CN1845911B - 稠环化合物及其应用 - Google Patents
稠环化合物及其应用 Download PDFInfo
- Publication number
- CN1845911B CN1845911B CN2004800250567A CN200480025056A CN1845911B CN 1845911 B CN1845911 B CN 1845911B CN 2004800250567 A CN2004800250567 A CN 2004800250567A CN 200480025056 A CN200480025056 A CN 200480025056A CN 1845911 B CN1845911 B CN 1845911B
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- CN
- China
- Prior art keywords
- dihydro
- amino
- carboxylic acid
- phenyl
- benzoyl
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 327
- -1 nitro, amino, hydroxyl Chemical group 0.000 claims description 302
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 169
- 238000002360 preparation method Methods 0.000 claims description 146
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 132
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 120
- 229920002554 vinyl polymer Polymers 0.000 claims description 88
- 125000001424 substituent group Chemical group 0.000 claims description 52
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 46
- 239000003814 drug Substances 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 37
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 28
- 125000002837 carbocyclic group Chemical group 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 23
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- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 125000003836 4-phenylbutoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical class 0.000 claims description 11
- 125000001118 alkylidene group Chemical group 0.000 claims description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
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- 238000005481 NMR spectroscopy Methods 0.000 description 231
- 239000002585 base Substances 0.000 description 164
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 140
- 239000000203 mixture Substances 0.000 description 132
- 229910052760 oxygen Inorganic materials 0.000 description 99
- 239000001301 oxygen Substances 0.000 description 98
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 96
- 238000000034 method Methods 0.000 description 90
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 89
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- 125000004122 cyclic group Chemical group 0.000 description 41
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 32
- 238000001035 drying Methods 0.000 description 31
- 238000003810 ethyl acetate extraction Methods 0.000 description 31
- 239000012044 organic layer Substances 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
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- 239000000651 prodrug Substances 0.000 description 26
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 16
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Abstract
本发明涉及下式(I)所示化合物(其中所有符号的含义参见本文)。该化合物拮抗cysLT2,因此其可用作预防和/或治疗呼吸性疾病如支气管哮喘、支气管哮喘、慢性阻塞性肺病、肺气肿、慢性支气管炎、肺炎(包括间质性肺炎等)、严重急性呼吸综合征(SARS)、急性呼吸窘迫综合征(ARDS)、过敏性鼻炎、鼻窦炎(包括急性鼻窦炎、慢性鼻窦炎等)等,并可作为去痰药或止咳药。
Description
技术领域
本发明涉及:
(1)下式(I)所示化合物,
其中所有符号的含义与下述的相同,和
(2)包括式(I)所示化合物的cysLT2受体拮抗剂。
背景技术
支气管哮喘是一种病理症状,其中气道由于气道收缩和炎症变狭窄,引起阵发性咳嗽、喘鸣和呼吸困难。治疗药物包括具有强力抗炎作用的吸入用甾族药物,作为支气管扩张药的β-刺激药和茶碱,和抑制递质的抗变应性药物,等等。
已知各种化学递质在支气管哮喘中有涉及,其中已知半胱氨酰白三烯(cysLTs)对气道的收缩作用是组胺的约1000倍。另外,cysLTs促进诱发气道炎症,通常为炎症细胞浸润、气道过敏性亢进和气道中粘液分泌,它们与支气管哮喘的基础病理学极度相关。
CysLTs是活体中的生理学活性物质,是通过5-脂氧合酶从花生四烯酸得到的代谢产物。CysLTs具有至少两种类型的受体,至今已经克隆了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并且其与支气管哮喘的发展有很大关系(Am.J.Respir.Crit.Care Med.,163,226-233,2001)。目前已经上市的白三烯(LT)受体拮抗剂如普仑司特水合物、孟鲁司特钠和扎鲁司特是选择性的cysLT1受体拮抗剂(Nature,399,789-793,1999),是有用的支气管哮喘治疗药,其改善各种症状和呼吸功能。然而已知上市的这些LT受体拮抗剂对于轻微症状或中等症状比对严重症状更有效。还已知对于一些具有轻微或中等症状的非奏效例,尚无有效药物。
另一方面,据报道,用于新克隆的cysLT2受体的配体为LTC4、LTD4和LTE4,并且cysLT2受体与CysLT1受体同样在支气管平滑肌中表达(J.Biol.Chem.,275,30531-30536,2000,Am.J.Respir.Crit.Care Med.,164,2098-2101,2001)。然而,在病理学状况下cysLT2受体的功能和作用尚未阐明。
因此,如果cysLT2受体以及cysLT1受体与支气管平滑肌收缩、气道炎症、反应性气道疾病和气道中粘液分泌有关,通过拮抗cysLT2受体,可能令人信服地生产比现有的LT受体拮抗剂更有用的呼吸性疾病治疗药。例如,希望这种治疗药对更严重的支气管哮喘患者和现存的LT受体拮抗剂非奏效例更有效。另外,还报道了cysLT2受体除了在支气管平滑肌中表达之外,还在心脏、脑和末梢血液白血球等中有表达(J.Biol.Chem.,275,30531-30536,2000)。因此希望cysLT2受体拮抗剂是用于治疗心血管、中枢神经系统和各种炎症性疾病的治疗药。
在Molecular Pharmacology(United States),2000,58,p.1601-1608中公开了下式(A)所示的化合物,
其拮抗cysLT1和cysLT2。
在JP9-169712公报中公开了下式(B)所示的苯甲酸衍生物,
其中,R1B为氢、具有至多6个碳的烷基、或取代的苯基;PB和QB各自为氧、硫或键;XB为氧、硫或-CONH-;TB为1,2-亚乙基、氧、硫或键;YB为-COOH、-NHSO2R3B或CONHSO2R3B;ZB为-COOH、COR4B、-CO(CH2)pBCO2H、-O(CH2)pBCO2H、-S(CH2)pBCO2H、NO2、-CONHWBCO2H或NHWBCO2H;mB为0-6的整数;并且nB为0-4的整数,
其表现为白三烯拮抗作用,可有效治疗呼吸性疾病,并且其拮抗cysLT1受体和cysLT2受体。
另外,在98th American Thoracic Society(2002,D38,F4)提纲中,描述了DUO-LT,其是临床目标为缺血性疾病和炎症性疾病的化合物,拮抗cysLT1和cysLT2受体。
在WO 2004/052839的说明书中公开了下式(C)所示的化合物,
其中所有符号的含义与说明书中的相同,具有对抗CysLT2受体的拮抗作用,并且该化合物可用于治疗和/或预防心血管疾病如心绞痛、心急梗塞等。
发明内容
本发明要解决的问题
如上所述,上市的那些LT受体拮抗剂已知对支气管哮喘的轻微和中等症状起作用,并且还已知在具有轻微和中等症状的患者中存在非奏效例,上述药物对所述病例无效。因此,希望具有比现有药物更有效的呼吸性疾病治疗药。
发明详述
本发明人进行了深入的研究以解决上述问题,并且已经发现拮抗cysLT2受体的下式(I)所示的化合物可用作呼吸性疾病治疗剂,并因此完成了本发明。
也就是说,本发明涉及:
下式(I)所示化合物,
[其中R1和R2各自独立地为可被保护的酸性基团,D和E各自独立地为键或主链含1-8个原子的间隔基,R3为取代基,环A为可进一步具有取代基的环状基团,环B为可进一步具有取代基的环状基团,Y和Z各自独立地为碳原子或氮原子,并且为单键或双键(如果Y和/或Z为氮原子,所述键为单键)],
其N-氧化物、其盐、其溶剂化物或其前药,
上述[1]所述的化合物,其中
为3,4-二氢-2H-1,4-苯并噁嗪、3,4-二氢-2H-1,4-苯并噻嗪、1,2,3,4-四氢喹喔啉、1,2,3,4-四氢喹啉、1,2-二氢喹啉、4H-1,4-苯并噁嗪、4H-1,4-苯并噻嗪、喹啉、异喹啉、喹喔啉、1,2,3,4-四氢异喹啉、1,2-二氮杂萘、2,3-二氮杂萘、4(1H)-喹啉酮、3,4-二氢-2(1H)-喹啉酮、2(1H)-喹啉酮、1H-吲哚或二氢吲哚环,
上述[1]所述的化合物,其中R3为
(其中环1为可具有取代基的环状基团,V为键或主链含1-8个原子的间隔基,环2为可具有取代基的环状基团,并且W为键或主链含1-8个原子的间隔基),
上述[1]所述的化合物,其中由R1和R2表示的酸性基团各自独立地为-COORA(其中RA为氢或C1-8烷基),-CONRB8O2RC(其中RB为氢或C1-8烷基,RC为C1-8烃),-SO2NRBCORC(其中所有符号的含义如上所述),
上述[1]所述的化合物,其为下式(I-X)所示化合物,
(其中R30为氢或取代基,m为0或1-4的整数,L为氮原子、氧原子、可被氧化的硫原子、碳原子或键,并且其它符号的含义同权利要求1和3,并且相邻的两个键不同时表示双键),
上述[3]或[5]所述的化合物,其中V为包括选自以下1-4个的组合的二价基团:任选具有1-2个取代基的-CH2-,任选具有1-2个取代基的-CH=CH-,-C≡C-,任选具有取代基的-NH-,-CO-,-O-,-S-,-SO-和SO2-,
上述[3]或[5]所述的化合物、其中-D-R1为-CO-(CH2)2-R1、-CO-(CH2)3-R1、-CO-(CH2)4-R1或C1-4亚烷基-R1,
上述[3]或[5]所述的化合物,其中E为键或C1-4亚烷基,
上述[3]或[5]所述的化合物,其中V为
上述[1]所述的化合物,其选自:
(1)4-(3-羧基丙基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(2)4-(3-羧基丙基)-8-({(2E)-3-[4-(4-苯基丁基)苯基]-2-丙烯酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(3)4-[8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸,
(4)4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苄基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(5)4-(3-羧基丙基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(6)4-(3-羧基丙基)-8-{2-[4-(4-苯基丁氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(7)(2S)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(8)(2R)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(9)4-(3-羧基丙基)-8-({4-[2-(2,3-二氢-1H-茚-2-基)乙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(10)4-(3-羧基丙基)-8-({4-[(5-苯基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(11)4-(3-羧基丙基)-8-({4-[(7-苯基庚基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(12)4-(3-羧基丙基)-8-({4-[(4-甲基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(13)4-(3-羧基丙基)-8-{[4-(4-苯氧基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(14)4-(3-羧基丙基)-8-({4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(15)4-(3-羧基丙基)-8-({4-[4-(4-氟苯基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(16)4-(3-羧基丙基)-8-({4-[4-(2-甲基苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(17)4-(3-羧基丙基)-8-({4-[4-(2-氟苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(18)4-(3-羧基丙基)-8-({4-[4-(2-氯苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(19)4-(3-羧基丙基)-8-[(4-{4-[2-(三氟甲基)苯氧基]丁氧基}苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(20)4-(3-羧基丙基)-8-({4-[3-(2-甲基苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(21)4-(2-({[(4-甲基苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(22)4-(2-{[(甲基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(23)4-(2-{[(苄基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(24)4-(3-羧基丙基)-8-{(E)-2-[4-(4-苯氧基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(25)4-(3-羧基丙基)-8-{(E)-2-[4-(2,3-二氢-1H-茚-2-基甲氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(26)4-(3-羧基丙基)-8-((E)-2-{4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(27)4-(3-羧基丙基)-8-((E)-2-{4-[(5-苯氧基戊基)氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(28)4-(3-羧基丙基)-8-((E)-2-{4-[4-(4-甲氧基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(29)4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-氟苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(30)4-(3-羧基丙基)-8-{(E)-2-[4-(3-苯氧基丙氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(31)4-(3-羧基丙基)-8-((E)-2-{4-[3-(2-氯苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(32)4-(3-羧基丙基)-8-{2-[4-(4-苯氧基丁氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(33)4-[8-{2-[4-(4-苯基丁氧基)苯基]乙基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸,
(34)4-[8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸,
(35)4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(36)4-(2-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(37)4-氧代-4-(8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,和
(38)4-(3-羧基丙基)-8-((4-(4-苯基丁氧基)苄基)氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
包括上述[1]所述的式(I)所示化合物或其N-氧化物、其盐、其溶剂化物或其前药的药学组合物,
上述[11]所述的药学组合物,其为用于预防和/或治疗由cysLT2介导的疾病的治疗剂,
上述[12]所述的药学组合物,其中由cysLT2介导的疾病为呼吸性疾病,
上述[13]所述的药学组合物,其中呼吸性疾病为哮喘或慢性阻塞性肺病,
包括上述[1]所述的式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药和选自cysLT1受体拮抗剂、甾族药物、抗组胺药、磷酸二酯酶4抑制剂、弹性蛋白酶抑制剂、抗胆碱能药和拟交感神经药中的一种或多种的医药,
预防和/或治疗由cysLT2介导的疾病的方法,其特征在于对哺乳动物给用有效量的上述[1]所述的式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药,
预防和/或治疗由cysLT2介导的疾病的方法,其特征在于对哺乳动物联合给用有效量的上述[1]所述的式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药以及cysLT1受体拮抗剂、甾族药物、抗组胺药、磷酸二酯酶4抑制剂、弹性蛋白酶抑制剂,抗胆碱能药和/或拟交感神经药,和
上述[1]所述的式(I)所示化合物在制备用于预防和/或治疗由cysLT2介导的疾病的药物中的应用。
在本说明书中,由环A表示的任选具有取代基的环状基团中的环状基团为C3-15碳环、或3-15元含1-5个选自氧、氮和/或硫的杂原子的单-、二-或三-环的部分或全部饱和的芳香杂环。
在本发明中,C3-15碳环包括C3-15单-、二-或三-环芳香碳环,其部分或全部饱和的环、螺双环碳环和桥接碳环,如环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环壬烷、环癸烷、环十一烷、环十二烷、环十三烷、环十四烷、环十五烷、环戊烯、环己烯、环庚烯、环辛烯、环戊二烯、环己二烯、环庚二烯、环辛二烯、苯、并环戊二烯、全氢并环戊二烯、薁、全氢薁、茚、全氢茚、茚满、萘、二氢萘、四氢萘、全氢萘、庚间三烯并庚间三烯、全氢庚间三烯并庚间三烯、联苯、as-indacene、s-indacene、苊、二氢苊、芴、菲那啉(phenalene)、菲、蒽、螺[4.4]壬烷、螺[4.5]癸烷、螺[5.5]十一癸烷、双环[2.2.1]庚烷、双环[2.2.1]庚-2-烯、双环[3.1.1]庚烷、双环[3.1.1]庚-2-烯、双环[2.2.2]辛烷、双环[2.2.2]辛-2-烯、金刚烷或降金刚烷(noradamantane)环,等。
在本发明中,3-15元的含1-5个选自氧、氮和/或硫的杂原子的单-、二-或三-环的部分或全部饱和的芳香杂环包括例如吡咯、咪唑、三唑、四唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、氮杂卓、二氮杂卓、呋喃、吡喃、氧杂卓、噻吩、噻喃、硫杂卓、噁唑、异噁唑、噻唑、异噻唑、呋咱、噁二唑、噁嗪、噁二嗪、氧氮杂卓、氧二氮杂卓、噻二唑、噻嗪、噻二嗪、硫氮杂卓、硫二氮杂卓、吲哚、异吲哚、中氮茚、苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、二硫杂萘、吲唑、喹啉、异喹啉、喹嗪、嘌呤、2,3-二氮杂萘、喋啶、1,5-二氮杂萘、喹喔啉、喹唑啉、1,2-二氮杂萘、苯并噁唑、苯并噻唑、苯并咪唑、苯并吡喃、苯并氧杂卓、苯并氧氮杂卓、苯并氧二氮杂卓、苯并硫杂卓、苯并硫氮杂卓、苯并硫二氮杂卓、苯并氮杂卓、苯并二氮杂卓、苯并呋咱、苯并噻二唑、苯并三唑、咔唑、β-咔啉、吖啶、吩嗪、二苯并呋喃、氧杂蒽、二苯并噻吩、吩噻嗪、吩噁嗪、苯并氧硫杂芑、噻蒽、菲啶、菲咯啉、萘嵌间二氮杂苯、吡唑并吡啶、氮丙啶、氮杂环丁烷、吡咯啉、吡咯烷、咪唑啉、咪唑烷、三唑啉、三唑烷、四唑啉、四唑烷、吡唑啉、吡唑烷、二氢吡啶、四氢吡啶、哌啶、二氢吡嗪、四氢吡嗪、哌嗪、二氢嘧啶、四氢嘧啶、全氢嘧啶、二氢哒嗪、四氢哒嗪、全氢哒嗪、二氢氮杂卓、四氢氮杂卓、全氢氮杂卓、二氢二氮杂卓、四氢二氮杂卓、全氢二氮杂卓、环氧乙烷、氧杂环丁烷、二氢呋喃、四氢呋喃、二氢吡喃、四氢吡喃、二氢氧杂卓、四氢氧杂卓、全氢氧杂卓、硫杂环丙烷、硫杂环丁烷、二氢噻吩、四氢噻吩、二氢噻喃、四氢噻喃、二氢硫杂卓、四氢硫杂卓、全氢硫杂卓、二氢噁唑、四氢噁唑(噁唑烷)、二氢异噁唑、四氢异噁唑(异噁唑烷)、二氢噻唑、四氢噻唑(噻唑烷)、二氢异噻唑、四氢异噻唑(异噻唑烷)、二氢呋咱、四氢呋咱、二氢噁二唑、四氢噁二唑(噁二唑烷)、二氢噁嗪、四氢噁嗪、二氢噁二嗪、四氢噁二嗪、二氢氧氮杂卓、四氢氧氮杂卓、全氢氧氮杂卓、二氢氧二氮杂卓、四氢氧二氮杂卓、全氢氧二氮杂卓、二氢噻二唑、四氢噻二唑(噻二唑烷)、二氢噻嗪、四氢噻嗪、二氢噻二嗪、四氢噻二嗪、二氢硫氮杂卓、四氢硫氮杂卓、全氢硫氮杂卓、二氢硫二氮杂卓、四氢硫二氮杂卓、全氢硫二氮杂卓、吗啉、硫代吗啉、氧硫杂环己烷、二氢吲哚、异二氢吲哚、二氢苯并呋喃、全氢苯并呋喃、二氢异苯并呋喃、全氢异苯并呋喃、二氢苯并噻吩、全氢苯并噻吩、二氢异苯并噻吩、全氢异苯并噻吩、二氢吲唑、全氢吲唑、二氢喹啉、四氢喹啉、全氢喹啉、二氢异喹啉、四氢异喹啉、全氢异喹啉、二氢2,3-二氮杂萘、四氢2,3-二氮杂萘、全氢2,3-二氮杂萘、二氢1,5-二氮杂萘、四氢1,5-二氮杂萘、全氢1,5-二氮杂萘、二氢喹喔啉、四氢喹喔啉、全氢喹喔啉、二氢喹唑啉、四氢喹唑啉、全氢喹唑啉、二氢1,2-二氮杂萘、四氢1,2-二氮杂萘、全氢1,2-二氮杂萘、苯并氧硫杂环己烷、二氢苯并噁嗪、二氢苯并噻嗪、吡嗪并吗啉、二氢苯并噁唑、全氢苯并噁唑、二氢苯并噻唑、全氢苯并噻唑、二氢苯并咪唑、全氢苯并咪唑、二氢苯并氮杂卓、四氢苯并氮杂卓、二氢苯并二氮杂卓、四氢苯并二氮杂卓、苯并二氧杂卓、二氢苯并氧氮杂卓、四氢苯并氧氮杂卓、二氢咔唑、四氢咔唑、全氢咔唑、二氢吖啶、四氢吖啶、全氢吖啶、二氢二苯并呋喃、二氢二苯并噻吩、四氢二苯并呋喃、四氢二苯并噻吩、全氢二苯并呋喃、全氢二苯并噻吩、二氧杂环戊烷、二氧杂环己烷、二硫杂环戊烷、二硫杂环己烷、二氧杂茚满、苯并二氧杂环己烷、色满、苯并二硫杂环戊烷、苯并二硫杂环己烷、氮杂螺[4.4]壬烷、氧杂氮杂螺[4.4]壬烷、二氧杂螺[4.4]壬烷、氮杂螺[4.5]癸烷、硫杂螺[4.5]癸烷、二硫杂螺[4.5]癸烷、二氧杂螺[4.5]癸烷、氧杂氮杂螺[4.5]癸烷、氮杂螺[5.5]十一癸烷、氧杂螺[5.5]十一癸烷、二氧杂螺[5.5]十一癸烷、氮杂双环[2.2.1]庚烷、氧杂双环[2.2.1]庚烷、氮杂双环[3.1.1]庚烷、氮杂双环[3.2.1]辛烷、氧杂双环[3.2.1]辛烷、氮杂双环[2.2.2]辛烷、二氮杂双环[2.2.2]辛烷、四氢-β-咔啉、六氢氮杂卓并吲哚、氧杂氮杂螺[2.5]辛烷、六氢氮杂卓并吲唑、六氢吡唑并吡啶并氮杂卓、四氢吡唑并异喹啉或四氢吡唑并1,5-二氮杂萘环等。
在本发明中,由环A表示的“可具有取代基的环状基团”中的“取代基”包括例如(1)可具有取代基的烷基、(2)可具有取代基的烯基、(3)可具有取代基的炔基、(4)可具有取代基的碳环、(5)可具有取代基的杂环、(6)可被保护的羟基、(7)可被保护的巯基、(8)可被保护的氨基、(9)可具有取代基的氨基甲酰基、(10)可具有取代基的氨基磺酰基、(11)羧基、(12)烷氧基羰基(例如C1-6烷氧基羰基如甲氧基羰基、乙氧基羰基,叔丁氧基羰基等)、(13)磺基、(14)亚磺基、(15)膦酰基、(16)硝基、(17)氰基、(18)酰胺基、(19)亚胺基、(20)二氢二羟硼基、(21)卤素(例如氟、氯、溴、碘等)、(22)烷基亚硫酰基(例如C1-4烷基亚硫酰基如甲基亚硫酰基、乙基亚硫酰基等)、(23)芳香环-亚硫酰基(例如C6-10芳香环-亚硫酰基如苯基亚硫酰基等)、(24)烷基磺酰基(例如C1-4烷基磺酰基如甲基磺酰基、乙基磺酰基等)、(25)芳香环-磺酰基(例如C6-10芳香环-磺酰基如苯基磺酰基等)、(26)酰基、(27)氧代、(28)硫代(thioxo)、(29)(C1-6烷氧基亚胺基)甲基(例如(甲氧基亚胺基)甲基等)、(30)甲酰基等,并且1-5个上述取代基可位于可接受的位置上。
在作为取代基的“(1)可具有取代基的烷基”中的烷基包括直链或支链C1-20烷基如甲基、乙基、N-丙基、异丙基、N-丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基等。
因此烷基的取代基包括例如羟基、氨基、羧基、硝基、叠氮基、单-或二-C1-6烷基氨基(例如甲基氨基、乙基氨基、丙基氨基、二甲基氨基、二乙基氨基等)、N-芳香环-氨基(例如N-苯基氨基等)、N-芳香环-N-烷基氨基(例如N-苯基-N-甲基氨基、N-苯基-N-乙基氨基、N-苯基-N-丙基氨基、N-苯基-N-丁基氨基、N-苯基-N-戊基氨基、N-苯基-N-己基氨基等)、酰基氨基、N-酰基-N-烷基氨基、C1-6烷氧基(例如甲氧基、乙氧基、丙氧基、异丙氧基、己氧基等)、C3-7环烷基-C1-6烷氧基(例如环己基甲基氧基、环戊基乙基氧基等)、C3-7环烷基氧基(例如环己氧基等)、C7-15芳烷基氧基(例如苯基甲基氧基、苯基乙基氧基、苯基丙基氧基、萘基甲基氧基、萘基乙基氧基等)、苯氧基、C1-6烷氧基羰基(例如甲氧基羰基、乙氧基羰基、叔丁氧基羰基等)、C1-6烷基羰基氧基(例如乙酰氧基、乙基羰基氧基等)、C1-4烷硫基(例如甲硫基、乙硫基、丙硫基、丁硫基等)、卤素(氟、氯、溴、碘)、烷基磺酰基(例如C1-4烷基磺酰基如甲基磺酰基、乙基磺酰基等)、芳香环-磺酰基(例如C6-10芳香环-磺酰基如苯基磺酰基等)、酰基、甲酰基、可具有取代基的碳环、可具有取代基的杂环等,并且1-4个所述取代基可位于可接受的位置上。
因此,酰基、酰基氨基和N-酰基-N-烷基氨基中的酰基与下文所述的作为取代基的“(26)酰基”具有相同含义,在N-酰基-N-烷基氨基中的“烷基”包括例如直链或支链C1-20烷基如甲基、乙基、N-丙基、异丙基、N-丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基等。
可具有取代基的碳环和可具有取代基的杂环分别与“(4)可具有取代基的碳环”和“(5)可具有取代基的杂环”具有相同含义。
在作为取代基的“(3)可具有取代基的炔基”中的炔基包括例如直链或支链C2-20炔基如乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。在这里,炔基的取代基与上述“可具有取代基的烷基”中的取代基具有相同含义。
在作为取代基的“(4)可具有取代基的碳环”中的碳环与“可具有取代基的环状环”的环状基团中的C3-15碳环具有相同含义。
在作为取代基的“(4)可具有取代基的碳环”中的碳环与上述由环A表示的“可具有取代基的环状基团”的环状基团中的C3-15碳环具有相同含义。本文中碳环的取代基包括例如C1-8烷基(例如甲基、乙基、N-丙基、异丙基、N-丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基等)、C2-8烯基(例如乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基等)、C2-8炔基(例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基等)、羟基、C1-6烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等)、C1-6烷氧基羰基(例如甲氧基羰基、乙氧基羰基、叔丁氧基羰基等)、C1-6烷基羰基氧基(例如乙酰氧基、乙基羰基氧基等)、巯基、C1-6烷硫基(例如甲硫基、乙硫基、丙硫基、丁硫基、戊硫基、己硫基等)、氨基、单-或二-C1-4烷基氨基(例如甲基氨基、乙基氨基、丙基氨基、二甲基氨基、二乙基氨基等)、卤素(氟、氯、溴、碘)、三卤甲基(例如三氟甲基等)、三卤甲氧基(例如三氟甲氧基等)、三卤甲硫基(例如三氟甲硫基等)、二卤甲氧基(例如二氟甲氧基等)、二卤甲硫基(例如二氟甲硫基等)、氰基、硝基、羧基、可具有取代基的环状基团,其中环状基团与由上述环A表示的“可具有取代基的环状基团”中的环状基团具有相同含义,并且所述取代基包括例如C1-8烷基(例如甲基、乙基、N-丙基、异丙基、N-丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基等)、C2-8烯基(例如乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基等)、C2-8炔基(例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基等)、羟基、C1-6烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等)、C1-6烷氧基羰基(例如甲氧基羰基、乙氧基羰基、叔丁氧基羰基等)、C1-6烷基羰基氧基(例如乙酰氧基、乙基羰基氧基等)、巯基、C1-6烷硫基(例如甲硫基、乙硫基、丙硫基、丁硫基、戊硫基、己硫基等)、氨基、单-或二-C1-4烷基氨基(例如甲基氨基、乙基氨基、丙基氨基、二甲基氨基、二乙基氨基等)、卤素(氟、氯、溴、碘)、三卤甲基(例如三氟甲基等)、三卤甲氧基(例如三氟甲氧基等)、三卤甲硫基(例如三氟甲硫基等)、二卤甲氧基(例如二氟甲氧基等)、二卤甲硫基(例如二氟甲硫基等)、氰基、硝基、羧基等。并且1-4个所述取代基可位于可接受的位置等上。
在作为取代基的“(5)可具有取代基的杂环”中的杂环与上述由环A表示的“可具有取代基的环状基团”中的含1-5个选自氧、氮和/或硫的杂原子的3-15元单-、二-或三-环的部分或全部饱和的芳香杂环具有相同含义。
本文中,杂环的取代基与上述“(4)可具有取代基的碳环”中的取代基具有相同含义。
