NO177594B - New esters of organic acids and alcohols derived from 19-nor-steroids, as well as preparations to prevent conception and abort pregnancy, containing the new esters - Google Patents
New esters of organic acids and alcohols derived from 19-nor-steroids, as well as preparations to prevent conception and abort pregnancy, containing the new esters Download PDFInfo
- Publication number
- NO177594B NO177594B NO940954A NO940954A NO177594B NO 177594 B NO177594 B NO 177594B NO 940954 A NO940954 A NO 940954A NO 940954 A NO940954 A NO 940954A NO 177594 B NO177594 B NO 177594B
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- Norway
- Prior art keywords
- denotes
- carbon atoms
- radical
- compound
- straight
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- 150000002148 esters Chemical class 0.000 title claims description 10
- 230000035935 pregnancy Effects 0.000 title claims description 7
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- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- -1 amine salt Chemical class 0.000 claims description 14
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- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 5
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- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000002036 chloroform fraction Substances 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Chemical class C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Chemical class SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960002433 cysteine Drugs 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 230000012173 estrus Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Chemical class OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000029849 luteinization Effects 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000003623 progesteronic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
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- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
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- 230000000717 retained effect Effects 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940077386 sodium benzenesulfonate Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-M succinate(1-) Chemical compound OC(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
Den foreliggende oppfinnelse angår nye estere av organiske syrer og alkoholer avledet fra 19-nor-steroider, hvilke estere er anvendelige for å hindre befruktning eller avbryte svangerskap. De nye estere er forbindelser med den generelle formel (I): The present invention relates to new esters of organic acids and alcohols derived from 19-nor steroids, which esters are useful for preventing fertilization or terminating pregnancy. The new esters are compounds with the general formula (I):
hvor: where:
G betegner et fenylradikal som eventuelt er substituert med ett eller flere radikaler valgt blant halogenatomer, mettede eller umettede, forgrenede eller rettkjedede alifatiske radikaler inneholdende 1-6 karbonatomer, rettkjedede eller forgrenede acylradikaler inneholdende 1-6 karbonatomer, alkialkjNfO),,,-, alk3S(0)p- eller alk40-, hvor alkx, alk2, alk3 og alk4, som kan være like eller forskjellige, uavhengig av hverandre betegner et hydrogenatom eller et rettkjedet eller forgrenet alkylradikal inneholdende 1-11 karbonatomer, m er 0 eller 1, p er 0, 1 eller 2, G denotes a phenyl radical which is optionally substituted with one or more radicals selected from halogen atoms, saturated or unsaturated, branched or straight-chain aliphatic radicals containing 1-6 carbon atoms, straight-chain or branched acyl radicals containing 1-6 carbon atoms, alkylalkjNfO),,,-, alk3S (0)p- or alk40-, where alkx, alk2, alk3 and alk4, which may be the same or different, independently of each other denote a hydrogen atom or a straight-chain or branched alkyl radical containing 1-11 carbon atoms, m is 0 or 1, p is 0, 1 or 2,
og enten: and either:
X betegner XA, idet XA er et hydrogenatom, et alkylradikal med 1-8 karbonatomer, et arylalkylradikal med 7-15 karbonatomer eller et acylradikal med 1-8 karbonatomer, i hvilke tilfeller Y betegner Ya, idet YA er en gruppe: hvor B betegner et toverdig, rettkjedet eller forgrenet, mettet eller umettet, alifatisk radikal med 1-8 karbonatomer, A betegner enten et toverdig radikal -(CH2)n- hvor n er et tall fra 2 til 6, eller A betegner et toverdig fenylenrådikal og Z betegner én av funksjonene -C00H og -S03H, idet disse funksjoner eventuelt kan foreligge i form av et salt med et X denotes XA, XA being a hydrogen atom, an alkyl radical with 1-8 carbon atoms, an arylalkyl radical with 7-15 carbon atoms or an acyl radical with 1-8 carbon atoms, in which cases Y denotes Ya, with YA being a group: where B denotes a divalent, straight-chain or branched, saturated or unsaturated, aliphatic radical with 1-8 carbon atoms, A denotes either a divalent radical -(CH2)n- where n is a number from 2 to 6, or A denotes a divalent phenylene radical and Z denotes one of the functions -C00H and -S03H, as these functions may possibly exist in the form of a salt with a
alkalimetall eller jordalkalimetall eller som et alkali metal or alkaline earth metal or as a
ammoniumsalt eller et aminsalt, ammonium salt or an amine salt,
eller: or:
X betegner XB, idet XB er en gruppe: X denotes XB, XB being a group:
hvor A og Z er som ovenfor angitt, og Y da betegner YB, idet YB er en gruppe valgt blant -ChC-R4, -CH=CH-R4 og -CH2-CH2-R4, hvor R4 betegner et hydrogenatom, et halogenatom eller et rettkjedet eller forgrenet alkylradikal med 1-6 karbonatomer. where A and Z are as stated above, and Y then denotes YB, YB being a group chosen from -ChC-R4, -CH=CH-R4 and -CH2-CH2-R4, where R4 denotes a hydrogen atom, a halogen atom or a straight-chain or branched alkyl radical with 1-6 carbon atoms.
I den ovenstående formel (I) betegner G fortrinnsvis et fenylradikal som er substituert i 4-stillingen med amino, metylamino, dimetylamino eller dets N-oksyd, dietylamino, di-propylamino, N-metyl-etylamino, N-metyl-isopropylamino, N-metyl-isobutylamino, N-metyl-isopentylamino, formyl, acetyl, metoksy, metyltio, etyltio, isopentyltio, metyl eller isopropyl, eller med et fluor-, klor- eller bromatom. In the above formula (I), G preferably denotes a phenyl radical substituted in the 4-position by amino, methylamino, dimethylamino or its N-oxide, diethylamino, dipropylamino, N-methylethylamino, N-methylisopropylamino, N -methyl-isobutylamino, N-methyl-isopentylamino, formyl, acetyl, methoxy, methylthio, ethylthio, isopentylthio, methyl or isopropyl, or with a fluorine, chlorine or bromine atom.
Når X betegner XA, hvor XA er et alkylradikal, er dette alkylradikal fortrinnsvis metyl, etyl eller propyl. When X denotes XA, where XA is an alkyl radical, this alkyl radical is preferably methyl, ethyl or propyl.
Når X betegner XA, og XA er et arylalkylradikal, er dette arylalkylradikal fortrinnsvis benzyl eller fenetyl. When X denotes XA, and XA is an arylalkyl radical, this arylalkyl radical is preferably benzyl or phenethyl.
Når X betegner XA, og XA er et acylradikal, er dette acylradikal fortrinnsvis formyl, acetyl, propionyl, butyryl eller benzoyl. . B betegner fortrinnsvis enten et mettet toverdig radikal, som f.eks. metylen, etylen, trimetylen eller tetra-metylene, eller et umettet toverdig radikal som f.eks. viny-len, propenylen, butenylen, etynylen, propynylen eller buty-nylen. When X denotes XA, and XA is an acyl radical, this acyl radical is preferably formyl, acetyl, propionyl, butyryl or benzoyl. . B preferably denotes either a saturated divalent radical, such as e.g. methylene, ethylene, trimethylene or tetramethylene, or an unsaturated divalent radical such as e.g. vinylene, propenylene, butenylene, ethynylene, propynylene or butynylene.
Når Z betegner en karboksy- eller sulfogruppe som danner et salt, er det fortrinnsvis tale om et salt av nat-rium, kalium, kalsium, magnesium eller ammonium eller et aminsalt benyttet ved fremstilling av medisiner, som f.eks. sal-tene av lysin, arginin, cystein, betain, carnitin, meglumin, kinin, sarcosin, procain, histidin eller N-metyl-glucamin. Når R4 betegner et alkylradikal, er dette fortrinnsvis metyl, etyl, propyl, butyl, isopropyl eller isobutyl. When Z denotes a carboxy or sulfo group which forms a salt, it is preferably a salt of sodium, potassium, calcium, magnesium or ammonium or an amine salt used in the manufacture of medicines, such as e.g. the salts of lysine, arginine, cysteine, betaine, carnitine, meglumine, quinine, sarcosine, procaine, histidine or N-methyl-glucamine. When R 4 denotes an alkyl radical, this is preferably methyl, ethyl, propyl, butyl, isopropyl or isobutyl.
