CN109125325A - 前列环素受体激动剂的医药用途 - Google Patents
前列环素受体激动剂的医药用途 Download PDFInfo
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- CN109125325A CN109125325A CN201811113332.5A CN201811113332A CN109125325A CN 109125325 A CN109125325 A CN 109125325A CN 201811113332 A CN201811113332 A CN 201811113332A CN 109125325 A CN109125325 A CN 109125325A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
本发明提供了一种符合通式I所示的化合物、其异构体或其药学上可接受的盐在制备治疗和/或高原病的药物组合物中的用途，所述的高原病选自在海拔2000m以上的高原环境下产生的急性高原病或慢性高原病。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及一种前列环素受体激动剂在制备治疗或预防高原病的药物组合物中的用途。
背景技术
高原反应即高原病，是人到达一定海拔高度后，身体为适应因海拔高度而造成的气压差、含氧量少、空气干燥等的变化而产生的自然生理反应。高原反应的症状一般表现为头疼、心慌、疲倦、胸闷、气短、呕吐、食欲减退、抽搐、意识恍惚、认知能力骤降等。体征为心率加快、呼吸加深、血压轻度异常、颜面或四肢水肿、口唇紫绀等。目前预防和调治高原反应的多为红景天、高原宁、西洋参、丹参丸、百服宁等药品或相关保健品。例如专利CN103829245A、CN103948896A、CN104274808A、CN104288262A、CN104288735A、CN104288476A、CN104721202A、CN104706771A、CN105168308A、CN105193839A等，但是这些药品或食品存在见效慢、副作用多等缺陷。
本发明人惊奇的发现一类前列环素受体(PGI2)激动剂化合物，其在治疗或预防高原病方面具有显著的疗效。
专利WO2002/88084公开了作为PGI2受体激动剂的化合物作为活性成分的医药组合物及在抑制血小板凝集、抑制3H-Iloprost与血小板膜的结合作用、增加血小板内cAMP的作用方面的医药用途。
专利WO2010/150865公开了一种晶体，该晶体是PGI2受体激动剂，以该晶体作用有效成分的药物组合物可以治疗或预防短暂性脑缺血发作、糖尿病性神经病变、糖尿病性坏疽、末梢循环障碍、胶原病、经皮冠状动脉成形术即PTCA后的再阻塞或再狭窄、动脉硬化、血栓症、高血压、肺动脉高压、缺血性疾病、心绞痛、肾小球肾炎、糖尿病性肾炎、慢性肾功能衰竭、过敏、支气管哮喘、溃疡、褥疮、经皮腔内斑块旋切术及支架置入等经皮冠状动脉介入治疗后的再狭窄、透析导致的血小板减少、脏器或组织的纤维化相关疾病、勃起障碍、炎性肠病、胃炎、胃溃疡、缺血性眼病、突发性聋、无血管性骨坏死、伴随非甾体类抗炎药即NSAIDs的给药而发生的肠道损伤、伴随椎管狭窄症而产生的症状等。但未公开本发明所述的化合物在制备治疗或预防高原病的药物组合物中的用途。
发明内容
本发明提供了一种符合通式I所示化合物、其异构体或其药学上可接受的盐在制备治疗或预防高原病的药物组合物中的用途；
其中，
n选自1或2；
R1选自H或F；
R2选自H、OH、NH2、卤素、C1-6烷基或C1-6杂烷基，其中所述C1-6烷基或C1-6杂烷基任选的被1、2或3个Rb取代；所述Rb分别独立的选自F、Cl、Br、I、OH、NH2；
R3选自H、OH、NH2、卤素、C1-6烷基或C1-6杂烷基，其中所述C1-6烷基或C1-6杂烷基任选被1、2或3个Rc取代；所述Rc分别独立的选自F、Cl、Br、I、OH、NH2；
