WO2020140730A1 - Use of thioguanine in preparation of drug for treating adsl deficiency - Google Patents
Use of thioguanine in preparation of drug for treating adsl deficiency Download PDFInfo
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- 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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- thioguanine
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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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Abstract
Disclosed is a use of thioguanine in the preparation of a drug for treating ADSL deficiency. By means of calculation and analysis using our own software, and through research involving experiments on cell biology and experiments on an animal model of ADSL deficiency, it is confirmed that thioguanine has the effect of treating ADSL deficiency.
Description
本发明涉及硫鸟嘌呤的新应用，特别涉及硫鸟嘌呤在制备治疗ADSL缺陷症药物中应用。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.
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 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).
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.]。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.]. In 1984, Jaeken and Van Berghe first detected the accumulation of this metabolite in the body fluids of several patients with bradykinesia and autism. Patients with adenylate succinate lyase deficiency usually have severe dysplasia, bradykinesia, sluggish eyesight, epilepsy, autism and other symptoms [Spiegel, EK, Colman, RF, and Patterson, D. (2006) .Adenylosuccinatelyasedeficiency.MolGenetMetab89,19-31.Clamadieu,C.,Cottin,X.,Rousselle,C.,andClaris,O.(2008).Adenylosuccinatelyasedeficiency:anunusualcauseofneonatal.seizure. 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 adenylosuccinatelyase definition: clinical,biochemical and molecularfindings in four patientss.Neuropediatrics33,186-189.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 sevenPolishpatientswith adenylosuccinatelyasedeficiency.MolGenetMetab94,435-442.].
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 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)，通用名，Tioguanine，结构式：
中文名：硫鸟嘌呤。硫鸟嘌呤主要用途如下：
DB00352 (https://www.drugbank.ca/drugs/DB00352), common name, Tioguanine, structural formula: Chinese name: thioguanine. The main uses of thioguanine are as follows:
1、能使白细胞出现明显一过性增生。临床用于各种放射性或药物引起的白细胞下降、非特异性血小板减少症的治疗，亦用于急、慢性肝炎。不良反应可见头晕、心悸、呕吐、胸闷和恶心。1. It can cause obvious transient hyperplasia of white blood cells. It is clinically used for the treatment of leukopenia and non-specific thrombocytopenia caused by various radioactivity or drugs. It is also used for acute and chronic hepatitis. Adverse reactions include dizziness, palpitations, vomiting, chest tightness, and nausea.
2、抗肿瘤药。对急性白血病和慢性粒细胞白血病有缓解作用。大剂量对绒癌有效有较好疗效。2. Antitumor drugs. It can relieve acute leukemia and chronic myeloid leukemia. Large doses have a good effect on choriocarcinoma.
3、蛋白激酶致活剂。为环磷腺苷的衍生物，作用和用途与之相同。也可用于心肌炎、心源性休克和手术后网膜下出血。用量大时可有嗜睡、头晕、眼花、乏力、食欲减退、恶心、呕吐等。3. 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.
4、抗肿瘤药。为嘌呤抗代谢药物，是一种DNA碱基的同类物，可作为一个错误的碱基掺入到DNA分子中，从而影响DNA的合成和功能。主要作用于S期，为细胞周期特异性药物。用于各类白血病的治疗，急性白血病更为常用。4. 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.
5、用于冠状动脉粥样硬化的防治和肝炎的治疗。也用于白细胞减少、原发性血小板减少性紫癜、由慢性肾机能不全引起的急性无尿、肾病综合征、***等各种代谢性辅助性治疗。5. For the prevention and treatment of coronary atherosclerosis and the treatment of hepatitis. It is also used for various metabolic auxiliary treatments such as leukopenia, primary thrombocytopenic purpura, acute anuria caused by chronic renal insufficiency, nephrotic syndrome, and uremia.
