富马酸福莫特罗,盐酸克仑特罗,盐酸马布特罗,昔萘酸沙美特罗,R,R-福莫特罗,妥洛特罗,盐酸吡布特罗,盐酸利托君,班布特罗,盐酸多培沙明,酒石酸美卢君,AR-C68397,左沙丁胺醇,KUR-1246,KUL-7211,AR-C89855,S-1319等。
在支气管扩张药中,副交感神经阻滞剂的实例包括异丙托溴铵,氟托溴铵,氧托溴铵,西托溴铵,替米维林,噻托溴铵,瑞伐托酯(UK-112166)等。
疫苗治疗剂的实例包括paspat,asthremedin,溴卡斯马间氨磺丁胺(broncasma berna),CS-560等。
金制剂的实例包括金硫丁二钠等。
基本的非类固醇抗炎药的实例包括盐酸噻拉米特,盐酸替诺立定,依匹唑,依莫法宗等。
5-脂氧合酶抑制剂的实例包括齐留通(Zyflo),多西苯醌,piripost,SCH-40120,WY-50295,E-6700,ML-3000,TMK-688,ZD-2138,甲磺酸达布非酮,R-68151,E-6080,DuP-654,SC-45662,CV-6504,NE-11740,CMI-977,NC-2000,E-3040,PD-136095,CMI-392,TZI-41078,Orf-20485,IDB-18024,BF-389,A-78773,TA-270,FLM-5011,CGS-23885,A-79175,ETH-615,AM-103,MK-0633等。
5-脂加氧酶激活蛋白拮抗剂的实例包括MK-591,MK-886,MK-0633,AM-103等。
白三烯合酶抑制剂的实例包括金诺芬,马来酸丙谷美新,L-674636,A-81834,UPA-780,A-93178,MK-886,REV-5901A,SCH-40120,MK-591,Bay-x-1005,Bay-y-1015,DTI-0026,氨来呫诺,E-6700等。
前列腺素的实例(下文简称为“PG”)包括PG受体激动剂,PG受体拮抗剂等。
PG受体的实例包括PGE受体(EP1,EP2,EP3,EP4),PGD受体(DP,CRTH2),PGF受体(FP),PGI受体(IP),TX受体(TP)等。
镇咳药的实例包括磷酸可待因,磷酸双氢可待因,羟蒂巴酚(oxymetebanol),氢溴酸右美沙芬,枸橼酸喷托维林,磷酸二甲啡烷,柠檬酸奥昔拉定,氯哌斯汀,磷酸苯丙哌林,盐酸氯苯达诺,盐酸福米诺苯,诺斯卡品,海苯酸替培定,盐酸依普拉酮,车前草提取物等。
祛痰剂的实例包括氨制茴香醑,碳酸氢钠,碘化钾,盐酸溴己新,樱桃树皮(bark)提取物,羧甲半胱氨酸,弗多司坦,盐酸氨溴索,盐酸氨溴索的控释制剂,盐酸美司坦,乙酰半胱氨酸,L-半胱乙酯盐酸盐,泰洛沙泊等。
上述其它药剂优选为白三烯受体拮抗剂,类固醇药或拟交感神经药。
目的在于实施本发明的剂型可以为药物制剂形式,所述药物制剂包含cysLT1/cysLT2受体拮抗剂化合物和用于补充和/或强化在一种剂型中配制的化合物的治疗作用的其他药物,或者所述药物制剂包包含各自加工成单独剂型的各组分。可以按照公知方法加工成这类剂型。
为了上述目的,一般通过全身或局部,口服或肠胃外给予包含本发明化合物的药物组合物或本发明化合物与其它药剂的组合药物。
剂量可以根据年龄,体重,症状,治疗效果,给药途径,治疗期限等的不同而改变。一般而言,对成年人而言,将1mg-1,000mg/剂量每天口服给药一次至几次(优选每天一次),或将0.1mg-100mg/剂量每天通过肠胃外(优选静脉内)给药一次至几次,或每天连续给药入静脉1-24小时。
当剂量根据如上所述的不同状况上下浮动时,低于上述具体剂量的剂量可以在某些情况中足够,而在某些情况中可能需要超过该剂量范围的剂量。
为了本发明的目的,以用于口服给药的固体制剂形式或用于口服给药的液体制剂形式,或用于肠胃外给药的可注射制剂,外用药,栓剂,滴眼液,吸入剂等形式给予所述化合物。
用于口服给药的固体剂型包括,例如片剂,丸剂,胶囊,粉剂和颗粒。胶囊包括硬胶囊和软胶囊。
在这类用于口服给药的固体制剂中,按照常用的方法直接配制一种或多种活性剂,或将其与赋形剂(乳糖,甘露糖醇,葡萄糖,微晶纤维素,淀粉等),粘合剂(羟丙基纤维素,聚乙烯吡咯烷酮,偏硅酸镁铝等),崩解剂(纤维素羟乙酸钙等),润滑剂(硬脂酸镁等),硬脂酸镁或增溶剂(谷氨酸,天冬氨酸等)等的一种或多种混合。如果必要,可以用包衣衣料(诸如糖,果胶,羟丙基纤维素或邻苯二甲酸羟丙基甲基纤维素)给制剂包衣,或可以使用两层或多层包衣。还包括由可吸收材料(诸如明胶)制成的胶囊。
用于口服给药的液体制剂包括药学上可接受的水溶液,混悬液,乳剂,糖浆剂,酏剂等。在这类液体制剂中,将活性剂中的一种或多种溶于,悬浮于常用稀释剂(例如,纯水,乙醇或其混合物)或在其中乳化。此外,这类液体制剂还可以包括湿润剂,悬浮剂,乳化剂,甜味剂,矫味剂,芳香剂,防腐剂或缓冲剂。
用于肠胃外给药的可注射制剂包括,例如溶液,混悬液,乳剂和在使用前溶于,悬浮于注射用溶剂或在其中乳化的用于注射的固体制剂。通过将一种或多种活性物质溶于,悬浮于溶剂或在其中乳化制备可注射制剂。溶剂的实例可以包括注射用蒸馏水,盐水,植物油,丙二醇,聚乙二醇或醇类(诸如乙醇)及其任意的组合。可注射制剂可以进一步包含稳定剂,增溶剂(谷氨酸,天冬氨酸,聚山梨醇酯80(注册商标)等),悬浮剂,乳化剂,安抚剂,缓冲剂或防腐剂等。通过在最终的过程中灭菌或通过无菌操作法制备它们。可选择地,可以在使用前通过首先生产无菌固体制剂(诸如冻干制剂)且将其溶于灭菌或无菌注射用蒸馏水或其它无菌溶剂使用它们。
用于肠胃外给药的滴眼液可以为滴眼液体,混悬液类型的滴眼液,乳剂类型的滴眼液或在实际应用时溶解的滴眼液或眼膏剂的形式。
通过公知方法制备这些滴眼液,例如,就液体滴眼液而言,可以通过适当选择和掺入张度剂(氯化钠,浓甘油等),缓冲剂(磷酸钠,乙酸钠等),表面活性剂(聚山梨醇酯80(商品名),聚氧乙烯40硬脂酸酯,聚氧乙烯-硬化蓖麻油等),稳定剂(柠檬酸钠,依地酸钠等)和杀菌剂(苯扎氯铵,对羟苯甲酸酯等)等制备它们,视需要而定。通过在最终的过程中灭菌或通过无菌操作法制备它们。
用于肠胃外给药的可吸入制剂可以为气溶胶,可吸入液体制剂或可吸入粉末的形式。可以在施用前将可吸入液体制剂溶于,悬浮于水或其它适宜的介质中或在其中乳化。
可以按照公知方法制备这些可吸入制剂。可以通过适当选择和掺入杀菌剂(苯扎氯铵,对羟苯甲酸酯等),着色剂,缓冲剂(磷酸钠,乙酸钠等),张度剂(氯化钠,浓甘油等),增稠剂(羧乙烯基聚合物等),吸收促进剂等制备可吸入液体制剂,视需要而定。
可以通过适当选择和掺入润滑剂(硬脂酸,其盐(例如硬脂酸镁)等),粘合剂(淀粉,糊精等),赋形剂(乳糖,纤维素等),着色剂,杀菌剂(苯扎氯铵,对羟苯甲酸酯等),吸收促进剂等制备可吸入粉末,视需要而定。
一般可以通过喷雾器(例如雾化器,喷洒器等)给予可吸入液体制剂并且可以通过使用用于粉末制剂的吸入器给予可吸入粉末。
用于肠胃外给药的其它制剂包括外用的液体制剂,软膏剂,搽剂喷雾剂,栓剂,用于阴道内给药的阴道栓剂等,其包含一种或多种活性物质并且可以通过常规方法加工。
喷雾剂除常用的稀释剂外还包括稳定剂,诸如亚硫酸氢钠,和张度传递缓冲剂,例如张度剂,诸如氯化钠,柠檬酸钠或柠檬酸。为了制备喷雾剂,其详细描述可以在例如美国专利号US 2,868,691和US 3,095,355中找到。
实施例
尽管通过下列实施例和生物学实施例更详细描述了本发明,但是本发明并不限于此。
如在色谱分离和TLC部分所示的加括号的溶剂表示使用的洗脱剂或展开溶剂,其比例基于体积。在NMR标题下所示的加括号的溶剂表示测定中使用的溶剂。
使用ACD/Name(6.00版,Advanced Chemistry DevelopmentInc.生产)命名下列实施例中的化合物。
在鉴定晶体的粉末X-射线衍射光谱中,衍射角(2θ)及其所有图案是重要的,且相对强度在一定程度上根据晶体生长,颗粒大小和测定条件的不同是可变的。此外,在鉴定晶体的差示扫描量热法(DSC)中,所有图案是重要的,而在一定程度上根据测定条件的不同可变。
实施例1
4-(7-溴-2-甲基-1H-吲哚-3-基)丁酸乙酯
向(2-溴苯基)肼盐酸盐(14g)在乙醇(60mL)中的溶液中加入5-乙酰基戊酸(9.0g)。将该反应混合物在50℃下搅拌40分钟,且向其中加入浓硫酸(6.0mL),随后在回流状态下加热16小时。向该反应混合物中加入饱和碳酸氢钠水溶液,然后用乙酸乙酯萃取并且用无水硫酸钠干燥,随后在减压下浓缩。通过柱色谱法纯化所得残余物(己烷∶乙酸乙酯=8∶1)而得到具有如下物理特性的标题化合物(15g)。
TLC:Rf 0.54(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ1.23,1.89-2.00,2.31,2.39,2.72,4.10,6.95,7.24,7.43,7.91
实施例2
4,4’-(7-溴-2-甲基-1H-吲哚-1,3-二基)二丁酸二乙酯
将实施例1中制备的化合物(18g)溶于二甲亚砜(110mL),并且向其中加入4-溴丁酸乙酯(76g)和碳酸铯(145g)。将该反应混合物在50℃下搅拌16小时。向该反应混合物中加入水,然后用乙酸乙酯萃取。用硫酸镁干燥有机层,且在减压下浓缩。通过中压制备型液相色谱仪W-prep 2XY(由Yamazen Corporation生产,柱:主柱4L,注射柱3L;己烷∶乙酸乙酯=9∶1→4∶1)纯化所得残余物而得到具有如下物理特性的标题化合物(24g)。
TLC:Rf 0.31(己烷∶丙酮=17∶3)
1H-NMR(CDCl3):δ1.24,1.26,1.83-1.98,1.98-2.12,2.30,2.36,2.39,2.73,4.09-4.20,4.47-4.52,6.88,7.26,7.42
实施例3
4,4’-(7-{[4-(乙酰氧基)苯基]乙炔基}-2-甲基-1H-吲哚-1,3-二基)二丁酸二乙酯
在氩气气氛中向实施例2中制备的化合物(5.5g)和乙酸4-乙炔基苯酯(3.8g)在乙腈(25mL)中的溶液中加入二异丙基胺(3.3mL)和双(三-叔丁膦)钯(320mg),随后在室温下搅拌15小时。将该反应混合物通过″Celite″(注册商标)过滤,且浓缩滤液。通过中压制备型液相色谱仪W-制备型2XY(由Yamazen Corporation生产,柱:主柱3L,注射柱2L;己烷∶乙酸乙酯=9∶1→7∶3)纯化所得残余物而得到具有如下物理特性的标题化合物(5.9g)。
TLC:Rf 0.26(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ1.21,1.24,1.86-1.98,2.10-2.22,2.25-2.37,2.75,4.04-4.14,4.59-4.65,7.03,7.11,7.32,7.50,7.55
实施例4
4,4’-{7-[(4-羟基苯基)乙炔基]-2-甲基-1H-吲哚-1,3-二基}二丁酸二乙酯
将碳酸钾(3.1g)加入到实施例3中制备的化合物(5.9g)在乙醇(11mL)和二甲氧基乙烷(11mL)中的溶液中,随后在室温下搅拌15小时。用水稀释该反应混合物且用乙酸乙酯萃取。依次用水和盐水洗涤有机层,用硫酸镁干燥,随后在减压下浓缩。通过中压制备型液相色谱仪W-制备型2XY(由Yamazen Corporation生产,柱:主柱2L,注射柱L;己烷∶乙酸乙酯=9∶1→6∶4)纯化所得残余物而得到具有如下物理特性的标题化合物(4.8g)。
TLC:Rf 0.29(己烷∶乙酸乙酯=2∶1)
1H-NMR(CDCl3):δ1.22,1.26,1.82-1.99,2.05-2.21,2.32,2.36,2.75,4.04-4.14,4.62,5.39,6.83,7.01,7.30,7.42.7.48
实施例5
4-(五氟苯基)丁-3-炔-1-醇
向1-溴-2,3,4,5,6-五氟苯(50g)在三乙胺(200mL)中的溶液中加入3-丁炔-1-醇(15g),三苯基膦(2.7g),二氯双三苯基膦钯(3.6g)和碘化亚铜(I)(1.9g),随后在80℃下搅拌16小时。将该反应混合物冷却至室温,且向其中加入叔丁基甲基醚(500mL),随后在0℃下搅拌30分钟。将该反应混合物通过″Celite″(注册商标)过滤,且浓缩滤液。通过急骤柱色谱法纯化所得残余物(己烷∶乙酸乙酯=95∶5→65∶35)而得到具有如下物理特性的标题化合物(43g)。
TLC:Rf 0.28(己烷∶乙酸乙酯=4∶1)
