WO2010034269A1 - 2,5-二羟基甲基-3,6-二甲基吡嗪及其衍生物在制药中的应用 - Google Patents

2,5-二羟基甲基-3,6-二甲基吡嗪及其衍生物在制药中的应用 Download PDF

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WO2010034269A1
WO2010034269A1 PCT/CN2009/075100 CN2009075100W WO2010034269A1 WO 2010034269 A1 WO2010034269 A1 WO 2010034269A1 CN 2009075100 W CN2009075100 W CN 2009075100W WO 2010034269 A1 WO2010034269 A1 WO 2010034269A1
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dimethylpyrazine
preparation
heart failure
carbon atoms
compound
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PCT/CN2009/075100
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English (en)
French (fr)
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李伟
陈龙
卞慧敏
文红梅
刘峥
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南京中医药大学
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Priority to AU2010200453A priority Critical patent/AU2010200453B8/en
Publication of WO2010034269A1 publication Critical patent/WO2010034269A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to the use of 2,5-dimethylol-3,6-dimethylpyrazine and its derivatives, and in particular to its use in the field of medicine.
  • Positive inotropic drugs are widely used in the treatment of congestive heart failure, especially when the disease is deteriorating. It is a very important treatment to improve myocardial contractility through positive inotropic drugs.
  • the currently used positive inotropic drugs are mainly:
  • cAMP-dependent positive inotropic drugs including:
  • Beta-agonists These drugs include dopamine, dobutamine, and norepinephrine, which are used to improve hemodynamic parameters in the acute phase of myocardial dysfunction in patients with heart failure.
  • the use of beta-agonists to treat such congestive heart failure is relatively ineffective due to signaling dysfunction (beta receptor down-regulation and signal uncoupling) that occurs early or late in congestive heart failure.
  • denomidine a novel oral 3 receptor partial agonist.
  • Phosphodiesterase (PDE) III inhibitor can directly regulate the contractility and relaxation of normal myocardium, producing positive muscle strength and positive relaxation. These drugs increase cAMP by inhibiting PDEIII from reducing cAMP degradation, such as amrinone, milrinone, olprinone, and vesnarinone.
  • Adenylate cyclase agonists include forskolin and colforsin daropate (Adehl, KH477).
  • cAMP-independent positive inotropic drugs mainly include:
  • Na7K + -ATPase inhibitor Increases Ca 2+ influx by inhibiting Na7K + -ATPase, such as digitalis glycosides digoxin, digotoxin and geranin C
  • calcium sensitizer The pimobendan (pimobendam), maleic stone oxazole (sulmazole) 11 and a plug opening Qin yl ketone (thiadizinone), etc., effects on the myocardium excitement - contraction coupling, causing Ca 2+ - through Increased sex, thereby increasing the sensitivity of the myofilament or the reactivity to Ca 2+ .
  • Ligustrazine is one of the active constituents of Chuanxiong, and it has significant effects on cardiovascular and cerebrovascular diseases with few side effects.
  • Liguzinediol is a derivative of ligustrazine, and 200710092853.2 discloses that 2,5-bis(phosphocholine)methyl-3,6-dimethylpyrazine obtained by this can inhibit C-reactive protein activity. The positive inotropic activity of the ligustrazine derivative has not been reported.
  • the invention content is a derivative of ligustrazine, and 200710092853.2 discloses that 2,5-bis(phosphocholine)methyl-3,6-dimethylpyrazine obtained by this can inhibit C-reactive protein activity.
  • the positive inotropic activity of the ligustrazine derivative has not been reported.
  • the present invention provides a use of 2,5-dimethylol-3,6-dimethylpyrazine (Liguzinediol) and a derivative thereof for the preparation of a medicament for treating and preventing heart failure diseases.
  • the technical solution of the present invention is: the use of a 2,5-dimethylol-3,6-dimethylpyrazine derivative for preparing a medicament for treating and preventing heart failure diseases, wherein the structural formula of the compound is :
  • R' R" is selected from the following substituents
  • R', R" of the 2,5-dimethylol-3,6-dimethylpyrazine derivative is hydrogen, an acyl group of 1 to 6 carbon atoms, an alkyl group of 1 to 6 carbon atoms or a diacid monoacyl group of 2 to 6 carbon atoms.
  • R', R" of the 2,5-dimethylol-3,6-dimethylpyrazine derivative are inorganic acid esters and salts thereof.
  • alkyl denotes a straight, branched or cyclic group and combinations thereof.
  • acyl denotes an acyl group having the number of carbon atoms and the linear, branched and cyclic structures. For example, formyl, acetyl, propionyl, butyryl, isobutyryl, cyclohexanoyl, benzoyl and the like.
  • the compounds mentioned in the invention are effective positive inotropic components.
  • the invention includes a composition of positive inotropic muscles and a disease for treating heart failure. These diseases include congestive heart failure, especially acute heart failure and severe end-stage of chronic heart failure, when the disease is in a stage of deterioration.
  • the compounds mentioned in the invention may also be effective for the treatment of diseases of heart failure caused by other causes.
  • the compounds mentioned in the invention may be used alone or in combination with other drugs to treat the above diseases.
  • the pharmaceutical composition of the compound of the invention comprises at least one compound of formula I or an acceptable pharmaceutical salt thereof, and may also comprise a pharmaceutical excipient, vehicle or carrier;
  • the term "acceptable medicine” "Salt” means a salt made of a pharmaceutically acceptable non-toxic acid or alkali.
  • the inventive compounds mentioned include the salts thereof; the term “salts” refers to the acid and/or base salts formed with inorganic and/or organic acids and bases; in addition, the salts may include zwitterions (internal salts), For example, when a compound of formula I includes both a basic moiety such as pyrazine and an acid moiety such as a carboxylic acid.
  • a salt of a compound of formula I may be prepared by a separation and purification step which may be employed during the preparation, for example, by ion exchange chromatography or by a free radical of a compound of formula I in stoichiometric amounts or in excess of an organic or inorganic acid in a suitable solvent. Medium reaction.
  • Non-toxic salts include those derived from mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, borate, thiocyanate and the like.
  • Salts prepared with organic acids include acetates (such as acetic acid or tri- 13 ⁇ 4 acetic acid, such as trifluoroacetic acid), propionate, butyrate, pivalate, hexanoate, heptanoate, undecanoate , cyclopentane propionate, benzoate, 3-phenylpropionate, oxalate, succinate, maleate, adipate, alginate, ascorbate, day (men) winter Salt, lactate, tartrate, citrate, camphorate, digluconate, fumarate, glucoheptonate, pectate, 7j salicylate, picrate, nicotinate , glycerol phosphate, sulfonate (such as methanesulfon
  • salts of acidic compounds are formed by their reaction with a suitable inorganic or organic base.
  • Typical salt groups include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts; alkaline earth metals such as calcium and magnesium salts, barium, zinc and aluminum salts; salts with organic bases such as organic amines having trialkylamines , such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephedrine, anthraquinone, ⁇ '-dibenzylidene diamine, dehydroabietylamine, hydrazine- Ethyl piperidine, benzylamine, dicyclohexylamine, or a similar pharmaceutically acceptable amine and a salt formed with an amino acid such as arginine, lysine or the like.
  • Basic nitrogen-containing groups may be associated with lower halogenated hydrocarbons (eg, methyl, ethyl, propyl, butyl chloride, bromide, iodide), dialkyl sulfates (eg, dimethyl, di-hexyl) , dibutyl and dipentyl sulfate), long chain! 3 ⁇ 4 hydrocarbons (eg mercapto, dodecyl, tetradecyl, octadecyl chloride, bromide, iodide), halogenated aromatics Quaternization (e.g., benzyl, phenethyl bromide).
  • Suitable salts include the hydrochloride, hydrogen sulfate, methanesulfonate, phosphate or nitrate salts.
  • the invention also refers to precursors and solvents for the compounds.
  • pharmaceutical precursor refers to a compound that is converted by metabolic or chemical processes to form formula (I), and/or a salt and/or solvent. For examples of these precursor derivatives, see:
  • the biohydrolyzable ester of the compound of formula (I) includes C w alkylbenzyl, 4-methoxybenzyl, 2,3-dihydroindenyl (C 9 H 9 - ), phthaloyl, methoxymethyl , C w alkanoyloxy-C w alkyl, such as acetoxymethyl, pivaloyloxymethyl, or propionyloxymethyl, alkoxycarbonyl-C ⁇ alkyl, such as methoxycarbonyl Base, or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolan-4-)- Base and other physiologically hydrolyzed esters that have been used, such as penicillin and cephalosporin.
  • the compounds of the invention may be in free form or in the form of a 7j complex.
  • the compounds of the present invention may be formulated with a drug-mediated or oral, topical, parenteral administration such as a muscle, intravenous, or subcutaneous injection of a diluent, or a formulation for inhalation spray.
  • the pharmaceutical formulation can be formulated in a conventional manner using solid or liquid vehicles, diluents and suitable addenda.
