CN101933925A - Huperzine A with abirritation and derivatives thereof - Google Patents
Huperzine A with abirritation and derivatives thereof Download PDFInfo
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Abstract
The invention relates to a method for treating pain, functional pain syndrome or organic pain syndrome. The method is characterized in that a compound shown in the formula (I) or salts thereof are applied to relieving or treating the pain, the functional pain syndrome or the organic pain syndrome of mammalian, wherein R expresses NR1R2, NHC(O)OR3 and N=CR4R5; R1 expresses H and C1-6 alkyl, R2 expresses H and C1-6 alkyl, R3 expresses C1-6 alkyl, heterocyclic and aryl, R4 expresses H, C1-6 alkyl, heterocyclic and aryl, and R5 expresses H, C1-6 alkyl, heterocyclic and aryl.
Description
The application's dividing an application that be the denomination of invention submitted on August 1st, 2005 for No. 200510014685.6 Chinese invention patent application of " huperzine A and derivant thereof " with analgesic activity.
Invention field:
The present invention relates to huperzine A and derivant thereof, and they are as the application of analgesic active ingredient.
Background of invention:
Pain, comprise pain that pain, tissue or organ injury that nerve compression that cancer patient cancerous tissue expansion causes or infringement cause cause, the various because pain that autoimmune response causes such as inflammation (arthritis, gastritis, hepatitis), pain, the especially migraine that various nervus centralis (cerebral tissue) causes unusually.Clinically, inclined to one side side of pulsation or bilatenal headache that migraine shows as outbreak repeatedly showed effect sustainable 4-72 hour at every turn, usually with symptoms such as nauseating, vomiting, photophobias.Some patient the special premonitory symptom of ten or twenty minute can occur continuing at premorbid, as vision symptom such as blind spot, flash of light and numbness, dizziness etc.With the quickening pace of modern life with the increase of operating pressure, migraine has presented the situation of continuous rising at the sickness rate of China, has become puzzlement modern's commonly encountered diseases.According to incompletely statistics, the migrainous prevalence of China adult reaches 3%-5%, and wherein female patient manys 3-4 doubly than the male patient, and most onset is in adolescence.In developed country, migrainous sickness rate is higher.The statistics of U.S.'s headache foundation (National Headache Foundation) shows that per ten philtrums of the U.S. suffer from migraine with regard to one, but patient more than half fails to check out effectively.Data from American National neurological disorders and apoplexy academy (National Institute of Neurological Disorders and Stroke) then show, the migraineur of the U.S. has reached 28,000,000, and migraine is lost 100,015,700 working days the U.S. every year.Therefore, migraine is one of common sympton in the health care, has not only influenced thousands of patient, and has brought tremendous loss to society.Thereby not only pain management is one of modal means in the symptomatic treatment, and migrainous treatment becomes the big hot fields of one in the health care.
The painful medicine in town commonly used at present mainly contains two classes, and a class is for being the opiate receptor antagonist of representative with the morphine, and this class analgesic has stronger analgesia drug effect, but has addiction; Second class is for being the non-opiate receptor antagonist of representative with the acetaminophen, this class analgesic is lead compound with aspirin, there is the analgesic of multiple analgesia mechanism in a new generation that succeeds in developing through modern drug design, screening and development process, the analgesic effect of this class analgesic a little less than, but generally do not form dependency, thereby, although the some of them chemical compound can cause the digestive tract infringement, but use extremely extensively, formed nearly 10,000,000,000 dollars market.
Recent two decades comes, the promoter of novel 5-hydroxy tryptamine (being called for short 5-HT)-absorption antagonist or 5-HT receptor is proved to be has definite curative effect to migraine, simultaneously, at the neuroreceptor mediator is that the analgesic of target has been researched and developed the focus neck city into new drug development, but most target tightening is on 5-HT receptor and dopamine (Dopamine) receptor, especially recently find for over ten years that 5-HT receptor and dopamine receptor also can be subdivided into a plurality of hypotypes, and the analgesic effect that both can keep or improve medicine during the wherein specific hypotype of antagonism, also can reduce or avoid after the toxic and side effects fully, these targets attract numerous attention, and each big or small drugmaker drops into lot of manpower and material resources research one after another.
