NZ199008A - 2,3,3a,4,5,6-hexahydro-ih-indolo(3,2,1-de)(1,5)-naphthyridines - Google Patents
2,3,3a,4,5,6-hexahydro-ih-indolo(3,2,1-de)(1,5)-naphthyridinesInfo
- Publication number
- NZ199008A NZ199008A NZ199008A NZ19900881A NZ199008A NZ 199008 A NZ199008 A NZ 199008A NZ 199008 A NZ199008 A NZ 199008A NZ 19900881 A NZ19900881 A NZ 19900881A NZ 199008 A NZ199008 A NZ 199008A
- Authority
- NZ
- New Zealand
- Prior art keywords
- naphthyridine
- acid addition
- pharmaceutically acceptable
- acceptable acid
- addition salts
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Secondary Cells (AREA)
- Electrolytic Production Of Metals (AREA)
- Carbon And Carbon Compounds (AREA)
- X-Ray Techniques (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number 1 99008
199008
Priority Date{s): . ........
Complete Specification Filed:
Class: QPn R *| )Q^ Publication Date:
P.O. Journal, No: . ¥)4oQ
$3 Pi
NEW ZEALAND
PATENTS ACT, 1953
No.: Date:
COMPLETE SPECIFICATION
"NAPHTHYRIDINE DERIVATIVES"
i/We, SYNTHELABO, a French Body Corporate of 58 Rue de la Glaciere, 75621 Paris Cedex 13, France,
hereby declare the invention for which £ / we pray that a patent may be granted to fi£8/us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
(followed bv Daae lal
1 99008
- ia-
DESCRIPTION "NAPHTHYRIDINE DERIVATIVES"
The present invention relates to 2/3/3a/4,5i6-hexahydro-lH-indolo[3/211-deJ[l/ 5-naphthyridine]' derivatives/ their addition salts with pharmaceutically acceptable acids/ their preparation and pharmaceutical compositions containing them.
The naphthyridine derivatives of the present invention are those compounds of the general formula:
in which R^ is in the 9- or 10-position and represents a hydrogen atom/ a halogen atom or a alkyl or C]__4 alkoxy radical and R^ represents a hydrogen atom or a alkyl radical/ and pharmaceutically acceptable acid addition salts thereof.
These compounds contain an asymmetric carbon atom in the 3a-position. The racemates and the optically active isomers of the compounds of general formula (I) form part of the present invention.
199008
The preferred compounds of the invention are those in which represents a hydrogen, chlorine, bromine or fluorine atom or the methyl or methoxy radical and R2 represents a hydrogen atom or the methyl 5 radical and, more particularly, those in which R^
represents a hydrogen/ fluorine/ chlorine or bromine atom and R2 represents a hydrogen atom.
The compounds of general formula (I) can be prepared, for example, by reducing the conqpounds of 10 the general formula:
0
in which R^ and R2 are as hereinbefore defined/ or an acid addition salt thereof/ e.g. the hydrochloride.
The compounds of general formula (II) have 15 already been described in the literature, in particular by R.G. Taborsky et al^ , J. Med. Chem. 7 (2)/ 135-41 (1964), by G. Hahn et al_. / Ber. 71B, 2163-75 (1938),
•and by ourselves in New Zealand Patent 183846.
/ " •
- /j- cV
:
t 9900
The process of the invention consists in reducing the compounds of general formula (II) in accordance with a conventional method for the conversion of the carbonyl group (HZC=0) to methylene 5 (i.e. -CE^-), for example by treating a compound of general formula (II) with a hydride, such as lithium aluminium hydride, in the presence of a Lewis acid such as aluminium chloride. The reaction is generally carried out at a temperature of from -40 to +80°C in 10 an organic solvent such as an anhydrous ether.
Pharmaceutically acceptable acid addition salts of the naphthyridine derivatives of general formula (I), e.g. methanesulphonates, mandelates, fumarates, citrates and hydrochlorides, may be obtained 15 by methods known per se, for example by treatment of the naphthyridine base in a solvent medium, e.g. an ether, with the appropriate acid in a solvent medium, e.g. an alkanol.
By the term 'methods known per se1 as used 20 in this specification is meant methods heretofore used or described in the literature.
The following Examples illustrate the preparation of naphthyridine•derivatives of the present invention.
The analyses and the IR and NMR spectra confirm the structure of the compounds.
