CN1066329C - 药物组合物的制备方法 - Google Patents
药物组合物的制备方法 Download PDFInfo
- Publication number
- CN1066329C CN1066329C CN96107466A CN96107466A CN1066329C CN 1066329 C CN1066329 C CN 1066329C CN 96107466 A CN96107466 A CN 96107466A CN 96107466 A CN96107466 A CN 96107466A CN 1066329 C CN1066329 C CN 1066329C
- Authority
- CN
- China
- Prior art keywords
- acid
- formula
- chemical compound
- tert
- decahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
本发明涉及用于治疗或预防病毒感染的药物组合物的制备方法,其包括将式Ⅰ化合物或其药用酸加成盐制成盖伦剂型。
Description
本发明涉及用于治疗或预防病毒感染的药物组合物的制备方法。
式Ⅰ的化合物及其药用酸加成盐为新型的,并具备有价值的药理特性的化合物,具体说,其可以抑制病毒起源的蛋白酶,可用于预防或治疗病毒感染。尤其是由HIV及其它后病毒引起的感染。
本发明的内容包括:式Ⅰ的化合物及前述的盐,以及用作有效的治疗物质,上述化合物及其盐的制备方法,用于该方法中的中间体,含有该化合物及其盐的药物,该化合物及盐在控制和预防疾病中的应用,尤其是用于治疗或预防病毒感染,以及应用该化合物及其盐制备用于治疗或预防病毒感染的药物。
式Ⅰ化合物的药用酸加成盐包括:与无机酸所形成的盐,例如,无机酸包括:氢卤酸、如盐酸或氢溴酸、硫酸、硝酸、磷酸等,或与有机酸所形成的盐,有机酸包括例如:乙酸、枸椽酸、马来酸、富马酸、酒石酸、甲磺酸、对甲苯磺酸等。
根据本发明所述方法,前述的式Ⅰ的化合物及其药用酸加成盐的制备是通过(a)2-[(3-(s)一氨基-2(R)-羟基-4-苯丁基]-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺(如下式)
(其中,R同前述定义)
(c)2-[3(s)-[(L-天冬酰胺酰)氨基]-2(R)-羟基-4-苯丁基]-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺(如下式)与生成苄氧基羰基或2-喹啉基羰基的试剂反应,及(a)如需要,将所得的式Ⅰ的化合物转变成药用酸加成盐。
方法(a)中,式Ⅱ的化合物与式Ⅲ的酸的反应可按肽化学中已知方法进行,因此,当使用式Ⅲ的酸时,反应优选在缩合剂,如羟基苯并三唑和二环已基碳化二亚胺存在下进行,该反应通常在惰性有机溶剂中如醚(如:乙醚,四氢呋喃等)或二甲基甲酰胺,且在低温下,适宜在约-10℃-+5℃间,尤其在约0℃时进行,适用的式Ⅲ酸的反应衍生物为:例如:相应的酰基卤(如:酰基氯),酸酐,混合酸酐;活化酯等,当使用反应衍生物时,反应在有机碱(如:N-乙基吗啉,二异丙基乙胺等)存在下,在惰性有机溶剂如:卤代脂肪烃(如:二氯甲烷等)或醚(如:乙醚、四氢呋喃等)中,和在低温下进行,适宜的温度为-10℃~+5℃,特别是约在0℃时。
方法(b)中式Ⅳ化合物的还原可按已知的羰基还原为羟基的方法进行,因此,还原反应可使用络合金属氢化物,如碱金属硼氢化物特别是硼氢化钠,于适宜的有机溶剂,如醇(如:甲醇、乙醇、丙醇、异丙醇等)中进行。还原通常在室温下进行,按常规方法,可从所得混合物中分离出所需的2(R)-羟基异构体,如层析法等。
方法(c)中,用于生成苄氧基羰基的试剂为苄基氯甲酸酯,用于生成2-喹啉基羰基的试剂是其相应的酸或反应衍生物,如相应的酰基卤(如:酰基氯),酸酐、混合酸酐、活化酯等。式Ⅴ的化合物与前述试剂的反应按与前述方法(a)相同的方法进行。
方法(a)中的式Ⅰ的化合物转变成药用酸加成盐的反应可按常规方法进行,即用无机酸;如氢卤酸(如:盐酸或氢溴酸),硫酸,硝酸,磷酸等;或用有机酸:如:乙酸,柠檬酸、马来酸、富马酸、酒石酸、甲磺酸,对甲苯磺酸等处理该化合物。
用做方法(a)的起始物的式Ⅱ的化合物为新的,其为本发明一项内容。
分子式Ⅱ化合物的制备可按下列方法进行,如:将下式化合物(其中,R1代表氨基保护基(如:叔丁氧基羰基,或苄氧基羰基)。而X代表氯或溴原子〕与下式的N二叔丁基-十氢-(4as,8as)异喹啉-3(s)-羧酰胺反应,
(其中,R1同前述定义)从所得混合物中分离出所需的2(R)-羟基异构体,且从所得的下式化合物中去掉R1基,得到式Ⅱ的化合物。
(其中,R1同前述定义)
当R1代表苄氧基羰基时的式Ⅵ化合物与式Ⅶ化合物的反应可按已知方法进行。如:在惰性有机溶剂中,如卤代脂肪烃(如:二氯甲烷),在碱存在下(如三烷基胺,如三乙基胺等),且方便地在室温下进行。
式Ⅷ的化合物还原为式Ⅸ化合物,随后将所需的2(R)-羟基异构体分离,该反应可按前述之本发明方法(b)进行(如:式Ⅳ化合物还原,并从所得混合物中分离出所需的2(R)-羟基异构体)。
从式Ⅸ化合物断裂去R1基的反应也可按已知方法进行,例如:使用强无机酸如氢卤酸或强有机酸(如:三氟醋酸等),方便地于0℃到室温下进行。可氢化断裂的氨基保护基R1还可以用氢在贵金属催化剂(如钯催化剂如钯-碳)存在下,在该反应条件下呈惰性的有机溶剂或溶剂混合物中进行(如:烷醇如乙醇,异丙醇等)烷基羧酸酯如乙酸乙酯等),可方便地在约室温下进行。
式Ⅱ化合物的另一个制备方法为:首先将下式化合物与前述的式Ⅶ化合物反应,
(其中R1同前述定义)
该反应便于在惰性有机溶剂如醇(如甲醇等),二甲基甲酰胺等中进行,在较高温度下,约60℃~120℃进行,随后,如前述方法,去掉反应产物(前述之式Ⅸ化合物)中的R1基。
方法(b)中用做起始物的分子式Ⅳ的化合物可按下法制备,如:从式Ⅷ化合物中去掉氨基保护基R1,将所得产物与式Ⅲ的酸或其反应衍生物反应,该反应可按与方法(a)类似的方法进行。
方法(c)中用做起始物的式Ⅴ的化合物为新的,其为本发明的另一项内容。
式Ⅴ的化合物可通过从式Ⅰ的化合物中去掉苄氧基羰基R(其中R代表苄氧基羰基或叔丁氧基羰基),得到与式Ⅰ相对应的化合物,但其中R代表叔丁氧基羰基。该R为叔丁氧基羰基的化合物可通过式Ⅱ的化合物与N-(叔丁氧基羰基)-L-天冬酰胺按方法(a)的方法反应制备。上述断裂反应与前述的从式Ⅷ的化合物中断裂R1基的方法类似。
式Ⅲ的起始物及其反应衍生物以及式Ⅵ,Ⅶ,和X的化合物到目前为止尚不属已知化合物或其类似物,其可按与已知化合物类似的方法或按实施例中将要叙述的方法或与其类似方法制备。而方法(c)中所用的试剂通常为已知化合物。
