CN109293695A - N-(3-羟基-3,3-二膦酰丙基)-n-甲基戊烷-1-胺氧化物及其类似物和用途 - Google Patents
N-(3-羟基-3,3-二膦酰丙基)-n-甲基戊烷-1-胺氧化物及其类似物和用途 Download PDFInfo
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- CN109293695A CN109293695A CN201811221005.1A CN201811221005A CN109293695A CN 109293695 A CN109293695 A CN 109293695A CN 201811221005 A CN201811221005 A CN 201811221005A CN 109293695 A CN109293695 A CN 109293695A
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
本发明属于医药技术领域,具体涉及一种N‑(3‑羟基‑3,3‑二膦酰丙基)‑N‑甲基戊烷‑1‑胺氧化物及其类似物及其制备方法和用于制备治疗肺动脉高压药物的用途。
Description
技术领域
本发明属于医药技术领域,具体涉及一种N-(3-羟基-3,3-二膦酰丙基)-N-甲基戊烷-1-胺氧化物及其类似物及其制备方法和用途。
背景技术
伊班膦酸钠(英文名:ibandronate sodium)是伊班膦酸属双膦酸盐化合物,能特异地作用于骨组织,对骨骼的特异性选择作用是由于双膦酸盐对骨骼中的无机物具有高度亲和性。其化学名称为[1-羟基-3-(N-甲基-N-戊胺基)亚丙基]-双膦酸单钠盐-水合物,即伊班膦酸钠一水合物,其结构式如下图所示:
伊班膦酸钠是第三代双膦酸盐化合物,属于氨基双膦酸盐。它最早于1996年在德国和奥地利以商品名Bondronat注册并用于临床。2003年美国FDA批准每日用药一次的Boniva上市,但由于制药公司又开发出更为便利的用药剂量,因此该药一直未上市。直到2005年,FDA批准其每月使用一次治疗骨质疏松症,Boniva正式在美国上市。
骨转移是恶性肿瘤晚期常见的转移方式据统计,全球每年有150万肿瘤患者发生骨转移,其中乳腺癌、前列腺癌和肺癌最常见。伊班膦酸钠的主要作用是抑制骨吸收。作为破骨细胞的强效抑制剂,伊班膦酸钠不但可以抑制破骨细胞活性及成熟,而且能诱导破骨细胞凋亡,进而阻断多种原因所致的骨吸收增加,还能在体外诱导多种肿瘤细胞凋亡,抑制肿瘤细胞分泌产生骨基质金属蛋白酶。甲状旁腺素相关蛋白和血管内皮生长因子等活性物质并抑制其活性,抑制乳腺癌和前列腺癌细胞对骨质的黏附作用,因而能有效防止骨转移的发生。伊班膦酸钠是目前适应证最广的双磷酸盐药物。
伊班膦酸钠注射液目前已有进口及国产药品上市,从其原料药化学结构可以看出,其结构中存在一个氮原子,氮原子上存在一对孤对电子,易发生氧化反应,发明人在对其进行研究中发现,该氮原子可以被氧化,生成相应氮氧化物,结构如下:
根据IUPAC命名法,其化学名为:(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钠。暂命名为化合物A。
其对应钾盐结构如下:
根据IUPAC命名法,其化学名为:(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钾。暂命名为化合物B。
其对应酸形式结构如下:
根据IUPAC命名法,其化学名为:N-(3-羟基-3,3-二膦酰丙基)-N-甲基戊烷-1-胺氧化物。暂命名为化合物C。
在原料药的长期储存,制剂的制备及长期储存中,均发现了上述化合物A和化合物C,作为降解杂质存在。
发明内容
本发明的目的提供一种式I所示的化合物,该化合物对于肺动脉高压具有非常好的治疗作用。
式I所示的化合物,结构如下:
其中,R为H,Na,或者K。
具体的,本发明化合物A的结构如下:
根据IUPAC命名法,其化学名为:(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钠。
具体的,本发明化合物B的结构如下:
根据IUPAC命名法,其化学名为:(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钾。
具体的,本发明化合物C的结构如下:
根据IUPAC命名法,其化学名为:N-(3-羟基-3,3-二膦酰丙基)-N-甲基戊烷-1-胺氧化物。
本发明的另一个目的在于提供式I所示的化合物的制备方法。
本发明所述的制备方法,包括以下步骤:
1)室温条件下,将氢氧化钠(5eq),双氧水(10eq)依次加至SM(1eq)的水溶液(0.1g/mL)中,加毕升至50℃搅拌3小时。将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得无色油状物,
2)将中间体(1eq),亚磷酸(2.5eq)混于氯苯中,氮气保护下升温至80℃,将三氯化磷(3eq)滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(6N)回流反应过夜。将反应液浓缩至干,油泵蒸馏得油状物,向体系加入水浓缩至干,再加入水,浓缩至干。向油状物中加入水,调节pH值,再滴加无水乙醇析出大量白色固体,过滤,得白色固体粗品。
优选的,本发明的制备方法,包括以下步骤:
1)室温条件下,将氢氧化钠(5eq),双氧水(10eq)依次加至SM(1eq)的水溶液(0.1g/mL)中,加毕升至50℃搅拌3小时。
后处理:
将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得无色油状物,收率100%
