ES2348360T3 - BENCIMIDAZOL DERIVATIVES: PREPARATION AND PHARMACEUTICAL APPLICATIONS. - Google Patents
BENCIMIDAZOL DERIVATIVES: PREPARATION AND PHARMACEUTICAL APPLICATIONS. Download PDFInfo
- Publication number
- ES2348360T3 ES2348360T3 ES04775628T ES04775628T ES2348360T3 ES 2348360 T3 ES2348360 T3 ES 2348360T3 ES 04775628 T ES04775628 T ES 04775628T ES 04775628 T ES04775628 T ES 04775628T ES 2348360 T3 ES2348360 T3 ES 2348360T3
- Authority
- ES
- Spain
- Prior art keywords
- hydroxy
- acrylamide
- benzimidazol
- alkyl
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title description 79
- 150000001875 compounds Chemical class 0.000 claims abstract description 239
- -1 heterocycloalkyloxy Chemical group 0.000 claims abstract description 226
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 135
- 125000003118 aryl group Chemical group 0.000 claims abstract description 114
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 112
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 109
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 107
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 103
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 103
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 94
- 125000002252 acyl group Chemical group 0.000 claims abstract description 86
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 85
- 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 83
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 80
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 77
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 73
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 72
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 69
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 66
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 65
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 64
- 150000002367 halogens Chemical class 0.000 claims abstract description 64
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 56
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 56
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 55
- 125000001424 substituent group Chemical group 0.000 claims abstract description 54
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 53
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 51
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 51
- 125000003302 alkenyloxy group Chemical group 0.000 claims abstract description 50
- 125000005133 alkynyloxy group Chemical group 0.000 claims abstract description 50
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 50
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 49
- 125000001769 aryl amino group Chemical group 0.000 claims abstract description 49
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims abstract description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 49
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 48
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 48
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 48
- 125000000262 haloalkenyl group Chemical group 0.000 claims abstract description 48
- 125000005553 heteroaryloxy group Chemical group 0.000 claims abstract description 47
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 45
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 45
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims abstract description 40
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims abstract description 39
- 125000004171 alkoxy aryl group Chemical group 0.000 claims abstract description 38
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 38
- 125000004465 cycloalkenyloxy group Chemical group 0.000 claims abstract description 36
- 125000000232 haloalkynyl group Chemical group 0.000 claims abstract description 36
- 125000006732 (C1-C15) alkyl group Chemical group 0.000 claims abstract description 18
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims abstract description 18
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims abstract description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 17
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 14
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims abstract description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000011734 sodium Substances 0.000 claims abstract description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000005018 aryl alkenyl group Chemical group 0.000 claims abstract description 6
- 239000011575 calcium Substances 0.000 claims abstract description 6
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 6
- 239000011777 magnesium Substances 0.000 claims abstract description 6
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 6
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 6
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 5
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- 150000003839 salts Chemical class 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 23
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 16
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- 201000004681 Psoriasis Diseases 0.000 claims description 11
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 claims description 10
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- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 208000010412 Glaucoma Diseases 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- OGPNRIPZGRWELK-UHFFFAOYSA-N n-hydroxy-3-[1-(2-hydroxyethyl)-2-(4-methoxyphenyl)benzimidazol-5-yl]prop-2-enamide Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC(C=CC(=O)NO)=CC=C2N1CCO OGPNRIPZGRWELK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 208000037803 restenosis Diseases 0.000 claims description 6
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 208000003120 Angiofibroma Diseases 0.000 claims description 5
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- 208000031888 Mycoses Diseases 0.000 claims description 5
- CLSQCMFFPCSKFA-UHFFFAOYSA-N N-hydroxy-3-[1-(2-hydroxyethyl)-2-pyridin-4-ylbenzimidazol-5-yl]prop-2-enamide Chemical compound N=1C2=CC(C=CC(=O)NO)=CC=C2N(CCO)C=1C1=CC=NC=C1 CLSQCMFFPCSKFA-UHFFFAOYSA-N 0.000 claims description 5
- IKNHRCJRYGVRLA-UHFFFAOYSA-N N-hydroxy-3-[1-(3-hydroxypropyl)-2-pyridin-2-ylbenzimidazol-5-yl]prop-2-enamide Chemical compound N=1C2=CC(C=CC(=O)NO)=CC=C2N(CCCO)C=1C1=CC=CC=N1 IKNHRCJRYGVRLA-UHFFFAOYSA-N 0.000 claims description 5
- FNOKUWISQMMAIS-UHFFFAOYSA-N N-hydroxy-3-[1-(3-hydroxypropyl)-2-pyridin-4-ylbenzimidazol-5-yl]prop-2-enamide Chemical compound N=1C2=CC(C=CC(=O)NO)=CC=C2N(CCCO)C=1C1=CC=NC=C1 FNOKUWISQMMAIS-UHFFFAOYSA-N 0.000 claims description 5
- PHZZVJAAIQRXDG-UHFFFAOYSA-N N-hydroxy-3-[1-(5-hydroxy-1-phenylpentan-2-yl)benzimidazol-5-yl]prop-2-enamide Chemical compound ONC(C=CC1=CC2=C(N(C=N2)C(CC2=CC=CC=C2)CCCO)C=C1)=O PHZZVJAAIQRXDG-UHFFFAOYSA-N 0.000 claims description 5
- YYDIQCHIHBQXBE-UHFFFAOYSA-N N-hydroxy-3-[1-[5-(2-oxopyrrolidin-1-yl)-1-phenylpentan-2-yl]benzimidazol-5-yl]prop-2-enamide Chemical compound ONC(C=CC1=CC2=C(N(C=N2)C(CC2=CC=CC=C2)CCCN2C(CCC2)=O)C=C1)=O YYDIQCHIHBQXBE-UHFFFAOYSA-N 0.000 claims description 5
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- 230000003176 fibrotic effect Effects 0.000 claims description 5
- GEKZXTDEIVOYAS-UHFFFAOYSA-N n-hydroxy-3-[1-(3-hydroxypropyl)-2-(3-methoxy-4-phenylmethoxyphenyl)benzimidazol-5-yl]prop-2-enamide Chemical compound COC1=CC(C=2N(C3=CC=C(C=CC(=O)NO)C=C3N=2)CCCO)=CC=C1OCC1=CC=CC=C1 GEKZXTDEIVOYAS-UHFFFAOYSA-N 0.000 claims description 5
- LLGDWRNFGQVXJV-UHFFFAOYSA-N n-hydroxy-3-[1-(3-hydroxypropyl)-2-thiophen-3-ylbenzimidazol-5-yl]prop-2-enamide Chemical compound N=1C2=CC(C=CC(=O)NO)=CC=C2N(CCCO)C=1C=1C=CSC=1 LLGDWRNFGQVXJV-UHFFFAOYSA-N 0.000 claims description 5
- 230000009385 viral infection Effects 0.000 claims description 5
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 108010040003 polyglutamine Proteins 0.000 claims description 4
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
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- IDJHTRCRTCGYIP-UHFFFAOYSA-N n-hydroxy-3-[1-(3-hydroxypropyl)-2-(2-phenylpropyl)benzimidazol-5-yl]prop-2-enamide Chemical compound N=1C2=CC(C=CC(=O)NO)=CC=C2N(CCCO)C=1CC(C)C1=CC=CC=C1 IDJHTRCRTCGYIP-UHFFFAOYSA-N 0.000 claims description 2
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
- Un compuesto de fórmula (I): **Fórmula** en donde: R 1 se selecciona del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, arilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR 6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, -CN, -NO2, -CF3, -OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, aminoalquilo, alcoxialquilo, -COOH, -C(O)OR 5 , -COR 5 , -SH, -SR 6 , -OR 6 y acilo; o R 1 = L; R 2 se selecciona del grupo que consiste en: H, halógeno, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, arilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR 6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, -CN, -NO2, -CF3, -OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, -COOH, -COR 5 , -C(O)OR 5 , -SH, -SR 6 , -OR 6 y acilo; o R 2 = L; R 3 se selecciona del grupo que consiste en H, alquilo C1-C6 y acilo; o un ion metálico seleccionado de sodio, calcio, magnesio; X e Y son iguales o diferentes y están seleccionados de modo independiente del grupo que consiste en: H, halógeno, - CN, -NO2, -CF3, -OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, -COOH -C(O)OR 5 , -COR 5 , -SH, -SR 6 , -OR 6 , acilo y -NR 7 R 8 ; cada R 4 se selecciona del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; cada R 5 está seleccionado de modo independiente del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; cada R 6 está seleccionado de modo independiente del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; cada R 7 y R 8 está seleccionado de modo independiente del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; L se selecciona del grupo que consiste en: a) L=Cy-L 1 -W- en donde: Cy es alquilo C1-C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, -CN, -NO2, -CF3, -OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, -COOH, - C(O)OR 5 , -COR 5 , -SH, -SR 6 , -OR 6 y acilo; L 1 se selecciona del grupo que consiste en alquilo C1-C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; -CN; -NO2; alquilo, alcoxi, acilamino y alquilamino; W se selecciona del grupo que consiste en un enlace simple, -O-, -S-, -S(O)-, -S(O)2-, -N(R 9 )-, - C(O)N(R 9 )-, -SO2N(R 9 )-, N(R 9 )C(O)-, N(R 9 )SO2- y -N(R 9 )- C(O)-N(R 10 )-; b) L=Cy-L 1 -W-L 2 en donde: Cy es alquilo C1-C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, -CN, -NO2, -CF3, -OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, -COOH, C(O)OR 5 , -COR 5 , -SH, -SR 6 , -OR 6 y acilo; L 1 y L 2 son iguales o diferentes y de modo independiente son alquilo C1-C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; -CN; -NO2; -CF3, -OCF3, alquilo, alcoxi, acilamino y alquilamino; W se selecciona del grupo que consiste en un enlace simple, -O-, -S-, -S(O)-, -S(O)2-, -N(R 9 )-, - C(O)N(R 9 )-, -SO2N(R 9 )-, N(R 9 )C(O)-, N(R 9 )SO2- y -N(R 9 )- C(O)-N(R 10 )-; c) L=Cy-(CH2)m-W- en donde: Cy es alquilo C1-C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, -CN, -NO2, -CF3, -OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, -COOH, C(O)OR 5 , -COR 5 , -SH, -SR 6 , -OR 6 y acilo; m es 0, 1, 2, 3, 4 o 5; W se selecciona del grupo que consiste en un enlace simple, -O-, -S-, -S(O)-, -S(O)2-, -N(R 9 )-, - C(O)N(R 9 )-, SO2N(R 9 )-, N(R 9 )C(O)-, N(R 9 )SO2- y -N(R 9 )- C(O)-N(R 10 )-; d) L=L 1 -W-L 2 L 1 y L 2 son iguales o diferentes y están seleccionados, de modo independiente, de alquilo C1-C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; -CN; -NO2; -CF3, -OCF3, alquilo, alcoxi, acilamino, alquilamino; W se selecciona del grupo que consiste en un enlace simple, -O-, -S-, -S(O)-, -S(O)2-, -N(R 9 )-, - C(O)N(R 9 )-, -SO2N(R 9 )-, N(R 9 )C(O)-, N(R 9 )SO2- y -N(R 9 )- C(O)-N(R 10 )-; R 9 y R 10 son iguales o diferentes y están sele- A compound of formula (I): ** Formula ** wherein: R 1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl , heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cicloalquilheteroalquilo, arylheteroalkyl, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl , acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR 6 and acyl, each of which may be unsubstituted or substituted with one or more substituents selected from independent mode of the group that cons is in: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy , hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl , aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (O) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; or R 1 = L; R 2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, arylalkyl, cycloalkyl, arylalkyl, cycloalkyl heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR 6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S , -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy , heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyl, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -CO, -C, C -CO, -C, -C, C -CO, -C, -C, C -SH, -SR 6, -OR 6 and acyl; or R 2 = L; R 3 is selected from the group consisting of H, C1-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium; X and Y are the same or different and are independently selected from the group consisting of: H, halogen, - CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl , cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino , aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (O) OR 5, -COR 5, -SH, -SR 6, -OR 6, acyl and -NR 7 R 8; each R 4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R 5 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R 6 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each R 7 and R 8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; L is selected from the group consisting of: a) L = Cy-L 1 -W- wherein: Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may optionally be substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (O) OR 5, -COR 5, -SH, -SR 6, -OR 6 and ac ilo; L 1 is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; -CN; -NO2; alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (O) 2-, -N (R 9) -, - C (O) N ( R 9) -, -SO2N (R 9) -, N (R 9) C (O) -, N (R 9) SO2- and -N (R 9) - C (O) -N (R 10) - ; b) L = Cy-L 1 -WL 2 wherein: Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected so independent of the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl , heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl , arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; L 1 and L 2 are the same or different and independently are C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; -CN; -NO2; -CF3, -OCF3, alkyl, alkoxy, acylamino and alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (O) 2-, -N (R 9) -, - C (O) N ( R 9) -, -SO2N (R 9) -, N (R 9) C (O) -, N (R 9) SO2- and -N (R 9) - C (O) -N (R 10) - ; c) L = Cy- (CH2) mW- wherein: Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents selected so independent of the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl , heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl , arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR 5, -COR 5, -SH, -SR 6, -OR 6 and acyl; m is 0, 1, 2, 3, 4 or 5; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (O) 2-, -N (R 9) -, - C (O) N ( R 9) -, SO2N (R 9) -, N (R 9) C (O) -, N (R 9) SO2- and -N (R 9) - C (O) -N (R 10) -; d) L = L 1 -WL 2 L 1 and L 2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting in: halogen; = O; = S; -CN; -NO2; -CF3, -OCF3, alkyl, alkoxy, acylamino, alkylamino; W is selected from the group consisting of a single bond, -O-, -S-, -S (O) -, -S (O) 2-, -N (R 9) -, - C (O) N ( R 9) -, -SO2N (R 9) -, N (R 9) C (O) -, N (R 9) SO2- and -N (R 9) - C (O) -N (R 10) - ; R 9 and R 10 are the same or different and are sele
Description
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención se refiere a compuestos de hidroxamato que son inhibidores de histona desacetilasa. Más particularmente, la presente invención se refiere a 5 compuestos que contienen bencimidazol y a métodos para su preparación. Estos compuestos pueden ser útiles como medicamentos para el tratamiento de trastornos proliferativos, además de otras enfermedades que incluyen, se refieren o se asocian a la desregulación de la histona 10 desacetilasa (HDAC). The present invention relates to hydroxamate compounds that are histone deacetylase inhibitors. More particularly, the present invention relates to compounds containing benzimidazole and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders, in addition to other diseases that include, refer to or are associated with the deregulation of histone 10 deacetylase (HDAC).
Por lo general, se reconoce la arquitectura de la cromatina local como factor importante en la regulación de la expresión génica. La arquitectura de la cromatina, un 15 complejo proteína–ADN, es fuertemente influenciado por las modificaciones postraduccionales de las histonas que son los componentes proteicos. La acetilación reversible de las histonas es un componente clave en la regulación de la expresión génica, por alteración de la accesibilidad de los 20 factores de transcripción a ADN. En general, se asocian los niveles aumentados de acetilación de histonas con mayor actividad de transcripción, mientras que los niveles disminuidos de acetilación se asocian con la represión de la expresión génica [Wadem P. A. Hum. Mol. Genet. 10, 693–698 25 (2001), De Ruijter A. J. M. et al., Biochem. J., 370, 737–749 (2003)]. En las células normales, las histona desacetilasas (HDAC) y la histona acetiltransferasa juntas controlar el nivel de acetilación de las histonas para mantener el equilibrio. Por inhibición de las HDAC se produce la 30 acumulación de las histonas acetiladas, lo cual causa diversas respuestas celulares dependientes del tipo de célula, tales como apoptosis, necrosis, diferenciación, In general, the architecture of the local chromatin is recognized as an important factor in the regulation of gene expression. The chromatin architecture, a protein-DNA complex, is strongly influenced by the post-translational modifications of histones that are the protein components. Reversible histone acetylation is a key component in the regulation of gene expression, by altering the accessibility of the 20 DNA transcription factors. In general, increased levels of histone acetylation are associated with increased transcription activity, while decreased levels of acetylation are associated with repression of gene expression [Wadem P. A. Hum. Mol. Genet 10, 693–698 25 (2001), De Ruijter A. J. M. et al., Biochem. J., 370, 737-749 (2003)]. In normal cells, histone deacetylases (HDAC) and histone acetyltransferase together control the level of histone acetylation to maintain balance. Due to HDAC inhibition, accumulation of acetylated histones occurs, which causes various cell responses depending on the type of cell, such as apoptosis, necrosis, differentiation,
supervivencia celular, inhibición de la proliferación y citostasis. cell survival, proliferation inhibition and cytostasis.
Se han estudiado los inhibidores de HDAC por sus efectos terapéuticos sobre las células cancerosas. Por ejemplo, el ácido suberoilanilidohidroxámico (SAHA) es un 5 poderoso inductor de la diferenciación y/o la apoptosis en líneas celulares murinas de eritroleucemia, vesicales y de mieloma [Richon V. M. et al., Proc. Natl. Acad. Sci. USA, 93: 5705–5708 (1996), Richon V. M. et al., Proc. Natl. Acad. Sci. USA, 95: 3003–3007 (1998)]. Se ha demostrado que SAHA suprime 10 el crecimiento de las células de cáncer de próstata in vitro e in vivo [Butler L. M. et al., Cancer Res. 60, 5165–5170 (2000)]. Entre otros inhibidores de HDAC ampliamente estudiados por sus actividades anticancerosas se incluyen tricostatina A (TSA) y trapoxina B [Yoshida M. et al, J. 15 Biol. Chem., 265, 17174 (1990); Kijima M. et al, J. Biol. Chem., 268, 22429 (1993)]. La tricostatina A es un inhibidor reversible de HDAC de mamífero. La trapoxina B es un tetrapéptido cíclico, que es un inhibidor irreversible de la HDAC de mamífero. Sin embargo, debido a la inestabilidad in 20 vivo de estos compuestos, tienen menor interés como fármacos anticancerosos. Recientemente se han puesto a disposición otras moléculas pequeñas inhibidoras de HDAC para su evaluación clínica [documento US 6.552.065]. Se han informado otros compuestos inhibidores de HDAC en la bibliografía 25 [Bouchain G. et al, J. Med. Chem., 46, 820–830 (2003)] y en patentes [documentos WO 03/066579 A2, WO 01/38322 A1]. La actividad in vivo de dichos inhibidores se puede monitorizar directamente por su capacidad para incrementar la cantidad de histonas acetiladas en la muestra biológica. Se ha informado 30 que los inhibidores de HDAC interfieren con los procesos neurodegenerativos, por ejemplo los inhibidores de HDAC frenan la neurodegeneración dependiente de poliglutamina HDAC inhibitors have been studied for their therapeutic effects on cancer cells. For example, suberylanilidohydroxamic acid (SAHA) is a powerful inducer of differentiation and / or apoptosis in murine erythroleukemia, bladder and myeloma cell lines [Richon V. M. et al., Proc. Natl Acad. Sci. USA, 93: 5705-5708 (1996), Richon V. M. et al., Proc. Natl Acad. Sci. USA, 95: 3003–3007 (1998)]. SAHA has been shown to suppress the growth of prostate cancer cells in vitro and in vivo [Butler L. M. et al., Cancer Res. 60, 5165-5170 (2000)]. Other HDAC inhibitors widely studied for their anti-cancer activities include trichostatin A (TSA) and trapoxin B [Yoshida M. et al, J. 15 Biol. Chem., 265, 17174 (1990); Kijima M. et al, J. Biol. Chem., 268, 22429 (1993)]. Tricostatin A is a reversible inhibitor of mammalian HDAC. Trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDAC. However, due to the in vivo instability of these compounds, they have less interest as anticancer drugs. Recently, other small HDAC inhibitor molecules have been made available for clinical evaluation [US 6,552,065]. Other HDAC inhibitor compounds have been reported in literature 25 [Bouchain G. et al, J. Med. Chem., 46, 820-830 (2003)] and in patents [WO 03/066579 A2, WO 01/38322 A1]. The in vivo activity of said inhibitors can be directly monitored for their ability to increase the amount of acetylated histones in the biological sample. It has been reported that HDAC inhibitors interfere with neurodegenerative processes, for example HDAC inhibitors curb polyglutamine-dependent neurodegeneration
[Nature, 413(6857): 739–43, 18 de octubre de 2001]. Además, se sabe que los inhibidores de HDAC inhiben la producción de citoquinas tales como TNF, IFN, IL–1, de las cuales se sabe que están implicadas en enfermedades inflamatorias y/o trastornos del sistema inmunitario. [J. Biol. Chem. 1990; 5 265(18): 10230–10237; Science, 1998; 281: 1001–1005; Dinarello C. A. y Moldawer L. L., “Proinflammatory and anti–inflammatory cytokines in rheumatoid arthritis. A primer for clinicians”, 2ª edición, Amergen Inc., 2000]. [Nature, 413 (6857): 739-43, October 18, 2001]. In addition, it is known that HDAC inhibitors inhibit the production of cytokines such as TNF, IFN, IL-1, which are known to be involved in inflammatory diseases and / or immune system disorders. [J. Biol. Chem. 1990; 5 265 (18): 10230-10237; Science, 1998; 281: 1001–1005; Dinarello C. A. and Moldawer L. L., “Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis. A first for clinicians ”, 2nd edition, Amergen Inc., 2000].
Sin embargo, aún es necesario proporcionar otros 10 inhibidores de HDAC, de los cuales cabe esperar que tengan propiedades farmacéuticas útiles y mejoradas, tales como agentes anticancerosos. However, it is still necessary to provide another 10 HDAC inhibitors, which are expected to have useful and improved pharmaceutical properties, such as anticancer agents.
En un aspecto, la presente invención proporciona 15 compuestos de la reivindicación 1 de fórmula (I): In one aspect, the present invention provides 15 compounds of claim 1 of formula (I):
- NNXYZONR3OFormula I7654321R4R1R2 Fórmula I NNXYZONR3O Formula I7654321R4R1R2 Formula I
en donde: where:
R1 se selecciona del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, 20 heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, arilheteroalquilo, heterocicloalquilheteroalquilo, 25 heteroarilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, R1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, 20 heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cicloalquilheteroalquilo, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,
arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR6 y acilo, cada uno de los cuales puede 5 estar no sustituido o sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, 10 heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, 15 heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; 20 arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be substituted or unsubstituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl cycloalkenyl, 10 heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, 15 heteroarylalkyl, arylalkyloxy, amino, alkylamino , acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfi nyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl; twenty
o R1 = L; or R1 = L;
R2 se selecciona del grupo que consiste en: H, halógeno, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, 25 cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, arilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, 30 cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, R2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, arylalkyl, cycloalkyl, arylalkyl, alkyl heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy 30, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl,
alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo 5 que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, 10 alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, 15 alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –COR5, –C(O)OR5, –SH, –SR6, –OR6 y acilo; alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from group 5 consisting of: halogen, = O, = S, –CN, –NO2, –CF3, –OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxy, alkoxy, alkoxy, alkyl 10 alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, 15 alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, - COOH, –COR5, –C (O) OR5, –SH, –SR6, –OR6 and acyl;
o R2 = L; or R2 = L;
R3 se selecciona del grupo que consiste en H, alquilo 20 C1–C6 y acilo; o un ion metálico seleccionado de sodio, calcio, magnesio; R3 is selected from the group consisting of H, C1-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium;
X e Y son iguales o diferentes y están seleccionados de modo independiente del grupo que consiste en: H, halógeno, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, 25 haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, 30 cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, 30 cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino ,
acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH –C(O)OR5, –COR5, –SH, –SR6, –OR6, acilo y –NR7R8; acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (O) OR5, -COR5, -SH, -SR6, -OR6, acyl and -NR7R8;
R4 se selecciona del grupo que consiste en: H, alquilo, 5 alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; R4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R5 está seleccionado de modo independiente del 10 grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; 15 each R5 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; fifteen
cada R6 está seleccionado de modo independiente del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y 20 acilo; each R6 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R7 y R8 está seleccionado de modo independiente del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, 25 heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; each R7 and R8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
L se selecciona del grupo que consiste en: L is selected from the group consisting of:
a) L=Cy–L1–W– a) L = Cy – L1 – W–
en donde: 30 where: 30
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be
opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, 5 cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, 10 heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –15 C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; optionally substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl 5 cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, 10 heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino , alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -15 C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl;
L1 se selecciona del grupo que consiste en alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; 20 =S; –CN; –NO2; alquilo, alcoxi, acilamino y alquilamino; L1 is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; 20 = S; –CN; –NO2; alkyl, alkoxy, acylamino and alkylamino;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–25 C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –25 C (O) –N (R10) -;
b) L=Cy–L1–W–L2 b) L = Cy – L1 – W – L2
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o 30 heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group that
consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, 5 hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, 10 alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; consists of: halogen, = O, = S, –CN, –NO2, –CF3, –OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy 5 hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, 10 alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl , aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl;
L1 y L2 son iguales o diferentes y de modo 15 independiente son alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, alquilo, alcoxi, acilamino y alquilamino; 20 L1 and L2 are the same or different and independently are C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; –CF3, –OCF3, alkyl, alkoxy, acylamino and alkylamino; twenty
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
c) L=Cy–(CH2)m–W– 25 c) L = Cy– (CH2) m – W– 25
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes 30 seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents 30 independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl,
haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, 5 cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, 10 aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, 5 cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl , arylalkyl, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, 10 aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl;
m es 0, 1, 2, 3, 4 o 5; m is 0, 1, 2, 3, 4 or 5;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –15 C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –15 C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
d) L=L1–W–L2 d) L = L1 – W – L2
L1 y L2 son iguales o diferentes y están seleccionados, de modo independiente, de alquilo C1–C5, 20 que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, alquilo, alcoxi, acilamino, alquilamino; 25 L1 and L2 are the same or different and are independently selected from C1-C5 alkyl, 20 which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; –CF3, –OCF3, alkyl, alkoxy, acylamino, alkylamino; 25
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
R9 y R10 son iguales o diferentes y están seleccionados, 30 de modo independiente, de H, alquilo C1–C6, cicloalquilo C4–C9, heterocicloalquilo C4–C9, arilo, heteroarilo, arilalquilo y heteroarilalquilo; y acilo; R9 and R10 are the same or different and are independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; and acyl;
Z es –CH=CH– en la posición 5 y en configuración “E”; Z is –CH = CH– in position 5 and in “E” configuration;
o una de sus sales farmacéuticamente aceptables. or one of its pharmaceutically acceptable salts.
Un género apropiado de compuestos hidroxámicos son los de fórmula (Ia): An appropriate genus of hydroxamic compounds are those of formula (Ia):
- NOOHR3Formula IaNNR2R1XY7654321Z Fórmula Ia NOOHR3 Formula IaNNR2R1XY7654321Z Formula Ia
5 5
en donde: where:
R1 se selecciona del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, 10 cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, arilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, 15 cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, 20 aminosulfonilo, SR6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, 25 haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, R1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-aryl-alkyl group-aryl-alkyl-aryl-alkyl group heterocicloalquilheteroalquilo, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, 15 cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl , alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, –CN, –NO2, –CF 3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl,
alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, 5 alquilsulfonilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, 5 alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, - COOH, –C (O) OR5, –COR5, –SH, –SR6, –OR6 and acyl;
o R1 = L; or R1 = L;
R2 se selecciona del grupo que consiste en: H, 10 halógeno, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, 15 heterocicloalquilheteroalquilo, heteroarilheteroalquilo, arilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, 20 arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios 25 sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, 30 hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, R2 is selected from the group consisting of: H, 10 halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, arylalkyl, cycloalkyl, arylalkyl, cycloalkyl 15 heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, 20 arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, –CN, –NO2, –CF3, –OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyphenyl, alkoxyphenyl alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,
heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –COR5, –C(O)OR5, –SH, –SR6, –OR6 y 5 acilo; heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH, -COR5, -C (O) OR5, -SH, –SR6, –OR6 and 5 acyl;
o R2 = L; or R2 = L;
R3 se selecciona del grupo que consiste en: H, alquilo C1–C6 y acilo; o un ion metálico seleccionado de sodio, calcio, magnesio; 10 R3 is selected from the group consisting of: H, C1-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium; 10
X e Y son iguales o diferentes y están seleccionados de modo independiente del grupo que consiste en: H, halógeno, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, 15 heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, 20 heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH –C(O)OR5, –COR5, –SH, –SR6, –OR6, acilo y –NR7R8; 25 X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl , cycloalkenyl, heterocycloalkyl, 15 heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, 20 heteroarylalkyl, arylalkyloxy, amino, alkylamino , acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (O) OR5, -COR5, -SH, -SR6, -OR6, acyl and -NR7R8; 25
cada R5 está seleccionado de modo independiente del grupo que consiste en: alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y 30 acilo; each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R6 está seleccionado de modo independiente del grupo que consiste en: alquilo, alquenilo, alquinilo, each R6 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl,
haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R7 y R8 está seleccionado de modo independiente 5 del grupo que consiste en: alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; 10 each R7 and R8 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; 10
L se selecciona del grupo que consiste en: L is selected from the group consisting of:
a) L=Cy–L1–W– a) L = Cy – L1 – W–
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi, o 15 heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, 20 haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, 25 cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, 30 aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy, or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, –CN, –NO2, –CF3, –OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy alkyl alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, arylalkyl, alkylamino, alkylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino, alkylsulfonylamino, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfon, alkylsulfonyl –COOH, –C (O) OR5, –COR5, –SH, –SR6, –OR6 and acyl;
L1 se selecciona del grupo que consiste en L1 is selected from the group consisting of
alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; alquilo, alcoxi, acilamino y alquilamino; 5 C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; alkyl, alkoxy, acylamino and alkylamino; 5
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
b) L=Cy–L1–W–L2 10 b) L = Cy – L1 – W – L2 10
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes 15 seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, 20 heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, 25 arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; 30 Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents 15 independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxy, alkoxy, alkoxy, alkyl , alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, 25 arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH , C (O) OR5, –COR5, –SH, –SR6, –OR6 and acyl; 30
L1 y L2 son iguales o diferentes y de modo independiente alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes L1 and L2 are the same or different and independently C1-C5 alkyl, which may be optionally substituted with one or more substituents
seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, alquilo, alcoxi, acilamino y alquilamino; independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; –CF3, –OCF3, alkyl, alkoxy, acylamino and alkylamino;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –5 C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –5 C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
c) L=Cy–(CH2)m–W– c) L = Cy– (CH2) m – W–
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, 10 heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, 15 alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, 20 alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, 25 sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, = O, = S , -CN, -NO2, -CF3, -OCF3, 15 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy 20 alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl 25, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH , C (O) OR5, –COR5, –SH, –SR6, –OR6 and acyl;
m es 0, 1, 2, 3, 4 o 5; m is 0, 1, 2, 3, 4 or 5;
W se selecciona del grupo que consiste en un 30 enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a single link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
d) L=L1–W–L2 d) L = L1 – W – L2
L1 y L2 son iguales o diferentes y están seleccionados, de modo independiente, de alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo 5 independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, alquilo, alcoxi, acilamino, alquilamino; L1 and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = O; = S; –CN; –NO2; –CF3, –OCF3, alkyl, alkoxy, acylamino, alkylamino;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –10 C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –10 C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
R9 y R10 son iguales o diferentes y están seleccionados, de modo independiente, de H, alquilo C1–C6, cicloalquilo C4–C9, heterocicloalquilo C4–C9, arilo, heteroarilo, arilalquilo, 15 heteroarilalquilo; y acilo; R9 and R10 are the same or different and are independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl;
Z es –CH=CH– en la posición 5 y en configuración “E”; Z is –CH = CH– in position 5 and in “E” configuration;
o una de sus sales farmacéuticamente aceptables. or one of its pharmaceutically acceptable salts.
Otro grupo de compuestos útiles son los de fórmula (Ib): 20 Another group of useful compounds are those of formula (Ib):
- Formula IbNOOHHNNR2R1XY7654321Z Fórmula Ib Formula IbNOOHHNNR2R1XY7654321Z Formula Ib
en donde: where:
R1 se selecciona del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, 25 heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, R1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroarylalkyl, heteroaryl, alkyl
arilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, 5 arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios 10 sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, 15 hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, 20 acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; arylheteroalkyl, heterocicloalquilheteroalquilo, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, 5 arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl , sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxy alkyl , alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, CO -alkoxy, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, aminoalkyl-CO, amino-alkyl COR5, –SH, –SR6, –OR6 and acyl;
o R1 = L; 25 or R1 = L; 25
R2 se selecciona del grupo que consiste en: H, halógeno, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, 30 heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, arilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, R2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroylalkyl, heteroylalkyl, heteroylalkyl, heteroylalkyl, heteroylalkyl, heteroylalkyl, heteroylalkyl, heteroylalkyl, heteroylalkyl, heteroaryl, alkyl heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy,
alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, 5 alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, 10 alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, 15 cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, 20 alcoxialquilo, –COOH, –COR5, –C(O)OR5, –SH, –SR6, –OR6 y acilo; alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, 5 alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl , SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3 10 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, 15 cycloalkenyloxy, heterocycloalkyloxy , heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyl uyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -COR5, -C (O) OR5, -SH, -SR6, -OR6 and acyl;
o R2 = L; or R2 = L;
X e Y son iguales o diferentes y están seleccionados de modo independiente del grupo que consiste en: H, halógeno, –25 CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, 30 alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, X and Y are the same or different and are independently selected from the group consisting of: H, halogen, –25 CN, –NO2, –CF3, –OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl 30, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,
heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH –C(O)OR5, –COR5, –SH, –SR6, acilo y –NR7R8; 5 heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (O) OR5, -COR5, -SH, -SR6, acyl and -NR8; 5
cada R5 está seleccionado de modo independiente del grupo que consiste en: alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y 10 acilo; each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R6 está seleccionado de modo independiente del grupo que consiste en: alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, 15 heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; each R6 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R7 y R8 está seleccionado de modo independiente del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, 20 arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; each R7 and R8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
L se selecciona del grupo que consiste en: L is selected from the group consisting of:
a) L=Cy–L1–W– 25 a) L = Cy – L1 – W– 25
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes 30 seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents 30 independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl,
haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, 5 cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, 10 aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, 5 cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl , arylalkyl, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, 10 aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl;
L1 se selecciona del grupo que consiste en alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo 15 independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; alquilo, alcoxi, acilamino y alquilamino; L1 is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents selected independently from the group consisting of: halogen; = O; = S; –CN; –NO2; alkyl, alkoxy, acylamino and alkylamino;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –20 C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –20 C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
b) L=Cy–L1–W–L2 b) L = Cy – L1 – W – L2
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, 25 heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, 30 alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, 30 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, 5 arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; 10 heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroarylamino, arylakylamino, arylakylamino, arylamino, amino , sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl; 10
L1 y L2 son iguales o diferentes y son, de modo independiente, alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, 15 alquilo, alcoxi, acilamino y alquilamino; L1 and L2 are the same or different and are, independently, C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; -CF3, -OCF3, alkyl, alkoxy, acylamino and alkylamino;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; 20 W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -; twenty
c) L=Cy–(CH2)m–W– c) L = Cy– (CH2) m – W–
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar 25 opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, 30 cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxy, alkoxy, alkoxy, alkyl ,
alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, 5 sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl 5, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalky, -COOH, C (O) OR5, –COR5, –SH, –SR6, –OR6 and acyl,
m es 0, 1, 2, 3, 4 o 5; m is 0, 1, 2, 3, 4 or 5;
W se selecciona del grupo que consiste en un 10 enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a single link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
d) L=L1–W–L2 d) L = L1 – W – L2
L1 y L2 son iguales o diferentes y están 15 seleccionados, de modo independiente, de alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, alquilo, alcoxi, acilamino, 20 alquilamino; L1 and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; -CF3, -OCF3, alkyl, alkoxy, acylamino, alkylamino;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; 25 W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -; 25
R9 y R10 son iguales o diferentes y están seleccionados, de modo independiente, de H, alquilo C1–C6, cicloalquilo C4–C9, heterociclo-alquilo C4–C9, arilo, heteroarilo, arilalquilo, heteroarilalquilo; y acilo; R9 and R10 are the same or different and are independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, heterocycle-C4-C9 alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl;
Z es –CH=CH– en la posición 5 y en configuración “E”; 30 Z is –CH = CH– in position 5 and in “E” configuration; 30
o una de sus sales farmacéuticamente aceptables. or one of its pharmaceutically acceptable salts.
Como con cualquier grupo de compuestos estructuralmente relacionados que poseen una utilidad particular, se prefieren As with any group of structurally related compounds that have a particular utility, preferred
determinados grupos para los compuestos de las fórmulas (I), (Ia) y (Ib) en su aplicación de uso final. certain groups for the compounds of the formulas (I), (Ia) and (Ib) in their end use application.
En determinadas formas de realización preferidas, R1 se selecciona del grupo que consiste en alquilo C1–C10, alquenilo, heteroalquilo, haloalquilo, alquinilo, arilo, 5 cicloalquilo, heterocicloalquilo, heteroarilo, heterocicloalquilalquilo C4–C9, cicloalquilalquilo, arilalquilo y heteroarilalquilo, cada uno de los cuales puede estar sustituido como se estableció con anterioridad. In certain preferred embodiments, R1 is selected from the group consisting of C1-C10 alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl C4-C9, cycloalkylalkyl, arylalkyl and heteroarylalkyl, each of which may be substituted as previously established.
En otra forma de realización, se prefiere que R1 se 10 seleccione del grupo que consiste en H, hidroxialquilo, alquilo, arilalquilo, heteroarilalquilo, alcoxialquilo, aminoalquilo y heterocicloalquilo, cada uno de los cuales puede estar sustituido como se estableció con anterioridad. In another embodiment, it is preferred that R 1 be selected from the group consisting of H, hydroxyalkyl, alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, aminoalkyl and heterocycloalkyl, each of which may be substituted as set forth above.
En otra forma de realización, se prefiere que R1 se 15 seleccione del grupo que consiste en H, hidroxialquilo, alquilo, alcoxialquilo y aminoalquilo, cada uno de los cuales puede estar sustituido como se estableció con anterioridad. In another embodiment, it is preferred that R1 is selected from the group consisting of H, hydroxyalkyl, alkyl, alkoxyalkyl and aminoalkyl, each of which may be substituted as set forth above.
En otra forma de realización, se prefiere que, si R1 es alquilo o heteroalquilo, entonces no esté sustituido con un 20 cicloalquilo, arilo, heteroarilo o heterocicloalquilo. In another embodiment, it is preferred that, if R1 is alkyl or heteroalkyl, then it is not substituted with a cycloalkyl, aryl, heteroaryl or heterocycloalkyl.
Valores de particular preferencia de R1 son: H; metilo; (piridin–2–il)metilo; (piridin–3–il)metilo; etilo; 2–hidroxi–etilo; 2–(piridin–2–il)etilo; 2–(piridin–3–il)etilo; 2–fenil–etilo; 2–carboxi–etilo; 2–(morfolin–4–il)–etilo; 2–25 (piperidin–1–il)–etilo; 2–(pirrolidin–1–il)–etilo; 2–dietilamino–etilo; propilo; 2,3–di–hidroxi–propilo; 3–hidroxi–propilo; 3–metoxi–propilo; 3–isopropoxi–propilo; 2,2–dimetil–propilo; 3–dimetilamino–propilo; 3–dimetilamino–2,2–dimetil–propilo; 3–(2–oxo–pirrolidin–1–il)–propilo; 3–30 (morfolin–4–il)–propilo; 3–(imadazol–1–il)–propilo; 3–(4–metil–piperidin–1–il)–propilo; 3–(pirrolidin–1–il)–propilo; 4–dimetilamino–butilo; 5–hidroxi–pentilo; alilo; bencilo; y Particularly preferred values of R1 are: H; methyl; (pyridin-2-yl) methyl; (pyridin-3-yl) methyl; ethyl; 2-hydroxy-ethyl; 2– (pyridin-2-yl) ethyl; 2– (pyridin-3-yl) ethyl; 2-phenyl-ethyl; 2-carboxy-ethyl; 2– (morpholin-4-yl) -ethyl; 2-25 (piperidin-1-yl) -ethyl; 2– (pyrrolidin-1-yl) -ethyl; 2-diethylamino-ethyl; propyl; 2,3-di-hydroxy-propyl; 3-hydroxy-propyl; 3-methoxy-propyl; 3-isopropoxy-propyl; 2,2-dimethyl-propyl; 3-dimethylamino-propyl; 3-dimethylamino-2,2-dimethyl-propyl; 3– (2-oxo-pyrrolidin-1-yl) -propyl; 3–30 (morpholin-4-yl) -propyl; 3– (imadazol-1-yl) -propyl; 3– (4-methyl-piperidin-1-yl) -propyl; 3– (pyrrolidin-1-yl) -propyl; 4-dimethylamino-butyl; 5-hydroxy-pentyl; allyl benzyl; Y
3,4,5–trimetoxibencilo. 3,4,5-trimethoxybenzyl.
En determinadas formas de realización preferidas, R2 se selecciona del grupo que consiste en H, halógeno, alquilo C1–C10, alquenilo, heteroalquilo, haloalquilo, alquinilo, arilo, cicloalquilo, heterocicloalquilo, heteroarilo, 5 heterocicloalquilalquilo C4–C9, cicloalquilalquilo, arilalquilo y heteroarilalquilo, cada uno de los cuales puede estar sustituido como se estableció con anterioridad. In certain preferred embodiments, R2 is selected from the group consisting of H, halogen, C1-C10 alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl C4-C9, cycloalkylalkyl, arylalkyl and heteroarylalkyl, each of which may be substituted as set forth above.
En otra forma de realización, se prefiere que R2 se seleccione del grupo que consiste en H, alquilo, arilalquilo, 10 arilo, heteroarilo, heteroalquilo, cicloalquilo y L, cada uno de los cuales puede estar sustituido como se estableció con anterioridad. In another embodiment, it is preferred that R2 be selected from the group consisting of H, alkyl, arylalkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl and L, each of which may be substituted as set forth above.
En otra forma de realización, se prefiere que R2 se seleccione del grupo que consiste en H, hidroxialquilo, 15 alquilo, alcoxialquilo y aminoalquilo, cada uno de los cuales puede estar sustituido como se estableció con anterioridad. In another embodiment, it is preferred that R2 is selected from the group consisting of H, hydroxyalkyl, alkyl, alkoxyalkyl and aminoalkyl, each of which may be substituted as set forth above.
En otra forma de realización, se prefiere que, si R2 es alquilo o heteroalquilo, entonces no esté sustituido con un cicloalquilo, arilo, heteroarilo o heterocicloalquilo. 20 In another embodiment, it is preferred that, if R2 is alkyl or heteroalkyl, then it is not substituted with a cycloalkyl, aryl, heteroaryl or heterocycloalkyl. twenty
Valores de particular preferencia de R2 son: H; metilo; bencilamino–metilo; dibencilamino–metilo; [2–(4–fluoro–fenil)–acetilamino]–metilo; [2–(4–metoxi–fenil)–acetilamino]–metilo; 4–metoxi–bencilamino–metilo; benciloxi–metilo; fenilacetilamino–metilo; 1–amino–2–fenil–etilo; 2–25 bencilamino–etilo; 2–(3–metoxi–fenil)–etilo; 2–(piridin–3–il)etilo; 2–(2–fenoxiacetilamino)–etilo; 2–bencensulfonilamino–etilo; 2–fenil–etilo; isopropilo; 2–fenil–propilo; 3–fenil–propilo; 3–fenoxi–propilo; 3–(1H–indol–3–il)–propilo; 4–metoxi–fenilo; 4–fluoro–fenilo; 4–30 benciloxi–3–metoxi–fenilo; isobutilo; ciclohexilo; octilo; bencilo; piridin–2–ilo; piridin–4–ilo; tiofen–3–ilo; bencilsulfanilo y 2–fenilmetansulfanilo. Particularly preferred values of R2 are: H; methyl; benzylamino-methyl; dibenzylamino methyl; [2– (4-fluoro-phenyl) -acetylamino] -methyl; [2– (4-methoxy-phenyl) -acetylamino] -methyl; 4-methoxy-benzylamino-methyl; benzyloxy methyl; phenylacetylamino-methyl; 1-amino-2-phenyl-ethyl; 2-25 benzylamino-ethyl; 2– (3-methoxy-phenyl) -ethyl; 2– (pyridin-3-yl) ethyl; 2– (2-phenoxyacetylamino) -ethyl; 2-benzenesulfonylamino-ethyl; 2-phenyl-ethyl; isopropyl; 2-phenyl-propyl; 3-phenyl-propyl; 3-phenoxy-propyl; 3– (1H-indole-3-yl) -propyl; 4-methoxy-phenyl; 4-fluoro-phenyl; 4-30 benzyloxy-3-methoxy-phenyl; isobutyl; cyclohexyl; octyl; benzyl; pyridin-2-yl; pyridin-4-yl; thiophene-3-yl; benzylsulfanyl and 2-phenylmethanesulfanyl.
Si R1 o R2 están sustituidos, los sustituyentes de particular preferencia se seleccionan del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, alquilo, alquenilo, heteroalquilo, haloalquilo, alquinilo, arilo, cicloalquilo, heterocicloalquilo, heteroarilo, hidroxi, hidroxialquilo, 5 alcoxi, alquilamino, aminoalquilo, acilamino, fenoxi, alcoxialquilo, benciloxi, alquilsulfonilo, arilsulfonilo, aminosulfonilo, –C(O)OR5, COOH, SH y acilo. If R1 or R2 are substituted, the substituents of particular preference are selected from the group consisting of: halogen, = O, = S, -CN, -NO2, alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C (O) OR5, COOH, SH and acyl.
X e Y pueden ser iguales o diferentes y son, preferentemente, H, halógeno, alquilo C1–C4, –CF3, –NO2, –10 C(O)R5, –OR6, –SR6, –CN y NR7R8. X and Y may be the same or different and are preferably H, halogen, C1-C4 alkyl, -CF3, -NO2, -10 C (O) R5, -OR6, -SR6, -CN and NR7R8.
X es, con máxima preferencia, H; X is, most preferably, H;
Y es, con máxima preferencia, H; And it is, most preferably, H;
X e Y están, con máxima preferencia, en las posiciones 4 y 7 del anillo aromático. 15 X and Y are, most preferably, in positions 4 and 7 of the aromatic ring. fifteen
R3 es, preferentemente, H, alquilo C1–C6 o acilo, con mayor preferencia, H o alquilo C1–C4, con máxima preferencia H; R3 is preferably H, C1-C6 alkyl or acyl, more preferably, H or C1-C4 alkyl, most preferably H;
R4 es, con preferencia, H o alquilo C1–C4, con máxima preferencia, H; 20 R4 is preferably H or C1-C4 alkyl, most preferably H; twenty
R5 es, con preferencia, alquilo C1–C4, heteroalquilo o acilo, con máxima preferencia, metilo; R5 is preferably C1-C4 alkyl, heteroalkyl or acyl, most preferably methyl;
R6 es, con preferencia, alquilo C1–C4, heteroalquilo o acilo, con máxima preferencia, alquilo C1–C4; R6 is preferably C1-C4 alkyl, heteroalkyl or acyl, most preferably C1-C4 alkyl;
R7 y R8 se seleccionan preferentemente del grupo que 25 consiste en H, alquilo C1–C6, cicloalquilo C4–C9, heterocicloalquilo C4–C9, arilo, heteroarilo, arilalquilo y heteroarilalquilo. R7 and R8 are preferably selected from the group consisting of H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl.
El resto Z es un grupo de fórmula –CH=CH–. El resto está en la configuración “E” y está en la posición 5. 30 The remainder Z is a group of formula –CH = CH–. The rest is in the “E” configuration and is in position 5. 30
Además de los compuestos de fórmula (I), las formas de realización descritas también se refieren a sales farmacéuticamente aceptables, profármacos farmacéuticamente In addition to the compounds of formula (I), the described embodiments also refer to pharmaceutically acceptable salts, pharmaceutically prodrugs.
aceptables y metabolitos farmacéuticamente activos de dichos compuestos, y sales farmacéuticamente aceptables de dichos metabolitos. En conjunto, dichos compuestos, sales, profármacos y metabolitos se denominan en ocasiones en la presente “agentes inhibidores de HDAC” o “inhibidores de 5 HDAC”. Acceptable and pharmaceutically active metabolites of said compounds, and pharmaceutically acceptable salts of said metabolites. Together, said compounds, salts, prodrugs and metabolites are sometimes referred to herein as "HDAC inhibitors" or "HDAC inhibitors."
La invención también se refiere a composiciones farmacéuticas que incluyen un compuesto de la invención con un portador, diluyente o excipiente farmacéuticamente aceptable. 10 The invention also relates to pharmaceutical compositions that include a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient. 10
La invención también proporciona agentes para el tratamiento de un trastorno causado por, asociado con o acompañado de alteraciones de la proliferación celular y/o la angiogénesis, incluyendo un compuesto de fórmula (I) como se describe en la presente. Con preferencia, el agente es un 15 agente anticanceroso. The invention also provides agents for the treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis, including a compound of formula (I) as described herein. Preferably, the agent is an anticancer agent.
Con preferencia, el agente contiene un compuesto de fórmula (Ia), con mayor preferencia un compuesto de fórmula (Ib). Preferably, the agent contains a compound of formula (Ia), more preferably a compound of formula (Ib).
Con preferencia, el trastorno se selecciona del grupo 20 que consiste en pero no está limitado a cáncer, enfermedades inflamatorias/trastornos del sistema inmunitario, angiofibroma, enfermedades cardiovasculares (por ejemplo, restenosis, arterioesclerosis), enfermedades fibróticas (por ejemplo, fibrosis hepática), diabetes, enfermedades 25 autoinmunes, enfermedades neurodegenerativas agudas y crónicas como alteraciones del tejido nervioso, enfermedad de Huntington y enfermedades infecciosas como infecciones fúngicas, bacterianas y virales. En otra forma de realización, el trastorno es un trastorno proliferativo. Con 30 preferencia, el trastorno proliferativo es cáncer. Preferably, the disorder is selected from group 20 which consists of but is not limited to cancer, inflammatory diseases / immune system disorders, angiofibroma, cardiovascular diseases (eg, restenosis, atherosclerosis), fibrotic diseases (eg, liver fibrosis) , diabetes, autoimmune diseases, acute and chronic neurodegenerative diseases such as nervous tissue disorders, Huntington's disease and infectious diseases such as fungal, bacterial and viral infections. In another embodiment, the disorder is a proliferative disorder. With preference, the proliferative disorder is cancer.
La invención también se refiere al uso de compuestos de fórmula (I) en la preparación de un medicamento para el The invention also relates to the use of compounds of formula (I) in the preparation of a medicament for
tratamiento de un trastorno causado por, asociado con o acompañado de alteraciones de la proliferación celular y/o angiogénesis. Con preferencia, el trastorno es un trastorno proliferativo, con mayor preferencia cáncer. treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis. Preferably, the disorder is a proliferative disorder, more preferably cancer.
Sorprendentemente, los compuestos de la presente 5 invención muestran baja toxicidad, junto con una poderosa actividad antiproliferativa. Surprisingly, the compounds of the present invention show low toxicity, together with a powerful antiproliferative activity.
La invención también proporciona agentes para el tratamiento de un trastorno, una enfermedad o una condición que se puede tratar por inhibición de la histona 10 desacetilasa, que incluye un compuesto de fórmula (I), con preferencia un compuesto de fórmula (Ia), con mayor preferencia un compuesto de fórmula (Ib), como se describe en la presente. Con preferencia, el agente es un agente anticanceroso. 15 The invention also provides agents for the treatment of a disorder, a disease or a condition that can be treated by inhibition of histone 10 deacetylase, which includes a compound of formula (I), preferably a compound of formula (Ia), with more preferably a compound of formula (Ib), as described herein. Preferably, the agent is an anticancer agent. fifteen
La invención también se refiere al uso de compuestos de fórmula (I), con preferencia un compuesto de fórmula (Ia), con mayor preferencia un compuesto de fórmula (Ib) en la preparación de un medicamento para el tratamiento de un trastorno, una enfermedad o una condición que se puede tratar 20 por inhibición de la histona desacetilasa. The invention also relates to the use of compounds of formula (I), preferably a compound of formula (Ia), more preferably a compound of formula (Ib) in the preparation of a medicament for the treatment of a disorder, a disease or a condition that can be treated by inhibition of histone deacetylase.
Con preferencia, el trastorno se selecciona del grupo que consiste en pero no está limitado a trastornos proliferativos (por ejemplo, cánceres); enfermedades neurodegenerativas tales como enfermedad de Huntington, 25 enfermedad de poliglutamina, enfermedad de Parkinson, enfermedad de Alzheimer, convulsiones, degeneración nigroestriada, parálisis supranuclear progresiva, distonía por torsión, tortícolis espasmódica y discinesia, temblor familiar, síndrome de Gilles de la Tourette, enfermedad 30 difusa por cuerpos de Lewy, parálisis supranuclear progresiva, enfermedad de Pick, hemorragia intracerebral, esclerosis lateral primaria, atrofia muscular espinal, Preferably, the disorder is selected from the group consisting of but not limited to proliferative disorders (eg, cancers); neurodegenerative diseases such as Huntington's disease, 25 polyglutamine disease, Parkinson's disease, Alzheimer's disease, seizures, nigrostriated degeneration, progressive supranuclear paralysis, torsion dystonia, spasmodic torticollis and dyskinesia, family tremor, Gilles de la Tourette syndrome, disease 30 diffuse by Lewy bodies, progressive supranuclear palsy, Pick's disease, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy,
esclerosis lateral amiotrófica, polineuropatía intersticial hipertrófica, retinitis pigmentaria, atrofia óptica hereditaria, paraplejia espástica hereditaria, ataxia progresiva y síndrome de Shy–Drager; enfermedades metabólicas incluyendo diabetes tipo 2; enfermedades degenerativas del 5 ojo, incluyendo glaucoma, degeneración macular asociada a la edad, glaucoma por rubéola; enfermedad inflamatoria y/o trastornos del sistema inmunitario, incluso artritis reumatoide (AR), osteoartritis, artritis crónica juvenil, enfermedad injerto versus huésped, psoriasis, asma, 10 espondiloartropatía, psoriasis, enfermedad de Crohn, enfermedad inflamatoria intestinal, colitis ulcerosa, hepatitis alcohólica, diabetes, síndrome de Sjoegren, esclerosis múltiple, espondilitis anquilosante, glomerulopatía membranosa, dolor discogénico, lupus 15 eritematoso sistémico; enfermedad que incluye angiogénesis, por ejemplo cáncer, psoriasis, artritis reumatoide; trastornos psicológicos que incluyen enfermedad bipolar, esquizofrenia, depresión y demencia; enfermedades cardiovasculares tales como insuficiencia cardíaca, 20 restenosis y arterioesclerosis; enfermedades fibróticas tales como fibrosis hepática, fibrosis quística y angiofibroma; enfermedades infecciosas tales como infecciones fúngicas, por ejemplo por Candida Albicans, infecciones bacterianas, infecciones virales, por ejemplo herpes simplex, infecciones 25 por protozoos, tales como malaria, infección por Leishmania, infección por Trypanosoma brucei, toxoplasmosis y coccidiosis, y trastornos hematopoyéticos tales como, por ejemplo talasemia, anemia y anemia por células falciformes. Amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, pigmentary retinitis, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and Shy-Drager syndrome; metabolic diseases including type 2 diabetes; degenerative diseases of the eye, including glaucoma, age-related macular degeneration, rubella glaucoma; inflammatory disease and / or immune system disorders, including rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis , diabetes, Sjoegren's syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus; disease that includes angiogenesis, for example cancer, psoriasis, rheumatoid arthritis; psychological disorders that include bipolar disease, schizophrenia, depression and dementia; cardiovascular diseases such as heart failure, restenosis and atherosclerosis; fibrotic diseases such as liver fibrosis, cystic fibrosis and angiofibroma; infectious diseases such as fungal infections, for example by Candida Albicans, bacterial infections, viral infections, for example herpes simplex, protozoan infections, such as malaria, Leishmania infection, Trypanosoma brucei infection, toxoplasmosis and coccidiosis, and hematopoietic disorders such such as thalassemia, anemia and sickle cell anemia.
La invención también proporciona un método para inhibir 30 la proliferación celular que incluye la administración de una cantidad efectiva de un compuesto de acuerdo con la fórmula (I). The invention also provides a method for inhibiting cell proliferation that includes the administration of an effective amount of a compound according to formula (I).
La invención también proporciona agentes para el tratamiento de un trastorno neurodegenerativo que incluyen un compuesto de fórmula (I), con preferencia un compuesto de fórmula (Ia), con mayor preferencia un compuesto de fórmula (Ib), como se describe en la presente. Con preferencia, el 5 agente es un agente contra la enfermedad de Huntington. The invention also provides agents for the treatment of a neurodegenerative disorder that include a compound of formula (I), preferably a compound of formula (Ia), more preferably a compound of formula (Ib), as described herein. Preferably, the agent is an agent against Huntington's disease.
La invención también se refiere al uso de compuestos de fórmula (I), con preferencia un compuesto de fórmula (Ia), con mayor preferencia un compuesto de fórmula (Ib) en la preparación de un medicamento para el tratamiento de un 10 trastorno neurodegenerativo. Con preferencia, el trastorno neurodegenerativo es la enfermedad de Huntington. The invention also relates to the use of compounds of formula (I), preferably a compound of formula (Ia), more preferably a compound of formula (Ib) in the preparation of a medicament for the treatment of a neurodegenerative disorder. Preferably, the neurodegenerative disorder is Huntington's disease.
La invención también proporciona agentes para el tratamiento de una enfermedad inflamatoria y/o trastorno del sistema inmunitario que incluyen un compuesto de fórmula (I), 15 con preferencia un compuesto de fórmula (Ia), con mayor preferencia un compuesto de fórmula (Ib), como se describe en la presente. The invention also provides agents for the treatment of an inflammatory disease and / or immune system disorder that include a compound of formula (I), preferably a compound of formula (Ia), more preferably a compound of formula (Ib) , as described herein.
La invención también se refiere al uso de compuestos de fórmula (I), con preferencia un compuesto de fórmula (Ia), 20 con mayor preferencia un compuesto de fórmula (Ib), en la preparación de un medicamento para el tratamiento de una enfermedad inflamatoria y/o trastorno del sistema inmunitario. En una forma de realización, la enfermedad inflamatoria y/o el trastorno del sistema inmunitario es 25 artritis reumatoide. En otra forma de realización, la enfermedad inflamatoria y/o el trastorno del sistema inmunitario es lupus eritematoso sistémico. The invention also relates to the use of compounds of formula (I), preferably a compound of formula (Ia), more preferably a compound of formula (Ib), in the preparation of a medicament for the treatment of an inflammatory disease and / or immune system disorder. In one embodiment, the inflammatory disease and / or immune system disorder is rheumatoid arthritis. In another embodiment, the inflammatory disease and / or immune system disorder is systemic lupus erythematosus.
Para monitorizar la eficacia de dichos compuestos, la invención describe un método adecuado para detectar y 30 cuantificar los niveles de histona acetilada en muestras de especies humanas o animales tales como tejido tumoral, encéfalo y sangre. El método se basa en un ensayo de To monitor the efficacy of said compounds, the invention describes a suitable method for detecting and quantifying levels of acetylated histone in samples of human or animal species such as tumor tissue, brain and blood. The method is based on a trial of
inmunoabsorción ligado a enzima (ELISA) y se puede usar para la cuantificación de histonas acetiladas en extractos o muestras celulares de especies humanas o animales tales como tejido tumoral, encéfalo y sangre. Preferentemente sobre los sistemas convencionales, el ELISA permite elevados 5 rendimientos, determinaciones cuantitativas de la concentración de histonas acetiladas como medida de la eficacia de los tratamientos farmacológicos o de la potencia del fármaco en el respectivo sistema biológico de prueba. Para una revisión general de las técnicas convencionales de 10 ELISA, se ruega hacer referencia al documento de Crowther JR (1995) “ELISA theory and practice” en “Method in molecular biology”, vol. 42, Humana. Enzyme-linked immunoabsorption (ELISA) and can be used for quantification of acetylated histones in extracts or cell samples of human or animal species such as tumor tissue, brain and blood. Preferably over conventional systems, the ELISA allows high yields, quantitative determinations of the concentration of acetylated histones as a measure of the efficacy of pharmacological treatments or the potency of the drug in the respective biological test system. For a general review of conventional ELISA techniques, please refer to Crowther JR (1995) "ELISA theory and practice" in "Method in molecular biology", vol. 42, Human.
Es útil un método para medir la concentración de histona acetilada en una muestra biológica usando un ensayo 15 de inmunoabsorción ligado a enzima, incluyendo el ensayo de inmunoabsorción ligado a enzima una combinación de un anticuerpo de captura primaria, una porción del mismo, y un anticuerpo de detección secundaria, o una porción del mismo. A method of measuring the concentration of acetylated histone in a biological sample using an enzyme-linked immunosorbent assay, including the enzyme-linked immunosorbent assay, a combination of a primary capture antibody, a portion thereof, and an antibody is useful. of secondary detection, or a portion thereof.
Con preferencia, el anticuerpo de captura primaria es 20 seleccionado del grupo formado por: un anticuerpo monoclonal anti–H3, un anticuerpo policlonal anti–H3 acetilado, un anticuerpo policlonal anti–H3 de cabra, un anticuerpo policlonal anti–H3 acetilado de cabra y combinaciones de los mismos. Con preferencia, el anticuerpo de detección 25 secundaria se selecciona del grupo formado por: un anticuerpo monoclonal anti–H3, un anticuerpo policlonal anti–H3 acetilado, un anticuerpo policlonal anti–H3 de cabra, un anticuerpo policlonal anti–H3 acetilado de cabra y una combinación de ellos. 30 Preferably, the primary capture antibody is selected from the group consisting of: an anti-H3 monoclonal antibody, an acetylated anti-H3 polyclonal antibody, a goat anti-H3 polyclonal antibody, a goat acetylated anti-H3 polyclonal antibody and combinations thereof. Preferably, the secondary detection antibody 25 is selected from the group consisting of: an anti-H3 monoclonal antibody, an acetylated anti-H3 polyclonal antibody, a goat anti-H3 polyclonal antibody, a goat acetylated anti-H3 polyclonal antibody and A combination of them. 30
El anticuerpo de captura primaria puede ser un anticuerpo monoclonal anti–H3 de ratón y el anticuerpo de detección secundaria puede ser un anticuerpo policlonal anti– The primary capture antibody can be a mouse anti-H3 monoclonal antibody and the secondary detection antibody can be an anti-polyclonal antibody.
H3 acetilado de rata. H3 rat acetylate.
La muestra de control se deriva de una célula que no ha sido tratada con un inhibidor de histona desacetilasa. La célula puede ser una célula tumoral. The control sample is derived from a cell that has not been treated with a histone deacetylase inhibitor. The cell can be a tumor cell.
Es útil un método para identificar el efecto 5 farmacológico de un inhibidor de histona desacetilasa en un sujeto, incluyendo el método las etapas de: A method of identifying the pharmacological effect of a histone deacetylase inhibitor in a subject, including the method, the steps of:
a) obtener una muestra biológica de un sujeto que ha sido tratado con un inhibidor de histona desacetilasa; a) obtain a biological sample from a subject that has been treated with a histone deacetylase inhibitor;
b) medir la concentración de histona acetilada en la 10 muestra biológica mediante un método de acuerdo con la invención según se describió antes; y b) measuring the concentration of acetylated histone in the biological sample by a method according to the invention as described above; Y
c) comparar la concentración de histona acetilada con la concentración de histona acetilada de una muestra de control. 15 c) compare the concentration of acetylated histone with the concentration of acetylated histone of a control sample. fifteen
La muestra de control puede ser una muestra biológica derivada de un sujeto que no ha sido tratado con un inhibidor de histona desacetilasa. The control sample may be a biological sample derived from a subject that has not been treated with a histone deacetylase inhibitor.
Con preferencia, en las enseñanzas de la invención la muestra biológica se selecciona del grupo que consiste en 20 tejido, sangre, suero, plasma, orina, saliva y una combinación de ellos. Preferably, in the teachings of the invention the biological sample is selected from the group consisting of tissue, blood, serum, plasma, urine, saliva and a combination thereof.
Se describen compuestos de hidroxamato, por ejemplo bencimidazoles que contienen ácido hidroxámico en uno de los 25 sustituyentes, que pueden ser inhibidores de desacetilasas, incluyendo pero no limitados a los inhibidores de histona desacetilasas. Los compuestos de hidroxamato pueden ser adecuados para la prevención o el tratamiento de un trastorno causado por, asociado con o acompañado de alteraciones de la 30 proliferación celular y/o angiogénesis cuando se usan solos o junto con un portador, diluyente o excipiente farmacéuticamente aceptable. Un ejemplo de dicho trastorno es Hydroxamate compounds, for example benzimidazoles containing hydroxamic acid in one of the 25 substituents, which may be deacetylase inhibitors, including but not limited to histone deacetylase inhibitors are described. The hydroxamate compounds may be suitable for the prevention or treatment of a disorder caused by, associated with or accompanied by alterations of cell proliferation and / or angiogenesis when used alone or together with a pharmaceutically acceptable carrier, diluent or excipient. An example of such a disorder is
cáncer. Cancer.
Tal como se usa en la presente, el término “cáncer” es un término general que pretende abarcar la vasta cantidad de condiciones que se caracterizan por el crecimiento anormal descontrolado de las células. 5 As used herein, the term "cancer" is a general term intended to cover the vast number of conditions that are characterized by abnormal uncontrolled cell growth. 5
Se prevé que los compuestos de la invención serán útiles para el tratamiento de diversos cánceres, incluyendo pero no limitados a los cánceres óseos, por ejemplo sarcoma de Ewing, osteosarcoma, condrosarcoma y similares, tumores encefálicos y tumores del SNC, por ejemplo neuroma acústico, 10 neuroblastomas, glioma y otros tumores cerebrales, tumores de la médula espinal, cánceres de mama, cánceres colorrectales, adenocarcinomas colorrectales avanzados, cánceres endocrinos que incluyen carcinoma adrenocortical, cáncer de páncreas, cáncer de hipófisis, cáncer de tiroides, cáncer de 15 paratiroides, cáncer de timo, neoplasma endocrino múltiple, cánceres gastrointestinales tales como cáncer de estómago, cáncer de esófago, cáncer de intestino delgado, cáncer de hígado, cáncer de conductos biliares extrahepáticos, tumores carcinoides gastrointestinales, cáncer de vesícula biliar, 20 cánceres genitourinarios tales como cáncer de testículo, cáncer de pene, cáncer de próstata, cánceres ginecológicos tales como cáncer cervical, cáncer de ovario, cáncer de vagina, cáncer de útero/endometrio, cáncer de vulva, cáncer trofoblástico gestacional, cáncer de trompa de Falopio, 25 sarcoma de útero, cánceres de cabeza y cuello que incluyen cáncer de cavidad oral, cáncer de labio, cáncer de glándulas salivales, cáncer de laringe, cáncer de hipofaringe, cáncer de orofaringe, cáncer nasal, cáncer paranasal, cáncer de nasofaringe, leucemias tales como leucemia de la infancia, 30 leucemia linfocítica aguda, leucemia mieloide aguda, leucemia linfocítica crónica, leucemia mieloide crónica, leucemia de células pilosas, leucemia promielocítica aguda, leucemia de It is envisioned that the compounds of the invention will be useful for the treatment of various cancers, including but not limited to bone cancers, for example Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain tumors and CNS tumors, for example acoustic neuroma, 10 neuroblastomas, glioma and other brain tumors, spinal cord tumors, breast cancers, colorectal cancers, advanced colorectal adenocarcinomas, endocrine cancers including adrenocortical carcinoma, pancreas cancer, pituitary cancer, thyroid cancer, 15 parathyroid cancer, thymus cancer, multiple endocrine neoplasm, gastrointestinal cancers such as stomach cancer, esophageal cancer, small intestine cancer, liver cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumors, gallbladder cancer, 20 genitourinary cancers such as cancer of testis, penile cancer, prostate cancer, gynecological cancers such as cervical cancer, ovarian cancer, vagina cancer, uterine / endometrial cancer, vulvar cancer, gestational trophoblastic cancer, fallopian tube cancer, 25 uterine sarcoma, head and neck cancers that include oral cavity cancer, lip cancer, salivary gland cancer, larynx cancer, hypopharyngeal cancer, oropharyngeal cancer, nasal cancer, paranasal cancer, nasopharyngeal cancer, leukemia such as childhood leukemia, 30 acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hair cell leukemia, acute promyelocytic leukemia, leukemia
células plasmáticas, mielomas, trastornos hematológicos tales como síndromes mielodisplásicos, trastornos mieloproliferativos, anemia aplásica, anemia de Fanconi, macroglobulinemia de Waldenstrom, cánceres de pulmón tales como cáncer de pulmón de células pequeñas, cáncer de pulmón 5 de células no pequeñas, linfomas tales como enfermedad de Hodgkin, linfoma no Hodgkin, linfoma de células cutáneas, linfoma de células T periféricas, linfoma relacionado con SIDA, cánceres de ojo tales como retinoblastoma, melanoma intraocular, cánceres de piel tales como melanoma, cáncer de 10 piel no melanoma, cáncer de células de Merkel, sarcomas de tejidos blandos tales como sarcoma de tejidos blandos de la infancia, sarcoma de tejidos blandos del adulto, sarcoma de Kaposi, cánceres de sistema urinario tales como cáncer de riñón, tumor de Wilms, cáncer de vejiga, cáncer de uretra y 15 cáncer de células de transición. plasma cells, myelomas, haematological disorders such as myelodysplastic syndromes, myeloproliferative disorders, aplastic anemia, Fanconi anemia, Waldenstrom macroglobulinemia, lung cancers such as small cell lung cancer, non-small cell lung cancer 5, lymphomas such as Hodgkin's disease, non-Hodgkin's lymphoma, skin cell lymphoma, peripheral T-cell lymphoma, AIDS-related lymphoma, eye cancers such as retinoblastoma, intraocular melanoma, skin cancers such as melanoma, non-melanoma skin cancer, cancer of Merkel cells, soft tissue sarcomas such as childhood soft tissue sarcoma, adult soft tissue sarcoma, Kaposi sarcoma, urinary system cancers such as kidney cancer, Wilms tumor, bladder cancer, urethra cancer and 15 transition cell cancer.
Con preferencia, los cánceres que se pueden tratar mediante los compuestos de la presente invención son cáncer de mama, cáncer de pulmón, cáncer de ovario, cáncer de próstata, cáncer de cabeza y cuello, cáncer de riñón, cáncer 20 de estómago y cáncer de cerebro. Preferably, the cancers that can be treated by the compounds of the present invention are breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, stomach cancer and cancer of 20 brain.
Con preferencia, los cánceres que se pueden tratar mediante los compuestos de las presentes invenciones son linfoma de células T cutáneas (CTCL) y linfoma de células T periféricas. 25 Preferably, cancers that can be treated by the compounds of the present inventions are cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. 25
Con preferencia, los cánceres que se pueden tratar mediante los compuestos de la presente invención incluyen tumores sólidos y enfermedades malignas hematológicas. Preferably, cancers that can be treated by the compounds of the present invention include solid tumors and hematological malignancies.
También se pueden usar los compuestos para el tratamiento de un trastorno que incluye, se refiere a o se 30 asocia con la desregulación de histona desacetilasa (HDAC). Compounds may also be used for the treatment of a disorder that includes, refers to or is associated with histone deacetylase deregulation (HDAC).
Hay un cierto núero de trastornos que se han vinculado con o se sabe que son mediados al menos en parte por la There are a number of disorders that have been linked to or are known to be mediated at least in part by the
actividad HDAC, donde se sabe que la actividad HDAC juega un papel importante en la iniciación de la aparición de la enfermedad, o cuyos síntomas se sabe o se ha demostrado que se alivian mediante inhibidores de HDAC. Se esperaría que los trastornos de este tipo capaces de ser tratados mediante 5 estos compuestos de la invención incluyan los siguientes, pero no estén limitados a ellos: trastornos proliferativos (por ejemplo, cánceres); enfermedades neurodegenerativas tales como enfermedad de Huntington, enfermedad de poliglutamina, enfermedad de Parkinson, enfermedad de 10 Alzheimer, convulsiones, degeneración nigroestriada, parálisis supranuclear progresiva, distonía de torsión, tortícolis espasmódica y discinesia, temblor familiar, síndrome de Gilles de la Tourette, enfermedad difusa de cuerpo de Lewy, parálisis supranuclear progresiva, enfermedad 15 de Pick, hemorragia intracerebral, esclerosis lateral primaria, atrofia muscular espinal, esclerosis lateral amiotrófica, polineuropatía intersticial hipertrófica, retinitis pigmentaria, atrofia óptica hereditaria, paraplejia espástica hereditaria, ataxia progresiva y síndrome de Shy–20 Drager; enfermedades metabólicas tales como diabetes tipo 2; enfermedades degenerativas del ojo tales como glaucoma, degeneración macular asociada a la edad, glaucoma de rubéola; enfermedades inflamatorias y/o trastornos del sistema inmunitario tales como artritis reumatoide (AR), 25 osteoartritis, artritis crónica juvenil, enfermedad injerto versus huésped, psoriasis, asma, espondiloartropatía, psoriasis, enfermedad de Crohn, enfermedad inflamatoria intestinal, colitis ulcerosa, hepatitis alcohólica, diabetes, síndrome de Sjoegren, esclerosis múltiple, espondilitis 30 anquilosante, glomerulopatía membranosa, dolor discogénico, lupus eritematoso sistémico; enfermedad que incluye angiogénesis tales como cáncer, psoriasis, artritis HDAC activity, where HDAC activity is known to play an important role in initiating the onset of the disease, or whose symptoms are known or proven to be relieved by HDAC inhibitors. It would be expected that disorders of this type capable of being treated by these compounds of the invention include the following, but are not limited to: proliferative disorders (eg, cancers); neurodegenerative diseases such as Huntington's disease, polyglutamine disease, Parkinson's disease, 10 Alzheimer's disease, seizures, nigrostriated degeneration, progressive supranuclear paralysis, torsion dystonia, spasmodic torticollis and dyskinesia, family tremor, Gilles de la Tourette syndrome, disease Diffuse of Lewy body, progressive supranuclear paralysis, Pick's disease 15, intracerebral hemorrhage, primary lateral sclerosis, spinal muscular atrophy, amyotrophic lateral sclerosis, hypertrophic interstitial polyneuropathy, pigmentary retinitis, hereditary optic atrophy, hereditary spastic paraplegia, progressive ataxia and syndrome Shy – 20 Drager; metabolic diseases such as type 2 diabetes; degenerative diseases of the eye such as glaucoma, age-related macular degeneration, rubella glaucoma; inflammatory diseases and / or immune system disorders such as rheumatoid arthritis (RA), osteoarthritis, juvenile chronic arthritis, graft versus host disease, psoriasis, asthma, spondyloarthropathy, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, alcoholic hepatitis , diabetes, Sjoegren's syndrome, multiple sclerosis, ankylosing spondylitis, membranous glomerulopathy, discogenic pain, systemic lupus erythematosus; disease that includes angiogenesis such as cancer, psoriasis, arthritis
reumatoide; trastornos psicológicos tales como enfermedad bipolar, esquizofrenia, manía, depresión y demencia; enfermedades cardiovasculares tales como insuficiencia cardíaca, restenosis y arterioesclerosis; enfermedades fibróticas tales como fibrosis hepática, fibrosis quística y 5 angiofibroma; enfermedades infecciosas tales como infecciones fúngicas, por ejemplo por Candida Albicans, infecciones bacterianas, infecciones virales, tales como herpes simplex, infecciones por protozoos, tales como malaria, infección por Leishmania, infección por Trypanosoma brucei, toxoplasmosis y 10 coccidiosis y trastornos hematopoyéticos tales como talasemia, anemia y anemia de células falciformes. rheumatoid; psychological disorders such as bipolar disease, schizophrenia, mania, depression and dementia; cardiovascular diseases such as heart failure, restenosis and atherosclerosis; fibrotic diseases such as liver fibrosis, cystic fibrosis and angiofibroma; Infectious diseases such as fungal infections, for example by Candida Albicans, bacterial infections, viral infections, such as herpes simplex, protozoal infections, such as malaria, Leishmania infection, Trypanosoma brucei infection, toxoplasmosis and 10 coccidiosis and hematopoietic disorders such as thalassemia, anemia and sickle cell anemia.
Los compuestos de hidroxamato de la presente invención tienen la siguiente estructura (I) de acuerdo con la reivindicación 1: 15 The hydroxamate compounds of the present invention have the following structure (I) according to claim 1: 15
- NNXYZONR3OFormula I7654321R4R1R2 Fórmula I NNXYZONR3O Formula I7654321R4R1R2 Formula I
en donde: where:
R1 se selecciona del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, 20 heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, arilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, 25 alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, R1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl, arylalkyl, arylalkyl, aryl-alkyl-aryl-alkyl, aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-alkyl-aryl-aryl-alkyl group-aryl-alkyl-aryl-alkyl group heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino
arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios 5 sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, 10 hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, 15 acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl , Hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyl, arylamino, amino, alkylamino, amino , arylsulfonyl, arylsulfinyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, –C (O) OR5, –COR5, –SH, –SR6, –OR6 and acyl;
o R1 = L; 20 or R1 = L; twenty
R2 se selecciona del grupo que consiste en: H, halógeno, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, 25 heteroarilalquilo, arilalquenilo, cicloalquilheteroalquilo, heterocicloalquilheteroalquilo, heteroarilheteroalquilo, arilheteroalquilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, heterocicloalquiloxi, ariloxi, heteroariloxi, 30 arilalquiloxi, amino, alquilamino, aminoalquilo, acilamino, arilamino, fenoxi, benciloxi, COOH, alcoxicarbonilo, alquilaminocarbonilo, sulfonilo, alquilsulfonilo, R2 is selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroylalkyl, heteroylalkyl, cycloalkyl, heteroylalkyl, heteroylalkyl, heteroaryl, alkyl heterocicloalquilheteroalquilo, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, 30 arylalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, phenoxy, benzyloxy, COOH, alkoxycarbonyl, alkylaminocarbonyl , sulfonyl, alkylsulfonyl,
alquilsulfinilo, arilsulfonilo, arilsulfinilo, aminosulfonilo, SR6 y acilo, cada uno de los cuales puede estar no sustituido o sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, 5 alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, 10 cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, 15 alcoxialquilo, –COOH, –COR5, –C(O)OR5, –SH, –SR6, –OR6 y acilo; alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, SR6 and acyl, each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, - NO2, -CF3, -OCF3, 5 alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy , cycloalkyloxy, cycloalkenyloxy 10, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl 15, -COOH, -COR 5, - C (O) OR5, -SH, -SR6, -OR6 and acyl;
o R2 = L; or R2 = L;
R3 se selecciona del grupo que consiste en H, alquilo C1–C6 y acilo; o un ion metálico seleccionado de sodio, 20 calcio, magnesio; R3 is selected from the group consisting of H, C1-C6 alkyl and acyl; or a metal ion selected from sodium, calcium, magnesium;
X e Y son iguales o diferentes y están seleccionados de modo independiente del grupo que consiste en: H, halógeno, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, 25 cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, 30 heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, X and Y are the same or different and are independently selected from the group consisting of: H, halogen, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, 30 heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino , acylamino, aminoalkyl, arylamino, sulfonyl,
alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH –C(O)OR5, –COR5, –SH, –SR6, acilo y –NR7R8; alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH -C (O) OR5, -COR5, -SH, -SR6, acyl and -NR7R8;
R4 se selecciona del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, 5 cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; R4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R5 está seleccionado de modo independiente del grupo que consiste en: alquilo, alquenilo, alquinilo, 10 haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; each R5 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
cada R6 está seleccionado de modo independiente del 15 grupo que consiste en: alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y acilo; 20 each R6 is independently selected from the group consisting of: alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; twenty
cada R7 y R8 está seleccionado de modo independiente del grupo que consiste en: H, alquilo, alquenilo, alquinilo, haloalquilo, heteroalquilo, cicloalquilo, heterocicloalquilo, arilo, heteroarilo, cicloalquilalquilo, heterocicloalquilalquilo, arilalquilo, heteroarilalquilo y 25 acilo; each R7 and R8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl;
L se selecciona del grupo que consiste en: L is selected from the group consisting of:
a) L=Cy–L1–W– a) L = Cy – L1 – W–
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, 30 heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents
seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, 5 heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, 10 arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, –C(O)OR5, –COR5, –SH, –SR6, –OR6 y acilo; 15 independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, 5 heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, 10 arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, -C (O) OR5, -COR5, -SH, -SR6, -OR6 and acyl; fifteen
L1 se selecciona del grupo que consiste en alquilo C1–C5, que puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; alquilo, alcoxi, acilamino y 20 alquilamino; L1 is selected from the group consisting of C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; alkyl, alkoxy, acylamino and alkylamino;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; 25 W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -; 25
b) L=Cy–L1–W–L2 b) L = Cy – L1 – W – L2
en donde: where:
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar 30 opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, –CN, –NO2, –CF3, –OCF3,
alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, 5 alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, 10 sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, C(O)OR6, –COR5, –SH, –SR6, –OR6 y acilo; alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, 5 alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy , aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyl, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, C (O) OR6, -C, -5, -C, -5, -C, 5 SR6, -OR6 and acyl;
L1 y L2 son iguales o diferentes y son, de modo independiente, alquilo C1–C5, que puede estar 15 opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, alquilo, alcoxi, acilamino y alquilamino; L1 and L2 are the same or different and are, independently, C1-C5 alkyl, which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; –CF3, –OCF3, alkyl, alkoxy, acylamino and alkylamino;
W se selecciona del grupo que consiste en un 20 enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a single link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
c) L=Cy–(CH2)m–W– c) L = Cy– (CH2) m – W–
en donde: 25 where: 25
Cy es alquilo C1–C15, aminoalquilo, heterocicloalquilo, cicloalquilo, arilo, ariloxi o heteroarilo, cada uno de los cuales puede estar opcionalmente sustituido con uno o varios sustituyentes seleccionados de modo independiente del grupo que 30 consiste en: halógeno, =O, =S, –CN, –NO2, –CF3, –OCF3, alquilo, alquenilo, alquinilo, haloalquilo, haloalquenilo, haloalquinilo, heteroalquilo, Cy is C1-C15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, = O, = S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl,
cicloalquilo, cicloalquenilo, heterocicloalquilo, heterocicloalquenilo, arilo, heteroarilo, hidroxi, hidroxialquilo, alcoxi, alcoxialquilo, alcoxiarilo, alcoxiheteroarilo, alqueniloxi, alquiniloxi, cicloalquiloxi, cicloalqueniloxi, heterocicloalquiloxi, 5 heterocicloalqueniloxi, ariloxi, heteroariloxi, arilalquilo, heteroarilalquilo, arilalquiloxi, amino, alquilamino, acilamino, aminoalquilo, arilamino, sulfonilo, alquilsulfonilo, arilsulfonilo, aminosulfonilo, aminoalquilo, alcoxialquilo, –COOH, 10 C(O)OR6, –COR5, –SH, –SR6, –OR6 y acilo; cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, 5 heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkyloxy, amino, alkylamino , acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, alkoxyalkyl, -COOH, 10 C (O) OR6, -COR5, -SH, -SR6, -OR6 and acyl;
m es 0, 1, 2, 3, 4 o 5; m is 0, 1, 2, 3, 4 or 5;
W se selecciona del grupo que consiste en un enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–15 C(O)–N(R10)–; W is selected from the group consisting of a simple link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N (R9 ) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –15 C (O) –N (R10) -;
d) L=L1–W–L2 d) L = L1 – W – L2
L1 y L2 son iguales o diferentes y están seleccionados, de modo independiente, de alquilo C1–C5, que puede estar opcionalmente sustituido con uno o 20 varios sustituyentes seleccionados de modo independiente del grupo que consiste en: halógeno; =O; =S; –CN; –NO2; –CF3, –OCF3, alquilo, alcoxi, acilamino, alquilamino; L1 and L2 are the same or different and are independently selected from C1-C5 alkyl, which may be optionally substituted with one or several substituents independently selected from the group consisting of: halogen; = O; = S; –CN; –NO2; –CF3, –OCF3, alkyl, alkoxy, acylamino, alkylamino;
W se selecciona del grupo que consiste en un 25 enlace simple, –O–, –S–, –S(O)–, –S(O)2–, –N(R9)–, –C(O)N(R9)–, –SO2N(R9)–, N(R9)C(O)–, N(R9)SO2– y –N(R9)–C(O)–N(R10)–; W is selected from the group consisting of a single link, –O–, –S–, –S (O) -, –S (O) 2–, –N (R9) -, –C (O) N ( R9) -, –SO2N (R9) -, N (R9) C (O) -, N (R9) SO2– and –N (R9) –C (O) –N (R10) -;
R9 y R10 son iguales o diferentes y están seleccionados, de modo independiente, de H, alquilo C1–C6, cicloalquilo C4–30 C9, heterocicloalquilo C4–C9, arilo, heteroarilo, arilalquilo, heteroarilalquilo; y acilo; R9 and R10 are the same or different and are independently selected from H, C1-C6 alkyl, C4-30 C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl; and acyl;
Z es –CH=CH– en la posición 5 y en configuración “E”; Z is –CH = CH– in position 5 and in “E” configuration;
o una de sus sales farmacéuticamente aceptables. or one of its pharmaceutically acceptable salts.
Tal como se usa en la presente, el término “no sustituido” significa que no hay sustituyentes o que los únicos sustituyentes son hidrógeno. As used herein, the term "unsubstituted" means that there are no substituents or that the only substituents are hydrogen.
“Halógeno” representa cloro, flúor, bromo o yodo. 5 "Halogen" represents chlorine, fluorine, bromine or iodine. 5
“Alquilo” como grupo o parte de un grupo se refiere a un grupo hidrocarbonado alifático lineal o ramificado, preferentemente un alquilo C1–C14, con mayor preferencia alquilo C1–C10, con máxima preferencia C1–C6, salvo que se indique otra cosa. Ejemplos de sustituyentes de alquilo C1–C6 10 lineales y ramificados apropiados incluyen metilo, etilo, n–propilo, 2–propilo, n–butilo, sec–butilo, t–butilo, hexilo y similares. "Alkyl" as a group or part of a group refers to a linear or branched aliphatic hydrocarbon group, preferably a C1-C14 alkyl, more preferably C1-C10 alkyl, most preferably C1-C6, unless otherwise indicated. Examples of suitable linear and branched C1-C6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl and the like.
“Alquilamino” incluye tanto monoalquilamino como dialquilamino, salvo que se especifique. “Monoalquilamino” 15 significa un grupo –NH–alquilo, “dialquilamino” significa un grupo –N(alquilo)2, en donde el alquilo es como se definió con anterioridad. El grupo alquilo es, con preferencia, un grupo alquilo C1–C6. "Alkylamino" includes both monoalkylamino and dialkylamino, unless specified. "Monoalkylamino" 15 means a group -NH-alkyl, "dialkylamino" means a group -N (alkyl) 2, wherein the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group.
“Arilamino” incluye tanto mono–arilamino como di–20 arilamino, salvo que se especifique. Mono–arilamino significa un grupo de fórmula aril–NH–, di–arilamino significa un grupo de fórmula (arilo2)N–, donde el arilo es como se define en la presente. "Arylamino" includes both mono-arylamino and di-20 arylamino, unless specified. Mono-arylamino means a group of formula aryl-NH–, di-arylamino means a group of formula (aryl2) N–, where aryl is as defined herein.
“Acilo” significa un grupo alquil–CO–, en donde el 25 grupo alquilo es como se describe en la presente. Ejemplos de acilo incluyen acetilo y benzoílo. El grupo alquilo es, con preferencia, un grupo alquilo C1–C6. "Acyl" means an alkyl-CO group, wherein the alkyl group is as described herein. Examples of acyl include acetyl and benzoyl. The alkyl group is preferably a C1-C6 alkyl group.
“Alquenilo” como grupo o parte de un grupo implica un grupo hidrocarbonado alifático que contiene al menos un doble 30 enlace carbono–carbono y que puede ser lineal o ramificado, preferentemente con 2–14 átomos de carbono, con mayor preferencia 2–12 átomos de carbono, con máxima preferencia, "Alkenyl" as a group or part of a group implies an aliphatic hydrocarbon group containing at least one double carbon-carbon bond and which can be linear or branched, preferably with 2–14 carbon atoms, more preferably 2–12 atoms carbon, most preferably,
2–6 átomos de carbono, en la cadena. El grupo puede contener una pluralidad de dobles enlaces en la cadena normal y la orientación respecto de ellos es, de modo independiente, E o Z. Los grupos alquenilo de ejemplo incluyen, pero sin limitación, etenilo y propenilo. 5 2–6 carbon atoms, in the chain. The group may contain a plurality of double bonds in the normal chain and the orientation thereto is, independently, E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl and propenyl. 5
“Alcoxi” se refiere a un grupo –O–alquilo, en donde el alquilo es como se definió en la presente. Con preferencia, el alcoxi es un alcoxi C1–C6. Ejemplos incluyen, pero sin limitación, metoxi y etoxi. "Alkoxy" refers to a group -O-alkyl, wherein the alkyl is as defined herein. Preferably, the alkoxy is a C1-C6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy.
“Alqueniloxi” se refiere a un grupo –O–alquenilo, en 10 donde el alquenilo es como se definió en la presente. Los grupos alqueniloxi preferidos son grupos alqueniloxi C1–C6. "Alkenyloxy" refers to a group -O-alkenyl, in which the alkenyl is as defined herein. Preferred alkenyloxy groups are C1-C6 alkenyloxy groups.
“Alquiniloxi” se refiere a un grupo –O–alquinilo, en donde el alquinilo es como se definió en la presente. Los grupos alquiniloxi preferidos son grupos alquiniloxi C1–C6. 15 "Alkynyloxy" refers to a group -O-alkynyl, wherein the alkynyl is as defined herein. Preferred alkynyloxy groups are C1-C6 alkynyloxy groups. fifteen
“Alcoxicarbonilo” se refiere a un grupo –C(O)–O–alquilo, en donde el alquilo es como se definió en la presente. El grupo alquilo es, con preferencia, un grupo alquilo C1–C6. Los ejemplos incluyen, pero sin limitación, metoxicarbonilo y etoxicarbonilo. 20 "Alkoxycarbonyl" refers to a group -C (O) -O-alkyl, wherein the alkyl is as defined herein. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. twenty
“Alquilsulfinilo” significa un grupo –S(O)–alquilo, en donde el alquilo es como se definió con anterioridad. El grupo alquilo es, con preferencia, un grupo alquilo C1–C6. Grupos de alquilsulfinilo de ejemplo incluyen, pero sin limitación, metilsulfinilo y etilsulfinilo. 25 "Alkylsulfinyl" means a group -S (O) -alkyl, wherein the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Exemplary alkylsulfinyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl. 25
“Alquilsulfonilo” se refiere a un grupo –S(O)2–alquilo, en donde el alquilo es como se definió con anterioridad. El grupo alquilo es, con preferencia, un grupo alquilo C1–C6. Los ejemplos incluyen, pero sin limitación metilsulfonilo y etilsulfonilo. 30 "Alkylsulfonyl" refers to a group -S (O) 2-alkyl, wherein the alkyl is as defined above. The alkyl group is preferably a C1-C6 alkyl group. Examples include, but are not limited to methylsulfonyl and ethylsulfonyl. 30
“Alquinilo como un grupo o parte de un grupo” significa un grupo hidrocarbonado alifático que contiene un enlace triple carbono–carbono y que puede ser lineal o ramificado, "Alkynyl as a group or part of a group" means an aliphatic hydrocarbon group that contains a carbon-carbon triple bond and which can be linear or branched,
preferentemente con 2–14 átomos de carbono, con mayor preferencia 2–12 átomos de carbono en la cadena, preferentemente 2–6 átomos de carbono en la cadena. Estructuras de ejemplo incluyen, pero sin limitación, etinilo y propinilo. 5 preferably with 2–14 carbon atoms, more preferably 2–12 carbon atoms in the chain, preferably 2–6 carbon atoms in the chain. Example structures include, but are not limited to, ethynyl and propynyl. 5
“Alquilaminocarbonilo” se refiere a un grupo alquilamino–carbonilo, en donde el alquilamino es como se definió con anterioridad. "Alkylaminocarbonyl" refers to an alkylaminocarbonyl group, wherein the alkylamino is as defined above.
“Cicloalquilo” se refiere a un carbociclo saturado o parcialmente saturado, monocíclico o fusionado o 10 espiropolicíclico, que preferentemente contiene de 3 a 9 carbonos por anillo, tales como ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo y similares, salvo que se especifique otra cosa. "Cycloalkyl" refers to a saturated or partially saturated carbocyclic, monocyclic or fused or 10 spiropolyclic, which preferably contains 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified.
El anterior análisis de los sustituyentes de alquilo y 15 cicloalquilo también se aplica a las porciones de alquilo de otros sustituyentes, tales como, sin limitación, sustituyentes de alcoxi, alquilaminas, alquilcetonas, arilalquilo, heteroarilalquilo, alquilsulfonilo y éster de alquilo y similares. 20 The above analysis of the alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as, without limitation, alkoxy, alkylamines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like. twenty
“Cicloalquilalquilo” significa un grupo cicloalquil–alquilo, en donde los restos de cicloalquilo y alquilo son como se describieron con anterioridad. Los grupos monocicloalquilalquilo de ejemplo incluyen ciclopropilmetilo, ciclopentilmetilo, ciclohexilmetilo y cicloheptilmetilo. 25 "Cycloalkylalkyl" means a cycloalkyl-alkyl group, wherein the cycloalkyl and alkyl moieties are as described above. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. 25
“Heterocicloalquilo” se refiere a un anillo que contiene de al menos un heteroátomo seleccionado de nitrógeno, azufre, oxígeno, preferentemente de 1 a 3 heteroátomos. Cada anillo tiene, con preferencia, de 3 a 4 miembros, con mayor preferencia de 4 a 7 miembros. Ejemplos 30 de sustituyentes de heterocicloalquilo apropiados incluyen pirrolidilo, tetrahidrofurilo, tetrahidrotiofuranilo, piperidilo, piperazilo, tetrahidropiranilo, morfilino, 1,3– "Heterocycloalkyl" refers to a ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms. Each ring preferably has 3 to 4 members, more preferably 4 to 7 members. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-
diazapan, 1,4–diazapan, 1,4–oxazepan y 1,4–oxatiapan. diazapan, 1,4-diazapan, 1,4-oxazepan and 1,4-oxatiapan.
“Heterocicloalquenilo” se refiere a un heterocicloalquilo como se describió con anterioridad, pero con al menos un doble enlace. "Heterocycloalkenyl" refers to a heterocycloalkyl as described above, but with at least one double bond.
“Heterocicloalquilalquilo” se refiere a un grupo 5 heterocicloalquil–alquilo, en donde los restos de heterocicloalquilo y alquilo son como se describieron previamente. Grupos heterocicloalquilalquilo de ejemplo incluyen (2–tetrahidrofuril)metilo, (2–tetrahidrotiofuranil)metilo. 10 "Heterocycloalkylalkyl" refers to a heterocycloalkyl-alkyl group, wherein the heterocycloalkyl and alkyl moieties are as previously described. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl) methyl, (2-tetrahydrothiofuranyl) methyl. 10
“Heteroalquilo” se refiere a un grupo alquilo de cadena lineal o de cadena ramificada que tiene preferentemente de 2 a 14 carbonos, con mayor preferencia 2 a 10 átomos en la cadena, uno o varios de los cuales son un heteroátomo seleccionado de S, O y N. Heteroalquilos de ejemplo incluyen 15 éteres de alquilo, alquilaminas secundarias y terciarias, sulfuros de alquilo y similares. "Heteroalkyl" refers to a straight chain or branched chain alkyl group having preferably 2 to 14 carbons, more preferably 2 to 10 atoms in the chain, one or more of which are a heteroatom selected from S, O and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkylamines, alkyl sulfides and the like.
“Arilo” como un grupo o parte de un grupo implica: (i) un carbocíclico monocíclico o policíclico fusionado, aromático, opcionalmente sustituido (estructura de anillo con 20 átomos de anillo que son todos carbonos) que preferentemente tiene de 5 a 12 átomos por anillo (ejemplos de grupos arilo incluyen fenilo, naftilo y similares); (ii) un resto carbocíclico aromático bicíclico opcionalmente sustituido, parcialmente saturado, en donde un grupo fenilo y un grupo 25 cicloalquilo C5–7 o cicloalquenilo C5–7 están fundidos juntos para formar una estructura cíclica, tal como tetrahidronaftilo, indenilo o indanilo. El grupo arilo puede estar sustituido por uno o varios grupos. "Aryl" as a group or part of a group implies: (i) a fused, aromatic, optionally substituted monocyclic or polycyclic carbocyclic (ring structure with 20 ring atoms that are all carbons) which preferably has 5 to 12 atoms per ring (examples of aryl groups include phenyl, naphthyl and the like); (ii) an optionally substituted, partially saturated bicyclic aromatic carbocyclic moiety, wherein a phenyl group and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The aryl group may be substituted by one or more groups.
“Arilalquenilo” significa un grupo aril–alquenilo–, en 30 donde el arilo y alquenilo son como se describieron previamente. Grupos arilalquenilo de ejemplo incluyen fenilalilo. "Arylalkenyl" means an aryl-alkenyl group, in which aryl and alkenyl are as previously described. Exemplary arylalkenyl groups include phenylalkyl.
“Arilalquilo” significa un grupo aril–alquilo–, en donde los restos arilo y alquilo son como se describieron previamente. Grupos arilalquilo preferidos contienen un resto de alquilo C1–5. Los grupos arilalquilo de ejemplo incluyen bencilo, fenetilo y naftelenmetilo. 5 "Arylalkyl" means an aryl-alkyl group, wherein the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthelemethyl. 5
“Cicloalquenilo” significa un sistema de anillos monocíclicos o multicíclicos no aromáticos, opcionalmente sustituidos, que contiene al menos un doble enlace carbono–carbono y que tiene preferentemente de 5 a 10 átomos de carbono por anillo. Los anillos cicloalquenilo monocíclicos 10 de ejemplo incluyen ciclopentenilo, ciclohexenilo o cicloheptenilo. El grupo cicloalquenilo puede estar sustituido con uno o varios grupos de sustituyentes. "Cycloalkenyl" means a non-aromatic, optionally substituted monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings 10 include cyclopentenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted with one or more substituent groups.
“Heteroarilo” se refiere a un heterociclo monocíclico o policíclico fusionado, aromático (estructura de anillo que 15 tiene preferentemente un anillo aromático de 5 a 7 miembros con uno o varios heteroátomos seleccionados de N, O y S). Típicos sustituyentes de heteroarilo incluyen furilo, tienilo, pirrol, pirazol, triazol, tiazol, oxazol, piridina, pirimidina, isoxazolilo, pirazina, indol, bencimidazol y 20 similares. "Heteroaryl" refers to a fused, aromatic monocyclic or polycyclic heterocycle (ring structure that preferably has a 5- to 7-membered aromatic ring with one or more heteroatoms selected from N, O and S). Typical heteroaryl substituents include furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazol, pyridine, pyrimidine, isoxazolyl, pyrazine, indole, benzimidazole and the like.
“Heteroarilalquilo” significa un grupo heteroaril–alquilo, en donde los restos de heteroarilo y alquilo son como se describieron previamente. Los grupos heteroarilalquilo preferidos contienen un resto de alquilo 25 inferior. Los grupos heteroarilalquilo de ejemplo incluyen piridilmetilo. "Heteroarylalkyl" means a heteroaryl-alkyl group, wherein the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
“Alquilo inferior” como un grupo significa, salvo que se especifique otra cosa, un grupo hidrocarbonado alifático que puede ser lineal o ramificado, que tiene 1 a 6 átomos de 30 carbono en la cadena, con mayor preferencia 1 a 4 carbonos, como ser metilo, etilo, propilo (n–propilo o isopropilo) o butilo (n–butilo, isobutilo o butilo terciario). "Lower alkyl" as a group means, unless otherwise specified, an aliphatic hydrocarbon group that can be linear or branched, having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary butyl).
En la fórmula (I), así como en las fórmulas (Ia) y (Ib) que definen subgrupos de compuestos dentro de fórmula (I), se muestra un sistema de anillo bencimidazol. Dentro de este sistema de anillos, hay posiciones sustituibles en las posiciones del anillo 4, 5, 6 y 7. En cada una de las 5 fórmulas (I), (Ia) y (Ib), existe el requisito de unir un resto de carácter ácido a una de las posiciones de anillo. Este resto de carácter ácido puede ser proporcionado, pero sin limitación, por grupos que contienen un ácido hidroxámico o derivados de sales de dicho ácido que, cuando se hidroliza, 10 proporcionaría el resto de carácter ácido. En determinadas formas de realización, el resto de carácter ácido puede estar unido a la posición del anillo a través de un grupo alquileno, como ser –CH2– o –CH2CH2–, o un grupo alquenilo como –CH=CH–. Las posiciones preferidas para la unión del 15 resto de carácter ácido son las posiciones de anillo 5 y 6. In formula (I), as well as in formulas (Ia) and (Ib) that define subgroups of compounds within formula (I), a benzimidazole ring system is shown. Within this ring system, there are substitutable positions in the positions of ring 4, 5, 6 and 7. In each of the 5 formulas (I), (Ia) and (Ib), there is a requirement to join a remainder of acid character to one of the ring positions. This acidic moiety may be provided, but not limited to, by groups containing a hydroxamic acid or salt derivatives of said acid which, when hydrolyzed, would provide the acidic moiety. In certain embodiments, the acidic moiety may be attached to the position of the ring through an alkylene group, such as -CH2- or -CH2CH2-, or an alkenyl group such as -CH = CH-. Preferred positions for joining the acidic residue are ring positions 5 and 6.
Se entiende que están incluidas en la familia de compuestos de fórmula (I) las formas isoméricas que incluyen diastereoisómeros, enantiómeros, tautómeros e isómeros geométricos en el isómero de configuración “E” o “Z” o una 20 mezcla de isómeros E y Z. También se entiende que algunas formas isoméricas tales como diastereoisómeros, enantiómeros e isómeros geométricos pueden ser separados por métodos físicos y/o químicos y por los expertos en la materia. It is understood that isomeric forms including diastereoisomers, enantiomers, tautomers and geometric isomers are included in the family of compounds of formula (I) in the "E" or "Z" configuration isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereoisomers, enantiomers and geometric isomers can be separated by physical and / or chemical methods and by those skilled in the art.
Algunos de los compuestos de las formas de realización 25 descritas pueden existir como estereoisómeros individuales, racematos y/o mezclas de enantiómeros y/o diastereoisómeros. Todos esos estereoisómeros individuales, racematos y mezclas de ellos pretenden estar dentro del alcance del objeto descrito y reivindicado. 30 Some of the compounds of the described embodiments may exist as individual stereoisomers, racemates and / or mixtures of enantiomers and / or diastereoisomers. All these individual stereoisomers, racemates and mixtures thereof are intended to be within the scope of the object described and claimed. 30
Además, la fórmula (I) pretende cubrir, cuando corresponde, las formas solvatadas y no solvatadas de los compuestos. En consecuencia, cada fórmula incluye compuestos In addition, formula (I) is intended to cover, where appropriate, the solvated and non-solvated forms of the compounds. Consequently, each formula includes compounds
con la estructura indicada, por ejemplo las formas hidratadas y no hidratadas. with the indicated structure, for example hydrated and non-hydrated forms.
Además de los compuestos de la fórmula, los agentes inhibidores de HDAC de las diversas formas de realización incluyen sales, profármacos y metabolitos activos 5 farmacéuticamente aceptables de tales compuestos, y sales farmacéuticamente aceptables de tales metabolitos. In addition to the compounds of the formula, the HDAC inhibitors of the various embodiments include pharmaceutically acceptable active salts, prodrugs and metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
El término “sales farmacéuticamente aceptables” se refiere a las sales que retienen la actividad biológica buscada de los compuestos antes identificados, e incluyen las 10 sales por adición de ácidos y las sales por adición de bases farmacéuticamente aceptables. Se pueden preparar sales por adición de ácidos adecuados farmacéuticamente aceptables de los compuestos de fórmula (I) a partir de un ácido inorgánico o a partir de un ácido orgánico. Entre los ejemplos de dichos 15 ácidos inorgánicos se cuentan ácido clorhídrico, sulfúrico y fosfórico. Los ácidos orgánicos apropiados se pueden seleccionar de las clases de ácidos orgánicos alifáticos, cicloalifáticos, aromáticos, carboxílicos heterocíclicos y sulfónicos, de los cuales son ejemplos los ácidos fórmico, 20 acético, propiónico, succínico, glicólico, glucónico, láctico, málico, tartárico, cítrico, fumárico, maleico, alquilsulfónico, arilsulfónico. Entre las sales por adición de bases de los compuestos de fórmula (I) se incluyen las sales metálicas preparadas a partir de litio, sodio, potasio, 25 magnesio, calcio, aluminio y zinc, y sales orgánicas preparadas a partir de bases orgánicas tales como colina, dietanolamina, morfolina. Otros ejemplos de sales orgánicas son: sales de amonio, sales cuaternarias tales como sal de tetrametilamonio; sales de adición de aminoácidos tales como 30 sales con glicina y arginina. Se puede hallar información adicional sobre sales farmacéuticamente aceptables en Remington’s Pharmaceutical Sciences, 18ª Edición, Mack The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the compounds identified above, and include the 10 salts by the addition of acids and the salts by the addition of pharmaceutically acceptable bases. Salts may be prepared by the addition of suitable pharmaceutically acceptable acids of the compounds of formula (I) from an inorganic acid or from an organic acid. Examples of said inorganic acids include hydrochloric, sulfuric and phosphoric acid. Appropriate organic acids may be selected from the classes of aliphatic, cycloaliphatic, aromatic, heterocyclic and sulfonic carboxylic acids, of which examples are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric acids, citric, fumaric, maleic, alkylsulfonic, arylsulfonic. Among the salts by adding bases of the compounds of formula (I) include metal salts prepared from lithium, sodium, potassium, magnesium, calcium, aluminum and zinc, and organic salts prepared from organic bases such as Choline, diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 18th Edition, Mack
Publishing Co., Easton, PA 1990. En el caso de los agentes que son sólidos, los expertos en la materia entienden que los compuestos de la invención, los agentes y las sales pueden existir en distintas formas cristalinas o polimórficas, todas las cuales pretenden estar dentro del alcance de la presente 5 invención y de las fórmulas especificadas. Publishing Co., Easton, PA 1990. In the case of agents that are solid, those skilled in the art understand that the compounds of the invention, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended be within the scope of the present invention and the specified formulas.
“Profármaco” significa un compuesto que es convertible in vivo por medios metabólicos (por ejemplo, por hidrólisis, reducción u oxidación) a un compuesto de fórmula (I). Por ejemplo, un profármaco éster de un compuesto de fórmula (I) 10 que contiene un grupo hidroxilo puede ser convertible por hidrólisis in vivo en la molécula progenitora. Los ésteres adecuados de los compuestos de fórmula (I) que contienen un grupo hidroxilo son por ejemplo acetatos, citratos, lactatos, tartratos, malonatos, oxalatos, salicilatos, propionatos, 15 succinatos, fumaratos, maleatos, metilen–bis––hidroxinaftoatos, gestisatos, isotionatos, di–p–toluiltartratos, metansulfonatos, etansulfonatos, bencensulfonatos, p–toluensulfonatos, ciclohexilsulfamatos y quinatos. Como otro ejemplo, un profármaco éster de un 20 compuesto de fórmula (I) que contiene un grupo carboxi puede ser convertible por hidrólisis in vivo en la molécula progenitora. (Son ejemplos de profármacos éster los descritos por F. J. Leinweber, Drug Metab. Res., 18:379, 1987). "Prodrug" means a compound that is convertible in vivo by metabolic means (for example, by hydrolysis, reduction or oxidation) to a compound of formula (I). For example, an ester prodrug of a compound of formula (I) 10 containing a hydroxyl group may be convertible by in vivo hydrolysis in the parent molecule. Suitable esters of the compounds of formula (I) containing a hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, smokers, maleates, methylene-bis--hydroxynaphtates, gestisates, isothionates, di-p-toluyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates. As another example, an ester prodrug of a compound of formula (I) containing a carboxy group can be convertible by in vivo hydrolysis in the parent molecule. (Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 18: 379, 1987).
Los posibles agentes inhibidores de HDAC incluyen los 25 que tienen un valor de IC50 de 1 M o inferior. Possible HDAC inhibitors include those that have an IC50 value of 1 µM or less.
La administración de los compuestos dentro de la fórmula (I) a humanos puede ser mediante cualquiera de los modos aceptados para la administración enteral, tales como oral o rectal, o por administración parenteral tal como las 30 vías subcutánea, intramuscular, intravenosa e intradérmica. La inyección puede ser en bolo o por infusión constante o intermitente. En general, el compuesto activo se incluye en The administration of the compounds within the formula (I) to humans can be by any of the modes accepted for enteral administration, such as oral or rectal, or by parenteral administration such as the subcutaneous, intramuscular, intravenous and intradermal routes. The injection can be bolus or by constant or intermittent infusion. In general, the active compound is included in
un portador o diluyente farmacéuticamente aceptable y en una cantidad suficiente para entregar al paciente una dosis terapéuticamente efectiva. En diversas formas de realización, el compuesto inhibidor puede ser selectivamente tóxico o más tóxico para las células de rápida proliferación, por ejemplo 5 tumores cancerosos, que para las células normales. a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, for example 5 cancerous tumors, than to normal cells.
El término “cantidad terapéuticamente efectiva” o “cantidad terapéutica” es una cantidad suficiente para producir resultados beneficiosos o buscados. Una cantidad efectiva se puede administrar en una o más administraciones. 10 En general, una cantidad efectiva es suficiente para paliar, aliviar, estabilizar, revertir, frenar o retrasar la progresión del estado patológico. The term "therapeutically effective amount" or "therapeutic amount" is an amount sufficient to produce beneficial or sought-after results. An effective amount can be administered in one or more administrations. 10 In general, an effective amount is sufficient to alleviate, relieve, stabilize, reverse, slow or slow the progression of the pathological state.
Para usar los compuestos de la invención, se pueden administrar en cualquier forma o modo que torna biodisponible 15 el compuesto. Un experto en la materia de preparar formulaciones puede seleccionar con facilidad la forma y el modo de administración adecuados, de acuerdo con las características particulares del compuesto seleccionado, la condición a tratar, el estado de la condición tratada y otras 20 circunstancias relevantes. Hágase referencia a Remingtons Pharmaceutical Sciences, 18ª edición, Mach Publishing Co. (1990) para información adicional. To use the compounds of the invention, they can be administered in any form or manner that makes the compound bioavailable. One skilled in the art of preparing formulations can easily select the appropriate form and mode of administration, according to the particular characteristics of the selected compound, the condition to be treated, the condition of the treated condition and other relevant circumstances. Reference Remingtons Pharmaceutical Sciences, 18th edition, Mach Publishing Co. (1990) for additional information.
Los compuestos de la presente invención se pueden administrar solos o bajo la forma de una composición 25 farmacéutica en combinación con un portador, diluyente o excipiente farmacéuticamente aceptable. Los compuestos de la invención, si bien son efectivos en sí mismos, en general se formulan y administran bajo la forma de sus sales farmacéuticamente aceptables, dado que en general estas sales 30 son más estables, cristalizan con mayor facilidad y tienen mayor solubilidad. The compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention, although effective in themselves, are generally formulated and administered in the form of their pharmaceutically acceptable salts, since in general these salts are more stable, crystallize more easily and have greater solubility.
Sin embargo, en general los compuestos se usan bajo la However, in general the compounds are used under the
forma de composiciones farmacéuticas que se formulan según el modo de administración de interés. Como tal, en otra forma de realización, la presente invención proporciona una composición farmacéutica que incluye un compuesto de fórmula (I) y un portador, diluyente o excipiente farmacéuticamente 5 aceptable. Las composiciones se preparan de formas bien conocidas en la materia. form of pharmaceutical compositions that are formulated according to the mode of administration of interest. As such, in another embodiment, the present invention provides a pharmaceutical composition that includes a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compositions are prepared in ways well known in the art.
Los compuestos de la invención se pueden usar o administrar en combinación con uno o más fármacos adicionales que son fármacos quimioterapéuticos o fármacos y/o 10 procedimientos inhibidores de HDAC (por ejemplo, cirugía, radioterapia) para el tratamiento del trastorno/enfermedad mencionado. Los componentes se pueden administrar en la misma formulación o en formulaciones distintas. Si se administran en formulaciones distintas, se pueden administrar los 15 compuestos de la invención en forma secuencial o simultánea con el o los otros fármacos. The compounds of the invention can be used or administered in combination with one or more additional drugs that are chemotherapeutic drugs or drugs and / or 10 HDAC inhibitor procedures (eg, surgery, radiotherapy) for the treatment of the mentioned disorder / disease. The components can be administered in the same formulation or in different formulations. If administered in different formulations, the 15 compounds of the invention can be administered sequentially or simultaneously with the other drug (s).
Las composiciones farmacéuticas de esta invención para la inyección parenteral comprenden soluciones, dispersiones, suspensiones o emulsiones acuosas o no acuosas estériles 20 farmacéuticamente aceptables, además de polvos estériles para la reconstitución en soluciones o dispersiones inyectables estériles justo antes del uso. Los ejemplos de portadores, diluyentes, solventes o vehículos acuosos y no acuosos adecuados incluyen agua, etanol, polioles (tales como 25 glicerol, propilenglicol, polietilenglicol y similares) y las correspondientes mezclas adecuadas, aceites vegetales (tales como aceite de oliva) y ésteres orgánicos inyectables tales como oleato de etilo. Se puede mantener la adecuada fluidez, por ejemplo, mediante el uso de materiales de cubierta tales 30 como lecitina, a través del mantenimiento del tamaño requerido de partículas, en el caso de dispersiones y mediante el uso de surfactantes. The pharmaceutical compositions of this invention for parenteral injection comprise sterile pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, in addition to sterile powders for reconstitution into sterile injectable solutions or dispersions just before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and corresponding suitable mixtures, vegetable oils (such as olive oil) and esters. Injectable organics such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of cover materials such as lecithin, by the maintenance of the required particle size, in the case of dispersions and by the use of surfactants.
Estas composiciones también pueden contener coadyuvantes tales como conservadores, agentes humectantes, agentes emulsionantes y agentes dispersantes. Se puede asegurar la prevención de la acción de los microorganismos mediante la inclusión de diversos agentes antibacterianos y 5 antifúngicos, por ejemplo parabeno, clorobutanol, ácido fenolsórbico y similares. También puede ser conveniente incluir agentes isotónicos tales como azúcares, cloruro de sodio y similares. La absorción prolongada de la forma farmacéutica inyectable se puede preparar mediante la 10 inclusión de agentes que retrasan la absorción, tales como monoestearato de aluminio y gelatina. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example paraben, chlorobutanol, phenolsorbic acid and the like. It may also be convenient to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be prepared by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.
Si se desea, y para una distribución más efectiva, se pueden incorporar los compuestos en sistemas de entrega de liberación lenta o dirigida tales como matrices poliméricas, 15 liposomas y microesferas. If desired, and for more effective distribution, the compounds can be incorporated into slow or directed delivery delivery systems such as polymer matrices, liposomes and microspheres.
Las formulaciones inyectables se pueden esterilizar, por ejemplo, por filtración a través de un filtro que retiene bacterias, o por la incorporación de agentes esterilizantes bajo la forma de composiciones sólidas estériles que se 20 pueden disolver o dispersar en agua estéril u otro medio inyectable estéril justo antes de su uso. Injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria, or by the incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium. just before use.
Las formas de dosificación sólidas para la administración oral incluyen cápsulas, comprimidos, píldoras, polvos y gránulos. En dichas formas de dosificación sólidas, 25 el compuesto activo se mezcla con al menos un excipiente o portador inerte farmacéuticamente aceptable tal como citrato de sodio o fosfato dicálcico y/o a) rellenos o extensores tales como almidones, lactosa, sacarosa, glucosa, manitol y ácido silícico, b) fijadores tales como, por ejemplo, 30 carboximetilcelulosa, alginatos, gelatina, polivinilpirrolidona, sacarosa y acacia, c) humectantes tales como glicerol, d) agentes desintegrantes tales como agar– Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert carrier or excipient such as sodium citrate or dicalcium phosphate and / or) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) fixatives such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar–
agar, carbonato de calcio, almidón de papa o tapioca, ácido algínico, ciertos silicatos y carbonato de sodio, e) agentes de retardo de solución tales como parafina, f) aceleradores de la absorción tales como compuestos de amonio cuaternario, g) agentes humectantes tales como, por ejemplo, alcohol 5 cetílico y monoestearato de glicerol, h) absorbentes tales como caolín y arcilla de bentonita e i) lubricantes tales como talco, estearato de calcio, estearato de magnesio, polietilenglicoles sólidos, laurilsulfato de sodio y sus mezclas. En el caso de las cápsulas, comprimidos y píldoras, 10 las formas de dosificación también pueden comprender agentes de amortiguación. agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Las composiciones sólidas de un tipo similar también se pueden utilizar como rellenos en cápsulas de gelatina blanda o dura mediante excipientes tales como lactosa o azúcar de 15 leche, además de polietilenglicoles de alto peso molecular y similares. Solid compositions of a similar type can also be used as fillers in soft or hard gelatin capsules by excipients such as lactose or milk sugar, in addition to high molecular weight polyethylene glycols and the like.
Las formas de dosificación sólida tales como comprimidos, grageas, cápsulas, píldoras y gránulos se pueden preparar con cubiertas y vainas tales como las cubiertas 20 entéricas y otras cubiertas bien conocidas en materia de formulación farmacéutica. Opcionalmente pueden contener agentes opacificantes, y también pueden tener una composición por la cual sólo liberan el o los ingredientes activos, o con preferencia, en cierta parte del tracto intestinal, 25 opcionalmente en forma retrasada. Entre los ejemplos de composiciones de inclusión que se pueden usar se cuentan sustancias poliméricas y ceras. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with covers and pods such as enteric covers and other covers well known in the field of pharmaceutical formulation. They may optionally contain opacifying agents, and they may also have a composition whereby only the active ingredient (s) is released, or preferably, in a certain part of the intestinal tract, optionally in a delayed form. Examples of inclusion compositions that can be used include polymeric substances and waxes.
Si se desea y para una distribución más efectiva, se pueden incorporar los compuestos en sistemas de entrega de 30 liberación lenta o dirigida, tales como matrices poliméricas, liposomas y microesferas. If desired and for a more effective distribution, the compounds can be incorporated into slow or directed delivery delivery systems, such as polymer matrices, liposomes and microspheres.
Los compuestos activos también pueden estar en forma The active compounds may also be in form.
microencapsulada, si corresponde, con uno o más de los excipientes antes mencionados. microencapsulated, if applicable, with one or more of the aforementioned excipients.
Las formas de dosificación líquida para la administración oral incluyen emulsiones, soluciones, suspensiones, jarabes y elíxires farmacéuticamente 5 aceptables. Además de los compuestos activos, las formas de dosificación líquida pueden contener diluyentes inertes de uso común en la materia tales como, por ejemplo, agua u otros solventes, agentes solubilizantes y emulsionantes tales como alcohol etílico, alcohol isopropílico, carbonato de etilo, 10 acetato de etilo, alcohol bencílico, benzoato de bencilo, propilenglicol, 1,3–butilenglicol, dimetilformamida, aceites (en particular, aceites de semillas de algodón, maní, maíz, germen, oliva, castor y sésamo), glicerol, alcohol tetrahidrofurfurílico, polietilenglicoles y ésteres de ácidos 15 grasos de sorbitano y mezclas de los mismos. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate. ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed oils, peanuts, corn, germ, olive, castor and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof.
Además de diluyentes inertes, las composiciones orales también pueden incluir coadyuvantes tales como agentes humectantes, agentes emulsionantes y de suspensión, agentes endulzantes, saborizantes y perfumantes. 20 In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. twenty
Las suspensiones, además de los componentes activos, pueden contener agentes de suspensión tales como, por ejemplo, alcoholes isoestearílicos etoxilados, polioxietilensorbitol y ésteres de sorbitano, celulosa microcristalina, metahidróxido de aluminio, bentonita, agar–25 agar y tragacanto, y sus mezclas. The suspensions, in addition to the active components, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-25 agar and tragacanth, and mixtures thereof.
Con preferencia, las composiciones para administración rectal o vaginal son supositorios que se pueden preparar mediante la mezcla de los compuestos de esta invención con excipientes o portadores no irritantes adecuados, tales como 30 manteca de cacao, polietilenglicol o una cera para supositorios que son sólidos a temperatura ambiente y líquidos a la temperatura del organismo, por lo que se funden Preferably, compositions for rectal or vaginal administration are suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax that are solid to ambient temperature and liquids at body temperature, so they melt
en el recto o la cavidad vaginal y liberan el componente activo. in the rectum or vaginal cavity and release the active component.
Las formas de dosificación para la administración tópica de un compuesto de la presente invención incluye polvos, parches, rocíos, ungüentos e inhalantes. El compuesto 5 activo se mezcla bajo condiciones de esterilidad con un portador farmacéuticamente aceptable y cualquier conservador, buffer o propulsores que se pudieran requerir. Dosage forms for topical administration of a compound of the present invention include powders, patches, sprays, ointments and inhalants. The active compound 5 is mixed under sterility conditions with a pharmaceutically acceptable carrier and any preservative, buffer or propellants that may be required.
Una dosificación preferida sería del rango de aproximadamente 0,01 a 300 mg por kilogramo de peso corporal 10 por día. Una dosificación de mayor preferencia estaría en el rango de 0,1 a 100 mg por kilogramo de peso corporal por día, con mayor preferencia desde 0,2 a 80 mg por kilogramo de peso corporal por día, con mayor preferencia aún desde 0,2 a 50 mg por kilogramo de peso corporal por día. Se puede administrar 15 una dosis adecuada en múltiples subdosis por día. A preferred dosage would be in the range of about 0.01 to 300 mg per kilogram of body weight 10 per day. A more preferred dosage would be in the range of 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, more preferably still from 0.2 at 50 mg per kilogram of body weight per day. An appropriate dose can be administered in multiple sub-doses per day.
Tal como se analizó antes, los compuestos de las formas de realización descritas inhiben las histona desacetilasas. La actividad enzimática de una histona desacetilasa se puede medir mediante metodologías conocidas [Yoshida M. et al, J. 20 Biol. Chem., 265, 17174 (1990); J. Taunton et al, Science 1996 272: 408]. En ciertas formas de realización, el inhibidor de histona desacetilasa interactúa y reduce la actividad de más de una histona desacetilasa conocida en la célula. En algunas otras formas de realización, el inhibidor 25 de histona desacetilasa interactúa y reduce predominantemente la actividad de una histona desacetilasa, por ejemplo HDAC–1, HDAC–3 o HDAC–8, que pertenecen a las enzimas HDAC clase I [De Ruijter A. J. M. et al, Biochem. J., 370, 737–749 (2003)]. Ciertos inhibidores preferidos de histona 30 desacetilasa son los que interactúan y reducen la actividad de una histona desacetilasa que interviene en la tumorigénesis, y estos compuestos pueden ser útiles para el As discussed above, the compounds of the described embodiments inhibit histone deacetylases. The enzymatic activity of a histone deacetylase can be measured by known methodologies [Yoshida M. et al, J. 20 Biol. Chem., 265, 17174 (1990); J. Taunton et al, Science 1996 272: 408]. In certain embodiments, the histone deacetylase inhibitor interacts and reduces the activity of more than one known histone deacetylase in the cell. In some other embodiments, histone deacetylase inhibitor 25 interacts and predominantly reduces the activity of a histone deacetylase, for example HDAC-1, HDAC-3 or HDAC-8, which belong to class I HDAC enzymes [De Ruijter AJM et al, Biochem. J., 370, 737-749 (2003)]. Certain preferred histone 30 deacetylase inhibitors are those that interact and reduce the activity of a histone deacetylase that is involved in tumorigenesis, and these compounds may be useful for the
tratamiento de enfermedades proliferativas. Entre los ejemplos de dichas enfermedades o condiciones de proliferación celular se incluyen cáncer y/o cualquier metástasis, psoriasis y restenosis. Los compuestos de la invención pueden ser de particular importancia para el 5 tratamiento de tumores tales como cáncer de mama, cáncer de pulmón, cáncer de ovario, cáncer de próstata, cáncer de cabeza y/o cuello, o cáncer renal, gástrico y cerebral. Además, los compuestos de la invención pueden ser útiles para el tratamiento de una enfermedad proliferativa que es 10 refractaria al tratamiento con otros agentes quimioterapéuticos; y para el tratamiento de condiciones hiperproliferativas tales como leucemias, psoriasis, restenosis. Treatment of proliferative diseases. Examples of such diseases or conditions of cell proliferation include cancer and / or any metastases, psoriasis and restenosis. The compounds of the invention may be of particular importance for the treatment of tumors such as breast cancer, lung cancer, ovarian cancer, prostate cancer, head and / or neck cancer, or renal, gastric and brain cancer. In addition, the compounds of the invention may be useful for the treatment of a proliferative disease that is refractory to treatment with other chemotherapeutic agents; and for the treatment of hyperproliferative conditions such as leukemia, psoriasis, restenosis.
Los compuestos adicionales de las distintas formas de 15 realización descritas en la presente pueden ser útiles para el tratamiento de enfermedades neurodegenerativas y enfermedades inflamatorias y/o enfermedades del sistema inmunitario. Additional compounds of the various embodiments described herein may be useful for the treatment of neurodegenerative diseases and inflammatory diseases and / or diseases of the immune system.
Con preferencia, el trastorno se selecciona del grupo 20 formado por cáncer, enfermedades inflamatorias y/o trastornos del sistema inmunitario (por ejemplo, artritis reumatoide, lupus eritematoso sistémico), angiofibroma, enfermedades cardiovasculares, enfermedades fibróticas, diabetes, enfermedades autoinmunes, enfermedades neurodegenerativas 25 crónicas y agudas como la enfermedad de Huntington, la enfermedad de Parkinson, las alteraciones del tejido nervioso y enfermedades infecciosas tales como las infecciones fúngicas, bacterianas y virales. En otra realización, el trastorno es un trastorno proliferativo. 30 Preferably, the disorder is selected from group 20 formed by cancer, inflammatory diseases and / or immune system disorders (eg rheumatoid arthritis, systemic lupus erythematosus), angiofibroma, cardiovascular diseases, fibrotic diseases, diabetes, autoimmune diseases, neurodegenerative diseases 25 chronic and acute such as Huntington's disease, Parkinson's disease, nervous tissue disorders and infectious diseases such as fungal, bacterial and viral infections. In another embodiment, the disorder is a proliferative disorder. 30
Los inhibidores de histona desacetilasa de la invención tienen significativos efectos antiproliferativos y favorecen la diferenciación, la detención del ciclo celular en las The histone deacetylase inhibitors of the invention have significant antiproliferative effects and favor differentiation, cell cycle arrest in the
fases G1 o G2 y la apoptosis. G1 or G2 phases and apoptosis.
Los agentes de las diversas formas de realización se pueden preparar mediante las vías de reacción y los esquemas de síntesis que se describen más adelante, que utilizan las 5 técnicas disponibles en la materia mediante materiales iniciales de fácil disponibilidad. La preparación de compuestos particulares de las formas de realización se describe en detalle en los siguientes ejemplos, pero el técnico reconocerá que las reacciones químicas descritas se 10 pueden adaptar con facilidad para preparar numerosos otros agentes de las diferentes formas de realización. Por ejemplo, se puede lograr con éxito la síntesis de compuestos no ejemplificados mediante modificaciones aparentes para los expertos en la materia, por ejemplo a través de grupos de 15 interferencia adecuadamente protectores, al modificarse a otros reactivos adecuados conocidos en la materia, o al hacer modificaciones de rutina de las condiciones de reacción. Se encuentra una lista de grupos protectores adecuados en la síntesis orgánica en el documento de T. W. Greene “Protective 20 Groups in Organic Synthesis”, John Wiley & Sons, 1981. Como alternativa, se reconocerán otras reacciones descritas en la presente o conocidas en la materia por su aplicabilidad para la preparación de otros compuestos de las diversas formas de realización. 25 The agents of the various embodiments can be prepared using the reaction pathways and synthesis schemes described below, which use the techniques available in the art by means of readily available initial materials. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the technician will recognize that the chemical reactions described can be easily adapted to prepare numerous other agents of the different embodiments. For example, the synthesis of non-exemplified compounds can be successfully achieved by apparent modifications to those skilled in the art, for example through suitably protective interference groups, by modifying to other suitable reagents known in the art, or by doing Routine modifications of reaction conditions. A list of suitable protecting groups in organic synthesis can be found in TW Greene's "Protective 20 Groups in Organic Synthesis" document, John Wiley & Sons, 1981. Alternatively, other reactions described herein or known in the art will be recognized. for its applicability for the preparation of other compounds of the various embodiments. 25
Los reactivos de utilidad para la síntesis de compuestos se pueden obtener o preparar de acuerdo con técnicas conocidas en la materia. Reagents useful for the synthesis of compounds can be obtained or prepared according to techniques known in the art.
A menos que se indique otra cosa, en los ejemplos descritos más adelante las temperaturas de las siguientes 30 descripciones están en grados Celsius y todas las partes y los porcentajes son en peso, a menos que se indique otra cosa. Unless otherwise indicated, in the examples described below the temperatures of the following 30 descriptions are in degrees Celsius and all parts and percentages are by weight, unless otherwise indicated.
Se adquirieron diversos materiales iniciales y otros reactivos de proveedores comerciales tales como ALDRICH CHEMICAL COMPANY o LANCASTER SYNTHESIS LTD. y se usaron sin ulterior purificación, a menos que se indique otra cosa. Se compraron tetrahidrofurano (THF) y N,N–dimetilformamida (DMF) 5 de ALDRICH en frascos SureSeal y se usaron como se recibieron. Todos los solventes se purificaron mediante métodos estándar en la materia a menos que se indica de otro modo. Various starting materials and other reagents were purchased from commercial suppliers such as ALDRICH CHEMICAL COMPANY or LANCASTER SYNTHESIS LTD. and were used without further purification, unless otherwise indicated. Tetrahydrofuran (THF) and N, N-dimethylformamide (DMF) 5 from ALDRICH were purchased in SureSeal bottles and used as received. All solvents were purified by standard methods in the art unless otherwise indicated.
Las reacciones expuestas más adelante se realizaron 10 bajo presión positiva de nitrógeno, argón o con un tubo de secado, a temperatura ambiente (a menos que se establezca otra cosa), en solventes anhidros, y los frascos de reacción de reacción se ajustan con tabiques de goma para introducir sustratos y reactivos mediante una jeringa. El material de 15 vidrio se secó en el horno y/o calor. Se realizó cromatografía analítica en capa fina sobre 254 placas de gel de sílice 60 F de base de vidrio (E Merck (0,25 mm)) y se eluyeron con las apropiadas relaciones de solventes (v/v). Las reacciones se ensayaron mediante TLC y se terminaron 20 según criterio por el consumo del material de inicio. The reactions set forth below were performed under positive pressure of nitrogen, argon or with a drying tube, at room temperature (unless otherwise stated), in anhydrous solvents, and the reaction reaction flasks are fitted with partitions. of rubber to introduce substrates and reagents by means of a syringe. The 15 glass material was dried in the oven and / or heat. Thin layer analytical chromatography was performed on 254 glass-based 60 F silica gel plates (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v / v). The reactions were tested by TLC and 20 were terminated according to criteria for the consumption of the starting material.
Las placas de TLC se visualizaron por absorción de UV o por reactivo en aerosol de p–anisaldehído o un reactivo de ácido fosfomolíbdico (Aldrich Chemical, 20% en peso de etanol) activado por calor, o por tinción en cámara de 25 yoduro. En general se realizaron trabajos por duplicación del volumen de reacción con el solvente de reacción o el solvente de extracción, y luego se lavaron con las soluciones acuosas indicadas mediante el 25% en volumen del volumen de extracción (a menos que se indique otra cosa). Las soluciones 30 de los productos se secaron sobre sulfato de sodio anhidro antes de la filtración y la evaporación de los solventes a presión reducida en un evaporador rotatorio, y se extrajeron The TLC plates were visualized by UV absorption or by aerosol reagent of p-anisaldehyde or a phosphomolibic acid reagent (Aldrich Chemical, 20% by weight ethanol) activated by heat, or by iodide chamber staining. In general, work was carried out by doubling the reaction volume with the reaction solvent or extraction solvent, and then washed with the indicated aqueous solutions by 25% by volume of the extraction volume (unless otherwise indicated) . The solutions 30 of the products were dried over anhydrous sodium sulfate before filtration and evaporation of the solvents under reduced pressure on a rotary evaporator, and extracted.
como solventes al vacío. Se realizó cromatografía flash en columna [Still et al, J. Org. Chem., 43, 2923 (1978)] con gel de sílice de grado E de Merck (47–61 mm) y una proporción de gel de sílice : material crudo de aproximadamente 20:1 a 50:1, a menos que se especifique otra cosa. Se realizó 5 hidrogenólisis a la presión indicada o a presión ambiente. As vacuum solvents. Flash column chromatography was performed [Still et al, J. Org. Chem., 43, 2923 (1978)] with Merck grade E silica gel (47–61 mm) and a ratio of silica gel: crude material of approximately 20: 1 to 50: 1, unless specified another thing. Hydrogenolysis was performed at the indicated pressure or at ambient pressure.
Se registraron espectros 1H RMN mediante un instrumento de Bruker que opera a 400 MHz y se registraron los espectros 13C–RMN operando a 100 MHz. Los espectros se RMN se obtienen como soluciones de CDCl3 (informados en ppm), con cloroformo 10 como estándar de referencia (7,25 ppm y 77,00 ppm) o CD3OD (3,4 y 4,8 ppm y 49,3 ppm), o un estándar interno de tetrametilsilano (0,00 ppm) cuando corresponda. Se usan otros solventes de RMN según necesidad. Cuando se informan multiplicidades de picos se utilizan las siguientes 15 abreviaturas: s = singulete, d = doblete, t = triplete, m = multiplete, br = ampliado, dd = doblete de dobletes, dt = doblete de tripletes. Las constantes de acoplamiento, cuando se dan, se informan en Hertz. 1H NMR spectra were recorded by a Bruker instrument operating at 400 MHz and 13C-NMR spectra operating at 100 MHz were recorded. NMR spectra are obtained as CDCl3 solutions (reported in ppm), with chloroform 10 as standard reference (7.25 ppm and 77.00 ppm) or CD3OD (3.4 and 4.8 ppm and 49.3 ppm), or an internal standard of tetramethylsilane (0.00 ppm) when applicable. Other NMR solvents are used as needed. When multiplicities of peaks are reported, the following 15 abbreviations are used: s = singlet, d = doublet, t = triplet, m = multiplet, br = extended, dd = doublet doublet, dt = doublet doublet. Coupling constants, when given, are reported in Hertz.
Se obtuvieron espectros de masa mediante LC/MS, ya sea 20 en ESI o en APCI. Todos los puntos de fusión se dan sin correcciones. Mass spectra were obtained by LC / MS, either in ESI or APCI. All melting points are given without corrections.
Todos los productos finales tenían una pureza superior al 90% (por HPLC con longitudes de onda de 220 nm y 254 nm). All final products had a purity greater than 90% (by HPLC with wavelengths of 220 nm and 254 nm).
Los siguientes ejemplos tienen por finalidad ilustrar 25 las formas de realización descritas y no para interpretarse como limitaciones. Se pueden preparar compuestos adicionales distintos de los descritos a continuación mediante el esquema de reacciones o las variaciones adecuadas o las correspondientes modificaciones. 30 The following examples are intended to illustrate the described embodiments and not to be construed as limitations. Additional compounds other than those described below can be prepared by the reaction scheme or suitable variations or corresponding modifications. 30
El esquema I ilustra el procedimiento usado para preparar compuestos de fórmula (Ib), en donde X e Y son Scheme I illustrates the procedure used to prepare compounds of formula (Ib), wherein X and Y are
hidrógenos, los compuestos (VI) de fórmula (Ia) pueden ser preparados por medio de un procedimiento análogo, por ejemplo, seleccionando el material de partida apropiado. Por ejemplo, en el caso de que Z sea –CH=CH– y está unido a la posición C5 en la fórmula (Ib), tales compuestos pueden 5 sintetizarse por medio de un método análogo ilustrado en el esquema I, partiendo con un ácido cinámico sustituido (por ejemplo, ácido trans–3–nitro–4–cloro–cinámico), componente de amina apropiado (R1NH2), componente de aldehído o ácido carboxílico (R2CHO o R2COOH) e hidroxilamina o N–10 alquilhidroxilamina apropiadas (NHR3OH, donde R3 es como se definió con anterioridad en la fórmula (Ia)). Hydrogens, the compounds (VI) of formula (Ia) can be prepared by an analogous process, for example, by selecting the appropriate starting material. For example, in the case where Z is –CH = CH– and is linked to the C5 position in formula (Ib), such compounds can be synthesized by means of an analogous method illustrated in Scheme I, starting with an acid substituted cinnamic (for example, trans-3-nitro-4-chloro-cinnamic acid), appropriate amine component (R1NH2), aldehyde or carboxylic acid component (R2CHO or R2COOH) and appropriate hydroxylamine or N-10 alkylhydroxylamine (NHR3OH, where R3 is as defined previously in formula (Ia)).
- Esquema I Scheme I
De modo específico, los compuestos de hidroxamato de fórmula (Ib) pueden sintetizarse a través de la ruta de 15 síntesis indicada en el esquema I. La reacción de ácido trans–4–cloro–3–nitrocinámico (I) con una amina en presencia de una base (por ejemplo, trietilamina) en un solvente apropiado (por ejemplo, dioxano) dio (II). El tratamiento de (II) en metanol bajo catálisis ácida (por ejemplo, ácido 20 sulfúrico) dio como resultado la esterificación que suministró (III). El grupo nitro de (III) puede ser reducido por medio de un agente de reducción apropiado (por ejemplo, Specifically, the hydroxamate compounds of formula (Ib) can be synthesized through the route of synthesis indicated in scheme I. The reaction of trans-4-chloro-3-nitrocinamic acid (I) with an amine in the presence of a base (for example, triethylamine) in an appropriate solvent (for example, dioxane) gave (II). Treatment of (II) in methanol under acid catalysis (for example, sulfuric acid) resulted in the esterification provided (III). The nitro group of (III) can be reduced by means of an appropriate reducing agent (for example,
cloruro de estaño) y la fenilendiamina resultante se ciclizó con un aldehído para dar (V). Los compuestos de hidroxamato (VI) se obtuvieron por medio de un método de síntesis conocido [J. Med. Chem., 2002, 45, 753–757]. Un método alternativo para preparar (VI) es por acoplamiento de (IV) 5 con un ácido apropiado y luego ciclación por calentamiento con ácido acético [J. Med. Chem. 2001, 44, 1516–1529]. tin chloride) and the resulting phenylenediamine was cyclized with an aldehyde to give (V). The hydroxamate compounds (VI) were obtained by means of a known synthesis method [J. Med. Chem., 2002, 45, 753-757]. An alternative method for preparing (VI) is by coupling (IV) 5 with an appropriate acid and then cyclization by heating with acetic acid [J. Med. Chem. 2001, 44, 1516–1529].
- Esquema II Scheme II
El esquema II ilustra otro procedimiento alternativo usado para preparar compuestos de fórmula (Ib), donde X e Y 10 son hidrógenos, R2=Cy–L1–W–L2. Por ejemplo, en el caso de que Z sea –CH=CH– y está unido a la posición C5 en la fórmula Scheme II illustrates another alternative procedure used to prepare compounds of formula (Ib), where X and Y 10 are hydrogens, R2 = Cy-L1-W-L2. For example, in the case that Z is –CH = CH– and is attached to position C5 in the formula
(Ib), tales compuestos (XV) pueden sintetizarse por medio de un método análogo ilustrado en el esquema II partiendo con (III) apropiado, aminoácidos Fmoc–protegidos apropiados, cloruros de ácidos apropiados o aldehídos e hidroxilamina. (Ib), such compounds (XV) can be synthesized by an analogous method illustrated in Scheme II starting with appropriate (III), appropriate Fmoc-protected amino acids, appropriate acid or aldehyde chlorides and hydroxylamine.
Más específicamente, por ejemplo, los compuestos de 5 hidroxamato de fórmula (Ib), donde X e Y son hidrógenos, R2=Cy–L1–W–L2 y Z está unido a la posición C5, pueden sintetizarse a través de la ruta de síntesis indicada en el esquema II. Los intermediarios apropiados (III) se redujeron con cloruro de estaño en las correspondientes diaminas (VII). 10 La reacción de acoplamiento con aminoácidos Fmoc–protegidos apropiados en presencia de PyBOP dio como resultado dos productos de acoplamiento (VIII) y (IX). Sin posterior separación, se sometió a (VIII) y (IX) a ciclación en condiciones ácidas y se obtuvo (X). El intermediario clave 15 (XI) puede obtenerse por tratamiento de (X) con 20% de piperidina. El tratamiento de (XI) con un cloruro de ácido apropiado o un cloruro de sulfonilo apropiado dio como resultado (XII) y se obtuvieron los compuestos objeto (XIII) usando un método similar descrito con anterioridad. 20 More specifically, for example, the hydroxamate compounds of formula (Ib), where X and Y are hydrogens, R2 = Cy-L1-W-L2 and Z is attached to the C5 position, can be synthesized through the path of synthesis indicated in scheme II. The appropriate intermediates (III) were reduced with tin chloride in the corresponding diamines (VII). 10 The coupling reaction with appropriate Fmoc-protected amino acids in the presence of PyBOP resulted in two coupling products (VIII) and (IX). Without further separation, (VIII) and (IX) were cyclized under acidic conditions and (X) was obtained. The key intermediate 15 (XI) can be obtained by treating (X) with 20% piperidine. Treatment of (XI) with an appropriate acid chloride or an appropriate sulfonyl chloride resulted in (XII) and the object compounds (XIII) were obtained using a similar method described above. twenty
Cuando (XI) se hizo reaccionar con un aldehído apropiado en condiciones de reducción (NaBH(OAc)3 / CH3COOH), se obtuvo (XIV) y puede transformarse en los correspondientes derivados de hidroxamato (XV) por medio de los mismos métodos descritos con anterioridad. 25 When (XI) was reacted with an appropriate aldehyde under reduction conditions (NaBH (OAc) 3 / CH3COOH), (XIV) was obtained and can be transformed into the corresponding hydroxamate derivatives (XV) by means of the same methods described with anteriority. 25
- Esquema III CHOH2NOOMeOMeHNOMeOOMeCO2HO2NClNONO2ClOOMeOMeR1NH2NONO2NHOOMeOMeR1HOHNONO2NHR1HOHNONNR2R1NaBH3CN, DCM/EtOH/AcOHDIC, DMAP, NMPDIEA, NMP, 60 °C95% TFA/DCMR2CHOSnCl2.2H2OMeOH/AcOHXVIXVIIXVIIIXIXVI Scheme III CHOH2NOOMeOMeHNOMeOOMeCO2HO2NClNONO2ClOOMeOMeR1NH2NONO2NHOOMeOMeR1HOHNONO2NHR1HOHNONNR2R1NaBH3CN, DCM / EtOH / AcOHDIC, DMAP, NMPDIEA, NMP, 2eXVIX, 2 ° CVIVIHIV, 2 ° CVIVI, OHVI, VIXVI, 2 OHV, OHVI, OHVI
Los compuestos de hidroxamato de fórmula (I) también pueden prepararse a través de una síntesis de fase sólida. El esquema III ilustra la síntesis de los compuestos de hidroxamato de fórmula (Ib). Por ejemplo, en el caso de que Z 5 sea –CH=CH– y esté unido a la posición C5, en la fórmula (Ib), tales compuestos (VI) pueden sintetizarse por medio de un método análogo ilustrado en el esquema III partiendo de resina SASRIN, una hidroxilamina apropiada (por ejemplo, O–(2,4–dimetoxi–fenil)–hidroxilamina), un ácido cinámico 10 apropiado (por ejemplo, ácido trans–4–cloro–3–nitro–cinámico), una amina apropiada y un aldehído. The hydroxamate compounds of formula (I) can also be prepared through a solid phase synthesis. Scheme III illustrates the synthesis of the hydroxamate compounds of formula (Ib). For example, in the case that Z 5 is –CH = CH– and is attached to position C5, in formula (Ib), such compounds (VI) can be synthesized by means of an analogous method illustrated in Scheme III starting from of SASRIN resin, an appropriate hydroxylamine (for example, O– (2,4-dimethoxy-phenyl) -hydroxylamine), an appropriate cinnamic acid (for example, trans-4-chloro-3-nitro-cinnamic acid), a appropriate amine and an aldehyde.
Específicamente, por ejemplo los compuestos de hidroxamato (VI) de fórmula (Ib) pueden sintetizarse a través de la ruta de síntesis indicada en el esquema IV. La resina 15 SASRIN tratada con O–(2,4–dimetoxi–fenil)–hidroxilamina en condiciones reductivas (NaBH3CN/CH3COOH) en un solvente apropiado dio el correspondiente compuesto (XVI). Se hizo reaccionar (XVI) con ácido trans–4–cloro–3–nitro–cinámico en Specifically, for example the hydroxamate (VI) compounds of formula (Ib) can be synthesized through the synthesis route indicated in scheme IV. SASRIN resin treated with O– (2,4-dimethoxy-phenyl) -hydroxylamine under reductive conditions (NaBH3CN / CH3COOH) in an appropriate solvent gave the corresponding compound (XVI). (XVI) was reacted with trans-4-chloro-3-nitro-cinnamic acid in
presencia de 4–dimetilaminopiridina para obtener (XVII). Un posterior tratamiento de (XVII) con aminas apropiadas dio como resultado (XVIII). Se trató (XIX) por escisión de la correspondiente resina (XVIII). Sin posterior purificación, se transformó (XIX) en los correspondientes compuestos de 5 hidroxamato (VI) usando el método descrito con anterioridad. presence of 4-dimethylaminopyridine to obtain (XVII). A subsequent treatment of (XVII) with appropriate amines resulted in (XVIII). It was treated (XIX) by cleavage of the corresponding resin (XVIII). Without further purification, (XIX) was transformed into the corresponding hydroxamate compounds (VI) using the method described above.
- Esquema IV Scheme IV
El esquema IV ilustra otro procedimiento para preparar los compuestos de hidroxamato de fórmula (I). Por ejemplo, en el caso de que Z sea –CH2CH2– y esté unido a la posición C5 en 10 la fórmula (Ib), tales compuestos pueden sintetizarse por medio de un método análogo ilustrado en el esquema IV partiendo con los intermediarios apropiados (V) a través de reducción y luego el producto resultante (XX) puede transformarse en los correspondientes compuestos de 15 hidroxamato (XXI) de fórmula (Ib). Los compuestos (XXIII), en los que Z es un grupo ciclopropileno () y está unido a la posición C5 en la fórmula (Ib), pueden ser preparados a partir de V por tratamiento con (CH3)3S(O)I, y los derivados de ciclopropilo resultantes (XXII) se convirtieron en los 20 correspondientes derivados de hidroxamato (XXIII) de acuerdo con los métodos descritos con anterioridad para la preparación de ácido hidroxámico. Scheme IV illustrates another process for preparing the hydroxamate compounds of formula (I). For example, in the case where Z is –CH2CH2– and formula (Ib) is attached to position C5 in 10, such compounds can be synthesized by an analogous method illustrated in Scheme IV starting with the appropriate intermediates (V ) through reduction and then the resulting product (XX) can be transformed into the corresponding compounds of hydroxamate (XXI) of formula (Ib). The compounds (XXIII), in which Z is a cyclopropylene group () and is attached to the C5 position in the formula (Ib), can be prepared from V by treatment with (CH3) 3S (O) I, and The resulting cyclopropyl derivatives (XXII) were converted into the corresponding hydroxamate derivatives (XXIII) according to the methods described above for the preparation of hydroxamic acid.
- Esquema V NHOHOH2NR1NHOHOO2NR1OHOHNNSOONNSSnCl2AcOH/MeOHNH2OH.HClNaOCH3CS2/MeOHR1R1R15R15NHONNSR1R15OHOONNSR1R15R15ONHONNSR1R15OHOH2O2/CH3COOHNH2OH.HClNaOCH3IIXXIVXXVXXVIXXVIIXXVIIIXXIX Scheme V NHOHOH2NR1NHOHOO2NR1OHOHNNSOONNSSnCl2AcOH / MeOHNH2OH.HClNaOCH3CS2 / MeOHR1R1R15R15NHONNSR1R15OHOONNSR1R15R15ONHONNSR1R15OHOH2O2 / CH3COOHNH2OH.HClNaOCH3IIXXIVXXVXXVIXXVIIXXVIIIXXIX
El esquema V ilustra otro procedimiento de síntesis de los compuestos de hidroxamato de fórmula (I). Por ejemplo, en el caso de que Z sea –CH=CH– y esté unido a la posición C5 en la fórmula (Ib), tales compuestos pueden sintetizarse por 5 medio de un método análogo ilustrado en el esquema V partiendo con los intermediarios apropiados (II) a través de reducción y luego el producto resultante (XXIV) se ciclizó, sin posterior purificación, para dar (XXV). El (XXV) se trató con un halogenuro de alquilo apropiado (por ejemplo, bromuro 10 de bencilo) en presencia de una base inorgánica (por ejemplo, carbonato de sodio) en un solvente apropiado para dar (XXVI). El tratamiento de (XXVI) con peróxido de hidrógeno en ácido acético condujo a (XXVIII). Utilizando el mismo método que se describió previamente, tanto (XXVI) como (XXVIII) se 15 transformaron en los correspondientes compuestos de hidroxamato (XXVII) y (XXIX), respectivamente. Scheme V illustrates another method of synthesis of the hydroxamate compounds of formula (I). For example, in the case where Z is –CH = CH– and is linked to the C5 position in formula (Ib), such compounds can be synthesized by means of an analogous method illustrated in Scheme V starting with the appropriate intermediates (II) through reduction and then the resulting product (XXIV) was cyclized, without further purification, to give (XXV). The (XXV) was treated with an appropriate alkyl halide (for example, benzyl bromide) in the presence of an inorganic base (for example, sodium carbonate) in a suitable solvent to give (XXVI). Treatment of (XXVI) with hydrogen peroxide in acetic acid led to (XXVIII). Using the same method as previously described, both (XXVI) and (XXVIII) were transformed into the corresponding hydroxamate compounds (XXVII) and (XXIX), respectively.
La siguiente preparación y los siguientes ejemplos se brindan para permitir a los especialistas en la materia una comprensión más clara y para poner en práctica el objeto de 20 The following preparation and the following examples are provided to allow specialists in the field a clearer understanding and to implement the purpose of
la presente. No deberían considerar limitativo el alcance de la descripción, sino meramente ilustrativo y representativo de ella. the present. They should not consider the scope of the description to be limiting, but merely illustrative and representative of it.
Ejemplo 1 Example 1
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–(2–fenil–5 propil)–1H–bencimidazol–5–il]–acrilamida (1) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2- (2-phenyl-5 propyl) -1H-benzimidazol-5-yl] -acrylamide (1)
Etapa 1 Stage 1
A una solución previamente agitada de ácido trans–4–cloro–3–nitrocinámico (1,0 g, 4,4 mmol) en dioxano (10 ml) se añadió trietilamina (2 ml), 3–amino–1–propanol (1,5 ml). La 10 solución resultante se calentó hasta 85C durante 19 horas y luego se enfrió hasta temperatura ambiente. El solvente se eliminó al vacío. Se añadió agua (100 ml) al residuo y el pH se ajustó hasta 1–1,5. El precipitado se recogió y se lavó con agua fría 2 veces y se secó. El producto ácido 3–[3–15 nitro–4–(hidroxipropilamina)–fenil]–acrílico se obtuvo en forma de sustancia sólida de color amarillo (1,10 g, 95%). MS (m/z): 267 (MH)+. To a previously stirred solution of trans-4-chloro-3-nitrocinamic acid (1.0 g, 4.4 mmol) in dioxane (10 ml) was added triethylamine (2 ml), 3-amino-1-propanol (1 , 5 ml). The resulting solution was heated to 85 ° C for 19 hours and then cooled to room temperature. The solvent was removed in vacuo. Water (100 ml) was added to the residue and the pH was adjusted to 1–1.5. The precipitate was collected and washed with cold water 2 times and dried. The 3– [3–15 nitro – 4– (hydroxypropylamine) -phenyl] -acrylic acid product was obtained as a yellow solid substance (1.10 g, 95%). MS (m / z): 267 (MH) +.
Etapa 2 Stage 2
Se añadió ácido sulfúrico concentrado (0,5 ml) a la 20 solución de ácido trans–4–(3–hidroxipropilamina)–3–nitrocinámico, (1,10 g, 3,9 mmol) y MeOH (15 ml). La solución resultante se calentó hasta reflujo durante 18 horas. La mezcla de reacción se enfrió a –10 hasta –15C durante 3 horas. Se recogió éster metílico del ácido 3–[3–nitro–4–25 (hidroxipropilamina)–fenil]–acrílico como una sustancia sólida cristalina de color amarillo (1,06 g, 91%). MS (m/z): 281 (MH)+. Concentrated sulfuric acid (0.5 ml) was added to the solution of trans-4– (3-hydroxypropylamine) -3-nitrocinamic acid, (1.10 g, 3.9 mmol) and MeOH (15 ml). The resulting solution was heated to reflux for 18 hours. The reaction mixture was cooled to –10 to –15C for 3 hours. 3– [3-Nitro-4–25 (hydroxypropylamine) -phenyl] -acrylic acid methyl ester was collected as a yellow crystalline solid substance (1.06 g, 91%). MS (m / z): 281 (MH) +.
Etapa 3 Stage 3
A una solución previamente agitada de trans–4–(3–30 hidroxipropilamina)–3–nitrocinamato de metilo (280 mg, 1,0 mmol) y 3–fenilbutiraldehído (500 mg, 3,4 mmol) en ácido acético glacial (5 ml), se añadió cloruro de estaño (1,18 g, To a previously stirred solution of trans – 4– (3–30 hydroxypropylamine) –3-methyl nitrocinamate (280 mg, 1.0 mmol) and 3-phenylbutyraldehyde (500 mg, 3.4 mmol) in glacial acetic acid (5 ml), tin chloride (1.18 g,
10,0 mmol). La solución resultante se calentó hasta 45C durante 17 horas y luego se enfrió hasta temperatura ambiente. El solvente se eliminó al vacío. Se añadieron agua (20 ml) y diclorometano (20 ml) al residuo y se agitó durante 30 minutos. La capa orgánica se secó (MgSO4), se filtró y se 5 concentró en un residuo oleoso. Se añadieron 100 ml de éter dietílico y se agitó durante 4 horas. El producto éster metílico del ácido 3–[1–(3–hidroxi–propil)–2–(2–fenil–propil)–1H–bencimidazol–5–il]–acrílico se obtuvo con un rendimiento del 34,9% (132,0 mg). MS (m/z): 379 (MH)+. 10 10.0 mmol). The resulting solution was heated to 45 ° C for 17 hours and then cooled to room temperature. The solvent was removed in vacuo. Water (20 ml) and dichloromethane (20 ml) were added to the residue and stirred for 30 minutes. The organic layer was dried (MgSO4), filtered and concentrated in an oily residue. 100 ml of diethyl ether was added and stirred for 4 hours. The methyl ester product of 3– [1– (3-hydroxy-propyl) -2- (2-phenyl-propyl) -1H-benzimidazol-5-yl] -acrylic acid was obtained in a yield of 34.9% ( 132.0 mg). MS (m / z): 379 (MH) +. 10
Etapa 4 Stage 4
Se añadió metóxido de sodio (30% en metanol) (782 mg, 4,1 mmol) a una solución previamente agitada de éster metílico del ácido 3–[1–(3–hidroxi–propil)–2–(2–fenil–propil)–1H–bencimidazol–5–il]–acrílico (130 mg, 0,34 mmol y 15 clorhidrato de hidroxilamina (242 mg, 3,4 mmol en MeOH (1,5 ml). La mezcla de reacción se agitó de manera continua durante 40 minutos a temperatura ambiente y luego se vertió en una solución de agua helada que contenía 1,0 ml de ácido clorhídrico concentrado. La mezcla se extrajo con 20 diclorometano. La capa orgánica se secó (MgSO4), se filtró y se concentró. El producto deseado se separó por HPLC preparativa de fase inversa. Tras liofilizar, se obtuvieron 7,8 mg (6%) de N–hidroxi–3–[1–(3–hidroxi–propil)–2–(2–fenil–propil)–1H–bencimidazol–5–il]–acrilamida en forma de polvo. 25 HPLC: 96%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 7,22 min; 92%. 1H RMN (400 MHz, DMSO–d6) 1,35 (3H, d, J = 30 6,5 Hz), 1,83 (2H, m), 3,00–4,00 (6H, m), 4,33 (2H, t, J = 7,1 Hz), 6,55 (1H, d, J = 15,8 Hz), 7,19–7,33 (5H, m), 7,62 Sodium methoxide (30% in methanol) (782 mg, 4.1 mmol) was added to a previously stirred solution of 3– [1– (3-hydroxy-propyl) -2- (2-phenyl) methyl ester propyl) -1H-benzimidazol-5-yl] -acrylic (130 mg, 0.34 mmol and 15 hydroxylamine hydrochloride (242 mg, 3.4 mmol in MeOH (1.5 ml). The reaction mixture was stirred from continuously for 40 minutes at room temperature and then poured into a solution of ice water containing 1.0 ml of concentrated hydrochloric acid.The mixture was extracted with dichloromethane.The organic layer was dried (MgSO4), filtered and concentrated The desired product was separated by preparative reverse phase HPLC After lyophilization, 7.8 mg (6%) of N-hydroxy-3– [1– (3-hydroxy-propyl) -2- (2– phenyl-propyl) -1H-benzimidazol-5-yl] -acrylamide in powder form 25 HPLC: 96%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B during 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid, solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.22 min; 92% 1 H NMR (400 MHz, DMSO – d6) 1.35 (3H, d, J = 30 6.5 Hz), 1.83 (2H, m), 3.00–4.00 (6H, m), 4.33 (2H, t, J = 7.1 Hz), 6.55 (1H, d, J = 15.8 Hz), 7.19–7.33 (5H, m), 7.62
(1H, d, J = 15,8 Hz), 7,70 (1H, d, J = 8,60 Hz), 7,82 (1H, d, J = 8,60 Hz), 7,92 (1H, s), 10,15 (1H, bs), 10,33 (1H, bs). MS (m/z): 380 [MH]+. (1H, d, J = 15.8 Hz), 7.70 (1H, d, J = 8.60 Hz), 7.82 (1H, d, J = 8.60 Hz), 7.92 (1H , s), 10.15 (1H, bs), 10.33 (1H, bs). MS (m / z): 380 [MH] +.
Ejemplo 2 Example 2
Preparación de N–hidroxi–3–[1–(3,4,5–trimetoxibencil)–2–(2–5 fenil–etil)–1H–bencimidazol–5–il]–acrilamida (2) Preparation of N-hydroxy-3– [1– (3,4,5-trimethoxybenzyl) –2– (2–5 phenyl-ethyl) –1H-benzimidazol-5-yl] -acrylamide (2)
El compuesto del título (2) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 91%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 10 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 7,22 min. 1H RMN (400 MHz, DMSO–d6) 3,08 (2H, t, J = 7,72 Hz), 3,48 (2H, t, 7,72 Hz), 3,63 (3H, s), 3,67 (6H, s), 5,58 (2H, s), 6,59 (2H, 15 s), 7,22–7,31 (7H, m), 7,63 (1H, d, J = 15,78 Hz), 7,71 (1H, d, J = 8,76 Hz), 7,83 (1H, d, J = 8,76 Hz), 7,98 (1H, s), 11,00 (2H, bs). MS (m/z): 488 [MH]+. The title compound (2) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 91%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 10 gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.22 min. 1 H NMR (400 MHz, DMSO – d6) 3.08 (2H, t, J = 7.72 Hz), 3.48 (2H, t, 7.72 Hz), 3.63 (3H, s), 3.67 (6H, s), 5.58 (2H, s), 6.59 (2H, 15 s), 7.22–7.31 (7H, m), 7.63 (1H, d, J = 15.78 Hz), 7.71 (1H, d, J = 8.76 Hz), 7.83 (1H, d, J = 8.76 Hz), 7.98 (1H, s), 11, 00 (2H, bs). MS (m / z): 488 [MH] +.
Ejemplo 3 Example 3
Preparación de N–hidroxi–3–[2–(4–benciloxi–3–metoxi–fenil)–1–20 metil–1H–bencimidazol–5–il]–acrilamida (3) Preparation of N-hydroxy-3– [2– (4-benzyloxy-3-methoxy-phenyl) –1–20 methyl-1H-benzimidazol-5-yl] -acrylamide (3)
El compuesto del título (3) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 92%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 25 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 7,32 min. 1H RMN (400 MHz, DMSO–d6) 3,87 (3H, s), 4,01 (3H, s), 5,24 (2H, s), 6,56 (1H, d, J = 15,80 Hz), 7,32–7,50 (8H, m), 7,74 (1H, 30 d, J = 8,72 Hz), 7,88 (1H, d, J = 8,72 Hz), 7,94 (1H, s), 10,85 (1H, bs). MS (m/z): 431 [MH]+. The title compound (3) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 92%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 25 gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.32 min. 1H NMR (400 MHz, DMSO – d6) 3.87 (3H, s), 4.01 (3H, s), 5.24 (2H, s), 6.56 (1H, d, J = 15, 80 Hz), 7.32–7.50 (8H, m), 7.74 (1H, 30 d, J = 8.72 Hz), 7.88 (1H, d, J = 8.72 Hz), 7.94 (1H, s), 10.85 (1H, bs). MS (m / z): 431 [MH] +.
Ejemplo 4 Example 4
Preparación de N–hidroxi–3–[2–(4–benciloxi–3–metoxi–fenil)–1–(3–hidroxi–propil)–1H–bencimidazol–5–il]–acrilamida (4) Preparation of N-hydroxy-3– [2– (4-benzyloxy-3-methoxy-phenyl) –1– (3-hydroxy-propyl) –1H-benzimidazol-5-yl] -acrylamide (4)
El compuesto del título (4) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los 5 materiales de partida apropiados. HPLC: 95%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 6,82 min. 1H RMN 10 (400 MHz, DMSO–d6) 1,96 (2H, m), 3,88 (3H, s), 4,48 (2H, t, J = 7,12 Hz), 5,24 (2H, s), 6,56 (1H, d, J = 15,76 Hz), 7,32–7,50 (8H, m), 7,65 (1H, d, J = 15,76 Hz), 7,74 (1H, d, J = 8,60 Hz), 7,91 (1H, d, J = 8,60 Hz), 7,95 (1H, s), 10,85 (1H, bs). MS (m/z): 474 [MH]+. 15 The title compound (4) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 95%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 6.82 min. 1 H NMR 10 (400 MHz, DMSO – d6) 1.96 (2H, m), 3.88 (3H, s), 4.48 (2H, t, J = 7.12 Hz), 5.24 ( 2H, s), 6.56 (1H, d, J = 15.76 Hz), 7.32–7.50 (8H, m), 7.65 (1H, d, J = 15.76 Hz), 7.74 (1H, d, J = 8.60 Hz), 7.91 (1H, d, J = 8.60 Hz), 7.95 (1H, s), 10.85 (1H, bs). MS (m / z): 474 [MH] +. fifteen
Ejemplo 5 Example 5
Preparación de N–hidroxi–3–[1–(2–hidroxi–etil)–2–(4–metoxi–fenil)–1H–bencimidazol–5–il]–acrilamida (5) Preparation of N-hydroxy-3– [1– (2-hydroxy-ethyl) -2- (4-methoxy-phenyl) -1H-benzimidazol-5-yl] -acrylamide (5)
El compuesto del título (5) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los 20 materiales de partida apropiados. HPLC: 98%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 4,12 min. 1H RMN 25 (400 MHz, DMSO–d6) 3,80 (2H, t, J = 5,36 Hz), 3,87 (3H, s), 4,39 (2H, t, J = 5,36 Hz), 6,56 (1H, d, 15,72 Hz), 7,17 (2H, d, J = 8,88 Hz), 7,61 (1H, d, J = 8,52 Hz), 7,62 (1H, d, J = 15,72 Hz), 7,78 (1H, d, J = 8,52 Hz), 7,88 (1H, d, J = 8,88 Hz), 7,90 (1H, s), 10,77 (1H, bs). MS (m/z): 354 [MH]+. 30 The title compound (5) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 4.12 min. 1H NMR 25 (400 MHz, DMSO – d6) 3.80 (2H, t, J = 5.36 Hz), 3.87 (3H, s), 4.39 (2H, t, J = 5.36 Hz), 6.56 (1H, d, 15.72 Hz), 7.17 (2H, d, J = 8.88 Hz), 7.61 (1H, d, J = 8.52 Hz), 7 , 62 (1H, d, J = 15.72 Hz), 7.78 (1H, d, J = 8.52 Hz), 7.88 (1H, d, J = 8.88 Hz), 7.90 (1H, s), 10.77 (1H, bs). MS (m / z): 354 [MH] +. 30
Ejemplo 6 Example 6
Preparación de N–hidroxi–3–[1–(2,3–hidroxi–propil)–2–(4–Preparation of N-hydroxy-3– [1– (2,3-hydroxy-propyl) –2– (4–
metoxi–fenil)–1H–bencimidazol–5–il]–acrilamida (6) methoxy-phenyl) -1H-benzimidazol-5-yl] -acrylamide (6)
El compuesto del título (6) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 98%, tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 5 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,39 min. RMN (400 MHz, DMSO–d6) 3,90 (3H, s), 4,01 (1H, m), 4,35 (2H, m), 4,58 (2H, dd, J = 2,48 y 14,48 Hz), 6,62 (1H, d, J = 15,84 10 Hz), 7,27 (2H, d, J = 8,92 Hz), 7,68 (1H, d, J = 15,84 Hz), 8,01(4H, m), 10,13 (1H, bs). MS (m/z): 383 [M]+. The title compound (6) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98%, tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 5 gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.39 min. NMR (400 MHz, DMSO – d6) 3.90 (3H, s), 4.01 (1H, m), 4.35 (2H, m), 4.58 (2H, dd, J = 2.48 and 14.48 Hz), 6.62 (1H, d, J = 15.84 10 Hz), 7.27 (2H, d, J = 8.92 Hz), 7.68 (1H, d, J = 15.84 Hz), 8.01 (4H, m), 10.13 (1H, bs). MS (m / z): 383 [M] +.
Ejemplo 7 Example 7
Preparación de N–hidroxi–3–[2–(4–benciloxi–3–metoxi–fenil)–1–(2,3–hidroxi–propil)–1H–bencimidazol–5–il]–acrilamida (7) 15 Preparation of N-hydroxy-3– [2– (4-benzyloxy-3-methoxy-phenyl) -1- (2,3-hydroxy-propyl) -1H-benzimidazol-5-yl] -acrylamide (7) 15
El compuesto del título (7) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 100%, tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 20 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,06 min. RMN (400 MHz, DMSO–d6) 4,04–4,38 (3H, m), 4,05 (3H, s), 4,49 (2H, m), 5,22 (2H, s), 6,55 (1H, d, J = 15,72 Hz), 7,29–7,94 (11H, m), 8,01 (1H, s). MS (m/z): 490 [MH]+. 25 The title compound (7) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 100%, tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.06 min. NMR (400 MHz, DMSO – d6) 4.04-4.38 (3H, m), 4.05 (3H, s), 4.49 (2H, m), 5.22 (2H, s), 6.55 (1H, d, J = 15.72 Hz), 7.29-7.94 (11H, m), 8.01 (1H, s). MS (m / z): 490 [MH] +. 25
Ejemplo 8 Example 8
Preparación de N–hidroxi–3–[1–(2,3–hidroxi–propil)–2–(2–piridil)–1H–bencimidazol–5–il]–acrilamida (9) Preparation of N-hydroxy-3– [1– (2,3-hydroxy-propyl) -2- (2-pyridyl) -1H-benzimidazol-5-yl] -acrylamide (9)
El compuesto del título (9) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los 30 materiales de partida apropiados. HPLC: 93,7%, tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, The title compound (9) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 93.7%, tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min,
gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,61 min. RMN (400 MHz, DMSO–d6) 3,20–3,37 (4H, m), 3,90 (1H, m), 4,90–4,95 (2H, m), 6,54 (1H, d, J = 15,52 Hz), 7,98 (1H, s), 8,04 (1H, 5 m), 8,27 (1H, m), 9,73 (1H, d, J = 8,0 Hz). MS (m/z): 355 [MH]+. gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.61 min. NMR (400 MHz, DMSO – d6) 3.20–3.37 (4H, m), 3.90 (1H, m), 4.90–4.95 (2H, m), 6.54 (1H , d, J = 15.52 Hz), 7.98 (1H, s), 8.04 (1H, 5 m), 8.27 (1H, m), 9.73 (1H, d, J = 8 , 0 Hz). MS (m / z): 355 [MH] +.
Ejemplo 9 Example 9
Preparación de N–hidroxi–3–[1–(2–hidroxi–etil)–2–(4–piridil)–1H–bencimidazol–5–il]–acrilamida (10) 10 Preparation of N-hydroxy-3– [1– (2-hydroxy-ethyl) -2- (4-pyridyl) -1H-benzimidazol-5-yl] -acrylamide (10) 10
El compuesto del título (10) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 97,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 15 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 1,14 min. RMN (400 MHz, DMSO–d6) 3,78 (2H, t, J = 5,80 Hz), 4,43 (2H, t, J = 5,80 Hz), 6,50 (1H, d, J = 15,80 Hz), 7,82 (2H, d, J = 8,56 Hz), 7,94 (1H, s), 8,00 (2H, d, J = 5,97 Hz), 8,81 (2H, d, J 20 = 5,97 Hz). MS (m/z): 325 [MH]+. The title compound (10) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 15 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.14 min. NMR (400 MHz, DMSO – d6) 3.78 (2H, t, J = 5.80 Hz), 4.43 (2H, t, J = 5.80 Hz), 6.50 (1H, d, J = 15.80 Hz), 7.82 (2H, d, J = 8.56 Hz), 7.94 (1H, s), 8.00 (2H, d, J = 5.97 Hz), 8 , 81 (2H, d, J 20 = 5.97 Hz). MS (m / z): 325 [MH] +.
Ejemplo 10 Example 10
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–(4–piridil)–1H–bencimidazol–5–il]–acrilamida (11) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2- (4-pyridyl) -1H-benzimidazol-5-yl] -acrylamide (11)
El compuesto del título (11) se preparó de acuerdo con 25 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 98,2%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 30 0,1% de ácido trifluoroacético; UV 254): 2,61 min. RMN (400 MHz, DMSO–d6) 1,91 (2H, m), 3,37 (2H, t, J = 5,84 Hz), 4,49 The title compound (11) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98.2%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.61 min. NMR (400 MHz, DMSO – d6) 1.91 (2H, m), 3.37 (2H, t, J = 5.84 Hz), 4.49
(2H, t, J = 7,84 Hz), 6,54 (1H, d, J = 15,52 Hz), 7,98 (1H, s), 8,06 (2H, d, J = 6,26 Hz), 8,90 (2H, d, J = 626 Hz). MS (m/z): 339 [MH]+. (2H, t, J = 7.84 Hz), 6.54 (1H, d, J = 15.52 Hz), 7.98 (1H, s), 8.06 (2H, d, J = 6, 26 Hz), 8.90 (2H, d, J = 626 Hz). MS (m / z): 339 [MH] +.
Ejemplo 11 Example 11
Preparación de N–hidroxi–3–[1–(3–piridilmetil)–2–(2–fenil–5 etil)–1H–bencimidazol–5–il]–acrilamida (12) Preparation of N-hydroxy-3– [1– (3-pyridylmethyl) -2- (2-phenyl-5 ethyl) –1H-benzimidazol-5-yl] -acrylamide (12)
El compuesto del título (12) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 97,9%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 10 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,32 min. RMN (400 MHz, DMSO–d6) 3,11 (2H, t, J = 8,40 Hz), 5,71 (2H, s), 6,51 (1H, d, J = 15,80 Hz), 7,20–7,31 (6H, m), 7,43 (1H, m), 7,40–15 7,57 (4H, m), 7,94 (1H, s), 8,57 (1H, s). MS (m/z): 399 [MH]+. The title compound (12) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 97.9%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 10 gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.32 min. NMR (400 MHz, DMSO – d6) 3.11 (2H, t, J = 8.40 Hz), 5.71 (2H, s), 6.51 (1H, d, J = 15.80 Hz) , 7.20–7.31 (6H, m), 7.43 (1H, m), 7.40–15 7.57 (4H, m), 7.94 (1H, s), 8.57 ( 1H, s). MS (m / z): 399 [MH] +.
Ejemplo 12 Example 12
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–(2–piridil)–1H–bencimidazol–5–il]–acrilamida (13) 20 Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2- (2-pyridyl) -1H-benzimidazol-5-yl] -acrylamide (13) 20
El compuesto del título (13) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 98,3%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 25 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,37 min. RMN (400 MHz, DMSO–d6) 1,98 (2H, m), 3,30 (2H, m), 4,86 (2H, t, J = 7,00 Hz), 6,51 (1H, d, J = 15,76 Hz), 7,77 (2H, d, J = 8,56 Hz), 7,94 (1H, s), 8,05 (1H, m), 8,30 (1H, d, J = 7,92 Hz), 30 8,78 (1H, d, J = 4,28 Hz). MS (m/z): 339 [MH]+. The title compound (13) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98.3%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 25 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.37 min. NMR (400 MHz, DMSO – d6) 1.98 (2H, m), 3.30 (2H, m), 4.86 (2H, t, J = 7.00 Hz), 6.51 (1H, d, J = 15.76 Hz), 7.77 (2H, d, J = 8.56 Hz), 7.94 (1H, s), 8.05 (1H, m), 8.30 (1H, d, J = 7.92 Hz), 30 8.78 (1H, d, J = 4.28 Hz). MS (m / z): 339 [MH] +.
Ejemplo 13 Example 13
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida (14) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide (14)
El compuesto del título (14) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 97,3%; tR = (LC/PDA: 5 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,63 min. RMN (400 MHz, DMSO–d6) 1,87 (2H, m), 3,18 (2, t, J = 7,40 Hz), 4,41 10 (2H, t, J = 7,0 Hz), 6,57 (1H, d, J = 17,60 Hz), 7,15 (5H, m), 7,64 (1, d, J = 17,60 Hz), 7,89 (1H, d, J = 8,64 Hz), 7,95 (1H, s). MS (m/z): 366 [MH]+. The title compound (14) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 97.3%; tR = (LC / PDA: 5 column Phenomenex Luna C18 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.63 min. NMR (400 MHz, DMSO – d6) 1.87 (2H, m), 3.18 (2, t, J = 7.40 Hz), 4.41 10 (2H, t, J = 7.0 Hz ), 6.57 (1H, d, J = 17.60 Hz), 7.15 (5H, m), 7.64 (1, d, J = 17.60 Hz), 7.89 (1H, d , J = 8.64 Hz), 7.95 (1H, s). MS (m / z): 366 [MH] +.
Ejemplo 14 Example 14
Preparación de N–hidroxi–3–(2–fenetil–1–(piridin–2–il)metil–15 1H–bencimidazol–5–il)–acrilamida (16) Preparation of N-hydroxy-3– (2-phenethyl-1– (pyridin-2-yl) methyl-15 1H-benzimidazol-5-yl) -acrylamide (16)
El compuesto del título (16) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,7%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 20 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,11 min. RMN (400 MHz, DMSO–d6) 3,31 (2H, t, J = 7,56 Hz), 5,81 (2H, s), 6,57 (1H, d, J = 17,60 Hz), 7,20–7,36 (6H, m), 7,52 (1H, m), 7,64 25 (1H, d, J = 17,60 Hz), 7,68 (1H, d, J = 8,48 Hz), 7,77 (1H, d, J = 8,48 Hz), 7,87 (1H, m), 8,44 (1H, d, J = 3,92Hz). MS (m/z): 399 [MH]+. The title compound (16) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.7%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 20 gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.11 min. NMR (400 MHz, DMSO – d6) 3.31 (2H, t, J = 7.56 Hz), 5.81 (2H, s), 6.57 (1H, d, J = 17.60 Hz) , 7.20–7.36 (6H, m), 7.52 (1H, m), 7.64 (1H, d, J = 17.60 Hz), 7.68 (1H, d, J = 8.48 Hz), 7.77 (1H, d, J = 8.48 Hz), 7.87 (1H, m), 8.44 (1H, d, J = 3.92Hz). MS (m / z): 399 [MH] +.
Ejemplo 15 Example 15
Preparación de N–hidroxi–3–[1–(3–dimetilamino–2,2–dimetil–30 propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida (17) Preparation of N-hydroxy-3– [1– (3-dimethylamino-2,2-dimethyl-30 propyl) –2-phenethyl-1H-benzimidazol-5-yl] -acrylamide (17)
El compuesto del título (17) se preparó de acuerdo con The title compound (17) was prepared according to
los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC:100% ; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 5 0,1% de ácido trifluoroacético; UV 254): 2,13 min. RMN (400 MHz, DMSO–d6) 1,08 (6H, s), 2,89 (6H, s), 4,30 (2H, s), 6,54 (1H, d, J = 15,80 Hz), 7,03 (1H, s), 7,16 (1H, s), 7,22–7,32 (6H, m), 7,65 (1H, d, J = 15,80 Hz), 7,91 (1H, s). MS (m/z): 421 [MH]+. 10 the procedures described in example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 5 0.1% trifluoroacetic acid; UV 254): 2.13 min. NMR (400 MHz, DMSO – d6) 1.08 (6H, s), 2.89 (6H, s), 4.30 (2H, s), 6.54 (1H, d, J = 15.80 Hz), 7.03 (1H, s), 7.16 (1H, s), 7.22–7.32 (6H, m), 7.65 (1H, d, J = 15.80 Hz), 7.91 (1H, s). MS (m / z): 421 [MH] +. 10
Ejemplo 16 Example 16
Preparación de N–hidroxi–3–[2–benciloximetil–1–(3–hidroxi–propil–1H–bencimidazol–5–il]–acrilamida (19) Preparation of N-hydroxy-3– [2-benzyloxymethyl-1– (3-hydroxy-propyl-1H-benzimidazol-5-yl] -acrylamide (19)
El compuesto del título (19) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los 15 materiales de partida apropiados. HPLC: 98,6%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 4,50 min. 1H RMN 20 (400 MHz, DMSO–d6) 1,94 (2H, m), 3,43 (2H, t, J = 5,8 Hz ), 4,42 (2H, t, J = 7,2 Hz), 4,67 (2H, s), 4,97 (2H, s), 6,53 (1H, d, J = 15,8 Hz), 7,38 (5H, m), 7,63 (1H, d, J = 15,8 Hz), 7,67 (1H, d, J = 9,1 Hz), 7,80 (1H, d, J = 8,6 Hz), 7,90 (1H, s), 10,77 (1H, bs). MS (m/z): 382 [MH]+. 25 The title compound (19) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98.6%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 4.50 min. 1H NMR 20 (400 MHz, DMSO – d6) 1.94 (2H, m), 3.43 (2H, t, J = 5.8 Hz), 4.42 (2H, t, J = 7.2 Hz), 4.67 (2H, s), 4.97 (2H, s), 6.53 (1H, d, J = 15.8 Hz), 7.38 (5H, m), 7.63 ( 1H, d, J = 15.8 Hz), 7.67 (1H, d, J = 9.1 Hz), 7.80 (1H, d, J = 8.6 Hz), 7.90 (1H, s), 10.77 (1H, bs). MS (m / z): 382 [MH] +. 25
Ejemplo 17 Example 17
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–tiofen–3–il–1H–bencimidazol–5–il]–acrilamida (20) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2-thiophene-3-yl-1H-benzimidazol-5-yl] -acrylamide (20)
El compuesto del título (20) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los 30 materiales de partida apropiados. HPLC: 97,9%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, The title compound (20) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 97.9%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min,
gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,06 min. 1H RMN (400 MHz, DMSO–d6), 1,98 (2H, m), 3,49 (2H, t, J = 5,8 Hz), 4,56 (2H, t, J = 7,2 Hz), 6,56 (1H, d, J = 15,8 Hz), 7,65 5 (1H, d, J = 15,8 Hz), 7,69 (1H, d, J = 8,7 Hz), 7,75 (1H, dd, J = 5,1 Hz, 1,2 Hz), 7,89 (2H, m), 7,93 (1H, s), 8,42 (1H, dd, J = 2,6 Hz), 10,90 (1H, bs);. MS (m/z): 344 [MH]+. gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.06 min. 1H NMR (400 MHz, DMSO – d6), 1.98 (2H, m), 3.49 (2H, t, J = 5.8 Hz), 4.56 (2H, t, J = 7.2 Hz), 6.56 (1H, d, J = 15.8 Hz), 7.65 5 (1H, d, J = 15.8 Hz), 7.69 (1H, d, J = 8.7 Hz ), 7.75 (1H, dd, J = 5.1 Hz, 1.2 Hz), 7.89 (2H, m), 7.93 (1H, s), 8.42 (1H, dd, J = 2.6 Hz), 10.90 (1H, bs) ;. MS (m / z): 344 [MH] +.
Ejemplo 18 Example 18
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–isobutil–10 1H–bencimidazol–5–il]–acrilamida (21) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2-isobutyl-10 1H-benzimidazol-5-yl] -acrylamide (21)
El compuesto del título (21) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 100%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 15 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,14 min. 1H RMN (400 MHz, DMSO–d6), 1,01 (6H, d, J = 6,6 Hz), 1,94 (2H, m), 2,28 (1H, m), 3,04 (2H, d, J = 7,4 Hz), 3,47 (2H, t, J = 5,8 20 Hz), 4,46 (2H, t, J = 7,1 Hz), 6,56 (1H, d, J = 15,8 Hz), 7,65 (1H, d, J = 15,8 Hz), 7,73 (1H, d, J = 8,6 Hz), 7,89 (1H, d, J = 8,6 Hz), 7,94 (1H, s). MS (m/z): 318 [MH]+. The title compound (21) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 15 gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.14 min. 1H NMR (400 MHz, DMSO – d6), 1.01 (6H, d, J = 6.6 Hz), 1.94 (2H, m), 2.28 (1H, m), 3.04 ( 2H, d, J = 7.4 Hz), 3.47 (2H, t, J = 5.8 20 Hz), 4.46 (2H, t, J = 7.1 Hz), 6.56 (1H , d, J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.89 (1H, d , J = 8.6 Hz), 7.94 (1H, s). MS (m / z): 318 [MH] +.
Ejemplo 19 Example 19
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–octil–1H–25 bencimi-dazol–5–il]–acrilamida (23) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2-octyl-1H-25 benzimi-dazol-5-yl] -acrylamide (23)
El compuesto del título (23) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 30 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con The title compound (23) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 30 gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with
0,1% de ácido trifluoroacético; UV 254): 7,38 min. 1H RMN (400 MHz, DMSO–d6) 0,86 (3H, t, J = 6,8 Hz), 1,32 (10H, m), 1,83 (2H, m), 1,94 (2H, m), 3,12 (2H, t, J = 7,7 Hz), 3,46 (2H, t, J = 5,8 Hz), 4,44 (2H, t, J = 7,0 Hz), 6,56 (1H, d, J = 15,8 Hz), 7,64 (1H, d, J = 15,8 Hz), 7,71 (1H, d, J = 8,6 5 Hz), 7,87 (1H, d, J = 8,6 Hz), 7,92 (1H, s). MS (m/z): 374 [MH]+. 0.1% trifluoroacetic acid; UV 254): 7.38 min. 1 H NMR (400 MHz, DMSO – d6) 0.86 (3H, t, J = 6.8 Hz), 1.32 (10H, m), 1.83 (2H, m), 1.94 (2H , m), 3.12 (2H, t, J = 7.7 Hz), 3.46 (2H, t, J = 5.8 Hz), 4.44 (2H, t, J = 7.0 Hz ), 6.56 (1H, d, J = 15.8 Hz), 7.64 (1H, d, J = 15.8 Hz), 7.71 (1H, d, J = 8.6 5 Hz) , 7.87 (1H, d, J = 8.6 Hz), 7.92 (1H, s). MS (m / z): 374 [MH] +.
Ejemplo 20 Example 20
Preparación de N–hidroxi–[2–ciclohexil–1–(3–hidroxi–propil)–1H–bencimidazol–5–il]–acrilamida (24) 10 Preparation of N-hydroxy– [2-cyclohexyl-1– (3-hydroxy-propyl) –1H-benzimidazol-5-yl] -acrylamide (24) 10
El compuesto del título (24) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 98,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 15 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 7,38 min. 1H RMN (400 MHz, DMSO–d6) 1,28–2,03 (12H, m), 3,33 (1H, m), 3,47 (2H, t, J = 5,7 Hz), 4,51 (2H, t, J = 6,9 Hz), 6,58 (1H, d, J = 15,8 Hz), 7,65 (1H, d, J = 15,8 Hz), 7,76 (1H, d, J = 8,6 20 Hz), 7,92 (1H, d, J = 8,7 Hz), 7,93 (1H, s), 10,85 (1H, bs). MS (m/z): 344 [MH]+. The title compound (24) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 15 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.38 min. 1H NMR (400 MHz, DMSO – d6) 1.28–2.03 (12H, m), 3.33 (1H, m), 3.47 (2H, t, J = 5.7 Hz), 4 , 51 (2H, t, J = 6.9 Hz), 6.58 (1H, d, J = 15.8 Hz), 7.65 (1H, d, J = 15.8 Hz), 7.76 (1H, d, J = 8.6 20 Hz), 7.92 (1H, d, J = 8.7 Hz), 7.93 (1H, s), 10.85 (1H, bs). MS (m / z): 344 [MH] +.
Ejemplo 21 Example 21
Preparación de N–hidroxi–3–(2–isobutil–1–fenetil–1H–bencimidazol–5–il]–acrilamida (25) 25 Preparation of N-hydroxy-3– (2-isobutyl-1-phenethyl-1H-benzimidazol-5-yl] -acrylamide (25) 25
El compuesto del título (25) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,1%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 30 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 6,51 min. 1H RMN The title compound (25) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.1%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 30 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 6.51 min. 1 H NMR
(400 MHz, DMSO–d6) 0,90 (6H, d, J = 6,6 Hz), 2,10 (1H, m), 2,70 (2H, d, J = 7,3 Hz), 3,11 (2H, t, J = 7,0 Hz), 4,66 (2H, t, J = 7,0 Hz), 6,57 (1H, d, J = 15,8 Hz), 7,14 (2H, m), 7,26 (3H, m), 7,64 (1H, d, J = 15,8 Hz), 7,70 (1H, d, J = 8,8 Hz), 7,86 (1H, d, J = 8,6 Hz), 7,92 (1H, s); 13C RMN (100 MHz, 5 DMSO–d6) 22,0. 26,9, 33,3, 34,5, 45,8, 113,0. 114,3, 119,7, 123,7, 126,9, 128,5, 129,0. 132,2, 132,7, 137,2, 137,8, 154,4, 162,5. MS (m/z): 364 [MH]+. (400 MHz, DMSO – d6) 0.90 (6H, d, J = 6.6 Hz), 2.10 (1H, m), 2.70 (2H, d, J = 7.3 Hz), 3.11 (2H, t, J = 7.0 Hz), 4.66 (2H, t, J = 7.0 Hz), 6.57 (1H, d, J = 15.8 Hz), 7, 14 (2H, m), 7.26 (3H, m), 7.64 (1H, d, J = 15.8 Hz), 7.70 (1H, d, J = 8.8 Hz), 7, 86 (1H, d, J = 8.6 Hz), 7.92 (1H, s); 13C NMR (100 MHz, 5 DMSO – d6) 22.0. 26.9, 33.3, 34.5, 45.8, 113.0. 114.3, 119.7, 123.7, 126.9, 128.5, 129.0. 132.2, 132.7, 137.2, 137.8, 154.4, 162.5. MS (m / z): 364 [MH] +.
Ejemplo 22 Example 22
Preparación de N–hidroxi–3–(1,2–difenetil–1H–bencimidazol–5–10 il]–acrilamida (26) Preparation of N-hydroxy-3– (1,2-diphenethyl-1H-benzimidazol-5–10 yl] -acrylamide (26)
El compuesto del título (26) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 98,3%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 15 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 7,68 min. 1H RMN (400 MHz, DMSO–d6) 2,99 (4H, m), 3,09 (2H, m), 4,59 (2H, t, J = 6,9 Hz), 6,56 (1H, d, J = 15,8 Hz), 7,07 (2H, m), 7,23 20 (6H, m), 7,31 (2H, m), 7,64 (1H, d, J = 15,5 Hz), 7,66 (1H, d, J = 7,2 Hz), 7,78 (1H, d, J = 8,6 Hz), 7,92 (1H, s); 13C RMN (100 MHz, DMSO–d6) 27,0, 31,9, 34,5, 45,6, 112,7, 114,7, 119,4, 123,5, 126,5, 126,9, 128,3, 128,5, 129,0. 131,8, 133,0, 137,3, 138,0, 139,5, 154,6, 162,6. MS (m/z): 25 412 [MH]+. The title compound (26) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98.3%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 15 gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.68 min. 1H NMR (400 MHz, DMSO – d6) 2.99 (4H, m), 3.09 (2H, m), 4.59 (2H, t, J = 6.9 Hz), 6.56 (1H , d, J = 15.8 Hz), 7.07 (2H, m), 7.23 20 (6H, m), 7.31 (2H, m), 7.64 (1H, d, J = 15 , 5 Hz), 7.66 (1H, d, J = 7.2 Hz), 7.78 (1H, d, J = 8.6 Hz), 7.92 (1H, s); 13C NMR (100 MHz, DMSO – d6) 27.0, 31.9, 34.5, 45.6, 112.7, 114.7, 119.4, 123.5, 126.5, 126.9 , 128.3, 128.5, 129.0. 131.8, 133.0, 137.3, 138.0, 139.5, 154.6, 162.6. MS (m / z): 25 412 [MH] +.
Ejemplo 23 Example 23
Preparación de N–hidroxi–3–(2–fenetil–1–(2–piridin–3–il–etil)–1H–bencimidazol–5–il]–acrilamida (27) Preparation of N-hydroxy-3– (2-phenethyl-1– (2-pyridin-3-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide (27)
El compuesto del título (27) se preparó de acuerdo con 30 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,9%; tR = (LC/PDA: The title compound (27) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.9%; tR = (LC / PDA:
columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,42 min. 1H RMN (400 MHz, DMSO–d6) 3,10 (4H, m), 3,28 (2H, t), 4,63 (2H, t) 5 6,53 (1H, d), 7,22–7,33 (7H, m), 7,54– 7,74 (4H, m), 8,5 (2H, d), 10,88 (1H, bs). MS (m/z): 413 [MH]+. Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.42 min. 1 H NMR (400 MHz, DMSO – d6) 3.10 (4H, m), 3.28 (2H, t), 4.63 (2H, t) 5 6.53 (1H, d), 7.22 –7.33 (7H, m), 7.54- 7.74 (4H, m), 8.5 (2H, d), 10.88 (1H, bs). MS (m / z): 413 [MH] +.
Ejemplo 24 Example 24
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–isobutil–1H–benci-midazol–5–il]–propionamida (29) 10 Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2-isobutyl-1H-benzimidazol-5-yl] -propionamide (29) 10
El compuesto del título (29) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,6%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 15 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,88 min. 1H RMN (400 MHz, DMSO–d6) 1,00 (6H, d, J = 6,4 Hz), 2,06 (2H, m), 2,27 (1H, m), 2,42 (2H, t, J = 7,6 Hz), 3,05–3,11 (4H, m), 3,57 (2H, t, J = 6,0 Hz), 4,52 (2H, t, J = 7,2 Hz), 7,45 (1H, 20 d, J = 8,0 Hz), 7,56 (1H, s), 7,78 (1H, d, J = 8,0 Hz); 13C RMN (100 MHz, MeOD) 20,6 (2C), 27,2, 30,4, 30,6, 32,7, 33,5, 41,5, 57,0. 112,0. 112,3, 112,4, 126,3, 129,9, 139,6, 152,3, 169,4. MS (m/z): 320 [MH]+. The title compound (29) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.6%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 15 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.88 min. 1 H NMR (400 MHz, DMSO – d6) 1.00 (6H, d, J = 6.4 Hz), 2.06 (2H, m), 2.27 (1H, m), 2.42 (2H , t, J = 7.6 Hz), 3.05–3.11 (4H, m), 3.57 (2H, t, J = 6.0 Hz), 4.52 (2H, t, J = 7.2 Hz), 7.45 (1H, 20 d, J = 8.0 Hz), 7.56 (1H, s), 7.78 (1H, d, J = 8.0 Hz); 13C NMR (100 MHz, MeOD) 20.6 (2C), 27.2, 30.4, 30.6, 32.7, 33.5, 41.5, 57.0. 112.0. 112.3, 112.4, 126.3, 129.9, 139.6, 152.3, 169.4. MS (m / z): 320 [MH] +.
Ejemplo 25 25 Example 25 25
Preparación de N–hidroxi–3–{1–[3–(2–oxo–pirrolidin–1–il)–propil]–2–fenetil–1H–bencimidazol–5–il}–acrilamida (30) Preparation of N-hydroxy-3– {1– [3– (2-oxo-pyrrolidin-1-yl) -propyl] –2-phenethyl-1H-benzimidazol-5-yl} -acrylamide (30)
El compuesto del título (30) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,7%; tR = (LC/PDA: 30 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con The title compound (30) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.7%; tR = (LC / PDA: 30 Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% B for 15.5 min, solvent A: H2O with
0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,88 min. 1H RMN (400 MHz, DMSO–d6) 1,84 (4H, m), 3,14–3,41 (8H, m), 4,29 (2H, t, J = 7,04 Hz), 6,54 (1H, d, J = 15,76 Hz), 7,21–7,33 (5H, m), 7,62 (1H, d, J = 15,76 Hz), 7,71 (1H, d, J = 8,36 5 Hz), 7,84 (1H, d, J = 8,36 Hz), 7,93 (1H, s). MS (m/z): 433 [MH]+. 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.88 min. 1 H NMR (400 MHz, DMSO – d6) 1.84 (4H, m), 3.14–3.41 (8H, m), 4.29 (2H, t, J = 7.04 Hz), 6 , 54 (1H, d, J = 15.76 Hz), 7.21–7.33 (5H, m), 7.62 (1H, d, J = 15.76 Hz), 7.71 (1H, d, J = 8.36 5 Hz), 7.84 (1H, d, J = 8.36 Hz), 7.93 (1H, s). MS (m / z): 433 [MH] +.
Ejemplo 26 Example 26
Preparación de N–hidroxi–3–[1–(3–morfolin–4–propil]–2–fenetil–1H–ben-cimidazol–5–il}–acrilamida (31) 10 Preparation of N-hydroxy-3– [1– (3-morpholin-4-propyl] –2-phenethyl-1H-ben-cimidazol-5-yl} -acrylamide (31) 10
El compuesto del título (31) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,7%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 15 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,16 min. 1H RMN (400 MHz, DMSO–d6) 2,12 (2H, m), 3,11 (6H, m), 3,39 (2H, t, J = 7,44 Hz), 4,39 (2H, t, J = 7,01 Hz), 6,56 (1H, d, J = 15,8 Hz), 7,23–7,33 (5H, m), 7,62 (1H, d, J = 15,8 Hz), 7,71 20 (1H, d, J = 8,60 Hz), 7,85 (1H, d, J = 8,60 Hz), 7,95 (1H, s). MS (m/z): 435 [MH]+. The title compound (31) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.7%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 15 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.16 min. 1H NMR (400 MHz, DMSO – d6) 2.12 (2H, m), 3.11 (6H, m), 3.39 (2H, t, J = 7.44 Hz), 4.39 (2H , t, J = 7.01 Hz), 6.56 (1H, d, J = 15.8 Hz), 7.23–7.33 (5H, m), 7.62 (1H, d, J = 15.8 Hz), 7.71 20 (1H, d, J = 8.60 Hz), 7.85 (1H, d, J = 8.60 Hz), 7.95 (1H, s). MS (m / z): 435 [MH] +.
Ejemplo 27 Example 27
Preparación de ácido 3–[5–(2–hidrocarbamoil–vinil)–2–fenetil–bencimi-dazol–1–il]–propiónico (32) 25 Preparation of 3– [5– (2-hydrocarbamoyl-vinyl) –2-phenethyl-benzimi-dazol-1-yl] -propionic acid (32) 25
El compuesto del título (32) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 95,6%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 30 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,55 min. 1H RMN The title compound (32) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 95.6%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 30 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.55 min. 1 H NMR
(400 MHz, DMSO–d6) 2,74 (2H, t, J = 6,68 Hz), 4,49 (2H, t, J = 6,68 Hz), 3,16 (2H, t, J = 7,44 Hz), 6,52 (1H, d, J = 15,76 Hz), 7,22–7,33 (5H, m), 7,62 (1H, d, J = 15,76 Hz), 7,66 (1H, d, J = 8,56 Hz), 7,82 (1H, d, J = 8,56 Hz), 7,89 (1H, s), 11,00 (1H, s) 5 (400 MHz, DMSO – d6) 2.74 (2H, t, J = 6.68 Hz), 4.49 (2H, t, J = 6.68 Hz), 3.16 (2H, t, J = 7.44 Hz), 6.52 (1H, d, J = 15.76 Hz), 7.22–7.33 (5H, m), 7.62 (1H, d, J = 15.76 Hz ), 7.66 (1H, d, J = 8.56 Hz), 7.82 (1H, d, J = 8.56 Hz), 7.89 (1H, s), 11.00 (1H, s ) 5
MS (m/z): 380 [MH]+. MS (m / z): 380 [MH] +.
Ejemplo 28 Example 28
Preparación de N–hidroxi–3–(1–bencil–2–fenetil–1H–bencimidazol–5–il}–acrilamida (33) Preparation of N-hydroxy-3– (1-benzyl-2-phenethyl-1H-benzimidazol-5-yl} -acrylamide (33)
El compuesto del título (33) se preparó de acuerdo con 10 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 15 0,1% de ácido trifluoroacético; UV 254): 7,82 min. 1H RMN (400 MHz, DMSO–d6) 3,08 (2H, t, J = 7,4 Hz), 3,34 (2H, t, J = 7,5 Hz), 5,62 (2H, s), 6,50 (1H, d, J = 15,8 Hz), 7,14 (2H, m), 7,30 (8H, m), 7,63 (3H, m), 7,92 (1H, s), 10,78 (1H, br); 13C RMN (100 MHz, DMSO–d6) 27,8, 32,2, 46,8, 112,1, 115,9, 20 118,6, 123,0. 126,4, 126,8, 127,9, 128,3, 128,4, 128,9, 131,0. 134,4, 135,7, 138,4, 139,9, 155,3, 162,7. MS (m/z): 398 [MH]+. The title compound (33) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 7.82 min. 1 H NMR (400 MHz, DMSO – d6) 3.08 (2H, t, J = 7.4 Hz), 3.34 (2H, t, J = 7.5 Hz), 5.62 (2H, s ), 6.50 (1H, d, J = 15.8 Hz), 7.14 (2H, m), 7.30 (8H, m), 7.63 (3H, m), 7.92 (1H , s), 10.78 (1H, br); 13C NMR (100 MHz, DMSO-d6) 27.8, 32.2, 46.8, 112.1, 115.9, 20 118.6, 123.0. 126.4, 126.8, 127.9, 128.3, 128.4, 128.9, 131.0. 134.4, 135.7, 138.4, 139.9, 155.3, 162.7. MS (m / z): 398 [MH] +.
Ejemplo 29 Example 29
Preparación de N–hidroxi–3–(1–bencil–2–isobutil–1H–25 bencimidazol–5–il}–acrilamida (34) Preparation of N-hydroxy-3– (1-benzyl-2-isobutyl-1H-25 benzimidazol-5-yl} -acrylamide (34)
El compuesto del título (34) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 89,2%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 30 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con The title compound (34) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 89.2%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 30 gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with
0,1% de ácido trifluoroacético; UV 254): 6,07 min. 1H RMN (400 MHz, CDCl3) 0,92 (6H, d, J = 6,6 Hz), 2,13 (1H, m), 3,02 (2H, d, J = 7,4 Hz), 5,72 (2H, s), 6,54 (1H, d, J = 15,8 Hz), 7,21 (2H, m), 7,35 (3H, m), 7,66 (3H, m), 7,96 (1H, s); 13C RMN (100 MHz, CDCl3) 22,0, 27,2, 34,0. 47,2, 112,8, 5 114,9, 119,4, 123,7, 126,8, 128,0, 128,9, 131,9, 133,6, 135,3, 138,0, 155,0, 162,6. MS (m/z): 350 [MH]+. 0.1% trifluoroacetic acid; UV 254): 6.07 min. 1H NMR (400 MHz, CDCl3) ,9 0.92 (6H, d, J = 6.6 Hz), 2.13 (1H, m), 3.02 (2H, d, J = 7.4 Hz), 5.72 (2H, s), 6.54 (1H, d, J = 15.8 Hz), 7.21 (2H, m), 7.35 (3H, m), 7.66 (3H, m ), 7.96 (1H, s); 13C NMR (100 MHz, CDCl3) 22.0, 27.2, 34.0. 47.2, 112.8, 5 114.9, 119.4, 123.7, 126.8, 128.0, 128.9, 131.9, 133.6, 135.3, 138.0, 155 , 0, 162.6. MS (m / z): 350 [MH] +.
Ejemplo 30 Example 30
Preparación de N–hidroxi–3–(1–bencil–1H–bencimidazol–5–il}–acrilamida (35) 10 Preparation of N-hydroxy-3– (1-benzyl-1H-benzimidazol-5-yl} -acrylamide (35) 10
El compuesto del título (35) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 97,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 15 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,69 min. 1H RMN (400 MHz, CD3OD) 5,68 (2H, s), 6,54 (1H, d, J = 15,7 Hz), 7,37 (5H, m), 7,66 (1H, d, J = 15,8 Hz), 7,75 (2H, s), 7,94 (1H, s), 9,36 (1H, br); 13C RMN (100 MHz, CD3OD) 51,7, 20 114,8, 116,1, 120,6, 126,5, 129,2, 130,2, 130,4, 135,0. 135,3, 140,1, 165,6. MS (m/z): 294 [MH]+. The title compound (35) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 15 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.69 min. 1H NMR (400 MHz, CD3OD) 5.68 (2H, s), 6.54 (1H, d, J = 15.7 Hz), 7.37 (5H, m), 7.66 (1H, d , J = 15.8 Hz), 7.75 (2H, s), 7.94 (1H, s), 9.36 (1H, br); 13C NMR (100 MHz, CD3OD) 51.7, 20 114.8, 116.1, 120.6, 126.5, 129.2, 130.2, 130.4, 135.0. 135.3, 140.1, 165.6. MS (m / z): 294 [MH] +.
Ejemplo 31 Example 31
Preparación de N–hidroxi–3–(2–fenetil–1–propil–1H–bencimidazol–5–il}–acrilamida (36) 25 Preparation of N-hydroxy-3– (2-phenethyl-1-propyl-1H-benzimidazol-5-yl} -acrylamide (36) 25
El compuesto del título (36) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 93,9%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 30 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 6,05 min. 1H RMN The title compound (36) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 93.9%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 30 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 6.05 min. 1 H NMR
(400 MHz, CD3OD) 0,90 (3H, t, J = 7,4 Hz), 1,70 (2H, m), 3,20 (2H, m), 3,48 (2H, t, J = 7,1 Hz), 4,21 (2H, t, J = 7,4 Hz), 6,54 (1H, d, J = 15,7 Hz), 7,20 (5H, m), 7,65 (1H, d, J = 15,7 Hz), 7,75 (1H, d, J = 8,8 Hz), 7,79 (1H, d, J = 8,6 Hz), 7,84 (1H, s); 13C RMN (100 MHz, CD3OD) 11,2, 23,6, 5 28,7, 34,0. 47,7, 114,4, 114,6, 120,5, 126,3, 128,3, 129,5, 130,0. 132,7, 134,0. 135,2, 139,9, 140,1, 155,5, 165,6. MS (m/z): 350 [MH]+. (400 MHz, CD3OD) 0.90 (3H, t, J = 7.4 Hz), 1.70 (2H, m), 3.20 (2H, m), 3.48 (2H, t, J = 7.1 Hz), 4.21 (2H, t, J = 7.4 Hz), 6.54 (1H, d, J = 15.7 Hz), 7.20 (5H, m), 7, 65 (1H, d, J = 15.7 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.79 (1H, d, J = 8.6 Hz), 7.84 ( 1H, s); 13C NMR (100 MHz, CD3OD) 11.2, 23.6, 5 28.7, 34.0. 47.7, 114.4, 114.6, 120.5, 126.3, 128.3, 129.5, 130.0. 132.7, 134.0. 135.2, 139.9, 140.1, 155.5, 165.6. MS (m / z): 350 [MH] +.
Ejemplo 32 Example 32
Preparación de N–hidroxi–3–(1–propil–1H–bencimidazol–5–il}–10 acrilamida (37) Preparation of N-hydroxy-3– (1-propyl-1H-benzimidazol-5-yl} -10 acrylamide (37)
El compuesto del título (37) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 95,2%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 15 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,92 min. 1H RMN (400 MHz, CD3OD) 0,97 (3H, t, J = 7,4 Hz), 1,98 (2H, m), 4,42 (2H, t, J = 7,3 Hz), 6,55 (1H, d, J = 15,8 Hz), 7,68 20 (1H, d, J = 15,8 Hz), 7,79 (1H, d, J = 8,7 Hz), 7,88 (1H, d, J = 8,7 Hz), 7,92 (1H, s), 9,24 (1H, s); 13C RMN (100 MHz, CD3CD) 11,1, 23,8, 48,4, 114,3, 116,1, 120,3, 126,4, 133,8, 134,9, 135,0. 140,3, 143,5, 165,7. MS (m/z): 246 [MH]+. The title compound (37) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 95.2%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 15 gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.92 min. 1H NMR (400 MHz, CD3OD) ,9 0.97 (3H, t, J = 7.4 Hz), 1.98 (2H, m), 4.42 (2H, t, J = 7.3 Hz), 6.55 (1H, d, J = 15.8 Hz), 7.68 20 (1H, d, J = 15.8 Hz), 7.79 (1H, d, J = 8.7 Hz), 7 , 88 (1H, d, J = 8.7 Hz), 7.92 (1H, s), 9.24 (1H, s); 13C NMR (100 MHz, CD3CD) 11.1, 23.8, 48.4, 114.3, 116.1, 120.3, 126.4, 133.8, 134.9, 135.0. 140.3, 143.5, 165.7. MS (m / z): 246 [MH] +.
Ejemplo 33 25 Example 33 25
Preparación de N–hidroxi–3–(1–etil–2–fenetil–1H–bencimidazol–5–il}–acrilamida (38) Preparation of N-hydroxy-3– (1-ethyl-2-phenethyl-1H-benzimidazol-5-yl} -acrylamide (38)
El compuesto del título (38) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,0%; tR = (LC/PDA: 30 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con The title compound (38) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.0%; tR = (LC / PDA: 30 Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% B for 15.5 min, solvent A: H2O with
0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 5,06 min. 1H RMN: (400 MHz, CD3OD) δ 1,37 (3H, t, J = 7,3 Hz), 3,26 (2H, t, J = 7,6 Hz), 3,53 (2H, t, J = 7,5 Hz), 4,78 (2H, dd, J = 7,3 Hz), 6,60 (1H, d, J = 15,8 Hz), 7,21–7,31 (5H, m), 7,72 (1H, d, J 5 = 15,8 Hz), 7,83–7,89 (3H, m). MS (m/z): 336 [MH]+. 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 5.06 min. 1H NMR: (400 MHz, CD3OD) δ 1.37 (3H, t, J = 7.3 Hz), 3.26 (2H, t, J = 7.6 Hz), 3.53 (2H, t, J = 7.5 Hz), 4.78 (2H, dd, J = 7.3 Hz), 6.60 (1H, d, J = 15.8 Hz), 7.21–7.31 (5H, m), 7.72 (1H, d, J 5 = 15.8 Hz), 7.83-7.89 (3H, m). MS (m / z): 336 [MH] +.
Ejemplo 34 Example 34
Preparación de N–hidroxi–3–(1–etil–1H–bencimidazol–5–il}–acrilamida (39) Preparation of N-hydroxy-3– (1-ethyl-1H-benzimidazol-5-yl} -acrylamide (39)
El compuesto del título (39) se preparó de acuerdo con 10 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 15 0,1% de ácido trifluoroacético; UV 254): 1,86 min. 1H RMN: (400 MHz, CD3OD) δ 1,64 (3H, t, J = 7,3 Hz), 4,55 (2H, dd, J = 7,3 Hz), 6,61 (1H, d, J = 15,8 Hz), 7,72 (1H, d, J = 15,8 Hz), 7,86–7,97 (3H, m), 9,38 (1H, s). MS (m/z): 232 [MH]+. The title compound (39) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.86 min. 1H NMR: (400 MHz, CD3OD) δ 1.64 (3H, t, J = 7.3 Hz), 4.55 (2H, dd, J = 7.3 Hz), 6.61 (1H, d, J = 15.8 Hz), 7.72 (1H, d, J = 15.8 Hz), 7.86–7.97 (3H, m), 9.38 (1H, s). MS (m / z): 232 [MH] +.
Ejemplo 35 20 Example 35 20
Preparación de hidroxiamida del ácido 1–(3–hidroxi–propil)–2–fenetil–1H–bencimidazol–5–carboxílico (40) Preparation of 1– (3-hydroxy-propyl) -2-phenethyl-1H-benzimidazole-5-carboxylic acid hydroxyamide (40)
El compuesto del título (40) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 96,0%. 1H RMN (400 25 MHz, CD3OD, ): 1,88 (2H, m), 3,16 (2H, t, J = 7,2 Hz), 3,46 (4H, m), 4,34 (2H, t, J = 7,2 Hz), 7,12–7,21 (5H, m), 7,82 (2H, m), 8,05 (1H, s). MS (m/z): 340 [MH]+. The title compound (40) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 96.0%. 1H NMR (400 25 MHz, CD3OD, ): 1.88 (2H, m), 3.16 (2H, t, J = 7.2 Hz), 3.46 (4H, m), 4.34 ( 2H, t, J = 7.2 Hz), 7.12–7.21 (5H, m), 7.82 (2H, m), 8.05 (1H, s). MS (m / z): 340 [MH] +.
Ejemplo 36 Example 36
Preparación de N–hidroxi–3–[1–(2–piridin–2–il–etil)–1H–30 bencimidazol–5–il]–acrilamida (42) Preparation of N-hydroxy-3– [1– (2-pyridin-2-yl-ethyl) –1H-30 benzimidazol-5-yl] -acrylamide (42)
El compuesto del título (42) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los The title compound (42) was prepared according to the procedures described in example 1, using the
materiales de partida apropiados. HPLC: 98,4%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 1,05 min. 1H RMN 5 (400 MHz, DMSO–d6) 3,43 (2H, t), 4,84 (2H, t), 6,53 (1H, d), 7,41 (2H, m), 7,64 (2H, m), 7,77–7,95 (4H, m), 8,56 (1H, s), 9,16 (1H, s). MS (m/z): 309 [MH]+. appropriate starting materials. HPLC: 98.4%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.05 min. 1H NMR 5 (400 MHz, DMSO-d6) 3.43 (2H, t), 4.84 (2H, t), 6.53 (1H, d), 7.41 (2H, m), 7, 64 (2H, m), 7.77-7.95 (4H, m), 8.56 (1H, s), 9.16 (1H, s). MS (m / z): 309 [MH] +.
Ejemplo 37 Example 37
Preparación de N–hidroxi–3–(1–etil–2–metil–1H–bencimidazol–5–10 il]–acrilamida (43) Preparation of N-hydroxy-3– (1-ethyl-2-methyl-1H-benzimidazol-5–10 yl] -acrylamide (43)
El compuesto del título (43) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 96,5%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 15 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,52 min. 1H RMN (400 MHz, DMSO–d6) 1,38 (3H, t), 2,85 (3H, s), 4,42 (2H, t), 6,58 (1H, d), 7,31 (1H, m), 7,50 (1H.d), 7,88 (2H, m), 20 10,31 (1H, bs), 11,18 (1H, bs). MS (m/z): 246 [MH]+. The title compound (43) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 96.5%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 15 gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.52 min. 1H NMR (400 MHz, DMSO – d6) 1.38 (3H, t), 2.85 (3H, s), 4.42 (2H, t), 6.58 (1H, d), 7.31 (1H, m), 7.50 (1H.d), 7.88 (2H, m), 10.31 (1H, bs), 11.18 (1H, bs). MS (m / z): 246 [MH] +.
Ejemplo 38 Example 38
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–1H–bencimidazol–5–il]–acrilamida (47) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -1H-benzimidazol-5-yl] -acrylamide (47)
El compuesto del título (47) se preparó de acuerdo con 25 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: >99%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 30 0,1% de ácido trifluoroacético; UV 254): 1,02 min. 1H RMN (400 MHz, CD3OD) 2,12 (2H, m), 3,58 (2H, t, J = 5,7 Hz), The title compound (47) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC:> 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.02 min. 1H NMR (400 MHz, CD3OD) 2.12 (2H, m), 3.58 (2H, t, J = 5.7 Hz),
4,57 (2H, t, J = 6,9 Hz), 6,55 (1H, d, J = 15,8 Hz), 7,67 (1H, d, J = 15,8 Hz), 7,79 (1H, d, J = 8,7 Hz), 7,89 (1H, d, J = 8,9 Hz), 7,92 (1H, s), 9,22 (1H, s); 13C RMN (100 MHz, MeOD) 32,7, 45,3, 59,2, 114,3, 116,1, 120,3, 126,4, 135,0. 140,3, 143,8, 165,7. MS (m/z): 262 [MH]+. 5 4.57 (2H, t, J = 6.9 Hz), 6.55 (1H, d, J = 15.8 Hz), 7.67 (1H, d, J = 15.8 Hz), 7, 79 (1H, d, J = 8.7 Hz), 7.89 (1H, d, J = 8.9 Hz), 7.92 (1H, s), 9.22 (1H, s); 13C NMR (100 MHz, MeOD) 32.7, 45.3, 59.2, 114.3, 116.1, 120.3, 126.4, 135.0. 140.3, 143.8, 165.7. MS (m / z): 262 [MH] +. 5
Ejemplo 39 Example 39
Preparación de N–hidroxi–3–(1–metil–2–fenetil–1H–bencimidazol–5–il)–acrilamida (48) Preparation of N-hydroxy-3– (1-methyl-2-phenethyl-1H-benzimidazol-5-yl) -acrylamide (48)
El compuesto del título (48) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los 10 materiales de partida apropiados. HPLC: 99%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 4,53 min. 1H RMN: 15 (400 MHz, CD3OD) δ 3,18 (2H, t, J = 7,5 Hz), 3,47 (2H, t, J = 7,4 Hz), 3,76 (3H, s), 6,54 (1H, d, J = 15,8 Hz), 7,10–7,26 (5H, m), 7,65 (1H, d, J = 15,8 Hz), 7,75–7,82 (3H, m). MS (m/z): 322 [MH]+. The title compound (48) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 4.53 min. 1H NMR: 15 (400 MHz, CD3OD) δ 3.18 (2H, t, J = 7.5 Hz), 3.47 (2H, t, J = 7.4 Hz), 3.76 (3H, s ), 6.54 (1H, d, J = 15.8 Hz), 7.10–7.26 (5H, m), 7.65 (1H, d, J = 15.8 Hz), 7.75 –7.82 (3H, m). MS (m / z): 322 [MH] +.
Ejemplo 40 20 Example 40 20
Preparación de N–hidroxi–3–(2–fenetil–1H–bencimidazol–5–il)–acrilamida (50) Preparation of N-hydroxy-3– (2-phenethyl-1H-benzimidazol-5-yl) -acrylamide (50)
El compuesto del título (50) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99%; tR = (LC/PDA: 25 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 4,36 min. 1H RMN (400 MHz, DMSO–d6) 3,16 (2H, t, J = 7,5 Hz), 3,36 (2H, t, J 30 = 7,9 Hz), 6,53 (1H, d, J = 15,8 Hz), 7,17–7,29 (5H, m), 7,58 (1H, d, J = 15,8 Hz), 7,66–7,87 (3H, m). MS (m/z): 308 [MH]+. The title compound (50) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: 25 Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 4.36 min. 1 H NMR (400 MHz, DMSO – d6) 3.16 (2H, t, J = 7.5 Hz), 3.36 (2H, t, J 30 = 7.9 Hz), 6.53 (1H, d, J = 15.8 Hz), 7.17–7.29 (5H, m), 7.58 (1H, d, J = 15.8 Hz), 7.66–7.87 (3H, m ). MS (m / z): 308 [MH] +.
Ejemplo 41 Example 41
Preparación de N–hidroxi–3–(1H–bencimidazol–5–il)–acrilamida (51) Preparation of N-hydroxy-3– (1H-benzimidazol-5-yl) -acrylamide (51)
El compuesto del título (51) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los 5 materiales de partida apropiados. HPLC: 99%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 0,99 min. 1H RMN 10 (400 MHz, DMSO–d6) 6,62 (1H, d, J = 15,8 Hz), 7,74 (1H, d, J = 15,8 Hz), 7,85–7,99 (3H, m), 9,32 (1H, s). MS (m/z): 204 [MH]+. The title compound (51) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 0.99 min. 1 H NMR 10 (400 MHz, DMSO – d6) 6.62 (1H, d, J = 15.8 Hz), 7.74 (1H, d, J = 15.8 Hz), 7.85–7, 99 (3H, m), 9.32 (1H, s). MS (m / z): 204 [MH] +.
Ejemplo 42 Example 42
Preparación de N–hidroxi–3–[1–metil–2–(3–fenil–propil)–1H–15 bencimida-zol–5–il]–acrilamida (52) Preparation of N-hydroxy-3– [1-methyl-2– (3-phenyl-propyl) –1H-15 benzimide-zol-5-yl] -acrylamide (52)
Etapa 1 Stage 1
A una solución previamente agitada de trans–4–(metilamina)–3–nitrocinamato de metilo (1,0 g, 4,0 mmol; preparado tal como se describió en el ejemplo 1) en 40 ml de 20 metanol y 10 ml de ácido acético glacial, se añadió cloruro de estaño (3,0 g, 16,0 mmol). La solución resultante se calentó hasta 55 C durante 24 horas y luego se enfrió hasta temperatura ambiente. El solvente se eliminó y la mezcla se neutralizó con bicarbonato de sodio hasta pH = 8. El producto 25 crudo se extrajo con diclorometano (20 ml) tres veces. Los extractos orgánicos se combinaron y se lavaron dos veces con agua (10 ml) y una con salmuera (10 ml) y luego se secaron sobre Na2SO4 durante 1 hora, se filtraron y se concentraron. El producto trans–4–(metilamina)–3–aminocinamato de metilo se 30 obtuvo con un rendimiento del 82,5% (726 mg). MS (m/z): 207 [MH]+. To a previously stirred solution of trans-4– (methylamine) –3-methyl nitrocinamate (1.0 g, 4.0 mmol; prepared as described in example 1) in 40 ml of methanol and 10 ml of glacial acetic acid, tin chloride (3.0 g, 16.0 mmol) was added. The resulting solution was heated to 55 ° C for 24 hours and then cooled to room temperature. The solvent was removed and the mixture was neutralized with sodium bicarbonate until pH = 8. The crude product was extracted with dichloromethane (20 ml) three times. The organic extracts were combined and washed twice with water (10 ml) and once with brine (10 ml) and then dried over Na2SO4 for 1 hour, filtered and concentrated. The trans-4– (methylamine) -3-methyl aminocinamate product was obtained in 82.5% yield (726 mg). MS (m / z): 207 [MH] +.
Etapa 2 Stage 2
Se mezclaron ácido 4–fenilbutírico (68 mg, 0,41 mmol), trans–4–(metilamina)–3–aminocinamato de metilo (85 mg, 0,40 mmol) y PyBOP (236 mg, 0,46 mmol) en un recipiente de fondo redondo de 25 ml con 10 ml de diclorometano seco. La mezcla 5 resultante se agitó bajo una atmósfera de nitrógeno durante 5 minutos. Se inyectó DIEA (288 ul, 1,62 mmol) y la mezcla resultante se agitó a temperatura ambiente durante otras 4 horas. El progreso de la reacción se monitorizó por CCD. Los productos de acoplamiento, éster metílico del ácido 3–{3–10 amino–4–[metil–(4–fenil–butiril)amino]–fenil}–acrílico y éster metílico del ácido 3–[4–metilamino–3–(4–fenil–butirilamino)–fenil]–acrílico, se obtuvieron (110 mg 78%) después de la purificación, usando cromatografía en columna. (Sistema de solventes: acetato de etilo : hexano = 1:1) MS 15 (m/z): 353 [MH]+. 4-Phenylbutyric acid (68 mg, 0.41 mmol), trans-4- (methylamine) -3-methyl aminocinamate (85 mg, 0.40 mmol) and PyBOP (236 mg, 0.46 mmol) were mixed in a 25 ml round bottom container with 10 ml of dry dichloromethane. The resulting mixture 5 was stirred under a nitrogen atmosphere for 5 minutes. DIEA (288 ul, 1.62 mmol) was injected and the resulting mixture was stirred at room temperature for another 4 hours. The progress of the reaction was monitored by CCD. Coupling products, 3– {3–10 amino-4– [methyl- (4-phenyl-butyryl) amino] –phenyl} -acrylic acid methyl ester and 3– [4-methylamino-3– (4-Phenyl-butylamino) -phenyl] -acrylic, were obtained (110 mg 78%) after purification, using column chromatography. (Solvent system: ethyl acetate: hexane = 1: 1) MS 15 (m / z): 353 [MH] +.
Etapa 3 Stage 3
Los productos de acoplamiento anteriores (59 mg, 0,17 mmol) se calentaron con 5 ml de ácido acético glacial a 70C durante 4 horas. Tras enfriar hasta temperatura ambiente, el 20 producto puro, éster metílico del ácido 3–[1–metil–2–(3–fenil–propil)–1H–bencimidazol–5–il]–acrílico, se obtuvo cuantitativamente eliminando el ácido acético glacial al vacío. 1H RMN (400 MHz, DMSO–d6) 2,14 (2H, m), 2,75 (2H, t), 3,14 (2H, t), 3,95 (3H, s), 6,58 (1H, d), 7,16–7,30 (5H, m), 25 7,65 (1H.d), 7,72 (1H, d), 7,90 (2H, m). MS (m/z): 335 [MH]+. The above coupling products (59 mg, 0.17 mmol) were heated with 5 ml of glacial acetic acid at 70C for 4 hours. After cooling to room temperature, the pure product, methyl ester of 3– [1-methyl-2– (3-phenyl-propyl) -1H-benzimidazol-5-yl] -acrylic acid, was obtained quantitatively by eliminating acetic acid vacuum glacial. 1 H NMR (400 MHz, DMSO – d6) 2.14 (2H, m), 2.75 (2H, t), 3.14 (2H, t), 3.95 (3H, s), 6.58 (1H, d), 7.16-7.30 (5H, m), 7.65 (1H.d), 7.72 (1H, d), 7.90 (2H, m). MS (m / z): 335 [MH] +.
Etapa 4 Stage 4
Se preparó el compuesto del título (52) de acuerdo con los procedimientos para preparar ácido hidroxámico tal como se describió en el ejemplo 1, usando los materiales de 30 partida apropiados. HPLC: 99,8%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5– The title compound (52) was prepared according to the procedures for preparing hydroxamic acid as described in example 1, using the appropriate starting materials. HPLC: 99.8%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–
65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 5,01 min. 1H RMN (400 MHz, DMSO–d6) 2,14 (2H, m), 2,75 (2H, t), 3,14 (2H, t), 3,95 (3H, s), 6,58 (1H, d), 7,16–7,30 (5H, m), 7,65 (1H.d), 7,72 (1H, d), 5 7,90 (2H, m), 10,89 (1H, bs).MS (m/z): 336 [MH]+. 65% B for 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 5.01 min. 1 H NMR (400 MHz, DMSO – d6) 2.14 (2H, m), 2.75 (2H, t), 3.14 (2H, t), 3.95 (3H, s), 6.58 (1H, d), 7.16–7.30 (5H, m), 7.65 (1H.d), 7.72 (1H, d), 5 7.90 (2H, m), 10.89 (1H, bs) .MS (m / z): 336 [MH] +.
Ejemplo 43 Example 43
Preparación de N–hidroxi–3–[1–(3–imidazol–1–il–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida (56) Preparation of N-hydroxy-3– [1– (3-imidazol-1-yl-propyl) –2-phenethyl-1H-benzimidazol-5-yl] -acrylamide (56)
El compuesto del título (56) se preparó de acuerdo con 10 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 98,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 15 0,1% de ácido trifluoroacético; UV 254): 3,50 min. 1H RMN (400 MHz, CD3OD) 2,20 (2H, m), 3,19 (2H, m), 3,39 (2H, t, J = 7,6 Hz), 4,28 (4H, t, J = 7,6 Hz), 6,52 (1H, d, J = 16,0 Hz), 7.,17 (5H, m), 7,52 (1H, t, J = 1,5 Hz), 7,58 (1H, t, J = 1,6 Hz), 7,65 (1H, d, J = 16,0 Hz), 7,68 (2H, s), 7,85 (1H, 20 s), 8,84(1H, s); 13C RMN (100 MHz, CD3OD) 29,3, 30,7, 34,4, 42,4, 47,6, 113,0. 116,2, 119,2, 121,6, 123,1, 125,7, 128,0. 129,6, 129,9, 133,7, 135,1, 136,6, 137,2, 140,7, 140,9, 156,5, 166,0. MS (m/z): 416 [MH]+. The title compound (56) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 98.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.50 min. 1H NMR (400 MHz, CD3OD) 2.20 (2H, m), 3.19 (2H, m), 3.39 (2H, t, J = 7.6 Hz), 4.28 (4H, t , J = 7.6 Hz), 6.52 (1H, d, J = 16.0 Hz), 7., 17 (5H, m), 7.52 (1H, t, J = 1.5 Hz) , 7.58 (1H, t, J = 1.6 Hz), 7.65 (1H, d, J = 16.0 Hz), 7.68 (2H, s), 7.85 (1H, 20 s ), 8.84 (1H, s); 13C NMR (100 MHz, CD3OD) 29.3, 30.7, 34.4, 42.4, 47.6, 113.0. 116.2, 119.2, 121.6, 123.1, 125.7, 128.0. 129.6, 129.9, 133.7, 135.1, 136.6, 137.2, 140.7, 140.9, 156.5, 166.0. MS (m / z): 416 [MH] +.
Ejemplo 44 25 Example 44 25
Preparación de N–hidroxi–3–[1–(4–dimetilamino–butil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida (57) Preparation of N-hydroxy-3– [1– (4-dimethylamino-butyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide (57)
El compuesto del título (57) se preparó de acuerdo con los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 97,0%; tR = (LC/PDA: 30 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con The title compound (57) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: 30 Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% B for 15.5 min, solvent A: H2O with
0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,70 min. 1H RMN (400 MHz, CD3OD) 1,71 (4H, m), 2,82 (6H, s), 3,05 (2H, t, J = 7,1 Hz), 3,21 (2H, t, J = 7,6 Hz), 3,44 (2H, t, J = 7,5 Hz), 4,27 (2H, t, J = 7,5 Hz), 6,53 (1H, d, J = 16,0 Hz), 5 7,20 (5H, m), 7,65 (1H, d, J = 16,0 Hz), 7,73 (2H, m), 7,85 (1H, s); 13C RMN (100 MHz, CD3OD) 22,8, 27,3, 29,1, 34,2, 43,5, 45,1, 58,3, 113,5, 115,6, 119,6, 125,9, 128,1, 129,5, 130,0. 134,2, 134,7, 140,4, 140,6, 156,2, 162,7, 165,9. MS (m/z): 407 [MH]+. 10 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.70 min. 1H NMR (400 MHz, CD3OD) 1.71 (4H, m), 2.82 (6H, s), 3.05 (2H, t, J = 7.1 Hz), 3.21 (2H, t , J = 7.6 Hz), 3.44 (2H, t, J = 7.5 Hz), 4.27 (2H, t, J = 7.5 Hz), 6.53 (1H, d, J = 16.0 Hz), 5 7.20 (5H, m), 7.65 (1H, d, J = 16.0 Hz), 7.73 (2H, m), 7.85 (1H, s) ; 13C NMR (100 MHz, CD3OD) 22.8, 27.3, 29.1, 34.2, 43.5, 45.1, 58.3, 113.5, 115.6, 119.6, 125 , 9, 128.1, 129.5, 130.0. 134.2, 134.7, 140.4, 140.6, 156.2, 162.7, 165.9. MS (m / z): 407 [MH] +. 10
Ejemplo 45 Example 45
Preparación de N–hidroxi–3–[1–(3–hidroxi–propil)–2–isobutil–1H–benci-midazol–5–il]–acrilamida (29) Preparation of N-hydroxy-3– [1– (3-hydroxy-propyl) -2-isobutyl-1H-benzimidazole-5-yl] -acrylamide (29)
Se hidrógeno éster metílico del ácido 3–[1–(3–hidroxi–15 propil)–2–isobutil–1H–bencimidazol–5–il]–acrílico (preparado de acuerdo con el ejemplo 1, etapas 1–3) (126,6 mg, 0,4 mmol) y Pd/C al 10% (40 mg) en 10 ml de MeOH, utilizando un balón de hidrógeno durante toda la noche. Después de filtrar a través de una columna corta de gel de sílice, el filtrado se 20 evaporó a presión reducida para dar éster metílico del ácido 3–[1–(3–hidroxi–propil)–2–isobutil–1H–bencimidazol–5–il]–propiónico (127 mg) con rendimiento cuantitativo: MS m/z (M+H)+: 319; 1H RMN (400 MHz, MeOD) 0,95 (6H, d, J = 6,4 Hz), 1,92 (2H, m), 2,19 (1H, m), 2,60 (2H, t, J = 8,0 Hz), 25 2,74 (2H, d, J = 7,2 Hz), 2,96 (2H, t, J = 7,6 Hz), 3,50 (2H, t, J = 4,1 Hz), 3,54 (3H, s), 4,25 (2H, t, J = 7,2 Hz), 7,05 (1H, d, J = 8,0 Hz), 7,30–7,40 (2H, m); 13C RMN (100 MHz, MeOD) 20,9 (2C), 27,3, 30,1, 31,5, 34,6, 35,3, 39,5, 50,1, 57,4, 109,1, 116,4, 122,1, 132,6, 134,2, 141,3, 154,2, 173,2. 30 Hydrogen ester of 3– [1– (3-hydroxy-15 propyl) -2-isobutyl-1H-benzimidazol-5-yl] -acrylic acid (prepared according to example 1, steps 1–3) (126 , 6 mg, 0.4 mmol) and 10% Pd / C (40 mg) in 10 ml of MeOH, using a hydrogen balloon overnight. After filtering through a short column of silica gel, the filtrate was evaporated under reduced pressure to give 3– [1– (3-hydroxy-propyl) -2-isobutyl-1H-benzimidazole-5 methyl ester –Il] –propionic (127 mg) with quantitative yield: MS m / z (M + H) +: 319; 1 H NMR (400 MHz, MeOD) ,95 0.95 (6H, d, J = 6.4 Hz), 1.92 (2H, m), 2.19 (1H, m), 2.60 (2H, t , J = 8.0 Hz), 25 2.74 (2H, d, J = 7.2 Hz), 2.96 (2H, t, J = 7.6 Hz), 3.50 (2H, t, J = 4.1 Hz), 3.54 (3H, s), 4.25 (2H, t, J = 7.2 Hz), 7.05 (1H, d, J = 8.0 Hz), 7 , 30-7.40 (2H, m); 13C NMR (100 MHz, MeOD) 20.9 (2C), 27.3, 30.1, 31.5, 34.6, 35.3, 39.5, 50.1, 57.4, 109, 1, 116.4, 122.1, 132.6, 134.2, 141.3, 154.2, 173.2. 30
El compuesto del título (29) se preparó de acuerdo con The title compound (29) was prepared according to
el método descrito previamente para la preparación de ácido hidroxámico: MS m/z (M+H)+: 320; 1H RMN (400 MHz, MeOD) 1,00 (6H, d, J = 6,4 Hz), 2,06 (2H, m), 2,27 (1H, m), 2,42 (2H, t, J = 7,6 Hz), 3,05–3,11 (4H, m), 3,57 (2H, t, J = 6,0 Hz), 4,52 (2H, t, J = 7,2 Hz), 7,45 (1H, d, J = 8,0 Hz), 7,56 5 (1H, s), 7,78 (1H, d, J = 8,0 Hz); 13C RMN (100 MHz, MeOD) 20,6 (2C), 27,2, 30,4, 30,6, 32,7, 33,5, 41,5, 57,0. 112,0. 112,3, 112,4, 126,3, 129,9, 139,6, 152,3, 169,4. the method previously described for the preparation of hydroxamic acid: MS m / z (M + H) +: 320; 1 H NMR (400 MHz, MeOD) 1.00 (6H, d, J = 6.4 Hz), 2.06 (2H, m), 2.27 (1H, m), 2.42 (2H, t , J = 7.6 Hz), 3.05–3.11 (4H, m), 3.57 (2H, t, J = 6.0 Hz), 4.52 (2H, t, J = 7, 2 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.56 5 (1H, s), 7.78 (1H, d, J = 8.0 Hz); 13C NMR (100 MHz, MeOD) 20.6 (2C), 27.2, 30.4, 30.6, 32.7, 33.5, 41.5, 57.0. 112.0. 112.3, 112.4, 126.3, 129.9, 139.6, 152.3, 169.4.
Ejemplo 46 Example 46
Preparación de N–hidroxi–3–[2–(bencilamino–metil)–1–metil–1H–10 benci-midazol–5–il]–acrilamida (60) Preparation of N-hydroxy-3– [2– (benzylamino-methyl) -1-methyl-1H-10 benzimidazole-5-yl] -acrylamide (60)
Etapa 1 Stage 1
Se disolvió éster metílico del ácido 3–[2–(N–Fmoc–aminometil)–1–metil–1H–bencimidazol–5–il]–acrílico (43 mg, 0,176 mmol, preparado de acuerdo con el ejemplo 42, etapas 1–15 3, usando los materiales de partida apropiados) en 10 ml de diclorometano. La solución resultante se trató con 2,0 ml de piperidina. La eliminación de todo el solvente y la piperidina al vacío dieron éster metílico del ácido 3–(2–aminometil–1–metil–1H–bencimidazol–5–il)–acrílico. MS (m/z): 20 246 [MH]+. 3– [2– (N-Fmoc-aminomethyl) -1-methyl-1H-benzimidazol-5-yl] -acrylic acid methyl ester was dissolved (43 mg, 0.176 mmol, prepared according to example 42, steps 1 –15 3, using the appropriate starting materials) in 10 ml of dichloromethane. The resulting solution was treated with 2.0 ml of piperidine. Removal of all solvent and vacuum piperidine gave 3- (2-aminomethyl-1-methyl-1H-benzimidazol-5-yl) -acrylic acid methyl ester. MS (m / z): 20 246 [MH] +.
Etapa 2 Stage 2
Se disolvieron benzaldehído (47 mg, 0,445 mmol), éster metílico del ácido 3–(2–aminometil–1–metil–1H–bencimidazol–5–il)–acrílico (109 mg, 80%, 0,445 mmol) y ácido acético (27 25 mg, 0,445 mmol) en 15 ml de diclorometano. La mezcla se agitó a temperatura ambiente durante 1 hora. Se añadió triacetoxiborhidruro de sodio (142 mg, 95%, 0,668 mmol) a la solución anterior. La reacción se completó al cabo de 12 horas y la capa orgánica se lavó dos veces con NaHCO3 30 saturado (10 ml), seguido de lavado dos veces con agua (10 ml), una vez con salmuera (10 ml) y luego se secó sobre Na2SO4. Después de filtrar, se obtuvo el producto crudo (100 Benzaldehyde (47 mg, 0.445 mmol), 3– (2-aminomethyl-1-methyl-1 H -benzimidazol-5-yl) -acrylic acid (109 mg, 80%, 0.445 mmol) and acetic acid were dissolved 27 25 mg, 0.445 mmol) in 15 ml of dichloromethane. The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (142 mg, 95%, 0.668 mmol) was added to the above solution. The reaction was completed after 12 hours and the organic layer was washed twice with saturated NaHCO3 (10 ml), followed by washing twice with water (10 ml), once with brine (10 ml) and then dried about Na2SO4. After filtering, the crude product was obtained (100
mg, rendimiento del 67,6%), éster metílico del ácido 3–[2–(bencilamino–metil)–1–metil–1H–bencimidazol–5–il]–acrílico, eliminando el solvente. MS (m/z): 336 [MH]+. mg, 67.6% yield), 3– [2– (benzylamino-methyl) -1-methyl-1H-benzimidazol-5-yl] -acrylic acid methyl ester, eliminating the solvent. MS (m / z): 336 [MH] +.
Etapa 3 Stage 3
El compuesto del título (60) se preparó de acuerdo con 5 los procedimientos descritos en la Etapa 4 del ejemplo 1, utilizando éster metílico del ácido 3–[2–(bencilamino–metil)–1–metil–1H–bencimidazol–5–il]–acrílico como material de partida. HPLC: 89,6%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 10 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,68 min. 1H RMN (400 MHz, DMSO–d6) 3,78(3H, s), 4,37 (2H, s), 4,58 (2H, s), 6,48 (1H, d), 7,46 (3H, m), 7,55 (3H, m) 7,64 (2H, t) 7,88 (1H, s), 9,88 (1H, bs), 10,74 (1H, 15 bs). MS (m/z): 337 [MH]+. The title compound (60) was prepared according to the procedures described in Step 4 of Example 1, using 3– [2– (benzylamino-methyl) -1-methyl-1H-benzimidazole-5– methyl ester il] –acrylic as starting material. HPLC: 89.6%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 10 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.68 min. 1 H NMR (400 MHz, DMSO – d6) 3.78 (3H, s), 4.37 (2H, s), 4.58 (2H, s), 6.48 (1H, d), 7.46 (3H, m), 7.55 (3H, m) 7.64 (2H, t) 7.88 (1H, s), 9.88 (1H, bs), 10.74 (1H, 15 bs). MS (m / z): 337 [MH] +.
Ejemplo 47 Example 47
Preparación de N–hidroxi–3–[1–(3–dimetilamino–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida (63) Preparation of N-hydroxy-3– [1– (3-dimethylamino-propyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide (63)
El compuesto del título (63) se preparó de acuerdo con 20 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 100%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 25 0,1% de ácido trifluoroacético; UV 254): 3,52 min. 1H RMN (400 MHz, DMSO–d6) 2,09 (2H, m), 2,75 (3H, s), 2,76 (3H, s), 3,12–3,22 (4H, m), 3,37 (2H, b), 4,50 (2H, b), 6,55 (1H, d, J = 15,76 Hz), 7,22–7,34 (5H, m), 7,63 (1H, d, J = 15,76 Hz), 7,66 (1H, d, J = 7,80 Hz), 7,82 (1H, d, 7,80 Hz), 7,92 30 (1H, s). MS (m/z): 393 [MH]+. The title compound (63) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.52 min. 1 H NMR (400 MHz, DMSO – d6) 2.09 (2H, m), 2.75 (3H, s), 2.76 (3H, s), 3.12–3.22 (4H, m) , 3.37 (2H, b), 4.50 (2H, b), 6.55 (1H, d, J = 15.76 Hz), 7.22–7.34 (5H, m), 7, 63 (1H, d, J = 15.76 Hz), 7.66 (1H, d, J = 7.80 Hz), 7.82 (1H, d, 7.80 Hz), 7.92 30 (1H , s). MS (m / z): 393 [MH] +.
Ejemplo 48 Example 48
Preparación de N–hidroxi–3–[2–(bencilamino–metil)–etil–1H–bencimida-zol–5–il]–acrilamida (64) Preparation of N-hydroxy-3– [2– (benzylamino-methyl) -ethyl-1H-benzimide-zol-5-yl] -acrylamide (64)
El compuesto del título (64) se preparó de acuerdo con los procedimientos descritos en el ejemplo 46, usando los materiales de partida apropiados. HPLC: 98,5%; tR = (LC/PDA: 5 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,52 min. 1H RMN (400 MHz, DMSO–d6) 1,31 (3H, t) 3,37(2H, m), 3,50 (2H, t), 10 4,28 (4H, m), 6,48 (1H, d), 7,43–50 (3H, m), 7,55 (3H, m) 7,73–7,83 (2H, t) 7,95 (1H, s), 9,25 (1H, bs), 10,76 (1H, bs). MS (m/z): 351 [MH]+. The title compound (64) was prepared according to the procedures described in example 46, using the appropriate starting materials. HPLC: 98.5%; tR = (LC / PDA: 5 column Phenomenex Luna C18 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.52 min. 1 H NMR (400 MHz, DMSO – d6) 1.31 (3H, t) 3.37 (2H, m), 3.50 (2H, t), 10 4.28 (4H, m), 6.48 (1H, d), 7.43–50 (3H, m), 7.55 (3H, m) 7.73–7.83 (2H, t) 7.95 (1H, s), 9.25 ( 1H, bs), 10.76 (1H, bs). MS (m / z): 351 [MH] +.
Ejemplo 49 Example 49
Preparación de N–hidroxi–3–(2–(bencil–1–metil–3–oxo–1H–15 bencimida-zol–5–il)–acrilamida (65) Preparation of N-hydroxy-3– (2– (benzyl-1-methyl-3-oxo-1H-15 benzimide-zol-5-yl) -acrylamide (65)
El compuesto del título (65) se preparó de acuerdo con los procedimientos descritos en el ejemplo 42, usando los materiales de partida apropiados. HPLC: 99%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 20 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 4,48 min. 1H RMN (400 MHz, DMSO–d6) 3,87 (3H, s), 4,59 (2H, s), 6,57 (1H, d, J =15,9 Hz), 7,09–7,36 (5H, m), 7,62 (1H, d, J = 15,8 Hz), 25 7,73–7,95 (3H, m). MS (m/z): 309 [MH]+. The title compound (65) was prepared according to the procedures described in example 42, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 20 gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 4.48 min. 1H NMR (400 MHz, DMSO – d6) 3.87 (3H, s), 4.59 (2H, s), 6.57 (1H, d, J = 15.9 Hz), 7.09–7 , 36 (5H, m), 7.62 (1H, d, J = 15.8 Hz), 7.73-7.95 (3H, m). MS (m / z): 309 [MH] +.
Ejemplo 50 Example 50
Preparación de N–hidroxi–3–[1–(2–dietilamino–etil)–2–fenetil–1H–benci-midazol–5–il]–acrilamida (66) Preparation of N-hydroxy-3– [1– (2-diethylamino-ethyl) -2-phenethyl-1H-benzimidazole-5-yl] -acrylamide (66)
El compuesto del título (66) se preparó de acuerdo con 30 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 100%; tR = (LC/PDA: The title compound (66) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA:
columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,72 min. 1H RMN (400 MHz, CD3OD) 1,29 (6H, t, J = 7,3 Hz), 3,26 (8H, m), 5 3,40 (2H, t, J = 7,5 Hz), 4,60 (2H, t, J = 8,0 Hz), 6,50 (1H, d, J = 16,0 Hz), 7,21 (5H, m), 7,62 (1H, d, J = 16,0 Hz), 7,70 (2H, m), 7,85 (1H, s); 13C RMN (100 MHz, CD3OD) 9,0. 29,4, 34,3, 39,9, 48,4, 50,3, 112,7, 116,6, 119,3, 125,8, 128,1, 129,6, 130,0. 133,9, 134,9, 137,6, 140,8, 157,0. 10 166,0. MS (m/z): 407 [MH]+. Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.72 min. 1H NMR (400 MHz, CD3OD) 1.29 (6H, t, J = 7.3 Hz), 3.26 (8H, m), 5. 3.40 (2H, t, J = 7.5 Hz) , 4.60 (2H, t, J = 8.0 Hz), 6.50 (1H, d, J = 16.0 Hz), 7.21 (5H, m), 7.62 (1H, d, J = 16.0 Hz), 7.70 (2H, m), 7.85 (1H, s); 13C NMR (100 MHz, CD3OD) 9.0. 29.4, 34.3, 39.9, 48.4, 50.3, 112.7, 116.6, 119.3, 125.8, 128.1, 129.6, 130.0. 133.9, 134.9, 137.6, 140.8, 157.0. 10 166.0. MS (m / z): 407 [MH] +.
Ejemplo 51 Example 51
Preparación de N–hidroxi–3–[2–fenetil–1–(piperidin–1–il–etil)–1H–benci-midazol–5–il]–acrilamida (67) Preparation of N-hydroxy-3– [2-phenethyl-1– (piperidin-1-yl-ethyl) –1 H –benzimidazole-5-yl] -acrylamide (67)
El compuesto del título (67) se preparó de acuerdo con 15 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 100%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 20 0,1% de ácido trifluoroacético; UV 254): 3,90 min. 1H RMN (400 MHz, CD3OD) 1,86 (6H, br s), 3,26 (8H, m), 3,40 (2H, t, J = 7,5 Hz), 4,62 (2H, t, J = 7,9 Hz), 6,50 (1H, d, J = 16,0 Hz), 7,23 (5H, m), 7,62 (1H, d, J = 16,0 Hz), 7,70 (2H), 7,84 (1H, s); 13C RMN (100 MHz, CD3OD) 22,5, 24,2, 29,4, 25 34,3, 39,6, 54,4, 54,9, 112,7, 116,6, 119,2, 125,7, 128,1, 129,6, 130,0. 133,8, 134,9, 137,8, 140,8, 157,0. 166,0. MS (m/z): 419 [MH]+. The title compound (67) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 20 0.1% trifluoroacetic acid; UV 254): 3.90 min. 1H NMR (400 MHz, CD3OD) 1.86 (6H, br s), 3.26 (8H, m), 3.40 (2H, t, J = 7.5 Hz), 4.62 (2H, t, J = 7.9 Hz), 6.50 (1H, d, J = 16.0 Hz), 7.23 (5H, m), 7.62 (1H, d, J = 16.0 Hz) , 7.70 (2H), 7.84 (1H, s); 13C NMR (100 MHz, CD3OD) 22.5, 24.2, 29.4, 25 34.3, 39.6, 54.4, 54.9, 112.7, 116.6, 119.2, 125.7, 128.1, 129.6, 130.0. 133.8, 134.9, 137.8, 140.8, 157.0. 166.0. MS (m / z): 419 [MH] +.
Ejemplo 52 Example 52
Preparación de N–hidroxi–3–[2–fenetil–1–(2–pirrolidin–1–il–30 etil)–1H–bencimidazol–5–il]–acrilamida (72) Preparation of N-hydroxy-3– [2-phenethyl-1– (2-pyrrolidin-1-yl-30 ethyl) –1H-benzimidazol-5-yl] -acrylamide (72)
El compuesto del título (72) se preparó de acuerdo con The title compound (72) was prepared according to
los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 100%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 5 0,1% de ácido trifluoroacético; UV 254): 3,71 min. 1H RMN (400 MHz, CD3OD) 2,06 (4H, br), 3,21 (2H, t, J = 7,4 Hz), 3,26 (4H, m), 3,37 (2H, t, J = 7,7 Hz), 3,42 (2H, t, J = 7,5 Hz), 4,57 (2H, t, J = 7,4 Hz), 6,47 (1H, d, J = 16,0 Hz), 7,21 (5H, m), 7,58 (1H, d, J = 16,0 Hz), 7,67 (1H, d, J = 8,6 10 Hz), 7,74 (1H, d, J = 8,6 Hz), 7,83 (1H, s); 13C RMN (100 MHz, CD3OD) 24,1, 29,4, 34,3, 41,1, 52,8, 55,7, 112,9, 116,5, 119,2, 125,8, 128,1, 129,6, 130,0. 133,9, 134,9, 137,2, 140,7, 140,8, 157,0. 165,9. MS (m/z): 405 [MH]+. the procedures described in example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 5 0.1% trifluoroacetic acid; UV 254): 3.71 min. 1H NMR (400 MHz, CD3OD) 2.06 (4H, br), 3.21 (2H, t, J = 7.4 Hz), 3.26 (4H, m), 3.37 (2H, t , J = 7.7 Hz), 3.42 (2H, t, J = 7.5 Hz), 4.57 (2H, t, J = 7.4 Hz), 6.47 (1H, d, J = 16.0 Hz), 7.21 (5H, m), 7.58 (1H, d, J = 16.0 Hz), 7.67 (1H, d, J = 8.6 10 Hz), 7 , 74 (1H, d, J = 8.6 Hz), 7.83 (1H, s); 13C NMR (100 MHz, CD3OD) 24.1, 29.4, 34.3, 41.1, 52.8, 55.7, 112.9, 116.5, 119.2, 125.8, 128 , 1, 129.6, 130.0. 133.9, 134.9, 137.2, 140.7, 140.8, 157.0. 165.9. MS (m / z): 405 [MH] +.
Ejemplo 53 15 Example 53 15
Preparación de N–hidroxi–3–[2–(2–bencilamino–etil)–1–etil––1H–benci-midazol–5–il]–acrilamida (74) Preparation of N-hydroxy-3– [2– (2-benzylamino-ethyl) –1-ethyl –– 1H-benzyl-midazol-5-yl] -acrylamide (74)
El compuesto del título (74) se preparó de acuerdo con los procedimientos descritos en el ejemplo 46, usando los materiales de partida apropiados. HPLC: 98,5%; tR = (LC/PDA: 20 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 3,52 min. 1H RMN (400 MHz, DMSO–d6) 1,31 (3H, t) 3,37(2H, m), 3,50 (2H, t), 25 4,28 (4H, m), 6,48 (1H, d), 7,43–50 (3H, m), 7,55 (3H, m) 7,73–7,83 (2H, t) 7,95 (1H, s), 9,25 (1H, bs), 10,76 (1H, bs). MS (m/z): 365 [MH]+. The title compound (74) was prepared according to the procedures described in example 46, using the appropriate starting materials. HPLC: 98.5%; tR = (LC / PDA: 20 Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.52 min. 1 H NMR (400 MHz, DMSO – d6) 1.31 (3H, t) 3.37 (2H, m), 3.50 (2H, t), 25 4.28 (4H, m), 6.48 (1H, d), 7.43–50 (3H, m), 7.55 (3H, m) 7.73–7.83 (2H, t) 7.95 (1H, s), 9.25 ( 1H, bs), 10.76 (1H, bs). MS (m / z): 365 [MH] +.
Ejemplo 54 Example 54
Preparación de N–hidroxi–3–[2–fenetil–1–(3–pirrolidin–1–il–30 propil)–1H–bencimidazol–5–il]–acrilamida (82) Preparation of N-hydroxy-3– [2-phenethyl-1– (3-pyrrolidin-1-yl-30 propyl) –1H-benzimidazol-5-yl] -acrylamide (82)
El compuesto del título (82) se preparó de acuerdo con The title compound (82) was prepared according to
los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 100%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 5 0,1% de ácido trifluoroacético; UV 254): 1,18 min. 1H RMN (400 MHz, CD3OD) 2,01 (2H), 2,17 (4H), 3,03 (2H), 3,26 (4H), 3,48 (2H), 3,62 (2H), 4,37 (2H), 6,60 (1H), 7,27 (5H), 7,71 (1H), 7,78 (2H), 7,91 (1H). MS (m/z): 419 [MH]+. the procedures described in example 1, using the appropriate starting materials. HPLC: 100%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 5 0.1% trifluoroacetic acid; UV 254): 1.18 min. 1H NMR (400 MHz, CD3OD) 2.01 (2H), 2.17 (4H), 3.03 (2H), 3.26 (4H), 3.48 (2H), 3.62 (2H) , 4.37 (2H), 6.60 (1H), 7.27 (5H), 7.71 (1H), 7.78 (2H), 7.91 (1H). MS (m / z): 419 [MH] +.
Ejemplo 55 10 Example 55 10
Preparación de N–hidroxi–3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–(2–piridin–3–il–etil)–1H–bencimidazol–5–il]–acrilamida (86) Preparation of N-hydroxy-3– [1– (3-dimethylamino-2,2-dimethyl-propyl) -2- (2-pyridin-3-yl-ethyl) –1H-benzimidazole-5-yl] -acrylamide ( 86)
El compuesto del título (86) se preparó de acuerdo con los procedimientos descritos en el ejemplo 42, usando los 15 materiales de partida apropiados. HPLC: 90,4%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 1,24 min. 1H RMN 20 (400 MHz, DMSO–d6) 1,00 (6H, s), 2,94 (6H, s), 3,32 (2H, m), 3,38 (4H, m) 4,35 (2H, m), 6,52 (1H, d), 7,58–7,86 (5H, m) 8,20 (1H, d), 8,65 (1H, m) 8,77 (1H, s), 9,50 (1H, s). MS (m/z): 422 [MH]+. The title compound (86) was prepared according to the procedures described in example 42, using the appropriate starting materials. HPLC: 90.4%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.24 min. 1 H NMR 20 (400 MHz, DMSO – d6) 1.00 (6H, s), 2.94 (6H, s), 3.32 (2H, m), 3.38 (4H, m) 4.35 (2H, m), 6.52 (1H, d), 7.58-7.86 (5H, m) 8.20 (1H, d), 8.65 (1H, m) 8.77 (1H, s), 9.50 (1H, s). MS (m / z): 422 [MH] +.
Ejemplo 56 25 Example 56 25
Preparación de hidroxiamida del ácido 2–[2–fenetil–1–(3,4,5–trimetoxi–bencil)–1H–bencimidazol–5–il]–ciclopropancarboxílico (88) Preparation of 2– [2-phenethyl-1– (3,4,5-trimethoxy-benzyl) -1H-benzimidazol-5-yl] -cyclopropancarboxylic acid hydroxyamide (88)
Etapa 1 Stage 1
A una solución de (CH3)3S(O)I (132 mg, 0,6 mmol) en 30 DMSO anhidro (1 ml) se añadió hidruro de sodio (28 mg, 60% en aceite mineral) a temperatura ambiente bajo gas nitrógeno, To a solution of (CH3) 3S (O) I (132 mg, 0.6 mmol) in anhydrous 30 DMSO (1 ml) was added sodium hydride (28 mg, 60% in mineral oil) at room temperature under nitrogen gas ,
luego se adicionó una solución del compuesto (244 mg, 0,5 mmol), éster metílico del ácido 3–[2–fenetil–1–(3,4,5–trimetoxi–bencil)–1H–bencimidazol–5–il]–acrílico (preparado de acuerdo con el ejemplo 1, etapas 1–3), en 4 ml de THF anhidro al cabo de 10 min. La mezcla resultante se agitó 5 luego a temperatura ambiente durante toda la noche. Después de una elaboración acuosa, el residuo se obtuvo en forma de aceite (135 mg), que luego se sometió a la siguiente etapa sin posterior purificación. then a solution of the compound (244 mg, 0.5 mmol), 3– [2-phenethyl-1– (3,4,5-trimethoxy-benzyl) -1H-benzimidazole-5-yl] acid methyl ester was added -Acrylic (prepared according to example 1, steps 1–3), in 4 ml of anhydrous THF after 10 min. The resulting mixture was then stirred at room temperature overnight. After an aqueous preparation, the residue was obtained as an oil (135 mg), which was then subjected to the next step without further purification.
Etapa 2 10 Stage 2 10
A una solución del producto bruto anterior en 0,5 ml de MeOH se añadió una solución madre de NH2OH 2,0 M previamente preparada como hicimos con anterioridad (2 ml). La mezcla resultante se agitó a temperatura ambiente durante 4 h. Tras neutralizar con TFA (0,4 ml), la mezcla resultante se sometió 15 a purificación con HPLC para obtener 10 mg del compuesto deseado que figura en el título (88). HPLC: 99%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: 20 acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 6,36 min. 1H RMN (400 MHz, CD3OD) 1,21–1,29 (1H, m), 1,45–1,52 (1H, m), 1,75–1,79 (1H, m), 2,48–2,55 (1H, m), 2,99 (2H, t, J = 8,0 Hz), 3,45 (2H, t, J = 8,0 Hz), 3,61 (6H, s), 3,64 (3H, s), 5,42 (2H, s), 6,40 (2H, s), 7,00–7,18 (5H, m), 7,26 25 (1H, d, J = 8,4 Hz), 7,45 (1H, s), 7,59 (1H, d, J = 8,4 Hz). MS (m/z): 502 [MH]+. To a solution of the above crude product in 0.5 ml of MeOH was added a stock solution of 2.0 M NH2OH previously prepared as we did previously (2 ml). The resulting mixture was stirred at room temperature for 4 h. After neutralizing with TFA (0.4 ml), the resulting mixture was subjected to HPLC purification to obtain 10 mg of the desired compound in the title (88). HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: 20 acetonitrile with 0.1% trifluoroacetic acid; UV 254): 6.36 min. 1H NMR (400 MHz, CD3OD) 1.21-1.29 (1H, m), 1.45-1.52 (1H, m), 1.75-1.79 (1H, m), 2, 48–2.55 (1H, m), 2.99 (2H, t, J = 8.0 Hz), 3.45 (2H, t, J = 8.0 Hz), 3.61 (6H, s ), 3.64 (3H, s), 5.42 (2H, s), 6.40 (2H, s), 7.00–7.18 (5H, m), 7.26 (1H, d , J = 8.4 Hz), 7.45 (1H, s), 7.59 (1H, d, J = 8.4 Hz). MS (m / z): 502 [MH] +.
Ejemplo 57 Example 57
Preparación de N–hidroxi–3–[2–bencilsulfanil–1–(3–dimetilamino–2–2,dimetil–propil)–1H–bencimidazol–5–il]–30 acrilamida (89) Preparation of N-hydroxy-3– [2-benzylsulfanyl-1– (3-dimethylamino-2–2, dimethyl-propyl) –1H-benzimidazol-5-yl] –30 acrylamide (89)
Etapa 1 Stage 1
Se mezclaron ácido 3–[4–(3–dimetilamino–2,2–dimetil– 3– [4– (3-Dimethylamino – 2,2-dimethyl–) acid was mixed
propila-mino)–3–nitro–fenil]–acrílico (1,93 g, 6,0 mmol, preparado tal como se describió en el ejemplo 1, etapa 1), cloruro de estaño (13,5 g, 60 mmol) y MeOH (50 ml) y se calentó a 45 C durante 20 horas. La mezcla de reacción se enfrió hasta temperatura ambiente y se eliminó el solvente a 5 presión reducida. Al residuo se añadieron 100 ml de diclorometano y 100 ml de agua. El pH se ajustó hasta 10 con amoníaco concentrado. Las capas se separaron y la fase acuosa se extrajo con 100 ml de diclorometano. Los extractos orgánicos se combinaron, se secaron sobre sulfato de sodio, 10 se filtraron y el solvente se eliminó a presión reducida. Al residuo resultante se añadió MeOH (100 ml), CS2 (18 ml) e hidróxido de potasio (3,4 g). La mezcla de reacción se calentó a 80C durante 16 horas, luego se enfrió hasta temperatura ambiente y los solventes se eliminaron a presión 15 reducida. El producto crudo resultante se recristalizó en MeOH. propylamino) -3-nitro-phenyl] -acrylic (1.93 g, 6.0 mmol, prepared as described in example 1, step 1), tin chloride (13.5 g, 60 mmol) and MeOH (50 ml) and heated at 45 ° C for 20 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. 100 ml of dichloromethane and 100 ml of water were added to the residue. The pH was adjusted to 10 with concentrated ammonia. The layers were separated and the aqueous phase was extracted with 100 ml of dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. To the resulting residue was added MeOH (100 ml), CS2 (18 ml) and potassium hydroxide (3.4 g). The reaction mixture was heated at 80C for 16 hours, then cooled to room temperature and the solvents were removed under reduced pressure. The resulting crude product was recrystallized from MeOH.
El producto, ácido 3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–tioxo–2,3–dihidro–1H–bencimidazol–5–il]–acrílico, se obtuvo con un rendimiento del 75% en dos etapas (1,5 g). 20 MS (m/z): 334 [MH]+. The product, 3– [1– (3-dimethylamino-2,2-dimethyl-propyl) -2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl] -acrylic acid, was obtained in a yield of 75% in two stages (1.5 g). 20 MS (m / z): 334 [MH] +.
Etapa 2 Stage 2
Se mezclaron ácido 3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–tioxo–2,3–dihidro–1H–bencimidazol–5–il]–acrílico (100 mg , 0,3 mmol), bromuro de bencilo (360 mg, 3,6 mmol) y 25 carbonato de potasio (0,83 g) con 10 ml de DMF. La mezcla resultante se agitó durante toda la noche a 45 C. El producto deseado, éster bencílico del ácido3–[2–bencilsulfanil–1–(3–dimetilamino–2,2–dimetil–propil)–2,3–dihidro–1H–bencimidazol–5–il]–acrílico, se purificó por HPLC 30 preparativa: 150 mg (rendimiento del 76,6%). 1H RMN (400 MHz, DMSO–d6) 1,08 (6H, s), 2,88 (3H, s), 2,89 (3H, s), 3,30 3– [1– (3-Dimethylamino-2,2-dimethyl-propyl) -2-thioxo-2,3-dihydro-1 H -benzimidazole-5-yl] -acrylic acid (100 mg, 0.3 mmol) ), benzyl bromide (360 mg, 3.6 mmol) and potassium carbonate (0.83 g) with 10 ml of DMF. The resulting mixture was stirred overnight at 45 ° C. The desired product, benzyl ester of 3-3-[2-benzylsulfanyl-1- (3-dimethylamino-2,2-dimethyl-propyl) -2,3-dihydro- 1H-benzimidazol-5-yl] -acrylic, was purified by preparative HPLC: 150 mg (76.6% yield). 1H NMR (400 MHz, DMSO – d6) 1.08 (6H, s), 2.88 (3H, s), 2.89 (3H, s), 3.30
(2H), 4,11 (2H, s), 4,65 (2H, s), 5,24 (2H, s), 6,72 (2H, d, J = 15,96 Hz), 7,26–7,47 (10H, m), 7,68(2H, bs), 7,83 (1H, d, J = 15,96 Hz), 8,00(1H, s). MS (m/z): 514 [MH]+. (2H), 4.11 (2H, s), 4.65 (2H, s), 5.24 (2H, s), 6.72 (2H, d, J = 15.96 Hz), 7.26 –7.47 (10H, m), 7.68 (2H, bs), 7.83 (1H, d, J = 15.96 Hz), 8.00 (1H, s). MS (m / z): 514 [MH] +.
Etapa 3 Stage 3
El compuesto del título (89) se obtuvo por tratamiento 5 del éster bencílico del ácido 3–[2–bencilsulfanil–1–(3–dimetilamino–2,2–dimetil–propil)–2,3–dihidro–1H–bencimidazol–5–il]–acrílico de acuerdo con el método previamente descrito para la preparación de ácido hidroxámico (Etapa 4 del ejemplo 1). HPLC: 99%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 10 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 2,87 min. 1H RMN (400 MHz, DMSO–d6) 1,09 (6H, s), 2,88 (3H, s), 2,89 (3H, s), 3,26 (2H), 4,11 (2H, s), 4,65 15 (2H, s), 6,48 (2H, d, J = 15,79 Hz), 7,26–7,47 (6H, m), 7,58(1H, d, J = 15,79 Hz), 7,65 (1H, d, J = 8,48 Hz), 7,80 (1H, s). MS (m/z): 439 [MH]+. The title compound (89) was obtained by treatment 5 of the 3– [2-benzylsulfanyl-1– (3-dimethylamino-2,2-dimethyl-propyl) -2,3-dihydro-1H-benzimidazole-acid benzyl ester 5 5-yl] -acrylic according to the method previously described for the preparation of hydroxamic acid (Step 4 of Example 1). HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 2.0 2.0 x 150 mm 5 column; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.87 min. 1H NMR (400 MHz, DMSO – d6) 1.09 (6H, s), 2.88 (3H, s), 2.89 (3H, s), 3.26 (2H), 4.11 (2H , s), 4.65 15 (2H, s), 6.48 (2H, d, J = 15.79 Hz), 7.26-7.47 (6H, m), 7.58 (1H, d , J = 15.79 Hz), 7.65 (1H, d, J = 8.48 Hz), 7.80 (1H, s). MS (m / z): 439 [MH] +.
Ejemplo 58 Example 58
Preparación de N–hidroxi–3–[1–(3–dimetilamino–2,2–dimetil–20 propil)–2–fenilmetansulfonil–1H–bencimidazol–5–il]–acrilamida (91) Preparation of N-hydroxy-3– [1– (3-dimethylamino-2,2-dimethyl-20 propyl) –2-phenylmethanesulfonyl-1H-benzimidazol-5-yl] -acrylamide (91)
Etapa 1 Stage 1
Se mezclaron 118 mg de éster bencílico del ácido 3–[2–bencilsulfanil–1–(3–dimetilamino–2,2–dimetil–propil)–2,3–25 dihidro–1H–bencimidazol–5–il]–acrílico (preparado de acuerdo con el ejemplo 57, etapas 1–2), 1,0 ml de peróxido de hidrógeno (30%) y 10 ml de ácido acético a 0 C en un baño de hielo. Sin añadir hielo adicional, la mezcla de reacción se agitó durante toda la noche. El producto, éster bencílico del 30 ácido 3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–fenilmetansulfinil–2,3–hidro–1H–bencimidazol–5–il]–acrílico, 118 mg of 3– [2-benzylsulfanyl-1– (3-dimethylamino-2,2-dimethyl-propyl) -2,3–25 dihydro-1 H -benzimidazole-5-yl] -acrylic acid benzyl ester was mixed prepared according to example 57, steps 1–2), 1.0 ml of hydrogen peroxide (30%) and 10 ml of acetic acid at 0C in an ice bath. Without adding additional ice, the reaction mixture was stirred overnight. The product, benzyl ester of 3– [1– (3-dimethylamino-2,2-dimethyl-propyl) -2-phenylmethanesulfinyl-2,3-hydro-1H-benzimidazole-5-yl] -acrylic acid,
se obtuvo de manera cuantitativa. MS (m/z): 530 [MH]+. It was obtained quantitatively. MS (m / z): 530 [MH] +.
Etapa 2 Stage 2
El compuesto del título (91) se obtuvo por tratamiento de éster bencílico del ácido 3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–fenilmetansulfinil–2,3–hidro–1H–5 bencimidazol–5–il]–acrílico de acuerdo con el método previamente descrito para la preparación de ácido hidroxámico (Etapa 4 del ejemplo 1). HPLC: 77,1%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido 10 trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 1,46 min. 1H RMN (400 MHz, DMSO–d6) 1,11 (6H, s), 2,90 (3H, s), 2,91 (3H, s), 3,12 (2H, s), 3,82 (2H, s), 4,79 (2H, s), 6,56 (1H, d, J = 15,80 Hz), 7,15–7,32 (5H, m), 7,59–7,66 (2H, m), 7,87 (1H, d, J = 8,68 Hz), 15 8,06(1H, s). MS (m/z): 455 [MH]+. The title compound (91) was obtained by treatment of benzyl ester of 3– [1– (3-dimethylamino-2,2-dimethyl-propyl) -2-phenylmethanesulfinyl-2,3-hydro-1H-5 benzimidazole-acid 5-yl] -acrylic according to the method previously described for the preparation of hydroxamic acid (Step 4 of Example 1). HPLC: 77.1%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.46 min. 1 H NMR (400 MHz, DMSO – d6) 1.11 (6H, s), 2.90 (3H, s), 2.91 (3H, s), 3.12 (2H, s), 3.82 (2H, s), 4.79 (2H, s), 6.56 (1H, d, J = 15.80 Hz), 7.15–7.32 (5H, m), 7.59–7, 66 (2H, m), 7.87 (1H, d, J = 8.68 Hz), 8.06 (1H, s). MS (m / z): 455 [MH] +.
Ejemplo 59 Example 59
Preparación de N–hidroxi–3–(2–bencil–1–etil–1H–bencimidazol–5–il)–acrilamida (92) Preparation of N-hydroxy-3– (2-benzyl-1-ethyl-1H-benzimidazol-5-yl) -acrylamide (92)
El compuesto del título (92) se preparó de acuerdo con 20 los procedimientos descritos en el ejemplo 42, usando los materiales de partida apropiados. HPLC: 97,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 25 0,1% de ácido trifluoroacético; UV 254): 1,60 min. 1H RMN (400 MHz, DMSO–d6) 1,17 (3H, t, J = 7,1 Hz), 4,34 (2H, dd, J = 6,8 Hz), 4,56 (2H, s), 6,55 (1H, d, J = 15,8 Hz), 7,31–7,40 (5H, m), 7,63 (1H, d, J = 15,8 Hz), 7,85–7,93 (3H, m). MS (m/z): 322 [MH]+. 30 The title compound (92) was prepared according to the procedures described in example 42, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.60 min. 1 H NMR (400 MHz, DMSO – d6) 1.17 (3H, t, J = 7.1 Hz), 4.34 (2H, dd, J = 6.8 Hz), 4.56 (2H, s ), 6.55 (1H, d, J = 15.8 Hz), 7.31–7.40 (5H, m), 7.63 (1H, d, J = 15.8 Hz), 7.85 –7.93 (3H, m). MS (m / z): 322 [MH] +. 30
Ejemplo 60 Example 60
Preparación de N–hidroxi–3–{1–etil–2–[3–(1H–indol–3–il)–Preparation of N-hydroxy-3– {1 – ethyl – 2– [3– (1H-indole-3-yl) -
propil]–1H–bencimidazol–5–il)–acrilamida (93) propyl] –1H – benzimidazol – 5-yl) –acrylamide (93)
El compuesto del título (93) se preparó de acuerdo con los procedimientos descritos en el ejemplo 42, usando los materiales de partida apropiados. HPLC: 98,5%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 5 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 1,98 min. 1H RMN (400 MHz, DMSO–d6) 1,33 (3H, t), 2,22 (2H, m), 2,87 (2H, t), 3,16 (2H, m), 4,37 (2H, m), 6,53 (1H, d), 6,98 (1H, m) 10 7,06 (1H, m) 7,19 (1H, s), 7,33 (1H.d), 7,54–7,88 (5H, d), 10,82 (2H, bs). MS (m/z): 389 [MH]+. The title compound (93) was prepared according to the procedures described in example 42, using the appropriate starting materials. HPLC: 98.5%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 5 gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.98 min. 1 H NMR (400 MHz, DMSO – d6) 1.33 (3H, t), 2.22 (2H, m), 2.87 (2H, t), 3.16 (2H, m), 4.37 (2H, m), 6.53 (1H, d), 6.98 (1H, m) 10 7.06 (1H, m) 7.19 (1H, s), 7.33 (1H.d), 7.54-7.88 (5H, d), 10.82 (2H, bs). MS (m / z): 389 [MH] +.
Ejemplo 61 Example 61
Preparación de N–hidroxi–3–{1–(3–dimetilamino–2,2–dimetil–propil)–2–[2–(3–metoxi–fenil)–etil]–1H–bencimidazol–5–il)–15 acrilamida (94) Preparation of N-hydroxy-3– {1– (3-dimethylamino-2,2-dimethyl-propyl) –2– [2– (3-methoxy-phenyl) -ethyl] –1H-benzimidazole-5-yl) - 15 acrylamide (94)
El compuesto del título (94) se preparó de acuerdo con los procedimientos descritos en el ejemplo 42, usando los materiales de partida apropiados. HPLC: 99,7%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, 20 gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 1,34 min. 1H RMN (400 MHz, DMSO–d6) 1,03 (6H, s), 2,90 (6H, s), 3,19 (2H, t), 3,34 (4H, s) 3,71 (3H, s) 4,29 (2H, t), 6,52 (1H, d), 25 6,80 (1H, m) 6,88 (2H, d) 7,22 (1H, m), 7,62 (2H.m), 7,83–7,89 (2H, m), 9,34 (1H, s), 10,77 (1H, bs). MS (m/z): 451 [MH]+. The title compound (94) was prepared according to the procedures described in example 42, using the appropriate starting materials. HPLC: 99.7%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, 20 gradient 5–65% B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.34 min. 1 H NMR (400 MHz, DMSO – d6) 1.03 (6H, s), 2.90 (6H, s), 3.19 (2H, t), 3.34 (4H, s) 3.71 ( 3H, s) 4.29 (2H, t), 6.52 (1H, d), 25 6.80 (1H, m) 6.88 (2H, d) 7.22 (1H, m), 7, 62 (2H.m), 7.83–7.89 (2H, m), 9.34 (1H, s), 10.77 (1H, bs). MS (m / z): 451 [MH] +.
Ejemplo 62 Example 62
Preparación de N–hidroxi–3–[1–etil–2–(3–fenoxi–propil)–1H–30 bencimida-zol–5–il]–acrilamida (96) Preparation of N-hydroxy-3– [1-ethyl-2– (3-phenoxy-propyl) –1H-30 benzimide-zol-5-yl] -acrylamide (96)
El compuesto del título (96) se preparó de acuerdo con The title compound (96) was prepared according to
los procedimientos descritos en el ejemplo 46, usando los materiales de partida apropiados. HPLC: 99,6%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 5 0,1% de ácido trifluoroacético; UV 254): 1,83 min. 1H RMN (400 MHz, DMSO–d6) 1,36 (3H, t), 2,32 (2H, m), 3,34 (2H, m), 4,12 (2H, m), 4,46 (2H, m), 6,58 (1H, d), 6,73 (2H, d) 6,90 (1H, m) 7,22 (2H, m), 7,65 (1H, d), 7,80 (1H, d), 7,94 (2H, m). MS (m/z): 366 [MH]+. 10 the procedures described in example 46, using the appropriate starting materials. HPLC: 99.6%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 5 0.1% trifluoroacetic acid; UV 254): 1.83 min. 1 H NMR (400 MHz, DMSO – d6) 1.36 (3H, t), 2.32 (2H, m), 3.34 (2H, m), 4.12 (2H, m), 4.46 (2H, m), 6.58 (1H, d), 6.73 (2H, d) 6.90 (1H, m) 7.22 (2H, m), 7.65 (1H, d), 7 , 80 (1H, d), 7.94 (2H, m). MS (m / z): 366 [MH] +. 10
Ejemplo 63 Example 63
Preparación de N–hidroxi–3–(2–{[2–(4–metoxi–fenil)–acetilamino]–metil}–1–metil–H–bencimidazol–5–il)–acrilamida (99) Preparation of N-hydroxy-3– (2 - {[2– (4-methoxy-phenyl) -acetylamino] -methyl} -1-methyl-H-benzimidazol-5-yl) -acrylamide (99)
El compuesto del título (99) se preparó de acuerdo con 15 los procedimientos descritos en el ejemplo 42, usando los materiales de partida apropiados. HPLC: 97,0%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 20 0,1% de ácido trifluoroacético; UV 254): 2,75 min. 1H RMN (400 MHz, DMSO–d6) 3,48 (2H, s), 3,67 (3H, s), 3,87 (3H, s), 4,71 (2H, m), 6,55 (1H, d), 6,86 (3H, m) 7,18 (3H, m) 7,84–7,92 (2H, m), 10,77 (1H, s). MS (m/z): 395 [MH]+. The title compound (99) was prepared according to the procedures described in example 42, using the appropriate starting materials. HPLC: 97.0%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 2.75 min. 1 H NMR (400 MHz, DMSO – d6) 3.48 (2H, s), 3.67 (3H, s), 3.87 (3H, s), 4.71 (2H, m), 6.55 (1H, d), 6.86 (3H, m) 7.18 (3H, m) 7.84-7.92 (2H, m), 10.77 (1H, s). MS (m / z): 395 [MH] +.
Ejemplo 64 25 Example 64 25
Preparación de hidroxiamida del ácido 2–(1–metil–2–fenetil–1H–benci-midazol–5–il)–ciclopropancarboxílico (100) Preparation of 2– (1-methyl-2-phenethyl-1 H -benzimidazol-5-yl) -cyclopropancarboxylic acid hydroxyamide (100)
El compuesto del título (100) se preparó de acuerdo con los procedimientos descritos en el ejemplo 56, usando los materiales de partida apropiados. HPLC: 99%; tR = (LC/PDA: 30 columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con The title compound (100) was prepared according to the procedures described in example 56, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: 30 Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% B for 15.5 min, solvent A: H2O with
0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 0,1% de ácido trifluoroacético; UV 254): 6,36 min 1H RMN (400 MHz, CDCl3, con una gota de d6–DMSO–d6) 1,25 (1H, m), 1,64 (1H, m), 1,88 (1H, m), 1,98 (3H, s), 2,63 (1H, m), 3,23 (2H, t, J = 8,0 Hz), 3,52 (2H, t, J = 8,0 Hz), 7,08–7,45 (7H, m), 5 7,57 (1H, s). MS (m/z): 336 [MH]+. 0.1% trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 6.36 min 1H NMR (400 MHz, CDCl3, with a drop of d6 – DMSO – d6) 1.25 (1H, m), 1.64 (1H, m), 1.88 (1H , m), 1.98 (3H, s), 2.63 (1H, m), 3.23 (2H, t, J = 8.0 Hz), 3.52 (2H, t, J = 8, 0 Hz), 7.08-7.45 (7H, m), 7.57 (1H, s). MS (m / z): 336 [MH] +.
Ejemplo 65 Example 65
Preparación de N–hidroxi–3–(1–metil–1H–bencimidazol–5–il)–acrilamida (49) Preparation of N-hydroxy-3– (1-methyl-1H-benzimidazol-5-yl) -acrylamide (49)
El compuesto del título (49) se preparó de acuerdo con 10 los procedimientos descritos en el ejemplo 1, usando los materiales de partida apropiados. HPLC: 99%; tR = (LC/PDA: columna Phenomenex Luna C18 2,0 x 150 mm 5; 0,8 ml/min, gradiente 5–65% de B durante 15,5 min, solvente A: H2O con 0,1% de ácido trifluoroacético; solvente B: acetonitrilo con 15 0,1% de ácido trifluoroacético; UV 254): 1,05 min. 1H RMN: (400 MHz, CD3OD) δ 4,05 (3H, s), 6,52 (1H, d, J = 15,8 Hz), 7,62 (1H, d, J = 15,8 Hz), 7,77–7,89 (3H, m), 9,19 (1H, s). MS (m/z): 218 [MH]+. The title compound (49) was prepared according to the procedures described in example 1, using the appropriate starting materials. HPLC: 99%; tR = (LC / PDA: Phenomenex Luna C18 column 2.0 x 150 mm 5; 0.8 ml / min, gradient 5–65% of B for 15.5 min, solvent A: H2O with 0.1% of trifluoroacetic acid; solvent B: acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.05 min. 1H NMR: (400 MHz, CD3OD) δ 4.05 (3H, s), 6.52 (1H, d, J = 15.8 Hz), 7.62 (1H, d, J = 15.8 Hz) , 7.77-7.89 (3H, m), 9.19 (1H, s). MS (m / z): 218 [MH] +.
Los siguientes compuestos son algunos ejemplos 20 representativos preparados por medio de métodos descritos o análogos a los descritos en los anteriores ejemplos 1–65. The following compounds are some representative examples prepared by methods described or analogous to those described in the above examples 1-65.
Los compuestos (29), (45), (58), (59), (65), (88), (98) y (100) no son compuestos de la invención. Compounds (29), (45), (58), (59), (65), (88), (98) and (100) are not compounds of the invention.
Tabla 1 25 Table 1 25
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 1 one
- NNNHOOHOH 380 NNNHOOHOH 380
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 2 2
- NNNHOOHOOO 488 NNNHOOHOOO 488
- 3 3
- NNNHOOHOO 431 NNNHOOHOO 431
- 4 4
- NNNHOOHOOOH 474 NNNHOOHOOOH 474
- 5 5
- NNNHOOHOHO 354 NNNHOOHOHO 354
- 6 6
- NNNHOOHOOHOH 383 NNNHOOHOOHOH 383
- 7 7
- NNNHOOHOOHOHO 490 NNNHOOHOOHOHO 490
- 8 8
- NNNHOOHOHOH 382 NNNHOOHOHOH 382
- 9 9
- NNNHOOHNOHOH 355 NNNHOOHNOHOH 355
- 10 10
- NNNHOOHNHO 325 NNNHOOHNHO 325
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 11 eleven
- NNNHOOHNOH 339 NNNHOOHNOH 339
- 12 12
- NNNHOOHN 399 NNNHOOHN 399
- 13 13
- NNNHOOHOHN 339 NNNHOOHOHN 339
- 14 14
- NNNHOOHOH 366 NNNHOOHOH 366
- 15 fifteen
- NNNHOOHO 380 NNNHOOHO 380
- 16 16
- NNNHOOHN 399 NNNHOOHN 399
- 17 17
- NNNHOOHN 421 NNNHOOHN 421
- 18 18
- NNNHOOHN 413 NNNHOOHN 413
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 19 19
- NNNHOOHOHO 382 NNNHOOHOHO 382
- 20 twenty
- NNNHOOHOHS 344 NNNHOOHOHS 344
- 21 twenty-one
- NNNHOOHOH 318 NNNHOOHOH 318
- 22 22
- NNNHOOHN 365 NNNHOOHN 365
- 23 2. 3
- NNNHOOHOH 374 NNNHOOHOH 374
- 24 24
- NNNHOOHOH 344 NNNHOOHOH 344
- 25 25
- NNNHOOH 364 NNNHOOH 364
- 26 26
- NNNHOOH 412 NNNHOOH 412
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 27 27
- NNNHOOHN 413 NNNHOOHN 413
- 28 28
- NNNHOOHON 429 NNNHOOHON 429
- 29 29
- NNNHOOHOH 320 NNNHOOHOH 320
- 30 30
- NNNHOOHNO 433 NNNHOOHNO 433
- 31 31
- NNNHOOHNO 435 NNNHOOHNO 435
- 32 32
- NNNHOOHOHO 380 NNNHOOHOHO 380
- 33 33
- NNNHOOH 398 NNNHOOH 398
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 34 3. 4
- NNNHOOH 350 NNNHOOH 350
- 35 35
- NNNHOOH 294 NNNHOOH 294
- 36 36
- NNNHOOH 350 NNNHOOH 350
- 37 37
- NNNHOOH 246 NNNHOOH 246
- 38 38
- NNNHOOH 336 NNNHOOH 336
- 39 39
- NNNHOOH 232 NNNHOOH 232
- 40 40
- NNNHOOHOH 340 NNNHOOHOH 340
- 41 41
- NNNHOOHN 427 NNNHOOHN 427
- 42 42
- NNNHOOHN 309 NNNHOOHN 309
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 43 43
- NNNHOOH 246 NNNHOOH 246
- 44 44
- NNNHOOHNO 421 NNNHOOHNO 421
- 45 Four. Five
- NNNHOOHOOO 490 NNNHOOHOOO 490
- 46 46
- NNOHNHOOH 304 NNOHNHOOH 304
- 47 47
- NNNHOOHOH 262 NNNHOOHOH 262
- 48 48
- NNNHOOH 322 NNNHOOH 322
- 49 49
- NNNHOOH 218 NNNHOOH 218
- 50 fifty
- NNHNHOOH 308 NNHNHOOH 308
- 51 51
- NNHNHOOH 204 NNHNHOOH 204
- 52 52
- NNNHOOH 336 NNNHOOH 336
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 53 53
- NNNHOOH 232 NNNHOOH 232
- 54 54
- NNNHOOHNHO 365 NNNHOOHNHO 365
- 55 55
- NNNHOOHNHON 352 NNNHOOHNHON 352
- 56 56
- NNNHOOHNN 308 NNNHOOHNN 308
- 57 57
- NNNHOOHN 204 NNNHOOHN 204
- 58 58
- NNNHOOH 336 NNNHOOH 336
- 59 59
- NNNHOOH 232 NNNHOOH 232
- 60 60
- NNNHOOHNH 365 NNNHOOHNH 365
- 61 61
- NNNHOOHN 427 NNNHOOHN 427
- 62 62
- NNNHOOHNHO 367 NNNHOOHNHO 367
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 63 63
- NNNHOOHN 393 NNNHOOHN 393
- 64 64
- NNNHOOHNH 351 NNNHOOHNH 351
- 65 65
- NNNHOHOO 309 NNNHOHOO 309
- 66 66
- NNNHOOHN 407 NNNHOOHN 407
- 67 67
- NNNHOOHN 419 NNNHOOHN 419
- 68 68
- NNNHOOHN 441 NNNHOOHN 441
- 69 69
- NNNHOOHNHOF 383 NNNHOOHNHOF 383
- 70 70
- NNNHOOHHNO 393 NNNHOOHHNO 393
- 71 71
- NNNHOOHHNSOO 415 NNNHOOHHNSOO 415
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 72 72
- NNNHOOHN 405 NNNHOOHN 405
- 73 73
- NNNHOOHHNOO 409 NNNHOOHHNOO 409
- 74 74
- NNNHOOHHN 365 NNNHOOHHN 365
- 75 75
- NNNHOOH 378 NNNHOOH 378
- 76 76
- ONHHONNN 481 ONHHONNN 481
- 77 77
- ONHHONNOH 352 ONHHONNOH 352
- 78 78
- ONHHONNHO 394 ONHHONNHO 394
- 79 79
- ONHHONNCH2 348 ONHHONNCH2 348
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 80 80
- ONHHONNOCH3H3C 408 ONHHONNOCH3H3C 408
- 81 81
- ONHHONNNNH3C 448 ONHHONNNNH3C 448
- 82 82
- NNNHOOHN 419 NNNHOOHN 419
- 83 83
- NNNHOOHN 435 NNNHOOHN 435
- 84 84
- NNNHOOHNF 439 NNNHOOHNF 439
- 85 85
- NNHNHOOHF 326 NNHNHOOHF 326
- 86 86
- NNNHOOHNN 422 NNNHOOHNN 422
- 87 87
- NNHNHOOHN 309 NNHNHOOHN 309
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 88 88
- NNNHOOHOOO 502 NNNHOOHOOO 502
- 89 89
- NNSNHOOHN 439 NNSNHOOHN 439
- 90 90
- NNNHOOHN 315 NNNHOOHN 315
- 91 91
- NNSNHOOHNO 455 NNSNHOOHNO 455
- 92 92
- NNNHOOH 322 NNNHOOH 322
- 93 93
- NNNHOOHHN 389 NNNHOOHHN 389
- 94 94
- NNNHOOHON 451 NNNHOOHON 451
- 95 95
- NNHNHOOHO 338 NNHNHOOHO 338
- Compuesto Compound
- Estructuras m/z [MH]+ Structures m / z [MH] +
- 96 96
- NNNHOOHO 366 NNNHOOHO 366
- 97 97
- NNNHOHOH2N(L) 336 NNNHOHOH2N (L) 336
- 98 98
- NHOOHNNHNO 297 NHOOHNNHNO 297
- 99 99
- NNNHOOHNHOO 395 NNNHOOHNHOO 395
- 100 100
- NNNHOOH 336 NNNHOOH 336
Por medio de métodos análogos a los descritos con anterioridad, se pudo preparar una amplia variedad de compuestos de fórmula (I), incluyendo los de la tabla 2(a): By methods analogous to those described above, a wide variety of compounds of formula (I) could be prepared, including those in Table 2 (a):
Tabla 2(a) 5 Table 2 (a) 5
- 101 101
- NNNHOOHN N–hidroxi–3–[1–metil–2–(2–piperidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida NNNHOOHN N-hydroxy-3– [1-methyl-2– (2-piperidin-1-yl-ethyl) -1H-benzimidazol-5-yl] -acrylamide
- 102 102
- NNNHOOHN N–hidroxi–3–[2–(2–dietilamino–etil)–1–metil–1H–bencimidazol–5–il]–acrilamida NNNHOOHN N-hydroxy-3– [2– (2-diethylamino-ethyl) -1-methyl-1H-benzimidazol-5-yl] -acrylamide
- 103 103
- NNNHOOHN N–hidroxi–3–[2–(2–ciclohexil–etil)–1–(2–piridin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida NNNHOOHN N-hydroxy-3– [2– (2-cyclohexyl-ethyl) –1– (2-pyridin-1-yl-ethyl) –1H-benzimidazole-5-yl] -acrylamide
- 104 104
- NNNOOHN N–hidroxi–N–metil–3–[2–(2–ciclohexil–etil)–1–(2–pirrolidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida NNNOOHN N-hydroxy-N-methyl-3– [2– (2-cyclohexyl-ethyl) –1– (2-pyrrolidin-1-yl-ethyl) –1H – benzimidazol-5-yl] -acrylamide
- 105 105
- NNNHOOH N–hidroxi–[2–(2–ciclohexil–etil)–1–metil–1H–bencimidazol–5–il]–acrilamida NNNHOOH N-hydroxy– [2– (2-cyclohexyl-ethyl) -1-methyl-1H-benzimidazole-5-yl] -acrylamide
- 106 106
- NNNHOOHN N–hidroxi–[2–(2–ciclopentil–etil)–1–(2–pirrolidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida NNNHOOHN N-hydroxy– [2– (2-cyclopentyl-ethyl) –1– (2-pyrrolidin-1-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- 107 107
- NNNHOOHN N–hidroxi–3–[1–metil–2–(2–pirrolidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida NNNHOOHN N-hydroxy-3– [1-methyl-2– (2-pyrrolidin-1-yl-ethyl) -1H-benzimidazol-5-yl] -acrylamide
- 108 108
- NNNHOOHHN (L)–N–hidroxi–3–[2–(1–bencilamino–2–fenil–etil)–1–metil–1H–bencimidazol–5–il]–acrilamida NNNHOOHHN (L) –N – hydroxy – 3– [2– (1-benzylamino-2-phenyl-ethyl) –1-methyl-1H-benzimidazol-5-yl] -acrylamide
- 109 109
- NNONHOOHN N–hidroxi–3–[2–benciloxi–1–(2–pirrolidin–1–etil)–1H–bencimidazol–5–il]–acrilamida NNONHOOHN N-hydroxy-3– [2-benzyloxy-1– (2-pyrrolidin-1-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- 110 110
- NNSNHOOH N–hidroxi–3–(2–bencilsulfanil–1–metil–1H–bencimidazol–5–il)–acrilamida NNSNHOOH N-hydroxy-3– (2-benzylsulfanyl-1-methyl-1H-benzimidazol-5-yl) -acrylamide
- 111 111
- NNHNNHOOHN N–hidroxi–3–[2–fenetilamino–1–(2–pirrolidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida NNHNNHOOHN N-hydroxy-3– [2-phenethylamino-1– (2-pyrrolidin-1-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- 112 112
- NNNHOOHN N–hidroxi–3–(1–metil–2–quinolin–3–ilmetil–1H–bencimidazol–5–il)–acrilamida NNNHOOHN N-hydroxy-3– (1-methyl-2-quinolin-3-ylmethyl-1H-benzimidazol-5-yl) -acrylamide
- 113 113
- NNNHOOHNS N–hidroxi–3–[1–(2–pirrolidin–1–il–etil)–2–(2–tiofen–2–il–etil)–1H–bencimidazol–5–il]–acrilamida NNNHOOHNS N-hydroxy-3– [1– (2-pyrrolidin-1-yl-ethyl) –2– (2-thiophen-2-yl-ethyl) –1H – benzimidazol-5-yl] -acrylamide
- 114 114
- NNNHOOH N–hidroxi–3–[1–metil–2–(2–naftalen–2–il–etil)–1H–bencimidazol–5–il]–acrilamida NNNHOOH N-hydroxy-3– [1-methyl-2– (2-naphthalen-2-yl-ethyl) -1H-benzimidazol-5-yl] -acrylamide
- 115 115
- NNNHOOHN N–hidroxi–3–(4,7–dimetil–2–fenetil–1–piridin–2–ilmetil–1H–bencimidazol–5–il)–acrilamida NNNHOOHN N-hydroxy-3– (4,7-dimethyl-2-phenethyl-1-pyridin-2-ylmethyl-1H-benzimidazol-5-yl) -acrylamide
- 116 116
- NNNHOOHON N–hidroxi–3–(7–benciloxi–4–metil–2–fenetil–1–fenetil–1–piridin–2–ilmetil–1H–bencimidazol–5–il)–acrilamida NNNHOOHON N-hydroxy-3– (7-benzyloxy-4-methyl-2-phenethyl-1-phenethyl-1-pyridin-2-ylmethyl-1H-benzimidazol-5-yl) -acrylamide
- 117 117
- NNNHOOHFFN N–hidroxi–3–(4,7–difluoro–2–fenetil–1–piridin–2–ilmetil–1H–bencimidazol–5–il)–acrilamida NNNHOOHFFN N-hydroxy-3– (4,7-difluoro-2-phenethyl-1-pyridin-2-ylmethyl-1H-benzimidazol-5-yl) -acrylamide
Por medio de métodos análogos a los descritos con anterioridad y variando los materiales de partida usados en la síntesis, se pudo preparar una amplia variedad de compuestos de fórmula (I), incluyendo los de la tabla 2(b): 5 By methods analogous to those described above and by varying the starting materials used in the synthesis, a wide variety of compounds of formula (I) could be prepared, including those in Table 2 (b):
NNONOR3R4R2R1XY NNONOR3R4R2R1XY
Tabla 2(b) Table 2 (b)
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 118 118
- H H H H CH3 H H H H CH3
- 119 119
- H HN CH3 H F OCH3 H HN CH3 H F OCH3
- 120 120
- H N H CH3 Cl CH3 H N H CH3 Cl CH3
- 121 121
- H AA=C,N,O,S CH3 CH3 Br H H AA = C, N, O, S CH3 CH3 Br H
- 122 122
- H N H H CH3 F H N H H CH3 F
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 123 123
- H N CH3 H OCH3 Cl H N CH3 H OCH3 Cl
- 124 124
- Propilo N H CH3 CF3 Br Propyl N H CH3 CF3 Br
- 125 125
- Propilo N CH3 CH3 CN CH3 Propyl N CH3 CH3 CN CH3
- 126 126
- Propilo NN H H OCF3 OCH3 Propyl NN H H OCF3 OCH3
- 127 127
- Propilo ON CH3 H NO2 CF3 Propyl ON CH3 H NO2 CF3
- 128 128
- Propilo AA=C,N,O,S H CH3 CH3 CN Propyl AA = C, N, O, S H CH3 CH3 CN
- 129 129
- Propilo NN CH3 CH3 OCH3 OCF3 Propyl NN CH3 CH3 OCH3 OCF3
- 130 130
- Propilo O H H F NO2 Propyl OR H H F NO2
- 131 131
- Propilo N CH3 H CH3 CH3 Propyl N CH3 H CH3 CH3
- 132 132
- H CH3 OCH3 OCH3 H CH3 OCH3 OCH3
- 133 133
- ON CH3 CH3 F H ON CH3 CH3 F H
- 134 134
- NO H H CH3 F NO H H CH3 F
- 135 135
- CH3 H OCH3 Cl CH3 H OCH3 Cl
- 136 136
- H CH3 F Br H CH3 F Br
- 137 137
- CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3
- 138 138
- H H CH3 OCH3 H H CH3 OCH3
- 139 139
- N CH3 H OCH3 CF3 N CH3 H OCH3 CF3
- 140 140
- H CH3 F CN H CH3 F CN
- 141 141
- CH3 CH3 F OCF3 CH3 CH3 F OCF3
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 142 142
- H H Cl NO2 H H Cl NO2
- 143 143
- CH3 H Br F CH3 H Br F
- 144 144
- H CH3 CH3 CH3 H CH3 CH3 CH3
- 145 145
- CH3 CH3 OCH3 OCH3 CH3 CH3 OCH3 OCH3
- 146 146
- H H CF3 CH3 H H CF3 CH3
- 147 147
- CH3 H CN H CH3 H CN H
- 148 148
- HO H CH3 OCF3 F HO H CH3 OCF3 F
- 149 149
- CH3 CH3 NO2 Cl CH3 CH3 NO2 Cl
- 150 150
- H H CH3 Br H H CH3 Br
- 151 151
- CH3 H CH3 CH3 CH3 H CH3 CH3
- 152 152
- H CH3 OCH3 OCH3 H CH3 OCH3 OCH3
- 153 153
- CH3 CH3 F CF3 CH3 CH3 F CF3
- 154 154
- H H CH3 CN H H CH3 CN
- 155 155
- CH3 H OCH3 OCF3 CH3 H OCH3 OCF3
- 156 156
- O H CH3 CH3 NO2 OR H CH3 CH3 NO2
- 157 157
- CH3 CH3 OCH3 CH3 CH3 CH3 OCH3 CH3
- 158 158
- H H F F H H F F
- 159 159
- CH3 H H CH3 CH3 H H CH3
- 160 160
- H CH3 F OCH3 H CH3 F OCH3
- 161 161
- CH3 CH3 Cl CH3 CH3 CH3 Cl CH3
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 162 162
- H H Br H H H Br H
- 163 163
- CH3 H CH3 F CH3 H CH3 F
- 164 164
- H CH3 OCH3 Cl H CH3 OCH3 Cl
- 165 165
- S CH3 CH3 CF3 Br S CH3 CH3 CF3 Br
- 166 166
- H H CN CH3 H H CN CH3
- 167 167
- CH3 H OCF3 OCH3 CH3 H OCF3 OCH3
- 168 168
- H CH3 NO2 CF3 H CH3 NO2 CF3
- 169 169
- CH3 CH3 CH3 CN CH3 CH3 CH3 CN
- 170 170
- H H OCH3 OCF3 H H OCH3 OCF3
- 171 171
- CH3 H F NO2 CH3 H F NO2
- 172 172
- N H CH3 CH3 CH3 N H CH3 CH3 CH3
- 173 173
- CH3 CH3 OCH3 H CH3 CH3 OCH3 H
- 174 174
- H H H F H H H F
- 175 175
- CH3 H F Cl CH3 H F Cl
- 176 176
- H CH3 Cl Br H CH3 Cl Br
- 177 177
- CH3 CH3 Br CH3 CH3 CH3 Br CH3
- 178 178
- H H CH3 OCH3 H H CH3 OCH3
- 179 179
- CH3 H OCH3 CF3 CH3 H OCH3 CF3
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 180 180
- H CH3 CF3 CN H CH3 CF3 CN
- 181 181
- CH3 CH3 CN OCF3 CH3 CH3 CN OCF3
- 182 182
- H H OCF3 NO2 H H OCF3 NO2
- 183 183
- CH3 H NO2 F CH3 H NO2 F
- 184 184
- H CH3 CH3 CH3 H CH3 CH3 CH3
- 185 185
- CH3 CH3 OCH3 OCH3 CH3 CH3 OCH3 OCH3
- 186 186
- H H F H H H F H
- 187 187
- CH3 H CH3 F CH3 H CH3 F
- 188 188
- H CH3 OCH3 Cl H CH3 OCH3 Cl
- 189 189
- CH3 CH3 CH3 Br CH3 CH3 CH3 Br
- 190 190
- H H OCH3 CH3 H H OCH3 CH3
- 191 191
- CH3 H CH3 OCH3 CH3 H CH3 OCH3
- 192 192
- H CH3 CH3 CF3 H CH3 CH3 CF3
- 193 193
- CH3 CH3 OCH3 CN CH3 CH3 OCH3 CN
- 194 194
- H H F OCF3 H H F OCF3
- 195 195
- CH3 H H NO2 CH3 H H NO2
- 196 196
- H CH3 F CH3 H CH3 F CH3
- 197 197
- CH3 CH3 Cl OCH3 CH3 CH3 Cl OCH3
- 198 198
- H H Br F H H Br F
- 199 199
- CH3 H CH3 CH3 CH3 H CH3 CH3
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 200 200
- H CH3 OCH3 OCH3 H CH3 OCH3 OCH3
- 201 201
- CH3 CH3 CF3 CH3 CH3 CH3 CF3 CH3
- 202 202
- H H CN F H H CN F
- 203 203
- CH3 H OCF3 CH3 CH3 H OCF3 CH3
- 204 204
- H CH3 NO2 OCH3 H CH3 NO2 OCH3
- 205 205
- CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3
- 206 206
- H H OCH3 H H H OCH3 H
- 207 207
- CH3 H CH3 F CH3 H CH3 F
- 208 208
- H CH3 OCH3 Cl H CH3 OCH3 Cl
- 209 209
- CH3 CH3 F Br CH3 CH3 F Br
- 210 210
- H H CH3 CH3 H H CH3 CH3
- 211 211
- CH3 H H OCH3 CH3 H H OCH3
- 212 212
- H CH3 F CF3 H CH3 F CF3
- 213 213
- CH3 CH3 Cl CN CH3 CH3 Cl CN
- 214 214
- H H Br OCF3 H H Br OCF3
- 215 215
- CH3 H CH3 NO2 CH3 H CH3 NO2
- 216 216
- H H OCH3 CH3 H H OCH3 CH3
- 217 217
- CH3 H CF3 F CH3 H CF3 F
- 218 218
- H CH3 CN CH3 H CH3 CN CH3
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 219 219
- CH3 CH3 OCF3 OCH3 CH3 CH3 OCF3 OCH3
- 220 220
- H H NO2 CH3 H H NO2 CH3
- 221 221
- CH3 H CH3 OCH3 CH3 H CH3 OCH3
- 222 222
- H CH3 H H H CH3 H H
- 223 223
- CH3 CH3 F F CH3 CH3 F F
- 224 224
- H H Cl Cl H H Cl Cl
- 225 225
- CH3 H Br Br CH3 H Br Br
- 226 226
- H CH3 CH3 CH3 H CH3 CH3 CH3
- 227 227
- CH3 CH3 OCH3 OCH3 CH3 CH3 OCH3 OCH3
- 228 228
- H H CF3 CF3 H H CF3 CF3
- 229 229
- CH3 H CN CN CH3 H CN CN
- 230 230
- H CH3 OCF3 OCF3 H CH3 OCF3 OCF3
- 231 231
- CH3 CH3 NO2 NO2 CH3 CH3 NO2 NO2
- 232 232
- H H CH3 CH3 H H CH3 CH3
- 233 233
- CH3 H OCH3 OCH3 CH3 H OCH3 OCH3
- 234 2. 3. 4
- H CH3 F F H CH3 F F
- 235 235
- CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3
- 236 236
- H H OCH3 OCH3 H H OCH3 OCH3
- 237 237
- CH3 H CH3 F CH3 H CH3 F
- R1 R2 R3 R4 X Y R1 R2 R3 R4 X Y
- 238 238
- H CH3 OCH3 CH3 H CH3 OCH3 CH3
- 239 239
- CH3 CH3 F OCH3 CH3 CH3 F OCH3
Expresión y purificación de GST–HDAC1 recombinante Expression and purification of recombinant GST – HDAC1
Se preparó una biblioteca de ADNc humano con células SW620 cultivadas. La amplificación de la región codificadora 5 de HDAC1 y HDAC8 humanos provenientes de esta biblioteca de ADNc se clonó por separado en la expresión en baculovirus del vector pDEST20 y el vector pFASTBAC, respectivamente (GATEWAY Cloning Technology, INVITROGEN PTE LTD). Las construcciones pDEST20–HDAC1 y pFASTBAC–HTGST–HDAC8 se confirmaron por 10 determinación de las secuencias de ADN. Se preparó el baculovirus recombinante mediante el método Bac–To–Bac, según las instrucciones del fabricante (INVITROGEN PTE LTD). Se determinó el título de Baculovirus mediante ensayo en placa en aproximadamente 108 PFU/ml. 15 A human cDNA library was prepared with cultured SW620 cells. The amplification of the coding region 5 of human HDAC1 and HDAC8 from this cDNA library was cloned separately in the baculovirus expression of the pDEST20 vector and the pFASTBAC vector, respectively (GATEWAY Cloning Technology, INVITROGEN PTE LTD). The pDEST20 – HDAC1 and pFASTBAC – HTGST – HDAC8 constructs were confirmed by determination of the DNA sequences. Recombinant baculovirus was prepared by the Bac-To-Bac method, according to the manufacturer's instructions (INVITROGEN PTE LTD). Baculovirus titer was determined by plaque assay at approximately 108 PFU / ml. fifteen
La expresión de GST–HDAC1 o HTGST–HDAC8 se realizó por infección de células SF9 (Invitrogen Pte Ltd) con baculovirus pDEST20–HDAC1 o pFASTBAC–GST–HDAC8 a MOI=1 durante 48 h. El lisado celular soluble se incubó con perlas preequilibradas de Glutation Sepharose 4B (Amersham) a 4ºC durante 2 h. Las 20 perlas se lavaron 3 veces con buffer PBS. La proteína GST–HDAC1 o la proteína GST–HDAC8 se eluyeron mediante buffer de elución que contenía Tris 50 mM, pH 8,0. NaCl 150 mM, 1% de Triton X–100 y glutatión reducido 10 mM o 20 mM. La proteína GST–HDAC1 purificada o la proteína GST–HDAC8 purificada se 25 dializó con buffer de almacenamiento HDAC que contenía Tris 10 mM, pH 7,5, NaCl 100 mM y MgCl2 3 mM. Se agregó 20% de glicerol a la proteína GST–HDAC1 purificada o la proteína GST–HDAC8 purificada antes de almacenarla a –80ºC. The expression of GST-HDAC1 or HTGST-HDAC8 was carried out by infection of SF9 cells (Invitrogen Pte Ltd) with baculovirus pDEST20-HDAC1 or pFASTBAC-GST-HDAC8 at MOI = 1 for 48 h. The soluble cell lysate was incubated with pre-equilibrated Glutathione Sepharose 4B beads (Amersham) at 4 ° C for 2 h. The 20 beads were washed 3 times with PBS buffer. GST-HDAC1 protein or GST-HDAC8 protein was eluted by elution buffer containing 50 mM Tris, pH 8.0. 150 mM NaCl, 1% Triton X-100 and reduced glutathione 10 mM or 20 mM. The purified GST-HDAC1 protein or the purified GST-HDAC8 protein was dialyzed with HDAC storage buffer containing 10 mM Tris, pH 7.5, 100 mM NaCl and 3 mM MgCl2. 20% glycerol was added to the purified GST-HDAC1 protein or the purified GST-HDAC8 protein before storage at -80 ° C.
Ensayo HDAC in vitro para la determinación de valores de IC50 In vitro HDAC assay for the determination of IC50 values
El ensayo se llevó a cabo en formato de 96 cavidades y se aplicó el ensayo de actividad de HDAC basado en fluorescencia BIOMOL. La mezcla de reacción compuesta por buffer de ensayo, que contenía Tris 25 mM, pH 7,5, NaCl 137 5 mM, KCl 2,7 mM, MgCl2 1 mM, 1 mg/ml de BSA, los compuestos de prueba, enzima HDAC8 500 nM o enzima HDAC1 600 nM, sustrato peptídico Flur de lys p53 200 M para la enzima HDAC8 o sustrato genérico Flur de lys 500 M para la enzima HDAC1, y luego se incubó a temperatura ambiente durante 2 h. Se agregó 10 desarrollador de Flur de lys y se incubó la mezcla de reacción durante 10 min. Brevemente, la desacetilación del sustrato lo sensibiliza al desarrollador, que entonces genera un fluoróforo (símbolo). El fluoróforo se excita con la luz de 360 nm y la luz emitida (460 nm) es detectada por un 15 lector de placa fluorométrico (sistema de detección Tecan Ultra Microplate, TECAN GROUP LTD.). The assay was carried out in 96 cavity format and the BIOMOL fluorescence based HDAC activity assay was applied. The reaction mixture composed of test buffer, containing 25 mM Tris, pH 7.5, 5 mM NaCl 137, 2.7 mM KCl, 1 mM MgCl2, 1 mg / ml BSA, test compounds, HDAC8 enzyme 500 nM or 600 nM HDAC1 enzyme, lys p53 200 µM Flur peptide substrate for the HDAC8 enzyme or lys 500 M Flur generic substrate for the HDAC1 enzyme, and then incubated at room temperature for 2 h. 10 developer of Flur de lys was added and the reaction mixture was incubated for 10 min. Briefly, the deacetylation of the substrate sensitizes the developer, who then generates a fluorophore (symbol). The fluorophore is excited with 360 nm light and the emitted light (460 nm) is detected by a fluorometric plate reader (Tecan Ultra Microplate detection system, TECAN GROUP LTD.).
Se usó el software analítico Prism 3.0 para generar IC50 a partir de una serie de datos. Los resultados de la inhibición de la enzima HDAC por los compuestos 20 representativos se muestran en la tabla 3. The Prism 3.0 analytical software was used to generate IC50 from a series of data. The results of HDAC enzyme inhibition by representative compounds are shown in Table 3.
Tabla 3 Table 3
- Compuesto Compound
- Actividad enzimática de HDAC1 IC50 (μM) Actividad enzimática de HDAC8 IC50 (M) Enzymatic activity of HDAC1 IC50 (μM) Enzymatic activity of HDAC8 IC50 (M)
- 1 one
- 0,051 0,119 0.051 0.119
- 2 2
- 0,026 0,355 0.026 0.355
- 3 3
- 1,37 1,71 1.37 1.71
- 4 4
- 1,34 0,790 1.34 0.790
- 5 5
- 4,32 0,401 4.32 0.401
- 6 6
- 1,38 0,262 1.38 0.262
- 7 7
- 1,52 0,336 1.52 0.336
- Compuesto Compound
- Actividad enzimática de HDAC1 IC50 (μM) Actividad enzimática de HDAC8 IC50 (M) Enzymatic activity of HDAC1 IC50 (μM) Enzymatic activity of HDAC8 IC50 (M)
- 8 8
- 0,286 0,454 0.286 0.454
- 9 9
- 1,34 0,344 1.34 0.344
- 10 10
- 2,66 0,883 2.66 0.883
- 11 eleven
- 0,846 0,161 0.846 0.161
- 12 12
- 0,131 0,202 0.131 0.202
- 13 13
- 0,385 0,141 0.385 0.131
- 14 14
- 0,171 0,251 0.171 0.251
- 15 fifteen
- 0,206 0,313 0.206 0.313
- 16 16
- 0,194 0,366 0.194 0.366
- 17 17
- 0,024 0,353 0.024 0.353
- 18 18
- 0,438 0,290 0.438 0.290
- 19 19
- 0,165 0,145 0.165 0.145
- 20 twenty
- 1,91 0,537 1.91 0.537
- 21 twenty-one
- 0,064 0,238 0.064 0.238
- 22 22
- 1,326 0,234 1,326 0.234
- 23 2. 3
- 0,529 0,402 0.529 0.402
- 24 24
- 3,24 0,203 3.24 0.203
- 25 25
- 1,32 0,601 1.32 0.601
- 26 26
- 0,876 1,005 0.876 1.005
- 27 27
- 0,092 0,329 0.092 0.329
- 28 28
- 0,206 0,300 0.206 0.300
- 29 29
- 49,06 33,96 49.06 33.96
- 30 30
- 0,195 0,724 0.195 0.724
- 31 31
- 0,246 1,09 0.246 1.09
- 32 32
- 2,21 1,89 2.21 1.89
- Compuesto Compound
- Actividad enzimática de HDAC1 IC50 (μM) Actividad enzimática de HDAC8 IC50 (M) Enzymatic activity of HDAC1 IC50 (μM) Enzymatic activity of HDAC8 IC50 (M)
- 33 33
- 0,449 1,45 0.449 1.45
- 34 3. 4
- 1,46 0,846 1.46 0.846
- 35 35
- 0,371 0,412 0.371 0.412
- 36 36
- 0,227 0.227
- 37 37
- 0,897 0.897
- 38 38
- 0,218 0,148 0.218 0.148
- 39 39
- 1,22 0,201 1.22 0.201
- 40 40
- 3,30 0,441 3.30 0.441
- 41 41
- 0,195 0,159 0.195 0.159
- 42 42
- 0,479 0,237 0.479 0.237
- 43 43
- 0,947 0,192 0.947 0.192
- 44 44
- 0,268 0,345 0.268 0.345
- 45 Four. Five
- 0,167 0.167
- 46 46
- 1,67 1.67
- 47 47
- 1,09 1.09
- 48 48
- 0,356 0,291 0.356 0.291
- 49 49
- 1,40 1.40
- 50 fifty
- 0,173 0.173
- 51 51
- 0,896 0.896
- 52 52
- 0,160 0.160
- 53 53
- 1,85 1.85
- 54 54
- 0,100 0.100
- 55 55
- 0,137 0.137
- 56 56
- 0,158 0.158
- 57 57
- 0,153 0.153
- Compuesto Compound
- Actividad enzimática de HDAC1 IC50 (μM) Actividad enzimática de HDAC8 IC50 (M) Enzymatic activity of HDAC1 IC50 (μM) Enzymatic activity of HDAC8 IC50 (M)
- 58 58
- 1,14 1.14
- 59 59
- 0,382 0.382
- 60 60
- 0,116 0.116
- 61 61
- 0,196 0.196
- 62 62
- 0,234 0.234
- 63 63
- 0,162 0.162
- 64 64
- 0,230 0.230
- 65 65
- 0,062 0.062
- 66 66
- 0,072 0,255 0.072 0.255
- 67 67
- 0,039 0,254 0.039 0.254
- 68 68
- 0,294 0.294
- 69 69
- 0,146 0.166
- 70 70
- 0,923 0.923
- 71 71
- 0,167 0.167
- 72 72
- 0,052 0.052
- 73 73
- 0,560 0.560
- 74 74
- 0,371 0.371
- 75 75
- 0,290 0.290
- 76 76
- 1,03 1.03
- 77 77
- 0,570 0.570
- 78 78
- >100 > 100
- 79 79
- 1,26 1.26
- 80 80
- 1,69 1.69
- 81 81
- 1,60 1.60
- 82 82
- 0,304 0.304
- Compuesto Compound
- Actividad enzimática de HDAC1 IC50 (μM) Actividad enzimática de HDAC8 IC50 (M) Enzymatic activity of HDAC1 IC50 (μM) Enzymatic activity of HDAC8 IC50 (M)
- 83 83
- 0,071 0.071
- 84 84
- 0,054 0.054
- 85 85
- 0,131 0.131
- 86 86
- 0,400 0.400
- 87 87
- 0,517 0.517
- 88 88
- 0,297 0.297
- 89 89
- 0,116 0.116
- 90 90
- 0,166 0.166
- 91 91
- 0,030 0.030
- 92 92
- 0,168 0.168
- 93 93
- 0,065 0.065
- 94 94
- 0,052 0.052
- 95 95
- 0,061 0.061
- 96 96
- 0,125 0.125
Ensayo de proliferación en base celular para la determinación de valores de GI50 Proliferation assay on a cellular basis for the determination of GI50 values
Se obtuvieron líneas celulares de cáncer de colon humano (Colo205 y HCT116), líneas celulares de cáncer de mama 5 humano (MDA–MB435 y MDA–MB231) y línea celular de cáncer de pulmón humana (A549) a partir de ATCC. Las células Colo205 se cultivaron en RPMI 1640 que contenía L–glutamina 2 mM, 5% de FBS, piruvato de Na 1,0 mM. Se cultivaron A549 y MDA–MB231 en RPMI 1640 que contenía L–glutamina 2 mM, 5% de FBS. Las 10 células MDA–MB435 se cultivaron en DMEM que contenía L–glutamina 2 mM, 5% de FBS. Las células HCT116 se cultivaron en IMEM que contenía L–glutamina 2 mM, 5% de FBS. Las células A549 y Colo205 se sembraron en placas de 96 cavidades con Human colon cancer cell lines (Colo205 and HCT116), human breast cancer 5 cell lines (MDA-MB435 and MDA-MB231) and human lung cancer cell line (A549) were obtained from ATCC. Colo205 cells were cultured in RPMI 1640 containing 2 mM L-glutamine, 5% FBS, 1.0 mM Na pyruvate. A549 and MDA-MB231 were grown in RPMI 1640 containing 2 mM L-glutamine, 5% FBS. The 10 MDA-MB435 cells were cultured in DMEM containing 2 mM L-glutamine, 5% FBS. HCT116 cells were grown in IMEM containing 2 mM L-glutamine, 5% FBS. A549 and Colo205 cells were seeded in 96 well plates with
2.000 y 5.000 células por cavidad, respectivamente. Las células MDA–MB435, HCT116, MDA–MB231 se sembraron en placas de 96 cavidades con 6.000 células por cavidad. Las placas se incubaron a 37ºC, 5% de CO2, durante 24 h. Las células se trataron con compuestos con distintas concentraciones durante 5 96 h. Luego se monitorizó el crecimiento celular mediante un ensayo de proliferación celular cuantitativo (INVITROGEN PTE LTD). Se graficaron las curvas de respuesta a la dosis para determinar los valores de GI50 para los compuestos mediante ajuste XL. 10 2,000 and 5,000 cells per cavity, respectively. MDA-MB435, HCT116, MDA-MB231 cells were seeded in 96-well plates with 6,000 cells per cavity. The plates were incubated at 37 ° C, 5% CO2, for 24 h. The cells were treated with compounds with different concentrations for 5 96 h. Cell growth was then monitored by a quantitative cell proliferation assay (INVITROGEN PTE LTD). The dose response curves were plotted to determine the GI50 values for the compounds by XL adjustment. 10
Los resultados de actividad celular de los compuestos representativos se muestran en la tabla 4. La tabla 5 resume las actividades antiproliferativas de compuestos seleccionados, incluyendo sus diferentes sales, para otras líneas de células cancerosas. Estos datos indican que los 15 compuestos de esta invención son muy activos en la inhibición del crecimiento de las células tumorales. The cellular activity results of representative compounds are shown in Table 4. Table 5 summarizes the antiproliferative activities of selected compounds, including their different salts, for other cancer cell lines. These data indicate that the compounds of this invention are very active in inhibiting the growth of tumor cells.
- Compuesto Compound
- GI50 (Colo205, M) GI50 (MDA–MB435, M) GI50 (Colo205, M) GI50 (MDA – MB435, M)
- 1 one
- 0,52 1,64 0.52 1.64
- 2 2
- 0,43 0,32 0.43 0.32
- 4 4
- 29,87 25,70 29.87 25.70
- 5 5
- >100 > 100
- 6 6
- >100 > 100
- 7 7
- >100 > 100
- 8 8
- 41,36 58,42 41.36 58.42
- 9 9
- >100 >100 > 100> 100
- 11 eleven
- >100 >100 > 100> 100
- 12 12
- 0,38 1,07 0.38 1.07
- 13 13
- 12,32 14,05 12.32 14.05
- 14 14
- 3,07 5,99 3.07 5.99
- 15 fifteen
- 1,99 4,07 1.99 4.07
- 16 16
- 0,94 0,98 0.94 0.98
- 17 17
- 0,06 0,56 0.06 0.56
- 18 18
- 4,69 6,16 4.69 6.16
- 19 19
- 4,10 3,97 4.10 3.97
- 20 twenty
- 30,86 37,22 30.86 37.22
- 21 twenty-one
- 25,91 30,26 25.91 30.26
- 22 22
- 13,47 13,35 13.47 13.35
- 23 2. 3
- 3,65 3,72 3.65 3.72
- 24 24
- 30,70 35,02 30.70 35.02
- 25 25
- 8,10 6,82 8.10 6.82
- 26 26
- 8,79 6,67 8.79 6.67
- 27 27
- 2,23 3,44 2.23 3.44
- 28 28
- 2,53 5,15 2.53 5.15
- 30 30
- 11,44 19,85 11.44 19.85
- 31 31
- 1,87 4,06 1.87 4.06
- 33 33
- 1,54 3,38 1.54 3.38
- 35 35
- 1,89 6,76 1.89 6.76
- 36 36
- 2,29 2,17 2.29 2.17
- 37 37
- 7,82 7,90 7.82 7.90
- 38 38
- 1,47 1,53 1.47 1.53
- 39 39
- 11,68 12,05 11.68 12.05
- 40 40
- 25,62 30,97 25.62 30.97
- 41 41
- 1,65 1,91 1.65 1.91
- 42 42
- 14,41 15,75 14.41 15.75
- 43 43
- 9,18 8,62 9.18 8.62
- 44 44
- 2,82 3,65 2.82 3.65
- 45 Four. Five
- 2,41 1,90 2.41 1.90
- 48 48
- 1,45 1,78 1.45 1.78
- 50 fifty
- 4,29 5,19 4.29 5.19
- 52 52
- 2,04 3,58 2.04 3.58
- 54 54
- 4,47 5,92 4.47 5.92
- 55 55
- >100 >100 > 100> 100
- 56 56
- >100 >100 > 100> 100
- 57 57
- 1,11 1,39 1.11 1.39
- 59 59
- 2,72 3,69 2.72 3.69
- 60 60
- 2,47 3,60 2.47 3.60
- 61 61
- 2,69 3,05 2.69 3.05
- 62 62
- 11,65 19,80 11.65 19.80
- 63 63
- 2,00 2.00
- 64 64
- 1,70 1.70
- 65 65
- 36,89 36.89
- 66 66
- 0,22 0.22
- 67 67
- 0,08 0.08
- 68 68
- 0,73 0.73
- 69 69
- 7,16 7.16
- 70 70
- 2,90 2.90
- 71 71
- 7,09 7.09
- 72 72
- 0,18 0.18
- 73 73
- 6,67 6.67
- 74 74
- 2,07 2.07
- 75 75
- 2,88 2.88
- 82 82
- 0,72 0.72
- 83 83
- 0,25 0.25
- 84 84
- 0,17 0.17
- 85 85
- 1,65 1.65
- 86 86
- 13,13 13.13
- 87 87
- 47,71 47.71
- 88 88
- 1,26 1.26
- 89 89
- 0,12 0.12
Tabla 5 Table 5
- Actividad Activity
- Compuesto 2 Compuesto 17 Compuesto 67 Compound 2 Compound 17 Compound 67
- Base libre Free base
- Sal de CF3COOH Base libre Sal de HCl Sal de ácido metan– sulfónico Sal de CF3COOH Base libre Sal de CF3COOH CF3COOH salt Free base HCl salt Methane sulphonic acid salt CF3COOH salt Free base CF3COOH salt
- IC50 (HDAC1, μM) IC50 (HDAC1, μM)
- 0,043 0,049 0,029 0,044 0,051 0,024 0,037 0,039 0.043 0.049 0.029 0.044 0.051 0.024 0.037 0.039
- IC50 (HDAC3, μM) IC50 (HDAC3, μM)
- 0,064 0,029 0,056 0.064 0.029 0.056
- IC50 (HDAC8, μM) IC50 (HDAC8, μM)
- 0,267 0,353 0,254 0.267 0.353 0.254
- GI50 (Colo205, μM) IG50 (Colo205, μM)
- 0,4 0,4 0,06 0,06 0,04 0,11 0,09 0,09 0.4 0.4 0.06 0.06 0.04 0.11 0.09 0.09
- GI50 (HCT116, μM) IG50 (HCT116, μM)
- 0,4 0,3 0,06 0.4 0.3 0.06
- GI50 (MDA–MB435, μM) GI50 (MDA – MB435, μM)
- 0,3 0,6 0,19 0.3 0.6 0.19
- GI50 (MDA–MB231, μM) GI50 (MDA – MB231, μM)
- 0,5 0,7 0,06 0.5 0.7 0.06
- GI50 (A549, μM) GI50 (A549, μM)
- 0,3 0,2 0,08 0.3 0.2 0.08
Ensayo de acetilación de histona H3 Histone H3 Acetylation Assay
Una característica de la inhibición de la histona desacetilasa (HDAC) es el incremento del nivel de acetilación de las histonas. La acetilación de la histona, por ejemplo 5 H3, H4 y H2A, se puede detectar por inmunotinción (western blot). Se sembraron células Colo205, aproximadamente 1,5 x 106 células/placa de 10 cm, en el medio antes descrito, se cultivaron durante 24 h y luego se trataron con agentes inhibidores de HDAC con 0,1, 1, 5 y 10 M de concentración 10 final. Después de 24 h se cosecharon las células y se lisaron de acuerdo con las instrucciones de Sigma Mammalian Cell Lysis Kit. La concentración de proteína se cuantificó mediante el método BCA (SIGMA PTE LTD). El lisado de proteína se separó mediante 4–12% de gel bis–tris SDS–PAGE (INVITROGEN 15 PTE LTD) y se transfirió a una membrana PVDF (BioRad Pte Ltd). Se aplicó una sonda por separado a la membrana mediante anticuerpo primario específica para H3 acetilado, H4 acetilado o H2A acetilado (UPSTATE PTE LTD). El anticuerpo de detección, anticuerpo anticonejo de cabra conjugado con HRP, 20 se usó de acuerdo con las instrucciones del fabricante (PIERCE PTE LTD). Después de extraer el anticuerpo de detección de la membrana se agregó a la membrana un sustrato con quimioluminiscencia aumentada para la detección de HRP (PIERCE PTE LTD). Después de extraer el sustrato se expuso la 25 membrana a una película de rayos X (Kodak) durante 1 s – 20 min. Se desarrolló la película de rayos X mediante el procesador de película de rayos X. La densidad de cada banda A characteristic of histone deacetylase (HDAC) inhibition is the increase in the level of histone acetylation. Histone acetylation, for example 5 H3, H4 and H2A, can be detected by immunostaining (western blot). Colo205 cells, approximately 1.5 x 10 6 cells / 10 cm plate, were seeded in the medium described above, grown for 24 h and then treated with HDAC inhibitors with 0.1, 1, 5 and 10 µM of final concentration 10. After 24 h the cells were harvested and lysed according to the instructions of Sigma Mammalian Cell Lysis Kit. The protein concentration was quantified by the BCA method (SIGMA PTE LTD). The protein lysate was separated by 4-12% of bis-tris SDS-PAGE gel (INVITROGEN 15 PTE LTD) and transferred to a PVDF membrane (BioRad Pte Ltd). A probe was applied separately to the membrane by primary antibody specific for acetylated H3, acetylated H4 or acetylated H2A (UPSTATE PTE LTD). The detection antibody, goat anti-rabbit antibody conjugated to HRP, was used according to the manufacturer's instructions (PIERCE PTE LTD). After extracting the membrane detection antibody, a substrate with enhanced chemiluminescence for the detection of HRP (PIERCE PTE LTD) was added to the membrane. After removing the substrate, the membrane was exposed to an X-ray film (Kodak) for 1 s-20 min. The X-ray film was developed using the X-ray film processor. The density of each band
observada en la película desarrollada se podía analizar mediante software UVP Bioimaging (UVP, INC, Upland, CA). Luego se normalizaron los valores contra la densidad de actina en las correspondientes muestras, a fin de obtener la expresión de la proteína. 5 observed in the developed film could be analyzed using UVP Bioimaging software (UVP, INC, Upland, CA). The values against actin density in the corresponding samples were then normalized, in order to obtain the expression of the protein. 5
Los resultados del ensayo de inmunotinción (inmunoblotting) mediante anticuerpos contra histona desacetilasa H3, H4 y H2A se muestran en la tabla 6. The results of the immunoblotting assay by antibodies against histone deacetylase H3, H4 and H2A are shown in Table 6.
- Compuesto Compound
- Actividades de acetilación de histona Histone acetylation activities
- Histona–3 Histone – 3
- Histona–4 Histona–2A Histona – 4 Histona – 2A
- 1 one
- Activo Activo Activo Active Active Active
- 2 2
- Activo Activo Activo Active Active Active
- 12 12
- Activo Activo Active asset
- 17 17
- Activo Activo Activo Active Active Active
- 67 67
- Activo Activo Activo Active Active Active
10 10
Estos datos demuestran que los compuestos de esta invención inhiben las histona desacetilasas, por lo que se obtiene una acumulación de histonas acetiladas. These data demonstrate that the compounds of this invention inhibit histone deacetylases, whereby an accumulation of acetylated histones is obtained.
Ensayo de acetilación de histona H3 – enfoque ELISA Histone H3 acetylation assay - ELISA approach
Se puede aplicar un ensayo de inmunoabsorción ligado a 15 enzima (ELISA) para detectar y cuantificar la histona 3 acetilada (AcH3) en el lisado de proteínas obtenido de las líneas de células cancerosas tratadas con inhibidores de HDAC. An enzyme-linked immunosorbent assay (ELISA) can be applied to detect and quantify acetylated histone 3 (AcH3) in the protein lysate obtained from cancer cell lines treated with HDAC inhibitors.
El ensayo ELISA se desarrolló para detectar el nivel de 20 AcH3 proveniente de la línea de células cancerosas de colon Colo205 tratadas con los compuestos inhibidores de HDAC 10 M HDAC. Los lisados de pro-teínas provenientes de Colo205 tratadas y no tratadas se obtuvieron como se describió antes. La concentración de proteína proveniente de las células 25 lisadas se determinó mediante el método BCA (SIGMA–ALDRICH The ELISA assay was developed to detect the level of 20 AcH3 from the Colo205 colon cancer cell line treated with the 10 M HDAC inhibitor compounds. Protein lysates from treated and untreated Colo205 were obtained as described above. The protein concentration from the lysed cells was determined by the BCA method (SIGMA-ALDRICH
PTE LTD). Se investigaron distintas combinaciones de anticuerpos (véase la tabla 7) que se podían usar como anticuerpo primario (anticuerpo de captura) o anticuerpo secundario, a fin de determinar los anticuerpos adecuados, además de optimizar las concentraciones de anticuerpo y las 5 condiciones del ensayo. Se halló que las combinaciones de anticuerpo monoclonal murino contra H3 y de anticuerpo policlonal de conejo contra AcH3 (Lys9/14) producían las mejores uniones con los antígenos, fueran péptidos o proteínas lisadas provenientes de la línea de células 10 cancerosas de colon Colo205 tratadas con los inhibidores de HDAC. No se observaron valores de fondo. El anticuerpo de detección utilizado en esta prueba de ELISA fue anticuerpo anticonejo de burro conjugado con peroxidasa. PTE LTD). Different combinations of antibodies (see Table 7) that could be used as primary antibody (capture antibody) or secondary antibody were investigated in order to determine the appropriate antibodies, in addition to optimizing antibody concentrations and assay conditions. It was found that combinations of murine monoclonal antibody against H3 and rabbit polyclonal antibody against AcH3 (Lys9 / 14) produced the best binding with the antigens, whether they were peptides or lysed proteins from the Colo205 colon cancer cell line treated with HDAC inhibitors No background values were observed. The detection antibody used in this ELISA test was donkey anti-rabbit antibody conjugated to peroxidase.
A fin de determinar EC50 cuando se indujo la histona 3 15 acetilada en un 50%, se cultivaron células Colo205 en una placa de 96 cavidades con 1,5 x 105 células/cavidad durante 24 h. Luego se trataron las células Colo205 con inhibidores HDAC en distintas dosis (por duplicado, en tratamiento con 9 dosis, en diluciones al cuarto a partir de 100 M). Después 20 de tratarlas durante 24 h se lisaron las células y se determinó la concentración de proteínas. In order to determine EC50 when 50% acetylated histone was induced in 50%, Colo205 cells were cultured in a 96-well plate with 1.5 x 105 cells / cavity for 24 h. The Colo205 cells were then treated with HDAC inhibitors in different doses (in duplicate, in treatment with 9 doses, in room dilutions from 100 µM). After treating them for 24 h, the cells were lysed and the protein concentration was determined.
La placa de ELISA (placa de inmulon 2HB, BIOLABORATORIES PTE LTD) se recubrió con 4 g/ml de anticuerpo monoclonal murino contra H3 a 4ºC durante la 25 noche. Después de extraer el anticuerpo monoclonal murino contra H3 se lavó la placa con buffer de PBS que contiene 0,05% de Tween–20 y se bloqueó con solución de superbloqueo (Pierce Pte Ltd) a 37ºC, 1 h. Se extrajo la solución de superbloqueo y se lavó la placa con buffer PBS que contenía 30 0,05% de Tween. Se aplicaron el péptido AcH3, el péptido H3 y los lisados proteicos provenientes de las células Colo205 tratadas con los inhibidores de HDAC. Se realizó la reacción The ELISA plate (2HB inmulon plate, BIOLABORATORIES PTE LTD) was coated with 4 µg / ml murine monoclonal antibody against H3 at 4 ° C overnight. After extracting the murine monoclonal antibody against H3, the plate was washed with PBS buffer containing 0.05% Tween-20 and blocked with superblock solution (Pierce Pte Ltd) at 37 ° C, 1 h. The superblock solution was extracted and the plate was washed with PBS buffer containing 0.05% Tween. AcH3 peptide, H3 peptide and protein lysates from Colo205 cells treated with HDAC inhibitors were applied. Reaction was performed
de captura entre el anticuerpo primario y el antígeno, que es histona 3 en las muestras, a 37ºC durante 1 h. Después de extraer as muestras se lavó la placa con buffer PBS que contenía 0,05% de Tween. El anticuerpo secundario, 0,5 g/ml de anticuerpo policlonal de conejo contra AcH3 (Lys9/14), se 5 aplicó para detectar la acetilación de H3 en las muestras a 37ºC durante 1 h. Después de extraer los anticuerpos secundarios se lavó la placa con buffer PBS que contenía 0,05% de Tween. Se aplicó el anticuerpo de detección para detectar el anticuerpo secundario que capturaba AcH3 en las 10 muestras a 37ºC durante 30 min. El sustrato, 1–step Turbo TMB (PIERCE PTE LTD) se aplicó durante 30 min hasta desarrollo de color. Se detuvo la reacción mediante H2SO4 1M. Se midió la absorbancia a DO450 nm con un lector Spectromax (MOLECULAR DEVICES CORPORATION, Sunnivale, CA). 15 of capture between the primary antibody and the antigen, which is histone 3 in the samples, at 37 ° C for 1 h. After extracting the samples, the plate was washed with PBS buffer containing 0.05% Tween. The secondary antibody, 0.5 µg / ml rabbit polyclonal antibody against AcH3 (Lys9 / 14), was applied to detect acetylation of H3 in the samples at 37 ° C for 1 h. After extracting the secondary antibodies, the plate was washed with PBS buffer containing 0.05% Tween. The detection antibody was applied to detect the secondary antibody that captured AcH3 in the 10 samples at 37 ° C for 30 min. The substrate, 1-step Turbo TMB (PIERCE PTE LTD) was applied for 30 min until color development. The reaction was stopped by 1M H2SO4. The absorbance at DO450 nm was measured with a Spectromax reader (MOLECULAR DEVICES CORPORATION, Sunnivale, CA). fifteen
Se graficó la curva estándar y se determinó la concentración de AcH3 [(Lys9/14), g/ml] en una muestra mediante el software Softmax de Spectromax. Se calculó la cantidad de AcH3 en una muestra en base a la siguiente fórmula: 20 The standard curve was plotted and the concentration of AcH3 [(Lys9 / 14), /g / ml] in a sample was determined using Spectromax Softmax software. The amount of AcH3 in a sample was calculated based on the following formula:
- Total de pg de AcH3 (Lys9/14)/g de proteína total Total pg of AcH3 (Lys9 / 14) / g of total protein
- = (g de AcH3 (Lys9/14) en el ensayo)*106 = (g of AcH3 (Lys9 / 14) in the trial) * 106
- g de proteína en el ensayo g of protein in the assay
Se graficaron las curvas de dosis–respuesta para determinar los valores de EC50 para los compuestos con ajuste XL–fit (ID Business Solution, Emeryville, CA). [Tabla 8] Dose-response curves were plotted to determine EC50 values for compounds with XL-fit fit (ID Business Solution, Emeryville, CA). [Table 8]
Tabla 7: Anticuerpos utilizados en la prueba de 25 reactividad cruzada entre especies y en los estudios de anticuerpos combinados Table 7: Antibodies used in the cross-reactivity test between species and in the combined antibody studies
- Anticuerpos utilizados como anti-cuerpo primario o secundario Antibodies used as primary or secondary anti-body
- Detección de anticuerpo conjugado con HRP (peroxidasa de rábano) Detection of HRP-conjugated antibody (horseradish peroxidase)
- Anticuerpo policlonal de conejo con-tra AcH3 (Lys9/14; UPSTATE PTE LTD) Rabbit polyclonal antibody with AcH3 (Lys9 / 14; UPSTATE PTE LTD)
- Anticonejo de burro (PIERCE PTE LTD) Donkey anti-rabbit (PIERCE PTE LTD)
- Anticuerpo policlonal de conejo con-tra AcH3 (Lys14; UPSTATE PTE LTD) Rabbit polyclonal antibody with AcH3 (Lys14; UPSTATE PTE LTD)
- Anticonejo de cabra (PIERCE PTE LTD) Goat anti-rabbit (PIERCE PTE LTD)
- Anticuerpo policlonal de conejo con-tra AcH3 (Lys9, UPSTATE PTE LTD) Rabbit polyclonal antibody with AcH3 (Lys9, UPSTATE PTE LTD)
- Antirratón de cabra (PIERCE PTE LTD) Goat anti-mouse (PIERCE PTE LTD)
- Anticuerpo policlonal de cabra contra AcH3 (Lys9/14, SANTA CRUZ PTE LTD) Goat polyclonal antibody against AcH3 (Lys9 / 14, SANTA CRUZ PTE LTD)
- Anticabra de conejo (PIERCE PTE LTD) Rabbit anti-goat (PIERCE PTE LTD)
- Anticuerpo policlonal de cabra contra H3 (N–20. SANTA CRUZ PTE LTD) Goat polyclonal antibody against H3 (N – 20. SANTA CRUZ PTE LTD)
- Anticabra de ratón (PIERCE PTE LTD) Mouse anti-goat (PIERCE PTE LTD)
- Anticuerpo monoclonal de ratón contra H3 (UPSTATE PTE LTD) Mouse monoclonal antibody against H3 (UPSTATE PTE LTD)
En la tabla 8 se presentan datos para los compuestos seleccionados, como concentración efectiva para la inducción de la acetilación de la histona 3 ([AcH3(Lys9/14)]) como señal del 50% (EC50). 5 Table 8 shows data for the selected compounds, as an effective concentration for the induction of histone 3 acetylation ([AcH3 (Lys9 / 14)]) as a 50% signal (EC50). 5
Tabla 8 Table 8
- Compuesto Compound
- Estructura EC50 (M) EC50 structure (M)
- 2 2
- 1.7 1.7
- 17 17
- 1.1 1.1
- 67 67
- 0.5 0.5
Efecto antineoplásico in vivo (o antitumoral) de los agentes inhibidores de HDAC In vivo (or antitumor) antineoplastic effect of HDAC inhibitors
En datos no mostrados se analizaron compuestos 10 seleccionados con la máxima dosis tolerada en ratones In data not shown, selected compounds with the maximum tolerated dose in mice were analyzed
normales, y se halló que eran bien tolerados por los ratones, sin signos de toxicidad o efectos secundarios en el rango de dosis aplicado (que puede ser > 200 mg/kg/día). normal, and were found to be well tolerated by mice, with no signs of toxicity or side effects in the dose range applied (which may be> 200 mg / kg / day).
Entonces se puede determinar la eficacia de los compuestos de la invención mediante estudios de xenoinjerto 5 in vivo en animales. The efficacy of the compounds of the invention can then be determined by studies of xenograft 5 in vivo in animals.
En estos estudios se hicieron implantes subcutáneos en el flanco de ratones atímicos desnudos (Harlan) hembras de 12–14 semanas de edad, con 5 x 106 células de carcinoma de colon humano HCT116 o con 1 x 106 células de carcinoma de 10 colon humano Colo205 suspendidas en 50% de Matrigel. Cuando el tumor alcanza un tamaño de 100 mm3, se aparearon los ratones desnudos con xenoinjerto en diversos grupos de tratamiento. Los inhibidores de HDAC seleccionados se disolvieron en los vehículos adecuados, tales como 10% 15 DMA/10% Cremophore/80% agua y se administraron por vía intraperitoneal en ratones desnudos con xenoinjerto diariamente durante 14 días. El volumen de la dosis era de 0,2 ml / 20 g de ratón. Se usó Paclitaxol como control positivo, preparado para la administración intravenosa en 10% 20 etanol/10% Cremophore/80% agua. El volumen de la dosis para Paclitaxol era de 0,015 ml / g de ratón. Se calculó el volumen del tumor día por medio después de la inyección, mediante la fórmula: Volumen del tumor (mm3) = (w2 x l) / 2, donde w = anchura y l = longitud en mm de un carcinoma HCT116 25 o Colo205. Los compuestos de esta invención estudiados mostraron significativa reducción del volumen tumoral respecto de los controles tratados sólo con el vehículo. Se debe reducir la actividad de la histona desacetilasa cuando se mide, y hay acumulación de la histona acetilada, respecto 30 del grupo control tratado con el vehículo. In these studies subcutaneous implants were performed on the flank of nude nude mice (Harlan) females 12–14 weeks old, with 5 x 106 human colon carcinoma cells HCT116 or with 1 x 106 carcinoma cells of 10 human colon Colo205 suspended in 50% of Matrigel. When the tumor reaches a size of 100 mm3, nude mice were paired with xenograft in various treatment groups. The selected HDAC inhibitors were dissolved in suitable vehicles, such as 10% DMA / 10% Cremophore / 80% water and administered intraperitoneally in nude mice with xenograft daily for 14 days. The dose volume was 0.2 ml / 20 g of mouse. Paclitaxol was used as a positive control, prepared for intravenous administration in 10% ethanol / 10% Cremophore / 80% water. The dose volume for Paclitaxol was 0.015 ml / g of mouse. The volume of the day tumor was calculated by means after the injection, using the formula: Tumor volume (mm3) = (w2 x l) / 2, where w = width and l = length in mm of an HCT116 25 or Colo205 carcinoma. The compounds of this invention studied showed significant reduction in tumor volume with respect to the controls treated only with the vehicle. The activity of histone deacetylase should be reduced when measured, and there is accumulation of acetylated histone, relative to the control group treated with the vehicle.
Claims (19)
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–(2–fenil–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2- (2-phenyl-propyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3,4,5–trimetoxibencil)–2–(2–fenil–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3,4,5-trimethoxybenzyl) -2- (2-phenyl-ethyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–(4–benciloxi–3–metoxi–fenil)–1–metil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (4-benzyloxy-3-methoxy-phenyl) -1-methyl-1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–[2–(4–benciloxi–3–metoxi–fenil)–1–(3–hidroxi–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (4-benzyloxy-3-methoxy-phenyl) –1– (3-hydroxy-propyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2–hidroxi–etil)–2–(4–metoxi–fenil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2-hydroxy-ethyl) -2- (4-methoxy-phenyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2,3–hidroxi–propil)–2–(4–metoxi–fenil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2,3-hydroxy-propyl) -2- (4-methoxy-phenyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–(4–benciloxi–3–metoxi–fenil)–1–(2,3–hidroxi–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (4-benzyloxy-3-methoxy-phenyl) –1– (2,3-hydroxy-propyl) -1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–[1–(2,3–hidroxi–propil)–2–(2–fenil–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2,3-hydroxy-propyl) -2- (2-phenyl-ethyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2,3–hidroxi–propil)–2–(2–piridil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2,3-hydroxy-propyl) -2- (2-pyridyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2–hidroxi–etil)–2–(4–piridil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2-hydroxy-ethyl) -2- (4-pyridyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–(4–piridil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2- (4-pyridyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–piridilmetil)–2–(2–fenil–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-pyridylmethyl) -2- (2-phenyl-ethyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–(2–piridil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2- (2-pyridyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2-phenethyl-1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–metoxi–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-methoxy-propyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(2–fenetil–1–(piridin–2–il)metil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (2-phenethyl-1– (pyridin-2-yl) methyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-dimethylamino-2,2-dimethyl-propyl) –2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–fenetil–1–(2–piridin–2–il–etil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-phenethyl-1– (2-pyridin-2-yl-ethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–benciloximetil–1–(3–hidroxi–propil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-benzyloxymethyl-1– (3-hydroxy-propyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–tiofen–3–il–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2-thiophene-3-yl-1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–isobutil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2-isobutyl-1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–[2–isobutil–1–(2–piridin–2–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-isobutyl-1– (2-pyridin-2-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–octil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2-octyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–[2–ciclohexil–1–(3–hidroxi–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy– [2 – cyclohexyl-1– (3-hydroxy-propyl) –1H – benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(2–isobutil–1–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– (2-isobutyl-1-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(1,2–difenetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1,2-diphenethyl-1H-benzimidazole-5-yl) -acrylamide
- N–hidroxi–3–[2–fenetil–1–(2–piridin–3–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-phenethyl-1– (2-pyridin-3-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–benciloximetil–1–(2–piridin–3–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-benzyloxymethyl-1– (2-pyridin-3-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–{1–[3–(2–oxo–pirrolidin–1–il)–propil]–2–fenetil–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– {1– [3– (2-oxo-pyrrolidin-1-yl) -propyl] –2-phenethyl-1H-benzimidazole-5-yl} -acrylamide
- N–hidroxi–3–[1–(3–morfolin–4–propil]–2–fenetil–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– [1– (3-morpholin-4-propyl] -2-phenethyl-1H-benzimidazol-5-yl} -acrylamide
- ácido 3–[5–(2–hidrocarbamoil–vinil)–2–fenetil–1H–bencimidazol–1–il]–propiónico 3– [5– (2-hydrocarbamoyl-vinyl) -2-phenethyl-1H-benzimidazole-1-yl] -propionic acid
- N–hidroxi–3–(1–bencil–2–fenetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-benzyl-2-phenethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(1–bencil–2–isobutil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-benzyl-2-isobutyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(1–bencil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-benzyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(2–fenetil–1–propil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (2-phenethyl-1-propyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(1–propil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-propyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(1–etil–2–fenetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-ethyl-2-phenethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(1–etil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-ethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–[2–(2–fenil–propil)–1–(2–piridin–3–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (2-phenyl-propyl) –1– (2-pyridin-3-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2–piridin–2–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2-pyridin-2-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(1–etil–2–metil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– (1-ethyl-2-methyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2–morfolin–4–il–etil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2-morpholin-4-yl-ethyl) –2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- NNOHNHOOH NNOHNHOOH
- N–hidroxi–3–[1–(3–hidroxi–propil)–2–isopropil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-hydroxy-propyl) -2-isopropyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(1–metil–2–fenetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-methyl-2-phenethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(1–metil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-methyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(2–fenetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (2-phenethyl-1H-benzimidazole-5-yl) -acrylamide
- N–hidroxi–3–(1H–bencimidazol–5–il)–archilamida N-hydroxy-3– (1H-benzimidazol-5-yl) -archylamide
- N–hidroxi–3–[1–metil–2–(3–fenil–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1-methyl-2– (3-phenyl-propyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(1,2–dimetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1,2-dimethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–[1–metil–2–(fenilacetilamino–metil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1-methyl-2– (phenylacetylamino-methyl) –1H-benzimidazol-5-yl] -acrylamide
- N–[5–(2–hidroxicarbomoil–vinil)–1–metil–1H–bencimidazol–2–ilmetil]–isonicotinamida N– [5– (2-hydroxycarbomoyl-vinyl) -1-methyl-1H-benzimidazol-2-ylmethyl] -isonicotinamide
- N–hidroxi–3–[1–(3–imidazol–1–il–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-imidazol-1-yl-propyl) –2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(4–dimetilamino–butil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (4-dimethylamino-butyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–(bencilamino–metil)–1–metil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (benzylamino-methyl) -1-methyl-1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–{2–[(dibencilamino)–metil]–1–metil–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– {2 - [(dibenzylamino) -methyl] -1-methyl-1H-benzimidazol-5-yl} -acrylamide
- N–hidroxi–3–{2–[(4–metoxi–bencilamino)–metil]–1–metil–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– {2 - [(4-methoxy-benzylamino) -methyl] -1-methyl-1H-benzimidazol-5-yl} -acrylamide
- N–hidroxi–3–[1–(3–dimetilamino–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-dimethylamino-propyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–(bencilamino–metil)–etil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (benzylamino-methyl) -ethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2–dietilamino–etil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2-diethylamino-ethyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–fenetil–1–(piperidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-phenethyl-1– (piperidin-1-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–{2–[(dibencilamino)–metil]–1–etil–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– {2 - [(dibenzylamino) -methyl] -1-ethyl-1H-benzimidazol-5-yl} -acrylamide
- N–hidroxi–3–(2–{[2–(4–fluoro–fenil)–acetilamino]–metil}–1–metil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (2 - {[2– (4-fluoro-phenyl) -acetylamino] -methyl} -1-methyl-1H-benzimidazole-5-yl) -acrylamide
- N–hidroxi–3–[1–etil–2–(2–fenilacetilamino–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1-ethyl-2– (2-phenylacetylamino-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–(2–bencensulfonilamino–etil)–1–etil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (2-benzenesulfonylamino-ethyl) -1-ethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–fenetil–1–(2–pirrolidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-phenethyl-1– (2-pyrrolidin-1-yl-ethyl) -1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–{1–etil–2–[2–(2–fenoxi–acetilamino)–etil]–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– {1-ethyl-2– [2– (2-phenoxy-acetylamino) -ethyl] –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–(2–bencilamino–etil)–1–etil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (2-benzylamino-ethyl) -1-ethyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2,2–dimetil–propil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2,2-dimethyl-propyl) -2-phenethyl-1H-benzimidazol-5-yl] -acrylamide
- ONHHONNN ONHHONNN
- N–hidroxi–3–[1–(1–bencil–piperidin–4–il)–2–fenetil–1H–bencimidazol–5–il]acrilamida N-hydroxy-3– [1– (1-benzyl-piperidin-4-yl) –2-phenethyl-1H-benzimidazol-5-yl] acrylamide
- ONHHONNOH ONHHONNOH
- N–hidroxi–3–[1–(2–hidroxietil)–2–fenetil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2-hydroxyethyl) -2-phenethyl-1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–[1–(5–hidroxi–pentil)–2–fentil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (5-hydroxy-pentyl) –2-fentil-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(1–alil–2–fenetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1-allyl-2-phenethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–(1–(3–isoproxi–propil)–2–fenetil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (1– (3-isoproxy-propyl) -2-phenethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–{1–[3–(4–metil–piperazin–1–il)–2–fenetil]–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– {1– [3– (4-methyl-piperazin-1-yl) –2-phenethyl] –1H-benzimidazol-5-yl} -acrylamide
- N–hidroxi–3–[2–fenetil–1–(3–pirrolidin–1–il–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-phenethyl-1– (3-pyrrolidin-1-yl-propyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–(3–fenil–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-dimethylamino-2,2-dimethyl-propyl) –2– (3-phenyl-propyl) –1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–{1–(3–dimetilamino–2,2–dimetil–propil)–2–[2–(4–fluoro–fenil)–etil]–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– {1– (3-dimethylamino-2,2-dimethyl-propyl) –2– [2– (4-fluoro-phenyl) -ethyl] –1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–{2–(4–fluoro–fenil)–etil]–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– {2– (4-fluoro-phenyl) -ethyl] –1H-benzimidazol-5-yl} -acrylamide
- N–hidroxi–3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–(2–piridin–3–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-dimethylamino-2,2-dimethyl-propyl) –2– (2-pyridin-3-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–(2–piridin–3–il–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2– (2-pyridin-3-yl-propyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[2–bencilsulfanil–1–(3–dimetilamino–2–2,dimetil–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [2-benzylsulfanyl-1– (3-dimethylamino-2–2, dimethyl-propyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(2–piperidin–1–il–etil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (2-piperidin-1-yl-ethyl) –1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–[1–(3–dimetilamino–2,2–dimetil–propil)–2–fenilmetansulfonil–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1– (3-dimethylamino-2,2-dimethyl-propyl) -2-phenylmethanesulfonyl-1H-benzimidazole-5-yl] -acrylamide
- N–hidroxi–3–(2–ben cil–1–etil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (2-benyl-1-ethyl-1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–{1–etil–2–[3–(1H–indol–3–il)–propil]–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– {1-ethyl-2– [3– (1H-indole-3-yl) -propyl] –1H-benzimidazol-5-yl) -acrylamide
- N–hidroxi–3–{1–(3–dimetilamino–2,2–dimetil–propil)–2–[2–(3–metoxi–fenil)–etil]–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– {1– (3-dimethylamino-2,2-dimethyl-propyl) –2– [2– (3-methoxy-phenyl) -ethyl] –1H-benzimidazole-5-yl) -acrylamide
- N–hidroxi–3–{2–(3–metoxi–fenil)–etil]–1H–bencimidazol–5–il}–acrilamida N-hydroxy-3– {2– (3-methoxy-phenyl) -ethyl] -1H-benzimidazol-5-yl} -acrylamide
- N–hidroxi–3–[1–etil–2–(3–fenoxi–propil)–1H–bencimidazol–5–il]–acrilamida N-hydroxy-3– [1-ethyl-2– (3-phenoxy-propyl) –1H-benzimidazol-5-yl] -acrylamide
- (L)–N–hidroxi–3–[2–(1–amino–2–fenil–etil)–1–metil–1H–bencimidazol–5–il]–acrilamida (L) –N – hydroxy – 3– [2– (1-amino-2-phenyl-ethyl) –1-methyl-1H-benzimidazol-5-yl] -acrylamide
- N–hidroxi–3–(2–{[2–(4–metoxi–fenil)–acetilamino]–metil}–1–metil–1H–bencimidazol–5–il)–acrilamida N-hydroxy-3– (2 - {[2– (4-methoxy-phenyl) -acetylamino] -methyl} -1-methyl-1H-benzimidazole-5-yl) -acrylamide
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US50421403P | 2003-09-22 | 2003-09-22 | |
US504214P | 2003-09-22 | ||
US530890P | 2003-12-22 |
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AR (1) | AR104985A2 (en) |
ES (1) | ES2348360T3 (en) |
ZA (1) | ZA200602181B (en) |
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TW201245115A (en) * | 2011-01-24 | 2012-11-16 | Chdi Foundation Inc | Histone deacetylase inhibitors and compositions and methods of use thereof |
CN103755595A (en) * | 2012-12-25 | 2014-04-30 | 中南大学 | Hydroxamic acid derivative and application thereof |
KR20180098593A (en) * | 2015-12-22 | 2018-09-04 | 칸세라 아베 | Useful as bicyclic hydroxamic acid inhibitors for histone deacetylase activity in mammals |
CN106565823B (en) * | 2016-11-10 | 2020-09-11 | 珠海诺贝尔国际生物医药研究院有限公司 | Eph receptor small molecule inhibitor and preparation method thereof |
CN106946873B (en) * | 2017-03-31 | 2020-03-27 | 牡丹江医学院 | Medicine for treating facial nerve injury and preparation method thereof |
WO2019223718A1 (en) * | 2018-05-22 | 2019-11-28 | 成都先导药物开发股份有限公司 | Immunomodulator |
CN110950848B (en) * | 2018-09-27 | 2024-03-26 | 徐诺药业 | Synthesis and application of novel aminopyrazole derivative |
WO2021027722A1 (en) * | 2019-08-09 | 2021-02-18 | 成都先导药物开发股份有限公司 | Immunomodulator |
CN112824398B (en) * | 2019-11-20 | 2022-10-21 | 成都先导药物开发股份有限公司 | Immunomodulator |
JP7514930B2 (en) * | 2020-07-03 | 2024-07-11 | 日本農薬株式会社 | Coccidiosis control agent and method for using the same |
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- 2004-09-21 ES ES04775628T patent/ES2348360T3/en not_active Expired - Lifetime
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