CN101128459B - 异*唑啉衍生物及其制备方法 - Google Patents
异*唑啉衍生物及其制备方法 Download PDFInfo
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- CN101128459B CN101128459B CN2006800059846A CN200680005984A CN101128459B CN 101128459 B CN101128459 B CN 101128459B CN 2006800059846 A CN2006800059846 A CN 2006800059846A CN 200680005984 A CN200680005984 A CN 200680005984A CN 101128459 B CN101128459 B CN 101128459B
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Abstract
本发明涉及用作半胱天冬酶抑制剂的具有环状羧酸半缩酮部分的异噁唑啉衍生物,其制备方法以及含有它的药物组合物。
Description
技术领域
背景技术
半胱天冬酶抑制剂是指可以抑制半胱天冬酶活性,从而调节由半胱天冬酶功能引起的炎症或细胞凋亡的化合物。在半胱天冬酶抑制剂中,已知不可逆抑制剂显示出更加有效的抑制活性,这是因为它不可逆地使酶灭活从而控制细胞凋亡(Wu J.等人,Methods:A Companionto Methods in Enzymology 1999,17,320)。已知下面的化合物是不可逆的抑制剂,它们共同具有3-氨基-5-氟-4-氧代戊酸部分。
对于可以通过施用上述化合物治疗或缓解的疾病而言,有类风湿性关节炎、炎性肠疾病、移植物-宿主疾病、败血症、骨关节炎、骨质疏松、急性和慢性髓细胞性白血病、髓膜炎、输卵管炎、败血症性休克、胆管炎、结肠炎、脑炎、心内膜炎、血管球性肾炎、肝炎、心肌炎、胰腺炎、I型糖尿病、多发性硬化、阿尔茨海默氏病、帕金森氏病、肝硬化等。
[参考文献:
痴呆:Arch Neurol 2003 Mar;60(3):369-76,Caspase geneexpression in the brain as a function of the clinical progression of Alzheimer disease.Pompl PN,Yemul S,Xiang Z,Ho L,Haroutunian V,Purohit D,Mohs R,Pasinetti GM.;
脑卒中:Proc Natl Acad Sci USA 2002 Nov12;99(23):15188-93,caspase activation and neuroprotection in Caspase-3-deficientmice after in vivo cerebral ischemia and in vitro oxygen glucosedeprivation.Le DA,Wu Y,Huang Z,Matsushita K,Plesnila N,Augustinack JC,Hyman BT,Yuan J,Kuida K,Flavell RA,MoskowitzMA.;
由AIDS引起的脑损伤:J Neurosci 2002 May15;22(10):4015-24,Caspase cascades in human immunodeficiency virus-associatedneurodegeneration.Garden GA,Budd SL,Tsai E,Hanson L,KaulM,D′Emilia DM,Friedlander RM,Yuan J,Masliah E,Lipton SA.;
糖尿病:Diabetes 2002 Jun;51(6):1938-48,Hyperglycemia-induced apoptosis in mouse myocardium:mitochondrial cytochromeC-mediated caspase-3 activationpathway.Cai L,Li W,Wang G,Guo L,Jiang Y,Kang YJ.;
胃溃疡:J Physiol Pharmacol 1998 Dec;49(4):489-500,Roleof basic fibroblast growth factor in the suppression ofapoptotic caspase-3 during chronic gastric ulcer healing.Slomiany BL,Piotrowski J,Slomiany A.;
肝炎引起的脑损伤:J Viral Hepat 2003 Mar;10(2):81-6,Cerebral dysfunction in chronic hepatitis C infection.FortonDM,Taylor-Robinson SD,Thomas HC.;
爆发性肝功能衰竭:Gastroenterology 2000Aug;119(2):446-60,Tumor necrosis factor alpha in the pathogenesis of humanand murine fulminant hepatic failure.Streetz K,Leifeld L,Grundmann D,Ramakers J,Eckert K,Spengler U,Brenner D,MannsM,Trautwein C.;
败血症:Nat Immunol 2000 Dec;1(6):496-501,Caspase inhibitors improve survival in sepsis:a critical role of thelymphocyte.Hotchkiss RS,Chang KC,Swanson PE,Tinsley KW,HuiJJ,Klender P,Xanthoudakis S,Roy S,Black C,Grimm E,AspiotisR,Han Y,Nicholson DW,Karl IE.;
