CN1046733C - 膦酸二酯衍生物 - Google Patents
膦酸二酯衍生物 Download PDFInfo
- Publication number
- CN1046733C CN1046733C CN94190067A CN94190067A CN1046733C CN 1046733 C CN1046733 C CN 1046733C CN 94190067 A CN94190067 A CN 94190067A CN 94190067 A CN94190067 A CN 94190067A CN 1046733 C CN1046733 C CN 1046733C
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- Prior art keywords
- phenyl
- compound
- bound
- singly
- group
- Prior art date
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- 150000005690 diesters Chemical class 0.000 title abstract 2
- -1 phosphonic acid diester Chemical class 0.000 claims description 47
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- 239000000203 mixture Substances 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000001118 alkylidene group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
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- 229910052801 chlorine Inorganic materials 0.000 description 1
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
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- 239000003589 local anesthetic agent Substances 0.000 description 1
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- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 239000011574 phosphorus Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
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- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
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- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
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- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- 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
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
- C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供下述通式(1)的膦酸二酯衍生物,所述膦酸二酯衍生物具有优秀的降血脂和降血糖活性并且副作用低,因此适用作高血脂症和糖尿病的治疗剂和预防剂及适用作白内障的治疗剂,其中R1、R2、R3和R4相同或不相同,并各自代表氢原子、低级烷基、低级烷氧基、卤代低级烷基、硝基、卤素原子、氰基、苯硫基、苯基亚磺酰基、苯磺酰基、苯基(低级)烷氧基、苯基(低级)烷硫基或者具有二(低级烷氧基)磷酰基(低级)烷基的苯甲酰氧基;且R3和R4可结合在一起代表式的基团;R5代表氢原子、低级烷基或苯基;R6和R7相同或不相同,并各自代表低级烷氧基、苯基或苯基(低级)烷氧基;A代表任选具有苯基取代基的低级亚烷基;B代表苯环或噻吩环;D代表式-CO-、-CS-或-SO2-的基团;E代表式的基团、式的基团或式的基团(其中R8代表低级烷基);-Z-代表单键或-O-;Y代表任选具有苯基取代基的低级亚烷基或1,2-亚乙烯基;且n为0或1的整数。
Description
技术领域
本发明涉及新型膦酸二酯衍生物。
先有技术
本发明的膦酸二酯衍生物是迄今为止尚未见于文献的新型化合物。
本发明的目的是提供具有如下所述的医药价值的化合物。
本发明的说明
本发明提供下述通式(Ⅰ)所示的膦酸二酯衍生物:(1)其中
R1、R2、R3和R4相同或不相同,并各自代表氢原子、低级烷基、低级烷氧基、卤代低级烷基、硝基、卤素原子、氰基、苯硫基、苯基亚磺酰基、表磺酰基、苯基(低级)烷氧基、苯基(低级)烷硫基或者具有二(低级烷氧基)磷酰基(低级)烷基的苯甲酰氧基;且
R3和R4可结合在一起代表式-CH=CH-CH=CH-的基团;
R5代表氢原子、低级烷基或苯基;
R6和R7相同或不相同,并各自代表低级烷氧基、苯基戊苯基级)烷氧基;
A代表任选具有苯基取代基的低级亚烷基;
B代表苯环或噻吩环;
D代表式-CO-的基团、式-CS-的基团、式-SO2-的基团;