在作为取代基的“(6)任选被保护的羟基”和“(7)任选被保护的巯基”和“(8)任选被保护的氨基”中的保护基包括例如可具有取代基的烷基(其与上述″(1)可具有取代基的烷基″具有相同含义),可具有取代基的碳环(其与上述″(4)可具有取代基的碳环″具有相同含义),可具有取代基的杂环(其与上述″(5)可具有取代基的杂环″具有相同含义),烷基磺酰基(例如C1-4烷基磺酰基如甲基磺酰基、乙基磺酰基等),芳香环-磺酰基(例如C6-10芳香环-磺酰基如苯基磺酰基等),酰基(其与后述的(26)酰基具有相同含义)等。
作为取代基的“(9)可具有取代基的氨基甲酰基”包括例如未取代的氨基甲酰基,N-单-C1-4烷基氨基甲酰基(例如N-甲基氨基甲酰基、N-乙基氨基甲酰基、N-丙基氨基甲酰基、N-异丙基氨基甲酰基、N-丁基氨基甲酰基等)、N,N-二-C1-4烷基氨基甲酰基(例如N,N-二甲基氨基甲酰基、N,N-二乙基氨基甲酰基、N,N-二丙基氨基甲酰基、N,N-二丁基氨基甲酰基等)、1-哌啶基羰基等。
作为取代基的“(10)可具有取代基的氨基磺酰基”包括例如未取代的氨基磺酰基、N-单-C1-4烷基氨基磺酰基(例如N-甲基氨基磺酰基、N-乙基氨基磺酰基、N-丙基氨基磺酰基、N-异丙基氨基磺酰基、N-丁基氨基磺酰基等)、N,N-二-C1-4烷基氨基磺酰基(例如N,N-二甲基氨基磺酰基、N,N-二乙基氨基磺酰基、N,N-二丙基氨基磺酰基、N,N-二丁基氨基磺酰基等)等。
作为取代基的“(26)酰基”包括例如可具有取代基的烷基羰基(其中可具有取代基的烷基与上述″(1)可具有取代基的烷基″具有相同含义),可具有取代基的烯基羰基(其中可具有取代基的烯基与上述″(2)可具有取代基的烯基″具有相同含义),可具有取代基的炔基羰基(其中可具有取代基的炔基与上述″(3)可具有取代基的炔基″具有相同含义),碳环-羰基(其中可具有取代基的碳环与上述″(4)可具有取代基的碳环″具有相同含义),杂环-羰基(其中可具有取代基的杂环与上述″(5)可具有取代基的杂环″具有相同含义)等。
在本说明书中,由环B表示的“可具有取代基的环状基团”与由上述环A表示的“可具有取代基的环状基团”具有相同含义。
在说明书中,由R1和R2表示的“可被保护的酸性基团”是指可被保护基保护的酸性基团。可被保护基保护的酸性基团中的“酸性基团”包括各种布朗斯台德酸、例如羧基(-COOH)、异羟肟酸(-CONHOH)、酰基氰胺(-CONHCN)、磺基(-SO3H)、磺酰胺(-SO2NH2或NR100SO3H,其中R100为氢或可具有取代基的烃(其与后文所述的可被保护基保护的酸性基团中的保护基中的“可具有取代基的烃基”具有相同含义))、酰基磺酰胺(-CONHSO2R100或SO2NHCOR100,其中R100与前述具有相同定义)、膦酰基(-P(=O)(OH)2)、磷酸亚基(=P(=O)OH)、氨基(羟基)磷酰基(-P(=O)(OH)(NH2))、苯酚(-C6H4OH)或包括可脱质子化氢原子的杂环残基。“布朗斯台德酸”表示对另一种物质提供氢离子的物质。“包括可脱质子化氢原子的杂环残基″包括例如,
可被保护基保护的酸性基团中的“保护基”包括例如可具有取代基的烃、C1-6烷氧基、任选被保护的氨基、1-哌啶基或4-吗啉基等。
“可具有取代基的烃”中的“烃”基包括例如C1-15烷基如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基等;C3-8环烷基如环丙基、环丁基、环戊基、环己基等;C2-10烯基如乙烯基、烯丙基、2-甲基烯丙基、2-丁烯基、3-丁烯基、3-辛烯基等;C2-10炔基如乙炔基、2-丙炔基、3-己炔基等;C3-10环烯基如环丙烯基、环戊烯基、环己烯基等;C6-14芳基如苯基、萘基等;C7-16芳烷基如苄基、苯基乙基等;(C3-8环烷基)-(C1-4烷基)如环己基甲基、环己基乙基、环己基丙基、1-甲基-1-环己基甲基等。
“可具有取代基的烃基”中的取代基包括例如(1)硝基、(2)羟基、(3)氧代、(4)硫代、(5)氰基、(6)氨基甲酰基、(7)被C1-8烃等取代的氨基羰基,如N-丁基氨基羰基、N-环己基甲基氨基羰基、N-丁基-N-环己基甲基氨基羰基、N-环己基氨基羰基、苯基氨基羰基、(8)羧基、(9)C1-4烷氧基羰基如甲氧基羰基、乙氧基羰基等、(10)磺基、(11)卤素,如氟、氯、溴、碘等、(12)C1-4低级烷氧基如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基等、(13)苯氧基、(14)卤代苯氧基如邻-、间-或对-氯苯氧基、邻-、间-或对-溴苯氧基、(15)C1-4低级烷硫基如甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、叔丁硫基等、(16)苯硫基、(17)C1-4低级烷基亚硫酰基如甲基亚硫酰基、乙基亚硫酰基等、(18)C1-4低级烷基磺酰基如甲基磺酰基、乙基磺酰基等、(19)氨基、(20)C1-6低级酰基氨基如乙酰基氨基、丙酰基氨基等、(21)被烃基取代的伯或仲氨基如甲基氨基、乙基氨基、正丙基氨基、异丙基氨基、正丁基氨基、二甲基氨基、二乙基氨基、环己基氨基、1-氨基甲酰基-2-环己基乙基氨基、N-丁基-N-环己基甲基氨基、苯基氨基(其中“烃基”与上述“烃基”具有相同含义并且其可被氧代、氨基、氨基甲酰基等取代)、(22)C1-4低级酰基如甲酰基、乙酰基等、(23)苯甲酰基、(24)5-6元杂环,包括1-4个除了碳原子之外的选自氧、硫、氮的杂原子,可具有1-4个选自以下的取代基:(a)卤素如溴、氯、氟等、(b)烃基如甲基、乙基、丙基、异丙基、苄基、环己基、环己基甲基、环己基乙基,其可被氧代、羟基等取代,其中“烃基”与上述“烃基”具有相同含义、(c)卤代苯氧基如邻-、间-或对-氯苯氧基、邻-、间-或对-溴苯氧基等,和(d)氧代等,例如2-或3-噻吩基、2-或3-呋喃基、3-、4-或5-吡唑基、4-四氢吡喃基、2-、4-或5-噻唑基、3-、4-或5-异噻唑基、2-、4-或5-噁唑基、3-、4-或5-异噁唑基、2-、4-或5-咪唑基、1,2,3-或1,2,4-三唑基、1H-或2H-四唑基、2-、3-或4-吡啶基、2-、4-或5-嘧啶基、3-或4-哒嗪基、喹啉基、异喹啉基、吲哚基等、(25)C1-10卤代烷基如二氟甲基、三氟甲基、三氟乙基、三氯乙基等、(26)羟基亚胺基,或(27)烷基氧基亚胺基,如甲基氧基亚胺基、乙基氧基亚胺基等。
“可具有取代基的烃基”可具有1-5个选自上述(1)-(27)的取代基,并且当“烃基”为环烷基、环烯基、芳基或芳烷基时,其可具有1-4个含1-4个原子的低级烷基如甲基、乙基、丙基、异丙基、丁基等作为取代基,并且当其具有多于一个的取代基时,所述取代基可相同或不同。
“可被保护的氨基”中的氨基的保护基作为可被保护基保护的酸性基团中的“保护基”包括例如上述的“可具有取代基的烃”。
作为可被保护基保护的酸性基团中的保护基的“C1-6烷氧基”包括例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
由R1和R2表示的“可被保护的酸性基团”包括例如酯基团如甲氧基羰基、乙氧基羰基等,酰胺基如氨基甲酰基等。
由R1和R2表示的“任选被保护的酸性基团”包括例如酯基团如甲氧基羰基、乙氧基羰基等,酰胺基如氨基甲酰基等。
在本说明书中,由D和E表示的“主链含1-8个原子的间隔基”是指1-8个原子连续间隔。本文中可计算“主链中的原子”使得主链中的原子最小化。本文中,“主链含1-8个原子的间隔基”包括例如含1-8个选自以下的二价基团:可具有1-2个取代基的-CH2-的二价基、可具有1-2个取代基的-CH=CH-、-C≡C-、可具有取代基的-NH-、-CO-、-O-、-S-、-SO-、-SO2-。本文中亚甲基和氮原子的取代基与由上述环A表示的可具有取代基的环中的“取代基”具有相同含义,具体为,例如-CR101R102-、-(CR101R102)2-、-(CR101R102)3-、-(CR101R102)4-、-CO(CR101R102)2-、-CO(CR101R102)3-、-CO(CR101R102)4-、-NR103-、-CO-、-O-、-S-、-NR103CO-、-CONR103-、-NR103COCR101R102-、-CONR103CR101R102-、-C(R101)=C(R102)-、-C≡C-(其中R101到R103为氢原子或取代基,所述取代基与由上述环A表示的可具有取代基的环状基团中的“取代基”具有相同含义)等。
在本说明书中,由R3表示的“取代基”包括例如,(1)可具有取代基的烷基,(2)可具有取代基的烯基,(3)可具有取代基的炔基,(4)可具有取代基的碳环,(5)可具有取代基的杂环,(6)可被保护的羟基,(7)可被保护的巯基,(8)可被保护的氨基,(9)可具有取代基的氨基甲酰基,(10)可具有取代基的氨基磺酰基,(11)羧基,(12)烷氧基羰基(例如C1-6烷氧基羰基如甲氧基羰基、乙氧基羰基、叔丁氧基羰基等),(13)磺基,(14)亚磺基,(15)膦酰基,(16)硝基,(17)氰基,(18)酰胺基,(19)亚胺基,(20)二氢二羟硼基,(21)卤素(例如氟、氯、溴、碘等),(22)烷基亚硫酰基(例如C1-4烷基亚硫酰基如甲基亚硫酰基、乙基亚硫酰基等),(23)芳香环-亚硫酰基(例如C6-10芳香环-亚硫酰基如苯基磺酰基),(24)烷基磺酰基(例如C1-4烷基磺酰基如甲基磺酰基、乙基磺酰基等),(25)芳香环-磺酰基(例如C6-10芳香环-磺酰基如苯基磺酰基等),(26)酰基,(27)氧代,(28)硫代,(29)(C1-6烷氧基亚胺基)甲基(例如(甲氧基亚胺基)甲基等),(30)甲酰基,
(31)
(其中,环1为可具有取代基的环状基团,V为键或主链含1-8个原子的间隔基)等。
作为R3由表示的“取代基”包括例如,(1)可具有取代基的烷基,(2)可具有取代基的烯基,(3)可具有取代基的炔基,(4)可具有取代基的碳环,(5)可具有取代基的杂环,(6)可被保护的羟基,(7)可被保护的巯基,(8)可被保护的氨基,(9)可具有取代基的氨基甲酰基,(10)可具有取代基的氨基磺酰基,和(26)酰基,与由上述环A表示的可具有取代基的环状基团中的“取代基”具有相同含义。
在本说明书中,由环1表示的可具有取代基的环状基团中的“环状基团与由环A表示的可具有取代基的环状基团中的“环状基团”具有相同含义。
在本说明书中,由环1表示的可具有取代基的环状基团中的“取代基”包括例如(1)可具有取代基的烷基,(2)可具有取代基的烯基,(3)可具有取代基的炔基,(4)可具有取代基的碳环,(5)可具有取代基的杂环,(6)可被保护的羟基,(7)可被保护的巯基,(8)可被保护的氨基,(9)可具有取代基的氨基甲酰基,(10)可具有取代基的氨基磺酰基,(11)羧基,(12)烷氧基羰基(例如C1-6烷氧基羰基如甲氧基羰基、乙氧基羰基、叔丁氧基羰基等),(13)磺基,(14)亚磺基,(15)膦酰基,(16)硝基,(17)氰基,(18)酰胺基,(19)亚胺基,(20)二氢二羟硼基,(21)卤原子(例如氟、氯、溴、碘等),(22)烷基亚硫酰基(例如C1-4烷基亚硫酰基如甲基亚硫酰基、乙基亚硫酰基等),(23)芳香环-亚硫酰基(例如C6-10芳香环-亚硫酰基如苯基亚硫酰基),(24)烷基磺酰基(例如C1-4烷基磺酰基如甲基磺酰基、乙基磺酰基等),(25)芳香环-磺酰基(例如C6-10芳香环-磺酰基如苯基磺酰基),(26)酰基,(27)氧代,(28)硫代,(29)(C1-6烷氧基亚胺基)甲基(例如(甲氧基亚胺基)甲基等),(30)甲酰基,(31)
(其中环2为可具有取代基的环状基团,W为键或主链含1-8个原子的间隔基)等,并且1-5个所述取代基可位于可接受的位置上。
在本说明书中,作为由环1表示的可具有取代基的环状基团中的“取代基”包括例如,(1)可具有取代基的烷基,(2)可具有取代基的烯基,(3)可具有取代基的炔基,(4)可具有取代基的碳环,(5)可具有取代基的杂环,(6)可被保护的羟基,(7)可被保护的巯基,(8)可被保护的氨基,(9)可具有取代基的氨基甲酰基,(10)可具有取代基的氨基磺酰基,和(26)酰基,与由环A表示的可具有取代基的环状基团中的“取代基”具有相同含义。
在本说明书中,由环2表示的可具有取代基的环状基团中的“环状基团”与上述任选具有取代基的“环状基团”具有相同含义。
在本说明书中,由环2表示的可具有取代基的环状基团中的“环状基团”与由环A表示的可具有取代基的环状基团中的“环状基团”具有相同含义。
在本说明书中,由环2表示的可具有取代基的环状基团中的“取代基”与由环A表示的可具有取代基的环状基团中的“取代基”具有相同含义。
在本说明书中,由V表示的“主链含1-8个原子的间隔基”与由D和E表示的“主链含1-8个原子的间隔基”具有相同含义。
在本说明书中,由W表示的“主链含1-8个原子的间隔基”与由D和E表示的“主链含1-8个原子的间隔基”具有相同含义。
在本说明书中,由L表示的“任选被氧化的硫原子”是指-S-、-S(O)-和-SO2。
环A优选为C3-15单-环芳香碳环、或其部分或全部饱和的环、或含1-5个选自氧、氮和/或硫的杂原子的可部分或全部饱和的3-15元单-环芳香杂环,更优选为C3-8单-环芳香碳环、或其部分或全部饱和的环,进一步优选环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、环戊烯、环己烯、环庚烯、环辛烯、环戊二烯、环己二烯、环庚二烯、环辛二烯、或苯环。
环B优选为C3-15单-环芳香碳环、其部分或全部饱和的环,或含1-5个选自氧、氮和/或硫的杂原子的可部分或全部饱和的3-15元单-环芳香杂环,更优选为含1-3个选自氧、氮和/或硫的杂原子的可部分或全部饱和的3-8元单-环芳香杂环,进一步优选吡咯、咪唑、三唑、四唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、氮杂卓、二氮杂卓、呋喃、吡喃、氧杂卓、噻吩、噻喃、硫杂卓(thiepin)、噁唑、异噁唑、噻唑、异噻唑、呋咱、噁二唑、噁嗪、噁二嗪、氧氮杂卓、氧二氮杂卓、噻二唑、噻嗪、噻二嗪、硫氮杂卓、硫二氮杂卓、氮丙啶、氮杂环丁烷、吡咯啉、吡咯烷、咪唑啉、咪唑烷、三唑啉、三唑烷、四唑啉、四唑烷、吡唑啉、吡唑烷、二氢吡啶、四氢吡啶、哌啶、二氢吡嗪、四氢吡嗪、哌嗪、二氢嘧啶、四氢嘧啶、全氢嘧啶、二氢哒嗪、四氢哒嗪、全氢哒嗪、二氢氮杂卓、四氢氮杂卓、全氢氮杂卓、二氢二氮杂卓、四氢二氮杂卓、全氢二氮杂卓、环氧乙烷、氧杂环丁烷、二氢呋喃、四氢呋喃、二氢吡喃、四氢吡喃、二氢氧杂卓、四氢氧杂卓、全氢氧杂卓、硫杂环丙烷、硫杂环丁烷、二氢噻吩、四氢噻吩、二氢噻喃、四氢噻喃、二氢硫杂卓、四氢硫杂卓、全氢硫杂卓、二氢噁唑、四氢噁唑(噁唑烷)、二氢异噁唑、四氢异噁唑(异噁唑烷)、二氢噻唑、四氢噻唑(噻唑烷)、二氢异噻唑、四氢异噻唑(异噻唑烷)、二氢呋咱、四氢呋咱、二氢噁二唑、四氢噁二唑(噁二唑烷)、二氢噁嗪、四氢噁嗪、二氢噁二嗪、四氢噁二嗪、二氢氧氮杂卓、四氢氧氮杂卓、全氢氧氮杂卓、二氢氧二氮杂卓、四氢氧二氮杂卓、全氢氧二氮杂卓、二氢噻二唑、四氢噻二唑(噻二唑烷)、二氢噻嗪、四氢噻嗪、二氢噻二嗪、四氢噻二嗪、二氢硫氮杂卓、四氢硫氮杂卓、全氢硫氮杂卓、二氢硫二氮杂卓、四氢硫二氮杂卓、全氢硫二氮杂卓、吗啉、硫代吗啉、氧硫杂环己烷、二氧杂环戊烷、二氧杂环己烷、二硫杂环戊烷或二硫杂环戊烷环。
Y优选为碳原子。
Z优选为碳原子。
优选为双键。
R1优选为-COORA(其中RA为氢或C1-8烷基)、-CONRBSO2RC(其中RB为氢或C1-8烷基,RC为C1-8烃)、-SO2NRBCORC(其中所有符号与前述具有相同含义)、-SO2NHCORC(其中RC与前述具有相同含义),
R2优选为-COORA、-CONRBSO2RC、-SO2NRBCORC(其中,RA,RB和RC与前述具有相同含义),
更优选-COOH、-CONHSO2RC、-SO2NHCORC(其中所有符号与前述具有相同含义),
或
由RA和RB表示的C1-8烷基包括例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基等。
由RC表示的C1-8烃包括例如C1-8烷基如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基等,C3-8环烷基如环丙基、环丁基、环戊基、环己基等,C2-8烯基如乙烯基、烯丙基、2-甲基烯丙基、2-丁烯基、3-丁烯基、3-辛烯基等,C2-8炔基如乙炔基、2-丙炔基、3-己炔基等,C3-8环烯基如环丁烯基、环戊烯基、环己烯基等,C6-8芳基如苯基等,C7-8芳烷基如苄基、苯基乙基等,(C3-8环烷基)-(C1-4烷基)如环己基甲基、环己基乙基、环戊基甲基、1-甲基-1-环戊基甲基等。
D优选为键或主链含1-6个原子的间隔基,更优选为含有以下1-6个的组合的二价基团:键、可具有1-2个取代基的-CH2-、可具有取代基的-NH-、-CO-、-O-、-S-、-SO-和-SO2-,进一步优选:键、-CO-(CH2)2-、-CO-(CH2)3-、-CO-(CH2)4-、C1-6亚烷基(例如亚甲基、1,2-亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基、1,6-亚己基等),特别优选-CO-(CH2)2-、-CO-(CH2)3-、-CO-(CH2)4-、C1-4亚烷基。
E优选为键或主链含1-5个原子的间隔基,更优选含有以下1-5个的组合的二价基:键、可具有1-2个取代基的-CH2-、可具有取代基的-NH-、-CO-、-O-、-S-、-SO-和-SO2-,进一步优选:键、-CO-(CH2)2-、-CO-(CH2)3-、-CO-(CH2)4-、C1-4亚烷基(例如亚甲基、1,2-亚乙基、1,3-亚丙基、1,4-亚丁基等),特别优选键或C1-4亚烷基。
R3优选为
(其中所有符号与前述具有相同含义),更优选
(其中所有符号与前述具有相同含义)。
环1的取代基优选为,
(其中所有符号与前述具有相同含义)、羟基、卤素、硝基、氨基、C5-10碳环、5-10元杂环、或C1-20直链或支链烷基、烯基或炔基(其中任选1-3个碳原子可被氧、硫、氮取代)、苯环、噻吩环、C4-7碳环、羰基或羰基氧基,并且其可进一步被1-3个卤素、羟基、羧基、叠氮基或硝基取代,更优选
(其中所有符号与前述具有相同含义)、或C1-10直链或支链烷基、烯基或炔基(其中任选1-2个碳原子可被氧、硫、氮取代)、苯环、噻吩或C4-7碳环,并且其可进一步被1-2个羟基取代,更优选
(其中所有符号与前述具有相同含义)、或C1-10直链或支链烷基、烯基或炔基(其中任选1-2个碳原子可被氧取代)、苯环、C5-7碳环,最优选
(其中所有符号与前述具有相同含义)、正丁基、正戊基、正己基、正庚基、正辛基、正壬基、正丁基氧基、正戊氧基、正己氧基、正庚基氧基、正辛基氧基、正壬基氧基、(2E)-2-戊烯基氧基、(2E)-2-己烯基氧基、(2E)-2-庚烯基氧基、(2E)-2-辛烯基氧基、(2E)-2-壬烯基氧基、7-辛烯基氧基、2-辛炔基氧基、(2E)-2,7-辛二烯基氧基、2-苯基乙氧基、3-苯基丙氧基、4-苯基丁氧基或5-苯基戊氧基。
环2的取代基优选为1-3个任意选自以下的取代基:硝基、氨基、羟基、C1-8烷基、卤素、C1-8烷氧基、C1-8烷硫基、被1-3个卤原子取代的C1-4烷基、被1-3个卤原子取代的C1-4烷氧基、C5-10碳环和5-10元杂环,更优选1-2个任意选自以下的取代基:羟基、甲基、乙基、丙基、正丁基、正戊基、正己基、氟、氯、溴、甲氧基、乙氧基、丙氧基、丁氧基、三氟甲基、甲硫基、苯基和吡啶基。
环1优选为C5-10碳环、或含1-5个选自氧、氮和/或硫的可部分或全部饱和的5-10元单-或双-环芳香碳环,更优选为C5-10单-或双-环芳香碳环、其部分或全部饱和的环、螺双环碳环和桥接双-环碳环,更优选环戊烷、环己烷、环庚烷、环辛烷、环壬烷、环癸烷、环戊烯、环己烯、环庚烯、环辛烯、环戊二烯、环己二烯、环庚二烯、环辛二烯、苯、并环戊二烯、全氢并环戊二烯、薁、全氢薁、茚、全氢茚、茚满、萘、二氢萘、四氢萘、全氢萘、螺[4.4]壬烷、螺[4.5]癸烷、螺[5.5]十一癸烷、双环[2.2.1]庚烷、双环[2.2.1]庚-2-烯、双环[3.1.1]庚烷、双环[3.1.1]庚-2-烯、双环[2.2.2]辛烷、双环[2.2.2]辛-2-烯、金刚烷和降金刚烷环,特别优选苯、萘和吡啶环。
环2优选为C5-10碳环、或含1-3个选自氧、氮和/或硫的可部分或全部饱和的5-10元单-或双-环芳香碳环,更优选为C5-10单-或双-环芳香碳环、其部分或全部饱和的环、螺双环碳环和桥接双-环碳环,进一步优选环戊烷、环己烷、环庚烷、环辛烷、环壬烷、环癸烷、环戊烯、环己烯、环庚烯、环辛烯、环戊二烯、环己二烯、环庚二烯、环辛二烯、苯、并环戊二烯、全氢并环戊二烯、薁、全氢薁、茚、全氢茚、茚满、萘、二氢萘、四氢萘、全氢萘、螺[4.4]壬烷、螺[4.5]癸烷、螺[5.5]十一癸烷、双环[2.2.1]庚烷、双环[2.2.1]庚-2-烯、双环[3.1.1]庚烷、双环[3.1.1]庚-2-烯、双环[2.2.2]辛烷、双环[2.2.2]辛-2-烯、金刚烷或降金刚烷环,特别优选苯、萘、茚满或吡啶环。
V优选为键或主链含1-5个原子的间隔基,更优选:键、含有选自以下1-6个的组合的二价基:任选具有1-2取代基的-CH2-、任选具有1-2取代基的-CH=CH-、-C≡C-、任选具有取代基的-NH-、-CO-、-O-、-S-、-SO-和SO2-,更优选-CONR103-、-NR103CO-、-CR101R102NR103-、-NR103CR101R102-、-NR103COCR101R102-、-CONR103CR101R102-、-O-CR101R102-、-CR101R102-O-、-NR103COCR101=CR102-、-CR101=CR102CONR103-、-NR103-CR101R102-、-CR101R102-NR103-、-(CR101R102)2-、-CR101=CR102-、-C≡C-(其中,R101到R103为氢或与由上述环A表示的可具有取代基的环状基团中的“取代基”具有相同含义),特别优选
(其中R110为氢或C1-8烷基,箭头表示其与环A连接)。
W优选为键或主链含1-6个原子的间隔基,更优选含有选自以下1-6个的组合的二价基:键、任选具有1-2取代基的-CH2-、任选具有取代基的-NH-、-CO-、-O-、-S-、-SO-、-SO2-,进一步优选:-O-CH2-、-O-(CH2)2-、-O-(CH2)3-、-O-(CH2)4-、-O-(CH2)5-、-CH2-O-、-(CH2)2-O-、-(CH2)3-O-、-(CH2)4-O-、-(CH2)5-O-、-O-(CH2)3-O-、-O-(CH2)4-O-、-O-(CH2)5-O-、C1-6亚烷基。
优选为3,4-二氢-2H-1,4-苯并噁嗪、色满、2,3-二氢-1,4-苯并氧硫杂芑、2,3-二氢-1,4-苯并二氧杂芑、3,4-二氢-2H-1,4-苯并噻嗪、硫代色满、2,3-二氢-1,4-苯并二硫杂芑、1,2,3,4-四氢喹喔啉、1,2,3,4-四氢喹啉、1,2,3,4-四氢萘、2H-苯并吡喃、2H-硫代苯并吡喃、1,2-二氢喹啉、1,2-二氢萘、4H-1,4-苯并噁嗪、4H-苯并吡喃、1,4-苯并氧硫杂芑、1,4-苯并二氧杂芑、4H-1,4-苯并噻嗪、4H-硫代苯并吡喃、1,4-苯并二硫杂芑、1,5-二氮杂萘、1,8-二氮杂萘、2,7-二氮杂萘、1,4-二氢萘、萘、喹啉、异喹啉、喹喔啉、1,2,3,4-四氢异喹啉、3,4-二氢-1H-异苯并吡喃、3,4-二氢-1H-异硫代苯并吡喃、1,2-二氮杂萘、2,3-二氮杂萘、4H-苯并吡喃-4-酮、4(1H)-喹啉酮、4H-硫代苯并吡喃-4-酮、3,4-二氢-2(1H)-喹啉酮、2(1H)-喹啉酮、2H-苯并吡喃-2-酮、茚满、二氢吲哚、2,3-二氢-1-苯并呋喃、1H-吲哚、1-苯并呋喃、1-苯并噻吩、1H-吲唑、1,2-苯并异噁唑、1,2-苯并异噻唑、1H-苯并咪唑、1,3-苯并噁唑或1,3-苯并噻唑环,更优选3,4-二氢-2H-1,4-苯并噁嗪、色满、2,3-二氢-1,4-苯并氧硫杂芑、2,3-二氢-1,4-苯并二氧杂芑、3,4-二氢-2H-1,4-苯并噻嗪、硫代色满、2,3-二氢-1,4-苯并二硫杂芑、1,2,3,4-四氢喹喔啉、1,2,3,4-四氢喹啉、1,2,3,4-四氢萘、2H-苯并吡喃、2H-硫代苯并吡喃、1,2-二氢喹啉、1,2-二氢萘、4H-1,4-苯并噁嗪、4H-苯并吡喃、1,4-苯并氧硫杂芑、1,4-苯并二氧杂芑、4H-1,4-苯并噻嗪、4H-硫代苯并吡喃、1,4-苯并二硫杂芑、1,4-二氢萘、萘、喹啉、异喹啉、喹喔啉、1,2,3,4-四氢异喹啉、3,4-二氢-1H-异苯并吡喃、3,4-二氢-1H-异硫代苯并吡喃、1,2-二氮杂萘、2,3-二氮杂萘、4H-苯并吡喃-4-酮、4(1H)-喹啉酮、4H-硫代苯并吡喃-4-酮、3,4-二氢-2(1H)-喹啉酮、2(1H)-喹啉酮、2H-苯并吡喃-2-酮环或1H-吲哚环,更优选3,4-二氢-2H-1,4-苯并噁嗪、3,4-二氢-2H-1,4-苯并噻嗪、1,2,3,4-四氢喹喔啉、1,2,3,4-四氢喹啉、1,2-二氢喹啉、4H-1,4-苯并噁嗪、4H-1,4-苯并噻嗪、喹啉、异喹啉、喹喔啉、1,2,3,4-四氢异喹啉、1,2-二氮杂萘、2,3-二氮杂萘、4(1H)-喹啉酮、3,4-二氢-2(1H)-喹啉酮、2(1H)-喹啉酮、二氢吲哚或1H-吲哚环,特别优选3,4-二氢-2H-1,4-苯并噁嗪、1,2,3,4-四氢喹啉、1,2-二氢喹啉、1H-吲哚环。
在式(I)所示化合物,优选下式(I-a)所示的化合物,
(其中所有符号与前述具有相同含义),更优选下式(I-b)所示的化合物,
(其中所有符号与前述具有相同含义),进一步优选下式(I-X)所示的化合物,
(其中所有符号与前述具有相同含义)。在式(I-X)中,R30为氢或取代基,所述取代基与由环A所述的“任选具有取代基的环状基团”中的“取代基”具有相同含义。R30优选为氢、羟基、任选被1-3个卤素取代的C1-4烷基、C1-4烷氧基、氨基、硝基或卤素。
在本发明中,优选的式(I)所示化合物包括例如,
(1)4-(3-羧基丙基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(2)4-(3-羧基丙基)-8-({(2E)-3-[4-(4-苯基丁基)苯基]-2-丙烯酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(3)4-[8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸,
(4)4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苄基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(5)4-(3-羧基丙基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(6)4-(3-羧基丙基)-8-{2-[4-(4-苯基丁氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(7)(2S)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(8)(2R)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(9)4-(3-羧基丙基)-8-({4-[2-(2,3-二氢-1H-茚-2-基)乙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(10)4-(3-羧基丙基)-8-({4-[(5-苯基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(11)4-(3-羧基丙基)-8-({4-[(7-苯基庚基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(12)4-(3-羧基丙基)-8-({4-[(4-甲基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(13)4-(3-羧基丙基)-8-{[4-(4-苯氧基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(14)4-(3-羧基丙基)-8-({4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(15)4-(3-羧基丙基)-8-({4-[4-(4-氟苯基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(16)4-(3-羧基丙基)-8-({4-[4-(2-甲基苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(17)4-(3-羧基丙基)-8-({4-[4-(2-氟苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(18)4-(3-羧基丙基)-8-({4-[4-(2-氯苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(19)4-(3-羧基丙基)-8-[(4-{4-[2-(三氟甲基)苯氧基]丁氧基}苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(20)4-(3-羧基丙基)-8-({4-[3-(2-甲基苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(21)4-(2-({[(4-甲基苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(22)4-(2-{[(甲基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(23)4-(2-{[(苄基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(24)4-(3-羧基丙基)-8-{(E)-2-[4-(4-苯氧基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(25)4-(3-羧基丙基)-8-{(E)-2-[4-(2,3-二氢-1H-茚-2-基甲氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(26)4-(3-羧基丙基)-8-((E)-2-{4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(27)4-(3-羧基丙基)-8-((E)-2-{4-[(5-苯氧基戊基)氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(28)4-(3-羧基丙基)-8-((E)-2-{4-[4-(4-甲氧基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(29)4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-氟苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(30)4-(3-羧基丙基)-8-{(E)-2-[4-(3-苯氧基丙氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(31)4-(3-羧基丙基)-8-((E)-2-{4-[3-(2-氯苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(32)4-(3-羧基丙基)-8-{2-[4-(4-苯氧基丁氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,
(33)4-[8-{2-[4-(4-苯基丁氧基)苯基]乙基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸,
(34)4-[8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸,
(35)4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(36)4-(2-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,
(37)4-氧代-4-(8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸,和
(38)4-(3-羧基丙基)-8-((4-(4-苯基丁氧基)苄基)氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸。
另外,本发明优选的化合物是在表1-57中所述的化合物和实施例中所示的化合物,及其盐、其溶剂化物、或其前药。
在各表中,R4为任选具有取代基的烷基、任选具有取代基的烯基、任选具有取代基的炔基、或
其中所有符号与前述具有相同含义。
表1
表2
表3
表4
表5
表6
表7
表8
表9
表10
表11
表12
表13
表14
表15
表16
表17
表18
表19
表20
表21
表22
表23
表24
表25
表26
表27
表28
表29
表30
表31
表32
表33
表34
表35
表36
表37
表38
表39
表40
表41
表43
表44
表45
表46
表47
表49
表50
表51
表53
表56
[本发明化合物的制备方法]
本发明的式(I)所示化合物可通过已知方法制备,例如,以下方法和/或实施例中所述方法的组合方法,实施例中所述方法是Comprehensive Organic Transformations:A Guide to Functional GroupPreparations,2nd Edition(Richard C.Larock,John Wiley&Sons Inc,1999)等中所述的更好的改进的方法。在以下每个制备方法中,可使用起始化合物的盐。可使用上述化合物(I)的盐。
a)在式(I)所示化合物中,其中
为由下式所示环
R1为羧基,R2为羧基或5-四唑基的化合物,即下式(I-1)所示化合物
(其中R200为羧基或5-四唑基,其它符号与上述含义相同)可通过下述方法制备。
式(I-1)所示化合物的制备为:可使下式(II)所示化合物
