GB1572952A - Cholecalciferol derivatives - Google Patents
Cholecalciferol derivatives Download PDFInfo
- Publication number
- GB1572952A GB1572952A GB9480/77A GB948077A GB1572952A GB 1572952 A GB1572952 A GB 1572952A GB 9480/77 A GB9480/77 A GB 9480/77A GB 948077 A GB948077 A GB 948077A GB 1572952 A GB1572952 A GB 1572952A
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- Prior art keywords
- dihydroxycholecalciferol
- acetate
- acetonide
- group
- compound
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Cholecalciferol derivatives of the formula <IMAGE> in which R1 is hydroxyl or lower alkanoyloxy, and the absolute configuration at C-24 is R or S, are prepared starting from corresponding 24,25-ketals. These compounds stimulate intestinal calcium transport and can therefore be used for therapeutic purposes.
Description
(54) CHOLECALCIFEROL DERIVATIVES
(71) We. F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT, a Swiss C6mpany of 124-184 Grenzacherstrasse, Basle, Swftzerland, do hereby de dare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention is concerned with cholecalciferol derivatives.
The isolation and characterisation of 24,23-dihydroxycholecalciferol (24,25-dihydroxy vitamin D3) (M. F. Holick et al., Biochemistry, 11 (4251) [1972]), and the subsequent finding that this second most abundant metabolite of vitamin D3 (J. L.
Omdahl and H. F. DeLuca, Physiological Reviews, 53, 327 [1973]) preferentially stimulates intestinal calcium transport without, at comparable dose levels, mobiles ing bone calcium, prompted extensive investigations into the physiological role played by this metabolite (see, for example, H. K. Schnoes and H. F. DeLuca, Vitamins and Hormones, 32 395 [1974]). These investigations have been hampered by the minute amounts of the metabolite available from natural sources, the lack of informa tion concerning the stereochemistry of the metabolic hydroxyl group at C24 and the effect of the configuration of this group on the biological activity exhibited by 24,25-dihydroxycholecalciferol.
Recently, M. Seki et al., Chem. Pharm. Bull. (Japan), 21, 2783 (1973) des- cribed the conversion of desmosterol acetate to 24t,25-dihydroxycholestero, a precursor of 24,25-dihydroxycholecalciferol. Shortly thereafter, H. Y. Lam et al., Biochemistry, 12, 4851 (1973) and J. Redel et al., Compt. rend. Acad. Sci (Paris), 278, 529 (1974) disclosed syntheses of 240,25-dihydroxycholecalciferol starting from 38- acetoxy-27-nor-5-cholesten-25-one and desmosterol acetate, respectively. These synthese are non-stereospecific, yielding mixtures of stereoisomers at C-24. M.Seki et al., Tetrahedron Letters, 15 (1975) recently described the separation of 225- dihydroxycholesterol into the 24R- and 24S-iso,:ners and the conversion of the 24Rand 24 S-isomers into 24R,25- and 24S,25-dihydroycholecalciferol, respectively. This synthesis suffers from the inherent disadvantages associated with the separation step.Thus, stereospecific syntheses of 24R,25- and 24S,25-dihydroxycholecalciferol using 24,25-dihydroxycholesterol derivatives of known stereochemistry at C24, overcoming the deficiences of the prior art processes and making this important metabolite of vitamin D3 readily available for biological, clinical and therapeutic use, would represent an important contribution to the advancement of the state of the art in the vitamin D field.
As used in this description and in the accompanying claims, the term "alkyl" refers to a straight-chain or branched-chain saturated monovalent substituent consisting solely of carbon and hydrogen and containing from 1 to 20 carbon atoms.
Examples of alkyl groups are methyl, ethyl, n-propy1, isopropyl, tert.-butyl, hexyl, octyl and so forth. The tenn "alkylene" refers to a straight-chain or branched-chain saturated divalent substituent consisting solely of carbon and hydrogen and containing from 1 to 20 carbon atoms. Examples of alkylene groups are methylene, ethylene propylene and so forth. The term "alkanoyloxy" refers to the residue of an alkanoic acid formed by removal of the hydrogen atom from the hydroxyl moiety of the carboxyl group. Examples of alkanoyloxy groups are formyloxy, acetoxy, butyryloxy, hexanoyloxy and so forth. The term "alkanol" refers to a compound derived by protonation of the oxygen atom of an alkoxy group.Examples of alkanols are methanol, ethanol, 2-propanol, 2-methyl-2-propanol and the like. The term "lower" as applied to any of the aforementioned groups refers to groups containing from 1 to 8 carbon atoms.
In the formulae given in this specification, the various substituents are shown as joined to the nucleus by one of these notations; namely, a solid line (-) indicating a substituent which has the jB-configuration (i.e. above the plane of the molecule), a broken line (111111) indicating a substituent which has the a-configuration (i.e. below the plane of the molecule) or a wavy line (m) indicating a substituent which may have the a- or ss-configuration. The formulae have all been drawn to show the com- pounds in their absolute stereochemical configurations. Since the starting materials are derived from naturally occurring stigmasterol, the products exist in the single absolute configuration depicted herein.
The Greek letter xi (t in the name of a vitamin D, intermediate or metabolite indicates that the stereochemistry of the substituent to which it refers is undefined or that the product consists of a mixture of compounds epimeric at the designated position.
The nomenclature adopted to define absolute configuration of sabstituents bound to carbon atom 24 of the nucleus is described in the Journal of Organic Chemistry, 34, 2849 (1970) under the title "IUPAC Tentative Rules for the Nomenclature of Organic Chemistry, Section E, Fundamental Stereochemistry ".
According to the present invention, we provide a process for the manufacture of 24R,25- and 24,23-dihydroxycholecalciferol and of the 3-(lower alkanoates) thereof, i.e. compounds of the general formula
wherein R, represents a hydroxy or lower alkanoyloxy group and the absolute
configuration at C-24 is R or S, which process comprises contacting a compound of the general formula
wherein R1 has the significance given earlier, R2 and R3 each independently
represent a lower alkyl group or R2 and R, together represent a lower alkylene
group and the absolute configuration at C-24 is R or S, with an add and a hydroxylic solvent.
The deketalisation of a compound of formula II is conveniently carried out by treatment with an excess of an alkanol containing an acid. Suitable acids include mineral adds such as hydrogen chloride, hydrogen bromide, sulphuric acid, boron trifluoride and the like, organic acids such as paratoluenesulphonic acid, trifluoroacetic add and the like and cationic exchange resins in the hydrogen ion form such as
Bio-Rad AG 50W-X4, Bio-Rad AG 5QW, Dowex 50W, Duolite C20, Amberlite 1R,
Zeocarb, Permutit Q, Nalcite and the like. (The words " Dowex ", " Duolite ", " Amberlite " and " Permutit" are registered Trade Marks.) Cationic exchange resins in the hydrogen ion form, particularly Bio-Rad AG 50W-X4, and organic acids, particularly parcaoluenesulphonic acid, are preferred. Suitable alkanols include methanol, ethanol, 2-propanol, 2-butanol, 2-pentanol and the like. Also included as suitable hydroxylic solvents are aliphatic diols such as ethyleneglycol, propyleneglycol and the like. Alkanols are preferred, with methanol being most preferred.
While the temperature at which the dekatilisation is carried out is not critical, it is desirable to carry out the deketalisation at a reduced temperature of from between 200 C and - 200 C and +200 C in order to avoid the formation of side products.
A temperature of about - 5 C is most preferred for the deketalisation.
A 24R,25- or 24S,25-dihydroxycholecalciferol-3-(lower alkanoate) of formula I, i.e. a compound of the general formula
wherein R'1 represents a lower alkanoyloxy group and the absolute configuration
atC-24isRorS, can be saponified to 24R,25- and 24S,25-dihydroxycholecalciferol, respectively. This saponification can be carried out according to well-known methods; for example, by dissolving the alkanoate of formula Ia in an alcoholic solution of an alkali metal hydroxide and allowing the solution to stand at a reduced temperature of from about - 20 C to about +20 C, with a temperature of about 0 C being preferred. It is also preferable to carry out the saponification under an inert atmosphere of nitrogen, helium and the like. Suitable alcholic solvents include methanol, ethanol, 2propanol and the like. Suitable alkali metal hydroxides include sodium and potassium hydroxide. Methanol is the preferred alcoholic solvent and potassium hydroxide is the preferred alkali metal hydroxide.
A compound of formula II can be obtained by heating a corresponding previtamin of the general formula
wherein R1, R2 and R have the significance given earlier and the absolute con
figuration at C-24 is R or S, in an inert organic solvent such as dioxane under an inert atmosphere such as argon according to well-known methods [see, for example, D. H. R. Barton et al., J. Am.
So: 98, 2748 (1973)].
Compounds of formula III are described and claimed in our divisional Application No. 16988/78 (Serial No. 1,572,969).
The products of formula Ia as well as the intermediates of formula II are novel and also form part of the present invention.
The following Examples illustrate the present invention. The word "Porasil" appearing in Examples 1--4 is a registered Trade Mark.
Example 1.
24R,25-Disydroxycholecalciferol-3-acetate-24)25-acetonide A solution of 0.250 g of 24R,25-dihydroxyprecholecalciferol-3-acetate-24,25- acetonide in 20 ml of dioxane was refluxed under argon for 1 hour. The solvent was then removed in vacuo and the residue purified with a Waters Associates liquid chromatograph Model 202 using a 8 foot by 3/8 Porasil A column and a 9:1 mixture of n-hexane and ethyl acetate as eluent to give 0.200 g of 24R,25-dihydroxycholecalciferol-3-acetate-24,25-acetonide as a thick oiL
Example 2.
24R2S-Dihydroxycholecalciferol-242S-ac A solution of 0.258 g of 24R,25-dihydroxyprecholecalciferol-24,25-acetonide in 20 ml of dioxane was reflexed under argon for 1 hour. The solvent was then removed in vacuo and the residue purified with a Waters Associates liquid chromatograph Model 202 using a 8 foot by 3/8 inch Porasil A column and a 4:1 mixture of n-hexane and ethyl acetate as eluent to give 0.200 g (77%) of 24R,23-dihydroxy- cholecalciferol-24,25-acetonide as a thick oil.
Example 3.
24S,25-Dihydroxycholecalciferol-3-acetate-24,25-acetonide A solution of 0.200 g of 24S,25-dihydroxyprecholecalciferol-3-acetare-24,25- acetonide in 20 ml of dioxane was reflexed under argon for 1 hour. The solvent was then removed in vacuo and the residue purified with a Waters Associates liquid chromatographed Model 202 using a 8 foot by 3/8 inch Porasil A column and a 9:1 mixture of n-hexane and ethyl acetate as eluent to give 0.170 g of 245,25-dihydroxy- cholecalciferol-3 -acetate-24,25 -acetonide as a thick oil.
Example 4.
24S,25-Dihydroxycholecalciferol-24,25-acetonide A solution of 0.340 g of 24S,25-dihydroxyprecholecalciferol-24,23-acetonide in 20 ml of dioxane was refluxed under argon for 1 hour. The solvent was then removed in vacuo and the residue purified with aa Waters Associates liquid chromatograph Model 202 using a 8 foot by 3/8 inch Porasil A column and a 4:1 mixture of n-hexane and ethyl acetate as eluent to give 0.240 g (70%) of 24S,25dihydroxycholecakiferol- 24,23-acetonide as a thick oil.
Example 5.
24R,25-Dihydroxycholecalciferol-3-acetate
A solution of 0.200 g of 24R,25-dihydroxycholecalciferol-3-acetate-24,25-acetonide in 5 ml of methanol, to which 0.500 g of the hydrogen ion form of a cation exchange resin (Bio-Rad AG 50W-X4) had been added, was stirred under argon for 40 hours at - 5 C. The mixture was then filtered, the exchange resin washed with three 10 ml portions of methanol and the combined methanol phases were evaporated ir. vacuo at 25 C to give 0;173 g of crude 24R,25-dihydroxycholecalciferol-3-acetate as a thick oil.
Example 6.
24R,25-Dihydroxycholecalcif erol A solution of 0.200 g of 24R,25-dihydroxycholecalciferol-24,25-acetonide in 5 ml of methanol, to which 500 mg of the hydrogen ion form of a cation exchange resin (Bio-Rad AG 50W-X4) had been added, was stirred under argon for 40 hours at - 5 C. The mixture was then filtered, the exchange resin washed with three 10 rnl portions of methanol and the combined methanol phases were evaporated in vacuo at 250 C.The residue was purified by liquid chromatography using a Waters Associates Model 202 liquid chromatograph and a 1:1 mixture of n-hexane and ethyl acetate as eluent to give 0.127 g (70%) of 24R,25-dihydroxycholecalciferol. Crystallisation from methyl formate gave 0.094 g (40%) of the desired product as white crystals of melting point 136 -137 C; [a]B25 = +113.00 (c = 0.33 in ethanol).
Example 7.
24S,25-D ihydroxych olecalciferol-3-acetate A solution of 0.200 g of 24S,25-dihydroxycholecaldferol-3-acetate-24,25-acetonide in 5 ml of methanol, to which 0.500 go of the hydrogen ion form of a cation exchange resin (Bio-Rad AG 50W-X4) had been added, was stirred under argon for 40 hours at -5 C. The mixture was then filtered, the exchange resin washed with three 10 ml portions of methanol and the combined methanol phases were evaporated in vacuo at 250 C to give 0.168 g of crude 24S,25-dihydroxycholecalciferol- 3-acetate as a thick oil.
Example 8.
24S,25-D ihydroxychoiecaiciferoi A solution of 0.170 g of 24S,25dihydroxycholecalcifero24,25-acetonide in 5 ml of methanol, to which 500 mg of the hydrogen form of a cation exchange resin (BioRad AG 50W-X4) had been added, was stirred under argon for 40 hours at - 5 C. The mixture was then filtered, the exchange resin washed with three 10 ml portions of methanol and the combined methanol phases were evaporated in vacuo at 25 C.The residue was purified by liquid chromatography using a Waters Associates Model 202 liquid chromatograph and a 1:1 mixture of n-hexane and ethyl acetate as eluent to give 0.86 g (60%) of 24S,25-dihydroxycholecalciferol. Crystallisation from methyl formate gave 0.045 g (29% of the desired product as white crystals of melting point 111 -112 C; [a]X25 = +9370 (c F 0.3 in ethanol).
Example 9.
24R,25-Dihydroxycholecalcif erol A solution of 0.173 g of crude 24R,25-dihydroxycholecalciferol-3-acetate (see
Example 5) and 0.200 g of potassium hydroxide in 5 ml of methanol was stirred at 0 C under argon for 6 hours. The methanol was then evaporated in vacuo and the residue mixed with 30 ml of water and extracted with three 50 ml of portions of methylene chloride. The combined organic. phases were washed with three 30 ml portions of saturated brine, dried over sodium sulphate, filtered and evaporated in vacuo at 25 C. The residue was purified by liquid chromatography using a Waters Associates Model 202 liquid chromatograph and a 1:1 mixture of n-hexane and ethyl acetate as eluent to give 0.132 g (84%) of 24R,25-dihydroxycholecalciferol. Crystallisation from methyl formate gave 0.098 g of the desired product as white crystals of melting point 1360--1370 C.
Example 10.
24S,25-Dihydroxycholecalciterol A solution of 0.168 g of crude 24S,25-dihydroxycholecalciferol-3-acetate (see
Example 7) and 0.200 g of potassium hydroxide in 5 ml of methanol was stirred at 0 C under argon for 6 hours. The methanol was then evaporated in vacuo and the residue mixed with 30 ml of water and extracted with three 50 ml portions of methylene chloride. The combined organic phases were washed with three 30 ml portions of saturated brine, dried over sodium sulphate, filtered and evaporated in vacuo at 25 C.The residue was purified by liquid chromatography using a Waters Associates Model 202 liquid chromatograph and a 1:1 mixture of n-hexane and ethyl acetate as eluent to give 0.126 g (82%) of 24S,25 dihydroxycholecalciferol. Crystallisation from methyl formate gave 0.085 g of the desired product as white crystals of melting point 111 112 C.
WHAT WE CLAIM IS:
1) A process for the manufacture of a compound of the general formula
wherein Rl represents a hydroxy group or a lower alkanoyloxy group and the
absolute configuration at C-24 is R or S, which process comprises contacting a compound of the general formula
wherein R1 has the significance given earlier, R2 and R3 each independently
represent a lower alkyl group or R2 and R, together represent a lower all:ylene group and the absolute configuration at C-24 is R or S, with an acid and a hydroxylic solvent.
2) A process according to claim 1, wherein said acid is an organic acid and said hydroxylic solvent is an alkanol.
3) A process according to claim 2, wherein said organic acid is paratoluenesulphonic acid and said alkanol is methanol.
4) A compound of the general formula
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (3)
1) A process for the manufacture of a compound of the general formula
wherein Rl represents a hydroxy group or a lower alkanoyloxy group and the
absolute configuration at C-24 is R or S, which process comprises contacting a compound of the general formula
wherein R1 has the significance given earlier, R2 and R3 each independently
represent a lower alkyl group or R2 and R, together represent a lower all:ylene group and the absolute configuration at C-24 is R or S, with an acid and a hydroxylic solvent.
2) A process according to claim 1, wherein said acid is an organic acid and said hydroxylic solvent is an alkanol.
3) A process for the manufacture of cholecalciferol derivatives as claimed in claims 1 to 3, substantially as hereinbefore described with reference to any one of
Examples 5 to 8.
3) A process according to claim 2, wherein said organic acid is paratoluenesulphonic acid and said alkanol is methanol.
4) A compound of the general formula
wherein Rl represents a hydroxy or lower alkanoyloxy group, R2 and R3 each
independently represent a lower alkyl group or R2 and R3 together represent a
lower alkylene group and the absolute configuration at C-24 is R or S.
5) A compound according to claim 4, wherein R2 and R3 each independently represent a lower alkyl group.
6) 24R,25-Dihydroxycholecalciferol-3 -acetate-24-25 -acetonide.
7) 24R,25 -Dihydroxycholecalciferol-24,25 -acetonide.
8) 24S-25-Dihydroxycholecalciferol-3-acetate-24,25 acetonide.
9) 24S,25-Dihydroxycholecalciferol-24,25-acetonide.
10) A compound of the general formula
wherein R'1 represents a lower alkanoyloxy group and the absolute configuration
at C-24 is R or S.
11) 24S,25-Dihydroxycholecalciferol-3-acetate.
12; 24R,25-Dihydroxycholecalciferol-3-acetate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/664,799 US4021423A (en) | 1976-03-08 | 1976-03-08 | Syntheses of 24R,25- and 24S,25-dihydroxycholecalciferol |
| US05/664,833 US4028349A (en) | 1976-03-08 | 1976-03-08 | Syntheses of 24R,25- and 24S,25-dihydroxycholesterol 24,25-ketals and alkanoyl derivatives thereof |
| US05/664,848 US4026882A (en) | 1976-03-08 | 1976-03-08 | Syntheses of 3,24R,25- and 3,24S,25-trihydroxy-5,7-cholestadiene 24,25-ketals and alkanoyl derivatives thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1572952A true GB1572952A (en) | 1980-08-06 |
Family
ID=27418118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9480/77A Expired GB1572952A (en) | 1976-03-08 | 1977-03-07 | Cholecalciferol derivatives |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS52108960A (en) |
| CH (4) | CH626336A5 (en) |
| DE (1) | DE2710062A1 (en) |
| FR (1) | FR2343727A1 (en) |
| GB (1) | GB1572952A (en) |
| IT (1) | IT1078064B (en) |
| NL (1) | NL7702484A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5735599A (en) * | 1980-08-05 | 1982-02-26 | Chugai Pharmaceut Co Ltd | 24,25-dihydroxycholestane and its preparation |
| ATE15050T1 (en) * | 1981-04-29 | 1985-09-15 | Hoffmann La Roche | PROCESSES FOR THE PREPARATION OF CHOLESTERIND DERIVATIVES AND INTERMEDIATE PRODUCTS THEREOF. |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1178427B (en) * | 1961-01-26 | 1964-09-24 | Olin Mathieson | Process for the preparation of 16ª ‡, 17ª ‡ -dihydroxysteroids of the pregnan series |
| US3715374A (en) * | 1972-05-05 | 1973-02-06 | Wisconsin Alumni Res Found | 24,25-dihydroxycholecalciferol |
| US3901928A (en) * | 1973-01-10 | 1975-08-26 | Robert Henry Hesse | 1' ,3' -dihydroxy steroid-5-enes method of preparing same and their use for preparing 1' -hydroxy-25-hydrogen vitamin d compounds |
| JPS51128417A (en) * | 1975-04-28 | 1976-11-09 | Teijin Ltd | A method for stabilizing active vitamin d3 derivatives |
-
1977
- 1977-02-08 CH CH149077A patent/CH626336A5/en not_active IP Right Cessation
- 1977-02-28 IT IT20765/77A patent/IT1078064B/en active
- 1977-03-04 JP JP2291477A patent/JPS52108960A/en active Pending
- 1977-03-04 FR FR7706407A patent/FR2343727A1/en active Granted
- 1977-03-07 GB GB9480/77A patent/GB1572952A/en not_active Expired
- 1977-03-08 DE DE19772710062 patent/DE2710062A1/en not_active Ceased
- 1977-03-08 NL NL7702484A patent/NL7702484A/en not_active Application Discontinuation
-
1981
- 1981-03-25 CH CH202081A patent/CH627159A5/en not_active IP Right Cessation
- 1981-03-25 CH CH202281A patent/CH627192A5/en not_active IP Right Cessation
- 1981-03-25 CH CH202181A patent/CH627764A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NL7702484A (en) | 1977-09-12 |
| JPS52108960A (en) | 1977-09-12 |
| IT1078064B (en) | 1985-05-08 |
| CH627192A5 (en) | 1981-12-31 |
| DE2710062A1 (en) | 1977-09-15 |
| FR2343727A1 (en) | 1977-10-07 |
| CH627764A5 (en) | 1982-01-29 |
| FR2343727B1 (en) | 1984-01-13 |
| CH626336A5 (en) | 1981-11-13 |
| CH627159A5 (en) | 1981-12-31 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |