CA1039282A - 1-(3-(naphth-1-yloxy)-2-hydroxy-propyl)-piperazine derivatives - Google Patents
1-(3-(naphth-1-yloxy)-2-hydroxy-propyl)-piperazine derivativesInfo
- Publication number
- CA1039282A CA1039282A CA219,883A CA219883A CA1039282A CA 1039282 A CA1039282 A CA 1039282A CA 219883 A CA219883 A CA 219883A CA 1039282 A CA1039282 A CA 1039282A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- piperazine
- process according
- reacting
- methoxyphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
- A61P9/12—Antihypertensives
Abstract
ABSTRACT OF THE DISCLOSURE
New 1-[3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine derivatives and their process of preparation are provided of the formula:
New 1-[3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine derivatives and their process of preparation are provided of the formula:
Description
The present invention is concerned with 1-[3-(naphth-l-yloxy)-2-hydroxypropyl]-piperazine derivatives and their preparation.
The new compounds of the invention possess outstanding blood pressure-lowering and thus anti-hypertensive properties.
Furthermore, in the case of rats, they inhibit the anaphylactoid reactions initiated by dextran.
In J. Org~ Chem., 23, 1935/1958, some 1-[3-(naphth-l-yloxy)-2-hydroxypropyl~-piperazines are described but there is no mention of their pharmacological action. As our investigations have shown, the new compounds of the present invention possess, surprisingly, a substantially better anti-hypertensive action than the previously described compounds.
According to the invention thereare provided new 1~~3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine derivatives of the formula (I):-O-CH2-CH-CH2-~ ~ ~ Q (I) ~ OCH~
and the pharmaceutically acceptable, pharmacologically compatible acid addition salts thereof.
According to another aspect of the invention, there is provided a process for preparing the above defined derivatives of formula (I) comprising:
a) reacting a compound of the formula (II):-~', - 1- ~
' ` ' ~:' ' ' :::
:
~L03~Z~3Z
.
OR~
; ~
in which Rl is a hydrogen atom and R2 is a halogen atom or in which Rl and R2 together represent a valency bond, with a ~; methoxyphenyl-piperazine of the formula (III)~
HN N ~
OCH
or b) reacting l-naphthol with a compound oE the formula (IV):- f ~
:' ` ;:
R2-CH2-ClH-cH2 \ ~ ~ (IV), ;` OCH3 ;~
in which Rl and R2 have the same meanings as above, whereafter, if desired, the compound obtained is converted into a pharma-ceutically acceptable, pharmacologically compatible acid addition salt. ~-When R2 represents a halogen atom, it may be selected ~ ;
from a fluorine, chlorine, bromine or iodine atom, preferably a chlorine atom.
The methoxy group in the benzene ring may be in the ~, ortho, meta or para position.
The reactions a) and b) can be carried out by mixing molar amounts of the reaction components and leaving the mixture ;
to stand at ambient temperature, the reactions can be accelerated `
by brief heating, suitably in a pressure vessel. If desired, a
The new compounds of the invention possess outstanding blood pressure-lowering and thus anti-hypertensive properties.
Furthermore, in the case of rats, they inhibit the anaphylactoid reactions initiated by dextran.
In J. Org~ Chem., 23, 1935/1958, some 1-[3-(naphth-l-yloxy)-2-hydroxypropyl~-piperazines are described but there is no mention of their pharmacological action. As our investigations have shown, the new compounds of the present invention possess, surprisingly, a substantially better anti-hypertensive action than the previously described compounds.
According to the invention thereare provided new 1~~3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine derivatives of the formula (I):-O-CH2-CH-CH2-~ ~ ~ Q (I) ~ OCH~
and the pharmaceutically acceptable, pharmacologically compatible acid addition salts thereof.
According to another aspect of the invention, there is provided a process for preparing the above defined derivatives of formula (I) comprising:
a) reacting a compound of the formula (II):-~', - 1- ~
' ` ' ~:' ' ' :::
:
~L03~Z~3Z
.
