DE2110722A1 - Water soluble steroids, hydrophilic substd acetoxy derivs - Google Patents
Water soluble steroids, hydrophilic substd acetoxy derivsInfo
- Publication number
- DE2110722A1 DE2110722A1 DE19712110722 DE2110722A DE2110722A1 DE 2110722 A1 DE2110722 A1 DE 2110722A1 DE 19712110722 DE19712110722 DE 19712110722 DE 2110722 A DE2110722 A DE 2110722A DE 2110722 A1 DE2110722 A1 DE 2110722A1
- Authority
- DE
- Germany
- Prior art keywords
- acetoxy
- steroids
- radical
- hydroxymethyl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003431 steroids Chemical class 0.000 title claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 7
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 title description 5
- 239000002253 acid Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 10
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims abstract 3
- -1 ace-toxy steroids Chemical class 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 150000003254 radicals Chemical class 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 3
- LLPWGHLVUPBSLP-UHFFFAOYSA-N (3,4-diacetyloxy-3,4-dihydro-2h-pyran-2-yl)methyl acetate Chemical compound CC(=O)OCC1OC=CC(OC(C)=O)C1OC(C)=O LLPWGHLVUPBSLP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 10
- 230000032050 esterification Effects 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000005042 acyloxymethyl group Chemical group 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 150000004880 oxines Chemical class 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 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 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229930002534 steroid glycoside Natural products 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BLJKPOLGWISUIM-UHFFFAOYSA-N 2-(hydroxymethyl)-3,4-dihydro-2H-pyran-3-ol Chemical compound OCC1OC=CCC1O BLJKPOLGWISUIM-UHFFFAOYSA-N 0.000 description 1
- FNVDGMNMKDYYNG-UHFFFAOYSA-N 3,3,3-trihydroxy-2,2-dimethylpropanoic acid Chemical compound OC(C(C(=O)O)(C)C)(O)O FNVDGMNMKDYYNG-UHFFFAOYSA-N 0.000 description 1
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- DNVPQKQSNYMLRS-APGDWVJJSA-N ergosterol group Chemical group [C@@H]1(CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)\C=C\[C@H](C)C(C)C DNVPQKQSNYMLRS-APGDWVJJSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 150000002338 glycosides Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
Description
Neue Triacyloxymethylacetoxy-Steroide Zusatz zur Patentanmeldung P 20 23 129.2 In der Patentanmeldung P 20 23 129.2 werden neue (RO.CH2)3-acetoxy-Steroide, worin R ein Wasserstoffatom oder einen niederen Acylrest bedeutet, beschrieben und ein Verfahren zu deren Herstellung vorgeschlagen, das dadurch gekennzeichnet ist, daß man die Hydroxygruppe eines entsprechenden Ausgangssteroids mit Tri-(acyloxymethyl)-essigsäure oder einem reaktionsfähigen Derivat davon in an sich bekannter Weise umsetzt und gewünschtenfalls anschließend die Acyloxymethylgruppen des primär eingeführten Lsterrestes ebenfells in an sich bekannter Weise verseift. New triacyloxymethylacetoxy steroids addition to the patent application P 20 23 129.2 In the patent application P 20 23 129.2 new (RO.CH2) 3-acetoxy steroids, wherein R denotes a hydrogen atom or a lower acyl radical, described and a method for their production proposed, which is characterized in that that the hydroxyl group of a corresponding starting steroid with tri- (acyloxymethyl) acetic acid or a reactive derivative thereof in a manner known per se and if desired, then the acyloxymethyl groups of the primarily introduced ester residue also saponified in a manner known per se.
Der Acylrest R der verfahrensgemäß angewendten Tri-(acyloxymethyl)-essigsäure leitet sich ab von niederen aliphatischen Carbonsäuren, wie insbesondere Ameinsäure, Essigsäure und Propionsäure.The acyl radical R of the tri- (acyloxymethyl) acetic acid used according to the process is derived from lower aliphatic carboxylic acids, such as in particular amic acid, Acetic acid and propionic acid.
In weiterer ausbildung der Patentanmeldung P 20 23 129.2 kann sich einer der Reste R auch von höheren Oxycarbonsäuren und von Derivaten des Pyrans ableiten.In further training of the patent application P 20 23 129.2 can one of the radicals R also of higher oxycarboxylic acids and derivatives of pyran derive.
Für viele Indikationen der medizinischen Praxis ist es erforderlich, daß der Steroidwirkstoff in wasserlöslicher Form vorliegt. Bekarnitermaßen wird in vielen Fällen die Wasserlöslichkeit dadurch erzielt, daß man einen Steroidalkohol z.B. mit einer Mineralsäure, vorzugsweise mit Schwefelsäure oder Phosphorsäure, oder mit Polycarbonsäuren, vorzugsweise Bernsteinsäure, verestert. Die Anwendung der so erhaltenen Fster als wasserlösliche Steroidwirksubstanzen erfolge dann in Form ihrer Salze, z.B. als Alkalisalze. Weitere Möglichkeiten bestehen darin, daß man einen Steroidalkohol mit z.B. Amincarbonsäuren, wie Aminoessigsäure, verestert oder in das Steroidmolekül eine basische Stickstoffgruppe, z.B. eine Aminogruppe, einführt und die so erhaltenen Ester bzw. N-substituierten Steroide als mineralsaure Salze, z.B. als Sulfat, Phosphat, Hydrochlorid oder ähnliche Salze, anwendet.For many indications in medical practice it is necessary that the steroid active ingredient is in water-soluble form. As is well known in many cases water solubility is achieved by using a steroid alcohol e.g. with a mineral acid, preferably with sulfuric acid or phosphoric acid, or esterified with polycarboxylic acids, preferably succinic acid. The application the window obtained in this way as water-soluble steroid active substances then takes place in Form of their salts, e.g. as alkali salts. Other possibilities are that a steroid alcohol is esterified with, for example, amine carboxylic acids, such as aminoacetic acid or in the steroid molecule a basic nitrogen group, e.g. an amino group, introduces and the esters or N-substituted steroids thus obtained as mineral acid Salts, e.g. as sulfate, phosphate, hydrochloride or similar salts.
Bei der Anwendung solcher wasserlöslichen Steroide ist jedoch zu beachten, daß bei bestimmten Indikationen die Verabfolung ionischer Salze nachteilig is-t. Deshalb ist es von Vorteil, einen Steroidalkohol in eine wasserlösliche Form zu bringen, indem man als hydrophile Gruppen Glycosidreste einführt.When using such water-soluble steroids, however, it should be noted that that in certain indications the administration of ionic salts is disadvantageous. This is why it is beneficial to convert a steroid alcohol into a water-soluble form bring by introducing glycoside residues as hydrophilic groups.
Diese Methode zur Herstellung wasserlöslicher Steroide hat insbesondere bei den herzwirksamen Steroiden große Bedeutung erlangt.This method of making water soluble steroids has in particular gained great importance in the field of cardiovascular steroids.
Bekanntlich iSt die Herstellung solcher Steroidglycoside, die chemisch als Acetale aufzufassen sind, mit experimentellen Schwierigkeiten verbunden. Die Verknüpfung von Zuckern und Steroidalkoholen über die Acetabildung wird üblicherweise in Gegenwart eines Überschusses von Cilber- oder Quecksilbersalzen durchgeführt, deren Abtrennung nch erfolter Umsetzung insbesondere bei der betriebsmäßigen Durchführung aufwendig ist. Die Ausbeuten an gewünschtem Steroidglycosid sind nur gering. Darüber hinaus besteht die Möglichkeit der Bildung von Epimerengemischen aM' Kohlenstoffatom C-1 des Zuckermoleküls.It is known that the production of such steroid glycosides is chemically are to be understood as acetals, associated with experimental difficulties. the Linking of sugars and steroid alcohols via the formation of acetates is common carried out in the presence of an excess of silver or mercury salts, their separation after implementation, especially during operational implementation is expensive. The yields of the desired steroid glycoside are only low. About that there is also the possibility of the formation of mixtures of epimers on the carbon atom C-1 of the sugar molecule.
Die Aufgabe der vorliegenden Erfindung ist es somit, neue wasserlösliche Steroide aufzufinden, deren hydrophiler Substituent einen ionischen Charakter hat, deren technische Herstellung weniger aufwendig ist und gleichzeitig höhere Ausbeuten an gewünschtem wasserlöslichen Steroid liefert.The object of the present invention is therefore to provide new water-soluble Find steroids whose hydrophilic substituent has an ionic character, their technical production is less expensive and at the same time higher yields of desired water-soluble steroid.