  • the compound can be formulated into tablets, capsules, granules, powders, troches, aqueous or oily suspensions and the like.
  • the components of the oral formulation can be prepared according to known pharmaceutical formulation methods which may include one or more components selected from the group consisting of sweeteners, toners, and preservatives.
  • the tablet comprises at least one compound of the formula (I) as defined above or a pharmaceutically acceptable salt thereof, which can be admixed with excipients such as lactose, starch, magnesium stearate, and cellulose derivatives.
  • excipients such as lactose, starch, magnesium stearate, and cellulose derivatives.
  • the tablets may be uncoated or coated to delay disintegration and absorption for a prolonged period of time.
  • the pharmaceutical preparation of the oral preparation of the present invention may be in the form of a hard capsule, wherein the active ingredient is mixed with a neutral solid diluent such as calcium carbonate or calcium onion; or in the form of a soft capsule, wherein the active ingredient is mixed with water and a solvent which is easy to mix.
  • a neutral solid diluent such as calcium carbonate or calcium onion
  • a soft capsule wherein the active ingredient is mixed with water and a solvent which is easy to mix.
  • the content of the compound of the present invention in the formulation ranges from 0.01% to 100% depending on the preparation process, and the content varies depending on the dose, administration route, indications and diseases.
  • the compound of the present invention is administered parenterally in an amount of 0.1 mg to 500 mg, or in the form of a tablet or a capsule, and the dose is in the range of 1 mg to 1000 mg, and the average body weight of 60-70 kg is once a day or It is administered several times.
  • the dosage unit of the drug prescription unit comprises an active ingredient ranging from 1 mg to 500 mg. Typically: lmg, 5mg, lOmg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg.
  • the formulation and dosage for the treatment of a particular patient comprising a compound of the invention will depend on a variety of factors including body shield, age, sex, medical condition, severity of the disease, route of administration and frequency.
  • the present invention provides the use of 2,5-dimethylol-3,6-dimethylpyrazine and its derivatives for the preparation of a medicament for treating and preventing heart failure diseases.
  • Figure 1 is a graph showing the effect of Compound 2 (Liguzinediol) on left ventricular pressure in rats.
  • 1 is the left ventricular pressure of the rat before administration
  • 2 is the left ventricular pressure of the rat after administration.
  • V Specific implementation methods
  • Example 1 Effect on isolated rat heart
  • Step 3 Effect of myocardial contractility on isolated rat hearts
  • Rats were intraperitoneally injected with urethane 1.2 g/kg. The hearts were removed, washed and trimmed in 100% oxygen-saturated 0 °C normal saline, and then ligated to a modified Langendorff cardiac perfusion device and retrogradely perfused through the aorta.
  • the perfusate was (in mmol/L): NaCl 117, KC1 5.7, CaCl 2 1.8, NaHC0 3 4.4, NaH 2 P0 4 1.5, MgCl 2 1.7, HEPES 20, Glucose 11, Creatine 10, Taurine 20, pH adjusted with NaOH To 7.3.
  • the baroreceptor probe was inserted into the left ventricle through the left atrium, the left ventricular pressure was recorded with a BioAmp amplifier, and the electrocardiogram was measured.
  • the results are shown in Table 1.
  • the results showed that Compounds 1 and 2 (0.1 mmol/L) significantly increased myocardial contractility, left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVEDP), and maximal left ventricular pressure (+)
  • LVSP left ventricular systolic pressure
  • LVEDP left ventricular diastolic pressure
  • LVEDP left ventricular diastolic pressure
  • the maximum value of dp/dtmax) and left ventricular pressure rise rate (-dp/dtmax) were significantly different, and there was no significant difference in heart rate changes (see attached figure). No arrhythmia was observed.
  • Figure 1 shows the effect of Compound 2 (Liguzinediol) on left ventricular pressure in rats, Figure la before administration, and Figure lb after administration.
  • Example 2 Effect on cardiac function and hemodynamic changes in normal rats
  • Rats were anesthetized with 20% urethane (Ulatan) lg/kg, placed supine on a thermostatic operating table, subcutaneously inserted into the ECG needle electrode, and input into the polygraph to measure the lead ECG and heart rate ( HR). After the ECG and temperature (37 ° C) were stabilized, the right common carotid artery was separated from the sternocleidomastoid muscle, the left ventricular cannula was ligated at the head end, and the left ventricular heart was measured by a pressure transducer connected with a multi-channel physiological recorder.
