CN1205689A - 新的2,3,5-三甲基-4-羟基-n-酰苯胺衍生物及其制备方法与应用 - Google Patents
新的2,3,5-三甲基-4-羟基-n-酰苯胺衍生物及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及了新的如通式Ⅰ所示的2,3,5-三甲基-4-羟基-N-酰苯胺衍生物,其中,优选R1是苯基,R2是H,R3是C12H25,且A是硫原子;本发明还涉及该类化合物的制备方法,以及至少含有一种该类化合物作为活性组分的药物组合物;并且还公开了这类衍生物在成高血胆固醇症和动脉粥样硬化疾病治疗药物制备方面的应用。
Description
本发明涉及新的N-酰苯胺衍生物及其制备方法与在治疗人体疾病中的应用。
本发明还涉及这些衍生物在用于治疗血胆固醇过多症和动脉粥状硬化症的药物制备中的应用。
饮食中的胆固醇是以游离胆固醇的形式被肠道细胞吸收,随后在血清ACTA酶(酰基-CoA:胆固醇O-酰基转移酶)的作用下酯化。对ACTA的抑制可以防止胆固醇的肠道吸收及其在动脉组织内的堆积。另外,经氧化后的低密度脂蛋白(LDL)可被清除剂受体捕获,进而形成起泡细胞,这种细胞是动脉粥样硬化蚀斑的起始位点(D.Steinberg等人,英国,J.Med.320,915-924,1989)。
本发明的目的是制得新的具有降低血胆固醇作用和抗氧化作用的衍生物。该衍生物对于LDL的数量和性质都产生影响,以便降低LDL致动脉粥样硬化的可能性及其对血管壁造成的长效有害作用。
本发明化合物如通式1所示:其中:
·R1和R2,二者相同或不同,彼此独立地代表:-氢-直链或支链的C1-C6烷基-芳基,例如苯基、萘基或吡啶基,这些基团视具体情况而定被一个或多个C1-C4烷基、C1-C4烷氧基、羟基或卤素基团取代
·R3表示直链或支链的C6-C15烷基链,或视具体情况而定被一个或多个C1-C4烷基、C1-C4烷氧基、羟基或卤素基团取代的苯基
·A代表氧原子或硫原子或次硫酸基。
由于通式Ⅰ所示的化合物可能含有不对称中心,所以本发明包括该类化合物的全部立体异构体和对映体及其混合物。
通式Ⅰ所示化合物可以用于制备药物组合物或药物,这些药物可用于治疗高血胆固醇症或动脉粥样硬化疾病。
最后,本发明还涉及通式Ⅰ化合物的制备方法。
通式Ⅰ所示化合物可以根据下列方法得到(反应流程图Ⅰ):方法A:a)将2,3,6-三甲基-4-氨基苯酚盐酸化物与α-卤代酰卤Ⅱ反应,反应是在含碱例如三乙胺的条件下进行,反应得到化合物Ⅲ;其中Hal和Hal’代表溴或氯,R1和R2与上述定义相同。b)将化合物Ⅱ与衍生物Ⅳ反应,反应是在钠/甲醇或叔丁醇钾/叔丁醇介质中进行,得到化合物Ⅰ;其中R3和A与上述定义相同。方法B:
-将2,3,6-三甲基-4-氨基苯酚盐酸化物与α-卤代酸Ⅴ反应,反应在活化剂和碱共存条件下进行,得到化合物Ⅲ,随后按照与方法A-b相同的步骤进一步反应;其中Hal、R1和R2基团与上述定义相同;所用活化剂例如是二环己基碳化二亚胺或2氯-1-甲基碘化吡啶;所用碱例如是三乙胺。方法C:
将2,3,6-三甲基-4-氨基苯酚盐酸化物与衍生物Ⅳ反应,反应在活化剂和碱共存的条件下进行,得到化合物Ⅰ;其中R1、R2、R3和A基团与上述定义相同;所用的活化剂例如是二环己基碳化二亚胺或2-氯-1-甲基碘化吡啶;所用的碱例如是三乙胺。
本发明还可以通过下列非限定性实施例作为优选实施方案来进一步说明。实施例1:(方法A)2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-丙酰苯胺a-2’,3’,5’-三甲基-4’-羟基-α-溴-N-丙酰苯胺la
在氮气氛中,向2,3,6-三甲基-4-氨基苯酚盐酸化物(1.87g;0.01mol)的二甲基甲酰胺溶液中加入三乙胺(3.48ml;0.25mol)。随后再滴加α-溴代丙酰氯(1.32ml;0.0125mol),并将反应混合物在室温下搅拌1小时。
用水稀释后,用乙酸乙酯萃取。有机相用1N盐酸和水洗涤,然后干燥(MgSO4)并真空浓缩至干。残留物溶于己烷,随后过滤、干燥,得到化合物1a(2.10g)。M.P.=186℃TLC:MERK产60F254硅胶,Rf=0.61(乙酸乙酯)b-2’,3’,5’三甲基-4’-羟基-α-十二烷硫基-N-丙酰苯胺1
将n-十二烷基硫醇(2.11ml;0.0088mol)溶于甲醇(20ml)中,再加入甲醇钠(0.47g;0.0088mol)。15分钟后再加入化合物1a(2.10g;0.0073mol),将反应混合物升温至60℃并保持2小时。随后,蒸除甲醇,所得残留物用乙酸乙酯萃取。
用水洗涤并干燥(MgSO4)有机相,然后将其在真空下浓缩至干。采用闪式色谱法纯化所得的残留物(洗脱液:30/70的乙酸乙酯/已烷),得到1.24g白色晶体(1)。M.P.=123℃TLC:MERK产60F254硅胶,Rf=0.59(50/50的乙酸乙酯/己烷)实施例2:2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-乙酰苯胺2
该化合物按照与实施例1相同的方法采用溴代乙酰氯进行制备。M.P.=99℃TLC:MERK产60F254硅胶,Rf=0.51(50/50的乙酸乙酯/己烷)实施例3:2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-丁酰苯胺3
