CA1325010C - Process for the preparation of quinoline carboxylic acid derivatives - Google Patents
Process for the preparation of quinoline carboxylic acid derivativesInfo
- Publication number
- CA1325010C CA1325010C CA000570183A CA570183A CA1325010C CA 1325010 C CA1325010 C CA 1325010C CA 000570183 A CA000570183 A CA 000570183A CA 570183 A CA570183 A CA 570183A CA 1325010 C CA1325010 C CA 1325010C
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- CA
- Canada
- Prior art keywords
- general formula
- stands
- process according
- halogen
- hydrogen
- 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.)
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Classifications
-
- 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
Abstract
A B S T R A C T
The invention relates to a new process for the preperation of compounds of the general Formula I
(I) (wherein R1 stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen);
R2 stands for piperazinyl or 4-methyl-piperazinyl;
R3 stands for hydrogen or fluorine) and pharmaceutically acceptable salts thereof which comprises reacting a compound of the general Formula II
(II) (wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms, R4 stands for fluorine or chlorine with a piperazine derivative of the general Formula III
(III) (wherein R5 stands for hydrogen or methyl) or a salt thereof and subjecting the compound of the general Formula IV
(IV) thus obtained (wherein R, R1, R2 and R3 are as stated above) to hydrolysis after or without isolation and if desired con-verting the compound of the general Formula I thus obtained into a salt thereof or setting free the same from its salt.
The compounds of the general Formula I are known antibacterial agents.
The advantage of the process of the present invention is that it makes the desired compounds of the general Formula I available in a simple manner, with high yields and in a short reaction time.
The invention relates to a new process for the preperation of compounds of the general Formula I
(I) (wherein R1 stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen);
R2 stands for piperazinyl or 4-methyl-piperazinyl;
R3 stands for hydrogen or fluorine) and pharmaceutically acceptable salts thereof which comprises reacting a compound of the general Formula II
(II) (wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms, R4 stands for fluorine or chlorine with a piperazine derivative of the general Formula III
(III) (wherein R5 stands for hydrogen or methyl) or a salt thereof and subjecting the compound of the general Formula IV
(IV) thus obtained (wherein R, R1, R2 and R3 are as stated above) to hydrolysis after or without isolation and if desired con-verting the compound of the general Formula I thus obtained into a salt thereof or setting free the same from its salt.
The compounds of the general Formula I are known antibacterial agents.
The advantage of the process of the present invention is that it makes the desired compounds of the general Formula I available in a simple manner, with high yields and in a short reaction time.
Description
':; "
PROCESS FOR THE PREPARATION OF QUINOLINE CARBOXYLIC ACID
DERIVATIVES
This invention relates to a new process for the preparation of 1-substituted-7-(optionally substit~ted piperazine)-6-fluoro-8-(optionally fluoro-substituted)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives of the general Formula I O
F ~ COOH
R2 ~ N /
and pharmaceutically acceptable salts thereof.
In the general Formula I ~
R1 stands for phenyl being optlonally subatituted by 1 or 2 ; -halogen atoms, or a group of the general Formula ---CH2CR6R7R8 (whereln R6, R7 and R8 stand for hydrogen or halogen);
R stands for piperazinyl or 4-methyl-piperazlnyl;
~3 stands for hydrogen or fluorine, provided that either R con~ains a halogen atom or R3 is fluorine. ; ;
It is known that a group of the 7-substituted- -carhoxylic derivatives of the general ~ormula I (wherein R2 stands for piperazinyl, 4-methyl-piperazinyl, R1 stands for a group of the general Formula -CH~CR6R7R3 (wherein R6, R7 and R8 stand for hydrogen or halogen) and R3 stands for fluorine) possesses high antibacterial activity (J.~ed. Chem. 1986, 29, ~ . .
PROCESS FOR THE PREPARATION OF QUINOLINE CARBOXYLIC ACID
DERIVATIVES
This invention relates to a new process for the preparation of 1-substituted-7-(optionally substit~ted piperazine)-6-fluoro-8-(optionally fluoro-substituted)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives of the general Formula I O
F ~ COOH
R2 ~ N /
and pharmaceutically acceptable salts thereof.
In the general Formula I ~
R1 stands for phenyl being optlonally subatituted by 1 or 2 ; -halogen atoms, or a group of the general Formula ---CH2CR6R7R8 (whereln R6, R7 and R8 stand for hydrogen or halogen);
R stands for piperazinyl or 4-methyl-piperazlnyl;
~3 stands for hydrogen or fluorine, provided that either R con~ains a halogen atom or R3 is fluorine. ; ;
It is known that a group of the 7-substituted- -carhoxylic derivatives of the general ~ormula I (wherein R2 stands for piperazinyl, 4-methyl-piperazinyl, R1 stands for a group of the general Formula -CH~CR6R7R3 (wherein R6, R7 and R8 stand for hydrogen or halogen) and R3 stands for fluorine) possesses high antibacterial activity (J.~ed. Chem. 1986, 29, ~ . .
- 2 - 13~01~
445; Dru3s of Fut. 1984, 9, 246; 23rd Intersci. Conf. Anti-microb. Agents Chemother. 1983, Abst. 658, 7th Int. Symp. Fut.
Trends Chemother. 1986, 86). These compounds can be prepared by reacting 6,7,~-trifluoro-4-cxo-1,4-dihydro-quinoline-3-c~rboxylic acid and cyclic amines (Belgian patent specifica-tion 887a74, Ga patent specification 2057444, Austrian patent specification 537813 and European patent specification 10644E9~.
