CN1066451C - 噻唑啉衍生物及其组合物和用途 - Google Patents
噻唑啉衍生物及其组合物和用途 Download PDFInfo
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- 150000003549 thiazolines Chemical class 0.000 title claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 25
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
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- 230000000694 effects Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
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- 230000005764 inhibitory process Effects 0.000 description 5
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical class C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
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- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- MWPIIMNHWGOFBL-UHFFFAOYSA-N dichloromethane;toluene Chemical compound ClCCl.CC1=CC=CC=C1 MWPIIMNHWGOFBL-UHFFFAOYSA-N 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
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- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
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- FGQJDHJXUZUTIQ-UHFFFAOYSA-N quinoline;1,3-thiazole Chemical compound C1=CSC=N1.N1=CC=CC2=CC=CC=C21 FGQJDHJXUZUTIQ-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
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- 235000017281 sodium acetate Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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Abstract
本发明提供如下式表示的噻唑啉衍生物或其药学容许的盐，该化合物不仅非经口给药、而且经口给药也具有优良的抑制血小板凝聚作用，
式中R1表示碳原子数1～4的烷基，R2表示氢原子或碳原子数1～4的烷基。
Description
技术领域
本发明涉及具有优良的抑制血小板凝聚作用的新型噻唑啉衍生物。
背景技术
本发明化合物已包含在WO 94/02472号申请的权利要求记载的通式1中，但在该申请的说明书中并未具体记载本发明化合物。WO 94/02472号申请的说明书中具体公开的化合物在非经口给药时具有优良的抑制血小板凝聚的作用，但是有经口给药时药理活性低等缺点。
本发明的目的在于提供经口给药时具有优良抑制血小板凝聚作用的化合物。
本发明的公开
本发明人等经过潜心研究，结果发现，某种的噻唑啉衍生物具有在WO94/02472号申请的说明书中具体公开的化合物所不具有的优良的经口给药活性，从而实现了前述本发明的目的，完成了本发明。
即，本发明是如下式表示的噻唑啉衍生物或其药学容许的盐，
式中R1表示碳原子数1～4的烷基，R2表示氢原子或碳原子数1～4的烷基。
本发明中，所说的碳原子数1～4的烷基，是指甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。所说的式(Ⅰ)化合物的药学容许的盐，只要是药理学上容许的，没有特别的限制，例如可以举出与碱金属类，碱土金属类，氨，烷基胺类，无机酸，羧酸，磺酸等形成的盐。具体例如可以举出钠盐，钾盐，钙盐，铵盐，铝盐，三乙胺盐，1-金刚烷胺盐，盐酸盐，氢溴酸盐，氢碘酸盐，硫酸盐，硝酸盐，磷酸盐，单甲硫酸盐，醋酸盐，丙酸盐，丁酸盐，琥珀酸盐，酒石酸盐，柠檬酸盐，单宁酸盐，苹果酸盐，己酸盐，戊酸盐，富马酸盐，马来酸盐，甲磺酸盐，甲基苯磺酸盐等，但不仅限于上述各盐。
本发明化合物可按照例如以下方法制备。
即，根据WO 94/02472号申请说明书中第4页记载的方法得到的如下式所示的化合物或其盐与4,4-亚乙二氧基哌啶或其盐反应，即可得到式(Ⅰ)化合物或其药学容许的盐，
上式中，R3表示低级烷基，R1与R2含义与前面相同。
制备R2为氢原子的式(Ⅰ)化合物或其药学容许的盐时，可通过将R2为碳原子数1～4的烷基的式(Ⅰ)化合物或其药学容许的盐的酯基部分水解得到。上述水解可采用一般的碱处理，矿酸或有机酸处理等方法进行。
另外，R2为碳原子数1～4的烷基的式(Ⅰ)化合物，也可通过如以酸作催化剂进行酯交换反应而相互转变。
