WO2020119784A1

WO2020119784A1 - New application of febuxostat and derivatives thereof

Info

Publication number: WO2020119784A1
Application number: PCT/CN2019/125151
Authority: WO
Inventors: 朱威; 潘武广
Original assignee: 广州君赫生物科技有限公司
Priority date: 2018-12-14
Filing date: 2019-12-13
Publication date: 2020-06-18

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

New applications of Febuxostat and its derivatives

Technical field

The present invention relates to new applications of compounds, in particular to Febuxostat and its derivatives.

Background technique

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.

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) 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.

Summary of the invention

The object of the present invention is to provide new applications of Febuxostat and its derivatives.

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.

The technical solutions adopted by the present invention are:

The first aspect of the present invention provides:

The application of Febuxostat and its derivatives in the preparation of drugs for treatment, improvement or prevention of diseases,

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.

In some examples of application, the disease is selected from tumor or adenylate succinate lyase deficiency; further, the disease is related to SAICAR accumulation;

The tumor has any of the following characteristics:

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.

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.

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.

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.

The second aspect of the present invention provides:

Febuxostat and its derivatives for the treatment, improvement or prevention of diseases,

The disease is associated with SAICAR accumulation; or

In some examples, the disease is selected from tumors or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;

The tumor has any of the following characteristics:

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.

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.

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 tumor has any of the following characteristics:

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.

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;

Further, the administration method includes oral administration, injection, transdermal absorption, and respiratory inhalation.

The tumor has any of the following characteristics:

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 beneficial effects of the present invention are:

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.

detailed description

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 and its derivatives especially include the compounds defined in the claims of US 5,614,520.

Preliminary experimental data:

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.

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.

After Febuxostat treatment, the phenotype of the ADSL gene-deficient nematode animal model can be restored to normal.

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.

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

The application of Febuxostat and its derivatives in the preparation of drugs for treatment, improvement or prevention of diseases is characterized by:

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 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;

The tumor has any of the following characteristics:

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 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.
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.
Febuxostat and its derivatives for the treatment, improvement or prevention of diseases are characterized by:

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 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;

The tumor has any of the following characteristics:

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 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.
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;

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 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;

The tumor has any of the following characteristics:

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 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.
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.
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:

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;

Further, the administration method includes oral administration, injection, transdermal absorption, and respiratory inhalation.
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;

The tumor has any of the following characteristics:

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 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.
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.