CN1849127A - Use of parapheny for maldehyde-O-beta-D-allose pyranoside for treating neurogenic pain - Google Patents
Use of parapheny for maldehyde-O-beta-D-allose pyranoside for treating neurogenic pain Download PDFInfo
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- CN1849127A CN1849127A CNA200480026262XA CN200480026262A CN1849127A CN 1849127 A CN1849127 A CN 1849127A CN A200480026262X A CNA200480026262X A CN A200480026262XA CN 200480026262 A CN200480026262 A CN 200480026262A CN 1849127 A CN1849127 A CN 1849127A
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- pain
- neuropathic pain
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Abstract
The present invention relates to the use of the compound of helicid, or its pharmaceutically acceptable salts, esters or solvates, for the manufacture of medicaments in treating neuropathic pain.
Description
The purposes invention field of neuropathic pain is treated to benzaldehyde-Ο-β-D- A Luo pyranosides
The present invention relates to medicinal chemistry art, specifically, the present invention relates to the new application to benzaldehyde-Ο-β A Luo pyranoside compounds.
Background of invention
According to durante dolors length, pain is clinically divided into two kinds of Acute Pain and chronic ache, both pain have essential distinction in genesis mechanism.Acute Pain is referred to as nociceptive pain, i.e., the pain as caused by tissue injury, with the reparation of tissue injury, and pain stops naturally, and analgestic can be used in stage of attack（Such as narcotic analgesics and nonsteroidal antipyretic-antalgic agent）Slow solves pain；Chronic ache is then based on the property pain of Shen Jing sources, and its pathogenesis is extremely complex, and is difficult treatment, is the basic and clinic studies of pain medicine and the frontier of medicament research and development.Foreign countries are risen about 30 years, and 10-15 research history is there are about in China.
One, neuropathic pain basic conceptions
Neuropathic pain is the chronic ache caused by wound, inflammation or other diseases etc. cause neurotrosis or lesion.Its typical example includes：Postherpetic neuralgia, Trigeminal Neuralgia, sciatica Te Do are sciatic nerve chronic constriction neuropathic pains, metabolic impairment nerve source property pain, lumbago, maincenter and chronic ache and intractable cancer pain etc. caused by the wound of periphery caused by phantom limb pain, intercostal neuralgia, central pain, phantom limb pain, stump pain, sympathetic nerve associated pain, complicated regional pain syndrome, spine disorderses compressing spinal cord or nerve root after particularly diabetic neuralgia, headstroke after pain syndrome, amputation.Because its complicated pathogenesis is with lacking effective medicine（Opiates and nonsteroidal analgesic-antipyretic be not good to this kind of pain effect）, neuropathic pain has become on clinical treatment more stubborn problem.Neuropathic pain is considered as progressive the nervous system disease, and the difference with Acute Pain is the persistent state of the pain sensation, the adaptive change of neural plasticity and secondary biochemical reaction etc..
Neuropathic pain Pathological Physiology feature is pain sensation high response, is mainly shown as：Hyperalgia（Hyperalgesia), nociceptive response is increased or is sensitized；Allodynia (allodynia), nociceptive response is produced to non-noxious stimulation；, there is pain under the conditions of non-stimulated in spontaneous pain (spontaneous pain).
Neuropathic pain pathogenesis
The pain sensation high response of neuropathic pain shows as pain threshold on animal experimental model
Decline, ectopic discharge etc. occurs in the electroactive enhancing of Primary Sensory Neuron.Remarkable break-throughs are obtained in the research of the mechanism of these phenomenons over nearly 5 years.The progress for being worth attracting attention has following L points：
1. the activation of pain sensation afferent nerve Chen Ji Yu dimensions and hyperalgia
Under normal circumstances, C transmitting fiber tows lead acuteness pain, A δ fibers conduction dull pain.10- in a little fibers20% is in " resting state " under normal circumstances, is referred to as silence（Silence) fiber.After neurotrosis, these nerve fibres are activated, and spontaneous and ectopic discharge are occurred, are played an important role in hyperalgia.
