CN110267658B - 用sGC刺激剂治疗CNS疾病 - Google Patents
用sGC刺激剂治疗CNS疾病 Download PDFInfo
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- CN110267658B CN110267658B CN201780080543.0A CN201780080543A CN110267658B CN 110267658 B CN110267658 B CN 110267658B CN 201780080543 A CN201780080543 A CN 201780080543A CN 110267658 B CN110267658 B CN 110267658B
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Landscapes
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Abstract
本发明涉及单独或与一种或多种额外药剂组合的可溶性鸟苷酸环化酶(sGC)的刺激剂、其药学上可接受的盐及包含它们的药物制剂或剂型用于治疗各种CNS疾病的用途,其中sGC刺激的增加,或一氧化氮(NO)或3’,5’‑环单磷酸鸟苷(cGMP)或两者的浓度的增加,或NO通路的上调为希望的。
Description
相关申请
本发明要求2016年11月8日提交的美国临时申请62/419,059在35U.S.C.§119(e)下的申请日权益,将其全部内容通过引用并入本发明。
技术领域
本发明涉及单独或与一种或多种额外药剂组合的可溶性鸟苷酸环化酶(sGC)的刺激剂、其药学上可接受的盐及包含它们的药物制剂或剂型用于治疗各种CNS疾病的用途,其中期望增加sGC刺激,或增加一氧化氮(NO)或3’,5’-环单磷酸鸟苷(cGMP)或两者的浓度,或上调NO通路。
背景技术
可溶性鸟苷酸环化酶(sGC)为体内一氧化氮(NO)的主要受体。sGC可经由NO依赖性及NO非依赖性机理活化。回应于此活化,sGC将5’-三磷酸鸟苷(GTP)转化成次级信使3’,5’-环单磷酸鸟苷(cGMP)。cGMP水平增加转而调节下游效应物的活性,所述下游效应物包括蛋白激酶、磷酸二酯酶(PDE)及离子通道。
在体内,NO由精氨酸及氧通过各种一氧化氮合酶(NOS)酶且通过无机硝酸盐的依序还原来合成。已经鉴定出NOS的三种不同的同工型:可诱导型NOS(iNOS或NOS II),其见于活化的巨噬细胞中;组成型神经元性NOS(nNOS或NOS I),其参与神经传送及长程增强效应;及组成型内皮NOS(eNOS或NOS III),其调控平滑肌松弛及血压。实验及临床证据指示,降低的浓度、生物利用度和/或对内源产生的NO的反应性有助于许多疾病的发展。
当与其它类型的sGC调节剂相比时,NO非依赖性、血红素依赖性sGC刺激剂具有若干重要的区别化特性,包括其活性对减少的辅血红素部分的存在的关键依赖性、与NO组合时的强协同酶活化及通过直接刺激sGC而不依赖于NO来刺激cGMP合成。苄基吲唑化合物YC-1为欲鉴定的第一种sGC刺激剂。自此已经开发了对sGC具有改善的效力及特异性的额外sGC刺激剂。
以NO非依赖性方式刺激sGC的化合物提供优于其它当前替代性疗法的显著优势,所述替代性疗法靶向异常NO通路或靶向可受益于NO通路上调的疾病。需要开发新颖的sGC刺激剂。这些化合物可用于治疗各种疾病,其中所述疾病或障碍为将受益于sGC刺激或受益于NO或cGMP或两者的浓度增加的疾病或障碍,或其中NO通路的上调为希望的。
可穿过血脑屏障且穿透脑的sGC刺激剂提供用于治疗中枢神经系统(CNS)疾病的额外益处。本发明中所述的sGC刺激剂由于其穿过血脑屏障的能力而用于治疗CNS疾病。
发明内容
本发明涉及一种治疗或预防有需要的受试者的CNS疾病、健康状况或障碍的方法,该方法包含单独或以组合疗法向该受试者给药治疗有效量的化合物或其药学上可接受的盐,其中该化合物选自表I中描绘的那些化合物。
本发明也涉及一种药物组合物,其包含表I的化合物或其药学上可接受的盐,及至少一种药学上可接受的赋形剂或载体。本发明也涉及一种包含该药物组合物的剂型。
本发明也涉及一种治疗或预防有需要的受试者的CNS疾病、健康状况或障碍的方法,该方法包含单独或以组合疗法给药包含表I中描绘的化合物或其药学上可接受的盐的药物组合物或剂型。
本发明进一步涉及表I中描绘的sGC刺激剂或其药学上可接受的盐,或包含其的药物组合物或剂型用于治疗CNS疾病的用途。
本发明进一步涉及一种sGC刺激剂或包含其的药物组合物或剂型,其用于治疗CNS疾病,其中该sGC刺激剂为表I中描绘的sGC刺激剂或其药学上可接受的盐。
表I
在一些实施方案中,CNS疾病、健康状况或障碍选自阿尔茨海默病(AD)、肌萎缩侧索硬化(ALS或Lou Gehrig病)、唐氏综合征、痴呆、血管性痴呆(VD)、血管型认知损害、混合型痴呆、宾斯旺格痴呆(皮层下动脉硬化性脑病)、伴有皮质下梗塞及脑白质病变的脑体常染色体显性动脉病(cerebral autosomal-dominant arteriopathy with subcorticalinfarcts and leukoencephalopathy)(CADASIL或CADASIL综合征)、额颞叶退化或痴呆、HIV相关性痴呆(包括无症状性神经认知损害(ANI)、轻微神经认知障碍(MND),及HIV相关性痴呆(HAD)(也称为AIDS痴呆复合征(AIDS dementia complex)[ADC]或HIV脑病)、Lewy体痴呆、早老性痴呆(轻度认知损害或MCI)、青光眼、亨廷顿病(亨廷顿舞蹈症,HD)、多发性硬化(MS)、多系统萎缩(MSA)、帕金森病(PD)、帕金森叠加(Parkinsonism Plus)、脊髓小脑共济失调、Steel-Richardson-Olszewski病(进行性核上麻痹)、注意力缺陷障碍(ADD)及注意力缺陷多动症(ADHD)。
在其它实施方案中,疾病、健康状况或障碍为选自阿尔茨海默病或前阿尔茨海默病、轻度至中度阿尔茨海默病或中度至重度阿尔茨海默病的CNS障碍或病症。
在其它实施方案中,CNS障碍选自外伤性(闭合性或开放性)穿透性头部损伤、外伤性脑损伤(TBI)、非外伤性脑损伤(例如,中风(特别是缺血性中风)、动脉瘤、缺氧),或认知损害或由脑损伤或神经退行性障碍导致的功能障碍。
在其它实施方案中,CNS疾病或障碍选自:张力失常,包括例如广泛性、病灶性、节段性、性、中间、遗传性/原发性的张力失常或急性相斥性反应;或运动障碍,包括例如急性、慢性/迟发性,及非运动性及左旋多巴诱发的运动障碍(LID)。
在其它实施方案中,CNS疾病或障碍选自特征在于突触可塑性及突触过程相对降低的障碍,包括例如脆性x染色体病、Rhett障碍、威廉斯综合征、Renpenning综合征、泛自闭症障碍(ASD)、自闭症、Asperger综合征、弥漫性发育障碍或童年瓦解性障碍。
在其它实施方案中,CNS障碍为神经性疼痛。
在其它实施方案中,CNS障碍为选自以下的精神病性、精神性、情绪或情感障碍:双相型障碍、精神分裂症、一般精神病、药物诱发的精神病、妄想症、情感性分裂症、强迫性障碍(OCD)、抑郁障碍、焦虑障碍、惊恐障碍或创伤后应激障碍(PTSD)。
在其它实施方案中,CNS障碍选自化疗脑(chemo brain)、左旋多巴诱发的成瘾行为、酒精中毒、麻醉药依赖(包括但不限于苯丙胺、阿片剂或其它物质)及物质滥用。
附图说明
图1为野生型(WT)小鼠海马切片(中间曲线)、R6/2小鼠海马切片(底部曲线)及用855nM化合物I-5处理的R6/2小鼠海马切片(顶部曲线)的长程增强效应图。
具体实施方式
现将详细参照本发明一些实施方案,所述实施方案的实例以所附结构及结构式予以说明。尽管本发明将结合列举的实施方案进行描述,但应了解,其不旨在将本发明局限于所述实施方案。相反,本发明旨在涵盖可包括处于由权利要求所界定的本发明范围内的所有替代物、修改及等同物。本发明不限于本发明中所述的方法及材料,但包括与本发明中所述的可用于本发明实践的那些方法及材料相似或等同的任何方法及材料。如果一个或多个所并入的参考文献、专利或类似材料与本发明(包括但不限于定义的术语、术语用法、所述技术或其类似物)不同或矛盾,则以本发明为准。
定义及通用术语
出于本发明的目的,化学元素是根据CAS版元素周期表和1994年第75版的Handbook of Chemistry and Physics加以鉴定。此外,有机化学的一般原理是描述于“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999及“March's Advanced Organic Chemistry”,第5版,Smith,M.B.及March,J.编John Wiley&Sons,New York:2001中,所述文献以全文引用的方式并入本发明中。
诸如表I的化合物或本发明中所述的其它化合物的化合物可以其游离形式(例如,非晶形形式,或结晶形式或多形体)存在。在一些条件下,化合物也可形成共晶形式(co-form)。如本发明所使用,术语共晶形式与术语多组分结晶形式同义。盐的形成由形成混合物的搭配物之间的pKa差异有多大来决定。出于本发明的目的,即使未明确指出术语“药学上可接受的盐”,化合物也包括药学上可接受的盐。
除非仅具体画出或命名一种异构体,否则本发明中所描绘的结构也旨在包括该结构的所有立体异构(例如,对映异构、非对映异构、阻转异构及顺反异构)形式;例如各不对称中心的R及S构型、各不对称轴的Ra及Sa构型、(Z)及(E)双键构型,及顺式及反式构象异构体。因此,本发明化合物的单一立体化学异构体以及外消旋体、及对映异构体、非对映异构体及顺反异构体(双键或构象)的混合物是处于本发明的范围内。除非另外陈述,否则本发明化合物的所有互变异构形式都处于本发明的范围内。
本发明也囊括与本发明中所述的那些化合物相同的经同位素标记的化合物,但以下事实除外:一个或多个原子经原子质量或质量数不同于通常在自然界中所见的原子质量或质量数的原子置换。如所规定的任何特定原子或元素的所有同位素都是在本发明化合物及其用途的考虑范围内。可掺入本发明化合物的示范性同位素包括氢、碳、氮、氧、磷、硫、氟、氯及碘的同位素,分别诸如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I及125I。一些经同位素标记的本发明化合物(例如,由3H及14C标记的那些化合物)可用于化合物和/或基质组织分布测定。氚化(也即,3H)及碳-14(也即,14C)同位素因其制备简便易行及可检测性而加以使用。进一步,用诸如氘(也即,2H)的较重同位素进行的取代可提供由于较大代谢稳定性(例如,体内半衰期增加或剂量需求减少)所致的一些治疗性优势,且因此在一些情况下可能为优选的。正电子发射同位素(诸如15O、13N、11C及18F)可用于正电子发射断层摄影术(PET)研究以检查基质受体占有率。经同位素标记的本发明化合物通常可通过按照与以下本发明中方案和/或实施例中所述的那些程序类似的程序、通过用经同位素标记的试剂取代非经同位素标记的试剂来制备。
化合物
本发明涉及表I的化合物、其药学上可接受的盐、药物组合物及剂型的医学用途。
表I
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药学上可接受的盐
如本发明所使用的词组“药学上可接受的盐”是指本发明所述的化合物(例如,表I的化合物)的药学上可接受的有机或无机盐。本发明中所述的化合物的药学上可接受的盐用于药物中。然而,非药学上可接受的盐可用于制备本发明中所述的化合物或其药学上可接受的盐。药学上可接受的盐可涉及包括另一分子,诸如乙酸根离子、琥珀酸根离子或其它抗衡离子。该抗衡离子可为使母体化合物上的电荷稳定的任何有机或无机部分。此外,药学上可接受的盐的结构中可具有一个以上带电原子。多个带电原子为药学上可接受的盐的一部分的情形中可具有多个抗衡离子。因此,药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
本发明中所述的化合物的药学上可接受的盐包括利用无机酸、有机酸、无机碱或有机碱自化合物衍生的那些盐。在一些实施方案中,盐可在化合物的最终分离及纯化期间原位制备。在其它实施方案中,盐可在分开的合成步骤中由游离形式的化合物制备。
当本发明中所述的化合物为酸性或含有足够酸性的生物等排体时,合适的“药学上可接受的盐”是指由药学上可接受的无毒性碱(包括无机碱及有机碱)制备的盐。衍生自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐及类似物。特定实施方案包括铵盐、钙盐、镁盐、钾盐及钠盐。衍生自药学上可接受的有机无毒性碱的盐包括以下的盐:伯胺、仲胺及叔胺、经取代的胺(包括天然存在的经取代胺)、环胺及碱离子交换树脂,诸如精氨酸、甜菜碱、咖啡碱、胆碱、N,N1-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡糖胺、组氨酸、哈胺(hydrabamine)、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、多元胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇及类似物。
当本发明中所述的化合物为碱性或含有足够碱性的生物等排体时,盐可由药学上可接受的无毒性酸(包括无机酸及有机酸)来制备。此类酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸及类似物。特定实施方案包括柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸及酒石酸。其它示范性盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟碱酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖二酸盐(saccharate)、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐及双羟萘酸盐(pamoate)(也即1,1'-亚甲基-双-(2-羟基-3-萘酸盐))盐。
以上所述的药学上可接受的盐及其它典型药学上可接受的盐的制备更完全地由Berg等人,“Pharmaceutical Salts,”J.Pharm.Sci.,1977:66:1-19描述,该文献以全文引用的方式并入于此。
除了本发明中所述的化合物之外,其药学上可接受的盐也可用于治疗或预防本发明鉴定的障碍的组合物中。
药物组合物、剂型及给药方法。
本发明中所述的化合物及其药学上可接受的盐可经配制为药物组合物或“制剂”。
典型制剂是通过混合本发明中所述的化合物或其药学上可接受的盐,及载体、稀释剂或赋形剂来制备。合适的载体、稀释剂及赋形剂为本领域技术人员熟知的,且包括诸如碳水化合物、蜡、水溶性和/或可溶胀聚合物、亲水性或疏水性材料、明胶、油、溶剂、水及类似物的材料。所使用的具体载体、稀释剂或赋形剂将取决于配制本发明中所述的化合物的手段及目的。溶剂通常是基于由本领域技术人员认为给药至哺乳动物是安全(GRAS—通常视为安全)的溶剂来选择。一般而言,安全溶剂为无毒性水性溶剂,诸如水及可溶于或可混溶于水的其它无毒性溶剂。合适的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400、PEG300)等及其混合物。制剂也可包括其它类型的赋形剂,诸如一种或多种缓冲剂、稳定剂、抗粘附剂、表面活性剂、湿润剂、润滑剂、乳化剂、粘合剂、悬浮剂、崩解剂、填充剂、吸附剂、包衣剂(例如,肠溶性或缓释)、防腐剂、抗氧化剂、遮光剂(opaquing agent)、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂及其它已知添加剂以提供药物(也即本发明所述的化合物或其药物组合物)的精美外观或有助于制造药物产品(也即药物)。
制剂可使用常规溶解及混合程序来制备。例如,在上述一种或多种赋形剂的存在下将散装药物物质(也即,本发明中所述的化合物、其药学上可接受的盐或稳定化形式的该化合物,诸如与环糊精衍生物或其它已知络合剂的络合物)溶于合适的溶剂中。具有希望纯度的化合物任选与药学上可接受的稀释剂、载体、赋形剂或稳定剂以冻干制剂、研磨粉末或水溶液的形式混合。配制可通过在环境温度,在适当pH,且以希望的纯度与生理上可接受的载体混合来进行。制剂的pH主要取决于特定用途及化合物浓度,但范围可为约3至约8。当本发明中所述的药剂为通过溶剂法形成的固体非晶形分散体时,可在形成混合物时将添加剂直接添加至喷雾干燥溶液中,诸如将添加剂溶解或悬浮在溶液中作为浆料,该浆料接着可经喷雾干燥。或者,添加剂可在喷雾干燥法之后添加以帮助形成最终配制产品。
本发明中所述的化合物或其药学上可接受的盐通常是配制成药物剂型以提供易可控剂量的药物,且实现患者对处方方案的依从性。本发明中所述的化合物或其药学上可接受的盐的药物制剂可制备用于各种给药途径及类型。可存在相同化合物的各种剂型,因为不同的医学条件可担保不同的给药途径。
