ES2524724T3 - Método para preparar 3alfa-hidroxi,3beta-metil-5alfa-pregnán-20-ona (ganaxolona) - Google Patents
Método para preparar 3alfa-hidroxi,3beta-metil-5alfa-pregnán-20-ona (ganaxolona) Download PDFInfo
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- ES2524724T3 ES2524724T3 ES10808696.8T ES10808696T ES2524724T3 ES 2524724 T3 ES2524724 T3 ES 2524724T3 ES 10808696 T ES10808696 T ES 10808696T ES 2524724 T3 ES2524724 T3 ES 2524724T3
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- Prior art keywords
- methyl
- titanium
- inert solvent
- halide
- methylating agent
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- PGTVWKLGGCQMBR-FLBATMFCSA-N Ganaxolone Chemical compound C([C@@H]1CC2)[C@](C)(O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 PGTVWKLGGCQMBR-FLBATMFCSA-N 0.000 title abstract description 5
- 229950006567 ganaxolone Drugs 0.000 title abstract description 5
- 238000000034 method Methods 0.000 title abstract 3
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 abstract description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- XMRPGKVKISIQBV-BJMCWZGWSA-N 5alpha-pregnane-3,20-dione Chemical compound C([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 XMRPGKVKISIQBV-BJMCWZGWSA-N 0.000 abstract description 3
- 229910003074 TiCl4 Inorganic materials 0.000 abstract description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 abstract description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 abstract description 2
- 239000012442 inert solvent Substances 0.000 abstract 8
- -1 methyl lithium halide Chemical class 0.000 abstract 8
- 239000012022 methylating agents Substances 0.000 abstract 7
- 125000002524 organometallic group Chemical group 0.000 abstract 7
- GNLJBJNONOOOQC-UHFFFAOYSA-N $l^{3}-carbane;magnesium Chemical compound [Mg]C GNLJBJNONOOOQC-UHFFFAOYSA-N 0.000 abstract 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 abstract 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract 2
- 229910052742 iron Inorganic materials 0.000 abstract 2
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 abstract 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract 1
- DNEWOQIRIUNXCU-UHFFFAOYSA-M CCO[Ti](C)(Cl)OCC Chemical compound CCO[Ti](C)(Cl)OCC DNEWOQIRIUNXCU-UHFFFAOYSA-M 0.000 abstract 1
- ITJHDXSUEINCDE-UHFFFAOYSA-N CCO[Ti](C)(OCC)OCC Chemical compound CCO[Ti](C)(OCC)OCC ITJHDXSUEINCDE-UHFFFAOYSA-N 0.000 abstract 1
- KFKFCEOMOZCKGN-UHFFFAOYSA-M C[Fe]Cl Chemical compound C[Fe]Cl KFKFCEOMOZCKGN-UHFFFAOYSA-M 0.000 abstract 1
- UHBKEKFHZYFRRU-UHFFFAOYSA-N C[Ti](C)(C)C Chemical compound C[Ti](C)(C)C UHBKEKFHZYFRRU-UHFFFAOYSA-N 0.000 abstract 1
- ZSURQIOGCDFZDR-UHFFFAOYSA-M C[Ti](C)(C)Cl Chemical compound C[Ti](C)(C)Cl ZSURQIOGCDFZDR-UHFFFAOYSA-M 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 abstract 1
- XWMCJIOSNAXGAT-UHFFFAOYSA-L [Cl-].[Cl-].C[Ti+2]C Chemical compound [Cl-].[Cl-].C[Ti+2]C XWMCJIOSNAXGAT-UHFFFAOYSA-L 0.000 abstract 1
- DGXOWMLKUUUVMZ-UHFFFAOYSA-K [Cl-].[Cl-].[Cl-].[Ti+3]C Chemical compound [Cl-].[Cl-].[Cl-].[Ti+3]C DGXOWMLKUUUVMZ-UHFFFAOYSA-K 0.000 abstract 1
- SDDQYJUEVKDWCP-UHFFFAOYSA-N carbanide;iron(2+) Chemical group [CH3-].[CH3-].[Fe+2] SDDQYJUEVKDWCP-UHFFFAOYSA-N 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- 239000010936 titanium Substances 0.000 abstract 1
- 229910052719 titanium Inorganic materials 0.000 abstract 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 10
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 10
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- AURFZBICLPNKBZ-YZRLXODZSA-N 3alpha-hydroxy-5beta-pregnan-20-one Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-YZRLXODZSA-N 0.000 description 2