-Z-代表单键或-O-;
Y代表任选具有苯基取代基的低级亚烷基或1,2-亚乙烯基;且
n为0或1的整数。
与上述通式(Ⅰ)有关的各基团包括下列实例。
低级烷基包括直链或支链的低级烷基,如甲基、乙基、丙基、异丙基、丁基、、异丁基、叔丁基、戊基、己基等等。
低级烷氧基包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等等。
卤代低级烷基包括三氟甲基、五氟乙基、七氟丙基、九氟丁基、十一氟戊基、十三氟己基等等。
卤素原子包括氟、氯、溴和碘。
低级亚烷基包括亚甲基、亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基、1,6-亚己基、甲基亚甲基、甲基亚乙基、二甲基亚甲基等等。
任选具有苯基取代基的低级亚烷基包括上述低级亚烷基、苯基、亚甲基、苄基亚甲基、苯基亚乙基、二苯基亚甲基等。
苯基(低级)烷氧基包括苄氧基、1-苯基乙氧基、2-苯基乙氧基、3-苯基丙氧基、4-苯基丁氧基、5-苯基戊氧基、6-苯基己氧基等等。
苯基(低级)烷硫基包括苄硫基、1-苯基乙硫基、2-苯基乙硫基、3-苯基丙硫基、4-苯基丁硫基、5-苯基戊硫基、6-苯基己硫基等等。
具有二(低级烷氧基)磷酰基(低级)烷基的苯甲酰氧基包括4-[(二乙氧基磷酰基)甲基]苯甲酰氧基、3-[(二乙氧基磷酰基)甲基]苯甲酰氧基、2-[(二乙氧基磷酰基)甲基]苯甲酰氧基、4-[(二甲氧基磷酰基)甲基]苯甲酰氧基、4-[(二丙氧基磷酰基)甲基]苯甲酰氧基、4-[2-(二乙氧基磷酰基)乙基]苯甲酰氧基、4-[3-(二乙氧基磷酰基)丙基]苯甲酰氧基等等。
在本发明的式(Ⅰ)膦酸二酯衍生物中,优选式(Ⅰ)的下述化合物,其中
R1、R2、R3和R4相同或不相同,且各自代表氢原子、低级烷基、低级烷氧基、卤代低级烷基、卤素原子或氰基;
R5代表氢原子或低级烷基;
R6和R7各自代表低级烷氧基;
A代表低级亚烷基;
B代表苯环;
D代表式-CO-基团;
-Z-代表单键或-O-;
Y代表低级亚烷基或1,2-亚乙烯基;且
n为0。
更优选下述式(1')和(1″)代表的本发明衍生物。式(1')中,
R1、R2、R3和R4相同或不相同,且各自代表氢原子、低级烷基、低级烷氧基、卤代低级烷基、卤素原子或氰基;
R5'代表氢原子或低级烷基;
R6′和R7'各自代表低级烷氧基;
-Z-如在上述式(1)中的定义;
式(1″)中,
R1″、R2″、R3″和R4″相同或不相同,且各自代表氢原子、低级烷基、低级烷氧基、卤代低级烷基或卤素原子;
R5″代表氢原子或低级烷基;
R6″和R7″各自代表低级烷氧基;
当E″代表式
基团时,-Z″-代表单键或-O-,且Y″代表亚甲基或1,2-亚乙烯基;
优选的本发明衍生物具体实例包括:
4-[N-(8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,
4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,
4-[N-(7-氯-8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,
4-[N-(8-氟-4H-[1]苯并吡喃并[4,3-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,和
4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)氨基甲酰基]苄基膦酸二乙酯。
最优选的本发明衍生物为
4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯。
本发明的式(Ⅰ)膦酸二酯衍生物具有优秀的降血脂和降血糖活性,并对白内障具有治疗和预防作用,因此可作为治疗血脂过多症、糖尿病和白内障的治疗剂,可治疗或防治各种疾病(高血脂疾病),例如血胆固醇过多、血甘油三酯过多、血磷脂过多和高游离脂肪酸血症、糖尿病和白内障。此外,本发明的膦酸二酯衍生物也具有降血压活性,因此具有降血压剂的功能而可用于治疗和防治高血压。另外,本发明的膦酸二酯衍生物对恶病质(如癌性恶病质和传染性恶病质)具有改善和治疗作用,可用作改善恶病质的治疗剂。此外,本发明的化合物几乎没有副作用,因此更适用于医疗用途。
本发明的膦酸二酯衍生物的制备方法将在下文中予以详细说明。例如所述化合物可用下述反应路线制得。
根据反应路线-1所示的方法,本发明的化合物(1a)可按下述方式制得:在惰性溶剂中,在酸受体存在下,使化合物(2)和酸卤化物(3)反应。上述惰性溶剂主要包括芳烃和脂肪烃,如苯、甲苯、二甲苯、石油醚等,无环醚和环醚,如乙醚、1,2-二甲氧基乙烷、四氢呋喃(THF)、1,4-二噁烷等,酮类,如丙酮、甲乙酮、苯乙酮等,以及卤代烃类,如二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷等等。优选的酸受体为叔胺,如三乙胺和4-二甲基氨基吡啶。在上述反应中采用的化合物(2)和酸卤化物(3)的比例并不关键。酸卤化物(3)对于化合物(2)的用量优选为等摩尔至稍过量。酸受体相对于所述酸卤化物的用量优选为等摩尔至过量。反应可在室温、冷却或加热下进行,通常在0℃至溶剂的回流温度间进行反应更有利。反应通常在约0.5~10小时完成。
按反应路线-2所述方法,本发明的化合物(1a)可以下述方式制得:在惰性溶剂中,在缩合剂存在下,使化合物(2)与化合物(4)反应。惰性溶剂可以是任何已知的非质子传递溶剂,并特别优选N,N-二甲基甲酰胺(DMF)等等。缩合剂包括例如N,N-二环己基碳二亚胺(DCC)、1-羟基苯并三唑、N-羟基琥珀酰亚胺、氰基膦酸二乙酯、二苯基磷酰叠氮化物等等。联合使用氰基膦酸二乙酯和三乙胺特别有利。在上述反应中化合物(2)和化合物(4)之间的比例并不关键,可在一个宽范围内自由选取。推荐的做法是相对于化合物(2),使用等摩尔至稍过量的化合物(4),优选使用近似等摩尔比例的化合物(4)。上述缩合剂希望相对于化合物(4)以等摩尔至稍过量比例使用,优选以稍过量比例使用。反应在冰冷至室温条件下进行约0.5-2小时。
