CN1219757C - 磺化去氢松香酸盐及其制备方法和其用途 - Google Patents
磺化去氢松香酸盐及其制备方法和其用途 Download PDFInfo
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- CN1219757C CN1219757C CNB011202890A CN01120289A CN1219757C CN 1219757 C CN1219757 C CN 1219757C CN B011202890 A CNB011202890 A CN B011202890A CN 01120289 A CN01120289 A CN 01120289A CN 1219757 C CN1219757 C CN 1219757C
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- Prior art keywords
- acid
- dehydrogenation
- salt
- sulfonated dehydro
- sylvic acid
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- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
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Abstract
本发明涉及一种可用于治疗消化道溃疡、急慢性胃炎及糜烂性胃炎等疾病的新磺化去氢松香酸盐及其方法和用途。该盐用通式(1)表示，其中R为Bi(OH)++、或2BiO。以工业煅烧的松香钙为原料，经酸、碱处理，有机溶媒提取制异构体较少的松香酸、采用钯/碳催化转位脱氢制备去氢松香酸、再经磺化、重结晶制得纯的磺化去氢松香酸。该磺化去氢松香酸根据酸碱中和原理、或盐置换原理制得磺化去氢松香酸铋盐。所制得的盐可为制备治疗消化道溃疡、胃炎的药物的应用。
Description
技术领域
本发明涉及一种制备可用于消化道溃疡、急慢性胃炎及糜烂性胃炎等疾病治疗药物制备的磺化去氢松香酸[化学名：1，4a-二甲基-1-羧基-6-磺基-7-异丙基-1，2，3，4，4a，9，10，10a-八氢菲]锌、铋盐及其制备方法和用途。
背景技术
消化道溃疡、胃炎与胃酸过多、胃蛋白酶活性、化学损伤及精神紧张等有关，幽门螺旋杆菌的感染也起着十分重要的作用。该类疾病发生率高，病程长，不易根治，且治疗费用高。临床上常采用酸中和剂如碳酸钙、氢氧化铝、组织胺受体阻断剂如雷尼替丁等、质子泵抑制剂如奥美拉唑、溃疡面保护剂如硫糖铝、生胃酮、金属铋盐等，或上述药物与抗生素的二联、三联疗法。然而，传统消化道溃疡的治疗药物如抗酸剂使用过多则易引起胃酸的过少，从而明显影响胃蛋白酶的消化活性，引起消化不良；且pH值过高又可引起继发性胃酸分泌过多；溃疡面保护剂如生胃酮具有类肾上腺皮质激素的作用，故可引起水钠潴留，出现水肿、血压升高、低血钾等症。各种抗生素虽然体外对幽门螺旋杆菌都具有较强的抑制作用，但临床上即使与质子泵类药物联合使用效果也不十分理想。这是因为一方面大多数抗生素在胃酸环境中不稳定，在胃粘膜表面很难达到有效的治疗浓度；另一方面易产生耐药性。因此，广泛推荐的二联、三联疗法也很难根除幽门螺旋杆菌的感染，且易复发。而一旦复发，则更会加速消化道癌变等其它疾病的发生。
因此，继续研究开发新型消化道溃疡药物十分必要。
本发明中涉及的磺化去氢松香酸早在三十年代即已报道，为制备纯去氢松香酸的中间体；七十年代报道其衍生物可用作去污剂，八十年代日本田边制药株式会社的研究发现其碱金属如钠、钾、锂盐，碱土金属如钙、镁及铝盐，以及各种含氮化合物等具有显著的胃粘膜保护、胃蛋白酶活性的抑制和无耐药性地杀灭幽门螺旋杆菌的作用等，因此可用作消化道溃疡及各种胃炎的治疗药物。同时，该类药物口服后主要从粪便中排出，尿中排出量很少，在大鼠组织、胎儿和母乳中均无药物残留，因此毒副作用很小。
