IE49385B1 - Nicotinic and 2-(4-chlorophenoxy)-2-methylpropanoic acid derivatives - Google Patents
Nicotinic and 2-(4-chlorophenoxy)-2-methylpropanoic acid derivativesInfo
- Publication number
- IE49385B1 IE49385B1 IE236/80A IE23680A IE49385B1 IE 49385 B1 IE49385 B1 IE 49385B1 IE 236/80 A IE236/80 A IE 236/80A IE 23680 A IE23680 A IE 23680A IE 49385 B1 IE49385 B1 IE 49385B1
- Authority
- IE
- Ireland
- Prior art keywords
- cycloalkyl
- pharmaceutically acceptable
- nicotinate
- acid addition
- addition salt
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Novel compounds of the formula wherein R is 3-pyridinyl or 2-(4- chlorophenoxy)-2-methyl-propyl; R<1> is hydrogen, C5-14 cycloalkyl, (C5-14 cycloalkyl)methyl, (C5-14 cycloalkyl)carbonyl, (C5-14 cycloalkyl)acetyl, 1-adamantyl, 1- adamantylmethyl, 1-adamantylcarbonyl, 1-adamantylacetyl, cumyl, p-chlorobenzoyl, piperidino or 2- pyrimidinyl; and R<2> is hydrogen, -(CH2)4-, halogen, C1-6 alkyl, cycloalkyl, methoxy, ethoxy, trifluoromethyl or nitro; provided that R<2> is C1-6 cycloalkyl or -(CH2)4- when R<1> is hydrogen; or a pharmaceutically acceptable acid addition salts thereof may be used in the treatment of hyperlipidemias.
Description
It is known that atherosclerosis is caused by the accumulation of lipids in the aorta and the coronary, cerebral and peripheral arteries. This results in an increased risk of thromboses or artery obstruction. Dependent on the nature of the increased plasma protein level, either the elevated chlorosterol or triglyceride level is of importance. Cholesterol levels exceeding 200-300 mg/100 ml serum and triglyceride levels of 45-66 mg/100 ml serum may be considered as extremely elevated.
The two most widely known classes of active substances used in the treatment of hyperlipidemias comprise clofibrate (2-(4-chlorophenoxy)-2-methylpropionic acid ethyl ester) and its salts, and nicotinic acid, which influence the serum lipids by different modes of action. While in test animals, doses of 30-500; mg/kg body weight mainly effect a lowering of the cholesterol level in addition to a slight reduction of the free fatty acids, nicotinyl alcohol and nicotinic acid and its salts bring about a great reduction of the free fatty acids even at low dosages of between 0.5 and 430 mg/kg body weight. However, none of these substances has a significant reducing influence on triglycerides. Besides, owing to its unpleasant and known side effects (flush, headache, nausea, vomiting), nicotinic acid can only be used conditionally, so that therapy often has to be discontinued prematurely.
It is known that clofibrate effects a fall of the initial values of triglycerides (TG) and pre-p-lipoproteins by up to 50%,
48388 this degree of lowering not being achieved in the case of cholesterol.
In about 20% of cases, the cholesterol (CH) in the 6- and a-lipoproteins is even further increased. Nicotinic acid and its derivatives, on the contrary, act predominantly on elevated cholesterol values and free fatty acids, whereas the decrease of the endogenous resynthesis of the triglycerides via inhibition of tissue lipolysis is only a secondary effect (cf. Verhandlungen der Deutschen Gesellschaft fur innere Medizin, 82. Kongress, gehalten zu Wiesbaden vom 25. bis 29.4.
1976, Teil 1, J.F. Bergmann Verlag Munchen).
1C French Patent Specification No. 6,975 disclosed clofibic acid nicotinyl ester as an effective lipid- and cholesterol-lowering component.
This compound, although being predominantly used in the form of the nicotinate, can only be administered in low dosage owing to the high portion of its pyridine component and the resulting side effects.
It is, therefore, of only little therapeutic benefit.
All the aforementioned substances effect a significant reduction of only one of the lipid components, e.g., the triglycerides, while the other lipid components are not, or only slightly, influenced, therapeutically. Such a therapeutic effect can only be achieved by a dose increase.
