CN103086862A - Hydroxydecyl quinone derivative for treating or preventing nerve diseases - Google Patents
Hydroxydecyl quinone derivative for treating or preventing nerve diseases Download PDFInfo
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- CN103086862A CN103086862A CN201310001087XA CN201310001087A CN103086862A CN 103086862 A CN103086862 A CN 103086862A CN 201310001087X A CN201310001087X A CN 201310001087XA CN 201310001087 A CN201310001087 A CN 201310001087A CN 103086862 A CN103086862 A CN 103086862A
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a hydroxydecyl quinone derivative for treating or preventing nerve diseases. Specifically, the invention relates to the hydroxydecyl quinone derivative as shown in formula I, a pharmaceutical composition containing the compound as shown in the formula I, and a preparation method and uses of the hydroxydecyl quinone derivative in preparation of medicaments for cerebrovascular diseases. The compound disclosed by the invention can effectively treat or prevent the diseases or disease symptoms: the cerebrovascular diseases, improve cerebral metabolism and improve mental symptoms, activate brain mitochondrial respiratory activity, improve cerebral energy metabolism of cerebral ischemia, improve the utilization rate of cerebral glucose, increase the production of cerebral triphosadenine, inhibit the generation of lipid hydroperoxide from brain mitochondria and inhibit the membrane disorder caused by overoxidation action of the brain mitochondrial membrane lipid, reduce impaired brain functions caused by chronic cerebrovascular diseases, cerebral trauma and the like, improve subjective symptoms, language, anxiety, depression, hypomnesia, intelligence decrease and other mental and behavioral disorders, promote the intelligence, and activate brain mitochondrial functions, improve the cerebral energy metabolism and improve brain functions.
Description
Technical field
The present invention relates to a kind of 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones.Specifically, the present invention relates to have the 6-(10-hydroxyl decyl)-2 of specified property, 3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones and preparation method thereof, and this 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the pharmaceutical applications of 4-benzoquinones.
Background technology
Recover syndrome after neuronal damage, neurodegenerative disease and syndrome (alzheimer's disease, multiple sclerosis, Friedreich ataxia (Friedrich ' s ataxia), brain and Spinal injury and neurotrauma, apoplexy, Parkinson's disease, alcoholism and narcolepsy (narcolepsy), operative results syndrome and anesthesia) and many other illnesss need effectively treatment and prevention.
Postoperative apoplexy and cognitive defect (POSCD) syndrome is common, particularly in the elderly who carries out the operation of surgical operation on a large scale such as heart or hip replacement surgery.In North America, surpass the 2500000 such surgical operations of example every year, and the sickness rate of POSCD surpasses 30%.Existence to interventional therapy in the urgent need to, and also do not have enough treatment to select for this distressful postoperative illness.In the U.S., only just surpass the operation of 2,000,000 exception sections every year with regard to heart operation.The rear recovery of the anesthesia of Lente anesthetic medicine causes the patient be in the state of significant disorientation and cognitive impairment and continue very over a long time usually.Even newer fugitive narcotic occurred, act on after also not alleviating the anesthesia of geratic surgery patient with operation.
After operation, the sickness rate of serious adverse events (comprising cognitive defect and apoplexy) is up to operating 30-35% on a large scale, and this has caused extensively and the hospital stay that extends and affected patient and health care supplier's thereof serious quality of life problem.With apoplexy after anesthesia from approximately 2.5% be reduced to 1.5% or will perform the operation after the cognitive defect improvement that basically can produce significant cost savings and quality of life handling problem from present approximately 30% ability that reduces.There are now a large amount of evidences to show that many gerontal patients are performing the operation by being subjected to cognitive decline.For the age〉in the perspective randomized test of the general anesthesia contrast epidural anesthesia (having sedative effect) carried out of 70 years old patient's total knee replacement, when estimating with psychometry, the patient of 4-6% preoperative baseline of cognitive Performance Ratio of six months after anesthesia and surgical operation is poor.Another large-scale perspective contrast international research confirms that 9.9% patient had cognitive defect in rear three months in operation, 3% similar damage is arranged and only have an appointment in the control group of age-matched.In the age surpassed the patient of 75 years old, 14% patient had lasting cognitive defect after general anesthesia and surgical operation.
In many cases, the neurodegeneration relevant with anoxic cause because blood circulation reduces, and with the excessive of free radical with to the inhibition of mitochondria activity.
Antioxidant is considered to reduce the possible protective material of the brain injury that causes due to general anesthesia on a large scale.Various materials---antioxidant and free-radical scavengers---have obtained test in animal model in vitro cell culture, exsomatize brain section and body.In these experiments, 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones have shown significant antioxidant activity and can protect significantly the damage of the not oxidated property of brain cell.6-(10-hydroxyl decyl)-2, 3-dimethoxy-5-methyl isophthalic acid, the oral form of 4-benzoquinones is used for the treatment of myocardial atrophy in Friedreich ataxia as hepatoprotective, and be used for the treatment of alzheimer's disease [United States Patent (USP) 5 on limited degree, 916, 925 " Pharmaceuticalcomposition for treatment of dementia " and United States Patent (USP)s 6, 133, the people such as 322Rustin P., " Quinonederivatves for treating or preventing diseases associated with iron overload "].
In the small-sized human research that the patient who nine is suffered from cerebrovascular disease carries out, give the 6-(10-hydroxyl decyl)-2 of 90mg every day, 3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones, and monitor cerebral electrograph and clinical symptom.Result shows 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, and the additional administration of 4-benzoquinones has produced improvement to these patients' EEG (electroencephalogram) and clinical symptom.
6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the cortical neuron that the protection of 4-benzoquinones is cultivated makes it the sex change of not necrosing property.It even still can save cortical neuron when using in 30 minutes after the NMDA pulse, this has shown described interfering effects of drug toxic reaction chain that triggers due to the overstimulation excitatory amino acid receptor again.
To the oral 6-of giving of the patient who suffers from Friedreich ataxia (10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones (every day 5mg/kg and lasting 8 weeks) has reduced the sign of oxidative dna damage significantly.6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, lipid peroxidation and myocardial damage that the 4-benzoquinones has prevented iron to induce in three patients that give 5mg/kg and continue 4-9 month every day, thus cause the reduction that in these patients, left ventricle enlarges.
In the cell culture experiment, 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the 4-benzoquinones has been removed various Kinds of Free Radicals.6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones also carry out redox couple with myohaemoglobin or the oxyphorase of high valence state kind, thereby have prevented the lipid peroxidation that promoted by these kinds.Similarly, shown 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones have suppressed the foundation of microsomal Lipid Peroxidation of being induced by ADP-iron complexes or organic hydroperoxide.Oneself shows 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, and the 4-benzoquinones has so prevented the destruction of Cytochrome P450, and the destruction of described Cytochrome P450 can be followed lipid peroxidation in addition.
Be reported in the experimental model that produces by cerebral embolism formation, cerebral ischemia or damage in Basal Forebrain of Rats, 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, it is disorderly that the 4-benzoquinones has improved learning and memory, and described basal forebrain is the origin area that projects the vagusstoff neuron system in pallium, hippocampus and amygdala.In clinical trial, it is effective that 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones are considered to for reducing mental defect (as decline and the disorientation of memory maintenance).
This area is still expected to be useful on and 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the method for the disease-related that the 4-benzoquinones can be treated.
Summary of the invention
The purpose of this invention is to provide a kind of for 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the method for the disease-related that the 4-benzoquinones can be treated.
The invention provides with the following formula I compound:
According to compound of the present invention, wherein comprise the following formula I Y compound as the trace of impurity:
According to compound of the present invention, it is in high effective liquid chromatography for measuring, the chromatographic purity that has greater than 98% (preferably has the chromatographic purity greater than 98.5%, preferably has the chromatographic purity greater than 99.0%, preferably has the chromatographic purity greater than 99.2%, preferably have the chromatographic purity greater than 99.3%, preferably have the chromatographic purity greater than 99.5%.
According to compound of the present invention, it is in high effective liquid chromatography for measuring, and the chromatogram content of impurity Y is lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.55%, preferably lower than 0.5%, preferably lower than 0.45%, preferably lower than 0.4%, preferably lower than 0.35%, preferably lower than 0.3%.In example, the chromatogram content of impurity Y is higher than 0.02%.
According to compound of the present invention, it is in high effective liquid chromatography for measuring, and in color atlas, total chromatogram content of each impurity peaks is lower than 1.2%, preferably lower than 1.0%, preferably lower than 0.9%, preferably lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.5%, preferably lower than 0.4%.
According to compound of the present invention, its total chromatogram content of each impurity peaks increased value after placing 150 days under 45 ° of C is no more than 1.5%, preferably is no more than 1.25%, preferably is no more than 1.0%, preferably is no more than 0.75%, preferably is no more than 0.5%.
