IE43210B1 - Nitrates of adenosine-5'-carboxylic acid derivatives, process for their manufacture, and pharmaceutical preparations containing them - Google Patents
Nitrates of adenosine-5'-carboxylic acid derivatives, process for their manufacture, and pharmaceutical preparations containing themInfo
- Publication number
- IE43210B1 IE43210B1 IE267/76A IE26776A IE43210B1 IE 43210 B1 IE43210 B1 IE 43210B1 IE 267/76 A IE267/76 A IE 267/76A IE 26776 A IE26776 A IE 26776A IE 43210 B1 IE43210 B1 IE 43210B1
- Authority
- IE
- Ireland
- Prior art keywords
- carboxylic acid
- nitroadenosine
- amino
- ethyl
- compounds
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
1489327 Adenosine nitrates F HOFFMANNLA ROCHE & CO AG 17 Feb 1976 [18 Feb 1975 4 July 1975] 06162/76 Heading C2C Novel compounds I and their acid addition salts in which R1 and R2 are H or NO 2 and at least one is NO 2 , and R5 is OH, C 1-6 alkoxy, amino optionally mono- or di-C 1-6 alkylated, aryl- C 1-6 alkylamino, [2 - (dimethylamino)ethyl]- amino, [2- (2,4 - dinitrophenyl) - ethyl]amino or (2 - nitrooxyethyl)amino, cycloalkylamino or an N-containing heterocyclic ring bonded via an N-atom are prepared by nitrating a compound II Compounds I affect the heart and circulatory dynamics and form with a carrier a pharmaceutical composition which may be administered orally or parenterally.
Description
The present invention relates to nitrates of adenosines’ -carboxylic acid derivatives, a process for the manufacture thereof, and pharmaceutical preparations containing same.
The compounds provided by the present invention are compounds of the general formula
wherein
2
R and R represent a hydrogen atom or a nitro group 1 2 with at least one of R and R representing a nitro group, and
R represents a hydroxy, lower alkojy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryl-(lower alkyl)amino, cycloalkylamino, [2-(dimethylamino)-ethyl]amino, [2-(2,4dinitrophenyl)-ethyl]-amino or [2-(nitro-oxy)-ethyl]-amino group, or a nitrogen-containing heterocyclic ring which is bonded via a nitrogen atom, and physiologically acceptable acid addition salts thereof.
In this specification, the expressions lower alkyl and lower alkoxy mean straight-chain or branched-chain groups containing 1-6 carbon atoms (e.g. methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, sec. butyl, sec.butoxy, tert.butyl and tert.butoxy). Examples of (lower alkyl)amino and di(lower alkyl)amino groups are methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and diisopropylamino). Examples of aryl-(lower alkyDamino groups, of which the phenyl-dower alkyl)amino groups are preferred, are the benzylamino and 1- and 2-phenylethylamino groups. The cycloalkylamino groups are especially those which contain up to 7 carbon atoms (e.g. cyclopentylamino and cyclohexylamino). The nitrogen-containing heterocyclic ring which is bonded via a nitrogen atom can contain, in addition to at least one nitrogen atom, other hetero atoms 3uch as oxygen or sulphur.
-membered and 6-membered heterocyclic rings are preferred. Examples of such rings are aziridino, azetidino, pyrrolidino, pyrrolo, imidazolidino, pyrazolino, thiazolino, thiazolidino, piperidino, morpholino and azepino.
Among “physiologically acceptable acid addition salts are salts of compounds of formula I with suitable organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, bisulphates, phosphates, acetates, lactates, oleates, nitrates, mesylates, tosylates, citrates, maleates, succinates and tartrates.
According to the process provided by the present invention, the compounds of formula I and their physiologically acceptable acid addition salts are manufactured by nitrating a compound o£ the general formula
wherein R^ has the significance given earlier, and, if desired, converting the product into a physiologically acceptable acid addition salt.
The nitration of a compound of formula Ii can be carried out according to methods known per.se.
