EP0607201A1 - Zusammensetzung enthaltend s-oxiracetam zur verwendung als nootropikum - Google Patents

Zusammensetzung enthaltend s-oxiracetam zur verwendung als nootropikum

Info

Publication number
EP0607201A1
EP0607201A1 EP92920534A EP92920534A EP0607201A1 EP 0607201 A1 EP0607201 A1 EP 0607201A1 EP 92920534 A EP92920534 A EP 92920534A EP 92920534 A EP92920534 A EP 92920534A EP 0607201 A1 EP0607201 A1 EP 0607201A1
Authority
EP
European Patent Office
Prior art keywords
oxiracetam
enantiomer
composition
compound
nootropic
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.)
Withdrawn
Application number
EP92920534A
Other languages
English (en)
French (fr)
Inventor
Laura Smithkline Beecham Farmaceutici Chiodini
Giancarlo Florence University Pepeu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline SpA
Original Assignee
Smithkline Beecham Farmaceutici SpA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Farmaceutici SpA filed Critical Smithkline Beecham Farmaceutici SpA
Publication of EP0607201A1 publication Critical patent/EP0607201A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to a pharmaceutical composition, in particular to composition of the S-stereoisomer of oxiracetam and to the therapeutic use of such composition.
  • Oxiracetam is usefully used in alleviating memory loss in senile dementia of different types and possesses an asymmetric carbon atom in the position 4 of the ring. Since oxiracetam is structurally related to 4-amino- 3-hydroxybutyric acid (GABOB) and to its betaine derivative, carnitine (Vitamine BT), and it is well known that these amino acids are more active (E. Roberts et al. 1981, J. Neurosci., 1, 132-140; LB. Fritz 1963, Adv. Res., 1, 283) in the absolute configuration R, we prepared both R and S forms of oxiracetam for their evaluation on tests predictive for activity on learning and memory.
  • GBOB 4-amino- 3-hydroxybutyric acid
  • Vitamine BT carnitine
  • S-oxiracetam maybe prepared using a stereospecific analogue, specifically for the S-oxiracetam, of the methods for preparing oxiracetam disclosed in US 4,173,569 and II Farmaco, Ed. Sci., 39 (1984) starting from S-4-amino-3-hydroxybutyric acid (S-GABOB). These methods are incorporated herein by reference:
  • S-GABOB S-4-amino-3-hydroxybutyric acid
  • R is an alkyl radical containing up to 4 carbon atoms or a trichlorophenyl, nitrophenyl or trichloroethyl radical
  • the asterisk represents a centre of asymmetry of the molecule, which is in the S-form.
  • the ammonolysis of the compound of formula II may be carried out under conventional ammonolysis conditions, for example the compound of formula II may be treated with ammonium hydroxide, conveniently at ambient temperature.
  • R* is a methyl or ethyl radical
  • X is a bromine, chlorine or iodine atom
  • M is a sodium, potassium or lithium atom and the asterisk represents a centre of asymmetry, which is in the S-form.
  • steps a, b and c of the above-mentioned process may be carried out without separation of the intermediates: ⁇ -Amino- ⁇ - hydroxybutyric acid V is treated under anhydrous conditions in an inert aprotic solvent, such as toluene, acetonitrile, dioxan and xylene, with an excess of a silylating agent at the boiling point of the solvent employed and the cyclised silyloxy derivative IV obtained is reacted with a halide derivative of an aliphatic acid ester XCH2COOR, wherein X and R have the same meanings as above, in an aprotic and preferably polar solvent, such asacetonitrile, dimethylformamide, dioxan, dimethyl sulphoxide or hexamethyl phosphoramide, and then with an alkali metal hydride, such as sodium, potassium or lithium hydride.
  • an inert aprotic solvent such as toluene, acet
  • the temperature used is not critical for the reaction but is preferably in the range of from 35 to 80°C, optionally with refluxing for a short period of time in order to complete the reaction for obtaining the compound III, from which the silyl protecting group is removed by hydrolysis to give the corresponding 4-hydroxy derivative II.
