CN114105902B - 噻唑苯甲酰胺衍生物及其在制备抗骨质疏松药物中的应用 - Google Patents
噻唑苯甲酰胺衍生物及其在制备抗骨质疏松药物中的应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Engineering & Computer Science (AREA)
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Abstract
本申请是申请号为201811623081.5、申请日为2018年12月28日、发明名称为“噻唑苯甲酰胺衍生在制备抗骨质疏松、抗骨关节炎药物中的应用”的分案申请。本发明公开了噻唑苯甲酰胺衍生物及其在制备抗骨质疏松药物中的应用。本发明提供的噻唑酰胺衍生物与当前临床上使用磷酸盐类、***类药物、以及甲状旁腺激素抑制剂等骨质疏松防治药物的分子骨架不同,且其破骨细胞分化抑制活性高、毒性小。因此,此类化合物可作为一种新化合物类型,用于防治由破骨细胞分化异常引起的相关疾病,尤其是骨质疏松或骨量减少症。
Description
本申请是申请号为201811623081.5、申请日为2018年12月28日、发明名称为“噻唑苯甲酰胺衍生在制备抗骨质疏松、抗骨关节炎药物中的应用”的分案申请。
技术领域
本发明涉及药物用途技术领域,更具体地,涉及噻唑苯甲酰胺衍生物及其在制备抗骨质疏松药物中的应用。
背景技术
骨质疏松和骨关节炎是骨科常见疾病。骨质疏松是指由于骨量减少、骨组织微结构退化导致骨脆性增加、骨折风险增加的骨骼疾病。随着我国社会老龄化加剧,本病发病率呈逐年上升趋势。流行病学调研显示,50岁以上的人群中,约有50%的女性和20%的男性有骨折的风险(Rachner,Khosla et al.2011)。国家***数据显示:到2050年,我国50岁以上的人口将近全国人口的一半(49%),约6.36亿,预计到2050年我国骨质疏松患者数目约为3亿人。可见,骨质疏松对我国国民健康危害极大。然而,骨质疏松问题尚未得到解决,临床上仍缺乏能有效治愈骨质疏松的药物。
当前临床上防治骨质疏松的药物主要有两种,一种是包括***受体调控剂、双磷酸盐类的骨吸收抑制剂,另一种是具有骨吸收抑制和骨形成促进双重作用的制剂如阿法骨化醇、骨化三醇等。然而,上述药物虽然能在一定程度上阻止骨密度下降,但不能显著降低非典型性骨折的风险,而且存在着不同程度的副作用,尚未能满足抗骨质疏松治疗的要求(Siris,Selby et al.2009)。因此,目前迫切需要开发一种新的抗骨质疏松的特效药,以解决当前临床用药无法满足治疗需求的问题。
破骨细胞(Osteoclast)和成骨细胞(Osteoblast)之间的比例失衡是骨质疏松产生的病理基础(Rachner,Khosla et al.2011)。破骨细胞分化相对增多或成骨细胞分化相对减少,都会造成骨量流失,引起骨质疏松。降低骨吸收、促进骨合成是当前临床上治疗骨质疏松的主要治疗手段。
核转录因子κB(nuclear factor-kappa B,NF-κB)是机体中极为重要的转录因子,参与机体的炎症与免疫反应、凋亡与抗凋亡以及细胞的周期调控与发育等诸多功能的调节。非经典NF-κB信号通路,即RANKL-NF-κB信号通路介导单核巨噬细胞向多核破骨细胞分化,是抗骨质疏松药物的重要靶标(Boyle,Simonet et al.2003,Kim and Kim 2016)。
发明内容
本发明针对于现有技术的不足,提供一种噻唑苯甲酰胺衍生物及其在制备抗骨质疏松药物中的应用。
本发明的目的是提供一种噻唑苯甲酰胺衍生物。
本发明另一目的是提供所述噻唑苯甲酰胺衍生物在制备抗骨质疏松药物中的应用。
本发明采用以下技术方案实现上述技术目的:
噻唑苯甲酰胺衍生物在制备抗骨质疏松、抗骨关节炎药物中的应用,所述噻唑苯甲酰胺衍生物的结构式如式(I)所示:
其中,R1为氢、烷基、羟基、苯基或取代苯基、五元或六元芳杂环、取代的五元或六元芳杂环;R2为氢、烷基、烷基取代的羰基或酯、苯基或取代苯基、五元或六元芳杂环、取代的五元或六元芳杂环、脂肪环、杂环、取代的苯胺或苯酚;R1、R2可成环,R3为氢、卤素原子、烷氧基、烷胺基、羟基、氨基、氰基、硝基、羧酸、烷基取代的羧基、酰胺或酯;R4为氢、卤素原子、烷氧基、烷胺基、羟基、氨基、氰基、硝基、羧酸、烷基取代的羧基、酰胺或酯;R5为氢、卤素原子、烷氧基、烷胺基、羟基、氨基、氰基、硝基、羧酸、烷基取代的羧基、酰胺或酯;R4、R5可成环;R6为氢、烷基、卤素原子、烷氧基、羧酸、烷基取代的羧基、酰胺或酯,R5、R6可成环,R7为氢、卤素原子、烷氧基、烷胺基、羟基、氨基、氰基、硝基、羧酸、烷基取代的羧基、酰胺或酯。
作为一种优选方案,R1为氢、C1~C6的烷基;R2为氢、C1~C6烷基、C1~C6不饱和烷基、苯基或取代苯基、羧酸及烷基取代的酯、烷基取代的醛、烷基取代的醚。
作为一种优选方案,R3为氢、C1~C6烷基、C1~C6烷氧基、卤素原子、羟基、氰基、羧酸及烷基取代的酯、烷基取代的醛、烷基取代的醚。
作为一种优选方案,R4为氢、C1~C6烷基、C1~C6烷氧基、羟基、氰基、卤素原子、羧酸及烷基取代的酯、烷基取代的醛、烷基取代的醚。
作为一种优选方案,R5为氢、C1~C6烷基、C1~C6烷氧基。
作为一种优选方案,R6为氢或甲基。
作为一种优选方案,R1、R2成环,R3、R4成环,R4、R5成环,成环为五元或六元芳环或非芳环。
作为一种优选方案,酯、醛和醚中的碳原子数为1~6。
作为一种优选方案,所述噻唑苯甲酰胺衍生物的结构式为如下结构式中的一种:
作为一种优选方案,所述药物包括药学上可接受的盐、载体和/或赋形剂。
本发明所述噻唑苯甲酰胺类衍生物是作为破骨细胞分化抑制剂在制备抗骨质疏松药物中的应用。
相对于现有技术,本发明具有如下的优点及效果:
本发明提供的噻唑苯甲酰胺衍生物结构新颖,活性测试结果显示此类化合物均能显著抑制破骨细胞分化;本发明提供的噻唑酰胺衍生物结构简单、易合成,而且此类化合物毒性小,可安全用于制备治疗和/或预防骨质疏松或骨量减少的药物。
附图说明
图1为1a细胞毒性和破骨细胞分化抑制曲线图。
图2为1b细胞毒性和破骨细胞分化抑制曲线图。
图3为1c细胞毒性和破骨细胞分化抑制曲线图。
图4为1d细胞毒性和破骨细胞分化抑制曲线图。
图5为1e细胞毒性和破骨细胞分化抑制曲线图。
图6为1f细胞毒性和破骨细胞分化抑制曲线图。
图7为1g细胞毒性和破骨细胞分化抑制曲线图。
图8为1h细胞毒性和破骨细胞分化抑制曲线图。
图9为1i细胞毒性和破骨细胞分化抑制曲线图。
图10为1j细胞毒性和破骨细胞分化抑制曲线图。
图11为1k细胞毒性和破骨细胞分化抑制曲线图。
图12为1l细胞毒性和破骨细胞分化抑制曲线图。
图13为1m细胞毒性和破骨细胞分化抑制曲线图。
图14为1n细胞毒性和破骨细胞分化抑制曲线图。
图15为1o细胞毒性和破骨细胞分化抑制曲线图。
图16为1p细胞毒性和破骨细胞分化抑制曲线图。
图17为1q细胞毒性和破骨细胞分化抑制曲线图。
图18为1r细胞毒性和破骨细胞分化抑制曲线图。
图19为1o在不同浓度下对破骨细胞的抑制图。
具体实施方式
以下结合具体实施例和附图来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,本发明所用试剂和材料均为市购。
实施例1:噻唑苯甲酰胺衍生物合成
实施例2:NF-κB信号通路抑制实验
S1.细胞培养。
体外培养稳定转染高表达NF-κB的RAW264.7细胞。使用含有10%胎牛血清,DMEM高糖培养基,在37℃,5%二氧化碳浓度条件下进行常规维持培养和传代。
S2.化合物干预。
收集对数期细胞,将细胞悬液浓度配成5×105个/ml,加入96孔细胞培养板中。于二氧化碳培养箱中培养24h后,将培养液换成含有不同化合物浓度的培养基,共同培养6h。使用DMSO将待测化合物配置为不同浓度的溶液。每个浓度设3个平行复孔,并设不经化合物处理的对照组进行比较。
S3.测试方法。
实验结束后,采用细胞裂解液裂解细胞,根据荧光检测试剂盒说明书对细胞裂解液的荧光进行检测,所得化学发光值反映NF-κB信号通路抑制活性情况。
S4.结果处理。
按下面的公式计算各个药物对NF-κB信号通路的抑制作用:
以抑制率为纵坐标,化合物浓度的log值为横坐标绘制各化合物对NF-κB信号通路抑制作用曲线图,根据各化合物对通路的抑制率,求出半数有效率IC50,即抑制信号通路达50%时药物浓度。
实施例3:化合物细胞的毒性测定
S1.细胞培养。
体外培养RAW264.7细胞。使用含有10%胎牛血清,DMEM高糖培养基,在37℃,5%二氧化碳浓度条件下进行常规维持培养和传代。
S2.化合物干预。
收集对数期细胞,将细胞悬液浓度配成1×105个/ml,加入96孔细胞培养板中。于二氧化碳培养箱中培养24h后,将培养液换成含有不同化合物浓度的培养基,连续培养2天,于第3天检测细胞毒性。使用DMSO将待测化合物配置为不同浓度的溶液。每个浓度设3个平行复孔,并设不经化合物处理的对照组进行比较。
S3.测试方法。
采用MTT[3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐]法测定经化合物处理6天之后的细胞。应用酶标仪(检测波长570nm,参考波长630nm)测定个孔吸光值(OD值)。
S4.结果处理。
按下面的公式计算各个药物对RAW264.7细胞的生长抑制率:
以RAW264.7细胞生长抑制率为纵坐标,化合物浓度得log值为横坐标绘制各化合物对细胞生长的抑制曲线图,根据各化合物对细胞抑制率,求出半数毒性浓度CC50,即抑制细胞生长达50%时药物浓度。
另按照公式:选择抑制常数(SI)=CC50/IC50计算各化合物的选择抑制常数,以评价各化合物的用药安全性。1a、1b、1c和1d四个化合物的选择抑制常数结果见表1。1a、1b、1c和1d四个化合物对RAW264.7细胞的毒性测定结果分别见图1~图4。
实施例4:破骨细胞分化抑制实验
S1.细胞培养。
体外培养RAW264.7细胞。使用含有10%胎牛血清,DMEM高糖培养基,在37℃,5%二氧化碳浓度条件下进行常规维持培养和传代。
S2.化合物干预。
收集对数期细胞,将细胞悬液浓度配成2×104个/mL,加入96孔细胞培养板中。于二氧化碳培养箱中培养24h后,将培养液换成含有100ng/ml RANKL及不同化合物浓度的培养基,连续培养5天,每2天换上相同RANKL浓度和化合物浓度的培养基,于第5天检测采用TRAP染色法对破骨细胞进行染色。每个浓度设3个平行复孔,并设不经化合物处理的对照组进行比较。
S3.测试方法。
采用TRAP试剂盒对分化形成的破骨细胞进行染色,计数≧3个细胞核融合的破骨细胞数目。
S4.结果处理。
按下面的公式计算各药物对RANKL诱导的破骨细胞分化抑制率:
以破骨细胞分化抑制率为纵坐标,化合物浓度的log值为横坐标绘制各化合物对破骨细胞分化抑制曲线图,根据各化合物对破骨细胞分化的抑制率,求出半数有效率IC50,即抑制破骨细胞分化达50%时药物浓度。其中1o的破骨细胞分化图见图19
另按照公式:选择抑制常数(SI)=CC50/IC50计算各化合物的选择抑制常数,以评价各化合物的用药安全性。1a、1b、1c和1d四个化合物的选择抑制常数结果见表1。1a、1b、1c和1d四个化合物对宿主细胞的毒性测定结果分别见图1~图4。
根据选择性指数SI=CC50/IC50值,按以下标准评价化合物的抗骨质疏松分化的效果。SI<1.0表明化合物有毒无效,1.0≤SI≤2.0表明化合物低效有毒即弱阳性,2.0<SI<10.0表明化合物有效低毒即阳性,SI≥10.0表明化合物高效低毒即强阳性。
由表1和图1~4的结果可见,本发明通过破骨细胞分化抑制实验,发现4个化合物对破骨细胞分化均有不同程度的抑制作用,其中1o活性最好,治疗指数最高,IC50为1.16,SI为328.29(见图15、表1);其次为1q,IC50为3.94,SI为6.36(见图17、表1);活性次之的是1p,IC50为3.98,SI为126.97(见图16、表1);化合物1j,IC50为4.00,SI为87.46(见图10,表1);与其它三个化合物相比,1c活性较差,IC50为11.43,SI为18.58(见图3、表1)。
表1药物筛选获得的化合物结构及其对破骨细胞分化的抑制作用
本发明通过计算机辅助药物设计相似度检索的方法发现一类噻唑酰胺衍生物。并通过破骨细胞分化抑制实验和细胞毒性(MTT)实验,发现此类化合物中,1o、1p、1q对破骨细胞分化抑制活性均小于10μM,细胞毒性小,治疗指数高。1o对破骨细胞分化半数抑制剂量(IC50)为1.16μM,细胞半致死剂量(CC50)为379.5μM,选择抑制常数(SI)为328.29(表1,图15);1p对破骨细胞分化半数抑制剂量(IC50)为3.98μM,细胞半致死剂量(CC50)为505.6μM,选择抑制常数(SI)为126.97(表1,图16);1q对破骨细胞分化半数抑制剂量(IC50)为3.98μM,细胞半致死剂量(CC50)为25.07μM,选择抑制常数(SI)为6.36(表1,图17);1c对破骨细胞分化半数抑制剂量(IC50)为11.43μM,选择抑制常数(SI)为18.58(表1,图3)。结果表明,此类化合物对破骨细胞分化的抑制活性高、细胞毒性小,可作为一类破骨细胞抑制剂用于制备骨质疏松或骨质减少防治药物。
Claims (4)
1.一种噻唑苯甲酰胺衍生物,其特征在于,所述噻唑苯甲酰胺衍生物为如下结构式中的一种:
、/>、/>。
2.一种噻唑苯甲酰胺衍生物及其药学上可接受的盐在制备抗骨质疏松药物中的应用,其特征在于,所述噻唑苯甲酰胺衍生物为如下结构式中的一种:
、/>、/>、/>、/>。
3.一种噻唑苯甲酰胺衍生物及其药学上可接受的盐在制备防治骨质减少药物中的应用,其特征在于,所述噻唑苯甲酰胺衍生物为如下结构式中的一种:
、/>、/>、/>、/>。
4.根据权利要求2或3所述的应用,其特征在于,所述药物包括所述噻唑苯甲酰胺衍生物药学上可接受的盐、载体和/或赋形剂。
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