可与载体材料组合以产生单一剂型的活性成分的量将取决于所治疗受试者及特定给药模式。例如,旨在用于向人类口服给药的延时释放制剂可含有与适当及方便量的载体材料混合的约1至1000mg活性材料,该载体材料可由总组合物的约5%变化至约95%(重量:重量)。可制备药物组合物以提供容易测量的给药量。例如,旨在用于静脉内输注的水溶液可含有每毫升溶液约3至500μg活性成分,以便可发生在约30mL/hr的速率的合适体积的输注。作为一般提议,所给药的抑制剂的初始药学上的有效量将处于每剂约0.01至100mg/kg,即每天约0.1至20mg/kg患者体重的范围内,其中所使用的化合物的典型初始范围为0.3至15mg/kg/天。
如本发明所使用的术语“治疗有效量”意指在组织、系统、动物或人类中引发研究人员、兽医、医学医生或其它临床医师所寻求的生物反应或医学反应的活性化合物或药剂的量。欲给药的化合物的治疗或药学上的有效量将受此类考虑因素支配,且为改善、治愈或治疗疾病或障碍或其一个或多个症状所必需的最小量。
表I中的化合物的药物组合物将以符合良好医学实践的方式(也即,量、浓度、时程、进程、媒介物及给药途径)来配制、给药及施用。在此情形下考虑的因素包括所治疗的特定障碍、所治疗的特定哺乳动物、个体患者的临床状况、障碍的病因、药剂递送部位、给药方法、给药时程及医学从业者已知的其它因素,诸如个体患者的年龄、体重及反应。
术语“预防有效量”是指有效预防或实质上减少获得疾病或障碍的机会或在获得之前降低疾病或障碍的严重性或在其症状发展之前降低症状中的一个或多个的严重性的量。粗略地,预防性措施分为一级预防(以预防疾病的发展)及二级预防(由此,疾病已经发展且保护病人免受此过程的恶化)。
可接受的稀释剂、载体、赋形剂及稳定剂为在所采用的剂量及浓度下对接受者无毒性的那些,且包括:缓冲剂,诸如磷酸盐、柠檬酸盐及其它有机酸;抗氧化剂,包括抗坏血酸及甲硫氨酸;防腐剂(诸如十八烷基二甲基苄基氯化铵;氯化六甲双铵(hexamethoniumchloride);苯扎氯铵(benzalkonium chloride);苄索氯铵(benzethonium chloride);苯酚;丁醇或苄醇;对羟苯甲酸烷基酯,诸如对羟苯甲酸甲酯或丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;及间-甲酚);蛋白质,诸如血清白蛋白、凝胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯基吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸,或赖氨酸;单糖、双糖,及其它碳水化合物,包括葡萄糖、甘露糖,或糊精;螯合剂,诸如EDTA;糖,诸如蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子,诸如钠离子;金属络合物(例如,Zn-蛋白质络合物);和/或非离子表面活性剂,诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。所述活性药物成分也可封闭于例如通过凝聚技术或界面聚合作用制备的微胶囊(例如分别为羟甲基纤维素或明胶微胶囊及聚(甲基丙烯酸甲酯)微胶囊)中;胶状药物递送系统(例如,脂质体、白蛋白微球、微乳液、纳米粒子及纳米胶囊)中或粗乳液中。这些技术描述于Remington's:TheScience and Practice of Pharmacy,第21版,University of the Sciences inPhiladelphia,Eds.,2005(下文中的“Remington’s”)中。
“药物控释系统”以精确受控的方式向身体供应药物,以适合药物及所治疗的病症。主要目的为在作用部位处得到治疗性药物浓度,达希望的持续时间。术语“控释”常常用于指修改药物从剂型中释放的各种方法。此术语包括标记为“延长释放”、“延迟释放”、“经修改释放”或“持续释放”的制剂。一般而言,可通过使用多种聚合物载体及控释系统来提供对本发明中所述的药剂的控释,所述多种聚合物载体及控释系统包括可蚀解及不可蚀解基质、渗透控制装置、各种贮器装置、肠溶性包衣及多颗粒控制装置。
“持续释放制剂”为控释的最常见应用。持续释放制剂的合适实例包括含有化合物的固体疏水性聚合物的半渗透基质,所述基质呈成形制品的形式,例如膜,或微胶囊。持续释放基质的实例包括聚酯、水凝胶(例如,聚(甲基丙烯酸2-羟乙基酯)或聚(乙烯醇))、聚交酯(诸如美国专利第3,773,919号中所述的那些聚交酯)、L-谷氨酸及γ-乙基-L-谷氨酸盐的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-乙醇酸共聚物及聚-D-(-)-3-羟丁酸。
也可制备“立即释放制剂”。这些制剂的目的为尽可能快速地使药物进入血流并到达作用部位。例如,为了快速溶解,大多数片剂被设计成经快速崩解成为颗粒且随后解聚为细粒子。这提供暴露于溶解介质的更大表面积,导致更快速的溶解速率。
可将本发明中所述的药剂掺入可蚀解或不可蚀解聚合物基质控释装置中。可蚀解基质意指水性可蚀解的或水可溶胀性的或水溶性的,其意为在纯水中可蚀解或可溶胀或可溶解,或需要存在酸或碱以便使聚合物基质充分电离,从而导致蚀解或溶解。当与使用的水性环境接触时,可蚀解聚合物基质吸入水且形成捕获本发明中所述的药剂的水性溶胀凝胶或基质。水性溶胀基质逐渐地蚀解、溶胀、崩解或溶解于使用的环境中,从而控制本发明中所述的化合物释放至使用的环境中。这种水溶胀基质的一种成分为水溶胀性、可蚀解性或可溶性聚合物,其通常可描述为渗透聚合物、水凝胶或水可溶胀性聚合物。此类聚合物可为线性的、分支的或交联的。该聚合物可为均聚物或共聚物。在一些实施方案中,它们可为衍生自乙烯基、丙烯酸酯、甲基丙烯酸酯、氨甲酸酯、酯及氧化物单体的合成聚合物。在其它实施方案中,它们可为天然存在的聚合物的衍生物,所述天然存在的聚合物诸如多糖(例如,壳多糖、脱乙酰壳多糖、葡聚糖及支链淀粉;琼胶、阿拉伯树胶、刺梧桐胶、刺槐豆胶、黄蓍树胶、角叉菜胶、印度树胶、瓜尔胶、黄原胶及硬葡聚糖)、淀粉(例如,糊精及麦芽糖糊精)、亲水性胶体(例如,果胶)、磷脂(例如,卵磷脂)、藻酸盐(例如,藻酸铵、藻酸钠、藻酸钾或藻酸钙、藻酸丙二醇酯)、明胶、胶原蛋白及纤维素制品。纤维素制品为纤维素聚合物,其已经通过糖重复单元上的至少一部分羟基与化合物反应来修饰以形成酯连接或醚连接的取代基。
例如,纤维素乙基纤维素具有附接至糖重复单元的醚连接的乙基取代基,而纤维素乙酸纤维素具有酯连接的乙酸酯取代基。在一些实施方案中,用于可蚀解基质的纤维素制品包含水溶性及水性可蚀解纤维素,其可包括例如乙基纤维素(EC)、甲基乙基纤维素(MEC)、羧甲基纤维素(CMC)、CMEC、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、乙酸纤维素(CA)、丙酸纤维素(CP)、丁酸纤维素(CB)、乙酸丁酸纤维素(CAB)、CAP、CAT、羟丙基甲基纤维素(HPMC)、HPMCP、HPMCAS、羟丙基甲基乙酸纤维素偏苯三酸酯(HPMCAT)及乙基羟乙基纤维素(EHEC)。在一些实施方案中,纤维素制品包含各种等级的低粘度(MW小于或等于50,000道尔顿,例如Dow MethocelTM系列E5、E15LV、E50LV及K100LY)及高粘度(MW大于50,000道尔顿,例如E4MCR、E10MCR、K4M、K15M及K100M以及MethocelTMK系列)HPMC。其它可商购获得的HPMC类型包括Shin Etsu Metolose 90SH系列。
可用作可蚀解基质材料的其它材料包括但不限于支链淀粉、聚乙烯吡咯烷酮、聚乙烯醇、聚乙酸乙烯酯、甘油脂肪酸酯、聚丙烯酰胺、聚丙烯酸、乙基丙烯酸或甲基丙烯酸的共聚物(Rohm America,Inc.,Piscataway,New Jersey)及其它丙烯酸衍生物,诸如甲基丙烯酸丁酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸(2-二甲基氨基乙基)酯及氯化甲基丙烯酸(三甲基氨基乙基)酯的均聚物及共聚物。
或者,本发明的药剂可通过不可蚀解基质装置给药或掺入不可蚀解基质装置中。在此类装置中,本发明中所述的药剂是分布在惰性基质中。药剂通过扩散通过惰性基质来释放。适用于惰性基质的材料的实例包括不可溶性塑料(例如,丙烯酸甲酯-甲基丙烯酸甲酯共聚物、聚氯乙烯、聚乙烯)、亲水性聚合物(例如,乙基纤维素、乙酸纤维素、交联聚乙烯吡咯烷酮(也称为交聚维酮))及脂肪化合物(例如,巴西棕榈蜡、微晶蜡及甘油三酯)。此类装置进一步描述于Remington:The Science and Practice of Pharmacy,第20版(2000)中。
如上所指出,本发明中所述的药剂也可掺入渗透控制装置中。此类装置通常包括:含有一种或多种如本发明中所述的药剂的核心;及围绕该核心的水可渗透性、非溶解性及非蚀解性涂层,该涂层控制水从使用的水性环境流入核心中,以便通过将一些或所有核心挤出至使用的环境中来导致药物释放。在一些实施方案中,涂层为聚合物的、水性可渗透的,且具有至少一个递送口。渗透装置的核心任选包含用于经由这种半渗透膜从周围环境吸入水的渗透剂。此装置的核心中包含的渗透剂可为水性可溶胀亲水性聚合物,或其可为渗透原,也称为渗透剂。压力是在装置内产生,该压力迫使药剂经由孔口(具有经设计成使溶质扩散最小化,同时防止静水压头建立的尺寸)从装置中离开。渗透控制装置的非限制性实例是描述于美国专利申请案序列号09/495,061中。
存在于核心中的水可溶胀性亲水性聚合物的量的范围可为约5至约80wt%(包括例如10至50wt%)。核心材料的非限制性实例包括亲水性乙烯基及丙烯酸聚合物、多糖诸如藻酸钙、聚环氧乙烷(PEO)、聚乙二醇(PEG)、聚丙二醇(PPG)、聚(丙烯酸2-羟乙基甲基酯)、聚(丙烯酸)、聚(甲基丙烯酸)、聚乙烯吡咯烷酮(PVP)及交联PVP、聚乙烯醇(PVA)、PVA/PVP共聚物及具有疏水性单体(诸如甲基丙烯酸甲酯、乙酸乙烯酯及类似物)的PVA/PVP共聚物、含有大PEO嵌段的亲水性聚氨酯、交联羧甲基纤维素钠、角叉菜胶、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素(CMC)及羧乙基纤维素(CEC)、藻酸钠、聚卡波非(polycarbophil)、明胶、黄原胶及羟基乙酸淀粉钠。其它材料包括水凝胶,该水凝胶包含可通过加聚或通过缩聚形成的聚合物的互穿网状结构,该水凝胶的组分可包含亲水性及疏水性单体,诸如刚刚提及的那些。水可溶胀性亲水性聚合物包括但不限于PEO、PEG、PVP、交联羧甲基纤维素钠、HPMC、羟基乙酸淀粉钠、聚丙烯酸及其交联形式或混合物。
核心也可包含渗透原(或渗透剂)。存在于核心中的渗透原的量的范围可为约2至约70wt%(包括例如10至50wt%)。合适的渗透原的典型种类为能够吸入水从而产生跨周围涂层的屏障的渗透压梯度的水溶性有机酸、盐及糖。典型的有用渗透原包括但不限于硫酸镁、氯化镁、氯化钙、氯化钠、氯化锂、硫酸钾、碳酸钠、亚硫酸钠、硫酸锂、氯化钾、硫酸钠、甘露醇、木糖醇、尿素、山梨醇、肌醇、棉子糖、蔗糖、葡萄糖、果糖、乳糖、柠檬酸、琥珀酸、酒石酸及其混合物。在一些实施方案中,渗透原为葡萄糖、乳糖、蔗糖、甘露醇、木糖醇、氯化钠,包括其组合。
药物递送的速率由如涂层的渗透性及厚度、含药物层的渗透压、水凝胶层的亲水性程度及装置的表面积的此类因素控制。本领域技术人员将认识到,增加涂层的厚度将降低释放速率,而以下中的任一个将增加释放速率:增加涂层的渗透性;增加水凝胶层的亲水性;增加含药物层的渗透压;或增加装置的表面积。
在一些实施方案中,希望在此类渗透装置的操作过程中将本发明中所述的药剂粒子夹带在挤出流体中。为了充分夹带粒子,在粒子有机会沉降在片剂核心中之前,将药剂药物形式分散在流体中。完成此目的的一个手段是通过添加崩解剂来进行,该崩解剂用于将压缩的核心破碎成其颗粒组分。标准崩解剂的非限制性实例包括诸如羟基乙酸淀粉钠(例如,ExplotabTMCLV)、微晶纤维素(例如,AvicelTM)、微晶硅化纤维素(例如,ProSolvTM)及交联羧甲基纤维素钠(例如,Ac-Di-SolTM)的材料,以及本领域技术人员已知的其它崩解剂。取决于特定制剂,一些崩解剂比其它更好地起作用。若干崩解剂倾向于在其被水溶胀时形成凝胶,因此阻碍从装置中递送药物。非胶凝、非溶胀性崩解剂提供在水进入核心时药物粒子在核心内的更快速的分散。在一些实施方案中,非胶凝、非溶胀性崩解剂为树脂,例如离子交换树脂。在一个实施方案中,树脂为AmberliteTMIRP 88(可自Rohm及Haas,Philadelphia,PA获得)。当使用时,崩解剂以核心药剂的约1至25%的量存在。
渗透装置的另一个实例为渗透胶囊。胶囊壳或胶囊壳的一部分可为半渗透性的。胶囊可通过由本发明中所述的药剂、吸入水以提供渗透势的赋形剂,和/或水可溶胀性聚合物或任选的增溶赋形剂组成的粉末或液体来填充。胶囊核心也可经制造成使得其具有类似于上述的双层、三层或同心几何结构的双层或多层药剂。
可用于本发明的另一类渗透装置包含例如如EP378404中所述的经包衣的可溶胀片剂。经包衣的可溶胀片剂包含:包含本发明中所述的药剂的片剂核心;及用膜包衣的溶胀材料,优选为亲水性聚合物,该溶胀材料包含孔或孔隙,在水性使用环境中亲水性聚合物可通过所述孔或孔隙挤出且将药剂运载出来。或者,膜可含有聚合物或低分子量水溶性致孔原(porosigen)。致孔原溶于水性使用环境,从而提供孔隙,亲水性聚合物及药剂可通过该孔隙挤出。致孔原的实例为水溶性聚合物,诸如HPMC、PEG及低分子量化合物,诸如甘油、蔗糖、葡萄糖及氯化钠。此外,孔隙可通过使用激光或其它机械构件在涂层中钻孔来在涂层中形成。在这类渗透装置中,膜材料可包含任何成膜聚合物,包括透水性或不透水性聚合物,条件是沉积在片剂核心上的膜为多孔的或含有水溶性致孔原或具有供水进入及药物释放的宏观孔。如例如EP378404中所述,这类持续释放装置的实施方案也可为多层的。
当本发明中所述的药剂为液体或油(诸如例如如WO05/011634中所述的脂质媒介物制剂)时,渗透控释装置可包含软凝胶或明胶胶囊,其由复合壁形成且包含液体制剂,其中壁包含在胶囊的外表面上形成的屏障层、在屏障层上形成的可膨胀层及在可膨胀层上形成的半渗透层。递送口将液体制剂与水性使用环境连接。此类装置描述于例如US6419952、US6342249、US5324280、US4672850、US4627850、US4203440及US3995631中。
如以上所进一步指出,本发明中所述的药剂可以微颗粒的形式提供,粒度范围通常为约10μm至约2mm(包括例如,直径为约100μm至1mm)。此类多颗粒可包装在例如胶囊(诸如明胶胶囊或由水溶性聚合物(诸如HPMCAS、HPMC或淀粉)形成的胶囊)中;作为液体中的悬浮液或浆料给药;或它们可通过压缩或本领域已知的其它方法来形成片剂、胶囊或丸剂。此类多颗粒可通过任何已知的方法(诸如湿法造粒及干法造粒、挤出/滚圆、辊压、熔融凝固)或通过喷雾包衣种核来制备。例如,在湿法造粒及干法造粒中,本发明中所述的药剂及任选赋形剂可经粒化以形成具有希望尺寸的多颗粒。
药剂可掺入通常为热力学稳定的微乳液、通过表面活性剂分子的界面膜稳定的两种不混溶液体(诸如油及水)的各向同性透明分散液中(Encyclopedia of PharmaceuticalTechnology,New York:Marcel Dekker,1992,第9卷)。为了制备微乳液,需要表面活性剂(乳化剂)、辅表面活性剂(辅乳化剂)、油相及水相。合适的表面活性剂包括可用于制备乳液的任何表面活性剂,例如通常用于制备乳膏剂的乳化剂。辅助表面活性剂(或“辅乳化剂”)通常选自由以下所组成的群组:聚甘油衍生物、甘油衍生物及脂肪醇。优选乳化剂/助乳化剂组合通常(尽管不一定)选自由以下所组成的群组:单硬脂酸甘油酯及聚氧乙烯硬脂酸酯;聚乙二醇及棕榈酸硬脂酸乙二醇酯;及辛酸及癸酸甘油三酯及油酰基聚乙二醇甘油酯。水相不仅包括水,而且通常也包括缓冲液、葡萄糖、丙二醇、聚乙二醇(优选为较低分子量聚乙二醇,例如PEG 300及PEG 400)和/或甘油及类似物,而油相一般将包含例如脂肪酸酯、改性植物油、硅油、单甘油酯、甘油二酯及甘油三酯的混合物、PEG的单酯及二酯(例如,油酰基聚乙二醇甘油酯)等。
本发明中所述的化合物可掺入药学上可接受的纳米粒子、纳米球及纳米胶囊制剂中(Delie及Blanco-Prieto,2005,Molecule 10:65-80)。纳米胶囊通常可以稳定且可再现的方式捕获化合物。为了避免由于细胞内聚合物过载而引起的副作用,超细粒子(尺寸经设计为约0.1μm)可使用能够在体内降解的聚合物(例如,可生物降解的聚氰基丙烯酸烷基酯纳米粒子)来设计。此类粒子描述于现有技术中。
用本发明化合物包衣的可植入装置为本发明的另一实施方案。化合物也可包衣在可植入医学装置(诸如珠)上或与聚合物或其它分子共配制,以提供“药物贮库”,从而容许药物与药物水溶液的给药相比用更长的时期释放。合适的涂层及涂覆的可植入装置的一般制备描述于美国专利第6,099,562号;第5,886,026号;及第5,304,121号中。涂层通常为生物相容性聚合物材料,诸如水凝胶聚合物、聚甲基二硅氧烷、聚己酸内酯、聚乙二醇、聚乳酸、乙烯乙酸乙烯酯及其混合物。涂层可任选进一步由氟硅酮、多糖、聚乙二醇、磷脂或其组合的合适的面涂层覆盖,以赋予组合物的控释特性。
制剂包括适用于本发明中详述的给药途径的那些制剂。制剂可便利地以单位剂型提供且可通过制药技术中熟知的任何方法制备。技术及制剂通常见于Remington’s中。此类方法包括使活性成分与构成一种或多种配合成分的载体缔合的步骤。一般而言,通过使活性成分与液体载体或精细分开的固体载体或两者进行均匀及密切地缔合、且必要时接着使产物成形来制备制剂。
