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GB2225322A - The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide - Google Patents

The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide Download PDF

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Publication number
GB2225322A
GB2225322A GB8926244A GB8926244A GB2225322A GB 2225322 A GB2225322 A GB 2225322A GB 8926244 A GB8926244 A GB 8926244A GB 8926244 A GB8926244 A GB 8926244A GB 2225322 A GB2225322 A GB 2225322A
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United Kingdom
Prior art keywords
ethyl
methylthio
oxo
pyrrolidineacetamide
desulphurizing
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GB8926244A
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GB8926244D0 (en
GB2225322B (en
Inventor
Eric Cossement
Genevieve Motte
Jean-Pierre Geerts
Jean Gobert
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UCB SA
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UCB SA
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Publication of GB2225322A publication Critical patent/GB2225322A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

S- alpha -Ethyl-2-oxo-1-pyrrolidineacetamide prepared by hydrogenolysis of (S)- alpha - [2-(methylthio)ethyl]-2-oxo-1- pyrrolidineacetamide in the presence of a desulphurizing reagent such as NaBH4/NiCl2.6H2O, Raney nickel W-2 or, preferably, Raney nickel T-1. (S)- alpha -ethyl-2-oxo-1-pyrrolidineacetamide is useful in the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system.

Description

A process for the preParation of (S)-a-ethyl-2- oro- 1-yrro1idineacetamide.
The present invention relates to a new process for the preparation of (S)-a-ethyl.2-oxo-l-pyrrolidineacetamide which has the formula
U.S. Patents No. 4,696,943 and No. 4,837,223 in the name of the Applicant describe this compound, which has the absolute S configuration and state that it has particular therapeutic properties which completely unexpectedly distinguish it from the racemic form. Thanks to its properties, the S enantiomer is more suitable than the racemic form for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system.
The preparation of (S)-a-ethyl-2-oxo-l-pyrrolidineacetamide is described in the above mentioned U.S. Patents No. 4,696,943 and No.
4,837,223. According to these patents, the compound cannot be obtained directly from the racemic mixture by separation of the two enantiomers.
It has to be prepared by other methods, and these U.S. patents specifically describe two processes for the preparation of the compound.
In the first process, (S)-a-ethyl-2-oxo-l-pyrrolidineacetic acid is reacted successively with an alkyl haloformate, preferably ethyl chloroformate, and with ammonia. In the second process, an alkyl (S)-4 [[l-(aminocarbonyl)propyljamino]butyrate or an (S)-N-[1 (aminocarbonyl)propyl]-4-halobutanamide is cyclized, the two compounds themselves being prepared from (S)-2-aminobutanamide.
These two processes have in common the same disadvantage. Both require the preparation of a starting reactant which already has the correct stereochemical configuration. This starting reactant is obtained by resolution of the corresponding racemic compound, respectively racemic (t)-a-ethyl-2-oxo-l-pyrrolidineacetic acid in the case of the first process and racemic (')-2-amino-butanamide in the case of the second process. Prior separation of the enantiomer with the desired configuration from the corresponding racemic compound necessarily causes, from the beginning, a loss of 50Z of the raw material employed.Moreover, if it is taken into account that recovery of an optical isomer is rarely carried out in a quantitative yield, the total loss of raw material incurred is much greater than 50Z of the starting racemic compound.
