WO2022095809A1 - New application of compounds influencing saicar expression - Google Patents

New application of compounds influencing saicar expression Download PDF

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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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cancer
acid
compound
pyrroloquinoline quinone
treating
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PCT/CN2021/127820
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French (fr)
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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    • 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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Abstract

It has been shown by means of computational analysis research that SAICAR has a certain association with multiple diseases, and through further computational analysis research and preliminary related disease model experimental research, it has been verified that: pyrroloquinoline quinone PQQ, MK2206, niclosamide, spermine, spermadine, benserazide, mercaptopurine, azathioprine, DB00746, DB00381, DB03516, DB00856, febuxostat, oxipurinol, allopurinol, tioguanine, or disulfiram can treat or ameliorate RA, ADSL defiency, Lesch-Nyhan syndrome, or a tumor having a specific indication.

Description

影响SAICAR表达量的化合物的新应用New applications of compounds affecting SAICAR expression 技术领域technical field
本发明涉及化合物的新应用，特别涉及影响SAICAR表达量的化合物的新应用。The present invention relates to new applications of compounds, in particular to new applications of compounds that affect the expression of SAICAR.
背景技术Background technique
嘌呤合成代谢是生物体普遍存在而又十分重要的生物代谢，其产物AMP和GMP不仅为生物体内DNA和RNA的生物合成提供原料，而且也为体内许多关键的辅酶(NAD、NADP、FAD和CoA)、信号分子(如cAMP)和重要的能量分子ATP 提供其合成所必需的嘌呤碱基。可见，嘌呤合成代谢在整个代谢网络中处于核心位置。嘌呤合成包括从头合成(de novo purine synthesis)和补救途径(salvage pathway)两个合成途径。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.
腺苷酸琥珀酸裂解酶缺陷症（adenylosuccinate lyase deficiency ADSL缺陷症）是一种在腺嘌呤从头合成以及嘌呤核苷酸代谢途径中产生缺失、混乱的代谢疾病。该疾病产生的原因主要是由于患者体内的腺苷酸琥珀酸裂解酶发生了突变或者缺失，从而导致细胞中该酶的底物SAICAR过度地积累而得不到及时的清除[Jaeken J, Van den Berghe G. (1984). An infantile autistic syndrome characterized by the presence of succinylpurines in body fluids. Lancet 8411: 1058-1061.]。1984年Jaeken 以及Van den Berghe首次在几个患有运动迟缓症和自闭症的患者体液中检测到该代谢物的积累。患有腺苷酸琥珀酸裂解酶缺陷症的患者通常会出现严重的发育不良、运动迟缓、目光呆滞、癫痫、自闭等症状[Spiegel, E.K., Colman, R.F., and Patterson, D. (2006). Adenylosuccinate lyase deficiency. Mol Genet Metab 89, 19-31. Clamadieu, C., Cottin, X., Rousselle, C., and Claris, O. (2008). Adenylosuccinate lyase deficiency: an unusual cause of neonatal seizure. Arch Pediatr 15, 135-138. Castro, M., Perez-Cerda, C., Merinero, B., Garcia, M.J., Bernar, J., Gil Nagel, A., Torres, J., Bermudez, M., Garavito, P., Marie, S., et al. (2002). Screening for adenylosuccinate lyase deficiency: clinical, biochemical and molecular findings in four patients. Neuropediatrics 33, 186-189. Jurecka, A., Zikanova, M., Tylki-Szymanska, A., Krijt, J., Bogdanska, A., Gradowska, W., Mullerova, K., Sykut-Cegielska, J., Kmoch, S., and Pronicka, E. (2008b). Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency. Mol Genet Metab 94, 435-442.]。 Adenylosuccinate lyase deficiency ( ADSL 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.]. The accumulation of this metabolite was first detected in the body fluids of several patients with bradykinesia and autism in 1984 by Jaeken and Van den Berghe. Patients with adenylate succinate lyase deficiency often present with severe dysplasia, motor retardation, glazed eyes, seizures, and autism [Spiegel, EK, Colman, RF, and Patterson, D. (2006) . Adenylosuccinate lyase deficiency. Mol Genet Metab 89, 19-31. Clamadieu, C., Cottin, X., Rousselle, C., and Claris, O. (2008). Adenylosuccinate lyase deficiency: an unusual cause of neonatal seizure. Arch Pediatr 15, 135-138. Castro, M., Perez-Cerda, C., Merinero, B., Garcia, MJ, Bernar, J., Gil Nagel, A., Torres, J., Bermudez, M., Garavito , P., Marie, S., et al. (2002). Screening for adenylosuccinate lyase deficiency: clinical, biochemical and molecular findings in four patients. Neuropediatrics 33, 186-189. Jurecka, A., Zikanova, M., Tylki -Szymanska, A., Krijt, J., Bogdanska, A., Gradowska, W., Mullerova, K., Sykut-Cegielska, J., Kmoch, S., and Pronicka, E. (2008b). Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency. Mol Genet Metab 94, 435-442.].
