CN103301132A - Ligustrazine secondary-alcohol and tertiary-alcohol derivative and application for same in pharmacy - Google Patents
Ligustrazine secondary-alcohol and tertiary-alcohol derivative and application for same in pharmacy Download PDFInfo
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Abstract
The invention discloses a ligustrazine secondary-alcohol and tertiary-alcohol derivative and an application for the same. The compound has the structural general formula defined in the specification, wherein R' is hydrogen or methyl; and R' is a saturated or unsaturated hydrocarbyl having 1-10 carbon atoms. The ligustrazine secondary-alcohol and tertiary-alcohol derivative disclosed by the invention reserves the biological activity of positive inotropic action of the ligustrazine secondary-alcohol and tertiary-alcohol derivativ, and obviously prolongs the half-life period of medicine metabolism.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to ligustrazine second month in a season, tertiary alcohols derivant and the application in pharmacy thereof.
Background technology
Heart failure is the result that cardiac function worsens due to the various cardiac disorders, also is one of main reason of most of cardiovascular patient death.Heart failure is that the oligemia of discharge, so that a kind of pathological and physiological condition of Arterial system hypoperfusion and body (lung) venous congestion claim again congestive heart failure clinically because cardiac pumping function reduces.In the therapeutic process of congestive heart failure, particularly ought be in the deterioration stage of disease, improve myocardium shrinkage function by inotropic agent and become a kind of very important Therapeutic Method.
Ligustrazine is one of effective ingredient of chuanxiong, and chemistry 2，3，5，6-tetramethylpyrazine by name has multiple pharmacologically active, especially cardiovascular and cerebrovascular disease is had significant curative effect.Liguzinediol be ligustrazine through structural modification and the ligustrazine diol, derivatives, chemical constitution is as follows:
Pharmacological research finds that liguzinediol has obvious positive inotropic action, and does not have the arrhythmia side effect.Study on mechanism shows, different from traditional positive inotropic medicament, liguzinediol brings into play positive inotropic action by the SERCA2a target spot that acts in the myocardial cell, this target spot is as the new treatment target spot of heart failure, (Long Chen* more and more gets more and more people's extensive concerning, Yi Xu, Wei Li, et al.The Novel Compound Liguzinediol Exerts Positive Inotropic Effects in Isolated Rat Heart via Sarcoplasmic Reticulum Ca
2+ATPase-dependent Mechanism, Life Sciences, 2012,91:402-408).
Yet, pharmacokinetic shows, liguzinediol is as micromolecular compound, and metabolic rate in animal body is relatively very fast, half-life only is 1.6h, and its reason mainly contains: (1) this chemical compound has formed glucuronide conjugate soon in vivo and has excreted; (2) methylol and pendant methyl all easily are oxidized to the larger chemical compound of polarity and water solublity and excrete.Because the Half-life in vivo of liguzinediol is shorter, therefore prolong the metabolic half life of this chemical compound by structural modification, keep simultaneously positive inotropic biological activity, this seems especially necessary to those skilled in the art.
Summary of the invention
In view of the deficiencies in the prior art, the present invention is from the angle of structure and metabolic rate and positive inotropic activity relation, the position that affects accretion rate is modified, thus a kind of long half time is provided and have that the ligustrazine of positive inotropic activity is secondary, tertiary alcohols derivant and the application in pharmacy thereof.
In order to realize above-mentioned purpose of the present invention, the inventor explores and research by lot of experiments, has finally obtained following technical scheme:
Ligustrazine is secondary, the tertiary alcohols derivant, has following general structure:
Wherein R ' is hydrogen or methyl; R " is the saturated or unsaturated alkyl of 1～10 carbon atom.
Preferably, the above-mentioned ligustrazine second month in a season, tertiary alcohols derivant, wherein R " is the saturated or unsaturated alkyl of 1～4 carbon atom.
Further preferably, above-mentioned ligustrazine is secondary, the tertiary alcohols derivant, and wherein R ' is hydrogen or methyl; R " is methyl, ethyl.