Another group of the 7-substituted-quinolinz-3-carboxylic acids of the general Formula I (wherein Rl stands ~ -Eor phenyl optionally substituted by 1 or 2 halogen atoms, R2 ~ ~ -stands for piperazinyl or 4-methyl-piperazinyl and R3 stands for hydrogen) has also high antibacterial activity (24th Intersci. Conf. Antimicrob. ~ents Chemother, 1984, Abst. 72-78., Amtimicrob. Agents Chemother. 1987., 619, Antimicrob.
Agents Chemother. 1986., 192-208). These compounds can be pre-pared by reacting l-substituted phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amines -in the presence of a solvent at a temperature of 100 C for 20 hours (European patent specification 131839, J. Med. Chem. -1985, 1558., J. Med. Chem. 1987. 504.). ~-According to the present invention there is provided a -ne" process for the preparation of quinoline-3-carboxylic acid ~ ~
derivatives of the general Formula I (wherein Rl stands for ~ -phenyl optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen), R2 stands for piperazinyl, ~-methyl-piperaizinyl and R3 stands for hydrogen or fluorine) ~ -"" -"'' . ' , ', ., .' ' ' .
445; Dru3s of Fut. 1984, 9, 246; 23rd Intersci. Conf. Anti-microb. Agents Chemother. 1983, Abst. 658, 7th Int. Symp. Fut.
Trends Chemother. 1986, 86). These compounds can be prepared by reacting 6,7,~-trifluoro-4-cxo-1,4-dihydro-quinoline-3-c~rboxylic acid and cyclic amines (Belgian patent specifica-tion 887a74, Ga patent specification 2057444, Austrian patent specification 537813 and European patent specification 10644E9~.
Another group of the 7-substituted-quinolinz-3-carboxylic acids of the general Formula I (wherein Rl stands ~ -Eor phenyl optionally substituted by 1 or 2 halogen atoms, R2 ~ ~ -stands for piperazinyl or 4-methyl-piperazinyl and R3 stands for hydrogen) has also high antibacterial activity (24th Intersci. Conf. Antimicrob. ~ents Chemother, 1984, Abst. 72-78., Amtimicrob. Agents Chemother. 1987., 619, Antimicrob.
Agents Chemother. 1986., 192-208). These compounds can be pre-pared by reacting l-substituted phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amines -in the presence of a solvent at a temperature of 100 C for 20 hours (European patent specification 131839, J. Med. Chem. -1985, 1558., J. Med. Chem. 1987. 504.). ~-According to the present invention there is provided a -ne" process for the preparation of quinoline-3-carboxylic acid ~ ~
derivatives of the general Formula I (wherein Rl stands for ~ -phenyl optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen), R2 stands for piperazinyl, ~-methyl-piperaizinyl and R3 stands for hydrogen or fluorine) ~ -"" -"'' . ' , ', ., .' ' ' .
- 3 - 1325010 - ~
and pharmaceutically acceptable salts thereof which comprises reactin~ a compound of the general Formula II
R \ / R
, B~
F O (II) R4 ~ N . ;:: .
'.
R3 R1 :-(~Jherein R stands for halogen, an aliphatic acyloxy group - ~:
containing 2 to 6 carbon atoms or aromatic acyloxy group containing 7 to ll carbon atoms, R4 stands for fluorine or chlorine, Rl and R2 are as stated above) with an amine of the general Formula III
R N NH (III) ~
(~nerein R5 stands for hydrogen or methyl) or a salt thereof ~:
and subjecting the compound of the general Formula IV ::
R / R
B
O 0~
¦¦ l (IV) ~2 R3 R1 ~-. ::
thus obtained (wherein R, R1, R2 and R3 are as stated above) to hydrolysis after or without isolation and if desired con-verting the compound of the general Formula I thus obtained -into a salt thereof or setting free the same from its salt. ~-The advantage of the process of the present invention is that it enables the preparation of the compounds of the general Formula I in a simple manner, with very high yields and in a short reaction time. - ;
The boron derivatives o~ the general Formula IV are ~
,: .
new compounds.
According to a preferred form of realization of the ~-process of the present invention the boron derivative of the ;
general Formula IV is converted into the desired quinoline-3-carboxylic acid of the ~eneral Formula I without isolation.
The boron derivatives of the general Formula II can be -- -reacted with the amine of the general Formula III if desired in the presence of an inert organic solvent and an acid . ~ .
binding agent.
As inert organic solvent preferably an acid amide - -;
(e.g. dimethyl formamide, dimethyl acetamide), a ketone (e.g. ~
.' ~ ' .
. ,. . - . . ~ J . . .: ~
5 1 3250 1 0 ~
acetone, methyl ethyl l<etone), an ether (e.g. dioxane, tetra-hydrofuran, diethyl ether), an ester (e.g. ethyl acetate, methyl acetate, ethyl propionate), a sulfoxide (e.g. dimethyl sulfoxide), an alcohol (e.g. methanol, ethanol, l-decanol, butanol) may be used.
As acid binding agent an organic or inorganic base may `~
be used. From the group of organic bases trialkyl amines (e.g.
triethyl amine, tributyl amine), cyclic amines (e.g. pyridine, 1,5-diazabicyclo/5,4,û/undec-5-ene, 1,5-diazabicyclo/4.3.0/-non-5-ene, 1,4-diazabicyclo/2.2.2/octane) can be mentioned, while as inorganic base preferably hydroxides or carbonates of ~
alkali or alkaline earth metals can be applied. Thus as acid -binding agent zdvantageously potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc.
or an excess of the amine of the general Formula III can be used.
The boron derivative of the general Formula II and the amine of the general Formula III can be reacted at a tempera-ture between 0 and 200 C, depending on the solvent used. The ~ -reaction time may vary between half an hour and 10 hours. The reaction time depends on the reaction temperature, too. If the reaction is carried out at higher temperature, the reaction time can be shortened. The above reaction conditions are - ;
.:- ..
preferable values and other conditions may be used as well.
The compounds of the general Formula IV can be hydro-lysed LO the desired quinoline-3-carboxylic acids of the general Formula I, after or without isolation, under acidic or basiG conditions. The compound of the general Formula IV pre-- 6 _ 1325010 ; ~ ' cipi-tates from the reaction mixture e.g. on cooling and can be scparated e.g. by filtration or centrifuging, if desired.
Basic hydrolysis may be preferably carried out by heating, with the aid of a hydroxide or carbonate of an alkali .:
metal or an alkaline earth metal hydroxide, used as aqueous ~
solution. One may preferably use an aqueous solution of sodium ~-hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide. However, organic amines (e.g. -triethyl amine) may also be applied in the hydrolysis step.
Acidic hydrolysis may preferably be accomplished by ~
using an aqueous mineral acid. One may preferably proceed by `
hydrolysing a compound of the general Formula IV by heating ith an aqueous solution of hydrochloric acid, hydrogen, ; -bromide, sulfuric acid or phosphoric acid. Hydrolysis may also ~ -., i ., . :
be accomplished with the aid or an organic acid (e.g. acetic acid, propionic acid, etc.).
Hydrolysis of the compounds o~ the general Formula IV ~--: .
may also be carried out in aqueous medium in the presence of a water-miscible organic solvent. For this purpose e.g. alcoholsi -(e.g. methanol, ethanol), a ketone (e.g. acetone), an ether . . .
(e.g. dioxane), an acid amide (e.g. dimethyl formamide), a sulfoxide ~e.g. dimethyl sulfoxide), or pyridine may be used.
The quinoline-3-carboxylic acid of the general Formula -I thus obtained may be isolated e.g. adjusting the pH value of the aqueous solution to a suitable value and separating the `
precipitated crystals e.g. by filtration or centrifuging or by liophyli2ing the aqueous reaction mixture. - -The compounds of the general Formula I can be con-. ~ : : ::: :~ : : .. :: : : :
_ 7 _ 1325010 verted into pharmaceutically acceptable salts thereof in a known manner. Thus preferably acid addition salts can be formed, e.g. salts formed ~ith hydrogen halides, sulfonic acids, sulfuric acid or organic acids. One may form preferably chlorides, bromides, aryl sulfonates, methane sulfonates, maleates, fumarates, benzoates, etc. The compounds of the general Formula I form salts with alkali or alkaline earth metals or nther metal ions as well. Accordingly the sodium, potassium, magnesium, silver, copper salts, etc. may be pre-pared.
The compounds of the general Formula I and pharma-ceutically acceptable salts thereof can be converted into hydrates (e.g. hemihydrates, trihydrates, etc.) by methods known per se.
According to a further aspect of the present invention there are provided new compounds of the general Formula IV
(wherein R, Rl, R2 and R3 are as stated~above). -~
The starting materials of the general formula II can -~
be prepared by reacting l-phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (European patent speci-fication 131.839) or 1-ethyl-6,7,8-triiluoro-4-oxo-1,4-di- ~-hydro-quinoline-3-carboxylic acid (G8 patent speciiication 2.057.440) with a boron derivative (e.g. with a compound of the general Formula V R
B - R (V) \ R
(wherein R is halogen or an aliphatic acyloxy group containing -a - 1325010 ~: ~
. .
. ,::.~. ,.
2 to 6 carbon atoms or an aromatic acyloxy 0roup containing 7 to 11 carbon a-toms) cr with fluoroborate in aqueous or in organic mcdium.
Further details of the present invention are to be found in the following Examples without limit~ng the scope of protection to the said Examples. ~u ':.:`. :' Example 1 -,.. ,:, ::
'.::'. i''`
1.59 9 of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-. . .
quinoline-7-carboxylate-03,04)-difluoro-boron are reacted with 1.29 9 of piperazine in 8 ml of dimethyl sulfoxide at 100 C
.: :~
for 3 hours. A 6 W/v% aqueous solution of 12.6 ml of sodium -,~:.: .:
hydroxide are added and hydrolysis is carried out by heating ~
for 2 nours. The reaction mixture is filtered, the pH value is -.",.~:, .~ ,.
adjusted to 7 ~Jith 96 W/v% acetic acid and diluted with 15 ml ~ :
of water. The crystalline reaction mixture is cooled overnight and the precipitated crystals are filtered, washed with water and dried. Thus 1.61 9 of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-pipera~ino-quinoline-3-carboxylic acid are obtained.
.p. is ~34-236 C.
Analysis for the For~ula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45% -Found: C=56.75% H=5.02% N=12.4d%.
.,,,:, .': :
. ' ~ ,.~, .
: .
