WO2020125550A1 - Utilisation d'un composé dans le traitement de maladies liées à l'accumulation de saicar - Google Patents

Utilisation d'un composé dans le traitement de maladies liées à l'accumulation de saicar Download PDF

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Publication number
WO2020125550A1
WO2020125550A1 PCT/CN2019/125152 CN2019125152W WO2020125550A1 WO 2020125550 A1 WO2020125550 A1 WO 2020125550A1 CN 2019125152 W CN2019125152 W CN 2019125152W WO 2020125550 A1 WO2020125550 A1 WO 2020125550A1
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WO
WIPO (PCT)
Prior art keywords
cancer
saicar
disease
tumor
accumulation
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PCT/CN2019/125152
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English (en)
Chinese (zh)
Inventor
朱威
潘武广
Original Assignee
广州君赫生物科技有限公司
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Publication of WO2020125550A1 publication Critical patent/WO2020125550A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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 invention relates to new applications of compounds, in particular to new applications of compounds.
  • 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 have 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 pyruvate kinase isoform M2 and promote cancer cell survival under glucose-limited 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 oncogene myc, which is due to the de novo anabolic anabolism
  • the abnormally accumulated SAICAR in the pathway promotes the proliferation and survival of tumor cells.
  • DB00746 https://www.drugbank.ca/drugs/DB00746), common name: Deferoxamine, structural formula: Chinese alias: deironing or deferoxamine. Deferoxamine, especially its methanesulfonate, can chelate and promote the excretion of ions through the urine by combining free iron or aluminum chelation in the blood, remove excess iron or aluminum, and reduce iron or aluminum to various organs and tissues (such as liver) damage. US5374771A discloses its synthesis method.
  • Amlodipine is a long-acting 1,4-dihydropyridine calcium channel blocker. It mainly acts on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in its inactive conformation. By inhibiting calcium influx in smooth muscle cells, amlodipine prevents calcium-dependent muscle cell contraction and vasoconstriction. The second proposed mechanism of drug vasodilation involves pH-dependent inhibition of calcium influx by inhibiting smooth muscle carbonic anhydrase. Some studies have shown that amlodipine also inhibits voltage-gated N-type calcium channels. N-type calcium channels located in the central nervous system may be involved in nociceptive signaling and pain. Amlodipine is used to treat hypertension and chronic stable angina.
  • Eniluracil is an oral active dihydropyrimidine dehydrogenase (DPD) inhibitor designed to enhance the activity of chemokines. It is generally used in combination with 5-fluorouracil (5-FU) to treat cancer.
  • DPD dihydropyrimidine dehydrogenase
  • Chlorphenesin is a muscle relaxant. It blocks the nerve impulse (or pain sensation) sent to the brain.
  • the object of the present invention is to provide new applications of compounds.
  • DB00746, DB00381, DB03516, DB00856 and their pharmaceutically acceptable derivatives can effectively reduce the accumulation of toxic intermediate metabolites R such as SAICA, SAICAr, S-Ado, etc.
  • Related diseases caused by the accumulation of toxic intermediate metabolites such as S-Ado have certain relief or treatment effects.
  • Preliminary experimental data confirms that the inventor's analysis is valid.
  • the first aspect of the present invention provides:
  • a compound in the preparation of a medicament for the treatment, improvement or prevention of diseases is DB00746, DB00381, DB03516, DB00856 and pharmaceutically acceptable derivatives thereof;
  • 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 associated with SAICAR accumulation;
  • the amount of SAICAR is higher than normal, 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, polymorphic glioblastoma, head and neck squamous Cell cancer, pancreatic cancer, gastric cancer, endometrial cancer, leukemia.
  • the tumor has a SAICAR amount 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, leukemia.
  • SAICAR SAICAR amount 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, leukemia.
  • the disease is a tumor
  • the drug further includes at least one compound and/or agent having a therapeutic effect on the tumor.
  • the second aspect of the present invention provides:
  • Compounds for the treatment, improvement or prevention of diseases are DB00746, DB00381, DB03516, DB00856 and their pharmaceutically acceptable 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 a tumor or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
  • the amount of SAICAR is higher than normal, 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 ingredients of the composition include at least one of DB00746, DB00381, DB03516, DB00856 and pharmaceutically acceptable derivatives thereof;
  • 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 a tumor or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
  • the amount of SAICAR is higher than normal, 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
  • the drug further includes at least one compound and/or agent having 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 or preventive amount of at least one of DB00746, DB00381, DB03516, DB00856, and pharmaceutically acceptable derivatives thereof,
  • 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 a tumor or adenylate succinate lyase deficiency; further, the disease is associated with SAICAR accumulation;
  • the amount of SAICAR is higher than normal, 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
  • the drug further includes at least one compound and/or agent having a therapeutic effect on the tumor.
  • compositions are well known to those skilled in the art and include, but are not limited to, pharmaceutically acceptable salts, esters, amides, simple modifications, and the like of the compound.
  • Compound pharmaceutically acceptable derivatives especially one of pharmaceutically acceptable salts and lower amides, that is, condensation of carboxylic acids, alcohols, amines with the parent compound having 1 to 6, preferably 2 to 6, 2 to 4 carbon atoms The derivative obtained.
  • the pharmaceutically acceptable pharmaceutical salts of the compound can be synthesized from the parent compound by conventional chemical methods, such as in Pharmaceuticals: Properties: Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: The method described in 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • these salts can be prepared by reacting the free base and acid of the compound in water or an organic solvent or a mixture of the two; usually, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used .
  • Acid addition salts can be prepared from various acids (inorganic and organic acids).
  • acid addition salts include salts made from acids selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (such as L-ascorbic acid), L-aspartic acid , Benzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, hexanoic acid, Caprylic acid, cinnamic acid, citric acid, cyclic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, fumaric acid, galactose Acid, gentisic acid, glucohe
  • the compounds and/or agents with therapeutic effects on tumors are known compounds and agents 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. In general, the dosage should be below the safe dose.
  • the invention extends the application of compounds.
  • the reduction and reduction or improvement of the disease has a better effect.
  • DB00746, DB00381, DB03516, DB00856 and their pharmaceutically acceptable derivatives can effectively reduce the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc., and then on SAICAR, SAICAr, S -Related diseases caused by the accumulation of toxic intermediate metabolites such as Ado have a certain relief or treatment effect.
  • DB00746, DB00381, DB03516 or DB00856 can effectively reduce the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc., and further accumulate toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc.
  • the related diseases caused have certain relief or treatment effect.
  • DB00746, DB00381, DB03516, DB00856 and their pharmaceutically acceptable derivatives can be used to treat tumors and adenylate succinate lyase deficiency caused by the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc.