Again further preferably, ligustrazine of the present invention is secondary, the tertiary alcohols derivant is following chemical compound: 2,5-two-(1-hydroxyethyl)-3,6-dimethyl pyrazine, 2,5-two-(1-hydroxypropyl)-3,6-dimethyl pyrazine, 2,5-two (1-methyl isophthalic acid-hydroxyethyl)-3,6-dimethyl pyrazine, 2,5-two (1-methyl isophthalic acid-hydroxypropyl)-3,6-dimethyl pyrazine.
In order to improve the one-tenth property of medicine of above-claimed cpd, such as character such as the chemical stability of chemical compound, water solublity, the present invention provides also that above-mentioned ligustrazine is secondary, the officinal salt of tertiary alcohols derivant.
Term " officinal salt " refers to the salt made with the acceptable nontoxic acid and alkali reaction of medicine.The salt made of the acceptable non-toxic acid of medicine comprises inorganic acid salt, hydrochlorate for example, hydrobromate, sulfate, phosphate, nitrate, borate, rhodanate etc.; The salt that makes with organic acid comprises acetate (such as acetic acid or three halogen acetic acid, trifluoroacetic acid), 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 (such as mesylate, esilate, the 2-isethionate, benzene sulfonate, toluene fulfonate, the 2-naphthalene sulfonate, camsilate etc.), lauryl sulfate etc.
Preferably, above-mentioned ligustrazine officinal salt secondary, the tertiary alcohols derivant is that ligustrazine is secondary, hydrochlorate, disulfate, mesylate, phosphate or the nitrate of tertiary alcohols derivant.These officinal salts are to obtain by ligustrazine is secondary, tertiary alcohols derivant and acid reaction correspondingly.
The ligustrazine second month in a season, tertiary alcohols derivant and the officinal salt thereof that the present invention relates to are effective positive inotropic medicament compositions, can treat the disease of 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.In addition, the chemical compound mentioned of the present invention may be also effective to the disease for the treatment of the heart failure that other reason causes.Based on this, the present invention also provides the pharmaceutical applications of above-claimed cpd, that is: the above-mentioned ligustrazine second month in a season, tertiary alcohols derivant and officinal salt thereof the application in the medicine of preparation treatment or prophylaxis of heart failure disease.In this pharmaceutical applications, described heart failure disease comprises acute heart failure, chronic heart failure serious whole latter stage.
The lead compound liguzinediol that relates among the present invention also can be designed to other derivants, by increasing sterically hindered its metabolic half life that prolongs, as being substituted with oxygen, two hydrogen on the hydroxyl carbon obtain 3,6-dimethyl-2,5-pyrazine dioctyl phthalate or the hydrogen on the hydroxyl replaced with alkyl make ether.But further studies show that 3,6-dimethyl-2, the active of 5-pyrazine dioctyl phthalate obviously descends; The ether derivative of liguzinediol is such as 2,5-dimethoxy methyl-3,6-dimethyl pyrazine, 2, and 5-diethoxy methyl-3, the 6-dimethyl pyrazine then can cause arrhythmia.
3,6-dimethyl-2,5-pyrazine dioctyl phthalate
2,5-dimethoxy methyl-3,6-dimethyl pyrazine 2,5-diethoxy methyl-3,6-dimethyl pyrazine
The present invention creatively is replaced as secondary alcohol or the tertiary alcohol with two primary alconols of liguzinediol, increase the sterically hindered of pendant hydroxyl group and methyl, thereby slow down the oxidation rate of side chain and the ability of being combined with glucuronic acid, resulting ligustrazine is secondary, the tertiary alcohols derivant has not only kept positive inotropic biological activity, and obviously prolonged the drug metabolism half-life, but can not cause arrhythmia.
Description of drawings
Curve (n=6) when figure is Oral Administration in Rats to the medicine of drug compound 2 rear basic, normal, high three dosage groups.
The specific embodiment
Following examples further describe preparation process, biological activity and the pharmacokinetics index of the compounds of this invention, embodiment only is used for the purpose of illustration, do not limit the scope of the invention, apparent change and modification that while those of ordinary skills make according to the present invention are also contained within the scope of the invention.Illustrate that as taking a single example in the present embodiment series compound of the present invention can obviously postpone the metabolic half life of chemical compound, be easy to infer according to the general knowledge of this area, the chemical compound that different big or small groups replace also can prolong metabolic half life to some extent.
Embodiment 1:2,5-two-(1-hydroxyethyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 1)
Step 1: intermediate 3,6-dimethyl-2, the preparation of 5-pyrazine dicarbaldehyde
Get 0.1mol (16.8g) liguzinediol (H168) and be dissolved in the 300ml chloroform, add 1.40mol manganese dioxide 120g, reflux 6h, cooling, sucking filtration, the reclaim under reduced pressure chloroform, residue is with silica gel chromatography, and petroleum ether (60～90 ℃)/ethyl acetate isocratic elution gets the glassy yellow crystallization, productive rate 75.2%, mp148.5～150.5 ℃.IR(KBr)cm
-1：2971、2857(CH
3)，1702(C＝0)，1424、1390(C＝N)，1239、1177(C＝C)；
1H-NMR(CDCl
3，300MHz)δ：3.06(6H，s，2×CH
3)，10.23(2H，s，2×CHO)；
13C-NMR(CDCl
3，75MHz)δ：23.56(CH
3)，148.72(C-3，6)，157.47(C-2，5)，178.63(CH0)；MS(m/z)：Calcd?for{[C
8H
9N
20
2]
+}165.0664，found165.0665。
Step 2: 2,5-two-(1-hydroxyethyl)-3, the preparation of 6-dimethyl pyrazine
With 3.28g (0.02mol) 3,6-dimethyl-2,5-pyrazine dicarbaldehyde is dissolved in the 60ml anhydrous tetrahydro furan, stirs lower 20ml methyl-magnesium-bromide (the 2M)-THF solution that slowly drips, and dropwises, and stirs 30min under the room temperature, continues reflux 10h.Reaction is cooled to room temperature after finishing, and slowly adds 40ml10% sulphuric acid, regulate pH10 with 20%NaOH solution, (6 * 60ml), merging chloroform extraction liquid is washed to neutrality with chloroform extraction, anhydrous magnesium sulfate drying, decompression and solvent recovery, residue be with the silica gel column chromatogram separating purification product, petroleum ether (60～90 ℃)/ethyl acetate gradient elution, get weak yellow liquid chemical compound (a), productive rate 44.9%.IR(KBr)cm
-1：3268(OH)，2974(CH
3)，2929(CH
2)，1463、1415(C＝N)，1300、1165(C＝C)，1098(C-0)；
1H-NMR(CDCl
3，300MHz)δ：1.44～1.42(6H，d，J＝6.3Hz，2×CH-CH
3)，2.53(6H，s，2×CH
3)，4.11～4.14(2H，brs，2×OH)，4.96～5.01(2H，q，J
1＝6.3Hz，J
2＝12.9Hz，2×H0-CH-)；
13C-NMR(CDCl
3，75MHz)δ：20.02(-CH
3)，23.61(＝C-
CH
3)，65.76(-CH-OH)，145.68(C-3，6)，153.55(C-2，5)；MS(m/z)：Calcd?for{[C
10H
17N
20
2]
+}197.1290，found197.1282。
Chemical compound 1
Embodiment 2:2,5-two-(1-hydroxypropyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 2)
Step 1 is with embodiment 1, and the methyl-magnesium-bromide with in ethylmagnesium bromide replacement embodiment 1 step 2 gets chemical compound 2 with legal system.White solid 1.70g, productive rate 38%.mp124～126℃。IR(KBr)cm
-1：3407(-OH)，2957、2970(CH
3)，2927(CH
2)，1455、1428、1372(C＝C)，1243、1154(C＝N)，1051(C-0)；
1H-NMR(CDCl
3，300MHz)δ：0.97～1.02(6H，t，2×CH
3)，1.53～1.86(4H，m，2×CH
2-)，2.52(6H，s，2×＝C-CH
3)，4.01～4.09(2H，brs，2×OH)，4.76～4.80(2H，t，2×CH-)；
13C-NMR(CDCl
3，75MHz)δ：9.68(-CH
3)，20.06(-CH
2-)，30.47(＝C-
CH
3)，70.55(-CH-OH)，145.88(C-3，6)，152.67(C-2，5)；MS(m/z)：Calcd?for{[C
12H
21N
20
2]
+}225.1603，found225.1617。
Chemical compound 2
Embodiment 3:2,5-two-(1-hydroxybutyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 3)
Step 1 is with embodiment 1, and the methyl-magnesium-bromide with in propyl group magnesium bromide replacement embodiment 1 step 2 gets chemical compound 3 with legal system.White solid 1.69g, productive rate 33.5%.mp117.5～119.5℃。IR(KBr)cm
-1：3402(OH)，2960、2871(CH
3)，2920(CH
2)，1451、1374(C＝C)，1315、1155(C＝N)，1073(C-0)；
1H-NMR(CDCl
3，300MHz)δ：0.93～0.98(6H，t，2×CH
3)，1.46～1.62(4H，m，2×CH
2-CH
3)，1.65～1.72(4H，m，2×CH
2-CH
2)，2.51(6H，s，2×＝C-CH
3)，4.12(2H，brs，2×OH)，4.81～4.85(2H，t，2×CH)；
13C-NMR(CDCl
3，75MHz)δ：13.87(-CH
3)，18.65(-
CH
2-CH
3)，20.02(H0-CH-
CH
2)，39.81(＝C-
CH
3)，69.16(-CH-OH)，145.75(C-3，6)，152.92(C-2，5)；MS(m/z)：Calcd?for{[C
14H
25N
20
2]
+}253.1916，found253.1923。
Chemical compound 3
Embodiment 4:2,5-two (1-methyl isophthalic acid-hydroxyethyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 4)
Step 1: 2,5-diacetyl-3, the preparation of 6-dimethyl pyrazine
With 2,5-dimethyl pyrazine 10.8g (0.1mol) and 40% acetaldehyde solution 151ml (47.1g, 1.07mol) be mixed in the sulfuric acid solution of 50ml3.4M, under the condition of ice bath, drip simultaneously 70% hydrogen peroxide tert-butyl alcohol 60ml (416mmol) and 400ml ferrous sulfate (134g, 480mmol) dropwise in 1h, continue ice bath 1h.After reaction finishes, and ethyl acetate extraction (5 * 300ml), combining extraction liquid is washed to neutrality, anhydrous sodium sulfate drying, and decompression and solvent recovery, residue is syrupy shape, places, and solid crystal is separated out in cooling.Use recrystallizing methanol, get golden yellow needle 6, productive rate 70.8%.mp98.5～102℃。IR(KBr)cm
-1：1169(C＝0)，1414、1373(C＝C)，1103(C＝N)；
1H-NMR(300Hz，CDCl
3)δ：2.72(6H，s，2×-CH
3)，2.81(6H，s，2×O＝C-CH
3)；
13C-NMR(75Hz，CDCl
3)δ：22.79(-CH
3)，27.80(0＝C-
CH
3)，146.64(＝
C-CH
3)，149.87(＝
C-C＝O)，200.99(C＝0)；MS(m/z)：Cacld?for{[C
10H
13N
20
2]
+}193.0730.found193.0697。
Step 2: 2,5-two (1-methyl isophthalic acid-hydroxyethyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 4)
