CN104095851A - T-细胞介导的疾病的治疗 - Google Patents
T-细胞介导的疾病的治疗 Download PDFInfo
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- CN104095851A CN104095851A CN201410280192.6A CN201410280192A CN104095851A CN 104095851 A CN104095851 A CN 104095851A CN 201410280192 A CN201410280192 A CN 201410280192A CN 104095851 A CN104095851 A CN 104095851A
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Abstract
本发明提供使用某些二酮哌嗪类来治疗T-细胞介导的疾病的方法和抑制T-细胞激活的方法。本发明也提供合成二酮哌嗪类的方法和包含某些二酮哌嗪类的药物组合物。本发明还提供通过增加或者减少组合物中二酮哌嗪类的含量来制备蛋白和肽的改良药物组合物的方法和所得的改良药物组合物。
Description
本申请是申请日为2004年5月14日的申请号为201310049225.1的中国发明专利申请“T-细胞介导的疾病的治疗”的分案申请。
技术领域
本发明涉及使用某些二酮哌嗪类来治疗T-细胞介导的疾病和抑制T-细胞的激活。本发明也涉及包含某些二酮哌嗪类的药物组合物并且涉及合成二酮哌嗪类的方法。本发明还涉及制备蛋白和肽的改良药物组合物的方法以增加或减少组合物中二酮哌嗪类的含量,并且涉及所得的改良药物组合物。
发明背景
T-细胞介导的疾病代表了大量的免疫系统疾病。具体地,T-细胞被认为是引发和保持自身免疫性疾病的细胞。自身免疫性疾病为只在美国就折磨着数百万人的一组80种严重的慢性疾病。自身免疫性疾病的特征在于免疫系统与内源性(自身)抗原的反应性。这些对自身抗原的免疫应答被自我-反应的T-细胞的持续或再发激活所维持,并且直接地或间接地,该自我-反应的T-细胞对自身免疫性疾病中所见的特征组织损伤和破坏负责。尽管已提出了自身免疫性疾病和其他T-细胞介导的疾病的很多种疗法,仍然存在对于其他疗法的需要。
发明概述
1)本发明提供治疗T-细胞介导的疾病的方法。该方法包括对需要其的动物给予有效量的具有下式的二酮哌嗪或其生理学上可接受的盐:
其中:
R1和R2,可以相同或不同,每个为:
(a)氨基酸的侧链,其中该氨基酸为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基异丁酸、2,4-二氨基丁酸、2,3-二氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸、丝氨酸、高丝氨酸、苏氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、赖氨酸、羟赖氨酸、组氨酸、精氨酸、高精氨酸、瓜氨酸、苯丙氨酸、对-氨基苯丙氨酸、酪氨酸、色氨酸、甲状腺素、半胱氨酸、高半胱氨酸、甲硫氨酸、青霉胺或鸟氨酸;然而条件是,当R1为天冬酰胺或谷氨酰胺的侧链时,那么R2不能为赖氨酸或鸟氨酸的侧链,并且当R1为赖氨酸或鸟氨酸的侧链时,R2不能为天冬酰胺或谷氨酰胺的侧链;
(b)R1为-CH2-CH2-CH2-或-CH2-CH(OH)-CH2-并且与邻近环氮形成脯氨酸或羟脯氨酸,和/或R2为-CH2-CH2-CH2-或-CH2-CH(OH)-CH2-并且与邻近环氮形成脯氨酸或羟脯氨酸;或
(c)氨基酸的侧链的衍生物,其中该氨基酸为(a)中所述的那些之一,并且该衍生化的侧链具有以下基团:
(i)-NH2基团被-NHR3或-N(R3)2基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(ii)-OH基团被-O-PO3H2或-OR3基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(iii)-COOH基团被-COOR3基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(iv)-COOH基团被-CON(R4)2基团所代替,其中每个R4可以独立地为H或被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(v)-SH基团被-S-S-CH2-CH(NH2)-COOH或
-S-S-CH2-CH2-CH(NH2)-COOH所代替;
(vi)-CH2-基团被-CH(NH2)-或-CH(OH)-基团所代替;
(vii)-CH3基团被-CH2-NH2或-CH2-OH基团所代替;和/或
(viii)连在碳原子上的H被卤素所代替。
2).根据1)的方法,其中R1、R2或这二者为天冬氨酸的侧链、谷氨酸的侧链,或者天冬氨酸或谷氨酸的侧链的衍生物,该衍生物中-COOH基团被-COOR3基团或-CON(R4)2基团所代替。
3).根据2)的方法,其中R1为天冬氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的天冬氨酸的侧链的衍生物,并且R2为丙氨酸的侧链。
4).根据2)的方法,其中R1为天冬氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的天冬氨酸的侧链的衍生物,并且R2为酪氨酸的侧链。
5).根据2)的方法,其中R1为谷氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的谷氨酸的侧链的衍生物,并且R2为丙氨酸的侧链。
6).根据2)的方法,其中R1为谷氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的谷氨酸的侧链的衍生物,并且R2为酪氨酸的侧链。
7).根据2)的方法,其中R1为天冬氨酸的或谷氨酸的侧链,并且R2为丙氨酸的侧链。
8).根据2)的方法,其中R1为天冬氨酸的或谷氨酸的侧链,并且R2为酪氨酸的侧链。
9).根据1)的方法,其中R1和R2都为疏水性侧链或疏水性侧链的衍生物。
10).根据9)的方法,其中:
(a)R1和R2,可以相同或不同,每个为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸或苯丙氨酸的侧链;
(b)R1为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸,并且R2为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸;或
(c)R1为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸或苯丙氨酸的侧链,并且R2为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸。
11).根据10)的方法,其中R1为甘氨酸的侧链,并且R2为亮氨酸的侧链。
12).根据10)的方法,其中R1为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸,并且R2为苯丙氨酸的侧链。
