CA2090301C - New sulfated diosmin derivative - Google Patents
New sulfated diosmin derivative Download PDFInfo
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- CA2090301C CA2090301C CA002090301A CA2090301A CA2090301C CA 2090301 C CA2090301 C CA 2090301C CA 002090301 A CA002090301 A CA 002090301A CA 2090301 A CA2090301 A CA 2090301A CA 2090301 C CA2090301 C CA 2090301C
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- Prior art keywords
- diosmin
- hydrogensulfate
- heptakis
- sodium salt
- aluminium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The diosmin heptakis (hydrogensulfate) aluminium complex is described, as well as its preparation procedure, characterized by reacting one mole of diosmin with seven moles of a sulfating agent in a dry medium and treatment with an aqueous aluminium hydroxychloride solution of the diosmin heptakis (hydrogensulfate) sodium salt thus obtained. A
description of pharmacological assays carried out to confirm the citoprotective action of the product is included.
description of pharmacological assays carried out to confirm the citoprotective action of the product is included.
Description
' 74514-3 NEW SULFATED DIOSMIN DERIVATIVE.
The present invention relates to the diosmin heptakis (hydrogensulfate) aluminum complex (formula I), useful in the treatment of ulcerous processes.
O
OR
OR
Formula I, R= S03 [A12 (OH) 5]
Formula II, R= S03Na An earlier patent by the same authors (Spanish patent no. 8702270) describes the preparation of a related substance, the diosmin octakis (hydrogensulfate) aluminium complex, by reacting diosmin with an excess of a sulfating agent and treating the obtained product with aluminium hydroxychloride.
This invention relates to a new sulfated diosmin derivative obtained by a controlled reaction in anhydrous pyridine or alkylpyridine of one mole of diosmin with seven moles of a sulfating agent and isolated as the sodium salt (formula II) and as the aluminium complex (formula I). The molar ratio of the sulfating agent to diosmin is critical to obtain the diosmin heptakis (hydrogensulfate). The sulfating agent is selected from sulfur trioxide complexes with picolines and alkyl-substituted picolines, especially 2-picoline and 5-ethyl-2-picoline, which favour to control the process and afford exclusively the diosmin heptakis (hydrogensulfate), which is isolated as the sodium salt from the reaction medium and transformed into diosmin heptakis (hydrogensulfate) aluminium complex.
' 74514-3 Both the sodium salt and the aluminium complex of the diosmin heptakis (hydrogensulfate) are of particular interest because of their pharmacological activities, especially the aluminium complex which has proved to be very effective as antiulcerous agent. The diosmin heptakis (hydrogensulfate) aluminium complex is a yellow solid, insoluble in water and organic solvents. Heated up to 350°C it does not melt nor undergoes any changes. The diosmin heptakis (hydrogensulfate) sodium salt is a white solid which melts at 143-6°C. The hydroxyl group which remains unsulfated is that of the 5 position (formulas I and II), as confirmed by proton nuclear magnetic resonance (NMR) determinations. Hydroxyls at 5 position in flavonoids are the least reactive in the molecule and the study published in Z. Naturforsch., 43c, 625-630 (1988), which refers to the preparation of sulfated derivatives of a group of flavonoids (kaempferol, quercetin, tamarixetin, rhamnetin, eupalitin, eupatolitin and veronicafolin), none of which has the said hydroxyl sulfated, is a good reference.
However, under appropriated reaction conditions, persulfation is achieved, as referred in the Spanish patent 8702270 for diosmin octakis (hydrogensulfate) and in international patent WO 82/00586 for rutin deca (hydrogensulfate) sodium salt. In any case, if one of the hydroxyls remains unsubstituted it is always that of the 5 position, as related also in the international patent WO 82/00586, which describes how, with appropriated reactions conditions, rutin nona (hydrogensulfate) sodium salt with the free hydroxyl at 5 position is obtained.
A free hydroxyl at 5 position in a flavone is easily detected by means of NMR, because of the corresponding proton appears at a very low field position, approximately at 12-13 ppm (K. R.
