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AR114150A1 - DOPAMINE-b-HYDROXYLASE INHIBITORS - Google Patents

DOPAMINE-b-HYDROXYLASE INHIBITORS

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Publication number
AR114150A1
AR114150A1 ARP180103525A ARP180103525A AR114150A1 AR 114150 A1 AR114150 A1 AR 114150A1 AR P180103525 A ARP180103525 A AR P180103525A AR P180103525 A ARP180103525 A AR P180103525A AR 114150 A1 AR114150 A1 AR 114150A1
Authority
AR
Argentina
Prior art keywords
hydrogen
optionally substituted
alkyl
membered
methyl
Prior art date
Application number
ARP180103525A
Other languages
Spanish (es)
Inventor
Francisco Cardona
Da Silva Patricio Manuel Vieira Araujo Soares
Pedro Nuno Leal Palma
Tino Rossi
Alexander Beliaev
Laszlo Erno Kiss
Original Assignee
Bial-Portela & Ca Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bial-Portela & Ca Sa filed Critical Bial-Portela & Ca Sa
Publication of AR114150A1 publication Critical patent/AR114150A1/en

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Abstract

La presente solicitud se refiere a: (a) compuestos de la fórmula (1) (con R¹, R⁴ a R⁶, n y A como se definieron con anterioridad) y sus sales o solvatos farmacéuticamente aceptables que son de utilidad como inhibidores de dopamina-b-hidroxilasa; (b) composiciones farmacéuticas que comprenden tales compuestos, sales o solvatos; (c) el uso de tales compuestos, sales o solvatos en terapia; (d) métodos terapéuticos de tratamiento que usan tales compuestos, sales o solvatos ; y (e) procesos e intermediarios de utilidad para la síntesis de tales compuestos. Reivindicación 1: Un compuesto de la fórmula (1) o una de sus sales o solvatos farmacéuticamente aceptables, en donde: R¹ es hidrógeno, alquilo C₁₋₆, alquilo C₁₋₆ parcial o totalmente deuterado o cicloalquilo C₃₋₆; R⁴ es hidrógeno o alquilo C₁₋₃; R⁵ es hidrógeno; o R⁴ y R⁵ se combinan, junto con los átomos de carbono a los que están unidos, para formar un anillo ciclopropilo; R⁶ es -COOH, -CHO o -(CH₂)ₘ-X, en donde: m es 1, 2 ó 3 y un resto -CH₂- dentro de -(CH₂)ₘ- puede y estar opcionalmente reemplazado por un resto de fórmula (2); X es hidroxi, alcoxi C₁₋₃, ciano, -N=CH(NHCN)(NH₂), -NH-C(pirrolidin-1-il)=NCN, heteroarilo de 5 ó 6 miembros opcionalmente sustituido con un grupo metilo, fenilo, -SO₂-R⁷, -NR⁸R⁹, -CO₂R¹⁰, -CH(CO₂R¹⁰)₂, -CONR¹¹R¹² o -NR¹³COR¹⁴; en donde: R⁷ es alquilo C₁₋₃; R⁸ es hidrógeno o alquilo C₁₋₃; R⁹ es hidrógeno, alquilo C₁₋₄ opcionalmente sustituido con hasta tres sustituyentes de fluoro o con un sustituyente seleccionado del grupo que consiste en hidroxi, metilsulfonilo, cicloalquilo C₃₋₆, fenilo, heterociclilo de 5 ó 6 miembros y heteroarilo de 5 ó 6 miembros opcionalmente sustituido con un sustituyente de metilo, cicloalquilo C₃₋₆, heteroarilo de 5 ó 6 miembros, o heterociclilo de 5 ó 6 miembros opcionalmente sustituido con uno o dos sustituyentes de oxo; o R⁸ y R⁹ se combinan junto con el átomo de N al que están unidos para formar un grupo N-heterociclilo de 5 ó 6 miembros opcionalmente sustituido con un sustituyente seleccionado de metilo, trifluorometilo, hidroxi, hidroximetilo, metoximetilo, metilsulfonilo, amido, (N,N-dimetil)acetamida y piridilo o con uno o dos sustituyentes seleccionados de fluoro y oxo o un grupo heteroespirociclilo de 9 ó 10 miembros; R¹⁰ es hidrógeno o alquilo C₁₋₃; R¹¹ es hidrógeno o alquilo C₁₋₃; R¹² es hidrógeno, alquilo C₁₋₄ opcionalmente