CN110407879A - Txs-wx类化合物的化学组成、制备方法及其在抗肿瘤中的应用 - Google Patents
Txs-wx类化合物的化学组成、制备方法及其在抗肿瘤中的应用 Download PDFInfo
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- CN110407879A CN110407879A CN201810395448.6A CN201810395448A CN110407879A CN 110407879 A CN110407879 A CN 110407879A CN 201810395448 A CN201810395448 A CN 201810395448A CN 110407879 A CN110407879 A CN 110407879A
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- alkyl
- alkynyl
- alkenyl
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Abstract
本发明属于生物医药技术领域,发明了一类新型的天然免疫通路激活剂(TXS-WX),该类激活剂化合物能通过有效激活免疫通路,激活免疫细胞(树突状细胞、CD8T细胞等),能够调节巨噬细胞功能,改变肿瘤微环境,进而达到免疫抗肿瘤的良好药效。该类化合物通过有机化学合成和生物合成相结合的综合方法制备,开辟了一条创新药物合成新思路。因此,这类新型化合物具有高效免疫抗肿瘤等重大疾病应用前景。
Description
技术领域
本发明属于生物医药技术领域 具体涉及一类新型免疫抗肿瘤药物的制备、组成及其在制备抗肿瘤药物中的应用。
背景技术
肿瘤是一类严重危害人类生命健康的重大疾病之一,表现为细胞过度增殖和分化异常。WHO专家预测,2020年全球人口肿瘤发病将达到2000万人,死亡人数将达到1200万人,肿瘤将成为本世纪人类第一杀手,对人类生存构成最严重的威胁。肺癌、结/直肠癌、胃癌、肝癌等的发病率和死亡率均居各类恶性肿瘤的前列。据全国肿瘤登记中心发布的(2012中国肿瘤登记年报》统计,每年新发生肿瘤病例约为312万例,平均每天8550人,全国每分钟有6人被诊断为癌症。从病种来看,肺癌、胃癌、结/直肠癌、肝癌和食管癌,居全国恶性肿瘤发病的前五位。随着恶性肿瘤发病率和死亡率的逐年增加,恶性肿瘤治疗需求越来越大。
天然免疫激活剂作为二级信使分子通过内质网膜上的受体蛋白通路诱导干扰素IFN-β和其他细胞因子的产生,调节下游蛋白质表达,诱导细胞生长停滞和凋亡。天然免疫通路可以调节免疫原性肿瘤的先天免疫识别,促进干扰素的抗肿瘤作用。IFN-γ在体内通过TRAIL(tumor necrosis factor-related apoptosis-inducing ligand)发挥抗肿瘤作用,促进肿瘤细胞凋亡。天然免疫通路的激活和加强能激活免疫细胞(树突状细胞、CD8T细胞等),能够调节巨噬细胞功能,改变肿瘤微环境,进而达到免疫抗肿瘤的良好药效。该类化合物通过有机化学合成和生物合成相结合的综合方法制备,开辟了一条创新药物合成新思路。因此,这类新型化合物具有高效免疫抗肿瘤等重大疾病应用前景。
发明内容
本发明的目的在于提供一类基于天然免疫通路激活的抗肿瘤药物的组成、制备方法及其在抗肿瘤和制备抗肿瘤药物中的应用。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好地阐述本发明,并不是用来限制本发明的范围。
实施例1:TXS-WX类化合物的制备
该类化合物合成所用的原料和试剂均购买于Sigma公司。制备方法和合成路线如下(附图5-9).
