CN1073683A - N,n′-二乙酰胱氨酸的有机盐 - Google Patents
N,n′-二乙酰胱氨酸的有机盐 Download PDFInfo
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- CN1073683A CN1073683A CN92113666A CN92113666A CN1073683A CN 1073683 A CN1073683 A CN 1073683A CN 92113666 A CN92113666 A CN 92113666A CN 92113666 A CN92113666 A CN 92113666A CN 1073683 A CN1073683 A CN 1073683A
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- diacetyl
- gelucystine
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Abstract
具有免疫调节作用的N,N′-二乙酰胱氨酸的新
结晶有机盐、其制备方法、含有该盐的药物组合物及
其药理应用方法。
Description
本发明涉及具有免疫调节活性的N,N′-二乙酰胱氨酸的有机盐、以及以这些盐为基础的药物组合物及其药理应用方法。本发明具体涉及制备含有无毒有机阳离子的盐的方法,这些盐是不吸湿且在化学上具有稳定性的结晶盐,可用于治疗表现出免疫系统缺陷症状的疾病。
N-乙酰-L-半胱氨酸是一种公知的化合物,常用作慢性阻塞性疾病和慢性支气管炎的治疗剂。虽然早在1964年就有人申请了有关该化合物的第一个专利(GB954268),但尚未阐明其作用机理。最近发现,N-乙酰-L-半胱氨酸的相应二硫化物,即N,N′-二乙酰-L-胱氨酸,具有强效免疫刺激剂的作用(瑞典专利申请SE9002067-8),其活性与现有的免疫刺激剂如二乙基二硫代氨基甲酸钠或2,2′-联硫基双乙醇差不多。
已有许多专利报道了制备N,N′-二乙酰胱氨酸的合成路线(美国专利4,827,016、4,724,239和4,708,965;欧洲专利300100;德国专利2326444)。但N,N′-二乙酰胱氨酸无定形且吸湿,因而难于分离和制成药物组合物,通常只能以水溶液形式施用。N,N′-二乙酰胱氨酸与无机或有机阳离子所成的盐,多数都具有与游离二酸相同的不利物理性质。专利文献中也出现了其他含硫氨基酸的盐的例子(美国专利3,647,834、日本专利56155298和法国专利8106592)。
现已出人意料地发现,有几种N,N′-二乙酰胱氨酸与有机碱所成的盐,具有不吸湿性与结晶性的有利组合,使这些盐能以固体形式分离出来并制成制剂,并能以固体形式吸入施用,如果临床上需要也可以以其他干制剂形式施用。
本发明提供具有式Ia或Ib的N,N′-二乙酰胱氨酸的有机盐:
其中R+有R2+分别为单质子化和二质子化的有机胺。该有机胺选自赖氨酸鎓、1,2-乙二胺、N,N′-二苄基-1,2-乙二铵、N-苄基-2-苯基乙铵、哌嗪鎓、1-金刚铵。
赖氨酸鎓可以是D型或L型。最优选的是L型。
本发明包括水合盐和溶剂化盐,例如被低级烷类溶剂化的盐。本发明包括N,N′-二乙酰胱氨酸盐的单个异构体,即D型、L型、内消旋型及外消旋型。最优选的是这些盐的L型。
我们发现,本发明的新型盐满足易于结晶、不吸湿及化学上稳定的要求,同时仍保留了N,N′-二乙酰胱氨酸的免疫调节活性,因而可在医学上使用。
因此,本发明所提供的化合物所具有的性质,有利于治疗可能由于无免疫反应、免疫反应失常或宿主防御无效而引起的疾病。这些疾病包括慢性支气管炎。据以前报道,免疫反应调节剂,如Biostim(Radermecker,M.等,Int.J.Immunopharm ac.10∶913-917,1988;Scheffer,J.等,Arzneim.Forsch/Drug Res.41∶815-820,1991)、Ribomunyl和Broncho Vaxom(Paupe,J.Respiration 58∶150-154,1991),以及N-乙酰半胱氨酸(参见Bergstrand,H.等,J.FreeRadic.Biol.Med.2∶119-127,1986),能降低慢性支气管炎的恶化速度。
这类疾病还包括某些形式的恶性疾病。因此,世界上许多研究机构都致力于寻找刺激各类恶性疾病患者免疫反应的途径,文献中也有许多综述阐述这一课题(Stevenson,F.K.FASEB J.5∶2250-2257,1991)。举一个例子:颅内肿瘤(神经胶质瘤)患者的免疫性大大降低,这可能是由于这些患者的T细胞内IL-2分泌和IL-2受体表达的缺陷(Roszman,T.等,Immunology Today 12∶370-374,1991)。另外据记载,免疫刺激剂在咪唑在黑素瘤和结肠癌的免疫疗法中有显著的辅助作用(Van Wauwe,J.和Janssen,P.A.J.,Int.J.Immunopharmac.13∶3-9,1991)。用IL-2在体内进行免疫治疗,或者用IL-2在体外处理患者的经过淋巴细胞活素活化的杀伤细胞,在所选择的患者体内引起癌的消退(Rosenberg,S.A.,Immunology Today 9∶58-,1988)。可望用化合物I产生有益效果的恶性疾病包括:间质起源的肿瘤,例如象纤维肉瘤、粘液肉瘤、脂肉瘤、软骨肉瘤、成骨肉瘤或脊索瘤一类的肉瘤;象血管肉瘤、内皮肉瘤、淋巴管肉瘤、滑膜肉瘤或间皮肉瘤一类的肉瘤;象粒细胞性白血病、单核细胞性白血病、淋巴细胞性白血病、恶性淋巴瘤、浆细胞瘤、网状细胞肉瘤或何杰金病一类的白血病和淋巴瘤;象平滑肌肉瘤或横纹肌肉瘤一类的肉瘤;上皮来源的肿瘤(癌),如鳞状上皮细胞癌、基底细胞癌、汗腺癌、皮脂腺癌、腺癌、乳头癌、乳头腺癌、囊腺癌、髓样癌、未分化癌、支气管癌、黑素瘤、肾细胞癌、肝细胞瘤-肝细胞癌、胆管癌、移行细胞癌、绒膜癌、精原细胞瘤或胚胎性癌;中枢神经系统肿瘤,如神经胶质瘤、脑膜瘤、成神经管细胞瘤、神经鞘瘤或室管膜瘤。
此外,这些化合物的性质还有利于治疗那些据以前报道可以用免疫刺激剂(如左咪唑)治疗来改善临床症状的慢性感染,如疱疹、口疮性口炎和微小变化综合症(minimal change syndrome);以及可受益于用免疫刺激剂(如Biostim、Broncho-Vaxom和Ribomunyl)治疗的尿道或耳、鼻、喉的其他慢性炎性疾病,或HIV感染或艾滋病。
另外据猜测,在诸如特应性皮炎、鼻炎和哮喘等特定性疾病中,存在着免疫反应的损害、缺陷或失调(Katz,D.H.Transplantation Reviews 41∶77-108,1977)。从理论上推测,刺激免疫反应可能是使免疫失调和自身免疫病康复的最佳途径(Varela,F.J.和Coutinho,A.Immunology Today 12∶159-166,1991),所以,可以预计这些化合物的性质也有利于治疗哮喘、鼻炎、特应性皮炎和自身免疫疾病,如非肥胖性糖尿病、全身性红斑狼疮、硬皮病、斯耶格伦综合症、皮肤肌炎或多发性硬化、类风湿性关节炎,可能还有牛皮癣。
另外,这些化合物由于具有免疫刺激性质,预计在各种形式的疫苗制剂中能够具有优异的佐剂性质。
最后,可以预计这些化合物的性质有利于治疗动脉粥样硬化,而不论它是否影响这种病症中公认的发炎过程(Hansson.G.K.等,Proc.Nat.Acad.Sci.USA 88∶10530,1991)。
治疗肿瘤生长的免疫刺激药的重要性,以我们的相关肿瘤生长测试体系来说明。下述的大鼠肿瘤实验模型,很清楚地反映了与业已成熟的免疫刺激药左咪唑相比,本发明化合物的肿瘤抑制效力。这些模型在临床上很清楚地反映了一种快速生长的肿瘤(乳腺癌)和一种缓慢进行性生长的肿瘤(神经胶质瘤)。在这两种体系中,上述药物对肿瘤生长都具有优异的抑制作用。
特别适于用本发明化合物治疗的疾病有:恶性肿瘤、例如黑素瘤、乳腺癌、胃肠癌、神经胶质瘤、膀胱癌、以及颈部和头部的鳞状上皮细胞癌;感染,例如慢性支气管炎、肝炎、感染后无反应、以及获得性免疫缺陷(如艾滋病);创伤后无免疫反应;有关的自身免疫疾病,例如类风湿性关节炎、多发性硬化和牛皮癣。
治疗上述疾病的有效剂量在每天0.1-100mg的范围,优选1.0-60mg。
制备方法
式Ia和Ib有机盐的一般制备方法是,将上述的N,N′-二乙酰胱氨酸和有机碱分别溶解或分散在溶剂或溶剂混合物中,再将二者混合起来。可以使用的溶剂有水、醇类、二元醇类、酮类、酰胺类、亚砜类、或其他极性溶剂或溶剂混合物。所生成的盐或者直接从反应混合物中沉淀出来,或者通过加入极性较弱的溶剂,或通过蒸发或冰冻干燥而得到。该反应依反应物在介质中的溶解度而在高温或室温下进行。也可以先在水溶液或醇溶液中氧化适当的N-乙酰半胱氨酸盐,再如上所述通过沉淀制得盐。既可以用化学方法利用(例如)过氧化氢或卤素进行氧化,也可用电化学法进行氧化。
