CN117180260A - 基于脱氧类黄酮的t淋巴细胞活性抑制组合物 - Google Patents
基于脱氧类黄酮的t淋巴细胞活性抑制组合物 Download PDFInfo
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- CN117180260A CN117180260A CN202311389630.8A CN202311389630A CN117180260A CN 117180260 A CN117180260 A CN 117180260A CN 202311389630 A CN202311389630 A CN 202311389630A CN 117180260 A CN117180260 A CN 117180260A
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- luteolin
- rutin
- quercetin
- mistletoe
- disease
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Abstract
本发明涉及基于脱氧类黄酮的T淋巴细胞活性抑制组合物,基于脱氧类黄酮的T淋巴细胞活性抑制组合物,包括木樨草素、芸香苷、桑寄生和槲皮素,所述木樨草素、芸香苷、桑寄生和槲皮素用于口服给药,所述木樨草素、芸香苷、桑寄生和槲皮素用于舌下给药,所述木樨草素、芸香苷、桑寄生和槲皮素用于口颊给药,所述木樨草素、芸香苷、桑寄生和槲皮素用于直肠给药。该基于脱氧类黄酮的T淋巴细胞活性抑制组合物,通过木樨草素、芸香苷、桑寄生和槲皮素组成的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,能对T淋巴细胞的活性进行有效抑制,以用于哺乳动物患者中的自身免疫病或炎性疾病的免疫抑制治疗。
Description
技术领域
本发明涉及医学治疗技术领域,具体为基于脱氧类黄酮的T淋巴细胞活性抑制组合物。
背景技术
类黄酮为多酚化合物,其普遍存在于植物来源的食物中,超过4000个结构上独特的类黄酮已在植物来源中鉴定,类黄酮存在于果实、蔬菜、坚果、种子、草药、香料、茎、花;以及茶和红葡萄酒,是柑橘类水果和其它食物来源的主要成分,通常在人食物中被食用,对于总类黄酮摄入的估计是困难的,因为只能获得有限的食物浓度的数据,有几项研究来定量测定不同类黄酮在分类的食用植物中的含量,根据资料显示,混合类黄酮的平均日摄入量仅为23mg/天。
最新证据表明类黄酮-糖苷(比糖苷配基)更易于被人吸收,并且,类黄酮的量和来源在不同国家中显著不同,它们可给体液和组织提供显著的药理学浓度,类黄酮典型地为酚类化合物,因此可用作有效的金属鳌合剂和自由基清除剂,且是有效的链断裂抗氧化剂,它们具有有益的健康效果,部分是由于这些抗氧化性质,类黄酮具有相当多的生化和药理学作用,其中一些表明这类化合物中的某些物质可能显著影响多个哺乳动物细胞系统的功能,早已知道,它们具有抗炎性、抗氧化性和抗变应性、护肝、抗血栓形成、抗病毒和抗癌活性,然而,Rimm及其同事没有发现在摄入类黄酮和总冠心病之间具有强的负相关,在大多数但非全部的预期流行病学研究中,黄酮醇和黄酮的摄入与随后的冠心病负相关。
植物或草药的复杂性质带来一些特殊的困难,植物典型地由多种组分组成,其中一些可能单独具有活性,或彼此组合后具有活性,这些多活性物质实体可能具有激动剂或拮抗剂的活性,尽管它们具有共同的结构主链,确定生物活性组分对于解决生物利用度问题和建立有意义的溶解度、生物利用度、效力度、均匀性和稳定性的标准是非常重要的,植物的复杂活性-组成关系对于理解制剂和工艺变量对于产品质量的作用和建立良好生产规范以确保可符合适当的质量和执行标准是特别困难的,环境变量和加工可显著影响浓度和生物活性。
糖尿病和自身免疫病一起影响约10%的全球人口,自身免疫病涉及细胞和体液介导的免疫的异常调节,通常与异常的或增强的T细胞、B细胞和巨噬细胞效应器功能相关,所述功能针对自体抗原,据信,这些针对自体抗原的细胞组分的活化涉及与自身耐受性相关的反馈机制的破坏,自身免疫病包括所有临床实体,尽管目标器官不同,但自身免疫病仍具有很多相似性,另外,这些疾病的特征都在于其慢性、临床缓解的倾向和不明原因的“突然发作”,并涉及其它器官,尽管存在自身抗体,II型抗原的不适当表达、巨噬细胞活化和T细胞渗透至目标器官基本上在所有的自身免疫病中都有描述,导致疾病活化的触发机制和疾病进展都没有完全理解,因此,这些疾病的治疗大部分是不满意的,涉及使用金盐、氨甲蝶呤、抗疟药、糖皮质激素(甲泼尼龙)、β-干扰素和其它免疫抑制剂,以及血浆去除术和引导耐受性的尝试,自身免疫病的治疗在过去10年内还没有显著改善,主要与使用非甾体和甾体抗炎药相关,以治疗疾病症状,很明显,尽管抑制针对宿主的特异免疫应答是必要的,但是利用糖皮质激素的全身免疫抑制在副作用方面具有很大的易感性,且免疫抑制病人倾向于对其它感染和非感染性疾病具有较大的风险。