13).根据10)的方法,其中R1为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸,并且R2为丙氨酸的侧链。
14).根据1)的方法,其中R1、R2或这二者为甲硫氨酸的侧链、精氨酸的侧链或这些侧链的衍生物。
15).根据14)的方法,其中R1为甲硫氨酸的侧链,并且R2为精氨酸的侧链。
16).根据1)~15)中任一项的方法,其中所述动物为人。
17).根据1)~15)中任一项的方法,其中所述T-细胞介导的疾病为移植排斥、移植物抗宿主病、不需要的迟发型超敏反应、T-细胞介导的肺部疾病或自身免疫疾病。
18).根据1)~15)中任一项的方法,其中所述T-细胞介导的疾病为多发性硬化症、神经炎、多发性肌炎、牛皮癣、白斑病、舍格伦综合症、类风湿性关节炎、1型糖尿病、自身免疫胰腺炎、炎性肠疾病、克隆病、溃疡性结肠炎、腹部疾病、肾小球肾炎、硬皮病、结节病、自身免疫性甲状腺病、桥本甲状腺炎、格雷夫斯病、重症肌无力、艾迪生病、自身免疫眼色素视网膜炎、寻常性天疱疮、原发性胆汁性肝硬变、恶性贫血、或全身性红斑狼疮。
19).根据1)~15)中任一项的方法,其中所述T-细胞介导的疾病为肺纤维化或特发性肺纤维化。
20)本发明也提供抑制T-细胞激活的方法。该方法包括对需要其的动物给予有效量的式I二酮哌嗪或其生理学上可接受的盐。
21).根据20)的方法,其中R1、R2或这二者为天冬氨酸的侧链、谷氨酸的侧链或者天冬氨酸或谷氨酸的侧链的衍生物,该衍生物中-COOH基团被-COOR3基团或-CON(R4)2基团所代替。
22).根据21)的方法,其中R1为天冬氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的天冬氨酸的侧链的衍生物,并且R2为丙氨酸的侧链。
23).根据21)的方法,其中R1为天冬氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的天冬氨酸的侧链的衍生物,并且R2为酪氨酸的侧链。
24).根据21)的方法,其中R1为谷氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的谷氨酸的侧链的衍生物,并且R2为丙氨酸的侧链。
25).根据21)的方法,其中R1为谷氨酸的侧链或-COOH基团被-COOR3基团或-CON(R4)2基团所代替的谷氨酸的侧链的衍生物,并且R2为酪氨酸的侧链。
26).根据21)的方法,其中R1为天冬氨酸的或谷氨酸的侧链,并且R2为丙氨酸的侧链。
27).根据21)的方法,其中R1为天冬氨酸的或谷氨酸的侧链,并且R2为酪氨酸的侧链。
28).根据21)的方法,其中R1和R2都为疏水性侧链或疏水性侧链的衍生物。
29).根据28)的方法,其中:
(a)R1和R2,可以相同或不同,每个为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸或苯丙氨酸的侧链;
(b)R1为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸,并且R2为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸;或
(c)R1为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸或苯丙氨酸的侧链,并且R2为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸。
30).根据29)的方法,其中R1为甘氨酸的侧链,并且R2为亮氨酸的侧链。
31).根据29)的方法,其中R1为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸并且R2为苯丙氨酸的侧链。
32).根据29)的方法,其中R1为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸并且R2为丙氨酸的侧链。
33).根据20)的方法,其中R1、R2或这二者为甲硫氨酸的侧链、精氨酸的侧链或这些侧链的衍生物。
34).根据33)的方法,其中R1为甲硫氨酸的侧链,并且R2为精氨酸的侧链。
35).根据20)~34)中任一项的方法,其中所述动物为人。
36).根据20)~34)中任一项的方法,其中所述二酮哌嗪用于治疗至少是部分地由于T-细胞的激活而引起或加重的炎症或炎性疾病。
37)本发明还提供包含药学上可接受的载体和具有下式的二酮哌嗪或其生理学上可接受的盐的药物组合物:
其中:
R5和R6,可以相同或不同,每个为:
(a)氨基酸的侧链,其中该氨基酸为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基异丁酸、2,4-二氨基丁酸、2,3-二氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸、丝氨酸、高丝氨酸、苏氨酸、赖氨酸、羟赖氨酸、组氨酸、精氨酸、高精氨酸、瓜氨酸、苯丙氨酸、对-氨基苯丙氨酸、酪氨酸、色氨酸、甲状腺素、或鸟氨酸;然而条件是,当R5为天冬酰胺或谷氨酰胺的侧链时,那么R6不能为赖氨酸或鸟氨酸的侧链,并且当R5为赖氨酸或鸟氨酸的侧链时,R6不能为天冬酰胺或谷氨酰胺的侧链;
(b)R5为-CH2-CH2-CH2-或-CH2-CH(OH)-CH2-并且与邻近环氮形成脯氨酸或羟脯氨酸,和/或R6为-CH2-CH2-CH2-或-CH2-CH(OH)-CH2-并且与邻近环氮形成脯氨酸或羟脯氨酸;或
(c)氨基酸的侧链的衍生物,其中该氨基酸为(a)中所述的那些之一,并且该衍生化的侧链具有以下基团:
(i)-NH2基团被-NHR3或-N(R3)2基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(ii)-OH基团被-O-PO3H2或-OR3基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(iii)-CH2-基团被-CH(NH2)-或-CH(OH)-基团所代替;
(iv)-CH3基团被-CH2-NH2或-CH2-OH基团所代替;和/或
(v)连在碳原子上的H被卤素所代替。
38).根据37)的组合物,其中R5和R6都为疏水性侧链或疏水性侧链的衍生物。
39).根据38)的组合物,其中:
(a)R5和R6,可以相同或不同,每个为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸或苯丙氨酸的侧链;
(b)R5为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸,并且R6为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸;或
(c)R5为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸或苯丙氨酸的侧链,并且R6为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸。
40).根据39)的组合物,其中R5为甘氨酸的侧链,并且R6为亮氨酸的侧链。
