IE63654B1 - Process for the preparation of quinolonecarboxylic acids - Google Patents

Process for the preparation of quinolonecarboxylic acids

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Publication number
IE63654B1
IE63654B1 IE225588A IE225588A IE63654B1 IE 63654 B1 IE63654 B1 IE 63654B1 IE 225588 A IE225588 A IE 225588A IE 225588 A IE225588 A IE 225588A IE 63654 B1 IE63654 B1 IE 63654B1
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IE
Ireland
Prior art keywords
compound
general formula
fluorine
abovementioned
chlorine
Prior art date
Application number
IE225588A
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IE882255L (en
Inventor
Rudolf Zerbes
Michael Preiss
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Bayer Ag
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Filing date
Publication date
Application filed by Bayer Ag filed Critical Bayer Ag
Publication of IE882255L publication Critical patent/IE882255L/en
Publication of IE63654B1 publication Critical patent/IE63654B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A novel method for the preparation of intermediates for pharmaceutically active quinolonecarboxylic acids in a single-step method.

Description

The invention relates to a new process for the preparation of 4-oxo-3-quinoline-carboxylic acids which are used as intermediates for the preparation of known quinolonecarboxylic acids having pharmaceutical activity.
It is known that l-cyclopropyl-7-chloro-6-fluoro-l,4- * dihydro-4-oxo-3-quinoline-carboxylic acids are obtained in the following way (EP-A-0 176 846): 1st stage: F COCI XX Cl Cl (1) (2) CH-COOR —* II base CH-N(CH3)2 (3) COOR . x· C II ch-n(ch3)2 2nd stage: (3) (4) -(CH3)2NH II F C COOR 'Lo (5) 3rd stage: (5) + K2CO3 4th stage; hydrolysis (6) It has also been disclosed to prepare the compound (7) in the following way: (EP-A-0 078 362) 1st stage; II F^J^^^COCI XC02R F^^^^C-CH(C02R)2 Cl Cl co2r Cl Cl 2nd stage: decarboxylation x^C02R 3rd stage: 4th stage: C>-NH 5th stage: 6th stage: hydrolysis However, all the known processes have the disadvantage 10 that the target compound is prepared via many intermediate stages.
Moreover, elaborate separation and drying operations must be carried out.
The washing procedures which are necessary mean that large amounts of solvents are produced which must either be incinerated or worked up.
Furthermore, it is necessary to apply elaborate analyti5 cal methods for the characterization of the intermediate stages.
The invention relates to a process for the preparation of quinolonecarboxylic acids of the general formula I in which R1 represents propyl, cyclopropyl, isopropyl or vinyl, X1 denotes fluorine, chlorine, Br, CN, N02 or hydrogen, and X2, X3 and X4 represent fluorine, chlorine, N02 or hydrogen, which is characterized in that a compound of the general formula II in which X1 to X4 have the abovementioned meanings and. Xs represents halogen, in particular chlorine or fluorine, is reacted, without isolation of the reaction products of the intermediate stages in a so-called one5 pot reaction, with a compound of the general formula III CH-C00R2 || (III) CH-NR3R3 in which R2 and R3 are identical or different and represent C1-C4- alkyl, in the presence of a solvent and of a base, where ap10 propriate heating to 50°C to 150°C, to give a compound of the general formula IV this compound IV is subjected to an amine exchange at temperatures of 50 to 120°C in the presence of the abovementioned solvents and in the presence of an amine of the general formula RXNH2 in which R1 has the abovementioned meaning, resulting in a compound of the general formula V having the abovementioned radical meanings, and subsequently the compound V is cyclized and hydrolysed at temperatures between 80 and 180°C in the presence of a base, and a compound of the general formula I is precipitated by addition of acid.
The compounds which are prepared according to the invention, in particular, are those in which R1 in the general formula I represents a cyclopropyl radical.
Preferably: X1 and X4 = hydrogen, X2 = chlorine and X3 = fluorine.
Additionally, preferred compounds of the general formula I are those in which R1 denotes cyclopropyl, X2 represents chlorine, and X1 and X3 denote fluorine, while X4 represents hydrogen.
Compounds which are furthermore preferred are those in which X3 represents fluorine, and X1 and X2 represent chlorine, while X4 denotes hydrogen.
Given the complicated course of the reaction, it has to be designated extremely surprising that, for example, the compound 1-cyclopropyl-7-chloro-6-fluoro-l,4-dihydro-4oxo-3-quinoline-carboxylic acid can be prepared without isolation of intermediate products in a one-pot reaction in excellent yields by the following route: a) acylation 7X"' Cl Cl tert. org. base -> inert org. solvent CH-COOR2 II 3 3 CH-NR^R·3 Suitable org. solvents are: toluene, xylene, cyclohexane, open-chain hydrocarbons (mixtures), DMF and DMSO.
