AR096041A1 - CARBOXYLIC ACID DERIVATIVES RENT REPLACED AS RPG AGONISTS - Google Patents

CARBOXYLIC ACID DERIVATIVES RENT REPLACED AS RPG AGONISTS

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AR096041A1
AR096041A1 ARP140101621A ARP140101621A AR096041A1 AR 096041 A1 AR096041 A1 AR 096041A1 AR P140101621 A ARP140101621 A AR P140101621A AR P140101621 A ARP140101621 A AR P140101621A AR 096041 A1 AR096041 A1 AR 096041A1
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alkyl
aryl
independently selected
halide
hydrogen
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ARP140101621A
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Spanish (es)
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Halder Somnath
Sharma Rajiv
Kumar Sanjay
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Piramal Entpr Ltd
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    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

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Abstract

El presente se relaciona con los derivados del ácido alquilo carboxílico (los compuestos de fórmula (1)), los procesos para su preparación, las composiciones farmacéuticas que contienen dichos compuestos, su uso como agonista GPR (receptor asociado de proteína G), particularmente como agonista GPR40 y métodos de uso de estos compuestos en el tratamiento con GPR40 de enfermedades o condiciones. Reivindicación 1: Un compuesto de fórmula (1); en el que, Z es -COOR¹ o -CON(R¹)₂; R¹ es hidrógeno o alquilo C₁₋₆; R² y R³ juntos forman un heterociclilo de 3- a 9-miembros saturado o parcialmente insaturado que contiene uno o dos heteroátomos seleccionados independientemente entre el grupo compuesto por O, N y S; o R² y R³ juntos forman un cicloalquilo C₄₋₈ saturado o parcialmente insaturado; R⁴ en cada ocurrencia es seleccionado independientemente entre el grupo que consiste de hidrógeno, alquilo C₁₋₆, halógeno, haluro-alquilo C₁₋₆, hidroxi, -O-alquilo C₁₋₆, arilo C₆₋₁₀, amino, ciano, nitro, -C(O)R⁹ o -S(O)ₚR⁶; Rᵛ y Rʷ son seleccionados independientemente entre el grupo que consiste de hidrógeno, halógeno, hidroxi, alquilo C₁₋₆, haluro-alquilo C₁₋₆, -O-alquilo C₁₋₆, amino, ciano, -C(O)R⁹, cicloalquilo C₃₋₈, arilo C₆₋₁₀, heterociclilo y heteroarilo; Rˣ y Rʸ son seleccionados independientemente entre el grupo que consiste de A-CH(R⁷)-X, A-X-CH(R⁷) y R⁵; dado que al menos uno de Rˣ y Rʸ es A-CH(R⁷)-X o A-X-CH(R⁷); R⁵ es hidrógeno, alquilo C₁₋₆, halógeno, haluro-alquilo C₁₋₆, hidroxi, -O-alquilo C₁₋₆, arilo C₆₋₁₀, amino, ciano, nitro, -C(O)R⁹ o -S(O)ₚR⁶; R⁶ es hidrógeno, alquilo C₁₋₆, amino, mono-alquilamino o di-alquilamino; R⁷ es hidrógeno o alquilo C₁₋₆; X es CR⁸R⁸, O, NR⁸ o S; Q es O, NR⁸ o S(O)ₚ; R⁸ en cada ocurrencia es seleccionado independientemente entre el grupo que consiste de hidrógeno, alquilo C₁₋₆, cicloalquilo C₃₋₈, arilo C₆₋₁₀, heterociclilo, heteroarilo, ciano, -C(O)alquilo