41).根据39)的组合物,其中R5为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸,并且R6为苯丙氨酸的侧链。
42).根据39)的组合物,其中R5为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸,并且R6为丙氨酸的侧链。
43).根据37)的组合物,其中R5、R6或这二者为甲硫氨酸的侧链、精氨酸的侧链或这些侧链的衍生物。
44).根据43)的组合物,其中R5为甲硫氨酸的侧链,并且R6为精氨酸的侧链。
45)本发明提供治疗T-细胞介导的疾病的另一种方法。该方法包括对需要其的动物给予有效量的包含在动物中正常发现的蛋白或肽的药物组合物,所述蛋白或肽已经被处理了,使所述组合物也包含至少一种衍生于该蛋白或肽的二酮哌嗪。
46)根据45)的方法,其中所述蛋白为白蛋白。
47)根据45)的方法,其中所述蛋白为免疫球蛋白。
48)根据45)的方法,其中所述蛋白为促红细胞生成素。
49)根据45)~48)中任一项的方法,其中所述药物组合物为口服给药。
50)根据45)~48)中任一项的方法,其中所述动物为人,并且所述蛋白或肽为人蛋白或肽。
51)本发明还提供一种抑制T-细胞激活的方法。该方法包括对需要其的动物给予有效量的包含在动物中正常发现的蛋白或肽的药物组合物,所述蛋白或肽已经被处理了,使所述组合物也包含至少一种衍生于该蛋白或肽的二酮哌嗪。
52)根据51)的方法,其中所述蛋白为白蛋白。
53)根据51)的方法,其中所述蛋白为免疫球蛋白。
54)根据51)的方法,其中所述蛋白为促红细胞生成素。
55)根据51)~54)中任一项的方法,其中所述药物组合物为口服给药。
56)根据51)~54)中任一项的方法,其中所述动物为人,并且所述蛋白或肽为人蛋白或肽。
57)此外,本发明提供合成二酮哌嗪类的方法。在一个实施方案中,该方法包括在有效地引起二酮哌嗪形成的条件下加热蛋白或肽溶液。在第二个实施方案中,该方法包括在有效产生二酮哌嗪类的条件下,使蛋白或肽溶液与切断该蛋白或肽的两个N-末端或两个C-末端氨基酸的酶相接触。
58)根据57)的方法,其中所述蛋白为白蛋白。
59)根据57)的方法,其中所述蛋白为免疫球蛋白。
60)根据57)的方法,其中所述蛋白为促红细胞生成素。
61)根据57)的方法,其中所述二酮哌嗪从溶液中纯化。
62)根据57)~61)中任一项的方法,其中所述加热为将蛋白或肽溶液于60℃加热4天。
63)根据57)的方法,其中所述酶为二肽基肽酶。
64)根据57)的方法,其中所述酶为羧肽酶。
65)本发明也提供蛋白或肽的改良药物组合物。所述改良在于该组合物包含降低含量的二酮哌嗪类。
66)根据65)的组合物,其中所述蛋白为白蛋白。
67)根据65)的组合物,其中所述蛋白为免疫球蛋白。
68)根据65)的组合物,其中所述蛋白为促红细胞生成素。
69)此外,本发明提供制备蛋白或肽的改良药物组合物的方法。该方法包括从该组合物中除去在该组合物中存在的至少一些二酮哌嗪类。
70)根据69)的方法,其中所述蛋白为白蛋白。
71)根据69)的方法,其中所述蛋白为免疫球蛋白。
72)根据69)的方法,其中所述蛋白为促红细胞生成素。
73)本发明还提供制备蛋白或肽的改良药物组合物的方法。该方法包括将该蛋白或肽的溶液进行处理以提高该组合物中二酮哌嗪类的含量。
74)根据73)的方法,其中所述溶液在引起二酮哌嗪类形成的条件下加热。
75)根据74)的方法,其中所述溶液于60℃加热4天。
76)根据73)的方法,其中在有效地产生二酮哌嗪类的条件下所述溶液与切断该蛋白或肽的两个N-末端或两个C-末端氨基酸的酶相接触。
77)根据76)的方法,其中所述酶为二肽基肽酶。
78)根据76)的方法,其中所述酶为羧肽酶。
79)根据73)的方法,其中所述蛋白为白蛋白。
80)根据73)的方法,其中所述蛋白为免疫球蛋白。
81)根据73)的方法,其中所述蛋白为促红细胞生成素。
82)本发明也提供蛋白或肽的改良药物组合物。所述改良在于该组合物包含增加含量的二酮哌嗪类。
83)根据82)的组合物,其中所述蛋白为白蛋白。
84)根据82)的组合物,其中所述蛋白为免疫球蛋白。
85)根据82)的组合物,其中所述蛋白为促红细胞生成素。
86)根据82)~85)中任一项的组合物,其适合于口服给药。
附图说明
图1:TriPS(从流感免疫供体中分离得的对血凝素特异性的CD4+T-细胞株)细胞的计数对ERK1/2浓度描记图,该TriPS细胞是以抗-CD3OKT3抗体刺激后第20天分离得到的并且用25ng佛波豆蔻酸(phorbal myristic acid)(PMA),以1:10稀释的HC-RBL(被加热的人初乳部分,分子量小于3kD并且含有MR-DKP)以及0.5mM的DA-DKP于37℃培养了15分钟。
图2:柱形图显示的是用抗-CD3OKT3抗体刺激后12天对TriPS细胞分泌肿瘤坏死因子α(TNFα)和IL-16的抑制。显示了人初乳(HC)2626(含有MR-DKP)DA-DKP带对TNFα和IL-16L两者分泌的抑制。使用以1:100和1:1000稀释的HC2626观察到的最大释放是归因于高浓度的人初乳的裂解作用。使用0.5mM的DA-DKP时没有观察到裂解,并且TNFα和IL-16L分泌被减少了。
图3:柱形图显示用抗CD3OKT3抗体刺激后10天,对TriPS细胞分泌TNFα的抑制。显示了需要进一步考察HC RBL和DA-DKP的如同用HC2626所见的滴定反应(titratable response as seen with HC2626)。可能表明了潜在的活性(May indicated a potent activity)。
图4:柱形图显示用抗-CD3OKT3抗体刺激后不同时间对TriPS细胞分泌TNFα的抑制。显示了在刺激周期的早期,DA-DKP和HC RBL是抑制作用的,而在该周期的晚期(第14天)是激活作用的。HC2626在所有时间都是抑制作用的,这大概是归因于其他的成分。
图5:柱形图显示对用抗-CD3OKT3抗体刺激后第7~10天的H4#9.25细胞(从多发性硬化症病人的尸体脑组织中分离得的对髓鞘碱性蛋白特异性的CD4+T-细胞株)分泌TNFα抑制情况。显示了在TNFα从该T-细胞株中的分泌也被HC2626、HC RBL和DA-DKP所抑制。
目前优选实施方案的详细说明
本发明提供治疗T-细胞介导的疾病的方法。本文所用的“治疗”是指减少(完全地或部分地)疾病的症状、持续时间或严重性,包括治愈该疾病,或者防止该疾病。
T-细胞介导的疾病包括移植排斥、移植物抗宿主病、不需要的迟发型超敏反应(比如迟发型变应性反应)、T-细胞介导的肺部疾病和自身免疫疾病。T-细胞介导的肺部疾病包括结节病、超敏性肺炎、急性间质性肺炎、肺泡炎、肺纤维化、特发性肺纤维化和以炎性肺损伤为特征的其他疾病。自身免疫疾病包括多发性硬化症、神经炎、多发性肌炎、牛皮癣、白斑病、舍格伦综合症、类风湿性关节炎、1型糖尿病、自身免疫胰腺炎、炎性肠疾病(例如克隆病和溃疡性结肠炎)、腹部疾病、肾小球肾炎、硬皮病、结节病、自身免疫性甲状腺病(例如桥本甲状腺炎和格雷夫斯病)、重症肌无力、艾迪生病、自身免疫眼色素视网膜炎(uveoretinitis)、寻常性天疱疮、原发性胆汁性肝硬变、恶性贫血、和全身性红斑狼疮。
通过对需要其的动物给予有效量的具有下式的二酮哌嗪类或其生理学上可接受的盐来治疗所述T-细胞介导的疾病:
其中:
R1和R2,可以相同或不同,每个为:
(a)氨基酸的侧链,其中该氨基酸为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基异丁酸、2,4-二氨基丁酸、2,3-二氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸、丝氨酸、高丝氨酸、苏氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、赖氨酸、羟赖氨酸、组氨酸、精氨酸、高精氨酸、瓜氨酸、苯丙氨酸、对-氨基苯丙氨酸、酪氨酸、色氨酸、甲状腺素、半胱氨酸、高半胱氨酸、甲硫氨酸、青霉胺或鸟氨酸;然而条件是,当R1为天冬酰胺或谷氨酰胺的侧链时,那么R2不能为赖氨酸或鸟氨酸的侧链,并且当R1为赖氨酸或鸟氨酸的侧链时,R2不能为天冬酰胺或谷氨酰胺的侧链;
(b)R1为-CH2-CH2-CH2-或-CH2-CH(OH)-CH2-并且与邻近环氮形成脯氨酸或羟脯氨酸,和/或R2为-CH2-CH2-CH2-或-CH2-CH(OH)-CH2-并且与邻近环氮形成脯氨酸或羟脯氨酸;或
(c)氨基酸的侧链的衍生物,其中该氨基酸为(a)中所述的那些之一,并且该衍生化的侧链具有以下基团:
(i)-NH2基团被-NHR3或-N(R3)2基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(ii)-OH基团被-O-PO3H2或-OR3基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(iii)-COOH基团被-COOR3基团所代替,其中每个R3可以独立地为被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(iv)-COOH基团被-CON(R4)2基团所代替,其中每个R4可以独立地为H或被取代的或未被取代的烷基、环烷基、杂环烷基、芳基、烷芳基、芳烷基或杂芳基;
(v)-SH基团被-S-S-CH2-CH(NH2)-COOH或
-S-S-CH2-CH2-CH(NH2)-COOH所代替;
(vi)-CH2-基团被-CH(NH2)-或-CH(OH)-基团所代替;
(vii)-CH3基团被-CH2-NH2或-CH2-OH基团所代替;和/或
(viii)连在碳原子上的H被卤素所代替。
“被代替”是指,根据氨基酸的侧链的式子,所述特定基团被所述其他特定基团代替。例如,异亮氨酸的侧链的式子为-CH(CH3)-CH2-CH3。如果该末端-CH3基被-CH2-OH基代替,那么所得的衍生异的亮氨酸侧链的式子就是-CH(CH3)-CH2-CH2-OH。作为另一个实例,丙氨酸的侧链式子为-CH3。如果所述氢原子之一被氯原子代替,那么所得的衍生丙氨酸的侧链就是-CH2-Cl。注意甘氨酸的侧链是-H,并且如果该H被氯(或其他卤素)原子代替,所得的侧链就是-Cl,该氯原子连到环碳上(例如R1=-Cl)。
优选的是如下二酮哌嗪类,其中R1、R2或这二者为天冬氨酸或谷氨酸的侧链,或这样侧链的-COOH基团被-COOR3基团或-CON(R4)2基团所代替的衍生物,其中R3和R4在上面定义了。在这组化合物中,最优选的是如下二酮哌嗪类,其包括天冬氨酸和丙氨酸的侧链(Asp-Ala DKP或DA-DKP)、谷氨酸和丙氨酸的侧链(Glu-Ala DKP或EA-DKP)、酪氨酸和天冬氨酸的侧链(Tyr-Asp DKP或YD-DKP)、酪氨酸和谷氨酸的侧链(Tyr-Glu DKP或YE-DKP)和这四种二酮哌嗪类的天冬氨酸或谷氨酸的侧链的衍生物,这些衍生物中-COOH基团被-COOR3基团或-CON(R4)2基团所代替,其中R3和R4在上面定义了。
还有,优选的是如下二酮哌嗪类,其中R1和R2二者都为疏水性侧链(例如苯丙氨酸的侧链)或疏水性侧链衍生物。“疏水性侧链衍生物”是指被衍生的侧链为疏水性。具体地,优选的是如下二酮哌嗪类,其中R1和/或R2可以相同或不同,R1和R2各为甘氨酸、丙氨酸、缬氨酸、正缬氨酸、α-氨基丁酸、亮氨酸、异亮氨酸、正亮氨酸或苯丙氨酸的侧链、和/或R1和/或R2为-CH2-CH2-CH2-并且与邻近的氮原子一起形成脯氨酸。这组化合物中,最优选的是包含甘氨酸和亮氨酸(Gly-Leu DKP或GL-DKP)、脯氨酸和苯丙氨酸(Pro-Phe DKP或PF-DKP)、以及丙氨酸和脯氨酸(Ala-Pro DKP或AP-DKP)的侧链的二酮哌嗪类。
此外优选的二酮哌嗪类为如下那些,其中R1、R2或这二者为甲硫氨酸的侧链、精氨酸的侧链或这些侧链的衍生物。这组中最优选的是R1为甲硫氨酸的侧链并且R2为精氨酸的侧链的二酮哌嗪类(Met-Arg DKP或MR-DKP)。
氨基酸的“侧链”是指连接到上面列出所有氨基酸的共同骨架上的氨基酸部分。例如,甘氨酸的侧链为-H,丙氨酸的侧链为-CH3,以及丝氨酸的侧链为-CH2OH。
“疏水性”是指侧链或侧链衍生物在生理pH下不带电并且被水性溶液排斥。
“烷基”是指含有1~10个,优选1~6个碳原子的饱和直链或支链烃。“低级烷基”是指含有1~6个碳原子的饱和直链或支链烃。
“环烷基”是指含有至少一个环的饱和环烃,每个环含有至少三个碳原子。优选地,该环烷基含有一个4~8个碳原子的环。
“杂环烷基”是指至少一个环的一个或多个环碳原子被O、S或N代替的环烷基。
“芳基”是指具有至少一个芳香环(例如苯基)的芳香基团。
“烷芳基”是指H被芳基代替的低级烷基(例如-CH2-C6H5或-CH3CH(C6H5)CH3)。
“芳烷基”是指H被低级烷基代替的芳基(例如-C6H4-CH3)。
“杂芳基”是指至少一个环的一个或多个环碳原子被O、S或N代替的芳基。
“被取代”是指所述部分被选自下述基团的一个或多个取代基所取代:-OH、NH2、-SH、-COOH和/或卤素原子。
“卤素”是指氯、氟、溴或碘。优选的是氯或溴。
式I的二酮哌嗪类在治疗T-细胞介导的疾病方面是有效的,因为它们抑制T-细胞的活化。因此,式I的二酮哌嗪类也能够用来治疗由活化的T-细胞引起的、加重的、或牵涉到活化的T-细胞的炎症或炎性疾病。本文所用的“抑制”是指降低(完整地或部分地)或防止。
制备二酮哌嗪类的方法是本领域中所熟知的,并且这些方法可以用来合成本发明的二酮哌嗪类。见例如美国专利号4,694,081、5,817,751、5,990,112、5,932,579和6,555,543,美国专利申请公开号2004/0024180,PCT申请WO96/00391和WO97/48685,以及Smith等Bioorg.Med.Chem.Letters,8,2369-2374(1998),这些文献完整公开内容在此引入作为参考。
例如,二酮哌嗪类能够通过首先合成二肽来制备。该二肽能够通过本领域中熟知的方法使用L-氨基酸、D-氨基酸或D-和L-氨基酸的组合来合成。优选的是固相多肽合成方法。当然,二肽也能够从大量的来源处商业获得,包括DMI Synthesis Ltd.,Cardiff,UK(委托合成),Sigma-Aldrich,St.Louis,MO(主要地委托合成),Phoenix Pharmaceuticals,Inc.,Belmont,CA(委托合成),Fisher Scientific(委托合成)和Advanced ChemTech,Louisville,KY.
