LV11462B - Enantiomers of 4- (5- fluoro- 2,3- dihydro- 1h- inden- 2- yl)- 1h- imidazole - Google Patents
Enantiomers of 4- (5- fluoro- 2,3- dihydro- 1h- inden- 2- yl)- 1h- imidazole Download PDFInfo
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- LV11462B LV11462B LVP-95-376A LV950376A LV11462B LV 11462 B LV11462 B LV 11462B LV 950376 A LV950376 A LV 950376A LV 11462 B LV11462 B LV 11462B
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- inden
- imidazole
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- fluoro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
1 LV 11462
ENANTIOMERS OF 4-(5-FLUORO-2,3-OIHYDRO-lH-INDEN-2-YL)-lH-IMIDAZOLE
The invention provides new optical isomers of 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole and pharmaceutically acceptable salts thereof, their use and preparation. Both optical isomers are potent in the treatment of 5 cognitive disorders, aithough somewhat different pharmacological profilēs may be ascribed to them. The (-)-enantiomer is the preferred one of the two enantiomers because it has a vvider therapeutic window than the (+)-enantiomer. It is a very powerful antagonist of ^-adrenoceptors without any aļ-agonism whereas the (+)-enantiomer is a moderate antagonist of 02-1 0 adrenoceptors and a full a-\ -agonist. Both enantiomers have good peroral bioavailability.
Valuable a2*adrenoceptor antagonist have been disciosed earlier e.g. in the European patent publications No. 183492, 247764 and 372954. PCT patent pubiication No. 91/18886 discloses the use of some indan-imidazoie 1 5 derivatives, especially atipamezole, in the treatment of age-related memory impairment and other cognitive disorders. International patent application No. PCT/FI92/00349 describes a group of new long-acting 4(5)-substituted indan-imidazoie derivatives vvhich are useful in the treatment of cognitive disorders. One of these indan-imidazoie derivatives is the racemate of 4-(5-fluoro-2,3-20 dihydro-1 H-inden-2-yl)-1 H-imidazole which has an asymmetric carbon atom in the position 2 of the indan ring:
The optically active enantiomers of 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole may be prepared e.g. by conversion of racemic 4-(5-fluoro-2,3-25 dihydro-1H-inden-2-yl)-1 H-imidazole into a mixture of diastereoisomers and separating these by fractional crystallization. Since 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole is a base, it may be converted into diastereoisomer salt mixture by reaction with an optically active acid, preferabiy with L-(+)- or D-(-)-tartaric acid. The diastereoisomers may be separated by repeated 3 0 crystallization e.g. from water. 2
Once the diastereoisomers have been separated the acid addition salts may be converted back to the free bases by making their aqueous Solutions alkaline with a basa (e.g. sodium hydroxide) and by extracting the llberated base into an appropriate organic solvent. 5 The (-)- and (+)-enantiomers of 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)- 1 H-imidazole react with organic or inorganic acids to form the corresponding acid addition salts, which have the same therapeutic activities as the bases. They can thus form many pharmaceutically useful acid addition salts such as chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, form ātes, 1 o tartrates, maleates, citrates, benzoates, salicylates and ascorbates.
The racemate of 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole may be prepared e.g. by nitrating 4-(2,3-dihydro-1H-inden-2-yl)-1 H-imidazole hydrochloride with a strong nitrating aģent such as ureanitrate in the presence of sulfuric acid and thereafter reducing the nitro compound to the corresponding 1 5 amino compound e.g by catalytic hydrogenation using Pt02 or Pd/C as cataiysts. The amino substituted compound is further converted to the corresponding diazonium fluoroborate with sodium nitrite in fluoboric acid at lowered temperatūra. The diazonium fluoroborate is then decomposed thermally to yield the racemate of 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H- 2 0 imidazole.
The compounds according to the invention may be administered enterally or parenterally. In the treatment of cognitive disorders the preferable daily dosage is from 0.1 to 10 mg/kg, especially preferably from 0.2 to 1 mg/kg.
The acute toxicity (LD50) for both enantiomers is about 100 mg/kg in mice 2 5 (p.o.) and about 50 mg/kg in rat.
The pharmaceutical carriers which are typically employed with the compound of the invention may be solid or liquid and are selected with the pianned manner of administration in mind. Choosing the auxiliary ingredients for the formulation is routine for those of ordinary skill in the art. 30 1. The α-adrenoceptor selectivity in vitro c^-Antagonism was determined by means of isolated, electrically stimulated prostatic portion of rat vas deferens preparation (Virtanen et al, Arch. Int. Pharmacodyn et Ther., 297,190-204, 1989). In this modei, <X2-agonist (detomidine) blocks electrically stimulated muscular contractions and the effect 3 LV 11462 of the 012-antagonist is seen by administering it prior to the agonist and by determining its pA£ value. The known a2*antagonist atipamezoie was used as a reference substance.
To obtain Information also on the selectivity of the antagonist betvveen a-\ - and 5 c^-receptors, its ability to inhibit or stimulate α-j-receptors was determined by means of isoiated epididymal portion of rat vas deferens. To determine a-j-antagonism, muscular contraction was induced by phenyiephrine and the pA2 value of the studied compound was determined as above. α-ļ -Agonist effect is presented as the pŪ2 value (negative logarithm of the moiar concentration of 1 o the compound producing 50 percent of maximal contraction). The results are given in Table 1.
Table 1. The selectivity of racemic 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazoie and its enantiomers in comparison with atipamezoie
Compound a2-Antagonism (pA2 vs detomidine) a-j-Antagonism (pA2 vs phenyl-ephrine) a-ļ-Agonism (PD2) (-)-enantiomer 9.7 6.7 no effect (+)-enantiomer 7.9 not tested 6.0 full agonist racemate 8.0 not tested 5.5 partial agonist Atipamezoie 8.0 5.0 no effect 15 2. Effects on memory
The effect of the (-)-enantiomer on leaming and memory in linear arm maze task in rats was studied. The linear arm maze is a modified version of radial arm maze, vvhich is a generally used memory tēst in rats. The (-)-enantiomer hydrochloride (0.1 mg/kg s.c.) was dissolved in distilled water. 20 Water was also used as control. Ali injections were made in a volume of 1 mi/kg.
Apparatus: The maze was a wooden platform in a shape of two crosses one after another. The stem (starting arm) was 90 cm long and 12 cm wide. The 4 five other arms (goal arms) were 50 cm long and 12 cm wide. Four goal arms vvere situated perpendiculariy to the stem and to the fifth arm vvhich located opposite to the stem. On either side of the stem and the arms were edges, 2.0 cm high. At the end of each goal arm a hole 1 cm deep and 3 cm in diameter, 5 served as a food cup. The starting platform (20 x 20 cm) was separated from the stem by a guillotine door. The door was 12 cm high and 7 cm wide. The door frame was 20 cm high and 20 cm wide. The maze was elevated 31 cm above the floor, in a low-iighted tēst room which contained other objects as well as the tēst apparatus. The holes at the end of the goal arms were baited with three 1 0 pellets of prize food (45 mg pellets Bio Serve Inc.).
Procedures: Two days prior to training, animals were piaced on a food deprivation scedule that reduces their body weights to 90% of initial vveights. During these days the rats were habituated to handling (three times/day), tēst room and prize food. On the second day they were also habituated to the 1 5 unbaited maze: three to five animals from the same cage at the same time for ten minūtes. On the third day the goal arms were baited, and the teaching trial, one rat at a time, was carried out. The rat received drug or distilled water and 60 minūtes later it was piaced in the starting platform. After ten seconds the door was opened and the rat was allowed to explore the maze until ali the baits were 20 found. Reentries into an arm previously visited during that session were counted as errors. The time to find ali the baits and correct choices made until the first mistake was recorded. At this time (teaching), every rat was allowed to stay in the maze for at least five minūtes. On the next day the proper memory and learning testing began and continued for four days (testing days 1 to 4). 2 5 Rats were given eight trials, two per day. Inter trial interval was 50 minūtes. The drug or distilled vvater were administered 30 minūtes before the first trial of the day. Othervvise testing trials were identical to the teaching trial. There were 20 animals in both groups.
Statistical analysis: The results were expressed as mean errors/trial, 3 o mean correct choices/trial and mean time/trial (seconds) .The analysis of variance for the repeated measurements (ANOVA) was used to compare the effects of the drug and the testing day on learning and memory.
