CN109232546A - 一种嘧啶磺酰胺类衍生物的医药用途 - Google Patents
一种嘧啶磺酰胺类衍生物的医药用途 Download PDFInfo
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- CN109232546A CN109232546A CN201811113581.4A CN201811113581A CN109232546A CN 109232546 A CN109232546 A CN 109232546A CN 201811113581 A CN201811113581 A CN 201811113581A CN 109232546 A CN109232546 A CN 109232546A
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
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，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和慢性高原病。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及一种嘧啶磺酰胺类衍生物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嘧啶磺酰胺类衍生物内皮素-1受体ETAR、ETBR双拮抗剂类化合物，其在治疗或预防高原病方面具有显著的疗效。
专利WO2002/053557公开了一种新颖的磺酰胺类化合物及其作为活性组分在制备治疗高血压、局部缺血、血管痉挛、心绞痛、癌、偏头痛、哮喘、高血脂或炎性疾病等药物组合物中的应用。专利CN102510719A公开了用于与细胞毒性化学治疗剂、放射疗法或两者组合在脑转移的预防或治疗中使用的内皮素受体拮抗剂。但均未公开本发明所述的符合通式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。
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；尤其有效抑制ET-1引起的缩血管效应。
其中，
R1选自H、F、Cl、Br、I、OH或NH2；
R2选自H或C1-3烷基，所述C1-3烷基任选的被1、2或3个X取代；
R3选自H、C1-6烷基、C1-6杂烷基、-C1-3烷基-C3-6环烷基、C3-6环烷基和-C1-3烷基-3～7元杂环烷基，所述C1-6烷基、C1-6杂烷基、-C1-3烷基-C3-6环烷基、C3-6环烷基或-C1-3烷基-3～7元杂环烷基任选被1、2或3个X取代；
或者，R2与R3连接形成一个任选被1、2或3个X取代的3-8元环；
环B选自3～7元杂环烷基或5～6元杂芳基，所述3～7元杂环烷基或5～6元杂芳基任选被1、2或3个X取代；
X分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、C1-6烷基或C1-6杂烷基，所述C1-6烷基或C1-6杂烷基任选被1、2或3个X’取代；
X’分别独立地选自F、Cl、Br、I、OH、NH2、CN、Me、CH2F、CHF2、CF3和Et；
所述C1-6杂烷基、3～7元杂环烷基和5～6元杂芳基分别包含1、2、3或4个独立选自N、-O-、-S-、-NH-、-S(＝O)2-或-S(＝O)-的杂原子或杂原子团。
优选的，所述X选自H、F、Cl、Br、I、OH、NH2、CN、C1-3烷基、C1-3烷基-S(＝O)2-或C1-3烷基-O-，所述C1-3烷基、C1-3烷基-S(＝O)2-或C1-3烷基-O-任选被1、2或3个X’取代。
进一步优选的，所述X选自H、F、Cl、Br、I、OH、NH2、CN、Me、Et、 所述Me、Et、任选被1、2或3个X’取代。
在本发明的一个具体实施方式中，所述的X选自H、F、Cl、Br、I、OH、NH2、CN、Me、CH2F、CHF2、CF3、Et、优选的，所述环B选自四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基，所述四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基任选被1、2或3个X取代。
进一步优选的，所述选自
优选的，所述的R2选自H或Me。
优选的，所述的R3选自H、C1-4烷基、C1-4烷基-O-C1-4烷基、环丁烷基、-C1-3烷基-环丁烷基、-C1-3烷基-环丙烷基、-C1-3烷基-四氢呋喃基和-C1-3烷基-四氢吡喃基，所述C1-4烷基、C1-4烷基-O-C1-4烷基、环丁烷基、-C1-3烷基-环丁烷基、-C1-3烷基-环丙烷基、-C1-3烷基-四氢呋喃基或-C1-3烷基-四氢吡喃基任选被1、2或3个X取代。
进一步优选的，所述的R3选自H、Me、Et、 其中，所述Me、Et、 任选的被1、2、3个X取代。