, many of which are novel,
We have now discovered -novel· compounds /which, even when administered in low dosages, can have a strong effect on both serum TG and CH levels. The neve! compounds of this invention are for therapeutic use and are nicotinic acid or 2-(4-chlorophenoxy)-2-methylpropanoic acid esters 26 of the formula
propyl wherein R is 3-pyridinyl or 2-(4-chlorophenoxy)-2rfeetiy4-ethyl·;
R1 is hydrogen, Cg_14 cycloalkyl, (C5_i4 cycloalkyl)methyl, (Cg_14 cycloalkyl)carbonyl), (Cg_14 cycloalkyl)acetyl (preferably, the cycloalkyl group is monocyclic or 1-adamantyl), cuiqyl, £-chlorobenzoyl, piperidino or 2-pyrimidinyl; and 2
R is hydrogen, -(CH2)4-, halogen, Cpg alkyl, cycloalkyl, methoxy, ethoxy, tri fluoromethyl or nitro;
provided that R is Cp6 cycloalkyl or -(CH2)4- when
R1 is hydrogen;
and include the pharmaceutically acceptable acid addition salts, which may be formed with organic or inorganic acids, thereof. _
The compounds of the invention may be prepared by conventional esterification procedures. For example equimolar amounts of nicotinic acid of dofibric acid and the appropriately 1 2
R /R -substituted phenol may be reacted together, often in the presence of an equimolar amount of an acid-binding substance such as pyridine.
A pharmaceutical composition according to the invention comprises an ester of the invention in association with a physiologically acceptable excipient. Such compositions may be administered orally _or parenterally._. _
-» The novel compounds are those in which I? is not hydrogen, when R^ is cyclohexyl. Preferred novel compounds and salts are those in which f is cyclohexyl and R2 is other than hydrogen, R being 3-pyvidyl.
Solid preparations for oral administration include capsules, tablets, pills, powders and granulates. In such solid preparations, the active substance is mixed with at least one inert diluent such as sugar cane, lactose or starch. Additional substances such as lubricants or buffers may also be added. The tablets or pills may be optionally coated.
Liquids for oral application include emulsions, solutions and suspensions containing the commonly used inert diluents such as water. Additionally, such liquid compositions may contain wetting, emulsifying and dispersing agents as well as sweeteners, flavourants and fragrances.
Preparations for parenteral application include sterile, aqueous or non-aqueous solutions, suspensions or emulsions. Substances known for this form of presentation are used as carrier material.
Depending on the mode of application and duration of treatment, the dosage of the active substances in the preparation may vary.
The following Examples illustrate how compounds of this invention may be prepared. The compounds of Examples 1 to 7 are preferred compounds of the invention, in free base or pharmaceutically acceptable acid addition salt form, e.g. the compound of Example 1 and its hydrochloride salt.
EXAMPLE 1
Preparation of £-cyclohexylphenyl nicotinate
17.6 g (100 mmol) of cyclohexylphenol and 19g (106 nmol) of nicotinic acid chloride hydrochloride were mixed with 250 ml of dry pyridine and kept at 40°C for 4 hours. Subsequently, the mixture was cooled in an ice bath, and water added in portions. After addition of 10 ml of water, a clear solution was obtained.
Water (50 ml) was admixed until strong turbidity appeared. After stirring the mixture for a longer period of time the product crystallized in the ice bath. The precipitate was sucked off, freed from pyridine by washing with water and dried. A second fraction was obtained fran the filtrate by further adding water (60 ml).
Yield: 70% of the theoretical value. MP : 103°C
Analysis
Calculated Found C 76.86 76.83 H 6.76 6.76 N 4.98 5.05
EXAMPLE 2
Preparation of £-(l-adamantyl)phenyl nicotinate
11.4 g (50 nmol) of £-(l-adamantyl)phenol and 10 g (56 mmol) of nicotinic acid chloride hydrochloride were mixed with 150 ml of dry pyridine and kept at 45°C for 4 hours. By adding 40 ml of water and stirring in an ice bath, the product formed a precipitate which was sucked off, washed with water and dried.
Yield: 78% of the theoretical value. MP.: 199°C
Analysis
Calculated Found c 79.27 78.01 H 6.90 6.82 N 4.20 4.50
EXAMPLE 3
Preparation of 2-(£-chlorophenoxy)isobutyric acid £-(1-adamantylacetyl)phenyl ester
6.75 g (25 rnnol) of j+-(1-adamantylacetyl)phenol and 6 g (25.7 mmol) of 2-(p-chlorophenoxy)isobutyric acid chloride were mixed with 60 ml of dry pyridine and kept at 40°C for 4 hours. After adding 40 ml of water, a crystalline product was obtained which was sucked off, washed with water and dried.