1H-NMR(CDCl3):δ1.81,2.78,3.86
实施例6
4-(五氟苯基)丁-1-醇
向实施例5中制备的化合物(43g)在乙醇(430mL)中的溶液中加入10%钯碳(50%含水量,4.3g)。用氩气替代反应体系内部的气体,随后在室温下和氢气气氛中搅拌6小时。向其中加入10%钯碳(50%含水量,4.3g),随后在室温下和氢气气氛中搅拌2小时。将该反应混合物通过″Celite″(注册商标)过滤,且浓缩滤液而得到具有如下物理特性的标题化合物(41g)。
TLC:Rf 0.31(己烷∶乙酸乙酯=4∶1)
1H-NMR(CDCl3):δ1.20-1.38,1.52-1.76,2.74,3.68
实施例7
4-甲基苯磺酸4-(五氟苯基)丁酯
将三乙胺(46mL)加入到实施例6中制备的化合物(40g)在甲苯(330mL)中的溶液中,随后在0℃下搅拌。向其中加入对-甲苯磺酰氯(41g)和三甲胺盐酸盐(1.6g),随后在0℃下搅拌2小时,且在室温下再搅拌20小时。将该反应混合物冷却至0℃,且向其中加入N,N-二甲基乙1,2-二胺(7.3g),随后搅拌15分钟。向该反应混合物中加入水,且通过添加2N盐酸使水层呈酸性,随后分离有机层。用甲苯萃取水层;依次用水和盐水洗涤合并的有机层;并且用无水硫酸镁干燥和过滤,随后在减压下蒸发溶剂。用己烷-乙酸乙酯(10∶1)洗涤固体成分而得到具有如下物理特性的标题化合物(52g)。
TLC:Rf 0.48(己烷∶乙酸乙酯=5∶1)
1H-NMR(CDCl3):δ1.55-1.77,2.45,2.66,4.05,7.35,7.78
实施例8
4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸二乙酯
将碳酸铯(220mg)加入到实施例4中制备的化合物(180mg)和实施例7中制备的化合物(150mg)在N,N-二甲基甲酰胺(1.0mL)中的溶液中,随后在室温下搅拌10小时。用水稀释该反应混合物,且用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。通过中压制备型液相色谱仪W-制备型2XY(由YamazenCorporation生产,柱:主柱M,注射柱S;己烷∶乙酸乙酯=9∶1→8∶2)纯化所得残余物而得到具有如下物理特性的标题化合物(160mg)。
TLC:Rf 0.52(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ1.19-1.26,1.71-2.00,2.05-2.10,2.25-2.40,2.68-2.85,3.99-4.18,4.62,6.87,7.01,7.31,7.42-7.52
实施例9
4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
将2N氢氧化钠水溶液(1.0mL)加入到实施例8中制备的化合物(150mg)在二甲氧基乙烷(2.0mL)和乙醇(2.0mL)中的溶液中,随后在室温下搅拌4小时。在冰冷却下将冰冷的2N盐酸(1.0mL)加入到该反应混合物中,随后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。用二异丙基醚-己烷(9∶1)洗涤所得残余物,且在减压下干燥而得到具有如下物理特性的标题化合物(120mg)。
TLC:Rf 0.40(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.63-1.82,1.87-2.02,2.14-2.24,2.33,2.67,2.76,4.03,4.54,6.94-7.03,7.22,7.44-7.54,12.08
实施例9(1)-(8)
通过与实施例8→实施例9中相同的操作,使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
实施例9(1)
4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.36(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.59-1.87,1.88-2.03,2.12-2.23,2.31,2.33,2.61-2.77,4.05,4.54,6.93-7.03,7.07-7.18,7.19-7.29,7.42-7.58,12.05
实施例9(2)
4,4’-[2-甲基-7-({4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.18(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.65-1.80,1.88-2.02,2.14-2.24,2.34,2.60-2.74,4.02,4.54,6.83-7.02,7.14-7.25,7.42-7.52,12.04
实施例9(3)
4,4’-[7-({4-[4-(2,3-二氟苯氧基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.37(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.66-1.81,1.83-2.02,2.13-2.24,2.34,2.62-2.74,4.05-4.12,4.13-4.20,4.49-4.60,6.91-7.06,7.07-7.18,7.22,7.44-7.56,12.08
实施例9(4)
4,4’-[7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.42(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.55-1.86,1.86-2.04,2.11-2.25,2.34,2.67,4.05,4.54,6.90-7.07,7.08-7.19,7.22,7.40-7.57,12.09
实施例9(5)
4,4’-[2-甲基-7-({4-[4-(2,3,4,5-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.35(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.64-1.81,1.87-2.04,2.13-2.24,2.33,2.62-2.76,4.03,4.49-4.60,6.92-7.03,7.22,7.33-7.54,12.08
实施例9(6)
4,4’-[2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.43(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.61-1.84,1.86-2.02,2.14-2.25,2.33,2.62-2.77,4.03,4.46-4.60,6.92-7.03,7.22,7.39-7.55,12.08
实施例9(7)
4,4’-[7-({4-[4-(4-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.33(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.52-1.85,1.87-2.05,2.12-2.24,2.26,2.33,2.60,2.67,4.04,4.54,6.83-7.05,7.09-7.28,7.39-7.56,12.09
实施例9(8)
4,4’-[7-({4-[4-(4-氟-3-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.35(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.59-1.84,1.87-2.05,2.17,2.18-2.24,2.33,2.67,4.05,4.54,6.92-7.05,7.08-7.18,7.22,7.44-7.56,12.09
实施例10
4-[7-溴-1-(2-乙氧基-2-氧代乙基)-2-甲基-1H-吲哚-3-基]丁酸乙酯
通过与实施例2中相同的操作,使用溴乙酸乙酯代替4-溴丁酸乙酯获得具有如下物理特性的标题化合物。
TLC:Rf 0.52(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ1.24,1.27,1.85-1.99,2.27,2.30,2.75,4.11,4.24,5.28,6.92,7.26,7.44
实施例11
4-[1-(羧甲基)-2-甲基-7-({4-[4-(2,3,4,5-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例10中制备的化合物代替实施例2中制备的化合物,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.25(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.66-1.81,2.16-2.24,2.25,2.62-2.76,3.99-4.08,5.38,6.94-7.03,7.19,7.32-7.45,7.45-7.53,12.02,12.96
实施例12
4-(7-溴-1-{[1-(2-乙氧基-2-氧代乙基)环丙基]甲基}-2-甲基-1H-吲哚-3-基)丁酸乙酯
向实施例1中制备的化合物(2.0g)在二甲亚砜(12mL)中的溶液中加入[1-(溴甲基)环丙基]乙腈(1.6g)和碳酸铯(3.0g),且将该反应混合物在室温下搅拌5小时。向其中加入碳酸铯(3.0g),随后搅拌过夜。此外,再加入碳酸铯(3.0g),随后搅拌9小时。向其中加入[1-(溴甲基)环丙基]乙腈(1.6g)和碳酸铯(2.0g),随后进一步搅拌过夜。向该反应混合物中加入水并且通过添加盐酸水溶液中和,随后用乙酸乙酯萃取。用水和盐水洗涤有机层并且用无水硫酸钠干燥,随后在减压下浓缩。通过硅胶柱色谱法纯化所得残余物(己烷∶乙酸乙酯=95∶5→75∶25))而得到N-烷基化合物(1.3g)。
向N-烷基化合物(1.7g)在乙醇(7.0mL)和乙二醇(3.5mL)中的溶液中加入12N氢氧化钠水溶液(3.4mL),随后在100℃下加热11小时,且在120℃下加热5小时。在冰冷却下,通过添加5N盐酸将该反应混合物调节至酸性pH,随后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩而得到二羧酸(1.3g)。
在氩气气氛中将碳酸钾(1.1g)和碘乙烷(2.2g)加入到二羧酸(1.3g)在二甲基甲酰胺(8.0mL)中的溶液中,随后在室温下搅拌17小时。用水稀释该反应混合物,且用乙酸乙酯萃取。依次用水和盐水洗涤有机层;用硫酸镁干燥,且过滤,随后在减压下浓缩。通过硅胶柱色谱法纯化所得残余物(己烷∶乙酸乙酯=95∶5→80∶20)而得到具有如下物理特性的标题化合物(1.5g)。
TLC:Rf 0.49(己烷∶乙酸乙酯=4∶1)
1H-NMR(CDCl3):δ0.16-0.29,0.30-0.47,1.18-1.34,1.79-1.96,2.28,2.35,2.42,2.71,4.04-4.21,4.89,6.85,7.21-7.28,7.39
实施例13
4-[1-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例12中制备的化合物代替实施例2中制备的化合物获得具有如下物理特性的标题化合物。
TLC:Rf 0.43(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.05-0.26,0.27-0.48,1.61-1.87,2.18,2.31,2.34,2.66,2.77,4.03,4.90,6.88-7.04,7.19,7.46,7.51,12.09
实施例13(1)-(6)
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例12中制备的化合物代替实施例2中制备的化合物,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