De nye forbindelser med den generelle formel (I) fremstilles ved en fremgangsmåte hvor: (A) en forbindelse med formel (IIA) eller formel (IIB): hvor XA og G er som ovenfor angitt, og R4a har de betydninger som ovenfor er angitt for R4 samt de tilsvarende betydninger hvor de reaktive funksjoner er beskyttet, (a) omsettes, i et nøytralt oppløsningsmiddel og i nærvær av en base, med en forbindelse med formelen (IIlj^): for dannelse - om nødvendig etter avbeskyttelse av de beskyttede reaktive funksjoner og, om ønskes overføring av karboksy-funksjonen til et salt - av en forbindelse med den generelle formel (I) svarende til henholdsvis formel (IA1) og formel Ubi)<:> hvor Z1 betegner et eventuelt forsaltet karboksyradikal, eller (b) omsettes, i et nøytralt oppløsningsmiddel og i nærvær av en base, med en forbindelse med formel (III2): eller et funksjonelt derivat av denne syre, hvor U betegner en av gruppene -COOH og -CO0R5, hvor R5 betegner et alkylradikal med 1-6 karbonatomer eller et arylalkylradikal med 7-12 karbonatomer eller -SH, for dannelse - om nødvendig etter avbeskyttelse av de beskyttede reaktive funksjoner - av en forbindelse med formel (IVR), henholdsvis (IVB): The new compounds of the general formula (I) are prepared by a process where: (A) a compound of formula (IIA) or formula (IIB): where XA and G are as above, and R4a has the meanings given above for R4 and the corresponding meanings where the reactive functions are protected, (a) is reacted, in a neutral solvent and in the presence of a base, with a compound with the formula (IIlj^): for formation - if necessary after deprotection of the protected reactive functions and, if desired, transfer of the carboxy function to a salt - of a compound of the general formula (I) corresponding to formula (IA1) and formula Ubi) <:> where Z1 denotes an optionally salted carboxy radical, or (b) is reacted, in a neutral solvent and in the presence of a base, with a compound of formula (III2): or a functional derivative of this acid, where U denotes one of the groups -COOH and -CO0R5, where R5 denotes an alkyl radical with 1-6 carbon atoms or an arylalkyl radical with 7-12 carbon atoms or -SH, for formation - if necessary after deprotection of the protected reactive functions - of a compound of formula (IVR), respectively (IVB):
hvilken forbindelse med formel (IVR), henholdsvis (IVB): which compound with formula (IVR), respectively (IVB):
(i) - i det tilfelle hvor U betegner en fri karboksylgruppe, og etter eventuell overføring til et salt - svarer til en forbindelse med formel (IR1), henholdsvis (IB1), (ii) - i det tilfelle hvor U betegner gruppen -COOR5, svarer til en forbindelse med formel (IVC), henholdsvis (IVD): som hydrolyseres eller forsåpes for dannelse av en forbindelse med formel (IR1), henholdsvis (IB1), og (iii) - i det tilfelle hvor U betegner gruppen -SH, svarer til en forbindelse med formel (IVE), henholdsvis (IVF): som oksyderes og om ønskes overføres til et salt for dannelse av en forbindelse med den generelle formel (I), svarende til formel (IA2), henholdsvis (IB2)<:>(i) - in the case where U denotes a free carboxyl group, and after possible transfer to a salt - corresponds to a compound of formula (IR1), respectively (IB1), (ii) - in the case where U denotes the group -COOR5 , corresponds to a compound of formula (IVC), respectively (IVD): which is hydrolyzed or saponified to form a compound of formula (IR1), respectively (IB1), and (iii) - in the case where U denotes the group -SH, corresponds to a compound of formula (IVE), respectively (IVF): which is oxidized and, if desired, transferred to a salt to form a compound with the general formula (I), corresponding to formula (IA2), respectively (IB2)<:>
hvor Z2 betegner en eventuelt forsaltet sulfogruppe, where Z2 denotes an optionally salted sulfo group,
eller or
(c) omsettes, i et nøytralt oppløsningsmiddel og i nærvær av en base, med en forbindelse med formelen (III3): (c) is reacted, in a neutral solvent and in the presence of a base, with a compound of formula (III3):
eller et funksjonelt derivat av denne syre for dannelse - om nødvendig etter avbeskyttelse av de reaktive funksjoner som inneholdes i R4a og om ønskes etter overføring til et salt - av en forbindelse med formel (Ia2), henholdsvis (IB2), or a functional derivative of this acid for the formation - if necessary after deprotection of the reactive functions contained in R4a and if desired after transfer to a salt - of a compound of formula (Ia2), respectively (IB2),
og ved at: and in that:
(B) forbindelsen med formel (IB1), (IB2) eller (IVD) om ønskes underkastes: (a) enten hydrogenering av trippelbindingene for dannelse av den tilsvarende forbindelse med formel (IB3), (IB4)/ henholdsvis (B) the compound of formula (IB1), (IB2) or (IVD) is optionally subjected to: (a) either hydrogenation of the triple bonds to form the corresponding compound of formula (IB3), (IB4)/ respectively
(VD): (CEO):
hvilken forbindelse, om ønskes, underkastes hydrogenering av dobbeltbindingene for dannelse av den respektive forbindelse med formel (IB5), (IB6)/ henholdsvis (VID): eller direkte hydrogenering av trippelbindingene til enkelt-bindinger, for dannelse av den respektive forbindelse med formel (<I>B5), (IB6), henholdsvis (VID), og (b) forbindelsen med formel (VD) eller (VID) enten hydrolyseres eller forsåpes for dannelse av den respektive forbindelse med formel (IB3), henholdsvis (IB5). which compound, if desired, is subjected to hydrogenation of the double bonds to form the respective compound of formula (IB5), (IB6)/ respectively (VID): or direct hydrogenation of the triple bonds to single bonds, to form the respective compound of formula ( <I>B5), (IB6), respectively (VID), and (b) the compound of formula (VD) or (VID) is either hydrolyzed or saponified to form the respective compound of formula (IB3), respectively (IB5).
I henhold til en foretrukken utførelse av den ovenfor beskrevne fremgangsmåte utføres reaksjonen mellom (IIIj) og (IIA) og (IIB) i nærvær av en base og i et nøytralt oppløs-ningsmiddel, idet den hydroksyfunksjon som eventuelt inneholdes i R4, beskyttes i form av en 2-tetrahydropyranyloksygruppe gjennom omsetning med 2,3-dihydropyran. According to a preferred embodiment of the method described above, the reaction between (IIIj) and (IIA) and (IIB) is carried out in the presence of a base and in a neutral solvent, the hydroxy function which may be contained in R4 being protected in the form of a 2-tetrahydropyranyloxy group through reaction with 2,3-dihydropyran.
Den senere avbeskyttelse av denne funksjon foretas ved hjelp av en sulfonisk harpiks (i den sure form) av han-delskvalitet eller ved behandling med syre. Det nøytrale oppløsningsmiddel som tjener som reaksjonsmiljø, kan utgjøres av kloroform, metylenklorid, acetonitril eller etyleter. Basen som benyttes, er fortrinnsvis en nitrogenholdig base, som f.eks. trietylamin, diisopropyletylamin, 4-dimetylaminopyri-din, pyridin eller N-metyl-morfolin. The subsequent deprotection of this function is carried out with the help of a sulphonic resin (in the acidic form) of commercial quality or by treatment with acid. The neutral solvent that serves as the reaction medium can be chloroform, methylene chloride, acetonitrile or ethyl ether. The base used is preferably a nitrogen-containing base, such as e.g. triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine or N-methylmorpholine.
Oksydasjonen av mercaptogruppen til en sulfogruppe foretas ved hjelp av salpetersyre eller bariumnitrat eller ved autooksydasjon i basisk miljø. The oxidation of the mercapto group to a sulpho group is carried out with the help of nitric acid or barium nitrate or by autoxidation in a basic environment.
Midlet for hydrogenering av trippelbindingen til en dobbeltbinding utgjøres av hydrogen i nærvær av en katalysator som f.eks. palladium på bariumsulfat. Midlet for hydrogenering av dobbeltbindinger eller trippelbindinger til enkle bindinger utgjøres av hydrogen i nærvær av en katalysator som f.eks. palladium på aktivt kull eller klor-tris-(trifenylfosfin)-rhodium. The agent for hydrogenating the triple bond to a double bond is constituted by hydrogen in the presence of a catalyst such as e.g. palladium on barium sulfate. The agent for hydrogenating double bonds or triple bonds to single bonds is constituted by hydrogen in the presence of a catalyst such as e.g. palladium on activated carbon or chlorotris-(triphenylphosphine)rhodium.
Med uttrykket funksjonelle derivater av syrene med formel (III2) eller (III3) forstås de anhydrider som fås "in situ" ved innvirkning av et alkylklorformiat, som f.eks. iso-butylklorformiat eller av et dicykloalkylkarbodiimid som f.eks. dicykloheksylkarbodiimid. The term functional derivatives of the acids with formula (III2) or (III3) means the anhydrides which are obtained "in situ" by the action of an alkyl chloroformate, such as e.g. iso-butyl chloroformate or of a dicycloalkylcarbodiimide such as e.g. dicyclohexylcarbodiimide.
Hydrolysen og forsåpningen av funksjonen -COOR5 og forsaltningen av karboksy- eller sulfofunksjonene foretas på den vanlige måte. The hydrolysis and saponification of the -COOR5 function and the salting out of the carboxy or sulfo functions are carried out in the usual way.
I henhold til en foretrukken utførelse av den ovenfor beskrevne analogifremgangsmåte for fremstilling av forbindelser med formel (I') går man frem således at man enten: According to a preferred embodiment of the above-described analogue method for the preparation of compounds of formula (I'), one proceeds such that one either:
a) omsetter forbindelsen med formel (II'a) eller (II'B): a) reacts the compound of formula (II'a) or (II'B):
hvor Rlr R2, R3 og G har de ovenfor angitte betydninger og R'4a har de betydninger som er angitt ovenfor for R'4 samt de betydninger hvor hydroksylfunksjonene er beskyttet, i et nøytralt oppløsningsmiddel og i nærvær av en base, med en forbindelse med formel (III'!): hvor n er et tall fra 2 til 6, for dannelse - om nødvendig etter avbeskyttelse av den beskyttede hydroksylfunksjon som inneholdes i R'4 og, om ønskes, overfører den frie karboksylgruppe til et salt ved innvirkning av en natriumbikarbonatopp-løsning - av henholdsvis forbindelsen med formel eller forbindelsen med formel (I' B1): where R1r R2, R3 and G have the meanings given above and R'4a has the meanings given above for R'4 as well as the meanings where the hydroxyl functions are protected, in a neutral solvent and in the presence of a base, with a compound of formula (III'!): where n is a number from 2 to 6, for formation - if necessary after deprotection of the protected hydroxyl function contained in R'4 and, if desired, transferring the free carboxyl group to a salt by the action of a sodium bicarbonate solution - of respectively the compound with formula or the compound with formula (I' B1):
hvor Z' 1 betegner en fri karboksylgruppe eller dennes natriumsalt, eller where Z' 1 denotes a free carboxyl group or its sodium salt, or
b) omsetter forbindelsen med den ovenfor angitte formel (II'A) med et kompleks av pyridin og en forbindelse med formel b) reacts the compound of the above formula (II'A) with a complex of pyridine and a compound of formula
(III'3)<:>(III'3)<:>
for dannelse - om nødvendig og om ønskes - ved saltdannelse med en natriumbikarbonatoppløsning, av en forbindelse med formelen (I' A2): for formation - if necessary and if desired - by salt formation with a sodium bicarbonate solution, of a compound with the formula (I' A2):
hvor Z'2 betegner en sulfogruppe eller dennes natriumsalt, where Z'2 denotes a sulfo group or its sodium salt,
og at en forbindelse med formel (I' B1) om ønskes omsettes med hydrogen i nærvær av en katalysator for dannelse av forbindelsene med formel (I' B3): and that a compound of formula (I' B1) is, if desired, reacted with hydrogen in the presence of a catalyst to form the compounds of formula (I' B3):
Forbindelsene med formler (IIa) og (IIB) som anvendes ved fremgangsmåten for fremstilling av forbindelsene med formel (I), er generelt kjent, og deres fremstilling er beskrevet i franske patentskrifter nr. 2377418, 2497807, 2522328 og 258434 og europeiske patentskrifter nr. 057115 og 190759. The compounds of formulas (IIa) and (IIB) used in the process for the preparation of the compounds of formula (I) are generally known, and their preparation is described in French patent documents Nos. 2377418, 2497807, 2522328 and 258434 and European patent documents no. 057115 and 190759.
Noen av forbindelsene med formler (Illi), (III2) og (III3) er forbindelser som fås i handelen. De øvrige lar seg fremstille etter metoder som er kjent i faget, se ETAIX, Annales de Chimie (7) 9 s. 371; LOVEN, J. Prakt. Chemie (2) 29 s. 376 og UHLENBROEK, Recueil des Travaux Chimiques des Pays-Bas (1957) 76 s. 129, 142. Some of the compounds of formulas (III), (III2) and (III3) are commercially available compounds. The others can be prepared according to methods known in the field, see ETAIX, Annales de Chimie (7) 9 p. 371; LOVEN, J. Prakt. Chemie (2) 29 p. 376 and UHLENBROEK, Recueil des Travaux Chimiques des Pays-Bas (1957) 76 pp. 129, 142.
Forbindelsene med den generelle formel (I) har inte-ressante egenskaper med hensyn til å hindre befruktning eller avbryte svangerskap. Undersøkelser av forbindelsenes virknin-ger på hormonreseptorene har vist at forbindelsene oppviser progestomimetisk eller anti-progestomimetisk, androgen eller anti-androgen aktivitet. Forbindelsene som oppviser antipro-gestomimetiske egenskaper, kan anvendes for fremstilling av nye befruktningshindrende eller svangerskapsavbrytende midler. The compounds of the general formula (I) have interesting properties with regard to preventing fertilization or terminating pregnancy. Investigations of the effects of the compounds on the hormone receptors have shown that the compounds exhibit progestomimetic or anti-progestomimetic, androgenic or anti-androgenic activity. The compounds which exhibit antiprogestomimetic properties can be used for the production of new contraceptives or pregnancy termination agents.
Forbindelsene ifølge oppfinnelsen kan også anvendes som syklusregulerende midler for kvinner og mer generelt for varmblodige hunndyr. The compounds according to the invention can also be used as cycle regulating agents for women and more generally for warm-blooded female animals.
Forbindelsene administreres i slike tilfeller i de perioder da progesteron spiller en viktig fysiologisk rolle, dvs. spesielt under syklusens luteale fase, på tidspunktet for eggfestingen (eller festingen av fosteret) og under svanger-skapet. En befruktningshindrende metode består i å gi kvinnen minst én av forbindelsene med formel (I) i fra 1 til 5 dager, fortrinnsvis på slutten av syklusen. Disse forbindelser administreres da fortrinnsvis oralt eller vaginalt, men de kan også gies parenteralt. The compounds are administered in such cases during the periods when progesterone plays an important physiological role, i.e. especially during the luteal phase of the cycle, at the time of the egg attachment (or the attachment of the fetus) and during pregnancy. A contraceptive method consists in giving the woman at least one of the compounds of formula (I) for from 1 to 5 days, preferably at the end of the cycle. These compounds are then preferably administered orally or vaginally, but they can also be administered parenterally.
De nye forbindelser kan også gies endonasalt. The new compounds can also be given endonasally.
Forbindelsene kan også anvendes for synkronisering av østrus hos oppdrettsdyr, spesielt storfe og småfe. The compounds can also be used for synchronizing oestrus in farmed animals, especially cattle and small cattle.
Likeledes kan forbindelsene anvendes for å regulere forplantningsdyktigheten hos husdyr, som f.eks. hunder og katter. Likewise, the compounds can be used to regulate the reproduction ability of domestic animals, such as e.g. dogs and cats.
Blant de nye forbindelser skal spesielt nevnes: 21-klor-lip-[4-(dimetylamino)-fenyl]-3-okso-19-nor-17a-pregna-4,9-dien-20-yn-17p-yl-natriumsuccinat, og Among the new compounds, special mention should be made of: 21-chloro-lip-[4-(dimethylamino)-phenyl]-3-oxo-19-nor-17a-pregna-4,9-dien-20-yn-17p-yl- sodium succinate, and
lip-[4-(metyltio)-fenyl]-3-okso-17a-(1-propynyl)-estra-4,9-dien-17 p-yl-natriumsuccinat. lip-[4-(methylthio)-phenyl]-3-oxo-17a-(1-propynyl)-estra-4,9-dien-17 p-yl sodium succinate.
Doseringen varierer med resultatene som ønskes oppnådd og med administreringsmetoden. Dosen kan således variere f.eks. fra 10 mg til 1 g pr. dag for voksne ved oral admini-strering . The dosage varies with the desired results and with the method of administration. The dose can thus vary, e.g. from 10 mg to 1 g per day for adults with oral administration.
De ovenfor angitte nye forbindelser kan anvendes for fremstilling av preparater som inneholder minst én av forbindelsene som aktiv bestanddel. The above-mentioned new compounds can be used for the preparation of preparations containing at least one of the compounds as an active ingredient.
De nye forbindelser anvendes gjennom fordøyelsessys-temet, parenteralt eller lokalt. De kan gies i form av enkle eller dragerte tabletter, granuler, gelatinbelagte stikkpil-ler, injiserbare preparater, pomader, kremer, geler, o.l., som kan anvendes i henhold til de vanlige metoder. The new compounds are used through the digestive system, parenterally or locally. They can be given in the form of simple or coated tablets, granules, gelatin-coated suppositories, injectable preparations, pomades, creams, gels, etc., which can be used according to the usual methods.
Den eller de aktive bestanddeler kan blandes med de eksipienter som det er vanlig å benytte i slike preparater, f.eks. med talk, gummi arabicum, laktose, stivelse, magnesium-stearat, kakaosmør, vandige eller ikke-vandige bærere, fett-stoffer av animalsk eller vegetabilsk opprinnelse, paraffin-derivater, glykoler, diverse fuktemidler, dispergeringsmidler eller emulgeringsmidler og konserveringsmidler. The active ingredient(s) can be mixed with the excipients that are commonly used in such preparations, e.g. with talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fats of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersing agents or emulsifying agents and preservatives.
De nye forbindelser med den generelle formel I hvor Z betegner en forsaltet karboksy- eller sulfogruppe, og spesielt forbindelser med formel (I') hvor Z' betegner -COONa eller -S03Na er meget vannoppløselige. Det kan f.eks. nevnes at forbindelsen ifølge eksempel 18 nedenfor har en oppløselighet som er enn 25 g pr. 100 ml vann. Dette gjør det mulig å anvende disse forbindelser i form av oppløsninger som er drikkbare eller som kan tas gjennom nesen eller ørene, eller i form av et collyrium eller i form av aerosoler, injiserbare oppløs-ninger (IM eller IV) eller i form av kapsler. The new compounds of the general formula I where Z denotes a salted carboxy or sulfo group, and especially compounds of formula (I') where Z' denotes -COONa or -SO3Na are very water soluble. It can e.g. it is mentioned that the compound according to example 18 below has a solubility which is less than 25 g per 100 ml of water. This makes it possible to use these compounds in the form of solutions that are drinkable or that can be taken through the nose or ears, or in the form of a collyrium or in the form of aerosols, injectable solutions (IM or IV) or in the form of capsules .
Eksemplene og redegjørelsen for egenskaper som er gitt nedenfor, illustrerer oppfinnelsen. The examples and description of properties given below illustrate the invention.
Eksempel 1 Example 1
Fremstilling av ( Z)- 3- 1" 11B- T4-( dimetylamino)- fenvll- 17B- hvd-roksy- 3- okso- estra- 4, 9- dien- 17a- vn- 2- propenvl- hvdrogensuc-cinat. Preparation of (Z)-3-1"11B-T4-(dimethylamino)-phenyl-17B-hvd-roxy-3-oxo-estra-4,9-diene-17a-vn-2-propenvl-hvdrogensuccinate.