2)将中间体(1eq),亚磷酸(2.5eq)混于氯苯中,氮气保护下升温至80℃,将三氯化磷(3eq)滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(6N)回流反应过夜。
后处理:
将反应液浓缩至干,油泵蒸馏得油状物,向体系加入水浓缩至干,再加入水,浓缩至干。向油状物中加入水,调节pH值,再滴加无水乙醇析出大量白色固体,过滤,得白色固体粗品。
产品精制:
将粗品用纯水溶解,控温至60-70℃,保持此温度滴加丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体。
进一步优选的,化合物A的制备方法,包括以下步骤:
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时,将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得无色油状物,
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液,向反应体系加入盐酸回流反应过夜,将反应液浓缩至干,油泵蒸馏得油状物,向体系加入20mL水浓缩至干,再加入20mL水,浓缩至干。向油状物中加入10mL水,用饱和氢氧化钠溶液调pH=4.1-4.3,再滴加10mL无水乙醇析出大量白色固体,过滤,得白色固体粗品,
(3)产品精制:将1.5g固体粗品用10mL纯水溶解,控温至60-70℃,保持此温度滴加10mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体。
进一步优选的,化合物B的制备方法,包括以下步骤:
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时,将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得无色油状物,
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液,向反应体系加入盐酸回流反应过夜,将反应液浓缩至干,油泵蒸馏得油状物,向油状物中加入20mL水打浆,用倾泻法移除上层清液,再加入四氢呋喃打浆,过滤,滤液浓缩至干,得无色油状物,
(3)产品精制:将3.3g粗品用20mL乙醚溶解,加水20mL洗涤,有机层浓缩得无色油状物。
进一步优选的,化合物C的制备方法,包括以下步骤:
室(1)温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时,将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得2g无色油状物,
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸回流反应过夜,将反应液浓缩至干,油泵蒸馏得油状物,向体系加入20mL水浓缩至干,再加入20mL水,浓缩至干,向油状物中加入10mL水,用饱和氢氧化钾溶液调pH=4.1-4.3,再滴加10mL无水乙醇析出大量白色固体,过滤,得白色固体粗品,
(3)产品精制:将3.66g粗品用10mL纯水溶解,控温至60-70℃,保持此温度滴加10mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体。
本发明的另一个目的在于提供式I所示的化合物在制备治疗肺动脉高压的药物中的应用。
其中,所述肺动脉高压,涵盖了己知多种致病机理导致的肺动脉高压,如动脉性肺动脉高压(包括特发性、可遗传性、药物和毒物所致及新生儿持续性)、左心疾病相关性肺动脉高压(包括心脏收缩功能不全、舒张功能不全和瓣膜病)、肺部疾病或低氧血症所致肺动脉高压(包括慢性阻塞性肺疾病、肺问质性疾病、睡眠呼吸暂停综合征、慢性高原病)、慢性血栓栓塞性肺动脉高压,以及其他不明因素所致肺动脉高压,其中,对于低氧血症所致的肺动脉高压应用效果更为显著。
本发明的另一个目的在于提供一种以式I所示的化合物为活性成分的药物组合物。
本发明所述的活性成分所占重量百分比可以是0.1-99.9%,其余为药物可接受的载体。
本发明的药物组合物可以制备成任何可药用的剂型,这些剂型包括:片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。本发明的制剂,优选的是片剂、散剂、颗粒剂、酊剂、丸剂、胶囊剂、口服液、雾化吸入剂、注射剂。
本发明的药物组合物,其口服给药的制剂可含有常用的赋形剂,诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂,必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物,例如羟基乙酸淀粉钠。适宜的润滑剂包括,例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
可通过混合,填充,压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂,或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂,诸如悬浮剂,例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪,乳化剂,例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶;非水性载体(它们可以包括食用油),例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇;防腐剂,例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸,并且如果需要,可含有常规的香味剂或着色剂。
