GB2073750A - 3,7,11,15-Tetramethyl- 2,4,6,10,14-hexadecapentaenoic Acid - Google Patents
3,7,11,15-Tetramethyl- 2,4,6,10,14-hexadecapentaenoic Acid Download PDFInfo
- Publication number
- GB2073750A GB2073750A GB8110160A GB8110160A GB2073750A GB 2073750 A GB2073750 A GB 2073750A GB 8110160 A GB8110160 A GB 8110160A GB 8110160 A GB8110160 A GB 8110160A GB 2073750 A GB2073750 A GB 2073750A
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- United Kingdom
- Prior art keywords
- compound
- general formula
- tetramethyl
- pharmaceutically acceptable
- acceptable salt
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- UUBHZHZSIKRVIV-KCXSXWJSSA-N (2e,6e,10e)-3,7,11,15-tetramethylhexadeca-2,4,6,10,14-pentaenoic acid Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\C=C\C(\C)=C\C(O)=O UUBHZHZSIKRVIV-KCXSXWJSSA-N 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 208000017520 skin disease Diseases 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 20
- 230000003780 keratinization Effects 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- -1 3,7,11,1 5-Tetramethyl-2,4,6,1 0,1 4-hexadecapentaenoic acid Chemical compound 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 230000000144 pharmacologic effect Effects 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 229940124597 therapeutic agent Drugs 0.000 abstract description 4
- 125000004494 ethyl ester group Chemical group 0.000 abstract description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000000862 absorption spectrum Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000011534 incubation Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010020915 Hypervitaminosis Diseases 0.000 description 4
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 4
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 208000003154 papilloma Diseases 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 231100000820 toxicity test Toxicity 0.000 description 4
- 235000019155 vitamin A Nutrition 0.000 description 4
- 239000011719 vitamin A Substances 0.000 description 4
- 229940045997 vitamin a Drugs 0.000 description 4
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- 206010011703 Cyanosis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 239000006059 cover glass Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HQMNCQVAMBCHCO-UHFFFAOYSA-N 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid ethyl ester Chemical compound CCOC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)C=C(OC)C(C)=C1C HQMNCQVAMBCHCO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 206010020649 Hyperkeratosis Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- HGFAGNRYCRACAH-UHFFFAOYSA-N 6,10,14-trimethylpentadeca-3,5,9,13-tetraen-2-one Chemical compound CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=O HGFAGNRYCRACAH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000002506 Darier Disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- 206010023369 Keratosis follicular Diseases 0.000 description 1
- 208000005775 Parakeratosis Diseases 0.000 description 1
- 241000101040 Pityriasis Species 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- 206010037575 Pustular psoriasis Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JIPWHZOYUGYXFA-UHFFFAOYSA-N ethyl 4-bromo-3-methylbut-2-enoate Chemical compound CCOC(=O)C=C(C)CBr JIPWHZOYUGYXFA-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 201000004607 keratosis follicularis Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000010914 pustulosis of palm and sole Diseases 0.000 description 1
- 208000011797 pustulosis palmaris et plantaris Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002678 retinoid group Chemical group 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/03—Monocarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
Abstract
3,7,11,15-Tetramethyl- 2,4,6,10,14-hexadecapentaenoic acid and its salts are anticancer agents and therapeutic agents for treatment of skin diseases with keratinisation. The preparation of the ethyl ester is described.
Description
SPECIFICATION 3,7,1 1,1 5-Tetramethyl-2,4,6,1 0,14- hexadecapentaeoic Acid
This invention relates to a novel compound of 3,7,1 1,1 5-tetramethyl-2,4,6,1 0,14hexadecapentaenoic acid having the general formula (I):
and a pharmaceuticairy acceptable salt thereof. This invention further relates to processes for the preparation of the same, an anticancer agent comprising the same, and a therapeutic agent for treatment of skin diseases with keratinization.
W. Bollag, et al. reported in Europ. J. Cancer, vol. 10, p 731 (1974) that retinoides such as ethyl 9-(2,3,6-trimethyl-4-methoxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate have anticancer activity.
These retinoide compounds, however, are highly toxic, and further have problems such as causing hypervitaminosis of Vitamin A when administered.
The compound of the above-mentioned general formula (I) provided by the present invention shows the anticancer activity, causes substantially no hypervitaminosis of Vitamin A, and is low in other toxicities.
The compound of the present invention can be prepared by the following processes.
Process A
This process comprises:
(1) reacting a compound of the general formula (ill):
and a Wittig reagent derived from a compound of the general formula (Ill): X-CH2-C02R1 (Ill) in which X represents a halogen atom, and R1 represents a lower alkyl group, to obtain a compound of the general formula (IV):
in which R1 has the same meaning as defined above; and
(2) hydrolyzing the compound of the general formula (IV) so obtained in the presence of a base to prepare the compound of the general formula (I).
Examples of the Wittig reagents employed in the above-described stage (1) and derived from a compound of the general formula (III) include phosphoric compounds produced by the reaction between the compound of the general formula (III) and triphenylphosphine, phenyldialkoxyphosphine, trialkylphosphite, or the like. The preparation of the reagent and the Wittig reaction employing the reagent are carried out by the conventional methods such as the method given by Wadworth, et al. in
J. Am. Chem. Soc., vol, 83, p. 1733 (1961), the method given by Greenwald, et al. in J. Org. Chem., vol. 28, p. 1128 (1963), and the method given by Horner, et al. in Ber. vol, 95, p. 581 (1962).
In the above-mentioned stage (2), the hydrolisis is carried out in the presence of a base generally employed for hydrolysis of carboxylic acid esters, such as sodium hydroxide and potassium hydroxide.
Process B
This process comprises:
(1) reacting a compound of the general formula (V)
and a Wittig reagent derived from a compound of the general formula (VI):
in which X represents a halogen atom, and R1 represents a lower alkyl group, to obtain a compound of the general formula (IV); and
(2) hydrolyzing the compound of the general formula (IV) so obtained in the presence of a base to prepare the compound of the general formula (I).
Each of the above-described stages (1) and (2) can be carried out in the same manner as in
Process A.
Process C
This process comprises:
(1) reacting a compound of the general formula (VII):
in which Y represents a lower alkyl group or an aryl group, and a compound of the general formula (VI), to obtain a compound of the general formula (VII I):
in which Y and R1 have the same meanings as defined above; and
(2) subjecting the compound of the general formula (VIII) so obtained to a desulfination followed by hydrolysis of the resulting ester in the presence of a base to prepare the compound of the general formula (I).
The stage (1) is carried out in the presence of a base. Examples of the bases include nbutyllithium and phenyllithium. Examples of the reaction solvents include tetrahydrofuran, diethyl ether and 1 ,2-dimethoxyethane. The reaction is generally carried out at a temperature lower than room temperature.
The stage (2) can be carried out in the same manner as the stage (2) of the aforementioned
Process A.
Examples of the substituents provided to the general formulae (III), (IV), (VI), (VII) and (VIII) are as follows:
Halogen atoms such as chlorine, bromine and iodine for the substituent X; lower alkyl groups such as methyl, ethyl and propyl for the substituent R1 and lower alkyl groups such as methyl, ethyl and propyl, and aryl groups such as phenyl and p-tolyl for the substituent Y.
Examples of the pharmaceutically acceptable salts of the compound of the general formula (I) include its sodium salt and its potassium salt.
The compound of the aforementioned general formula (I) provided by the present invention also shows therapeutic activity for treatment of skin diseases with keratinization.
Examples of the slain disease with keratinization which can be treated by the compound of the general formula (I) include skin diseases showing symptoms such as hyperkeratosis, parakeratosis and dyskeratosis. More concretely, examples of the skin diseases include psoriasis, acne, acne vulgaris,
Darier's disease, palmoplantar pustulosis, lichen planus, ichthyosis, erythroderma, pityriasis rubra pilasis, and keratosis senilis.
There are employed steroide-type external preparations for the treatment of the skin diseases with keratinization. These preparations, however, have strong side-effects, so that these are not applicable to the repeated administration for a long period and the treatment with administration of a great amount of the preparation.
In contrast, 3,7,11,1 5-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid of the present invention has the activity for inhibition of keratinization of skin and shows low toxicity.
The results of the pharmacological tests and toxicity tests on the compound of the present invention are set forth below.
Pharmacological Tests (Anticancer Activity) (1) Experimental Procedure
A mouse (ICR, female, 60 days age) was shaved at the back of the neck (5 cm2). 7,12
Dimethylbenzo-[2]-anthracene was dissolved in acetone to give 75 mg/1 00 ml solution. The so prepared solution was applied to the mouse on the 60th aged day and further on the 75th aged day in the amount of 0.2 ml per mouse.
Crotonic oil was dissolved in acetone to give 250 mg/1 00 ml solution, and the so prepared solution was applied to the mouse in the amount of 0.2 ml per mouse, twice a week until the beginning of the treatment When 3-7 papillomata (diameter of 3-8 mm for each, and total diameter of 3060 mm) were produced per mouse, the treatment was started.
The test compound was dissolved in groundnut oil to give 20 mg/ml solution, and administered orally to the mouse. The solution was administered 10 times for 14 days (once a day), and the diameters of the papillomata were measured on the 14th day to determine the total diameter for each mouse.
(2) Test Compound 3,7,1 1,1 5-Tetramethyl-2,4,6, 10,1 4-hexadecapentaenoic acid (the compound according to the present invention).
Ethyl-9-(2,3,6-trimethyl-4-m ethoxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (control compound).
(3) The Results are Set Forth in Table 1
Table 1 Papilloma (total diameter/mouse) Number Ratio of
of Mean Value Mean Value Increase or
Test Compound mice (Oth day) (14th day) Decrease
Groundnut oil
only 3 33.9 mm 39.7 mm +17.1%
Compound of the
invention
(200 mg/Kg/day) 5 37.5 mm 21.3 mm 43.2% Control compound
(40 mg/Kg/ 3 58.1 mm 32.7 mm -43.7% day)
As seen from the above Table 1, the compound of the invention is effective against the papilloma.
Pharmacological Tests (Inhibition of Keratinization)
(1) Experminental Procedure
Into a Petri dish (diameter 6 cm) in which 8 coverglasses (diameter 1 5 mm) were placed was
poured 5 ml of a suspension of the variant epthelial cell of rat bladder named BES 20B (approximately 2x 105 cells/ml), and the incubation was carried out at 370C, for 24 hours and at 5% carbon dioxide
concentration. Each of the so treated coverglasses was placed in 2 ml of Eagle's MEM medium
containing the test compound at different concentrations, and then another incubation was carried out
at 370C and at 5% carbon dioxide concentration. The medium was renewed at intervals of 2-3 days.
On the 2nd, 5th, 8th and 14th days from the beginning of the incubation, the cover glass was taken out
of the medium and subjected to the Papanicolaou stain to observe the degree of keratinization. The
observation was carried out by the measurement of the absorption spectrum in the region of 400
750 nm, and the KI (keratinization Index) was calculated from the following equation.
Absorption peak in the vicinity of 490 nm ascribed
to the keratinized cells
Kl=
Absorption peak in the vicinity of 640 nm ascribed
to the non-keratinized cells
A value of the KI of 1.0 or higher indicates a high keratinization, and a value of the Kl of 0.5 or
less indicates substantially no keratinization.
The BES 20B cell was incubated in a medium containing no compound of the invention, for
comparison.
(2) Test Compound 3,7,11,1 5-Tetramethyl-2,4,6,1 0,1 4-hexadecepentaenoic acid (the compound according to the
present invention).
(3) Experimental Results
The results are set forth in Table 2.
Table 2 Kl Period of Incubation
2 days 5 days 8 days 14 days
Control 0.43 1.10 3.27 3.08
Compound of the Invention 0.1 jug/ml 0.43 0.67 0.55 0.52 1.0 ,ug/mI 0.42 0.46 0.38 0.39
5.0 yg/ml 0.48 0.50 - 0.22
In the experiment on the control, the Kl value exceeded 1.0 on the 5th day from the beginning of incubation, which indicates high keratinization. In contrast to the result on the control, the results given by different concentrations of the compound of the present invention showed the KI values of less than
1.0 for all runs to indicate inhibition of Keratinization.
Toxicity Tests (1) Experimental Procedure
The test compound was administered repeatedly to a group of 6 mice (ICR strain, female) for 14 days. The amount of the administration was 40 mg/Kg/day, 200 mg/Kg/day and 400 mg/Kg/day for the compound of the present invention, and 200 mg/Kg/day for the control compound. In the course of the administration, increase or decrease of the weight of the mouse, occurrence of death, etc. were observed.
(2) Test Compound
The compounds described in the pharmacological tests (anticancer activity) were employed.
(3) Experimental Results
(a) Increase and decrease of the weight. The results are set forth in Table 3.
(b) Death.
All mice treated with the control compound in the amount of 200 mg/Kg/day died by the 8th day, and no death was observed on the mice treated with the compound of the present invention.
c) Falling-out of hair.
Falling-out of hair was observed by the 6th day on every mouse treated with the control compound in the amount of 200 mg/Kg/day, and no falling-out of hair was observed on the mouse treated with the compound of the present invention.
(d) Cyanosis
Cyanosis was observed by the 7th day on every mouse treated with the control compound in the amount of 200 mg/Kg/day, and no cyanosis was observed on the mouse treated with the compound of the present invention.
Table 3
Amount
of Average of Weight (g) Admini
striation
Test tmg/Kg/ Compound day) 0 2 4 6 8 10 12 14
No administration 20.5 22.3 22.1 22.1 22.0 22.3 23.0 23.6
Compound
of
the Invention 40 20.9 22.4 22.2 22.6 23.1 23.0 22.6 24.0
200 21.4 21.7 20.0 21.9 22.8 22;9 23.3 24.1
400 25.4 26.5 28.0 26.4 26.3 26.6 26.3 27.0
Control 40 21.2 21.8 20.7 20.5 19.6 18.8 17.3 15.6
Compound 200 21.5 18.9 15.0 13.3 11.5 - - - (death) (death) (death)
Among the subjects in the toxicity tests, the falling-out of hair and the weight change are known to indicate the hypervitaminosis of Vitamin A. Since the falling-out of hair and decrease of the weight were observed at a prominently high level on the group of mice treated with the control compound, it is thought that the hypervitaminosis of Vitamin A occurred.In contrast, there was observed no such problem on the group of mice treated with the compound of the present invention.
In view of the pharmacological test results and the toxicity test results hereinbefore described, the compound of the present invention is considered to be of high safety and to be of value as an anticancer agent and a therapeutic agent for treatment of skin diseases with keratinization.
Therefore, the compound of the present invention can be employed for the prevention and treatment of cancer and precancerous conditions, and also employed for the treatment of skin diseases with keratinization such as acne and psoriasis vulgaris and the treatment of allergic and inflammatory skin diseases. Moreover, the compound of the present invention can be employed for the treatment of muscosal diseases caused by inflammation, degeneration and displastic change.
For the applications as the anticancer agent and the therapeutic agent for treatment of skin disease with keratinization, the compound of the present invention is administered orally in the form of powder, granule, pellet, hard capsule, etc., or parenterally in the form of ointment, suppository, injection solution, etc. The dosage is generally 40 mg 4 g/day for an adult. If the compound of the present invention is employed in the form of an external preparation, the dosage can be varied depending on the conditions of the disease. The compound of the present invention can be combined with a generally employable carrier for the medical use in the conventional manner to give the preparations described above.
The processes for the preparation of the compound of the present invention are illustrated by the following examples, but these examples are not intended to restrict the present invention.
Example 1
To a suspension of 5.0 g of 55% sodium hydride (oily) in 60 ml of n-hexane was added 28.6 g of triethyl phosphonoacetate. The mixture was then heated under reflux, and 20 g of 6,10,14-trimethyl 3,5,9,1 3-pentadecatetraen-2-on was added dropwise to the mixture under stirring. After 30 minutes, the reaction liquid was poured into 200 ml of water, and then 500 ml of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml portions of a mixture of methanol and water (2:1) and concentrated. The so obtained concentrate was purified by the silica gel column chromatography to give 1 8 g of ethyl 3,7,11 , 1 5-tetramethyl-2,4,6, 10,14- hexadecapentaenoate.
To 10 g of the ethyl 3,7,1 1,1 5-tetramethyl-2,4,6,1 0,1 4-hexadecapentaenoate obtained in the above was added a solution of 3.9 g of potassium hydroxide in 30 ml of isopropyl alcohol, and the mixture was stirred at 500C for 1 hour. The reaction liquid was then poured into ice-water, made acidic by addition of hydrochloric acid, and extracted with 100 ml of ethyl ether. The ether phase was washed with water, dried over magnesium sulfate, and concentrated to give 9.0 g of an oil. The oil was dissolved in 50 ml of n-hexane and crystallized at -200C to give 4.0 g of 3,7,11,15-tetramethyl- 2,4,6,10,1 4-hexadecapentaenoic acid in the form of pale yellow needles.
M.p.: 78.40C.
Mass spectrum (m/e): 302 (M+).
Infrared absorption spectrum (cm', KBr tablet): 3450, 2900, 1680, 1595.
NMR spectrum (S CDCI3): 1,61 (6H, s), 1,68 (3H, s), 1.86 (3H, 5) 1.92-2.24 (8H, b), 2.35 (3H, s), 5.10(2H, b), 5.76 (1H, bs), 5,98 (1H, d, J=11 Hz), 6.20 (1H, d,J=15 Hz), 6,90 (1H, dd, J=11 Hz, 15 Hz), 11.63(1H,b).
Ultraviolet absorption spectrum: .trnnetXhan 304 nm.
Example 2
To a suspension of 4.8 g of sodium ethoxide in 100 ml of n-hexane was added 1 8 g of diethyl 3ethoxycarbonyl-2-methyl-2-propenylphosphate. To the mixture was added 10 g of 3,7,11 -trimethyl 2,6,1 O-dodecatrien-1 -al under stirring at room temperature. After 1 hour, the reaction liquid was poured into 50 ml of water, and the n-hexane phase was separated. The n-hexane phase was washed with two 50 ml portions of a mixture of methanol and water (2:1), and concentrated. The so obtained concentrate was purified by the silica gel column chromatography to give 14.5 g of ethyl 3,7,11,1 5- tetramethyl-2,4,6,1 0,1 4-hexadecapentaenoate.
10 g of the ethylester obtained in the above was hydrolyzed in the same manner as in Example 1 to give 3.5 g of 3,7,11,1 5-tetramethyl-2,4,6,1 0,1 4-hexadecapentaenoic acid in the form of yellow needles.
The so obtained product was identified in the same manner as in Example 1, namely, by m.p., mass spectrum, NMR spectrum, infrared absorption spectrum, and ultraviolet absorption spectrum.
Example 3 In 100 ml of tetrahydrofuran was dissolved 10 g of 1-p-tolysulfonyl-3,7,1 1-trimethyl-2,6,10- dodecatriene, and the solution was chilled to -500C. To the solution was added dropwise 1 8.5 ml of 1 5% n-butyllithium-n-hexane solution under stirring and in a stream of nitrogen, maintaining the temperature of the solution at --500C. Then, 300 ml of tetrahydrofuran solution containing 5.7 g of ethyl 4-bromo-3-methyl-2-butenate was added dropwise to the so produced solution. After 30 minutes, 100 ml of 10% aqueous ammonium chloride solution was added, and subsequently the mixture was treated to reach room temperature. The mixture was then extracted with two 200 ml portions of n-hexane.The n-hexane phase was washed with three 100 ml portions of water, dried over magnesium sulfate, and concentrated to give 13 g of ethyl 3,7,11,1 5-tetramethyl-5-p-tolysulfonyl- 2,6,10,1 4-hexadecatetraenoate.
To 10 g of the ethylester obtained in the above was added a solution of 4.6 g of potassium hydroxide in 50 ml of isopropyl alcohol, and the mixture was stirred at 500C for 3 hours. The reaction liquid was then poured into icewater, made acidic by addition of hydrochloric acid, and extracted with 100 ml of ethyl ether. The ethyl ether phase was washed with water, dried over magnesium sulfate, and concentrated to give 6 g of an oil. The oil was dissolved in 30 ml of n-hexane and crystallized at -200C to give 1.8 g of 3,7,11,1 5-tetramethyl-2,4,8,1 0,1 4-hexadecapentaenoic acid in the form of pale yellow needles.
The so obtained product was identified in the same manner as in Example 1, namely, by m.p., mass spectrum. NMR spectrum, infrared absorption spectrum, and ultraviolet absorption spectrum.
Example 4
Pellet 3,7,11,1 5-Tetramethyl-2,4,6,1 0,1 4-hexadecapentaenoic acid 50 g
Silicic acid anhydride 30 g
Crystalline cellulose 50 g
Corn starch 36 g
Hydroxypropylcellulose 10 g
Magnesium stearate 4g
The above compcsition was processed in the conventional manner to give a pellet (180 mg for a pellet).
Claims (9)
1. 3,7,11,1 5-Tetramethyl-2,4,6,1 0,1 4-hexadecapentaenoic acid of the general formula (I):
or a pharmaceutically acceptable salt thereof.
2. A process for the preparation of a compound of the general formula (I):
or a pharmaceutically acceptable salt thereof, which comprises: reacting a compound of the general formula (ill):
and a Wittig reagent derived from a compound of the general formula (III): X-CH2-C02R1 (Ill) in which X represents a halogen atom, and R, represents a lower alkyl group, to obtain a compound of the general formula (IV):
in which R, has the same meaning as defined above; and hydrolyzing the compound so obtained in the presence of a base.
3. A process for the preparation of a compound of the general formula (I):
or a pharmaceutically acceptable salt thereof, which comprises: reacting a compound of the general formula (V):
and a Wittig reagent derived from a compound of the general formula (VI):
in which X represents a halogen atom, and R, represents a lower alkyl group, to obtain a compound of the general formula (IV):
in which R, has the same meaning as defined above; and hydrolyzing the compound so obtained in the presence of a base.
4. A process for the preparation of a compound of the general formula (I):
or a pharmaceutically acceptable salt thereof, which comprises: reacting a compound of the general formula (VII):
in which Y represents a lower alkyl group or an aryl group, and a compound of the general formula (VI):
in which X represents a halogen atom, and R, represents a lower alkyl group, to obtain a compound of the general formula (VIII):
in which Y and R, have the same meanings as defined above; and subjecting the compound so obtained to a desulfination followed by hydrolysis of the resulting ester in the presence of a base.
5. A composition comprising 3,7,11,1 5-tetramethyl-2,4,6,1 0,1 4-hexadecepantaenoic acid of the general formula (I):
or a pharmaceutically acceptable salt thereof and a pharmacological carrier.
6. A method for preventing and treating cancer by administering the composition defined in
Claim 5.
7. A method for treating skin disease with keratinization by administering the composition defined in Claim 5.
8. A process for preparing a compound as claimed in Claim 1, substantially as hereinbefore described with reference to any one of Examples 1 to 3.
9. A composition as claimed in Claim 5, and substantially as hereinbefore described with reference to Example 4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4455880A JPS56140949A (en) | 1980-04-07 | 1980-04-07 | 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenic acid |
| JP10442080A JPS5731615A (en) | 1980-07-31 | 1980-07-31 | Remedy for skin disease with keratinization |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2073750A true GB2073750A (en) | 1981-10-21 |
| GB2073750B GB2073750B (en) | 1984-02-22 |
Family
ID=26384501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8110160A Expired GB2073750B (en) | 1980-04-07 | 1981-04-01 | 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid |
Country Status (11)
| Country | Link |
|---|---|
| AU (1) | AU537402B2 (en) |
| CA (1) | CA1179370A (en) |
| CH (1) | CH646682A5 (en) |
| DE (1) | DE3113149A1 (en) |
| DK (1) | DK158457C (en) |
| ES (2) | ES501124A0 (en) |
| FR (1) | FR2479807A1 (en) |
| GB (1) | GB2073750B (en) |
| IT (1) | IT1194141B (en) |
| NL (1) | NL191744C (en) |
| SE (1) | SE447243B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0090378A1 (en) * | 1982-03-26 | 1983-10-05 | Eisai Co., Ltd. | Isoprenylcarboxylic acid-containing composition for external use |
| EP0107188A1 (en) * | 1982-10-21 | 1984-05-02 | Eisai Co., Ltd. | A pharmaceutical composition and the use thereof for the treatment of inflammation |
| EP0175171A2 (en) * | 1984-08-31 | 1986-03-26 | Eisai Co., Ltd. | Use of 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid for enhancing the effect of anti-tumour agents |
| US4917829A (en) * | 1980-04-07 | 1990-04-17 | Eisai Co., Ltd. | 3,7,11,15-Tetramethyl-2,4,6,10,14,-hexadecapentaendic acid |
| EP0729354A4 (en) * | 1993-11-12 | 1996-07-15 | Univ Ramot | Farnesyl derivatives and pharmaceutical compositions containing them |
| WO2001080854A1 (en) | 2000-04-24 | 2001-11-01 | Nikken Chemicals Co., Ltd. | Activators for peroxisome proliferator-activated receptor |
| CN116041172A (en) * | 2023-02-01 | 2023-05-02 | 宝鸡文理学院 | Preparation method of nervonic acid |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57106638A (en) * | 1980-12-24 | 1982-07-02 | Eisai Co Ltd | Conjugated polyprenylcarboxylic acid and its derivative |
| DE3163920D1 (en) * | 1980-12-24 | 1984-07-05 | Eisai Co Ltd | Pharmaceutical preparations comprising polyprenyl compounds, especially as anti-cancer agents, and pharmaceutical compositions for the prevention and treatment of cancer and skin diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2171497A5 (en) * | 1972-02-02 | 1973-09-21 | Rhone Poulenc Sa | 1,5-dimethyl-1,5-hexadienylidene sulphone derivs - - intermediates for terpenes |
| JPS52131507A (en) * | 1976-04-24 | 1977-11-04 | Sankyo Co Ltd | Polyprenyl derivatives |
-
1981
- 1981-04-01 NL NL8101630A patent/NL191744C/en not_active IP Right Cessation
- 1981-04-01 GB GB8110160A patent/GB2073750B/en not_active Expired
- 1981-04-01 DE DE19813113149 patent/DE3113149A1/en active Granted
- 1981-04-03 SE SE8102161A patent/SE447243B/en not_active IP Right Cessation
- 1981-04-06 FR FR8106874A patent/FR2479807A1/en active Granted
- 1981-04-06 CH CH231781A patent/CH646682A5/en not_active IP Right Cessation
- 1981-04-06 DK DK155081A patent/DK158457C/en not_active IP Right Cessation
- 1981-04-06 ES ES501124A patent/ES501124A0/en active Granted
- 1981-04-06 CA CA000374715A patent/CA1179370A/en not_active Expired
- 1981-04-07 IT IT20967/81A patent/IT1194141B/en active
- 1981-04-07 AU AU69159/81A patent/AU537402B2/en not_active Ceased
-
1982
- 1982-02-25 ES ES509913A patent/ES509913A0/en active Granted
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4917829A (en) * | 1980-04-07 | 1990-04-17 | Eisai Co., Ltd. | 3,7,11,15-Tetramethyl-2,4,6,10,14,-hexadecapentaendic acid |
| EP0090378A1 (en) * | 1982-03-26 | 1983-10-05 | Eisai Co., Ltd. | Isoprenylcarboxylic acid-containing composition for external use |
| EP0107188A1 (en) * | 1982-10-21 | 1984-05-02 | Eisai Co., Ltd. | A pharmaceutical composition and the use thereof for the treatment of inflammation |
| EP0175171A2 (en) * | 1984-08-31 | 1986-03-26 | Eisai Co., Ltd. | Use of 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid for enhancing the effect of anti-tumour agents |
| EP0175171A3 (en) * | 1984-08-31 | 1989-08-30 | Eisai Co., Ltd. | use of 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid for enhancing the effect of anti-tumour agents |
| EP0729354A1 (en) * | 1993-11-12 | 1996-09-04 | Ramot University Authority For Applied Research & Industrial Development Ltd. | Farnesyl derivatives and pharmaceutical compositions containing them |
| EP0729354A4 (en) * | 1993-11-12 | 1996-07-15 | Univ Ramot | Farnesyl derivatives and pharmaceutical compositions containing them |
| US5705528A (en) * | 1993-11-12 | 1998-01-06 | Ramot University Authority For Applied Research & Industrial Development | Farnesyl derivatives and pharmaceutical compositions containing them |
| USRE39682E1 (en) * | 1993-11-12 | 2007-06-05 | Ramot At Tel Aviv University Ltd. | Farnesyl derivatives and pharmaceutical compositions containing them |
| WO2001080854A1 (en) | 2000-04-24 | 2001-11-01 | Nikken Chemicals Co., Ltd. | Activators for peroxisome proliferator-activated receptor |
| EP1277469A1 (en) * | 2000-04-24 | 2003-01-22 | Nikken Chemicals Company, Limited | Activators for peroxisome proliferator-activated receptor |
| EP1277469A4 (en) * | 2000-04-24 | 2008-05-21 | Nikken Chemicals Co Ltd | Activators for peroxisome proliferator-activated receptor |
| US7547730B2 (en) | 2000-04-24 | 2009-06-16 | Kowa Company, Ltd. | Activators of peroxisome proliferator-activated receptors |
| US8017652B2 (en) | 2000-04-24 | 2011-09-13 | Kowa Company Ltd. | Activators of peroxisome proliferator-activated receptors |
| CN116041172A (en) * | 2023-02-01 | 2023-05-02 | 宝鸡文理学院 | Preparation method of nervonic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CA1179370A (en) | 1984-12-11 |
| FR2479807A1 (en) | 1981-10-09 |
| SE8102161L (en) | 1981-10-08 |
| ES8304058A1 (en) | 1983-02-16 |
| ES8205190A1 (en) | 1982-06-01 |
| SE447243B (en) | 1986-11-03 |
| IT8120967A0 (en) | 1981-04-07 |
| DE3113149C2 (en) | 1988-11-10 |
| NL191744B (en) | 1996-02-01 |
| ES501124A0 (en) | 1982-06-01 |
| IT1194141B (en) | 1988-09-14 |
| NL8101630A (en) | 1981-11-02 |
| AU6915981A (en) | 1981-10-15 |
| ES509913A0 (en) | 1983-02-16 |
| FR2479807B1 (en) | 1984-07-20 |
| DE3113149A1 (en) | 1982-01-28 |
| DK158457C (en) | 1990-10-08 |
| DK155081A (en) | 1981-10-08 |
| AU537402B2 (en) | 1984-06-21 |
| GB2073750B (en) | 1984-02-22 |
| CH646682A5 (en) | 1984-12-14 |
| NL191744C (en) | 1996-06-04 |
| DK158457B (en) | 1990-05-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19980401 |