CN110606860B - 一种吡啶磺酰胺磷酸酯类化合物、其制备方法及其用途 - Google Patents
一种吡啶磺酰胺磷酸酯类化合物、其制备方法及其用途 Download PDFInfo
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- -1 Pyridine sulfonamide phosphate compound Chemical class 0.000 title claims abstract description 25
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
- A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及生物医药技术领域,具体涉及一种吡啶磺酰胺磷酸酯类化合物、其制备方法及其用途,其结构如式1所示:
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种吡啶磺酰胺磷酸酯类化合物、其制备方法及其用途。
背景技术
托拉塞米化学名为1-[4-(3-甲基苯基)氨基吡啶-3-基]磺酰-3-异丙基脲,是新一代高效髓袢利尿剂,其pKa值为6.44,在水中几乎不溶,略溶于0.1mol/L的氢氧化钠溶液。20多年临床应用证实,托拉塞米适应症广,利尿作用迅速、强大且持久,是临床上值得推广的一类高效利尿剂。
目前托拉塞米上市剂型有注射剂、片剂、胶囊剂。在注射剂的制备过程中,希望原料药具有较高的水溶性。托拉塞米在水中极微溶解(European Journal of Pharmaceuticsand Biopharmaceutics 53(2002)75–86),在制备托拉塞米注射剂型时,需加入氢氧化钠及大量辅料助溶,所用辅料包括:聚乙二醇400、氨丁三醇、氢氧化钠、盐酸等。上述辅料的加入带来了诸多不利:1)氢氧化钠水溶液溶解托拉塞米过程中放热明显,易产生制剂降解杂质;2)聚乙二醇400、氨丁三醇等有机助溶剂的加入,对注射剂用药安全性带来隐患。人们总是期望减少配方的成分种类以便减少病人可能产生的副反应。因此开发更高水溶性、更利于制剂制备的新型髓袢利尿剂成为一大挑战。
文献(Drugs 41(1):81-103,1991)报道了托拉塞米体内活性代谢物M3,M3药理活性与托拉塞米相当。M3与托拉塞米相比,虽苯环上引入了酚羟基,但水溶性依然没有得到有效改善,制剂生产困难。因此,发明人试图在M3的基础上进一步改造以得到既具有良好水溶性,又能够保持良好利尿作用的药物。
发明内容
本发明的目的在于提供一种吡啶磺酰胺磷酸酯类化合物或其药用盐,其结构如式1所示:
其中X为O、CH2或X不存在;Y为C H2或Y不存在;当X、Y均不存在时,O直接与P相连;当X存在而Y不存在时,X直接与O相连;当Y存在而X不存在时,Y直接与P相连。
所述药用盐,例如,可包括金属盐、与无机/有机碱形成的盐、与碱性氨基酸形成的盐等。金属盐的非限制性实例包括但不限于碱金属的盐,例如钠盐、钾盐等,碱土金属的盐,例如钙盐、镁盐、钡盐、铝盐等;所述有机碱的非限制性实例包括但不限于三甲胺、三乙胺、三丙胺、三丁胺或二异丙基乙基胺。
优选的,所述吡啶磺酰胺磷酸酯类化合物或其药用盐选自如下化合物:
表1
本发明的第二方面在于提供一种吡啶磺酰胺磷酸酯类化合物或其药用盐的制备方法,包括以下步骤:
M3经与POCl3反应制得式I化合物;式I化合物再分别与氢氧化钠、氢氧化钾、三乙胺或三正丁胺反应,分别获得式I-1、I-2、I-3、I-4化合物。
或M3与多聚甲醛经羟甲基化、氯化、酯化、氢化脱苄基制得式II化合物;式II化合物再分别与氢氧化钠、氢氧化钾反应,分别获得式II-1、II-2化合物;