- 241000349731 Afzelia bipindensis Species 0.000 description 2
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 description 2
- 229950007402 eltanolone Drugs 0.000 description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- FGRBYDKOBBBPOI-UHFFFAOYSA-N 10,10-dioxo-2-[4-(N-phenylanilino)phenyl]thioxanthen-9-one Chemical compound O=C1c2ccccc2S(=O)(=O)c2ccc(cc12)-c1ccc(cc1)N(c1ccccc1)c1ccccc1 FGRBYDKOBBBPOI-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000556679 Pholis Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229910000856 hastalloy Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Método para la preparación de 3α-hidroxi, 3ß-metil-5α-pregnán-20-ona (ganaxolona), que comprende: hacer reaccionar 5α-pregnán-3,20-diona, con un agente metilante organometálico, en un solvente inerte, comprendiendo dicho método por lo menos una de las etapas siguientes: (a) generar el agente metilante organometálico mediante la adición de aproximadamente 2 a aproximadamente 4 equivalentes de haluro de metil-magnesio o metil-litio a haluro férrico anhidro o haluro ferroso anhidro en un solvente inerte; (b) generar el agente metilante organometálico mediante la adición de aproximadamente 0,1 a aproximadamente 4 equivalentes de cloruro de litio a haluro de hierro en un solvente inerte, previamente a la adición de 3 a 4 equivalentes (basado en haluro de hierro) de haluro de metil-magnesio; (c) generar el agente metilante organometálico mediante la adición de aproximadamente 1 equivalente de haluro de metil-magnesio o metil-litio a una solución de cloruro de tri(alcoxi C1-C3)-titanio en un solvente inerte; (d) generar el agente metilante organometálico mediante la adición de aproximadamente 1 equivalente de haluro de metil-magnesio o metil-litio a una solución de dicloruro de di(alcoxi C1-C3)-titanio anhidro en un solvente inerte; y (e) generar el agente metilante organometálico mediante la adición de aproximadamente 1 a aproximadamente 4 equivalentes de haluro de metil-magnesio o metil-litio a TiCl4 en un solvente inerte; en el que: - el agente metilante organometálico es dimetil-hierro (Me2Fe), metil-trietoxi-titanio, metilcloro-dietoxi-titanio ((CH3)Cl(CH3CH2O)2Ti), metil-tricloro-titanio (CH3Cl3Ti), tetrametil-titanio ((CH3)4Ti), dimetil-dicloro-titanio ((CH3)Cl2Ti), trimetil-cloro-titanio ((CH3)3ClTi), o cloruro de metil-hierro (CH3FeCl); - el solvente inerte es tetrahidrofurano, glima, éter t-butil-metílico, 1,4-dioxano, dimetoxietano o éter dietílico; y - el solvente inerte se mantiene a una temperatura de aproximadamente -40ºC a aproximadamente 35ºC durante la reacción.
Description
E10808696
24-11-2014
Se cargó THF (anhidro, 120 g) y LiCl (anhidro, 2,12 g, 50 mmoles) en un matraz de fondo redondo de 3 cuellos de
5 500 ml seco. El matraz se enfrió a -10ºC y se añadió FeCl3 (anhidro, 1,28 g, 7,9 mmoles). Se enfrió la mezcla a 35ºC bajo nitrógeno. Se añadió lentamente la solución de MeMgCl en tetrahidrofurano (3 M, 13,3 ml, 39,9 mmoles), manteniendo simultáneamente una temperatura interna de entre -27ºC y -35ºC durante la adición. Tras la adición, se añadió 5α-pregnán-3,20-diona (10 g, 31,6 mmoles) de una vez y la mezcla resultante se agitó a una temperatura de entre -25ºC y -20ºC bajo nitrógeno. Se realizó un seguimiento de la reacción mediante HPLC de la manera siguiente:
10 se extrajo una alícuota, se desactivó con HCl 3 N y se extrajo con acetato de etilo. La capa orgánica se lavó con NaOH 3 N y agua, y se evaporó a sequedad. El residuo blanco se disolvió en metanol y se analizó mediante HPLC (Tabla 1, entrada 11).
- Tabla 1. Conversión de 5α-pregnán-3,20-diona en ganaxolona
- Entrada
- % (3) % de diona (2) % (5) % de mono C-20 (6) % de ganaxolona (1) % (4) Condiciones de reacción
- TRR
- 0,68 0,75 0,82 0,9 1 1,09
- 1
- 8,64 39,94 13,13 9,98 11,16 18,06 MeLi (1,0 eq.); -25ºC a -20ºC, 1h
- 2
- 8,47 0,99 11,47 1,57 30,08 44,98 Me3Al (3,0 eq.); 0ºC a 15ºC, 16h
- 3
- 17,16 1,26 0,52 ND 75,86 2,06 Ti(OEt)4 (1,3 eq.), TiCl4 (0,4 eq.), MeMgCl (1,6 eq.), 40ºC
- 4
- 5,40 4,36 0,57 0,09 80,24 8,48 FeCl3 (1,2 eq.), MeMgCl (4,8 eq.); -40ºC a -20ºC, 2h
- 5
- 0,93 1,19 ND ND 94,73 2,44 FeCl3 (1,1 eq.), MeLi (1,1 eq.), MeMgCl (3,3 eq.), PhOLi (1,0 eq.); -50ºC a -20ºC
- 6
- 1,22 0,96 ND ND 94,46 2,18 FeCl3 (1,1 eq.), LiCl (1,6 eq.), MeMgCl (4,4 eq.); -40ºC a -18ºC
- 7
- 1,15 1,16 ND ND 95,28 1,72 FeCl3 (1,1 eq.), LiCl (2,1 eq.), MeMgCl (4,0 eq.); -35ºC a -15ºC
- 8
- 1,52 1,47 ND ND 94,25 1,93 FeCl3 (1,0 eq.), LiCl (3,3 eq.), MeMgCl (4,0 eq.); -23ºC a -15ºC
- 9a
- 23,37 3,33 2,86 ND 58,06 5,12 FeCl3 (1,05 eq.), MeMgCl (4,0 eq.), LiCl (1,58 eq.); 1h, 0 a 15ºC
- 10
- 1,33 1,29 0,47 0,31 70,92 24,5 FeCl3 (1,1 eq.), MeMgCl (5,5 eq.), LiCl (1,58 eq.), 1h, -25ºC a -20ºC
- 11b
- 0,65 52,08 0,51 ND 45,44 0,18 FeCl3 (0,25 eq.), MeMgCl (1,25 eq.), LiCl (1,58 eq.), 1h, -25ºC a -20ºC
a
15 Se detectaron mediante HPLC cuatro producto secundarios desconocidos adicionales. b La reacción no se había completado tras 20 h, restando aproximadamente 30% del material de partida de 3,20-diona.
20 Se cargaron THF (anhidro, 9,65 kg) y LiCl (anhidro, 0,21 kg) en un reactor de Hastelloy de 50 l purgado con N2. La mezcla se agitó bajo N2 y se enfrió a -10ºC durante 1 h. Se cargó FeCl3 (anhidro, 0,515 kg) en el reactor bajo
10
13
- Tabla 2. Perfiles de pureza de lotes de ganaxolona antes y después de las purificaciones
- Perfil de pureza
- Pregnanolona* 20-dimetil-20hidroxi-5αpregnán-3ol** 3-Epi (3) 3,20-diona 2 Metilación 3-Epi C-20 (5) Metilación de C-20 (6) GNX 1 4 7*** PD PD PD PD PD
- Entrada
- TRR 0,57 0,63 0,68 0,75 0,82 0,9 1,00 1,09 1,44 1,63 1,77 2,27 2,41 2,78
- 1
- Ejemplo 12A (en bruto) 0,46 0,08 0,86 0,20 ND ND 95,57 1,35 ND 0,08 0,43 0,12 0,47 0,33
- 2
- Ejemplo 13A (purificado) 0,05 0,07 0,05 0,03 ND ND 99,71 0,07 ND ND ND ND ND ND
- 3
- Ejemplo 13B (purificado) 0,02 0,07 0,01 ND ND ND 99,83 0,07 ND ND ND ND ND ND
- 4
- Ejemplo 12A (en bruto) 0,43 0,07 0,68 0,08 ND ND 97,33 0,59 0,06 ND 0,08 ND 0,67 ND
- 5
- Ejemplo 13C (purificado) 0,03 0,04 0,05 ND ND ND 99,81 0,06 ND ND ND ND ND ND
- 6
- Ejemplo 13D (en bruto) 0,27 0,08 0,45 0,45 ND ND 97,97 0,31 ND 0,09 0,38 ND ND ND
- 7
- Ejemplo 13D (purificado) 0,07 0,08 0,07 0,03 ND ND 99,69 0,06 ND ND ND ND ND ND
- 8
- Ejemplo 13E (en bruto) 0,45 0,03 0,59 0,57 0,05 0,03 88,79 9,23 0,06 0,07 0,12 ND ND ND
- 9
- Ejemplo 13E (purificado) 0,03 ND 0,06 ND ND ND 99,86 0,06 ND ND ND ND ND ND
* Transferido de 5α-pregnán-3,20-diona; ** Probablemente formado mediante metilación del carbonilo de C20 de la pregnanolona; *** producto de deshidratación de 20-OH de la impureza 4; PD: producto desconocido; ND: no detectado.
Claims (1)
-
imagen1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23355309P | 2009-08-13 | 2009-08-13 | |
| US233553P | 2009-08-13 | ||
| PCT/US2010/045176 WO2011019821A2 (en) | 2009-08-13 | 2010-08-11 | METHOD FOR MAKING 3α-HYDROXY, 3β- METHYL-5α-PREGNAN-20-ONE (GANAXOLONE) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2524724T3 true ES2524724T3 (es) | 2014-12-11 |
Family
ID=43586809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10808696.8T Active ES2524724T3 (es) | 2009-08-13 | 2010-08-11 | Método para preparar 3alfa-hidroxi,3beta-metil-5alfa-pregnán-20-ona (ganaxolona) |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US8362286B2 (es) |
| EP (1) | EP2464653B1 (es) |
| JP (1) | JP5745517B2 (es) |
| KR (1) | KR101778603B1 (es) |
| CN (1) | CN102549007B (es) |
| AU (1) | AU2010282570B2 (es) |
| BR (1) | BR112012003085B1 (es) |
| CA (1) | CA2769820C (es) |
| EA (1) | EA024269B1 (es) |
| ES (1) | ES2524724T3 (es) |
| HK (1) | HK1171761A1 (es) |
| IL (1) | IL217857A (es) |
| MX (1) | MX2012001728A (es) |
| NZ (1) | NZ597940A (es) |
| WO (1) | WO2011019821A2 (es) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2008006888A (es) | 2005-11-28 | 2008-09-30 | Marinus Pharmaceuticals | Formulas y metodos para la manufactura y uso de la ganaxolona. |
| US9629853B2 (en) | 2014-05-21 | 2017-04-25 | Wisconsin Alumni Research Foundation | Uses of ganaxolone |
| CZ2015130A3 (cs) * | 2015-02-25 | 2016-03-30 | Vysoká škola chemicko - technologická v Praze | (3α,5β,20S)-3-Nitrooxy-pregnan-20-karboxylová kyselina |
| EA036155B1 (ru) | 2015-10-16 | 2020-10-06 | Маринус Фармасьютикалс, Инк. | Инъекционные составы нейростероида, содержащие наночастицы |
| CN106279326A (zh) * | 2016-08-09 | 2017-01-04 | 南京臣功制药股份有限公司 | 一种醋酸甲羟孕酮胶囊的有关物质及其分析检测方法 |
| CN106366149B (zh) * | 2016-08-09 | 2018-01-23 | 南京臣功制药股份有限公司 | 一种醋酸甲羟孕酮分散片的有关物质及其分析检测方法 |
| EP4233861A3 (en) | 2016-08-11 | 2023-10-11 | Ovid Therapeutics, Inc. | Compositions for treatment of essential tremor |
| US10391105B2 (en) | 2016-09-09 | 2019-08-27 | Marinus Pharmaceuticals Inc. | Methods of treating certain depressive disorders and delirium tremens |
| IT201800009683A1 (it) * | 2018-10-22 | 2020-04-22 | Ind Chimica Srl | Processo per la preparazione di 3α-idrossi-5α-pregnan-20-one (brexanolone) |
| US11266662B2 (en) | 2018-12-07 | 2022-03-08 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in prophylaxis and treatment of postpartum depression |
| MX2022001553A (es) | 2019-08-05 | 2022-04-18 | Marinus Pharmaceuticals Inc | Ganaxolona para su uso en el tratamiento del estado epileptico. |
| CN114828889A (zh) | 2019-12-06 | 2022-07-29 | 马瑞纳斯制药公司 | 用于治疗结节性硬化症的加奈索酮 |
| IT202000021316A1 (it) * | 2020-09-09 | 2022-03-09 | Ind Chimica Srl | PROCESSO PER LA PREPARAZIONE DI (3α,5α)-3-IDROSSI-3-METIL-PREGNAN-20-ONE (GANAXOLONE) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3953429A (en) * | 1970-12-17 | 1976-04-27 | Glaxo Laboratories Limited | Anaesthetic steroids of the androstance and pregnane series |
| US5319115A (en) | 1987-08-25 | 1994-06-07 | Cocensys Inc. | Method for making 3α-hydroxy, 3β-substituted-pregnanes |
| US5232917A (en) * | 1987-08-25 | 1993-08-03 | University Of Southern California | Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series |
| AU698834B2 (en) * | 1993-05-24 | 1998-11-12 | Purdue Pharma Ltd. | Methods and compositions for inducing sleep |
| FR2720747B1 (fr) * | 1994-06-02 | 1996-07-12 | Roussel Uclaf | Nouveau procédé de préparation d'un stéroïde 16béta-méthyl et nouveaux intermédiaires. |
| GEP20002033B (en) * | 1994-11-23 | 2000-04-10 | Cocensys Inc Us | Androstane and Pregnane Series Compounds for Allosteric Modulation of GABA Receptor |
| WO2006010085A1 (en) * | 2004-07-09 | 2006-01-26 | Roxro Pharma, Inc. | Use of neurosteroids to treat neuropathic pain |
| MX2008006888A (es) * | 2005-11-28 | 2008-09-30 | Marinus Pharmaceuticals | Formulas y metodos para la manufactura y uso de la ganaxolona. |
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| IL217857A0 (en) | 2012-03-29 |
| US20110040112A1 (en) | 2011-02-17 |
| CN102549007B (zh) | 2015-03-18 |
| AU2010282570A1 (en) | 2012-02-23 |
| JP5745517B2 (ja) | 2015-07-08 |
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| WO2011019821A2 (en) | 2011-02-17 |
| KR101778603B1 (ko) | 2017-09-14 |
| HK1171761A1 (en) | 2013-04-05 |
| BR112012003085A2 (pt) | 2020-12-01 |
| KR20120084715A (ko) | 2012-07-30 |
| NZ597940A (en) | 2013-03-28 |
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| CN102549007A (zh) | 2012-07-04 |
| JP2013501803A (ja) | 2013-01-17 |
| EP2464653A2 (en) | 2012-06-20 |
| CA2769820C (en) | 2017-06-27 |
| EA201270241A1 (ru) | 2013-09-30 |
| US8362286B2 (en) | 2013-01-29 |
| BR112012003085B1 (pt) | 2021-06-01 |
| MX2012001728A (es) | 2012-06-01 |
| WO2011019821A3 (en) | 2011-06-16 |
| AU2010282570B2 (en) | 2014-04-24 |
| EP2464653B1 (en) | 2014-10-22 |
| IL217857A (en) | 2016-03-31 |
| EP2464653A4 (en) | 2013-01-16 |
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