CN116675680B - 一种氘代化合物及其制备方法、药物和应用 - Google Patents
一种氘代化合物及其制备方法、药物和应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明提供一种氘代化合物及其制备方法、药物和应用,所述氘代化合物为式Ⅰ化合物或其药学上可接受的盐:;其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23和R24各自独立地为H或氘,且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23和R24不同时为H,n=2。所述氘代化合物可作为GLP‑1受体激动剂,其给药剂量小,毒副作用小。
Description
技术领域
本发明属于生物医药领域,具体涉及一种氘代化合物及其制备方法、药物和应用。
背景技术
胰高血糖素样肽-1受体(glucagon-like peptide-1 receptor,GLP-1R)属于7次跨膜的G蛋白偶联受体B家族中的胰岛血糖系受体亚家族,表达于胰腺或胰腺外组织,所述胰腺外组织包括中枢神经系统、心血管及胃肠道等。人胰腺组织高表达GLP-1R,胰高血糖素样肽-1 (Glucagon-like peptide-1,GLP-1)受体激动剂可与GLP-1R结合从而促进胰岛素的合成与分泌,并刺激胰岛β细胞的增殖,还会抑制其凋亡。GLP-1受体激动剂不但可以刺激人体胰岛素分泌,且降解速度较慢,并具备降低体重、改善血脂及降低血压的临床作用。
Danuglipron(PF-06882961,2-[[4-[6-[(4-氰基-2-氟苯基)甲氧基]-2-吡啶基]-1-哌啶基]甲基]-1-[(2S)-2-氧杂环丁烷基甲基]-1H-苯并咪唑-6-羧酸)是由辉瑞公司开发的口服GLP-1受体激动剂,目前完成了临床二期研究。临床结果显示,在二型糖尿病患者中,Danuglipron显著降低患者的糖化血红蛋白(HbA1c)、空腹血糖水平和体重。接受最高剂量Danuglipron治疗患者的HbA1c降低1.16个百分点,体重减少4.17公斤。但是,Danuglipron易于代谢,因此需要的给药剂量较大,而大剂量给药易产生毒副作用。
发明内容
为了解决上述现有技术的问题,本发明提供一种氘代化合物及其制备方法、药物和应用,所述氘代化合物可作为GLP-1受体激动剂,改善Danuglipron的药代动力学性质,降低给药剂量和可能的毒副作用。
本发明通过以下技术方案实现:
一种氘代化合物,所述氘代化合物为式Ⅰ化合物或其药学上可接受的盐:
其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23和R24各自独立地为H或氘,且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23和R24不同时为H,n=2。
优选的,所述式Ⅰ化合物为如下化合物中的一种:
优选的,所述药学上可接受的盐为甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
所述的氘代化合物的制备方法,包括:
将式Ⅰ-1化合物和式Ⅰ-2化合物用第一溶剂溶解,加入第一催化剂,在氮气保护条件下进行加热搅拌反应,得到第一中间体;
将第一中间体和式Ⅰ-3化合物用第二溶剂溶解,再加入第二催化剂,在氮气保护条件下进行加热反应,得第二中间体;
将第二中间体用第三溶剂溶解,再加入三氟乙酸,室温搅拌反应,然后萃取,得第三中间体;
将第三中间体用第四溶剂溶解,加入式Ⅰ-4化合物和碳酸钾,加热搅拌反应,然后萃取,得第四中间体;
将第四中间体用第五溶剂溶解,加入LiOH后,室温搅拌反应,反应完全后滴入HCl溶液,调节溶液pH值至3~4,有固体析出,收集固体,得式Ⅰ化合物。
优选的,所述第一催化剂为[1,1'-双(二苯基膦基)二茂铁]二氯化钯和碳酸铯;所述第二催化剂为三(二亚苄基丙酮)二钯、1,1'-联萘-2,2'-双二苯膦和碳酸铯。
一种药物,由所述的氘代化合物添加或不添加药学上可接受的载体构成。
所述的氘代化合物在制备GLP-1受体激动剂中的应用。
所述的氘代化合物在制备治疗二型糖尿病药物中的应用。
所述的氘代化合物在制备治疗超重或肥胖症药物中的应用。
所述的氘代化合物在制备治疗超重或肥胖症的相关性合并症药物中的应用。
与现有技术相比,本发明具有如下的有益效果:
本发明提供的氘代化合物,是将Danuglipron分子的一个或多个碳氢键用碳氘键替代,氘代化合物改善了原有Danuglipron的药代动力学性质,克服了药物原有的易于代谢的缺陷,因而能够降低给药剂量和可能的毒副作用。
进一步的,本发明对化合物的不同位点进行了氘代,包括哌啶、吡啶、碳单键三个单元上的位点及各单元互相之间的组合位点,得到了八种效果优异的氘代化合物。