在本发明的一个具体实施方式中，所述的R3选自H、Me、Et、
本发明所述的R2与R3连接形成一个6-8元杂环烷基，所述得到6-8元杂环烷基任选的被1、2、3个X取代。
优选的，所述选自其中，所述 任选的被1、2、3个X取代。
进一步优选的，所述选自
优选的，所述R1选自H、F、Cl、Br、I、OH或NH2；所述X选自H、F、Cl、Br、I、OH、NH2、CN、Me、CH2F、CHF2、CF3、Et、 所述环B选自四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基，所述四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基任选被1、2或3个X取代；所述R2选自H或Me；所述R3选自H、Me、Et、
进一步优选的，所述R1选自F、Cl、Br或I；所述选自 所述R2为H；所述R3选自
在本发明的一个具体实施方式中，所述的符合通式I所示化合物选自下列中的一种：
优选的，所述的符合通式I所示化合物中，所述R1为Br，所述为所述R2为H，所述R3为
在本发明的一个具体实施方式中，所述的通式I所示化合物为SC0062，所述的SC0062的结构式为：
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，所述的高原环境为海拔2000m以上，具有低压、缺氧的条件。
进一步优选的，所述的高原环境为海拔2700m以上，具有低压、缺氧的条件下。
在本发明的一个具体实施方式中，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。
本发明还提供了一种符合通式I的化合物、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、二氯甲烷、羟丙基-β-环糊精、聚乙二醇-15-羟基硬脂酸酯、丙酮或乙酸乙酯中的一种或两种以上的组合。优选的，所述的溶剂选自水、羟丙基-β-环糊精或聚乙二醇-15-羟基硬脂酸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烯醇或吐温-80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，所述的增塑剂选自甘油或山梨醇中的一种或其组合。
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，所述的崩解剂选自交联聚维酮或低取代羟丙纤维素中的一种或其组合。
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，所述填充剂选自微晶纤维素、碳酸钙或赤藓醇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，所述粘合剂选自预胶凝淀粉、羟甲基纤维素钠、麦芽糊精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，所述的甜味剂选自甜菊糖苷、三氯蔗糖或薄荷脑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，所述润滑剂选自硬脂酰醇富马酸钠、滑石粉、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、其异构体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“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。
具体实施方式
下面将结合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
目标化合物X的制备步骤如下：
第一步：合成化合物F
1)室温下，将化合物A(30.00g，211.97mmol，18.40mL)溶解于二氯甲烷(200mL)中，随后冷却至0℃，缓慢加入叔丁醇(15.71g，211.97mmol，20.40mL)的二氯甲烷(100mL)溶液(滴加时间约1小时)，反应混合物升至室温并搅拌1小时。目标化合物B(粗品)保留在反应溶剂二氯甲烷中，直接用于后续的反应。
2)室温下，将化合物2–甲氧基乙胺(2.00g，26.63mmol，2.33mL)和三乙胺(5.39g，53.26mmol，7.38mL)溶解于二氯甲烷(100.00mL)中，随后反应混合物冷却至0℃，缓慢将化合物B(26.63mmol，粗品)的二氯甲烷溶液加入到上述反应液中(滴加时间约0.5小时)，反应混合物升至室温并搅拌15小时。反应完毕后，减压除去溶剂，所得残余物加入水(100mL)，用1M盐酸调节pH至5，乙酸乙酯(100mL x3)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，得到目标化合物C(白色固体，6.00g，收率：88.59％)。1H NMR(400MHz，CDCl3)δ：7.37(s，1H)5.50(br s，1H)3.53(t，J＝5.0Hz，2H)，3.40(s，3H)，3.26(d，J＝4.8Hz，2H)1.51(s，9H)。