其药理作用类似巯嘌呤，在体内转化成硫鸟嘌呤苷酸(6-TGRP)后才具有活性。最后转变成脱氧鸟嘌呤核苷酸，干扰DNA功能，产生抗癌作用。为S期特异性抗肿瘤药，对S/G2边界有延缓作用。属于抑制嘌呤合成途径的常用嘌呤代谢拮抗药物，是细胞周期特异性药物，对处于S期细胞最敏感，除能抑制细胞DNA的合成外，对RNA的合成亦有轻度抑制作用。 本品是鸟嘌呤的类似物，在人体内必需由磷酸核糖转移酶转为6－TG核糖核苷酸方具活性，本品的作用环节与巯嘌呤相似，此外，6－TG核糖核苷酸通过对鸟苷酸激酶的抑制作用，可阻止一磷酸鸟苷(GMP)磷酸化为二磷酸鸟苷(GDP)。本品经代谢为脱氧核糖三磷酸后，能掺入DNA，因而进一步抑制核酸的生物合成，巯嘌呤无此作用。本品与巯嘌呤有效交叉耐药，而与阿糖胞苷等药物合用，可提高疗效。Its pharmacological action is similar to mercaptopurine, and it is only active after it is converted into thioguanine uridine (6-TGRP) in the body. Finally, it is converted into deoxyguanine nucleotides, which interferes with DNA function and produces anti-cancer effects. It is an S-phase specific antitumor drug, which has a delaying effect on the S/G2 boundary. Commonly used purine metabolism antagonists that inhibit the purine synthesis pathway are cell cycle-specific drugs that are most sensitive to cells in the S phase. In addition to inhibiting the synthesis of cellular DNA, they also have a slight inhibitory effect on RNA synthesis. This product is an analogue of guanine. It must be converted from phosphoribosyltransferase to 6-TG ribonucleotide in the human body to be active. The action of this product is similar to that of mercaptopurine. In addition, 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. This product is effectively cross-resistance with mercaptopurine, and combined with cytarabine and other drugs can improve the efficacy.
发明内容Summary of the invention
本发明的目的在于提供硫鸟嘌呤在制备治疗或改善ADSL缺陷症药物中应用。The object of the present invention is to provide thioguanine in the preparation or treatment of ADSL deficiency medicine.
发明内容：Summary of the invention:
本发明的第一个方面，提供：The first aspect of the present invention provides:
硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物在制备治疗或改善ADSL缺陷症组合物中应用。Thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites are used in the preparation of compositions for treating or improving ADSL deficiency.
在一些实例中，硫鸟嘌呤药学上可接受的衍生物硫鸟嘌呤的药用盐、低级酰胺中的一种。In some examples, the pharmaceutically acceptable derivative of thioguanine is one of pharmaceutically acceptable salts and lower amides of thioguanine.
在一些实例中，所述组合物为药物，还包括可接受的药用辅料。In some examples, the composition is a drug and also includes acceptable pharmaceutical excipients.
本发明的第二个方面，提供：The second aspect of the present invention provides:
治疗或改善ADSL缺陷症的化合物，化合物为硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物中的一种。A compound for treating or improving ADSL deficiency. The compound is one of thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites.
在一些实例中，硫鸟嘌呤药学上可接受的衍生物硫鸟嘌呤的药用盐、低级酰胺中的一种。In some examples, the pharmaceutically acceptable derivative of thioguanine is one of pharmaceutically acceptable salts and lower amides of thioguanine.
治疗或改善ADSL缺陷症的组合物，组合物的活性成分包括硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物中的一种。A composition for treating or improving ADSL deficiency. The active ingredients of the composition include one of thioguanine and its pharmaceutically acceptable derivatives, prodrugs, and active metabolites.
在一些实例中，硫鸟嘌呤药学上可接受的衍生物硫鸟嘌呤的药用盐、低级酰胺中的一种。In some examples, the pharmaceutically acceptable derivative of thioguanine is one of pharmaceutically acceptable salts and lower amides of thioguanine.
一种治疗或改善ADSL缺陷症的方法，包括如下步骤：给予ADSL缺陷症病人治疗量或改善量的硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物中的一种。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.
在一些实例中，给予方式包括口服、吸入、注射、透皮吸收或经呼吸道吸入等为本领域技术人员所熟知的。In some examples, 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.
本发明的有益效果：The beneficial effects of the invention:
发明人通过自有软件计算分析，并经过细胞生物学实验和ADSL缺陷症动物模型实验研究确证，硫鸟嘌呤具备显著的ADSL缺陷症治疗效果。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.
化合物药学上可接受的衍生物，尤其药用盐、低级酰胺中的一种，即碳原子数在1～6，优选为2～6，2～4的羧酸、醇、胺与母化合物缩合得到的衍生物。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.
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***、乙酸乙酯、乙醇、异丙醇或乙腈。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. Generally speaking, 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 .