如前所述,式Ⅰ的化合物及其药用酸加成盐抑制病毒起源的蛋白酶,可用于治疗或预防病毒感染,尤其是由HIV及其它后病毒引起的感染。
本发明化合物对HIV蛋白酶的体外抑制由下列试验得到验证。
HIV蛋白酶是从大肠杆菌中得到,该细菌的可溶性提取物经硫酸铵分馏(0~30%)得到部分纯化。蛋白酶活性用保护的六肽,琥珀酰-丝-亮-天冬酰胺-酪-脯-异亮异丁酰胺(S1)或保护的七肽:琥珀酰-缬-丝-谷氨酰胺-天冬酰胺-苯丙-脯-异亮异丁酰胺(S2)为底物测定。底物的断裂可通过分光光度检测N端脯氨酸,计算H-脯-异亮-异丁酰胺的产量来定量。
将1.25mM底物溶于含有0.125mg/ml吐温20的125mM柠檬酸盐缓冲液中(PH5。5)。往80μl该缓冲底物中加10μl不同浓度的试验化合物溶液(溶于甲醇或二甲基亚砜,用含0.1%吐温20的水稀释)和10μl蛋白酶。于37℃进行一段时间消化后,加1ml显色剂(含30μg/ml靛红和1.5mg/ml 2-(4-氯苯甲酰基)苯甲酸的含10%丙酮的乙醇(体积比)进行测定。溶液于水溶中加热,着色的残余物重新溶于1ml含1%焦棓酚、33%水的丙酮(重量/体积/体积)中,用分光光度法在599nm测定溶液的光密度。将试验化合物存在时H-脯-异亮异丁酰胺的生成量与对照品进行比较。利用所用的不同浓度试验化合物的曲线:测定50%抑制(I50)所需的试验化合物浓度。
式Ⅰ化合物的体外抗病毒活性于下列检测中得到证实。
抗HIV活性:
该检测使用生长于C8166细胞(一种人CD4+T淋巴细胞系)中的HILV-Ⅲ(RF株),使用RPMI 1640培养基,含有碳酸氢盐缓冲液、抗生素及10%胎牛血清。
细胞混悬液用10倍于TCD50的病毒感染,于37℃进行吸附90分钟,细胞用培养基洗3次,试验在6ml的组织培养管中进行,每管盛有含2×105感染细胞的1.5ml培养基,根据试验化合物的溶解性,将其溶于水溶性培养基或二甲基亚砜中,并加15μl该溶液于培养管中,培养物于37℃、和空气中含有5%二氧化碳的湿润的环境中孕育72小时,随后将培养物离心,将可分量的上清液用NO nidet P40溶解,并经抗原捕获检测,使用具有抗病毒蛋白24特殊活性的初级抗血清和辣根过氧化物酶检测系统,分光光度法测定所产生的颜色,且对试验物质的浓度画图,测定导致50%保护的浓度(I50)。
为确定抗病毒的选择性,基于染料吸收、代谢或放射标记的氨基酸结合的细胞毒性检测可与上述检测同时进行。
利用式Ⅰ化合物进行上述试验所得结果列于下列表中
表
化合物ⅠR | I50 | ||
HIV蛋白酶的抑制(uM) | 抗HIV活性(nM) | ||
S1 | S2 | 202 | |
苄氧基羰基2-喹啉基羰基 | ≤0.024≤0.033 | ≤0.0027≤0.00037 |
式Ⅰ的化合物及其药用酸加成盐可以药用,(如:以药物制剂的形式)。该药物制剂可以肠道给药:如口服(如:片剂、包衣片剂、糖衣丸剂、硬及软明胶胶囊剂、溶液剂、乳剂或混悬剂),经鼻给药(如鼻喷雾剂)或直肠给药(如:栓剂)。但是也可经非肠道给药,如肌注或静注(如:注射液剂型)。
为了制备片剂、包衣片、糖衣丸及软硬明胶囊,式Ⅰ的化合物及其药用酸加成盐可用药用惰性的,无机或有机赋形剂处理,可使用乳糖,玉米淀粉或其衍生物,滑石,硬脂酸或其盐等做为片剂、糖衣丸、硬明胶胶囊的赋形剂。
软明胶胶囊适宜的赋形剂为:如植物油,蜡、脂肪、半固体和液体多元醇等。
制备溶液剂和糖浆剂适宜的赋形剂有:如水、多元醇、蔗糖、转化糖、葡萄糖等。
制备注射剂适宜的赋形剂有:如水、乙醇、多元醇、甘油、植物油等。
栓剂的适宜赋形剂有:例如:天然的或硬化油、蜡、脂肪、半固体或液体多元醇等。
药用制剂还可含有保鲜剂、助溶剂、增粘物质、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、改变渗透压的盐、缓冲剂、包衣剂或抗氧化剂,还可含有其它有治疗价值的物质。
本发明中,式Ⅰ的化合物及其药用酸加成盐可用于病毒感染的治疗和预防,尤其是逆病毒感染,剂量可在很宽的范围内变化,并可根据具体病例的需要而调整。通常,口服给药每日剂量为约3mg~3g,优选10mg~1g。(如:约每人300mg),优选分为1-3份剂量(可以等分)。当特别指明时,上述的剂量上限可被超出。
下列实施例说明了本发明。
实施例1
将含有561mg 2-〔3(S)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺和372mg N-(苄氧基羰基)-L-天冬酰胺的20ml干燥四氢呋喃溶液于冰盐混合物中冷却,往其中加189mg羟基苯并三唑、161mg N-乙基吗啉和317mg二环己基碳化二亚胺,将混合物搅拌16小时,随后用乙酸乙酯稀释并过滤,滤液用碳酸氢钠水溶液和氯化钠溶液洗,蒸除溶剂,残余物经硅胶层析,用二氯甲烷/甲醇(9∶1)为流动相,从甲醇/乙醚中得到434mg 2-〔3(S)-〔〔N-(苄氧基羰基)-L-天冬酰胺酰基〕氨基〕-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体;MS:m/e 650〔M+H〕+;HMR:δ(a4CH3OH,400MHz):7.33(5H,m,PhCH2O),7.25(2H,m),7.18(2H,m),7.09(1H,m),5.05(2H,s,PhCH2O),4.42(1H,dd,Asn aJ=7.8,6.1),4.22(1H,m,-CH2CHCH(OH)-J=10.7,about 4,about 4),3.85(1H,m,-CHCH(OH)CH2-J=8.0,6.2,about 4),3.02(1H,dd,PhCH(H)CHJ=-13.9,about 4),3.02(1H,dd,leq J=-12.0,small),2.69(1H,dd,PhCH(H)CH-J=-13.9,10.7),2.63(1H,dd,-CH(OH)CH(H)N-J=-12.6,8.0),2.62(1H,dd,H3ax J=about 11,small),2.57(1H,dd,Asn B1 J=-15.2,6.1),2.38(1H,dd,Asn B2 J=-15.2,7.8),2.19(1H,dd,-CH(OH)CH(H)N- J=-12.6,6.2),2.17(1H,dd,1axJ=-12.0,3.2),2.07(1H,m,H4ax J=-12.7,about 11,about 11.5),1.78(1H,m,H4a J4a-4ax=about 11.5,J4a-4eq=small,J4a-8a=small),1.63(1H,m,H8aJ8a-1ax=3.2,J8a-1eq=small,J8a-4a=small),1.35(1H,m,H4eq J=-12.7,small,small),1.30(9H,s,t-butyl),2.0-1.2(8H,m).
