CN100378064C - Active metabolic product of phencynonate and its medicinal use - Google Patents
Active metabolic product of phencynonate and its medicinal use Download PDFInfo
- Publication number
- CN100378064C CN100378064C CNB2004100295964A CN200410029596A CN100378064C CN 100378064 C CN100378064 C CN 100378064C CN B2004100295964 A CNB2004100295964 A CN B2004100295964A CN 200410029596 A CN200410029596 A CN 200410029596A CN 100378064 C CN100378064 C CN 100378064C
- Authority
- CN
- China
- Prior art keywords
- benzene ring
- acceptable salt
- ring pelargonate
- pharmacy acceptable
- demethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- AUKYHFFECJXLHI-HCMPJQJDSA-N [(1s,5r)-3-methyl-3-azabicyclo[3.3.1]nonan-9-yl] 2-cyclopentyl-2-hydroxy-2-phenylacetate;hydrochloride Chemical compound Cl.C1([C@@H]2CCC[C@H]1CN(C2)C)OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 AUKYHFFECJXLHI-HCMPJQJDSA-N 0.000 title description 16
- 230000002503 metabolic effect Effects 0.000 title 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 20
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- FBUKVWPVBMHYJY-UHFFFAOYSA-M nonanoate Chemical compound CCCCCCCCC([O-])=O FBUKVWPVBMHYJY-UHFFFAOYSA-M 0.000 claims description 46
- -1 α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl Chemical group 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 14
- 208000012886 Vertigo Diseases 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000000812 cholinergic antagonist Substances 0.000 claims description 6
- 231100000889 vertigo Toxicity 0.000 claims description 6
- CEUXIAUEIGSQSZ-UHFFFAOYSA-N 2-cyclopentylacetaldehyde Chemical compound O=CCC1CCCC1 CEUXIAUEIGSQSZ-UHFFFAOYSA-N 0.000 claims description 4
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- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
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- 239000011777 magnesium Substances 0.000 claims description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 2
- 238000005809 transesterification reaction Methods 0.000 claims description 2
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 claims 5
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- 241001676635 Lepidorhombus whiffiagonis Species 0.000 abstract 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to N-demethyl benzene ring pelargonic ester as the active metabolite of benzene ring pelargonic ester, or pharmaceutically acceptable salt thereof, a preparation method thereof and applications thereof in preparing medicines for preventing and treating various kinds of megrim caused by motion sickness of car sickness, seasickness, etc. and the paroxysm of meniere's diseases, etc. The active metabolite or the pharmaceutically acceptable salt thereof can also be used for treating or relieving parkinson diseases or parkinsonism, and can reduce or avoid the side effect of the benzene ring pelargonic ester.
Description
Technical field:
The present invention relates to the active metabolism product of benzene ring pelargonate and pharmacy acceptable salt thereof, its preparation method with and be used to prepare the purposes of the medicine that prevents and/or treats illnesss such as vertigo.
Background technology
Formula (I) phencynonate hydrocloride (systematic naming method is 2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride) be a kind of selectivity anticholinergic agent, clinically be used for various motion sicknesses such as control is carsick, seasick.CN1089838A and US6028198 disclose the purposes of phencynonate hydrocloride as anti-kinetosis (carsickness, ship, machine etc.) medicine; CN97125424.9, GB2297255 and ES549796A disclose the preparation method of phencynonate hydrocloride.WO02067933 discloses phencynonate hydrocloride treatment Parkinson's disease/syndromic purposes and treatment thereof or has alleviated the purposes of vertigo acute attacks such as Meniere and positional vertigo.
Symptoms such as motion sickness syndrome is meant dizziness that people occur when taking the various vehicles, feels sick, pale complexion, cold sweat, vomiting.At present the primary pathogeny of generally acknowledging is that human body vestibular cholinergic system is overexcited because of irriate in the environment of motion, produces a series of maincenters and the periphery cholinergic function is hyperfunction.The clinical efficacy of various motion sicknesses such as phencynonate hydrocloride control is carsick, seasick is comparatively sure, and effect is better than Scopolamine, but also has some untoward reactions in clinical application, as drowsy, dry etc.Wherein grace is slept and have potential threat for being engaged in some Industry Personnel such as officer.