该化合物按照与实施例1相同的方法采用2-溴丁酰溴进行制备。M.P.=127℃TLC:MERK产60F254硅胶,Rf=0.61(50/50的乙酸乙酯/己烷)实施例4:2’,3’,5,-三甲基-4’-羟基-α-十二烷硫基-N-己酰苯胺4
该化合物按照与实施例1相同的方法采用2-溴己酰溴进行制备。M.P.=80℃TLC:MERK产60F254硅胶,Rf=0.36(30/70的乙酸乙酯/己烷)实施例5:2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-异戊酰苯胺5
该化合物按照与实施例1相同的方法采用2-溴异戊酰氯制备。M.P.=123℃TLC:MERK产60F254硅胶,Rf=0.30(30/70的乙酸乙酯/己烷)实施例6:2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-戊酰苯胺6
该化合物按照与实施例1相同的方法采用2-溴戊酰溴制备。M.P.=116℃TLC:MERK产60F254硅胶,Rf=0.39(30/70的乙酸乙酯/己烷)实施例7:(方法B)2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-苯基-N-乙酰苯胺7a)-2’,3’,5’-三甲基-4’-羟基-α-氯-α-苯基-N-乙酰苯胺7a
在氮气氛中,向2,3,6-三甲基-4-氨基苯酚盐酸化物(1.27g;0.0067mol)的二氯甲烷(35ml)悬浮液中加入三乙胺(0.94ml;0.0067mol)。
然后加入α-氯代苯基乙酸(1.27g;0.0074mol)和二环己基碳化二亚胺(1.54g;0.0074mol),反应混合物在室温下剧烈搅拌2小时。
此后,过滤生成的二环己基脲,依次用0.1N盐酸、水、盐水溶液洗涤有机相。干燥(MgSO4)后在真空下蒸发至干,用乙醚溶解残留物。过滤出生成的晶体并干燥,得到化合物7a(1.22g)。M.P.=199℃TLC:MERK产60F254硅胶,Rf=0.68(50/50的乙酸乙酯/己烷)b)-2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-苯基-N-乙酰苯胺7
以化合物7a为起始物,采用实施例1b的方法制备化合物7M.P.=129℃TLC:MERK产60F254硅胶,Rf=0.64(50/50的乙酸乙酯/己烷)实施例8:(方法C)2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-异丁酰苯胺8
将2,3,6-三甲基-4-氨基苯酚盐酸化物(3.52g;0.018mol)、α-十二烷硫基异丁酸(5.4lg;0.018mol)和三乙胺(9.4ml;0.067mol)依次加入到2-氯-1-甲基碘化吡啶(5.75g;0.022mol)的氯仿(225ml)悬浮液内,然后,加热回流2小时。随后,冷却反应混合物,用乙醚(350ml)稀释并过滤。有机相依次用1N盐酸、水和盐水洗涤。干燥(MgSO4)后在真空下浓缩至干,残留物用异丙醚溶解并过滤,得到7.32g白色结晶化合物8。M.P.=71℃TLC:MERK产60F254硅胶,Rf=0.65(50/50的乙酸乙酯/己烷)实施例9:
以α-对氯苯硫基异丁酸为起始物,采用实施例8的方法制得化合物9。M.P.=134℃TLC:MERK产60F254硅胶,Rf=0.54(50/50的乙酸乙酯/己烷)实施例10:2’,3’,5’-三甲基-4’-羟基-α-对氯苯基亚磺酰基-N-异丁酰苯胺10
以α-对氯苯基亚磺酰基异丁酸为起始物,采用实施例8的方法制得化合物10。M.P.=157-158℃TLC:MERK产60F254硅胶,Rf=0.33(50/50的乙酸乙酯/己烷)实施例11:
向冷却至0℃的对氯苯氧异丁酸(2.14g;0.01mol)和三乙胺(1.48ml;0.0105mol)的四氢呋喃(25ml)溶液中滴加氯甲酸乙酯(0.96ml;0.01mol)。搅拌20分钟后,将所得的混合酸酐缓慢加入到2,3,6-三甲基-4-氨基苯酚盐酸化物(1.87g;0.01mol)的二甲基甲酰胺(10ml)和三乙胺(1.48ml;0.0105mol)悬浮液中。
在持续通入氮气流和5℃条件下,将反应混合物继续搅拌1小时,再在室温下搅拌12小时,然后倾入水中并用乙酸乙酯萃取。有机相用水、盐水洗涤,MgSO4干燥,随后真空蒸发至干。残留物在乙醚中结晶并在乙酸乙酯中重结晶,得到化合物11。M.P.=175℃TLC:MERK产60F254硅胶,Rf=0.30(30/70的乙酸乙酯/己烷)实施例12:2’,3’,5’-三甲基-4’-羟基-α-十二烷基亚磺酰基N-异丁酰苯胺12
以α-十二烷基亚磺酰基异丁酸为起始物,采用实施例8的方法制得化合物12。M.P.=73℃TLC:MERK产60F254硅胶,Rf=0.43(乙酸乙酯/己烷)实施例13:2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-(3,5-二叔丁基-4-羟基)苯基-N-乙酰苯胺13
以α-十二烷硫基-3,5二叔丁基-4-羟基苯基乙酸为起始物,采用实施例11的方法制得化合物13。M.P.=150℃TLC:MERK产60F254硅胶,Rf=0.31(乙酸乙酯/己烷30-70)实施例14:2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-对甲氧基苯基N-乙酰苯胺14
