NO127298B - - Google Patents
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- NO127298B NO127298B NO142170A NO142170A NO127298B NO 127298 B NO127298 B NO 127298B NO 142170 A NO142170 A NO 142170A NO 142170 A NO142170 A NO 142170A NO 127298 B NO127298 B NO 127298B
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- Prior art keywords
- formula
- phenoxyaliphatic
- acid derivative
- derivative
- carboxylic acid
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- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical class C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 claims description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- -1 4-methylcyclohexylidene Chemical group 0.000 claims description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000012374 esterification agent Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- FNIATMYXUPOJRW-UHFFFAOYSA-N cyclohexylidene Chemical group [C]1CCCCC1 FNIATMYXUPOJRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 18
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 11
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 239000012429 reaction media Substances 0.000 description 6
- 201000001320 Atherosclerosis Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229930194542 Keto Natural products 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 239000003529 anticholesteremic agent Substances 0.000 description 3
- 229940127226 anticholesterol agent Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 150000008050 dialkyl sulfates Chemical class 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- DJHGAFSJWGLOIV-UHFFFAOYSA-N Arsenic acid Chemical compound O[As](O)(O)=O DJHGAFSJWGLOIV-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229930185605 Bisphenol Natural products 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 229940000488 arsenic acid Drugs 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Analogifremgangsmåte til fremstilling av terapeutisk Analogy method for the preparation of therapeutic
aktive fenoksyalifatiske karboksylsyrederivater. active phenoxyaliphatic carboxylic acid derivs.
Foreliggende oppfinnelse angår en analogifremgangsmåte til fremstilling av nye anti-aterosklerosemidler, og mer spesielt fremstilles nye fenoksyalifatiske karboksylsyrederivater som kan brukes for å senke et for høyt innhold av cholesterol eller lipider i blodet, og som har den generelle formel: The present invention relates to an analogue method for the production of new anti-atherosclerosis agents, and more particularly new phenoxyaliphatic carboxylic acid derivatives are produced which can be used to lower an excessively high content of cholesterol or lipids in the blood, and which have the general formula:
1 2 12 1 2 12
hvor R-;.og R;; er;-metyl; eller:,R og R; kan sammen danne cykloheksyliden eller 4-metylcykloheksyliden sammen meddet tilknyttede karbonatom, where R-;.and R;; er;-methyl; or:, R and R; can together form cyclohexylidene or 4-methylcyclohexylidene together with the associated carbon atom,
R og R er alkyl med 1-3 karbonatomer, Y er hydroksyl eller etoksy, og' A er hydrogen eller en gruppe, med. formelen: R and R are alkyl with 1-3 carbon atoms, Y is hydroxyl or ethoxy, and' A is hydrogen or a group, with. the formula:
3 4 hvor R j R og Y har den ovenfor angitte betydning... Aterosklerose.er.en sykdom som gjerne opptrer i noe fremskredende alder og som man- hittil ikke har funnet noen tilfredsstillende midler mot. Skjønt årsaken til at aterosklerose hittil ikke er kjent til tross for meget omfattende undersøkelser, så er det generelt fastslått at en av de mest betydelige histo-patologiske manifestasjoner på aterosklerose, er en avsetning av lipider i blod. Man har følgelig gjort meget omfattende undersøkelser med hensyn til lipidenes metabolisme, da spesielt de forhold som fører til et meget høyt cholesterolnivå i.blodet. .Det er i litteraturen rapportert en rekke eksperimentelle og kliniske fakta som indikerer at det er et forhold mellom aterosklerose og et høyt. blodcholesterol eller lipidnivå. Man har følgelig ansett det som meget viktig for å utvikle midler som kunne senke innholdet av cholesterol eller lipider i blodet, for derved å kunne hindre aterosklerose.. 3 4 where R j R and Y have the meaning stated above... Atherosclerosis.is.a disease which tends to appear in somewhat advanced age and for which no satisfactory remedies have been found so far. Although the cause of atherosclerosis is still not known despite very extensive investigations, it is generally established that one of the most significant histo-pathological manifestations of atherosclerosis is a deposit of lipids in the blood. Consequently, very extensive investigations have been carried out with regard to lipid metabolism, especially the conditions that lead to a very high level of cholesterol in the blood. A number of experimental and clinical facts have been reported in the literature which indicate that there is a relationship between atherosclerosis and a high. blood cholesterol or lipid level. Consequently, it has been considered very important to develop agents that could lower the content of cholesterol or lipids in the blood, thereby preventing atherosclerosis.