药物制剂
按照本发明,式Ia和Ib化合物可以用或不用可药用载体配成制剂,以供吸入给药及以其他途径给药,如口服或局部给药。
这些物质可以由加压定量吸入器吸入,也可以由干粉吸入器如Turbuhaler吸入,也可以由使用明胶胶囊、塑料胶囊或其他胶囊的干粉吸入器吸入。可以在粉状物质中加入化学上惰性的无毒物质,例如乳糖、海藻糖、甘露糖醇或葡萄糖。
该物质也可以以胶囊剂或片剂的形式口服给药,其中的胶囊、药片或活性物质本身,可以包衣也可以不包衣。这种包衣可以由(例如)异丙醇或其他合适溶剂中的羟丙基纤维素和高分散硅胶组成。可以在粉状物质中加入化学上惰性的无毒物质,以达到理想的物理或药学性质。
这些新化合物也可以肠胃外给药。
药理实验
化合物N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐(Ia;R=赖氨酸)调节免疫反应的能力,以其在小鼠迟发型超敏反应(DTH)的动物试验中的效力来说明。
使用体重为18-20克的雄性和雌性Balb/c小鼠(得自丹麦的Bomholtsgaard)。4-乙氧基亚甲基-2-苯基噁唑啉-5-酮(OXA)购自BDH(英格兰),在本试验中作为抗原。
在第0天给小鼠腹部备皮,用含有3%OXA的150μl无水乙醇-丙酮(3∶1)溶液涂在腹部上表皮上,使小鼠致敏。致敏后立即开始口服二硫化物盐或媒液(0.9%NaCl)处理,并保持每天处理一次,直到第6天。致敏7天后(第6天),所有小鼠的两只耳朵都在两侧局部涂以20μl1%OXA的花生油溶液进行激发。激发前、激发24小时或48小时后,用Oditest弹簧卡尺测量耳厚。激发和测量在轻微戊巴比妥麻醉下进行。
DTH反应的强度以下式表示:Tt24/48-TtO(μm),其中t0、T24和t48分别代表各次试验(T)中激发前、激发24小时或48小时后的耳厚。结果以平均值±平均标准误差来表示。用“学生”双尾t检验法计算出各组平均值之间的显著性水平。表1和表2分别显示了由一个代表性实验得到的24小时和48小时测量的结果。耳厚的增加比之对照组有显著性差异,反映了化合物的免疫刺激效力。例如,处理组动物24小时后的反应约为对照组动物的两倍(15μm比8μm,表1)。
表1
用所示剂量的N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐或媒液(NaCl)处理过的动物激发24小时后的耳厚
剂量 N 差值 平均标准误差 症状
(微摩尔/千克) Tt24-Tt0
NaCl 10 8.25 0.56
0.03 10 15.00 0.42 ***
3.0 10 15.80 0.77 ***
***P<0.001.
表2
用所示剂量的N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐或媒液(NaCl)处理过的动物激发48小时后的耳厚
剂量 N 差值 平均标准误差 症状
(微摩尔/千克) Tt48-Tt0
NaCl 10 8.83 0.31
0.03 10 12.55 0.41 ***
3.0 10 13.20 0.28 ***
***P<0.001.
同一试验化合物(Ia,R=赖氨酸)延长或增加患有肿瘤的大鼠存活时间的能力,用两个不同的大鼠肿瘤接种实验来说明。
将Wistar Furth品系大鼠分为两组,每组10只,给每只大鼠皮下接种104个乳腺癌细胞,每周测量肿瘤大小两次。一组大鼠饮用普通水,另一组大鼠饮用试验化合物的水溶液达到每千克动物体重每天0.03微摩尔的剂量。38天后,饮水组中只有一只动物仍然存活,而饮化合物组有七只动物存活。
在另一个实验中,将Lewis品系大鼠分为三组,每组10只,给每只大鼠皮下接种106个神经胶质瘤细胞,每周测量肿瘤大小两次。一组大鼠饮用普通水,第二组大鼠饮用试验化合物的水溶液达到每千克动物体重每天0.03微摩尔的剂量,而第三组大鼠饮用含左咪唑(一种公知的抗癌药)的水,其剂量也是每千克动物体重每天0.03微摩尔。119天后,饮水组中已没有大鼠存活。在饮用试验化合物那一组中,有六只大鼠仍然存活,而饮用左咪唑那一组中,119天后有三只大鼠存活。
在两个肿瘤实验中,肿瘤阳性动物的出现频率都比较低。在两个实验中,饮用化合物水溶液的实验组中已形成的肿瘤的生长都受到抑制。