实施例13(1)
4-[1-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]丁酸
TLC:Rf 0.43(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.06-0.24,0.28-0.45,1.56-1.86,2.18,2.29-2.33,2.34,2.59-2.78,4.05,4.90,6.89-7.03,7.06-7.22,7.25,7.46,7.52,12.09
实施例13(2)
4-[1-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
TLC:Rf 0.40(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.12-0.19,0.34-0.42,1.66-1.79,2.18,2.31,2.34,2.60-2.70,3.99-4.05,4.90,6.91-7.02,7.15-7.25,7.46,7.49-7.54,12.08
实施例13(3)
4-[1-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]丁酸
TLC:Rf 0.43(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.06-0.25,0.28-0.47,1.57-1.88,2.12-2.23,2.31,2.34,2.59-2.78,4.05,4.90,6.88-7.05,7.08-7.17,7.19,7.46,7.52,12.09
实施例13(4)
4-[1-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(4-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]丁酸
TLC:Rf 0.44(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.06-0.24,0.28-0.45,1.56-1.85,2.18,2.26,2.31,2.34,2.56-2.71,4.05,4.90,6.86-7.06,7.12-7.24,7.47,7.52,12.11
实施例13(5)
4-[1-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
TLC:Rf 0.44(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.05-0.26,0.27-0.47,1.59-1.85,2.18,2.31,2.34,2.59-2.77,4.03,4.90,6.89-7.04,7.19,7.37-7.58,12.09
实施例13(6)
4-[1-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(2,3,6-三氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
TLC:Rf 0.44(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.04-0.25,0.28-0.47,1.60-1.86,2.18,2.31,2.34,2.66,2.73,4.03,4.90,6.89-7.03,7.04-7.15,7.19,7.28-7.42,7.46,7.51,12.09
实施例14
4,4’-[4-氟-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
通过与实施例1→实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用(2-溴-5-氟苯基)肼(按照下列操作制备:在冰冷却下,将2-溴-5-氟苯胺(20g)倾倒入5N盐酸(200mL),随后搅拌20分钟,且向其中缓慢加入亚硝酸钠(8.0g)在水(20mL)中的溶液,随后搅拌40分钟。在冰冷却下,将该反应混合物和5N氢氧化钠水溶液(150mL)加入到亚硫酸钠(33g)和磷酸二氢钠(1.7g)的水溶液(200mL)中,同时维持pH为6或6以上,随后在75℃下搅拌1小时。将该反应混合物冷却至室温并且过滤,且在减压下浓缩滤液。在60℃下将所得残余物倾入浓盐酸,随后搅拌2小时,且在室温下搅拌过夜。在冰冷却下用12N氢氧化钠水溶液中和该反应混合物。过滤沉淀的固体;用水洗涤;且溶于乙酸乙酯。用硫酸镁干燥有机层,且在减压下浓缩而得到肼化合物)代替(2-溴苯基)肼盐酸盐,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.43(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.64-1.84,1.88-2.02,2.14-2.23,2.33,2.68-2.82,4.02,4.49-4.59,6.76,6.97,7.19,7.47,12.08
实施例14(1)-(3)
通过与实施例1→实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
实施例14(1)
4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-4-氟-2-甲基-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.35(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.57-1.84,1.86-2.03,2.12-2.23,2.30,2.32,2.65-2.79,4.05,4.55,6.76,6.99,7.07-7.30,7.48,12.08
实施例14(2)
4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.58(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.59-1.85,1.87-2.05,2.10-2.26,2.32,2.59-2.82,4.05,4.48-4.63,6.76,6.91-7.06,7.08-7.16,7.20,7.48,12.08
实施例14(3)
4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
TLC:Rf 0.57(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.61-1.83,1.87-2.02,2.13-2.23,2.32,2.64-2.79,4.02,4.49-4.61,6.76,6.97,7.20,7.38-7.58,12.08
实施例15
4-[1-(羧甲基)-4-氟-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
通过与实施例1→实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐,并且使用溴乙酸乙酯代替4-溴丁酸乙酯获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.38(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.62-1.84,2.18,2.24,2.66-2.83,4.03,5.40,6.78,6.97,7.18,7.48,12.02,13.07
实施例15(1)
4-[1-(羧甲基)-7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-4-氟-2-甲基-1H-吲哚-3-基]丁酸
通过与实施例1→实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐;使用溴乙酸乙酯代替4-溴丁酸乙酯,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.30(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.57-1.85,2.19,2.24,2.31,2.65-2.80,4.04,5.40,6.78,6.98,7.08-7.22,7.26,7.48,12.05,13.10
实施例16
4-[1-{[1-(羧甲基)环丙基]甲基}-4-氟-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
通过与实施例1→实施例12→实施例3→实施例4→实施例8→实施例9中相同的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.38(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.10-0.21,0.35-0.44,1.64-1.84,2.11-2.21,2.29-2.32,2.33,2.65-2.83,4.03,4.91,6.74,6.98,7.18,7.51,12.09
实施例16(1)-(3)
通过与实施例1→实施例12→实施例3→实施例4→实施例8→实施例9中相同的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
实施例16(1)
4-[1-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-4-氟-2-甲基-1H-吲哚-3-基]丁酸
TLC:Rf 0.35(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.11-0.20,0.36-0.44,1.60-1.86,2.12-2.21,2.31,2.33,2.66-2.77,4.02-4.10,4.91,6.73,6.99,7.07-7.21,7.25,7.46-7.55,12.08
实施例16(2)
4-[1-{[1-(羧甲基)环丙基]甲基}-4-氟-2-甲基-7-({4-[4-(2,3,5,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
TLC:Rf 0.38(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.07-0.22,0.29-0.46,1.61-1.86,2.16,2.31,2.33,2.71,2.79,4.04,4.91,6.74,6.99,7.18,7.51,7.74,12.09
实施例16(3)
4-[1-{[1-(羧甲基)环丙基]甲基}-4-氟-2-甲基-7-({4-[4-(2,3,4,5-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]丁酸
TLC:Rf 0.30(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.12-0.19,0.35-0.45,1.64-1.82,2.16,2.31,2.33,2.63-2.78,4.03,4.91,6.74,6.95-7.03,7.18,7.33-7.45,7.47-7.58,12.09
实施例17
{1-[(7-溴-2-甲基-1H-吲哚-3-基)甲基]环丙基}乙腈
在氩气气氛中和冰冷却下,将溴化乙基镁(3.0M乙醚溶液,72mL)缓慢滴加到[1-(溴甲基)环丙基]乙腈(15g)和7-溴-2-甲基-1H-吲哚(45g)在甲苯(250mL)中的溶液中,随后在100℃下搅拌80分钟。将该反应混合物冷却至室温;用饱和氯化铵水溶液猝灭,用水稀释;且用乙酸乙酯萃取。依次用水和盐水洗涤有机层。用硫酸钠干燥有机层,且在减压下浓缩。通过纯化系统CombiFlash CompanionXL(由Isco,Co.,Ltd.生产,柱:RediSep 350g;己烷∶乙酸乙酯=95∶5→70∶30)纯化所得残余物而得到具有如下物理特性的标题化合物(14g)。TLC:Rf 0.64(己烷∶乙酸乙酯=2∶1)