器官移植排斥:Xenotransplantation 2001 May;8(2):115-24,Invitro prevention of cell-mediated xeno-graft rejection via theFas/FasL-pathway in CrmA-transducted porcine kidney cells.FujinoM,Li XK,Suda T,Hashimoto M,Okabe K,Yaginuma H,Mikoshiba K,Guo L,Okuyama T,Enosawa S,Amemiya H,Amano T,Suzuki S.;
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缺血性心脏病:Am J Physiol Heart Circ Physiol 2002 Sep;283(3):H990-5,Hypoxia-induced cleavage of caspase-3 andDFF45/ICAD in human failed cardiomyocytes.Todor A,Sharov VG,Tanhehco EJ,Silverman N,Bernabei A,Sabbah HN.;
抗炎:J Immunol 2003 Mar 15;170(6):3386-91,Abroad-spectrum caspase inhibitor attenuates allergic airwayinflammation in murine asthma model.Iwata A,Nishio K,Winn RK,Chi EY,Henderson WR Jr,Harlan JM.;
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另一方面,对于半胱天冬酶抑制剂的3-氨基-5-氟-4-氧代戊酸部分,本领域已知下面反应流程图1的制备方法(Revesz等人,Tetrahedron Lett.1994,35,9693):
反应流程图1
发明概述
本申请发明人长期致力于研究可用作半胱天冬酶有效抑制剂的化合物、及其制备方法。
结果他们发现根据本发明的具有环状羧酸半缩酮部分的异噁唑啉衍生物具有良好的半胱天冬酶抑制活性,并且可以通过使用结晶诱导的动态转化高收率制备得到,从而完成了本发明。
因此,本发明一目的在于提供下式(1)的具有异噁唑啉结构和环状羧酸半缩酮部分的化合物、以及有效制备它的新方法。
本发明另一目的在于提供下式(1)化合物的中间体下式(4)的胺衍生物、及其制备方法。
本发明另一目的在于提供用于治疗炎症或预防细胞凋亡的药物组合物,其中含有下式(1)化合物和可药用载体。
本发明另一目的在于提供在对象中治疗炎症或预防细胞凋亡的方法,所述方法包括向对象施用治疗有效量的下式(1)化合物。
本发明另一目的在于提供下式(1)化合物制备用于治疗炎症或预防细胞凋亡的药物的用途。
本发明另一目的在于提供具有良好稳定性的下式(1)化合物的结晶形式。
附图简述
图1是根据本发明的式(1)化合物(R1=异喹啉基,R2=异丙基)的结晶形式的X-射线衍射光谱。
图2是示出根据本发明的式(1)化合物(R1=异喹啉基,R2=异丙基)的结晶形式和无定形形式的稳定性测试结果的图。
发明内容
本发明中使用的部分重要术语可以如下定义。
在本发明使用的结构式和反应流程图中,烷基是指由1-8个碳原子组成的直链或支链烷基,或者由3-10个碳原子组成的环烷基。
另外,芳基包括所有芳香基团、杂芳香基团及其部分还原衍生物。所述芳香基团是指简单或稠合环状形式的5-至15-元不饱和烃,所述杂芳香基团是指具有1-5个选自氧、硫和氮中的杂原子的芳香基团。
此外,所述烷基和所述芳基中的一个或多个氢可以被其它取代基取代。可选择的取代基的实例包括酰基、氨基、烷氧基、羧基、羧氨基(carboxyamino)、氰基、卤素、羟基、硝基、巯基(thiol)、烷基、环烷基、烷氧基、芳氧基、硫氧基(sulfoxy)、胍基等。
本发明涉及用作半胱天冬酶抑制剂的下式(1)的具有环状羧酸半缩酮基团的异噁唑啉衍生物:
其中
R1是烷基或芳基,以及
R2是烷基。
优选地,R1是异喹啉基、喹啉基或萘基,以及
R2是甲基、乙基、丙基或丁基。
更优选地,R1是异喹啉基,以及R2是异丙基。
其中R1是异喹啉基以及R2是异丙基的式(1)化合物可以以示出下述X-射线衍射图案的结晶形式存在
D(X) | 相对强度(I/I0) | 2θ角 |
9.665 | 0.555 | 9.15 |
7.284 | 0.397 | 12.15 |
5.825 | 0.260 | 15.21 |
5.563 | 0.228 | 15.93 |
5.372 | 0.302 | 16.5 |
4.840 | 1.000 | 18.33 |
4.695 | 0.477 | 18.9 |
4.341 | 0.454 | 20.46 |
3.663 | 0.230 | 24.3 |
3.414 | 0.219 | 26.1 |
另外,本发明涉及制备式(1)化合物的方法,所述方法包括:
(a)活化下式(2)化合物,然后将其与下式(4)化合物反应生成下式(13)化合物;
(b)水解下式(13)化合物生成下式(14)化合物;
(c)脱保护下式(14)化合物;以及
(d)进行结晶诱导的动态转化;
其中,
R1是烷基或芳基,
R2是烷基,
R3和R′3各自是烷基,或者
R3和R′3与和它们相连的氧原子一起形成杂环,以及
R4是烷基。
优选地,
R1是异喹啉基、喹啉基或萘基,
R2是甲基、乙基、丙基或丁基,
R3和R′3各自是甲基、乙基或丙基,或者