By Meniere acute attack or caused vertigo of vertebro-basilar artery insufficiency and positional vertigo etc. is that vestibular organ is subjected to intense stimulus and a kind of disease of causing, often with have a dizzy spell, nausea and vomiting, can not open eyes, can not sitting etc. syndrome be feature, be the common disease of Otorhinolaryngologic Department and Neurology Department.It can be by due to ear's illness (peripheral vertigo) and the brain disorder multiple diseases such as (central vertigos).Anticholinergic agent such as Scopolamine are common drug, but efficient not high, and have side effect.Clinical study is the result show, the total effective rate of the acute dizzy and positional vertigo that the acute attack of phencynonate hydrocloride treatment Meniere is produced is up to 94.0%, and the total effective rate of diphenidol has only 67.9%.
Parkinson's disease are many to be taken place in the elderly, and its pathogeny is also not fully aware of, but evidence suggests black substance, striatal dopamine neuron degeneration in patient's brain, causes dopaminergic system hypofunction in the brain, the cholinergic system hyperfunction.It mainly show as the disorderly symptoms of a series of centrum external systems as tremble, stiff, motion can not, attitudinal reflex disappears or the like.In case be the lifelong participation disease.In recent years, increasing neurosurgeon with the maincenter anticholinergic drug as the early stage choice drug of morbidity, can postpone the time that begins to take the Dopaminergics medicine like this, reduce the Dopaminergics dosage, thereby lower greatly and postpone the insufferable side effect that is produced when the Dopaminergics medicine is taken for a long time.
With the Parkinson's disease identical a series of centrum external system disorders of parkinson's syndrome for cause dopamine system hypofunction in the brain, cholinergic system hyperfunction to occur by medicine, environmental factors or other neuropathy.If can eliminate the cause of disease, can cure.Drug-induced parkinson's syndrome, for example phenothiazines (as chlorpromazine), thioxanthene class (as tardan) or the butyrophenones (as haloperidol) etc. taken of schizophrenia patient.For their side effect is controlled in the therapeutic action that keeps these medicines simultaneously, unique adoptable be the maincenter anticholinergic drug.These medicines are identical with antiparkinsonism drug, mainly are Trihexyphenidyl, benztropine and kemadrin.When taking antipsychotic drug and the extrapyramidal system side effect occurs, add them with the control side effect.
The compound of seeking biologically active from metabolite is the important channel of finding new drug.As the product of bio-transformation, metabolite has the predictability or the controllability of pharmacokinetic property, and individual difference is little, drug interaction is few (need further metabolism), and onset faster (itself is activity form), effect is stronger or side effect is littler.For example active metabolite fexofenadine (fexofenadine) and the decarboxylation loratadine (Desloratadine) as terfenadine and Loratadine has stronger anti-allergic effects respectively, and side effect still less.
Summary of the invention
The inventor discovers that now benzene ring pelargonate has following several meta-bolites in the rat body:
Further studies show that, meta-bolites II wherein is N-demethyl benzene ring pelargonate or is called and falls benzene ring pelargonate and have cholinolytic effect and the m receptor keying action stronger than parent drug benzene ring pelargonate, simultaneously can alleviate or avoid some side effects that benzene ring pelargonate has, thereby finish the present invention.
Therefore, one aspect of the present invention relates to formula II N-demethyl benzene ring pelargonate or its pharmacy acceptable salt:
Another aspect of the present invention relates to and contains formula II N-demethyl benzene ring pelargonate or its pharmacy acceptable salt pharmaceutical composition as activeconstituents and one or more pharmaceutical carrier or vehicle.
Another aspect of the present invention relates to the preparation method of formula II N-demethyl benzene ring pelargonate or its pharmacy acceptable salt, described method comprises according to method of the prior art, prepare intermediate α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl acetate, obtain benzene ring pelargonate through hydrolysis, esterification and transesterify again, after the denitrogenation methyl makes N-demethyl benzene ring pelargonate.
Further aspect of the present invention relates to formula II N-to be gone first benzene ring pelargonate or its pharmacy acceptable salt to be used to prepare anticholinergic agent, prevents and/or treats the purposes of the medicine of the various vertigo that carsick motion sickness, Meniere such as seasick cause, and the purposes that is used to prepare treatment or alleviates the medicine of Parkinson's disease or Parkinson.
Further, formula II N-demethyl benzene ring pelargonate of the present invention or its pharmacy acceptable salt can prepare by following synthetic route:
In said synthesis route, formula (I) benzene ring pelargonate can be with reference to the described method preparation of Chinese patent CN97125424.9.
Specifically, the preparation method of formula II N-demethyl benzene ring pelargonate of the present invention may further comprise the steps:
(a) make oxalic acid diethyl ester and cyclopentyl bromination magnesium grignard reaction, obtain the Cyclopentylacetaldehyde acetoacetic ester;
(b) product and the phenyl-magnesium-bromide grignard reaction that step (a) is obtained made intermediate α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl acetate, and hydrolysis obtains α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate;
(c) step (b) product obtains α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate through esterification, and it further obtains benzene ring pelargonate with N-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems-9 α-alcohol through transesterification reaction;
(d) make benzene ring pelargonate that step (c) obtains with 2,2,2-trichlorine methylamino ethoxy acyl chlorides (commercially available getting) denitrogenation methyl obtains N-demethyl benzene ring pelargonate;
(e) randomly, step (d) product is converted into its pharmacy acceptable salt.
Term among the present invention " pharmacy acceptable salt " is meant the salt that forms with pharmaceutically useful mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Or the salt that forms with pharmaceutically useful organic acid, for example acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc.
The compounds of this invention can be separately or with the form administration of pharmaceutical composition, and can be mixed with various suitable formulations according to route of administration.That described route of administration comprises is oral, spraying suction, nasal cavity applied medicine, cheek medication, local application, non-enterally administer (as subcutaneous, vein, intramuscular).Wherein preferred oral or intravenous administration mode.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.Randomly, also can add some sweeting agents, perfume compound or tinting material in the above oral preparations form.
When used the part, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents was suspended or was dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene are fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
It may be noted that in addition, the using dosage of The compounds of this invention and using method depend on all multifactor, comprise the severity of patient's age, body weight, sex, natural health situation, nutritional status, Time of Administration, metabolic rate, illness and diagnosis and treatment doctor's subjective judgement.Preferred using dosage is between 0.01～100mg/kg body weight/day.
Embodiment
Following embodiment will more specifically explain the present invention.Yet scope of the present invention is not limited to following embodiment.
The preparation of preparation example 1. Cyclopentylacetaldehyde acetoacetic esters (VIII)
To place in the 1L there-necked flask through exsiccant 117g (0.80mol) oxalic acid diethyl ester, anhydrous diethyl ether 120ml; the ice bath cooling; be used for dry nitrogen protection; drip the anhydrous ether solution 350ml of freshly prepd cyclopentyl bromination magnesium Grignard reagent (0.40mol); temperature of reaction is no more than 0 ℃, drips off in about 2.5 hours.Stirring at room 2 hours, drip the aqueous solution 120mL that contains 21g ammonium chloride in the cooling downhill reaction miscellany, stirring at room 20 minutes is separated the ether layer, washing, anhydrous magnesium sulfate drying filters, and reclaims solvent, the residue underpressure distillation, collect 122-124 ℃/15mmHg cut, get 37.3g colorless oil title compound (VIII), productive rate 53%.Mass spectrum m/z:170 (M
+)
The preparation of preparation example 2. α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl acetate (IX) and α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (X)
41g (0.24mol) Cyclopentylacetaldehyde acetoacetic ester (VIII), anhydrous diethyl ether 350ml are placed in the 1L flask; the ice bath cooling; protect with drying nitrogen; drip the anhydrous ether solution (300ml) of freshly prepd phenyl-magnesium-bromide Grignard reagent (0.27mol); temperature of reaction is no more than 0 ℃, drips off in about 2 hours.Stirring at room 1 hour, drip the aqueous solution 100mL that contains 20g ammonium chloride in the cooling downhill reaction miscellany, stirring at room 20 minutes, separate the ether layer, washing, anhydrous magnesium sulfate drying filters, reclaim solvent, 94-96 ℃/20 μ mHg cuts are collected in the residue underpressure distillation, get yellow oily compound (IX), mix with 400mL 5% potassium hydroxide methanol solution, 50 ℃ of stirring in water bath 4 hours remove methanol solvate under reduced pressure, add α-phenyl-α-cyclopentyl-Alpha-hydroxy potassium salt that the 150mL water dissolution generates, ether washing three times, the ice bath cooling drips the 2N hydrochloric acid soln and makes it acidifying, and the adularescent solid is separated out, filter α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (X) 25.3g, productive rate 53%.Fusing point: 144-145 ℃.
The preparation of preparation example 3. α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate (XI)
2.2g (0.01mol) α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate is dissolved in the 20mL ether, imports diazomethane to solution and be light yellow.The evaporate to dryness ether.The resistates underpressure distillation, the cut of 85-87 ℃/35mmHg of collection gets colorless oil title compound α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate (XI) 2.1g, yield 89.6%.