3)室温下，将化合物C(6.00g，23.59mmol)加入到水(100.00mL)中，反应混合物加热至100℃并搅拌1小时。反应完毕后，冷却至室温，用乙酸乙酯(100mL x 3)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，得到目标化合物D(黄色固体，2.00g，收率：54.99％)。1H NMR(400MHz,CDCl3)δ:5.52(br s,2H),3.58–3.48(m,2H),3.41–3.19(m,5H)。
4)室温下，将化合物D(1.12g，7.24mmol)和叔丁醇钾(2.22g，19.75mmol)加入到二甲亚砜(20.00mL)中，反应混合物在室温下搅拌0.5小时，随后将5–溴–4,6–二氯嘧啶(1.50g，6.58mmol)加入到上述反应液中，反应混合物在室温下继续搅拌6小时。反应完毕后，加入水(100mL)，用1M稀盐酸调节pH至6，乙酸乙酯(100mL x 3)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：二氯甲烷/甲醇＝30/1，体积比)，得到目标化合物E(黄色固体，1.40g，收率：61.56％)。1H NMR(400MHz,CDCl3)δ:8.57(s,1H),7.89(br s,1H),5.99(br s,1H),3.36(brd,J＝2.3Hz,2H),3.32–3.20(m,5H)。
5)室温下，将叔丁醇钾(1.36g，12.15mmol)加入到乙二醇(22.20g，357.66mmol，20.00mL)中，反应混合物加热至40℃并搅拌0.5小时，随后将化合物E(1.40g，4.05mmol)的乙二醇二甲醚(10.00mL)溶液加入到上述溶液中，反应混合物加热至110℃并继续搅拌12小时。反应完毕后，冷却至室温，加入水(50mL)，用1M稀盐酸调节pH至3，乙酸乙酯(50mL x 3)萃取。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：二氯甲烷/甲醇＝20/1，体积比)，得到目标化合物F(黄色固体，1.20g，收率：76.63％)。MS–ESI m/z:370.8[M+H]+,372.8[M+H]+。1H NMR(400MHz,CDCl3)δ:8.39(s,1H),7.64(br s,1H),6.03–5.94(m,1H),4.65–4.54(m,2H),3.99(d,J＝3.0Hz,2H),3.49(t,J＝5.0Hz,2H),3.33–3.19(m,5H),2.39(t,J＝5.3Hz,1H)。
第二步：合成化合物H
室温下，将化合物G(3.00g，14.92mmol)、联硼酸嚬哪醇酯(7.58g，29.84mmol)和醋酸钾(4.39g，44.76mmol)加入到1,4–二氧六环(30.00mL)中，随后加入[1,1′–双(二苯基膦)二茂铁]二氯化钯(3.28g，4.48mmol)，在氮气保护下反应混合物加热至80℃并搅拌16小时。反应完毕后，冷却至室温，过滤，滤液减压除去溶剂，所得残余物加入水(30mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，无水硫酸钠干燥。过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–100/1，体积比)，得到目标化合物H。1H NMR(400MHz,CDCl3)δ:7.38(dd,J＝7.8,0.8Hz,1H),7.26(s,1H),6.85(d,J＝7.8Hz,1H),5.97(s,2H),1.35(s,12H)。
第三步：合成化合物I
室温下，将化合物F(300.00mg)、化合物H(419.04mg)和磷酸钾(537.83mg，2.53mmol)加入到N,N–二甲基甲酰胺(20.00mL)中，随后加入[1,1′–双(二苯基膦)二茂铁]二氯化钯(185.39mg，253.37μmol)，在氮气保护下反应混合物加热至80℃并搅拌16小时。反应完毕后，冷却至室温，加入水(100mL)，用乙酸乙酯(20mL×1)萃取，有机相丢弃。水相用3M稀盐酸调节pH至5–6，乙酸乙酯(20mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残留物经过制备层析板分离(洗脱剂：石油醚/乙酸乙酯＝1/2，体积比)，得到化合物I。
第四步：合成化合物X