Thus, the nitration can be carried out, for example, using nitric acid. Hydrolysis (by water formed in the reaction) or deamination (by nitrous acid which may be present) is expediently suppressed by the addition of a water-binding agent such as concentrated sulphuric acid, oleum, phosphorus pentoxide, acetic anhydride and/or a nitrile acceptor such as urea.
The nitration is expediently carried out at low temperatures, preferably at -30°C to 25°C and especially at -10°C to O°C.
There are usually obtained mixtures of the 2'-0-nitro,
31-0-nitro and 21,3'-di-0-nitro compounds in question, which mixtures can be separated according to generally known methods (e.g. chromatography) and worked-up to give the pure compounds. It is, however, also possible to control the process so that the 21,3'-di-O-nitro compounds are isolated as the sole products, which is predominantly the case when the aforementioned water-binding agents are used.
The conversion of the compounds of formula I into physiologically acceptable acid addition salts as well as the formation of such salts from addition salts which are not physiologically acceptable can be carried out in the usual manner.
The compounds of formula I and their physiologically acceptable acid addition salts possess valuable effects on the heart and on the circulatory dynamics and can accordingly a used as medicaments, inter alia, for the treatment of angina pectoris or essential hypertonia. As dosage guidelines, an amount of 0,010-30 mg/kg body weight per day can le considered. Such dosage can be administered not only as a single dose but preferably several times daily in divided doses.
The coronary-dilating activity can be measured according to the following method:
Mongrels weighing between 20 and 38 kg are used for t -e examinations. The test animals are narcotised with ca ι mg/kg i.v. pentobarbital. The narcosis is maintained w th chloralose-urethane. The animals are artifically r spired with room air. After opening the thorax, the heart is exposed and a previously calibrated flow probe of an electromagnetic flow-meter is placed around the Ramus
- 5 43210 eircumflexus of the left coronary artery to measure the amount of blood flowing through. The arterial blood pressure is measured via a catheter in the Arteria femoralis with a pressure transducer. Further, a calibrated extensible measuring strip is sutured on to the surface of the left ventricle for the direct measurement of myocardial contraction force. The pulse wave of the blood pressure triggers a tachograph for the measurement of the heart rate. The compounds are dissolved in propylene glycol and administered either intravenously or intraduodenally as a suspension in gum arabic. The maximum action of a substance is calculated in per cent of the starting value according to each dosage. In the measurement of the coronary blood flow, special attention is paid to the duration of action.
The results obtained are compiled in the following Table in which n signifies the number of animals used.
- 6 43210
0 fe ϊ Θ 0 rH φ Η ffl •Ρ •Η d •Ρ Κ Ρ □ d Ρ s c ρ Ρ 0 d C Μ Φ 0 q Κ υ 0 Ιί II II fe fe κ ο ffl
ffl
The Compounds provided by the present invention can be used as medicaments in the form of pharmaceutical preparations, having direct or delayed release of the active ingredient, which contain them in association with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols or petroleum jelly. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragees, suppositories or capsules), in a semi-solid form (e.g. as salves) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers, flavourimproving agents, salts for varying the osmotic pressure or buffers. The pharmaceutical preparations can be prepared in manner known per se.
The starting materials of formula II hereinbefore are known or can be prepared from known compounds in a nanner known per se.
The following Examples illustrate the process provided by the present invention:
Example 1.
6.7 g of urea were slowly added at -15°C to 90 ml of fuming nitric acid (d = 1.5) at such a rate that the temperature did not exceed -10°C. To this solution there were added successively at -10°C 10.8 g of adenosine-5'-carboxylic acid ethyl ester. The solution was stirred for 3 hours in an icebath and thereafter introduced into a mixture of
225 g of potassium bicarbonate and 1000 g of icewater; the precipitated crude product (4.4 g) was filtered off under suction. 3y extraction of the filtrate with chloroform/ methanol (95:5), there were obtained a further 4.4 g of the crude product which, by chromatography on silica gel with chloroform/ethyl acetate/methanol (45:45:10), yielded the following nitroadenosines:
2.65 g of 21,3'-di-0-nitroadenosine-5'-carboxylic icid ethyl ester of melting point greater than 135°C (decomposition) (after recrystallisation from ethyl acetate/ chloroform):
0.41 g of 2'-nitroadenosine-5 1-carboxylic acid ethyl ester of melting point 170°-171°C (decomposition) (after recrystallisation from ethyl acetate/diethyl ether);
1.3 g of 3'-O-nitroadenosine-5 1-carboxylic acid ethyl ester of melting point I66.5°-167°C (decomposition) (after recrystallisation from ethanol).