发明内容
针对现有技术的不足,本发明提供了基于脱氧类黄酮的T淋巴细胞活性抑制组合物,具备抑制效果更好好等优点,解决了现有的基于脱氧类黄酮的T淋巴细胞活性抑制组合物抑制效果差的问题。
为实现上述目的,本发明提供如下技术方案:基于脱氧类黄酮的T淋巴细胞活性抑制组合物,包括木樨草素、芸香苷、桑寄生和槲皮素。
进一步,所述木樨草素、芸香苷、桑寄生和槲皮素用于口服给药。
进一步,所述木樨草素、芸香苷、桑寄生和槲皮素用于舌下给药。
进一步,所述木樨草素、芸香苷、桑寄生和槲皮素用于口颊给药。
进一步,所述木樨草素、芸香苷、桑寄生和槲皮素用于直肠给药。
进一步,所述木樨草素、芸香苷、桑寄生和槲皮素用于经皮给药。
进一步,所述木樨草素、芸香苷、桑寄生和槲皮素通过注射给药。
与现有技术相比,本申请的技术方案具备以下有益效果:
该基于脱氧类黄酮的T淋巴细胞活性抑制组合物,通过木樨草素、芸香苷、桑寄生和槲皮素组成的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,能对T淋巴细胞的活性进行有效抑制,以用于哺乳动物患者中的自身免疫病或炎性疾病的免疫抑制治疗。
附图说明
图1为本发明毛地黄黄酮对于KV1.3通道电流的作用的结构示意图;
图2为本发明通过3-脱氧类黄酮来抑制T淋巴细胞的细胞毒性的结构示意图;
图3为本发明通过3-脱氧类黄酮木樨草素和3’,4’,5’,5,7-五羟黄酮抑制钙黄绿素释放的结构示意图;
图4为本发明木樨草素对于II型糖尿病小鼠的剂量效果的结构示意图;
图5为本发明小鼠变化的结构示意图;
图6为本发明木樨草素治疗和血糖浓度的结构示意图;
图7为本发明血糖数据的结构示意图;
图8为本发明定期测量病人的血糖的结构示意图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本实施例中的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,包括木樨草素、芸香苷、桑寄生和槲皮素。
其中,木樨草素、芸香苷、桑寄生和槲皮素用于口服给药,木樨草素、芸香苷、桑寄生和槲皮素用于舌下给药,木樨草素、芸香苷、桑寄生和槲皮素用于口颊给药,木樨草素、芸香苷、桑寄生和槲皮素用于直肠给药,木樨草素、芸香苷、桑寄生和槲皮素用于经皮给药,木樨草素、芸香苷、桑寄生和槲皮素通过注射给药。
另外,桑寄生有补益肝肾的作用,适合肝肾亏虚的患者服用,能够帮助改善头晕耳鸣、身体乏力、腰膝酸痛等症状;桑寄生还适合久病体虚的老人以及筋骨无力者服用,可以起到强健筋骨、增强体质、提高抗病能力的作用,桑寄生还有祛风除湿的功效,对于因为风湿侵入关节引起的关节疼痛、肿胀有较好的缓解作用,女性还可以使用桑寄生来治疗经血过多、崩漏等病症,怀孕期间若出现胎动不安的情况,也可以在医生的指导下使用桑寄生改善。
还有,槲皮素是一种天然的黄酮类化合物,具有抗氧化、抗炎、抗癌等多重功效,下面将详细介绍槲皮素的主要作用及其对人体健康的益处:
1.抗氧化作用:槲皮素具有很强的抗氧化能力,可以清除体内的自由基,减缓细胞衰老,保护细胞免受氧化损伤,这有助于预防心血管疾病、神经系统疾病等与氧化应激相关的疾病。
2.抗炎作用:槲皮素可以抑制炎症反应,减轻炎症症状,这对于缓解关节炎、哮喘等炎症性疾病的症状具有一定的帮助。
3.抗癌作用:研究发现,槲皮素具有抗癌作用,可以抑制癌细胞的生长和扩散,虽然目前的研究尚不足以证明槲皮素可以完全治愈癌症,但它可以作为辅助治疗手段,降低癌症发生的风险。
4.保护心血管:槲皮素可以降低血压、降低胆固醇,从而降低心血管疾病的风险,同时,槲皮素还可以改善血管内皮功能,预防动脉粥样硬化。
5.抗过敏作用:槲皮素可以抑制组胺的释放,从而减轻过敏症状,如鼻炎、皮炎等。
总之,槲皮素具有多种对人体有益的作用,可以帮助预防和缓解多种疾病,然而,槲皮素并非万能药,不能完全替代传统医学治疗,在使用槲皮素时,建议遵循医生的建议,结合其他治疗手段,以达到最佳的治疗效果。
根据本发明,通过给人或家畜患者施用一定量的能抑制T淋巴细胞的化合物,从而提供可抑制患者的T淋巴细胞的活化或增生的方法,所述化合物具有下式I:
其中,X选自O和S;
R1至R5和R9至R12选自H、OH、卤素如F或Cl、烷基、氨基、NHMe、SH、Sme、氰基、羧基、羧基烷基、甲酰胺、烷氧羰基、O-羟烷基、CF3、O-烷基、O-SO3H、O-SO2H、O-PO3H、O-糖苷、O-葡糖苷酸和O-氨基酸,包括O-CO-A-(CH2)n-NR′R″,其中A为苯基、取代的苯基或空缺;n为0至5;R′和R″选自H、低级烷基、羟烷基、氨基烷基、一和二烷基氨基烷基、羧基烷基,或R′和R″可组合形成环,任选地被O、S、NH或N-烷基取代,与氮原子相邻的亚甲基可任选地被氨基烷基、羧基或羧基烷基和O-CO-NH-(CH2)m-CH-(NH2)COOH取代,其中m为1至4;
