CN112513018A - 乙胺嘧啶的酸加成盐 - Google Patents
乙胺嘧啶的酸加成盐 Download PDFInfo
- Publication number
- CN112513018A CN112513018A CN201980033670.4A CN201980033670A CN112513018A CN 112513018 A CN112513018 A CN 112513018A CN 201980033670 A CN201980033670 A CN 201980033670A CN 112513018 A CN112513018 A CN 112513018A
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- CN
- China
- Prior art keywords
- pyrimethamine
- pharmaceutical composition
- acid addition
- mesylate
- methanesulfonic acid
- 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.)
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Abstract
本发明公开了乙胺嘧啶((5‑4‑氯苯基)‑6‑乙基‑2,4‑嘧啶二胺)和甲烷磺酸的酸加成盐,其制备方法和包含该酸加成盐的药物组合物。
Description
技术领域
本发明涉及一种新的乙胺嘧啶酸加成盐、其制备方法和包含其的药物组合物。
背景技术
乙胺嘧啶(5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺)是一种具有抗寄生虫特性的二氢叶酸还原酶(DHFR)抑制剂,已批准用于治疗疟疾。它对疟原虫和弓形虫的活性是基于对叶酸转化的选择性抑制,导致亚叶酸合成的失败,这对核酸形成至关重要。最近,该化合物在用于治疗慢性淋巴细胞性白血病的I/II期临床研究中进行了评估。用于治疗常染色体显性多囊性肾脏疾病的临床前研究也在进行,用于治疗家族肌萎缩侧索硬化症的I/II期临床研究也在进行。在美国,该化合物被指定为孤儿药,用于治疗GM-2神经节苷脂沉积病,包括Tay-Sachs病和Sandhoff病;在日本则用于治疗弓形虫病。
美国专利2,576,939公开了一些具有抗疟疾特性的2,4-二胺-5-苯基6-烷基嘧啶衍生物。
乙胺嘧啶在水中极低的溶解度(10毫克/升)对其生物利用度产生不利的影响。先前提高乙胺嘧啶溶解度的尝试包括与环糊精形成复合物(J.Pharm.Pharmaceutical Sci.,2012,4(4),102),低分子量琥珀酰聚糖二聚体(Bull.Korean Chem.Soc.;2012,33(8),2731),或用聚电解质稳定的纳米悬浮液(J.Bionanosci.;2010,4(1-2),123))。还报道了乙酰丙酸(JP 46034992B)、帕莫酸和柠嗪酸(GB 986812A)的乙胺嘧啶盐。尽管描述了一些普通酸(马来酸、琥珀酸、邻苯二甲酸、富马酸、戊二酸或甲酸)的乙胺嘧啶盐的合成和晶体学特征(Crystal Growth and Design,2002,2/6,631;2003,3/5,823)但没有提及它们在水中的溶解度。乙胺嘧啶和无机酸(如盐酸或硫酸)的某些盐在本领域中也是已知的。
为了找到将乙胺嘧啶衍生化为它的更可溶和可生物利用的衍生物的方法,已经制造了一些乙胺嘧啶盐,并且它们在水中以及水与最常用的增溶剂(例如非离子表面活性剂/乳化剂,例如聚氧乙烯脱水山梨糖醇脂肪酸酯(Tween 80)或聚氧乙烯氢化蓖麻油衍生物(Cremophor RH 40))的混合物中的溶解性已被测试。满足最大可能范围内的溶解度标准的是乙胺嘧啶和甲磺酸盐。
附图说明
图1表示乙胺嘧啶甲磺酸盐分子的结构(ORTEP)。
图2表示KBr片剂中记录的乙胺嘧啶甲磺酸盐的红外吸收光谱。
图3表示和模拟XRPD对比的结晶乙胺嘧啶甲磺酸盐X射线粉末衍射图(XRPD)。
