WO2022063134A1 - Csf1r激酶抑制剂及其用途 - Google Patents
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- WO2022063134A1 WO2022063134A1 PCT/CN2021/119663 CN2021119663W WO2022063134A1 WO 2022063134 A1 WO2022063134 A1 WO 2022063134A1 CN 2021119663 W CN2021119663 W CN 2021119663W WO 2022063134 A1 WO2022063134 A1 WO 2022063134A1
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Definitions
- the present application generally relates to the field of medicine, in particular to CSF1R kinase inhibitors and their application (as CSF1R kinase inhibitor drugs) in treating diseases related to CSF1R kinase signal transduction pathway or improving the immunosuppressive state of tumors.
- Diseases related to the CSF1R kinase signal transduction pathway described in this application include cancer or tumor, hyperplasia, immune disorders, inflammation, and the like.
- the disease is cancer or tumor.
- the cancer or tumor is a CSF1/CSF1R-dependent cancer or tumor or a TAMs-enriched tumor.
- CSF1/CSF1R-dependent cancers or tumors include CSF1/CSF1R-dependent leukemias, giant cell tumors of the tendon sheath, etc.; TAMs-enriched tumors include, but are not limited to, gliomas, brain metastases, or nodules Rectal cancer.
- CSF1/CSF1R-dependent cancers or tumors include CSF1/CSF1R-dependent leukemias, giant cell tumors of the tendon sheath, etc.; TAMs-enriched tumors include, but are not limited to, gliomas, brain metastases, or nodules Rectal cancer.
- the present application also provides a compound comprising a therapeutically effective amount of the compounds of the general formulae (A) to (F) or a pharmaceutically acceptable salt thereof, especially Compound I or a pharmaceutically acceptable salt thereof
- a pharmaceutical composition for inhibiting the proliferation of macrophages with a partial M2 polarized phenotype also provides a compound comprising a therapeutically effective amount of the compounds of the general formulae (A) to (F) or a pharmaceutically acceptable salt thereof, especially Compound I or a pharmaceutically acceptable salt thereof.
- the pharmaceutical combination product in this application not only includes the product form in which two or more active pharmaceutical ingredients are formulated into a single pharmaceutical composition, but also includes the form of a kit product, for example, two or more active pharmaceutical ingredients are formulated separately as separate products.
- a pharmaceutical composition and exists in a physically phase-separated form in the product.
- the CSF1/CSF1R-dependent cancer or tumor refers to a cancer or tumor with high CSF1/CSF1R expression or activation.
- the high expression or high activation of CSF1/CSF1R refers to those skilled in the art using conventional detection methods in the field (including but not limited to enzyme-linked immunosorbent assay, immunohistochemistry, flow cytometry, Western blotting, tissue chip, gene detection and other methods) to detect the expression level or activation level of CSF1/CSF1R in the tissues and/or cells of cancer or tumor, and its expression level or activation level is more than 130% of the normal level, preferably more than 150%, preferably more than 175%, preferably 200% % or more, preferably 250% or more, or preferably 300% or more.
- IC50 values were calculated using the four-parameter method, and each experiment was independently repeated three times.
- the CCK8 kit was used to detect the in vitro proliferation inhibitory activity of compound I on BMDM cells, and the statistical IC 50 results are shown in Table 2.
- Compound I can significantly inhibit the proliferation of CSF1-stimulated BMDM cells with an average IC 50 of 0.093 ⁇ 0.024 ⁇ M, which is slightly weaker than the positive drug PLX3397 (0.030 ⁇ 0.009 ⁇ M).
- the human glioma U87MG cell line was inoculated subcutaneously in the right armpit of nude mice, and the cell inoculation amount was 5 ⁇ 10 6 / mouse. After the transplanted tumor was formed, it was passed down in nude mice for 1 passage before use.
- test compound I 40mg/kg, 20mg/kg and 10mg/kg groups, orally administered twice a day for three consecutive weeks, can significantly inhibit the growth of human brain glioma U87MG nude mice subcutaneously transplanted tumor, on the 21st day
- the resulting T/C percentages were 9.77%, 8.14% and 11.91%, respectively.