40ml methyl-magnesium-bromide-THF solution (2M) is placed the round bottom reaction bulb, drip 2.88g (0.015mol) 2 under the room temperature, 5-diacetyl-3, the tetrahydrofuran solution 50ml of 6-dimethyl pyrazine dropwises, and continues room temperature 30min.Then change the reflux device into, 60 ℃ of reaction 8h, TLC follows the tracks of and detects to reacting completely, be cooled to room temperature, slowly drip the 50ml saturated ammonium chloride solution, transfer pH9.0 with 20%NaOH, with chloroform extraction (5 * 80ml), combining extraction liquid, washing, anhydrous sodium sulfate drying, residue is with the silica gel column chromatography separating purification product, petroleum ether (60～90 ℃)/ethyl acetate isocratic elution gets white solid, productive rate 29.4%.mp126.5～128.5℃。IR(KBr)cm
-1：3416(-OH)，2981、2932(-CH
3)，1449、1406、1366(C＝C)，1156、1117(C＝N)；
1H-NMR(300Hz，CDCl
3)δ：1.61(12H，s，4×-CH
3)，2.69(6H，s，2×-CH
3)，5.81(2H，s，2×-C-OH)；
13C-NMR(75Hz，CDCl
3)δ：23.01(-CH
3)，28.71(＝C-
CH
3)，70.77(C-OH)，144.47(＝
C-CH
3)，155.26(＝
C-C-OH)；MS(m/z)：Cac?l?d?for{[C
12H
15N
20
2]
+}225.1334，found225.1341。
Chemical compound 4
Embodiment 5:2,5-two (1-methyl isophthalic acid-hydroxypropyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 5)
Step 1 is with embodiment 4, and the methyl-magnesium-bromide with in ethylmagnesium bromide replacement embodiment 4 step 2 gets chemical compound 6 with legal system.Brown solid 1.45g, productive rate 38.4%.mp58～60.5℃。IR(KBr)cm
-1：3376(OH)，2972、2935、2878(CH
3)，1457、1413、1370、1339(C＝C)，1191、1168、1125(C＝N)；
1H-NMR(300Hz，CDCl
3)δ：0.68～0.75(6H，m，2×-CH
2-CH
3)，1.58(6H，s，2×-CH
3)，1.91～2.04(4H，m，2×-CH
2-)，2.67(6H，s，2×N＝C-CH
3)，5.82(2H，brs，2×OH)；
13C-NMR(75Hz，CDCl
3)δ：8.04(-CH
2-CH
3)，22.9(OH-C-CH
3)，27.2(-CH
3)，33.5(-CH
2-)，73.2(-C-OH)，144.6(N＝
C-CH
3)，154.2(N＝
C-C-OH)；MS(m/z)：Cacld?for{[C
14H
25N
2O
2]
+}253.1607，found253.1603。
Chemical compound 5
Embodiment 6:2,5-two (1-methyl isophthalic acid-hydroxybutyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 6)
Step 1 is with embodiment 4, and the methyl-magnesium-bromide with in propyl group magnesium bromide replacement embodiment 4 step 2 gets chemical compound 7 with legal system.Weak yellow liquid 1.45g, productive rate 34.5%.IR(KBr)cm
-1：3469(OH)，2962(CH
3)，1694(C＝C)，1409(C＝N)，1079(C-H)；
1H-NMR(300Hz，CDCl
3)δ：0.86(6H，t，2×-CH
3)，1.37(4H，m，2×-CH
2-)，1.57(6H，s，-CH
3)，1.91(4H，m，2×-CH
2-)，2.67(6H，s，2×-CH
3)，5.84(2H，brs，2×-OH)；
13C-NMR(75Hz，CDCl
3)δ：14.2(-CH
3)，１7.1(-CH
2-)，22.9(-
CH
3-C-OH)，27.6(-CH
2-)，43.11(N＝C-
CH
3)，72.95(C-OH)，144.5(N＝
C-CH
3)，154.4(N＝
C-C-OH)；MS(m/z)：Cacld?for{[C
16H
29N
2O
2]
+}281.1891，found?281.1883。
Chemical compound 6
Embodiment 7:2,5-two (1,3-dimethyl-1-hydroxybutyl)-3, the preparation of 6-dimethyl pyrazine (chemical compound 7)
Step 1 is with embodiment 4, and the methyl-magnesium-bromide with in 2-methyl-propyl magnesium bromide replacement embodiment 4 step 2 gets chemical compound 8 with legal system.Rufous liquid 1.38g, productive rate are 29.4%.UV (MeOH) enters