在另一个实验中,将SCID小鼠(患有严重联合免疫缺陷病的小鼠)分为两组,每组8只,分别用2×103个乳腺癌细胞接种,每周测量其生长两次。一组小鼠饮用普通水,第二组小鼠饮用试验化合物的水溶液达到每千克动物体重每天0.03微摩尔的剂量。这两组的生长速度和发病率都没有显著性差异。这表明,该化合物对肿瘤细胞并没有直接的影响,而是通过免疫系统而起作用的。
在一个狼疮(实验性鼠全身性红斑狼疮(SLE))动物模型中,MRL 1pr/1pr小鼠自发产生淋巴增生、皮炎、关节炎和肾小球性肾炎。在这个鼠狼疮模型中,研究了N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐对由肾小球性肾炎引起的蛋白尿和血尿以及动物存活率的影响。N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐在饮用水中给予,并通过计算使平均剂量为0.03微摩尔/千克/天。对照小鼠则给予自来水。两组小鼠均随意摄取饮用水。在动物达到8周龄时开始进行处理,并持续到死亡或46周龄,届时结束实验。
蛋白尿和血尿的评定用Boehringer Mannheim公司的Eour-Test试剂条进行。
给予N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐后,存活率比对照小鼠显著提高。未处理组(21只)的死亡率在25周龄左右时达到50%。而经过N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐处理的MRL-lpr/lpr小鼠(12只),直到44周龄时死亡率仍未达到50%。
这种形式的处理还使蛋白尿和血尿的评分都比未处理组显著改善,这种评分是以试剂条的任意单位来量度的。
这些结果表明了本发明化合物的免疫调节效力,尤其是对全身性红斑狼疮的免疫调节效力。
实施例
药物制剂
下列实施例代表准备以不同方式局部施用和全身性施用的药物制剂。
实施例1
供吸入的加压气雾剂
该气雾剂体系设计成每个计量剂量含 0.1-1.0mg。
粉碎的化合物Ia或Ib 1.0%(W/W)
脱水山梨糖醇三油酸酯 0.7%(W/W)
三氯一氟甲烷 24.4%(W/W)
二氯四氟乙烷 24.4%(W/W)
二氯二氟甲烷 49.5%(W/W)
实施例2
供吸入纯物质的粉末气雾剂
制备供由Turbuhaler吸入的纯物质。
每个单次剂量含0.1-1.0mg。
经过加工的化合物Ia或Ib 0.1-1.0mg
实施例3
供吸入的粉末气雾剂
每个单次剂量含0.1-1.0mg/胶囊。
粉碎的化合物I 0.1-1.0mg
乳糖 50mg
实施例4
供喷雾的溶液
该溶液每毫升含1.0-10.0mg,每个单次剂量可施用1-3ml。
化合物I 1.0-10.0mg
注射和水 加至1.0ml
实施例5
片剂
每片含:
化合物I 0.1-100mg
玉米淀粉 50mg
乳糖 150mg
聚乙烯吡咯烷酮 7mg
微晶纤维素 20mg
硬脂酸镁 2mg
实施例6
口服液
一个10ml的单次剂量含10-100mg。
化合物I 1-10mg
70%山梨糖醇 150mg
甘油 100mg
苯甲酸钠 1mg
调味剂 适量
纯化水 加至1.0ml
实施例7
缓释片剂
1片中含有:
化合物I 1-100mg
特种石蜡 145mg
乳糖粉末 50mg
胶体二氧化硅 5mg
10厘泊的乙基纤维素 13mg
99.5%(体积)乙醇 85mg
硬脂酸镁 2.5mg
实施例8
缓释粒剂
1克粒含有:
化合物I 1-100mg
乙基纤维素分散体 10mg
乙酰柠檬酸三丁酯 0.5mg
Eudragit L 100-55 55mg
柠檬酸三乙酯 5mg
滑石 30mg
新蒸水 350mg
中性颗粒 加至1000mg
实施例9
注射液
1ml的一个单次剂量含有1.0-10.0mg。
化合物Ia或Ib 1.0-10.0mg
氯化钠 8.9-7.7mg
注射用水 加至1.0ml
实施例10
供局部涂用的霜剂
1克霜剂含有:
化合物I 0.1-1mg
软白石蜡 75mg
液体石蜡 10mg
十六醇十八醇混合物 75mg
聚乙二醇1000单鲸蜡基醚 20mg
尼泊金甲酯 0.8mg
尼泊金丙酯 0.2mg
纯化水 加至1.0g
实施例11
供局部涂用的软膏
1克软膏含有:
化合物I 0.1-1mg
液体石蜡 150mg
软白石蜡 加至1.0g
实施例12
滴眼液
一个2滴的剂量含有0.01-0.1mg化合物I。
化合物I 0.1-1mg
洁尔灭 0.1mg
氯化钠 9.0mg