1H-NMR(CDCl3):δ0.53-0.60,0.60-0.68,2.27,2.46,2.89,6.97,7.27,7.47,8.03
实施例18
{1-[(7-溴-2-甲基-1H-吲哚-3-基)甲基]环丙基}乙酸
将氢氧化钠(28g)在水(100mL)中的溶液加入到实施例17中制备的化合物(14g)在乙醇(100mL)和乙二醇(50mL)中的溶液中,随后在100℃下搅拌1.5天。在冰冷却下用5N盐酸中和该反应混合物,且用乙酸乙酯萃取。用盐水洗涤有机层,用硫酸镁干燥,且在减压下浓缩而得到具有如下物理特性的标题化合物(19g)。
TLC:Rf 0.68(己烷∶乙酸乙酯=1∶2)
1H-NMR(DMSO-D6):δ0.28-0.40,2.11,2.31,2.80,6.86,7.16,7.42,10.90,12.00
实施例19
{1-[(7-溴-2-甲基-1H-吲哚-3-基)甲基]环丙基}乙酸乙酯
向实施例18中制备的化合物(19g)在N,N-二甲基甲酰胺(100mL)中的溶液中加入碳酸钾(16g)和乙基碘(11g),随后在室温下搅拌3小时。用水稀释该反应混合物,且用乙酸乙酯萃取。依次用水和盐水洗涤有机层,用硫酸镁干燥,且然后在减压下浓缩。通过纯化系统CombiFlash CompanionXL(由Isco,Co.,Ltd.生产,柱:RediSep 80g;己烷∶乙酸乙酯=80∶20)纯化所得残余物而得到具有如下物理特性的标题化合物(16g)。
TLC:Rf 0.58(己烷∶乙酸乙酯=4∶1)
1H-NMR(CDCl3):δ0.38-0.50,1.25,2.23,2.40,2.95,4.11,6.93,7.22,7.46,7.98
实施例20
(7-溴-3-{[1-(2-乙氧基-2-氧代乙基)环丙基]甲基}-2-甲基-1H-吲哚-1-基)乙酸乙酯
向实施例19中制备的化合物(16g)在N,N-二甲基甲酰胺(100mL)中的溶液中加入碳酸铯(38g)和溴乙酸乙酯(12g),随后在室温下搅拌15小时。另外,进一步向其中加入碳酸铯(6.0g)和溴乙酸乙酯(1.5g),随后在室温下搅拌4.5小时并且在50℃下再搅拌2小时。用水稀释该反应混合物,且用乙酸乙酯萃取。依次用水和盐水洗涤有机层,用硫酸镁干燥,且在减压下浓缩。通过纯化系统CombiFlashCompanionXL(由Isco,Co.,Ltd.生产,柱:RediSep 120g;己烷∶乙酸乙酯=100∶0→80∶20)纯化所得残余物而得到具有如下物理特性的标题化合物(18g)。
TLC:Rf 0.42(己烷∶乙酸乙酯=4∶1)
1H-NMR(CDCl3):δ0.33-0.41,1.26,1.27,2.27,2.28,2.97,4.15,4.23,5.29,6.90,7.23,7.48
实施例21
[3-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1-基]乙酸
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例20中制备的化合物代替实施例2中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.46(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.31,1.55-1.89,2.16,2.25,2.76,2.88,4.03,5.39,6.83-7.06,7.19,7.41-7.60,12.13,12.86
实施例21(1)-(2)
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例20中制备的化合物代替实施例2中制备的化合物,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
实施例21(1)
(1-{[1-(羧甲基)-7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]甲基}环丙基)乙酸
TLC:Rf 0.43(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.31,1.58-1.72,1.72-1.85,2.17,2.25,2.31,2.70,2.89,4.05,5.39,6.92-7.06,7.07-7.29,7.41-7.56,12.19,12.81
实施例21(2)
[3-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1-基]乙酸
TLC:Rf 0.43(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.31,1.61-1.72,1.73-1.84,2.17,2.25,2.67,2.88,4.04,5.39,6.89-7.03,7.11,7.15-7.23,7.43-7.57,12.05,12.79
实施例22
4-(7-溴-1H-吲哚-3-基)-4-氧代丁酸乙酯
将7-溴-1H-吲哚(18g)溶于二氯甲烷(50mL),且在冰冷却下向其中加入氯化铝(III)(6.8g)和乙基琥珀酰基氯(8.4g)。将该反应混合物在室温下搅拌5小时。向该反应混合物中加入冰冷的水,然后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。用二异丙基醚洗涤所得残余物,且在减压下干燥而得到具有如下物理特性的标题化合物(6.0g)。
TLC:Rf 0.53(己烷∶乙酸乙酯=1∶1)
1H-NMR(CDCl3):δ1.27,2.79,3.23,4.16,7.17,7.44,7.97,8.32,8.72
实施例23
4-(7-溴-1H-吲哚-3-基)丁酸乙酯
在冰冷却下将硼氢化钠(760mg)和三氟化硼-乙醚复合物(5.8mL)加入到实施例22中制备的化合物(5.0g)在四氢呋喃(150mL)中的溶液中,随后在0℃下搅拌2小时。向该反应混合物中加入饱和氯化铵水溶液,随后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。通过中压制备型液相色谱仪W-制备型2XY(由Yamazen Corporation生产,柱:主柱2L,注射柱L;己烷∶乙酸乙酯=90∶10→85∶15)纯化所得残余物而得到具有如下物理特性的标题化合物(2.9g)。
TLC:Rf 0.53(己烷∶乙酸乙酯=2∶1)
1H-NMR(CDCl3):δ1.24,1.98-2.08,2.36,2.79,4.12,6.99,7.06,7.34,7.55,8.14
实施例24
4,4’-(7-溴-1H-吲哚-1,3-二基)二丁酸二乙酯
将实施例23中制备的化合物(4.4g)溶于二甲亚砜(14mL),且加入4-溴丁酸乙酯(5.5g)和碳酸铯(9.2g)。将该反应混合物在50℃下搅拌14小时。向该反应混合物中加入水,随后用己烷和乙酸乙酯的混合溶剂(1∶1)萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。通过中压制备型液相色谱仪W-制备型2XY(由Yamazen Corporation生产,柱:主柱L,注射柱L;己烷∶乙酸乙酯=95∶5→85∶15)纯化所得残余物而得到具有如下物理特性的标题化合物(5.9g)。
TLC:Rf 0.31(己烷∶丙酮=17∶3)
1H-NMR(CDCl3):δ1.22-1.27,1.91-2.05,2.08-2.12,2.27-2.38,2.74,4.08-4.16,4.52,6.85,6.91,7.33,7.51
实施例25
4,4’-[7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例24中制备的化合物代替实施例2中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.48(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.62-1.92,1.99-2.19,2.26,2.68,2.76,4.03,4.56-4.62,6.93-7.05,7.16,7.29,7.49,7.57,12.07
实施例26
4-溴-1-(苯基磺酰基)-1H-吲哚
在氮气气氛中,将4-溴-1H-吲哚(200g)在四氢呋喃(2.0L)中的溶液冰冷却至0℃,且向其中加入氢化钠(49g),随后在冰冷却下搅拌1小时。在冰冷却下向该反应混合物中滴加苯磺酰氯(200g),且除去冰浴,随后在室温下搅拌。向该反应混合物中加入饱和氯化铵水溶液,随后用乙酸乙酯萃取。用盐水洗涤有机层并且用硫酸镁干燥,随后过滤。用异丙基醚-己烷(1∶1,1.0L)洗涤所得残余物,且然后干燥而得到具有如下物理特性的标题化合物(310g)。
TLC:Rf 0.68(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ6.74,7.18,7.36-7.51,7.52-7.60,7.63,7.84-7.92,7.92-8.00
实施例27
4-溴-2-甲基-1-(苯基磺酰基)-1H-吲哚
在氮气气氛中将正-丁基锂(1.6M己烷溶液,420mL)加入到四氢呋喃(100mL)中,随后冷却至10℃。向其中滴加二异丙基胺(68g),且除去冰浴,随后在室温下搅拌30分钟。在干冰-甲醇浴中将该反应混合物冷却至-60℃。在约1小时内向其中滴加实施例26中制备的化合物(150g)在四氢呋喃(1.0L)中的溶液,且将温度温至0℃。将该反应混合物在干冰-甲醇浴中冷却至-60℃,然后在约20分钟内向其中滴加碘甲烷(95g),随后温至10℃。在通过TLC证实反应完成后,向其中滴加饱和氯化铵水溶液(500mL),随后进一步添加水(500mL)并且用乙酸乙酯(1.0L)萃取两次。用1N盐酸(1.0L)和盐水(500mL)洗涤有机层且用硫酸镁干燥,随后过滤。用甲醇(500mL)洗涤所得残余物并且干燥而得到具有如下物理特性的标题化合物(140g)。
TLC:Rf 0.48(己烷∶乙酸乙酯=6∶1)
1H-NMR(CDCl3):δ2.61,6.39-6.48,7.07-7.17,7.36,7.39-7.48,7.50-7.59,7.72-7.81,8.07-8.15
实施例28
4-溴-2-甲基-1H-吲哚
在氩气气氛中向实施例27中制备的化合物(12g)在乙醇(35mL)中的溶液中加入5N氢氧化钠水溶液(35mL)和二甲氧基乙烷(11mL),随后在回流状态下加热6小时。在减压下浓缩该反应混合物,且将所得残余物冷却至10℃。此后通过添加5N盐酸将该反应混合物调整至pH 5,随后用乙酸乙酯萃取两次。依次用饱和碳酸氢钠水溶液,水和盐水洗涤有机层,且用硫酸镁干燥。在过滤和在减压下浓缩后,通过硅胶柱色谱法纯化所得残余物(己烷∶乙酸乙酯=95∶5→85∶15)而得到具有如下物理特性的标题化合物(7.3g)。
TLC:Rf 0.37(己烷∶乙酸乙酯=6∶1)
1H-NMR(CDCl3):δ2.41-2.49,6.24-6.31,6.90-7.00,7.18-7.24,7.99
实施例29
1-(4-溴-2-甲基-1H-吲哚-3-基)-N,N-二甲基甲胺
在氩气气氛中将实施例28中制备的化合物(140g)和N,N-二甲基亚甲基铵氯化物(68g)加入到N,N-二甲基甲酰胺(1.4L)中,随后在室温下搅拌1小时。将该反应混合物加入到5N冰冷的氢氧化钠水溶液(800mL)中,且向其中加入水(2.0L),随后用乙酸乙酯萃取两次(2.0L)。用水(1.0L)将有机层洗涤两次并且用盐水(1.0L)洗涤且用硫酸镁干燥,随后在减压下浓缩。用己烷(500mL)洗涤所得残余物且然后干燥而得到具有如下物理特性的标题化合物(140g)。
TLC:Rf 0.23(丁醇∶乙酸∶水=3∶1∶1)
1H-NMR(CDCl3):δ2.30,2.31,3.71,6.87,7.10-7.26,7.20
实施例30
(4-溴-2-甲基-1H-吲哚-3-基)乙腈
在氮气气氛中将硫酸二甲酯(71g)加入到四氢呋喃(1.0L)中,随后冷却至5℃或5℃以下。在1小时内滴加实施例29中制备的化合物(140g)在四氢呋喃(500mL)中的溶液,随后在10℃下搅拌1小时。在减压下蒸发反应溶剂。通过添加水(1.5L)和N,N-二甲基甲酰胺(600mL)将所得残余物溶解,随后添加氰化钾(50g)且在80℃下搅拌2小时。将该反应混合物冷却至20℃,且用乙酸乙酯(1.0L)萃取三次。用水(1.0L)将有机层洗涤三次并且用盐水(1.0L)洗涤,且用硫酸镁干燥。在过滤并且在减压下浓缩后,用异丙基醚(200mL)洗涤所得残余物,且且然后干燥而得到具有如下物理特性的标题化合物(100g)。
TLC:Rf 0.20(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ2.45,4.11,6.94-7.02,7.22-7.24,7.25-7.29,8.10
实施例31
(4-溴-2-甲基-1H-吲哚-3-基)乙酸
向实施例30中制备的化合物(20g)在乙醇(130mL),二甲氧基乙烷(70mL)和乙二醇(70mL)中的溶液中加入12N氢氧化钠水溶液(67mL),随后在回流状态下加热32小时。在冰冷却下向该反应混合物中加入5N盐酸(160mL),随后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。在过滤并且在减压下浓缩后,用己烷洗涤所得残余物,且在减压下干燥而得到具有如下物理特性的标题化合物(22g)。
TLC:Rf 0.46(己烷∶乙酸乙酯=1∶4)
1H-NMR(DMSO-D6):δ2.27,3.80,6.87,7.70,7.25,11.19,12.06
实施例32
(4-溴-2-甲基-1H-吲哚-3-基)乙酸乙酯
向实施例31中制备的化合物(22g)在N,N-二甲基甲酰胺(80mL)中的溶液中加入碳酸钾(22g)和碘乙烷(19g),随后在室温下搅拌15小时。在冰冷却下,向反应混合物中加入水,随后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。在过滤并且在减压下浓缩后,用己烷洗涤所得残余物,且在减压下干燥而得到具有如下物理特性的标题化合物(22g)。
TLC:Rf 0.43(己烷∶乙酸乙酯=2∶1)
1H-NMR(CDCl3):δ1.28,2.26,3.48,3.96,4.20,6.89,7.13,7.19,8.10
实施例33
(4-溴-1-{[1-(氰基甲基)环丙基]甲基}-2-甲基-1H-吲哚-3-基)乙酸乙酯
将实施例32中制备的化合物(10g)溶于二甲亚砜(40mL)。向其中加入[1-(溴甲基)环丙基]乙腈(13g)和碳酸铯(99g),且将该反应混合物在40℃下搅拌25小时。将水加入到反应混合物中,随后用乙酸乙酯萃取。用硫酸镁干燥有机层,且在减压下浓缩。用二异丙基醚和己烷洗涤所得残余物,且在减压下干燥而得到具有如下物理特性的标题化合物(11g)。
TLC:Rf 0.32(己烷∶乙酸乙酯=2∶1)
1H-NMR(CDCl3):δ0.58-0.70,1.26,2.29,2.38,4.02,4.17,4.25,6.97,7.22,7.27
实施例34
(4-溴-1-{[1-(羧甲基)环丙基]甲基}-2-甲基-1H-吲哚-3-基)乙酸
向实施例33中制备的化合物(12g)在乙醇(80mL),二甲氧基乙烷(40mL)和乙二醇中的溶液中加入12N氢氧化钠水溶液(38mL)随后在回流下加热29小时。在冰冷却下向该反应混合物中加入5N盐酸(95mL),随后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,且在减压下浓缩。在过滤并且在减压下浓缩后,用己烷洗涤所得残余物,且在减压下干燥而得到具有如下物理特性的标题化合物(11g)。
TLC:Rf 0.38(二氯甲烷∶甲醇=9∶1)
1H-NMR(CDCl3):δ0.43-0.60,2.25,2.34,4.10,4.25,6.95,7.20,7.29
实施例35
(4-溴-1-{[1-(2-乙氧基-2-氧代乙基)环丙基]甲基}-2-甲基-1H-吲哚-3-基)乙酸乙酯
向实施例34中制备的化合物(11g)在N,N-二甲基甲酰胺(30mL)中的溶液中加入碳酸钾(14g)和碘乙烷(14g),随后在室温下搅拌8小时。在冰冷却下向该反应混合物中加入水,随后用乙酸乙酯萃取。依次用水和盐水洗涤有机层并且用硫酸镁干燥,随后在减压下浓缩。在过滤并且在减压下浓缩后,用二异丙基醚和己烷洗涤所得残余物,且在减压下干燥而得到具有如下物理特性的标题化合物(12g)。
TLC:Rf 0.42(己烷∶乙酸乙酯=2∶1)
1H-NMR(CDCl3):δ0.40-0.48,1.24,1.25,2.28,2.35,4.01,4.09-4.19,4.32,6.92,7.18,7.28
实施例36
[1-{[1-(羧甲基)环丙基]甲基}-2-甲基-4-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]乙酸
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例35中制备的化合物代替实施例2中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.50(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.23-0.44,1.60-1.85,2.23,2.32,2.76,3.93-4.07,4.34,6.90-6.99,6.99-7.07,7.08-7.15,7.41,7.45-7.53,12.13
实施例36(1)-(3)
通过与实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例35中制备的化合物代替实施例2中制备的化合物,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
实施例36(1)
[1-{[1-(羧甲基)环丙基]甲基}-4-({4-[4-(4,5-二氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]乙酸
TLC:Rf 0.24(氯仿∶甲醇∶水=10∶1∶0.1)
1H-NMR(DMSO-D6):δ0.24-0.47,1.56-1.86,2.23,2.33,2.55-2.65,3.96-4.10,4.34,6.93-6.99,7.00-7.07,7.07-7.14,7.17-7.23,7.41,7.45-7.54,12.12
实施例36(2)
[1-{[1-(羧甲基)环丙基]甲基}-2-甲基-4-({4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]乙酸
TLC:Rf 0.36(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.25-0.34,0.37-0.43,1.64-1.78,2.23,2.33,2.60-2.68,3.94-4.11,4.35,6.92-6.99,7.04,7.12,7.16-7.27,7.42,7.47-7.55,12.14
实施例36(3)
(1-{[3-(羧甲基)-4-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1-基]甲基}环丙基)乙酸
TLC:Rf 0.46(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.26-0.36,0.36-0.46,1.56-1.89,2.23,2.31,2.32,2.65-2.75,3.95-4.10,4.34,6.96,7.03,7.08-7.18,7.21-7.29,7.41,7.50,12.13
实施例37
4-[3-(羧甲基)-4-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-7-氟-2-甲基-1H-吲哚-1-基]丁酸
通过与实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例32中制备的化合物代替实施例1中制备的化合物,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.24(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.57-1.94,2.24,2.31,2.33,2.66-2.74,3.96-4.08,4.23,6.87,6.93-7.01,7.05-7.18,7.21-7.29,7.43-7.56,12.14
实施例37(1)
4-[3-(羧甲基)-2-甲基-4-({4-[4-(2,3,4,5-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1-基]丁酸
通过与实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例32中制备的化合物代替实施例1中制备的化合物,并且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.28(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.67-1.78,1.78-1.90,2.24-2.31,2.33,2.65-2.76,3.96-4.06,4.10-4.19,6.92-6.99,7.01-7.09,7.10-7.16,7.31-7.43,7.43-7.47,7.48-7.54,12.13
实施例38
[1-{[1-(羧甲基)环丙基]甲基}-4-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-3-基]乙酸
通过与实施例29→实施例30→实施例31→实施例32→实施例33→实施例34→实施例35→实施例3→实施例4→实施例8→实施例9中相同的操作,使用4-溴-1H-吲哚代替实施例28中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.45(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.46-0.54,0.63-0.74,1.60-1.86,2.03,2.76,3.95-4.09,4.18,6.96,7.07-7.22,7.34,7.41-7.48,7.50,12.17
实施例39
4-[3-(羧甲基)-4-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1-基]丁酸
通过与实施例29→实施例30→实施例31→实施例32→实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用4-溴-1H-吲哚代替实施例28中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.39(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.62-1.82,1.88-2.04,2.19,2.76,3.98,4.02,4.16,6.90-6.99,7.07-7.19,7.31,7.41-7.56,12.13
实施例40
4-溴-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶
在冰冷却下向4-溴-1H-吡咯并[2,3-b]吡啶(6.9g,按照Organic Letters,2003,vol.5,5023-5025中所述的方法制备)和氯化苄基三乙基铵(210mg)在二氯甲烷(150mL)中的溶液中加入氢氧化钠(4.3g)和苯磺酰氯(5.5mL)。将该反应混合物在室温下搅拌1小时并且通过″Celite″(注册商标)过滤,且浓缩滤液。通过纯化系统CombiFlash CompanionXL(由Isco,Co.,Ltd.生产,柱:RediSep120g;己烷∶乙酸乙酯=95∶5→60∶40)纯化所得残余物而得到具有如下物理特性的标题化合物(9.8g).