上述反应中采用碱时，作为碱例如可采用碱金属盐类(如碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、dimsyl sodium、氢化钠、氨基钠、或叔丁基钾)，胺类(如三乙胺、二异丙基乙基胺、吡啶)，醋酸钠、醋酸钾等；无机酸例如盐酸、氢溴酸、氢碘酸、硝酸、硫酸；有机酸例如醋酸、甲磺酸、对甲苯磺酸。4,4-亚乙二氧基哌啶的盐可采用如醋酸盐等的有机酸盐，盐酸盐等的无机酸盐。作为反应溶剂，可采用如水，醇类(如甲醇、乙醇、异丙醇或叔丁醇)，醚类(如二噁烷、四氢呋喃)，二甲基甲酰胺、二甲亚砜、吡啶、二氯甲烷、氯仿、丙酮、醋酸等对反应惰性的溶剂。工业上的实用性
按照上述方法得到的本发明化合物，不仅在非经口给药时，而且即便在经口给药时具有优良的抑制血小板凝聚作用。
因此，本发明化合物可作为血栓症、脑梗塞、心肌梗塞等缺血性疾病，动脉硬化症等疾病的预防和治疗药物而起作用。
为达到上述目的，本发明化合物可添加入常用的增量剂、粘合剂、崩解剂、pH调整剂、增溶剂等，通过常用的制剂技术制成片剂、丸剂、胶囊剂、颗粒剂、散剂、液剂、乳胶、混悬剂、注射剂等。
本发明化合物对于成人患者，可采用1～1000毫克/日的剂量，分数次给药。上述给药量可根据疾病种类、患者年龄、体重、症状进行适当增减。
以下举出试验例对本发明化合物的优良作用进行说明。试验例〔豚鼠经口给药抑制血小板凝聚作用试验〕
试验中采用禁食一夜的雄性Hartley系豚鼠，4周龄，体重250～300克，1组4只。试验药混悬于10％Tween 80溶液内按1毫克/千克药量经口给药。对照组仅给予溶剂。经口给药30分钟后，以戊巴比妥(30毫克/千克，ip)麻醉，开腹，自腹主动脉用塑料注射器(3.8％柠檬酸钠与血液体积比为1∶9)采血。将血液以120g离心分离10分钟，所得上清液作为多血小板血浆(platelet rich plasma,PRP)，剩余血浆继续以1100g离心分离10分钟，得到贫血小板血浆(platelet poor plasma,PPP)。将PRP中血小板数以PPP稀释至4～6×105个/微升。
血小板凝聚的测定是根据Born G.V.R的方法〔Born,G.V.R,Nature，194卷，927页(1962年)〕，凝聚引发物质采用二磷酸腺苷(Sigma公司出品，以下简称为ADP)。即，将作为凝聚引发剂的ADP(最终浓度3μM)/肾上腺素(最终浓度10μM)25微升加入250微升PRP中，以血小板凝聚能力测定装置(Aggricoda PAM-8C；Mebanix公司)测定5分钟，以给予溶剂组作为对照组，按下式计算试验药给药组的凝聚抑制率相对于对照组最大凝聚率的凝聚抑制率，计算50％抑制浓度(IC50值)。
另外，将94/02472号说明书记载的化合物N-(2-羧乙基)-2-(4-脒基苯甲酰亚氨基)-3-异丙基-4-甲基-3H-噻唑啉-5-甲酰胺·氢溴酸盐作为对照药进行同样试验，结果如表1所示。
表1
| 试验药 | 抑制率±SD(％) |
| 化合物3对照药 | 99.3±0.715.0±5.7 |
实施发明的最佳方式
以下，举出实施例对本发明进行更详细地说明。参考例
N-(2-甲氧羰基乙基)-2-〔4-(甲硫基亚氨甲基)苯甲酰亚氨基〕-3,4-二甲基-3H-噻唑啉-5-甲酰胺·甲基硫酸盐(化合物1)
N-(2-甲氧羰基乙基)-2-(4-硫代氨甲酰基苯甲酰亚氨基)-3,4-二甲基-3H-噻唑啉-5-甲酰胺(104克)、硫酸二甲酯(86.1毫升)、N,N-二甲基甲酰胺(400毫升)的混和物室温搅拌4小时。冰冷却下加入1.5升丙酮，滤取析出的结晶，以丙酮洗涤后即得到标题化合物126.5克。
熔点164～167℃
实施例1
N-(2-甲氧羰基乙基)-2-{4-〔(4,4-亚乙二氧基哌啶-1-基)亚氨甲基〕苯甲酰亚氨基}-3,4-二甲基-3H-噻唑啉-5-甲酰胺·甲基硫酸盐(化合物2)
化合物1(10.0克)、4,4-亚乙二氧基哌啶(3.93克)、醋酸(1.57毫升)以及丙酮(100毫升)的混和物80℃下搅拌90分钟。反应混和物放冷后，滤取析出的结晶，用甲醇与甲苯的混和溶剂洗涤，得到标题化合物7.66克。
熔点215～216℃(分解)
实施例2
N-(2-羧乙基)-2-{4-〔(4,4-亚乙二氧基哌啶-1-基)亚氨甲基〕苯甲酰亚氨基}-3,4-二甲基-3H-噻唑啉-5-甲酰胺·三水合物(化合物3)
化合物2(7.0克)、5％氢氧化钠水溶液(19.2毫升)、2-丙醇(70毫升)的混和物室温搅拌1小时。反应混和物中加入1％磷酸水溶液(60毫升)，滤取析出的结晶，得到标题化合物5.3克。
熔点233～234℃(分解)
实施例3
N-(2-甲氧羰基乙基)-2-{4-〔(4,4-亚乙二氧基哌啶-1-基)亚氨甲基〕苯甲酰亚氨基}-3,4-二甲基-3H-噻唑啉-5-甲酰胺·氢碘酸盐(化合物4)
N-(2-甲氧羰基乙基)-2-〔4-(甲硫亚氨酰基)苯甲酰亚氨基〕-3,4-二甲基-3H-噻唑啉-5-甲酰胺·氢碘酸盐(1.0克)、4,4-亚乙二氧基哌啶(0.5克)、醋酸(0.2毫升)以及甲醇(15毫升)的混和物加热回流搅拌1.5小时。反应混和物减压浓缩，残渣用二氯甲烷-甲苯重结晶，得到标题化合物1.0克。
熔点212～214℃(分解)
实施例4
N-(2-羧乙基)-2-{4-〔(4,4-亚乙二氧基哌啶-1-基)亚氨甲基〕苯甲酰亚氨基}-3,4-二甲基-3H-噻唑啉-5-甲酰胺·二水合物(化合物5)
化合物4(0.4克)、10％氢氧化钠水溶液(1毫升)、甲醇(15毫升)的混和物加热回流搅拌40分钟。反应混和物减压浓缩，用少量水溶解之后加入3％盐酸中和，滤取析出的结晶，得到标题化合物0.3克。
熔点166～169℃(分解)
Claims (3)
1、如下式表示的噻唑啉衍生物或其药学容许的盐，
式中R1表示碳原子数1～4的烷基，R2表示氢原子或碳原子数1～4的烷基。
2、由权利要求1记载的噻唑啉衍生物或其药学容许的盐和医药载体组成的用于抑制血小板凝聚的药物组合物。
3、根据权利要求1记载的噻唑啉衍生物或其药学容许的盐在制备用于抑制血小板凝聚的药物中的应用。
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| WO1994002472A1 (en) * | 1992-07-15 | 1994-02-03 | Taisho Pharmaceutical Co., Ltd. | Thiazoline derivative |
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