关于本发明的化合物、组合物或制剂的术语“给药(administer,administering,administration)”意指将化合物引入需要治疗的动物的系统中。当与一种或多种其它活性剂组合提供本发明的化合物时,“给药”及其变体各自应理解为包括同时和/或依序引入该化合物及其它活性剂。
本发明中所述的组合物可取决于所治疗的疾病的严重性及类型以以下方式给药:经全身或经局部,例如经口服(例如,使用胶囊、粉末、溶液、悬浮液、片剂、舌下片剂及类似物)、通过吸入(例如,用气雾剂、气体、吸入器、喷雾器或类似物)、给药至耳(例如,使用滴耳剂)、局部(例如,使用乳膏剂、凝胶剂、擦剂、洗剂、软膏剂、糊剂、经皮贴片等)、经眼(例如,用滴眼剂、眼用凝胶剂、眼用软膏剂)、经直肠(例如,使用灌肠剂或栓剂)、经鼻、经颊、经阴道(例如,使用冲洗剂、子宫内装置、阴道栓剂、阴道环或片剂等)、经由植入的贮器或类似物或肠胃外。如本发明所用的术语“肠胃外”包括但不限于皮下、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内及颅内注射或输注技术。优选地,组合物是经口服、经腹膜内或经静脉内给药。
本发明中所述的药物组合物可以任何经口服可接受的剂型(包括但不限于胶囊、片剂、水性悬浮液或溶液)来经口服给药。用于口服给药的液体剂型包括但不限于药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性化合物之外,液体剂型也可含有常用于本领域中的惰性稀释剂,诸如水或其它溶剂;增溶剂及乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体为棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油及芝麻油)、甘油、四氢糠醇、聚乙二醇以及脱水山梨醇的脂肪酸酯,及其混合物。除惰性稀释剂之外,口服组合物也可包含佐剂,诸如湿润剂、乳化剂及悬浮剂、甜味剂、调味剂及芳香剂。
用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉末及颗粒。在这些固体剂型中,活性化合物与以下各项混合:至少一种惰性的药学上可接受的赋形剂或载体(诸如柠檬酸钠或磷酸二钙)和/或a)填充剂或增量剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及硅酸,b)粘合剂,诸如(例如)羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖及阿拉伯胶,c)保湿剂,诸如甘油,d)崩解剂,诸如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、一些硅酸盐及碳酸钠,e)溶液阻滞剂,诸如石蜡,f)吸收加速剂,诸如季铵化合物,g)湿润剂,诸如(例如)鲸蜡醇及单硬脂酸甘油酯,h)吸附剂,诸如高岭土及膨润土,及i)润滑剂,诸如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物。片剂可为未包衣的,或可通过包括微囊化的已知技术来包衣以掩盖令人不悦的味道或延迟在胃肠道中的崩解及吸收,且从而在较长时期内提供持续的作用。例如,可单独或与蜡一起采用时间延迟型材料,诸如单硬脂酸甘油酯或二硬脂酸甘油酯。可采用水溶性掩味材料,诸如羟丙基甲基纤维素或羟丙基纤维素。
适用于口服给药的本发明中所述的化合物的制剂可制备为离散单元,诸如片剂、丸剂、糖锭剂、锭剂、水性或油性悬浮液、可分散粉末或颗粒、乳液、硬胶囊或软胶囊(例如,明胶胶囊)、糖浆或酏剂。旨在用于口服使用的化合物的制剂可根据本领域已知用于制备药物组合物的任何方法来制备。
经压缩的片剂可通过于适合的机器中将任选与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合的呈诸如粉末或颗粒的自由流动形式的活性成分压缩来制备。模制片剂可通过在合适机器中模制以惰性液体稀释剂湿润的粉末状活性成分的混合物来制成。
用于口服使用的制剂也可作为硬明胶胶囊存在,其中活性成分与惰性固体稀释剂混合,该惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土;或作为软明胶胶囊存在,其中活性成分与水溶性载体(诸如聚乙二醇)或油性介质混合,该油性介质例如花生油、液体石蜡或橄榄油。
活性化合物也可呈具有一种或多种如上所指出的赋形剂的微囊化形式。
当水性悬浮液为口服使用所需时,将活性成分与乳化剂及悬浮剂组合。若需要,可添加一些甜味剂和/或调味剂。糖浆及酏剂可用甜味剂(例如甘油、丙二醇、山梨醇或蔗糖)配制。此类制剂也可含有缓和剂、防腐剂、调味剂及着色剂以及抗氧化剂。
本发明中所述的组合物的无菌可注射形式(例如,用于肠胃外给药)可为水性或油性悬浮液。这些悬浮液可根据本领域中已知的技术使用合适分散剂或湿润剂及悬浮剂加以配制。无菌可注射制剂也可为于无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如呈于1,3-丁二醇中的溶液形式。可采用的可接受的媒介物及溶剂尤其为水、林格溶液(Ringer's solution)及等张氯化钠溶液。此外,常规上将无菌、非挥发性油用作溶剂或悬浮介质。出于此目的,可采用任何温和不挥发性油,包括合成单甘油酯或甘油二酯。诸如油酸的脂肪酸及其甘油酯衍生物适用于制备可注射剂,诸如橄榄油或蓖麻油的天然药学上可接受的油也如此,尤其以其聚氧乙基化形式。这些油溶液或悬浮液也可含有长链醇稀释剂或分散剂,诸如羧甲基纤维素或通常用于配制药学上可接受的剂型(包括乳液及悬浮液)的类似分散剂。通常用于制造药学上可接受的固体、液体或其它剂型的其它通常使用的表面活性剂(诸如Tween、Span)及其它乳化剂或生物利用度增强剂也可用于可注射制剂。
油性悬浮液可通过将本发明中所述的化合物悬浮于植物油(例如,花生油、橄榄油、芝麻油或椰子油)或矿物油(诸如液体石蜡)中来配制。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可添加甜味剂(诸如以上陈述的那些甜味剂)及调味剂以提供可口的口服制剂。这些组合物可通过添加抗氧化剂(诸如丁羟茴醚或α-生育酚)来保存。
本发明中所述的化合物的水性悬浮液含有与适用于制备水悬浮液的赋形剂混合的活性材料。此类赋形剂包括:悬浮剂,诸如羧甲基纤维素钠、交联羧甲基纤维素、聚维酮、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶及阿拉伯树胶;及分散剂或润湿剂,诸如天然存在的磷脂(例如,卵磷脂)、环氧烷与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如,十七碳乙烯氧基鲸蜡醇)、环氧乙烷与衍生自脂肪酸的偏酯及己糖醇酐的缩合产物(例如,聚氧乙烯脱水山梨醇单油酸酯)。水性悬浮液还可含有一种或多种防腐剂,诸如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯;一种或多种着色剂;一种或多种调味剂;及一种或多种甜味剂,诸如蔗糖或糖精。
可例如通过经滤菌过滤器(bacterial-retaining filter)的过滤或通过掺入呈无菌固体组合物形式的灭菌剂来将可注射制剂灭菌,所述灭菌剂可于使用之前溶解或分散于无菌水或其它无菌可注射介质中。
为延长本发明中所述的化合物的作用,常需要减缓对来自皮下或肌肉内注射的化合物的吸收。这可通过使用水溶性不良的结晶或非晶形物质的液体悬浮液来得到。化合物的吸收速率则取决于其溶解速率,该溶解速率又可取决于晶体尺寸及结晶形式。或者,通过将化合物溶解或悬浮于油媒介物中来实现肠胃外给药的化合物形式的延迟吸收。可注射积存形式是通过在诸如聚丙交酯-聚乙交酯的生物可降解聚合物中形成化合物的微囊化基质来制备。取决于化合物与聚合物的比率及所使用特定聚合物的性质,可控制化合物释放速率。其它生物可降解聚合物的实例包括聚(原酸酯)及聚(酸酐)。积存可注射制剂也通过将化合物包埋在与身体组织相容的脂质体或微乳液中来制备。
可注射溶液或微乳液可通过局部推注注射来引入患者的血流中。或者,以维持本发明化合物的恒定循环浓度的方式给药溶液或微乳液可能是有利的。为维持这种恒定浓度,可利用连续的静脉递送装置。这种设备的实例为Deltec CADD-PLUSTM 5400型静脉注射泵。
用于经直肠或经阴道给药的组合物优选为栓剂,其可通过以下方法来制备:混合本发明中所述的化合物与在环境温度为固体但在体温下为液体、且因此在直肠或阴道腔中熔融并释放活性化合物的合适非刺激性赋形剂或载体(诸如可可脂、蜂蜡、聚乙二醇或栓剂蜡)。适用于阴道给药的其它制剂可作为子宫托、棉塞、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾剂来提供。
本发明中所述的药物组合物也可以局部方式给药,尤其是当治疗目标包括可易于通过局部用药到达的区域或器官时,包括眼、耳、皮肤或下肠道疾病。用于每种这些区域或器官的合适局部制剂易于制备。
用于局部或经皮给药本发明中所述的化合物的剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、粉末、溶液、喷雾剂、吸入剂或贴片。活性组分在无菌条件下与药学上可接受的载体及如可为所需的任何所需防腐剂或缓冲剂混合。眼用制剂、滴耳剂及滴眼剂也考虑在本发明的范围内。另外,本发明考虑使用经皮贴片,其具有将化合物提供至身体的受控递送的附加优势。这些剂型可通过将化合物溶解或分配于适当介质中来制备。吸收增强剂也可用于增加化合物穿过皮肤的通量。速率可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中加以控制。用于下肠道的局部用药可以直肠栓剂制剂(参见上文)形式或以合适灌肠剂制剂形式实现。也可使用局部经皮贴片。
对于局部用药,药物组合物可以含有悬浮或溶解于一种或多种载体中的活性组分的合适软膏剂形式配制。用于本发明化合物的局部给药的载体包括但不限于矿物油、液体石蜡脂、白石蜡脂、丙二醇、聚氧化乙烯、聚氧化丙烯化合物、乳化蜡及水。或者,药物组合物可以含有悬浮或溶解于一种或多种药学上可接受的载体中的活性组分的合适洗剂或乳膏剂形式配制。合适载体包括但不限于矿物油、脱水山梨醇单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇(cetearyl alcohol)、2辛基十二烷醇、苄醇及水。
对于眼用使用,药物组合物可在有或没有诸如氯化苯甲烃铵(benzylalkoniumchloride)的防腐剂下配制成于等张、pH值调整的无菌盐水中的微粒化悬浮液,或优选配制成于等张、pH值调整的无菌盐水中的溶液。或者,对于眼用使用,药物组合物可以诸如石蜡脂的软膏剂形式配制。为了治疗眼或其它外部组织(例如,口腔及皮肤),制剂可作为含有例如0.075至20%w/w的活性成分的局部软膏剂或乳膏剂来用药。当配制成软膏剂时,活性成分可与油基、石蜡或水混溶性软膏剂基材一起使用。
或者,活性成分可用水包油乳膏剂基材配制成乳膏剂。若需要,乳膏剂基材的水相可包括多元醇,也即具有二个或更多个羟基的醇,诸如丙二醇、1,3-丁二醇、甘露醇、山梨醇、甘油及聚乙二醇(包括PEG 400)及其混合物。局部制剂可理想地包括增强活性成分通过皮肤或其它受影响区域吸收或穿透的化合物。此类皮肤穿透增强剂的实例包括二甲基亚砜及相关的类似物。
使用本发明中所述的化合物制备的乳液的油相可由已知成分以已知方式构成。虽然该相可仅包含乳化剂(另外称为利泄剂(emulgent)),但是其理想地包含至少一种乳化剂与脂肪或油或与脂肪及油两者的混合物。亲水性乳化剂可与用作稳定剂的亲脂性乳化剂一起被包括在内。在一些实施方案中,乳化剂包括油及脂肪两者。总之,具有或没有稳定剂的乳化剂构成所谓的乳化蜡,且蜡与油和脂肪一起构成所谓的乳化软膏剂基材,其形成乳膏剂制剂的油性分散相。适用于配制本发明中所述的化合物的利泄剂及乳化稳定剂包括TweenTM-60、SpanTM-80、鲸蜡硬脂醇、苄醇、肉豆蔻醇、单硬脂酸甘油酯及月桂基硫酸钠。
药物组合物也可通过鼻气雾剂或吸入来给药。这些组合物是根据药物制剂领域中熟知的技术制备且可采用苄醇或其它合适防腐剂、增强生物利用度的吸收促进剂、氟碳化合物和/或其它常规增溶剂或分散剂制备成于盐水中的溶液。适用于肺内或鼻给药的制剂具有的粒子尺寸的范围例如为0.1至500微米(包括以诸如0.5、1、30、35微米等的增量微米介于0.1与500微米之间范围内的粒子),其是通过通过鼻通道快速吸入或通过通过口吸入以便达到肺泡囊来给药。
供使用的药物组合物(或制剂)可以多种方式封装,所述方式取决于用于给药药物的方法。一般地,用于分布的物品包括其中沉积有适当形式的药物制剂的容器。合适容器为本领域技术人员所熟知且包括诸如瓶子(塑料及玻璃)、药囊、安瓿、塑料袋、金属圆筒及其类似物的材料。该容器也可包括防开启总成以防止轻率接近封装的内含物。此外,容器上也放置有描述容器内含物的标签。该标签也可包括适当警示。
制剂可包装在单位剂量或多剂量容器,例如密封安瓿和小瓶中,并且可在冷冻干燥(冻干)条件下储存,仅需要在即将使用之前添加无菌液体载体,例如水,以用于立即注射。临时注射溶液及悬浮液由先前描述种类的无菌粉末、颗粒及片剂来制备。优选单位剂量制剂为含有如以上所述的日剂量或单位日亚剂量或其适当分数的活性成分的那些制剂。
在另一方面中,本发明中所述的化合物或其药学上可接受的盐可配制在包含兽医学载体的兽医学组合物中。兽医学载体为可用于给药该组合物的目的的材料且可为固体、液体或气体材料,所述材料在其它方面为惰性的。在兽医学领域中,且与活性成分相容。这些兽医学组合物可肠胃外、经口服或通过任何其它希望途径给药。
治疗方法
本发明涉及一种治疗或预防有需要的受试者的CNS疾病、健康状况或障碍的方法,该方法包含单独或以组合疗法向该受试者给药治疗有效量的化合物或其药学上可接受的盐,其中该化合物选自表I中描绘的那些化合物。
本发明也涉及一种药物组合物,其包含表I的化合物或其药学上可接受的盐,及至少一种药学上可接受的赋形剂或载体。本发明也涉及一种包含该药物组合物的剂型。
本发明也涉及一种治疗或预防有需要的受试者的CNS疾病、健康状况或障碍的方法,该方法包含单独或以组合疗法给药包含表I中描绘的化合物或其药学上可接受的盐的药物组合物或剂型。
本发明进一步涉及表I中描绘的sGC刺激剂或其药学上可接受的盐,或包含其的药物组合物或剂型用于治疗CNS疾病的用途。
本发明进一步涉及一种sGC刺激剂或包含其的药物组合物或剂型,其用于治疗CNS疾病,其中该sGC刺激剂为表I中描绘的sGC刺激剂或其药学上可接受的盐。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗特征在于神经炎症增加的疾病及障碍。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来减少有需要的受试者的神经炎症的方法。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗特征在于神经毒性增加的疾病及障碍。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来在有需要的受试者中减小神经毒性的方法。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗特征在于受损神经再生的疾病及障碍。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来在有需要的受试者中恢复神经再生的方法。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗特征在于受损突触功能的疾病及障碍。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来恢复有需要的受试者的突触功能的方法。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗特征在于下调的神经递质的疾病及障碍。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来使有需要的受试者的神经递质正常化的方法。具体而言,疾病为阿尔茨海默病。具体而言,疾病为混合型痴呆。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗特征在于受损脑血流量的疾病及障碍。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来恢复有需要的受试者的脑血流量的方法。具体而言,疾病为血管性痴呆或阿尔茨海默病。具体而言,疾病为混合型痴呆。在其它实施方案中,CNS障碍选自外伤性(闭合性或开放性、穿透性头部损伤)、外伤性脑损伤(TBI),或非外伤性(中风(特别是缺血性中风)、动脉瘤、缺氧)脑损伤,或认知损害或由脑损伤或神经退行性障碍导致的功能障碍。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗特征在于增加的神经退化的疾病及障碍。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来减少有需要的受试者的神经退化的方法。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其为神经保护性的。特别地,表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型可用于保护有需要的受试者的神经元。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗孤儿疼痛适应症(orphan pain indication)。本发明的一个实施方案为一种通过向受试者给药表I中描绘的化合物或其药学上可接受的盐或包含其的药物组合物或剂型中任一个来治疗有需要的受试者的孤儿疼痛适应症的方法。特别地,孤儿疼痛适应症选自乙酰唑胺反应性肌强直、自体红细胞致敏综合征、2V型常染色体显性夏马图三氏病、伴有神经性疼痛的常染色体显性中间型夏马图三氏病、2A型常染色体隐性肢带肌营养不良、离子通道病变相关的先天性疼痛不敏感、引起脊柱内痛觉缺失的慢性疼痛、复合区域性疼痛综合征、1型复合区域性疼痛综合征、2型复合区域性疼痛综合征、伴有多汗症的先天性疼痛不敏感、伴有严重智力残疾的先天性疼痛不敏感、先天性疼痛不敏感-少汗综合征、伴有疼痛性龟裂的弥漫性掌跖角化病、家族性发作性疼痛综合征、伴有显著下肢受累的家族性发作性疼痛综合征、伴有显著上体受累的家族性发作性疼痛综合征、遗传性疼痛性胼胝、4型遗传性感觉及自主神经病、5型遗传性感觉及自主神经病、7型遗传性感觉及自主神经病、间质性膀胱炎、疼痛性眼眶及全身神经纤维瘤-马方体型综合征、阵发性极端疼痛障碍、持续性特发性面部疼痛、卡配因的定性或定量缺陷及痛性眼肌麻痹综合征。
