NZ204754A - Eburnane derivatives and pharmaceutical compositions - Google Patents
Eburnane derivatives and pharmaceutical compositionsInfo
- Publication number
- NZ204754A NZ204754A NZ204754A NZ20475483A NZ204754A NZ 204754 A NZ204754 A NZ 204754A NZ 204754 A NZ204754 A NZ 204754A NZ 20475483 A NZ20475483 A NZ 20475483A NZ 204754 A NZ204754 A NZ 204754A
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- racemic
- eburnane
- pharmaceutical compositions
- optically active
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £04754
204754
Priority Date(s): 30.T. fe 7
Complete Specification Filed:
Class: .C<P.?.P.4-£>} .86) h 3) jA7t$ .
Publication Date: mmmz P.O. Journal, No: . ;
NO JRAWIHfiS
Patents Form No. 5
NEW ZEALAND PATENTS ACT 1953
COMPLETE SPECIFICATION
"NOVEL EBURNANE OXIME DERIVATIVES AND PROCESS FOR PREPARING SAME"
-lr,WE RICHTER GEDEON VEGYESZETI GYAR RT. , of Budapest X. Gyomroi ut 21. Hungary, a Hungarian company,
hereby declare the invention, for which 5/we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement
(followed by paj»e t A >
2047 3 4
Eburnane-oxiine derivatives, process for their preparation, and pharmaceutical compositions containing these compounds
This invention relates to new eburnane-oxime derivatives and pharmaceutical compositions containing them as active ingredient, furthermore the invention relates to a process for preparing same active ingredient. More particularly, the invention concerns new racemic 10 or optically active eburnane-oxime derivatives of the formulae (la) and/or (lb),
(la)
N R
N R
@ X0H
(lb)
204754
wherein
R represents an alicyl group having 1 to 6 carboy atoms , and.
the configuration of the hydrogen atom in the 3-position and 5 R is Qc,oc and/or 13,13 or cc, B and/or 13,oc,-and acid addition salts thereof.
According to a further aspect of the invention there is provided a process for the preparation of racemic or optically active eburnane-oxime derivatives 10 of the formulae (la) and/or (lb) (wherein R and the configuration of the 3-hydrogen and R are as defined above), and acid addition salts thereof,
which process comprises oximating a racemic or optically active eburnamonine derivative of the formula (ll)
(n)
(wherein R and its configuration related to the 3-25 -hydrogen are the same as defined above) and, if desired, separating the ZE-isomeric mixture of the eburnane--oxime derivatives of the formulae (la) and/or (lb) obtained or, if desired, converting a Z-isomer of the formula (la) into an E-isomer of the formula (lb) and/or,
204754
if desired, resolving a raceinic eburnane-oxiiue derivative of the formula (la) or (lb) and/or, if desired, treating a racemic or optically active eburnane-oxime derivative of the formula (la) or (lb) with an acid.
The new compounds of the formula (la) possess valuable antihypoxial activity.
The term "alkyl group having 1 to 6 carbon atoms" as used herein means straight or branched chained aliphatic hydrocarbon groups having 1 to 6 carbon atoms 10 (e.g. methyl, ethyl, n-propyl, xsopropyl, n-butyl, sec.--butyl, tert.-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl, etc.).
The starting ccnpcamds of the formula (II) are prepared for example according to the Belgian patent specification No. 802,387
*-5 (available on request) and U.S. Patent Specification No. 3,753,995 or as described in the French Patent Specification No. 2,268,016 ^available on request.
The oximation of the compounds of the formula (II) is generally carried out with a tertiary g-alkyl nitrite, such as tert.-butyl nitrite, tert.—amy1 nitrite 20 or isoamyl nitrite, in the presence of a strong base,
such as an alkali metal alcoholate, e.g. potassium or sodium tert.-butylate, sodium or potassium isoamylate, potassium tert.-amylate, an alkali metal amide, e.g. lithium diisopropyl amide, or organic metal compounds, ^5 e.g. butyl-lithium. The oximation is preferably performed in an apolar organic solvent inert under the reaction conditions, preferably in an aromatic hydrocarbon, such as benzene, toluene or xylene.
2O4754
The oximation affords a mixture of the Z-isomer of the formula (la) and of the E-isomer of the formula
(lb), in which mixture the Z-isomer is the major component,
if the reaction temperature is moderate, preferably t o
D between 15 and 50 C, and the pH of the reaction mixture is neutral or slightly acidic and preferably is between 3 and "7. For example, if the reaction mixture of oximation is decomposed with an aqueous ammonium chloride solution at room temperature, essentially the Z-isomer of the 10 formula (la) is obtained, while if a dilute aqueous sulfuric acid solution is used for the decomposition, the two isomers are obtained in about equal proportion. The Z--isomer of the formula (la) is a kinetic product, which can be partially transisomerized into the thermodynamical— 15 ly more stable E-isomer of the formula (lb) by heating, especially in the presence of protons.