反应路线-3所示的化合物(1b)转化为化合物(1c)的反应以下述方式进行:在非质子传递溶剂中,用五硫化二磷处理化合物(1b)。非质子传递溶剂的实例有叔胺,如吡啶、三乙胺和N,N-二甲基苯胺,芳烃,如苯、甲苯和二甲苯,以及乙腈。其中,苯和吡啶的混合溶剂很适用。五硫化二磷的用量并不关键,可在一个很宽的范围内选取。相对于化合物(1b),五硫化二磷常以等摩尔至过量比例使用,优选相对于每摩尔化合物(1b)以约1.5~2.5摩尔的量使用。反应通常在室温至溶剂回流温度间、优选在约70~90℃进行约2~10小时。
在用作反应路线-1和-2的起始化合物的化合物(2)中,下述式(2a)和(2b)的化合物例如可用下述反应路线-4和-5所述方法制得。
反应路线4
反应路线5其中R1、R2、R3、R4、R5、Y和Z定义如前,Q代表卤素原子。
反应路线-4和-5中化合物(5)和(8)的卤化反应可分别在惰性溶剂中采用卤化剂进行。惰性溶剂主要包括氯仿、二氯甲烷、1,2-二氯乙烷,以及这些溶剂和低级醇(如甲醇和乙醇)的混合溶剂。卤化剂包括三溴化-N-苯基三甲铵、溴、碘等。如果用简单卤素(如溴和碘)作卤化剂时,则反应优选在路易斯酸(如氯化铝和三氟化硼)存在下进行。相对于化合物(5)或(8),卤化剂优选以等摩尔至稍过量比例使用。反应在冰冷至室温条件下进行约2~5小时。
反应所得的卤化物(6)和(9)分别与硫脲衍生物(7)反应,转化为化合物(2a)和(2b)。反应在惰性溶剂中,在约110°~130℃下,用硫脲衍生物(7)进行约1~3小时,硫脲衍生物(7)用量相对于卤化物(6)和(9)为大约等摩尔比例,惰性溶剂的实例有乙醇、甲醇、乙二醇、水等。
在起始化合物(2)中,下述式(2c)和(2d)的化合物例如可用下述反应路线-6所示方法制得。
依据反应路线-6所示的方法,目标化合物(2c)可通过下述方式获得:在惰性溶剂(如甲醇、乙醇、水、乙腈和乙醇/水混合物)中使化合物(10)与化合物(11)反应。化合物(11)的用量相对于化合物(10)优选为等摩尔至过量化例。反应在室温至溶剂回流温度下进行约1~24小时。
所需化合物(2d)可以下述方式获得:使化合物(10)与化合物(12)反应,并使所得化合物(13)进行环化反应。
化合物(10)和化合物(12)的反应可按下述方式进行:在惰性溶剂(如甲醇、乙醇、乙腈、二甲基甲酰胺、吡啶等)中,使这些化合物在室温至约溶剂沸点下,以约等摩尔的量反应约1~10小时,从而得到化合物(13)。
化合物(13)的环化反应可在惰性溶剂(如二氯甲烷、氯仿、1,2-二氯乙烷等)中在3~5当量的环化剂存在下进行。优选用氯化汞(Ⅱ)、乙酸汞(Ⅱ)、氧化汞(Ⅱ)等作环化剂。环化反应在室温至溶剂的回流温度下进行约1~20小时。
上述每一种方法中的目的化合物可用常规的分离方法容易地进行分离和提纯。这类方法包括吸附色谱、制备薄层色谱、溶剂萃取、重结晶等等。
在本发明的化合物中,某些化合物可以光学异构体的形式存在,当然它们也被认为是在本发明的概念中。上述光学异构体可很容易地用常规的拆分方法进行拆分,例如使用光学拆分试剂的方法。
本发明的化合物用适用的药用载体制成药物组合物供使用。适用的药用载体包括各种常规的稀释剂或赋形剂,如填充剂、体积组分(volume builder)、粘结剂、湿润剂、崩解剂、表面活性剂、润滑剂等,并且依据所需的单位剂型选择使用。
上述药物组合物可依据计划进行的治疗而提供许多不同的单位剂型。典型的例子有片剂、丸剂、粉剂、溶液剂、悬液剂、乳液剂、颗粒剂、胶囊剂、栓剂、注射剂(溶液、悬液等)及软膏剂。
片剂的塑形可采用赋形剂、粘结剂、崩解剂、表面活性剂、崩解抑制剂、吸附促进剂、湿润剂、吸收剂和润滑剂作为所述药用载体而进行。赋形剂例如乳糖、蔗糖、氯化钠、葡萄糖、脲、淀粉、碳酸钙、高岭土、结晶纤维素、硅酸、磷酸钾等,粘结剂例如水、乙醇、丙醇、单糖浆、葡萄糖浆、淀粉溶液、明胶溶液、羟甲基纤维素、羧丙基纤维素、甲基纤维素、聚乙烯吡咯烷酮等;崩解剂例如羧甲基纤维素钠、羧甲基纤维素钙、低取代的羟丙基纤维素、干淀粉、藻酸钠、琼脂粉、海带多糖粉、碳酸氢钠、碳酸钙等;表面活性剂例如聚氧乙烯脱水山梨醇脂肪酸脂、十二烷基硫酸钠、硬脂酸单甘油酯等;崩解抑制剂例如蔗糖、硬脂精、可可油、氢化油等;吸附促进剂例如季铵碱、十二烷基硫酸钠等;吸收剂例如淀粉、乳糖、高岭土、膨润土、硅胶等;润滑剂例如纯化滑石、硬脂酸盐、硼酸粉、聚乙二醇等等。另外,如果需要,这类片剂可被包衣,得到糖衣片、明胶衣片、肠溶衣片、包膜片等,或制成双层或多层片剂。
制备丸剂时,可使用的药用载体有各种赋形剂、粘结剂和崩解剂,赋形剂例如葡萄糖、乳糖、淀粉、可可油、氢化植物油、高岭土、滑石粉等;粘结剂例如阿拉伯树胶粉、黄蓍树胶粉、明胶、乙醇等;崩解剂例如海带多糖、淀粉等。
制备栓剂时,可用下列物质作载体:聚乙二醇、可可油、高级醇或它们的酯、明胶、半合成甘油酯等。
胶囊剂可用常规方法以下述方式制成:将本发明的化合物和上述任意各种药用载体混合并将所得到的组合物填充入硬质明胶胶囊壳、软质胶囊壳等之内。
当本发明的化合物以注射剂型(如溶液、乳液或悬液)提供时,制剂优选进行灭菌并对于血液等渗化。在这类制剂中可用下列物质作为稀释剂:水、乙醇、聚乙二醇、丙二醇、乙氧基异硬脂醇、多乙氧基异硬脂醇、聚氧乙烯脱水山梨醇脂肪酸酯等。在操作过程中,可向组合物中加入足量的氯化钠、葡萄糖或甘油,得到等渗溶液。也可加入常规的增溶剂、缓冲剂、局部麻醉剂等。
在上述各种剂型的组合物中还可任选加入着色剂、防腐剂、香料、调味剂、增甜剂或其他生理活性物质。
对本发明药物组合物的治疗方案没有特别的限制。因此,可依据具体的剂型、病人的年龄、性别及其他特征、疾病的严重程度和其他情况确定适当的方案。例如,所述片剂、丸剂、溶液剂、悬液剂、乳液剂、颗粒剂和胶囊剂通过口服给药。注射剂经静脉单独给药或与常规的葡萄糖、氨基酸或其他输注液混合经静脉给药,需要时单独经肌内、皮内、皮下或腹膜内给药。栓剂经直肠内给药。