2. A betas participate in pain sensation conduction and allodynia
Under normal circumstances, Α betas are only involved in the transmission of tactile, vibration and feeling of stress, and its Neuronal soma is in dorsal horn deep layer（Π and IV layers of Ι）, and in shallow-layer（I and Π layers）The Neuronal soma of dimension is not in contact with.Α betas are not only electroactive active after neurotrosis, and its cell space of JL launches fiber to I, II layers of growth, and synaptic contact is formed with the Neuronal soma of C and Α δ fibers, thus make script not cause the stimulation of pain also to activate pain sensation transmission and hold back road.Research at present thinks that the neurotransmitter of Α β activation C and Α δ fiber nerve members is mainly atmosphere base acid and peptide matters.
3. sympathetic nerve basket structure and spontaneous pain and allodynia
Under normal circumstances, sympathetic nerve mainly dominates its peripheral vessels, regulating blood flow at DRGs.After peripheral nerve injury, sympathetic nerve also launches fiber extension to Dorsal root multilayer ^ Neuronal somas, forms basket structure with Α β pericaryons, and activate the Α β ^ of silence through member, enhancing induction property is electroactive, causes spontaneous pain and allodynia to react.
4. ion channel and neuropathic pain
The electric discharge of aixs cylinder and cell space from damage location without being generated from tip receptor, you are ectopic discharge, and ectopic discharge is to the generation of neuropathic pain with remaining most important：The main cause of production ectopic discharge is probably the bad property Na of voltage agriculture on peripheral nerve injury position and DRG cell spaces+Passage, voltage-dependent Ca2+The mrna expression amount of passage plasma channel and hold back protein density increase and current anomaly, it is the one of the main reasons that chronic ache occurs to be presently believed that the reconstruct of neuron membrane ion channel and the physiological change of functional compensation.On neuropathic pain model, low dose of tetraodotoxin local application blocks TTXs Na+ electric currents and the quick behavior of pain.Voltage-dependent Ca2+Passage and its electric current also assist in neuralgic morbidity.N-type Ca2+Carrier frequency channel break is neat, and J conotoxins are effective to neuropathic pain, and foreign countries carry out clinical research at present.The anticonvulsant Gabapentin of neuropathic pain is treated on present ^ beds（Gabapentine J) can also be reduced
The calcium current of foster hippocampus of rats, find ion channel isoform selective inhibitors turns into the important development direction of medicine from now on.
5. inflammatory process, inflammatory factor and neuropathic pain
Secondary cases injury after nerve damage changes generally all with inflammatory reaction.Therefore, in the mechanism for inquiring into neuropathic pain, some scholars focus onto the change and its Pathological Physiology effect of inflammatory factor.These inflammatory factors include Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, Calmodulin Gene related peptide, monoamine, ATP, nitric oxide, leukotriene, prostaglandin, nerve growth factor etc..
It is worth noting that recently（After the mid-90）It was found that Slow kassinin kinins（Brady kinin) system, also there is change in neuralgia, it was observed that Slow kassinin kinin B1 and B2 receptor up-regulations.Slow kassinin kinins are by activating B1 and B2 acceptors, directly excited nociceptor, B2Receptor antagonist has analgesic activity.Inflammatory process and pain after the main mediate injury of acceptor.Suppress the system comprehensively.There may be good effect to neuropathic pain.
Three, neuropathic pain medicines
At present, the key agents for the treatment of neuropathic pain belong to old medicine and newly used, and most of had found that it is likely that effectively by clinic trial, then carries out system clinical research, is then return to laboratory research, inquire into its mechanism, promote the developmental research of new drug.These medicines are roughly divided into four types：Anti-epilepsy medicine, antidepressant, local anesthetic and other.
