WO2022095809A1 - Nouvelle application de composés influençant l'expression de saicar - Google Patents

Nouvelle application de composés influençant l'expression de saicar Download PDF

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Publication number
WO2022095809A1
WO2022095809A1 PCT/CN2021/127820 CN2021127820W WO2022095809A1 WO 2022095809 A1 WO2022095809 A1 WO 2022095809A1 CN 2021127820 W CN2021127820 W CN 2021127820W WO 2022095809 A1 WO2022095809 A1 WO 2022095809A1
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WIPO (PCT)
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cancer
acid
compound
pyrroloquinoline quinone
treating
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PCT/CN2021/127820
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English (en)
Chinese (zh)
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潘武广
朱威
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广州君赫生物科技有限公司
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Publication of WO2022095809A1 publication Critical patent/WO2022095809A1/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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to new applications of compounds, in particular to new applications of compounds that affect the expression of SAICAR.
  • 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 organisms, but also provide many key coenzymes (NAD, NADP, FAD and CoA) in vivo. ), signaling molecules such as cAMP, and the important energy molecule 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 including de novo synthesis (de novo purine synthesis) and salvage pathway pathway) two synthetic pathways.
  • Adenylosuccinate lyase deficiency is a metabolic disorder in which de novo adenine synthesis and purine nucleotide metabolism pathways are produced.
  • the cause of the disease is mainly due to the mutation or deletion of adenylate succinate lyase in the patient, which leads to the excessive accumulation of SAICAR, the substrate of this enzyme in the cells, which cannot be cleared in time [Jaeken J, Van den] Berghe G. (1984).
  • An infantile autistic syndrome characterized by the presence of succinylprines in body fluids. Lancet 8411: 1058-1061.].
  • ADSL deficiency There are three consecutive major 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. Onset is generally seen from birth to infancy. Cases have been reported with fatal neonatal encephalopathy (manifesting hypokinesia, intractable epilepsy, respiratory disturbances), and moderate intellectual disability. All patients had intellectual deficits, most had various types of epilepsy, and about one-third had autistic features (inability to make eye contact, sensitivity to light and sound, repetitive behavior, restlessness, tantrums, self-injury and self-harm).
  • Other less common clinical manifestations include psychomotor delay, hyperactivity, language impairment, hypotonia, muscle atrophy, and spasticity. Severe patients usually have microcephaly. Antenatal clinical manifestations have been reported as impaired intrauterine growth, microcephaly, fetal hypokinesia, and absent fetal heart rate variability.
  • ADSL enzyme adenylate succinate lyase
  • Gitiaux, C. Ceballos-Picot, I., Marie, S., Valayannopoulos, V., Rio, M., Verrieres, S., Benoist, J.F., Vincent, M.F., Desguerre, I., and Bahi-Buisson, N. (2009). Misleading behavioural phenotype with adenylosuccinate lyase deficiency.
  • Mierzewska, H., Schmidt-Sidor, B. Jurkiewicz, E., Bogdanska, A., Kusmierska, K., and Stepien, T. (2009).
  • SAICAr is the dephosphorylation product of SAICAR
  • S-Ado is the dephosphorylation product of S-AMP
  • Aminoimidazolyl succinylcarbamoyl nucleotide synthase/aminoimidazole nucleotide carboxylase or PAICS (phosphoribosylaminoimidazole succinocarboxamide synthetase /phosphoribosylaminoimidazole carboxylase) is an important bifunctional enzyme in the de novo purine synthesis pathway, it has SAICAR synthase (4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase, SAICARs) and AIR carboxylase (5-aminoimidazole)
  • SAICAR synthase 4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase
  • AIR carboxylase 5-aminoimidazole
  • Pyruvate kinase isoenzyme 2 isoform M2, PKM2 Pyruvate kinase isoenzyme 2 isoform M2, PKM2
  • PKM2 Pyruvate kinase isoenzyme 2 isoform M2, PKM2
  • various pharmacological agents targeting the enzymatic activity of PKM2 affect cell growth and proliferation, which also suggests that by targeting the enzymatic activity of PKM2, further changing the way of tumor metabolism has become a new way of tumor therapy.