本发明所述的氘代化合物,可作为GLP-1受体激动剂,用于制备治疗二型糖尿病、超重、肥胖症及超重或肥胖症的相关性合并症的药物。
具体实施方式
为了进一步理解本发明,下面结合实施例对本发明进行描述,这些描述只是进一步解释本发明的特征和优点,并非用于限制本发明的权利要求。
本发明所述氘代化合物,为如下式Ⅰ化合物或其药学上可接受的盐:
其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23和R24各自独立地为H或氘,且R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23和R24不同时为H,n=2。
本发明所述式Ⅰ化合物为如下结构中的一种:
本发明所述药学上可接受的盐为甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
本发明所述氘代化合物的制备方法,包括:
将式Ⅰ-1化合物和式Ⅰ-2化合物用第一溶剂溶解,加入第一催化剂,在氮气保护条件下进行加热搅拌反应,得到第一中间体;
将第一中间体和式Ⅰ-3化合物用第二溶剂溶解,再加入第二催化剂,在氮气保护条件下进行加热反应,得第二中间体;
将第二中间体用第三溶剂溶解,再加入三氟乙酸,室温搅拌反应,然后萃取,得第三中间体;
将第三中间体用第四溶剂溶解,加入式Ⅰ-4化合物和碳酸钾,加热搅拌反应,然后萃取,得第四中间体;
将第四中间体用第五溶剂溶解,加入LiOH后,室温搅拌反应,反应完全后滴入HCl溶液,调节溶液pH值至3~4,有固体析出,收集固体,得式Ⅰ化合物。
本发明所述的氘代化合物可作为GLP-1受体激动剂,用于制备治疗二型糖尿病、超重、肥胖症(例如下丘脑性肥胖症和单基因肥胖症)及超重或肥胖症的相关性合并症(例如骨关节炎和尿失禁)的药物。
本发明含所述的氘代化合物的药物,包括作为活性成分的所述氘代化合物,还可以包括或不包括药学上可接受的载体。
本发明含所述的氘代化合物的药物,其剂型为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
实施例1 化合物1的合成
化合物1的合成路线如下:
将中间体1-1(5 mmol)和1-2(5 mmol)用1,4-二氧六环溶解,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2,0.25 mmol)和碳酸铯(8 mmol),氮气保护条件下,置于90℃搅拌过夜反应。TLC监测反应完全,经硅藻土过滤,浓缩后经柱层析纯化得中间体1-3。
将中间体1-3(3 mmol)和(4-氰基-2-氟苯基)甲醇(3 mmol)用甲苯溶解,再加入三(二亚苄基丙酮)二钯(Pd2(dba)3,0.25 mmol),1,1'-联萘-2,2'-双二苯膦(BINAP,0.3mmol)和碳酸铯(4 mmol)。氮气保护后,置于100℃反应一天。TLC监测反应完全,经硅藻土过滤,浓缩后经柱层析纯化得中间体1-4。
将中间体1-4(1 mmol)用二氯甲烷(5 mL)溶解,再加入三氟乙酸(0.5 mL),室温搅拌反应两小时,TLC监测反应完全,加入水(10 mL),再加入30 mL二氯甲烷,萃取,水洗,经浓缩后得中间体1-5。
中间体1-6根据专利文献CN110325530B中中间体23的合成方法制得。
将中间体1-5(1 mmol)用乙腈(5 mL)溶解,加入中间体1-6(1 mmol)和碳酸钾(4mmol),置于50℃搅拌反应过夜,TLC监测反应完全,加入水(10 mL),再加入30 mL乙酸乙酯,萃取,水洗,经浓缩后得中间体1-7。
将中间体1-7(1 mmol)用3 mL四氢呋喃/甲醇/水(THF/ MeOH/ H2O,THF、MeOH和H2O体积比为1:1:1)混合溶液溶解,加入LiOH(2 mmol),室温搅拌两小时后,TLC监测反应完全,滴入10% HCl溶液,调节溶液pH至3,有固体析出,过滤,收集固体,干燥得化合物1。1H NMR(400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.92 (d,J= 5.0 Hz, 1H), 7.60 (d,J=4.8 Hz, 1H), 7.54 (dd,J= 7.5, 2.0 Hz, 1H), 7.47 (dt,J= 7.4, 1.0 Hz, 1H), 7.42(t,J= 8.1 Hz, 1H), 7.34 (s, 1H), 7.10 (dd,J= 8.0, 0.9 Hz, 1H), 6.57 (dd,J=8.1, 1.1 Hz, 1H), 5.33 (d,J= 1.0 Hz, 2H), 4.33 (d,J= 12.5 Hz, 1H), 4.17 –4.10 (m, 4H), 3.85 (d,J= 6.0 Hz, 1H), 3.72 (d,J= 6.0 Hz, 1H), 3.45 (s, 1H),2.17 – 2.03 (m, 2H).
