NO130461B - - Google Patents
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- NO130461B NO130461B NO00170746A NO17074667A NO130461B NO 130461 B NO130461 B NO 130461B NO 00170746 A NO00170746 A NO 00170746A NO 17074667 A NO17074667 A NO 17074667A NO 130461 B NO130461 B NO 130461B
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- Prior art keywords
- testosterone
- esters
- solution
- propionate
- ethyl acetate
- Prior art date
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- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 38
- 229960003604 testosterone Drugs 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 11
- 229960004719 nandrolone Drugs 0.000 claims description 8
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 claims description 8
- 230000001548 androgenic effect Effects 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 230000001195 anabolic effect Effects 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 19
- 230000000694 effects Effects 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 210000001625 seminal vesicle Anatomy 0.000 description 9
- 201000010653 vesiculitis Diseases 0.000 description 9
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 210000002307 prostate Anatomy 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- -1 pyridine Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 description 2
- 229960003484 testosterone enanthate Drugs 0.000 description 2
- 150000003515 testosterones Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
- B41F—PRINTING MACHINES OR PRESSES
- B41F15/00—Screen printers
- B41F15/08—Machines
- B41F15/0886—Machines for printing on conical or frusto-conical surfaces
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
- B41F—PRINTING MACHINES OR PRESSES
- B41F15/00—Screen printers
- B41F15/08—Machines
- B41F15/0872—Machines for printing on articles having essentially cylindrical surfaces
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B41—PRINTING; LINING MACHINES; TYPEWRITERS; STAMPS
- B41F—PRINTING MACHINES OR PRESSES
- B41F17/00—Printing apparatus or machines of special types or for particular purposes, not otherwise provided for
- B41F17/28—Printing apparatus or machines of special types or for particular purposes, not otherwise provided for for printing on curved surfaces of conical or frusto-conical articles
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Screen Printers (AREA)
- Printing Methods (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av 17-estere av testosteron og 19-nortestosteron. Process for the production of 17-esters of testosterone and 19-nortestosterone.
Oppfinnelsen angår en fremgangsmåte til fremstilling av hittil ukjente 17-estere av testosteron og 19-nortestosteron. The invention relates to a method for the production of hitherto unknown 17-esters of testosterone and 19-nortestosterone.
De androgene hormoner, som testosteron og 19-nortestosteron, administreres of-test ved injeksjoner, idet den androgene effekt i regelen svekkes ved oral inngift. Ved injeksjonene anvendes stoffene især oppløst eller oppslemmet i oljer, som se-samolje og andre vegetabilske oljer. The androgenic hormones, such as testosterone and 19-nortestosterone, are administered off-test by injections, as the androgenic effect is generally weakened by oral administration. For the injections, the substances are mainly used dissolved or suspended in oils, such as sesame oil and other vegetable oils.
Det er kjent, at esterifisering av stero-idhormoner, som inneholder en hydroksyl-gruppe, i visse tilfeller intensiverer og for-lenger hormonvirkningen. F. eks. har man således i atskillige år anvendt testosteron i form av dets propionat. It is known that esterification of steroid hormones, which contain a hydroxyl group, in certain cases intensifies and prolongs the hormone action. For example Testosterone in the form of its propionate has thus been used for several years.
Selv om der med testosteronpropionat er oppnådd vesentlig bedre terapeutiske resultater enn med testosteron, har etter-forskningen etter nye estere med ennu bedre virkning vært fortsatt, jfr. f. eks. Ott et al, Journ. Clinical Endocrinology (Meta-bolism) 12: 15—27 (1952) og D. Gould et al, J. Am. Chem. Soc. 79, 4472—5 (1957), og som resultat herav er der fremkommet en rekke nye estere, av hvilke de beste for-mentlig er p-fenylpropionatet, ønantatet, heksahydrobenzoatet og [3-cyklopentylpro-pionatet. Although significantly better therapeutic results have been achieved with testosterone propionate than with testosterone, research into new esters with even better effects has continued, cf. e.g. Ott et al., Journ. Clinical Endocrinology (Metabolism) 12: 15-27 (1952) and D. Gould et al, J. Am. Chem. Soc. 79, 4472-5 (1957), and as a result of this a number of new esters have appeared, of which the best are probably the p-phenylpropionate, the enoanthate, the hexahydrobenzoate and the [3-cyclopentylpropionate.
Som mål for et androgens aktivitet As a measure of an androgen's activity
benyttes den vekt, som prostata eller sed-blære hos kastrerte dyr antar etter en enkelt injeksjon av androgenet. Nedenstående tabell I viser for et antall kjente testo-steronestere aktiviteter bestemt på kastrerte rotter. For hver av esterene er aktivite-ten angitt som vekt i mg av henholdsvis the weight that the prostate or seminal vesicle of castrated animals assumes after a single injection of the androgen is used. Table I below shows the activities of a number of known testosterone esters determined on castrated rats. For each of the esters, the activity is indicated as weight in mg of respectively
den ventrale prostatalapp (VL) og sedblæren (SV) 42 dager etter en enkelt subku-tan injeksjon av esteren. Esterene er i alle tilfelle gitt like store volum jordnøttolje, og der er til hver bestemmelse benyttet en gruppe på 7 forsøksdyr, således at de i tabellen anførte aktiviteter hver represente-rer middelverdien av 7 organvekter. the ventral lobe of the prostate (VL) and the seminal vesicle (SV) 42 days after a single subcutaneous injection of the ester. The esters are in all cases given equal volumes of peanut oil, and a group of 7 experimental animals is used for each determination, so that the activities listed in the table each represent the mean value of 7 organ weights.
Det fremgår av disse resultater at |3-fenylpropionatets virkninger kun ved den store dose er vesentlig bedre enn propio-natets, mens der for de øvrige esteres ved-kommende er en vesentlig forbedring selv ved doser på kun en fjerdedel av de, hvori propionatet er anvendt. It appears from these results that the effects of |3-phenylpropionate are only significantly better at the large dose than that of the propionate, while for the other esters there is a significant improvement even at doses of only a quarter of those in which the propionate is used.
Det er et formål med den foreliggende oppfinnelse å fremskaffe en gruppe hittil ukjente estere av de androgene steroider testosteron og 19-nortestosteron, som i organismen kan tilveiebringe det angjeldende steroids anaboliske, androgene eller bå-de anaboliske og androgene virkning i forsterket grad. Det har et ytterligere formål med den foreliggende oppfinnelse å fremskaffe hittil ukjente estere av testosteron og 19-nortestosteron, som i organismen kan opprettholde den nevnte virkning over et lengre tidsrom enn det ikke-forestrede steroid eller de kjente estere. Derved kan med forminskede doser og ferre injeksjoner oppnåes den samme eller bedre virkning enn hittil It is an aim of the present invention to provide a group of previously unknown esters of the androgenic steroids testosterone and 19-nortestosterone, which can provide the anabolic, androgenic or both anabolic and androgenic effect of the steroid in question to an enhanced degree in the organism. It is a further purpose of the present invention to provide hitherto unknown esters of testosterone and 19-nortestosterone, which in the organism can maintain the aforementioned effect over a longer period of time than the non-esterified steroid or the known esters. Thereby, with reduced doses and fewer injections, the same or better effect can be achieved than before
De i esterene ifølge oppfinnelsen inn-gående syrer er (3-(p-alkoksyfenyl)-propi-onsyrer av formelen: The acids included in the esters according to the invention are (3-(p-alkoxyphenyl)-propionic acids of the formula:
hvor R er en alkylgruppe med inntil 12 kullstoffatomer, og fremstillingen av esterene skjer ifølge oppfinnelsen ved, at det angjeldende steroid forestres i 17-stillingen med et derivat av en syre av denne art. where R is an alkyl group with up to 12 carbon atoms, and the preparation of the esters takes place according to the invention by esterifying the steroid in question in the 17-position with a derivative of an acid of this kind.
Særlig hensiktsmessig anvendes ifølge oppfinnelsen et syreklorid eller et anhy-drid av den angjeldende syre, hvorved re-aksjonen alminneligvis forløper glatt og med tilfredsstillende utbytte ved tempera-turer, som ikke overskrider romtemperatur. According to the invention, an acid chloride or an anhydride of the acid in question is particularly expediently used, whereby the reaction generally proceeds smoothly and with a satisfactory yield at temperatures which do not exceed room temperature.
De lavere ledd av serien av p-(p-alk-oksyfenyl)-propionsyrer med 1, 3 og 4 kullstoffatomer i alkylgruppen, som inngår i esterene ifølge oppfinnelsen, er beskrevet i J. Am. Chem. Soc. 70, 255 (1948), hvor også de tilsvarende syreklorider beskrives. The lower members of the series of p-(p-alk-oxyphenyl)-propionic acids with 1, 3 and 4 carbon atoms in the alkyl group, which are part of the esters according to the invention, are described in J. Am. Chem. Soc. 70, 255 (1948), where the corresponding acid chlorides are also described.
