BE554202A - - Google Patents
Info
- Publication number
- BE554202A BE554202A BE554202DA BE554202A BE 554202 A BE554202 A BE 554202A BE 554202D A BE554202D A BE 554202DA BE 554202 A BE554202 A BE 554202A
- Authority
- BE
- Belgium
- Prior art keywords
- hydrocortisone
- ethyl
- acid
- hydroxyl
- heptylate
- Prior art date
Links
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 25
- 229960000890 hydrocortisone Drugs 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims 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 claims description 2
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
- 229940093471 ethyl oleate Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- 239000004359 castor oil Substances 0.000 claims 1
- 235000019438 castor oil Nutrition 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- -1 ethyl octyl Chemical group 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims 1
- 229940058352 levulinate Drugs 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229960001067 hydrocortisone acetate Drugs 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- DAPZDAPTZFJZTO-UHFFFAOYSA-N heptanoyl heptanoate Chemical compound CCCCCCC(=O)OC(=O)CCCCCC DAPZDAPTZFJZTO-UHFFFAOYSA-N 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
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L'hydrocortisone et l'acétate d'Hydrocortisone ne peuvent être utilisés, en raison de leur insolubilité, dans les solvants que sous forme de suspension micro cristallines. Il y avait dès,lors intérêtà réaliser une forme pharmaceutique permettant d'injecter cette hormone en solution et de réaliser en mené temps un médicament retard en augmentant la durée d'action.
En tenant compte du fait que les esters à longue chaîne de diverses hormones possèdent des groupements hydroxyles qui augmentent d, façon considérables l'intensité de l'action initiale et sa durée tout en présentant l'avantage d'être mieux solubles dans les solvants huileux.
<Desc/Clms Page number 2>
L"objet de l'invention consiste en un procède de traitement permetant de rendre soluble et injectable en solution l'hydrocortisone et l'acétate d'Hydrocortisone.
Il se caractérise par les moyens mis en oeuvre pris aussi bien dans leur ensemble que séparément et plus particulièrement en estérifiant de fe façon sélective d'hydroxyle en 21 de l'Hydrocortisone par des acides à longue chaîne de façon à préparer des corps dont la solubilité dans ce-¯ 'juins solvants organiques est considérable, le tout afin de préparer les solutés injectables concentrés à action retardée.
L'ester le plus intéressant à ce point de vue est l'heptylate d'hydro. cortisone qui a été préparé suivant les procédés connus en condensant l'hydroxyle en 21 de 1'Hydrocortisone avec le chlorure d'acide ou l'anhy- dride de l' acide heptalique.
Ce corps est extrêmement soluble.dans des solvants tels que :
EMI2.1
l'Oenanthate d 1 éthyl, l'oléate d'éthyle et les esters de l'acide l,.Jvl1lÜtuC et de l'acide lactique et permettra d'atteindre facilement des concentrations de 20% d'hydrocortisons dans les solutés injectables.
Les solubilités du corps sont résumées dans le tableau ci-dessous :
EMI2.2
vivant Oleate r Lactate Heptylate # Lérulinate lthralinate huile, d'dthyle ! .'éthyle d'éthyle d'éthyle d'octylc de rie !Ol-abilito> 26-28 47-52 28-30 41-44 35-37 15-20
Les solubilités ont été mesurées en dis-solvant par agitation, des quantités croissantes 'd'ester dans I cm3 de solvant, placé dans une ampoule.
Le récipient est scellé et les solutés sont examinés après 24 heures de repos à la température ambiante. Les pourcentages indiqués correspondent à la zone de solubilité maximum, le deuxième. chiffre correspondant à des solutions où des cristaux restent perceptibles.
EXEMPLE 1 5 Grs d'hydrocortisone sont mélangés avec 10 ce de chloroforme et l gr?20 de pyridine anhydre. L'addition goutte à goutte de 3 grs 15 de chlorure d'oenanthyle dilué de 10 ce de chloroforme donne une solution complète qui est chauffée 30 minutes au bain-marie, en agitant. Le produit rdactionnel
<Desc/Clms Page number 3>
est lavé à l'eau et le solvant est évaporé. L'ester cristallise. Il est séché sous vide et lavé à l'éther de pétrôle.
Rendement : 7grs 50 de produit.
P.F.: 98 - 102 [Ó] D = + 141 5 (méthanol) EXEMPLE 2 .
3 Grs 62 d'hydrocortisone sont dilués avec 15 cc de pyridine et le mélange est aduitionné, goutte à goutte, de 2 grs 60 d'anhydride oenanthique. Après dissolution complète et chauffage 30 minutes à 60 , la solution est jetée dans 50 cm3 d'eau. L'ester cristallise à la glacière. Il est essoré, lavé à l'eau puis à l'éther de.pétrole et séché sous vide.
Rendement- : 4 gr 3 . P?F, : 98 - 102
L'invention se caractérise en la préparation de l'heptylol 21 hydrocortisone, ' afin d'obtenir sa solubilité dans des solvants injectables, tels que les esters de l'acide lévulique et de l'acide lactique.
Ces solutions injectables ont une action retard et renferment 20% d'hydrocort. tisone.
Toutefois les quantités, qualités et nature des agents ainsi que leurs traitements pourront varier dans la 1mite des équivalents sans changer pour cela la conception générale de l'invention qui vient d'être décrite.
<Desc / Clms Page number 1>
Hydrocortisone and Hydrocortisone acetate can only be used, because of their insolubility, in solvents in the form of microcrystalline suspension. There was therefore an interest in producing a pharmaceutical form making it possible to inject this hormone in solution and to produce a depot drug in short time while increasing the duration of action.
Taking into account that the long chain esters of various hormones have hydroxyl groups which considerably increase the intensity of the initial action and its duration while having the advantage of being better soluble in oily solvents .
<Desc / Clms Page number 2>
The object of the invention consists of a treatment process making it possible to make hydrocortisone and hydrocortisone acetate soluble and injectable in solution.
It is characterized by the means used, taken both as a whole and separately, and more particularly by selectively esterifying the 21-hydroxyl of hydrocortisone with long-chain acids so as to prepare bodies whose solubility in this organic solvent is considerable, all in order to prepare the concentrated injectable solutions with delayed action.
The ester of most interest from this point of view is hydro heptylate. cortisone which has been prepared according to known methods by condensing the 21-hydroxyl of hydrocortisone with the acid chloride or anhydride of heptalic acid.
This body is extremely soluble in solvents such as:
EMI2.1
Ethyl oenanthate, ethyl oleate, and esters of l, .Jvl1lÜtuC acid and lactic acid and will easily achieve concentrations of 20% hydrocortisons in injectable solutions.
Body solubilities are summarized in the table below:
EMI2.2
Alive Oleate r Lactate Heptylate # Lérulinate lthralinate Oil, Ethyl! .'ethyl ethyl ethyl octyl rie! Ol-abilito> 26-28 47-52 28-30 41-44 35-37 15-20
The solubilities were measured in dissolvent by stirring, increasing amounts of ester in 1 cm 3 of solvent, placed in an ampoule.
The container is sealed and the solutes are examined after standing for 24 hours at room temperature. The percentages indicated correspond to the zone of maximum solubility, the second. figure corresponding to solutions where crystals remain perceptible.
EXAMPLE 1 5 g of hydrocortisone are mixed with 10 cc of chloroform and 1 g of anhydrous pyridine. The dropwise addition of 3 grams of oenanthyl chloride diluted with 10 cc of chloroform gives a complete solution which is heated for 30 minutes in a water bath with stirring. The editorial product
<Desc / Clms Page number 3>
is washed with water and the solvent is evaporated off. The ester crystallizes. It is dried under vacuum and washed with petroleum ether.
Yield: 7grs 50 of product.
M.p .: 98-102 [Ó] D = +141 (methanol) EXAMPLE 2.
3 grs 62 of hydrocortisone are diluted with 15 cc of pyridine and the mixture is added, dropwise, with 2 grs 60 of enanthic anhydride. After complete dissolution and heating for 30 minutes at 60, the solution is poured into 50 cm3 of water. The ester crystallizes in the cooler. It is drained, washed with water then with petroleum ether and dried under vacuum.
Yield-: 4 gr 3. P? F,: 98 - 102
The invention is characterized by the preparation of heptylol 21 hydrocortisone, in order to obtain its solubility in injectable solvents, such as the esters of levulic acid and of lactic acid.
These injectable solutions have a depot action and contain 20% hydrocort. tisone.
However, the quantities, qualities and nature of the agents as well as their treatments may vary within the limit of equivalents without thereby changing the general conception of the invention which has just been described.
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BE554202A true BE554202A (en) |
Family
ID=178729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BE554202D BE554202A (en) |
Country Status (1)
| Country | Link |
|---|---|
| BE (1) | BE554202A (en) |
-
0
- BE BE554202D patent/BE554202A/fr unknown
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