sustituido con hasta tres sustituyentes de fluoro o con un sustituyente seleccionado del grupo que consiste en ciano, hidroxi, metilsulfonilo, alcoxi C₁₋₂, dimetilamino, cicloalquilo C₃₋₆, fenilo, heteroarilo de 5 ó 6 miembros opcionalmente sustituido con un sustituyente de metilo y heterociclilo de 5 ó 6 miembros opcionalmente sustituido con un grupo t-Boc o con uno o dos sustituyentes de fluoro, cicloalquilo C₃₋₆ opcionalmente sustituido con un sustituyente seleccionado del grupo que consiste en ciano, hidroxi, hidroximetilo y oxo, ciano, metilsulfonilo, CH₂COO(alquilo C₁₋₃), heteroarilo de 5 ó 6 miembros opcionalmente sustituido con un sustituyente de metilo, heterociclilo de 4, 5 ó 6 miembros opcionalmente sustituido con uno o dos sustituyentes seleccionados de oxo y metilo, CH₂CH(NH₂)(COOH) o CH(CH₃)CONH₂; o R¹¹ y R¹² se combinan junto con el átomo de N al que están unidos para formar un grupo N-heterociclilo de 5 ó 6 miembros opcionalmente sustituido con un sustituyente seleccionado de monoflurometilo, trifluorometilo, hidroxi, hidroximetilo, metoximetilo, metilsulfonilo, ciano, amido, (N,N-dimetil)acetamida y piridilo o con uno o dos sustituyentes seleccionados de fluoro, metilo y oxo u opcionalmente fusionado con un anillo ciclopropilo que puede estar sustituido con uno o dos sustituyentes de metilo o un grupo heteroespirociclilo de 9 ó 10 miembros; R¹³ es hidrógeno o alquilo C₁₋₃; R¹⁴ es alquilo C₁₋₄ opcionalmente sustituido con hasta tres sustituyentes de fluoro o con un sustituyente seleccionado del grupo que consiste en hidroxi, metilsulfonilo, cicloalquilo C₃₋₆ y fenilo, cicloalquilo C₃₋₆, heteroarilo de 5 ó 6 miembros, o heterociclilo de 5 ó 6 miembros opcionalmente sustituido con uno o dos sustituyentes de oxo; A es cicloalquilo C₅₋₇, furanilo, tiofenilo, metiltiofenilo o un compuesto de fórmula (3), en donde: X¹ es hidrógeno, halo o metilo; X¹’ es hidrógeno o halo; X² es hidrógeno, halo o metilo; X²’ es hidrógeno o halo; X³ es hidrógeno o fluoro; n es 0 ó 1 y cuando n es 0 un enlace simple se une con los átomos de carbono a los que el resto de CH₂ se uniría si n fuera 1; para usar en terapia.The present application refers to: (a) compounds of formula (1) (with R¹, R⁴ to R⁶, n and A as defined above) and their pharmaceutically acceptable salts or solvates that are useful as dopamine-b inhibitors -hydroxylase; (b) pharmaceutical compositions comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; (d) therapeutic methods of treatment using such compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of such compounds. Claim 1: A compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ is hydrogen, C₁₋₆ alkyl, partially or fully deuterated C₁₋₆ alkyl or C₃₋₆ cycloalkyl; R⁴ is hydrogen or C₁₋₃ alkyl; R⁵ is hydrogen; or R⁴ and R⁵ combine, together with the carbon atoms to which they are attached, to form a cyclopropyl ring; R⁶ is -COOH, -CHO or - (CH₂) ₘ-X, where: m is 1, 2 or 3 and a -CH₂- moiety within - (CH₂) ₘ- can and can be optionally replaced by a moiety of formula (two); X is hydroxy, C₁₋₃ alkoxy, cyano, -N = CH (NHCN) (NH₂), -NH-C (pyrrolidin-1-yl) = NCN, 5- or 6-membered heteroaryl optionally substituted with a methyl group, phenyl , -SO₂-R⁷, -NR⁸R⁹, -CO₂R¹⁰, -CH (CO₂R¹⁰) ₂, -CONR¹¹R¹² or -NR¹³COR¹⁴; where: R⁷ is C₁₋₃ alkyl; R⁸ is hydrogen or C₁₋₃ alkyl; R⁹ is hydrogen, C₁₋₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C₃₋₆ cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, and 5- or 6-membered heteroaryl optionally substituted with a methyl, C₃₋₆ cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl substituent optionally substituted with one or two oxo substituents; or R⁸ and R⁹ combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with a substituent selected from methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, amido, ( N, N-dimethyl) acetamide and pyridyl or with one or two substituents selected from fluoro and oxo or a 9 or 10 membered heterospyrocyclyl group; R¹⁰ is hydrogen or C₁₋₃ alkyl; R¹¹ is hydrogen or C₁₋₃ alkyl; R¹² is hydrogen, C₁₋₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of cyano, hydroxy, methylsulfonyl, C₁₋₂ alkoxy, dimethylamino, C₃₋₆ cycloalkyl, phenyl, 5 or 5-heteroaryl 6-membered optionally substituted with a 5 or 6-membered methyl and heterocyclyl substituent optionally substituted with a t-Boc group or with one or two fluoro substituents, C₃₋₆ cycloalkyl optionally substituted with a substituent selected from the group consisting of cyano, hydroxy, hydroxymethyl and oxo, cyano, methylsulfonyl, CH₂COO (C₁₋₃ alkyl), 5- or 6-membered heteroaryl optionally substituted with a methyl substituent, 4-, 5-, or 6-membered heterocyclyl optionally substituted with one or two substituents selected from oxo and methyl, CH₂CH (NH₂) (COOH) or CH (CH₃) CONH₂; or R¹¹ and R¹² combine together with the N atom to which they are attached to form a 5- or 6-membered N-heterocyclyl group optionally substituted with a substituent selected from monofluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxymethyl, methylsulfonyl, cyano, amido , (N, N-dimethyl) acetamide and pyridyl or with one or two substituents selected from fluoro, methyl and oxo or optionally fused with a cyclopropyl ring that may be substituted with one or two methyl substituents or a 9 or 10 heterospirocyclyl group members; R¹³ is hydrogen or C₁₋₃ alkyl; R¹⁴ is C₁₋₄ alkyl optionally substituted with up to three fluoro substituents or with one substituent selected from the group consisting of hydroxy, methylsulfonyl, C₃₋₆ cycloalkyl and phenyl, C₃₋₆ cycloalkyl, 5- or 6-membered heteroaryl, or heterocyclyl from 5 or 6 membered optionally substituted with one or two oxo substituents; A is C₅₋₇ cycloalkyl, furanyl, thiophenyl, methylthiophenyl, or a compound of formula (3), wherein: X¹ is hydrogen, halo, or methyl; X¹ 'is hydrogen or halo; X² is hydrogen, halo, or methyl; X² 'is hydrogen or halo; X³ is hydrogen or fluoro; n is 0 or 1 and when n is 0 a single bond is attached to the carbon atoms to which the CH₂ remainder would attach if n were 1; for use in therapy.

ARP180103525A 2017-12-04 2018-12-03 DOPAMINE-b-HYDROXYLASE INHIBITORS AR114150A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GBGB1720189.8A GB201720189D0 (en) 2017-12-04 2017-12-04 Dopamine-B-hydroxylase inhibitors

Publications (1)

Publication Number Publication Date
AR114150A1 true AR114150A1 (en) 2020-07-29

Family

ID=60950212

Family Applications (1)

Application Number Title Priority Date Filing Date
ARP180103525A AR114150A1 (en) 2017-12-04 2018-12-03 DOPAMINE-b-HYDROXYLASE INHIBITORS

Country Status (2)

Country Link
AR (1) AR114150A1 (en)
GB (1) GB201720189D0 (en)

Also Published As

Publication number Publication date
GB201720189D0 (en) 2018-01-17

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