Bases which can be used are: tert. org. amines such as R3N with R = Cj^-C^-alkyl, benzyl, cycl. amines ’-Ο» , , I pyridine, etc., with R = C1-C4-alkyl.
The temperatures for the acylation of the dimethylaminoacrylic ester are between 50 and 150°C, preferably 80 to 120°C.
Hydrochloride, which precipitates out during the reaction, of the auxiliary base can be separated out via a filter or be removed by extraction by stirring with water.
The org. phase with the aroylacrylic ester is further reacted with cyclopropylamine.
The reaction can be carried out in the same solvent or, after evaporation (in vacuo or under atmospheric pressure) , in another solvent. b) amine exchange 11 2 /COOR C II CH-N(CH3)2 Cl Cl -3>2nh Suitable solvents are: toluene, xylene, cyclohexane, open-chain hydrocarbons (mixtures), alcohols, DMF, DMSO and butylglycol.
The temperatures for the amine exchange are 50 to 120°C, preferably 65 to 85°C.
The reaction mixture is maintained further at the elevated temperature until the evolution of gas (dimethylamine) ceases.
If the amine exchange is carried out in a low-boiling diluent such as, for example, cyclohexane, the solvent is evaporated off before the cyclization (in vacuo or under atmospheric pressure) and replaced by a higher-boiling diluent such as, for example, butylglycol. c) cyclization II 00R Suitable solvents are: higher alcohols such as 10 butyl glycol, i-propyl alcohol, ethylene glycol, butanol, trietbylene glycol, polyethylene glycol, amino alcohols such as diethylaminoethanol, DMF, DMSO, dioxane and N-methylpyrrolidone.
The cyclization to give the quinolone system is carried 20 out at temperatures between 80 and 180°C, preferably at 130 to 160°C, in the presence of a base.
Bases which can be used are Na tert. -butylate NaH and The base is used in an equimolar amount up to an excess of 3 mole-equivalents, preferably in an excess of 0.1 to 0.5 mole-equivalents. d) hydrolysis and precipitation O OOH For the hydrolysis, the reaction mixture is cooled to 10 about 100°C and water is added.
Owing to the excess of base in the cyclization, the hydrolysis is complete within a short time at temperatures of 50 to 100°C.
The quinolone carboxylic acid is precipitated by addition 15 of a mineral acid or an org. acid and is isolated.
Suitable and preferred acids are: sulphuric acid, hydrochloric acid and acetic acid.
Example 1 28.8 g of ethyl Ν,Ν-dimethylamino-acrylate and 26 g of N,N-dime thy lbenzylamine in 71 ml of toluene are heated to 90°C and, at this temperature, 40 g of 2,4-dichloro-5fluorobenzoyl chloride are added dropwise in 60 min.
The mixture is then stirred for 15 min, and the precipitated Ν,Ν-dimethylbenzylamine hydrochloride is separated off through a suction filter.
The filtrate is substantially evaporated in vacuo, and 80 ml of butylglycol are added to the residue. g of cyclopropylamine are added dropwise at 70-75°C in 30 min and, after addition is complete, the mixture is maintained at 100°C for 1 hour until the evolution of gas ceases. 27.9 g of potassium carbonate and 100 ml of butylglycol are added to the reaction mixture, which is then slowly heated to 135-145°C.
During this, about 40 ml of low-boiling constituents distil out.
The temperature is maintained for 1.5 h.
It is then cooled to 100-120°C, and 130 ml of water are added to the reaction mixture.
The mixture is stirred at 90°C for 15 min and, at this temperature, 27 ml of acetic acid are added dropwise in 15 min. The contents of the flask are cooled, and the solid is separated off through a suction filter.
The product is washed with 27 ml of water and 50 ml of methanol, sucked thoroughly dry and dried at 70°C in vacuo for 24 h.
Yield: 37 g = 74.9% of theory.
Example 2 43.2 g of ethyl Ν,Ν-dimethylamino-acrylate in 84 ml of toluene are heated to 100°C, and 40 ml of triethylamine are added.
At the reflux temperature, 60 g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 30 min, and then the precipitated triethylamine hydrochloride is separated off through a suction filter.
After washing with 65 ml of toluene, 16.2 g of cyclopropylamine are added dropwise to the filtrate at 70°C in 20 min.
The mixture is heated at 100°C until evolution of gas ceases.
Then 42 g of potassium carbonate and 270 ml of butylglycol are added, and the mixture is slowly heated to 135-145°C. During this, about 180 ml of toluene and lowboiling constituents distil out.
The temperature is maintained at 135-145°C for 1.5 h and, after the reaction mixture has been cooled to 100°C, 200 ml of water are added.
After 15 min, 40.5 ml of acetic acid are added dropwise at 90°C, and the precipitated solid is filtered off with suction through a suction filter.