- Nude mice were anesthetized by intraperitoneal injection of 50 mg/kg Shutai 50, and the nude mice were placed in a prone position in a stereotaxic apparatus to fix their heads. A longitudinal incision was made at the intersection of the medial canthal line and the sagittal midline of the head to separate and expose the skull. The skull was drilled 2mm to the right at the level of the bregma and 0.5mm anterior. U87MG cells were inoculated into the right caudate nucleus of nude mice at 5 ⁇ 10 5 /cell. The incision was closed with sterile medical sutures, and the animal was kept warm until awake. Randomization was performed on day 7 after vaccination (day 0 of vaccination), and treatment with different compounds started on day 8.
- Compound I 40 mg/kg or 20 mg/kg group was orally administered twice a day, and the mice were continuously administered until natural death.
- the positive control drug Axitinib 40 mg/kg group was orally administered twice a day until the mice died naturally; the solvent group (Vehicle) was given the same amount of water for injection; the blank formulation group was given the same amount of blank formulation.
- the mice were weighed twice a week. During the experiment, the death of the mice was recorded and the survival rate was calculated. The experimental data were analyzed by Log-rank, and p ⁇ 0.05 was considered a significant difference.
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Abstract
Description
原辅料 | 用量 |
化合物I | 60mg |
中链甘油三酸酯 | 1ml |
聚氧乙烯40氢化蓖麻油 | 1.5ml |
二乙二醇单乙基醚 | 2.5ml |
油酸 | 1ml |
乙醇∶乙酸乙酯(1∶1)作为潜溶剂 | 15~20ml |
Claims (44)
- 以下通式(A)的化合物或其药学上可接受的盐在制备治疗CSF1R激酶信号转导通路相关疾病的药物和/或CSF1R激酶抑制剂药物中的用途:其中:R 1位于萘环上5-8位上的任一位置,且为以下结构:其中,R 4选自氢、卤素、C1-C3烷基和C1-C3烷氧基,R 3选自氢、C1-C6烷基、C3-C6环烷基、取代或未取代的苯基和含有选自N、O和S中的1至5个杂原子的取代或未取代的5-10元杂芳基;在取代的情况下,所述取代基为1-3个取代基,所述的取代基各自独立地选自C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基、卤代C1-C3烷氧基、羟基、氨基、硝基和卤素;