1. antiepileptic
Nineteen forty-two Bergonignaii reports dilantin sodium first can effectively treat trigeminal neuralgia, not paid attention to.Blom in 1962 reports carbamazepine first also can effectively treat trigeminal neuralgia.But until in the 80's, just proceed by the clinical research of system.Current clinical research is proved carbamazepine and Gabapentin（Gabapetin neuralgic validity) is treated, U.S. FDA approved carbamazepine is used for the treatment of trigeminal neuralgia.The analgesic effect of dilantin sodium is weaker.Lamotrigine（Lamotrigine) the contradictory report of analgesic effect, need further clinical research.Phenobarbital, clonazepam, valproic acid, Topiramate（Topiramate), pregabalin and Tiagabine etc. is effective on animal model, does not obtain the confirmation of clinical system research also.Wherein valproic acid has been approved by the FDA in the United States treatment antimigraine.Carbamazepine blocks Na+Passage, suppresses Na+ transmembrane conductors, prevents action potential from being formed, and weakens the centripetal conduction of pessimal stimulation, suppresses ectopic discharge.In addition it may also suppress rabbit trigeminal neuralgia caused by Slow kassinin kinins.Gabapentin analgesic mechanism research report is less, and someone reports it to Na+Passage, may be with blocking Ca without influence2+Passage is relevant, because it can be with N-type Ca2+Channel α2Delta-subunit is combined.
2. antidepressant
Tricyclic antidepressants has analgesic activity to neuropathic pains such as postherpetic neuralgia, chronic low back pain, chronic tension headache, diabetic keratopathy and non-diabetic polyneuritis pains, has obtained the confirmation of clinical system research.
It is amitriptyline that research reports more earliest（Amitriptyline), but by Chu, the medicine has the adverse reactions such as obvious calmness, anticholinergic, and postural hypotension can be caused.Later clinical research proves that other tricyclic antidepressants include nortriptyline, go Yue imipramine, chlorimipramine similarly effective, and adverse reaction is less than amitriptyline.However, tricyclic antidepressants belongs to the more medicine of adverse reaction, Clinical practice is restricted, for this, it is external just in the less second generation of system research adverse reaction, the analgesic effect of third generation antidepressant, including selective 5- HT cell reabsorption inhibitors, norepinephrine and 5-HT double-absorption inhibitor etc..The former has Paroxetine（Paroxetine), cedilanid（Citaloprame) etc., the latter is mainly Effexor (venlafaxine) etc..
3. local anesthetic
Local anesthetic lidocaine is typical Ca2+Channel blocker, finding within 1961 can Slow solution postoperative pain, 19 after venous perfusion8The report such as 2 years Boas can solve maincenter and peripheral neuralgia with this method with Slow, be used to ability is more at the beginning of the 90's.After vein or subcutaneous injection, there is obvious analgesic effect, the effective blood drug concentration of venous perfusion is 0.62-5 g/ml, and subcutaneous injection jfc concentrations also can reach 2-5 g/ml.In addition also there is the report of perfusion in ejector sleeve, but using less.Due to the adverse reaction and the inconvenience of route of administration of cardiac toxic and central nervous system, P is blunt to make its Clinical practice scope.Tried out again can be oral antiarrhymic mexiletine (mexiletine), its chemical constitution is approximate with lidocaine, is also a Na+Channel blocker.Lidocaine patch is have approved to latter stage nineties U.S. FDA（Lidoderm), the neuropathic pain of local application treatment herpes zoster, also effective to other neuropathic pains.
Compound is to benzene Yue aldehyde -0- A Luo pyranosides, its general entitled helicidum (Helicid), and former name is Helicid, is from Chinese Yunnan Province wild plant Proteaceae radish tree（Helicia essatia Hook) fruit bean curd in the active ingredient extracted, the chemical constitution and Gastrodin of the compound（Gastrodin) (to hydroxyl Yue base benzene-β-D- glucopyranosides）There is similar monomer glucosides.Molecular formula to benzaldehyde -0- P-D- A Luo pyranosides is C13H1607, structural formula is as follows：
The invention provides the new application to benzaldehyde-Ο-β A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate, i.e., prepared by the purposes in being used to treat the medicine of neuropathic pain disease to benzene Yue aldehyde A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate.
Detailed description of the invention
Prepared by the purposes in being used to treat the medicine of neuropathic pain to benzaldehyde -0- β A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate the invention provides following formula：
In a preferred embodiment of the present invention, the neuropathic pain is the chronic ache caused by wound, operation, inflammation or other diseases cause neurotrosis or lesion.
In further preferred embodiment of the present invention, the neuropathic pain be selected from postherpetic neuralgia, Trigeminal Neuralgia, sciatica, metabolic impairment nerve source ' pain, the phantom limb pain after headstroke after pain syndrome, amputation, intercostal neuralgia, maincenter ' pain, phantom limb pain, stump pain, sympathetic nerve associated pain, complicated regional pain syndrome, spine disorderses compressing spinal cord or lumbago, maincenter and chronic ache and intractable cancer pain caused by the wound of periphery caused by nerve root.
