CN112969464A - 用于预防或治疗干燥综合征的组合物 - Google Patents
用于预防或治疗干燥综合征的组合物 Download PDFInfo
- Publication number
- CN112969464A CN112969464A CN201980069731.2A CN201980069731A CN112969464A CN 112969464 A CN112969464 A CN 112969464A CN 201980069731 A CN201980069731 A CN 201980069731A CN 112969464 A CN112969464 A CN 112969464A
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- CN
- China
- Prior art keywords
- acid
- alkyl
- oxo
- chlorobenzoylamino
- dihydroquinolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000003254 radicals Chemical class 0.000 claims description 39
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
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- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 6
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Abstract
本发明涉及用于预防或治疗干燥综合征的组合物,根据本发明的一实施方式的用于预防或治疗干燥综合征的组合物包含由特定的化学式表示的化合物或其药剂学上可接受的盐,并具有预防或治疗干燥综合征的效果。
Description
技术领域
本发明涉及用于预防或治疗干燥综合征的组合物。
背景技术
干燥综合征(Sjogren's syndrome)是外分泌腺的慢性炎症性疾病,其尤其以唾腺和泪腺的正常组织被破坏,导致眼泪和唾液的生成减少为特征。该疾病于1888年首次由Johann Mikulicz报告,1933年,瑞典的眼科医生Henrik Sjogren通过患有类风湿性关节炎的患者描述了本疾病,本疾病由此得名。
该疾病的主要症状有口眼干燥,但是除了侵犯唾腺和泪腺以外,还可侵犯皮肤及支气管、女性的阴道粘膜、肺和肾脏,由此引起多种症状。
干燥综合征有时还伴随类风湿性关节炎、全身性红斑性狼疮、硬皮症或皮肤肌炎之类的其他类风湿性疾病,此时被称为继发性干燥综合征。另一方面,在没有特定的类风湿性疾病的情况下出现干燥综合征的各种症状时,被称为原发性干燥综合征。伴随继发性干燥综合征的最常见的疾病是类风湿性关节炎,15%左右的类风湿性关节炎患者伴有干燥综合征。
干燥综合征的女性发病率比男性高约9倍,中年女性易患干燥综合征,预计发病率为每1万名女性人口当中有8名左右。
干燥综合征的病因尚未完全明确,但是目前被认为与多种因素相关,据报道,其原因在于,如家族史的遗传因素和病菌、细胞因子以及自身免疫抗体。
目前,尚未公开根治该疾病的方法,治疗的主要目的在于,症状的缓解与并发症的预防。具体治疗方法根据原发性或继发性等症状的严重程度而不同。
韩国公开专利第10-2018-0084153号涉及具有BTK抑制活性的嘧啶及吡啶化合物的组合物及制备方法,作为其治疗用途,公开了包括癌症、狼疮、过敏疾病、斯耶格伦氏病(Sjogren's disease)及类风湿性关节炎的过度增生性疾病。
韩国公开专利第10-2018-0049144号公开具有非常高的皮肤及膜渗透率的非甾体抗炎类药(NSAIA)药物前驱体及其新医药用途。
(专利文献1)韩国公开专利第10-2018-0084153号
(专利文献2)韩国公开专利第10-2018-0049144号
发明内容
技术问题
本发明的目的在于,提供用于预防或治疗干燥综合征的组合物。但是,本发明要解决的问题并不限定于以上描述的问题,本领域普通技术人员将通过以下的记载内容明确理解未描述的其他问题。
技术方案
本发明的一实施方式,提供包含由以下化学式1表示的化合物或其药剂学上可接受的盐的用于预防或治疗干燥综合征的组合物。
[化学式1]
在上述式中,
X为氧、氮或硫中的任一个;
Y为C1-C6烷基、C1-C6卤代烷基、(C1-C3烷氧基)C1-C6烷基、(C2-C6烯氧基)C1-C6烷基、(C1-C6烷基羰基氧基)C1-C6烷基、(C1-C6烷基硫烷基)C1-C6烷基、(芳基硫烷基)C1-C6烷基、(芳基磺酰基)C1-C6烷基、(C1-C6烷基氨基)C1-C6烷基、[(C1-C6烷基)(C1-C6烷基)氨基]C1-C6烷基、[(C1-C3烷基)(芳基)氨基]C1-C6烷基、[(C1-C3烷基)(芳基)C1-C3烷基]氨基C1-C6烷基、[(C1-C3烷基)(杂芳基)氨基]C1-C6烷基、(芳基羰基氨基)C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6氧代烷基、C3-C8环烷基、(C3-C8环烷基)C1-C6烷基、(C3-C8环烯基)C1-C6烷基、(C3-C8杂环烷基)C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基]C1-C6烷基、[(芳基)C1-C3烷基]C3-C8杂环烷基C1-C6烷基、[(C1-C6烷氧基羰基)C3-C8杂环烷基]C1-C6烷基、[(C1-C3烷氧基羰基)C3-C8杂环烷基]C1-C6烷基、(C3-C8杂环烷基)C1-C6烯基、[(C1-C3烷基)C3-C8杂环烯基]C1-C6烷基、(芳基)C1-C6烷基、[(C1-C3烷基)芳基]C1-C6烷基、[(C1-C3烷氧基)芳基]C1-C6烷基、[(芳基氧基)芳基]C1-C6烷基、[(C1-C3烷基硫烷基)芳基]C1-C6烷基、[(C1-C3烷氧基羰基)芳基]C1-C6烷基、[(芳基氧基羰基)芳基]C1-C6烷基、(芳基)C3-C6烯基、(杂芳基)C1-C6烷基、[(烷氧基羰基)杂芳基]C1-C6烷基、[(C1-C3烷基)C3-C8杂芳基]C1-C6烷基、[(C3-C8环烷基)杂芳基]C1-C6烷基、[(芳基)杂芳基]C1-C6烷基、[(C1-C3烷基)杂芳基]C1-C6烷基、[(芳基)C1-C3烷基]杂芳基C1-C6烷基、(C1-C6烷氧基羰基)C1-C6烷基、[(C3-C8杂环烷基)C1-C6烷氧基羰基]C1-C6烷基、(C3-C8杂环烷基羰基)C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基羰基]C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基羰基]C1-C6烷基、[(C3-C8环烷基)氧基羰基氧基]C1-C6烷基、[(C3-C8杂环烷基)氧基羰基氧基]C1-C6烷基、(脲基)C1-C6烷基、(芳基脲基)C1-C6烷基、[(芳基)(C1-C3烷基脲基]C1-C6烷基、(C1-C6烷基氨基羰基)C1-C6烷基、[(C3-C8杂环烷基)氨基羰基]C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基]氨基羰基C1-C6烷基、[(C1-C3烷基)(C1-C3烷氧基)氨基羰基]C1-C6烷基或(氧代C3-C8杂环烷基)C1-C6烷基,
此时,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6氧代烷基、C3-C8环烷基、C3-C8环烯基、C3-C8杂环烯基、芳基或杂芳基能够以选自由C1-C3烷基、氟代、氯代、溴代、羟基、氧代、硝基及氰基组成的组的一种以上取代基取代。
根据本发明的一实施方式,所述盐可以是由药剂学上可接受的游离酸(freeacid)形成的酸加成盐。
根据本发明的一实施方式,所述游离酸可以是有机酸或无机酸。
根据本发明的一实施方式,所述有机酸可选自由柠檬酸、醋酸、乳酸、酒石酸、马来酸、延胡索酸、甲酸、丙酸、草酸、二氯乙酸、三氟乙酸、己二酸、抗坏血酸、苯甲酸、4-乙酰氨基苯甲酸、葡萄糖酸、磺酸、甲磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、环拉酸、十二烷基磺酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、半乳糖二酸、龙胆酸、戊二酸、2-氧代戊二酸、甘油磷酸、马尿酸、油酸、乳清酸、棕榈酸、扑酸、焦谷氨酸、皮脂酸、硬脂酸、硫代氰酸、十一烯酸、异丁酸、月桂酸、扁桃酸、萘-1,5-二磺酸、萘-2-磺酸、萘甲酸、烟酸、乙醇酸、琥珀酸、4-甲苯磺酸、樟脑磺酸、谷氨酸、天冬氨酸、水杨酸、4-氨基水杨酸、丙二酸、苹果酸及苯并磺酸组成的组,所述无机酸可选自由盐酸、溴酸、硫酸、硝酸及磷酸组成的组。
根据本发明的一实施方式,所述化学式1的化合物的药剂学上可接受的盐可选自:
1)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙醇酸酯;
2)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乳酸酯;
