CN104856983A - Synthesis and application of bornyl ferulate - Google Patents
Synthesis and application of bornyl ferulate Download PDFInfo
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- CN104856983A CN104856983A CN201510243181.5A CN201510243181A CN104856983A CN 104856983 A CN104856983 A CN 104856983A CN 201510243181 A CN201510243181 A CN 201510243181A CN 104856983 A CN104856983 A CN 104856983A
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- MWOOGOJBHIARFG-UHFFFAOYSA-N COc(cc(C=O)cc1)c1O Chemical compound COc(cc(C=O)cc1)c1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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Abstract
The invention discloses bornyl ferulate, bornyl ferulate and a pharmaceutically acceptable prodrug thereof, which are applied to pharmacy, wherein the bornyl ferulate is applied to the treatment of cerebrovascular diseases, and the bornyl ferulate comprises ferulaThe acid dextroborneol ester and the ferulic acid levoborneol ester have two structures, wherein the structural general formula of the ferulic acid dextroborneol ester is shown in the specificationThe structural general formula of the ferulic acid levo borneol ester isThe L-borneol ferulate is an enantiomer of the D-borneol ferulate. The synthesis process of the bornyl ferulate is short, the raw materials are economical and easy to obtain, and the synthesis process is easy to control; no harmful by-products are produced, the process is environment-friendly and economical, and can be widely applied to the production of medicaments for treating cerebrovascular diseases.
Description
Technical field
The invention belongs to chemical medicine, be specifically related to synthesis and application that norbornene ester is revolved on the ferulic acid right side (left side).
Background technology
Ferulic acid (Ferulic acid), find in the seed and leaf of plant at first, a kind ofly there is the phenolic acid extracted in the plants such as Radix Angelicae Sinensis, Rhizoma Chuanxiong, Resina Ferulae, it has antiinflammatory, antioxidation, antithrombotic and multiple physiologically active, is widely used in the fields such as health product, cosmetics, medicine, pesticide and food additive.
Find through research; ferulic acid can anticoagulant and release; can obvious Inhibition test thrombosis, regulate immunity of organism, clear and suppress radical reaction, ferulic acid molecule can be played a protective role to the 26S Proteasome Structure and Function of biomacromolecule in body by number of ways.
But ferulic acid molecular hydrophylic is strong, fat-soluble difference, and its internal metabolism speed is fast, brain distribution is few, more difficultly to play a role through blood brain barrier, make it restricted greatly in the application for the treatment of cerebrovascular disease field, the current application clinically of marketed drug injection of sodium ferulate mainly biases toward the treatment of cardiovascular disease.Therefore, carrying out modifying preparation derivant to improve the fat-soluble research of molecule to ferulic acid molecule is the key solving ferulic acid molecular defect, and it is improve its fat-soluble and best approach that is result of use that ferulic acid and alcohol are reacted into ferulic acid ester.
Chinese medicine Borneolum Syntheticum has refreshment of having one's ideas straightened out, promotes agent permeates therethrough blood brain barrier, has the effect such as two-ways regulation and protective effect to central nervous system, also has good curative effect for apoplexy disease treatment, and this is the invention provides a splendid Research Thinking.
Recent research display, the occurrence cause of numerous disease is not only a kind of, and corresponding treatment means also can have multiple, if suppress multiple target spots of the generation of disease simultaneously, can produce better curative effect.Mutiple Targets medicine be based on improve curative effect and (or) improve the overall goal of safety and appropriate design, can act on and multiple target spot of certain disease association and produce the drug molecule of more than one pharmacologically actives.The combination of medicine is one of approach of many targets drug design.Ferulic acid and Borneolum Syntheticum, according to the theory of Mutiple Targets drug design, react and form ferulic acid norbornene ester, for the patient suffering from cerebrovascular disease finds a good medicine by the application.
