CN102241636A - Derivative of ligustrazine - Google Patents
Derivative of ligustrazine Download PDFInfo
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- CN102241636A CN102241636A CN201110122322XA CN201110122322A CN102241636A CN 102241636 A CN102241636 A CN 102241636A CN 201110122322X A CN201110122322X A CN 201110122322XA CN 201110122322 A CN201110122322 A CN 201110122322A CN 102241636 A CN102241636 A CN 102241636A
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Abstract
The invention relates to the field of antithrombotic medicines, and provides a ligustrazine derivative with a structure as described in formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides a preparation method for the derivative or the pharmaceutically acceptable salt thereof, a pharmaceutical composition of the derivative or the salt, and application of the derivative or the salt as an active ingredient in preparing medicines for treating cerebral thrombus, cerebral infarction, angina pectoris, myocardial infarction, coronary heart disease and arrhythmia related to thrombus.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to a kind of ligustrazine derivant or its pharmacy acceptable salt that a class obtains through chemosynthesis, the preparation method of derivative or its pharmacy acceptable salt, pharmaceutical composition and as effective constituent in the purposes aspect preparation treatment cerebral thrombosis, cerebral infarction, stenocardia, myocardial infarction, coronary heart disease, the medicines such as irregular pulse relevant with thrombus.
Background technology
The whole world annual cerebral thrombosis, cerebral infarction, stenocardia, myocardial infarction etc. and thrombosis diseases associated seize up to ten million people's life.Cardiovascular and cerebrovascular diseases has become the No.1 formidable enemy who has a strong impact on health of people and life.
Tetramethylpyrazine (tetramethylpyrazine), have another name called Ligustrazine (Ligustrazine), being that Chinese scholar is separated the alkaloid monomer of purifying out from umbelliferae Ligustrum plant Ligusticum wallichii (Ligusticum wallichii), is one of effective constituent of Ligusticum wallichii.Also can from meta-bolites, rye grass and the galbanum of Bacillus subtilus, separate and obtain.
Modern pharmacology studies have shown that: it has vasodilation, increases coronary blood flow and cerebral blood flow, anticoagulant and reduction biologically active pdgf, brings high blood pressure down, improves myocardial hypoxia tolerance etc.Clinical coronary heart disease, stenocardia, vasculitis and the acute obliterative vascular disease of being used for, as the treatment of cerebral blood supply insufficiency, cerebral thrombosis, cerebral arteries infraction, cerebral arteriosclerosis etc., curative effect is sure.Clinical application is in recent years expanded to some extent, myocardial infarction, reperfusion arrhythmia, migraine, hyperlipidemia, pulmonary heart disease, heart failure, renal failure etc. there is certain curative effect, dosage seldom has untoward reaction to take place from 40mg to 2000mg, illustrates that the Ligustrazine safety range is very big.But find that in application Ligustrazine has shortcomings such as metabolism is fast, the transformation period is short, bioavailability is low, and curative effect and unsatisfactory, life-time service has the serum globulin of causing to reduce the possibility of chronic toxicity effects such as serum flesh is intoxicated, blood sugar increase.
2-methylol-3,5,6-trimethylpyrazine are the interior metabolism product of Ligustrazine, this meta-bolites also has anticoagulation and other vasoactive, be a good lead compound, synthesize its derivative by structural modification, expectation searches out better antithrombotic reagent.
Summary of the invention
One object of the present invention is, discloses a kind of ligustrazine derivant, 2-methylol-3,5,6-trimethylpyrazine derivative or its pharmacy acceptable salt.
Another object of the present invention is, discloses 2-methylol-3,5, the synthetic method of 6-trimethylpyrazine derivative or its pharmaceutically-acceptable salts.
A further object of the present invention is, discloses with 2-methylol-3,5, and 6-trimethylpyrazine derivative or its pharmacy acceptable salt are the pharmaceutical composition of activeconstituents.
A further object of the invention is, 2-methylol-3 is disclosed, 5,6-trimethylpyrazine derivative or its pharmacy acceptable salt are as the application of antithrombotic reagent aspect, especially for the purposes of medicine aspects such as preparation treatment cerebral thrombosis, cerebral infarction, stenocardia, myocardial infarction.
The present invention relates to compound or its pharmacy acceptable salt of general formula (I) structure:
Wherein, R is:
(1)NO
2；
Representative compound is:
(3,5,6-trimethylpyrazine-2-yl) methyl alcohol nitric ether (ZPR01)
4-((nitre acyloxy) methyl) phenylformic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester (ZPR02)
The 3-methyl isophthalic acid, 2,5-oxadiazoles-2-oxide compound-4-formic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester (ZPR03)
4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-ketobutyric acid (3-nitryl oxygen methyl) phenol ester (ZPR04)
2-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-2-oxo alcohol nitrate ester (ZPR05)
3-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-3-oxo propyl alcohol nitric ether (ZPR06)
Nicotinicum Acidum 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester (ZPR07)
3-(4-hydroxyl-3-methoxyl group-phenyl) vinylformic acid 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester (ZPR08)
The compound of general formula (I) structure contains the pyrazine parent nucleus, and pharmacy acceptable salt is meant the salt that generates with organic acid, inorganic acid reaction.Mineral acid has hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid etc., and organic acid has Citric Acid, methylsulfonic acid, fumaric acid, propanedioic acid etc.
The preparation method of formula I compound of the present invention.With 2-methylol-3,5, the 6-trimethylpyrazine is a starting raw material, obtains formula I compound of the present invention through a step or polystep reaction.
2-methylol-3,5, the 6-trimethylpyrazine is one of interior metabolism product of Ligustrazine, further discover 2-methylol-3,5, the 6-trimethylpyrazine can obviously prolong mouse electrocardio extinction time and blood coagulation time, obviously reduce the rat aorta blood pressure, but the rat heart rate is not had obvious influence, this illustrates that this compound has effects such as the myocardial hypoxia tolerance of improvement and step-down, anti-freezing.Compare with Ligustrazine, both have similar pharmacologically active, are reducing aspect there was no significant differences such as blood viscosity, anticoagulant, but 2-methylol-3,5, the toxicity of 6-trimethylpyrazine is lower, and is water-soluble higher.
2-methylol-3,5, and the synthetic existing bibliographical information of 6-trimethylpyrazine (.2-methylol-3,5 such as Chen Xuemin, 6-trimethylpyrazine synthetic and to the influence of hemorheological property. Chinese pharmaceutical chemistry magazine, 1996,6 (4): 254-256.).With the Ligustrazine is initial reactant, generates single oxide compound with the hydrogen peroxide oxidation Ligustrazine, and the latter refluxes in aceticanhydride, and rearrangement reaction takes place, obtain 2-acetyl-o-methyl-3,5, the 6-trimethylpyrazine, then 2-methylol-3,5 has been synthesized in hydrolysis under alkaline condition, the 6-trimethylpyrazine.
(1) when R be NO
2, the preparation method one:
2-methylol-3,5,6-trimethylpyrazine (A) obtains product with nitric acid reaction in the presence of diacetyl oxide, acetate.Wherein nitric acid has rare nitric acid, concentrated nitric acid and nitrosonitric acid, preferred nitrosonitric acid.Be expressed as follows with reaction formula:
The preparation method two:
In the presence of benzoyl peroxide, Ligustrazine and bromo-succinimide (NBS) are reacted in the solvent tetracol phenixin and are obtained 2-brooethyl-3,5, and the 6-trimethylpyrazine reacts in tetrahydrofuran (THF) with Silver Nitrate and obtains product.As shown below:
The technology toxicity of finding in test preparation method two is big, the cost height; The product purity that obtains is also not as good as preparation method one, so the present invention adopts preparation method one.
(2) as R be
The preparation method:
In the presence of triethylamine, 2-methylol-3,5,6-trimethylpyrazine (A) with chloromethyl benzoic acid chlorides (B) is reacted in methylene dichloride, trichloromethane, ethyl acetate equal solvent, generation is to chloromethyl benzoic acid (2-methylol-3,5,6-trimethylpyrazine) ester (C); Chloromethyl benzoic acid (2-methylol-3,5,6-trimethylpyrazine) ester (C) reacts in tetrahydrofuran (THF), acetonitrile with Silver Nitrate and obtains product.
Chloromethyl benzoic acid chlorides is prepared: with 4-(methylol) phenylformic acid is raw material, makes with sulfur oxychloride/phosphorus trichloride reaction.
Be expressed as follows with reaction formula:
(3) as R be
The preparation method:
In the presence of pyridine, 2-methylol-3,5,6-trimethylpyrazine (A) reacts in methylene dichloride with furazan oxynitrides (D), obtains product.
Be expressed as follows with reaction formula:
The synthetic method of furazan oxynitrides (D), document [Di Stilo A, et al, Med.Chem.Res., 3,554-557 (1993); Fruttero R, et al, J.Heterocyclic.Chem., 26,1345-1349 (1989)] existing report, make the 3-methyl isophthalic acid earlier, 2,5-oxadiazoles-2-oxide compound-4-formaldehyde with Jones oxidation agent, sulfur oxychloride reaction, can make title compound successively easily.This understands those skilled in the art person.Synthetic route is as shown below:
(4) as R be
The preparation method:
In the presence of to dimethylamino pyridine, 2-methylol-3,5,6-trimethylpyrazine (A) reacts in tetrahydrofuran (THF) with the anhydrides compd E, generates intermediate F; Intermediate F and alcohol compound G reaction obtain product.The anhydrides compound is Succinic anhydried, Pyroglutaric acid, adipic anhydride etc.Intermediate F is for there being substituent carboxylic acid, and at dicyclohexyl carbon imide (DCC) and catalytic amount 4-N, N-Dimethylamino pyridine (DMAP) acts on down, reacts in methylene dichloride with alcohol compound G to obtain product.
Alcohol compound G R
1OH represents, wherein R
1Representative:
First kind of R wherein
1OH is the furazan oxynitrides, and chemical name is: 3-methylol-4-phenyl-1,2, and 5-oxadiazoles-2-oxide compound, reference literature (Xu Xin, Zhang Yihua, etc.China Medicine University's journal, 2005,36 (6): 488-495) preparation.
Second kind of R wherein
1OH, reference literature (Wang Weidong, Zhang Yihua, etc.China Medicine University's journal, 2003,34 (1): 13-16) preparation.
The third R wherein
1OH is an elanfan long, need not make by oneself, and supply of commodities is arranged.
The 4th kind of R wherein
1OH is a 2-methylol-3,5,6-trimethylpyrazine, i.e. compd A.
Be expressed as follows with reaction formula:
(5) as R be
Wherein n is 2,3, R
2Be NO
2,
The preparation method:
A. in the presence of to dimethylamino pyridine, 2-methylol-3,5,6-trimethylpyrazine (A) reacts in methylene dichloride with lactone compound H, generates intermediate J;
B. the reaction of intermediate J and compound K obtains product.
Wherein, compound K is the organic carboxyl acid compounds, uses R
2OH represents, wherein R
2Representative
The time, intermediate J is for there being substituent alcohol, and at dicyclohexyl carbon imide (DCC) and catalytic amount 4-N, N-Dimethylamino pyridine (DMAP) acts on down, reacts in methylene dichloride with carboxylic acid compound K to obtain product.
Wherein, compound K R
2OH represents, R
2Be nitro (NO
2), promptly during nitric acid, intermediate J obtains product with nitric acid reaction for substituent alcohol is arranged in the presence of diacetyl oxide, acetate.Wherein nitric acid has rare nitric acid, concentrated nitric acid and nitrosonitric acid, preferred nitrosonitric acid.
N is 0-3, R
2Be NO
2, the preparation method:
A.2-methylol-3,5,6-trimethylpyrazine (A) in the presence of the dimethylamino pyridine with bromo alkyl acyl bromide compounds L reaction, generate intermediate M;
B. the reaction of intermediate M and Silver Nitrate obtains product.
Two kinds of preparation methods are expressed as follows with reaction formula successively:
Formula one,
Formula two,
Wherein, R
1, R
2, m, n the compound of the same general formula of definition (I) structure described in.
This compounds is effective for the human thrombotic diseases of treatment.Although compound of the present invention can be without the direct administration of any preparation, described all cpds is preferably to use with pharmaceutics pharmaceutic adjuvant acceptable pharmaceutical compositions.The pharmaceutics pharmaceutic adjuvant acceptable comprises thinner, lubricant, tackiness agent, disintegrating agent, stablizer, solvent etc.
Thinner of the present invention includes but not limited to starch, Microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose, low molecular dextran etc.; Described lubricant includes but not limited to Magnesium Stearate, stearic acid, sodium-chlor, sodium oleate, DL-leucine, sodium laurylsulfate, Macrogol 4000-6000, the husky mother in pool Lip river etc.; Described tackiness agent includes but not limited to water, ethanol, starch slurry, syrup, gelatin, methylcellulose gum, Vltra tears, Xylo-Mucine, sodium alginate, polyvinylpyrrolidone etc.; Described disintegrating agent includes but not limited to that starch, sodium starch glycolate, effervescent mixture are sodium bicarbonate and Citric Acid, tartrate, low-substituted hydroxypropyl cellulose etc.; Described stablizer comprises but is not limited to polysaccharide such as kordofan gum, agar, alginic acid, acryllic acid resin, ether of cellulose and carboxymethyl crust ester etc.; Described solvent includes but not limited to water, phosphate buffered saline buffer, equilibrated salts solution etc.;
Described composition can be made various preparation according to the difference of treatment needs, comprises various solid orally ingestibles, liquid oral medicine, injection etc.The acceptable oral preparation solid preparation of pharmaceutics has: conventional tablet, dispersible tablet, enteric coated tablet, particle, capsule, dripping pill, powder etc., and oral liquid has oral liquid, emulsion; Injection has: little liquid drugs injection, transfusion, freeze-dried powder etc.Each preparation can form according to the prepared of routine.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can be according to patient's the state of an illness, specific being applied of situation of diagnosis, the amount of used compound or concentration are regulated in the scope of a broad, usually, the weight range of active compound is 1%～90% (weight) of composition.
Further specify The compounds of this invention to thrombotic restraining effect below by experiment.
Anticoagulant active is measured
This experiment is by measuring activated partial thromboplastin time (APTT), zymoplasm (solidifying) time (TT) and 3 kinds of indexs of prothrombin time (PT) as judgement criteria, preliminary study 2-methylol-3,5, the anticoagulant active of 6-trimethylpyrazine derivative.
The preparation of derivative solution: with 2-methylol-3,5,6-trimethylpyrazine derivative makes 2.2 * 10 respectively
-5The solution of mol/ml.And with 2N aqueous hydrochloric acid adjust pH 4.5-5.
Anticoagulant active is measured:
The mensuration of APTT: 0.1ml blood plasma adds 0.1ml specimen solution, behind preheating (37 ℃) 3min, adds 0.1ml partial thromboplastin activation 3min, puts to test board adding 0.1ml calcium chloride solution (30mmol/L), can measure APTT.
The mensuration of TT: 0.12ml blood plasma adds 0.12ml specimen solution, behind preheating (37 ℃) 3min, puts the zymoplasm to test board adding 0.12ml, can measure TT.
The mensuration of PT: 0.1ml blood plasma adds 0.1ml specimen solution, behind preheating (37 ℃) 3min, puts the sodium chloride aqueous solution that adds the 0.2ml thrombogen to test board, can measure PT.
Derivative to the influence of APTT, TT and PT (x ± s, n=4)
The platelet aggregation-against experiment
With 3% Nembutal vein anesthetic rabbit, operation separates the arteria carotis communis intubate and gets blood, (get Trisodium Citrate 3.8g with 3.8% Sodium Citrate, adding distil water is to 100mL, and the dissolving after-filtration is bottled, 121 ℃ of autoclaving 15min) be antithrombotics (V: V=1: 9), 1000r/min, 5min is centrifugal, with preparation platelet rich plasma (PRP); 3000r/min, the centrifugal preparation platelet poor plasma of 15min (PPP). PRP is moved into 37 ℃ of incubation 5min in the silication cuvette, survey it in 600nm place absorbancy (A), transfer the A value of PRP 0.6～0.7 with PPP, the PRP that 1.7mL is mixed up moves in another silication cuvette, add and be subjected to the A value of reagent 200 μ L before the 600nm place surveys adding ADP, add ADP (100 μ L) (final concentration is 4 μ mol/L) subsequently, measure to add behind the ADP 2 respectively, the A of 600nm place value during 5min, calculate platelet aggregation rate (AR) as follows:
A value behind the preceding A value of AR=[(adding ADP-adding ADP)/the preceding A value of adding ADP] * 100%
Calculate medicine simultaneously to hematoblastic inhibiting rate (AIR):
AIR=[1-(delivery tube is assembled percentage/control tube and assembled hundred rates)] * 100%.
Obtain the half-inhibition concentration (IC50) of medicine with return law of the straight line, the platelet aggregation inhibitory activity data see the following form.
Compound is to the inhibition activity of platelet aggregation
Figure of description
The structural formula of Fig. 1 ligustrazine derivant.
Embodiment:
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way.The compound of invention is through high performance liquid chromatography (HPLC), or thin-layer chromatography (TLC), or fusing point (m.p.) detects, and adopts mass spectrum (MS), and its structure is proved conclusively in ultimate analysis.
Reference example 1:2-methylol-3,5,6-trimethylpyrazine (A)
Reference (.2-methylol-3,5 such as Chen Xuemin, 6-trimethylpyrazine synthetic and to the influence of hemorheological property. Chinese pharmaceutical chemistry magazine, 1996,6 (4): 254-256.) method can make title compound easily.Synthetic route is as shown below:
Product
Be white solid, m.p.71 ℃-73 ℃, HPLC:98.86%, ESI-MS:151.1 (M-H)
Ultimate analysis: (theoretical value/measured value C (63.13/63.01), H (7.95/7.78), N (18.41/18.26).