3)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯水杨酸酯;
4)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯草酸酯;
5)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯丙二酸酯;
6)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苹果酸酯;
7)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯酒石酸酯;
8)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯马来酸酯;
9)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯延胡索酸酯;
10)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯柠檬酸酯;
11)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苯磺酸酯;
12)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲苯磺酸酯;
13)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯盐酸盐;
14)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硫酸酯;
15)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯磷酸酯;
16)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙酸酯;
17)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯二氯乙酸酯;
18)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯己二酸酯;
19)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯抗坏血酸酯;
20)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苯甲酸酯;
21)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯4-乙酰氨基苯甲酸酯;
22)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯癸酸酯;
23)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯己酸酯;
24)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯辛酸酯;
25)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯碳酸酯;
26)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯肉桂酸酯;
27)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯环拉酸酯;
28)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯十二烷基磺酸酯;
29)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙烷-1,2-二磺酸酯;
30)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙烷磺酸酯;
31)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-羟基乙烷磺酸酯;
32)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲酸酯;
33)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯半乳糖二酸酯;
34)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯龙胆酸酯;
35)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯谷氨酸酯;
36)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯戊二酸酯;
37)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-氧代戊二酸酯;
38)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甘油磷酸酯;
39)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯马尿酸酯;
40)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯油酸酯;
41)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乳清酸酯;
42)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯棕榈酸酯;
43)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯扑酸酯;
44)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯丙酸酯;
45)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯焦谷氨酸酯;
46)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯4-氨基水杨酸酯;
47)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯皮脂酸酯;
48)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硬脂酸酯;
49)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硫代氰酸酯;
50)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯十一烯酸酯;
51)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯氢溴酸酯;
52)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯异丁酸酯;
53)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯月桂酸酯;
54)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯DL-扁桃酸酯;
55)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲磺酸酯;
56)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯萘-1,5-二磺酸酯;
57)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯萘-2-磺酸酯;
58)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-萘甲酸酯;
59)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯烟酸酯;
60)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硝酸酯;
61)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯琥珀酸酯;
62)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯;以及
63)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯L-天冬氨酸酯。
根据本发明的一实施方式,所述组合物还可包含载体、赋形剂、稀释剂、填充剂、抗凝剂、润滑剂、湿润剂、香料、乳化剂或防腐剂。
根据本发明的一实施方式,所述组合物能够配置成粉末、颗粒剂、片剂、乳剂、糖浆剂、气雾剂、软明胶胶囊或硬明胶胶囊、无菌注射剂或无菌粉末的形式配置。
根据本发明的一实施方式,所述组合物可增加泪液量及唾液分泌量。
根据本发明的一实施方式,所述组合物可减少泪腺及唾腺组织内免疫细胞衍生的炎症性细胞因子和趋化性细胞因子的mRNA表达量。