Summary of the invention
For solving the problems of the technologies described above; the invention provides the synthetic method of ferulic acid norbornene ester; the ferulic acid norbornene ester that the present invention obtains is fat-soluble good, effectively can improve the cerebral blood circulation disorder of cerebral apoplexy patient, play a good protection to the cerebral nerve of patient.
For achieving the above object, technical scheme of the present invention is as follows:
A kind of ferulic acid norbornene ester and pharmaceutically acceptable salt thereof and prodrug application pharmaceutically, described ferulic acid norbornene ester is applied in treatment cerebrovascular disease, be applied in treatment apoplexy disease especially, it comprises ferulic acid dextrorotation norbornene ester and ferulic acid L-Borneol ester two kinds of structures, and the general structure of described ferulic acid dextrorotation norbornene ester is
the general structure of described ferulic acid L-Borneol ester is
described ferulic acid L-Borneol ester is the enantiomer of described ferulic acid dextrorotation norbornene ester.
In a preferred embodiment of the present invention, comprise further, the synthetic line of described ferulic acid dextrorotation norbornene ester is:
Wherein, 1a is dextrorotation Borneolum Syntheticum, and 2 is the ferulic acid that phenolic hydroxyl group is protected, and R is protecting group, the ferulic acid that phenolic hydroxyl group is protected obtains the ferulic acid dextrorotation norbornene ester 3a that phenolic hydroxyl group is protected under condensing agent catalysis with the condensation of dextrorotation Borneolum Syntheticum, then obtains ferulic acid dextrorotation norbornene ester through deprotection;
The synthetic line of described ferulic acid L-Borneol ester also comprises:
Wherein, 1b is L-Borneol, and the ferulic acid that phenolic hydroxyl group is protected obtains the ferulic acid L-Borneol ester 3b that phenolic hydroxyl group is protected under condensing agent catalysis with L-Borneol condensation, then obtains ferulic acid L-Borneol ester through deprotection.
In a preferred embodiment of the present invention, comprise further, described protecting group comprise following in any one: methyl, the tert-butyl group, trityl group, methoxy, trimethyl silicon based, t-Butyldimethylsilyl, benzyl, THP trtrahydropyranyl; Described condensing agent comprise following one or more: dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, DMAP, I-hydroxybenzotriazole and 4-pyrollidinopyridine.
In a preferred embodiment of the present invention, comprise further, the synthetic line of described ferulic acid dextrorotation norbornene ester also comprises:
Haloacetyl dextrorotation norbornene ester 4a and organophosphorus reagent are obtained by reacting wittig phosphorus reagent 5a, and then wittig phosphorus reagent 5a carries out wittig with 3-methoxyl group-4 hydroxy benzaldehyde 6 again and is obtained by reacting ferulic acid dextrorotation norbornene ester under the effect of alkali;
The synthetic line of described ferulic acid L-Borneol ester also comprises:
Haloacetyl L-Borneol ester 4b and organophosphorus reagent are obtained by reacting wittig phosphorus reagent 5b, and then wittig phosphorus reagent 5b carries out wittig with 3-methoxyl group-4 hydroxy benzaldehyde 6 again and is obtained by reacting ferulic acid L-Borneol ester under the effect of alkali;
Wherein X is Cl, Br or I, and R is PPh
3x, P (O) Ph
2or P (O) (OEt)
2.
In a preferred embodiment of the present invention, comprise further, described organophosphorus reagent comprise following in any one: in triphenyl phosphorus, ethoxy diphenyl base phosphorus and NSC 5284; Described alkali comprise following one or more: Lithium Aluminium Hydride, Feldalat NM, Sodium ethylate, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, Lithium hydrate and potassium carbonate.
In a preferred embodiment of the present invention, comprise further, pharmaceutical composition, it comprises the ferulic acid norbornene ester described in above any one, and described pharmaceutical composition comprises ferulic acid norbornene ester or its pharmaceutically acceptable salt, solvate or the prodrug for the treatment of effective dose.
The invention has the beneficial effects as follows:
The synthesis technique of one, ferulic acid norbornene ester of the present invention is brief, and raw material economics is easy to get, and synthesis process is easy to control.