  • urethane Ulatan
  • the right femoral vein was inserted into the venous cannula for intravenous administration, and the non-inserted end was filled with a syringe filled with 40 IU/ml of heparin saline, and the multi-channel physiological signal collection system recorded data.
  • the measurement index was stable, one minute before the administration was recorded as a blank control, and Liguzinediol was dissolved in physiological saline at a dose of 5, 10, 20 mg/kg as the low, medium and high dose groups.
  • Table 2 after intravenous administration. There were no arrhythmias caused by Liguzinediol in the three dose groups after administration.
  • Liguzinediol was made into an aqueous solution, and the mice were injected into the tail vein. Liguzinediol all survived at the end of 1.5 g/kg, indicating that the compound has good safety.

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Description

2,5-二羟曱基 -3,6-二曱基吡嗪及其衍生物在制药中的应用 一、 技术领域
本发明涉及 2,5-二羟甲基 -3,6-二甲基吡嗪（ Liguzinediol )及其衍生物的应 用， 尤其涉及其在医药领域的用途。 二、 背景技术
正性肌力药被广泛地用于充血性心力衰竭的治疗， 特别是当处于疾病的恶化 阶段， 通过正性肌力药来改善心肌收缩功能是一种非常重要的治疗方法。
目前常用的正性肌力药主要有：
一、 cAMP依赖的正性肌力药， 包括：
1. β-受体激动剂： 此类药物包括多巴胺、 多巴酚丁胺和去甲肾上腺素， 用于 改善心力衰竭患者心肌功能障碍急性恶化阶段的血流动力学参数。 由于发生于充 血性心力衰竭早期或晚期的信号功能障碍 （β受体下调和信号解偶联)， 使用 β受体 激动剂治疗此类充血性心力衰竭疗效相对较差。 还有地诺帕明， 为新型口服 3受 体部分激动剂。
2. 磷酸二酯酶（PDE ) III抑制剂： cAMP可以直接调节正常心肌的收缩性和 舒张性， 产生正性肌力和正性松弛性的作用。 此类药物通过抑制 PDEIII减少 cAMP的降解来增加 cAMP, 如氨力农 （amrinone)、 米力农 （milrinone)、 奥普力农 (olprinone)和维司力农 (vesnarinone)等。
3. 腺苷酸环化酶激动剂： 此类药物有弗司扣林 (forskolin) 和达普酸考福新 (colforsin daropate, Adehl, KH477)等。
二、 cAMP非依赖的正性肌力药， 主要有：
1. Na7K+-ATP酶抑制剂： 通过抑制 Na7K+-ATP酶从而增加 Ca2+内流， 如洋地 黄类强心苷地高辛 （ digoxin ) 、 洋地黄毒苷 （ digotoxin ) 和毛花苷 C
( lanatoside ) 。
2. 钙增敏剂： 如匹莫苯 ( pimobendam ) 、 石克马唑 ( sulmazole ) 及11塞唑口秦酮 ( thiadizinone ) 等， 作用于心肌兴奋-收缩偶联过程， 引起 Ca2+—过性增加， 从而 增加肌丝的敏感性或对 Ca2+的反应性。
过去数十年来， 在正性肌力药物的研究方面取得了进步， 然而已有药物均有 不同程度的副作用， 特别是在心率失常等方面较为明显， 治疗效果不尽人意， 改 进空间仍然很大。
川芎嗪是川芎的有效成分之一， 对心脑血管疾病有显著疗效， 副作用小。 Liguzinediol是川芎嗪的衍生物， 200710092853.2公开了以其为先导得到的 2, 5- 二（磷酸胆碱） 甲基 -3 , 6-二甲基吡嗪可以抑制 C-反应蛋白活性。 有关川芎嗪衍 生物的正性肌力活性还未见报道。 三、 发明内容
技术问题： 本发明提供一种 2,5-二羟甲基 -3,6-二甲基吡嗪（ Liguzinediol )及 其衍生物在制备治疗、 预防心力衰竭疾病药物中的应用。 技术方案： 本发明的技术解决方案为： 2,5-二羟甲基 -3,6-二甲基吡嗪衍生物 在制备治疗、 预防心力衰竭疾病药物中的应用， 所述化合物的结构式为：
Figure imgf000003_0001
式中 R' R"从下列取代基中选出
(a)
(b) 1-26个碳原子的酰基及取代酰基；
(c) 1- 26个碳原子的烷基及取代烷基；
(d) 2- 10个碳原子的二酸单酰基；
(e) 磷酸单酰基及其酯；
(f) 硫酸单酰基及其酯；
(g) 硝基；
(h) 上述各基团的交叉组合。
所述 2, 5-二羟甲基 -3,6-二甲基吡嗪衍生物的 R'、 R"为氢、 1-6个碳原子的酰 基、 1-6个碳原子的烷基或 2-6个碳原子的二酸单酰基。
所述 2,5-二羟甲基 -3,6-二甲基吡嗪衍生物的 R'、 R"为无机酸酯及其盐。
2,5-二羟甲基 -3,6-二甲基吡嗪在制备治疗、 预防心力衰竭疾病药物中的应 用 所述化合物的结构式为：
Figure imgf000003_0002
2,5-二乙酰氧甲基 -3,6-二甲基吡嗪在制备治疗、 预防心力衰竭疾病药物中的 应用， 所述化合物的结构式为：
Figure imgf000003_0003
术语烷基表示直链、 支链或环状的基团以及它们的组合。 例如甲基、 乙基、 丙基、 异丙基、 丁基、 S-和 t-丁基、 戊基、 己基、 环己基、 苯基、 卞基等。
术语酰基表示具有注明碳原子数量和直链、 支链和环状结构的酰基基团。 例 如甲酰基、 乙酰基、 丙酰基、 丁酰基、 异丁酰基、 环己甲酰基、 苯甲酰基等。
发明提到的化合物是有效的正性肌力作用成分。 发明包括正性肌力的药物组 成及治疗心力衰竭的疾病。 这些疾病包括充血性心力衰竭， 特别是急性心力衰竭 及慢性心力衰竭严重的终末期， 当疾病处于恶化阶段。 发明提到的化合物可能对 治疗其它原因引起的心力衰竭的疾病也有效。
发明提到的化合物可以单独使用或者与其它药物混用治疗上述疾病。
发明提到的化合物的药物组成至少包括分子式 I的一种化合物或者它的一种 可接受的医药用盐， 也可能包含一种医药用赋形剂、 媒介物或载体； 术语"可接受 的医药用盐"是指由医药可接受的无毒酸、 碱制成的盐。 除非另外注明， 提到的发 明化合物包括其中的盐； 术语"盐"指与无机和 /或有机酸和碱形成的酸和 /或碱盐； 另外， 盐可能包括两性离子 （内盐） ， 例如， 当分子式 I的一种化合物既包括碱 性部分如吡嗪又包括酸部分如羧酸。 医药可接受的盐 （无毒， 生理可接受） ， 例 如可接受的金属和胺盐中的阳离子不产生大的毒性和生物活性。 然而， 其它盐也 可能是有用的， 因此其它盐也在本发明研究范围内。 可能在制备过程中釆用的分 离和提纯步骤， 可以制备分子式 I化合物的盐， 例如， 通过离子交换色谱或通过 分子式 I化合物游离碱基以化学计算量或过量的有机或无机酸在适当的溶剂中反 应。 医药可接受的无毒盐包括得自于无机酸例如盐酸、 氢溴酸、 硫酸、 磷酸、 硝 酸， 硼酸盐， 硫氰酸盐等。 用有机酸制得的盐包括醋酸盐 （如醋酸或三 1¾醋酸， 例如三氟乙酸） ， 丙酸盐， 丁酸盐， 新戊酸盐， 己酸盐， 庚酸盐， 十一酸盐， 环 戊烷丙酸盐， 苯甲酸盐， 3-苯丙酸盐， 草酸盐， 琥珀酸盐， 马来酸盐， 己二酸 盐， 褐藻酸盐， 抗坏血酸盐， 天（门）冬氨酸盐， 乳酸盐， 酒石酸盐， 柠檬酸盐， 樟脑酸盐， 二葡萄糖酸盐， 延胡索酸盐， 葡庚糖酸盐， 果胶酸盐， 7j杨酸盐， 苦 味酸盐， 烟酸盐， 甘油磷酸盐， 磺酸盐（如甲磺酸盐， 乙磺酸盐， 2-羟基乙磺酸 盐， 苯磺酸盐， 甲苯磺酸盐， 2-萘磺酸盐， 樟脑磺酸盐等)， 十二烷基硫酸盐等。
同样， 酸性化合物的盐由其与适当的无机或有机碱反应形成。 典型的盐基团 包括铵盐， 碱金属盐如钠、 锂、 钾盐； 碱土金属如钙和镁盐、 钡、 锌和铝盐； 与 有机碱（例如有机胺）形成的盐有三烷基胺， 如三乙胺、 普鲁卡因、 二苄胺、 N- 苄基 -β-苯乙胺、 1-麻黄胺、 Ν, Ν'-二亚苄基二胺、 脱氢枞胺、 Ν-乙基哌啶、 苄 胺、 二环己胺、 或类似的医药可接受的胺和与氨基酸如精氨酸、 赖氨酸等形成的 盐。 碱性含氮基团可能与低级卤代烃 （例如甲基、 乙基、 丙基、 丁基的氯化物、 溴化物、 碘化物） 、 二烷基硫酸酯 （例如二甲基、 二已基、 二丁基和二戊基硫酸 酯） 、 长链! ¾代烃 （例如癸基、 十二烷基、 十四烷基、 十八烷基氯化物， 溴化 物、 碘化物） 、 卤代芳烃 （例如苄基、 苯乙基溴化物）等季铵化。
适宜的盐包括盐酸盐、 硫酸氢盐、 甲磺酸盐、 磷酸盐或硝酸盐。 发明亦提到该化合物的前体和溶剂。 术语"医药前体"指一化合物通过代谢或 化学过程转换生成分子式 (I) , 和 /或一盐和 /或溶剂。 有关这些前体衍生物的例 子， 参见：
( a ) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42 , p. 309-396 , edited by K. Widder, et al. (Acamedic Press, 1985);
( b ) A Textbook of Drug Design and Development , edited by Krosgaard- Larsen and H. Bundgaard, Chapter 5 , "Design and Application of Prodrugs, " by H. Bundgaard, p. 113-191 (1991);
(c) H. Bundgaard , Advanced Drug Delivery Reviews , 8, 1-38 (1992) 由于包含羟基、 羧基化合物能形成可生物水解的酯， 它作为医药前体在体内 水解产生分子式 I化合物。 许多发生水解的实例是受消化酶的影响而发生的， 所 以该种医药前体是通过口服给药。 如果酯本身具有活性， 或者在血液里可发生水 解， 可以釆用非肠道给药方式。 分子式 (I)化合物的可生物水解酯包括 Cw烷苄 基， 4-甲氧苄基， 2,3-二氢茚基（C9H9- ) , 邻苯二甲酰， 甲氧甲基， Cw烷酰氧- Cw烷基， 如乙酰氧甲基、 新戊酰氧甲基、 或丙酰氧甲基， 烷氧甲酰氧 -C^烷 基， 如甲氧甲酰氧甲基、 或乙氧甲酰氧甲基、 甘氨酰氧甲基、 苯甘氨酰氧甲 基、 （5-甲基 -2-氧 -1,3-二氧戊环 -4- ) -甲基和其它已釆用的生理水解酯， 例如青 霉素和头孢菌素。
本发明的化合物可能是游离形式或 7j合物形式。
本发明的化合物可与药物介盾或口服、 局部、 非肠道给药如肌肉、 静脉、 或 皮下注射调配稀释剂， 或吸入喷雾的调配剂组成配方。 药物配方可以釆用固体或 液体媒介、 稀释液和适当的附加物用传统方法调配。 口服制剂， 化合物可制成片 剂、 胶嚢、 颗粒、 粉剂、 锭剂、 水性或油性悬浮液等。 口服配方的组分可以根据 已知的药物配方方法制备， 该配方可能包括一个或多个从甜味剂、 调色剂和防腐 剂中选出的组分。 例如， 片剂至少包含上述定义的分子式（ I )的一种化合物或它 的医药可接受的盐， 能与赋形剂如乳糖、 淀粉、 硬脂酸镁、 纤维素衍生物共同混 合。 片剂可以无包衣或包衣以延緩崩解与吸收而保持长时间的作用。
本发明中口服制剂的药物处方可以硬胶嚢形式， 其中有效成分与中性固体稀 释剂如碳酸钙、 碑酸钙混合； 或以软胶嚢形式， 其中有效成分与水、 易混合的溶 剂如丙烯乙二醇， 聚乙二醇和乙醇， 或油性溶剂如花生油或液体石蜡混合。 本发 明化合物在处方中的含量从 0.01%到 100%取决于制备过程， 含量不同取决于剂 量、 给药途径、 适应症和疾病等。
本发明中的化合物以注射剂非肠道给药的剂量为 O. lmg到 500mg, 或以片 剂或胶嚢形式口服， 剂量在 lmg到 lOOOmg范围内， 平均体重 60-70公斤的成人 每天一次或分几次给药。 药物处方单位剂量组成包括活性成分范围 lmg-500mg, 典型地：lmg , 5mg , lOmg , 25mg , 50mg , lOOmg , 200mg , 300mg , 400mg , 500mg。
含本发明化合物的用于治疗具体病人所用的处方和剂量取决于多种因素， 包 括体盾量、 年龄、 性别、 医学条件、 疾病轻重、 给药途径及频率。
有益效果： 本发明提供 2,5-二羟甲基 -3,6-二甲基吡嗪（ Liguzinediol )及其衍 生物在制备治疗、 预防心力衰竭疾病药物中的应用。 四、 附图说明
图 1为化合物 2(Liguzinediol)对大鼠左心室内压的影响图。 图中 1为给药前大 鼠左心室内压； 2为给药后大鼠左心室内压。 五、 具体实施方式
下面结合实施例对本发明做进一步说明， 举例是为了更好地阐述本发明， 不 暗示本发明的范围局限。
实施例 1: 对大鼠离体心脏的作用
步骤一： 2,5-二乙酰氧甲基 -3,6-二甲基吡嗪（化合物 1 ) 的制备
Figure imgf000006_0001
将无水川芎嗪 (6.80g, 50mmol)、 水醋酸（10mL)和盾量浓度为 30 %过氧化氢 (l lmL, 300mmol)的混合物于 98°C加热反应 12h, 冷却至室温， 0.03Mpa减压浓 缩至 8mL, 加盾量浓度为 20 %氢氧化钠调 pH 9.0, 滤出析出的固体， 乙酸乙酯重 结晶， 得白色针状结晶川芎嗪双氮氧化物 5.80g (产率 68.7%)。 IR KB cm : 1523 , 1504(C=N) , 1335(C=C) , 1306(CH3) 。 EI-MS /z(%): 168.1(100) , 152.1(37.96), 151.1(19.28), 135.1(18.99), 134.1(38.35), 93.1(15.71), 53.0(37.20)。
将川芎嗪双氮氧化物 （1.68g, lOmmol )置圆底烧瓶中， 加入 12mL 乙酸酐， 100°C加热 4h, O.OlMPa减压蒸除过量的醋酐， 残留物用硅胶柱层析纯化， 得到 淡黄色液体 0.81g , 产率 32.1% 。 IR(KBr)cm-1: 1743(C=0), 1458(C=C) , 1376(C=N), 1236(CH3), 1059(C-O)。 EI-MSw/z(%): 252.1(0.94) , 210.1(21.32) , 209.1(17.15), 150.1(95.39), 149.1(100), 43.0(20.14)。
步骤二： Liguzinediol (化合物 2 ) 的制备
Figure imgf000006_0002
将 2,5-二乙酰氧甲基 -3,6-二甲基吡嗪（化合物 1 ) (2.52g, lOmmol)加入盾量 浓度为 20%氢氧化钠溶液 10mL, 混合均匀， 放置 lh, 加乙酸调 pH 7, 0.03MPa 减压蒸千， 残留物硅胶柱层析分离， 得到白色针状结晶 1.10g (产率 65.5% ) 。 mpll6~117°C。 UV(MeOH) xnm: 223, 278.5; IR(KBr)cm-1: 3243(-OH), 2858 (CH3), 2922 (CH2), 1425, 1365(C=C), 1316, 1250(C=N); 1H- MR(DMSO- D6, 500MHz) δ: 4.56(4H, d), 5.15(2H, t), 2.51(6H, s); 13C- MR (DMSO-D6, 500MHz) δ: 151.15, 148.12, 62.85(CH2), 20.13(CH3); EI-MS m/z(%): 168.1(76.38), 167.1(28.90), 151.1(11.95), 150.1(18.66), 139.1(100), 138.1(26.9), 122.1(13.41), 121.1(61.54), 110.1(15.87)。
步骤三： 对大鼠离体心脏心肌收缩力的影响
大鼠腹腔注射乌拉坦 1.2g/kg, 取心脏， 在 100 %氧饱和的 0 °C生理盐水中清 洗修剪后， 连接于改良的 Langendorff 心脏灌流装置上， 经主动脉逆行灌流。 灌 流液为 （in mmol/L ) ： NaCl 117, KC1 5.7, CaCl2 1.8, NaHC03 4.4, NaH2P04 1.5, MgCl21.7, HEPES 20, Glucose 11, Creatine 10, Taurine 20, 用 NaOH调节 pH至 7.3。 压力感受器探头经左心房插入左心室， 用 BioAmp放大器记录左心室 内压， 同时测量心电图， 结果见表 1。 结果表明， 化合物 1和 2 (0.1mmol/L) 能 够明显增加大鼠离体心脏心肌收缩力， 左心室收缩压 (LVSP), 左心室舒张压 (LVEDP), 左心室压上升速度最大值 （+dp/dtmax) 、 左心室压下升速度最大值 ( -dp/dtmax ) 均具有显著性差异， 心率变化无显著性差异 （见附图）， 未见心律失 常。
表 1 化合物 1和 2对大鼠离体心脏心肌收缩力的影响
