ES2574529T3 - Imidazo[1,2a]pirazinas y composiciones que las incluyen para el tratamiento de enfermedades parasíticas - Google Patents
Imidazo[1,2a]pirazinas y composiciones que las incluyen para el tratamiento de enfermedades parasíticas Download PDFInfo
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- ES2574529T3 ES2574529T3 ES14156496.3T ES14156496T ES2574529T3 ES 2574529 T3 ES2574529 T3 ES 2574529T3 ES 14156496 T ES14156496 T ES 14156496T ES 2574529 T3 ES2574529 T3 ES 2574529T3
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- 208000030852 Parasitic disease Diseases 0.000 title description 5
- 239000000203 mixture Substances 0.000 title description 2
- 150000005236 imidazo[1,2-a]pyrazines Chemical class 0.000 title 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 20
- -1 benzo [d] [1,3] dioxol-5-yl Chemical group 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 229910052799 carbon Inorganic materials 0.000 abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 33
- 239000001257 hydrogen Substances 0.000 abstract 18
- 125000000623 heterocyclic group Chemical group 0.000 abstract 11
- 125000000217 alkyl group Chemical group 0.000 abstract 8
- 125000005843 halogen group Chemical group 0.000 abstract 8
- 150000002431 hydrogen Chemical group 0.000 abstract 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 5
- 229920006395 saturated elastomer Polymers 0.000 abstract 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 4
- 125000005842 heteroatom Chemical group 0.000 abstract 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 abstract 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 3
- 125000002947 alkylene group Chemical group 0.000 abstract 3
- 125000004193 piperazinyl group Chemical group 0.000 abstract 3
- 125000003386 piperidinyl group Chemical group 0.000 abstract 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
- 125000003118 aryl group Chemical group 0.000 abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 abstract 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 2
- 125000003226 pyrazolyl group Chemical group 0.000 abstract 2
- 125000004076 pyridyl group Chemical group 0.000 abstract 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 abstract 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 101100240521 Caenorhabditis elegans nhr-16 gene Proteins 0.000 abstract 1
- KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical compound C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 133
- 238000005160 1H NMR spectroscopy Methods 0.000 description 125
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 20
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 19
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000000921 elemental analysis Methods 0.000 description 7
- 208000009182 Parasitemia Diseases 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- CGNLCCVKSWNSDG-UHFFFAOYSA-N SYBR Green I Chemical compound CN(C)CCCN(CCC)C1=CC(C=C2N(C3=CC=CC=C3S2)C)=C2C=CC=CC2=[N+]1C1=CC=CC=C1 CGNLCCVKSWNSDG-UHFFFAOYSA-N 0.000 description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 2
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- 230000009089 cytolysis Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
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- WDGBSZVDSDOMAT-UHFFFAOYSA-N (1-aminocyclopentyl)-[2-(4-fluorophenyl)-3-(4-methylanilino)-6,8-dihydro-5h-imidazo[1,2-a]pyrazin-7-yl]methanone Chemical compound C1=CC(C)=CC=C1NC1=C(C=2C=CC(F)=CC=2)N=C2N1CCN(C(=O)C1(N)CCCC1)C2 WDGBSZVDSDOMAT-UHFFFAOYSA-N 0.000 description 1
- KNIXVJBVCXLWGG-XMMPIXPASA-N (2r)-1-[2-(4-fluorophenyl)-3-(4-methylanilino)-6,8-dihydro-5h-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3-phenylpropan-1-one Chemical compound C1=CC(C)=CC=C1NC1=C(C=2C=CC(F)=CC=2)N=C2N1CCN(C(=O)[C@H](O)CC=1C=CC=CC=1)C2 KNIXVJBVCXLWGG-XMMPIXPASA-N 0.000 description 1
- CQVOREZBQOLTPD-JOCHJYFZSA-N (2s)-1-[2-(4-fluorophenyl)-3-(4-methylanilino)-6,8-dihydro-5h-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-3,3-dimethylbutan-1-one Chemical compound C1=CC(C)=CC=C1NC1=C(C=2C=CC(F)=CC=2)N=C2N1CCN(C(=O)[C@@H](O)C(C)(C)C)C2 CQVOREZBQOLTPD-JOCHJYFZSA-N 0.000 description 1
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- LWQPWQPRZFSJET-DEOSSOPVSA-N (3s)-1-[2-(4-fluorophenyl)-3-(4-methylanilino)-6,8-dihydro-5h-imidazo[1,2-a]pyrazin-7-yl]-3-hydroxy-3-phenylpropan-1-one Chemical compound C1=CC(C)=CC=C1NC1=C(C=2C=CC(F)=CC=2)N=C2N1CCN(C(=O)C[C@H](O)C=1C=CC=CC=1)C2 LWQPWQPRZFSJET-DEOSSOPVSA-N 0.000 description 1
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- WGZXNKBUTRIHCG-UHFFFAOYSA-N 1-[2-(4-fluorophenyl)-3-(4-methylanilino)-6,8-dihydro-5h-imidazo[1,2-a]pyrazin-7-yl]-2-hydroxy-2-(4-methoxyphenyl)ethanone Chemical compound C1=CC(OC)=CC=C1C(O)C(=O)N1CC2=NC(C=3C=CC(F)=CC=3)=C(NC=3C=CC(C)=CC=3)N2CC1 WGZXNKBUTRIHCG-UHFFFAOYSA-N 0.000 description 1
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- 239000003430 antimalarial agent Substances 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- 229930101531 artemisinin Natural products 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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Abstract
Un compuesto de Formula Ia:**Fórmula** en la que: n se selecciona entre 0, 1, 2, 3 y 4; m >= 0 Ra se selecciona de -X3NR7R8, -X3OR8, -X3S(O)0-2R8, -X3C(O)NR7R8, y bencilo opcionalmente sustituido con 1 a 3 radicales seleccionados independientemente entre halo, alquilo C1-4, alquilo C1-4 halosustituido, alcoxi C1-4 y alcoxi C1-4 halosustituido; en donde X3 se selecciona entre un enlace y alquileno C1-4; R1 se selecciona entre -OR13, -C(O)OR13, -NR13R14, arilo C6-10 y un anillo heterociclico de 4-9 miembros saturado, insaturado o parcialmente insaturado que contiene un maximo de tres atomos de nitrogeno; en donde R13 se selecciona entre hidrogeno, alquilo C1-6, alquilo C1-6 halo-sustituido, alquilo C1-6 hidroxi-sustituido, aril C6-10-alquilo C0-4, cicloalquil C3-8-alquilo-C0-4, -X1NHC(O)R15, -X1C(NH)NHR15, -XiC(O)NHR15, -X1NHR15, -X1OR15, -C(O)R15 y -C(O)OR15; en donde X1 se selecciona entre un enlace y alquileno C1-4; R15 se selecciona entre hidrogeno, alquilo C1-6, alquilo C1-6 halo-sustituido y bencilo; R14 se selecciona entre hidrogeno, alquilo C1-6 y alquilo C1-6 hidroxi-sustituido; o R13 y R14 junto con el atomo de nitrogeno al que R13 y R14 estan unidos forman un anillo heterociclico de 5-9 miembros saturado, insaturado o parcialmente insaturado que contiene un maximo de tres heteroatomos seleccionados entre N, NR30, S(O)0-2 y O; en donde R30 se selecciona entre hidrogeno y alquilo C1-6; en donde dicho heterociclico forma la combinacion de R13 y R14 esta opcionalmente sustituido con 1-3 radicales seleccionados independientemente entre halo, hidroxi, alquilo C1-6, alquilo C1-6 aminosustituido y alquilo C1-6 halosustituido; cualquier arilo o heterociclico de R1 esta opcionalmente sustituido con 1-3 radicales seleccionados independientemente entre halo, alquilo C1-6, alquilo C1-6 halo-sustituido, alcoxi C1-6 y alcoxi C1-6 halosustituido; R2 se selecciona entre hidrogeno, alquilo C1-6, amino, cicloalquil C3-8-alquilo-C0-4, aril C6-10-alquilo-C0-4, alquilo C1-6 halosustituido, alquilo C1-6 hidroxisustituido y heterociclil-alquilo C0-4; en donde dicho heterociclilo es un anillo heterociclico de 5-9 miembros saturado, insaturado o parcialmente insaturado que contiene un maximo de tres heteroatomos seleccionados entre N, NR30, S(O)0-2 y O; en donde R30 se selecciona entre hidrogeno y alquilo C1-6; dichos arilo C6-10 o heterociclico de R2 estan opcionalmente sustituidos con de 1 a 3 radicales seleccionados independientemente entre halo, hidroxi, ciano, nitro, -NHR17, -(CH2)0-2NHC(O)R17, alquilo C1-6, alquilo C1-6 halo-sustituido, alquilo C1-6 aminosustituido y alcoxi C1-6; en donde R17 se selecciona entre hidrogeno y alquilo C1-6; R3 se selecciona entre hidrogeno, alquilo C1-6, aril C6-10-alquilo-C0-4, -X2C(O)OR16, -X2S(O)0-2R16, -X2OR16, -X2C(O)NHR16 y -X2NHC(O)R16; en donde X2 se selecciona entre un enlace y alquileno C1-4; y R16 se selecciona entre hidrogeno, alquilo C1-6 y aril C6-10 alquilo-C0-4; en donde dicho arilo de R16 esta opcionalmente sustituido con 1-3 radicales seleccionados independientemente entre halo, alquilo C1-6, alquilo C1-6 halo-sustituido, alcoxi C1-6 y alcoxi C1-6 halosustituido; o R2 y R3 junto con el atomo de carbono al que R2 y R3 estan unidos forman un cicloalquilo C3-8; o R2 y R13, junto con los atomos a los que R2 y R13 estan unidos, forman un anillo heterociclico de 5-9 miembros saturado, insaturado o parcialmente insaturado, individual o condensado que contiene un maximo de tres heteroatomos o grupos seleccionados entre N, C(O), NR30, S(O)0-2 y O; en donde R30 se selecciona entre hidrogeno y alquilo C1-6; en donde dicho anillo heterociclico forma la combinacion de R2 y R13 esta opcionalmente sustituido con 1 a 3 radicales seleccionados independientemente entre halo, hidroxi, alquilo C1-6 y alquilo C1-6 halosustituido; R4 se selecciona entre hidrogeno y alquilo C1-6; R5 se selecciona entre hidrogeno y alquilo C1-6; o R4 y R5 junto con el atomo de carbono al que R4 y R5 estan unidos forman un cicloalquilo C3-8; R6 se selecciona entre arilo C6-10; cicloalquilo C3-8 y un anillo heterociclico de 5-9 miembros saturado, insaturado o parcialmente insaturado, individual o condensado, que contiene un maximo de tres heteroatomos o grupos seleccionados entre N, C(O), NR30, S(O)0-2 y O; en donde R30 se selecciona entre hidrogeno y alquilo C1-6; en donde dichos arilo o heterociclico de R6 estan opcionalmente sustituidos con 1 a 3 radicales seleccionados independientemente entre halo, hidroxi, alquilo C1-6 y alcoxi C1-6; R7 se selecciona entre hidrogeno, metilo, etilo e isopropilo; R8 se selecciona entre fenilo, bencilo, benzo[d][1,3]dioxol-5-ilo, ciclobutilo, ciclopentilo, cicloheptilo, ciclohexilo, biciclo[2.2.1]heptilo, tetrahidro-2H-piranilo, piridinilo, piperidinilo, piperazinilo, quinolinilo, pirrolidinilo y pirazolilo; en donde dichos fenilo, bencilo, benzo[d][1,3]dioxol-5-ilo, ciclobutilo, ciclopentilo, cicloheptilo, ciclohexilo, biciclo[2.2.1]heptilo, tetrahidro-2H-piranilo, piridinilo, piperidinilo, piperazinilo, quinolinilo, pirrolidinilo o pirazolilo de R8 estan opcionalmente sustituidos con 1 a 3 radicales seleccionados independientemente entre halo, ciano, metilo, etilo, t-butilo, trifluorometilo, trifluorometoxi, dimetilamino, difluorometoxi, carboxi, metoxicarbonilo, metil sulfonilamino, metilsulfonilo, metilaminocarbonilo, fenilo, piperidinilo, piperidinil-metilo, piperazinilo y piperazinil-metilo; R9 se selecciona entre hidrogeno y alquilo C1-6; R10 se selecciona entre hidrogeno y alquilo C1-6; R11 se selecciona entre hidrogeno y alquilo C1-6; y R12 se selecciona entre hidrogeno y alquilo C1-6; o R11 y R12 se combinan para formar C(O); o una de sus sales farmaceuticamente aceptables.
Description
(2S)-2-amino-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-feniletan-1-ona; 1-{[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]carbonil}ciclopropan-1-ol; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-3-hidroxi-3-metibutan-1-ona; N-[(5S)-5-amino-6-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-6-oxohexil]acetami
5 da; N-[(5S)-5-amino-6-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-6-oxohexil]-2,2,2-tr ifluoroacetamida; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-3-hidroxipropan-1-ona; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-3-metilbutan-1-ona; (1S,2S)-2-{[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]carbonil}ciclopentan-1-ol; (2S)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-3-fenilpropan-1-ona; 2-(4-fluorofenil)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxietan-1-ona ; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-3-hidroxibutan-1-ona; (2R)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-3-fenilpropan-1-ona;
15 (2S)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-3,3-dimetilbutan-1-on a; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-fenilpropan-1-ona; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2,2-difeniletan-1-ona; 2-(4-fluorofenil)-N-(4-metilfenil)-5H,6H,7H,8H-imidazo[1,2-a]pirazin-3-amina; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-(trifluorometil)butan-1-o na; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-metilpropan-1-ona; 1-{[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]carbonil}ciclopentan-1-ol; 1-{[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]carbonil}ciclohexan-1-ol; (2R)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-fenilbutan-1-ona;
25 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-3-hidroxi-2,2-dimetil-3-(4-metilfenil) propan-1-ona; 4,4,4-trifluoro-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-3-hidroxi-3-metilbutan -1-ona; (2S)-2-ciclohexil-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxietan-1-on a; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-(4-metoxifenil)etan-1-on a; 2-(3,5-difluorofenil)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxietan-1ona;
35 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-[3-(trifluorometil)fenil]eta n-1-ona; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-metoxi-2-feniletan-1-ona; 2-(4-bromofenil)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxietan-1-on a; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-[4-(trifluorometil)fenil]eta n-1-ona; 3,3,3-trifluoro-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-metoxi-2-fenil-prop an-1-ona; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-(3-hidroxifenil)etan-1-on
45 a; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-(4-hidroxifenil)etan-1-on a; 2-(2-clorofenil)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxietan-1-ona; 2-(4-bromo-2-fluorofenil)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxiet an-1-ona; 2-(4-clorofenil)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxietan-1-ona; (2S)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-4-metil-pentan-1-ona ; (3S)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-3-hidroxi-3-fenilpropan-1-ona; 2-(4-fluorofenil)-N-(4-metilfenil)imidazo[1,2-a]pirazin-3-amina;
55 (2R)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-feniletan-1-ona; (2S)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxi-2-feniletan-1-ona; 7-[(1-aminociclobutil)carbonil]-2-(4-fluorofenil)-N-(4-metilfenil)-5H,6H,7H,8H-imidazo[1,2-a]pirazin-3-amina; 7-[(1-aminociclopentil)carbonil]-2-(4-fluorofenil)-N-(4-metilfenil)-5H,6H,7H,8H-imidazo[1,2-a]pirazin-3-amina; 7-[(1-aminociclohexil)carbonil]-2-(4-fluorofenil)-N-(4-metilfenil)-5H,6H,7H,8H-imidazo[1,2-a]pirazin-3-amina; 2-amino-4,4,4-trifluoro-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]butan-1-ona; 1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-3-hidroxi-3-metilpentan-1-ona; 2-amino-3,3,3-tnfluoro-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]propan-1-ona ; (2S)-3-ciclohexil-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]-2-hidroxipropan-1
65 ona; 2-(bencilamino)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]etan-1-ona; 2-(dipropilamino)-1-[2-(4-fluorofenil)-3-[(4-metilfenil)amino]-5H,6H,7H,8H-imidazo[1,2-a]pirazin-7-il]etan-1-ona;
Tabla 1
- Compuesto
- Estructura Datos físicos MS (m/z) y/o RMN 1H
- Comp. ref. 1
- [M+H] = 335,2 RMN1Н (CDCl3), 400 MHz) δ 7,64 (d, J = 7,2 Hz, 2H), 7,91-7,94 (m, 3H), 7,21-7,27 (m, 3H), 6,59 (d, J = 8,4 Hz, 1 H), 6,26 (d, J = 2,0 Hz, 1H), 5,99 (dd, J = 2,0, 9,2 Hz, 1H), 5,83 (s, 2H), 4,48 (s, 2H), 3,89 (s, 2H), 3,38 (s, 2H).