OR~
; ~
in which Rl is a hydrogen atom and R2 is a halogen atom or in which Rl and R2 together represent a valency bond, with a ~; methoxyphenyl-piperazine of the formula (III)~
HN N ~
OCH
or b) reacting l-naphthol with a compound oE the formula (IV):- f ~
:' ` ;:
R2-CH2-ClH-cH2 \ ~ ~ (IV), ;` OCH3 ;~
in which Rl and R2 have the same meanings as above, whereafter, if desired, the compound obtained is converted into a pharma-ceutically acceptable, pharmacologically compatible acid addition salt. ~-When R2 represents a halogen atom, it may be selected ~ ;
from a fluorine, chlorine, bromine or iodine atom, preferably a chlorine atom.
The methoxy group in the benzene ring may be in the ~, ortho, meta or para position.
The reactions a) and b) can be carried out by mixing molar amounts of the reaction components and leaving the mixture ;
to stand at ambient temperature, the reactions can be accelerated `
by brief heating, suitably in a pressure vessel. If desired, a
- 2 -'' ~,' - ::; : : : , ~ : : ~ . . , .: .
~392~3~
solvent, for example a lower alcohol, can also be included in the reaction mixture.
An acid addition salt of a metho~yphenyl-pipexazine of formula (III), such as a hydrochloride salt, may be e~ploy~d in reaction a) in place of the free base, ~or the preparation of the acid addition salts, the compounds of the present invention are reacted with pharmacologi-cally compatible, non-toxic inorganic or organic acids, for example, hvdrochloric acid, sulphuric acid, phosphoric acid, lactic acid, citric acid or an alkyl-sulphonic acid. ~
In the specification, it will be understood that the `
qualification that the acid addition salts are "pharmaceutically acceptable" means that the salts have the necessary physical 1, characteristics, for example, stability, to render them suitable ;j for formulation into pharmaceutical compositions. The qualiEica-tion that the acid addition salts be "pharmacologically compatible"
is to be understood as extending to acid addition salts of non- ;
toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be unsuitable for administera-tion to living bodies.
Acid addition salts of derivatives of formula (I) which are not pharmaceutically acceptable and pharmacologically 1~ compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, such as by double decomposition reactions, to different acid addition i `, salts having the required physical and chemical characteristics ``~ to make them suitable for administeration in pharmaceutical . .:
compositions to living bodies.
;, For the preparation of pharmaceutical compositions, at `~ 30 least one of the new compounds according to the present invention and/or at least one salt thereof is mi~ed with a solid or liquid pharmaceutical diluent or carrier and optionally also with an :, .~. .,
~392~3~
solvent, for example a lower alcohol, can also be included in the reaction mixture.
An acid addition salt of a metho~yphenyl-pipexazine of formula (III), such as a hydrochloride salt, may be e~ploy~d in reaction a) in place of the free base, ~or the preparation of the acid addition salts, the compounds of the present invention are reacted with pharmacologi-cally compatible, non-toxic inorganic or organic acids, for example, hvdrochloric acid, sulphuric acid, phosphoric acid, lactic acid, citric acid or an alkyl-sulphonic acid. ~
In the specification, it will be understood that the `
qualification that the acid addition salts are "pharmaceutically acceptable" means that the salts have the necessary physical 1, characteristics, for example, stability, to render them suitable ;j for formulation into pharmaceutical compositions. The qualiEica-tion that the acid addition salts be "pharmacologically compatible"
is to be understood as extending to acid addition salts of non- ;
toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be unsuitable for administera-tion to living bodies.
Acid addition salts of derivatives of formula (I) which are not pharmaceutically acceptable and pharmacologically 1~ compatible form a useful aspect of the invention of the novel derivatives, inasmuch as they can be readily converted, such as by double decomposition reactions, to different acid addition i `, salts having the required physical and chemical characteristics ``~ to make them suitable for administeration in pharmaceutical . .:
compositions to living bodies.
;, For the preparation of pharmaceutical compositions, at `~ 30 least one of the new compounds according to the present invention and/or at least one salt thereof is mi~ed with a solid or liquid pharmaceutical diluent or carrier and optionally also with an :, .~. .,
3 -, :'.. ~ ': ~., ' ' :
~(?39Z8Z ~`~
odoriferous, flavouring or colouriny material and then formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example olive oil.
A typical composition -for the treatment of hypertonias may contain about 1 my. of the active ingredient which may be administered in amounts of 1 to about 20 mg. of active ingredient daily. In the case of ampoules, these may be formulated to ;~
contain, for example, 1 mg. of active material in a 1 ml. ampoule.