(图5)
(1)如图5所示,首先原料4,5,6-三氨基嘧啶和亚硝酸钠反应生成中间体1a(8-氮杂腺嘌呤),之后在酶嗜水气单胞菌的作用下发生糖基化生成中间体1b(8-氮杂腺苷),中间体1b与三氯氧磷发生反应,生成中间体1c(8-氮杂腺苷酸),最后中间体1c在相关酶的催化下与GTP发生环合反应,生成最终产物TXS-WX-1。
(图6)
(2)如图6所示,化合物1a与三氯硫磷发生反应,生成中间体2a(8-氮杂α位硫代的腺苷酸),中间体2a在相关酶的催化下与GTP发生环合反应,生成最终产物TXS-WX-2。
(图7)
(3)如图7所示,原料8-氮杂鸟嘌呤在酶嗜水气单胞菌的作用下,发生糖基化反应,生成中间体3a(8-氮杂鸟嘌核苷),中间体3a与三氯氧磷发生反应,生成中间体3b(8-氮杂鸟苷酸),最后中间体3b在相关酶的催化下与1c发生环合反应,生成最终产物TXS-WX-3。
(图8)
(4)如图8所示,化合物3a与三氯硫磷发生反应,生成中间体4a(8-氮杂α位硫代的鸟苷酸),中间体4a在相关酶的催化下与1c发生环合反应,生成最终产物TXS-WX-4。
(图9)
(5)如图9所示,化合物4a在相关酶的催化下与化合物2a发生环合反应,生成最终产物TXS-WX-5。
实施例2:采用荷瘤鼠模型进行检测TXS-WX类化合物的抗肿瘤作用即对动物皮下移植瘤生长的抑制作用
动物
种属、品系、性别、体重、来源、合格证
BALB/c普通小鼠、C57/BL6普通小鼠,雄性,体重20-25g, 6-8周龄, SPF级,购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号:SCXK (沪)2007-0005 ] 。
饲养条件
所有小鼠均自由觅食和饮水,在室温(23±2)℃下饲养。饲料及水均经高压灭菌处理,全部实验饲养过程为SPF级。
药物剂量设置
皮下注射小鼠,TXS-WX类化合物,设置1个剂量组:10 mg/kg; 每天一次给药。
试验对照
阴性对照:生理盐水溶液
阳性对照:cGAMP (购于Sigma公司),剂量10 mg/kg (每天一次)。
给药方法
给药途径:皮下注射给药
给药体积:100 微升/只
给药次数:连续30天给药,每天1次。
每组动物数:10只
肿瘤细胞株
小鼠结直肠癌细胞株CT26,小鼠肺癌Lewis瘤株 LL/2,人黑色素瘤细胞株A375,人胃癌细胞株MNK-45,人卵巢癌细胞株SK-OV-3,均购自中国科学院细胞库。
试验主要步骤
1.肿瘤模型鼠的建立与干预
细胞培养,传代,在细胞对数期收集细胞,做成浓度为(1.0×106)每毫升的细胞悬液,小鼠右前肢腋下注射0.2 ml细胞悬液 (细胞数目为2.0×106个/只),10 天左右肿瘤长至直径约5 mm,致瘤成功。分别制备皮下移植瘤模型:小鼠结直肠癌细胞株CT26,移植到BalB/C普通小鼠;小鼠肺癌Lewis瘤株 LL/2,人黑色素瘤细胞株A375,人胃癌细胞株MNK-45,人卵巢癌细胞株SK-OV-3,移植到C57/BL6小鼠,观察抗肿瘤效果。随机均分为7组。分别为A:阴性对照组(皮下注射生理盐水); B:阳性对照组(皮下注射cGAMP,10 mg/kg); C、D、E、F、G:(皮下分别注射TXS-WX-1、TXS-WX-2、TXS-WX-3、TXS-WX-4、TXS-WX-5,10mg/Kg), 连续给药30天。 30天后,处死小鼠并称瘤体重量,抑瘤率=[1-实验组平均瘤重/A组平均瘤重]]×100%。
2.统计分析
数据用x±s表示,利用SPSS10.0软件进行处理,采用单因素方差分析(one-way ANOVA)检验比较各组瘤重差异的显著性,显著性水平a=0.05。
结果
小鼠皮下接种肿瘤细胞后制备成功皮下移植瘤模型,TXS-WX类创新药均可显著抑制肿瘤生长,给药30天后的瘤重均显著低于阴性对照组(P<0.05 ,P<0.01)。具体结果见表1-5:
表1、TXS-WX类抗肿瘤药对BalB/C小鼠结直肠癌细胞CT26皮下移植瘤的抑制作用
(n=10,mean±SD)
组别 平均瘤重(g) 平均抑瘤率(%)
阴性对照组 2.267±0.240 (g) -
cGAMP组 0.741 ± 0.181 (g)** 67.0
TXS-WX-1组 0.276 ± 0.122 (g)** 87.8
TXS-WX-2组 0.254 ± 0.143 (g)** 88.8
TXS-WX-3组 0.287 ± 0.153 (g)** 87.3
TXS-WX-4组 0.247 ± 0.146 (g)** 89.1
TXS-WX-5组 0.239 ± 0.163 (g)** 89.5
注:*P<0.05 vs 阴性对照组;**P<0.01 vs 阴性对照组.
