CN101209993A - Medical use for levorotatory phencynonate as nerve protecting agent - Google Patents
Medical use for levorotatory phencynonate as nerve protecting agent Download PDFInfo
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- CN101209993A CN101209993A CNA2006101715789A CN200610171578A CN101209993A CN 101209993 A CN101209993 A CN 101209993A CN A2006101715789 A CNA2006101715789 A CN A2006101715789A CN 200610171578 A CN200610171578 A CN 200610171578A CN 101209993 A CN101209993 A CN 101209993A
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- benzene ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
The invention provides a levorotation phencynonate that has neuro protection effect, non-toxic salt thereof that can be used in pharmacy and medical composition that contains the levorotation phencynonate and non-toxic salt as active constituents and uses thereof as a neuroprotectant. The structure of the levorotation phencynonate is showed in formula Ia.
Description
Technical field
The invention provides left-handed benzene ring pelargonate and atoxic pharmaceutically available salt thereof, contain the pharmaceutical composition of these compounds as activeconstituents with neuroprotective, and the purposes of left-handed benzene ring pelargonate or benzene ring pelargonate neuroprotective.
Background technology
Formula I phencynonate hydrocloride (phencynonate hydrocloride, 2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ester hydrochloride in the ninth of the ten Heavenly Stems] is a kind of selectivity anticholinergic agent, the clinical control various motion sicknesses such as carsick, seasick that are used for.Chinese patent CN1089838A and United States Patent (USP) (US6028198) disclose the purposes of phencynonate hydrocloride as anti-kinetosis (carsickness, ship, machine etc.) medicine; Chinese patent CN97125424.9, English Patent (GB2297255) and Spain patent ES 549796A disclose the preparation method of phencynonate hydrocloride.The Chinese patent publication number is that CN 01104881.6 has applied for phencynonate hydrocloride treatment Parkinson's disease/syndromic purposes; The Chinese patent publication number is the pharmaceutical use that CN 01104881.6 has applied for phencynonate hydrocloride treatment or vertigo acute attacks such as alleviation Meniere and positional vertigo.
By structure I as can be seen, contain a chiral carbon atom in the molecular structure of benzene ring pelargonate, have a pair of optical isomer, clinical application at present be the raceme form.
The a pair of optical isomer of chiral molecules has identical physics or chemical property when not existing outside chirality to influence, as fusing point, solubleness, chromatographic retention, infrared spectra and nuclear magnetic resonance spectrum etc.But different optical isomers shows opposite optical activity, and they can make plane polarized light (dextrorotation) or rotation (left-handed) counterclockwise in the direction of the clock.
The absolute configuration that can represent the optical isomer chiral centre with prefix D and L or R and S.Also can represent the polarimetry nature of molecule with prefix d and l or (+) and (-), show that as d-tartrate or (+)-tartrate this isomer is dextral; And 1-tartrate or (-)-tartrate shows that this isomer is left-handed.
Summary of the invention
The purpose of this invention is to provide left-handed benzene ring pelargonate and atoxic pharmaceutically available salt thereof, contain the pharmaceutical composition of these compounds as activeconstituents with neuroprotective, and the purposes of left-handed benzene ring pelargonate or benzene ring pelargonate neuroprotective.
The present invention is unexpected to be found, (structure I a) has the effect of the nerve injury due to the antagonism NMDA to left-handed benzene ring pelargonate, can be used as neuroprotective.
Term among the present invention " pharmacologically acceptable salt " can be medicinal inorganic or organic salt.The compound that has basic group among the formula I of the present invention can form pharmaceutical salts with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can form pharmaceutical salts, for example acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc. with organic acid.
The compounds of this invention or its pharmacologically acceptable salt can form solvate, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges described activeconstituents in vivo after the metabolism.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.Pharmaceutical composition of the present invention can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they help active compound is processed into can be at the preparation that pharmaceutically uses.The appropriate formulations form depends on selected route of administration, can make according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows when having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.The compounds of this invention also can be prepared and be used for administered parenterally or transdermal administration or mucosal.Perhaps adopt the mode administration of suppository or implants.It will be understood by those skilled in the art that The compounds of this invention can adopt suitable drug delivery system (DDS) to obtain more favourable effect.
It may be noted that in addition, The compounds of this invention using dosage and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.
Left-handed benzene ring pelargonate can be by splitting racemization benzene ring pelargonate or the preparation of following synthetic method with known resolution reagent: with the R amygdalic acid is chiral template, utilize hydroxyl in the amygdalic acid molecule earlier to carry out with special valeral that alcohol aldehyde contracts and, hydroxyl in the hemiacetal molecule that forms carries out intramolecular condensation with carboxyl again, and stereoselectivity obtains interior ester products IIa; Then, the IIa of cyclopentanone and enol form carries out three-dimensional controlled Michael addition reaction, and adduct IIIa dehydration, hydrogenation, deprotection can obtain the R-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (VIa) of optical purity more than 99% easily; After latter's esterification, carry out transesterification reaction with alcohol in 9 α-[N-methyl-3-azabicyclo (3,3, the 1) ninth of the ten Heavenly Stems] (VIII) and promptly get target compound.Concrete synthetic route is as follows:
Embodiment
Specify the present invention with embodiment below, these embodiment should not be construed as the limitation of the present invention that goes up in all senses.
Embodiment 1, (2R, 5S)-2-tertiary butyl-5-phenyl-1, the preparation of 3-diox-4-ketone (IIa)
R-amygdalic acid 20g (0.13mol) is dissolved in the 200mL Skellysolve A, and (content 80% 0.16mol), adds trifluoromethanesulfonic acid 0.5mL then, and water trap is installed, and refluxes 6 hours, anhydrates with water trap to add special valeral 21.2mL.Cool to room temperature, add 8% sodium hydrogen carbonate solution 100mL, the pressure reducing and steaming Skellysolve A, filtration obtains (2R, 5S)-and 2-tertiary butyl-5-phenyl-1,3-diox-4-ketone (IIa) 27.1g, fusing point 100-102 ℃, productive rate 95%, ultimate analysis theoretical value %C 70.89H 7.32 experimental value C 70.81H 7.39.Proton nmr spectra: δ (ppm, CDCl
3), 1.10 (s, 9H), 5.25 (s, 1H), 5.38 (s, 1H), 7.47 (m, 5H).
Embodiment 2, (2S, 5R)-2-tertiary butyl-5-phenyl-1, the preparation of 3-diox-4-ketone (IIb)
With reference to the method for embodiment 1, be raw material with (S)-amygdalic acid, synthetic (2R, 5R)-and 2-tertiary butyl-5-phenyl-1,3-diox-4-ketone (IIb), fusing point 100-102 ℃, productive rate 97%, ultimate analysis theoretical value %C 70.89 H 7.32 experimental value C 70.83 H 7.30.Proton nmr spectra: δ (ppm, CDCl
3), 1.12 (s, 9H), 5.23 (s, 1H), 5.36 (s, 1H), 7.49 (m, 5H).
Embodiment 3, (2R, 5R)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1, the preparation of 3-diox-4-ketone (IIIa)
10g (45mmol) (2R, 5S)-2-tertiary butyl-5-phenyl-1,3-diox-4-ketone is dissolved in the 70mL dry tetrahydrofuran, is cooled to-78 ℃, adding 60mL two (front three is silica-based) Lithamide (tetrahydrofuran solution, 1.0M).Stir and drip cyclopentanone 65mmol down, stirring reaction 2 hours, drip saturated sodium hydrogen phosphate solution of 15mL and 200mL saturated ammonium chloride solution, tell organic layer, the water layer ethyl acetate extraction, merge organic layer, drying, steam solvent obtain (2R, 5R)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-diox-4-ketone (IIIa) 10.5g, productive rate 74%.Proton nmr spectra: δ (ppm, CDCl
3), 0.88 (s, 9H), 1.52-2.06 (m, 8H), 5.52 (s, 1H), 7.31 (m, 3H), 7.78 (dd, J=1.5,8.3Hz, 2H).
Embodiment 4, (2S, 5S)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1, the preparation of 3-diox-4-ketone (IIIb)
With reference to the method for embodiment 3, (2S, 5R)-2-tertiary butyl-5-phenyl-1,3-diox-4-ketone (IIb) and cyclopentanone reaction, obtain (2S, 5S)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-diox-4-ketone (IIIb), productive rate 71%.Proton nmr spectra: δ (ppm, CDCl
3), 0.89 (s, 9H), 1.51-2.07 (m, 8H), 5.54 (s, 1H), 7.30 (m, 3H), 7.76 (dd, J=1.5,8.3Hz, 2H).
