CN103038210A - 作为消炎、免疫调节和抗增殖剂的新型化合物的钙盐 - Google Patents
作为消炎、免疫调节和抗增殖剂的新型化合物的钙盐 Download PDFInfo
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- CN103038210A CN103038210A CN2011800332745A CN201180033274A CN103038210A CN 103038210 A CN103038210 A CN 103038210A CN 2011800332745 A CN2011800332745 A CN 2011800332745A CN 201180033274 A CN201180033274 A CN 201180033274A CN 103038210 A CN103038210 A CN 103038210A
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Abstract
本发明涉及通式(I)的化合物的钙盐或其水合物，其中X选自CH2、S或O；D为O或S；R8为氢或烷基；E为任选取代的亚苯基基团；Y为单环或双环的取代或未取代的6—9元环系，其可含有一个或多个选自N或S的杂原子并含有至少一个芳族环；n为0或1，且q为0或1；条件是不包括其中X=CH2、q=0、Y=未取代的苯基且E=未取代的亚苯基的化合物。
Description
技术领域
本发明涉及可用作消炎、免疫调节和抗增殖剂的新型化合物的钙盐。特别地，本发明涉及抑制二氢乳清酸脱氢酶（DHODH）的新型化合物的钙盐、其制造方法、含有所述钙盐的药物组合物，并且涉及它们治疗和预防疾病的用途，尤其是它们在用于其中对于抑制二氢乳清酸脱氢酶（DHODH）具有优势的疾病中的用途。
背景技术
类风湿性关节炎（RA），尤其是在老年人中是一种非常常见的疾病。利用普通药物如非甾体类消炎药对其进行治疗不太令人满意。从人口日趋老龄化考虑，尤其是在发达的西方国家或在日本，迫切需要开发用于治疗RA的新型药物。
WO2003/006425描述了某些特定的化合物，据报道，其可用于治疗和预防疾病，其中在抑制二氢乳清酸脱氢酶（DHODH）方面具有优势。然而，未公开根据该发明的特定盐类。
WO99/38846和EP0646578公开了据报道可用于治疗RA的化合物。
近来，利用新作用机制抵抗类风湿性关节炎的药物来氟米特（leflunomide）已经由Aventis公司在商品名ARAVA下投放市场[EP780128、WO97/34600]。来氟米特具有免疫调节和消炎的性能[EP217206、DE2524929]。所述作用机制是以抑制嘧啶生物合成酶二氢乳清酸脱氢酶（DHODH）为基础的。
De Julian-Ortiz （J.Med.Chem.1999，42，3308-3314）描述了具有环戊烯酸部分的一些潜在抗疱疹化合物。
DE3346814Al描述了用于治疗、预防和减轻与大脑功能障碍相关的疾病和由此造成的症状的一些碳酸酰胺衍生物。
在身体内，DHODH催化合成细胞生长所需要的嘧啶。抑制DHODH，就抑制了（病态）快速增殖细胞的生长，而以正常速度生长的细胞可从正常的代谢循环中得到其所需要的嘧啶碱。用于免疫反应的最重要类型的细胞淋巴细胞专门使用嘧啶的合成以用于其生长并且对于抑制DHODH反应特别敏感。抑制淋巴细胞生长的物质是治疗自身免疫病的重要药物。
DHODH抑制剂来氟米特（ARAVA）是治疗类风湿性关节炎的这类化合物（来氟米特）的第一药物。WO99/45926是公开用作DHODH抑制剂的化合物的另外的文献。
JP-A-50-121428公开了作为除草剂的N-取代的环戊烯-1,2-二羧酸单酰胺及其合成。例如，通过使1-环戊烯-1,2-二羧酸酐与4-氯苯胺反应制造N-(4-氯苯基)-1-环戊烯-1,2-二羧酸单酰胺。
在Journal ofMed.Chemistry，1999，第42卷，第3308-3314页中，描述了新型潜在抗疱疹化合物的虚拟组合合成和计算机筛选。在3313页上的表3中，对于2-(2,3-二氟苯基氨基甲酰)-l-环戊烯-l-羧酸、2-(2,6-二氟苯基氨基甲酰)-l-环戊烯-l-羧酸和2-(2,3,4-三氟苯基-氨基甲酰)-1-环戊烯-1-羧酸，提供了关于IC50和细胞毒性的实验结果。
DE3346814和US4661630公开了羧酸酰胺。这些化合物可用于与大脑功能障碍相关的疾病，并且还具有抗溃疡、抗哮喘、消炎和降胆固醇的活性。
在EP0097056、JP55157547、DE2851379和DE2921002中，描述了四氢邻氨甲酰苯甲酸衍生物。
发明内容
本发明的目的是提供备选的有效药剂，特别是其钙盐形式的药剂，所述药剂能够用于治疗需要抑制DHODH的疾病。
特别地，先前已经发现，在下文中显示的通式(I)的化合物例如2-(3-氟-3'-甲氧基-联苯-4-基氨基甲酰)-环戊-1-烯羧酸（INN Vidofludimus），显示了好的消炎活性，并且已确定其可用于治疗自身免疫病如类风湿性关节炎或消炎肠道疾病的口服治疗。然而，在中性pH下上述化合物在含水介质中的溶解度小于1 mg/ml。
化合物的溶解度是药物发现中的重要特征，因为其充当配方开发的起点。此外，在口服给药之后，将药物从肠吸收入循环系统中至少部分取决于其溶解度。只有溶解的物质可被吸收，从而可预期，提高溶解度可导致在胃肠道中更好地摄取化合物，即导致更好的口服生物利用度并且因此提高药动学性质。期望提供具有提高的生物利用度的化合物，以便改进其作为口服用药物化合物的用途。
因此，本发明人已经就提高化合物在含水介质中的溶解度并且由此提高其生物利用度作出了努力。在该动机下，对开发新型盐形式的化合物进行了研究，制得了出乎意料地显示出明显改进的物理化学性质的盐。
已经发现，如下文中所述的式(I)化合物的钙盐，例如2-(3-氟-3'-甲氧基-联苯-4-基氨基甲酰)-环戊-1-烯羧酸的钙盐，显示了有利的物理化学性质例如改进的水溶解度，同时保持了好的长期稳定性。此外发现，通常并不是所述化合物的所有盐都将水溶解度提高至相同程度；事实上，尽管试验的盐的溶解度均比游离酸的高，但是它们明显相互不同。更重要的是，与其它盐或游离酸相比，钙盐令人惊奇地显示出明显更高的生物利用度。
因此，发现了对DHODH、尤其是人体DHODH具有抑制效果的新类别的化合物的钙盐。
因此，本发明涉及通式(I)的化合物的钙盐或其水合物
其中
X选自CH2、S或O；
D为O或S；
R8为氢或烷基，优选氢或甲基；
E为任选取代的亚苯基基团；
Y为单环或双环的取代或未取代的6—9元环系，其可以含有一个或多个选自N或S的杂原子并含有至少一个芳族环；优选地，Y为取代或未取代的苯基；
n为0或1，优选0；且
q为0或1，优选0；
条件是不包括其中q=0、Y=未取代的苯基且E=未取代的亚苯基的化合物。
E优选为未取代的亚苯基基团或用一个或多个独立地选自卤素、硝基或烷氧基的基团取代的亚苯基基团；更优选地，E是用一个氟或氯原子、一个甲氧基基团或用四个氟原子取代的亚苯基基团。甚至更优选地，E是用一个或四个氟原子、还甚至更优选一个氟原子取代的亚苯基基团。
Y优选为任选取代的苯基、吡啶或苯并噻吩基团。更优选地，Y为未取代的苯基基团或用一个或多个独立地选自卤素、烷基、烷氧基、卤代烷氧基、卤代烷基或CN的基团取代的苯基基团。甚至更优选地，E为用一个或多个独立地选自氟、氯、CN、甲氧基、乙氧基、三氟甲基或三氟甲氧基的基团取代的苯基基团。还甚至更优选地，E为用一个或多个独立地选自甲氧基或三氟甲氧基的基团、还甚至更优选地甲氧基取代的苯基基团。
如无其它规定，则烷基基团优选为1至6个碳原子的饱和直链或支链，优选甲基、乙基、丙基、异丙基、丁基、叔丁基、异丁基、戊基或己基基团，更优选甲基、乙基、异丙基或叔丁基基团，甚至更优选甲基或乙基基团，还甚至更优选甲基基团。
烷氧基基团是指O-烷基基团，所述烷基基团为如上所定义的。
卤代烷基基团是指用一个或多个卤素原子取代的烷基基团，所述烷基基团为如上所定义的；优选三氟甲基。
卤代烷氧基基团是指用一个或多个卤素原子取代的烷氧基基团，所述烷氧基基团为如上所定义的；优选OCF3。
卤素优选为氯、溴、氟或碘，优选氟、氯或溴，更优选氟。
本发明还提供如下的药物组合物，其包含如上所述式(I)的化合物的钙盐或还包含在药物学上可接受的用于所述钙盐的稀释剂或载体。
在另一方面，本发明还提供用于治疗或预防其中对于抑制二氢乳清酸脱氢酶（DHODH）具有优势的病变的方法，所述方法包括给药有效量的如上所述式(I)化合物的钙盐。
本发明还涉及如上所述式(I)化合物的钙盐用于制造预防和治疗疾病的药物的用途，其中抑制嘧啶的生物合成是有利的。
本发明还包括根据本发明的盐的水合物，其指定可得自所述盐的晶体以特定的化学计量或亚化学计量的量含有水，所述计量的量例如为每分子此处所述式(I)或式(Ia)的化合物中0.5、1或2个水分子。
在如下项[1]至[8]中对本发明另外优选的方面进行了总结：
[1]式(Ia)的化合物的盐
碱选自钙（Ca）、二乙胺（DEA）、N-甲基-D-葡糖胺（NMG）、锂（Li）、锌（ZN）、L-精氨酸、4-(2-羟乙基)吗啉（HEM）、L-赖氨酸（LYS）、胆碱（CHO）和氨（NH3）。
[2]项[1]的化合物，其为具有任何选自钙（Ca）、二乙胺（DEA）、N-甲基-D-葡糖胺（NMG）的碱的2-(3-氟-3'-甲氧基-联苯-4-基氨基甲酰)-环戊-1-烯羧酸的盐。
[3]药物组合物，其包含如项[1]至[2]的任何项中所限定的化合物以及在药物学上可接受的稀释剂或载体。
[4]根据项[1]至[2]的化合物作为药物的用途。
[5]如项[1]至[2]任何项中所限定的式(Ia)化合物在制造用于治疗疾病或治疗适应证的药物中的用途，其中抑制二氢乳清酸脱氢酶和/或白细胞介素-17（IL-17）是有利的。
[6]项[5]的用途，其中所述疾病或适应证是自身免疫病。
[7]项[6]的用途，其中所述自身免疫病选自强直性脊柱炎、自身免疫性甲状腺炎、腹腔疾病、毒性弥漫性甲状腺肿（Grave’s disease）、炎症性肠病（克隆（Crohn）病、溃疡性结肠炎）、1型糖尿病、系统性红斑狼疮、多发性硬化、白癜风、骨性关节炎、银屑病、银屑病性关节炎或类风湿性关节炎。
[8]如项[1]至[2]的任何项中所限定的式(Ia)化合物在制造用于治疗任何形式肿瘤的药剂中的用途。
另外，本发明提供用于制备本发明化合物例如式(I)的希望的酰胺的方法，以及用于制备其如上所述的钙盐的方法。
用于合成式(I)酰胺的第一种方法包括使式(II)的酸酐与式(III)的胺反应的步骤。
用于制备式(I)化合物的本发明第二种方法包括使式(IV)的胺与通式(V)的芳基-硼酸(HO)2B-E-[D-(CHR3)n]q-Y反应的步骤[M.P.Winters，Tetrahedron Lett，39，(1998)，2933-2936]。
用于制备式(I)化合物的本发明第三种方法包括使式(VI)的卤素衍生物与通式(VII)的芳基-硼酸反应的步骤[N.E.Leadbeater，S.M.Resouly，Tetrahedron，55，1999，11889-11894]。Q为卤素基团，例如氯、溴、氟或碘，优选溴。
在此处所描绘的式II至VII的结构中，残基X、E、D、Y和R8以及变量n和q具有如此处关于式I所限定的含义。
优选地，本发明的盐为从选自下述化合物1至76的化合物得到的钙盐：
1.2-((4-(苄氧基)苯基)氨基甲酰)环戊-1-烯羧酸
13.2-((2'-氟-[l,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
14.2-((2'-氯-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
15.2-((2'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
16.2-((4-((2,6-二氟苄基)氧基)苯基)氨基甲酰)环戊-1-烯羧酸
17.2-((2'-乙氧基-3-氟-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
18.2-((2-氯-3'-氰基-[l,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
19.2-((2-氯-4'-甲氧基-[l,l'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
22.2-((3-氯-4-(6-甲氧基吡啶-3-基)苯基)氨基甲酰)环戊-1-烯羧酸
23.2-((4'-甲氧基-2-甲基-[l,l'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
24.2-((3,5-二溴-4-((2,5-二氟苄基)氧基)苯基)氨基甲酰)环戊-1-烯羧酸
25.2-((3,5-二溴-4-((3,4-二氟苄基)氧基)苯基)氨基甲酰)环戊-1-烯羧酸
26.2-((3-氟-3'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
27.2-((3,3'-二氟-[l,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
29.4-((4-(苄氧基)-3,5-二溴苯基)氨基甲酰)-2,5-二氢噻吩-3-羧酸
30.2-((3,4',5-三氟-3'-甲基-[l,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
31.2-((3,5-二氟-2'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
32.2-((2'-甲氧基-3-硝基-[l,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
33.2-((3-甲氧基-[l,l'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
34.2-((2'-氯-3-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
35.2-((3-甲氧基-3'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
36.2-((2'-氟-3-甲氧基-[l,l'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
37.2-((2',3,4'-三甲氧基-[l,l'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
38.2-((3'-乙氧基-3-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
39.2-((3,3'-二甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
40.2-((3,5-二溴-4-((2-氯-6-氟苄基)氧基)苯基)氨基甲酰)环戊-1-烯羧酸
41.4-((2'-氯-[1,1'-联苯]-4-基)氨基甲酰)-2,5-二氢噻吩-3-羧酸
42.2-((4-(间甲苯基硫)苯基)氨基甲酰)环戊-1-烯羧酸
43.2-((3'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
44.2-((4-(苯并[b]噻吩-2-基)苯基)氨基甲酰)环戊-1-烯羧酸
45.2-((4-(苯并[b]噻吩-2-基)-2-氟苯基)氨基甲酰)环戊-1-烯羧酸
46.2-((3'-乙氧基-3-氟-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
47.4-((3,5-二氟-2'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)-2,5-二氢呋喃-3-羧酸
50.2-((4-苯氧基苯基)氨基甲酰)环戊-1-烯羧酸
52.4-((3,5-二溴-4-((2-氯-6-氟苄基)氧基)苯基)氨基甲酰)-2,5-二氢噻吩-3-羧酸
53.2-((3-氯-2'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
54.2-((2-氯-2'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
56.2-((2,3,5,6-四氟-2'-甲氧基-[l,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
57.2-((2'-甲氧基-3-甲基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
58.2-((3,5-二氯-2'-甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
62.2-((2'-乙氧基-3,5-二氟-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
63.2-((3'-乙氧基-3,5-二氟-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
64.2-((3,5-二氟-3'-(三氟甲氧基)-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
65.2-((2'-氯-3,5-二氟-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
66.2-((2',3,5-三氟-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
67.2-((3,5-二氟-2',4'-二甲氧基-[1,1'-联苯]-4-基)氨基甲酰)环戊-1-烯羧酸
68.2-((3-氯-4-((2-(三氟甲基)苄基)氧基)苯基)氨基甲酰)环戊-1-烯羧酸
69.2-((3-氯-4-((2-氯-6-氟苄基)氧基)苯基)氨基甲酰)环戊-1-烯羧酸
72.2-((4-(苄氧基)-3-氯苯基)氨基甲酰)环戊-1-烯羧酸
74.2-((3-氯-4-((2-氟苄基)氧基)苯基)氨基甲酰)环戊-1-烯羧酸
76.2-(((3-氟-2'-甲氧基-[1,1'-联苯]-4-基)氧基)氨基甲酰)环戊-1-烯羧酸
优选地，本发明的钙盐为上述钙盐，其中式(I)的化合物选自下表1中所示的化合物：
可通过多种方法，包括在JP-A-50-121428中所述的方法，得到式(I)的化合物。在本发明方法的优选实施方式中，使用两种如下的合成方法。
方法1：在第一步骤中，可从相应的α,α'-二溴烷二羧酸得到环烯-1,2-二羧酸，如R.N.Mc Donald和R.R.Reitz，J.Org.Chem.37，(1972)2418-2422所述的。也可由庚二酸得到大量的环戊烯-1,2-二羧酸[D.C.Owsley和J.J.Bloomfield，Org.Prep.Proc.Int.3，(1971)61-70；R.
J.Chem.Soc.(1926)，655-663]。
通常，通过氰醇合成，可合成在环系中或在环系上取代的二羧酸[Shwu-Jiüan Lee等人，Bull.Inst.Chem.Academia Sinica Number 40，(1993)，1-10或B.R.Baker等人J.Org.Chem.13，1948，123-133；以及B.R.Baker等人，J.Org.Chem.12，1947，328-332；L. A.Paquette等人，J.Am.Chem.Soc.97，(1975)，6124-6134]。
然后，通过使所述二羧酸与乙酸酸酐反应可将所述二羧酸转化成相应的酸酐[P.Singh和S.M.Weinreb，Tetrahedron 32，(1976)，2379-2380]。
在如下文献中也描述了制备式(II)的不同酸酐的其它方法：V.A.Montero等人，J.Org.Chem.54，(1989)，3664-3667；P.ten Haken，J.Heterocycl.Chem.7，(1970)，1211-1213；K.Alder，H.Holzrichter，J.Lieb.Annalen d.Chem.524，(1936)，145-180；K.Alder，E.Windemuth，J.Lieb.Annalen d.Chem.543，(1940)，56-78；以及W.Flaig，J.Lieb.Annalend.Chem.568，(1950)，1-33。
然后，可使这些酸酐与相应的胺反应以形成期望的式(I)的酰胺。通过使用如J.V.de Julian Ortiz等人，J.Med.Chem.42，(1999)，3308中所述的反应条件（实施例1中的设计路线A）或通过使用4-二甲基氨基吡啶（实施例1中的设计路线B），可实施该反应。
方法2：通过使式(IV)的胺与通式(V)的芳基硼酸反应也能够合成式(I)的酰胺[M.P,Winters，Tetrahedron Lett.，39，(1998)，2933-2936]。
通常通过钯偶联能够合成二芳基苯胺[G.W.Kabalka等人，Chem.Commun.，(2001)，775；A.Demeter，Tetrahedron Lett.38;(1997)，5219-5222；V.Snieckus， Chem.Commun.22，(1999)，2259-2260]。
方法3：通过使式(VI)的卤素衍生物与通式(VII)的芳基硼酸反应也能够合成式(I)的酰胺[N.E.Leadbeater，S.M.Resouly，Tetrahedron，55，1999，11889-11894]。
本发明的钙盐可用于多种人和动物的疾病，优选人的疾病，其中抑制嘧啶的代谢是有利的。这样的疾病为：
-纤维化、葡萄膜炎、鼻炎、哮喘或关节病，尤其是关节病
-所有形式的风湿病
-急性免疫学事件和紊乱，例如脓毒症、脓毒症休克、内毒素休克、革兰氏阴性脓毒症、中毒性休克综合症、急性呼吸窘迫综合症、中风、再灌注损伤、CNS损伤、严重形式的过敏、移植物抗宿主和宿主抗移植物反应、阿尔茨海默病或发热、再狭窄、慢性肺部炎性疾病、矽肺病、肺部肉瘤病、骨吸收疾病。这些免疫学事件还包括对免疫系统的希望的调节和抑制；
-所有类型的自身免疫病，特别是类风湿性关节炎、类风湿性脊椎炎、骨性关节炎、痛风性关节炎、多发性硬化、胰岛素依赖的糖尿病和非胰岛素依赖的糖尿病，和红斑狼疮、溃疡性结肠炎、克隆氏症、炎性肠病，以及其它慢性炎症、慢性腹泻；
-皮肤病学紊乱如银屑病；
-渐进性视网膜萎缩；
-所有类型的感染，包含机会性感染。
根据本发明的钙盐和用其制备的药物通常用于治疗细胞增殖紊乱，用于治疗或预防免疫学疾病和病变（例如炎性疾病、神经免疫学疾病、自身免疫病等）。
本发明的钙盐还可用于开发免疫调节药物和消炎药物，或更普遍地用于治疗疾病，其中抑制嘧啶的生物合成是有利的。
本发明的钙盐还可用于治疗由恶性细胞增殖引起的疾病，例如所有形式的血液和实体肿瘤。因此，根据本发明的化合物和用其制备的药物通常可用于调节细胞活化、细胞增殖、细胞存活、细胞分化、细胞周期、细胞成熟和细胞死亡，或在代谢中诱发系统变化例如在糖、脂质或蛋白质代谢中的变化。它们还可用于支持细胞生成，包括在如由例如毒剂、辐射、免疫疗法、生长缺陷、营养不良、吸收不良、免疫失调、贫血等引起的细胞清除或损伤之后血液细胞的生长和生成（前造血效应），或用于提供组织产生和退化的治疗控制，以及细胞和组织维护和血液细胞体内平衡的治疗矫正。
这些疾病和病变包括但不限于作为血液肿瘤（例如白血病、淋巴瘤、骨髓瘤）或实体肿瘤（例如乳房、前列腺、肝、膀胱、肺、食管、胃、结肠直肠、泌尿生殖器、胃肠、皮肤、胰腺、大脑、子宫、结肠、头和颈以及卵巢、黑色素瘤、星形细胞瘤、小细胞肺癌、胶质瘤、基底和鳞状细胞肿瘤、作为卡波西肉瘤和骨肉瘤的肉瘤）的癌症，涉及T细胞的紊乱例如再生障碍性贫血和迪格奥尔格综合症、毒性弥漫性甲状腺肿的治疗。
先前发现来氟米特在细胞培养中抑制HCMV复制。眼疱疹是发达国家中传染性致盲的最常见原因。仅在美国每年就有大约50,000例，其中90%会复发初始感染。用抗病毒药和皮质甾体类治疗复发。巨细胞病毒，另一种疱疹病毒是具有艾滋病的患者中发生视网膜损伤和致盲的常见原因。本发明的化合物可单独使用或以与其它抗病毒化合物如更昔洛韦（Ganciclovir）和膦甲酸（Foscarnet）组合的方式使用以治疗这样的疾病。
另外可将本发明的钙盐用于由人体和动物中原生动物的侵袭引起的疾病。这种兽医学和人体致病性原生动物优选是顶复体门（phylumApicomplexa）或肉足鞭毛亚门（Sarcomastigophora）的细胞内的活性寄生虫，尤其是锥虫（Trypanosoma）、疟原虫（Plasmodia）、利什曼虫（Leishmania）、八贝西虫（Babesia）和泰勒虫（Theileria）、隐孢子虫属（Cryptosporidia）、肉孢子虫属（Sacrocystida）、变形虫（Amoebia）、球虫（Coccidia）和毛滴虫（Trichomonadia）。这些活性物质或相应的药物尤其适用于治疗由恶性疟原虫（Plasmodium falciparum）引起的热带性疟疾（Malaria tropica）、由间日疟原虫（Plasmodium vivax）或卵形疟原虫（Plasmodium ovale）引起的间日疟（Malaria tertiana），并适用于治疗由三日疟原虫（Plasmodium malariae）引起的三日疟（Malariaquartana）。它们还适用于治疗由弓形虫（Toxoplasma gondii）引起的弓形体病（Toxoplasmosis）、由例如贝氏等孢球虫（Isospora belli）引起的球虫病（Coccidiosis）、由肉孢子虫（Sarcocystis suihominis）引起的肠内肉孢子虫病（intestinal Sarcosporidiosis）、由痢疾变形虫（Entamoeba histolytica）引起的痢疾（dysentery）、由隐孢子虫（Cryptosporidium parvum）引起的隐孢子虫病（Cryptosporidiosis）、由美洲锥虫（Trypanosoma cruzi）引起的南美锥虫病（Chargas′disease）、由罗得西亚锥虫（Trypanosoma brucei rhodesiense）或冈比亚锥虫（gambiense）引起的昏睡症、皮肤和内脏以及其它形式的利什曼病（Leishmaniosis）。它们还适用于治疗被兽医学致病性原生动物感染的动物，所述兽医学致病性原生动物的例子如下：泰勒原虫（Theileriaparva），引起牛东海岸热（bovine East coast fever）的病原体，刚果锥虫（Trypanosoma congolense congolense）或活动锥虫（Trypanosomavivax vivax）、布氏锥虫（Trypanosoma brucei brucei），在非洲引起非洲锥虫病牛的疾病（Nagana cattle disease）的病原体，引起苏拉病（Surra）的布氏锥虫伊氏亚种（Trypanosoma brucei evansi），双芽巴贝斯虫（Babesia bigemina），在牛和水牛中引起德克萨斯牛瘟（Texas fever）的病原体，牛巴贝斯虫（Babesia bovis），引起欧洲牛巴贝斯虫病（bovineBabesiosis）以及在狗、猫和羊中引起巴贝斯虫病（Babesiosis）的病原体，犬羊猫肉孢子虫（Sarcocystis ovicanis和ovifelis），在绵羊、牛和猪中引起肉孢子虫病的病原体，隐孢子虫属，在牛和鸟中引起隐孢子虫病的病原体，艾美球虫属（Eimeria）和等孢子球虫属（Isospora）物种，在兔子、牛、绵羊、山羊、猪和鸟尤其是小鸡和火鸡中引起球虫病的病原体。特别是对于治疗球虫病或疟疾感染，或用于制备治疗这些疾病的药物或饲料原料，优选使用本发明的化合物。这种治疗可为预防性的或治疗性的。在疟疾的治疗中，本发明的化合物可与其它抗疟疾药剂组合。
本发明的钙盐还可用于病毒感染或由例如卡氏肺孢子虫（Pneumocystis carinii）引起的其它感染。
优选地，用根据本发明的钙盐治疗或预防的疾病或医疗病变选自移植物抗宿主和宿主抗移植物反应、类风湿性关节炎、多发性硬化、红斑狼疮、炎性肠病以及银屑病。
就疗法本身，作为与另一种物质的混合物，或以允许肠内使用或注射使用并且作为活性成分除惯用药物无害赋形剂和添加剂之外还含有有效剂量的至少一种式(I)化合物的上述钙盐的形式，可将式(I)的化合物的钙盐给药给动物，优选哺乳动物并且特别是人、狗和鸡。
所述疗法可为口服，口服的形式例如为丸剂、片剂、包衣片剂、糖衣片剂、硬和软的明胶胶囊、溶液、糖浆剂、乳剂或悬浮剂或气雾剂混合物。然而，还可例如以栓剂的形式通过直肠实施给药，例如以注射或输液的形式通过注射实施给药，或例如以软膏剂、乳膏或酊剂的形式经由皮肤实施给药。
除了式(I)的活性化合物的上述盐之外，所述药物组合物还可包含惯用的、通常呈惰性的载体材料或赋形剂。由此，所述药物制剂还可包含添加剂，例如填料、增量剂、崩解剂、粘合剂、助流剂、润湿剂、稳定剂、乳化剂、防腐剂、甜味剂、着色剂、调味品或香料、缓冲物质，此外还有溶剂或增溶剂或实现贮存效果的试剂，以及用于改变渗透压的盐、包覆剂或抗氧化剂。它们还可含有两种或更多种式(I)化合物的上述盐，并且还可含有其它治疗活性物质。
因此，本发明的盐可单独使用或以与其它活性化合物组合的方式使用，例如与已知用于治疗上述疾病的药物组合使用，由此在后一种情况中观察到有利添加的、放大的效果。服用给人的合适的量为5—500mg。
为了制备所述药物制剂，可使用在药物学上呈惰性的无机或有机赋形剂。为了制备丸剂、片剂、包衣片剂和硬明胶胶囊，可使用例如乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等。用于软明胶胶囊和栓剂的赋形剂为例如脂肪、蜡、半固体和液体多元醇、天然油或氢化油等。用于生产溶液和糖浆剂的合适赋形剂为例如水、蔗糖、转化糖、葡萄糖、多元醇等。用于生产注射溶液的合适赋形剂为例如水、醇、甘油、多元醇或植物油。
在各种个体情况中，所述剂量可在宽界限内变化且适合于个体的病变。关于上述用途，适当的剂量将随服用模式、要治疗的特殊病变和所期望的效果而变化。然而，通常，在约1至100mg/kg动物体重、优选1至50mg/kg动物体重的剂量率下实现满意的结果。对于更大的哺乳动物例如人，合适的剂量率为约10mg至3g/天的数量级，其可方便地每天服用一次、每天分开剂量服用2～4次或以缓释形式服用。
通常，在口服的情况中，对于每个单独的人，约10mg至5000mg、优选50至500mg的日剂量是合适的，所述口服是根据本发明的优选服用形式。在其它服用形式的情况中，所述日剂量也在类似范围内。
附图说明
图1：由以100μM的浓度使用2-(联苯-4-基氨基甲酰)-环戊-1-烯羧酸引起的人体T细胞增殖的下降；
图2：在单次口服剂量10mg/kg体重之后在大鼠中Vidofludimus游离酸（实心点）及其钙盐（空心点）的血浆水平的比较。
图3：Ca盐（上部曲线）和游离酸（下部）的拉曼光谱。
图4：vidofludimus Ca盐的使用正交偏振片的光学显微照片。
图5：vidofludimus Ca盐的PXRD。
图6：vidofludimus游离酸的PXRD。
具体实施方式
实施例
通过如下非限制性实例进一步示例本发明。关于上表1中描绘的特定化合物所显示的数据也与本发明的具体实施例相关。
实验/仪器设置
1H-NMR：使用质子频率为300.13 MHz、激发脉冲为30°且循环延迟为1秒的Bruker DPX300谱仪对1H-NMR频谱进行记录。累积16次扫描，D2O；使用MeOD或d6-DMSO作为溶剂。
DSC：用Perkin Elmer DSC-7仪器（在N2气氛下封闭的金试样盘）实施差示扫描量热法。在10K/分钟的速率下将试样加热至最高达熔点，然后冷却（冷却速率200 K/分钟），并且在其后再次在10K/分钟的速率下加热。
DVS（SMS）：Surface Measurement Systems Ltd.的DVS-1水蒸气吸附分析仪。将试样放在铂试样盘上并使得其在给定的相对湿度（r.h.）通常为50%r.h.下达到平衡。然后，在5%r.h.的扫描速率下启动预限的湿度程序，每小时改变一次。第一步骤：从50%r.h.至0%r.h.（在可能水合物作为起始材料的情况中为50至95%r.h.），第二步骤：从0%至95%r.h.（在可能水合物作为起始材料的情况中为95至0%r.h.）。
FT-拉曼光谱法：在具有在1064nm下运行的近红外Nd:YAG激光器和液氮冷却的锗检测器的Bruker RFS100FT-拉曼系统上记录FT-拉曼光谱。对于每一试样，在2 cm-1分辨率的情况下累积扫描最少64次。使用300mV的标称激光器功率。在3500至100cm-1的区域内显示了FT-拉曼数据。在低于100cm-1的区域，数据由于瑞利滤波器截止而不可靠。
光学显微镜法：安装有Leica DFC280照相机和IM50v.5图像捕集软件的Leitz Orthoplan 110680显微镜。在使用或不使用正交偏振片的情况下在4×、10×和25×的放大倍率下记录图像。
粉末X射线衍射：Bruker D8；铜Ka辐射，40kV/40mA；LynxEye检测器，0.02°2θ步长大小，37秒的步长时间。试样制备：通常在除施加轻微压力以得到平坦表面外不进行任何特殊处理的条件下对试样进行测量。使用硅单晶试样保持器（0.1、0.5或1mm深）。在测量期间旋转试样。
拉曼光谱法：Renishaw inVia Reflex拉曼系统。具有785nm激发的稳定二极管激光器和NIR增强的Peltier冷却CCD照相机作为检测器。用长工作距离20×的物镜实施测量。波长范围为2000—100cm-1，10秒检测时间，每个光谱三次累积。
溶剂：对于所有实验，都使用Fluka、Merck或ABCR分析级溶剂。
TG-FTIR：用连接到Bruker FTIR Spectrometer Vector22或IFS28上的Netzsch Thermo-Microbalance TG209实施热重测量（具有针孔的试样盘，N2气氛，加热速率10℃/分钟，25℃至350℃）。
HPLC：用Dionex液相色谱仪实施HPLC，所述液相色谱仪包括溶剂架、真空脱气装置、二元泵（mikro）、静态混合器（500μl）、自动进样器、25μl的试样回路、100μl的注射器、柱温箱和DAD检测器（半微量的测量池），对所述液相色谱仪进行设置以用于UV分析。利用
SP3进行数据分析。在PhenomenexOnyxTM Monolithic CI850×2mm柱上在30℃下对化合物进行分离。注射体积为2μl且检测波长为305nm。作为移动相，使用在HPLC级水/乙腈中0.1%的甲酸梯度，在5%乙腈的浓度下开始。将起始浓度保持1分钟，然后在2分钟期间中将梯度线性升至95%乙腈，在95%乙腈下保持0.7分钟，其后在0.1分钟内将其返回至5%乙腈并保持恒定0.7分钟以使得柱重新平衡。移动相的流速为1.5ml/分钟。
实施例1.合成式(I)的化合物
在WO2003/0006425中详细描述了式(I)的化合物的合成，通过参考将其并入本文中。
实施例2.DHODH活性的抑制试验
标准试验混合物含有50μΜ去环泛醌（decyclo ubichinone）、100μΜ二氢乳清酸、60μΜ2,6-二氯靛酚以及20mU DHODH。所使用的重组酶的体积活度为30U/ml。在1ml最终体积中在30℃下在50mMTrisHCl（150mM KC1，0.1%Triton X-100，pH8.0）中进行测量。将所述组分混合，并且通过添加二氢乳清酸使反应开始。在反应过程之后，用光谱法测量2分钟在600nm下吸收的下降。
用另外可变量的抑制剂在标准评价中进行抑制研究。为了确定IC50值（抑制50%所需要的抑制剂的浓度），应用至少五种不同的抑制剂浓度。
用重组人以及由德国马堡M.教授提供的重组小鼠DHODH[M.Loffler，Chem.Biol.Interact.124，（2000），61-76]实施这些研究。
作为对照，使用来氟米特A77-1726的活性代谢物（化合物12）[J.
等人，Biochemical Pharmacology 56（1998），1053-1060]。
将抑制试验的结果示于上表1中。根据IC50值的比较可清楚得出，用于制备根据本发明的盐的化合物不仅对人体酶具有与来氟米特活性代谢物相当或甚至更好的抑制活性，而且对人体酶具有更高的特异性。
实施例3.人体T细胞的增殖评价
从健康志愿者得到人体外围的血液单核细胞（PBMC）并将其转移至含有10%透析胎牛血清的PMI1640细胞培养基中。以每个孔80,000个细胞的方式将所述细胞移入96-孔板中并以磷酸盐缓冲液的方式添加植物血球凝集素（PHA）至20μg/ml的最终浓度，以促进T细胞的增殖。在二甲基亚砜（DMSO，最终浓度：0.1体积%）中添加Vidofludimus至20nM至50μΜ的最终浓度。在培养48小时之后，根据制造商的指南使用“细胞增殖ELISA BrdU”（Roche）对细胞的增殖进行定量。使用4参数S形曲线拟合对半最大抑制（IC50）进行了计算。通过Vidofludimus抑制了T细胞的增殖，其IC50为4.1μM（参见图1）。
实施例4：制备钙盐
将300.4mg Vidofludimus游离酸溶于18mL DCM/MeOH（3:1）中并超声处理8分钟。将31.5mg氢氧化钙悬浮在3mL DCM/MeOH（3:1）中；将其缓慢添加到Vidofludimus游离酸溶液中。在25℃下将该轻悬浮液搅拌过夜。在25℃下在氮气流下部分蒸发所述溶剂。观察到稠的亮黄色悬浮液。通过过滤对固体进行回收并用DCM/MeOH（3:1）洗涤该固体。将所述材料在25℃下在真空下干燥15分钟。使用下述方法，显示所述材料是晶体。
根据元素分析，计算了氟对钙之比。该元素组成基本符合半钙盐。
新形成的化合物的拉曼光谱显示了与游离酸的不同（关于两个光谱都参见图3）。应注意，如下拉曼光谱可与盐对应，该拉曼光谱不是游离酸、盐前体和溶剂的光谱的简单叠加，例如其中观察到新峰或位移峰的拉曼光谱。
然而，单根据拉曼光谱不能确定是否形成了结晶盐。峰的位移在原理上也可能是因为游离酸与作为非晶产物的盐构成物的络合、因为游离酸或盐构成物的多形体、因为杂质或因为降解产物。因此，通过lH-NMR确定分子结构的完整性。
另外，示于图5中的粉末X射线衍射显示，得到了结晶的材料，然而其图案与游离酸的不同（参见图6）。用光学显微镜对晶体进行观察（图4），DSC（差示扫描量热仪）显示了约155℃的熔点（显示溶剂化物和非溶剂化形式的熔点），TG-FTIR（热重分析联合傅里叶转换红外）表明，可能形成了甲醇溶剂化物和水合物，且动态蒸汽吸附表明了去溶剂化，随后在约85%r.h.下摄取0.3%的水并在95%r.h.下摄取0.4%的水（不可逆）。
实施例5：化合物的溶解度的考察
对Vidofludimus游离酸（2-(3-氟-3'-甲氧基联苯-4-基氨基甲酰)-环戊-1-烯羧酸）、其钾盐和其钙盐的水溶解度进行了检验。所述方法的原理是以关于化学品的试验，105，“水溶解度”的OECD指南为基础的。称量2mg试验化合物并将其放入1.5ml的微量离心管中。随后，添加水以达到5mg/ml的浓度。在制备溶解度试样之后，在连续震荡下在23℃下培养24小时。然后，对试样离心以将沉淀物与溶解的化合物分离。将上清液转移至带标记的HPLC小瓶中以通过HPLC-UV进行定量。最后，在HPLC-UV系统上对这些HPLC试样进行分析并根据校准曲线计算它们的含量。在上清液中化合物的浓度等于其在水中的溶解度。关于Vidofludimus游离酸及其钾盐和钙盐，发现了如下水溶解度：
表2—Vidofludimus钙盐与钾盐和游离酸的溶解度的比较
实施例6：确定生物利用度
在雄性Wistar大鼠中对Vidofludimus的钙盐和游离酸的口服生物利用度进行了比较。将游离酸或钙盐填充入明胶胶囊中，且动物以每千克体重约10mg游离酸当量的剂量水平接收单次给药。
用Vidofludimus游离酸或其钙盐对每组四只雄性Wistar大鼠（体重范围：250～275g）进行治疗。使用服药装置将胶囊给药至动物的食管中。在给药之后的如下时间点处在异氟醚麻醉下从动物抽取静脉血试样：30分钟、1小时、2小时、4小时、6小时、8小时、24小时、28小时、32小时和48小时。使用Na-肝素抑制凝固并通过对血液试样进行离心以产生血浆。关于Vidofludimus用LC-MS/MS对血浆试样进行分析，并根据混合对数线性梯形法对药动学参数进行了计算。
为了检验所述钾盐，在30mg/kg（游离酸当量）的剂量水平下，用Vidofludimus游离酸或其钾盐对六只雌性Lewis大鼠（体重：约200g）进行治疗。在0.5%的甲基纤维素在磷酸盐缓冲液中配制所述化合物，并通过口服强饲法对动物进行治疗。在服用之后的如下时间点处在异氟醚麻醉下从动物抽取静脉血试样：30分钟、1小时、2小时、4小时、8小时、26小时、33小时、48小时和72小时。使用Na-肝素抑制凝固并通过对血液试样进行离心以产生血浆。关于Vidofludimus用LC-MS/MS对血浆试样进行了分析，并根据线性梯形规则法对药动学参数（AUC）进行了计算。
通过将服用所述盐之后Vidofludimus在血浆浓度-时间曲线（AUC）下的面积和获得的最大血浆浓度（Cmax值）与在给药所述游离酸之后观察到的那些值进行比较，对所述盐的口服生物利用度进行评价。将这些比例示于表3和图2中。
表3：在向大鼠口服应用Vidofludimus之后PK参数的比较
| 化合物 | AUCinf/AUCinf，游离酸 | Cmax/Cmax，游离酸 |
| Vidofludimus游离酸 | 1 | 1 |
| 钾盐 | 0.96 | 1.09 |
| 钙盐 | 1.72 | 1.67 |
实施例7：确定长期稳定性
将所述化合物在环境条件（20—25℃，30—60%的相对湿度）下储存18个月，并且随后通过HPLC分析其纯度。
*对于水解产物的LOD：0.1μg/ml
Claims (13)
1.通式(I)的化合物的钙盐或其水合物
其中
X选自CH2、S或O；
D为O或S；
R8为氢或烷基；
E为任选取代的亚苯基基团；
Y为单环或双环的取代或未取代的6—9元环系，其可含有一个或多个选自N或S的杂原子并含有至少一个芳族环；
n为0或1；并且
q为0或1；
条件是不包括其中X=CH2、q=0、Y=未取代的苯基且E=未取代的亚苯基的化合物的钙盐。
2.根据权利要求1所述的钙盐或其水合物，其中R8是氢或甲基。
3.根据权利要求1或2所述的钙盐或其水合物，其中Y是取代的或未取代的苯基。
4.根据权利要求1至3中的任一项所述的钙盐或其水合物，其中q是0。
5.根据权利要求1至4中的任一项所述的钙盐或其水合物，其中E为未取代的亚苯基基团或用一个或多个独立地选自卤素、硝基或烷氧基的基团取代的亚苯基基团。
6.根据权利要求1至5中的任一项所述的钙盐或其水合物，其中Y为未取代的苯基基团或用一个或多个独立地选自卤素、烷基、烷氧基、卤代烷氧基、卤代烷基或CN的基团取代的苯基基团。
7.根据权利要求1至5中的任一项所述的钙盐或其水合物，其中E是用一个或多个独立地选自甲氧基或三氟甲氧基的基团、还甚至更优选甲氧基取代的苯基基团。
8.根据权利要求1至7中的任一项所述的钙盐或其水合物，其中式1的化合物为2-(3-氟-3'-甲氧基-联苯-4-基氨基甲酰)-环戊-1-烯羧酸。
9.一种药物组合物，其包含如权利要求1至8的任一项中所限定的盐或其水合物，以及药物学上可接受的稀释剂或载体。
10.根据权利要求1至8中的任一项所述的钙盐或其水合物作为药物的用途。
11.根据权利要求1至8中的任一项所述的钙盐或其水合物在制造用于治疗疾病或治疗适应证的药物中的用途，所述疾病或治疗适应证选自风湿病、急性免疫紊乱、自身免疫病、由恶性细胞增殖引起的疾病、发炎疾病、由原生动物在人体和动物内侵袭引起的疾病、由病毒感染和卡氏肺孢子虫引起的疾病、纤维化、葡萄膜炎、鼻炎、哮喘或关节病。
12.根据权利要求11所述的用途，其中所述疾病或治疗适应证选自移植物抗宿主和宿主抗移植物反应、类风湿性关节炎、多发性硬化、红斑狼疮、炎性肠病和银屑病。
13.一种用于制备如权利要求1至8的任一项中所限定的钙盐或其水合物的方法，其包括如下步骤：
a）将氢氧化钙在有机溶剂中的悬浮液添加至如上述权利要求1至9的任一项中所限定式(I)化合物的游离酸溶液中；
b）对在步骤a）中得到的悬浮液进行搅拌；
c）至少部分蒸发所述有机溶剂以得到所述式(I)化合物的钙盐的悬浮液；
d）从在步骤c）中得到的混合物中回收所述式(I)化合物的钙盐；和
e）用所述有机溶剂洗涤在步骤d）中得到的所述式(I)化合物的钙盐。
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| CN2011800332001A Pending CN103097338A (zh) | 2010-07-01 | 2011-07-01 | 作为抗炎剂、免疫调节剂和抗增殖剂的新型盐 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653260A (zh) * | 2017-03-28 | 2018-10-16 | 厦门大学 | 一种法尼醇受体的配体的用途 |
| CN110251498A (zh) * | 2018-03-12 | 2019-09-20 | 厦门大学 | 一类调节法尼醇受体活性的化合物及其用途 |
| CN111836795A (zh) * | 2018-03-16 | 2020-10-27 | 埃慕尼克股份公司 | 作为抗炎剂、免疫调节剂和抗增殖剂的新型钙盐多晶型物 |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018177151A1 (en) * | 2017-03-28 | 2018-10-04 | Xiamen University | Compounds modulating activity of farnesoid x receptor and methods for the use thereof |
| BR112020009477A2 (pt) * | 2017-11-23 | 2020-11-03 | Immunic Ag | compostos e regime de dosagem para uso na prevenção ou tratamento de doenças inflamatórias e/ou autoimunes |
| EP3750892A1 (en) | 2019-06-14 | 2020-12-16 | Yerevan State University | Novel 5-cyclopropyl-furo[3,4-c]pyridine-3,4(1h,5h)-dione 1,1' substituted derivatives and their uses |
| MA53193A (fr) * | 2020-04-21 | 2021-10-27 | Immunic Ag | Vidofludimus à utiliser dans le traitement ou la prévention de maladies virales |
| BR112023020806A2 (pt) | 2021-04-09 | 2023-12-12 | Immunic Ag | Inibidores de dhodh deuterados |
| US11877994B2 (en) | 2021-08-02 | 2024-01-23 | Immunic Ag | Treatment of multiple sclerosis comprising DHODH inhibitors |
| WO2023118576A1 (en) | 2021-12-23 | 2023-06-29 | Immunic Ag | Dhodh inhibitors containing a carboxylic acid bioisostere |
| WO2023232884A1 (en) | 2022-06-01 | 2023-12-07 | Immunic Ag | Treatment of ulcerative colitis comprising vidofludimus or a pharmaceutically acceptable salt thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1525954A (zh) * | 2001-07-10 | 2004-09-01 | 4SC�ɷݹ�˾ | 用作抗炎、免疫调节及抗增殖药剂的新化合物 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50121428A (zh) | 1974-03-12 | 1975-09-23 | ||
| NL186239B (nl) | 1975-06-05 | Hoechst Ag | Werkwijze voor de bereiding van een geneesmiddel met antiflogistische en/of analgetische werking, alsmede werkwijze voor de bereiding van een 2-hydroxyethylideencyaanazijnzuuranilide geschikt voor toepassing bij deze werkwijze. | |
| IL56012A (en) | 1977-11-29 | 1983-07-31 | Takeda Chemical Industries Ltd | N-(2-fluoro-4-bromo(or chloro)phenyl)-3,4,5,6-tetrahydrophthalamic acid derivatives,their preparation,and herbicidal compositions comprising them |
| JPS54154737A (en) | 1978-05-25 | 1979-12-06 | Mitsubishi Chem Ind Ltd | Cyclohexenedicarboxylic acid diamide and herbicide |
| JPS55157547A (en) | 1979-05-28 | 1980-12-08 | Takeda Chem Ind Ltd | Tetrahydrophthalamide derivative, its preparation and herbicide |
| AU1526483A (en) | 1982-06-14 | 1983-12-22 | Nippon Kayaku Kabushiki Kaisha | N-substituted-3,4,5,6-tetrahydrophthalamic acids |
| JPS59118750A (ja) | 1982-12-27 | 1984-07-09 | Eisai Co Ltd | カルボン酸アミド化合物およびその誘導体 |
| DE3534440A1 (de) | 1985-09-27 | 1987-04-02 | Hoechst Ag | Arzneimittel gegen chronische graft-versus-host-krankheiten sowie gegen autoimmunerkrankungen, insbesondere systemischen lupus erythematodes |
| GB9320299D0 (en) | 1993-10-01 | 1993-11-17 | Roussel Lab Ltd | Isoxazole derivatives |
| DE19547648A1 (de) | 1995-12-20 | 1997-06-26 | Hoechst Ag | Zubereitung, enthaltend High Density Lipoproteine und Crotonsäureamidderivate |
| DE19610955A1 (de) | 1996-03-20 | 1997-09-25 | Hoechst Ag | Kombinationspräparat, enthaltend 5-Methylisoxazol-4-carbonsäure-(4-trifluormethyl)- anilid und N-(4-Trifluormethylphenyl)-2-cyan-3- hydroxycrotonsäureamid |
| AU2108099A (en) | 1998-01-30 | 1999-08-16 | Procept, Inc. | Immunosuppressive agents |
| GB9804343D0 (en) | 1998-02-27 | 1998-04-22 | Univ Cardiff | Chemical compounds |
| US7247736B2 (en) * | 2002-12-23 | 2007-07-24 | 4Sc Ag | Method of identifying inhibitors of DHODH |
| BRPI0921258A2 (pt) * | 2008-11-07 | 2018-10-23 | 4Sc Ag | terapia combinatória compreendendo inibidor de dhodh e metotrexato para o tratamento de doença autoimune |
| TWI530286B (zh) * | 2009-05-04 | 2016-04-21 | 帕納特斯製藥格斯有限公司 | 作為抑制病毒化合物之抗發炎劑 |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1525954A (zh) * | 2001-07-10 | 2004-09-01 | 4SC�ɷݹ�˾ | 用作抗炎、免疫调节及抗增殖药剂的新化合物 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653260A (zh) * | 2017-03-28 | 2018-10-16 | 厦门大学 | 一种法尼醇受体的配体的用途 |
| CN110251498A (zh) * | 2018-03-12 | 2019-09-20 | 厦门大学 | 一类调节法尼醇受体活性的化合物及其用途 |
| CN111836795A (zh) * | 2018-03-16 | 2020-10-27 | 埃慕尼克股份公司 | 作为抗炎剂、免疫调节剂和抗增殖剂的新型钙盐多晶型物 |
| CN111836795B (zh) * | 2018-03-16 | 2024-03-29 | 埃慕尼克股份公司 | 作为抗炎剂、免疫调节剂和抗增殖剂的钙盐多晶型物 |
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