19900
EXAMPLE 1
2 , 3, 3a / 4, 5 / 6-Hexahydro-lH — indolcf 3,2/ 1-de] [l, 5-naphthyridine1 and its methanesulphonate
.4 g (0.04 mol) of aluminium chloride are 5 placed in a one litre three-necked flask. 50 ml of anhydrous diethyl ether are added all at once. 2.3 g (0.06 mol) of lithium aluminium hydride are added gradually to the solution obtained. The suspension obtained is stirred for 10 minutes. 10 A suspension of 5.3 g (0.02 mol) of 1,2/3/3a,4,5-hexa-hydro-6H-indolo[3 / 2,1-deJ[l,5-naphthyridineJ-6-one hydrochloride in 70 ml of anhydrous tetrahydrofuran is added gradually thereto. The mixture is stirred at ambient temperature for 30 minutes. It is then cooled 15 in an ice-bath and 10 ml of water are added slowly. The mixture is stirred for 10 minutes and 10 ml of sodium hydroxide solution (d = 1.38), 150 ml of ethyl acetate and 100 ml of water are then added successively. The mixture is stirred for 15 minutes. The organic 20 phase is decanted. The aqueous phase is extracted twice with 60 ml of ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and evaporated in vacuo on a water-bath. This yields an oil/ which is dried by azeotropic distillation 25 with toluene. The base obtained is pure according to thin layer chromatography.
199008
This oil is solubilised in 80 ml of anhydrous diethyl ether. A solution of 2 g (0.02 mol) of methanesulphonic acid in 20 ml of ethanol is added. The mixture is stirred for 30 minutes at ambient 5 temperature. The white precipitate obtained is filtered off, washed with diethyl ether and dried in a desiccator. The methanesulphonate salt of the naphthyridine product is recrystallised from 80 ml of ethanol. Its melting point is 246-248°C.
EXAMPLE 2
-Chloro-2/313ai 4/5,6-hexahydro-lH-indolo-[3,2,1-deJ[l,5-naphthyridineJ and its methane-sulphonate
2.25 g (0.0168 mol) of anhydrous aluminium 15 chloride, 25 ml of anhydrous diethyl ether and 0.96 g (0.0252 mol) of lithium aluminium hydride are placed in a 500 cc three-necked round-bottomed flask. A suspension of 2.5 g (0.0084 mol) of 10-chloro-1/2/3,3a,4,5-hexahydro~6H-indolo[3,2,1-deJ[l, 5-20 naphthyridine]-6-one hydrochloride in 60 ml of anhydrous tetrahydrofuran is added to the resulting suspension, whilst stirring. When the introduction has ended, a grey solution is obtained, which is stirred for half an hour. The complete disappearance of the starting 25 material is monitored by thin layer chromatography.
1 9900
The complex is destroyed by slowly adding 5 ml of water and then 15 ml of sodium hydroxide solution (d = 1.38). The medium is diluted with 150 ml of water and extraction is then carried out three times with 70 ml of ethyl acetate. The extract is washed with water and then dried over sodium sulphate.
It is filtered.
A solution of 0.9 g (0.0093 mol) of methanesulphonic acid in 2 ml of ethyl acetate is added to the filtrate. The resulting precipitate is filtered off, and recrystallised from about 50 ml of methanol in the presence of decolorising charcoal. The mixture is filtered hot. The filtrate deposits crystals. These are filtered off and dried. The methanesulphonate of the naphthyridine product melts at 275-278°C.
The following Table shows the compounds of the invention which were prepared by way of •examples in accordance with the method described above.
199008
TABLE
R,
Compound
R1
R2
Base or salt
Melting point
(°c)
1
(Example 1)
H
H
m. s.
246-248
2
io-ch3
H
base
122-3
3
io-ch3o
H
m. s.
248-250
4
-F
H
HC1
>300
(Example 2)
-Cl
H
base m. s.
142-3 275-8
6
H
ch3
m. s.
>260
- 7
9-Cl
H
m. s.
251-253
8
-Br
H
m • s.
265
9
9-CH30
H
m. s.
214-6
(m.s. = methane sulphonate)
1 990
The compounds of the invention formed the subject of a pharmacological study.
1. TOXICITY
The 50% lethal dose (LD 50) of the compounds 5 is determined on mice of the CD1 strain by a graphical method. The LD 50 is from 120 to 500 mg/kg/ administered intraperitoneally.