R4选自OH、C1-6烷氧基或C1-6烷基-S(＝O)2-NH-，其中所述C1-6烷氧基或C1-6烷基-S(＝O)2-NH-任选被1、2或3个Rd取代；所述Rd分别独立的选自F、Cl、Br、I、OH、NH2；
环A选自苯基或5～6元杂芳基；
环B选自苯基、5～6元杂芳基、C3-6环烷基或3～6元杂环烷基；
T1选自N或CH；
T2选自N或CH；
T3选自N或CH；
T4选自N或C(R5)；
T5选自N、CH或C；
选自
R5选自H、OH、NH2、卤素、C1-6烷基或C1-6杂烷基，其中所述C1-6烷基或C1-6杂烷基任选被1、2或3个Re取代；所述Re分别独立的选自F、Cl、Br、I、OH、NH2；
所述C1-6杂烷基、3～6元杂环烷基或5～6元杂芳基分别包含1、2或3个独立选自-O-、-NH-、-S-或N的杂原子或杂原子团。
优选的，R2选自H、OH、NH2、卤素、C1-3烷基或C1-3烷氧基，其中所述C1-3烷基或C1-3烷氧基任选被1、2或3个Rb取代。
进一步优选的，R2分别独立地选自H、F、Cl、Br、I、OH、NH2、Me或所述Me和任选1、2或3个Rb取代。
优选的，所述的卤素选自F、Cl、Br或I。
在本发明的一个具体实施方式中，所述通式I中，所述R2选自H、F、Cl、Br、I、OH、NH2、Me、CF3、
优选的，所述R3选自H、OH、NH2、卤素、C1-3烷基或C1-3烷氧基，其中所述C1-3烷基或C1-3烷氧基任选被1、2或3个Rc取代。
进一步优选的，所述R3选自H、F、Cl、Br、I、OH、NH2、Me或所述Me或任选1、2或3个Rc取代。
在本发明的一个具体实施方式中，所述通式I中，所述R3选自H、F、Cl、Br、I、OH、NH2、Me、CF3、
优选的，所述R4选自OH、C1-3烷氧基或C1-3烷基-S(＝O)2-NH-，其中所述C1-3烷氧基或C1-3烷基-S(＝O)2-NH-任选被1、2或3个Rd取代。
进一步优选的，所述R4选自OH、其中所述 任选被1、2或3个Rd取代。
在本发明的一个具体实施方式中，所述通式I中，所述R4选自OH、
优选的，R5选自H、OH、NH2、卤素、C1-3烷基或C1-3烷氧基，其中所述C1-3烷基或C1-3烷氧基任选被1、2或3个Re取代。
进一步优选的，所述R5选自H、OH、NH2、F、Cl、Br、I、Me或其中所述Me或任选被1、2或3个Re取代。
在本发明的一个具体实施方式中，所述通式I中，R5选自H、OH、NH2、F、Cl、Br、I、Me或
优选的，所述通式I中，环A选自苯基或吡啶基。
进一步优选的，所述通式I中，选自
更进一步优选的，所述通式I中，选自
在本发明的一个具体实施方式中，所述通式I中，选自
优选的，所述通式I中，环B选自苯基、吡啶基、噻唑基或环己烷基。
进一步优选的，选自
更进一步优选的，选自
在本发明的一个具体实施方式中，选自
在本发明的一个具体实施方式中，所述的通式I选自下列结构式中的任一个：
在本发明的一个具体实施例中，所述通式I中，n为1，R1为F，R2为F，R3为H，R4为OH，环A为环B为苯基，T1为CH，T2为N，T3为CH，T4为N，T5为N，为
在本发明的另一个具体实施方式中，所述的通式I所示化合物为sc0253，所述的sc0253的结构式为：其结构式为
本发明所述的高原病选自在高原环境下产生的急性高原病和慢性高原病。
优选的，所述的急性高原病选自高原昏迷、高原脑水肿、高原肺水肿或脑、肺异常症状同时存在的混合型疾病；和/或所述的慢性高原病选自高原心脏病、高原红细胞增多症、高原高血压、高原低血压或心脏病、红细胞增多症同时存在的混合型疾病。
优选的，所述高原病的临床表现选自头疼、头昏、心慌、心率加快、疲倦、胸闷、气短、呼吸加深、恶心、呕吐、失眠、乏力、眼花、嗜睡、食欲减退、抽搐、意识恍惚、手足麻木、唇指发绀、颜面水肿、四肢水肿或认知能力骤降中的一种或两种以上的组合。
本发明所述的药物组合物中包含作为活性成分的具有通式I的化合物、其异构体或其药学上可接受的盐，和药物辅料。
优选的，所述的药物辅料选自溶剂、乳化剂、增塑剂、崩解剂、填充剂、粘合剂、甜味剂或润滑剂中的一种或两种以上的组合。