The results: The effects of the (-)-enantiomer on learning and memory are presented in the Figurēs 1,2 and 3. The drug decreased the number of errors 3 5 i.e. reentries into the arms already visited during the same trial (Fig 1). The (-)-enantiomer also increased the number of correct choices made before the first 5 LV 11462 error of the trial (Fig 2). These are thought to mean an effect on working memory and on the ability to concentrate on the trial, respectiveiy. The drug also tended to decrease the time to soive the task (Fig 3). It is considered as an effect on speed to make decisions, in this case the correct choices. The number of errors 5 and time decreased and the number of correct choices increased trial by trial which indicates learning also in the control group. There were no group x trial interactions, which means that the effect of the (-)-enantiomer did not depend on the trial. These results suggest that the (-)-enantiomer has learning and memory enhancing effects on adult rats. 1 o 3. The preparation of the optically active isomers
Racemic 4-f5-fluoro-2.3-dihvdro-1 H-inden-2-vn-1 H-imidazole
Concentrated sulphuric acid (58 ml) was cooled to -10°C and the mixture of 4-(2,3-dihydro-1H-inden-2-yl)-1 H-imidazole hydrochloride (Karjalainen, A. J. et al U.S. 4,689,339; 13.8 g, 0.0625 mol) and ureanitrate (7.70 g, 0.0625 mol) 1 5 was added in small portions to the acid solution at -10°C. After the reaction the solution was poured onto ice. The solution was made alkaline and extracted three times with ethyl acetate. The organic extracts were combined, dried and evaporated to dryness. The yield 13.0 g, 91 % of 4-(2,3-dihydro-5-nitro-1 H-inden-2-yl)-1 H-imidazole. 2 0 Reduction of 4-(2,3-dihydro-5-nitro-1 H-inden-2-yl)-1 H-imidazole to 4-(5- amino-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole was carried out by adding 1.0 g of 10% palladium on carbon to 11.7 g (0.0512 mol) of 4-(2,3-dihydro-5-nitro-1 H-inden-2-yl)-1 H-imidazole in 100 ml of ethanol and shaking the mixture in a hydrogen atmosphere at the room temperature. When the reduction came to a 2 5 standstill the catalyst was ramoved. The filtrate was concentrated to give 9.63 g (94 %) of 4-(5-amino-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole. The product was purified by flash chromatography eluting with methylene chloride -methanol (9.5:0.5). A flask containing fluoboric acid (48 wt. % solution in vvater, 120 ml) and 3 0 9.50 g (0.0475 mol) of 4-(5-amino-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole was placed in an ice-salt bath and cooled to 0 °C. A solution of 3.30 g (0.0478 mol) of sodium nitrite in 10 ml of water was run in slowly while the temperatūra was ķept at 0 °C. The mixture was stirred for an hour at 0 °C and then for an hour at the room temperatūra. The reaction mixture was 3 5 evaporated twice to dryness with toluene. The thermal decomposition was 6 carried out in a flask vvhich was heated with an electric heating mantle. When the generation of vvhite tumes of boron trifluoride ceased the heating was stopped. The crude product was dissoived in methanoi, the solution was filtered and evaporated to dryness. The yield of the crude 4-(5-fluoro-2,3-dihydro-1 H-5 inden-2-yl)-1 H-imidazole was 9.51 g, 99 %. The product was purified by flash chromatography (the eluent methylene chloride - methanoi 9.5:0.5). 1H NMR (300 MHz, CD3OD): δ 2.96-3.08 (2H, m, one H-1 and one H-3), 3.19-3.27 (2H, m, another H-1 and another H-3), 3.68 (1H, quintet, 3Jhh 8.3 Hz, H-2), 6.80-6.86 (1H, m, H-6), 6.83 (1H, s, im-5), 6.92 (1H, dd, 3JHF8.9 1 0 Hz, 4Jhh 2.4 Hz, H-4), 7.16 (1H, dd, 3JHH 8.1 Hz, 4JhF 5.3 Hz, H-7), 7.59 (1H, s, im-4)
Separation of the enantiomers 1 5 D-(-)-Tartaric acid (0.44 g, 0.00293 mol) was dissoived in 2.5 ml of vvater at 60 °C. The racemate of 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole (1,1.03 g, 0.00509 mol) and 178 μΙ of concentrated hydrochloric acid were added at 60 °C. The mixture was stirred at 60 °C until it became a clear solution. The solution was allowed to cool slowly. The precipitates were collected and 2 0 recrystallized five times from water to give the D-(-)-tartaric acid salt of the (-)- enantiomer: mp 186-187 °C.