图4表示结晶乙胺嘧啶甲磺酸盐的热重分析。
发明内容
本发明提供了作为新的化学实体的5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺的甲磺酸盐,以下称为乙胺嘧啶甲磺酸盐。
尽管有可能(即在摩尔比为1:1或2:1时)形成甲磺酸与乙胺嘧啶的两种加成盐,然而看起来,不考虑试剂的比例,仅形成了乙胺嘧啶的单甲磺酸盐(1:1)。因此,新的盐,即根据本发明的乙胺嘧啶甲磺酸盐,由式(I)表示。
本发明还提供了一种制备由式(I)表示的乙胺嘧啶甲磺酸盐的方法,其特征在于,使分散或溶解在有机溶剂中的5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺与甲磺酸反应。
形成盐的起始化合物5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺(乙胺嘧啶碱)可以根据本领域已知的任何方法获得,例如通过在美国专利2,576,939的说明书中公开的方法。优选地,在与甲磺酸的反应中,使用化学纯的乙胺嘧啶碱,其在多羟基醇、例如在乙二醇中重结晶。
使用相对于乙胺嘧啶碱稍微摩尔过量的甲磺酸进行成盐反应。通常,甲磺酸与乙胺嘧啶碱的摩尔比为1.01:1至1.10:1。
在本发明的优选实施方式中,乙胺嘧啶甲磺酸盐的制备方法包括:
(i)将5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺与甲磺酸在有机溶剂中结合,
(ii)将混合物在10℃至回流范围内的温度加热,直到固体完全溶解,
(iii)任选地,向反应混合物中加入抗溶剂和/或晶种,
(iv)将反应后混合物冷却至结晶温度(0℃-25℃),
(v)结晶和分离结晶产物,以及
(vi)干燥结晶产物。
合适的有机溶剂选自包括极性C1-C3脂肪族醇、C3-C5酮、多羟基醇(乙二醇)或它们的混合物的组。优选的反应溶剂是乙醇、丙酮、或乙二醇和丙酮的混合物。
向反应后混合物中添加C3-C5酮类抗溶剂和/或晶种可以促进形成的晶体的沉淀。
将反应后混合物冷却至结晶温度(通常在5℃至室温(约20-25℃)的范围内)后,结晶产物沉淀出来。以常规的方式分离晶体,例如通过过滤、倾析或溶剂蒸发。进行溶剂蒸发以达到药物活性成分通常接受的并在ICH指南中进行了说明的水平。
以起始的乙胺嘧啶碱计算,按照本发明的方法获得的乙胺嘧啶甲磺酸盐具有高于70%的高收率。从反应后混合物中分离出的结晶乙胺嘧啶甲磺酸盐,其化学纯度非常高,与起始乙胺嘧啶碱的纯度无关。通常,未经任何进一步纯化,通过超高效液相色谱法(UHPLC)测定的乙胺嘧啶甲磺酸盐的纯度超过99.0%。
如果需要,可以通过重结晶另外纯化结晶乙胺嘧啶甲磺酸盐。
1H-NMR质子磁共振光谱以及元素分析证实,本发明的盐含有摩尔比为1∶1的乙胺嘧啶碱和甲磺酸。
通过单晶X射线衍射分析阐明结晶的乙胺嘧啶甲磺酸盐的结构。乙胺嘧啶甲磺酸盐的分子结构(ORTEP)示于图1。
乙胺嘧啶甲磺酸盐在P-1空间群的三斜晶系中结晶。表1列出了晶体学数据,特别是晶胞尺寸,每个晶胞的体积,计算的密度和测量参数。
表1.乙胺嘧啶甲磺酸盐分子的晶体学数据和结构细化
通过傅里叶变换红外光谱(FTIR)从KBr小球记录到的乙胺嘧啶甲磺酸盐的独特的红外吸收光谱在图2中示出。
结晶的乙胺嘧啶甲磺酸盐的特征在于,使用波长λ为的CuKα辐射源记录的X射线粉末衍射图(XRPD),其示出了以反射角2θ(°)、平面间距和相对于最强衍射峰的相对强度I/I0(%)之间的关系呈现的特征峰,如表2所示:
表2.乙胺嘧啶甲磺酸盐的X射线粉末衍射
通过傅里叶变换红外光谱(FTIR)从KBr小球中记录到的乙胺嘧啶甲磺酸盐的独特的红外吸收光谱在图2中示出。
结晶的乙胺嘧啶甲磺酸盐的特征在于,使用波长λ为的CuKα辐射源记录的X射线粉末衍射图(XRPD),其示出以反射角2θ(°)、平面间距和相对于最强衍射峰的相对强度I/I0(%)之间的关系呈现的特征峰,如表2所示:
表2.乙胺嘧啶甲磺酸盐的X射线粉末衍射
表2.乙胺嘧啶甲磺酸盐的X射线粉末衍射
根据热重分析(TGA)的单差热分析(SDTA)曲线,乙胺嘧啶甲磺酸盐的熔点确定为起始温度,其为基线切线和熔融峰前沿的交点(图4)。SDTA信号显示盐在T起始=283.10℃时熔化。