2. HYPOXIA CAUSED BY PRESSURE REDUCTION
Mice of the CD1 strain are kept in an oxygen-10 depleted atmosphere produced by creating a partial vacuum (190 mm of mercury/ corresponding to 5.25% of oxygen).
The survival time of the animals is noted.
This time is increased by agents which are capable of 15 assisting the oxygenation of tissues and in particular of the brain. The compounds studied are administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control 20 animalS/are calculated. The mean active dose (MAD), that is to say the dose which increases the survival time by 100%/ is determined graphically. The MAD is from 10 to 15 mg/kg.
3. ACTION ON THE DURATION OF THE "SLEEP" INDUCED BY 25 SODIUM 4-HYDROXBUTYRATE
This action was determined by the influence
\ 99008
_ 9 _
of a compound on the duration of the "sleep" induced in curarised rats by sodium 4-hydroxybutyrate (GMB).
The animals used are male rats of the Charles River strain/ weighing 200 + 20 g. The 5 animals/ which have been curarised with alloferine at a rate of 1 mg/kg, administered intraperitoneally/ are placed under artificial respiration with the aid of a mask applied to the snout (breathing rate: 50/minute; breathing volume: 14 cc).
The oesophagus is ligated beforehand in order to prevent air from entering the stomach.
Fronto-parietal and fronto-occipital cortical electrodes make it possible to record the electrocorticographic activity on a model 79 P Grass 15 polygraph at a speed of 6 mm/second.
The animal is prepared under local anaesthetic (2% strength xylocaine). The rats are kept at constant temperature (37.5°C) throughout the experiment. Ten minutes after the rat has been 20 prepared/ a 200 mg/kg dose of sodium 4-hydroxybutyrate is injected intravenously into the tail.
A 10 mg/kg dose of the compound to be studied is administered intraperitoneally/ 3 minutes after the administration of the sodium 4-hydroxybutyrate. 25 The graphs are evaluated at 15-minute intervals for 75 minutes after the injection of the
1 9900
"GHB". During this period of analysis/ the total duration of the "sleep" is determined. A series of 15 controls makes it possible to specify the duration of the "GHB sleep".
Statistical analysis of the results is carried out using the Mann-Whitney "U" test.
The reduction in the duration of the "sleep" is from 25 to 40%.
The pharmacological study of the compounds 10 of the invention shows that they are active in the test for the hypoxia caused in mice by pressure reduction/ whilst at the same time being only slightly toxic/ and that they exert a significant waking action in the test for the "sleep" induced by 15 sodium 4-hydroxybutyrate.
The compounds of the invention, which possess an anti-anoxia action and a psychotropic action, can be used in therapy for the treatment of vigilance disorders/ in particular for combating 20 the behavioural disorders which can be attributed to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics/ and also for the treatment of epileptic vertigo due to cranial traumatisms/ for the treatment of metabolic 25 encephalopathies and for the treatment of depressive states.
1 9900
- n -
The invention consequently includes pharmaceutical compositions containing, as active ingredient, a naphthyridine derivative of general formula (I), or a pharmaceutically acceptable acid 5 addition salt thereof, in association with any excipients which are suitable for their administration, in particular their oral or parenteral administration.
The methods of administration can be oral and parenteral.
The daily posology can range from 10 to 100 mg of naphthyridine derivative. The dosage units can therefore contain, for example, 2 to 50 mg doses of active substance associated with customary excipients, and can be presented in the form of tablets, coated 15 tablets, capsules, suspensions or solutions to be taken orally or injected.
Particularly preferred naphthyridine derivatives of the invention are 2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de][l,5-naphthyridine], 20 10-chloro-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de]-[l,5-naphthyridine], 10-fluoro-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de][1,5-naphthyridine] and 10-bromo-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de]-[l,5-naphthyridine], and their pharmaceutically 25 acceptable acid addition salts.
199008
Claims (15)
1. 2/3/3a,4,5/6-Hexahydro-lH-indolo-[3,2,1-de][1/5-naphthyridine] derivatives/ in the form of racemates or enantiomers/ of the general formula: in which R^ is in the 9- or 10-position and represents a hydrogen atom/ a halogen atom or a C2.-4 or (~'i_4 alkoxy radical and R2 represents a hydrogen atom or a C^_^ alkyl radical/ and pharmaceutically acceptable acid addition salts thereof.
2. Naphthyridine" derivatives according to claim 1 in which R^ represents a hydrogen or halogen atom or a alkyl or cj__4 alkoxy radical and R2 represents an alkyl radical/ and pharmaceutically acceptable acid addition salts thereof.