TLC:Rf 0.58(己烷∶乙酸乙酯=2∶1)
1H-NMR(DMSO-D6):δ6.78,7.56-7.67,7.68-7.76,8.05,8.08-8.17,8.21-8.27
实施例41
4-溴-2-甲基-1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶
在氩气气氛中将二异丙基乙胺(7.8mL)在四氢呋喃(60mL)中的溶液冷却至-78℃,且向其中加入正-丁基锂(1.63M的己烷溶液,34mL),随后搅拌30分钟。在-25℃下向该反应混合物中加入实施例40中制备的化合物(9.3g)在四氢呋喃(60mL)中的溶液,随后搅拌30分钟。向其中加入碘甲烷(1.9mL)在四氢呋喃(10mL)中的溶液,随后搅拌2小时。向该反应混合物中加入饱和氯化铵水溶液(100mL),随后猝灭,用水(200mL)稀释,且用乙酸乙酯萃取。用硫酸镁干燥有机层,且在减压下浓缩。通过纯化系统CombiFlash CompanionXL(由Isco,Co.,Ltd.生产,柱:RediSep 120g;己烷∶乙酸乙酯=100∶0→80∶20→70∶30)纯化所得残余物而得到具有如下物理特性的标题化合物(3.0g)。
TLC:Rf 0.38(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ2.75,6.36,7.31,7.44-7.52,7.54-7.62,8.10-8.20
实施例42
4-溴-2-甲基-1H-吡咯并[2,3-b]吡啶
在冰冷却下将氟化四丁基铵(1.0M四氢呋喃溶液,17mL)加入到实施例41中制备的化合物(3.0g)在四氢呋喃(8.0mL)中的溶液中,随后在室温下搅拌4小时。在减压下浓缩该反应混合物。向所得残余物中加入饱和氯化铵水溶液,随后用乙酸乙酯萃取。用硫酸镁干燥有机层,且在减压下浓缩。通过纯化系统CombiFlash CompanionXL(由Isco,Co.生产,Ltd.,柱:RediSep 40g;己烷∶乙酸乙酯=90∶10→80∶20→70∶30)纯化所得残余物而得到具有如下物理特性的标题化合物(590mg)。
TLC:Rf 0.14(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ2.54,6.24,7.23,8.00,10.98
实施例43
1-(4-溴-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基)-N,N-二甲基甲胺
将N,N-二甲基亚甲基铵氯化物(410mg)加入到实施例42中制备的化合物(590mg)在正-丁醇(10mL)中的溶液中,随后在135℃下搅拌1小时,且冷却至室温。向该反应混合物中加入叔丁基甲基醚和1N盐酸,随后分离有机层。此后用叔丁基甲基醚萃取水层。在冰冷却下用5N氢氧化钠水溶液中和水层,且用二氯甲烷萃取水层。用硫酸镁干燥有机层和在减压下浓缩而得到具有如下物理特性的标题化合物(510mg)。
TLC:Rf 0.09(二氯甲烷∶甲醇=9∶1)
1H-NMR(CDCl3):δ2.32,2.51,3.69,7.23,7.96,10.69
实施例44
(4-溴-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基)乙腈
在冰冷却下将硫酸二甲酯(0.41mL)加入到实施例43中制备的化合物(510mg)在四氢呋喃(7.5mL)中的溶液中,随后在室温下搅拌1小时。通过倾析弃去上清液,且用四氢呋喃洗涤固体,随后在减压下干燥。向其中加入水(7.5mL)和氰化钾(200mg),随后在75℃下搅拌4小时。过滤该反应混合物并且用水洗涤,在减压下干燥而得到具有如下物理特性的标题化合物(270mg)。
TLC:Rf 0.18(己烷∶乙酸乙酯=1∶1)
1H-NMR(DMSO-D6):δ2.40,4.09,7.28,7.97,12.03
实施例45
(4-溴-2-甲基-1H-吡咯并[2,3-b]吡啶-3-基)乙酸乙酯
在冰冷却下将氯三甲基硅烷(1.4mL)加入到实施例44中制备的化合物(510mg)在乙醇(5.0mL)中的溶液中,随后在80℃下搅拌4小时。向其中加入硫酸(0.10mL),随后搅拌2.5小时。向该反应混合物中加入二甲氧基乙烷(4.0mL),随后在80℃下搅拌15小时,且向其中加入硫酸(0.10mL),随后搅拌20小时。用饱和碳酸氢钠水溶液稀释该反应混合物,且用乙酸乙酯萃取。用硫酸镁干燥有机层,且在减压下浓缩而得到具有如下物理特性的标题化合物(280mg)。
TLC:Rf 0.44(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.17,2.31,3.85,4.07,7.20,7.91,11.80
实施例46
4-[3-(羧甲基)-2-甲基-4-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吡咯并[2,3-b]吡啶-1-基]丁酸
通过与实施例2→实施例3→实施例4→实施例8→实施例9中相同的操作,使用实施例45中制备的化合物代替实施例1中制备的化合物,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.25(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.62-1.81,1.82-1.96,2.23,2.40,2.76,3.96,4.04,4.25,6.94-7.04,7.09,7.52-7.61,8.11,12.17
实施例47
4-[7-{(E)-2-[4-(乙酰氧基)苯基]乙烯基}-1-(2-乙氧基-2-氧代乙基)-2-甲基-1H-吲哚-3-基]丁酸乙酯
向实施例10中制备的化合物(250g)在1,4-二噁烷(2.5L)中的溶液中加入苯乙酸4-乙烯酯(110g),二环己基甲基胺(150g),三(二亚苄基丙酮)二钯(57g)和三叔丁膦(25g),随后在100℃下搅拌2小时。将该反应混合物通过″Celite″(注册商标)过滤,且在减压下浓缩滤液。通过硅胶柱色谱法纯化所得残余物(己烷∶乙酸乙酯=5∶1→6∶4),且用己烷固化而得到具有如下物理特性的标题化合物(210g)。
TLC:Rf 0.44(己烷∶乙酸乙酯=2∶1)
1H-NMR(CDCl3):δ1.22,1.24,1.94,2.372.28,2.30,2.32,2.76,4.10,4.20,4.96,6.85,7.12-7.04,7.16,7.58-7.44
实施例48
4-{1-(羧甲基)-2-甲基-7-[(E)-2-{4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙烯基]-1H-吲哚-3-基}丁酸
通过与实施例4→实施例8→实施例9中相同的操作,使用实施例47中制备的化合物代替实施例3中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.49(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.60-1.84,2.21,2.25,2.61-2.77,3.99,4.99,6.82-6.94,6.98,7.14,7.38,7.41-7.58
实施例48(1)
4-{1-(羧甲基)-7-[(E)-2-{4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙烯基]-2-甲基-1H-吲哚-3-基}丁酸
通过与实施例4→实施例8→实施例9中相同的操作,使用实施例47中制备的化合物代替实施例3中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.44(二氯甲烷∶甲醇∶乙酸=90∶10∶1)
1H-NMR(DMSO-D6):δ1.52-1.86,2.21,2.25,2.31,2.61-2.79,4.02,5.01,6.81-7.05,7.07-7.19,7.22-7.31,7.34-7.43,7.43-7.59
实施例49
4-{3-(羧甲基)-2-甲基-4-[(E)-2-{4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙烯基]-1H-吲哚-1-基}丁酸
通过与实施例2→实施例47→实施例4→实施例8→实施例9中相同的操作,使用实施例32中制备的化合物代替实施例1中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.36(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.66-1.76,1.78-1.90,2.28,2.36,2.64,3.77,3.92-4.05,4.12,6.77-7.41,7.52,7.72,12.25
实施例50
(1-{[1-(羧甲基)环丙基]甲基}-4-[(E)-2-{4-[4-(五氟苯基)丁氧基]苯基}乙烯基]-1H-吲哚-3-基)乙酸
通过与实施例29→实施例30→实施例31→实施例32→实施例33→实施例34→实施例35→实施例47→实施例4→实施例8→实施例9中相同的操作,使用4-溴-1H-吲哚代替实施例28中制备的化合物,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.33(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ0.45-0.52,0.62-0.69,1.63-1.82,2.05,2.76,3.85,4.01,4.15,6.92,7.00-7.16,7.24-7.37,7.52,7.62,12.26
实施例50(1)
(1-{[1-(羧甲基)环丙基]甲基}-4-[(E)-2-{4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙烯基]-1H-吲哚-3-基)乙酸
通过与实施例29→实施例30→实施例31→实施例32→实施例33→实施例34→实施例35→实施例47→实施例4→实施例8→实施例9中相同的操作,使用4-溴-1H-吲哚代替实施例28中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.51(氯仿∶甲醇∶水=40∶8∶1)
1H-NMR(DMSO-D6):δ0.41-0.73,1.62-1.80,2.05,2.65,3.84,3.93-4.06,4.15,6.87-6.96,6.99-7.37,7.51,7.62,12.25
实施例51
4-[7-溴-1-(2-乙氧基-2-氧代乙基)-1H-吲哚-3-基]丁酸乙酯
通过与实施例2中相同的操作,使用实施例23中制备的化合物代替实施例1中制备的化合物,且使用溴乙酸乙酯代替4-溴丁酸乙酯,获得具有如下物理特性的标题化合物。
TLC:Rf 0.32(己烷∶乙酸乙酯=4∶1)
1H-NMR(CDCl3):δ1.22-1.28,1.95-2.07,2.36,2.75,4.12,4.23,5.21,6.79,6.93,7.32,7.51
实施例52
4-{1-(羧甲基)-7-[(E)-2-{4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙烯基]-1H-吲哚-3-基}丁酸
通过与实施例47→实施例4→实施例8→实施例9中相同的操作,使用实施例51中制备的化合物代替实施例10中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物,获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.60(二氯甲烷∶甲醇∶乙酸=90∶10∶1)
1H-NMR(DMSO-D6):δ1.61-1.77,1.78-1.92,2.28,2.58-2.71,3.92-4.10,5.12,6.86-6.96,7.02,7.08,7.15-7.30,7.37-7.61,11.67-13.79
实施例53
(3-{[1-(羧甲基)环丙基]甲基}-7-[(E)-2-{4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙烯基]-2-甲基-1H-吲哚-1-基)乙酸
通过与实施例47→实施例4→实施例8→实施例9中相同的操作,使用实施例20中制备的化合物代替实施例10中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的本发明的化合物。
TLC:Rf 0.60(氯仿∶甲醇∶乙酸=85∶15∶1)
1H-NMR(DMSO-D6):δ0.23-0.39,1.58-1.87,2.17,2.18,2.24,2.62-2.72,2.88,4.02,5.01,6.87,6.91-7.06,7.08-7.19,7.39,7.44-7.56,12.05,12.93-13.35
实施例54