或M3与羟甲基膦酸二乙酯(9)反应,再经脱乙酯制得式III化合物;将式III化合物再分别与氢氧化钠、氢氧化钾反应,分别获得式III-1、III-2化合物;
本发明的第三方面在于提供一种药物组合物,其包括治疗量的吡啶磺酰胺磷酸酯类化合物和/或其药用盐,以及其他药学上可接受的辅料。
所述载体是指药学领域常规的载体,如:稀释剂、赋形剂如水等;粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮等;填充剂如淀粉等;崩裂剂如碳酸钙、碳酸氢钠;另外,还可以在组合物中加入其他辅助剂如香味剂和甜味剂。
本发明的组合物的各种剂型可以采用医学领域常规的方法进行制备,其中活性成分的含量为0.1%~99.5%(重量比)。
本发明的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等进行变化,其日剂量为0.001~30mg/kg体重(口服)或0.005~30mg/kg体重(注射)。
本发明的第四方面提供吡啶磺酰胺磷酸酯类化合物或其药用盐在制备利尿剂中的用途。
本发明的有益效果在于提供的吡啶磺酰胺磷酸酯类化合物具有溶解度高、稳定性高、制备制剂方便等特点,易于产业化放大并用于医药用途。
具体实施方式
以下结合实施例对本发明作进一步作具体描述,但不局限于此。
实施例1式I化合物的制备
步骤1:式3化合物的制备
500mL反应瓶中加入无水乙醇(300mL)、化合物2(18.5g,0.15mol,1.05eq),搅拌、加热至75℃左右,分批加入化合物1(27.5g,0.143mol,1.0eq),加完后保持此温度搅拌反应1h,有固体析出。降温至内温20-25℃,加入碳酸钠(15.9g,0.15mol,1.5eq),搅拌下分批加入多聚甲醛(15g,0.5mol,5eq)。加完后,升温至内温80-85℃反应2h,缓慢降至内温20-25℃,过滤,抽干,得淡黄色滤饼为式3化合物(36.5g,收率81%),MS:280[M+1]。
步骤2:式M3化合物的制备
500mL反应瓶中加入丙酮(200mL)、式3化合物(35g,0.11mol,1.0eq)和氢氧化钠(8.87g,0.22mol,2.0eq),控制内温20-25℃下滴加化合物4(11.2g,0.13mol,1.2eq),滴加完成后升温至内温45~50℃搅拌1小时,反应完全,降温至內温8~12℃,再维持1小时。过滤,抽干,得类白色湿品。该湿品加入纯化水(200mL)中,控制内温20-25℃下滴加6%醋酸水溶液,调节pH至6~7(pH试纸)。搅拌半小时,过滤,用纯化水洗涤滤饼,抽干,得M3湿品。湿品于55~60℃下真空干燥至恒重,制得化合物M3(34g,收率85%),MS:365[M+1]。
步骤3:式I化合物的制备
250mL反应瓶中加入四氢呋喃(150mL)、化合物M3(15g,41.2mmol,1.0eq)、二异丙基乙胺(5.3g,41.2mmol,1.0eq),降温至内温0-5℃,搅拌下滴加三氯氧磷(6.3g,41.2mmol,1.0eq),滴加完成后,0-5℃反应2h。保持此温度,加水(5mL)淬灭反应,浓缩溶剂至干,得浓缩剩余物,该剩余物经中性氧化铝过柱(洗脱液:二氯甲烷/甲醇10:1),所得流分经浓缩,40~45℃下真空干燥至恒重,制得化合物I(11.9g,收率65%),MS:445[M+1]。1H NMR(400MHz,D2O)δ:8.66(s,1H),8.05-8.06(d,J=5.2Hz,1H),7.29(m,1H),7.21-7.22(d,J=5.2Hz,1H),6.88(m,1H),6.58(s,1H),4.27(m,1H),2.27(s,3H),0.95(s,3H),0.94(s,3H)。