本发明所述的溶剂选自水、醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、羟丙基-β-环糊精(HP-β-CD)、亚砜或羧酸中的一种或两种以上的组合。
优选的，所述的溶剂选自甲醇、乙醇、异丙醇、羟丙基-β-环糊精、聚乙二醇-15-羟基硬脂酸酯、二氯甲烷丙酮或乙酸乙酯中的一种或两种以上的组合。
本发明所述的乳化剂选自聚乙二醇油酸酯、聚乙烯醇、甘油硬脂酸酯或吐温-80中的一种或两种以上的组合。优选的，所述的乳化剂选自聚乙二醇油酸酯或甘油硬脂酸酯中的一种或其组合。
本发明所述的增塑剂选自聚乙二醇、蓖麻油、甘油或山梨醇中的一种或两种以上的组合。优选的，所述的增塑剂选自聚乙二醇或蓖麻油中的一种或其组合。
本发明所述的崩解剂选自交联聚维酮、羟甲纤维素钠、甲基纤维素钠淀粉或低取代羟丙纤维素中的一种或两种以上的组合。优选的，所述的崩解剂选自羟甲纤维素钠或甲基纤维素钠淀粉中的一种或其组合。
本发明所述的填充剂选自微晶纤维素、赤藓醇、山梨醇、甘露醇、预胶化淀粉、碳酸钙、蔗糖或乳糖中的一种或两种以上的组合。优选的，所述填充剂选自山梨醇、甘露醇、预胶化淀粉或乳糖中的一种或两种以上的组合。
本发明所述的粘合剂选自聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、明胶、瓜尔胶、羟甲基纤维素钠、羟丙甲纤维素、硅酸镁铝、乙基纤维素、羟乙基纤维素、预胶凝淀粉、阿拉伯胶、聚乙烯醇、聚维酮、麦芽糊精或海藻酸钠中的一种或两种以上的组合。优选的，所述粘合剂选自硅酸镁铝、羟甲基纤维素钠或聚乙烯吡咯烷酮中的一种或两种以上的组合。
本发明所述的甜味剂选自阿司帕坦、木糖醇、薄荷脑、薄荷香精、安塞蜜、甜菊糖苷、或三氯蔗糖中的一种或两种以上的组合。优选的，所述的甜味剂选自薄荷香精、三氯蔗糖或安塞蜜中的一种或两种以上的组合。
本发明所述的润滑剂选自滑石粉、氢化硬脂酸钙、十二烷基硫酸镁、硬脂酰醇富马酸钠、水合硅胶钠、氢化蓖麻油、硬脂酸锌、硬脂酸镁或中的一种或两种以上的组合。优选的，所述润滑剂选自氢化蓖麻油、硬脂酸锌或氢化硬脂酸钙中的一种或两种以上的组合
优选的，通过口服、静脉内或腹膜内的途径向体内施加药物组合物。
在本发明的具体实施方式中，通过口服的途径向体内施加药物组合物。
优选的，所述的药物组合物的剂型为口服液、丸剂、颗粒剂、片剂或胶囊中的一种或两种以上的组合。
本发明还提供了一种符合通式I的化合物、其异构体或其药学上可接受的盐在制备高原环境下保护心肺功能的药物组合物中的用途。
本发明所述的保护心肺功能为预防或治疗高原环境下心肺损伤和/或血管损伤。优选的，所述的心肺损伤和/或血管损伤为肺动脉高压和/或右室肥厚。
本发明所述的高原环境为海拔2000m以上，具有低压、缺氧的条件。优选的，所述的高原环境为海拔2700m以上，具有低压、缺氧的条件下。
在本发明的具体实施方式中，所述的高原环境为海拔5500m以上，具有低压、缺氧的条件下。
本发明还进一步提供了一种含有通式I的化合物、其异构体或其药学上可接受的盐的药物组合物的制备方法，包括1)将含有通式I的化合物或其药学上可接受的盐均匀分散到药物辅料中；2)混合压制成片剂、颗粒剂、将颗粒装入胶囊壳中制成胶囊、热熔后滴加至冷凝液中制成滴丸。
本发明进一步提供了符合通式I的化合物、其异构体或其药学上可接受的盐在制备5500m高原环境下保护大鼠心肺功能的药物组合物中的用途。
本发明所述的“烷基”表示直链或支链的饱和的碳氢基团，其可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。优选的，所述烷基为C1-20烷基。所述的C1-20烷基选自甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、2-乙基丁基、正戊基、异戊基、1-甲基戊基、1,3-二甲基丁基、正己基、1-甲基己基、正庚基、异庚基、1,1,3,3-四甲基丁基、1-甲基庚基、3-甲基庚基、正辛基、2-乙基己基、1,1,3-三甲基己基、1,1,3,3-四甲基戊基、壬基、癸基、十一烷基、1-甲基十一烷基、十二烷基、1,1,3,3,5,5-六甲基己基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基及二十烷基。进一步优选的，所述烷基为C1-6烷基，包括但不限于甲基(Me)，乙基(Et)，丙基(包括n-丙基和异丙基)，丁基(包括n-丁基，异丁基，s-丁基和t-丁基)，戊基(包括n-戊基，异戊基和新戊基)、己基。