Two, the synthetic route of ferulic acid norbornene ester of the present invention is without the generation of harmful side product, is environmental protection and economy type technique, can be extensively adapted to treat in the production of cerebrovascular disease medicament.
Three, ferulic acid norbornene ester of the present invention is fat-soluble good, can be applied in the medicine of antithrombotic, blood fat reducing and treatment apoplexy, and have no apparent side effect.
Accompanying drawing explanation
In order to be illustrated more clearly in the technical scheme in embodiment of the present invention technology, be briefly described to the accompanying drawing used required in the description of embodiment technology below, apparently, accompanying drawing in the following describes is only some embodiments of the present invention, for those of ordinary skill in the art, under the prerequisite not paying creative work, other accompanying drawing can also be obtained according to these accompanying drawings.
Fig. 1 is the nuclear-magnetism figure of ferulic acid dextrorotation norbornene ester of the present invention.
Fig. 2 is the mass spectrum of ferulic acid dextrorotation norbornene ester of the present invention.
Fig. 3 is the nuclear-magnetism figure of ferulic acid L-Borneol ester of the present invention.
Fig. 4 is the effect experiment blank group brain section figure that the ferulic acid right side (left side) of the present invention revolves norbornene ester.
Fig. 5 is the effect experiment sodium ferulate group brain section figure that the ferulic acid right side (left side) of the present invention revolves norbornene ester.
Fig. 6 is the effect experiment nimodipine group brain section figure that the ferulic acid right side (left side) of the present invention revolves norbornene ester.
Fig. 7 is the effect experiment L-Borneol ester group brain section figure that the ferulic acid right side (left side) of the present invention revolves norbornene ester.
Fig. 8 is the effect experiment dextrorotation norbornene ester group brain section figure that the ferulic acid right side (left side) of the present invention revolves norbornene ester.
Detailed description of the invention
Below in conjunction with the accompanying drawing in the embodiment of the present invention, be clearly and completely described the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
Embodiment 1
Disclose a kind of synthetic route of ferulic acid dextrorotation norbornene ester and concrete synthetic method in the present embodiment, wherein synthetic route is:
Wherein, 1a is dextrorotation Borneolum Syntheticum, and 2 is the ferulic acid that phenolic hydroxyl group is protected, and R is protecting group, the ferulic acid that phenolic hydroxyl group is protected obtains the ferulic acid dextrorotation norbornene ester 3a that phenolic hydroxyl group is protected under condensing agent catalysis with the condensation of dextrorotation Borneolum Syntheticum, then obtains ferulic acid dextrorotation norbornene ester through deprotection; Above-mentioned protecting group comprise following in any one: methyl, the tert-butyl group, trityl group, methoxy, trimethyl silicon based, t-Butyldimethylsilyl, benzyl and THP trtrahydropyranyl; Above-mentioned condensing agent comprises: dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, DMAP, I-hydroxybenzotriazole and 4-pyrollidinopyridine.
The synthetic method of described ferulic acid dextrorotation norbornene ester comprises the following steps:
A. by 4-benzyl ferulic acid (7.5g, 0.026mol) put in dichloromethane (50ml), after cryosel bath is cooled to 0 DEG C, add dicyclohexylcarbodiimide (5.43g, 0.026mol) with DMAP (0.96g, 0.008mol), add drying tube, reaction 1h; Dextrorotation Borneolum Syntheticum (4.065g, 0.026mol) to be dissolved in dichloromethane in (25ml), to be added drop-wise in reactant liquor; After dropwising, remove cryosel bath, naturally heat up, reaction is spent the night; After reaction terminates, filtering solids, filter cake q. s. methylene chloride washs, filtrate evaporate to dryness, and residue obtains compound 3a (9.8g) through column chromatography.
B. compound 3a (9g, 0.021mol) is put in oxolane (90ml), stir, add ammonium formate (6.84g, 0.105mol), adding palladium charcoal (1.8g, 0.147mol), reaction 3h.After reaction terminates, with diatomite filtration palladium charcoal, and wash with appropriate oxolane, filtrate evaporate to dryness.Residue petroleum ether or recrystallisation from isopropanol, obtain compound ferulic acid dextrorotation norbornene ester.
Confirmed by the structure magnetic nuclear resonance method of the ferulic acid dextrorotation norbornene ester obtained in the present embodiment, as shown in fig. 1, the architectural feature of described ferulic acid dextrorotation norbornene ester is its collection of illustrative plates:
1h-NMR (CDCl
3, 500MHz) 0.88, 0.90, 0.94 (each 3H, s, H-8, 9, 10), 1.05 (1H, dd, J=13.3, 3.3Hz, H-3b), 1.29 (1H, m, H-5b), 1.31 (1H, m, H-6b), 1.71 (1H, m, H-4), 1.78 (1H, m, H-5a), 2.06 (1H, m, H-6a), 2.41 (1H, dddd, J=13.8, 10.0, 4.0, 3.5Hz, H-3a), 3.94 (3H, s, OMe), 5.01 (1H, ddd, J=10.0, 3.3, 1.8Hz, H-2), 6.31 (1H, d, J=15.9Hz, H-8 '), 6.92 (1H, d, J=8.5Hz, H-5 '), 7.04 (1H, dd, J=8.5, 2.0Hz, H-6 '), 7.06 (1H, d, J=2.0Hz, H-2 '), 7.59 (1H, d, J=15.9Hz, H-7 ').Authenticating compound is ferulic acid dextrorotation norbornene ester.
The structural information of the ferulic acid dextrorotation norbornene ester obtained in the present embodiment is confirmed by mass spectrography, as shown in Figure 2, and EI-MS M/Z 331.6 [M
+], 329.6 [M
-].
Embodiment 4
Present embodiment discloses a kind of synthetic route of ferulic acid L-Borneol ester, route is as follows:
Wherein, 1b is L-Borneol, and the ferulic acid that phenolic hydroxyl group is protected obtains the ferulic acid L-Borneol ester 3b that phenolic hydroxyl group is protected under condensing agent catalysis with L-Borneol condensation, then obtains ferulic acid L-Borneol ester through deprotection.
Above-mentioned protecting group comprise following in any one: methyl, the tert-butyl group, trityl group, methoxy, trimethyl silicon based, t-Butyldimethylsilyl, benzyl and THP trtrahydropyranyl; The ferulic acid that phenolic hydroxyl group is protected obtains the ferulic acid L-Borneol ester that phenolic hydroxyl group is protected under condensing agent catalysis with L-Borneol condensation, then obtains ferulic acid L-Borneol ester through deprotection.
Concrete synthetic method:
A. by 4-benzyl ferulic acid (7.5g, 0.026mol) put in dichloromethane (50ml), after cryosel bath is cooled to 0 DEG C, add DIC (5.43g, 0.026mol) with I-hydroxybenzotriazole and 4-pyrollidinopyridine (0.96g, 0.008mol), add drying tube, reaction 1h; L-Borneol (4.065g, 0.026mol) to be dissolved in dichloromethane in (25ml), to be added drop-wise in reactant liquor; After dropwising, remove cryosel bath, naturally heat up, reaction is spent the night; After reaction terminates, filtering solids, filter cake q. s. methylene chloride washs, filtrate evaporate to dryness, and residue obtains compound 3b (10.5g) through column chromatography.
B. compound 3b (9g, 0.021mol) is put in oxolane (90ml), stir, add ammonium formate (6.84g, 0.105mol), adding palladium charcoal (1.8g, 0.147mol), reaction 3h.After reaction terminates, with diatomite filtration palladium charcoal, and wash with appropriate oxolane, filtrate evaporate to dryness.Residue petroleum ether or recrystallisation from isopropanol, obtain compound ferulic acid L-Borneol ester.