But acetylcholine, this found the earliest neurotransmitter, and corresponding acetylcholinergic receptor and acetylcholinesterase are as the rare report of research of the exploitation target of analgesic.EP-A413667 and US Pat.No.5,010,083 has respectively disclosed a compounds, and these can be used for treating the loss of memory and alleviating pain, and prompting improves memory has certain related with analgesia, thereby the raising of announcement levels of acetylcholine may be able to be eased pain.
In addition, Stoyan reported once that alkaloid Nivalin and Syntostigmine can alleviate migraine [Stoyan Iv Ikonomoff, Archives Suisses de Neurologie, Neurochirurgie et de Psychiatrie, Vol.102, Fascicule, page299-312 (1968)].But found the activity of these two chemical compound acetylcholine esterase inhibitions afterwards.May since they to press down enzymatic activity not high enough, or since they to see through the ability of blood brain barrier not high enough, these two chemical compounds, and proof subsequently other acetylcholinesteraseinhibitors inhibitors need higher dosage competence exertion go out curative effect.In this case, have only injection just can reach to the blood drug level that can obviously alleviate the migraine drug effect.Like this, on the one hand, so high blood drug level causes a lot of toxic and side effects, and on the other hand, drug administration by injection is extremely inconvenient, thereby, acetylcholinesteraseinhibitors inhibitors is used for the treatment of migrainous research has been abandoned.This is to propose for the first time acetylcholinesteraseinhibitors inhibitors is used for the treatment of these new approaches of migraine.
The breakthrough in this field comes from the breakthrough in the research and development of nearest acetylcholinesteraseinhibitors inhibitors of new generation.With this acetylcholinesteraseinhibitors inhibitors of many naphthalenes piperazine Qi Wei representative in generation have active high, suppress the selectivity height, more easily see through characteristics such as blood brain barrier at the maincenter acetylcholinesterase, should overcome above-mentioned first generation acetylcholinesteraseinhibitors inhibitors comprehensively and be used for the treatment of shortcoming on the migraine.True like this really, many naphthalenes piperazine is observed together clinically to migraine effective in cure (US Pat.No.6608088).
Huperzine A has selective inhibitory to acetylcholinesterase (ACHE), easily by blood, cerebrospinal fluid barrier.Has the effect that promotes that memory represents and hypermnesis keep.But do not see that the bibliographical information huperzine A can be used for pain control, especially migrainous treatment.
In sum, can promote that acetylcholine is a kind of reliably new pharmacological mechanism in analgesic as the ways and means of neurotransmitter function, thereby, active high, to the maincenter acetylcholinesterase suppress the selectivity height, the acetylcholinesteraseinhibitors inhibitors of new generation that easily sees through blood brain barrier, long action time, taking convenience will control to pain, especially migrainous treatment is brought again once and breaks through.We find that huperzine A and derivant thereof have the analgesia drug effect than the naphthalene of manying piperazine Qi Genggao by zoopery, in addition, we find that in clinical research oral huperzine A can alleviate, treat migraine, but and find the outbreak that long-term low dose is taken the huperzine A prevention of migraine.
Summary of the invention:
Correspondingly, the present invention relates to a kind of treatment pain, functional pain syndrome or organ pain syndrome method is characterized by the compound or its salt shown in the application formula (I), and R represents NR
1R
2, NHC (O) OR
3, N=CR
4R
5
R
1Expression H, C
1-6Alkyl; R
2Expression H, C
1-6Alkyl; R
3Expression C
1-6Alkyl, heterocyclic radical, aromatic radical;
R
4Expression H, C
1-6Alkyl, heterocyclic radical, aromatic radical; R
5Expression H, C
1-6Alkyl, heterocyclic radical, aromatic radical
Or R represents N=CR
4R
5With=CR
4R
5Representative ring fork base,
Come the pain of releasing mammal, functional pain syndrome, organ pain syndrome.
R
1, R
2, R
3, R
4, R
5Expression C
1-6Can be straight-chain alkyl, branched hydrocarbyl or loop chain alkyl during alkyl, can be saturated or undersaturated alkyl, and can be by replacements such as one or more fluorine, hydroxyl, alkoxyl, ester group, amido, amide groups, carboxyls.
R
1, R
2, R
3, R
4, R
5Expression during heterocyclic radical can be five, six, seven, octatomic ring, can be saturated or undersaturated ring, can contain one or more O, N, S atom, and can be by replacements such as one or more fluorine, hydroxyl, alkoxyl, ester group, amido, amide groups, carboxyls.
