CN101648951A - pentoxifylline derivative - Google Patents
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- CN101648951A CN101648951A CN200910144474A CN200910144474A CN101648951A CN 101648951 A CN101648951 A CN 101648951A CN 200910144474 A CN200910144474 A CN 200910144474A CN 200910144474 A CN200910144474 A CN 200910144474A CN 101648951 A CN101648951 A CN 101648951A
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Abstract
The invention discloses a pentoxifylline derivative shown as the formula (1) or pharmaceutically acceptable salt, solvate, optical isomer or polymorph and a pharmaceutical composition containing the compounds, wherein R represents straight chain or branch chain C1-C5 alkyl, C3-C6 naphthenic base or C4-C8 naphthenic alkyl. The invention also discloses a preparation method of the pentoxifylline derivative and application in preparing a medicament with nerve protection function. The compound has favorable effects of hemangiectasis and nerve protection and higher application value in the field ofmedicines.
Description
One, technical field
The present invention relates to a kind of medicinal compound and its production and application, be specifically related to a kind of new pentoxifylline alkali derivant and its production and application, especially for treatment or prevention of brain vascular disease.
Two, background technology
The death of neurocyte reaches by its fatal afunction that causes after the local asphyxia, and its corresponding serious nerve and/or spiritual disease are the common Clinical symptoms of most of cerebrovascular diseases.Comprise as apoplexy, the outbreak of transient ischemia's property, multi-infarct dementia, blood vessel and degeneration (presenile dementia) mixed type dementia, Spinal injury and because big cerebral trauma that head injuries causes or the like.
In clinical practice, apoplexy (also claiming cerebrovascular accident or cerebral apoplexy) accounts for main flow, and it is the major cause in 15% all death, therefore occupies the 3rd in cause of death statistics, is only second to heart trouble and cancer.It has high case fatality rate and disability rate, mainly is divided into hemorrhagic cerebral apoplexy (hematencephalon or subarachnoid hemorrhage) and ischemia apoplexy (cerebral infarction, cerebral thrombosis) two big classes, and is the most common with cerebral infarction.Cerebral apoplexy morbidity is anxious, and the case fatality rate height is one of most important fatal disease in the world.The mortality ratio of apoplexy also has the trend that rises with age growth, owing to lack therapy measure always.
As survive apoplexy; it can stay permanent damage usually; for example numbness, wry mouth and heterotropia, central paralysis, lower motor neuron paralysis, hemiplegia, aphasia, agnosia and appraxia; this feasible necessary long-term care patient; the patient is greatly painful, and the burden that relatives' burden has spent aspect health service is equally very heavy.
Therefore, develop and set up a kind of effective pharmacological agent, it can reduce acute death and nerve injury degree and recurrence rate, thereby improves the huge challenge that quality of life after the apoplexy is society and medical meaning in the drug research.
To the trial of new basic treatment, concentrate on the reaction of specific intervention pathologic at present stopping the ischemic progressive process of acute brain as far as possible, thereby forever control the loss of neurocyte after the local asphyxia.At present, follow two kinds of strategies basically: be dredge Arterial system in early days molten to the bolt of blood vessel embolism and arterial thrombosis retardance on the one hand with Taka-proteinase such as streptokinase, urokinase or recombinant tissue Profibrinolysin activator; On the other hand, purpose is the cytoprotection of under the local asphyxia state neurocyte being survived.
The neurocyte protection principle that the clinicist fully studied comprises that EAA antagonists (as competitive and noncompetitive N-methyl D-aspartic acid and non-nmda antagonist) or gangliosides suppress to flow in the cell unit calcium as using calcium antagonist (as nimodipine, nicardipine, CN and flunarizine); Block the arachidonic acid cyclization and remove its deleterious meta-bolites with Phospholipid hydrolase, cyclooxygenase and phosphorus oxidation enzyme inhibitors or platelet activation factor, thromboxane and leukotriene antagonist; Suppress the peroxidation of lipid with oxygen-cent red radical scavenging agent (for example superoxide dismutase, catalase, alpha-tocopherol, vitamins C, Ginkgo Leaf, allopurinol and melatonin etc.) or heavy metal chelant (for example Deferoxamine, EDTA-2Na, BAPTA etc.); With the diffusion of Ivy extract active substance (as reflunomide) restriction oedema, reduce the thrombus tendency with antithrombotics (as heparin) anticoagulant (as ticlopidine, clopidogrel, acetylsalicylic acid, prostacyclin etc.); With serotonin 1A agonist (as urapidil), the activator of adenosine conditioning agent (as propentofylline and vinpocetin etc.) or neurotrophic factor and release thereof is assisted the endogenous protection factor.Maximum success is given the credit to multiple factor and is intervened pathologic reaction cascade, crosses merging different choice active medicine, the perhaps medicine realization of more advantageously composing by the wideest a kind of pharmacological action with mutual enhanced medium system Netcom.