MaxNm:236.7,290; IR (KBr) cm
-1: 3401 (OH), 2956,2872 (CH
3), 1461,1413,1370 (C=C), 1165,1126 (C=N), 1061 (C-H):
1H-NMR (300Hz, CDCl
3) δ: 0.92 (6H, d, J=6.6Hz, 2 *-CH
3), 0.96 (6H, d, J=6.6Hz, 2 *-CH
3), 1.52 (2H, m, 2 *-CH-), 1.58 (6H, s, 2 *-OH-C-
CH
3), 1.85 (4H, m, 2 *-CH
2-), 2.60 (6H, s, 2 * N-
CH
3), 5.90 (2H, brs, 2 *-OH);
13C-NMR (75Hz, CDCl
3) δ: 22.95 (CH
3), 23.50 (CH
3), 23.72 (CH
2-), 24.20 (CH-), 28.61 (OH-C-
CH
3), 49.0 (N-
CH
3), 73.1 (C-OH), 144.62 (N=
C-CH
3), 154.31 (N=
C-C-OH); MS (m/z): Cacld for{[C
18H
33N
2O
2]
+309.2166, found 309.2158.
Chemical compound 7
The stripped positive inotropic activity experimental study of embodiment 8 chemical compounds
Adopt isolated heart Langendorff perfusion method, to normal isolated rat heart left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), maximal ascending rate of internal pressure of left ventricle (+dp/dt
Max), maximal descending rate of internal (dp/dt
Max) and the index such as heart rate (HR) observe.
Rats by intraperitoneal injection urethane 1.2g/kg cores dirty, 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 HEPES 20, Glucose 11, and Creatine 10, and Taurine 20, regulate pH to 7.3 with NaOH.The pressure receptor probe inserts left ventricle through left atrium, with BioAmp amplifier record left ventricular pressure, measures simultaneously electrocardiogram, the results are shown in Table 1.The result shows, 1～7 pair of normal isolated rat heart of chemical compound has comparatively significantly positive inotropic action, left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVEDP), maximal ascending rate of internal pressure of left ventricle (+dp/dtmax), maximal descending rate of internal (dp/dtmax) all has significant difference, and present dose dependent, and heart rate is had no significant effect.
Table 1 ligustrazine is secondary, tertiary alcohol derivant is on the impact of normal Cardiac Function in Rat
Adopt variance analysis to compare in twos:
aWith compare P＜0.05 before the administration;
bWith compare P＞0.05 before the administration;
cWith 1 μ mL
-1Compare P＜0.05;
dWith 1 μ mL
-1Compare P＞0.05;
eWith 10 μ mL
-1Compare P＜0.05;
fWith 10 μ mL
1-Compare P＞0.05.
Embodiment 9 ligustrazine are secondary, the test of the pharmacokinetic of tertiary alcohols derivant
18 of Sprague-Dawley (SD) rats (250 ± 20g,
♀ half and half), fasting 12h before the test freely drinks water.Give 2,5-two-(1-hydroxypropyl)-3 by gavage and tail vein injection dual mode respectively, 6-dimethyl pyrazine (chemical compound 2) aqueous solution 10,20,40mgkg
-1, before administration and after the administration 0.08,0.17,0.25,0.50,1,2,3,4,6,8,10,12,24h eye socket blood sampling, anticoagulant heparin, 5000rmin
-1Centrifugal 5min divides and gets blood plasma, puts-20 ℃ and saves backup.