所述二肽被合成或买到之后,被环化形成二酮哌嗪。这能够通过许多种技术来完成。
例如,美国专利申请公开号2004/0024180说明了一种环化二肽的方法。简要地,将所述二肽在有机溶剂中加热同时通过蒸馏除去水份。优选地,该有机溶剂为水低沸共沸物,比如乙腈、烯丙醇、苯、苯甲醇、正-丁醇、2-丁醇、叔-丁醇、乙酸丁酯、四氯化碳、氯苯氯仿、环己胺、1,2-二氯乙烷、二乙基乙缩醛、二甲基乙缩醛、乙酸乙酯、庚烷、甲基异丁基酮、3-戊醇、甲苯和二甲苯。所述温度取决于环化发生的反应速度和所用的共沸剂的类型。反应优选在50~200℃进行,更优选80~150℃。环化发生所在的pH范围能够容易地被本领域技术人员所确定。有利的是,pH为2-9,优选3-7。
当所述二肽的一个或两个氨基酸在其侧链上具有或衍生为具有羧基时(例如天冬氨酸或谷氨酸),所述二肽优选按照美国专利号6,555,543所说明的进行环化。简要地,将侧链羧基仍然被保护着的该二肽在中性条件下加热。典型地,将该二肽于大约80℃~大约180℃加热,优选大约120℃。所述溶剂为中性溶剂。例如,所述溶剂可以包括醇(比如丁醇、甲醇、乙醇、和高级醇,但不为苯酚)和共沸共溶剂(比如甲苯、苯、或二甲苯)。优选地,所述醇为丁-2-醇,并且所述共沸共溶剂为甲苯。加热一直持续到反应完全,并且这些时间能够凭经验确定。典型地,所述二肽通过回流大约8~24小时优选18小时来环化。最后,将所述保护基团从该二酮哌嗪上除去。在这样做的时候,应该避免使用强酸(无机酸,比如硫酸或盐酸)、强碱(碱金属的碱(alkalinebases),比如氢氧化钾或氢氧化钠)、和强还原剂(例如氢化铝锂),以保持最终化合物的手性。
固相树脂上制备的二肽能够通过一步来环化并从树脂上释放。见例如美国专利号5,817,751。例如,将附有N-烷基化二肽的树脂悬浮于有乙酸(例如1%)或三乙胺(例如4%)存在的甲苯或甲苯/乙醇中。典型地,优选碱性环化条件,因为它们具有更快的环化时间。
为了制备式I和II的氨基酸的侧链被衍生的二酮哌嗪,在二肽的合成中可以使用氨基酸衍生物,二肽能够被衍生化和/或二酮哌嗪类能够被衍生化,如本领域公知的那样。见例如上述引用的那些参考文献。
环化二肽和制备二酮哌嗪类的其他方法是本领域已知的,并且能够在对本发明实践中有用的二酮哌嗪类的制备中使用。见例如上述引用的那些参考文献。此外,适合于在本发明中使用的很多二酮哌嗪类能够按照下面的说明由蛋白和肽制备。还有,在本发明实践中使用的二酮哌嗪类能够从例如DMISynthesis Ltd.,Cardiff,UK(委托合成)商业获得。
式I和II的二酮哌嗪类除包括能够通过变化个体手性中心、轴线或表面的构型得到的之外,还包括所有可能的立体异构体。用另一种说法,式I和II的二酮哌嗪类包括所有可能的非对映体和所有的光学异构体(对映体)。
本发明二酮哌嗪类的生理学上可接受的盐也可以在本发明实践中使用。生理学上可接受的盐包括常规的非毒性盐,比如衍生于无机酸(比如盐酸的、氢溴酸的、硫酸的、磷酸的、硝酸等)的盐,衍生于有机酸(比如乙酸、丙酸、琥珀酸、乙醇酸(glycolic)、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、谷氨酸、天冬氨酸、苯甲酸、水杨酸、草酸、抗坏血酸等)的盐,或衍生于碱(比如药学上可接受的金属阳离子的或衍生于N,N-二苄基乙二胺、D-葡糖胺或乙二胺的有机阳离子的氢氧化物、碳酸盐或碳酸氢盐)。这些盐以常规的方法制备,例如通过用酸中和所述化合物的游离碱形式。
如上说明的,本发明的二酮哌嗪或其生理学上可接受的盐能够用来治疗T-细胞介导的疾病或用来抑制T-细胞的活化。为了这样做,对需要治疗的动物给予二酮哌嗪或其生理学上可接受的盐。优选地,所述动物为哺乳动物,比如家兔、山羊、狗、猫、马或人。本发明化合物的有效剂型、给药方式和剂量可以凭经验决定,并且做出这样决定是在本领域的技术之内的。本领域的技术人员应当理解剂量将随着具体使用的化合物、所要治疗的疾病或病症、疾病或病症的严重性、给予的途径、化合物的排泄速度、治疗的持续时间、对所述动物给予的其他药物的鉴定、所述动物的年龄、尺寸和种类等医药和兽医领域公知的因素而变化。一般地,本发明化合物的适合日剂量为该化合物有效产生治疗效果的最低剂量。然而,该日剂量将由主治医师或兽医在合适的医疗判断范围内决定。如果期望,有效日剂量可以以二、三、四、五、六或更多的分次剂量全天以适当的间隔地分别地给予。该化合物的给予应当持续到达到了可接受的应答为止。
本发明化合物(即二酮哌嗪类和其生理学上可接受的盐)可以以任何适合的给药途径给予治疗的动物患者,给药途径包括口服、经鼻、直肠、阴道、非经肠(例如静脉、脊柱内、腹腔、皮下、或肌肉)、脑内、经皮、颅内、大脑内、和局部(包括向颊和舌下)给药。优选的给药途径为口服和静脉给药。
尽管单独给予本发明化合物是可能的,仍然优选以药物制剂(组合物)的形式给予该化合物。本发明药物组合物包括在一种或多种药学上可接受的载体以及任选地一种或多种其他化合物、药物或其他材料的混合物中作为活性成分的本发明一种化合物或多种化合物。每种载体必须是“可接受的”意味着与制剂中的其他成分相容并且对所述动物无害。药学上可接受的载体在本领域中是熟知的。不管选择何种给药途径,本发明化合物都通过本领域技术人员公知的常规方法来制成药学上可接受的剂型。见例如Remington'sPharmaceutical Sciences。
适合于口服给予的本发明制剂可以为胶囊、扁胶囊、丸剂、片剂、散剂、颗粒剂的形式或作为溶液或在水性或非水性液体中的悬浮剂、或水包油或油包水乳剂的形式,或作为酏剂或糖浆的形式,或锭剂(使用惰性基质,比如明胶和甘油,或蔗糖和阿拉伯胶)等的形式,每个含有预定量的本发明一种或多种化合物作为活性成分。本发明的一种或多种化合物也可以作为大丸、药糖剂、或膏给予。
口服给药的本发明的固体剂型中(胶囊、片剂、丸剂、锭剂、散剂、颗粒剂等),活性成分(即一种或多种本发明的二酮哌嗪类和/或其生理学上可接受的盐)与一种或多种药学上可接受的载体相混合,比如柠檬酸钠或磷酸二钙,和/或下列任一:(1)填充剂或补充剂、比如淀粉、乳糖、蔗糖、葡萄糖、甘露醇、和/或硅酸;(2)粘合剂,比如,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)湿润剂,比如甘油;(4)崩解剂,比如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐、和碳酸钠;(5)溶液阻滞剂,比如石蜡;(6)吸收促进剂,比如季胺类化合物;(7)湿润剂,比如,例如鲸蜡醇和单硬脂酸甘油酯;(8)吸收剂,比如高岭土和胶质陶土;(9)润滑剂,比如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠和其混合物;以及(10)着色剂。在胶囊、片剂和丸剂的情况下,该药物组合物也可以包含缓冲剂。相似类型的固体组合物可以用作填装入使用乳糖或乳糖类(milk sugars)及高分子量聚乙二醇等辅料的软和硬明胶胶囊的填料。
片剂可以任选地与一种或多种配合剂一起压制或模塑来制备。压制的片剂可以使用粘合剂(例如明胶或羟丙甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如乙醇酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模制的片剂可以通过在适合的机器中将用惰性液体稀释剂弄湿的粉末化合物混合物进行模塑来制备。