本发明所述的“杂烷基”表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。所述的杂原子选自B、O、N或S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。进一步优选的，所述的杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。所述的杂烷基包括但不限于-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2(CH3)2、-CH2-CH2-O-CH3、-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)(CH2CH3)、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2、-CH2-SCH2-CH3、-CH2-CH2、-S(＝O)-CH3、-CH2-CH2-S(＝O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3或–CH＝CHN(CH3)-CH3。
本发明所述的“环”为被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂化炔基、芳基或杂芳基。所述的环包括单环、联环、螺环、并环或桥环。所述的“杂环”为包含杂原子或杂原子团的单环、双环或三环，可以是饱和的、部分饱和的或不饱和的(例如：芳香族)，所述的杂原子或杂原子团包括碳、氢外的原子或原子团，例如：氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
本发明所述的“杂环烷基”包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、二恶烷基、二噻烷基、异恶唑烷基、异噻唑烷基、1,2-恶嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
本发明所述的“环烷基”包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。所述的环烷基包括但不限于环丙基、降冰片烷基、[2.2.2]二环辛烷或[4.4.0]二环癸烷。
本发明所述的“杂芳基”可通过杂原子连接到分子的其余部分。芳基或杂芳基包括但不限于苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基或6-喹啉基，以及1、2、3或4个位点被取代基取代。
本发明所述的“烷氧基”代表通过氧桥连接的具有特定数目碳原子的烷基，除非另有规定，C1-6烷氧基包括C1、C2、C3、C4、C5或C6的烷氧基。优选的，所述的烷氧基为C1-3烷氧基。所述的烷氧基的包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
本发明所述的“异构体”可以为顺式异构体或反式异构体，(-)-对对映体或(+)-对对映体，(R)-对映体或(S)-对映体，非对应异构体、(D)-异构体、(L)-异构体，或其外消旋混合物。
本发明所述的“活性成分”指化学实体，可以治疗目标紊乱、疾病或病症。
本发明所述的“和/或”包括择一列出的项目以及任何数量的项目组合。
本发明所述的“包括”是开放式的描述，含有所描述的指定成分或步骤，以及不会实质上影响的其他指定成分或步骤。
本发明所述的“任选”指随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