实施例2式I-1化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式I化合物(2.5g,5.6mmol,1.0eq),搅拌下滴加25%氢氧化钠溶液(0.45g,11.3mmol,2.0eq),加完后搅拌反应1h。向反应液中加入丙酮(20mL),并继续搅拌30min,过滤,得二钠盐粗品。所得粗品加入丙酮(20mL)/H2O(2mL)体系重结晶,过滤,滤饼真空干燥(50℃)得式I-1化合物(1.8g,收率65%),HPLC纯度99.25%。MS:489[M+1],1H NMR(400MHz,D2O)δ:8.63(s,1H),8.06-8.07(d,J=5.2Hz,1H),7.27(m,1H),7.22-7.23(d,J=5.2Hz,1H),6.89(m,1H),6.57(s,1H),4.25(m,1H),2.25(s,3H),0.95(s,6H)。钠含量:9.45%。
实施例3式I-2化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式I化合物(2.5g,5.6mmol,1.0eq),搅拌下滴加20%氢氧化钾溶液(0.63g,11.3mmol,2.0eq),加完后搅拌反应1h。向反应液中加入丙酮(20mL),并继续搅拌30min,过滤,得二钾盐粗品。所得粗品加入丙酮(20mL)/H2O(2mL)体系重结晶,过滤,滤饼真空干燥(50℃)得式I-2化合物(1.7g,收率59%),HPLC纯度99.05%。MS:521[M+1],1H NMR(400MHz,D2O)δ:8.65(s,1H),8.07(m,1H),7.22-7.26(m,2H),6.88(m,1H),6.56(s,1H),4.27(m,1H),2.26(s,3H),0.94(s,6H)。钾含量:15.00%。
实施例4式I-3化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式I化合物(2.5g,5.6mmol,1.0eq)、三乙胺(0.57g,5.6mmol,1.0eq),搅拌反应1h。浓缩溶剂至干得泡沫状固体,该固体经丙酮(10mL)重结晶,过滤,滤饼真空干燥(40℃)得式I-3化合物(1.7g,收率56%),HPLC纯度98.60%。MS:445[M+1],1H NMR(400MHz,D2O)δ:8.56(s,1H),7.97(d,J=4.0Hz,1H),7.25(m,2H),6.87(m,1H),6.61(s,1H),4.28(m,1H),3.08(m,6H),2.27(s,3H),1.09(m,9H),0.94(s,6H)。
实施例5式I-4化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式I化合物(2.5g,5.6mmol,1.0eq)、三正丁胺(1.04g,5.6mmol,1.0eq),搅拌反应1h。浓缩溶剂至干得泡沫状固体,该固体经丙酮(10mL)重结晶,过滤,滤饼真空干燥(40℃)得式I-4化合物(1.8g,收率51%),HPLC纯度98.75%。MS:445[M+1],1H NMR(400MHz,D2O)δ:8.59(s,1H),7.98(d,J=4.0Hz,1H),7.27(m,2H),6.88(m,1H),6.65(s,1H),4.21(m,1H),3.05(m,6H),2.23(s,3H),1.35-1.42(m,12H),0.93(s,6H),0.87(m,9H)。
实施例6式II化合物的制备
步骤1:式5化合物的制备
500mL反应瓶中加入无水乙醇(300mL)、化合物M3(15g,41.2mmol,1.0eq)、碳酸钠(6.5g,61.7mmol,1.5eq),搅拌下分批加入多聚甲醛(6.2g,0.21mol,5.0eq)。加完后,升温至内温80-85℃反应2h,缓慢降至内温20-25℃,有白色固体析出,过滤、水洗。滤饼真空干燥(40℃)得式5化合物(12.8g,收率79%),MS:395[M+1]。
