WO2020119784A1 - New application of febuxostat and derivatives thereof - Google Patents
New application of febuxostat and derivatives thereof Download PDFInfo
- Publication number
- WO2020119784A1 WO2020119784A1 PCT/CN2019/125151 CN2019125151W WO2020119784A1 WO 2020119784 A1 WO2020119784 A1 WO 2020119784A1 CN 2019125151 W CN2019125151 W CN 2019125151W WO 2020119784 A1 WO2020119784 A1 WO 2020119784A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- saicar
- disease
- tumor
- accumulation
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to new applications of compounds, in particular to Febuxostat and its derivatives.
- Febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid, Chinese trade name febuxostat, febuxostat) is a new generation of xanthine oxidase inhibition It is used clinically to treat gout (hyperuricemia).
- the treatment of gout is usually taken by: promoting uric acid excretion and inhibiting uric acid production, and adopting appropriate measures to improve related symptoms.
- SAICAR (S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate) is a substrate of the multifunctional protein ADE2.
- SAICAR is an intermediate for purine metabolism.
- SAICAR is converted from 5-amino-1-(5-phosphate-D-ribosyl)imidazole-4-carboxylic acid ester by phosphoribosylaminoimidazole-succinamide synthase (EC: 6.3.2.6) or SAICAR synthase. This enzyme catalyzes the seventh step in the biosynthesis of purine nucleotides.
- SAICAriboside succinylaminoimidazole carboxamide riboside
- S-Ado succinyl inosine
- Deficiency of adenylate succinate lyase results in a series of symptoms involving bradykinesia, usually accompanied by seizures and autism.
- SAICAR can act as an oncometabolite, a metabotoxin and acidogen.
- Collagen metabolites are compounds that promote tumor growth and survival.
- An acidic substance is an acidic compound that can induce acidosis and has many adverse effects on many organ systems.
- Endotoxins are endogenously produced metabolites that cause adverse health effects at long-term high levels.
- high levels of SAICAR stimulate the pyruvate kinase isoform M2 and promote cancer cell survival under glucose restriction conditions, such as aerobic glycolysis (PMID: 23086999).
- SAICAR is associated with acidosis.
- Abnormally high levels of organic acids in the blood (organic acidemia), urine (organic aciduria), the brain and other tissues cause general metabolic acidosis. Acidosis usually occurs when the arterial pH is below 7.35.
- the initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia) and lack of energy (sleepiness). These can develop into heart, liver and kidney abnormalities, seizures, coma and possible death. These are also characteristic symptoms of untreated adenylate succinate lyase deficiency. Many children with organic acidemia develop mental retardation or stunting. Recent studies have found that SAICAR accumulates highly under glucose-limited conditions, thereby altering energy levels, sugar uptake, and lactic acid production in tumor cells. These phenomena did not occur in adult epidermal cells and lung fibroblasts.
- SAICAR can induce the enzyme activity of PKM2 and promote the survival of tumor cells, and the combination of SAICAR-PKM2 can induce the phosphorylation of Erk1/2, and high concentration of SAICAR can also induce the up-regulated expression of the oncogene myc, which is due to the de novo anabolism of adenine
- the abnormally accumulated SAICAR in the pathway promotes the proliferation and survival of tumor cells.
- the object of the present invention is to provide new applications of Febuxostat and its derivatives.
- the first aspect of the present invention provides:
- the disease is associated with SAICAR accumulation; or
- the disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
- the disease is selected from tumor or adenylate succinate lyase deficiency; further, the disease is related to SAICAR accumulation;
- the amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioblastoma, head and neck squamous Cell cancer, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, Liver cancer, cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- SAICAR SAICAr
- S-Ado including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, Liver cancer, cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the disease is a tumor, and further includes administration of at least one compound and/or agent having a therapeutic effect on the tumor.
- the second aspect of the present invention provides:
- the disease is associated with SAICAR accumulation; or
- the disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
- the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
- the amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cell carcinoma , Pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
- SAICAR SAICAr
- S-Ado including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
- the third aspect of the present invention provides:
- a composition for treating, ameliorating or preventing diseases, the active ingredient of the composition includes at least one of Febuxostat or its derivatives;
- the disease is associated with SAICAR accumulation; or
- the disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
- the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
- the amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cell carcinoma , Pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
- SAICAR SAICAr
- S-Ado including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
- the disease is a tumor, and further includes the administration of at least one compound and/or agent that has a therapeutic effect on the tumor.