本发明所述的“治疗”表示在疾病已开始发展后减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性，但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。
本发明所述的“或其药学上可接受的盐”指由药学上可接受的无毒性的酸或碱制备而来的盐，其中的酸或碱包括无机酸或碱或有机酸或碱。所述的无机酸选自盐酸、氢溴酸、磷酸、氢碘酸或硫酸。所述的无机碱选自钙、镁、锂、钠、锌、铝或钾。所述的有机酸选自甲酸、羟基乙酸、丙酸、醋酸、琥珀酸、甲磺酸、乙磺酸、顺丁烯二酸、谷氨酸、苯甲酸、硬脂酸、海藻酸、苯磺酸、葡萄糖醛酸、双羟萘酸或半乳糖醛酸。所述的有机碱选自二乙醇胺、胆碱、普鲁卡因、赖氨酸或1,2-乙二胺。
附图说明
以下，结合附图来详细说明本发明的实施例，其中：
图1：各组(空白对照组、模型组、试验组A及试验组B)大鼠平均肺动脉压(mPAP)的变化；
图2：各组(空白对照组、模型组、试验组A及试验组B)大鼠右室射血分数(RVEF)的变化；
图3：各组(空白对照组、模型组、试验组A及试验组B)大鼠右室短轴缩短分数(RVFS)的变化；
图4：各组(空白对照组、模型组、试验组A及试验组B)大鼠右心室肥厚指数(RV/(LV+OS))的变化。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的部分实施例，而不是全部。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
步骤1：化合物A的合成
合成路线：
将2-氨基-5-氟吡啶(2g，17.84mmol)，苯硼酸(4.35g，35.68mmol)，醋酸铜(3.24g，17.84mmol)和吡啶(2.82g，35.68mmol)加入到二氯甲烷(20mL)中，反应液在氧气氛围(15psi)、25℃下搅拌14小时后，浓缩得到粗品。粗品经柱分离(洗脱剂：石油醚/乙酸乙酯＝25/1)得到化合物A。MS m/z:189.0[M+H]+。
步骤2：化合物B的合成
合成路线：
将化合物B-1(2g，8.57mmol)用盐酸乙酸乙酯(10.00mL)混合均匀，混合液在20℃搅拌0.5小时，反应完毕将反应液过滤得到B-2。
将化合物B-2(3g)和哌啶甲醇(2.44g，21.14mmol)，三乙胺(2.24g，22.15mmol，3.08mL)加到二氧六环(60.00mL)中，混合均匀，反应液在105℃搅拌2小时。反应完毕减压除去溶剂，所得残留物经柱层析分离(展开剂：石油醚/乙酸乙酯＝10/1～3/1)得到B-3。
将化合物B-3(3g)和四丁基硫酸氢铵(4.47g，13.18mmol)溶于甲苯(60.00mL)中，将温度冷却到0℃并搅拌10分钟，向反应液中加入40％氢氧化钾溶液(60mL)并搅拌20分钟后，向反应液中加入溴乙酸叔丁酯(7.71g，39.53mmol，5.84mL)，反应液在30℃下搅拌12小时。倒入水(20mL)中，用乙酸乙酯(30mL)萃取，分离得到的有机相用饱和食盐水(20mL)洗涤，用无水硫酸钠干燥。过滤除去干燥剂后，减压除去溶剂，所得残留物经柱层析分离(展开剂：乙酸乙酯/石油醚＝1/4)得到目标化合物B。MS m/z:360.0[M+H]+。1H NMR(400MHz,METHANOL-d4)δppm 8.16(s,1H),7.74(s,1H),4.24(br d,J＝13.6Hz,2H),4.07(s,2H),3.63(d,J＝19.2Hz,2H),3.37(d,J＝3.0Hz,1H),3.30(d,J＝3.0Hz,1H),2.04-1.73(m,4H),1.50(s,9H)。
步骤3：化合物C的合成
向化合物A(54.77mg)的二氧六环(10mL)溶液加入化合物B(0.1g)，碳酸铯(285.95mg，877.62μmol)，xantphos(33.85mg，58.51μmol)和Pd(dba)2(16.82mg，29.25μmol)，反应体系在氮气保护、100℃下搅拌12小时。向反应体系加入水(20mL)稀释，用乙酸乙酯(10mL*3)萃取。合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。过滤，滤液浓缩得到粗品。粗品经制备薄层层析(石油醚/四氢呋喃＝2/1)分离得到化合物C。MS m/z:512.2[M+H]+。