Embodiment 5, (2R, 5S)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1, the preparation of 3-diox-4-ketone (IVa)
With 3.6g (10mmol) (2R, 5R)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-diox-4-ketone is dissolved in the 70mL dry tetrahydrofuran solution, cooling is down to 0 ℃, add 2mL sulfur oxychloride and 3mL pyridine, stirring reaction 1 hour, add the 60mL saturated ammonium chloride solution, tell organic layer, the water layer ethyl acetate extraction, merge organic layer, drying, steam solvent obtain (2R, 5S)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1,3-diox-4-ketone (IVa) 3.7g, productive rate 95%.Proton nmr spectra: δ (ppm, CDCl
3), 1.07 (s, 9H), 1.92-2.50 (m, 6H), 5.22 (s, 1H), 6.03 (m, 1H), 7.25 (m, 4H), 7.59 (m, 1H).
Embodiment 6, (2S, 5R)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1, the preparation of 3-diox-4-ketone (IVb)
With reference to the method for embodiment 5, by IIIb obtain (2S, 5R)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1,3-diox-4-ketone (IVb), productive rate 92%.Proton nmr spectra: δ (ppm, CDCl
3), 1.05 (s, 9H), 1.90-2.51 (m, 6H), 5.23 (s, 1H), 6.01 (m, 1H), 7.28 (m, 4H), 7.57 (m, 1H).
The preparation of embodiment 7, (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (VIa)
(2R, 5S)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1,3-diox-4-ketone (IVa) is dissolved in 50mL methyl alcohol, adds 0.2g 10%Pd/C, 1 normal atmosphere H with 2.8g (10mmol)
2Reduced 8 hours.Filter, the filtrate decompression steaming is desolventized, obtain (2R, 5S)-2-tertiary butyl-5-phenyl-5-cyclopentyl-1,3-diox-4-ketone (Va).(Va) is dissolved in methyl alcohol and water mixed solution, adds KOH, stirring and refluxing reaction 3 hours.Be cooled to room temperature, the normal heptane extraction, drying steams solvent and obtains (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (VIa), 1.3g, productive rate 60%,
(MeOH, c=4), fusing point: 118-120 ℃.
Synthesizing of embodiment 8, (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate (VIIa)
With 2.2g (0.01mol) (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (VIa) is dissolved in the 20mL ether, import 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 (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate (VIIa) 2.1g, yield 89.6%.
(MeOH，c＝5)。
The preparation of embodiment 9 (R)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride (Ia)
In the 250mL there-necked flask, add 2.28g (0.01mol) (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy methyl acetate and 1.4g (0.01mol) 9 α-[N-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] alcohol (VIII), anhydrous normal heptane of 50ml and 0.1g sodium hydride (content 80%).The oil bath heated and stirred slowly steams liquid, constantly replenishes normal heptane.Reaction 3h.Most of solvent is extracted in decompression out, splashes into 2N hydrochloric acid soln 5ml 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 2N hydrochloric acid soln 5ml, stir and separate out solid.Filter collection solid, 95% ethyl alcohol recrystallization is used in the frozen water washing, gets product I a 2.3g, productive rate 65%, fusing point: 209-210 ℃.
(CH
3Cl，c＝0.3)。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).
Cytotoxic provide protection due to 10 couples of NMDA of embodiment
The PC12 cell cultures in the DMEM substratum that contains 5%FBS and 10%HS, inoculum density 2 * 10
4Cells/ml went down to posterity once in per 5～7 days.Add 6% FBS, 6% HS and the NGF of 50ng/ml in the substratum and induce differentiation, the next day change liquid once.After 7 days, the cytodifferentiation above 95% is the nervosa cell.
Nutrient solution is abandoned in suction, is changed to the fresh culture that contains different concns NMDA.Earlier with the benzene ring pelargonate or the left-handed benzene ring pelargonate pre-treatment 10min of different concns, the NMDA that adds damage dose is then hatched 24h jointly with cell.Nutrient solution is abandoned in suction, adds the serum-free medium contain MTT (0.5mg/ml), 37 ℃ hatch 4h after, the careful suction abandoned nutrient solution, every hole adds 150ml dimethyl sulfoxide (DMSO) (DMSO) lucifuge concussion 15min, measures its OD of 570nm place value with microplate reader (Wellscans MK3), calculates cell survival rate.
The left-handed benzene ring pelargonate of table 1 is to the provide protection of NMDA induced mice death
The provide protection of 11 pairs of NMDA induced mice of embodiment death
Kunming mice, ♂, 20 ± 2g is provided by Military Medical Science Institute's animal center, and 12h/12h illumination every day, alternately dark is freely drunk water and is ingested.The kunming mice random packet, 9 every group.The benzene ring pelargonate of abdominal injection various dose or, animal all gives the NMDA (ip) of lethal dose behind the 30min, observes survival condition in the mouse 2h, calculates survival rate.
The left-handed benzene ring pelargonate of table 2 is to the provide protection of NMDA induced mice death
Embodiment 12 chmice acute toxicity tests
Kunming mouse 18-22g, male and female half and half, random packet, intraperitoneal injection, interior reaction of animals of 24h and death toll after the observation administration, the Bliss method is calculated benzene ring pelargonate LD
50Be 332.00 ± 48.72mg/Kg, left-handed benzene ring pelargonate LD
50Be 490.50 ± 36.46mg/kg.
Claims (6)
1. by left-handed benzene ring pelargonate shown in the structural formula Ia and atoxic pharmacologically acceptable salt thereof,
2. according to the left-handed benzene ring pelargonate of claim 1, wherein said non-toxicity pharmacologically acceptable salt comprises with mineral acid forming pharmaceutical salts, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can form pharmaceutical salts, for example acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc. with organic acid.
3. can form solvate, for example hydrate, alcohol adduct etc. according to wherein left-handed benzene ring pelargonate of claim 1 or 2 and atoxic pharmacologically acceptable salt thereof.
4. pharmaceutical composition, it comprises according to the arbitrary left-handed benzene ring pelargonate of claim 1-4 and atoxic pharmacologically acceptable salt thereof as activeconstituents and medicinal excipient.
5. according to claim 1 or 2, left-handed benzene ring pelargonate wherein and atoxic pharmacologically acceptable salt thereof still are its prodrug or the form that discharges described activeconstituents in vivo after the metabolism metabolism.
6. according to the left-handed benzene ring pelargonate of one of claim 1-4, its atoxic pharmacologically acceptable salt or benzene ring pelargonate or the phencynonate hydrocloride purposes in the preparation neuroprotective.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101715789A CN101209993A (en) | 2006-12-30 | 2006-12-30 | Medical use for levorotatory phencynonate as nerve protecting agent |
| PCT/CN2007/003159 WO2008086678A2 (en) | 2006-12-30 | 2007-11-07 | The medical use of levo-phencynonate as neuroprotective agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101715789A CN101209993A (en) | 2006-12-30 | 2006-12-30 | Medical use for levorotatory phencynonate as nerve protecting agent |
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| CN101209993A true CN101209993A (en) | 2008-07-02 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2006101715789A Pending CN101209993A (en) | 2006-12-30 | 2006-12-30 | Medical use for levorotatory phencynonate as nerve protecting agent |
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| WO (1) | WO2008086678A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101492384B (en) * | 2009-03-06 | 2013-04-10 | 南京医科大学 | Uses of aminosalicylic acid derivative as neuroprotective agent |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1189173C (en) * | 2002-11-12 | 2005-02-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel use of phencynonate hydrochloride |
| CN100434422C (en) * | 2004-03-26 | 2008-11-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Optical isomer of phencynonate and its use in preparing medicine |
| CN100420674C (en) * | 2004-11-30 | 2008-09-24 | 中国人民解放军军事医学科学院毒物药物研究所 | Process for preparing phencynonate optical isomer |
-
2006
- 2006-12-30 CN CNA2006101715789A patent/CN101209993A/en active Pending
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2007
- 2007-11-07 WO PCT/CN2007/003159 patent/WO2008086678A2/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101492384B (en) * | 2009-03-06 | 2013-04-10 | 南京医科大学 | Uses of aminosalicylic acid derivative as neuroprotective agent |
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| Publication number | Publication date |
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| WO2008086678A3 (en) | 2008-09-04 |
| WO2008086678A2 (en) | 2008-07-24 |
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Inventor after: Zhong Bohua Inventor after: Peng Shuangqing Inventor after: Ren Zhenyu Inventor after: Liu He Inventor after: Chen Lanfu Inventor after: Liu Keliang Inventor after: Shi Weiguo Inventor after: Zhang Zhenqing Inventor after: Xie Jianwei Inventor before: Zhong Bohua Inventor before: Peng Shuangqing Inventor before: Ren Zhenyu Inventor before: Liu He Inventor before: Chen Lanfu Inventor before: Liu Keliang |
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Free format text: CORRECT: INVENTOR; FROM: ZHONG BOHUA PENG SHUANGQING REN ZHENYU LIU HE CHEN LANFU LIU KELIANG TO: ZHONG BOHUA PENG SHUANGQING REN ZHENYU LIU HE CHEN LANFU LIU KELIANG SHI WEIGUO ZHANG ZHENQING XIE JIANWEI |
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Open date: 20080702 |