CN105982894A - Application of isoindolinone compounds in preparing medicines for preventing and treating inflammatory bowel diseases and preparation for preventing and treating inflammatory bowel diseases - Google Patents
Application of isoindolinone compounds in preparing medicines for preventing and treating inflammatory bowel diseases and preparation for preventing and treating inflammatory bowel diseases Download PDFInfo
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Abstract
本发明公开了吲哚啉酮类化合物中的至少一种在制备预防和治疗炎性肠病的药物中的应用，所述吲哚啉酮类化合物包括式(1)所示的化合物和式(2)所示的化合物，其中，在式(1)和式(2)中，R1和R2相同或不同，各自独立地为H或R，且R为n为0-2的整数，X为氢或卤素。本发明还公开了一种用于预防和治疗炎性肠病的制剂，该制剂中含有活性成分和辅料，所述活性成分包括吲哚啉酮类化合物中的至少一种，所述吲哚啉酮类化合物包括式(1)所示的化合物和式(2)所示的化合物。将含有本发明所述的吲哚啉酮类化合物的药物用于预防和治疗炎性肠病时能够取得很好的预防和治疗效果。 The invention discloses the application of at least one of indolinone compounds in the preparation of medicines for preventing and treating inflammatory bowel disease. The indolinone compounds include compounds represented by formula (1) and formula ( 2) the compound shown, wherein, in formula (1) and formula (2), R 1 and R 2 are identical or different, each independently is H or R, and R is n is an integer of 0-2, and X is hydrogen or halogen. The invention also discloses a preparation for preventing and treating inflammatory bowel disease. The preparation contains active ingredients and auxiliary materials. The active ingredients include at least one of indolinone compounds, and the indoline Ketone compounds include compounds represented by formula (1) and compounds represented by formula (2). Good preventive and therapeutic effects can be achieved when the medicine containing the indolinone compound described in the present invention is used for the prevention and treatment of inflammatory bowel disease.
Description
技术领域technical field
本发明涉及医药领域，具体地，涉及一种吲哚啉酮类化合物在制备预防和治疗炎性肠病的药物中的应用以及一种用于预防和治疗炎性肠病的制剂。The present invention relates to the field of medicine, in particular to the application of an indolinone compound in the preparation of medicines for preventing and treating inflammatory bowel disease and a preparation for preventing and treating inflammatory bowel disease.
背景技术Background technique
炎性肠病，简称IBD，是一种特殊的慢性肠道炎症性疾病，主要包括克罗恩病(CD)和结肠炎(特别地，例如溃疡性结肠炎(UC))。近30年来，我国IBD发病率有不断攀升的趋势。根据国内文献报道，近5年的病例数是上世纪90年代同期的8倍，IBD已逐渐成为我国消化科的常见病。IBD的病因和发病机制尚未完全明确，已知肠道粘膜免疫系统异常反应所导致的炎症反应在IBD发病中起重要作用，认为这是由多因素相互作用所致，主要包括环境、遗传、感染和免疫因素，其中特定基因突变或缺失导致的遗传易感性是一个重要因素。Inflammatory bowel disease, referred to as IBD, is a special chronic intestinal inflammatory disease, mainly including Crohn's disease (CD) and colitis (especially, such as ulcerative colitis (UC)). In the past 30 years, the incidence of IBD in my country has been on the rise. According to domestic literature reports, the number of cases in the past five years is eight times that of the same period in the 1990s. IBD has gradually become a common disease in gastroenterology in my country. The etiology and pathogenesis of IBD have not yet been fully clarified. It is known that the inflammatory response caused by the abnormal response of the intestinal mucosal immune system plays an important role in the pathogenesis of IBD. It is believed that this is caused by the interaction of multiple factors, mainly including environment, genetics, infection and immune factors, of which genetic susceptibility due to mutations or deletions of specific genes is an important factor.