- the fourth aspect of the present invention provides:
- a method of treating, ameliorating or preventing a disease comprising administering to a patient a therapeutic amount or a preventive amount of Febuxostat or at least one of its derivatives,
- the disease is associated with SAICAR accumulation; or
- the disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR;
- the administration method includes oral administration, injection, transdermal absorption, and respiratory inhalation.
- the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
- the amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
- Warburg effect high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cell carcinoma , Pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
- SAICAR SAICAr
- S-Ado including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
- the disease is a tumor, and further includes the administration of at least one compound and/or agent that has a therapeutic effect on the tumor.
- Febuxostat and its derivatives especially include the compounds defined in the claims of US 5,614,520.
- the disclosure of US 5,614,520 is incorporated herein by reference in its entirety.
- the therapeutic compounds and/or agents for tumors are known in the art, including but not limited to various chemotherapeutic drugs, targeted drugs and the like.
- the therapeutic or preventive amount of the drug can be determined by a method known in the art, or by a doctor based on his experience. Generally speaking, the dosage should be below the safe dose.
- the invention extends the application of Febuxostat and its derivatives. It is better to use Febuxostat and its derivatives to treat diseases related to the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr or S-Ado or diseases that can be alleviated or improved by the reduction of the accumulated amount of toxic intermediate metabolites such as SAICAR, SAICAr or S-Ado Effect.
- Febuxostat can effectively reduce the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc., and have certain effects on the related diseases caused by the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc. Relief or therapeutic effect.
- the phenotype of the ADSL gene-deficient nematode animal model can be restored to normal.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a new application of Febuxostat and derivatives thereof. Febuxostat can effectively reduce accumulation of toxic intermediate metabolites such as SAICAR, SAICAr and S-Ado, and thus may relieve or treat to a certain extent the related diseases caused by accumulation of toxic intermediate metabolites such as SAICAR, SAICAr and S-Ado. The related diseases may be selected from the group consisting of tumors and adenylosuccinate lyase deficiency.
Description
本发明涉及化合物的新应用,特别涉及Febuxostat及其衍生物的新应用。The present invention relates to new applications of compounds, in particular to Febuxostat and its derivatives.
Febuxostat(2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid,中文商品名非布索坦,非布司他)是新一代黄嘌呤氧化酶抑制剂,临床上用于治疗痛风(尿酸过高症)。痛风的治疗通常采取的手段是:促进尿酸排泄和抑制尿酸生成,并采用适当措施改善相关症状。Febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid, Chinese trade name febuxostat, febuxostat) is a new generation of xanthine oxidase inhibition It is used clinically to treat gout (hyperuricemia). The treatment of gout is usually taken by: promoting uric acid excretion and inhibiting uric acid production, and adopting appropriate measures to improve related symptoms.
Febuxostat相关的专利申请有很多,其中US5614520公开了Febuxostat及其衍生物。DrugBank的数据(https://www.drugbank.ca/drugs/DB04854)公开了Febuxostat已有应用。There are many patent applications related to Febuxostat, of which US5614520 discloses Febuxostat and its derivatives. DrugBank data (https://www.drugbank.ca/drugs/DB04854) discloses that Febuxostat has been used.