(3-(p-isopropoksyfenyl)-, p-(p-isobutoksy-fenyl)- og p-(p-isopentoksyfenyl)-propion-syre er beskrevet i Chemical Abstracts 49, 13 936i, (1955). (3-(p-isopropoxyphenyl)-, p-(p-isobutoxy-phenyl)- and p-(p-isopentoxyphenyl)-propionic acid are described in Chemical Abstracts 49, 13 936i, (1955).
Syrer med annen alkylkjede kan enten fremstilles på analog måte eller av p-(p-hydroksyfenyl)-propionsyre eller estere derav, f. eks. som beskrevet i J. Am. Chem.. Soc. 68, 2598 (1946). For noen ikke tidligere Acids with a different alkyl chain can either be prepared in an analogous way or from p-(p-hydroxyphenyl)-propionic acid or esters thereof, e.g. as described in J. Am. Chem.. Soc. 68, 2598 (1946). For some, not before
i litteraturen beskrevne syrer av denne art er funnet de i nedenstående tabell angitte smeltepunkter. acids of this type described in the literature have the melting points indicated in the table below.
i in
I Smeltepunkter for syrer av formelen I Melting points of acids of the formula
Syrekloridene kan fremstilles på kjent måte, f. eks. ved oppvarmning av de tilsvarende syrer på dampbad med overskudd av tionylklorid. Syreanhydridene kan fremstilles på den i J. Chem. Soc. 741 (1952) angitte måte. The acid chlorides can be prepared in a known manner, e.g. by heating the corresponding acids on a steam bath with an excess of thionyl chloride. The acid anhydrides can be prepared on it in J. Chem. Soc. 741 (1952) stated manner.
Forestringen ifølge oppfinnelsen går særlig glatt i nærvær av en organisk base, som pyridin, som også kan tjene som opp-løsningsmiddel under forestringen. Der kan dog også være andre oppløsningsmidler til-stede, som ikke reagerer med syrederivatet, f. eks. kloroform, benzen eller eter. The esterification according to the invention proceeds particularly smoothly in the presence of an organic base, such as pyridine, which can also serve as a solvent during the esterification. However, there may also be other solvents present, which do not react with the acid derivative, e.g. chloroform, benzene or ether.
Nedenstående tabell II viser for det kjente testosteronønantat og for en rekke av esterene ifølge oppfinnelsen aktiviteter bestemt på kastrerte rotter. Hver av aktivitetene er middelverdien av vektene av henholdsvis den ventrale prostatalapp (VL) og sedblæren (SV) fra 10 dyr 42 dager etter en enkelt injeksjon av det undersøkte stoff. Alle injeksjoner er gitt subkutant i like store volum isopropylmyristat. Table II below shows for the known testosterone enanthate and for a number of the esters according to the invention activities determined on castrated rats. Each of the activities is the mean value of the weights of the ventral prostate lobe (VL) and the seminal vesicle (SV), respectively, from 10 animals 42 days after a single injection of the investigated substance. All injections are given subcutaneously in equal volumes of isopropyl myristate.
Tabellen viser, at virkningen av estre-ae ifølge oppfinnelsen står på høyde med og især for heksoksy-forbindelsens ved-kommende langt overstiger ønantatets. I et ytterligere forsøk er testosteronønantat og heksoksy-, heptoksy- og otoksy-fenylpro-pionater ifølge oppfinnelsen i like store volum jordnøttolje injisert subkutant på kastrerte rotter. Resultatene fremgår av tabell III, hvor hver av aktivitetene er middeltallet av vektene av henholdsvis den ventrale prostatalapp (VL) og sedblæren (SV) fra 9 dyr 42 dager etter injeksjonen. The table shows that the effect of the ester according to the invention is on a par with and, especially for the hexoxy compound, far exceeds that of the enanthate. In a further experiment, testosterone enanthate and hexoxy-, heptoxy- and otoxy-phenylpropionates according to the invention in equal volumes of peanut oil are injected subcutaneously into castrated rats. The results appear in Table III, where each of the activities is the mean number of the weights of the ventral prostate lobe (VL) and the seminal vesicle (SV) respectively from 9 animals 42 days after the injection.
Av tabellen fremgår, at der oppnåes særlig gode resultater, når den i estrene ifølge oppfinnelsen i fenylgruppen inngå-ende p-alkoksygruppe har 6, 7 eller 8 kullstoffatomer, idet man med vesentlig redu-serte doser kan oppnå høyere virkning enn ved den kjente ester.'It appears from the table that particularly good results are achieved when the p- alkoxy group included in the phenyl group in the esters according to the invention has 6, 7 or 8 carbon atoms, since with significantly reduced doses a higher effect can be achieved than with the known ester .'