According to compound of the present invention, wherein said high performance liquid chromatography is measured according to two appendix VD high performance liquid chromatography standards of Chinese Pharmacopoeia version in 2010, and described high effective liquid chromatography for measuring mode is:
(1) chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, take methanol-water (70:30) as moving phase, the ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, number of theoretical plate is pressed 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the peak calculating of 4-benzoquinones is not less than 2000;
(2) preparation of test soln: get the compounds of this invention, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg in every 1ml, as need testing solution; Separately get impurity Y-shaped IY compound, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg in every 1ml, as impurity Y solution; Precision measures need testing solution and each 1ml of impurity Y solution, puts in the measuring bottle of same 100ml, is diluted to scale with moving phase, shakes up, as the contrast solution that comprises formula I compound and formula IY compound;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at principal constituent peak be about 10% of full range, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography respectively records color atlas to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area (be the peak area of formula I compound, this peak area can be expressed as A1 in the present invention) and retention time thereof, and record peak area and the retention time thereof of impurity Y;
(4ii) record need testing solution color atlas main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof;
(4iii) in the need testing solution color atlas, any chromatographic peak of 0.05 times less than A1 is ignored, (this peak area can be expressed as Am in the present invention greater than the impurity peak area of 0.05 times of A1 to record each peak area in the need testing solution color atlas, m represents m peak area greater than the impurity peaks of 0.05 times of A1, and wherein impurity Y is also in these impurity one) and retention time;
(4iv) according to the retention time of impurity Y in the contrast solution color atlas, determine impurity Y and peak area thereof in the need testing solution color atlas, and calculate the assorted chromatogram content of impurity Y.
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, the chromatographic purity of the compounds of this invention can be calculated as follows:
(in above calculating formula, the n identifier adds up to the number of calculating all dirt that requires, impurity Y can be a member wherein, Σ An identifier adds up to the summation of the area of calculating all dirt that requires, all has this implication when similar statement occurring in the context of the invention);
Perhaps, the chromatographic purity of the compounds of this invention can be calculated as follows:
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with the main peak retention time, calculate the relative retention time of each impurity peaks.
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with the main peak retention time, calculate the relative retention time of each impurity peaks, the relative retention time of a certain impurity peaks (RRt) can be calculated as follows:
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, in the compounds of this invention, the chromatogram content of single impurity can be calculated as follows:
(in above calculating formula, the m identifier adds up to the impurity that is numbered m of calculating requirement, and Am represents the peak area of m impurity, all has this implication when similar statement occurring in the context of the invention, and the chromatogram content of impurity Y also available following formula calculates);
Perhaps, in the compounds of this invention, the chromatogram content of single impurity can be calculated as follows:
The chromatogram content of impurity Y also available following formula calculates.
According to compound of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, in the compounds of this invention, total chromatogram content of each impurity can be calculated as follows:
Perhaps, in the compounds of this invention, total chromatogram content of each impurity can be calculated as follows:
Further, the present invention another aspect provides a kind of pharmaceutical composition, wherein comprises the described compound of first aspect present invention, and the optional acceptable auxiliary material of pharmacy.
According to pharmaceutical composition of the present invention, wherein comprise with the following formula I compound:
And the acceptable auxiliary material of pharmacy.
According to pharmaceutical composition of the present invention, wherein comprise the following formula I Y compound as the trace of impurity:
according to pharmaceutical composition of the present invention, it is in high effective liquid chromatography for measuring, disregard (or deduction) relative retention time less than 0.2 impurity peaks, disregard any chromatographic peak of 0.05 times less than A1 in (or deduction) need testing solution color atlas, disregard (or deduction) auxiliary material chromatographic peak, this pharmaceutical composition has the chromatographic purity greater than 98%, preferably has the chromatographic purity greater than 98.5%, preferably has the chromatographic purity greater than 99.0%, preferably has the chromatographic purity greater than 99.2%, preferably has the chromatographic purity greater than 99.3%, preferably has the chromatographic purity greater than 99.5%.
According to compound of the present invention, it is in high effective liquid chromatography for measuring, and total chromatogram content of impurity Y is lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.55%, preferably lower than 0.5%, preferably lower than 0.45%, preferably lower than 0.4%, preferably lower than 0.35%, preferably lower than 0.3%.
According to pharmaceutical composition of the present invention, it is in high effective liquid chromatography for measuring, and in color atlas, total chromatogram content of each impurity peaks is lower than 1.2%, preferably lower than 1.0%, preferably lower than 0.9%, preferably lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.5%, preferably lower than 0.4%.
According to pharmaceutical composition of the present invention, its total chromatogram content of each impurity peaks increased value after placing 150 days under 45 ° of C is no more than 1.5%, preferably is no more than 1.25%, preferably is no more than 1.0%, preferably is no more than 0.75%, preferably is no more than 0.5%.
According to pharmaceutical composition of the present invention, wherein said high performance liquid chromatography is measured according to two appendix VD high performance liquid chromatography standards of Chinese Pharmacopoeia version in 2010, and described high effective liquid chromatography for measuring mode is:
(1) chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, take methanol-water (70:30) as moving phase, the ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, number of theoretical plate is pressed 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the peak calculating of 4-benzoquinones is not less than 2000;
(2) preparation of test soln: get pharmaceutical composition of the present invention appropriate, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg formula I compound in every 1ml, as need testing solution; Separately get impurity Y-shaped IY compound, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg in every 1ml, as impurity Y solution; Precision measures need testing solution and each 1ml of impurity Y solution, puts in the measuring bottle of same 100ml, is diluted to scale with moving phase, shakes up, in contrast solution; Separately get the auxiliary material in pharmaceutical composition of the present invention, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the concentration corresponding with 0.2mg/ml formula I compound concentration, as auxiliary material solution;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at principal constituent peak be about 10% of full range, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography respectively records color atlas to 2.5 times of principal constituent peak retention time; Separately get auxiliary material solution 20 μ l injection liquid chromatographies, the injection liquid chromatography records color atlas to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area (this peak area can be expressed as A1 in the present invention) and retention time thereof, and record peak area and the retention time thereof of impurity Y;
(4ii) record need testing solution color atlas main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof; Record the chromatographic peak that in auxiliary material solution color atlas, auxiliary material forms;
(4iii) in the need testing solution color atlas, the chromatographic peak corresponding with the auxiliary material retention time disregarded (perhaps disregard further or deduct relative retention time less than 0.2 impurity peaks), in the need testing solution color atlas, any chromatographic peak of 0.05 times less than A1 is ignored, (this peak area can be expressed as Am in the present invention greater than the impurity peak area of 0.05 times of A1 to record each peak area in the need testing solution color atlas, m represents m peak area greater than the impurity peaks of 0.05 times of A1, and wherein impurity Y is also in these impurity one) and retention time.
(4iv) according to the retention time of impurity Y in the contrast solution color atlas, determine impurity Y and peak area thereof in the need testing solution color atlas, and calculate the assorted total chromatogram content of impurity Y.
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, the chromatographic purity of pharmaceutical composition of the present invention can be calculated as follows:
Perhaps, the chromatographic purity of pharmaceutical composition of the present invention can be calculated as follows:
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with the main peak retention time, calculate the relative retention time of each impurity peaks.
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, be as the criterion with the main peak retention time, calculate the relative retention time of each impurity peaks, the relative retention time of a certain impurity peaks (RR) can be calculated as follows:
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, can be calculated as follows according to the chromatogram content of single impurity in pharmaceutical composition of the present invention:
Perhaps, the chromatogram content according to single impurity in pharmaceutical composition of the present invention can be calculated as follows:
According to pharmaceutical composition of the present invention, in the need testing solution color atlas of wherein said high-performance liquid chromatogram determination, can be calculated as follows according to total chromatogram content of each impurity in pharmaceutical composition of the present invention:
Perhaps, the total chromatogram content according to each impurity in pharmaceutical composition of the present invention can be calculated as follows:
Again further, the present invention another aspect provides the preparation method of the compounds of this invention, and it comprises the following steps:
(i) with the dissolving crude product of formula I compound in good solvent;
(ii) add the first anti-solvent in step (i) gained solution, mixing, then add the second anti-solvent, be heated to 30-40 ° of C and make solution clarification, heat filtering;
(iii) make filtrate slowly be cooled to 10 ° below C, make crystallization, leach crystallization, drying, and get final product.
The method according to this invention, wherein the good solvent described in step (i) is selected from methylene dichloride, ethyl acetate or its combination.In one embodiment, the feed ratio of described good solvent and formula I chemical combination is 3 ~ 8:1 (v:w), preferred 4 ~ 6:1.
The method according to this invention, wherein the first anti-solvent described in step (ii) is selected from Skellysolve A, sherwood oil or its combination.In one embodiment, the feed ratio of the described first anti-solvent and formula I chemical combination is 2 ~ 10:1 (v:w), preferred 3 ~ 8:1.
The method according to this invention, wherein the second anti-solvent described in step (ii) is selected from normal hexane, hexanaphthene or its combination.In one embodiment, the feed ratio of the described second anti-solvent and formula I chemical combination is 10～20:1 (v:w), preferred 13 ~ 18:1.
The method according to this invention, wherein the heating described in step (ii) is to be heated to 35-37 ° of C.