- Comp. ref. 2
-
imagen28 [M+H] = 319,2 RMN1Н (CDCl3), 400 MHz) δ 7,34 (s, 2H), 7,10 (s, 2H), 6,79-6,81 (m, 2H), 6,70-6,74 (m, 1H), 6,40 (a, 1H), 5,19 (s, 2H), 4,22 (s, 2H), 3,92 (s, 2H), 1,98 (s, 6H).
- Comp. ref. 3
- [M+H] = 301,2
- Comp. ref. 4
- [M+H] = 283,2
- Comp. ref. 5
- [M+H] = 291,2
- Comp. ref. 6
- [M+H] = 349,2
- Comp. ref. 7
- [M+H] = 327,2
- Comp. ref. 8
- [M+H] = 309,2
- Comp. ref. 9
-
imagen29 [M+H] = 363,1
- Comp. ref. 10
- [M+H] = 345,1
- Comp. ref. 11
- [M+H] = 379,2
- Comp. ref. 12
- [M+H] = 315,2
- Comp. ref. 13
- [M+H] = 310,2
- Comp. ref. 14
- [M+H] = 315,0
- Comp. ref. 15
- [M+H] = 387,1
- Comp. ref. 16
- [M+H] = 323,2
- Comp. ref. 17
- [M+H] = 327 RMN1H. (300 MHz, DMSO-d6): δ 7,81-7,72 (m, 2H), 7,11 (m, 2H), 6,97 (m, 2H), 6,56-6,52 (m, 2H), 3,86 (s, 2H), 3,55 (m, 2H), 3,02 (m, 2H)
- Comp. ref. 18
- [M+H] = 311,9
- Comp. ref. 19
- [M+H] = 229 RMN1H (300 MHz, CDCl3): δ 8,82 (s, 1H), 8,28 (d, J = 4,8 Hz, 1H), 8,05-8,09 (m, 2H), 7,76 (d, J = 4,5 Hz, 1H), 7,27-7,33 (m, 2H) 5,79 (s, 2H)
- Comp. ref. 20
- [M+H] = 327,2
- Comp. ref. 21
- [M+H] = 324,3
- Comp. ref. 22
- [M+H] = 343,2
- Comp. ref. 23
- [M+H] = 323,2
- Comp. ref. 24
- [M+H] = 339,1
- Comp. ref. 25
- [M+H] = 387,1
- Comp. ref. 26
- [M+H] = 343,2
- Comp. ref. 27
- [M+H] = 345,1
- Comp. ref. 28
- [M+H] = 377,1
- Comp. ref. 29
- [M+H] = 323 RMN1H (400 MHz, CD3OD) δ 7,73 (d, J = 6,8 Hz, 2H), 7,00-6,99 (m, 4H), 6,49 (d, J = 8,0 Hz, 2H), 4,01 (s, 2H), 3,72 (s, 2H), 3,15 (s, 2H), 2,19 (s, 3H).
- Comp. ref. 30
- [M+H] = 343 RMN1H. (300 MHz, DMSO-d6): � 7,94 (s, 1H), 7,80-7,74(m, 2H), 7,18-7,09(m, 4H), 6,56 (d, J = 8,7 Hz, 2H), 3,87 (s, 2H), 3,55 (s, 2H), 3,02(t, J = 5,4 Hz, 2H).
- Comp. ref. 31
- [M+H] = 341 RMN1H (300 MHz, CDCl3) δ 7,70-7,62 (m, 1H), 7,01 (d, J = 8,1 Hz, 2H), 6,92-6,76 (m, 2H), 6,52 (d, J = 8,1 Hz, 2H), 5,33 (s, 1H), 4,23 (s, 2H), 3,77 (m, 2H), 3,26 (m, 2H), 2,25 (s, 3H).
- Comp. ref. 32
- [M+H] = 229 RMN1H (300 MHz, DMSO-d6) δ 8,83 (s, 1H), 8,30-8,28 (m, 1H), 7,89-7,76 (m, 3H), 7,54-7,47 (m, 1H), 7,12-7,17 (m, 1H), 5,94 (s, 2H).
- Comp. ref. 33
- [M+H] = 243,1
- Comp. ref. 34
- [M+H] = 452,2
- Comp. ref. 35
- [M+H] = 482 RMN 1H: (400 MHz, CD3OD) δ 7,84-7,81 (m, 2H), 7,14 (t, J = 8,8 Hz, 2H), 4,09-4,01 (m, 4H), 3,81 (t, J = 4,8 Hz, 2H), 1,89 (s, 6H), 1,46 (s, 9H).
- Comp. ref. 36
- [M+H] = 515,0
- Comp. ref. 37
- [M+H] = 452,2
- Comp. ref. 38
- [M+H] = 243 RMN1H: (300 MHz, DMSO-d6) δ 8,79 (d, J = 0,9 Hz, 1H), 8,26-8,24(m, 1H), 7,93-7,86(m, 1H), 7,85-7,83(m, 1H), 7,74(d, J = 4,8 Hz, 1H), 7,21(t, J = 9,3 Hz, 1H), 5,80 (s, 2H), 2,29(d, J = 13,5 Hz, 3H
- Comp. ref. 39
- [M+H] = 263 RMN1H (300 MHz, DMSO-d6): δ 8,83 (d, J = 1,2 Hz, 1H), 8,30-8,28(m, 1H), 8,18-8,15(m, 1H), 8,06-8,00(m, 1H), 7,78(d, J = 4,5 Hz, 1H), 7,51(d, J = 9 Hz, 1H), 5,91 (s, 2H)
- Comp. ref. 40
- [M+H] = 263 RMN1H. (300 MHz, DMSO-d6) δ 8,84 (1H, d, J = 1,2 Hz), 8,30-8,28 (1H, m), 7,99-7,88 (2H, m), 7,77 (1H, d, J = 4,8 Hz), 7,66 (1H, t, J = 8,1 Hz), 6,01 (2H, s)
- Comp. ref. 41
-
imagen30 [M+H] = 260 RMN1H: (300 MHz, CDCl3) δ 7,75-7,70 (m, 2H), 7,10-7,03(m, 3H), 3,89 (s, 2H), 3,78 (s, 2H), 2,43 (s, 3H), 1,19 (s, 6H).
- Comp. ref. 42
- [M+H] = 481,0
- Comp. ref. 43
- [M+H] = 445,0
- Comp. ref. 44
- RMN1H: (400 MHz, CDCl3) δ 7,88-7,92 (m, 2H), 7,07-7,11 (m, 2H), 4,88 (s, 1H), 4,87 (s, 2H), 3,84 (s, 1H), 1,55 (s, 6H), 1,51 (s, 6H), 1,37 (s, 9H).
- Comp. ref. 45
- [M+H] = 351,2
- Comp. ref. 46
-
imagen31 [M+H] = 338,0
- Comp. ref. 47
- [M+H] = 458,0
- Comp. ref. 48
- RMN1H: (400 MHz, CDCl3) δ 7,65-7,69 (m, 2H), 7,14 (s, 1H); 7,03 (t, J = 8,8 Hz, 2H), 4,62 (s, 2H), 3,11 (s, 3H), 1,70 (m, 6H).
- Comp. ref. 49
- [M+H] = 481,1
- Comp. ref. 50
-
imagen32 RMN1H: (400 MHz, CDCl3) δ 7,87-7,90 (m, 2H), 7,07 (t, J = 8,8 Hz, 2H), 3,86 (t, J = 5,6 Hz, 2H), 3,03 (t, J = 5,6 Hz, 2H), 2,44 (s, 3H), 1,50 (s, 6H).
- Comp. ref. 51
-
imagen33 [M+H] = 232 RMN1H (300 MHz, DMSO-d6) δ 4,47 (s, 2H), 4,65 (s, 2H), 7,15-7,21 (m, 2H), 7,55 (s, 1H), 7,74-7,79 (m, 2H), 8,48 (s, 1H)
- Comp. ref. 52
- [M+H] = 277,0 RMN1H: (400 MHz, CD3OD) δ 7,12-7,07 (m, 2H), 4,95 (t, J = 2,0 Hz, 2H), 4,57 (t, J = 2,00 Hz, 2H).
- Comp. ref. 53
- [M+H] = 306 RMN1H: (300 MHz, CDCl3): δ 8,44-8,46 (m, 2H), 7,79 (m, 2H), δ 7,06-7,09 (d, J = 8,1 Hz, 2H), 6,60-6,63 (d, J = 8,4 Hz, 2H), 5,57 (s, 1H), 3,90 (s, 2H), 3,81 (m, 2H), 3,43 (s, 1H), 3,03 (m, 2H), 2,29 (s, 3H)
- Comp. ref. 54
- [M+H] = 335 RMN1H: (300 MHz, CDCl3): δ 7,67 (d, J = 6 Hz, 1H), 7,25 (d, J = 6,6 Hz, 1H), 7,01 (t, J = 4,2 Hz, 2H), 6,94 (t, J = 8,1 Hz, 2H), 6,52 (d, J = 8,1 Hz, 2H), 5,87 (s, 1H), 4,20 (s, 2H), 3,83 (s, 3H), 3,75 (m, 2H), 3,49 (s, 1H), 3,22 (m, 2H), 2,24 (s, 3H)
- Comp. ref. 55
- [M+H] = 338 RMN1H: (300 MHz, DMSO-d6) δ 8,76 (s, 1H), 7,94-7,89(m, 2H), 7,31-7,25(m, 2H), 4,57 (s, 2H), 1,56 (s, 6H).
- Comp. ref. 56
- RMN1H: (400 MHz, CD3OD) δ 7,61-7,57 (m, 2H), 7,16 (s, 1H); 7,00-6,96 (m, 2H), 3,96 (t, J = 5,2 Hz, 2H), 3,77 (t, J = 5,2 Hz, 2H), 1,76 (s, 6H), 1,42 (s, 9H).
- Comp. ref. 57
-
imagen34 [M+H] = 302,2
- Comp. ref. 58
- [M+H] = 274 RMN1H: (300 MHz, CDCl3): δ 7,73-7,78 (m, 2H), 7,06-7,13(m, 3H), 6,73 (s, 1H), 4,77 (s, 2H), 4,72 (s, 1H); 2,51-2,58(m, 1H), δ 1,09-1,12 (d, J = 6,9 Hz, 3H), 0,87-0,91 (d, J = 6,9 Hz, 3H)
- Comp. ref. 59
- [M+H] = 278 RMN1H: (300 MHz, CDCl3): δ 7,60-7,64 (m, 1H), 7,42-7,60(m, 1H), 7,12-7,22 (m, 1H), 7,08 (s, 1H), 6,94 (s, 1H), 4,72 (s, 2H)
- Comp. ref. 60
-
imagen35 RMN1H: (300 MHz, DMSO-d6) δ 8,60 (s, 1H), 7,75-7,79 (m, 2H), 7,54 (s, 1H), 7,16-7,22 (m, 2H), 4,62-4,73 (m, 3H), 1,51 (d, J = 6,3 Hz, 3H)
- Comp. ref. 61
- [M+H] = 274 RMN1H (300 MHz, CDCl3): δ 7,76-7,71 (m, 2H), 7,12 (m, 3H), 6,61 (s, 1H), 4,71 (s, 3H), 2,53-2,48(m, 1H), 1,11-1,08(m, 3H), 0,91-0,88(m, 3H).
- Comp. ref. 62
- [M+H] = 246 RMN1H (300 MHz, DMSO-d6): � 8,60 (s, 1H), 7,80-7,74 (m, 2H), 7,54 (s, 1H), 7,23-7,15 (m, 2H), 4,73-4,61 (m, 3H), 1,51 (d, J = 6,3 Hz, 3H),
- Comp. ref. 63
- [M+H] = 496 RMN1H (300 MHz, CDCl3) δ -5,62-5,65 (m, 1H), 5,39 (s, 1H), 5,02-5,07(m, 1H), 4,62 (m, 1H), 3,77-4,11(m, 6H), 3,35-3,39(m, 1H), 2,31 (s, 1H), 1,47 (s, 9H), 1,26-1,34(m, 3H); δ 0,88-1,13 (m, 3H),
- Comp. ref. 64
- [M+H] = 467 RMN1H: (300 MHz, CDCl3) δ 7,88-7,92 (t, J = 6,6 Hz, 2H), 7,10-7,15 (m, 2H), 5,41-5,51 (m, 1H), 5,02-5,19 (m, 2H), 4,05-4,11 (m, 4H), 3,70-3,88 (m, 2H), 3,30 (m, 1H), 1,71-1,74 (m, 2H), 1,61-1,63 (m, 1H), 1,47 (s, 9H).
- Comp. ref. 65
- [M+H] = 467
- Comp. ref. 66
- [M+H] = 496 RMN1H: (300 MHz, DMSO-d6): δ 7,93-7,86 (m, 2H), 7,31-7,25(m, 2H), 6,89 (s, 1H), 5,30-5,16 (m, 1H), 4,75-4,65 (m, 1H), 4,35-4,26(m, 1H), 3,99-3,66(m, 4H), 2,28-2,15(m, 1H), 1,62-1,39(m, 10H), 1,01-0,88 (m, 3H).
- Comp. ref. 67
- [M+H] = 338 RMN1H (300 MHz, DMSO-d6) δ 8,76 (s, 1H), 7,78 (m, 1H), 7,65 (m, 1H), 7,53-7,45(m, 1H), 7,18-7,12(m, 1H), 4,58 (s, 1H), 1,58 (s, 6H).
- [M+H] = 345
- RMN1H: (300 MHz, CDCl3) δ 7,76-7,72 (m,
- Comp. ref. 68
- 2H) 7,08-6,99 (m, 3H); 6,50-6,43 (m, H) 6,38-6,35 (m, 1H) 5,26 (s, H) 4,17 (s, 2H)
- 3,73-3,69 (m, 2H) 3,27-3,23 (m, 2H) 2,05 (s,
- 2H)
- [M+H] = 361
- RMN1H (300 MHz, DMSO-d6) δ 8,27 (s, 1H),
- Comp. ref. 69
- 7,58 (d, J = 7,8 Hz, 1H), 7,48 (d, J = 7,2 Hz, 1H), 7,28-7,38 (m, 2H), 6,94-7,00 (m, 1H),
- 6,42-6,52 (m, 2H), 3,88 (s, 2H), 3,57 (s, 2H),
- 3,04 (t, J = 5,1 Hz, 2H)
- [M+H] = 361
- RMN1H (400 MHz, CDCl3) δ 7,75-7,70 (m,
- Comp. ref. 70
- 2H) 7,25-7,19 (m, H), 7,05-7,02 (m, 2H),
- 6,48-6,41 (m, 2H), 4,16 (s, 2H), 13,70 (m,
- 2H), 3,24 (m, 2H).
Compuesto de referencia 1
N-(benzo[d][1,3]dioxol-5-il-amino)-2-fenil-5,6,7,8-tetrahidroimidazo[1,2-a]pirazin-3-amina
El Compuesto de referencia 1 se preparó de la siguiente forma:
Una solución agitada del Compuesto 1-1 (685 mg, 10 mmol) en 10 ml de formiato de etilo se calentó a 120 ºC durante 2 horas en un horno microondas. El disolvente se eliminó y el residuo se sometió a purificación mediante HPLC desencadenada por MS para obtener 728 mg de Compuesto 1-2 como un aceite de color marrón después de la 15 neutralización. A una solución del Compuesto 1-2 (728 mg, 4,4 mmol) en 20 ml de DCM se añadieron DIEA (2,30 ml, 13,2 mmol) y POCl3 (0,45 ml, 4,84 mmol) a 0 ºC. La mezcla de reacción se agitó a la misma temperatura durante 2 horas y a temperatura ambiente durante 2 horas. El disolvente se eliminó y el residuo se sometió a purificación mediante HPLC desencadenada por MS para obtener 281 mg de Compuesto 1-3 como un sólido de color amarillo después de la neutralización. RMN1Н (CDCl3), 400 MHz) δ 6,88 (dd, J= 2,0, 8,4 Hz, 1H), 6,79 (d, J= 1,6 Hz, 1H), 6,74
20 (d, J= 8,4 Hz, 1H), 6,01 (s, 2H).
- Compuesto
- Estructura Datos físicos MS (m/z) y/o RMN 1H
- Comp. ref. 71
- [M+1] = 481 RMN1H (400 MHz, CDCl3): δ 7,77 (d, J = 7,2 Hz, 2H), 7,05 (d, J = 8,8 Hz, 2H), 4,67-4,82 (m, 2H), 4,05 (s, 2H), 3,55-3,78 (m, 2H), 1,71 (s, 3H), 1,67 (s, 3H), 1,41 (s, 9H).
- Comp. ref. 72
- [M+1] = 409 RMN1H (400 MHz, CD3OD): δ 7,61-7,65 (m, 2H), 7,31 (d, J = 8,4 Hz, 2H), 7,23-7,26 (m, 2H), 7,08 (d, J = 8,4 Hz, 2H), 4,26 (s, 2H), 4,15 (s, 2H), 4,11 (s, 2H), 3,88 (s, 2H), 2,08 (s, 6H).
- Comp. ref. 73
-
imagen56 [M+1] = 383
- Comp. ref. 74
- [M+1] = 424 RMN1H (400 MHz, CDCl3): δ 7,87-7,90 (m, 2H), 7,08 (t, J = 8,8 Hz, 2H), 3,88-3,94 (m, 4H), 1,85 (s, 6H), 1,53 (s, 9H).
- Comp. ref. 75
- [M+1] = 475
- Comp. ref. 76
- [M+1] = 242
- Comp. ref. 77
-
imagen57 [M+1] = 228 RMN1H (400 MHz, CDCl3): δ 7,94-7,80 (m, 3H), 7,52 (dt, J = 1,2, 9,2 Hz, 1H), 7,10-7,15 (m, 3H), 6,81 (dt, J = 1,2, 6,8 Hz, 1H), 3,33 (a, 2H)
Lo siguiente ejemplos que no entran dentro del alcance de las reivindicaciones son ejemplos de referencia.
Ejemplo 1
2-amino-1-(3-(benzo[d][1,3]dioxol-5-il-amino)-2-fenil-5,6-dihidroimidazo[1,2-a]pirazin-7(8H)-il-)etanona
Tabla 2
- Compuesto
- Estructura Datos físicos MS (m/z) y/o RMN 1H CE50 cepa 3D7 (µM) CE50 cepa W2 (µM)
- 1
- 392,5 (M+1). 0,46 0,473
- 2
- 376,4 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,93 (d, J = 7,6 Hz, 2H); 7,33 (t, J = 7,6 Hz, 2H); 7-19 (t, J = 7,6 Hz, 2H); 6,97 (d, J = 7,6 Hz, 2H); 6,81 (d, J = 7,6 Hz, 1H); 5,08 (m, 1H); 4,85-4,67 (m, 2H); 3,93-3,38 (1H, 6H); 2,17-2,08 (ss, 6H). 3,48 3,348
- 3
-
imagen79 412,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,70 7,67 (m, 2H); 7,22 (t, J= 8,8 Hz, 2K), 6,97(t, J = 8,8 Hz, 2H), 6,8-6,77 (1H, 2H); 5,16 (s, 2H); 4,24 (m, 2H), 4,07 (m, 2H); 1,76 (s, 6H). Análisis elemental: (compuesto + 2HCl + 0,50 H2O): Análisis elemental: % C, 53,56; H, 5,31; N, 14,19 (calculado). %C =53,98/53,69; %N = 14,07/13,97; %H = 5,16/4,98 (experimental). 0,02 0,025
- 4
- 384,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,59-7,56 (m, 2H); 7,12 (t, J = 8,8 Hz, 2H); 6,86 (t, J = 8,8 Hz, 2H); 6,68-6,65 (m, 2H); 5,04-5,00 (m, 2H); 4,08-3,92 (m, 6H). 0,02 0,023
- 5
- 438,2 (M+1). 4,33 >8,9
- 6
-
imagen80 358,4 (M+1). 4,38 4,643
- 7
-
imagen81 340,4 (M+1). 15,82 7,78
- 8
- 376,4 (M+1). 0,62 0,501
- 9
- 434,4 (M+1). 13,84 3,988
- 10
-
imagen82 412,4 (M+1) 1,39 1,284
- 11
- 394,4 (M+1). 0,2 0,168
- 12
- 448,4 (M+1). 7,4 2,956
- 13
- 430,4 (M+1). 0,26 0,137
- 14
- 464,5 (M+1). 3,59 5,871
- 15
- 400,4 (M+1). 2,63 2,111
- 16
- 395,4 (M+1). 14,13 3,325
- 17
- 398,4 (M+1). 0,09 0,064
- 18
- 412,2 (M+1). 12,27 8,139
- 19
- 474,2 (M+1). 0,07 0,059
- 20
- 474,2 (M+1). 0,11 0,121
- 21
-
imagen83 474,0 (M+1). 0,1 0,078
- 22
-
imagen84 412,2 (M+1) 1,3 0,691
- 23
- 408,2 (M+1). >10,58 10,489
- 24
- 320,3 (M+1). 8,92 2,862
- 25
- 426,2 (M+1). >10,6 4,347
- 26
- 323,3 (M+1). >10 5,521
- 27
-
imagen85 400,2 (M+1). 9,61 5,984
- 28
- 327,2 (M+1) RMN 1H (300 MHz, DMSO-d6: δ 7,81-7,72 (m, 2H), 7,11 (m, 2H), 6,97 (m, 2H), 6,56-6,52 (1H, 2H), 3,86 (s, 2H), 3,55 (m, 2H), 3,02 (m, 2H) 0,2 0,175
- 29
-
imagen86 430,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,64-7,70 (m, 1H); 6,95-6,91 (m, 3H); 6,33-6,39 (1H, 1H); 6,27-6,22 (1H, 1H); 4,97 (s, 2H); 4,17 (m, 2H); 3,73 (t, J = 2,8 Hz, 2H); 1,36 (s, 6H). Análisis elemental: (compuesto + 2HCl + 0,40 H2O): Análisis elemental: % C, 51,85; %H, 4,91; %N, 0,03 0,036
- 30
-
imagen87 13,74; (calculado). %C = 51,73, 51,85; %N = 13,5-13,51; %H =4,87, 4,94 (experimental). 402,1 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,64-7,59 (2H, 6,96-6,89 (m, 2H), 6,38-6,34 (m, 1H); 6,27-6,23 (m, 1H); 4,74-4,63 (m, 2H); 3,94-3,41 (m, 6H). 0,03 0,023
- 31
- 397,2 (M+1) 13,08 6,893
- 32
- 398,2 (M+1). 0,21 0,219
- 33
- 438,2 (M+1) 0,74 1,617
- 34
-
imagen88 398,4 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,64-7,60 (m, 2H); 6,93-6,87 (m, 2H); 6,80-6,75 (m, 2H), 6,49-6,45 (m, 2H), 4,71-4,70 (m, 2H), 3,85 (t, J = 5,2 Hz, 1H); 3,82 (t, J = 5,2 Hz, 1H) 3,72 (t, J= 5,2 Hz, 1H); 3,63 (t, J = 5,2 Hz, 1H); 2,83 (m, 2H); 2,54 (m, 2H). 0,07 0,075
- 35
- 412,2 (M+1) 0,12 0,105
- 36
- 384,4 (M+1). 0,05 0,034
- 37
-
imagen89 408,2 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,72 (d, 2H); 7,18 (t, J = 8,0 Hz, 2H); 7,02 (m, 2H), 6,7 (m, 2H); 5,19 (s, 2H); 4,07 (m, 2H), 2,21 (s, 6H); 1,77 (s, 6H) 0,05 0,043
- 38
- 380,4 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,74-7,71 (m, 2H); 7,21- 7,17(m, 2H); 7,03 (t, J= 8,8 Hz, 2H); 6,67 (d, J = 8,4 Hz, 2H); 5,17-5,15 (1H, 2H); 4,22-3,98 (m, 6H); 2,22 (s, 3H). 0,01 0,013
- 39
-
imagen90 428,1 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,70 (m, 2H); 7,21 (m, 4H); 6,81 (m, 2H), 4,26 (m, 2H); 4,0 (m, 2H), 1,77 (s, 6H) 0,02 0,024
- 40
- 400,1 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,59-7,56 (m, 2H); 7,15-7,09 (1H, 4H); 6,68-6,65 (m, 2H), 5,05 (m, 2H); 4,04-3,87 (2H, 0,01 0,009
- 41
- 454,2 (M+1). 2,65 1,79
- 42
- 502,3 (M+1). 6,1 4,611
- 43
- 488,2 (M+1). 0,18 0,149
- 44
- 385,2 (M+1) 0,72 0,477
- 45
- 410,2 (M+1) 0,98 1,335
- 46
- 454,2 (M+1) 13,99 3,11
- 47
- 409,2 (M+1) 6,98 6,183
- 48
- 417,2 (M+1) 1,84 1,752
- 49
- 518,2 (M+1) 2,29 1,9
- 50
- 452,2 (M+1) 0,18 0,187
- 51
- 400,2 (M+1) 0,07 0,062
- 52
- 380,2 (M+1) 3,14 3,36
- 53
- 396,2 (M+1) 2,27 1,703
- 54
- 445,3 (M+1) 1,29 0,764
- 55
- 400. 3 (M+1) 0,66 0,437
- 56
- 384,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,55-753 (m, 1H); 7,47-7,45 (m, 2H); 7,15 (m, 1H); 6,96-6,94 (m, 2H); 6,84-6,81 (1H, 2H); 5,20 (m, 2H); 4,25-4,20 (m, 6H), 3,35 (s, NH). 0,01 0,013
- 57
-
imagen91 474,2 (M+1) 0,31 0,294
- 58
- 456,2 (M+1) 0,47 0,28
- 59
- 456,2 (M+1) 1,09 0,735
- 60
- 470,2 (M+1) 2,46 2,129
- 61
- 520,2 (M+1) 9,24
- 62
-
imagen92 488,2 (M+1) 4,74 4,738
- 63
-
imagen93 520,2 (M+1) 1,95 1,606
- 64
- 468,2 (M+1) 9,37 6,465
- 65
- 448,2 (M+1) 0,47 0,509
- 66
- 430,2 (M+1) 0,22 0,244
- 67
- 402,2 (M+1) 0,19 0,197
- 68
-
imagen94 424,2 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 7,71-7,67 (m, 2H); 7,22 (t, J= 8,8 Hz, 2H); 6,97-6,95 (m, 2H), 6,8-6,77 (m, 2H); 5,15 (s, 2H); 4,19-3,99 (m, 4H, 3,74-3,58 (m, 2H); 2,9-2,82 (m, 1H); 0,98- 0,97 (m, 4H). 0,15 0,264
- 69
- 440,2 (M+1). 0,08 0,094
- 70
- 412,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,50-7,48 (m, 2H); 7,44-7,40 (m, 2H); 7,18 (m, 1H); 6,98 (t, J = 8,8 Hz, 2H); 6,82-6,79 (1H, 2H); 5,18 (m, 2H); 4,25 (t, J = 4,8 Hz, 2H); 4,07 (t, J = 4,8 Hz, 2H) 1,76 (s, 6H). 0,05 0,079
- 71
- 418,1 (M+1) RMN 1H: (MeOH-d4, 400 Hz δ 7,7 2H); 7,28-7,22 (m, 2H), 6,71 (m, 1H); 6,64 (m, 1H); 5,16 (s, 2H); 4,18-4,01 (1H, 6H). 0,0 0,004
- 72
-
imagen95 462,2 (M+1) 0,95 0,589
- 73
- 434,2 (M+1) 0,08 0,059
- 74
- 484,2 (M+1) 0,07 0,067
- 75
- 394,2 (M+1) 0,25 0,19
- 76
- 504,2 (M+1) 0,06 0,061
- 77
- 414,2 (M+1) 0,06 0,039
- 78
- 418,0 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,72-7,68 (m, 2H); 7,23 (t, J = 8,8 Hz, 2H); 7,08 (t, J= 8,8 Hz. 6,91 (dd, J = 3,2 Hz, J = 5,8 Hz, 1H); 5,16 (m, 2H); 4,22-4,05, 6H). 0,01
- 79
- 430,2 (M+1) 0,11 0,09
- 80
- 402,2 (M+1) 0,06 0,063
- 81
- 395,2 (M+1) 0,3 0,449
- 82
- 457,2 (M+1) 0,0 0,007
- 83
- 394,2 (M+1) 0,08 0,131
- 84
- 394,2 (M+1) 0,05 0,074
- 85
- 408,2 (M+1) 0,02 0,031
- 86
- 434,2 (M+1) 0,71 0,755
- 87
- 434,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,71-7,68 (m, 2H); 7,21 (t, J = 8,8 Hz, 2H); 7,03 (d, J = 8,0 Hz, 2H), 6,67 (d, J = 8,4 Hz, 2H); 5,35-4,96 (m, 2H), 4,37-3,88 (1H, 4H); 3,49-3,31 (1H, 3H); 3,25- 3,13(m, 2H); 2,23 (s, 3H); 2,11-1,8 (1H, 4H) 0,02 0,012
- 88
- 422,6 (M+1) 0,15 0,081
- 89
- 406,2 (M+1) 0,05 0,073
- 90
- 420,2 (M+1) 0,65 0,6
- 91
- 420,2 (M+1) 0,12 0,154
- 92
- 434,2 (M+1) 1,3 1,484
- 93
-
imagen96 434,2 (M+1) 1,67 1,512
- 94
- 446,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,59-7,56 (m, 2H); 7,2-7,11 (1H, 3H); 6,6-6,57 (1H, 2H); 5,04 (s, 2H); 4,14 (m, 2H); 3,97 (m, 2H); 1,69 (s, 6H). 0,04 0,052
- 95
- 420,2 (M+1) 1,54 0,707
- 96
- 420,2 (M+1) 0,58 0,321
- 97
- 456,2 (M+1) 0,04 0,021
- 98
- 456,2 (M+1) 0,01 0,008
- 99
-
imagen97 407,2 (M+1) 0,81 0,658
- 100
- 423,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,78-7,68 (m, 2H); 7,16 (t, J = 8,8 Hz, 2H); 7,02 (d, J = 8,0 Hz, 2H) 6,64-6,60 (m, 2H) 5,17-5,07 (m, 2H); 4,13-3,86 (m, 4H); 2,7 (s, 2H); 2,22 (2, 3H); 1,32 (s, 6H). 0,15 0,143
- 101
- 493,6 (M+1) 5,09 4,373
- 102
- 547,6 (M+1) 0,65 0,426
- 103
- 395,2 (M+1) 1,02
- 104
- 423,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 8,04-7,73 (m, 2H); 7,02- 6,95(m, 4H); 6,49 (m, 2H), 4,96-4,80 (m, 2H); 4,25-4,08 (1H, 1H); 3,83-3,73 (1H, 2H); 3,76-3,73 (m, 2H); 2,20 (s, 3H); 1,98 (m, 1H); 0,96 (t, J = 6,8 Hz, 6H). 0,01 0,007
- 105
-
imagen98 435,2 (M+1) 0,85
- 106
- 471,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 8,64-7,59 (m, 2H); 7,13-6,85 (m, 9H); 6,83 (t, J = 8,4 Hz, 2H); 4,73-4,35 (1H, 3H); 3,94-3,49 (1H, 4H); 4,03-3,87, 2H); 2,93-2,88 (1H, 2H); 2,11 (s, 3H), 0,0 0,004
- 107
-
imagen99 475,2 (M+1) 0,01 0,01
- 108
-
imagen100 409,2 (M+1) 0,96
- 109
- 471,2 (M+1) 0,04
- 110
-
imagen101 437,2 (M+1) RMN 1H: CMeOH-Cl4, 400 Hz) δ 7,65-7,62 (m, 2H); 6,92-6,84(m, 4H); 6,49 (m, 2H), 6,39 (t, J = 8,8 Hz, 2H) 4,95-4,62 (m, 2H); 4,18 (d, J=8,4 Hz, 1H); 4,03-3,87 (1H, 2H); 3,74-3,64, 2H); 2,1 (s, 3H); 0,9 (d, J=7,2 Hz, 9H). 0,02 0,015
- 111
- 471,2 (M+1) 0,02
- 112
- 533,6 (M+1) 1,43
- 113
-
imagen102 323,2 (M+1) RMN 1H (400 MHz, CD3OD) δ 7,73 (d, J = 6,8 Hz, 2H), 7,00-6,99 (1H, 4H), 6,49 (d, J = 8,0 Hz, 2H), 4,01 (s, 2H), 3,72 (s, 2H), 3,15 (s, 2H), 2,19 (s, 3H). 0,15 0,146
- 114
- 409,2 (M+1) 1,34 1,35
- 115
- 477,2 (M+1) 0,15 0,153
- 116
- 435,2 (M+1) 1,64 1,509
- 117
- 449,2 (M+1) 1,26 1,186
- 118
- 485,6 (M+1) 0,15 0,135
- 119
- 513,4 (M+1) 4,74
- 120
- 477,2 (M+1) 0,11 0,123
- 121
- 463,4 (M+1). 0,02 0,033
- 122
- 487,2 (M+1) 0,18 0,154
- 123
- 493,2 (M+1) 0,03
- 124
-
imagen103 525,2 (M+1) 0,04 0,028
- 125
- 471,3 (M+1). 0,05 0,044
- 126
- 536,2 (M+1) 0,1 0,08
- 127
- 525,4 (M+1). 0,06 0,051
- 128
- 539,2 (M+1) 1,18 0,743
- 129
- 473,2 (M+1) 0,01 0,006
- 130
- 473,2 (M+1) 0,01
- 131
- 492,0 (M+1) 0,04 0,03
- 132
- 554,2 (M+1) 0,1 0,082
- 133
- 492,0 (M+1) 0,05 0,039
- 134
-
imagen104 437,1 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 8,04-7,73 (m, 2H); 7,02- 6,95(m, 4H); 6,50 (d, J=7,2 Hz, 2H), 4,95-4,72 (1H, 2H); 4,59-4,51 (m, 1H); 4,08-3,51 (1H, 4H); 2,20 (s, 3H); 1,86 (m, 1H); 1,59 (m, 1H); 1,48 (m, 1H); 0,96 (d, J=7,2 Hz, 6H), 0,01 0,007
- 135
- 471,2 (M+1) 0,05 0,033
- 136
- 319,1 (M+1) RMN 1H (400 MHz, CD3OD) δ 9,04 (s, 1H); 8,03 (dd, J = 1,2 Hz/4,8 Hz, 1H), 7,97 (m, 2H), 6,90 (d, J=8,0 Hz, 2H), 6,41 (d, J = 8,4 Hz. 2H) 2,1 (s, 3H). 2,02 2,693
- 137
- 457,2 (M+1) 0,01 0,012
- 138
- 457,2 (M+1) 0,01 0,015
- 139
- 420,2 (M+1) 0,16 0,165
- 140
- 434,2 (M+1) 0,09 0,128
- 141
- 448,2 (M+1) 0,07 0,09
- 142
- 462,4 (M+1). 0,08 0,12
- 143
- 437,2 (M+1) 0,15 0,219
- 144
- 448,2 (M+1) 0,05 0,073
- 145
- 477,5 (M+1). 0,09 0,068
- 146
- 470,5 (M+1). 0,02 0,014
- 147
- 464,5 (M+1). 2,43 1,519
- 148
- 478,5 (M+1) 4,06 1,432
- 149
- 484,5 (M+1). 0,02 0,011
- 150
- 642,5 (M+1) 0,96 0,673
- 151
- 628,5 (M+1). 0,82 0,386
- 152
- 685,4 (M+1). 3,87 0,873
- 153
- 420,5 (M+1) 0,06 0,032
- 154
- 493,5 (M+1). 4,27 3,411
- 155
- 671,6 (M+1). 2,14 0,491
- 156
- 451,5 (M+1) 1,83 0,458
- 157
- 485,5 (M+1). 0,1 0,097
- 158
- 521,5 (M+1). 7,54 4,763
- 159
- 925,1 (M+1). 5,7 2,91
- 160
- 527,5 (M+1). 4,32 2,39
- 161
- 468,2 (M+1) 0,54 0,51
- 162
- 420,5 (M+1). 1,78 1,376
- 163
-
imagen105 410,1 (M+1) 0,02 0,026
- 164
- 506,2 (M+1) >9,81 3,757
- 166
-
imagen106 423,2 (M+1) 2,87 2,229
- 167
-
imagen107 422,2 (M+1) 0,18 0,145
- 168
-
imagen108 456,2 (M+1) 0,01 0,011
- 169
-
imagen109 422,5 (M+1) RMN 1H: MeOH-d* 400 Hz) δ 7,59-7,56 (m, 2H); 7,13-7,00 (m, 2H); 6,95-6,93 (1H, 2H); 6,56-6,54 (m, 2H); 5,17-4,8 (m, 2H); 4,37-3,72 (1H, 5H); 1,23- 1,19(m, 1H); 1,03 (d, J = 8,8 Hz, 3H); 1,03 (d, J = 8,8 Hz, 3H); 0,95 (d, J = 8,8 Hz, 3H). 0,04
- 170
-
imagen110 436,2 (M+1) 0,09 0,054
- 171
-
imagen111 563,2 (M+1) 0,17 0,214
- 172
-
imagen112 538,4 (M+1). 0,1 0,088
- 173
-
imagen113 489,2 (M+1). 0,14 0,133
- 174
-
imagen114 503,5 (M+1). 6,06 1,475
- 175
-
imagen115 455,2 (M+1) 0,08 0,105
- 176
-
imagen116 472,2 (M+1) 2,75 1,791
- 177
-
imagen117 498,5 (M+1). 0,43 0,43
- 178
-
imagen118 491,5 (M+1). 3,05 3,321
- 179
-
imagen119 491,5 (M+1). 4,79 1,072
- 180
-
imagen120 498,5 (M+1). 0,73 0,609
- 181
-
imagen121 511,5 (M+1). 2,68 1,811
- 182
-
imagen122 484,5 (M+1). 1,37 1,076
- 183
-
imagen123 514,5 (M+1). 1,9 1,342
- 184
-
imagen124 490,5 (M+1). 3,65 0,859
- 185
-
imagen125 641,3 (M+1) 0,35 0,136
- 186
-
imagen126 579,3 (M+1). 5,63 2,56
- 187
-
imagen127 541,3 (M+1). 6,68 3,551
- 188
-
imagen128 493,6 (M+1) 0,79 1,097
- 189
-
imagen129 479,6 (M+1) 0,37 0,392
- 190
-
imagen130 462,2 (M+1) 0,94 1,073
- 191
-
imagen131 327,2 (M+1) RMN 1H, (300 MHz, DMSO-d6): δ 2,50-2,52 (2H, t, J = 1,5 Hz), 3,54-3,58 (2H, t, J = 2,1 Hz), 3,87 (s, 2H), 6,53-6,58 (m, 2H), 6,91-7,02 (1H, 3H), 7,27-7,36 (m, 1H), 7,50 (1H, d, J = 10,5 Hz), 7,62 (1H, d, J = 7,8 Hz), 7,79 (s, 1H) 0,17 0,151
- 192
-
imagen132 361,1 (M+1) RMN 1H (400 MHz, CDCl3) δ 7,75-7,70 (m, 2H) 7,25-7,19 (m, H), 7,05-7,02 (m, 2H), 6,48-6,41 (1H, 2H) 4,16 (s, 2H), 3,70 (m, 2H), 3,24 (m, 2H). 0,11 0,095
- 193
-
imagen133 434,2 (M+1) 0,09 0,075
- 194
-
imagen134 486,2 (M+1) 0,05
- 195
-
imagen135 452,1 (M+1) 0,02 0,02
- 196
-
imagen136 452,1 (M+1) 0,32 0,344
- 197
-
imagen137 555,3 (M+1). 4,16 1,04
- 198
-
imagen138 409,2 (M+1) 1,36
- 199
-
imagen139 421,2 (M+1) 0,24 0,157
- 200
-
imagen140 421,2 (M+1) 0,91
- 201
-
imagen141 485,6 (M+1) 0,24 0,131
- 202
-
imagen142 471,2 (M+1) 0,16 0,102
- 203
-
imagen143 505,1 (M+1). 0,97 0,369
- 204
-
imagen144 423,2 (M+1) 0,01 0,01
- 205
-
imagen145 423,2 (M+1). 0,0 0,004
- 206
-
imagen146 443,2 (M+1). 1,2 1,17
- 207
-
imagen147 357,1 (M+1). 9,31 2,421
- 208
-
imagen148 513,2 (M+1). 5,87 1,057
- 209
-
imagen149 435,2 (M+1). 11,62 4,362
- 210
-
imagen150 515,2 (M+1). 0,04 0,026
- 211
-
imagen151 435,2 (M+1). 0,3 0,283
- 212
-
imagen152 421,2 (M+1) 1,95 1,984
- 213
-
imagen153 499,1 (M+1). 3,8 4,823
- 214
-
imagen154 476,3 (M+1). 2,85 2,008
- 215
-
imagen155 435,2 (M+1). 0,83 0,65
- 216
-
imagen156 449,2 (M+1). 0,3 0,248
- 217
-
imagen157 361,1 (M+1) RMN 1H (300 MHz, DMSO-d6), δ 3,04 (2H, t, J = 5,1 Hz), 3,57 (s, 2H), 3,88 (s, 2H), 6,42-6,52 (m, 2H), 6,94-7,00 (m, 1H), 7,28-7,38 (1H, 2H), 7,48 (1H, d, J = 7,2 Hz), 7,58 (1H, d, J = 7,8 Hz), 8,27 (s, 1H) 0,13 0,106
- 218
-
imagen158 569,0 (M+1). 4,71 4,015
- 219
-
imagen159 555,9 (M+1). 4,97 3,414
- 220
-
imagen160 448,2 (M+1) 1,13 0,937
- 221
-
imagen161 486,0 (M+1). 0,09 0,083
- 222
-
imagen162 493,0 (M+1). 0,14 0,103
- 223
-
imagen163 493,0 (M+1). 0,26 0,206
- 224
-
imagen164 469,1 (M+1). 0,02 0,018
- 225
-
imagen165 469,1 (M+1). 0,55 0,316
- 226
-
imagen166 509,1 (M+1). 0,48 0,348
- 227
-
imagen167 442,2 (M+1). 0,09 0,103
- 228
-
imagen168 417,9 (M+1). 0,01 0,008
- 229
-
imagen169 446,2 (M+1). 0,01 0,007
- 230
-
imagen170 510,2 (M+1). 0,32 0,255
- 231
-
imagen171 483,3 (M+1). 0,09 0,07
- 232
-
imagen172 455,2 (M+1). 0,05 0,044
- 233
-
imagen173 459,2 (M+1). 0,01 0,015
- 234
-
imagen174 461,0 (M+1). 0,13 0,111
- 235
-
imagen175 427,2 (M+1). 0,54 0,496
- 236
-
imagen176 666,2 (M+1). 5,25 2,063
- 237
-
imagen177 632,3 (M+1). 7,19 5,722
- 238
-
imagen178 653,2 (M+1). 3,56 1,305
- 239
-
imagen179 619,3 (M+1). 1,84 0,629
- 240
-
imagen180 576,2 (M+1). 10,49 6,99
- 241
-
imagen181 542,2 (M+1). 5,27 2,36
- 242
-
imagen182 624,1 (M+1). 2,09 0,288
- 243
-
imagen183 589,3 (M+1). 2,97 0,697
- 244
-
imagen184 423,2 (M+1). 2,4 1,329
- 245
-
imagen185 439,2 (M+1). 2,53 1,804
- 246
-
imagen186 585,3 (M+1). 3,88 1,791
- 247
-
imagen187 618,1 (M+1). 1,42 3,937
- 248
-
imagen188 583,3 (M+1). 7,01 4,559
- 249
-
imagen189 334,3 (M+1). 5,39 5,055
- 250
-
imagen190 611,7 (M+1). 3,88 3,979
- 251
-
imagen191 463,3 (M+1). 3,68 2,548
- 252
-
imagen192 707,3 (M+1). 3,03 0,631
- 253
-
imagen193 679,2 (M+1) 0,78 0,254
- 254
-
imagen194 673,4 (M+1). 3,44 0,727
- 255
-
imagen195 517,3 (M+1). 0,61 0,653
- 256
-
imagen196 483,2 (M+1). 1,16 1,475
- 257
-
imagen197 511,3 (M+1). 6,68 7,003
- 258
-
imagen198 608,1 (M+1). 4,92 3,513
- 259
-
imagen199 579,2 (M+1). 5,32 3,022
- 260
-
imagen200 573,3 (M+1). 7,64 5,009
- 261
-
imagen201 545,1 (M+1). 7,06 4,126
- 262
-
imagen202 343,1 (M+1) RMN 1H, (DMSO, ppm): � 7,94 (s, 1H), 7,80-7,74 (m, 2H), 7,18- 7,09(m, 4H), 6,56 (d, J = 8,7 Hz, 2H), 3,87 (s, 2H), 3,55 (s, 2H), 3,02(t, J = 5,4 Hz, 2H). 0,24 0,267
- 263
-
imagen203 419,2 (M+1). 0,35 0,653
- 264
-
imagen204 391,2 (M+1). 0,11 0,154
- 265
-
imagen205 434,2 (M+1). 1,35 1,585
- 266
-
imagen206 319,2 (M+1) RMN 1H, (300 MHz, CDCl3) δ 7,70 (s, 1H), 7,56 (1H, d, J = 7,8 Hz), 7,21-7,15 (1H, t, J = 7,5 Hz), 7,04 (3H, d, J = 8,1 Hz), 5,21 (1H, s), 4,18 (s, 2H), 3,73-3,68 (t 2H, J = 5,4 Hz), 3,23-3,18 (t 2H, J = 5,4 Hz), 2,34 (s, 3H), 2,29 (s, 3H) 1,17 1,313
- 267
-
imagen207 655,4 (M+1). 0,99 0,474
- 268
-
imagen208 513,2 (M+1). 0,01 0,012
- 269
-
imagen209 527,2 (M+1). 0,01 0,006
- 270
-
imagen210 541,2 (M+1). 0,05
- 271
-
imagen211 479,0 (M+1). 0,44 0,385
- 272
-
imagen212 555,7 (M+1). 3,59 3,26
- 273
-
imagen213 531,7 (M+1) 3,33 3,471
- 274
-
imagen214 517,7 (M+1) 5,14 5,673
- 275
-
imagen215 529,3 (M+1). 3,83 3,95
- 276
-
imagen216 506,1 (M+1).
- 277
-
imagen217 465,1 (M+1).
- 278
-
imagen218 341,2 (M+1) RMN 1H (400 MHz, CDCl3) δ 7,70-7,53 (m, 2H), 7,12-7,04 (1H, 3H), 6,58 (d, J=8,4 Hz, 2H), 5,12 (s, 1H), 4,18 (s, 2H), 3,73 (m, 2H), 3,23 (m, 2H), 2,98 (s, 1H), 2,29 (s, 3H). 0,21 0,269
- 279
-
imagen219 339,1 (M+1) RMN 1H (300 MHz, CDCl3) δ 7,70-7,62 (m, 1H), 7,24-7,15 (1H, 2H), 7,05 (d, J=8,1 Hz, 2H), 6,59 (d, J = 8,1 Hz, 2H), 5,15 (s, 1H), 4,18 (s, 2H), 3,72 (m, 2H), 3,22 (m, 2H), 2,29 (s, 3H) 3,52 3,828
- 280
-
imagen220 341,2 (M+1) RMN 1H (300 MHz, CDCl3) δ 7,70-7,62 (m, 1H), 7,01 (d, J = 8,1 Hz, 2H), 6,92-6,76 (1H, 2H), 6,52 (d, J = 8,1 Hz, 2H), 5,33 (s, 1H), 4,23 (s, 2H), 3,77 (m, 2H), 3,26 (m, 2H), 2,25 (s, 3H). 4,71 4,652
- 281
-
imagen221 566,3 (M+1). 0,82 0,596
- 282
-
imagen222 566,3 (M+1). 0,12 0,117
- 284
-
imagen223 410,2 (M+1). 0,05 0,037
- 285
-
imagen224 424,2 (M+1). 0,18 0,177
- 286
-
imagen225 486,1 (M+1). 1,38 1,502
- 287
-
imagen226 438,2 (M+1) 4,36 7,262
- 288
-
imagen227 472,2 (M+1). 0,89 1,388
- 289
-
imagen228 436,1 (M+1). 3,88 0,747
- 290
-
imagen229 512,2 (M+1). 0,44 0,397
- 291
-
imagen230 526,2 (M+1). 1,2 0,567
- 292
-
imagen231 375,1 (M+1) RMN 1H, (300 MHz, CDCl3): δ 7,66-7,60 (m, 2H), 7,29-7,21 (1H, 1H), 7,01-6,99 (1H, 2H), 6,55-6,50 (m, 1H), 6,43-6,40 (1H, 1H), 4,28 (s, 2H), 3,75-3,64 (1H, 2H), 3,32-3,25, 5H) 0,15 0,156
- 293
-
imagen232 432,0 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,47-7,43 (m, 2H); 7,27-7,22 (m, 1H); 7,14-7,07 (1H, 2H); 6,7 (m, 1H); 6,53 (m, 1H); 4,99-4,80, 2H); 4,04 (m, 2H); 3,85 (m, 4H). 0,02
- 294
-
imagen233 460,2 (M+1) 0,11 0,113
- 295
-
imagen234 512,4 (M+1). 0,21 0,283
- 296
-
imagen235 526,7 (M+1). 0,28 0,424
- 297
-
imagen236 289,2 (M+1) RMN 1H, (300 MHz, CDCl3): 7,72-7,75 (m, 2H), 7,03-7,10 (1H, 2H), 4,16 (s, 2H), 3,86 (t, J = 5,4 Hz, 2H), 3,23 (t, J = 5,4 Hz, 2H), 1,04 (s, 9H). 5,29 8,505
- 298
-
imagen237 930,5 (M+1). 0,61 0,193
- 299
-
imagen238 337,2 (M+1) >8,74 9,398
- 300
-
imagen239 337,2 (M+1). 1,11 1,169
- 301
-
imagen240 462,2 (M+1). 0,03 0,047
- 302
-
imagen241 480,2 (M+1). 0,17 0,149
- 303
-
imagen242 518,3 (M+1). 0,54 0,439
- 304
-
imagen243 516,2 (M+1) 3,21 2,946
- 305
-
imagen244 494,2 (M+1) 0,09 0,094
- 306
-
imagen245 519,2 (M+1) 0,42 0,334
- 307
-
imagen246 422,2 (M+1) 0,03 0,022
- 308
-
imagen247 450,3 (M+1). 0,06 0,068
- 309
-
imagen248 438,2 (M+1) 0,08 0,068
- 310
-
imagen249 452,2 (M+1) 0,52 0,397
- 311
-
imagen250 509,0 (M+1) 0,09 0,072
- 312
-
imagen251 553,0 (M+1) 1,64 0,897
- 313
-
imagen252 460,2 (M+1) 0,02 0,004
- 314
-
imagen253 432,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,59-7,55 (m, 2H); 7,22-7,12 (m, 3H); 6,60-6,51 (1H, 2H); 5,13-4,89, 2H); 4,49 (m, 2H); 4,02-3,90 (1H, 3H); 1,43 (d, J = 6,8 Hz, 3H). 0,03 0,02
- 315
-
imagen254 515,2 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 8,94-8,90 (m, 2H); 7,59-7,44 (m, 2 H); 7,21-7,13 (m, 3H); 6,59-6,51 (m, 2H); 5,24-5,09 (1H, 2H); 4,04-3,85 (m, 5H); 3,38-3,28 (m, 2H). 0,02 0,008
- 316
-
imagen255 526,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,59-7,52 (m, 2H); 7,27-7,22 (m, 2H); 7,03-6,92 (1H, 2H); 6,53-6,44 (m, 2H); 5,17 (m, 1H); 4,23 (m, 1H); 3,92-3,72 (1H, 3H); 3,51-3,42 (1H, 2H); 3,22 (m, 1H); 3,09-3,06 (m, 1H). 0,02 0,014
- 317
-
imagen256 474,0 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,59-7,56 (m, 2H); 7,22-7,11 (m, 3H); 6,58-6,49 (1H, 2H); 5,24-88, 2H); 4,5-3,62 (m, 5H); 1,91-1,88 (1H, 1H); 1,5-1,46 (m, 1H); 1,27-0,87 (m, 7H). 0,02
- 318
-
imagen257 460,2 (M+1) 0,15 0,098
- 319
-
imagen258 544,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,58-7,53 (m, 2H); 7,22-7,12 (m, 6H); 6,59-6,49 (1H, 2H); 5,3-5,25 (m, 1H); 4,93-4,73 (1H, 2H); 4,05-3,65 (1H, 4H); 3,15-3,1 (m, 1H); 3,07- 2,97(m, 1H). 0,04 0,027
- 320
-
imagen259 460,2 (M+1). 0,17 0,103
- 321
-
imagen260 444,2 (M+1) RMN 1H: MeOH-d* 400 Hz) δ 7,58-7,55 (m, 2H); 7,22-7,14 (m, 3H); 6,61-6,51 (1H, 2H) 5,34-5,20 (m, 2H); 4,53-4,39 (1H, 2H); 4,15-4,1 (1H, 2H); 4,02-3,95 (m, 3H); 1,18 (m, 1H); 1,06 (d, J = 7,2 Hz, 2H); 0,963 (d, J = 7,2 Hz, 2H). 0,02 0,011
- 322
-
imagen261 474,2 (M+1). 0,04
- 323
-
imagen262 474,2 (M+1). 1,73 1,329
- 324
-
imagen263 508,2 (M+1) 0,03 0,03
- 325
-
imagen264 486,2 (M+1). 0,03 0,029
- 326
-
imagen265 474,2 (M+1) 0,03 0,022
- 327
-
imagen266 432,2 (M+1) 0,03 0,021
- 328
-
imagen267 533,2 (M+1) 0,34 0,229
- 329
-
imagen268 337,2 (M+1). 0,15 0,116
- 330
-
imagen269 341,2 (M+1) RMN 1H, (300 Hz, DMSO-d6) δ 8,47 (s, 1H), 7,32 (1H, d, J = 4,5 Hz), 7,17 (1H, d, J = 3,6 Hz), 7,05 (s, 1H), 3,91 (2H, d, J = 7,5 Hz), 6,44 (2H, d, J = 7,8 Hz), 3,87 (s, 2H), 3,55 (s, 2H), 3,02 (s, 2H), 2,15 (s, 3H) 4,47
- 331
-
imagen270 345,1 (M+1) RMN 1H (300 MHz, CDCl3) δ 7,76-7,72 (m, 2H) 7,08-6,99 (m, 6,50-6,43 (m, H) 6,38-6,35 (m, 1H) 5,26 (s, H) 4,17 (s, 2H) 3,73-3,69 (m, 2H) 3,27-3,23 (m, 2H) 2,05 (s, 2H). 0,14
- 332
-
imagen271 570,3 (M+1). 1,04
- 333
-
imagen272 563,2 (M+1) 1,11
- 334
-
imagen273 509,2 (M+1) 0,05
- 335
-
imagen274 565,2 (M+1) 2,3
- 336
-
imagen275 495,2 (M+1) 0,04
- 337
-
imagen276 486,2 (M+1) >10
- 338
-
imagen277 458,2 (M+1) 0,19
- 339
-
imagen278 500,2 (M+1). 0,52
- 340
-
imagen279 458,2 (M+1). 0,2
- 341
-
imagen280 522,3 (M+1). 0,01
- 342
-
imagen281 506,2 (M+1). 5,24
- 343
-
imagen282 506,2 (M+1). 7,5
- 344
-
imagen283 601,2 (M+1). 0,21
- 345
-
imagen284 587,2 (M+1).
- 346
-
imagen285 585,1 (M+1) >8,8
- 347
-
imagen286 520,3 (M+1). 5,92
- 348
-
imagen287 499,9 (M+1). 0,05
- 349
-
imagen288 481,6 (M+1). 7,48
- 350
-
imagen289 409,2 (M+1). 0,66
- 351
-
imagen290 439,2 (M+1). 1,24
- 352
-
imagen291 394,2 (M+1). 0,01
- 353
-
imagen292 437,2 (M+1) 0,21
- 354
-
imagen293 306,2 (M+1) RMN H (300 MHz, CDCl3): 2,29 (s, 3H), 3,03 (m, 2H), 3,43 (s, 1H), 3,81 (m, 2H), 3,90 (s, 2H), 5,57 (s, 1H), 6,60-6,63 (2H, d, J = 8,4 Hz), 7,06-7,09 (2H, d, J = 8,1 Hz), 7,79 (m, 2H), 8,44-8,46(m, 2H) 6,32 0,564
- 355
-
imagen294 600 (M+1). 2,81 2,266
- 356
- 459,2 (M+1) 1,26 0,872
- 357
- 532,3 (M+1). 7,49 4,712
- 358
-
imagen295 475,2 (M+1) 0,13 0,049
- 359
-
imagen296 511,2 (M+1). 0,14 0,108
- 360
-
imagen297 461,2 (M+1) 0,03 0,015
- 361
-
imagen298 490,3 (M+1). 2,35 1,141
- 362
-
imagen299 470,6 (M+1). 0,81 0,203
- 363
-
imagen300 532,2 (M+1). 1,75 1,133
- 364
-
imagen301 514,6 (M+1). 4,95 3,742
- 365
-
imagen302 562,1 (M+1) 0,61 0,26
- 366
-
imagen303 462,2 (M+1). 3,47 1,824
- 367
-
imagen304 474,2 (M+1). 0,19 0,148
- 368
-
imagen305 562,2 (M+1). 0,52 0,286
- 369
-
imagen306 529,2 (M+1). 0,11 0,084
- 370
-
imagen307 516,1 (M+1). 4,35 8,345
- 371
-
imagen308 546,6 (M+1). 1,52 1,283
- 372
-
imagen309 488,2 (M+1). 0,69 0,554
- 373
-
imagen310 474,3 (M+1). 0,43 0,32
- 374
-
imagen311 484,3 (M+1). 0,59 0,248
- 375
-
imagen312 480,2 (M+1). 1,13 0,679
- 376
- 436,2 (M+1). 0,06 0,079
- 377
-
imagen313 450,3 (M+1). 0,574
- 378
-
imagen314 450,3 (M+1). 0,06 0,063
- 379
-
imagen315 426,2 (M+1) 0,06 0,05
- 380
-
imagen316 498,3 (M+1). 1,13 1,789
- 381
-
imagen317 392,2 (M+1). 1,97 1,798
- 382
-
imagen318 363,2 (M+1). 1,05 1,039
- 383
-
imagen319 396,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,62-7,59 (m, 2H); 7,14 7,04 (m, 2H); 6,85 (d, J=2,4 Hz, 1H); 6,65-6,5 (dd, J = 2,7 Hz, J = 8,4 Hz, 1H); 4,0-3,98 (m, 4H); 2,16 (s, 3H); 2,00 (s, 6H); 1,64 (s, 6H). 0,05 0,032
- 384
-
imagen320 484,3 (M+1). 0,47 0,889
- 385
-
imagen321 398,2 (M+1). 0,02 0,02
- 386
-
imagen322 498,3 (M+1). 2,62 3,028
- 387
-
imagen323 398,2 (M+1). 0,11 0,08
- 388
-
imagen324 498,3 (M+1). 3,22 1,772
- 389
- 450,3 (M+1). 0,06 0,051
- 390
-
imagen325 473,3 (M+1). 0,03 0,028
- 391
-
imagen326 441,2 (M+1). 0,01 0,007
- 392
-
imagen327 436,3 (M+1). 0,03 0,039
- 393
-
imagen328 446,2 (M+1). 0,02
- 394
-
imagen329 474,0 (M+1). 0,05 0,043
- 395
-
imagen330 426,2 (M+1). 0,44 0,246
- 396
-
imagen331 440,2 (M+1). 0,03 0,022
- 397
-
imagen332 424,2 (M+1). 2,45 1,673
- 398
-
imagen333 391,2 (M+1). 2,73 2,685
- 399
-
imagen334 436,2 (M+1). 0,22 0,196
- 400
-
imagen335 518,2 (M+1). 0,18 0,105
- 401
-
imagen336 434,2 (M+1). 0,02 0,012
- 402
-
imagen337 484,3 (M+1). 0,12 0,122
- 403
-
imagen338 484,3 (M+1). 0,51 0,543
- 404
- 420,2 (M+1) 0,02 0,012
- 405
-
imagen339 524,2 (M+1). 0,02 0,012
- 406
-
imagen340 412,2 (M+1). 0,06 0,04
- 407
-
imagen341 484,3 (M+1). 0,71 0,523
- 408
-
imagen342 426,2 (M+1) 0,93 0,908
- 409
-
imagen343 408,1 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 7,79-7,69 (m, 2H), 7,21 (t, J= 8,4 Hz, 2H), 7,04 (d, J = 8,0 Hz, 2H), 6,76 (d, J = 8,2 Hz, 2H), 4,11 (s, 2H), 3,88 (m, 4H), 2,22 (s, 3H), 2,12 (s, 6H). 0,01 0,006
- 410
- 463,3 (M+1). 0,06 0,037
- 411
- 378,2 (M+1). 0,14 0,106
- 412
-
imagen344 412,1 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,61-7,57 (in, 2H), 6,94 (2H, J = 8,8 Hz, t), 6,81 (2H, J = 8,8 Hz, t), 6,47 (m, 2H), 3,72 (m, 2H), 3,58 (m, 2H), 3,42 (m, 2H), 1,85 (s, 6H). Análisis elemental: (compuesto + 0,65 H2O): C, 62,44; N, 16,55; H, 5,79, (calculado). C = 62,54/62,44; N =16,.35/16,29; H = 5,52/5,61 (experimental) 0,01 0,006
- 413
-
imagen345 389,1 (M+1) RMN 1H, (300 Hz, DMSO-d6) δ 7,59 (m, 2H), 7,35(t, J = 6,6 Hz, 1H), 7,12 (t, J=6,6, 2H), 6,68(d, J = 8,7 Hz, 1H), 6,42(d, J = 6,9 Hz, 1H), 3,88(d, J = 1,5 Hz, 2H), 3,68-3,61(m, 2H), 3,57 - 3,50 (m, 2H), 3,02(t, J = 4,2 Hz, 2H), 1,04(t, J = 5,4 Hz, 3H) 0,18 0,131
- 414
-
imagen346 436,2 (M+1). 0,16 0,156
- 415
-
imagen347 351,2 (M+1). 0,01 0,013
- 416
-
imagen348 371,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,77-7,73 (m, 2H); 7,25-7,18 (m, 4H); 6,84-6,82 (m, 2H); 4,38 (m, 2H); 3,95 (m, 2H); 2,11 (s, 6H). 0,01 0,016
- 417
-
imagen349 428,1 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,75-7,71 (m, 2H), 7,13-7,1 (1H, 2H), 6,59 (t, J = 8,8 Hz, 2H), 6,58 (d, J = 8,8 Hz, 2H), 3,80 (m, 2H), 3,65 (m, 2H), 3,31 (m, 2H), 1,95 (s, 6H). Análisis elemental: (compuesto + 0,33 H2O): Análisis elemental: C, 60,11; N, 15,93; H, 5,57; (calculado). %C, 60,93/60,79; %N, 15,99/16,08; %H, 5,54/5,40 (experimental) 0,01 0,006
- 418
-
imagen350 398,2 (M+1). 0,09 0,146
- 419
-
imagen351 446,2 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,59-7,55 (m, 2H); 7,20-7,13 (m, 3H); 6,60 (dd, J = 10,8 Hz, J = 11,2 Hz, 1H); 6,53 (dd, J = 0,8 Hz, J = 2,4 Hz, 1H); 4,0 (m, 4H); 3,78 (m, 2H); 2,00 (s, 6H). 0,03 0,024
- 420
- 389,8 (M+1). 0,02 0,028
- 421
-
imagen352 430,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,73-7,69 (m, 2H); 7,07-6,99 (1H, 3H); 6,46-6,40 (1H, 1H); 6,34-6,32 (m, 1H); 3,78 (m, 2H), 3,62 (m, 2H), 3,5 (m, 2H); 1,98 (s, 6H); 1,48 (s, 6H). 0,003 0,005
- 422
-
imagen353 373,2 (M+1). 0,01 0,021
- 423
-
imagen354 446,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,70 7,66 (m, 2H); 7,18-7,14 (m, 3H); 7,07 (t, J = 9,2 Hz, 1H); 6,8-6,78 (1H, 1H), 6,64-6,60 (m, 1H); 2,04 (s, 6H). 0,01 0,009
- 424
- 389,1 (M+1). 0,02 0,03
- 425
- 419,1 (M+1) RMN 1H: (MeOHd4 400 Hz) δ 7,68-7,65 (m, 2H); 7,54 (d, J = 8,8 Hz, 2H); 7,17 (t, J = 8,8 Hz, 2H); 6,83 (d, J = 8,4 Hz, 2H); 4,07 (s, 2H); 4,03 (s, 2H); 3,82 (m, 2H); 2,06 (s, 6H). 0,01 0,012
- 426
-
imagen355 362,1 (M+1) RMN 1H: (MeOH-d4, 400 Hz) 7,69 (m, 2H); 7,51 (d, J = 8,4 Hz, 2H); 7,07 (t, J = 8,8 Hz, 2H); 6,73 (d, J = 8,8 Hz, 2H); 4,01 (m, 2H); 3,78 (m, 2H); 1,86 (s, 6H). 0,18 0,271
- 427
-
imagen356 460,2 (M+1). 0,21 0,436
- 428
-
imagen357 440,2 (M+1). 0,17 0,242
- 429
-
imagen358 470,2 (M+1) 0,02 0,036
- 430
-
imagen359 445,2 (M+1) 0,01 0,019
- 431
-
imagen360 499,2 (M+1) 0,07 0,08
- 432
-
imagen361 506,2 (M+1) 0,06 0,067
- 433
-
imagen362 528,2 (M+1) 0,04 0,049
- 434
-
imagen363 444,2 (M+1) 0,02 0,019
- 435
-
imagen364 416,2 (M+1) 0,05 0,098
- 436
-
imagen365 496,3 (M+1). 0,03 0,052
- 437
-
imagen366 442,2 (M+1) 0,02 0,028
- 438
-
imagen367 456,3 (M+1). 0,02 0,023
- 439
-
imagen368 458,3 (M+1). 0,03 0,04
- 440
-
imagen369 445,2 (M+1) 0,02 0,028
- 441
-
imagen370 428,2 (M+1) 0,06 0,081
- 442
-
imagen371 458,2 (M+1) 0,02 0,033
- 443
-
imagen372 510,2 (M+1) 0,05 0,055
- 444
-
imagen373 403,2 (M+1) RMN 1H, (300 MHz, CDCl3) δ 7,60-7,55 (m, 2H), 7,28-7,21 (m, 1H), 7,03- 6,97(m, 2H), 6,58-6,53 (m, 1H), 6,44- 6,39(m, 1H), 4,29 (s, 2H), 4,19-4,10 (m, 1H), 3,79 (a, 1H), 3,55 (a, 1H), 3,30 - 3,26 (a, 2H), 1,18-1,16 (a, 3H), 1,01-0,99 (a, 3H). 7,22 5,965
- 445
-
imagen374 369,2 (M+1). 2,6 3,272
- 446
-
imagen375 355,2 (M+1) RMN H: (DMSO, 300 Hz) δ 7,67- 7,63 (m, 2H), 7,23-7,16 (m, 1H), 7,03-6,97(m, 2H), 6,57-6,41 (m, 3H), 4,22 (s, 1H), 3,69- 3,55(m, 4H), 3,24(t, J = 4,8 Hz, 2H), 2,61 (s, 2H), 1,17(t, J = 7,2 Hz, 3H) 0,31 0,243
- 447
-
imagen376 361,0 (M+1) RMN 1H, (300 MHz, CDCl3) δ 7,16-7,71 (m, 2H), 7,25-7,19 (1H, 1H), 7,05-6,99 (m, 2H), 6,48-6,41 (1H, 2H), 5,44 (s, H), 4,17 (s, 2H), 3,73-3,70 (1H, 2H), 3,27-3,23, 2H) 0,23
- 448
-
imagen377 414,2 (M+1). 0,02 0,022
- 449
-
imagen378 442,2 (M+1) 0,03 0,026
- 450
-
imagen379 440,2 (M+1) 0,02 0,015
- 451
-
imagen380 454,2 (M+1) 0,03 0,019
- 452
-
imagen381 469,0 (M+1) 0,02 0,019
- 453
-
imagen382 456,2 (M+1) 0,02 0,021
- 454
-
imagen383 456,2 (M+1). 0,02 0,008
- 455
-
imagen384 443,0 (M+1). 0,01 0,008
- 456
-
imagen385 443,0 (M+1). 0,02 0,015
- 457
-
imagen386 494,2 (M+1). 0,02 0,011
- 458
-
imagen387 508,2 (M+1). 0,02 0,017
- 459
-
imagen388 504,2 (M+1) 0,04 0,024
- 460
-
imagen389 526,2 (M+1). 0,04 0,033
- 461
-
imagen390 497,2 (M+1). 0,03 0,022
- 462
- 426,2 (M+1) 0,05 0,037
- 463
-
imagen391 456,2 (M+1). 0,04 0,024
- 464
-
imagen392 426,2 (M+1) 0,03 0,024
- 465
-
imagen393 424,2 (M+1). 0,0019 0,002
- 466
-
imagen394 438,2 (M+1). 0,03
- 467
-
imagen395 452,2 (M+1). 0,02 0,016
- 468
-
imagen396 440,2 (M+1). 0,03 0,02
- 469
-
imagen397 440,2 (M+1) 0,02 0,016
- 470
-
imagen398 427,1 (M+1). 0,01 0,012
- 471
-
imagen399 427,1 (M+1). 0,03 0,03
- 472
-
imagen400 478,2 (M+1) 0,05 0,037
- 473
-
imagen401 492,2 (M+1) 0,03 0,021
- 474
-
imagen402 488,2 (M+1) 0,13 0,088
- 475
-
imagen403 510,0 (M+1) 0,04 0,03
- 476
-
imagen404 480,9 (M+1). 0,04 0,027
- 477
-
imagen405 410,0 (M+1). 0,07 0,055
- 478
-
imagen406 440,0 (M+1). 0,06 0,039
- 479
-
imagen407 448,2 (M+1) 0,02 0,012
- 480
-
imagen408 436,2 (M+1) 0,03 0,022
- 481
-
imagen409 436,2 (M+1) 0,02 0,014
- 482
-
imagen410 474,2 (M+1) 0,02 0,009
- 483
-
imagen411 488,2 (M+1) 0,05 0,025
- 484
-
imagen412 484,3 (M+1). 0,04 0,023
- 485
-
imagen413 506,2 (M+1) 0,03 0,023
- 486
-
imagen414 477,0 (M+1). 0,03 0,016
- 487
-
imagen415 458 (M+1) 0,04 0,031
- 488
-
imagen416 472,2 (M+1) 0,02 0,013
- 489
-
imagen417 461,2 (M+1) 0,01 0,009
- 490
- 512,2 (M+1) 0,05 0,033
- 491
-
imagen418 458 (M+1). 0,08 0,055
- 492
-
imagen419 446,2 (M+1) 0,05
- 493
-
imagen420 355,1 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 7,62-7,58 (m, 2H); 7,12-7,08 (1H, 2H); 6,68-6,63 (1H, 2H); 6,67 (m, 2H); 4,16 (m, 2H); 3,78 (m, 2H); 1,92 (s, 6H). 0,004 0,005
- 494
-
imagen421 337,2 (M+1) 2,82 2,141
- 495
-
imagen422 426,0 (M+1) 0,09 0,039
- 496
-
imagen423 442,2 (M+1) 0,03 0,008
- 497
-
imagen424 357,1 (M+1) 8,0 5,825
- 498
-
imagen425 357,1 (M+1) 6,34 6,738
- 499
-
imagen426 408,2 (M+1) 0,01 0,006
- 500
-
imagen427 419,0 (M+1). 1,56 1,1
- 501
-
imagen428 369,2 (M+1). 0,4 0,305
- 502
-
imagen429 502,3 (M+1). 1,39 1,373
- 503
- 450,3 (M+1). 0,12 0,095
- 504
- 424,0 (M+1) 0,09 0,093
- 505
-
imagen430 424,2 (M+1) 0,14 0,116
- 506
-
imagen431 420,3 (M+1) 0,19 0,198
- 507
-
imagen432 365,2 (M+1) 0,14 0,136
- 508
-
imagen433 385,0 (M+1). 0,13 0,126
- 509
-
imagen434 387,2 (M+1) 0,13 0,134
- 510
-
imagen435 387,2 (M+1) 2,05 1,564
- 511
- 403,1 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 7,74-7,70 (m, 2H); 7,21 (t, J = 8,4 Hz, 1H), 7,08 (m, 2H); 6,49-6,40 (m, 2H); 4,43 (s, 2H) 1,72 (s, 6H). 0,04 0,065
- 512
-
imagen436 369,2 (M+1) 0,19 0,165
- 513
-
imagen437 403,0 (M+1). 0,17 0,195
- 514
-
imagen438 355,1 (M+1) 0,03 0,024
- 515
-
imagen439 405,1 (M+1). 0,04 0,034
- 516
-
imagen440 451,2 (M+1). 0,03 0,026
- 517
-
imagen441 394,1 (M+1). 0,05 0,051
- 518
-
imagen442 422,2 (M+1). 4,98 2,888
- 519
-
imagen443 414,2 (M+1). 0,84 0,59
- 520
-
imagen444 414,2 (M+1) 0,16 0,158
- 521
-
imagen445 442,2 (M+1). 5,0 3,026
- 522
-
imagen446 437,0 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,61-7,57 (m, 2H); 7,15-7,07 (1H, 4H); 7,02- 7,01 (m, 1H); 4,0 (m, 4H); 3,81 (m, 2H); 2,01 (s, 6H). 0,0017 0,002
- 523
-
imagen447 399,0 (M+1). 13,11 11,649
- 524
-
imagen448 380,2 (M+1). 0,04 0,057
- 525
-
imagen449 433,5 (M+1). 0,01 0,013
- 526
-
imagen450 395,0 (M+1). 1,12 0,974
- 527
-
imagen451 376,1 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,61-7,57 (m, 2H); 7,15-7,07 (1H, 4H); 7,02- 7,01 (m, 1H); 4,0 (m, 4H); 3,81 (m, 2H); 2,01 (s, 6H). 0,004 0,006
- 528
-
imagen452 501,2 (M+1) 0,15 0,121
- 529
-
imagen453 436,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,78-7,75 (m, 2H); 7,06-6,97 (1H, 4H); 6,56 (d, J = 8,4 Hz, 2H), 5,16 (s, NH); 4,33 (t, J= 4,8 Hz, 2H), 3,74 (t, J = 4,8 Hz, 2H); 4,16 (m, 2H); 2,29 (s, 3H); 1,95 (s, 6H); 1,45 (s, 6H). 0,002 0,004
- 530
-
imagen454 482,2 (M+1) 1,23 6,422
- 531
-
imagen455 400,1 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,67-7,63 (m, 2H) 7,21-7,17 (t, J= 8,8 Hz, 2H), 4,15 (m, 2H); 3,79 (m, 2H); 2,72 (m, 1H); 1,95 (s, 6H); 1,72 (m, 2H); 1,58 (m, 2H); 1,46 (m, 1H); 1,1-1,05 (m, 5H); 0,04 0,057
- 532
-
imagen456 442,2 (M+1) 0,02 0,009
- 533
-
imagen457 426,2 (M+1) 0,03 0,022
- 534
-
imagen458 453,2 (M+1) 0,04 0,019
- 535
-
imagen459 390,2 (M+1) 2,72 2,351
- 536
-
imagen460 397,2 (M+1) 6,4 5,93
- 537
-
imagen461 394,2 (M+1) 11,91 8,342
- 538
-
imagen462 407,2 (M+1) 7,67 8,065
- 539
-
imagen463 393,2 (M+1) 3,06 3,123
- 540
-
imagen464 375,2 (M+1) RMN 1H: (300 Hz, CD3OD) δ 7,74- 7,69 (m, 2H), 7,42 (s, 1H), 7,13-7,07 (m, 2H), 4,84 (s, 2H), 4,19-3,97 (6H, m), 1,47 (9H, s) 8,42 9,807
- 541
-
imagen465 369,2 (M+1) 0,01 0,01
- 542
-
imagen466 369,2 (M+1) 0,002 0,003
- 543
-
imagen467 405,2 (M+1) 0,17 0,305
- 544
-
imagen468 383,2 (M+1) RMN 1H: MeOH-d4, 400 Hz) δ 7,65-7,62 (m, 2H); 6,95-6,91 (m, 1H); 6,72 (t, J = 9,2 Hz, 1H) 6,28-6,25 (m, 1H); 4,30 (s, 2H) 2,04 (s, 3H) 1,81 (s, 6H). 0,02 0,037
- 545
-
imagen469 382,2 (M+1) 3,38 5,618
- 546
-
imagen470 399,1 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 7,60-7,56 (m, 2H); 7,09-7,05 (m, 2H), 6,99 (d, J=8,0 Hz, 1H), 6,67(d, J = 2,4 Hz, 2H); 6,46 (dd, J = 2,4 Hz, J = 8,0 Hz, 1H); 4,44 (s, 2H) 2,13 (s, 3H) 1,71 (s, 6H). 0,03 0,052
- 547
-
imagen471 366,2 (M+1) 1,82 4,662
- 548
-
imagen472 410,0 (M+1). 2,63 5,549
- 549
-
imagen473 399,1 (M+1). 1,7 3,261
- 550
-
imagen474 417,1 (M+1). 2,56 3,6
- 551
-
imagen475 421,0 (M+1). 0,04 0,098
- 552
-
imagen476 487,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,27-7,67 (m, 4H); 7,2 (t, J = 8,8 Hz, 2H); 6,8 (d, J = 8,4 Hz, 2H), 4,01 (m, 4H), 3,86 (t, J=4,4 Hz, 2H); 2,88 (s, 3H); 2,1 (s, 6H). 2,52 4,482
- 553
-
imagen477 451,2 (M+1) 2,37 4,658
- 554
-
imagen478 448,0 (M+1). 0,0 0,007
- 555
-
imagen479 391,2 (M+1) 0,01 0,016
- 556
-
imagen480 385,2 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,72-7,69 (m, 2H); 7,19-7,15 (4H, m); 6,67 (2H, J= 9,2 Hz, d); 4,64 (s, 2H); 4,64 (s, 2H); 3,99 (s, 2H), 2,91 (s, 2H), 1,43 (s, 6H). 0,06 0,075
- 557
-
imagen481 428,2 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) 87,74 (m, 2H); 7,19-7,15(m, 2H); 6,69 (d, J =8,8 Hz, 2H); 4,88 (s, 2H); 4,08 (s, 2H); 3,99 (s, 2H), 2,91 (s, 2H), 1,54 (s, 6H). 0,02 0,02
- 558
-
imagen482 371,1 (M+1) RMN 1H: (CDCl3), 400 Hz) δ 7,75-7,71 (m, 2H); 7,18 (d, J = 9,2 Hz, 2H); 6,99 (t, J= 8,8 Hz, 2H); 6,56 (d, J = 8,8 Hz, 2H); 5,37 (s, NH); 4,15 (s, 2H); 3,49 (s, NH); 3,42 (s, 2H); 1,22 (s, 6H). 0,06 0,089
- 559
-
imagen483 389,0 (M+1). 0,53 0,642
- 560
-
imagen484 369,2 (M+1) 3,61 5,219
- 561
-
imagen485 386,2 (M+1) 7,17 4,403
- 562
-
imagen486 417,2 (M+1) 4,82 6,293
- 563
-
imagen487 371,0 (M+1). 0,31 0,445
- 564
-
imagen488 389,0 (M+1). 0,25 0,359
- 565
-
imagen489 371,0 (M+1). 0,07 0,105
- 566
-
imagen490 402,2 (M+1) 5,48 4,463
- 567
-
imagen491 429,2 (M+1) 6,46 8,458
- 568
-
imagen492 449,0 (M+1). >8,04 >11,3
- 569
-
imagen493 463,3 (M+1). 9,27 7,916
- 570
-
imagen494 472,2 (M+1) 5,68 5,562
- 571
-
imagen495 492,1 (M+1). 6,2 7,48
- 572
-
imagen496 435,1 (M+1). 11,18 8,73
- 573
-
imagen497 408,2 (M+1) 0,04 0,055
- 574
-
imagen498 412,1 (M+1) 0,08 0,111
- 575
-
imagen499 430,2 (M+1) 0,08 0,081
- 576
-
imagen500 446,2 (M+1) 0,2 0,234
- 577
-
imagen501 437,1 (M+1). 0,63 0,611
- 578
-
imagen502 351,2 (M+1) 0,25 0,339
- 579
-
imagen503 355,2 (M+1) 0,18 0,146
- 580
-
imagen504 373,2 (M+1) 0,15 0,169
- 581
-
imagen505 380,2 (M+1) 0,65 0,668
- 582
-
imagen506 471,1 (M+1). 5,56 5,919
- 583
-
imagen507 440,1 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,66- (dd, J = 5,2 Hz, J = 9,2 Hz, 2H); 7,11(t, J = 8,8 Hz, 2H); 6,81 (t, J = 8,8 Hz, 2H); 6,72- 6,68(m, 2H); 4,04-3,99 (m, 4H); 2,01 (s, 6H); 1,66 (s, 6H). 0,01 0,009
- 584
-
imagen508 456,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,60-7,59 (m, 2H); 7,16-7,09 (m, 4H); 6,7(d, J = 8,4 Hz, 2H); 4,01 (m, 4H); 2,01 (s, 6H); 1,65 (s, 6H). 0,02 0,021
- 585
-
imagen509 458,1 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,63-7,60 (m, 2H); 7,14 (t, J = 8,4 Hz, 2H); 7,01 (dd, J = 8,8 Hz, J = 18,8 Hz, 1H); 6,68-6,63 (1H, 1H); 6,5 (m, 1H); 4,03 (m, 2H); 4,01 (m, 2H); 2,01 (s, 6H); 1,66 (s, 6H). 0,01 0,007
- 586
-
imagen510 474,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,63-7,59 (m, 2H); 7,13 (t, J= 8,8 Hz, 2H); 6,97 (t, J = 9,2 Hz, 1H); 6,84 (t, J= 3,6 Hz, 1H); 4,03 (m, 2H); 4,01 (m, 2H); 2,01 (s, 6H); 1,66 (s, 6H). 0,01 0,007
- 587
-
imagen511 491,2 (M+1) 0,01 0,012
- 588
-
imagen512 454,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,73-7,70 (m, 2H); 7,21 (t, J= 8,8 Hz, 2H); 6,87 (t, J = 8,8 Hz, 1H); 6,68 (m, 1H); 4,12 (m, 4H); 2,17 (s, 3H); 2,15 (s, 6H); 1,76 (s, 6H). 0,01 0,004
- 589
-
imagen513 470,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,62-7,59 (m, 2H); 7,16-7,06 (m, 3H); 6,66 (d, J =2,4 Hz, 1H); 6,50 (dd, J=2,8 Hz, J = 8,4 Hz, 1H); 3,99 (m, 4H), 2,17 (s, 3H); 2,01 (s, 6H); 1,65 (s, 6H). 0,01 0,006
- 590
-
imagen514 461,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,32-7,59 (m, 2H); 7,14 (m, 3H); 6,97 (m, 2H); 4,01 (m, 4H), 2,29 (s, 3H); 2,02 (s, 6H); 1,81 (s, 6H). 0,03 0,018
- 591
- 481,0 (M+1) 0,06 0,046
- 592
-
imagen515 451,2 (M+1) 6,01 5,256
- 593
- 436,2 (M+1) 5,06 3,937
- 594
-
imagen516 408,2 (M+1) RMN 1H: CMeOH-Cl4, 400 Hz) δ 7,58-7,40 (m, 3H); 7,13 (t, J= 8,4 Hz, 1H); 6,99 (m, 2H); 6,61 (d, J=8,0 Hz, 2H); 5,17-5,14 (m, 2H); 4,28-3,92 (m, 4H); 2,20 (s, 3H), 1,70 (s, 3H), 1,65 (s, 3H). 0,02 0,032
- 595
-
imagen517 460,2 (M+1) 0,34 0,485
- 596
- 432,2 (M+1) 0,03 0,029
- 597
-
imagen518 432,2 (M+1) 0,03 0,024
- 598
-
imagen519 383,2 (M+1) 0,04 0,074
- 599
- 499,3 (M+1) 0,12 0,134
- 600
-
imagen520 412,2 (M+1) RMN 1H (400 MHz, MeOH-d4) δ 7,76- (dd, J = 5,2 Hz, J = 8,8 Hz, 2H); 7,29 (t, J = 8,4 Hz, 2H); 4,26 (s, 2H); 4,16 (s, 2H); 4,00 (s, 2H); 3,76 (s, 3H); 1,92 (s, 6H); 2,14 (s, 6H). 0,07 0,05
- 601
-
imagen521 412,2 (M+1). 3,96 4,117
- 602
- 460,2 (M+1) 0,17 0,204
- 603
- 383,2 (M+1) 0,05 0,073
- 604
-
imagen522 399,2 (M+1) 0,04 0,049
- 605
-
imagen523 403,0 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 7,43 (td, J = 8,0 Hz, J = 1,0 Hz 1H); 7,38-7,34 (m, 1H); 7,24-7,18 (m, 1H, 7,11 (t, J = 8,40 Hz, 1H); 6,87-6,8 (m, 1H); 6,37 (dd, J = 11,2 Hz, J = 2,40 Hz 1H); 6,33-6,30 (m, 1H); 4,33 (s, 2H), 1,62 (s, 6H). 0,04 0,057
- 606
-
imagen524 369,1 (M+1) RMN 1H: (MeOH-Cl4, 400 Hz) δ 7,63-7,59 (m, 2H); 7,11 (t, J = 8,40 Hz, 211); 6,85 (t, J = 8,40 Hz, 211); 6,7-6,68 (1H, 2H); 4,3 (m, 2H); 3,87 (m, 2H); 3,01 (s, 3H); 1,97 (s, 6H). 0,02 0,028
- 607
-
imagen525 385,2 (M+1) 0,03 0,048
- 608
-
imagen526 385,1 (M+1) 6,91 5,562
- 609
-
imagen527 403,2 (M+1) 7,02 4,929
- 610
-
imagen528 399,1 (M+1) 6,25 4,903
- 611
- 387,1 (M+1) 7,67 5,762
- 612
-
imagen529 390,2 (M+1) 6,9 6,082
- 613
-
imagen530 523,2 (M+1) 6,27 5,711
- 614
-
imagen531 519,2 (M+1) 5,02 4,524
- 615
-
imagen532 417,0 (M+1) 6,41 5,609
- 616
-
imagen533 413,2 (M+1) 5,72 4,562
- 617
- 397,2 (M+1) 6,33 6,878
- 618
-
imagen534 403,8 (M+1) 2,13 2,887
- 619
-
imagen535 399,2 (M+1) 0,57 0,713
- 620
-
imagen536 428,0 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,48-7,41 (m, 3H); 7,16-7,14 (m, 3H); 6,71 (d, J = 8,4 Hz, 2H); 5,17-5,14 (m, 2H); 4,28-3,92 (m, 4H); 1,71 (s, 3H), 1,66 (s, 3H). 0,04 0,041
- 621
-
imagen537 412,2 (M+1) 0,04 0,045
- 622
-
imagen538 430,2 (M+1) 0,1 0,121
- 623
-
imagen539 446,2 (M+1) 0,03 0,032
- 624
-
imagen540 446,2 (M+1) 0,1 0,167
- 625
-
imagen541 426,2 (M+1) 0,17 0,194
- 626
-
imagen542 442,0 (M+1) RMN 1H: (MeOH-d4, 400 Hz) δ 7,47-7,39 (m, 2H); 7,19-7,11 (1H, 2H); 6,67 (s, 1H); 6,52 (d, J = 8,0 Hz. 1H); 5,15 (s, 2H); 4,27-3,91 (m, 2H); 2,24 (s, 3H), 1,71 (s, 3H), 1,65 (s, 3H). 0,02 0,017
- 627
-
imagen543 403,2 (M+1) 0,17 0,194
- 628
-
imagen544 426,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,69-7,73 (m, 2H), 7,18 (t, J = 8,8 Hz, 2H), 6,87 (t, J = 8,8 Hz, 2H), 6,62-6,63 (m, 1H), 6,51-6,55 (m, 1H), 5,12 (s, 2H), 4,21 (t, J = 4,8 Hz, 2H), 4,02 (t, J= 4,8 Hz, 2H), 2,17 (s, 3H), 1,75 (s, 6H). 0,033 0,04
- 629
-
imagen545 442,1 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,70-7,73 (m, 2H), 7,22 (t, J = 8,0 Hz, 2H), 7,17 (d, J = 7,2 Hz, 1H), 6,77 (s, 1H), 6,62 (d, J =6,0 Hz, 1H), 5,20 (s, 2H), 4,27 (s, 2H), 4,08 (s, 2H), 2,27 (s, 3H), 1,78 (s, 6H). 0,017 0,023
- 630
-
imagen546 433,3 (M+1). 0,035 0,085
- 631
-
imagen547 426,3 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,72-7,76 (m, 2H), 7,22 (t, J = 8,8 Hz, 2H), 7,06 (t, J= 8,8 Hz, 1H), 8,56 (s, 1H), 6,53-6,54 (m, 1H), 5,20 (s, 2H), 4,27 (t, J = 4,8 Hz, 2H), 4,09 (t, J= 4,8 Hz, 2H), 2,13 (s, 3H), 1,79 (s, 6H). 0,049 0,062
- 632
-
imagen548 442,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,71-7,74 (m, 2H), 7,22 (t, J = 8,8 Hz, 2H), 7,11 (d, J=8,4 Hz, 1H), 6,85 (d, J = 2,4 Hz, 1H), 6,67 (dd, J = 2,4, 8,4 Hz, 1H), 5,20 (s, 2H), 4,27 (t, J = 4,2 Hz, 2H), 4,09 (t, J= 4,2 Hz, 2H), 2,24 (s, 3H), 1,78 (s, 6H). 0,015 0,016
- 633
- 496,1 (M+1). 0,528 0,331
- 634
-
imagen549 480,1 (M+1). 0,467 0,447
- 635
-
imagen550 487,1 (M+1). 0,94 1,758
- 636
-
imagen551 437,2 (M+1) 0,21 0,183
- 637
-
imagen552 422,3 (M+1). 0,027 0,026
- 638
-
imagen553 408,3 (M+1) 0,065 0,068
- 639
-
imagen554 428,2 (M+1) 0,082 0,093
- 640
-
imagen555 478,2 (M+1) 3,95 4,51
- 641
-
imagen556 422,2 (M+1) 0,799 1,285
- 642
-
imagen557 460,2 (M+1) 2,01 2,497
- 643
-
imagen558 478,2 (M+1) 2,798 2,171
- 644
-
imagen559 462,1 (M+1). 0,31 0,49
- 645
-
imagen560 426,1 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,75-7,78 (m, 2H), 6,95-7,01 (m, 3H), 6,44-6,50 (m, 1H), 6,32-6,36 (m, 1H), 4,19 (dd, J = 1,6, 6,8 Hz, 2H), 4,00 (dd, J = 1,6/6,8 Hz, 2H), 1,47 (s, 6H). 5,13 7,6
- 646
-
imagen561 428,1 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,59-7,63 (m, 2H), 7,09 (t, J = 6,4 Hz, 2H), 6,95-7,02 (m, 1H), 6,46-6,52 (m, 1H), 6,34-6,38 (m, 1H), 5,92 (s, 1H), 4,33 (dd, J = 4,4, 14 Hz, 1H), 3,96 (dd, J = 4,8, 13,2 Hz, 1H), 3,70-3,78 (m, 1H), 3,46-3,54 (m, 1H), 1,73 (s, 3H), 1,36 (s, 3H) 5,68 6,13
- 647
-
imagen562 470,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,72-7,76 (m, 2H), 7,50-7,54 (m, 4H), 7,39 (t, J= 8,0 Hz, 2H), 7,27 (t, J = 7,2 Hz, 1H), 7,20 (t, J= 8,8 Hz, 2H), 6,82 (d, J = 8,4 Hz, 2H), 4,07-4,10 (m, 4H), 3,84 (t, J = 4,8 Hz, 2H), 0,279 0,25
- 2,09 (s, 6H).
- 648
-
imagen563 422,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,76-7,71 (m, 2H), 7,21 (t, J = 8,8 Hz, 2H), 7,07 (d, J = 8,4 Hz, 2H), 6,67 (d, J = 8,4 Hz, 2H), 4,05-4,08 (m, 4H), 3,83-3,85 (m, 2H), 2,55 (q, J=7,6 Hz, 2H), 2,09 (s, 6H), 1,18 (t, J= 7,6 Hz, 3H) 0,009 0,008
- 649
-
imagen564 478,1 (M+1). 0,024 0,018
- 650
-
imagen565 478,1 (M+1). 0,012 0,009
- 651
-
imagen566 428,1 (M+1). 0,008 0,005
- 652
-
imagen567 462,1 (M+1). 0,019 0,012
- 653
-
imagen568 419,1 (M+1). 0,006 0,009
- 654
-
imagen569 422,2 (M+1) 0,005 0,006
- 655
- 487,1 (M+1). 0,017 0,02
- 656
-
imagen570 422,1 (M+1). 0,006 0,007
- 657
-
imagen571 480,1 (M+1). 0,618 1,086
- 658
-
imagen572 496,0 (M+1) 0,005 0,006
- 659
-
imagen573 442,6 (M+1) 4,39 5,28
- 660
-
imagen574 436,1 (M+1). 0,003 0,006
- 661
-
imagen575 476,2 (M+1) 0,339 0,52
- 662
-
imagen576 468,1 (M+1). 0,038 0,033
- 663
-
imagen577 456,2 (M+1) 1,062 1,658
- 664
-
imagen578 414,2 (M+1) 3,69 4,08
- 665
-
imagen579 414,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,71-7,74 (m, 2H), 7,29 (t, J = 8,8 Hz, 2H), 4,20 (t, J= 4,8 Hz, 2H), 4,12 (s, 2H), 3,86 (t, J = 4,8 Hz, 2H), 3,02-3,09 (m, 1H), 2,02 (s, 6H), 1,79-1,86 (m, 2H), 1,57-1,63 (m, 2H), 1,48-1,52 (m, 4H), 1,39-1,46 (m, 2H), 1,21-1,30 (m, 2H) 0,102 0,069
- 666
-
imagen580 442,2 (M+1) >10 4,97
- 667
-
imagen581 412,2 (M+1) 0,104 0,082
- 668
-
imagen582 415,7 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,59-7,63 (m, 2H), 7,32 (t, J = 8,8 Hz, 2H), 4,25 (d, J = 4,8 Hz, 2H), 4,13 (s, 2H), 3,97-4,04 (m, 1H), 3,88 (d, J = 4,8 Hz, 2H), 3,49-3,54 (m, 1H), 3,41-3,47 (m, 2H), 3,25-3,30 (m, 1H), 2,92 (s, 6H), 2,45-2,53 (m, 1H), 2,23-2,28 (m, 1H), 2,01 (s, 6H). 3,43 >10
- 669
-
imagen583 469,7 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,47-7,51 (m, 2H), 7,22 (t, J = 8,8 Hz, 2H), 4,13 (t, J = 4,4 Hz, 2H), 4,03 (s, 2H), 3,42 (d, J = 11,6 Hz, 2H), 3,15 (d, J = 12,4 Hz, 2H), 2,90 (dd, J = 10,8, 22,4 Hz, 4H), 2,00-2,03 (m, 2H), 1,90 (s, 6H), 1,68-1,87 (m, 6H), 1,37 - 1,47 (m, 1H); 3,98 >10
- 670
-
imagen584 386,6 (M+1) 0,402 0,711
- 671
-
imagen585 372,3 (M+1) 1,286 1,087
- 672
-
imagen586 402,3 (M+1) 9,84 7,14
- 673
-
imagen587 8,87 >8,72
- 674
-
imagen588 6,28 6,31
- 675
-
imagen589 446,5 (M+1) 0,014 0,021
- 676
-
imagen590 415,7 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,59-7,63 (m, 2H), 7,32 (t, J = 8,8 Hz, 2H), 4,25 (d, J = 4,8 Hz, 2H) 4,13 (s, 2H), 3,97-4,04 (m, 1H), 3,88 (d, J = 4,8 Hz, 2H), 3,49-3,54 (m, 1H), 3,41-3,47 (m, 2H), 3,25-3,30 (m, 1H), 2,92 (s, 6H), 2,45-2,53 (m, 1H), 2,23-2,28 (m, 1H), 2,01 (s, 6H), 0,032 0,031
- 677
-
imagen591 469,7 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,47-7,51 (m, 2H), 7,22 (t, J = 8,8 Hz, 2H), 4,13 (t, J = 4,4 Hz, 2H), 4,03 (s, 2H), 3,42 (d, J = 11,6 Hz, 2H), 3,15 (d, J = 12,4 Hz, 2H), 2,90 (dd, J = 10,8, 22,4 Hz, 4H), 2,00-2,03 (m, 2H), 1,90 (s, 6H), 1,68-1,87 (m, 6H), 1,37 - 1,47 (m, 1H); 0,08 0,076
- 678
-
imagen592 415,7 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,59-7,63 (m, 2H), 7,32 (t, J = 8,8 Hz, 2H), 4,25 (d, J = 4,8 Hz, 2H), 4,13 (s, 2H), 3,97-4,04 (m, 1H), 3,88 (d, J = 4,8 Hz, 2H), 3,49-3,54 (m, 1H), 3,41-3,47 (m, 2H), 3,25-3,30 (m, 1H), 2,92 (s, 6H), 2,45-2,53 (m, 1H), 2,23-2,28 (m, 1H), 2,01 (s, 6H 0,053 0,047
- 679
-
imagen593 469,7 (M+1) RMN 1H (400, MHz, CD3OD): δ 7,47-7,51 (m, 2H), 7,22 (t, J = 8,8 Hz, 2H), 4,13 (t, J = 4,4 Hz, 2H), 4,03 (s, 2H), 3,42 (d, J = 11,6 Hz, 2H), 3,15 (d, J = 12,4 Hz, 2H), 2,90 (dd, J = 10,8, 22,4 Hz, 4H), 2,00-2,03 (m, 2H), 1,90 (s, 6H), 1,68-1,87 (m, 6H), 1,37 - 1,47 (m, 1H); 0,173 0,153
- 680
-
imagen594 415,7 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,59-7,63 (m, 2H), 7,32 (t, J = 8,8 Hz, 2H), 4,25 (d, J = 4,8 Hz, 2H), 4,13 (s, 2H), 3,97-4,04 (m, 1H), 3,88 (d, J = 4,8 Hz, 2H), 3,49-3,54 (m, 1H), 3,41-3,47 (m, 2H), 3,25-3,30 (m, 1H), 2,92 (s, 6H), 2,45-2,53 (m, 1H), 2,23-2,28 (m, 1H), 2,01 (s, 6H). 0,085 0,173
- 681
-
imagen595 454,1 (M+1). 0,272 0,196
- 682
-
imagen596 470,1 (M+1). 0,124 0,111
- 683
-
imagen597 454,1 (M+1). 0,125 0,112
- 684
-
imagen598 470,1 (M+1). 0,03 0,017
- 685
-
imagen599 474,1 (M+1). 0,173 0,131
- 686
-
imagen600 452,2 (M+1) 0,628 0,524
- 687
-
imagen601 412,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,70-7,74 (m, 2H), 7,21 (t, J = 8,4 Hz, 2H), 6,96 (d, J = 7,6 Hz, 2H), 6,62 (s, 1H), 6,50 (d, J = 7,6 Hz, 1H), 5,19 (s, 2H), 4,25 (s, 2H), 4,07 (s, 2H), 1,77 (s, 6H). 3,42 (NF54) 3,35
- 688
-
imagen602 413,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,67-7,71 (m, 2H), 7,15-7,21 (m, 2H), 6,92-6,97 (m, 2H), 6,71-6,76 (m, 2H), 4,57-4,63 (dm, 1H), 3,76-3,79 (m, 1H), 3,68-3,70 (m, 1H), 1,91 (s, 3H), 1,84 (s, 3H) 0,106 (NF54) 0,134
- 689
-
imagen603 440,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,33-7,42 (m, 3H), 7,06-7,08 (m, 1H), 6,70 (t, J= 9,2 Hz, 2H), 6,69-6,71 (m, 1H), 6,58-6,62 (m, 1H), 4,38 (s, 2H), 3,66 (t, J= 8,0 Hz, 2H), 2,89 (t, J= 8,0 Hz, 2H), 2,25 (d, J = 1,6 Hz, 3H), 1,88-1,95 (m, 2H), 1,77 (s, 6H). 0,512 0,295
- 690
-
imagen604 441,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,51-7,54 (m, 1H), 7,44-7,48 (m, 1H), 7,37-7,42 (m, 1H), 7,05-7,12 (m, 1H), 6,86 (dt, J = 1,6, 9,2 Hz, 1H), 6,57-6,61 (m, 1H), 6,47-6,53 (m, 1H), 4,58 (d, J = 2,0 Hz, 2H), 3,91 (t, J = 6,0 Hz, 1H), 3,64-3,72 (m, 3H), 3,36 (s, 3H), 2,17 (d, J = 1,2 Hz, 2H), 1,91 (s, 3H), 1,89 (s, 3H) 0,866 0,76
- 691
-
imagen605 455,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,37-7,43 (m, 2H), 7,31-7,34 (m, 1H), 7,06-7,11 (m, 1H), 6,97 (t, J = 8,8 Hz, 1H), 6,71-6,73 (m, 1H), 6,58-6,62 (m, 1H), 4,39 (s, 2H), 3,62-3,65 (m, 2H), 3,36 (a, 5H), 3,34 (s, 1H), 3,26 (s, 3H), 2,24 (d, J = 2,0 Hz, 3H), 1,79 (s, 6H). 0,068 0,06
- 692
-
imagen606 469,2 (M+1) 6,45 5,34
- 693
-
imagen607 411,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,58-7,62 (m, 2H), 7,30 (d, J = 8,8 Hz, 2H), 7,21 (dd, J = 5,6, 8,8 Hz, 2H), 7,08 (d, J=8,8 Hz, 2H), 4,23 (s, 2H), 4,06-4,09 (m, 4H), 3,83 (d, J = 5,6 Hz, 2H), 2,05 (s, 6H). 0,008 0,008
- 694
-
imagen608 407,3 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,59-7,62 (m, 2H), 7,29 (t, J = 8,4 Hz, 2H), 7,16 (d, J = 8,0 Hz, 2H), 7,06 (d, J = 8,0 Hz, 2H), 4,19 (s, 2H), 4,04-4,08 (m, 4H), 3,80 (t, J = 4,8 Hz, 2H), 2,31 (s, 3H), 2,04 (s, 6H). 0,011 0,007
- 695
-
imagen609 423,1 (M+1). 0,017 0,019
- 696
-
imagen610 429,2 (M+1) 0,02 0,022
- 697
-
imagen611 411,1 (M+1). 0,362 0,256
- 698
-
imagen612 415,3 (M+1) 8,81 9,02
- 699
-
imagen613 399,3 (M+1) 0,678 (NF54) ND
- 700
-
imagen614 407,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,73-7,77 (m, 3H), 7,21-7,30 (m, 6H), 4,82-4,86 (m, 1H), 4,13-4,18 (m, 2H), 4,61 (s, 1H), 3,71-3,77 (m, 1H), 3,53-3,58 (m, 1H), 3,09-3,21 (m, 1H), 2,34 (s, 3H), 2,01 (s, 3H), 1,99 (s, 3H) >9,51 7,0
- 701
-
imagen615 425,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,76-7,79 (m, 3H), 7,32-7,38 (m, 1H), 7,28 (t, J= 8,8 Hz, 2H), 7,11 (d, J=4,0 Hz, 1H), 7,06 (dt, J = 10, 2,4 Hz, 1H), 6,99 (dt, J = 2,8, 8,4 Hz, 1H), 4,62 (t, J = 6,4 Hz, 1H), 4,35 (t, J = 4,8 Hz. 2H), 3,84-3,98 (m, 2H), 2,79-2,87 (m, 2H), 8,27 7,35
- 702
-
imagen616 2,14-2,20 (m, 2H), 2,04 (s, 3H), 2,03 (s, 3H) 441,2 (M+1) 6,03 5,85
- 703
-
imagen617 399,3 (M+1) RMN 1H (400 MHz, CD3OD): � 7,81 (s, 1H), 7,76-7,80 (m, 2H), 7,29 (t, J = 8,8 Hz, 2H), 4,60-4,64 (m, 2H), 4,40-4,43 (m, 2H), 3,92-3,95 (m, 2H), 2,05 (s, 3H), 2,04 (s, 3H), 1,70-1,83 (m, 6H), 1,49-1,53 (m, 1H), 1,20-1,42 (m, 4H), 0,99-1,35 (m, 2H) 8,57 8,29
- 704
-
imagen618 393,3 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,42-7,46 (m, 2H), 7,31-7,39 (m, 4H), 7,13 (t, J= 8,8 Hz, 2H), 4,09-4,12 (m, 4H), 3,82 (t, J = 4,8 Hz, 2H), 2,42 (s, 3H), 2,08 (s, 6H). 0,236 0,232
- 705
-
imagen619 397,3 (M+1) 1,241 0,76
- 706
-
imagen620 431,2 (M+1) 0,252 0,237
- 707
-
imagen621 383,1 (M+1). 6,54 >10
- 708
-
imagen622 440,1 (M+1). 0,809 1,134
- 709
-
imagen623 413,1 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,67-7,71 (m, 2H), 7,09-7,17 (m, 6H), 4,06 (s, 2H), 4,02 (t, J= 4,8 Hz, 2H), 3,80 (t, J= 4,8 Hz, 2H), 2,04 (s, 6H). 0,003 0,008
- 710
-
imagen624 429,1 (M+1). 0,028 (NF54) ND
- 711
-
imagen625 431,1 (M+1). 0,034 (NF54) ND
- 712
-
imagen626 427,2 (M+1) 0,019 (NF54) ND
- 713
-
imagen627 425,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,83-7,87 (m, 2H), 7,22 (t, J = 8,8 Hz, 2H), 7,16 (d, J =8,4 Hz, 2H), 7,04 (d, J = 8,8 Hz, 2H), 4,11 (t, J = 4,4 Hz, 2H), 3,98 (s, 2H), 3,83 (t, J= 4,4 Hz, 2H), 2,29 (s, 3H), 1,98 (s, 6H). 0,008 ND
- 714
-
imagen628 429,2 (M+1) 0,007 0,004
- 715
-
imagen629 429,1 (M+1). 0,006 0,006
- 716
-
imagen630 445,1 (M+1). 0,002 0,001
- 717
-
imagen631 439,2 (M+1) 0,026 0,016
- 718
-
imagen632 447,1 (M+1). 0,008 0,006
- 719
-
imagen633 445,1 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,58-7,62 (m, 2H), 7,23 (d, J = 8,4 Hz, 2H), 7,14 (t, J = 8,4 Hz, 2H), 6,89 (s, 1H), 6,67 (d, J = 7,6 Hz, 1H), 5,09 (s, 2H), 4,17 (s, 2H), 3,99 (s, 2H), 1,67 (s, 6H). 0,481 0,361
- 720
-
imagen634 445,1 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,60-7,63 (m, 2H), 7,11 (t, J = 8,4 Hz, 2H), 6,75-6,80 (m, 1H), 6,59 (d, J = 4,8 Hz, 1H), 6,50 (a, 1H), 5,09 (s, 2H), 4,16 (s, 2H), 3,97 (s, 2H), 2,07 (s, 3H), 1,67 (s, 6H). 0,07 0,069
- 721
-
imagen635 441,0 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,78-7,82 (m, 2H), 7,60 (d, J = 8,4 Hz, 2H), 7,44 (d, J = 8,0 Hz, 2H), 7,35 (t, J = 8,8 Hz, 2H), 4,61-4,65 (m, 1H), 4,08 (s, 2H), 3,77-3,92 (m, 3H), 2,43 (s, 3H), 2,07 (s, 3H), 2,05 (s, 3H), 0,042 ND
- 722
-
imagen636 455,1 (M+1). 0,381 0,281
- 723
-
imagen637 463,1 (M+1). 0,089 0,068
- 724
-
imagen638 461,1 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,70-7,74 (m, 2H), 7,21 (t, J = 8,4 Hz, 2H), 6,96 (d, J = 7,6 Hz, 2H), 6,62 (s, 1H), 6,50 (d, J = 7,6 Hz, 1H), 5,19 (s, 2H), 4,25 (s, 2H), 4,07 (s, 2H), 1,77 (s, 6H). 0,509 0,287
- 725
-
imagen639 457,1 5,21 (NF54) ND
- 726
-
imagen640 544,3 (M+1) 1,925 1,48
- 727
-
imagen641 634,3 (M+1) 6,56 2,969
- 728
-
imagen642 615,3 (M+1) 5,4 1,485
- 729
-
imagen643 705,3 (M+1) >10 6,29
- 730
-
imagen644 601,2 (M+1) 1,365 0,474
- 731
-
imagen645 734,2 (M+1) 2,27 (NF54) 5,61
- 732
-
imagen646 905,4 (M+1) 1,223 (NF54) 1,438
- 737
-
imagen647 305,2 (M+1) RMN 1H (400 MHz, CDCl3): � 9,27 (s, 1H), 8,76 (d, J = 8,0 Hz, 1H), 8,55 (d, J = 3,2 Hz, 1H), 7,79 (t, J = 3,2 Hz, 1H), 7,33 (a, 1H), 6,99 (d, J = 8,4 Hz, 2H), 6,56 (d, J = 8,4 Hz, 2H), 3,87 (s, 2H), 3,14 (s, 2H), 2,22 (s, 3H), 2,02 (s, 4H) 7,85 4,09
- 738
-
imagen648 328,5 (M+1) 3,24 1,555
- 739
-
imagen649 412,6 (M+1) 0,768 0,881
- 740
-
imagen650 367,2 (M+1) 9,33 8,73
- 741
-
imagen651 404,6 (M+1) 5,25 4,83
- 742
-
imagen652 388,2 (M+1) 6,43 11,6
- 743
-
imagen653 401,2 (M+1) 2,675 3,003
- 744
-
imagen654 437,6 (M+1) 5,24 2,813
- 745
-
imagen655 390,2 (M+1) 3,57 4,23
- 746
-
imagen656 382,2 (M+1) >10 6,94
- 747
-
imagen657 388,2 (M+1) 2,234 4,48
- 748
-
imagen658 332,2 (M+1) RMN 1H (400 MHz, CD3OD): � 8,09 (s, 1H), 7,75-7,79 (m, 4H), 7,17 (t, J = 8,8 Hz, 2H), 6,93(d, J = 8,0 Hz, 1H), 6,49 (d, J = 8,4 Hz, 2H), 2,35 (s, 3H), 2,14 (s, 3H) 3,44 4,15
- 749
-
imagen659 360,8 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,64-7,67 (m, 2H), 7,20-7,29 (m, 3H), 6,64 (dd, J = 2,8, 11,2 Hz, 1H), 6,55-6,58 (m, 1H), 3,90 (t, J= 5,6 Hz, 2H), 3,11 (t, J = 5,6 Hz, 2H), 2,05-2,12 (m, 4H) 1,053 0,814
- 750
-
imagen660 322,2 (M+1) 477 4,96
- 751
-
imagen661 318,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 8,39 (d, J = 6,8 Hz, 1H), 7,89-8,02 (m, 4H), 7,47 (dt, J = 1,2/6,8 Hz, 1H), 7,29 (d, J=8,8 Hz, 2H), 7,04 (d, J = 8,0 Hz, 2H), 6,61 (d, J = 8,4 Hz, 2H), 2,24 (s, 3H) 1,792 4,55
- 752
-
imagen662 370,8 (M+1) 1,619 2,381
- 753
- 336,2 (M+1) RMN 1H (400 MHz, CD3OD): δ 7,65-7,68 (m, 2H), 7,19 (t, J = 8,8 Hz, 2H), 7,03 (d, J = 8,4 Hz, 2H), 6,62 (dd, J = 2,0/6,4 Hz, 1H), 4,00-4,05 (m, 1H), 3,35-3,38 (m, 0,376 0,592
- 1H), 3,17-3,24 (m, 1H), 3,05-3,14 (m, 1H), 2,24 (s, 3H), 2,12-2,21 (m, 2H), 1,67-1,77 (m, 1H), 1,12 (d, J = 6,4 Hz, 3H)
- 754
-
imagen663 374,8 (M+1) 0,104 0,19
Ensayos
Los compuestos de la invención se pueden ensayar para medir su capacidad de inhibir la proliferación de la 5 parasitemia en eritrocitos infectados. La proliferación se cuantifica por adición del colorante SYBR Green I (INVITROGEN)® que tienen una elevada afinidad por el ADN bicatenario.
El siguiente ensayo ilustra la invención sin limitar de forma alguna el alcance de la invención. Este ensayo de proliferación de parásitos mide el aumento en el contenido de ADN de parásito usando un colorante de intercalación en
10 el ADN, SYBR Green®.
La cepa 3D7 de P. falciparum se hizo crecer en un medio de cultivo completo hasta que la parasitemia alcanzó de 3 % al 8 % en eritrocitos humanos O+. 20 µl del medio de cribado se dispensó en placas de ensayo de 384 pocillos. 50 nl de los compuestos de la invención (en DMSO), incluyendo los controles antipalúdicos (mefloquina, pirimetamina y 15 artemisinina), se transfirieron a continuación a las placas de ensayo, así como el DMSO solo para servir como control negativo de la inhibición. A continuación una suspensión de 30 µl de eritrocitos infectados con P. falciparum 3d7 en medio de selección se dispensaron a las placas de ensayo de forma que el hematocrito final es 2,5 % con una parasitemia final de 0,3 %. Las placas se colocaron en una incubadora a 37 ºC durante 72 horas en un entorno con bajo contenido en oxígeno que contiene una mezcla de gases de N2 al93 %,CO2 al 4 %, y O2 al 3 %. 10 µl de tampón
20 de lisis (saponina, triton-X, EDTA) que contenía una solución 10X de SYBR Green I® en medio RPMI se dispensó a las placas. Las placas se taparon y se mantuvieron a temperatura ambiente durante toda la noche para la lisis de los eritrocitos infectados. Se midió la intensidad de la fluorescencia (excitación 425 nm, emisión 530 nm) usando el sistema Envision™ (Perkin Elmer). El porcentaje de inhibición del 50 %, CE50, se calcula para cada compuesto.
25 Los compuestos de la invención tienen un valor de CE50 de 10 µM o menos, preferentemente menos de 1 µM, 750 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM y 50 nM. Los compuestos de la invención pueden retrasar significativamente el aumento de la parasitemia.
Claims (1)
-
imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 imagen7 imagen8 imagen9 imagen10 imagen11 imagen12 imagen13 imagen14 imagen15 imagen16
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- 2012-01-09 EC EC2012011585A patent/ECSP12011585A/es unknown
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- 2012-01-19 CO CO12007883A patent/CO6491060A2/es active IP Right Grant
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2013
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2014
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2015
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