无菌水 加至1.0ml
化学
实施例13
N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐(Ia;R=H2N(COOH)CH(CH2)4NH3):
将N-乙酰-L-半胱氨酸(22摩尔,3.59千克)溶于2.6升去离子水中。在搅拌下加入45%氢氧化钠水溶液(22摩尔,1.92千克),温度保持低于20℃。将温度调节到5℃,然后在90分钟时间内小心滴加过氧化氢(11.0摩尔,0.95升)。在滴加过程中温度保持不超过10℃。在所得溶液中加入9升经过活化的强酸型阳离子交换剂。搅拌10分钟后pH为2.0,滤掉离子交换剂。利用由纯物质制得的标准物,用HPLC法测得滤液中含有9.65摩尔N,N′-二乙酰-L-胱氨酸。在这个粗制溶液中加入L-赖氨酸(19.3摩尔,3.17千克)。将形成的粘稠溶液缓慢地加到50升含有0.23千克结晶N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐的回流乙醇中。加完后,使该浆液冷却,滤出晶体。用乙醇(8升)洗涤并干燥(真空,40℃)12小时,得到5.36千克(90%)标题物质,为白色结晶固体。
物理数据:Mp:210℃(分解);[α]D 25=-70°(c=0.54,H2O);1H-NMR(D2O)δ:1.36-1.60[4H,m,LysγCH2],1.73[4H,p,LysδCH2],1.84-1.96[4H,m,LysβCH2],2.05[6H,s,CH3],2.95[2H,dd,CH2S],3.02[4H,t,LysεCH2],3.25[2H,dd,CH2S],3.76[2H,t,LysαCH],4.50[2H,dd,CHN]13C-NMR(D2Oδ:24.27;24.80;29.24;32.72;41.89;42.78;52.96;57.30;176.53;177.41;179.74;元素分析计算值:C22H44O10N6S2,C:42.8H:7.2N:13.6实测值C:42.6H:7.4N:13.7;MSm/z=325(MH+),m/z=471(MLysH+),m/z=617(MLys2H+).
实施例14
N,N′-二乙酰-L-胱氨酸-1,2-乙二铵盐(Ib;R=H3NCH2CH2NH3):
在N,N′-二乙酰-L-胱氨酸(30.9毫摩尔,10克)的20ml水溶液中,加入1,2-乙二胺(61.8毫摩尔,3.73克)和乙醇(30ml)。将该溶液浓缩成粘稠糊状物,并重新溶解于80ml乙醇中。在10℃下搅拌2小时后出现结晶。过滤并干燥后得到6.2克(45%)标题化合物。
物理数据:Mp185.2-192.4℃.1H-NMR(D2O)δ;2.06[6H,s,CH3],2.96[2H,dd,CH2S],3.26[2H,dd,CH2S],3.28[4H,sH,H3N+CH2CH2N+H3],4.50[2H,dd,CHN].
13C-NMR(D2O)δ:24.78;39.99;42.74;56.98;176.55;179.82;元素分析计算值C:37.5,H:6.3,N:14.6,S:16.7.实测值C:37.3,H:6.8,N:15.3,S:15.2;MS m/z=385[M(H2NCH2CH2NH2)H+]
实施例15
N,N′-二乙酰-L-胱氨酸N,N′-二苄基-1,2-乙二铵盐(Ib;R=PhCH2NH2CH2CH2NH2CH2Ph):
在N,N′-二乙酰-L-胱氨酸(67毫摩尔,21.8克)的63%水溶液中,加入N,N′-二苄基-1,2-乙二胺(67毫摩尔,16.0克)。经过放热反应,得到一种略呈油性的产物,可以用水使其重结晶而得到12.0克(32%)标题物质,为白色针状结晶。
物理数据:Mp 163.8-165.3℃.1H-NMR(D2O)δ:2.04[6H,s,CH3],2.93[2H,dd,CH2S],3.22[2H,dd,CH2S],3.44[4H,s,CH2NBn],4.27[4H,s,PhCH2N],4.47[2H,dd,CHN],7.44-7.54[10H,m,Ph].13C-NMR(D2O)δ:24.82,42.82,45.71,54.47,56.99,132.22,132.58,132.67,133.52,176.56,179.80.元素分析(单水合物)计算值C:53.6,H:6.6,N:9.6,S:11.0.实测值C:54.5,H:6.6,N:9.6,S:11.2.