R
1, R
2, R
3, R
4, R
5During the expression aromatic radical can be five yuan or hexatomic ring, can be one or two ring, can contain one or more O, N, S atom, and can be by replacements such as one or more fluorine, hydroxyl, alkoxyl, ester group, amido, amide groups, carboxyls.
R represents N=CR
4R
5The time can be the mixture of E body, Z body or E body and Z body.
The chemical compound that is suitable as the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome shown in the formula (I) in the chemical compound is that R represents NR
1R
2, R wherein
1, R
2Be expressed as those chemical compounds of hydrogen, methyl, ethyl, propyl group, isopropyl or butyl respectively; The chemical compound that relatively is suitable as the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome is that R represents NR
1R
2, R wherein
1, R
2Be expressed as those chemical compounds of hydrogen, methyl, ethyl respectively; The chemical compound that is suitable as most the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome is that R represents NR
1R
2, R wherein
1, R
2Be expressed as those chemical compounds of hydrogen, methyl respectively.
The chemical compound that is suitable as the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome shown in the formula (I) in the chemical compound is that R represents NHC (O) OR
3, R wherein
3Be expressed as methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, tertiary butyl, new butyl, the 1-amyl group, the 1-methyl butyl, the 2-methyl butyl, the 3-methyl butyl, 1, the 1-dimethyl propyl, 2, the 2-dimethyl propyl, 1, the 2-dimethyl propyl, cyclopenta, cyclohexyl, hexyl, phenyl, the 2-Cl phenyl, the 3-Cl phenyl, the 4-Cl phenyl, the 2-OH phenyl, the 3-OH phenyl, the 4-OH phenyl, the 2-aminophenyl, the 3-aminophenyl, the 4-aminophenyl, 2-methylamino phenyl, 3-methylamino phenyl, 4-methylamino phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, the 2-methoxyphenyl, the 3-methoxyphenyl, the 4-methoxyphenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, the 2-pyridine radicals, the 3-pyridine radicals, those chemical compounds of 4-pyridine radicals; The chemical compound that is suitable as most the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome is that R represents N=CR
4R
5, R wherein
4, R
5Those chemical compounds of representing hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, cyclohexyl, phenyl, 3-OH-4-methoxyphenyl, 3-hydroxy phenyl, 4-methoxyphenyl, 3-fluorophenyl, 4-pyridine radicals respectively.
What the present invention relates to is used for the treatment of pain, chemical compound and various pharmaceutically acceptable inorganic acid salt or acylate shown in the formula (I) of functional pain syndrome or organ pain, and the suitable dosage that it is characterized by described chemical compound is the 0.001-500 milligram; Relatively the dosage of Shi Heing is the 0.01-100 milligram; Optimal dosage is the 0.05-50 milligram.
Except having at least shown in a kind of formula (I) the chemical compound, also can contain carrier mass, filler, solvent, diluent, coloring agent, adhesive in the medicine that the present invention relates to.The selection of these adjuvant materials and consumption thereof depend on medicine be by gastrointestinal tract, suck, in the vein, abdominal cavity, intradermal, intramuscular injection, nasal cavity, ophthalmic, suction, anus, intravaginal, percutaneous absorb or other administering mode administrations.
The medicine that the present invention relates to can be prepared into slow releasing preparation and use.
The medicine that the present invention relates to also can be made compound recipe with other suitable active constituents of medicine and use.
Pain of the present invention comprises the discomfort that all have pain, functional pain syndrome or organ pain, it is characterized by described pain, functional pain syndrome and organic property pain syndrome include but not limited to nervous headache, especially migraine (migraine), fibrillar muscle pain (primary fibromyalgia), because the pain (amputation) that rupture causes, the pain (tumoral denervation) that the neural injury of tumor causes, pain (traumatic denervation) that the nerve injury that injury causes causes or the pain that causes by autoimmune mechanism (autoimmune mechanism) pathological changes.
Specific embodiments:
Embodiment 1
(5R, 9R, 11E)-and 5-amino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone (huperzine A) also.Grind those chemical compounds of 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, benzyl available from Military Medical Science Institute's drugs and toxicants; The chemical compound that relatively is suitable as the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome is that R represents NHC (O) OR
3, R wherein
3Be expressed as those chemical compounds of methyl, ethyl, propyl group, isopropyl, normal-butyl, tertiary butyl, phenyl, 2-Cl phenyl, 3-Cl phenyl, 4-Cl phenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, benzyl; The chemical compound that is suitable as most the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome is that R represents NHC (O) OR
3, R wherein
3Be expressed as those chemical compounds of ethyl, propyl group, isopropyl, normal-butyl, tertiary butyl, phenyl, benzyl.