在其它实施方案中,此处披露的化合物为sGC刺激剂,其可用于预防和/或治疗高海拔(山)病、脑小血管疾病、脑血管炎、脑血管痉挛、肝性脑病变、烟雾病、帕金森氏吞咽困难、共济失调毛细血管扩张症(ataxia telangliectasia)、泛自闭症障碍、慢性疲劳、慢性外伤性脑病变(CTE)、与糖尿病相关的认知损害、与多发性硬化相关的认知损害、与阻塞性睡眠呼吸中止相关的认知损害、与精神分裂症相关的认知损害(CIAS)、与镰状细胞相关的认知损害、脑震荡、视网膜病变、糖尿病性视网膜病变(包括增生性及非增生性)、吞咽困难、眼纤维化、法布里病、戈谢病、神经胶质母细胞瘤、由脑疟疾引起的脑炎症(SoC)、由感染性疾病引起的脑炎症、智力残疾、近视性脉络膜新血管生成、视神经脊髓炎、伴有多发性硬化的神经性疼痛、伴有带状疱疹(shingles)(带状疱疹(herpes zoster))的神经性疼痛、伴有脊柱手术的神经性疼痛(neuropathic pain with spine surgery)、帕金森氏痴呆、周边及自主神经病变、周边性视网膜退化、创伤后压力综合征、疱疹后神经痛、术后痴呆、增生性玻璃体视网膜病变、放射诱发的脑纤维化、神经根病、难治性癫痫、视网膜静脉阻塞、脊髓损伤、脊椎性肌肉萎缩、脊椎半脱位、Tau病变(tauopathies)及年龄有关的湿性黄斑退化。
可受益于用本发明的sGC刺激剂治疗的CNS疾病为可需要增加NO浓度或增加cGMP浓度或两者或上调NO通路的那些CNS疾病。
作为能够穿过血脑屏障的sGC刺激剂的本发明中所述的化合物以及其药学上可接受的盐可用于预防和/或治疗可受益于脑中sGC刺激的CNS疾病、病症及障碍。
在一些实施方案中,CNS疾病、健康状况或障碍选自阿尔茨海默病(AD)、肌萎缩侧索硬化(ALS或Lou Gehrig病)、唐氏综合征、痴呆、血管性痴呆(VD)、血管性认知损害、混合型痴呆、宾斯旺格痴呆(皮层下动脉硬化性脑病)、伴有皮质下梗塞及脑白质病变的脑体常染色体显性动脉病(CADASIL或CADASIL综合征)、额颞叶退化或痴呆、HIV相关性痴呆(包括无症状性神经认知损害(ANI)、轻微神经认知障碍(MND),及HIV相关性痴呆(HAD)(也称为AIDS痴呆复合征(AIDS dementia complex)[ADC]或HIV脑病)、Lewy体痴呆、早老性痴呆(轻度认知损害或MCI)、青光眼、亨廷顿病(亨廷顿舞蹈症,HD)、多发性硬化(MS)(包括临床孤立综合征(CIS)、复发性缓解型MS(RRMS)、原发性进行性MS(PPMS)及继发性进行性MS(SPMS))、多系统萎缩(MSA)、帕金森病(PD)、帕金森叠加、脊髓小脑共济失调、Steel-Richardson-Olszewski病(进行性核上麻痹)、注意力缺陷障碍(ADD)及注意力缺陷多动症(ADHD)。
在其它实施方案中,疾病、健康状况或障碍为选自阿尔茨海默病或阿尔茨海默病前、轻度至中度阿尔茨海默病或中度至重度阿尔茨海默病的CNS障碍或病症。
在其它实施方案中,CNS障碍选自外伤性(闭合性或开放性)穿透性头部损伤、外伤性脑损伤(TBI)(包括,例如脑震荡及慢性外伤性脑病(CTE))、非外伤性脑损伤(例如,中风(包括缺血性中风)、动脉瘤、缺氧),或认知损害或由脑损伤或神经退行性障碍导致的功能障碍。
在其它实施方案中,CNS疾病或障碍选自:张力失常,包括例如广泛性、病灶性、节段性、性、中间、遗传性/原发性张力失常或急性张力失常反应;或运动障碍,包括例如急性、慢性/迟发性,及非运动性及左旋多巴诱导的运动障碍(LID)。
在其它实施方案中,CNS疾病或障碍选自特征在于突触可塑性及突触过程相对降低的障碍,包括例如脆性x染色体病、Rhett障碍、威廉斯综合征、Renpenning综合征、泛自闭症障碍(ASD)、自闭症、Asperger综合征、弥漫性发育障碍或童年瓦解性障碍。
在其它实施方案中,CNS障碍为神经性疼痛。
在其它实施方案中,CNS障碍为选自以下的精神病性、精神性、情绪或情感障碍:双相型障碍、精神分裂症、一般精神病、药物诱发的精神病、妄想症、情感性分裂症、强迫性障碍(OCD)、抑郁障碍、焦虑障碍、惊恐障碍、创伤后应激障碍(PTSD)。
在进一步的实施方案中,CNS障碍选自年龄相关的记忆损伤、混合型痴呆、睡眠觉醒障碍及斯内登氏综合征(Sneddon's syndrome)。
在进一步的实施方案中,疾病或病症选自急性疼痛、中枢性疼痛综合征、化疗诱发的神经病变及神经性疼痛、糖尿病性神经病、纤维肌痛、炎性疼痛、神经性疼痛、与CNS疾病相关的神经性疼痛、疼痛性糖尿病性周围神经病变、术后疼痛、紧张性疼痛及内脏疼痛。
在其它实施方案中,CNS障碍选自化疗脑、左旋多巴诱发的成瘾行为、酒精中毒、麻醉药依赖(包括但不限于苯丙胺、阿片剂或其它物质)及物质滥用。
术语“疾病”、“障碍”、“健康状况”及“病症”可在此处互换使用,以指CNS的sGC、cGMP和/或NO介导的医学或病理学障碍或可以其它方式受益于NO通路上调的CNS的疾病。
如本发明所使用,术语“受试者”及“患者”可互换使用。术语“受试者”及“患者”是指动物(例如鸟,诸如鸡、鹌鹑或火鸡,或哺乳动物),特别是包括非灵长类动物(例如,牛、猪、马、绵羊、兔、豚鼠、大鼠、猫、狗,及小鼠)及灵长类动物(例如,猴、黑猩猩及人类)的“哺乳动物”,且更具体地为人类。在一些实施方案中,受试者为非人类动物,诸如农场动物(例如,马、牛、猪或绵羊),或宠物(例如,狗、猫、豚鼠或兔)。在一些实施方案中,受试者为人类。
本发明也提供一种用于治疗受试者的以上疾病、病症及障碍中的一个的方法,该方法包含向需要治疗的受试者给药治疗有效量的本发明中所述的化合物或其药学上可接受的盐。或者,本发明提供本发明中所述的化合物或其药学上可接受的盐在治疗需要治疗的受试者的这些疾病、病症及障碍中的一个中的用途。
如本发明所使用,术语“生物样品”是指体外或离体样品,且包括而不限于细胞培养物或其提取物;自哺乳动物获得的活检材料或其提取物;血液、唾液、尿、粪便、精液、泪、淋巴液、眼液、玻璃体液、脑脊髓液(CSF)或其它体液或其提取物。
关于障碍或疾病的“治疗(treat,treating,treatment)”是指减轻或消除障碍或疾病的原因和/或影响。如本发明所使用,术语“治疗(treat,treating,treatment)”是指由给药一种或多种疗法(例如,一种或多种治疗剂,诸如表I的化合物或其组合物或剂型)所引起的sGC、cGMP和/或NO介导的病症或将受益于NO通路上调的病症的进展、严重性和/或持续时间的减少或改善,或该病症的一种或多种症状(优选地,一种或多种可辨别症状)的改善(也即“管理”而未“治愈”病症)。在具体实施方案中,术语“治疗(treat,treating,treatment)”是指sGC、cGMP和/或NO介导的病症或将受益于NO通路上调的疾病的至少一种可测量物理参数的改善。在其它实施方案中,术语“治疗(treat)”、“治疗(treatment)”及“治疗(treating)”是指在物理上(例如通过可辨别症状的稳定)或在生理上(通过例如身体参数的稳定)或两者抑制了sGC、cGMP和/或NO介导的病症或将受益于NO通路上调的疾病的进展。
如本发明所使用的术语“预防”是指预先给药药物以避免或预先阻止疾病或障碍的一种或多种症状的出现。医学领域中的普通技术人员认识到术语“预防”不为绝对术语。在医学领域中,其是理解为指预防性给药药物以实质上减少病症的可能性或严重性或病症的症状,且此为本发明中预期的意义。医师桌面参考(Physician’s Desk Reference)(即本领域中的标准文本)使用术语“预防”达数百次。如其中所使用,关于障碍或疾病的术语“预防(prevent,preventing,prevention)”是指在疾病或障碍其自身完全显现之前或在确诊障碍之前避免疾病或障碍的原因、影响、症状或进展。
在一个实施方案中,本发明的方法为对具有患上sGC、cGMP和/或NO有关的疾病、障碍或症状的倾向(例如,遗传倾向)的患者(具体地为人类)的预防性或“先发制人性”措施。
在其它实施方案中,本发明的方法为患有疾病、障碍或病症的患者(具体地为人类)的预防性或“先发制人性”措施,该疾病、障碍或病症使该患者处于患上sGC、cGMP或NO有关的疾病、障碍或症状的风险中。
此处所述的化合物及组合物也可用于伴侣动物、外来动物及农场动物(包括而不限于狗、猫、小鼠、大鼠、仓鼠、沙鼠、豚鼠、兔、马、猪及牛)的兽医学治疗。
在其它实施方案中,本发明提供一种刺激生物样品的sGC活性的方法,该方法包含使该生物样品与表I的化合物或其药学上可接受的盐、组合物或剂型接触。sGC刺激剂在生物样品中的用途可用于本领域技术人员已知的多种目的。此类目的的实例包括而不限于生物测定及生物试样储存。
本发明中所述的化合物及药物组合物可单独或以组合疗法用于治疗或预防由sGC、cGMP和/或NO介导、调控或影响的疾病或障碍。
组合疗法
本发明中所述的化合物及药物组合物可以组合疗法与一种或多种额外治疗剂一起使用。对于用多于一种活性剂进行的组合治疗,在活性剂处于分开的剂量制剂中的情况下,可分开或联合给药活性剂。此外,一种成分的给药可在另一种药剂的给药之前、与其同时或在其之后。
当与其它药剂“共给药”时,例如当与另一药物共给药时,第二药剂的“有效量”将取决于所使用药物的类型。经批准药剂的合适剂量为已知的,且可由本领域技术人员根据受试者的病症、所治疗的病症的类型及所使用的本发明中所述的化合物的量来调整。在未明确指出量的情况下,应假定有效量。例如,本发明中所述的化合物可以范围为以下的剂量向受试者给药:介于约0.01至约10,000mg/kg体重/天、约0.01至约5000mg/kg体重/天、约0.01至约3000mg/kg体重/天、约0.01至约1000mg/kg体重/天、约0.01至约500mg/kg体重/天、约0.01至约300mg/kg体重/天、约0.01至约100mg/kg体重/天之间。
当采用“组合疗法”时,可使用第一量的表I的化合物或其药学上可接受的盐及第二量的额外合适的治疗剂来得到有效量。
在本发明的一个实施方案中,表I的化合物或其药学上可接受的盐及额外治疗剂各自以有效量(也即,各自以若单独给药则将为治疗有效的量)给药。在另一个实施方案中,表I的化合物或其药学上可接受的盐及额外治疗剂各自以单独未提供治疗效果的量(亚治疗剂量)给药。在又一个实施方案中,表I的化合物可以有效量给药,而额外治疗剂以亚治疗剂量给药。在仍另一个实施方案中,表I的化合物可以亚治疗剂量给药,而额外治疗剂(例如,合适的癌症治疗剂)以有效量给药。
如本发明所使用,术语“组合”或“共给药”可互换使用,以指使用多于一种疗法(例如,一种或多种预防剂和/或治疗剂)。术语的使用不限制向受试者给药疗法(例如,预防剂和/或治疗剂)的次序。
共给药涵盖以基本上同时的方式诸如以单一药物组合物(例如具有固定比率的第一及第二量的胶囊或片剂)或以多个各自分开的胶囊或片剂给药第一及第二量的化合物。此外,此类共给药也涵盖以依序方式以任一次序使用各化合物。当共同给药涉及分开给药第一量的表I的化合物及第二量的额外治疗剂时,化合物的给药在时间上足够接近以具有希望治疗效果。例如,可产生希望治疗效果的各给药之间的时期的范围可为数分钟至数小时,且可考虑各化合物的性质(诸如效力、溶解度、生物利用度、血浆半衰期及动力学曲线)来确定。例如,表I的化合物及第二治疗剂可以任何次序彼此相差约24小时内、彼此相差约16小时内、彼此相差约8小时内、彼此相差约4小时内、彼此相差约1小时内或彼此相差约30分钟内给药。
更具体而言,第一疗法(例如,预防剂或治疗剂,诸如本发明中所述的化合物)可在向受试者给药第二疗法(例如,预防剂或治疗剂,诸如抗癌剂)之前(例如,之前5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周)、与其同时,或在其之后(例如,之后5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周)给药。
可与表I的化合物或其药学上可接受的盐组合(分开给药或在同一药物组合物中给药)的其它治疗剂的实例包括但不限于:
(1)内皮源性释放因子(EDRF)或NO气体。
(2)NO供体,诸如亚硝基硫醇、亚硝酸盐、斯德酮亚胺(sydnonimine)、NO-亲核复合体(NONOate)、N-亚硝胺、N-羟基亚硝胺、亚硝基亚胺、硝基酪氨酸、二氧化二氮杂环丁烯(diazetine dioxide)、氧杂三唑5-亚胺、肟、羟胺、N-羟基胍、羟基脲或氧化呋咱环(furoxan)。这些类型的化合物的一些实例包括:三硝酸甘油酯(也称为GTN、硝酸甘油、硝化甘油及三硝基甘油(trinitrogylcerin))、甘油的硝酸酯;硝普钠(SNP),其中一氧化氮分子与金属铁配位形成方形双锥体络合物;3-吗啉代斯德酮亚胺(SIN-1),由吗啉及斯德酮亚胺组合形成的两性离子化合物;S-亚硝基-N-乙酰青霉胺(SNAP),具有亚硝基硫醇官能团的N-乙酰化氨基酸衍生物;二亚乙基三胺/NO(DETA/NO),共价连接至二亚乙基三胺的一氧化氮化合物;乙酰水杨酸的间硝氧甲基苯基酯。这些类型的NO供体中的一些的更具体实例包括:典型的硝基血管扩张剂,诸如有机硝酸酯及亚硝酸酯,包括硝酸甘油、亚硝酸戊酯、二硝酸异山梨醇酯、5-单硝酸异山梨醇酯及尼可地尔;异山梨醇 3-吗啉代斯德酮亚胺;水合氯化林西多明(linsidomine chlorohydrate)(“SIN-1”);S-亚硝基-N-乙酰青霉胺(“SNAP”);S-亚硝基谷胱甘肽(GSNO)、硝普钠、S-亚硝基谷胱甘肽单乙酯(GSNO-酯)、6-(2-羟基-1-甲基-亚硝基肼基)-N-甲基-1-己胺或二乙胺NO-亲核复合体。
(3)增强cGMP浓度的其它物质,诸如原卟啉IX、花生四烯酸及苯肼衍生物。
(4)一氧化氮合酶基质:例如基于N-羟基胍的类似物,诸如N(G)-羟基-L-精氨酸(NOHA)、1-(3,4-二甲氧基-2-氯亚苄基氨基)-3-羟基胍,及PR5(1-(3,4-二甲氧基-2-氯亚苄基氨基)-3-羟基胍);L-精氨酸衍生物(诸如高-Arg、高-NOHA、N-叔丁氧基及N-(3-甲基-2-丁烯基)氧基-L-精氨酸、刀豆氨酸、ε胍-己酸(epsilon guanidine-carpoic acid)、胍丁胺、羟基-胍丁胺及L-酪氨酰-L-精氨酸);N-烷基-N’-羟基胍(诸如N-环丙基-N’-羟基胍及N-丁基-N’-羟基胍)、N-芳基-N’-羟基胍(诸如N-苯基-N’-羟基胍及其分别带有-F、-Cl、-甲基、-OH取代基的对位取代衍生物);胍衍生物,诸如3-(三氟甲基)丙基胍。
(5)增强eNOS转录的化合物。
(6)NO非依赖性血红素非依赖性sGC活化剂,包括但不限于:
BAY 58-2667(在专利公开DE19943635中描述)
HMR-1766(阿他西哌钠(ataciguat sodium),在专利公开WO2000002851中描述)
S 3448(2-(4-氯-苯基磺酰基氨基)-4,5-二甲氧基-N-(4-(硫代吗啉-4-磺酰基)-苯基)-苯甲酰胺(在专利公开DE19830430及WO2000002851中描述)
及
HMR-1069(Sanofi-Aventis)。
(7)血红素依赖性、NO非依赖性sGC刺激剂,包括但不限于:
YC-1(参见专利公开EP667345及DE19744026)
利奥西哌(BAY 63-2521,在DE19834044中描述)/>
内利西哌(BAY 60-4552,在WO 2003095451中描述)
维利西哌(BAY 1021189)
BAY 41-2272(在专利公开案DE19834047及DE19942809中描述)
BAY 41-8543(在DE19834044中描述)