The D-(-)-tartaric acid adduct of the (-)-enantiomer was dissoived in vvater at 60 °C and ethy! acetate was added. The solution was made alkaline (pH 10) with diluted sodium hydroxide. The ethyl acetate phase was separated 25 and the vvater phase was extracted tvvice with ethyl acetate. The combined organic phases were vvashed with vvater. Ethyl acetate vvas evaporated to dryness and the residue vvas crystallized from ethyl acetate. The product vvas filtered by suction and vvashed vvith cold ethyl acetate: mp 139 °C (DSC), specific rotation at 20 °C in methanoi solution -3.7° (c»20 mg/ml). 30 The (-)-enantiomer base vvas dissoived in ethyl acetate and filtered by
Millipore. The filtrate vvas made acidic (pH 1) vvith dry hydrochloric acid - ethyl acetate solution and cooled to -10 °C. The precipitate vvas filtered by suction and vvashed vvith ethyl acetate. Recrystallization from ethyl acetate gavē the hydrochloride salt of (-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole as 3 5 a vvhite crystalline solid: mp 191 °C (DSC); chromatographic purity 99.8 % LV 11462 7 (HPLC); optical purity 99.9 %(HPLC); specific rotation at ambient temperatūra in water solution -3.5° (c=20 mg/ml).
The (+)-enantiomer was resolved in the same way as the (-)-isomer using L-(+)-tartaric acid as a resolving aģent to give the L-(+)-tartaric acid adduct of the 5 (+)-enantiomer: mp 187-189 °C. The base and hydrochloride salt (mp 190 °C) were made as described above. The chromatographic purity of the hydrochloride salt was 98.7 % (HPLC); optical purity 99.6 % (HPLC); specific rotation at ambient temperatūra in water solution +3.2 ° (c-20 mg/ml). 8 LV 11462
C LAIMS 1. The (-)-enantiomer of 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole and pharmaceutically acceptable salts thereof. 5 2. A method for the preparation of the (-)-enantiomer of 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole which comprises converting racemic 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole into a diastereoisomer salt mixture by reaction with an optically active acid, and then separating the mixture 1 o of diastereoisomeric salts by fractional crystallization and converting the separated (-)-enantiomer of the 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole salt to the free base. 3. The method according to ciaim 2, vvherein the optically active acid is 1 5 D-(-)-tartaric acid. 4. The (+)-enantiomer of 4-(5-fluoro-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole and pharmaceutically acceptable salts thereof. 2 0 5. A method for separating the (+)-enantiomer of 4-(5-fluoro-2,3-dihydro-1H- inden-2-yl)-1 H-imidazole which comprises converting racemic 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole into a diastereoisomer salt mixture by reaction with an optically active acid, and then separating the mixture of diastereoisomeric salts by fractional crystallization and converting the 25 separated (+)-enantiomer of the 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole salt to the free base. 6. The method according to ciaim 5, vvherein the opticaily active acid is L-(+)-tartaric acid.
Claims (6)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB939312669A GB9312669D0 (en) | 1993-06-18 | 1993-06-18 | New opticla isomers |
PCT/FI1994/000263 WO1995000492A1 (en) | 1993-06-18 | 1994-06-16 | Enantiomers of 4-(5-fluoro-2,3-dihydro-1h-inden-2-yl)-1h-imidazole |
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LV11462A LV11462A (en) | 1996-08-20 |
LV11462B true LV11462B (en) | 1996-12-20 |
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LVP-95-376A LV11462B (en) | 1993-06-18 | 1995-12-19 | Enantiomers of 4- (5- fluoro- 2,3- dihydro- 1h- inden- 2- yl)- 1h- imidazole |
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EP (1) | EP0703903A1 (en) |
JP (1) | JPH08511554A (en) |
CN (1) | CN1125439A (en) |