  • LNS Lesch-Nyhan Syndrome
  • HGPRT purine phosphoroglycosidase
  • LNS A disorder that occurs almost exclusively in men, LNS is characterized by neurological and behavioral abnormalities and an overproduction of uric acid.
  • Uric acid is a waste product of normal chemical processes and is found in blood and urine. Excess uric acid is released from the bloodstream and builds up under the skin, leading to gouty arthritis (arthritis caused by the accumulation of uric acid in the joints). The accumulation of uric acid can also cause kidney and bladder stones.
  • Nervous system and behavioral disorders of the LNS include abnormal voluntary muscle movements such as tension of various muscles (dystonia), twitching (choreography), and wiggling of the limbs (dystonia). People with LNS are often unable to walk, need help sitting, and often use a wheelchair. Self-harm (including biting and head impact) is the most common and significant behavioral problem in LNS patients.
  • WO1994017183A1 discloses the use of cHPRT to treat LNS.
  • US4575498A discloses the use of 5-amino-4-imidazolecarboxamide nucleotides riboside), 5-amino-4-imidazolecarboxamide (5-amino-4-imidazolecarboxamide), and their pharmaceutically acceptable salts, for the treatment of LNS by increasing the replenishment rate of the purine nucleotide pool in deficient tissues.
  • US20130116215A1 discloses that the combination of at least two compounds is used for the treatment of neurological diseases, and it is generally mentioned that it can be used for the treatment of LNS, but there is no solid data to prove its efficacy.
  • RA Rheumatoid arthritis
  • SARS-CoV-2 spreads rapidly in many parts of the world after the outbreak, and COVID-19 caused by SARS-CoV-2 infection shows a trend of global spread. It poses a huge threat to global public health security, causing huge Economic losses.
  • the first aspect of the present invention provides: the use of a compound in the preparation of a composition for treating or improving rheumatoid arthritis, the compound is selected from: pyrroloquinoline quinone PQQ, MK2206 (CAS registration number: 1032349-93-1), Niclosamide, spermine, spermidine, Benserazide, mercaptopurine, azathioprine, DB00746 (Deferoxamine), DB00381 (Amlodipine), DB03516 (Eniluracil), DB00856 (Chlorphenesin), Febuxostat, Oxypurinol, Allopurinol, Thioguanine or Disulfiram and acceptable salts thereof.
  • the composition is oral or injectable.
  • the oral agent is selected from tablets, capsules, solid beverages, functional foods.
  • the salt of the compound is an acid or base addition salt of the compound selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg, 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, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclonic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, formic acid, Fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic
  • the second aspect of the present invention provides: the use of a compound in the preparation of a composition for treating or improving ADSL deficiency or Raney syndrome, the compound is selected from: pyrroloquinoline quinone PQQ, MK2206, niclosamide and its derivatives Accepted salt.
  • the composition is oral or injectable.
  • the oral agent is selected from tablets, capsules, solid beverages, functional foods.
  • the third aspect of the present invention provides: the use of a compound in the preparation of a composition for treating or improving tumors, the compound is selected from: pyrroloquinoline quinone PQQ, MK2206, niclosamide and acceptable salts thereof, the tumor There is at least one indication of excessive accumulation of SAICAR, excessive accumulation of SAICAr, abnormally high expression of PAICS gene, abnormally low expression of ADSL gene, or loss or decline of function.
  • tumors with different indications generally respond differently to drugs. By determining the specific characteristics of the tumor and targeting the drug, better outcomes can generally be achieved.
  • the tumor is selected from acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, colorectal cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma, cervical cancer, nasopharyngeal cancer cancer, breast cancer, skin cancer, bladder cancer.
  • the composition is oral or injectable.
  • the oral agent is selected from tablets, capsules, solid beverages, functional foods.
  • the fourth aspect of the present invention provides: the use of pyrroloquinoline quinone PQQ and its salts in the preparation of compositions for preventing, improving or treating COVID-19.