In especially preferred embodiment of present invention, the neuropathic pain is sciatica, especially sciatic nerve chronic constriction neuropathic pain.
In another of the invention particularly preferred embodiment, the neural source ' the very painful pains of I are metabolic impairment nerve source property pain, particularly diabetic neuralgia.
Demonstrated in following article embodiment, benzaldehyde -0- P-D- A Luo pyranoside compound antinociception the times are long, therefore can be by benzaldehyde-Ο-β-D- A Luo pyranosides compounds and the anti-neuropathic pain medicine of fast-acting type such as Gabapentin administering drug combinations, it so can both start anti-neuropathic pain curative effect rapidly, curative effect can be extended again.
Therefore, in one embodiment, the invention provides the combination to benzaldehyde -0- β-D- A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate and the anti-neuropathic pain medicine of fast-acting type for treating neuropathic pain.In preferred embodiments, the anti-neuropathic pain medicine of the fast-acting type is Gabapentin.In the Group of this invention is closed, benzaldehyde-Ο-β-D- A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate and the anti-neuropathic pain medicine of fast-acting type can be simultaneously or sequentially administered.
In another embodiment, the invention provides for treat neural source ' very painful pain medicine
Compositions, wherein comprising benzaldehyde-Ο-β-D- A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate and the anti-neuropathic pain medicine of fast-acting type, and optionally include pharmaceutically acceptable excipient, carrier or adjuvant.In preferred embodiments, the anti-neuropathic pain medicine of the fast-acting type is Gabapentin.
Following examples are experiments prove that the purposes of the present invention, but this is B month property of illustrating, without limiting the scope of the present invention.
Embodiment
One, neuropathic pain animal models
Hot plate, whipping, writhing are the thing models of the classical Acute Pain antalgesic of conventional screening, are not appropriate for for screening neuropathic pain medicine.Neural source, the foundation development of property animal models of pain, great impetus is played to the mechanism of action and drug research of neuropathic pain in recent years.
According to neuropathic pain pathogenesis, laboratory usually manufactures animal model, Bennett GJ in 1988 using damaging peripheral nerve or nervous centralis[ 1 ]Establish the graceful sexual oppression damage model of sciatic nerve（Referred to as CCI models）, because the relatively easy , Knot fruits of the model manipulation are reliable, thus it is widely accepted quickly.Although being found that more animal models[ 2— 3 ], ^a cci models are still the main models of neuropathic pain evaluating drug effect in medicament research and development.Face the Shang medicine such as antidepressants effective to neuropathic pain, antiepileptic Gabapentin and:The many cacaines of ^ j（Na+Channel blocker）, conotoxin（N type calcium channel blockers）Deng showing analgesic effect on this model[ 4 ~ 6 ].The present inventor's early stage also uses CCI models in research and development neuropathic pain medicine, successively observes antidepressant, tetraodotoxin（Na+ channel blockers）Good anti-pain effect is shown with antiepileptic Gabapentin, and active compound is found that adding bar ^ fourth analogs Return to choose[ 7 ]。
Diabetic neuralgia model is also conventional metabolic impairment nerve source property pain model, Streptozotocin（STZ) single intraperitoneal injection, can damage rat Langerhans islet Langerhans cells, produce hyperglycemic symptoms.1 after administration5-3There is within 0 day most diabetic mice to produce peripheral nerve source property pain symptom, show as hyperalgia and allodynia symptom, the model is also internationally recognized neuropathic pain model as CCI models, a variety of neural sources for the treatment of) medicines of the very painful pains of ■ also produces analgesic effect on the mold.Therefore, we employ the two model evaluations and the anti-neuropathic pain of benzene Yue aldehyde-Ο-β-D- A Luo pyranosides are acted on[ 8- helicidum treats the pharmacodynamic study of neuropathic pain
(-) experiment purpose：Acted on by the anti-neuropathic pain of rat sciatic nerve chronic constriction neuropathic pain model and diabetic neuralgia model evaluation helicidum.