Example 2.
100 ml of fuming nitric acid (d = 1.50) were cautiously treated at -20 C with 6.7 g of urea. 10.8 g of adenosine51-carboxylic acid ethylamide were dissolved in this solution, the temperature being maintained at -20°C. The mixture was subsequently stirred firstly at -20°C, then slowly warmed to -5°C and, after a total of 5 hours, introduced slowly into excess aqueous potassium bicarbonate solution (230 g of potassium bicarbonate in 800 ml of water). After filtering under suction and washing the precipitate with water, the filtrate was extracted five times, each time with 400 ml of a mixture of ethyl acetate and 5% tetrahydrofuran. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The total yield of crude product amounted to 11.5 g.
In order to separate the crude product into the 3 nitrate esters, it was recrystallised several times from ethanol, there being obtained pure 31-0-nitroadenosine-51 carboxylic acid ethylamide. 2',3'-Di-O-nitroadenosine-51 carboxylic acid ethylamide could be obtained from the mother liquors by crystallisation from acetonitrile, while the complete separation of the mother liquors by chromatography on silica gel with chloroform/methanol/glacial acetic acid (90:10:1, v/v) also yielded 2'-0-nitroadenosine51-carboxylic acid ethylamine.
The total yields were:
3.0 g (24%) of 3'-0-nitroadenosine-51-carboxylic acid ethylamide of melting point 210°C (decomposition) (after recrystallisation from ethanol);
2.5 g (17.8%) of 21,31-di-0-nitroadenosine-5'-carboxylic acid ethylamide of melting point 164°C (decomposition) (after recrystallisation from acetonitrile) and
0.77 g (6.2%) of 21-O-nitroadenosine-51-carboxylic acid ethylamide of melting point 2O8°C (decomposition) (after recrystallisation from ethanol).
Example 3.
ml of fuming nitric acid were cautiously treated at -20°C v/ith 4.9 g of urea. 6.9 g of adenosine-5
- 10 43310 carboxylic acid amide were slowly introduced into this solution, care being taken that the temperature of the mixture did not rise above -15°C. The mixture was stirred 'or a further 5 hours while cooling to at least -5°C and hen slowly added dropwise into excess aqueous potassium bicarbonate solution (175 g of potassium bicarbonate in 500 ml of water), whereby a portion of the product precipitated. After filtering under suction and washing with water, there were obtained 2.9 g of a mixture of 2',3'-di10 ')-nitroadenosine-5'-carboxylic acid amide and 3'-0-nitro-denosine-5'-carboxylic acid amide. The aqueous solution vas extracted three times with 150 ml of chloroform and
% ethanol each time and subsequently three times with 150 ml of ethyl acetate and 5% tetrahydrofuran each time.
After washing with saturated sodium chloride solution and drying over magnesium sulphate, there were obtained, after concentration of the chloroform/ethanol extract, 2.0 g of almost pure 2',3'-di-0-nitroadenosine-5'-carboxylic acid amide and, from the ethyl acetate/tetrahydrofuran extract,
.7 g of a mixture of 3'-0-nitroadenosine-5'-carboxylic iijid Eimide and 2 1-0-nitroadenosine-5 1-carboxylic acid amide.
repeated recrystallisation af the residue obtained from the c lloroform/ethanol extract gave 1.17 g (12.8%) of pure 2!,31-di-0-nitroadenosine-5'-carboxylic acid amide of melt25 i ig point 172.5°C (decomposition). Repeated recrystallisa ion of the residue obtained from the ethyl acetate/tetrahydrofuran extract from ethanol/isopropanol and subsequently from niethanoi/water gave 2.25 g (23.1%) of 3'-0-nitroadenosine-51-carboxylic acid amide of melting point 211°C (decomposition).