ADSL缺陷症有3种连续的主要表型：新生儿致死型、重度（Ⅰ型）和轻到中度（Ⅱ型）。临床上发现即便是来自同一家族的患者也具有不同的表型。发病一般见于出生至婴幼儿期。已报导的病例有致死的新生脑病变（表现有运动功能减退、难治性癫痫、呼吸障碍），中度智力缺陷。所有的患者均存在智力缺陷，大多数存在不同类型的癫痫，约1/3的存在自闭症特征（无法进行眼神交流、对声光敏感、重复性行为、躁动、乱发脾气、自伤和自残）。其他不常见的临床表现包括心理运动延迟、过度活跃、语言障碍、肌肉张力减退、肌肉萎缩和痉挛。重度患者通常小头畸形。产前临床表现报导的有：宫内生长受损、小头畸形、胎儿运动功能减退以及胎儿心率变化缺失。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.
在腺嘌呤从头合成的代谢途径中，腺苷酸琥珀酸裂解酶（以下简称ADSL酶）主要参与将SAICAR裂解催化形成AICAR以及S-AMP生成AMP的反应[Spiegel, E.K., Colman, R.F., and Patterson, D. (2006). Adenylosuccinate lyase deficiency. Mol Genet Metab 89, 19-31.  Clamadieu, C., Cottin, X., Rousselle, C., and Claris, O. (2008). Adenylosuccinate lyase deficiency: an unusual cause of neonatal seizure. Arch Pediatr 15, 135-138.  Castro, M., Perez-Cerda, C., Merinero, B., Garcia, M.J., Bernar, J., Gil Nagel, A., Torres, J., Bermudez, M., Garavito, P., Marie, S., et al. (2002). Screening for adenylosuccinate lyase deficiency: clinical, biochemical and molecular findings in four patients. Neuropediatrics 33, 186-189.]。腺苷酸琥珀酸裂解酶缺陷患者由于ADSL酶发生了突变或者缺失，导致有害代谢物SAICAR得不到及时的清除，通常会出现很严重的神经以及生理的症状，比如癫痫，大脑发育失常，运动呆滞等[Ciardo, F., Salerno, C., and Curatolo, P. (2001). Neurologic aspects of adenylosuccinate lyase deficiency. J Child Neurol 16, 301-308.  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. Eur J Hum Genet 17, 133-136.  Mierzewska, H., Schmidt-Sidor, B., Jurkiewicz, E., Bogdanska, A., Kusmierska, K., and Stepien, T. (2009). Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI, clinical, biochemical and neuropathological findings of Polish patients. Folia Neuropathol 47, 314-320.]。在患者的脑脊液、体液中，通常会大量积累中间代谢物SAICAr及S-Ado（SAICAr是SAICAR脱去磷酸的产物，S-Ado是S-AMP去磷酸的产物）[Spiegel, E.K., Colman, R.F., and Patterson, D. (2006). Adenylosuccinate lyase deficiency. Mol Genet Metab 89, 19-31. Mierzewska, H., Schmidt-Sidor, B., Jurkiewicz, E., Bogdanska, A., Kusmierska, K., and Stepien, T. (2009). Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI, clinical, biochemical and neuropathological findings of Polish patients. Folia Neuropathol 47, 314-320.]。Van den Berghe等人发现体液中S-do与SAICAr的比值与患者的病症严重性有一定的相关性[Van den Bergh F, Vincent MF, Jaeken J, Van den Berghe G. (1993). Residual adenylosuccinase activities in fibroblasts of adenylosuccinase-deficient children: parallel deficiency with adenylosuccinate and succinyl-AICAR in profoundly retarded patients and non-parallel deficiency in a mildly retarded girl, J. Inherit. Metab.Dis. 16 (2) 415–424.]。目前，临床上并没有有效的，可以治愈ADSL缺陷症治疗方案。In the metabolic pathway of de novo adenine synthesis, adenylate succinate lyase (hereinafter referred to as ADSL enzyme) is mainly involved in the cleavage of SAICAR to form AICAR and S-AMP to form AMP [Spiegel, E.K., Colman, R.F., and Patterson, D. (2006). Adenylosuccinate lyase deficiency. Mol Genet Metab 89, 19-31. Clamadieu, C., Cottin, X., Rousselle, C., and Claris, O. (2008). Adenylosuccinate lyase deficiency: an unusual cause of neonatal seizure. Arch Pediatr 15, 135-138. Castro, M., Perez-Cerda, C., Merinero, B., Garcia, M.J., Bernar, J., Gil Nagel, A., Torres, J., Bermudez, M., Garavito, P., Marie, S., et al. (2002). Screening for adenylosuccinate lyase deficiency: clinical, biochemical and molecular findings in four patients. Neuropediatrics 33, 186-189.]