Having thus generally described the invention, reference will now be made to the following Examples illustrating preferred err~odiments only~
Example 1.
1-(2-Methoxyphenyl)-~ naphth-l-yl-oxy)-2-hydroxypropyl~-piperazine.
A mixture of 30.0 g. (0.15 mol) 2,3-epoxy-1-(1-naphthyloxy)-propane and 28,8 g. (0.15 mol) 1-(2-methoxy-phenyl)-piperazine is heated to 120C. and maintained at this temperature for 5 hours. After cooling, a red solidified product is obtained which is recrystallized from isopropanol and has a melting point of 125 - 126C. There are obtained 46.5 g. (79% of theory) 1-(2-methoxyphenyl)-4-C3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine. The corresponding dihydrochloride, after recrystalli-zation from methanol/ethanol (1:2), has a melting point of 212 -213 C.
'',~ ~, ' 1~(4-Met_oxyphenyl) 4- r3-(naphth-1-ylo~)-2-hydroxypropyll-piperazine.
20.0 g. (0.1 mol) 2,3-epoxy-1-(1-naphthyloxy)-propane ., .
are mixed with 30 ml~ ethanol and 19.2 g. (0.1 mol) 1-(4-methoxy-` phenyl)-piperazine, whereafter the reaction mixture is heated to ;
60&. and maintained at ~his temperature for 6 hours. The ~ -- 4 --:
1()392~3Z
reaction mixture is then left to stand overnight and the ethanol ~
subsequently evaporated off. The oil residue is dissolved in :
chloroform, hydrogen chloride is passed through the chloroform solution and then ether is added, the dihydrochloride thereby precipitating out. This is filtered off with suction and ~ .
recrystallized from methanol/ethanol (1:3). There is obtained -1-(4-methoxyphenyl)-4-C3-(naphth-1-yloxy)-2-hydroxypropyl]-~ .
piperazine in a yield of 76% of.theory. The product has a melting ~ :
.
point of 237 - 238C.
., : ~ .
.
., ' ' ~:
.' ~ , .,~` ' ~
,, :~ :
.",~, ', ., '1 `, .
., _ 5 _ ~ .
,~
~(?39Z8Z ~`~
odoriferous, flavouring or colouriny material and then formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example olive oil.
A typical composition -for the treatment of hypertonias may contain about 1 my. of the active ingredient which may be administered in amounts of 1 to about 20 mg. of active ingredient daily. In the case of ampoules, these may be formulated to ;~
contain, for example, 1 mg. of active material in a 1 ml. ampoule.
Having thus generally described the invention, reference will now be made to the following Examples illustrating preferred err~odiments only~
Example 1.
1-(2-Methoxyphenyl)-~ naphth-l-yl-oxy)-2-hydroxypropyl~-piperazine.
A mixture of 30.0 g. (0.15 mol) 2,3-epoxy-1-(1-naphthyloxy)-propane and 28,8 g. (0.15 mol) 1-(2-methoxy-phenyl)-piperazine is heated to 120C. and maintained at this temperature for 5 hours. After cooling, a red solidified product is obtained which is recrystallized from isopropanol and has a melting point of 125 - 126C. There are obtained 46.5 g. (79% of theory) 1-(2-methoxyphenyl)-4-C3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine. The corresponding dihydrochloride, after recrystalli-zation from methanol/ethanol (1:2), has a melting point of 212 -213 C.
'',~ ~, ' 1~(4-Met_oxyphenyl) 4- r3-(naphth-1-ylo~)-2-hydroxypropyll-piperazine.
20.0 g. (0.1 mol) 2,3-epoxy-1-(1-naphthyloxy)-propane ., .
are mixed with 30 ml~ ethanol and 19.2 g. (0.1 mol) 1-(4-methoxy-` phenyl)-piperazine, whereafter the reaction mixture is heated to ;
60&. and maintained at ~his temperature for 6 hours. The ~ -- 4 --:
1()392~3Z
reaction mixture is then left to stand overnight and the ethanol ~
subsequently evaporated off. The oil residue is dissolved in :
chloroform, hydrogen chloride is passed through the chloroform solution and then ether is added, the dihydrochloride thereby precipitating out. This is filtered off with suction and ~ .
recrystallized from methanol/ethanol (1:3). There is obtained -1-(4-methoxyphenyl)-4-C3-(naphth-1-yloxy)-2-hydroxypropyl]-~ .
piperazine in a yield of 76% of.theory. The product has a melting ~ :
.
point of 237 - 238C.