在药物组合物中本发明的式(Ⅰ)化合物的比例并不关键,可在一个很宽的范围内自由选取。优选本发明化合物占最终组合物的约1~70wt%(重量百分数)。药物组合物的给药剂量依据选择的方案、患者年龄、性别及其它特征、疾病的严重程度和其它情况选定。本发明化合物即活性成分的剂量优选约0.05-100mg/(千克体重·天),且这一剂量可分1~4次给药。
实施发明的最佳方式
下述实施例用于更详细地说明本发明。在这些实施例中,参考实施例用于制备本发明化合物制备中所需的起始化合物,实施例用于制备本发明的化合物,药理实验实施例指就本发明化合物进行的实验。
参考实施例1
2-氨基-8H-茚并[1,2-d]噻唑(氢溴酸化物)的制备。
将6.61g1-茚酮溶于由80ml氯仿和20ml甲醇构成的混合溶剂中。在室温、搅拌下向溶液中加入20.35g三溴化-N-苯基三甲铵。在室温下继续搅拌5小时,然后用100ml水稀释反应混合物,并用氯仿萃取。氯仿层用无水硫酸钠干燥,溶剂在减压条件下蒸出。将残留物溶于100ml乙醇中,向其中加入3.81g硫脲,然后加热回流混合物2小时。反应混合物自行冷却至室温,过滤收集沉淀。所得粗晶体用乙醇-正己烷进行重结晶,得到7.03g目的化合物(熔点257-260℃)。所得化合物(化合物1a)的结构示于表1中。
参考实施例2-32
在表1中列出的化合物2a-32a以与参考实施例1相同方式进行制备,这些化合物的结构也示于表1中。
参考实施例33~53
在表1中列出的化合物33a~53a以与参考实施例1相同方式制备,它们的结构也示于表1中。
Ph=苯基
化合物 | R1 | R2 | R3 | R4 | R5 | -Z- | Y |
1a | H | H | H | H | H | 单键 | -CH2- |
2a | H | CH3 | H | H | H | 单键 | -CH2- |
3a | H | C2H5 | H | H | H | 单键 | -CH2- |
4a | H | OCH3 | H | H | H | 单键 | -CH2- |
5a | H | F | H | H | H | 单键 | -CH2- |
6a | H | Cl | H | H | H | 单键 | -CH2- |
7a | H | Br | H | H | H | 单键 | -CH2- |
8a | H | H | OCH3 | H | H | 单键 | -CH2- |
9a | H | H | F | H | H | 单键 | -CH2- |
10a | H | H | Cl | H | H | 单键 | -CH2- |
11a | H | H | Br | H | H | 单键 | -CH2- |
12a | H | H | H | CH3 | H | 单键 | -CH2- |
13a | H | H | H | Cl | H | 单键 | -CH2- |
14a | H | H | H | CF3 | H | 单键 | -CH2- |
15a | H | OCH3 | OCH3 | H | H | 单键 | -CH2- |
16a | OCH3 | OCH3 | OCH3 | H | H | 单键 | -CH2- |
17a | OCH3 | OCH3 | OCH3 | Br | H | 单键 | -CH2- |
表1(续)实施例1
4-[N-(8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯的制备
将一份3.76g的化合物1a和10ml吡啶溶于30ml无水二氯甲烷中。在冰冷、搅拌下,向其中缓缓滴加5.81克4-[(二乙氧基磷酰)甲基]苯甲酰氯在10ml无水二氯甲烷中的溶液。在室温下继续搅拌10小时,然后用30ml 10%碳酸氢钠水溶液稀释反应混合物,并用氯仿萃取。氯仿层依次用30ml 10%盐酸和30ml水洗涤,并用无水硫酸钠干燥。溶剂在减压下蒸出。残留物用硅胶柱色谱处理(洗脱液∶氯仿∶乙酸乙酯=1∶10),所得粗晶体用乙醇-正己烷重结晶,得到3.79克目的化合物,为无色晶体。这样得到的化合物(化合物1)的结构和熔点示于表2。
实施例2-35
表2中所列化合物2~35以与实施例1相同的方式制备,它们的结构和熔点也示于表2中。
实施例36-66
表2中所列化合物36~66以与实施例1相同的方式制备,它们的结构和熔点也示于表2中。
Ph=苯基
化合物 | R1 | R2 | R3 | R4 | R5 | R6=R7 | Z | Y | Mp(℃) |
1 | H | H | H | H | H | OC2H5 | 单键 | -CH2- | 191-193(乙醇-正己烷) |
2 | H | H | H | H | H | OCH3 | 单键 | -CH2- | 198-200(乙醇-正己烷) |
3 | H | H | H | H | H | OCH(CH3)2 | 单键 | -CH2- | 191-193(乙醇-正己烷) |
4 | H | CH3 | H | H | H | OC2H5 | 单键 | -CH2- | 220-222(乙醇-正己烷) |
5 | H | C2H5 | H | H | H | OC2H5 | 单键 | -CH2- | 226-228(乙醇-正己烷) |
表2(续)
化合物 R1 R2 R3 R4 R5 R6=R7 Z Y Mp(℃) |
217-2196 H OCH3 H H H OC2H5 单键 -CH2- (乙醇-正己烷) |
205-2067 H F H H H OC2H5 单键 -CH2- (乙醇-正己烷) |
198-2008 H Cl H H H OC2H5 单键 -CH2- (乙醇-正己烷) |
209-2109 H Br H H H OC2H5 单键 -CH2- (乙醇-正己烷) |
198-20010 H H OCH3H H OC2H5 单键 -CH2- (乙醇-正己烷) |
216-21811 H H F H H OC2H5 单键 -CH2- (乙醇-正己烷) |
222-22412 H H Cl H H OC2H5 单键 -CH2- (乙醇-正己烷) |
表2(续)
化合物 | R1 | R2 | R3 | R4 | R5 | R6=R7 | Z | Y | Mp(℃) |