A process which would not have this disadvantage, while remaining relatively easy to carry out, would be extremely desirable.
The present invention thus provides a new process for the preparation of (S)-a-ethyl-2-ozo-1-pyrrolidineacetamide which does not have the disadvantage of the previous processes and which, as a consequence, is more economical. Moreover, this new process also offers the advantage of using a naturally occurring amino acid, L-methionine, or its readily accessible amide as the starting material.
The process according to the present invention for the preparation of (S) a-ethyl-2-oxo-l-pyrrolidineacetamide comprises hydrogenolysis of (S)-a- [2- (methylthio ) ethyl] 2-oxo-l-pyrrolidineacetamide by means of a desulphurizing reagent, in accordance with the equation
The desulphurization of (S) -a- (methylthio)ethyl ]-2-oxo-l- pyrrolidineacetamide is stereoselective. This reaction is generally carried out in water at a temperature between 50 en 100C in the presence of a desulphurizing reagent such as NaBH4!NiCl2.6H20 (R.B. BOAR et al., J.Chem.Soc., Perkin Trans.I (1973),654), Raney nickel W-2 or, preferably, Raney nickel T-1 under normal or increased pressure (X. DOMINGUEZ et al., J.Org.Chem.26,(1961),1625).
The (S )-a- [2-(methylthio)ethyl].2-oxo-l.pyrrolidineacetamide which is the starting compound in this process is a new compound. It can be prepared by one or other of the following two methods: 1) reacting (S)-2-amino-4-(methylthio)butanamide hydrochloride with a 4 halobutyryl halide of the formula HalCH2CH2CH2COHal in which Hal is a halogen atom, preferably a chlorine atom, in accordance with the equation
This reaction is generally carried out in an inert solvent, for example dichloromethane, at a temperature of about OOC in the presence of a catalyst, such as tetrabutylammonium bromide in the presence of powdered potassium hydroxide.
2) a) reacting first (S)-2-amino-4-(methylthio)butanamide with an alkyl 4-halobutyrate of the formula XCH2CH2CH2COOR. in wich X is a halogen atom and R is an alkyl radical having 1 to 4 carbon atoms, in accordance with the equation
This reaction is generally carried out by heating for several hours at a temperature between 80 and 1000C in an inert solvent, such as toluene, in the presence of an acid acceptor such as a tertiary organic base, such as, for example, triethylamine.
b) then cyclizing the alkyl (S)-4-[[l-(aminocarbonyl)-3 (methylthio)propyl]amino]-butyrate obtained in step a), in accordance with the equation
This cyclization is generally carried out in an inert solvent, such as for example toluene or :ylene, by heating at a temperature between 100 and 1300C for several hours in the presence of a catalyst, such as 2-hydro:ypyridine.
(S)-2-Amino-4-(methylthio)butanamide, as the free base, can be prepared from L-methionine according to the method of E. SANDRIN and R.A.
BOISSONNAS, Helv.Chim.Acta,46,(1963),1637-1669.
22 M.P.: 50-510C. [a]' - 27.70 Cc = 2, dimethylformamide).
(S)-2-Amino-4-(methylthio)butanamide hydrochloride. which is a known compound, can be prepared from the base according to the process described by A. EBERLE et al., Helv.Chim,Acta,61,(1978),2360-74.
25 M.P.: 212-2150C. ta]D - +26.40 (c - 1, dimethylformamide).
The following erample is given for the purpose of illustrating the invention.
In this example, the optical purity of the final product was verified by calorimetric determination of the differential enthalpies (C.
FOUQUEY and J. JACQUES, Tetrahedron,23,(1967),4009-19).
Example.
I. Preparation of the starting (S)-a-[2-(methylthio)ethyl]2-oxo-l- pyrrolidineacetamide.