Example 2 1.99 9 of (1-ethyl-6,7,~-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,D4)-bis(diacetate-0)-boron are re-acted with 1.29 9 of piperazine in 8 ml of dimethyl sulfoxide at 110 C for 2 hours. A 3 W/v% aqueous solution of 20 ml of 3 W/v% sodium hydroxide are added. The reaction mixture is re-fluxed Ior an hour whereupon filtered and the pH value is adjusted to 7 with 96 W/v% acetic acid. After cooling and ~--diluting with 10 ml of water the precipitated crystals are ;
filtered and dried. Thus 1.59 9 of ochre coloured 1-ethyl-6,~-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid are obtained. M.p. is 234 C.
Analysis for the Formula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45%
Found: C=57.03% H=5.11% rJ=12.51%.
Exame~
According to Example 2 1.06 9 of (1-ethyl-6,7,~-tri-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- ~ -(propionato-0)-boron are reacted with 0.64 9 of piperazine in ~, ml of dimethyl sulfoxide. A 6 W/v% of aqueous solution of -6.3 ml of scdium hydroxide are added and the reaction mixture is refluxed for an hour. After filtration the pH value is adjusted to 7 with 96 W/v% acetic acid, 10 ml of water are added and the reaction mixture is cooled overnight. The pre-cipitated crystals are filtered, washed with water and dried.
- lO - 1 3 2 5 0 1 0 ~:
Thus 0.74 9 of 1-etbyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid are obtained. M.p. is ~ ~
232-236 C. - -Analysis for the formula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45%
Found: C=56.85% H=5.00% N=12.39%.
. '- .
Example 4 According to Example 1 1.59 9 of (1-ethyl-6,7,8-tri-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-di-fluoro-boron are reacted with 1.5 9 of l-methyl-piperazine in 8 ml of dimethyl sulfoxide. Thus 1.54 9 of 1-ethyl-6,8-di- ~ -fluoro-l,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinoline-3-' ' ,.
carboxylic acid are obtained. M.p. is 237-240 C.
Analysis for the Formula C17H19F2N3û3: -Calculated: C=58.10% H=5.45% N=11.91%
Found: C=58.00% H=5.46% N=11.95%.
....
Example 5 According to Example 2 1.99 9 of (1-ethyl-6,7,8-tri-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- , ' ' (acetato-0)-boron are reacted with 1.5 9 of l-methyl-pipera-. . -, . .
zine. Thus 1.5 9 of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(l-methyl-piperazino)-quinoline-3-carboxylic acid are obtained. M.p. is 238-240 C. ;
... :..
Analysis for the formula C17HlgF2N303:
Calculated: C=58.1û% H=5.45% ~I=11.91%
8~und: C=58.19% H=5.53% N=11.87%. ~-;''~'.'-, 1325010 - ~
Example 6 According to Example 3 1.06 9 oi (1-ethyl-6,7,8-trl-- ~
fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- `;
~propionato-0)-boron are reacted with 0.75 g oi l-methyl-plpe-razine. Thus 0.79 9 oi 1-ethyl-6,8-diiluoro-1,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinollne-3-carboxylic acid are ob-tained. M.p. is 239-24û C.
Analysis for the Formula C17H19F2N303:
Calculated: C=58.10% H=5.45% N=11.91%
Found: C=57.95% H=5.37% N=11.90%.
"~".' Examole 7 0.46 9 oi 1-(4'-iluoro-phenyl)-6-iluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis(acetato-0)-boron are reacted with 0.6 9 oi N-methyl-piperazine in 5 ml of dimethyl sulfoxide at 110 C ior an hour. 10 ml O~ 5 w/v~ ;
aqueous sodium hydrogen carbonate solution are added, the re-action mixture is reiluxed ior 2 hours whereupon the pH value is adjusted to 7 with 96 W/v% acetic acid. The reaction -- ~
mixture is cooled and the precipitated crystals are iiltered : -and ~ashed with cold water. Thus 0.359 oi 1-~4'-fluoro-phenyl)-6-fluoro-7-(N-methyl-piperazinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained. M.p. is 2a2-284 C. ~-The carboxylic acid thus obtained is dissolved in a weak solution of hydrochloride acid under heating, the solution is evaporated in V3CUO and thus the hydrochloric salt oi 1-(4'-{, ~ "'. ' ' ~ !, i, -: .. : ' '~ ' - 12 - 1325010 :~:
fluoro-phenyl)-6-fluorn-7-(N-methyl-piperazinyl)-1,4-dihydro- :. :
.. -: . - .
and pharmaceutically acceptable salts thereof which comprises reactin~ a compound of the general Formula II
R \ / R
, B~
F O (II) R4 ~ N . ;:: .
'.
R3 R1 :-(~Jherein R stands for halogen, an aliphatic acyloxy group - ~:
containing 2 to 6 carbon atoms or aromatic acyloxy group containing 7 to ll carbon atoms, R4 stands for fluorine or chlorine, Rl and R2 are as stated above) with an amine of the general Formula III
R N NH (III) ~
(~nerein R5 stands for hydrogen or methyl) or a salt thereof ~:
and subjecting the compound of the general Formula IV ::
R / R
B
O 0~
¦¦ l (IV) ~2 R3 R1 ~-. ::
thus obtained (wherein R, R1, R2 and R3 are as stated above) to hydrolysis after or without isolation and if desired con-verting the compound of the general Formula I thus obtained -into a salt thereof or setting free the same from its salt. ~-The advantage of the process of the present invention is that it enables the preparation of the compounds of the general Formula I in a simple manner, with very high yields and in a short reaction time. - ;
The boron derivatives o~ the general Formula IV are ~
,: .
new compounds.