(two）Materials and methods：
1. experimental animal：SD rats, male, first body weight 120-140g, 220-240g, two grade, by dimension tonneau, magnificent reality Examination zoo technicals Co., Ltd provides.
2. medicine is prepared and medication：Helicidum（Once code name WN-7-6 is used), provided by Beikenuodun Pharmaceutical Co., Ltd., Kunming, add distilled water to maximum dose concentration before use, water-bath is heated up to complete drug dissolution, and is diluted to required concentration.Administration is emitted with 2ml/kg volume single intraperitoneal injection and filling.Experiment sets distilled water group as blank control.
3. experimental method
1) sciatic nerve chronic constriction neuropathic pain animal model（CCI models）
SD rats（Male, 150-180g), anaesthetized with yellow Jackets (40mg/kg), sciatic nerve is separated in right lateral side mid-thigh.In sciatic nerve i.e. by the leading portion of bifurcated, sciatic nerve is separated with surrounding tissue with sterile glass hook, sterile chromic catgut is used（No. 4, diameter 0.15mm) untwisting pricks 4 rings, and each interannular locally spreads penicillin medicinal powder away from l-2min, and musculature and skin are sutured respectively, is placed in the cage for being covered with cork dust.Sham-operation group instrument exposes sciatic nerve, and other processing are ibid.Experimental selection postoperative 14The animal of ~ 31 days, determines the pressure of foundation threshold of pain before administration, eliminates Basic Pain Threshold and is more than 4g or the animal less than 0.6g, remaining animal is grouped at random, every group give various dose respectively medicine, the measuring pressures pain threshold between difference after administration.
Evaluation method：The observation of mechanical hyperalgesia：Rat is placed in metal cage, with the filament of different grammes per square metres（Von Frey Hair) its vola sole center position is stimulated, persistently stimulate 5 seconds, each stimulus intervals 5 seconds, find the filaments for causing 4 times to 6 times rats lift foot reactions in 10 stimulations, this filametntary grammes per square metre is pressure pain threshold（Unit：Gram）.Maximum pain threshold is set as 26 grams.
5. statistical method：Threshold statistical uses the maximum pain thresholds of non-parametric test Wilcoxon 2-Sample Test and Kruskal-Wallis Test for 26 g.
2) influence of the helicidum to diabetic neuralgia rat allodynia
SD rats（Male, 220-240g), Streptozotocin is injected intraperitoneally75Mg/kg, about 3 weeks or so, with the filament of different grammes per square metres（Von Frey Hair) thorn ' its vola sole center position, persistently stimulate 5 seconds, each stimulus intervals 5 seconds, find the filaments for causing the lift foot reaction of 4 times to 6 times rats in stimulating for 10 times, this filametntary grammes per square metre Jis the Wei Wind power threshold of pain
Value（Unit：Gram）.Maximum pain threshold is set as 26 grams.It is Basic Pain Threshold value to measure pain pavilion before the administration of each group rat, and the rat of symptom occurs in screening, and it is qualified that the threshold of pain is considered as less than 8g.Every group give various dose respectively medicine, in after administration different time points determine pressure pain it is wealthy.
(three）Experimental result：
1. sciatic nerve spinal cord in chronic compression（CCI) the change of the Post operation different number of days rat pressure threshold of pain
There is allodynia in 7 days to CCI groups in the mat woven of fine bamboo strips after surgery, shows as operation lateral pressure pain threshold and is significantly lower than No operation side（) and sham-operation group PO.01（Ρ<0·01 ) .Allodynia phenomenon is aggravated for 10 days after surgery, and pressure pain threshold is significantly reduced（Compared Ρ with No operation Side<0.001) it is, and at least lasting31 day（It the results are shown in Table 1)
The postoperative different number of days rat pressure pain thresholds of table 1.CCI
Pressure pain threshold（Gram）
Group postoperative days number of animals
The sham-operation group 76 16.83 ± 4.49 17.20 ± 4.92 of No operation side 06 17.83 scholar of operation side normal group 6.61 17.83 ± 6.61
The * * of CCI groups 7 10 15.75 ± 4.34 4.62 ± 1.59#
10 10 14.50±4.34 3.77±1.85 ***
14 10 18.67±5.68 3.00±1.55 ***
28 10 21.60 ±7.69 3.30±2.24
31 10 24.17 ±4.49 3.20±1.33 ***
Ρ<0.001, compared with No operation side；##Ρ<0.01, compared with sham-operation group.