C₁₋₆, -C(O)O-alquilo C₁₋₆, -C(O)NH₂ y S(O)ₚR⁶; en el que R⁶ es según se lo definió más arriba; R⁹ es alquilo C₁₋₆, -O-alquilo C₁₋₆, hidroxi o amino; A es cicloalquilo C₃₋₈, arilo C₆₋₁₀, heterociclilo, heteroarilo, un resto de fórmula (2), de fórmula (3), o de fórmula (4); R¹⁰, R¹¹, R¹² y R¹³ son seleccionados independientemente entre el hidrógeno y alquilo C₁₋₆; o R¹⁰ y R¹¹ pueden formar juntos un anillo de cicloalquilo C₃₋₈ y R¹² y R¹³ son hidrógeno; o R¹² y R¹³ pueden formar juntos un anillo de cicloalquilo C₃₋₈ y R¹⁰ y R¹¹ son hidrógeno; R¹⁴ en cada ocurrencia es seleccionado independientemente entre el grupo que consiste de hidrógeno, alquilo C₁₋₆, halógeno, haluro-alquilo C₁₋₆, hidroxi, -O-alquilo C₁₋₆, -O-cicloalquilo C₃₋₈, -O-alquilo C₁₋₆heterociclilo, -O-heterociclilo, haluro-alcoxi C₁₋₆, -O-alquilo C₁₋₆-S(O)ₚR⁶, arilo C₆₋₁₀, -O-alquilo C₁₋₆arilo C₆₋₁₀, amino, ciano, nitro, -C(O)R⁹, -S(O)ₚR⁶, -(CH₂)ₛNR¹⁵R¹⁶ y -X(CH₂)ₛNR¹⁵R¹⁶; en el que X, R⁶ y R⁹ son según se los define más arriba; R¹⁵ y R¹⁶ son seleccionados independientemente del grupo que consiste de hidrógeno, alquilo C₁₋₆ y -(CH₂)ₜOH; n es un entero del 1 al 3; m es un entero del 1 al 4; p es un entero del 0 al 2 ; q es un entero del 1 al 4; r es un entero del 1 al 5; s es un entero del 1 al 4; t es un entero del 1 al 4; * indica el punto de unión a -CH de CH(R⁷)-X o X de -X-CH(R⁷); en el que alquilo C₁₋₆ es insustituido o sustituido con uno o más grupos seleccionados independientemente entre el grupo que consiste de alquilo C₁₋₆, alquenilo C₂₋₈, alquinilo C₂₋₈, halógeno, haluro-alquilo C₁₋₆, hidroxi, -O-alquilo C₁₋₆, cicloalquilo C₃₋₈, arilo C₆₋₁₀, heterociclilo, heteroarilo, amino, ciano, nitro, -C(O)R⁹ y -O-alquilo C₁₋₆-S(O)ₚR⁶; en el que R⁶, R⁹, y p son según se los define más arriba; -O-alquilo C₁₋₆ es insustituido o sustituido con uno o más grupos seleccionados independientemente entre el grupo que consiste de alquilo C₁₋₆, cicloalquilo C₃₋₈, arilo C₆₋₁₀, heterociclilo, hidroxi, halógeno, amino, ciano, -alquilo C₁₋₆-S(O)ₚR⁶, -S(O)ₚR⁶, -NR¹⁵R¹⁶ y -(CH₂)ₛNR¹⁵R¹⁶; en el que R⁶, R¹⁵, R¹⁶, p y s son según se los define más arriba; arilo C₆₋₁₀ es insustituido o sustituido con uno o más grupos seleccionados independientemente entre el grupo que consiste de alquilo C₁₋₆, alquenilo C₂₋₈, alquinilo C₂₋₈, halógeno, haluro-alquilo C₁₋₆, hidroxi, -O-alquilo C₁₋₆, haluro-alcoxi C₁₋₆, cicloalquilo C₃₋₈, arilo C₆₋₁₀, -O-arilo C₆₋₁₀, alquilo C₁₋₆heterociclilo, heterociclilo, heteroarilo, amino, ciano, nitro, -C(O)R⁹, -O-alquilo C₁₋₆-S(O)ₚR⁶ y -O(CH₂)ₛC[=N-O-alquilo C₁₋₆]R⁸; en el que R⁶, R⁸, R⁹, s y p son según se los define más arriba; heterociclilo es un anillo de entre 3 y 9 miembros, el cual es insustituido o sustituido con uno o más grupos seleccionados independientemente entre el grupo que consiste de alquilo C₁₋₆, alquenilo C₂₋₈, alquinilo C₂₋₈, halógeno, haluro-alquilo