R6和R7为H,或可以组合形成双键;
R8选自H、卤素如F或Cl、烷基、氨基、氰基、羧基、羧基烷基、甲酰胺、烷氧羰基和CF3。
此外,当R1至R5和R9至R12为OH,并存在于环的相邻碳原子上时,那么它们可通过亚甲基(-O-CH2-O-)或羰基(-O-CO-O-)来形成环,最优选的是6,7和7,8-亚甲二氧基和3′,4’-羰基氧基(环状碳酸酯)衍生物。
这些方法可被实施用于治疗以过量或异常的T淋巴细胞活性为特征的疾病或病症,这些疾病和病症包括,但不一定限于:自身免疫病、糖尿病、肌萎缩性脊髓侧索硬化症(ALS)、类风湿性关节炎、系统性红斑狼疮(SLE)、移植-宿主疾病、移植排斥、斑秃、关节强硬性脊椎炎、抗磷脂综合症、自身免疫艾迪生(Addison′s)病、自身免疫性溶血性贫血、自身免疫肝炎、贝赫切特病、大疱性类天疱疮、心肌病、腹型斯泼卢腹泻(Celiac Sprue)皮炎、慢性疲劳免疫缺陷综合症(CFIDS)、慢性炎症脱髓鞘多发性神经病、丘-斯(Churg-Strauss)综合症、瘢痕性类天疱疮、波综合症、冷凝集素病、克罗恩氏病、盘形狼疮、本态性混合冷球蛋白血症、纤维肌痛-纤维肌炎、格雷夫斯病、吉兰-巴雷病、桥本甲状腺炎、突发性肺纤维化、突发性血小板减少紫癜(ITP)、IgA肾病、胰岛素依赖型糖尿病、幼年型关节炎、扁平苔癣、梅尼埃(Ménière’s)病、混合型结缔组织病、多发性硬化、重症肌无力、慢性天疱疮、恶性贫血、多发性结节性动脉炎、多软骨炎、多腺综合症、风湿性多肌痛、多肌炎和皮肌炎、原发性丙种球蛋白缺乏症、夏科氏肝硬化、牛皮癣、雷诺氏现象、赖特尔综合症、风湿热、肉样瘤病、硬皮病、舍格伦综合症(原发性和继发性)、全身肌强直综合征、高安动脉炎、颞动脉炎/巨细胞性动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、白斑、韦格纳肉芽肿病等,以及多种炎症和其它的疾病和病症,它们在本文下面部分详细描述。
仍根据本发明,当实施上述方法以治疗糖尿病或稳定病人的血糖水平时,化合物可包括通式I的任意化合物,除了木樨草素(即,通式I的3’,4’,5,7-四羟基黄酮化合物,其中X=O,且其中R2、R3、R9、R11=OH)、木樨草素的5位糖苷、木樨草素的7位糖苷、或芹菜素。
还根据本发明,当实施上述方法来治疗或预防肌萎缩性脊髓侧索硬化(ALS),该方法可包括施用通式I的一种或多种化合物,除了单独的木樨草素、单独的染料木黄素、或单独的大豆黄素、或选自木樨草素、染料木黄素、大豆黄素的两种或多种化合物的可能的组合。
还根据本发明,提供了抑制离子流通过某些细胞内离子通道如Kv1.3通道的方法,通过施用有效量的上述通式I的化合物来实现,这些化合物包括例如取代的3-脱氧类黄酮,通式I的这些化合物可组合其它药剂来给药,所述其它药剂为例如其它IKCa1阻滞剂,如克霉唑、1-[(2-氯苯基)二苯基甲基]-1H-吡唑、2-氯苯基二苯基氰基甲烷或环孢菌素A、或TNF-α抑制剂、或其它T淋巴细胞抑制剂如来氟米特、其代谢物A-771726[N-(4-三氟甲基苯基)-1-氰基-2-酮丙基-甲酰胺]或[N-[4-(三氟甲基)苯基]-2-羟基-6-氧代环戊基甲酰胺或N-[4-(三氟甲基)苯基]-2-羟基苯甲酰胺,并可用于自身免疫病的免疫抑制治疗方法中,通过将治疗有效量的这些化合物施用至哺乳动物患者来实现,通过抑制Kv1.3通道,通式I的化合物可降低和稳定I型和II型糖尿病患者的血糖水平,并可改善红斑狼疮的症状,这是一种感染几个器官的自身免疫病,至少在一些患者中,I型糖尿病为自身免疫病,其中自身反应淋巴细胞破坏胰腺β-细胞,而II型糖尿病的病因学是由于胰岛素形成不足和胰岛素影响其靶向终末器官的能力下降,因为离子通道在淋巴细胞和胰腺β细胞信号传导中具有重要作用,最可能的是类黄酮的至少一些治疗效果可通过阻滞离子通道而显现,使用膜片钳(patch-clamp)实验,已发现,Kv1.3作为可调节人T淋+巴细胞的有丝分裂发生的电压门控K通道,可以通过上述通式I的化合物来阻滞,这些类黄酮的无毒性质使它们有可能成为营养药品,来补充或代替现有的药物和治疗。
还根据本发明,上述方法可包括施用通式I的化合物以及基本的钒或含钒化合物,正在临床上研究钒化合物的拟胰岛素效果,微摩尔浓度的钒酸盐和过氧化钒化合物促进体内和体外的己糖吸收、葡萄糖氧化和脂肪生成,临床试验表明,偏钒酸钠和硫酸氧钒可改善胰岛素敏感性、固定血糖水平,这暗示了在糖尿病的辅助疗法中可使用这些药剂,可能的是,钒化合物和3-脱氧类黄酮的组合可以附加的方式或以可能的协同方式与淋巴细胞和胰岛细胞相互作用,并与它们所提出的临床应用相关,产生治疗糖尿病和自身免疫病的新方法。