对于注射剂,制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度,可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中,在将其装入一种适宜的小瓶或安瓿前过滤消毒,然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性,可在装入小瓶以后将这种组合物冰冻,并在真空下将水除去。
本发明的制剂,在制备成药剂时可选择性的加入适合的药物可接受的载体,所述药物可接受的载体选自:甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠,一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
具体实施方式
通过以下具体实施例对本发明作进一步的说明,不作为本发明的限制。
实施例1:(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钠的制备
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时。
后处理:
将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得2g无色油状物,收率100%。
1H NMR(d6-DMSO)1H(ppm)0.872(t,3H,-(CH2)4CH3),1.251-1.326(m,4H,-CH2CH2CH3),1.716-1.746(m,2H,-CH2CH2CH2CH3),2.865(t,2H,-CH2COOH),3.342(s,3H,-CH3N),3.588(t,2H,-CH2(CH2)3CH3),3.826(t,2H,-CH2CH2COOH),12.088(s,1H,-COOH).
HR-MS[M+H]+:190.14。
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(12mL,6N)回流反应过夜。
后处理:
将反应液浓缩至干,油泵蒸馏得油状物,向体系加入20mL水浓缩至干,再加入20mL水,浓缩至干。向油状物中加入10mL水,用饱和氢氧化钠溶液调pH=4.1-4.3,再滴加10mL无水乙醇析出大量白色固体,过滤,得白色固体粗品3.5g。
(3)产品精制:
将1.5g固体粗品用10mL纯水溶解,控温至60-70℃,保持此温度滴加10mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体3.1g,收率86%。
1H NMR(D2O)1H(ppm)0.832(t,3H,-(CH2)4CH3),1.289-1.295(m,4H,-CH2CH2CH3),1.783-1.806(m,2H,-CH2CH2CH2CH3),2.438(t,2H,-CH2COOH),3.344(s,3H,-CH3N),3.559(t,2H,-CH2(CH2)3CH3),3.893(t,2H,-CH2CH2COOH).
HR-MS[M+H]+:336.10。
实施例2:(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钠的制备
(1)室温条件下,将4.75g氢氧化钠,27g双氧水依次加至5gSM的50mL水溶液中,加毕升至50℃搅拌3小时。
后处理:
将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得5g无色油状物,收率100%。
1H NMR(d6-DMSO)1H(ppm)0.872(t,3H,-(CH2)4CH3),1.251-1.326(m,4H,-CH2CH2CH3),1.716-1.746(m,2H,-CH2CH2CH2CH3),2.865(t,2H,-CH2COOH),3.342(s,3H,-CH3N),3.588(t,2H,-CH2(CH2)3CH3),3.826(t,2H,-CH2CH2COOH),12.088(s,1H,-COOH).
HR-MS[M+H]+:190.14。
(2)将5g中间体,5g亚磷酸混于20mL氯苯中,氮气保护下升温至80℃,将6.75mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(30mL,6N)回流反应过夜。
后处理:
将反应液浓缩至干,油泵蒸馏得油状物,向体系加入50mL水浓缩至干,再加入50mL水,浓缩至干。向油状物中加入25mL水,用饱和氢氧化钠溶液调pH=4.1-4.3,再滴加25mL无水乙醇析出大量白色固体,过滤,得白色固体粗品8.8g。
(3)产品精制:
将8.8g粗品用25mL纯水溶解,控温至60-70℃,保持此温度滴加25mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体7.6g,收率86%。
1H NMR(D2O)1H(ppm)0.834(t,3H,-(CH2)4CH3),1.290-1.297(m,4H,-CH2CH2CH3),1.786-1.810(m,2H,-CH2CH2CH2CH3),2.433(t,2H,-CH2COOH),3.346(s,3H,-CH3N),3.561(t,2H,-CH2(CH2)3CH3),3.894(t,2H,-CH2CH2COOH).