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，以及酰化氨基酸和阳离子交换树脂组成的组。Acid addition salts can be prepared from various acids (inorganic and organic acids). Examples of 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, glucoheptonic acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), α-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, The group consisting of succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, as well as acylated amino acids and cation exchange resins.
发明人通过自有软件计算分析，并经过细胞生物学实验和ADSL缺陷症动物模型实验研究确证，硫鸟嘌呤具备显著的ADSL缺陷症治疗效果。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.
| 化合物名称Compound name | 研究方法research method | 研究结果Research result |
| 硫鸟嘌呤Thioguanine | 软件计算分析Software calculation analysis | 可以治疗ADSL缺陷症Can treat ADSL deficiency |
| 硫鸟嘌呤Thioguanine | 细胞生物学实验Cell Biology Experiment | SAICAR降低效果显著SAICAR reduction effect is significant |
| 硫鸟嘌呤Thioguanine | ADSL缺陷症动物模型实验Animal model experiment of ADSL deficiency | 疾病治疗效果显著The disease treatment effect is remarkable |
硫鸟嘌呤处理后，可以使ADSL基因缺陷线虫动物模型的表型恢复正常。After thioguanine treatment, the phenotype of the ADSL gene-deficient nematode animal model can be restored to normal.
ADSL缺陷转基因小鼠在给予硫鸟嘌呤后，实验证明SAICAR、SAICAr、S-Ado等有毒中间代谢产物的累积量显著下降，ADSL得到显著改善。After the administration of thioguanine in ADSL-deficient transgenic mice, experiments have shown that the accumulation of toxic intermediate metabolites such as SAICAR, SAICAr, S-Ado, etc. has decreased significantly, and ADSL has been significantly improved.
类似的，硫鸟嘌呤药学上可接受的衍生物、前药及活性代谢产物，也具有ADSL缺陷症治疗效果。Similarly, thioguanine pharmaceutically acceptable derivatives, prodrugs and active metabolites also have the therapeutic effect of ADSL deficiency.
Claims (9)
- 硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物在制备治疗或改善ADSL缺陷症组合物中应用。Thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites are used in the preparation of compositions for treating or improving ADSL deficiency.
- 根据权利要求1所述的应用，其特征在于：硫鸟嘌呤药学上可接受的衍生物硫鸟嘌呤的药用盐、低级酰胺中的一种。The use according to claim 1, characterized in that it is one of a pharmaceutically acceptable salt of thioguanine derivative thioguanine and a lower amide.
- 根据权利要求1所述的应用，其特征在于：所述组合物为药物，还包括可接受的药用辅料。The use according to claim 1, characterized in that the composition is a medicament and further includes acceptable pharmaceutical excipients.
- 治疗或改善ADSL缺陷症的化合物，其特征在于：化合物为硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物中的一种。The compound for treating or improving ADSL deficiency is characterized in that the compound is one of thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites.
- 根据权利要求4所述的化合物，其特征在于：硫鸟嘌呤药学上可接受的衍生物硫鸟嘌呤的药用盐、低级酰胺中的一种。The compound according to claim 4, characterized in that it is one of a pharmaceutically acceptable salt of thioguanine derivative thioguanine and a lower amide.
- 治疗或改善ADSL缺陷症的组合物，其特征在于：组合物的活性成分包括硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物中的一种。A composition for treating or improving ADSL deficiency, characterized in that the active ingredient of the composition includes one of thioguanine and its pharmaceutically acceptable derivatives, prodrugs and active metabolites.
- 根据权利要求6所述的组合物，其特征在于：硫鸟嘌呤药学上可接受的衍生物硫鸟嘌呤的药用盐、低级酰胺中的一种。The composition according to claim 6, characterized in that it is one of a pharmaceutically acceptable salt of thioguanine derivative thioguanine and a lower amide.
- 一种治疗或改善ADSL缺陷症的方法，包括如下步骤：给予ADSL缺陷症病人治疗量或改善量的硫鸟嘌呤及其药学上可接受的衍生物、前药及活性代谢产物中的一种。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.
- 根据权利要求8所述的方法，其特征在于：给予方式包括口服、吸入、透皮吸收或经呼吸道吸入。The method according to claim 8, wherein the method of administration includes oral administration, inhalation, transdermal absorption or inhalation through the respiratory tract.
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