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  • 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)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés DB00746, DB00381, DB03516 et DB00856 et une composition les contenant, et l'utilisation des composés ci-dessus dans le traitement, l'amélioration ou la prévention d'une maladie liée à l'accumulation de SAICAR, la maladie étant choisie parmi une tumeur ou un déficit en adénylosuccinate lyase.
PCT/CN2019/125152 2018-12-19 2019-12-13 Utilisation d'un composé dans le traitement de maladies liées à l'accumulation de saicar WO2020125550A1 (fr)

Applications Claiming Priority (2)

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CN201811556701 2018-12-19
CN201811556701.8 2018-12-19

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WO2020125550A1 true WO2020125550A1 (fr) 2020-06-25

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101068549A (zh) * 2004-12-03 2007-11-07 阿迪赫里克斯技术公司 与5－fu和5－fu前药组合施用dpd抑制剂的方法
WO2018147612A1 (fr) * 2017-02-07 2018-08-16 주식회사 온코크로스 Composition destinée à inhiber la métastase cancéreuse et à traiter le cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101068549A (zh) * 2004-12-03 2007-11-07 阿迪赫里克斯技术公司 与5－fu和5－fu前药组合施用dpd抑制剂的方法
WO2018147612A1 (fr) * 2017-02-07 2018-08-16 주식회사 온코크로스 Composition destinée à inhiber la métastase cancéreuse et à traiter le cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
张旭 等 (ZHANG, XU ET AL.): "氨氯地平对小鼠黑色素细胞瘤B16 细胞自发性肺转移的抑制作用及其机制 (Inhibitory Effect of Amlodipine on Spontaneous Pulmonary Metastasis of Murine Melanoma B16 Cells and Relevant Mechanism)", 中国生物制品学杂志 (CHINESE JOURNAL OF BIOLOGICALS), vol. 24, no. 3, 31 March 2011 (2011-03-31), DOI: 20200224155145X *
贾国存 等 (JIA, GUOCUN ET AL.): "铁剥夺对白血病细胞凋亡相关基因表达的影响 (Effect of Iron Chelator on Related Genes Expression of Apoptosis in K562 Cells)", 实用儿科临床杂志 (JOURNAL OF APPLIED CLINICAL PEDIATRICS), vol. 20, no. 1, 31 January 2005 (2005-01-31), DOI: 20200224155239X *

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