4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
在50℃下将实施例9中制备的化合物(50mg)溶于甲基叔丁基醚(1.5mL)。在室温下向该溶液中加入正-庚烷(0.75mL),然后使其稳定30分钟。过滤沉淀的固体并且在减压下干燥而得到标题化合物(39mg)。
在下列条件下测定的晶体的粉末X-射线衍射光谱和差示扫描量热法(DSC)数据分别如图1和图2中所示。
[1]粉末X-射线衍射光谱
仪器:BRUKER axs,D8 DISCOVER与GADDS
靶:Cu
电压:40kV
电流:40mA
晶体的特征可以在于使用Cu-Kα辐射获得的粉末X-射线衍射光谱,下表1中显示了衍射角(2θ)和相对强度。
表1
衍射角(2θ) | 相对强度 |
8.45 | 25 |
9.23 | 98 |
9.95 | 19 |
11.88 | 44 |
13.14 | 20 |
13.82 | 26 |
14.63 | 44 |
15.00 | 23 |
15.52 | 100 |
16.11 | 15 |
16.78 | 38 |
17.88 | 18 |
18.54 | 23 |
19.60 | 49 |
19.94 | 24 |
20.71 | 23 |
21.11 | 63 |
衍射角(2θ) | 相对强度 |
21.74 | 88 |
22.76 | 21 |
23.26 | 22 |
23.68 | 48 |
24.28 | 49 |
24.73 | 45 |
[2]差示扫描量热法(DSC)
仪器:METTLER TOLEDO,DSC822e
样品量:1.37mg
样品池:铝盘(40μL)
N2气流速:40mL/min
编程速率:5℃/min(扫描范围:25-300℃)
实施例54(1)
4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸二甲酯
通过与实施例2→实施例3→实施例4→实施例8中相同的操作,使用4-(7-溴-2-甲基-1H-吲哚-3-基)丁酸甲酯(如实施例1中的操作,使用甲醇代替乙醇制备)代替实施例1中制备的化合物,且使用4-溴丁酸甲酯代替4-溴丁酸乙酯获得具有如下物理特性的标题化合物。
TLC:Rf 0.40(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ1.72-2.00,2.06-2.20,2.26-2.40,2.68-2.84,3.61,3.64,4.01,4.63,6.88,7.01,7.30,7.40-7.50
还可以通过与实施例9中相同的操作,使用实施例54(1)中制备的化合物代替实施例8中制备的化合物制备实施例9的本发明化合物。
实施例55
4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸
在60℃下将实施例14(2)中制备的化合物(30mg)溶于甲基叔丁基醚(2.4mL)。将该溶液冷却至室温以便引发结晶。过滤沉淀的固体并且在减压下干燥而得到标题化合物(24mg)。
在下列条件下测定的晶体的粉末X-射线衍射光谱和差示扫描量热(DSC)数据分别如图3和图4中所示。
[1]粉末X-射线衍射光谱
仪器:BRUKER axs,D8 二SCOVER与GADDS
靶:Cu
电压:40kV
电流:40mA
晶体的特征可以在于使用Cu-Kα辐射获得的粉末X-射线衍射光谱,下表2中显示了衍射角(2θ)和相对强度。
表2
衍射角(2θ) | 相对强度 |
5.81 | 47 |
6.49 | 41 |
8.23 | 16 |
9.33 | 23 |
11.42 | 22 |
13.36 | 29 |
13.77 | 27 |
16.38 | 100 |
17.13 | 71 |
衍射角(2θ) | 相对强度 |
18.81 | 19 |
20.61 | 18 |
23.69 | 46 |
24.43 | 26 |
[2]差示扫描量热法(DSC)
仪器:METTLER TOLEDO,DSC822e
样品量:3.30mg
样品池:铝盘(40μL)
N2气流速:40mL/min
编程速率:5℃/min(扫描范围:25-300℃)
实施例55(1)
4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸二甲酯
通过与实施例2→实施例3→实施例4→实施例8中相同的操作,使用4-(7-溴-4-氟-2-甲基-1H-吲哚-3-基)丁酸甲酯(如实施例1中的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐,且使用甲醇代替乙醇制备)代替实施例1中制备的化合物,使用4-溴丁酸甲酯代替4-溴丁酸乙酯;且使用4-甲基苯磺酸4-(3-氟-2-甲基苯基)丁酯代替实施例7中制备的化合物获得具有如下物理特性的标题化合物。
TLC:Rf 0.36(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ1.70-2.00,2.10-2.20,2.23,2.30-2.40,2.70,2.82,3.62,3.63,4.02,4.62,6.67,6.85-6.92,6.94,7.05-7.10,7.21,7.44
还可以通过与实施例9中相同的操作,使用实施例55(1)中制备的化合物代替实施例8中制备的化合物制备实施例14(2)的本发明化合物。
实施例56
4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸
在70℃下将实施例14(3)中制备的化合物(50mg)溶于乙酸乙酯(1.4mL)。在室温下向该溶液中加入正庚烷(0.68mL),然后冷却至0℃。过滤沉淀的固体并且在减压下干燥而得到标题化合物(39mg)。
在下列条件下测定的晶体的粉末X-射线衍射光谱和差示扫描量热(DSC)数据分别如图5和图6中所示。
[1]粉末X-射线衍射光谱
仪器:BRUKER axs,D8二SCOVER与GADDS
靶:Cu
电压:40kV
电流:40mA
晶体的特征可以在于使用Cu-Kα辐射获得的粉末X-射线衍射光谱,下表3中显示了衍射角(2θ)和相对强度。
表3
衍射角(2θ) | 相对强度 |
6.85 | 16 |
7.61 | 16 |
10.03 | 26 |
10.54 | 18 |
12.40 | 23 |
13.17 | 19 |
13.57 | 78 |
14.35 | 60 |
15.33 | 25 |
16.64 | 24 |
18.24 | 21 |
18.53 | 91 |
19.03 | 69 |
19.49 | 96 |
衍射角(2θ) | 相对强度 |
20.15 | 17 |
20.48 | 18 |
20.88 | 44 |
23.04 | 20 |
23.35 | 49 |
23.97 | 39 |
24.32 | 100 |
24.83 | 47 |
[2]差示扫描量热法(DSC)
仪器:METTLER TOLEDO,DSC822e
样品量:4.70mg
样品池:铝盘(40μL)
N2气流速:40mL/min
编程速率:5℃/min(扫描范围:25-300℃)
实施例56(1)
4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸二甲酯
通过与实施例2→实施例3→实施例4→实施例8中相同的操作,使用4-(7-溴-4-氟-2-甲基-1H-吲哚-3-基)丁酸甲酯代替实施例1中制备的化合物,使用4-溴丁酸甲酯代替4-溴丁酸乙酯;且使用4-甲基苯磺酸4-(2,3,4,6-四氟苯基)丁酯代替实施例7中制备的化合物获得具有如下物理特性的标题化合物。
TLC:Rf 0.39(己烷∶乙酸乙酯=3∶1)
1H-NMR(CDCl3):δ1.70-2.00,2.06-2.20,2.26-2.38,2.74,2.81,3.62,3.63,4.00,4.62,6.66,6.69-6.80,6.87,7.20,7.43
还可以通过与实施例9中相同的操作,使用实施例56(1)中制备的化合物代替实施例8中制备的化合物制备实施例14(3)的本发明化合物。
实施例57
4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸二钠
将0.1mo/L氢氧化钠水溶液(0.33mL)加入到实施例9中制备的化合物(10mg)在四氢呋喃(0.10mL)中的溶液中,在减压下浓缩该混合物而得到具有如下物理特性的标题化合物。
1H-NMR(甲醇-D4):δ1.71-1.93,2.00-2.15,2.16-2.26,2.41,2.73,2.78-2.86,4.03,4.56-4.66,6.88-6.96,7.18,7.44-7.52
实施例58
4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸二钠
通过与实施例57中相同的操作,使用实施例14(2)中制备的化合物代替实施例9中制备的化合物获得具有如下物理特性的标题化合物。
1H-NMR(甲醇-D4):δ1.68-1.95,2.00-2.13,2.15-2.25,2.40,2.68-2.76,2.80,4.03,4.56-4.67,6.60,6.80-6.88,6.89-6.99,7.04-7.17,7.47
实施例59
4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸二钠
通过与实施例57中相同的操作,使用实施例14(3)中制备的化合物代替实施例9中制备的化合物获得具有如下物理特性的标题化合物。
1H-NMR(甲醇-D4):δ1.70-1.95,1.98-2.13,2.15-2.25,2.40,2.70-2.85,4.02,4.57-4.68,6.60,6.91,6.96-7.08,7.12,7.46
实施例60
双(2,6-二铵基己酸酯)4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸酯
将0.1mo/L赖氨酸溶液(0.33mL)加入到实施例9中制备的化合物(10mg)在四氢呋喃(0.10mL)中的溶液中。在减压下浓缩该混合物而得到具有如下物理特性的标题化合物。
1H-NMR(甲醇-D4):δ1.39-1.56,1.57-1.74,1.74-1.98,1.99-2.14,2.15-2.27,2.40,2.69-2.85,2.86-2.93,3.52,3.96-4.08,4.58-4.69,6.89-6.99,7.19,7.39-7.54
实施例61
双(2,6-二铵基己酸酯)4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸酯
通过与实施例60中相同的操作,使用实施例14(2)中制备的化合物代替实施例9中制备的化合物获得具有如下物理特性的标题化合物。
1H-NMR(甲醇-D4):δ1.40-1.56,1.58-1.95,2.01-2.14,2.15-2.25,2.39,2.68-2.76,2.81,2.86-2.93,3.53,4.04,4.60-4.68,6.62,6.81-6.88,6.90-6.99,7.03-7.11,7.14,7.46
实施例62
双(2,6-二铵基己酸酯)4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸酯
通过与实施例60中相同的操作,使用实施例14(3)中制备的化合物代替实施例9中制备的化合物获得标题化合物。
实施例63
4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸二钠三水合物
在53℃下将实施例57中制备的化合物(10g)溶于水(40mL)和甲醇(40mL)。向该溶液中加入2-丙醇(1900mL)并且冷却至5℃。过滤沉淀的固体并且在40℃和减压下干燥。将该化合物维持在60%相对湿度和25℃下2天而得到具有如下物理特性的标题化合物(8.2g)。
1H-NMR(甲醇-D4):δ1.72-1.92,2.01-2.14,2.16-2.25,2.41,2.73,2.77-2.87,4.03,4.58-4.67,6.87-6.96,7.18,7.45-7.52
实施例64
4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸二钠八水合物
在53℃下将实施例58中制备的化合物(10g)溶于水(20mL)和甲醇(20mL)。向该溶液中加入丙酮(750mL)并且冷却至15℃。过滤沉淀的固体并且在40℃和减压下干燥。将该化合物维持在75%相对湿度和40℃下10天而得到具有如下物理特性的标题化合物(8.2g)。
1H-NMR(甲醇-D4):δ1.68-1.95,2.00-2.13,2.15-2.25,2.40,2.68-2.76,2.80,4.04,4.56-4.68,6.61,6.80-6.88,6.89-6.99,7.04-7.17,7.47
实施例65
4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸二钠水合物
在60℃下将实施例59中制备的化合物(8.5g)溶于水(22mL)和甲醇(22mL)。在室温下向该溶液中加入丙酮(430mL)并且冷却至2℃。过滤沉淀的固体并且在50℃和减压下干燥而得到具有如下物理特性的标题化合物(7.8g)。
1H-NMR(甲醇-D4):δ1.67-1.96,2.00-2.14,2.15-2.25,2.39,2.69-2.85,3.99,4.56-4.68,6.60,6.91,6.94-7.06,7.12,7.45
对比例1
4,4’-{2-甲基-7-[(E)-2-{4-[4-(五氟苯基)丁氧基]苯基}乙烯基]-1H-吲哚-1,3-二基}二丁酸
通过与实施例47→实施例4→实施例8→实施例9相同的操作,使用实施例2中制备的化合物代替实施例10中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的对比化合物。
TLC:Rf 0.69(氯仿∶甲醇=6∶1)
1H-NMR(DMSO-D6):δ1.62-1.81,1.81-1.94,2.19,2.31,2.60-2.84,3.90-4.08,4.19-4.32,6.82-7.02,7.13,7.31-7.43,7.54,7.69,11.91-12.21
对比例2
4,4’-{4-氟-7-[(E)-2-{4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙烯基]-2-甲基-1H-吲哚-1,3-二基}二丁酸
通过与实施例47→实施例4→实施例8→实施例9相同的操作,使用4,4’-(7-溴-4-氟-2-甲基-1H-吲哚-1,3-二基)二丁酸二乙酯(通过与实施例1→实施例2中相同的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐制备)代替实施例10中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的对比化合物。
TLC:Rf 0.44(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.57-1.95,2.13-2.25,2.17,2.30,2.60-2.80,4.02,4.19-4.31,6.71,6.82,6.88-7.19,6.93,7.53,7.61,12.08
对比例3
4,4’-{4-氟-2-甲基-7-[(E)-2-{4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙烯基]-1H-吲哚-1,3-二基}二丁酸
通过与实施例47→实施例4→实施例8→实施例9相同的操作,使用4,4’-(7-溴-4-氟-2-甲基-1H-吲哚-1,3-二基)二丁酸二乙酯(通过与实施例1→实施例2中相同的操作,使用(2-溴-5-氟苯基)肼代替(2-溴苯基)肼盐酸盐制备)代替实施例10中制备的化合物,且使用相应的磺酸酯代替实施例7中制备的化合物获得具有如下物理特性的对比化合物。
TLC:Rf 0.44(二氯甲烷∶甲醇=9∶1)
1H-NMR(DMSO-D6):δ1.58-1.95,2.12-2.24,2.30,2.65-2.80,4.00,4.26,6.71,6.82,6.91,7.04,7.38-7.50,7.52,7.61,12.07
可以通过下列实验证实本发明式(I)的化合物的作用。尽管实验方法如下所述,但是本发明并不限于此。
生物学实施例1:化合物对LTD4诱导的胞内钙水平增加的作用
将表达人cysLT1受体的中国仓鼠卵巢(CHO)细胞以0.4×105个细胞/孔的密度接种入96-孔平板并且在37℃下和在有5%CO2存在下的F-12培养基中培养24小时。在37℃下在包含7.5μM Fura2-AM,20mM 2-[4-(2-羟基乙基)-1-哌嗪基]乙磺酸(HEPES)和2.5mM丙磺舒的培养基中将细胞孵育约60分钟。用测定缓冲液(包含20mM HEPES的Hank′s缓冲液)将Fura2-AM-加载的细胞洗涤一次,且使用FDSS2000(Hamamatsu Photonics K.K.生产)测定LTD4-诱导的胞内钙内流。在LTD4刺激前30分钟施加本发明的化合物,且在150秒内测定100nM LTD4引起的反应的时程改变。在LTD4刺激后至多150秒获得的最大荧光强度方面评价本发明化合物的受体拮抗活性,且对每个化合物计算50%抑制浓度(IC50)。
作为结果,式(I)的化合物表现出10μM或10μM以下的IC50值。例如实施例9,9(1),11,21(1),14(2),21(2)和14(3)中制备的那些化合物分别表现出1.1,1.5,0.21,0.16,1.8,0.24和7.0nM的IC50值。
生物学实施例2:化合物对LTD4诱导的胞内钙水平增加的作用
将表达人cysLT2受体的HEK293细胞以1×105个细胞/孔的密度接种入96-孔平板并且在37℃下和在有5%CO2存在下的Dulbecco改进的Eagle培养基(DMEM)中培养24小时。在37℃下在包含7.5μMFura2-AM,20mM 2-[4-(2-羟基乙基)-1-哌嗪基]乙磺酸(HEPES)和2.5mM丙磺舒的培养基中将细胞孵育约60分钟。用测定缓冲液(包含20mM HEPES的Hank′s缓冲液)将Fura2-AM-加载的细胞洗涤一次,且使用FDSS2000(Hamamatsu Photonics K.K.生产)测定LTD4-诱导的胞内钙内流。在LTD4刺激前30分钟施加本发明的化合物,且在150秒内测定100nM LTD4引起的反应的时程改变。在LTD4刺激后至多150秒获得的最大荧光强度方面评价本发明化合物的受体拮抗活性,且对每个化合物计算50%抑制浓度。
作为结果,式(I)的化合物表现出10μM或10μM以下的IC50值。例如实施例9,9(1),11,21(1),14(2),21(2)和14(3)中制备的那些化合物分别表现出2.8,6.6,0.77,2.1,44,2.9和15nM的IC50值。
生物学实施例3:化合物对LTD4-诱导的豚鼠支气管收缩的作用
通过注射戊巴比妥钠(75mg/kg,i.p.)麻醉豚鼠,且将聚乙烯套管插入切开的气管。为了给予LTD4的目的,将导管插入动物颈静脉。将插入气管的套管一侧与容积控制呼吸器连接以便在5mL换气量和70次/min换气率下进行人工呼吸。通过静脉内给予LTD4以便诱导支气管收缩,且使用Konzett-Rossler方法测定气道阻力。在LTD4-攻击后测定支气管收缩反应10分钟,且测定支气管收缩反应比例并且表示为通过松弛气管获得的吸入压力的最大增加百分比。在这方面,在用LTD4攻击前1,2,4,8,12,18,24,36和48小时口服给予本发明的化合物。在本实施例中,将大于95%的支气管收缩抑制比例评价为支气管收缩完全抑制。下表4和5表明在用LTD4攻击前2和24小时口服给予测试化合物的结果。
作为结果,可以看出,就口服给药而言,式(I)表示的具有三键的乙炔基吲哚化合物在豚鼠中表现出对支气管收缩的完全抑制。此外,证实了该三键乙炔基吲哚化合物不仅在用LTD4攻击前2小时给予化合物的情况下显示对支气管收缩的完全抑制,而且在用LTD4攻击前24小时给予化合物的情况下显示对支气管收缩的完全抑制。例如,如表4中所示,就口服给药而言,实施例9,14(2)和14(3)的化合物表现出对豚鼠支气管收缩的完全抑制。在表4中,加括号的数字表示测试化合物剂量,且表中的数字表示抑制比(%)。
表4
实施例9(1mg/kg) | 实施例14(2)(1mg/kg) | 实施例14(3)(1mg/kg) | |
LTD4攻击前2小时给药 | 98.5 | 99.5 | 99.6 |
LTD4攻击前24小时给药 | 99.2 | 98.9 | 98.1 |
即,证实了式(I)的乙炔基吲哚化合物为甚至在口服给药时也具有长效作用的化合物,且适用作呼吸性疾病的口服治疗剂。
在这方面,对给予对应于表4化合物的相同剂量的对比例1-3的具有双键的乙烯基吲哚化合物测定对支气管收缩的抑制比。正如下表5中所示,在某些情况中,如果在用LTD4攻击前2小时给予所述化合物,那么存在完全抑制,而如果在用LTD4攻击前24小时给予所述化合物,那么无法获得完全抑制。在表5中,加括号的数字表示测试化合物剂量,且表中的数字表示抑制比(%)。
表5
对比例1(1mg/kg) | 对比例2(1mg/kg) | 对比例3(1mg/kg) | |
LTD4攻击前2小时给药 | 98.6 | 97.5 | 53.2 |
LTD4攻击前24小时给药 | 74.1 | 43.2 | 16.1 |
制剂实施例
应用于本发明实际应用的制剂实施例如下所示。
制剂实施例1
以常规方式混合4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸(100g),羧甲基纤维素钙(崩解剂,20g),硬脂酸镁(润滑剂,10g)和微晶纤维素(870g)并且压制成10,000片,其中每片含10mg活性组分。
制剂实施例2
以常规方式混合4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸(200g),甘露糖醇(2kg)和蒸馏水(50L)。然后通过防尘过滤器过滤该溶液,且然后将5ml等分部分加入到安瓿中。对安瓿高压灭菌而得到10,000支安瓿,其中每支安瓿含20mg活性组分。
[本发明的作用]
本发明式(I)的化合物为具有优良长效作用与有效cysLT1/cysLT2受体拮抗活性的化合物,且因此在口服给药中极为有用地作为治疗呼吸性疾病的长效活性剂。
Claims (5)
3.权利要求2的化合物,其中R1为3-羧基丙基且R3为3-羧基丙基。
4.权利要求1的化合物,其中该化合物为
(1)4,4’-[2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(2)4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(3)4,4’-[2-甲基-7-({4-[4-(3,4,5-三氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(4)4,4’-[7-({4-[4-(2,3-二氟苯氧基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(5)4,4’-[7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(6)4,4’-[2-甲基-7-({4-[4-(2,3,4,5-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(7)4,4’-[2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(8)4,4’-[7-({4-[4-(4-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(9)4,4’-[7-({4-[4-(4-氟-3-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(10)4,4’-[4-氟-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(11)4,4’-[7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-4-氟-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(12)4,4’-[4-氟-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1,3-二基]二丁酸,
(13)4,4’-[4-氟-2-甲基-7-({4-[4-(2,3,4,6-四氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸,
(14)[3-{[1-(羧甲基)环丙基]甲基}-2-甲基-7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1-基]乙酸,
(15)(1-{[1-(羧甲基)-7-({4-[4-(3-氯-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-3-基]甲基}环丙基)乙酸,
(16)[3-{[1-(羧甲基)环丙基]甲基}-7-({4-[4-(3-氟-2-甲基苯基)丁氧基]苯基}乙炔基)-2-甲基-1H-吲哚-1-基]乙酸,或
(17)4,4’-[7-({4-[4-(五氟苯基)丁氧基]苯基}乙炔基)-1H-吲哚-1,3-二基]二丁酸。
5.药物组合物,包含权利要求1描述的式(I)的化合物或其盐,溶剂合物或前体药物作为活性组分。
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