., : ~ .
.
., ' ' ~:
.' ~ , .,~` ' ~
,, :~ :
.",~, ', ., '1 `, .
., _ 5 _ ~ .
,~
Claims (17)
1. Process for the preparation of a piperazine derivative of the formula (I):- (I) comprising a) reacting a compound of the formula (II):- (II) in which R1 is a hydrogen atom and R2 is a halogen atom or R1 and R2 together represent a valency bond, with a methoxyphenyl-piperazine of the formula (III):- (III) or b) reacting 1-naphthol with a compound of the formula (IV):- (IV) in which R1 and R2 are as defined above,
2. A process according to claim 1 for the preparation of a piperazine derivative of the formula (I) as defined in claim 1, comprising reacting a compound of the formula (II):- (II) in which R1 is a hydrogen atom and R2 is a halogen atom or R1 and R2 together represent a valency bond, with a methoxyphenyl-piperazine of the formula (III):-(III)
3. A process according to claim 1 for the preparation of a piperazine derivative of the formula (I) as defined in claim 1, comprising reacting 1-naphthol with a compound of the formula (IV):-(IV) in which R1 is a hydrogen atom and R2 is a halogen atom or R1 and R2 together represent a valency bond.
4. A process according to claim 1, 2 or 3, wherein the reaction is carried out in a solvent.
5, A process according to claim 1 including the step of reacting said compound of formula (I) with a pharmacologically compatible non-toxic inorganic or organic acid to produce a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof.
6. A process according to claim 2 including the step of reacting said compound of formula (I) with a pharmacologically compatible non-toxic inorganic or organic acid to produce a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof.
7. A process according to claim 3 including the step of reacting said compound of formula (I) with a pharmacologically compatible non-toxic inorganic or organic acid to produce a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof.
8. A process according to claim 2 or 3 wherein R1 is a hydrogen atom and R2 is a chlorine atom.
9. A process according to claim 2 or 3 wherein R1 and R2 together represent a valency bond.
10. A process according to claim 2 or 3 wherein molar amounts of the reaction components are mixed and the resulting reaction mixture is subjected to heating.
11. A process according to claim 2 for preparing 1-(2-methoxyphenyl)-4-[3-(naphth-1-yl-oxy)-2-hydroxypropyl]-piperazine comprising reacting 2,3-epoxy-1-(1-naphthyloxy)-propane with 1-(2-methoxyphenyl)-piperazine.
12. A process according to claim 2 for preparing 1-(4-methoxyphenyl)-4-[3-(naphth-1-yloxy)-2-hydroxypropyl]--piperazine comprising reacting 2,3-epoxy-1-(1-naphthyloxy)-propane with 1-(4-methoxyphenyl)-piperazine.
13. Piperazine derivatives of the formula (I):-(I) whenever prepared by the process of claim 1, 2 or 3, or by an obvious chemical equivalent.
14. A pharmaceutically acceptable, pharmacologically compatible acid addition salt of a compound of formula (I) as defined in claim 1, whenever prepared by the process of claim 5, or by an obvious chemical equivalent.
15. A pharmaceutically acceptable, pharmacologically compatible acid addition salt of a piperazine derivative of formula (I) as defined in claim 1, whenever prepared by the process of claims 6 or 7, or by an obvious chemical equivalent.
16. 1-(2-Methoxyphenyl)-4-[3-(naphth-1-yloxy)-2-hydroxy-propyl]-piperazine, whenever prepared by the process of claim 11, or by an obvious chemical equivalent.
17. 1-(4-Methoxyphenyl)-4-[3-(naphth-1-yloxy)-2-hydroxy-propyl]-piperazine, whenever prepared by the process of claim 12, or by an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2408804A DE2408804C2 (en) | 1974-02-23 | 1974-02-23 | 1- (2-Methoxyphenyl) -4- [3- (naphth-1-yl-oxy) -2-hydroxypropyl] -piperazine, its salts, processes for their preparation and pharmaceuticals which contain these compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1039282A true CA1039282A (en) | 1978-09-26 |
Family
ID=5908286
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA219,883A Expired CA1039282A (en) | 1974-02-23 | 1975-02-12 | 1-(3-(naphth-1-yloxy)-2-hydroxy-propyl)-piperazine derivatives |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US3997666A (en) |
| JP (1) | JPS6029712B2 (en) |
| AR (1) | AR206339A1 (en) |
| AT (1) | AT340937B (en) |
| BE (1) | BE825755A (en) |
| CA (1) | CA1039282A (en) |
| CH (2) | CH612958A5 (en) |
| DE (1) | DE2408804C2 (en) |
| DK (1) | DK135124C (en) |
| ES (1) | ES434829A1 (en) |
| FI (1) | FI59248C (en) |
| FR (1) | FR2261770B1 (en) |
| GB (1) | GB1445548A (en) |
| IE (1) | IE40678B1 (en) |
| NL (2) | NL175059B (en) |
| PL (1) | PL92131B1 (en) |
| SE (1) | SE405601B (en) |
| SU (2) | SU549085A3 (en) |
| YU (2) | YU37156B (en) |
| ZA (1) | ZA751031B (en) |
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| US9272980B2 (en) | 2014-06-06 | 2016-03-01 | Ktn Biotec, Inc. | Anticancer agent |
| WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
| CN113574055A (en) | 2019-01-18 | 2021-10-29 | 阿斯利康(瑞典)有限公司 | PCSK9 inhibitors and methods of use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA967965A (en) * | 1968-12-24 | 1975-05-20 | Hoffmann-La Roche Limited | Aromatic ethers and process for the manufacture thereof |
| GB1317479A (en) * | 1970-11-10 | 1973-05-16 | Pfizer Ltd | 1-2-hydroxy-3-phenoxy or phenylthiopropyl-4-phenyl-piperazine derivatives |
| DE2235597A1 (en) * | 1972-07-20 | 1974-01-31 | Boehringer Mannheim Gmbh | SINGLE SQUARE CLIP ON 3- (5,6,7,8TETRAHYDRONAPHTH-1-YL-OXY) -PROPYL SQUARE CLIP FOR -PIPERAZINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
-
0
- NL NLAANVRAGE7501877,A patent/NL175059C/en active
-
1974
- 1974-02-23 DE DE2408804A patent/DE2408804C2/en not_active Expired
-
1975
- 1975-01-01 AR AR257639A patent/AR206339A1/en active
- 1975-01-28 US US05/544,719 patent/US3997666A/en not_active Expired - Lifetime
- 1975-02-12 CA CA219,883A patent/CA1039282A/en not_active Expired
- 1975-02-17 GB GB656975A patent/GB1445548A/en not_active Expired
- 1975-02-18 ES ES434829A patent/ES434829A1/en not_active Expired
- 1975-02-18 NL NLAANVRAGE7501877,A patent/NL175059B/en not_active IP Right Cessation
- 1975-02-18 FI FI750449A patent/FI59248C/en not_active IP Right Cessation
- 1975-02-18 DK DK58175A patent/DK135124C/en not_active IP Right Cessation
- 1975-02-18 YU YU0382/75A patent/YU37156B/en unknown
- 1975-02-19 ZA ZA00751031A patent/ZA751031B/en unknown
- 1975-02-20 JP JP50021386A patent/JPS6029712B2/en not_active Expired
- 1975-02-20 SE SE7501911A patent/SE405601B/en not_active IP Right Cessation
- 1975-02-20 BE BE153540A patent/BE825755A/en not_active IP Right Cessation
- 1975-02-21 FR FR7505511A patent/FR2261770B1/fr not_active Expired
- 1975-02-21 SU SU2112509A patent/SU549085A3/en active
- 1975-02-21 PL PL1975178230A patent/PL92131B1/pl unknown
- 1975-02-21 IE IE359/75A patent/IE40678B1/en unknown
- 1975-02-21 AT AT132375A patent/AT340937B/en not_active IP Right Cessation
- 1975-02-21 CH CH1023478A patent/CH612958A5/xx not_active IP Right Cessation
- 1975-02-21 CH CH218575A patent/CH609342A5/xx not_active IP Right Cessation
-
1976
- 1976-01-07 SU SU2308659A patent/SU561514A3/en active
-
1981
- 1981-04-21 YU YU1044/81A patent/YU37157B/en unknown
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