The above-mentioned theophylline class medicine that also comprised.Existing xanthine structure of also having studied with regard to Pharmaceutical Chemist, pharmacologist and clinicist of the applicant and tool pharmaceutically active compounds are done one and are simply listed in table 1.
Table 1 xanthine drug structure
The applicant has also carried out a large amount of structural transformation when the above structure activity relationship of research, find unexpectedly, works as R
1For
R
2Be CH
3, R
3For
R
4During for H, obtained the compound more superior (the relative experimental model of animal) than above-mentioned pentoxifylline and propentofylline, because pentoxifylline and propentofylline are to prevent and treat the cerebrovascular disease excellent drug clinically, therefore, this has the treatment potential of bigger prevention and treatment cerebrovascular disease.
Three, summary of the invention
The objective of the invention is for a kind of new pentoxifylline alkali derivant with prevention and the effect of treatment cerebrovascular disease therapy potential is provided, or it is at pharmacy acceptable salt, solvate, optical isomer or polymorphic form, and its structural formula is shown in (I):
In the formula, the R representative is straight or branched C
1～C
5Alkyl or C
3～C
6Cycloalkyl or C
4～C
8Cycloalkylalkyl.
Among the present invention, what described pentoxifylline alkali derivant was preferable is 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine.
Among the present invention, described pharmacy acceptable salt is preferable is and mineral acid or the salt that forms with organic acid.What wherein, described mineral acid was preferable is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid; What described organic acid was preferable is nicotinic acid, fumaric acid, toxilic acid, tartrate, L-glutamic acid, aspartic acid, citric acid, picric acid, succsinic acid, lactic acid, oxysuccinic acid, propionic acid, oxalic acid, Phenylsulfonic acid or propanedioic acid.Among the present invention, that described pharmaceutically acceptable solvate is preferable is hydrate or C
1～C
4The solvate of alcohol.
The invention still further relates to a class pharmaceutical composition, this pharmaceutical composition comprises the above-mentioned pentoxifylline alkali derivant for the treatment of significant quantity, or it is at pharmacy acceptable salt, solvate, optical isomer or polymorphic form and pharmaceutically acceptable carrier.
The present invention relates in one aspect in addition at present and use medicine of the present invention in the treatment cerebrovascular disease.Described methods of treatment as suppress the local asphyxia outbreak primarily prevent act on, the emergent management of local asphyxia outbreak back restriction tissue infraction and the secondary prevention measure that local asphyxia outbreak back reduces recurrence rate; On the other hand, the present invention relates to use the medicament of pharmaceutical compositions, particularly parenterai administration and oral administration, rectum or transdermal administration in case of necessity.
The suitable solid or the medicament forms of liquid have, for example, and particle, powder, tablet, coating tablet, micro-capsule, syrup, emulsion, suspensoid, gel, sustained release preparation, suppository, aerosol, drops, little liquid drugs injection, freeze-dried powder, transfusion; Normally used auxiliary agent such as vehicle, disintegrating agent, tackiness agent, Drug coating, swelling agent, glidant or lubricant, correctives, sweeting agent or solubilizing agent in the preparation.
The various formulations of pharmaceutical composition of the present invention can adopt the method for medical field routine to be prepared, wherein the content of activeconstituents is 0.1%～99.5% (weight ratio), in the preparation, the weight content of compound of the present invention is 0.1%～99.9%, and preferred content is 0.5%～90%.