  • the silylating agent may be, for example, hexamethyl disilazane, bis- trimethylsilylurea or bis-trimethylsilylacetamide: in practice, the silylating agent is preferably employed in the presence of a small quantity of trimethylchlorosilane.
  • the enantiomeric alkyl butanoates VI can be obtained by cyclization of the corresponding halohydiins VTH
  • Cyclization of halohydrins VIII can be obtained either by treatment with silver oxide according to J.D. McClure, J. Org. Chem., 32, 3888 (1967), or especially in the case of X* is iodine, by a novel method entailing the use of an anion exchange resin in carbonate form (these kind of epoxides are very sensitive to base catalyzed rearrangment, and cannot be obtained by action of conventional bases on the halohydrins, see J. D. McClure, loc. cit).
  • the R-enantiomer of oxiracetam may be prepared by using analogous methods to those described above.
  • compositions of the invention When used in the therapeutic treatment of humans and animals, the compositions of the invention are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises oxiracetam in the form of its S-enantiomer, substantially free of its R-enantiomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • compositions of the invention may be administered in standard manner for the treatment of the indicated diseases, for example orally, parenterally, rectally, transdermally or by transmucosal (for example sub- lingual, or buccal or insuf ⁇ latory) administration.
  • compositions of the invention which are active when given orally or via sub-lingual or buccal administration can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, starch, lactose and sucrose.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be utilised, for example aqueous gums, celluloses, silicates or oils are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound of the invention in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycocl, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycocl, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • a typical suppository formulation comprises a compound of the invention which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats.
  • Typical transdermal formulations ⁇ comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or can be in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet or capsule, so that the patient may administer to himself a single dose.
  • Each dosage unit for oral administration contains suitably from 0.05 mg/kg to 20 mg/kg, and preferably from 0.1 mg kg to 5 mg/kg, and each dosage unit for parenteral administration contains suitably from 0.05 mg kg to 10 mg kg, of a compound of the invention.
  • the daily dosage regimen for oral administration is suitably about 0.05 mg/kg to 50 mg kg, more suitably about 0.1 mg kg to 20 mg/kg of a compound of the invention.
  • the active ingredient may be administered from 1 to 6 times daily.
  • the compositions of the invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially, particularly with other compounds used in the treatment of elderly patients e.g. tranquillisers, diuretics, antihypertensives, vasodilators and inotropic agents.
  • S-oxiracetam is a particularly effective nootropic agent:
  • a composition which comprises oxiracetam in the form of its S-enantiomer, substantially free of its R-enantiomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use as a nootropic agent.
  • the invention also provides the use of a composition which comprises oxiracetam in the form of its S-enantiomer, substantially free of its R- enantiomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for use as a nootropic agent.
  • the activity of the S-isomer is demonstrated as follows: it was found that the S enantiomer of oxiracetam is more active than the R, in inducing long term potentiation (LTP) in the rat hippocampal slices "in vitro", in potentiating glutamate stimulated Ca++ uptake in cultured cerebellar granule cells and in reverting the scopolamine induced amnesia in rats.
  • LTP long term potentiation
  • Hippocampal LTP is widely accepted to be the synaptic basis of learning and memory.
  • Compounds able to improve memory functions such as piracetam (Olpe M.R., 1982 , et al. Eur. J. Pharmacol., 80, 415-419) aniracetam (Satoh M. et al., 1986 Neurosci. Lett., 68, 216-220) and phorbol-esters (Malenka Q.C. et al., 1986, Nature 321, 171-177) are able to potentiate LTP.
  • electroconvulsive shock As electroconvulsive shock (Anwyl L. et al., 1987, Brain Res.
  • LTP aminophosphonovaleric acid
  • NMDA N-methyl-D-aspartic acid
  • Ca++ entry into the postsynaptic cells triggers a series of intracellular biochemical events that lead to LTP of synaptic signal transmission wich lasts hours or even weeks.
  • Transverse slices 400 um thick, prepared from hippocampi removed from adult male Wistar rats were superfused with oxygenated artifical cerebrospinal fluid. (Corradetti R., et al., 1983 J. Neurochem., 41, 1518- 1525).
  • Test pulses 80 us - 0.1 Hz
  • evoked orthodromic potentials were extracellularly recorded from the pyramidal cells of the CAl region.
  • Percentage changes in amplitude of population spike or in excitatory post synaptic potential (e.p.s.p.) were calculated as indexes of synaptic efficiency.
  • the compounds R and S were added to the superfusion medium at concentrations ranging from 10-5 to 10-8 M. Compound S clearly increased the amplitude of the evoked potentials starting from the concentration of 10-7M while the compound R was active only at the concentration of 10-5M as reported in the table 1.
  • cerebellar granular cells glutamatergic neurons
  • Glutamate added to the medium stimulates dose dependently the 45Ca2+ uptake at concentrations from 10 to 100 uM (Table 2).
  • Scopolamine (0.66 mg/kg sc) administered 60 minutes before the learning session completely abolished the acquisition of the passive avoidance task as indicated by the fall of the 2nd at 1st LT level; furthermore the 1st LT is not affected by scopolamine treatment suggesting that the amnestic effect is quite specific.
  • S enantiomer administered thirty minutes before scopolamine, significantly protects animals from the disrupting effect of scopolamine at all tested doses of 25-50-100 mg/kg i.p.. R enantiomer, tested in the same experimental conditions and doses, was completely inactive as shown in Table 4.
  • the formulation is prepared by mixing together S-oxiracetam and pregelatinized starch. The resulting mixture is wetted with purified water, granulated through a stainless steel screen and dried with warm air. The dried granules are mixed with croscarmellose sodium and magnesium stearate and then compressed into tablets of 430 mg each.
  • the formulation is prepared by mixing together S-oxiracetam, corn starch, croscarmellose sodium and magnesium stearate. The resulting mixture is filled into hard gelatine capsules (filled weight: 425 mg each capsule).
  • the formulation is prepared by dissolving S-oxiracetam in water for injections.
  • the solution is made up to final volume (1250 ml) with water for injections and then filtered through a 0.22 /urn membrane.
  • the filtered solution is filled into glass ampouls (2.5 ml each ampoule) and then the ampoules are heat-sealed.
  • the filled and sealed ampoules are sterilized by pressurized steam at 121oC for 20 minutes.
  • the pH of the injectable solution ranges from 5 to 7.
  • the formulation is prepared by dissolving S-oxiracetam and sorbitol in purified water, and by dissolving lemon aroma, methyl parahydroxy ⁇ benzoate and propyl parahydroxybenzoate in propylene glycol.
  • the two solution are mixed and then made up to final volume (2500 ml) with purified water.
  • the solution is filtered and then filled into glass bottles.
  • the pH of the syrup ranges from 4 to 6.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP92920534A 1991-10-08 1992-10-03 Zusammensetzung enthaltend s-oxiracetam zur verwendung als nootropikum Withdrawn EP0607201A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9121289 1991-10-08
GB919121289A GB9121289D0 (en) 1991-10-08 1991-10-08 Composition and use
PCT/EP1992/002295 WO1993006826A1 (en) 1991-10-08 1992-10-03 Composition comprising s-oxiracetame for use as nootropic