室温下，将钠氢(145.30mg，3.63mmol，纯度：60％)加入到无水四氢呋喃(20mL)中，随后分别加入化合物I(180.00mg,454.06μmol)的无水N,N–二甲基甲酰胺(1mL)溶液和5–溴–2–氯嘧啶(175.66mg，908.13μmol)的无水四氢呋喃(1mL)溶液，在氮气保护下反应混合物加热至70℃并搅拌2小时。反应完毕后，冷却至室温，加入饱和氯化铵溶液(30mL)，用1M稀盐酸调节pH至4–5，乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残留物经制备HPLC分离得到目标化合物X。1HNMR(400MHz，CDCl3)δ：8.49(s，2H)，8.46(s，1H)，6.97(s，1H)，6.79(d，J＝8.3Hz，1H)，6.68–6.43(m，2H)，6.02–5.91(m，3H)，4.71–4.61(m，2H)，4.60–4.52(m，2H)，3.42(t，J＝5.0Hz，2H)，3.22(s，3H)，3.13–3.01(m，2H)。LCMS数据：MS–ESI m/z：569.0[M+H]+，571.0[M+H+2]+。
实施例2
一、材料与方法
1、实验动物及饲养：
健康SD大鼠40只，雄性，体重180-220g，购自北京维通利华实验动物技术有限公司，SPF级，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，温度22-25℃，湿度30％-50％。
2、试剂与样品组别
SC0062为本发明实施例1制备的化合物X；
solutol购于北京泰泽嘉业科技发展有限公司；
HP-β-CD购于solaxbio，25mg装，CAS：128446-35-5；
溶剂配置：5％DMSO+95％(10％HP-β-CD的生理盐水)pH＝9。
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sc0062(15mg/kg)+溶剂
试验组B：低压低氧舱灌胃sc0062(30mg/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)；
全自动动物血液细胞分析仪(迈瑞公司)；
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组置于低压低氧舱中，调节氧舱压力至380mmHg，模拟海拔5500米的高原环境，每天打开低压低氧舱1小时，以便给动物添加食物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。3组大鼠在缺氧14天后分别灌胃给予溶剂(模型组)、sc0062(15mg/kg)+溶剂(试验组A)、sc0062(30mg/kg)+溶剂(试验组B)，并持续14天。第四组(空白对照组)大鼠放在同一房间中常压常氧环境下饲养。
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：PAT/PET(肺动脉血流加速时间/右室射血前期)；右室射血分数EF；右室缩短分数FS；三尖瓣收缩期位移TAPSE。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，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。取血并处死大鼠。取出心脏及肺组织，去除心房组织及大动脉根部，分离左右心室，在PBS冲洗净血迹，滤纸吸干水分，分别称取右心室(RV)、左心室及房室膈(LV+IS)的重量。按公式计算如下：右心室肥厚指数＝RV/(LV+IS)。
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SPSS 22.0软件包进行统计学处理。
二、实验结果
1、对大鼠心脏超声的影响
低压低氧舱内模型组(溶剂组)右室功能明显降低，与空白对照组相比有明显差异。EF值，FS值，TAPSE值显著降低(p＜0.01)，PAT/PET值降低，均具有统计学差异(p＜0.05)。与模型组相比，试验组A及试验组B的EF值、FS值显著改善，TAPSE值、PAT/PET值明显回升，具体数据见表1。
表1对各组大鼠心脏超声后，参数EF、FS、TAPSE及PAT/PET的变化
2、对大鼠血流动力学的影响
低压低氧舱内模型组(溶剂组)肺动脉平均压明显升高，与空白对照组相比有显著差异(p＜0.01)。SC0062治疗组(试验组A及B)与模型组相比，肺动脉平均压显著升高(p＜0.01)，具体数据见表2。
表2本发明实施例1制备的化合物对模型大鼠肺动脉高压的影响
| 组别 | mPVP |
| 空白对照组 | 14.35±3.41 |
| 模型组 | 36.63±3.03 |
| 试验组A：sc0062(15mg/kg) | 31.39±3.90 |
| 试验组B：sc0062(30mg/kg) | 26.91±4.35 |
3、对大鼠右室肥厚的影响
低压低氧舱内模型组(溶剂组)右室肥厚指数明显升高，与空白对照组相比有显著差异(p＜0.01)，SC0062组(试验组A及B)与模型组相比，右室肥厚指数降低，有统计学差异(p＜0.05)，具体数据见表3。
表3各组大鼠右室肥厚指数变化情况