  • the composition is oral or injectable.
  • the oral agent is selected from tablets, capsules, solid beverages, functional foods.
  • a fifth aspect of the present invention provides:
  • a method of treating or ameliorating rheumatoid arthritis comprising administering a sufficient amount of a compound selected from the group consisting of: pyrroloquinoline quinone PQQ, MK2206, niclosamide, spermine, spermidine, Benserazide, mercaptopurine, At least one of azathioprine, DB00746, DB00381, DB03516, DB00856, Febuxostat, oxypurinol, allopurinol, thioguanine or disulfiram and pharmaceutically acceptable salts thereof.
  • a compound selected from the group consisting of: pyrroloquinoline quinone PQQ, MK2206, niclosamide, spermine, spermidine, Benserazide, mercaptopurine, At least one of azathioprine, DB00746, DB00381, DB03516, DB00856, Febuxostat, oxypurinol, all
  • the sixth aspect of the present invention provides: a method for treating or improving ADSL deficiency or Raney syndrome, comprising administering a sufficient amount of a compound selected from the group consisting of: pyrroloquinoline quinone PQQ, MK2206, niclosamide and at least one of its pharmaceutically acceptable salts.
  • the seventh aspect of the present invention provides: a method for treating or ameliorating tumors, comprising administering a sufficient amount of a compound selected from the group consisting of: pyrroloquinoline quinone PQQ, MK2206, niclosamide and acceptable salts thereof,
  • the tumor has at least one indication of excessive accumulation of SAICAR, excessive accumulation of SAICAr, abnormally high expression of PAICS gene, abnormally low expression of ADSL gene, or loss or decline of function.
  • the tumor is selected from acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, colorectal cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma, cervical cancer, nasopharyngeal cancer cancer, breast cancer, skin cancer, bladder cancer.
  • the eighth aspect of the present invention provides: a method for preventing, improving or treating COVID-19, comprising administering to a human at least one of pyrroloquinoline quinone PQQ and its salts in a preventive, ameliorating or therapeutic amount.
  • the mode of administration is oral or injection.
  • Pyrroloquinoline quinone PQQ, MK2206, niclosamide can treat or improve ADSL deficiency or Raney syndrome.
  • Pyrroloquinoline quinone PQQ, MK2206, and niclosamide can treat or improve tumors with at least one indication of SAICAR, excessive accumulation of SAICAr, abnormally high expression of PAICS gene, abnormally low expression of ADSL gene, or loss of function or decline. Targeted treatment of tumors.
  • Pyrroloquinoline quinone PQQ can prevent, improve or treat COVID-19.
  • salts of compounds can be synthesized from the parent compound by conventional chemical methods, as described in Pharmaceutical Salts: 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 of the compound with an acid in water or an organic solvent or a mixture of the two; usually, using a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile .
  • Acid addition salts can be prepared from a variety of acids (inorganic and organic).
  • acid addition salts include salts made from acids selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg L-ascorbic acid), L-aspartic acid , benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, Caprylic acid, cinnamic acid, citric acid, cyclonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-isethionic acid, formic acid, fumaric acid, galactose acid, gentisic acid, glucoheptonic acid, D
  • Table 4 Summary data for treating or ameliorating tumors with at least one indication of SAICAR, SAICAr excess accumulation, abnormally high expression of PAICS gene, abnormally low expression of ADSL gene, or loss or decline of function:
  • the inventors confirmed through computational studies and preliminary experimental studies on relevant disease models:
  • Pyrroloquinoline quinone PQQ, MK2206, niclosamide can treat or improve ADSL deficiency or Raney syndrome.
  • Pyrroloquinoline quinone PQQ, MK2206, and niclosamide can treat or improve tumors with at least one indication of excess accumulation of SAICAR, excess accumulation of SAICAr, abnormally high expression of PAICS gene, abnormally low expression of ADSL gene, or loss of function or decline. More targeted treatment of tumors.