以α-十二烷硫基-α-对甲氧基苯基乙酸为起始物,采用实施例7a的方法制得化合物14。M.P.=122℃TLC:MERK产60F254硅胶,Rf=0.74(30/70的乙酸乙酯/己烷)实施例15:2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-萘基N-乙酰苯胺15
以α-十二烷硫基-α-萘基乙酸为起始物,采用实施例7a的方法制得化合物15。M.P.=134℃TLC:MERK产60F254硅胶,Rf=0.60(95/5的二氯甲烷/乙酸乙酯)实施例16:(+)-2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-苯基-N-乙酰苯胺16
以(+)α-十二烷硫基-α-苯基乙酸为起始物,按照实施例7a的方法制得化合物16。M.P.=128℃TLC:MERK产60F254硅胶,Rf=0.64(50/50的乙酸乙酯/己烷)αD 25=+34.7°(C=0.5;乙醇)
在药理实验中,本发明化合物对高血胆固醇症和动脉粥样硬化疾病表现出了显著的治疗功效。
一方面,我们研究了本发明化合物对大鼠ACAT的抑制作用及其血胆固醇降低作用,另一方面,本发明还对这些化合物的抗氧化作用进行了研究。1)ACAT抑制作用
采用H.Chautan等人所述的技术(分析生物化学,173,436-439,1988),通过体外试验对本发明化合物的ACAT(酰基-CoA:胆固醇O-酰基转移酶)抑制作用进行评价。
借助本发明化合物得到了以50%抑制浓度(IC50)表示的活性结果,结果记录在表1中:
表1
2)血胆固醇降低活性:
化合物NO. | IC50 |
234567891116CI 976DUP128 | 0.300.310.160.630.110.180.191.121.100.161.040.1 |
以Altromin C 1061类型的致高血胆固醇饮食来喂食雄鼠(160-180g)并持续4天,在此同时还口服本发明化合物;其中本发明化合物悬浮在含有2%吐温80的蒸馏水溶液中。
第五天,将未禁食的受试动物用乙醚麻醉,自其腹部主动脉部位取血并将血样置于EDTA中。立即离心该血样并将血浆贮存在4℃下。
采用CHOD-PAP方法(Boehringer-Mannheim参考号:237574)分析血浆内胆固醇含量。半数有效剂量(ED50)是指:相对于空白受试动物而言,将血浆胆固醇浓度降低至一半时的剂量。
3)抗氧化活性
化合物No. | ED50(mg/kg) |
23456881416CI 976DUP 128 | >1040.5110.21010.18.31.1 |
a)化学过氧化作用
在Fe3+和ADP(腺苷二磷酸)存在下,二羟基富马酸发生自氧化作用,产生氧自由基。氧自由基使肝微粒体脂质发生过氧化作用。
在大鼠肝脏微粒体内的这种过氧化作用可按照S.Y.H Tse等人公开的硫巴比妥酸检测技术(形成TBARS)来测定。(生物化学药学,第42卷,第3期,459-464页,1991)
化合物No. | IC50(μM) |
2345678CI 976DUP 128维生素 E | 5>100.550.30.63>10>102.3 |
(b)LDL的氧化
人体LDL(Sigma L 2139)被10μM CuSO4氧化,保温6小时后,根据TBARS技术,利用分光光度计在532nm下估译过氧化作用。
化合物No. | IC50(μM) |
471216CI 976DUP 128维生素 E | 1013341003010 |
本发明化合物是降血胆固醇药物,该类化合物可以抑制ACAT和氧化剂,因此可以用于治疗高血胆固醇症和动脉粥样硬化疾病。
本发明药物组合物可制成口服、肠胃外或局部给药的剂型,例如胶囊、片剂、粒剂、溶液、糖浆剂或混悬液,该组合物中还可以含有适当的赋形剂。
日剂量在10-3000mg范围内。
Claims (8)
2)根据权利要求1的通式Ⅰ化合物,选自下列物质:
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-丙酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-乙酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-丁酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-己酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-异戊酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-N-戊酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-苯基-N-乙酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-(十二烷硫基-)N-异丁酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-对氯苯硫基-N-异丁酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-对氯苯基亚磺酰基-N-异丁酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-对氯苯氧基-N-异丁酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷基亚磺酰基-N-异丁酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-(3,5-二叔丁基-4-羟基)苯基-N-乙酰苯胺;
2’,3’,5’-三甲基-4’-羟基-α-十二烷硫基-α-对甲氧苯基N-乙酰苯胺;
2’,3’,5’-三甲基-4’羟基-α-十二烷硫基-α-萘基-N-乙酰苯胺;
(+)-2’,3’,5’-三甲基4’-羟基-α-十二烷硫基-α-苯基-N-乙酰苯胺;
3)权利要求1或2的化合物的制备方法,其特征在于:
a)-第一步,将2,3,6-三甲基-4-氨基苯酚盐酸化物与α-卤代酰卤Ⅱ反应,反应在碱,例如三乙胺存在下进行,反应得到中间体Ⅲ;其中,R1和R2与权利要求1中的定义相同,Hal代表溴或氯原子;
b)-将中间体Ⅱ与衍生物R3(A)H反应,反应是在钠/甲醇或叔丁醇钾/叔丁醇介质中进行,其中R3和A与权利要求1的定义相同。
4)权利要求3的化合物的制备方法,其特征在于:将2,3,6-三甲基-4-氨基苯酚盐酸化物与α-卤酸在活化剂和碱共存的条件下反应,得到中间体Ⅲ;其中,该活化剂例如是二环己基碳化二亚胺或2-氯-1-甲基碘化吡啶;所用碱例如是三乙胺。
6)权利要求1或2的通式Ⅰ化合物作为治疗用药物,尤其是作为治疗例如高血胆固醇症和动脉粥样硬化之类疾病的药物的用途。
7)药物组合物,其特征在于:除了可药用载体以外,还含有至少一种权利要求1或2的通式Ⅰ所示化合物。
8)权利要求1或2中通式Ⅰ所示化合物在治疗高血胆固醇症和动脉粥样硬化疾病的药物制备方面的应用。
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FR9514086A FR2741619B1 (fr) | 1995-11-28 | 1995-11-28 | Nouveaux derives de 2,3,5-trimethyl-4-hydroxy-anilides, leur preparation et leur application en therapeutique |
FR95/14086 | 1995-11-28 |
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CN1205689A true CN1205689A (zh) | 1999-01-20 |
CN1072645C CN1072645C (zh) | 2001-10-10 |
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CN96199274A Expired - Fee Related CN1072645C (zh) | 1995-11-28 | 1996-11-27 | 新的2,3,5-三甲基-4-羟基-n-酰苯胺衍生物及其制备方法与应用 |
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US (1) | US5990173A (zh) |
EP (1) | EP0874812B1 (zh) |
JP (1) | JP2000500771A (zh) |
KR (1) | KR100417275B1 (zh) |
CN (1) | CN1072645C (zh) |
AT (1) | ATE191473T1 (zh) |
AU (1) | AU701186B2 (zh) |
BR (1) | BR9611790A (zh) |
CA (1) | CA2238845C (zh) |
DE (1) | DE69607650T2 (zh) |
DK (1) | DK0874812T3 (zh) |
ES (1) | ES2147399T3 (zh) |
FR (1) | FR2741619B1 (zh) |
GR (1) | GR3033786T3 (zh) |
MX (1) | MX9804226A (zh) |
NZ (1) | NZ322959A (zh) |
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CN101450911B (zh) * | 2007-11-30 | 2012-02-29 | 山东轩竹医药科技有限公司 | 被金刚烷取代的苯甲酸衍生物 |
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FR2823207B1 (fr) | 2001-04-10 | 2004-12-03 | Pf Medicament | Complexes d'anilides a chaine polycarbonee et de cyclodestrines, leur preparation et leur application en tant que medicamment en particulier pour le traitement des dislipidemies |
HUP0401696A2 (hu) * | 2001-08-28 | 2004-11-29 | Sankyo Co., Ltd. | Angiotenzin-II receptor antagonistát tartalmazó gyógyászati készítmény |
FR2830760B1 (fr) * | 2001-10-12 | 2004-06-04 | Pf Medicament | Procede de preparation d'un compose d'interaction de substances actives avec un support poreux par fluide supercritique |
FR2830761B1 (fr) * | 2001-10-12 | 2003-12-12 | Pf Medicament | Procede de preparation d'un compose d'interaction d'un derive anilide avec un support poreux par fluide supercritique |
US20050119314A1 (en) * | 2002-04-05 | 2005-06-02 | Sankyo Company, Limited | Pharmaceutical composition comprising an ACAT inhibitor and an insulin resistance reducing agent |
FR2845991B1 (fr) * | 2002-10-16 | 2005-02-04 | Pf Medicament | Derives d'alpha-phenyl acetanilides et leur application en therapeutique humaine |
US20060247458A1 (en) * | 2003-02-28 | 2006-11-02 | Shogo Yamamoto | Process for the production of optically active compounds having substituents at the 2-position |
FR2854079B1 (fr) | 2003-04-25 | 2007-11-30 | Pf Medicament | Procede de preparation de complexes moleculaires |
GEP20084406B (en) | 2003-05-30 | 2008-06-25 | Ranbaxy Lab Ltd | Substituted pyrrole derivatives and their use as hmg-co inhibitors |
WO2005051298A2 (en) | 2003-11-19 | 2005-06-09 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing thyromimetics |
KR101021828B1 (ko) * | 2004-10-27 | 2011-03-17 | 다이이찌 산쿄 가부시키가이샤 | 2 이상의 치환기를 갖는 벤젠 화합물 |
AU2006313430B2 (en) | 2005-11-08 | 2012-09-06 | Ranbaxy Laboratories Limited | Process for (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt |
FR2918889B1 (fr) * | 2007-07-19 | 2009-10-23 | Galderma Res & Dev | Utilisation de l'eflucimibe pour la preparation d'un medicament destine a prevenir ou a traiter une maladie due a un dysfonctionnement des glandes sebacees chez l'homme ou l'animal |
US8741966B2 (en) | 2007-11-09 | 2014-06-03 | Pronova Biopharma Norge As | Lipid compounds for use in cosmetic products, as food supplement or as a medicament |
EP2147910A1 (en) * | 2008-07-15 | 2010-01-27 | Pronova BioPharma Norge AS | Novel lipid compounds |
US20120046364A1 (en) | 2009-02-10 | 2012-02-23 | Metabasis Therapeutics, Inc. | Novel Sulfonic Acid-Containing Thyromimetics, and Methods for Their Use |
EP2248798A1 (en) * | 2009-05-08 | 2010-11-10 | Pronova BioPharma Norge AS | Novel lipid compounds |