13 | H | H | Br | H | H | OC2H5 | 单键 | -CH2- | 224-226(乙醇-正己烷) |
14 | H | H | H | CH3 | H | OC2H5 | 单键 | -CH2- | 235-237(乙醇-正己烷) |
15 | H | H | H | Cl | H | OC2H5 | 单键 | -CH2- | 231-233(乙醇-正己烷) |
16 | H | H | H | CF3 | H | OC2H5 | 单键 | -CH2- | 216-218(乙醇-正己烷) |
17 | H | OCH3 | OCH3 | H | H | OC2H5 | 单键 | -CH2- | 218-220(乙酸乙酯-正己烷) |
18 | OCH3 | OCH3 | OCH3 | H | H | OC2H5 | 单键 | -CH2- | 194-196(乙醇-正己烷) |
19 | OCH3 | OCH3 | OCH3 | Br | H | OC2H5 | 单键 | -CH2- | 217-219(乙醇-正己烷) |
表2(续)
表2(续)
表2(续)
化合物 | R1 | R2 | R3 | R4 | R5 | R6=R7 | Z | Y | Mp(℃) |
34 | H | H | CH | H | Ph | OC2H5 | 单键 | -CH2- | 123-125(乙酸乙酯-正己烷) |
35 | H | H | CH | H | CH3 | OC2H5 | 单键 | -CH2- | 155-157(乙醇-正己烷) |
36 | CH3 | H | H | H | H | OCH3 | 单键 | -CH2- | 2O8-211(乙醇-正己烷) |
37 | CH3 | H | H | H | H | OC2H5 | 单键 | -CH2 | 185-187(乙醇-正己烷) |
38 | OCH3 | H | H | H | H | OC2H5 | 单键 | -CH2- | 211-213(乙醇-正己烷) |
39 | H | H | CH3 | H | H | OC2H5 | 单键 | -CH2- | 206-208(乙醇-正己烷) |
40 | H | H | Cl | H | H | OCH3 | 单键 | -CH2- | 223-225(乙醇-正己烷) |
表2(续)
化合物 | R1 | R2 | R3 | R4 | R5 | R6=R7 | Z | Y | Mp(℃) |
41 | H | H | Cl | H | C2H5 | OC2H5 | 单键 | -CH2- | 88-90(乙酸乙酯-正己烷) |
42 | H | H | Cl | H | H | OCH(CH3)2 | 单键 | -CH2- | 221-223(乙醇正己烷) |
43 | H | H | Cl | H | H | O(CH2)3CH3 | 单键 | -CH2- | 165-167(乙酸乙酯-正己烷) |
44 | H | H | CN | H | H | OC2H5 | 单键 | -CH2- | 246-247(乙醇-正己烷) |
45 | H | H | SPh | H | H | OC2H5 | 单键 | -CH2- | 182-183(乙醇-正己烷) |
46 | H | H | SOPh | H | H | OC2H5 | 单键 | -CH2- | 161-163(乙醇-正己烷) |
47 | H | H | SO2Ph | H | H | OC2H5 | 单键 | -CH2- | 229-231(乙醇-正己烷 |
表2(续)
化合物 | R1 | R2 | R3 | R4 | R5 | R6=R7 | Z | Y | Mp(℃) |
54 | H | H | H | H | H | OCH3 | 单键 | -C2H4- | 183-186(乙醇-正己烷) |
55 | H | H | H | OCH2Ph | H | OC2H5 | 单键 | -C2H4- | 201-203(乙醇-正己烷) |
56 | H | H | H | H | H | OC2H5 | 单键 | -CH=CH- | 182-184(乙醇-正己烷) |
57 | H | H | H | H | H | OCH3 | 单键 | -C3H6- | 216-218(乙醇-正己烷) |
58 | H | H | H | H | H | OC2H5 | 单键 | -C3H6- | 181-183(乙醇-正己烷) |
59 | H | H | H | H | H | OCH(CH3)2 | 单键 | -C3H6- | 169-171(乙酸乙酯-正己烷) |
60 | H | F | H | H | H | OC2H5 | 单键 | -C3H6- | 208-210(乙醇-正己烷) |
Table表2(续)
实施例67-82
化合物 R1 R2 R3 R4 R5 R6=R7 Z Y Mp(℃) |
203-20561 H F H H H OCH3 -O- -CH2- (乙醇-正己烷) |
173-17562 H F H H H OCH(CH3)2 -O- -CH2- (乙醇-正己烷) |
194-19663 H H H Cl H OC2H5 -O- -CH2- (乙醇-正己烷) |
247-25064 H H H NO2 H OC2H5 -O- -CH2- (乙醇-正己烷) |
231-23365 H H H F H OC2H5 单键 -CH2- (乙醇-正己烷) |
205(Doc.)66 H H -CH-CH-CH-CH- H OC2H5 单键 -C2H4- (氯仿-正己烷) |
表3中所列化合物67-82用与实施例1相同的方式制备,它们的结构和熔点地示于表3中。
4-[N-(8H-茚并[1,2-d]噻唑-2-基]氨磺酰]苄基膦酸二乙酯的制备
采用在参考实施例1中所得化合物1a和4-[(二乙氧基磷酰)甲基]苯磺酰氯,重复实施例1中的步骤,得到目的化合物。
熔点:196-198℃(分解)(重结晶溶剂:甲醇-氯仿-正己烷)
实施例84