R3和R′3与和它们相连的氧原子一起形成二氧戊环或二氧杂环己烷,以及
R4是甲基、乙基、丙基或丁基。
式(1)化合物的上述制备方法中的每步可以如下进行更详细的描述。
至于在上述步骤(a)中活化式(2)化合物的活化试剂,优选使用 选自草酰氯、三甲基乙酰氯、磷酰氯和亚硫酰氯中的一种。
另外,优选步骤(a)中的反应在选自三乙胺、三(正丁基)胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶和4-(4-甲基-哌啶-1-基)-吡啶中的碱的存在下进行,优选所述碱以式(2)化合物的1.0-10.0当量的用量使用。
此外,优选步骤(a)中的反应在一种或多种选自二氯甲烷、氯仿、四氢呋喃、二甲氧乙烷、二氧杂环己烷和乙酸乙酯中的溶剂中进行。
另一方面,优选步骤(a)中的式(4)化合物以式(2)化合物的1.0-3.0当量的用量使用。
优选步骤(b)中的水解在选自氢氧化锂(优选无水或一水合物结晶)、氢氧化钠、氢氧化钾和氢氧化钙中的碱的存在下进行,还优选所述碱以式(13)化合物的0.1-10.0当量的用量使用。
此外,优选步骤(b)中的反应在一种或多种选自甲醇、乙醇、正丙醇、异丙醇、四氢呋喃、二甲氧乙烷、二氧杂环己烷和二氯甲烷中的溶剂、或者在上述溶剂和水的混和溶剂中进行。
优选步骤(c)中的脱保护反应在选自盐酸、硫酸和三氟乙酸中的酸的存在下进行,优选所述酸以式(14)化合物的0.1-20.0当量的用量使用。
另外,优选步骤(c)中的脱保护反应在存在或不存在选自二氯甲烷或氯仿中的溶剂的条件下进行。
步骤(d)中的结晶诱导的动态转化反应可以通过加入式(1)化合物作为晶种进行,或者在晶种和催化用量的碱的存在下进行,其中所述碱优选为选自三乙胺、三(正丁基)胺、二异丙基乙基胺、二异丙基胺、吡啶、4-二甲氨基吡啶、4-(4-甲基-哌啶-1-基)-吡啶、旋光1-苯基乙胺和旋光1-萘基乙胺中的胺。
在步骤(d)中,所述胺优选以式(14)化合物的0.001-1.0当量的用量使用,更优选使用0.03-0.5当量。如果所使用胺的用量太少,反应速率变得较慢,如果用量太大,则式(1)化合物收率将降低。
另外,优选步骤(d)中的结晶诱导的动态转化反应在一种或多种选自甲苯、苯、二氯苯、四氢呋喃、二甲氧乙烷、二氧杂环己烷、 乙酸乙酯、二氯甲烷、乙腈、甲基叔丁基醚和乙醚中的溶剂中进行。
下面参照反应流程图2,将对根据本发明的制备式(1)化合物的方法进行更详细的解释。
按照由本申请人于2004年8月17日提交的PCT/KR2004/002060中公开的方法制备具有高旋光活性的式(2)的异噁唑啉衍生物,然后将其与式(4)化合物合并生成式(13)化合物。式(13)化合物随后酯水解生成式(14)化合物,式(14)化合物中的缩酮部分进行脱保护反应得到式(15)和式(16)化合物的混合物,将其通过选择性动态结晶有效转化为式(1)化合物。
特别地,如果将式(15)和式(16)化合物的混合物溶解于有机溶剂中,向溶液中加入式(1)化合物的晶种,则只有混合物中的式(15)化合物转化为以固体形式分离的式(1)化合物。
反应流程图2
其中,
R1是烷基或芳基,
R2是烷基,
R3和R′3各自是烷基,或者
R3和R′3与和它们相连的氧原子一起形成杂环,以及
R4是烷基。
另外,如果将式(15)和式(16)化合物的混合物使用催化用量的 碱以及晶种处理,式(15)化合物和式(16)化合物均转化为式(1)化合物,高收率地生成式(1)化合物(反应流程图3)。由于溶液中存在碱,因此式(15)化合物与式(16)化合物平衡。另外,式(15)化合物与式(17)和式(1)化合物平衡,式(16)化合物与式(18)和式(19)化合物平衡。其中,具有良好结晶特性的式(1)化合物选择性沉淀析出,使得全部化合物的平衡向式(1)化合物移动,从而选择性地由式(15)和式(16)化合物的混合物仅仅高收率地得到式(1)化合物。
反应流程图3
另外,本发明涉及下式(4)化合物,它是用于制备式(1)化合物的中间体:
其中
R3和R′3各自是烷基,或者
R3和R′3与和它们相连的氧原子一起形成杂环,以及
R4是烷基。
优选地,
R3和R′3各自是甲基、乙基或丙基,或者
R3和R′3与和它们相连的氧原子一起形成二氧戊或二氧杂环己烷,以及
R4是甲基、乙基、丙基或丁基。
另外,本发明还涉及制备式(4)化合物的方法,所述方法包括:
(a)将下式(9)化合物保护和脱保护生成下式(10)化合物;
(b)式(10)化合物进行碳碳偶联反应生成下式(11)化合物;
(c)式(11)化合物与苄胺反应,然后还原生成式(12)化合物;以及
(d)氢化式(12)化合物;
其中
R3和R′3各自是烷基,或者
R3和R′3与和它们相连的氧原子一起形成杂环,以及
R4是烷基。
优选地,
R3和R′3各自是甲基、乙基或丙基,或者
R3和R′3与和它们相连的氧原子一起形成二氧戊或二氧杂环己烷,以及
R4是甲基、乙基、丙基或丁基。
下面将更具体地描述上述制备式(4)化合物的方法。
在步骤(a)中,优选将式(9)化合物通过使用原甲酸三甲酯或原甲酸三乙酯保护,脱保护反应在选自氢氧化钠、氢氧化钾、碳酸钠和碳酸氢钠中的碱的存在下进行。此外,优选上述脱保护反应中的碱以式(9)化合物的1.0-2.0当量的用量使用。
另外,优选步骤(a)中的保护反应在甲醇或乙醇溶剂中进行,脱保护反应在一种或多种选自甲醇、乙醇、二氯甲烷、氯仿和水中的溶剂中进行。
另外,优选步骤(b)中的反应通过使用氯代甲酸乙酯或氯代甲酸甲酯,在选自正丁基锂、二异丙基胺化锂或六甲基二硅氮烷化锂(Lithiumhexamethyldisilazide)中的碱的存在下进行,所述碱以 式(10)化合物的0.5-3.0当量的用量使用,所述氯代甲酸乙酯或氯代甲酸甲酯以式(10)化合物的0.5-3.0当量的用量使用。
另外,优选步骤(b)中的反应在选自四氢呋喃、乙醚和甲基叔丁基醚中的溶剂中进行。