Get the caffeine internal standard substance an amount of, accurately weighed, add methanol and make the solution that every 1ml contains 100 μ g, as inner mark solution.
The accurate rat plasma 100 μ L that draw put in the 2ml rub oral examination tube, accurate inner mark solution 10 μ L and ethanol 1ml, supersound extraction 5min, the centrifugal (5000rmin of adding
-1) 5min, the accurate supernatant 0.9mL that draws places the 1.5mL centrifuge tube, N in 40 ℃ of water-baths
2Dry up, methanol 200 μ L redissolve, ultrasonic 3min, 10000rmin
-1Centrifugal 3min draws supernatant and namely gets need testing solution.
Get chemical compound 2 reference substances an amount of, accurately weighed, add methanol and make the solution that 1mL contains 1mg, in contrast the product storing solution.Accurate absorption reference substance storing solution is an amount of, accurate inner mark solution 10 μ L and the methanol 180 μ L of adding, and mixing makes respectively the reference substance solution that every 1mL contains 0.4,2.0,10,50 μ g.
Measure the content of chemical compound 2 in each plasma sample with the HPLC method, chromatographic column: Phecd
x-C18 (4.6mm * 250mm, 5 μ m); Mobile phase: with methanol-water solution gradient eluting (seeing Table 2); Flow velocity: 1mlmin
-1Column temperature: 30 ℃; Detect wavelength: 278nm; Sample size: 20 μ l.
Table 2 eluent gradient elution program table
Assay method verifies through methodology, and the blood drug level of chemical compound 2 is respectively at 0.28～73mgL
-1Be linear in the scope, extraction recovery all＞80% in a few days, day to day precision RSD＜10%, meets the biological sample analysis requirement.
Chemical compound in the rat plasma after the administration 2 is measured, calculated content with the ratio (Ai/As) of the peak area (Ai) of chemical compound 2 and interior mark peak area (As), with the match of DAS2.0 software and calculate its pharmacokinetic parameter.The t of chemical compound 2 basic, normal, high three dosage
1/2Be respectively 3.7h, 3.6h and 3.5h; AUC is 34mghL respectively
-1, 70mghL
-1And 135mghL
1-, CL is about 0.3Lh
-1Kg
-1Bioavailability reaches 90%.
Claims (8)
1. secondary, the tertiary alcohols derivant of ligustrazine has following general structure:
Wherein R ' is hydrogen or methyl; R " is the saturated or unsaturated alkyl of 1～10 carbon atom.
2. secondary, the tertiary alcohols derivant of ligustrazine according to claim 1 is characterized in that: R " being the saturated or unsaturated alkyl of 1～4 carbon atom.
3. secondary, the tertiary alcohols derivant of ligustrazine according to claim 1, it is characterized in that: R ' is hydrogen or methyl; R " is methyl or ethyl.
4. the officinal salt of secondary, the tertiary alcohols derivant of the arbitrary described ligustrazine of claim 1-3.
5. the officinal salt of secondary, the tertiary alcohols derivant of ligustrazine according to claim 4 is characterized in that, described officinal salt is hydrochlorate, disulfate, mesylate, phosphate or nitrate.
6. secondary, the application of tertiary alcohols derivant in the medicine of preparation treatment or prophylaxis of heart failure disease of the arbitrary described ligustrazine of claim 1-3.
7. the application of officinal salt in the medicine of preparation treatment or prophylaxis of heart failure disease of secondary, the tertiary alcohols derivant of the described ligustrazine of claim 4.
8. application according to claim 7 is characterized in that: described heart failure disease comprises acute heart failure, chronic heart failure serious whole latter stage.
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| WO2024061367A1 (en) * | 2022-09-23 | 2024-03-28 | 山东如至生物医药科技有限公司 | Novel compound, pharmaceutical composition thereof, and use thereof |
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| CN102204913A (en) * | 2011-04-02 | 2011-10-05 | 南京中医药大学 | Application of ligustrazine derivative to preparation of medicament for treating melanoma |
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