依崔西哌(在WO 2003086407中描述)
CFM-1571(在专利公开WO2000027394中描述)
A-344905、其丙烯酰胺类似物A-350619及氨基嘧啶类似物A-778935
/>
及公开US20090209556、US8455638、US20110118282(WO2009032249)、US20100292192、US20110201621、US7947664、US8053455(WO2009094242)、US20100216764、US8507512、(WO2010099054)US20110218202(WO2010065275)、US20130012511(WO2011119518)、US20130072492(WO2011149921)、US20130210798(WO2012058132)的任一个中所述的其它sGC刺激剂,及Tetrahedron Letters(2003),44(48):8661-8663中所述的其它化合物。
(8)抑制cGMP降解的化合物,诸如:
PDE5抑制剂,诸如,例如,西地那非及有关药剂,诸如阿伐那非、洛地那非、米罗那非、柠檬酸西地那非/>他达拉非(/>或/>)、伐地那非及乌地那非;前列地尔;双嘧达莫及PF-00489791;
PDE9抑制剂,诸如,例如PF-04447943;及
PDE10抑制剂,诸如,例如PF-02545920(PF-10)。
(9)以下类型的钙通道阻断剂:
二氢吡啶钙通道阻断剂,诸如胺氯地平(asamlodipine)阿雷地平阿折地平/>巴尼地平/>贝尼地平/>西尼地平/>氯维地平/>地尔硫/>依福地平非洛地平/>拉西地平/> 乐卡地平/>马尼地平/>尼卡地平(/>Carden/>)、硝苯地平尼伐地平/>尼莫地平/>尼索地平 尼群地平/>普拉地平/>伊拉地平/>
苯基烷基胺钙通道阻断剂,诸如维拉帕米
及戈洛帕米(D600);
苯并硫氮杂诸如地尔硫/>
及/>
非选择性钙通道抑制剂,诸如咪拉地尔、苄普地尔、氟司必林及芬地林。
(10)内皮素受体拮抗剂(ERA),诸如双重(ETA及ETB)内皮素受体拮抗剂波生坦西他生坦/>或安贝生坦(ambrisentan)/>
(11)前列环素衍生物或类似物,诸如前列腺环素(前列腺素I2)、依前列醇(合成前列环素,)、曲罗尼尔/>伊洛前列素/>伊洛前列素及正在开发的口服及吸入形式的/>
(12)抗高脂血药,诸如以下类型:
胆汁酸螯合剂,如考来烯胺、考来替泊、考来替兰、考来维仑或司维拉姆;
他汀类,如阿托伐他汀、辛伐他汀、洛伐他汀、氟伐他汀、匹伐他汀、罗舒伐他汀及普伐他汀;
胆固醇吸收抑制剂,诸如依泽替米贝;
其它降脂剂,诸如二十碳五烯酸乙酯、ω-3-酸乙酯、reducol;
纤维酸衍生物,诸如氯贝丁酯、苯扎贝特、克利贝特、吉非贝齐、氯烟贝特、比尼贝特、非诺贝特、环丙贝特、非诺贝特胆碱;
烟酸衍生物,诸如阿昔莫司及烟酸;
他汀类、烟酸及肠胆固醇吸收抑制补充剂(依泽替米贝及其它补充剂)及纤维酸盐的组合;及
抗血小板疗法,诸如硫酸氢氯吡格雷。
(13)抗凝剂,诸如下列类型:
香豆素(维生素K拮抗剂),诸如华法林醋硝香豆醇(cenocoumarol)、苯丙香豆素及苯茚二酮;
肝素及衍生物,诸如低分子量肝素、磺达肝素及依达肝素(idraparinux);
直接凝血酶抑制剂,诸如阿加曲班、来匹卢定、比伐卢定、达比加群及希美加群及
组织血纤维蛋白溶酶原活化剂,其用于溶解血凝块及使动脉解除阻塞,诸如阿替普酶。
(14)抗血小板药物,例如topidogrel、噻氯匹定、双嘧达莫及阿司匹林。
(15)ACE抑制剂,例如以下类型:
含硫氢基药剂,诸如卡托普利及佐芬普利;
含二羧酸盐药剂,诸如依那普利雷米普利喹那普利/>培哚普利赖诺普利/>及贝那普利/>
含膦酸盐药剂,诸如福辛普利;
天然存在的ACE抑制剂,诸如作为酪蛋白及乳清的降解产物的casokinin及lactokinin,它们在乳制品,特别是发酵乳的摄取后天然存在;
乳三肽Val-Pro-Pro及Ile-Pro-Pro,它们由益生菌瑞士乳杆菌(Lactobacillushelveticus)产生或衍生自酪蛋白,也具有抑制ACE及抗高血压功能;
其它ACE抑制剂,诸如阿拉普利、地拉普利、西拉普利、咪达普利、群多普利、替莫普利、莫昔普利及螺普利(pirapril)。
(16)补充氧疗法。
(17)β阻断剂,诸如下列类型:
非选择性药剂,诸如阿普洛尔、布新洛尔、卡替洛尔、卡维地洛、拉贝洛尔、纳多洛尔、喷布洛尔、吲哚洛尔、氧烯洛(oxprenonol)、醋丁洛尔、索他洛尔、甲吲洛尔、塞利洛尔、阿罗洛尔、特他洛尔、氨磺洛尔、尼普地洛、普萘洛尔及噻吗洛尔;
β1-选择性药剂,诸如醋丁洛尔(cebutolol)、阿替洛尔、倍他洛尔、比索洛尔、塞利洛尔、盐酸多巴酚丁胺、马来酸依索拉定、卡维地洛、他林洛尔、艾司洛尔、美托洛尔及奈必洛尔;及
β2-选择性药剂,诸如布他沙明。
(18)抗心律失常药剂,诸如以下类型:
I型(钠通道阻断剂),诸如奎尼丁、利多卡因、苯妥英、普罗帕酮;
III型(钾通道阻断剂),诸如胺碘酮、多非利特及索他洛尔;及
V型,诸如腺苷及地高辛。
(19)利尿剂,诸如噻嗪类利尿剂,例如氯噻嗪、氯噻酮及氢氯噻嗪、苄氟噻嗪、环戊噻嗪、甲氯噻嗪、泊利噻嗪、喹乙宗、希帕胺、美托拉宗、吲达帕胺、西氯他宁;髓袢利尿剂,诸如呋塞米及托拉塞米(toresamide);保钾利尿剂,诸如阿米洛利、螺内酯、坎利酸钾、依普利酮及氨苯蝶啶;这些药剂的组合;其它利尿剂,诸如乙酰唑胺及卡培立肽。
(20)直接作用血管扩张剂,诸如盐酸肼苯哒嗪、二氮嗪、硝普钠、卡屈嗪;其它血管扩张剂,诸如硝酸异山梨醇酯及5-单硝酸异山梨醇酯。
(21)外源性血管扩张剂,诸如及α阻断剂。
(22)α-1-肾上腺素受体拮抗剂,诸如哌唑嗪、吲哚拉明、乌拉地尔、布那唑嗪、特拉唑嗪及多沙唑嗪;心房钠尿肽(ANP)、乙醇、组胺诱导剂、四氢大麻酚(THC)及罂粟碱。
(23)以下类型的支气管扩张剂:
短效β2激动剂,诸如沙丁胺醇(albutamol)或沙丁胺醇(albuterol)及特布他林;
长效β2激动剂(LABA),诸如沙美特罗及福莫特罗;
抗胆碱剂,诸如异丙托溴铵(pratropium)及噻托溴铵;及
茶碱、支气管扩张剂及磷酸二酯酶抑制剂。
(24)皮质类固醇,诸如倍氯米松、甲泼尼龙、倍他米松、泼尼松、泼尼松龙、曲安西龙、地塞米松、氟替卡松、氟尼缩松、氢化可的松及皮质类固醇类似物,诸如布地奈德。
(25)膳食补充剂,诸如,例如ω-3油;叶酸、烟碱酸、锌、铜、韩国红参、银杏、松树皮、刺蒺藜(Tribulus terrestris)、精氨酸、燕麦(Avena sativa)、淫羊藿、马卡根、巴西榥榥木、锯棕榈及瑞典花粉;维生素C、维生素E、维生素K2;睾酮补充剂、睾酮经皮贴片;zoraxel、纳曲酮、布雷默浪丹(bremelanotide)及美拉诺坦II。
(26)PGD2受体拮抗剂。
(27)免疫抑制剂,诸如环孢菌素(环孢菌素A,)、他罗利姆(FK-506,/>)、雷帕霉素/>及其它FK-506型免疫抑制剂、霉酚酸酯,例如麦考酚酸吗乙酯/>
(28)非类固醇抗哮喘剂,诸如β2-激动剂,如特布他林、奥西那灵、非诺特罗、异他林、沙丁胺醇、沙美特罗、比托特罗及吡布特罗;β2-激动剂-皮质类固醇组合,诸如沙美特罗-氟替卡松福莫特罗-布地奈德/>茶碱、色甘酸、色甘酸钠、奈多罗米、阿托品、异丙托铵、异丙托溴铵及白三烯生物合成抑制剂(齐留通,BAY1005)。
(29)非类固醇抗炎剂(NSAID),诸如丙酸衍生物,如阿明洛芬、苯噁洛芬、布氯酸、卡洛芬、芬布芬、非诺洛芬、氟洛芬、氟比洛芬、布洛芬、吲哚洛芬、酮洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、普拉洛芬、舒洛芬、噻洛芬酸及硫噁洛芬);乙酸衍生物,诸如吲哚美辛、阿西美辛、阿氯芬酸、环氯茚酸、双氯芬酸、芬氯酸、芬克洛酸、芬替酸、呋罗芬酸、异丁芬酸、伊索克酸、欧比那酸(oxpinac)、舒林酸、硫平酸、托美丁、齐多美辛及佐美酸;芬那酸衍生物,诸如氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟灭酸及托芬那酸;联苯羧酸衍生物,诸如二氟尼柳及氟苯柳;昔康类,诸如伊索昔康、吡罗昔康、舒多昔康及替诺昔康;水杨酸盐类,诸如乙酰水杨酸及柳氮磺胺吡啶;及吡唑酮类,诸如阿扎丙宗、贝比派瑞(bezpiperylon)、非普拉宗、莫非布宗、羟布宗及保泰松。
(30)环氧合酶-2(COX-2)抑制剂,诸如塞来昔布罗非昔布/>伐地昔布、艾托考昔、帕瑞考昔及鲁米考昔;阿片类镇痛药,诸如可待因、芬太尼、氢吗啡酮、左啡诺、哌替啶、美沙酮、吗啡、羟可酮、羟吗啡酮、丙氧芬、丁丙诺啡、布托啡诺、地佐辛、纳布啡及喷他佐辛;
(31)抗糖尿病剂,诸如胰岛素及胰岛素模拟物;磺脲类,诸如格列本脲、优降糖(glybenclamide)、格列吡嗪、格列齐特、格列喹酮、格列美脲、美格那肽(meglinatide)、甲苯磺丁脲、氯磺丙脲、醋磺己脲及妥拉磺脲(olazamide);双胍类,诸如二甲双胍α-葡萄糖苷酶抑制剂,诸如阿卡波糖、依帕司他、伏格列波糖、米格列醇;噻唑烷酮化合物,诸如罗格列酮/>曲格列酮/>环格列酮、吡格列酮/>及恩格列酮;胰岛素致敏剂,诸如吡格列酮及罗格列酮;胰岛素促分泌剂,诸如瑞格列奈、那格列奈及米格列奈;肠降血糖素模拟物,诸如依泽那太(exanatide)及利拉鲁肽(liraglutide);淀粉素类似物,诸如普兰林肽;葡萄糖降低剂,诸如吡啶甲酸铬,其任选与生物素组合;二肽基肽酶IV抑制剂,诸如西他列汀(sitagliptin)、维达列汀(vildagliptin)、沙格列汀(saxagliptin)、阿格列汀(alogliptin)及利格列汀(linagliptin)。
(32)HDL胆固醇增加剂,诸如anacetrapib及达塞曲匹(dalcetrapib)。
(33)抗肥胖药,诸如盐酸甲基苯丙胺、盐酸安非拉酮苯丁胺/>盐酸苄非他明/>酒石酸苯甲曲嗪/> 马吲哚奥利司他/>盐酸西布曲明单水合物/>利莫那班/>安非拉酮、吡啶甲酸铬;诸如苯丁胺/托吡酯、安非他酮/纳曲酮、西布曲明/二甲双胍、缓释安非他酮/缓释唑尼沙胺、沙美特罗、昔萘酸酯/丙酸氟替卡松的组合;盐酸氯卡色林(lorcaserin hydrochloride)、苯丁胺/托吡酯、西替利司他(cetilistat)、依泽那太、利拉鲁肽、盐酸二甲双胍、西布曲明/二甲双胍、缓释安非他酮/缓释唑尼沙胺、CORT-108297、卡格列净(canagliflozin)、吡啶甲酸铬、GSK-1521498、LY-377604、美曲普汀、obinepitide、P-57AS3、PSN-821、昔萘酸沙美特罗/丙酸氟替卡松、钨酸钠、生长激素(重组物)、替莫瑞林(tesamorelin)、特索芬辛(tesofensine)、韦利贝特(velneperit)、唑尼沙胺、本洛拉尼半草酸盐(beloranib hemioxalate)、促胰岛素、白藜芦醇、sobetirome、四氢次大麻酚(tetrahydrocannabivarin)及β-拉帕醌。
(34)血管收缩素受体阻断剂,诸如氯沙坦、缬沙坦、坎地沙坦、环庚塞、依普沙坦(eprosaran)、厄贝沙坦、替米沙坦、奥美沙坦(olmesartran)、medoxomil、阿齐沙坦(azilsartan)及medoxomil。
(35)肾素抑制剂,诸如阿利吉仑半富马酸盐。
(36)中枢作用α-2-肾上腺素受体激动剂,诸如甲基多巴、可乐定及胍法辛。
(37)肾上腺素能神经元阻断剂,诸如胍乙啶及胍那决尔。
(38)咪唑啉I-1受体激动剂,诸如磷酸利美尼定(rimenidine dihydrogenphosphate)及盐酸莫索尼定水合物。
(39)醛固酮拮抗剂,诸如螺内酯及依普利酮。
(40)钾通道活化剂,诸如吡那地尔。
(41)多巴胺D1激动剂,诸如甲磺酸非诺多泮;其它多巴胺激动剂,诸如异波帕胺、多培沙明及多卡巴胺。
(42)5-HT2拮抗剂,诸如酮色林。
(43)加压素拮抗剂,诸如托伐普坦。
(44)钙通道致敏剂诸如左西孟旦或活化剂诸如尼可地尔。
(45)PDE-3抑制剂,诸如胺力农、米力农、依诺昔酮、维司力农、匹莫苯及奥普力农。
(46)腺苷酸环化酶活化剂,诸如盐酸考福新达罗帕特(colforsin dapropatehydrochloride)。
(47)正性肌力剂,诸如地高辛及甲地高辛;代谢强心剂,诸如泛癸利酮;脑钠尿肽,诸如奈西立肽。
(48)用于治疗勃起功能障碍的药物,诸如前列地尔、阿肽地尔及甲磺酸酚妥拉明。
(49)用于治疗肥胖症的药物,包括但不限于盐酸甲基苯丙胺盐酸安非拉酮/>苯丁胺/>盐酸苄非他明/>盐酸苯甲曲嗪马吲哚/>及奥利司他/>
(50)用于治疗阿尔茨海默病及痴呆的药物,诸如以下类型
乙酰胆碱酯酶抑制剂,包括加兰他敏利斯的明/>多奈哌齐/>及他克林/>/>
NMDA受体拮抗剂,诸如美金刚及
氧化还原酶抑制剂,诸如艾地苯醌。
(51)精神科药物,诸如下列类型:
齐拉西酮(GeodonTM)、利培酮(RisperdalTM)、奥氮平(ZyprexaTM)、丙戊酸盐;
多巴胺D4受体拮抗剂,诸如氯氮平;
多巴胺D2受体拮抗剂,诸如奈莫必利;
混合型多巴胺D1/D2受体拮抗剂,诸如珠氯噻醇;
GABA A受体调节剂,诸如卡马西平;
钠通道抑制剂,诸如拉莫三嗪;
单胺氧化酶抑制剂,诸如吗氯贝胺及茚洛秦;
匹莫范色林(primavanserin)、哌罗匹隆;及
PDE4抑制剂,诸如罗氟司特(rolumilast)。
(52)用于治疗运动障碍或症状的药物,诸如以下类型:
儿茶酚-O-甲基转移酶抑制剂,诸如恩他卡朋;
单胺氧化酶B抑制剂,诸如司立吉林;
多巴胺受体调节剂,诸如左旋多巴;
多巴胺D3受体激动剂,诸如普拉克索;
脱羧酶抑制剂,诸如卡比多巴;
其它多巴胺受体激动剂,诸如培高利特、罗匹尼罗、卡麦角林;
ritigonide、伊曲茶碱(istradefylline)、他利克索;唑尼沙胺及沙芬酰胺(safinamide);及
突触小泡胺运输蛋白抑制剂(synaptic vesicular amine transporterinhibitor),诸如丁苯那嗪。
(53)用于治疗情绪或情感障碍或OCD的药物,诸如以下类型
三环类抗抑郁剂,诸如阿米替林地昔帕明/>丙咪嗪阿莫沙平/>去甲替林及氯米帕明;
选择性血清素再吸收抑制剂(SSRI),诸如帕罗西汀氟西汀/>舍曲林/>及西酞普兰(citralopram)/>
多塞平曲唑酮/>及阿戈美拉汀;
选择性去甲肾上腺素再吸收抑制剂(SNRI),诸如文拉法辛、瑞波西汀及阿托西汀;多巴胺能抗抑郁剂,诸如安非他酮及安咪奈丁。
(54)用于增强突触可塑性的药物,诸如以下类型:
烟碱受体拮抗剂,诸如美卡拉明;及
混合型5-HT、多巴胺及去甲肾上腺素受体激动剂,诸如鲁拉西酮(lurasidone)。
(55)用于治疗ADHD的药物,诸如安非他明;5-HT受体调节剂,诸如沃替西汀(vortioxetine)及α-2肾上腺素受体激动剂,诸如可乐定。
(56)中性内肽酶(NEP)抑制剂,诸如沙库巴曲(sacubitril)、奥马曲拉;及(57)亚甲蓝(MB)。
试剂盒
本发明中所述的化合物及药物制剂可容纳在试剂盒中。试剂盒可包括各自单独包装或配制的单剂量或多剂量的二种或更多种药剂;或以组合形式包装或配制的单剂量或多剂量的二种或更多种药剂。因此,一种或多种药剂可存在于第一容器中,且试剂盒可任选在第二容器中包括一种或多种药剂。一个或多个容器置于包装内,且包装可任选包括给药或剂量说明书。试剂盒可包括额外组件,诸如注射器或用于给药药剂以及稀释剂的其它构件或用于配制的其它构件。因此,试剂盒可包含:a)包含本发明中所述的化合物及药学上可接受的载体、媒介物或稀释剂的药物组合物;及b)容器或包装。试剂盒可任选包含说明书,其描述在本发明中所述的一种或多种方法中使用药物组合物的方法(例如,预防或治疗本发明中所述的一种或多种疾病及障碍)。试剂盒可任选包含第二药物组合物,其包含一种或多种本发明中所述的用于辅疗法用途的额外药剂、药学上可接受的载体、媒介物或稀释剂。包含本发明中所述的化合物的药物组合物及试剂盒中容纳的第二药物组合物可任选组合在同一药物组合物中。
试剂盒包括用于容纳药物组合物的容器或包装,且也可包括分开的容器,诸如分开的瓶或分开的箔片包。容器可为例如纸或纸板盒、玻璃或塑料的瓶或罐、可再密封袋(例如,以保持向不同的容器中“再填充”片剂)或泡罩包装,该泡罩包装具有单独剂量以根据治疗时程从包装中压出。可行的是,可将多于一个容器一起用于单一包装以销售单一剂型。例如,片剂可容纳在一个瓶中,该瓶继又容纳在盒内。
试剂盒的实例为所谓的泡罩包装。包装工业中熟知泡罩包装且正将其广泛用于包装药物单位剂型(片剂、胶囊及类似物)。泡罩包装通常由相对硬的材料片材与覆盖其的优选透明塑料材料的箔片组成。在包装过程期间,于塑料箔片中形成凹部。该凹部具有欲包装的单独片剂或胶囊的尺寸及形状,或可具有适应欲包装的多个片剂和/或胶囊的尺寸及形状。接着,将片剂或胶囊相应地置于所述凹部中且将相对硬的材料片材密封于塑料箔片的与形成凹部的方向相对的箔片面上。因此,根据需要将片剂或胶囊分别密封或共同密封于介于塑料箔片与片材之间的凹部中。优选地,片材的强度使得片剂或胶囊可通过手动施压于凹部由此于片材中凹部的位置处形成开口从而自泡罩包装移除。接着可经由该开口移除片剂或胶囊。