步骤4：化合物X的合成
往化合物C的甲醇(10mL)溶液加入10％氢氧化钠(8mL)，反应体系在45℃搅拌0.5小时。将反应液浓缩，用水(20mL)稀释并搅拌2分钟，反应体系用稀盐酸(2N)调节pH＝5，用乙酸乙酯(30mL*2)萃取。合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，真空下浓缩得到粗品。粗品经HPLC(中性)分离得到化合物X。MS m/z:456.0[M+H]+。1H NMR(CHLOROFORM-d,400MHz)δppm 8.21(d,J＝2.4Hz,1H),7.70(s,1H),7.43-7.35(m,4H),7.28-7.24(m,1H),7.19(d,J＝7.2Hz,2H),7.10(dd,J＝3.6,8.8Hz,1H),4.14(s,2H),3.90(d,J＝13.6Hz,2H),3.58(br d,J＝19.2Hz,2H),3.19(t,J＝12.0Hz,2H),1.92-1.86(m,2H),1.76-1.59(m,2H)。
实施例2
一、材料与方法
1、实验动物及饲养
SD大鼠40只(200g左右，雄性，清洁级)，购自北京维通利华实验动物有限公司，许可证号：SCXK(京)2016-0006。低压氧舱饲养，定时给予全价营养饲料喂食，室温22-25℃，湿度30％-50％。
2、试剂与样品组别
化合物sc0253为本发明实施例1制备的化合物X；
HP-β-CD购买自solaxbio；
溶剂配置：20％HP-β-CD+80％双蒸水，pH＝8。
组别：
空白对照组：常压常氧饲养
模型组：低压低氧舱灌胃溶剂
试验组A：低压低氧舱灌胃sc0253(5mg/kg)+溶剂
试验组B：低压低氧舱灌胃sc0253(10mg/kg)+溶剂
3、仪器
多因素复合环境模拟医学科学实验舱(型号DYC-3285，北京军事医学科学院仪器中心)；
小动物呼吸机(kent scientific,美国)；
多功能生理仪(Millar,美国)；
小动物超声(Visual Sonics Inc,加拿大)。
4、实验设计与过程
将40只大鼠随机分为4组，每组10只。其中3组置于实验舱中，调节舱内压力至380mmHg，模拟海拔5500米的高原环境，每天打开实验舱1小时，以便给动物添加饲料和水及给予相应的药物处理，同时保持大鼠所处的环境12：12小时昼夜交替，14天后分别灌胃给予溶剂(模型组)、sc0253(5mg/kg)+溶剂(试验组A)或sc0253(10mg/kg)+溶剂(试验组B)，每日两次并持续14天。第4组大鼠放在同一房间中常压常氧环境下饲养(空白对照组)。
5、指标检测方法
3％的戊巴比妥钠，0.2mL/100g腹腔注射麻醉大鼠，行超声检测。记录超声数据如下：右室射血分数RVEF；右室缩短分数RVFS。之后将麻醉好的大鼠仰卧位固定于手术台上，气管切管，连接呼吸机，开胸，暴露心脏，导管插入右心室，行右心导管检查，记录右心室收缩压。再缓慢向前推进，可经右心室流出道到达肺动脉，观察监视器的压力波形，并记录平均肺动脉压mPAP。处死大鼠，取出心脏，去除心房组织及附着脂肪，分离左右心室，滤纸吸干水分，分别称重并计算(RV/(LV+OS))。
6、统计学方法
所有数据用x±s表示，组间比较为单因素方差分析，P＜0.05为差异有统计学意义，采用SPSS19.0软件包进行统计学处理。
二、实验结果
1、对大鼠mPAP的影响
大鼠在低压低氧环境饲养14天后，与空白对照组相比，模型组大鼠的mPAP明显升高，差异具有显著性(P＜0.001)。在低压低氧环境下，与模型组相比，试验组A(化合物sc0253-5mg/kg)和试验组B(sc0253-10mg/kg)的大鼠mPAP明显降低，差异有统计学意义(P＜0.05)。
2、对大鼠RVEF和RVFS的影响