Another object of the present invention provides the preparation method of pentoxifylline alkali derivant of the present invention, special optimised form compound 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine. and the preparation method of salt, concrete steps are as follows:
Intermediate compound I: the preparation of (N-methyl-N-hydroxyethyl) aminomethyl chloroethanol:
The preparation method of general formula (I):
When R is CH
3The time, be exactly optimizing compound of the present invention, its synthetic method is followed the prescribed rules.
By the salt of general formula (I) expression compound, synthesizing of optimised form compound salt particularly of the present invention can be synthetic according to following method.By compound with general formula (I), be dissolved in methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, isopropyl ether, acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide, in the single or blended appropriate solvent such as methyl-2-pyrrolidone, under-10 ℃～100 ℃, be preferably under 10 ℃～50 ℃, stir with the acid of correspondence, in case of necessity corresponding acid is dissolved in methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, isopropyl ether, acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide, in the single or blended appropriate solvent such as methyl-2-pyrrolidone, drip stirring reaction 0.1～20 hour, just can finish reaction in best 0.3～1 hour.。
Above-mentioned manufacture method, only one of method of expression manufacturing general formula of the present invention (I) compound example.The manufacture method of The compounds of this invention is not limited in these methods, in the embodiment of this specification sheets, owing to more particularly understand the manufacture method of The compounds of this invention, so, those skilled in the art are according to the above description with the explanation of specific embodiment, as required, the suitable in addition modification to this just can produce the compound that is included in above-mentioned general formula (I) or their salt.
Among the present invention, the synthetic of intermediate compound I can be according to the method preparation of document (DD, 122093,1976) with document (Arzneimittel-Forsch, 1962,12:672～675), and other agents useful for same and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: the pentoxifylline alkali derivant of the present invention shown in general formula (I), or it has good vasodilation and neuroprotective at pharmacy acceptable salt, solvate, optical isomer or polymorphic form.
Four, embodiment
The following examples can further be described the present invention, yet these embodiment should be as limitation of the scope of the invention.
Among the following method embodiment, the fusing point of compound is measured with the capillary melting point determination instrument, and thermometer is not proofreaied and correct, nuclear-magnetism
1HNMR,
13CNMR is interior mark by Varian AM-400 type nmr determination with TMS, and chemical shift is with δ (ppm) expression, and mass spectrum is measured with Q-TOF type mass spectrograph.
The silica gel column chromatography thin layer plate is produced (GF254 type) with Haiyang Chemical Plant, Qingdao.
Preparation example 1: intermediate compound I: the preparation of (N-methyl-N-hydroxyethyl) aminomethyl chloroethanol
1, the preparation of N-Mono Methyl Ethanol Amine
In the 2000ml four-hole boiling flask, electric mixer, reflux condensing tube, thermometer and gas absorbing device are installed, to the aqueous methylamine solution 220.4g (7.097mol) that wherein adds 25%～40%, what stirs down for 25～40 ℃ and feeds ethylene oxide gas 58.2g (7.096mol), and ventilation finishes, and heated and stirred slowly is warming up to 120 ℃, distill, collect 120～180 ℃ of cuts, carry out second distillation again, n is collected in control
D 201.4385 cut, be N-Mono Methyl Ethanol Amine 45.6g, directly in the next step.
2, the preparation of (N-methyl-N-hydroxyethyl) aminomethyl chloroethanol
In reaction flask, add epoxy chloropropane 37g (0.4mol) and Virahol (i-PrOH) 20ml, stirring and dissolving is cooled to 18～22 ℃, the compound 37.5g (0.499mol) of step preparation on agitation and dropping under this temperature, finish, at 20～25 ℃ of stirring reaction 1h.Get the aqueous isopropanol of (N-methyl-N-hydroxyethyl) aminomethyl chloroethanol, need not handle and be directly used in next step.
