AR113820A1 - Compuestos bicíclicos en puente como moduladores del receptor farnesoide x - Google Patents
Compuestos bicíclicos en puente como moduladores del receptor farnesoide xInfo
- Publication number
- AR113820A1 AR113820A1 ARP180103177A ARP180103177A AR113820A1 AR 113820 A1 AR113820 A1 AR 113820A1 AR P180103177 A ARP180103177 A AR P180103177A AR P180103177 A ARP180103177 A AR P180103177A AR 113820 A1 AR113820 A1 AR 113820A1
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- Prior art keywords
- independently
- alkyl
- haloalkyl
- nrcrc
- aminoalkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title abstract 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 12
- 125000000623 heterocyclic group Chemical group 0.000 abstract 12
- 125000004103 aminoalkyl group Chemical group 0.000 abstract 11
- 125000001188 haloalkyl group Chemical group 0.000 abstract 11
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 10
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 abstract 10
- 125000003118 aryl group Chemical group 0.000 abstract 9
- -1 cyano, hydroxyl Chemical group 0.000 abstract 9
- 229910052739 hydrogen Inorganic materials 0.000 abstract 9
- 239000001257 hydrogen Substances 0.000 abstract 9
- 125000004438 haloalkoxy group Chemical group 0.000 abstract 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 8
- 125000003545 alkoxy group Chemical group 0.000 abstract 7
- 125000004452 carbocyclyl group Chemical group 0.000 abstract 7
- 125000005843 halogen group Chemical group 0.000 abstract 7
- 229910052760 oxygen Inorganic materials 0.000 abstract 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 7
- 229910052717 sulfur Inorganic materials 0.000 abstract 7
- 125000003282 alkyl amino group Chemical group 0.000 abstract 6
- 125000001072 heteroaryl group Chemical group 0.000 abstract 6
- 229910052757 nitrogen Inorganic materials 0.000 abstract 5
- 125000002947 alkylene group Chemical group 0.000 abstract 4
- 125000004474 heteroalkylene group Chemical group 0.000 abstract 4
- 102100038495 Bile acid receptor Human genes 0.000 abstract 3
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 abstract 3
- 125000004043 oxo group Chemical group O=* 0.000 abstract 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 2
- 229910052799 carbon Inorganic materials 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 abstract 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 2
- 150000003839 salts Chemical class 0.000 abstract 2
- 239000012453 solvate Substances 0.000 abstract 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 abstract 1
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 abstract 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 abstract 1
- 125000004011 3 membered carbocyclic group Chemical group 0.000 abstract 1
- 125000001845 4 membered carbocyclic group Chemical group 0.000 abstract 1
- 206010016654 Fibrosis Diseases 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 208000001132 Osteoporosis Diseases 0.000 abstract 1
- 206010052779 Transplant rejections Diseases 0.000 abstract 1
- 239000000556 agonist Substances 0.000 abstract 1
- 125000004450 alkenylene group Chemical group 0.000 abstract 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 abstract 1
- 125000004414 alkyl thio group Chemical group 0.000 abstract 1
- 125000004419 alkynylene group Chemical group 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 abstract 1
- 125000005884 carbocyclylalkyl group Chemical group 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 abstract 1
- 230000008482 dysregulation Effects 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 230000004761 fibrosis Effects 0.000 abstract 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 abstract 1
- 125000004992 haloalkylamino group Chemical group 0.000 abstract 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 abstract 1
- 208000027866 inflammatory disease Diseases 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 230000001575 pathological effect Effects 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P13/00—Drugs for disorders of the urinary system
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
Compuestos de la fórmula (1), o estereoisómeros, tautómeros, o sales o solvatos de aquellos aceptables desde el punto de vista farmacéutico, en donde todas las variables son como se definen en la presente. Estos compuestos modulan la actividad del receptor farnesoide X (FXR), por ejemplo, como agonistas. También composiciones farmacéuticas que comprenden estos compuestos y métodos para tratar una enfermedad, trastorno o afección asociados a la desregulación del FXR, tales como fibrosis patológica, rechazo de trasplante, cáncer, osteoporosis y trastorno inflamatorio, mediante el uso de compuestos y composiciones farmacéuticas. Reivindicación 1: Un compuesto caracterizado por la fórmula (1), o un estereoisómero, un tautómero, una sal o un solvato de aquel aceptables desde el punto de vista farmacéutico; en donde: el anillo B es un cicloheteroalquilo o cicloalquilo en puente de 5 a 8 miembros; y el punto de unión a L¹ o Z es un átomo de carbono; X¹ y X⁴ son, cada uno independientemente, C o N; X² y X³ son, cada uno independientemente, CR³, N, NR⁴, O ó S; E¹ y E³ son, cada uno independientemente, un enlace covalente, O, S, N, NR⁶, CR⁵ o CR⁵ᵃR⁵ᵇ; E² es O, S, N, NR⁸, CR⁷ o CR⁷ᵃR⁷ᵇ; en donde (E¹ y E²) o (E³ y E²) forman un enlace simple o un enlace doble; siempre que [1] los enlaces entre (E¹ y E²) y (E³ y E²) no sean ambos enlaces dobles; y [2] no más de uno de E¹, E² y E³ sea O, S, N o NR⁸; L¹ es un enlace covalente, O, S, NR¹⁶, -C(S)NH-, C₁₋₃ alquileno, C₁₋₃ heteroalquileno, C₂₋₄ alquenileno, C₂₋₄ alquinileno, arilo, o un heteroarilo de 5 a 6 miembros que contiene 1 a 4 heteroátomos seleccionados independientemente de N, O y S; en donde el alquileno, heteroalquileno, arilo y heteroarilo se sustituyen, cada uno independientemente, con 0 a 3 R⁹; Z es arilo de 6 a 10 miembros, heteroarilo de 5 a 10 miembros, carbociclilo de 3 a 10 miembros o heterociclilo de 4 a 10 miembros, en donde el arilo, heteroarilo, carbociclilo y heterociclilo se sustituyen, independientemente, con 0 a 5 R¹⁰; L² son, cada uno independientemente, un enlace covalente, O, S, NR¹⁷, C₁₋₃ alquileno o C₁₋₃ heteroalquileno, en donde el alquileno y el heteroalquileno se sustituyen, independientemente, con 0 a 3 R¹¹; RX es -(CR¹²ᵃR¹²ᵇ)ₑ-RZ o -O(CR¹²ᵃR¹²ᵇ)ₑ-RZ; e es 0 ó 1; RZ se selecciona de -CN, -OH, -O(O)OR¹³, -C(O)NR¹⁴ᵃR¹⁴ᵇ, o un resto del grupo de fórmulas (2); Rᵉ es C₁₋₆ alquilo, C₃₋₆ cicloalquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo o fenilo; R¹ es C₁₋₆ alquilo, C₃₋₅ cicloalquilo o C₄₋₆ heterociclilo, en donde el alquilo, cicloalquilo y heterociclilo se sustituyen, cada uno independientemente, con 0 a 3 R¹⁵; R² es arilo de 6 a 10 miembros, heteroarilo de 5 a 10 miembros, carbociclilo de 3 a 10 miembros o heterociclilo de 4 a 10 miembros, en donde el arilo, heteroarilo, carbociclilo y heterociclilo se sustituyen, independientemente, con 0 a 5 R¹⁶; R³ y R⁷ son, cada uno independientemente, hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; R⁴, R⁶, R⁸, R¹⁶ y R¹⁷ son, cada uno independientemente, hidrógeno, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo o haloalcoxialquilo; R⁵ es hidrógeno, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo o haloalcoxialquilo; R⁵ᵃ, R⁵ᵇ, R⁷ᵃ y R⁷ᵇ son, cada uno independientemente, hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; R⁹ y R¹¹ son, cada uno independientemente, halo, oxo, ciano, hidroxilo, amino, C₁₋₆ alquilo, C₃₋₆ cicloalquilo, C₄₋₆ heterociclilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; a es un entero de 0, 1, 2 ó 3; R¹⁰ y R¹⁶ son, cada uno independientemente, halo, ciano, hidroxilo, amino, oxo, -ORᵃ, -SRᵃ, =S, -NRᶜRᶜ, =NH, =N-OH, =NRᵃ, =N-ORᵃ, -NO₂, -S(O)₂Rᵃ, -S(O)₂NHRᵇ, -S(O)₂NRᶜRᶜ, -S(O)₂ORᵇ, -OS(O)₂Rᵇ, -OS(O)₂ORᵇ, -P(O)(ORᵇ)(ORᵇ), -C(O)Rᵇ, -C(NRᵇ)Rᵇ, -C(O)ORᵇ, -C(O)NRᶜRᶜ, -C(NRᵇ)NRᶜRᶜ, -OC(O)Rᵇ, -NRᵇC(O)Rᵇ, -OC(O)ORᵇ, -NRᵇC(O)ORᵇ, -OC(O)NRᶜRᶜ, -NRᵇC(O)NRᶜRᶜ, -NRᵇC(NRᵇ)Rᵇ, -NRᵇC(NRᵇ)NRᶜRᶜ, C₁₋₆ alquilo, C₁₋₆ haloalquilo, arilo, arilalquilo, heteroarilo, carbociclilo o heterociclilo; en donde el alquilo, arilo, heteroarilo, carbociclilo y heterociclilo, en sí mismos o como parte de otro grupo, se sustituyen, cada uno independientemente, con 0 a 5 Rᵈ; Rᵃ se selecciona de C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, arilo, arilalquilo, heteroarilo, heteroarilalquilo, carbociclilo, carbociclilalquilo, heterociclilo y heterociclilalquilo; Rᵇ es, cada uno independientemente, hidrógeno o Rᵃ; Rᶜ es, cada uno independientemente, Rᵇ o, alternativamente, los dos Rᶜ se toman junto con el átomo de nitrógeno al que están unidos para formar un heterociclilo de 4, 5, 6 ó 7 miembros; Rᵈ se seleccionan, cada uno independientemente Rᵃ, alcoxi, haloalcoxi, alquilamino, cicloalquilamino, heterociclilamino, haloalquilo, hidroxialquilo, aminoalquilo, cicloalcoxi, heterocicliloxi, haloalcoxi, alcoxialcoxi, haloalquilamino, alcoxialquilamino, haloalcoxialquilamino, arilamino, aralquilamino, ariloxi, aralquiloxi, heteroariloxi, heteroarilalquiloxi, alquiltio, halo, ciano, hidroxilo, amino, oxo, -ORᵃ, -SRᵃ, =S, -NRᶜRᶜ, =NH, =N-OH, =NRᵃ, =N-ORᵃ, -NO₂, -S(O)₂Rᵃ, -S(O)₂NHRᵇ, -S(O)₂NRᶜRᶜ, -S(O)₂ORᵇ, -OS(O)₂Rᵇ, -OS(O)₂ORᵇ, -P(O)(ORᵇ)(ORᵇ), -C(O)Rᵇ, -C(NRᵇ)Rᵇ, -C(O)ORᵇ, -C(O)NRᶜRᶜ, -C(NRᵇ)NRᶜRᶜ, -OC(O)Rᵇ, -NRᵇC(O)Rᵇ, -OC(O)ORᵇ, -NRᵇC(O)ORᵇ, -NRᵇC(O)NRᶜRᶜ, -NRᵇC(NRᵇ)Rᵇ y -NRᵇC(NRᵇ)NRᶜRᶜ; R¹²ᵃ y R¹²ᵇ son, cada uno independientemente, hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; o, alternativamente, R¹²ᵃ y R¹²ᵇ, junto con los átomos a los que están unidos, forman un anillo carbocíclico o heterocíclico de 3 ó 4 miembros; R¹³ es hidrógeno, C₁₋₁₀ alquilo o glucosilo; R¹⁴ᵃ y R¹⁴ᵇ son, cada uno independientemente, hidrógeno, C₁₋₆ alquilo, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi; y R¹⁵ es hidrógeno, halo, ciano, hidroxilo, amino, C₁₋₆ alquilo, alquilamino, haloalquilo, hidroxialquilo, aminoalquilo, alcoxialquilo, haloalcoxialquilo, alcoxi o haloalcoxi.
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