还根据本发明,通式I的某些化合物如木樨草素已知在口服和通过胃肠道粘膜吸收时发生首过代谢,因此,这些化合物可通过非肠道途径(即其中化合物基本上通过除了胃和/或肠粘膜的其它组织来吸收的途径)来给药,如舌下、口腔、鼻内、经皮等,这些化合物的非肠道给药可增加化合物的循环血液水平和/或延迟化合物的代谢,从而增加它们的效力。
还根据本发明,木樨草素和通式I的至少一些其它化合物的作用效力和/或持续时间可通过施用芸香苷、或芸香苷同源物、或芸香苷衍生物组合通式I的这些化合物来增强,芸香苷和/或芸香苷同源物或衍生物的加强效果可能是由于抑制了一种或多种肝酶(例如,某些细胞色素P450酶),从而减慢木樨草素或通式I的其它化合物的代谢失活。
还根据本发明,提供了治疗糖尿病或稳定血糖水平的方法,通过施用有效量的通式I的化合物来实现,除了木樨草素、木樨草素的5位(即,Rq)糖苷、木樨草素的7位(即,R11)-糖苷、和芹菜素(即,通式I的4’,5,7-三羟基黄酮化合物,其中X=O,且R3、R9、R11为OH)。
还根据本发明,提供了治疗人或家畜患者的肌萎缩性脊髓侧索硬化症(ALS)的方法,通过给病人施用治疗有效量的通式I化合物来实现,除了木樨草素(即通式I的3′,4′,5,7-四羟基黄酮化合物,其中X=O,且其中R2、R3、R9、R11=OH)、染料木黄素(即,5,7-二羟基-3-(4-羟基苯基)-4H-1-苯并吡喃-4-酮或4’,5,7-三羟基异黄酮)或大豆黄素(7-羟基-3-(4-羟基苯基)-4H-1-苯并吡喃-4-酮或4’,7-二羟基异黄酮)。
根据本发明,提供了抑制细胞因子分泌和/或治疗自身免疫病的方法,所述自身免疫病包括糖尿病、多发性硬化、系统性红斑狼疮、类风湿性关节炎和间质性膀胱炎,通过给哺乳动物患者施用治疗有效量的具有上述通式I结构的至少一种化合物来实现。
还根据本发明,提供了具有下式II的物质的新型组合物:
其中,X选自O和S;和
i)当X为O时:
R1、R4、R5和R8为H或F;
R6和R7组合形成双键;
R2和R3选自H、OH、SH、卤素如F或Cl、烷基、氨基、NHMe、氰基、羧基、羧基烷基、甲酰胺、烷氧羰基、O-羟烷基、CF3、O-烷基、O-SO3H、O-SO2H、O-PO3H、O-糖苷、O-葡糖苷酸和O-氨基酸,包括O-CO-A-(CH2)n-NR′R″,其中A为苯基、取代的苯基或空缺;n为0至5;R′和R″选自H、低级烷基、羟烷基、氨基烷基、一和二烷基氨基烷基、羧基烷基,或者,R′和R″可组合形成环,任选地被O、S、NH或N-烷基取代,与氮原子相邻的亚甲基可以任选地被氨基烷基、羧基或羧基烷基和O-CO-NH-(CH2)m-CH-(NH2)COOH取代,其中m为1至4;且当R2和R3为OH或氨基时,它们可任选地通过亚甲基或羰基组合;
R9选自OH、氨基、NHMe、SH或SMe;和
R10和R11或R11和R12为亚甲二氧基(O-CH2-O)或环状碳酸酯(O-CO-O),或R12为H,R10、R11选自H、OH、卤素如F或Cl、烷基、氨基、氰基、羧基、羧基烷基、甲酰胺、烷氧羰基、O-羟烷基、CF3、O-烷基、O-SO3H、O-SO2H、O-PO3H、O-糖苷、O-葡糖苷酸和O-氨基酸,包括O-CO-A-(CH2)n-NR′R″,其中A为苯基、取代的苯基或空缺;n为0至5;R′和R″选自H、低级烷基、羟烷基、氨基烷基、一和二烷基氨基烷基、羧基烷基,或者,R′和R″可组合形成环,任选地被O、S、NH或N-烷基取代,靠近氮原子的亚甲基可任选地被氨基烷基、羧基或羧3
基烷基和O-CO-NH-(CH2)m-CH-(NH2)COOH取代,其中m为1至4;前提条件是,当R2和/或R为H、OH、OMe、Cl或氨基时,那么R9、R10和R11不相同。
ii)当X为S时:
R1至R5和R9至R12选自H、OH、卤素如F或Cl、SH、SMe、烷基、氨基、NHMe、氰基、羧基、羧基烷基、甲酰胺、烷氧羰基、O-羟烷基、CF3、O-烷基、O-SO3H、O-SO2H、O-PO3H、O-糖苷、O-葡糖苷酸和O-氨基酸,包括O-CO-A-(CH2)n-NR′R″,其中A为苯基、取代的苯基或空缺;其中n为0至5,其中R′和R”选自H、低级烷基、羟烷基、氨基烷基、一和二烷基氨基烷基、羧基烷基,或其中R′和R”组合形成环,所述环任选地被O、S、NH或N-烷基取代,且其中与氮原子相邻的亚甲基可任选地被氨基烷基、羧基或羧基烷基和O-CO-NH-(CH2)m-CH-(NH2)COOH取代,其中m为1至4;
R6和R7组合形成双键;
R8选自H或F;和
当R1至R5和R9至R12为OH、SH或氨基,并存在于环的相邻碳原子上时,那么它们可通过亚甲基(-O-CH2-O-)或羰基(-O-CO-O-、O-CO-NH-或-S-CO-NH-)组合形成环。