The product is then washed with 140 ml of water and 75 ml of methanol, thoroughly sucked dry and dried at 70°C in vacuo for 24 h.
Yield: 58.5 g 79% of theory.
Example 3 44.7 g of ethyl Ν,Ν-dimethylaminoacrylate and 17.1 g of N,N'-dimethylpiperazine in 95 ml of cyclohexane are heated to reflux. g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 1 h.
The precipitated dimethylbenzylamine hydrochloride is separated off through a suction filter, and the filtrate is evaporated to dryness in vacuo.
The residue ie dissolved in 125 ml of butylglycol and, at 90°C, 20.2 g of cyclopropylamine are added dropwise to the solution.
After the evolution of gas ceases, 43.4 g of potassium carbonate and 165 ml of butylglycol are added, and the mixture is heated at 145°C for 1.5 h. Initially during this small amounts of low-boiling constituents distil out.
After 1.5 h, the mixture is cooled to 100°C, 205 ml of water are added, and the mixture ie then stirred at 95°C for 15 min.
Then 42 g of acetic acid are added dropwise in 15 min, the mixture ie cooled to 30°C, and the precipitated solid is separated off through a suction filter.
The filter cake is washed with 180 ml of water and 80 ml of 80% strength isopropanol and is dried at 70°C in vacuo overnight.
Yield: 60.1 g = 78.1% of theory.
Example 4 33.7 g of methyl Ν,Ν-dimethylamino-acrylate are heated with 40.5 g of Ν,Ν-dimethylbenzylamine in 95 ml of toluene at 110°C.
At the reflux temperature, 62 g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 1 h, and then the precipitated dimethylbenzylamine hydrochloride is removed through a suction filter.
The solvent is distilled off in vacuo, 130 ml of butylglycol are added and, at 90°C, 20.2 g of cyclopropylamine are added dropwise in 20 min.
After the evolution of gas ceases, 43.4 g of potassium carbonate and 150 ml of butylglycol are added to the reaction mixture which is then slowly heated to 140 °C. During this, small amounts of low-boiling solvents distil out.
The mixture is then stirred at 140°C for 1.5 h. After cooling to 100 °C, 205 ml of water are added to the reaction mixture and it is stirred at 90°C for 15 min.
While cooling slightly, 100 ml of 30% strength sulphuric acid are added, and the solid is filtered off with suction through a suction filter and is washed with 200 ml of water and 200 ml of isopropanol.
The solid is dried in vacuo at 70°C overnight.
Yield: 59.4 g = 77.2% of theory.
Example 5 55.6 g of tributylamine are added to 44.7 g of ethyl N,Ndimethylamino-acrylate in 95 ml of cyclohexane and, at 85-95°C, 62 g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 1 h.
Then 250 ml of water are added to the reaction mixture, and the aqueous salt phase is separated off.
The aqueous phase is extracted once more by stirring with 50 ml of cyclohexane, and the combined org. phases are evaporated to dryness under water pump vacuum.
The residue is taken up in 125 ml of butylglycol, and the mixture is heated to 70°C and 20.2 g of oyclopropylamine are added dropwise in 15 min.
After the evolution of gas ceases, a further 160 ml of 5 butylglycol and 44 g of potassium carbonate are added, and the mixture is slowly heated to 140°C.
After the mixture hrs reached 140°C, it is stirred for 1.5 h and then cooled to 100°C, and 205 ml of water are added.
After 15 min, 42 g of acetic acid are added dropwise in *10 min, and the mixture is cooled to room temperature.
The precipitate is isolated through a suction filtez* funnel and is washed with water and isopropanol.
The yield obtained after drying at 50°C in vacuo over15 night is 54.6 g = 71% of theozry.
Example 6 105 g of tributylamine and 86 g of methyl N,N-dimethylamino -aery late in 148 ml of toluene are heated to 105°C, and 124 g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise in 1 h.
After the reaction mixture has been cooled to 50°C, it is extracted twice with 250 ml of water each time.
The organic phase is substantially concentrated under water pump vacuum, and 37.5 g of cyclopropylamine are added dropwise to the residue at an internal temperature of 70-75°C. This results in gaseous dimethylamine escaping until the reaction is complete. 86.8 g of potassium carbonate and 500 ml of butylglycol are added to the reaction mixture which is then slowly heated to 135 -145°C. During this, small amounts of lowboiling solvents distil out.
The temperature is maintained at 135 - 145°C for 1.5 h, and then the mixture is cooled to 100°C and 535 ml of a % strength acetic acid are added dropwise.
The resulting suspension is cooled to room temperature, and the solid is separated off throx'gh a suction filter funnel and washed with 175 ml of water and 200 ml of 80% strength isopropanol.
The product is dried in vacuo at 70°C overnight.
Yield: 220 g = 78.1% of theory.