4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)氨基甲酰基]苄基膦酸二乙酯的制备
采用2-氨基-1-甲基-1H-萘基[1,2-d]-咪唑(市售)和4-[(二乙氧基磷酰基)甲基)苯甲酰氯,重复实施例1的步骤,得到目的化合物。
熔点:173℃(分解)(重结晶溶剂:氯仿-正己烷)。
实施例85
4-[N-(4H-茚并(2,1-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯的制备
采用2-氨基-4H-茚[2,1-d]噻唑和4-[(二乙氧基磷酰基)甲基]苯甲酰氯,重复实施例1的步骤,得到目的化合物。
熔点:190℃(分解)(重结晶溶剂:氯仿-正己烷)。
实施例86
4-[N-(7-氯-8H-茚并[1,2-d]噻唑-2-基)硫代氨基甲酰基]苄基膦酸二乙酯的制备
将一份2.3g在实施例15中得到的化合物和2.2g五硫化二磷悬浮于由20ml无水吡啶和20ml无水苯构成的混合物中。所得悬浮液搅拌回流10小时。反应混合物自然冷却至室温,倒入冰水中,用氯仿萃取。氯仿层用无水硫酸钠干燥,溶剂在减压条件下蒸发脱除。残留物用硅胶柱色谱处理(洗脱液∶氮仿∶甲醇=60∶1),所得粗晶体用乙酸乙酯-正乙烷重结晶,得到0.5g主题化合物,为黄色晶体。
熔点:179.5-180.5℃
除所述实施例中的化合物外,本发明的化合物还包括,例如:
4-[N-(8H-茚并[1,2-d]噻唑-2-基)硫代氨基甲酰基]苄基膦酸二乙酯,
4-[N-(4H-茚并[1,2-d]噻唑-2-基)氨磺酰基]苄基膦酸二乙酯,
4-[N-(4H-茚并[1,2-d]噻唑-2-基)硫代氨基甲酰基]苄基膦酸二乙酯,
4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)硫代氨基甲酰基]苄基膦酸二乙酯,
4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)-氨磺酰基]苄基膦酸二乙酯,
4-[N-(8-氟-4H-[1]苯并吡喃并[4,3-d]噻唑-2-基)硫代氨基甲酰基]苄基膦酸二乙酯,
4-[N-(8-氟-4H-[1]苯并吡喃并[4,3-d]噻唑-2-基)氨磺酰基]苄基膦酸二乙酯,
4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)硫代氨基甲酰基]苄基膦酸二乙酯,
4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)氨磺酰基]苄基膦酸二乙酯,
3-{4-[N-(6-氮-8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苯氧基}丙基膦酸二乙酯,
3-(4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)硫代氨基甲酰基]苯氧基}丙基膦酸二乙酯,
3-{4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)氨磺酰基]苯氧基}丙基膦酸二乙酯,
2-{4-[N-(4H-茚并[2,1-d]噻唑-2-基)氨基甲酰基]苯氧基}乙基膦酸二乙酯,
2-{4-[N-(4H-茚并[2,1-d]噻唑-2-基)硫代氨基甲酰基]苯氧基}乙基膦酸二乙酯,
2-{4-[N-(4H-茚并[2,1-d]噻唑-2-基)氨磺酰基]苯氧基}乙基膦酸二乙酯,
2-{4-[N-(8-氟-4H-[1]苯并吡喃[4,3-d]噻唑-2-基]硫代氨基甲酰基]苯氧基}乙基膦酸二乙酯,
2-{4-[N-(8-氟-4H-[1]苯并吡喃[4,3-d]噻唑-2-基]氨磺酰基]苯氧基}乙基膦酸二乙酯,
2-{4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)氨基甲酰基]苯氧基}乙基膦酸二乙酯,
2-{4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)硫代氨基甲酰基]苯氧基}乙基膦酸二乙酯,
2-{4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)氨磺酰基]苯氧基}乙基膦酸二乙酯,
4-[N-(4H-茚并[2,1-d]噻唑-2-基]-N-甲基氨基甲酰基]苄基膦酸二乙酯,
4-[N-(8-氟-4H-[1]苯并吡喃并[4,3-d]噻唑-2-基)-N-甲基氨基甲酰基]苄基膦酸二乙酯,
4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)-N-甲基氨基甲酰基]苄基膦酸二乙酯,
4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)-N-乙基硫代氨基甲酰基]苄基膦酸二乙酯,
4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)-N-乙基氨磺酰基]苄基膦酸二乙酯,
3-{4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)-N-乙基硫代氨基甲酰基]苯氧基}丙基膦酸二乙酯,
3-{4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)-N-乙基氨磺酰基]苯氧基}丙基膦酸二乙酯,
药理实验实施例1
用具Triton诱导的血脂过高症[用Kuroda等的方法,Biochem.Biophys.Acta,489,119(1977)]的鼠按下述方式确定本发明化合物对血脂过高症的预防和治疗作用。
用5个一组的(实验组)6至7周龄的雄性Wistar鼠进行实验,将300mg/kg Triton(Triton WR1339)的生理盐水溶液施至尾静脉中,同时按100mg/kg剂量给予口服悬浮于0.5%CMC-Na溶液中的试验化合物。作为对照组,给予Triton的5只一组鼠口服0.5%的CMC-Na水溶液。
