ES2565238T3 - Inhibidores de la c-fms quinasa - Google Patents
Inhibidores de la c-fms quinasa Download PDFInfo
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- ES2565238T3 ES2565238T3 ES07760840.4T ES07760840T ES2565238T3 ES 2565238 T3 ES2565238 T3 ES 2565238T3 ES 07760840 T ES07760840 T ES 07760840T ES 2565238 T3 ES2565238 T3 ES 2565238T3
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Abstract
Compuesto de Fórmula I**Fórmula** o un solvato, hidrato, tautómero o sal farmacéuticamente aceptable del mismo, en el que: W es**Fórmula** en el que cada R4 es independientemente H, F, CI, Br, I, OH, OCH3, OCH2CH3, SalquiloC(1-4), SOalquiloC(1-4), SO2alquiloC(1-4), -alquiloC(1-3), CO2Rd, CONReRf, C≡Rg o CN; en el que Rd es H o -alquiloC(1-3); Re es H o -alquiloC(1-3); Rf es H o alquiloC(1-3); y Rg es H, -CH2OH o -CH2CH2OH, R2 es cicloalquilo, cicloalquenilo espiro-sustituido, piperidinilo o fenilo, cualquiera de los cuales puede estar sustituido independientemente con uno o dos de cada uno de los siguientes: cloro, fluoro, hidroxi, alquiloC(1-3) y alquiloC(1-4); Z es H, F o CH3; J es CH o N; X es**Fórmula** en el que R1 es -alquiloC(1-4), -ORa, -CN, -NA1A2, -SO2CH3, -COORa, -CO2CH3, -CH2-NA1A2, -CONA1A260 , -CH2ORa, -OalquiloC(1-4)ORa, -NHCH2CH2CO2Ra, -NHCH2CH2ORa, -NRaCH2CH2NA1A2, -OalquiloC(1-4)NA1A2, -OCH2CO2Ra, -CH2CO2Ra, -CH2CH2SO2alquiloC(1-4), -SO2CH2CH2NA1A2, -SOCH2CH2NA1A2, -SCH2CH2NA1A2, -NHSO2CH2CH2NA1A2, fenilo, imidazolilo, tiazolilo, 4H-[1,2,4]oxadiazol-5-onilo, 4H-pirrolo[2,3-b]pirazinilo, piridinilo, [1,3,4]oxadiazolilo, 4H-[1,2,4]triazolilo, tetrazolilo, pirazolilo, [1,3,5]triazinilo y [1,3,4]tiadiazolilo; Rz y Ry son independientemente H o -alquiloC(1-4), en el que ambos Rz pueden tener estereoquímica syn o anti; como alternativa ambos Rz en una relación syn juntos pueden formar -(CH2)n-, en el que n es 2 ó 3; R3 es H, alquiloC(1-4), alquiloC(1-3)-CF3, CH2CH2NH2, CH2CH2ORa, -COCH3, CONH2 o CO2Ra; A1 es H, -alquiloC(1-4) o CH2CH2ORa; A2 es H, -alquiloC(1-4), CORa, CH2CON(CH3)2, -CH2CH2ORa, -CH2CH2SalquiloC(1-4), -CH2CH2SOalquiloC(1-4) o -CH2CH2SO2alquiloC(1-4); como alternativa, A1 y A2 pueden formar, junto con el nitrógeno al que están fijados, un anillo heterocíclico seleccionado de entre los siguientes:**Fórmula** en el que Ra es H o alquiloC(1-4); Raa es H o alquiloC(1-4); y Rbb es H, -alquiloC(1-4), -CH2CH2OCH2CH2OCH3, -CH2CO2H, -C(O)alquiloC(1-4) o -CH2C(O)alquiloC(1-4) en el que el cicloalquilo es un anillo saturado o parcialmente insaturado compuesto por 3 a 8 átomos de carbono; y en el que el cicloalquenilo espiro-sustituido es un par de anillos cicloalquilo que comparten un solo átomo de carbono y al menos uno de los anillos está parcialmente insaturado.
Description
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en los que cada R4 es independientemente H, F, Cl, Br, I, OH, OCH3, OCH2CH3, SalquiloC(1-4), SOalquiloC(1-4), SO2alquiloC(1-4), -alquiloC(1-3), CO2Rd, CONReRf, C≡CRg o CN; en los que Rd es H o -alquiloC(1-3); Re es H o -alquiloC(1-3); Rf es H o -alquiloC(1-3); y Rg es H, -CH2OH o -CH2CH2OH;
R2
es cicloalquilo (incluidos ciclohexenilo y cicloheptenilo), cicloalquenilo espiro-sustituido (incluidos espiro[2.5]oct-5-enilo, espiro[3.5]non-6-enilo, espiro[4.5]dec-7-enilo y espiro[5.5]undec-2-enilo), piperidinilo o fenilo, cualquiera de los cuales puede estar sustituido independientemente con uno o dos de cada uno de los siguientes: cloro, fluoro, hidroxi, alquiloC(1-3) y alquiloC(1-4) (dichos cicloalquilos sustituidos incluyen 4,4-dimetil ciclohexenilo, 4,4-dietil ciclohexenilo, 4-metil ciclohexenilo, 4-etil ciclohexenilo, 4-n-propil ciclohexenilo, 4-isopropil ciclohexenilo y 4-terc-butil ciclohexenilo; dichos piperidinilos sustituidos incluyen 4-metil piperidinilo, 4-etil piperidinilo, 4-(1’hidroxiet-2’il)piperidinilo y 4,4 dimetil piperidinilo); Z es H,F o CH3; J es CH o N; X es
en los que R1 es -alquiloC(1-4), -ORa, -CN, -NA1A2, -SO2CH3, -COORa, -CO2CH3, -CH2-NA1A2, -CONA1A2, -CH2ORa, -OalquiloC(1-4)ORa, -NHCH2CH2CO2Ra, -NHCH2CH2ORa, -NRaCH2CH2NA1A2, -OalquiloC(1-4)NA1A2, -OCH2CO2Ra, -CH2CO2Ra, -CH2CH2SO2alquiloC(1-4), -SO2CH2CH2NA1A2, -SOCH2CH2NA1A2, -SCH2CH2NA1A2, -NHSO2CH2CH2NA1A2, fenilo, imidazolilo, tiazolilo, 4H-[1,2,4]oxadiazol-5-onilo, 4H-pirrolo[2,3-b]pirazinilo, piridinilo, [1,3,4]oxadiazolilo, 4H-[1,2,4]triazolilo, tetrazolilo, pirazolilo, [1,3,5]triazinilo y [1,3,4]tiadiazolilo; Rz y Ry son independientemente H o -alquiloC(1-4), en los que ambos Rz pueden tener estereoquímica syn o anti; como alternativa ambos Rz en una relación syn juntos pueden formar -(CH2)n-, en el que n es 2 ó 3; R3 es H, alquiloC(1-4), CH2CH2NH2, CH2CH2ORa, -COCH3, CONH2 o CO2Ra; A1 es H, -alquiloC(1-4) o CH2CH2ORa; A2 es H, -alquiloC(1-4), CORa, CH2CON(CH3)2, -CH2CH2ORa (incluido -CH2CH2OCH3), -CH2CH2SalquiloC(1-4) (incluido -CH2CH2SCH3), -CH2CH2SOalquiloC(1-4) (incluido -CH2CH2SOCH3) o -CH2CH2SO2alquiloC(1-4) (incluido -CH2CH2SO2CH3); como alternativa, A1 y A2 pueden formar, junto con el nitrógeno al que están fijados, un anillo heterocíclico seleccionado de entre los siguientes:
en los que Ra es H o alquiloC(1-4); Raa es H o alquiloC(1-4); Rbb es H, -alquiloC(1-4), -CH2CH2OCH2CH2OCH3, -CH2CO2H, -C(O)alquiloC(1-4) o -CH2C(O)alquiloC(1-4).
En una forma de realización preferente de la invención:
W es
11
Rbb es H, -alquiloC(1-4), -CH2CO2H o -COCH3; Ry es H o -CH3; Rz es H, -CH3, o juntos pueden formar -CH2CH2-; R3 es H, -COCH3, -CH3, -CO2CH3, -CONH2 o -CO2H; así como solvatos, hidratos, tautómeros y sales farmacéuticamente aceptables de los mismos.
En otra forma de realización de la invención:
W es
R2
es
Z es H; J es CH o N; X es
en los que R1 es -OH, -NH2, -N(CH3)2, -SO2CH3, -COOH, -CO2CH3, -CH2-morfolinilo, -CONH2, -CON(CH3)2, -CH2OH, -OCH2CH2N(CH3)2, -NHCH2CH2OCH3, -OCH2CO2H, morfolinilo, piperazinilo, N-metil piperazinilo, piperazinil-CH2CO2H o tetrazolilo; Rz es H o -CH3; R3 es -COCH3 o -CO2H;
y solvatos, hidratos, tautómeros y sales farmacéuticamente aceptables de los mismos.
Otra forma de realización de la invención es un compuesto seleccionado del grupo que consiste en:
16
15 A una suspensión de [2-(4,4-dimetil-ciclohex-1-enil)-4-(4-hidroxi-tetrahidro-piran-4-il)-fenil]-amida del ácido 4-ciano1H-imidazol-2-carboxílico (preparada como en el Ejemplo 1, etapa (h), 50,0 mg, 0,120 mmol) en 1,5 ml de DCM a 0°C, se añadió SOCl2 (26,0 µl, 0,360 mmol) en atmósfera de Ar. Después de agitar a TA durante 2 horas, la mezcla se enfrió a 0°C. A continuación, se añadió a la reacción 2-metoxietilamina (104 µl, 1,20 mmol) y la mezcla resultante se agitó a 0°C durante 2 horas. La mezcla se diluyó con EtOAc (30 ml) y se lavó con H2O (2 x 10 ml) y salmuera (10 ml). Después de secar sobre Na2SO4 y concentrar a vacío, el residuo se purificó mediante cromatografía en gel de sílice (MeOH al 1%-4%/DCM) para proporcionar el compuesto del título (36,8 mg, 65%) como un sólido blanco.1H-RMN (CD3OD/CDCl3 1:5; 400 MHz): δ 8,31 (d, 1H, J = 8,6 Hz), 7,70 (s, 1H), 7,30 (dd, 1H, J = 8,6, 2,3 Hz), 7,20 (d, 1H, J = 2,3 Hz), 5,77 (m, 1H), 3,94 (m, 2H), 3,69 (m, 2H), 3,41 (t, 2H, J = 6,1 Hz), 3,28 (s, 3H), 2,38 (t, 2H, J = 6,1 Hz), 2,28 (m, 2H), 2,07-2,20 (m, 4H), 1,88 (m, 2H), 1,59 (t, 2H, J = 6,3 Hz), 1,10 (s, 6H). Espectro de masas (ESI,
25 m/z): Calc. para C27H35N5O3, 476,3 (M-H), encontrado 476,3. Los Ejemplos 5-9 se prepararon según el procedimiento del Ejemplo 4
35
45
55
- Ejemplo
- Nombre Estructura Espectro de masas
- 5
- [4-(4-amino-tetrahidro-piran-4il)-2-(4,4-dimetil-ciclohex-1enil)-fenil]-amida del ácido 5ciano-1H-imidazol-2carboxílico (ESI, m/z): Calc. para C24H29N5O2, 418,2 (M-H), encontrado 417,9
- 6
- [2-(4,4-dimetil-ciclohex-1-enil)4-(4-morfolin-4-il-tetrahidropiran-4-il)-fenil]-amida del ácido del ácido 5-ciano-1Himidazol-2-carboxílico (APGI, m/z): Calc. para C28H35N5O3, 488,3 (M-H), encontrado 488,4.
- 7
- [4-(4-dimetilamino-tetrahidropiran-4-il)-2-(4,4-dimetilciclohex-1-enil)-fenil]-amida del ácido 5-ciano-1H-imidazol2-carboxílico (APCI, m/z): Calc. para C26H33N5O2, 446,3 (M-H), encontrado 446,5.
45
5
15
- 8
- {2-(4,4-dimetil-ciclohex-1enil)-4-[4-(4-metil-piperazin1-il)-tetrahidro-piran-4-il]fenil}-amida del ácido 5ciano-1H-imidazol-2carboxílico (APCI, m/z): Calc. para C29H38N6O2, 501,3 (M-H), encontrado 501,4.
- 9
- [2-(4,4-dimetil-ciclohex-1enil)-4-(4-piperazin-1-iltetrahidro-piran-4-il)-fenil]amida del ácido 5-ciano-1Himidazol-2-carboxílico (APCI, m/z): Calc. para C28H36N6O2, 487,3 (M-H), encontrado 487,4.
Ejemplo 10
Sal del ácido trifluoroacético del ácido (4-{4-[4-[(5-ciano-1H-imidazol-2-carbonil)-amino]-3-(4,4-dimetilciclohex-1-enil)-fenil]-tetrahidropiran-4-il}-piperazin-1-il)-acético
35
45
A una solución de sal del ácido trifluoroacético de [2-(4,4-dimetil-ciclohex-1-enil)-4-(4-piperazin-1-iltetrahidro-piran-4-il)-fenil]-amida del ácido 5-ciano-1H-imidazol-2-carboxílico (22 mg, 0,036 mmol) (preparada en el Ejemplo 1, etapa (h)) en DCM (0,3 ml), se añadió NEt3 (0,015 ml, 0,11 mmol) y bromoacetato de etilo (0,0044 ml, 0,040 mmol) y la mezcla se agitó durante 10 horas a TA. La mezcla se concentró y se añadió el residuo disuelto en 1 ml de EtOH y KOH 7N (0,031 ml, 0,22 mmol) y la mezcla se agitó durante 3 horas a TA. La mezcla se diluyó con 5 ml de H2O, se ajustó el pH a 2, y el compuesto del título se purificó mediante RP-HPLC en una columna C18 eluyendo con un gradiente lineal de CH3CN al 20%-50% en TFA al 0,1%/H2O durante 10 minutos para dar 22 mg (91%) de un sólido blanco. 1H-RMN (400 MHz, CD3OD): δ 8,41 (d, J = 8,6 Hz, 1H), 8,01 (s, 1 H), 7,44 (dd, J = 8,6,
55 2,2 Hz, 1H), 7,31 (d, J = 2,2 Hz, 1H), 5,81 (m, 1H), 4,00-3,92 (m, 2H), 3,70 (s, 2H), 3,42-3,34 (m, 2H), 3,26-2,86 (m, 8H), 2,70-2,58 (m, 2H), 2,38-2,29 (m, 2H), 2,23-2,05 (m, 4H), 1,60 (t, J = 6,3 Hz, 2H), 1,10 (s, 6H). Espectro de masas (APCI, m/z): Calc. para C30H38N6O4, 545,3 (M-H), encontrado 545,3.
Ejemplo 11
[2-(4,4-dimetil-ciclohex-1-enil)-4-(4-hidroxi-tetrahidro-tiopiran-4-il)-fenil]-amida del ácido 4-ciano-1H-imidazol2-carboxílico
65
46
- Nº de ej.
- Nombre Estructura Referencia del procedimiento Reactivos
- 36
-
{2-(4,4-dimetil-ciclohex1-enil)-4-[4-(2-pirrolidin1-il-etilamino)tetrahidro-piran-4-il]fenil}-amida del ácido 4ciano-1H-imidazol-2carboxílico
imagen70 Ejemplo 4imagen71
- 37
- [4-[4-(2-acetilaminoetilamino)-tetrahidropiran-4-il]-2-(4,4-dimetilciclohex-1-enil)-fenil]amida del ácido 4ciano-1H-imidazol-2carboxílico Ejemplo 4
- 38
- {4-[4-(2-acetilaminoetilamino)-tetrahidropiran-4-il]-2-ciclohex-1enil-fenil}-amida del ácido 4-ciano-1Himidazol-2-carboxílico Ejemplo 4
- 39
- {2-(4,4-dimetil-ciclohex1-enil)-4-[4-(2-metoxietilamino)-tetrahidropiran-4-il]-fenil}-amida del ácido 4-ciano-1Hpirrol-2-carboxílico Ejemplo 1, etapas (f), (h); Ejemplo 4
- 40
- [4-[4-(4-acetilpiperazin-1-il)tetrahidro-piran-4-il]-2(4,4-dimetil-ciclohex-1enil)-fenil]-amida del ácido 4-ciano-1Himidazol-2-carboxílico Ejemplo 4
- 41
- [4-(4-amino-1,1-dioxohexahidro-1λ6-tiopiran4-il)-2-(4,4-dimetilciclohex-1-enil)-fenil]amida del ácido 4ciano-1H-imidazol-2carboxílico Ejemplo 12; Ejemplo 4 NH4OH
67
- 42
-
[4-(4-dimetilamino1,1-dioxohexahidro-1λ6 -tiopiran-4-il)-2-(4,4dimetil-ciclohex-1enil)-fenil]-amida del ácido 4-ciano1H-imidazol-2carboxílico
imagen72 Ejemplo 12; Ejemplo 4 HNMe2
- 43
- [4-(1-acetil-4dimetilaminopiperidin-4-il)-2-(4,4dimetil-ciclohex-1enil)-fenil]-amida del ácido 4-ciano1H-imidazol-2carboxílico Ejemplo 35; Ejemplo 4 HNMe2
- 44
- {2-(4,4-dimetilciclohex-1-enil)-4[4-(2-pirrolidin-1-iletoxi)-tetrahidropiran-4-il]-fenil}amida del ácido 4ciano-1H-imidazol2-carboxílico Ejemplo 2
- 45
- {2-(4,4-dimetilciclohex-1-enil)-4[4-(2-pirrolidin-1-iletoxi)-tetrahidropiran-4-il]-fenil}amida del ácido 4ciano-1H-pirrol-2carboxílico Ejemplo 1, etapas (f), (h); Ejemplo 2
- 46
-
[4-[4-(2dimetilamino-etoxi)tetrahidro-piran-4il]-2-(4,4-dimetilciclohex-1-enil)fenil]-amida del ácido 4-ciano-1Hpirrol-2-carboxílico
imagen73 Ejemplo 1, etapas (f),(h); Ejemplo 2imagen74
- 47
- {2-(4-metilpiperidin-1-il)-4-[4(2-pirrolidin-1-iletilamino)tetrahidropiran-4-il]fenil}-amida del ácido 4-ciano-1Himidazol-2carboxílico Ejemplo 1, etapas (f)-(h); Ejemplo 4
68
- 48
- [4-[4-(2-dimetilaminoetilamino)tetrahidropiran-4-il]-2-(4metil-piperidin-1-il)-fenil]amida del ácido 4-ciano1H-imidazol-2-carboxílico Ejemplo 1, etapas (f)-(h); Ejemplo 4
- 49
-
[4-[4-(2-dimetilaminoetoxi)-tetrahidro-piran-4il]-2-(4-metil-piperidin-1il)-fenil]-amida del ácido 4-ciano-1H-imidazol-2carboxílico
imagen75 Ejemplo 1, etapas (f)-(h); Ejemplo 2imagen76
- 50
- {2-(4-metil-piperidin-1-il)4-[4-(2-pirrolidin-1-iletoxi)-tetrahidro-piran-4il]-fenil}-amida del ácido 4-ciano-1H-imidazol-2carboxílico Ejemplo 1, etapas (f)-(h); Ejemplo 2
- 51
- [4-(4-amino-tetrahidro- Ejemplo 1,
- piran-4-il)-2-(4-metil-
- Etapas (f)-(h);
- piperidin-1-il)-fenil]-
- Ejemplo 4
- amida del ácido 4-ciano
- 1H-imidazol-2-carboxílico
- 52
- [4-(4-dimetilamino- Ejemplo 1,
- tetrahidro-piran-4-il)-2-(4-
- Etapas (f)-(h);
- metil-piperidin-1-il)-fenil]-
- Ejemplo 4
- amida del ácido 4-ciano
- 1H-imidazol-2-carboxílico
- 53
- [2-(4-metil-piperidin-1-il)4-(4-pirrolidin-1-iltetrahidro-piran-4-il)fenil]-amida del ácido 4ciano-1H-imidazol-2carboxílico Ejemplo 1, Etapas (f)-(h); Ejemplo 4
69
- 54
-
[4-(1,1-dioxo-4-pirrolidin1-il-hexahidro-1λ6 -tiopiran-4-il)-2-(4-metilpiperidin-1-il)-fenil]-amida del ácido 4-ciano-1Himidazol-2-carboxílico
imagen77 Ejemplo 1, Etapas (f)(h); Ejemplo 12; Ejemplo 4imagen78
- imagen79
- 55
- [4-(1-acetil-4-pirrolidin-1- Ejemplo 1,
- il-piperidin-4-il)-2-(4-metil-
- Etapas (f)
- piperidin-1-il)-fenil]-amida
- (h);
- del ácido 4-ciano-1H-
- Ejemplo 4
- imidazol-2-carboxílico
- 56
- [2-(4,4-dimetil-ciclohex-1enil)-4-(4-pirrolidin-1ilmetil-tetrahidropiran-4il)-fenil]-amida del ácido 4-ciano-1H-imidazol-2carboxílico Ejemplo 26, etapa (b)
- 57
- [4-(4-dimetilaminometiltetrahidro-piran-4-il)-2(4,4-dimetil-ciclohex-1enil)-fenil]-amida del ácido 4-ciano-1Himidazol-2-carboxílico Ejemplo 26, etapa (b) HNMe2
70
- 58
- [4-(4dimetilaminometil-1,1dioxo-hexahidro-1λ6 -tiopiran-4-il)-2-(4,4dimetil-ciclohex-1-enil)fenil]-amida del ácido 4-ciano-1H-imidazol-2carboxílico Ejemplo 16; etapa (a); Ejemplo 12; Ejemplo 16, Etapas (b)(f); Ejemplo 25; Ejemplo 26, etapas (a)(b)
- 59
- [2-(4,4-dimetil-ciclohex1-enil)-4-(4-hidroxi-2,6dimetil-tetrahidrotiopiran-4-il)-fenil]amida del ácido 4ciano-1H-imidazol-2carboxílico Ej. 1, etapa (h)
- 60
- [2-(4,4-dimetil-ciclohex- Ej. 1, etapa
- 1-etil)-4-(4-hidroxi-2,6
- (h)
- dimetil-1,1-dioxo
- hexahidro-1λ6-tiopiran
- 4-il)-fenil]-amida del
- ácido 4-ciano-1H
- imidazol-2-carboxílico
- 61
- [2-(4,4-dimetil-ciclohex1-enil)-4-(3-hidroxi-8,8dioxo-8λ6-tiabiciclo[3.2.-1]oct-3-il)fenil]-amida del ácido 4-ciano-1H-imidazol-2carboxílico Ej. 1, etapa (h)
- 62
- [2-(4,4-dimetil-ciclohex1-enil)-4-(3-hidroxi-8metil-8-azabiciclo[3.2.1]oct-3-il)fenil]-amida del ácido 4-ciano-1H-imidazol-2carboxílico Ej. 1, etapa (h)
- 63
- [2-(4,4-dimetil-ciclohex- Ej. 1, etapa
- 1-enil)-4-(4-hidroxi
- (h)
- 1,2,6-trimetil-piperidin
- 4-il)-fenil]-amida del
- ácido 4-ciano-1H
- imidazol-2-carboxílico
71
- 64
- [2-(4,4-dimetil-ciclohex1-enil)-4-(4-hidroxi1,2,2,6,6-pentametilpiperidin-4-il)-fenil]amida del ácido 4ciano-1H-imidazol-2carboxílico Ej. 1, etapa (h)
- 65
- {2-(4,4-dimetil-ciclohex1-enil)-4-[4-(2-metoxietilamino)-2,6-dimetil1,1dioxo-hexahidro1λ6-tiopiran-4-il]-fenil}amida del ácido 4ciano-1H-imidazol-2carboxílico Ej. 1, etapa (h)
- 66
-
{2-(4,4-dimetil-ciclohex1-enil)-4-[1,2,2,6,6pentametil-4-(2morfolin-4-il-etilamino)piperidin-4-il]-fenil}amida del ácido 4ciano-1H-imidazol-2carboxílico
Ej. 1, etapa (h)
imagen80
- 67
-
Éster metílico del ácido 3-{4-[4-[(4-ciano-1Himidazol-2-carbonil)amino]-3-(4,4-dimetilciclohex-1-enil)-fenil]1,2,6-trimetil-piperidin4-ilamino}-propiónico
imagen81 Ej. 1, etapa (h)imagen82
- 68
- (2-(4,4-dimetil-ciclohex- Ej. 1, etapa
- 1-enil)-4-{2,6-dimetil-4
- (h)
- [2-(4-metil-piperazin-1
- il)-etilamino]-1,1-dioxo
- hexahidro-1λ6-tiopiran
- 4-il}-fenil)-amida del
- ácido 4-ciano-1H
- imidazol-2-carboxílico
- 69
- [2-ciclohex-1-enil-4-(4hidroxi-1,2,6-trimetilpiperidin-4-il)-fenil]amida del ácido 4ciano-1H-imidazol-2carboxílico Ej. 14, etapa (d)
72
- 70
- {2-ciclohex-1-enil-4- Ej. 14,
- [1,2,6-trimetil-4-(2
- etapa (d)
- morfolin-4-il-etoxi)-
- Ej. 2
- piperidin-4-il]-fenil}
- amida del ácido 4
- ciano-1H-imidazol
- 2-carboxílico
- 71
- {2-ciclohex-1-enil-4- Ej. 14,
- [1,2,6-trimetil-4-(2
- etapa (d)
- pirrolidin-1-il-etoxi)-
- Ej. 2
- piperidin-4-il]-fenil}
- amida del ácido 4
- ciano-1H-imidazol
- 2-carboxílico
- 72
- (2-ciclohex-1-enil-4{4-[2-(1,1-dioxo-1λ6 -tiomorfolin-4-il)etoxi]-1,2,6-trimetilpiperidin-4-il}-fenil)amida del ácido 4ciano-1H-imidazol2-carboxílico Ej. 14, etapa (d) Ej. 2
Ejemplo 73
[4-(4-aminometil-tetrahidro-piran-4-il)-2-(4,4-dimetil-ciclohex-1-enil)-fenil]-amida del ácido 4-ciano-1Himidazol-2-carboxílico
a) 4-(4-nitro-fenil)-tetrahidro-piran-4-carbonitrilo
73
- Nº de ej.
- Nombre Estructura Referencia del procedimiento Reactivos
- 79
- [4-[(4-acetilamino-metil)- Ej. 73, etapas
- tetrahidro-piran-4-il]-2-(4,4
- (a)-(c); Ej. 22,
- dietilciclohex-1-enil)-fenil]
- etapa (c) y Ej.
- amida del ácido 4-ciano
- 1, etapas (e)
- 1H-imidazol-2-carboxílico
- (g)
- 80
- [4-(1-acetil-4metilaminometil-piperidin4-il)-2-(4,4-dietil-ciclohex1-enil)-fenil]-amida del ácido 4-ciano-1H-pirrol-2carboxílico Ej. 77, Etapas (a) y (b)
- 81
- [2-(4,4-dimetil-ciclohex-1enil)-4-(4-metilaminometil1,1-dioxo-hexahidro-1λ6 -tiopiran-4-il)-fenil]-amida del ácido 4-ciano-1Himidazol-2-carboxílico Ej. 74, etapa (a); Ej. 73, etapa (b)-(d); Ej. 76, etapa (a)
Ejemplo 82
{2-(4,4-dimetil-ciclohex-1-enil)-6-[4-(4-metil-piperazin-1-il)-tetrahidro-piran-4-il]-piridin-3-il}-amida del ácido 4ciano-1H-imidazol-2-carboxílico
a) [2-(4,4-dimetil-ciclohex-1-enil)-6-(4-hidroxi-tetrahidro-piran-4-il)-piridin-3-il]-amida del ácido 4-ciano-1Himidazol-2-carboxílico
79
Se preparó el compuesto del título a partir [6-bromo-2-(4,4-dimetil-ciclohex-1-enil)-piridin-3-il]-amida del ácido 5ciano-1H-imidazol-2-carboxílico (preparada como en el Ejemplo 32, etapa (d)) y tetrahidro-piran-4-ona según el procedimiento del Ejemplo 1, etapa (h).
b) {2-(4,4-dimetil-ciclohex-1-enil)-6-[4-(4-metil-piperazin-1-il)-tetrahidro-piran-4-il]-piridin-3-il}-amida del ácido 4-ciano-1H-imidazol-2-carboxílico
Se prepara el compuesto del título a partir de [2-(4,4-dimetil-ciclohex-1-enil)-6-(4-hidroxi-tetrahidro-piran-4-il)-piridin3-il]-amida del ácido 4-ciano-1H-imidazol-2-carboxílico (preparada como en la etapa anterior) y N-metilpiperazina según el procedimiento del Ejemplo 4.
Los siguientes ejemplos se producen según los procedimientos de los ejemplos anteriores con los reactivos correspondientes como se indica en la siguiente tabla:
Ejemplo 86
[2-(4-metil-piperidin-1-il)-4-(4-pirrolidin-1-ilmetil-tetrahidropiran-4-il)-fenil]-amida del ácido 4-ciano-1Himidazol-2-carboxílico
80
Ensayo de macrófagos procedentes de médula ósea de ratón activados por CSF-1
Los macrófagos se obtienen cultivando médula ósea de ratón en alfa-MEM complementado con FCS al 10% y 50 ng/ml de CSF-1 recombinante de ratón en placas bacteriológicas. El sexto día, los macrófagos se separan de las placas, se lavan y se resuspenden a 0,05 millones de células/ml en alfa-MEM que contiene FCS al 10%. Se distribuyen cien ul de la suspensión de células por pocillo en placas de cultivo de 96 pocillos. Los pocillos se complementan adicionalmente añadiendo 50 ul de medio que contiene 15 ng/ml de CSF-1, 3 indometacina uM, y 3X de una serie de diluciones de los compuestos de ensayo. Las células se cultivan durante 30 horas a 37 grados y CO2 al 5%. Durante las últimas seis horas, los cultivos se complementan con 30 ul más de medio que contiene una dilución 1:500 de bromodesoxiuridina (BrDU). Al final del periodo de cultivo, las placas se centrifugan a 1.000 RPM durante 1 minuto y se aspiran 130 ul de medio con una pipeta y se sustituyen con 150 ul de solución de fijación durante 1 hora a temperatura ambiente. A continuación, se elimina el fijador de las placas y se dejan secar las placas al aire. Se cuantifica la incorporación de BrDU en las células fijadas y secas mediante un ELISA específico.
La Tabla 2 enumera los resultados de los ensayos para los compuestos representativos de la invención. Tabla 2
- Nº de ejemplo
- c-fms 1 nM; CI-50 del ensayo Pi del péptido (µM) CI-50 de la proliferación de BMDM activada por mCSF (ratón) (µM)
- 1
- 0,0007 0,004
- 2
- 0,00042 0,0022
- 3
- 0,0017 N/A
- 4
- 0,0018 0,014
- 5
- 0,0005 0,0024
- 6
- 0,0016 0,015
- 7
- 0,00067 0,011
- 8
- 0,004 0,015
- 9
- 0,0019 0,1
- 10
- 0,0079 >0,3
- 11
- 0,0029 0,035
- 12
- 0,0011 0,031
- 13
- 0,0008 0,0081
- 14
- 0,0039 0,0095
- 15
- 0,0029 0,014
- 16
- 0,00067 0,046
- 17
- 0,00056 >0,3
- 18
- 0,0036 0,3
- 19
- 0,0018 0,019
- 20
- 0,0018 0,02
- 21
- 0,0016 0,0079
- 22
- 0,0008 >0,3
- 23
- 0,0064 >0,3
- 24
- 0,0008 0,014
- 25
- 0,00049 0,0065
- 26
- 0,003 0,0053
- 27
- 0,0029 0,0045
- 28
- 0,0084 0,028
- 29
- 0,0016 0,011
- 30
- 0,0032 0,007
- 31
- 0,0014 0,003
- 32
- 0,0032 0,019
- 33
- 0,0037 0,033
- 34
- 0,0015 0,0172
- 35
- 0,0007 0,0058
- 87
- 0,0011 0,0082
- 88
- 0,0024 0,0064
- 89
- 0,013 0,02
- 90
- 0,0065 0,04
- 91
- -0,21 0,061
- 92
- 0,0022 0,012
- 93
- 0,0029 0,0089
- 94
- 0,082 >0,1
- 95
- 0,026 0,029
90
Claims (2)
-
imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 imagen7 97imagen8 imagen9 imagen10 imagen11 imagen12 y solvatos, hidratos, tautómeros y sales farmacéuticamente aceptables del mismo. - 7. Compuesto seleccionado del grupo que consiste en:102
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