SAICAR((S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate)是多功能蛋白质ADE2的底物。SAICAR是嘌呤代谢的中间体。SAICAR由5-氨基-1-(5-磷酸-D-核糖基)咪唑-4-羧酸酯通过磷酸核糖基氨基咪唑-琥珀酰胺合酶(EC:6.3.2.6)或SAICAR合酶转化。该酶催化嘌呤核苷酸生物合成中的第七步。琥珀酰氨基咪唑甲酰胺核苷(SAICAriboside)和琥珀酰肌苷的出现(S-Ado)在脑脊液,尿液中,以及在较小程度上在血浆中,是遗传性缺陷的特征,称为腺苷酸琥珀酸裂解酶缺乏症。腺苷酸琥珀酸裂解酶缺乏导致一系列涉及精神运动迟缓的症状,通常伴有癫痫发作和自闭症特征。当存在于足够高的水平,SAICAR可以充当一个oncometabolite,一个metabotoxin和acidogen。胶原代谢物是促进肿瘤生长和存活的化合物。一种酸性物质是一种酸性化合物,可诱发酸中毒,对许多器官系统有多种不良影响。内毒素是内源性产生的代谢物,其在长期高水平下引起不利的健康影响。作为一种代谢产物,高水平的SAICAR刺激丙酮酸激酶同种型M2并在葡萄糖限制条 件下促进癌细胞存活,例如有氧糖酵解(PMID:23086999)。作为有机酸,SAICAR与酸中毒有关。血液中的异常高水平的有机酸(有机酸血症),尿液(有机酸尿症),大脑和其他组织导致一般的代谢性酸中毒。酸中毒通常发生在动脉pH值低于7时.35。在患有酸中毒的婴儿中,最初的症状包括喂养不良,呕吐,食欲不振,肌张力弱(张力减退)和精力不足(嗜睡)。这些可以发展为心脏,肝脏和肾脏异常,癫痫发作,昏迷和可能的死亡。这些也是未处理的腺苷酸琥珀酸裂解酶缺乏症的特征性症状。许多患有有机酸血症的患儿会出现智力障碍或发育迟缓。近期研究发现,在葡萄糖受限的条件下高度积累SAICAR,从而改变了肿瘤细胞中能量水平、糖摄取和乳酸的产生,而这些现象并未发生在成人表皮细胞以及肺成纤维细胞中。SAICAR能够诱导PKM2的酶活性,促进肿瘤细胞的存活,而且SAICAR-PKM2的结合能够诱导Erk1/2的磷酸化,高浓度的SAICAR也可诱导癌基因myc的上调表达,这些由于腺嘌呤从头合成代谢途径中异常积累的SAICAR促进肿瘤细胞的增殖和存活。SAICAR((S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate) is a substrate of the multifunctional protein ADE2. SAICAR is an intermediate for purine metabolism. SAICAR is converted from 5-amino-1-(5-phosphate-D-ribosyl)imidazole-4-carboxylic acid ester by phosphoribosylaminoimidazole-succinamide synthase (EC: 6.3.2.6) or SAICAR synthase. This enzyme catalyzes the seventh step in the biosynthesis of purine nucleotides. The appearance of succinylaminoimidazole carboxamide riboside (SAICAriboside) and succinyl inosine (S-Ado) in cerebrospinal fluid, urine, and to a lesser extent in plasma, is a characteristic of genetic defects, called glands Glycosyl succinate lyase deficiency. Deficiency of adenylate succinate lyase results in a series of symptoms involving bradykinesia, usually accompanied by seizures and autism. When present at a sufficiently high level, SAICAR can act as an oncometabolite, a metabotoxin and acidogen. Collagen metabolites are compounds that promote tumor growth and survival. An acidic substance is an acidic compound that can induce acidosis and has many adverse effects on many organ systems. Endotoxins are endogenously produced metabolites that cause adverse health effects at long-term high levels. As a metabolite, high levels of SAICAR stimulate the pyruvate kinase isoform M2 and promote cancer cell survival under glucose restriction conditions, such as aerobic glycolysis (PMID: 23086999). As an organic acid, SAICAR is associated with acidosis. Abnormally high levels of organic acids in the blood (organic acidemia), urine (organic aciduria), the brain and other tissues cause general metabolic acidosis. Acidosis usually occurs when the arterial pH is below 7.35. In infants with acidosis, the initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia) and lack of energy (sleepiness). These can develop into heart, liver and kidney abnormalities, seizures, coma and possible death. These are also characteristic symptoms of untreated adenylate succinate lyase deficiency. Many children with organic acidemia develop mental retardation or stunting. Recent studies have found that SAICAR accumulates highly under glucose-limited conditions, thereby altering energy levels, sugar uptake, and lactic acid production in tumor cells. These phenomena did not occur in adult epidermal cells and lung fibroblasts. SAICAR can induce the enzyme activity of PKM2 and promote the survival of tumor cells, and the combination of SAICAR-PKM2 can induce the phosphorylation of Erk1/2, and high concentration of SAICAR can also induce the up-regulated expression of the oncogene myc, which is due to the de novo anabolism of adenine The abnormally accumulated SAICAR in the pathway promotes the proliferation and survival of tumor cells.
发明内容Summary of the invention
本发明的目的在于提供Febuxostat及其衍生物的新应用。The object of the present invention is to provide new applications of Febuxostat and its derivatives.