Markham and T.J. Mabry, "The Flavonoids", J. Harborne, T. Marby and H. Marby Eds., page 69, Chapman and Hall Ltd., London (1975)). In the diosmin heptakis (hydrogensulfate) sodium salt NMR spectrum the 5 position hydroxyl appears at 13.1 ppm.
The present invention relates to the diosmin heptakis (hydrogensulfate) aluminum complex (formula I), useful in the treatment of ulcerous processes.
O
OR
OR
Formula I, R= S03 [A12 (OH) 5]
Formula II, R= S03Na An earlier patent by the same authors (Spanish patent no. 8702270) describes the preparation of a related substance, the diosmin octakis (hydrogensulfate) aluminium complex, by reacting diosmin with an excess of a sulfating agent and treating the obtained product with aluminium hydroxychloride.
This invention relates to a new sulfated diosmin derivative obtained by a controlled reaction in anhydrous pyridine or alkylpyridine of one mole of diosmin with seven moles of a sulfating agent and isolated as the sodium salt (formula II) and as the aluminium complex (formula I). The molar ratio of the sulfating agent to diosmin is critical to obtain the diosmin heptakis (hydrogensulfate). The sulfating agent is selected from sulfur trioxide complexes with picolines and alkyl-substituted picolines, especially 2-picoline and 5-ethyl-2-picoline, which favour to control the process and afford exclusively the diosmin heptakis (hydrogensulfate), which is isolated as the sodium salt from the reaction medium and transformed into diosmin heptakis (hydrogensulfate) aluminium complex.
' 74514-3 Both the sodium salt and the aluminium complex of the diosmin heptakis (hydrogensulfate) are of particular interest because of their pharmacological activities, especially the aluminium complex which has proved to be very effective as antiulcerous agent. The diosmin heptakis (hydrogensulfate) aluminium complex is a yellow solid, insoluble in water and organic solvents. Heated up to 350°C it does not melt nor undergoes any changes. The diosmin heptakis (hydrogensulfate) sodium salt is a white solid which melts at 143-6°C. The hydroxyl group which remains unsulfated is that of the 5 position (formulas I and II), as confirmed by proton nuclear magnetic resonance (NMR) determinations. Hydroxyls at 5 position in flavonoids are the least reactive in the molecule and the study published in Z. Naturforsch., 43c, 625-630 (1988), which refers to the preparation of sulfated derivatives of a group of flavonoids (kaempferol, quercetin, tamarixetin, rhamnetin, eupalitin, eupatolitin and veronicafolin), none of which has the said hydroxyl sulfated, is a good reference.
However, under appropriated reaction conditions, persulfation is achieved, as referred in the Spanish patent 8702270 for diosmin octakis (hydrogensulfate) and in international patent WO 82/00586 for rutin deca (hydrogensulfate) sodium salt. In any case, if one of the hydroxyls remains unsubstituted it is always that of the 5 position, as related also in the international patent WO 82/00586, which describes how, with appropriated reactions conditions, rutin nona (hydrogensulfate) sodium salt with the free hydroxyl at 5 position is obtained.
A free hydroxyl at 5 position in a flavone is easily detected by means of NMR, because of the corresponding proton appears at a very low field position, approximately at 12-13 ppm (K. R.
Markham and T.J. Mabry, "The Flavonoids", J. Harborne, T. Marby and H. Marby Eds., page 69, Chapman and Hall Ltd., London (1975)). In the diosmin heptakis (hydrogensulfate) sodium salt NMR spectrum the 5 position hydroxyl appears at 13.1 ppm.
The following examples of the preparation of the sodium salt and the aluminium complex of diosmin heptakis (hydrogensulfate) illustrate the invention but are not exhaustive.
Diosmin heptakis (hydrogensulfate) sodium salt 60 ml of 5-ethyl-2-picoline are introduced into a reaction flask provided with a condenser and a pressure compensated separatory funnel. A nitrogen stream is continuously flushed through the system, while is externally ice-water cooled.