还根据本发明,用于制备本发明的化合物(通式I和II)的合成反应和方法是现有技术中已知的,并可通过本领域技术人员来实施,作为一个实例,羟基取代的黄酮可用卤代乙酰基卤化物来处理,然后用胺处理卤代烷基酯产物,得到相关的O-氨基酰基衍生物,类似地,在有碱存在的情况下,儿茶酚衍生物可用碳酸二乙酯或碳酸乙二酯来处理,以插入-O-CO-O-官能团。
下面的详细描述和实例用于提出本发明的实施例,而不是以任何方式来限制本发明的范围。
本发明包括药物制剂,其包含Kv1.3通道抑制剂如取代的3-脱氧类黄酮化合物作为活化剂,任选地包含IKCa1阻滞剂如克霉唑、1-[(2-氯苯基)二苯基甲基]-1H-吡唑、2-氯苯基二苯基氰基甲烷或环孢菌素A、或TNF-A抑制剂、或其它T淋巴细胞抑制剂如来氟米特,其代谢物A-771726[N-(4-三氟甲基苯基)-1-氰基-2-酮丙基-甲酰胺]或[N-[4-(三氟甲基)苯基]-2-羟基-6-氧代环戊基甲酰胺、或N-[4-[(三氟甲基)]苯基]-2-羟基苯甲酰胺,本发明还包括自身免疫病的免疫抑制治疗方法,通过施用治疗有效量的这些化合物至哺乳动物患者来实现。
此外,本发明涉及构成一组分子靶的离子通道,通过所述分子靶,这些3-脱氧类黄酮可发挥生物学效力,本发明的类黄酮化合物可降低和稳定I型和II型糖尿病患者的血糖水平,并可改善红斑狼疮的症状,这是一种影响几个器官的自身免疫病,I型糖尿病是一种自身免疫病,其中自身反应淋巴细胞破坏胰腺β-细胞,而II型糖尿病的病因是由于胰岛素产生不足和胰岛素影响靶向终末器官的能力降低,因为离子通道在淋巴细胞和胰腺β-细胞信号传导中具有重要作用,所以最有可能的是,通过阻滞离子通道,类黄酮至少可产生一些治疗效果,使用膜片钳实验,本申请人意外地发现,Kv1.3作为可调节人T淋巴细胞的有丝分裂发生的电压门控的K+通道,可通过这些3-脱氧类黄酮(通式I)来阻滞,这些类黄酮对人的无毒性质使它们有可能成为营养药品,来补充或代替现有的药物和治疗。
本发明涉及在需要治疗的患者体内抑制免疫系统的方法,具体地,本发明的方法可用于自身免疫病,如类风湿性关节炎、系统性红斑狼疮、桥本甲状腺炎、ALS、多发性硬化、重症肌无力、I型和II型糖尿病、肾病综合征、甾体依赖性和甾体耐性肾病、掌趾脓疱病、变应性脑脊髓炎、肾小球性肾炎、贝赫切特综合症、关节强硬性脊椎炎、多肌炎、纤维肌炎等。
根据本发明,提供了抑制T淋巴细胞的活性(并从而抑制细胞因子分泌和/或治疗自身免疫病,包括糖尿病、ALS、多发性硬化、系统性红斑狼疮、类风湿性关节炎和间质性膀胱炎或在上述“发明概述”部分列出的其它疾病或病症中的任意一种)的方法,通过给哺乳动物患者施用治疗有效量的至少一种上述通式I的化合物来实现,目前,通式I的下列化合物优选用于本发明的方法中:
6,7-亚甲二氧基-3′,4′,5-三羟基黄酮;
7,8-亚甲二氧基-3′,4′,5-三羟基黄酮;
6,7-羰基氧基-3′4′,5-三羟基黄酮;
3′,4′-羰基氧基-5,7-二羟基黄酮;
3′,5,7-三羟基黄酮-4′-磷酸酯;
3′,5,7-三羟基-4’-(2-氨基-1-羧基丙氧基)黄酮;
5-羟基-3′,4′,7-三羧基甲氧基黄酮。
另外,异类黄酮也包括在本发明中,其中在通式I中的苯基取代基位于3位,具体地,除了一种或多种3-脱氧类黄酮之外,组合物还可包含一种或多种异黄酮,更具体地,是染料木黄素(即,5,7-二羟基-3-(4-羟基苯基)-4H-1-苯并吡喃-4-酮或4′,5,7-三羟基异黄酮)和/或大豆黄素(即,7-羟基-3-(4-羟基苯基)-4H-1-苯并吡喃-4-酮或4′,7-二羟基异黄酮)。
当用于治疗糖尿病时,优选上述通式I的化合物不是木樨草素(即,其中R2、R3、R9、R11为OH(3′,4′,5,7-四羟基黄酮))、或木樨草素的5位(R9)糖苷、或木樨草素的7位(R11)糖苷、或芹菜素(即,其中R3、R9、R11为OH(4’,5,7-三羟基黄酮)。
当用于治疗肌萎缩性脊髓侧索硬化症(ALS)时,优选上述通式I的化合物不是单独的木樨草素、单独的染料木黄素、或单独的大豆黄素。
本发明的化合物还可用于治疗炎性、增生性和高度增生性皮肤疾病,和免疫介导疾病的皮肤表现,所述疾病为例如牛皮癣、牛皮癣关节炎、特应性皮炎、接触性皮炎和其它湿疹皮炎、皮脂溢皮炎、扁平苔癣、天疱疮、大疱性天疱疹、大疱型表皮松解症、皮肤血管炎、血管炎、红斑、皮肤嗜酸粒细胞增多、痤疮、斑秃和动脉硬化。
本发明的化合物还另外用于治疗呼吸道疾病,例如肉样瘤病、纤维性肺、特发性间质性肺炎、和可逆性阻塞性气道疾病,包括疾病如哮喘,包括支气管哮喘、变应性哮喘、内源性哮喘、外因性气喘和尘埃性哮喘、支气管炎等,化合物还可用于治疗与局部缺血相关的肝损伤。
化合物还可治疗某些眼病如角膜结膜炎、春季结膜炎、角膜炎、葡萄膜炎、角膜白斑、眼天疱疮、莫伦(Mooren′s)溃疡、巩膜炎、格雷夫斯眼病、交感性眼炎等。