1) From a 4-halobutyryl halide.
84 g of anhydrous sodium sulphate are added to a suspension of 92.25 g (0.5 mole) of (S)-2-amino4.(methylthio)butanamide in 600 ml of dichloromethane at room temperature. The mixture is then cooled to 0 C and 115 g of ground potassium hydroxide and 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane are added in succession. A solution containing 77.5 g (0.55 mole) of 4-chlorobutyryl chloride in 100 ml of dichloromethane is added dropwise at the same temperature, and with vigorous stirring. During the addition, the reaction medium is diluted by simultaneous introduction of 550 ml of dichloromethane. After stirring at OOC for two hours, 29 g of ground potassium hydroxide are added to the mixture.After four and a half hours'reaction, a further 29 g of ground potassium hydroxide are added and stirring is continued for one hour at OOC.
The reaction mixture is then filtered over Hyflocel and the filtrate is evaporated under reduced pressure. The residue is purified by chromatography over silica (eluent: mixture of dichloromethane-methanol-ammonia 95.5:4.5:0.2 vlvlv). 66 g of (S) a- (2- (methylthio ) ethyl] -2-oxo-1-pyrrolidineacetamide are obtained 25 in the form of a white powder. [a]D5 = - 39.10 (c = 1, methanol).
Yield:61X.
Analysis for C9H16N202S in Z: calc. : C 50.00 H 7.41 N 12.96 found : 50.15 7.80 12.94 2) From an alkyl 4-halobutyrate.
a) Ethyl (S)-4-[[1-(aminocarbonyl)-3-(methylthio)propyl]- aminoZbutyrate.
10.57 ml (76 mmoles) of triethylamine are added to a suspension of 10 g (68 mmoles) of (S)-2-amino-4-(methylthio)butanamide in 100 ml of toluene. The mixture is heated to 80-850C, with vigorous stirring, and 13.26 g (68 mmoles) of ethyl 4 bromobutyrate are added dropwise. This temperature is maintained for 8 hours. The solvent is then evaporated off under reduced pressure and the residue is taken up in 100 ml of dichloromethane. The mixture is heated under reflux for 30 minutes and filtered hot. The filtrate is evaporated to dryness and the residue obtained is purified by chromatography over silica (eluent: mixture of ethyl acetate-methanol-ammonia 10:0.1:0.1 vlvlv). 6.2 g of ethyl (S)-4-[[l-(aminocarbonyl)-3 (methylthio)propyl]amino]butyrate are thus obtained.
25 [a]42356- -14.1 (c = 1, methanol). Yield: 35X.
This intermediate compound is used as such without further purification for carrying out the final cyclization.
b) 0.6 g (2.29 mmoles) of the crude product obtained in a) and 21.3 mg (0.225 mmole) of 2-hydroxypyridine are mixed in 1.15 ml of p xylene. The mixture is heated at 1300C under nitrogen for 4 and a half hours. It is then cooled and stirred for 30 minutes at room temperature. The precipitate which forms is filtered off and recrystallized from ethyl acetate. 0.18 g of (S)-a-[2 methylthio)-ethyl]-2-oxo-1-pyrrolidineacetamide are obtained.
25 o:D - -36.50 (c - 1, methanol). Yield: 36Z.
Analysis for C9H16N202S 2 in in Z: calc.: C 50.00 H 7.41 N 12.96 found: 49.88 7.49 12.68 II. Preparation of (S)-a-ethyl-2-oro-l-pyrrolidineacetamide 50 g of Raney nickel T-1 (X.A. DOMINGUEZ et al., J.Org.Chem.26, (1961),1625), 386 ml of water and 7 g (0.0324 mole) of (S)-a-[2 (methylthio)ethyl]-2-oxo-1-pyrrolidineacetamide are introduced successively into a one litre three-necked round-bottomed flask. The mixture is heated to 750C and stirred at this temperature for one hour. It is filtered and the water is evaporated off under reduced pressure. The residue (5.3 g) is recrystallized from 60 ml of ethyl acetate. 3.87 g of (S)-a-ethyl-2-oxo-l-pyrrolidineacetamide are 25 obtained. M.P.: 112-1150C. [a]25 ^ -900 (c = 1, acetone).
Yield: 69Z.
Analysis for C8H14N202 in Z: calc.: C 56.45 H 8.29 N 16.46 found: 56.30 8.42 16.18