3. Naphthyridine derivatives according to claim 1 in which R^ represents a halogen atom or a C^_^ alkyl or alkoxy radical and R2 represents a hydrogen atom or a al^yl radical/ and pharmaceutically acceptable acid addition salts thereof. 199008 - 13 -
4. Naphthyridine derivatives according to claim 1 in which represents a hydrogen, chlorine, bromine or fluorine atom or the methyl or methoxy radical and R2 represents a hydrogen atom or the methyl radical/ and pharmaceutically acceptable acid addition salts thereof.
5. Naphthyridine derivatives according to claim 1 in which R^ represents a hydrogen, fluorine^ chlorine or bromine atom and R2 represents a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof.
6. 2,3.3a,4,5, 6-Hexahydro-lH-indolo[3, 2,1-del-[l,5-naphthyridineJ and its pharmaceutically acceptable acid addition salts.
7. 10-Chloro-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-deJ[l,5-naphthyridine] and its 1 pharmaceutically acceptable acid addition salts.
8. 10-Fluoro-2,3,3a,4,5,6-hexahydro-lH-indolo{3,2,1-de][1«5-naphthyridine] and its pharmaceutically acceptable acid addition salts.
9. 10-Bromo-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de][l,5-naphthyridine] and its pharmaceutically acceptable acid addition salts.
10. A process for the preparation of a naphthyridine derivative of the general formula depicted 1 9900 - 14 - in claim 1 which comprises reducing the carbonyl group of a compound of the general formula: (wherein R-^ and R2 are as defined in claim 1) , or an acid addition salt thereof, to methylene.
11. A process according to claim 10 in which a hydridei in the presence of a Lewis acid* is used for the reduction.
12. A process according to claim 10 in which the reduction of the carbonyl group to methylene is carried out with lithium aluminium hydride in the presence of aluminium chloride.
13. A process according to claim 10, 11 or 12 followed by the step of converting by methods known per se a naphthyridine derivative of the general formula depicted in claim 1 so obtained into an acid addition salt.
14. Pharmaceutical compositions which comprise, as active ingredient, at least one naphthyridine derivative as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable acid addition salt thereof, in association with any suitable excipient. 1 9900 15
15. Naphthyridine derivatives of the general formula depicted in claim 1, wherein and R2 are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, for use as a medicament and/ more especially, for the treatment of vigilance disorders/ in particular for combating the behavioural disorders which can be attributed to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics/ and also for the treatment of epileptic vertigo due to cranial traumatisms, for the treatment of metabolic encephalopathies and for the treatment of depressive states. :;'^°risod A^'nte" '"!• J- • ..v a CL a!
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8024717A FR2494693A1 (en) | 1980-11-21 | 1980-11-21 | DERIVATIVES OF HEXAHYDRO-2,3,3A, 4,5,6 1H-INDOLO (3,2,1-DE) (NAPHTHYRIDINE-1,5), THEIR PREPARATION AND THEIR THERAPEUTIC USE |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ199008A true NZ199008A (en) | 1984-07-31 |
Family
ID=9248208
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ199008A NZ199008A (en) | 1980-11-21 | 1981-11-20 | 2,3,3a,4,5,6-hexahydro-ih-indolo(3,2,1-de)(1,5)-naphthyridines |
Country Status (22)
Country | Link |
---|---|
JP (1) | JPS57116070A (en) |
AT (1) | AT379594B (en) |
AU (1) | AU546924B2 (en) |
BE (1) | BE891204A (en) |
CA (1) | CA1162544A (en) |
CH (1) | CH649549A5 (en) |
DE (1) | DE3143179A1 (en) |