The method according to this invention, wherein cooling described in step (iii) is to be cooled to 0 ~ 10 ° of C, preferred 0 ~ 5 ° of C, preferred 0～2 ° of C.
The method according to this invention, wherein slowly cooling described in step (iii) is that the speed of preferred 0.05 ~ 0.5 ° of C/min is cooling with 0.01 ~ 1 ° of C/min.
The method according to this invention, wherein the drying described in step (iii) is vacuum-drying under 20 ~ 45 ° of C, preferably at room temperature vacuum-drying.
Again further, the present invention provides the compounds of this invention or the purposes of pharmaceutical composition in the preparation medicine in another aspect again.
According to purposes of the present invention, wherein said medicine is used for following either side or many-sided disease or illness: cerebro-vascular diseases; Improve the brain metabolism, improve mental symptom; Activate the brain mitochondria respiratory activity, improve cerebral ischemia brain energy metabolism, improve glucose utilization rate in brain, ATP in brain produced increase, suppress brain mitochondria to generate lipid peroxide, suppress the film obstacle due to the brain mitochondria lipid peroxidation; The caused Brain function damages such as chronic cerebral vascular disease and cerebral trauma; Improve subjective symptom, language, anxiety, depression, hypomnesis, the lower degradation mental act obstacle of intelligence; Promote intelligence; Compose the brain mitochondria function of living, improve brain energy metabolism, improve the brain function; Improve that cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis cause feel down in spirits, realize is low, affective disorder, aphasis etc.; Improve brain metabolism, protection cranial nerve cell; Mitochondriopathy; Anticoagulant, improve microcirculation; Anti-oxidant; Treatment or prevention FRDA (ataxia); Treatment or prevention neurological disorder; And the improvement illness relevant to neuronal damage.
In the present invention, described neurological disorder is caused by neurotrauma.More preferably, described neurological disorder is apoplexy.More preferably, described neurological disorder is encephalomyelitis.Preferably, neurological disorder is relevant to mitochondria dysfunction.Preferably, described neurological disorder is relevant to anoxic condition.Preferably, neurological disorder is alcohol withdrawal syndrome or fetal alcohol syndrome.Preferably, neurological disorder is relevant to the neuronal damage that is caused by bacterium infection or virus infection.
Well-knownly be, formula I compound itself has above-mentioned therepic use, so the compounds of this invention or pharmaceutical composition have such use equally.
In the described compound of first aspect present invention arbitrary embodiment can with other scheme arbitrary combination, also can with the described pharmaceutical composition of second aspect in appoint arbitrary embodiment arbitrary combination; Similarly, in the described pharmaceutical composition of second aspect present invention arbitrary embodiment can with other scheme arbitrary combination, also can with the described compound of first aspect in appoint arbitrary embodiment arbitrary combination; As long as these combinations are not conflicting.
In the present invention, when calculating each impurity peak area sum, this peak area sum can be expressed as Σ An in the present invention, namely meets peak area greater than all dirt peak of 0.05 times of A1 (n 's altogether) peak area sum, disregards or deducts solvent peak, auxiliary material peak.As well known to those skilled in the art, in high performance liquid chromatography, therefore the chromatographic peak that " relative retention time less than 0.2 impurity peaks " normally formed by solvent can directly deduct these chromatographic peaks in the present invention, and does not think that they are chromatographic peaks in various material of the present invention.
In the present invention, mention that the compounds of this invention or pharmaceutical composition " the total chromatogram content of each impurity peaks increased value is no more than 1.5% after placing 150 days under 45 ° of C " refer to the compounds of this invention or pharmaceutical composition are placed under 45 ° of C and placed 150 days, after disposal relatively more like this, with the difference of disposing the total chromatogram content of each impurity peaks in front sample, namely the total chromatogram content of each impurity peaks increased value=each impurity peaks total chromatogram content (%)-45 of 45 ° of C placements after 150 days ° C places the total chromatogram content of each impurity peaks (%) before 150 days.For example, if this bright compound total chromatogram content of each impurity peaks when placing disposal in 150 days without 45 ° of C is 0.6%, and the total chromatogram content of each impurity peaks is 1.0% after measured after placing disposal in 150 days through 45 ° of C, and the compounds of this invention " the total chromatogram content of each impurity peaks increased value after placing 150 days under 45 ° of C " is 0.4%.
In the present invention, term " main peak " for example at " contrast solution color atlas main peak area " and " main peak " mentioned, represents the formed look peak-to-peak of principal constituent formula I compound in this chromatographic peak in " need testing solution color atlas main peak area ".accordingly, in the present invention, term " impurity peaks " expression is except principal constituent formula I compound and other chromatographic peak known or the basic formation of unknown materials, its precondition is to disregard (perhaps deducting in advance when calculating) " any chromatographic peak of 0.05 times less than A1 in the need testing solution color atlas ", also disregard in the need testing solution color atlas due to test with the reagent (chromatographic peak that produces of solvent for example, for example dosing solvent and moving phase difference) chromatographic peak that produces of the component (for example medicament auxiliary material) that adds especially in the chromatographic peak that produces or composition.
In the present invention, term " each impurity peak area sum " represents the peak area of any one " any chromatographic peak of 0.05 times less than A1 in the need testing solution color atlas " (disregarding equally the chromatographic peak that solvent or auxiliary material produce), they add and.
The inventor has been found that the RRt of impurity Y between 0.70～0.90, preferably between 0.75～0.85
As well known to those skilled in the art, for the HPLC method is calculated content, can usable floor area normalization method computing method, can also use the contrast solution computing method, that the present invention uses is the latter, and take 1% contrast solution as calculating, it is more accurate in area normalization method that this kind method compares.Difference due to different HPLC chromatographic processes and condition determination causes the chromatographic behavior of principal constituent and impurity to have nuance in addition, thereby causes measurement result variant, and this is also that those skilled in the art are acceptable.Yet those skilled in the art know, as long as chromatographic condition is fixed, the chromatographic behavior of material will be relatively fixing, will be relatively fixing between measurement result; Therefore for the compounds of this invention, under the chromatographic condition of the present invention's regulation, itself and impurity thereof just have relatively-stationary chromatographic behavior.
In the present invention, when carrying out chromatographic determination, the retention time of formula I compound can be allowed in wider time range, for example can be in the scope of 5～30min, for example can be in the scope of 10～25min, for example can in the scope of 10～25min, require as long as satisfy " chromatographic condition and system suitability ".Those skilled in the art are known, for satisfying this requirement, specification that can be by suitable selection chromatographic column and/or regulate the mode such as flow rate of mobile phase and realize, for example operable column diameter is 4.6mm, the weighting agent granularity can be 5 μ m, its column length can be 15～30cm (for example approximately 15cm, 20cm, 25cm, 30cm), and flow rate of mobile phase can be adjusted in the scope of 0.8 ~ 1.5ml/min, can be easy to realize above-mentioned requirements by regulating column length and flow rate of mobile phase.This is particularly conventional technical ability for the pharmaceutical analysis those skilled in the art for this area.In the present invention, when carrying out chromatographic determination, as specifying in addition, use filler to be the chromatographic column of octadecylsilane chemically bonded silica, i.e. usually said C18 post, the granularity of weighting agent is 5 μ m, but the length 25cm of post.
In the present invention, the active constituents of medicine formula I compound of mentioning, its chemistry 6-(10-hydroxyl decyl)-2 by name, 3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones, molecular formula C
19H
30O
5Molecular weight 338.44, usually also being called also benzoquinones (Idebenone) of Chinese mugwort soil, is a kind of effective cerebro-vascular diseases medication, and this medicine is that brain metabolism, mental symptom are improved medicine, can activate the brain mitochondria respiratory activity, improve the brain energy metabolism of cerebral ischemia, improve glucose utilization rate in brain, make ATP generation increase in brain, film obstacle due to inhibition brain mitochondria generation lipid peroxide, inhibition brain mitochondria lipid peroxidation.This product toxic side effects is low, LD50 mouse, rat〉10000mg/kg, rat 20mgkgd oral half a year, dog 100mgkgd had no the overt toxicity reaction in oral 1 year, without teratogenesis, carcinogenic, mutagenesis.According to document announcement, 6 routine apoplexy sequela patient oral meal this product 30mg, Tmax is 3.31 hours, and Cmax is 290 μ gml, and eliminating the transformation period is 7.69 hours, does not detect the original shape medicine in urine, is metabolite, excretion rate 7.32% in urine in 24 hours.This medicine indication clinically is: the caused Brain function damages such as chronic cerebral vascular disease and cerebral trauma, can improve subjective symptom, language, anxiety, depression, hypomnesis, the lower degradation mental act obstacle of intelligence.The each 30mg of oral adult (1), every day 3 times, one after each meal.Its formulation products is generally tablet and every amount is generally 30mg.The compounds of this invention is orange-yellow to orange crystallization, crystalline powder or block, odorless; Very easily be dissolved in chloroform, methyl alcohol or dehydrated alcohol, be soluble in ethyl acetate, be insoluble in normal hexane, water-soluble hardly.mp52~55°C。Be used for intelligence and promote medicine, can compose the brain mitochondria function of living, improve brain energy metabolism, improve the brain function.To feeling down in spirits of causing of cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis, realize low, affective disorder, aphasis etc. and be improved effect.
The compounds of this invention is present unique medicine with brain metabolism and the dual improvement of mental symptom, at present temporarily without the direct competitive opponent; And its be cerebral metabolism, nerve cell protection agent, mitochondriopathy effectively, anticoagulant, improve microcirculation, effectively antioxygenation, FRDA (ataxia) choice drug.
In addition, the compounds of this invention or pharmaceutical composition also can be used for treating neurological disorder, and are used for improving the illness relevant to neuronal damage.
Preferably, described neurological disorder is caused by neurotrauma.More preferably, described neurological disorder is apoplexy.More preferably, described neurological disorder is encephalomyelitis.
Preferably, described neurological disorder is relevant to mitochondria dysfunction.Preferably, described neurological disorder is relevant to anoxic condition.Preferably, described neurological disorder is alcohol withdrawal syndrome or fetal alcohol syndrome.Preferably, described neurological disorder is relevant to the neuronal damage that is caused by bacterium infection or virus infection.
Embodiment
Following embodiment is intended to illustrate some preferred embodiment of the present invention, and limitation of the present invention does not disclose by the content of these embodiment.
In various tests hereinafter, to various materials (crude product of formula I compound or highly finished product, impurity Y, intermediate, add the pharmaceutical composition of auxiliary material etc.), all adopt high-performance liquid chromatogram determination, specifically carry out according to two appendix VD high performance liquid chromatography standards of Chinese Pharmacopoeia version in 2010, the mensuration mode is as follows:
(1) chromatographic condition and system suitability: be the chromatographic column (4.6 * 250mm of weighting agent with octadecylsilane chemically bonded silica, 5 μ m), take methanol-water (70:30) as moving phase, flow velocity 1.0ml/min, the ultraviolet detection wavelength is 278nm, and column temperature is 30 ° of C, and number of theoretical plate is pressed 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the peak calculating of 4-benzoquinones is not less than 2000;
(2) preparation of test soln: get testing compound, intermediate or pharmaceutical composition appropriate, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg formula I compound or concentration suitable with it in every 1ml, as need testing solution; Precision measures this trial-product 1ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, as the contrast solution of principal constituent; Separately get impurity Y-shaped IY compound, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg in every 1ml, as impurity Y solution; Precision measures need testing solution and each 1ml of impurity Y solution, puts in the measuring bottle of same 100ml, is diluted to scale with moving phase, shakes up, as the principal constituent that comprises formula I compound and formula IY compound-impurity contrast solution; Separately get it filled auxiliary material in compositions, accurately weighed, add the moving phase dissolving and quantitatively dilution make the concentration corresponding with 0.2mg/ml formula I compound concentration, as auxiliary material solution;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at principal constituent peak be about 10% of full range, precision measures need testing solution and each 20 μ l of various contrast solution again, injection liquid chromatography respectively records color atlas to 2.5 times of principal constituent peak retention time; Separately get auxiliary material solution 20 μ l injection liquid chromatographies, the injection liquid chromatography records color atlas to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area (this peak area can be expressed as A1 in the present invention) and retention time thereof;
(4ii) record need testing solution color atlas main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof; Record the chromatographic peak that in auxiliary material solution color atlas, auxiliary material forms;
(4iii) in the need testing solution color atlas, the chromatographic peak corresponding with the auxiliary material retention time disregarded (perhaps disregard further or deduct relative retention time less than 0.2 impurity peaks), in the need testing solution color atlas, any chromatographic peak of 0.05 times less than A1 is ignored, record in the need testing solution color atlas each peak area greater than the impurity peak area of 0.05 times (this peak area can be expressed as Am in the present invention, and m represents that m peak area is greater than the impurity peaks of 0.05 times of A1) and the retention time thereof of A1.
The chromatographic purity of testing compound, impurity Y, intermediate or pharmaceutical composition can be calculated as follows:
Perhaps, the chromatographic purity of testing compound, intermediate or pharmaceutical composition can be calculated as follows:
In the need testing solution color atlas of testing compound, impurity Y, intermediate or pharmaceutical composition high-performance liquid chromatogram determination, be as the criterion with the main peak retention time, calculate the relative retention time of each impurity peaks, the relative retention time of a certain impurity peaks (RRt) can be calculated as follows:
In the need testing solution color atlas of the high-performance liquid chromatogram determination of testing compound, impurity Y, intermediate or pharmaceutical composition, the chromatogram content of single impurity can be calculated as follows:
Perhaps, in testing compound, impurity Y, intermediate or pharmaceutical composition, the chromatogram content of single impurity can be calculated as follows:
In testing compound, impurity Y, intermediate or pharmaceutical composition, total chromatogram content of each impurity can be calculated as follows:
Perhaps, in testing compound, impurity Y, intermediate or pharmaceutical composition, total chromatogram content of each impurity can be calculated as follows:
Embodiment 1: the preparation the compounds of this invention
The general reaction process of the present embodiment is as follows:
(i), the preparation of 10-acetoxyl group capric acid (2)
In reaction flask, add sodium hydroxide 115g (2.875mol), water 40ml, Viscotrol C 150g and cresols 45g, stir (initial reaction stage has the phenomenon of foaming, and needs rapid stirring), backflow 3h in 180～I95 ° of C.Volatile matter is removed in distillation, adds entry 1.5L in residuum, transfers to pH acidity with 50% sulfuric acid (containing Congo red), is heated to boil.Separating funnel with preheating divides oil-yielding stratum, ether washing, anhydrous sodium sulfate drying.Filter, filtrate is reclaimed solvent, adds diacetyl oxide 350ml in residuum, and heated and stirred refluxes after 5 ~ 6h, and reactant is fallen in the appropriate ice of people, and placement is spent the night.With ether extraction for several times, merge organic layer, washing, anhydrous sodium sulfate drying.Filter, after filtrate was reclaimed solvent, bp136 ~ 160 ° C/26.7Pa fraction was collected in underpressure distillation, bp140 ~ 146 ° C/26.7Pa fraction is collected in underpressure distillation for the second time, last underpressure distillation, collect bp140 ~ 142 ° C/26.7Pa fraction, get (2) yield 45.6%.
(ii), the preparation of 10-acetoxyl group decanoyl chloride (3)
In reaction flask, add 10-acetoxyl group capric acid (2), the methylene dichloride of 230g (1.0mol), after stirring and dissolving, add carefully phosphorus pentachloride (1.2mol, available phosphorus trichloride replaces), in stirring at room 2h.Reaction is finished, and reclaims solvent, and bp135 ~ 138 ° C/66.7Pa fraction is collected in underpressure distillation, gets (3).
1H-NMR(CDCl
3)：δ4.03(t,2H,J=7Hz，CH
2O)，2.91(t，2H，J=6Hz，CH
2CO)，2.02(s，3H，COCH
3)，1.1~1.8(m，14H，7×CH
2)。
(iii), 6-(10-hydroxyl-1-oxo decyl)-2, the preparation of 3-dimethoxy-5-cresylol (5)
In the dry reaction bottle, add (3) (0.11mol), 3,4,1 of 5-trimethoxytoluene (0.1mol) and drying, 2-ethylene dichloride 300ml solution under 0 ~ 5 ° of C stirs, adds the anhydrous alchlor powder of people 28.lg (0.207mol), continue to stir 2h in 5 ° of C, 20 ° are stirred 70h.Reaction is finished, and reaction solution is poured in appropriate frozen water, with dichloromethane extraction for several times, merges organic layer, washing, anhydrous sodium sulfate drying.Filter, filtrate is reclaimed solvent, gets oily residuum (4).Add sodium hydroxide 0.118mol and methyl alcohol 150ml solution in (4), in stirring at room 2h.After reclaiming solvent, residuum is poured in suitable quantity of water, crystallization, drying gets crude product (5).With ether-hexane recrystallization, get colourless needle crystal (5), yield 79%, mp67 ° of C.
1H-NMR(CDCl
3):δ1.2~1.9(m,14hH,7×CH
2)，2.41(s,3H，Ar-CH
3),2.86(t，2H，J=7Hz，CH
2CO)，3.61(t，2H，J=7Hz，CH
2OH)，3.84，3.87(s，6H，2×CH
3O)，6.27(s，1H，Ar-H)，9.92(s，1H，Ar-OH)。
(iv), 6-(10-acetoxyl group decyl)-2, the preparation of 3-dimethoxy-5-cresylol (6)
In reaction flask, add (5) (0.05mol), 5%Pd-C2g, glacial acetic acid 150ml (contains 70% HClO
4(0.3ml)), under the room temperature normal pressure, logical hydrogen hydrogenation 24h.Reaction is finished, and filters, and reclaims catalyzer (applying mechanically), and filtrate decompression reclaims solvent.In the oily residuum, add methylene dichloride 150ml, 5% sodium hydrogen carbonate solution 100ml, stir, standing, tell organic layer, anhydrous sodium sulfate drying.Filter, filtrate gets colorless oil residuum (6), yield 97% after reclaiming solvent.