根据TGA曲线在30至220℃的温度范围内测得的质量损失(Δm/m,%)为0.36%,表明乙胺嘧啶甲磺酸盐为非溶剂化物形式。
与乙胺嘧啶的其他盐相反,乙胺嘧啶甲磺酸盐甚至在室温下也可自由溶于水,而无需添加表面活性剂和/或乳化剂。
可以预料到,乙胺嘧啶甲磺酸盐将具有与乙胺嘧啶碱相同的药理特性。
新的乙胺嘧啶甲磺酸盐具有良好的耐受性和药学接受性(参见,Handbook ofPharmaceutical Salts,ed.P.H.Stahl.C.G.Wermuth,Verlag Helvetica Chimica Acta,2002)。由于其有利的理化和毒理学性质,它可以用于治疗和预防人类的不同疾病。
对于治疗用途,活性物质乙胺嘧啶甲磺酸盐可以本身或作为药物组合物施用于患者,所述药物组合物包含治疗有效量的活性物质以及至少一种药学上可接受的载体和/或赋形剂。
因此,本发明还提供了包含乙胺嘧啶甲磺酸盐作为活性成分的药物组合物,其可以根据给药方式以合适的药物剂型给予需要治疗的患者。口服或肠胃外给药的药物剂型是优选的。
活性物质剂量的选择和治疗方案取决于疾病的进展、年龄、体重和患者的状况,并且可以由技术人员基于适合于这种疾病的已知治疗和预防方案来确定。
适当的日剂量的乙胺嘧啶甲磺酸盐可以单次日剂量或以2次或更多次分剂量的形式通过单一疗法或与其他疗法联合给予患者。这样的组合的组分可以以一种组合的固定剂量药物制剂的形式或以技术人员确定的顺序和时间间隔一个接一个地以单独的制剂的形式给予患者。
根据本发明的药物组合物可以本领域技术人员熟知的药物形式给药,例如参见Remington's Pharmaceutical Sciences,第18版,red.A.R.Gennaro,Mack Publ.Co.,1990,Easton,Pensylwania。
药物组合物可用于口服给药,尽管也设想了通过其他途径(例如肠胃外)给药的组合物。
药物口服剂型包括固体剂型(例如片剂、包衣片剂、粉末、颗粒剂,小丸剂或胶囊)和液体剂型(例如混悬剂、酏剂、溶液和糖浆)。除活性物质外,它们还包含药学上可接受的填充剂和/或赋形剂。药学上可接受的填充剂和/或赋形剂是本领域公知的不发挥其自身药理作用的物质或其混合物。
用于常规释放活性物质的固体剂型中的合适的填充剂包括淀粉、乳糖、微晶纤维素、蔗糖、山梨糖醇、滑石粉、甘露醇、一元或二元磷酸钙、预糊化淀粉、甘氨酸等。
固体口服剂型可进一步包含赋形剂,所述赋形剂促进制造过程并赋予最终剂型所需的物理机械性能。
其他赋形剂可以选自崩解剂,例如淀粉和淀粉衍生物,交联羧甲基纤维素钠,微晶纤维素,交联的聚乙烯吡咯烷酮,淀粉羟乙酸钠或其他基于交联聚合物的产品;粘合剂,例如聚乙烯吡咯烷酮,明胶,天然和合成树胶,纤维素衍生物,例如羟丙基甲基纤维素,羟乙基纤维素,羟丙基纤维素;润滑剂,如十二烷基硫酸钠;助流剂,例如胶体二氧化硅,硬脂酸,硬脂酸镁,滑石粉,富马酸等。
片剂可以任选地按照例如“Pharmaceutical Dosage Forms and Drug DeliverySystems,H.C.Ansel,L.V.Allen,N.G.Popovich,VIIth ed.(1999),Lippincott Williams&Wilkins”中描述的那样进行包衣。包衣制剂优选包含选择用来使得包衣在所需胃肠道部分溶解或破碎的膜包衣物质,以及药物赋形剂,例如增塑剂、填充剂、遮光剂、着色剂和抛光剂。膜包衣物质优选为聚合物,例如纤维素衍生物、丙烯酸类聚合物和共聚物、高分子量聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇等。合适的增塑剂可以是多元醇,例如甘油;有机酯,例如邻苯二甲酸酯、癸二酸酯或柠檬酸酯等。
也可以考虑包含乙胺嘧啶甲磺酸的药物组合物的肠胃外剂型的给药,例如用于静脉内、皮下或肌内给药。肠胃外组合物包括无菌水、水-有机和非水溶液和悬浮液,适合临时重建的冻干产物和片剂。对于液体制剂,可以应用:在液相中提供均匀的活性物质分布的悬浮剂,例如聚山梨酸酯、卵磷脂、聚氧乙烯和聚氧丙烯共聚物;胶溶剂,例如磷酸盐、多磷酸盐和柠檬酸盐,水溶性聚合物,例如羧甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮、氢化油、树胶或明胶。