The chemical compound that is suitable as treatment pain, functional pain syndrome or organ pain syndrome shown in the formula (I) in the chemical compound is that R represents N=CR
4R
5, R wherein
4, R
5Be expressed as hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, tertiary butyl, new butyl, 1-amyl group, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 1 respectively, 1-dimethyl propyl, 2,2-dimethyl propyl, 1,2-dimethyl propyl, cyclopenta, cyclohexyl, hexyl, phenyl, 2-Cl phenyl, 3-Cl phenyl, 4-Cl phenyl, 2-OH phenyl, 3-OH phenyl, 4-OH phenyl, 3,4-dihydroxy phenyl, 3-OH-4-C
1-5Oxyl phenyl, 3-C
1-5Oxyl-4-C
1-5The oxyl phenyl, the 2-aminophenyl, the 3-aminophenyl, the 4-aminophenyl, 2-methylamino phenyl, 3-methylamino phenyl, 4-methylamino phenyl, the 2-dimethylaminophenyl, the 3-dimethylaminophenyl, the 4-dimethylaminophenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, the 2-methoxyphenyl, the 3-methoxyphenyl, the 4-methoxyphenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, the 2-thiophene phenyl, the 3-thiophene phenyl, the 2-furyl, the 3-furyl, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, those chemical compounds of benzyl; The chemical compound that relatively is suitable as the active constituents of medicine of treatment pain, functional pain syndrome or organ pain syndrome is that R represents N=CR
4R
5, R wherein
4, R
5Represent hydrogen, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, tertiary butyl, new butyl, cyclopenta, cyclohexyl, hexyl, phenyl, 2-Cl phenyl, 3-Cl phenyl, 4-Cl phenyl, 2-OH phenyl, 3-OH phenyl, 4-OH phenyl, 3 respectively, 4-dihydroxy phenyl, 3-OH-4-methoxyphenyl, 3-methoxyl group-4-methoxyphenyl, 2-aminomethyl phenyl, study carefully institute.
Embodiment 2
(5R, 9R, 11E)-and 5-methylamino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
10 milligrams of huperzine As, 37% formalin 0.5mL, back flow reaction is 1 hour in the 2mL isopropyl alcohol, revolves to boil off solvent, adds anhydrous THF 5mL, NaBH (OOCCH
3) 0.15g, stirring reaction 4 hours is crossed the elimination solid, uses preparation TLC purification (chloroform: methanol=9: 1), get 6 milligrams behind the concentrated filtrate.MS：257(M+1)。
Embodiment 3
(5R, 9R, 11E)-and 5-dimethylamino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
With the method for embodiment 2, by (5R, 9R, 11E)-and 5-methylamino-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering also [b] pyridine-2 (1H) ketone replaces the huperzine A preparation and gets.MS：271(M+1)。
Embodiment 4
(5R, 9R, 11E)-and 5-ethylamino--11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
With the method for embodiment 2, replace prepared formaldehyde and get by acetaldehyde.MS：271(M+1)。
Embodiment 5
(5R, 9R, 11E)-and 5-butylamine base-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
With the method for embodiment 2, replace prepared formaldehyde and get by butyraldehyde.MS：299(M+1)。
Embodiment 6
(5R, 9R, 11E)-and 5-(ethoxy carbonyl amino)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
10 milligrams of huperzine As, triethylamine is dissolved in anhydrous THF 5mL and is cooled to 0 ℃ for 5 milligrams, adds ethyl chloroformate (5 milligrams), and stirring reaction 4 hours is crossed the elimination solid, uses preparation TLC purification (chloroform: methanol=9: 1), get 8 milligrams behind the concentrated filtrate.MS：315(M+1)。
Embodiment 7
(5R, 9R, 11E)-and 5-(2-methyl propoxyl group carbonylamino)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 6 replaces ethyl chloroformate to make by isobutyl chlorocarbonate.
Embodiment 8
(5R, 9R, 11E)-and 5-(tert-butoxy carbonylamino)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 6 replaces ethyl chloroformate to make by the special butyl ester of chloro-carbonic acid.