HR-MS[M+H]+:336.10
实施例3:(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钠的制备
(1)室温条件下,将9.5g氢氧化钠,54g双氧水依次加至10gSM的100mL水溶液中,加毕升至50℃搅拌3小时。
后处理:
将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得10g无色油状物,收率100%。
1H NMR(d6-DMSO)1H(ppm)0.872(t,3H,-(CH2)4CH3),1.251-1.326(m,4H,-CH2CH2CH3),1.716-1.746(m,2H,-CH2CH2CH2CH3),2.865(t,2H,-CH2COOH),3.342(s,3H,-CH3N),3.588(t,2H,-CH2(CH2)3CH3),3.826(t,2H,-CH2CH2COOH),12.088(s,1H,-COOH).
HR-MS[M+H]+:190.14。
(2)将10g中间体,10g亚磷酸混于40mL氯苯中,氮气保护下升温至80℃,将13.5mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(60mL,6N)回流反应过夜。
后处理:
将反应液浓缩至干,油泵蒸馏得油状物,向体系加入100mL水浓缩至干,再加入100mL水,浓缩至干。向油状物中加入50mL水,用饱和氢氧化钠溶液调pH=4.1-4.3,再滴加50mL无水乙醇析出大量白色固体,过滤,得白色固体粗品18g。
(3)产品精制:
将18g粗品用50mL纯水溶解,控温至60-70℃,保持此温度滴加50mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体15。8g,收率88.5%。
1H NMR (D2O) 1H (ppm) 0.831 (t, 3H, -(CH2)4CH3),1.291-1.299(m,4H,-CH2CH2CH3),1.782-1.803 (m,2H,-CH2 CH2CH2CH3),2.439(t,2H,-CH2COOH),3.346(s,3H,-CH3N),3.562(t,2H,-CH2(CH2)3CH3),3.894(t,2H,-CH2CH2COOH).
HR-MS[M+H]+:336.10。
实施例4 N-(3-羟基-3,3-二膦酰丙基)-N-甲基戊烷-1-胺氧化物
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时。
后处理:
将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得2g无色油状物,收率100%。
1H NMR (d6-DMSO) 1H (ppm) 0.872 (t, 3H, -(CH2)4CH3),1.251-1.326(m,4H,-CH2CH2CH3),1.716-1.746(m,2H,-CH2 CH2CH2CH3),2.865(t,2H,-CH2COOH),3.342(s,3H,-CH3N),3.588(t,2H,-CH2(CH2)3CH3),3.826(t,2H,-CH2CH2COOH),12.088(s,1H,-COOH).
HR-MS[M+H]+:190.14。
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(12mL,6N)回流反应过夜.
后处理:
将反应液浓缩至干,油泵蒸馏得油状物。向油状物中加入20mL水打浆,用倾泻法移除上层清液,再加入四氢呋喃打浆,过滤,滤液浓缩至干,得无色油状物3.3g.
(3)产品精制:
将3.3g粗品用20mL乙醚溶解,加水20mL洗涤,有机层浓缩得无色油状物2.8g,收率83%.
1H NMR(d6-DMSO)1H(ppm)0.932(t,3H,-(CH2)4CH3),1.390-1.396(m,4H,-CH2CH2CH3),1.890-1.915(m,2H,-CH2CH2CH2CH3),2.547(t,2H,-CH2COOH),3.468(s,3H,-CH3N),3.660(t,2H,-CH2(CH2)3CH3),3.996(t,2H,-CH2CH2COOH).
HR-MS[M+H]+:336.10。
实施例5(1-羟基-3-(甲氧基(戊基)氮烷基)-1-膦酰基丙基)膦酸氢钾的制备
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时。
后处理:
将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得2g无色油状物,收率100%。
1H NMR(d6-DMSO)1H(ppm)0.872(t,3H,-(CH2)4CH3),1.251-1.326(m,4H,-CH2CH2CH3),1.716-1.746(m,2H,-CH2CH2CH2CH3),2.865(t,2H,-CH2COOH),3.342(s,3H,-CH3N),3.588(t,2H,-CH2(CH2)3CH3),3.826(t,2H,-CH2CH2COOH),12.088(s,1H,-COOH).
HR-MS[M+H]+:190.14
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(12mL,6N)回流反应过夜.