Adopt nuclear-magnetism method to confirm its structure to the ferulic acid L-Borneol ester of above-mentioned acquisition, as shown in Figure 3, the result obtained is:
1h-NMR (CDCl
3, 500MHz) 0.88, 0.90, 0.95 (each 3H, s, H-8, 9, 10), 1.05 (1H, dd, J=13.9, 3.4Hz, H-3b), 1.29 (1H, m, H-5b), 1.31 (1H, m, H-6b), 1.71 (1H, m, H-4), 1.78 (1H, m, H-5a), 2.06 (1H, m, H-6a), 2.41 (1H, dddd, J=13.3, 9.7, 3.8, 3.4Hz, H-3a), 3.94 (3H, s, OMe), 5.07 (1H, dd, J=9.7, 3.0, H-2), 6.31 (1H, d, J=15.9Hz, H-8 '), 6.92 (1H, d, J=8.5Hz, H-5 '), 7.04 (1H, dd, J=8.5, 2.0Hz, H-6 '), 7.06 (1H, d, J=2.0Hz, H-2 '), 7.59 (1H, d, J=15.9Hz, H-7 ').Authenticating compound is ferulic acid dextrorotation norbornene ester.
Embodiment 5
A kind of synthetic route of ferulic acid dextrorotation norbornene ester is disclosed in the present embodiment:
Haloacetyl dextrorotation norbornene ester 4a and organophosphorus reagent are obtained by reacting wittig phosphorus reagent 5a, and then wittig phosphorus reagent 5a carries out wittig with 3-methoxyl group-4 hydroxy benzaldehyde 6 again and is obtained by reacting ferulic acid dextrorotation norbornene ester under the effect of alkali.
Wherein, X is Cl, Br or I, and R is PPh
3x, P (O) Ph
2or P (O) (OEt)
2.
Organophosphorus reagent comprises: in triphenyl phosphorus, ethoxy diphenyl base phosphorus and NSC 5284; Described alkali comprises: Lithium Aluminium Hydride, Feldalat NM, Sodium ethylate, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, Lithium hydrate and potassium carbonate.
The concrete grammar step of said synthesis route is:
Step one: by chloracetyl dextrorotation norbornene ester 4a (21.5g, 93.2mmol), triphenylphosphine (48.9g, 186mmol), toluene (215ml) joins in reaction bulb, be warming up to backflow, reaction 12h, evaporated under reduced pressure, residue from dichloromethane/petroleum ether recrystallization, obtains compound 5a (34.2g).
Step 2: under nitrogen protection; by compound 5a (34.2g; 69.4mmol) join in anhydrous tetrahydro furan (342ml); be cooled to-78 DEG C, drip n-BuLi (11.0g, 173mmol); drip rear reaction 0.5h; drip oxolane (70ml) solution of Vanillin 6 (13.3g, 87.5mmol), add rear maintenance-78 DEG C reaction 3h.React rear and be naturally warming up to room temperature, saturated sodium bicarbonate solution (200ml) is dripped in reactant liquor, ethyl acetate (150ml × 3) extracts, merge organic facies, saturated common salt water washing, anhydrous sodium sulfate drying 4h, filter, filtrate is concentrated into dry, residue petroleum ether or recrystallisation from isopropanol, obtains compound ferulic acid dextrorotation norbornene ester.
Embodiment 6
The synthetic line of ferulic acid L-Borneol ester is disclosed in the present embodiment, as follows:
Haloacetyl L-Borneol ester 4b and organophosphorus reagent are obtained by reacting wittig phosphorus reagent 5b, and then wittig phosphorus reagent 5b carries out wittig with 3-methoxyl group-4 hydroxy benzaldehyde again and is obtained by reacting ferulic acid L-Borneol ester under the effect of alkali;
Wherein X is Cl, Br or I, and R is PPh
3x, P (O) Ph
2or P (O) (OEt)
2.Organophosphorus reagent comprises: in triphenyl phosphorus, ethoxy diphenyl base phosphorus and NSC 5284; Above-mentioned alkali comprises: Lithium Aluminium Hydride, Feldalat NM, Sodium ethylate, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, Lithium hydrate and potassium carbonate.