Example 4.
6.16 g of adenosine-5'-carboxylic acid dimethylamide were dissolved at -40°C in 60 ml of fuming nitric acid (d =
L.50). A mixture, cooled to -20°C, of 30 ml of oleum, and 30 ml of nitromethane was added dropwise to this solution within 30 minutes at such a rate that the temperature did not rise above -30°C. The mixture was stirred for 45 minutes at a temperature between -30°C and -25°C and then poured on to a solution of 325 g of potassium bicarbonate in 1 litre of water. By extraction with chloroform or with chloroform containing 5% n-propanol, there was obtained practically pure 21,3'-di-0-nitroadenosine-51-carboxylic acid dimethylamide which melted at 156.5°C (decomposition) after tecrystallisation from alcohol. The yield was 5.78 g (72.7% of theory).
Xn an analogous manner, the following 2 ',3'-di-O-nitro- , adenosines were obtained:
21,3'-di-O-nitroadenosine-5'-carboxylic acid isopropylamide of melting point 183°C (decomposition), yield 77.4%;
h
2*, 3 ' -di-0-nitroadenosine-5 ‘ -carboxylic acid cyclohexylamide of melting point 168°C (decomposition), yield 69.6%;
2',3'-di-O-nitroadenosine-5'-carboxylic acid [2-(dimethylamino) -ethyl] -amide of melting point 169°C (decomposition), yield 63%;
2',31-di-O-nitroadenosine-5'-carboxylic acid [2-(2,4d i.nitrophenyl) -ethyl] -amide of melting point 134°C (decomposition), yield 30.6%;
2’,31-di-O-nitroadenosine-5'-carboxylic acid piperidide oi' melting point 160°C (decomposition), yield 76.2%;
3 210
2',3'-di-O-nitrosdenosine-5'-carboxylic acid [2-(nitrooxy)-ethyl]-amide of melting point 164° C (decomposition), yield 58.9%;
21,31-di-O-nitroadenosine-5'-carboxylic acid isopropyl 5 ester of melting point 158°C (decomposition), yield 71.6%.
Example 5.
The reaction of 6.16 g of adenosine-5 1-carboxylic acid dimethylamide with 60 ml of fuming nitric acid and working-up in the manner described in Example 4, but without the addition of oleum/nitromethane, yielded a mixture of 3'-0nitroadenosine-5'-carboxylic acid dimethylamide of melting point 214°c (decomposition), yield 21% of theory, with 2*,3'di-0-nitroadenosine-5'-carboxylic acid dimethylamide of melting point 156°C (decomposition), yield S.3% of theory.
Claims (15)
1. 2 R and li represent a hydrogen atom or a nitro group 1 2 with at least one of R and R representing a nitro group, and r5 represents a hydroxy, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryl-(lower alkyDamino, cycloalkylamino, [2-(dimethylamino)-ethyl]-amino, [2-(2,4dinitrophenyl)-ethyl]-amino or [2-(nitro-oxy)-ethyl]-amino group, or a nitrogen-containing heterocyclic ring which is bonded via a nitrogen atom, and physiologically acceptable acid addition salts thereof. . 5
2. Compounds according to claim 1, wherein R represents a hydroxy, lower alkoxy, amino, (lower alkyDamino or di(lower alkyl)amino group.
3. 2',3'-Di-O-nitroadenosine-5'-carboxylic acid ethyl ester. 4. 3 210 2 1· A process for the manufacture of the compounds cJ limed in Claim 1., substantially as hereinbefore described with reference to any of Examples 1 and 3 to 5. 22., Compounds as set forth in Claim 1, when manufactured by the process claimed in Claim 21. 23. A pharmaceutical preparation containing a compound as set forth in any one of Claims 2 to 5 and 9 to 19 in association with a compatible pharmaceutical carrier material. 24. Λ |>r.>'’ess for ι lie mnnufacLui <: of 'he compound.'·;
4. 2'-O-Nitroadenosine-5*-carboxylic acid ethyl ester 4331ο
5. 3'-O-Nitroadenosine-5'-carboxylic acid ethyl ester.