AU (1) | AU6972594A (en) |
BG (1) | BG100218A (en) |
CA (1) | CA2165459A1 (en) |
CZ (1) | CZ332195A3 (en) |
EE (1) | EE9400010A (en) |
GB (1) | GB9312669D0 (en) |
HU (1) | HU211271A9 (en) |
IL (1) | IL109984A0 (en) |
LT (1) | LT3468B (en) |
LV (1) | LV11462B (en) |
NO (1) | NO955056L (en) |
NZ (1) | NZ267427A (en) |
PL (1) | PL312194A1 (en) |
SK (1) | SK157095A3 (en) |
WO (1) | WO1995000492A1 (en) |
ZA (1) | ZA944346B (en) |
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US6613907B2 (en) | 2000-11-08 | 2003-09-02 | Amr Technology, Inc. | Process for the production of piperidine derivatives with microorganisms |
US8188126B2 (en) | 2002-05-16 | 2012-05-29 | Pierre Fabre Medicament | Imidazolic compounds and use thereof as alpha-2 adrenergic receptors |
FR2839719B1 (en) * | 2002-05-16 | 2004-08-06 | Pf Medicament | NOVEL IMIDAZOLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
GB0226076D0 (en) * | 2002-11-08 | 2002-12-18 | Rp Scherer Technologies Inc | Improved formulations containing substituted imidazole derivatives |
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GB2167408B (en) * | 1984-11-23 | 1988-05-25 | Farmos Oy | Substituted imidazole derivatives and their preparation and use |
FI81092C (en) | 1986-05-15 | 1990-09-10 | Farmos Oy | Process for the preparation of therapeutically active 4 (5) - (2,3-dihydro-1H-inden-2-yl) imidazole derivatives |
GB2225782A (en) | 1988-12-09 | 1990-06-13 | Farmos Group Limited | Imidazole derivatives useful for treatment of diabetes |
GB2244431A (en) | 1990-05-31 | 1991-12-04 | Farmos Oy | Treatment of age related memory impairment and other cognitive disorders |
GB9127050D0 (en) * | 1991-12-20 | 1992-02-19 | Orion Yhtymae Oy | Substituted imidazole derivatives and their preparation and use |
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1993
- 1993-06-18 GB GB939312669A patent/GB9312669D0/en active Pending
-
1994
- 1994-06-10 IL IL10998494A patent/IL109984A0/en unknown
- 1994-06-15 EE EE9400010A patent/EE9400010A/en unknown
- 1994-06-16 CZ CZ953321A patent/CZ332195A3/en unknown
- 1994-06-16 WO PCT/FI1994/000263 patent/WO1995000492A1/en not_active Application Discontinuation
- 1994-06-16 JP JP7502468A patent/JPH08511554A/en active Pending
- 1994-06-16 CN CN94192476A patent/CN1125439A/en active Pending
- 1994-06-16 NZ NZ267427A patent/NZ267427A/en unknown
- 1994-06-16 SK SK1570-95A patent/SK157095A3/en unknown
- 1994-06-16 AU AU69725/94A patent/AU6972594A/en not_active Abandoned
- 1994-06-16 EP EP94918395A patent/EP0703903A1/en not_active Withdrawn
- 1994-06-16 PL PL94312194A patent/PL312194A1/en unknown
- 1994-06-16 CA CA002165459A patent/CA2165459A1/en not_active Abandoned
- 1994-06-17 LT LTIP1959A patent/LT3468B/en not_active IP Right Cessation
- 1994-06-17 ZA ZA944346A patent/ZA944346B/en unknown
-
1995
- 1995-06-23 HU HU95P/P00421P patent/HU211271A9/en unknown
- 1995-12-13 BG BG100218A patent/BG100218A/en unknown
- 1995-12-13 NO NO955056A patent/NO955056L/en unknown
- 1995-12-19 LV LVP-95-376A patent/LV11462B/en unknown
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Publication number | Publication date |
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GB9312669D0 (en) | 1993-08-04 |
BG100218A (en) | 1996-06-28 |
IL109984A0 (en) | 1994-12-29 |
WO1995000492A1 (en) | 1995-01-05 |
EP0703903A1 (en) | 1996-04-03 |
CN1125439A (en) | 1996-06-26 |
JPH08511554A (en) | 1996-12-03 |
NO955056D0 (en) | 1995-12-13 |
NO955056L (en) | 1995-12-13 |
NZ267427A (en) | 1996-10-28 |
LT3468B (en) | 1995-10-25 |
CA2165459A1 (en) | 1995-01-05 |
EE9400010A (en) | 1995-12-15 |
LTIP1959A (en) | 1995-01-31 |
ZA944346B (en) | 1995-02-15 |
PL312194A1 (en) | 1996-04-01 |
AU6972594A (en) | 1995-01-17 |
HU211271A9 (en) | 1995-11-28 |
CZ332195A3 (en) | 1996-05-15 |
LV11462A (en) | 1996-08-20 |
SK157095A3 (en) | 1996-06-05 |
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