Claims (12)

  1. CLAIMS 1. A process for the preparation of (S)-a-ethyl- 2-oxo-l-pyrrolidineacetamide, characterized in that (S) -a- (2- (methylthio) ethyl) -2-oxo-l-pyrrolidine- acetamide is subjected to hydrogenolysis by means of a desulphurizing reagent.
  2. 2. A process according to claim 1, characterized in that the desulphurizing reagent is Raney nickel T-l.
  3. 3. A process according to claim 1, characterized in that the desulphurizing reagent is NaBH4/NiCl2.6H20.
  4. 4. A process according to claim 1, characterized in that the desulphurizing reagent is Raney nickel W-2.
  5. 5. A process according to any of claim 1 to 4, characterized in that the hydrogenolysis is carried out in water at a temperature between 50 and 1000C.
  6. 6. (S)-a-(2-(methylthio)ethyl)-2-oxo-lpyrrolidineacetamide.
  7. 7. A process for preparing (S)-a-(2-(methylthio) ethyl) -2-oxo-l-pyrrolidineacetamide comprising reacting (S) -2-amino-4- (methylthio )butanamide hydrochloride with a 4-halobutyryl halide, in which the halogen is preferably chlorine.
  8. 8. A process as claimed in claim 7 characterised in that said reaction is carried out in an inert solvent, preferably dichloromethane.
  9. 9. A process as claimed in claim 8 characterized in that said reaction is carried out in the presence of a catalyst, which catalyst is preferably tetrabutylainmonium bromide and powdered potassium hydroxide.
  10. 10. A process for producing (S)-a-(2-(methylthio) ethyl)-2-oxo-l-pyrrolidineacetamide, comprising reacting (S)-2-amFno-4- (methylthio) butanamide with an alkyl 4-halobutyrate of the formula XCH2CH2CH2COOR, in which X represents a halogen atom and R represents an alkyl radical having 1 to 4 carbon atoms, to form an (S)-4-((1-(aminocarbonyl)-3-(methylthio)-propyl)amino)butyrate, which is then cyclized in an inert solvent, preferably toluene or xylene, by heating at a temperature between 100 and 1300C in the presence of a catalyst, which catalyst is preferably 2-hydroxypyridine.
  11. 11. A process as claimed in claim 10 characterized in that said reaction is carried out at a temperature between 80 and 1000C in an inert solvent, such as toluene, in the presence of an acid acceptor, which is preferably triethylamine.
  12. 12. A process substantially as hereinbefore described.
GB8926244A 1988-11-23 1989-11-21 A process for the preparation of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide Expired - Lifetime GB2225322B (en)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0645139A1 (en) 1993-09-24 1995-03-29 U C B, S.A. Use of (S)-(-)-alpha-ethyl-2-oxo-1-pyrrolidine-acetamide for the preparation of a medicament for the treatment of anxiety
US6107492A (en) * 1998-05-08 2000-08-22 Ucb, S.A. Process for the preparation of levetiracetam
RU2216322C1 (en) * 2002-02-28 2003-11-20 Закрытое акционерное общество "АСГЛ-Фармацевтические Инновации" Agent eliciting anti-ischemic, hypotensive, anti- -arrhythmic and nootropic activity
EP1477478A2 (en) 2000-02-23 2004-11-17 UCB Farchim S.A. (AG - LTD) 2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses.
WO2005028435A1 (en) * 2003-09-24 2005-03-31 Ucb, S.A. Process for preparing 2-oxo-1-pyrrolidine derivatives
EP1600169A2 (en) 1999-12-01 2005-11-30 Ucb, S.A. A pyrrolidineacetamide derivative alone or in combination for treatment of CNS disorders
US7132552B2 (en) * 2003-02-03 2006-11-07 Teva Pharmaceutical Industries, Ltd. Process for producing levetiracetam
EP1806339A1 (en) 2005-12-21 2007-07-11 Ucb, S.A. Process for the preparation of 2-oxo-1-pyrrolidine derivatives
WO2009050735A1 (en) * 2007-10-15 2009-04-23 Lupin Limited A novel polymorph of levetiracetam and a process for its preparation
EP2147911A1 (en) 2008-07-24 2010-01-27 ZaCh System S.p.A. Process for the preparation of levetiracetam
US7902380B2 (en) 2004-11-22 2011-03-08 Apotex Pharmachem Inc. Process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and (R)-alpha-ethyl-2-oxo-pyrrolidineacetamide
EP2308867A2 (en) 2005-06-01 2011-04-13 UCB Pharma S.A. 2-oxo-1-pyrrolidine deriatives, processes for preparing them and their uses
US7939676B2 (en) 2009-09-17 2011-05-10 Zach System S.P.A. Process for the preparation of levetiracetam
WO2015110435A1 (en) 2014-01-21 2015-07-30 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

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ES2214147B1 (en) * 2003-02-28 2005-10-01 Farma-Lepori S.A. PROCEDURE FOR OBTAINING AN ANTIEPILEPTIC AGENT.

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GB1309692A (en) * 1970-02-13 1973-03-14 Ucb Sa N-substituted lactams
EP0162036A1 (en) * 1984-05-15 1985-11-21 U C B, S.A. (S)-alpha-ethyl-2-oxo-1-pyrrolidinacetamide

