CN101361740B - Pharmacy use of 2,5- bis (hydroxymethyl)-3,6-dimethyl pyrazine and derivates thereof - Google Patents
Pharmacy use of 2,5- bis (hydroxymethyl)-3,6-dimethyl pyrazine and derivates thereof Download PDFInfo
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Abstract
The invention relates to the application of 2, 5-dihydroxytoluene-3, 6-dimethylpyrazine and the derivative thereof in preparing the drugs for curing or preventing cardiac failure. The structure formula of the compound is shown on the right.
Description
One, technical field
The present invention relates to 2,5-dihydroxymethyl-3, the application of 6-dimethyl pyrazine (Liguzinediol) and derivant thereof relates in particular to its purposes at field of medicaments.
Two, background technology
Inotropic agent is widely used in the treatment of congestive heart failure, particularly ought be in the deterioration stage of disease, and improving myocardium shrinkage function by inotropic agent is a kind of very important Therapeutic Method.
Inotropic agent commonly used at present mainly contains:
One, the inotropic agent of cAMP dependence comprises:
1. beta-receptor agonist: this type of medicine comprises dopamine, dobutamine and norepinephrine, is used to improve the heart failure patient myocardial dysfunction hemodynamic parameter in acute exacerbation stage.Owing to betide the congestive heart failure semiotic function obstacle in early stage or late period (beta receptor be in harmonious proportion down signal uncoupling), use this type of congestive heart failure curative effect of beta receptor agonist treatment relatively poor relatively.Also have denopamine, be new oral β1Shou Ti partial agonist.
2. phosphodiesterase (PDE) III inhibitor: cAMP can directly regulate the contractility and the diastole of normal myocardium, produces the effect of positive inotropic and positivity lusitropic.This type of medicine increases cAMP by the degraded that suppresses PDEIII minimizing cAMP, as amrinone (amrinone), milrinone (milrinone), olprinone (olprinone) and vesnarinone (vesnarinone) etc.
3. adenyl cyclase agonist: this type of medicine Forskolin (forskolin) is arranged and reach general sour colforsin (colforsin daropate, Adehl, NKH477) etc.
Two, the inotropic agent of the non-dependence of cAMP mainly contains:
1.Na
+/ K
+-atpase inhibitor: by suppressing Na
+/ K
+Thereby-ATP enzyme increases Ca
2+Interior stream is as Folium Digitalis Purpureae class cardiac glycoside digoxin (digoxin), Digitoxin (digotoxin) and lanatoside C (lanatoside).
2. calcium sensitizer: as pimobendan (pimobendam), sulmazole (sulmazole) and thiazole piperazine ketone (thiadizinone) etc., act on myocardium E-C coupling process, cause Ca
2+One crosses the property increase, thereby increases the sensitivity of myofilament or to Ca
2+Reactivity.
Obtaining progress aspect the research of positive inotropic medicament, yet existing medicine all had side effect in various degree recent decades in past, and particularly comparatively obvious at aspects such as arrhythmias, therapeutic effect is unsatisfactory, and room for improvement is still very big.
Ligustrazine is one of effective ingredient of Rhizoma Chuanxiong, and cardiovascular and cerebrovascular disease is had significant curative effect, and side effect is little.Liguzinediol is the derivant of ligustrazine, 200710092853.2 disclose with its be the guide obtain 2,5-two (phosphocholine) methyl-3, the 6-dimethyl pyrazine can suppress C-reactive protein activity.The positive inotropic activity of relevant ligustrazine derivant yet there are no report.
Three, summary of the invention
Technical problem: the invention provides a kind of 2,5-dihydroxymethyl-3, the application in preparation treatment, prophylaxis of heart failure disease medicament of 6-dimethyl pyrazine (Liguzinediol) and derivant thereof.
Technical scheme: technical solution of the present invention is: 2, and 5-dihydroxymethyl-3, the application of 6-dimethyl pyrazole oxazine derivatives in preparation treatment, prophylaxis of heart failure disease medicament, the structural formula of described chemical compound is:
R ', R in the formula " from following substituent group, select:
(a) hydrogen;
(b) acyl group of 1-26 carbon atom and substituted acyl;
(c) alkyl of 1-26 carbon atom and substituted alkyl;
(d) the diacid monoacyl of 2-10 carbon atom;
(e) mono phosphoric acid ester acyl group and ester thereof;
(f) sulphuric acid monoacyl and ester thereof;
(g) nitro;
(h) combined crosswise of above-mentioned each group.
Described 2,5-dihydroxymethyl-3, R ', the R of 6-dimethyl pyrazole oxazine derivatives " be the acyl group of hydrogen, a 1-6 carbon atom, the alkyl of a 1-6 carbon atom or the diacid monoacyl of 2-6 carbon atom.
Described 2,5-dihydroxymethyl-3, R ', the R of 6-dimethyl pyrazole oxazine derivatives " be inorganic acid ester and salt thereof.
2,5-dihydroxymethyl-3, the application of 6-dimethyl pyrazine in preparation treatment, prophylaxis of heart failure disease medicament, the structural formula of described chemical compound is:
2,5-diethyl acyl-oxygen methyl-3, the application of 6-dimethyl pyrazine in preparation treatment, prophylaxis of heart failure disease medicament, the structural formula of described chemical compound is:
The term alkyl is represented straight chain, side chain or cyclic group and their combination.For example methyl, ethyl, propyl group, isopropyl, butyl, S-and t-butyl, amyl group, hexyl, cyclohexyl, phenyl, Bian Ji etc.
The term acyl group represents to have the carboxyl groups of dated amount of carbon atom and straight chain, side chain and circulus.For example formoxyl, acetyl group, propiono, bytyry, isobutyryl, cyclohexylcarbonyl, benzoyl etc.
The chemical compound that invention is mentioned is effective positive inotropic action composition.Invention comprises that positive inotropic medicine is formed and the disease of treatment heart failure.These diseases comprise congestive heart failure, and acute heart failure and chronic heart failure serious whole latter stage particularly is when disease is in the deterioration stage.The chemical compound mentioned of invention may be also effective to the disease for the treatment of the heart failure that other reason causes.
The chemical compound that invention is mentioned can use separately or use the above-mentioned disease of treatment with other medicines.
The medicine of the chemical compound that invention is mentioned is formed and is comprised a kind of chemical compound of molecular formula I or its a kind of acceptable pharmaceutical salt at least, also may comprise a kind of pharmaceutical excipient, vehicle or carrier; Term " acceptable pharmaceutical salt " is meant the salt of being made by the acceptable non-toxic acid of medicine, alkali.Unless indicate in addition, the invention chemical compound of mentioning comprises salt wherein; Term " salt " refers to acid and/or the alkali salt with inorganic and/or organic bronsted lowry acids and bases bronsted lowry formation; In addition, salt may comprise amphion (inner salt), for example, and when a kind of chemical compound of molecular formula I had not only comprised basic moiety such as pyrazine but also comprised acid moieties such as carboxylic acid.Medicine acceptable salt (nontoxic, physiology can be accepted), the cation in for example acceptable metal and the amine salt does not produce big toxicity and biological activity.Yet other salt also may be useful, so other salt is also in research range of the present invention.The separation that may in preparation process, adopt and purification step, the salt that can prepare molecular formula I chemical compound, for example, in appropriate solvent, react with stoichiometric amount or excessive organic or inorganic acid by ion exchange chromatography or by the free base of molecular formula I chemical compound.The acceptable nontoxic salts of medicine comprises and is obtained from mineral acid for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, borate, rhodanate etc.The salt that makes with organic acid comprises acetate (as acetic acid or three halogen acetic acid, for example trifluoroacetic acids), propionate, butyrate, Pivalate, caproate, enanthate, undecylate, cyclopentane propionate, benzoate, 3-phenpropionate, oxalates, succinate, maleate, adipate, alginate, Ascorbate, my god (door) winter propylhomoserin salt, lactate, tartrate, citrate, camphorate, digluconate, fumarate, gluceptate, pectate, Salicylate, picrate, nicotinate, glycerophosphate, and sulfonate (as mesylate, esilate, the 2-isethionate, benzene sulfonate, toluene fulfonate, the 2-naphthalene sulfonate, camsilate etc.), lauryl sulfate etc.
Equally, the salt of acid compound is formed by itself and the reaction of suitable inorganic or organic base.Typical salt group comprises ammonium salt, alkali metal salt such as sodium, lithium, potassium salt; Alkaline-earth metal such as calcium and magnesium salt, barium, zinc and aluminum salt; The salt that forms with organic base (for example organic amine) has trialkylamine, as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-Herba Ephedrae amine, N, N '-dibenzylidene diamidogen, dehydroabietylamine, N-ethylpiperidine, benzylamine, hexanamine or similar medical acceptable amine and the salt that forms with aminoacid such as arginine, lysine etc.The alkalescence nitrogen-containing group may be quaternized with lower halogenated hydrocarbon (for example chloride of methyl, ethyl, propyl group, butyl, bromide, iodide), dialkylsulfates (for example dimethyl, two base, dibutyl and diamyl sulfuric ester), long-chain halogenated hydrocarbons (for example decyl, dodecyl, myristyl, octadecyl chlorination thing, bromide, iodide), halogenated aryl hydrocarbon (for example benzyl, phenethyl bromination thing) etc.
Suitable salt comprises hydrochlorate, disulfate, mesylate, phosphate or nitrate.
The precursor and the solvent of this chemical compound also mentioned in invention.Term " medical precursor " refers to that a chemical compound generates molecular formula (I) by metabolism or chemical process conversion, and/or salt and/or solvent.The example of relevant these precursor-derived things, referring to:
(a)Design?of?Prodrugs，edited?by?H.Bundgaard，(Elsevier，1985)andMethods?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，Chapter5，“Design?and?Application?of?Prodrugs，”byH.Bundgaard，p.113-191(1991)；
(c)H.Bundgaard，Advanced?Drug?Delivery?Reviews，8，1-38(1992)
But owing to comprise the ester that hydroxyl, carboxyl compound can form biological hydrolysis, it is as medical precursor hydrolysis generation molecular formula I chemical compound in vivo.The example of many generation hydrolysis is taken place by the influence of digestive enzyme, so the medical precursor of this kind is to pass through oral administration.If itself has activity ester, in blood hydrolysis can take place perhaps, can adopt the parenterai administration mode.Molecular formula (I) but the biological hydrolysis ester of chemical compound comprises C
1-6The alkane benzyl, 4-methoxybenzyl, 2,3-dihydro indenyl (C
9H
9-), phthalyl, methoxyl methyl, C
1-6Alkyloyloxyethyl-C
1-6Alkyl is as acetyl-o-methyl, pivaloyl oxygen methyl or propionyl oxygen methyl, C
1-6Carbalkoxyl oxygen-C
1-6Alkyl is as methoxycarbonyl oxygen methyl or methylamino ethoxy acyl-oxygen methyl, glycyl oxygen methyl, benzene glycyl oxygen methyl, (5-methyl-2-oxygen-1,3-dioxolanes-4-)-methyl and other physiology ester hydrolysis that has adopted, for example penicillin and cephalosporin.
Chemical compound of the present invention may be free form or hydrate forms.
Chemical compound of the present invention can with drug media or oral, local, parenterai administration such as muscle, vein or subcutaneous injection allotment diluent, or suck the blender compositing formula of spraying.Pharmaceutical formulation can adopt solid or liquid media, diluent and suitable additament to allocate with traditional method.Oral formulations, chemical compound can be made into tablet, capsule, granule, powder, lozenge, aqueous or oily suspensions etc.The component of formula of oral can be according to the preparation of known drug compounding method, and this prescription may comprise one or more components of selecting from sweeting agent, toner and antiseptic.For example, tablet comprises a kind of chemical compound of molecular formula (I) of above-mentioned definition or its medical acceptable salt at least, can with excipient such as lactose, starch, magnesium stearate, cellulose derivative mixed together.Tablet can not have coating or coating with delay disintegration and absorption and keep long effect.
The drug prescription of oral formulations can form of hard gelatin capsules among the present invention, and wherein effective ingredient and neutral solid diluent such as calcium carbonate, calcium phosphate mix; Or with the soft capsule form, wherein effective ingredient and water, miscible solvent such as propyleneglycoles, Polyethylene Glycol and ethanol, or oil-based solvent such as Oleum Arachidis hypogaeae semen or liquid paraffin mix.The content of The compounds of this invention in prescription from 0.01% to 100% depends on preparation process, and the content difference depends on dosage, route of administration, indication and disease etc.
Chemical compound among the present invention with the dosage of injection parenterai administration be 0.1mg to 500mg, or oral with tablet or capsule form, in the 1000mg scope, the per day for adults of average weight 60-70 kilogram is once or divide administration several times at 1mg for dosage.The drug prescription unit dose is formed and is comprised active component scope 1mg-500mg, typically: 1mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg.
Contain the used prescription mediating recipe amount of concrete patient of being used for the treatment of of The compounds of this invention and depend on multiple factor, comprise body constitution amount, age, sex, medical condition, disease weight, route of administration and frequency.
Beneficial effect: the invention provides 2,5-dihydroxymethyl-3, the application in preparation treatment, prophylaxis of heart failure disease medicament of 6-dimethyl pyrazine (Liguzinediol) and derivant thereof.
Four, description of drawings
Fig. 1 is the influence figure of chemical compound 2 (Liguzinediol) to the rat left ventricular pressure.1 is rat left ventricular pressure before the administration among the figure; 2 are rat left ventricular pressure after the administration.
Five, the specific embodiment
The present invention will be further described below in conjunction with embodiment, is in order to set forth the present invention better, not hint scope limitation of the present invention for example.
Embodiment 1: to the effect of isolated rat heart
Step 1: 2,5-diethyl acyl-oxygen methyl-3, the preparation of 6-dimethyl pyrazine (chemical compound 1)
With anhydrous ligustrazine (6.80g, 50mmol), glacial acetic acid (10mL) and mass concentration are 30% hydrogen peroxide (11mL, mixture 300mmol) is in 98 ℃ of reacting by heating 12h, be cooled to room temperature, 0.03Mpa be evaporated to 8mL, adding mass concentration is that 20% sodium hydroxide is transferred pH9.0, leaches the solid of separating out, re-crystallizing in ethyl acetate gets white, needle-shaped crystals ligustrazine dinitrogen oxide 5.80g (productive rate 68.7%).IR(KBr)cm
-1：1523，1504(C＝N)，1335(C＝C)，1306(CH
3)。EI-MSm/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)。
(1.68g 10mmol) puts in the round-bottomed flask, adds the 12mL acetic anhydride, and 100 ℃ are heated 4h, and 0.01MPa removes excessive acetic anhydride under reduced pressure, and the residue purification by silica gel column chromatography obtains weak yellow liquid 0.81g, productive rate 32.1% with ligustrazine dinitrogen oxide.IR(KBr)cm
-1：1743(C＝O)，1458(C＝C)，1376(C＝N)，1236(CH
3)，1059(C-O)。EI-MSm/z(％)：252.1(0.94)，210.1(21.32)，209.1(17.15)，150.1(95.39)，149.1(100)，43.0(20.14)。
The preparation of step 2: Liguzinediol (chemical compound 2)
With 2,5-diethyl acyl-oxygen methyl-3,6-dimethyl pyrazine (chemical compound 1) (2.52g, 10mmol) adding mass concentration is 20% sodium hydroxide solution 10mL, and mix homogeneously is placed 1h, add acetic acid and transfer pH7,0.03MPa evaporated under reduced pressure, the residue silica gel column chromatography separates, and obtains white, needle-shaped crystals 1.10g (productive rate 65.5%).mp116～117℃。UV(MeOH)λ
maxnm：223，278.5；IR(KBr)cm
-1：3243(-OH)，2858(CH
3)，2922(CH
2)，1425，1365(C＝C)，1316，1250(C＝N)；
1H-NMR(DMSO-D6，500MHz)δ：4.56(4H，d)，5.15(2H，t)，2.51(6H，s)；
13C-NMR(DMSO-D6，500MHz)δ：151.15，148.12，62.85(CH
2)，20.13(CH
3)；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)。
Step 3: to the influence of isolated rat heart myocardial contraction
Rats by intraperitoneal injection urethane 1.2g/kg, it is dirty to core, and after cleaning is pruned in 100% oxygen-saturated 0 ℃ of normal saline, is connected on the Langendorff cardiac perfusion device of improvement, through the retrograde perfusion of aorta.Perfusate is (in mmol/L): NaCl117, KCl5.7, CaCl
21.8, NaHCO
34.4, NaH
2PO
41.5, MgCl
21.7, HEPES20, Glucose11, Creatine10, Taurine20 regulates pH to 7.3 with NaOH.The pressure receptor probe inserts left ventricle through left atrium, with BioAmp amplifier record left ventricular pressure, measures electrocardiogram simultaneously, the results are shown in Table 1.The result shows, chemical compound 1 and 2 (0.1mmol/L) can obviously increase the isolated rat heart myocardial contraction, left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVEDP), left ventricular pressure rate of climb maximum (+dp/dtmax), the lifting speed maximum (dp/dtmax) all has significant difference under the left ventricular pressure, changes in heart rate there was no significant difference (seeing accompanying drawing) is not seen arrhythmia.
The influence of table 1 chemical compound 1 and 2 pairs of isolated rat heart myocardial contractions
With comparison before the administration,
*P＜0.05,
*P＜0.01,
ΔP〉0.5
Accompanying drawing 1 has shown the influence of chemical compound 2 (Liguzinediol) to the rat left ventricular pressure, before Fig. 1 a is administration, after Fig. 1 b is administration.
Embodiment 2: to the influence of normal rat cardiac function and hemodynamics variation
Rat is anaesthetized with 20% urethanes (urethane) 1g/kg, and lie on the back and be fixed on the constant temperature operating-table, the subcutaneous insertion electrocardiogram of extremity needle electrode, input is led instrument more and is surveyed II lead electrocardiogram (ECG) and heart rate (HR).After treating that electrocardio, temperature (37 ℃) are stablized, the inboard right common carotid artery of separating of sternocleidomastoid, head end ligation row left ventricular cannulation, link to each other with polygraph through pressure transducer and to measure the left ventricle parameters of left ventricular function, separate right lateral thigh vein row vein intubate simultaneously and be used for intravenously administrable, non-insertion termination is full of the syringe of 40IU/ml heparin-saline, leads physiological signal acquisition processing system record data more.Treat that its measurement index is stable, last minute of administration of record is as blank, with physiological saline solution Liguzinediol respectively by 5,10,20mg/kg is as basic, normal, high three dosage groups, the results are shown in Table 2, three dosage groups in the intravenous administration 1min and after administration, do not see caused arrhythmia by Liguzinediol.The result is liguzinediol5,10,20mgkg as can be known
-1All can significantly increase LVSP ,+dp/dt
MaxAnd-dp/dt
MaxEtc. parameters of left ventricular function, reduce LVEDP, illustrate that liguzinediol can obviously strengthen the left ventricle contractility, improves the diastolic function of rat heart.
Table 2Liguzinediol is to the X ± s that influences of normal rat cardiac function, n=10
With comparison before the administration,
*P＜0.05,
*P＜0.01
Toxicity test
For the single administration acute toxicity test, Liguzinediol is made aqueous solution, to the mouse tail vein injection administration, all survive during Liguzinediol tail vein injection 1.5g/kg, show that this chemical compound has good safety.
Claims (3)
1.2,5-dihydroxymethyl-3, the application of 6-dimethyl pyrazole oxazine derivatives in preparation treatment, prophylaxis of heart failure disease medicament, the structural formula of described chemical compound is:
R ', R in the formula " from following substituent group, select:
(a) hydrogen;
(b) acetyl group;
(c) combined crosswise of above-mentioned each group.
2.5-dihydroxymethyl-3, the application of 6-dimethyl pyrazine in preparation treatment, prophylaxis of heart failure disease medicament, the structural formula of described chemical compound is:
3.2,5-diethyl acyl-oxygen methyl-3, the application of 6-dimethyl pyrazine in preparation treatment, prophylaxis of heart failure disease medicament, the structural formula of described chemical compound is:
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|---|---|---|---|
| CN2008101571404A CN101361740B (en) | 2008-09-25 | 2008-09-25 | Pharmacy use of 2,5- bis (hydroxymethyl)-3,6-dimethyl pyrazine and derivates thereof |
| PCT/CN2009/075100 WO2010034269A1 (en) | 2008-09-25 | 2009-11-24 | Use of 2,5-dihydroxy-3,6-dimethylpyrazine and derivatives thereof in medicaments preparation |
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| CN2008101571404A CN101361740B (en) | 2008-09-25 | 2008-09-25 | Pharmacy use of 2,5- bis (hydroxymethyl)-3,6-dimethyl pyrazine and derivates thereof |
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| AU2010200453B8 (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 |
| CN101361740B (en) * | 2008-09-25 | 2010-11-17 | 南京中医药大学 | Pharmacy use of 2,5- bis (hydroxymethyl)-3,6-dimethyl pyrazine and derivates thereof |
| CN102204913B (en) * | 2011-04-02 | 2012-09-19 | 南京中医药大学 | Application of ligustrazine derivative in preparation of medicament for treating melanoma |
| CN102198137B (en) * | 2011-04-02 | 2012-08-01 | 南京中医药大学 | Application of ligustrazine derivant in preparing medicine for treating hepatic fibrosis |
| CN103242247B (en) * | 2013-05-10 | 2016-03-30 | 南京中医药大学 | The synthesis of H168 and process for purification |
| CN107827827A (en) * | 2017-12-13 | 2018-03-23 | 南京中医药大学 | A kind of synthesis technique of H168 |
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| CN101361740B (en) * | 2008-09-25 | 2010-11-17 | 南京中医药大学 | Pharmacy use of 2,5- bis (hydroxymethyl)-3,6-dimethyl pyrazine and derivates thereof |
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Non-Patent Citations (3)
| Title |
|---|
| 刘建建.川芎嗪衍生物的设计、合成及其生物活性研究.山东大学硕士学位论文.2006,30,49. * |
| 瞿红旗等.川芎嗪治疗心力衰竭的临床观察.中原医刊27 10.2000,27(10),45-46. |
| 瞿红旗等.川芎嗪治疗心力衰竭的临床观察.中原医刊27 10.2000,27(10),45-46. * |
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