表2、TXS-WX类抗肿瘤药对C57小鼠肺癌Lewis瘤株 LL-2皮下移植瘤的抑制作用
(n=10,mean±SD)
组别 平均瘤重(g) 平均抑瘤率(%)
阴性对照组 2.654 ± 0.181 (g) -
cGAMP组 0.780 ± 0.162(g)** 70.6
TXS-WX-1组 0.581 ± 0.262(g)** 78.1
TXS-WX-2组 0.316 ± 0.183 (g)** 88.1
TXS-WX-3组 0.325 ± 0.132 (g)** 87.7
TXS-WX-4组 0.319 ± 0.121(g)** 88.0
TXS-WX-5组 0.308 ± 0.122 (g)** 88.4
注:*P<0.05 vs 阴性对照组;**P<0.01 vs 阴性对照组.
表3、 TXS-WX类抗肿瘤药对人黑色素瘤细胞株A375鼠皮下移植瘤的抑制作用
(n=10,mean±SD)
组别 平均瘤重(g) 平均抑瘤率(%)
阴性对照组 2.678 ± 0.151 (g) -
cGAMP组 0.760 ± 0.162 (g)** 71.3
TXS-WX-1组 0.558 ± 0.131 (g)** 79.1
TXS-WX-2组 0.412 ± 0.143 (g)** 84.6
TXS-WX-3组 0.489 ± 0.134 (g)** 81.7
TXS-WX-4组 0.378 ± 0.135 (g)** 85.9
TXS-WX-5组 0.359 ± 0.141(g)** 86.6
注:*P<0.05 vs 阴性对照组;**P<0.01 vs 阴性对照组.
表4、 TXS-WX类抗肿瘤药对人胃癌细胞株MNK-45鼠皮下移植瘤的抑制作用
(n=10,mean±SD)
组别 平均瘤重(g) 平均抑瘤率(%)
阴性对照组 2.687 ± 0.188 (g) -
cGAMP组 0.786 ± 0.163 (g)** 70.7
TXS-WX-1组 0.589 ± 0.171 (g)** 78.1
TXS-WX-2组 0.388 ± 0.125 (g)** 85.6
TXS-WX-3组 0.418 ± 0.188 (g)** 84.4
TXS-WX-4组 0.364 ± 0.132 (g)** 86.5
TXS-WX-5组 0.352 ± 0.151 (g)** 86.9
注:*P<0.05 vs 阴性对照组;**P<0.01 vs 阴性对照组.
表5、 TXS-WX类抗肿瘤药对人卵巢癌细胞株SK-OV-3鼠皮下移植瘤的抑制作用
(n=10,mean±SD)
组别 平均瘤重(g) 平均抑瘤率(%)
阴性对照组 2.756±0.136 (g) -
cGAMP组 0.768±0.158 (g)** 72.1
TXS-WX-1组 0.538 ± 0.125 (g)** 80.5
TXS-WX-2组 0.426 ± 0.115 (g)** 84.5
TXS-WX-3组 0.394 ± 0.136 (g)** 85.7
TXS-WX-4组 0.357 ± 0.133 (g)** 87.0
TXS-WX-5组 0.339± 0.156 (g)** 87.8
注:*P<0.05 vs 阴性对照组;**P<0.01 vs 阴性对照组.