Claims (7)

1. Process for the preparation of quinolonecarboxylic acids of the general formula I in which 5 R 1 represents propyl, cyclopropyl, isopropyl or vinyl, X 1 denotes fluorine, chlorine, Br, CN, N0 2 or hydrogen, and X 2 , X 3 and X 4 represent fluorine, chlorine, N0 2 or 10 hydrogen, characterized in that a compound of the general formula II in which X 1 to X 4 have the abovementioned meaning, and 15 X s represents halogen, in particular chlorine or fluorine, is reacted, without isolation of reaction products of the intermediate stages in a so-called one-pot reaction, with a compound of the general formula III (III) CH-COOR 2 II 9 , ch-nr 3 r 3 In which R 2 and R 3 are identical or different and represent C^-C*-alkyl, in the presence of a solvent and of a base, where appropriate heating to 50 to 150°C, to give a compound of the general formula IV (IV) this compound IV is subjected to an amine exchange at temperatures of 50 to 120°C in the presence of the abovementioned solvents and in the presence of an amine of the general formula Rj^NHj in which R 1 has the abovementioned meaning, resulting in a compound of the general formula V (V) having the abovementioned radical meanings, and subsequently the compound V is cyclized and hydrolysed at temperatures between 80 and 180 °C in the presence of a base, and the compound of the general formula I is precipitated by addition of acid.
2. Process for the preparation of quinolonecarboxylic acids of the general formula I in which R 1 represents cyclopropyl, 5 X 1 denotes fluorine, chlorine, Br, CN, N0 2 or hydrogen, and X 2 , X 3 and X 4 represent fluorine, chlorine, N0 2 or hydrogen, characterized in that a compound of the general 10 formula II in which X 1 to X 4 have the abovementioned meaning, and X s represents halogen, in particular chlorine or fluorine, 15 is reacted, without isolation of reaction products of the intermediate stages in a so-called one-pot reaction, with a compound of the general formula III CH-COOR 2 || (III) CH-NR
3.R 3 in which R 2 and R 3 are identical or different and represent Cx-Cj-alkyl, in the presence of a solvent and of a base, where appropriate heating to 50 to 150°C, to give a compound of the general formula IV (IV) this compound IV is subjected to an amine exchange at temperatures of 50 to 120°C in the presence of the abovementioned solvents and in the presence of cyclopropylamine, resulting in a compound of the general formula V (V) having the abovementioned radical meanings, and subsequently the compound V is cyclized and hydrolysed at temperatures between 80 and 180°C in the presence of a base, and the compound of the general formula I is precipitated by addition of acid. Process for the preparation of quinolonecarboxylic acids of the general formula I OOH (I) in which R 1 represents cyclopropyl, X 1 , X 2 and X 3 are identical or different and represent fluorine or chlorine, and X 4 represents hydrogen, characterized in that a compound of the general formula II in which X 1 to X 4 have the abovementioned meaning, and X 5 represents halogen, in particular chlorine or fluorine, is reacted, without isolation of reaction products of the intermediate stages in a so-called one-pot reaction, with a compound of the general formula III CH-COOR 2 Il ch-nr 3 r 3 in which R 2 and R 3 are identical or different and represent: C 1 -C 4 -alkyl, t in the presence of a solvent and of a base, where appropriate heating to 50 to 150°C, to give a compound of the general formula IV this compound IV is subjected to an amine exchange at temperatures of 50 to 120°C in the presence of the abovementioned solvents and in the presence of cyclopropylamine, resulting in a compound of the general formula V having the abovementioned radical meanings, and subsequently the compound V is cyclized and hydrolysed at temperatures between 80 and 180°C in the presence of a base, and the compound of the general formula I is precipitated by addition of acid.