Triton给药24小时后,从鼠中抽取血样,分别采用CholesterolC-Test Wako和Triglycride G-Test Wako(均可由Wako PureChemical Industries,Ltd获得)测定血浆总胆固醇和甘油三酯量。用测自对照组的值作参考,用下式计算实验组中血浆总胆固醇和甘油三酯的下降率(%):
实验鼠在施以Triton前至完成血样采取止禁食,但可自由获取饮水。
表4示出了结果。
表4
实验化合物(实施例号) | 降低率(%) | |
总胆固醇 | 甘油酯 | |
1 | 55 | 86 |
2 | 45 | 90 |
3 | 35 | 86 |
8 | 30 | 74 |
11 | 78 | 96 |
12 | 64 | 90 |
13 | 50 | 85 |
15 | 42 | 87 |
16 | 46 | 88 |
18 | 29 | 70 |
28 | 46 | 64 |
30 | 68 | 92 |
35 | 58 | 91 |
37 | 48 | 88 |
40 | 37 | 67 |
41 | 44 | 88 |
42 | 46 | 77 |
44 | 35 | 59 |
56 | 25 | 60 |
63 | 42 | 80 |
65 | 44 | 78 |
84 | 52 | 87 |
本发明化合物的制剂实施例如下。
制剂实施例1 片剂的制备
用实施例12中所得的化合物作活性成分,按下述配方制备每片含250mg活性成分的片剂(1000片)。
成分 量(g)
实施例12的化合物 500
乳糖(Japanese Pharmacopeia(JP)产品) 33.5
玉米淀粉(JP) 16.5
羧甲基纤维素钙(JP) 12.5
甲基纤维素(JP) 40
硬脂酸镁 1.5
总量 320.0
按上述配方,将实施例12的化合物、乳糖、玉米淀粉和羧甲基纤维素钙用甲基纤维素水溶液进行充分混合并成粒。成粒的混合物通过24目筛,过筛后的颗粒与硬脂酸镁混合,并压制成片剂。
制剂实施例2 胶囊剂的制备
用实施例1中所得化合物作为活性成分,按下述配方制备各含250mg活性成分的硬质明胶胶囊(1000单位)。
成分 量(g)
实施例1的化合物 250
结晶纤维素(JP) 30
玉米淀粉(JP) 17
滑石(JP) 2
硬脂酸镁(JP) 1
总量 300
因此,按上述配方,各成分仔细分散,所得粉末经混合得到均一的组合物。该组合物填入用于口服给药的适宜尺寸的明胶胶囊壳内,得到目的胶囊剂。
制剂实施例3 颗粒剂的制备
用在实施例30中所得的化合物作活性成分,按下述配方,制得每克颗粒剂含500mg活性成分的颗粒剂(1000g)。
成分 量(g)
实施例30的化合物 500
结晶纤维素(JP) 100
玉米淀粉(JP) 250
乳糖(JP) 100
羧甲基纤维素钙(JP) 40
羟丙基甲基纤维素(JP) 10
总量 1000
这样,按上述配方,将实施例30的化合物、乳糖、玉米淀粉、结晶纤维素和羧甲基纤维素钙完全混合,并用羟丙基甲基纤维素捏合。所得组合物用挤出成粒机成粒,在50℃下干燥2小时,得到目的颗粒剂。
Claims (7)
2.根据权利要求1的膦酸二酯衍生物,其中在式(1)中:
R1、R2、R3和R4相同或不相同,且各自代表氢原子、低级烷基、低级烷氧基、卤代低级烷基、卤素原子或氰基;
R5代表氢原子或低级烷基;
R6和R7各自代表低级烷氧基;
A代表低级亚烷基;
-Z-代表单键或-O-;
Y代表低级亚烷基;且
n为0。
3.根据权利要求2的膦酸二酯衍生物,其中A代表-CH2-。
4.根据权利要求3的膦酸二衍生物,选自
4-[N-(8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,
4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,
4-[N-(7-氯-8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,
4-[N-(8-氟-4H-[1]苯并吡喃并[4,3-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯,和
4-[N-(1-甲基-1H-萘并[1,2-d]咪唑-2-基)氨基甲酰基]苄基膦酸二乙酯。
5.根据权利要求4的膦酸二酯衍生物,为4-[N-(6-氯-8H-茚并[1,2-d]噻唑-2-基)氨基甲酰基]苄基膦酸二乙酯。
6.抗高血脂组合物,包括按权利要求1-5中任一项的膦酸二酯衍生物作为活性成分。
7.权利要求1-5中任一项的膦酸二酯衍生物的应用,用于生产含有所述膦酸二酯衍生物作为活性成分和可药用载体的抗高血脂组合物。
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CN114681454B (zh) * | 2022-03-17 | 2024-05-07 | 江南大学 | 噻唑类化合物在制备抗sars-cov-2新型冠状病毒药物中的应用 |
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EP0273444A2 (en) * | 1986-12-29 | 1988-07-06 | Otsuka Pharmaceutical Factory, Inc. | Use of carboxamide compounds for the preparation of a medicament for treating hyperlipidemia |
GB2220206A (en) * | 1988-06-29 | 1990-01-04 | Otsuka Pharma Co Ltd | Dialkoxyphosphinoylmethyl-benzamide compounds |
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AU523040B2 (en) * | 1978-05-15 | 1982-07-08 | Kanebo Limited | Calcium -antagonistic composition |