According to a preferred form of realization of the ~-process of the present invention the boron derivative of the ;
general Formula IV is converted into the desired quinoline-3-carboxylic acid of the ~eneral Formula I without isolation.
The boron derivatives of the general Formula II can be -- -reacted with the amine of the general Formula III if desired in the presence of an inert organic solvent and an acid . ~ .
binding agent.
As inert organic solvent preferably an acid amide - -;
(e.g. dimethyl formamide, dimethyl acetamide), a ketone (e.g. ~
.' ~ ' .
. ,. . - . . ~ J . . .: ~
5 1 3250 1 0 ~
acetone, methyl ethyl l<etone), an ether (e.g. dioxane, tetra-hydrofuran, diethyl ether), an ester (e.g. ethyl acetate, methyl acetate, ethyl propionate), a sulfoxide (e.g. dimethyl sulfoxide), an alcohol (e.g. methanol, ethanol, l-decanol, butanol) may be used.
As acid binding agent an organic or inorganic base may `~
be used. From the group of organic bases trialkyl amines (e.g.
triethyl amine, tributyl amine), cyclic amines (e.g. pyridine, 1,5-diazabicyclo/5,4,û/undec-5-ene, 1,5-diazabicyclo/4.3.0/-non-5-ene, 1,4-diazabicyclo/2.2.2/octane) can be mentioned, while as inorganic base preferably hydroxides or carbonates of ~
alkali or alkaline earth metals can be applied. Thus as acid -binding agent zdvantageously potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc.
or an excess of the amine of the general Formula III can be used.
The boron derivative of the general Formula II and the amine of the general Formula III can be reacted at a tempera-ture between 0 and 200 C, depending on the solvent used. The ~ -reaction time may vary between half an hour and 10 hours. The reaction time depends on the reaction temperature, too. If the reaction is carried out at higher temperature, the reaction time can be shortened. The above reaction conditions are - ;
.:- ..
preferable values and other conditions may be used as well.
The compounds of the general Formula IV can be hydro-lysed LO the desired quinoline-3-carboxylic acids of the general Formula I, after or without isolation, under acidic or basiG conditions. The compound of the general Formula IV pre-- 6 _ 1325010 ; ~ ' cipi-tates from the reaction mixture e.g. on cooling and can be scparated e.g. by filtration or centrifuging, if desired.
Basic hydrolysis may be preferably carried out by heating, with the aid of a hydroxide or carbonate of an alkali .:
metal or an alkaline earth metal hydroxide, used as aqueous ~
solution. One may preferably use an aqueous solution of sodium ~-hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide. However, organic amines (e.g. -triethyl amine) may also be applied in the hydrolysis step.
Acidic hydrolysis may preferably be accomplished by ~
using an aqueous mineral acid. One may preferably proceed by `
hydrolysing a compound of the general Formula IV by heating ith an aqueous solution of hydrochloric acid, hydrogen, ; -bromide, sulfuric acid or phosphoric acid. Hydrolysis may also ~ -., i ., . :
be accomplished with the aid or an organic acid (e.g. acetic acid, propionic acid, etc.).
Hydrolysis of the compounds o~ the general Formula IV ~--: .
may also be carried out in aqueous medium in the presence of a water-miscible organic solvent. For this purpose e.g. alcoholsi -(e.g. methanol, ethanol), a ketone (e.g. acetone), an ether . . .
(e.g. dioxane), an acid amide (e.g. dimethyl formamide), a sulfoxide ~e.g. dimethyl sulfoxide), or pyridine may be used.
The quinoline-3-carboxylic acid of the general Formula -I thus obtained may be isolated e.g. adjusting the pH value of the aqueous solution to a suitable value and separating the `
precipitated crystals e.g. by filtration or centrifuging or by liophyli2ing the aqueous reaction mixture. - -The compounds of the general Formula I can be con-. ~ : : ::: :~ : : .. :: : : :
_ 7 _ 1325010 verted into pharmaceutically acceptable salts thereof in a known manner. Thus preferably acid addition salts can be formed, e.g. salts formed ~ith hydrogen halides, sulfonic acids, sulfuric acid or organic acids. One may form preferably chlorides, bromides, aryl sulfonates, methane sulfonates, maleates, fumarates, benzoates, etc. The compounds of the general Formula I form salts with alkali or alkaline earth metals or nther metal ions as well. Accordingly the sodium, potassium, magnesium, silver, copper salts, etc. may be pre-pared.
The compounds of the general Formula I and pharma-ceutically acceptable salts thereof can be converted into hydrates (e.g. hemihydrates, trihydrates, etc.) by methods known per se.
According to a further aspect of the present invention there are provided new compounds of the general Formula IV
(wherein R, Rl, R2 and R3 are as stated~above). -~
The starting materials of the general formula II can -~
be prepared by reacting l-phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (European patent speci-fication 131.839) or 1-ethyl-6,7,8-triiluoro-4-oxo-1,4-di- ~-hydro-quinoline-3-carboxylic acid (G8 patent speciiication 2.057.440) with a boron derivative (e.g. with a compound of the general Formula V R
B - R (V) \ R
(wherein R is halogen or an aliphatic acyloxy group containing -a - 1325010 ~: ~
. .
. ,::.~. ,.
2 to 6 carbon atoms or an aromatic acyloxy 0roup containing 7 to 11 carbon a-toms) cr with fluoroborate in aqueous or in organic mcdium.