化合物也可用于治疗炎性肠疾病(例如克罗恩氏病)、神经疾病(包括吉兰-巴雷综合症、梅尼埃病、神经根病)、内分泌疾病(包括甲状腺机能亢进和巴泽多(Basedow′s)病)、血液学疾病(包括单纯性红细胞再生不良、再生障碍性贫血、再生不良性贫血、特发性血小板减少性紫癜、自身免疫性溶血性贫血、粒细胞缺乏症和红细胞发生不能)、骨病(包括骨质疏松)、呼吸道疾病(包括肉样瘤病、特发性间质性肺炎)、皮肤病(包括皮肌炎、寻常白斑病、光变应敏感性和皮肤T细胞淋巴瘤)、生殖器疾病(睾丸炎、外阴炎)、循环系统疾病(包括动脉硬化、多发性结节性动脉炎、血管炎、伯格(BuergeR′s)病和心肌病)、胶原疾病(包括硬皮病、主动脉炎综合征、嗜酸性筋膜炎、韦格纳肉芽肿病、舍格伦综合症、牙周病)、肾脏疾病(包括肾病综合征、溶血-尿毒综合症、古德帕斯丘(Goodpasture′s)综合症)和肌肉萎缩,化合物也可用于治疗疾病,包括肠炎/变态反应如腹腔病、直肠炎、溃疡性结肠炎、嗜酸性胃肠炎、肥大细胞病、克罗恩氏病和溃疡性结肠炎和食物相关的变应性疾病,其具有远离胃肠道的症状表现,如偏头痛、鼻炎和湿疹,另外,本发明可用于治疗预防或治疗粘膜或血管的炎症(如白细胞三烯介导的疾病)、胃溃疡、由局部缺血和血栓形成引起的血管损伤、局部缺血性肠病,另外,本发明可用于治疗肿瘤细胞的多药耐药性(即,增强化学治疗剂的活性和/或敏感性)。
化合物可用于治疗和预防肝病如免疫原性疾病(例如,慢性自身免疫肝病,其包括自身免疫肝炎、原发性胆汁性肝硬化和硬化性胆管炎)、部分肝切除术、急性肝坏死(例如,由毒素引起的坏死、病毒性肝炎、休克或缺氧)、乙型肝炎、非甲型/乙型肝炎、肝硬化。
现在,已证明,通过对I型和II型糖尿病志愿者的无对照研究,通式I的3-脱氧类黄酮可降低糖尿病患者的胰岛素需求,并可对其它基于离子通道阻滞的自身免疫病具有附加的有益效果,这些正在进行的研究的结果已表明,当3-脱氧类黄酮以粉末或速溶片剂口服时,顽抗性高血糖水平和糖基化血红蛋白(HbA1C)急剧降低、具有显著较少的胰岛素的I型血糖水平正常化、和其它症状如晚期糖尿病的周围神经系统疾病减少,据信,3-脱氧类黄酮的最大生物吸收通过口颊和舌下粘膜发生,对于志愿者的无对照研究还表明3-脱氧类黄酮对红斑狼疮和多发性硬化的效力,另外,我们还认为,淋巴细胞或胰腺钾离子通道的抑制有助于通式I的3-脱氧类黄酮的多种生物活性,这包括抗痉挛、抗炎、LDL胆甾醇降低、抗诱变和抗致癌效应,通式I包括的某些化合物为安全的天然黄酮,这些化合物可用作营养药品。
非常重要的是,通过以特定通道或通道组合为靶子,可通过小分子来无毒性地抑制原发性的和继发性的免疫应答,此外,应理解,单独阻滞Kv1.3通道或同时还阻滞IKCa1通道可对多发性硬化和其它自身免疫病提供甚至更有效的治疗模式。
尽管在上述说明中,已涉及某些优选实施方案来描述了本发明,且描述了许多细节来进行说明,但是对本领域的技术人员显而易见的是,本发明易于改变为其它的实施方案,且本文描述的某些细节可显著改变,这不会背离本发明的基本原则。
下列具体实施例用于详细说明本发明,不应认为以任何方式来限制本发明。
实施例1
利用Fanger(2000)J.Biol Chem.276:12249描述的膜片钳方法来抑制Kv1.3通道,由下面的图1可发现,在20μM浓度时,木樨草素阻滞了约25%的Kv1.3通道电流,在100μM浓度时,木樨草素阻滞了100%的Kv1.3通道电流,对照曲线也示于图1中,结果清楚地表明,木樨草素和相关的3-脱氧类黄酮可有效地阻滞Kv1.3通道,因此可以有效地治疗自身免疫病。
实施例2
3-脱氧类黄酮对于T淋巴细胞的细胞毒性的作用
细胞毒T淋巴细胞系(CTL-名称为CTL264)特异作用于得自肿瘤抑制蛋白p53的肽抗原(aa 264-272,称为264肽),该T淋巴细胞系用作靶子来测试木樨草素是否对264肽脉冲T2靶细胞的CTL细胞毒性具有任何作用,T2靶细胞用264肽脉冲2小时,标以Calceln-AM,30分钟后,洗涤三次,将T2细胞和CTL264混合物培育4小时,将100μl上清液转移至96孔平底微量滴定板,读取荧光(538nm),测量由于细胞溶解所释放的钙黄绿素,我们意外地发现,按照浓度依赖性方式,木樨草素显著抑制了对于264-脉冲T2靶细胞的CTL细胞毒性(图2)。
实施例3
在细胞毒T淋巴细胞中,自发的钙黄绿素释放量由RPMI-10中的靶细胞培育来确定,最大钙黄绿素释放量由Triton X-100中的靶细胞培育来确定,数据记录为三次测定的平均值,图3显示了通过3-脱氧类黄酮木樨草素和3’,4’,5’,5,7-五羟黄酮抑制钙黄绿素释放。
实施例4
检查木樨草素治疗对于慢性I型(BBWor)糖尿病小鼠的效果,在这个研究中,将瘦的雄性糖尿病小鼠随机分为3个治疗组(每组3至4只小鼠),各组分别接受以下一种试验:
(1)胃内给予3mg剂量的木樨草素;
(2)皮下注射PZI胰岛素(0.9-1.2mU/天);
(3)没有治疗措施,从0至6小时,评估血糖,数据表示为相对于治疗后时间的平均血糖。
接受单次胰岛素注射的小鼠显示在6小时注射时间内血糖水平下降75%(415至112mg/dl),这种反应与我们先前在I型(BBWor)小鼠模型中的研究完全一致,相当明显地,接受木樨草素的糖尿病小鼠显示在6小时内,其血糖水平降低31%(445至307mg/dl)。
作为比较,在对照组中经相同的时间间隔,高血糖状态没有降低(414至404mg/dl),因此,对于胰岛素依赖性糖尿病(I型BBWor)小鼠,单次3mg剂量的木樨草素能够在6小时内将高血糖降低多达31%。
实施例5
木樨草素也能够通过减少慢性II型糖尿病小鼠的高血糖来评估其效果,在这个研究中,提高木樨草素治疗的剂量和频率,以补偿肥胖小鼠的增强代谢,首先,对于9只慢性II型小鼠进行24小时的基线研究,经24小时分析,在糖尿病小鼠中没有发现高血糖的显著变化,然后将这些相同的小鼠随机分为3组,在24小时内分三次(上午11点、下午2点和晚上8点)每次施用50、150和250mg剂量的木樨草素,每2小时进行血糖分析。
图4显示了木樨草素对于II型糖尿病小鼠的剂量效果,一天三次接受最低剂量50mg(共150mg)的小鼠显示,其血糖水平在24小时的治疗时间内降低了10.2%,作为比较,接受中等剂量150mg(共450mg)的小鼠显示其血糖水平降低22.9%,在第三组接受最高剂量250mg(共750mg)的小鼠显示血糖水平的最大变化,即降低了27.7%,有趣的是,给一只小鼠施用的中等剂量使其血糖水平在18小时的治疗时间内降低了52%(777至372mg/dl),不幸的是,在给药期间,由于意外的食管穿孔,该动物在24小时时间点前的某一时候死去,这些结果表明,木樨草素治疗使II型糖尿病小鼠的高血糖在24小时内显著降低了10-28%,这些观察都具有剂量依赖性。
实施例6
在这个实施例中,在与实施例5相同的一组II型BBZDR小鼠中,木樨草素的剂量被定为每天三次,每次50mg,治疗时间延长为两周,方案的变化导致血糖的进一步降低,对于每只小鼠,数据表示为相对于各个单独的治疗前水平的血糖水平变化百分比。
在图5中,在接受50mg(每天三次)木樨草素的肥胖II型(BBZDR)糖尿病小鼠中,经两周治疗后,除了一只小鼠(#3),几乎所有小鼠都显示其血糖水平降低了(范围为36%至54%),对#3小鼠的尸体检查发现食管瘘,表明血糖的9.3%增加可能抑制了有效剂量给药和对治疗的反应,总地来说,在II型糖尿病小鼠中血糖水平平均降低了41.1%(660至389mg/dl)。
实施例7
具有I型糖尿病抗体的7岁大的男孩自2岁起服用预防性胰岛素(每晚2单位NPH),在7岁4个月时,该儿童具有血糖为260mg/dl的症状,开始每晚服用4单位NPH来控制血糖,在用胰岛素治疗约45天后,给病人施用75-150mg木樨草素粉末(75%木樨草素,25%芸香苷)以代替胰岛素,舌下给药,每天四次,不需要任何胰岛素,就可维持平均血糖为约105mg/dl,在约20天的木樨草素粉末(75%木樨草素,25%芸香苷)治疗后,木樨草素粉末(75%木樨草素,25%芸香苷)的剂量逐渐减为25mg粉末(75%木樨草素,25%芸香苷),每天四次,这具有连续的血糖控制和葡萄糖耐受性的改善,收集病人的血液,分析综合代谢酶,包括肝功能、脂类和糖基化血红蛋白(HbA1c),所有的酶系统为正常,HbA1 C为8.0,木樨草素粉末(75%木樨草素,25%芸香苷)治疗为每次25mg,每天四次,在90天后,发现该儿童的血糖浓度不高于125mg/dl,平均血糖浓度为95mg/dl,HbA1c为6.3,木樨草素(75%木樨草素,25%芸香苷)治疗和血糖浓度显示于图6。
实施例8
对患有II型糖尿病的69岁的男性高加索人施用Glucotrol XL,每天2次,每次10mg;Actos 45mg,每天1次;二甲双胍,1000mg,每天2次,1年后,其平均血糖为约170mg/dl,其上一年的血糖数据示于图7,给病人施用实施例12所述的组合物,每天三次,定期测量病人的血糖,如图8所示,数据显示经约60天的时期,血糖持续降低,这是使用本领域目前的处方药物所不能达到的。
实施例9
47岁,145磅的高加索女性,患有15年的多发性硬化,其为急性发作模式,诉有眼睛和四肢的剧烈疼痛,按照病人的身体状况,给她服用β-干扰素,给病人施用100毫克木樨草素粉末(45%木樨草素,55%芸香苷),舌下给药,每天四次,患者注意到在很短的时间内其神经系统疾病症状发生变化,这与快速舌下或口腔吸收一致,在24小时内,她的症状减少了约50%,在72小时内,她的症状消失,在14天用100mg木樨草素粉末(45%木樨草素,55%芸香苷)治疗,每天四次,在停止服用木樨草素(45%木樨草素,55%芸香苷)后,患者在5天内经历了多发性硬化的复发,然后给她施用250mg木樨草素粉末(45%木樨草素,55%芸香苷),每天四次,共一天;此后连续每天服用100mg木樨草素粉末(45%木樨草素,55%芸香苷),观察到MS(多发性硬化)症状缓解,共持续30天。
