WO2020140730A1 - Utilisation de thioguanine dans la préparation d'un médicament pour traiter un déficit en adsl - Google Patents

Utilisation de thioguanine dans la préparation d'un médicament pour traiter un déficit en adsl Download PDF

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Publication number
WO2020140730A1
WO2020140730A1 PCT/CN2019/125153 CN2019125153W WO2020140730A1 WO 2020140730 A1 WO2020140730 A1 WO 2020140730A1 CN 2019125153 W CN2019125153 W CN 2019125153W WO 2020140730 A1 WO2020140730 A1 WO 2020140730A1
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WO
WIPO (PCT)
Prior art keywords
thioguanine
acid
pharmaceutically acceptable
treating
adsl deficiency
Prior art date
Application number
PCT/CN2019/125153
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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 WO2020140730A1 publication Critical patent/WO2020140730A1/fr

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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the new application of thioguanine, in particular to the application of thioguanine in the preparation of drugs for treating ADSL deficiency.
  • Purine anabolism is a ubiquitous and important biological metabolism in organisms. Its products AMP and GMP not only provide raw materials for the biosynthesis of DNA and RNA in the organism, but also provide many key coenzymes (NAD, NADP, FAD and CoA) ), signaling molecules (such as cAMP) and important energy molecules ATP provide the purine bases necessary for their synthesis. It can be seen that purine anabolism is at the core of the entire metabolic network. Purine synthesis includes de novo synthesis (synthesis) and salvage pathway (salvage).
  • Adenyl succinate lyase deficiency (adenylosuccinatelyasedeficiencyADSLdeficiency) is a metabolic disease that produces deletions and confusions in de novo adenine synthesis and purine nucleotide metabolism.
  • the cause of the disease is mainly due to the mutation or deletion of adenylate succinate lyase in the patient's body, resulting in the excessive accumulation of SAICAR, the substrate of the enzyme, in the cell and not being cleared in time [Jaeken J, Van Den Berghe G. (1984). An fantile aesthetical characterized by the presence of succinylpurines in body fluids. Lancet 8411:1058-1061.].
  • ADSL deficiency There are three consecutive main phenotypes of ADSL deficiency: neonatal lethal, severe (type I) and mild to moderate (type II). It is clinically found that even patients from the same family have different phenotypes. The onset is generally seen from birth to infancy. Reported cases include fatal neonatal brain lesions (expressing motor dysfunction, refractory epilepsy, and respiratory disorders), and moderate intellectual impairment. All patients have intellectual deficiencies, most of them have different types of epilepsy, and about 1/3 have autistic features (no eye contact, sensitivity to sound and light, repetitive behavior, restlessness, tantrums, self-injury and Self-mutilation). Other uncommon clinical manifestations include delayed mental movements, hyperactivity, language disorders, hypotonia, muscle atrophy and cramps. Severe patients usually have microcephaly. Prenatal clinical manifestations are reported: impaired intrauterine growth, microcephaly, fetal motor dysfunction, and loss of fetal heart rate.
  • DB00352 https://www.drugbank.ca/drugs/DB00352
  • Tioguanine structural formula: Chinese name: thioguanine.
  • the main uses of thioguanine are as follows:
  • Antitumor drugs It can relieve acute leukemia and chronic myeloid leukemia. Large doses have a good effect on choriocarcinoma.
  • Protein kinase activator It is a derivative of cycloadenosine, and its function and use are the same. It can also be used for myocarditis, cardiogenic shock, and submental hemorrhage after surgery. When the dosage is large, there may be drowsiness, dizziness, vertigo, fatigue, loss of appetite, nausea, vomiting, etc.
  • Antitumor drugs It is a kind of purine antimetabolite, which is a kind of DNA base. It can be incorporated into DNA molecules as a wrong base, thus affecting the synthesis and function of DNA. It mainly acts on S phase and is a cell cycle specific drug. For the treatment of various types of leukemia, acute leukemia is more commonly used.
  • 6-TG ribonucleotide By inhibiting guanylate kinase, the phosphorylation of guanosine monophosphate (GMP) to guanosine diphosphate (GDP) can be prevented. After being metabolized to deoxyribose triphosphate, this product can be incorporated into DNA, thus further inhibiting the biosynthesis of nucleic acid, mercaptopurine has no such effect.
  • GMP guanosine monophosphate
  • GDP guanosine diphosphate
  • this product After being metabolized to deoxyribose triphosphate, this product can be incorporated into DNA, thus further inhibiting the biosynthesis of nucleic acid, mercaptopurine has no such effect.
  • This product is effectively cross-resistance with mercaptopurine, and combined with cytarabine and other drugs can improve the efficacy.
  • the object of the present invention is to provide thioguanine in the preparation or treatment of ADSL deficiency medicine.
  • the first aspect of the present invention provides:
  • Thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites are used in the preparation of compositions for treating or improving ADSL deficiency.
  • the pharmaceutically acceptable derivative of thioguanine is one of pharmaceutically acceptable salts and lower amides of thioguanine.
  • the composition is a drug and also includes acceptable pharmaceutical excipients.
  • the second aspect of the present invention provides:
  • a compound for treating or improving ADSL deficiency is one of thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites.
  • the pharmaceutically acceptable derivative of thioguanine is one of pharmaceutically acceptable salts and lower amides of thioguanine.
  • compositions for treating or improving ADSL deficiency include one of thioguanine and its pharmaceutically acceptable derivatives, prodrugs, and active metabolites.
  • the pharmaceutically acceptable derivative of thioguanine is one of pharmaceutically acceptable salts and lower amides of thioguanine.
  • a method for treating or ameliorating ADSL deficiency includes the steps of: giving a therapeutic amount or an improved amount of thioguanine and its pharmaceutically acceptable derivatives, prodrugs, and active metabolites to patients with ADSL deficiency.
  • administration methods include oral, inhalation, injection, transdermal absorption, or inhalation through the respiratory tract, etc., which are well known to those skilled in the art.
  • the inventors calculated and analyzed through their own software, and confirmed through cell biology experiments and ADSL deficiency animal model experimental studies that thioguanine has a significant ADSL deficiency treatment effect.
  • 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 carbon atoms, preferably 2 to 6, 2 to 4 carbon atoms The derivative obtained.
  • Compound pharmaceutically acceptable pharmaceutically acceptable salts 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 inventors calculated and analyzed through their own software, and confirmed through cell biology experiments and ADSL deficiency animal model experimental studies that thioguanine has a significant ADSL deficiency treatment effect.
  • the phenotype of the ADSL gene-deficient nematode animal model can be restored to normal.
  • thioguanine pharmaceutically acceptable derivatives, prodrugs and active metabolites also have the therapeutic effect of ADSL deficiency.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)

Abstract

L'invention concerne une utilisation de thioguanine dans la préparation d'un médicament pour le traitement d'un déficit en ADSL. Au moyen du calcul et de l'analyse utilisant notre propre logiciel, et par la recherche impliquant des expériences sur la biologie cellulaire et des expériences sur un modèle animal de déficit en ADSL, il est confirmé que la thioguanine a pour effet de traiter un déficit en ADSL.
PCT/CN2019/125153 2018-12-30 2019-12-13 Utilisation de thioguanine dans la préparation d'un médicament pour traiter un déficit en adsl WO2020140730A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811645136.2 2018-12-30
CN201811645136 2018-12-30

Publications (1)

Publication Number Publication Date
WO2020140730A1 true WO2020140730A1 (fr) 2020-07-09

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1286632A (zh) * 1997-09-02 2001-03-07 儿童医疗中心有限公司 嘌呤核苷用于调节中枢神经系统神经元的轴突突出生长
CN1690058A (zh) * 2004-04-19 2005-11-02 蔡文革 一种制备硫鸟嘌呤的方法
WO2009108633A2 (fr) * 2008-02-25 2009-09-03 Expression Drug Designs, Llc. Antagonisme de la sphingosine 1-phosphate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1286632A (zh) * 1997-09-02 2001-03-07 儿童医疗中心有限公司 嘌呤核苷用于调节中枢神经系统神经元的轴突突出生长
CN1690058A (zh) * 2004-04-19 2005-11-02 蔡文革 一种制备硫鸟嘌呤的方法
WO2009108633A2 (fr) * 2008-02-25 2009-09-03 Expression Drug Designs, Llc. Antagonisme de la sphingosine 1-phosphate

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JIAN ZHANG ET AL: "Characterizing and optimizing human anticancer drug targets based on topological properties in the context of biological pathways.", JOURNAL OF BIOMEDICAL INFORMATICS, vol. 54, 30 April 2015 (2015-04-30), pages 132 - 140, XP055716470, ISSN: 1532-0464, DOI: 10.1016/j.jbi.2015.02.007 *
MR ATKINSON; RK MORTON; AW MURRAY: "Inhibition of adenylosuccinate synthetase and adenylosuccinate lyase from Ehrlich ascites-tumour cells by 6-thioinosine 5′-phosphate", BIOCHEMICAL JOURNAL, vol. 92, no. 2, 31 August 1964 (1964-08-31), pages 398 - 404, XP009521838, ISSN: 0264-6021, DOI: 10.1042/bj0920398 *
WANG, YE ET AL: "Research Progress of Adenylosuccinate Lyase Gene", CHINA POULTRY, vol. 33, no. 16, 31 August 2011 (2011-08-31), CN, pages 47 - 49, XP009521814, ISSN: 1004-6364 *
WILLIAM A BRIDGER ET AL: "The mechanism of inhibition of adenylosuccinate lyase by 6-mercaptopurine nucleotide", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 73, no. 3, 9 July 1963 (1963-07-09), pages 514 - 516, XP023562154, ISSN: 0926-6569, DOI: 10.1016/0926-6569(63)90143-3 *

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