根据本发明的一实施方式,所述组合物可激活组成唾腺和泪腺组织的细胞的生存及生长。
发明的效果
根据本发明的一实施方式的用于预防或治疗干燥综合征的组合物可增加泪液量和唾液(saliva)分泌量,并可减少泪腺、唾腺组织内免疫细胞衍生的炎症性细胞因子和趋化性细胞因子的mRNA表达量。
并且,根据本发明的一实施方式的用于预防或治疗干燥综合征的组合物,可减少唾腺和泪腺组织内的细胞因子蛋白质表达量,可缓解炎症,并且具有使细胞的生长增加等组织再生能力,从而可缓解干燥综合征的发病,因此可以以预防或治疗干燥综合征为目的来使用。
附图说明
图1为表示干燥综合征疾病模型的泪液量的图表。
图2为表示干燥综合征疾病模型的唾液分泌量的图表。
图3为IL-17A和p-AKT的蛋白质表达和定量结果。
图4a及图4b为炎症性及趋化性细胞因子(pro-inflammatory cytokines andchemotactic cytokines)的mRNA的定量结果。
图5为表示血浆(plasma)内IL-17A和自身抗体(autoantibodies)(抗SSA/Ro,抗SSB/La)的蛋白质表达的结果。
图6为表示疾病动物模型的炎症程度表现类型变化的照片。
图7是对表现类型变化进行评分并以疾病谱(disease score)评价的结果。
具体实施方式
以下,详细说明本发明,使得本发明所属技术领域的普通技术人员可容易实施。
本发明能够以多种不同的形态实现,且不局限于在此说明的实例及实施例。
在本发明说明书全文中,当一个部分“包括”一个结构要素时,除非有特别相反的记载,则意味着还可包括其他结构要素,而不是排除其他结构要素。在本发明说明书全文中使用的术语“约”、“实质上”等示出了对所提及的含义有固有的制造及物质允许公差时,以该数值或接近于其数值的含义使用,以防止不道德的侵权人不当地利用为了帮助理解本发明而提及的准确或绝对的数值的公开内容。在本发明说明书全文中使用的术语“~(的)步骤”或“~的步骤”不意味着“用于~的步骤”。
在本发明说明书全文中,马库什(Markush)形式的表现中所含的“它们的组合”这一术语意味着选自由马库什形式的表现中所记载的多个结构要素组成的组中的一种以上的混合或组合,意味着包括选自由所述多个结构要素组成的组中的一种以上。
在本发明说明书全文中,“A和/或B”这一记载意味着“A或B,或者A及B”。
本发明中使用的术语"杂环烷基"或"杂环烯基"是指由氮、氧或硫中的任一个代替饱和碳进行取代,或者一个、两个或三个相同原子或不同原子相邻或不相邻地取代。作为所述杂环烷基或杂环烯基的例子,可列举氮丙啶、环氧乙烷、氮杂环丁烷、氧杂环丁烷、吡咯烷、吡咯啉、吡唑烷、吡唑啉、咪唑烷、咪唑啉、三唑烷、噁唑烷、四氢呋喃、四氢噻吩、噻唑烷、二氧戊环、间二氧杂环戊烯、氧硫杂环戊烷、吗啉、硫代吗啉、二噻烷、哌啶、哌嗪、吡喃、二噁烷或氮杂环庚烷,但不限定于此。
并且,本发明中使用的术语"芳基"的具体示例,可列举苯、萘、蒽或菲,但不限定于此。进而,本发明中使用的术语"杂芳基"是指由氮、氧或硫中的任一个取代,或者单一、两个或三个相同原子或不同原子相邻或不相邻地取代的芳基。作为所述杂芳基的具体示例,可列举吡咯、咪唑、吡唑、三唑、呋喃、噻吩、噁唑、异噁唑、噻唑、异噻唑、噁二唑、噻二唑、吡啶、嘧啶、吡嗪、哒嗪、三嗪、吖庚因、吲哚、苯并咪唑、吲唑、苯并噁唑、苯并异噁唑、苯并噻唑、苯并三唑、苯并呋喃、苯并噻吩、喹啉、异喹啉、喹喔啉、喹唑啉、噌啉、萘啶、酞嗪、苯并吡喃、苯并噁嗪、苯并三嗪、色烷、色烯、苯并二噁烷,吖啶、吩噻嗪、吩噁嗪或咔唑,但不限定于
本发明涉及用于预防或治疗干燥综合征的组合物,根据本发明的用于预防或治疗干燥综合征的组合物可包含由以下化学式1表示的化合物或其药剂学上可接受的盐。
干燥综合征是炎症细胞渗入到泪腺和唾腺等,引起不明原因的慢性炎症的自体免疫性疾病。据悉,这种疾病由于人体防御系统的免疫系统失控而产生。因此,炎症细胞渗入到用于保持身体湿度的分泌腺的泪腺、唾腺等,破坏正常细胞,从而导致无法继续保持其功能。根据本发明的一实施方式的组合物可进行口服,由此可增加泪液量和唾液(saliva)分泌量,并可减少泪腺、唾腺组织内免疫细胞衍生的炎症性细胞因子和趋化性细胞因子的mRNA表达量。并且,可减少唾腺和泪腺组织内的细胞因子蛋白质表达量,可缓解炎症,并且具有使细胞的生长增加等组织再生能力,从而可缓解干燥综合征的发病,因此可以使用为干燥综合征的治疗剂。
以下,更具体说明本发明的一实施方式的用于预防或治疗干燥综合征的组合物的成分及特征。
根据本发明的一实施方式的用于预防或治疗干燥综合征的组合物可包含由以下化学式1表示的化合物或其药剂学上可接受的盐。
[化学式1]
在上述式中,
X为氧、氮或硫中的任一个;
Y可以是C1-C6烷基、C1-C6卤代烷基、(C1-C3烷氧基)C1-C6烷基、(C2-C6烯氧基)C1-C6烷基、(C1-C6烷基羰基氧基)C1-C6烷基、(C1-C6烷基硫烷基)C1-C6烷基、(芳基硫烷基)C1-C6烷基、(芳基磺酰基)C1-C6烷基、(C1-C6烷基氨基)C1-C6烷基、[(C1-C6烷基)(C1-C6烷基)氨基]C1-C6烷基、[(C1-C3烷基)(芳基)氨基]C1-C6烷基、[(C1-C3烷基)(芳基)C1-C3烷基]氨基C1-C6烷基、[(C1-C3烷基)(杂芳基)氨基]C1-C6烷基、(芳基羰基氨基)C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6氧代烷基、C3-C8环烷基、(C3-C8环烷基)C1-C6烷基、(C3-C8环烯基)C1-C6烷基、(C3-C8杂环烷基)C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基]C1-C6烷基、[(芳基)C1-C3烷基]C3-C8杂环烷基C1-C6烷基、[(C1-C6烷氧基羰基)C3-C8杂环烷基]C1-C6烷基、[(C1-C3烷氧基羰基)C3-C8杂环烷基]C1-C6烷基、(C3-C8杂环烷基)C1-C6烯基、[(C1-C3烷基)C3-C8杂环烯基]C1-C6烷基、(芳基)C1-C6烷基、[(C1-C3烷基)芳基]C1-C6烷基、[(C1-C3烷氧基)芳基]C1-C6烷基、[(芳基氧基)芳基]C1-C6烷基、[(C1-C3烷基硫烷基)芳基]C1-C6烷基、[(C1-C3烷氧基羰基)芳基]C1-C6烷基、[(芳基氧基羰基)芳基]C1-C6烷基、(芳基)C3-C6烯基、(杂芳基)C1-C6烷基、[(烷氧基羰基)杂芳基]C1-C6烷基、[(C1-C3烷基)C3-C8杂芳基]C1-C6烷基、[(C3-C8环烷基)杂芳基]C1-C6烷基、[(芳基)杂芳基]C1-C6烷基、[(C1-C3烷基)杂芳基]C1-C6烷基、[(芳基)C1-C3烷基]杂芳基C1-C6烷基、(C1-C6烷氧基羰基)C1-C6烷基、[(C3-C8杂环烷基)C1-C6烷氧基羰基]C1-C6烷基、(C3-C8杂环烷基羰基)C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基羰基]C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基羰基]C1-C6烷基、[(C3-C8环烷基)氧基羰基氧基]C1-C6烷基、[(C3-C8杂环烷基)氧基羰基氧基]C1-C6烷基、(脲基)C1-C6烷基、(芳基脲基)C1-C6烷基、[(芳基)(C1-C3烷基脲基]C1-C6烷基、(C1-C6烷基氨基羰基)C1-C6烷基、[(C3-C8杂环烷基)氨基羰基]C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基]氨基羰基C1-C6烷基、[(C1-C3烷基)(C1-C3烷氧基)氨基羰基]C1-C6烷基或(氧代C3-C8杂环烷基)C1-C6烷基。
所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6氧代烷基、C3-C8环烷基、C3-C8环烯基、C3-C8杂环烯基、芳基或杂芳基能够以选自由C1-C3烷基、氟代、氯代、溴代、羟基、氧代、硝基及氰基组成的组的一种以上取代基取代。
在本发明中,X-Y表示氨基酸或氨基酸(C1-C3烷基)酯。氨基酸是指甘氨酸、亮氨酸、甲硫氨酸、缬氨酸、丙氨酸、异亮氨酸、脯氨酸、色氨酸、苯丙氨酸、丝氨酸、苏氨酸、天门冬酰胺、谷氨酸、赖氨酸、组胺酸或酪氨酸,但不限于此。
根据本发明的用于预防或治疗干燥综合征的组合物包含由所述化学式1表示的化合物或其药剂学上可接受的盐,由此通过实验确认了对干燥综合征的预防或治疗有效果。
由所述化学式1表示的化合物是瑞巴派特前药(rebamipide prodrug),其为体内吸收率相比于瑞巴派特(rebamipide)更突出的结构。
根据本发明的一实施方式的由所述化学式1表示的化合物的药剂学上可接受的盐可以是由药剂学上可接受的游离酸(free acid)形成的酸加成盐。作为所述游离酸可使用有机酸和无机酸。所述有机酸包含柠檬酸、醋酸、乳酸、酒石酸、酒石酸,马来酸、延胡索酸、甲酸、丙酸、草酸、二氯乙酸、三氯乙酸、三氟乙酸、己二酸、抗坏血酸、苯甲酸、4-乙酰氨基苯甲酸、葡萄糖酸、磺酸、甲磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、环拉酸、十二烷基磺酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、半乳糖二酸、龙胆酸、戊二酸、2-氧代戊二酸、甘油磷酸、马尿酸、油酸、乳清酸、棕榈酸、扑酸、焦谷氨酸、皮脂酸、硬脂酸、硫代氰酸、十一烯酸、异丁酸、月桂酸、扁桃酸、萘-1,5-二磺酸、萘-2-磺酸、萘甲酸、烟酸、乙醇酸、琥珀酸、4-甲苯磺酸、樟脑磺酸、谷氨酸、天冬氨酸、水杨酸、4-氨基水杨酸、丙二酸、苹果酸及苯并磺酸,但不限定于此。并且,所述无机酸包含盐酸、溴酸、硫酸、硝酸、碘酸及磷酸,但不限定于此。
根据本发明的一实施方式,作为所述瑞巴派特前药的盐化合物可列举以下盐化合物,但不限定于此。
1)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙醇酸酯;
2)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乳酸酯;
3)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯水杨酸酯;
4)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯草酸酯;
5)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯丙二酸酯;
6)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苹果酸酯;
7)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯酒石酸酯;
8)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯马来酸酯;
9)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯延胡索酸酯;
10)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯柠檬酸酯;
11)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苯磺酸酯;
12)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲苯磺酸酯;
13)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯盐酸盐;
14)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硫酸酯;
15)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯磷酸酯;
16)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙酸酯;
17)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯二氯乙酸酯;
18)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯己二酸酯;
19)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯抗坏血酸酯;
20)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苯甲酸酯;
21)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯4-乙酰氨基苯甲酸酯;
22)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯癸酸酯;
23)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯己酸酯;
24)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯辛酸酯;
25)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯碳酸酯;
26)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯肉桂酸酯;
27)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯环拉酸酯;
28)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯十二烷基磺酸酯;
29)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙烷-1,2-二磺酸酯;
30)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙烷磺酸酯;
31)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-羟基乙烷磺酸酯;
32)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲酸酯;
33)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯半乳糖二酸酯;
34)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯龙胆酸酯;
35)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯谷氨酸酯;
36)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯戊二酸酯;
37)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-氧代戊二酸酯;
38)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甘油磷酸酯;
39)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯马尿酸酯;
40)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯油酸酯;
41)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乳清酸酯;
42)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯棕榈酸酯;
43)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯扑酸酯;
44)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯丙酸酯;
45)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯焦谷氨酸酯;
46)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯4-氨基水杨酸酯;
47)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯皮脂酸酯;
48)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硬脂酸酯;
49)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硫代氰酸酯;
50)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯十一烯酸酯;
51)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯氢溴酸酯;
52)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯异丁酸酯;
53)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯月桂酸酯;
54)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯DL-扁桃酸酯;
55)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲磺酸酯;
56)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯萘-1,5-二磺酸酯;
57)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯萘-2-磺酸酯;
58)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-萘甲酸酯;
59)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯烟酸酯;
60)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硝酸酯;
61)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯琥珀酸酯;
62)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯;以及
63)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯L-天冬氨酸酯。
根据本发明的一实施方式,由所述化学式1表示的化合物可由以下化学式1-1至1-6中的任一个表示。
[化学式1-1]
[化学式1-2]
[化学式1-3]
[化学式1-4]
[化学式1-5]
[化学式1-6]
另一方面,根据本发明的化学式1的化合物的药剂学上可接受的盐可由将以下化学式2的化合物与以下化学式3的化合物进行反应而制备的化学式1的化合物制得。
[化学式2]
[化学式3]
Y-Z
在上述式中,
X及Y如上所述,Z为羟基、氨基、胺、卤素或离去基(Leaving group)。
*在本发明的一实施方式中,Z为羟基、-NH2、Cl、Br、烷基磺酰基或芳基磺酰基。
具体地,根据本发明的化学式1的化合物的药剂学上可接受的盐可由通过以下[反应式1]中标记的方法制备的化学式1的化合物制得,但是不限定于此。
[反应式1]
(在上述式中,X为氧、氮或硫中的任一个)
在所述[反应式1]中用作起始物质的[化学式2]的化合物可通过美国专利第4,578,381号中描述的方法来制备。所述[反应式1]中标记的无机盐可以是碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钾或碳酸铯之类的无机碱,溶剂可以是丙酮、二甲基甲酰胺、二甲基亚砜或乙腈,反应可在10至100℃下进行1至24小时。在所述反应式中,DCC是指二环己基碳二亚胺;DMAP是指4-二甲氨基吡啶;HOBT是指1-羟基苯并三唑;以及EDCI是指1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸,Y-OMs或Y-OTs包含如磺酰基、甲磺酰基之类的烷基磺酰基;或者对甲苯磺酰基、苯磺酰基或4-硝基苯磺酰基之类的芳基磺酰基。
在所述[反应式1]中,X为硫的[化学式2]的化合物可根据以下[反应式2]的过程制备。
[反应式2]
在所述[反应式2]中,硫氢化钠可使用1至10当量,优选地可使用4至6当量,硫化钠可使用1至5当量,优选地可使用2至3当量。在所述[反应式2]中,溶剂可使用二甲基甲酰胺、二甲基亚砜或乙腈,反应可在10至100℃下进行1至24小时反应。在所述反应式中,NCS指称N-氯代琥珀酰亚胺。
根据本发明的由化学式1表示的化合物或其盐的药剂学有效剂量可以是每日0.5~100mg/kg体重,具体可以为每日1~30mg/kg体重。但是,药剂学有效量可根据疾病症状的程度、患者的年龄、体重、健康状态、性别、给药途径及治疗时间等而适当变化。
并且,本发明的组合物还可包含药剂学上可接受的添加剂。所述“药剂学上可接受的”是指在生理学上可接受,当给予人体时,通常不引起胃肠障碍、晕眩症等过敏性反应或与其类似的反应。所述添加剂的例如可以为载体、赋形剂及稀释剂等。所述载体、赋形剂及稀释剂的例如可以为乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油。并且,还可包含填充剂、抗凝剂、润滑剂、湿润剂、香料、乳化剂及防腐剂等。
并且,本发明的药剂学组合物可使用本领域公知的方法配置成制剂,以便在给予哺乳动物之后实现活性成分的快速、持续或延迟的释放。制剂可以是散剂、颗粒、片剂、乳液、糖浆、气雾剂、软明胶胶囊或硬明胶胶囊、无菌注射剂、无菌粉末的形态。
本发明的药剂学组合物可通过包括口服、经皮、皮下、静脉或肌肉注射的多种途径进行给药,活性成分的给药量可根据给药途径、患者的年龄、性别、体重及患者的严重程度等多种因素来适当选择,根据要治疗的疾病的种类,可与公知的对上述疾病有预防或治疗用途的化合物相结合而给药。
以下,利用干燥综合征的疾病模型(Nfkbiz-/-or IkB-ξ-deficient mice,C57BL/6),具体说明根据本发明的一实施方式的基于组合物的口服给药的抗炎功效及组织再生等功效的确认实验。
1.实验准备
1.1实验动物及条件
从首尔峨山医院收到7-12周龄的干燥综合征自体免疫性疾病模型(Nfkbiz-/-orIkB-ξ-deficient male mice,C57BL/6)进行了实验。动物实验室的环境温度为25±5℃,湿度为55-70%,并且进行12小时光照/12小时黑暗处理。自由摄取灭菌的卧草、实验动物用颗粒(pellet)型固体饲料Teklad 2018S(Envigo,sterilizable)以及灭菌净化水。收到实验动物后,立即称重,并考虑到周龄以及干燥综合征表现类型进行分组筛选。本研究中的所有动物实验在三进制药(株)内部动物实验伦理委员会的批准(批准号;SJ-2016-001)之下按照标准操作流程(Standard Operation Procedures)执行。
1.2实验道具及试剂
-实验道具:灭菌笼子、灭菌水、加湿器、除湿器、恒温恒湿计、1cc注射器、记号笔、天平、20ml小瓶、探空仪(进料针)、手术道具、电子管、解剖显微镜、无尘工作台、微量吸管。
-试剂及材料:酚红棉线(Zone-Quick;Oasis Glendora,CA)、iQ SYBR Green超混液(Bio-rad)、cDNA转换试剂盒(BR170-8891,Bio-rad)、阿法沙龙(麻醉剂)、磷酸化Akt(S473)抗体(Cell signaling,#4060)、IL-17A抗体(Santacruz,#sc-374218)、β-肌动蛋白抗体(sigma aldrich,#A5316)、盐酸匹罗卡品(sigma,P6503)、肝素(绿十字株式会社)
-RIPA裂解液(50mM Tris-Cl pH7.4、150mM NaCl、1mM EDTA、1%Triton X-100、0.1%SDS、1%去氧硫酸钠、0.5mM苯甲基磺酰氟、2ug/ml亮肽素、2ug/ml抑肽酶、10mM NaF和1mM原钒酸钠)
-ELISA试剂盒:IL-17A(Signosis,#EA-2516)、抗SSA(Signosis,#EA-5202)、抗SSB(Signosis,#EA-5204)
1.3.实验组及赋形剂组成
【表1】
装备(Arms) | 指定的干预措施(Assigned Interventions) |
安慰剂比较器(N/C,Ctrl) | 药物:安慰剂(vehicle,3%吐温80) |
活性比较器SA001(80mg/kg b.i.d) | 药物:SA001每天口服2次,服用5周 |
所述SA001为2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯丙二酸酯,其通过如下方法制备。
使2-吗啉-4-基乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯1g(2.07mmol)及丙二酸0.22g(2.07mmol)进行反应,获得白色固体的标题化合物(1.1g)。
1H-核磁共振(400MHz,DMSO-d6):11.71(s,1H),9.06(d,1H),7.83(t,3H),7.59(s,1H),7.56(s,1H),7.52(t,1H),7.32(d,1H),7.24(t,1H),6.46(s,1H),4.77(m,1H),4.24(m,2H),3.51-3.46(m,5H),3.29(q,1H),3.19(s,2H),2.70-2.61(m,2H),2.51(t,2H),2.47(br-s,4H)
2.实验方法
2.1给药方法及给药时间
:口服给药(oral administration,P.O),一天两次(10h,16h),给药5周(35天)
2.2麻醉(I.V)
:阿法沙龙(13mg/kg;PBS diluted)
2.3泪液量测定(Schirmer test)
将动物麻醉1分钟之后,使用酚红棉线(Zone-Quick;Oasis,Glendora,CA)测定了泪液量。将一端放在动物眼睛的外眼角下眼睑,搁置60秒,通过毛细管现象使泪液润湿之后,测定了发生颜色变化的线的长度(mm)。当泪液分泌量减少时,将促进由于因干燥综合征导致的干眼症,因此可以确定,分泌量越多,受试物质的效果就越大。
2.4唾液分泌量测定(Saliva Flow Rate)
每只动物腹腔注射100ul(腹膜内注射)酸盐毛果芸香碱盐(Sigma,P6503,PBS中使之配成1mg/ml的浓度,在4℃下保管),2分钟之后麻醉,用微量移液管(micro pipet)收集(collecting)唾液(saliva)3分钟,由此测定了唾液分泌量。
*唾液流速(μL/minute)=唾液(μL)/3
2.5泪腺及唾腺组织的分离和蛋白质表达定量(免疫印迹分析,Immuno Blottinganalysis)
分离试验动物的泪腺和唾腺组织,放入PBS,实施均质化(在冰上)。将粉碎的组织分别放入RIPA裂解液(50mM Tris-Cl pH7.4、150mM NaCl、1mM EDTA、1%Triton X-100、0.1%SDS、1%去氧硫酸钠、0.5mM苯甲基磺酰氟、2ug/ml亮肽素、2ug/ml抑肽酶、10mM NaF和1mM原钒酸钠)1ml中,反应5分钟(在冰上)。离心分离(13000rpm,20mins),仅取下上清液之后,校正蛋白质。将样品放入抗Akt(1:400)和抗白介素17A(1:200)抗体中,在免疫共沉淀(IP)(过夜)之后取样。对每个样品实施SDS-PAGE,转移到聚偏氟乙烯膜(PVDF)上,使Akt-IP样品的磷酸化Akt(S473)以及IL-17A-IP样品的IL-17A原发性抗体在封闭缓冲液(TBS+吐温20)+0.1%脱脂乳中以1:100,000的比率在4℃下过夜反应,对HRP共轭的二级抗体(HRP-conjugated secondary antibody)进行反应处理后,最终在暗室利用ECL溶液发光,暴露于X射线胶片(X-ray film)进行定量。
2.6泪腺及唾腺组织内总mRNA的分离和定量(quantitative RT-PCR)
通过使用TRIzol的制造商的实验方案(manufacturer's protocol)来分离总RNA,利用反转录系统(reverse transcription system)将用PBS粉碎的组织的一半转化为cDNA(iScript cDNA合成BR170-8891,Bio-Rad,U.S)。利用实时聚合酶链式反应,对mRNA进行定量。PCR中使用的引物由专业制造公司Bionic株式会社(Seoul,Korea)订购及合成。订购的引物为小鼠细胞因子;IL-2(正向5'-TTG AGT GCC AAT TCG ATG AT-3'和反向5'-TTG AGGGCT TGT TGA GAT GA-3')、IL-17A(正向5'-TGT CTC TGA TGC TGT TGC TG-3'和反向5'-AGT CCT TGG CCT CAG TGT TT-3')、IFN-g(正向5'-AGC TCT TCC TCA TGG CTG TT-3'和反向5'-TTT GCC AGT TCC TCC AGA TA-3')、BAFF(正向5'-GGT GAC CCT GTT CCG ATG TA-3'和反向5'-CTC CGT TGC GTG AAA TCT GT-3')、FLT3L(正向5'-TGG CAG GGT CTA AGA TGCAA-3'和反向5'-AGG TGG GAG ATG TTG GTC TG-3')、IL-1(正向5'-AGC TTC AAA TCT CGCAGC AG-3'和反向5'-TCT CCA CAG CCA CAA TGA GT-3')、IL-6(正向5'-GAC TGA TGC TGGTGA CAA CC-3'和反向5'-AGA CAG GTC TGT TGG GAG TG-3')、IL-12A(正向5'-CCT GCACTG CTG AAG ACA TC-3'和反向5'-CCA GGC AAC TCT CGT TCT TG-3')、IL-18(正向5'-GCTGCC ATG TCA GAA GAC TC-3'和反向5'-ACT GCG GTT GTA CAG TGA AG-3')、IL-21(正向5'-AGT GGC CCA TAA ATC AAG CC-3'和反向5'-AAA GCT GCA TGC TCA CAG T-3')、IL-22(正向5'-AAT CAG CTC AGC TCC TGT CA-3'和反向5'-TCG CCT TGA TCT CTC CAC TC-3')、TNF-(正向5'-TCT CTT CAA GGG ACA AGG CT-3'和反向5'-GGC AGA GAG GAG GTT GAC TT-3')、IFN-(正向5'-GCT CTG TGC TTT CCT GAT GG-3'和反向5'-GTA CCA GGA GTG TCA AGGCT-3')、趋化因子;CXCL13(正向5'-ATG AGG CTC AGC ACA GCA A-3'和反向5'-GAA TACCGT GGC CTG GAG AG-3')、CXCR5(正向5'-CTC AAC CGA GAC CTT CCT GT-3'和反向5'-GTGCAG AGC GAT CAC AGT TT-3')、以及GAPDH(正向5'-TGG AGA AAC CTG TAT GTA TGG G-3'和反向5'-GGC CTG ATA AGA ACA AAC CC-3')。利用PCR(CFX connect,Bio-Rad,U.S)设备,使SsoAdvanced◎Universal SYBR Green超混液(Bio-rad)和引物(0.5pmole)及模板cDNA进行反应,并且按照如下条件执行。在95℃下初期变性3分钟,在95℃下变性10秒钟,在55℃下退火30秒钟,如此循环39次,并且在65℃下延伸)5秒钟。
2.7血浆内的自身抗体及细胞因子(IL-17A)的定量(ELISA)
为了确认作为干燥综合征的标志物的核糖核酸蛋白颗粒系列的自身抗体抗SSA/Ro(Signosis,#EA-5202,US)和抗SSB/La(Signosis,#EA-5204,US)以及自体免疫性疾病的发病相关的白介素-17细胞因子(Signosis,#EA-2516,US)的血清内分泌及生成,利用酶联免疫吸附试验(Enzyme-linked ImmunoSorbent Assay,ELISA)来定量。
2.8动物的炎症程度表现类型分析(疾病谱,Disease Score)
对动物模型的炎症程度进行评分和分析。
1:periorbital swelling(眶周肿胀)
2:eyes with discharge that were difficult to open(难以睁眼的程度)
3:periocular skin erosion(眼周皮肤糜烂)
4:inflammation reaching perioral skin(皮肤周围的炎症)
5:erosion and loss of hair in whole face(脸部整体糜烂和严重的脱发)。
2.9统计
实验结果由平均值±标准误差(SE)表示,利用IBM SPSS Statics 21(IBMCorporation,Poughkeepsie,NY,USA)进行单因素方差分析(one-way analysis ofvariance,ANOVA)之后,通过Dunnett's-t检验进行了分析。当概率(p)值<0.05时,统计学上将其定义为“显著”。
3.实验结果
3.1泪液分泌效果。
图1为表示干燥综合征疾病模型的泪液量的图表。参照图1,可确认干燥综合征疾病模型的泪液量在施用本发明的组合物时显著增加(mean±SE.,N=11)。*p<0.05与对照(Ctrl)组进行比较
3.2唾液分泌效果。
图2为表示干燥综合征疾病模型的唾液分泌量的图表。参照图2,可确认当施用本发明的组合物之后,唾液的分泌量(1.00.2)相比对照组(0.750.05)显著增加(mean±SE.,N=11)。*p<0.05与对照(Ctrl)组进行比较
3.3唾腺和泪腺中的细胞因子(IL-17A)和磷酸化Akt蛋白质表达效果。
图3为IL-17A和p-AKT的蛋白质表达和定量的结果。
自体免疫性疾病(autoimmune diseases)主要因辅助性T细胞17(helper 17 Tcell,Th17)的分化及激活而发病,通过对由这些T细胞生成的促炎性细胞因子白细胞介素17A(pro-inflammatory cytokine interleukin-17A,IL-17A)表达的增加进行定量化,可确认自体免疫性疾病的程度。
通过定量以100mg/kg施用根据本发明的组合物的组的泪腺(lacrimal glands)和唾腺(salivary glands)组织内的IL-17A的蛋白质表达,可以确认到与对照组相比有了显著减少。
并且,对与细胞生长及成长相关的Akt的激活形态p-AKT的定量的结果显示,在施用根据本发明的组合物的给药组中出现了显著增加(mean±SE.,N=3)。*p<0.05与对照(Ctrl)组进行比较。由此,可确认到根据本发明的组合物具有炎症缓解作用及组织再生效果。
3.4唾腺和泪腺中的多种炎症性及趋化性细胞因子的mRNA表达效果。
图4a及图4b是炎症性及趋化性细胞因子(pro-inflammatory cytokines andchemotactic cytokines)的mRNA定量结果。
与泪腺和唾腺组织内的自体免疫性疾病相关的免疫细胞(T cell andBlymphocytes)衍生的炎症性及趋化性细胞因子(pro-inflammatory cytokines andchemotactic cytokines)的mRNA定量结果与对照组的比较结果如下。
IL-2(唾腺:1.3倍,泪腺:4.5倍)、干扰素-g(唾腺:1.3倍,泪腺:1.3倍)、IL-17A(唾腺:3.3倍,泪腺:2.8倍)、BAFF(唾腺:无显著性,泪腺:1.6倍)、CXCL13(唾腺:5倍,泪腺:2.5倍)、CXCR5(唾腺:2.5倍,泪腺:无显著性)、FLT3L(唾腺:13倍,泪腺:2.5倍)、IL-1γ(唾腺:10倍,泪腺:2倍)、IL-6(唾腺:2.5倍,泪腺:2倍)、IL-12(唾腺:无显著性,泪腺:10倍)、IL-18(唾腺:1.6倍,泪腺:无显著性)、IL-21(唾腺:20倍,泪腺:1.6倍)、IL-22(唾腺:1.6倍,泪腺:1.7倍)、TNF-α(唾腺:2.2倍,泪腺:1.6倍)、IFN-α(唾腺:40倍,泪腺:1.6倍),可以看出,大部分已显著减少(mean±SE.,N=6)。*p<0.05,#p<0.01与对照(Ctrl)组进行比较。
3.5疾病动物模型血浆内的自身抗体(抗SSA/Ro,抗SSB/La)和细胞因子(IL-17A)分泌量变化效果。
图5为表示血浆(plasma)内IL-17A和自身抗体(抗SSA/Ro,抗SSB/La)的蛋白质表达的结果。
*随着干燥综合征的发病,体内自体抗原SSA/Ro、SSB/La增加。由此,免疫系统的B细胞会生产自身抗体。测定该自身抗体(抗SSA/Ro,抗SSB/La)是否存在,由此可确认干燥综合征的发病程度。
参照以下表2及图5可知,在施用根据本发明的组合物(SA001)的给药组中,相比对照组,血浆内抗SSA(40%)和抗SSB(30%)均(表1)显著减少,IL-17A也有减少(mean±SE.,N=3)。*p<0.05与对照(Ctrl)组进行比较
【表2】
3.6疾病动物模型的炎症程度表现类型变化(disease score)
图6为表示疾病动物模型的炎症度表现类型变化的照片,图7是对表现类型变化进行评分并以疾病谱(disease score)评价的结果。
随着干燥综合征的发病,外观上角质会增加,并且会发生眼球严重干燥和唾液干燥症状,从而引起炎症。由此,如图6所示,通过表现类型将评分方式划分为5个阶段,以疾病谱(disease score)进行评价。Score越高,炎症程度就会增加。参照图7,观察到从给药2周后起,相比对照组,SA001给药组的发病有显著延迟的现象(mean±SE.,N=11)。*p<0.05与对照(Ctrl)组进行比较
如上所述,在本实验中,比较了泪液量(tear production)和唾腺分泌(salivaryscan)、多种组织(lacrimal glands,salivary glands)内的炎症性细胞因子(pro-inflammatory cytokines)以及血浆(plasma)内的自身抗体(抗SSA/Ro,抗SSB/La)与IL-17A差异。
泪液量和唾液(saliva)分泌量,在本发明的组合物给药组中,泪液量和唾液(saliva)分泌量显著增加。由泪腺、唾腺组织内免疫细胞衍生的炎症性细胞因子和趋化性细胞因子的mRNA表达量在药物给药组中显著减少。通过唾腺和泪腺组织内的IL-17A细胞因子(IL-17A cytokine)蛋白质表达量的减少和用于确认构成组织的细胞的生存及生长的激活的Akt(phosphor-Akt),还确认了缓解炎症及组织再生的可能性。干燥综合征的发病会引起血浆内干燥综合征的标志物自身抗体(抗SSA,抗SSB)的增加,而其在根据本发明的组合物的给药组中显著减少,并且观察到了IL-17A细胞因子的分泌减少。通过观察外观的表现类型来比较炎症程度的结果显示,通过施用本发明的组合物,可起到延缓发病的效果。即,经确认,通过施用本发明的组合物,可延缓疾病模型的发病,并确认到具有使直接相关的泪腺和唾腺组织内的炎症缓解细胞和构成细胞的生长增加的可能性。由此,可以判断本发明的组合物具有预防和治疗干燥综合征的效果。
前述的本发明的说明是示例性的,本发明所属技术领域的普通技术人员应当理解在不改变本发明的技术思想或必要特征的情况下,能够以其他的具体形态容易地变形。故而,应当要理解以上描述的实施例在所有方面上是示例性的,而不是限定性的。例如,被描述为单一类型的每个构成要素可以以分布式方式实施,同理,被描述为分布式的构成要素也可以以结合的形态实施。
本发明的权利范围根据所附的权利要求书体现出来,而不是根据上述详细说明,从权利要求书的含义、范围以及其等同概念中推导出的所有改变或修改的实施方式应当被解释为包括在本发明的范围内。
Claims (11)
1.一种用于预防或治疗干燥综合征的组合物,包含由以下化学式1表示的化合物或其药剂学上可接受的盐;
[化学式1]
在所述化学式1中,
X为氧、氮或硫中的任一个;
Y为C1-C6烷基、C1-C6卤代烷基、(C1-C3烷氧基)C1-C6烷基、(C2-C6烯氧基)C1-C6烷基、(C1-C6烷基羰基氧基)C1-C6烷基、(C1-C6烷基硫烷基)C1-C6烷基、(芳基硫烷基)C1-C6烷基、(芳基磺酰基)C1-C6烷基、(C1-C6烷基氨基)C1-C6烷基、[(C1-C6烷基)(C1-C6烷基)氨基]C1-C6烷基、[(C1-C3烷基)(芳基)氨基]C1-C6烷基、[(C1-C3烷基)(芳基)C1-C3烷基]氨基C1-C6烷基、[(C1-C3烷基)(杂芳基)氨基]C1-C6烷基、(芳基羰基氨基)C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6氧代烷基、C3-C8环烷基、(C3-C8环烷基)C1-C6烷基、(C3-C8环烯基)C1-C6烷基、(C3-C8杂环烷基)C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基]C1-C6烷基、[(芳基)C1-C3烷基]C3-C8杂环烷基C1-C6烷基、[(C1-C6烷氧基羰基)C3-C8杂环烷基]C1-C6烷基、[(C1-C3烷氧基羰基)C3-C8杂环烷基]C1-C6烷基、(C3-C8杂环烷基)C1-C6烯基、[(C1-C3烷基)C3-C8杂环烯基]C1-C6烷基、(芳基)C1-C6烷基、[(C1-C3烷基)芳基]C1-C6烷基、[(C1-C3烷氧基)芳基]C1-C6烷基、[(芳基氧基)芳基]C1-C6烷基、[(C1-C3烷基硫烷基)芳基]C1-C6烷基、[(C1-C3烷氧基羰基)芳基]C1-C6烷基、[(芳基氧基羰基)芳基]C1-C6烷基、(芳基)C3-C6烯基、(杂芳基)C1-C6烷基、[(烷氧基羰基)杂芳基]C1-C6烷基、[(C1-C3烷基)C3-C8杂芳基]C1-C6烷基、[(C3-C8环烷基)杂芳基]C1-C6烷基、[(芳基)杂芳基]C1-C6烷基、[(C1-C3烷基)杂芳基]C1-C6烷基、[(芳基)C1-C3烷基]杂芳基C1-C6烷基、(C1-C6烷氧基羰基)C1-C6烷基、[(C3-C8杂环烷基)C1-C6烷氧基羰基]C1-C6烷基、(C3-C8杂环烷基羰基)C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基羰基]C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基羰基]C1-C6烷基、[(C3-C8环烷基)氧基羰基氧基]C1-C6烷基、[(C3-C8杂环烷基)氧基羰基氧基]C1-C6烷基、(脲基)C1-C6烷基、(芳基脲基)C1-C6烷基、[(芳基)(C1-C3烷基脲基]C1-C6烷基、(C1-C6烷基氨基羰基)C1-C6烷基、[(C3-C8杂环烷基)氨基羰基]C1-C6烷基、[(C1-C3烷基)C3-C8杂环烷基]氨基羰基C1-C6烷基、[(C1-C3烷基)(C1-C3烷氧基)氨基羰基]C1-C6烷基或(氧代C3-C8杂环烷基)C1-C6烷基,
此时,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6氧代烷基、C3-C8环烷基、C3-C8环烯基、C3-C8杂环烯基、芳基或杂芳基能够以选自由C1-C3烷基、氟代、氯代、溴代、羟基、氧代、硝基及氰基组成的组的一种以上取代基取代。
3.根据权利要求1所述的用于预防或治疗干燥综合征的组合物,其中,所述盐为由药剂学上可接受的游离酸形成的酸加成盐。
4.根据权利要求3所述的用于预防或治疗干燥综合征的组合物,其中,所述游离酸为有机酸或无机酸。
5.根据权利要求4所述的用于预防或治疗干燥综合征的组合物,其中,所述有机酸选自由柠檬酸、醋酸、乳酸、酒石酸、马来酸、延胡索酸、甲酸、丙酸、草酸、二氯乙酸、三氟乙酸、己二酸、抗坏血酸、苯甲酸、4-乙酰氨基苯甲酸、葡萄糖酸、磺酸、甲磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、环拉酸、十二烷基磺酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、半乳糖二酸、龙胆酸、戊二酸、2-氧代戊二酸、甘油磷酸、马尿酸、油酸、乳清酸、棕榈酸、扑酸、焦谷氨酸、皮脂酸、硬脂酸、硫代氰酸、十一烯酸、异丁酸、月桂酸、扁桃酸、萘-1,5-二磺酸、萘-2-磺酸、萘甲酸、烟酸、乙醇酸、琥珀酸、4-甲苯磺酸、樟脑磺酸、谷氨酸、天冬氨酸、水杨酸、4-氨基水杨酸、丙二酸、苹果酸及苯并磺酸组成的组,所述无机酸选自由盐酸、溴酸、硫酸、硝酸及磷酸组成的组。
6.根据权利要求1所述的用于预防或治疗干燥综合征的组合物,其中,
所述化学式1的化合物的药剂学上可接受的盐选自:
1)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙醇酸酯;
2)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乳酸酯;
3)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯水杨酸酯;
4)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯草酸酯;
5)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯丙二酸酯;
6)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苹果酸酯;
7)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯酒石酸酯;
8)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯马来酸酯;
9)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯延胡索酸酯;
10)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯柠檬酸酯;
11)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苯磺酸酯;
12)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲苯磺酸酯;
13)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯盐酸盐;
14)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硫酸酯;
15)2-(吗啉-4-基)乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯磷酸酯;
16)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙酸酯;
17)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯二氯乙酸酯;
18)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯己二酸酯;
19)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯抗坏血酸酯;
20)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯苯甲酸酯;
21)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯4-乙酰氨基苯甲酸酯;
22)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯癸酸酯;
23)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯己酸酯;
24)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯辛酸酯;
25)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯碳酸酯;
26)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯肉桂酸酯;
27)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯环拉酸酯;
28)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯十二烷基磺酸酯;
29)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙烷-1,2-二磺酸酯;
30)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乙烷磺酸酯;
31)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-羟基乙烷磺酸酯;
32)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲酸酯;
33)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯半乳糖二酸酯;
34)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯龙胆酸酯;
35)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯谷氨酸酯;
36)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯戊二酸酯;
37)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-氧代戊二酸酯;
38)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甘油磷酸酯;
39)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯马尿酸酯;
40)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯油酸酯;
41)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯乳清酸酯;
42)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯棕榈酸酯;
43)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯扑酸酯;
44)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯丙酸酯;
45)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯焦谷氨酸酯;
46)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯4-氨基水杨酸酯;
47)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯皮脂酸酯;
48)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硬脂酸酯;
49)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硫代氰酸酯;
50)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯十一烯酸酯;
51)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯氢溴酸酯;
52)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯异丁酸酯;
53)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯月桂酸酯;
54)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯DL-扁桃酸酯;
55)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯甲磺酸酯;
56)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯萘-1,5-二磺酸酯;
57)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯萘-2-磺酸酯;
58)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯2-萘甲酸酯;
59)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯烟酸酯;
60)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯硝酸酯;
61)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯琥珀酸酯;
62)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯;以及
63)2-吗啉-4-基-乙基2-(4-氯苯甲酰基氨基)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯L-天冬氨酸酯。
7.根据权利要求1所述的用于预防或治疗干燥综合征的组合物,其中,所述组合物还包含载体、赋形剂、稀释剂、填充剂、抗凝剂、润滑剂、湿润剂、香料、乳化剂或防腐剂。
8.根据权利要求1所述的用于预防或治疗干燥综合征的组合物,其中,所述组合物以粉末、颗粒剂、片剂、乳剂、糖浆剂、气雾剂、软明胶胶囊或硬明胶胶囊、无菌注射剂或无菌粉末的形式配置。
9.根据权利要求1所述的用于预防或治疗干燥综合征的组合物,其中,所述组合物增加泪液量及唾液分泌量。
10.根据权利要求1所述的用于预防或治疗干燥综合征的组合物,其中,所述组合物减少泪腺及唾腺组织内免疫细胞衍生的炎症性细胞因子和趋化性细胞因子的mRNA表达量。
11.根据权利要求1所述的用于预防或治疗干燥综合征的组合物,其中,所述组合物激活组成唾腺和泪腺组织的细胞的生存及生长。
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CN105142637A (zh) * | 2013-04-18 | 2015-12-09 | 三进制药株式会社 | 用于预防或治疗干眼症的含瑞巴派特或其前药的口服药物组合物 |
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CN105142637A (zh) * | 2013-04-18 | 2015-12-09 | 三进制药株式会社 | 用于预防或治疗干眼症的含瑞巴派特或其前药的口服药物组合物 |
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