- 如权利要求1所述用途,其中所述CSF1R激酶信号转导通路相关疾病选自癌症或肿瘤、超常增生、免疫病症、炎症;优选地,所述CSF1R激酶信号转导通路相关疾病为癌症或肿瘤;更优选地,所述癌症或肿瘤为CSF1/CSF1R依赖性癌症或肿瘤、或肿瘤相关巨噬细胞(TAMs)富集性肿瘤;进一步优选地,所述CSF1/CSF1R依赖性癌症或肿瘤为CSF1/CSF1R依赖性白血病或腱鞘巨细胞瘤,和/或所述TAMs富集性肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 权利要求1定义的通式(A)的化合物或其药学上可接受的盐在制备调节免疫的药物中的用途;优选地,所述调节免疫为增强免疫;更优选地,所述增强免疫为改善肿瘤免疫抑制状态;进一步优选地,所述改善肿瘤免疫抑制状态为抑制偏M2型巨噬细胞的存活、逆转 巨噬细胞偏M2型极化表型以及巨噬细胞偏M2型极化表型对CD8 +T细胞的抑制作用,和/或重塑肿瘤免疫微环境。
- 权利要求1定义的通式(A)的化合物或其药学上可接受的盐在制备抑制偏M2型巨噬细胞增殖的药物中的用途。
- 权利要求1定义的通式(A)的化合物或其药学上可接受的盐在制备治疗或抑制对免疫检查点药物不敏感的肿瘤的药物中的用途;优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 权利要求1定义的通式(A)的化合物或其药学上可接受的盐在制备增强免疫检查点药物抗肿瘤药效的药物中的用途;优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 权利要求1定义的通式(A)的化合物或其药学上可接受的盐在制备和免疫检查点药物联合抗肿瘤的药物中的用途;优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 如权利要求1-7中任一项所述用途,其中所述药物还包含其它治疗组分;优选地,所述其它治疗组分为抗肿瘤药物或免疫调节剂;更优选地,所述其它治疗组分为免疫检查点药物;进一步优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体。
- 如权利要求1-8中任一项所述用途,其中所述药物制成临床上可接受的剂型;优选地,所述剂型为口服剂型、注射剂型、局部给药剂型或外用剂型。
- 如权利要求1-9中任一项所述用途,其中所述药物含有治疗有效量的通式(A)的化合物或其药学上可接受的盐;优选地,单位剂量形式中的所述治疗有效量为0.01-2000mg,更优选1-500mg。
- 一种复方药物或药物组合产品,所述复方药物或药物组合产品包含治疗有效量的权利要求1定义的通式(A)的化合物或其药学上可接受的盐,和其它治疗组分,所述复方药物或药物组合产品用于治疗受试者的CSF1R激酶信号转导通路相关疾病;优选地,所述CSF1R激酶信号转导通路相关疾病为癌症或肿瘤、超常增生、免疫病症、炎症;更优选地,所述CSF1R激酶信号转导通路相关疾病为癌症或肿瘤。
- 如权利要求11所述的复方药物或药物组合产品,其中所述癌症或肿瘤选自CSF1/CSF1R依赖性癌症或肿瘤或TAMs富集性肿瘤;优选地,所述CSF1/CSF1R依赖性癌症或肿瘤为CSF1/CSF1R依赖性白血病或腱鞘巨细胞瘤,和/或TAMs富集性肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 如权利要求11或12所述的复方药物或药物组合产品,其中所述其它治疗组分选自抗肿瘤药物或免疫调节剂;优选地,所述其它治疗组分为免疫检查点药物;更优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体。
- 治疗CSF1R激酶信号转导通路相关疾病的方法,包括将治疗有效量的权利要求1定义的通式(A)的化合物或其药学上可接受的盐施用于需要治疗的个体;优选地,所述个体为哺乳动物,更优选为人。
- 如权利要求14所述方法,其中所述CSF1R激酶信号转导通路相关疾病选自癌症或肿瘤、超常增生、免疫病症、炎症;优选地,所述CSF1R激酶信号转导通路相关疾病为癌症或肿瘤;更优选地,所述癌症或肿瘤为CSF1/CSF1R依赖性癌症或肿瘤、或肿瘤相关巨噬细胞(TAMs)富集性肿瘤;进一步优选地,所述CSF1/CSF1R依赖性癌症或肿瘤为CSF1/CSF1R依赖性白血病或腱鞘巨细胞瘤,和/或所述TAMs富集性肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 调节免疫的方法,包括将治疗有效量的权利要求1定义的通式(A)的化合物或其药学上可接受的盐施用于有需要的个体;优选地,所述个体为哺乳动物,更优选为人。
- 如权利要求16所述方法,其中所述调节免疫为增强免疫;优选地,所述增强免疫为改善肿瘤免疫抑制状态;更优选地,所述改善肿瘤免疫抑制状态为抑制偏M2型巨噬细胞的 存活、逆转巨噬细胞偏M2型极化表型以及巨噬细胞偏M2型极化表型对CD8+T细胞的抑制作用,和/或重塑肿瘤免疫微环境。
- 治疗或抑制对免疫检查点药物不敏感的肿瘤的方法,包括将治疗有效量的权利要求1定义的通式(A)的化合物或其药学上可接受的盐施用于需要治疗或抑制对免疫检查点药物不敏感的肿瘤的个体;优选地,所述个体为哺乳动物,更优选为人。