Under good stirring 4.58 ml of chlorosulfonic acid are added dropwise. Then 6 g of anhydrous diosmin are introduced in the flask and the mixture heated during 3 hours at 60°C. The solution is then neutralized with aqueous sodium hydroxide solution to a pH of 7.0-8.0 and the two layers obtained are separated by using a separating funnel. The aqueous layer is washed with ethyl acetate and again separated, being the diosmin heptakis (hydrogensulfate) sodium salt precipitated by adding slowly and under stirring 20 ml of ethanol. The resulting solid is filtered and washed several times with ethanol and dried. It could be purified by dissolution in water and precipitation by adding ethanol. 7.1 g of the product are obtained, m. p. 143-6°C.
Elemental analysis for C28H25Na7036S7:
C Na S
Calculated (%) 25.43 12.17 16.93 Found (%) 25.02 12.56 16.68 1H NMR (DMSO-d6): 8 13.1 (lH,s,5).
Diosmin heptakis (hydrogensulfate) sodium salt 60 ml of 5-ethyl-2-picoline are introduced into a reaction flask provided with a condenser and a pressure compensated separatory funnel. A nitrogen stream is continuously flushed through the system, while is externally ice-water cooled.
Under good stirring 4.58 ml of chlorosulfonic acid are added dropwise. Then 6 g of anhydrous diosmin are introduced in the flask and the mixture heated during 3 hours at 60°C. The solution is then neutralized with aqueous sodium hydroxide solution to a pH of 7.0-8.0 and the two layers obtained are separated by using a separating funnel. The aqueous layer is washed with ethyl acetate and again separated, being the diosmin heptakis (hydrogensulfate) sodium salt precipitated by adding slowly and under stirring 20 ml of ethanol. The resulting solid is filtered and washed several times with ethanol and dried. It could be purified by dissolution in water and precipitation by adding ethanol. 7.1 g of the product are obtained, m. p. 143-6°C.
Elemental analysis for C28H25Na7036S7:
C Na S
Calculated (%) 25.43 12.17 16.93 Found (%) 25.02 12.56 16.68 1H NMR (DMSO-d6): 8 13.1 (lH,s,5).
To a diluted aqueous solution of 13.4 g of diosmin heptakis (hydrogensulfate) sodium salt 95 ml of a 15~ aluminium hydroxychloride aqueous solution are added. The solid which forms is filtered and washed several times with water, then suspended in water and pH adjusted between 5.5 and 6.5 with diluted aqueous sodium hydroxide solution. The solid is filtered, washed with water and dried at room temperature under vacuum, yielding 16.8 g of the diosmin heptakis (hydrogensulfate) aluminum complex as a yellow solid. M. p.. It does not melt at 350°C.
Elemental analysis for C28H60A11407157:
Calculated (°s) 15.75 17.70 10.49 Found (%) 16.14 17.40 10.82 The diosmin heptakis (hydrogensulfate) aluminium complex has shown to be pharmacologically active in experimental gastric and duodenal ulcer models, induced by different mechanisms (acid gastric hypersecretion, non steroidal antiinflammatories, cysteamine, stress and cold, etc.). It also shows an excellent citoprotector activity against gastric lesions induced by absolute ethanol, with a mechanism of action partially related to an increase in the synthesis and/or intraluminal release of protective prostaglandins.
The results of two pharmacological studies carried out with diosmin heptakis (hydrogensulfate) aluminium complex are described for illustrative purposes:
~ To study its protective action against indomethacin-induced gastric lesions in the rat the method of Brodie and col. (Toxicol. Appl. Pharmacol., 17, 615-624 (1970)) was used.
' 74514-3 _ 5 _ Male Wistar rats weighing 220 g were used and gastric lesions were induced by oral admininstration of indomethacin (40 mg/kg) suspended in water. A control group received only water.
Treated animals received the diosmin heptakis (hydrogensulfate) aluminium complex 30 minutes before inducing the lesions. In Table I the obtained results are shown. Code F-316 corresponds to the diosmin heptakis (hydrogensulfate) aluminium complex.
Table I. - F-316 action on indomethacin-induced gastric lesions, administered 30 minutes before the ulcerogenic agent.