Preparation example 4.2 '-cyclopentyl-2 '-phenyl-2 '-preparation of oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride (I)
Get the 5L there-necked flask, add α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate (XI) 228g (0.97mol), 141g (0.91mol) N-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems-9 α-alcohol, the anhydrous normal heptane of 2500mL, 8.2g sodium hydride (content 80%).The oil bath heating is also started stirring, and liquid is slowly steamed.Reaction 3h.Most of solvent is extracted in decompression out, splashes into the 50mL2N hydrochloric acid soln under the cooling, stirs, and separates out white solid.Solid filtering and dislocation in beaker, are added the strong aqua alkalization, and ether extracts.With the cooling of ether layer, add 50mL 2N hydrochloric acid soln, stir and separate out solid.Filter collection solid, the frozen water washing with 95% ethanol 80mL recrystallization, 80 ℃ of oven dry of baking oven, gets 232g title compound (I).Productive rate 65%, fusing point: 209-210 ℃.
Proton nmr spectra: δ (ppm, CD
3Cl), 10.87 (s, 1H), 7.64 (m, 2H), 7.35 (m, 3H), 5.00 (s, 1H), 3.73-3.82 (m, 2H), 2.97-3.01 (m, 4H), 2.89 (s, 3H), 2.27 (s, 1H), 2.06 (s, 1H), 2.00 (m, 2H), 1.33-1.70 (m, 12H).
Preparation example 5.2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[N (2,2,2-trichlorine ethoxy acetyl)-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (XII) synthetic
With 10g 2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride (I) places the 80mL ether, the dropping ammonia alkalization, making (I) change into free alkali is dissolved in the ether, washing, ether is reclaimed in dry back, add dry-out benzene 20mL, reclaim benzene, triplicate, free alkali is dissolved in the 30mL dry-out benzene, in this solution, add 8.3g 2,2, the 20mL benzole soln of 2-trichlorine methylamino ethoxy acyl chlorides, add the 300mg Anhydrous potassium carbonate again, stirring heating is 5 hours in 85 ℃ of oil baths, and cooling back elimination solid is with the filtrate decompression evaporate to dryness.With ether 40mL dissolution residual substance, use weak ammonia and water washing successively, after the Anhydrous potassium carbonate drying, the pressure reducing and steaming solvent gets the little yellow transparent viscose glue of 12.2g shape title compound (XII).
Ultimate analysis C
24H
30NO
5Cl
3: theoretical value % C 55.30 H 5.80 N 2.69; Experimental value %C 54.94 H 5.75 N 2.53;
Mass spectrum (FAB) m/z (%) 518 (M
+-1,14.67), 317 (18.00), 175 (100.00).
Embodiment 1.2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] preparation of ester (II)
The formula (XII) that obtains in the 11g preparation example 5 is dissolved in the 30mL ethyl acetate, adds 25mL 90% acetic acid solution, gradation adds the 7g zinc powder, stirs, and keeps 50 ℃ of temperature.After adding zinc powder,, add 25mL 90% acetic acid solution again, the 5g zinc powder in 40 ℃ of stirred in water bath heating 2 hours.In 50 ℃ of stirred in water bath heating 12 hours.Silica gel thin-layer detects, and reaction is (developping agent: chloroform: ethyl acetate (2: 1), R substantially fully
fValue (I), 0.89; (II), 0.12).The elimination solid is used the washing with alcohol filter cake.With the filtrate decompression evaporate to dryness.Add ether 150mL,, make free alkali be dissolved in ether with the alkalization of 5% sodium hydroxide solution.Tell the ether layer, wash with water to neutrality, behind anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent gets little yellow solid, uses recrystallizing methanol, gets 5.3g colourless crystallization title compound (II), fusing point 124-126 ℃.
Ultimate analysis C
21H
29NO
3: theoretical value %C 73.44 H 8.51 N 4.08; Experimental value %C 73.49H 8.66 N 3.96.
Proton nmr spectra: δ (ppm, CD
3Cl), 7.70 (m, 2H), 7.31 (m, 3H), 4.63 (s, 1H), 3.86 (s, 1H), 2.96-3.19 (m, 5H), 2.16 (m, 1H), 2.00 (m, 1H), 1.90 (s, 1H), 1.32-1.69 (m, 14H).
Biological experiment
With suppressing the contraction of cavy intestines, suppress the salivation effect and expanding the cholinolytic effect that benzene ring pelargonate meta-bolites N-demethyl benzene ring pelargonate is measured in the pupil effect; Measure the avidity of benzene ring pelargonate meta-bolites N-demethyl benzene ring pelargonate with the receptor competition antagonistic effect to m receptor.
Effect-the methylarecaidin of embodiment 2. anti-Parkinson Cotards brings out the mouse model that trembles
With 190 of male mices, body weight 18-26 gram, back subcutaneous injection methylarecaidin (0.8mg/ml, 8.0mg/kg).The number of mice that the record injectable drug trembled after 10 minutes.
Administration group subcutaneous injection methylarecaidin was irritated phencynonate hydrocloride and the N-demethyl benzene ring pelargonate that stomach gives various dose in preceding 45 minutes.Calculate ED
50Value the results are shown in Table 1.
The anti-Parkinson Cotard effect of table 1. phencynonate hydrocloride and N-demethyl benzene ring pelargonate relatively
| Medicine | ED 50(mg/kg, oral) | |
| The haloperidol model | The methylarecaidin model | |
| Phencynonate hydrocloride N-demethyl benzene ring pelargonate | 10.52 5.20 | 1.93 1.26 |
Above-mentioned stiff and bring out the experimental result that mouse trembles on the model by methylarecaidin and show that the effect of quivering of the antidetonation of N-demethyl benzene ring pelargonate significantly is better than benzene ring pelargonate itself mouse that haloperidol causes.
Embodiment 3. cholinolytic effects-inhibition cavy intestines contraction (anti-M effect)
Cavy (200-250 gram) male and female are not limit.Tapping the head causes dizzy back by the carotid artery sacrificed by exsanguination, fetches the intestines epimere and puts in the tyrode's solution, 37 ℃ of water-baths, logical oxygen.50 μ mol/L cause contraction with Tonocholin B, trace shrinkage curve by mechanical transducer on desk-top registering instrument.Added after 5 minutes by reagent and add Tonocholin B again, observe the shrinkage curve decreased extent.Calculate the ED that is subjected to the reagent thing anti-acetylcholine to be caused the intestines contraction with the Logit method
50Value the results are shown in Table 2.
The restraining effect that the cavy intestines that table 2. phencynonate hydrocloride and N-demethyl benzene ring pelargonate cause Tonocholin B shrink
| Compound | IC 50，M |
| Phencynonate hydrocloride N-demethyl benzene ring pelargonate | 0.85×10 -7 0.49×10 -7 |
Embodiment 4. cholinolytic effects-inhibition salivation effect
Kunming mouse (18-22 gram), male and female half and half, control animal subcutaneous injection oxotremorine 0.3mg/kg, salivation all appears in 10 animals in 15 minutes; Be subjected to the reagent thing to irritate stomach after 30 minutes, subcutaneous injection oxotremorine 0.3mg/kg observes the number of animals that occurs salivation in 15 minutes.Calculate the ED of the salivation that medicine antagonism oxotremorine causes with the Bliss method
50Value the results are shown in Table 3.
Embodiment 5. cholinolytic effects-expansion pupil effect
Kunming mouse (18-22 gram), male and female half and half.Under indoor fixed light source, observe to be subjected to the reagent thing to irritate stomach pupil diameter after 30 minutes.Expand before with pupil diameter and to be twice the positive reaction of above person than administration.Calculate the ED that medicine expands the pupil effect with the Bliss method
50Value the results are shown in Table 3.
Cholinolytic effect (the ED of table 3. phencynonate hydrocloride and N-demethyl benzene ring pelargonate
50, mg.kg, ip)
| Compound | The antidetonation effect of quivering | The secretion inhibitor effect | Expand the pupil effect |
| Phencynonate hydrocloride N-demethyl benzene ring pelargonate | 0.57 0.22 | 0.60 0.28 | 1.08 1.06 |
Embodiment 6. receptor competition antagonistic effects
Rat body weight 200 grams, the male and female dual-purpose, broken end is got brain, isolates hemicerebrum and striatum, add the 0.3M sucrose solution by 10: 1 (V/W) after weighing and make homogenate, centrifugal twice, taking precipitate is suspended in phosphate buffered saline buffer (0.05M, pH7.4) in, after measuring protein content, be stored in-20 ℃ standby, face with before being diluted to 5mg/mL.