Embodiment 9
(5R, 9R, 11E)-and 5-(benzyloxy carbonylamino)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 6 replaces ethyl chloroformate to make by the chloro-carbonic acid benzene methyl.
Embodiment 10
(5R, 9R, 11E)-and 5-(4-hydroxy 3-methoxybenzene methene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
10 milligrams of huperzine As, 8 milligrams of vanillin, back flow reaction is 3 hours in the 5mL isopropyl alcohol, revolves to boil off solvent, gets 16 milligrams of products.MS：377(M+1)。
Embodiment 11
(5R, 9R, 11E)-and 5-(3-hydroxyl-4-methoxybenzene methene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by isovanillin.MS：377(M+1)。
Embodiment 12
(5R, 9R, 11E)-and 5-benzene methene amido-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by benzaldehyde.MS：331(M+1)。
Embodiment 13
(5R, 9R, 11E)-and 5-(4-pyrrole heavy stone used as an anchor methene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by the 4-pyridine carboxaldehyde.MS：332(M+1)。
Embodiment 14
(5R, 9R, 11E)-and 5-(cyclohexylidene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by Ketohexamethylene.MS：323(M+1)。
Embodiment 15
(5R, 9R, 11E)-5-[4-(1-methyl piperidine) pitches amido]-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by 1-methyl piperidine-4-ketone.MS：338(M+1)。
Embodiment 16
(5R, 9R, 11E)-and 5-(cyclohexyl methene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by hexahydrobenzaldehyde.
Embodiment 17
(5R, 9R, 11E)-and 5-(2-fourth fork amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by butanone.
Embodiment 18
(5R, 9R, 11E)-and 5-(1-fourth fork amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by butyraldehyde.
Embodiment 19
(5R, 9R, 11E)-and 5-(4-methoxybenzene methene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by the 4-methoxybenzaldehyde.MS：361(M+1)。
Embodiment 20
(5R, 9R, 11E)-and 5-(3-hydroxy benzenes methene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by the 3-hydroxy benzaldehyde.MS：347(M+1)。
Embodiment 21
(5R, 9R, 11E)-and 5-(3-fluorobenzene methene amido)-11-ethidine-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring suffering is [b] pyridine-2 (1H) ketone also
Method with embodiment 10 replaces vanillin to make by the 3-fluorobenzaldehyde.MS：349(M+1)。
Hot plate method is measured the analgesic activity of gastric infusion to mice
1, test material
1.1 experimental animal
Kunming kind white mice, secondary, female, body weight 20 ± 2g purchases in the department of the Chinese Academy of Sciences of Department Of Medicine, Peking University's laboratory animal section the animal credit number: SCXK capital 2002-0001.
1.2 trial drug
1.2.1 synthetic sample is mixed with medicinal liquid for the mouse stomach administrable with normal saline respectively with sample during test.
1.2.2 AP-237: the 30mg/ sheet, Lik-Sang pharmaceutical factory in Tianjin produces, lot number: 0201001, the medicinal liquid that is mixed with 1.5mg/ml with normal saline is used for mouse stomach.
2, test method
The mice hot plate method is adopted in test, and water bath with thermostatic control is adjusted to 55 ± 0.5 ℃, the bottom contact water surface of metal dish, and the heating back is as stimulating.From dropping into hot plate to the pain threshold of the time that metapedes occurs licking (s) as this Mus, test the female mice with 20 ± 2 gram body weight with stopwatch record mice, measure the threshold of pain secondary of every mice before the administration earlier, it is qualified being no more than 30s person with meansigma methods.With qualified mice random packet, 10 every group, test.Survey respectively earlier and organize respectively that pain threshold is the basic threshold of pain before the administration, the administration group is irritated the medicine that stomach gives various dose respectively, and matched group gives normal saline, and administration volume 0.2ml/10g body weight is measured the pain threshold of every treated animal different time respectively after the administration, the results are shown in Table 1.Test data is organized a t test statistics with SPSS10.. statistics software and is handled.
Table 1 test-compound to the influence of the mice hot plate threshold of pain (x ± s, n=10)
Annotate: compare p＜0.05 with matched group
*P＜0.01
*P＜0.001
* *
Oral huperzine A sheet treatment migraine
Medicament: Huperzine A-Zhulin Antun (Henan bamboo grove all living creatures pharmaceutical factory produces for huperzine A sheet, 50 micrograms/sheet).