DOSE LESION INDEX (mm) INHIBITION
PRODUCT mg/kg Mean + S.D. PERCENTAGE
VEHICLE - 0.00 -VEHICLE -+ 18.571 _+ 1.98 -+ 10.568 _+ 3.37 -43.09*
+ 7.965 _+ 2.26 -57.11**
+ 6.536 _+ 2.75 -64.85**
INDOMETHACIN
* p < 0.05 ** p < 0.01 according to Student's t test.
~ Diosmin heptakis (hydrogensulfate) aluminium complex action on oesophagic lesions caused by simultaneous ligation of the pylorus and the glandular-aglandular transition area of the stomach of the rat has been studied, according to the procedure of Nakamura and col. (Japan J. Pharmacol., 32, 445-456 (1982)).
It has been verified that the diosmin heptakis (hydrogensulfate) aluminium complex significantly protects the oesophagic mucose against gastric juice induced lesions. In - 5a -the same way, the disomin heptakis (hydrogensulfate) sodium salt also attains similar protection values. In Table II are shown the obtained results. Code F-316 corresponds to diosmin heptakis (hydrogensulfate) aluminium complex and F-706 to diosmin heptakis (hydrogensulfate) sodium salt.
Table II. - Effect of compounds F-316 and F-706 on acute oesophagic lesions induced by simultaneous ligation of the pylorus and the glandular-aglandular transition area in the stomach of the rat. Reference product: Aluminium hydroxide.
Treatment Dose Lesion Lesion Protection grade (mg/kg) Index 0 (LI ) Vehicle - 1 1 1 1 16 87.5 -F-316 25 9 0 0 0 1 10 88.51 Aluminium 200 2 1 3 3 1 50 42.86 Hydroxide F-706 25 7 1 1 1 0 15 82.8 Based on their pharmacological properties, the diosmin heptakis (hydrogensulfate) sodium salt and the diosmin heptakis (hydrogensulfate) aluminium complex both are useful in the therapy of ulcerous processes. They can be administered alone or formulated with appropriated excipients, using conventional pharmaceutical forms. Suitable pharmaceutical forms for oral administration include solid and liquid unit oral dosage forms such as tablets, capsules, suspensions, powders and the like, whereas for dermic application formulations as cream and ointment are preferred.
Elemental analysis for C28H60A11407157:
Calculated (°s) 15.75 17.70 10.49 Found (%) 16.14 17.40 10.82 The diosmin heptakis (hydrogensulfate) aluminium complex has shown to be pharmacologically active in experimental gastric and duodenal ulcer models, induced by different mechanisms (acid gastric hypersecretion, non steroidal antiinflammatories, cysteamine, stress and cold, etc.). It also shows an excellent citoprotector activity against gastric lesions induced by absolute ethanol, with a mechanism of action partially related to an increase in the synthesis and/or intraluminal release of protective prostaglandins.
The results of two pharmacological studies carried out with diosmin heptakis (hydrogensulfate) aluminium complex are described for illustrative purposes:
~ To study its protective action against indomethacin-induced gastric lesions in the rat the method of Brodie and col. (Toxicol. Appl. Pharmacol., 17, 615-624 (1970)) was used.
' 74514-3 _ 5 _ Male Wistar rats weighing 220 g were used and gastric lesions were induced by oral admininstration of indomethacin (40 mg/kg) suspended in water. A control group received only water.
Treated animals received the diosmin heptakis (hydrogensulfate) aluminium complex 30 minutes before inducing the lesions. In Table I the obtained results are shown. Code F-316 corresponds to the diosmin heptakis (hydrogensulfate) aluminium complex.
Table I. - F-316 action on indomethacin-induced gastric lesions, administered 30 minutes before the ulcerogenic agent.
DOSE LESION INDEX (mm) INHIBITION
PRODUCT mg/kg Mean + S.D. PERCENTAGE
VEHICLE - 0.00 -VEHICLE -+ 18.571 _+ 1.98 -+ 10.568 _+ 3.37 -43.09*
+ 7.965 _+ 2.26 -57.11**
+ 6.536 _+ 2.75 -64.85**
INDOMETHACIN
* p < 0.05 ** p < 0.01 according to Student's t test.