可希望为医师、药剂师或受试者提供含有关于何时服用药物的信息和/或说明的书面记忆帮助物。“日剂量”可为给定日服用的单个片剂或胶囊或若干片剂或胶囊。当试剂盒含有分开的组合物时,试剂盒的一种或多种组合物的日剂量可由一个片剂或胶囊组成,而试剂盒的另一种或多种组合物的日剂量可由若干片剂或胶囊组成。试剂盒可采取分配器的形式,该分配器是设计成按其旨在使用的次序一次一个地分配日剂量。分配器可配备记忆辅助物,以便进一步促进与方案的依从性。此种记忆帮助物的实例为机械计数器,其指示已经分配的日剂量的数目。此种记忆帮助物的另一个实例为与液晶读出器耦接的电池供电微芯片内存或可听式提醒信号,该可听式提醒信号例如读出已服用上一次日剂量的日期和/或提醒何时要服用下一剂量。
实施例
实施例中提供的所有参考文献以引用的方式并入本发明中。如本发明中所使用,所有缩写、符号及惯例都与当代科学文献中使用的那些一致。参见,例如,Janet S.Dodd编写的The ACS Style Guide:A Manual for Authors and Editors,第2版,Washington,D.C.:American Chemical Society,1997,其以全文引用的方式并入本发明中。本发明中所述的化合物是根据以下来制备:Roberts等(Bioorg.Med.Chem.Lett.,21,6515-6518(2011))。
实施例1:化合物合成
中间体1(1-((2-甲基嘧啶-5-基)甲基)-1H-吡唑并[3,4-b]吡啶-3-甲腈):
以2个步骤合成标题化合物。
步骤1:1H-吡唑并[3,4-b]吡啶-3-甲腈的合成
在环境温度,将氰化锌(II)(1.0g,8.6mmol)及2-碘-1H-吡唑并[3,4-b]吡啶(1.4g,5.7mmol)在DMF(40mL)中混合,且将氮气流鼓泡通过溶液5分钟。添加[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷络合物(Pd(dppf)Cl2·CH2Cl2)(0.33g,0.40mmol),且将溶液脱气另外10分钟。将反应物维持在正压氮气氛下,且在130℃加热48小时。将混合物冷却至环境温度,过滤,且将残余物用乙酸乙酯洗涤。将合并的滤液在真空中浓缩至上,且通过柱色谱法(20至70%EtOAc/己烷梯度)纯化,以得到呈浅黄色固体状的标题化合物(0.51g,62%产率)。
1H NMR(500MHz,甲醇-d4)δ(ppm)8.67(dd,1H),8.34(dd,1H),7.44(dd,1H)。
步骤2:1-((2-甲基嘧啶-5-基)甲基)-1H-吡唑并[3,4-b]吡啶-3-甲腈的合成
将三苯基膦(0.19g,0.72mmol)于DCM/THF(1:1,4.0mL)中的溶液冷却至0℃,且经2分钟滴加偶氮二甲酸二异丙酯(DIAD)(0.14mL,0.72mmol)。30分钟后,在0℃将反应混合物添加至(2-甲基嘧啶-5-基)甲醇(0.09g,0.72mmol)及1H-吡唑并[3,4-b]吡啶-3-甲腈(0.08g,0.56mmol)于THF(4.0mL)中的溶液中。经3小时使所得混合物温热至环境温度。将反应物用乙酸乙酯(100mL)稀释,且用水(3x 10mL)及盐水洗涤。将有机相经Na2SO4干燥,过滤,且在真空中浓缩。通过柱色谱法(25至100%EtOAc/己烷梯度)纯化,得到呈白色固体状的标题化合物(89mg,64%产率)。
1H NMR(500MHz,氯仿-d)δ(ppm)8.81(s,2H),8.72(dd,1H),8.23(dd,1H),7.41(dd,1H),5.77(s,2H),2.74(s,3H)。
以下有关中间体是可商购获得的或根据文献方法(Roberts,L.R.等Bioorg.Med.Chem.Lett.2011,21,6515-6518)来合成。
1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-甲腈;
8-(2-氟苄基)咪唑并[1,5-a]嘧啶-6-甲腈;
7-(2-氟苄基)咪唑并[1,5-b]哒嗪-5-甲腈;
1-((2-甲基嘧啶-5-基)甲基)咪唑并[1,5-a]吡啶-3-甲腈;
1-(嘧啶-5-基甲基)咪唑并[1,5-a]吡啶-3-甲腈;及
1-(2-氟苄基)咪唑并[1,5-a]吡啶-3-甲腈。
化合物I-1
此化合物通过通用程序A来合成:
向1-((2-甲基嘧啶-5-基)甲基)-1H-吡唑并[3,4-b]吡啶-3-甲腈(中间体1,85mg,0.34mmol)于无水乙醇(3.0mL)(注意:也可使用无水甲醇作为溶剂)中的溶液添加无水肼(0.10g,3.2mmol)。在环境温度搅拌3天且接着在60℃搅拌1天后,观察到起始材料完全消失。将反应物在真空中浓缩,且将残余物在真空中干燥过夜。将残余物吸收于DCM(5.0mL)中,且滴加2,2,2-三氟乙酸酐(0.05mL,0.34mmol)。在环境温度搅拌反应物直至完全消耗脒腙中间体。添加甲苯(5.0mL),随后滴加三氯化磷酰(0.10mL,1.0mmol)。
在65℃于密封小瓶中加热所得混合物30分钟。将反应混合物倒入EtOAc(100mL)中,且用10%NaHCO3水溶液(2x 10mL)及盐水(10mL)洗涤。将有机层经Na2SO4干燥,过滤,且在真空中浓缩。通过柱色谱法(30至100%EtOAc/己烷梯度)纯化,得到呈白色固体状的标题化合物(74mg,60%产率)。
1H NMR(500MHz,氯仿-d)δ(ppm)14.5(br s,1H),9.03(s,2H),8.83(dd,1H),8.72(dd,1H),7.40(dd,1H),5.84(s,2H),2.87(s,3H)。
化合物I-2
根据通用程序A合成,其呈白色固体状(54mg,40%产率)。根据需要修改反应条件(诸如试剂比率、温度及反应时间)。
1H NMR(500MHz,DMSO-d6)δ(ppm)15.7(br s,1H),8.76(dd,1H),8.67(dd,1H),7.50(dd,1H),7.37(m,1H),7.24(m,1H),7.21(m,1H),7.16(app.t,1H),5.90(s,2H)。
化合物I-3
根据通用程序A合成,其呈白色固体状(85mg,58%产率)。根据需要修改反应条件(诸如试剂比率、温度及反应时间)。
1H NMR(500MHz,甲醇-d4)δ(ppm)9.29-9.35(m,1H),7.63-7.69(m,1H),7.29-7.35(m,1H),7.19-7.26(m,1H),6.92-7.11(m,4H),4.35(d,2H)。
化合物I-4
根据通用程序A合成,其呈白色固体状(34mg,58%产率)。根据需要修改反应条件(诸如试剂比率、温度及反应时间)。
1H NMR(500MHz,DMSO-d6)δ(ppm)15.6(br s,1H),9.22(d,1H),8.67(s,2H),7.96(d,1H),7.10(m,2H),4.33(s,2H),2.56(s,3H)。
化合物I-5
根据文献方法(Roberts,L.R.等Bioorg.Med.Chem.Lett.2011,21,6515-6518)来合成,其呈浅棕色固体状(800mg)。根据需要修改反应条件(诸如试剂比率、温度及反应时间)。
1H NMR(500MHz,DMSO-d6)δ(ppm)15.60(s,1H),9.22(d,1H),9.05(s,1H),8.80(s,2H)7.99(d,1H),7.08–7.14(m,2H),4.40(s,2H)。
化合物I-6
根据通用程序A合成,其呈黄色固体状(12mg,24%产率)。根据需要修改反应条件(诸如试剂比率、温度及反应时间)。
1H NMR(500MHz,甲醇-d4)δ(ppm)8.58(dd,1H),8.36(dd,1H),7.25-7.33(m,2H),7.07-7.13(m,2H),6.99(dd,1H),4.58(s,2H)。
化合物I-7
向8-(2-氟苄基)咪唑并[1,5-a]嘧啶-6-甲腈(110mg,0.44mmol)于无水甲醇(3.0mL)中的溶液添加无水肼(0.08mL,2.7mmol)。在环境温度搅拌46小时后,观察到起始材料完全消失。将反应物在真空中浓缩,且将残余物在真空中干燥过夜。将残余物(5-氨基-4-(2-氟苄基)-1H-咪唑-2-亚氨代甲酰肼)吸收于THF(3.0mL)中,且滴加2,2,2-三氟乙酸酐(0.07mL,0.54mmol)。添加额外量的2,2,2-三氟乙酸酐(0.05mL,0.36mmol)以驱使脒腙中间体完全消耗。将反应物在真空中浓缩,且将残余物溶解于DCM/甲苯(1:1比率,6.0mL)中,随后滴加三氯化磷酰(0.13mL,1.3mmol)。在75℃在密封小瓶中加热反应混合物过夜。冷却至环境温度后,添加NaOH水溶液(1.0N,15mL)及DCM(20mL)。搅拌3天后,用6.0N HCl溶液将所得混合物中和至pH约6至7,且用DCM/异丙醇(5:1比率,4x 30mL)提取。将合并的有机层经Na2SO4干燥,过滤且浓缩,以提供棕色油。将残余物(4-(2-氟苄基)-2-(3-(三氟甲基)-1H-1,2,4-三唑-5-基)-1H-咪唑-5-胺)吸收于无水乙醇(4.0mL)中,且用1,1,3,3-四甲氧基丙烷(0.37mL,2.2mmol)处理。在微波中加热5小时后,添加额外量的1,1,3,3-四甲氧基丙烷(0.18mL,1.1mmol),且将混合物在微波中加热额外6小时。将反应混合物在真空中浓缩,且使用反相制备性HPLC(具有0.1%甲酸作为添加剂的30至80%乙腈/水梯度)纯化残余物以分离呈浅棕色固体状的标题化合物(6.4mg,4.0%产率)。
1H NMR(500MHz,DMSO-d6)δ(ppm)15.8(br s,1H),9.42(dd,1H),8.45(dd,1H),7.31-7.23(m,2H),7.19-7.14(m,2H),7.09(app.t,1H),4.38(s,2H)。
化合物I-8至I-16的合成是描述于Roberts,L.R.等Bioorg.Med.Chem.Lett.2011,21,6515-6518中。
实施例2:通过384孔格式的基于cGMP GloSensor细胞的测定进行生物活性测量
使用表达GloSensorTM 40F cGMP的人胚胎肾细胞(HEK293)细胞(部件号:CS182801,Promega)来评估测试化合物的活性。掺入这些细胞中的发光生物传感器(工程化荧光素酶)检测由刺激sGC酶的化合物形成的cGMP且发光。
将cGMP GloSensor细胞维持在补充有胎牛血清(FBS,10%最终浓度)及潮霉素(200ug/ml)的Dulbecco改良Eagle培养基(DMEM)中。在测定前一天,在聚D-赖氨酸涂覆的384孔平坦白底板(Corning目录号35661)中,将细胞以1.5x104个细胞/孔的密度接种在50μL体积的具有10%FBS的DMEM中。将细胞在具有5%CO2的潮湿室中在37℃孵育过夜。第二天,将培养基移除,且将细胞用40ul/孔的2mM GloSensorTM(Promega目录号E1291)置换。将细胞在25℃处理90分钟以使基质在细胞中平衡。将测试化合物及二亚乙基三胺NONOate(DETA-NONOate)在无血清CO2非依赖性培养基中稀释至3mM(20x),且以4x稀释度连续稀释以产生5X剂量曲线,将其中10ul添加至孔中(xμM浓度的化合物溶液及10μM浓度的DETA-NONOate溶液;其中x为以下最终浓度之一:30μM、7.5μM、1.9μM、469nM、117nM、29.3nM、7.3nM、1.83nM、0.46nM、0.11nM、0.03nM)
对于动力学研究,立即用Envision(Perkin Elmer)测量发光0.2秒/孔。对于终点SAR筛选,在室温孵育55分钟后收集数据。
使用以下方程式将数据针对高对照归一化:100*(样品-低对照)/(高对照-低对照),其中低对照为用1%DMSO处理的16个样品的平均值,且高对照为用30μM的以下描绘的化合物Y处理的16个样品的平均值。使用GraphPad Prism软件第5版,使用4参数拟合(log(激动剂)对反应-可变斜率)拟合数据。对所有化合物,n=2。绝对值(Ab)EC50从曲线拟合中内插,且定义为给定化合物在如上所述的数据归一化之后引发50%的高对照反应所处的浓度。将未能引发50%最小反应的化合物报告为>30μM或ND。对于一式两份或以高于2的n次运行的化合物,本发明给出的结果为获得的若干结果的几何平均值。表2总结了在本测定中针对所选本发明化合物获得的结果。
表2.针对表I中化合物的384孔格式的基于GloSensor细胞的测定(实施例2)的全细胞活性。
化合物 | Glo sensor Ab EC50(nM) |
I-5 | B |
I-2 | A |
I-6 | B |
I-4 | B |
I-3 | B |
I-7 | B |
I-1 | B |
通过GloSensor测定确定HEK细胞的sGC酶活性值。sGC酶活性值的(~)代码定义是表示为绝对值EC50,其定义为给定化合物在数据归一化之后引发50%的高对照反应(化合物Y)所处的浓度:Ab EC50≤10nM=A;10nM<Ab EC50≤100nM=B;100nM<Ab EC50=C。将未能引发50%最小反应的化合物报告为>30μM或ND。
实施例3.通过基于cGMP神经元细胞的测定进行生物活性测量
自18天怀孕的史-道二氏雌性鼠的胎儿中分离大鼠初级神经元。将胎儿在汉克斯平衡盐溶液(HBSS)中收集,且迅速移除脑。将脑海马分离且以机械方式破碎。在37℃在没有Ca2+及Mg2+的HBSS中用0.25%(wt/vol)胰蛋白酶溶液进行进一步的组织消化达15分钟。胰蛋白酶消化后,将细胞洗涤且重悬于补充有0.5mM L-谷氨酰胺、12.5μM谷氨酸、2%B-27,及100U/mL青霉素及100μg/mL链霉素的neurobasal培养基中。将细胞以4x104个细胞/孔的密度接种在聚-D-赖氨酸涂覆的384孔平坦透明底板(Corning目录号354662)中。将细胞在具有5%CO2的潮湿室中在37℃孵育6至7天。将培养基移除,将细胞用含有Ca2+及Mg2+的HBSS洗涤1次,且用含有0.5mM IBMX的40uL HBSS置换,且在37℃孵育15分钟。添加10uL具有二亚乙基三胺NONOate(DETA-NO)的测试化合物的5X储备液。DETA-NO的最终浓度为30μM。将细胞在37℃孵育20分钟。移除培养基,添加50uL冰冷的10%乙酸,且在4℃孵育60分钟。在4℃以1000xg离心5分钟以使细胞碎片团块化后,将上清液抽吸至干净的板,且分析样品的cGMP含量。使用LC-MS/MS自各样品确定cGMP浓度。
使用以下方程式将数据针对高对照归一化:100*(样品-低对照)/(高对照-低对照),其中低对照为用1%DMSO处理的15个样品的平均值,且高对照为用10μM已知sGC刺激剂化合物Y(实施例2中描绘)处理的15个样品的平均值。使用GraphPad Prism软件第5版,使用4参数拟合(log(激动剂)对反应-可变斜率)拟合数据。对所有化合物,n=2。绝对值EC50从曲线拟合中内插,且定义为给定化合物在数据归一化之后引发50%的高对照反应所处的浓度。将未能引发50%最小反应的化合物报告为>30μM。对于一式两份或以高于2的n次运行的化合物,本发明给出的结果为获得的若干结果的几何平均值。表3总结了在本测定中针对所选本发明化合物获得的结果。
表3.针对表I中化合物的基于cGMP神经元细胞的测定(实施例3)的生物活性。
基于神经元的细胞测定。Ab EC50≤100nM=A;100nM<Ab EC50≤1000nM=B;1000nM<Ab EC50=C。将未能引发50%最小反应的化合物报告为>30μM或ND。
实施例4:大鼠脑脊髓液(CSF)药代动力学性质
规程:
在口服给药后确定大鼠的PK。对于口服(PO)实验,使用小脑延髓池中置有留置导管的一组6只雄性史-道二氏大鼠。用配制作为PEG400中的溶液的3或10mg/kg化合物对PO组给药。将PO剂量通过口服强饲法给药且使用注射器及强饲管递送至胃。口服剂量给药后,用约0.5mL水冲洗强饲管以确保全剂量的完全递送。
如下收集血浆及CSF样品:在给药后1小时及2小时时收集CSF及血液的样品。通过脑池内导管收集CSF样品(0.05mL)。通过眼眶取样收集血液样品(0.25mL)。将这些样品保存在冰上,直至对血浆进行处理。将血液样品在收集1小时内在约5℃以3200rpm离心5分钟。将血浆直接转移至96孔板管(0.125mL)中。将塞帽置于管上,且将管在约-70℃冻结且储存直至分析。
收集血浆且分析化合物的存在。
化合物的定量
通过沉淀自血浆及CSF提取所讨论的化合物及内标物。使用液相色谱法(LC)及串联质谱检测(MS/MS)使用电喷雾离子化分析样品。标准曲线范围为1至1000ng/mL。下文表4中说明本测定中本发明中所述的化合物的结果。
Kp,uu定义为CSF中未结合的药物与血浆中未结合药物的浓度比。通过将总血浆浓度乘以通过血浆蛋白结合确定的未结合分数来计算血浆中未结合的药物(或游离血浆浓度)。接着将CSF浓度除以游离血浆浓度以确定Kp,uu。(参见,例如Di等人,J.Med.Chem.,56,2-12(2013))。
表4:针对表I中化合物(剂量为10mg/kg)的所选的本发明中所述的化合物的CSFPK性质(实施例4)
实施例5:评估本发明化合物对于R6/2小鼠海马切片中的突触传导及可塑性损伤
据信如由长程增强效应(LTP)所测量的突触传导及可塑性的改善指示化合物增强记忆的潜力。LTP为通常被称为驱动学习及记忆的细胞现象的电生理现象。
规程.