实施例16
N,N′-二乙酰-L-胱氨酸二(1-金刚铵)盐(Ia;R=[C(1)CH(3,5,7)CH2(2,4,6,8,9,10)NH3]
在N,N′-二乙酰-L-胱氨酸(5.35毫摩尔,1.73克)的5ml水溶液中,加入1-金刚胺(10.7毫摩尔,1.61克)。向该溶液中滴加60ml丙酮。滤出所得的结晶盐并真空干燥,得到2.3克(67%)标题化合物。
物理数据:Mp 162℃,1H-NMR(D2O)δ:1.71[12H,宽 dd,CH2(4,6,10)],1.87[12H,d,CH2(2,8,9)],2.05[6H,s,CH3],2.17[6H,宽 s,CH(3,5,7)],2.96[2H,dd,CH2S],3.26[2H,dd,CH2S],4.50[2H,dd,CHN]
实施例17
N,N′-二乙酰-L-胱氨酸二(N-苄基-2-苯基乙铵)盐(Ia;R=PhCH2CH2NH2CH2Ph):
在N,N′-二乙酰-L-胱氨酸(28.7毫摩尔,9.3克)的20ml水溶液中,加入N-苄基-2-苯基乙胺(57.4毫摩尔,12.1克)。将该溶液浓缩成粘稠糊状物,从中缓慢结晶出盐,分离并干燥结晶的标题化合物。
物理数据:Mp87℃.1H-NMR(D2O)δ:2.05[6H,s,CH3],2.95[2H,dd,CH2S],3.04[4H,t,PhCH2C],3.24[2H,dd,CH2S],3.33[4H,t,CH2NBn],4.25[4H,s,PhCH2N],4.49[2H,dd,CHN],7.30-7.52[20H,m,Ph]
实施例18
N,N′-二乙酰-L-胱氨酸哌嗪鎓盐(Ib;R=NH2(1,4)CH2(2,3,5,6)]
在N,N′-二乙酰-L-胱氨酸(4.60毫摩尔,1.49克)的5ml水溶液中,加入哌嗪(4.60毫摩尔,0.90克)。向该溶液中加入足够的异丙醇形成油状物,该油状物缓慢固化。分离出盐并干燥。
物理数据:Mp>170℃(分解)1H-NMR(D2O)δ:2.05[6H,s,CH3],2.96[2H,dd,CH2S],3.26[2H,dd,CH2S],3.42[8H,s,CH2(2,3,5,6)],4.49[2H,dd,CHN]
实施例19
N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐(Ia;R=H2N(COOH)CH(CH2)4NH3)
将N-乙酰-L-半胱氨酸(37毫摩尔,6.0克)和L-赖氨酸(37毫摩尔,5.4克)溶于10ml去离子水中。搅拌下滴加过氧化氢(18毫摩尔,1.5ml),并保持温度低于25℃。将该溶液再搅拌4小时。将该粘稠溶液缓慢加到150ml含有0.50克结晶N,N′-二乙酰-L-胱氨酸二-L-赖氨酸鎓盐的回流乙醇中。加完后使溶液冷却,滤出结晶。用乙醇(20ml)洗涤并干燥(真空,45℃)24小时,得到10.0克(84%)标题物质,为白色结晶固体。
物理数据:Mp:208℃;[α]25D=-73°(c=0.54,H2O)
Claims (14)
2、根据权利要求1的N,N′-二乙酰-L-胱氨酸的盐。
3、一种制备如权利要求1或2所述化合物的盐的方法,该方法包括:用有机碱或含有有机碱阳离子的盐处理N,N′-二乙酰胱氨酸,其中各反应物溶解或分散在溶剂或溶剂混合物中;分离该盐,其中该盐可以是水合形式或溶剂化形式。
4、一种制备如权利要求1或2所述盐的方法,该方法包括,氧化N-乙酰半胱氨酸和有机碱的盐,并分离出N,N′-二乙酰胱氨酸的盐,其中该盐可以是水合形式或溶剂化形式。
5、一种药物组合物,该组合物包含根据权利要求1或2的N,N′-二乙酰胱氨酸盐作为活性成分。
6、一种如权利要求5所述的药物组合物,该组合物用于由加压定量吸入器施用、由干粉吸入器施用、或者由使用明胶胶囊、塑料胶囊或其他胶囊的干粉吸入器施用。
7、如权利要求5或6所述的药物组合物,该组合物中加有可药用的载体。
8、如权利要求5所述的药物组合物,其形式为胶囊剂或片剂。
9、如权利要求8所述的药物组合物,该组合物含有可药用的载体。
10、如权利要求5所述的药物组合物,该组合物用于以溶液形式喷雾施用。
11、根据权利要求1或2的盐,该盐作为具有治疗活性的物质使用。
12、根据权利要求1或2的盐,该盐用于治疗恶性疾病。
13、根据权利要求1或2的盐在制备且有免疫调节活性的药物中的应用。
14、根据权利要求1或2的盐在制备用于治疗恶性疾病的药物中的应用。
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CN92113666A Expired - Fee Related CN1039586C (zh) | 1991-11-29 | 1992-11-28 | 制备n,n′-二乙酰胱氨酸的有机盐的方法 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1059907C (zh) * | 1997-05-23 | 2000-12-27 | 中国石油化工集团公司巴陵石化岳阳石油化工总厂 | 一种含共轭二烯轻聚合物的选择氢化方法 |
Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3865463A (en) * | 1973-11-12 | 1975-02-11 | Busch & Co Inc Ag | Electrical adapter plug |
EP0715853A1 (en) * | 1991-01-10 | 1996-06-12 | Transcend Therapeutics, Inc. | Use of glutathione esters for the treatment of pulmonary diseases |
US5747459A (en) * | 1991-02-04 | 1998-05-05 | Nestec, Ltd. | Method for insuring adequate intracellular glutathione in tissue |
US5430045A (en) * | 1992-04-23 | 1995-07-04 | Free Radical Sciences, Inc. | Method of reducing or preventing bone marrow hypoplasia |
US5447712A (en) * | 1993-12-09 | 1995-09-05 | Free Radical Sciences | Method of reducing cyclophosphamide induced hemorrhagic cystitis |
SE9500897D0 (sv) * | 1995-03-14 | 1995-03-14 | Astra Ab | The pharmacological use of certain cystine derivatives |
SE9602262D0 (sv) * | 1996-06-06 | 1996-06-06 | Astra Ab | New use of derivatives of cystine |
AR007398A1 (es) * | 1996-06-18 | 1999-10-27 | Astrazeneca Ab | Proceso para preparar sales inorganicas de n-n'-diacetilcistina |
US6017959A (en) * | 1996-06-18 | 2000-01-25 | Astra Aktiebolag | Forms of organic salts of N,N'-diacetylcystine |