实施例4 TXS-WX抗肿瘤药的急性毒性研究
实验材料
ICR 小鼠20 只(购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号:SCXK (沪)2007-0005 ] ),雌雄各半,体重21~25g,动物以颗粒饲料喂养,自由摄食和饮水。
-WX抗肿瘤药由实施例1制备,用生理盐水配制成浓度为200 mg/mL 的溶液。
实验方法
ICR小鼠按体重单次尾静脉注射200 mg/kg 的TXS-WX抗肿瘤药缓释药物,观察给药后小鼠14天内的毒性反应及死亡情况。结果发现,小鼠单次尾静脉注射给药后,小鼠活动正常。给药后14天内,小鼠未出现死亡,第15天,全部小鼠处死,解剖,肉眼检查各脏器,均未见明显病变。
实验结果
上述急性毒性实验结果表明,静脉注射给药最大耐受量MTD 不低于200mg/Kg,说明TXS-WX类抗肿瘤药的急性毒性低。
附图说明:
附图1-4.XST-WX系列化合物的结构式及其说明
附图5-9. XST-WX系列化合物制备方法及反应路线。
Claims (5)
1.TXS-WX类化合物的化学组成,该类化合物的结构及其化学组成说明见附图1-4
XST-WX-1,见图1;XST-WX类系列化合物见图2-4,
其中Z1和Z2为或者; Z3和Z4是=CRbb或者=N-; Z5是或者;
Z6是或者=N-;Z7是-CRccRdd,-O-或者-NRee-;
其中R1的结构组成见图3, Ra, Rb和Rc可以分别为以下基团其中的一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rd、-L1、-Re;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Rh基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Ri基团取代;
Rd可以为以下基团的其中一个:-CN,-NO2, -OH,-SH,-NH2,-C(=W)-WH,-C(=WH)-NH2,-C(=W)-NH-WH,-C=N-OH,-C(=NH)-NH2,-W-C(=W)-WH,-W-C(=W)-NH2,-S(=O)2-NH2,-S(=O)2-NH-W-,-NH-NH2,-NH-WH,NH-C(=W)-NH2,-NH-S(=O)2-NH2,和-NH-C(=NH)-NH2;
L1可以为以下基团的其中一个:-O-,-S-,-S(=O)-,-S(=O)2-,-C(=W)-,-C(=W)-W-,-C(=W)-NRf-,-C(=W)-NRf-W-,-C=N-O-,-C(=NRf)NRf-,-C(NRfRf)=N-,-W-C(=W)-,-W-C(=W)-W-,-W-C(=W)-NRf-,-S(=O)2-NRf-,-S(=O)2-NRf-W-,-NRf-,-N=CRg-,-NRf-W,-NRf-NRf-,-NRf-C(=NRf)NRf-,-NRf-C(NRfRf)=N-,-NRf-C(=W)-,-NRf-C(=W)-W-,-NRf-C(=W)-NRf-,-NRf-S(=O)2-NRf-和-NRf-S(=O)2-;
Re可以为以下基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Rh基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Ri基团取代;
Rg可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;同时如果L1是-NH-,Re可以是N的保护基;
Rf可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Rh基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Ri基团取代;
Rg可以为以下基团的其中一个:-H, 卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;
Rh如果取代在碳原子上,可以是下面基团的其中一个:=O,卤素,碳环基,杂环基,芳基,杂芳基,Rd和L2-Rj;Rh如果取代在氮原子上,可以是下面基团的其中一个:碳环基,杂环基,芳基,杂芳基,RL和L3-Rk;同时碳环基,杂环基,芳基,杂芳基可以被一个或者多个Ri基团取代;
Ri如果取代在碳原子上,可以是下面基团的其中一个:=O,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rd和-L2-Rj;Ri如果取代在氮原子上,可以是下面基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-RL和-L3-Rk;
Rj和Rk可以分别为以下基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Ro基团取代;碳环基,杂环基,可以分别被一个或者多个Rp基团取代;而芳基,杂芳基可以分别被一个或者多个Rq基团取代;
RL可以为以下基团的其中一个:-OH,-SH,-NH2,-C(=W)-WH,-C(=W)-NH2,-C(=WH)-NH2,和-S(=O2)-NH2; L2可以为以下基团的其中一个:-O-,-S-,-S(=O)2-,-C(=W)-,-C(=W)-W-,-C(=W)-NRm-,-C(=W)-NRm-W-,-C=N-O-,-C(=NRm)NRm-,-C(NRmRm)=N-,-W-C(=W)-,-W-C(=W)-W-,-W-C(=W)-NRm-,-S(=O)2-NRm-,-S(=O)2-NRm-W-,-NRm-,-N=CRn-,-NRm-W,-NRm-NRm-,-NRm-C(=NRm)NRm-,-NRm-C(NRmRm)=N-,-NRm-C(=W)-,-NRm-C(=W)-W-,-NRm-C(=W)-NRm-,-NRm-S(=O)2-NRm-和-NRm-S(=O)2-;L3可以为以下基团的其中一个:-O-, -S-, -NRm-, -C(=W)-, -C(=W)-W-, -C(=W)-NRm-, -C(=NRm)NRm-, -C(NRmRm)=N-,-S(=O)2-NRm-,和-S(=O)2-;
Rm可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Ro基团取代;碳环基,杂环基,可以分别被一个或者多个Rp基团取代;而芳基,杂芳基可以分别被一个或者多个Rq基团取代;
Rn可以为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Ro基团取代;碳环基,杂环基,可以分别被一个或者多个Rp基团取代;而芳基,杂芳基可以分别被一个或者多个Rq基团取代;
Ro可以为以下基团的其中一个:=O,-OH,-SH,-NH2,-CN,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;
Rp可以为以下基团的其中一个:=O,-OH,-SH,-NH2,-CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;
Rq可以为以下基团的其中一个:卤素,-OH,-SH,-NH2,-CN,-NO2,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;其中R2的结构和化学组成见附图1D,其中,Raa可以为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rff和-L11-Rgg;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;Rbb,Rcc和Rdd可以分别为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rff和-L11-Rgg;其中Rcc和Rdd也可以一起作为下面几个基团:=O, =CRhhRhh,=N-ORii,=N-Rii或者=N-NRiiRii;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;Ree可以为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rjj和-L22-Rkk;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;Rff可以为以下基团的其中一个:-CN,-NO2, -OH,-SH,-NH2,-C(=W)-WH,-C(=WH)-NH2,-C(=W)-NH-WH,-C=N-OH,-C(=NH)-NH2,-W-C(=W)-WH,-W-C(=W)-NH2,-S(=O)2-NH2,-S(=O)2-NH-W-,-NH-NH2,-NH-WH,NH-C(=W)-NH2,-NH-S(=O)2-NH2,和-NH-C(=NH)-NH2;L11可以为以下基团的其中一个:-O-,-S-,-S(=O)-,-S(=O)2-,-C(=W)-,-C(=W)-W-,-C(=W)-NRLL-,-C(=W)-NRLL-W-,-C=N-O-,-C(=NRLL)NRLL-,-C(NRLLRLL)=N-,-W-C(=W)-,-W-C(=W)-W-,-W-C(=W)-NRLL-,-S(=O)2-NRLL-,-S(=O)2-NRLL-W-,-NRLL-,-N=CRmm-,-NRLL-W,-NRLL-NRLL-,-NRLL-C(=NRLL)NRLL-,-NRLL-C(NRLLRLL)=N-,-NRLL-C(=W)-,-NRLL-C(=W)-W-,-NRLL-C(=W)-NRLL-,-NRLL-S(=O)2-NRLL-和-NRLL-S(=O)2-;Rgg可以为以下基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;同时如果L11是-NH-,Rgg可以是N的保护基;Rhh可以为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基;Rii可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;Rjj可以为以下基团的其中一个:-OH,-SH,-NH2,-C(=W)-WH,-C(=W)-NH2,-C(=WH)-NH2,和-S(=O2)-NH2;Rkk可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;L22可以为以下基团的其中一个:-O-, -S-, -NRnn-, -C(=W)-, -C(=W)-W-, -C(=W)-NRnn-, -C(=NRnn)NRnn-, -C(NRnnRnn)=N-,-S(=O)2-NRnn-,和-S(=O)2-;RLL可以为以下基团的其中一个:可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;Rmm可以为以下基团的其中一个:-H, 卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;Rnn可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Roo基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;Roo如果取代在碳原子上,可以是下面基团的其中一个:=O,卤素,碳环基,杂环基,芳基,杂芳基,Rff和L33-Rqq;Roo如果取代在氮原子上,可以是下面基团的其中一个:碳环基,杂环基,芳基,杂芳基,Rjj和L44-Rrr;同时碳环基,杂环基,芳基,杂芳基可以被一个或者多个Rpp基团取代;Rpp如果取代在碳原子上,可以是下面基团的其中一个:=O,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rff和-L33-Rqq;Rpp如果取代在氮原子上,可以是下面基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基,-Rjj和-L44-Rrr;Rqq和Rrr可以分别为以下基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Ruu基团取代;碳环基,杂环基,可以分别被一个或者多个Rvv基团取代;而芳基,杂芳基可以分别被一个或者多个Rww基团取代;L33可以为以下基团的其中一个:-O-,-S-,-S(=O)2-,-C(=W)-,-C(=W)-W-,-C(=W)-NRss-,-C(=W)-NRss-W-,-C=N-O-,-C(=NRss)NRss-,-C(NRssRss)=N-,-W-C(=W)-,-W-C(=W)-W-,-W-C(=W)-NRss-,-S(=O)2-NRss-,-S(=O)2-NRss-W-,-NRss-,-N=CRtt-,-NRss-W,-NRss-NRss-,-NRss-C(=NRss)NRss-,-NRss-C(NRssRss)=N-,-NRss-C(=W)-,-NRss-C(=W)-W-,-NRss-C(=W)-NRss-,-NRss-S(=O)2-NRss-和-NRss-S(=O)2-;L4可以为以下基团的其中一个:-O-, -S-, -NRm-, -C(=W)-,-C(=W)-W-, -C(=W)-NRss-, -C(=NRss)NRss-, -C(NRssRss)=N-,-S(=O)2-NRss-,和-S(=O)2-;Rss可以为以下基团的其中一个:-H,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Ruu基团取代;碳环基,杂环基,可以分别被一个或者多个Rvv基团取代;而芳基,杂芳基可以分别被一个或者多个Rww基团取代;Rtt可以为以下基团的其中一个:-H,卤素,烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基;其中烷基,烯基,炔基,杂烃基,可以分别被一个或者多个Ruu基团取代;碳环基,杂环基,可以分别被一个或者多个Rvv基团取代;而芳基,杂芳基可以分别被一个或者多个Rww基团取代;Ruu可以为以下基团的其中一个:=O,-OH,-SH,-NH2,-CN,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;Rvv可以为以下基团的其中一个:=O,-OH,-SH,-NH2,-CN,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;Rww可以为以下基团的其中一个:卤素,-OH,-SH,-NH2,-CN,-NO2,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺,C1-6烷基二胺,N连接的杂环烷基,其中C1-6烷基,C2-6烯基,C2-6炔基和C1-6烷氧基,C1-6含硫烷基,C1-6含亚砜烷基,C1-6含砜烷基,C1-6烷基胺和C1-6烷基二胺可以被-OH,-SH,NH2,卤素,C1-6烷氧基,C1-6卤代的烷氧基,C1-6含硫烷基,C1-6卤代的含硫烷基,C1-6含亚砜烷基,C1-6卤代的含亚砜烷基,C1-6含砜烷基,C1-6卤代的含砜烷基,C1-6烷基胺,C1-6烷基二胺和N连接的杂环烷基这些基团一个或者多个进行取代;
R3和R4可以分别是-OH,-ORa,-SH,-SRa,-BH2,-SeH
Ra可以为以下基团的其中一个:烷基,烯基,炔基,杂烃基,碳环基,杂环基,芳基,杂芳基和-C(=O)Re;其中烷基,烯基,炔基,杂烃基,可以被一个或者多个Rh基团取代,而碳环基,杂环基,芳基,杂芳基可以被一个或者多个Ri基团取代;
R5和R6可以分别为以下基团的其中一个:-H,-OH,卤素和-ORa。
2.TXS-WX类化合物的制备方法和合成路线,TXS-WX类化合物的制备方法和合成路
线见附图5-9。
3.TXS-WX这一类化合物在抗肿瘤中的应用及其在制备抗肿瘤药物中的应用,包括这类化
合物与抗肿瘤化药、生物药的联合用药或与放疗联合抗肿瘤中的应用,该类药物的抗肿
瘤适应症包括但不限于结直肠癌、乳腺癌、黑色素瘤、胃癌、卵巢癌、肝癌、胰腺癌、
淋巴癌等。
4. TXS-WX类化合物具有调节天然免疫通路的功能,因此,该类化合物可应用于治疗基于免疫调节机制的其它类疾病药物,包括但不限于神经退行性疾病(阿尔茨海默病、帕金森病、侧索硬化症等)、心脑血管疾病、糖尿病、类风湿关节炎、多发性硬化症等。
5.根据权利要求1-4,该类化合物药物,包含不同规格的单位制剂及药学上可接受的载体制备的药物制剂,采取口服或注射(包括静脉注射、静脉滴注、肌肉注射或皮下注射等中的一种或多种)等中的一种或多种给药途径进行肿瘤及其直接相关疾病的预防或治疗。
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