后处理:
将反应液浓缩至干,油泵蒸馏得油状物,向体系加入20mL水浓缩至干,再加入20mL水,浓缩至干。向油状物中加入10mL水,用饱和氢氧化钾溶液调pH=4.1-4.3,再滴加10mL无水乙醇析出大量白色固体,过滤,得白色固体粗品3.66g。
(3)产品精制:
将3.66g粗品用10mL纯水溶解,控温至60-70℃,保持此温度滴加10mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体3.2g,收率85%。
1H NMR(D2O)1H(ppm)0.847(t,3H,-(CH2)4CH3),1.296-1.305(m,4H,-CH2CH2CH3),1.797-1.813(m,2H,-CH2CH2CH2CH3),2.441(t,2H,-CH2COOH),3.359(s,3H,-CH3N),3.570(t,2H,-CH2(CH2)3CH3),3.904(t,2H,-CH2CH2COOH)。
HR-MS[M+H]+:336.10。
实施例6化合物A,化合物B和化合物C对低氧所致肺动脉高压的影响试验
SD大鼠,雄性,体重200±20g,随机分为十一组,即正常对照组、模型对照组、化合物A低剂量组(l0mg/kg/d)、化合物A中剂量组(20mg/kg/d)、化合物A高剂量组(60mg/kg/d),化合物B低剂量组(l0mg/kg/d)、化合物B中剂量组(20mg/kg/d)、化合物B高剂量组(60mg/kg/d),化合物C低剂量组(l0mg/kg/d)、化合物C中剂量组(20mg/kg/d)、化合物C高剂量组(60mg/kg/d)每组10只。正常对照组大鼠在常压环境饲养,其余各组大鼠置于全自动调节低压低氧舱内(大气压约50kPa,氧浓度10%)饲养,进行间断性低氧,每天进行8小时,持续6周。化合物A,化合物B和化合物C治疗组是建模开始2周后,在每次缺氧前灌胃给药1次,持续4周。正常对照组和模型对照组在建模开始2周后,于每次缺氧前灌胃给予相当量的溶剂(生理盐水)作为对照。
(1)血流动力学指标测定:自大鼠右侧颈外静脉插入充有肝素溶液(0.9%氯化钠溶液+肝素l0U/ml)的聚乙烯塑料微导管,导管的另一端与微型压力传感器相连监测压力变化,在压力波形的引导下,导管经上腔静脉进入右房、三尖瓣口、右室(RV),最后进入肺动脉干,测定平均肺功脉压(mPAP)等。另一充盈肝素溶液的微导管插入左侧颈总动脉通过微型压力传感器测定平均颈总动脉压(mCAP)。稳定30min后,应用POWERLAB多道智能生理信号采集和记录系统采集、记录和分析各项指标。
根据表1的试验结果可以看出,低氧模型对照组的平均肺动脉压显著高于常压正常对照组(P<0.01),说明低氧处理诱导了明显的肺动脉高压,化合物A,化合物B和化合物C低、中、高给药组的平均肺动脉压均显著低于低氧模型对照组(P<0.05或P<0.01),表明化合物A,化合物B和化合物C有显著降低低氧诱发的肺动脉高压的作用。研究结果还提示,化合物A,化合物B和化合物C在降低肺动脉压的同时对体循环血压(平均颈总动脉压)也有一定的降低作用。
表1各组大鼠血流动力学指标比较
(2)右心室(RV)肥厚指标的测定:实验结束后,剖胸取出小鼠心脏,剪去心房组织。沿室间隔边缘分离出右心室RV,左心室(LV)和室间隔(S),用滤纸吸干水分后称量RV,LV和S的重量,以RVI(LV+S)比值来反映RV肥厚程度。
(3)肺血管病理检测:从右肺下叶相同部位取组织块,置于10%中性甲醛(pH7.4)中固定2天。常规石蜡包埋,连续切片,苏木精-伊红染色及弹力纤维染色(Har't改良法染色弹力纤维,VanGieson复染),光镜下观察肺小动脉形态学变化。并用图像分析仪测量弹力纤维染色切片中与呼吸性细支气管及肺泡管伴行的肺小动脉(直径小于lOOμm)的外径(ED)、动脉中层壁厚(MT)、管壁中层横截面积(MA)、血管管腔横截面积(VA)和血管总横截面积(TAA),然后分别计算血管壁中层厚度占外径的百分比(MT%),血管壁中层横截面积占血管总横截面积的百分比(MA%),反映肺小血管管壁增厚程度。每只大鼠肺切片共测量6~10条肺小动脉的上述指标,计算出均数作为该只大鼠的血管指标并行统计学分析。
根据表2的试验结果可以看出,正常对照组右心室无增厚,模型对照组右心室明显肥厚,右心室肥厚指数RVI(LV+S)明显升高。病理检测发现:右心室可见肥大的心肌细胞,肺小动脉壁增厚,管腔狭窄。而化合物A,化合物B和化合物C各剂量组可有效改善这些病例症状,且有一定的剂量依赖性。