Publications (1)

Publication Number Publication Date
EP0607201A1 true EP0607201A1 (de) 1994-07-27

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EP92920534A Withdrawn EP0607201A1 (de) 1991-10-08 1992-10-03 Zusammensetzung enthaltend s-oxiracetam zur verwendung als nootropikum

Country Status (4)

Country Link
EP (1) EP0607201A1 (de)
AU (1) AU2645692A (de)
GB (1) GB9121289D0 (de)
WO (1) WO1993006826A1 (de)

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ES2183587T3 (es) 1998-07-24 2003-03-16 Samsung Fine Chemicals Co Ltd Procedimiento continuo para la preparacion de derivados de acido (s) -3-4-dihidroxibutirico opticamente puros..
US6713290B2 (en) 1998-07-24 2004-03-30 Samsung Fine Chemicals Co., Ltd. Process for preparing optically pure (S)-3-hydroxy-γ-butyrolactone
RU2224514C2 (ru) * 2002-05-07 2004-02-27 Закрытое акционерное общество "Брынцалов - А" Ноотропное средство "ноотобрил" в форме раствора для инъекций
CN104173336B (zh) * 2010-03-31 2018-02-02 重庆润泽医药有限公司 左旋奥拉西坦在制备预防或治疗认知功能障碍药物中的应用
CN102204904B (zh) * 2010-03-31 2014-10-01 重庆润泽医药有限公司 左旋奥拉西坦在制备预防或治疗认知功能障碍药物中的应用
CN102249974B (zh) * 2010-05-21 2014-10-15 重庆润泽医药有限公司 一种(s)-4-羟基-2-氧代-1-吡咯烷乙酰胺的制备方法
CN102558013B (zh) 2011-08-11 2013-12-18 重庆润泽医药有限公司 (s)- 4-羟基-2-氧代-1-吡咯烷乙酰胺晶型ⅱ及其制备方法
CN102531989B (zh) 2011-08-11 2014-02-05 重庆润泽医药有限公司 一种（s）-奥拉西坦的纯化方法
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CN102600130A (zh) * 2012-03-26 2012-07-25 北京阜康仁生物制药科技有限公司 奥拉西坦及其光学异构体的新临床用途
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CN103553998B (zh) * 2013-11-06 2015-11-25 温州智创科技有限公司 (s)-奥拉西坦晶型iii的制备方法
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EP3299016B1 (de) * 2015-05-18 2020-12-16 Chongqing Runze Pharmaceutical Co. Ltd. Verwendung von rechtsdrehendem oxiracetam im pharmazeutischen bereich
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CN106619529A (zh) * 2015-10-27 2017-05-10 重庆润泽医药有限公司 一种含量均匀性好的左旋奥拉西坦颗粒及其制备方法
CN106619525A (zh) * 2015-10-27 2017-05-10 重庆润泽医药有限公司 一种含量均匀的（s）-4-羟基-2氧代-1-吡咯烷乙酰胺颗粒及其制备方法
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CN105853473B (zh) * 2016-03-31 2019-12-13 海南合瑞制药股份有限公司 一种奥拉西坦的药物组合物及其制备方法
CN107281135B (zh) * 2016-03-31 2020-09-29 重庆润泽医药有限公司 一种注射用左旋奥拉西坦冻干粉及其制备方法
CN107397722B (zh) * 2016-05-20 2020-08-11 重庆润泽医药有限公司 注射用(s)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉及其制备方法
CN107432861B (zh) * 2016-05-26 2020-08-11 重庆润泽医药有限公司 注射用左旋奥拉西坦冻干组合物及其制备方法
CN107510656A (zh) * 2016-06-15 2017-12-26 重庆润泽医药有限公司 一种稳定性好的(s)-4-羟基-2氧代-1-吡咯烷乙酰胺颗粒及其制备方法
CN107510665A (zh) * 2016-06-15 2017-12-26 重庆润泽医药有限公司 一种含量均匀性好的左旋奥拉西坦颗粒及其制备方法
CN107625747A (zh) * 2016-07-13 2018-01-26 重庆润泽医药有限公司 一种(s)‑4‑羟基‑2氧代‑1‑吡咯烷乙酰胺缓释胶囊及其制备方法
CN107661315A (zh) * 2016-07-28 2018-02-06 重庆润泽医药有限公司 一种缓释释放的左旋奥拉西坦胶囊及其制备方法
CN107661314A (zh) * 2016-07-28 2018-02-06 重庆润泽医药有限公司 一种稳定性好的（s）‑4‑羟基‑2氧代‑1‑吡咯烷乙酰胺缓释胶囊及其制备方法
CN114621128A (zh) * 2022-03-10 2022-06-14 成都百途医药科技有限公司 一种（s）-奥拉西坦的制备方法

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Publication number Publication date
AU2645692A (en) 1993-05-03
GB9121289D0 (en) 1991-11-20
WO1993006826A1 (en) 1993-04-15

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