发明人通过自有软件分析,发现Febuxostat可以有效减少SAICAR的累积,进而对SAICAR累积造成的相关病症具有一定的缓解或治疗作用。初步的实验数据证实发明人的这一分析是成立的。The inventors found through their own software that Febuxostat can effectively reduce the accumulation of SAICAR, and thus have a certain relief or treatment effect on the related diseases caused by the accumulation of SAICAR. Preliminary experimental data confirms that the inventor's analysis is valid.
本发明所采取的技术方案是:The technical solutions adopted by the present invention are:
本发明的第一个方面,提供:The first aspect of the present invention provides:
Febuxostat及其衍生物在制备治疗、改善或预防疾病药物中的应用,The application of Febuxostat and its derivatives in the preparation of drugs for treatment, improvement or prevention of diseases,
所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or
所述疾病可因SAICAR累积量的减少而减轻或改善。The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
在一些应用的实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;In some examples of application, the disease is selected from tumor or adenylate succinate lyase deficiency; further, the disease is related to SAICAR accumulation;
所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
在一些应用的实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples of applications, the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, multiform glioblastoma, head and neck squamous Cell cancer, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
在一些应用的实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr 或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples of application, the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, Liver cancer, cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
在一些应用的实例中,所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。In some application examples, the disease is a tumor, and further includes administration of at least one compound and/or agent having a therapeutic effect on the tumor.
本发明的第二个方面,提供:The second aspect of the present invention provides:
用于治疗、改善或预防疾病的Febuxostat及其衍生物,Febuxostat and its derivatives for the treatment, improvement or prevention of diseases,
所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or
所述疾病可因SAICAR累积量的减少而减轻或改善。The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
在一些实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;In some examples, the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
在一些实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples, the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cell carcinoma , Pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
在一些实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples, the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
本发明的第三个方面,提供:The third aspect of the present invention provides:
一种治疗、改善或预防疾病的组合物,组合物的活性成分包括Febuxostat或其衍生物中的至少一种;A composition for treating, ameliorating or preventing diseases, the active ingredient of the composition includes at least one of Febuxostat or its derivatives;
所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or
所述疾病可因SAICAR累积量的减少而减轻或改善。The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
在一些实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;In some examples, the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
在一些实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples, the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cell carcinoma , Pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
在一些实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples, the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
在一些实例中,所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。In some examples, the disease is a tumor, and further includes the administration of at least one compound and/or agent that has a therapeutic effect on the tumor.
本发明的第四个方面,提供:The fourth aspect of the present invention provides:
一种治疗、改善或预防疾病的方法,包括给予病人治疗量或预防量的Febuxostat或其衍生物中的至少一种,A method of treating, ameliorating or preventing a disease, comprising administering to a patient a therapeutic amount or a preventive amount of Febuxostat or at least one of its derivatives,
所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or
所述疾病可因SAICAR累积量的减少而减轻或改善;The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR;
进一步的,给药方式包括口服、注射、透皮吸收、呼吸道吸入。Further, the administration method includes oral administration, injection, transdermal absorption, and respiratory inhalation.
在一些实例中,所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;In some examples, the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:
SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;
沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
在一些实例中,所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples, the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polyglioblastoma, head and neck squamous cell carcinoma , Pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
在一些实例中,所述肿瘤存在SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积,包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。In some examples, the tumor has SAICAR levels higher than normal, and there is excessive accumulation of SAICAR, SAICAr, or S-Ado, including lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, Cholangiocarcinoma, esophageal cancer, polymorphic glioblastoma, squamous cell carcinoma of the head and neck, pancreatic cancer, gastric cancer, endometrial cancer, and leukemia.
在一些实例中,所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。In some examples, the disease is a tumor, and further includes the administration of at least one compound and/or agent that has a therapeutic effect on the tumor.
Febuxostat及其衍生物尤其包括US5,614,520权利要求中所限定化合物。US5,614,520公开的内容被全部通过援引并入本文。Febuxostat and its derivatives especially include the compounds defined in the claims of US 5,614,520. The disclosure of US 5,614,520 is incorporated herein by reference in its entirety.
所述肿瘤有治疗作用的化合物和/或试剂为本领域已知的化合物和试剂,包括但不限于各 种化疗药物、靶向药物等。The therapeutic compounds and/or agents for tumors are known in the art, including but not limited to various chemotherapeutic drugs, targeted drugs and the like.