In the starting compounds of the formula (il) the mutual configuration of the 3-hydx*ogen and the R substituent is not changed during the process of the 20 present invention. Therefore, the configuration of the 3-hydrogen and R in the starting compounds of the formula (il) and the end products of the formulae (la) and/or (lb) is the same.
For the preparation of salts of the compou 25 of the formula (i) for example the following acids can be used: inorganic acids, such as hydrogen halide^Svk* e.g. hydrochloric acid, hydrogen bromidej sulfuric acidj phosphoric iieitJj u:itr;iu :icid; or porhuloio acids , such
, 7 5
as perchloric acid; or organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, furaaric acid, malic acid,
citric acid, ascorbic acid, salicylic acid, lactic acid, 5 cinnamic acid, benzoic acid, phenylacetic acid, j>--amino-benzoic acid, jj-hyd.ro-benzoic acid, £-amino--benzoic acid, ja-amino-salicylic acid, etc.; alkyl-sulfonic acids, such as methanesulfonic acid, ethane-sulfonic acid, etc.; cycloaliphatic sulfonic acids, I® such as eyelohexanesulfonic acid; arylsulfonic acids,
such as |>-toluene-sulfonic acid, naphthylsulfonic acid, sulfanilic acid, etc.; amino acids, such as asparaginic acid., glutaminic acid, etc.
The salts are prepared in an inert organic 15 solvent, for example an aliphatic alcohol having 1 to 6 carbon atoms, for example by dissolving a racemic or optically active compound of the formula (la) or (lb) in said solvent, and adding a corresponding acid to the solution obtained, as such or in the foxm of a solution 20 with the above solvent until the mixture becomes slightly acidic (about pH 5-6). The precipitated acid addition salt can thereafter be separated from the reaction mixture by conventional technique, e.g. by filtration.
The racemic compounds of the formula (la) 25 or (lb) can be resolved in a known manner but optically active starting materials of the formula (il) may also be employed when optically active end products are desired. Preferably-racemic compounds of the formula (la)
<i' _ ' >V /■* 4-~l'-Tr7
£ • • 4 / D
or (lb) are prepared from racemic compounds of the formula (II), while optically active compounds of the formula (la) or (lb) are obtained starting from optically active compounds of the formula (il).
If desired., the optically active or racemic compounds of the formula (la) or (lb) or acid addition salts thereof may be subjected to further purification, e.g. recrystallization. The solvents used for recrystalliza-tion are selected depending on the solubility and crys-10 tallizability of the compounds to be crystallized.
According to a still further aspect of the present invention there are provided pharmaceutical compositions which comprise as an active ingredient at least one racemic or optically active compound of the formula 15 (la) or (lb) or a pharmaceutically acceptable salt thereof, in admixture with inert solid or liquid pharmaceutical carriers and/or additives.
Hie pharmaceutical compositions can be formulated in forms suitable for parenteral or enteral administra-20 tion. As carriers for example water, gelatine, lactose,
milk sugar, starch, pectine, magnesium stearate, stearic acid., talc, vegetable oils, such as peanut oil, olive oil, etc. can be used. The compositions may be finished in the form of solid, e.g. tablets, lozenges, dragees, 25 capsules, such as hard gelatine capsules, suppositories,
et.c, , or liquid, e.g. oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc, formula-
/Lm \-.j/ y tions. The quantity of the solid, carrier can be varied within a wide range but preferably is about between 25 and 1 g. The pharmaceutical compositions optionally can contain also conventional pharmaceutical additives, such 5 as preservatives, stabilizing, wetting, emulsifying agents, salts capable of adjusting the osmotic pressure, buffers, flavouring agents, aroma agents, etc. Optionally further pharmaceutically active compounds can also be present in the formulations.
The pharmaceutical compositions are preferably manufactured in dosage units, suitable for the desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which comprise for example screening, admixing, granulating, pressing 15 or dissolving of the components. The compositions obtain^ ed can be subjected to further operations conventionally used in the pharmaceutical industry, for example sterilization.
Further details of the present invention are 20 to be found in the following Examples which are, however, by no means intended to limit the scope of the protection sought.
