ES2655911T3 - Compuestos de tetraciclina sustituidos con C7-fluoro - Google Patents

Compuestos de tetraciclina sustituidos con C7-fluoro Download PDF

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Publication number
ES2655911T3
ES2655911T3 ES15180611.4T ES15180611T ES2655911T3 ES 2655911 T3 ES2655911 T3 ES 2655911T3 ES 15180611 T ES15180611 T ES 15180611T ES 2655911 T3 ES2655911 T3 ES 2655911T3
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alkyl
alkoxy
independently selected
halo
heteroaryl
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Robert B. Zahler
Roger B. Clark
Diana Katharine Hunt
Louis Plamondon
Xiao-Yi Xiao
Jingye Zhou
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Tetraphase Pharmaceuticals Inc
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Tetraphase Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Abstract

Un compuesto representado por la Formula Estructural (II):**Fórmula** o una sal farmaceuticamente aceptable del mismo, en la que: X esta seleccionado entre hidrogeno, -alquilo (C1-C7), carbociclilo, arilo y heteroarilo; cada uno de R1 y R2 estan seleccionados independientemente entre hidrogeno, alquilo (C1-C7), cicloalquil (C3- C6)- alquilo (C1-C4), alcoxi (C1-C7)-alquilo (C1-C4), cicloalcoxi (C3-C6)-alquilo (C1-C4), cicloalquilo (C3-C6), arilo, arilalquilo (C1-C4), ariloxialquilo (C1-C4), ariltioalquilo (C1-C4), arilsufinil-alquilo (C1-C4), arilsulfonilalquilo (C1-C4) y - O-alquilo (C1-C7), o R1 y R2, tomados junto con el atomo de nitrogeno al que estan enlazados, forman un heteroarilo monociclico o biciclico, o un heterociclo monociclico, condensado biciclico, puenteado biciclico o espiro biciclico, en donde el heteroarilo o el heterociclo contienen opcionalmente uno o dos heteroatomos adicionales seleccionados independientemente entre N, O y S; y RF esta seleccionado entre hidrogeno, alquilo (C1-C7), carbociclilo, arilo y heteroarilo; en donde cada resto alquilo, cicloalquilo, alcoxi y cicloalcoxi en los grupos representados por R1 y R2 y cada heterociclo representado por NR1R2 tomados juntos esta opcionalmente sustituido con uno o mas sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo (C1-C4), halo, -OH, alcoxi (C1-C4), alquiltio (C1-C4), alquilsulfinilo (C1-C4), alquilsulfonilo (C1-C4), alcoxi (C1-C4)-alquilo (C1-C4) y -N(R3)(R4); y cada resto arilo, ariloxi, ariltio, arilsufinilo y arilsulfonilo en los grupos representados por R1 y R2 y cada heteroarilo representado por NR1R2 tomados juntos estan opcionalmente sustituidos con uno o mas sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo (C1-C4), halo, -OH, alcoxi (C1-C4), -Salquilo (C1-C4), -S(O)alquilo (C1-C4), -S(O)2alquilo (C1-C4), alcoxi (C1-C4)-alquilo (C1-C4), -N(R3)(R4); -CN, haloalquilo (C1-C4) y haloalcoxi (C1-C4), y cada uno de R3 y R4 esta seleccionado independientemente entre el grupo que consiste en -H y alquilo (C1-C4), en donde el alquilo (C1-C4) representado por R3 y R4 esta opcionalmente sustituido con uno o mas sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo (C1-C4), halo, -OH, alcoxi (C1-C4) y alcoxi (C1-C4)-alquilo (C1-C4), y cada carbociclilo, arilo o heteroarilo en los grupos representados por X y RF esta opcionalmente e independientemente sustituido con uno o mas sustituyentes seleccionados independientemente entre halo, -alquilo (C1-C4), -OH, >=O, -O-alquilo (C1-C4), -alquil (C1-C4)-O-alquilo (C1-C4), -alquilo (C1-C4) halo sustituido, -O-alquilo (C1-C4) halo sustituido, -C(O)-alquilo (C1-C4), -C(O)-(alquilo (C1-C4) fluoro sustituido), - S(O)m-alquilo (C1-C4), -N(RG)(RG) y CN; en donde m es 1 o 2; cada RG es hidrogeno o alquilo (C1-C4), en donde cada alquilo en el grupo representado por RG esta opcionalmente e independientemente sustituido con uno o mas sustituyentes seleccionados independientemente entre -alquilo (C1-C4), cicloalquilo (C3-C6), halo, -OH, -O-alquilo (C1-C4) y alquil (C1-C4)-O-alquilo (C1-C4).

Description

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"Alquilo" se refiere un radical hidrocarburo alifático, monovalente de cadena lineal o ramificada que tiene el número especificado de átomos de carbono. Por lo tanto, "alquilo (C1-C7) " significa un radical que tiene de 1-7 átomos de carbono en una disposición lineal o ramificada. "alquilo (C1-C7)" incluye metilo, etilo, propilo, butilo, pentilo, hexilo y
5 heptilo. Las sustituciones adecuadas para un "alquilo sustituido" incluyen, pero sin limitación, -halógeno, -OH, alquilo (C1-C4), alcoxi (C1-C4), alquiltio (C1-C4), alquilsulfinilo (C1-C4), alquilsulfonilo (C1-C4), alcoxi (C1-C4)-alquilo (C1-C4) y N(R3)(R4), donde R3 y R4 son como se han descrito anteriormente.
"Cicloalquilo" se refiere a un radical hidrocarburo cíclico, alifático, saturado que tiene el número especificado de
10 átomos de carbono. El Cicloalquilo (C3-C6) incluye ciclopropilo, ciclobutilo, ciclopentilo y ciclohexilo. Los sustituyentes adecuados para a "cicloalquilo sustituido" incluyen halógeno, -OH, alquilo (C1-C4), alcoxi (C1-C4), alquiltio (C1-C4), alquilsulfinilo (C1-C4), alquil (C1-C4)-sulfonilo, alcoxi (C1-C4)-alquilo (C1-C4) y -N(R3)(R4), donde R3 y R4 son como se han descrito anteriormente.
15 "Heterociclo" se refiere a un anillo heterocíclico saturado o parcialmente insaturado de 4-12 miembros que contiene 1, 2 o 3 heteroátomos seleccionados independientemente entre N, O o S. Cuando un heteroátomo es S, éste puede estar opcionalmente mono o dioxigenado (es decir -S(O)-o -S(O)2-). El heterociclo puede ser monocíclico, bicíclico condensado, bicíclico puenteado o espiro bicíclico.
20 Los ejemplos de heterociclo monocíclico incluyen, pero sin limitación, azetidina, pirrolidina, piperidina, piperazina, hexahidropirimidina, tetrahidrofurano, tetrahidropirano, morfolina, tiomorfolina, 1,1-dioxido tiomorfolina, tetrahidro-2H1,2-tiazina, 1,1-dióxido de tetrahidro-2H-1,2-tiazina, isotiazolidina, 1,1-dioxido de isotiazolidina.
Un heterociclo bicíclico condensado tiene dos anillos que tienen dos átomos adyacentes en el anillo en común. El
25 primer anillo es un heterociclo monocíclico y el segundo anillo es un cicloalquilo, carbociclo parcialmente insaturado, fenilo, heteroarilo o un heterocilo monocíclico. Por ejemplo, el segundo anillo es un cicloalquilo (C3-C6), tal como ciclopropilo, ciclobutilo, ciclopentilo y ciclohexilo. Como alternativa, el segundo anillo es fenilo. Los ejemplos de heterociclos bicíclicos condensados incluyen, pero sin limitación, indolina, isoindolina, 2,3-dihidro-1Hbenzo[d]imidazol, 2,3-dihidrobenzo[d]oxazol, 2,3-dihidrobenzo[d]tiazol, octahidrobenzo[d]oxazol, octahidro-1H
30 benzo[d]imidazol, octahidrobenzo[d]tiazol, octahidrociclopenta[c]pirrol, 3-azabiciclo[3,1,0]hexano y 3azabiciclo[3,2,0]heptano.
Un heterociclo espiro bicíclico tiene dos anillos que tienen únicamente un átomo de anillo en común. El primer anillo es un heterociclo monocíclico y el segundo anillo es un cicloalquilo, carbociclo parcialmente insaturado o un
35 heterociclo bicíclico. Por ejemplo, el segundo anillo es un cicloalquilo (C3-C6). Los ejemplos de heterociclo espiro bicíclico incluyen, pero sin limitación, azaespiro[4,4]nonano, 7-azaespiro[4,4]nonano, azaesprio[4,5]decano, 8azaespiro[4,5]decano, azaespiro[5,5]undecano, 3-azaespiro[5,5]undecano y 3,9-diazaespiro[5,5]undecano.
Un heterociclo bicíclico puenteado tiene dos anillos que tienen tres o más átomos adyacentes en el anillo en común.
40 El primer anillo es un heterociclo monocíclico y el otro anillo es un cicloalquilo (tal como cicloalquilo (C3-C6)), carbociclo parcialmente insaturado o un heterociclo bicíclico. Los ejemplos de heterocíclicos bicíclicos puenteados incluyen, pero sin limitación, azabiciclo[3,3,1]nonano, 3-azabiciclo[3,3,1]nonano, azabiciclo[3,2,1]octano, 3azabiciclo[3,2,1]octano, 6-azabiciclo[3,2,1]octano y azabiciclo[2,2,2]octano, 2-azabiciclo[2,2,2]octano.
14
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terapéutico puede ser cualquier agente que sea capaz de tratar, prevenir o reducir los síntomas de una enfermedad
o trastorno sensible a tetraciclina. Como alternativa, el otro agente terapéutico puede ser cualquier agente beneficioso para un paciente cuando se administra en combinación con el compuesto de tetraciclina en la presente invención.
5 Aunque la presente invención se ha mostrado y descrito particularmente con referencias a realizaciones de ejemplo de la misma, se entenderá por los expertos en la materia que pueden hacerse diversos cambios en la forma de los mismos sin alejarse del ámbito de la invención abarcada por las reivindicaciones adjuntas.
10 Ejemplos
Las siguientes abreviaturas y términos tienen los significados indicados:
Abreviatura/Término
Significado
Ac
acetilo
AIBN
2,2'-azobis(2-metilpropionitrilo)
ac.
acuoso
Bn
bencilo
salmuera
cloruro sódico acuoso saturado
Boc
terc-butoxi carbonilo o t-butoxi carbonilo
(Boc)2O
dicarbonato de di-terc-butilo
BBr3
tribromuro de boro
Bu
butilo
Cbz
benciloxicarbonilo
CH2Cl2
cloruro de metileno
CH3CN o ReCN
acetonitrilo
Cy
triciclohexilfosfina
dba
dibencilidenoacetona
DIBAL-H
hidruro de diisobutilaluminio
DIEA
N,N-diisopropiletilamina
DMAP
4-(dimetilamino)piridina
DME
1,2-dimetoxietano
DMF
N,N-dimetilformamida
DMPU
1,3-dimetil-3,4-5,6-tetrahidro-2(1 H)-pirimidona
DMSO
dimetilsulfóxido
EDC
N-(3-dimetilaminopropil)-N'-etilcarbodiimida
IEN
ionización por electronebulización
equiv.
equivalente
Et
etilo
Et2O
éter etílico
EtOAc
acetato de etilo
h
hora
HCl
ácido clorhídrico
KHPO4
hidrogenofosfato potásico
HPLC
cromatografía líquida de alto rendimiento
HOBt
1-hidroxibenzotriazol
i
iso
IBX
ácido 2-yodoxibenzoico
LDA
diisopropilamida de litio
LHMDS
bis(trimetilsilil)amida de litio
LTMP
2,2,6,6-tetrametilpiperiduro de litio
Me
metilo
MeOH
metanol
MeI
yoduro de metilo
min
minuto
Ms
metanosulfonilo
EM
espectro de masas
MTBE
metil terc-butil éter
PM
peso molecular
NaHCO3
bicarbonato sódico
NaOH
hidróxido sódico
Na2SO4
sulfato sódico
NBS
N-bromosuccinimida
24
imagen18
imagen19
imagen20
a la mezcla de reacción. La reacción se agitó de -78 ºC a 25 ºC durante 1 h, se detuvo con NH4Cl saturado y se extrajo con EtOAc. Los extractos de EtOAc combinados se secaron (Na2SO4) y se concentraron para producir el producto en bruto. La purificación por HPLC preparativa de fase inversa en un sistema Waters Autopurification usando una columna OBD Prep C18 de Sunfire [5 μm, 19 x 50 mm; caudal, 20 ml/min; Disolvente A: H2O con 5 HCO2H al 0,1 %; Disolvente B: CH3CN con HCO2H al 0,1 %; volumen de inyección: 4,0 ml (CH3CN); gradiente: B al 80→100 % durante 15 min; recogida de fracción dirigida a masas]. Las fracciones con el PM deseado, eluyendo a 6,3-8,0 min, se recogieron y se concentraron en un evaporador rotatorio a ta para retirar la mayoría del acetonitrilo. La solución, en su mayoría acuosa, resultante se extrajo con EtOAc. Los extractos de EtOAc combinados se secaron (Na2SO4) y se concentraron para dar 185 mg de 5 puro (35 %): RMN 1H (400 MHz, CDCl3) δ 15,67 (s, 1 H), 7,51
10 7,46 (m, 2 H), 7,39-7,29 (m, 3 H), 7,21 (dd, J= 8,9, 8,9 Hz, 1 H), 7,03 (dd, J =8,9, 4,0 Hz, 1 H), 5,34 (s, 2 H), 3,93 (d, J= 10,4 Hz, 1 H), 3,30-3,21 (m, 1 H), 3,10-3,00 (m, 1 H), 2,57-2,41 (m, 3 H), 2,48 (s, 6 H), 2,17-2,12 (m, 1 H), 1,53 (s, 9 H), 0,82 (s, 9 H), 0,26 (s, 3 H), 0,12 (s, 3 H); EM (IEN) m/z 735,45 (M+H).
Compuesto de Preparación 6 15
imagen21
Se añadieron HF acuoso (3 ml, 48 %) y TFA (4 μl) a una solución en CH3CN (7 ml) de 5 (210 mg, 0,29 mmol) en un tubo de polipropileno a 25 ºC. La reacción se agitó a 25 ºC durante 18 h. La mezcla resultante se vertió en una 20 solución acuosa de K2HPO4 (21 g, se disolvió en 150 ml de agua). La mezcla se extrajo con EtOAc. Los extractos de EtOAc combinados se secaron (Na2SO4) y se concentraron para producir 180 mg de 6 en bruto: RMN 1H (400 MHz, CDCl3) δ 14,64 (s, 1 H), 11,47 (s, 1 H), 7,49-7,45 (m, 2 H), 7,39-7,32 (m, 3 H), 7,14 (dd, J= 9,2, 8,8 Hz, 1 H), 6,77 (dd, J= 9,2, 4,3 Hz, 1 H), 5,36 (s, 2 H), 3,68 (d, J= 3,7 Hz, 1 H), 3,09 (dd, J= 15,6, 4,6 Hz, 1 H), 3,02-2,92 (m, 1 H), 2,84-2,79 (m, 1 H), 2,49 (s, 6 H), 2,34-2,22 (m, 1 H), 2,09-2,02 (m, 1 H), 1,55-1,44 (m, 1 H); EM (IEN) m/z 521,30
25 (M+H).
Compuesto de Preparación 7
imagen22
30 Se añadió paladio sobre carbono (35 mg, 10 % en peso) a una solución en MeOH/dioxano (4 ml/4 ml) de 6 en bruto (180 mg). La reacción se purgó con hidrógeno y se agitó en una atmósfera de H2 (globo) a 25 ºC durante 1 h. La mezcla de reacción se filtró a través de un lecho corto de Celite. El filtrado se concentró para producir el producto en bruto. La purificación por HPLC preparativa de fase inversa en un sistema Waters Autopurification usando una
35 columna 10 μ RP-1 100A de Phenomenex Polymerx [10 μm, 150 x 21,20 mm; caudal, 20 ml/min; Disolvente A: HCl 0,05 N/agua; Disolvente B: CH3CN; volumen de inyección: 4,0 ml (HCl 0,05 N/agua); gradiente: B al 0→100 % durante 15 min; recogida de fracción dirigida a masas]. Las fracciones con el PM deseado, eluyendo a 6,4-8,2 min, se recogieron y se deshidrataron por congelación para producir 51 mg del compuesto 7 (41 % en 2 etapas): RMN 1H (400 MHz, CD3OD) δ 7,26 (dd, J= 9,2, 9,2 Hz, 1 H), 6,80 (dd, J= 9,2, 4,3 Hz, 1 H), 4,09 (s a, 1 H), 3,14 (dd, J=
40 15,0, 4,6 Hz, 1 H), 3,04 (s, 3 H), 2,96 (s, 3 H), 3,09-2,91 (m, 2 H), 2,31-2,18 (m, 2 H), 1,68-1,56 (m, 1 H); EM (IEN) m/z 433,28 (M+H).
Compuesto de Preparación 8
imagen23
28
imagen24
varias veces con más cantidad de éter dietílico. Después, el lecho de Celite se eluyó con MeOH hasta que el eluyente se volvió incoloro. El eluyente de MeOH de color amarillo se recogió y se concentró a presión reducida para proporcionar 32 en bruto. Se realizó purificación por HPLC preparativa de fase inversa en un sistema Waters Autopurification, usando una columna 10 μ RP-1 100A de Phenomenex Polymem [10 μm, 150 x 21,20 mm, caudal, 5 20 ml/min; Disolvente A: HCl 0,05 N; Disolvente B: CH3CN; volumen de inyección: 2,0 ml (HCl 0,05 N/agua); gradiente: B 10→20 % durante 30 min, recogida de fracción dirigida a masas]. Las fracciones con el PM deseado, eluyendo a 10,8-12,5 min, se recogieron y se deshidrataron por congelación para producir 2,0 mg de 32 puro: RMN 1H (400 MHz, CD3OD) δ 8,18 (d, J= 11,0 Hz, 1 H), 4,41 -4,31 (m, 2 H), 4,32 (s, 2 H), 4,24-4,13 (m, 2), 4,08 (s a, 1 H), 3,18-2,86 (m, 3 H), 3,03 (s, 3 H), 2,95 (s, 3 H), 2,71-2,57 (m, 1 H), 2,54-2,42 (m, 1 H), 2,33-2,16 (m ,2 H), 1,69
10 1,57 (m, 1 H), EM (IEN) m/z 545,20 (M+H).
Los Compuestos 12-31 y los Compuestos 33-46 se prepararon de manera similar a los Compuestos 11 o 32, sustituyendo cloruro de 2-t-butilaminoacetilo en la síntesis del Compuesto 11 por el haluro de acilo adecuado, o azetidina por amina cíclica en la síntesis del Compuesto 32.
15 Compuesto 12
imagen25
20 RMN 1H (400 MHz, CD3OD) δ 8,23 (d, J= 11,2 Hz, 1 H), 4,08 (s, 3 H), 3,17-2,97 (m, 11 H), 2,31 (dd, J= 14,8, 14,8 Hz, 1 H), 2,24 (dd, J= 14,0, 5,2, 2,8 Hz, 1H), 1,79-1,72 (m, 2 H), 1,66 (ddd, J= 13,6, 13,6, 13,6 Hz, 1 H), 1,05 (t, J= 7,2 Hz, 3 H); EM (IEN) m/z 547,2 (M+H).
Compuesto de Referencia 13 25
imagen26
RMN 1H (400 MHz, CD3OD) δ 8,23 (d, J= 11,2 Hz, 1 H), 4,08 (s, 3 H), 3,16-2,97 (m, 11 H), 2,30 (dd, J= 14,8, 14,8 Hz, 1 H), 2,24 (ddd, J= 14,4, 5,2, 2,8 Hz, 1 H), 1,75-1,69 (m, 2 H), 1,66 (ddd, J= 13,6, 13,6, 13,6 Hz, 1 H), 1,49-1,41 30 (m, 2 H), 1,01 (t, J= 7,2 Hz, 3 H); EM (IEN) m/z 561,2 (M+H).
Compuesto 14
imagen27
35
RMN 1H (400 MHz, CD3OD) δ 8,21 (d, J = 11,2 Hz, 1 H), 4,08 (s, 1 H), 4,06 (s, 2 H), 3,16-2,96 (m, 11 H), 2,28 (dd, J = 14,8, 14,8 Hz, 1 H), 2,22 (ddd, J = 14,4, 5,2, 2,8 Hz, 1H), 1,77-1,71 (m, 2 H), 1,66 (ddd, J = 14,0, 14,0, 14,0 Hz, 1 H), 1,43-1,35 (m, 6 H),0,93 (t, J = 7,2 Hz, 3 H); EM (IEN) m/z 589,2 (M+H).
40
30
imagen28
imagen29
imagen30
imagen31
Compuesto 34
imagen32
RMN 1H (400 MHz, CD3OD) δ 8,22 (d, J= 11,0 Hz, 1H), 4,33 (s, 2H), 4,10 (s, 1H), 3,83-3,72 (m, 2H), 3,25-2,89 (m, 12H), 2,32-2,00 (m, 6H), 1,69-1,56 (m, 1H); EM (IEN) m/z 559,39 (M+H).
Compuesto 35
imagen33
10
RMN 1H (400 MHz, CD3OD) δ 8,25 (d, J= 11,0 Hz, 1H), 5,54-5,31 (m, 1H), 4,39-4,20 (m, 2H), 4,09-4,01 (m, 1H), 3,40-3,30 (m, 2H), 3,09-2,89 (m, 12H), 2,50-2,34 (m, 2H), 2,34-2,25 (m, 1H), 2,24-2,16 (m, 1H), 1,71-1,58 (m, 1H); EM (IEN) m/z 577,32 (M+H).
15 Compuesto 36
imagen34
20 RMN 1H (400 MHz, CD3OD) δ 8,23 (d, J= 10,4 Hz, 1H), 5,57-5,37 (m, 1H), 4,47-4,33 (m, 2H), 4,15-3,87 (m, 2H), 3,72-3,40 (m, 1H), 3,17-2,83 (m, 12H), 2,55-2,34 (m, 2H), 2,33-2,18 (m, 2H), 1,69-1,57 (m, 1H); EM (IEN) m/z 577,37 (M+H).
Compuesto 37 25
imagen35
RMN 1H (400 MHz, CD3OD) δ 8,28 (d, J= 10,7 Hz, 1H), 4,08 (s, 1H), 4,00-3,91 (m, 2H), 3,09-2,57 (m, 18H), 3,263,18 (m, 3H), 2,49-2,34 (m, 2H), 2,35-2,06 (m, 2H), 1,72-1,59 (m, 1H); EM (IEN) m/z 602,37 (M+H).
Compuesto 38
imagen36
35
imagen37
imagen38
imagen39
imagen40
Compuesto 58
imagen41
5 RMN 1H (400 MHz, CD3OD) δ 8,24 (d, J= 10,8 Hz, 1 H), 4,48 (s, 2 H), 4,12 (s, 1 H), 4,10-4,07 (m, 2 H), 3,93-3,86 (m, 2 H), 3,19-2,90 (m, 9 H), 2,79-2,67 (m, 2 H), 2,37-2,21 (m, 2 H), 1,59-1,51 (m, 1 H); EM (IEN) m/z 595,0 (M+H).
Ejemplo 2. Síntesis de Compuestos de la Fórmula Estructural (I), en la que R1 y R2 tomados junto con el nitró nitrógeno al que están enlazados forman un heteroarilo monocíclico o bicíclico.
10
imagen42
Los siguientes compuestos se prepararon de acuerdo con el Esquema 2. 15 Compuesto de Preparación 2-1
imagen43
En un matraz de fondo redondo de 250 ml se añadió el compuesto 3 (14,47 g, 56,30 mmol, 1,0 equiv, en bruto), 20 bromuro de tetrabutilamonio (0,90 g, 2,80 mmol, 0,05 equiv.), 1,2-dicloroetano (60 ml) y agua (60 ml). La bi-fase transparente se enfrió en un baño de agua a 20 ºC. Se añadió ácido cítrico (7,2 ml, 70 % en peso, 112,60 mmol, 2,0
40
imagen44
imagen45
imagen46
imagen47
imagen48
imagen49
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imagen84
Punto del Pocillo
1 2 3 4 5 6
Factor de Dilución
102 103 104 105 106 107
Cepas bacterianas
Se examinaron quince cepas bacterianas, enumeradas a continuación, en ensayos de concentración inhibidora mínima (MIC).
ID
Organismo Fuente Resistencia Comentarios Rx Gram
SA100
S. aureus ATCC 13709 MSSA Cepa Smith (modelo animal) positivo
SA101
S. aureus ATCC 29213 MSSA control positivo
SA158
S. aureus MR, SK75 resistente a tet: tetK (salida) positivo
SA161
S. aureus Micromyx, LLC resistente a tet: tet(M) protección ribosómica positivo
EF103
E. faecalis ATCC 29212 intermedio de tet/resistente – mecanismo no especificado control positivo
EF159
E. faecalis MR, DS160 resistente a tet:tetM (protección de rib) cip-R, ery-1 positivo
SP106
S. pneumoniae ATCC 49619 wt control positivo
SP160
S. pneumoniae MR, 54 resistente a tet:tet M (protección de rib) pen-R, ery-R positivo
EC107
E. coli ATCC 25922 wt control negativo
EC155
E. coli MR, 10 resistente a tet:tetA (salida) negativo
KP109
K. pneumoniae ATCC 13883 wt negativo
KP153
K. pneumoniae MR, 1 resistente a tet: tetA (salida) cip-R, gen-R negativo
EC108
E. cloacae ATCC 13047 wt negativo
AB110
A. baumanii ATCC 19606 wt negativo
PA111
P. aeruginosa ATCC 27853 wt control negativo
MSSA = S. aureus susceptible a meticilina wt = natural ATCC = Colección Americana de Cultivos Tipo MR = Marilyn Roberts, Universidad de Washington tet = tetraciclina cip = ciprofloxacina R = resistente gen = gentamicina ery = eritromicina pen = penicilina
Resultados Se proporcionan los valores de concentración inhibidora mínima (MIC) para los compuestos en las Tablas 1a, 1b, 2a, 10 2by3. Tabla 1a
ID del compuesto
MIC (µg/ml)
SA101
SA100 SA161 SA158 EF103 EF159 SP106 S0160
11
0,125 0,25 0,25 0,0625 0,0625 0,125 ≤0,0156 ≤0,0156
12
≤0,0156 ≤0,0156 0,125 0,5 ≤0,0156 0,0625 ≤0,0156 ≤0,0156
13
≤0,0156 ≤0,0156 0,0625 0,25 ≤0,0156 0,0625 ≤0,0156 ≤0,0156
14
0,5 0,25 0,5 0,25 0,125 0,25 0,03 0,125
15
0,5 0,5 0,5 0,25 0,5 0,5 0,016 0,016
16
0,125 0,25 0,25 0,5 0,0625 0,0625 ≤0,0156 ≤0,0156
17
0,25 0,5 1 2 0,25 1 0,0625 0,0625
18
0,0625 ≤0,0156 0,0625 0,125 ≤0,0156 0,0313 ≤0,0156 ≤0,0156
19
0,125 0,25 0,25 0,25 ≤0,0156 0,125 ≤0,0158 ≤0,0156
20
≤0,0156 0,25 0,25 0,5 ≤0,0156 0,0625 ≤0,0156 ≤0,0156
21
0,25 0,25 0,5 4 0,125 1 ≤0,0156 0,0625
22
1 1 2 4 2 4 0,5 1
23
≤0,0156 0,5 0,125 0,25 ≤0,0156 0,0313 ≤0,0156 ≤0,0156
24
0,25 0,25 0,125 0,125 ≤0,0156 ≤0,0156 ≤0,0156 ≤0,0156
25
0,125 0,125 0,125 0,0313 ≤0,0156 0,0625 ≤0,0156 ≤0,0156
82
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87
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