Endelig er der i nedenstående tabell IV gitt resultater av et forsøk, hvor vektbe-stemmelsene av henholdsvis den ventrale prostatalapp (VL) og sedblæren (SV) fra forsøksdyrene (kastrerte rotter) først er foretatt 60 dager etter injeksjonen. Alle injeksjoner ble gitt subkutant i like store volum jordnøttolje. Hver av aktivitetene i tabell IV er middelverdien av organvekter fra 5 dyr. Finally, Table IV below gives the results of an experiment, where the weight determinations of the ventral prostate lobe (VL) and the seminal vesicle (SV) from the test animals (castrated rats) were first made 60 days after the injection. All injections were given subcutaneously in equal volumes of peanut oil. Each of the activities in Table IV is the mean value of organ weights from 5 animals.
En sammenlikning med verdiene i tabell III viser, at protraheringen er bedre ved esteren ifølge oppfinnelsen enn ved den kjente ester. A comparison with the values in Table III shows that the protraction is better with the ester according to the invention than with the known ester.
Fremstillingen av en rekke testoste-ronestere ifølge oppfinnelsen belyses i nedenstående eksempler. The production of a number of testosterone esters according to the invention is illustrated in the following examples.
Eksempel 1: Example 1:
Til oppløsning av 3 g testosteron i 15 ml tørr pyridin settes ved en temperatur omkring 0° C under omrøring dråpevis en oppløsning av 4,2 g p-(p-metoksyf enyl) - propionylklorid i 15 ml tørr kloroform. Etter avsluttet tilsetning henstår reaksjonsblandingen i 15 timer ved romtemperatur. Derpå tilsettes finknust is til hydrolyse av overskuddet av syreklorid. Til den resulterende blanding settes en blanding lav like deler eter og etylacetat, hvorpå der jvaskes med fortynnet saltsyre, vann, na-itriumbikarbonatoppløsning og vann i den iangitte rekkefølge. Den resulterende eter-[etylacetatfase inndampes etter tørring til 'tørrhet. Inndampningsresten omkrystalliseres av etylacetat. Det derved vundne testosteron-p- (p-metoksyf enyl) -propionat smelter ved 145—146° C. [a]D = + 83° (c = 1 i dioksan). To a solution of 3 g of testosterone in 15 ml of dry pyridine, a solution of 4.2 g of p-(p-methoxyphenyl)-propionyl chloride in 15 ml of dry chloroform is added dropwise at a temperature of around 0° C with stirring. After the addition is complete, the reaction mixture is allowed to stand for 15 hours at room temperature. Finely crushed ice is then added to hydrolyze the excess of acid chloride. To the resulting mixture is added a mixture of equal parts of ether and ethyl acetate, after which it is washed with dilute hydrochloric acid, water, sodium bicarbonate solution and water in the order indicated. The resulting ether-[ethyl acetate phase is evaporated to dryness after drying. The evaporation residue is recrystallized from ethyl acetate. The testosterone-p-(p-methoxy enyl)-propionate thus obtained melts at 145-146° C. [a]D = + 83° (c = 1 in dioxane).
Eksempel 2: Example 2:
Til en oppløsning av 1 g testosteron i 25 ml tørr pyridin settes 2,4 g p-(p-met-oksyf enyl) -propionsyreanhydrid (smeltepunkt 60—62° C), hvorpå reaksjonsblandingen henstår 15 timer ved romtemperatur. Etter hydrolyse med is skjer oppar-beidningen på samme måte som i eksempel 1. Etter omkrystallisasjonen på etylacetat fåes testosteron-p-(p-metoksyf e-nyl)-propionat med smeltepunkt 145— 146° C. To a solution of 1 g of testosterone in 25 ml of dry pyridine is added 2.4 g of p-(p-meth-oxyphenyl)-propionic anhydride (melting point 60-62° C), after which the reaction mixture is allowed to stand for 15 hours at room temperature. After hydrolysis with ice, the oppar treatment takes place in the same way as in example 1. After the recrystallization from ethyl acetate, testosterone-p-(p-methoxyphenyl)-propionate with a melting point of 145-146°C is obtained.