Es wurde nun gefunden, daß (RO.CH2)3-acetoxy-Steroide, worin einer der Rest R der Acylrest einer höheren Oxycarbonsäure oder ein substituierter Pyranrest ist, die gewünschten Eigenschaften besitzen und deren Herstellung unter Vermeidung der oben aufgezeigten Nachteile in sehr guten Ausbeuten möglich ist.It has now been found that (RO.CH2) 3-acetoxy steroids, wherein one the radical R is the acyl radical of a higher oxycarboxylic acid or a substituted pyran radical have the desired properties and avoid their production the disadvantages outlined above is possible in very good yields.
Als höhere Oxycarbonsäure sind solchen mit einer oder auch mehreren Hydroxygruppen geeignet. Insbesondere wird die Trihydroxy pivalinsäure und als substituiertes Pyran das 2-Hydroxymethyl-3-hydroxy-2,3-dihydropyran genannt.The higher oxycarboxylic acids are those with one or more Suitable for hydroxyl groups. In particular, the trihydroxy pivalic acid and as substituted Pyran called the 2-hydroxymethyl-3-hydroxy-2,3-dihydropyran.
Die Erfindung betrifft somit neue (RO.CH2)3-acetoxy-Steroide, worin einer der Reste R der Acylrest einer höheren Oxycarbonsäure oder ein subst-ituiert-er Pyranrest ist, und ein Verfjiren zu deren Herstellung, dadurch gekennzeichnet, daß man gemäß Patentanmeldung P 20 23 129.2 hergestellte (RO.CH2)3-acetoxy-Steroide, worin R Wasserstoff bedeutet, mit einem reaktionsfähigen Derivat einer höheren Oxycarbonsäure oder einem X an in an sich bekannter Weise umsetzt.The invention thus relates to new (RO.CH2) 3-acetoxy steroids, in which one of the radicals R is the acyl radical of a higher oxycarboxylic acid or a substituted one Is pyran radical, and a process for their preparation, characterized in that (RO.CH2) 3-acetoxy steroids produced according to patent application P 20 23 129.2, wherein R is hydrogen with a reactive derivative of a higher oxycarboxylic acid or an X on in a manner known per se.
Das Molekül der Ausgangs steroide karni in üblicher Weise substituiert sein. Als mögliche Substituenten seien beispielsweise genannt zusätzliche freie oder veresterte «- oder ß-konfigurierte Hydroxygruppen in 1-, 5-, 6 , 11-, 12-, 17-, 14--, 15-, oder 16-Stellung, Ketongruppen in 3-, 6-, 11-, 17- oder 20-Stellung, Epoxygruppen, vorzugsweise in 14.15-Stellung, gesättigte oder ungesättigte Alkylgruppen in 1-, 6-, 16- oder 18-Stellung, oder Halogenatome, vorzugsweise Chlor oder Fluor, in 2-, 4-, 6- oder 9-Stellung. In den Ringen A, B, C und D können die Ausgangssteroide gesättigt oder ungesättigt, z.B. in 1-, 4-, 5-, 9(11)-@ 14(15)- oder 16-Stellung, sein. Neben den Steroiden der Androstan-und Fregnanreihe sind auch solche geeignet, die in 17-Stellung durch die Cholesterin- oder Ergosterin-Seitenkette oder den ß-ständigen Butenolidring substituiert sind.The molecule of the starting steroids karni is substituted in the usual way be. Possible substituents which may be mentioned are, for example, additional free ones or esterified «- or ß-configured hydroxyl groups in 1-, 5-, 6, 11-, 12-, 17-, 14-, 15- or 16-position, ketone groups in the 3-, 6-, 11-, 17- or 20-position, Epoxy groups, preferably in the 14.15 position, saturated or unsaturated alkyl groups in the 1-, 6-, 16- or 18-position, or halogen atoms, preferably chlorine or fluorine, in the 2-, 4-, 6- or 9-position. In the rings A, B, C and D the starting steroids can saturated or unsaturated, e.g. in 1-, 4-, 5-, 9 (11) - @ 14 (15) - or 16 position. Besides the steroids the androstane and fregnan series are also suitable those in the 17-position through the cholesterol or ergosterol side chain or the ß-butenolide ring are substituted.
Bevorzugte Ausgangssteroide leiten sich insbesondere ab von solchen der allgemeinen Formel I worin R Wasserstoff, R1 eine Hydroxygruppe und R2 Wasserstoff, eine Hydroxy- oder Acyloxygruppe, wobei sich der Acylrest von einer aliphatischen oder aromatischen Carbonsaure nit 1 - 12 Kohlenstoffatomen herleitet, oder R1 und R2 gemeinsam einen ß-ständigen Oxidoring und C4@@@C5 eine einfache oder doppelte Kohlenstoff-Kohlenstoffbindung bedeuten, und die Substituenten in 3- und 15-Stellung und ein in 5-Stellung anwesenden Wasserstoffatom a- oder ß-ständig sein können.Preferred starting steroids are derived in particular from those of the general formula I. where R is hydrogen, R1 is a hydroxyl group and R2 is hydrogen, a hydroxyl or acyloxy group, the acyl radical being derived from an aliphatic or aromatic carboxylic acid having 1 - 12 carbon atoms, or R1 and R2 together have a β-oxide ring and C4 @@@ C5 mean a single or double carbon-carbon bond, and the substituents in the 3- and 15-position and a hydrogen atom present in the 5-position can be α or β.
Die Durchführung der Veresterung erfolgt nach Methoden, wie sie dem Fachmann dafür allgemein geläufig sind. Vorzugsweise löst man das Trihydroxymethylacetoxy-Steroid in einer organischen Base, z.B. in Fyridin oder. Collidin, versetzt diese Lösung mit einem Überscfluß an Carbonsäurehalogenid, wie z.B.The esterification is carried out according to methods such as those used in the Experts are generally familiar with this. The trihydroxymethylacetoxy steroid is preferably dissolved in an organic base, e.g. in fyridine or. Collidine, added to this solution with an excess of carboxylic acid halide, e.g.
das Carbonsäurechlorid, und läßt das Reaktionsgemisch bei vorzugsweise Raumtemperatur reagieren. Der Reaktionsablauf wird zur genauen Endpunktsbestimmung der gewünschten Veresterung zweckmäßigerweise im Dünnschichtchromatogramm analytisch verfolgt Die Einführung eines substituierten Pyranrestes erfolgt gleichfalls nach an sich bekannten Methoden. Vorzugsweise löst man das Trihydroxymethylacetoxy-Steroid in Tetrahydrofuran und versetzt mit einem ueberschuß von Tri-0-acetyl-D-glucal in Gegenwart von Fhosphoroxy'-chlorid. Das Reaktionsprodukt wird in Alkohol gelöst und die Acetoxygruppen werden durch milde alkalische Hydrolyse, z.B. mit Kaliumbicarbonat, abgespalten.the carboxylic acid chloride, and leaves the reaction mixture at preferably React at room temperature. The course of the reaction is used to determine the exact endpoint the desired esterification expediently analytically in the thin-layer chromatogram pursued The introduction of a substituted pyran residue also takes place after methods known per se. The trihydroxymethylacetoxy steroid is preferably dissolved in tetrahydrofuran and treated with an excess of tri-0-acetyl-D-glucal in Presence of phosphoroxy'-chloride. The reaction product is dissolved in alcohol and the acetoxy groups are removed by mild alkaline hydrolysis, e.g. with potassium bicarbonate, cleaved.
Dem Reaktionsgemisch können auch zusätzlich Lösungsvermittler oder Verdünnungsmittel, die gegen die erfindungsgen('lß anwendbaren Reaktionspartner indifferent sind, zugesetzt werden. Beispielsweise genannt seinen insbesondere Halogenkohlenwasserstoffe, wie Methylenchlorid, Äthylenchlorid, Chloroform u.ä., oder Kohlenwasserstoffe, wie Benzol, Toluol oder Äther, wie Diäthyläther, Dioxan u.a.The reaction mixture can also additionally solubilizers or Diluents which can be used against the reactants according to the invention are indifferent, are added. For example, its especially called halogenated hydrocarbons, such as methylene chloride, ethylene chloride, chloroform and the like, or hydrocarbons such as Benzene, toluene or ethers such as diethyl ether, dioxane, etc.
Die erfindungsgemäß herstellbaren Verbindungen sind wertvolle wasserlösliche Arzneimittelwirkstoffe.The compounds which can be prepared according to the invention are valuable water-soluble ones Active pharmaceutical ingredients.
Die nachfolgenden Ausführungsbeispiele erläutern die Erfindung.The following exemplary embodiments explain the invention.
Beispiel I Man acyliert 2 g 3ß-[Tri-(hydroxymethyl)-acetoxy]-14.15ß epoxy-14ß-carda-4.20(22)-dienolid in 20 ml absolutem Pyridin mit 4,6 g Triacetoxypivalylchlorid 3 Tage bei Raumtemperatur, gießt das Reaktionsgemisch in Eiswasser ein, extrahiert mit Methylenchlorid, troclrnet die organische Phase und engt im Vakuum zur Trockne ein.Example I 2 g of 3 [tri (hydroxymethyl) acetoxy] -14.15 [beta] are acylated epoxy-14ß-carda-4.20 (22) -dienolide in 20 ml of absolute pyridine with 4.6 g of triacetoxypivalyl chloride 3 days at room temperature, the reaction mixture is poured into ice water and extracted with methylene chloride, the organic phase dries and evaporates to dryness in vacuo a.
Man löst d.en Rückstand in 540 ml Methanol, gibt eine Lösung.The residue is dissolved in 540 ml of methanol and a solution is added.
von 3,7 g Natriumbicarbonat in 135 ml Wasser hinzu und läßt 10 Tage bei Raumtemperatur stehen. Nan verdünnt mit 1,5 1 Wasser und extrahiert 3 mal mit je 300 ml Chloroform und danach 3 mal mit Chloroform, das 10 °ó Äthanol enthält. Die Extrakte engt man ein und chromatographiert den Rückstand an Silicagel. Man eluiert mit steigenden Mengen Essigester in Tetrachlorkohlenstoff und anschließend mit Äthanol in Essigester. Die Fraktionen mit 10 bis 33 % Äthanol in Essigester dampft man in Vakuum ein und kristallisiert zweimal aus Athanol um. Man erhält o,6 g 3ß-#[Bis-(hydroxymethyl)]-[tri-(hydroxymethyl)-acetoxymethyl]-acetoxy#-14.15ß-epoxy-14ßcarda-4.20(22)-dienolid vom Schmelzpunkt 150 - 152 00.of 3.7 g of sodium bicarbonate in 135 ml of water are added and left for 10 days stand at room temperature. Nan diluted with 1.5 l of water and extracted 3 times with 300 ml of chloroform each and then 3 times with chloroform, which contains 10 ° ó ethanol. The extracts are concentrated and the residue is chromatographed on silica gel. Man elutes with increasing amounts of ethyl acetate in carbon tetrachloride and then with ethanol in ethyl acetate. The fractions with 10 to 33% ethanol in ethyl acetate it is evaporated in vacuo and recrystallized twice from ethanol. One obtains o, 6 g 3β - # [bis (hydroxymethyl)] - [tri- (hydroxymethyl) acetoxymethyl] acetoxy # -14.15β-epoxy-14βcarda-4.20 (22) -dienolide with a melting point of 150 - 152 00.
Beispiel 2 Nan acyliert 2 g 4-Chlor-3ß-[tri-(hydroxymethyl)-acetoxy] 14.15ß-epoxy-14ß-carda-4.20(22)-dienolid in gleicher Weise wie in Beispiel 1 beschrieben, verseift anschließend mit Kaliumbicarbonat und reinigt chromatographisch an Silicagel. Nach Umkristallisieren aus Essigester/Methanol erhält man 23o mg 4-Chlor-3ß-{[bis-(hydroxymethyl)]-[tri-(hydroxymethyl)-acetoxymethyl]-acetoxy}-14.15ß-epoxy-14ß-carda-4.20(22)-dienolid vom Schmelzpunkt 148 - 150°C.Example 2 Nan acylates 2 g of 4-chloro-3ß- [tri- (hydroxymethyl) acetoxy] 14.15ß-epoxy-14ß-carda-4.20 (22) -dienolide in the same way as described in Example 1, then saponified with potassium bicarbonate and purified by chromatography on silica gel. After recrystallization from ethyl acetate / methanol, 23o mg of 4-chloro-3ß - {[bis- (hydroxymethyl)] - [tri- (hydroxymethyl) -acetoxymethyl] -acetoxy} -14.15ß-epoxy-14ß-carda-4.20 (22 ) -dienolid with a melting point of 148 - 150 ° C.
Beispiel 3 Man löst 320 mg 14-Hydroxy-3ß-[tri-(hydroxymethyl)-acetoxy]-5ß.14ß-card -20(22)-enolid in 5 ml absolutem Tetrahydrofuran gibt o,57 g D-Glucal-triacetat hinzu, rErt die Lösung bei Raumtemperatur und versetzt sie mit einigen Tropfen einer Lösung von o,l ml Phosphoroxychlorid in absolutem Tetrahydrofuran (lo ml). Han verfolgt den Verlauf der Reaktion im Dünnschichtchromatogramm. Nach 48 Stunden gießt man in Eiswasser und extrshiert mit Chloroform. Nach dem Trocknen zieht man die Chloroformphase zur trockne ab, kocht den Rückstand mit Äther aus, um überschüssiges D-Glucal-triecetat zu entfernen, und unterwirft das Ätherunlösliche der Verseifung.Example 3 320 mg of 14-hydroxy-3β- [tri- (hydroxymethyl) acetoxy] -5β.14β-card are dissolved -20 (22) enolide in 5 ml of absolute tetrahydrofuran gives 0.57 g of D-glucal triacetate add the solution to room temperature and add a few drops of a Solution of 0.1 ml of phosphorus oxychloride in absolute tetrahydrofuran (lo ml). Han pursued the course of the reaction in the thin-layer chromatogram. After 48 hours it is poured in ice water and extracted with chloroform. After drying, the chloroform phase is drawn off to dryness, boil the residue with ether to remove excess D-glucal acetate to remove, and subjects the ether-insoluble to saponification.
Man löst in 50 ml Methanol, versetzt die Lösung mit 0,47 g Kaliumbicarbonat in 15 ml Wasser und läßt eine Woche bei Raumtemperatur stehen. Man zieht das Lösungsmittel im Vakuum ab, versetzt mit 30 ml Wasser und extrahiert 5 nal mit äe 30 ml Chloroform, das 10 % Äthanol enthält. Man zieht die Extrakte im Vakuum zur Trockne ab, kocht den Rückstand mit Äther aus, löst das Ätherunlösliche in Aceton und versetzt langsam mit Äther. Kali filtriert ab und erhält 0,21 g 14-Hydroxy-3ß-(2'-[2".3"-didesoxy-2"-dehydro-D-glucopyranos-1"-yloxymethyl]-3'.4'-dihydroxy-isobuturyloxy)-5ß.14ß-card -20(22)-enolid vom Schmelzpunkt 170 - 180 °C.It is dissolved in 50 ml of methanol, and 0.47 g of potassium bicarbonate is added to the solution in 15 ml of water and let stand for a week at room temperature. One draws the solvent in vacuo, treated with 30 ml of water and extracted 5 times with ae 30 ml of chloroform, which contains 10% ethanol. The extracts are drawn off to dryness in a vacuum and boiled remove the residue with ether, dissolve the ether-insoluble in acetone and slowly add with ether. Potash is filtered off and 0.21 g of 14-hydroxy-3ß- (2 '- [2 ".3" -dideoxy-2 "-dehydro-D-glucopyranos-1" -yloxymethyl] -3'.4'-dihydroxy is obtained -isobuturyloxy) -5ß.14ß-card -20 (22) -enolide with a melting point of 170 - 180 ° C.
Claims (1)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712110722 DE2110722A1 (en) | 1971-03-04 | 1971-03-04 | Water soluble steroids, hydrophilic substd acetoxy derivs |
| FR7116012A FR2100630A1 (en) | 1970-05-05 | 1971-05-04 | Water soluble steroids, hydrophilic substd acetoxy derivs |
| BE766738A BE766738A (en) | 1970-05-05 | 1971-05-05 | NEW TRIACYLOXYMETHYL-ACETOXYSTEROIDS AND THEIR PREPARATION PROCESS |
| NL7106174A NL7106174A (en) | 1970-05-05 | 1971-05-05 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712110722 DE2110722A1 (en) | 1971-03-04 | 1971-03-04 | Water soluble steroids, hydrophilic substd acetoxy derivs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2110722A1 true DE2110722A1 (en) | 1972-09-07 |
Family
ID=5800703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19712110722 Pending DE2110722A1 (en) | 1970-05-05 | 1971-03-04 | Water soluble steroids, hydrophilic substd acetoxy derivs |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2110722A1 (en) |
-
1971
- 1971-03-04 DE DE19712110722 patent/DE2110722A1/en active Pending
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