(其中R200-1为被保护基保护的羧基或5-四唑基,R3-1和E1的含义同R3和E,其中由R3-1和E1表示的基团中包括的羧基、羟基、氨基或巯基如果需要可被保护)与下式(III)所示化合物反应,
X-D1-CO2R100-1 (III)
(其中X为离去基团,诸如例如卤素,甲磺酰氧基,甲苯磺酰氧基,氧代等,R100-1为羧基的保护基,D1的含义同D,由R3-1和E1表示的基团中包含的羧基、羟基、氨基或巯基如果需要被保护),任选然后进行保护基的脱保护反应。
其中在式(III)所示化合物中X-D1为活性酰基的化合物,即下式(III-1)所示化合物,
(其中D1-1表示主链含1-7个原子的间隔基,其中由R3-1和E1表示的基团中包含的羧基、羟基、氨基或巯基如果需要被保护,并且其它符号与上述具有相同含义)和式(II)所示化合物的反应可如下进行,例如,
(1)使用酰基卤的方法,
(2)使用混合酸酐的方法,
(3)使用缩合剂的方法,等。
具体说明上述方法:
(1)使用酰基卤的方法例如可如下进行:使羧酸与酸-卤化剂(例如草酰氯、亚硫酰氯等)在有机溶剂中(例如氯仿、二氯甲烷、二乙醚、四氢呋喃等)、或在没有溶剂条件下反应,反应温度为约-20℃到回流温度,然后将如此得到的酰基卤与胺在碱(例如吡啶、三乙胺、二甲基苯胺、二甲基氨基吡啶、二异丙基乙基胺等)的存在下,在有机溶剂(例如氯仿、二氯甲烷、二乙醚、四氢呋喃、乙腈、乙酸酯等)中在约0-40℃下反应。另外,反应也可如下进行:使如此得到的酰基卤与胺在有机溶剂(例如二氧杂环己烷、四氢呋喃、二氯甲烷等)中反应,使用碱性水溶液(例如碳酸氢钠、氢氧化钠的水溶液等),在存在或不存在相转移催化剂(例如四铵盐如四丁基氯化铵、三乙基苄基氯化铵、三正辛基甲基氯化铵、三甲基癸基氯化铵、四甲基溴化铵等)在约0-40℃下反应;
(2)使用混合酸酐的方法例如可如下进行:使羧酸与酰基卤(例如新戊酰基氯、甲苯磺酰基氯、甲磺酰基氯等)或酸的衍生物(例如氯乙基甲酸酯、氯异丁基甲酸酯等)在有机溶剂(例如氯仿、二氯甲烷、二乙醚、四氢呋喃等)中、或在没有溶剂的条件下,在碱(吡啶、三乙胺、二甲基苯胺、二甲基氨基吡啶、二异丙基乙基胺等)的存在下在0-40℃下反应,然后使如此得到的混合酸酐与胺在有机溶剂(例如氯仿、二氯甲烷、二乙醚,四氢呋喃等)中在约0-40℃下反应;
(3)使用缩合剂的方法例如可如下进行:使羧酸与胺在有机溶剂(例如氯仿、二氯甲烷、二甲基甲酰胺、二乙醚、四氢呋喃等)中、或在没有溶剂的条件下,在存在或不存在碱(例如吡啶、三乙胺、二甲基苯胺、二甲基氨基吡啶等)的条件下,使用缩合剂(例如1,3-双环己基碳二亚胺(DCC)、1-乙基-3-[3-(二甲基氨基)丙基]碳二亚胺(EDC)、1,1′-羰基二咪唑(CDI)、2-氯-1-甲基吡啶碘化鎓、1-丙基膦酸环酐(PPA)等),在存在或不存在1-羟基苯并三唑(1-HOBt)的条件下在约0-40℃温度下反应。
反应(1),(2)和(3)理想地在惰性气体(氩气、氮气)和无水条件下进行。
式(III)所示化合物(其中X-D1具有甲酰基),即下式(III-2)所示化合物
(其中所有符号与前述具有相同含义)和式(II)所示化合物的反应例如如下进行:在有机溶剂(例如四氢呋喃、二乙醚、二氯乙烷、二氯甲烷、二甲基甲酰胺、乙酸、甲醇、乙醇或其混合物等)中,在还原剂(三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠、氢氧化锌、二异丁基氢化铝等)的存在下,在在约0-40℃的温度下,或者在溶剂(例如醚如四氢呋喃、二氧杂环己烷、二甲氧基乙烷、二乙醚等;醇如甲醇、乙醇等;苯类如苯、甲苯等;酮如丙酮、甲基乙基酮等;腈如乙腈等;酰胺如二甲基甲酰胺等;水、乙酸乙酯、乙酸,或上述两种或多种的混合物等)中,在催化剂(例如钯-碳、钯黑、氢氧化钯、氧化钯、兰铌镍等)的存在下,在常压或加压氢气氛下,在约0-200℃温度下进行。
羧基、羟基、氨基、巯基或四唑基的保护基的脱保护反应是公知的并且包括例如(1)碱水解,(2)酸性条件下的脱保护,(3)通过水合脱保护,(4)甲硅烷基的脱保护,(5)使用金属的脱保护反应,(6)使用金属配合物的脱保护反应等。
具体说明这些方法:
(1)通过碱水解的脱保护反应例如如下进行:在有机溶剂(甲醇、四氢呋喃、1,4-二氧杂环己烷等)中使用碱金属的氢氧化物(氢氧化钠、氢氧化钾、氢氧化锂等)、碱土金属的氢氧化物(氢氧化钡、氢氧化钙等)、碳酸盐(碳酸钠、碳酸钾等)或其溶液、或其混合物在0-40℃下进行。
(2)在酸性条件下的脱保护反应例如如下进行:在有机溶剂(二氯甲烷、氯仿、二氧杂环己烷、乙酸乙酯、苯甲醚等)中,在有机酸(乙酸、三氟乙酸、甲磺酸、对甲苯磺酸等)或无机酸(氢氯酸、硫酸等)或其混合物(氢溴酸/乙酸等)中,在存在或不存在2,2,2-三氟乙醇条件下,在0-100℃下进行;
(3)通过水合的脱保护反应例如如下进行:在溶剂(例如醚如四氢呋喃、1,4-二氧杂环己烷、二甲氧基乙烷、二乙醚等;醇如甲醇、乙醇等;苯类如苯、甲苯等;酮如丙酮、甲基乙基酮等;腈如乙腈等;酰胺如二甲基甲酰胺等;水、乙酸乙酯、乙酸,或上述两种或多种溶剂的混合物)中,在催化剂(钯-碳、钯黑、氢氧化钯、氧化钯、兰铌镍等)的存在下,在常压或加压氢气氛下,或在甲酸铵的存在下,在0-200℃下进行;
(4)甲硅烷基的脱保护反应例如如下进行:在可与水混溶的有机溶剂(四氢呋喃、乙腈等)中使用四丁基氟化铵在0-40℃温度下进行;
(5)使用金属的脱保护反应例如如下进行:在酸性溶剂(乙酸、pH为4.2-7.2的缓冲液,或其溶液和有机溶剂如四氢呋喃等的混合物等)中,在锌粉的存在下在0-40℃的温度下在任选超声处理条件下进行;
(6)使用金属配合物的脱保护反应例如如下进行:在有机溶剂(二氯甲烷、二甲基甲酰胺、四氢呋喃、乙酸乙酯、乙腈、二氧杂环己烷、乙醇等)、水或其混合物中,在捕获剂(三丁基氢化锡、三乙基硅烷、双甲酮、吗啉、二乙基胺、吡咯烷等)、有机酸(乙酸、甲酸、2-乙基己烷等)和/或有机酸的盐(2-乙基己酸钠、2-乙基己酸钾等)的存在下,在存在或不存在膦试剂(三苯基膦等)的条件下,使用金属配合物(四(三苯基膦)钯(O)、二(三苯基膦)二氯化钯(II)、乙酸钯(II)、三(三苯基膦)氯化铑(I)等,在0-40℃温度下进行。
除了上述之外,还可使用例如T.W.Greene,Protective Groups inOrganic Synthesis,Wiley,New York,1999中所述方法进行脱保护反应。
用于羧基的保护基包括例如甲基、乙基、烯丙基、叔丁基、三氯乙基、苄基(Bn)、苯甲酰甲基、对甲氧基苄基、三苯甲基、2-氯三苯甲基或含有这些结构的固体载体等。
用于羟基的包括机包括例如甲基、三苯甲基、甲氧基甲基(MOM)、1-乙氧基乙基(EE)、甲氧基乙氧基甲基(MEM)、2-四氢吡喃基(THP)、三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、叔丁基二甲基甲硅烷基(TBDMS)、叔丁基二苯基甲硅烷基(TBDPS)、乙酰基(Ac)、新戊酰基、苯甲酰基、苄基(Bn)、对甲氧基苄基、烯丙基氧基羰基(Alloc)或2,2,2-三氯乙氧基羰基(Troc)等。
用于氨基的保护基包括例如苯基甲基氧基羰基、叔丁氧基羰基、烯丙基氧基羰基(Alloc)、1-甲基-1-(4-联苯基)乙氧基羰基(Bpoc)、三氟乙酰基、9-芴基甲氧基羰基、苄基(Bn)、对甲氧基苄基或苄氧基甲基(BOM)、2-(三甲基甲硅烷基)乙氧基甲基(SEM)等。
用于巯基的保护基包括例如苄基、甲氧基苄基、甲氧基甲基(MOM)、2-四氢吡喃基(THP)、二苯基甲基、乙酰基(Ac)等。
用于四唑基的保护基包括例如叔丁基、甲氧基羰基、苄氧基羰基、叔丁氧基羰基、烯丙基氧基羰基(Alloc)、1-甲基-1-(4-联苯基)乙氧基羰基(Bpoc)、三氟乙酰基、9-芴基甲氧基羰基、苄基(Bn)、α,α-二甲基苄基、三苯甲基、对甲氧基苄基、苄氧基甲基(BOM)、2-(三甲基甲硅烷基)乙氧基甲基(SEM)、三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)或2-氰基乙基等。
用于羧基、羟基、氨基、巯基或四唑基的保护基不限于上述所列举的那些,可被容易地和选择性地除去的基团是可接受的。例如使用T.W.Greene,Protective Groups in Organic Synthesis,Wiley,New York,1999中所述那些基团。
本领域技术人员可以理解,本发明的目标化合物可通过选择这些脱保护反应而容易地制备。
b)在式(I)所示化合物中,其中
为下式表示的环
R1为羧基,R2为-CONHSO2R100的化合物,即下式(I-2)所示化合物,
(其中R100与前述具有相同含义)的制备为:使其中R200为羧基的式(I-1)所示化合物,即下式(I-1-a)所示化合物
(其中所有符号与前述具有相同含义)与由H2NSO2R200所示化合物经历酰胺化反应,然后进行羧酸保护基的脱保护反应。
酰胺化反应和羧酸保护基的脱保护反应是已知的,并且它们可通过前述相同的方法进行。
c)在(I)式所示化合物中,其中
为由下式表示的环
R1为-CONHSO2R100,R2为羧基的化合物,即下式(I-3)所示化合物
(其中所有符号与前述具有相同含义)的制备为:使其中R1为羧基且R2为CO2R100-1的式(I-1)所示化合物,即下式(I-1-b)所示化合物,
(其中所有符号与前述具有相同含义)和式H2NSO2R200所示化合物经历酰胺化反应,然后进行羧酸保护基的脱保护反应。
酰胺化反应和保护基的脱保护反应是已知的,并且它们可通过前述相同的方法进行。
d)在式(I)所示化合物中,其中
为由下式表示的环
R1为羧基,R2为
的化合物,即下(I-4)式所示化合物,
(其中Q为氧或硫)的制备为:使下式(I-5)所示化合物,
(其中所有符号与前述具有相同含义)与羰基二咪唑(CDI)或硫代羰基二咪唑(TCDI)反应,然后进行羧基保护基的脱保护反应。
式(I-5)所示化合物和CDI或TCDI的反应是已知的,并且可在例如CDI或TCDI的存在下在惰性有机溶剂(乙酸乙酯、四氢呋喃、二氯甲烷、氯仿、苯、甲苯等)中,在-78℃到回流温度下进行。
环化反应是已知的并且可例如如下进行:使所得化合物经历化合物(I-5)与CDI或TCDI的反应,然后进一步经历在存在或不存在酸性催化剂(例如路易斯酸如三氟硼烷-二乙醚配合物、氯化钛、氯化铁、氯化铝等;无机酸如盐酸、硫酸、硝酸等;有机酸如乙酸、丙酸、乳酸、草酸、苯甲酸等;硅胶;等)或碱(例如吡啶、三乙胺、二甲基苯胺、二甲基氨基吡啶、二异丙基乙基胺、二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)、1,5-二氮杂双环[4.3.9]壬-5-烯(DBN)等)条件下,在惰性有机溶剂(氯仿、二氯甲烷、二乙醚、四氢呋喃、二氧杂环己烷、N,N-二甲基甲酰胺等)中,在-78℃到回流温度下进行的反应。
羧基保护基的脱保护反应是已知的并且它们可通过前述相同的方法进行。
式(II)所示化合物可根据图解1中所述方法制备。式(I-4)所示化合物可根据图解2中所述方法制备。在这些反应图解中,所有符号与前述具有相同含义。
反应图解1
反应图解2
式(III),(III-1),(III-2),(IV)和(V)所示化合物,它们作为起始原料或试剂,是本领域公知的,并且可通过已知方法容易地制备,所述方法为″Comprehensive Organic Transformations:A Guide to FunctionalGroup Preparations 2nd Edition(Richard C.Larock,John Wiley&SonsInc,1999)″中所述方法。
在本发明式(I)所示化合物中,除了上述化合物之外的化合物可通过本说明书实施例中所述方法和/或已知方法的组合方法制备,例如已知方法为″Comprehensive Organic Transformations:A Guide to FunctionalGroup Preparations 2nd Edition(Richard C.Larock,John Wiley&SonsInc,1999)″中所述方法。
在本发明的各反应中,反应伴随加热,这是本领域技术人员公知的,可在水浴、油浴、沙浴中进行,或者可使用微波进行。
在本发明的各反应中,如果需要,可使用承载在高分子量聚合物(例如聚苯乙烯、聚丙烯酰胺、聚丙烯、聚乙二醇等)上的反应试剂。
在本说明书的各反应中,反应产物可通过常规方法纯化,所述常规方法为例如在大气气氛或减压条件下蒸馏,使用硅胶或硅酸镁的高效液相色谱法、薄层色谱法或离子交换色谱法,洗涤,重结晶等,纯化可在各个反应后进行,或者在一系列反应后进行。
在本发明中,本领域的技术人员可以容易地理解:
符号表示与其连接的取代基在平面后(即α-位),
符号表示与其连接的取代基以α-位、β-位、或其混合的方式连接,并且
除非另外指明,本发明包括所有的异构体。例如,烷基、烯基、炔基、烷氧基、烷硫基、亚烷基、亚烯基或亚炔基包括直链或支链基团。另外,在双键、环、稠环上的异构体(E-,Z-,顺式-,反式-异构体)、由不对称碳原子产生的异构体(R-,S-,α-,β-异构体,对映异构体,非对映异构体)、具有光学活性的活学活性异构体(D-,L-,d-,1-异构体)、互变异构体、通过色谱分离产生的极性化合物(极性较大的化合物,极性较小的化合物)、平衡态化合物、rotational异构体、以任选比例混合的其混合物,和外消旋混合物也包括在本发明的范围内。
式(I)所示化合物的盐包括所有可药用盐,优选无毒的水溶性可药用盐。优选的盐包括例如碱金属(钾、钠、锂等)的盐、碱土金属(钙、镁等)的盐、铵盐(四甲基铵盐、四丁基铵盐等)、有机胺盐(三乙胺、甲基胺、二甲基胺、环戊基胺、苄基胺、苯基乙基胺、哌啶、单乙醇胺、二乙醇胺、三(羟基甲基)甲基胺、赖氨酸、精氨酸、N-甲基-D-葡糖胺等)、酸加成盐(无机酸盐如氢氯酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、硝酸盐等;有机酸盐如乙酸盐、三氟乙酸盐、乳酸盐、酒石酸盐、草酸盐、富马酸盐、马来酸盐、苯甲酸酯、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、2-羟乙基磺酸盐、葡糖醛酸盐、葡糖酸盐等;等)。
式(I)所示化合物的N-氧化物表示其中氮原子被氧化的式(I)所示化合物,另外,本发明化合物的N-氧化物可转化为碱(土)金属盐、铵盐、有机胺盐或酸加成盐。
式(I)所示化合物的适当的溶剂化物包括例如水的溶剂化物或醇溶剂(乙醇等)的溶剂化物。优选溶剂为无毒的和水溶性的。在本发明中,溶剂化物包括碱(土)金属的盐、铵盐、有机胺盐、酸加成盐或N-氧化物的溶剂化物。
本发明的化合物可通过已知方法转化为前述的溶剂化物。
式(I)所示化合物的前药是指在体内通过酶、胃酸等转化为化合物(I)的化合物。
当式(I)所示化合物具有氨基时,式(I)所示化合物的前药为,氨基被酰基化、烷基化、磷酰基化(例如式(I)所示化合物的氨基被二十碳烷酸化、丙氨酰基化、戊基氨基酰基化,(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲氧基酰基化、四氢呋喃基化、吡咯烷基甲基化、新戊酰基氧基甲基化、乙酰氧基甲基化、叔丁基化等);当式(I)所示化合物具有羟基时,式(I)所示化合物的前药为,羟基被酰基化、烷基化、磷酰基化、硼酸化(例如式(I)所示化合物的羟基被乙酰基化、棕榈酰基化、丙酰基化、新戊酰基化、琥珀酰基化、富马酰基化、丙氨酰基化、二甲基氨基甲基酰基化等);当式(I)所示化合物具有羧基时,式(I)所示化合物的前药为,羧基被酯化或酰胺化(例如式(I)所示化合物的羧基转化为乙基酯、苯基酯、羧基甲基酯、二甲基氨基甲基酯、新戊酰基氧基甲基酯、乙氧基羰基氧基乙基酯、2-苯并呋喃酮基酯,(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基酯、环己基羰基乙基酯、甲酰胺等)等,这些化合物可通过已知方法制备。化合物(I)的前药可为水合物或非水合物。另外,式(I)所示化合物的前药在如″Development of pharmaceuticals″Vol.7,1990年中的″Molecular Design″,163-198页中所述的生理条件下可转化为式(I)所示化合物。式(I)所示化合物可用同位素标记(例如3H、14C、35S、125I等)。
式(I)所示化合物的毒性非常低,可用于药用。
因为式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药拮抗cysLT2受体,因此,可用作气道收缩抑制剂、炎症性细胞(例如噬酸性粒细胞、噬中性粒细胞、淋巴细胞、噬碱性粒细胞等)浸润的抑制剂、粘液分泌抑制剂或气道高敏性抑制剂。式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药还可用于预防和/或治疗涉及到cysLT2受体的那些疾病,例如呼吸性疾病(例如支气管哮喘、慢性阻塞性肺病、肺气肿、慢性支气管炎、肺炎(包括间质性肺炎等)、严重急性呼吸综合征(SARS)、急性呼吸窘迫综合征(ARDS)、过敏性鼻炎、鼻窦炎(包括急性鼻窦炎、慢性鼻窦炎等)等,并可作为去痰药或止咳药。另外,本发明的式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药为还可用作呼吸机能改善剂。
呼吸机能的定义为,例如,空气进出肺的机能(即肺活量),氧从肺进入血液的机能和二氧化碳从血液排到体外的机能(即氧交换机能),和呼吸抵抗机能。
在本发明中,呼吸器官是指与呼吸有关的身体部件,如气道、口腔、鼻腔、鼻窦、气管、支气管、细支气管、肺等。
CysLT2受体还与心血管疾病有关,心血管疾病例如心绞痛、心肌梗塞、急性冠脉综合征、心衰、心率不齐、心肌病(扩张型心肌病、肥厚型心肌病等)、心包炎、心瓣炎、心肌炎、心包压塞、低心输出量综合症、二尖瓣狭窄等。式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药可用于治疗和/或预防上述疾病。
在本发明中,非奏效例是指现有的LT受体拮抗剂不给出足够的效果或者没有作用的患者。因为本发明的治疗剂比现有的LT受体拮抗剂更适用于呼吸性疾病,优选对非奏效例和那些患有严重的呼吸机能病症的患者(重症支气管哮喘患者)给用本发明的化合物。
在本发明中,针对cysLT2受体的拮抗作用的IC50值或Ki值的测量方法没有特别的限制,可通过已知方法进行。例如,根据J.Biol.Chem.,275,30531-30536,(2000),Mol.Pharmacol.,58,1601-1608,(2000),或Biochem.Biophys.Res.Commun.,274,316-322,(2000)中所述方法等测量。
在本发明中,式(I)所示化合物除了具有拮抗cysLT2受体的作用之外,还可具有拮抗cysLT1受体的作用。cysLT2受体拮抗剂可为式(I)所示化合物的前药的形式。
式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药可与其它药物联合给用,用于(1)补充和/或增强本发明治疗剂的预防和/或治疗作用,(2)改善本发明治疗剂的动力学和吸收,降低剂量,和/或(3)减小本发明治疗剂的副作用。
本发明的治疗剂和其它药剂的联合用药剂可以以下方式给用:其中两种组分配合在单一制剂中的形式,或者为分开的制剂形式。当使用分开的制剂进行给用时,包括同时给用和不同时间的给用。在不同时间给用时,可首先给用本发明的治疗剂、然后给用另一种药剂,反之亦然。每种给用方法可相同或不同。
上述的其它药剂可为低分子化合物、高分子蛋白、多肽、多核苷酸(DNA、RNA、基因)、反义物(anti-sense)、诱骗物(decoy)、抗体、疫苗等。另一种药剂的剂量可参考临床用剂量适当地进行确定。本发明的治疗剂和其它药剂的比可根据患者的年龄、体重、给药途径、给药时间、和目标疾病、症状或者各种情况的综合而确定,例如,相对于本发明的治疗剂可使用约0.01-100重量%的其它药剂。一种或多种其它药剂可选自下述相同的或不同的组中,并可单独使用或以任选比例组合使用。补充和/或增强本发明治疗剂的预防和/或治疗作用的其它药剂不仅包括已经发现的,而且包括到目前为止基于上述机制将要发现的那些。
对联合用药剂发挥预防和/或治疗作用的那些疾病没有特别的限制,包括其中本发明的预防和/或治疗作用得以补充和/或增强的那些疾病。
例如用于补充和/或增强本发明治疗剂抗呼吸性疾病的预防和/或治疗作用的其它药剂包括例如cysLT1受体拮抗剂、抗组胺药、磷酸二酯酶4抑制剂、弹性蛋白酶抑制剂、抗胆碱能药、抗变应性药物(例如化学递质释放抑制剂、组胺拮抗剂、血栓烷合酶抑制剂、血栓烷拮抗剂、Th2细胞因子抑制剂)、甾族药物、支气管扩张药(例如黄嘌呤衍生物、拟交感神经药、副交感神经阻滞药)、疫苗治疗药、金制剂、汉方药、碱性非甾体抗炎药、5-脂氧合酶抑制剂、5-脂氧合酶活化蛋白拮抗剂、白三烯合成抑制剂、前列腺药、cannabinoid(大麻的化学成分)-2受体激动剂、止咳药、去痰药或得自接种牛痘病毒的炎症性家兔皮肤的提取物。
CysLT1受体拮抗剂包括例如普仑司特水合物、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、ZD-3705等。
CysLT1受体拮抗剂优选为普仑司特水合物、孟鲁司特钠、扎鲁司特或MK-571,更优选为普仑司特水合物、孟鲁司特钠或扎鲁司特。
抗组胺药包括例如盐酸苯海拉明、盐酸双苯拉林、双苯拉林氯茶碱、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、盐酸氮异丙嗪、盐酸高氯环嗪、羟嗪、盐酸赛庚啶、盐酸左卡巴斯汀、阿司咪唑、bepotastine、地氯雷他定、TAK-427、ZCR-2060、NIP-530、糠酸莫美他松、咪唑斯汀、BP-294、安多司特、金诺芬、阿伐司汀、双羟萘酸羟嗪、特非那定、美喹他嗪等。
磷酸二酯酶4抑制剂包括例如咯利普兰、西洛司特(商品名:Ariflo)、Bay19-8004、NIK-616、roflumilast(BY-217)、西潘茶碱(BRL-61063)、atizoram(CP-80633)、SCH-351591、YM-976、V-11294A、PD-168787、D-4396或IC-485等。
弹性蛋白酶抑制剂包括例如西维来司钠水合物(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。
抗胆碱能药包括例如异丙托溴铵、氧化托溴铵、氟托溴铵、西托溴铵、替米维林、噻托溴铵、瑞伐托酯(UK-112166)等。
在抗变应性药中,化学递质释放抑制剂包括例如色甘酸钠、曲尼司特、anlexanox、瑞吡司特、异丁司特、potassium pemilolast、他扎司特、奈多罗米、色甘酸盐、israpafant等。
在抗变应性药中,组胺拮抗剂包括例如富马酸酮替芬、盐酸氮卓斯汀、奥沙米特、美喹他嗪、特非那定、富马酸依美斯汀、盐酸依匹斯汀、ebastin、盐酸西替利嗪、盐酸奥洛他定、氯马斯汀、非索非那定等。
在抗变应性药中,血栓烷合成酶抑制剂包括例如盐酸奥扎格雷或咪曲司特钠等。
在抗变应性药中,血栓烷拮抗剂为例如西拉达司、ramatoroban、水合多米曲班钙、KT-2-962等。
在抗变应性药中,TH2细胞因子抑制剂包括例如甲磺司特等。
作为外用药的甾族药物包括例如丙酸氯倍他索、乙酸双氟拉松、氟轻松、糠酸莫美他松、双丙酸倍他米松、丁酸丙酸倍他米松、戊酸倍他米松、地氟孕甾丁酯、布地奈德、戊酸双氟可龙、安西萘德、哈西奈德、地塞米松、丙酸地塞米松、戊酸地塞米松、乙酸地塞米松、乙酸氢化可的松、丁酸氢化可的松、丁酸丙酸氢化可的松、丙酸迪普罗酮、戊酸乙酸泼尼松龙、乙酸氟轻松、二丙酸倍氯米松、乙酸曲安奈德、戊酸双氟美松、二丙酸阿氰米松、丁酸氯倍他松、泼尼松龙、二丙酸倍氯米松、氟氢缩松等。内用药物和注射用药物包括例如乙酸可的松、氢化可的松、氢化可的松磷酸钠、氢化可的松琥珀酸钠、乙酸氟氢缩松、泼尼松龙、乙酸泼尼松龙、泼尼松龙琥珀酸钠、丁基泼尼松龙乙酸酯、泼尼松龙磷酸喃、乙酸卤泼尼松、甲基泼尼松龙、甲基泼尼松龙乙酸酯、甲基泼尼松龙钠琥珀酸酯、曲安奈德、乙酸曲安奈德、乙酰(acetonide)曲安奈德、地塞米松、乙酸地塞米松、地塞米松磷酸钠、棕榈算地塞米松、乙酸帕拉米松、倍他米松等。吸入用药包括例如二丙酸氯培他米松、丙酸氟替卡松、布地奈德、氟尼缩松、曲安奈德、ST-126P、环索奈德、地塞米松paromitionate、糠酸莫美他松、磺酸普拉睾酮、地夫可特、六甲强龙、sleptanate、六甲强龙琥珀酸钠等。
在支气管扩张药中,黄嘌呤衍生物包括例如氨茶碱、茶碱、多索茶碱、cipamphilline、diprophilline、羟丙茶碱、胆茶碱等。
在支气管扩张药中,拟交感神经药包括例如血浆肾上腺素、盐酸麻黄碱、盐酸d1-二甲基麻黄碱、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、trimetoquinolhydrochloride、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、羟萘甲酸沙美特罗、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、酒石酸酸美卢群、AR-C68397、左旋沙丁胺醇、AR-C68397、左旋沙丁胺醇、KUR-1246、KUL-7211、AR-C89855、S-1319等。
在支气管扩张药中,副交感神经阻滞药包括例如异丙托溴铵、氟托溴铵、氧化托溴铵、西托溴铵、替米维林、噻托溴铵、瑞伐托酯(UK-112166)等。
疫苗治疗药包括例如paspat、astremesin、broncasma berna、CS-560等。
金制剂包括例如硫代苹果酸钠金等。
碱性非甾体抗炎药包括例如盐酸噻拉米特、盐酸替诺立定、依匹唑、依莫法宗等。
5-脂氧合酶抑制剂包括例如diruton、多西苯醌、piripost、SCH-40120、WY-50295、E-6700、ML-3000、TMK-688、ZD-2138、甲磺酸达布非龙、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或ETH-615等。
5-脂氧合酶活化蛋白拮抗剂包括例如MK-591或MK-886等。
白三烯合酶抑制剂包括例如金诺芬、马来酸丙谷美辛、L-674636、A-R1834、UPA-780、A-93178、MK-886、REV-5901A、SCH-40120、MK-591、Bay-x-1005、Bay-y-1015、DTI-0026、氨来占诺或E-6700等。
前列腺素(下文中缩写为PG)包括例如PG受体激动剂、PG受体拮抗剂等。
PG受体包括例如PGE受体(EP1、EP2、EP3、EP4)、PGD受体(DP、CRTH2)、PGF受体(FP)或PGI受体(IP)、TX受体(TP)等。
止咳药包括例如磷酸可待因、磷酸二氢可待因、氢溴酸右美沙芬、喷托维林柠檬酸盐、磷酸待每莫芬、柠檬酸奥昔拉定、氯哌啶、磷酸苯丙哌林、盐酸氯苯达诺、盐酸福米诺苯、那可丁、海苯酸替培啶、盐酸依普拉酮、车前草等。
去痰药包括例如茴香铵精油、碳酸氢钠、碘化钾、盐酸溴己新、樱桃树皮提取物、羧甲基半胱氨酸、福多舒坦、盐酸氨溴索、盐酸氨溴索延时释放药物、盐酸半胱氨酸甲酯、乙酰半胱氨酸、盐酸左旋乙基半胱氨酸、半胱氨酸、泰洛沙泊等。
与本发明化合物联合使用的其它药物优选为cysLT1受体拮抗剂、甾族药物或拟交感神经药。
本发明使用的制剂可含有cysLT2受体拮抗剂和其它补充和/或增强本发明化和物效果的药物,它们配合在单一制剂中或配制在不同制剂中。可通过已知方法配制。
通常通过全身或局部、口或胃肠外途径给用本发明的制剂,用于本发明的目的。
可根据年龄、体重、症状、疗效、给药途径、疗程等确定剂量。通常,对于成年人,口服给用每剂量约1mg到1000mg,每天一次到多次,或胃肠外给用约1mg到100mg,每天一次到多次,或每天从静脉连续给用1到24小时。
如上所述,因为剂量根据上述各种条件改变,因此可使用低于或高于上述剂量的剂量。
化合物以口服固体组合物或口服液体组合物的形式,或以注射组合物、外用药、栓剂、眼膏、吸入剂等胃肠外形式,用于本发明目的。
口服固体制剂包括例如片剂、丸剂、胶囊、粉剂、颗粒剂等。
胶囊包括硬胶囊和软胶囊。
在所述固体制剂中,所述一种或多种活性成分自身根据常用方法进行配制,或与一种或多种赋形剂(乳糖、甘露醇、葡萄糖、微晶纤维素、淀粉等)、粘合剂(羟基丙基纤维素、聚乙烯基吡咯烷酮、硅酸铝镁等)、崩解剂(纤维素乙二醇酸钙、羧甲基纤维素、淀粉、结晶纤维素等)、润滑剂(硬脂酸镁等)、稳定剂或增溶剂(谷氨酸、天冬氨酸等)等进行配制。如果必要的话,制剂可包有包衣剂如糖、明胶、羟基丙基纤维素、羟基丙基甲基纤维素邻苯二甲酸盐,或包有两层或多层包衣。或者,固体制剂可装囊在吸收性材料如明胶中。
口服液体制剂包括可药用水溶液、悬浮液、乳剂、糖浆剂、酏剂等。在这些制剂中,一种或多种活性成分溶解、悬浮或乳化在常用的稀释剂(例如纯净水、乙醇、或其混合物)中。另外,这些液体制剂可包括润湿剂(甘油、D-山梨醇、1,3-丙二醇等)、悬浮剂(阿拉伯胶、羟基丙基纤维素、甲基纤维素、popidon等)、乳化剂(聚山梨醇酯80等)、甜味剂(果糖、葡萄糖、单糖浆剂、白糖等)、调味剂、芳香剂、防腐剂(苯甲酸、苯甲酸钠等)、缓冲剂(柠檬酸钠、酒石酸、乙酸钠、磷酸氢钠等)等。
胃肠外给用的注射剂包括例如溶液、悬浮液、乳剂、或用时溶解或悬浮的固体制剂。注射剂可通过将一种或多种活性成分溶解、悬浮或乳化在增溶剂中制备而成。增溶剂包括例如注射用蒸馏水、食盐水、植物油、1,3-丙二醇、聚乙二醇或醇如乙醇、及其组合。注射剂可进一步含有稳定剂(乙二胺四乙酸二钠、硫代乙醇酸等)、增溶剂(谷氨酸、天冬氨酸、聚山梨醇酯80、1,3-丙二醇等)、悬浮剂(阿拉伯胶、羟基丙基纤维素、甲基纤维素、popidon等)、乳化剂(聚山梨醇酯80等)、顺滑剂(苄基醇等)、等渗剂(氯化钠、甘油、浓甘油、甘露醇等)、缓冲剂(柠檬酸钠、酒石酸、乙酸钠、磷酸氢钠等)或防腐剂(氯丁醇等)等。这些在最终步骤中经过灭菌或通过无菌操作制备而成。可制备无菌固体制剂如冻干制剂,在用前经过灭菌或溶解在注射用无菌蒸馏水或其它无菌溶剂中。
胃肠外用滴眼剂可为滴眼液、滴眼乳剂、或用时溶解在溶剂中的滴眼剂,或眼膏。
可通过已知方法制备这些滴眼剂。例如,在液体滴眼液的情况下,可通过适当选择和含有一种或多种试剂如等渗剂(氯化钠、甘油、浓甘油、甘露醇等)、缓冲剂(柠檬酸钠、柠檬酸、乙酸钠、磷酸氢钠、硼酸、硼砂等)、表面活性剂(Polysolvate 80(商品名)、聚氧硬脂酸酯40、聚氧化乙烯-硬化蓖麻油等)、稳定剂(酸式硫酸酸氢钠、柠檬酸钠、乙二胺四乙酸钠等)、和防腐剂(苯扎氯铵、对羟基苯甲酸类等)等。根据需要,滴眼剂在最终步骤进行灭菌或通过无菌方法制备。
胃肠外用吸入剂可为气雾剂、吸入用粉末或吸入用液体制剂的形式。吸入用液体制剂用时可溶解或悬浮在水或其它适当的液体中。
可通过已知方法制备上述的吸入剂。
例如吸入用液体制剂可进一步含有杀菌剂(苯扎氯铵、对羟基苯甲酸类等)、着色剂、缓冲剂(柠檬酸钠、柠檬酸、乙酸钠、磷酸氢钠、硼酸、硼砂等)、等渗剂(氯化钠、甘油、浓甘油、甘露醇等)、增稠剂(羧基乙烯基聚合物等)、吸收促进剂等。
吸入用粉末可通过适当选择并包括一种或多种试剂如润滑剂(硬脂酸、其盐等)、粘合剂(淀粉、环糊精等)、赋形剂(乳糖、纤维素等)、着色剂、杀菌剂(苯扎氯铵、对羟基苯甲酸类等)、吸收促进剂等制备而成。
吸入用液体制剂通常可通过喷雾装置(例如雾化器、喷雾器等)给用,吸入用粉末可通过使用粉末制剂用吸入器给用。其它胃肠外组合物包括外用液体制剂、膏剂、搽剂、喷雾剂、栓剂、阴道内用阴道栓剂等。
喷雾制剂除了常用的稀释剂外,还含有稳定剂(硫酸氢钠、柠檬酸钠、乙二胺四乙酸钠等)、缓冲剂(例如柠檬酸钠、柠檬酸、乙酸钠、磷酸氢钠、硼酸、硼砂等)、等渗剂(例如氯化钠、甘油、浓甘油、甘露醇等)等。为了制备喷雾剂,可使用美国专利2,868,691和3,095,355中所述方法。
发明效果
式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药拮抗cysLT2受体,因此,可用作气道收缩抑制剂、炎症性细胞(例如噬酸性粒细胞、噬中性粒细胞、淋巴细胞、噬碱性粒细胞等)浸润的抑制剂、粘液分泌抑制剂或气道高敏性抑制剂。式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药还可用于预防和/或治疗涉及到cysLT2受体的那些疾病,例如呼吸性疾病(例如支气管哮喘、慢性阻塞性肺病、肺气肿、慢性支气管炎、肺炎(包括间质性肺炎等)、严重急性呼吸综合征(SARS)、急性呼吸窘迫综合征(ARDS)、过敏性鼻炎、鼻窦炎(包括急性鼻窦炎、慢性鼻窦炎等)等,并可作为去痰药或止咳药。另外,本发明的式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药为还可用作呼吸机能改善剂。
CysLT2受体还与心血管疾病有关,心血管疾病为例如心绞痛、心肌梗塞、急性冠脉综合征、心衰、心率不齐、心肌病(扩张型心肌病、肥厚型心肌病等)、心包炎、心瓣炎、心肌炎、心包压塞、低心输出量综合症、二尖瓣狭窄等。式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药可用于治疗和/或预防上述疾病。
本发明的最佳实施方式
本发明通过以下非限制性实施例和生物实施例进行说明。
色谱分离和TLC中括号内的溶剂表示洗脱剂或展开剂,色谱分离和TLC中所用溶剂的比为体积比。NMR表示1H-NMR并且NMR中括号内的溶剂表示测量时所用的溶剂。TFA表示三氟乙酸。
本发明的命名法根据ACD/Name(商品名;Advanced ChemistryDevelopment Inc.),其产生IUPAC规则命名法。
实施例1:2-(苯基甲基氧基)-3-硝基苯甲酸
向2-羟基-3-硝基苯甲酸(36.6g)的N,N-二甲基甲酰胺(500mL)溶液中加入苄基溴(50.0mL)和碳酸钾(66.3g),混合物在60℃搅拌过夜,将反应混合物倾入到水中,所得混合物用乙酸乙酯和正己烷(1∶1)的混合物提取,有机层用水和饱和食盐水,无水硫酸钠干燥并浓缩,将残余物溶解在四氢呋喃(100mL)和甲醇(200mL)的混合物中,所得混合物在50℃搅拌30分钟,将反应混合物浓缩,残余物用2N盐酸酸化,用乙酸乙酯提取,有机层用水和饱和食盐水洗,无水硫酸钠干燥并浓缩,残余物从异丙醇(50mL)/正己烷(200mL)重结晶,得到标题化合物(31.99g),具有如下物理数据。
TLC:Rf 0.43(二氯甲烷∶甲醇∶乙酸=19∶1∶0.1).