~ Diosmin heptakis (hydrogensulfate) aluminium complex action on oesophagic lesions caused by simultaneous ligation of the pylorus and the glandular-aglandular transition area of the stomach of the rat has been studied, according to the procedure of Nakamura and col. (Japan J. Pharmacol., 32, 445-456 (1982)).
It has been verified that the diosmin heptakis (hydrogensulfate) aluminium complex significantly protects the oesophagic mucose against gastric juice induced lesions. In - 5a -the same way, the disomin heptakis (hydrogensulfate) sodium salt also attains similar protection values. In Table II are shown the obtained results. Code F-316 corresponds to diosmin heptakis (hydrogensulfate) aluminium complex and F-706 to diosmin heptakis (hydrogensulfate) sodium salt.
Table II. - Effect of compounds F-316 and F-706 on acute oesophagic lesions induced by simultaneous ligation of the pylorus and the glandular-aglandular transition area in the stomach of the rat. Reference product: Aluminium hydroxide.
Treatment Dose Lesion Lesion Protection grade (mg/kg) Index 0 (LI ) Vehicle - 1 1 1 1 16 87.5 -F-316 25 9 0 0 0 1 10 88.51 Aluminium 200 2 1 3 3 1 50 42.86 Hydroxide F-706 25 7 1 1 1 0 15 82.8 Based on their pharmacological properties, the diosmin heptakis (hydrogensulfate) sodium salt and the diosmin heptakis (hydrogensulfate) aluminium complex both are useful in the therapy of ulcerous processes. They can be administered alone or formulated with appropriated excipients, using conventional pharmaceutical forms. Suitable pharmaceutical forms for oral administration include solid and liquid unit oral dosage forms such as tablets, capsules, suspensions, powders and the like, whereas for dermic application formulations as cream and ointment are preferred.
Claims (2)
1. Diosmine heptakis (hydrogen sulfate) aluminium complex with molecular formula in which R represents SO3(Al2(OH)5].
2. A use of a compound according to claim 1 in the treatment of an ulcerous disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES9200414 | 1992-02-25 | ||
| ES09200414A ES2041216B1 (en) | 1992-02-25 | 1992-02-25 | PROCEDURE FOR THE PREPARATION OF A NEW SULPHATE DERIVATIVE OF DIOSMINE. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2090301A1 CA2090301A1 (en) | 1993-08-26 |
| CA2090301C true CA2090301C (en) | 2000-04-11 |
Family
ID=8276183
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002090301A Expired - Fee Related CA2090301C (en) | 1992-02-25 | 1993-02-24 | New sulfated diosmin derivative |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5296469A (en) |
| EP (1) | EP0558435B1 (en) |
| JP (1) | JPH069677A (en) |
| KR (1) | KR100272646B1 (en) |
| AT (1) | ATE184014T1 (en) |
| AU (1) | AU661553B2 (en) |
| CA (1) | CA2090301C (en) |
| DE (1) | DE69326176T2 (en) |
| DK (1) | DK0558435T3 (en) |
| ES (1) | ES2041216B1 (en) |
| FI (1) | FI930812A (en) |
| GR (1) | GR3031972T3 (en) |
| MX (1) | MX9301042A (en) |
| NO (1) | NO179709C (en) |
| TW (1) | TW305845B (en) |
| ZA (1) | ZA931300B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1975297A (en) * | 1996-02-21 | 1997-09-10 | Glycomed Incorporated | Sialyl lewisx mimetics containing flavanoid backbones |
| ES2158774B1 (en) * | 1999-04-12 | 2002-03-16 | Faes Fabrica Espanola De Produ | NEW PROCEDURE FOR THE INDUSTRIAL PREPARATION OF DOSMALFATE IN POVO. |