Figure imgf000007_0001
与给药前比较， *p<0.05, **p<0.01, Ap > 0.5
附图 1显示了 化合物 2(Liguzinediol)对大鼠左心室内压的影响， 图 la为 给 药前， 图 lb为 给药后。 实施例 2: 对正常大鼠心功能和血流动力学变化的影响
大鼠用 20%的氨基甲酸乙酯 （乌拉坦） lg/kg麻醉， 仰卧固定于恒温手术台 上， 四肢皮下插入心电图针形电极， 输入多导仪测 II导联心电图（ECG) 和心率 (HR)。 待心电、 温度（37°C )稳定后， 胸锁乳突肌内侧分离右颈总动脉， 头端结 扎行左心室插管， 经压力换能器与多道生理记录仪相连测量左心室心功能指标， 同时分离右侧股静脉行静脉插管用于静脉给药， 非插入端接充满 40IU/ml肝素生 理盐水的注射器， 多导生理信号釆集处理系统记录数据。 待其测量指标稳定， 记 录给药前一分钟作为空白对照， 以生理盐水溶解 Liguzinediol 分别按 5、 10、 20mg/kg作为低、 中、 高三个剂量组， 静脉注射给药 lmin内结果见表 2, 三个剂 量组在给药后未见由 Liguzinediol 所引起的心率失常。 结果可知 liguzinediol 5、 10、 20 mg.kg-1均能显著增加 LVSP、 +dp/dtmax及 -dp/dtmax等心功能指标， 降低 LVEDP , 说明 liguzinediol 能明显增强左心室收缩性， 改善大鼠心脏的舒张功 表 2 Liguzinediol对正常大鼠心功能的影响 X 士 s , n=10
Figure imgf000008_0001
与给药前比较， *P < 0.05 , **P < 0.01 毒性试验
对于一次给药急性毒性试验， Liguzinediol制成水溶液， 对小鼠尾静脉注射 给药， Liguzinediol尾静脉注射 1.5g/kg 时全部存活， 表明该化合物具有很好的安 全性。

Claims

权 利 要 求 书
2,5-二羟甲基 -3,6-二甲基吡嗪衍生物在制备治疗、 预防心力衰竭疾病药物 中的应用， 所述化合物的结构式为：
Figure imgf000009_0001
式中 R'、 R"从下列取代基中选出：
(a) 氢；
(b) 1 -26个碳原子的酰基及取代酰基；
(c) 1 -26个碳原子的烷基及取代烷基；
(d) 2- 10个碳原子的二酸单酰基；
(e) 磷酸单酰基及其酯；
(f) 硫酸单酰基及其酯；
(g) 硝基；
(h) 上述各基团的交叉组合。
根据权利要求 1所述的 2,5-二羟甲基 -3,6-二甲基吡嗪衍生物在制备治疗、 预防心力衰竭疾病药物中的应用， 其特征在于所述 2,5-二羟甲基 -3,6-二甲 基吡嗪衍生物的 R'、 R"为氢、 1-6 个碳原子的酰基、 1-6 个碳原子的烷 基或 2-6个碳原子的二酸单酰基。
根据权利要求 1所述的 2,5-二羟甲基 -3,6-二甲基吡嗪衍生物在制备治疗、 预防心力衰竭疾病药物中的应用， 其特征在于所述 2,5-二羟甲基 -3,6-二甲 基吡嗪衍生物的 R'、 R"为无机酸酯及其盐。
2,5-二羟甲基 -3,6-二甲基吡嗪在制备治疗、 预防心力衰竭疾病药物中的应 用， 所述化合物的结构式为：
Figure imgf000009_0002
2,5-二乙酰氧甲基 -3,6-二甲基吡嗪在制备治疗、 预防心力衰竭疾病药物中 的应用， 所述化合物的结构式为：
Figure imgf000009_0003
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010200453B2 (en) * 2008-09-25 2014-05-29 Nanjing University of Chinese Medicine The application of 2,5-dihyroxymethyl-3,6-dimethyl pyrazine and its derivates in pharmacy
AU2010200453A8 (en) * 2008-09-25 2014-11-13 Nanjing University of Chinese Medicine The application of 2,5-dihyroxymethyl-3,6-dimethyl pyrazine and its derivates in pharmacy

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