US4434162A (en) * | 1981-02-17 | 1984-02-28 | Kanebo, Ltd. | Phosphonic acid ester, pharmaceutical compositions containing the same and method of using the same |
US4822780A (en) * | 1987-07-08 | 1989-04-18 | Otsuka Pharmaceutical Factory, Inc. | Carboxamide compounds |
JPH0745508B2 (ja) * | 1988-06-29 | 1995-05-17 | 株式会社大塚製薬工場 | カルボン酸アミド誘導体 |
JP2584336B2 (ja) * | 1989-05-30 | 1997-02-26 | 株式会社大塚製薬工場 | カルボン酸アミド誘導体 |
ATE188704T1 (de) * | 1992-05-21 | 2000-01-15 | Otsuka Pharma Co Ltd | Phosphonsäurediester-derivat |
-
1994
- 1994-02-08 TW TW083101072A patent/TW260664B/zh active
- 1994-02-10 KR KR1019940703674A patent/KR100296163B1/ko not_active IP Right Cessation
- 1994-02-10 CA CA002118007A patent/CA2118007C/en not_active Expired - Fee Related
- 1994-02-10 EP EP94906377A patent/EP0638581B1/en not_active Expired - Lifetime
- 1994-02-10 CN CN94190067A patent/CN1046733C/zh not_active Expired - Fee Related
- 1994-02-10 DE DE69415436T patent/DE69415436T2/de not_active Expired - Fee Related
- 1994-02-10 DK DK94906377T patent/DK0638581T3/da active
- 1994-02-10 AT AT94906377T patent/ATE174923T1/de not_active IP Right Cessation
- 1994-02-10 JP JP6517889A patent/JP2926273B2/ja not_active Expired - Fee Related
- 1994-02-10 AU AU60107/94A patent/AU660125B2/en not_active Ceased
- 1994-02-10 WO PCT/JP1994/000209 patent/WO1994018212A1/ja active IP Right Grant
- 1994-02-10 ES ES94906377T patent/ES2126097T3/es not_active Expired - Lifetime
-
1995
- 1995-01-12 US US08/318,860 patent/US5480874A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0273444A2 (en) * | 1986-12-29 | 1988-07-06 | Otsuka Pharmaceutical Factory, Inc. | Use of carboxamide compounds for the preparation of a medicament for treating hyperlipidemia |
GB2220206A (en) * | 1988-06-29 | 1990-01-04 | Otsuka Pharma Co Ltd | Dialkoxyphosphinoylmethyl-benzamide compounds |
Also Published As
Publication number | Publication date |
---|---|
CA2118007C (en) | 2003-12-02 |
TW260664B (zh) | 1995-10-21 |
CN1102528A (zh) | 1995-05-10 |
AU6010794A (en) | 1994-08-29 |
US5480874A (en) | 1996-01-02 |
KR950700917A (ko) | 1995-02-20 |
EP0638581A1 (en) | 1995-02-15 |
DK0638581T3 (da) | 1999-08-23 |
KR100296163B1 (ko) | 2001-11-05 |
ES2126097T3 (es) | 1999-03-16 |
WO1994018212A1 (en) | 1994-08-18 |
CA2118007A1 (en) | 1994-08-18 |
DE69415436D1 (de) | 1999-02-04 |
ATE174923T1 (de) | 1999-01-15 |
AU660125B2 (en) | 1995-06-08 |
EP0638581B1 (en) | 1998-12-23 |
DE69415436T2 (de) | 1999-06-02 |
JP2926273B2 (ja) | 1999-07-28 |
EP0638581A4 (en) | 1995-04-12 |
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