Det har vært utviklet en rekke tilike midler for å senke innholdet av cholesterol eller lipider i blodet, og en rekke av disse forbindelser er også blitt testet klinisk, men ingen har hittil vist seg å være fullt ut tilfredsstillende. En rekke av disse forbindelser er relativt effektive, men frembringer relativt store bivirkninger mens andre har en,liten effektivitet slik at de må administreres i meget store doser. A number of similar agents have been developed to lower the content of cholesterol or lipids in the blood, and a number of these compounds have also been tested clinically, but none have so far proved to be fully satisfactory. A number of these compounds are relatively effective, but produce relatively large side effects, while others have a low effectiveness so that they must be administered in very large doses.
En gruppe forbindelser som i praksis anvendes for det foreliggende formål, innbefatter etyl a-(p-klorfenoksy)-isobutyrat. Imidlertid er denne forbindelses effektivitet ikke særlig høy, og den har en tendens til å frembringe skadelige bivirkninger såsom hypertrofi i leveren. A group of compounds which are used in practice for the present purpose includes ethyl α-(p-chlorophenoxy)-isobutyrate. However, the efficiency of this compound is not very high, and it tends to produce harmful side effects such as hypertrophy of the liver.
De nye forbindelsene '(I) er meget effektive som chole-sterclsenkende midler og er I alt vesentlig ikke-toksiske. The new compounds (I) are very effective as cholesterol-lowering agents and are essentially non-toxic.
Ifølge foreliggende oppfinnelse.fremstilles forbindelsene med formel I ved at man According to the present invention, the compounds of formula I are prepared by
a) omsetter et bisfenolderivat med formelen: a) reacts a bisphenol derivative with the formula:
hvor R 1 og R 2 har den ovenfor angitte betydning, med en ketonforbind-else med formelen: hvor R 3 og R 4 har den ovenfor angitte betydning, og kloroform i nærvær av en alkalisk forbindelse, hvorved man får fremstilt et fenoksyalifatisk syrederivat med formelen: 12 3 4 hvor R , R , R og R nar den ovenfor angitte betydning, og A' er et hydrogenatom eller en gruppe med formelen: where R 1 and R 2 have the meaning given above, with a ketone compound of the formula: where R 3 and R 4 have the meaning given above, and chloroform in the presence of an alkaline compound, whereby a phenoxyaliphatic acid derivative of the formula is produced : 12 3 4 where R , R , R and R have the meaning given above, and A' is a hydrogen atom or a group with the formula:
3 4 3 4
hvor R og R har den ovenfor angitte betydning og eventuelt omsetter et fenoksyalifatisk karboksylsyrederivat med formel Ia med et forestringsmiddel, eller where R and R have the above meaning and optionally react a phenoxyaliphatic carboxylic acid derivative of formula Ia with an esterification agent, or
b) omsetter et bisfenolderivat med formelen: b) reacts a bisphenol derivative with the formula:
hvor R og R har den ovenfor angitte betydning, med et alifatisk where R and R have the meaning given above, with an aliphatic
karboksylsyrederivat med formelen: carboxylic acid derivative with the formula:
3 4 3 4
hvor X er halogen eller hydroksyl, og R , R og Y har den ovenfor angitte betydning, hvorved man får fremstilt et fenoksyalifatisk karboksylsyrederivat med formel I. where X is halogen or hydroxyl, and R , R and Y have the meaning stated above, whereby a phenoxyaliphatic carboxylic acid derivative of formula I is produced.
De ovennevnte fremgangsmåter er mer detaljert beskrevet i det etterfølgende.. The above methods are described in more detail in what follows.
Fremgangsmåte a). Procedure a).
Reaksjon mellom et bisfenolderivat (II) med kloroform og en ketoforbindelse ( III) i nærvær av et alkali. Reaction between a bisphenol derivative (II) with chloroform and a keto compound (III) in the presence of an alkali.
For å utføre denne reaksjon bør minst 1 mol kloroform dråpevis tilsettes en blanding inneholdende 1 mol av et bisfenolderivat (II) og minst 1 mol av en ketoforbindelse (III) i nærvær av minst 3 mol alkali. Eksempler på alkali som kan anvendes innbefatter natriumhydroksyd og kaliumhydroksyd. Reaksjonstemperaturen kan variere fra 20-150°C, mens reaksjonstiden kan variere fra 3-40 timer. For å oppnå som hovedprodukt enten et fenoksyalifatisk monokarboksylsyrederivat med formel (Ia) hvor A' = H eller et fenoksyalifatisk To carry out this reaction, at least 1 mol of chloroform should be added dropwise to a mixture containing 1 mol of a bisphenol derivative (II) and at least 1 mol of a keto compound (III) in the presence of at least 3 mol of alkali. Examples of alkali that can be used include sodium hydroxide and potassium hydroxide. The reaction temperature can vary from 20-150°C, while the reaction time can vary from 3-40 hours. To obtain as the main product either a phenoxyaliphatic monocarboxylic acid derivative of formula (Ia) where A' = H or a phenoxyaliphatic
dikarboksylsyrederivat med formel (Ia) hvor A' = dicarboxylic acid derivative of formula (Ia) where A' =
bør reaksjonsbetingelsene med hensyn til mengdeforholdet mellom reaktantene, reaksjonstemperaturen og reaksjonstiden reguleres meget nøyaktig. I de tilfelle hvor man anvender ca. 1 mol av ketoforbindelsen (III), ca. 1 mol av kloroform og/eller ca. 3 mol alkali pr. anvendt 1 mol av bisfenolderivatet (II), får man fremstilt et fenoksyalifatisk monokarboksylsyrederivat med formel (Ia) hvor A' = H, som hovedproduktet. Hvis derimot både ketoforbindelsen, kloroformen og nevnte alkali brukes i stort overskudd, så får man fremstilt som hovedprodukt et bisfenoksyalifatisk dikarboksylsyrederivat med formel (Ia), hvor Når man får fremstilt et fenoksyalifatisk monokarboksylsyrederivat, dvs. A' = H og et fenoksyalifatisk dikarboksylsyrederivat (Ia) (dvs. A' = the reaction conditions with regard to the quantity ratio between the reactants, the reaction temperature and the reaction time should be regulated very precisely. In cases where approx. 1 mol of the keto compound (III), approx. 1 mol of chloroform and/or approx. 3 moles of alkali per using 1 mol of the bisphenol derivative (II), a phenoxyaliphatic monocarboxylic acid derivative with formula (Ia) where A' = H, is produced as the main product. If, on the other hand, both the keto compound, chloroform and said alkali are used in large excess, then a bisphenoxyaliphatic dicarboxylic acid derivative with formula (Ia) is produced as the main product, where When a phenoxyaliphatic monocarboxylic acid derivative is produced, i.e. A' = H and a phenoxyaliphatic dicarboxylic acid derivative (Ia ) (ie A' =
på samme tid, så kan disse separeres at the same time, then these can be separated
ved hjelp av vanlige kjente fremgangsmåter, f.eks. omkrystallisering eller kromatografi. by means of commonly known methods, e.g. recrystallization or chromatography.
Reaksjonen kan utføres i nærvær av et overskudd av kloroform og/eller ketoforbindelsen (III) eller i nærvær eller i fravær av et inert reaksjonsmedium. Eksempler på egnede reaksjonsmedia innbefatter dioksan, benzen og toluen. The reaction can be carried out in the presence of an excess of chloroform and/or the keto compound (III) or in the presence or in the absence of an inert reaction medium. Examples of suitable reaction media include dioxane, benzene and toluene.
Bisfenolderivater med formel (II) som anvendes som ut-gangsforbindelse, kan fremstilles ved en fremgangsmåte av den type som f.eks. er angitt i J.A.C.S., 61, side 3^5 (1939). Bisphenol derivatives with formula (II), which are used as starting compounds, can be prepared by a method of the type that e.g. is given in J.A.C.S., 61, pp. 3^5 (1939).
Fremgangsmåte b). Procedure b).
Kondensasjonsreaksjon mellom et bisfenolderivat (II) Condensation reaction between a bisphenol derivative (II)
og et ot- halogen- eller hydroksy- alifatisk karboksylsyrederivat ( IV). and an ot-halogen or hydroxy-aliphatic carboxylic acid derivative (IV).
Hvis X er et halogenatom, bør 1 mol av et bisfenolderi- If X is a halogen atom, 1 mol of a bisphenol deriv.
vat (II) oppløses eller suspenderes i et. inert reaksjonsmedium og kontaktes minst 1 mol av en alkalisk forbindelse for fremstilling av et alkalisk salt, hvoretter minst 1 mol av et a-halogenert alifatisk syrederivat (IV) (dvs. X = halogen) tilsettes den resulterende reak-sj onsblanding for å starte kondensasjonsreaksjonen. Etter at reaksjonen er over, kan blandingen behandles på vanlig måte, for fremstilling av det ønskede fenoksyalifatiske karboksylsyrederivat (I). Eksempler på inerte reaksjonsmedia som kan anvendes i denne fremgangsmåte, omfatter benzen og toluen. Eksempler på alkaliske forbindelser som kan anvendes, omfatter kaliumhydroksyd, natriumhydroksyd, alkali-metallalkoholater, alkalimetallkarbonater, metallisk natrium, natriumhydrid og organiske tertiære aminer, såsom, trimetylamin, trietylamin r og pyridin. Reaksjonen krever en temperatur fra 20J-120°C. , vat (II) is dissolved or suspended in et. inert reaction medium and is contacted with at least 1 mol of an alkaline compound to produce an alkaline salt, after which at least 1 mol of an α-halogenated aliphatic acid derivative (IV) (ie X = halogen) is added to the resulting reaction mixture to initiate the condensation reaction . After the reaction is over, the mixture can be treated in the usual way, to produce the desired phenoxyaliphatic carboxylic acid derivative (I). Examples of inert reaction media that can be used in this method include benzene and toluene. Examples of alkaline compounds which may be used include potassium hydroxide, sodium hydroxide, alkali metal alcoholates, alkali metal carbonates, metallic sodium, sodium hydride and organic tertiary amines such as trimethylamine, triethylamine and pyridine. The reaction requires a temperature from 20J-120°C. ,
For i alt vesentlig å oppnå enten et fenoksyalifatisk , monokarboksylsyrederivat med formel (I) hvor A = H eller et fenoksyalifatisk dikarboksylsyrederivat med formel (I) hvor Essentially in order to obtain either a phenoxyaliphatic, monocarboxylic acid derivative of formula (I) where A = H or a phenoxyaliphatic dicarboxylic acid derivative of formula (I) where
A = A =
bør reaksjonsbetingelsene med hensyn til mengdeforholdet <' < : mellom reaktantene, reaksjonstemperaturen og reaksjonstiden kontrol- j! r leres meget nøyaktig. Hvis den alkaliske forbindelse og/eller det a-halogen-alifatiske syrederivat (IV) anvendes i en ekvimolar mengde 1 forhold til bisfenolderivatet (II), så får man fremstilt i alt should the reaction conditions with respect to the quantity ratio <' < : between the reactants, the reaction temperature and the reaction time control- j! r is read very accurately. If the alkaline compound and/or the α-halo-aliphatic acid derivative (IV) is used in an equimolar amount 1 relative to the bisphenol derivative (II), then a total of
vesentlig et fenoksyalifatisk monokarboksylsyrederivat med formel (I) essentially a phenoxyaliphatic monocarboxylic acid derivative of formula (I)
hvor A = H. Hvis man derimot anvender både- den alkaliske forbindelse og nevnte a-halogen-alifatiske syrederivat (IV) i mengder på mer enn 2 mol pr. mol av nevnte bisfenolderivat (II), så får man fremstilt et fenoksyalifatisk dikarboksylsyrederivat med formel (I)- hvor where A = H. If, on the other hand, one uses both the alkaline compound and said α-halo-aliphatic acid derivative (IV) in quantities of more than 2 mol per mol of said bisphenol derivative (II), then a phenoxyaliphatic dicarboxylic acid derivative with formula (I) is produced - where
A = A =
Hvis X er en. hydroksylgruppe, kontaktes 1 mol av et bisfenolderivat (II) med minst 1 mol av et a-hydroksyalifatisk syrederivat (IV) (dvs. X = OH) i nærvær av en syrekatalysator såsom svovelsyre, p-toluensulfonylklorid, arsensyre, borsyre, natriumhydrogensulfat og kaliumhydrogensulfat i nærvær eller i fravær av et inert reak-sjonsmedlum. Eksempler på reaksjonsmedia som kan anvendes, innbefatter benzen, tolueh' og dioksan . Syrekatalysatoren anvendes i mengder på fra 0,01-0,5 mol pr. 1 mol av nevnte bisfenolderivat. Reaksjonen krever temperaturer fra 10-90°C. If X is one. hydroxyl group, 1 mol of a bisphenol derivative (II) is contacted with at least 1 mol of an α-hydroxyaliphatic acid derivative (IV) (ie X = OH) in the presence of an acid catalyst such as sulfuric acid, p-toluenesulfonyl chloride, arsenic acid, boric acid, sodium hydrogen sulfate and potassium hydrogen sulfate in the presence or in the absence of an inert reaction medium. Examples of reaction media that can be used include benzene, toluene and dioxane. The acid catalyst is used in quantities of from 0.01-0.5 mol per 1 mol of said bisphenol derivative. The reaction requires temperatures from 10-90°C.
Por at man hovedsakelig enten skal oppnå et fenoksyalifatisk monokarboksylsyrederivat med formel (I) hvor A = H, eller i alt vesentlig et fenoksyalifatisk dikarboksylsyrederivat med Por that one mainly either obtains a phenoxyaliphatic monocarboxylic acid derivative with formula (I) where A = H, or essentially a phenoxyaliphatic dicarboxylic acid derivative with
formel (I) hvor A = formula (I) where A =
bør reaksjorisbetingelsene med hensyn should the reaction conditions with respect
til reaktantenes mengdeforhold, reaksjonstemperatur og reaksjonstid, reguleres meget nøyaktig. to the quantity ratio of the reactants, reaction temperature and reaction time, are regulated very precisely.
Porestring av et fenoksyalifatisk syrederivat (Ia) oppnådd ved fremgangsmåte a). Poration of a phenoxyaliphatic acid derivative (Ia) obtained by method a).
Et fenoksyalifatisk karboksylsyrederivat (Ia) eller dens reaktive ester kan omdannes til en ester ved vanlig forestring, f.eks. .ved en behandling med et forestringsmiddel. Med begrepet "reaktiv ester" av et fenoksyalifatisk karboksylsyrederivat (Ia) forståes et A phenoxyaliphatic carboxylic acid derivative (Ia) or its reactive ester can be converted to an ester by conventional esterification, e.g. .by a treatment with an esterification agent. With the term "reactive ester" of a phenoxyaliphatic carboxylic acid derivative (Ia) is understood a
eller alkylhalogenid, et mtramolekylært syreanhydrid, en ester av syreny et salt av syren, mens begrepet "forestringsmiddel" forståes or alkyl halide, an intramolecular acid anhydride, an ester of an acid or a salt of the acid, while the term "esterifying agent" is understood
eller en alkohol, .fenol, diazometan, et dialkylsulfat, et alkylhalogemdY et alkylha-logensulfitt or an alcohol, phenol, diazomethane, a dialkyl sulfate, an alkyl halide, and an alkyl halosulfite
En forestring av et fenoksyalifatisk monokarboksylsyrederivat (Ia) (dvs. A' = hydrogen) gir bare et monoesterderivat, mens en forestring av et fenoksyalifatisk dikarboksylsyrederivat gir et diesterderivat og et monoesterderivat, alt avhengig av reaksjonsbetingelsene, f.eks. mengdeforholdet mellom reaktantene, reaksjonstemperaturen og reaksjonstiden. An esterification of a phenoxyaliphatic monocarboxylic acid derivative (Ia) (ie A' = hydrogen) gives only a monoester derivative, while an esterification of a phenoxyaliphatic dicarboxylic acid derivative gives a diester derivative and a monoester derivative, all depending on the reaction conditions, e.g. the quantity ratio between the reactants, the reaction temperature and the reaction time.
Man får f.eks. fremstilt en diester når man omsetter 1 mol av et fenoksyalifatisk dikarboksylsyrederivat med minst 2 mol av en alkohol eller minst 2 -mol diazometan, eller ved å reagere 1 mol av et salt av nevnte fenoksyalifatiske dikarboksylsyrederivat med minst 2 mol av et dialkylsulf at, et alkylhalogenid eller et alkylhalo.gen-sulfitt, eller ved å omsette 1 mol av et syrehalogenid eller et intra-molekylært syreanhydrid av nevnte fenoksyalifatiske dikarboksylsyrederivat med minst 2 mol av en alkohol eller en fenol. Reaksjonen mellom nevnte intramolekylære syreanhydrid av fenoksyalifatiske di-karboksylsyrederivater med en.alkohol eller en fenol, kan også gi en monoester. You get e.g. prepared a diester when reacting 1 mol of a phenoxyaliphatic dicarboxylic acid derivative with at least 2 mol of an alcohol or at least 2 mol of diazomethane, or by reacting 1 mol of a salt of said phenoxyaliphatic dicarboxylic acid derivative with at least 2 mol of a dialkyl sulfate, an alkyl halide or an alkylhalogen sulfite, or by reacting 1 mole of an acid halide or an intramolecular acid anhydride of said phenoxyaliphatic dicarboxylic acid derivative with at least 2 moles of an alcohol or a phenol. The reaction between said intramolecular acid anhydrides of phenoxyaliphatic dicarboxylic acid derivatives with an alcohol or a phenol can also give a monoester.
De fenoksyalifatiske karboksylsyrederivater (I) hvor Y er hydroksyl og/eller A er hydrogen, kan omdannes til salter ved behandling med alkali. Saltene dannes ved. karboksylgruppen og/eller fenoliske hydroksylgruppe. Et alkalimetallsalt kan f.eks. fremstilles ved å kontakte- det fenoksyalifatiske karboksylsyrederivat (I) hvor Y er hydroksyl og/eller A er hydrogen, med. natriumhydroksyd, kaliumhydroksyd, natriumkarbonat, kaliumkarbonat, natriumbikarbonat eller ammoniakk, eller med et alkdholat av et alkalimetall, f.eks. natrium-metylat i et organisk oppløsningsmiddel, fortrinnsvis i en lavere alkanol såsom metanol eller Metanol, eller med et hydroksyd, karbonat eller bikarbonat av et alkalimétall i et organisk oppløs-ningsmiddel, fortrinnsvis i aceton eller metanol, og hvis det er nødvendig, i nærvær av en mindre mengde ..vann. Det således frem-stilte alkalimetallsalt kan deretter omdannes til et jordalkali-metallsalt ved en behandling med et salt av et jordalkalimetall, f.eks. kalsiumklorid. The phenoxyaliphatic carboxylic acid derivatives (I) where Y is hydroxyl and/or A is hydrogen, can be converted into salts by treatment with alkali. The salts are formed by the carboxyl group and/or phenolic hydroxyl group. An alkali metal salt can e.g. is produced by contacting the phenoxyaliphatic carboxylic acid derivative (I) where Y is hydroxyl and/or A is hydrogen, with sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or ammonia, or with an alkholate of an alkali metal, e.g. sodium methylate in an organic solvent, preferably in a lower alkanol such as methanol or Methanol, or with a hydroxide, carbonate or bicarbonate of an alkali metal in an organic solvent, preferably in acetone or methanol, and if necessary, in the presence of a smaller amount of ..water. The alkali metal salt thus produced can then be converted into an alkaline earth metal salt by treatment with a salt of an alkaline earth metal, e.g. calcium chloride.
De cholesterolsenkende midler som fremstilles ifølge foreliggende, oppfinnelse kan f.eks. administreres oralt. Den orale dose er vanligvis fra 0,01 - 10 g pr. døgn for en voksen person, fortrinnsvis 0,05.- 3 g pr. døgn for en voksen person. De cholesterolsenkende midler kan opparbeides i egnede former av den type som er vanlig for oral administrasjon. De kan således innkapsles i kapsler, eller de kan være i flytende form, i tablettform eller i pulverform. Ved fremstilling av nevnte preparater kan den aktive forbindelse blandes med eller impregneres' i egnede faste bærere. The cholesterol-lowering agents produced according to the present invention can e.g. administered orally. The oral dose is usually from 0.01 - 10 g per day for an adult, preferably 0.05 - 3 g per day for an adult. The cholesterol-lowering agents can be prepared in suitable forms of the type that are common for oral administration. They can thus be encapsulated in capsules, or they can be in liquid form, in tablet form or in powder form. When preparing said preparations, the active compound can be mixed with or impregnated in suitable solid carriers.
Følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksemplene 1- 6. Examples 1-6.
Generell fremgangsmåte. General procedure.
En blanding av et bishydroksyfenylderivat og en ketonfor-bindelse ble tilsatt knust kaliumhydroksyd eller natriumhydroksyd. Kloroform ble dråpevis tilsatt nevnte blanding under omrøring ved A mixture of a bishydroxyphenyl derivative and a ketone compound was added crushed potassium hydroxide or sodium hydroxide. Chloroform was added dropwise to said mixture while stirring at
20 til 80°C, og den resulterende blanding ble oppvarmet ved temperaturer fra 50 til 150°C for å gjøre reaksjonen. fullstendig. Reak-. sj onsblandingen ble deretter konsentrert til et residium-. Dette residium ble så tilsatt vann. Etter avkjøling ble den resulterende blanding behandlet med aktivert trekull og surgjort ved hjelp av fortynnet saltsyre eller svovelsyre, hvorved man fikk et oljeaktig stoff. Dette ble ekstrahert med eter, og eteroppløsningen ble kon- ■ taktet en vandig, fortynnet Na2C0^-oppløsning. Det utskilte vandige 20 to 80°C, and the resulting mixture was heated at temperatures from 50 to 150°C to effect the reaction. complete. React-. The sea mixture was then concentrated to a residue. This residue was then added to water. After cooling, the resulting mixture was treated with activated charcoal and acidified with dilute hydrochloric or sulfuric acid to give an oily substance. This was extracted with ether, and the ether solution was contacted with an aqueous, dilute Na 2 CO 3 solution. The secreted watery
lag ble vasket med eter, surgjort og igjen ekstrahert med eter. Det oppnådde eterlag. ble, tørket ..over yannfritt..natriumsulfat og konsen- layer was washed with ether, acidified and again extracted with ether. It achieved ether layer. was, dried ..over yann-free..sodium sulfate and concen-
trert til et råprodukt, som så ble renset ved omkrystallisering eller kromatografi. converted to a crude product, which was then purified by recrystallization or chromatography.
De oppnådde resultater er angitt i tabell 1. The results obtained are shown in table 1.
Eksemplene 7 ~ 9- The examples 7 ~ 9-
Generell fremgangsmåte. General procedure.
En blanding bestående av et bis-(4-hydroksy-fenyl)deri-vat og tørr toluen ble tilsatt en toluensuspensjon av natriumhydrid under avkjøling. Etter en kort omrøring ble en blanding av et a-brom -alifatisk syrederivat og toluen dråpevis tilsatt blandingen, hvoretter det hele ble oppvarmet under omrøring i flere timer.. Etter avkjøling ble reaksjonsblandingen vasket med vann. Toluenet ble fradestillert, hvorved man fikk et råprodukt som så ble renset ved omkrystallisering eller søylekromatografi. A mixture consisting of a bis-(4-hydroxy-phenyl) derivative and dry toluene was added to a toluene suspension of sodium hydride with cooling. After a short stirring, a mixture of an α-bromo-aliphatic acid derivative and toluene was added dropwise to the mixture, after which the whole was heated with stirring for several hours. After cooling, the reaction mixture was washed with water. The toluene was distilled off, whereby a crude product was obtained which was then purified by recrystallization or column chromatography.
De oppnådde resultater er angitt i tabell 2. The results obtained are shown in table 2.
Eksemplene 10 og 11. Examples 10 and 11.
, Generell fremgangsmåte. , General procedure.
En blanding bestående av et fenoksyalifatisk syrederivat, en alkohol, et par dråper konsentrert svovelsyre og, hvis nød-vendig, benzen, ble kokt under tilbakeløp i et bestemt tidsrom sam-tidig som man fjernet fremstilt vann sammen med oppløsningsmiddel. A mixture consisting of a phenoxyaliphatic acid derivative, an alcohol, a few drops of concentrated sulfuric acid and, if necessary, benzene, was refluxed for a certain period of time while removing produced water together with solvent.
Det anvendte oppløsningsmiddel ble tilsatt reaksjonsblandingen for å holde et konstant volum. Etter at reaksjonen var ovér, ble blandingen vask et med vann, tørket over vannfri natriumsulfat og konsentrert til et råprodukt, som deretter ble renset ved omkrystallisering eller søylekromatografi. The solvent used was added to the reaction mixture to maintain a constant volume. After the reaction was over, the mixture was washed with water, dried over anhydrous sodium sulfate and concentrated to a crude product, which was then purified by recrystallization or column chromatography.
De oppnådde resultater er angitt i tabell 3. The results obtained are shown in table 3.
Hanmus som veide fra 15 til 18 g ble foret med et nor-malt kommersielt pelletfor. Musene ble oppdelt i grupper; 6 dyr eller mer i hver gruppe3 og injisert intravenøst med 500 mg/kg. av "Triton WR 1339" (oksyetylert tert.-oktylfenol-formaldehydpolymer). Porsøksforbindelsene ble administrert oralt i egnede doseringsnivåer umiddelbart etter injeksjonen av "Triton". En gruppe mus ble injisert med "Triton" og ble bare gitt et bærermateriale (uten forsøks-forb_åndelse) og ble således benyttet som en "Triton"-injisert kon-trollprøve og en annen gruppe som ikke fikk noen behandling tjente som en normal kontrollprøve. 24 timer etter "Triton"-injeksjonen undersøkte man musene med hensyn til serum kolesterol. Male mice weighing from 15 to 18 g were fed a standard commercial pellet feed. The mice were divided into groups; 6 animals or more in each group3 and injected intravenously at 500 mg/kg. of "Triton WR 1339" (oxyethylated tert.-octylphenol-formaldehyde polymer). The porsok compounds were administered orally at appropriate dosage levels immediately after the injection of "Triton". One group of mice was injected with "Triton" and given only a vehicle (no experimental compound) and thus served as a "Triton"-injected control and another group that received no treatment served as a normal control. Twenty-four hours after the "Triton" injection, the mice were examined for serum cholesterol.
Den kolesterol-senkende aktivitet er uttrykt som følger: / " Triton"- inj isert kontroll/ - / Behandlet mus/ -^qq j—"Triton"-injisert kontroll/ - £~Normal kontroll/ Parentesen betyr serum kolesterol-nivåer. I_ "Triton"-inj isert kontroll/ betyr eksempelvis verdien for serum kolesterol-nivåer (mg/dl) for en "Triton"-injisert kontrollgruppe. The cholesterol-lowering activity is expressed as follows: / "Triton"-injected control/ - / Treated mouse/ -^qq j—"Triton"-injected control/ - £~Normal control/ The parentheses mean serum cholesterol levels. I_ "Triton"-injected control/ means, for example, the value for serum cholesterol levels (mg/dl) for a "Triton"-injected control group.
De oppnådde resultater er angitt i tabell 4, hvor for-bindelsenes nummer tilsvarer nummerene på de ovennevnte eksempler. The results obtained are indicated in table 4, where the numbers of the compounds correspond to the numbers of the above-mentioned examples.
Claims (1)
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
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JP2990569A JPS5010298B1 (en) | 1969-04-16 | 1969-04-16 | |
JP2990769A JPS5010299B1 (en) | 1969-04-16 | 1969-04-16 | |
JP3416769 | 1969-05-02 | ||
JP3416669 | 1969-05-02 | ||
JP8004169 | 1969-10-03 | ||
JP8004269A JPS5010308B1 (en) | 1969-10-03 | 1969-10-03 | |
JP10280969 | 1969-12-19 | ||
JP10419469A JPS4939995B1 (en) | 1969-12-23 | 1969-12-23 |
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NO127298B true NO127298B (en) | 1973-06-04 |
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1970
- 1970-04-15 NO NO142170A patent/NO127298B/no unknown
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