实施例2:(2-(苯基甲基氧基)-3-硝基苯基)氨基甲酸叔丁基酯
室温下向实施例1制备的化合物(30.0g)和三乙胺(16.2mL)的甲苯(440mL)溶液中滴加二苯基磷酰基叠氮化物(24.9mL),反应混合物在80℃搅拌2小时,向反应混合物中加入叔丁醇(52.6mL),混合物在80℃搅拌3小时,将反应混合物冷却到室温,连续地用水、0.1N盐酸、水、饱和碳酸氢钠水溶液和饱和食盐水洗,硫酸钠干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=9∶1),得到标题化合物(32.98g),具有如下物理数据。
TLC:Rf0.40(正己烷∶乙酸乙酯=9∶1).
实施例3:(2-(苯基甲基氧基)-3-硝基苯基)胺盐酸盐
向实施例2制备的化合物(20.66g)中加入4N盐酸的二氧杂环己烷(120mL)溶液,混合物在室温下搅拌过夜,向反应混合物中加入正己烷(120mL),所得混合物在冰冷却条件下搅拌1小时,过滤收集所得固体,用乙酸乙酯洗,得到标题化合物(15.2g),具有如下物理数据。
TLC:Rf0.40(正己烷∶乙酸乙酯=2∶1).
实施例4:N-(2-(苯基甲基氧基)-3-硝基苯基)-4-(4-苯基丁氧基)苯甲酰胺
向4-(4-苯基丁氧基)苯甲酸(5.40g)在二氯甲烷(20mL)中的悬浮液中加入草酰氯(2.09mL)和N,N-二甲基甲酰胺(1滴),所得混合物在室温下搅拌2小时,然后浓缩,向实施例3制备的化合物(5.61g)的二氯甲烷(60mL)溶液中加入吡啶(4.85mL)和预先制备的酰基氯-二氯甲烷(20mL)同时用冰冷却,所得混合物在室温下搅拌3小时,将反应混合物浓缩,残余物用乙酸乙酯稀释,稀释后的溶液连续用水、1N盐酸、水、饱和碳酸氢钠水溶液和饱和食盐水洗,无水硫酸钠干燥并浓缩,残余物从乙酸乙酯(100mL)和正己烷(100mL)的混合溶液重结晶,得到标题化合物(8.58g),具有如下物理数据。
TLC:Rf0.54(正己烷∶乙酸乙酯=2∶1).
实施例5:N-(3-氨基-2-羟基苯基)-4-(4-苯基丁氧基)苯甲酰胺
在氢气氛下搅拌实施例4制备的化合物(8.58g)、10%钯-碳(429mg)、四氢呋喃(60mL)和甲醇(30mL)的混合物5.5小时,滤除催化剂并浓缩滤液,残余物从异丙醇(13mL)和正己烷(52mL)的混合溶剂中重结晶,得到标题化合物(6.07g),具有如下物理数据。
TLC:Rf0.46(正己烷∶乙酸乙酯=1∶1).
实施例6:8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
向实施例5制备的化合物(3.76g)的丙酮(40mL)溶液中加入碳酸钾(4.15g)和2,3-二溴丙酸乙基酯(1.74mL),混合物在50℃搅拌过夜,将反应混合物浓缩,残余物用乙酸乙酯稀释,稀释后的溶液用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=(4∶1)到(2∶1)),得到标题化合物(3.51g),具有如下物理数据。
TLC:Rf0.48(正己烷∶乙酸乙酯=1∶1).
实施例7:4-(4-甲氧基-4-氧代丁酰基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
向实施例6制备的化合物(776mg)的吡啶(5mL)溶液中加入3-(甲氧基羰基)丙酰基氯(302μL),混合物在室温下搅拌1小时,将反应混合物倾入到水中,所得混合物用乙酸乙酯提取,有机层用1N盐酸、水、饱和碳酸氢钠水溶液和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物从乙酸乙酯(5mL)和正己烷(5mL)的混合溶剂重结晶,得到标题化合物(711mg),具有如下物理数据。
TLC:Rf0.38(正己烷∶乙酸乙酯=1∶1).
实施例8:4-(3-羧基丙酰基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
向实施例7制备的化合物(700mg)、四氢呋喃(2mL)和乙醇(2mL)的混合物中加入2N氢氧化钠水溶液(2mL),混合物在室温下搅拌1小时,反应混合物用2N盐酸酸化并用乙酸乙酯提取,有机层用水和饱和食盐水、无水硫酸钠顺序洗涤,干燥并浓缩,残余物从重结晶乙醇,得到本发明的标题化合物(486mg),具有如下物理数据。
TLC:Rf 0.21(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(CD3CO2D):δ1.73-1.92(m,4H),2.60-2.97(m,5H),2.98-3.14(m,1H),4.05-4.22(m,3H),4.38(dd,1H),5.19(t,1H),6.97-7.06(m,3H),7.11-7.30(m,6H),7.90-7.98(m,2H),8.13(br.s.,1H).
实施例8(1)-实施例8(4)
使用相应的羟基硝基苯甲酸代替2-羟基-3-硝基苯甲酸,使用相应的酰基氯代替3-(甲氧羰基)丙酰基氯,根据实施例1→实施例2→实施例3→实施例4→实施例5→实施例6→实施例7→实施例8的方法制备具有以下物理数据的本发明的化合物。
实施例8(1):4-(4-羧基丁酰基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.25(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.74(m,6H),2.24(m,2H),2.64(m,4H),3.69(m,1H),4.07(m,2H),4.47(m,1H),5.15(m,1H),6.92(t,1H),7.03(d,2H),7.21(m,6H),7.67(m,1H),7.91(d,2H),9.30(s,1H),12.06(br.s.,1H).
实施例8(2):4-(5-羧基戊酰基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.32(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.53(m,4H),1.72(m,4H),2.20(m,2H),2.60(m,4H),3.67(m,1H),4.07(m,2H),4.48(m,1H),5.14(m,1H),6.91(t,1H),7.03(d,2H),7.21(m,6H),7.66(m,1H),7.91(d,2H),9.29(s,1H),12.71(br.s.,1H).
实施例8(3):4-(3-羧基丙酰基)-6-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.26(二氯甲烷∶甲醇∶乙酸=40∶10∶1);
NMR(CD3CO2D):δ1.72-1.92(m,4H),2.61-2.84(m,4H),2.85-3.02(m,1H),3.01-3.23(m,1H),3.95(dd,1H),4.07(t,2H),4.42-4.61(m,1H),5.06(br.s.,1H),6.94-7.07(m,3H),7.11-7.33(m,5H),7.36-7.77(m,1H),7.77-8.29(m,3H).
实施例8(4):4-(3-羧基丙酰基)-7-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.25(二氯甲烷∶甲醇∶乙酸=40∶10∶1);
NMR(CD3CO2D):δ1.73-1.91(m,4H),2.60-2.96(m,5H),2.96-3.17(m,1H),3.93(dd,1H),4.07(t,2H),4.42-4.64(m,1H),4.97-5.15(m,1H),6.95-7.03(m,2H),7.10-7.63(m,8H),7.89-7.98(m,2H).
实施例9:8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-碳酰胺
向实施例6制备的化合物(1.80g)的乙醇(11mL)溶液中加入28v/v%氨水溶液(2.6mL)同时用冰冷却,得到的混合物在室温下搅拌过夜,反应混合物用2N盐酸中和并用乙酸乙酯提取,有机层用水和盐水顺序洗涤,无水硫酸钠干燥,残余物在加热下在异丙醇(20mL)中搅拌30分钟,过滤得到固体,所得固体干燥,得到标题化合物(1.37g),具有如下物理数据。
TLC:Rf 0.47(二氯甲烷∶甲醇∶乙酸=90∶10∶1).
实施例10:N-(2-氰基-3,4-二氢-2H-1,4-苯并噁嗪-8-基)-4-(4-苯基丁氧基)苯甲酰胺
向实施例9制备的化合物(1.11g)的吡啶(10mL)溶液中加入三氟乙酸酐(1.06ml)同时用冰冷却,混合物搅拌15分钟,在室温下进一步搅拌30分钟。将反应混合物倾入到2N盐酸中并用乙酸乙酯提取,有机层用水、饱和碳酸氢钠水溶液和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,向残余物中加入四氢呋喃(5ml)和乙醇(5mL),向其中进一步加入1N碳酸钾水溶液(2.5mL),混合物搅拌15分钟,进一步加入1N碳酸钾水溶液(2.5mL)后,混合物在室温下搅拌15分钟,将反应混合物倾入到水中,用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=1∶1),然后从异丙醇(2mL)和正己烷(2mL)的混合溶剂重结晶,得到标题化合物(870mg),具有如下物理数据。
TLC:Rf 0.52(正己烷∶乙酸乙酯=2∶3).
实施例11:4-(2-氰基-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)-4-氧代丁酸甲基酯
向实施例10制备的化合物(214mg)的吡啶(2mL)溶液中加入3-(甲氧基羰基)丙酰基氯(92μL),混合物在室温下搅拌过夜,向其中加入另外的3-(甲氧羰基)丙酰基氯(92μL),所得混合物搅拌4小时,将反应混合物倾入到1N盐酸中,用乙酸乙酯提取,有机层用水、饱和碳酸氢钠水溶液和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物从乙酸乙酯和正己烷(1∶1)的混合溶剂重结晶,得到标题化合物(200mg),具有如下物理数据。
TLC:Rf0.37(正己烷∶乙酸乙酯=2∶3).
实施例12:4-氧代-4-(8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
向实施例11制备的化合物(196mg)的N,N-二甲基甲酰胺(2mL)的溶液中加入叠氮化钠(71mg)和氯化铵(58mg),混合物在室温下搅拌1小时,将反应混合物倾入到1N盐酸中,所得混合物用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,将残余物溶解在四氢呋喃(1mL)和甲醇(1mL)的混合物中,向其中加入1N氢氧化钠水溶液(1mL),所得混合物在室温下搅拌2小时,反应混合物用2N盐酸酸化,用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物在加热条件下在乙酸乙酯(4mL)中搅拌30分钟,过滤收集所得固体,干燥,得到本发明的标题化合物(177mg),具有如下物理数据。
TLC:Rf 0.40(二氯甲烷∶甲醇∶乙酸=80∶20∶1);
NMR(CD3CO2D):δ1.71-1.92(m,4H),2.58-2.81(m,4H),2.82-3.06(m,2H),4.07(t,2H),4.42(br.s.,2H),6.13(t,1H),6.96-7.30(m,8H),7.50(br.s.,1H),7.84(br.s.,1H),7.95(d,2H).
实施例12(1)-实施例12(4)
使用相应的羟基硝基苯甲酸代替2-羟基-3-硝基苯甲酸,使用相应的酰基氯代替3-(甲氧羰基)丙酰基氯,以实施例1→实施例2→实施例3→实施例4→实施例5→实施例6→实施例9→实施例10→实施例11→实施例12的方法制备具有以下物理数据的本发明的化合物。
实施例12(1):5-氧代-5-(8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)戊酸
TLC:Rf 0.44(二氯甲烷∶甲醇∶乙酸=80∶20∶1);
NMR(DMSO-d6):δ1.72(m,6H),2.22(m,2H),2.63(m,4H),4.06(m,2H),4.22(m,2H),6.09(t,1H),6.97(t,1H),7.03(d,2H),7.22(m,5H),7.45(m,1H),7.68(m,1H),7.90(d,2H),9.40(s,1H),12.02(br.s.,1H).
实施例12(2):6-氧代-6-(8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)己酸
TLC:Rf 0.50(二氯甲烷∶甲醇∶乙酸=80∶20∶1);
NMR(DMSO-d6):δ1.49(m,4H),1.72(m,4H),2.20(m,2H),2.62(m,4H),4.06(m,2H),4.21(m,2H),6.09(t,1H),6.96(t,1H),7.04(d,2H),7.22(m,5H),7.47(m,1H),7.67(m,1H),7.90(d,2H),9.41(s,1H),11.99(br.s.,1H).
实施例12(3):4-氧代-4-(6-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf 0.36(二氯甲烷∶甲醇∶乙酸=40∶10∶1);
NMR(CD3CO2D):δ1.73-1.91(m,4H),2.58-2.84(m,4H),2.91-3.12(m,2H),3.99-4.29(m,3H),4.46-4.70(m,1H),5.88-6.01(m,1H),6.99(d,2H),7.05(d,1H),7.11-7.34(m,5H),7.45-7.84(m,1H),7.86-8.17(m,3H).
实施例12(4):4-氧代-4-(7-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf 0.39(二氯甲烷∶甲醇∶乙酸=40∶10∶1);
NMR(CD3CO2D):δ1.73-1.91(m,4H),2.58-2.86(m,4H),2.88-3.05(m,2H),3.97-4.38(m,3H),4.41-4.71(m,1H),5.91-6.07(m,1H),6.96-7.03(m,2H),7.10-7.59(m,7H),7.62-7.87(m,1H),7.90-7.97(m,2H).
实施例13:苯甲酸2-羟基苯基酯
向邻苯二酚(55g)的水(230mL)溶液中加入碳酸钠(63.6g),在剧烈搅拌下,在2小时内,向所得混合物中滴加苯甲酰基氯(58mL),反应混合物在室温下搅拌2小时,通过滴加2N盐酸(350mL)使反应混合物小心酸化,然后用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物从乙酸乙酯(100mL)和正己烷(400mL)的混合溶剂重结晶,得到标题化合物(64.6g),具有如下物理数据。
TLC:Rf0.50(正己烷∶乙酸乙酯=2∶1).
实施例14:苯甲酸2-羟基-3-硝基苯基酯
在10℃在约1小时内向实施例13制备的化合物(53.56g)在乙酸(500mL)中的悬浮液中滴加浓硝酸(61%,18.7mL),搅拌1小时后,将反应混合物倾入到冰-水(1L)中,沉淀的固体用水洗涤,固体从异丙醇重结晶,得到标题化合物(19.6g),具有如下物理数据。
TLC:Rf0.68(正己烷∶乙酸乙酯=2∶1).
实施例15:苯甲酸2-(苯基甲基氧基)-3-硝基苯基酯
向实施例14制备的化合物(24.6g)-N,N-二甲基甲酰胺(95mL)中加入碳酸钾(19.7g)和苄基溴(12.4mL),混合物在室温下搅拌过夜,将反应混合物倾入到水中,所得混合物用乙酸乙酯提取,有机层用水和盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物从乙酸乙酯(50mL)和正己烷(200mL)的混合物重结晶,得到标题化合物(29.4g),具有如下物理数据。
TLC:Rf0.47(正己烷∶乙酸乙酯=4∶1).
实施例16:2-(苯基甲基氧基)-3-硝基苯酚
向实施例15制备的化合物(27.9g)、四氢呋喃(100mL)和乙醇(100mL)的混合物中加入2N氢氧化钠水溶液(100mL),混合物在50℃搅拌30分钟,将反应混合物用冰冷却,向其中加入1N盐酸(120mL),然后浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=5∶1),得到标题化合物(19.6g),具有如下物理数据。
TLC:Rf0.40(正己烷∶乙酸乙酯=2∶1).
实施例17:2-(苯基甲基氧基)-1-(甲氧基甲氧基)-3-硝基苯
在0℃向实施例16制备的化合物(3.92g)的二氯甲烷(48mL)溶液中加入N,N-二异丙基乙胺(4.18mL)和氯甲基甲基醚(1.46mL),混合物在25℃搅拌1小时,将反应混合物浓缩,向所得残余物中加入水,然后混合物用乙酸乙酯提取,有机层用0.5N盐酸、水、饱和碳酸氢钠水溶液和盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到标题化合物(4.63g),具有如下物理数据。
TLC:Rf0.58(正己烷∶乙酸乙酯=2∶1).
实施例18:2-氨基-6-(甲氧基甲氧基)苯酚
向实施例17制备的化合物(12.5g)、乙酸乙酯(75mL)和乙醇(75mL)的混合物中加入10%钯-碳(314mg),混合物在氢气氛下搅拌5小时,滤除催化剂并浓缩滤液,残余物从乙酸乙酯和正己烷的混合物重结晶,得到标题化合物(5.45g),具有如下物理数据。
TLC:Rf0.50(正己烷∶乙酸乙酯=1∶1).
实施例19:8-(甲氧基甲氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
在氩气气氛下向实施例18制备的化合物(777mg)的丙酮(20mL)溶液中加入2,3-二溴丙酸乙基酯(1.0mL)和碳酸钾(1.90g),混合物在50℃搅拌过夜,在氩气气氛下进一步加入2,3-二溴丙酸乙基酯(1.0mL)和碳酸钾(1.90g)后,混合物在50℃搅拌2小时,将反应混合物倾入到水中,用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸镁干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(二氯甲烷∶乙酸乙酯=40∶1),得到标题化合物(416mg),具有如下物理数据。
TLC:Rf0.53(二氯甲烷∶乙酸乙酯=10∶1).
实施例20:8-(甲氧基甲氧基)-4-(4-甲氧基-4-氧代丁酰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
向实施例19制备的化合物(416mg)的吡啶(10mL)溶液中加入3-(甲氧羰基)丙酰基氯(288μl),混合物在室温下搅拌1.5小时,反应混合物用水稀释,用乙酸乙酯提取,有机层用1N盐酸、水、饱和碳酸氢钠水溶液和饱和食盐水洗涤,无水硫酸镁干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=3∶2),得到标题化合物(509mg),具有如下物理数据。
TLC:Rf0.38(正己烷∶乙酸乙酯=1∶1).
实施例21:8-羟基-4-(4-甲氧基-4-氧代丁酰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
向实施例20制备的化合物(509mg)中加入4N盐酸-乙酸乙酯(1.6mL),混合物在0℃搅拌45分钟,将反应混合物浓缩,将残余物与苯共沸,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=1∶1),得到标题化合物(437mg),具有如下物理数据。
TLC:Rf0.32(正己烷∶乙酸乙酯=1∶1).
实施例22:4-(4-甲氧基-4-氧代丁酰基)-8-((4-(4-苯基丁氧基)苄基)氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
向实施例21制备的化合物(430mg)、1-(氯甲基)-4-(4-苯基丁氧基)苯(420mg)和N,N-二甲基甲酰胺(5mL)的混合物中加入碳酸钾(263mg),混合物在室温下搅拌3小时,在50℃下搅拌5小时,反应混合物用水稀释,用乙酸乙酯提取,有机层用水和饱和食盐水洗,无水硫酸镁干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=2∶1),得到标题化合物(540mg),具有如下物理数据。
TLC:Rf0.42(苯∶乙酸乙酯=4∶1).
实施例23:4-(3-羧基丙酰基)-8-((4-(4-苯基丁氧基)苄基)氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
向实施例22制备的化合物(193mg)、四氢呋喃(1mL)和乙醇(1mL)的混合物中加入2N氢氧化钠水溶液(1mL),混合物在室温下搅拌2小时,在50℃搅拌1小时,将反应混合物浓缩,残余物用水稀释,用2N盐酸酸化,用乙酸乙酯提取,有机层用水和饱和食盐水洗,无水硫酸镁干燥并浓缩,得到的固体从乙酸乙酯、四氢呋喃和正己烷的混合物重结晶,得到本发明的标题化合物(57mg),具有如下物理数据。
TLC:Rf0.44(二氯甲烷∶甲醇=5∶1);
NMR(DMSO-d6):δ1.71(m,4H),2.32-2.94(m,6H),3.67(dd,1H),3.98(m,2H),4.37(dd,1H),4.92-5.12(m,3H),6.74-6.96(m,4H),7.12-7.31(m,6H),7.35(d,2H).
实施例24:4-(4-甲氧基-4-氧代丁基)-8-((4-(4-苯基丁氧基)苄基)氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
在氩气气氛下在冰冷却下向实施例22制备的化合物(301mg)的无水四氢呋喃(3mL)溶液中加入硼烷-二甲硫醚配合物(148μl),混合物在室温下搅拌45小时,向反应混合物中加入丙酮,混合物再搅拌30分钟,将反应混合物浓缩,向所得残余物中加入乙酸乙酯,有机层用水和饱和食盐水顺序洗涤,无水硫酸镁干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=3∶1),得到标题化合物(136mg),具有如下物理数据。
TLC:Rf0.51(正己烷∶乙酸乙酯=1∶1).
实施例25:4-(3-羧基丙基)-8-((4-(4-苯基丁氧基)苄基)氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
向实施例24制备的化合物(134mg)、四氢呋喃(1mL)和乙醇(1mL)的混合物中加入2N氢氧化钠水溶液(715(L),混合物在室温下搅拌2小时,将反应混合物浓缩,残余物用水稀释,溶液用2N盐酸酸化,并用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物从乙酸乙酯、四氢呋喃和正己烷的混合物重结晶,得到本发明的标题化合物(84mg),具有如下物理数据。
TLC:Rf0.64(二氯甲烷∶甲醇=5∶1);
NMR(CDCl3):δ1.73-1.95(m,6H),2.37(t,2H),2.68(m,2H),3.07(m,1H),3.42(m,1H),3.52(d,2H),3.95(m,2H),4.94(t,1H),5.02(d,1H),5.08(d,1H),6.38(m,2H),6.73(t,1H),6.85(d,2H),7.14-7.37(m,7H).
实施例25(1):4-(4-羧基丁基)-8-((4-(4-苯基丁氧基)苄基)氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
使用相应的酸代替3-(甲氧羰基)丙酰基氯,以实施例20→实施例21→实施例22→实施例24→实施例25的方法制备具有以下物理数据的本发明的化合物。
TLC:Rf 0.43(二氯甲烷∶甲醇=5∶1);
NMR(CDCl3):δ1.53-1.74(m,4H),1.75-1.85(m,4H),2.30-2.39(m,2H),2.68(m,2H),3.00(m,1H),3.34-3.60(m,3H),3.95(m,2H),4.97(t,1H),5.04(d,1H),5.10(d,1H),6.38(m,2H),6.72(dd,1H),6.85(d,2H),7.14-7.22(m,3H),7.24-7.37(m,4H).
实施例26:(3-氨基-2-羟基苯基)氨基甲酸叔丁基酯
在氩气气氛下向实施例2制备的化合物(2.93g)的乙醇(20mL)溶液中加入10%钯-碳(50w/w%,吸湿性,400mg),混合物在氢气氛下搅拌5.5小时,滤除催化剂并浓缩滤液,得到标题化合物,具有如下物理数据。
TLC:Rf0.32(正己烷∶乙酸乙酯=3∶1).
实施例27:8-((叔丁氧基羰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
用实施例26中制备的化合物代替实施例18制备的化合物,以实施例19的方法,制备具有以下物理数据的化合物(1.61g)。
TLC:Rf0.24(正己烷∶乙酸乙酯=2∶1).
实施例28:4-(8-((叔丁氧基羰基)氨基)-2-(乙氧基羰基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
在氩气气氛下,向实施例27制备的化合物(100mg)的4-氧代丁酸(15w/w%水溶液,422mg)和乙酸(45mg)的乙醇溶液中加入10%钯-碳(50w/w%,吸湿性,10mg),混合物在室温下在氢气氛下搅拌30分钟,滤除催化剂并浓缩滤液,将残余物溶解在饱和碳酸氢钠水溶液中,所得混合物用乙酸乙酯提取,有机层用饱和食盐水洗涤,无水硫酸镁干燥并浓缩,得到标题化合物(110mg),具有如下物理数据。
TLC:Rf0.34(正己烷∶乙酸乙酯=1∶2).
实施例29:8-((叔丁氧基羰基)氨基)-4-(4-甲氧基-4-氧代丁基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
将实施例28制备的化合物(110mg)溶解在乙酸乙酯(2mL)中,并向该溶液中加入三甲基甲硅烷基重氮甲烷(2M的己烷溶液,0.40mL),混合物在室温搅拌1小时并浓缩,残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=85∶15→80∶20),得到标题化合物(65mg),具有如下物理数据。
TLC:Rf0.28(正己烷∶乙酸乙酯=3∶1).
实施例30:4-(4-甲氧基-4-氧代丁基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
用实施例29制备的化合物(61mg)代替实施例2制备的化合物,以实施例3→实施例4的方法制备标题化合物(26mg)。
TLC:Rf0.26(正己烷∶乙酸乙酯=2∶1).
实施例31:4-(3-羧基丙基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
使用实施例30制备的化合物(25mg)代替实施例7制备的化合物,以实施例8的方法制备标题化合物(15mg)。
TLC:Rf0.12(二氯甲烷∶甲醇=9∶1);
NMR(DMSO-d6):δ1.64-1.80(m,6H),2.14-2.34(m,2H),2.63(t,2H),3.08-3.38(m,4H),4.05(t,2H),4.49-4.56(m,1H),6.47(d,1H),6.68(t,1H),7.02(d,2H),7.13-7.31(m,6H),7.85(d,2H),9.07(s,1H).
实施例32:4-(2-羧基乙基)-8-{[4-(4-苯基丁氧基)苄基]氧基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
用3-氯-3-氧代丙酸甲基酯代替3-(羧甲氧基)丙酰基氯,以实施例20→实施例21→实施例22→实施例24→实施例25的方法制备具有以下物理数据的本发明的化合物。
TLC:Rf0.43(二氯甲烷∶甲醇=5∶1);
NMR(CDCl3):δ1.79(m,4H),2.50(m,1H),2.63-2.86(m,3H),3.36(m,1H),3.53(m,2H),3.77(m,1H),3.93(m,2H),4.96(br,1H),5.02(d,1H),5.08(d,1H),6.26(d,1H),6.42(d,1H),6.72(dd,1H),6.84(d,2H),7.14-7.23(m,3H),7.25-7.37(m,4H).
实施例33:4-(2-(乙氧基羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
以实施例28相同的方法,使用实施例6或实施例9制备的化合物代替实施例27制备的化合物,获得具有以下物理数据的本发明的化合物。
TLC:Rf0.52(二氯甲烷∶甲醇=9∶1);
NMR(CDCl3):δ1.28(t,3H),1.75-2.00(m,6H),2.43(t,2H),2.70(t,2H),3.22-3.40(m,2H),
3.48-3.59(m,2H),4.03(t,2H),4.25(q,2H),4.86-4.89(m,1H),6.49(dd,1H),6.86-6.95(m,3H),7.19-7.32(m,5H),7.87(d,2H),7.90-7.93(m,1H),8.49(s,1H).
实施例33(1):4-(2-(氨基羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf 0.53(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.63-1.76(m,6H),2.26(t,2H),2.63(t,2H),3.19-3.49(m,4H),4.04(t,2H),4.70(t,1H),6.64(dd,1H),6.73-6.81(m,2H),7.01(d,2H),7.12-7.30(m,5H),7.41(brs,1H),7.89(d,2H),8.13(brs,1H),9.68(s,1H).
实施例34:4-(3-羧基丙基)-8-({(2E)-3-[4-(4-苯基丁基)苯基]-2-丙烯酰基}氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
用实施例29制备的化合物代替实施例2制备的化合物,用(2E)-3-[4-(4-苯基丁基)苯基]丙烯酸代替4-(4-苯基丁氧基)苯甲酸,以实施例3→实施例4→实施例25的方法制备具有以下物理数据的本发明的化合物。
TLC:Rf0.52(二氯甲烷∶甲醇∶乙酸=85∶15∶1);
NMR(DMSO-d6):δ1.51-1.78(m,6H),2.26(t,2H),2.54-2.68(m,4H),3.12-3.53(m,4H),5.02(t,1H),6.52(d,1H),6.72(t,1H),7.09-7.27(m,8H),7.43-7.53(m,4H),9.16(s,1H),12.50(brs,1H).
实施例35:4-[8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸
使用实施例10制备的化合物代替实施例27制备的化合物,根据实施例28→实施例29→实施例12的方法,制备具有以下物理数据的标题化合物。
TLC:Rf0.41(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.80(m,6H),2.24(t,2H),2.63(t,2H),3.22-3.38(m,2H),3.65-3.76(m,2H),4.06(t,2H),5.84(t,1H),6.61(dd,1H),6.81(t,1H),7.03(d,2H),7.09-7.29(m,6H),7.90(d,2H),9.46(s,1H),12.07(brs,1H),16.51(brs,1H).