- 如权利要求18所述方法,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 增强免疫检查点药物抗肿瘤药效的方法,包括将治疗有效量的权利要求1定义的通式(A)的化合物或其药学上可接受的盐施用于正在接受或将要接受免疫检查点药物的肿瘤治疗的个体;优选地,所述个体为哺乳动物,更优选为人。
- 如权利要求20所述方法,其中所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 治疗或抑制肿瘤的方法,包括将治疗有效量的权利要求1定义的通式(A)的化合物或其药学上可接受的盐与免疫检查点药物联合施用于需要治疗或抑制肿瘤的个体;优选地,所述个体为哺乳动物,更优选为人。
- 如权利要求22所述方法,其中所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 如权利要求14-23中任一项所述方法,还包括将其它治疗组分施用于所述个体;优选地,所述其它治疗组分为抗肿瘤药物或免疫调节剂;更优选地,所述其它治疗组分为免疫检查点药物;进一步优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体。
- 如权利要求14-24中任一项所述方法,其中通式(A)的化合物或其药学上可接受的盐制成临床上可接受的剂型;优选地,所述剂型为口服剂型、注射剂型、局部给药剂型或外用剂型。
- 如权利要求14-25中任一项所述方法,其中单位剂量形式中的治疗有效量的通式(A)的化合物为0.01-2000mg,更优选1-500mg。
- 包含权利要求1定义的通式(A)的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用作CSF1R激酶抑制剂。
- 包含权利要求1定义的通式(A)的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用于治疗CSF1R激酶信号转导通路相关疾病。
- 如权利要求28所述用途的药物组合物,其中所述CSF1R激酶信号转导通路相关疾病选自癌症或肿瘤、超常增生、免疫病症、炎症;优选地,所述CSF1R激酶信号转导通路相关疾病为癌症或肿瘤;更优选地,所述癌症或肿瘤为CSF1/CSF1R依赖性癌症或肿瘤、或肿瘤相关巨噬细胞(TAMs)富集性肿瘤;进一步优选地,所述CSF1/CSF1R依赖性癌症或肿瘤为CSF1/CSF1R依赖性白血病或腱鞘巨细胞瘤,和/或所述TAMs富集性肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 包含权利要求1定义的通式(A)的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用于调节免疫;优选地,所述调节免疫为增强免疫;更优选地,所述增强免疫为改善肿瘤免疫抑制状态;进一步优选地,所述改善肿瘤免疫抑制状态为抑制偏M2型巨噬细胞的存活、逆转巨噬细胞偏M2型极化表型以及巨噬细胞偏M2型极化表型对CD8+T细胞的抑制作用,和/或重塑肿瘤免疫微环境。
- 包含权利要求1定义的通式(A)的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用于抑制偏M2型极化表型的巨噬细胞增殖。
- 包含权利要求1定义的通式(A)的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用于治疗或抑制对免疫检查点药物不敏感的肿瘤;优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 包含权利要求1定义的通式(A)的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用于增强免疫检查点药物抗肿瘤药效;优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体,和/或所述肿瘤为脑胶质瘤、脑转移瘤或结直肠癌。
- 包含权利要求1定义的通式(A)的化合物或其药学上可接受的盐的药物组合物,所述药物组合物用于与免疫检查点药物联合使用以在个体中治疗或抑制肿瘤
- 如权利要求27-34中任一项所述用途的药物组合物,其中所述药物组合物还包含其它治疗组分;优选地,所述其它治疗组分为抗肿瘤药物或免疫调节剂;更优选地,所述其它治疗组分为免疫检查点药物;进一步优选地,所述免疫检查点药物为抗PD-1抗体或抗PD-L1抗体。
- 如权利要求27-35中任一项所述用途的药物组合物,其中所述药物组合物制成临床上可接受的剂型;优选地,所述剂型为口服剂型、注射剂型、局部给药剂型或外用剂型。
- 如权利要求27-36中任一项所述用途的药物组合物,其中所述药物组合物含有治疗有效量的权利要求1定义的通式(A)的化合物或其药学上可接受的盐;优选地,单位剂量形式中的所述治疗有效量为0.01-2000mg,更优选1-500mg。