实施例2 化合物2的合成
将实施例1合成路线中,中间体1-1替换成4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)哌啶-1-甲酸叔丁酯,中间体1-2替换成2,6-二氯吡啶-3,4,5-氘,可制得化合物2。1H NMR (300 MHz, Chloroform-d) δ 7.97 (d,J= 5.0 Hz, 1H), 7.93 (s, 1H), 7.61(d,J= 4.8 Hz, 1H), 7.54 (dd,J= 7.5, 2.0 Hz, 1H), 7.47 (dt,J= 7.3, 1.0 Hz,1H), 7.34 (s, 1H), 5.23 (d,J= 0.9 Hz, 2H), 4.33 (d,J= 12.5 Hz, 1H), 4.19 –4.09 (m, 2H), 3.85 (d,J= 6.0 Hz, 1H), 3.77 – 3.66 (m, 3H), 3.03 (s, 1H), 2.78(s, 2H), 2.49 (s, 2H), 2.26 (d,J= 11.0 Hz, 1H), 2.05 (s, 2H), 1.97 (d,J= 11.0Hz, 1H).
实施例3 化合物3的合成
将实施例1合成路线中,中间体1-1替换成4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)哌啶-1-甲酸叔丁酯,(4-氰基-2-氟苯基)甲醇替换成3-氟-4-(羟甲基-d2)苄腈,可制得化合物3。1H NMR (400 MHz, Chloroform-d) δ 8.20 (d,J= 5.0 Hz, 1H), 7.95(s, 1H), 7.65 (d,J= 5.0 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.41 – 7.31 (m, 2H),7.18 (dd,J= 8.1, 0.9 Hz, 1H), 6.75 (dd,J= 8.0, 1.0 Hz, 1H), 4.33 (d,J= 12.5Hz, 1H), 4.18 – 4.08 (m, 2H), 3.85 (d,J= 6.0 Hz, 1H), 3.76 – 3.68 (m, 3H),3.07 (s, 1H), 2.77 (s, 2H), 2.45 (s, 2H), 2.26 (d,J= 11.0 Hz, 1H), 2.03 –1.93 (m, 3H).
实施例4 化合物4的合成
将实施例1合成路线中,中间体1-2替换成2,6-二氯吡啶-3,4,5-氘,可制得化合物4。1H NMR (400 MHz, Chloroform-d) δ 8.02 (d,J= 5.0 Hz, 1H), 7.93 (s, 1H), 7.65(d,J= 4.8 Hz, 1H), 7.54 (dd,J= 7.5, 2.0 Hz, 1H), 7.47 (dt,J= 7.5, 1.0 Hz,1H), 7.34 (d,J= 2.1 Hz, 1H), 5.23 (d,J= 1.0 Hz, 2H), 4.33 (d,J= 12.5 Hz, 1H),4.20 – 4.08 (m, 4H), 3.85 (d,J= 6.0 Hz, 1H), 3.72 (d,J= 6.0 Hz, 1H), 3.47 (s,1H), 2.20 – 2.01 (m, 2H).
实施例5 化合物5的合成
将实施例1合成路线中,(4-氰基-2-氟苯基)甲醇替换成3-氟-4-(羟甲基-d2)苄腈,可制得化合物5。1H NMR (400 MHz, Chloroform-d) δ 8.04 (d,J= 5.0 Hz, 1H),7.93 (s, 1H), 7.65 (d,J= 4.9 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.45 – 7.33 (m,2H), 7.05 (dd,J= 8.0, 1.0 Hz, 1H), 6.75 (dd,J= 8.0, 1.0 Hz, 1H), 4.33 (d,J=12.5 Hz, 1H), 4.19 – 4.08 (m, 4H), 3.85 (d,J= 6.0 Hz, 1H), 3.72 (d,J= 6.0 Hz,1H), 3.45 (s, 1H), 2.18 – 2.01 (m, 2H).