. Patients with adenylate succinate lyase deficiency have mutations or deletions in the ADSL enzyme, resulting in the inability of the harmful metabolite SAICAR to be cleared in time, and usually have serious neurological and physiological symptoms, such as epilepsy, brain development disorders, and exercise. sluggish etc. [Ciardo, F., Salerno, C., and Curatolo, P. (2001). Neurologic aspects of adenylosuccinate lyase deficiency. J Child Neurol 16, 301-308.  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. Eur J Hum Genet 17, 133-136. Mierzewska, H., Schmidt-Sidor, B., Jurkiewicz, E., Bogdanska, A., Kusmierska, K., and Stepien, T. (2009). Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI, clinical, biochemical and neuropathological findings of Polish patients. Folia Neuropathol 47, 314-320.]. In the cerebrospinal fluid and body fluids of patients, the intermediate metabolites SAICAr and S-Ado are usually accumulated in large quantities (SAICAr is the dephosphorylation product of SAICAR, and S-Ado is the dephosphorylation product of S-AMP) [Spiegel, E.K., Colman, R.F. , and Patterson, D. (2006). Adenylosuccinate lyase deficiency. Mol Genet Metab 89, 19-31. Mierzewska, H., Schmidt-Sidor, B., Jurkiewicz, E., Bogdanska, A., Kusmierska, K., and Stepien, T. (2009). Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI, clinical, biochemical and neuropathological findings of Polish patients. Folia Neuropathol 47, 314-320.]. Van den Berghe et al. found that the ratio of S-do to SAICAr in body fluids is related to the severity of the patient's disease [Van den Bergh F, Vincent MF, Jaeken J, Van den Berghe G. (1993). Residual adenylosuccinase activities in fibroblasts of adenylosuccinase-deficient children: parallel deficiency with adenylosuccinate and succinyl-AICAR in profoundly retarded patients and non-parallel deficiency in a mildly retarded girl, J. Inherit. Metab.Dis. 16 (2) 415–424.]. At present, there is no clinically effective and curative treatment for ADSL deficiency.
氨基咪唑琥珀基氨甲酰核苷酸合成酶/氨基咪唑核苷酸羧化酶，即PAICS (phosphoribosylaminoimidazole succinocarboxamide synthetase /phosphoribosylaminoimidazole carboxylase)是一种嘌呤从头合成途径中重要的双功能酶，它具有SAICAR合成酶(4-(N-succinylcarboxamide)-5-aminoimidazole ribonucleotide synthetase，SAICARs)和AIR羧化酶(5-aminoimidazole ribonucleotide carboxylase，AIRc)的功能，催化嘌呤从头合成代谢第六步、第七步反应，其中的一个关键反应过程为：ATP + 1-(5-Phospho-D-ribosyl)-5-amino-4-imidazolecarboxylate + L-Aspartate <=> ADP + Orthophosphate + 1-(5'-Phosphoribosyl)-5-amino-4-(N-succinocarboxamide)-imidazole (www.genome.jp/entry/R04591)。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) The function of ribonucleotide carboxylase, AIRc), catalyzes the sixth and seventh steps of de novo purine synthesis and metabolism, one of the key reaction processes is: ATP + 1-(5-Phospho-D-ribosyl)-5-amino-4-imidazolecarboxylate + L-Aspartate <=> ADP + Orthophosphate + 1-(5'-Phosphoribosyl)-5-amino-4-(N-succinocarboxamide)-imidazole (www.genome.jp/entry/R04591).
癌细胞的一个重要的标志是代谢重编程，包括提高葡萄糖摄取和非氧依赖的乳酸发酵，也常被称为沃伯格效应(Warburg effect) [1, 2]。这种重新编程对于肿瘤的生长和存活是必要，特别是外界低氧等压力条件下。然而，对于肿瘤细胞代谢重整与肿瘤快速增殖、分化、迁移等相关性的重要分子机制以及作用方式仍然不清楚。An important hallmark of cancer cells is metabolic reprogramming, including increased glucose uptake and oxygen-independent lactic acid fermentation, also often referred to as the Warburg effect. effect) [1, 2]. This reprogramming is necessary for tumor growth and survival, especially under stressful conditions such as hypoxia. However, the important molecular mechanisms and modes of action of tumor cell metabolic remodeling in relation to rapid tumor proliferation, differentiation, and migration remain unclear.