6. 2 1 ,3'-Di-O-nitroadenosine-5'-carboxylic acid ethylamide.
7. 2'-O-Nitroadenosine-5'-carboxylic acid ethylamide.
8. 3'-O-Nitroadenosine-5 1 -carboxylic acid ethylamide.
9. 2',3 1 -Di-O-nitroadenosine-5'-carboxylic acid amide. 10. Ol limed in Claim 1, sub.··.'antially as hereinbefore described with reference to Example 2. 25. Compounds as set forth in Claim 1, when manufactured by the process claimed in Claim 20 or Claim 22.
10. 2 1 -O-Nitroadenosine-5'-carboxylic acid amide.
11. 3 1 -O-Nitroadenosine-5 1 -carboxylic acid amide.
12. 2',3 1 -Di-O-nitroadenosine-5'-carboxylic acid dimethylamide.
13. 2 1 ,3'-Di-O-nitroadenosine-5'-carboxylic acid i-sopropylamide.
14. 2',3'-Di-O-nitroadenosine-5'-carboxylic acid cyclohexylawide. 15. 2',3 1 -Di-O-nitroadenosine-5'-carboxylic acid I2-(dimethylamino)-ethyl]-amide. 16. 2',3 1 -Di-O-nitroadenosine-5'-carboxylic acid 12-(2,4-dinitrophenyl)-ethyl]-amide. 17. 2',3'-Di-O-nitroadenosine-5 1 -carboxylic acid piperidide. 18. 2 ', 3 1 -Di-O-nitroadenosine-5'-carboxylic acid ι2-(nitro-oxy)-ethylj-amide, 19. 2',3'-Di-O-nitroadenosine-5'-carboxylic acid i sopropyl ester. 20. A process for the manufacture of the compounds claimed in claim 1, which process comprises nitrating a compound of the general formula - 15 43310 wherein R has the significance given in claim 1, and, if desired, conveeting the product into a physiologically acceptable acid addition salt.
15. 26. a pharmaceutical preparation containing a compound as set forth in any one of Claims 1 and 6 to 8 in association wiih a compatible pharmaceutical carrier material.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH203275A CH606084A5 (en) | 1975-02-18 | 1975-02-18 | (Di) nitrates of adenosine -5'-carboxylic acid derivs |
| CH874875 | 1975-07-04 | ||
| CH1609475A CH612948A5 (en) | 1975-12-11 | 1975-12-11 | Process for the preparation of adenosine nitrates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE43210L IE43210L (en) | 1976-08-18 |
| IE43210B1 true IE43210B1 (en) | 1981-01-14 |
Family
ID=27173417
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE267/76A IE43210B1 (en) | 1975-02-18 | 1976-02-11 | Nitrates of adenosine-5'-carboxylic acid derivatives, process for their manufacture, and pharmaceutical preparations containing them |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS51105095A (en) |
| AR (1) | AR217398A1 (en) |
| AU (1) | AU497075B2 (en) |
| BR (1) | BR7600997A (en) |
| CA (1) | CA1050534A (en) |
| DD (1) | DD124252A5 (en) |
| DE (1) | DE2606532A1 (en) |
| DK (1) | DK136957B (en) |
| ES (1) | ES445234A1 (en) |
| FI (1) | FI61194C (en) |
| FR (1) | FR2301264A1 (en) |
| GB (1) | GB1489327A (en) |
| GR (1) | GR59304B (en) |
| HU (1) | HU172959B (en) |
| IE (1) | IE43210B1 (en) |
| IL (1) | IL48854A (en) |
| LU (1) | LU74356A1 (en) |
| NL (1) | NL7600663A (en) |
| NO (1) | NO141652C (en) |
| NZ (1) | NZ179785A (en) |
| PH (1) | PH15859A (en) |
| PT (1) | PT64811B (en) |
| SE (1) | SE423237B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5310731A (en) * | 1984-06-28 | 1994-05-10 | Whitby Research, Inc. | N-6 substituted-5'-(N-substitutedcarboxamido)adenosines as cardiac vasodilators and antihypertensive agents |
| EP2876166B1 (en) | 2013-11-20 | 2016-12-14 | Roche Diagnostics GmbH | New compound for sequencing by synthesis |
-
1976
- 1976-01-16 IL IL48854A patent/IL48854A/en unknown
- 1976-01-20 NZ NZ179785A patent/NZ179785A/en unknown
- 1976-01-20 AU AU10428/76A patent/AU497075B2/en not_active Expired
- 1976-01-22 NL NL7600663A patent/NL7600663A/en not_active Application Discontinuation
- 1976-01-27 FI FI760184A patent/FI61194C/en not_active IP Right Cessation
- 1976-02-04 CA CA245,008A patent/CA1050534A/en not_active Expired
- 1976-02-11 IE IE267/76A patent/IE43210B1/en unknown
- 1976-02-11 HU HU76HO00001875A patent/HU172959B/en unknown
- 1976-02-13 PH PH18105A patent/PH15859A/en unknown
- 1976-02-16 SE SE7601725A patent/SE423237B/en unknown
- 1976-02-16 JP JP51014997A patent/JPS51105095A/ja active Pending
- 1976-02-16 FR FR7604163A patent/FR2301264A1/en active Granted
- 1976-02-16 LU LU74356A patent/LU74356A1/xx unknown
- 1976-02-16 GR GR50064A patent/GR59304B/en unknown
- 1976-02-17 DD DD191276A patent/DD124252A5/en unknown
- 1976-02-17 ES ES445234A patent/ES445234A1/en not_active Expired
- 1976-02-17 PT PT64811A patent/PT64811B/en unknown
- 1976-02-17 GB GB6162/76A patent/GB1489327A/en not_active Expired
- 1976-02-17 NO NO760520A patent/NO141652C/en unknown
- 1976-02-17 DK DK62776AA patent/DK136957B/en not_active IP Right Cessation
- 1976-02-17 BR BR7600997A patent/BR7600997A/en unknown
- 1976-02-18 DE DE19762606532 patent/DE2606532A1/en not_active Withdrawn
- 1976-03-05 AR AR262163A patent/AR217398A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| FI61194B (en) | 1982-02-26 |
| FI61194C (en) | 1982-06-10 |
| FR2301264B1 (en) | 1980-06-20 |
| DE2606532A1 (en) | 1976-08-26 |
| AR217398A1 (en) | 1980-03-31 |
| NO141652C (en) | 1980-04-16 |
| GR59304B (en) | 1977-12-12 |
| IE43210L (en) | 1976-08-18 |
| FI760184A (en) | 1976-08-19 |
| IL48854A0 (en) | 1976-03-31 |
| BR7600997A (en) | 1976-09-14 |
| GB1489327A (en) | 1977-10-19 |
| IL48854A (en) | 1979-12-30 |
| AU497075B2 (en) | 1978-11-23 |
| LU74356A1 (en) | 1977-09-12 |
| ES445234A1 (en) | 1977-06-01 |
| SE7601725L (en) | 1976-08-19 |
| PH15859A (en) | 1983-04-13 |
| DK136957B (en) | 1977-12-19 |
| NO141652B (en) | 1980-01-07 |
| JPS51105095A (en) | 1976-09-17 |
| NL7600663A (en) | 1976-08-20 |
| PT64811A (en) | 1976-03-01 |
| DK62776A (en) | 1976-08-19 |
| PT64811B (en) | 1978-02-06 |
| AU1042876A (en) | 1977-07-28 |
| FR2301264A1 (en) | 1976-09-17 |
| DK136957C (en) | 1978-05-29 |
| DD124252A5 (en) | 1977-02-09 |
| CA1050534A (en) | 1979-03-13 |
| NO760520L (en) | 1976-08-19 |
| HU172959B (en) | 1979-01-28 |
| SE423237B (en) | 1982-04-26 |
| NZ179785A (en) | 1978-04-28 |
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