溃疡性结肠炎是IBD的主要形式之一，典型特征为结肠及直肠的慢性炎症。近年来，UC发病率呈现逐渐升高的趋势。UC病人出现黏液性或非黏液性血便、腹痛、发热及体重下降。UC致病机制主要是由于在大肠内部出现未知环境因素导致的异常免疫反应。研究表明多种炎症细胞因子，包括IL-4、IL-5、IL-6、IL-10及TNFα等在介导免疫反应中发挥重要作用。对其发病机制的深入研究引发了UC的多种靶向炎症因子的治疗药物的发现。这些靶向药物与传统药物不同，不会抑制整体的免疫系统，作用机制也更特异。在这些炎症因子中，对TNFα的研究最为广泛。TNFα由活化的巨噬细胞及T淋巴细胞分泌，并导致巨噬细胞及T淋巴细胞的进一步活化、血管内皮细胞上黏附分子的表达及中性粒细胞的聚集，最终引起炎症程度不断增强。在UC病人的结肠组织、血清、粪便及尿液中可检测到TNFα的水平明显升高。因此，TNFα是生物制剂的非常有吸引力的靶点。Ulcerative colitis is one of the major forms of IBD and is typically characterized by chronic inflammation of the colon and rectum. In recent years, the incidence of UC has gradually increased. Patients with UC presented with mucoid or nonmucous bloody stools, abdominal pain, fever, and weight loss. The pathogenic mechanism of UC is mainly due to the abnormal immune response caused by unknown environmental factors in the large intestine. Studies have shown that a variety of inflammatory cytokines, including IL-4, IL-5, IL-6, IL-10 and TNFα, play an important role in mediating immune responses. The in-depth study of its pathogenesis has led to the discovery of a variety of therapeutic drugs targeting inflammatory factors for UC. Unlike traditional drugs, these targeted drugs do not suppress the overall immune system and have a more specific mechanism of action. Among these inflammatory factors, TNFα has been most extensively studied. TNFα is secreted by activated macrophages and T lymphocytes, and leads to the further activation of macrophages and T lymphocytes, the expression of adhesion molecules on vascular endothelial cells, and the aggregation of neutrophils, and finally causes the degree of inflammation to increase continuously. The level of TNFα was significantly increased in the colon tissue, serum, feces and urine of UC patients. Therefore, TNFα is a very attractive target for biologics.
美国FDA已经批准三种TNFα拮抗剂用于治疗UC和克罗恩病(CD)。虽然TNFα拮抗剂的治疗取得了一定成效，但仍有部分病人需要皮质激素类治疗发生原发或继发性的TNFα拮抗剂抗性。The US FDA has approved three TNFα antagonists for the treatment of UC and Crohn's disease (CD). Although the treatment of TNFα antagonists has achieved certain results, there are still some patients who need corticosteroids to develop primary or secondary resistance to TNFα antagonists.
治疗失效的情况一般分为两类：原发性失效和继发性失效。在原发失效病人中，初次使用治疗药物并不能缓解临床症状。在继发性失效病人中，初次治疗有效，但后续治疗中则逐渐丧失疗效。因此，其他的炎症通路关键因子也被开发为治疗药物的靶点。这些因子包括参与淋巴细胞迁移的黏附分子(整合素，ICAM，VCAM等)，其他细胞因子(如IL-12、IL-23、IL-10)及T淋巴细胞受体(CD28、CD25)等。Treatment failures generally fall into two categories: primary failures and secondary failures. In patients with primary failure, initial treatment with drugs does not relieve clinical symptoms. In patients with secondary failure, the initial treatment is effective, but the effect is gradually lost with subsequent treatment. Therefore, other key factors of inflammatory pathways have also been developed as targets for therapeutic drugs. These factors include adhesion molecules involved in lymphocyte migration (integrin, ICAM, VCAM, etc.), other cytokines (such as IL-12, IL-23, IL-10) and T lymphocyte receptors (CD28, CD25).
结肠炎是结肠癌发生的最重要风险因素。溃疡性结肠炎的患者发生结肠癌的几率高于正常人，统计显示：左半结肠炎患者的癌变率是正常人的2.8倍，全结肠炎患者的癌变率是正常人15倍，而幼年起病的全结肠炎患者的癌变率是正常人的162倍。Colitis is the most important risk factor for the development of colon cancer. The incidence of colon cancer in patients with ulcerative colitis is higher than that of normal people. Statistics show that the canceration rate of patients with left side colitis is 2.8 times that of normal people, and the canceration rate of patients with pancolitis is 15 times that of normal people. The cancer rate of patients with pancolitis is 162 times that of normal people.
因此，开发一种新的用于预防和治疗炎性肠病疾病的药物具有重要意义。Therefore, it is of great significance to develop a new drug for the prevention and treatment of inflammatory bowel disease.
发明内容Contents of the invention
本发明的目的是提供一种吲哚啉酮类化合物在制备预防和治疗炎性肠病的药物中的应用以及一种用于预防和治疗炎性肠病的制剂。The object of the present invention is to provide an application of an indolinone compound in the preparation of a drug for preventing and treating inflammatory bowel disease and a preparation for preventing and treating inflammatory bowel disease.
为了实现上述目的，一方面，本发明提供一种吲哚啉酮类化合物中的至少一种在制备预防和治疗炎性肠病的药物中的应用，所述吲哚啉酮类化合物包括式(1)所示的化合物和式(2)所示的化合物，In order to achieve the above object, on the one hand, the present invention provides an application of at least one of the indolinone compounds in the preparation of drugs for the prevention and treatment of inflammatory bowel disease, the indolinone compounds comprising the formula ( 1) the compound shown in and the compound shown in formula (2),
其中，在式(1)和式(2)中，R1和R2相同或不同，各自独立地为H或R，且R为n为0-2的整数，X为氢或卤素。Wherein, in formula (1) and formula (2), R 1 and R 2 are the same or different, each independently is H or R, and R is n is an integer of 0-2, and X is hydrogen or halogen.
另一方面，本发明提供一种用于预防和治疗炎性肠病的制剂，该制剂中含有活性成分和辅料，所述活性成分包括吲哚啉酮类化合物中的至少一种，以所述制剂的总重量计，所述吲哚啉酮类化合物的含量为0.5-100重量％，所述吲哚啉酮类化合物包括式(1)所示的化合物和式(2)所示的化合物，In another aspect, the present invention provides a preparation for preventing and treating inflammatory bowel disease, the preparation contains active ingredients and excipients, the active ingredients include at least one of indolinone compounds, and the Based on the total weight of the preparation, the content of the indolinone compounds is 0.5-100% by weight, and the indolinone compounds include compounds represented by formula (1) and compounds represented by formula (2),
其中，在式(1)和式(2)中，R1和R2相同或不同，各自独立地为H或R，且R为n为0-2的整数，X为氢或卤素。Wherein, in formula (1) and formula (2), R 1 and R 2 are the same or different, each independently is H or R, and R is n is an integer of 0-2, and X is hydrogen or halogen.
将含有本发明所述的吲哚啉酮类化合物的药物用于预防和治疗炎性肠病时能够取得很好的预防和治疗效果，而且，本发明所述的含有吲哚啉酮类化合物的药物毒性低、生物利用度高。Good preventive and therapeutic effects can be achieved when the medicine containing the indolinone compound described in the present invention is used for the prevention and treatment of inflammatory bowel disease, and the medicine containing the indolinone compound described in the present invention The drug has low toxicity and high bioavailability.
进一步地，本发明所述的用于预防和治疗炎性肠病的制剂在预防和治疗炎性肠病时具有很好的预防和治疗效果，而且，本发明所述的用于预防和治疗炎性肠病的制剂还具有毒性低和生物利用度高的优点。Further, the preparation for preventing and treating inflammatory bowel disease according to the present invention has a good preventive and therapeutic effect when preventing and treating inflammatory bowel disease, and the preparation for preventing and treating inflammatory bowel disease according to the present invention Preparations for venereal enteropathy also have the advantages of low toxicity and high bioavailability.
特别地，从本发明的实施例的结果可以看出：吲哚啉酮类化合物能够预防炎性肠病，并且抑制小鼠体重下降，在给予DSS后预先服用吲哚啉酮类化合物的小鼠的疾病指数明显低于未预先服用吲哚啉酮类化合物的小鼠的疾病指数。而且，吲哚啉酮类化合物能够抑制DSS引起的小鼠结肠长度缩短。病理检测发现预先服用吲哚啉酮类化合物可抑制DSS诱导的结肠结构破坏及炎细胞浸润。In particular, from the results of the examples of the present invention, it can be seen that indolinone compounds can prevent inflammatory bowel disease and inhibit the weight loss of mice. The disease index of the mice was significantly lower than that of mice not pre-administered with indolinone compounds. Moreover, indolinone compounds can inhibit the shortening of colon length in mice induced by DSS. Pathological examination found that pre-administration of indolinone compounds could inhibit DSS-induced colonic structural destruction and inflammatory cell infiltration.
进一步地，本发明的实施例的结果还表明：吲哚啉酮类化合物能够治疗炎性肠病，并且抑制小鼠体重下降，在给予DSS后，各组小鼠的体重普遍降低，疾病指数增高，而在给药吲哚啉酮类化合物后，能够明显抑制小鼠的体重降低，降低疾病指数，并呈现剂量效应相关性。而且，吲哚啉酮类化合物能够治疗由DSS引起的小鼠结肠长度缩短。病理检测发现吲哚啉酮类化合物可治疗由DSS诱导的结肠结构破坏及炎细胞浸润。Further, the results of the examples of the present invention also show that indolinone compounds can treat inflammatory bowel disease and inhibit weight loss in mice. After administration of DSS, the weight of mice in each group generally decreased and the disease index increased , and after administration of indolinone compounds, it can significantly inhibit the weight loss of mice, reduce the disease index, and present a dose-effect correlation. Furthermore, indolinones were able to treat the shortened colon length in mice induced by DSS. Pathological examination found that indolinone compounds can treat colon structural destruction and inflammatory cell infiltration induced by DSS.
本发明的其它特征和优点将在随后的具体实施方式部分予以详细说明。Other features and advantages of the present invention will be described in detail in the detailed description that follows.
具体实施方式detailed description
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于说明和解释本发明，并不用于限制本发明。Specific embodiments of the present invention will be described in detail below. It should be understood that the specific embodiments described here are only used to illustrate and explain the present invention, and are not intended to limit the present invention.