4. Process for the preparation of quinolonecarboxylic acids of the general formula I in which 15 R 1 represents cyclopropyl, X 1 and X 4 denote hydrogen, X 3 represents fluorine, and X 2 denotes chlorine, characterized in that a compound of the general formula II in which X 1 to X 4 have the abovementioned meaning, and X 5 represents halogen, in particular chlorine or fluorine, is reacted, without isolation of reaction products of the intermediate stages in a so-called one-pot reaction, with a compound of the general formula (III) CH-COOR 2 II , , ch-nr 3 r 3 in which (Ill) R 2 and R 3 are identical or different and represent C^-C*-alkyl, in the presence of a solvent and of a base, where appropriate heating to 50 to 150°C, to give a compound of the general formula IV this compound IV is subjected to an amine exchange at temperatures of 50 to 120°C in the presence of the abovementioned solvents and in the presence of cyclopropylamine, resulting in a compound of the general formula V having the abovementioned radical meanings, and 5 subsequently the compound V is cyclized and hydrolysed at temperatures between 80 and 180°C in the presence of a base, and the compound of the general formula I is precipitated by addition of acid. 10
5. Process for the preparation of quinolonecarboxylic acids of the general formula I in which R 1 represents cyclopropyl, X 1 and X 2 represent chlorine, and 15 X 3 denotes fluorine, and X 4 denotes hydrogen, characterized in that a compound of the general formula II in which X 1 to X 4 have the abovementioned meaning, and X s represents halogen, in particular chlorine or fluorine, is reacted, without isolation of the reaction products of intermediate stages in a so-called one-pot reaction, with a compound of the general formula III CH-COOR 2 11 3 3 ch-nr 3 r 3 in which (III) R 2 and R 3 are identical or different and represent Cj^-C^- alkyl. in the presence of a solvent and of a base, where appropriate heating to 50 to 150°C, to give a compound of the general formula IV this compound IV is subjected to an amine exchange at temperatures of 50 to 120°C in the presence of the abovementioned solvents and in the presence of cyclopropylamine, resulting in a compound of the general formula V having the abovementioned radical meanings, and subsequently the compound V is cyclized and hydrolysed at temperatures between 80 and 180 °C in the presence of a base, and the compound of the 5.general formula I is precipitated by addition of acid.
6. A process according to Claim 1 for the preparation of a quinolonecarboxylic acid of the general formula I as specified in Claim 1, substantially as hereinbefore 10 described with particular reference to the accompanying Examples.
7. A quinolonecarboxylic acid of the general formula I given and defined in Claim 1, whenever prepared by a 15 process' claimed in a preceding claim.
IE225588A 1987-07-24 1988-07-22 Process for the preparation of quinolonecarboxylic acids IE63654B1 (en)