Case one:
Guo xx, the woman, 38 years old, suffered from the migraine medical history 5 years, during sick sending out with feeling sick, the time vomiting arranged.Heavily take " Bufferin Plus " treatment, feel that closely this type of analgesic effect weakens.During sick sending out, oral at every turn " Huperzine A-Zhulin Antun " two.Readme was taken medicine back 20 minutes in, and the headache complete obiteration has only and feels side effect.One month on probation, totally 8 times, good efficacy is arranged all.
Case two:
Open xx, the woman, 41 years old, suffered from the migraine medical history 2 years, reused the treatment of Ergota amine medicine, sufferer feels that such effect of drugs is poor.During sick sending out, oral at every turn " Huperzine A-Zhulin Antun " two, headache disappeared in half an hour after readme was taken medicine, and bad sensation is not arranged.Used one month, and totally ten times, good efficacy was arranged all.
Oral huperzine A sheet prevention of migraine
Case three:
Clock xx, the woman 41 years old, suffered from the migraine medical history 3 years, readme morbidity in every month 8-12 time.Give orally with Huperzine A-Zhulin Antun, every day, a slice did not have outbreak in one month.
Claims (10)
1. the compound or its salt shown in the formula (I), hydrate and the various crystal formation purposes in the medicine of preparation treatment pain,
Wherein
R represents NR
1R
2, NHC (O) OR
3Or N=CR
4R
5
R
1Expression H or C
1-6Alkyl;
R
2Expression H or C
1-6Alkyl, and R
1During expression H, R
2Be not H simultaneously;
R
3Expression C
1-6Alkyl, heterocyclic radical or aromatic radical;
R
4Expression H, C
1-6Alkyl, heterocyclic radical or aromatic radical;
R
5Expression H, C
1-6Alkyl, heterocyclic radical or aromatic radical;
Or R represents N=CR
4R
5With=CR
4R
5Representative ring fork base.
2. the described purposes of claim 1, wherein said pain is functional pain syndrome or organ pain syndrome.
3. the described purposes of claim 2, wherein said pain is nervous headache, is preferably migraine.
4. the described purposes of arbitrary claim in the claim 1 to 3, wherein R represents NR
1R
2The time, R
1And R
2Represent H or C respectively
1-3Alkyl, and R
1During expression H, R
2Be not H simultaneously.
5. the described purposes of claim 4, wherein R represents NR
1R
2The time, R
1And R
2Represent H, methyl or ethyl respectively, and R
1During expression H, R
2Be not H simultaneously.
6. the described purposes of arbitrary claim in the claim 1 to 3, wherein R represents NHC (O) OR
3The time, R
3Expression methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, tertiary butyl or benzyl.
7. the described purposes of arbitrary claim in the claim 1 to 3, wherein R represents N=CR
4R
5The time ,=CR
4R
5Representative ring fourth fork base, cyclopentylidene base, cyclohexylidene base or 1-methyl piperidine-4-pitch base.
8. the described purposes of arbitrary claim in the claim 1 to 3, wherein R represents N=CR
4R
5The time, R
4And R
5Represent H, C respectively
1-3The phenyl of alkyl, phenyl or replacement, 2-pyrrolinyl, 3-pyridine radicals, 4-pyridine radicals or cyclohexyl.
9. the described purposes of arbitrary claim in the claim 1 to 3, the using dosage of chemical compound in described medicine shown in the wherein said formula (I) are 10 micrograms-100 milligram.
10. the described purposes of arbitrary claim in the claim 1 to 3, wherein said medicine by gastrointestinal tract, suck, in the vein, abdominal cavity, intradermal, intramuscular injection, nasal cavity, ophthalmic, suction, anus, vagina or the administration of epidermis administering mode.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010274197XA CN101933925A (en) | 2005-08-01 | 2005-08-01 | Huperzine A with abirritation and derivatives thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010274197XA CN101933925A (en) | 2005-08-01 | 2005-08-01 | Huperzine A with abirritation and derivatives thereof |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005100146856A Division CN1907974B (en) | 2005-08-01 | 2005-08-01 | Huperzine with analgesic function and derivative thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101933925A true CN101933925A (en) | 2011-01-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010274197XA Pending CN101933925A (en) | 2005-08-01 | 2005-08-01 | Huperzine A with abirritation and derivatives thereof |
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| Country | Link |
|---|---|
| CN (1) | CN101933925A (en) |
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2005
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Application publication date: 20110105 |