CN116478211B - 一种新型cgrp受体拮抗剂及其用途 - Google Patents
一种新型cgrp受体拮抗剂及其用途 Download PDFInfo
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- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开CGRP受体拮抗剂及其用途,所述的CGRP受体拮抗剂具有式I‑0所示的结构,或式I‑0结构的药学上可接受的盐、及其盐的异构体。本发明还提供了式I‑0的化合物在制备用于预防和/或治疗哮喘病等相关呼吸道疾病中的应用。
Description
技术领域
本申请涉及一系列新的化合物,具有CGRP受体拮抗功能,可用作缓解和/或治疗与CGRP受体相关的哮喘病、慢性阻塞性肺疾病(COPD)、肺心病相关疾病的作用。
背景技术
降钙素基因相关肽(Calcitonin gene related peptide,CGRP)是一种感觉神经肽,含有37个氨基酸,在心血管、呼吸、消化和内分泌系统中广泛分布,是神经―免疫系统相互调节的重要介质之一。CGRP分为α和β两种构型,其生物学效应相似。
在生物体内CGRP可以与其特异性受体结合产生多种生物学效应,主要有舒张血管、促使气道平滑肌收缩等作用。目前对CGRP的研究越来越多,有研究表明由内皮素转换酶-1(Endothelin Converting Enzyme-1,ECE-1)产生的CGRP降解可促使气道炎症浸润,进而刺激肥大细胞脱颗粒,导致多种血管活性物质释放,这种效应会直接导致血管的通透性问题或气道炎症问题。在肺部CGRP可促进肺部炎症部位的迁移和浸润,严重的可加重肺微血管通透性,进而导致肺损伤。CGRP还可通过参与cAMP/PKA(Protein Kinase A,PKA)信号途径,使气道免疫调节机制发生改变,引起气道出现变应性炎症并进而引起发作哮喘病,临床的数据也表明在哮喘病发病人群中血液中CGRP含量明显升高,并且与哮喘病的严重程度呈现线性关系。CGRP还可以激活CGRP受体,进而引发内皮细胞增殖,增强对气道平滑肌的收缩作用。因此,CGRP及其受体的过度表达,可加重气道血管的通透性,增加粘液分泌量,导致严重的哮喘。
目前,无论是在人或者是在动物模型实验中,研究结果均表明CGRP拮抗剂可明显减弱CGRP对气道上皮细胞的刺激效应,在抑制气道炎症、改善气道结构方面具有明显的作用,可大大缓解哮喘症状。截止目前,在神经肽受体拮抗剂研究方面取得了不错的进展,随着研究的不断深入,也使神经肽受体拮抗剂成为新药的可能性越来越大。
发明内容
本发明一方面提供了种新颖结构的CGRP受体拮抗剂,对CGRP受体具有显著的拮抗作用,并且没有明显的细胞毒性。
本发明的另一方面提供的化合物在体内具有显著的舒张血管的作用,同时在大鼠体内具有显著的治疗哮喘病的作用,并且未表明出明显的毒副作用,取得了显著的有益技术效果。
本发明的第三方面提供的意外地发现化合物在体内可以快速达到最高血药浓度,起效更快,取得了意想不到的技术效果。
本发明涉及一种式I-0的化合物:
X、Y各自独立地为CH、或N;
R1为-H、-Cl、-OH、-CF3、-CH3、-CH2CH3、-CN、-OCH3、-OCH2CH3、-Ar;
R2为-H;
R3为-H、-OH、-NH2、-OR7、-NHR7、或
其中,上述Ra1、Ra2、Rb1和Rb2分别独立地选自氢、或被基团A取代或未取代的下列基团:C1-C8烷基、C3-C8环烷基、杂环烷基、C6-C18芳基、C3-C12杂芳基;
R4为-H;
R5为被一个或多个氢、卤素、羟基、氨基、硝基、氰基、三氟甲基、甲氧基、乙氧基、羧基、乙酰基、甲醛基、羟甲基、羟乙基、甲磺酰基、乙磺酰基取代的C6-C18芳基;
R6为-O(CO)R8、-NH(CO)R8;
R7为甲基、乙基、乙酰基、丙酰基、苄基、苯甲酰基、甲磺酰基、乙磺酰基、丙磺酰基、对甲苯磺酰基;
R8为
R9为
R10为或Rd;
其中,上述Rd选自氢、或
当Rd为氢时,R3为
上述m1和m3分别独立地选自1、2、3、或4;
m2和m4分别独立地选自0、1、或2,且m2和m4不可同时为0;
n1和n3分别独立地选自1、2、3、或4;
n2和n4分别独立地选自1、或2;
Rf为C1-C10烷基、C1-C10烷氧基、C3-C10碳环基、C2-C10杂环基、C6-C18芳基、C3-C12杂芳基,上述基团可任选地被一个或者多个卤素、氨基、羟基、羧基、三氟甲基、氰基、甲氧基、乙氧基、乙酰基、甲基、乙基取代;
Rg1、Rg2、Rh1和Rh2各自独立地为氢、卤素、C1-C8烷基、C1-C8烷氧基;
Re为卤素、氨基、羟基、羧基、硝基、三氟甲基、氰基、甲氧基、乙氧基、乙酰基、甲基、乙基;
R11为卤素、氨基、羟基、羧基、硝基、三氟甲基、氰基、甲氧基、乙氧基、乙酰基、甲基、乙基;
R12、R13分别为氢或被一个或者多个卤素、氨基、羟基、羧基、硝基、三氟甲基、氰基、甲氧基、乙氧基、乙酰基、甲基、乙基取代的下列基团:(C1-C10)烷基、(C1-C10)烷氧基、(C1-C10)烷氨基、(C2-C10)烯基、(C2-C10)炔基、(C3-C10)碳环基、(C2-C10)杂环基、(C6-C18)芳基、(C3-C12)杂芳基或R12和R13相连成环;
R14为(C1-C10)烷基、(C1-C10)烷氧基、(C3-C10)碳环基、(C2-C10)杂环基、(C6-C18)芳基、(C3-C12)杂芳基可任选地被一个或者多个卤素、氨基、羟基、羧基、三氟甲基、氰基、甲氧基、乙氧基、乙酰基、甲基、乙基取代;
或者所述化合物的药学上可接受的盐、或者所述化合物及其盐的异构体。
所述基团A为:C1-C10的烷基、羟基、氨基、 巯基、卤素、氰基、醛基、硝基、三氟甲基、C3-C12的环烷基、C1-C10的烷氧基、C6-C18的芳基、C6-C18的芳基氧基。
所述的化合物,其特征在于所述的化合物具有如下式Ⅱ-0的结构:
式II-0中取代基的定义如式I-0所定义的。
所述的化合物,其特征在于所述的化合物具有如下式Ⅲ-0的结构:
式III-0中取代基的定义如式I-0所定义的。
所述的化合物,其选自:
或者所述化合物的药学上可接受的盐、或者所述化合物及其盐的异构体。
所述的化合物作为降钙素基因相关肽(Calcitonin gene related peptide,CGRP)受体拮抗剂。
一种药物组合物,包含所述的化合物、或者所述化合物及其盐的异构体与药学上可接受的添加剂。
所述化合物及所述组合物,可用于缓解和/或治疗哮喘病(Bronchial asthma)、慢性阻塞性肺疾病(Chronic Obstructive Pulmonary Disease,COPD)、肺心病、头痛、偏头痛、器官疼痛相关疾病的作用。
所述组合物缓解和/或治疗哮喘病、慢性阻塞性肺疾病、肺心病相关疾病可通过口服、鼻腔内、口腔内、皮肤表面、静脉注射对人或其他哺乳动物给药。
本发明中,为更详尽的理解本发明,各术语具有如下定义。
本文中的“氨基”是指具有1个氮原子及0至2个氢原子的官能团。
本文中的卤素指氟原子、氯原子、溴原子或碘原子。
本文中的“C1-C10烷基”是指碳原子数1~10的直链或支链烷基。例如甲基、乙基、异丙基、仲丁基、叔丁基、异戊基等;本文中的“C1-C8烷基”是指碳原子数1~8的直链或支链烷基。例如甲基、乙基、异丙基、仲丁基、叔丁基、异戊基等。
本文中的“C1-C10烷氧基”是指在碳原子数1~10的直链或支链烷基任意合理的位置插入O、或OH基团的基团。例如甲氧基、乙氧基、2-乙氧丙基等。
本文中的“C1-C10烷氨基”是指在“C1-C10烷基”任意合理的位置插入N、NH、或NH2原子团的基团。例如乙氨基、二异丙胺基、N-乙基异丙氨基、N-仲丁基正丙氨基等。
本文中的“C2-C10烯基”是指碳原子数2~10的直链、支链或环状的烯基。例如烯丙基、顺-2-戊烯基、反-2-已烯基、(-)-柠檬烯基等。
本文中的“C2-C10炔基”是指碳原子数2~10的直链、支链或环状的炔基。例如2-丙炔基、4-辛炔基、丙-1-炔基环丙烷基、1-戊炔基等。
本文中的“C3-C10碳环基”是指碳原子数3~10个的饱和或不饱和脂肪环状烃基。例如环丙基、环丁基、环戍基、甲基环戊基、1-甲基-1-环己烯基等;本文中的“C3-C8碳环基”是指碳原子数3~8个的饱和或不饱和脂肪环状烃基。例如环丙基、环丁基、环戍基、甲基环戊基、1-甲基-1-环己烯基等。
本文中的“C2-C10杂环基”是指碳原子数2~10个的至少一个环含有氮、硫、磷、或氧原子的饱和或不饱和单环或多环基团,此类多环杂环烷基的各个环可具有不同的连方式,比如稠合、桥连、螺环等。例如吡咯烷基、N-乙基哌啶基、呋喃基、四氢-3-硫酚基、4-甲基-1-哌嗪乙基等。
本文中的“C6-C18芳基”是指碳原子数6~18个的至少含一个芳香环的基团,除了共价基团外,多环芳基的各个环可具有不同的连方式,比如稠合、桥连等,并且稠合的环可以是饱和的或者不饱和的。例如苯基、二苯基甲基、α-四氢萘基、苯并环丁烯基等。
本文中的“C3-C12杂芳基”是指碳原子数3~12个的并且含有至少一个选自氧原子、氮原子和硫原子的芳香族杂环基。例如呋喃基、噻吩基、咪唑基、惡唑基、吡啶基、嘧啶基、哒嗪基等。
本发明含有双键的化合物包括所有的构型异构体(如顺式和反式异构体)。
本发明化合物具有非对称中心,因此本发明涉及所有这些化合物的光学异构体和立体异构体及它们的混合物的用途。
本发明还涉及具有互变异构体的化合物及它们的混合物的用途。
本发明的化合物含有碱性氮原子(杂环或者脂肪氨基等),易被氧化剂如空气中的氧、过氧化氢氧化为N-氧化物以生成本发明的其他化合物。因此,转化成的N-氧化物衍生物作为本发明化合物的一部分。
本文中的术语“一”、“一种”或者类似的术语表示的是包括一种和多种个数的对象,或其混合物,不仅限于一或一种。
本发明中的术语“独立地”指具有超过1个变量,则取代基的每一实例从可用的变量定义中的选择与其他选择定义变量无关。因此,每一取代基可与其他取代基相同或不同。
本发明中的术语“拮抗剂”指化合物及其组合物可以与受体有较强的亲和力,能阻断激动药与受体结合,因而对抗或取消激动药的作用的物质。
本发明中的术语“化合物的药学上可接受的盐”是指化合物与相应的酸结合成的络合物,此性质取决于化合物的特性,所述的化合物与酸的加成盐,例如无机酸盐如盐酸盐、硫酸盐、氢溴酸盐盐等。有机酸盐如马来酸盐、富马酸盐、乙酸盐、丙酸盐、苹果酸盐、酒石酸盐、丙二酸盐、琥珀酸盐、枸橼酸盐、肉桂酸盐、扁桃酸盐、甲磺酸盐、对甲苯磺酸盐、水杨酸盐等;本发明中的术语“化合物的药学上可接受的盐”同时也指本发明所述的化合物与碱的加成盐,无机碱的盐如钠盐、钾盐、铵盐、钙盐、镁盐等。有机胺的盐如二乙胺盐、乙二胺盐、葡甲胺盐、氨基丁三醇盐、精氨酸盐、赖氨酸盐、组氨酸盐、哌啶盐等。
本发明中的术语“药学上可接受的添加剂”是指有助于个体服用或吸收药物组合物中的活性物质的物质,并且对患者或个体不会造成明显不良影响,包括崩解剂、填充剂、调味剂、润滑剂、羟甲基纤维素、稳定剂、乳化剂、着色剂等。
本发明中的术语“缓解和/或治疗”是指通过给予需要治疗的对象或个体有效治疗量的化合物及其组合物达到减弱需要治疗的对象或个体病情甚至逆转病症的效果。
本发明中的哺乳动物指温血动物,例如大鼠、豚鼠、小鼠、沙鼠、兔、狗、猪、羊、猴、鸡、鸭、鹅、猫、牛、马、黑猩猩等。
本发明中的术语“治疗”表示对所适用的障碍或者一个或者多个病症进行抑制其进展、或者逆转症状的行为,同时亦包含对病症的辅助治疗。
本发明的化合物可以适用无机酸或有机酸的衍生为盐的形式使用,此性质取决于化合物的特性,如可增强药物的稳定性,水溶性,达到让人满意的溶解度。亦可作为分离、纯化和/或拆分的辅助手段。
附图说明
图1显示化合物对大鼠气道阻力的影响。
具体实施方式
以下结合实施例进一步描述本发明,但这些实施例并非限制着本发明的范围。下述实施例中所用的实验溶剂或试剂如无特殊说明,均通过市场购得,不做进一步纯化,直接使用。
合成过程所用的化合物1、化合物2、化合物3均可通过文献Org.Lett.2012,14,18,4938–4941报道的方法合成,结构如下:
实施例1:化合物DSC5601的制备及特征
化合物4:氮气保护下向中间体1(8.81g/20.0mmol)的120mL甲苯溶液中加入二氢吡喃(1.85g/22.0mmol)与对甲苯磺酸(0.34g/2.0mmol),所得混合物在室温下反应18小时,过滤,用0.1M的碳酸氢钠溶液洗涤,减压浓缩干燥得10.2g粗品,乙腈/水重结晶得6.9g目标化合物4(66%的收率)。MS:523.3[M+1]。直接用于下一步。
化合物5:氮气保护下向中间体4(5.23g/10.0mmol)的100mL四氢呋喃溶液中加入四丁基氟化铵(3.40g/13.0mmol),所得混合物在室温下反应3小时,过滤,浓缩,加入100mL乙酸乙酯,水洗与饱和食盐水洗,减压浓缩干燥得3.5g粗品,乙腈/水重结晶得2.6g目标化合物5(71%的收率)。MS:369.2[M+1]。直接用于下一步。
化合物6:向1-苄氧羰基氮杂环丁烷-3-酮(4.10g/20.0mmol)的100mL四氢呋喃溶液中加入1-Boc-哌嗪(3.72g/20.0mmol)与0.1mL乙酸,所得混合物在室温下反应1小时,加入三乙酰氧基硼氢化钠(6.36g/30.0mmol),所得混合物在室温下反应3小时,过滤,浓缩,加入100mL乙酸乙酯,水洗与饱和食盐水洗,减压浓缩后柱层析分离得6.5g粗品,加入100mL甲醇中,加入0.7g钯碳(10%),氢气氛围下室温反应12小时,过滤,浓缩,柱层析分离得3.1g目标化合物6(65%的收率)。MS:242.1[M+1]。直接用于下一步。
化合物7:氮气保护下向中间体6(2.41g/10.0mmol)的100mL干燥二氯甲烷溶液中加入N,N'-羰基二咪唑(1.62g/10.0mmol),所得混合物在回流状态下反应3小时,过滤,水洗,浓缩,柱层析分离得2.7g目标化合物7(82%的收率)。MS:336.2[M+1]。直接用于下一步。
化合物8:氮气保护下向中间体5(1.84g/5.0mmol)的100mL干燥四氢呋喃溶液中加入中间体7(1.67g/5.0mmol),所得混合物在60℃下反应3小时,过滤,浓缩所得固体溶解于0.01M的甲醇/盐酸(1:1)溶液中,所得混合物在室温下反应2小时,浓缩,加入乙酸乙酯,0.01M的碳酸氢溶液洗,饱和食盐水洗,浓缩,乙腈/水重结晶得1.2g目标化合物8(52%的收率)。MS:452.3[M+1]。直接用于下一步。
化合物DSC5601:氮气保护下向中间体8(0.90g/2.0mmol)的30mL干燥四氢呋喃溶液中加入NaH(0.12g/3.0mmol),所得混合物在室温下反应1小时,加入(二乙基)(氯甲基)磷酸酯(0.61g/3.0mmol),所得混合物在室温下反应3小时,过滤,加入0.5mL甲醇,浓缩所得固体加入二氯甲烷,水洗,饱和食盐水洗,浓缩,柱层析分离得0.4g目标化合物DSC5601(32%的收率)。MS:618.3[M+1]。1H NMR(CDCl3)δ7.32-7.30(m,4H),7.21-7.19(m,1H),7.00(s,1H),6.94(d,J=6.5Hz,1H),6.89(d,J=6.4Hz,1H),5.65-5.63(m,1H),5.25(s,2H),5.12-5.10(m,1H),4.03-4.00(m,6H),3.79-3.77(m,2H),3.69(s,3H),3.33-3.31(m,1H),3.02-3.00(m,1H),2.35-2.29(m,8H),1.95-1.93(m,2H),1.64-1.60(m,2H),1.30-1.26(m,6H)。
实施例2:化合物DSC5603的制备及特征
化合物9:氮气保护下向中间体2(8.94g/20.0mmol)的120mL甲苯溶液中加入二氢吡喃(1.85g/22.0mmol)与对甲苯磺酸(0.34g/2.0mmol),所得混合物在室温下反应18小时,过滤,用0.01M的碳酸氢钠溶液洗涤,减压浓缩干燥得10.5g粗品,乙腈/水重结晶得7.5g目标化合物9(71%的收率)。MS:532.2[M+1]。直接用于下一步。
化合物10:氮气保护下向中间体9(5.31g/10.0mmol)的100mL四氢呋喃溶液中加入四丁基氟化铵(3.40g/13.0mmol),所得混合物在室温下反应3小时,过滤,浓缩,加入100mL乙酸乙酯,水洗与饱和食盐水洗,减压浓缩干燥得3.6g粗品,乙腈/水重结晶得2.5g目标化合物10(68%的收率)。MS:376.1[M+1]。直接用于下一步。
化合物11:氮气保护下向4-溴哌啶-1-甲酸苄酯(2.98g/10.0mmol)的100mL二氯甲烷溶液中加入1H,2H,3H,4H-吡啶并[2,3-b]吡嗪-4-羧酸叔丁酯(2.35g/10.0mmol)与三乙胺(1.52g/15.0mmol),所得混合物在室温下反应3小时,过滤,水洗与饱和食盐水洗,减压浓缩,乙腈/水重结晶后干燥得4.0g粗品,加入100mL甲醇中,加入0.4g钯碳(10%),氢气氛围下室温反应12小时,过滤,浓缩,加入乙腈/水重结晶得1.7g目标化合物11(54%的收率)。MS:319.1[M+1]。直接用于下一步。
化合物12:氮气保护下向中间体11(1.59g/5.0mmol)的50mL干燥二氯甲烷溶液中加入N,N'-羰基二咪唑(0.81g/5.0mmol),所得混合物在回流状态下反应3小时,过滤,水洗,浓缩,柱层析分离得1.6g目标化合物12(79%的收率)。MS:413.2[M+1]。直接用于下一步。
化合物13:氮气保护下向中间体10(1.88g/5.0mmol)的100mL干燥四氢呋喃溶液中加入中间体12(2.06g/5.0mmol),所得混合物在60℃下反应3小时,过滤,浓缩所得固体溶解于0.01M的甲醇/盐酸(1:1)溶液中,所得混合物在室温下反应2小时,浓缩,加入乙酸乙酯,0.01M的碳酸氢溶液洗,饱和食盐水洗,浓缩,乙腈/水重结晶得1.5g目标化合物13(56%的收率)。MS:536.1[M+1]。直接用于下一步。
化合物DSC5603:氮气保护下向中间体13(1.07g/2.0mmol)的30mL干燥四氢呋喃溶液中加入NaH(0.12g/3.0mmol),所得混合物在室温下反应1小时,加入(二乙基)(氯甲基)磷酸酯(0.61g/3.0mmol),所得混合物在室温下反应3小时,过滤,加入0.5mL甲醇,浓缩所得固体加入二氯甲烷,水洗,饱和食盐水洗,浓缩,柱层析分离得0.35g目标化合物DSC5603(25%的收率)。MS:701.2[M+1]。1H NMR(CDCl3)δ8.42(d,J=6.3Hz,1H),8.01(d,J=6.2Hz,1H),7.68(d,J=6.5Hz,1H),7.20-7.18(m,1H),7.09-7.06(m,3H),6.77-6.75(m,1H),6.50-6.48(m,3H),5.85-5.83(m,1H),5.67(s,2H),5.11-5.09(m,1H),4.02-4.00(m,4H),3.56-3.50(m,4H),3.25-3.21(m,4H),3.01-2.98(m,1H),2.66-2.63(m,1H),1.95-1.91(m,3H),1.70-1.61(m,5H),1.29-1.26(m,6H)。
实施例3:化合物DSC5604与DSC5605的制备及特征
化合物14:氮气保护下向N-氯代丁二酰亚胺(1.34g/10.0mmol)100mL干燥四氢呋喃溶液中缓慢加入三苯基膦(2.62g/10.0mmol),搅拌10分钟后缓慢滴加DSC5605(7.02g/10.0mmol)的四氢呋喃溶液,室温反应6小时后过滤,浓缩,柱层析分离得4.7g目标化合物14(65%的收率)。MS:720.2[M+1]。直接用于下一步。
化合物15:氮气保护下向14(3.60g/5.0mmol)的干燥60mL DMF溶液中缓慢加入叠氮化钠(1.62g/25.0mmol),50℃下搅拌反应18小时,降温,过滤,加入200mL水,乙酸乙酯萃取,浓缩,柱层析分离得1.85g目标化合物15(51%的收率)。直接用于下一步。
化合物DSC5604:氮气保护下向15(1.45g/2.0mmol)的30mL四氢呋喃溶液中缓慢加入三甲基膦(0.49g/6.0mmol)的甲苯溶液6mL(1.0M),室温反应2小时后加入0.1mL水,继续反应3小时,反应结束后过滤,浓缩,加入水,乙酸乙酯萃取,浓缩,柱层析分离得0.76g目标化合物DSC5604(54%的收率)。MS:701.1[M+1]。1H NMR(CDCl3)δ8.40(d,J=6.4Hz,1H),7.99(d,J=6.5Hz,1H),7.64(d,J=6.3Hz,1H),7.17-7.15(m,1H),7.05-7.02(m,3H),6.73-6.70(m,1H),6.48-6.45(m,3H),5.82-5.80(m,1H),5.65(s,2H),5.10-5.08(m,1H),4.00-3.97(m,4H),3.53-3.49(m,4H),3.22-3.18(m,4H),3.00-2.96(m,1H),2.64-2.61(m,1H),1.93-1.90(m,3H),1.69-1.61(m,5H),1.28-1.26(m,6H)。
化合物DSC5605:氮气保护下向DSC5606(0.70g/1.0mmol)的30mL干燥的二氯甲烷溶液中缓慢加入三乙胺(0.20g/2.0mmol),缓慢加入乙酰氯(0.08g/1.0mmol),室温反应2小时后加入10mL水洗,饱和食盐水洗,浓缩,柱层析分离得0.44g目标化合物DSC5605(60%的收率)。MS:743.3[M+1]。1HNMR(CDCl3)δ8.40(d,J=6.3Hz,1H),7.97(d,J=6.5Hz,1H),7.63(d,J=6.5Hz,1H),7.16-7.14(m,1H),7.04-7.02(m,3H),6.72-6.70(m,1H),6.46-6.44(m,3H),5.82-5.79(m,1H),5.63(s,2H),5.10-5.07(m,1H),4.02-3.98(m,4H),3.51-3.47(m,4H),3.21-3.18(m,4H),3.01-2.96(m,1H),2.62-2.58(m,1H),1.92-1.89(m,3H),1.87(s,3H),1.67-1.60(m,5H),1.27-1.24(m,6H)。
实施例4:化合物DSC5606的制备及特征
化合物16:氮气保护下向4-溴哌啶-1-甲酸苄酯(2.98g/10.0mmol)的100mL二氯甲烷溶液中加入2-氧代-1,2-二氢-3H-咪唑并[4,5-b]吡啶-3-羧酸叔丁酯(2.35g/10.0mmol)与三乙胺(1.52g/15.0mmol),所得混合物在室温下反应3小时,过滤,水洗与饱和食盐水洗,减压浓缩,乙腈/水重结晶后干燥得4.1g粗品,加入100mL甲醇中,加入0.4g钯碳(10%),氢气氛围下室温反应12小时,过滤,浓缩,柱层析分离得3.1g目标化合物13(65%的收率)。MS:242.1[M+1]。直接用于下一步。加入乙腈/水重结晶得2.3g目标化合物16(72%的收率)。MS:319.4[M+1]。直接用于下一步。
化合物17:氮气保护下向中间体18(1.59g/5.0mmol)的50mL干燥二氯甲烷溶液中加入N,N'-羰基二咪唑(0.81g/5.0mmol),所得混合物在回流状态下反应3小时,过滤,水洗,浓缩,柱层析分离得1.5g目标化合物17(75%的收率)。MS:413.3[M+1]。直接用于下一步。
化合物18:氮气保护下向中间体10(1.88g/5.0mmol)的100mL干燥四氢呋喃溶液中加入中间体17(2.06g/5.0mmol),所得混合物在60℃下反应3小时,过滤,浓缩所得固体溶解于0.01M的甲醇/盐酸(1:1)溶液中,所得混合物在室温下反应2小时,浓缩,加入乙酸乙酯,0.01M的碳酸氢溶液洗,饱和食盐水洗,浓缩,乙腈/水重结晶得1.47g目标化合物18(55%的收率)。MS:535.2[M+1]。直接用于下一步。
化合物19:氮气保护下向中间体18(1.06g/2.0mmol)的30mL干燥四氢呋喃溶液中加入NaH(0.12g/3.0mmol),所得混合物在室温下反应1小时,加入(二乙基)(氯甲基)磷酸酯(0.61g/3.0mmol),所得混合物在室温下反应3小时,过滤,加入0.5mL甲醇,浓缩所得固体加入二氯甲烷,水洗,饱和食盐水洗,浓缩,柱层析分离得0.49g目标化合物19(35%的收率)。MS:701.3[M+1]。直接用于下一步。
化合物20:氮气保护下向N-氯代丁二酰亚胺(1.34g/10.0mmol)100mL干燥四氢呋喃溶液中缓慢加入三苯基膦(2.62g/10.0mmol),搅拌10分钟后缓慢滴加19(7.00g/10.0mmol)的四氢呋喃溶液,室温反应6小时后过滤,浓缩,柱层析分离得0.58g目标化合物20(81%的收率)。MS:719.4[M+1]。直接用于下一步。
化合物21:氮气保护下向20(3.59g/5.0mmol)的干燥60mL DMF溶液中缓慢加入叠氮化钠(1.62g/25.0mmol),50℃下搅拌反应18小时,降温,过滤,加入200mL水,乙酸乙酯萃取,浓缩,柱层析分离得2.03g目标化合物21(56%的收率)。直接用于下一步。
化合物DSC5606:氮气保护下向21(1.45g/2.0mmol)的30mL四氢呋喃溶液中缓慢加入三甲基膦(0.49g/6.0mmol)的甲苯溶液6mL(1.0M),室温反应2小时后加入0.1mL水,继续反应3小时,反应结束后过滤,浓缩,加入水,乙酸乙酯萃取,浓缩,柱层析分离得0.73g目标化合物DSC5606(52%的收率)。MS:700.3[M+1]。1H NMR(CDCl3)δ8.46(d,J=6.3Hz,1H),8.11(d,J=6.3Hz,1H),8.05(d,J=6.5Hz,1H),7.97(d,J=6.4Hz,1H),7.21-7.18(m,2H),7.10-7.08(m,3H),5.88(s,2H),5.84-5.82(m,1H),4.17-4.15(m,1H),4.01-3.98(m,4H),3.64-3.59(m,3H),3.48-3.45(m,2H),3.02-2.99(m,1H),2.00-1.96(m,2H),1.74-1.68(m,4H),1.25-1.23(m,6H)。
实施例5:化合物DSC5610的制备及特征
化合物DSC5612:氮气保护下向DSC5606(1.40g/2.0mmol)的50mL二氯甲烷溶液中缓慢加入TMSCN(1.20g/12.0mmol),室温反应12小时后加入三乙胺(1.52g/15.0mmol)与水,继续反应1小时,反应结束后过滤,浓缩,水/异丙醇重结晶得0.32g目标化合物DSC5610(25%的收率)。MS:645.2[M+1]。1HNMR(CDCl3)δ8.42(d,J=6.5Hz,1H),8.10(d,J=6.4Hz,1H),8.02(d,J=6.5Hz,1H),7.94(d,J=6.3Hz,1H),7.20-7.18(m,2H),7.08-7.06(m,3H),5.84(s,2H),5.80-5.77(m,1H),4.15-4.12(m,1H),3.63-3.59(m,3H),3.46-3.42(m,2H),3.00-2.97(m,1H),2.00-1.94(m,2H),1.71-1.67(m,4H)。
实施例6:化合物DSC5614的制备及特征
化合物22:氮气保护下向中间体18(1.06g/2.0mmol)的30mL干燥四氢呋喃溶液中加入NaH(0.12g/3.0mmol),所得混合物在室温下反应1小时,加入氯甲基甲基碳酸酯(0.37g/3.0mmol),所得混合物在室温下反应3小时,过滤,加入0.5mL甲醇,浓缩所得固体加入二氯甲烷,水洗,饱和食盐水洗,浓缩,柱层析分离得0.46g目标化合物22(37%的收率)。MS:624.1[M+1]。直接用于下一步。
化合物23:氮气保护下向N-氯代丁二酰亚胺(1.34g/10.0mmol)100mL干燥四氢呋喃溶液中缓慢加入三苯基膦(2.62g/10.0mmol),搅拌10分钟后缓慢滴加22(6.24g/10.0mmol)的四氢呋喃溶液,室温反应6小时后过滤,浓缩,柱层析分离得4.8g目标化合物23(74%的收率)。MS:642.2[M+1]。直接用于下一步。
化合物24:氮气保护下向23(3.21g/5.0mmol)的干燥60mL DMF溶液中缓慢加入叠氮化钠(1.62g/25.0mmol),50℃下搅拌反应18小时,降温,过滤,加入200mL水,乙酸乙酯萃取,浓缩,柱层析分离得1.78g目标化合物24(55%的收率)。直接用于下一步。
化合物DSC5614:氮气保护下向24(1.30g/2.0mmol)的30mL四氢呋喃溶液中缓慢加入三甲基膦(0.49g/6.0mmol)的甲苯溶液6mL(1.0M),室温反应2小时后加入0.5mL水,继续反应3小时,反应结束后过滤,浓缩,加入水,乙酸乙酯萃取,浓缩,柱层析分离得0.62g目标化合物DSC5614(50%的收率)。MS:623.2[M+1]。1H NMR(CDCl3)δ8.45(d,J=6.3Hz,1H),8.11(d,J=6.3Hz,1H),8.04(d,J=6.2Hz,1H),7.97(d,J=6.4Hz,1H),7.23-7.21(m,2H),7.10-7.07(m,3H),6.01(s,2H),5.82-5.79(m,1H),4.17-4.14(m,1H),3.81(s,3H),3.66-3.62(m,3H),3.49-3.45(m,2H),3.01-2.97(m,1H),2.02-1.97(m,2H),1.73-1.69(m,4H)。
实施例7:化合物PYCD-01的制备及特征
步骤1:化合物1-氯乙基碳酸甲酯的制备
将1-氯乙基氯甲酸酯(14.3g,0.1mol)加入到无水二氯甲烷(300mL)中,加入甲醇(6.4g,0.2mol),并在冷水冷却下逐滴添加吡啶(15.8g,0.2mol),然后搅拌2小时。体系补入二氯甲烷(200mL),并用2N盐酸洗涤有机层两次,水洗涤有机层一次,分离有机层,无水硫酸钠,干燥,过滤,减压浓缩至干,得化合物1-氯乙基碳酸甲酯(9.5g),收率68.5%。MS:139.01[M+1]。
步骤2:化合物PYCD-0104的制备
氮气保护下,将化合物18(2.7g,5.0mmol)溶于四氢呋喃(50mL)中,加入碳酸钾(3.5g,25mmol),然后缓慢加入甲醛水溶液(35~40%,2.5g),升温至55℃反应8h,TLC检测反应完全,体系浓缩,加入水和二氯甲烷,振摇,分液,水相再次二氯甲烷萃取,合并二氯甲烷相,无水硫酸钠干燥,过滤,剩余物过柱纯化分离,得化合物PYCD-0104(1.15g),收率40.6%。ESI-MS(+):m/z=566.21。
步骤3:化合物PYCD-0103的制备
氮气保护下,将化合物PYCD-0104(1.14g,2.0mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入钠氢(0.16g,4.0mmol),室温搅拌1小时,氮气氛围下缓慢加入1-氯乙基碳酸甲酯(0.56g,4.0mmol),室温反应6小时,体系加入水,二氯甲烷萃取3次,合并有机相,无水硫酸钠干燥,浓缩,剩余物柱层析分离得化合物PYCD-0103(0.48g),收率36.4%。ESI-MS(+):m/z=668.25。
步骤4:化合物PYCD-0102的制备
氮气保护下,将N-氯代丁二酰亚胺(0.67g,5.0mmol)加入到干燥四氢呋喃(100mL)中,然后缓慢加入三苯基膦(1.31g,5.0mmol),搅拌10分钟后缓慢滴加化合物PYCD-0103(3.33g,5.0mmol)的四氢呋喃溶液,室温反应6小时后过滤,浓缩,剩余物柱层析分离得化合物PYCD-0102(1.53g),收率44.6%。MS:686.21[M+1]。
步骤5:化合物PYCD-0101的制备
氮气保护下,将PYCD-0102(3.43g,5.0mmol)加入到干燥N,N-二甲基甲酰胺(60mL),然后缓慢加入叠氮化钠(1.62g/25.0mmol),50℃下搅拌反应18小时,降温,过滤,体系加水淬灭,乙酸乙酯萃取,浓缩,柱层析分离得化合物PYCD-0101(1.50g),收率43.4%。MS:693.23[M+1]。
步骤6:化合物PYCD-01的制备
氮气保护下,将化合物PYCD-0101(1.30g,2.0mmol)加入到四氢呋喃(30mL)中,然后缓慢加入三甲基膦(0.49g,6.0mmol)的甲苯溶液(6mL),室温反应2小时后加入少量水,继续反应3小时,反应结束后过滤,浓缩,剩余物加入水,乙酸乙酯萃取,浓缩,柱层析分离得化合物PYCD-01(0.53g),收率39.7%。MS:667.52[M+1]。1H NMR(CDCl3)δ8.48(d,J=6.2Hz,1H),8.13(d,J=6.4Hz,1H),8.06(d,J=6.5Hz,1H),7.93(d,J=6.0Hz,1H),7.27-7.26(m,2H),7.14-7.12(m,3H),6.22-6.18(m,3H),5.85-5.83(m,1H),4.21-4.18(m,1H),3.84(s,3H),3.69-3.65(m,3H),3.53-3.47(m,2H),3.04-3.00(m,1H),2.04-1.99(m,2H),1.76-1.72(m,4H),1.60(d,J=11.7Hz,3H)。
实施例8:化合物PYCD-05的制备及特征
参考实施例7中步骤3-步骤6的操作工序,用特戊酸氯甲酯替换1-氯乙基碳酸甲酯,最终制备得化合物PYCD-05(0.54g),总收率3.1%。MS:649.29[M+1]。1H NMR(CDCl3)δ8.46(d,J=6.4Hz,1H),8.15(d,J=6.0Hz,1H),8.07(d,J=6.3Hz,1H),7.90(d,J=6.1Hz,1H),7.26-7.24(m,2H),7.15-7.13(m,3H),5.99-5.97(m,2H),4.26-4.23(m,1H),3.71-3.68(m,3H),3.54-3.49(m,2H),3.05-3.02(m,1H),2.02-1.99(m,2H),1.74-1.71(m,4H),1.31(s,9H)。
实施例9:化合物PYCD-06的制备
参考实施例7中步骤3-步骤6的操作工序,用异丁酸氯甲酯替换1-氯乙基碳酸甲酯,最终制备得化合物PYCD-06(0.47g),总收率2.8%。MS:635.26[M+1]。1H NMR(CDCl3)δ8.41(d,J=6.3Hz,1H),8.17(d,J=6.2Hz,1H),8.06(d,J=6.0Hz,1H),7.89(d,J=6.4Hz,1H),7.27-7.25(m,2H),7.14-7.11(m,3H),6.01-6.00(m,2H),4.28-4.26(m,1H),3.52-3.49(m,2H),3.06-3.03(m,1H),2.11-1.99(m,3H),1.77-1.74(m,4H),1.20-1.18(m,6H)。
实施例10:化合物PYCD-07的制备
步骤1:化合物PYCD-0701的制备
将Boc-甘氨酸(0.23g,1.3mmol)加入到四氢呋喃(30mL)中,室温下加入三乙胺(0.20g,2.0mmol),搅拌半小时后加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU,0.42g,1.1mmol),溶液变为白色浑浊,随后将SM4(0.53g,1.0mmol)加入到上述悬浮液中,反应室温下搅拌72小时,体系逐渐澄清,TLC检测,反应完毕。体系减压浓缩,剩余物过柱纯化得化合物PYCD-0701(0.50g),收率72.4%。MS:691.30[M+1]。
步骤2:化合物PYCD-07的制备
将化合物PYCD-0701(0.50g,0.72mmol)加入到三氟乙酸(8mL)中,室温反应半小时,TLC检测反应完毕。体系加入到2M氢氧化钠水溶液中,调pH~7,有白色固体析出,乙酸乙酯萃取,分液,有机相干燥,过滤,滤液浓缩,剩余物柱层析得到白色固体为目标物化合物PYCD-07(0.15g),收率35.8%。MS:592.25[M+1]。1H NMR(CDCl3)δ8.89-8.87(m,1H),8.44(d,J=6.0Hz,1H),8.14-8.12(m,2H),8.07(d,J=6.4Hz,1H),7.98(d,J=6.0Hz,1H),7.26-7.24(m,2H),7.13-7.11(m,3H),5.84-5.82(m,1H),4.18-4.15(m,1H),3.67-3.60(m,5H),3.50-3.46(m,2H),3.01-2.98(m,1H),2.06-2.01(m,2H),1.77-1.73(m,4H)。
采用类似的合成方法,制备了下列实施例化合物:
实施例11:化合物细胞毒性测试
将MDCK(Madin-Daby Canine Kidney Cells)细胞悬浮液接种至96孔板中,细胞密度在1×105个/mL左右,置于37℃培养箱中孵育24h,弃除原DMEM培养液,更换为新鲜DMEM培养液,加入相应化合物的药液(0.1M母液,含0.1%的DMSO助溶),控制最终每孔的药液浓度为20.0μM,每个给药孔设置三个复孔,空白组不加入药液,仅加入相应体积的DMEM培养液,继续孵育60h。完毕后于避光条件下每孔加入MTT溶液20.0μL,继续孵育3.0h后每孔加入200μL的DMSO,混匀后测定每个孔在490nm波长下吸光度值(Optical Density,OD),计算细胞存活率(%)=(给药组OD/正常组OD)×100%。计算最终结果如表1:
表1:化合物对细胞毒性测定
表1数据表明本发明提供的化合物在20.0μM浓度下对MDCK细胞无明显毒性,细胞存活率均在60%以上,尤其是化合物DSC5601、DSC5614、PYCD-06在MDEM培养液给药后MDCK细胞的存活率在80%以上,而瑞美吉泮硫酸盐处理的孔板中细胞存活率只有51.2%,说明本发明的化合物作为药物的预期安全性更高。
实施例12:化合物对大鼠血管舒张作用
取体重180±20gSD大鼠,腹腔注射5.0%水合氯乙醛溶液,待大鼠麻醉后解剖取出主动脉血管,置于Krebs液中,于温度为0~4℃下保存,去除血液后截取4.0cm长的血管环,一端固定后浸入37.0℃恒温Krebs溶液中,并持续通入95%O2和5%CO2的混合气体,使pH保持7.4。另一端与计算机的张力换能器连接,调节血管环的静息张力至2.0g,平衡后加入50mM KC1溶液预收缩血管环,重新平衡20分钟后加入2.5μM苯肾上腺素收缩血管环,收缩稳定后,加入选择性的竞争性辣椒素受体拮抗剂10.0μM的Capsazepine,继续孵育15分钟,加入10.0μM的CGRP耗竭剂Capsaicin,继续孵育15分钟后分别加入10.0μM的瑞美吉泮硫酸盐(阳性对照化合物)、DSC5601、DSC5614、PYCD-06溶液,继续孵育15分钟,期间连续记录血管环张力的变化,记录数据如表2。
表2:化合物的舒血管作用能力
化合物 | 浓度 | 血管舒张力百分比 | 化合物 | 浓度 | 血管舒张力百分比 |
瑞美吉泮硫酸盐 | 10.0μM | 39% | DSC5614 | 10.0μM | 56% |
DSC5601 | 10.0μM | 53% | PYCD-06 | 10.0μM | 62% |
数据表明,辣椒素Capsaicin将CGRP完全消耗后,与阳性对照药瑞美吉泮硫酸盐相比,化合物DSC5601、DSC5614、PYCD-06的血管舒张力百分比明显增加,说明本发明的上述化合物通过促进CGRP的释放而发挥舒张血管的作用,且效果明显优于瑞美吉泮硫酸盐。
实施例13:化合物治疗大鼠哮喘活性实验
取SD大鼠60只,雌雄各半,体重200±20g,适应性饲养一周后,随机分为6组,每组10只,雌雄各半,分别为:正常对照组、哮喘模型对照组、瑞美吉泮硫酸盐组(阳性对照化合物)、DSC5601组、DSC5614组、PYCD-06组。实验开始的第1天和第8天正常对照组除外的每组大鼠分别腹腔注射100mg卵清白蛋白(OVA)与100mg氢氧化铝(0.2%生理盐水稀释),从实验开始的第15天起正常对照组除外的每组大鼠分别灌胃给予对应剂量的化合物,给予化合物的剂量均为30mg/kg/天,连续给予20天,哮喘模型对照组给予相应体积的生理盐水。给予化合物后每隔一日于给药30分钟后分别将大鼠置于雾化室,雾化吸入3%OVA(5.0mL)1.0小时,连续雾化吸入10次。每次雾化吸入后观察并记录动物的一般情况,并按照表3标准评分:
表3:动物一般情况评分标准
按照每组的加权平均分值作为最终评价得分,结果如下表4:
表4:大鼠一般生理情况评分结果
数据表明,与正常对照组相比,哮喘模型组生理情况评分明显增高,实验期间实验动物出现精神萎靡、反应迟钝、呼吸急促、口唇紫绀等生理状况;与模型对照组相比,化合物DSC5601、DSC5614、PYCD-06组生理情况评分明显降低,说明上述化合物对哮喘大鼠的一般情况具有明显的改善作用。与阳性对照组瑞美吉泮硫酸盐组相比,化合物DSC5601、DSC5614、PYCD-06组生理情况评分明显降低,说明上述化合物对哮喘大鼠的一般情况改善明显优于瑞美吉泮硫酸盐组。结果表明本发明的化合物DSC5601、DSC5614、PYCD-06对哮喘大鼠的一般情况表现出了明显的改善作用,且优于瑞美吉泮硫酸盐。
上述各组大鼠于末次给药后24小时用戊巴比妥钠溶液(0.3%)将麻醉,前颈部皮肤切口,使呼吸气道暴露,切口成“V”形,将软气管插入大鼠呼吸气道,使用动物肺功能仪记录大鼠的气道阻力(AP),统计结果采用加权平均值表示,并采用最终数据的百分值表示,如图1所示。
图1数据表明,与正常组相比,哮喘模型组大鼠的气道阻力明显升高,说明造模成功;与哮喘模型组相比,给药组大鼠的气道阻力明显降低,说明化合物DSC5601、DSC5614、PYCD-06组及瑞美吉泮硫酸盐组对大鼠哮喘病均具有明显的治疗作用;与瑞美吉泮硫酸盐相比,化合物DSC5601、DSC5614、PYCD-06的治疗作用更为显著。
上述实验完毕后,立即取大鼠颈动脉血1.0mL,于37±1℃下静置1小时,取血清0.2mL,严格按照说明书采用酶联免疫法测定(Enzyme Linked Immunosorbent Assay,ELISA)大鼠血清中的CGRP含量,数据结果如下表5:
表5:大鼠血清中CGRP水平
表5数据表明,与正常对照组相比,模型对照组大鼠血清中的CGRP水平明显升高;与模型对照组相比,化合物DSC5601、DSC5614、PYCD-06组及瑞美吉泮硫酸盐组大鼠血清中的CGRP水平明显降低;与瑞美吉泮硫酸盐组相比,化合物DSC5601、DSC5614、PYCD-06组大鼠血清中CGRP水平明显降低。结果表明本发明的化合物DSC5601、DSC5614、PYCD-06在体内对CGRP的具有明显的拮抗作用,并且强于瑞美吉泮硫酸盐。
实施例14:化合物DSC5614在大鼠体内药动学研究:
(1)实验方法:取雄性SD大鼠适量,适应性饲养三天后取体重200±20g大鼠12只,随机分为4组:第一组(编号:1~3)、第二组(编号:4~6)、第三组(编号:7~9)、第四组(编号:10~12),每组3只,2个供试品瑞美吉泮硫酸盐与DSC5614分别口服灌胃/静脉注射给药,单次给药。给药前禁食12小时以上,给药后禁食4小时,全程不禁水。给药的方式和剂量如表6:
表6:化合物给药方式与给药剂量
(2)实验方法:药物配制
口服灌胃给药样品配制:分别称取供试品适量,分别置于试剂瓶中,分别置于试剂瓶中,加入适量1%甲基纤维素溶液,配制给药溶液。现配现用。
静脉注射给药样品配制:分别称取供试品适量,分别置于试剂瓶中,分别置于试剂瓶中,加入适量混合溶剂(10% DMSO:30% PEG400:60%注射用生理盐水)。配制相应浓度的给药溶液,使用前在无菌台用微孔滤膜过滤,置于无菌中转瓶中。现配现用。
(3)采血
单次口服灌胃给药前(0h),给药后0.25h、1h、1.5h、2h、2.5h、3h、5h、10h、24h取血。
单次静脉注射给药前(0h),给药后0.083h、0.25h、0.5h、1h、2h、4h、8h、24h取血。
(4)血样采集处理:每个采血时间点,经大鼠眼球取静脉血约300μL,置于冰浴上的肝素化的离心管中,静置15分钟后,于4℃、4000rpm、离心10min,取50μL血浆,测定血浆中瑞美吉泮的浓度,并计算主要药动学参数。计算结果如表7和表8:
表7:化合物灌胃给药代谢研究
表8:化合物静脉注射给药代谢研究
计算数据表明,DSC5614口服给药后在体内可完全代谢为活性成分瑞美吉泮,并且可以快速的被吸收,达峰时间明显快于瑞美吉泮硫酸盐,提示本发明的化合物DSC5614可以在体内快速起效。并且DSC5614口服给药组的Cmax明显高于瑞美吉泮硫酸盐组的口服给药Cmax,约提高28%,预示本发明的化合物可以以较低的剂量达到预期的效果。
通过以上具体对本专利的具体说明,本领域技术人员可以透彻地理解本本发明的特征,同时,对本发明的改良性结果也落在本申请所附权利要求范围内。
Claims (4)
1.一种化合物,其选自:
2.权利要求1中所述的化合物在制备作为降钙素基因相关肽受体拮抗剂药物中应用。
3.一种药物组合物,包含权利要求1中所述的化合物及其盐与药学上可接受的添加剂。
4.权利要求1所述化合物或权利要求3所述组合物,在制备缓解和/或治疗哮喘病、慢性阻塞性肺疾病、肺心病、器官疼痛相关疾病的药物中的应用。
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WO2012050764A1 (en) * | 2010-10-12 | 2012-04-19 | Bristol-Myers Squibb Company | Process for the preparation of cycloheptapyridine cgrp receptor antagonists |
CN102656159A (zh) * | 2009-10-14 | 2012-09-05 | 百时美施贵宝公司 | Cgrp受体拮抗剂 |
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CN102656159A (zh) * | 2009-10-14 | 2012-09-05 | 百时美施贵宝公司 | Cgrp受体拮抗剂 |
WO2012050764A1 (en) * | 2010-10-12 | 2012-04-19 | Bristol-Myers Squibb Company | Process for the preparation of cycloheptapyridine cgrp receptor antagonists |
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