Further details of the present invention are to be found in the following Examples without limit~ng the scope of protection to the said Examples. ~u ':.:`. :' Example 1 -,.. ,:, ::
'.::'. i''`
1.59 9 of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-. . .
quinoline-7-carboxylate-03,04)-difluoro-boron are reacted with 1.29 9 of piperazine in 8 ml of dimethyl sulfoxide at 100 C
.: :~
for 3 hours. A 6 W/v% aqueous solution of 12.6 ml of sodium -,~:.: .:
hydroxide are added and hydrolysis is carried out by heating ~
for 2 nours. The reaction mixture is filtered, the pH value is -.",.~:, .~ ,.
adjusted to 7 ~Jith 96 W/v% acetic acid and diluted with 15 ml ~ :
of water. The crystalline reaction mixture is cooled overnight and the precipitated crystals are filtered, washed with water and dried. Thus 1.61 9 of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-pipera~ino-quinoline-3-carboxylic acid are obtained.
.p. is ~34-236 C.
Analysis for the For~ula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45% -Found: C=56.75% H=5.02% N=12.4d%.
.,,,:, .': :
. ' ~ ,.~, .
: .
Example 2 1.99 9 of (1-ethyl-6,7,~-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,D4)-bis(diacetate-0)-boron are re-acted with 1.29 9 of piperazine in 8 ml of dimethyl sulfoxide at 110 C for 2 hours. A 3 W/v% aqueous solution of 20 ml of 3 W/v% sodium hydroxide are added. The reaction mixture is re-fluxed Ior an hour whereupon filtered and the pH value is adjusted to 7 with 96 W/v% acetic acid. After cooling and ~--diluting with 10 ml of water the precipitated crystals are ;
filtered and dried. Thus 1.59 9 of ochre coloured 1-ethyl-6,~-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid are obtained. M.p. is 234 C.
Analysis for the Formula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45%
Found: C=57.03% H=5.11% rJ=12.51%.
Exame~
According to Example 2 1.06 9 of (1-ethyl-6,7,~-tri-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- ~ -(propionato-0)-boron are reacted with 0.64 9 of piperazine in ~, ml of dimethyl sulfoxide. A 6 W/v% of aqueous solution of -6.3 ml of scdium hydroxide are added and the reaction mixture is refluxed for an hour. After filtration the pH value is adjusted to 7 with 96 W/v% acetic acid, 10 ml of water are added and the reaction mixture is cooled overnight. The pre-cipitated crystals are filtered, washed with water and dried.
- lO - 1 3 2 5 0 1 0 ~:
Thus 0.74 9 of 1-etbyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid are obtained. M.p. is ~ ~
232-236 C. - -Analysis for the formula C16H17F2N303:
Calculated: C=56.90% H=5.07% N=12.45%
Found: C=56.85% H=5.00% N=12.39%.
. '- .
Example 4 According to Example 1 1.59 9 of (1-ethyl-6,7,8-tri-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-di-fluoro-boron are reacted with 1.5 9 of l-methyl-piperazine in 8 ml of dimethyl sulfoxide. Thus 1.54 9 of 1-ethyl-6,8-di- ~ -fluoro-l,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinoline-3-' ' ,.
carboxylic acid are obtained. M.p. is 237-240 C.
Analysis for the Formula C17H19F2N3û3: -Calculated: C=58.10% H=5.45% N=11.91%
Found: C=58.00% H=5.46% N=11.95%.
....
Example 5 According to Example 2 1.99 9 of (1-ethyl-6,7,8-tri-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- , ' ' (acetato-0)-boron are reacted with 1.5 9 of l-methyl-pipera-. . -, . .
zine. Thus 1.5 9 of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(l-methyl-piperazino)-quinoline-3-carboxylic acid are obtained. M.p. is 238-240 C. ;
... :..
Analysis for the formula C17HlgF2N303:
Calculated: C=58.1û% H=5.45% ~I=11.91%
8~und: C=58.19% H=5.53% N=11.87%. ~-;''~'.'-, 1325010 - ~
Example 6 According to Example 3 1.06 9 oi (1-ethyl-6,7,8-trl-- ~
fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis- `;
~propionato-0)-boron are reacted with 0.75 g oi l-methyl-plpe-razine. Thus 0.79 9 oi 1-ethyl-6,8-diiluoro-1,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinollne-3-carboxylic acid are ob-tained. M.p. is 239-24û C.
Analysis for the Formula C17H19F2N303:
Calculated: C=58.10% H=5.45% N=11.91%
Found: C=57.95% H=5.37% N=11.90%.
"~".' Examole 7 0.46 9 oi 1-(4'-iluoro-phenyl)-6-iluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03,04)-bis(acetato-0)-boron are reacted with 0.6 9 oi N-methyl-piperazine in 5 ml of dimethyl sulfoxide at 110 C ior an hour. 10 ml O~ 5 w/v~ ;
aqueous sodium hydrogen carbonate solution are added, the re-action mixture is reiluxed ior 2 hours whereupon the pH value is adjusted to 7 with 96 W/v% acetic acid. The reaction -- ~
mixture is cooled and the precipitated crystals are iiltered : -and ~ashed with cold water. Thus 0.359 oi 1-~4'-fluoro-phenyl)-6-fluoro-7-(N-methyl-piperazinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained. M.p. is 2a2-284 C. ~-The carboxylic acid thus obtained is dissolved in a weak solution of hydrochloride acid under heating, the solution is evaporated in V3CUO and thus the hydrochloric salt oi 1-(4'-{, ~ "'. ' ' ~ !, i, -: .. : ' '~ ' - 12 - 1325010 :~:
fluoro-phenyl)-6-fluorn-7-(N-methyl-piperazinyl)-1,4-dihydro- :. :
.. -: . - .