Preparation example 2: compound 3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] the xanthine preparation
In the what reaction flask, add 125ml dehydrated alcohol and 2.86g (0.124) sodium Metal 99.5, stirring makes sodium Metal 99.5 molten entirely, adds the pulverous 3-methyl purine of 20.8g (0.124mol) again, and reflux obtained the sodium salt of 3-methyl purine in 10 minutes.Slowly splash into the aqueous isopropanol 20.7g (0.124mol) of 1/4th (N-methyl-N-hydroxyethyl) aminomethyl chloroethanol of above-mentioned preparation example 1, add the stirring and refluxing that finishes, thin layer identification reaction terminal point (developping agent: ethyl acetate: ethanol: Glacial acetic acid=5: 2; 0.1 v: v: v), approximately 4.5h finishes reaction.Be cooled to 0～-5 ℃, filter, solid dissolves with the NaOH solution of an amount of 1N then, regulating the pH value with 0.5N HCl, control pH value is 11.5, the solid filtering that obtains, with 200ml methyl alcohol/chloroform=1: 1 recrystallization, obtain the 31.3g white crystalline powder, fusing point＞250 ℃, yield: 85.1%..
Embodiment 1: compound 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine. preparation
In the 500ml four-hole boiling flask, electric mixer, reflux condensing tube, thermometer and N are installed
2Airway, to wherein adding 27g (0.09mol) preparation example 2 compounds, 16.8g (0.158mol) Anhydrous potassium carbonate and 250ml DMF, the what room temperature condition stirs adding 16g (0.09mol) 5-oxo-hexyl bromide 1 bromohexane down, adds the back mixture at N successively
2Be heated to 120～125 ℃ of reactions 30 minutes under the protection, thin layer identification reaction terminal point (developping agent: ethyl acetate: ethanol: Glacial acetic acid=5: 2; 0.1 v: v: v), reaction finishes, and adds 50ml distilled water in mixture, stirs, and uses 200ml * 3 chloroform extractions then, aqueous phase discarded, organic layer anhydrous sodium sulfate drying.Filter, be concentrated into dried, resistates promptly gets 29.5g white crystalline powder 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group with the dehydrated alcohol recrystallization] xanthine., 125～128 ℃ of fusing points, yield: 83.1%.HPLC content is 99.1%.
1H-NMR(400MHz，CDCl
3)：
δ 1.58～1.65 (4H, multiplet, J=8.1Hz, 13, No. 14 hydrogen); δ 2.17 (3H, unimodal, No. 17 hydrogen); δ 2.26 (3H,, unimodal, No. 28 hydrogen); δ 2.43 (2H, triplet, J=7.2Hz, No. 15 hydrogen); δ 2,51～2.55 (2H, triplet, J=8.1Hz, No. 25 hydrogen); δ 2.69～2.74 (2H, multiplet, J=8.1Hz, No. 22 hydrogen); δ 3.38 (3H, unimodal, No. 19 hydrogen); δ 3.48 (2H, triplet, J=8.1Hz, No. 26 hydrogen); δ 3.74～3.96 (1H, multiplet, J=6.5Hz, No. 21 hydrogen); δ 4.05～4.09 (2H, multiplet, J=8.1Hz, No. 20 hydrogen); δ 4.16 (2H, multiplet, J=7.5Hz, No. 12 hydrogen); δ 8.5 (1H, unimodal, No. 8 hydrogen).
13C-NMR(400MHz，CDCl
3)：
δ 19.4 (No. 14 C); δ 27.2 (No. 13 C); δ 31.5 (No. 17 C); δ 32.4 (No. 19 C); δ 43.8 (No. 12 C); δ 43.7 (No. 15 C); δ 49.0 (No. 28 C); δ 52.7 (No. 20 C); δ 63.1 (No. 26 C); δ 67.3 (No. 22 C); δ 68.1 (No. 25 C); δ 83.5 (No. 21 C); δ 11.2 (No. 5 C); δ 145.3 (No. 8 C); δ 148.4～158.3 (2,4, No. 6 C); δ 216.3 (No. 16 C);
MS：m/z(M
+)395.2(100％)，396.2(20％)。
Embodiment 2:1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine. the preparation of nicotinate
In three mouthfuls of round-bottomed flasks of 250ml, to wherein adding 7g (0.0237mol) two 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine. (embodiment 1 compound) and dehydrated alcohol 150ml, be heated to molten entirely, at this moment, add 2.9g (0.0237mol) nicotinic acid, stirring and refluxing 20min under boiling temperature, fully cooling in the what refrigerator, the crystallization that suction filtration is separated out, get 8.2g1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine nicotinate white crystalline powder, yield 83% is measured in accordance with the law.
Embodiment 3:1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine. the preparation of hydrochloride
In three mouthfuls of round-bottomed flasks of 250ml, to wherein adding 7g (0.0237mol) two 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine and Virahol 100ml, room temperature is heated to molten entirely, to wherein adding 2N HCl 5ml, stir 5min, be cooled to 0 ℃, the crystallization that suction filtration is separated out, get 5.9g 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine nicotinate white crystalline powder, yield 76% is measured in accordance with the law.
Embodiment 4:1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine. the preparation of fumarate
In three mouthfuls of round-bottomed flasks of 250ml, to wherein adding 7g (0.0237mol) two 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine and dehydrated alcohol 80ml, be heated to backflow, at this moment, to the 30ml hot ethanol solution that wherein adds 2.8g (0.0237mol) fumaric acid, stirring and refluxing 5min under boiling temperature, fully cooling in the what refrigerator, the crystallization that suction filtration is separated out, get 7.3g 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine fumarate white crystalline powder, yield 74% is measured in accordance with the law.
Other salt is synthetic by that analogy.
Pharmacological evaluation and result
Can in the suitable model of clinical relevant experimentation on animals, prove the tangible neuroprotective of optimizing compound of the present invention; with the pentoxifylline is reference product; experimental result shows; this compound obviously is better than reference product, therefore the treatment potential with better treatment and prevention of brain vascular disease.
1, the neuroprotective in pallasiomy transience ischemia model is got the male mongolian gerbils of 12 body weight between 50～60g and is divided into two groups at random, 6 every group, carries out this experiment.First treated animal gave the fc-specific test FC thing by peritoneal injection in 30 minutes behind ischemic, second group of CMC-Na that only gives same dose,
In order to make cerebral ischemia before the transience, with the halothane anesthesia animal and lie on the back and be fixed on heating later on the operating table, the careful carotid artery that exposes both sides, pressed from both sides closed 3 minutes with arteriole, after 7 days 3 minute ischemic stages, with halothane anesthesia animal and sacrificed by decapitation, remove decerebration rapidly and carefully, dipping is fixed in the Carnoy s solution (ethanol/chloroform/acetate=6: 3: 1) earlier, is embedded into then in the paraffin, then prepares the hat section of 4～6 micron thickness from hippocampus, (in about bregma level), and with hematoxylin with affix one's name to red colouring.Then, in experiment blindly, with sxemiquantitative histopathology numerical value (0=does not have, and 1=is slight, 2-moderate, 3=is serious, 4=is downright bad fully) acidophilic necrosis's degree of the pyramidal cell in mensuration hippocampus CA1 district under opticmicroscope.With the quantity of estimating neuroprotective is to compare with the untreated control group, and the percentage ratio of product group evaluation of tissue pathology quantity changes, and experimental result is as shown in table 1.
The restraining effect of table 1 pair pallasiomy ischemic neural cell injury
Can prove in following testing program that also compound of the present invention has unexpected good neuroprotective activity, just this method comprises finer method and technology.
2, to the restraining effect of the nervous symptoms of the permanent focus cerebral ischemic model of rat
Experimental animal is an adult male SD rats, body weight 300～400g, and by the closed permanent mesencephalic arteries, laboratory preparation focus cerebral infarction.
Surgery is prepared to need 20 to 30 minutes, with carrying out under the nitrous oxide anesthesia that contains the 1%-1.2% haloalkane.Right femoral artery and vein (in order to measure blood pressure) intubate, blood sampling, after testing phenology then, amplify closed left middle cerebral artery by surgery microscope, through pass through electrocoagulation separating blood vessel subsequently under the volume under the situation of not removing muscle, surgical procedure detects by the continuous recording arterial pressure, after the operation, animal is revived from narcosis, make body temperature maintain 37 ℃ normal range with thermostatically heating cloth.