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DE19873724466 DE3724466A1 (en) 1987-07-24 1987-07-24 PROCESS FOR THE PREPARATION OF CHINOLON CARBOXYANESE

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IE63654B1 true IE63654B1 (en) 1995-05-31

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DE4015299A1 (en) * 1990-05-12 1991-11-14 Bayer Ag METHOD FOR PRODUCING 3-AMINO-2- (HET) -AROYL-ACRYLIC ACID DERIVATIVES
ES2039301B1 (en) * 1991-11-20 1994-05-16 Genesis Para La Investigacion PROCEDURE FOR OBTAINING NEW USEFUL SYNTHESIS INTERMEDIATES FOR THE PREPARATION OF FLUOROQUINOLONS.
DE4342186A1 (en) 1993-12-10 1995-06-14 Bayer Ag One-pot process for the production of 3-quinolonecarboxylic acid derivatives
ES2143644T3 (en) * 1994-08-02 2000-05-16 Procter & Gamble PROCEDURE TO PREPARE ANTIMICROBIAL COMPOUNDS.
DE19826050A1 (en) 1998-06-12 1999-12-16 Bayer Ag Process for the preparation of quinolonic and naphthyridonecarboxylic acids and their esters
ES2203254T3 (en) * 1998-11-18 2004-04-01 Asahi Glass Company Ltd. DERIVATIVES OF AMINOACRYLIC ACID AND CORRESPONDING PRODUCTION PROCEDURE.
US20080139574A1 (en) 2006-11-30 2008-06-12 Cadila Healthcare Limited Novel quinoline derivatives
CN101781299B (en) * 2010-01-13 2012-06-27 杭州师范大学 One-pot synthesis method for key intermediate of carbostyril medicaments
CN104292159B (en) * 2014-10-10 2016-12-07 浙江同丰医药化工有限公司 A kind of preparation method of norfloxacin, ciprofloxacin and enrofloxacin
CN111269131B (en) * 2020-03-12 2021-12-28 江苏飞宇医药科技股份有限公司 Process for preparing cyclopropyl ethyl amide by taking tri-n-propylamine as acid acceptor
CN115385856A (en) * 2022-09-05 2022-11-25 常州大学 Method for synthesizing norfloxacin intermediate by one-pot method

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PT88078A (en) 1989-06-30
AU1902488A (en) 1989-01-27
JPS6440460A (en) 1989-02-10
IL87185A (en) 1993-06-10
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AR243509A1 (en) 1993-08-31
DD281806A5 (en) 1990-08-22
UA8018A1 (en) 1995-12-26
KR890002020A (en) 1989-04-07
AU602226B2 (en) 1990-10-04
PT88078B (en) 1995-03-31
FI883452A (en) 1989-01-25
NO883046L (en) 1989-01-25
EP0300311A3 (en) 1990-12-19
SU1660582A3 (en) 1991-06-30
ZA885332B (en) 1989-04-26
HU205082B (en) 1992-03-30
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EP0300311B1 (en) 1994-09-21
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ATE111898T1 (en) 1994-10-15
DK412488A (en) 1989-01-25
CN1030911A (en) 1989-02-08
KR970010175B1 (en) 1997-06-21
IL87185A0 (en) 1988-12-30
DK412488D0 (en) 1988-07-22
FI883452A0 (en) 1988-07-21
IE882255L (en) 1989-01-24
PH25098A (en) 1991-02-19
CA1333715C (en) 1994-12-27
NO174773B (en) 1994-03-28
HUT48598A (en) 1989-06-28
JP2812956B2 (en) 1998-10-22
NO883046D0 (en) 1988-07-07
NO174773C (en) 1994-07-06
ES2058186T3 (en) 1994-11-01
DE3724466A1 (en) 1989-02-02

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