2. influence of the helicidum to the sciatic nerve chronic constriction neuralgia rat pressure threshold of pain
25 12.5 6.25 3.125 mg/kg of single intraperitoneal injection helicidum is after 2 hours, allodynia caused by each dosage group to some extent Slow solutions CCI.Compared with before administration, it (is respectively xO.O that helicidum 12.5mg/kg and 6.25mg/kg, which are remarkably improved mechanical hyperalgesia pressure pain threshold,5With<0.001), illustrate that helicidum has anti-chronic neuropathic pains activity on this model.Different time has Slow solutions effect to some extent to allodynia caused by CCI after single intraperitoneal injection helicidum 6.25mg/kg, and effect in 1 hour is not still obvious after administration, can significantly improve within 2 hours pressure pain pavilion value (P<0.001), analgesic activity up to more than 24 hours (<0.05), event resolves after 48h.（As a result such as table 2, shown in table 3）.
Oral helicidum can improve pain threshold dose-dependant, show analgesic activity, beans
Rotten fruit glycosides works for 2 hours, and later analgesic effect gradually increases, declined at 24 hours:After administration 48 hours effectively.It the results are shown in Table 4.
Influence helicidum dosage of the single intraperitoneal injection various dose helicidum of table 2. to CCI rat pressure pain thresholds
Pressure pain pavilion value (g)
(mg/kg) number of animals
Before administration after ^ medicines
Native 1.41 12.5 8 3.10 ± 1.26 5.50 scholars 1.77 of 25.0 2.56+1.34 4.00:The note of 6.25 8 2.60 ± 1.19 9.75 soil 3.73 ", 3.125 8 3.58+1.20,4.83 scholars 2.68：Select postoperative 14 31 days, administration before pressure of foundation pain it is wealthy be grouped at random in 4g to the rat between 0-6g, every group give various dose respectively helicidum, resurvey pressure pain threshold within 2 hours after administration.As a result represented with ± s, Τ ^ Ο Ο5, ***Ρ<0.001, compared with pressure pain threshold before administration.
The intraperitoneal injection helicidum of table 3. (6.25mg/kg) influence of the different time to CCI rat pressure pain thresholds afterwards
Helicidum is acted on
Number of animals pressure pain threshold (g)
Time (h)
After the preceding 8 2.60+1.19 administrations of administration:1 8 4.00±1.85
2 8 9.75+3.73"*
3 7 9.57±5.13**
6 4 10.00+5.83*
24 6 8.33±5.82*
48 6 3.90 ± 2.31 notes：Pressure of foundation threshold of pain different time after 4g to the rat between 0.6g, intraperitoneal injection helicidum 6.25mg/kg resurveys pressure pain threshold before selecting postoperative 14 ~ 31 days and being administered.As a result represented with native s,<0·05, "ixO.01 , ***p<0.001, compared with pressure pain threshold before administration.
Influence of the oral helicidum different time of table 4. to CCI rat pressure pains pavilion value
6.25mg/kg 12.5mg/kg 25mg/kg 50mg/kg
The administration preceding 3.3 ± 1.2 3.3 ± 1.2 2.8 ± 1.1 2.8 ± 1.1 of the n of the n of the n of n=6=4=6=6
2h 6·2±1.2 8.5±3.0 7.7±4. 8.4+3.9 x
3h 11.7±3.2·χ· 13.5±1.2 -χ- 14.9±8.4Χ 5δ 16.3±6.24 ^
4h 11.7±2.9 13.5±1.2^' 18.0±7.9™
24h 8.3±5.9^ 14.8+8.1^ 85 11.9±8.0;¾ 13.9±4.7Ή
48h 6.7+3.0 12.5+9.1χ：！Scholar ^ ※ 9.7+4.0 ^
P<0.05, ** χο·οι, ***Ρ<0001, explain value with pressure pain before administration and compared.