Yield: 77% of the theoretical value. MP.: 114°C
Analysis
Calculated Found
C 72.03 72.12
EXAMPLE 4
Preparation of £-cyclododecylphenyl nicotinate
8g (308 mmol) of £-cyclododecylpbenol and 5.9 g (33.2 mmol) of nicotinic acid chloride hydrochloride were mixed with 140 ml of dry pyridine and kept at 30°C for 15 hours. Subsequently, ml of water were added slowly drop by drop, and the mixture cooled to 0°C. The crystallized precipitate was sucked off, freed frcm pyridine by washing with water and dried.
Yield: 85% of the theoretical value. M.P. : 98°C
Analysis Calculated Found C 78.91 79.01 5 H 8.50 8.54
EXAMPLE 5
Preparation of £-(cyclohexylacetyl)phenyl nicotinate g (50 mmol) of £-cyclohexylacetylphenol and 9.6 g (54 mmol) of nicotinic acid chloride hydrochloride were mixed with 160 ml of dry pyridine and stirred for 8 hours at 40°C. Subsequently, water (66 ml) was added drop by drop until the solution was turbid.
The solution was placed in the ice bath, the precipitate sucked off, freed from pyridine by washing with water and dried.
Yield: 55% of the theoretical value. MP. : 103°C Analysis Calculated Found C 74.30 74.07 H 6.50 6.51
EXAMPLE 6
Preparation of o-cyclohexylphenyl nicotinate hydrochloride g (85 nmol) of o-cyclohexylphenol and 16.5 g (93 mmol) of nicotinic acid chloride hydrochloride were mixed with 200 ml of dry pyridine and stirred for 24 hours at 30°C. After cooling, precipitated pyridine hydrochloride was sucked off and 300 ml of
49365 water added. The precipitated raw product was washed with two ZOO mi portions of water, dissolved in alcohol and reduced by means of a rotary evaporator. The remaining viscous oil was dissolved in 500 ml of dry ether and hydrochlorinated with HCI gas. Subsequently, the mixture was filtered, washed with ether and dried.
Yield: 52% of the theoretical value. M.P. : 151-2°C
Analysis
Calculated Found c 68.03 68.11 10 H 6.29 6.30 Cl 11.18 11.20
EXAMPLE 7
Preparation of 5, 6, 7, 8-tetrahydro-1-naphthyl-nicotinate g (47 mmol) of 5, 6, 7, 8 - tetrahydro-l-naphthol and 15 9 g (50 mmol) of nicotinic acid chloride hydrochloride were mixed with
130 ml of dry pyridine and stirred for 24 hours at 30°C. After cooling, precipitated pyridine hydrochloride was sucked off, and the filtrate mixed with 300 ml of water. The crude precipitate was washed with two 200 ml portions of water and recrystallized from methanol.
Yield: 65% of the theoretical value. MP. : 86°C
Analysis
Calculated Found C 75.88 75.81 H 5.93 6.07
EXAMPLE 8
In a similar manner, £-cumylphenyl nicotinate was prepared.
EXAMPLE 9
In a similar manner, £-(£-chlorobenzoyl)phenyl nicotinate was 5 prepared.
Toxicity tests have been conducted on the compounds of Examples 1 and 2 and on, as standards, clofibrate (A) and nicotinic acid (8). The results are given in Table 1.
TABLE 1
Compound LDg0 (mouse) (mg/kg) Human daily dose (mg) Therapeutic Index 1 2200 300 0.13 2 3200 300 0.093 A 1500 1500 1.0 B 4000 3000 0.75
Additionally, experiments on female Wistar rats have been conducted. For a period of three weeks, the animals received a special diet with a very high fat content. Starting from the second week, half the rats were treated with 100 mg/kg body weight of an active conpound selected from those of Examples 1, 2, 3, 8 and 9 and the standards A and B.
After the third week, blood samples were taken 18 hours after the
48386 administration of the last dose. Triglyceride and chlesterol concentrations (determined by the Boehringer enzymatic test) were compared with those of the untreated animals. The results are shown in Table 11.