实施例36:4-(5-羧基戊基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
使用实施例6制备的化合物代替实施例27制备的化合物,根据实施例28→实施例25的方法,制备具有以下物理数据的标题化合物。
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.23-1.33(m,2H),1.44-1.56(m,4H),1.68-1.78(m,4H),2.19(t,2H),2.63(t,2H),3.12-3.54(m,4H),4.05(t,2H),4.97(t,1H),6.52(dd,1H),6.75(t,1H),7.02(d,2H),7.12-7.30(m,6H),7.86(d,2H),9.16(s,1H),12.47(brs,1H).
实施例37
使用相应的化合物代替1-(氯甲基)-4-(4-苯基丁氧基)苯,以实施例22→实施例24→实施例25的方法,制备具有以下物理数据的本发明的化合物
实施例37:4-(3-羧基丙基)-8-({4-[(3-苯基丙氧基)甲基]苄基}氧基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.26(二氯甲烷∶甲醇=5∶1);
NMR(CDCl3):δ1.81-1.97(m,4H),2.37(t,2H),2.70(t,2H),3.05(m,1H),3.37-3.60(m,5H),4.48(s,2H),4.99(t,1H),5.12(d,1H),5.18(d,1H),6.36(m,2H),6.70(dd,1H),7.13-7.20(m,3H),7.24-7.36(m,4H),7.41(d,2H).
实施例37(1):8-({4-[3-(苯基甲基氧基)丙基]苄基}氧基)-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.25(二氯甲烷∶甲醇=5∶1);
NMR(CDCl3):δ1.80-1.97(m,4H),2.37(t,2H),2.69(t,2H),3.06(m,1H),3.37-3.60(m,5H),4.50(s,2H),4.98(t,1H),5.07(d,1H),5.14(d,1H),6.35(d,1H),6.40(d,1H),6.72(dd,1H),7.15(d,2H),7.25-7.36(m,3H).
实施例37(2):4-(3-羧基丙基)-8-{[4-(4-苯氧基丁基)苄基]氧基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇=5∶1);
NMR(CDCl3):δ1.70-1.94(m,6H),2.37(t,2H),2.66(m,2H),3.07(m,1H),3.34-3.61(m,3H),3.96(m,2H),4.98(m,1H),5.07(d,1H),5.14(d,1H),6.37(m,2H),6.71(dd,1H),6.85-6.96(m,3H),7.17(d,2H),7.27(m,2H),7.34(d,2H).
实施例38:2-(苯基甲基氧基)-3-硝基-N-[4-(4-苯基丁氧基)苯基]苯甲酰胺
向实施例1制备的化合物(3.40g)的二甲基甲酰胺(20mL)的溶液中加入1-羟基苯并三唑水合物(2.47g)和1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(3.11g),混合物在室温下搅拌30分钟,向反应混合物中加入[4-(4-苯基丁氧基)苯基]胺(3g)和三乙胺(1.75mL),混合物搅拌过夜,将反应混合物倾入到冰-水中,混合物用乙酸乙酯提取,提取物用饱和碳酸氢钠水溶液、水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物用正己烷和乙酸乙酯(1∶1)的混合物洗涤,得到标题化合物(4.33g),具有如下物理数据。
TLC:Rf0.60(正己烷∶乙酸乙酯=2∶1);
NMR(DMSO-d6):δ1.65-1.76(m,4H),2.63(t,2H),3.95(t,2H),5.06(s,2H),6.90(d,2H),7.12-7.30(m,10H),7.45(t,1H),7.56(d,2H),7.85(dd,1H),8.03(dd,1H).
实施例39:4-(3-羧基丙基)-8-({[4-(4-苯基丁氧基)苯基]氨基}羰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
使用实施例38制备的化合物代替实施例4制备的化合物,根据实施例5→实施例6→实施例28→实施例29→实施例25,制备具有以下物理数据的本发明的化合物。
TLC:Rf 0.44(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.69-1.75(m,6H),2.28(t,2H),2.58-2.65(m,2H),3.28(t,2H),3.46-3.59(m,2H),3.88-3.95(m,2H),5.02(t,1H),6.84-6.89(m,4H),6.98-7.04(m,1H),7.12-7.29(m,5H),7.63(d,2H),10.41(s,1H).
实施例40:4-(4-甲氧基-4-氧代丁基)-8-{[4-(4-苯基丁氧基)苄基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
将8-氨基-4-(4-甲氧基-4-氧代丁基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯(80mg;使实施例3制备的化合物经历实施例29所述相同步骤制备而成)和4-(4-苯基丁氧基)苯甲醛(60mg)溶解在1,2-二氯乙烷(4mL)中,向该溶液中加入三乙酰氧基硼氢化钠(96mg)同时使用冰冷却,混合物在室温搅拌2小时,向反应混合物中加入水,所得混合物用乙酸乙酯提取,提取物用饱和碳酸氢钠水溶液和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=8∶2),得到标题化合物(121mg),具有如下物理数据。
TLC:Rf0.59(正己烷∶乙酸乙酯=3∶2);
NMR(CDCl3):δ1.26(t,3H),1.76-1.95(m,6H),2.36(t,2H),2.66-2.71(m,2H),3.16-3.34(m,2H),3.47-3.48(m,2H),3.67(s,3H),3.93-3.96(m,2H),4.18-4.26(m,2H),4.28(s,2H),4.53(brs,1H),4.76-4.78(m,1H),6.10-6.14(m,2H),6.70(t,1H),6.84(d,2H),7.18-7.21(m,3H),7.25-7.30(m,4H).
实施例41:4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苄基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
用实施例40制备的化合物代替实施例24制备的化合物,根据实施例25的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.51(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.61-1.72(m,6H),2.23(t,2H),2.56-2.67(m,2H),3.15(t,2H),3.38(d,2H),3.91-3.98(m,2H),4.18(s,2H),4.83-4.85(m,1H),5.03(brs,1H),5.90(d,1H),6.04(d,1H),6.48(t,1H),6.83(d,2H),7.11-7.28(m,7H).
实施例42:2-[(4-甲氧基苄基)氧基]-3-硝基苯甲醛
向2-羟基-3-硝基苯甲醛(3g)的二甲基甲酰胺(20mL)溶液中顺序加入碳酸钾(3.72g)、四正丁基氟化铵(331mg)和1-(氯甲基)-4-甲氧基苯(3.37g),混合物在室温搅拌11小时,将反应混合物倾入到冰-水,所得混合物用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物用叔丁基甲基醚洗涤,得到标题化合物(4.17g),具有如下物理数据。
TLC:Rf0.55(正己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ3.81(s,3H),5.12(s,2H),6.90(d,2H),7.27-7.38(m,3H),8.05(dd,1H),8.12(dd,1H),10.15(s,1H).
实施例43:2-[(4-甲氧基苄基)氧基]-1-硝基-3-{(Z)-2-[4-(4-苯基丁氧基)苯基]乙烯基}苯和2-[(4-甲氧基苄基)氧基]-1-硝基-3-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}苯的混合物
将实施例42制备的化合物(950mg)和三苯基[4-(4-苯基丁氧基)苄基]氯化磷(6.20g)在四氢呋喃(6mL)中的悬浮液冷却到-25℃,向其中加入叔丁醇钾(1.26g)-四氢呋喃(6mL),混合物在-40到30℃搅拌1小时,向反应混合物中加入水,混合物用乙酸乙酯提取,提取物用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=92∶8),得到标题化合物(1.85g;E-异构体和Z-异构体的混合物).
TLC(E异构体):Rf0.55(正己烷∶乙酸乙酯=3∶1);
TLC(Z异构体):Rf0.60(正己烷∶乙酸乙酯=3∶1).
实施例44:2-硝基-6-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}苯酚
向实施例43制备的化合物(1.68g)的甲苯(35mL)溶液中加入对甲苯磺酸水合物(112mg),混合物回流3小时,将反应混合物冷却到室温,向其中加入水,所得混合物用乙酸乙酯提取,提取物用饱和碳酸氢钠水溶液和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物用二异丙基醚洗涤,得到标题化合物(700mg),具有如下物理数据。
TLC:Rf0.42(正己烷∶乙酸乙酯=6∶1);
NMR(CDCl3):δ1.80-1.84(m,4H),2.70(t,2H),4.00(t,2H),6.89(d,2H),6.97(t,1H),7.15(d,1H),7.19-7.21(m,3H),7.25-7.32(m,2H),7.34(d,1H),7.48(d,2H),7.86(dd,1H),8.00(dd,1H),11.17(s,1H).
实施例45:2-氨基-6-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}苯酚
向实施例44制备的化合物(860mg)的乙醇(30mL)溶液中加入水合氯化锡(4.99g),混合物回流4小时,将反应混合物冷却到室温,反应混合物用碳酸氢钠水溶液碱化,通过celite过滤收集沉淀的固体,滤液用乙酸乙酯提取,提取物用饱和食盐水洗涤,无水硫酸钠干燥并浓缩,得到标题化合物(618mg),具有如下物理数据。
TLC:Rf0.37(正己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ1.72-1.91(m,4H),2.69(t,2H),3.99(t,2H),6.72(dd,1H),6.78(t,1H),6.88(d,2H),6.95-7.04(m,2H),7.13(d,1H),7.19-7.21(m,2H),7.25-7.31(m,2H),7.43(d,2H).
实施例46:4-(2-(乙氧基羰基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
通过实施例6→实施例28所述相同方法,使用实施例45制备的化合物代替实施例5制备的化合物制备而成。
TLC:Rf0.50(二氯甲烷∶甲醇=9∶1);
NMR(CDCl3):δ1.26(t,3H),1.73-1.98(m,6H),2.43(t,2H),2.69(t,2H),3.21-3.41(m,2H),3.53(d,2H),3.98(t,2H),4.19-4.30(m,2H),4.87(t,1H),6.59(dd,1H),6.81-6.89(m,3H),6.98-7.01(m,1H),7.07(d,1H),7.16-7.31(m,5H),7.37(d,1H),7.45(d,2H).
实施例47:4-(4-乙氧基-4-氧代丁基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
向实施例46制备的化合物(330mg)的二甲基甲酰胺(5mL)溶液中加入碳酸钾(252mg)和碘乙烷(142mg),混合物在室温搅拌2小时,向反应混合物中加入水,混合物用乙酸乙酯提取,提取物用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=8∶2),得到标题化合物(210mg),具有如下物理数据。
TLC:Rf0.49(正己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ1.23-1.29(m,6H),1.75-1.98(m,6H),2.36(t,2H),2.69(t,2H),3.21-3.39(m,2H),3.51-3.53(m,2H),3.96-4.00(m,2H),4.08-4.28(m,4H),4.86(t,1H),6.60(dd,1H),6.81-6.87(m,3H),6.98(dd,1H),7.07(d,1H),7.18-7.21(m,3H),7.26-7.31(m,2H),7.36(d,1H),7.45(d,2H).
实施例48:4-(4-乙氧基-4-氧代丁基)-8-{2-[4-(4-苯基丁氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸乙基酯
在氩气气氛下和加压氢气氛下向实施例47制备的化合物(100mg)的乙醇(3mL)溶液中加入10%钯-碳(50w/w%,吸湿性,20mg),混合物在室温搅拌3小时,通过celite过滤混合物,浓缩滤液,得到标题化合物(103mg),具有如下物理数据。
TLC:Rf0.61(正己烷∶乙酸乙酯=2∶1);
NMR(CDCl3):δ1.25(t,6H),1.74-1.95(m,6H),2.35(t,2H),2.68(t,2H),2.77-2.95(m,4H),3.18-3.35(m,2H),3.50(d,2H),3.92-3.97(m,2H),4.14(q,2H),4.22(q,2H),4.80(t,1H),6.51(dd,1H),6.57(dd,1H),6.75(t,1H),6.80(d,2H),7.14(d,2H),7.18-7.21(m,3H),7.25-7.30(m,2H)。
实施例49-实施例49(1)
通过用实施例47→实施例48制备的化合物代替实施例2制备的化合物,根据实施例25的方法制备具有以下物理数据的本发明的化合物。
实施例49:4-(3-羧基丙基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.45(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.78(m,6H),2.26(t,2H),2.58-2.65(m,2H),3.18-3.30(m,2H),3.44(d,2H),3.95-4.02(m,2H),4.97(t,1H),6.62(d,1H),6.74(t,1H),6.88-6.94(m,3H),7.08(d,1H),7.13-7.29(m,6H),7.42(d,2H).
实施例49(1):4-(3-羧基丙基)-8-{2-[4-(4-苯基丁氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.43(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.63-1.75(m,6H),2.25(t,2H),2.59-2.88(m,6H),3.19(t,2H),3.35-3.46(m,2H),3.91(t,2H),4.91(t,1H),6.38(dd,1H),6.55-6.64(m,2H),6.78(d,2H),7.08(d,2H),7.12-7.28(m,5H).
实施例50:(2S)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸和(2R)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸(光学分离)
使用光学分离柱对实施例31制备的化合物进行光学分离;得到保留时间为29.8分钟(21mg,>97%e.e.)的化合物和保留时间为34.5分钟(21mg>98%e.e.)的化合物,这两种化合物对应于实施例31制备的化合物的两种非对映异构体。
未确定立体化学,但是一个为(2S)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸,另一个为(2R)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸。
分离条件和纯化方法如下所示:
柱:CHIRALCEL OD(10mmI.D.x250mm)
洗脱液:0.1%TFA的正己烷溶液/0.1%TFA的异丙醇溶液=70∶30
流速:2ml/分钟
柱温:40℃
注射量200μL(实施例3制备的化合物(45mg)的异丙醇(6mL)溶液)
注射次数:30
分离级分的纯化方法:为了除去TFA,向收集的级分中加入三乙胺(5mL),浓缩混合物,向残余物中加入乙酸乙酯和水,得到的混合物被提取,提取物用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到目标光学活性的异构体。
根据以下分析条件测量光学纯度。
柱:CHIRALCEL OD(0.46mmI.D.x250mm)
洗脱液:0.1%TFA的正己烷溶液/0.1%TFA的异丙醇溶液=70∶30
流速:0.5mL/分钟
柱温:40℃
注射量:1μL[化合物(1mg)的异丙醇(1mL)溶液]
实施例51:4-(3-羧基丙基)-8-{[2-甲基-4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
根据实施例47→实施例3→实施例4→实施例25所述相同方法,使用实施例28制备的化合物代替实施例46制备的化合物,使用2-甲基-4-(4-苯基丁氧基)苯甲酸代替4-(4-苯基丁氧基)苯甲酸,得到具有以下物理数据的化合物。
TLC:Rf0.41(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.62-1.78(m,6H),2.26(t,2H),2.39(s,3H),2.59-2.68(m,2H),3.18-3.48(m,4H),3.96-4.08(m,2H),4.91-4.99(m,1H),6.56(d,1H),6.72-6.83(m,3H),7.12-7.29(m,6H),7.44(d,1H),8.87(s,1H).
实施例52:
根据实施例28→实施例25所述相同方法,使用相应的化合物代替实施例27制备的化合物,得到具有以下物理数据的化合物。
实施例52:4-(3-羧基丙基)-8-{[2,6-二甲基-4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.63-1.85(m,6H),2.15-2.39(m,8H),2.58-2.78(m,2H),3.11-3.35(m,2H),3.39-3.60(m,2H),3.96-4.11(m,2H),4.79-4.88(m,1H),6.50-6.82(m,5H),7.11-7.40(m,5H),8.64(brs.,1H).
实施例52(1):4-(3-羧基丙基)-8-({4-[(E)-2-(7-氯-2-喹啉基)乙烯基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.27(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.63-1.78(m,2H),2.24-2.29(m,2H),3.23-3.30(m,2H),3.41-3.52(m,2H),4.96-5.01(m,1H),6.61(d,1H),6.78(t,1H),7.19(d,1H),7.58-7.64(m,2H),7.87-8.03(m,8H),8.43(d,1H),9.39(s,1H).
实施例52(2):4-(3-羧基丙基)-8-{(Z)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.45(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.60-1.81(m,6H),2.26(t,2H),2.60(t,2H),3.22(t,2H),3.83-3.97(m,2H),4.90(t,1H),6.36(dd,1H),6.44-6.47(m,2H),6.51-6.60(m,2H),6.74(d,2H),7.12-7.28(m,7H),12.59(brs,1H).
实施例52(3):4-(3-羧基丙基)-8-({4-[2-(2,3-二氢-1H-茚-2-基)乙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=95∶5∶0.5);
NMR(DMSO-d6):δ1.67-1.77(m,2H),1.91-1.98(m,2H),2.27(t,2H),2.55-2.67(m,3H),2.98-3.07(m,2H),3.22-3.30(m,2H),3.41-3.52(m,2H),4.14(t,2H),5.00(t,1H),6.60(dd,1H),6.77(t,1H),7.04-7.25(m,7H),7.89(d,2H),9.20(s,1H).
实施例52(4):8-{[4-(苯基甲基氧基)苯甲酰基]氨基}-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.39(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.66-1.76(m,2H),2.26(t,2H),3.20-3.30(m,2H),3.40-3.51(m,2H),4.99(t,1H),5.19(s,2H),6.59(dd,1H),6.76(t,1H),7.11-7.18(m,3H),7.32-7.46(m,5H),7.88(d,2H),9.20(s,1H),12.13(brs,1H),13.00(brs,1H).
实施例52(5):4-(3-羧基丙基)-8-[(4-羟基苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.32(二氯甲烷∶甲醇∶乙酸=80∶20∶1);
NMR(DMSO-d6):δ1.63-1.78(m,2H),2.26(t,2H),3.20-3.30(m,2H),3.39-3.51(m,2H),5.00(t,1H),6.57(d,1H),6.75(t,1H),6.85(d,2H),7.19(d,1H),7.77(d,2H),9.09(s,1H).
实施例52(6):4-(3-羧基丙基)-8-{[4-(3-苯基丙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.24(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.65-1.77(m,2H),1.97-2.08(m,2H),2.27(t,2H),2.74(t,2H),3.20-3.30(m,2H),3.40-3.50(m,2H),4.03(t,2H),5.00(t,1H),6.59(d,1H),6.76(t,1H),7.04(d,2H),7.15-7.30(m,6H),7.87(d,2H),9.19(s,1H).
实施例52(7):4-(3-羧基丙基)-8-({4-[(5-苯基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.38-1.47(m,2H),1.57-1.79(m,6H),2.26(t,2H),2.59(t,2H),3.21-3.30(m,2H),3.39-3.50(m,2H),4.02(t,2H),4.91-4.98(m,1H),6.57(d,1H),6.75(t,1H),7.02(d,2H),7.12-7.28(m,6H),7.86(d,2H),9.16(s,1H).
实施例52(8):4-(3-羧基丙基)-8-({4-[(6-苯基己基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.33(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.26-1.51(m,4H),1.52-1.65(m,2H),1.65-1.83(m,4H),2.27(t,2H),2.57(t,2H),3.12-3.30(m,2H),3.38-3.56(m,2H),4.02(t,2H),4.90-4.98(m,1H),6.58(d,1H),6.76(t,1H),7.02(d,2H),7.09-7.40(m,6H),7.87(d,2H).
实施例52(9):4-(3-羧基丙基)-8-[(2,3-二氢-1H-茚-2-基乙酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.29(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.55-1.87(m,2H),2.26(t,2H),2.41-2.90(m,5H),2.94-3.12(m,2H),3.13-3.31(m,2H),3.34-3.60(m,2H),4.94(t,1H),6.52(d,1H),6.70(t,1H),7.04-7.14(m,2H),7.15-7.32(m,3H),8.98(s,1H),12.55(s,2H).
实施例52(10):4-(3-羧基丙基)-8-({4-[(7-苯基庚基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.20-1.48(m,6H),1.50-1.64(m,2H),
1.64-1.84(m,4H),2.27(t,2H),2.56(t.2H),3.14-3.59(m,4H),4.03(t,2H),4.98(t,1H),6.59(d,1H),6.77(t,1H),7.03(d,2H),7.09-7.34(m,6H),7.87(d,2H),9.18(s,1H),12.61(s,2H).
实施例52(11):4-(3-羧基丙基)-8-{[4-(环庚基氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.56(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.34-1.83(m,12H),1.84-2.08(m,2H),2.26(t,2H),2.94-3.73(m,4H),4.46-4.73(m,1H),4.77-5.04(m,1H),6.56(d,1H),6.74(t,1H),6.99(d,2H),7.23(d,1H),7.85(d,2H),9.14(s,1H).
实施例52(12):8-{[2-(苄基苯基甲基氧基)苯甲酰基]氨基}-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.33(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.54-1.84(m,2H),2.26(t,2H),3.00-3.60(m,4H),4.50-4.81(m,1H),5.48(s,2H),6.53(d,1H),6.76(t,1H),7.09(t,1H),7.22-7.41(m,4H),7.42-7.60(m,3H),7.80(d,1H),8.06(dd,1H),10.53(s,1H).
实施例52(13):8-{[3-(苯基甲基氧基)苯甲酰基]氨基}-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.33(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.53-1.88(m,2H),2.27(t,2H),3.08-3.59(m,4H),4.97(t,1H),5.17(s,2H),6.60(d,1H),6.78(t,1H),7.09-7.28(m,2H),7.27-7.66(m,8H),9.29(s,1H),11.85-13.34(m,2H).
实施例52(14):4-(3-羧基丙基)-8-{[4-(2-苯基乙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.49(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.57-1.83(m,2H),2.27(t,2H),2.93-3.14(m,2H),3.15-3.63(m,4H),4.27(t,2H),4.98(t,1H),6.58(d,1H),6.76(t,1H),7.05(d,2H),7.12-7.62(m,6H),7.87(d,2H),9.19(s,1H).
实施例52(15):4-(3-羧基丙基)-8-{[2-(3-苯基丙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.26(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.59-1.79(m,2H),2.05-2.21(m,2H),2.26(t,2H),2.59-2.85(m,2H),3.04-3.58(m,4H),4.03-4.46(m,2H),4.86(t,1H),6.39-6.63(m,1H),6.76(t,1H),7.02-7.37(m,7H),7.42-7.66(m,1H),7.82(d,1H),8.07(dd,1H),10.28(s,1H).
实施例52(16):4-(3-羧基丙基)-8-{[3-(3-苯基丙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.27(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.59-1.83(m,2H),1.92-2.13(m,2H),2.27(t,2H),2.64-2.87(m,2H),3.06-3.60(m,4H),4.04(t,2H),4.96(t,1H),6.51-6.68(m,1H),6.78(t,1H),7.07-7.56(m,10H),9.30(s,1H).
实施例52(17):4-(3-羧基丙基)-8-({2-[(5-苯基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.38(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.28-1.49(m,2H),1.50-1.92(m,6H),2.26(t,2H),2.47-2.59(m,2H),3.08-3.63(m,4H),4.24(t,2H),5.00(t,1H),6.53(dd,1H),6.75(t,1H),7.03-7.29(m,7H),7.47-7.58(m,1H),7.81(dd,1H),8.08(dd,1H),10.32(s,1H).
实施例52(18):4-(3-羧基丙基)-8-({2-[(6-苯基己基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.34(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.12-1.63(m,6H),1.60-1.99(m,4H),2.27(t,2H),2.38-2.63(m,2H),2.95-3.66(m,4H),4.01-4.44(m,2H),4.83-5.11(m,1H),6.53(d,1H),6.75(t,1H),7.01-7.32(m,7H),7.41-7.63(m,1H),7.81(d,1H),8.08(d,1H),10.31(s,1H).
实施例52(19):4-(3-羧基丙基)-8-[(2-羟基苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.40(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.72(t,2H),2.27(t,2H),3.23-3.25(m,2H),3.47-3.49(m,2H),5.03(dd,1H),6.53(d,1H),6.74(dd,1H),6.92-7.01(m,2H),7.38(ddd,1H),7.72(d,1H),7.99(dd,1H),10.65(s,1H),11.71(s,1H),12.15(s,1H),13.28(s,1H).
实施例52(20):4-(3-羧基丙基)-8-[(3-羟基苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.20(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.69-1.76(m,2H),2.27(t,2H),3.22-3.25(m,2H),3.41-3.52(m,2H),5.01(dd,1H),6.59(dd,1H),6.77(dd,1H),6.94-6.98(m,1H),7.22-7.31(m,4H),9.13(s,1H),9.76(s,1H),12.22(s,1H),12.91(s,1H).
实施例52(21):4-(3-羧基丙基)-8-{[2-(2-苯基乙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.72(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.61-1.80(m,2H),2.27(t,2H),3.16(t,2H),3.23-3.32(m,2H),3.39-3.60(m,2H),4.30-4.54(m,2H),5.05(t,1H),6.55(dd,1H),6.77(dd,1H),7.12(dd,1H),7.16-7.35(m,6H),7.53(ddd,1H),7.79(dd,1H),8.08(dd,1H),10.29(s,1H),12.19(s,2H).
实施例52(22):4-(3-羧基丙基)-8-{[2-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.72(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.63-1.78(m,4H),1.79-1.93(m,2H),2.27(t,2H),2.61(t,2H),3.19-3.26(m,2H),3.35-3.55(m,2H),4.28(t,2H),4.93(t,1H),6.53(dd,1H),6.76(dd,1H),7.05-7.27(m,7H),7.53(ddd,1H),7.80(dd,1H),8.07(dd,1H),10.29(s,1H),12.31(s,2H).
实施例52(23):4-(3-羧基丙基)-8-{[3-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.61(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.69-1.79(m,6H),2.27(t,2H),2.58-2.70(m,2H),3.20-3.28(m,2H),3.42-3.49(m,2H),4.01-4.10(m,2H),4.97(t,1H),6.61(d,1H),6.78(dd,1H),7.05-7.32(m,7H),7.36-7.50(m,3H),9.29(s,1H),12.47(s,2H).
实施例52(24):4-(3-羧基丙基)-8-{[3-(2-苯基乙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.59(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.72(qd,2H),2.27(t,2H),3.06(t,2H),3.15-3.29(m,2H),3.39-3.51(m,2H),4.27(t,2H),4.98(t,1H),6.57-6.65(m,1H),6.78(dd,1H),7.11-7.25(m,3H),7.28-7.36(m,4H),7.38-7.49(m,3H),9.32(s,1H),12.30(s,2H).
实施例52(25):4-(3-羧基丙基)-8-({3-[(6-苯基己基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.53(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.29-1.51(m,4H),1.59(dt,2H),1.67-1.78(m,4H),2.27(t,2H),2.52-2.60(m,2H),3.22-3.35(m,2H),3.41-3.51(m,2H),4.02(t,2H),4.96(t,1H),6.61(dd,1H),6.78(dd,1H),7.11-7.20(m,5H),7.21-7.29(m,2H),7.38-7.48(m,3H),9.29(s,1H),12.37(s,2H).
实施例52(26):4-(3-羧基丙基)-8-({3-[(5-苯基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.53(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.39-1.52(m,2H),1.56-1.83(m,6H),2.27(t,2H),2.54-2.64(m,2H),3.16-3.27(m,2H),3.40-3.50(m,2H),4.03(t,2H),4.95(d,1H),6.60(d,1H),6.78(dd,1H),7.10-7.30(m,7H),7.36-7.50(m,3H),9.29(s,1H).
实施例52(27):4-(3-羧基丙基)-8-{[4-(4-戊烯基氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.61-1.94(m,4H),2.10-2.34(m,4H),3.13-3.27(m,2H),3.38-3.57(m,2H),4.05(t,2H),4.92-5.10(m,3H),5.73-5.98(m,1H),6.59(dd,1H),6.77(dd,1H),6.99-7.09(m,2H),7.19(d,1H),7.88(d,2H),9.19(s,1H),12.17(s,2H).
实施例52(28):4-(3-羧基丙基)-8-({4-[(4-甲基-3-戊烯基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.47(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.53-1.81(m,8H),2.16-2.32(m,2H),2.35-2.47(m,2H),3.18-3.28(m,2H),3.39-3.56(m,2H),4.02(t,2H),4.99(s,1H),5.12-5.26(m,1H),6.59(d,1H),6.77(dd,1H),7.03(d,2H),7.12-7.26(m,1H),7.88(d,2H),9.19(s,1H),12.09(s,2H).
实施例52(29):4-(3-羧基丙基)-8-{[4-(5-己烯基氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.64(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.43-1.58(m,2H),1.66-1.80(m,4H),2.03-2.14(m,2H),2.27(t,2H),3.20-3.27(m,2H),3.39-3.54(m,2H),4.05(t,2H),4.92-5.08(m,3H),5.74-5.91(m,,1H),6.59(dd,1H),6.77(dd,1H),6.99-7.07(m,2H),7.18(dd,1H),7.83-7.91(m,2H),9.19(s,1H),12.13(s,1H),12.91(s,1H).
实施例52(30):4-(3-羧基丙基)-8-({4-[(4-甲基戊基)氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.66(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ0.88(s,3H),0.90(s,3H),1.22-1.36(m,2H),1.57(td,1H),1.67-1.80(m,4H),2.27(t,2H),3.19-3.26(m,2H),3.38-3.54(m,2H),4.03(t,2H),5.00(t,1H),6.59(d,1H),6.77(dd,1H),7.03(d,2H),7.18(d,1H),7.87(d,2H),9.19(s,1H),12.12(s,1H),13.00(s,1H).
实施例52(31):4-(3-羧基丙基)-8-{[4-(4-氟丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.52(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.63-1.92(m,6H),2.19-2.34(m,2H),3.16-3.28(m,2H),3.39-3.57(m,2H),4.09(t,2H),4.43(t,1H),4.59(t,1H),5.01(t,1H),6.59(dd,1H),6.77(dd,1H),7.05(d,2H),7.18(d,1H),7.78-7.97(m,2H),9.19(s,1H),12.07(s,1H),13.02(s,1H).
实施例52(32):4-(3-羧基丙基)-8-{[4-(4,4,4-三氟丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.55(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.64-1.79(m,2H),1.88-2.03(m,2H),2.23-2.32(m,2H),2.34-2.46(m,2H),3.17-3.27(m,2H),3.39-3.54(m,2H),4.12(t,2H),5.00(t,1H),6.60(dd,1H),6.77(dd,1H),7.03-7.11(m,2H),7.18(d,1H),7.82-7.97(m,2H),9.20(s,1H),12.09(s,1H),13.02(s,1H).
实施例52(33):4-(3-羧基丙基)-8-{[4-(2-苯氧基乙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.64(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.63-1.81(m,2H),2.28(t,2H),3.16-3.27(m,2H),3.38-3.55(m,2H),4.30-4.36(m,2H),4.38-4.43(m,2H),4.98-5.05(m,1H),6.60(d,1H),6.77(dd,1H),6.91-7.02(m,3H),7.07-7.14(m,2H),7.18(dd,1H),7.25-7.34(m,2H),7.90(d,2H),9.22(s,1H),12.16(s,1H),12.95(s,1H).
实施例52(34):4-(3-羧基丙基)-8-({4-[(5-甲基-3-异噁唑基)甲氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.50(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.64-1.80(m,2H),2.27(t,2H),2.40(s,3H),3.19-3.27(m,2H),3.37-3.55(m,2H),5.00(t,1H),5.24(s,2H),6.34(s,1H),6.60(dd,1H),6.77(dd,1H),7.06-7.21(m,3H),7.84-7.93(m,2H),9.22(s,1H),12.07(s,1H),12.90(s,1H).
实施例52(35):8-({4-[3-(苯基甲基氧基)丙氧基]苯甲酰基}氨基)-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.70(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.64-1.80(m,2H),1.94-2.09(m,2H),2.22-2.32(m,2H),3.18-3.27(m,2H),3.38-3.53(m,2H),3.60(t,2H),4.14(t,2H),4.48(s,2H),5.00(dd,1H),6.59(d,1H),6.77(dd,1H),6.97-7.08(m,2H),7.19(dd,1H),7.22-7.37(m,4H),7.81-7.91(m,2H),9.18(s,1H),12.09(s,1H),13.03(s,1H).
实施例52(36):8-{[4-(1,3-苯并噻唑-2-基甲氧基)苯甲酰基]氨基}-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.58(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.65-1.80(m,2H),2.20-2.34(m,2H),3.19-3.27(m,2H),3.39-3.53(m,2H),4.99(t,1H),5.71(s,2H),6.55-6.63(m,1H),6.77(dd,1H),7.16(d,1H),7.19-7.28(m,2H),7.41-7.50(m,1H),7.51-7.59(m,1H),7.87-7.95(m,2H),7.99-8.06(m,1H),8.09-8.16(m,1H),9.24(s,1H),12.13(s,1H),12.93(s,1H).