Example 1
(+ )-l4-Oxo-15-hydroxyimino-eburnane(3oc, l6oc)
(Z-isomer) and. its hydrochloride To a solution of 4,0 g, (13.6 minoles) of (-)-vincamone (3oc,l6oc) in 80 ml. of absolute benzene
f) '
w 4 /
13.6 ml. (l48 mmoles) of freshly distilled tert.-butyl nitrite and some minutes later 3*8 g. (3k mmoles) of potassium tert.-butylate are added. The solution is stirred at room temperature under nitrogen atmosphere 5 for 1 to 1.5 hours. The reaction mixture is decomposed with a solution of 15 g» of ammonium chloride in 150 ml of water, under ice cooling. The organic phase is separated., and the aqueous phase is shaken with three 30-ml. portions of dichloromethane. The organic phases 10 are combined, dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in vacuo. The residual oil is crystallized from methanol. 2.05 g. of the aimed compound are obtained.
Yield: 47 %.
According to thin layer chromatography the R^,--value of the end product is higher than that of the starting compound (KG-G, dichloromethane/methanol). Melting point: 158 to 159 °C (methanol).
[oOj) = +78.4° (o=1.15, chloroform).
Analysis for C^Hgi^Og (323.38):
calculated: C 70.57 %, H 6.54 N 12.99 found: C 70.60 %, H 6.60 %, N 12.92 %.
IR spectrum (KBr): 3200-2600 (broad, chelate OH), 25 1710 (CO), 1630 cm"1 (CsN).
Mass spectrum (m/e,$): 324 (M+1,24), 323 (M+,100),
306 (15), 294 (4o), 277 (53), 276 (42), 264 (10), 253 (12) ...
2 04 7 54
^H-NMR spectnun (CDCl^, <T ): 14.47 ( W, a , N-OH) , 8.40-7.27 (4H,m,aromatic), 4.26 (lH,s,3-H), 1.03 (3H,t, j=3Hz,CH2-CH3).
X3C-NMR spectrum (CDCl^,/): 158.0 (CO), 148.0 (C=N), 134.0 (C-13), 130.7 (C-2), 129.9 (C-8), 125.3-125.0 (C-10/C-ll), 118.6 (C-9), 116.8 (C-12), 115-1 (C-7), 53.5 (C-3), 50.7 (C-5), ^.8 (C-19), 44.2 (C-16), 31.0 (C-20), 23.5 (C-17), 20.6 (C-18), 16.3 (C-6), 9.0 (C-21).
To the mother liquor of the methanolic crystallization. hydrochloric acid in methanol is added, until pH=3 to yield a further 0.9 g• batch (18.3 %) of the aimed compound as a hydrochloride.
Total yield: 65-3
Example 2
( +) -l4-Oxo-15-hydroxyimino-eburnane ( 3oc , l6oc) (Z-isomer) and (-)-l4-oxo-15-hydroxyimino--eburnane (3oc,l6oc) (E-isomer)
The procedure described in Example 1 is followed until the decomposition of the reaction mixture with ammonium chloride. After decomposition of the reaction mixture the separated benzene phase is extracted with three 15-ml. portions of a 2.5 % aqueous sulfuric acid solution, the extract is alkalized until pH 9 with a concentrated, aqueous ammonium hydroxide solution under cooling with ice, whereupon it is extracted with three 30-ml. portions of dichloromethane, The organic
Z 0 4 7 5
phases are combined, dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is distilled off in vacuo. 2.4 g. of an oily product (55 $) are obtained. The product is separated by thin layer 5 chromatography into two components (KG-PFg ,
dichloromethane:methanol = 20:2, elution with acetone, the R^-value of the Z-isomer is higher than that of the E-isomer).
By crystallization of the components having 10 a higher R^-value from methanol 1.04 g. of the Z-isomer given in the title are obtained.
Yield: 24
The material having a lower R^-value is brought into a filterable state with petroleum ether, filtered 15 and dried. 0.9 g. of the E-isomer given in the title are obtained.
Yield: 20.5 %.
Melting point: 202-203 °C (petroleum ether).
[cc]^g = -198° (c=l, chloroform).
Analysis for (323.38):
calculated: N 12.99 %,
found: N 12.80 %.