3. influence of the helicidum to the diabetic neuralgia rat pressure threshold of pain
The mg/kg of Streptozotocin 75 is injected intraperitoneally, diabetic neuralgia rat model is caused, is determined during after administration 14-18 days and gives influence of the Streptozotocin to the diabetic neuralgia rat pressure threshold of pain.As a result show, the diabetic neuralgia rat pressure threshold of pain is significantly raised after the oral 2h of helicidum various dose, and the oral mg/kg of helicidum 50 and oral Gabapentin 60mg/kg analgesia hundred points of rates point Do is：68.2% and 60.8%, helicidum analgesia time is up to 48 hours.
The threshold of pain after pain is administered before number of animals after the influence group dosage administration at diabetic neuralgia rat pressure pain pavilion is administered the various dose helicidum of table 5.（G) mg/kg time thresholds（g )
(hour h)
The lh 6 3.0 ± 1.1 17.0 ± 10. of Gabapentin 60
The 2h 84 ± 0 11.3 ± 9.4 of helicidum 6.25
12.5 2h, 8 11.5 ± 9.2 25.0 8 3.3 ± 1.0 11.0 ± 2.6 50.0 2h of 2h 8 3.8,1.3 20.4 ± 8.0' of soil
* <0.05, **P<0.01 , * P<0.001, compared with pressure pain threshold before administration.
Shadow of the different time to the diabetic neuralgia rat pressure threshold of pain after the administration of the helicidum of table 6.
50mg/kg 25mg/kg
Time（Hour）
n=8 n=6-8
Native 1.3 3.3 soil 1.0 of administration preceding 3.8
2h soil ^ ※ ※ ※
3h 21.3 ± 6.7™
24h 17.1 i S.l85 8^' 20.3 ± 9.8· ^^
48h 16.5 ± 8.5-χ ·χ18.3 soil 11.9
The soil 3.2 of 7.3 soil 1.2 (n=3) of 72h 6.3
* <0.05, **Ρ<001,4"Ρ<0.001, compared with pressure pain threshold before administration.Thus illustrate, the compounds of this invention：- Ο-β-D- A Luo pyranosides, i.e. helicidum are taken advantage of to benzene first, with obvious antinociception, can be used for treating neuropathic pain disease.
The helicidum compound of the present invention can be prepared into the medicine of the various formulations for treating neuropathic pain disease.The medicine antinociception time is long, and dosage is low, and toxicity is low, suitable for long-term taking, overcomes the larger shortcoming of the adverse reactions such as antidepressant, local anesthetic, there is preferable new drug development prospect.Bibliography
1. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107
2. LiLi X,et al Animal and cellular models of chronic pain. Advanced Prng Delivery Rev, 2003;55:949-965],
3. Yang Hong chrysanthemums etc., the comparison in difference of neuropathic pain animal model, Chinese Clinical rehabilitation, 2003,31： 4272-4273
4. Ardid O, et al. Antinociceptive effects of acute and chronic injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats. Pain, 1992;49:279-287
5. Xia WH, et al. Gabapentin has an antinociceptive effect
mediated via a spinal side of action in a rat model of painful peripheral neuropathy. Analgesia, 1996;2:267-273
6. Lesley JS, Andre S et al. Coninnal systemic infusion of lidocaine provides analgesia in an animal model of neuropathic pain. Pain, 2002,97:267-273]
7. Yang Hong-Ju, et al. Effect of gabapentin derivates on mechanical allodynia-like behaviour in a rat model of chronic sciatic constriction injury Bioorganic & Medicinal Chemistry Letters 14 (2004) 2537 2541
8. Malcangio. Marzia.Tomiinson. David R. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain Volume: 76, Issue: 1-2, May, 1998, pp. 151-157
9. Kara dag. Hakan C:.Ulugol. Ahmet; Tamer. Melek: Ipci. Yesim: Dokmeci. Is met .Systemic agmatine attenuates tactile allodynia in two experimental neuropathic pain models in rats Neuroscience Letters ,VoIume: 339, Issue: 1, March 13, 2003, pp. 88-90
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Claims (11)
- Claim1. the purposes to benzaldehyde -0- β-D- A Luo pyranoside compound or pharmaceutically acceptable salt thereof esters or solvate in preparing for treating the medicine of neuropathic pain of following formula：