一方面，本发明提供了一种吲哚啉酮类化合物中的至少一种在制备预防和治疗炎性肠病的药物中的应用，所述吲哚啉酮类化合物包括式(1)所示的化合物和式(2)所示的化合物，In one aspect, the present invention provides an application of at least one of the indolinone compounds in the preparation of drugs for the prevention and treatment of inflammatory bowel disease, the indolinone compounds comprising formula (1) The compound shown in the compound and formula (2),
其中，在式(1)和式(2)中，R1和R2相同或不同，各自独立地为H或R，且R为n为0-2的整数，X为氢或卤素。Wherein, in formula (1) and formula (2), R 1 and R 2 are the same or different, each independently is H or R, and R is n is an integer of 0-2, and X is hydrogen or halogen.
在本发明中，所述n可以为0、1和2中的任意整数。In the present invention, the n may be any integer among 0, 1 and 2.
在本发明中，所述卤素包括氟、氯、溴和碘中的至少一种。In the present invention, the halogen includes at least one of fluorine, chlorine, bromine and iodine.
在本发明中，需要特别说明的是，在R中，对所述X的取代位置没有特别的限定，可以为邻位、间位和对位取代中的任意一种。In the present invention, it should be noted that, in R, the substitution position of X is not particularly limited, and it can be any one of ortho, meta and para substitutions.
在本发明中，对各种吲哚啉酮类化合物的用量比没有特别的限定，本领域技术人员在了解了本发明的技术方案后可以根据本领域内的常规用量比例进行选择。In the present invention, there is no special limitation on the dosage ratio of various indolinone compounds, those skilled in the art can select according to the conventional dosage ratio in the field after understanding the technical scheme of the present invention.
在本发明中，对所述吲哚啉酮类化合物的制备方法没有特别的限定，本领域技术人员可以根据本领域内的公知常识制备本发明所述的吲哚啉酮类化合物。特别优选情况下，本发明所述的吲哚啉酮类化合物可以根据CN101314584A中提供的方法制备得到。In the present invention, the preparation method of the indolinone compound is not particularly limited, and those skilled in the art can prepare the indolinone compound described in the present invention according to common knowledge in the field. Particularly preferably, the indolinone compounds described in the present invention can be prepared according to the method provided in CN101314584A.
优选情况下，在本发明中，所述吲哚啉酮类化合物可以包括式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物，Preferably, in the present invention, the indolinone compounds may include compounds represented by formula (3), compounds represented by formula (4), compounds represented by formula (5) and compounds represented by formula (6) Compounds shown,
也就是说，在本发明的吲哚啉酮类化合物中的至少一种在制备预防和治疗炎性肠病的药物中的应用中，所述吲哚啉酮类化合物可以包括式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物中的至少一种。That is to say, in the application of at least one of the indolinone compounds of the present invention in the preparation of drugs for the prevention and treatment of inflammatory bowel disease, the indolinone compounds may include formula (3) At least one of the compounds shown in the formula, the compound shown in the formula (4), the compound shown in the formula (5) and the compound shown in the formula (6).
根据本发明的一种优选的具体实施方式，在本发明中，所述吲哚啉酮类化合物为上述式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物。在本发明中，当所述吲哚啉酮类化合物为式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物时，对式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物的用量比例没有特别的限定，本领域技术人员可以在极其宽泛的范围内选择上述四种化合物的用量比，例如，本发明的实施例中示例性地使用了相同摩尔比的上述四种化合物用来制备治疗炎性肠病的药物，本领域技术人员不应理解为对本发明的范围的限制。According to a preferred embodiment of the present invention, in the present invention, the indolinone compound is the compound represented by the above formula (3), the compound represented by the formula (4), the compound represented by the formula (5) The compound shown and the compound shown in formula (6). In the present invention, when the indolinone compound is a compound shown in formula (3), a compound shown in formula (4), a compound shown in formula (5) and a compound shown in formula (6) When, there is no special limitation to the dosage ratio of the compound shown in formula (3), the compound shown in formula (4), the compound shown in formula (5) and the compound shown in formula (6), those skilled in the art The dosage ratio of the above four compounds can be selected within an extremely wide range. For example, the above four compounds in the same molar ratio are used to prepare the medicine for treating inflammatory bowel disease in the embodiments of the present invention. It should not be construed by skilled artisans as limiting the scope of the present invention.
根据本发明的另一种优选的具体实施方式，在本发明中，所述吲哚啉酮类化合物为式(3)所示的化合物，According to another preferred embodiment of the present invention, in the present invention, the indolinone compound is a compound represented by formula (3),
在本发明的吲哚啉酮类化合物中的至少一种在制备预防和治疗炎性肠病的药物中的应用中，在所述药物中，所述吲哚啉酮类化合物的含量可以为0.5-100重量％，特别优选情况下，所述吲哚啉酮类化合物的含量为5-95重量％。In the application of at least one of the indolinone compounds of the present invention in the preparation of drugs for the prevention and treatment of inflammatory bowel disease, in the drug, the content of the indolinone compounds may be 0.5 -100% by weight, especially preferably, the content of the indolinone compound is 5-95% by weight.
根据本发明的吲哚啉酮类化合物中的至少一种在制备预防和治疗炎性肠病的药物中的应用，所述药物可以为丸剂、膏剂、片剂、口服液剂、皮下注射剂和静脉注射剂中的至少一种。According to the application of at least one of the indolinone compounds of the present invention in the preparation of medicines for the prevention and treatment of inflammatory bowel disease, the medicines can be pills, ointments, tablets, oral liquids, subcutaneous injections and intravenous At least one of the injections.
根据本发明的吲哚啉酮类化合物中的至少一种在制备预防和治疗炎性肠病的药物中的应用，优选所述炎性肠病包括结肠炎。According to the use of at least one of the indolinone compounds of the present invention in the preparation of medicaments for the prevention and treatment of inflammatory bowel disease, preferably the inflammatory bowel disease includes colitis.
另一方面，本发明提供了一种用于预防和治疗炎性肠病的制剂，该制剂中含有活性成分和辅料，所述活性成分包括吲哚啉酮类化合物中的至少一种，以所述制剂的总重量计，所述吲哚啉酮类化合物的含量为0.5-100重量％，所述吲哚啉酮类化合物包括式(1)所示的化合物和式(2)所示的化合物，In another aspect, the present invention provides a preparation for preventing and treating inflammatory bowel disease, which contains active ingredients and excipients, and the active ingredients include at least one of indolinone compounds, so that Based on the total weight of the preparation, the content of the indolinone compound is 0.5-100% by weight, and the indolinone compound includes the compound shown in formula (1) and the compound shown in formula (2) ,
其中，在式(1)和式(2)中，R1和R2相同或不同，各自独立地为H或R，且R为n为0-2的整数，X为氢或卤素。Wherein, in formula (1) and formula (2), R 1 and R 2 are the same or different, each independently is H or R, and R is n is an integer of 0-2, and X is hydrogen or halogen.
根据本发明所述的用于预防和治疗炎性肠病的制剂，优选情况下，所述吲哚啉酮类化合物的含量为5-95重量％。According to the preparation for preventing and treating inflammatory bowel disease of the present invention, preferably, the content of the indolinone compound is 5-95% by weight.
根据本发明所述的用于预防和治疗炎性肠病的制剂，优选所述吲哚啉酮类化合物包括式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物，According to the preparation for preventing and treating inflammatory bowel disease according to the present invention, preferably, the indolinone compounds include compounds represented by formula (3), compounds represented by formula (4), compounds represented by formula (5) The compound shown and the compound shown in formula (6),
特别优选情况下，在本发明所述的用于预防和治疗炎性肠病的制剂中，所述吲哚啉酮类化合物为式(3)所示的化合物，Particularly preferably, in the preparation for preventing and treating inflammatory bowel disease according to the present invention, the indolinone compound is a compound represented by formula (3),
在本发明所述的用于预防和治疗炎性肠病的制剂中，所述制剂可以包括丸剂、膏剂、片剂、口服液剂、皮下注射剂和静脉注射剂中的至少一种。In the preparation for preventing and treating inflammatory bowel disease according to the present invention, the preparation may include at least one of pills, ointments, tablets, oral liquids, subcutaneous injections and intravenous injections.
将含有本发明所述的吲哚啉酮类化合物的药物用于预防和治疗炎性肠病时能够取得很好的预防和治疗效果，而且，本发明所述的含有吲哚啉酮类化合物的药物毒性低、生物利用度高。Good preventive and therapeutic effects can be achieved when the medicine containing the indolinone compound described in the present invention is used for the prevention and treatment of inflammatory bowel disease, and the medicine containing the indolinone compound described in the present invention The drug has low toxicity and high bioavailability.
进一步地，本发明所述的用于预防和治疗炎性肠病的制剂在预防和治疗炎性肠病时具有很好的预防和治疗效果，而且，本发明所述的用于预防和治疗炎性肠病的制剂还具有毒性低和生物利用度高的优点。Further, the preparation for preventing and treating inflammatory bowel disease according to the present invention has a good preventive and therapeutic effect when preventing and treating inflammatory bowel disease, and the preparation for preventing and treating inflammatory bowel disease according to the present invention Preparations for venereal enteropathy also have the advantages of low toxicity and high bioavailability.