肠胃外制剂可以进一步包含药学上可接受的添加剂,例如增溶剂、防腐剂、pH调节剂,缓冲剂和张度剂。
本发明提供了以在水性介质中的高溶解度为特征的稳定的结晶乙胺嘧啶甲磺酸盐。本发明进一步提供了结晶形式的高色谱纯度的乙胺嘧啶甲磺酸盐的有效、可重复的制备方法。
具体实施方式
通过以下非限制性实施例进一步说明本发明。
实施例
分析方法
√UHPLC法测定化学纯度
使用具有分光光度检测器(DAD 3000 RS,Dionex Softron GmbH)的超高效液相色谱仪(UHPLC,DionexUltiMate300RS)进行化学纯度的测定。使用“Acquity UPLC CSH苯基己基,100×2.1mm,1.7μm(水)反相分析柱”,在以下条件下进行色谱分离:
·洗脱液A:0.01%H3PO4水溶液(v/v)
·洗脱液B:ACN
·流速:0.5mL/分钟
·梯度洗脱参数:
时间[分钟] | 洗脱液A[%] | 洗脱液B[%] |
0.0 | 95 | 5 |
7.0 | 5 | 95 |
7.5 | 5 | 95 |
8.0 | 95 | 5 |
12.0 | 95 | 5 |
·柱温:30℃
高效液相色谱法分析测定甲磺酸
甲磺酸的分析测定是使用具有荷电气溶胶检测器(Corona CAD,ThermoScientific)的高效液相色谱仪(UHPLC,DionexUltiMate300RS)进行的。使用“SynergyFusion RP 150×4.6mm,4.0μm(Phenomenex)反相分析柱”在以下条件下进行色谱分离:
·洗脱液A:0.1%CH3COOH水溶液(v/v)
·洗脱液B:MeOH
·流速:0.8mL/分钟
·梯度洗脱参数:
时间[分钟] | 洗脱液A[%] | 洗脱液B[%] |
0.0 | 95 | 5 |
4.0 | 75 | 25 |
6.0 | 25 | 75 |
8.0 | 25 | 75 |
8.2 | 95 | 5 |
12.0 | 95 | 5 |
·柱温:30℃
√FT-IR
在Nicolet iS10(Thermo Scientific)光谱仪上用傅立叶变换在4000至400cm-1范围内记录KBr小球的红外吸收光谱,光谱分辨率为4cm-1。
√1H-NMR
在Bruker Avance 500MHz光谱仪上记录核磁共振1H-NMR光谱。
√热重分析
通过TGA/SDTA851 cell(Mettler Toledo)进行TGA测量。将约5mg的研究样品称入标准铝盘(40μL)中。测量前将盘密封并打孔。在氮气气氛中以10℃/min将样品从30℃加热到300℃。该测量是空白曲线校正的。
√XRPD和单晶测量
X射线粉末衍射(XRPD)图在MiniFlex衍射仪(Rigaku Coporation)上用CuKα1辐射和闪烁体检测器记录。将样品压在玻璃板上。仪器操作的2θ范围为3至40°,扫描速度为0.5°/分钟,θ/2θ轴步距角为0.02°。测量温度:室温。使用PDXL2软件(RigakuCoporation)建立和处理获得的衍射图。
使用具有CuKα辐射的单晶衍射仪Agilent Technologies SuperNova DualSource分析晶体结构。
实施例1
乙胺嘧啶(30g)(纯度99.83%,含有0.16%杂质,Rf=2.53)在乙二醇(3×60mL)中结晶。将获得的晶体在乙醇(50mL)中回流,过滤并在60℃减压干燥。得到25g的乙胺嘧啶,其含有0.09%的Rf=2.53杂质。将获得的产物(24.9g,0.1mol)悬浮在丙酮(250mL)中,并将甲磺酸(24.0g,0.25mol)加入该悬浮液中。反应在室温下搅拌60分钟,然后收集白色沉淀物,并用丙酮(500mL)洗涤。将产物悬浮在乙醇(250mL)中,并在搅拌下回流15分钟。然后,将悬浮液冷却至室温,收集沉淀物,用乙醇(250mL)洗涤,并在60℃减压(20mmHg)干燥。获得白色晶体的产物,产量为24.0g(70%)。通过电位滴定法测得盐中酸的含量:28.15%(计算值:27.87%)。
1H NMR(500MHz,DMSO-d6)δ(ppm):1.01(t(J=7.5Hz),3H,H-8);2.18(k(J=7.5Hz),2H,H-7);2.47(s.3H,H-CH3盐);6.87(s.1H,H-14);7.29(d(J=8.5Hz),2H.H-10);7.54(d(J=8.5Hz),2H,H-11);7.76(bs.2H,H-13);8.12(s,1H,H-14);
13C NMR(125MHz,DMSO-d6)δ(ppm):12.54(C-8);23.55(C-7);39.73(C-CH3盐);107.18(C-5);129.44(C-11);130.06(C-9);132.48(C-10);133.59(C-12);154.46(C-6);154.76(C-2);164.11(C-4)。
MS(45.43%-C;4.80%-H;16.37%-N;9.25%-S;10.37%-Cl;计算值:45.28%-C;4.97%-H;16.25%-N;9.30%-S;10.28%-Cl)。
实施例2
将乙胺嘧啶(24.9g,0.1mol)溶解在热乙二醇(100mL)中,将甲磺酸(24.0g,0.25mol)加入溶液中,并将反应混合物冷却至室温。然后,加入丙酮(200mL),并将混合物在室温下放置12小时。收集沉淀物,用丙酮(50mL)洗涤,并在60℃减压(20mm Hg)干燥。获得的产物为白色晶体,产量18.0g(52%)。通过电位滴定法测得盐中的酸含量:28.20%(计算值:27.87%)。
实施例3
将乙胺嘧啶(249g,1mol)悬浮在96%乙醇(1L)中,并加入甲磺酸(240g=162mL,2.5mol)。将反应混合物在室温搅拌60分钟。然后回流30分钟。冷却后,收集白色沉淀物,并用乙醇(500mL)洗涤。将产物悬浮在乙醇(1L)中,并在搅拌下回流15分钟。然后将混合物冷却至室温,收集沉淀物,依次用乙醇(200mL)、丙酮(1L)和再次用乙醇10(200mL)洗涤。将产物在60℃减压(20mm Hg)干燥,得到白色晶体,产量为278g(81%)。酸含量:27.92%(计算值:27.87%)。
实施例4
乙胺嘧啶盐的溶解度
根据欧洲药典9.2中关于药物活性成分描述的一般建议,评价了乙胺嘧啶盐在不同的有机酸和无机酸中的溶解度。根据欧洲药典9.2,“溶解度”是指每克溶质对应的以毫升为单位的近似溶剂体积。物质的溶解度分为七类,从极易溶解(小于1毫升每克)到几乎不溶于水(超过10,000毫升每克)。但是,由于某些盐的溶解度极低,无法根据欧洲药典确定确切的值。因此根据自己的方法确定了在20℃和60℃这两个温度下的溶解度。结果列于下表3中。
表3.乙胺嘧啶盐的溶解度
“-”-不溶的;“+”-可溶;“/+”-冷却后不会沉淀;“/+(-)”-冷却后不沉淀,但在储存过程中结晶
*-由于溶解度低于预期,根据欧洲药典确定确切值是不可能的
**-文献数据
***-根据欧洲药典9.2的溶解度:
实施例5
肠胃外制剂
实施例6
口服液制剂
实施例7
固体口服剂形(片剂、胶囊)
Claims (18)
1.摩尔比为1∶1的5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺与甲磺酸的酸加成盐。
4.根据权利要求2所述的酸加成盐,其特征在于实验X射线粉末衍射图(XRPD)基本上如图3(下图)所示。
5.根据权利要求2所述的酸加成盐,其特征在于,熔点确定为热重分析(TGA)的单差热分析(SDTA)曲线的起始温度,T起始=283.10℃,干燥损失<1.0%。
6.一种制备乙胺嘧啶甲基磺酸盐的方法,其特征在于,使分散或溶解在有机溶剂中的5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺(乙胺嘧啶碱)与略微摩尔过量的甲磺酸反应。
7.根据权利要求6所述的方法,其中执行所述方法,使用的甲磺酸与乙胺嘧啶碱的摩尔比范围为1.01:1至1.10:1。
8.根据权利要求6-7中任一项所述的方法,其中所述有机溶剂选自包括极性C1-C3脂肪族醇、C3-C5酮、多羟基醇(乙二醇)或其混合物的组。