The concrete grammar step of said synthesis route is:
Step one: by 2-chloracetyl L-Borneol ester 4b (21.5g, 93.2mmol), triphenylphosphine (48.9g, 186mmol), toluene (215ml) joins in reaction bulb, be warming up to backflow, reaction 12h, evaporated under reduced pressure, residue from dichloromethane/petroleum ether recrystallization, obtains compound 5b (35.8g).
Step 2: under nitrogen protection; by compound 5b (35.8g; 72.6mmol) join in anhydrous tetrahydro furan (358ml); be cooled to-78 DEG C, drip n-BuLi (11.6g, 182mmol); drip rear reaction 0.5h; drip oxolane (70ml) solution of Vanillin 6 (13.9g, 91.4mmol), add rear maintenance-78 DEG C reaction 3h.React rear and be naturally warming up to room temperature, saturated sodium bicarbonate solution (200ml) is dripped in reactant liquor, ethyl acetate (150ml × 3) extracts, merge organic facies, saturated common salt water washing, anhydrous sodium sulfate drying 4h, filter, filtrate is concentrated into dry, residue petroleum ether or recrystallisation from isopropanol, obtains compound ferulic acid L-Borneol ester.
Embodiment 7
In the present embodiment, the ferulic acid dextrorotation norbornene ester obtained in above-described embodiment and ferulic acid L-Borneol ester are carried out effect experiment, by ferulic acid norbornene ester therapeutic administratp to its drug effect in apoplexy disease treatment of the effect appraise of rat permanent cerebral ischemia induced brain injury.
Above-mentioned experimental program is:
1, cleaning grade male SD rat 100 (becoming mould rate to be 50%) is prepared, body weight 250-300g, internal carotid artery line brush is adopted to prepare intraluminal middle cerebral artery occlusion in rats obturation (MCAO) model: rat 3% chloral hydrate (300mg/kg) lumbar injection (ip) is anaesthetized, on supine surgical platform, cervical region median incision, expose right carotid, outside traction digastric and sternocleidomastoid, dissociated successively by common carotid artery crotch head-end, ligation also cuts off the branch of external carotid artery: tremulous pulse and superior thyroid artery under occipital bone.In the ligation of external carotid artery far-end, it is for subsequent use that cut-out external carotid artery makes its trunk dissociate.Then be separated internal carotid artery, make a call to one release with silk thread at external carotid artery root, folder closes common carotid artery and internal carotid artery.By fishing line (long 40mm, diameter 0.26mm) through external carotid artery trunk otch, slowly enter cranium direction to internal carotid artery and advance, when unclamping the bulldog clamp on internal carotid artery after fishing line enters internal carotid artery.With common carotid artery crotch for labelling, advance during about 18mm and feel resistance, namely reach in thinner anterior cerebral artery, all blood having blocked MCA, for source, are tightened external carotid artery root and are released.Skin suture, completes MCAO and causes permanent cerebral ischemia model.
2, after rats in sham-operated group anesthesia, only aortic bifurcation inside and outside neck is exposed, not inaccessible MCA.After model completes, 2h tail intravenously administrable, is divided into 5 groups, often organizes 20, is respectively: sodium ferulate group, ferulic acid dextrorotation norbornene ester group, ferulic acid L-Borneol ester, positive control nimodipine group and blank group (giving isometric normal saline); Every day intravenously administrable once, successive administration 3 days, administration volume is 0.2ml/100g body weight.
3, neurological deficit standards of grading: carry out rank scores by the method for Bederson to the neurological deficit of animal, standard is as follows:
0 point: do not observe nervous symptoms.
1 point: carry tail unsettled time, the operation offside forelimb of animal shows as wrist elbow flexing, shoulder inward turning, elbow abduction, is close to thoracic wall.