实施例52(37):4-(3-羧基丙基)-8-[(4-{4-[(4’-甲氧基-1,1’-二苯基-4-基)氧基]丁氧基}苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.76(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.73(t,2H),1.85-1.94(m,4H),2.21-2.36(m,2H),3.19-3.26(m,2H),3.40-3.51(m,2H),3.77(s,3H),3.99-4.19(m,4H),4.88-5.04(m,1H),6.59(dd,1H),6.77(dd,1H),6.92-7.02(m,4H),7.03-7.12(m,2H),7.20(d,1H),7.44-7.58(m,4H),7.83-7.98(m,2H),9.18(s,1H),12.01(s,1H),12.94(s,1H).
实施例52(38):4-(3-羧基丙基)-8-{[4-(3-苯氧基丙氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.41(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.62-1.82(m,2H),2.08-2.37(m,4H),3.15-3.27(m,2H),3.36-3.52(m,2H),4.13(t,2H),4.22(t,2H),5.00(t,1H),6.59(d,1H),6.77(dd,1H),6.85-6.98(m,3H),7.07(d,2H),7.18(d,1H),7.24-7.38(m,2H),7.89(d,2H),9.19(s,1H),12.16(s,1H),12.92(s,1H).
实施例52(39):4-(3-羧基丙基)-8-{[4-(4-苯氧基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.43(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.63-1.79(m,2H),1.83-1.95(m,4H),2.23-2.33(m,2H),3.18-3.28(m,2H),3.38-3.53(m,2H),3.97-4.07(m,2H),4.08-4.17(m,2H),4.99(t,1H),6.59(dd,1H),6.77(dd,1H),6.86-6.98(m,3H),7.05(d,2H),7.16-7.21(m,1H),7.23-7.33(m,2H),7.88(d,2H),9.19(s,1H),12.19(s,1H),13.02(s,1H).
实施例52(40):8-({4-[2-(苯基甲基氧基)乙氧基]苯甲酰基}氨基)-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.40(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.65-1.81(m,2H),2.27(t,2H),3.19-3.27(m,2H),3.39-3.55(m,2H),3.73-3.83(m,2H),4.19-4.27(m,2H),4.56(s,2H),5.01(t,1H),6.59(dd,1H),6.77(dd,1H),7.07(d,2H),7.18(d,1H),7.24-7.39(m,5H),7.88(d,2H),9.20(s,1H),12.09(s,1H),12.81(s,1H).
实施例52(41):4-(3-羧基丙基)-8-({4-[2-(2-萘基)乙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.38(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.59-1.81(m,2H),2.27(t,2H),3.17-3.27(m,2H),3.37-3.55(m,2H),4.38(t,2H),4.92-5.03(m,2H),5.37(s,1H),6.59(dd,1H),6.77(dd,1H),7.01-7.23(m,3H),7.38-7.63(m,3H),7.81-8.03(m,6H),9.14-9.25(m,1H),12.14(s,1H),12.90(s,1H).
实施例52(42):4-(3-羧基丙基)-8-({4-[2-(1-萘基)乙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.38(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.63-1.80(m,2H),2.27(t,2H),3.14-3.30(m,2H),3.38-3.52(m,2H),3.56(t,2H),4.39(t,2H),4.84-5.02(m,1H),6.58(d,1H),6.76(dd,1H),7.05(d,2H),7.18(d,1H),7.42-7.62(m,4H),7.79-7.99(m,4H),8.17(d,1H),9.18(s,1H),12.51(s,2H).
实施例52(43):4-(3-羧基丙基)-8-{[4-(2,3-二氢-1H-茚-2-基甲氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.56(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.61-1.80(m,2H),2.27(t,2H),2.74-2.84(m,2H),2.86-2.99(m,1H),3.02-3.17(m,2H),3.17-3.28(m,2H),3.38-3.55(m,2H),4.06(d,2H),4.93-5.03(m,1H),6.59(dd,1H),6.77(dd,1H),6.96-7.30(m,7H),7.82-7.95(m,2H),9.19(s,1H),12.10(s,2H).
实施例52(44):4-(3-羧基丙基)-8-{[4-(2-萘基甲氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.32(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.54-1.79(m,2H),2.27(t,2H),3.12-3.27(m,2H),3.38-3.58(m,2H),4.93-5.03(m,1H),5.37(s,2H),6.52-6.63(m,1H),6.77(dd,1H),7.13-7.25(m,3H),7.46-7.65(m,3H),7.84-8.05(m,6H),9.20(s,1H),12.23(s,2H).
实施例52(45):4-(3-羧基丙基)-8-{[4-(1-萘基甲氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.28(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.64-1.80(m,2H),2.17-2.33(m,2H),3.17-3.27(m,2H),3.39-3.53(m,2H),4.90-5.05(m,1H),5.65(s,2H),6.52-6.63(m,1H),6.77(dd,1H),7.12-7.28(m,3H),7.44-7.63(m,3H),7.70(d,1H),7.83-8.02(m,4H),8.06-8.20(m,1H),9.21(s,1H),12.44(s,1H),12.98(s,1H).
实施例52(46):4-(3-羧基丙基)-8-{[4-(2,3-二氢-1H-茚-2-基氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.39(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.59-1.87(m,2H),2.27(t,2H),3.04(dd,2H),3.18-3.27(m,2H),3.32-3.56(m,4H),5.00(t,1H),5.24-5.44(m,1H),6.54-6.64(m,1H),6.77(d,1H),7.00-7.10(m,2H),7.11-7.31(m,5H),7.79-7.95(m,2H),9.19(s,1H),12.18(s,1H),12.93(s,1H).
实施例52(47):4-(3-羧基丙基)-8-({4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.40(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.53-1.93(m,7H),2.13-2.33(m,2H),2.57(t,2H),3.00(d,1H),3.05(d,1H),3.17-3.27(m,2H),3.38-3.54(m,2H),4.08(t,2H),4.99(t,1H),6.59(dd,1H),6.77(dd,1H),6.96-7.12(m,4H),7.14-7.23(m,3H),7.88(d,2H),9.18(s,1H),12.19(s,1H),12.99(s,1H).
实施例52(48):4-(3-羧基丙基)-8-{[(1-苯基-5-丙基-1H-吡唑-4-基)羰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.26(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ0.72(t,3H),1.43(sixtet,2H),1.73(五重峰,2H),2.27(t,2H),2.92(t,2H),3.23-3.30(m,2H),3.44-3.46(m,2H),4.94(t,1H),6.58(d,1H),6.76(t,1H),7.16(d,1H),7.47-7.60(m,5H),8.19(s,1H),9.01(s,1H),12.48(bs,2H).
实施例52(49):4-(3-羧基丙基)-8-[(2-喹喔啉基羰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.24(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.75(五重峰,2H),2.29(t,2H),3.28-3.31(m,2H),3.54(d,2H),5.16(t,1H),6.62(d,1H),6.85(t,1H),7.79(d,1H),8.01-8.06(m,2H),8.20-8.26(m,2H),9.61(s,1H),10.44(s,1H),12.09(bs,1H),13.26(bs,1H).
实施例52(50):8-[(1-苯并噻吩-2-基羰基)氨基]-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.21(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.74(五重峰,2H),2.27(t,2H),3.24-3.30(m,2H),3.47-3.50(m,2H),5.02(t,1H),6.64(d,1H),6.79(t,1H),7.09(d,1H),7.43-7.51(m,2H),7.96-8.06(m,2H),9.61(s,1H),12.09(bs,1H),13.03(bs,1H).
实施例52(51):4-(3-羧基丙基)-8-[(4-戊基苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.32(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ0.86(t,3H),1.22-1.34(m,4H),1.60(五重峰,2H),1.73(五重峰,2H),2.26-2.30(m,2H),2.62(t,2H),3.25-3.30(m,2H),3.46-3.48(m,2H),4.99-5.01(m,1H),6.60(d,1H),6.78(t,1H),7.21(d,1H),7.34(d,2H),7.83(d,2H),9.23(bs,1H),12.05(bs,1H),13.02(bs,1H).
实施例52(52):8-[(1,1’-联苯基-4-基羰基)氨基]-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.27(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.74(五重峰,2H),2.28(t,2H),3.23-3.30(m,2H),3.47-3.48(m,2H),4.96-4.98(m,1H),6.61(d,1H),6.79(t,1H),7.23(d,1H),7.39-7.44(m,1H),7.49(d,1H),7.51(d,1H),7.75(d,2H),7.83(d,2H),8.01(d,2H),9.36(s,1H),12.43(bs,2H).
实施例52(53):4-(3-羧基丙基)-8-({[3-(2-氯苯基)-5-甲基-4-异噁唑基]羰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.66(五重峰,2H),2.23(t,2H),2.76(s,3H),3.16-3.21(m,2H),3.28-3.42(m,2H),4.62(t,1H),6.49(t,1H),6.69(t,1H),7.37-7.40(m,1H),7.48-7.62(m,4H),8.25(s,1H),12.28(bs,2H).
实施例52(54):4-(3-羧基丙基)-8-(庚酰基氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.17(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ0.85(t,3H),1.23-1.39(m,6H),1.55(五重峰,2H),1.70(五重峰,2H),2.26(t,2H),2.34(t,2H),3.19-3.40(m,2H),3.43(dd,2H),4.95(t,1H),6.52(d,1H),6.68(t,1H),7.22(d,1H),8.86(s,1H),12.45(bs,2H).
实施例52(55):4-(3-羧基丙基)-7-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.23(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.49-1.93(m,6H),2.26(t,2H),2.63(t,2H),3.11-3.56(m,4H),4.05(t,2H),4.85(t,1H),6.67(d,1H),6.99(d,2H),7.06-7.42(m,7H),7.87(d,2H),9.75(s,1H).
实施例52(56):4-(3-羧基丙基)-7-{[3-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.33(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.51-1.98(m,6H),2.27(t,2H),2.65(t,2H),2.95-3.60(m,4H),3.92-4.24(m,2H),4.84(t,1H),6.69(d,1H),6.99-7.34(m,8H),7.33-7.70(m,3H),9.87(s,1H).
实施例52(57):4-(3-羧基丙基)-8-({4-[4-(4-氟苯基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.30(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.62-1.82(m,6H),2.27(t,2H),2.63(t,2H),3.15-3.27(m,2H),3.38-3.58(m,2H),4.06(t,2H),4.99(t,1H),6.58(dd,1H),6.76(dd,1H),6.92-7.13(m,4H),7.15-7.33(m,3H),7.78-7.99(m,2H),9.17(s,1H),12.13(s,2H).
实施例52(58):4-(3-羧基丙基)-6-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.31(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.62-1.87(m,6H),2.28(t,2H),2.64(t,2H),3.09-3.56(m,4H),3.96-4.15(m,2H),4.83(t,1H),6.69(d,1H),7.01(d,2H),7.07-7.40(m,7H),7.89(d,2H),9.74(s,1H).
实施例52(59):4-(3-羧基丙基)-6-{[3-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.31(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.64-1.90(m,6H),2.27(t,2H),2.56-2.71(m,2H),3.10-3.57(m,4H),3.92-4.17(m,2H),4.81(t,1H),6.69(d,1H),7.00(dd,1H),7.05-7.53(m,10H),9.85(s,1H).
实施例52(60):8-({4-[4-(苯基甲基氧基)丁氧基]苯甲酰基}氨基)-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.37(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.51-1.96(m,6H),2.27(t,2H),3.11-3.58(m,6H),4.06(t,2H),4.46(s,2H),4.99(t,1H),6.59(d,1H),6.77(t,1H),7.03(d,2H),7.13-7.42(m,6H),7.87(d,2H),9.18(s,1H).
实施例52(61):4-(3-羧基丙基)-8-({4-[4-(4-甲基苯基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.37(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.58-1.84(m,6H),2.14-2.34(m,5H),2.59(t,2H),3.14-3.31(m,2H),3.37-3.59(m,2H),4.06(t,2H),4.99(t,1H),6.59(t,1H),6.77(t,1H),6.95-7.13(m,6H),7.19(d,1H),7.87(d,2H),9.17(s,1H).
实施例52(62):4-(3-羧基丙基)-8-({4-[4-(4-甲氧基苯基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.37(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.56-1.87(m,6H),2.17-2.36(m,2H),2.58(t,2H),3.12-3.38(m,2H),3.38-3.56(m,2H),3.71(s,3H),4.06(t,2H),4.83-5.12(m,1H),6.59(dd,1H),6.77(t,1H),6.80-6.89(m,2H),7.03(d,2H),7.07-7.17(m,2H),7.19(d,1H),7.87(d,2H),9.17(s,1H).
实施例52(63):4-(3-羧基丙基)-8-({4-[4-(2-甲基苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.58-2.03(m,6H),2.12(s,3H),2.27(t,2H),3.11-3.61(m,4H),3.96-4.09(m,2H),4.13(t,2H),4.92(t,1H),6.52-6.63(m,1H),6.69-6.86(m,2H),6.91(d,1H),7.05(d,2H),7.09-7.17(m,2H),7.21(d,1H),7.88(d,2H),9.16(s,1H).
实施例52(64):4-(3-羧基丙基)-8-({4-[4-(3-甲基苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.58-2.02(m,6H),2.17-2.34(m,5H),3.09-3.56(m,4H),3.95-4.05(m,2H),4.06-4.19(m,2H),4.80-4.97(m,1H),6.57(dd,1H),6.66-6.83(m,4H),7.05(d,2H),7.14(t,1H),7.22(d,1H),7.74-8.00(m,2H),9.16(s,1H).
实施例52(65):4-(3-羧基丙基)-8-({4-[4-(4-甲基苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.63-1.95(m,6H),2.21(s,3H),2.27(t,2H),3.14-3.54(m,4H),3.92-4.05(m,2H),4.11(t,2H),4.96(t,1H),6.58(dd,1H),6.69-6.87(m,3H),6.97-7.12(m,4H),7.13-7.25(m,1H),7.88(d,2H),9.17(s,1H).
实施例52(66):4-(3-羧基丙基)-8-({4-[4-(2-氟苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.58-1.97(m,6H),2.26(t,2H),3.03-3.57(m,4H),4.03-4.23(m,4H),4.76-4.94(m,1H),6.56(d,1H),6.74(t,1H),6.85-6.97(m,1H),6.98-7.31(m,6H),7.87(d,2H),9.17(s,1H).
实施例52(67):4-(3-羧基丙基)-8-({4-[4-(2-甲氧基苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.56-2.03(m,6H),2.26(t,2H),3.143.54(m,4H),3.73(s,3H),4.00(t,2H),4.12(t,2H),4.75-4.96(m,1H),6.56(d,1H),6.74(t,1H),6.81-6.99(m,4H),7.05(d,2H),7.22(d,1H),7.88(d,2H),9.17(s,1H).
实施例52(68):4-(3-羧基丙基)-8-({4-[4-(2-氯苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.58-2.03(m,6H),2.27(t,2H),3.11-3.56(m,4H),4.05-4.20(m,4H),4.95(t,1H),6.58(dd,1H),6.76(t,1H),6.89-6.98(m,1H,)7.05(d,2H),7.12-7.23(m,2H),7.24-7.33(m,1H),7.41(dd,1H),7.88(d,2H),9.19(s,1H).
实施例52(69):4-(3-羧基丙基)-8-[(4-{4-[2-(三氟甲基)苯氧基]丁氧基}苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.60-2.00(m,6H),2.27(t,2H),2.93-3.61(m,4H),3.96-4.29(m,4H),4.95(t,1H),6.58(dd,1H),6.76(t,1H),6.99-7.13(m,3H),7.19(d,1H),7.26(d,1H),7.56-7.68(m,2H),7.88(d,2H),9.19(s,1H).
实施例52(70):4-(3-羧基丙基)-8-({4-[3-(2-氟苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.35(甲醇∶二氯甲烷∶乙酸=1∶9∶0.1);
NMR(DMSO-d6):δ1.60-1.82(m,2H),2.09-2.36(m,4H),3.13-3.61(m,4H),4.10-4.33(m,4H),5.00(t,1H),6.58(d,1H),6.77(t,1H),6.85-6.99(m,1H),7.01-7.30(m,6H),7.88(d,2H),9.21(s,1H).
实施例52(71):4-(3-羧基丙基)-8-({4-[3-(3-氟苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.34(甲醇∶二氯甲烷∶乙酸=1∶9∶0.1);
NMR(DMSO-d6):δ1.61-1.81(m,2H),2.10-2.34(m,4H),3.10-3.56(m,4H),4.05-4.31(m,4H),4.89-5.06(m,1H),6.59(d,1H),6.68-6.88(m,4H),7.07(d,2H),7.13-7.37(m,2H),7.88(d,2H),9.20(s,1H).
实施例52(72):4-(3-羧基丙基)-8-({4-[3-(3-氯苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.79(m,2H),2.13-2.32(m,4H),3.20-3.28(m,2H),3.40-3.50(m,2H),4.12-4.25(m,4H),4.96-4.92(s,1H),6.58(d,1H),6.76(t,1H),6.90-7.11(m,5H),7.20(d,1H),7.29(t,1H),7.89(d,2H),9.19(s,1H).
实施例52(73):4-(3-羧基丙基)-8-({4-[3-(2-氯苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.78(m,2H),2.17-2.32(m,4H),3.20-3.30(m,2H),3.43-3.50(m,2H),4.18-4.29(m,4H),4.98(t,1H),6.59(d,1H),6.76(t,1H),6.91-6.98(m,1H),7.07(d,2H),7.18(d,2H),7.25-7.33(m,1H),7.41(dd,1H),7.89(d,2H),9.21(s,1H).
实施例52(74):4-(3-羧基丙基)-8-[(4-{3-[3-(三氟甲基)苯氧基]丙氧基}苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.78(m,2H),2.16-2.31(m,4H),3.20-3.29(m,2H),3.43-3.48(m,2H),4.19-4.27(m,4H),4.97(t,1H),6.58(d,1H),6.76(t,1H),7.07(d,2H),7.17(d,1H),7.23-7.31(m,3H),7.51(t,1H),7.88(d,2H),9.20(s,1H).
实施例52(75):4-(3-羧基丙基)-8-[(4-{3-[2-(三氟甲基)苯氧基]丙氧基}苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.64-1.79(m,2H),2.16-2.31(m,4H),3.19-3.31(m,2H),3.40-3.52(m,2H),4.22(t,2H),4.28(t,2H),5.01(t,1H),6.59(d,1H),6.77(t,1H),7.01-7.13(m,3H),7.16(d,1H),7.29(d,1H),7.56-7.67(m,2H),7.88(d,2H),9.21(s,1H).
实施例52(76):4-(3-羧基丙基)-8-({4-[3-(2-甲基苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.64-1.81(m,2H),2.14(s,3H),2.16-2.31(m,4H),3.19-3.29(m,2H),3.39-3.55(m,2H),4.13(t,2H),4.25(t,2H),5.01(t,1H),6.59(d,1H),6.73-6.86(m,2H),6.94(d,1H),7.08(d,2H),7.10-7.15(m,2H),7.17(dd,1H),7.89(d,2H),9.21(s,1H).
实施例52(77):4-(3-羧基丙基)-8-({4-[3-(4-氟苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.23(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.64-1.80(m,2H),2.20(t,2H),2.27(t,2H),3.18-3.26(m,2H),3.42-3.54(m,2H),4.11(t,2H),4.21(t,2H),4.97(s,1H),6.57-6.63(m,2H),6.76(t,1H),6.86-7.19(m,6H),7.88(d,2H),9.20(s,1H),12.49(bs,2H).
实施例52(78):4-(3-羧基丙基)-8-({4-[3-(2-氯-4-氟苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.23(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.83(m,2H),2.10-2.39(m,4H),3.19-3.29(m,2H),3.41-3.54(m,2H),4.13-4.42(m,4H),4.96(s,1H),6.58(d,1H),6.76(t,1H),7.00-7.30(m,5H),7.42(dd,1H),7.88(d,2H),9.21(s,1H),12.41(bs,2H).
实施例52(79):4-(3-羧基丙基)-8-({4-[3-(4-氯苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.49(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.66-1.81(m,2H),2.12-2.36(m,4H),3.19-3.29(m,2H),3.39-3.54(m,2H),4.13(t,2H),4.21(t,2H),5.01(t,1H),6.60(d,1H),6.77(t,1H),6.99(d,2H),7.07(d,2H),7.19(d,1H),7.31(d,2H),7.88(d,2H),9.20(s,1H).
实施例52(80):4-(3-羧基丙基)-8-({4-[3-(4-甲基苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.51(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.66-1.81(m,2H),2.11-2.21(m,2H),2.21(s,3H),2.27(t,2H),3.20-3.28(m,2H),3.40-3.55(m,2H),4.09(t,2H),4.21(t,2H),5.00(t,1H),6.59(d,1H),6.77(t,1H),6.84(d,2H),7.03-7.12(m,4H),7.19(d,1H),7.88(d,2H),9.19(s,1H).
实施例52(81):4-(3-羧基丙基)-8-({4-[3-(3-甲基苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.48(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.67-1.80(m,2H),2.12-2.25(m,2H),2.23-2.34(m,5H),3.19-3.29(m,2H),3.39-3.56(m,2H),4.12(t,2H),4.21(t,2H),5.00(t,1H),6.59(d,1H),6.70-6.82(m,4H),7.07(d,2H),7.11-7.24(m,2H),7.89(d,2H),9.19(s,1H).
实施例52(82):4-(3-羧基丙基)-8-({4-[4-(3-氯苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.25(二氯甲烷∶甲醇=4∶1);
NMR(DMSO-d6):δ0.76-1.29(m,4H),1.67-1.78(m,2H),1.82-1.95(m,4H),2.20-2.34(m,2H),3.98-4.18(m,4H),4.63-4.77(m,1H),6.54(d,1H),6.63-7.37(m,8H),7.88(d,2H),9.15(brs,1H).
实施例52(83):4-(3-羧基丙基)-8-({4-[3-(2,6-二氯苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.50(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.66-1.81(m,2H),2.18-2.32(m,4H),3.20-3.28(m,2H),3.40-3.54(m,2H),4.16(t,2H),4.30(t,2H),4.97-5.02(m,1H),6.59(d,1H),6.76(t,1H),7.08(d,2H),7.12-7.22(m,2H),7.44-7.51(m,2H)7.85-7.94(d,2H),9.20(s,1H).
实施例52(84):4-(3-羧基丙基)-8-({4-[3-(2,6-二甲基苯氧基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.50(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.66-1.81(m,2H),2.13-2.24(m,8H),2.28(t,2H),3.20-3.28(m,2H),3.39-3.56(m,2H),3.90(t,2H),4.30(t,2H),5.01(t,1H),6.60(d,1H),6.77(t,1H),6.85-6.94(m,1H),6.96-7.03(m,2H),7.10(d,2H),7.19(d,1H),7.90(d,2H),9.21(s,1H).
实施例52(85):4-(3-羧基丙基)-8-({4-[4-(2,6-二氟苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.27(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.62-2.01(m,6H),2.27(t,2H),3.16-3.55(m,4H),4.04-4.23(m,4H),4.98(t,1H),6.59(d,1H),6.77(t,1H),6.98-7.29(m,6H),7.88(d,2H),9.18(s,1H).
实施例52(86):4-(3-羧基丙基)-8-({4-[4-(2,6-二氯苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.34(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.61-2.08(m,6H),2.27(t,2H),3.16-3.57(m,4H),3.97-4.26(m,4H)4.98(t,1H)6.59(d,1H),6.77(t,1H),7.06(d,2H),7.12-7.26(m,2H),7.49(d,2H),7.89(d,2H),9.19(s,1H).
实施例53:4-(4-甲氧基-4-氧代丁基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
向实施例30制备的化合物(145mg)的异丙醇(1mL)-四氢呋喃(1mL)溶液中加入2M氢氧化钠水溶液(0.126mL),混合物在冰冷却下搅拌4小时,在室温下搅拌11小时,向混合物中加入2M盐酸(0.126mL),反应混合物用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(二氯甲烷∶甲醇=99∶1to 96∶4),得到标题化合物(101mg).
TLC:Rf0.41(二氯甲烷∶甲醇=85∶15);
NMR(CDCl3/CD3OD):δ1.71-1.91(m,6H),2.35(t,2H),2.65(t,2H),3.14-3.31(m,2H),3.40-3.55(m,2H),3.63(s,3H),3.97(t,2H),4.70-4.75(m,1H),6.53(d,1H),,6.79(t,1H),6.91(d,2H),7.10-7.26(m,5H),7.34(d,1H),7.85(d,2H).
实施例54:4-(8-[4-(4-苯基丁氧基)苯甲酰基]氨基-2-[(苯基磺酰基)氨基]羰基-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸甲基酯
向实施例53制备的化合物(100mg)的二氯甲烷(2mL)溶液中加入苯磺酰胺(29mg)、1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺(42mg)和4-二甲基氨基吡啶(27mg),所得混合物在室温搅拌15小时,向混合物中加入氯化铵的饱和水溶液和乙酸乙酯,所得混合物用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(二氯甲烷∶乙酸乙酯=90∶10→二氯甲烷∶甲醇=97∶3→80∶20),得到所需化合物(68mg)。
TLC:Rf0.57(二氯甲烷∶甲醇=90∶10);
NMR(CD3OD):δ1.63-1.93(m,6H),2.22-2.78(m,2H),2.69(t,2H),3.02-3.18(m,2H),3.30-3.34(m,1H),3.49(dd,1H),3.65(s,3H),4.05-4.10(m,2H),4.78(t,1H),6.60(dd,1H),6.85(t,1H),6.90-6.96(m,1H),7.01(d,2H),7.12-7.28(m,5H),7.41-7.47(m,2H),7.53-7.59(m,1H),7.78-7.80(m,2H),7.95(d,2H).
实施例55:4-(8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-{[(苯基磺酰基)氨基]羰基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
用实施例7制备的化合物代替实施例54制备的化合物,根据实施例8的方法制备具有以下物理数据的本发明的化合物。
TLC:Rf0.48(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.43-1.82(m,6H),2.16(t,2H),2.64(t,2H),2.98-3.18(m,2H),3.24-3.42(m,2H),4.02-4.16(m,2H),4.93-5.03(m,1H),6.58-6.61(m,1H),6.79-6.89(m,2H),7.05(d,2H),7.13-7.30(m,5H),7.50-7.55(m,2H),7.65(t,1H),7.75(d,2H),7.94(d,2H),9.83(brs,1H),12.06(brs,1H),12.55(brs,1H).
实施例55(1)-实施例55(21)
使用实施例30制备的化合物或其相应的化合物并且使用苯磺酰胺或其相应的磺酰胺,根据实施例53→实施例54→实施例8的方法,制备具有以下物理数据的本发明的化合物。
实施例55(1):4-(2-({[(2-甲基苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.48(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.36-1.61(m,2H),1.66-1.83(m,4H),2.12(t,2H),2.28(s,3H),2.65(t,2H),2.96-3.15(m,2H),3.16-3.49(m,2H),4.02-4.15(m,2H),4.84-5.13(m,1H),6.55-6.67(m,1H),6.76-6.92(m,2H),7.05(d,2H),7.11-7.60(m,8H),7.80-8.10(m,3H),9.94(s,1H),12.04(s,1H),12.62(s,1H).
实施例55(2):4-(2-({[(4-甲基苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.47(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.45-1.64(m,2H),1.66-1.87(m,4H),2.17(t,2H),2.36(s,3H),2.65(t,2H),2.97-3.14(m,2H),3.19-3.54(m,2H),3.95-4.22(m,2H),4.79-5.07(m,1H),6.60(d,1H),6.76-6.96(m,2H),7.06(d,2H),7.12-7.45(m,7H),7.63(d,2H),7.95(d,2H),9.81(s,1H),12.05(s,1H),12.45(s,1H).
实施例55(3):4-(2-({[(2-氯苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.58(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(CDCl3):δ1.59-1.93(m,6H),2.17(t,2H),2.71(t,2H),2.99-3.09(m,1H),3.14-3.35(m,2H),3.69(dd,1H),4.04(t,2H),4.82(s,1H),6.62-6.70(m,2H),6.89(t,1H),6.95(d,2H),7.14-7.34(m,4H),7.34-7.52(m,3H),7.74(s,1H),7.93(d,2H),8.25(d,1H).
实施例55(4):4-(2-({[(3-氯苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.60(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(CDCl3):δ1.62-1.94(m,6H),2.28(t,2H),2.71(t,2H),3.04-3.24(m,2H),3.29(dd,1H),3.64(dd,1H),4.05(t,2H),4.71-4.85(m,1H),6.61(t,2H),6.89(t,1H),6.97(d,2H),7.12-7.42(m,5H),7.43-7.58(m,1H),7.71(s,1H),7.81(d,1H),7.85-7.99(m,2H).
实施例55(5):4-(2-({[(4-氯苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.56(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.62-1.64(m,2H),1.73-1.75(m,4H),2.21(t,2H),2.65(t,2H),3.12-3.14(m,2H),3.30-3.40(m,2H),4.05-4.08(m,2H),4.72(bs,1H),6.54(d,1H),6.77(t,1H),7.04(d,2H),7.10-7.38(m,6H),7.48-7.51(m,2H),7.71(d,2H),7.91(d,2H),9.41(bs,1H),12.06(bs,1H),12.64(bs,1H).
实施例55(6):4-(2-{[(甲基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.59(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(CDCl3):δ1.72-2.02(m,6H),2.40(t,2H),2.70(t,2H),3.13-3.22(m,1H),3.21(s,3H),3.32-3.27(m,2H),3.73(dd,1H),4.02(t,2H),4.87(s,1H),6.64(t,2H),6.85(t,1H),6.93(d,2H),7.15-7.24(m,2H),7.24-7.36(m,2H),7.80(s,1H),7.88(d,2H).
实施例55(7):4-(2-{[(苄基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.30(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.73-1.78(m,6H),2.31(t,2H),2.64(t,2H),3.30-3.38(m,1H),3.45-3.55(m,1H),4.03-4.05(m,2H),4.71(s,2H),5.06(s,1H),6.72(d,1H),6.83(t,1H),6.93-7.05(m,3H),7.14-7.30(m,10H),7.80(t,2H),9.68(bs,1H),11.98(bs,1H),12.09(bs,1H).
实施例55(8):4-[8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-({[(三氟甲基)磺酰基]氨基}羰基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸
TLC:Rf 0.35(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(CDCl3):δ1.82-1.83(m,6H),2.24-2.26(m,2H),2.69(t,2H),3.03-3.08(m,1H),3.31(t,2H),3.60-3.64(m,1H),3.98-4.00(m,2H),4.78(s,1H),6.49-6.53(m,1H),6.78-6.80(m,1H),6.91(d,2H),7.16-7.20(m,3H),7.26-7.31(m,3H),7.80(d,2H).
实施例55(9):4-(2-({[(4-甲氧基苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.52(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.52-1.59(m,2H),1.74-1.76(m,4H),2.16-2.20(m,2H),2.54-2.66(m,2H),3.06-3.10(m,2H),3.24-3.42(m,2H),3.82(s,3H),4.07-4.09(s,2H),4.96(s,1H),6.63(d,1H),6.80-6.90(m,2H),7.05(dd,4H),7.15-7.31(m,5H),7.71(d,2H),7.95(d,2H),9.81(bs,1H),12.06(bs,1H),12.37(bs,1H).
实施例55(10):4-(2-({[(6-甲基-2-吡啶基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.43(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.57-1.66(m,2H),1.74-1.75(m,4H),2.20(t,2H),2.37(s,3H),2.62-2.66(m,2H),3.14(t,2H),3.39-3.33(m,2H),4.06-4.08(m,2H),4.95(s,1H),6.62(d,1H),6.81(t,1H),7.02-7.03(m,3H),7.14-7.30(m,5H),7.85-7.94(m,4H),8.48(s,1H),9.68(bs,1H),12.06(bs,1H),12.58(bs,1H).
实施例55(11):4-(8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-{[(2-噻吩基磺酰基)氨基]羰基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.45(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.58-1.66(m,2H),1.74-1.76(m,4H),2.21(t,2H),2.65(t,2H),3.10-3.14(m,2H),3.41-3.47(m,2H),4.07-4.08(m,2H),5.00(s,1H),6.61(d,1H),6.81(t,1H),6.92(d,1H),7.05(d,2H),7.14-7.31(m,6H),7.66(d,1H),7.94(d,2H),7.99(d,1H),9.79(bs,1H),12.06(bs,1H),12.64(bs,1H).