步骤2:式6化合物的制备
250mL反应瓶中加入二氯甲烷(100mL)、N,N-二甲基甲酰胺(2mL)、化合物5(12g,30.4mmol,1.0eq),搅拌下滴加二氯亚砜(10.9g,91.3mmol,3.0eq)。加完后,升温至内温60-65℃反应2h,反应结束后,倒入500mL烧杯中,冰浴下分批滴加入10%碳酸钠水溶液(50mL),分液漏斗分液除去水层,有机层再水洗2次(50mL x2)、饱和食盐水(50mL)洗涤一次,分液、无水硫酸钠干燥、浓缩至干。剩余物经乙酸乙酯(50mL)打浆洗涤,过滤,滤饼真空干燥(40℃)得式6化合物(10.7g,收率85%),MS:413[M+1]。
步骤3:式8化合物的制备
250mL反应瓶中加入乙腈(100mL)、化合物6(10g,24.2mmol,1.0eq)、碳酸钠(5.1g,48.4mmol,2.0eq)、磷酸二苄酯钠盐7(8.0g,26.6mmol,1.1eq),搅拌下升温至内温80-85℃反应8h,趁热过滤去除无机盐,滤液浓缩至干。浓缩剩余物加甲苯(50mL)重结晶,过滤。滤饼真空干燥(50℃)得式8化合物(7.1g,收率45%),MS:655[M+1]。
步骤4:式II化合物的制备
将无水乙醇(400mL)、化合物8(7g,10.7mmol,1.0eq)、10%钯碳(0.7g,10%重量比)加入高压反应釜中,氮气置换3次,通氢气至压力2MPa,搅拌下室温反应5h,反应结束,过滤,滤液浓缩至干,得白色固体式II化合物(4.1g,收率81%),MS:475[M+1]。1H NMR(400MHz,D2O)δ:8.65(s,1H),7.99(d,J=4.0Hz,1H),7.24(m,2H),6.91(m,1H),6.59(s,1H),5.93(s,2H),4.25(m,1H),2.25(s,3H),0.95(s,6H)。
实施例7式II-1化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式II化合物(2g,4.2mmol,1.0eq),搅拌下滴加25%氢氧化钠溶液(0.34g,8.4mmol,2.0eq),加完后搅拌反应1h。向反应液中加入丙酮(10mL),并继续搅拌30min,过滤,得二钠盐粗品。所得粗品加入丙酮(10mL)/H2O(1mL)体系重结晶,过滤,滤饼真空干燥(50℃)得式II-1化合物(1.3g,收率60%),HPLC纯度98.75%。MS:519[M+1],1H NMR(400MHz,D2O)δ:8.64(s,1H),8.07-8.08(d,J=5.2Hz,1H),7.25(m,2H),6.89(m,1H),6.59(s,1H),5.94(s,2H),4.27(m,1H),2.27(s,3H),0.94(s,6H)。钠含量:8.85%。
实施例8式II-2化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式I化合物(2g,4.2mmol,1.0eq),搅拌下滴加20%氢氧化钾溶液(0.47g,8.4mmol,2.0eq),加完后搅拌反应1h。向反应液中加入丙酮(10mL),并继续搅拌30min,过滤,得二钾盐粗品。所得粗品加入丙酮(10mL)/H2O(1mL)体系重结晶,过滤,滤饼真空干燥(50℃)得式II-2化合物(1.3g,收率56%),HPLC纯度99.15%。MS:551[M+1],1H NMR(400MHz,D2O)δ:8.63(s,1H),8.07(d,J=5.2Hz,1H),7.26(m,2H),6.92(m,1H),6.61(s,1H),5.93(s,2H),4.25(m,1H),2.25(s,3H),0.95(s,6H)。钾含量:14.21%。
实施例9式III化合物的制备
步骤1:式10化合物的制备
