ES2563304T3 - Derivados azaespiro alcano como inhibidores de metaloproteasas - Google Patents

Derivados azaespiro alcano como inhibidores de metaloproteasas Download PDF

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Publication number
ES2563304T3
ES2563304T3 ES04760368.3T ES04760368T ES2563304T3 ES 2563304 T3 ES2563304 T3 ES 2563304T3 ES 04760368 T ES04760368 T ES 04760368T ES 2563304 T3 ES2563304 T3 ES 2563304T3
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octane
carbonyl
methyl
azaspiro
dihydropyridin
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ES04760368.3T
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Wenqing Yao
Jincong Zhou
Meizhong Xu
Fenglei Zhang
Brian Metcalf
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Incyte Holdings Corp
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Incyte Holdings Corp
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract

Compuesto de Fórmula II:**Fórmula** o un enantiómero, diastereómero, solvato o sal farmacéuticamente aceptable del mismo, en el que: A es CONHOH; B es CH2; G es CH2; X es CH2NRb; Y es CH2; M es CO; U está ausente; V es azetidin-1-ilo, 2,5-dihidro-1H-pirrol-1-ilo, piperidin-1-ilo, piperazin-1-ilo, pirrolidin-1-ilo, isoquinol-2-ilo, piridin- 1-ilo, 3,6-dihidropiridin-1-ilo, 2,3-dihidroindol-1-ilo, 1,3,4,9-tetrahidrocarbolin-2-ilo, tieno[2,3-c]piridin-6-ilo, 3,4,10,10a-tetrahidro-1H-pirazino[1,2-a]indol-2-ilo, 1,2,4,4a,5,6-hexahidro-pirazino[1,2-a]quinolin-3-ilo, pirazino[1,2-a]quinolin-3-ilo, diazepan-1-ilo, 1,4,5,6-tetrahidro-2H-benzo[f]isoquinolin-3-ilo, 1,4,4a,5,6,10bhexahidro- 2H-benzo[f]isoquinolin-3-ilo, 3,3a,8,8a-tetrahidro-1H-2-aza-ciclopenta[a]inden-2-ilo ó 2,3,4,7-tetrahidro- 1H-azepin-1-ilo, azepan-1-ilo; U' está ausente; V' es carbociclilo C3-13 sustituido con 0-5 Re; cada Re es, independientemente, H, T, alquileno C1-8-T, alquenileno C2-8-T, alquinileno C2-6-T, C(O)NRa'(CRb'Rc')r-T, C(O)O(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, Br, I, CN, NO2, NRIRII, CORIII, COORIV, ORIV, CONRIRII, NRICONRIRII, OCONRIRII, NRICORII, SO2NRIRII, NRISO2RII, NRISO2NRIRII, OSO2NRIRII, SOpRV, haloalquilo C1-8, carbociclilo C3-13, heterociclilo, carbociclilalquilo o heterociclilalquilo, en el que cada uno de dichos grupos carbociclilo, heterociclilo, carbociclilalquilo y heterociclilalquilo está opcionalmente sustituido por uno o más alquilo C1-8, alcoxi, halo, haloalquilo, haloalcoxi, ciano, nitro, amino, alquilamino, dialquilamino, carboxi, éster de carboxialquilo, éster de carboxiarilo, aminocarbonilo, alquilaminocarbonilo, dialquilaminocarbonilo, sulfonilo, aminosulfonilo, alquilaminosulfonilo, dialquilaminosulfonilo, arilsulfinilo, alquilsulfonilo o arilsufonilo; Rb es H, C(O)O(CRb'Rc')r-T o C(O)(CRb'Rc')r-T; cada T es independientemente H, alquilo C1-10, alquinilo C2-10, o heterociclilo; Ra' es H o alquilo C1-6; Rb' y Rc' son ambos H; R1 es hidrógeno; R2 es hidrógeno; R4' es H; R5' es H; RI y RII son cada uno, independientemente, H, alquilo C1-6 o carbociclilo C3-13; RIII y RIV son cada uno, independientemente, H, alquilo C1-6, haloalquilo, carbociclilo, heterociclilo, carbociclilalquilo o heterociclilalquilo, en el que cada uno de dichos carbociclilo, heterociclilo, carbociclilalquilo o heterociclilalquilo está opcionalmente sustituido por uno o más halo, alquilo C1-4 o alcoxi C1-4; RV es alquilo C1-6, haloalquilo, carbociclilo o heterociclilo; p>= 1 ó 2; y r>= 0, 1 ó 2; en el que, salvo que se indique otra cosa, cada arilo es arilo C6-20; cada alquilo es alquilo C1-20; cada carbociclilo es carbociclilo C3-30; y cada heterociclilo es un grupo carbocíclico saturado o insaturado que contiene de 3 a 14 átomos que forman el anillo en el que al menos un átomo de carbono del anillo está reemplazado por un heteroátomo seleccionado de entre O, S y N; a condición de que NRb no tenga enlaces N-N ni N-O.

Description

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Y está ausente, es (CH2)j, alquileno C1-10 sustituido con 0 a 3 Ra, alquenileno C2-10 sustituido con 0 a 2 Ra, N, O, NRb, S(O)m, C=O, NRbC(O), NRbC(O)O, NRbC(O)NRb, C(O)O, OC(O), S(O)mNRb, NRbS(O)m, NRbS(O)mNRb, (CRdRf)jNRb, NRb(CRdRf)j, o combinaciones de los mismos; M es CO o S(O)i; U está ausente, es alquileno C1-10 sustituido con 0 a 5 Ra, alquenileno C2-10 sustituido con 0 a 2 Ra, N, O, NRb, NRbC(O), NRbC(O)O, NRbC(O)NRb, NRbS(O)m, NRbS(O)NRb o combinaciones de los mismos; V está ausente, es H, carbociclilo C3-13 sustituido con 0-5 Re o heterociclilo sustituido con 0-5 Re; U’ está ausente, es alquileno C1-10 sustituido con 0 a 5 Ra, alquenileno C2-10 sustituido con 0 a 2 Ra, N, O, NRbS(O)m, C=O, NRbC(O), NRbC(O)O, NRbC(O)NRb, C(O)O, OC(O), S(O)mNRb, NRbS(O)m, NRbS(O)NRb o combinaciones de los mismos; V’ es H, alquilo C1-8, NRbRc, carbociclilo C3-13 sustituido con 0-5 Re o heterociclilo sustituido con 0-5 Re; Ra y Re son cada uno, independientemente, H, T, alquileno C1-8-T, alquenileno C2-8-T, alquinileno C2-6-T, C(O)NRa’(CRb’Rc’)r-T, C(O)O(CRb’Rc’)r-T, S(O)p(CRb’Rc’)r-T, (CRb’Rc)r-O-(CRb’Rc’)r-T, OH, Cl, F, Br, I, CN, NO2, NRIRII , CORIII , COORIV , ORIV , CONRIRII , NRICONRIRII , OCONRIRII , NRICORII , SO2NRIRII , NRISO2RII , NRISO2NRIRII , OSO2NRIRII , SOpRV, haloalquilo C1-8, carbociclilo C3-13, heterociclilo, carbociclilalquilo o heterociclilalquilo, en los que cada uno de dichos grupos carbociclilo, heterociclilo, carbociclilalquilo y heterociclilalquilo está opcionalmente sustituido por uno o más alquilo C1-8, alcoxi, halo, haloalquilo, haloalcoxi, ciano, nitro, amino, alquilamino, dialquilamino, carboxi, éster de carboxialquilo, éster de carboxiarilo, aminocarbonilo, alquilaminocarbonilo, dialquilaminocarbonilo, sulfonilo, aminosulfonilo, alquilaminosulfonilo, dialquilaminosulfonilo, arilsulfonilo, arilsulfinilo, alquilsulfonilo o arilsufonilo; Rb y Rc son cada uno, independientemente, H, T, alquileno C1-6-T, alquenileno C2-8-T, alquinileno C2-6-T, C(O)NRa’(CRc’Rb’)r-T, C(O)O(CRb’Rc’)r-T, C(O)(CRb’Rc’)r-T, S(O)p(CRb’Rc’)r-T, (CRc’Rb’)r-O-(CRc’Rb’)r-T, C(NRa’Ra’)(=N-CN) o C(NRa’Ra’)(=CHNO2); Rd y Rf son cada uno, independientemente, H, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, T, alquileno C1-6-T, alquenileno C2-8-T, alquinileno C2-6-T, C(O)NRa’(CRc’Rb’)r-T, C(O)O(CRb’Rc’)r-T, S(O)p(CRb’Rc’)r-T o (CRc’Rb’)r-O(CRc’Rb’)r-T, OH, Cl, F, Br, I, CN, NO2, NRIRII, CORIII, COORIV, ORIV, CONRIRII, RINCONR1RII, OCONRIRII , RINCORII, SO2NRIRII, NRISO2RII. NRISO2NRIRII, OSO2NRIRII, SOpRV, haloalquilo C1-8, carbociclilo, heterociclilo, carbociclilalquilo, heterociclilalquilo, carbocicliloxi o heterocarbocicliloxi, en los que cada uno de dichos grupos carbociclilo, heterociclilo, carbociclilalquilo, heterociclilalquilo, carbocicliloxi o heterocarbocicliloxi está opcionalmente sustituido por uno o más alquilo C1-8, alcoxi, halo, haloalquilo, haloalcoxi, ciano, nitro, amino, alquilamino, dialquilamino, carboxi, éster de carboxialquilo, éster de carboxiarilo, aminocarbonilo, alquilaminocarbonilo, dialquilaminocarbonilo, sulfonilo, aminosulfonilo, alquilaminosulfonilo, dialquilaminosulfonilo, arilsulfonilo, arilsulfinilo, alquilsulfonilo o arilsufonilo; T es H, alquilo C1-10 sustituido con 0 a 5 Rb’ ; alquenilo C2-10 sustituido con 0 a 5 Rb’, alquinilo C2-10 sustituido con 0 a 5 Rb’, carbociclilo C3-13 sustituido con 0-3 Rb’, heterociclilo sustituido con 0-5 Rb’; Ra’, Rb’ y Rc’ son cada uno, independientemente, H, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, OH, Cl, F, Br, I, CN, NO2, NRIRII , CORIII , COORIV , ORIV , CONRIRII , RINCONRIRII , OCONRIRII , RINCORII , SO2NRIRII , NRISO2RII , NRISO2NRIRII , OSO2NRIRII , SOpRV, haloalquilo C1-8, carbociclilo, heterociclilo, carbociclilalquilo, heterociclilalquilo, carbocicliloxi o heterocarbocicliloxi, en los que cada uno de dichos grupos carbociclilo, heterociclilo, carbociclilalquilo, heterociclilalquilo, carbocicliloxi o heterocarbocicliloxi está opcionalmente sustituido por uno o más alquilo C1-8, alcoxi, halo, haloalquilo, haloalcoxi, ciano, nitro, amino, alquilamino, dialquilamino, carboxi, éster de carboxialquilo, éster de carboxiarilo, aminocarbonilo, alquilaminocarbonilo, dialquilaminocarbonilo, sulfonilo, aminosulfonilo, alquilaminosulfonilo, dialquilaminosulfonilo, arilsulfonilo, arilsulfinilo, alquilsulfonilo o arilsufonilo; R1 es hidrógeno, alquilo C1-6, SR10, OR10 o NR11R12; R2 es hidrógeno, alquilo C1-6, SR10, OR10 o NR11R12; R3 es:
(i)
alquilo C1-10, alquenilo C2-8 o alquinilo C2-8;
(ii)
carbociclilo C3-13 opcionalmente sustituido con uno o más sustituyentes seleccionados de entre halógeno, alquilo C1-6, SR13, NR11R12, OR13, heterociclilo, arilo, =S, =O, CN, NO2, NRβRβ’, CORγ,RγNC(O)NRγRγ’, OC(O)NRγRγ’, C(O)ORγ, C(O)NRγRγ’, o RγNC(O)O;
(iii) arilo opcionalmente sustituido con uno o más sustituyentes seleccionados de entre halógeno, alquilo C1-6, SR13, NR11R12, OR13, heterociclilo, arilo, =S, =O, CN, NO2, NRβRβ’, CORγ,RγNC(O)NRγRγ’, OC(O)NRγRγ’, C(O)ORγ, C(O)NRγRγ’, o RγNC(O)O;
(iv)
heterociclilo opcionalmente sustituido con uno o más sustituyentes seleccionados de entre halógeno, alquilo C1-6, SR13, NR11R12, OR13, heterociclilo, arilo, =S, =O, CN, NO2, NRβRβ’, CORγ,RγNC(O)NRγRγ’, OC(O)NRγRγ’, C(O)ORγ, C(O)NRγRγ’, y RγNC(O)O;
(v)
NR14(CH2)lNR14R15; o
(vi)
NR16R17;
R4 y R5 son cada uno, independientemente, H, halógeno, T, alquileno C1-6-T, alquinileno C2-6-T, C(O)NRa’(CRc’Rb’)r-T, CO(CRb’Rc’)r-T, C(O)O(CRb’Rc’)r-T, S(O)p(CRb’Rc’)r-T, (CRc’Rb’)r-O-(CRc’Rb’)r-T, NR11R12, OR18 o SR18; R4’ es H, halógeno, T, alquileno C1-6-T, alquinileno C2-6-T, C(O)NRa’(CRc’Rb’)r-T, CO(CRb’Rc’)r-T, C(O)O(CRb’Rc’)r -T, S(O)p(CRb’Rc’)r-T, o (CRc’Rb’)r-O-(CRc’Rb’)r-T, NR11R12, SR18, o OR18;
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Además de las formas de sal, la presente invención proporciona compuestos que pueden estar en forma de profármaco. Los profármacos de los compuestos descritos en el presente documento son aquellos compuestos que experimentan fácilmente cambios químicos en condiciones fisiológicas para proporcionar los compuestos de la presente invención. Además, los profármacos pueden convertirse en los compuestos de la presente invención mediante métodos químicos o bioquímicos en un entorno ex vivo. Por ejemplo, los profármacos pueden convertirse lentamente en los compuestos de la presente invención cuando se colocan en un depósito de parche transdérmico con una enzima o reactivo químico adecuado.
En algunas formas de realización, la presente invención proporciona un compuesto seleccionado de entre:
N-hidroxi-5-metil-6-{[4-(3-metilfenil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-fenilpiperazin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-({4-[3-(trifluorometil)fenil]piperazin-1-il}carbonil)-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(2-metilfenil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(4-clorofenil)piperazin-1-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(2-metil-4-nitrofenil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-fenilpiperidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-[(4-hidroxi-4-fenilpiperidin-1-il)carbonil]-5-metil-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-quinolin-2-ilpiperazin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(2,3-diclorofenil)piperazin-1-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-quinolin-4-ilpiperazin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(2-metilquinolin-4-il)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(2-feniletil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-piridin-4-ilpiperidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(4-nitrofenil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(2-metoxifenil)piperazin-1-il]carbonil}-5-metil-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-fenoxipiperidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; 6-(3,4-dihidroisoquinolin-2(1H)-ilcarbonil)-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; 6-(4,7-dihidrotieno[2,3-c]piridin-6(5H)-ilcarbonil)-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; 6-[(3-bencilpirrolidin-1-il)carbonil]-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(4-piridin-2-ilpiperazin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(2-piridin-4-iletil)piperidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-({4-[5-(trifluorometil)piridin-2-il]piperazin-1-il}carbonil)-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-({4-[3-(trifluorometil)piridin-2-il]piperazin-1-il}carbonil)-5-azaespiro[2.5]octano-7-carboxamida; 6-(1,4’-bipiperidin-1’-ilcarbonil)-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(piridin-2-ilmetil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(piridin-4-ilmetil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(piridin-3-ilmetil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[4-(2-metilfenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(3-metilfenil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-(1,3,4,9-tetrahidro-2H-β-carbolin-2-ilcarbonil)-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(9-metil-1,3,4,9-tetrahidro-2H-β-carbolin-2-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(2-fluorofenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(2-clorofenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(4-nitrofenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-fenil-3,6-dihidropiridin-1(2H)-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(2-metil-4-nitrofenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7carboxamida; N(7)-hidroxi-N(6),5-dimetil-N(6)-(3-fenilpropil)-5-azaespiro[2.5]octano-6,7-dicarboxamida; N(7)-hidroxi-N(6)-isobutil-5-metil-5-azaespiro[2.5]octano-6,7-dicarboxamida; N-hidroxi-5-metil-6-{[4-(2-nitrofenil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N(7)-hidroxi-N(6)-isobutil-N(6),5-dimetil-5-azaespiro[2.5]octano-6,7-dicarboxamida; N(7)-hidroxi-5-metil-N(6)-(2-fenoxietil)-5-azaespiro[2.5]octano-6,7-dicarboxamida; N(7)-hidroxi-N(6)-[2-(4-metoxifenil)etil]-5-metil-5-azaespiro[2.5]octano-6,7-dicarboxamida; N(7)-hidroxi-5-metil-N(6)-(4-fenilbutil)-5-azaespiro[2.5]octano-6,7-dicarboxamida; N(7)-hidroxi-5-metil-N(6)-[3-(2-oxopirrolidin-1-il)propil]-5-azaespiro[2.5]octano-6,7-dicarboxamida; N-hidroxi-5-metil-6-[(10a)-3,4,10,10a-tetrahidropirazino[1,2-a]indol-2(1H)-ilcarbonil]-5-azaespiro[2.5]octano-7carboxamida; (5,6-trans)-N-hidroxi-5-{[4-(2-metil-4-nitrofenil)piperazin-1-il]carbonil}espiro[2.5]octano-6-carboxamida; (5,6-trans)-N-hidroxi-6-{[4-(3-metilfenil)piperazin-1-il]carbonil}espiro[2.5]octano-5-carboxamida; (5,6-trans)-N-hidroxi-5-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]espiro[2.5]octano-6-carboxamida; (5,6-trans)-N-hidroxi-5-{[4-(3-metilfenil)piperazin-1-il]carbonil}espiro[2.5]octano-6-carboxamida; (5,6-trans)-N-hidroxi-6-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]espiro[2.5]octano-5-carboxamida; N-hidroxi-6-(3,4,10,10a-tetrahidropirazino[1,2-a]indol-2(1H)-ilcarbonil)-5-azaespiro[2.5]octano-7-carboxamida;
15
imagen13
5
15
25
35
45
55
65
6-{[3-(4-fluorofenil)pirrolidin-1-il]carbonil}-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; 6-{[3-(4-clorofenil)pirrolidin-1-il]carbonil}-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-({3-[4-(trifluorometil)fenil]pirrolidin-1-il}carbonil)-5-azaespiro[2.5]octano-7-carboxamida; 6-{[3-(4-metoxifenil)pirrolidin-1-il]carbonil}-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; 6-{[3-(4-fenoxifenil)pirrolidin-1-il]carbonil}-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(3-metoxifenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(4-ciano-3-metilfenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; 6-{[3-(3-metoxifenil)pirrolidin-1-il]carbonil}-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-[(3-piridin-4-ilpirrolidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(3-trifluorometoxifenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[5-(metoximetil)-4-fenil-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-(1,4,5,6-tetrahidrobenzo[f]isoquinolin-3(2H)-ilcarbonil)-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(5-metoxi-2-metilfenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(4-metoxi-2-metilfenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida;
6-[(4-ciano-4-fenilpiperidin-1-il)carbonil]-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida;
7-[(hidroxiamino)carbonil]-6-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]-5-azaespiro[2.5]octano-5-carboxilato
de
etilo;
7-[(hidroxiamino)carbonil]-6-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]-5-azaespiro[2.5]octano-5-carboxilato
de
propilo;
7-[(hidroxiamino)carbonil]-6-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]-5-azaespiro[2.5]octano-5-carboxilato
de
isopropilo;
7-[(hidroxiamino)carbonil]-6-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]-5-azaespiro[2.5]octano-5-carboxilato
de
isobutilo; y
N-hidroxi-6-[(5-metil-4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida.
Los compuestos de la invención incluyen adicionalmente:
6-(1,4,4a,5,6,10b-hexahidrobenzo[f]isoquinolin-3(2H)-ilcarbonil)-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(4-fluorofenil)-3-hidroxipiperidin-1-il]carbonil}-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-(3,3a,8,8a-tetrahidroindeno[1,2-c]pirrol-2(1H)-ilcarbonil)-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(4-fenil-1,3-tiazol-2-il)piperidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(4-terc-butil-1,3-tiazol-2-il)piperidin-1-il]carbonil}-5-azaespiro[2.5.]octano-7-carboxamida; N-hidroxi-6-[(4-metil-4-fenilpiperidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(4-etil-1,3-tiazol-2-il)piperidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[(trans)-3-metil-4-fenilpirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(2-fluorofenil)piperazin-1-il]carbonil}-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; 6-{[4-(3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-il]carbonil}-N-hidroxi-5-metil-5-azaespiro[2.5]octano-7-carboxamida; 7-((hidroxiamino)carbonil)-6-((4-fenilpiperazin-1-il)carbonil)-5-azaespiro[2.5]octano-5-carboxilato de tetrahidro-2Hpiran-4-ilo; 7-((hidroxiamino)carbonil))-6-((4-fenilpiperazin-1-il)carbonil-5-azaespiro[2.5]octano-5-carboxilato de etilo; 7-[(hidroxiamino)carbonil]-6-[(4-fenilpiperazin-1-il)carbonil]-5-azaespiro[2.5]octano-5-carboxilato de metilo; N-hidroxi-6-[(4-pirazin-2-ilpiperazin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-[(4-quinolin-2-ilpiperazin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[3-(5,6,7,8-tetrahidronaftalen-2-il)pirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-{[(3R)-3-fenilpirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; 7-[(hidroxiamino)carbonil]-6-{[(3R)-3-fenilpirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-5-carboxilato de metilo; N-hidroxi-6-[(3-piridin-3-ilpirrolidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-[(3-piridin-2-ilpirrolidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-[(3-metil-3-fenilpirrolidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-[(3-fenilazetidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(3-metil-3-fenilpirrolidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-5-metil-6-[(3-fenilazetidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; 6-(1,3,3a,4,5,9b-hexahidro-2H-benzo[e]isoindol-2-ilcarbonil)-N-hidroxi-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[3-(2-naftil)pirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(2-tienil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[3-(3-tienil)pirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[3-(2-tienil)pirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(2-tienil)piperidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[3-(2-metilfenil)pirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[3-(4-metilfenil)pirrolidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; 5-acetil-N-hidroxi-6-[(4-fenil-3,6-dihidropiridin-1(2H)-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(3-tienil)-3,6-dihidropiridin-1(2H)-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-[(3-fenilpiperidin-1-il)carbonil]-5-azaespiro[2.5]octano-7-carboxamida; N-hidroxi-6-{[4-(3-tienil)piperidin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida;
17
imagen14
imagen15
5
15
25
35
45
55
65
hidroxiamida del ácido 5-metil-6-[4-(3-trifluorometil-fenil)-piperazina-1-carbonil]-5-aza-espiro[2.5]octano 7carboxílico; hidroxiamida del ácido 5-metil-6-(4-o-tolil-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(4-cloro-fenil)-piperazina-1-carbonil]-5-metil-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-[4-(2-metil-4-nitro-fenil)-piperazina-1-carbonil]-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 5-metil-6-(4-fenil-piperidina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-(4-hidroxi-4-fenil-piperidina-1-carbonil)-5-metil-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-quinolin-2-il-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(2,3-dicloro-fenil)-piperazina-1-carbonil]-5-metil-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-quinolin-4-il-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-[4-(2-metil-quinolin-4-il)-piperazina-1-carbonil]-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 5-metil-6-(4-fenetil-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(3,4,5,6-tetrahidro-2H-[4,4’]bipiridinil-1-carbonil)-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 5-metil-6-[4-(4-nitro-fenil)-piperazina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(2-metoxi-fenil)-piperazina-1-carbonil]-5-metil-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-fenoxi-piperidina-1-carboni])-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-(3,4-dihidro-1H-isoquinolina-2-carbonil)-5-metil-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-(4,7-dihidro-5H-tieno[2,3-c]piridina-6-carbonil)-5-metil-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(3-bencil-pirrolidina-1-carbonil)-5-metil-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-piridin-2-il-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-[4-(2-piridin-4-il-etil)-piperidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-[4-(5-trifluorometil-piridin-2-il)-piperazina-1-carbonil]-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 5-metil-6-[4-(3-trifluorometil-piridin-2-il)-piperazina-1-carbonil]-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-([1,4’]bipiperidinil-1’-carbonil)-5-metil-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-piridin-2-ilmetil-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-piridin-4-ilmetil-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-piridin-3-ilmetil-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 5-metil-6-(4-o-tolil-3,6-dihidro-2H-piridina-1-carbonil)-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(4-m-tolil-piperazina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-(1,3,4,9-tetrahidro-b-carbolina-2-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-(9-metil-1,3,4,9-tetrahidro-b-carbolina-2-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico;
hidroxiamida
del ácido 6-[4-(2-fluoro-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-aza-espiro[2.2]octano-7
carboxílico;
hidroxiamida
del ácido 6-[4-(2-cloro-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-aza-espiro[2.5]octano-7
carboxílico;
hidroxiamida del ácido 6-[4-(4-nitro-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(2-metil-4-nitro-fenil)-piperazina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; 7-hidroxiamida 6-[metil-(3-fenil-propil)-amida del ácido 5-metil-5-aza-espiro[2.5]octano-6,7-dicarboxílico; 7-hidroxiamida 6-(isobutil-amida) del ácido 5-metil-5-aza-espiro[2.5]octano-6,7-dicarboxílico; hidroxiamida del ácido 5-metil-6-[4-(2-nitro-fenil)-piperazina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; 7-hidroxiamida 6-(isobutilmetil-amida) del ácido 5-metil-5-aza-espiro[2.5]octano-6,7-dicarboxílico; 7-hidroxiamida 6-[(2-fenoxi-etil)-amida] del ácido 5-metil-5-aza-espiro[2.5]octano-6,7-dicarboxílico; 7-hidroxiamida 6-{[2-(4-metoxi-fenil)-etil]-amida} del ácido 5-metil-5-aza-espiro[2.5]octano-6,7-dicarboxílico; 7-hidroxiamida 6-[(4-fenilbutil)-amida] del ácido 5-metil-5-aza-espiro[2.5]octano-6,7-dicarboxílico; 7-hidroxiamida 6-{[3-(2-oxo-pirrolidin-1-il)-propil]-amida} del ácido 5-metil-5-aza-espiro[2.5]octano-6,7dicarboxílico; hidroxiamida del ácido 6-(3,4,10,10a-tetrahidro-1H-pirazino[1,2-a]indol-2-carbonil)-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 5-[4-(2-metil-4-nitro-fenil)-piperazina-1-carbonil]-espiro[2.5]octano-6-carboxílico; hidroxiamida del ácido 6-(4-m-tolil-piperazina-1-carbonil)-espiro[2.5]octano-5-carboxílico; hidroxiamida del ácido 5-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-espiro[2.5]octano-6-carboxílico; hidroxiamida del ácido 5-(4-m-tolil-piperazina-1-carbonil)-espiro[2.5]octano-6-carboxílico; hidroxiamida del ácido 6-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-espiro[2.5]octano-5-carboxílico; hidroxiamida del ácido 6-(3,4,10,10a-tetrahidro-1H-pirazino[1,2-a]indol-2-carbonil)-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(1,2,4,4a,5,6-hexahidro-pirazino[1,2-a]quinolina-3-carbonil)-5-metil-5-azaespiro[2.5]octano-7-carboxílico;
20
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5
15
25
35
45
55
65
hidroxiamida del ácido 6-[4-(2,3-dihidro-benzofuran-5-il)-3,6-dihidro-2H-piridina-1-carbonil]-5-metil-5-azaespiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(3-isopropil-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-metil-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(3-fenil-pirrolidina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-(3-fenil-pirrolidina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(3-trifluorometil-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(3-cloro-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(3-fluoro-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(4-fluoro-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(4-cloro-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(4-trifluorometil-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(4-metoxi-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[3-(4-Fenoxi-fenil)-pirrolidina-1-carbonil]-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(3-metoxi-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-[4-(4-ciano-3-metil-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(3-piridin-4-il-pirrolidina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(3,5-dimetil-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-[4-(3-trifluorometoxi-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(5-metoximetil-4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(1,4,5,6-tetrahidro-2H-benzo[f]isoquinolina-3-carbonil)-5-aza-espiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(4-m-tolil-piperidina-1-bonil)-5-aza-espiro[2.5]octano-7-carboxílico; hidroxiamida del ácido 6-[4-(5-metoxi-2-metil-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-[4-(4-metoxi-2-metil-fenil)-3,6-dihidro-2H-piridina-1-carbonil]-5-azaespiro[2.5]octano-7carboxílico; hidroxiamida del ácido 6-(4-ciano-4-fenil-piperidina-1-carbonil)-5-aza-espiro[2.5]octano-7-carboxílico; éster etílico del ácido 7-hidroxicarbamoil-6-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5-azaespiro[2.5]octano-5carboxílico; éster propílico del ácido 7-hidroxicarbamoil-6-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5-azaespiro[2.5]octano-5carboxílico; éster isopropílico del ácido 7-hidroxicarbamoil-6-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5azaespiro[2.5]octano-5-carboxílico; éster isobutílico del ácido 7-hidroxicarbamoil-6-(4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5-azaespiro[2.5]octano5-carboxílico; e hidroxiamida del ácido 6-(5-metil-4-fenil-3,6-dihidro-2H-piridina-1-carbonil)-5-aza-espiro[2.5]octano-7carboxílico.
Síntesis
Los compuestos novedosos de la presente invención pueden prepararse en diversas formas conocidas para un experto en la técnica de la síntesis orgánica. Los compuestos de la presente invención pueden sintetizarse utilizando los métodos que se describen más adelante, junto con métodos de síntesis conocidos en la técnica de la química orgánica sintética o variaciones de los mismos como entenderán los expertos en la materia.
Los compuestos de la presente invención pueden prepararse a partir de materiales de partida de fácil adquisición utilizando los siguientes métodos y procedimientos generales. Se entenderá que cuando se dan condiciones de proceso típicas o preferentes (es decir, temperaturas de reacción, tiempos, relaciones molares de reaccionantes, disolventes, presiones, etc.), también pueden utilizarse otras condiciones de proceso a menos que se indique otra cosa. Las condiciones de reacción óptimas pueden variar en función de los reactantes o disolventes concretos utilizados, pero un experto en la materia puede determinar tales condiciones mediante procedimientos de optimización rutinarios.
Los procesos descritos en el presente documento pueden supervisarse según cualquier método adecuado conocido en la técnica. Por ejemplo, la formación de producto puede supervisarse mediante medios espectroscópicos, tales como espectroscopia de resonancia magnética nuclear (por ejemplo, 1H o 13C) espectroscopia infrarroja, espectrofotometría (por ejemplo, UV-visible), o espectrometría de masas, o mediante cromatografía tal como cromatografía de líquidos de alto rendimiento (HPLC) o cromatografía en capa fina.
22
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Como alternativa, como se muestra en el Esquema 4 (en el que R1 y R2 de las fórmulas 28 y 29 corresponden a sustituyentes apropiados que proporcionen los compuestos de la invención), se eliminó primero el grupo terc-butilo del compuesto 26, seguido de acoplamiento convencional para dar la amida 28. La hidrólisis básica de 28 en condición de reflujo proporcionó el ácido, a continuación el ácido se convirtió en el compuesto final 29 utilizando el procedimiento convencional de acoplamiento.
imagen20
Los compuestos de estructura general 30 pueden prepararse utilizando el procedimiento esbozado en el
55 Esquema 5 (en el que R1 y R2 de las fórmulas 30 y 32 corresponden a sustituyentes apropiados que proporcionen los compuestos de la invención). La cetona 24 se convirtió en el correspondiente ditiocetal 31. El grupo éster etílico se hidrolizó al ácido, seguido de acoplamiento con la amina para proporcionar la amida 32. Siguiendo un procedimiento similar al descrito en el Esquema 3, el compuesto 32 se convirtió en el compuesto final 30. Pueden prepararse varios compuestos de fórmulas 33 y 34 siguiendo la síntesis esboza en el Esquema 6 (en el que R1 y R2 de las fórmulas 33 y 34 corresponden a sustituyentes apropiados que proporcionen los compuestos de la invención). La cetona 24 se trató con aliltrimetilsilano en presencia de TiCl4 para dar 35. La hidroboración seguida de oxidación proporcionó el alcohol primario 36. El alcohol primario se activó y se cicló al correspondiente tetrahidrofurano 37. La conversión de 37 en la amida y finalmente en el ácido hidroxámico 33 ó 34 transcurrió a través del mismo enfoque descrito anteriormente.
65
25
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imagen22
La serie de 4-aril-1,2,3,6-tetrahidro-piridina de fórmula 45 y 4-aril-piperidina de fórmula 46 puede prepararse siguiendo el Esquema 9. Por ejemplo, el acoplamiento de Suzuki catalizado por paladio del éster terc-butílico del ácido 4-trifluorometanosulfoniloxi-3,6-dihidro-2H-piridina-1-carboxílico 47 con ácido arilborónico puede proporcionar compuestos de fórmula 48 utilizando procedimientos convencionales (por ejemplo, Y. Deng, L. Gong, A Mi, H. Liu, Y. Jiang, Synthesis, 2003, 337-339). El grupo protector Boc puede eliminarse mediante tratamiento de la correspondiente amina con TFA o HCl. Utilizando un método convencional de hidrogenación, la 4-aril-1,2,3,6
35 tetrahidro-piridina puede convertirse en la correspondiente 4-aril-piperidina.
imagen23
La invención se ilustra mediante los siguientes ejemplos, que no pretenden en modo alguno ser limitativos.
55 EJEMPLOS
Los reactivos y disolventes utilizados más adelante pueden obtenerse de fuentes comerciales tales como Aldrich Chemical Co. (Milwaukee, Wis., EE.UU.). Los resultados de la espectrometría de masas se presentan como la relación entre masa y carga, seguido de la abundancia relativa de cada ion (entre paréntesis). En las tablas, se presenta un solo valor m/e para el ion M+H (o, como se ha indicado, M-H) que contiene los isótopos atómicos más comunes. Los patrones isotópicos corresponden a la fórmula esperada en todos los casos.
Ejemplo 1
65 (6S,7S)-N-hidroxi-5-metil-6-{[4-(3-metilfenil)piperazin-1-il]carbonil}-5-azaespiro[2.5]octano-7-carboxamida
27
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9
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo Me 370
11
A 4-quinolin-2-ilpiperazin-1-ilo Me 424,3
12
A 4-(2,3-diclorofenil)piperazin-1-ilo Me 441
13
A 4-quinolin-4-ilpiperazin-1-ilo Me 424,3
14
A 4-(2-metilquinolin-4-il)piperazin-1-ilo Me 438,4
15
A 4-(2-feniletil)piperazin-1-ilo Me 401,3
16
A 4-piridin-4-ilpiperidin-1-ilo Me 373,3
17
A 4-(4-nitrofenil)piperazin-1-ilo Me 418,3
18
A 4-(2-metoxifenil)piperazin-1-ilo Me 403
19
A 4-fenoxipiperidin-1-ilo Me 388,3
20
A 3,4-dihidroisoquinolin-2(1H)-ilo Me 344,3
21
A 4,7-dihidrotieno[2,3-c]piridin-6(5H)-ilo Me 350,2
22
A 3-bencilpirrolidin-1-ilo Me 372,3
23
A 4-piridin-2-ilpiperazin-1-ilo Me 374,2
24
A 4-(2-piridin-4-iletil)piperidin-1-ilo Me 401,3
25
A 4-[5-(trifluorometil)piridin-2-il]piperazin-1-ilo Me 442,3
26
A 4-[3-(trifluorometil)piridin-2-il]piperazin-1-ilo Me 442,3
27
A 1,4’-bipiperidin-1’-ilo Me 379,3
28
A 4-(piridin-2-ilmetil)piperazin-1-ilo Me 388,3
29
A 4-(piridin-4-ilmetil)piperazin-1-ilo Me 388,3
30
A 4-(piridin-3-ilmetil)piperazin-1-ilo Me 388,3
31
A 4-(2-metilfenil)-3,6-dihidropiridin-1(2H)-ilo Me 384,1
32
A 4-(3-metilfenil)piperazin-1-ilo H 373,1
33
A 1,3,4,9-tetrahidro-2H-β-carbolin-2-ilo Me 383
34
A 9-metil-1,3,4,9-tetrahidro-2H-β-carbolin-2-ilo Me 396,9
35
A 4-(2-fluorofenil)-3,6-dihidropiridin-1(2H)-ilo Me 388
36
A 4-(2-clorofenil)-3,6-dihidropiridin-1(2H)-ilo Me 404
37
A 4-(4-nitrofenil)-3,6-dihidropiridin-1(2H)-ilo Me 415,1
38
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo H 356
39
A 4-(2-metil-4-nitrofenil)piperazin-1-ilo H 418
40
A N-metil-N’-(3-fenilpropil)amino Me 360,1
41
A isobutilamino Me 284
42
A 4-(2-nitrofenil)piperazin-1-ilo Me 418
43
A N-metil-N’-(isobutil)amino Me 298
44
A (2-fenoxietil)-amino Me 348
45
A 2-(4-metoxifenil)etilamino Me 362
46
A 4-fenilbutilamino Me 360
47
A 3-(2-oxopirrolidin-1-il)propilamino Me 353
48
A 3,4,10,10a-tetrahidropirazino[1,2-a]indol-2(1H)-ilo H 385
49
D 4-(2-metil-4-nitrofenil)piperazin-1-ilo 417,2
50
B 372,2
51
D 4-fenil-3,6-dihidropiridin-1(2H)-ilo 355
52
D 4-(3-metilfenil)piperazin-1-ilo 372
53
B 4-fenil-3,6-dihidropiridin-1(2H)-ilo 355
54
A 3,4,10,10a-tetrahidropirazino[1,2-a]indol-2(1H)-ilo H 371,2
55
A 1,2,4,4a,5,6-hexahidro-3H-pirazino[1,2-a]quinolin-3-ilo Me 399,4
56
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo metoxicarbonilo 414
57
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo benciloxicarbonilo 490
58
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo metilsulfonilo 434
59
A 3-(3-metoxifenil)piperidin-1-ilo Me 402,4
60
A 3-(2-feniletil)pirrolidin-1-ilo Me 386
61
A 4-(3-metoxifenil)piperidin-1-ilo Me 402,4
62
A 4-[3-(aminocarbonil)fenil]-3,6-dihidropiridin-1(2H)-ilo H 398,9
63
A 4-(2-metoxifenil)piperidin-1-ilo Me 402,4
64
A 4-(3-fluoro-2-metilfenil)piperazin-1-ilo H 391,3
65
A 4-(2-metil-3-nitrofenil)piperazin-1-ilo H 418,3
66
A 3’,6’-dihidro-3,4’-bipiridin-1’(2’H)-ilo H 357,4
67
A N-(4-metoxifenil)-N’-metilamino H 334
68
A 4-(3-metoxifenil)piperazin-1-ilo Me 403
69
A 4-(3-clorofenil)piperazin-1-ilo Me 407,3
70
A 4-Fenil-[1,4]diazepan-1-ilo H 373
73
71
A 3-metil-4-(3-metilfenil)piperazin-1-ilo H 387
72
A 4-(3-metoxifenil)piperidin-1-ilo H 388,4
73
B 3-fenilpirrolidin-1-ilo 343,3
74
A 4-isobutirilpiperazin-1-ilo H 353
75
A 4-(4-ciano-2-metilfenil)-3,6-dihidropiridin-1(2H)-ilo H 395
76
A 4-[(2-metilquinolin-4-il)metoxi]fenilamino Me 475,4
77
A 4-[(2-metilquinolin-4-il)metoxi]fenilamino H 461
78
A 4-(4-cianofenil)piperazin-1-ilo H 384
79
C 4-fenilpiperidin-1-ilo H 358
80
A 4-fenilpiperidin-1-ilo H 358
81
A 4-fenilpiperazin-1-ilo H 359
82
A 4-[3-(metoximetil)fenil]piperidin-1-ilo H 402
83
A 4-(3-metoxicarbonilfenil)piperidin-1-ilo H 416
84
A 3-ciclohexilpirrolidin-1-ilo H 350,4
85
A 4-(3-isopropilfenil)-3,6-dihidropiridin-1(2H)-ilo H 398,4
86
A 4-(3-Isopropilfenil)piperidin-1-ilo H 400,4
87
A 4-(4-propilfenil)-3,6-dihidropiridin-1(2H)-ilo H
88
A 4-(4-etilfenil)-3,6-dihidropiridin-1(2H)-ilo H 384,4
89
A 4-(4-etilfenil)piperidin-1-ilo H 386
90
A 4-(4-ciano-2-metilfenil)piperazin-1-ilo H 398
91
A 4-(3-isopropoxifenil)-3,6-dihidropiridin-1(2H)-ilo H 414,4
92
A 4-(3-metilfenil)-3,6-dihidropiridin-1(2H)-ilo H 370,3
93
A 4-(3-metilfenil)piperazin-1-ilo H 372,4
94
A 4-(4-tert-butilfenil)piperazin-1-ilo H 415,4
95
A 4-piridin-4-ilpiperazin-1-ilo H 360
96
A 3-bencilpiperidin-1-ilo H 371,9
97
A 5-metoxi-2,3-dihidro-1H-indol-1-ilo H 346,3
98
A 5-[(2-metilquinolin-4-il)metoxi]-2,3-dihidro-1H-indol-1-ilo H 487,4
99
A 5-[(2-metilquinolin-4-il)metoxi]-2,3-dihidro-1H-indol-1-ilo Me 501,4
100
A 5-(benciloxi)-2,3-dihidro-1H-indol-1-ilo H 422,3
101
A 1,3-dihidro-1’H-spiro[indeno-2,4’-piperidin]-1’-ilo H 384,4
102
A 4-(3-isopropoxifenil)piperidin-1-ilo H 416,4
103
A 4-(2-metil-4-metoxicarbonilfenil)-3,6-dihidropiridin-1(2H)-ilo H 427,9
104
A 4-(2-metil-4-nitrofenil)-3,6-dihidropiridin-1(2H)-ilo H 414,8
105
A 4-(2-etilfenil)piperidin-1-ilo H 385,9
106
A 4-(2-metil-4-metoxicarbonilfenil)piperidin-1-ilo H 429,9
107
A 4-(2,3-dihidro-1-benzofuran-5-il)-3,6-dihidropiridin-1(2H)-ilo Me 412,2
108
A 4-(3-isopropilfenil)-3,6-dihidropiridin-1(2H)-ilo Me 412,2
109
A (3R)-3-fenilpirrolidin-1-ilo H 344,1
110
A (3S)-3-fenilpirrolidin-1-ilo H 344,1
112
A 3-[3-(trifluorometil)fenil]pirrolidin-1-ilo H 412,1
113
A 3-(3-clorofenil)pirrolidin-1-ilo H 378,1
114
A 3-(3-fluorofenil)pirrolidin-1-ilo H 362,1
115
A 3-(4-fluorofenil)pirrolidin-1-ilo H 362,1
116
A 3-(4-clorofenil)pirrolidin-1-ilo H 378,1
117
A 3-[4-(trifluorometil)fenil]pirrolidin-1-ilo H 412,1
118
A 3-(4-metoxifenil)pirrolidin-1-ilo H 374,1
119
A 3-(4-fenoxifenil)pirrolidin-1-ilo H 436,2
120
A 4-(3-metoxifenil)-3,6-dihidropiridin-1(2H)-ilo H 386,1
121
A 4-(4-ciano-3-metilfenil)-3,6-dihidropiridin-1(2H)-ilo H 395,1
122
A 3-(3-metoxifenil)pirrolidin-1-ilo H 374,1
123
A 3-piridin-4-ilpirrolidin-1-ilo H 345,2
124
A 4-(3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo H 384,2
125
A 4-(3-trifluorometoxifenil)-3,6-dihidropiridin-1(2H)-ilo H 440,1
126
A 5-(metoximetil)-4-fenil-3,6-dihidropiridin-1(2H)-ilo H 400
127
A 1,4,5,6-tetrahidrobenzo[f]isoquinolin-3(2H)-ilo H 381,9
129
A 4-(5-metoxi-2-metilfenil)-3,6-dihidropiridin-1(2H)-ilo H 400,2
130
A 4-(4-metoxi-2-metilfenil)-3,6-dihidropiridin-1(2H)-ilo H 400,2
131
A 4-ciano-4-fenilpiperidin-1-ilo 383,2
132
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo Etoxicarbonilo 426,1
74
133
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo Propionoxicarbonilo 440,2 *
134
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo isopropionoxicarbonilo 440,2 *
135
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo iso-butoxicarbonilo 454,2 *
136
A 5-metil-4-fenil-3,6-dihidropiridin-1(2H)-ilo H 370
143
A 1,4,4a,5,6,10b-hexahidrobenzo[f]isoquinolin-3(2H)-ilo H 384,2
144
A 4-(4-fluorofenil)-3-hidroxipiperidin-1-ilo H 392,1
145
A 3,3a,8,8a-tetrahidroindeno[1,2-c]pirrol-2(1H)-ilo H 356,1
146
A 4-(4-fenil-1,3-tiazol-2-il)piperidin-1-ilo H 441,3
147
A 4-(4-tert-Butil-1,3-tiazol-2-il)piperidin-1-ilo H 421,1
148
A 4-metil-4-fenilpiperidin-1-ilo H 372,2
149
A 4-(4-etil-1,3-tiazol-2-il)piperidin-1-ilo H 393,1
150
A 3-metil-4-fenilpirrolidine-1-ilo H 358,2
151
A 4-(2-fluorofenil)piperazin-1-ilo H 377,2
152
A 4-(3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo Me 398,1
153
A 4-fenilpiperazin-1-ilo tetrahidro-2H-piran4-oxicarbonilo 487,1
154
A 4-fenilpiperazin-1-ilo etoxicarbonilo 431,2
155
A 4-fenilpiperazin-1-ilo metoxicarbonilo 417,1
156
A 4-pirazin-2-ilpiperazin-1-ilo H 361,2
157
A 4-quinolin-2-ilpiperazin-1-ilo H 410,1
158
A 3-(5,6,7,8-tetrahidronaftalen-2-il)pirrolidin-1-ilo H 398,2
159
A (3R)-3-fenilpirrolidin-1-ilo Me 358,1
160
A (3R)-3-fenilpirrolidin-1-ilo metoxicarbonilo 402,1
161
A 3-piridin-3-ilpirrolidin-1-ilo H 345,1
162
A 3-piridin-2-ilpirrolidin-1-ilo H 345,1
163
A 3-metil-3-fenilpirrolidine-1-ilo H 358,2
164
A 3-fenilazetidin-1-ilo H 330,3
165
A 3-metil-3-fenilpirrolidine-1-ilo Me 372,4
166
A 3-fenilazetidin-1-ilo Me 344,4
168
A 1,3,3a,4,5,9b-hexahidro-2H-benzo[e]isoindol-2-ilo H 370,4
169
A 3-(2-naftil)pirrolidin-1-ilo H 394,4
170
A 4-(2-tienil)-3,6-dihidropiridin-1(2H)-ilo H 362,1
171
A 3-(3-tienil)pirrolidin-1-ilo H 350,1
172
A 3-(2-tienil)pirrolidin-1-ilo H 350,2
173
A 4-(2-tienil)piperidin-1-ilo H 364,1
174
A 3-(2-metilfenil)pirrolidin-1-ilo H 358,2
175
A 3-(4-metilfenil)pirrolidin-1-ilo H 358,2
176
A 4-fenil-3,6-dihidropiridin-1(2H)-ilo Ac 396,2
177
A 4-(3-tienil)-3,6-dihidropiridin-1(2H)-ilo H 362,1
178
A 3-fenilpiperidin-1-ilo H 358,2
179
A 4-(3-tienil)piperidin-1-ilo H 364,1
180
A 4-(3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo metoxicarbonilo 442,2
181
A 4-(3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo metanosulfonilo 462,1
182
A 4-(3,5-difluorofenil)-3,6-dihidropiridin-1(2H)-ilo H 392,2
183
A 4-(3,5-diclorofenil)-3,6-dihidropiridin-1(2H)-ilo H 424,1
184
A 4-[3,5-bis(trifluorometil)fenil]-3,6-dihidropiridin-1(2H)-ilo H 492,1
185
A 4-fenilpiperazin-1-ilo metanosulfonilo 437,2
186
A 4-fenilpiperazin-1-ilo formilo 387,2
187
A 4-(3,5-difluorofenil)piperidin-1-ilo H 394,2
188
A 4-(2,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo H 384,1
189
A 4-(2,4,5-trimetilfenil)-3,6-dihidropiridin-1(2H)-ilo H 398,2
190
A 4-bifenil-3-ilpiperidin-1-ilo H 434,2
191
A 4-dibenzo[b,d]furan-4-ilpiperidin-1-ilo H 448,2
192
A 4-(2,5-dimetilfenil)piperidin-1-ilo H 386,2
193
A 4-(2,4,5-trimetilfenil)piperidin-1-ilo H 400,2
194
A 4-(3-metoxicarbonil-6-metilfenil)-3,6-dihidropiridin-1(2H)-ilo H 428,2
195
A 5-fenil-2,3,4,7-tetrahidro-1H-azepin-1-ilo H 370,2
196
A 4-[3-(dimetilamino)fenil]-3,6-dihidropiridin-1(2H)-ilo H 399,2
197
A 4-(3-metoxicarbonil-6-metilfenil)piperidin-1-ilo H 430,2
198
A 5-fenilazepan-1-ilo H 372,2
199
A 4-[3-(dimetilamino)fenil]piperidin-1-ilo H 401,2
75
200
A 4-(2-metilfenil)-3,6-dihidropiridin-1(2H)-ilo H 370,2
201
A 3-fenil-2,5-dihidro-1H-pirrol-1-ilo H 342,1
202
A 4-(4-ciano-2-metilfenil)piperidin-1-ilo H 397,2
203
A 3,3-dimetil-4-fenil-3,6-dihidropiridin-1(2H)-ilo H 384,1
204
A 3,3-dimetil-4-fenilpiperidin-1-ilo H 386,2
205
A 3-fenil-2,5-dihidro-1H-pirrol-1-ilo metanosulfonilo 420,2
206
A 3-fenil-2,5-dihidro-1H-pirrol-1-ilo metoxicarbonilo 400,2
207
A 3-fenil-2,5-dihidro-1H-pirrol-1-ilo Me 356,2
208
A 4-(4-ciano-3-metilfenil)piperidin-1-ilo H 397,2
209
A 4-[3-(benciloxi)fenil]-3,6-dihidropiridin-1(2H)-ilo H 462,2
210
A 4-[3-etilfenil]-3,6-dihidropiridin-1(2H)-ilo H 384,1
211
A 4-[3-(etiloxi)fenil]-3,6-dihidropiridin-1(2H)-ilo H 400,1
212
A 4-(3-etilfenil)piperidin-1-ilo H 386,1
213
A 4-(3-etoxifenil)piperidin-1-ilo H 402,1
214
A 4-(3-ciclopropilfenil)-3,6-dihidropiridin-1(2H)-ilo H 396,2
215
A 4-(4-metoxi-3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo H 414,2
216
A 4-(3,5-dimetil-4-metoxifenil)piperidin-1-ilo H 416,2
217
A 4-(4-ciano-3-etilfenil)-3,6-dihidropiridin-1(2H)-ilo H 409,2
218
A 4-(4-ciano-3-etilfenil)piperidin-1-ilo H 411,2
219
A 4-(4-ciano-3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo H 409,2
220
A 4-(4-ciano-3,5-dimetilfenil)piperidin-1-ilo H 411,4
221
A 4-(1,3-benzotiazol-6-il)-3,6-dihidropiridin-1(2H)-ilo H 413,1
222
A 4-(1-metil-1H-indazol-6-il)-3,6-dihidropiridin-1(2H)-ilo H 410,2
223
A 4-(1-metil-1H-indazol-6-il)piperidin-1-ilo H 412,3
224
A 4-(4-ciano-3-isopropilfenil)-3,6-dihidropiridin-1(2H)-ilo H 423,2
225
A 4-(4-ciano-3-isopropilfenil)piperidin-1-ilo H 425,2
236
A 4-(4-ciano-3-etilfenil)-3,6-dihidropiridin-1(2H)-ilo Me 423,2
237
A 4-(4-ciano-3,5-dimetilfenil)-3,6-dihidropiridin-1(2H)-ilo Me 423,2
238
A 4-(1-etil-1H-benzimidazol-6-il)-3,6-dihidropiridin-1(2H)-ilo H 424,3
239
A 4-(1-metil-1H-indazol-5-il)-3,6-dihidropiridin-1(2H)-ilo H 410,2
240
A 4-(1-etil-1H-benzimidazol-6-il)piperidin-1-ilo H 426,2
241
A 4-(1-metil-1H-indazol-5-il)piperidin-1-ilo H 412,2
242
A 4-(1-etil-1H-indazol-5-il)-3,6-dihidropiridin-1(2H)-ilo H 424,2
243
A 4-(1-etil-1H-benzimidazol-6-il)piperidin-1-ilo tetrahidro-2H-piran4-oxicarbonilo 554,3
244
A 4-(1-etil-1H-benzimidazol-6-il)-3,6-dihidropiridin-1(2H)-ilo metoxicarbonilo 482,2
245
A 4-(1-etil-1H-benzimidazol-6-il)-3,6-dihidropiridin-1(2H)-ilo metanosulfonilo 502,2
246
A 4-(1-etil-1H-benzimidazol-6-il)piperidin-1-ilo metoxicarbonilo 484,2
247
A 4-(1-etil-1H-benzimidazol-6-il)piperidin-1-ilo metanosulfonilo 504,2
248
A 4-(4-ciano-2-metilfenil)piperidin-1-ilo metanosulfonilo 476,2
249
A 4-(4-ciano-2-metilfenil)piperazin-1-ilo metoxicarbonilo 456,2
250
A 4-(1-etil-1H-benzimidazol-6-il)piperazin-1-ilo H 427,5
251
A 4-(1-metil-1H-benzimidazol-6-il)piperazin-1-ilo metoxicarbonilo 485,3
252
A 4-(1-etil-1H-benzimidazol-6-il)piperazin-1-ilo metanosulfonilo 505,2
253
A 4-(4-ciano-2-metilfenil)piperazin-1-ilo tetrahidro-2H-piran4-oxicarbonilo 526,3
254
A 4-(1-etil-1H-benzimidazol-6-il)piperazin-1-ilo tetrahidro-2H-piran4-oxicarbonil
255
A 3-metil-4-fenilpiperidin-1-ilo H 372,1
256
A 5-(aminocarbonil)-4-fenil-3,6-dihidropiridin-1(2H)-ilo H
257
A 4-(4-cianofenil)-5-metil-3,6-dihidropiridin-1(2H)-ilo H 395,2
258
A 4-(4-cianofenil)-3-metilpiperidin-1-ilo H 397,1
259
A 5-metil-4-(4-nitrofenil)-3,6-dihidropiridin-1(2H)-ilo H 415,2
260
A 5-metil-4-(3-nitrofenil)-3,6-dihidropiridin-1(2H)-ilo H 415,1
262
A 4-dibenzo[b,d]furan-2-il-3,6-dihidropiridin-1(2H)-ilo H 446,1
263
A 4-dibenzo[b,d]furan-2-ilpiperidin-1-ilo H 448,1
264
A 4-(3,3-dimetil-2,3-dihidro-1-benzofuran-5-il)-3,6dihidropiridin-1(2H)-ilo H 426,1
265
A 4-(3,3-dimetil-2,3-dihidro-1-benzofuran-5-il)piperidin-1-ilo H 428,1
266
A 3-fenil-2,5-dihidro-1H-pirrol-1-il isopropionoxicarbonilo 428,1
76
267
A 3-fenil-2,5-dihidro-1H-pirrol-1-ilo (3S)tetrahidrofuran-3oxicarbonilo 456,1
268
A 3-fenil-2,5-dihidro-1H-pirrol-1-ilo ciclohexoxicarbonilo 468,2
269
A 3-fenil-2,5-dihidro-1H-pirrol-1-ilo tetrahidro-2H-piran4-oxicarbonilo 470,2
270
B 4-fenilpiperazin-1-ilo 358,2
271
B (3R)-3-fenilpirrolidin-1-ilo 343,3
272
B 4-(2-metil-4-nitrofenil)piperazin-1-ilo 417,2
273
B 4-fenil-3,6-dihidropiridin-1(2H)-ilo 355,2
274
A 4-fenilpiperazin-1-ilo (3S)tetrahidrofuran-3oxicarbonilo 473,2
275
A 4-fenilpiperazin-1-ilo (3R)tetrahidrofuran-3oxicarbonilo 473,2
276
A 4-fenilpiperazin-1-ilo 2metoxietoxicarbonil o 461,1
277
A 4-fenilpiperazin-1-ilo fenilsulfonilo 499,1
278
A 4-fenilpiperazin-1-ilo propionoxicarbonilo 445,2
279
A 4-fenilpiperazin-1-ilo isopropionoxicarbonilo 445,2
280
A 4-(3,5-difluorofenil)-3,6-dihidropiridin-1(2H)-ilo metoxicarbonilo 450,2
281
A 4-(3,5-difluorofenil)-3,6-dihidropiridin-1(2H)-ilo metanosulfonilo 470,2
282
A 4-(4-isopropilfenil)piperazin-1-ilo H
283
A 4-(3,5-difluorofenil)piperidin-1-ilo metanosulfonilo 472,1
284
A 4-(4,5-dimetil-1,3-tiazol-2-il)piperidin-1-ilo H 393,1
*M-H
La capacidad de los compuestos novedosos de la invención para inhibir las metaloproteasas puede determinarse utilizando una prueba de detección adecuada, tal como un ensayo de cribado de alto rendimiento. Por ejemplo, puede ensayarse un agente en un ensayo de acidificación extracelular, un ensayo de flujo de calcio, un ensayo de unión a ligando o un ensayo de quimiotaxis. A continuación se presentan ejemplos de ensayos.
Ensayo de TNFα
En algunas formas de realización, la capacidad de los compuestos de la invención para servir de inhibidores de la producción de TNFα puede determinarse utilizando el siguiente procedimiento. Se incuba una solución 100 µM del inhibidor a ensayar, o diluciones del mismo, a 37°C en una atmósfera de CO2 al 5% con células THP-1 (monocitos humanos) suspendidas en RPM1 1640 y β-mercaptoetanol 20 µM a una densidad celular de 1x106/ml y se estimulan con LPS. Después de 18 horas, se ensaya el sobrenadante para determinar los niveles de TNFα utilizando un kit ELISA disponible en el mercado. La actividad en presencia de 0,1 mM de inhibidor, o diluciones del mismo, se compara con la actividad en un control que carece de inhibidor y los resultados se expresan como la concentración de inhibidor que logra una inhibición del 50% de la producción de TNFα.
Ensayo de PBMC que mide la actividad de TNFα
Se obtiene una leucoforesis de Biological Specialties, Colmar PA, a partir de donantes normales sin fármacos (sin aspirina, ibuprofeno, AINE, etc.). En un tubo cónico de 50 ml (VWR, NJ), se añaden 20 ml de sangre y 20 ml de solución salina estéril al 0,9% (Baxter Healthcare, Dearfield, IL) y se mezclan bien. Se pone una base de 10 ml de Ficoll-Paque sin endotoxina (Pharmacia, Uppsala, Suecia) y se centrifuga a 3.000 rpm durante 30 minutos. Se elimina la capa de glóbulos blancos y se lava con 50 ml de solución salina al 0,9%. Se realiza el recuento de células y se añaden 0,250 ml a una placa de 96 pocillos (Costar/Corning VWR, NJ) a 2 x 106 c/ml, en medio RPMI 1640 (Gibco BRL). Se añaden los compuestos y se preincuban con las células durante 10 minutos antes de añadir LPS (Calbiochem, CA) a 1 ug/ml durante 5 horas. Se recoge el sobrenadante y se ensaya para determinar la producción de TNFα mediante ELISA de tipo sándwich convencional (R&D Systems, Minneapolis, MN). La inhibición por el compuesto se determinó con respecto a las células cultivadas con LPS en solitario.
Ensayo para la actividad de Her-2 sheddasa
Se sembró una línea celular de cáncer de mama humano BT474 (ATCC, Manassas, Virginia), a 2 x 104 células/pocillo en 100 µl en una placa de 96 pocillos (Costar/Corning VWR, NJ) en medio RPMI 1640 (Invitrogen, Carlsbad, CA) que contenía suero bovino fetal al 10% (Hyclone, Lenexa, KS), y se incubaron durante la noche a
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