  • Pyrroloquinoline quinone PQQ can prevent, improve or treat COVID-19.

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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)
  • Organic Chemistry (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Il a été démontré au moyen d'une recherche d'analyse computationnelle que le SAICAR a une certaine association avec de multiples maladies, et par l'intermédiaire d'une autre recherche d'analyse computationnelle et d'une recherche expérimentale de modèle de maladie associée préliminaire, il a été vérifié que : la pyrroloquinoléine quinone PQQ, le MK2206, le niclosamide, la spermine, la spermadine, le bensérazide, la mercaptopurine, l'azathioprine, la DB00746, la DB00381, la DB03516, la DB00856, le fébuxostat, l'oxipurinol, l'allopurinol, la tioguanine, ou le disulfirame, peuvent traiter ou soulager l'AR, la déficience en ADSL, le syndrome de Lesch-Nyhan, ou une tumeur ayant une indication spécifique.
PCT/CN2021/127820 2020-11-03 2021-11-01 Nouvelle application de composés influençant l'expression de saicar WO2022095809A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001142A1 (fr) * 1992-07-06 1994-01-20 The Children's Medical Center Corporation Compositions et methodes therapeutiques a base de 2,7,9-tricarboxy-pyrroloquinoleine (pqq)
WO1996001635A1 (fr) * 1994-07-12 1996-01-25 The Children's Medical Center Corporation Limitation de la resorption osseuse par la pyrroloquinoline quinone (pqq) et composes concernes
CN107106554A (zh) * 2014-09-22 2017-08-29 国立大学法人名古屋大学 新型寿命延长剂、使用该寿命延长剂的寿命延长方法、新型双氧化酶活化剂、双氧化酶活化剂的活化方法、寿命延长剂的制造、以及双氧化酶活化剂的制造
CN107281192A (zh) * 2016-03-31 2017-10-24 三菱瓦斯化学株式会社 一种减轻、治疗及预防类风湿性关节炎的组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001142A1 (fr) * 1992-07-06 1994-01-20 The Children's Medical Center Corporation Compositions et methodes therapeutiques a base de 2,7,9-tricarboxy-pyrroloquinoleine (pqq)
WO1996001635A1 (fr) * 1994-07-12 1996-01-25 The Children's Medical Center Corporation Limitation de la resorption osseuse par la pyrroloquinoline quinone (pqq) et composes concernes
CN107106554A (zh) * 2014-09-22 2017-08-29 国立大学法人名古屋大学 新型寿命延长剂、使用该寿命延长剂的寿命延长方法、新型双氧化酶活化剂、双氧化酶活化剂的活化方法、寿命延长剂的制造、以及双氧化酶活化剂的制造
CN107281192A (zh) * 2016-03-31 2017-10-24 三菱瓦斯化学株式会社 一种减轻、治疗及预防类风湿性关节炎的组合物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIU ZHONGBING; SUN CHI; TAO RAN; XU XINBAO; XU LIBIN; CHENG HONGBING; WANG YOUHUA; ZHANG DONGMEI: "Pyrroloquinoline Quinone Decelerates Rheumatoid Arthritis Progression by Inhibiting Inflammatory Responses and Joint Destruction via Modulating NF-κB and MAPK Pathways", INFLAMMATION., PLENUM PRESS, NEW YORK, NY., US, vol. 39, no. 1, 30 August 2015 (2015-08-30), US , pages 248 - 256, XP035910568, ISSN: 0360-3997, DOI: 10.1007/s10753-015-0245-7 *
NAVEED, MUHAMMAD; TARIQ, KOMAL; SADIA, HALEEMA; MUMTAZ, ABDUL SAMAD: "The Life History of Pyrroloquinoline Quinone (PQQ): A Versatile Molecule with Novel Impacts on Living Systems", INTERNATIONAL JOURNAL OF MOLECULAR BIOLOGY, vol. 1, no. 1, 28 December 2016 (2016-12-28), pages 1 - 20, XP009536626, ISSN: 2573-2889, DOI: 10.15406/ijmboa.2016.01.00005 *

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