以下将通过实施例对本发明进行详细描述。以下实施例中，在没有特别说明的情况下，所使用的各种试剂和材料均来自市售。The present invention will be described in detail below by way of examples. In the following examples, unless otherwise specified, all reagents and materials used are commercially available.
在以下实施例中，所使用的吲哚啉酮类化合物根据CN101314584A中提供的方法制备得到。In the following examples, the indolinone compounds used were prepared according to the method provided in CN101314584A.
葡聚糖硫酸酯钠(DSS)诱导的小鼠炎性肠病(结肠炎)模型是目前应用最为广泛的模型，已经作为IBD及结肠癌研究中的重要工具。本发明在以下实施例中采用DSS诱导的结肠炎模型评价吲哚啉酮类化合物对IBD，特别地，对结肠炎的预防和治疗作用。The mouse inflammatory bowel disease (colitis) model induced by dextran sulfate sodium (DSS) is currently the most widely used model and has been used as an important tool in the research of IBD and colon cancer. In the following examples, the present invention uses a DSS-induced colitis model to evaluate the preventive and therapeutic effects of indolinone compounds on IBD, especially colitis.
在以下实施例中所使用的小鼠购自维通利华实验动物技术有限公司。在以下实施例中，所述小鼠的体重均为各组小鼠的体重平均值±标准差(g)。The mice used in the following examples were purchased from Weitong Lihua Experimental Animal Technology Co., Ltd. In the following examples, the weights of the mice are the mean ± standard deviation (g) of the weights of the mice in each group.
在以下实施例中，疾病指数的评价方法如表1中所示：In the following examples, the evaluation method of the disease index is as shown in Table 1:
表1Table 1
实施例1Example 1
本实施例用于说明本发明所述的式(3)所示的化合物在制备预防炎性肠病的药物中的应用。This example is used to illustrate the application of the compound represented by formula (3) of the present invention in the preparation of medicaments for preventing inflammatory bowel disease.
选50只小鼠，随机分成5组，分别命名为低剂量组、中剂量组、高剂量组、对照组1和对照组2。按照各剂量组的剂量要求，分别取适量式(3)所示的化合物溶于0.5重量％的羧甲基纤维素钠(CMC-Na)水溶液中，按照表2中的剂量采用灌胃方式对各小鼠给药，给药周期为7天，且每天一次，同时，每次对对照组1和对照组2给予相同体积(200微升，下同)的0.5重量％的CMC-Na水溶液进行灌胃处理，按照上述给药方式给药7天后停止给药，改为对低剂量组、中剂量组、高剂量组和对照组1小鼠均给予喂造模水(该造模水中含有3重量％的DSS，下同)7天，而对照组2给予连续正常喂水(该水中不含有DSS，下同)7天，并且每天测量各组小鼠的体重，取各组小鼠的体重平均值±标准差(g)记录于表3中，7天后断颈处死各组小鼠，解剖并检测各组小鼠结肠的平均长度和病理情况，记录于表2中。并且评价处死前各组小鼠的疾病指数(腹泻、大便潜血的综合评价指标)，记录于表2中。50 mice were selected and randomly divided into 5 groups, named as low-dose group, middle-dose group, high-dose group, control group 1 and control group 2, respectively. According to the dosage requirement of each dosage group, get respectively the compound shown in appropriate formula (3) and be dissolved in the aqueous solution of 0.5% by weight of carboxymethylcellulose sodium (CMC-Na), according to the dosage in Table 2, adopt gastric infusion mode to treat Each mouse was administered, and the administration cycle was 7 days, and once a day, at the same time, the 0.5% by weight CMC-Na aqueous solution of the same volume (200 microliters, the same below) was given to the control group 1 and the control group 2 each time. Intragastric treatment, stop administration after 7 days of administration according to the above-mentioned administration method, change to low-dose group, middle-dose group, high-dose group and matched group 1 mice all give and feed modeling water (this modeling water contains 3 % by weight of DSS, the same below) for 7 days, while the control group 2 was given continuous normal water feeding (the water did not contain DSS, the same below) for 7 days, and the body weight of each group of mice was measured every day, and the body weight of each group of mice was obtained The average value ± standard deviation (g) is recorded in Table 3. After 7 days, the mice in each group were killed by neck dislocation. And evaluate the disease index (comprehensive evaluation index of diarrhea and fecal occult blood) of mice in each group before execution, and record them in Table 2.
在上述给式(3)所示的化合物和DSS周期中，每天按正常食量给予各组小鼠喂食并且测量并记录小鼠的体重平均值±标准差(g)。During the period of giving the compound represented by formula (3) and DSS, the mice in each group were fed with normal food every day, and the average body weight ± standard deviation (g) of the mice was measured and recorded.