TABLE 11
Compound % reduction of cholesterol % reduction of triglycerides 1 45 19 2 28 47 3 27 35 8 24 1 9 29 - A - 8 B 7 1
Claims (5)
1. / An ester of the formula propyl wherein R is 3-pyridinyl or 2-(4-chlorophenoxy)-2yfflethj4-ethyl·; 5 R^ is hydrogen, C 5 _^ 4 cycloalkyl, (^5-)4 cycloalkyl)methyl, (C g _]4 cycloalkyl)carbonyl, ( C 5-i4 cycloalkyl)acetyl, cumyl, £-chlorobenzoyl, piperidino or 2-pyrimidinyl; and R is hydrogen, -(CHg^-. halogen, Cp 6 alkyl, cycloalkyl, methoxy, ethoxy, trifluoromethyl or nitro; 10 provided that R is C^_g cycloalkyl or -(01)2)4- w ** en r1 is hydrogen; or a pharmaceutically acceptable acid addition salt thereof.
2. -4-. A compound as claimed in claim-A wherein any cycloalkyl group in R 1 * * * * 6 7 8 is monocyclic or 1-ad^mantyl. . . — , --------»- 4 pharmaceutical- composition comprising 15 5
3. : /£-Cyclohexyl phenyl nicotinate or a pharmaceutically acceptable acid addition salt thereof. A pharmaceutical composition comprising 6-
4. -. / p-Cyclohexylphenyl nicotinate. A pharmaceutical composition comprising 7- 5-. / £-Cyclohexylphenyl nicotinate hydrochloride. 8- 4. £-( 1-Adamantyl)phenyl nicotinate or a pharmaceutically acceptable 20 acid addition salt thereof. 94-. 2-(4-Chlorophenoxy)-2-methylpropanoic acid 4-(l-adamantylacetyl)phenyl ester or a pharmaceutically acceptable salt thereof. +2. An ester of the formula defined in claim 1, with the additional proviso that is not hydrogen when Ft is cyclohexyl, or a pharmaceutically acceptable acid addition salt thereof <-♦4. An ester of the formula defined in claim 1, wherein R is 3-pyridyl, R 1 is cyolohexyl and n is other than hydrogen, or a pharmaaeutioally acceptable salt thereof 48385 10 -frr £-Cyclododecylphenyl nicotinate or a pharmaceutically acceptable acid addition salt thereof. 11 -ifc £-(Cyclohexylacetyl)phenyl nicotinate or a pharmaceutically acceptable acid addition salt thereof.
5. 12 4O-. o-Cyclohexylphenyl nicotinate or a pharmaceutically acceptable acid addition salt thereof. 15 -Ή-. o-Cyclohexylphenyl nicotinate hydrochloride, 14 -42-. 5, 6, 7, 8-Tetrahydro-1-naphthyl nicotinate or a pharmaceutically acceptable acid addition salt thereof. 1025 A compound as claimed in claim-4r substantially as described in 2 to S any of the Examples^ 16 4+-. A pharmaceutical composition comprising a compound as claimed in^a^y o ^recei?ng- 2 fefjiim ol? in association with a physiologically acceptable excipient.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2904757 | 1979-02-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE800236L IE800236L (en) | 1980-08-08 |
| IE49385B1 true IE49385B1 (en) | 1985-10-02 |
Family
ID=6062456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE236/80A IE49385B1 (en) | 1979-02-08 | 1980-02-07 | Nicotinic and 2-(4-chlorophenoxy)-2-methylpropanoic acid derivatives |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS55129245A (en) |
| AR (1) | AR228251A1 (en) |
| AT (1) | AT374797B (en) |
| AU (1) | AU532208B2 (en) |
| BE (1) | BE881626A (en) |
| CA (1) | CA1135689A (en) |
| CH (1) | CH644092A5 (en) |
| DK (1) | DK152360C (en) |
| ES (1) | ES8101552A1 (en) |
| FR (1) | FR2448532A1 (en) |
| GB (1) | GB2041937B (en) |
| GR (1) | GR73905B (en) |
| HU (1) | HU182099B (en) |
| IE (1) | IE49385B1 (en) |
| IL (1) | IL59337A (en) |
| IT (1) | IT1141197B (en) |
| MX (1) | MX6377E (en) |
| NL (1) | NL8000826A (en) |
| PL (1) | PL123379B1 (en) |
| SE (1) | SE450381B (en) |
| SG (1) | SG51185G (en) |