优选步骤(c)中的还原反应通过使用乙酸和硼氢化钠进行,所述硼氢化钠以式(11)化合物的1.0-5.0当量的用量使用,所述乙酸以式(11)化合物的1.0-20.0当量的用量使用。
另外,优选步骤(c)中的所述苄胺以式(11)化合物的1.0-10.0当量的用量使用。
另外,优选步骤(c)中的反应在存在或不存在选自乙酸乙酯、四氢呋喃、乙醚和甲基叔丁基醚中的溶剂的条件下进行,如果需要的话,可以以一锅反应的形式进行。
优选步骤(d)中的反应在金属催化剂、更优选钯族催化剂或兰尼氏镍族催化剂的存在下进行。具体地说,承载在选自碳、二氧化硅和氧化铝中的载体上的具有1-20重量%钯(Pd)的钯族催化剂或者具有1重量%或更多兰尼氏镍的兰尼氏镍族催化剂以其金属组分计算,可以以式(12)化合物的0.01-10重量%的用量使用。
另外,优选步骤(d)中的反应在一种或多种选自甲醇、乙醇、正丙醇、异丙醇、四氢呋喃、二甲氧乙烷、二氧杂环己烷、乙酸乙酯和二氯甲烷中的溶剂中进行。
此外,优选步骤(d)中的氢化反应在0-50℃的温度和1-100atm的氢气压下进行。
如下面的反应流程图4所示,本发明人已经开发出一种高收率制备式(4)化合物、用于式(1)化合物的中间体的新方法。
反应流程图4
其中
R3和R′3各自是烷基,或者
R3和R′3与和它们相连的氧原子一起形成杂环,以及
R4是烷基。
另外,本发明涉及用于治疗炎症或预防细胞凋亡的药物组合物,其中含有上述式(1)化合物和可药用载体,尤其是用于治疗痴呆、脑卒中、由AIDS引起的脑损伤、糖尿病、胃溃疡、由肝炎病毒引起的脑损伤、由肝炎病毒引起的肝病、急性肝炎、爆发性肝功能衰竭、肝硬化、败血症、器官移植排斥、类风湿性关节炎或由于缺血性心脏病引起的心脏细胞坏死的药物组合物。
另外,本发明涉及在对象中治疗炎症或预防细胞凋亡的方法,所述方法包括向对象施用治疗有效量的上述式(1)化合物,尤其是治疗痴呆、脑卒中、由AIDS引起的脑损伤、糖尿病、胃溃疡、由肝炎病毒引起的脑损伤、由肝炎病毒引起的肝病、急性肝炎、爆发性肝功能衰竭、肝硬化、败血症、器官移植排斥、类风湿性关节炎或由缺血性心脏病引起的心脏细胞坏死的方法。
另外,本发明涉及上述式(1)化合物制备用于治疗炎症或预防细胞凋亡的药物的用途,尤其,是用于治疗痴呆、脑卒中、由AIDS引起的脑损伤、糖尿病、胃溃疡、由肝炎病毒引起的脑损伤、由肝炎病毒引起的肝病、急性肝炎、爆发性肝功能衰竭、肝硬化、败血症、器官移植排斥、类风湿性关节炎或由于缺血性心脏病引起的心脏细胞坏死的药物。
根据本发明的式(1)化合物可以配制成实现给药目的的各种药 形式。为了制备根据本发明的药物组合物,将有效量的式(1)化合物与可药用载体混和,其中可药用载体可以根据待制备的制剂采取各种各样的形式。
式(1)化合物根据其应用目的,可以配制为非肠道注射剂或经皮或口服制剂。为了方便给药和保证剂型均匀性,将组合物配制成单位剂型是特别有利的。
对于口服制剂,可以使用任意的常用药物载体。例如,水、乙二醇、油类、醇类等可用于口服液体制剂例如混悬剂、糖浆剂、酏剂和溶液剂;或者淀粉、糖类、高岭土、润滑剂、粘合剂、崩解剂等可用于固体制粒例如散剂、丸剂、胶囊剂和片剂。由于方便给药,片剂和胶囊剂是最有利的单元剂型。另外还希望将片剂和丸剂配制成肠溶衣包衣制剂。
对于非肠道制剂,通常使用无菌水作为载体,但是也可以使用其它成分例如助溶剂。注射剂例如无菌水性或油性注射混悬剂可以按照已知步骤,使用适宜的分散剂、润湿剂或助悬剂制备。可用于制备注射剂的溶剂包括水、Ringer’s流体和等渗NaCl溶液,无菌不挥发油通常也被用作溶剂或助悬介质。任何无刺激性不挥发油包括甘油单酯、甘油二酯可用于实现上述目的。脂肪酸例如油酸也可以用于注射剂。
对于经皮制剂,载体可以包括助渗剂和/或适宜的润湿剂,同时任选与不具有明显皮肤刺激性的适宜添加剂合并。所述添加剂可以促进通过皮肤给药和/或有助于所需组合物的制备。这些经皮制剂通过各种方式例如透皮贴剂、点洒剂(spot-on)或软膏剂给药。
当式(1)化合物用于临床目的时,优选以0.1-100mg/kg体重/天的用量施用给患者对象。总的日剂量可以一次或分数次给药。然而,针对个体患者的具体给药剂量可能随所使用的具体化合物、患者对象的体重、性别、卫生条件或饮食、给药时间或方法、排泄速率、药剂的混和比例、待治疗的疾病严重程度等变化而变化。
下文中将参照下面的实施例对本发明进行更详细的描述,但是本发明的范围不能理解为以任何方式受其限制。
制备实施例1
1-氟-4-三甲基甲硅烷基-3-丁炔-2-酮(9)
将49.1g(499mmol)三甲基甲硅烷基乙炔溶解于250mL无水四氢呋喃中,内部温度降至大约-55℃,然后在25分钟内向其中加入210mL(525mmol)2.5M n-BuLi的正己烷溶液,同时保持内部温度低于-30℃。搅拌大约40分钟后,在5分钟内向反应混合物中加入52.9g(499mmol)氟代乙酸乙酯,同时保持内部温度低于-25℃,然后在15分钟内向其中加入74.4g(524mmol)BF3·OEt,同时保持内部温度为-55℃至-65℃。加料完成后,反应混合物在20℃下搅拌2小时,向其中加入250mL10%氯化铵水溶液结束反应。有机层分离后,水层用200mL乙酸乙酯萃取。合并的有机相用250mL盐水洗涤,然后减压浓缩。残余物在10mbar和68℃下真空蒸馏,得到式(9)化合物(67.3g,85%),为透明油状物。
1H NMR(500MHz,CDCl3):4.90(d,J=47.1Hz,2H),0.26(s,9H)
13C NMR(125MHz,CDCl3):181.0(d,J=21.5Hz),104.0,98.1,84.8(d,J=187Hz)
制备实施例2
4-氟-3,3-二甲氧基-1-丁炔(10,R3,R′3=甲基)
将33.6g(316mmol)原甲酸三甲酯和6.0g(31.5mmol)p-TsOH-H2O以及50.0g(316mmol)由制备实施例1得到的式(9)化合物一起投入260mL甲醇中,在回流温度(内部温度60~64℃)下搅拌大约6小时。反应混合物减压浓缩除去大约130mL溶剂,然后用260mL二氯甲烷洗涤。向其中加入130mL10%碳酸氢钠水溶液,分离各层,水层使用130mL二氯甲烷萃取。合并的有机层减压浓缩得到中间体4-氟-3,3-二甲氧基-1-三甲基甲硅烷基丁炔(59.0g,92%),即目标化合物(10)的前体化合物。该化合物直接用于接下来的反应中不再进一步纯化。
1H NMR(500MHz,CDCl3):4.38(d,J=47.1Hz,2H),3.40(s,6H),0.20(s,9H)
将59.0g(289mmol)前面得到的目标化合物(10)的前体化合物4-氟-3,3-二甲氧基-1-三甲基甲硅烷基丁炔溶解于280mL二氯甲烷中,用59mg(0.183mmol)四溴化正丁基铵和347mL(347mmol)1N氢氧化钠水溶液处理,同时搅拌大约2小时。有机层分离后,水层用110mL二氯甲烷萃取。合并的有机层用110mL盐水洗涤,减压浓缩得到目标化合物(10,R3,R′3=甲基;40.9g,定量收率)。该化合物直接用于接下来的反应中不再进一步纯化。
1H NMR(500MHz,CDCl3):4.42(d,J=47.1Hz,2H),3.42(s,6H),2.64(s,1H)
13C NMR(125MHz,CDCl3):96.1(d,J=20.3Hz),82.9(d,J=180Hz),77.5,75.5,51.0
制备实施例3
5-氟-4,4-二甲氧基-2-戊炔酸乙酯(11,R3,R′3=甲基,R4=乙基)
将40.9g(405mmol)二异丙基胺在270mL四氢呋喃中的溶液冷却至0℃,在大约1小时内向其中加入112g(405mmol)2.5M n-BuLi的正己烷溶液,同时保持内部温度低于14℃。反应混合物在0℃下搅拌大约30分钟,同时温度调节至-78℃。将41.0g(311mmol)由前面制备实施例2得到的化合物(10,R3,R′3=甲基)溶解于160mL四氢呋喃中的溶液在大约2小时内加入至反应混合物中,同时保持内部温度低于-40℃,然后在大约1小时内向其中加入60.4g(557mmol)氯代甲酸乙酯,同时保持内部温度低于-40℃,反应混合物进一步在0℃下搅拌大约2小时。向反应混合物中加入250mL10%氯化铵水溶液结束反应,分离有机层。水层用100mL乙酸乙酯萃取,合并的有机层用100mL盐水洗涤,减压浓缩得到粗目标化合物(11,R3,R′3=甲基,R4=乙基;95.0g,计算收率70%)。该化合物直接用于接下来的反应中不再进一步纯化。
1H NMR(500MHz,CDCl3):4.45(d,J=46.5Hz,2H),4.25(q,J=7.1Hz,2H),3.43(s,6H),1.31(t,J=7.3Hz,3H)
制备实施例4
3-(苄氨基)-5-氟-4,4-二甲氧基戊酸乙酯(12,R3,R′3=甲基,R4=乙基)
将88g(431mmol)来自前面制备实施例3的粗化合物(11,R3,R′3=甲基,R4=乙基)溶解于430mL甲基叔丁基醚(MTBE)中,同时温度调节至0℃。向反应混合物中加入31.4g(293mmol)苄胺,在20℃下搅拌大约1小时,用450mL甲基叔丁基醚稀释。再次调节反应混合物的温度至0℃,向反应混合物中加入33g(873mmol)NaBH4,然后在大约30分钟内向其中加入259g(4320mmol)乙酸。反应混合物保持于0℃,在大约2小时内向其中缓慢加入880mL(2640mmol)3N氢氧化钠水溶液。分离有机层,分离后的有机层用880mL10%氯化铵水溶液洗涤,然后向其中加入880mL 1N盐酸水溶液。分离水层,用400mL甲基叔丁基醚洗涤,使用246mL 10N氢氧化钠水溶液碱化,用700mLx2甲基叔丁基醚萃取。合并的有机层用400mL盐水洗涤,减压浓缩得到目标化合物[12,R3,R′3=甲基,R4=乙基;60.0g,44%,根据式(10)化合物计算为65%]。该化合物直接用于接下来的反应中不再进一步纯化。
1H NMR(400MHz,CDCl3):7.35-7.21(m,5H),4.53(2dd,J=46.8,10.4Hz,2H),4.13(q,J=7.2Hz,2H),3.80(2d,J=12.8Hz,2H),3.53(dd,J=8.4,4.0Hz,1H),3.30(s,3H),3.22(s,3H),2.79(dd,J=15.6,3.6Hz,1H),2.40(ddd,J=15.6,8.0,1.6Hz,1H),1.25(t,J=7.2Hz,3H)
实施例1
3-氨基-5-氟-4,4-二甲氧基戊酸乙酯(4,R3,R′3=甲基,R4=乙基)
将18.3g(58.5mmol)由前面制备实施例4得到的化合物(12,R3,R′3=甲基,R4=乙基)溶解于180mL乙醇中,使用活性炭5%钯催化剂(5%Pd/C)在50 psi氢气压下进行大约4小时的脱苄基反应。反应混合物通过5.0g硅藻土垫过滤,用90mL乙醇洗涤,滤液减压浓缩得到目标化合物(4,12.8g,98%)。该化合物直接用于接下来的步骤中不再进一步纯化。
1H NMR(500MHz,CDCl3):4.53(2dd,J=46.5,10.4Hz,2H),4.14(q,J=7.3Hz,2H),3.57(dd,J=11.0,1.9Hz,1H),3.29(d,J=11.7Hz,6H),2.73(dd,J=16.5,2.5Hz,1H),2.36(ddd,J=16.5,10.4,2.5Hz,1H),1.25(t,J=7.3Hz,3H)
制备实施例5
5-氟-3-[((R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-异噁唑-5-羰基)-氨基]-4,4-二甲氧基-戊酸乙酯(13,R1=1-异喹啉基,R2=异丙基,R3,R′3=甲基,R4=乙基)
将15.5g(54.5mmol)(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑羧酸(2,R1=1-异喹啉基,R2=异丙基)溶解于150mL二氯甲烷中,温度调节至0℃,然后向其中加入7.1mL(81.7mmol)草酰氯和0.2mL(2.6mmol)DMF,同时保持内部温度低于12℃。反应混合物在20℃下搅拌大约2小时,然后减压浓缩。反应混合物溶解于150mL二氯甲烷中,温度调节至0℃,向其中加入三乙胺,然后在20分钟内向其中缓慢加入12.8g(57.4mmol)由实施例1得到的化合物(4,R3,R′3=甲基,R4=乙基)溶解于30mL二氯甲烷中的溶液。反应混合物在25℃下搅拌1.5小时,向其中加入120mL 10%碳酸氢钠水溶液和60mL1N氢氧化钠水溶液的混合溶液,结束反应。有机层分离后,水层用150mLx3二氯甲烷萃取。合并的有机层减压浓缩得到目标化合物(13,R1=1-异喹啉基,R2=异丙基,R3,R′3=甲基,R4=乙基;30.1g,定量收率)。该化合物直接用于接下来的步骤中不再进一步纯化。
1H NMR(500MHz,CDCl3):9.12(q,1H),8.53(m,1H),7.85-7.25(m,4H),4.80(m,1H),4.54-4.34(m,2H),4.14(q,J=7.4Hz,2H),3.99(2d,J=18.4Hz,1H),3.81(m,1H),3.78(2d,J=8.6Hz,1H),3.33(d,3H),3.20(d,3H),2.75(m,3H),2.53(m,1H),2.39(七重峰,J=6.7Hz,1H),1.27(t,J=7.4Hz,1.5H),1.07(m,6H),0.97(t,J=7.4Hz,1.5H)
制备实施例6
5-氟-3-[((R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-异噁唑-5-羰基)-氨基]-4,4-二甲氧基-戊酸(14,R1=1-异喹啉基,R2=异丙基,R3,R′3=甲基)
将30.1g(61.6mmol)来自前面制备实施例5的化合物(13,R1=1-异喹啉基,R2=异丙基,R3,R′3=甲基,R4=乙基)以及7.76g(185mmol)氢氧化锂单水合物一起溶解于含有168mL四氢呋喃和42mL水的混合溶剂中,在大约40℃下搅拌4小时。反应混合物减压浓缩除去溶剂中的四氢呋喃,向其中加入180mL 1N氢氧化钠水溶液,混合物用120mLx2甲苯洗涤。水层用66mL6N盐酸水溶液酸化,用150mLx3二氯甲烷萃取,合并的有机层减压浓缩得到目标化合物(14,R1=1-异喹啉基,R2=异丙基,R3,R′3=甲基;25.4g,89%)。该化合物直接用于接下来的步骤中不再进一步纯化。
1H NMR(400MHz,CDCl3):9.10-8.92(m,1H),8.52(m,1H),7.86-7.13(m,4H),4.77(m,1H),4.54-4.34(m,2H),3.95(2d,J=8.0Hz,1H),3.75(2d,J=18.4Hz,1H),3.35-3.16(2d,6H),2.78(2dd,J=16.0,4.4Hz1H),2.54(m,1H),2.39(m,1H),2.35(s,1H),1.06(m,6H)
实施例2
(4S,5S)-5-氟甲基-5-羟基-4-({[(5R)-5-异丙基-3-(1-异喹啉基)-4,5-二氢-5-异噁唑基]羰基}氨基)-2-二氢呋喃酮(1,R1=1-异喹啉基,R2=异丙基)
将17.0g(36.9mmol)由前面制备实施例6得到的化合物(14,R1=1-异喹啉基,R2=异丙基,R3,R′3=甲基)和6.6mL(110mmol)乙酸溶解于123mL(738mmol)6N盐酸水溶液中,搅拌大约4小时。调节反应混合物内部温度至0℃,向其中加入150mL乙酸乙酯。缓慢加入220mL(660mmol)3N氢氧化钠水溶液,调节pH至大约3。有机层分离后,水层用150mLx2乙酸乙酯萃取。合并的有机相用100mL盐水洗涤,然后减压浓缩。残余物用50mL甲苯稀释,再次减压浓缩得到式(15)和式(16)化合物的混合物(R1=1-异喹啉基,R2=异丙基)(15.4g,定量收率,化学纯度:87.0%)。
1H NMR(500MHz,DMSO-d6):8.99(m,1H),8.65(m,1H),8.19-7.78(m,4H),5.15(m,1.5H),4.77(m,1H),4.42(m,0.5H),3.91(2d,J=17.6Hz,1H),3.74(m,1H),2.99(m,0.2H),2.82(m,1H),2.63(m,0.8H),2.33(m,1H),0.97(m,6H)
向146mL甲苯中加入14.6g(35.2mmol)式(15)和式(16)化合物的混合物(R1=1-异喹啉基,R2=异丙基)(化学纯度:87.0%),混合物加热至100℃以完全溶解。然后,向其中加入14mg目标化合物晶种(1,R1=1-异喹啉基,R2=异丙基),温度缓慢降至20℃,反应混合物搅拌生成固体。向其中加入0.25mL(1.8mmol)二异丙基胺,在20℃下搅拌大约2周,通过HPLC证实式(15)化合物和式(16)化合物(R1=1-异喹啉基,R2=异丙基)之间的比例为92.8∶7.2。反应混合物减压浓缩除去甲苯,向其中加入88mL乙酸乙酯,混合物加热至65℃以完全溶剂。然后向其中加入88mL正己烷,缓慢降低温度,在大约20℃下搅拌2天。所得到的固体过滤后,用15mL乙酸乙酯和15mL正己烷的混和溶剂洗涤。固体用氮气干燥后,得到目标化合物,为白色固体(1,R1=1-异喹啉基,R2=异丙基),按式(2)化合物计算收率为54.7%(8.0g,化学纯度98.6%)。
该结晶形式的固体NMR数据使用VACP MAS(可变振幅交叉偏振磁角旋转)在9kH旋转速率下获得。
1H NMR(CDCl3):9.02(bs,1H),8.54(d,J=5.5Hz,1H), 7.85(d,J=7.95Hz,1H),7.70(m,3H),7.60(bs,1H),4.86(bs,1H),4.2-5.2(bs,2H),4.05(b,J=19.0Hz,1H),3.78(b,J=19.0Hz,1H),2.7-3.1(bm,2H),2.40(m,1H).1.08(dd,J=6.7,4.9Hz,6H)
13C NMR(CDCl3):173.8,172.4,160.2,147.6,141.7,136.8,130.7,129.0,127.4,127.3,126.8,122.9,92.3,82.7(d,J=215Hz),48.9(b),44.6,34.4,33.9,17.7,16.3
13C NMR(固体):176.4,171.8,160.3,150.2,139.5,137.5,132.3(2C),127.7(3C),123.0,104.3,94.1,86.4,48.8,42.9,32.7(2C),19.6,15.4
质量(ESI):416.14(M+1)
实验实施例1
稳定性测试
如图2所示,关于对式(1)化合物(R1=1-异喹啉基,R2=异丙基)的无定形形式和结晶形式的稳定性测试结果,观察到50%的无定形形式在严苛条件(60℃)下28天后被破坏,而定量的结晶形式在相同条件(60℃)下甚至28天几乎没有任何减少。因此,应该理解结晶形式具有比无定形形式更好的稳定性,足以用于抑制剂或治疗剂的配制。
实验实施例2
对小鼠中由LPS诱导的急性肝炎的治疗效果
步骤1:制备血样
将雄性Ba1b/c小鼠(6周大,Charles River Laboratory,大阪,日本)在22℃和55%相对湿度下饲养,同时每隔12小时不断改变黑夜/白天。无限制地供给食物和水。将LPS(脂多糖)和D-半乳糖胺溶解于无热原盐水中,浓度分别为0.4mg/mL和280mg/mL,然后以1:1比例混和。将溶液以5ml/kg的量注射入小鼠中。注射LPS和D-半乳糖胺后,立即向测试动物注射溶解了测试化合物的溶酶(由 PEG400:乙醇:Tween80以15:7.5:2.5组成的混合物,用盐水1/5稀释)或者单独的溶酶。药物注射8小时后,由小鼠心脏获得血样。
步骤2:血浆转氨酶活性测试
由步骤1得到的血样的血浆ALT活性使用ALT测试试剂盒(Asanpharmaceutical company)按照制造商说明进行测量。观察到施用LPS和D-半乳糖胺迅速提高了血浆中的ALT活性,测试物质以依赖于剂量的方式抑制上述酶活性的增加。根据这些结果,使用Prism软件(GraphPad Co.)计算每种测试物质的ED50值。
实验实施例3
对小鼠中由Fas抗体诱导的急性肝炎的治疗效果
将雄性Balb/c小鼠(6周大,Charles River Laboratory,大阪,日本)在22℃和55%相对湿度下饲养,同时每隔12小时改变黑夜/白天。无限制地供给食物和水。将Fas抗体溶解于无热原盐水中,浓度为30ug/mL,然后以5ml/kg的量向小鼠中注射该溶液。注射Fas抗体之后,立即向测试动物注射溶解了测试化合物的溶酶(由PEG400:乙醇:Tween80以15:7.5:2.5组成的混合物,用盐水1/5稀释)或者单独的溶酶。注射药物8小时后,由小鼠心脏获得血样。所得到的血样的ED50值使用上述测试方法计算。下表1示出了根据由前面实施例2和3得到的式(1)化合物的给药途径在急性肝炎模型中的药理学效果测试结果。
表1
工业实用性
根据本发明式(1)的具有环状羧酸半缩酮的异噁唑啉衍生物具有出色的半胱天冬酶抑制活性和出色的稳定性。此外,根据本发明的方法通过使用结晶诱导的动态转化制备仅仅得到一种高纯度的非对映异构体。另外,如果根据本发明的具有缩酮的胺衍生物作为中间体使用,则本领域技术人员可以方便地制备得到具有环状羧酸半缩酮的异噁唑啉衍生物,而不需另外纯化。
Claims (20)
1.式(1)化合物:
其中
R1是异喹啉基、喹啉基或萘基,以及
R2是甲基、乙基、丙基或丁基。
2.权利要求1的化合物,其中
R1是异喹啉基,以及R2是异丙基。
4.权利要求3的方法,其中
R3和R′3各自是甲基、乙基或丙基,或者
R3和R′3与和它们相连的氧原子一起形成二氧戊环或二氧杂环己烷,以及
R4是甲基、乙基、丙基或丁基。
5.权利要求3或4的方法,其中在步骤(a)中式(2)化合物通过选自草酰氯、三甲基乙酰氯、磷酰氯和亚硫酰氯中的活化试剂活化。
6.权利要求3或4的方法,其中步骤(a)中的反应在选自三乙胺、三(正丁基)胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶和4-(4-甲基 -哌啶-1-基)-吡啶中的碱的存在下进行。
7.权利要求3或4的方法,其中步骤(b)中的水解在选自氢氧化锂、氢氧化钠、氢氧化钾和氢氧化钙中的碱的存在下进行。
8.权利要求3或4的方法,其中步骤(c)中的脱保护反应在选自盐酸、硫酸和三氟乙酸中的酸的存在下进行。
9.权利要求3或4的方法,其中步骤(c)中的脱保护反应在存在或不存在选自二氯甲烷或氯仿中的溶剂的条件下进行。
10.权利要求3或4的方法,其中步骤(d)中的结晶诱导的动态转化反应通过加入式(1)化合物作为晶种进行。
11.权利要求10的方法,其中步骤(d)中的结晶诱导的动态转化反应在晶种和催化用量的碱的存在下进行。
12.权利要求11的方法,其中所述碱选自三乙胺、三(正丁基)胺、二异丙基乙基胺、二异丙基胺、吡啶、4-二甲氨基吡啶、4-(4-甲基-哌啶-1-基)-吡啶、旋光1-苯基乙胺和旋光1-萘基乙胺。
13.权利要求12的方法,其中所述碱以式(14)化合物的0.001-1.0当量的用量使用。
14.用于治疗炎症或预防细胞凋亡的药物组合物,其中含有根据权利要求1的式(1)化合物和可药用载体。
15.权利要求2的化合物,其中所述化合物是显示出下面的X-射线衍射图案的结晶形式:
16.根据权利要求1的式(1)化合物制备用于治疗炎症或预防细胞凋亡的药物的用途。
18.药物组合物,包含权利要求17的化合物和一种或多种可药用载体。
19.制备权利要求17的化合物的方法,所述方法包括:
(a)脱保护式(14)化合物得到式(15)和式(16)的化合物的混合物;
(b)用催化量的碱和式(1)化合物的晶种处理该式(15)和式(16)的化合物的混合物以使式(15)化合物和式(16)化合物都转化成式(1)化合物,
其中,所述式(15)化合物与所述式(16)、式(17)和式(1)化合物处于平衡,而且所述式(16)化合物与所述式(18)和式(19)化合物处于平衡,
20.权利要求17的化合物制备用于治疗炎症或预防细胞凋亡的药物中的用途。
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KR101299720B1 (ko) * | 2006-08-16 | 2013-08-28 | 주식회사 엘지생명과학 | 3-아미노-5-플루오로-4-디알콕시펜탄산 에스테르의 새로운제조방법 |
KR20090099886A (ko) * | 2008-03-18 | 2009-09-23 | 주식회사 엘지생명과학 | 캐스파제 저해제의 프로드럭 |
TW201012816A (en) * | 2008-07-11 | 2010-04-01 | Gilead Sciences Inc | Method of treatment and pharmaceutical compositions |
TW201011014A (en) * | 2008-07-11 | 2010-03-16 | Gilead Sciences Inc | Method of treatment and pharmaceutical compositions |
AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
WO2014048940A2 (en) * | 2012-09-28 | 2014-04-03 | Bayer Cropscience Ag | Nitrogen-containing heterocyclic compounds for plant disease control |
JP2017095353A (ja) * | 2014-03-27 | 2017-06-01 | 日本曹達株式会社 | イソオキサゾリン−5−カルボキサミド化合物および有害生物防除剤 |
CN113354708B (zh) * | 2017-01-23 | 2024-05-14 | 正大天晴药业集团股份有限公司 | 作为Caspase抑制剂的联环化合物 |
JP2022529973A (ja) * | 2019-04-19 | 2022-06-27 | エルジー・ケム・リミテッド | カスパーゼ阻害剤のプロドラッグ |
WO2020222541A1 (ko) * | 2019-04-30 | 2020-11-05 | 주식회사 엘지화학 | 캐스파제 저해제의 프로드럭 |
CN113891704A (zh) * | 2019-05-31 | 2022-01-04 | 株式会社Lg化学 | 半胱天冬酶抑制剂前药注射用组合物 |
US20220226234A1 (en) * | 2019-05-31 | 2022-07-21 | Lg Chem, Ltd. | Injectable composition containing prodrug of caspase inhibitors, and preparation method therefor |
JP2023537012A (ja) * | 2020-08-05 | 2023-08-30 | エルジー・ケム・リミテッド | 変形性関節症の緩和又は治療するためのカスパーゼ阻害剤の使用 |
EP4248950A4 (en) | 2020-11-30 | 2024-04-10 | LG Chem, Ltd. | INJECTABLE COMPOSITION CONTAINING CASPAS INHIBITOR AND MANUFACTURING METHOD THEREFOR |
KR102670554B1 (ko) * | 2022-01-04 | 2024-05-30 | 주식회사 이노보테라퓨틱스 | 캐스파제 저해제로서의 신규한 이소인돌리논 유도체 화합물 |
KR20230114203A (ko) | 2022-01-24 | 2023-08-01 | 주식회사 엘지화학 | 이소옥사졸린 유도체를 포함하는 주사용 제제 |
KR20230126654A (ko) | 2022-02-23 | 2023-08-30 | 주식회사 엘지화학 | 이소옥사졸린 유도체를 포함하는 주사용 제제 및 이의 제조방법 |
KR20230141971A (ko) | 2022-03-24 | 2023-10-10 | 주식회사 엘지화학 | 이소옥사졸린 유도체를 포함하는 주사용 제제 및 이의 제조방법 |
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WO2001021599A1 (en) | 1999-09-17 | 2001-03-29 | Lg Chemical Ltd. | Caspase inhibitor |
TWI256952B (en) * | 2003-08-27 | 2006-06-21 | Sk Corp | Chroman carboxylic acid derivatives for the treatment of diabetes and lipid disorders |
KR100594544B1 (ko) * | 2003-08-27 | 2006-06-30 | 주식회사 엘지생명과학 | 이소옥사졸린 구조를 갖는 캐스파제 저해제 |
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