500mL反应瓶中加入无水四氢呋喃(200mL)、化合物M3(15g,41.2mmol,1.0eq)、化合物9(6.9g,41.2mmol,1.0eq)、PPh3(1.6g,6.2mmol,0.15eq)和DEAD(1g,6.2mmol,0.15eq),30-35℃搅拌下反应24h,浓缩反应液至干,剩余物经硅胶柱层析纯化(流动相二氯甲烷),得式10化合物(13.8g,收率65%),MS:515[M+1]。
步骤2:式III化合物的制备
250mL反应瓶中加入二氯甲烷(100mL)、化合物10(12g,23.3mmol,1.0eq),搅拌下降温至内温0-5℃,滴加TMSBr(3.6g,23.3mmol,1.0eq),20-25℃搅拌下反应24h,浓缩反应液至干,剩余物经硅胶柱层析纯化(流动相中二氯甲烷/甲醇=10:1),得式III化合物(6.2g,收率58%),MS:459[M+1]。
实施例10式III-1化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式III化合物(3g,6.5mmol,1.0eq),搅拌下滴加25%氢氧化钠溶液(0.52g,13.1mmol,2.0eq),加完后搅拌反应1h。向反应液中加入丙酮(10mL),并继续搅拌30min,过滤,得二钠盐粗品。所得粗品加入丙酮(10mL)/H2O(1mL)体系重结晶,过滤,滤饼真空干燥(50℃)得式III-1化合物(2.2g,收率68%),HPLC纯度98.95%。MS:503[M+1]。钠含量:9.13%。
实施例11式III-2化合物的制备
50mL反应瓶中加入无水乙醇(20mL)、式III化合物(3g,6.5mmol,1.0eq),搅拌下滴加20%氢氧化钾溶液(0.73g,13.1mmol,2.0eq),加完后搅拌反应1h。向反应液中加入丙酮(10mL),并继续搅拌30min,过滤,得二钾盐粗品。所得粗品加入丙酮(10mL)/H2O(1mL)体系重结晶,过滤,滤饼真空干燥(50℃)得式III-2化合物(2.3g,收率66%),HPLC纯度99.19%。MS:535[M+1]。钾含量:14.65%。
实施例12式I-1化合物注射液的制备
制剂组成:式I-1化合物10g,注射用水2000mL。
制备方法:
(1)量取注射用水2000mL,加入式I-1化合物10g,搅拌均匀,经板框过滤器进行预过滤,得溶液A;
(2)将步骤(1)中溶液A用两道0.22μm聚醚砜滤芯进行除菌过滤,得中间产品B;
(3)中间体B经灌装、熔封、包装,既得产品。
实施例13式II-1化合物冻干粉针制备
制剂组成:式II-1化合物10g,注射用水2000mL。
制备过程如下:
(1)取70%选定体积注射用水,加入选定重量的式II-1化合物,搅拌至完成溶解,得溶液A;
(2)取30%选定体积注射用水,加入至上述溶液A中,搅拌下调节pH值8.5至9.5,经板框过滤器进行预过滤,得溶液B;
(3)将步骤(2)中溶液B用两道0.22μm聚醚砜滤芯进行除菌过滤,得溶液C,灌装,半压塞,得中间产品D;
(4)将所述中间体D在温度为-40℃~-50℃,压力为10Pa~22Pa的条件下进行冷冻干燥处理,所述冷冻干燥处理采用如下程序进行升温:
(a)设置温度为-45℃~-30℃,进行预冻2.0h;
(b)升温至温度为-30℃~-20℃,进行升华4.0h;
(c)升温至温度为-20℃~-10℃,进行升华1.5h;
(d)升温至温度为-10℃~0℃,进行升华1.0h;
(e)升温至温度为0℃~15℃,进行升华1.5h;
(f)升温至温度为15℃~25℃,进行保温2.0h;
保温完成后压塞、出箱、扎盖,即得式II-1化合物冻干粉针。
实施例14溶解性比较
对托拉塞米、M3、I、I-1、I-2、I-3、I-4、II、II-1、II-2、III、III-1和III-2进行了溶解性比较,结果如下:
表2、化合物水溶性比较
样品 | API:水 | 现象 | 结论 |
托拉塞米 | 3mg:10mL | 全溶 | 极微溶解 |
M3 | 15mg:10mL | 全溶 | 微溶 |
化合物I | 1.6g:10mL | 全溶 | 易溶 |
化合物I-1 | 2.1g:10mL | 全溶 | 易溶 |
化合物I-2 | 2.1g:10mL | 全溶 | 易溶 |
化合物I-3 | 1.9g:10mL | 全溶 | 易溶 |
化合物I-4 | 1.9g:10mL | 全溶 | 易溶 |
化合物II | 1.8g:10mL | 全溶 | 易溶 |
化合物II-1 | 2.2g:10mL | 全溶 | 易溶 |
化合物II-2 | 2.0g:10mL | 全溶 | 易溶 |
化合物III | 1.7g:10mL | 全溶 | 易溶 |
化合物III-1 | 2.0g:10mL | 全溶 | 易溶 |
化合物III-2 | 1.9g:10mL | 全溶 | 易溶 |
溶解度实验结果表明,实施例1~11中吡啶磺酰胺磷酸酯类化合物溶解性优于托拉塞米和M3,具有较好的成药性优势。
实施例15利尿作用比较
SD雄性大鼠(体重180±20g)随机分为14组,每组3只,每只给予30mL/kg生理盐水灌胃。生理盐水灌胃后,除空白对照组外,每组给予一种药物(10mg/kg,ig,1mg/mL,制剂处方:生理盐水溶解),收集4h排尿情况,结果如表3所示:
表3、不同化合物排尿量比较
化合物 | 给药剂量及方式 | 排尿量(mL/kg,4h) |
空白对照 | -- | 19.2 |
托拉塞米 | 10mg/kg,ig | 105.3 |
M3 | 10mg/kg,ig | 107.2 |
化合物I | 10mg/kg,ig | 121.4 |
化合物I-1 | 10mg/kg,ig | 127.6 |
化合物I-2 | 10mg/kg,ig | 119.8 |
化合物I-3 | 10mg/kg,ig | 123.4 |
化合物I-4 | 10mg/kg,ig | 125.6 |
化合物II | 10mg/kg,ig | 119.3 |
化合物II-1 | 10mg/kg,ig | 131.4 |
化合物II-2 | 10mg/kg,ig | 135.2 |
化合物III | 10mg/kg,ig | 113.7 |
化合物III-1 | 10mg/kg,ig | 123.8 |
化合物III-2 | 10mg/kg,ig | 124.5 |
利尿作用实验结果表明,实施例1~11中吡啶磺酰胺磷酸酯类化合物具有与托拉塞米相似利尿作用,或优于托拉塞米利尿作用,具有较好的成药性优势。
本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。
Claims (11)
2.如权利要求1所述的吡啶磺酰胺磷酸酯类化合物或其药用盐,其特征在于,所述药用盐包括与无机/有机碱形成的盐。
3.如权利要求2所述的吡啶磺酰胺磷酸酯类化合物或其药用盐,其特征在于,所述有机碱选自三甲胺、三乙胺、三丙胺、三丁胺或二异丙基乙基胺。
4.如权利要求1所述的吡啶磺酰胺磷酸酯类化合物或其药用盐,其特征在于,所述药用盐包括金属盐、或与碱性氨基酸形成的盐。
5.如权利要求4所述的吡啶磺酰胺磷酸酯类化合物或其药用盐,其特征在于,所述金属盐选自碱金属盐、碱土金属盐或铝盐,所述碱金属盐选自钠盐或钾盐,所述碱土金属盐选自钙盐、镁盐、或钡盐。
10.一种药物组合物,其包括治疗量的如权利要求1~6任一项所述的吡啶磺酰胺磷酸酯类化合物和/或其药用盐,以及其他药学上可接受的辅料。
11.如权利要求1~6任一项所述的吡啶磺酰胺磷酸酯类化合物或其药用盐在制备利尿剂中的用途。
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