急性小鼠海马切片的制备。用Jackson实验室(USA)提供的11至12周龄R6/2及WT小鼠进行实验。在冰冷充氧的蔗糖溶液(蔗糖250、葡萄糖11、NaHCO3 26、KCl 2、NaH2PO4 1.2、MgCl2 7及CaCl2 0.5,以mM计)中用Macllwain组织切片机切割海马切片(350μm厚度)。将切片在具有以下组成的ACSF中在室温孵育1小时:葡萄糖11、NaHCO3 25、NaCl 126、KCl 3.5、NaH2PO4 1.2、MgCl2 1.3及CaCl2 2,以mM计。接着,使切片恢复至少1小时。
切片灌注及温度控制。在实验过程中,用蠕动泵(MEA室体积:约1mL)以3mL/min的速率用ACSF(用95%O2至5%CO2鼓泡)连续灌注切片。在溶液转换20秒后,在MEA室内得到完全溶液交换。在即将到达具有加热灌注插管的MEA室(PH01,多通道系统,Reutlingen,德国)之前,将灌注液在37℃连续预热。用位于MEA放大器顶台(MEA amplifier headstage)中的加热组件将MEA室的温度维持在37±0.1℃。
刺激规程/化合物应用。
输入/输出(I/O)曲线:100至800μA,步长100μA。接着针对短期及长期突触可塑性测量将刺激强度设定为250μA的固定值。
短期可塑性性质:施加两个具有逐渐减少的刺激间间隔(例如,300ms、200ms、100ms、50ms、25ms)的脉冲。化合物应用:在对照条件下记录fEPSP达10分钟(以验证基线稳定性),随后进行15分钟化合物暴露(或仅针对对照切片于媒介物的存在下暴露25分钟)。如先前所述,在化合物的连续存在下,应用第二I/O规程及成对脉冲规程。
长程增强效应(LTP):在10分钟的对照期(在用于对照切片的化合物或媒介物的存在下)后,通过10X TBS诱导LTP。接着监测突触传导的增益达额外60分钟时期(针对对照切片于化合物或媒介物的连续存在下)。
结果
在R6/2海马切片中,在暴露于855nM化合物I-5后,I/O特性显著更高(p值=0.0146,双向ANOVA)。在R6/2海马切片中,在暴露于855nM化合物I-5后,成对脉冲性质显著增加(p值<0.001,双向ANOVA)。暴露于855nM化合物I-5达15分钟未改变fEPSP幅度。
在WT小鼠海马切片(对照条件)中,HFS触发诱发反应幅度的增益,该增益在35%附近稳定(fEPSP在终点处增加36±3%)。在R6/2小鼠海马切片(对照条件)中,HFS触发诱发反应幅度的增益,该增益在15%附近稳定(在终点处,fEPSP增加15±2%)。在暴露于855nM化合物I-5后,HFS触发诱导反应幅度的增益,该增益在40%附近(在终点处,fEPSP增加40±6%)(图1)。因此,与R6/2对照切片相比,R6/2切片的增益显著增加(p值=0.0002,双向ANOVA)。
结论.
在R6/2小鼠海马切片中,在暴露于855nM化合物I-5后,I/O特性及成对脉冲性质增加。对于15分钟暴露期,855nM化合物I-5对R6/2小鼠海马切片的基础突触传导没有影响。在暴露于855nM化合物I-5后,海马R6/2切片的LTP缺陷恢复至WT海马切片的LTP的幅度水平。
实施例6:小鼠脑中的化合物诱导的cGMP
目的.为了确定本发明化合物在小鼠脑的不同区域(皮质、海马、小脑及纹状体)中于cGMP反应方面的影响。
规程.将小鼠(根据实验条件,n=9-10)用媒介物(1%羟丙基甲基纤维素,0.2%Tween80,0.5%甲基纤维素)以P.O.方式给药,用10mg/Kg化合物I-2以P.O.方式给药。给药后三十分钟,在异氟烷麻醉下,将各小鼠断头,且将其脑移除且置于含有浆状解剖溶液(用95%O2.5%CO2饱和)的冰冷培养皿中。如下图所示(非按比例,仅为方案),使用冰冷的刮勺,将脑转移到具有冠状间距的小鼠脑基质中,以便以1mm间隔进行切片。
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将切片的脑转移回至含有具有IBMX 0.5mM的浆状解剖溶液(用95%O2、5%CO2饱和)的培养皿中。首先解剖背侧纹状体,第二随后为海马,第三随后为内侧前额叶皮质,且第四最后为小脑。在解剖各区域之后,立即将组织“块”置于已经预先置于干冰上30分钟的eppendorf中。在约10秒钟内,小片组织非常快速地冻结。在将所有区域置于eppendorf后,通过浸入液氮中来速冻eppendorf。将组织样品在-80℃储存。通过LC/MS确定脑中的cGMP水平。在由80:20(V/V%)水:乙酸组成的水性缓冲液中使用超声发生器探针将脑样品均质化。通过以下方式自脑组织提取含有sGC化合物和/或cGMP的脑均质物:用含有内标物(IS)的有机溶剂进行蛋白质沉淀,随后进行过滤且使用PhreeTM磷脂去除板进行磷脂去除。使用液相色谱法(LC)及串联质谱检测(MS/MS)使用电喷雾离子化分析样品。用于定量cGMP和/或sGC化合物的标准曲线浓度的范围为0.2至400ng/mL。使用BCA蛋白质测定试剂盒确定脑样品的蛋白质定量。
结论.小鼠中以P.O.方式进行的10mg/Kg化合物的急性给药诱导海马(ANOVA p=0.0022;媒介物对化合物I-2p=0.0035)、小脑(ANOVA p<0.0001;媒介物对化合物I-2p=0.0001)及皮质(ANOVA p=0.012;媒介物对化合物I-2p=0.017)中cGMP的显著增加。
表6a:针对样品中蛋白质浓度归一化的小鼠海马中cGMP的浓度。
表6b.针对样品中蛋白质浓度归一化的小鼠纹状体中cGMP的浓度。
表6c:针对样品中蛋白质浓度归一化的小鼠小脑中cGMP的浓度。
表6d:针对样品中蛋白质浓度归一化的小鼠皮质中cGMP的浓度。
实施例7.新颖对象辨认(NOR)测试
目的.为了在雄性Long Evans大鼠中使用新颖对象辨认(NOR)测试评定本发明化合物逆转由MK-801诱导的记忆破坏方面的功效。NOR为辨认学习及记忆检索的测试,其利用啮齿动物相较于熟悉对象而调查新颖对象的自发偏好(Ennaceur及Delacour,1988)。研究指示,NOR程序涉及若干脑区域,包括鼻周皮质(Ennaceur等1996,1997以及Aggleton等1997)及海马(Wood等人1993以及Clark等人2000)。NOR测试已被广泛用于评定新颖测试化合物的潜在认知增强性质。因为NOR典范未涉及奖励或有害刺激,所以当转变成在人类临床试验中进行的类似测试时,其提供较少混扰变量。在本研究中,使用记忆挽救模型来测试新颖化合物——MK-801(联苯西平),使用NMDA受体的非竞争性拮抗剂来引起识别记忆缺陷。本发明的化合物是通过其逆转记忆损伤的功效来评估。
材料及方法.
动物.在本研究中使用成年雄性Long-Evans大鼠(来自Envigo,Indianapolis,IN,到达时为275至299克)。将大鼠置于实验室中且分配唯一识别号(尾部标记)。将大鼠每笼2只圈养在具有过滤器顶部(filter top)的聚碳酸酯笼中,且在测试前适应至少7天。将动物室维持在12/12小时明/暗循环(东部时间07.00时照明)中、22±1℃,及约50%的相对湿度下。提供食物及水的任意采食。在研究之前,对所有动物进行检查、处置及称重,以确保足够健康且使与测试相关的非特异性应激最小化。将各动物随机分配在治疗组中。在动物的明循环阶段进行实验。
测试化合物.本研究中使用以下化合物:
在NOR训练前15分钟,将MK-801(0.1mg/kg;Sigma-Aldrich)溶解于盐水中且以IP方式注射。
在训练前15分钟,将加兰他敏(1mg/kg;Tocris)溶解于盐水中,且以IP方式注射。
在训练前60分钟,口服给药化合物I-2(0.1、1及10mg/kg)。媒介物为于过滤水中的0.5%甲基纤维素、0.2%Tween及1%HPMC。剂量体积为4ml/kg
实验程序.在置于消音室内的开放场域(40x 40cm)中在昏暗照明下进行NOR测试。分别测试各大鼠,且通过在试验与大鼠之间用70%酒精清洁场地及测试对象来谨慎去除嗅觉/味觉提示。对所有训练及测试试验进行视频录像,且由对治疗盲化的观察员来评分。
在第1天及第2天时,允许大鼠自由探索场地(内部无对象),达5分钟的习惯期。在第3天(训练及测试日)时,向大鼠给药媒介物(盐水)、加兰他敏或化合物溶液,随后给药MK-801或媒介物(盐水)。在预处理时间之后,在两个相同对象的存在下将各动物置于测试场地中。将各大鼠置于相同位置处的面向相同方向的场地中,且记录在3分钟训练期(T1)期间积极探索对象所花费的时间。训练后,使大鼠返回至其家笼。在T1后1小时进行NOR测试(T2)。在一个熟悉对象及一个新颖对象的存在下将各大鼠放回至测试场地中5分钟,且在0至1、0至3及0至5分钟时间范围期间记录探索两个对象所花费的时间。在大鼠之间随机化T2中对象的呈现次序及位置(左/右),以防止来自次序或位置偏好的偏差。
统计分析.NOR测试(T2)的数据表示为辨认指数,其定义为测试时段期间探索新颖对象所花费的时间与探索两个对象所花费的总时间的比率(新颖/(熟悉+新颖)×100%)。通过使用单向ANOVA然后分别在0至1、0至3及0至5分钟时间范围进行费雪LSD事后检验来分析数据,其中显著性设定为P<0.05。在5分钟测试时段中,将总体对象探索时间少于10秒的动物淘汰;也将辨认指数高于90%或低于30%的大鼠淘汰,因为它们表明两个对象之间的强(非记忆)偏差。且接着从最终分析中移除高于或低于两个标准平均值偏差的统计异常值。
结果.本研究中的大鼠在任何剂量下都未显示明显的副作用。大鼠维持对对象的正常警觉性、活动及探索水平。ANOVA在0至1分钟时间范围期间对辨认指数显示出不显著的主要治疗效果[F(5.79)=1.305,P>0.05],主要是因为MK-801治疗的大鼠在此时间范围时维持相对好的辨认记忆。0至1分钟时的此结果在此版本的NOR中不罕见,因为在测试开始时,对象的“新颖性”及“熟悉度”为相对清晰的。通常,除非应用记忆增强剂,否则在MK-801组中大鼠表现逐步变差。在0至3分钟时间范围期间,ANOVA发现显著的主要治疗效果[F(5.79)=4.237,P<0.01]。事后检验显示MK-801 0.1mg/kg引起强的记忆缺陷,其中辨认指数接近机会水平(50%)。加兰他敏(1mg/kg)及0.1mg/kg的化合物I-2显著逆转MK-801诱导的记忆缺陷(与媒介物/MK-801组相比,分别为P<0.001及P<0.05)。相似地,ANOVA在0至5分钟时间范围期间显示显著的主要治疗效果[F(5.79)=3.851,P<0.01]。事后检验显示0.1mg/kg的MK-801引起强的记忆缺陷,其中辨认指数接近机会水平(50%)。加兰他敏(1mg/kg)及0.1mg/kg的化合物I-2显著逆转MK-801诱导的记忆缺陷(与媒介物/MK-801组相比,分别为P<0.001及P<0.05)。
表10.辨认指数测量值的总结(0至3分钟时间箱)
对“媒介物+MK-801”治疗组进行统计比较。当p值小于0.05时,视为统计显著性。
总结.参考化合物加兰他敏(1mg/kg)显著逆转由MK-801 0.1mg/kg诱导的认知缺陷,表明测试的有效性。在MK-801处理后0.1mg/kg的测试化合物I-2也显示出挽救NOR记忆的功效,表明此化合物具有记忆增强的特性。
实施例8:大鼠原代神经元中的pCREB磷酸化
目的.为了评定化合物I-5活化大鼠原代神经元中cAMP反应元件结合蛋白(CREB)的能力。CREB为细胞转录因子。其结合至称为cAMP反应元件(CRE)的DNA序列,且调控下游基因的转录(参见,Bourtchuladze R等人,Cell1994;79(1):59-68)。CREB在脑中神经元可塑性及长期记忆形成方面具有良好记录的作用,且已经显示是在空间记忆的形成方面不可或缺的(参见,Silva AJ等人,Annual Review of Neuroscience 1998;21:127-148)。通过各种激酶(包括cAMP依赖性蛋白激酶或蛋白激酶A(PKA)、cGMP依赖性蛋白激酶或蛋白激酶G(PKG)及Ca2+/钙调蛋白依赖性蛋白激酶)使丝氨酸133磷酸化来活化CREB蛋白。(参见,Shaywitz AJ及Greenberg ME,Annual Review of Biochemistry 1999;68(1):821–861以及Wong JC等人,J Cell Biochem 2012:113(11):3587-98)。CREB的刺激可能对认知、神经元可塑性和/或神经元功能受损的疾病具有治疗益处。
材料及方法.