C₁₋₆, hidroxi, -O-alquilo C₁₋₆, haluro-alcoxi C₁₋₆, cicloalquilo C₃₋₈, arilo C₆₋₁₀, heterociclilo, heteroarilo, amino, ciano, nitro, -alquilo C₁₋₆-OH, alquilo C₁₋₆-O-alquilo C₁₋₆, -C(O)R⁹ y -O-alquilo C₁₋₆-S(O)ₚR⁶; en el que R⁶, R⁹, y p son según se los define más arriba; heteroarilo es un anillo de entre 3 y 10 miembros, el cual es insustituido o sustituido con uno o más grupos seleccionados independientemente entre el grupo que consiste de alquilo C₁₋₆, alquenilo C₂₋₈, alquinilo C₂₋₈, halógeno, haluro-alquilo C₁₋₆, hidroxi, -O-alquilo C₁₋₆, haluro-alcoxi C₁₋₆, cicloalquilo C₃₋₈, arilo C₆₋₁₀, heterociclilo, heteroarilo, amino, ciano, nitro, -C(O)R⁹ y -O-alquilo C₁₋₆-S(O)ₚR⁶; en el que R⁶, R⁹, y p son según se los define más arriba; halógeno es cloro, bromo, iodo, o fluoro; o una forma isotópica, un estereoisómero, un tautómero, una sal farmacéuticamente aceptable, un solvato farmacéuticamente aceptable, un profármaco, un polimorfo, N-óxido, S-óxido, o un isóstero de ácido carboxílico de él.This is related to carboxylic acid derivatives (the compounds of formula (1)), the processes for their preparation, pharmaceutical compositions containing said compounds, their use as a GPR agonist (G protein associated receptor), particularly as GPR40 agonist and methods of using these compounds in the treatment with GPR40 of diseases or conditions. Claim 1: A compound of formula (1); where, Z is -COOR¹ or -CON (R¹) ₂; R¹ is hydrogen or C₁₋₆ alkyl; R² and R³ together form a 3- or 9-membered saturated or partially unsaturated heterocyclyl containing one or two heteroatoms independently selected from the group consisting of O, N and S; or R² and R³ together form a saturated or partially unsaturated C₄₋₈ cycloalkyl; R⁴ at each occurrence is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen, halide-C alquilo alkyl, hydroxy, -O-C₁₋₆ alkyl, C₆₋₁₀ aryl, amino, cyano, nitro, -C (O) R⁹ or -S (O) ₚR⁶; Rᵛ and Rʷ are independently selected from the group consisting of hydrogen, halogen, hydroxy, C₁₋₆ alkyl, halide-C alquilo alkyl, -O-C₁₋₆ alkyl, amino, cyano, -C (O) R⁹, cycloalkyl C₃₋₈, C₆₋₁₀ aryl, heterocyclyl and heteroaryl; Rˣ and Rʸ are independently selected from the group consisting of A-CH (R⁷) -X, A-X-CH (R⁷) and R⁵; since at least one of Rˣ and Rʸ is A-CH (R⁷) -X or A-X-CH (R⁷); R⁵ is hydrogen, C₁₋₆ alkyl, halogen, halide-C alquilo alkyl, hydroxy, -O-C₁₋₆ alkyl, C₆₋₁₀ aryl, amino, cyano, nitro, -C (O) R⁹ or -S (O ) ₚR⁶; R⁶ is hydrogen, C₁₋₆ alkyl, amino, mono-alkylamino or di-alkylamino; R⁷ is hydrogen or C₁₋₆ alkyl; X is CR⁸R⁸, O, NR⁸ or S; Q is O, NR⁸ or S (O) ₚ; R⁸ at each occurrence is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, heterocyclyl, heteroaryl, cyano, -C (O) C₁₋₆ alkyl, -C (O ) O-C₁₋₆ alkyl, -C (O) NH₂ and S (O) ₚR⁶; in which R⁶ is as defined above; R⁹ is C₁₋₆ alkyl, -O-C₁₋₆ alkyl, hydroxy or amino; A is