大鼠在低压低氧环境饲养14天后，与空白对照组相比，模型组大鼠的RVEF和RVFS明显降低，差异具有显著性(P＜0.05)。在低压低氧环境下，与模型组相比，试验组B(化合物sc0253-10mg/kg)大鼠的RVEF和RVFS明显升高，差异有统计学意义(P＜0.01)。
3、对大鼠RV/(LV+OS)的影响
大鼠在低压低氧环境饲养14天后，与空白对照组相比，模型组大鼠的RV/(LV+OS)明显升高，差异具有显著性(P＜0.01)。在低压低氧环境下，与模型组相比，试验组B(化合物sc0253-10mg/kg)大鼠的RV/(LV+OS)明显降低，差异有统计学意义(P＜0.01)。
综上所述，本发明所述的化合物对高原低压低氧环境下产生的高原病具有治疗和/或预防的作用，尤其对于高原低压、低氧环境下的心肺具有极强的保护作用，可以开发成高原病的防治药物，尤其在抗高原心肺及血管损伤的防治药物。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
Claims (11)
1.符合通式I所示化合物、其异构体或其药学上可接受的盐在制备治疗或预防高原病的药物组合物中的用途；
其中，
n选自1或2；
R1选自H或F；
R2选自H、OH、NH2、卤素、C1-6烷基或C1-6杂烷基，其中所述C1-6烷基或C1-6杂烷基任选的被1、2或3个Rb取代；所述Rb分别独立的选自F、Cl、Br、I、OH、NH2；
R3选自H、OH、NH2、卤素、C1-6烷基或C1-6杂烷基，其中所述C1-6烷基或C1-6杂烷基任选被1、2或3个Rc取代；所述Rc分别独立的选自F、Cl、Br、I、OH、NH2；
R4选自OH、C1-6烷氧基或C1-6烷基-S(＝O)2-NH-，其中所述C1-6烷氧基或C1-6烷基-S(＝O)2-NH-任选被1、2或3个Rd取代；所述Rd分别独立的选自F、Cl、Br、I、OH、NH2；
环A选自苯基或5～6元杂芳基；
环B选自苯基、5～6元杂芳基、C3-6环烷基或3～6元杂环烷基；
T1选自N或CH；
T2选自N或CH；
T3选自N或CH；
T4选自N或C(R5)；
T5选自N、CH或C；
选自
R5选自H、OH、NH2、卤素、C1-6烷基或C1-6杂烷基，其中所述C1-6烷基或C1-6杂烷基任选被1、2或3个Re取代；所述Re分别独立的选自F、Cl、Br、I、OH、NH2；
所述C1-6杂烷基、3～6元杂环烷基或5～6元杂芳基分别包含1、2或3个独立选自-O-、-NH-、-S-或N的杂原子或杂原子团。
2.根据权利要求1所述的用途，其特征在于，所述通式I中，所述R2选自H、F、Cl、Br、I、OH、NH2、Me、CF3、
3.根据权利要求1所述的用途，其特征在于，所述通式I中，所述R3选自H、F、Cl、Br、I、OH、NH2、Me、CF3、
4.根据权利要求1所述的用途，其特征在于，所述通式I中，所述R4选自OH、
5.根据权利要求1所述的用途，其特征在于，所述通式I中，R5选自H、OH、NH2、F、Cl、Br、I、Me或
6.根据权利要求1所述的用途，其特征在于，所述通式I中，环A选自苯基或吡啶基。
7.根据权利要求1所述的用途，其特征在于，所述通式I中，环B选自苯基、吡啶基、噻唑基或环己烷基。
8.根据权利要求1-7任一所述的用途，其特征在于，所述的通式I所示化合物为sc0253，所述的sc0253的结构式为：
9.根据权利要求1-8任一所述的用途，其特征在于，所述的高原病选自在高原环境下产生的急性高原病和慢性高原病。
10.根据权利要求9所述的用途，其特征在于，所述的急性高原病选自高原昏迷、高原脑水肿、高原肺水肿或脑、肺异常症状同时存在的混合型疾病；和/或所述的慢性高原病选自高原心脏病、高原红细胞增多症、高原高血压、高原低血压或心脏病、红细胞增多症同时存在的混合型疾病。
11.根据权利要求1-8任一所述的用途，其特征在于，所述的药物组合物中包含作为活性成分的具有通式I的化合物、其异构体或其药学上可接受的盐，和药物辅料。
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