表2各组大鼠右心室肥厚指标比较
Claims (10)
1.一种式I所示的化合物,其特征在于,化学结构如下:
其中R为-H,-Na,-K。
2.如权利要求1所述的化合物,其特征在于,化学结构如下:
3.如权利要求1所述的化合物,其特征在于,化学结构如下:
4.如权利要求1所述的化合物,其特征在于,化学结构如下:
5.如权利要求1所述的化合物的制备方法,其特征在于,包括以下步骤:
1)室温条件下,将氢氧化钠(5eq),双氧水(10eq)依次加至SM(1eq)的水溶液(0.1g/mL)中,加毕升至50℃搅拌3小时。将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得无色油状物,
2)将中间体(1eq),亚磷酸(2.5eq)混于氯苯中,氮气保护下升温至80℃,将三氯化磷(3eq)滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸(6N)回流反应过夜。将反应液浓缩至干,油泵蒸馏得油状物,向体系加入水浓缩至干,再加入水,浓缩至干。向油状物中加入水,调节pH值,再滴加无水乙醇析出大量白色固体,过滤,得白色固体粗品。
6.如权利要求5所述的化合物的制备方法,其特征在于,包括以下步骤:
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时,将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得无色油状物,
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液,向反应体系加入盐酸回流反应过夜,将反应液浓缩至干,油泵蒸馏得油状物,向体系加入20mL水浓缩至干,再加入20mL水,浓缩至干。向油状物中加入10mL水,用饱和氢氧化钠溶液调pH=4.1-4.3,再滴加10mL无水乙醇析出大量白色固体,过滤,得白色固体粗品,
(3)产品精制:将1.5g固体粗品用10mL纯水溶解,控温至60-70℃,保持此温度滴加10mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体。
7.如权利要求5所述的化合物的制备方法,其特征在于,包括以下步骤:
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时,将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得无色油状物,
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液,向反应体系加入盐酸回流反应过夜,将反应液浓缩至干,油泵蒸馏得油状物,向油状物中加入20mL水打浆,用倾泻法移除上层清液,再加入四氢呋喃打浆,过滤,滤液浓缩至干,得无色油状物,
(3)产品精制:将3.3g粗品用20mL乙醚溶解,加水20mL洗涤,有机层浓缩得无色油状物。
8.如权利要求5所述的化合物的制备方法,其特征在于,包括以下步骤:
(1)室温条件下,将1.9g氢氧化钠,10.8g双氧水依次加至2gSM的20mL水溶液中,加毕升至50℃搅拌3小时,将反应液用浓盐酸调pH=1,浓缩至干,加入四氢呋喃打浆,过滤,滤液浓缩至干得2g无色油状物,
(2)将2g中间体,2g亚磷酸混于8mL氯苯中,氮气保护下升温至80℃,将2.7mL三氯化磷滴加至反应体系,保温反应4小时,体系会逐渐固化,形成固液两相,用倾泻法移除上层清液。向反应体系加入盐酸回流反应过夜,将反应液浓缩至干,油泵蒸馏得油状物,向体系加入20mL水浓缩至干,再加入20mL水,浓缩至干,向油状物中加入10mL水,用饱和氢氧化钾溶液调pH=4.1-4.3,再滴加10mL无水乙醇析出大量白色固体,过滤,得白色固体粗品,
(3)产品精制:将3.66g粗品用10mL纯水溶解,控温至60-70℃,保持此温度滴加10mL丙酮,滴加完毕缓慢降温搅拌析晶,温度降至室温后,静置过夜,抽滤,真空干燥,得白色固体。
9.以式I所示的化合物为活性成分的药物组合物。
10.式I所示的化合物在制备治疗肺动脉高压的药物中的应用。
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