本发明药物组合物的片剂和其他固体剂型,比如锭剂、胶囊、丸剂和颗粒剂,可以任选地用包衣和壳来压痕或制备,比如肠溶衣和药学制剂领域中熟知的其他包衣。它们也可以制剂以提供活性成分的缓慢或控制释放,在其中使用例如不同比例的羟丙甲基纤维素以提供期望的释放分布型、其他聚合物基质、脂质体和/或微球。它们可以例如通过除菌过滤器过滤来灭菌。这些组合物也可以任选地含有遮光剂并且也可以是只在或优先在胃肠道的某个部分任选地以延迟的方式释放活性成分的组合物。能够使用的埋置组合物的实例包括聚合物质和蜡。该活性成分也能够存在于微囊形式中。
本发明化合物的口服给药液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、悬浮剂、糖浆剂和酏剂。除了活性成分外,该液体剂型可以含有本领域中通常的惰性稀释剂,比如,例如水或其他溶剂、增溶剂和乳化剂,比如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(尤其是绵籽、落花生、玉米、种子、橄榄、蓖麻和芝麻油)、甘油、四氢呋喃基甲醇、聚乙二醇和脱水山梨醇脂肪酸酯和其混合物。
除了惰性稀释剂外,所述口服组合物也能包括辅助剂比如湿润剂、乳化剂和悬浮化剂、增甜剂、调味剂、着色剂、加香剂和防腐剂。
悬浮剂,除了所述活性成分外,例如可以含有悬浮化剂,如异硬脂醇乙氧基化物、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨润土、琼脂和西黄蓍胶和其混合物。
本发明药物组合物用于直肠或阴道给药的制剂可以是栓剂,该栓剂可以通过将一种或多种本发明化合物与一种或多种适合的非刺激性赋形剂或载体混合来制备,该赋形剂或载体包含例如可可脂、聚乙二醇、栓剂蜡或水杨酸盐,并且在室温时是固体而在体温时是液体,因此在直肠或阴道腔内融化并且释放活性化合物。本发明适合阴道给药的制剂也包括含有本领域公知为适当的载体的阴道栓剂、擦剂、乳膏剂、凝胶剂、膏剂、泡沫剂或喷雾剂。
本发明化合物用于局部或经皮给予的剂型包括散剂、喷雾剂、软膏剂、膏剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴剂、滴剂和吸入剂。活性成分可以在无菌条件下与药学上可接受的载体混合,并且与任何需要的缓冲剂或推进剂混合。
软膏剂、膏剂、乳膏剂和凝胶剂除了活性成分外还可以包含赋形剂,比如动物或植物脂肪、油、蜡、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌或其混合物。
散剂和喷雾剂除了活性成分外还能够含有赋形剂,比如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚胺粉末或这些物质的混合物。喷雾剂能够还含有常用的推进剂比如氯氟烃和挥发性的未被取代的烃比如丁烷和丙烷。
经皮贴剂具有提供使本发明化合物可控递送到人体的额外优点。这样的剂型能够通过将一种或多种本发明化合物溶解、分散或以其他形式引入到适当的介质比如弹性基质材料中来制备。也能够用吸收促进剂来提高所述化合物透过皮肤的流量。该流量的速度能够通过提供可控速膜或将该化合物分散到聚合物基质或凝胶中来进行控制。
药物制剂包括适合于吸入或吹入给予或者经鼻或眼内给予的那些。对于通过吸入给予到上(鼻)或下呼吸道的,本发明化合物方便地从吹入器、喷雾器或加压包装或其他递送喷雾剂便利的装置中递送。加压包装可以包含适合的推进剂比如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他适合的气体。在加压气溶胶的情况下,剂量单位可以通过提供阀以递送计量的量的方式来测定。
或者,对于吸入或吹入给药,所述组合物可以采用干粉的形式,例如本发明一种或多种化合物与适合的粉末基质比如乳糖或淀粉的粉末混合物。该粉末组合物可以以单位剂量的形式存在于例如胶囊或药筒或例如明胶或水泡包装中,该粉末可以在吸入器、吹入器或计量剂量吸入器的帮助下从上述中给药。
对于鼻内给药,本发明化合物可以通过滴鼻或液体喷雾的方法给予,比如凭借塑料瓶喷雾器或计量剂量吸入器。典型的喷雾器为Mistometer(Wintrop)和Medihaler(Riker)。
滴剂,比如滴眼剂或滴鼻剂,可以用也包含一种或多种分散剂、增溶剂或悬浮化剂的水性或非水性基质来制备。液体喷雾剂方便地从加压包装中递送。滴剂能够凭借简单的加盖滴眼瓶或塑料瓶来给药,该塑料瓶是以特殊形状闭合物的方式适应于液体内容物的滴加。
适合于非经肠给予的本发明药物组合物包含一种或多种本发明化合物联合一种或多种药学上可接受的无菌等渗水性或非水性溶液、分散体、悬浮液或乳剂,或恰恰在使用前可以被再分散到无菌可注射溶液或分散体中的粉末,它们可以含有抗氧剂、缓冲剂、使制剂与受试者血液等渗的溶质、或悬浮化剂或增稠剂。
可以在本发明药物组合物中使用的适合的水性或非水性载体的实例包括水、乙醇、多元醇(比如甘油、丙二醇、聚乙二醇等)和其适合的混合物,植物油比如橄榄油和可注射的有机酯比如油酸乙酯。适当的流动性能够例如通过使用包衣材料比如卵磷脂、如果是分散体的话通过保持其所需的颗粒大小以及通过使用表面活性剂来保持。
这些组合物也可以含有辅助剂比如湿润剂、乳化剂和分散剂。在组合物中也期望包括等渗剂比如蔗糖、氯化钠等。此外,延迟吸收剂比如单硬脂酸铝和明胶的加入可以使该可注射药物制剂产生延长吸收。
在一些情况下,为了延长药物的效果,期望延缓药物从皮下或肌肉注射剂中的吸收。这可以通过使用具有弱水溶性的晶形或非晶形物质的液体悬浮剂来实现。那么药物吸收的速率就依赖于溶出速率,依次地溶出速率可以依赖于晶粒大小和晶型。或者,非经肠给予药物的延迟吸收是通过将该药物溶解于或悬浮于油载体中来实现。
可注射的储库(depot)制剂通过在生物可降解聚合物比如聚乳酸-聚乙醇酸中形成药物的微囊基质来制备。依赖于药物与聚合物的比率和具体使用的聚合物的性质,能够控制药物释放的速率。其他生物可降解聚合物的实例包括聚(原酸酯)和聚(酐)。可注射的储库制剂也通过将药物包埋至与机体组织相容的脂质体或微乳中来制备。所述可注射的材料能够以例如通过除菌过滤器过滤的方法来灭菌。
制剂可以存在于单位剂量或多剂量密封的容器例如安瓿和管形瓶中,并且可以以只需恰在使用前添加无菌液体载体例如注射用水的冻干的条件储存。临时注射溶液和悬浮剂可以由上述说明类型的无菌粉末、颗粒剂和片剂来制备。
已经发现适合于本发明应用的二酮哌嗪类出现在含有白蛋白、免疫球蛋白和促红细胞生成素的一些可购得的静脉给予药物组合物中。在这些药物制剂中出现的二酮哌嗪类是通过制备这些药物组合物中常用的加热步骤来形成的。加热导致蛋白的两个N-末端和/或两个C-末端氨基酸断裂和环化形成二酮哌嗪类。
据此,在本发明中使用的二酮哌嗪类能够通过加热白蛋白、免疫球蛋白、促红细胞生成素和其他蛋白和肽的溶液来制备。例如制备了白蛋白、免疫球蛋白、促红细胞生成素或其他蛋白质或肽的中性pH磷酸盐缓冲液溶液。优选地,该溶液为浓缩溶液(例如大约100~500mM)以实现N-末端和/或C-末端氨基酸的质子化。将该溶液在60℃加热大约2小时~几天,优选大约4天,以引起二酮哌嗪类的形成。优选地应当避免蛋白变性。这能够通过使用缩短的时间和/或通过加入辛酸或N-乙酰基色氨酸各大约0.02M来实现。