1H-NMR(CDC1
3):δ6.25(s，1H，Ar-H)，5.80(s，1H，Ar-OH)，4.0G(t，2H，J=6Hz，CH
2O)，3.85(8，6H，2×CH
3O)，3.81，2.57(t，2H，J=7Hz，Ar-CH
2)，2.23(s，3H，Ar-CH
3)，2.03(s，3H，CH
3CO)，1.2~1.8(m，16H，CH
2)。
(v), 6-(10-hydroxyl decyl)-2, the preparation of 3-dimethoxy-5-cresylol (7)
In reaction flask, add (6) 0.101mol, sodium hydroxide 0.101mol and methyl alcohol 300ml solution, stir 24h in 5 ° of C.Reaction is finished, and reclaims solvent.Cooling, add methylene dichloride 100ml, water 100ml in residuum, stir, tell organic layer, anhydrous sodium sulfate drying filters, and filtrate is reclaimed solvent, gets colorless oil residuum (7), yield 95%.
1H-NMR(CDCl
3):δ6.24(s,1H,Ar-H),5.86(s,2H，Ar-OH)，3.84(s，6H，2×CH
3O)，3.80，3.61(t，2H，J=7Hz，Ar-CH
2)。
(vi), 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones (1) synthetic
In reaction flask, add freshly prepd FremyShi salt (that is, nitroso-group disulfonic acid potassium [ON (SO
3K)
2]) 16g, (7) 0.022mol, DMF-water-methanol (1:1:1) 100ml and 0.17mol/L potassium dihydrogen phosphate 10ml, stir 72h in 5 ° of C.Reaction is finished, and adds water 200ml, with dichloromethane extraction for several times, merges organic layer, washing, anhydrous sodium sulfate drying.Filter, filtrate is reclaimed solvent, and is cooling, separates out solid, and drying gets (1) yield 83%.IR(KBr):3550(OH),1650,1640cm
-1。
1H-NMR (CDCl
3): δ 3.97 (s, 6H, 2 * CH
3O), 2.0 (s, 3H, CH
3), 2.43 (t, 2H, J=7Hz, quinone ring-CH
2), 3.63 (t, J=6Hz, CH
3O), 1.2 ~ 1.3 (m, 14H, 7 * CH
2).MS:m/z338(M
+),320,308,195。This crude product is measured according to HPLC method of the present invention, chromatographic purity 98.2%, and the chromatogram content of maximum single contaminant is 1.27%.
(vii), 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones (1) refining
Step (i) products therefrom 1.0g is placed in the glass crystallizer of the jacketed of a 200mL, at room temperature formula I compound is dissolved fully 5mL methylene dichloride (can be described as in the present invention good solvent, the solvent that namely formula I compound is had better solubleness).In crystallizer, temperature is carried out temperature programmed control (initial temperature is 24-27 ° of C, mentions that " room temperature " also refers in 24-27 ° of C temperature range when not indicating especially) with the refrigerating/heating circulator bath, stirs with magnetic stirring apparatus in crystallizer.Under room temperature, the 5mL sherwood oil (be can be described as the first anti-solvent in the present invention, anti-solvent refers to solvent that formula I compound is had bad solubleness) add in crystallizer, mixing, add again 15ml normal hexane (can be described as in the present invention the second anti-solvent), it is muddy that settled solution becomes, and the heated solution temperature makes solution become clarification to 35-37 ° of C.With the clear liquor filtered while hot, filtrate is placed in the 35-37 ° of C crystallizer of another 200mL, and constant temperature 30 minutes, and be cooled to 0-2 ° of C and crystallization slowly with the speed of 0.1 ° of C/min filters, with the second anti-solvent wash 2 times.Lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h under room temperature, obtaining yellow needle crystal is formula I compound 0.937g, yield is 91.7%.mp54~54.5°C。
Embodiment 2: the preparation the compounds of this invention
Use embodiment 1 step (vi) products therefrom, carry out according to the method for embodiment 1 step (vii), different is to use: the 5mL methylene dichloride is that the first anti-solvent, 15ml hexanaphthene are the second anti-solvent as good solvent, 5mL sherwood oil; The crystallization speed of cooling is 0.05 ° of C/min.Yield is 91.3%.mp54.5~55°C。
Embodiment 3: the preparation the compounds of this invention
Use embodiment 1 step (vi) products therefrom, carry out according to the method for embodiment 1 step (vii), different is to use: the 4mL methylene dichloride is that the first anti-solvent, 13ml normal hexane are the second anti-solvent as good solvent, 7mL Skellysolve A; The crystallization speed of cooling is 0.5 ° of C/min.Yield is 90.9%.mp54~54.5°C。
Embodiment 4: the preparation the compounds of this invention
Use embodiment 1 step (vi) products therefrom, carry out according to the method for embodiment 1 step (vii), different is to use: the 4mL methylene dichloride is that the first anti-solvent, 13ml hexanaphthene are the second anti-solvent as good solvent, 6mL Skellysolve A.The crystallization speed of cooling is 0.2 ° of C/min.Yield is 90.8%.mp54~55°C。
Embodiment 5: the preparation the compounds of this invention
Use embodiment 1 step (vi) products therefrom, carry out according to the method for embodiment 1 step (vii), different is to use: the 4mL ethyl acetate is that the first anti-solvent, 13ml normal hexane are the second anti-solvent as good solvent, 5mL sherwood oil.Yield is 91.5%.mp53.5~54.5°C。
Embodiment 6: the preparation the compounds of this invention
Use embodiment 1 step (vi) products therefrom, carry out according to the method for embodiment 1 step (vii), different is to use: the 4mL ethyl acetate is that the first anti-solvent, 15ml hexanaphthene are the second anti-solvent as good solvent, 4mL sherwood oil.Yield is 91.7%.mp54~54.5°C。
Embodiment 7: the preparation the compounds of this invention
Use embodiment 1 step (vi) products therefrom, carry out according to the method for embodiment 1 step (vii), different is to use: the 4mL ethyl acetate is that the first anti-solvent, 18ml normal hexane are the second anti-solvent as good solvent, 3mL Skellysolve A.Yield is 91.1%.mp54~54.5°C。
Embodiment 8: the preparation the compounds of this invention
(i), prepare 6-(10-acetoxyl group-1-oxo decyl)-2,3-dimethoxy-5-methylphenol
in the 5L of dried and clean reaction flask, mechanical stirring is installed, thermometer, add 1 under stirring, 2-ethylene dichloride 2000ml, 3,4,5-trimethoxytoluene 182g (approximately 1mol), 10-acetoxyl group decanoyl chloride 273g (approximately 1.5mol), add again fresh aluminum trichloride (anhydrous) powder 333g (approximately 2.5mol), after being cooled to 5 ° of C, ice-water bath begins reaction, control 0～5 ° of C of temperature, react after 4 days, reaction finishes, in impouring 5000ml frozen water, tell organic layer, add again 1,2-ethylene dichloride 2000ml extracts, merge organic layer, wash with water three times, each 1000ml, at last, desolventize with steaming after anhydrous sodium sulfate drying, activated carbon decolorizing, get colorless oil 311g, be 6-(10-acetoxyl group-1-oxo decyl)-2,3-dimethoxy-5-methylphenol, calculating its molar yield is 81.6%, HPLC chromatographic purity 97.8%.
(ii), prepare 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol
In the 5L hydriding reactor, the 6-(10-acetoxyl group-1-oxo decyl)-2 that adds 380g to be made by step (1), the 5%Pd-C of 3-dimethoxy-5-methylphenol (approximately 1.0mo1), DMF3000ml, 19g (quality is 6-(10-acetoxyl group-1-oxo decyl)-2,3-dimethoxy-5-methylphenol 5%).Under normal temperature and pressure, the shortening stirring reaction is extremely no longer inhaled hydrogen, then adds dewatering agent DCC206g (approximately 1mol), continues stirring reaction 7h under normal temperature and pressure, continues the above hydrogen of extremely no longer inhaling of catalytic hydrogenation 10h under normal temperature and pressure.After reaction finishes, filtration catalizer, filtrate concentrates to get light oily matter 352g, is 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol;
(iii), hydrolysis
Add sodium hydroxide 40g (1mol), methyl alcohol 1200ml in above-mentioned oily matter, be cooled to 5 ° of C, underpressure distillation desolventizing after stirring 24h, then add the dissolving of 1500ml methylene dichloride, wash 3 times, be evaporated to dried after anhydrous sodium sulfate drying, get colorless oil 310.5g and be 6-(10-hydroxy decyl)-2,3-dimethoxy-5-methylphenol, calculating molar yield is 95.9%, HPLC chromatographic purity 98.2%, the chromatogram content of maximum single contaminant is 0.79%.
(iv), prepare 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones
Add 6-(10-hydroxyl decyl)-2 in the 5L stills for air blowing, 3-dimethoxy-5-methylphenol 324.5g (approximately 1mol), DMF3000ml, Cu (salen) 10g (quality be reaction substrate 3%).35～40 ° of C of temperature control, logical purity oxygen carries out catalytic oxidation, and approximately about 70h, TLC tracks to raw material point and disappears.Elimination catalyzer after reaction is completed is evaporated to driedly, then adds entry 2000ml dilution, with dichloromethane extraction 2 times, and each 1000ml, organic layer merges after washing 3 times, each 1000ml, anhydrous sodium sulfate drying, underpressure distillation are to doing.With normal hexane-ether mixed solvent recrystallization, getting tangerine look needle-like product is formula I compound of the present invention, yield 75%.It is measured according to HPLC method of the present invention, and chromatographic purity 98.73%, the chromatogram content of maximum single contaminant are 0.59% (RRt＜0.7), and the RRt approximately chromatogram content of 0.8 impurity is 0.56%.
(v) use above step (iv) products therefrom, carry out with reference to the method for embodiment 1 step (vii), use: the 5mL methylene dichloride is that the first anti-solvent, 15ml normal hexane are the second anti-solvent as good solvent, 5mL sherwood oil.
Yield is 91.7%.mp54~54.5°C。
Embodiment 9: the preparation the compounds of this invention
Use embodiment 8 steps (iv) products therefrom, carry out with reference to the method for embodiment 1 step (vii), different is to use: the 4mL ethyl acetate is that the first anti-solvent, 18ml normal hexane are the second anti-solvent as good solvent, 3mL Skellysolve A.
Yield is 92.1%.mp54.5~55.0°C。
Embodiment 10: the preparation the compounds of this invention
(i), prepare 6-(10-acetoxyl group-1-oxo decyl)-2,3-dimethoxy-5-methylphenol
in the 5L of dried and clean reaction flask, mechanical stirring is installed, thermometer, add 1 under stirring, 2-ethylene dichloride 2000ml, 3, 4, 5-trimethoxytoluene 182g (approximately 1mol), 10-acetoxyl group decanoyl chloride 273g (approximately 1.5mol), add again fresh anhydrous aluminium acetate powder 390g (approximately 2.5mol), after being cooled to 5 ° of C, ice-water bath begins reaction, 0～5 ° of C of temperature control, react after 4 days, finish reaction, in impouring 5000ml frozen water, tell organic layer, add again 1, 2-ethylene dichloride 2000ml extracts, merge organic layer, wash 3 times, each 1000ml, organic layer is through anhydrous sodium sulfate drying, activated carbon decolorizing, steaming desolventizes, get colorless oil, yield 87.8%, HPLC chromatographic purity 97.4%.
(ii), prepare 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol
In the 5L hydriding reactor, add 6-(10-acetoxyl group-1-oxo decyl)-2, the 5%Pd-C of 3-dimethoxy-5-methylphenol 380g (approximately 1.0mol), DMF3000ml, 26.6g (quality be reaction substrate 7%).Under normal temperature and pressure, the shortening stirring reaction is extremely no longer inhaled hydrogen, then adds dewatering agent DCC206g (approximately 1mol), continues stirring reaction 7h under normal temperature and pressure, continues the above hydrogen of extremely no longer inhaling of catalytic hydrogenation 10h under normal temperature and pressure.Filtration catalizer after reaction is finished, filtrate concentrates to get light oily matter 356g, is 6-(10-acetoxyl group decyl)-2,3-dimethoxy-5-methylphenol.
(iii), hydrolysis
Add sodium hydroxide 40g (1mol), methyl alcohol 1200ml in above-mentioned oily matter, be cooled to 5 ° of C, after stirring 24h, solvent is removed in underpressure distillation, then adds the dissolving of 1500ml methylene dichloride, wash 3 times, each 1000ml is evaporated to driedly after anhydrous sodium sulfate drying, get colorless oil 313g and be 6-(10-hydroxy decyl)-2,3-dimethoxy-5-methylphenol, calculate molar yield 96.2%, HPLC chromatographic purity 98.2%, the chromatogram content of maximum single contaminant is 0.86%.
(iv), add 6-(10-hydroxy decyl)-2 in the 5L stills for air blowing, 3-dimethoxy-5-methylphenol 324.5g (approximately 1mol), DMF3000ml, Cu (salen) 10g (quality be reaction substrate 3%).35～40 ° of C of temperature control, the mixed gas of logical oxygen: nitrogen=1:1 carries out catalytic oxidation, and approximately about 70h, TLC tracks to raw material point and disappears.Elimination catalyzer after reaction is completed, be evaporated to dried, add again ordinary water 2000ml dilution, with dichloromethane extraction (1000ml * 2), organic layer merges after washing 3 times, each 1000ml, after anhydrous sodium sulfate drying, underpressure distillation is to doing, with normal hexane-ether mixed solvent recrystallization, get tangerine look needle-like product and be formula I end product of the present invention, molar yield 75.7%.Measure according to HPLC method of the present invention, chromatographic purity 98.77%, the chromatogram content of maximum single contaminant is 0.57%(RRt＜0.7), the RRt approximately chromatogram content of 0.8 impurity is 0.53%.
(v) use above step (iv) products therefrom, carry out with reference to the method for embodiment 1 step (vii), use: the 5mL methylene dichloride is that the first anti-solvent, 13ml normal hexane are the second anti-solvent as good solvent, 8mL Skellysolve A.
Yield is 90.9%.mp54~54.5°C。
Embodiment 11: the preparation the compounds of this invention
Use embodiment 10 steps (iv) products therefrom, carry out with reference to the method for embodiment 1 step (vi), different is to use: the 6mL ethyl acetate is that the first anti-solvent, 15ml hexanaphthene are the second anti-solvent as good solvent, 5mL sherwood oil.
Yield is 92.3%.mp54.0~54.5°C。
Reference examples 1: preparation I compound
Take 1.0g embodiment 1 step (vi) products therefrom in the glass crystallizer of the jacketed of a 200mL, measure the 5mL methylene dichloride with graduated cylinder and add under room temperature in crystallizer formula I compound is dissolved fully.In crystallizer, temperature is carried out temperature programmed control by a refrigerating/heating circulator bath, stirs and adopts magnetic stirring apparatus.The normal hexane that measures again 35mL adds in crystallizer under room temperature, and it is muddy that settled solution becomes.Heated solution temperature to 36 ° C, dirty solution becomes clarification.With the clear liquor filtered while hot, filtrate is placed in the crystallizer of another 200mL, and this moment, solution temperature slightly reduced, then continued to be heated to 36 ° of C, constant temperature 30 minutes, and be cooled to 0 ° of C with the speed of 0.1 ° of C/min.Along with the reduction of temperature, formula I compound crystal is slowly separated out, and filters washing (with normal hexane washing 2 times).Under room temperature, lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h, obtain 0.795g needle-like crystal product, and yield is 79.5%.
Reference examples 2: preparation I compound
Take 2.0g embodiment 8 steps (iv) products therefrom in the glass crystallizer of the jacketed of a 200mL, measure the 10mL methylene dichloride with graduated cylinder and add under room temperature in crystallizer formula I compound is dissolved fully.In crystallizer, temperature is carried out temperature programmed control by a refrigerating/heating circulator bath, stirs and adopts magnetic stirring apparatus.The normal hexane that measures again 70mL adds in crystallizer under room temperature, and it is muddy that settled solution becomes.Heated solution temperature to 36 ° C, dirty solution becomes clarification.With the clear liquor filtered while hot, filtrate is placed in the crystallizer of another 200mL, and this moment, solution temperature slightly reduced, then continued to be heated to 36 ° of C, constant temperature 30 minutes, and be cooled to 0 ° of C with the speed of 0.1 ° of C/min.Along with the reduction of temperature, end product formula I compound crystal is slowly separated out, and filters washing (with normal hexane washing 2 times).Under room temperature, lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h, obtain 1.58g needle-like crystal product, and yield is 79%.
The method 1 for preparing impurity Y:
Get embodiment 1 step I) gained end product (for the crude product of formula I compound) is starting material, uses the preparation liquid phase process to obtain impurity Y.Preparing chromatography system used: chromatographic column is Pure2811-C18,250mm * 8mm, particle diameter, 20 ~ 40um; Moving phase: methyl alcohol: water=70:30 (v/v); Detect wavelength 254nm; Sampling volume 2.5mL; Sample size 100mg; Column temperature is room temperature.Monitor after advancing the product sample introduction, collect the elutriant at the maximum contaminant peak except the effluent liquid of principal constituent peak formula I compound; After concentrated desolventizing, the gained resistates repeats the preparative liquid chromatography wash-out again, intercepts the elutriant of above-mentioned impurity elution peak; Repeat the preparative chromatography purifying 1 time, the product that obtains reaches 99.2% with analysis mode liquid chromatography for measuring chromatographic purity mentioned above again.
Structural Identification: FAB mass spectrum (m/z): 309 (M+H)
+Ultimate analysis: measured value: C-70.11%, H-9.16%, O-20.73%.M.W.=308.31。
1H-NMR(DMSO-D
6，400mHz):δ1.26(2H,m),1.29(10H,m),1.43(2H,m),1.54(2H,m),2.41(2H,q),2.50(3H,s),3.50(2H,t),3.65(1H,s),3.80(3H,s),8.08(1H,s)。
13C-NMR(DMSO-D
6，400mHz):δ12.7(1C),21.1(1C),25.6(1C),27.2(1C),29.5(5C),32.2(1C),58.1(1C),62.8(1C),108.2(1C),142.8(1C),144.5(1C),161.1(1C),182.6(1C),187.2(1C)。Analyze accordingly, gained impurity Y is the compound with formula IY structure mentioned above.