Eksempel 3: Example 3:
Til en oppløsning av 3 g testosteron i 15 ml tørr pyridin settes ved en temperatur omkring 0° C dråpevis under omrøring en oppløsning av 4,7 g p-(p-propoksyfenyl).-propionylklorid i 15 ml tørr kloroform. Etter avsluttet tilsetning henstår reaksjonsblandingen 15 timer ved romtemperatur. Etter hydrolysering med is skjer opparbeidelsen som i eksempel 1, hvorved der ved inndampningen av eter-etylacetat-oppløs-ningen fåes en olje, som krystalliseres av vannholdig etanol. Det således vundne testosteron-p- (p-propoksyf enyl) -propionat smelter ved 110—111° C. To a solution of 3 g of testosterone in 15 ml of dry pyridine, a solution of 4.7 g of p-(p-propoxyphenyl).-propionyl chloride in 15 ml of dry chloroform is added dropwise with stirring at a temperature of around 0° C. After the addition has been completed, the reaction mixture is allowed to stand for 15 hours at room temperature. After hydrolysis with ice, the work-up takes place as in example 1, whereupon the evaporation of the ether-ethyl acetate solution yields an oil, which is crystallized from aqueous ethanol. The testosterone-p-(p-propoxy enyl)-propionate thus obtained melts at 110-111° C.
[a]D = + 79° (c = 1 i dioksan). [a]D = + 79° (c = 1 in dioxane).
Eksempel 4: Til en oppløsning av 3 g testosteron i 15 ml tørr pyridin settes dråpevis under omrøring ved omkring 0° C en oppløsning av 5,6 g p-(p-heksoksyf enyl)-propionylklo-rid i 15 ml tørr kloroform. Etter avsluttet tilsetning henstår reaksjonsblandingen 15 timer ved romtemperatur. Den hydrolyseres deretter med is, og opparbeidelsen skjer som i eksempel 1, hvorved der ved inndampningen av eter-etylacetat-oppløsnin-gen fåes en olje, som krystalliseres fra vannholdig metanol. Det således vundne testosteron-p- (p-heksoksyfenyl) -propionat smelter ved 59—60° C. Example 4: To a solution of 3 g of testosterone in 15 ml of dry pyridine, a solution of 5.6 g of p-(p-hexoxyphenyl)-propionyl chloride in 15 ml of dry chloroform is added dropwise with stirring at around 0° C. After the addition has been completed, the reaction mixture is allowed to stand for 15 hours at room temperature. It is then hydrolysed with ice, and the work-up takes place as in example 1, whereupon the evaporation of the ether-ethyl acetate solution yields an oil, which is crystallized from aqueous methanol. The testosterone-p-(p-hexoxyphenyl)-propionate thus obtained melts at 59-60° C.
[a]D = + 76° (c = 1 i dioksan). [a]D = + 76° (c = 1 in dioxane).
Eksempel 5: Example 5:
Til en oppløsning av 1,5 g testosteron i en blanding av 10 ml tørr kloroform og 5 ml tørr pyridin settes dråpevis under omrystning ved en temperatur omkring 0° C en oppløsning av 3,9 g p-(p-dodecyloksy-fenyl)-propionylklorid i 10 ml tørr kloroform. Etter avsluttet tilsetning henstår reaksjonsblandingen 15 timer ved romtemperatur, hvoretter den hydrolyseres med is og opparbeides som i eksempel 1, hvorved der ved inndampningen av eter-etylacetat-oppløsningen fåes en olje, som krystalliseres fra metanol. Det derved vundne testosteron-p-(p-dodecyloksyf enyl) - propionat smelter ved 58—59° C. To a solution of 1.5 g of testosterone in a mixture of 10 ml of dry chloroform and 5 ml of dry pyridine, a solution of 3.9 g of p-(p-dodecyloxy-phenyl)- propionyl chloride in 10 ml of dry chloroform. After the addition has been completed, the reaction mixture is allowed to stand for 15 hours at room temperature, after which it is hydrolysed with ice and worked up as in example 1, whereupon the evaporation of the ether-ethyl acetate solution yields an oil which is crystallized from methanol. The testosterone-p-(p-dodecyloxy enyl)-propionate thus obtained melts at 58-59° C.
[a]D = + 64° (c = 1 i dioksan). [a]D = + 64° (c = 1 in dioxane).