药物的治疗量或预防量可以通过本领域的公知方法确定,或由医生基于其经验确定。一般而言,其用量应当在安全剂量之下。The therapeutic or preventive amount of the drug can be determined by a method known in the art, or by a doctor based on his experience. Generally speaking, the dosage should be below the safe dose.
本发明的有益效果是:The beneficial effects of the present invention are:
本发明扩展了Febuxostat及其衍生物的应用。使用Febuxostat及其衍生物治疗SAICAR、SAICAr或S-Ado等有毒中间代谢产物累积相关疾病或可因SAICAR、SAICAr或S-Ado等有毒中间代谢产物累积量的减少而减轻或改善的疾病具有较好的效果。The invention extends the application of Febuxostat and its derivatives. It is better to use Febuxostat and its derivatives to treat diseases related to the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr or S-Ado or diseases that can be alleviated or improved by the reduction of the accumulated amount of toxic intermediate metabolites such as SAICAR, SAICAr or S-Ado Effect.
发明人通过自有软件分析,发现Febuxostat可以有效减少SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积,进而对SAICAR、SAICAr、S-Ado等有毒中间代谢产物累积造成的相关病症具有一定的缓解或治疗作用。The inventors found through their own software that Febuxostat can effectively reduce the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc., and have certain effects on the related diseases caused by the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc. Relief or therapeutic effect.
Febuxostat及其衍生物尤其包括US5,614,520权利要求中所限定化合物。Febuxostat and its derivatives especially include the compounds defined in the claims of US 5,614,520.
初步的实验数据:Preliminary experimental data:
在培养的乳腺癌细胞MD231中加入Febuxostat,发现SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积量显著下降抗癌效果显著。When Febuxostat was added to the cultured breast cancer cells MD231, it was found that the cumulative amount of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc. decreased significantly and the anticancer effect was significant.
在培养的肺癌细胞H1299中加入Febuxostat,SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积量显著下降,抗癌效果显著。When Febuxostat is added to the cultured lung cancer cell H1299, the cumulative amount of toxic intermediate metabolites such as SAICAR, SAICAr, and S-Ado is significantly reduced, and the anticancer effect is significant.
Febuxostat处理后,可以使ADSL基因缺陷线虫动物模型的表型恢复正常。After Febuxostat treatment, the phenotype of the ADSL gene-deficient nematode animal model can be restored to normal.
ADSL缺陷转基因小鼠在给予Febuxostat后,实验证明SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积量显著下降。After administration of Febuxostat in ADSL-deficient transgenic mice, experiments showed that the cumulative amount of toxic intermediate metabolites such as SAICAR, SAICAr, and S-Ado decreased significantly.
初步的细胞生物学实验和动物实验证明Febuxostat可以有效减少SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积,进而对SAICAR、SAICAr、S-Ado等有毒中间代谢产物累积造成的相关病症具有一定的缓解或治疗作用。Preliminary cell biology experiments and animal experiments prove that Febuxostat can effectively reduce the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc., and have certain effects on the related diseases caused by the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc. Relief or treatment.
Claims (15)
- Febuxostat及其衍生物在制备治疗、改善或预防疾病药物中的应用,其特征在于:The application of Febuxostat and its derivatives in the preparation of drugs for treatment, improvement or prevention of diseases is characterized by:所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or所述疾病可因SAICAR累积量的减少而减轻或改善。The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
- 根据权利要求1所述的应用,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;The use according to claim 1, characterized in that the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- 根据权利要求2所述的应用,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。The use according to claim 2, characterized in that the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, polymorphic colloid Cell tumor, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- 根据权利要求2或3所述的应用,其特征在于:所述疾病为肿瘤,所述药物还包括至少一种对肿瘤有治疗作用的化合物和/或试剂。The use according to claim 2 or 3, characterized in that the disease is a tumor, and the medicine further comprises at least one compound and/or agent having a therapeutic effect on the tumor.
- 用于治疗、改善或预防疾病的Febuxostat及其衍生物,其特征在于:Febuxostat and its derivatives for the treatment, improvement or prevention of diseases are characterized by:所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or所述疾病可因SAICAR累积量的减少而减轻或改善。The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
- 根据权利要求5所述的Febuxostat及其衍生物,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;The Febuxostat and its derivatives according to claim 5, characterized in that: the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- 根据权利要求6所述的Febuxostat及其衍生物,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。The Febuxostat and its derivatives according to claim 6, characterized in that the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, bile duct cancer, esophageal cancer, multiple Glioblastoma, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- 一种治疗、改善或预防疾病的组合物,其特征在于:组合物的活性成分包括Febuxostat或其衍生物中的至少一种;A composition for treating, ameliorating or preventing diseases, characterized in that the active ingredient of the composition includes at least one of Febuxostat or its derivatives;所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or所述疾病可因SAICAR累积量的减少而减轻或改善。The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR.
- 根据权利要求8所述的组合物,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;The composition according to claim 8, characterized in that the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- 根据权利要求9所述的组合物,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。The composition according to claim 9, characterized in that the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, and multi-forming gel Squamous cell tumor, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- 根据权利要求8~10所述的组合物,其特征在于:所述疾病为肿瘤,所述药物还包括至少一种对肿瘤有治疗作用的化合物和/或试剂。The composition according to claims 8 to 10, wherein the disease is a tumor, and the drug further includes at least one compound and/or agent having a therapeutic effect on the tumor.
- 一种治疗、改善或预防疾病的方法,包括给予病人治疗量或预防量的Febuxostat或其衍生物中的至少一种,其特征在于:A method for treating, ameliorating or preventing diseases, which comprises administering to a patient a therapeutic amount or a preventive amount of Febuxostat or at least one of its derivatives, characterized by:所述疾病与SAICAR累积相关;或The disease is associated with SAICAR accumulation; or所述疾病可因SAICAR累积量的减少而减轻或改善;The disease can be alleviated or improved due to the decrease in the cumulative amount of SAICAR;进一步的,给药方式包括口服、注射、透皮吸收、呼吸道吸入。Further, the administration method includes oral administration, injection, transdermal absorption, and respiratory inhalation.
- 根据权利要求12所述的方法,其特征在于:所述疾病选自的肿瘤或腺苷酸琥珀酸裂解酶缺陷症;进一步的,所述疾病与SAICAR累积相关;The method according to claim 12, characterized in that the disease is selected from a tumor or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;所述肿瘤具有如下任一种特性:The tumor has any of the following characteristics:SAICAR量高于正常水平、存在SAICAR、SAICAr或S-Ado过度累积;The amount of SAICAR is higher than normal, and there is excessive accumulation of SAICAR, SAICAr or S-Ado;沃伯格效应、癌基因myc高表达、PAICS高表达、与Erk1/2相关和PKM2基因高表达。Warburg effect, high expression of oncogene myc, high expression of PAICS, correlation with Erk1/2 and high expression of PKM2 gene.
- 根据权利要求13所述的方法,其特征在于:所述肿瘤包括肺癌、乳腺癌、结肠癌、直肠癌、前列腺癌、膀胱癌、宫颈癌、肝癌、胆管癌、食道癌、多形成性胶质细胞瘤、头颈鳞状细胞癌、胰腺癌、胃癌、子宫内膜癌、白血病。The method according to claim 13, wherein the tumors include lung cancer, breast cancer, colon cancer, rectal cancer, prostate cancer, bladder cancer, cervical cancer, liver cancer, cholangiocarcinoma, esophageal cancer, and polymorphic glial Cell tumor, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
- 根据权利要求12~14所述的方法,其特征在于:所述疾病为肿瘤,还包括给予至少一种对肿瘤有治疗作用的化合物和/或试剂。The method according to claims 12 to 14, characterized in that the disease is a tumor, further comprising administering at least one compound and/or agent having a therapeutic effect on the tumor.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811538957 | 2018-12-14 | ||
CN201811538957.6 | 2018-12-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020119784A1 true WO2020119784A1 (en) | 2020-06-18 |
Family
ID=71076724
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/125151 WO2020119784A1 (en) | 2018-12-14 | 2019-12-13 | New application of febuxostat and derivatives thereof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2020119784A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101505755A (en) * | 2006-06-22 | 2009-08-12 | 日本化学医药株式会社 | Agent for overcoming resistance to anti-cancer agent |