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。
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，
R1选自H、F、Cl、Br、I、OH或NH2；
R2选自H或C1-3烷基，所述C1-3烷基任选的被1、2或3个X取代；
R3选自H、C1-6烷基、C1-6杂烷基、-C1-3烷基-C3-6环烷基、C3-6环烷基和-C1-3烷基-3～7元杂环烷基，所述C1-6烷基、C1-6杂烷基、-C1-3烷基-C3-6环烷基、C3-6环烷基或-C1-3烷基-3～7元杂环烷基任选被1、2或3个X取代；
或者，R2与R3连接形成一个任选被1、2或3个X取代的3-8元环；
环B选自3～7元杂环烷基或5～6元杂芳基，所述3～7元杂环烷基或5～6元杂芳基任选被1、2或3个X取代；
X分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、C1-6烷基或C1-6杂烷基，所述C1-6烷基或C1-6杂烷基任选被1、2或3个X’取代；
X’分别独立地选自F、Cl、Br、I、OH、NH2、CN、Me、CH2F、CHF2、CF3和Et；
所述C1-6杂烷基、3～7元杂环烷基和5～6元杂芳基分别包含1、2、3或4个独立选自N、-O-、-S-、-NH-、-S(＝O)2-或-S(＝O)-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，所述的X选自H、F、Cl、Br、I、OH、NH2、CN、Me、CH2F、CHF2、CF3、Et、
3.根据权利要求1所述的用途，其特征在于，所述环B选自四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基，所述四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基任选被1、2或3个X取代。
4.根据权利要求1所述的用途，其特征在于，所述的R2选自H或Me。
5.根据权利要求1所述的用途，其特征在于，所述的R3选自H、Me、Et、
6.根据权利要求1-3任一所述的用途，其特征在于，所述R2与R3连接形成一个6-8元杂环烷基，所述得到6-8元杂环烷基任选的被1、2、3个X取代。
7.根据权利要求1所述的用途，其特征在于，所述R1选自H、F、Cl、Br、I、OH或NH2；所述X选自H、F、Cl、Br、I、OH、NH2、CN、Me、CH2F、CHF2、CF3、Et、 所述环B选自四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基，所述四氢呋喃基、四氢噻吩基、1，3-二氧戊环基、吡咯烷基、噻唑基、吡唑基或咪唑基任选被1、2或3个X取代；所述R2选自H或Me；所述R3选自H、Me、Et、
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SC0062，所述的SC0062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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| WO2020062912A1 (zh) * | 2018-09-25 | 2020-04-02 | 中国人民解放军总医院 | 一种嘧啶磺酰胺类衍生物的医药用途 |
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| WO2020233694A1 (zh) * | 2019-05-22 | 2020-11-26 | 石家庄智康弘仁新药开发有限公司 | 一种嘧啶磺酰胺类化合物的晶型及其制备方法 |
| CN113874364A (zh) * | 2019-05-22 | 2021-12-31 | 石家庄智康弘仁新药开发有限公司 | 一种嘧啶磺酰胺类化合物的晶型及其制备方法 |
| CN113874364B (zh) * | 2019-05-22 | 2024-04-05 | 无锡智康弘义生物科技有限公司 | 一种嘧啶磺酰胺类化合物的晶型及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3851435A1 (en) | 2021-07-21 |
| US11628168B2 (en) | 2023-04-18 |
| CN109232546B (zh) | 2020-09-04 |
| WO2020062912A1 (zh) | 2020-04-02 |
| US20210393627A1 (en) | 2021-12-23 |
| EP3851435A4 (en) | 2021-11-24 |
| EP3851435B1 (en) | 2023-08-09 |
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