TWI558395B (zh) * | 2009-05-08 | 2016-11-21 | 普諾華生物製藥諾治股份有限公司 | 新穎的脂質化合物 |
EA028535B1 (ru) | 2010-11-05 | 2017-11-30 | Пронова Биофарма Норге Ас | Способы лечения с применением липидных соединений |
FR2973374B1 (fr) * | 2011-04-04 | 2013-08-23 | Pf Medicament | Nouveaux alkylthioethers, leur preparation et leur application en therapeutique |
EP3578170A1 (en) | 2013-02-28 | 2019-12-11 | Basf As | A composition comprising a lipid compound, a triglyceride, and a surfactant, and methods of using the same |
KR102644400B1 (ko) | 2015-04-28 | 2024-03-06 | 바스프 에이에스 | 비알코올성 지방간염의 예방 및/또는 치료를 위한 구조적으로 강화된 함황 지방산의 용도 |
CA3084728A1 (en) | 2017-12-06 | 2019-06-13 | Basf As | Fatty acid derivatives for treating non-alcoholic steatohepatitis |
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JPS6040898A (ja) * | 1983-03-31 | 1985-03-04 | Suzuki Shiyoukan:Kk | 真空断熱容器或は貯蔵の製作方法 |
WO1992009572A1 (fr) * | 1990-11-26 | 1992-06-11 | Taisho Pharmaceutical Co., Ltd. | Derive d'anilide |
FR2673625B1 (fr) * | 1991-03-08 | 1993-05-07 | Adir | Nouveaux derives d'acylaminophenol, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
AU660346B2 (en) * | 1991-12-25 | 1995-06-22 | Taisho Pharmaceutical Co., Ltd. | Anilide derivative |
JP2842147B2 (ja) * | 1992-05-26 | 1998-12-24 | 大正製薬株式会社 | Acat阻害剤 |
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CN101450911B (zh) * | 2007-11-30 | 2012-02-29 | 山东轩竹医药科技有限公司 | 被金刚烷取代的苯甲酸衍生物 |
Also Published As
Publication number | Publication date |
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ATE191473T1 (de) | 2000-04-15 |
EP0874812A1 (fr) | 1998-11-04 |
GR3033786T3 (en) | 2000-10-31 |
US5990173A (en) | 1999-11-23 |
AU7700096A (en) | 1997-06-19 |
PT874812E (pt) | 2000-09-29 |
WO1997019918A1 (fr) | 1997-06-05 |
CN1072645C (zh) | 2001-10-10 |
DE69607650D1 (de) | 2000-05-11 |
AU701186B2 (en) | 1999-01-21 |
DK0874812T3 (da) | 2000-09-11 |
JP2000500771A (ja) | 2000-01-25 |
CA2238845C (fr) | 2006-08-29 |
BR9611790A (pt) | 1999-07-13 |
KR100417275B1 (ko) | 2004-05-20 |
DE69607650T2 (de) | 2000-11-30 |
ES2147399T3 (es) | 2000-09-01 |
CA2238845A1 (fr) | 1997-06-05 |
KR19990071679A (ko) | 1999-09-27 |
FR2741619A1 (fr) | 1997-05-30 |
FR2741619B1 (fr) | 1998-02-13 |
MX9804226A (es) | 1998-09-30 |
NZ322959A (en) | 2001-05-25 |
EP0874812B1 (fr) | 2000-04-05 |
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