化合物.将化合物I-5溶解于DMSO中作为10mM溶液,且在-20℃储存。为了得到希望测试浓度,将储存浓度连续稀释至DMSO中,且接着在测定缓冲液中稀释至适当的浓度。
大鼠原代神经元培养.在胚胎第18天(E18)时自史-道二氏大鼠胚胎分离神经元。自各大鼠获得约10个胚胎,且自胚胎中分离整个脑。使用两对精密镊子在立体显微镜下自脑解剖海马及皮质。小心移除脑膜。解剖后,将组织切碎且用15mL锥形管中的10mL不含Ca2+及Mg2+的汉克氏溶液(HBSS,Corning目录号21-022-CM)轻轻洗涤一次。洗涤后,将5mL0.25%胰蛋白酶(Invitrogen目录号15090-046)及0.1%脱氧核糖核酸酶I(DNase I,Sigma目录号DN-25)的溶液添加至管中的组织中,接着将其在37℃孵育15分钟。在孵育且用酶消化后,将组织用冰冷的HBSS洗涤三次。洗涤后,向管中添加3mL0.1%DNase I溶液,且使用玻璃巴斯德吸管缓慢吸取12次,且接着以500×g离心10分钟。将细胞团块重悬于培养基(Neurobasal培养基,Gibco目录号21103-049)、2%B27补充物(Gibco目录号17504-044)、0.5mM L-谷氨酰胺(Corning目录号25-005-Cl)、25μM L-谷氨酸(Sigma目录号G1251)及1%青霉素/链霉素(Gibco目录号15070-063))中。随后,将细胞悬浮体以100,000个细胞/孔接种至聚-L-赖氨酸涂覆的96孔板中。接种后二十四小时,移除一半的培养基,且用如上所述但没有谷氨酸的培养基置换。将细胞维持在37℃具有5%CO2的湿润孵育箱中且在第6至10天之间使用。
测定条件.对于各测试浓度,将化合物I-5在100%DMSO中稀释至其最终测定浓度的100倍。紧接在测定之前,将化合物I-5在含有100μM DETA-NONOate(10x最终测定浓度)的HBSS(含有钙及镁)(10x最终测定浓度)中稀释10倍。移除培养基,且用90μL HBSS(Corning目录号21-023-CV)洗涤细胞一次。接着将细胞与90μL HBSS一起在37℃孵育30分钟。将来自测试物/HBSS/DETA-NONOate板的10μL添加至细胞中,将所述细胞在37℃孵育额外30分钟。最终DMSO浓度为1%,最终DETA-NONOate浓度为30μM;且最终化合物I-5浓度为10,000nM、1000nM、100nM、10nM、1nM、0.1nM、0.01nM及0.0nM。将培养基移除且将细胞裂解,且根据Cisbio规程(磷-CREB(Ser133)目录号64CREPEG)执行测定,且使用Envision仪器(PerkinElmer)来读板。
数据分析.使用GraphPad Prism软件第7版,用4参数拟合(log(激动剂)对反应-可变斜率)分析数据。EC50从曲线拟合中内插,且定义为化合物I-5引发其50%的最大反应所处的浓度。
结果.由化合物I-5刺激的Ser133处的CREB的磷酸化为浓度依赖性的,其中EC50为0.55nM。95%信赖区间的范围为0.07nM至4.44nM。
实施例9.本发明化合物在疼痛模型及测试中的评估
目的.为了评估本发明化合物在急性及紧张性疼痛、神经性疼痛、炎性疼痛、术后疼痛及内脏疼痛中的功效。
材料及方法:
爪压力测试.测量静态机械性痛觉过敏。此测试要求对介于平坦表面与钝指针之间的后爪施加逐渐增加的压力。为了评估化合物的镇痛作用,动物的一只后爪通过注射来发炎或通过结扎来损伤,而另一只后爪未受伤或发炎。该装置对后爪施加稳定的逐渐增加的力。反应阈值是确定为引发爪缩回和/或发声所需的压力(g)。由实验者轻轻处理动物,且评定两只后爪的静态机械性痛觉过敏两次。
轻打尾测试.对尾部上施加辐射热。当大鼠感到不适时,其通过突然尾部移动(轻打尾)而反应,该突然尾部移动自动停止刺激及通过动物反应时间或感知伤害的反应潜伏期(自刺激开始至动物反应的检测的时期)进行的测量的定时器。为防止组织损伤,将截断值预先固定在10秒。
乙酸测试.通过在大鼠中腹腔注射0.6%乙酸溶液诱导腹部收缩(10mL/kg)。自注射后第5分钟至第15分钟记录扭体数目(由于疼痛而引起的扭转或扭曲)。
福尔马林测试.通过跖下途径将2.5%福尔马林溶液注入右后爪中。根据以下评分,每3分钟在大鼠中执行疼痛行为评分,持续36分钟:
0=经注射后肢支撑身体的正常行为
1=轻微碰触地板上的经注射爪以轻微支撑或不支撑身体
2=经注射爪的完全缩回
3=舔、咬或摇动经注射爪。
本内特模型.在D-14时通过松结扎麻醉大鼠(甲苯噻嗪10mg/kg i.p、氯胺酮60mg/kg i.p.)中的坐骨神经来诱导周边单神经病变。简单地说,通过钝解剖穿过股二头肌来将常见的坐骨神经暴露于大腿中间的水平处。靠近坐骨三根分叉部,将四根结扎线以约1mm的间距松散地缠绕在坐骨三根分叉部周围。非常小心地系上结扎线,使得神经的直径看起来几乎未收缩。手术后,使动物恢复4天,在恢复期后10天(也即手术后14天)进行测试。
奥沙利铂.诱发:在测试前30小时通过单次腹膜内注射奥沙利铂(6mg/kg,i.p)诱发急性周边神经病变。丙酮测试:使用丙酮测试测量冷异常性疼痛。在此测试中,对于两个后爪,交替地以约2至3分钟的间隔,向两个后爪的跖表面施加一滴丙酮(50μL)三次,然后测量后爪缩回的潜伏期。
角叉菜胶.诱发:在使用爪压力测试评定伤害感阈之前三个小时,将100μL 2%角叉菜胶悬浮液注射至右后爪的跖面。接着如上所述进行爪压测试。
高岭土.诱发:在大鼠中,通过在气体麻醉下(3.5%异氟烷/3L/min)将10%高岭土悬浮液以关节内方式注射至右后爪的膝关节中来诱发单侧关节炎。步态评分:将在高岭土给药后3小时30分钟通过以下来评估步态评分:
0:正常步态
1:轻度残疾
2:爪的间歇性举起
3:爪抬高。
布瑞南模型(Brennan Model).手术:在气体麻醉下(2.5%异氟烷/3L/min)进行手术。对于所有大鼠,使左后爪的跖面暴露,且使用手术刀通过足的跖面的皮肤及筋膜(自足跟的近侧边缘0.5cm开始且向脚趾延伸)进行1cm纵向切开。将跖肌抬高且纵向切开,而将肌肉终点(insertion)保持完整。轻轻压迫止血后,用两根缝线缝合皮肤。手术后,使动物在其笼中恢复。
电子冯弗雷测试(Electronic Von Frey Test).在手术后24小时使用电子冯弗雷测试评定触觉异常性疼痛。测试要求对后爪的跖面施加增加的压力。所述器械对后爪施加稳定的力。将反应阈值确定为引发爪缩回所需的压力(g)。对于两个后爪,以约2至3分钟的间隔重复各反应阈值测量三次。
TNBS.手术:在行为测试前7天(D-7),通过手术给药TNBS来诱发结肠敏感性。禁食(过夜)的动物经历手术。简单地说,在麻醉下(甲苯噻嗪10mg/kg i.p.,氯胺酮60mg/kgi.p.),向结肠近侧部分(距离盲肠1cm)中进行TNBS(50mg/kg,1mL/kg)的注射。手术后,使动物返回其规定的环境中的家笼中,且任意采食喂养,直至D-1(动物在扩张前24小时禁食)。结肠直肠扩张:在TNBS注射后七天(D0),通过测量诱发结肠扩张期间的行为反应所需的结肠内压力,评定禁食(过夜)的动物的结肠敏感性。为了进行扩张,将5-cm气球轻轻地插入昏迷动物的距离肛门10cm处的结肠中,且将导管粘贴至尾部的基部。在具有插入气球的30分钟适应期之后,将结肠压力自5mm Hg通过每30秒5mm Hg步骤逐渐增加至75mm Hg(截断),直至证实疼痛行为。疼痛行为的特征在于对应于严重绞痛的动物身体后部抬高及清晰可见的腹部收缩。执行两次测定。
用10mg/kg化合物I-1PO治疗的动物的急性及紧张性疼痛、神经性疼痛、炎性疼痛、术后疼痛及内脏痛模型及测试的结果是显著的,且在下文呈现。
结果.
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测试:治疗后120分钟。N=4/模型/测试。各组的结果表示为自媒介物治疗的动物的平均值计算的活性的百分比,且根据测试来与初始动物、对照爪或截断值进行比较。
结论.化合物I-2在急性疼痛的乙酸及福尔马林测试中证实有效果。化合物I-2在神经性疼痛的本内特模型/爪压力测试及奥沙利铂—丙酮测试模型中证实有效果。化合物I-2在炎性疼痛的角叉菜胶—爪压力测试及高岭土—步态评分模型中证实有效果。化合物I-2在术后疼痛的布瑞南模型—电子冯弗雷测试模型中证实有效果。化合物I-2在内脏疼痛的TNBS—结肠直肠扩张测试模型中证实有效果。
实施例10.小鼠脑中的剂量反应性化合物诱导的cGMP
目的.为了确定不同剂量的本发明化合物在小鼠脑(大脑)中的cGMP反应方面的影响
规程.实验第1天:使小鼠在任意饮水的情况下禁食过夜。实验第2天:将小鼠(根据实验条件,n=10)用媒介物(1%羟丙基甲基纤维素,0.2%Tween80,0.5%甲基纤维素)、媒介物中制备的3或10mg/Kg化合物I-2以P.O.方式给药。给药三十分钟后,在异氟烷麻醉下,将各小鼠断头且将其脑移除。将大脑自各脑中分离,且置于分开的15ml falcon管中,且通过浸入液氮中来快速冻结。将组织样品在-80℃储存。通过LC/MS确定脑中的cGMP水平。在由80:20(V/V%)水:乙酸组成的水性缓冲液中使用超声发生器探针将脑样品均质化。通过以下方式自脑组织提取含有sGC化合物和/或cGMP的脑均质物:用含有内标物(IS)的有机溶剂进行蛋白质沉淀,随后进行过滤且使用PhreeTM磷脂去除板进行磷脂去除。使用液相色谱法(LC)及串联质谱检测(MS/MS)使用电喷雾离子化分析样品。用于定量cGMP和/或sGC化合物的标准曲线浓度的范围为0.2至400ng/mL。使用BCA蛋白质测定试剂盒确定脑样品的蛋白质定量
结论.与媒介物给药的动物相比,10及3mg/Kg化合物I-2P.O.的急性给药增加小鼠脑中的cGMP(p<0.0001且p<00.31,ANOVA之后进行计划的比较)。
实施例11:对大鼠背侧纹状体的BDNF蛋白的影响
目的.为了在喹啉酸诱发的脑病灶模型中确定化合物I-2治疗在大鼠纹状体中的BDNF表达方面的影响
规程.实验第1天:将大鼠用异氟醚深度麻醉,且各大鼠在背侧纹状体中单侧输注0.25μl的50mM喹啉酸(QA)(在左或右半球上,12.5纳摩尔QA)。各大鼠上的QA输注对侧的背侧纹状体接受0.25μl PBS的对照输注(对照侧)。QA输注后约30分钟,将一些动物用媒介物(n=5)或10mg/Kg化合物I-2(n=6)以S.C.方式给药。实验第2至8天:每24小时将大鼠用媒介物或10mg/Kg化合物I-2以P.O.方式给药一次。最后一次给药媒介物或化合物I-2后约24小时,将大鼠麻醉,用PBS灌注,随后用PBS中的4%多聚甲醛输注;将脑组织收集,且在4℃置于用PBS中的4%多聚甲醛(PAF)覆盖的falcon管中约14小时,且接着由具有30%蔗糖溶液的PBS置换,达约48小时。将脑组织切成40μm冠状切片且在4℃储存在PBS中。将含有背侧纹状体的切片通过以下方式来染色:用小鼠抗NeuN及兔抗BDNF第一抗体孵育,随后用缀合至Alexa Fluor 594的抗兔及缀合至Alexa Fluor 488的抗小鼠第二抗体孵育。使用共焦荧光显微术拍摄QA病灶周围的背内侧区域或对照半球上的等同区域的影像。使用imageJ软件分析影像以确定NeuN阳性细胞中的平均BDNF强度。
结论.与对照半球(对照侧)中的NeuN阳性细胞相比,QA病灶(QA侧)周围的NeuN阳性细胞的BDNF染色的平均强度显著降低;p<0.0001,ANOVA,然后进行多重比较。与媒介物治疗相比,用10mg/kg化合物I-2一天一次治疗7天导致QA病灶周围的NeuN阳性细胞的BDNF平均强度增加;p<0.01,ANOVA,然后进行多重比较。与媒介物治疗相比,用10mg/kg化合物I-2一天一次治疗7天导致没有病灶的背内侧纹状体(对照侧)中NeuN阳性细胞的BDNF平均强度增加;p<0.0001,ANOVA,然后进行多重比较。
本发明的各种实施方案可在以下文本中描述:
[1].一种表I中描绘的化合物或其药学上可接受的盐。
[2].一种药物组合物,其包含至少一种药学上可接受的赋形剂或载体以及上文[1]或根据本发明的其它实施方案的化合物或药学上可接受的盐。
[3].一种剂型,其包含上文[2]或根据本发明的其它实施方案的药物组合物。
[4].一种治疗有需要的受试者的CNS疾病、健康状况或障碍的方法,其包含单独或以组合疗法给药治疗有效量的上文或根据本发明的其它实施方案的[1]、[2]或[3]。
[5].如以上[4]或根据本发明的其它实施方案的方法,其中该CNS疾病选自阿尔茨海默病(AD)、肌萎缩侧索硬化(ALS或Lou Gehrig病)、唐氏综合征、痴呆、血管性痴呆(VD)、血管性认知损害、混合型痴呆、宾斯旺格痴呆(皮层下动脉硬化性脑病)、伴有皮质下梗塞及脑白质病变的脑体常染色体显性动脉病(CADASIL或CADASIL综合征)、额颞叶退化或痴呆、HIV相关性痴呆(包括无症状性神经认知损害(ANI)、轻微神经认知障碍(MND),及HIV相关性痴呆(HAD)(也称为AIDS痴呆复合征[ADC]或HIV脑病)、Lewy体痴呆、早老性痴呆(轻度认知损害或MCI)、青光眼、亨廷顿病(或者亨廷顿舞蹈症,HD)、多发性硬化(MS)、多系统萎缩(MSA)、帕金森病(PD)、帕金森叠加、脊髓小脑共济失调、Steel-Richardson-Olszewski病(进行性核上麻痹)、注意力缺陷障碍(ADD)或注意力缺陷多动症(ADHD)。
[6].如上文[5]或根据本发明的其它实施方案的方法,其中该CNS疾病为阿尔茨海默病。
[7].如上文[6]或根据本发明的其它实施方案的方法,其中该轻度至中度阿尔茨海默病或中度至重度阿尔茨海默病。
[8.]如上文[5]或根据本发明的其它实施方案的方法,其中该CNS疾病为血管性痴呆。如上文[5]或根据本发明的其它实施方案的方法,其中该CNS疾病为混合型痴呆。
[9].如上文[5]或根据本发明的其它实施方案的方法,其中该CNS疾病为亨廷顿病。
[10].如上文[5]或根据本发明的其它实施方案的方法,其中该CNS疾病为帕金森氏病。
[11].如上文[5]或根据本发明的其它实施方案的方法,其中该CNS疾病为CADASIL。
[12].如上文[5]或根据本发明的其它实施方案的方法,其中该CNS疾病为轻度认知损害。
[13].如上文[4]或根据本发明的其它实施方案的方法,其中该CNS疾病选自外伤性(闭合性或开放性)穿透性头部损伤、外伤性脑损伤(TBI)、非外伤性脑损伤、中风(特别是缺血性中风)、动脉瘤、缺氧、认知损害或由脑损伤或神经退行性障碍导致的功能障碍。
[14].如上文[4]或根据本发明的其它实施方案的方法,其中该CNS疾病选自:张力失常,包括广泛性、病灶性、节段性、性、中间、遗传性/原发性张力失常或急性张力失常反应;或运动障碍,包括急性、慢性/迟发性,或非运动性及左旋多巴诱发的运动障碍(LID)。
[15].如上文[4]或根据本发明的其它实施方案的方法,其中该CNS疾病为选自以下的精神病性、精神性、情绪或情感障碍:双相型障碍、精神分裂症、一般精神病、药物诱发的精神病、妄想症、情感性分裂症、强迫性障碍(OCD)、抑郁障碍、焦虑障碍、惊恐障碍或创伤后应激障碍(PTSD)。
[16].如上文[4]或根据本发明的其它实施方案的方法,其中该CNS疾病选自特征在于突触可塑性及突触过程相对降低的障碍,包括脆性x染色体病、Rhett障碍、威廉斯综合征、Renpenning综合征、泛自闭症障碍(ASD)、自闭症、Asperger综合征、弥漫性发育障碍或童年瓦解性障碍。
[17].如上文[4]或根据本发明的其它实施方案的方法,其中该CNS障碍选自化疗脑、左旋多巴诱发的成瘾行为、酒精中毒、麻醉药依赖(包括苯丙胺、阿片剂或其它物质)或物质滥用。
[18].上文或根据本发明的其它实施方案的[1]、[2]或[3],其用于治疗CNS疾病。
[19].如上文[1]、[2]或[3]或根据本发明的其它实施方案的用途,其用于治疗CNS疾病。
虽然已经出于说明的目的陈述典型的实施方案,但是前面的描述及实施例不应认为限制本发明的范围。相应地,在不脱离本发明的精神及范围的情况下,本领域技术人员可进行各种改良、改造及替代。
Claims (13)
1.选自表I中描绘的那些化合物或其药学上可接受的盐或包含该化合物或其药学上可接受的盐的药物组合物或剂型在制备用于在有需要的受试者中增强记忆或逆转记忆损伤的药物中的用途:
表I
。
2.选自表I中描绘的那些化合物或其药学上可接受的盐或包含该化合物或其药学上可接受的盐的药物组合物或剂型在制备用于在有需要的受试者中改善或恢复突触传导和可塑性的药物中的用途:
表I
。
3.选自表I中描绘的那些化合物或其药学上可接受的盐或包含该化合物或其药学上可接受的盐的药物组合物或剂型在制备用于增加受试者脑中一种或多种物质的浓度的药物中的用途,其中所述物质选自cGMP、磷酸化CREB、BDNF,及其组合:
表I
。
4.权利要求3的用途,其中所述物质是cGMP。
5.权利要求3的用途,其中所述物质是磷酸化CREB。
6.权利要求3的用途,其中所述物质是BDNF。
7.选自表I中描绘的那些化合物或其药学上可接受的盐或包含该化合物或其药学上可接受的盐的药物组合物或剂型在制备用于减少有需要的受试者脑中的神经炎症的药物中的用途:
表I
。
8.选自表I中描绘的那些化合物或其药学上可接受的盐或包含该化合物或其药学上可接受的盐的药物组合物或剂型在制备用于减轻受试者疼痛的药物中的用途:
表I
。
9.权利要求8的用途,其中所述疼痛为急性疼痛、中枢性疼痛综合征、化疗诱发的神经病变及神经性疼痛、糖尿病性神经病、纤维肌痛、炎性疼痛、神经性疼痛、与CNS疾病相关的神经性疼痛、疼痛性糖尿病性周围神经病变、术后疼痛、紧张性疼痛、内脏疼痛或孤儿疼痛。
10.权利要求9的用途,其中所述孤儿疼痛是乙酰唑胺反应性肌强直、自体红细胞致敏综合征、2V型常染色体显性夏马图三氏病、伴有神经性疼痛的常染色体显性中间型夏马图三氏病、2A型常染色体隐性肢带肌营养不良、离子通道病变相关的先天性疼痛不敏感、引起脊柱内痛觉缺失的慢性疼痛、复合区域性疼痛综合征、1型复合区域性疼痛综合征、2型复合区域性疼痛综合征、伴有多汗症的先天性疼痛不敏感、伴有严重智力残疾的先天性疼痛不敏感、先天性疼痛不敏感-少汗综合征、伴有疼痛性龟裂的弥漫性掌跖角化病、家族性发作性疼痛综合征、伴有显著下肢受累的家族性发作性疼痛综合征、伴有显著上体受累的家族性发作性疼痛综合征、遗传性疼痛性胼胝、4型遗传性感觉及自主神经病、5型遗传性感觉及自主神经病、7型遗传性感觉及自主神经病、间质性膀胱炎、疼痛性眼眶及全身神经纤维瘤-马方体型综合征、阵发性极端疼痛障碍、持续性特发性面部疼痛、卡配因的定性或定量缺陷及痛性眼肌麻痹综合征。
11.权利要求8的用途,其中所述疼痛是急性及紧张性疼痛、神经性疼痛、炎性疼痛、术后疼痛或内脏疼痛。
12.权利要求8的用途,其中所述疼痛是急性、紧张性、神经性、炎性、术后及内脏疼痛。
13.权利要求8的用途,其中所述疼痛是神经性疼痛。
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