传统中药松香中主要含有松香酸、松香酸酐、及多种松香酸的异构体，因此传统提取方法制备的松香酸得率均较低，且含有多种较难纯化除去的同分异构体，因此催化转位脱氢后很难得到纯的、单一构型的去氢松香酸，而必须先制备其易纯化的磺化去氢松香酸，再水解消除磺酸基得去氢松香酸，提取制备去氢松香酸的收率较低(均低于25％)。
发明内容
本发明所要解决的技术问题是实现一种磺化去氢松香酸盐及其制备方法和其用途。本发明的这种新磺化去氢松香酸盐可治疗消化道溃疡、急慢性胃炎及糜烂性胃炎等疾病，采用本发明的方法制备磺化去氢松香酸及其盐，工艺简单，收率好。
为了解决上述技术问题，本发明采取以下技术方案：
一种磺化去氢松香酸盐，该化合物用下述通式(1)表示：
其中，R为Bi(OH)++、或2BiO，
n＝0-10。
本发明的磺化去氢松香酸盐的制备方法包括下述步骤：
(1)将松香与1∶0.1-1∶1.5倍重量的消石灰在160-600℃温度下搅拌1-5小时，得到固体松香钙；
(2)将上述固体松香钙采用C1-6的脂肪醇及其含水混合溶液、或是脂肪酸酯溶解，所用上述溶媒为固体松香钙的0.5-10倍，单位比为ml/g，并用矿酸调节上述溶液的pH值为5-9，获得松香酸；
(3)将上述松香酸在0.1-5％重量的5％-10％的钯/碳的催化剂作用下在200-300℃下反应1-5小时；或是直接在220-380℃高温下进行反应，反应后经冷却后，再加入0.5-10体积的溶媒，溶媒为甲醇、乙醇、丙醇、乙酸乙酯、苯、和甲苯中的任意一种，并继续回流1-3小时后，趁热过滤，冷却，放置过夜，析出结晶，过滤得去氢松香酸；
(4)将所得到去氢松酸加入予先冷却到-20～20℃的1-10倍重量的90-98％的硫酸中，搅拌反应0.5-10小时后，倾入冰水中，冰水的重量为硫酸重量的5-50倍，大量白色沉淀析出，过滤，滤饼水洗，并吸去水分后，用滤饼重量的0.5-10倍的冰醋酸加热溶解，放冷，析出结晶，过滤后干燥得磺化去氢松香酸；
或是，
(5)将得到的磺化去氢松香酸按照常规的方法制成磺化去氢松香酸单、双碱金属盐或碱土金属盐；
(6)在C1-6的脂肪醇，水、DMF和DIMSO中的任一种溶媒中，以所制成的磺化去氢松香酸单、双碱金属盐或碱土金属盐与硝酸铋盐、次硝酸铋或氢氧化铋等。通过置换反应制得磺化去氢松香酸铋盐，即通式(1)表示的化合物；
或是，
(5)’在C1-6的脂肪醇，水、DMF和DMSO中的任意一种溶媒中，用所得的磺化去氢酸与硝酸铋或碱式硝酸铋进行中和反应制得磺化去氢松香酸铋盐，即通式(1)表示的化合物。
本发明中采用的工业松香钙系松香在高温下与消石灰反应，冷却后所得。松香与消石灰高温反应，首先使其中的松香酸酐转化为松香钙，从而提高下一步制备松香酸的得率；同时，利用高温使松香中松香酸的各种同分异构体第一次发生转位，减少所获得松香酸中异构体的含量。事实上采用本发明可直接获得光谱纯的松香酸，并可直接催化转位脱氢得到纯去氢松香酸，工艺简单，收率好(超过35％)。
本发明的的磺化去氢松香酸盐的用途，通式(1)所表示的化合物作为制备消化道溃疡、及胃炎药的应用。
(1)松香(I)与1∶0.1～1∶1.5倍量的消石灰在高温下搅拌1～5小时，冷却得淡黄色几乎透明的固体松香钙(II)；
其中，松香与消石灰的比例以1∶0.5为佳。反应温度控制在160～600℃，以200～300℃为佳。搅拌时间在2～3小时为佳；
(2)上述松香钙(II)采用适当的溶媒溶解，并以矿酸调节溶液pH值至5～9，过滤，滤液放置过夜，析出结晶，过滤得松香酸(III)。
其中，溶媒指C1～6的脂肪醇及其含水混合溶液、脂肪酸酯等，其中脂肪醇含水混合溶液的浓度为10-95％(重量)。以甲醇、乙醇、乙酸乙酯为佳；所用溶媒量为原料的0.5～10倍(ml/g)，以1～5倍量为佳；矿酸包括盐酸、硫酸、磷酸、硝酸等，本发明中以浓度为90％-98％(重量)的浓盐酸为佳；pH值控制在6～8最为合适；
所获得结晶松香酸，可经过重结晶得到纯的松香酸，亦可直接用于催化脱氢转位；
(3)松香酸(III)脱氢转位形成去氢松香酸(IV)，可在适当的催化剂作用下进行，亦可直接在220～380℃的高温下进行。加入适当的催化剂可提高脱氢转位率，缩短反应时间。本发明中采用0.1～5％量的5％～10％的钯/碳，在200～300℃下反应1～5小时，适当冷却后加入溶媒，并继续回流1～3小时后，趁热过滤，冷却，放置过夜，析出结晶，过滤得去氢松香酸(IV)。
其中，催化剂量在0.7～3％为佳，尤以2％最佳；所用适当溶媒为甲醇、乙醇、丙醇、乙酸乙酯、苯、甲苯，以乙醇为佳；可以采用10-95％(重量)浓度的乙醇水溶液，溶媒体积为0.5～10倍，以1～3倍为佳；
(4)将所得去氢松香酸加入预先冷却到-20～20℃的1～10倍量硫酸中，搅拌反应0.5～10小时后，倾入适当量的冰水中，大量白色沉淀析出，过滤，滤饼水洗，并尽量吸去水分后用冰醋酸加热溶解，放冷，析出结晶，过滤后干燥得磺化去氢松香酸(V)。
本发明中磺化在-20～20℃下进行，反应过程中控制在-10～10℃为佳；硫酸以98％含量为好，其用量在1～10倍，尤以4～6倍为佳；反应时间在0.5～10小时，1～2小时为佳；冰水量为硫酸的5～50倍，以15～25倍最佳；重结晶用醋酸量为0.5～10倍，以1.5～2.3倍为佳。
本发明中尚提供了制备磺化去氢松香酸有关锌、铋盐及其含水化合物的方法。
(1)本发明中涉及的磺化去氢松香酸锌、铋盐可根据盐置换原理，在适当的溶媒系统中以磺化去氢松香酸单、双碱金属盐、碱土金属盐与锌盐、铋盐通过置换反应制备而得。
其中磺化去氢松香酸的单、双碱金属、碱土金属盐是钠、钾、锂、镁、钙等的无水、或含结晶水合物，尤其是钠的无水或多个结晶水合物为佳；置换用锌盐指氯化锌、硫酸锌、硝酸锌等；铋盐指硝酸铋；
适当溶媒是C1～6的脂肪醇、水、DMF、DMSO，以0～100倍量水为佳；
(2)本发明中的锌、铋盐亦可直接用氧化锌、氢氧化锌、碱式硝酸铋等在适当的溶媒系统中与磺化去氢松香酸根据酸碱中和原理制备而得。
(3)本发明中涉及的锌、铋盐可以以无水形式存在，亦可以不同结晶水合物的形式存在，其中含1～8个水时较稳定。
本发明的磺化去氢松香酸盐作为制备消化道溃疡及胃炎药的应用时，可以采用口服或非口服给药，但口服给药效果较好。口服给药的形式有片剂、胶囊、散剂、颗粒剂、乳剂等剂型。口服制剂中可加入药用辅料及佐剂如黏合剂、轿味剂、稀释剂等。
本发明中化合物的药用剂量，一般根据患者的年龄、体重、状态和疾病的不同而改变。通常每天约10～400mg/Kg，以40～130mg/Kg为佳。
本发明化合物无激素样作用，具有优良的抗溃疡作用，对消化道溃疡及胃炎等胃肠道疾病有治疗和预防功能。其中所谓的消化道溃疡系指胃、十二指肠溃疡。
实验例1本发明的磺化去氢松香酸锌(NIPWZ)和碱式磺化去氢松香酸铋(NIPWB)对胃酸及胃蛋白酶的抑制作用。
Wister大鼠(200～250g)，雌雄各半，实验前禁食不禁水48小时后结扎幽门。术后立即按2.0ml/Kg灌胃给药，空白对照组给于同样体积的0.5％MC。给药5小时后处死动物，结扎贲门，取出胃，收集胃液于离心管中，250rpm离心，10min，记录去残渣体积为胃液总体积。取离心上清胃液进行胃酸度和胃蛋白酶活性的测定。
(a)胃液酸度测定：准确取胃液0.5ml，加蒸馏水约20ml，用酸度计进行测定，滴定液为0.01N NaOH溶液，滴定至pH＝7.0，记录用去0.01N NaOH溶液的体积。计算：相当于0.01N NaOH滴定至pH＝7.0时的体积(T.AC)。
胃液的酸浓度(MEL)＝(T.AC/2)×1000
胃液内总酸量(MEAH)＝MELX(酸液总体积/1000)
胃液分泌抑制率％＝[(空白组胃液体积-给药组胃液体积)/空白组胃液体积]×100％
胃液总酸量抑制率％＝[(空白组MEAH-给药组MEAH)/空白组胃液MEAH)]×100％
(b)胃蛋白酶活性的测定(Mett管法)：准确取胃液0.5ml于50ml洁净具塞的锥形瓶中，摇匀，然后加入0.05N HCl溶液15.0ml，同时加入3.0-4.0cm长的Mett管两根，塞好塞子，摇匀，置37℃24h，精密测定Mett管两端透明部分的长度(mm)，以四端值求平均值。计算胃蛋白酶活性单位(U)。
胃蛋白酶活性抑制率＝[(空白组胃蛋白酶活性-给药组胃蛋白酶活性)/空白组蛋白酶]×100％
试验结果
表1.口服NIPWZ和NIPWB对幽门结扎大鼠胃液分泌的影响(n＝8，X±S)
| 组别 | 剂量(mg/Kg) | 胃液总体积(ml) | T.AC | MEL(103) | MEAH | 胃蛋白酶活性(U) |
| 空白对照NIPWZNIPWB | 5010050100 | 9.1±3.27.2±2.97.0±3.16.5±2.57.6±2.9 | 6.42±3.113.83±2.934.41±2.644.85±3.584.32±3.30 | 3.21±1.561.92±1.472.21±1.322.42±1.792.16±1,65 | 29.3±4.913.8±4.2**15.5±4.1**15.9±4.5**16.3±4.7** | 1.49±0.300.88±0.33**0.66±0.340.74±0.610.36±0.20** |
注：与空白对照组比较，*P＜0.05，**P＜0.01
表2.口服NIPWZ和NIPWB对胃液分泌的抑制作用(n＝8，X±S)
| 组别 | 剂量(mg/Kg) | 胃液分泌抑制(％) | 总酸量抑制率(％) | 胃蛋白酶活性抑制率(％) |
| 空白对照NIPWZ | 50 | --20.9 | --52.9 | --40.5 |
| NIPWB | 10050100 | 23.128.616.5 | 47.145.744.4 | 55.450.075.7 |
本发明磺化去氢松香酸锌盐和铋盐在50、100mg/Kg剂量时对胃液总酸量及胃蛋白酶活性有显著性的抑制作用(P＜0.01)。对总酸量的抑制率在44％以上，对胃蛋白酶的抑制率在40％以上。
实验例2.本发明的磺化氢松酸铋盐(NIPWB)小鼠口服急性毒性的测定。
二级昆明种小鼠20只，体重20.1±1.3g，雌雄各半。口服给药，溶剂为0.5％MC，分两次给予，给药容积最大1ml/Kg。详细记录给药后动物出现的异常反应及死亡情况，连续观察14天，死亡东海物做大体解剖。
小鼠口服NIPWZ8000mg/Kg后连续观察14天无异常及反应死亡(LD50≥8000mg/Kg)。
实验例3本发明的磺化去氢松酸锌盐(NIPWZ)小鼠口服急性毒性的测定。
二级昆明种小鼠50只，体重20.0±1.2g，♀♂各半并随机分成5组，每组各10只，灌胃一次给药40ml/Kg，溶剂为0.5％MC。5个剂量组剂量分别为：4480，3000，2010，1350，910mg/Kg，相邻间剂量比值1∶0.67。详细记录给药后动物出现的异常反应及死亡情况，连续观察14天，死亡动物做大量解剖。LD50计算方法：Bliss’s法。
表3.NIPWZ口服后计算半数致死量(Bliss’s法)LD50
剂量 对数剂量 动物数 死 亡 分 布 死亡数 死亡率
mg/Kg X 只 2h 4h 24h 72h 只(♀∶♂) ％
4480 3.65 10 7 3 0 0 10(5∶5) 100
3000 3.48 10 0 7 1 0 8(5∶3) 80
2010 3.30 10 0 0 7 0 7(5∶2) 70
1350 3.13 10 0 0 3 1 4(1∶3) 40
910 2.96 10 0 0 0 0 0(0∶0) 0
NIPWZ口服后LD50＝1728mg/Kg，约相当于临床拟用量的104倍(以60Kg人1000mg/日)计。
具体实施方式
实施例1.
100g松香酸及50g消石灰加至500ml反应瓶中，加热至350℃反应2h，自然冷却后凝固成几乎透明的固体松香钙，软化点130～135℃。
实施例2.
松香钙700g研碎后加入600ml乙酸乙酯及90ml浓盐酸，加热回流10min.溶解后过滤，静置析晶得140g松香酸。Mp.162～166℃1H NMR(300MHz，in CDCl3，J in Hz)δppm：7.430(1H，brs)，5.757(1H，brs)，5.332(1H，brs)，2.213(1H，seq.)，1.186(3H，s)，1.10(3H，d，J＝7.2)，1.000(3H，d，J＝7.2)，0.803(3H，s)。
实施例3.
松香酸115g置1000ml三颈瓶中加2.3g5％钯/碳，250℃(油浴)搅拌加热2h，稍冷后加人200ml95％乙醇，回流至全部溶解，趁热过滤，滤液静置析晶，过滤得70g去氢松香酸。mp.168～170℃1H NMR(300MHz，in CDCl3，J inHz)δppm：7.167(1H，d，J＝7.8)，7.005(1H，dd，J＝1.2，7.8)，6.886(1H，d，J＝1.2)，2.904(2H，m)，2.822(1H，seq.，J＝7.2)，2.303(1H，brd，J＝13.2)，2.245(1H，dd，J＝2.0，13.2)，1.279(3H，s)，1.221(6H，d，J＝7.2)，1.215(3H.S)。
实施例4.
将250ml浓H2SO4置1000ml三颈瓶中，冷却至-8℃左右。将50g研碎的去氢松香酸在搅拌下加入上述浓硫酸中，加毕继续搅拌1.5h后慢慢倾入1000ml的冰水中，并继续剧烈搅拌20min.后过滤，冰水适量洗涤至滤液呈云状。滤饼转移至，500ml三颈瓶中，加入约200ml冰醋酸并加热回流，过滤，滤液放置过夜，析出结晶，过滤得37g磺化去氢松香酸。mp.210～215℃，1H NMR(300MHz，in CDCl3，J in Hz)ppm：7.839(1H，s)，7.058(1H，s)，3.985(1H，seq.，J＝6.9)，2.872(2H，dt)，2.373(1H，brd，J＝12)，2.188(1H，dd，J＝1.8，12)，1.265(3H，s)，1.238(3H，d，J＝6.9)，1.230(3H，d，J＝6.9)，1.201(3H，s)。
实施例5.
将40g磺化去氢松香酸溶解于400ml水中，pH1～2。搅拌下加入8.4gNaOH，pH＞10。加入2g活性炭回流0.5h后趁热过滤，滤液减压浓缩至80ml，放置析晶，过滤，滤饼用约10ml水洗涤，阳光下风干48h，得35g磺化去氢松香酸双钠81/2水化物。mp.＞300℃。
实施例6.
将5g磺化去氢松香酸加入至100ml水中，并加入1gZnO，加热至90℃反应15min.，趁热过滤，滤饼分别用50ml水和95％乙醇50ml洗涤，在60℃干燥48h，得3.1g磺化去氢松香酸锌的5水化合物。Mp.＞300℃；IRνmax(KBr)：3474，3039，2948，2869，1700，1634，1539，1396，1364，1185，1168，1100，1059，1045，1035，1009，977，913，886，716，697，661，621，582-cm。元素分析：C43.65，H6.89，S5.90，Zn11.76；计算值：C43.52，H6.94，S5.81，Zn11.85；分子式：C20H26O5SZn*6H2O
实施例7.
1gZnSO4.7H2O溶解于20m1水中，搅拌下加入含1.78g磺化去氢松香酸双钠盐的20ml水溶液，加毕在60℃左右继续搅拌半小时，冷却至室温过滤，50℃水洗涤至中性，60℃下干燥48h，得1.02g目标物，mp.＞300℃；IR等与实施例6相同。
实施例8
5g磺化去氢松香酸溶解于200ml水中，加入5g次硝酸铋，90℃继续搅拌1h，冷却过滤，在60℃干燥60h，得6.7g磺化去氢松香酸次铋盐，mp.＞300℃；IRVmax(KBr)：3381，3035，2910，2883，1699，1623，1553，1484，1384，1357，1316，1186，1444，1097，1056，1024，1008，975，713，697，662，624，579cm-1。分子式：C20H26O7SBi2 *10H2O，计算值：Bi41.43％，水份17.86％，EDTA滴定Bi 41.13％，水份17.6％。
实施例9
5g磺化去氢松香酸溶解于200ml水中，加入6.23g硝酸铋，并加热至90-100℃，搅拌1小时，降温至60℃过滤，水及95％乙醇、稀酸反复洗涤数遍，滤饼60℃干燥60h，得7g磺化去氢松香酸次铋盐：mp.＞300℃。
IRV max(Kbr)：
3433，3041，2937，2885，1698，1631，1553，1486，1362，1185，1144，1097，1057，1044，1030，1009，977，910，580cm-1。元素分析：C36.76，H4.88，S5.14；EDTA滴定，Bi31.63；计算值：C36.48，H5.05，S4.87，Bi：31.73，分子式：C20H27O6SBi·3H2O，水份测定(TGA)：2.77。
Claims (3)
1、一种磺化去氢松香酸盐，其特征在于：该化合物用下述通式(1)表示：
其中，R为Bi(OH)++、或2BiO，
n＝0-10。
2、一种权利要求1的磺化去氢松香酸盐的制备方法，其特征在于：该方法包括下述步骤：
(1)将松香与1∶0.1-1∶1.5倍重量的消石灰在160-600℃温度下搅拌1-5小时，得到固体松香钙；
(2)将上述固体松香钙采用C1-6的脂肪醇及其含水混合溶液、或是脂肪酸酯溶解，所用上述溶媒为固体松香钙的0.5-10倍，单位比为ml/g，并用矿酸调节上述溶液的pH值为5-9，获得松香酸；
(3)将上述松香酸在0.1-5％重量的5％-10％的钯/碳的催化剂作用下在200-300℃下反应1-5小时；或是直接在220-380℃高温下进行反应，反应后经冷却后，再加入0.5-10体积的溶媒，溶媒为甲醇、乙醇、丙醇、乙酸乙酯、苯、和甲苯中的任意一种，并继续回流1-3小时后，趁热过滤，冷却，放置过夜，析出结晶，过滤得去氢松香酸；
(4)将所得到去氢松酸加入予先冷却到-20～20℃的1-10倍重量的90-98％的硫酸中，搅拌反应0.5-10小时后，倾入冰水中，冰水的重量为硫酸重量的5-50倍，大量白色沉淀析出，过滤，滤饼水洗，并吸去水分后，用滤饼重量的0.5-10倍的冰醋酸加热溶解，放冷，析出结晶，过滤后干燥得磺化去氢松香酸；
或是，
(5)将得到的磺化去氢松香酸按照常规的方法制成磺化去氢松香酸单、双碱金属盐或碱土金属盐；
(6)在C1-6的脂肪醇，水、DMF和DIMSO中的任一种溶媒中，以所制成的磺化去氢松香酸单、双碱金属盐或碱土金属盐与硝酸铋、或次硝酸铋、或氢氧化铋，通过置换反应制得磺化去氢松香酸铋盐，即通式(1)表示的化合物；
或是，
(5)’在C1-6的脂肪醇，水、DMF和DMSO中的任意一种溶媒中，用所得的磺化去氢酸与硝酸铋或碱式硝酸铋进行中和反应制得磺化去氢松香酸铋盐，即通式(1)表示的化合物。
3、根据权利要求1所述的磺化去氢松香酸盐的用途，其特征在于：通式(1)所表示的化合物作为制备消化道溃疡、及胃炎药的应用。
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| CNB011202890A CN1219757C (zh) | 2001-07-16 | 2001-07-16 | 磺化去氢松香酸盐及其制备方法和其用途 |
| US10/483,774 US7015343B2 (en) | 2001-07-16 | 2002-06-04 | Sulphonated dehydrogenated sylvate, the preparation and use |
| PCT/CN2002/000387 WO2003093225A1 (fr) | 2001-07-16 | 2002-06-04 | Sylvate deshydrogene et sulfone, preparation et utilisation de ce sylvate |
| AU2002315737A AU2002315737A1 (en) | 2001-07-16 | 2002-06-04 | Sulphonated dehydrogenated sylvate, the preparation and use |
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| CN107628972A (zh) * | 2017-10-13 | 2018-01-26 | 重庆康乐制药有限公司 | 一种依卡倍特的三氧化硫卤代烃溶液磺化制备方法 |
