CZ2009521A3 - 3alpha-Hydroxy-21xi, 22-oxide-21-homo-5alpha-pregnan-20-one, process if its preparation and its use - Google Patents
3alpha-Hydroxy-21xi, 22-oxide-21-homo-5alpha-pregnan-20-one, process if its preparation and its use Download PDFInfo
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Abstract
3.alfa.-Hydroxy-21.ksi.,22-oxido-21-homo-5.alfa.-pregnan-20-on vzorce II. Zpusob jeho výroby, který spocívá v Mannichove kondensaci formaldehydu a dimethylaminu, a rozkladu príslušného meziproduktu na 3.alfa.-hydroxy-21-homo-5.alfa.-pregn-21-en-20-on vzorce V, který se epoxiduje peroxidem vodíku v alkalickém prostredí. 3.alfa.-Hydroxy-21.ksi.,22-oxido-21-homo-5.alfa.-pregnan-20-on vzorce II se dále používá pro výrobu léciva urceného k predcházení a potlacení epileptických záchvatu.3.alpha.-Hydroxy-21, 22-oxido-21-homo-5.alpha.-pregnan-20-one of formula II. The method of its production, which consists of Mannich condensation of formaldehyde and dimethylamine, and the decomposition of the corresponding intermediate to 3.alpha.-hydroxy-21-homo-5.alpha.-pregn-21-en-20-one of formula V, which is epoxidized with peroxide hydrogen in alkaline medium. 3.alpha.-Hydroxy-21'-22-oxido-21-homo-5.alpha.-pregnan-20-one of formula II is further used for the manufacture of a medicament for preventing and suppressing epileptic seizures.
Description
3a-Hydroxy-2^,22-oxido-21-homo-5a-pregnan-20-on, způsob jeho výroby a jeho použití3a-Hydroxy-2 ', 22-oxido-21-homo-5a-pregnan-20-one, process for its production and use
Oblast technikyTechnical field
Tento vynález se týká 3a-hydroxy-21č,22-oxido-21-homo-5a-pregnan-20-onu, způsobu jeho výroby a jeho použití při potlačení epileptických záchvatů.The present invention relates to 3α-hydroxy-21β, 22-oxido-21-homo-5α-pregnan-20-one, to a process for its manufacture and to its use in the control of epileptic seizures.
Dosavadní stav technikyBACKGROUND OF THE INVENTION
Epileptické záchvaty jsou projevem náhlých elektrických impulsů projevujících se v části či celém mozku, pri němž může, ale nemusí dojít k poruše vědomí. Záchvat může být ztišen řadou látek, které tlumí přenos nervových signálů, jako jsou benzodiazepiny a barbituráty, které působí prostřednictvím receptoru γ-aminomáselné kyseliny (GABA). Nově může být tento receptor modulován i neurosteroidy typu allopregnanolonu vzorce IEpileptic seizures are a manifestation of sudden electrical impulses manifesting in part or all of the brain in which consciousness may or may not occur. The seizure may be attenuated by a number of substances that inhibit the transmission of nerve signals, such as benzodiazepines and barbiturates, which act via the γ-aminobutyric acid (GABA) receptor. Newly, this receptor can also be modulated by allopregnanolone type I neurosteroids
Tyto látky působí jako pozitivní allosterické modulátory GABA receptorů tím, že zvyšují proudy jak co do frekvence otevření iontového kanálu, tak i délky jeho otevření. Neurosteroidy tedy mohou být použity jako anestHetika, anxiolytika i látky s protikřečovým účinkem [Veleiro AS, Burton G. Structure-Activity Relationships of Neuroactive Steroids Acting on the GABA(A) Receptor. Curr Med Chem 2009;Jd:455-72] [Scaglione JB, Jastrzebska I, Krishnan K, Li P, Akk G, Manion BD, Benz A, Tailor A, Rath NP, Evers AS, Zorumski CF, Mennerick S, Covey DF. Neurosteroid analogues. 11. Alternativě ring systém scaffolds: gamma-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes. JMed Chem 2006;49:4595-605], [Eisenman LN, Shu H-J, Akk G, Wang C, Manion BD, Kress GJ, Evers AS, Steinbach JH, Covey DF, Zorumski CF, Mennerick S. Anticonvulsant and anesthetic effects of a fluoresccnt neurosteroid analog activated by visible light. Nátuře Neurosci 2007,70:523-30],These substances act as positive allosteric modulators of the GABA receptors by increasing currents both in the frequency of opening of the ion channel and its length of opening. Thus, neurosteroids can be used as anesthetics, anxiolytics and antispasmodic agents [Veleiro AS, Burton G. Structure-Activity Relationships of Neuroactive Steroids Acting on the GABA (A) Receptor. Curr Med Chem 2009; Jd: 455-72] [Scaglione JB, Jastrzebska I, Krishnan K, Li P, Akk, Manion BD, Benz A, Tailor A, Rath NP, Zorumski CF, Mennerick S, Covey DF . Neurosteroid analogues. 11. Alternative ring system scaffolds: gamma-aminobutyric acid receptor modulation and anesthetic actions of benz [f] indenes. JMed Chem 2006; 49: 4595-605], Eisenman LN, Shu HJ, Akk G, Wang C, Manion BD, Kress GJ, Evers AS, Steinbach JH, Covey DF, Zorumski CF, Mennerick S. Anticonvulsant and anesthetic effects of and a fluorescent neurosteroid analog activated by visible light. Nature Neurosci 2007,70: 523-30],
Nevýhodou endogenního allopregnanoíonu (I) je, že se v těle rychle metabolizuje. Proto byla hledána analoga allopregnanoíonu, která byla založena na nejrůznějších modifikacích steroidního skeletu [Veleiro AS, Burton G. Structure-Activity Relationships of Neuroactive Steroíds Acting on the GABA(A) Receptor. Curr Med Chem 2009, 76:455-72].The disadvantage of endogenous allopregnanone (I) is that it metabolizes rapidly in the body. Therefore, allopregnanone analogs have been sought based on various modifications of the steroid skeleton [Veleiro AS, Burton G. Structure-Activity Relationships of Neuroactive Steroids Acting on the GABA (A) Receptor. Curr Med Chem 2009, 76: 455-72].
Nyní jsme překvapivě zjistili, že námi syntetizovaná nová sloučenina, 3a-hydroxy-2^,22oxido-21-homo-5a-pregnan-20-on vzorce IIWe have now surprisingly found that the novel compound we synthesized, 3α-hydroxy-2β, 22oxido-21-homo-5α-pregnan-20-one of formula II
(II) se váže na GABAa receptor in vitro a v souladu stím i potlačuje dva typy křečí indukovaných pentylen^etrazolem u potkanů srovnatelně s účinky ganaxolonu. Příprava látky vzorce II a její biologická aktivita je předmětem tohoto vynálezu.(II) binds to the GABAa receptor in vitro and, accordingly, suppresses two types of pentylene-etrazole-induced seizures in rats comparable to the effects of ganaxolone. The preparation of the compound of formula II and its biological activity is the object of the present invention.
Podstata vynálezuSUMMARY OF THE INVENTION
Tento vynález se týká 3a-hydroxy-2K,22-oxido-21-homo-5a-pregnan-20-onu vzorce IIThis invention relates to 3α-hydroxy-2K, 22-oxido-21-homo-5α-pregnan-20-one of formula II
(II),(II),
Dále se tento vynález týká syntézy 3a-hydroxy-21g22-oxido-2l-homo-5a-pregnarr20-onuFurthermore, the present invention relates to the synthesis of 3α-hydroxy-21g22-oxido-21-homo-5α-pregnarr20-one
II, která spočívá v tom, že se známý allopregnanolon vzorce III, characterized in that the known allopregnanolone of the formula I is known
se za podmínek Mannichovy kondensace převede na amin III,is converted to amine III under conditions of Mannich condensation,
· í' Λ <' x j *7 1 jehož;methobromid vzorce IV· '' Λ <' x j * 7 1 whose ; methobromide of formula IV
se rozloží na 21-homo-3a-hydroxy-5a-pregn-21-en-20-on vzorce Vis decomposed to 21-homo-3α-hydroxy-5α-pregn-21-en-20-one of formula V
který se oxiduje peroxidem vodíku na látkuwhich is oxidized by hydrogen peroxide to the substance
Tento vynález bude podrobněji ilustrován na následujících příkladech, které není možné brát jako omezení předloženého vynálezu, ale pouze jako jeho ilustraci.The present invention will be illustrated in more detail by the following examples, which are not to be construed as limiting the present invention but merely to illustrate it.
Příklady provedení vynálezuDETAILED DESCRIPTION OF THE INVENTION
Příklad 1Example 1
Výroba 3a-hydroxy-21£,22-oxido-21-homo-5a-pregnan-20-onu (II)Production of 3α-hydroxy-21α, 22-oxido-21-homo-5α-pregnan-20-one (II)
Roztok vodného peroxidu vodíku (33%, 2,0 mL) a hydroxidu sodného (4 N, 0.4 mL) v methanolu (8,0 mL) se přidá k roztoku olefinu V (150 mg, 0,45 mmol) ve směsi methanolu a THF (25 mL, 1:1) při 0 °C. Po 4 hodinách se rozpouštědlo částečně odpaří ve vakuu a produkt se vysráží přidáním nasyceného vodného roztoku chloridu sodného. Extrakce octanem ethylnatým poskytne bílé krystaly látky II (120 mg, 76 %). Tt 172-175 °C (aceton/heptan). [a]D +122 (CHClj, c 0,3). IR (CHCI3): 3616, 3489,1001 (OH); 3063 (epoxid); 1712 (OO). Pro C22H34O3 (346,5) vypočteno: 76.26 %C, 9.89 %H; nalezeno: 76,04 %C, 10.14 %H. Pro NMR spektrum, viz Tabulka 1.A solution of aqueous hydrogen peroxide (33%, 2.0 mL) and sodium hydroxide (4 N, 0.4 mL) in methanol (8.0 mL) was added to a solution of olefin V (150 mg, 0.45 mmol) in a mixture of methanol and THF (25 mL, 1: 1) at 0 ° C. After 4 hours the solvent was partially evaporated in vacuo and the product precipitated by addition of saturated aqueous sodium chloride solution. Extraction with ethyl acetate gave white crystals of compound II (120 mg, 76%). Mp 172-175 ° C (acetone / heptane). [α] D +122 (CHCl 3, c 0.3). IR (CHCl 3): 3616, 3489.1001 (OH); 3063 (epoxide); 1712 (OO). For C 22 H 34 O 3 (346.5) calculated: 76.26% C, 9.89% H; Found:% C, 76.04;% H, 10.14. For the NMR spectrum, see Table 1.
Příklad 2Example 2
Výroba 3a’Hydroxy-21-homo-5a-pregn-21-en-20-onu (V)Production of 3a’Hydroxy-21-homo-5a-pregn-21-en-20-one (V)
Allopregnanolon (I) byl podroben Mannichově reakci a rozkladu příslušné kvartémí amoniové base podle japonských autorů [Hikino H, Okuyama T, Arihara S, Hikino Y, Takemoto T, Mori H, Shibata K. Steroids. 24. Shidasterone, an insect metamorphosing substance fřom Blechnum-niponicum - structure. Chem Pharm Bull 1975;23:1458-79]. Látka V tvoří bílé krystaly, tt 153-154 °C (aceton/heptan). [a]o +127 (CHCI3, c 0.2). IR (CHCh): 3616,3479,1002 (OH); 1689,1664,1618,1609,986,960 (C=C-C=O). Pro C22H34O2 (330.5) vypočteno: 79,95 %C, 10.37 %H; nalezeno: 79,55 %C, 10,45 %H. NMR spektrum viz následující tabulka.Allopregnanolone (I) was subjected to Mannich reaction and decomposition of the respective quaternary ammonium base according to Japanese authors [Hikino H, Okuyama T, Arihara S, Hikino Y, Takemoto T, Mori H, Shibata K. Steroids. 24. Shidasterone, an insect metamorphosing substance of Blechnum-niponicum - structure. Chem Pharm Bull 1975; 23: 1458-79]. Compound V forms white crystals, mp 153-154 ° C (acetone / heptane). [α] D +127 (CHCl 3, c 0.2). IR (CHCl3): 3616,3479, 1002 (OH); 1689, 1664, 1618, 1609, 986,960 (C = C-C = O). For C 22 H 34 O 2 (330.5) calculated: 79.95% C, 10.37% H; Found:% C, 79.55;% H, 10.45. The NMR spectrum is as follows.
Tabulka 1 13C a lH NMR spektra popisovaných látek 13 C and 1 H NMR spectra of the compounds described
Příklad 3Example 3
AktivitaActivity
Látka II vykázala v GABAa receptorovém testu s použitím TBPS jako radioligandu tuto aktivitu: látka modulovala GABAa receptor s mohutností účinnosti IC50 = 50nM a efektivitou Imax = 40 %. Tento výsledek ukazuje, že tato sloučenina je účinná při ovlivňování stavů řízených inhibičními účinky γ-aminomáselné kyseliny, např. epileptických záchvatů.Compound II showed the following activity in the GABAa receptor assay using TBPS as a radioligand: the compound modulated the GABAa receptor with a potency of IC50 = 50nM and an efficacy of I max = 40%. This result shows that this compound is effective in influencing conditions controlled by the inhibitory effects of γ-aminobutyric acid, eg epileptic seizures.
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