实施例55(12):4-(2-({[(4-氯-3-吡啶基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.66(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.52-1.60(m,2H),1.73-1.76(m,4H),2.19(t,2H),2.65(t,2H),3.04-3.13(m,2H),3.41-3.45(m,2H),4.07-4.09(m,2H),5.01(s,1H),6.60(d,1H),6.80-6.92(m,2H),7.06,2H),7.15-7.31(m,5H),7.72(d,1H),7.94(d,2H),8.11(dd,1H),8.71(d,1H),9.81(bs,1H),12.10(bs,1H),12.70(bs,1H).
实施例55(13):4-(2-({[(3-甲基苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.45(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.50-1.57(m,2H),1.75-1.77(m,4H),2.16(t,2H),2.33(s,3H),2.65(t,2H),3.03-3.09(m,2H),3.39-3.45(m,2H),4.07-4.09(m,1H),5.00(s,1H),6.50-6.63(m,1H),6.80-6.85(m,2H),7.06(d,2H),7.16-7.31(m,5H),7.39-7.50(m,2H),7.53-7.57(m,2H),7.96(d,2H),9.88(bs,1H),12.06(bs,1H),12.50(bs,1H).
实施例55(14):4-(2-{[(乙基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.68(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.06(t,3H),1.73-1.75(m,6H),2.28(t,2H),2.65(t,2H),3.24(t,2H),3.37-3.31(m,2H),3.54(dd,2H),4.07(t,2H),5.08(s,1H),6.66(d,1H),6.82(t,1H),6.90(t,1H),7.04(d,2H),7.14-7.30(m,5H),7.92(d,2H),9.82(bs,1H),12.01(bs,1H),12.08(bs,1H).
实施例55(15):4-{8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-[({[(E)-2-苯基乙烯基]磺酰基}氨基)羰基]-2,3-二氢-4H-1,4-苯并噁嗪-4-基}丁酸
TLC:Rf0.54(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.64-1.74(m,6H),2.20(t,2H),2.65(t,2H),3.19(t,2H),3.31-3.56(m,1H),3.48(dd,1H),4.06-4.05(m,2H),4.99(s,1H),6.62(d,1H),6.80(t,1H),6.95(d,1H),7.02(d,2H),7.20-7.33(m,5H),7.38-7.58(m,5H),7.69-7.72(m,2H),7.92(d,2H),9.73(bs,1H),12.06(bs,1H),12.24(bs,1H).
实施例55(16):4-(2-({[(1,2-二甲基-1H-咪唑-4-基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.46(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.75(m,6H),2.22-2.24(m,2H),2.25(s,3H),2.65(t,2H),3.19(t,2H),3.31-3.35(m,2H),3.57(s,3H),4.06-4.07(m,2H),4.83(s,1H),6.59(d,1H),6.79(t,1H),7.05(t,2H),7.04-7.11(m,1H),7.14-7.30(m,5H),7.75-7.81(m,1H),7.92(d,2H),9.58(bs,1H),12.11(bs,2H).
实施例55(17):4-(2-({[(3,5-二甲基-4-异噁唑基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.56(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.51-1.58(m,2H),1.74-1.76(m,4H),2.04(s,3H),2.17(t,2H),2.54(s,3H),2.65(t,2H),3.09(t,2H),3.31-3.24(m,1H),3.50(dd,1H),4.08(t,1H),5.11(s,1H),6.64(d,1H),6.75-6.78(m,1H),6.83(t,1H),7.05(d,2H),7.15-7.31(m,5H),7.95(d,2H),10.04(bs,1H),12.05(bs,1H),12.88(bs,1H).
实施例55(18):4-{8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-[({[4-(三氟甲基)苯基]磺酰基}氨基)羰基]-2,3-二氢-4H-1,4-苯并噁嗪-4-基}丁酸
TLC:Rf0.54(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.50-1.56(m,2H),1.74-1.76(m,4H),2.15(t,2H),2.65(t,2H),3.02-3.04(m,2H),3.30-3.44(m,2H),4.07-4.08(m,2H),5.02(s,1H),6.58(d,1H),6.82(t,1H),6.85-6.90(m,1H),7.06(d,2H),7.15-7.30(m,5H),7.91-7.97(m,6H),9.85(bs,1H),12.05(bs,1H),12.87(bs,1H).
实施例55(19):4-(2-({[(4-叔丁基苯基)磺酰基]氨基}羰基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.55(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.27(s,9H),1.56-1.72(m,2H),1.74-1.76(m,4H),2.18(t,2H),2.65(t,2H),3.01-3.11(m,2H),3.30-3.41(m,2H),4.07-4.08(s,2H),4.95(s,1H),6.59(d,1H),6.82(t,1H),6.85-6.98(m,1H),7.06(d,2H),7.15-7.30(m,5H),7.50-7.53(m,2H),7.66(d,2H),7.94(d,2H),9.80(bs,1H),12.05(bs,1H),12.47(bs,1H).
实施例55(20):4-(2-{[(叔丁基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.57(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.18(s,9H),1.70-1.78(m,6H),2.26-2.31(m,2H),2.61-2.67(m,2H),3.19-3.25(m,2H),3.32-3.38(m,1H),3.55-3.58(m,1H),4.07-4.08(m,2H),5.09(s,1H),6.64-6.68(m,1H),6.81-6.84(m,2H),7.03(d,2H),7.15-7.31(m,5H),7.92(d,2H),9.85(bs,1H),11.59(bs,1H),12.07(bs,1H).
实施例55(21):4-(8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2-{[(苯基磺酰基)氨基]羰基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
TLC:Rf0.29(二氯甲烷∶甲醇∶乙酸=95∶5∶0.5);
NMR(DMSO-d6):δ1.56-1.78(m,6H),2.23(t,2H),2.59-2.63(m,2H),3.15-3.18(m,2H),3.30-3.42(m,2H),3.92-4.02(m,2H),4.81-4.90(m,1H),6.58(d,1H),6.73(t,1H),6.88-6.93(m,3H),7.04(d,1H),7.10-7.30(m,6H),7.40(d,2H),7.56-7.61(m,2H),7.66-7.71(m,1H),7.90(d,2H),12.08(brs,1H),12.46(brs,1H).
实施例56:4-{4-[(甲基磺酰基)氨基]-4-氧代丁基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
使用实施例33制备的化合物代替实施例53制备的化合物,使用甲磺酰胺代替苯磺酰胺,根据实施例54→实施例8的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf 0.31(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(CDCl3):δ1.74-2.08(m,6H),2.20-2.40(m,2H),2.69(t,2H),2.93-3.05(m,1H),3.20(s,3H),3.34-3.55(m,2H),3.66-3.74(m,1H),4.02(t,2H),4.92-4.98(m,1H),6.55-6.61(m,1H),6.80-6.99(m,2H),6.94(d,2H),7.16-7.31(m,5H),7.85(d,2H),7.95(brs,1H).
实施例57:4-(3-羧基丙基)-7-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
使用3-羟基-4-硝基苯甲醛代替2-羟基-3-硝基苯甲醛,使用(溴甲基)苯代替1-(氯甲基)-4-甲氧基苯,根据实施例42→实施例43→实施例44→实施例45→实施例6→实施例28→实施例8的方法,制备本发明的化合物。
TLC:Rf0.33(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.48-1.86(m,6H),2.26(t,2H),2.54-2.70(m,2H),3.06-3.60(m,4H),3.85-4.17(m,2H),4.85(t,1H),6.69(d,1H),6.81-7.02(m,5H),7.10-7.32(m,6H),7.42(d,1H).
实施例57(1)-实施例57(39)
使用相应的化合物代替三苯基[4-(4-苯基丁氧基)苄基]氯化鏻,根据实施例43→实施例44→实施例45→实施例6→实施例28→实施例8的方法,制备本发明的化合物。
实施例57(1):4-(3-羧基丙基)-8-((E)-2-{4-[(5-苯基戊基)氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.48(二氯甲烷∶甲醇∶乙酸=9∶1∶0.05);
NMR(DMSO-d6):δ1.25-1.49(m,2H),1.54-1.85(m,6H),2.13-2.34(m,2H),2.54-2.71(m,2H),3.02-3.27(m,2H),3.45(d,2H),3.96(t,2H),4.98(t,1H),6.63(dd,1H),6.75(dd,1H),6.86-7.01(m,3H),7.03-7.31(m,7H),7.37-7.52(m,2H),12.22(s,2H).
实施例57(2):4-(3-羧基丙基)-8-{(E)-2-[4-(4-苯氧基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.44(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.72(五重峰,2H),1.84-1.88(m,4H),2.26(t,2H),3.22-3.30(m,2H),3.42-3.44(m,2H),4.02-4.04(m,4H),4.83(t,1H),6.61(d,1H),6.73(t,1H),6.88-6.94(m,6H),7.10(d,1H),7.23-7.30(m,3H),7.43(d,2H),12.60(bs,2H).
实施例57(3):4-(3-羧基丙基)-8-{(E)-2-[4-(3-苯基丙氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.47(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.73(五重峰,2H),2.01(五重峰,2H),2.27(t,2H),2.74(t,2H),3.21-3.26(m,2H),3.45(d,2H),3.97(t,2H),4.98(t,1H),6.64(d,1H),6.75(t,1H),6.91-6.95(m,3H),7.07-7.31(m,7H),7.43(d,2H),12.28(bs,2H).
实施例57(4):4-(3-羧基丙基)-8-{(E)-2-[4-(2,3-二氢-1H-茚-2-基甲氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.43(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.72(五重峰,1H),2.27(t,2H),2.71-2.94(m,3H),3.04-3.12(m,2H),3.21-3.25(m,2H),3.45(d,2H),3.99(d,2H),4.98(t,1H),6.65(d,1H),6.75(t,1H),6.93-6.96(m,3H),7.04-7.14(m,3H),7.19-7.24(m,3H),7.43(d,2H),12.34(bs,2H).
实施例57(5):4-(3-羧基丙基)-8-((E)-2-{4-[(7-氯-2-喹啉基)甲氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.42(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.72(五重峰,2H),2.26(t,2H),3.20-3.25(m,2H),3.43(d,2H),4.83(s,1H),5.38(s,2H),6.61(d,1H),6.73(t,1H),6.91(d,1H),7.05-7.12(m,3H),7.28(d,1H),7.46(d,2H),7.65(dd,1H),7.71(d,1H),8.05(d,2H),8.46(d,1H),12.61(bs,2H).
实施例57(6):4-(3-羧基丙基)-8-{(E)-2-[4-({3-[(7-氯-2-喹啉基)甲氧基]苄基}氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.44(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.70-1.77(m,2H),2.27(t,2H),3.21-3.30(m,2H),3.46(d,2H),5.00(t,1H),5.08(s,2H),5.38(s,2H),6.64(d,1H),6.76(t,1H),6.93-6.95(m,3H),6.99-7.15(m,4H),7.24(d,1H),7.31(t,1H),7.39(d,2H),7.65(dd,1H),7.69(d,1H),8.03-8.07(m,2H),8.44(d,1H),12.06(bs,1H),13.09(bs,1H).
实施例57(7):4-(3-羧基丙基)-8-{(E)-2-[4-(2,3-二氢-1H-茚-2-基氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.34(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.62-1.81(m,2H)2.27(t,2H),2.96-3.07(m,2H),3.13-3.58(m,6H),4.89-5.05(m,1H),5.15-5.34(m,1H),6.64(d,1H),6.75(t,1H),6.89-6.98(m,3H),7.03-7.21(m,3H),7.21-7.33(m,3H),7.45(d,2H).
实施例57(8):4-(3-羧基丙基)-8-((E)-2-{4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.50(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.55-1.64(m,2H),1.70-1.82(m,4H),2.27(t,2H),2.38-2.59(m,3H),3.02(dd,2H),3.21-3.30(m,2H),3.44-3.45(m,2H),4.00(t,2H),4.97-4.98(m,1H),6.63(d,1H),6.75(t,1H),6.91-6.94(m,3H),7.07-7.28(m,6H),7.43(d,2H),12.54(bs,2H).
实施例57(9):8-((E)-2-{4-[4-(苯基甲基氧基)丁氧基]苯基}乙烯基)-4-(3-羧基丙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.48(氯仿∶甲醇∶乙酸乙酯=90∶10∶1);
NMR(DMSO-d6):δ1.62-1.80(m,6H),2.27(t,2H),3.21-3.29(m,2H),3.45-3.51(m,4H),3.99(t,2H),4.46(s,2H),4.99(t,1H),6.64(d,1H),6.76(t,1H),6.92(dd,2H),7.10(d,1H),7.25(d,1H),7.26-7.46(m,8H),12.45(bs,2H).
实施例57(10):4-(3-羧基丙基)-8-((E)-2-{4-[(5-苯氧基戊基)氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.43(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.41-1.64(m,2H),1.70-1.85(m,6H),2.27(t,2H),3.21-3.29(m,2H),3.45(d,2H),3.99(q,4H),4.97(t,1H),6.63(dt,1H),6.75(t,1H),6.88-6.95(m,6H),7.10(d,1H),7.22-7.29(m,3H),7.43(d,2H),12.48(bs,2H).
实施例57(11):4-(3-羧基丙基)-8-((E)-2-{4-[4-(3-甲氧基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.47(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.66-1.78(m,2H),1.84-1.99(m,4H),2.27(t,2H),3.21-3.26(m,2H),3.45(d,2H),3.71(s,3H),4.01-4.05(m,4H),4.97(d,1H),6.48-6.53(m,3H),6.63(d,1H),6.75(t,1H),7.10(d,1H),7.18(t,1H),7.24(d,1H),7.44(d,2H),12.45(bs,2H).
实施例57(12):4-(3-羧基丙基)-8-((E)-2-{4-[4-(4-甲氧基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.55(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.66-1.78(m,2H),1.79-1.89(m,4H),2.27(t,2H),3.16-3.28(m,2H),3.41-3.49(m,2H),3.68(s,3H),3.90-3.99(m,2H),3.99-4.08(m,2H),4.98(t,1H),6.63(d,1H),6.75(t,1H),6.81-6.86(m,4H),6.89-6.97(m,3H),7.10(d,1H),7.25(d,1H),7.44(d,2H).
实施例57(13):4-(3-羧基丙基)-8-((E)-2-{4-[4-(3-甲基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.38(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.77(m 2H),1.84-1.86(m,4H),2.27(s,3H),2.27(t,3H),3.21-2.25(m,2H),3.44(d,2H),3.97-4.04(m,4H),4.95(t,1H),6.62(d,1H),6.69-6.77(m,4H),6.92-6.95(m,3H),7.07-7.16(m,2H),7.26(d,1H),7.44(d,2H),12.60(bs,2H).
实施例57(14):4-(3-羧基丙基)-8-((E)-2-{4-[4-(3-氟苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.39(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.77(m,2H),1.85-1.87(m,4H),2.27(t,2H),3.21-3.27(m,2H),3.45(d,2H),4.03-4.05(m,4H),4.96(t,1H),6.63(d,1H),6.70-6.83(m,4H),6.92-6.95(m,3H),7.10(d,1H),7.23-7.33(m,2H),7.44(d,2H),12.61(bs,2H).
实施例57(15):4-(3-羧基丙基)-8-((E)-2-{4-[4-(2-甲基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.53(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.62-1.81(m,2H),1.83-1.94(m,4H),2.13(s,3H),2.27(t,2H),3.17-3.30(m,2H),3.45(d,2H),3.96-4.11(m,4H),4.99(t,1H),6.63(d,1H),6.75(t,1H),6.81(t,1H),6.87-6.98(m,4H),7.05-7.17(m,3H),7.25(d,1H),7.43(d,2H).
实施例57(16):4-(3-羧基丙基)-8-((E)-2-{4-[4-(4-氟苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.47(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.63-1.80(m,2H),1.78-1.93(m,4H),2.27(t,2H),3.15-3.31(m,2H),3.38-3.49(m,2H),3.91-4.11(m,4H),4.74-4.86(m,1H),6.61(d,1H),6.72(t,1H),6.87-6.97(m,5H),7.04-7.15(m,3H),7.25(d,1H),7.43(d,2H).
实施例57(17):4-(3-羧基丙基)-8-((E)-2-{4-[4-(4-甲基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.47(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.79(m,2H),1.81-1.90(m,4H),2.21(s,3H),2.27(t,2H),3.18-3.28(m,2H),3.44(d,2H),3.92-4.10(m,4H),4.96(t,1H),6.63(d,1H),6.74(t,1H),6.81(d,2H),6.90-6.97(m,3H),7.03-7.14(m,3H),7.25(d,1H),7.43(d,2H).
实施例57(18):4-(3-羧基丙基)-8-((E)-2-{4-[4-(2-甲氧基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.46(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.64-1.81(m,2H),1.82-1.93(m,4H),2.27(t,2H),3.17-3.29(m,2H),3.41-3.53(m,2H),3.73(s,3H),3.95-4.10(m,4H),4.92-4.98(m,1H),6.62(d,1H),6.74(t,1H),6.83-6.99(m,7H),7.09(d,1H),7.25(d,1H),7.44(d,2H).
实施例57(19):4-(3-羧基丙基)-8-((E)-2-{4-[4-(2-氟苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.53(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.64-1.79(m,2H),1.81-1.95(m,4H),2.27(t,2H),3.17-3.29(m,2H),3.45(d,2H),4.00-4.16(m,4H),4.98(t,1H),6.63(d,1H),6.75(t,1H),6.87-6.99(m,4H),7.06-7.21(m,4H),7.24(d,1H),7.43(d,2H).
实施例57(20):4-(3-羧基丙基)-8-[(E)-2-(4-{4-[2-(甲基亚磺基(sulfanil))苯氧基]丁氧基}苯基)乙烯基]-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.41(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.66-1.76(m,2H),1.85-1.93(m,4H),2.27(t,2H),2.35(s,3H),3.21-3.26(m,2H),3.36-3.38(m,2H),4.04-4.09(m,4H),4.99(t,1H),6.63(d,1H),6.75(t,1H),6.92-6.97(m,5H),7.07-7.14(m,3H),7.25(d,1H),7.43(d,2H),12.11(bs,1H),12.99(bs,1H).
实施例57(21):4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-氯苯基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.39(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.75(m,2H),2.00(五重峰,2H),2.27(t,2H),2.73(t,2H),3.21-3.26(m,2H),3.44(d,2H),3.96(t,2H),4.99(t,1H),6.63(t,1H),6.75(t,1H),6.90-6.95(m,3H),7.10(d,1H),7.22-7.34(m,5H),7.43(d,2H),12.14(bs,1H),12.94(bs,1H).
实施例57(22):4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-甲氧基苯基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.37(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.76(m,2H),1.97(五重峰,2H),2.27(t,2H),2.67(t,2H),3.21-3.26(m,2H),3.45(d,2H),3.70(s,3H),3.95(t,2H),4.99(t,1H),6.63(d,1H),6.75(t,1H),6.83(t,2H),6.90-6.95(m,3H),7.07-7.15(m,3H),7.25(d,1H),7.43(d,2H),12.07(bs,1H),12.94(bs,1H).
实施例57(23):4-(3-羧基丙基)-8-((E)-2-{4-[3-(3-甲基苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.36(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.75(m,2H),2.15(五重峰,2H),2.25(s,3H),2.22-2.29(m,2H),3.21-3.26(m,2H),3.45(d,2H),4.07-4.15(m,4H),4.98(t,1H),6.63(d,1H),6.71-6.77(m,4H),6.93-6.96(m,3H),7.07-7.17(m,2H),7.26(d,1H),7.43-7.46(m,2H),12.65(bs,2H).
实施例57(24):4-(3-羧基丙基)-8-((E)-2-{4-[3-(3-氟苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.40(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.75(m,2H),2.16(五重峰,2H),2.27(t,2H),3.21-3.26(m,2H),3.45(d,2H),4.11-4.17(m,4H),4.98(s,1H),6.63(d,1H),6.72-6.86(m,4H),6.85-6.96(m,3H),7.10(d,1H),7.23-7.34(m,2H),7.44(d,2H),12.54(bs,2H).
实施例57(25):4-(3-羧基丙基)-8-((E)-2-{4-[3-(3-甲氧基苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.38(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.75(m,2H),2.15(五重峰,2H),2.26(t,2H),3.21-3.25(m,2H),3.44(d,2H),3.71(s,3H),4.12(q,4H),4.97(t,1H),6.49-6.54(m,3H),6.63(d,1H),6.75(t,1H),6.92-6.96(m,3H),7.07-7.29(m,3H),7.44(d,2H),12.49(bs,2H).
实施例57(26):4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-甲基苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.67(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.79(m,2H),2.09-2.19(m,2H),2.21(s,3H),2.27(t,2H),3.19-3.29(m,2H),3.45(d,2H),4.04-4.17(m,4H),5.00(t,1H),6.64(d,1H),6.75(t,1H),6.83(d,2H),6.91-6.99(m,3H),7.03-7.15(m,3H),7.26(d,1H),7.44(d,2H).
实施例57(27):4-(3-羧基丙基)-8-((E)-2-{4-[3-(2-甲基苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.65(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.79(m,2H),2.14(s,3H),2.16-2.23(m,2H),2.27(t,2H),3.19-3.28(m,2H),3.45(d,2H),4.12(t,2H),4.17(t,2H),5.00(t,1H),6.64(d,1H),6.75(t,1H),6.82(t,1H),6.91-6.99(m,4H),7.06-7.17(m,3H),7.25(d,1H),7.44(d,2H).
实施例57(28):4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-氟苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.39(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.64-1.80(m,2H),2.08-2.22(m,2H),2.27(t,2H),3.17-3.28(m,2H),3.45(d,2H),4.06-4.17(m,4H),4.93-5.02(m,1H),6.63(d,1H),6.75(t,1H),6.90-7.01(m,5H),7.04-7.16(m,3H),7.26(d,1H),7.44(d,2H).
实施例57(29):4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-甲氧基苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.61-1.81(m,2H),2.04-2.20(m,2H),2.27(t,2H),3.15-3.30(m,2H),3.45(d,2H),3.68(s,3H),4.06(t,2H),4.09-4.17(m,2H),4.91-5.02(m,1H),6.63(dd,1H),6.75(t,1H),6.79-6.99(m,7H),7.10(d,1H),7.26(d,1H),7.44(d,2H).
实施例57(30):4-(3-羧基丙基)-8-((E)-2-{4-[3-(3-氯苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.50(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.76(m,2H),2.16(五重峰,2H),2.26(t,2H),3.19-3.25(m,2H),3.43-3.44(m,2H),4.14(q,4H),4.92-4.94(m,1H),6.62(d,1H),6.74(t,1H),6.92-7.12(m,7H),7.23-7.32(m,2H),7.44(d,2H),12.59(bs,2H).
实施例57(31):4-(3-羧基丙基)-8-((E)-2-{4-[2-(2,3-二氢-1H-茚-2-基)乙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.49(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.66-1.77(m,2H),1.89-1.95(m,2H),2.27(t,2H),2.48-2.67(m,3H),2.99-3.07(m,2H),3.21-3.26(m,2H),3.45(d,2H),4.07(t,2H),4.98(t,1H),6.63(d,1H),6.75(t,1H),6.94-6.97(m,3H),7.08-7.29(m,6H),7.45(d,2H),12.58(bs,2H).
实施例57(32):4-(3-羧基丙基)-8-{(E)-2-[4-(3-苯氧基丙氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.63-1.82(m,2H),2.08-2.32(m,4H),3.09-3.52(m,4H),4.07-4.18(m,4H),4.77-4.98(m,1H),6.62(d,1H),6.73(t,1H),6.86-7.00(m,6H),7.09(d,1H),7.21-7.32(m,3H),7.44(d,2H).
实施例57(33):4-(3-羧基丙基)-8-((E)-2-{4-[3-(2-氯苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.62-1.81(m,2H),2.11-2.34(m,4H),3.11-3.55(m,4H),4.09-4.29(m,4H),4.93(t,1H),6.58-6.66(m,1H),6.74(t,1H),6.88-7.00(m,4H),7.10(d,1H),7.14-7.35(m,3H),7.36-7.50(m,3H).
实施例57(34):4-(3-羧基丙基)-8-((E)-2-{4-[4-(2-氯苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.31(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.63-1.80(m,2H),1.83-1.96(m,4H),2.27(t,2H),3.19-3.26(m,2H),3.45(d,2H),4.02-4.17(m,4H),4.95(t,1H),6.63(d,1H),6.75(t,1H),6.89-6.99(m,4H),7.03-7.34(m,4H),7.36-7.48(m,3H),12.49(bs,2H).
实施例57(35):4-(3-羧基丙基)-8-((E)-2-{4-[4-(3-氯苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.32(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.62-1.79(m,2H),1.73-1.86(m,4H),2.27(t,2H),3.19-3.26(m,2H),3.44(d,2H),3.95-4.12(m,4H),4.93(t,1H),6.62(d,1H),6.74(t,1H),6.85-7.04(m,6H),7.09(d,1H),7.20-7.34(m,2H),7.44(d,2H),12.43(bs,2H).
实施例57(36):4-(3-羧基丙基)-8-((E)-2-{4-[4-(2,6-二氯苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.37(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.62-1.81(m,2H),1.86-2.00(m,4H),2.27(t,2H),3.17-3.26(m,2H),3.45(d,2H),3.97-4.15(m,4H),4.97(t,1H),6.63(d,1H),6.75(t,1H),6.93-6.95(m,1H),6.94(d,2H),7.10(d,1H),7.16(dd,1H),7.26(d,1H),7.44(d,2H),7.49(d,2H),12.65(bs,2H).
实施例57(37):4-(3-羧基丙基)-8-((E)-2-{4-[4-(2,6-二甲基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.32(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.63-1.80(m,2H),1.81-2.02(m,4H),2.21(s,6H),2.27(t,2H),3.19-3.27(m,2H),3.44(d,2H),3.78(t,2H),4.07(t,2H),4.93(t,1H),6.63(d,1H),6.75(t,1H),6.83-7.05(m,6H),7.26(d,1H),7.10(d,1H),7.44(d,2H),12.58(bs,2H).
实施例57(38):4-(3-羧基丙基)-8-((E)-2-{4-[4-(2-氯-6-甲基苯氧基)丁氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.33(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.66-1.80(m,2H),1.85-2.02(m,4H),2.27(s,3H),2.25-2.29(t,2H),3.18-3.26(m,2H),3.44(d,2H),3.93(t,2H),4.07(t,2H),4.90(t,1H),6.63(d,1H),6.74(t,1H),6.88-7.34(m,8H),7.44(d,2H),12.50(bs,2H).
实施例57(39):4-(3-羧基丙基)-7-{(E)-2-[4-(4-苯基乙氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.26(二氯甲烷∶甲醇∶乙酸=90∶10∶0.5);
NMR(DMSO-d6):δ1.59-1.82(m,2H),2.27(t,2H),3.03(t,2H),3.17-3.28(m,2H),3.44(d,2H),4.20(t,2H),4.91-5.03(m,1H),6.57-6.67(m,1H),6.75(t,1H),6.88-6.98(m,3H),7.09(d,1H),7.15-7.37(m,7H),7.43(d,2H).
实施例58:4-(3-羧基丙基)-8-{2-[4-(4-苯氧基丁氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
使用三苯基[4-(4-苯氧基丁氧基)苄基]氯化鏻代替三苯基苯基[4-(4-苯基丁氧基)苄基]氯化鏻,根据实施例43→实施例44→实施例45→实施例6→实施例28→实施例47→实施例48→实施例49的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.47(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.71(五重峰,2H),1.81-1.87(m,4H),2.25(td,2H),2.67-2.89(m,4H),3.18-3.23(m,2H),3.36-3.40(m,2H),3.98-4.03(m,4H),4.78(t,1H),6.38(dd,1H),6.54-6.64(m,2H),6.81(d,2H),6.88-6.93(m,3H),7.11(d,2H),7.24-7.29(m,2H),12.55(bs,2H).
实施例58(1)-实施例58(17)
用相应的化合物代替三苯基苯基[4-(4-苯基丁氧基)苄基]氯化鏻,根据实施例43→实施例44→实施例45→实施例6→实施例28→实施例47→实施例48→实施例49的方法,制备具有以下物理数据的本发明的化合物。
实施例58(1):4-(3-羧基丙基)-8-{2-[4-(3-苯基丙氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.55(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.63-1.78(m,2H),1.94-2.03(m,2H),2.26(t,2H),2.67-2.85(m,6H),3.21(t,2H),3.42(t,2H),3.91(t,2H),4.92(t,1H),6.40(dd,1H),6.56-6.66(m,2H),6.80(d,2H),7.10(d,2H),7.15-7.30(m,5H),12.34(bs,2H).
实施例58(2):4-(3-羧基丙基)-8-{2-[4-(2,3-二氢-1H-茚-2-基甲氧基)苯基]乙基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.54(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.71(五重峰,2H),2.26(t,2H),2.66-2.90(m,7H),3.03-3.10(m,2H),3.21(t,2H),3.42(t,2H),3.92(d,2H),4.91(t,1H),6.40(dd,1H),6.55-6.66(m,2H),6.83(d,2H),7.08-7.14(m,4H),7.19-7.23(m,2H),12.36(bs,2H).
实施例58(3):4-(3-羧基丙基)-8-(2-{4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.56(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.55-1.60(m,2H),1.69-1.80(m,4H),2.26(t,2H),2.39-2.58(m,3H),2.66-2.84(m,4H),3.01(dd,2H),3.19(t 2H),3.40-3.41(m,2H),3.93(t,2H),4.80-4.81(m,1H),6.38(d,1H),6.54-6.64(m,2H),6.80(d,2H),6.06-7.18(m,6H),12.50(bs,2H).
实施例58(4):4-(3-羧基丙基)-8-(2-{4-[(5-苯氧基戊基)氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.59(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.33-1.62(m,2H),1.69-1.81(m,6H),2.26(d,2H),2.68-2.86(m,4H),3.18-3.25(m,2H),3.37-3.41(m,2H),3.91-3.99(m,4H),4.79(bs,1H),6.38(d,1H),6.54-6.66(m,2H),6.80(d,2H),6.88-6.92(m,3H),7.10(d,2H),7.23-7.29(m,2H),12.17(bs,2H).
实施例58(5):4-(3-羧基丙基)-8-(2-{4-[4-(3-甲氧基苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.53(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.58-1.77(m,2H),1.82-1.84(m,4H),2.26(t,2H),2.66-2.86(m,4H),3.18-3.23(m,2H),3.40-3.42(m,2H),3.71(s,3H),3.97-4.00(m,4H),4.90(t,1H),6.40(d,1H),6.47-6.51(m,3H),6.56-6.66(m,2H),6.81(d,2H),7.10(d,2H),7.15(t,1H),12.54(bs,2H).
实施例58(6):4-(3-羧基丙基)-8-(2-{4-[4-(4-甲氧基苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.59(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.66-1.76(m,2H),1.78-1.88(m,4H),2.26(t,2H),2.63-2.87(m,4H),3.15-3.25(m,2H),3.37-3.46(m,2H),3.68(s,3H),3.89-4.02(m,4H),4.84-4.89(m,1H),6.37-6.41(m,1H),6.53-6.66(m,2H),6.77-6.87(m,6H),7.10(d,2H).
实施例58(7):4-(3-羧基丙基)-8-(2-{4-[4-(3-甲基苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.41(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.77(m,2H),1.82-1.84(m,4H),2.25(s,3H),2.23-2.27(m,2H),2.66-2.86(m,4H),3.18-3.23(m,2H),3.40-3.42(m,2H),3.97-3.98(s,4H),4.85-4.87(m,1H),6.39(d,1H),6.55-6.65(m,2H),6.69-6.73(m,3H),6.81(d,2H),7.09-7.16(m,3H),12.64(bs,2H).
实施例58(8):4-(3-羧基丙基)-8-(2-{4-[4-(3-氟苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.43(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.65-1.75(m,2H),1.83-1.85(m,4H),2.26(t,2H),2.66-2.85(m,4H),3.18-3.23(m,2H),3.40-3.42(m,2H),3.97-4.03(m,4H),4.85-4.87(m,1H),6.39(d,1H),6.55-6.65(m,2H),6.71-6.82(m,4H),7.11(d,2H),7.25-7.33(m,2H),12.59(bs,2H).
实施例58(9):4-(3-羧基丙基)-8-(2-{4-[4-(2-甲基苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.63(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.77(m,2H),1.83-1.92(m,4H),2.13(s,3H),2.26(t,2H),2.60-2.87(m,4H),3.16-3.26(m,2H),3.39-3.45(m,2H),3.94-4.05(m,4H),4.90(t,1H),6.39(d,1H),6.54-6.66(m,2H),6.76-6.85(m,3H),6.90(d,1H),7.05-7.16(m,4H).
实施例58(10):4-(3-羧基丙基)-8-(2-{4-[4-(4-甲基苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.60(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.65-1.77(m,2H),1.78-1.88(m,4H),2.21(s,3H),2.26(t,2H),2.62-2.87(m,4H),3.15-3.25(m,2H),3.38-3.45(m,2H),3.91-4.01(m,4H),4.86-4.92(m,1H),6.39(d,1H),6.53-6.66(m,2H),6.77-6.85(m,4H),7.02-7.13(m,4H).
实施例58(11):4-(3-羧基丙基)-8-(2-{4-[4-(2-甲氧基苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf 0.67(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.63-1.78(m,2H),1.79-1.89(m,4H),2.26(t,2H),2.62-2.89(m,4H),3.15-3.25(m,2H),3.39-3.46(m,2H),3.73(s,3H),3.94-4.04(m,4H),4.89(t,1H),6.36-6.42(m,1H),6.53-6.66(m,2H),6.81(d,2H),6.83-6.90(m,2H),6.91-6.99(m,2H),7.10(d,2H).
实施例58(12):4-(3-羧基丙基)-8-(2-{4-[4-(2-氟苯氧基)丁氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.64(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.64-1.78(m,2H),1.81-1.93(m,4H),2.26(t,2H),2.64-2.88(m,4H),3.15-3.25(m,2H),3.39-3.45(m,2H),3.98(t,2H),4.09(t,2H),4.91(t,1H),6.40(d,1H),6.54-6.66(m,2H),6.81(d,2H),6.87-6.96(m,1H),7.06-7.24(m,5H).
实施例58(13):4-(3-羧基丙基)-8-(2-{4-[3-(4-甲基苯氧基)丙氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.64(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.64-1.77(m,2H),2.06-2.17(m,2H),2.21(s,3H),2.26(t,2H),2.62-2.86(m,4H),3.16-3.25(m,2H),3.39-3.45(m,2H),4.06(t,4H),4.91(t,1H),6.36-6.43(m,1H),6.53-6.67(m,2H),6.82(d,4H),7.06(d,2H),7.10(d,2H).
实施例58(14):4-(3-羧基丙基)-8-(2-{4-[3-(2-甲基苯氧基)丙氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.69(二氯甲烷∶甲醇∶水=8∶2∶0.2);
NMR(DMSO-d6):δ1.64-1.78(m,2H),2.11-2.21(m,2H),2.14(s,3H),2.26(t,2H),2.64-2.87(m,4H),3.16-3.25(m,2H),3.39-3.45(m,2H),4.11(t,4H),4.92(t,1H),6.37-6.42(m,1H),6.54-6.67(m,2H),6.78-6.87(m,3H),6.93(d,1H),7.07-7.17(m,4H).
实施例58(15):4-(3-羧基丙基)-8-(2-{4-[3-(3-甲基苯氧基)丙氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.38(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.55-1.83(m,2H),2.12(五重峰,2H),2.25(s,3H),2.24-2.27(m,2H),2.72-2.85(m,4H),3.16-3.23(m,2H),3.40-3.43(m,2H),4.07(d,4H),4.90(s,1H),6.39(q,1H),6.56-6.64(m,2H),6.71-6.75(m,3H),6.83(d,2H),7.09-7.16(m,3H).
实施例58(16):4-(3-羧基丙基)-8-(2-{4-[3-(3-氟苯氧基)丙氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.41(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.75(m,2H),2.09-2.17(m,2H),2.23-2.27(m,2H),2.72-2.80(m,4H),3.18-3.25(m,2H),3.42-3.50(m,2H),4.05-4.15(m,4H),4.88(s,1H),6.39(d,1H),6.55-6.64(m,2H),6.71-6.84(m,5H),7.10(d,2H),7.24-7.32(m,1H).
实施例58(17):4-(3-羧基丙基)-8-(2-{4-[3-(3-甲氧基苯氧基)丙氧基]苯基}乙基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
TLC:Rf0.42(氯仿∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.67-1.75(m,2H),2.10-2.16(m,2H),2.24-2.27(m,2H),2.72-2.82(m,4H),3.20-3.26(m,2H),3.49-3.51(m,2H),3.71(s,3H),4.08(d,4H),4.92(s,1H),6.39(d,1H),6.48-6.62(m,4H),6.82(d,1H),7.09-7.18(m,4H).
实施例59:4-[8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸乙基酯
使用实施例24制备的化合物代替实施例10制备的化合物,根据实施例28→实施例47→实施例48→实施例10→实施例12的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.39(二氯甲烷∶甲醇=9∶1);
NMR(DMSO-d6):δ1.15(t,3H),1.62-1.82(m,6H),2.30(t,2H),2.64(t,2H),3.25-3.30(m,2H),3.62-3.78(m,2H),4.00-4.08(m,4H),5.86(t,1H),6.61(d,1H),6.81(t,1H),7.03(d,2H),7.08-7.29(m,6H),7.90(d,2H),9.48(s,1H).
实施例59(1):4-[8-{2-[4-(4-苯基丁氧基)苯基]乙基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸
使用实施例45制备的化合物代替实施例5制备的化合物,根据实施例6→实施例9→实施例28→实施例47→实施例10→实施例12→实施例48→实施例8的方法,制备具有以下物理数据的化合物。
TLC:Rf0.40(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.61-1.79(m,6H),2.25(t,2H),2.55-2.87(m,6H),3.20-3.38(m,2H),3.51-3.68(m,2H),3.80-3.95(m,2H),5.61(dd,1H),6.45(d,1H),6.65-6.76(m,4H),7.03(d,2H),7.12-7.28(m,5H),12.07(brs,1H).
实施例59(2):4-[8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸乙基酯
使用实施例45制备的化合物代替实施例5制备的化合物,根据实施例6→实施例9→实施例28→实施例47→实施例10→实施例12的方法,制备具有以下物理数据的化合物。
TLC:Rf0.32(二氯甲烷∶甲醇=9∶1);
NMR(CDCl3):δ1.24(t,3H),1.73-1.96(m,6H),2.29-2.34(m,2H),2.69(t,2H),3.22-3.38(m,2H),3.55(dd,1H),3.75(dd,1H),3.98(t,2H),4.12(q,2H),5.82(dd,1H),6.67(dd,1H),6.84-6.92(m,3H),7.00-7.05(m,2H),7.15-7.31(m,6H),7.42(d,2H).
实施例59(3):4-[8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基]丁酸
使用实施例45制备的化合物代替实施例5制备的化合物,根据实施例6→实施例9→实施例28→实施例47→实施例10→实施例12→实施例8的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.46(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.61-1.83(m,6H),2.28(t,2H),2.63(t,2H),3.30-3.41(m,2H),3.60(dd,1H),3.74(dd,1H),3.95-4.02(m,2H),5.73(dd,1H),6.70(d,1H),6.82(t,1H),6.91(d,2H),6.99(d,1H),7.08(d,1H),7.14-7.30(m,5H),7.36(d,1H),7.48(d,2H),12.12(brs,1H).
实施例60:4-(2-(氨基羰基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
使用实施例45制备的化合物代替实施例5制备的化合物,根据实施例6→实施例9→实施例28的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.54(正己烷∶乙酸乙酯=1∶3);
NMR(CDCl3):δ1.72-1.99(m,6H),2.38-2.43(m,2H),2.69(t,2H),3.10-3.20(m,1H),3.37-3.50(m,2H)3.53(dd,1H),3.99(t,2H),4.83(dd,1H),6.38(brs,1H),6.46(brs,1H),6.62(dd,1H),6.84-6.89(m,3H),6.98-7.06(m,2H),7.16-7.31(m,6H),7.44(d,2H).
实施例61:4-(2-[(Z)-氨基(羟基亚胺基)甲基]-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
(1)向盐酸羟胺(129mg)的二甲基亚砜(1mL)的溶液中加入三乙胺(0.26mL),混合物在室温搅拌0.5小时,过滤收集不溶性物质,固体用四氢呋喃洗涤,然后浓缩,向残余物中加入4-(2-氰基-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸乙基酯(用实施例10制备的化合物代替实施例27制备的化合物,根据实施例28→实施例47的方法制备而成)(200mg),混合物在室温搅拌3小时,向反应混合物中加入乙酸乙酯和水,所得混合物用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,无水硫酸钠干燥并浓缩,残余物用叔丁基甲基醚/正己烷(3∶1)洗涤,得到4-(2-[氨基(羟基亚胺基)甲基]-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸乙基酯(202mg).
TLC:Rf0.29(正己烷∶乙酸乙酯=1∶2);
NMR(CDCl3):δ1.25(t,3H),1.75-2.00(m,6H),2.38(t,2H),2.70(t,2H),3.21-3.52(m,4H),4.02(t,2H),4.14(q,2H),4.73-4.76(m,1H),4.94(brs,2H),6.48(brs,1H),6.55(dd,1H),6.87-6.95(m,3H),7.16-7.32(m,5H),7.71(dd,1H),7.81(d,2H),8.16(s,1H).
(2)用上述步骤(1)制备的化合物代替实施例7制备的化合物,根据实施例8的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.63(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(DMSO-d6):δ1.62-1.81(m,6H),2.28(t,2H),2.64(t,2H),3.20-3.42(m,4H),4.01-4.12(m,2H),4.52-4.50(m,1H),5.75(brs,2H),6.59(d,1H),6.76(t,1H),7.02(d,2H),7.09-7.30(m,6H),7.87(d,2H),9.26(brs,1H),9.29(brs,1H),12.10(brs,1H).
实施例62:4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
(1)向实施例61的步骤(1)中制备的化合物(70mg)的二氯甲烷(3mL)溶液中加入硫代羰基二咪唑(29mg)同时使用冰冷却,混合物在冰冷却下搅拌0.5小时,向反应混合物中加入水,反应混合物用乙酸乙酯提取,浓缩有机层,向所得残余物中加入二氯甲烷(2mL)和三氟硼烷-二乙基醚配合物(35μL),所得混合物在-78℃搅拌小时,向反应混合物中加入乙酸乙酯,所得混合物用水和盐水顺序洗涤,无水硫酸钠干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(正己烷∶乙酸乙酯=(7∶3)-(6∶4),得到4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸乙基酯(16mg).
TLC:Rf0.42(正己烷∶乙酸乙酯=2∶3);
NMR(CDCl3):δ1.27(t,3H),1.76-1.98(m,6H),2.33(t,2H),2.70(t,2H),3.32(t,2H),3.56(dd,1H),3.86(dd,1H),4.03(t,2H),4.14(q,2H),5.26(t,1H),6.63-6.66(m,2H),6.87(t,1H),6.94(d,2H),7.16-7.32(m,5H),7.68(s,1H),7.89(d,2H),12.59(brs,1H).
(2)向上述步骤(1)制备的化合物(即4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-[4-(4-苯基丁氧基)苯甲酰基]氨基-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸乙基酯)(90mg)在四氢呋喃(1mL)和乙醇(1mL)混合物中的溶液中加入2N氢氧化钠水溶液(0.29m1),混合物在室温搅拌3小时,向反应混合物中加入2M盐酸(0.29mL)和水,所得混合物用乙酸乙酯提取,有机层用水和盐水顺序洗涤,干燥并浓缩,残余物用叔丁基甲基醚/正己烷洗涤,得到标题化合物(4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸)(69mg).
TLC:Rf0.56(二氯甲烷∶甲醇∶乙酸=90∶10∶1).
NMR(DMSO-d6):δ1.62-1.71(m,6H),2.25(t,2H),2.64(t,2H),3.32-3.35(m,2H),3.53(dd,1H),3.62(dd,1H),4.06(t,2H),5.30-5.39(m,1H),6.62(dd,1H),6.79(t,1H),7.02-7.29(m,8H),7.88(d,2H),9.55(s,1H),12.08(brs,1H),13.16(brs,1H).
实施例62(1):4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
用4-(2-[氨基(羟基亚胺基)甲基]-8-{(Z)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸乙基酯代替实施例61的步骤(1)中制备的化合物,根据实施例62的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.33(二氯甲烷∶甲醇=95∶5);
NMR(DMSO-d6):δ1.61-1.82(m,6H),2.27(t,2H),2.55-2.67(m,2H),3.17-3.30(m,2H),3.45-3.61(m,2H),3.90-4.03(m,2H),5.14-5.17(m,1H),6.66(d,1H),6.79(t,1H),6.89-6.96(m,3H),7.06(d,1H),7.12-7.29(m,5H),7.34(d,1H),7.47(d,2H),12.10(brs,1H),13.27(brs,1H).
实施例63:4-(2-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
(1)用实施例45制备的化合物代替实施例5制备的化合物,根据实施例6→实施例9→实施例10→实施例28→实施例47的方法,制备具有以下物理数据的(4-(2-[氨基(羟基亚胺基)甲基]-8-[4-(4-苯基丁氧基)苯乙烯基]-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸乙基酯。
TLC:Rf0.47(正己烷∶乙酸乙酯=1∶4);
NMR(CDCl3):δ1.26(t,3H),1.78-2.20(m,6H),2.38(t,2H),2.69(t,2H),3.21-3.54(m,4H),3.98(t,2H),4.16(q,2H),4.74(dd,1H),4.90(brs,2H),6.64(dd,1H),6.38-6.89(m,3H),6.96-6.98(m,1H),7.03(d,1H),7.19-7.31(m,6H),7.43(d,2H).
(2)将上述步骤(1)制备的化合物(40mg)溶解在二氯甲烷(1mL),向所得溶液中加入1,1’-羰基二咪唑(15mg),在室温搅拌0.5小时,向混合物中加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(0.032mL),所得混合物在室温搅拌0.5小时,向反应混合物中加入水和乙酸乙酯,所得混合物用乙酸乙酯提取,有机层用水、氯化铵饱和水溶液和饱和食盐水顺序洗涤,干燥并浓缩,残余物用叔丁基甲基醚/正己烷(1∶2)洗涤,得到4-(2-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸乙基酯(34mg),具有如下物理数据。
TLC:Rf0.49(乙酸乙酯);
NMR(CDCl3):δ1.24(t,3H),1.72-1.99(m,6H),2.36(t,2H),2.68(t,2H),3.32(t,2H),3.51(dd,1H),3.62(dd,1H),3.97(t,2H),4.12(q,2H),5.30-5.33(m,1H),6.68(d,1H),6.84-7.03(m,5H),7.15-7.30(m,6H),7.42(d,2H).
(3)用上述步骤(2)制备的化合物代替实施例7制备的化合物,根据实施例8的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.26(二氯甲烷∶甲醇=95∶5);
NMR(DMSO-d6):δ1.62-1.80(m,6H),2.27(t,2H),2.63(t,2H),3.22-3.30(m,2H),3.49(dd,1H),3.59(dd,1H),5.34(dd,1H),6.68(d,1H),6.81(t,1H),6.91(d,2H),6.96(d,1H),7.06(d,1H),7.14-7.32(m,6H),7.47(d,2H).
实施例64:5-(苯基甲基氧基)-1-(4-甲氧基-4-氧代丁基)-1-1H-吲哚-2-羧酸乙基酯
在0℃向5-(苯基甲基氧基)-1H-吲哚-2-羧酸乙基酯(295mg)的二甲基甲酰胺(2.00mL)溶液中加入氢化钠(60%,42.0mg),混合物在室温搅拌30分钟分钟,在0℃向混合物中滴加4-碘丁酸甲基酯(251mg),混合物在室温搅拌3小时,在0℃向其中加入水后,反应混合物用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,干燥并浓缩,得到的残余物通过硅胶柱色普法纯化(乙酸乙酯∶正己烷=1∶4),得到标题化合物(395mg),具有如下物理数据。
TLC:Rf0.43(正己烷∶乙酸乙酯=7∶3);
NMR(CDCl3):δ1,40(t,3H),2.10-2.16(m,2H),2.31-2.36(m,2H),3.66(s,3H),4.35(q,2H),4.58-4.63(m,2H),5.10(s,2H),7.09-7.13(m,2H),7.21(s,1H),7.32-7.49(m,6H).
实施例65:5-(苯基甲基氧基)-1-(3-羧基丙基)-1H-吲哚-2-羧酸
使用实施例64制备的化合物代替实施例7制备的化合物,根据实施例8的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.50(甲醇∶二氯甲烷=1∶4);
NMR(DMSO-d6):δ1.88-1.91(m,2H),2.16(t,2H),4.52-4.57(m,2H),5.10(s,2H),7.04-7.53(m,9H),12.4(brs,2H).
实施例65(1)-实施例65(3)
用相应的化合物代替5-(苯基甲基氧基)-1H-吲哚-2-羧酸乙基酯,根据实施例64→实施例8的方法,制备具有以下物理数据的本发明的化合物。
实施例65(1):1-(3-羧基丙基)-5-({3-[(7-氯-2-喹啉基)甲氧基]苄基}氧基)-1H-吲哚-2-羧酸
TLC:Rf0.56(甲醇∶二氯甲烷=1∶4);
NMR(DMSO-d6):δ1.87-1.91(m,2H),2.16(t,2H),4.51-4.55(m,2H),5.07(s,2H),5.38(s,2H),6.97-7.33(m,7H),7.48(d,1H),7.63-7.71(m,2H),8.02-8.07(m,2H),8.45(d,1H),12.4(brs,2H).
实施例65(2):1-(3-羧基丙基)-5-[(7-氯-2-喹啉基)甲氧基]-1H-吲哚-2-羧酸
TLC:Rf0.41(甲醇∶二氯甲烷=1∶4);
NMR(DMSO-d6):δ1.87-1.94(m,2H),2.16(t,2H),4.53(t,2H),5.39(s,2H),7.10(s,1H),7.14(dd,1H),7.25(d,1H),7.55(d,1H),7.64(dd,1H),7.74(d,1H),8.05(d,1H),8.08(d,1H),8.45(d,1H),12.45(brs,2H).
实施例65(3):5-({4-[3-(苯基甲基氧基)丙基]苄基}氧基)-1-(3-羧基丙基)-1H-吲哚-2-羧酸
TLC:Rf0.45(甲醇∶二氯甲烷=1∶9);
NMR(DMSO-d6):δ1.78-1.89(m,4H),2.16(t,2H),3.31-3.44(m,4H),4.44(s,2H),4.53(t,2H),5.04(s,2H),7.03(dd,1H),7.11(s,1H),7.18-7.37(m,10H),7.51(d,1H),12.60(brs,2H).
实施例66:4-(2-(乙氧基羰基)-8-{2-[4-(4-苯基丁氧基)苯基]乙基}-2,3-二氢-4H-1,4-苯并噁嗪-4-基)丁酸
用实施例46制备的化合物代替实施例47制备的化合物,根据实施例48的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.53(二氯甲烷∶甲醇=9∶1);
NMR(CDCl3):δ1.25(t,3H),1.72-1.99(m,6H),2.43(t,2H),2.66-2.70(m,2H),2.75-3.00(m,4H),3.20-3.40(m,2H),3.41-3.56(m,2H),3.92-3.96(m,2H),4.23(q,2H),4.81(t,1H),6.51-6.58(m,2H),6.74(d,1H),6.80(d,2H),7.13(d,2H),7.18-7.30(m,5H).
实施例67:4-(5-羧基戊基)-8-({[4-(4-苯基丁氧基)苯基]氨基}羰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
用实施例38制备的化合物代替实施例4制备的化合物,用6-氧代己酸代替4-氧代丁酸,根据实施例5→实施例6→实施例28→实施例29→实施例25的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf0.39(甲醇∶二氯甲烷=1∶4);
NMR(DMSO-d6):δ1.28-1.34(m,2H),1.48-1.56(m,4H),1.68-1.74(m,4H),2.21(t,2H),2.51-2.66(m,2H),3.24-3.32(m,4H),3.49(dd,1H),3.59(dd,1H),3.93-3.96(m,2H),5.12(t,1H),6.82-6.88(m,2H),6.89(d,2H),7.04(dd,1H),7.16-7.30(m,5H),7.62(d,2H),10.10(s,1H).
实施例67(1):4-(3-羧基丙基)-8-({甲基[4-(4-苯基丁氧基)苯基]氨基}羰基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
(1)在0℃向实施例38制备的化合物(497mg)的二甲基甲酰胺(3.00mL)溶液中加入氢化钠(60%,44.0mg),混合物在室温搅拌30分钟,在0℃向混合物中加入碘甲烷(213mg),混合物在室温搅拌2小时,在0℃向反应混合物中加入水并用乙酸乙酯提取,有机层用水和饱和食盐水顺序洗涤,干燥并浓缩,得到的残余物通过硅胶柱色谱法纯化(乙酸乙酯∶正己烷=3∶7),得到2-(苯基甲基氧基)-N-甲基-3-硝基-正[4-(4-苯基丁氧基)苯基]苯甲酰胺(454mg).
TLC:Rf0.15(正己烷∶乙酸乙酯=7∶3);
NMR(CDCl3):δ1.71-1.75(m,4H),2.60-2.67(m,2H),3.40(s,3H),3.81(t,2H),5.21(s,2H),6.58(d,2H),6.85(d,2H),7.06(dd,1H),7.14-7.46(m,9H),7.54(dd,2H),7.69(dd,1H).
(2)用实施例4制备的化合物代替上述步骤(1)的化合物,根据实施例5→实施例6→实施例28→实施例8的方法,制备具有以下物理数据的本发明的化合。
TLC:Rf0.40(甲醇∶二氯甲烷∶乙酸=1∶9∶0.1);
NMR(CDCl3):δ1.75-1.91(m,6H),2.39(t,2H),2.66(t,2H),3.23-3.30(m,2H),3.48(s,3H),3.67(dd,1H),3.75(dd,1H),3.89(t,2H),4.86(m,1H),6.09(dd,1H),6.51(dd,1H),6.57(dd,1H),6.74(d,2H),7.04(d,2H),7.16-7.20(m,2H),7.25-7.31(m,3H).
实施例68:4-(3-羧基丙酰基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸
从实施例45制备的化合物,使用实施例6→实施例7→实施例8所述类似的方法,制备具有以下物理数据的本发明的化合物。
TLC:Rf 0.46(甲醇∶二氯甲烷∶乙酸=1∶9∶0.1);
NMR(DMSO-d6):δ1.57-1.86(m,4H),2.35-2.99(m,6H),3.80-4.08(m,3H),4.15-4.35(m,1H),4.97-5.25(m,1H),6.83-7.01(m,3H),7.09-7.35(m,7H),7.41-7.65(m,4H).
本发明式(I)所示化合物的效果通过以下非限制性的实验进行说明。
生物实施例1:对LTD4诱导的细胞内钙增加的作用
将cysLT2受体表达细胞(HEK293)种在96孔板上,每个孔含有1×105个细胞,使用DMEM(Dulbecco’s Modified Eagle Medium)将细胞在37℃在5%CO2条件下培养24小时。细胞在7.5μM Fura2-AM、20mMHEPES(2-[4-(2-羟基乙基)-1-哌嗪基]乙磺酸)和2.5mM丙磺酸中在37℃培养约30分钟。摄取了Fura2-AM的细胞用试验缓冲液(Hank′s缓冲液,含有20mM HEPES)洗涤一次,通过FDSS2000(Hamamatsu PhotonicsK.K.)测量由LTD4诱导的细胞内钙内流。在用LTD4刺激前180秒给用本发明的化合物,在90秒内测量由100nM LTD4诱导的反应。通过最大荧光强度评价本发明化合物的作用,计算各化合物的50%抑制浓度(IC50)。
结果是,式(I)所示化合物的IC50值低于10μM。例如实施例12的IC50值为101nmol/L,实施例25的IC50值为30nmol/L。
生物实施例2:对LTC4诱导的豚鼠气管收缩的作用
在本实验中使用每组4只Hartley雄性豚鼠(Charles RiverLaboratories Japan,Inc.)豚鼠,通过通过颈动脉失血处死豚鼠,立刻除去气管。用刀片以Z字形切开气管制备3mm宽的样品。将样品保持在37℃下并悬浮在37℃的10mL含有Tyrode溶液(NaCl 137mM,KCl 2.68mM,MgCl2 1.05mM,CaCl2 1.80mM,NaHCO3 11.9mM,NaH2PO4 0.417mM和葡萄糖5.55mM)的Magnus试管中,所述溶液用混合气体(95%O2+5%CO2)充满。气管样品受到1G拉伸,并且每15分钟用Tyrode溶液洗涤三次,当应答达到稳定时,在LTC4刺激前,将样品在45mM丝氨酸-硼酸盐的配合物和3mM半胱氨酸中培育。通过等容传感器的等容拉伸的改变,测量由LTC4诱导的气管收缩,在LTC4刺激前15分钟给用本发明的化合物,观察由LTC4诱导的拉伸时程,从在最终浓度为1mM乙酰胆碱时的最大应答测量由LTC4诱导的气管收缩速率,本发明化合物的拮抗LT的作用通过给出pA2值的Schild图示分析进行测定。
结果表明式(I)所示化合物显著抑制豚鼠气管收缩,pA2值为6或更高,实施例12化合物的pA2值为8.5±0.1,实施例25化合物的pA2值为为9.2±0.3。
生物实施例3:对豚鼠体内内源性LT所涉及的OVA诱导的支气管收缩的作用
通过腹膜内给用含1mg卵白蛋白(含有5×109个杀死的百日咳杆菌(bordetella pertussis)细胞)的1ml食盐水对豚鼠进行反应性增敏,增敏2或3周后,豚鼠用戊巴比妥钠(75mg/kg,i.p.)麻痹,将聚乙烯管插入已经切开的气管中。对于本发明化合物和OVA的给用,对颈静脉进行插管,气管套管的一侧与恒定体积呼吸机连接,以70下/分钟对动物人工通入5mL恒定体积的呼吸气体。通过静脉内给用OVA诱导支气管收缩,通过Konzett&Rssler法测量气道抵抗性,为了避免环氧合酶代谢物合和组胺的影响,在给予OVA前3分钟和1分钟静脉内给用吲哚美辛(5mg/kg/mL)和新安体根(1mg/kg/mL)。在给用OVA后20分钟测量支气管收缩,根据时间计算支气管收缩速率,其中将完全夹住气管时获得的最大吹入压力设为100%。
从结果可知式(I)所示化合物显著抑制支气管收缩,可用于治疗呼吸性疾病,特别是支气管哮喘。
[制剂实施例]
如下所示为实现本发明所用的制剂。
制剂实施例1
通过常规方法混合以下组分,从而获得10,000个片剂,每片含有10mg活性成分。
·4-(3-羧基丙酰基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸(100g);
·羧甲基纤维素钙(崩解剂)(20g);
·硬脂酸镁(润滑剂)(10g);
·微晶纤维素(870g)。
制剂实施例2
通过常规方法混合以下组分,通过除灰过滤器过滤,以5ml装入安瓿中,用压热器进行压热灭菌,得到每颗含20mg活性成分的10,000颗胶囊。
·4-(3-羧基丙酰基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并噁嗪-2-羧酸(200g);
·甘露醇(2kg);
·注射用蒸馏水(50L)。
工业实用性
因为式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药拮抗cysLT2受体,因此其可用作气道收缩抑制剂、炎症性细胞(例如噬酸性粒细胞、噬中性粒细胞、淋巴细胞、噬碱性粒细胞等)浸润的透抑制剂、粘液分泌抑制剂或气道高敏性抑制剂。式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药还可用于预防和/或治疗涉及到cysLT2受体的那些疾病,例如呼吸性疾病(例如支气管哮喘、慢性阻塞性肺病、肺气肿、慢性支气管炎、肺炎(例如间质性肺炎等)、严重急性呼吸综合征(SARS)、急性呼吸窘迫综合征(ARDS)、过敏性鼻炎、鼻窦炎(例如急性鼻窦炎、慢性鼻窦炎等)等,并可作为去痰药或止咳药。本发明的式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药还可用作呼吸机能改善剂。
CysLT2受体还与心血管疾病有关,心血管疾病为例如心绞痛、心肌梗塞、急性冠脉综合征、心衰、心率不齐、心肌病(扩张型心肌病、肥厚型心肌病等)、心包炎、心瓣炎、心肌炎、心包压塞、低心输出量综合症、二尖瓣狭窄等。式(I)所示化合物、其N-氧化物、其盐、其溶剂化物或其前药可用于治疗和/或预防上述疾病。
Claims (5)
1.下式(I-b)所示化合物:
其中
R1和R2各自独立地为其中RA为氢或C1-8烷基的-COORA、其中RB为氢或C1-8烷基且RC为C1-8烷基的-CONRBSO2RC、其中所有符号的含义如上所述的-SO2NRBCORC、
-D-R1为-CO-(CH2)2-R1、-CO-(CH2)3-R1、-CO-(CH2)4-R1或C1-4亚烷基-R1
E为键或C1-4亚烷基,
V为
其中R110为氢或C1-8烷基,并且箭头表示其与环A连接,
环1和环2各自独立地为C5-10碳环,其中环2具有1-3个任意选自以下的取代基:硝基、氨基、羟基、C1-8烷基、卤素、C1-8烷氧基、被1-3个卤原子取代的C1-4烷基和被1-3个卤原子取代的C1-4烷氧基,和
W为-O-CH2-、-O-(CH2)2-、-O-(CH2)3-、-O-(CH2)4-、-O-(CH2)5-、-CH2-O-、-(CH2)2-O-、-(CH2)3-O-、-(CH2)4-O-、-(CH2)5-O-、-O-(CH2)3-O-、-O-(CH2)4-O-、-O-(CH2)5-O-或C1-6亚烷基,
或其盐。
2.权利要求1所述的化合物,其选自
(1)4-(3-羧基丙基)-8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(5)4-(3-羧基丙基)-8-{(E)-2-[4-(4-苯基丁氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(7)(2S)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(8)(2R)-4-(3-羧基丙基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(9)4-(3-羧基丙基)-8-({4-[2-(2,3-二氢-1H-茚-2-基)乙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(13)4-(3-羧基丙基)-8-{[4-(4-苯氧基丁氧基)苯甲酰基]氨基}-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(14)4-(3-羧基丙基)-8-({4-[3-(2,3-二氢-1H-茚-2-基)丙氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(15)4-(3-羧基丙基)-8-({4-[4-(4-氟苯基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(17)4-(3-羧基丙基)-8-({4-[4-(2-氟苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(18)4-(3-羧基丙基)-8-({4-[4-(2-氯苯氧基)丁氧基]苯甲酰基}氨基)-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(19)4-(3-羧基丙基)-8-[(4-{4-[2-(三氟甲基)苯氧基]丁氧基}苯甲酰基)氨基]-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(22)4-(2-{[(甲基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并嗪-4-基)丁酸,
(23)4-(2-{[(苄基磺酰基)氨基]羰基}-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并嗪-4-基)丁酸,
(29)4-(3-羧基丙基)-8-((E)-2-{4-[3-(4-氟苯氧基)丙氧基]苯基}乙烯基)-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(30)4-(3-羧基丙基)-8-{(E)-2-[4-(3-苯氧基丙氧基)苯基]乙烯基}-3,4-二氢-2H-1,4-苯并嗪-2-羧酸,
(33)4-[8-{2-[4-(4-苯基丁氧基)苯基]乙基}-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并嗪-4-基]丁酸,
(35)4-(2-(5-氧代-4,5-二氢-1,2,4-噻二唑-3-基)-8-{[4-(4-苯基丁氧基)苯甲酰基]氨基}-2,3-二氢-4H-1,4-苯并嗪-4-基)丁酸,
(37)4-氧代-4-(8-((4-(4-苯基丁氧基)苯甲酰基)氨基)-2-(1H-四唑-5-基)-2,3-二氢-4H-1,4-苯并嗪-4-基)丁酸,和
3.包括权利要求1所述的式(I-b)所示化合物或其盐的药学组合物。
4.包括权利要求1所述的式(I-b)所示化合物或其盐和选自cysLT1受体拮抗剂、甾族药物、抗组胺药、磷酸二酯酶4抑制剂、弹性蛋白酶抑制剂、抗胆碱能药和拟交感神经药中的一种或多种的医药。
5.权利要求1所述的式(I-b)所示化合物或其盐在制备用于预防和/或治疗由cysLT2介导的疾病的药物中的应用。
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