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| CN101590031B (zh) * | 2008-06-17 | 2011-10-12 | 浙江爱生药业有限公司 | 磺化去氢松香酸二钠组合物的制备方法 |
| CN103772241B (zh) * | 2014-01-07 | 2015-08-26 | 珠海亿邦制药股份有限公司 | 一种磺化去氢松香酸盐的制备方法 |
| CN103896814B (zh) * | 2014-01-07 | 2015-07-08 | 珠海亿邦制药股份有限公司 | 一种磺化去氢松香酸的制备方法 |
| CN104086465B (zh) * | 2014-07-30 | 2016-08-17 | 重庆康乐制药有限公司 | 一种依卡倍特钠的制备方法 |
| CN104151208A (zh) * | 2014-08-07 | 2014-11-19 | 广西众昌树脂有限公司 | 磺化脱氢松香酸的制备方法 |
| CN104382936B (zh) * | 2014-11-21 | 2018-01-26 | 珠海亿邦制药股份有限公司 | 一种磺化去氢松香酸铋的口服固体制剂及其制备方法 |
| CN104447432B (zh) * | 2014-11-21 | 2018-01-26 | 珠海亿邦制药股份有限公司 | 一种新的磺化去氢松香酸铋的制备方法 |
| CN108690473B (zh) * | 2017-07-25 | 2020-07-17 | 山东科耀化工有限公司 | 松香酸改性醇酸树脂锌盐防污涂料的制备方法 |
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| JP3059092B2 (ja) * | 1995-11-15 | 2000-07-04 | 田辺製薬株式会社 | ドライアイおよびドライアイを原因とする疾患の予防・治療剤 |
| TW585762B (en) * | 1999-11-11 | 2004-05-01 | Tanabe Seiyaku Co | Pharmaceutical composition for prophylaxis or treatment of inflammatory bowel diseases |
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| CN1396154A (zh) | 2003-02-12 |
| US20040162341A1 (en) | 2004-08-19 |
| WO2003093225A1 (fr) | 2003-11-13 |
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Effective date of registration: 20210202 Address after: 102629 room 409-36, 4 / F, building 1, 38 Yongda Road, Daxing biomedical industrial base, Zhongguancun Science and Technology Park, Daxing District, Beijing (cluster registration) Patentee after: Beijing aoxinda Pharmaceutical Research Institute Co.,Ltd. Address before: No.9, East jinhaian Avenue, Sanzao, Jinwan District, Zhuhai City, Guangdong Province, 519000 Patentee before: Zhuhai Yibang Pharmaceutical Co.,Ltd. |
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Address after: 102629 3rd floor, building 16, courtyard 50, Huatuo Road, Daxing biomedical industrial base, Zhongguancun Science and Technology Park, Daxing District, Beijing Patentee after: AoXin sunshine (Beijing) Pharmaceutical Technology Co.,Ltd. Address before: 102629 room 409-36, 4 / F, building 1, 38 Yongda Road, Daxing biomedical industrial base, Zhongguancun Science and Technology Park, Daxing District, Beijing (cluster registration) Patentee before: Beijing aoxinda Pharmaceutical Research Institute Co.,Ltd. |
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Granted publication date: 20050921 |