9.根据权利要求6-8中任一项所述的方法,其中有机溶剂是乙醇、丙酮、或乙二醇和丙酮的混合物。
10.根据权利要求6至9中任一项所述的方法,包括以下步骤:
(i)将5-(4-氯苯基)-6-乙基-2,4-嘧啶二胺与甲磺酸在有机溶剂中混合,
(ii)将混合物在10℃至回流范围的温度下加热,直到固体完全溶解,
(iii)任选地,向反应混合物中加入抗溶剂和/或晶种,
(iv)将反应后混合物冷却至结晶温度(0℃-25℃),
(v)结晶和分离结晶产物,以及
(vi)干燥结晶产物。
11.根据权利要求6-10中任一项所述的方法,其中所述抗溶剂是C3-C5酮。
12.根据权利要求6-11中任一项所述的方法,其中在步骤a)中,化学纯的乙胺嘧啶碱在多羟基醇,例如乙二醇中重结晶后使用。
13.一种药物组合物,其包含治疗有效量的式(I)的乙胺嘧啶甲磺酸盐以及至少一种药学上可接受的载体和/或赋形剂。
14.根据权利要求13所述的药物组合物,其为肠胃外剂型。
15.根据权利要求13所述的药物组合物,其为口服剂型。
16.根据权利要求15所述的药物组合物,其为口服溶液剂型。
17.根据权利要求13所述的药物组合物,其为片剂形式。
18.根据权利要求13所述的药物组合物,其为胶囊形式。
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JPS60502255A (ja) * | 1983-05-26 | 1985-12-26 | ザ ユニバ−ステイ オブ アストン イン バ−ミンガム | ピリミジン誘導体 |
CN101918378A (zh) * | 2008-01-16 | 2010-12-15 | 格林威治大学 | 环状叠氮和重氮钠通道阻滞剂 |
WO2012012404A1 (en) * | 2010-07-19 | 2012-01-26 | Bayer Healthcare Llc | Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
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US2576939A (en) | 1951-12-04 | -diamino-s-phenyl-e-alkyl- | ||
US3161641A (en) * | 1964-12-15 | pyrimethamwe salt with fluorescein | ||
CH397695A (fr) * | 1961-01-23 | 1965-08-31 | Parke Davis & Co | Procédé de préparation des sels de la 2,4-diamino-5-(p-chlorophényl)-6-éthyl-pyrimidine |
US20110195985A1 (en) * | 2010-02-09 | 2011-08-11 | The Hospital For Sick Children | Compounds for the treatment of lysosomal storage diseases |
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JPS60502255A (ja) * | 1983-05-26 | 1985-12-26 | ザ ユニバ−ステイ オブ アストン イン バ−ミンガム | ピリミジン誘導体 |
CN101918378A (zh) * | 2008-01-16 | 2010-12-15 | 格林威治大学 | 环状叠氮和重氮钠通道阻滞剂 |
WO2012012404A1 (en) * | 2010-07-19 | 2012-01-26 | Bayer Healthcare Llc | Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
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