DK (1) | DK515681A (en) |
ES (1) | ES8207176A1 (en) |
FR (1) | FR2494693A1 (en) |
GB (1) | GB2087889B (en) |
GR (1) | GR78026B (en) |
IE (1) | IE52160B1 (en) |
IL (1) | IL64328A (en) |
IT (1) | IT1195292B (en) |
LU (1) | LU83775A1 (en) |
NL (1) | NL8105282A (en) |
NO (1) | NO813945L (en) |
NZ (1) | NZ199008A (en) |
PT (1) | PT74019B (en) |
SE (1) | SE8106918L (en) |
ZA (1) | ZA818082B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2527210A1 (en) * | 1982-05-18 | 1983-11-25 | Synthelabo | ENANTIOMERS OF HEXAHYDRO-2,3,3A, 4,5,6 1H-INDOLO (3,2,1-DE) (NAPHTHYRIDINE-1,5), THEIR SEPARATION METHOD AND THEIR THERAPEUTIC APPLICATION |
US4997831A (en) * | 1988-09-01 | 1991-03-05 | Glaxo Group Limited | Lactam derivatives |
CN113214250B (en) * | 2021-04-28 | 2022-06-14 | 华南理工大学 | Synthetic method of fused hexahydro-1, 6-naphthyridine compound |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DD129791A5 (en) * | 1976-04-13 | 1978-02-08 | Synthelabo | PROCESS FOR THE PREPARATION OF NAPHTYRIDINE DERIVATIVES |
GB1550496A (en) * | 1976-12-31 | 1979-08-15 | Logeais Labor Jacques | 1,2,3,3a4,5-hexahydro-canthine derivatives a process for their preparation and their therapeutic applications |
-
1980
- 1980-11-21 FR FR8024717A patent/FR2494693A1/en active Granted
-
1981
- 1981-10-30 DE DE19813143179 patent/DE3143179A1/en not_active Withdrawn
- 1981-11-17 GR GR66585A patent/GR78026B/el unknown
- 1981-11-19 LU LU83775A patent/LU83775A1/en unknown
- 1981-11-20 IL IL64328A patent/IL64328A/en unknown
- 1981-11-20 NZ NZ199008A patent/NZ199008A/en unknown
- 1981-11-20 DK DK515681A patent/DK515681A/en not_active Application Discontinuation
- 1981-11-20 AU AU77700/81A patent/AU546924B2/en not_active Ceased
- 1981-11-20 PT PT74019A patent/PT74019B/en unknown
- 1981-11-20 ZA ZA818082A patent/ZA818082B/en unknown
- 1981-11-20 IE IE2722/81A patent/IE52160B1/en unknown
- 1981-11-20 JP JP56187652A patent/JPS57116070A/en active Pending
- 1981-11-20 CA CA000390531A patent/CA1162544A/en not_active Expired
- 1981-11-20 GB GB8135005A patent/GB2087889B/en not_active Expired
- 1981-11-20 IT IT25212/81A patent/IT1195292B/en active
- 1981-11-20 BE BE0/206615A patent/BE891204A/en not_active IP Right Cessation
- 1981-11-20 ES ES507317A patent/ES8207176A1/en not_active Expired
- 1981-11-20 NO NO813945A patent/NO813945L/en unknown
- 1981-11-20 CH CH7460/81A patent/CH649549A5/en not_active IP Right Cessation
- 1981-11-20 AT AT0501381A patent/AT379594B/en not_active IP Right Cessation
- 1981-11-20 SE SE8106918A patent/SE8106918L/en not_active Application Discontinuation
- 1981-11-23 NL NL8105282A patent/NL8105282A/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
PT74019B (en) | 1983-12-07 |
NL8105282A (en) | 1982-06-16 |
AU546924B2 (en) | 1985-09-26 |
ZA818082B (en) | 1982-10-27 |
GB2087889A (en) | 1982-06-03 |
DE3143179A1 (en) | 1982-06-24 |
FR2494693B1 (en) | 1983-03-04 |
ATA501381A (en) | 1985-06-15 |
BE891204A (en) | 1982-05-21 |
IE812722L (en) | 1982-05-21 |
IL64328A0 (en) | 1982-02-28 |
GB2087889B (en) | 1984-01-25 |
NO813945L (en) | 1982-05-24 |
CA1162544A (en) | 1984-02-21 |
JPS57116070A (en) | 1982-07-19 |
GR78026B (en) | 1984-09-26 |
IE52160B1 (en) | 1987-07-22 |
LU83775A1 (en) | 1983-09-01 |
PT74019A (en) | 1981-12-01 |
CH649549A5 (en) | 1985-05-31 |
FR2494693A1 (en) | 1982-05-28 |
DK515681A (en) | 1982-05-22 |
SE8106918L (en) | 1982-05-22 |
AT379594B (en) | 1986-01-27 |
IT1195292B (en) | 1988-10-12 |
ES507317A0 (en) | 1982-09-01 |
IT8125212A0 (en) | 1981-11-20 |
AU7770081A (en) | 1982-05-27 |
IL64328A (en) | 1985-02-28 |
ES8207176A1 (en) | 1982-09-01 |
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