Hi -NMR spectrum (CDCl^, DMSO-dg,/): 8.38-7.27 (4H,m, aromatic), 4.30 (lH,s,3-H), 0.98 (3H,t, J=8Hz, CH2CH3 ). 25 13C-NMR(CDC13, DMS0-d6,/): 156.8 (CO), 150.7 (C=7), 134.6 (13-C), 130.9 (C—2), 130.3 (C-8), 124.0 (C-10), 123.9 (C-ll), 118.2 (C-9), 116.0 (C-12), 112.4 (C-7), 52.0 (C-3), 51.4 (C-5), 45.3 (C-19), 45.1 (C-16),
Claims (2)
1 V - 11 - 2047 5 28.3 (C-20), 25.7 (C-17), 20.3 (C-18), 16.0 (C-6), 10.2 (C-21). IR spectrum (KBr): 3250 (OH, broad), 1700 (CO), 1630 cm""1 (C=N). 5 Mass spectrum (m/e,%): 324 (M+1.24), 323 (M+,100), 306 (27), 294 (46), 277 (66), 276 (62), 264 (16), 253 (13)... » - 12 - 2 047 5 4 WHAT -T7WE CLAIM IS:- rialmoi 1. Racemic or optically active eburnane-oxime derivatives of the formulae (la) and/or (lb), 10 (la) 15 20 N R OH (lb) 25 wherein R • represents an alkyl group having 1 to 6 carbon atoms, and the configuration of the hydrogen atom in the 3-position - 13 - 1J4/54 and R is «c,oc and/or (i,(i or «,Q and/or 13,oc, and acid addition salts thereof.
2. Pharmaceutical compositions, which comprise as an active ingredient at least one racemic or optically 5 active compound of the formula (la) or (Xb) (as defined in claim l) or a pharmaceutically acceptable acid addition salt thereof, in admixture with inert solid or liquid pharmaceutical carriers and/or additives. 3# Pharmaceutical compositions as claimed in claim 2 10 in forms suitable for parenteral or enteral administration. k. Pharmaceutical compositions as claimed in either of claims 2 and 3 in dosage unit form. »» - lit - i. %J 7 5 5. A process for the preparation of racemic or optically active eburnane-oxime derivatives of the formulae (la) and/or (lb) 10 (la) 15 20 . I (lb) 25 wherein R represents atoms, and an alkyl group having 1 to 6 carbon - 15 - 204754 the configuration of the hydrogen atom in the 3-position and R is a,a and/or £,fl or oc, 13 and/or £,oc, ana acid addition salts thereof, which process comprises oximating a racemic or optically active erburnamonine; derivative of the formula (II) as hereinbefore defined (wherein R and its oanfiguratioai related to the 3-*iydrogen are the same as defined above), and, if desired, separating the ZE-isomeric mixture of the eburnane-oxime derivatives of the formulae (la) and/or (lb) obtained or, if desired, converting a Z-isomer of the formula (la) into an E-isomer of the formula (lb) and/or, if desired, resolving a racemic eburnane--oxime derivative of the formula (la) or (lb) and/or, if desired, treating a racemic or optically active eburnane-oxime derivative of the formula (la) or (lb) with an acid - to form the acid addition salt thereof. 6. A process as claimed in claim 5> wherein the oximation is carried out with a tert.-C^ g-alkyl nitrite, in the presence of a strong base. 7. A process for the preparation of pharmaceutical compositions, which process comprises admixing at least one racemic or optically active compound of the formula (la) or (lb) (as defined in claim 5) or a pharmaceutically acceptable acid addition salt thereof with inert solid or liquid carriers and/or additives. 204354 - 16 - 8. A compound as claimed in claim 1 and as specifically set forth herein. 9. A process for preparing a compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU822131A HU190400B (en) | 1982-06-30 | 1982-06-30 | Process for preparing new eburnan-oxime derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ204754A true NZ204754A (en) | 1985-11-08 |
Family
ID=10957920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ204754A NZ204754A (en) | 1982-06-30 | 1983-06-29 | Eburnane derivatives and pharmaceutical compositions |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5962591A (en) |
| AT (1) | AT385990B (en) |
| AU (1) | AU554196B2 (en) |
| BE (1) | BE897148A (en) |
| CA (1) | CA1199919A (en) |
| CH (1) | CH656881A5 (en) |
| DE (1) | DE3323606A1 (en) |
| DK (1) | DK300583A (en) |
