ES2621528T3 - Derivados de 3-(4’-sustituido)-bencil éter de pregnenolona - Google Patents

Derivados de 3-(4’-sustituido)-bencil éter de pregnenolona Download PDF

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ES2621528T3
ES2621528T3 ES13795536.5T ES13795536T ES2621528T3 ES 2621528 T3 ES2621528 T3 ES 2621528T3 ES 13795536 T ES13795536 T ES 13795536T ES 2621528 T3 ES2621528 T3 ES 2621528T3
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pregnenolone
substituted
benzyl ether
mmol
ether derivatives
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Pier Vincenzo PIAZZA
Monique VALLEE
François-Xavier FELPIN
Jean-Michel REVEST
Sandy FABRE
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Sc Belenos
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Bordeaux
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Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Bordeaux
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    • 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
    • A—HUMAN NECESSITIES
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    • 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
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    • C—CHEMISTRY; METALLURGY
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    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • 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

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Abstract

Compuesto de fórmula I o una sal farmacéuticamente aceptable del mismo,**Fórmula** en donde: R1 es: alquilo C1-8, alcoxilo C1-8, CN, NO2, amino, COOH, COOCH3, OH, N3, o halógeno y R2 es: H, OH, alquilo C1-8, alcoxilo C1-8, alquenilo C2-C6, halógeno, Bn-O-, Bn- opcionalmente sustituido con alquilo C1-8, alcoxilo C1-8, CN, NO2, amino, COOH o halógeno o Ph- opcionalmente sustituido con alquilo C1-8, alcoxilo C1-8, CN, NO2, amino, COOH o halógeno.

Description

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5 Como se muestra más adelante, a una solución de pregnenolona (477 mg; 1,51 mmol; 1 eq.) en ,,trifluorotolueno anhidro (9 mL) se le agregaron MgO (121 mg; 3,02 mmol; 2,0 eq.) y después Triflato de 2-(pBromobenciloxi)-1-metilpiridinio (1,29 g; 3,02 mmol; 2,0 eq.). El medio de reacción se agitó por 20 horas a 100 °C y después se filtró sobre celite. Se agregó agua y el producto se extrajo con AcOEt. La fase orgánica se seca (Na2SO4) y después se evapora bajo vacío. El residuo se purificó por medio de cromatografía sobre gel de sílice
10 (eluyente: ciclohexano/AcO/Et96/4) y después se trituró con acetona para dar la 3-(p-bromobenciloxi)-pregnenolona (375 mg; 49 %) como un sólido blanco.
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le agregaron sucesivamente MgO (63 mg; 1,58 mmol; 2,0 eq.), 2-(4-metoxibenciloxi)-4-metilquinoleína (441 mg; 1,58 mmol; 2,0 eq.) y triflato de metilo (MeOTf) (180 µl; 1,58 mmol; 2 eq). El medio de reacción se agitó por 20 horas a 60
20 °C y después se filtró sobre celite. Se agregó agua y el producto se extrajo con AcOEt. La fase orgánica se seca (Na2SO4) y después se evapora bajo vacío. El residuo se purificó por medio de cromatografía sobre gel de sílice (eluyente: ciclohexano/AcO/Et96/1) para dar la 3-(p-metoxibenciloxi)-pregnenolona (160 mg; 43 %) como un sólido blanco.
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La 17-metil-pregnenolona se sintetizó como se mostró anteriormente.
30 A una solución de 17-metil-pregnenolona (170 mg; 0,5 mmol; 1 eq.) en tolueno anhidro se le agregaron sucesivamente MgO (40 mg; 1 mmol; 2 eq.), 2-(4-metoxibenciloxi)-4-metilquinoleína (290 mg; 1 mmol; 2 eq), y triflato de metilo (MeOTf) (0,11 ml; 1 mmol; 2 eq). El medio de reacción se agitó por una noche a 85 °C y después se filtró sobre celite. Se agregó agua y el producto se extrajo con AcOEt. La fase orgánica se seca (Na2SO4) y después se
35 evapora bajo vacío. El residuo se purificó por medio de cromatografía sobre gel de sílice (eluyente: ciclohexano/AcO/Et de 1/0 a 95/5) y después se trituró con acetona para dar la 3-(p-metoxibenciloxi)-17-metilpregnenolona (80 mg; 35 %) como un sólido blanco.
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Cuadro 1: Metabolismo de pregnenolona
ALO EPIALO PREG DHEA TESTO
Cultivos celulares de control
0,00 0,00 96,92 0,00 0,00
Células tratadas con pregnenolona (1 µM)
Niveles de esteroides pg/ml 3529,99 16963,84 11440,66 0,00 0,00
Los derivados de pregnenolona que tienen C3 sustituido con benciloxi se pusieron a prueba usando una prueba in vitro en células de CHO.
5 Los resultados se muestran en el Cuadro 2 más adelante. Los resultados expresados como cambios en porcentaje de células de CHO tratadas con Pregnenolona o como pg/ml (0 = concentraciones por debajo del límite de detección).
CUADRO 2
10
Cuadro 2: Metabolismo reducido
Porcentaje de cambios de células tratadas con Pregnenolona pg/ml
No.
Nombre Estructura ALLO EPIALLO PREG DHEA TESTO
42
3β-Benciloxi-17-metilpregnenolona -99,87 -99,94 -100,00 0,00 0,00
63
17-Bencil-3β-benciloxipregnenolona -99,01 -99,84 -99,87 0,00 0,00
41
3β-Benciloxipregnenolona -98,82 -99,88 -99,35 0,00 0,00
68
3β-(p-metoxi-benciloxi)17-metil-pregnenolona imagen19 -100,00 -100,00 -100,00 0,00 0,00
Como se muestra en el Cuadro 2, el compuesto 68, 3β-(p-Metoxibenciloxi)-17-metil-pregnenolona, no se metaboliza en Pregnenolona y los compuestos 63 y 41 no se metabolizan significativamente en Pregnenolona (metabolización < 1 %).
15 Los derivados de pregnenolona que contienen una función de 3-benciloxi (sustituido o no) no muestran metabolización detectable del derivado de Pregnenolona en DHEA y Testosterona y metabolización muy baja en Alopregnanolona y Epialopregnanolona.
20 Estos resultados muestran la presencia de un grupo OBn-R en C3 que evita la conversión de derivados de Pregnenolona en Pregnenolona y derivados de Pregnenolona, en particular metabolitos cuya pregnenolona es precursora y que están dotados con propiedades progestativas, androgénicas, estrogénicas, de actividad glucocorticoide o neuromoduladoras.
25 Referencias
A lo largo de esta solicitud, varias referencias describen el estado de la técnica al cual pertenece esta invención. Las divulgaciones de estas referencias se incorporan por este medio como referencia en la presente divulgación.
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rapid, nongenomic effects. Pharmacol Rev. 2000 Dec;52(4):513-56. García-Estrada J, Luquín S, Fernández AM, Garcia-Segura LM.Dehydroepiandrosterone, pregnenolone and sex
steroids down-regulate reactive astroglia in the male rat brain after a penetrating brain injury. Int J DevNeurosci. 1999 Apr;17(2):145-51. Gasior M, Carter RB, Witkin JM. Neuroactive steroids: potential therapeutic use in neurological and psychiatric
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bromo-ketones.Nuclear magnetic resonance spectra of 11-keto-steroids J. Chem. Soc., 1965, 2933-2944.
Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Progress in Neurobiology.2003; 71:67–80. Majewska MD, Harrison NL, Schwartz RD, Barker JL and Paul SM Steroid hormone metabolites are barbiturate-like
modulators of the GABA receptor. Science (Wash DC) (1986) 232:1004–1007.
Marshall C.W., Kritchevsky T.H., Lieberman S., and Gallagher T.F. Preparation of 17-Ketosteroids from Enol Acetates of 20-Ketosteroids. J. Am. Chem. Soc., 1948, 70 (5), pp 1837–1839 Mathis C, Paul SM, Crawley JN. The neurosteroidpregnenolonesulfate blocks NMDA antagonist-induced deficits in a
passive avoidance memory task. Psychopharmacology (Berl). 1994 Oct;116(2):201-6.
Nwoye, E. O.and Dudley, G. B. A method for the synthesis of para-methoxybenzyl (PMB) ethers under effectively neutral conditions. Chem. Commun. 2007, 1436-1437. Paul SM, Purdy RH. Neuroactive steroids FASEB J. 1992 Mar;6(6):2311-22. Review. Poon KWC. and Dudley G.B., Mix-and-Heat Benzylation of Alcohols Using a Bench-Stable Pyridinium Salt J. Org.
Chem., 2006, 71, 3923-3927
Reddy DS, Rogawski MA. Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy. Journal of Pharmacology and Experimental Therapeutics. 2000a; 294:909–915. Reddy DS. Pharmacology of endogenous neuroactive steroids. Critical Reviews in Neurobiology. 2003; 15:197–234. Reddy DS. Mass spectrometric quantification and physiological-pharmacological activity of androgenic neurosteroids.
Neurochemistry International. 2008; 52(4–5):541–553. Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010;186:113-37. Review.
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Claims (1)

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ES13795536.5T 2012-11-28 2013-11-27 Derivados de 3-(4’-sustituido)-bencil éter de pregnenolona Active ES2621528T3 (es)

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