Eksempel 6: Example 6:
Til en oppløsning av 100 mg 19-nortestosteron i 5 ml tørr pyridin settes 500 mg p-(p-metoksyfenyl) - propionsyreanhydrid* og reaksjonsblandingen henstår 15 timer ved romtemperatur. Deretter hydrolyserés med is og opparbeides som i eksempel 1, hvorved der ved inndampningen av eter-etylacetat-oppløsningen fåes en olje, som krystalliseres fra metanol. Det derved vundne 19-nortestosteron-p- (p-metoksy-fenyl)-propionat smelter ved 126—127° C. To a solution of 100 mg of 19-nortestosterone in 5 ml of dry pyridine is added 500 mg of p-(p-methoxyphenyl)-propionic anhydride* and the reaction mixture is allowed to stand for 15 hours at room temperature. It is then hydrolysed with ice and worked up as in example 1, whereupon the evaporation of the ether-ethyl acetate solution yields an oil, which is crystallized from methanol. The thus obtained 19-nortestosterone-p-(p-methoxy-phenyl)-propionate melts at 126-127° C.
[a]D = + 50° (c = 1 i dioksan). [a]D = + 50° (c = 1 in dioxane).
Eksempel 7: Example 7:
Til en oppløsning av 5 g testosteron i 25 ml tørr pyridin settes 10,9 g p-(p-heks-oksyf enyl) -propionsyreanhydrid (smeltepunkt 47—48° C), hvorpå reaksjonsblandingen henstår 15 timer ved romtemperatur. Etter at den derpå er hydrolysert med is, skjer opparbeidelsen på samme måte som i eksempel 1, idet det dog ved inndampningen av eter-etylacetat-oppløsnin-gen vundne produkt omkrystalliseres fra vannholdig metanol. Derved fåes testosteron-p-(p-heksoksyf enyl)-propionat med smeltepunkt 60—61° C. To a solution of 5 g of testosterone in 25 ml of dry pyridine is added 10.9 g of p-(p-hexoxyphenyl)-propionic anhydride (melting point 47-48° C), after which the reaction mixture is allowed to stand for 15 hours at room temperature. After it has then been hydrolysed with ice, processing takes place in the same way as in example 1, although the product obtained by evaporating the ether-ethyl acetate solution is recrystallized from aqueous methanol. This gives testosterone-p-(p-hexoxy enyl)-propionate with a melting point of 60-61° C.
Eksempel 8: Example 8:
Til en oppløsning av 2 g testosteron i 25 ml tørr pyridin settes 4,2 g p-(p-isopropoksyfenyl) -propionsyreanhydrid (isolert i form av en olje), hvorpå reaksjonsblandingen henstår 15 timer ved romtemperatur. Etter hydrolyse med is opparbeides på samme måte som i eksempel 1, hvorved der ved inndampningen av eter-etylacetat-oppløsningen fåes en olje, som krystalliseres fra vannholdig metanol. Det således vundne testosteron-p- (p-isopropoksyfenyl) To a solution of 2 g of testosterone in 25 ml of dry pyridine is added 4.2 g of p-(p-isopropoxyphenyl)-propionic anhydride (isolated in the form of an oil), after which the reaction mixture is allowed to stand for 15 hours at room temperature. After hydrolysis with ice, it is worked up in the same way as in example 1, whereupon the evaporation of the ether-ethyl acetate solution yields an oil, which is crystallized from aqueous methanol. The thus obtained testosterone-p-(p-isopropoxyphenyl)
-propionat smelter ved 109—110° C, -propionate melts at 109—110° C,
[a]D = + 75° (c = 1 i dioksan). [a]D = + 75° (c = 1 in dioxane).
Eksempel 9: Example 9:
Til en oppløsning av 1,5 g testosteron i 15 ml tørr pyridin settes 3,5 g p-(p-pent-oksyf enyl) -propionsyreanhydrid (smeltepunkt 45—46° C), hvorpå reaksjonsblandingen henstår 15 timer ved romtemperatur. Etter hydrolyse med is skjer opparbeidelsen som i eksempel 1, idet inndampningsresten fra eter-etylacetat-oppløsnin-gen omkrystalliseres fra vannholdig metanol. Der vinnes herved testosteron-p-(p-pentoksyfenyl) -propionat med smeltepunkt 63—64° C. To a solution of 1.5 g of testosterone in 15 ml of dry pyridine is added 3.5 g of p-(p-pentoxyphenyl)-propionic anhydride (melting point 45-46° C), after which the reaction mixture is allowed to stand for 15 hours at room temperature. After hydrolysis with ice, the work-up takes place as in example 1, with the evaporation residue from the ether-ethyl acetate solution being recrystallized from aqueous methanol. Testosterone-p-(p-pentoxyphenyl)-propionate with a melting point of 63-64° C is thereby obtained.
[<x]D = + 76° (c .= li dioksan). [<x]D = + 76° (c .= li dioxane).
Eksempel 10: Example 10:
Til en oppløsning av 1,5 g testosteron i 15 ml tørr pyridin settes 4,0 g p-(p-hept-oksyf enyl) -propionsyreanhydrid (smeltepunkt 50—51° C), hvoretter reaksjonsblandingen henstår 15 timer ved romtemperatur. Etter hydrolyse med is skjer opparbeidelsen som i eksempel 1, idet inndampningsresten fra eter-etylacetat-oppløsnin-gen omkrystalliseres fra vannholdig metanol. Der vinnes herved testosteron-p-(p-heptoksyfenyl)-propionat med smeltepunkt 57—58° C. To a solution of 1.5 g of testosterone in 15 ml of dry pyridine is added 4.0 g of p-(p-heptoxyphenyl)-propionic anhydride (melting point 50-51° C), after which the reaction mixture is allowed to stand for 15 hours at room temperature. After hydrolysis with ice, the work-up takes place as in example 1, with the evaporation residue from the ether-ethyl acetate solution being recrystallized from aqueous methanol. Testosterone-p-(p-heptoxyphenyl)-propionate with a melting point of 57-58° C is thereby obtained.
[a]D = + 69° (c = 1 i dioksan). [a]D = + 69° (c = 1 in dioxane).
Eksempel 11: Example 11:
Til en oppløsning av 1,5 g testosteron i 15 ml tørr pyridin settes 4,2 g p-(p-okt-oksyf enyl) -propionsyreanhydrid (smeltepunkt 48—50° C), hvoretter reaksjonsblandingen henstår 15 timer ved romtemperatur. Etter hydrolyse med is skjer opparbeidelsen som i eksempel 1, idet inndampningsresten fra eter-etylacetat-opp-løsningen omkrystalliseres fra vannholdig metanol. Der vinnes herved testosteron-|3-(p-oktoksyfenyl-propionat med smeltepunkt 49—50° C. To a solution of 1.5 g of testosterone in 15 ml of dry pyridine is added 4.2 g of p-(p-oct-oxyphenyl)-propionic anhydride (melting point 48-50° C), after which the reaction mixture is allowed to stand for 15 hours at room temperature. After hydrolysis with ice, the work-up takes place as in example 1, with the evaporation residue from the ether-ethyl acetate solution being recrystallized from aqueous methanol. Testosterone-|3-(p-octoxyphenyl-propionate with a melting point of 49-50° C) is thereby obtained.
[<x]D = + 67° (c = 1 i dioksan). [<x]D = + 67° (c = 1 in dioxane).
Claims (2)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR85541A FR1513389A (en) | 1966-11-30 | 1966-11-30 | Decorating machine in several colors |
Publications (2)
Publication Number | Publication Date |
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NO130461B true NO130461B (en) | 1974-09-09 |
NO130461C NO130461C (en) | 1974-12-18 |
Family
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Application Number | Title | Priority Date | Filing Date |
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NO170746A NO130461C (en) | 1966-11-30 | 1967-11-29 |
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US (1) | US3521298A (en) |
JP (1) | JPS4929688B1 (en) |
BE (1) | BE706741A (en) |
CH (1) | CH479398A (en) |
CS (1) | CS156413B2 (en) |
DE (1) | DE1611319A1 (en) |
DK (1) | DK124594B (en) |
ES (1) | ES347699A1 (en) |
FR (1) | FR1513389A (en) |
GB (1) | GB1212845A (en) |
LU (1) | LU54833A1 (en) |
MC (1) | MC687A1 (en) |
NL (1) | NL150050B (en) |
NO (1) | NO130461C (en) |
SE (1) | SE342578B (en) |
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Publication number | Priority date | Publication date | Assignee | Title |
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US3672296A (en) * | 1968-06-11 | 1972-06-27 | Wilfried Kammann | Screen printing machine for printing cylindrical and conical articles |
US3792657A (en) * | 1969-06-26 | 1974-02-19 | W Kammann | Screen printing machine for cylindrical or conical bodies |
IT989517B (en) * | 1971-12-10 | 1975-06-10 | Produ Ag | NETWORK PRINTING MACHINE |
US4109573A (en) * | 1974-01-22 | 1978-08-29 | Werner Kamman Maschinenfabrik | Article, screen and squeegee drive for screenprinter |