用做起始物的2-[3(S)-氨基-2(R)-羟基-4-苯基丁基]-N-叔丁基-十氢-(4as,8as)-异喹啉-3(S)-羧酰胺如下述方法制备。(ⅰ)将含有12.676g(71.6mmol)的1,2,3,4-四氢-3(S)-异喹啉羧酸(Chem.Pharm.Bull,1983,31,312)的200ml90%乙酸混悬液于80℃,于140大气压下,在5%铑-碳上氢化24小时,混合物冷至室温,将催化剂滤除,蒸发滤液,得到的胶状物溶于10ml乙酸乙酯,将其缓慢加到100ml猛烈搅拌的异丙醚中,生成树脂状沉淀。上清液用倾析法除去沉淀用热乙酸乙酯提取,将该热溶液倒入猛烈搅拌的150ml乙醚/异丙醚(1∶1)的混合物中,得到浅灰色固体,过滤收集,用乙醚洗并干燥,得到5.209g十氢异喹啉-3(s)-羧酸的混合物,其中包括:主要为(约65%)为4as,8as异构体,和4aR,8aR异构体(约25%)及大约10%的反向异构体;MS: m/e l84[M+H]+。(ⅱ)将9.036g(49.4mmol)的前述十氢异喹啉-3(S)-羧酸的混合物溶于50ml(50mmol)的1M氢氧化钠溶液中,所得溶液冷至0℃,在冷却保持0~5℃温度下,在1小时内往其中滴加7.40ml(51.87mmol)苄基氯甲酸酯和58.7ml(58.7mmol)1M氢氧化钠溶液,随后将混合物再搅拌2小时,此时混合物升至室温。往其中加100ml乙醚,混合物被过滤,除去不溶的R,R-异构体,滤液的水层被分离出,加浓盐酸调pH1.5~2,得到油状沉淀物,混合物用乙酸乙酯提取两次,每次用100ml,合并的有机相用水洗,无水硫酸钠干燥,蒸发得到油状物,该油状物溶于35ml乙酸乙酯,将2.85ml(25mmol)环己胺加入,过滤收集白色沉淀,通过甲醇/乙酸乙酯几次分级重结晶,得到2.38g 2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(S)-羧酸的环己胺盐:MS:m/e 318[M+H]+。(ⅲ)将2.334g的2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(s)-羧酸的环己胺盐分配于50ml乙酸乙酯和50ml 10%柠檬溶液中,分出有机相,用水洗,过滤,蒸发得到1.87g 2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(S)-羧酸为无色胶状物:MS:m/e 318(M+H)+。(Ⅳ)将含有0.634g(2.0mmol)2-(苄氧基羰基)-十氢-(4as,8as)-异喹啉-3(s)-羧酸的6ml二甲氧基乙烷溶液用0.23g(2.0mmol)的N-羟基琥珀酰亚胺和0.412g(2.0mmol)二环己基碳化二亚胺处理,混合物于室温下搅拌18小时,混合物过滤,蒸发滤液得到0.879g浅黄色油状物,即前述酸的N-羟基琥珀酰亚胺酯,将含有0.828g(2.0mmol)前述的N-羟基琥珀酰亚胺酯的5ml二氯甲烷溶液搅拌,冷至0℃,用0.219g(3.0mmol)叔丁胺处理,混合物于0℃搅拌2小时,随后于室温搅拌4.5小时,混合物随后用2M盐酸,碳酸钠溶液,和氯化钠溶液洗涤,无水硫酸镁干燥,蒸发,残余物溶于20ml乙醚,并过液,蒸发滤液,得到0.712g 2-(苄氧基羰基)-N0-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体;MS:m/e 373[M+H]+。(Ⅴ)将含有0.689g(1.85mmol)2-(苄氧基羰基)-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺的20ml乙醇溶液在室温,大气压下,且有0.01g 10%钯-碳存在下氢化反应18小时,过滤除去催化剂,蒸发除去溶剂,得到一定产率的N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺,为澄清油状物;MS:m/e 239[M+H]+,其未经进一步纯化而用于下一步反应。(Ⅵ)将含有440mg N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺和549mg 3(s)-(苄氧基甲酰胺基)-1,2(s)-环氧-4-苯基丁烷的6ml乙醇溶液于60℃搅拌7小时,再加54mg 3(s)-(苄氧基甲酰胺基)-1,2(s)-环氧-4-苯基丁烷,将该溶液于20℃搅拌16小时。蒸发除去溶剂,残余物经硅胶层析(用乙醚/正己烷/甲醇(47.5∶47.5∶5)做流动相,得到771mg 2-〔3(s)-(苄氧基甲酰胺基)-2(R)-羟基-4-苯基丁基-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体,MS:m/e 536(M+H]+。(Ⅶ)含有747mg 2-[3(s)-(苄氧基甲酰胺基)-2(R)-羟基-4-苯基丁基-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺的40ml乙醇溶液于10%的钯-碳上于20℃,大气压下氢化反应5小时,过滤除去催化剂,蒸发滤液得到561 mg2-〔3(s)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺,米色固体,不经进一步纯化而用于下一步骤。
实施例2
含有154mg 2-〔3(s)-〔(L-天冬酰胺酰基)氨基〕-2(R)-羟基-4-苯基丁基]-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺和52mg喹哪啶酸的6ml干燥四氢呋喃溶液于冰盐混合物中冷却。随后加41mg羟基苯并三唑,35mg N-乙基吗啉和68mg二环己基碳化二亚胺,混合物搅拌64小时,随后用乙酸乙酯稀释,并过滤,滤液用碳酸氢钠水溶液,和氯化钠水溶液洗,蒸发,残余物经硅胶层析,用二氯甲烷/甲醇(9∶1)做流动相,得到50mg M-叔丁基-十氢-2-〔2(R)-羟基-4--苯基-3(s)-〔〔N-(2-喹啉基羰基)-L-天冬酰胺酰基〕氨基〕-丁基〕-(4as,8as)-异喹啉-3(s)-羧酰胺白色固体;MS:m/e671〔M+H〕+;NMR:δ(a4 CH3 OH400MHz);8.52(1H,m),8.18(1H,m),8.14(1H,m),8.02(1H,m),7.84(1H,m),7.69(1H,m),7.18(2H,m),6.90(2H,m),6.72(1H,m), 4.93 (1H, dd, AsnαCH J=6.6,6.8),4.27(1H,m,-CH2CHCH(OH)-J=3.8,3.8,11.0),3.89(1H,m,-CHCH(OH)CH2-J=7.2,6.4,3.8),3.06(1H,dd,H1eqJ=-12.0,3.0),3.02(1H,dd, PhCH(H)CH- J=-14.0,3.8),2.77 (1H, dd,Asn B1 J=-15.6,6.6),2.68(1H,dd,AsnB2J=-15.6,6.8),2.68(1H,dd,PhCH(H)CH- J=-14.0,11.0),about 2.68(1H,dd,-CH(OH)CH(H)N- J=-12.0,7.2)2.63(1H,dd,H3ax J=11.0,2.2),2.22(1H,dd,-CH(OH)CH(H)N- Jax=-12.0,6.4),2.18(1H,dd,H1axJ=-12.0,2.2),2.06(1H,m,H4ax J=-11.0,11.0,11.0),1.78(1H,m,4aJ4a-4ax=11.0,J4a-4eq=about4,J4a-8a=about 4), 1.65(1H,m,8a J8a-1ax=2.2J8a-1eg=3.0 J8a-4a=about 4),1.37(1H,m,H4eqJ=-11.0,2.2,about 4),1.30(9H,s,t-butyl),2.0-1.2(8H,m).