4-cxo-~uinoline-3-carboxylic acid is obtained.
The proouct decomposes over 270 C.
, ~ - ., . ~. . .
Analysis for the Formula C21H19F2N303~
Calculated: C=63.15% H=~.79% N=10.52% .:
Found: C=63.27% H=4.89%N=10.35~..................................... .
,,' .''"
- .
'' :''-:...
~; ;'' ''' '~' ', ',", .:
--.. ..
.'..'. .' .:
: ~ . ~-:, . .;':, :
, "'-''''~
'',' ' : ' .
The proouct decomposes over 270 C.
, ~ - ., . ~. . .
Analysis for the Formula C21H19F2N303~
Calculated: C=63.15% H=~.79% N=10.52% .:
Found: C=63.27% H=4.89%N=10.35~..................................... .
,,' .''"
- .
'' :''-:...
~; ;'' ''' '~' ', ',", .:
--.. ..
.'..'. .' .:
: ~ . ~-:, . .;':, :
, "'-''''~
'',' ' : ' .
Claims (13)
1. Process for the preparation of compounds of the general Formula I
(I) (wherein R1 stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen);
R2 stands for piperazinyl or 4-methyl-piperazinyl;
R3 stands for hydrogen or fluorine, provided that either R1 contains a halogen atom or R3 is fluorine) and pharmaceutically acceptable salts thereof which comprises reacting a compound of the general Formula II
(II) (wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms, R4 stands for fluorine or chlorine with a piperazine derivative of the general Formula III
(III) (wherein R5 stands for hydrogen or methyl) or a salt thereof and subjecting the compound of the general Formula IV
(IV) thus obtained (wherein R, R1, R2 and R3 are as stated above) to hydrolysis after or without isolation and if required converting the compound of the general Formula I thus obtained into a salt thereof or setting free the same from its salt.
(I) (wherein R1 stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen);
R2 stands for piperazinyl or 4-methyl-piperazinyl;
R3 stands for hydrogen or fluorine, provided that either R1 contains a halogen atom or R3 is fluorine) and pharmaceutically acceptable salts thereof which comprises reacting a compound of the general Formula II
(II) (wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms, R4 stands for fluorine or chlorine with a piperazine derivative of the general Formula III
(III) (wherein R5 stands for hydrogen or methyl) or a salt thereof and subjecting the compound of the general Formula IV
(IV) thus obtained (wherein R, R1, R2 and R3 are as stated above) to hydrolysis after or without isolation and if required converting the compound of the general Formula I thus obtained into a salt thereof or setting free the same from its salt.
2. Process according to claim 1 which comprises reacting a compound of the general Formula II with an amine of the general Formula III in the presence of an organic solvent.
3. Process according to claim 2 wherein the organic solvent is an acid amide, sulfoxide, ketone, alcohol, ether or ester.
4. Process according to claim 2 wherein the organic solvent is dimethyl sulfoxide.
5. Process according to claim 1 which comprises carrying out the reaction of the compounds of the general Formulae II and III in the presence of an acid binding agent.
6. Process according to claim 5 which comprises using an amine or an excess of the compound of the general Formula III as acid binding agent.
7. Process according to claim 1 wherein the hydrolysis is carried out in acidic medium.
8. Process according to claim 7 wherein the reaction is carried out using an organic or inorganic acid.
9. Process according to claim 8 wherein the reaction is carried out using hydrochloric acid, sulfuric acid or acetic acid.
10. Process according to claim 1 wherein the hydrolysis is carried out in alkaline medium.
11. Process according to claim 10 wherein the alkaline medium comprises an alkaline metal hydroxide, an alkaline earth metal hydroxide or an organic base.
12. Process according to claim 11 wherein the alkaline medium is an aqueous triethylamine solution.
13. Compounds of the general Formula IV
(IV) (wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms;
R1 stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen);
R2 stands for piperazinyl or 4-methyl-piperazinyl;
R3 stands for hydrogen or fluorine, provided that either R1 contains a halogen atom or R3 is fluorine.