C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, heterocyclyl, heteroaryl, a moiety of formula (2), of formula (3), or of formula (4); R¹⁰, R¹¹, R¹² and R¹³ are independently selected from hydrogen and C₁₋₆ alkyl; or R¹⁰ and R¹¹ can together form a cycloalkyl ring C₃₋₈ and R¹² and R¹³ are hydrogen; or R¹² and R¹³ can together form a cycloalkyl ring C₃₋₈ and R¹⁰ and R¹¹ are hydrogen; R¹⁴ at each occurrence is independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen, halide-C alquilo alkyl, hydroxy, -O-C₁₋₆ alkyl, -O-C₃₋₈ cycloalkyl, -O- C₁₋₆heterocyclyl alkyl, -O-heterocyclyl, halide-C₁₋₆ alkoxy, -O-C₁₋₆-S (O) alkyl ₚR alquilo, C₆₋₁₀ aryl, -O-C₁₋₆aryl C₆₋₁₀ alkyl, amino, cyano , nitro, -C (O) R⁹, -S (O) ₚR⁶, - (CH₂) ₛNR¹⁵R¹⁶ and -X (CH₂) ₛNR¹⁵R¹⁶; wherein X, R⁶ and R⁹ are as defined above; R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen, C₁₋₆ alkyl and - (CH₂) ₜOH; n is an integer from 1 to 3; m is an integer from 1 to 4; p is an integer from 0 to 2; q is an integer from 1 to 4; r is an integer from 1 to 5; s is an integer from 1 to 4; t is an integer from 1 to 4; * indicates the -CH junction point of CH (R⁷) -X or X of -X-CH (R⁷); wherein C alquilo alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₁₋₆ alkyl halide, hydroxy, -O-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C (O) R⁹ and -O-C₁₋₆-S (O) ₚR⁶ alkyl; in which R⁶, R⁹, and p are as defined above; -O-C₁₋₆ alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, heterocyclyl, hydroxy, halogen, amino, cyano, - C₁₋₆-S (O) ₚR⁶, -S (O) ₚR⁶, -NR¹⁵R¹⁶ and - (CH₂) ₛNR¹⁵R¹⁶ alkyl; wherein R⁶, R¹⁵, R¹⁶, p and s are as defined above; C₆₋₁₀ aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, C₁₋₆ alkyl halide, hydroxy, -O- C₁₋₆ alkyl, Curo halide-alkoxy, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, -O-C₆₋₁₀ aryl, C₁₋₆heterocyclyl alkyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C (O) R⁹, -O-C₁₋₆-S (O) alkyl ₚR⁶ and -O (CH₂) ₛC [= NO-C₁₋₆ alkyl] R⁸; wherein R⁶, R⁸, R⁹, s and p are as defined above; heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, halide-alkyl C₁₋₆, hydroxy, -O-C₁₋₆ alkyl, Curo halide-alkoxy, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C₁₋₆-OH alkyl, alkyl C₁₋₆-O-C₁₋₆ alkyl, -C (O) R⁹ and -O-C₁₋₆-S (O) alkyl ₚR⁶; in which R⁶, R⁹, and p are as defined above; heteroaryl is a 3-10 membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, halogen, halide-alkyl C₁₋₆, hydroxy, -O-C₁₋₆ alkyl, Curo halide-alkoxy, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C (O) R⁹ and -O -C₁₋₆-S (O) ₚR⁶ alkyl; in which R⁶, R⁹, and p are as defined above; halogen is chlorine, bromine, iodine, or fluoro; or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or an isoster of carboxylic acid thereof.

ARP140101621A 2013-04-17 2014-04-16 CARBOXYLIC ACID DERIVATIVES RENT REPLACED AS RPG AGONISTS AR096041A1 (en)

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