SE9602416D0 (sv) * | 1996-06-18 | 1996-06-18 | Astra Ab | New forms of an organic salt of N'N-diacetylcystine |
US6197749B1 (en) * | 1997-10-29 | 2001-03-06 | Ajinomoto Co., Inc. | Method of suppressing immune responses by reducing intracellular content of glutathione in macrophages and monocytes |
US20030203006A1 (en) * | 1997-10-29 | 2003-10-30 | Ajinomoto Co. Inc. | Immunomodulator |
SE9800932D0 (sv) * | 1998-03-20 | 1998-03-20 | Astra Ab | New compunds |
EP1004302A3 (en) * | 1998-10-29 | 2003-06-04 | Ajinomoto Co., Inc. | Immunomodulator |
SE9900438D0 (sv) * | 1999-02-10 | 1999-02-10 | Astra Ab | The pharmacological use of certian cystine derivatives |
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
SE518784C2 (sv) * | 2000-12-27 | 2002-11-19 | Nactilus Ab | "N-Acetyl-L-cystein med kompositioner för behandling av neoplasier" |
JPWO2002072040A1 (ja) * | 2001-03-13 | 2004-07-02 | 味の素株式会社 | 化粧料または皮膚外用剤 |
WO2003080149A2 (en) | 2002-03-20 | 2003-10-02 | Mannkind Corporation | Inhalation apparatus |
DE602005024413D1 (de) | 2004-08-20 | 2010-12-09 | Mannkind Corp | Katalyse der diketopiperazinsynthese |
ES2540886T3 (es) | 2004-08-23 | 2015-07-14 | Mannkind Corporation | Sales de dicetopiperazina para la administración de fármacos |
KR101557502B1 (ko) | 2005-09-14 | 2015-10-06 | 맨카인드 코포레이션 | 결정질 미립자 표면에 대한 활성제의 친화력의 증가를기반으로 하는 약물 제제의 방법 |
AU2007216966C1 (en) | 2006-02-22 | 2014-03-20 | Mannkind Corporation | A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent |
US8438729B2 (en) * | 2006-03-09 | 2013-05-14 | Canon Kabushiki Kaisha | Method of producing liquid discharge head |
PL2293833T3 (pl) * | 2008-06-13 | 2016-08-31 | Mannkind Corp | Inhalator proszkowy i układ do dostarczania leku |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
EP2609954B1 (en) * | 2008-06-20 | 2021-12-29 | MannKind Corporation | An interactive apparatus for real-time profiling of inhalation efforts |
TWI532497B (zh) | 2008-08-11 | 2016-05-11 | 曼凱公司 | 超快起作用胰島素之用途 |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
EP2405963B1 (en) | 2009-03-11 | 2013-11-06 | MannKind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
KR20180079458A (ko) | 2009-06-12 | 2018-07-10 | 맨카인드 코포레이션 | 한정된 비표면적을 갖는 디케토피페라진 마이크로입자 |
US9016147B2 (en) | 2009-11-03 | 2015-04-28 | Mannkind Corporation | Apparatus and method for simulating inhalation efforts |
CA2801936C (en) | 2010-06-21 | 2021-06-01 | Mannkind Corporation | Dry powder drug delivery system and methods |
EP2694402B1 (en) | 2011-04-01 | 2017-03-22 | MannKind Corporation | Blister package for pharmaceutical cartridges |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
EP2776053A1 (en) | 2011-10-24 | 2014-09-17 | MannKind Corporation | Methods and compositions for treating pain |
CN102491926B (zh) * | 2011-12-15 | 2013-09-25 | 青岛市药品检验所 | 一种硫普罗宁二硫化物的制备和纯化方法 |
AU2013289957B2 (en) | 2012-07-12 | 2017-02-23 | Mannkind Corporation | Dry powder drug delivery systems and methods |
EP2911690A1 (en) | 2012-10-26 | 2015-09-02 | MannKind Corporation | Inhalable influenza vaccine compositions and methods |
KR102499439B1 (ko) | 2013-03-15 | 2023-02-13 | 맨카인드 코포레이션 | 미세결정성 디케토피페라진 조성물 및 방법 |
MX2020009878A (es) | 2013-07-18 | 2022-07-27 | Mannkind Corp | Composiciones farmaceuticas en polvo seco estables al calor y metodos. |
JP2016530930A (ja) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | 通気装置及び方法 |
