ES2558512T3 - Compuestos de tetraciclina sustituida con C7-fluoro - Google Patents

Compuestos de tetraciclina sustituida con C7-fluoro Download PDF

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Publication number
ES2558512T3
ES2558512T3 ES13172357.9T ES13172357T ES2558512T3 ES 2558512 T3 ES2558512 T3 ES 2558512T3 ES 13172357 T ES13172357 T ES 13172357T ES 2558512 T3 ES2558512 T3 ES 2558512T3
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alkyl
hydrogen
structural formula
alkylene
represented
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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 Pharm Inc
Tetraphase Pharmaceuticals Inc
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Tetraphase Pharm Inc
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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    • 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
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    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
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Abstract

Un compuesto representado por la siguiente fórmula estructural:**Fórmula** o una sal farmacéuticamente aceptable del mismo.

Description

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compuesto está representado por la Fórmula Estructural (I) o (II), o una sal farmacéuticamente aceptable del mismo, en la que:
R1 es -H o alquilo (C1-C7); y R2 se selecciona entre alquilo (C1-C7), cicloalquil (C3-C6)-alquilo (C1-C4), alcoxi (C1-C7)-alquilo (C1-C4), fenilo, fenil-alquilo (C1-C4), cicloalquilo (C3-C6) y haloalquilo (C1-C4), en el que cada resto alquilo, alcoxi o cicloalquilo en los grupos representados por R2 está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo (C1-C4) y halo; y cada resto fenilo en los grupos representados por R2 está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo (C1-C4), halo, alcoxi (C1-C4), alcoxi (C1-C4)-alquilo (C1-C4), -CN, haloalquilo (C1-C4) y haloalcoxi (C1-C4). Como alternativa, R2 se selecciona entre el grupo que consiste en ciclopropilo, ciclobutilo, ciclopentilo, ciclopropilmetilo, ciclobutilmetilo, fenilo, bencilo, -(CH2)2-O-CH3, -(CH2)3-OCH3, -C(CH3)3, -CH(CH3)2, -CH2C(CH3)3, -CH2CH(CH3)2, -CH2-CF3, -(CH2)2-CH2F y -(CH2)nCH3, en el que n es 0, 1, 2, 3, 4, 5 o 6; y en el que el grupo fenilo o bencilo representado por R2 está opcionalmente sustituido con uno o más sustituyentes seleccionados independientemente entre el grupo que consiste en alquilo (C1-C4), halo, alcoxi (C1-C4), alcoxi (C1-C4)-alquilo (C1-C4), -CN, haloalquilo (C1-C4) y balo-alcoxi (C1-C4). En otra alternativa, el grupo fenilo o bencilo representado por R2 está sin sustituir. En otra alternativa, R2 se selecciona entre ciclopropilo, ciclopropilmetilo, ciclobutilo, ciclopentilo, ciclohexilo, -(CH2)2-O-CH3, -C(CH3)3, -CH(CH3)2, -CH2-CF3, -CH2CH(CH3)2, -CH3 y -CH2CH3.
En un segundo aspecto alternativo, para compuestos representados por la Fórmula Estructural (I) o (II), R1 es hidrógeno, metilo o etilo; y los valores y valores alternativos para R2 son como se han descrito anteriormente para el primer aspecto alternativo.
En un tercer aspecto alternativo, para compuestos representados por la Fórmula Estructural (I) o (II), R1 es hidrógeno, alquilo (C1-C4) o -O-alquilo (C1-C4); R2 se selecciona entre alquilo (C1-C7), cicloalquil (C3-C6)-alquilo (C1-C4), alcoxi (C1-C7)-alquilo (C1-C4), fenilo, cicloalquilo (C3-C6) y fluoro-alquilo (C1-C4); o R1 y R2, tomados junto con el átomo de nitrógeno al que están enlazados, forman un anillo seleccionado entre pirrolidinilo, morfolinilo, azetidinilo, piperidinilo, octahidrociclopenta[c]pirrolilo, isoindolinilo, indazolilo, imidazolilo, pirazolilo, triazolilo y tetrazolilo, en el que el anillo formado por R1 y R2, tomado junto con el átomo de nitrógeno al que están enlazados está opcionalmente sustituido con flúor, -OH, -OCH3 o N(CH3)2. Más específicamente, R1 es hidrógeno, metilo, etilo, metoxi o terc-butoxi.
En un cuarto aspecto alternativo, para los compuestos representados por la Fórmula Estructural (I) o (II), R1 es hidrógeno, metilo o etilo; R2 se selecciona entre metilo, etilo, n-propilo, isopropilo, n-butilo, 2,2-dimetilpropilo, t-butilo, isobutilo, n-pentilo, cicloalquilo (C4-C6), cicloalquilmetilo (C3-C5), metoxietilo y 2-fluoroetilo; o R1 y R2, tomados junto con el átomo de nitrógeno al que están enlazados, forman un anillo seleccionado entre azetidinilo, pirrolidinilo, piperidinilo, tetrazolilo u octahidrociclopenta[c]pirrolilo y en el que el anillo formado por R1 y R2, tomado junto con el átomo de nitrógeno al que están enlazados está opcionalmente sustituido con flúor.
En un quinto aspecto alternativo, para los compuestos representados por la Fórmula Estructural (A), cuando X es hidrógeno, Y se selecciona entre hidrógeno, -alquilo (C1-C4), -alquileno (C1-C4)-N(RA)(RB), -alquileno (C1-C4)-N(RF)-C(O)-[C(RD)(RE)]0-4-N(RA)(RB), -CH=N-ORA, N(RA)(RB), -N(RF')-C(O)-[C(RD)(RE)]1-4-N(RA)(RB), -NH-C(O)-C(RD')(RE)-N(RA)(RB), -N(RF)-C(O)-N(RA)(RA), -N(RF)-C(O)-alquilo (C1-C6), N(RF)-C(O)-heterociclilo, -N(RF)-C(O)-heteroarilo, N(RF)-C(O)-carbociclilo, -N(RF)-C(O)-arilo -N(RF)-S(O)m-alquileno (C1-C4)-N(RA)(RB), -N(RF)-S(O)m-alquileno (C1-C4)carbociclilo, -N(RF)-S(O)m-alquileno (C1-C4)-arilo; RD' se selecciona entre alquilo (C1-C6), carbociclilo, arilo, heteroarilo, heterociclilo y un resto de cadena lateral de aminoácido que aparece en la naturaleza, o RD' y RE tomados junto con el átomo de carbono al que están enlazados forma un carbociclilo de 3-7 miembros, o un heterociclilo 4-7 miembros, en el que el heterociclilo formado por RD' y RE comprende opcionalmente de uno a dos heteroátomos adicionales seleccionados independientemente entre N, S y O; y RF' se selecciona entre alquilo (C1-C7), carbociclilo, arilo y heteroarilo. Los valores y valores alternativos para el resto de las variables son como se han descrito anteriormente para la Fórmula Estructural (A'). Como alternativa, RF' se selecciona entre alquilo (C1-C4) y fenilo, y el resto de las variables son como se han descrito anteriormente en la quinta alternativa.
En una sexta alternativa, para los compuestos representados por la Fórmula Estructural (A'), X se selecciona entre hidrógeno, metilo, etilo y fenilo; e Y se selecciona entre hidrógeno, -(alquilo C1-C4), -alquileno (C1-C4)-N(RA)(RB), alquileno (C1-C4)-NH-C(O)-[CH2]0-1-N(RA)(RB), -N(RA)(RB), -NH-C(O)-carbociclilo, -NH-C(O)-arilo, -NH-C(O)heterociclilo, -NH-C(O)-heteroarilo, -NH-C(O)-N(RA)(RA), -N(RF')-C(O)-CH2-N(RA)(RB), -NH-C(O)-C(RD')(RE)-N(RA)(RB) y -NH-S(O)m-alquileno (C1-C4)-N(RA)(RB); o X se selecciona entre metilo, etilo y fenilo; e Y es -NH-C(O)-CH2-N(RA)(RB), en el que:
cada RA se selecciona independientemente entre hidrógeno y metilo; RB se selecciona entre hidrógeno, alquilo (C1-C7), -alquileno (C0-C6)-carbociclilo, -alquileno (C0-C6)-arilo, alquileno (C0-C6)-heteroarilo, -S(O)m-alquilo (C1-C6), -alquileno (C0-C4)-S(O)m-carbociclil-alquileno (C0-C4)-S(O)m
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con uno o más sustituyentes seleccionados independientemente entre -alquilo (C1-C4), -alquilo (C1-C4) halosustituido (por ejemplo. -CF3), -OH, -O-alquilo (C1-C4) y -N(RG)(RG), donde RG es hidrógeno o alquilo (C1-C4).
En un duodécimo aspecto alternativo, para los compuestos representados por la Fórmula Estructural (A), Y está
5 representado por -N(RA)(RB), donde cada uno de RA y RB se selecciona independientemente entre hidrógeno, alquilo (C1-C7), -alquil (C1-C4)-cicloalquilo (C3-C6), en el que el alquilo (C1-C7) está opcionalmente sustituido con -N(RG)(RG), donde RG es hidrógeno o alquilo (C1-C4). Los valores y valores alternativos para el resto de las variables son como se han descrito anteriormente para la Fórmula Estructural (A).
10 En un décimotercer aspecto alternativo, para compuestos representados por la Fórmula Estructural (A), Y está representado por -CH2-N (RA)(RB), donde cada uno de RA y RB se selecciona independientemente entre hidrógeno, alquilo (C1-C7), -alquil (C1-C4)-cicloalquilo (C3-C6), o RA y RB tomados junto con el átomo de nitrógeno a los que están enlazados forma un heterociclilo, en el que el alquilo (C1-C7) representado por RA o RB está opcional e independientemente sustituido con -N(RG)(RG), en el que RG es hidrógeno o alquilo (C1-C4), y el alquilo (C1-C4)
15 representado por RG está opcionalmente sustituido con -F. Los valores y valores alternativos para el resto de las variables son como se han descrito anteriormente para la Fórmula Estructural (A).
En un decimocuarto aspecto alternativo, para compuestos representados por la Fórmula Estructural (A), Y está representado por -CH2-NH-C(O)-(CH2)0-1-N(RA)(RB), donde cada uno de RA y RB se selecciona independientemente
20 entre hidrógeno, alquilo (C1-C7), -alquil (C1-C4)-cicloalquilo (C3-C6). Los valores y valores alternativos para el resto de las variables son como se han descrito anteriormente para la Fórmula Estructural (A).
Los inventores desvelan los compuestos de referencia que se muestran en la Tabla posterior y sales farmacéuticamente aceptables de los mismos, así como compuestos descritos en los Ejemplos 1-12 posteriores y
25 sales farmacéuticamente aceptables de los mismos
COMPUESTO DE REFERENCIA N.º
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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),
13
imagen7
imagen8
imagen9
imagen10
imagen11
imagen12
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imagen15
imagen16
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
NCS
N-clorosuccinimida
RMN
espectrometría de resonancia magnética nuclear
Ph
fenilo
Pr
propilo
s
secundario
t
terciario
RP
fase inversa
TMEDA
tetrametiletilendiamina
TBS
terc-butildimetilsililo
TEA
trietilamina
Tf
trifluorometanonesulfonilo
24
imagen17
imagen18
imagen19
imagen20
imagen21
imagen22
imagen23
Compuesto de Referencia 23
imagen24
RMN 1H (400 MHz, CD3OD) δ 8,24 (d, J= 11,0 Hz, 1H), 4,24 (s, 2H), 4,09 (s, 1H), 3,14-2,93 (m, 15H), 2,24-2,18 (m, 2H), 1,65 (dt, J= 13,4, 11,6 Hz, 1H), EM (IEN) m/z 533,17 (M+H).
Compuesto de Referencia 24
imagen25
10 RMN 1H (400 MHz, CD3OD) δ 8,23 (d, J= 10,4 Hz, 1H), 4,29 (d, J= 16,5 Hz, 1H), 4,18 (d, J= 15,9 Hz, 1H), 4,09 (s, 1H), 3,19-2,89 (m, 14H), 2,36-2,17 (m, 2H), 1,70-1,58 (m, 1H), 1,38 (t, J= 7,32 Hz, 3H); EM (IEN) m/z 547,25 (M+H). 15 Compuesto de Referencia 25
imagen26
RMN 1H (400 MHz, CD3OD) δ 8,21 (d, J= 10,8 Hz, 1 H), 4,25 (s, 2 H), 4,10 (s, 1 H), 3,35 (t, J= 7,2 Hz, 3 H), 3,34 (t, 20 J= 7,2 Hz, 3 H), 3,13-2,99 (m, 9 H), 2,31 (dd, J= 14,8, 14,8 Hz, 1 H), 2,27 (ddd, J= 14,8, 5,2, 2,8 Hz, 1H), 1,78-1,74 (m, 2 H), 1,68 (dd, J= 13,6, 13,6, 13,6 Hz, 1 H), 1,38 (t, J= 7,2 Hz, 6 H); EM (IEN) m/z 561,2 (M+H).
Compuesto de Referencia 26
imagen27
25
RMN 1H (400 MHz, CD3OD) δ 8,23 (d, J= 11,2 Hz, 1 H), 4,10 (s, 3 H), 3,16-2,96 (m, 11 H), 2,31 (dd, J= 14,4, 14,4 Hz, 1H), 2,24 (ddd, J= 14,4, 5,2, 2,8 Hz, 1H), 1,78-1,71 (m, 2 H), 1,66 (ddd, J= 14,0, 14,0, 14,0 Hz, 1 H), 1,45-1,38 (m, 4 H),0,98 (t, J= 7,2 Hz, 3 H); EM (IEN) m/z 575,2 (M+H).
30 Compuesto de Referencia 27
imagen28
32
imagen29
imagen30
imagen31
imagen32
imagen33
imagen34
imagen35
imagen36
imagen37
imagen38
imagen39
imagen40
imagen41
imagen42
imagen43
imagen44
imagen45
imagen46
imagen47
imagen48
imagen49
imagen50
imagen51
imagen52
imagen53
imagen54
imagen55
imagen56
imagen57
imagen58
imagen59
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imagen63
imagen64
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imagen66
imagen67
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imagen69
imagen70
imagen71
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imagen73
imagen74
imagen75
imagen76
contaron las colonias en puntos que contenían colonias distintas. Se calculó el recuento viable multiplicando el número de colonias por el factor de dilución.
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
10 Resultados
Se proporcionan los valores de concentración inhibidora mínima (MIC) para los compuestos desvelados en el presente documento en las Tablas 1a, 1b, 2a, 2b y 3. El compuesto 66 es el compuesto de la invención. Los otros compuestos son compuestos de referencia.
15 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
81 Tabla 1b
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
26
1 1 1 1 0,25 0,5 ≤0,0156 ≤0,0156
27
2 2 4 16 2 4 0,125 0,5
28
1 2 2 1 1 1 0,125 0,0625
29
4 4 4 2 2 2 1 1
30
2 1 4 2 2 2 2 4
31
1 2 2 1 0,5 1 0,25 0,25
ID del compuesto
MIC (µg/ml)
EC107
EC155 AB110 PA111 EC108 KP109 KP153
11
0,25 2 0,5 16 1 1 2
12
0,25 8 1 16 1 1 4
13
0,125 4 0,25 16 1 0,5 2
14
0,5 4 0,25 16 2 1 2
15
1 4 0,125 16 4 2 4
16
0,5 8 1 16 1 1 4
17
2 32 0,5 32 8 4 32
18
0,125 4 0,25 16 0,5 0,5 4
19
0,25 4 0,25 16 2 1 4
20
0,25 8 1 8 1 1 4
21
1 16 2 16 4 2 8
22
16 >32 2 >32 >32 32 >32
23
0,125 8 0,125 8 1 0,5 8
24
0,5 8 0,0313 16 2 1 8
25
0,5 8 0,125 32 2 2 8
26
0,5 4 0,25 16 2 2 4
27
4 32 16 >32 16 8 32
28
2 16 0,5 >32 8 4 16
29
8 8 8 >32 8 8 8
30
>32 >32 8 >32 >32 >32 >32
31
2 8 0,5 >32 8 4 8
82 Tabla 2a
ID del compuesto
MIC (µg/ml)
SA101
SA100 SA161 SA158 EF103 EF159 SP106 SP160
32
0,125 0,5 0,25 0,5 0,0625 0,125 ≤0,0156 ≤0,0156
33
0,25 0,5 1 2 0,25 1 ≤0,0156 0,125
34
≤0,0156 0,0625 0,0625 0,125 ≤0,0156 ≤0,0156 ≤0,0156 ≤0,0156
35
0,25 0,25 0,5 0,5 0,125 0,25 0,016 0,016
36
0,25 0,5 0,5 1 0,25 0,25 ≤0,0156 ≤0,0156
37
8 8 >32 >32 16 16 2 4
38
8 8 16 32 8 16 2 8
39
2 2 2 16 2 2 0,25 0,5
40
1 1 1 16 1 1 0,0625 0,5
41
1 1 2 1 1 2 0,125 0,125
42
0,5 1 2 1 0,5 1 0,125 0,0625
43
0,5 0,5 1 0,5 0,25 0,5 ≤0,0156 ≤0,0156
44
4 4 8 8 8 8 0,5 1
45
0,5 0,5 1 0,5 0,25 0,5 0,125 0,06
46
0,25 0,25 0,5 0,25 0,25 0,5 0,125 0,125
Tabla 2b
ID del compuesto
MIC (µg/ml)
EC107
EC155 AB110 PA111 EC108 KP109 KP153
32
0,25 8 2 8 1 1 4
33
2 >32 4 >32 16 4 >32
34
0,25 2 0,125 16 1 0,5 2
35
1 16 0,25 >32 8 4 8
36
2 32 0,125 >32 4 4 32
37
>32 >32 >32 >32 >32 >32 >32
38
>32 >32 >32 >32 >32 >32 >32
39
4 >32 32 >32 16 16 >32
40
4 >32 8 32 4 8 32
41
4 16 0,5 >32 16 8 16
42
4 16 0,5 >32 16 8 16
43
1 4 0,125 32 4 2 4
44
32 >32 8 >32 >32 >32 >32
45
1 2 0,06 >32 4 2 4
46
2 4 0,125 >32 32 4 32
83
imagen77
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