丙酮酸激酶同工酶2（Pyruvate kinase isoform M2，PKM2）作为一个代谢过程中重要的酶在快速增殖和多数肿瘤细胞中高表达，且对肿瘤细胞的代谢和生长影响巨大。此外，针对PKM2酶活性的各种药理试剂影响细胞生长和增殖，这也提示通过靶向PKM2的酶活性为代表，进一步改变肿瘤代谢的方式成为肿瘤治疗的一种新途径。Pyruvate kinase isoenzyme 2 isoform M2, PKM2), as an important enzyme in the metabolic process, is highly expressed in the rapid proliferation and most tumor cells, and has a huge impact on the metabolism and growth of tumor cells. In addition, 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.
雷尼综合征（Lesch-Nyhan Syndrome，LNS），又称莱-尼氏综合症，是一种罕见的伴X染色体遗传性疾病，由位于X染色体上的HPRT基因突变引起的次黄嘌呤-鸟嘌呤磷酸糖苷转移酶(HGPRT)缺陷所致。LNS的发病率约为38万分之一（ghr.nlm.nih.gov/condition/lesch-nyhan-syndrome、en.wikipedia.org/wiki/Lesch%E2%80%93Nyhan_syndrome）。Lesch-Nyhan Syndrome (LNS), also known as Lesch-Nyhan Syndrome, is a rare X-linked genetic disorder caused by mutations in the HPRT gene located on the X chromosome. Caused by deficiency of purine phosphoroglycosidase (HGPRT). The incidence of LNS is about 1 in 380,000 (ghr.nlm.nih.gov/condition/lesch-nyhan-syndrome, en.wikipedia.org/wiki/Lesch%E2%80%93Nyhan_syndrome).
LNS几乎只发生在男性身上的疾病，它的特点是神经和行为异常和尿酸的过量生产。尿酸是正常化学过程的废物，存在于血液和尿液中。过量的尿酸会从血液中释放出来，积聚在皮肤下面，导致痛风性关节炎(由关节中尿酸的积累引起的关节炎)。尿酸的积累也会引起肾结石和膀胱结石。LNS的神经系统和行为障碍包括不正常的随意肌运动，如各种肌肉的紧张(肌张力障碍)、抽搐(舞蹈)和肢体的摆动(弹力障碍)。患有LNS的人通常不能走路，需要帮助坐着，通常使用轮椅。自残(包括咬人和头部撞击)是LNS患者最常见和最显著的行为问题。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.
临床上LNS没有特别有效的治疗方法，WO1994017183A1公开了使用cHPRT治疗LNS。US4575498A公开了使用5-氨基-4-咪唑甲酰胺核苷酸（5-amino-4-imidazolecarboxamide riboside）、5-氨基-4-咪唑甲酰胺（5-amino-4-imidazolecarboxamide）及其药学上可接受的盐，通过提高缺陷组织中嘌呤核苷酸库的补充速率，治疗LNS。US20130116215A1公开了至少两种化合物的组合用于治疗神经疾病，并泛泛提及其可以用于治疗LNS，并没有确实的数据证实其疗效。There is no particularly effective treatment method for LNS clinically, and 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.
类风湿关节炎（RA）是一种病因未明的慢性、以炎性滑膜炎为主的系统性疾病。其特征是手、足小关节的多关节、对称性、侵袭性关节炎症，经常伴有关节外器官受累及血清类风湿因子阳性，可以导致关节畸形及功能丧失。Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis-based systemic disease of unknown etiology. It is characterized by polyarticular, symmetrical, and aggressive joint inflammation of the facet joints of the hands and feet, often accompanied by extra-articular organ involvement and positive serum rheumatoid factor, which can lead to joint deformity and loss of function.
新型冠状病毒（SARS-CoV-2爆发后在全球多个地区快速传播，SARS-CoV-2感染引起的COVID-19呈现全球蔓延的趋势。对全球公共卫生安全构成了巨大威胁，造成了巨大的经济损失。The novel coronavirus (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.
技术问题technical problem
有效治疗或改善这些疾病，具有非常实际的意义。Effective treatment or improvement of these diseases has very practical significance.
技术解决方案technical solutions
本发明的第一方面，提供：化合物在制备治疗或改善类风湿关节炎组合物中的应用，所述化合物选自：吡咯喹啉醌PQQ、MK2206 (CAS注册号：1032349-93-1)、氯硝柳胺、精胺、亚精胺、Benserazide、巯嘌呤、硫唑嘌呤、DB00746 (Deferoxamine)、DB00381 (Amlodipine)、DB03516 (Eniluracil)、DB00856 (Chlorphenesin)、Febuxostat、奥昔嘌醇、别嘌醇、硫鸟嘌呤或双硫仑及其可接受的盐。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.
在一些实例中，所述组合物为口服剂或注射剂。In some instances, the composition is oral or injectable.
在一些实例中，所述口服剂选自片剂、胶囊、固体饮料、功能性食品。In some examples, the oral agent is selected from tablets, capsules, solid beverages, functional foods.
在一些实例中，所述化合物的盐为化合物的酸或碱加成盐，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸（如L-抗坏血酸）、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸（如D-葡萄糖醛酸）、谷氨酸（如L-谷氨酸）、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。 In some examples, 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 acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), alpha-ketopentane Diacid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2- Naphthoic acid, niacin, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p -toluenesulfonic acid, undecylenic acid and valeric acid, and the group consisting of acylated amino acids ; Described alkali is the hydroxide of alkali metal and alkaline earth metal.
本发明的第二方面，提供：化合物在制备治疗或改善ADSL缺陷症或雷尼综合症组合物中的应用，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其可接受的盐。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.
在一些实例中，所述组合物为口服剂或注射剂。In some instances, the composition is oral or injectable.
在一些实例中，所述口服剂选自片剂、胶囊、固体饮料、功能性食品。In some examples, the oral agent is selected from tablets, capsules, solid beverages, functional foods.
本发明的第三方面，提供：化合物在制备治疗或改善肿瘤组合物中的应用，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其可接受的盐，所述肿瘤存在SAICAR过量积累、SAICAr过量积累、PAICS基因异常高表达、ADSL基因异常低表达或功能缺失或下降至少一种指征。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.
基于现有研究，具有不同指征的肿瘤，一般对药物的反应是不同的反应。通过确定肿瘤的具体表征情况并针对性地使用药物，一般可以取得更好的疗效。Based on existing studies, 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.
在一些实例中，所述肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌。In some examples, 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.
在一些实例中，所述组合物为口服剂或注射剂。In some instances, the composition is oral or injectable.
在一些实例中，所述口服剂选自片剂、胶囊、固体饮料、功能性食品。In some examples, the oral agent is selected from tablets, capsules, solid beverages, functional foods.
本发明的第四方面，提供：吡咯喹啉醌PQQ及其盐在制备预防、改善或治疗COVID-19组合物中的应用。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.
在一些实例中，所述组合物为口服剂或注射剂。In some instances, the composition is oral or injectable.
在一些实例中，所述口服剂选自片剂、胶囊、固体饮料、功能性食品。In some examples, the oral agent is selected from tablets, capsules, solid beverages, functional foods.
本发明的第五方面，提供：A fifth aspect of the present invention provides:
一种治疗或改善类风湿关节炎的方法，包括给予足够量的化合物，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺、精胺、亚精胺、Benserazide、巯嘌呤、硫唑嘌呤、DB00746、DB00381、DB03516、DB00856、Febuxostat、奥昔嘌醇、别嘌醇、硫鸟嘌呤或双硫仑及其药学上可接受的盐中的至少一种。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.
本发明的第六方面，提供：一种治疗或改善ADSL缺陷症或雷尼综合症的方法，包括给予足够量的化合物，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其药学上可接受的盐中的至少一种。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.
本发明的第七方面，提供：一种治疗或改善肿瘤的方法，包括给予足够量的化合物，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其可接受的盐，所述肿瘤存在SAICAR过量积累、SAICAr过量积累、PAICS基因异常高表达、ADSL基因异常低表达或功能缺失或下降至少一种指征。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.
在一些实例中，所述肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌。In some examples, 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.
本发明的第八方面，提供：一种预防、改善或治疗COVID-19的方法，包括给予人预防、改善或治疗量的吡咯喹啉醌PQQ及其盐中的至少一种。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.
在一些实例中，所述给予的方式为口服或注射。In some instances, the mode of administration is oral or injection.
有益效果beneficial effect
发明人通过计算分析研究表明，SAICAR与多种疾病存在一定的关联，经进一步的计算分析研究和初步的相关疾病模型实验研究证实：The inventors have shown through computational analysis and research that SAICAR is associated with a variety of diseases. Further computational analysis and preliminary experimental studies on related disease models have confirmed:
1)      吡咯喹啉醌PQQ、MK2206、氯硝柳胺、精胺、亚精胺、Benserazide、巯嘌呤、硫唑嘌呤、DB00746、DB00381、DB03516、DB00856、Febuxostat、奥昔嘌醇、别嘌醇、硫鸟嘌呤或双硫仑可以治疗或改善类风湿关节炎（RA）。1) Pyrroloquinoline quinone PQQ, MK2206, niclosamide, spermine, spermidine, Benserazide, mercaptopurine, azathioprine, DB00746, DB00381, DB03516, DB00856, Febuxostat, Oxypurinol, Allopurinol, Thioguan Purines or disulfiram can treat or improve rheumatoid arthritis (RA).
2)      吡咯喹啉醌PQQ、MK2206、氯硝柳胺可以治疗或改善ADSL缺陷症或雷尼综合症。2) Pyrroloquinoline quinone PQQ, MK2206, niclosamide can treat or improve ADSL deficiency or Raney syndrome.
3)      吡咯喹啉醌PQQ、MK2206、氯硝柳胺可以治疗或改善存在SAICAR、SAICAr过量积累、PAICS基因异常高表达、ADSL基因异常低表达或功能缺失或下降至少一种指征的肿瘤，可以更有针对性地治疗肿瘤。3) 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.
4)      吡咯喹啉醌PQQ可以预防、改善或治疗COVID-19。4)  Pyrroloquinoline quinone PQQ can prevent, improve or treat COVID-19.
本发明的实施方式Embodiments of the present invention
高表达的含义为本领域公认的，即与正常组织相比，其含量相对显著提高。The meaning of high expression is recognized in the art, that is, its content is relatively significantly increased compared to normal tissue.
化合物药学上可接受的药用盐可以通过常规的化学方法从母体化合物合成，如在 Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor),ISBN:3-90639-026-8, Hardcover, 388 pages, August 2002中描述的方法。一般来说，这些盐可以由化合物的游离碱和酸在水或有机溶剂或二者的混合液中反应制得；通常，使用非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。 Pharmaceutically acceptable 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. Generally, 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 .
酸加成盐可以通过各种酸（无机酸和有机酸）制得。酸加成盐的实例包括由酸制成的盐，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸（如L-抗坏血酸）、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸（如D-葡萄糖醛酸）、谷氨酸（如L-谷氨酸）、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组。 Acid addition salts can be prepared from a variety of acids (inorganic and organic). Examples of 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-gluconic acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), alpha-ketoglutaric acid, glycolic acid, Hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L- Malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, niacin, Nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, Succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p -toluenesulfonic acid, undecylenic acid and valeric acid, and the group consisting of acylated amino acids.
初步的实验数据总结如下：The preliminary experimental data are summarized as follows:
表1、治疗或改善类风湿关节炎（RA）的总结数据：Table 1. Summary data for the treatment or improvement of rheumatoid arthritis (RA):
化合物compound 计算研究分值Calculate Research Score 细胞或动物模型实验确证Cell or animal model experimental confirmation 综合结果Comprehensive results
吡咯喹啉醌pyrroloquinoline quinone 7171 显著有效Significantly effective 显著有效Significantly effective
MK2206MK2206 8282 显著有效Significantly effective 显著有效Significantly effective
氯硝柳胺Niclosamide 8686 显著有效Significantly effective 显著有效Significantly effective
精胺spermine 7575 显著有效Significantly effective 显著有效Significantly effective
亚精胺spermidine 7777 显著有效Significantly effective 显著有效Significantly effective
BenserazideBenserazide 6868 显著有效Significantly effective 显著有效Significantly effective
巯嘌呤mercaptopurine 6262 显著有效Significantly effective 显著有效Significantly effective
硫唑嘌呤Azathioprine 6363 显著有效Significantly effective 显著有效Significantly effective
DB00746DB00746 6060 显著有效Significantly effective 显著有效Significantly effective
DB00381DB00381 6262 显著有效Significantly effective 显著有效Significantly effective
DB03516DB03516 6969 显著有效Significantly effective 显著有效Significantly effective
DB00856DB00856 9191 显著有效Significantly effective 显著有效Significantly effective
FebuxostatFebuxostat 7474 显著有效Significantly effective 显著有效Significantly effective
奥昔嘌醇Oxypurinol 8181 显著有效Significantly effective 显著有效Significantly effective
别嘌醇allopurinol 7474 显著有效Significantly effective 显著有效Significantly effective
硫鸟嘌呤Thioguanine 6363 显著有效Significantly effective 显著有效Significantly effective
双硫仑disulfiram 6565 显著有效Significantly effective 显著有效Significantly effective
注：计算分值60及以上为显著有效。Note: Calculated scores of 60 and above are significantly effective.
表2、治疗或改善ADSL缺陷症的总结数据：Table 2. Summary data for treatment or improvement of ADSL deficiency:
化合物compound 计算研究分值Calculate Research Score 细胞或动物模型实验确证Cell or animal model experimental confirmation 综合结果Comprehensive results
吡咯喹啉醌pyrroloquinoline quinone 6060 显著有效Significantly effective 显著有效Significantly effective
MK2206MK2206 9292 显著有效Significantly effective 显著有效Significantly effective
氯硝柳胺Niclosamide 9595 显著有效Significantly effective 显著有效Significantly effective
注：计算分值60及以上为显著有效。Note: Calculated scores of 60 and above are significantly effective.
表3、治疗或改善雷尼综合症的总结数据：Table 3. Summary data for the treatment or improvement of Rainey syndrome:
化合物compound 计算研究分值Calculate Research Score 细胞或动物模型实验确证Cell or animal model experimental confirmation 综合结果Comprehensive results
吡咯喹啉醌pyrroloquinoline quinone 6969 显著有效Significantly effective 显著有效Significantly effective
MK2206MK2206 8787 显著有效Significantly effective 显著有效Significantly effective
氯硝柳胺Niclosamide 9696 显著有效Significantly effective 显著有效Significantly effective
注：计算分值60及以上为显著有效。Note: Calculated scores of 60 and above are significantly effective.
表4、治疗或改善存在SAICAR、SAICAr过量积累、PAICS基因异常高表达、ADSL基因异常低表达或功能缺失或下降至少一种指征的肿瘤的总结数据：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:
化合物compound 计算研究分值Calculate Research Score 细胞或动物模型实验确证Cell or animal model experimental confirmation 综合结果Comprehensive results
吡咯喹啉醌pyrroloquinoline quinone 7171 显著有效Significantly effective 显著有效Significantly effective
MK2206MK2206 8484 显著有效Significantly effective 显著有效Significantly effective
氯硝柳胺Niclosamide 9191 显著有效Significantly effective 显著有效Significantly effective
注：计算分值60及以上为显著有效。Note: Calculated scores of 60 and above are significantly effective.
表5、预防、改善或治疗COVID-19疾病的数据总结：Table 5. Summary of data for preventing, ameliorating or treating COVID-19 disease:
化合物compound 计算研究分值Calculate Research Score 细胞或动物模型实验确证Cell or animal model experimental confirmation 综合结果Comprehensive results
吡咯喹啉醌pyrroloquinoline quinone 9393 显著有效Significantly effective 显著有效Significantly effective
注：计算分值60及以上为显著有效。Note: Calculated scores of 60 and above are significantly effective.
发明人通过计算研究和初步的相关疾病模型实验研究证实：The inventors confirmed through computational studies and preliminary experimental studies on relevant disease models:
1)      吡咯喹啉醌PQQ、MK2206、氯硝柳胺、精胺、亚精胺、Benserazide、巯嘌呤、硫唑嘌呤、DB00746、DB00381、DB03516、DB00856、Febuxostat、奥昔嘌醇、别嘌醇、硫鸟嘌呤或双硫仑可以治疗或改善类风湿关节炎（RA）。1) Pyrroloquinoline quinone PQQ, MK2206, niclosamide, spermine, spermidine, Benserazide, mercaptopurine, azathioprine, DB00746, DB00381, DB03516, DB00856, Febuxostat, Oxypurinol, Allopurinol, Thioguan Purines or disulfiram can treat or improve rheumatoid arthritis (RA).
2)      吡咯喹啉醌PQQ、MK2206、氯硝柳胺可以治疗或改善ADSL缺陷症或雷尼综合症。2) Pyrroloquinoline quinone PQQ, MK2206, niclosamide can treat or improve ADSL deficiency or Raney syndrome.
3)      吡咯喹啉醌PQQ、MK2206、氯硝柳胺可以治疗或改善存在SAICAR过量积累、SAICAr过量积累、PAICS基因异常高表达、ADSL基因异常低表达或功能缺失或下降至少一种指征的肿瘤，可以更有针对性地治疗肿瘤。3) 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.
4)      吡咯喹啉醌PQQ可以预防、改善或治疗COVID-19。4)  Pyrroloquinoline quinone PQQ can prevent, improve or treat COVID-19.

Claims (13)

  1. 化合物在制备治疗或改善类风湿关节炎组合物中的应用，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺、精胺、亚精胺、Benserazide、巯嘌呤、硫唑嘌呤、DB00746、DB00381、DB03516、DB00856、Febuxostat、奥昔嘌醇、别嘌醇、硫鸟嘌呤或双硫仑及其可接受的盐。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, niclosamide, spermine, spermidine, Benserazide, mercaptopurine, azathioprine , DB00746, DB00381, DB03516, DB00856, Febuxostat, Oxypurinol, Allopurinol, Thioguanine or Disulfiram and acceptable salts thereof.
  2. 化合物在制备治疗或改善ADSL缺陷症或雷尼综合症组合物中的应用，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其可接受的盐。Use of a compound in the preparation of a composition for treating or improving ADSL deficiency or Raney's syndrome, the compound is selected from the group consisting of pyrroloquinoline quinone PQQ, MK2206, niclosamide and acceptable salts thereof.
  3. 化合物在制备治疗或改善肿瘤组合物中的应用，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其可接受的盐中的至少一种，所述肿瘤存在SAICAR过量积累、SAICAr过量积累、PAICS基因异常高表达、ADSL基因异常低表达或功能缺失或下降至少一种指征。Use of a compound in the preparation of a composition for treating or improving tumors, the compound is selected from at least one of pyrroloquinoline quinone PQQ, MK2206, niclosamide and acceptable salts thereof, and the tumor has excess accumulation of SAICAR , Excessive accumulation of SAICAr, abnormally high expression of PAICS gene, abnormally low expression of ADSL gene or loss of function or decline at least one indication.
  4. 吡咯喹啉醌PQQ及其盐在制备预防、改善或治疗COVID-19组合物中的应用。Application of pyrroloquinoline quinone PQQ and its salts in the preparation of compositions for preventing, improving or treating COVID-19.
  5. 根据权利要求1～4任一项所述的应用，其特征在于：所述组合物为口服剂或注射剂。The application according to any one of claims 1 to 4, wherein the composition is an oral preparation or an injection.
  6. 根据权利要求4所述的应用，其特征在于：所述口服剂选自片剂、胶囊、固体饮料、功能性食品。The application according to claim 4, characterized in that: the oral agent is selected from tablets, capsules, solid beverages, and functional foods.
  7. 根据权利要求3所述的应用，其特征在于：所述肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌。The application according to claim 3, wherein the tumor is selected from acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, colon cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma cancer, cervical cancer, nasopharyngeal cancer, breast cancer, skin cancer, bladder cancer.
  8. 一种治疗或改善类风湿关节炎的方法，包括给予足够量的化合物，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺、精胺、亚精胺、Benserazide、巯嘌呤、硫唑嘌呤、DB00746、DB00381、DB03516、DB00856、Febuxostat、奥昔嘌醇、别嘌醇、硫鸟嘌呤或双硫仑及其药学上可接受的盐中的至少一种。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.
  9. 一种治疗或改善ADSL缺陷症或雷尼综合症的方法，包括给予足够量的化合物，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其药学上可接受的盐中的至少一种。A method of treating or ameliorating 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 pharmaceutically acceptable salts thereof at least one of.
  10. 一种治疗或改善肿瘤的方法，包括给予足够量的化合物，所述化合物选自：吡咯喹啉醌PQQ、MK2206、氯硝柳胺及其可接受的盐，所述肿瘤存在SAICAR过量积累、SAICAr过量积累、PAICS基因异常高表达、ADSL基因异常低表达或功能缺失或下降至少一种指征。A method of treating or ameliorating a tumor, 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 excess accumulation of SAICAR, SAICAr At least one indication of excess accumulation, abnormally high expression of PAICS gene, abnormally low expression of ADSL gene, or loss or decline of function.
  11. 根据权利要求10所述的方法，其特征在于：所述肿瘤选自急性淋巴细胞性白血病、肺癌、神经胶质瘤、前列腺癌、结直癌、胃癌、肝癌、食管癌、大肠癌、恶性淋巴瘤、子宫颈癌、鼻咽癌、乳腺癌、皮肤癌、膀胱癌。The method according to claim 10, wherein the tumor is selected from acute lymphoblastic leukemia, lung cancer, glioma, prostate cancer, colon cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, malignant lymphoma cancer, cervical cancer, nasopharyngeal cancer, breast cancer, skin cancer, bladder cancer.
  12. 一种预防、改善或治疗COVID-19的方法，包括给予人预防、改善或治疗量的吡咯喹啉醌PQQ及其盐中的至少一种。A method of preventing, ameliorating or treating COVID-19, comprising administering to a human a preventive, ameliorating or therapeutic amount of at least one of pyrroloquinoline quinone PQQ and salts thereof.
  13. 根据权利要求8～12任一项所述的方法，其特征在于：所述给予的方式为口服或注射。The method according to any one of claims 8 to 12, wherein the mode of administration is oral administration or injection.
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