用做起始物的2-〔3(s)-〔(L-天冬酰胺酰基)氨基〕-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺按下列方法制备:
将含有195mg 2-〔3(s)-〔〔N-(苄氧基羰基)-L-天冬酰胺酰基〕氨基〕-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺的20ml乙醇溶液于室温下,大气压下,在10mg 10%的钯-碳上氢化反应18小时,过滤除去催化剂,减压蒸发滤液,得到154mg 2-〔3(s)-〔(L-夫冬酰胺酰基)氨基〕-2-(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺,其不经纯化而用于下步反应。
实施例3
将含有287mg N-(2-喹啉基羰基)-L-天冬酰胺和401mg 2〔3(s)-氨基-2(R)-羟基-4-苯基丁基〕-N-叔丁基-十氢-(4as,8as)-异喹啉-3(s)-羧酰胺(于实施例1(ⅰ)-(Ⅶ)制备)的3ml四氢呋喃溶液冷至-10℃,往其中加163mg 3-羟基-1,2,3-苯并三嗪-4(3H)-酮和220mg二环己基碳化二亚胺,混合物于-10℃搅拌2小时,于20℃搅拌16小时,随后用乙酸乙酯稀释并过滤,滤液用饱和碳酸氢钠溶液和饱和氯化钠溶液洗,并蒸发,残余物经硅胶层析;用含4%(体积)甲醇的二氯甲烷作流动相,得到537mg N-叔丁基-十氢-2-〔2(R)-羟基-4-苯基-3(s)-〔〔N-(2-喹啉基羰基)-L-天冬酰胺酰基〕氨基〕丁基〕-(4as,8as)-异喹啉-3(s)-羧酰胺,其与实例2笫一段中所得到的产物相同。
用做起始物的N-(2-喹啉基羰基)-L-天冬酰胺按下列方法制备:
将含有540mg喹哪啶酸琥珀酰胺酯和300mg L-天冬酰胺单水合物及2ml二甲基甲酰胺的混合物于20℃搅拌96小时,蒸除溶剂,得到的白色固体残余物于10ml二氯甲烷中猛烈搅拌,过滤用二氯甲烷洗,得到431mg N-(2-喹啉基羰基)-L-天冬酰胺,白色固体;MS:m/e 288[M+H]+。
下列实施例介绍了以式Ⅰ的化合物或其药用酸加成盐为活性成分的药物制剂的制备方法:
实施例A
活性成分的水溶液经无菌过滤,温热时与无菌明胶溶液混合,其含有酚做防腐剂。每1,00ml所得溶液含有3.0mg活性成分,150.0mg明胶4.7mg酚及蒸馏水加至1.0ml,混合物在无菌操作条件下充入容量为1.0ml的管形瓶中。
Claims (1)
1.用于治疗或预防病毒感染的药物组合物的制备方法,其包括将式Ⅰ化合物或其药用酸加成盐制成盖伦剂型,其中R为苄氧基羰基或2-喹啉基羰基。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8927913.7 | 1989-12-11 | ||
GB898927913A GB8927913D0 (en) | 1989-12-11 | 1989-12-11 | Amino acid derivatives |
SG120493A SG120493G (en) | 1989-12-11 | 1993-11-02 | N-tert-Butyl-decahydro-2(3-amino-2-hydroxy-4-phenyl-butyl) isoquinoline-3-carboxamide and asparaginyl derivatives thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN90109931A Division CN1034805C (zh) | 1989-12-11 | 1990-12-10 | 氨基酸衍生物的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1138983A CN1138983A (zh) | 1997-01-01 |
CN1066329C true CN1066329C (zh) | 2001-05-30 |
Family
ID=26296345
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96107466A Expired - Lifetime CN1066329C (zh) | 1989-12-11 | 1990-12-10 | 药物组合物的制备方法 |
CN90109931A Expired - Lifetime CN1034805C (zh) | 1989-12-11 | 1990-12-10 | 氨基酸衍生物的制备方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN90109931A Expired - Lifetime CN1034805C (zh) | 1989-12-11 | 1990-12-10 | 氨基酸衍生物的制备方法 |
Country Status (48)
Families Citing this family (120)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6878728B1 (en) | 1999-06-11 | 2005-04-12 | Vertex Pharmaceutical Incorporated | Inhibitors of aspartyl protease |
US20040122000A1 (en) * | 1981-01-07 | 2004-06-24 | Vertex Pharmaceuticals Incorporated. | Inhibitors of aspartyl protease |
US5614533A (en) * | 1987-03-13 | 1997-03-25 | Bio-Mega/Boehringer Ingelheim Research, Inc. | Substituted pipecolinic acid derivatives as HIV protease inhibitors |
USH1649H (en) | 1987-07-31 | 1997-05-06 | Barrish; Joel C. | HIV protease inhibitor combinations |
CA1340588C (en) * | 1988-06-13 | 1999-06-08 | Balraj Krishan Handa | Amino acid derivatives |
GB8927915D0 (en) * | 1989-12-11 | 1990-02-14 | Hoffmann La Roche | Novel alcohols |
US5430041A (en) * | 1991-05-10 | 1995-07-04 | Hoffmann-La Roche Inc. | Amino acid derivatives having antiviral activity |
US5508407A (en) * | 1991-07-10 | 1996-04-16 | Eli Lilly And Company | Retroviral protease inhibitors |
CN1071930A (zh) * | 1991-07-10 | 1993-05-12 | 伊莱利利公司 | 用作治疗艾滋病的人免疫缺陷病毒蛋白酶的抑制剂 |
WO1993008184A1 (en) * | 1991-10-23 | 1993-04-29 | Merck & Co., Inc. | Hiv protease inhibitors |
US5413999A (en) * | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
DE69224703T2 (de) * | 1991-11-08 | 1998-10-15 | Merck & Co Inc | HIV-Protease-Inhibitoren verwendbar in der AIDS-Behandlung |
RU2126794C1 (ru) | 1992-03-11 | 1999-02-27 | Нархекс Лимитед | Аминопроизводные оксо- или гидроксизамещенных гидразинов, способ их получения и фармацевтические композиции для ингибирования ретровирусной протеазы |
US6071895A (en) | 1992-03-11 | 2000-06-06 | Narhex Limited | Polar-substituted hydrocarbons |
US5888992A (en) | 1992-03-11 | 1999-03-30 | Narhex Limited | Polar substituted hydrocarbons |
EP0560268B1 (en) * | 1992-03-13 | 1995-01-04 | Bio-Mega/Boehringer Ingelheim Research Inc. | Substituted pipecolinic acid derivatives as HIV protease inhibitors |
EP1148050A1 (en) * | 1992-05-21 | 2001-10-24 | Monsanto Company | Retroviral protease inhibitors |
US5559256A (en) * | 1992-07-20 | 1996-09-24 | E. R. Squibb & Sons, Inc. | Aminediol protease inhibitors |
KR100336699B1 (ko) | 1992-08-25 | 2002-05-13 | 윌리암스 로저 에이 | 레트로바이러스 프로테아제 저해제로서 유용한히드록시에틸아미노 술폰아미드 |
US5723490A (en) * | 1992-09-08 | 1998-03-03 | Vertex Pharmaceuticals Incorporated | THF-containing sulfonamide inhibitors of aspartyl protease |
IS2334B (is) | 1992-09-08 | 2008-02-15 | Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) | Aspartyl próteasi hemjari af nýjum flokki súlfonamíða |
US5783701A (en) * | 1992-09-08 | 1998-07-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
TW372972B (en) * | 1992-10-23 | 1999-11-01 | Novartis Ag | Antiretroviral acyl compounds |
US5380849A (en) * | 1992-11-09 | 1995-01-10 | Merck & Co., Inc. | Process for optically pure decahydroisoqiunolines |
US5430150A (en) * | 1992-12-16 | 1995-07-04 | American Cyanamid Company | Retroviral protease inhibitors |
US5484926A (en) | 1993-10-07 | 1996-01-16 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
US5846993A (en) * | 1992-12-22 | 1998-12-08 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
MX9308025A (es) * | 1992-12-22 | 1994-08-31 | Lilly Co Eli | Compuestos inhibidores de la proteasa del virus dela inmunodeficiencia humana, procedimiento para supreparacion y formulacion farmaceutica que los contiene. |
MX9308016A (es) * | 1992-12-22 | 1994-08-31 | Lilly Co Eli | Compuestos inhibidores de la proteasa del virus de la inmunodeficiencia humana, procedimiento para su preparacion y formulacion farmaceutica que los contiene. |
US5491166A (en) * | 1992-12-22 | 1996-02-13 | Eli Lilly And Company | Inhibitors of HIV protease useful for the treatment of AIDS |
US5434265A (en) * | 1992-12-22 | 1995-07-18 | Eli Lilly And Company | Inhibitors of HIV protease |
US5733906A (en) * | 1993-10-12 | 1998-03-31 | Eli Lilly And Company | Inhibitors of HIV Protease useful for the treatment of Aids |
WO1994017096A1 (en) * | 1993-01-17 | 1994-08-04 | Schering Corporation | Peptides having anti-hiv activity |
US5939430A (en) * | 1993-02-22 | 1999-08-17 | Merrell Pharmaceuticals Inc. | Combinations of retroviral inhibitors |
US5455353A (en) * | 1993-03-24 | 1995-10-03 | Hoffmann-La Roche Inc. | 4-(benzyl-2-oxo-oxazolidin-5 ylmethyl)N tertbutyl-decahydroisoquinoline-3-carboxamides |
ES2125077T3 (es) | 1993-07-15 | 1999-02-16 | Hoffmann La Roche | Procedimiento de obtencion de una n-tert-butilamida. |
AU8074894A (en) * | 1994-02-02 | 1995-08-21 | Eli Lilly And Company | Hiv protease inhibitors and intermediates |
CN1146201A (zh) * | 1994-03-07 | 1997-03-26 | 沃泰克斯药物股份有限公司 | 用作天冬氨酰蛋白酶抑制剂的磺胺衍生物 |
US5527829A (en) * | 1994-05-23 | 1996-06-18 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
US5470979A (en) * | 1994-07-01 | 1995-11-28 | American Cyanamid Company | Asymmetric synthesis of bicyclic amino acid esters |
US5591885A (en) * | 1994-09-23 | 1997-01-07 | Hoffman-La Roche Inc. | Process for the preparation of halogenated α-aminoketone compounds |
US5523463A (en) * | 1994-09-23 | 1996-06-04 | Hoffmann-La Roche Inc. | Method of producing halogenated and alpha-aminoalchohols |
US5691372A (en) * | 1995-04-19 | 1997-11-25 | Vertex Pharmaceuticals Incorporated | Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease |
TR199701541T1 (xx) * | 1995-06-06 | 1998-03-21 | F.Hoffmann-La Roche Ag | Proteinaz engelleyici ve tekli gliserid i�eren farmas�tik bile�im. |
US6008228A (en) * | 1995-06-06 | 1999-12-28 | Hoffman-La Roche Inc. | Pharmaceutical compositions containing proteinase inhibitors |
US6004957A (en) * | 1995-06-07 | 1999-12-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
AU759386B2 (en) * | 1995-06-29 | 2003-04-10 | Abbvie Inc. | Use of Ritonavir (ABT-538) for improving the pharmacokinetics of drugs metabolized by cytochrome P450 in a method of treating AIDS |
US6037157A (en) | 1995-06-29 | 2000-03-14 | Abbott Laboratories | Method for improving pharmacokinetics |
EP0861085B1 (en) | 1995-11-13 | 2005-07-20 | Vitaleech Bioscience N.V. | Anti-viral isolates obtained from leeches |
US5914332A (en) | 1995-12-13 | 1999-06-22 | Abbott Laboratories | Retroviral protease inhibiting compounds |
US5883252A (en) * | 1996-01-26 | 1999-03-16 | Vertex Pharmaceuticals Incorporated | Aspartyl protease inhibitors |
US5587481A (en) * | 1996-02-20 | 1996-12-24 | The Monsanto Company | Preparation of (S)-decahydroisoquinoline-3-carboxylic acid t-butylamide |
EP0823424A1 (de) * | 1996-08-09 | 1998-02-11 | F. Hoffmann-La Roche Ag | Verfahren zur Herstellung von Chinargin |
US5914404A (en) * | 1996-08-09 | 1999-06-22 | Hoffmann-La Roche Inc. | Process for the preparation of quinargine |
US5705647A (en) * | 1996-09-05 | 1998-01-06 | Agouron Pharmaceuticals, Inc. | Intermediates for making HIV-protease inhibitors |
US5962725A (en) | 1996-09-05 | 1999-10-05 | Agouron Pharmaceuticals, Inc. | Intermediate compounds useful for making HIV protease inhibitors such as nelfinavir |
US5925759A (en) | 1996-09-05 | 1999-07-20 | Agouron Pharmaceuticals, Inc. | Methods of making HIV-protease inhibitors and intermediates for making HIV-protease inhibitors |
US6232333B1 (en) | 1996-11-21 | 2001-05-15 | Abbott Laboratories | Pharmaceutical composition |
ATE236880T1 (de) | 1996-12-11 | 2003-04-15 | Hoffmann La Roche | Verfahren zur herstellung gemischter anhydride |
US6001851A (en) * | 1997-03-13 | 1999-12-14 | Agouron Pharmaceuticals, Inc. | HIV protease inhibitors |
US6084107A (en) * | 1997-09-05 | 2000-07-04 | Agouron Pharmaceuticals, Inc. | Intermediates for making HIV-protease inhibitors |
US6143742A (en) * | 1997-12-11 | 2000-11-07 | Fuisz Technologies Ltd | Treatment for necrotizing infections |
US6436989B1 (en) * | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
FR2779653B1 (fr) * | 1998-06-11 | 2002-12-20 | Inst Nat Sante Rech Med | Utilisation de composes modulateurs du proteasome en therapie |
AP1717A (en) | 1998-06-19 | 2007-01-30 | Vertex Pharma | Sulfonamide inhibitors of aspartyl protease. |
KR100277723B1 (ko) | 1998-12-14 | 2001-01-15 | 남창우 | 광학적으로 순수한 데카하이드로이소퀴놀린카르복사미드의 연속제조공정 |
US7115584B2 (en) * | 1999-01-22 | 2006-10-03 | Emory University | HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine |
US7635690B2 (en) * | 1999-01-22 | 2009-12-22 | Emory University | HIV-1 mutations selected for by β-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine |
US6765019B1 (en) | 1999-05-06 | 2004-07-20 | University Of Kentucky Research Foundation | Permeable, water soluble, non-irritating prodrugs of chemotherapeutic agents with oxaalkanoic acids |
CN101361723B (zh) * | 1999-06-04 | 2013-11-06 | Abbvie公司 | 改进的药物制剂 |
AU6109500A (en) * | 1999-07-20 | 2001-02-05 | Merck & Co., Inc. | Alpha-hydroxy-gamma-(((carbocyclic-or heterocyclic-substituted)amino)carbonyl)alkanamide derivatives and uses thereof |
US6589962B1 (en) | 1999-07-20 | 2003-07-08 | Merck & Co., Inc. | Alpha-hydroxy-gamma-[[(carbocyclic-or heterocyclic-substituted)amino]carbonyl]alkanamide derivatives and uses thereof |
EP1242426B1 (en) | 1999-11-24 | 2007-10-31 | Merck & Co., Inc. | Gamma-hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as hiv protease inhibitors |
IT1313682B1 (it) * | 1999-11-25 | 2002-09-09 | Archimica Spa | Procedimento per la preparazione di (s)-n-terbutil-1,2,3,4-tetraidroisochinolin-3-carbossiammide. |
ATE395049T1 (de) | 2000-01-19 | 2008-05-15 | Abbott Lab | Verbesserte pharmazeutische zusammensetzungen von hiv-proteasehemmern |
AU2001259817A1 (en) | 2000-05-04 | 2001-11-12 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, The National Institutes Of Health | Methods of and compounds for inhibiting calpains |
WO2003079972A2 (en) | 2002-02-22 | 2003-10-02 | New River Parmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
IT1318986B1 (it) * | 2000-10-09 | 2003-09-19 | Archimica S P A Ora Clariant L | Procedimento per la preparazione di (s)-n-terbutil-1,2,3,4-tetraidroisochinolin-3-carbossiammide. |
GB0028483D0 (en) | 2000-11-22 | 2001-01-10 | Hoffmann La Roche | Hydroxyethylamine HIV protease inhibitors |
US20030191121A1 (en) * | 2001-08-09 | 2003-10-09 | Miller Ross A. | Piperazine carboxamide intermediates of HIV protease inhibitors and processes for their preparation |
AU2002359721A1 (en) | 2001-12-19 | 2003-07-09 | Bristol-Myers Squibb Company | Pichia pastoris formate dehydrogenase and uses therefor |
US20040067216A1 (en) * | 2002-02-22 | 2004-04-08 | Karki Shyam B. | Hiv protease inhibitors supported on cation exchange resins for oral administration |
US7157489B2 (en) * | 2002-03-12 | 2007-01-02 | The Board Of Trustees Of The University Of Illinois | HIV protease inhibitors |
JP2005529953A (ja) * | 2002-06-17 | 2005-10-06 | サネシス ファーマシューティカルズ, インコーポレイテッド | アスパルチルプロテアーゼインヒビター |
US7115652B2 (en) * | 2002-06-17 | 2006-10-03 | Sunesis Pharmaceuticals, Inc. | Aspartyl protease inhibitors |
EA015349B1 (ru) * | 2003-07-11 | 2011-06-30 | Ф. Хоффманн-Ля Рош Аг | Твёрдая разовая пероральная фармацевтическая дозированная форма саквинавирмезилата и способ её изготовления |
EP1604662A1 (en) * | 2004-06-08 | 2005-12-14 | Santhera Pharmaceuticals (Deutschland) Aktiengesellschaft | 1-[(3R)-Amino-4-(2-fluoro-phenyl)-butyl]-pyrrolidine-(2R)-carboxylic acid benzyl amine derivatives and related compounds as dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment of type 2 diabetes mellitus |
ME01945B (me) | 2004-07-27 | 2011-12-31 | Gilead Sciences Inc | Nukleozid-fosfonatni konjugati kao sredstva protiv hiv-a |
WO2006134612A1 (en) * | 2005-06-16 | 2006-12-21 | Hetero Drugs Limited | A process for the preparation of saquinavir using novel intermediate |
US8598364B2 (en) | 2007-03-12 | 2013-12-03 | Nektar Therapeutics | Oligomer-protease inhibitor conjugates |
CA2692101A1 (en) * | 2007-06-29 | 2009-01-08 | Gilead Sciences, Inc. | Combination of 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and a compound that inhibits a ugt pathway or ugt metabolism |
SG182228A1 (en) * | 2007-06-29 | 2012-07-30 | Gilead Sciences Inc | Therapeutic compositions and uses thereof |
EP2203420A1 (en) * | 2007-09-25 | 2010-07-07 | Merck Sharp & Dohme Corp. | Hiv protease inhibitors |
WO2009114151A1 (en) * | 2008-03-12 | 2009-09-17 | Nektar Therapeutics | Oligomer-amino acid and olgomer-atazanavir conjugates |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
NZ593110A (en) | 2008-12-09 | 2013-06-28 | Gilead Sciences Inc | pteridinone derivatives as MODULATORS OF TOLL-LIKE RECEPTORS |
NZ617066A (en) * | 2008-12-23 | 2015-02-27 | Gilead Pharmasset Llc | Nucleoside analogs |
CA2748057C (en) | 2008-12-23 | 2018-07-03 | Pharmasset, Inc. | Nucleoside phosphoramidates |
EP2671888A1 (en) | 2008-12-23 | 2013-12-11 | Gilead Pharmasset LLC | 3',5'-cyclic nucleoside phosphate analogues |
US8497383B2 (en) | 2009-05-27 | 2013-07-30 | Merck Sharp & Dohme Corp. | HIV protease inhibitors |
US20120108501A1 (en) | 2009-06-12 | 2012-05-03 | Nektar Therapeutics | Protease Inhibitors |
DE102010004957A1 (de) | 2010-01-14 | 2011-07-21 | Universitätsklinikum Jena, 07743 | Biologisch wirksame Moleküle zur Beeinflussung von Virus-, Bakterien-, Parasiten-infizierten Zellen und/oder Tumorzellen und Verfahren zu deren Anwendung |
US20110223131A1 (en) | 2010-02-24 | 2011-09-15 | Gilead Sciences, Inc. | Antiviral compounds |
CL2011000716A1 (es) | 2010-03-31 | 2012-04-20 | Gilead Pharmasset Llc | Formas cristalinas 1 6 de (s)-isopropil-2-(((s)-(((2r.3r.4r.5r)-5-(2,4-dioxo-3,4-dihidropirimidin-1(2h)-il)-4-fluoro-3-hidroxi-4-metil tetrahidrofuran-2-il)metoxi)(fenoxi)fosforil)amino)propanoato; composicion y combinacion farmaceutica; y su uso para tratar una infeccion por el virus de la hepatitis c. |
US9079834B2 (en) | 2010-10-28 | 2015-07-14 | Merck Canada Inc. | HIV protease inhibitors |
EP2392926A1 (en) | 2011-02-09 | 2011-12-07 | Roche Diagnostics GmbH | Urinary biomarkers in HIV infected subjects |
US9133157B2 (en) | 2011-10-26 | 2015-09-15 | Merck Canada Inc. | HIV protease inhibitors |
WO2013105118A1 (en) | 2012-01-10 | 2013-07-18 | Council Of Scientific & Industrial Research | A process for synthesis of syn azido epoxide and its use as intermediate the synthesis of amprenavir & saquinavir |
AU2013315833A1 (en) | 2012-09-11 | 2015-03-05 | Merck Canada Inc. | HIV protease inhibitors |
WO2014068265A1 (en) | 2012-10-29 | 2014-05-08 | Cipla Limited | Antiviral phosphonate analogues and process for preparation thereof |
WO2015013835A1 (en) | 2013-07-31 | 2015-02-05 | Merck Sharp & Dohme Corp. | Piperazine derivatives as hiv protease inhibitors |
US9834526B2 (en) | 2013-12-19 | 2017-12-05 | Merck Sharp & Dohme Corp. | HIV protease inhibitors |
EP3083609B1 (en) | 2013-12-19 | 2018-08-15 | Merck Sharp & Dohme Corp. | Hiv protease inhibitors |
WO2015134366A1 (en) | 2014-03-06 | 2015-09-11 | Merck Sharp & Dohme Corp. | Hiv protease inhibitors |
US10138255B2 (en) | 2014-03-10 | 2018-11-27 | Merck Sharp & Dohme Corp. | Piperazine derivatives as HIV protease inhibitors |
WO2016001907A1 (en) | 2014-07-02 | 2016-01-07 | Prendergast Patrick T | Mogroside iv and mogroside v as agonist/stimulator/un-blocking agent for toll-like receptor 4 and adjuvant for use in human/animal vaccine and to stimulate immunity against disease agents. |
US11116774B2 (en) | 2014-07-11 | 2021-09-14 | Gilead Sciences, Inc. | Modulators of toll-like receptors for the treatment of HIV |
US9738664B2 (en) | 2014-10-29 | 2017-08-22 | Wisconsin Alumni Research Foundation | Boronic acid inhibitors of HIV protease |
WO2017048727A1 (en) | 2015-09-15 | 2017-03-23 | Gilead Sciences, Inc. | Modulators of toll-like recptors for the treatment of hiv |
WO2021209563A1 (en) | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0190058A1 (fr) * | 1985-01-07 | 1986-08-06 | Adir | Nouveaux dérivés peptidiques à structure polycyclique azotée, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
EP0282374A1 (fr) * | 1987-02-13 | 1988-09-14 | Adir Et Compagnie | Nouveaux dérivés peptidiques à structure polycyclique azotée, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB933968A (en) * | 1960-10-26 | 1963-08-14 | May & Baker Ltd | New phthalimide derivatives |
US4123543A (en) * | 1971-09-16 | 1978-10-31 | Ab Kabi | Derivatives of substituted indoline lactans with effect on the central nervous system |
US3901897A (en) * | 1972-10-05 | 1975-08-26 | Squibb & Sons Inc | 1,2,3,4,4a,5,6,7-octahydro-7-aryl-isoquinolines and derivatives thereof |
US4329473A (en) * | 1979-06-01 | 1982-05-11 | Almquist Ronald G | Oxoalkanoic acid derivatives as inhibitors of angiotensin converting enzyme |
SE421551B (sv) * | 1980-03-26 | 1982-01-04 | Sandvik Ab | Borrverktyg for rotations- och/eller slagborrning |
US4470973A (en) * | 1982-07-19 | 1984-09-11 | E. R. Squibb & Sons, Inc. | Substituted peptide compounds |
US4812442A (en) * | 1984-05-29 | 1989-03-14 | Merck & Co., Inc. | Tripeptide renin inhibitors |
AT383762B (de) * | 1985-12-23 | 1987-08-25 | Plansee Metallwerk | Verfahren zur herstellung mehrkomponentiger, kongruent erschmelzender lotmaterialien |
CA1286989C (en) * | 1985-12-26 | 1991-07-30 | A. Arthur Gottlieb | Immunoamplifiers and related compositions |
WO1988000939A1 (en) * | 1986-07-25 | 1988-02-11 | Banyu Pharmaceutical Co., Ltd. | Optically active amino alcohol derivatives and process for their preparation |
US4851387A (en) * | 1986-10-14 | 1989-07-25 | Banyu Pharmaceutical Co., Ltd. | 5-substituted amino-4-hydroxy-pentanoic acid derivatives and their use |
US4863905A (en) * | 1987-02-04 | 1989-09-05 | Warner-Lambert Company | Renin inhibitors II |
DE3717631A1 (de) * | 1987-05-26 | 1988-12-15 | Merck Patent Gmbh | Aminosaeurederivate |
DE3733296A1 (de) * | 1987-10-02 | 1989-04-20 | Merck Patent Gmbh | Aminosaeurederivate |
IL89900A0 (en) * | 1988-04-12 | 1989-12-15 | Merck & Co Inc | Hiv protease inhibitors useful for the treatment of aids and pharmaceutical compositions containing them |
CA1340588C (en) * | 1988-06-13 | 1999-06-08 | Balraj Krishan Handa | Amino acid derivatives |
DE4033062A1 (de) * | 1990-10-18 | 1992-04-23 | Merck Patent Gmbh | Aminosaeurederivate |
GB8927915D0 (en) * | 1989-12-11 | 1990-02-14 | Hoffmann La Roche | Novel alcohols |
-
1989
- 1989-12-11 GB GB898927913A patent/GB8927913D0/en active Pending
-
1990
- 1990-11-12 IN IN905MA1990 patent/IN172553B/en unknown
- 1990-11-13 EG EG68190A patent/EG19722A/xx active
- 1990-11-14 ZW ZW174/90A patent/ZW17490A1/xx unknown
- 1990-11-15 MT MT1075A patent/MTP1075B/xx unknown
- 1990-11-19 MW MW88/90A patent/MW8890A1/xx unknown
- 1990-11-19 US US07/615,534 patent/US5196438A/en not_active Expired - Lifetime
- 1990-11-21 SK SK5765-90A patent/SK280249B6/sk unknown
- 1990-11-21 CA CA002030433A patent/CA2030433C/en not_active Expired - Lifetime
- 1990-11-21 CZ CS905765A patent/CZ280558B6/cs not_active IP Right Cessation