2 points: be placed in by animal in smooth flat, when pushing hands art side shoulder moves to offside, resistance reduces.
3 points: to operation side ring turned when animal freely walks or turn-take.
4 points; Collapse from physical exhaustion, limbs are without spontaneous activity.
Experiment terminates to carry out preliminary pharmacodynamic results statistics to above-mentioned four groups of experiments afterwards, neurological deficit score and the statistical result of cerebral infarction volume as shown in table 1:
Table 1 pharmacodynamic experiment result statistical table
| Group | n | Neurological deficit score | Cerebral infarction volume (mm 2) |
| Blank group | 10 | 2.50±0.53 | 35.2±4.38 |
| Sodium ferulate group | 10 | 2.30±0.54 | 33.8±4.85 |
| Nimodipine group | 10 | 1.40±0.52 * | 20.0±5.13 * |
| Ferulic acid L-Borneol ester group | 9 | 1.60±0.55 * | 21.8±4.78 * |
| Ferulic acid dextrorotation norbornene ester group | 10 | 1.40±0.50 * | 18.1±5.43 * |
* P < 0.05, compares with blank group.
Added up from the neurological deficit score in Fig. 4-8 and table 1 and cerebral infarction volume, therapeutic effect is there is hardly in marketed drug sodium ferulate for apoplexy disease, and ferulic acid L-Borneol ester and ferulic acid dextrorotation norbornene ester all show good drug effect, wherein ferulic acid L-Borneol ester is suitable with positive control drug nimodipine, and ferulic acid dextrorotation norbornene ester is better than positive control drug nimodipine.
By obtaining in the above embodiment of the present invention, the synthesis technique of ferulic acid norbornene ester of the present invention is brief, and raw material economics is easy to get, nontoxic, and synthesis process is easy to control; Without the generation of harmful side product, be environmental protection and economy type technique, can be extensively adapted to treat in the production of cerebrovascular disease medicament.
Ferulic acid norbornene ester good water solubility of the present invention, can be applied in the medicine of antithrombotic, blood fat reducing and treatment cerebrovascular disease, and have no apparent side effect.
To the above-mentioned explanation of the disclosed embodiments, professional and technical personnel in the field are realized or uses the present invention.To be apparent for those skilled in the art to the multiple amendment of these embodiments, General Principle as defined herein can without departing from the spirit or scope of the present invention, realize in other embodiments.Therefore, the present invention can not be restricted to these embodiments shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (6)
1. a ferulic acid norbornene ester, ferulic acid norbornene ester and pharmaceutically acceptable salt thereof and prodrug are applied in pharmacy, it is characterized in that, described ferulic acid norbornene ester is applied in treatment apoplexy disease, described ferulic acid norbornene ester comprises ferulic acid dextrorotation norbornene ester and ferulic acid L-Borneol ester two kinds of structures, and the general structure of described ferulic acid dextrorotation norbornene ester is
the general structure of described ferulic acid L-Borneol ester is
described ferulic acid L-Borneol ester is the enantiomer of described ferulic acid dextrorotation norbornene ester.
2. ferulic acid norbornene ester according to claim 1, is characterized in that, the synthetic line of described ferulic acid dextrorotation norbornene ester is:
Wherein, 1a is dextrorotation Borneolum Syntheticum, and 2 is the ferulic acid that phenolic hydroxyl group is protected, and R is protecting group, the ferulic acid that phenolic hydroxyl group is protected obtains the ferulic acid dextrorotation norbornene ester 3a that phenolic hydroxyl group is protected under condensing agent catalysis with the condensation of dextrorotation Borneolum Syntheticum, then obtains ferulic acid dextrorotation norbornene ester through deprotection;
The synthetic line of described ferulic acid L-Borneol ester also comprises:
Wherein, 1b is L-Borneol, and the ferulic acid that phenolic hydroxyl group is protected obtains the ferulic acid L-Borneol ester 3b that phenolic hydroxyl group is protected under condensing agent catalysis with L-Borneol condensation, then obtains ferulic acid L-Borneol ester through deprotection.
3. ferulic acid norbornene ester according to claim 2, it is characterized in that, described protecting group comprise following in any one: methyl, the tert-butyl group, trityl group, methoxy, trimethyl silicon based, t-Butyldimethylsilyl, benzyl, THP trtrahydropyranyl; Described condensing agent comprise following one or more: dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, DMAP, I-hydroxybenzotriazole and 4-pyrollidinopyridine.
4. ferulic acid norbornene ester according to claim 1, is characterized in that, the synthetic line of described ferulic acid dextrorotation norbornene ester also comprises:
Haloacetyl dextrorotation norbornene ester 4a and organophosphorus reagent are obtained by reacting wittig phosphorus reagent 5a, and then wittig phosphorus reagent 5a carries out wittig with 3-methoxyl group-4 hydroxy benzaldehyde 6 again and is obtained by reacting ferulic acid dextrorotation norbornene ester under the effect of alkali;
The synthetic line of described ferulic acid L-Borneol ester also comprises:
Haloacetyl L-Borneol ester 4b and organophosphorus reagent are obtained by reacting wittig phosphorus reagent 5b, and then wittig phosphorus reagent 5b carries out wittig with 3-methoxyl group-4 hydroxy benzaldehyde 6 again and is obtained by reacting ferulic acid L-Borneol ester under the effect of alkali;
Wherein X is Cl, Br or I, and R is PPh
3x, P (O) Ph
2or P (O) (OEt)
2.
5. ferulic acid norbornene ester according to claim 4, is characterized in that, described organophosphorus reagent comprise following in any one: in triphenyl phosphorus, ethoxy diphenyl base phosphorus and NSC 5284; Described alkali comprise following one or more: Lithium Aluminium Hydride, Feldalat NM, Sodium ethylate, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, Lithium hydrate and potassium carbonate.
6. pharmaceutical composition, it comprises the ferulic acid norbornene ester described in claim 1-5 any one, it is characterized in that, described pharmaceutical composition comprises ferulic acid norbornene ester or its pharmaceutically acceptable salt, solvate or the prodrug for the treatment of effective dose.
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| CN201510243181.5A CN104856983B (en) | 2015-05-13 | 2015-05-13 | Synthesis and application of bornyl ferulate |
| PCT/CN2015/089396 WO2016179932A1 (en) | 2015-05-13 | 2015-09-10 | Synthesis and application of bornyl ferulate |
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| WO2016179932A1 (en) * | 2015-05-13 | 2016-11-17 | 苏州沪云肿瘤研究中心股份有限公司 | Synthesis and application of bornyl ferulate |
| WO2016180206A1 (en) * | 2015-05-13 | 2016-11-17 | 苏州沪云肿瘤研究中心股份有限公司 | Borneol ferulate injection, and preparation method therefor and application therefof |
| WO2016180205A1 (en) * | 2015-05-13 | 2016-11-17 | 苏州沪云肿瘤研究中心股份有限公司 | Dextro borneol ferulate crystal form, and preparation method therefor and application therefof |
| CN107619376A (en) * | 2017-11-09 | 2018-01-23 | 宁波职业技术学院 | A kind of valine norbornene ester and its preparation method and application |
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| WO2016180205A1 (en) * | 2015-05-13 | 2016-11-17 | 苏州沪云肿瘤研究中心股份有限公司 | Dextro borneol ferulate crystal form, and preparation method therefor and application therefof |
| CN107619376A (en) * | 2017-11-09 | 2018-01-23 | 宁波职业技术学院 | A kind of valine norbornene ester and its preparation method and application |
| CN108084030A (en) * | 2017-12-30 | 2018-05-29 | 苏州沪云肿瘤研究中心股份有限公司 | A kind of cinnamic acid esters compound and its preparation method and application |
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| WO2016179932A1 (en) | 2016-11-17 |
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