2. the purposes of claim 1, wherein the neuropathic pain be by wound, operation, inflammation or other diseases bow 1 Shen through the chronic ache caused by damage or lesion.3. the purposes of claim 2, wherein the neuropathic pain, which is selected from phantom limb pain after postherpetic neuralgia, Trigeminal Neuralgia, sciatica, metabolic impairment nerve source property pain, headstroke after pain syndrome, amputation, intercostal neuralgia, central pain, phantom limb pain, stump pain, sympathetic nerve associated pain, complicated regional pain syndrome, spine disorderses compressing spinal cord or lumbago, maincenter and chronic ache caused by the wound of periphery caused by nerve root and stubbornness 4, gives birth to pain caused by cancer.4. the purposes of claim 3, wherein the neuropathic pain is sciatica.5. the purposes of claim 4, wherein the sciatica is sciatic nerve chronic constriction neuropathic pain.6. the purposes of claim 3, wherein the neuropathic pain is metabolic impairment nerve source property pain.7. the purposes of claim 6, wherein the metabolic impairment nerve source property pain is diabetic keratopathy ^ dysmenorrhoea.8. the combination to benzaldehyde -0- β-D- A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate and the anti-neuropathic pain medicine of fast-acting type for treating neuropathic pain.9. claim 8 ^ is combined, wherein the anti-neuropathic pain medicine of the fast-acting type is Gabapentin.10. the pharmaceutical composition for treating neuropathic pain, wherein including benzene Yue aldehyde- D- A Luo pyranosides compound or pharmaceutically acceptable salt thereof, ester or solvate and the anti-neuropathic pain medicine of fast-acting type, instead optionally to include pharmaceutically acceptable excipient, carrier or adjuvant.11. the pharmaceutical composition of claim 10, wherein the anti-neuropathic pain medicine of the fast-acting type is Gabapentin.
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| CN100413877C (en) * | 2006-11-17 | 2008-08-27 | 中国科学院昆明植物研究所 | Helicid modifier and its preparation method and uses |
| CN101029065B (en) * | 2007-04-11 | 2010-05-19 | 昆明贝克诺顿制药有限公司 | Bean-curd pectin analogue and its use in medicine for preventing depression |
| CN101837000B (en) * | 2010-03-16 | 2011-11-09 | 云南大学 | Application of 2-fluroin-beta-D-glycoside in treating neuropathic pain |
| CN101933932B (en) * | 2010-03-16 | 2012-05-23 | 云南大学 | Application of 4-cyan-beta-D-glucoside in treating chronic neurogenic pain |
| CN101829132B (en) * | 2010-05-18 | 2012-05-23 | 云南大学 | Application of 7-O-beta-D-acetylation sugar-coumarin compounds in treating chronic neuropathic pains |
| CN101829126B (en) * | 2010-05-18 | 2012-05-23 | 云南大学 | Application of 3-carbethoxy phenyl-beta-D-glucoside in treating chronic neuropathic pains |
| CN101829128B (en) * | 2010-05-18 | 2012-05-23 | 云南大学 | Application of 4-formylphenyl-beta-D-glucoside compounds in treating chronic neuropathic pains |
| CN102716295B (en) * | 2012-06-28 | 2013-12-04 | 陈慧婷 | White paeony root Chinese medicinal preparation for treating hypochondriac pain and preparation method thereof |
| CN104069067B (en) * | 2013-03-29 | 2017-03-08 | 昆药集团股份有限公司 | A kind of helicidum dry suspensoid agent of preventing and treating ischemic angiocardiopathy and cerebrovascular disease and preparation method and application |
| CN104069062B (en) * | 2013-03-29 | 2017-01-25 | 昆药集团股份有限公司 | Hilicidum injection for preventing and treating ischemic cardiovascular and cerebrovascular diseases as well as preparation method and application thereof |
| WO2014205654A1 (en) * | 2013-06-25 | 2014-12-31 | 昆明贝克诺顿制药有限公司 | Compound pharmaceutical compositions for treating pain |
| CN105541936A (en) * | 2016-01-21 | 2016-05-04 | 昆明贝克诺顿制药有限公司 | 4-carboxyphenyl-beta-D-allosupranoside and application thereof to preparation of chronic neuropathic pain-resisting drug |
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