Closed blood vessel is after 15 minutes, group of products animals received tester, and the peritoneal injection administration, predose is 10mg/kg, is that 24 hours continuous infusion 0.1mg/kg/min of transvenous catheter continue processing with specific not rotary screw button; The animal of untreated control group is only accepted physiological saline with identical approach.Closed blood vessel is before 15 minutes and promptly, and beginning continuous infusion tester or carrier detect arterial blood gas and pH and hematocrit and glucose level soon to survey the physiology degree of irregularity; Remove arterial cannulation then.In addition, begin before off-test, to measure in several minutes the temperature and the rectal temperature of both sides frontalis from the operation in 10 minutes of beginning continuous infusion.Behind the vessel sealing 24 hours, stop continuous infusion, determine because the nerve disappearance degree that local asphyxia causes below is a judgement criteria with the four point symptom numerical value of Bederson etc.:
0=does not have neural disappearance sign
The bending of 1=forelimb
2=reduces resistance to thruster, but does not have pitch of the laps
3=and 2 same symptoms, but pitch of the laps
Analyze experimental data with biostatistics, be evenly distributed (conspicuous level P＜0.5) with what t detected neural numerical value in the relatively product and control group.Wherein, with untreated control animal (2.3 ± 0.5; On average ± SD) compare, embodiment 1 compound is to nerve disappearance (1.1 ± 0.4; On average ± SD) cause remarkable reduction (conspicuous level P＜0.01), corresponding to having improved 52% neural state and be free from side effects (physiological parameter of research).
Claims (9)
1, a kind of pentoxifylline alkali derivant shown in general formula (I), or it is at pharmacy acceptable salt, solvate, optical isomer or polymorphic form:
Wherein:
R is straight or branched C
1～C
5Alkyl or C
3～C
6Cycloalkyl or C
4～C
8Cycloalkylalkyl.
2, the described pentoxifylline alkali derivant of claim 1, or it is characterized in that at pharmacy acceptable salt, solvate optical isomer or polymorphic form: and R is C
1～C
3Alkyl.
3, the described pentoxifylline alkali derivant of claim 1, or it is characterized in that at pharmacy acceptable salt, solvate, optical isomer or polymorphic form: described pentoxifylline alkali derivant is: 1-(5 '-oxo-hexyl)-3-methyl-7-[2 '-hydroxyl-3 '-[(2-methylol) methylamino] propyl group] xanthine.
4, the described pentoxifylline alkali derivant of claim 1, or it is characterized in that at pharmacy acceptable salt, solvate, optical isomer or polymorphic form: described pharmacy acceptable salt for mineral acid or the salt that forms with organic acid; Described solvate is hydrate or C
1～C
4The solvate of alcohol.
5, the described pentoxifylline alkali derivant of claim 1, or it is characterized in that at pharmacy acceptable salt, solvate, optical isomer or polymorphic form: and described mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid; Shown organic acid is nicotinic acid, fumaric acid, toxilic acid, tartrate, L-glutamic acid, aspartic acid, citric acid, picric acid, succsinic acid, lactic acid, oxysuccinic acid, propionic acid, oxalic acid, Phenylsulfonic acid or propanedioic acid.
6, contain the treatment significant quantity as each described pentoxifylline alkali derivant in the claim 1～5, or it is at the pharmaceutical composition of pharmacy acceptable salt, solvate, optical isomer or polymorphic form.
7, each described pentoxifylline alkali derivant in the claim 1～5, or it is used for the treatment of or prevents application in the cerebrovascular disease medicament in preparation at pharmacy acceptable salt solvate, optical isomer or polymorphic form.
8, the purposes of claim 7 is used for the treatment of and preventing apoplectic, the outbreak of transient ischemia's property, multi-infarct dementia, blood vessel and degeneration (presenile dementia) mixed type dementia, Spinal injury and because the big cerebral trauma that head injuries causes.
9, the purposes of claim 7 and 8 arbitrary claims is used for non-enteron aisle, oral, rectum or transdermal administration.
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|---|---|---|---|
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113214259A (en) * | 2021-05-25 | 2021-08-06 | 海南通用康力制药有限公司 | Synthesis method of pentoxifylline |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113214259A (en) * | 2021-05-25 | 2021-08-06 | 海南通用康力制药有限公司 | Synthesis method of pentoxifylline |
| CN113214259B (en) * | 2021-05-25 | 2022-06-10 | 海南通用康力制药有限公司 | Synthesis method of pentoxifylline |
| WO2022247065A1 (en) * | 2021-05-25 | 2022-12-01 | 海南通用康力制药有限公司 | Synthesis method for pentoxifylline |
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