Get above-mentioned protein solution 0.1mL, the testing sample solution 20ul that adds different concns, (3H) QNB (2nM) 20uL, phosphate buffer 1 .9mL is put in 30 ℃ of water-baths insulation 30 minutes with reaction tubes, takes out, add the ice-cold phosphate buffered saline buffer termination reaction of 3mL, behind glass fibre filter disc suction filtration, wash filter disc 3 times with phosphate buffered saline buffer, filter disc was in 80 ℃ of bakings 20 minutes.Measure the radiation counting.Be calculated as follows the percentage of medicine inhibition (3H) QNB and receptors bind:
With the dosage mapping of I% and specimen, the calculating medicine suppresses the concentration IC in conjunction with 50% again
50, the results are shown in Table 4.
Table 4. phencynonate hydrocloride and N-demethyl benzene ring pelargonate
To the combine competitive antagonism of (3H) QNB with the rat brain m receptor
| Compound | IC 50，M |
| Phencynonate hydrocloride N-demethyl benzene ring pelargonate | 4.8×10 -9 2.2×10 -9 |
By table 4 as seen, the m receptor competitive antagonism of N-demethyl benzene ring pelargonate is better than benzene ring pelargonate itself.
Claims (7)
1. formula II N-demethyl benzene ring pelargonate or its pharmacy acceptable salt:
2. contain the pharmaceutical composition that the described formula II N-of claim 1 removes first benzene ring pelargonate or its pharmacy acceptable salt and one or more pharmaceutical carriers or vehicle.
3. the preparation method of the described formula II N-of claim 1 demethyl benzene ring pelargonate or its pharmacy acceptable salt, described method comprises:
(a) make oxalic acid diethyl ester and cyclopentyl bromination magnesium grignard reaction, obtain the Cyclopentylacetaldehyde acetoacetic ester;
(b) product and the phenyl-magnesium-bromide grignard reaction that step (a) is obtained made intermediate α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl acetate, and hydrolysis obtains α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate;
(c) product that obtains of step (b) obtains α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate through esterification, further obtains benzene ring pelargonate with N-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems-9 α-alcohol through transesterification reaction;
(d) make benzene ring pelargonate that step (c) obtains with 2,2,2-trichlorine methylamino ethoxy acyl chlorides denitrogenation methyl obtains N-demethyl benzene ring pelargonate;
(e) randomly, step (d) products therefrom is converted into its pharmacy acceptable salt.
4. the described formula II N-of claim 1 demethyl benzene ring pelargonate or its pharmacy acceptable salt are used to prepare the purposes of anticholinergic agent.
5. the described formula II N-of claim 1 demethyl benzene ring pelargonate or its pharmacy acceptable salt are used to prepare the purposes of the medicine of motion sicknesses such as prevention and treatment be carsick, seasick.
6. the described formula II N-of claim 1 demethyl benzene ring pelargonate or its pharmacy acceptable salt are used to prepare the purposes of the medicine that prevents and/or treats the various vertigo that Meniere's onste etc. causes.
7. the described formula II N-of claim 1 demethyl benzene ring pelargonate and pharmacy acceptable salt thereof are used to prevent and/or alleviate the purposes of the medicine of Parkinson's disease or Parkinson.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100295964A CN100378064C (en) | 2004-03-26 | 2004-03-26 | Active metabolic product of phencynonate and its medicinal use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100295964A CN100378064C (en) | 2004-03-26 | 2004-03-26 | Active metabolic product of phencynonate and its medicinal use |
Publications (2)
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|---|---|
| CN1673209A CN1673209A (en) | 2005-09-28 |
| CN100378064C true CN100378064C (en) | 2008-04-02 |
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| CN101209994B (en) * | 2006-12-30 | 2010-12-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Selectivity M4 acceptor antagonist and medical use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1089838A (en) * | 1993-10-22 | 1994-07-27 | 中国人民解放军军事医学科学院毒物药物研究所 | The syndromic pharmaceutical composition of a kind of control motion sickness |
| CN1182738A (en) * | 1997-12-09 | 1998-05-27 | 中国人民解放军军事医学科学院毒物药物研究所 | Method for preparing benzene ring nonyl ester |
| EP1302458A1 (en) * | 2000-07-11 | 2003-04-16 | Banyu Pharmaceutical Co., Ltd. | Ester derivatives |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1089838A (en) * | 1993-10-22 | 1994-07-27 | 中国人民解放军军事医学科学院毒物药物研究所 | The syndromic pharmaceutical composition of a kind of control motion sickness |
| CN1182738A (en) * | 1997-12-09 | 1998-05-27 | 中国人民解放军军事医学科学院毒物药物研究所 | Method for preparing benzene ring nonyl ester |
| EP1302458A1 (en) * | 2000-07-11 | 2003-04-16 | Banyu Pharmaceutical Co., Ltd. | Ester derivatives |
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