实施例6 化合物6的合成
将实施例2合成路线中,(4-氰基-2-氟苯基)甲醇替换成3-氟-4-(羟甲基-d2)苄腈,可制得化合物6。1H NMR (400 MHz, Chloroform-d) δ 8.04 (d,J= 5.0 Hz, 1H),7.93 (s, 1H), 7.64 (d,J= 5.0 Hz, 1H), 7.51 – 7.46 (m, 2H), 7.39 (d,J= 7.3 Hz,1H), 4.33 (d,J= 12.5 Hz, 1H), 4.24 – 4.11 (m, 2H), 3.85 (d,J= 6.0 Hz, 1H),3.79 – 3.62 (m, 3H), 3.03 (s, 1H), 2.78 (s, 2H), 2.49 (s, 2H), 2.26 (d,J=11.0 Hz, 1H), 2.05 (s, 2H), 1.97 (d,J= 11.0 Hz, 1H).
实施例7 化合物7的合成
将实施例1的合成路线中,中间体1-2替换成2,6-二氯吡啶-3,4,5-氘,(4-氰基-2-氟苯基)甲醇替换成3-氟-4-(羟甲基-d2)苄腈,可制得化合物7。1H NMR (400 MHz,Chloroform-d) δ 8.00 (d,J= 5.0 Hz, 1H), 7.93 (s, 1H), 7.63 (d,J= 5.0 Hz,1H),7.52 – 7.46 (m, 2H), 7.39 (d,J= 7.3 Hz, 1H), 4.33 (d,J= 12.5 Hz, 1H), 4.19 –4.02 (m, 4H), 3.85 (d,J= 6.0 Hz, 1H), 3.72 (d,J= 6.0 Hz, 1H), 3.47 (s, 1H),2.20 – 1.99 (m, 2H).
实施例8 化合物8的合成
将实施例7的合成路线中,中间体(4-氰基-2-氟苯基)甲醇替换成3-氟-4-(羟甲基-d2)苄腈-2,5,6-d3,可制得化合物8。1H NMR (400 MHz, Chloroform-d) δ 8.12 (s,1H), 7.94 (d,J= 5.0 Hz, 1H), 7.75 (d,J= 4.5 Hz, 1H), 4.32 (d,J= 12.5 Hz, 1H),4.11 – 4.00 (m, 2H), 3.88 (d,J= 5.9 Hz, 1H), 3.73 (d,J= 6.0 Hz, 1H), 2.10 –2.01 (m, 2H).
试验例1:GLP-1R结合力测试
使用Biacore S200系统和CM5芯片检测本发明氘代化合物和GLP-1R的结合力数据,实验操作遵循Biacore S200操作手册完成,本发明氘代化合物使用5%二甲基亚砜(DMSO)的PBS溶液进行配制,以Danuglipron为对照化合物。结合力数据使用Biacore S200Evaluation Software进行分析处理。结果如表1所示。
表1 本发明氘代化合物与GLP-1R结合力测试
化合物1-8表现出优异的GLP-1R结合活性,与Danuglipron相比,氘代化合物展现出更优的GLP-1R结合活性,多位点氘代化合物表现出更好的活性提升,表明本发明氘代化合物的氘代位点合理,可提高GLP-1R受体结合活性。
试验例2:本发明氘代化合物对HEK293细胞环磷酸腺苷(cAMP)活性测试
通过测量HEK293细胞中的细胞内cAMP,来证明在本发明氘代化合物存在下的GLP-1R功能活性。用含有100μΜ 3-异丁基-1-甲基黄嘌呤的检定缓冲液(钙/镁HBSS(BioWhittaker#10-527F)和0.1%BSA(Sigma Aldrich#A7409-1L))将本发明的氘代化合物溶于DMSO中(10μΜ),3倍稀释9次,在37℃处理30分钟。将HEK293细胞在完全培养基中传代,在大约48小时增殖后,在细胞测定当天,用各浓度的化合物处理30分钟后,加入10μL的cAMP和抗cAMP抗体,室温培育60分钟后,通过均相时间分辨荧光技术(Cisbio Bioassays,Bedford,MA),使用Dynamic 2测定法测量cAMP。相应cAMP浓度由比值计算法和外部标准推出。使用四参数逻辑斯蒂方程,检验测试化合物的S形剂量反应。结果如表2所示。
表2 HEK293细胞中GLP-1R功能活性测定
化合物1-8表现出优异的GLP-1R激动活性,与Danuglipron相比,氘代化合物展现出更优的GLP-1R激动活性,氘代化合物3表现出最好的GLP-1R激动活性,表明本发明氘代化合物的氘代位点合理,可提高GLP-1R激动活性。
试验例3:本发明氘代化合物的药代动力学实验
(一)实验仪器和材料
高速冷冻离心机,涡旋振荡器(Vortex Genius3),高速离心机(Eppendorf5415D),一次性使用注射器,移液枪(Eppendorf),实验所用SD雄性大鼠均购自扬州大学,EDTA-K2真空采血管,生理盐水。所有口服组大鼠在给药前禁食12h,自由饮水,给药期间自由进水和进食。
(二)实验步骤
本发明氘代化合物、Danuglipron使用二甲基亚砜/聚乙二醇-15羟基硬脂酸酯/水(DMSO/solutol/H2O,DMSO、solutol和H2O体积比为10:10:80)溶解制成澄清溶液,口服给药(i.p.)时化合物剂量5 mg/kg,尾静脉给药(i.v.)时化合物的剂量为1 mg/kg。于尾静脉给药后的2 min、10 min、30 min、1 h、2 h、3 h、5 h、8 h、12 h、16 h和24 h,分别从眼底静脉丛连续取血0.5 mL,置于肝素管中;于口服给药后的5 min、15 min、30 min、1 h、2 h、3 h、5h、8 h、12 h、16 h和24 h,分别从眼底静脉丛连续取血0.5 mL,置于肝素管中。将血样在8000 r、4 ℃条件下离心10 min后,取上层血浆0.15 mL,-20℃条件下保存,之后进行LC-MS/MS分析。数据通过WinNolin非房室模型分析,得到关键药代动力学参数。
(三)实验结果
表3药代动力学参数
相对于Danuglipron,化合物1-8口服给药的半衰期提高明显,可以有效降低给药剂量,从而降低高剂量给药的毒副作用。
综上,根据酶活性、细胞活性以及药代动力学活性数据显示,本发明制备的氘代化合物相对于阳性药Danuglipron,GLP-1R激动活性进一步提高,成药性更为良好,具备显著降低给药毒副作用和提高药物安全性的特性,显示出氘代化合物的活性和成药性的优势。
最后有必要说明的是,以上对本发明的具体实施例进行了详细描述,但其只作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (8)
1.一种氘代化合物,其特征在于,所述氘代化合物为式Ⅰ化合物或其药学上可接受的盐:
其特征在于,选自以下化合物:
。
2. 根据权利要求1所述的氘代化合物,其特征在于,所述药学上可接受的盐为甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
3.权利要求1所述的氘代化合物的制备方法,其特征在于,包括:
将式Ⅰ-1化合物和式Ⅰ-2化合物用第一溶剂溶解,加入第一催化剂,在氮气保护条件下进行加热搅拌反应,得到第一中间体;
将第一中间体和式Ⅰ-3化合物用第二溶剂溶解,再加入第二催化剂,在氮气保护条件下进行加热反应,得第二中间体;
将第二中间体用第三溶剂溶解,再加入三氟乙酸,室温搅拌反应,然后萃取,得第三中间体;
将第三中间体用第四溶剂溶解,加入式Ⅰ-4化合物和碳酸钾,加热搅拌反应,然后萃取,得第四中间体;
将第四中间体用第五溶剂溶解,加入LiOH后,室温搅拌反应,反应完全后滴入HCl溶液,调节溶液pH值至3~4,有固体析出,收集固体,得式Ⅰ化合物;所述第一催化剂为[1,1'-双(二苯基膦基)二茂铁]二氯化钯和碳酸铯;所述第二催化剂为三(二亚苄基丙酮)二钯、1,1'-联萘-2,2'-双二苯膦和碳酸铯。
4.一种药物,其特征在于,由权利要求1~2中任意一项所述的氘代化合物添加或不添加药学上可接受的载体构成。
5.权利要求1~2任一项所述的氘代化合物在制备GLP-1受体激动剂中的应用。
6.权利要求1~2任一项所述的氘代化合物在制备治疗二型糖尿病药物中的应用。
7.权利要求1~2任一项所述的氘代化合物在制备治疗超重或肥胖症药物中的应用。
8.权利要求1~2任一项所述的氘代化合物在制备治疗超重或肥胖症的相关性合并症药物中的应用。
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