In addition, the inventor has been found that in test the formula I raw materials of compound medicine for the preparation of each batch of the present invention, its in HPLC described herein analyzes, the peak area of impurity Y the maximum in all dirt normally in color atlas.In addition, the inventor also finds, above-mentioned retention time with the prepared product formula IY of preparative liquid chromatography method and the impurity Y in formula I raw materials of compound medicine of the present invention is in full accord, proves that namely the preparation-obtained molecular weight of above-mentioned preparative liquid phase method is that 308.4 material and the acrobatics in bulk drug are same substances.
The inventor finds to use C/MS (liquid chromatography-mass spectrography) (LC-ESI-MS) coupling in other test, measure impurity Y in bulk drug, shows that in the ESI-MS collection of illustrative plates molecular weight is 308.3, with above the molecular weight of the impurity Y of preparation is consistent especially.
Composition example 1: prepare pharmaceutical composition of the present invention (tablet)
Formula (1000 amounts): embodiment 1 step (vii) gained end product 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones 30g, one Lactose hydrate 40g, Microcrystalline Cellulose 30g, PEG4000 consumption 9g, sodium starch glycolate 9g, Magnesium Stearate 1g, colloid silica 1g.
Method for making: activeconstituents, lactose, Microcrystalline Cellulose and the 4.5g sodium starch glycolate of recipe quantity are mixed, pulverize and cross 80 mesh sieves; Add PEG4000 and the colloid silica of pulverizing in advance and cross 80 mesh sieves, mix, it is the sheet of 20mm that dry method is pressed into the sheet footpath, then 20 mesh sieves are smashed and crossed to this sheet; Gained material and Magnesium Stearate are mixed, compressing tablet, every contains activeconstituents is 30mg, and get final product.
Composition example 2: prepare pharmaceutical composition of the present invention (capsule)
Formula (1000 amounts): embodiment 8 steps (v) gained end product 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinones 30g, a Lactose hydrate 38g, Microcrystalline Cellulose 30g, Magnesium Stearate 1g, colloid silica 1g.
Method for making: each mixing of materials of recipe quantity is even, be filled in Capsules, every contains activeconstituents is 30mg, and get final product.
Test example 1: the chromatogram feature of measuring each material
(for example embodiment 1 is at the final formula I compound of step (vii) acquisition for the formula I compound that above each embodiment, reference examples, composition example obtain in final step, for example embodiment 8 is at the final formula I compound of step (v) acquisition) or the preparation compositions (content of test capsule shell when measuring capsule, and do not consider capsule shell), measure according to HPLC method of the present invention, the parameters such as total chromatogram content of the RRt of the chromatographic purity of compound, impurity Y and the chromatogram content of this impurity, each impurity see Table 1.
In addition, during the formula I compound that above each embodiment, reference examples, composition example are obtained in final step or pharmaceutical composition are sealed in Brown Glass Brown glass bottles and jars only, placed 150 days under 45 ° of C, measure the total chromatogram content of each impurity peaks increased value, namely each impurity peaks total chromatogram content (%) of 45 ° of C placements after 150 days deducts each impurity peaks total chromatogram content (%) the gained difference of 45 ° of C placements before 150 days, the results are shown in Table 1.
Table 1:
* be illustrated in the color atlas of this material, except impurity Y peak, also have the impurity peaks of a RRt=0.829, total chromatogram content of two impurity peaks is 0.25%.
From the table result as seen, the compounds of this invention or composition have lower specific impurities and total impurities, and the compounds of this invention and composition also lower in high-temperature treatment rear impurity increasing amount.
In addition, the contriver uses the same little solvent of this polarity of iso-pentane and Skellysolve A or sherwood oil to use as the first anti-solvent in embodiment 1 ~ 5 step (vii) separately, result shows in each product of gained, impurity Y chromatogram content is all more than 0.7%, and total chromatogram content of each impurity is more than 1.3%.
In addition, the contriver uses pentamethylene or this polarity of the normal heptane solvent suitable with hexanaphthene with normal hexane to use as the second anti-solvent in embodiment 1 ~ 8 step (vii) separately, result shows in each product of gained, impurity Y chromatogram content is all more than 0.75%, and total chromatogram content of each impurity is more than 1.4%.
In addition, the contriver uses the suitable solvent of propyl carbinol or this polarity of dehydrated alcohol and methylene dichloride or ethyl acetate to use as good solvent in embodiment 1 ~ 4 step (vii) separately, result shows in each product of gained, impurity Y chromatogram content is all more than 0.7%, and total chromatogram content of each impurity is more than 1.4%.
In addition, the contriver is in embodiment 1～3 step (vii) separately, only use the first anti-solvent and need not the second anti-solvent, be about to the second anti-solvent alternative with the first anti-solvent of equivalent, result shows in each product of gained, impurity Y chromatogram content is all more than 0.65%, and total chromatogram content of each impurity is more than 0.9%.
In addition, the contriver is in embodiment 1～2 step (vii) separately, only use the second anti-solvent and need not the first anti-solvent, be about to the first anti-solvent alternative with the second anti-solvent of equivalent, result shows in each product of gained, impurity Y chromatogram content is all more than 0.6%, and total chromatogram content of each impurity is more than 1.1%.
In addition, the contriver finds, in each above-mentioned embodiment of the present invention, reach 0.015% when following at the chromatogram content that repeatedly repeats its final re-crystallization step and make impurity Y, the compounds of this invention yield can reach below 65%, and when the chromatogram content of allowing impurity Y reaches 0.02% yield when above can be more than 85%.Therefore in an example of the present invention, the lower limit of impurity Y can be 0.02%.
Test example 2: mensuration has the performance of different chromatogram feature materials
Some products (for example embodiment 1 step (vi) product, embodiment 8 steps (iv) product, embodiment 10 steps (iv) product) that obtain in embodiment are above made further recrystallization to be processed, solvent for use is seen following table 2, obtains different recrystallized product.The concrete mode of recrystallization is roughly, in the crystallizer of 35-37 ° of C, treating material is dissolved in good solvent (formula I compound is the high solvent of solubleness therein), add again anti-solvent (formula I compound is the low solvent of solubleness therein), mix filtered while hot, filtrate insulation 30 minutes, be cooled to 0-2 ° of C and crystallization slowly with the speed of 0.1 ° of C/min again, filter, with anti-solvent wash 2 times.Lucifuge, vacuum-drying (vacuum tightness 50mbar) 24h under room temperature, and get final product.Repeat in case of necessity crystallization.
In addition, above each embodiment, reference examples and above-mentioned recrystallization are processed the formula I compound that obtains to be sealed in Brown Glass Brown glass bottles and jars only, placed 150 days under 45 ° of C, measure the total chromatogram content of each impurity peaks increased value, namely each impurity peaks total chromatogram content (%) of 45 ° of C placements after 150 days deducts each impurity peaks total chromatogram content (%) the gained difference of 45 ° of C placements before 150 days, the results are shown in Table 2.
Table 2:
| Sample | Impurity Y | 0 o'clock always assorted | High temperature is assorted increment always |
| Ex8S () product | 0.09% | 0.37% | 0.27% |
| The Ex3 product | 0.11% | 0.29% | 0.29% |
| The Ex9 product | 0.15% | 0.42% | 0.48% |
| The Ex2 product | 0.17% | 0.33% | 0.32% |
| The Ex11 product | 0.17% | 0.46% | 0.29% |
| The Ex7 product | 0.18% | 0.33% | 0.28% |
| The Ex6 product | 0.20% | 0.47% | 0.33% |
| Ex1S (vii) product | 0.23% | 0.41% | 0.36% |
| The Ex4 product | 0.25% | 0.47% | 0.33% |
| The Ex5 product | 0.27% | 0.51% | 0.42% |
| Ex10S () product | 0.31% | 0.62% | 0.41% |
| Ex8S (iv) product normal hexane-ether (3:1) recrystallization 3 times | 0.34% | 0.52% | 0.31% |
| Ex8S (iv) product normal hexane-ether (3:1) recrystallization 2 times | 0.37% | 0.48% | 0.47% |
| Ex8S (iv) product normal hexane-ether (3:1) recrystallization 1 time | 0.42% | 0.63% | 0.63% |
| Ex10S (iv) product normal hexane-ether (2:1) recrystallization 1 time | 0.46% | 0.72% | 1.08% |
| Ex10S (iv) product normal hexane-ethanol (4:1) recrystallization 1 time | 0.49% | 0.86% | 1.24% |
| Ex1S (i) product normal hexane-ether (3:1) recrystallization 3 times | 0.51% | 1.09% | 1.42% |
| Ex10S (iv) product | 0.53% | 1.23% | 1.63% |
| Ex1S (i) product normal hexane-ether (3:1) recrystallization 2 times | 0.54% | 1.07% | 1.57% |
| Ex8S (iv) product | 0.56% | 1.27% | 1.86% |
| Ex1S (vi) product normal hexane-ether (3:1) recrystallization 1 time | 0.62% | 1.33% | 1.97% |
| The Co1 product | 0.68% | 1.51% | 2.19% |
| The Co2 product | 0.73% | 1.44% | 2.35% |
| Ex1Si) product normal hexane-ethanol (4:1) recrystallization is 3 times | 0.80% | 1.53% | >3.0% |
| Ex1S (i) product normal hexane-ethanol (4:1) recrystallization 2 times | 0.92% | 1.79% | >5.0% |
| Ex1S (i) product normal hexane-ethanol (4:1) recrystallization 1 time | 1.06% | 1.94% | >7.5% |
| Ex1S (vi) product | 1.27% | 2.24% | >10.0% |
In upper table " sample " hurdle, Ex represents embodiment, for example " Ex1 " expression embodiment 1; Co represents reference examples, for example " Co1 " expression reference examples 1; S represents step, for example " S (v) " expression step (v).The chromatogram content of upper table " impurity Y " expression impurity Y; Total chromatogram content of " 0 o'clock always assorted " 0 o'clock each impurity of expression; " high temperature is assorted increment always " 45 ° of C of expression placed after 150 days, the total chromatogram content of each impurity peaks increased value, namely each impurity peaks total chromatogram content (%) of 45 ° of C placements after 150 days deducts each impurity peaks total chromatogram content (%) the gained difference of 45 ° of C placements before 150 days.The inventor unexpectedly finds, at impurity Y content lower than 0.45%, particularly lower than 0.4% the time, formula I compound changes lower in the increasing amount of total impurities after high-temperature treatment, and work as this foreign matter content higher than 0.4%, particularly higher than 0.45% the time, formula I compound increases greatly in the increasing amount of total impurities after high-temperature treatment.
Claims (10)
1. with the following formula I compound:
2. the compound of claim 1 wherein comprises the following formula I Y compound as the trace of impurity:
3. the compound of claim 1 to 2, it is in high effective liquid chromatography for measuring, it is in high effective liquid chromatography for measuring, the chromatographic purity that has greater than 98% (preferably has the chromatographic purity greater than 98.5%, preferably has the chromatographic purity greater than 99.0%, preferably have the chromatographic purity greater than 99.2%, preferably have the chromatographic purity greater than 99.3%, preferably have the chromatographic purity greater than 99.5%.
4. the compound of claims 1 to 3, it is in high effective liquid chromatography for measuring, total chromatogram content of impurity Y is lower than 0.8%, preferably lower than 0.7%, preferably lower than 0.6%, preferably lower than 0.55%, preferably lower than 0.5%, preferably lower than 0.45%, preferably lower than 0.4%, preferably lower than 0.35%, preferably lower than 0.3%.
5. the compound of claim 1 to 4, its total chromatogram content of each impurity peaks increased value after placing 150 days under 45 ° of C is no more than 1.5%, preferably is no more than 1.25%, preferably is no more than 1.0%, preferably is no more than 0.75%, preferably is no more than 0.5%.
6. the compound of claim 1 to 5, wherein said high performance liquid chromatography is measured according to two appendix VD high performance liquid chromatography standards of Chinese Pharmacopoeia version in 2010, and described high effective liquid chromatography for measuring mode is:
(1) chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, take methanol-water (70:30) as moving phase, the ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, number of theoretical plate is pressed 6-(10-hydroxyl decyl)-2,3-dimethoxy-5-methyl isophthalic acid, the peak calculating of 4-benzoquinones is not less than 2000;
(2) preparation of test soln: get the compounds of this invention, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg in every 1ml, as need testing solution; Separately get impurity Y-shaped IY compound, accurately weighed, add the moving phase dissolving and quantitatively dilute and make the solution that approximately contains 0.2mg in every 1ml, as impurity Y solution; Precision measures need testing solution and each 1ml of impurity Y solution, puts in the measuring bottle of same 100ml, is diluted to scale with moving phase, shakes up, as the contrast solution that comprises formula I compound and formula IY compound;
(3) chromatogram test: get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at principal constituent peak be about 10% of full range, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography respectively records color atlas to 2.5 times of principal constituent peak retention time;
(4) chromatographic computation:
(4i) record contrast solution color atlas main peak area (be the peak area of formula I compound, this peak area can be expressed as A1 in the present invention) and retention time thereof, and record peak area and the retention time thereof of impurity Y;
(4ii) record need testing solution color atlas main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof;
(4iii) in the need testing solution color atlas, any chromatographic peak of 0.05 times less than A1 is ignored, (this peak area can be expressed as Am in the present invention greater than the impurity peak area of 0.05 times of A1 to record each peak area in the need testing solution color atlas, m represents m peak area greater than the impurity peaks of 0.05 times of A1, and wherein impurity Y is also in these impurity one) and retention time;
(4iv) according to the retention time of impurity Y in the contrast solution color atlas, determine impurity Y and peak area thereof in the need testing solution color atlas, and calculate the assorted chromatogram content of impurity Y.
7. a pharmaceutical composition, wherein comprise the described compound of claim 1-6, and the optional acceptable auxiliary material of pharmacy; Its further feature as in specification sheets about as described in any or a plurality of technical scheme of pharmaceutical composition.
8. the preparation method of the described compound of claim 1-6, it comprises the following steps:
(i) with the dissolving crude product of formula I compound in good solvent;
(ii) add the first anti-solvent in step (i) gained solution, mixing, then add the second anti-solvent, be heated to 30-40 ° of C and make solution clarification, heat filtering;
(iii) make filtrate slowly be cooled to 10 ° below C, make crystallization, leach crystallization, drying, and get final product.
9. the method for claim 8, wherein:
Described good solvent is selected from methylene dichloride, ethyl acetate or its combination;
The feed ratio of described good solvent and formula I chemical combination is 3 ~ 8:1 (v:w);
The described first anti-solvent is selected from Skellysolve A, sherwood oil or its combination;
The feed ratio of the described first anti-solvent and formula I chemical combination is 2 ~ 10:1 (v:w);
The described second anti-solvent is selected from normal hexane, hexanaphthene or its combination;
The feed ratio of the described second anti-solvent and formula I chemical combination is 10～20:1 (v:w);
Heating described in step (ii) is to be heated to 35-37 ° of C;
Cooling described in step (iii) is to be cooled to 0 ~ 10 ° of C;
Slowly cooling described in step (iii) is with 0.01 ~ 1 ° of C/min; And/or
Drying described in step (iii) is vacuum-drying under 20 ~ 45 ° of C.
10. the described compound of claim 1-6 or the described pharmaceutical composition of claim 7, the purposes in the preparation medicine, wherein said medicine is used for following either side or many-sided disease or illness: cerebro-vascular diseases; Improve the brain metabolism, improve mental symptom; Activate the brain mitochondria respiratory activity, improve cerebral ischemia brain energy metabolism, improve glucose utilization rate in brain, ATP in brain produced increase, suppress brain mitochondria to generate lipid peroxide, suppress the film obstacle due to the brain mitochondria lipid peroxidation; The caused Brain function damages such as chronic cerebral vascular disease and cerebral trauma; Improve subjective symptom, language, anxiety, depression, hypomnesis, the lower degradation mental act obstacle of intelligence; Promote intelligence; Compose the brain mitochondria function of living, improve brain energy metabolism, improve the brain function; Improve that cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis cause feel down in spirits, realize is low, affective disorder, aphasis etc.; Improve brain metabolism, protection cranial nerve cell; Mitochondriopathy; Anticoagulant, improve microcirculation; Anti-oxidant; Treatment or prevention FRDA (ataxia); Treatment or prevention neurological disorder; And the improvement illness relevant to neuronal damage.Further, described neurological disorder is caused by neurotrauma.More preferably, described neurological disorder is apoplexy.More preferably, described neurological disorder is encephalomyelitis.Preferably, neurological disorder is relevant to mitochondria dysfunction.Preferably, described neurological disorder is relevant to anoxic condition.Preferably, neurological disorder is alcohol withdrawal syndrome or fetal alcohol syndrome.Preferably, neurological disorder is relevant to the neuronal damage that is caused by bacterium infection or virus infection.
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Effective date of registration: 20160620 Address after: 570216, No. A11, Haikou Free Trade Zone, No. 168 Nanhai Avenue, Hainan, Haikou Patentee after: HAIKOU QILI PHARMACEUTICAL Co.,Ltd. Address before: 100079 No. 7, building 15, Jia Jia garden, Beijing, Fengtai District Patentee before: Beijing Sanquan Pharmaceutical Technology Co.,Ltd. |
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Denomination of invention: Hydroxydecylbenzoquinone derivatives used for the treatment or prevention of neurological disorders Effective date of registration: 20231229 Granted publication date: 20150429 Pledgee: Bank of Hainan Co.,Ltd. Chengmai technology sub branch Pledgor: HAIKOU QILI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980075705 |
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