| YU (1) | YU33880A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2221681A (en) * | 1988-01-22 | 1990-02-14 | Kh Nii Endokrinolog I Khim | Undecylic ether n-chlorophenoxyisobutyric acid and a pharmaceutical preparation for treating hyperlipemia based on it |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3175M (en) * | 1963-06-25 | 1965-03-08 | Analyses Et De Rech S Biolog M | New chemical compounds with peripheral vasodilating action. |
| DE2352012A1 (en) * | 1972-11-01 | 1974-05-09 | Ciba Geigy Ag | NEW ALIPHATICALLY SUBSTITUTED ARYLCHALCOGENO-HYDROCARBON DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
| ES438246A1 (en) * | 1975-06-04 | 1977-01-16 | Alter Sa | Process for purifying the mixed ester, ethylene glycol 1-(2-p-chlorophenoxy)-2-methylpropionate nicotinate |
| JPS57102866A (en) * | 1980-12-19 | 1982-06-26 | Kyorin Pharmaceut Co Ltd | Nicotinic acid derivative and its preparation |
-
1980
- 1980-02-06 SE SE8000962A patent/SE450381B/en not_active IP Right Cessation
- 1980-02-07 IE IE236/80A patent/IE49385B1/en not_active IP Right Cessation
- 1980-02-07 ES ES488345A patent/ES8101552A1/en not_active Expired
- 1980-02-07 IL IL59337A patent/IL59337A/en not_active IP Right Cessation
- 1980-02-07 DK DK053680A patent/DK152360C/en not_active IP Right Cessation
- 1980-02-07 MX MX808635U patent/MX6377E/en unknown
- 1980-02-08 CA CA000345303A patent/CA1135689A/en not_active Expired
- 1980-02-08 AU AU55355/80A patent/AU532208B2/en not_active Ceased
- 1980-02-08 PL PL1980221888A patent/PL123379B1/en unknown
- 1980-02-08 YU YU00338/80A patent/YU33880A/en unknown
- 1980-02-08 GB GB8004310A patent/GB2041937B/en not_active Expired
- 1980-02-08 CH CH106380A patent/CH644092A5/en active IP Right Maintenance
- 1980-02-08 AR AR279916A patent/AR228251A1/en active
- 1980-02-08 BE BE0/199326A patent/BE881626A/en not_active IP Right Cessation
- 1980-02-08 AT AT0070380A patent/AT374797B/en not_active IP Right Cessation
- 1980-02-08 FR FR8002783A patent/FR2448532A1/en active Granted
- 1980-02-08 JP JP1374980A patent/JPS55129245A/en active Granted
- 1980-02-08 GR GR61163A patent/GR73905B/el unknown
- 1980-02-08 IT IT19782/80A patent/IT1141197B/en active
- 1980-02-08 NL NL8000826A patent/NL8000826A/en not_active Application Discontinuation
- 1980-02-08 HU HU80289A patent/HU182099B/en not_active IP Right Cessation
-
1985
- 1985-06-27 SG SG511/85A patent/SG51185G/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU532208B2 (en) | 1983-09-22 |
| IT8019782A0 (en) | 1980-02-08 |
| DK53680A (en) | 1980-08-09 |
| ATA70380A (en) | 1983-10-15 |
| AT374797B (en) | 1984-05-25 |
| ES488345A0 (en) | 1980-12-16 |
| CA1135689A (en) | 1982-11-16 |
| IE800236L (en) | 1980-08-08 |
| SE8000962L (en) | 1980-08-09 |
| GB2041937B (en) | 1983-04-13 |
| SE450381B (en) | 1987-06-22 |
| NL8000826A (en) | 1980-08-12 |
| SG51185G (en) | 1986-01-24 |
| AU5535580A (en) | 1980-08-14 |
| CH644092A5 (en) | 1984-07-13 |
| HU182099B (en) | 1983-12-28 |
| YU33880A (en) | 1983-06-30 |
| FR2448532B1 (en) | 1984-12-14 |
| IT1141197B (en) | 1986-10-01 |
| JPS55129245A (en) | 1980-10-06 |
| PL123379B1 (en) | 1982-10-30 |
| IL59337A (en) | 1984-10-31 |
| PL221888A1 (en) | 1980-10-20 |
| DK152360B (en) | 1988-02-22 |
| ES8101552A1 (en) | 1980-12-16 |
| DK152360C (en) | 1988-08-01 |
| GR73905B (en) | 1984-05-21 |
| GB2041937A (en) | 1980-09-17 |
| BE881626A (en) | 1980-08-08 |
| MX6377E (en) | 1985-05-23 |
| FR2448532A1 (en) | 1980-09-05 |
| AR228251A1 (en) | 1983-02-15 |
| JPS6126993B2 (en) | 1986-06-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |