ES2562452T3 - Compuestos químicos - Google Patents

Compuestos químicos Download PDF

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ES2562452T3
ES2562452T3 ES09800991.3T ES09800991T ES2562452T3 ES 2562452 T3 ES2562452 T3 ES 2562452T3 ES 09800991 T ES09800991 T ES 09800991T ES 2562452 T3 ES2562452 T3 ES 2562452T3
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methyl
oxy
mmol
carbonyl
carbonate
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Brian Alvin Johns
Jason Gordon Weatherhead
Yasunori Aoyama
Toshikazu Hakogi
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Shionogi and Co Ltd
ViiV Healthcare Co
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ViiV Healthcare Co
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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Abstract

Un compuesto de fórmula (I):**Fórmula** donde: R1 es alquilo C1-C8, arilo C6-C10 o LR2; L es alquileno; R2 es a) hidroxi; b) alcoxi; c) OR3 donde R3 es P(O)(OH)2, alcoxi o alquilen-alcoxi; d) heterociclilo opcionalmente sustituido con oxo o alquilo C1-C8; e) C(O)OR4 donde R4 es H, alquilo C1-C8, o XR5 donde X es alquileno y R5 es arilo C6-C10, heterociclilo, o NR6R7 donde R6 y R7 se seleccionan independientemente entre el grupo que consiste en H y alquilo C1-C8; f) NR6R7; g) C(O)NR8R9 donde R8 y R9 se seleccionan independientemente entre el grupo que consiste en H y XR5; o h) C(O)R10 donde R10 es heterociclilo opcionalmente sustituido con XR11 donde R11 es heterociclilo; o una sal farmacéuticamente aceptable del mismo.

Description

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5 Se pretende que los siguientes ejemplos sean únicamente ilustrativos y no se pretende que limiten el alcance de la invención de ninguna manera.
Preparación 1: sal sódica de (3S,11aR)-N-[(2,4-difluorofenil)metil]-6-hidroxi-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3,2-a]pirido[1,2 10 -d]pirazina-8-carboxamida (compuesto 1b, esquema 2)
11
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Ejemplo 1: carbonato de {[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3,2-a] pirido[1,2-d]pirazin-6-il]oxi}metilo y metilo
imagen14
5
a) Carbonato de clorometilo y metilo. Se disolvió clorurocarbonato de clorometilo (3 ml, 33,7 mmol) en diclorometano (10 ml) y se enfrió a 0 ºC. Se añadió gota a gota metanol (1,36 ml, 33,7 mmol), seguido de piridina (2,73 ml, 33,7 mmol) gota a gota. La suspensión de color blanco se agitó a 0 ºC y se dejó calentar a temperatura
10 ambiente y se agitó durante 14 horas. La suspensión se inactivó con agua, se diluyó con ácido cítrico acuoso, se extrajo con diclorometano, se lavó con bicarbonato sódico, solución salina saturada, se secó sobre sulfato sódico y se concentró a presión reducida para dar carbonato de clorometilo y metilo en forma de un aceite incoloro transparente. RMN 1H (CDCl3) δ 5,72 (s, 2 H), 3,96 (s, 3 H).
15 b) Carbonato de yodometilo y metilo. Se disolvió carbonato de clorometilo y metilo (2,05 g, 16,46 mmol) en acetona y se añadió yoduro sódico (3,70 g, 24,69 mmol) y la reacción se calentó a 40 ºC durante 15 horas. La suspensión de color amarillo se dejó enfriar a temperatura ambiente, se concentró a presión reducida, se diluyó con agua y tiosulfato sódico acuoso, se extrajo con diclorometano, se lavó con solución salina saturada, se secó sobre sulfato sódico, y se concentró a presión reducida para dar carbonato de yodometilo y metilo en forma de un aceite de color
20 amarillo transparente. RMN 1H (CDCl3) δ 5,92 (s, 2 H), 3,93 (s, 3 H).
c) Carbonato de {[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3, 2-a]pirido[1,2-d]pirazin-6-il]oxi}metilo y metilo. Se suspendieron 1b (30 mg, 0,070 mmol) y carbonato potásico
25 (29 mg, 0,209 mmol) en agua y se añadió hidrogenosulfato de tetrabutilamonio (24 mg, 0,070 mmol) seguido de diclorometano. La agitación durante 5 min proporcionó una solución bifásica transparente. Se añadió carbonato de yodometilo y metilo (19,5 mg, 0,091 mmol) en forma de una solución en diclorometano. La agitación durante 3 horas proporcionó la reacción completa. La reacción se diluyó con agua, diclorometano, se extrajo con diclorometano, se lavó con bicarbonato sódico, solución salina saturada, se secó sobre sulfato sódico, y se purificó
30 por cromatografía sobre gel de sílice (elución en gradiente de 1-12 % de metanol/ diclorometano) para dar el compuesto del título. RMN 1H (CDCl3) δ 10,21 (m, 1 H), 8,44, (s, 1 H), 7,32 (m, 1 H), 6,80 (m, 2 H), 5,88 (d, J = 6,8 Hz, 1 H), 5,79 (d, J = 6,4 Hz, 1 H), 5,31 (m, 1 H), 4,49 (d, J = 6 Hz, 2 H), 4,43-4,32 (m, 3 H), 3,92 (m, 1 H), 3,81 (s, 3 H), 3,67 (m, 1 H), 1,39 (d, J = 6,4 Hz, 3 H). ES+ EM: 494 (M+1).
35 Ejemplo 2: carbonato de {[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3,2-a] pirido[1,2-d]pirazin-6-il]oxi}metilo y 2-(metiloxi)etilo
imagen15
El compuesto del título se preparó a partir de carbonato de yodometilo y 2-(metiloxi)etilo (122 mg, 0,468 mmol), 1b (50 mg, 0,117 mmol), carbonato potásico (48 mg, 0,351 mmol), e hidrogenosulfato de tetrabutilamonio (40 mg, 0,117 mmol), usando un proceso similar al que se ha descrito en el ejemplo 1. RMN 1H (CDCl3) δ 10,20 (m. 1 H), 8,42
15
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añadió gota a gota una solución 1 normal de ácido clorhídrico (0,06 ml) y la reacción se agitó 3 horas a temperatura ambiente. La mezcla se enfrió a 0 ºC y trituró con dietil éter y el sólido se recogió por filtración al vacío. La recristalización a partir de una mezcla de metanol/diclorometano/ acetato de etilo proporcionó el compuesto del título en forma de un sólido cristalino de color blanco. RMN 1H (metanol-d4/ CDCl3) δ 10,17 (m, 1 H), 8,31 (s, 1 H), 7,27 (m, 1
5 H), 6,77 (m, 2 H), 5,98 (d, J = 6,8 Hz, 1 H), 5,72 (d, J = 6,8 Hz, 1 H), 5,24 (dd, J = 9,6, 3,6 Hz, 1 H), 4,70-4,35 (m, 8 H), 4,11-3,90 (m, 3 H), 3,65 (m, 1 H), 3,45-3,32 (m, 3 H), 3,06 (m, 1 H), 2,70-2,50 (m, 3 H), 1,32 (d, J = 6,4 Hz, 3 H). ES+ EM: 593 (M+1).
Ejemplo 13:
10 ({[({[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3,2 -a]pirido[1,2-d]pirazin-6-il]oxi}metil)oxi]carbonil}oxi)acetato de fenilmetilo
imagen22
15 El compuesto del título se preparó a partir de ({[(yodometil)oxi]carbonil}oxi)acetato de fenilmetilo (819 mg, 2,34 mmol), 1b (500 mg, 1,17 mmol), carbonato potásico (485 mg, 3,51 mmol), e hidrogenosulfato de tetrabutilamonio (397 mg, 1,17 mmol), usando un proceso similar al que se ha descrito en el ejemplo 1. RMN 1H (CDCl3) δ 10,18 (m, 1 H), 8,36 (s, 1 H), 7,34-7,27 (m, 6 H), 6,76 (m, 2 H), 5,98 (d, J = 6,8 Hz, 1 H), 5,85 (d, J = 6,4 Hz, 1 H), 5,27 (dd, J = 10, 4 Hz, 1 H), 5,15 (s, 2 H), 4,66 (s, 2 H), 4,60 (m, 2 H), 4,39-4,23 (m, 3 H), 3,88 (m, 1 H), 3,64 (m, 1 H), 1,35 (d, J = 6,4 Hz, 3 H). ES+
20 EM: 628 (M+1).
Ejemplo 14: sal sódica de ácido ({[({[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3,2 -a]pirido[1,2-d]pirazin-6-il]oxi}metil)oxi]carbonil}oxi)acético
25
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a) Ácido ({[({[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[ 3,2-a]pirido[1,2-d]pirazin-6-il]oxi}metil)oxi]carbonil}oxi)acético. Se agitaron 30 ({[({[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[ 3,2-a]pirido[1,2-d]pirazin-6-il]oxi}metil)oxi]carbonil}oxi)acetato de fenilmetilo (preparado como se ha descrito en el ejemplo 17) (247 mg, 0,394 mmol) paladio al 10 % en peso sobre carbono (190 mg) en una mezcla de acetato de etilo/metanol mixture en una atmósfera de hidrógeno de 1 atm durante 30 minutos. La reacción se filtró a través de Celite y se concentró a presión reducida para producir un sólido de color blanco. RMN 1H (CDCl3) δ 10,28 (m, 1 H),
35 8,32 (s, 1 H), 7,28 (m, 1 H), 6,76 (m, 2 H), 5,92 (d, J = 6,4 Hz, 1 H), 5,86 (d, J = 6,4 Hz, 1 H), 5,28 (dd, J = 10, 3,2 Hz, 1 H), 4,55 (s a, 4 H), 4,37-4,28 (m, 3 H), 3,91 (m, 1 H), 3,63 (m, 1 H), 3,35 (m, 1 H), 1,34 (d, J = 6 Hz, 3 H). ES+ EM: 538 (M+1).
b) Sal sódica de ácido de 40 ({[({[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[
22
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baño de hielo-agua. Se añadió ácido clorhídrico (0,24 ml, solución 1 normal) y la reacción se agitó 15 minutos. Se retiró parcialmente el diclorometano a presión reducida y la mezcla se enfrió y se trituró con dietil éter. El sólido resultante se recogió por filtración al vacío para producir el compuesto del título en forma de un sólido de color amarillo. RMN 1H (DMSO-d6) δ 10,21 (m, 1 H), 8,55 (s, 1 H), 7,36 (m, 1 H), 7,22 (m, 1 H), 7,03 (m, 1 H), 5,78 (d, J = 6,4 Hz, 1 H), 5,61 (d,
5 J = 6,4 Hz, 1 H), 5,33 (dd, J = 9,6, 3,2 Hz, 1 H), 4,78 (m, 2 H), 4,49 (m, 1 H), 4,27 (m, 1 H), 4,19 (m, 1 H), 3,99 (m, 1 H), 3,70-3,10 (m, 19 H), 2,62-2,80 (m, 2 H), 1,89 (s a, 2 H), 1,22 (d, J = 6 Hz, 3 H). ES+ EM: 703 (M+1).
Ejemplo 17: ({([{(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11ahexahidro[1,3]oxazolo[3,2-a]pirido[1,2-d]pirazin-6-il]oxi}metil)oxi]carbonil}oxi)acetato de metilo
10 El compuesto del título se preparó a partir de ({[(yodometil)oxi]carbonil}oxi)acetato de metilo (103 mg, 0,374 mmol), 1b (80 mg, 0,187 mmol), carbonato potásico (78 mg, 0,5621 mmol), e hidrogenosulfato de tetrabutilamonio (64 mg,
imagen25
15 0,187 mmol), usando un proceso similar al que se ha descrito en el ejemplo 1. RMN 1H (CDCl3) δ 10,20 (m, 1 H), 8,39 (s, 1 H), 7,33 (m, 1 H), 6,78 (m, 2 H), 6,00 (d, J = 6,8 Hz, 1 H), 5,88 (d, J = 6,8 Hz, 1 H), 5,30 (dd, J = 10, 4 Hz, 1 H), 4,63-4,58 (m, 4 H), 4,43-4,28 (m, 4 H), 3,93 (m, 1 H), 3,73 (s, 2 H), 3,66 (m, 1 H), 1,38 (d, J = 6 Hz, 3 H). ES+ EM: 552 (M+1).
20 Ejemplo 18: sal de ácido clorhídrico de carbonato de {[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3,2-a] pirido[1,2-d]pirazin-6-il]oxi}metilo y 2-oxo-2-[(2-piridinilmetil)amino]etilo
imagen26
25 a) Carbonato de {[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3, 2-a]pirido[1,2-d]pirazin-6-il]oxi}metilo y 2-oxo-2-[(2-piridinilmetil)amino]etilo. El compuesto del título se preparó a partir de ácido ({[({[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-di-oxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo
30 [3,2-a]pirido[1,2-d]pirazin-6-il]oxi}metil)oxi]carbonil}oxi)acético (64 mg, 0,119 mmol), (2-piridinilmetil)amina (0,02 ml, 0,179 ml), N,N-diisopropiletilamina (0,03 ml, 0,179 ml), y HATU (69 mg, 0,179 mmol), usando un proceso similar al que se ha descrito en el ejemplo 16, etapa (a). La purificación por cromatografía sobre gel de sílice produjo el compuesto del título en forma de un sólido de color blanco. RMN 1H (CDCl3) δ 10,09 (m, 1 H), 8,46 (d, J = 5,2 Hz, 1 H), 8,38 (s, 1 H), 7,75 (m, 1 H), 7,59 (m, 1 H), 7,34-7,26 (m, 2 H), 7,14 (m, 1 H), 6,78 (m, 2 H), 6,04 (d,
35 J = 6,8 Hz, 1 H), 5,87 (d, J = 6,8 Hz, 1 H), 5,27-5,22 (m, 2 H), 4,80-4,52 (m, 5 H), 4,32-4,22 (m, 3 H), 3,82 (m, 1 H), 3,61 (m, 1 H), 1,26 (d, J = 6 Hz, 3 H). ES+ EM: 628 (M+1).
b) Sal de ácido clorhídrico de carbonato de {[(3S,11aR)-8-({[(2,4-difluorofenil)metil]amino}carbonil)-3-metil-5,7-dioxo-2,3,5,7,11,11a-hexahidro[1,3]oxazolo[3,
24
imagen27
imagen28
imagen29
imagen30

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