- 如权利要求1-37中任一项所述的用途、复方药物或药物组合产品、方法或药物组合物,在通式(A)中,R 3选自氢、C1-C3烷基、C3-C6环烷基、取代或未取代的苯基和含有选自N、O和S中的1至3个杂原子的取代或未取代的5-6元杂芳基;在取代的情况下,所述取代基为1-3个取代基,所述的取代基各自独立地选自C1-C3烷基、甲氧基、三氟甲基、三氟甲氧基、羟基、氨基、硝基、F、Cl和Br;R 2为氢、F、Cl或Br。
- 如权利要求1-38中任一项所述的用途、复方药物或药物组合产品、方法或药物组合物,其中R 4选自氢、F、Cl、Br、甲基和甲氧基。
- 如权利要求1-37中任一项所述的用途、复方药物或药物组合产品、方法或药物组合物,其中通式(A)的化合物为以下通式(B)所示的化合物:其中:R 3选自氢、C1-C6烷基、C3-C6环烷基、取代或未取代的苯基和含有选自N、O和S中的1至5个杂原子的取代或未取代的5-10元杂芳基;在取代的情况下,所述取代基为1-3个取代基,所述的取代基各自独立地选自C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基、卤代C1-C3烷氧基、羟基、氨基、硝基和卤素;Z为C(R 5)=CH、S或O;Y为NH、NMe、O、CH=C(R 6)或CH=N;R 5选自氢、卤素、C1-C3烷基和C1-C3烷氧基;R 6选自氢、吡唑基、C1-C3烷基取代的吡唑基和羟基C1-C3烷基取代的吡唑基。
- 如权利要求40所述的用途、复方药物或药物组合产品、方法或药物组合物,其中R 5选自氢、F、Cl、Br、甲基和甲氧基;R 6选自氢、吡唑基、甲基取代的吡唑基和羟乙基取代的吡唑基。
- 如权利要求1-37中任一项所述的用途、复方药物或药物组合产品、方法或药物组合物,其中通式(A)的化合物为以下通式(C)、(D)、(E)或(F)所示的化合物:其中:R 3选自氢、C1-C6烷基、C3-C6环烷基、取代或未取代的苯基和含有选自N、O和S中的1至5个杂原子的取代或未取代的5-10元杂芳基;在取代的情况下,所述取代基为1-3个取代基,所述的取代基各自独立地选自C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基、卤代C1-C3烷氧基、羟基、氨基、硝基和卤素;R 4选自氢、卤素、C1-C3烷基和C1-C3烷氧基;V为S或O;W为N或C(R 7);R 7选自氢、吡唑基、C1-C3烷基取代的吡唑基和羟基C1-C3烷基取代的吡唑基。
- 如权利要求42所述的用途、复方药物或药物组合产品、方法或药物组合物,其中R 4选自氢、F、Cl、Br、甲基和甲氧基;R 7选自氢、吡唑基、甲基取代的吡唑基和羟乙基取代的吡唑基。
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JP2023518507A JP2023543197A (ja) | 2020-09-23 | 2021-09-22 | Csf1rキナーゼ阻害剤およびその使用 |
CA3196283A CA3196283A1 (en) | 2020-09-23 | 2021-09-22 | Csf1r kinase inhibitor and use thereof |
AU2021348477A AU2021348477B2 (en) | 2020-09-23 | 2021-09-22 | Csf1r kinase inhibitor and use thereof |
EP21871504.3A EP4219456A1 (en) | 2020-09-23 | 2021-09-22 | Csf1r kinase inhibitor and use thereof |
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WO2007005668A2 (en) * | 2005-06-30 | 2007-01-11 | Amgen Inc. | Bis-aryl kinase inhibitors and their use in the treatment of inflammation, angiogenesis and cancer |
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US20230382871A1 (en) | 2023-11-30 |
KR20230074533A (ko) | 2023-05-30 |
AU2021348477B2 (en) | 2023-12-21 |
CA3196283A1 (en) | 2022-03-31 |
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