US10307464B2 (en) | 2014-03-28 | 2019-06-04 | Mannkind Corporation | Use of ultrarapid acting insulin |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
US20230157939A1 (en) * | 2020-04-28 | 2023-05-25 | Conopco, Inc., D/B/A Unilever | Personal care compositions with enhanced solubility actives |
EP4216939A1 (en) * | 2020-09-28 | 2023-08-02 | Georgia Tech Research Corporation | Use of cystine and derivatives thereof as anti-thrombotic and thrombolytic agents |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB592631A (en) * | 1945-04-04 | 1947-09-24 | Du Pont | Cysteine and cystine |
GB954268A (en) | 1962-02-26 | 1964-04-02 | Mead Johnson & Co | Decongestant compositions comprising n-acylated sulphydryl compounds |
FR8205M (zh) * | 1968-12-20 | 1970-09-14 | ||
US3647834A (en) * | 1969-08-11 | 1972-03-07 | Mead Johnson & Co | Zinc mercaptide n-acetylcysteine carboxylate salts |
US3878305A (en) * | 1972-05-25 | 1975-04-15 | Procter & Gamble | Fortification of foodstuffs with n-acyl derivatives of sulphur-containing l-amino acids |
US3952115A (en) * | 1975-04-02 | 1976-04-20 | The Procter & Gamble Company | Fortification of foodstuffs with N-acyl derivatives of sulfur-containing L-amino acid esters |
US4141734A (en) * | 1975-09-11 | 1979-02-27 | Ciba-Geiby Ag | Photographic developing process |
US4093739A (en) * | 1977-06-15 | 1978-06-06 | Mead Johnson & Company | Mercaptoacylamidobenzoyl glycine and mucolytic process |
JPS6011888B2 (ja) * | 1978-10-11 | 1985-03-28 | 参天製薬株式会社 | リウマチ疾患治療薬 |
JPS56155298A (en) | 1980-05-02 | 1981-12-01 | Tanabe Seiyaku Co | Shampoo composition |
GB2097256B (en) * | 1981-04-02 | 1985-05-30 | Morelle Jean V | Compositions containing n-butyryl alphaaminoacids |
FR2503151A1 (fr) * | 1981-04-02 | 1982-10-08 | Morelle Jean | Butyryminoacides soufres. mode de preparation. emploi comme element keratogenique chez l'homme et l'animal et comme agent de fertilisation chez les vegetaux |
JPS58164566A (ja) * | 1982-03-09 | 1983-09-29 | Kenji Okawa | シスチン類の製造法 |
US4708965A (en) * | 1985-09-16 | 1987-11-24 | Morgan Lee R | Method of treating herpes virus infections with N,N'-diacetylcystine and derivatives |
US4827016A (en) * | 1985-09-16 | 1989-05-02 | Morgan Lee R | Method and compounds for reducing dermal inflammations |
US4724239A (en) * | 1985-09-16 | 1988-02-09 | Morgan Lee R | Method of treating chemical ulcers with N,N'-diacetylcystine, N-acetyl homocysteine and N-acetyl cysteine |
JPH0660157B2 (ja) * | 1985-11-20 | 1994-08-10 | 三井東圧化学株式会社 | システインからシスチンを製造する方法 |
JPS62195356A (ja) * | 1986-02-20 | 1987-08-28 | Seiwa Kasei:Kk | シスチン誘導体及びその塩 |
AT402931B (de) * | 1986-11-07 | 1997-09-25 | Pharmacia Gmbh | Verfahren zur herstellung von neuen cystinverbindungen und derenverwendung |
SE8704542D0 (sv) * | 1987-11-19 | 1987-11-19 | Draco Ab | New derivatives of cysteine |
IL98310A (en) * | 1990-06-08 | 1996-08-04 | Astra Ab | Medicinal preparations containing a history of cystine |
TW221376B (zh) * | 1990-06-28 | 1994-03-01 | Astra Ab | |
GB9111885D0 (en) * | 1991-06-03 | 1991-07-24 | Erba Carlo Spa | Nerve growth factor for use in the prevention and treatment of viral infections |
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1991
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1059907C (zh) * | 1997-05-23 | 2000-12-27 | 中国石油化工集团公司巴陵石化岳阳石油化工总厂 | 一种含共轭二烯轻聚合物的选择氢化方法 |
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