- 1990-12-04 FI FI905983A patent/FI100883B/fi active IP Right Grant
- 1990-12-04 MC MC902159A patent/MC2195A1/xx unknown
- 1990-12-04 ZA ZA909743A patent/ZA909743B/xx unknown
- 1990-12-04 RO RO146474A patent/RO107942B1/ro unknown
- 1990-12-05 IL IL9655090A patent/IL96550A/en not_active IP Right Cessation
- 1990-12-05 HU HU908076A patent/HU207298B/hu unknown
- 1990-12-06 MX MX023619A patent/MX173630B/es unknown
- 1990-12-07 IS IS3651A patent/IS1803B/is unknown
- 1990-12-07 KR KR90020078A patent/KR970005912B1/ko not_active IP Right Cessation
- 1990-12-07 AU AU67876/90A patent/AU634319B2/en not_active Expired
- 1990-12-07 SI SI9012315A patent/SI9012315B/sl unknown
- 1990-12-10 BG BG93425A patent/BG51452A3/xx unknown
- 1990-12-10 DE DE69019481T patent/DE69019481T2/de not_active Expired - Lifetime
- 1990-12-10 DZ DZ900221A patent/DZ1467A1/fr active
- 1990-12-10 JP JP2409792A patent/JP2807093B2/ja not_active Expired - Lifetime
- 1990-12-10 GB GB9026776A patent/GB2239016B/en not_active Expired - Lifetime
- 1990-12-10 LU LU90014C patent/LU90014I2/fr unknown
- 1990-12-10 CN CN96107466A patent/CN1066329C/zh not_active Expired - Lifetime
- 1990-12-10 NO NO905322A patent/NO176566C/no not_active IP Right Cessation
- 1990-12-10 ES ES90123697T patent/ES2072959T3/es not_active Expired - Lifetime
- 1990-12-10 EP EP90123697A patent/EP0432695B1/en not_active Expired - Lifetime
- 1990-12-10 CN CN90109931A patent/CN1034805C/zh not_active Expired - Lifetime
- 1990-12-10 DK DK90123697.6T patent/DK0432695T3/da active
- 1990-12-10 AT AT90123697T patent/ATE122661T1/de active
- 1990-12-10 MA MA22289A patent/MA22014A1/fr unknown
- 1990-12-10 PT PT96145A patent/PT96145B/pt not_active IP Right Cessation
- 1990-12-10 CU CU90197A patent/CU22305A3/es unknown
- 1990-12-10 IE IE445390A patent/IE67523B1/en not_active IP Right Cessation
- 1990-12-10 BR BR909006264A patent/BR9006264A/pt not_active Application Discontinuation
- 1990-12-10 DE DE1996175051 patent/DE19675051I2/de active Active
- 1990-12-11 RU SU904831985A patent/RU2071470C1/ru active
- 1990-12-11 OA OA59914A patent/OA09334A/xx unknown
- 1990-12-11 PL PL90288201A patent/PL165225B1/pl unknown
-
1991
- 1991-08-28 ID IDP14891A patent/ID1018B/id unknown
-
1993
- 1993-03-12 HR HRP-2315/90A patent/HRP930341B1/xx not_active IP Right Cessation
- 1993-08-16 LT LTIP862A patent/LT3682B/lt not_active IP Right Cessation
- 1993-11-02 SG SG120493A patent/SG120493G/en unknown
- 1993-11-25 HK HK1290/93A patent/HK129093A/xx not_active IP Right Cessation
-
1995
- 1995-06-16 HU HU95P/P00230P patent/HU211342A9/hu unknown
- 1995-08-11 GR GR950402228T patent/GR3017114T3/el unknown
-
1996
- 1996-05-24 LV LV960153A patent/LV5738B4/xx unknown
-
1997
- 1997-03-07 NL NL970013C patent/NL970013I2/nl unknown
- 1997-10-06 FI FI973895A patent/FI973895A/fi unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0190058A1 (fr) * | 1985-01-07 | 1986-08-06 | Adir | Nouveaux dérivés peptidiques à structure polycyclique azotée, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
EP0282374A1 (fr) * | 1987-02-13 | 1988-09-14 | Adir Et Compagnie | Nouveaux dérivés peptidiques à structure polycyclique azotée, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1066329C (zh) | 药物组合物的制备方法 | |
US5296604A (en) | Proline derivatives and compositions for their use as inhibitors of HIV protease | |
US4294832A (en) | Tetrahydroisoquinoline compounds and a pharmaceutical composition thereof | |
RU2130016C1 (ru) | Производные сукциноиламиногидроксиэтиламиносульфонамида, фармацевтическая композиция, способ ингибирования ретровирусной протеазы, способ лечения ретровирусной инфекции, способ лечения вич-инфекции | |
KR910003348B1 (ko) | 펩티딜아미노 디올 | |
JPH02191243A (ja) | 製剤学的活性を有する化合物 | |
KR0173034B1 (ko) | 선택적 트롬빈 억제제 | |
US6348448B1 (en) | Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine protease inhibitors | |
DE60221508T2 (de) | Aminosäurederivate als hiv-protease-inhibitoren | |
JPS6323897A (ja) | タフトシン類似体、その製法及び医薬組成物 | |
JPH11503422A (ja) | プロテアーゼを阻害するコハク酸誘導体 | |
CN1172486A (zh) | 作为人类白细胞弹性蛋白酶抑制剂使用的脯氨酸衍生物 | |
CN1168673A (zh) | 具有n-末端磺酰基或氨基磺酰基的新颖二肽对-脒基苄基酰胺 | |
EP1165492A1 (en) | Hydroxyphenyl derivatives with hiv integrase inhibitory properties | |
JPH0347196A (ja) | 酵素阻害剤 | |
JPH07502255A (ja) | 抗ウイルス化合物類 | |
EP0261017B1 (fr) | Esters d'aminoacides d'alcools cycloaliphatiques, procédé de préparation et utilisation comme médicaments | |
JPH04334349A (ja) | 3−クロロ−2−クロロメチル−1−プロペンから誘導されたレトロウイルスのプロテアーゼ阻害因子 | |
JPH02218654A (ja) | 安息香酸誘導体、それらの製造方法およびそれらを含有する薬剤 | |
US6362165B1 (en) | Hydroxyphenyl derivatives with HIV integrase inhibitory properties | |
JPH04275263A (ja) | キラルα−アミノアルデヒドからの、ヒドロキシエステル、ヒドロキシアミド及びラクトン化合物の立体制御された製造法 | |
CN112500308A (zh) | 金色酰胺醇酯及其氟化衍生物及制备方法和应用 | |
US4322555A (en) | Nonaprenylamine derivatives | |
EP0575500A1 (en) | Hiv protease inhibitors | |
KR100367379B1 (ko) | 항바이러스제로유용한마크로시클릭디플루오로스타톤유도체 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C06 | Publication | ||
PB01 | Publication | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
OR01 | Other related matters | ||
C17 | Cessation of patent right | ||
CX01 | Expiry of patent term |
Expiration termination date: 20101210 Granted publication date: 20010530 |