表2Table 2
表3table 3
实施例2Example 2
本实施例用于说明本发明所述的式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物形成的组合物在制备预防炎性肠病的药物中的应用，其中，在本实施例中，所使用的式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物的用量摩尔比为1：1：1：1。This embodiment is used to illustrate the compound shown in the formula (3) of the present invention, the compound shown in the formula (4), the compound shown in the formula (5) and the composition formed by the compound shown in the formula (6) Application in the preparation of medicines for preventing inflammatory bowel disease, wherein, in this embodiment, the compound represented by formula (3), the compound represented by formula (4), and the compound represented by formula (5) are used The molar ratio of the compound represented by the formula (6) is 1:1:1:1.
本实施例采用与实施例1相同的方法进行，所不同的是，吲哚啉酮类化合物的种类不同，也就是说，实施例1中使用的吲哚啉酮类化合物仅为式(3)所示的化合物，而本实施例中使用的吲哚啉酮类化合物为摩尔比为1：1：1：1的式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物。其余均与实施例1中相同。The present embodiment adopts the same method as Example 1 to carry out, and the difference is that the types of indolinone compounds are different, that is to say, the indolinone compounds used in Example 1 are only formula (3) The compound shown, and the indolinone compound used in the present embodiment is the compound shown in the formula (3) that molar ratio is 1:1:1:1, the compound shown in formula (4), the formula ( A compound represented by 5) and a compound represented by formula (6). All the other are the same as in Example 1.
本实施例中各组小鼠的相应情况列于表4和表5中。The corresponding situation of each group of mice in this embodiment is listed in Table 4 and Table 5.
表4Table 4
表5table 5
从上述实施例1和实施例2的结果可以看出，吲哚啉酮类化合物能够预防结肠炎，并且抑制小鼠体重下降，在给予DSS后预先服用吲哚啉酮类化合物的小鼠的疾病指数明显低于未预先服用吲哚啉酮类化合物的小鼠的疾病指数，并呈现剂量效应相关性。而且，吲哚啉酮类化合物能够抑制DSS引起的小鼠结肠长度缩短。病理检测发现预先服用吲哚啉酮类化合物可抑制DSS诱导的结肠结构破坏及炎细胞浸润。As can be seen from the results of the above-mentioned Example 1 and Example 2, indolinone compounds can prevent colitis, and inhibit the loss of body weight in mice. The index was significantly lower than the disease index of mice not pre-administered indolinone compounds, and showed a dose-effect correlation. Moreover, indolinone compounds can inhibit the shortening of colon length in mice induced by DSS. Pathological examination found that pre-administration of indolinone compounds could inhibit DSS-induced colonic structural destruction and inflammatory cell infiltration.
实施例3Example 3
本实施例用于说明本发明所述的式(3)所示的化合物在制备治疗炎性肠病的药物中的应用。This example is used to illustrate the application of the compound represented by formula (3) of the present invention in the preparation of drugs for treating inflammatory bowel disease.
选50只小鼠，随机分成5组，取1组命名为对照组2，其余4组随机混养并待进一步分组。对对照组2给予连续正常喂水，对其余4组均给予喂造模水(含有3重量％的DSS)，连续7天。7后，将上述混养的4组重新进行随机分组，并且分别命名为低剂量组、中剂量组、高剂量组和对照组1。按照表6中的剂量要求分别对各剂量组进行给药，具体给药方法为：分别取适量式(3)所示的化合物溶于0.5重量％的CMC-Na水溶液中，按照表6中的剂量采用腹腔注射方式(注射量为200微升)分别对低剂量组、中剂量组和高剂量组小鼠进行给药，而对照组1则给予腹腔注射相同体积的0.5重量％的CMC-Na水溶液，给药周期为7天，每天给药一次，对照组2仍然给予正常喂水，每天测量各组小鼠的体重±标准差(g)，记录于表7中。50 mice were selected and randomly divided into 5 groups, one group was named as control group 2, and the remaining 4 groups were mixed randomly and were to be further grouped. The control group 2 was given continuous normal water feeding, and the other 4 groups were given modeling water (containing 3% by weight of DSS) for 7 consecutive days. After 7 days, the above-mentioned 4 groups of mixed culture were re-randomly divided into groups, and named as low-dose group, middle-dose group, high-dose group and control group 1 respectively. According to the dosage requirements in Table 6, each dosage group is administered respectively, and the specific administration method is: respectively take an appropriate amount of compounds shown in formula (3) and dissolve them in 0.5% by weight of CMC-Na aqueous solution, according to Table 6 Dosage adopts intraperitoneal injection mode (injection volume is 200 microliters) to low dose group, middle dose group and high dose group mice are administered respectively, and control group 1 then gives the CMC-Na of 0.5 weight % of same volume Aqueous solution, administration period is 7 days, administration once a day, control group 2 is still given normal water feeding, and the body weight ± standard deviation (g) of each group of mice is measured every day, and is recorded in Table 7.
7天后停止实验，评价各组小鼠的疾病指数于表6中，并断颈处死低剂量组、中剂量组、高剂量组、对照组1和对照组2的小鼠，解剖并检测各组小鼠结肠的平均长度和病理情况，记录于表6中。After 7 days, the experiment was stopped, and the disease index of each group of mice was evaluated in Table 6, and the mice in the low-dose group, the middle-dose group, the high-dose group, the control group 1 and the control group 2 were killed by neck dissection, and each group was dissected and detected The average length and pathological conditions of mouse colon are recorded in Table 6.
表6Table 6
表7Table 7
实施例4Example 4
本实施例用于说明本发明所述的式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物形成的组合物在制备治疗炎性肠病的药物中的应用，其中，在本实施例中，所使用的式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物的用量摩尔比为1：1：1：1。This embodiment is used to illustrate the compound shown in the formula (3) of the present invention, the compound shown in the formula (4), the compound shown in the formula (5) and the composition formed by the compound shown in the formula (6) Application in the preparation of medicines for treating inflammatory bowel disease, wherein, in this embodiment, the compound shown in formula (3), the compound shown in formula (4) and the compound shown in formula (5) are used The molar ratio of the compound represented by the formula (6) is 1:1:1:1.
本实施例采用与实施例3相同的方法进行，所不同的是，吲哚啉酮类化合物的种类不同，也就是说，实施例3中使用的吲哚啉酮类化合物仅为式(3)所示的化合物，而本实施例中使用的吲哚啉酮类化合物为摩尔比为1：1：1：1的式(3)所示的化合物、式(4)所示的化合物、式(5)所示的化合物和式(6)所示的化合物。其余均与实施例3中相同。This embodiment adopts the same method as Example 3 to carry out, the difference is that the types of indolinone compounds are different, that is to say, the indolinone compounds used in Example 3 are only formula (3) The compound shown, and the indolinone compound used in the present embodiment is the compound shown in the formula (3) that molar ratio is 1:1:1:1, the compound shown in formula (4), the formula ( A compound represented by 5) and a compound represented by formula (6). All the other are the same as in Example 3.
本实施例中各组小鼠的相应情况列于表8和表9中。即，表8为各组小鼠给吲哚啉酮类化合物的剂量、在实验周期中的疾病指数以及解剖后获得的结肠平均长度和病理情况；表9表示各组小鼠在给药吲哚啉酮类化合物的周期中每天的体重平均值±标准差(g)。The corresponding situation of each group of mice in this embodiment is listed in Table 8 and Table 9. That is, Table 8 shows the dose of indolinone compounds given to mice in each group, the disease index in the experimental cycle, and the average colon length and pathological conditions obtained after dissection; Table 9 shows that mice in each group were treated with indole Body weight mean ± standard deviation (g) per day during the phenone period.
表8Table 8
表9Table 9
从上述实施例3和实施例4的结果可以看出，吲哚啉酮类化合物能够治疗结肠炎，并且抑制小鼠体重下降，在给予DSS后，各组小鼠的体重普遍降低，而且疾病指数高，而在给药吲哚啉酮类化合物后，能够明显抑制小鼠的体重降低并且在给药吲哚啉酮类化合物的周期的后期能够明显使得小鼠的体重增加，而疾病指数明显降低，并呈现剂量效应相关性。而且，吲哚啉酮类化合物能够治疗由DSS引起的小鼠结肠长度缩短。病理检测发现吲哚啉酮类化合物可治疗由DSS诱导的结肠结构破坏及炎细胞浸润。As can be seen from the results of the above-mentioned Example 3 and Example 4, indolinone compounds can treat colitis and inhibit the weight loss of mice. After giving DSS, the body weight of mice in each group generally decreased, and the disease index High, and after the administration of indolinone compounds, it can significantly inhibit the weight loss of mice and can significantly increase the body weight of mice in the later period of the cycle of administration of indolinone compounds, while the disease index is significantly reduced , and showed a dose-effect correlation. Furthermore, indolinones were able to treat the shortened colon length in mice induced by DSS. Pathological examination found that indolinone compounds can treat colon structural destruction and inflammatory cell infiltration induced by DSS.
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention. These simple modifications All belong to the protection scope of the present invention.
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。In addition, it should be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way if there is no contradiction. The combination method will not be described separately.
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。In addition, various combinations of different embodiments of the present invention can also be combined arbitrarily, as long as they do not violate the idea of the present invention, they should also be regarded as the disclosed content of the present invention.
Claims (10)
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| CN107773559A (en) * | 2016-08-31 | 2018-03-09 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Application of the indoline ketone compounds in the medicine for preparing prophylactic treatment pulmonary fibrosis and the preparation for prophylactic treatment pulmonary fibrosis |
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