I en kolbe utstyrt med en magnetisk rører oppløses 900 mg llB-[4-(dimetylamino)-fenyl]-17B-hydroksy-17a-[(Z)-3-hydroksy-l-propenyl]-estra-4,9-dien-3-on i 9 ml kloroform, hvoretter det tilsettes 304 mg ravsyreanhydrid og 1,45 ml trietylamin. Den dannede blanding omrøres i 15 timer ved romtemperatur, hvoretter den inndampes til tørrhet. De oppnådde 1,443 g residuum renses ved kromatografering på en silikakolonne [elueringsmiddel: (90 deler etylacetat-10 deler cyklo-heksan) eddiksyre 3%]. Etter omkrystallisering fra en blanding av metanol og vann (60-40) fås 695 mg av den ønskede forbindelse i form av gule krystaller. Smeltepunkt ca. 145°C. Ved tynnskiktkromatografering oppnås Rf = ,60 (bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). In a flask equipped with a magnetic stirrer, dissolve 900 mg of 11B-[4-(dimethylamino)-phenyl]-17B-hydroxy-17a-[(Z)-3-hydroxy-1-propenyl]-estra-4,9-diene -3-one in 9 ml of chloroform, after which 304 mg of succinic anhydride and 1.45 ml of triethylamine are added. The resulting mixture is stirred for 15 hours at room temperature, after which it is evaporated to dryness. The obtained 1.443 g of residue is purified by chromatography on a silica column [eluent: (90 parts ethyl acetate-10 parts cyclohexane) acetic acid 3%]. After recrystallization from a mixture of methanol and water (60-40), 695 mg of the desired compound are obtained in the form of yellow crystals. Melting point approx. 145°C. By thin-layer chromatography, Rf = .60 is obtained (carrier: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 2 Example 2
Fremstilling av ( Z)- 3- rilB- r4-( dimetylamino)- fenvl1- 17p- hyd-roksv- 3- okso- estra- 4, 9- dien- 17a- vll- 2- propenyl- natriumsuccinat. Preparation of (Z)-3-arylB-r4-(dimethylamino)-phenyl1-17p-hydroxy-3-oxo-estra-4,9-diene-17a-vll-2-propenyl- sodium succinate.
I en kolbe utstyrt med en magnetisk rører oppløses 93 mg natriumbikarbonat i 20 ml vann. Det tildryppes så en oppløsning av 639 mg av forbindelsen fremstilt i eksempel 1 i 20 ml etanol. Etanolen fjernes ved azeotropdestillasjon, og den derved oppnådde vandige oppløsning filtreres gjennom en 0,45 um membran "Millipore", hvoretter den frysetørres. Det oppnås 654 mg av den ønskede forbindelse i form av et kremfar-get pulver. [a]D = +101° ±2° (c = 1%). Ved tynnskiktkromatografering oppnås Rf = 0,62. (bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). In a flask equipped with a magnetic stirrer, dissolve 93 mg of sodium bicarbonate in 20 ml of water. A solution of 639 mg of the compound prepared in Example 1 in 20 ml of ethanol is then added dropwise. The ethanol is removed by azeotropic distillation, and the aqueous solution thus obtained is filtered through a 0.45 µm "Millipore" membrane, after which it is freeze-dried. 654 mg of the desired compound is obtained in the form of a cream-coloured powder. [a]D = +101° ±2° (c = 1%). By thin-layer chromatography, Rf = 0.62 is obtained. (carrier: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 3 Example 3
Fremstilling av 3- rilB- r4-( dimetylamino)- fenyl1- 17B- hvdroksv-3- okso- estra- 4. 9- dien- 17a- yl1- 2- propynyl- hydrogensuccinat. Preparation of 3-rylB-r4-(dimethylamino)-phenyl1-17B-hydroxy-3-oxo-estra-4.9-dien-17a-yl1-2-propynyl-hydrogensuccinate.
I en kolbe utstyrt med en magnetisk rører oppløses 900 mg lip-[4-(dimetylamino)-fenyl]-17p-hydroksy-17a-(3-hyd-roksy-l-propynyl)-estra-4,9-dien-3-on i 9 ml kloroform. Det tilsettes deretter 303 mg ravsyreanhydrid og 1,4 ml trietylamin, og den derved oppnådde blanding omrøres i 17 timer ved romtemperatur. Etter inndampning til tørrhet renses de oppnådde 1,685 g uren forbindelse ved kromatografering på en kolonne av "Bondapack C18" (idet det elueres med en 60-40 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Det fås derved 1,104 g av den ønskede forbindelse. Rf = 0,63 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). In a flask equipped with a magnetic stirrer, dissolve 900 mg of lip-[4-(dimethylamino)-phenyl]-17β-hydroxy-17α-(3-hydroxy-1-propynyl)-estra-4,9-dien-3 -one in 9 ml of chloroform. 303 mg of succinic anhydride and 1.4 ml of triethylamine are then added, and the resulting mixture is stirred for 17 hours at room temperature. After evaporation to dryness, the obtained 1.685 g of impure compound is purified by chromatography on a "Bondapack C18" column (eluting with a 60-40 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate). 1.104 g of the desired compound is thereby obtained. Rf = 0.63 (thin layer chromatography; support: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 4 Example 4
Fremstilling av 3- flip- r4-( dimetylamino)- feny11- 17p- hydroksy-3- okso- estra- 4, 9- dien- 17a- vn- 2- propynyl- natriumsuccinat. Preparation of 3-flip-r4-(dimethylamino)-phenyl-11-17p-hydroxy-3-oxo-estra-4,9-diene-17a-vn-2-propynyl- sodium succinate.
Man går frem på samme måte som i eksempel 2, idet man benytter 141 mg natriumbikarbonat i 29 ml vann og 964 mg av forbindelsen fremstilt i eksempel 3 i 29 ml etanol. Det fås derved 935 mg av den ønskede forbindelse. [a]D = +55° ± 1,5° (c = 1% i vann). The procedure is the same as in example 2, using 141 mg of sodium bicarbonate in 29 ml of water and 964 mg of the compound prepared in example 3 in 29 ml of ethanol. 935 mg of the desired compound is thereby obtained. [a]D = +55° ± 1.5° (c = 1% in water).
Rf = 0,63 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.63 (thin layer chromatography; support: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 5 Example 5
Fremstilling av llB- r4-( dimetvlamino)- fenyl"|- 3- okso- 17a-( l-propvnyl)- estra- 4. 9- dien- 17B- vl- hvdrogensuccinat. Preparation of 11B-r4-(dimethylamino)-phenyl"|-3-oxo-17a-(1-propynyl)-estra-4.9-diene-17B-vl-hydrogen succinate.
Reaksjonsblandingen tilberedes ved at 2,15 g ravsyreanhydrid, 2,2 ml trietylamin og 215 mg 4-(dimetylamino)-pyridin tilsettes til en oppløsning av 2,15 g lip-[4-(dimetylamino) -f enyl] -17p-hydroksy-17a-(1-propynyl)-estra-4,9-dien-3-on i 22 ml kloroform. Blandingen kokes deretter med tilbake-løpskjøling i 42 timer, og det tilsettes så 430 mg 4-(dimetylamino) -pyridin og 4,4 ml trietylamin. Kokingen med tilbake-løpskjøling fortsettes i 26 timer, hvoretter oppløsningen helles over i en blanding av vann og is. Etter dekantering av den organiske fase blir denne vasket med vann og deretter tørket. Kloroformen avdestilleres, hvorved det oppnås en brunfarget, tørr ekstrakt. Den vandige fase surgjøres med 0,5 M saltsyre og nøytraliseres deretter gjennom tilsetning av natriumacetat. Det foretas på ny ekstraksjon med etylacetat, og den nye organiske fase vasket med vann og tørkes. Etter avdestillering av oppløsningsmidlet fås et residuum som føres sammen med det tidligere oppnådde. Produktet renses på en silikakolonne, idet det elueres med en 9-1 blanding av eter og etylacetat inneholdende 3% eddiksyre. Det foretas omkrystallisering to ganger fra en blanding av eter og metylenklorid. Det oppnås derved 1,435 g av den ønskede forbindelse. Smeltepunkt ca. 165°C. [a]D = +97° (c = 0,8% i CHC13). The reaction mixture is prepared by adding 2.15 g of succinic anhydride, 2.2 ml of triethylamine and 215 mg of 4-(dimethylamino)-pyridine to a solution of 2.15 g of lip-[4-(dimethylamino)-phenyl]-17p-hydroxy -17α-(1-propynyl)-estra-4,9-dien-3-one in 22 ml of chloroform. The mixture is then refluxed for 42 hours, and 430 mg of 4-(dimethylamino)-pyridine and 4.4 ml of triethylamine are then added. Boiling with reflux cooling is continued for 26 hours, after which the solution is poured into a mixture of water and ice. After decanting the organic phase, this is washed with water and then dried. The chloroform is distilled off, whereby a brown-coloured, dry extract is obtained. The aqueous phase is acidified with 0.5 M hydrochloric acid and then neutralized by adding sodium acetate. Extraction is carried out again with ethyl acetate, and the new organic phase is washed with water and dried. After distilling off the solvent, a residue is obtained which is taken together with the previously obtained. The product is purified on a silica column, eluting with a 9-1 mixture of ether and ethyl acetate containing 3% acetic acid. Recrystallization is carried out twice from a mixture of ether and methylene chloride. 1.435 g of the desired compound is thereby obtained. Melting point approx. 165°C. [α]D = +97° (c = 0.8% in CHCl 3 ).
Rf = ca. 0,40 (tynnskiktkromatografering; bærer: Si02; elueringsmiddel : 9 deler etylacetat og 1 del 3% eddiksyre). Rf = approx. 0.40 (thin layer chromatography; support: SiO2; eluent: 9 parts ethyl acetate and 1 part 3% acetic acid).
Eksempel 6 Example 6
Fremstilling av 11B- T4-( dimetylamino)- fenyl 1 - 3- okso- 17a-( 1-propynyl)- estra- 4, 9- dien- 17p- yl- natriumsuccinat. Preparation of 11B-T4-(dimethylamino)-phenyl 1-3-oxo-17a-(1-propynyl)-estra-4,9-diene-17p-yl- sodium succinate.
I en kolbe utstyrt med en magnetisk rører innføres 3 g av forbindelsen fremstilt i eksempel 5 og 94 ml etanol, hvoretter det innføres en oppløsning av 433 mg natriumbikarbonat i 94 ml vann. Etter omrøring i 30 minutter ved romtemperatur avdrives etanolen ved azeotropdestillasjon. Den tilbakeblivende oppløsning filtreres gjennom en 0,45 um "Millipore" membran og frysetørres. Det oppnås derved 2,88 g av den ønskede forbindelse. 3 g of the compound prepared in Example 5 and 94 ml of ethanol are introduced into a flask equipped with a magnetic stirrer, after which a solution of 433 mg of sodium bicarbonate in 94 ml of water is introduced. After stirring for 30 minutes at room temperature, the ethanol is driven off by azeotropic distillation. The remaining solution is filtered through a 0.45 µm "Millipore" membrane and freeze-dried. 2.88 g of the desired compound is thereby obtained.
[a]D = +48,5° + 1,5° (c = 1% i vann). [a]D = +48.5° + 1.5° (c = 1% in water).
Rf = 0,54 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.54 (thin layer chromatography; carrier: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 7 Example 7
Fremstilling av lip- T4-( dimetylamino)- fenyll- 3- okso- 17a- 1" ( Z)-1- propenyl)- estra- 4. 9- dien- 17B- yl- hvdrogensuccinat. Preparation of lip-T4-(dimethylamino)-phenyl-3-oxo-17a-1"(Z)-1-propenyl)-estra-4.9-dien-17B-yl-hydrogen succinate.
I en kolbe utstyrt med en magnetisk rører innføres 2,462 g av forbindelsen fremstilt i eksempel 5, og det tilsettes 150 ml etylacetat inneholdende 2% pyridin, samt 15 ml vann og 50 mg 10% palladiumhydroksyd på bariumsulfat. Etter hydrogenering under omrøring i 5,5 timer filtreres reaksjonsblandingen, hvoretter pyridinet avdrives og den tilbakeblivende oppløsning inndampes til tørrhet. Det oppnådde residuum renses ved to på hverandre følgende kromatograferinger på en kolonne av "Bondapack C 18", idet det elueres med en 65-35 blanding av metanol og en 0,05 M vandig ammoniumacetatoppløsning. Det oppnås derved 576 mg av den ønskede forbindelse. Rf = 0,50 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). 2.462 g of the compound prepared in example 5 are introduced into a flask equipped with a magnetic stirrer, and 150 ml of ethyl acetate containing 2% pyridine, as well as 15 ml of water and 50 mg of 10% palladium hydroxide on barium sulphate are added. After hydrogenation with stirring for 5.5 hours, the reaction mixture is filtered, after which the pyridine is driven off and the remaining solution is evaporated to dryness. The obtained residue is purified by two consecutive chromatography on a "Bondapack C 18" column, eluting with a 65-35 mixture of methanol and a 0.05 M aqueous ammonium acetate solution. 576 mg of the desired compound is thereby obtained. Rf = 0.50 (thin layer chromatography; support: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 8 Example 8
Fremstilling av lip- r4-( dimetylamino)- fenvn- 3- okso- 17a- r( Z)-1- propenyl)- estra- 4. 9- dien- 17B- yl- natriumsuccinat. Preparation of lip-r4-(dimethylamino)-phenvn-3-oxo-17a-r(Z)-1-propenyl)-estra-4.9-dien-17B-yl sodium succinate.
Ved at man går frem på samme måte som i eksempel 2, idet man anvender en oppløsning av 100 mg natriumbikarbonat i 21 ml vann og 665 mg av forbindelsen fremstilt i eksempel 7 i By proceeding in the same way as in example 2, using a solution of 100 mg of sodium bicarbonate in 21 ml of water and 665 mg of the compound prepared in example 7 in
21 ml etanol, fås 583 mg av den ønskede forbindelse. 21 ml of ethanol, 583 mg of the desired compound are obtained.
[a]D = +56,5° ± 1,5° (c = 1% i vann). [a]D = +56.5° ± 1.5° (c = 1% in water).
Rf = 0,50 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig Rf = 0.50 (thin layer chromatography; support: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous
0,05 M oppløsning av ammoniumacetat). 0.05 M solution of ammonium acetate).
Eksempel 9 Example 9
Fremstilling av 21- klor- llB- r4-( dimetvlamino)- fenyl~ l- 3- okso-19- nor- 17a- pregna- 4, 9- dien- 20- yn- 17B- yl- hydrogensuccinat. Preparation of 21-chloro-11B-r4-(dimethylamino)-phenyl~1-3-oxo-19-nor-17a-pregna-4,9-dien-20-yn-17B-yl-hydrogensuccinate.
I en kolbe utstyrt med en magnetisk rører oppløses 1,854 g 21-klor-llB-[4-(dimetylamino)-fenyl]-17B-hydroksy-17a-pregna-4,9-dien-20-yn-3-on i 18,5 ml kloroform, hvoretter det tilsettes 2,497 g ravsyreanhydrid, 7 ml trietylamin og 0,936 g 4-(dimetylamino)-pyridin. Blandingen kokes med tilbakeløpskjø-ling i 42 timer, hvoretter den helles over i 31 ml 2 N saltsyre. Ph-verdien bringes så tilbake til 6-7 gjennom tilsetning av natriumacetat. Kloroformfasen fraskilles, hvoretter det på ny ekstraheres to ganger med kloroform. De oppnådde ekstrakter slås sammen, vaskes med vann og tørkes over natriumsulfat, hvoretter de konsentreres under redusert trykk. Det oppnås 3,85 g av et mørkebrunt residuum, som renses ved kromatografering på en kolonne av silikagel under eluering først med etyleter og deretter med etyleter inneholdende 3% eddiksyre. Det oppnås 1,8 g råprodukt, som omrkystalliseres fra en blanding av metylenklorid og etyleter og deretter fra en blanding av metylenklorid og etyleter. Det fås derved 1,21 g av den ønskede forbindelse. Smeltepunkt ca. 165°C. In a flask equipped with a magnetic stirrer, 1.854 g of 21-chloro-11B-[4-(dimethylamino)-phenyl]-17B-hydroxy-17a-pregna-4,9-dien-20-yn-3-one is dissolved in 18 .5 ml of chloroform, after which 2.497 g of succinic anhydride, 7 ml of triethylamine and 0.936 g of 4-(dimethylamino)-pyridine are added. The mixture is boiled with reflux cooling for 42 hours, after which it is poured into 31 ml of 2 N hydrochloric acid. The pH value is then brought back to 6-7 through the addition of sodium acetate. The chloroform phase is separated, after which it is again extracted twice with chloroform. The extracts obtained are combined, washed with water and dried over sodium sulfate, after which they are concentrated under reduced pressure. 3.85 g of a dark brown residue is obtained, which is purified by chromatography on a column of silica gel eluting first with ethyl ether and then with ethyl ether containing 3% acetic acid. 1.8 g of crude product is obtained, which is recrystallized from a mixture of methylene chloride and ethyl ether and then from a mixture of methylene chloride and ethyl ether. 1.21 g of the desired compound is thereby obtained. Melting point approx. 165°C.
[a]D = +63° ± 1,5° (c = 1% i CHC13). [a]D = +63° ± 1.5° (c = 1% in CHCl 3 ).
Ved tynnskiktkromatografering fås Rf = 0,53 (bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). By thin-layer chromatography, Rf = 0.53 is obtained (carrier: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 10 Example 10
Fremstillin<g> av 21- klor- llB- r4-( dimetylamino)- fenyll- 3- okso-19- nor- 17a- pregna- 4. 9- dien- 20- yn- 17B- yl- natriumsuccinat. Preparation of 21-chloro-11B-r4-(dimethylamino)-phenyl-3-oxo-19-nor-17a-pregna-4.9-dien-20-yn-17B-yl sodium succinate.
I en kolbe utstyrt med en magnetisk rører blandes 817 mg av forbindelsen fremstilt i eksempel 9 og 25 ml etanol. Det tildryppes så 113 mg natriumbikarbonat i 25 ml vann, hvoretter reaksjonsblandingen omrøres i 30 minutter ved romtemperatur. Etanolen fjernes deretter ved azeotropdestillasjon, og den tilbakeblivende oppløsning filtreres gjennom en 0,45 um "Millipore" membran, hvoretter den frysetørkes. Det oppnås 813 mg produkt bestående av den ønskede forbindelse. In a flask equipped with a magnetic stirrer, 817 mg of the compound prepared in Example 9 and 25 ml of ethanol are mixed. 113 mg of sodium bicarbonate are then added dropwise in 25 ml of water, after which the reaction mixture is stirred for 30 minutes at room temperature. The ethanol is then removed by azeotropic distillation, and the remaining solution is filtered through a 0.45 µm "Millipore" membrane, after which it is freeze-dried. 813 mg of product consisting of the desired compound is obtained.
[a]D = +16,5° ±1° (c = 1% i H20). [a]D = +16.5° ±1° (c = 1% in H20).
Rf = 0,54 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.54 (thin layer chromatography; carrier: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 11 Example 11
Fremstilling av 11B- r4-( metyltio)- fenyl1- 3- okso- 17a-( 1- propy-nyl)- estra- 4, 9- dien- 17B- vl- hvdrogensuccinat. Preparation of 11B-r4-(methylthio)-phenyl1-3-oxo-17a-(1-propynyl)-estra-4,9-diene-17B-vl-hydrogen succinate.
I en kolbe utstyrt med en magnetisk rører og en kjø-ler blandes 1,5 g 17B-hydroksy-llB-[4-(metyltio)-fenyl]-17a-(1-propynyl)-estra-4,9-dien-3-on og 15,3 ml kloroform, hvoretter det tilsettes 1,86 g ravsyreanhydrid, 6 ml trietylamin og 794 mg 4-(dimetylamino)-pyridin, og det hele kokes med til-bakeløpskjøling i 94 timer, helles over i 1 N saltsyre og ekstraheres med kloroform. Kloroformfasen vaskes med vann og tør-kes over natriumsulfat, og oppløsningsmidlet fjernes under In a flask equipped with a magnetic stirrer and a cooler, 1.5 g of 17B-hydroxy-11B-[4-(methylthio)-phenyl]-17a-(1-propynyl)-estra-4,9-diene- 3-one and 15.3 ml of chloroform, after which 1.86 g of succinic anhydride, 6 ml of triethylamine and 794 mg of 4-(dimethylamino)-pyridine are added, and the whole is refluxed for 94 hours, poured into 1 N hydrochloric acid and extracted with chloroform. The chloroform phase is washed with water and dried over sodium sulphate, and the solvent is removed below
redusert trykk ved 40°C. Det oppnås 2,26 g urent produkt som kromatograferes på en kolonne av silikagel "Kieselgel 60H" reduced pressure at 40°C. 2.26 g of impure product is obtained which is chromatographed on a column of silica gel "Kieselgel 60H"
(elueringsmiddel: 97,6 deler metylenklorid og 2,5 deler metanol, med 1% eddiksyre). Etter omkrystallisering fra en blanding av metylenklorid og isopropyleter fås 826 mg krystaller av den ønskede forbindelse. Smeltepunkt 158°C. (eluent: 97.6 parts methylene chloride and 2.5 parts methanol, with 1% acetic acid). After recrystallization from a mixture of methylene chloride and isopropyl ether, 826 mg of crystals of the desired compound are obtained. Melting point 158°C.
Rf = 0,61 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 70-30 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.61 (thin layer chromatography; support: KC 18 "Whatman": eluent: a 70-30 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 12 Example 12
Fremstilling av llB- r4-( metvltio)- fenvn- 3- okso- 17a-( l- propy-nvl)- estra- 4. 9- dien- 17B- vl- natriumsuccinat. Preparation of 11B-r4-(methylthio)-phenvn-3-oxo-17a-(1-propy-nvl)-estra-4.9-diene-17B-vl- sodium succinate.
Ved at man går frem på samme måte som i eksempel 2, men benytter 108 mg natriumbikarbonat i 21,5 ml vann og 719 mg av forbindelsen fremstilt i eksempel 11 i 21,5 ml etanol, fås 720 mg av et lyofilisat svarende til den ønskede forbindelse. By proceeding in the same way as in example 2, but using 108 mg of sodium bicarbonate in 21.5 ml of water and 719 mg of the compound prepared in example 11 in 21.5 ml of ethanol, 720 mg of a lyophilisate corresponding to the desired connection.
[a]D = +74,5° ± 1,5° (c = 1% i vann). [a]D = +74.5° ± 1.5° (c = 1% in water).
Rf = 0,61 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 70-30 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.61 (thin layer chromatography; support: KC 18 "Whatman": eluent: a 70-30 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 13 Example 13
Fremstilling av 3- T3- TUB- T4-( dimetylamino)- fenvll- 17B- hvdrok-sy- 3- okso- estra- 4. 9- dien- 17a- vl1- 2- propynvloksykarbonvll- ben-zensulfonsyre. 1 g 11B-[4-(dimetylamino)-fenyl]-17B-hydroksy-17a-(3-hydroksy-l-propynyl)-estra-4,9-dien-3-on oppløses i 10 ml kloroform, og det tilsettes 1,5 g av komplekset pyridin-3-(klorsulfonyl)-benzoesyre og deretter 1,25 ml trietylamin. Blandingen kokes med tilbakeløpskjøling i 45 minutter, hvoretter det på ny tilsettes 0,5 g av det nevnte kompleks og kokingen med tilbakeløpskjøling fortsettes i 30 minutter. Etter avkjøling og avdampning av oppløsningsmidlet oppløses i resi-duet i vann. Oppløsningen destilleres så i nærvær av toluen. Den oppnådde tørre ekstrakt oppløses i kloroform og filtreres gjennom en silikakolonne, idet det elueres med kloroform inneholdende 5% etanol og deretter med kloroform inneholdende 10% etanol. Den sure fraksjon oppsamles, og det isoleres fra denne 1,7 g av den ønskede forbindelse i form av en blekgul harpiks. Preparation of 3-T3-TUB-T4-(dimethylamino)-phenvll-17B-hydroxy-3-oxo-estra-4.9-diene-17a-vl1-2-propynevloxycarbonvll-benzenesulfonic acid. 1 g of 11B-[4-(dimethylamino)-phenyl]-17B-hydroxy-17a-(3-hydroxy-1-propynyl)-estra-4,9-dien-3-one is dissolved in 10 ml of chloroform, and it is added 1.5 g of the complex pyridine-3-(chlorosulfonyl)-benzoic acid and then 1.25 ml of triethylamine. The mixture is boiled under reflux for 45 minutes, after which 0.5 g of the said complex is added again and the reflux is continued for 30 minutes. After cooling and evaporation of the solvent, the residue dissolves in water. The solution is then distilled in the presence of toluene. The dry extract obtained is dissolved in chloroform and filtered through a silica column, eluting with chloroform containing 5% ethanol and then with chloroform containing 10% ethanol. The acidic fraction is collected, and 1.7 g of the desired compound is isolated from this in the form of a pale yellow resin.
Eksempel 14 Example 14
Fremstilling av 3- r3- rilB- r4-( dimetvlamino)- fenyl1- 17B- hvdrok-sy- 3- okso- estra- 4. 9- dien- 17a- yll- 2- propynvloksykarbonyll- nat-riumbenzensulfonat. 25 ml av en etanolisk oppløsning av natriumacetat (0,24 mmol/ml) tilsettes til den sure fraksjon som ble oppnådd i det foregående eksempel, og den derved dannede oppløsning inndampes til tørrhet. Den tørre ekstrakt tas opp i metanol inneholdende 33% vann, og det foretas kromatografering på en kolonne av "Lichrosorb KC 18" [elueringsmidler: metanol-vann (3-6), metanol-vann (1-1) og deretter metanol-vann (6-3)]. Elueringsmidlene omgrupperes, filtreres på ny og inndampes til tørrhet, og det oppnådde pulver tørkes, hvorved det oppnås 1,35 g av den ønskede forbindelse. [a]jD = 107° (c = 0,2 i etanol). Preparation of 3-r3-arylB-r4-(dimethylamino)-phenyl1-17B-hydroxy-3-oxo-estra-4.9-diene-17a-yl-2-propynyloxycarbonyl-sodium benzenesulfonate. 25 ml of an ethanolic solution of sodium acetate (0.24 mmol/ml) is added to the acidic fraction obtained in the previous example, and the resulting solution is evaporated to dryness. The dry extract is taken up in methanol containing 33% water, and chromatography is carried out on a column of "Lichrosorb KC 18" [eluents: methanol-water (3-6), methanol-water (1-1) and then methanol-water (6-3)]. The eluents are regrouped, filtered again and evaporated to dryness, and the powder obtained is dried, whereby 1.35 g of the desired compound is obtained. [α]jD = 107° (c = 0.2 in ethanol).
Mikroanalyse: Microanalysis:
Eksempel 15 Example 15
Fremstilling av lip-( 4- acetylfenyl)- 3- okso- 17a-( 1- propynyl)-estra- 4. 9- dien- 17B- yl- hydrogensuccinat. Preparation of lip-(4-acetylphenyl)-3-oxo-17a-(1-propynyl)-estra-4.9-dien-17B-yl hydrogensuccinate.
1,8 g lip-(4-acetylfenyl)-17p-hydroksy-17a-(l-propy-nyl)-estra-4,9-dien-3-on oppløses i 18 ml kloroform, hvoretter det tilsettes 2,54 g ravsyreanhydrid, 7 ml trietylamin og 0,95 g 4-dimetylamino-pyridin. Oppløsningen kokes med tilbakeløps-kjøling og holdes ved denne temperatur i 70 timer. Etter av-kjøling til romtemperatur helles reaksjonsblandingen over i 2 N saltsyre, og det foretas ekstraksjon med kloroform. Den organiske fase vaskes med vann, tørkes over natriumsulfat og inndampes til tørrhet i vakuum. Det derved oppnådde råprodukt kromatograferes på en silikakolonne "Kieselgel 60", under eluering først med etyleter og deretter med etyleter inneholdende 3% eddiksyre. Det fås 1,37 g råprodukt som renses ved krystallisering fra en blanding av metylenklorid og etyleter og deretter omkrystallisering fra den samme blanding. Det oppnås derved 1,027 g av den ønskede forbindelse. Smeltepunkt ca.l68°C. 1.8 g of lip-(4-acetylphenyl)-17p-hydroxy-17a-(1-propynyl)-estra-4,9-dien-3-one are dissolved in 18 ml of chloroform, after which 2.54 g are added succinic anhydride, 7 ml of triethylamine and 0.95 g of 4-dimethylamino-pyridine. The solution is boiled with reflux cooling and kept at this temperature for 70 hours. After cooling to room temperature, the reaction mixture is poured into 2 N hydrochloric acid, and extraction is carried out with chloroform. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is chromatographed on a silica column "Kieselgel 60", eluting first with ethyl ether and then with ethyl ether containing 3% acetic acid. 1.37 g of crude product is obtained which is purified by crystallization from a mixture of methylene chloride and ethyl ether and then recrystallization from the same mixture. 1.027 g of the desired compound is thereby obtained. Melting point approx.168°C.
Rf = 0,32 (tynnskiktkromatografering; bærer: Si02F254 "Merck 60"; elueringsmiddel: en blanding av etyleter og etylacetat (90-10), inneholdende 3% eddiksyre). Rf = 0.32 (thin layer chromatography; support: SiO 2 F 254 "Merck 60"; eluent: a mixture of ethyl ether and ethyl acetate (90-10), containing 3% acetic acid).
Eksempel 16 Example 16
Fremstilling av lip-( 4- acetylfenyl)- 3- okso- 17a-( l- propynvl)-estra- 4. 9- dien- 17 B- vl- natriumsuccinat. Preparation of lip-(4-acetylphenyl)-3-oxo-17a-(1-propynvl)-estra-4.9-diene-17B-vl- sodium succinate.
0,874 g av forbindelsen fremstilt i eksempel 15 oppløses i 30 ml etanol. Denne oppløsning dryppes til en oppløsning av 0,132 g natriumbikarbonat i 30 ml vann. Etanolen fjernes så ved azeotropdestillasjon, og den derved oppnådde vandige oppløsning filtreres gjennom en 0,45 pm "Millipore" membran, hvoretter den frysetørres. Det fås derved 0,908 g av det ønskede natriumsalt. 0.874 g of the compound prepared in example 15 is dissolved in 30 ml of ethanol. This solution is dripped into a solution of 0.132 g of sodium bicarbonate in 30 ml of water. The ethanol is then removed by azeotropic distillation, and the aqueous solution thus obtained is filtered through a 0.45 µm "Millipore" membrane, after which it is freeze-dried. 0.908 g of the desired sodium salt is thereby obtained.
[a]D = +67° ± 1,5° (c = 1% i vann). [a]D = +67° ± 1.5° (c = 1% in water).
Rf = 0,73 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.73 (thin layer chromatography; support: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 17 Example 17
Fremstilling av llB- r4-( N- metyl- isopropylamino)- fenvl1- 3- okso-17a-( 1- propynyl)- estra- 4. 9- dien- 17B- vl- hvdrogensuccinat. Preparation of 11B-r4-(N-methyl-isopropylamino)-phenyl1-3-oxo-17a-(1-propynyl)-estra-4.9-diene-17B-v1-hydrogen succinate.
En oppløsning inneholdende 2,159 g llB-[4-(N-metyl-isopropylamino)-fenyl]-17B-hydroksy-17a-(1-propynyl)-estra-4,9-dien-3-on, 22 ml trietylamin, 2,52 g ravsyreanhydrid, A solution containing 2.159 g of 11B-[4-(N-methyl-isopropylamino)-phenyl]-17B-hydroxy-17a-(1-propynyl)-estra-4,9-dien-3-one, 22 ml of triethylamine, 2 .52 g of succinic anhydride,
8,1 ml trietylamin og 1,07 g 4-dimetylamino-pyridin kokes med tilbakeløpskjøling og holdes ved denne temperatur i 24 timer. Det tilsettes så 0,339 g ravsyreanhydrid og kokingen med til-bakeløpskjøling fortsettes i 74 timer. Etter avkjøling helles reaksjonsblandingen over i 36 ml 2 N saltsyre og Ph-verdien innstilles på 6 ved tilsetning av natriumacetat. Etter dekantering av den organiske fase ekstraheres den vandige fase på ny med kloroform. Kloroformfåsene slås sammen og vaskes med vann, hvoretter de tørkes over natriumsulfat og inndampes til tørrhet i vakuum. Det oppnådde residuum kromatograferes på en kolonne med 300 g silika av typen "Kieselgel 60" under eluering først med etyleter og deretter med etyleter inneholdende 3% eddiksyre. Det fås 1,493 g urent produkt som omkrystalli-seres fra en blanding av metylenklorid og etyleter. Det fås der ved 1,082 g av det ønskede sure ravsyresalt. Smeltepunkt ca. 155°C. 8.1 ml of triethylamine and 1.07 g of 4-dimethylaminopyridine are boiled with reflux cooling and kept at this temperature for 24 hours. 0.339 g of succinic anhydride is then added and the boiling with reflux cooling is continued for 74 hours. After cooling, the reaction mixture is poured into 36 ml of 2 N hydrochloric acid and the Ph value is set to 6 by adding sodium acetate. After decanting the organic phase, the aqueous phase is extracted again with chloroform. The chloroform fractions are combined and washed with water, after which they are dried over sodium sulfate and evaporated to dryness in vacuo. The obtained residue is chromatographed on a column with 300 g of silica of the "Kieselgel 60" type, eluting first with ethyl ether and then with ethyl ether containing 3% acetic acid. 1.493 g of impure product is obtained which is recrystallized from a mixture of methylene chloride and ethyl ether. 1.082 g of the desired acidic succinic acid salt is obtained there. Melting point approx. 155°C.
Rf = 0,47 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.47 (thin layer chromatography; support: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
Eksempel 18 Example 18
Fremstilling av 11B- r4-( N- metvl- isopropylamino)- fenyl1- 3- okso-17a-( 1- propynyl)- estra- 4. 9- dien- 17B- vl- natriumsuccinat. Preparation of 11B-r4-(N-methyl-isopropylamino)-phenyl1-3-oxo-17a-(1-propynyl)-estra-4.9-diene-17B-vl- sodium succinate.
Man går frem på samme måte som i eksempel 16, idet det benyttes 0,128 g natriumbikarbonat i 30 ml vann og 0,933 g av forbindelsen fremstilt i eksempel 17 i 30 ml etanol. Det oppnås derved 0,915 g av det ønskede natriumsalt. The procedure is the same as in example 16, using 0.128 g of sodium bicarbonate in 30 ml of water and 0.933 g of the compound prepared in example 17 in 30 ml of ethanol. 0.915 g of the desired sodium salt is thereby obtained.
[a]D = + 40,5° ± 1,5° (c = 1% i vann). [a]D = + 40.5° ± 1.5° (c = 1% in water).
Rf = 0,47 (tynnskiktkromatografering; bærer: KC 18 "Whatman": elueringsmiddel: en 80-20 blanding av metanol og en vandig 0,05 M oppløsning av ammoniumacetat). Rf = 0.47 (thin layer chromatography; support: KC 18 "Whatman": eluent: an 80-20 mixture of methanol and an aqueous 0.05 M solution of ammonium acetate).
FARMAKOLOGISKE UNDERSØKELSER PHARMACOLOGICAL STUDIES
1) Måling av den relative affinitet for steroidhormonenes reseptorer r 1) Measurement of the relative affinity for the steroid hormones' receptors r
Rottebrisselens glucocorticoid- reseptor: The rat thymus glucocorticoid receptor:
Binyrene fjernes på hannrotter av vekt 160-200 g. Fra 4 til 8 dager etter denne bortskjæring avlives dyrene, og brislene tas ut og homogeniseres ved 0°C ved hjelp av en Potter homogenisator av teflonbelagt glass i en buffer (TSD) med Tris 10 Mm, saccharose 0,25 M, ditiotreitol 2 Mm og Hel til Ph 7,4 (1 g vev pr. 10 ml TSD). Homogenatet blir så ultra-sentrifugert (ved 105.000 g i 90 minutter) ved 0°C. Alikvotdeler av den derved oppnådde overflytende, "cytosol" inkuberes ved 0°C i 4 timer og i 24 timer med tritiumbehandlet dexamethason av konstant konsentrasjon (T = 2,5 Nm) i nærvær av økende konsentrasjoner (0-2500 Nm) av kaldt dexamethason eller av forbindelsen som skal testes, i kald tilstand. Konsentrasjonen av det bundne tritiumbehandlede dexamethason (B) måles deretter i hvert inkubat ved hjelp av teknikken med adsorpsjon med karbon-dextran. The adrenal glands are removed from male rats weighing 160-200 g. From 4 to 8 days after this removal, the animals are euthanized, and the adrenal glands are removed and homogenized at 0°C using a Potter homogenizer made of Teflon-coated glass in a buffer (TSD) with Tris 10 Mm, sucrose 0.25 M, dithiothreitol 2 Mm and Hel to Ph 7.4 (1 g tissue per 10 ml TSD). The homogenate is then ultra-centrifuged (at 105,000 g for 90 minutes) at 0°C. Aliquots of the thereby obtained supernatant, "cytosol", are incubated at 0°C for 4 hours and for 24 hours with tritiated dexamethasone of constant concentration (T = 2.5 Nm) in the presence of increasing concentrations (0-2500 Nm) of cold dexamethasone or of the compound to be tested, in the cold state. The concentration of the bound tritiated dexamethasone (B) is then measured in each incubate using the carbon-dextran adsorption technique.
Progesteronreseptoren i livmoren hos kaniner: The progesterone receptor in the rabbit uterus:
Ikke kjønnsmodne hunnkaniner av vekt ca. 1 kg påføres 25 ug østradiol på huden. 5 dager etter denne behandling avlives dyrene. Livmoren tas ut, veies og homogeniseres ved 0°C ved hjelp av en Potter homogenisator av teflonbelagt glass i en buffer (TS) med 10 Mm Tris, 0,25 M saccharose og Hel til Ph 7,4 (1 g vev pr. 50 ml TS). Homogenatet blir deretter ultra-sentrifugert (ved 105.000 g i 90 minutter) ved 0°C. Alikvotdeler av den derved oppnådde overflytende "cytosol" inkuberes ved 0°C i 2 timer og ved 24 timer med en konstant konsentrasjon (T = 5 Nm) av tritiert R 5020 (17,21-dimetyl-19-nor-4,9-pregnadien-3,20-dion), som er et kraftig progestomimetikum med stor affinitet for progesteronreseptoren, i nærvær av økende konsentrasjoner (0-2500 Nm) av kaldt progesteron eller av forbindelsene som skal testes. Not sexually mature female rabbits weighing approx. 1 kg applies 25 ug estradiol to the skin. 5 days after this treatment, the animals are killed. The uterus is removed, weighed and homogenized at 0°C using a Potter homogenizer made of Teflon-coated glass in a buffer (TS) with 10 Mm Tris, 0.25 M sucrose and Hel to Ph 7.4 (1 g tissue per 50 mL TS). The homogenate is then ultra-centrifuged (at 105,000 g for 90 minutes) at 0°C. Aliquots of the resulting supernatant "cytosol" are incubated at 0°C for 2 hours and at 24 hours with a constant concentration (T = 5 Nm) of tritiated R 5020 (17,21-dimethyl-19-nor-4,9- pregnadiene-3,20-dione), which is a potent progestomimetic with high affinity for the progesterone receptor, in the presence of increasing concentrations (0-2500 Nm) of cold progesterone or of the compounds to be tested.
Konsentrasjonen av bundet, tritiert R 5020 (B) måles deretter i hvert inkubat ved hjelp av teknikken med adsorpsjon med karbon-dekstran. The concentration of bound, tritiated R 5020 (B) is then measured in each incubate using the carbon-dextran adsorption technique.
Androgenreseptoren i prostata hos rotter. The androgen receptor in the rat prostate.
Hannrotter av vekt 160-200 g kastreres. 24 timer etter kastreringen avlives dyrene, og prostata tas ut, veies og homogeniseres ved 0°C ved hjelp av en Potter homogenisator av teflonbelagt glass i en buffer (TSDPM) med 10 Mm Tris, 0,25 M saccharose, 0,1 Nm fenylmetansulfonylfluorid, 20 Mm molyb-dat, 2 Mm ditiotreitol og Hel til Ph 7,4 (1 g vev pr. 5 ml TSDPM). Homogenisatet ultrasentrifugeres deretter (105.000 g i 60 minutter) ved 0°C. Alikvotdeler av den derved oppnådde overflytende "cytosol" inkuberes ved 0°C med en konstant konsentrasjon (0-1000 Nm) kaldt testosteron eller av forbindelsen som skal testes. Etter 30 minutters og 24 timers inkubering måles konsentrasjonen av bundet, tritiert testosteron (B) i hvert inkubat ved hjelp av teknikken med adsorpsjon med karbon-dekstran. Male rats weighing 160-200 g are castrated. 24 hours after castration, the animals are killed, and the prostate is removed, weighed and homogenized at 0°C using a Teflon-coated glass Potter homogenizer in a buffer (TSDPM) with 10 Mm Tris, 0.25 M sucrose, 0.1 Nm phenylmethanesulfonyl fluoride , 20 Mm molybdate, 2 Mm dithiothreitol and Hel to Ph 7.4 (1 g tissue per 5 ml TSDPM). The homogenate is then ultracentrifuged (105,000 g for 60 minutes) at 0°C. Aliquots of the thus obtained supernatant "cytosol" are incubated at 0°C with a constant concentration (0-1000 Nm) of cold testosterone or of the compound to be tested. After 30 minutes and 24 hours of incubation, the concentration of bound, tritiated testosterone (B) in each incubate is measured using the technique of adsorption with carbon-dextran.
Beregning av den relative affinitet av bindingen. Calculation of the relative affinity of the binding.
Beregningen av de relative affinitet av bindingen (ARL) er den samme for samtlige av reseptorene. The calculation of the relative affinity of the binding (ARL) is the same for all of the receptors.
De to følgende kurver trekkes opp: prosentandelen bundet, tritiert hormon B/T som funksjon av logaritmen til konsentrasjonen av det kalde referansehormon, og B/T som funksjon av logaritmen til konsentrasjonen av den kalde, testede forbindelse. The following two curves are plotted: the percentage of bound tritiated hormone B/T as a function of the logarithm of the concentration of the cold reference hormone, and B/T as a function of the logarithm of the concentration of the cold test compound.
Den rette linje for ligningen The straight line for the equation
bestemmes. I denne ligning er: is determined. In this equation is:
B maks = prosentandelen av det bundne, tritierte hormon ved T en inkubering av dette tritierte hormon ved konsentrasjonen T. B max = the percentage of the bound, tritiated hormone at T an incubation of this tritiated hormone at the concentration T.
B min = prosentandelen av det bundne, tritierte hormon ved T en inkubering av dette tritierte hormon ved konsentrasjonen T i nærvær av et stort overskudd av kaldt hormon (2500.10-<9>M). B min = the percentage of the bound, tritiated hormone at T an incubation of this tritiated hormone at the concentration T in the presence of a large excess of cold hormone (2500.10-<9>M).
Skjæringspunktene mellom den rette linje I50 og kur-vene gjør det mulig å bestemme konsentrasjonene av det kalde referansehormon (CH) og av den kalde, testede forbindelse (CX) som med 50% hemmer bindingen av det tritierte hormon til re-septoren . The intersection points between the straight line I50 and the curve make it possible to determine the concentrations of the cold reference hormone (CH) and of the cold, tested compound (CX) which inhibits the binding of the tritiated hormone to the receptor by 50%.
Den relative affinitet av bindingen (ARL) for den testede forbindelse bestemmes ved ligninen ARL = 100 ( CH) The relative affinity of the bond (ARL) for the tested compound is determined by the lignin ARL = 100 ( CH)
(CX) (CX)
De oppnådde resultater er som følger: The results obtained are as follows:
Forbindelsene ifølge eksempler 12 og 10 oppviser en god antiprogesteronaktivitet. 2) Antiqlucocorticoid- aktivitet vis- å- vis dexamethason. Undersøkelse in vitro. The compounds according to examples 12 and 10 show a good antiprogesterone activity. 2) Antiglucocorticoid activity relative to dexamethasone. Investigation in vitro.
Innføring av uridin i thymocyttene hos rotter. Introduction of uridine into the thymocytes of rats.
Glucocorticoidene frembringer i lymfevevet en hemning av innlemmelsen av nukleosidene. Måling av innlemmelsen av radioaktivt uridin i tymocyttene i nærvær av en forbindelse som testes, gjør det mulig å bestemme denne forbindelses glu-cocorticoide aktivitet. The glucocorticoids produce in the lymph tissue an inhibition of the incorporation of the nucleosides. Measuring the incorporation of radioactive uridine into the thymocytes in the presence of a compound being tested makes it possible to determine the glucocorticoid activity of that compound.
Metode. Method.
Metoden er basert på den teknikk som er beskrevet av Dausse og Coll (3). Brisselen fra en rotte av vekt 160-180 g som har fått fjernet binyrene, tas ut, hakkes opp og homogeniseres langsomt ved hjelp av en homogenisator av teflonbelagt glass i en Hanks-oppløsning. Den oppnådde cellesuspensjon filtreres gjennom florduk og sentrifugeres deretter ved 800 g i 10 minutter. Det foretas så en ny sentrifugering ved 800 g i The method is based on the technique described by Dausse and Coll (3). The spleen from a rat weighing 160-180 g that has had its adrenal glands removed is taken out, chopped up and homogenized slowly using a Teflon-coated glass homogenizer in a Hanks solution. The resulting cell suspension is filtered through cheesecloth and then centrifuged at 800 g for 10 minutes. A new centrifugation is then carried out at 800 g in
10 minutter. Den dermed oppnådde kake oppslemmes på ny i et næringsmedium (M.E.M. Gibco) og cellekonsentrasjonen innstilles på ca. 20.10<6> celler pr. ml. Alikvotdeler å 250 ul inkuberes deretter under carbogen i 3 timer ved 37°C med 5. IO"8 dexamethason i nærvær eller fravær av forbindelse i økende konsentrasjoner (10"<8>M-10"<6>M). Det tilsettes deretter i hvert inkubat 0,1 uCi tritiert uridin, og inkuberingen fortsettes i 1 time. Inkubatene kjøles deretter, og det tilsettes 1 ml av en 5% 10 minutes. The thus obtained cake is resuspended in a nutrient medium (M.E.M. Gibco) and the cell concentration is set to approx. 20.10<6> cells per ml. Aliquots of 250 µl are then incubated under carbogen for 3 hours at 37°C with 5.10"8 dexamethasone in the presence or absence of compound in increasing concentrations (10"<8>M-10"<6>M). It is then added to each incubate 0.1 uCi of tritiated uridine, and the incubation is continued for 1 hour. The incubates are then cooled, and 1 ml of a 5%
(vekt/vol) kald oppløsning av trikloreddiksyre (TCA). Utfel-ningene oppsamles på "Whatman GF/C" filtere og vaskes med 4 x 2 ml iskald 5% TCA. Radioaktiviteten som er tilbakeholdt på filtrene (som representerer det tritierte uridin som er blitt innlemmet i thymocyttene) måles ved hjelp av et væske-scintillasj onsspektrometer. (wt/vol) cold solution of trichloroacetic acid (TCA). The precipitates are collected on "Whatman GF/C" filters and washed with 4 x 2 ml of ice-cold 5% TCA. The radioactivity retained on the filters (representing the tritiated uridine incorporated into the thymocytes) is measured using a liquid scintillation spectrometer.
Th<y>mocvtter Th<y>mocvtter
% hemning av uridininnlemmelsen % inhibition of the uridine incorporation
Forbindelsene ifølge eksempler 5 og 12 oppviser en god antiglucocorticoid aktivitet. The compounds according to examples 5 and 12 exhibit a good antiglucocorticoid activity.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO940954A NO177594C (en) | 1989-08-08 | 1994-03-16 | New esters of organic acids and alcohols derived from 19-nor-steroids, as well as preparations to prevent conception and abort pregnancy, containing the new esters |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8910648A FR2650748B1 (en) | 1989-08-08 | 1989-08-08 | NOVEL ESTERS OF ORGANIC ACIDS WITH ALCOHOLS DERIVED FROM 19-NOR STEROIDS AND THEIR SALTS, THEIR PREPARATION METHOD AND THE INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM |
| NO903475A NO177595C (en) | 1989-08-08 | 1990-08-07 | Analogous Process for the Preparation of Therapeutically Eesters of Organic Acids and Alcohols Derived from 19-North Steroids |
| NO940954A NO177594C (en) | 1989-08-08 | 1994-03-16 | New esters of organic acids and alcohols derived from 19-nor-steroids, as well as preparations to prevent conception and abort pregnancy, containing the new esters |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO940954L NO940954L (en) | 1991-04-11 |
| NO940954D0 NO940954D0 (en) | 1994-03-16 |
| NO177594B true NO177594B (en) | 1995-07-10 |
| NO177594C NO177594C (en) | 1995-10-18 |
Family
ID=27251964
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO940954A NO177594C (en) | 1989-08-08 | 1994-03-16 | New esters of organic acids and alcohols derived from 19-nor-steroids, as well as preparations to prevent conception and abort pregnancy, containing the new esters |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO177594C (en) |
-
1994
- 1994-03-16 NO NO940954A patent/NO177594C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO177594C (en) | 1995-10-18 |
| NO940954D0 (en) | 1994-03-16 |
| NO940954L (en) | 1991-04-11 |
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