US3933091A (en) * | 1974-06-17 | 1976-01-20 | New Products Corporation | Apparatus for screen printing bottles |
JPS5640554A (en) * | 1979-09-10 | 1981-04-16 | Yakult Honsha Co Ltd | Continuous type multicolor printing press |
JPS56120350A (en) * | 1980-02-28 | 1981-09-21 | Yakult Honsha Co Ltd | Continuous multicolor printer for tapered section circular body |
US4479429A (en) * | 1982-03-22 | 1984-10-30 | Yoshino America Corporation | Multi-color printing apparatus of surfaces of bodies of rotation |
DE4023135A1 (en) * | 1990-07-20 | 1992-01-23 | Alt Peter | METHOD AND DEVICE FOR COATING ENGINE PISTON |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
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US3273618A (en) * | 1966-09-20 | Flodin asparagus trimmer | ||
US2066351A (en) * | 1934-01-23 | 1937-01-05 | Johnson Alfred | Striping or banding machine |
US2121491A (en) * | 1934-02-14 | 1938-06-21 | Owens Illinois Glass Co | Machine for decorating surfaces by stencil method |
US2132818A (en) * | 1936-06-18 | 1938-10-11 | Owens Illinois Glass Co | Method of and apparatus for decorating bottles and like articles |
US2198565A (en) * | 1938-03-31 | 1940-04-23 | Libbey Glass Co | Tumbler decorating apparatus |
US2183223A (en) * | 1938-04-30 | 1939-12-12 | Owens Illinois Glass Co | Stenciling apparatus |
US2757606A (en) * | 1951-01-02 | 1956-08-07 | Dubuit Louis Gilbert | Silk-screen printing machines |
US2739531A (en) * | 1951-08-29 | 1956-03-27 | Hagerman Lawrence | Decorating machine |
US2920556A (en) * | 1956-11-21 | 1960-01-12 | Owens Illinois Glass Co | Machine for decorating round surfaces |
US2975705A (en) * | 1958-02-12 | 1961-03-21 | Gilman Louis | Silk screen process press |
US3113510A (en) * | 1961-12-18 | 1963-12-10 | Dubuit Louis Gilbert | Silk-screen printing device |
US3195451A (en) * | 1962-09-11 | 1965-07-20 | Kamru Products Corp | Decorating means |
US3172357A (en) * | 1963-03-04 | 1965-03-09 | Strutz & Co Inc Carl | Pneumatically operated stenciling apparatus |
US3263603A (en) * | 1964-01-03 | 1966-08-02 | M & M Res Engineering Co | Silk screen printing apparatus |
US3253538A (en) * | 1964-07-13 | 1966-05-31 | Strutz & Co Inc Carl | Bottle decorating apparatus |
-
1966
- 1966-11-30 FR FR85541A patent/FR1513389A/en not_active Expired
-
1967
- 1967-11-07 MC MC725A patent/MC687A1/en unknown
- 1967-11-08 SE SE15285/67A patent/SE342578B/xx unknown
- 1967-11-09 LU LU54833D patent/LU54833A1/xx unknown
- 1967-11-14 DE DE19671611319 patent/DE1611319A1/en active Pending
- 1967-11-16 CH CH1605067A patent/CH479398A/en not_active IP Right Cessation
- 1967-11-18 ES ES347699A patent/ES347699A1/en not_active Expired
- 1967-11-20 BE BE706741D patent/BE706741A/xx not_active IP Right Cessation
- 1967-11-21 US US684786A patent/US3521298A/en not_active Expired - Lifetime
- 1967-11-21 GB GB53011/67A patent/GB1212845A/en not_active Expired
- 1967-11-29 NO NO170746A patent/NO130461C/no unknown
- 1967-11-29 CS CS844567A patent/CS156413B2/cs unknown
- 1967-11-29 DK DK597867AA patent/DK124594B/en not_active IP Right Cessation
- 1967-11-30 JP JP42076528A patent/JPS4929688B1/ja active Pending
- 1967-11-30 NL NL676716292A patent/NL150050B/en not_active IP Right Cessation
Also Published As
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FR1513389A (en) | 1968-02-16 |
NL150050B (en) | 1976-07-15 |
DE1611319A1 (en) | 1971-05-19 |
NL6716292A (en) | 1968-05-31 |
ES347699A1 (en) | 1969-02-16 |
MC687A1 (en) | 1968-09-03 |
NO130461C (en) | 1974-12-18 |
LU54833A1 (en) | 1968-02-02 |
SE342578B (en) | 1972-02-14 |
JPS4929688B1 (en) | 1974-08-06 |
CS156413B2 (en) | 1974-07-24 |
CH479398A (en) | 1969-10-15 |
DK124594B (en) | 1972-11-06 |
BE706741A (en) | 1968-04-01 |
GB1212845A (en) | 1970-11-18 |
US3521298A (en) | 1970-07-21 |
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