NO136253B - - Google Patents
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- NO136253B NO136253B NO761345A NO761345A NO136253B NO 136253 B NO136253 B NO 136253B NO 761345 A NO761345 A NO 761345A NO 761345 A NO761345 A NO 761345A NO 136253 B NO136253 B NO 136253B
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- Prior art keywords
- formula
- oxo
- hydroxy
- hydrogen
- pregn
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- 150000001875 compounds Chemical class 0.000 claims description 25
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 16
- 229910052783 alkali metal Inorganic materials 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 150000001340 alkali metals Chemical class 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 13
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 13
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 239000011591 potassium Substances 0.000 claims description 12
- 239000012736 aqueous medium Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- -1 ethoxy, methoxy Chemical group 0.000 claims 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 1
- 150000002763 monocarboxylic acids Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000002211 ultraviolet spectrum Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 238000005292 vacuum distillation Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 4
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000004683 dihydrates Chemical class 0.000 description 3
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 3
- 229960002256 spironolactone Drugs 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Steroid Compounds (AREA)
Description
Foreliggende oppfinnelse angår fremstilling av diuretisk virksomme 173-hydroksy-3-okso-17a-pregn-4-en-7j21-karboksylsyrer, samt estere og salter The present invention relates to the production of diuretically active 173-hydroxy-3-oxo-17a-pregn-4-ene-7j21-carboxylic acids, as well as esters and salts
derav, hvilke forbindelser har den generelle formel: hence, which compounds have the general formula:
hvor Z er hydrogen, alkalimetall, jordalkalimetall/2 eller alkyl; where Z is hydrogen, alkali metal, alkaline earth metal/2 or alkyl;
Z' er hydrogen, alkalimetall eller jordalkalimetall/2; og hvor den stiplede linje indikerer den eventuelle tilstedeværelse av en A-umettet binding, og den bølgede linje indikerer den alternative a- og 6-konfigurasjon. Z' is hydrogen, alkali metal or alkaline earth metal/2; and where the dashed line indicates the possible presence of an A-unsaturated bond, and the wavy line indicates the alternative a and 6 configuration.
Ifølge oppfinnelsen fremstilles de ovenfor angitte forbindelser med formel I ved According to the invention, the above-mentioned compounds of formula I are prepared by
a) en forbindelse med formelen: a) a compound with the formula:
hvor den stiplede og bølgede linje har den ovenfor angitte betydning, og Z" er alkyl med 1-7 karbonatomer eller hydrogen, bringes i kontakt med henholdsvis en eller to ekvivalenter av en passende base i et vandig medium for dannelse av det tilsvarende mono- eller bis-(alkalimetall)- eller (jordalkalimetall/2)-salt av formel I, og, om ønsket, fulgt av kort utsettelse for en protonkilde for dannelse av den tilsvarende mono- eller dikarboksylsyre av formel I, eller where the dashed and wavy lines have the meaning given above, and Z" is alkyl of 1-7 carbon atoms or hydrogen, is brought into contact with one or two equivalents of a suitable base in an aqueous medium respectively to form the corresponding mono- or bis-(alkali metal) or (alkaline earth metal/2) salt of formula I, and, if desired, followed by brief exposure to a proton source to form the corresponding mono- or dicarboxylic acid of formula I, or
b) en forbindelse med formel I, hvor Z er hydrogen eller alkyl og Z' er hydrogen, bringes i kontakt med en mengde av en passende b) a compound of formula I, wherein Z is hydrogen or alkyl and Z' is hydrogen, is contacted with an amount of a suitable
base ekvivalent med mengden av tilstedeværende syrehydrogen, i et vandig medium, for dannelse av det tilsvarende mono- eller bis-(alkalimetall)- eller -(jordalkalimetall/2)-salt av formel.I. base equivalent to the amount of acid hydrogen present, in an aqueous medium, to form the corresponding mono- or bis-(alkali metal) or -(alkaline earth metal/2) salt of formula.I.
Fremgangsmåter for fremstilling av de nye utgangs-materialene med formel II som angitt ovenfor, er beskrevet i norsk patent nr. 13^.990. Procedures for the production of the new starting materials with formula II as indicated above are described in Norwegian patent no. 13^990.
Foretrukne forbindelser med formel I er de hvori substituenten i 7~stillingen er en 7a-alkoksykarbonylgruppe og Z' er alkalimetall eller jordalkalimetall/2, idet spesielt foretrukne forbindelser har en mettet 1,2-binding- Preferred compounds of formula I are those in which the substituent in the 7~-position is a 7a-alkoxycarbonyl group and Z' is alkali metal or alkaline earth metal/2, particularly preferred compounds having a saturated 1,2-bond-
Foretrukne alkalimetaller og jordalkalimetaller som omfattes av Z og Z<r> er kalium, natrium, litium, magnesium og' kalsium. Fagmannen vil forstå at betegnelsen "j-ordalkalimetall/2" ikke betyr noe annet enn at jordalkalimetallene er toverdige, mens andre grupper representert ved Z og Z'.er enverdige. Når f. eks. Z'er Ca/2 og Z er alkyl i f.ormel I, så vil de angjeldende salter hensiktsmessig kunne angis på følgende måte: Preferred alkali metals and alkaline earth metals encompassed by Z and Z<r> are potassium, sodium, lithium, magnesium and calcium. The person skilled in the art will understand that the designation "j-ordalkaline metal/2" does not mean anything other than that the alkaline earth metals are divalent, while other groups represented by Z and Z' are monovalent. When e.g. Z' is Ca/2 and Z is alkyl in formula I, then the salts in question can conveniently be specified as follows:
Blant alkylradikalene som omfattes av Z er alkylradi-kaler som f.eks. metyl, etyl, propyl, isopropyl, butyl, isobutyl, sek.-butyl, tert.-butyl, pentyl, neopentyl, heksyl, isoheksyl og heptyl, med den empiriske formel: Among the alkyl radicals covered by Z are alkyl radicals such as e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl and heptyl, with the empirical formula:
hvor n er et tall lavere enn 8. where n is a number lower than 8.
Ekvivalent med forbindelsene med formel I er, for det foreliggende formål, solvater hvor det er tilstede biologisk ubetydelige mengder oppløsningsmiddel. Equivalent to the compounds of formula I, for the present purpose, are solvates in which biologically insignificant amounts of solvent are present.
Forbindelsene med formel I er verdifulle på grunn av sine biologiske egenskaper. De er f.eks. diuretisk virksomme idet de reverserer, effekten av desoksykrotikosteron-acetat (DCA) på innholdet av natrium og kalium i urinen. De har også blod-trykksenkende egenskaper. The compounds of formula I are valuable because of their biological properties. They are e.g. diuretically active in that they reverse the effect of desoxycroticosterone acetate (DCA) on the sodium and potassium content of the urine. They also have blood-pressure-lowering properties.
De fremstilte forbindelsers evne til å reversere nyre-elektrolytt-effektene av DCA fremgår fra resultatene av en standardisert prøve på denne egenskap som ble utført på rotter, The ability of the prepared compounds to reverse the renal-electrolyte effects of DCA is evident from the results of a standardized test of this property carried out on rats,
i alt vesentlig slik det er beskrevet av CM. Kagawa i kapittel 34 i volum II av "Evaluation of Drug Activities: Pharmacometrics", av D.R. Laurence og A.L. Bacharach. Detaljer vedrørende slike prøver er beskrevet i US-patent 3-422.096. Idet man anvendte samme generelle fremgangsmåte ble det utført ytterligere en 6 punkt bioprøve (2 forbindelser x-3 doser) for å bedømme anti-DCA-virkningen for representative forbindelser fremstilt ifølge oppfinnelsen i forhold til et kjent diuretikum, nemlig spironolakton. Detaljer i denne prøve fremgår av følgende: substantially as described by CM. Kagawa in Chapter 34 of Volume II of "Evaluation of Drug Activities: Pharmacometrics", by D.R. Laurence and A.L. Bacharach. Details regarding such samples are described in US Patent 3-422,096. Using the same general procedure, a further 6-point bioassay (2 compounds x-3 doses) was performed to assess the anti-DCA effect of representative compounds prepared according to the invention in relation to a known diuretic, namely spironolactone. Details of this test can be seen from the following:
.Grupper på 4 hanrotter som hver veide mellom 150 og .Groups of 4 male rats each weighing between 150 and
200 g ble binyreektomisert og holdt deretter på sukkerbiter og vann ad libitum i ca. 24 timer. Dyrene ble så behandlet sukses-sivt med følgende: 12 yg desoksykortikosteronacetat (DCA)-opp-løst i 0,1 ml maisolje injisert subkutant, en utvalgt dose av prøveforbindelsen tilført oralt og 2,5 ml av en 0,85 % vandig natriumkloridoppløsning injisert subkutant. Natrium og kalium i urinen ble deretter målt ved standardteknikk på urinprøver som ble oppsamlet i løpet av 4 timer etter behandlingen. En lignende fremgangsmåte ble anført parallelt på andre grupper som ble behandlet med to andre doser av prøveforbindelsen foruten på grupper som ble behandlet på tre forskjellige dosenivåer av standarden, nemlig spironolakton. Dosen av standarden var van-ligvis 0,3, 0,9 og 2,7 ml/rotte, mens dosene av prøveforbindel-sen ble valgt slik at de ga et midlere biologisk utslag som til-svarte omtrent det tilsvarende fra standarden. Basert på denne 6 punkts bioprøve, idet man anvendte en økning av urin-logaritmen 200 g were adrenalectomized and then kept on sugar cubes and water ad libitum for approx. 24 hours. The animals were then treated successively with the following: 12 µg of desoxycorticosterone acetate (DCA) dissolved in 0.1 ml of corn oil injected subcutaneously, a selected dose of the test compound administered orally and 2.5 ml of a 0.85% aqueous sodium chloride solution injected subcutaneously. Sodium and potassium in the urine were then measured by standard technique on urine samples collected within 4 hours after treatment. A similar procedure was performed in parallel on other groups treated with two other doses of the test compound besides on groups treated at three different dose levels of the standard, namely spironolactone. The dose of the standard was usually 0.3, 0.9 and 2.7 ml/rat, while the doses of the test compound were chosen so that they produced an average biological result that corresponded approximately to that from the standard. Based on this 6-point bioassay, using an increment of the urine logarithm
(Na x 10)/K-forhold som indeks for anti-DCA-aktivitet, ble det• bestemt at en rekke representative fremstilte forbindelser er mer virksomme enn spironolakton. Spesielt virksomme i denne bioprøve var kalium-17-hydroksy-7a-metoksykarbonyl-3-okso-17a-pregn-1,4-dien-21-karboksylat, kalium-17-hydroksy-7a-metoksy-karbonyl-3-okso-17a-pregn-4-en-21-karboksylat og kalium-17-hydroksy-7a-isopropoksykarbonyl-3-okso-17a-pregn-4-en-21-karbok-sylat. (Na x 10)/K ratio as an index of anti-DCA activity, it was determined that a number of representative compounds prepared are more potent than spironolactone. Particularly effective in this bioassay were potassium 17-hydroxy-7a-methoxycarbonyl-3-oxo-17a-pregn-1,4-diene-21-carboxylate, potassium 17-hydroxy-7a-methoxy-carbonyl-3-oxo- 17α-pregn-4-ene-21-carboxylate and potassium 17-hydroxy-7α-isopropoxycarbonyl-3-oxo-17α-pregn-4-ene-21-carboxylate.
Omsetning av en forbindelse med formel II med henholdsvis en eller to ekvivalenter av en passende base i et vandig medium, gir de tilsvarende mono- eller bis-(alkalimetall) eller jordalkalimetall/2-salter av forbindelser med formel I. Hvis det er ønskelig kan det resulterende salt med formel I ekspone-res over for en protonkilde i et kort tidsrom, hvorved man får den tilsvarende mono- eller dikarboksylsyre med formel I. Når således utgangsmaterialet med formel II er en 7_ester, så kan denne forbindelse oppvarmes med en ekvivalent av et alkalimetall eller jordalkalimetallhydroksyd i et vandig medium, hvorved man får den tilsvarende forbindelse med formel I hvor Z er alkyl og Z' er alkalimetall eller jordalkaIimetall/2. -Denne reaksjon kan fortrinnsvis utføres i en vandig alkanol som inneholder samme antall karbonatomer som er tilstede i 7-alkoksygruppen i utgangsmaterialet, d.v.s. at saltet av en 7-metoksykarbonylforbindelse fremstilles i metanol, saltet åv en 7-etoksykarbonylforbindelse fremstilles i etanol, etc, noe som sikrer at utgangsforbindel-sens estergruppe bibeholdes i sluttproduktet. Når utgangsfor-bindelsen er en syre, så kan denne oppvarmes med to ekvivalenter av alkalimetall eller jordalkalimetallhydroksyd i et vandig medium, hvorved man får den tilsvarende forbindelse med formel I hvor både Z og Z' er alkalimetall eller jordalkalimetall/2. Som oppløsningsmiddel i dette tilfelle kan man hensiktsmessig anvende en vandig alkanol. En kort etterfølgende kontakt av disse salter med en mineralsyre, f.eks. salpetersyre, under meget fortynnede betingelser, gir de tilsvarende 21-mono- og 7,21-dikarboksylsyrer. Reaction of a compound of formula II with respectively one or two equivalents of a suitable base in an aqueous medium gives the corresponding mono- or bis-(alkali metal) or alkaline earth metal/2-salts of compounds of formula I. If desired, the resulting salt with formula I is exposed to a proton source for a short period of time, whereby the corresponding mono- or dicarboxylic acid with formula I is obtained. Thus, when the starting material with formula II is a 7-ester, this compound can be heated with an equivalent of an alkali metal or alkaline earth metal hydroxide in an aqueous medium, whereby the corresponding compound of formula I is obtained where Z is alkyl and Z' is alkali metal or alkaline earth metal/2. -This reaction can preferably be carried out in an aqueous alkanol which contains the same number of carbon atoms as are present in the 7-alkoxy group in the starting material, i.e. that the salt of a 7-methoxycarbonyl compound is prepared in methanol, the salt of a 7-ethoxycarbonyl compound is prepared in ethanol, etc., which ensures that the ester group of the starting compound is retained in the final product. When the starting compound is an acid, this can be heated with two equivalents of alkali metal or alkaline earth metal hydroxide in an aqueous medium, thereby obtaining the corresponding compound of formula I where both Z and Z' are alkali metal or alkaline earth metal/2. An aqueous alkanol can suitably be used as a solvent in this case. A short subsequent contact of these salts with a mineral acid, e.g. nitric acid, under very dilute conditions, gives the corresponding 21-mono- and 7,21-dicarboxylic acids.
Hvis man bringer en forbindelse med formel I hvor Z er hydrogen eller alkyl og Z' er hydrogen, i kontakt med en mengde av en passende base ekvivalent til den tilstedeværende mengde av syrehydrogen, så vil dette i et .vandig medium gi det tilsvarende mono- eller bis(alkalimetall)- eller (jordalkalimetall/2)-salt med formel I. Således vil reaksjon mellom en 7-ester med formel I og med en syregruppe i 21-stillingen, med en ekvivalent av en egnet base, f.eks. et alkalimetall- eller jordalkalimetallhydroksyd i et vandig medium, fortrinnsvis i en vandig alkanol, inneholdende samme antall karbonatomer som i utgangsmaterialets 7-alkoksy-gruppe, gi den ønskede 7-ester 21-salt. På lignende måte kan forbindelser med formel I hvor både Z og Z<1> er alkalimetall eller jordalkalimetall/2, fremstilles ved at man oppvarmer den tilsvarende 7,21-dikarboksylsyre med to ekvivalenter av en passende base, f.eks. et alkalimetall- eller jordalkalimetallhydroksyd i et vandig medium, f.eks. en vandig alkanol. If one brings a compound of formula I where Z is hydrogen or alkyl and Z' is hydrogen, into contact with an amount of a suitable base equivalent to the amount of acid hydrogen present, this will give, in an aqueous medium, the corresponding mono- or bis(alkali metal) or (alkaline earth metal/2) salt of formula I. Thus, reaction between a 7-ester of formula I and with an acid group in the 21-position, with an equivalent of a suitable base, e.g. an alkali metal or alkaline earth metal hydroxide in an aqueous medium, preferably in an aqueous alkanol, containing the same number of carbon atoms as in the starting material's 7-alkoxy group, give the desired 7-ester 21-salt. In a similar way, compounds of formula I where both Z and Z<1> are alkali metal or alkaline earth metal/2 can be prepared by heating the corresponding 7,21-dicarboxylic acid with two equivalents of a suitable base, e.g. an alkali metal or alkaline earth metal hydroxide in an aqueous medium, e.g. an aqueous alkanol.
Følgende eksempler illustrerer oppfinnelsen. I disse eksempler er alle mengder angitt i vektdeler hvis ikke volumdeler spesielt er angitt. Forholdet mellom vektdeler og volumdeler er det samme som mellom gram og milliliter. Spesifikk rotasjon refererer seg til D-linjen for natrium og oppløsnings-midlet er kloroform ved romtemperatur hvis intet annet er angitt. The following examples illustrate the invention. In these examples, all quantities are given in parts by weight unless parts by volume are specifically stated. The ratio between parts by weight and parts by volume is the same as between grams and milliliters. Specific rotation refers to the D line for sodium and the solvent is chloroform at room temperature unless otherwise stated.
Eksempel 1 Example 1
En oppløsning av 43 deler 17-hydroksy-7ct-metoksykarbo-ny 1-3_okso-17ct-pregn-4-en-21-karboksylsyre-Y-lakton og 135 deler vandig 4 % kaliumhydroksyd i 2000 deler metanol beskyttet av en nitrogenatmosfære, ble oppvarmet til 40°C i løpet av 5 min. og' deretter omrørt ved romtemperatur over natten. Oppløsningen ble så oppvarmet til kokepunktet under tilbakeløp i 2 timer, hvoretter oppløsningsmidlet ble fjernet ved vakuumdestillasjon, hvoretter den gjenværende oppløsning ble fortynnet med 3000 deler vann. Den oppnådde oppløsning ble vasket med etylacetat og så destillert, noe som gjenlot en gummiaktig rest som ble oppløst i en minimum mengde av etanol. Tilstrekkelig etylacetat ble tilsatt for å få utfelt kalium-17-hydroksy-7a-metoksykarbo-nyl-3-okso-17ct-pregn-4-en-21-karboksylat som et hvitt flokkulent faststoff. Denne forbindelse viser et MeOH-maksimum ved 243 my (e = 14,610) i det ultrafiolette spektrum og absorbsjon i det infrarøde spektrum (KBr) ved l680 og 1580 cm Eksempel 2 A solution of 43 parts of 17-hydroxy-7ct-methoxycarbo-ny 1-3_oxo-17ct-pregn-4-ene-21-carboxylic acid Y-lactone and 135 parts of aqueous 4% potassium hydroxide in 2000 parts of methanol protected by a nitrogen atmosphere was heated to 40°C within 5 min. and' then stirred at room temperature overnight. The solution was then heated to reflux for 2 hours, after which the solvent was removed by vacuum distillation, after which the remaining solution was diluted with 3000 parts of water. The resulting solution was washed with ethyl acetate and then distilled, leaving a gummy residue which was dissolved in a minimum amount of ethanol. Sufficient ethyl acetate was added to precipitate potassium 17-hydroxy-7a-methoxycarbonyl-3-oxo-17ct-pregn-4-ene-21-carboxylate as a white flocculent solid. This compound shows a MeOH maximum at 243 my (e = 14.610) in the ultraviolet spectrum and absorption in the infrared spectrum (KBr) at 1680 and 1580 cm Example 2
En oppløsning av 1 del kalium-17-hydroksy-7a-metoksy-karbonyl-3~okso-17a-pregn-4-én-21-karboksylat i 70 deler vann ble tilsatt 20 deler 5 % saltsyre. Det resulterende bunnfall ble frafiltrert, vasket med vann og tørket i luft. Det således isolerte stoff var 17-hydroksy-7a-metoksykarbonyl-3-okso-17a-pregn-4-en-21-karboksylsyre som viser et MeOH-maksimum ved 243 A solution of 1 part of potassium 17-hydroxy-7a-methoxy-carbonyl-3~oxo-17a-pregn-4-ene-21-carboxylate in 70 parts of water was added to 20 parts of 5% hydrochloric acid. The resulting precipitate was filtered off, washed with water and dried in air. The substance thus isolated was 17-hydroxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21-carboxylic acid which shows a MeOH maximum at 243
mp i UV-spekteret. mp in the UV spectrum.
Eksempel 3 Example 3
En oppløsning av 106 deler 17-hydroksy-3-okso-17ct-pregn-4-en-7ctj21-dikarboksylsyre-Y-lakton monohydrat i 730 deler vandig 4 % kaliumhydroksyd ble fortynnet med 2 volumdeler vann. Den resulterende oppløsning ble holdt på 90-95°C i 30.min. og så befridd for vann ved hjelp av vakuumdestillasjon. Resten ble ekstrahert méd 2-propanol. Propanol-oppløsningen ble filtrert og befridd for oppløsningsmiddel ved vakuumdestillasjon, hvorved man fikk et gult pulver som ble tørket i vakuum ved 65°C i 24 timer, så igjen oppløst i 10000 deler varm 2-propanol. Denne oppløsning ble filtrert og filtratet ble konsentrert til 1/5 volum ved vakuum-destillasjon. Det dannede bunnfall i det avkjølte konsentrat var dikalium-17-hydroksy-3-okso-17a-pregn-4-en-7a,21-dikarboksylatdihydrat, som ble frafiltrert og tørket i luft. Krystallisasjonsvann ble fjernet fra dihydratet ved opp- • varming i-vakuum omkring 80°C. A solution of 106 parts of 17-hydroxy-3-oxo-17ct-pregn-4-ene-7ctj21-dicarboxylic acid Y-lactone monohydrate in 730 parts of aqueous 4% potassium hydroxide was diluted with 2 parts by volume of water. The resulting solution was held at 90-95°C for 30 min. and then freed from water by means of vacuum distillation. The residue was extracted with 2-propanol. The propanol solution was filtered and freed of solvent by vacuum distillation, whereby a yellow powder was obtained which was dried in vacuum at 65°C for 24 hours, then redissolved in 10,000 parts of hot 2-propanol. This solution was filtered and the filtrate was concentrated to 1/5 volume by vacuum distillation. The precipitate formed in the cooled concentrate was dipotassium 17-hydroxy-3-oxo-17α-pregn-4-ene-7α,21-dicarboxylate dihydrate, which was filtered off and dried in air. Water of crystallization was removed from the dihydrate by heating in vacuum to around 80°C.
Eksempel 4 Example 4
En oppløsning av 2 deler dikalium-17-hydroksy-3-okso-17a-pregn-4-en-7ot, 21-dikarboksylatdihydrat i 80 deler vann ble tilsatt 10 deler 5 % saltsyre. Det fargeløse bunnfall som dannet seg ble frafiltrert, vasket med vann og tørket i luft. Det således isolerte produkt var 17_hydroksy-3_okso-17a-pregn-4-en-7a,21-dikarboksylsyre som viser et MeOH-maksimum ved 243 my i UV-spekteret. A solution of 2 parts of dipotassium-17-hydroxy-3-oxo-17a-pregn-4-en-7ot,21-dicarboxylate dihydrate in 80 parts of water was added to 10 parts of 5% hydrochloric acid. The colorless precipitate that formed was filtered off, washed with water and dried in air. The product thus isolated was 17_hydroxy-3_oxo-17a-pregn-4-ene-7a,21-dicarboxylic acid which shows a MeOH maximum at 243 my in the UV spectrum.
Eksempel 5 Example 5
En oppløsning av 100 deler 17-hydro.ksy-3-okso-17a-pregn-1,4-dien-.7a, 21-dikarboksylsyre-y-lakton og 744 deler vandig 4 % kaliumhydroksyd i 4000 deler metanol ble. oppvarmet under tilbakeløp i 20 timer. All væske ble så fjernet fra den resulterende oppløsning ved vakuumdestillasjon og den gule gummiaktige rest ble videre tørket azeotropt ved fradestillasjon .av etanol. Den fargeløse rest som man da oppnådde ble omkrystallisert fra etylacetat, hvorved man fikk dikalium-17_hydroksy-3-okso-17cx-pregna-l,4-dien-7a,21-dikarboksylat som viser et MeOH-maksimum ved 241 my i UV-spekteret.' A solution of 100 parts of 17-hydroxy-3-oxo-17a-pregn-1,4-diene-7a,21-dicarboxylic acid-y-lactone and 744 parts of aqueous 4% potassium hydroxide in 4000 parts of methanol was heated under reflux for 20 hours. All liquid was then removed from the resulting solution by vacuum distillation and the yellow gummy residue was further azeotropically dried by distillation from ethanol. The colorless residue that was then obtained was recrystallized from ethyl acetate, whereby dipotassium 17_hydroxy-3-oxo-17cx-pregna-1,4-diene-7a,21-dicarboxylate was obtained which shows a MeOH maximum at 241 my in UV- the spectrum.'
Eksempel 6 Example 6
Ved å anvende 2 deler dikalium-17-hydroksy-3-okso-17a-pregna-1,4-dien~7a,21-dikarboksylat i fremgangsmåten for eksempel kan man få fremstilt 17-hydroksy-3-okso-17a-pregna-l,4-dien-7ct,21-dikarboksylsyre. Denne forbindelse viser et MeOH-maksimum ved 24l my i UV-spekteret. By using 2 parts of dipotassium 17-hydroxy-3-oxo-17a-pregna-1,4-diene~7a,21-dicarboxylate in the process, for example, 17-hydroxy-3-oxo-17a-pregna- 1,4-diene-7α,21-dicarboxylic acid. This compound shows a MeOH maximum at 24l my in the UV spectrum.
Eksempel 7 Example 7
En oppløsning av 200 deler 17_hydroksy-7a-metoksykar-bonyl-3-okso-17oi-pregn-4-en-21-karboksylsyre-Y-lakton i 7000 deler metanol ble under nitrogen og omrøring tilsatt 397 deler vandig 5 % natriumhydroksyd. Den resulterende blanding ble ved 40°C omrørt i 2 timer, hvoretter oppløsningsmidler ble fjernet ved vakuumdestillasjon. Resten ble vasket ved utrøring i etylacetat og så tørket i luft. Det isolerte produkt var natrium-17-hydroksy-7oi-metoksykarbonyl-3-okso-17a-pregn-4-enr 21karboksy-lat, som viser et MeOH-maksimum ved 240 my i UV-spekteret. A solution of 200 parts of 17_hydroxy-7a-methoxycarbonyl-3-oxo-17oi-pregn-4-ene-21-carboxylic acid Y-lactone in 7000 parts of methanol was added under nitrogen and stirring to 397 parts of aqueous 5% sodium hydroxide. The resulting mixture was stirred at 40°C for 2 hours, after which solvents were removed by vacuum distillation. The residue was washed by stirring in ethyl acetate and then dried in air. The isolated product was sodium 17-hydroxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-enr 21carboxylate, which shows a MeOH maximum at 240 my in the UV spectrum.
Eksempel 8 Example 8
En blanding av 2O0- deler 17-hydroksy-7a-metoksykarbo-nyl-3-okso-17ot-pregn-4-en-21-karboksylsyre, 19 deler kalsium-hydroksyd og 4000 deler metanol ble omrørt under nitrogen og ved 40°C i 2 timer. Oppløsningsmidlet ble så fjernet ved vakuum-destillasjon og resten ble- omkrystallisert fra etylacetat. Det isolerte produkt var kalsium bis (17-hydroksy-7ot-metoksykarbonyl-3-okso-17ot-pregn-4-en-21-karboksylat), som viser et MeOH-maksimum ved 240 my i UV-spekteret. A mixture of 2O0 parts 17-hydroxy-7a-methoxycarbonyl-3-oxo-17o-pregn-4-ene-21-carboxylic acid, 19 parts calcium hydroxide and 4000 parts methanol was stirred under nitrogen and at 40°C for 2 hours. The solvent was then removed by vacuum distillation and the residue was recrystallized from ethyl acetate. The isolated product was calcium bis(17-hydroxy-7o-methoxycarbonyl-3-oxo-17o-pregn-4-ene-21-carboxylate), which shows a MeOH maximum at 240 my in the UV spectrum.
Eksempel 9 Example 9
En oppløsning av 43 deler 17-hydroksy-7a-isopropoksy-karbonyl-3-okso-17a-pregn-4-en-21-karboksylsyre-Y-lakton og 130 volumdeler 0,73 normal vandig kaliumhydroksydoppløsning i ca. 785 deler 2-propanol ble hensatt ved romtemperatur over natten, deretter oppvarmet til 50-55°C i 20 min. på et vannbad. Reak-. sjonsblandingen ble avkjølt, konsentrert i vakuum og vasket med etyleter, og man fikk fremstilt som et lyst gult fast stoff kalium-17-'hydroksy-7ct-isopropoksykarbonyl-3-okso-17a-pregn-4-en-21-karboksylat. Dette produkt viser et MeOH-maksimum ved 240 my (e = 15^410) i UV-spekteret og absorbsjon i IR-spekteret (KBr) ved 1730, 1660 og 1580 cm<-1.>A solution of 43 parts of 17-hydroxy-7a-isopropoxy-carbonyl-3-oxo-17a-pregn-4-ene-21-carboxylic acid-Y-lactone and 130 parts by volume of 0.73 normal aqueous potassium hydroxide solution in approx. 785 parts of 2-propanol were left at room temperature overnight, then heated to 50-55°C for 20 min. in a water bath. React-. The reaction mixture was cooled, concentrated in vacuo and washed with ethyl ether to give potassium 17-hydroxy-7ct-isopropoxycarbonyl-3-oxo-17a-pregn-4-ene-21-carboxylate as a light yellow solid. This product shows a MeOH maximum at 240 my (e = 15^410) in the UV spectrum and absorption in the IR spectrum (KBr) at 1730, 1660 and 1580 cm<-1.>
Ovennevnte fremgangsmåte ble gjentatt idet man anvendte 7oi-etoks<y>karbon<y>l-17-h<y>droksy-3-okso-17a-pregn-4-en-21-karbok-sylsyre-y-lakton som utgangsmateriale og etanol som reaksjons-oppløsningsmiddel. Det urene produkt ble vasket med etylacetat og etyleter hvilket ga kalium-7a-etoksykarbonyl-17-hydroksy-3-okso-17a-pregn-4-en-21-karboksylatmonohydrat. Produktet hadde en spesifikk rotasjon på +4,89° i vann,. The above procedure was repeated using 70i-ethoxycarbonyl-1-17-hydroxy-3-oxo-17a-pregn-4-ene-21-carboxylic acid-y-lactone as starting material and ethanol as reaction solvent. The crude product was washed with ethyl acetate and ethyl ether to give potassium 7α-ethoxycarbonyl-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylate monohydrate. The product had a specific rotation of +4.89° in water.
Fra 7a-etoksykarbonyl-17-hydroksy-3-okso-17ct-pregna-1,4-dien-21-karboksylsyre-y-lakton,- 17-hvdroksy-7a-metoksykarbo-nyl- 3_ ok so- 17ot-pr egna-1, 4-dien-21--karboksylsyre-y-lakton og 17_hydroksy-7ot-isopropoksykarbonyl-3-okso-17ot-pregna-l, 4-dien-21-karboksylsyre-y-lakton, kan man på lignende måte fremstille kal ium-7ot-et oksy karbonyl-17-hy dr oksy-3--oks o-l 7a-pr egna-1,4-dien-21-karboksylat med MeOH-maksimum ved 24l my i UV-spekteret, kal ium-17_hydroksy-7oi-met oksy karbonyl-3-okso-17o:-pr egna-1,4-dien-21-karboksylat med IR-absorbsjon ■(KBr) ved 1742, 1675 og 1580 cm "'"•og kalium-17-hydroksy-7a-isopropoksykarbonyl-3-okso-17ot-pregna-l, 4-dien-21-karboksylat med IR-absorbsj on (KBr) ved 1745, 1680 og 1560 cm"<1>, respektivt. From 7a-ethoxycarbonyl-17-hydroxy-3-oxo-17ct-pregna-1,4-diene-21-carboxylic acid-y-lactone,- 17-hvdroxy-7a-methoxycarbonyl-3_ ok so- 17ot-pr egna -1,4-diene-21-carboxylic acid-γ-lactone and 17_hydroxy-70-isopropoxycarbonyl-3-oxo-170-pregna-1,4-dien-21-carboxylic acid-y-lactone can be prepared in a similar way potassium-7ot-et oxycarbonyl-17-hy dr oxy-3--ox o-l 7a-pr egna-1,4-diene-21-carboxylate with MeOH maximum at 24l my in the UV spectrum, potassium ium-17_hydroxy -7oi-met oxy carbonyl-3-oxo-17o:-pr egna-1,4-diene-21-carboxylate with IR absorption ■(KBr) at 1742, 1675 and 1580 cm "'"•and potassium-17- hydroxy-7α-isopropoxycarbonyl-3-oxo-170-pregna-1,4-diene-21-carboxylate with IR absorption (KBr) at 1745, 1680 and 1560 cm"<1>, respectively.
Claims (2)
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NO761345A NO136253C (en) | 1971-08-25 | 1976-04-21 | ANALOGICAL PROCEDURES FOR THE PREPARATION OF DIURETIC ACTIVITIES 17BETA-HYDROXY-3-OXO-17ALFA-PREGN-4-EN-7,21-CARBOXYLIC ACIDS, AND ESTERS AND SALTS THEREOF. |
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US17492271A | 1971-08-25 | 1971-08-25 | |
NO3032/72A NO134990C (en) | 1971-08-25 | 1972-08-24 | |
NO761345A NO136253C (en) | 1971-08-25 | 1976-04-21 | ANALOGICAL PROCEDURES FOR THE PREPARATION OF DIURETIC ACTIVITIES 17BETA-HYDROXY-3-OXO-17ALFA-PREGN-4-EN-7,21-CARBOXYLIC ACIDS, AND ESTERS AND SALTS THEREOF. |
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