本发明使用的二酮哌嗪类也能够通过使白蛋白、免疫球蛋白、促红细胞生成素或其他蛋白或肽的溶液与能从该蛋白或肽切断两个N-末端氨基酸的酶(例如二肽基肽酶)或能从该蛋白或肽切断两个C-末端氨基酸的酶(羧肽酶)相接触来制备。适合的二肽基肽酶和羧肽酶可购得,例如购自sigma。反应应该在pH6~8,优选在缓冲液比如磷酸盐缓冲液中进行,温度足够高到加速该反应但不够高到使蛋白变性(例如37℃)。
大量的蛋白和肽的氨基酸序列是已知的,并且能够使用任一方法来选择具有期望的N-末端和/或C-末端序列的蛋白或肽用来产生期望的二酮哌嗪(类)。具有期望序列的肽也能够用熟知的方法来合成并且使用。
所述二酮哌嗪类能够从含有它们的溶液中包括从含有白蛋白、免疫球蛋白和促红细胞生成素的药物组合物中纯化,通过熟知的方法比如分子筛析色谱法(例如Centricon滤过)、亲合色谱(例如使用在珠粒(beads)上附有针对期望的二酮哌嗪类的一种抗体或多种抗体或针对截短的蛋白或肽的一种或多种抗体的柱子)、阴离子交换或阳离子交换。纯化了的二酮哌嗪类能够被使用或引入到上述说明的药学组合物中。
取代对二酮哌嗪类的纯化,包含白蛋白、免疫球蛋白和促红细胞生成素和通常在受试动物中发现的其他蛋白和/或肽的药学组合物能够用于治疗T-细胞介导的疾病并且能够用来抑制T-细胞的活化。尽管包含这些蛋白和/或肽的当前可购得的组合物如果含有二酮哌嗪类就能够被使用,但高度优选的是在给予这些改良组合物之前按照上述说明对白蛋白、免疫球蛋白和促红细胞生成素和/或其他蛋白和/或肽进行处理以提高期望的二酮哌嗪类的含量。动物优选是人,并且所述蛋白和/或肽优选人蛋白和/或肽。组合物的口服给药是优选的。
所述蛋白和/或肽组合物的有效剂量能够凭经验决定,并且作这样的决定是本领域的技术之内的。尤其,为了决定蛋白和/或肽组合物的有效剂量,能够测量所述组合物中存在的一种或多种二酮哌嗪类的量,并且能够对动物给予足够产生该有效量二酮哌嗪类的量的组合物。本领域的技术人员应当理解剂量将随着具体使用的化合物、所要治疗的疾病或病症、疾病或病症的严重性、给予的途径、化合物的排泄速度、治疗的持续时间、对所述动物给予的其他药物的鉴定、所述动物的年龄、尺寸和种类等医药和兽医领域公知的因素而变化。一般地,蛋白和/或肽组合物的适合日剂量为有效产生治疗效果的最低剂量。然而,该日剂量将由主治医师或兽医在合适的医疗判断范围内决定。如果期望,有效日剂量可以以二、三、四、五、六或更多的分次剂量全天以适当的间隔分别地给予。给药应当持续到达到了可接受的应答为止。
如上说明的,已知可购得的包含白蛋白、免疫球蛋白和促红细胞生成素的静脉给予药物组合物中发现了二酮哌嗪类,这些组合物的制备中涉及一个或多个加热步骤(例如灭菌)。二酮哌嗪类也可能出现在组合物的制备中涉及加热步骤的其他蛋白和肽药物组合物中。如本文说明的,很多二酮哌嗪类具有抑制T-细胞活化的能力。因此,在很多条件下不希望对病人给予白蛋白、免疫球蛋白、促红细胞生成素或含有二酮哌嗪类的其他蛋白或肽的组合物。例如,白蛋白经常给予那些患有外伤的病人,免疫球蛋白经常给予患有传染或免疫缺陷的病人,以及促红细胞生成素给予免疫系统经常妥协的贫血癌症或慢性病病人。据此,本发明提供了从这些组合物中除去至少一些优选基本上全部除去二酮哌嗪类的方法。该二酮哌嗪类可以按照上面的说明来除去例如分子筛析色谱法(例如Centricon滤过)、亲合色谱(例如使用在珠粒上附有针对期望的二酮哌嗪类的一种抗体或多种抗体或针对截短的蛋白或肽的一种或多种抗体的柱子)、阴离子交换或阳离子交换以产生白蛋白、免疫球蛋白、促红细胞生成素和其他蛋白或肽的改良组合物。
实施例
实施例1:Asp Ala DKP(DA-DKP)和Glu Ala DKP(EA-DKP)从大鼠肠的吸收
将大鼠肠的幽门括约肌至直肠段游离并通过肠系膜动脉用以红细胞为基础的含有牛血清白蛋白的灌流液灌流。用门静脉插管收集从肠中流出的灌流液并且再循环(再充氧之后)。平衡期过后,将含有大约1mg的Asp-Ala二酮哌嗪(DA-DKP)或1.4mg的Glu-Ala二酮哌嗪(EA-DKP)的溶液大约1ml注射给予到该十二指肠的管腔中。
在给药之后,按照一定时间隔收集一系列的灌流液样品直到给药后2小时。将这些样品离心并且血浆以液相色谱法与质谱联用(LC-MS)的方法用于这两种环二肽的分析。
结果显示,在灌流后仅2小时,DA-DKP和EA-DKP从肠腔吸收入循环的量分别达到了给予剂量的95%和100%(事实上是112%)。
因此,两种环二肽都快速地被吸收并且有效地从肠腔进入到了血液,在从肠壁转运的过程中没有代谢的证明。因此可以通过口服来进行这些潜在的治疗。
无变化的DA-DKP和EA-DKP从胃肠道进入到血液中的快速吸收并且在分离的灌流的大鼠肝脏中两种化合物都缺乏首过肝清除(没有列出数据),显示系统前清除较低。因此口服给药将是理想的给药途径。
此外,对分离的灌流大鼠肾脏的研究显示,不象很多被肾肽酶广泛代谢的直链肽,两种环二肽的肾脏清除率相对较低。
所有这些数据提示二酮哌嗪类低日剂量给药范围对于治疗目的可能是足够的。
大鼠口服给药后的初步药动学数据与两种二肽的上述数据一致,在口服剂量1.1~3.7mg/kg体重(DA-DKP)和1.5~4.8mg/kg体重(EA-DKP)后,Tmax值为30~60分钟并且Cmax值为4~6μg/ml(DA-DKP)和0.6~1.1μg/ml(EA-DKP),(Tmax是达到最大浓度的时间,Cmax是达到的最大浓度;这两者都是由所得数据的曲线相应的方程计算得来的。)
初步数据提示DA-DKP和其他二酮哌嗪类通过血脑屏障。因此,DA-DKP和本发明的其他二酮哌嗪类应该对治疗神经系统疾病比如多发性硬化症是有用的。
实施例2:含有Met-Arg DKP(MR-DKP)的人初乳部分和Asp-AlaDKP(DA-DKP)在体外抑制人T-淋巴细胞因子的产生
A材料
该实施例例证了DA-DKP、含有MR-DKP的人初乳(HC2626)和也含有MR-DKP的人初乳的低分子量部分(HC RBL;含有通过脱脂初乳Centricon过滤制备的分子量低于3000的组分的人初乳部分)抑制人T-淋巴细胞因子的产生。DA-DKP和MR-DKP为从DMI Synthesis,Ltd.,Cardiff,UK.得到的。这两种二酮哌嗪类为对炎症的生理应答过程中产生的小的天然产生化合物。它们也有时在人静脉给予的免疫球蛋白(IVIg)、人白蛋白和其他生物制品中被发现。
B.抑制T-细胞因子产生
对两种不同CD-4阳性人T-淋巴细胞克隆进行了试验。这些细胞株的一种(TRiPS)是从流感免疫供体中分离得的并且对血球凝集素肽307~319是特异性的。另外一种细胞株(H4#9.25)是从多发性硬化症的供体的尸体解剖脑组织中分离得的并且对髓鞘质碱性蛋白(氨基酸87~99)是特异性的。在用(1)特异性抗原加HLA-DR2-显阳性细胞或(2)抗-CD3加抗-CD28抗体在体外刺激后,两种T-淋巴细胞克隆都产生白介素8(IL-8)、IL-16、干扰素-γ(IFN-γ)和肿瘤坏死因子α(TNF-α)。
在预先刺激后第18~20天用大约4×105个细胞进行所述T-淋巴细胞株的刺激传代。用冷的Iscove Modified Dulbecco Minimal EssentialMedium(IMDM,Sigma)加10%的胎牛血清(FBS;美国菌种保藏中心(ATCC))将细胞洗涤一次,并且重悬于含有1:500稀释的抗-CD3单克隆抗体OKT3(由小鼠腹水液体制备)的1.0ml冷IMDM培养基中。细胞在冰上与抗体培养30分钟,然后用无FBS的冷培养基洗涤,并在加入了50U/ml人IL-2(Xenometrix)的培养基中,作为饲养细胞,与大约2×106个4000R-照射的正常人供体的外周血白细胞(PBL)合并。通过在第三天加入含有FBS加IL-2的新鲜IMDM培养基扩大培养。培养的天数从用OKT3刺激的当天计算。从第7天(最大增殖)开始细胞能够用于实验,典型地是在第14天(对再刺激最敏感)并且直到第21天(静息细胞临近衰老)。
回收一小份细胞并用温(37℃)IMDM培养基洗涤两次来进行活化实验。对于每个特异性试验,将2×105个活细胞在含有特定量处理添加剂(例如,HC2626,DA-DKP,PMA等)的总体积0.9ml的温IMDM培养基中于37℃预培养15分钟。之后加入具有2×105个CD3/CD28Dynabeads(Dynal)作为活化刺激物的温IMDM0.1ml并且所述培养物于37℃过夜培养(18小时)。在通过离心使细胞沉淀后收集细胞培养物的上清液。以特异性ELISA(例如,TNFα,IFNγ,IL-8,IL-16;Endogen)分析细胞因子含量。
如图1~5显示的,人初乳(HC2626)以剂量依赖的方式抑制这两种T-淋巴细胞株的体外细胞因子的产生。也如图1~5显示的,HC RBL和DA-DKP以剂量依赖的方式在刺激周期的早期抑制这两种T-细胞株的体外细胞因子的产生。然而,HC RBL和DA-DKP在该周期晚期(第14天或更迟)是刺激作用的(见图4)。HC2626和HC RBL都含有MR-DKP(如用质谱法确定的),但HC2626除了可能对细胞周期晚期抑制作用负责的MR-DKP外,含有其他组分(包括为相应脱磷酸化蛋白因而可抗炎的酪蛋白,如在2003年11月25日提交的共同在审申请10/723,247中说明)。据此,HC RBL和HC2626(两者都含有MR-DKP)、MR-DKP和DA-DKP应该对在T-细胞介导的和/或自身免疫疾病比如多发性硬化症中的炎症细胞因子应答的下调是有用的,因为它们在刺激周期早期都抑制T-细胞的细胞因子产生。这些结果也提示HC RBL、HC2626、MR-DKP和DA-DKP选择性地影响抗原-特异性T-细胞而不影响静息T-细胞。
C.作用机理
对DA-DKP和HC2626(含有MR-DKP)的作用机理进行了研究。为了这样做,将1×106个第18天TRiPS细胞于37℃培养30分钟,同时什么都不加("全无"),加入CD3/CD28Dynabeads(CD3/CD28珠粒),加入CD3/CD28珠粒和0.5mM DA-DKP,或者加入CD3/CD28珠粒和1:500稀释的HC2626。培养之后,将细胞在细胞裂解的哺乳动物细胞提取试剂(Sigma)中裂解。
然后将该细胞提取物于室温用重复的Hypromatrix阵列分离地培养,之后按照制造厂家(Hypromatrix)的方案洗涤两次。该Hypromatrix阵列是用表1中列出的转录因子的抗体印迹过的尼龙膜(Hypromatrix定做的)。加入对磷酸化酪氨酸、磷酸化丝氨酸和磷酸化苏氨酸特异性的抗体混合物(Zymed),培养1小时。然后加入用生物素标记的抗-免疫球蛋白抗体。洗去该抗-免疫球蛋白-生物素后,加入链霉抗生物素蛋白-过氧化物酶,并且在加入过氧化物酶-反应发光底物之前对芯片进行最后的洗涤。
通过暴光胶片可以使结果直观化并且如表2所示的将结果按照0(阴性)或+~++++(阳性)评分。如表2显示的,一些细胞转录因子的活化(ERK1/2)和预成(pe-formed)细胞因子的释放被HC2626(含有MR-DKP)和DA-DKP所抑制。
表1:Hypromatrix阵列(定做的):用于磷酸化的蛋白
表2:结果
实施例3:Gly-Leu DKP(GL-DKP)和Ala-Pro DKP(AP-DKP)在体外抑制人T-淋巴细胞因子的产生
按照实施例2中所说明的使用TRiPS和H4#9.25细胞株对GL-DKP和AP-DKP(从DMI Synthesis,Ltd.,Cardiff,UK得到)进行试验。发现GL-DKP和AP-DKP以剂量依赖方式抑制这两种T-淋巴细胞株的体外细胞因子产生。该作用机理如实施例2中所述当前处在研究中,并且细胞因子转录因子的激活和预成的细胞因子的释放都被影响。
实施例4:Asp Ala DKP(DA-DKP)和Tyr Glu DKP(YE-DKP)在体外抑制人T-淋巴细胞因子的产生
用Histopaque(Sigma)从正常人供体的外周血液中分离正常人淋巴细胞。然后,将3-4×105个该淋巴细胞悬浮于1ml无血清的IMDM中。通过加入25μl的1:2000稀释的抗-CD3抗体(Pharmingen,San Diego,CA)来刺激细胞,并于37℃培养18小时。
然后将三种DKP制剂中的一种和地塞米松(终浓度为10-5M)加入到三份培养物中。所述三种DKP制剂为:
1.DA-DKP(从DMI Synthesis,Ltd.,Cardiff,UK得到;在培养物中的终浓度为25μg/ml)。
2.DKP-ZLB,一种25%白蛋白制剂(从ZLB Bioplasma,AG3000Berne22Switzerland得到),它于60℃加热了4天,之后经质谱法测定发现其含有0.5mM DA-DKP(培养物中DA-DKP的终浓度为14μg/ml)。
3.DKP-γ-球蛋白---在pH7.4的磷酸盐缓冲盐水中含有12mg/mlγ-球蛋白的γ-球蛋白制剂(从Sigma得到,编号G-4386)用Centricon3000过滤器过滤,并且使用该滤液(含有分子量小于3000的组分)。如阴离子交换HPLC与阴性电喷射质谱联用所测定的,该滤液含有一个292的分子量,其为Tyr-GluDKP(YE-DKP)的分子量。该滤液在培养物中以1:4的最终稀释液来使用。
加入DKP制剂或地塞米松之后,该培养物于37℃培养18小时。然后用ELISA(Pierce Biotechnology,Rockford,IL61105)测定释放到每种培养物中的IL-2、IFNγ和TNFα的量。
结果在下面表3中显示。如所见的,使用DKP-γ-球蛋白取得了所有这三种细胞因子释放的最大减少。观察CD69+T-细胞(CD69是在活化的T-细胞上发现的标记)数量的流式细胞术也显示尽管T-细胞受体复合物内化,DKP-γ-球蛋白大约减少了90%的CD69+T-细胞数量,相比较地地塞米松减少了大约50%的。
表3
Claims (6)
1.一种药物组合物,其含有蛋白或肽的溶液的滤液,其中,所述滤液是通过使蛋白或肽的溶液通过超滤膜而制备的,所述超滤膜具有能保留选自白蛋白、免疫球蛋白和促红细胞生成素中的蛋白的截留分子量,所述滤液包含选自YE-DKP、MR-DKP和DA-DKP中的二酮哌嗪。
2.权利要求1的组合物,其中所述滤液包含分子量小于3000的组分。
3.权利要求1的组合物,其中所述蛋白或肽为人蛋白或肽。
4.权利要求1的组合物,其中所述蛋白或肽为人白蛋白。
5.权利要求2的组合物,其中所述蛋白或肽为人蛋白或肽。
6.权利要求2的组合物,其中所述蛋白或肽为人白蛋白。
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