(IV) (wherein R stands for halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms or an aromatic acyloxy group containing 7 to 11 carbon atoms;
R1 stands for phenyl being optionally substituted by 1 or 2 halogen atoms, or a group of the general Formula -CH2CR6R7R8 (wherein R6, R7 and R8 stand for hydrogen or halogen);
R2 stands for piperazinyl or 4-methyl-piperazinyl;
R3 stands for hydrogen or fluorine, provided that either R1 contains a halogen atom or R3 is fluorine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU2858/87 | 1987-06-24 | ||
| HU285887A HU200175B (en) | 1987-06-24 | 1987-06-24 | Process for producing quinolinecarboxylic acid derivatives |
| HU3146/87 | 1987-07-10 | ||
| HU873146A HU199822B (en) | 1987-07-10 | 1987-07-10 | Process for production of derivatives of quinoline carbonic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1325010C true CA1325010C (en) | 1993-12-07 |
Family
ID=26317564
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000570183A Expired - Fee Related CA1325010C (en) | 1987-06-24 | 1988-06-23 | Process for the preparation of quinoline carboxylic acid derivatives |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0329719A1 (en) |
| JP (1) | JP2693988B2 (en) |
| KR (1) | KR970005911B1 (en) |
| CN (1) | CN1025028C (en) |
| CA (1) | CA1325010C (en) |
| CS (1) | CS274677B2 (en) |
| DK (1) | DK84089A (en) |
| ES (1) | ES2006994A6 (en) |
| FI (1) | FI91400C (en) |
| WO (1) | WO1988010253A1 (en) |
| YU (1) | YU46570B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4562852A (en) * | 1984-08-20 | 1986-01-07 | Britt Franklin J | Safety valve |
| US4606367A (en) * | 1985-04-04 | 1986-08-19 | Britt Franklin J | Apparatus and method for relieving pressure within a high pressure tank |
| HU198709B (en) * | 1987-04-08 | 1989-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing quinoline-carboxylic acid derivatives |
| DE548224T1 (en) * | 1990-09-11 | 1993-10-14 | Schering Corp | METHOD FOR THE PRODUCTION OF ALBUTERO AND ARYLGLYOXAL, ACETAL, HEMIACETAL AND HYDRATE INTERMEDIATES. |
| JP3165742B2 (en) * | 1991-07-16 | 2001-05-14 | 中外製薬株式会社 | Method for producing quinolone carboxylic acid derivative |
| US5869661A (en) * | 1991-07-16 | 1999-02-09 | Chugai Seiyaku Kabushiki Kaisha | Method of producing a quinolonecarboxylic acid derivative |
| ES2049636B1 (en) * | 1992-04-15 | 1994-12-16 | Genesis Para La Investigacion | PROCEDURE FOR THE PREPARATION OF QUINOLINCARBOXILIC ACID DERIVATIVES. |
| ES2077490B1 (en) * | 1992-11-18 | 1996-10-16 | Marga Investigacion | TRIMETILSILILIC ESTERS AND SOLVATES OF CHELATES OF QUINOLIN-3-CARBOXYL ACIDS. PREPARATION AND APPLICATION TO THE QUINOLON PROCESS. |
| ES2092963B1 (en) * | 1995-04-12 | 1997-12-16 | Sint Quimica Sa | PROCEDURE FOR THE PREPARATION OF ACID 1-CICLOPROPIL-6-FLUORO-1, 4-DIHIDRO-7- (1S, 4S) -5-METHYL-2,5-DIAZABICICLO (2.2.1) HEPT-2-IL) -4 -OXO-3-QUINOLINCARBOXILICO AND ITS SALTS. |
| ES2095809B1 (en) * | 1995-07-27 | 1997-12-16 | Sint Quimica Sa | PROCEDURE FOR THE PREPARATION OF NAFTIRIDIN CARBOXYLIC ACIDS AND THEIR SALTS. |
| FR2916446B1 (en) | 2007-05-24 | 2009-08-21 | Biocodex Sa | NOVEL PROCESS FOR SYNTHESIZING FLUOROQUINOLONES |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59122470A (en) * | 1982-12-27 | 1984-07-14 | Dai Ichi Seiyaku Co Ltd | Preparation of quinoline-3-carboxylic acid derivative |
| NZ208470A (en) * | 1983-07-18 | 1988-06-30 | Abbott Lab | 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives and antibacterial compositions containing such |
-
1988
- 1988-05-20 JP JP63504328A patent/JP2693988B2/en not_active Expired - Lifetime
- 1988-05-20 EP EP88904603A patent/EP0329719A1/en not_active Ceased
- 1988-05-20 KR KR1019890700325A patent/KR970005911B1/en not_active IP Right Cessation
- 1988-05-20 WO PCT/HU1988/000036 patent/WO1988010253A1/en not_active Application Discontinuation
- 1988-06-14 CS CS412388A patent/CS274677B2/en unknown
- 1988-06-21 ES ES8801926A patent/ES2006994A6/en not_active Expired
- 1988-06-23 CA CA000570183A patent/CA1325010C/en not_active Expired - Fee Related
- 1988-06-23 YU YU121788A patent/YU46570B/en unknown
- 1988-06-24 CN CN88103892A patent/CN1025028C/en not_active Expired - Fee Related
-
1989
- 1989-02-15 FI FI890723A patent/FI91400C/en not_active IP Right Cessation
- 1989-02-23 DK DK084089A patent/DK84089A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1032166A (en) | 1989-04-05 |
| YU121788A (en) | 1989-12-31 |
| KR970005911B1 (en) | 1997-04-22 |
| KR890701564A (en) | 1989-12-21 |
| CN1025028C (en) | 1994-06-15 |
| JP2693988B2 (en) | 1997-12-24 |
| CS412388A2 (en) | 1990-11-14 |
| YU46570B (en) | 1993-11-16 |
| FI91400B (en) | 1994-03-15 |
| WO1988010253A1 (en) | 1988-12-29 |
| FI890723A0 (en) | 1989-02-15 |
| JPH02500366A (en) | 1990-02-08 |
| FI890723A (en) | 1989-02-15 |
| DK84089D0 (en) | 1989-02-23 |
| FI91400C (en) | 1994-06-27 |
| ES2006994A6 (en) | 1989-05-16 |
| CS274677B2 (en) | 1991-09-15 |
| EP0329719A1 (en) | 1989-08-30 |
| DK84089A (en) | 1989-02-23 |
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