| ES (1) | ES523695A0 (en) |
| FR (1) | FR2529551B1 (en) |
| GB (1) | GB2124215B (en) |
| GR (1) | GR77525B (en) |
| HU (1) | HU190400B (en) |
| IL (1) | IL69107A (en) |
| NL (1) | NL8302298A (en) |
| NZ (1) | NZ204754A (en) |
| PT (1) | PT76951B (en) |
| SE (1) | SE457641B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU191403B (en) * | 1984-04-02 | 1987-02-27 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for preparing new, raceme and optically active 14-hydroxyimino-eburnane |
| US4735943A (en) * | 1984-06-29 | 1988-04-05 | Sanwa Kagaku Kenkyusho Co., Ltd. | Eburnamonine oxime derivatives, salts thereof, and pharmaceutical agents containing the same |
| USD1035816S1 (en) | 2022-01-14 | 2024-07-16 | Maxim Defense Industries, LLC | Combined firearm suppressor core, mount body, tube, and spring |
| USD1036611S1 (en) | 2022-01-14 | 2024-07-23 | Maxim Defense Industries, LLC | Combined firearm suppressor core, mount body, and tube |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2085630A1 (en) * | 1970-04-07 | 1971-12-31 | Le Men Georges | Vincamone compsn - having vasodilator ganglioplegic and antihistamine activity |
| FR2206090A1 (en) * | 1972-11-16 | 1974-06-07 | Omnium Chimique Sa | Homovincamone-contg. medicaments - with vasodilating, spasmolytic anti-arrhythmic and anti-ischaemic properties |
| US4315011A (en) * | 1978-07-12 | 1982-02-09 | Richter Gedeon Vegyeszeti Gyar Rt. | 1-Alkyl-9-bromohexahydroindolo quinolizium salts and use thereof to increase blood flow |
| FR2454808A1 (en) * | 1979-04-26 | 1980-11-21 | Roussel Uclaf | Syn. and anti E homo eburnane oxime - having cerebral circulation regulating activity |
-
1982
- 1982-06-30 HU HU822131A patent/HU190400B/en not_active IP Right Cessation
-
1983
- 1983-06-28 BE BE1/10823A patent/BE897148A/en not_active IP Right Cessation
- 1983-06-28 CH CH3529/83A patent/CH656881A5/en not_active IP Right Cessation
- 1983-06-29 AU AU16396/83A patent/AU554196B2/en not_active Ceased
- 1983-06-29 NZ NZ204754A patent/NZ204754A/en unknown
- 1983-06-29 ES ES523695A patent/ES523695A0/en active Granted
- 1983-06-29 GR GR71804A patent/GR77525B/el unknown
- 1983-06-29 CA CA000431474A patent/CA1199919A/en not_active Expired
- 1983-06-29 NL NL8302298A patent/NL8302298A/en not_active Application Discontinuation
- 1983-06-29 FR FR8310734A patent/FR2529551B1/en not_active Expired
- 1983-06-29 IL IL69107A patent/IL69107A/en unknown
- 1983-06-29 PT PT76951A patent/PT76951B/en unknown
- 1983-06-29 AT AT0239083A patent/AT385990B/en not_active IP Right Cessation
- 1983-06-29 JP JP58116245A patent/JPS5962591A/en active Pending
- 1983-06-29 DK DK300583A patent/DK300583A/en not_active Application Discontinuation
- 1983-06-29 GB GB08317612A patent/GB2124215B/en not_active Expired
- 1983-06-29 SE SE8303719A patent/SE457641B/en not_active IP Right Cessation
- 1983-06-30 DE DE19833323606 patent/DE3323606A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CA1199919A (en) | 1986-01-28 |
| ES8500619A1 (en) | 1984-11-01 |
| AT385990B (en) | 1988-06-10 |
| HU190400B (en) | 1986-08-28 |
| FR2529551A1 (en) | 1984-01-06 |
| FR2529551B1 (en) | 1985-10-18 |
| ES523695A0 (en) | 1984-11-01 |
| IL69107A (en) | 1986-03-31 |
| CH656881A5 (en) | 1986-07-31 |
| NL8302298A (en) | 1984-01-16 |
| AU1639683A (en) | 1984-01-05 |
| PT76951A (en) | 1983-07-01 |
| ATA239083A (en) | 1987-11-15 |
| DE3323606A1 (en) | 1984-01-12 |
| SE8303719L (en) | 1983-12-31 |
| GB8317612D0 (en) | 1983-08-03 |
| DK300583D0 (en) | 1983-06-29 |
| GR77525B (en) | 1984-09-24 |
| JPS5962591A (en) | 1984-04-10 |
| GB2124215B (en) | 1985-08-29 |
| AU554196B2 (en) | 1986-08-14 |
| SE8303719D0 (en) | 1983-06-29 |
| GB2124215A (en) | 1984-02-15 |
| DK300583A (en) | 1983-12-31 |
| SE457641B (en) | 1989-01-16 |
| BE897148A (en) | 1983-12-28 |
| IL69107A0 (en) | 1983-10-31 |
| PT76951B (en) | 1986-01-24 |
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