Reference example 2: to chloromethyl benzoic acid chlorides (B)
In reaction flask, add 15 grams to hydroxymethyl-benzoic acid, 51 gram sulfur oxychlorides and 1 gram phosphorus trichloride, back flow reaction 12 hours.Concentrating under reduced pressure to steaming sulfur oxychloride and phosphorus trichloride to the greatest extent, gets solid, does not need purifying, and is standby.ESI-MS：187.0(M-H)
Reference example 3:3-methyl isophthalic acid, 2,5-oxadiazoles-2-oxide compound-4-formyl chloride (D)
Reference [Di Stilo A, et al, Med.Chem.Res., 3,554-557 (1993); Fruttero R, et al, J.Heterocyclic.Chem., 26,1345-1349 (1989)] reported method, make the 3-methyl isophthalic acid earlier, 2,5-oxadiazoles-2-oxide compound-4-formaldehyde with Jones oxidation agent, sulfur oxychloride reaction, can make title compound successively easily.Synthetic route is as shown below:
Get solid product, ESI-MS:160.9 (M-H) does not need purifying.
Reference example 4:3-methylol-4-phenyl-1,2,5-oxadiazoles-2-oxide compound
Reference literature (Xu Xin, Zhang Yihua, etc.China Medicine University's journal, 2005,36 (6): 488-495) method preparation.HPLC:99.31%, ultimate analysis: (theoretical value/measured value), C (56.25/56.14), H (4.20/4.15), N (14.58/14,49).
Reference example 5:3-nitryl oxygen methylphenol
Reference literature (Wang Weidong, Zhang Yihua, etc.China Medicine University's journal, 2003,34 (1): 13-16) method preparation.HPLC:99.31%, ultimate analysis: (theoretical value/measured value), C (49.71/49.70), H (4.17/4.10), N (8.28/8,19).
Example 1:(3,5,6-trimethylpyrazine-2-yl) the methyl alcohol nitric ether
In reaction flask, add 2-methylol-3,5,6-trimethylpyrazine (A) 15.2g, 60ml acetate, the 10ml diacetyl oxide under the stirring at room, drips the 7.5g nitrosonitric acid, dropwised in 20 minutes, insulation reaction is 16 hours then, and the TLC detection reaction is complete, stopped reaction.Under stirring reaction solution is added in the 200g trash ice, add the 120ml ethyl acetate, tell ethyl acetate layer, anhydrous magnesium sulfate drying.Ethyl acetate is to the greatest extent steamed in decompression, and resistates gets (3,5,6-trimethylpyrazine-2-yl) methyl alcohol nitric ether 9.6g through silica gel column chromatography (dichloromethane/ethyl acetate, 9: 1) purifying.HPLC:99.1%, ultimate analysis: (theoretical value/measured value), C (48.73/48.62), H (5.62/5.55), N (21.31/21.29), ESI-MS:196.1 (M-H).
Example 2:4-((nitre acyloxy) methyl) phenylformic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester
A. in reaction flask, add 2-methylol-3,5,6-trimethylpyrazine (A) 7.6g, the 80ml methylene dichloride, the 8.0g triethylamine stirs down in 15 ℃-20 ℃ and adds 9.5g to chloromethyl benzoic acid chlorides (B), then 30 ℃ of insulation reaction 3 hours.The TLC monitoring, reaction finishes, stopped reaction.Add 50ml water, leave standstill after the stirring, tell dichloromethane layer, anhydrous magnesium sulfate drying.Methylene dichloride is to the greatest extent steamed in decompression, and resistates gets 9.8g to chloromethyl benzoic acid (2-methylol-3,5,6-trimethylpyrazine) ester (C) through silica gel column chromatography (n-hexane/ethyl acetate, 9: 2) purifying.HPLC：98.11％，ESI-MS：303.1(M-H)。
B. in reaction flask, add chloromethyl benzoic acid (2-methylol-3,5,6-trimethylpyrazine) ester (C) 6.0g, the 120ml acetonitrile is heated to 65 ℃ under stirring, and adds 5.2g Silver Nitrate (being dissolved in the 50ml acetonitrile) again, 78 ℃ of lucifuge insulation reaction 5 hours.Stopped reaction filters, and removes the silver chloride of generation.Remove acetonitrile under reduced pressure, resistates gets 4-((nitre acyloxy) methyl) phenylformic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester 3.4g, HPLC:99.31%, ESI-MS:330.1 (M-H) through silica gel column chromatography (petrol ether/ethyl acetate, 6: 4) purifying.Ultimate analysis: (theoretical value/measured value), C (58.00/58.02), H (5.17/5.08), N (12.68/12.58).
Example 3:3-methyl isophthalic acid, 2,5-oxadiazoles-2-oxide compound-4-formic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester
In reaction flask, add 2-methylol-3,5,6-trimethylpyrazine (A) 7.6g, the 160ml methylene dichloride, the 6.5g pyridine stirs down in 20 ℃ of adding 8.9g3-methyl isophthalic acids, 2,5-oxadiazoles-2-oxide compound-4-formyl chloride (D) is then room temperature insulation reaction 4.5 hours.The TLC monitoring, reaction finishes, stopped reaction.Add 80ml water, leave standstill after the stirring, tell dichloromethane layer, methylene dichloride is to the greatest extent steamed in decompression, resistates is through silica gel column chromatography (n-hexane/ethyl acetate, 7: 2) purifying, get solid 7.7g, i.e. 3-methyl isophthalic acid, 2,5-oxadiazoles-2-oxide compound-4-formic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester.HPLC：99.16％，ESI-MS：277.1(M-H)。
Example 4:4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-ketobutyric acid (3-nitryl oxygen methyl) phenol ester
A. in reaction flask, add 2-methylol-3,5,6-trimethylpyrazine (A) 15.2g, Succinic anhydried 12.5g to dimethylamino pyridine 14.4g, is dissolved in the 130ml tetrahydrofuran (THF) (THF) heating reflux reaction 16h.Remove solvent under reduced pressure, add chloroform 150ml and 70ml saturated aqueous common salt in the residuum, leave standstill after the stirring, tell chloroform layer, anhydrous magnesium sulfate drying spends the night.Chloroform is to the greatest extent steamed in decompression, separates out solid, suction filtration, and filtration cakes torrefaction is used the dehydrated alcohol recrystallization, gets white solid 18.9g, i.e. 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-ketobutyric acid.HPLC：98.86％，ESI-MS：251.1(M-H)。
B. in reaction flask, add 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-and 4-ketobutyric acid 5.0g, 3-nitryl oxygen methylphenol 3.4g, dicyclohexyl carbon imide (DCC) 4.9g, 4-N, N-Dimethylamino pyridine (DMAP) 0.5g is dissolved in the 230mL anhydrous methylene chloride, and room temperature reaction spends the night.Remove by filter insolubles, filtrate is evaporated to dried through anhydrous magnesium sulfate drying.Residue obtains wax through column chromatography (sherwood oil (60～90 ℃)/ethyl acetate, volume ratio 5: 1) purifying, i.e. 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-ketobutyric acid (3-nitryl oxygen methyl) phenol ester, yield 50.7%.HPLC：99.36％，ESI-MS：402.1(M-H)。
Salify: 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-ketobutyric acid (3-nitryl oxygen methyl) phenol ester is dissolved in the dehydrated alcohol, adds appropriate hydrochloric acid ethanol, promptly get hydrochloride.
Example 5:2-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-2-oxo alcohol nitrate ester
A. in reaction flask, add 2-methylol-3,5,6-trimethylpyrazine (A) 7.6g, 60ml methylene dichloride, 7.3g are to dimethylamino pyridine, and in about 10 ℃ of adding 10.1g bromoacetyl bromides, insulation reaction is 3 hours then under stirring.The TLC monitoring, reaction finishes, stopped reaction.Add saturated aqueous common salt 50ml, leave standstill after the stirring, tell dichloromethane layer, anhydrous sodium sulfate drying.Methylene dichloride is to the greatest extent steamed in decompression, and resistates gets 2-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-2-oxo monobromethane 6.4g through silica gel column chromatography (n-hexane/ethyl acetate, 9: 1) purifying.HPLC：98.67％，ESI-MS：271.0(M-H)。
B. in reaction flask, add 2-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-2-oxo monobromethane 5.4g, the 90ml acetonitrile is heated to 60 ℃ under stirring, and adds 8.6g Silver Nitrate (being dissolved in the 80ml acetonitrile) again, 80 ℃ of insulation reaction 7 hours.Stopped reaction filters, and removes the Silver monobromide of generation.Remove acetonitrile under reduced pressure, resistates gets 2-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-2-oxo alcohol nitrate ester 3.8g, HPLC:99.16%, ESI-MS:254.1 (M-H) through silica gel column chromatography (petrol ether/ethyl acetate, 7: 2) purifying.
Salify: 2-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-2-oxo alcohol nitrate ester is dissolved in the methyl alcohol, adds equimolar methylsulfonic acid, get mesylate.
Example 6:3-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-3-oxo propyl alcohol nitric ether
By preparation method and process that embodiment 8 provides, only with the bromoacetyl bromide among the bromopropionyl bromide replacement embodiment 8 (a), the mol ratio of reactant is constant, can make 3-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-3-oxo propyl alcohol nitric ether 4.1g.HPLC：99.19％，ESI-MS：268.1(M-H)。
Example 7: Nicotinicum Acidum 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester
In reaction flask, add 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-and 4-oxobutanol 4.8g, Nicotinicum Acidum 2.5g, dicyclohexyl carbon imide (DCC) 5.0g, 4-N, N-Dimethylamino pyridine (DMAP) 0.45g is dissolved in the 260mL anhydrous methylene chloride, and room temperature reaction spends the night.Remove by filter insolubles, filtrate is evaporated to dried through anhydrous magnesium sulfate drying.Residue obtains solids through column chromatography (sherwood oil (60～90 ℃)/ethyl acetate, volume ratio 5: 2) purifying, i.e. Nicotinicum Acidum 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester.Yield 54.3%.HPLC：99.15％，ESI-MS：342.2(M-H)。
Example 8: pyridine-4-formic acid 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester
Preparation method and process by embodiment 12 provides only replace Nicotinicum Acidum with pyridine-4-formic acid, obtain pyridine-4-formic acid 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester.Yield 55.8%.HPLC：99.12％，ESI-MS：342.2(M-H)。
For 2-methylol-3,5 of the present invention is described more fully, the pharmaceutical composition of 6-trimethylpyrazine derivative provides following example of formulations, and described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any compound in the The compounds of this invention.
Embodiment 9:
The compound 20g of preparation adds dextrin 20g among the embodiment 1, and lactose 80g with 60% alcohol granulation, drying, encapsulated, makes 1000 seed lac wafers.
Embodiment 10:
The compound 50g of preparation adds 860g (lactose-microcrystalline cellulose 5: 1), stearic acid 1% among the embodiment 2, promptly gets 1000 tablets of tablets with 70% alcohol granulation, compressing tablet.
Embodiment 11:
The hydrochloride 80g of the compound of preparation among the embodiment 4 adds the dissolving of 1000ml water for injection, supplies water for injection to 4000ml, adds proper amount of active carbon and removes thermal source, and the 0.2um millipore filtration filters, and can makes 2000 little liquid drugs injections.
Embodiment 12:
The phosphoric acid salt 50g of the compound of preparation among the embodiment 6, N.F,USP MANNITOL 50g adds the dissolving of 1000ml water for injection, supplies water for injection to 2000ml, adds proper amount of active carbon and removes thermal source, the filter of 0.2um micropore
The membrane filtration mistake, can, lyophilize makes 2000 freeze-dried powders.Injection for intravenous is used.
Claims (8)
1. the compound or its pharmacy acceptable salt that have a kind of ligustrazine derivant of formula I structure.
Wherein, R is:
(1)NO
2；
2. the compound described in claim 1, representative compound is:
(3,5,6-trimethylpyrazine-2-yl) methyl alcohol nitric ether
4-((nitre acyloxy) methyl) phenylformic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester
The 3-methyl isophthalic acid, 2,5-oxadiazoles-2-oxide compound-4-formic acid (3,5,6-trimethylpyrazine-2-yl) methyl alcohol ester
4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-ketobutyric acid (3-nitryl oxygen methyl) phenol ester
2-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-2-oxo alcohol nitrate ester
3-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-3-oxo propyl alcohol nitric ether
Nicotinicum Acidum 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester
3-(4-hydroxyl-3-methoxyl group-phenyl) vinylformic acid 4-((3,5,6-trimethylpyrazine-2-yl) methoxyl group)-4-oxobutanol ester
3. as claim 1, the pharmacy acceptable salt of compound described in 2 is meant claim 1, the salt that compound described in 2 and organic acid, inorganic acid reaction generate.
4. the preparation method of formula I compound of the present invention;
(1) when R be NO
2, it is characterized in that:
2-methylol-3,5,6-trimethylpyrazine (A) obtains product with nitric acid reaction in the presence of diacetyl oxide.Be expressed as follows with reaction formula:
(2) as R be
It is characterized in that:
A.2-methylol-3,5,6-trimethylpyrazine (A) in the presence of triethylamine with to chloromethyl benzoic acid chlorides (B) reaction, generate chloromethyl benzoic acid (2-methylol-3,5,6-trimethylpyrazine) ester (C);
B. chloromethyl benzoic acid (2-methylol-3,5,6-trimethylpyrazine) ester (C) obtains product with the Silver Nitrate reaction.
Be expressed as follows with reaction formula:
(3) as R be
2-methylol-3,5,6-trimethylpyrazine (A) react in the presence of pyridine with (E), generate (F).
Be expressed as follows with reaction formula:
(4) as R be
A.2-methylol-3,5,6-trimethylpyrazine (A) in the presence of the dimethylamino pyridine with the compd E reaction, generate intermediate D;
B. intermediate D and compound G reaction obtains product.
Be expressed as follows with reaction formula:
(5) as R be
Wherein n is 2,3, R
2Be NO
2,
The preparation method:
A.2-methylol-3,5,6-trimethylpyrazine (A) in the presence of the dimethylamino pyridine with the compound H reaction, generate intermediate J;
B. the reaction of intermediate J and compound K obtains product.
N is 0-3, R
2Be NO
2, the preparation method:
A.2-methylol-3,5,6-trimethylpyrazine (A) in the presence of the dimethylamino pyridine with bromo alkyl acyl bromide compounds L reaction, generate intermediate M;
B. the reaction of intermediate M and Silver Nitrate obtains product.
Two kinds of preparation methods are expressed as follows with reaction formula successively:
Formula one,
Formula two,
Wherein, R
1, R
2, m, n definition with 1 described.
5. antithrombotic pharmaceutical composition, it comprises formula I compound and one or more pharmaceutical excipients of the claim 1-3 that treats significant quantity.
6. the described pharmaceutical composition of claim 5 comprises various solid orally ingestibles, liquid oral medicine, injection.
7. claim 1-3 Chinese style I compound is in the application that is used to prepare aspect the antithrombotic reagent.
8. application as claimed in claim 7 is in the purposes that is used to prepare aspect treatment cerebral thrombosis, cerebral infarction, stenocardia, myocardial infarction, coronary heart disease, the antiarrhythmic medicament relevant with thrombus.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864815A (en) * | 2014-02-21 | 2014-06-18 | 温州医科大学 | Compound for targeting binding of TFAM (Mitochondrial Transcription Factor A) of mitochondrial DNA (Desoxvribose Nucleic Acid) and application thereof |
| CN104341358A (en) * | 2013-07-25 | 2015-02-11 | 昆明制药集团股份有限公司 | Compound, preparation method and applications thereof |
| CN106928155A (en) * | 2017-01-20 | 2017-07-07 | 贵州医科大学 | Ligustrazine butylphenyl phthaleine split class compound and preparation method thereof and the application in medicine |
| WO2022022678A1 (en) * | 2020-07-31 | 2022-02-03 | 深圳市橄榄生物医药科技有限公司 | Pyrazine compound, preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101786992A (en) * | 2010-03-10 | 2010-07-28 | 天津市汉康医药生物技术有限公司 | 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof |
-
2011
- 2011-05-12 CN CN201110122322XA patent/CN102241636A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101786992A (en) * | 2010-03-10 | 2010-07-28 | 天津市汉康医药生物技术有限公司 | 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104341358A (en) * | 2013-07-25 | 2015-02-11 | 昆明制药集团股份有限公司 | Compound, preparation method and applications thereof |
| CN104341358B (en) * | 2013-07-25 | 2016-05-18 | 昆药集团股份有限公司 | A kind of compound and preparation method thereof and application |
| CN103864815A (en) * | 2014-02-21 | 2014-06-18 | 温州医科大学 | Compound for targeting binding of TFAM (Mitochondrial Transcription Factor A) of mitochondrial DNA (Desoxvribose Nucleic Acid) and application thereof |
| CN106928155A (en) * | 2017-01-20 | 2017-07-07 | 贵州医科大学 | Ligustrazine butylphenyl phthaleine split class compound and preparation method thereof and the application in medicine |
| CN106928155B (en) * | 2017-01-20 | 2021-07-16 | 贵州医科大学 | Ligustrazine-butylphthalide split compound, preparation method thereof and application thereof in medicines |
| WO2022022678A1 (en) * | 2020-07-31 | 2022-02-03 | 深圳市橄榄生物医药科技有限公司 | Pyrazine compound, preparation method and application thereof |
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