实施例10
32岁的高加索男性,患有10年的纤维肌痛,这是由一次严重的车祸引起的,用抗炎化合物和止痛药治疗都不成功,他的关节疼痛超过体力工作的耐受性,所以他经常卧床休息,没有剧烈疼痛时也不能移动,给患者施用50毫克木樨草素粉末(75%木樨草素,25%芸香苷),每天3次,在两周内,他观察到症状显著减轻了,能够恢复工作,他不再需要止痛药物,其症状也没有复发。
实施例11
下列组合物描述了减轻自身免疫病的典型配方,对于各种疾病的组合物可以变化,不应理解为固定不变。
β-胡萝卜素6000IU
棕榈酸视黄酯6000IU抗坏血酸375mg
抗坏血酸棕榈酸酯25mg胆钙化醇400IUTPGS500mg
维生素K1150mcg
维生素B115mg
维生素B215mg
烟酸15mg
烟酰胺1450mg
吡哆醇盐酸盐22.5mg吡哆醛-5-磷酸酯2.5mg叶酸800mcg
维生素B1260mcg
维生素H3mg
泛酸100mg
钙200mg
碘(KI)150mcg
镁500mg
锌15mg
硒300mcg
铜2mg
锰5mg
吡啶甲酸铬400mcg
钼100mcg
硼3mg
二氧化硅10mg
硫酸氧钒5mg
胆碱酒石酸氢盐50mg
柑橘生物类黄酮提取物500mg
硫辛酸50mg
叶黄素3mg3-脱氧类黄酮25mg
番茄红素2mg
N-乙酰半胱氨酸200mg
牛磺酸500mg4-羧基-2-噻唑烷酮100mg
PEG-40025mg
实施例12
制备包括下列成分的口服片剂组合物:
维生素C(抗坏血酸和抗坏血酸钙)65mg
维生素D(胆钙化醇)50IU
维生素E(dl-α醋酸生育酚酯)5IU
烟酸(烟酰胺)10mg
维生素H100mcg
钙(碳酸钙)160mg
铬(多聚烟酸铬)100mcg
钒(硫酸氧钒)10mcg3-脱氧类黄酮(50%木樨草素,50%芸香苷)25mg微晶纤维素35mg
Croscarmellose钠7mg
硬脂酸10.5mg
硬脂酸镁3.2mg
二氧化硅1.8mg
OpadryNSY-40-191333.5mg
尽管本发明已参照具体实施方案进行了描述,但是应理解,本领域技术人员可作出各种变化,可用等价物来代替,而不背离本发明的范围。另外,可作出许多修改来适应具体情况、物质、物质组合物、方法和/或方法步骤,这都在本发明的范围内。因此,本发明的范围应参照所附的权利要求书以及与那些权利要求相当的等价物来确定。
需要说明的是,在本文中,诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来,而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下,由语句“包括一个……”限定的要素,并不排除在包括所述要素的过程、方法、物品或者设备中还存在另外的相同要素。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (7)
1.基于脱氧类黄酮的T淋巴细胞活性抑制组合物,其特征在于:包括木樨草素、芸香苷、桑寄生和槲皮素。
2.根据权利要求1所述的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,其特征在于:所述木樨草素、芸香苷、桑寄生和槲皮素用于口服给药。
3.根据权利要求1所述的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,其特征在于:所述木樨草素、芸香苷、桑寄生和槲皮素用于舌下给药。
4.根据权利要求1所述的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,其特征在于:所述木樨草素、芸香苷、桑寄生和槲皮素用于口颊给药。
5.根据权利要求1所述的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,其特征在于:所述木樨草素、芸香苷、桑寄生和槲皮素用于直肠给药。
6.根据权利要求1所述的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,其特征在于:所述木樨草素、芸香苷、桑寄生和槲皮素用于经皮给药。
7.根据权利要求1所述的基于脱氧类黄酮的T淋巴细胞活性抑制组合物,其特征在于:所述木樨草素、芸香苷、桑寄生和槲皮素通过注射给药。
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