| US7034054B2 (en) * | 2000-12-15 | 2006-04-25 | Galileo Pharmaceuticals, Inc. | Methods for the prevention and treatment of cerebral ischemia using non-alpha tocopherols |
| CN102272129B (en) * | 2009-01-03 | 2014-10-08 | 静冈县公立大学法人 | Sulfated c-glycoside, method for isolating same and method for synthesizing same |
| WO2020224452A1 (en) | 2019-05-05 | 2020-11-12 | 广州新创忆药物临床研究有限公司 | Compound for regulating body weight imbalance, composition thereof and application thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL58513A (en) * | 1978-12-04 | 1982-11-30 | American Cyanamid Co | Rutin poly(h-)sulfate salts and the preparation thereof |
| US4334058A (en) * | 1979-07-31 | 1982-06-08 | American Cyanamid Company | Rutin poly(H--)sulfate salts and related compounds |
| US4414207A (en) * | 1980-08-25 | 1983-11-08 | American Cyanamid Company | Rutin poly(H-)sulfate salts and related compounds |
| ES8707969A1 (en) * | 1986-05-09 | 1987-10-01 | Espanola Prod Quimicos | Preparation of a new diosmine derivate. |
| IT1245371B (en) * | 1991-03-28 | 1994-09-20 | Geymonat Spa | FLAVONI DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1992
- 1992-02-25 ES ES09200414A patent/ES2041216B1/en not_active Expired - Fee Related
-
1993
- 1993-02-24 CA CA002090301A patent/CA2090301C/en not_active Expired - Fee Related
- 1993-02-24 EP EP93500023A patent/EP0558435B1/en not_active Expired - Lifetime
- 1993-02-24 DE DE69326176T patent/DE69326176T2/en not_active Expired - Fee Related
- 1993-02-24 ZA ZA931300A patent/ZA931300B/en unknown
- 1993-02-24 FI FI930812A patent/FI930812A/en unknown
- 1993-02-24 AT AT93500023T patent/ATE184014T1/en not_active IP Right Cessation
- 1993-02-24 DK DK93500023T patent/DK0558435T3/en active
- 1993-02-24 AU AU33787/93A patent/AU661553B2/en not_active Ceased
- 1993-02-25 US US08/022,571 patent/US5296469A/en not_active Expired - Fee Related
- 1993-02-25 MX MX9301042A patent/MX9301042A/en not_active IP Right Cessation
- 1993-02-25 JP JP5036957A patent/JPH069677A/en not_active Withdrawn
- 1993-02-25 NO NO930670A patent/NO179709C/en not_active IP Right Cessation
- 1993-02-25 KR KR1019930002682A patent/KR100272646B1/en not_active IP Right Cessation
- 1993-03-23 TW TW082102160A patent/TW305845B/zh active
-
1999
- 1999-11-29 GR GR990403065T patent/GR3031972T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK0558435T3 (en) | 2000-03-27 |
| DE69326176D1 (en) | 1999-10-07 |
| ATE184014T1 (en) | 1999-09-15 |
| MX9301042A (en) | 1993-12-01 |
| AU661553B2 (en) | 1995-07-27 |
| AU3378793A (en) | 1993-08-26 |
| GR3031972T3 (en) | 2000-03-31 |
| NO179709C (en) | 1996-12-04 |
| EP0558435A1 (en) | 1993-09-01 |
| NO930670L (en) | 1993-08-26 |
| ZA931300B (en) | 1993-12-20 |
| FI930812A0 (en) | 1993-02-24 |
| EP0558435B1 (en) | 1999-09-01 |
| TW305845B (en) | 1997-05-21 |
| JPH069677A (en) | 1994-01-18 |
| ES2041216B1 (en) | 1994-06-16 |
| KR930017916A (en) | 1993-09-20 |
| ES2041216A1 (en) | 1993-11-01 |
| DE69326176T2 (en) | 2000-04-20 |
| KR100272646B1 (en) | 2000-11-15 |
| FI930812A (en) | 1993-08-26 |
| US5296469A (en) | 1994-03-22 |
| NO179709B (en) | 1996-08-26 |
| CA2090301A1 (en) | 1993-08-26 |
| NO930670D0 (en) | 1993-02-25 |
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