CN104981242A (en) * | 2012-10-23 | 2015-10-14 | 帝人制药株式会社 | Therapeutic or prophylactic agent for tumor lysis syndrome |
-
2019
- 2019-12-13 WO PCT/CN2019/125151 patent/WO2020119784A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101505755A (en) * | 2006-06-22 | 2009-08-12 | 日本化学医药株式会社 | Agent for overcoming resistance to anti-cancer agent |
CN104981242A (en) * | 2012-10-23 | 2015-10-14 | 帝人制药株式会社 | Therapeutic or prophylactic agent for tumor lysis syndrome |
Non-Patent Citations (3)
Title |
---|
MASAAKI KONISH ET AL.: "Febuxostat improves outcome in a rat model of cancer cachexia", JOURNAL OF CACHEXIA, SARCOPENIA AND MUSCLE, vol. 6, 31 December 2015 (2015-12-31), XP055713599, DOI: 20200304232625A * |
洪士开 等 (HONG, SHIKAI ET AL.): "黄嘌呤氧化还原酶的表达与胃癌侵袭转移的关系 (Expression of Xanthine Oxidoreductase and Its Correlation with Tumor Invasion and Metastasis in Gastric Carcinoma)", 实用医学杂志 (THE JOURNAL OF PRACTICAL MEDICINE), vol. 27, no. 24, 31 December 2011 (2011-12-31), DOI: 20200304232218 * |
肖兵民 等 (XIAO, BINGMIN ET AL.): "非布司他治疗恶性肿瘤并发肾脏病合并高尿酸血症75例疗效观察 (Non-official translation: Observations on the efficacy of Febuxostat in the treatment of 75 cases of malignant tumor complicated with nephropathy and hyperuricemia)", 临床应用研究 (CLINICAL APPLICATION RESEARCH), vol. 25, 31 May 2018 (2018-05-31), DOI: 20200304232411A * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
BR112020001285A2 (en) | beta-hydroxybutyrate and butanediol s-enantiomers and methods for their use | |
Gomez et al. | Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B | |
JP2008505960A (en) | Multidrug cancer treatment | |
KR20010053252A (en) | A pharmaceutical combination comprising a cox-2 inhibitor and a inos inhibitor | |
US20120232142A1 (en) | Novel use of dimethylfumarate | |
TW201625243A (en) | Drug combination to treat melanoma | |
EP4279489A1 (en) | Application of pyrido[1,2-a]pyrimidinone analog | |
US20190105341A1 (en) | Compositions and Methods for Treating Alzheimer's Disease and Other Tauopathies | |
Wang | The efficacy of febuxostat and allopurinol in the treatment of gout with hyperuricemia. | |
WO2020119784A1 (en) | New application of febuxostat and derivatives thereof | |
KR101901001B1 (en) | A Pharmaceutical composition comprising PPAR-β inhibitor for enhancing Anti-cancer effect | |
CN110225767B (en) | Intracellular ATP enhancers | |
US12048711B2 (en) | Composition and use thereof in the manufacture of medicament for treating cancer | |
JP2020536890A (en) | Combination of MDM2 Inhibitors and ERK Inhibitors to Treat Cancer | |
US20190209569A1 (en) | Pharmaceutical composition for suppressing appetite, containing n2-(m-trifluorobenzyl), n6-(p-nitrobenzyl)purine (tnp) or pharmaceutically acceptable salt thereof as active ingredient | |
EP3964217A1 (en) | Use of compound or pharmaceutically acceptable salt, dimer or trimer thereof in preparation of drug for treating cancer | |
US20140343149A1 (en) | Method of inhibiting angiogenesis | |
WO2020125550A1 (en) | Use of compound in treating diseases related to saicar accumulation | |
UA126123U (en) | METHOD OF CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH NON-ALCOHOLIC STEATOGEPATITIS AND CHRONIC DISEASE DISEASE | |
RU2720134C1 (en) | Pharmaceutical composition for parenteral drop introduction | |
TWI672145B (en) | Use and pharmaceutical composition for metabolic disease prevention and/or treatment | |
WO2016139740A1 (en) | Hepatic fibrosis-ameliorating agent | |
UA126122U (en) | METHOD OF TREATMENT OF INSULIN RESISTANCE IN PATIENTS WITH TYPE 2 DIABETES WITH SUB-ALCOHOLIC STEATOGEPATITIS | |
US20040229805A1 (en) | Agents for producing the health-benefits of repeated exercise | |
Lou et al. | Targeting MTAP creates a therapeutic vulnerability to PARP inhibition in brain metastatic TNBC by disrupting MAT2A mediated methionine metabolism |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19897462 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 20.10.2021) |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19897462 Country of ref document: EP Kind code of ref document: A1 |