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0645139A1 (en) 1993-09-24 1995-03-29 U C B, S.A. Use of (S)-(-)-alpha-ethyl-2-oxo-1-pyrrolidine-acetamide for the preparation of a medicament for the treatment of anxiety
US6107492A (en) * 1998-05-08 2000-08-22 Ucb, S.A. Process for the preparation of levetiracetam
EP1600169A2 (en) 1999-12-01 2005-11-30 Ucb, S.A. A pyrrolidineacetamide derivative alone or in combination for treatment of CNS disorders
EP1477478A2 (en) 2000-02-23 2004-11-17 UCB Farchim S.A. (AG - LTD) 2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses.
US6969770B2 (en) 2000-02-23 2005-11-29 U.C.B. Farchim S.A. 2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses
EP1604979A1 (en) 2000-02-23 2005-12-14 UCB Farchim S.A. 2-oxo-1-pyrrolidine derivative and its pharmaceutical uses
US7217826B2 (en) 2000-02-23 2007-05-15 Ucb Farchim S.A. 2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses
RU2216322C1 (en) * 2002-02-28 2003-11-20 Закрытое акционерное общество "АСГЛ-Фармацевтические Инновации" Agent eliciting anti-ischemic, hypotensive, anti- -arrhythmic and nootropic activity
US7132552B2 (en) * 2003-02-03 2006-11-07 Teva Pharmaceutical Industries, Ltd. Process for producing levetiracetam
WO2005028435A1 (en) * 2003-09-24 2005-03-31 Ucb, S.A. Process for preparing 2-oxo-1-pyrrolidine derivatives
US7629474B2 (en) 2003-09-24 2009-12-08 Ucb Pharma S.A. Process for preparing 2-oxo-1-pyrrolidine derivatives
EA010306B1 (en) * 2003-09-24 2008-08-29 Юсб, С.А. Process for preparing 2-oxo-1-pyrrolidine derivatives
US7902380B2 (en) 2004-11-22 2011-03-08 Apotex Pharmachem Inc. Process for the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and (R)-alpha-ethyl-2-oxo-pyrrolidineacetamide
US8518943B2 (en) 2005-06-01 2013-08-27 Ucb Pharma, S.A. 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses
US8183241B2 (en) 2005-06-01 2012-05-22 Ucb Pharma, S.A. 2-oxo-1-pyrrolidine derivatives
US8586623B2 (en) 2005-06-01 2013-11-19 Ucb Pharma, S.A. 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses
EP2308867A2 (en) 2005-06-01 2011-04-13 UCB Pharma S.A. 2-oxo-1-pyrrolidine deriatives, processes for preparing them and their uses
EP2308870A2 (en) 2005-06-01 2011-04-13 UCB Pharma S.A. 2-oxo-1-pyrrolidine deriatives, processes for preparing them and their uses
US8178533B2 (en) 2005-06-01 2012-05-15 Ucb Pharma, S.A. 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses
EP1806339A1 (en) 2005-12-21 2007-07-11 Ucb, S.A. Process for the preparation of 2-oxo-1-pyrrolidine derivatives
WO2009050735A1 (en) * 2007-10-15 2009-04-23 Lupin Limited A novel polymorph of levetiracetam and a process for its preparation
EP2147911A1 (en) 2008-07-24 2010-01-27 ZaCh System S.p.A. Process for the preparation of levetiracetam
US7939676B2 (en) 2009-09-17 2011-05-10 Zach System S.P.A. Process for the preparation of levetiracetam
WO2015110435A1 (en) 2014-01-21 2015-07-30 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
EP3827830A1 (en) 2014-01-21 2021-06-02 Janssen Pharmaceutica NV Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US12048696B2 (en) 2014-01-21 2024-07-30 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

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HUT53072A (en) 1990-09-28
SG89392G (en) 1992-12-04
NO894649L (en) 1990-05-25
GB8926244D0 (en) 1990-01-10
RU1797607C (en) 1993-02-23
NO173823B (en) 1993-11-01
FI91961B (en) 1994-05-31
ES2023532A6 (en) 1992-01-16
AT392781B (en) 1991-06-10
HU896132D0 (en) 1990-02-28
PL161781B1 (en) 1993-07-30
GB2225322B (en) 1992-03-25
KR900007797A (en) 1990-06-02
CN1020604C (en) 1993-05-12
NO894649D0 (en) 1989-11-22
BG51041A3 (en) 1993-01-15
PT92365A (en) 1990-05-31
PT92365B (en) 1995-07-18
ATA266689A (en) 1990-11-15
GR890100769A (en) 1990-12-31
HU204508B (en) 1992-01-28
GR1000719B (en) 1992-11-23
PH26332A (en) 1992-04-29
KR0157610B1 (en) 1998-11-16
CN1042904A (en) 1990-06-13
NO173823C (en) 1994-02-09
FI91961C (en) 1994-09-12
FI895562A0 (en) 1989-11-22
GB8827389D0 (en) 1988-12-29
HK102492A (en) 1992-12-24
CY1672A (en) 1993-05-14

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