AR084515A1 - NITROGEN HETEROCICLICAL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME IN THE TREATMENT OF DISEASES ASSOCIATED WITH THE CENTRAL NERVOUS SYSTEM SUCH AS PARKINSON AND ALZHEIMER, BETWEEN OTHER - Google Patents

NITROGEN HETEROCICLICAL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME IN THE TREATMENT OF DISEASES ASSOCIATED WITH THE CENTRAL NERVOUS SYSTEM SUCH AS PARKINSON AND ALZHEIMER, BETWEEN OTHER

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AR084515A1
AR084515A1 ARP110104854A ARP110104854A AR084515A1 AR 084515 A1 AR084515 A1 AR 084515A1 AR P110104854 A ARP110104854 A AR P110104854A AR P110104854 A ARP110104854 A AR P110104854A AR 084515 A1 AR084515 A1 AR 084515A1
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alkyl
amino
pyrimidin
optionally substituted
trifluoromethoxy
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Bjoern Krueger
Holger Kubas
Udo Meyer
Ronalds Zemribo
Ulrich Abel
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Merz Pharma Gmbh & Co Kgaa
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    • 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
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Abstract

Reivindicación 1: Un compuesto caracterizado porque se selecciona entre los de la formula (1), donde X representa CR6(C=O)R7 o NR8; R1 representa H, alquilo C1-6, o F; R2 representa H, alquilo C1-6, o F; o R1 y R2 junto con el átomo de carbono al cual se encuentran unidos forman un grupo carbonilo; o R1 y R2 junto con el átomo de carbono al cual se encuentran unidos forman un anillo de entre 3 y 7 miembros que puede ser saturado o insaturado, donde el anillo opcionalmente puede contener uno o dos heteroátomos seleccionados entre azufre, oxígeno, y nitrógeno y donde el anillo puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alquilo C1-6, alcoxi C1-6, amino, hidroxi, ciano, acilo, alquil C1-6amino, di-(alquil C1-6)amino, alquil C1-6carbonilamino, y oxo; R3 representa H, alquilo C1-6, o F; R4 representa H, alquilo C1-6, o F; o R3 y R4 junto con el átomo de carbono al cual se encuentran unidos forman un anillo de entre 3 y 7 miembros que puede ser saturado o insaturado, donde el anillo opcionalmente puede contener uno o dos heteroátomos seleccionados entre azufre, oxígeno, y nitrógeno y donde el anillo puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alquilo C1-6, alcoxi C1-6, amino, hidroxi, ciano, acilo, alquil C1-6amino, di-(alquil C1-6)amino, alquil C1-6carbonilamino, y oxo; R5 representa una porción monocíclica seleccionada entre arilo, heteroarilo, cicloalquilo C3-6, y heterociclilo; R6 representa H, alquilo C1-6 que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, o F; R7 representa alquilo C1-6, que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di(alquil C1-6)amino, cicloalquilo C3-6, heterociclilo, o NR11R12; o R6 y R7 junto con los átomos de carbono a los cuales se encuentran unidos forman un anillo de entre 3 y 7 miembros que puede ser saturado o insaturado, donde el anillo opcionalmente puede contener uno o dos heteroátomos seleccionados entre azufre, oxígeno, y nitrógeno y donde el anillo puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alquilo C1-6, alcoxi C1-6, amino, hidroxi, ciano, acilo, alquil C1-6amino, di-(alquil C1-6)amino, alquil C1-6carbonilamino, y oxo; R8 representa alquilo C1-6 que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, cicloalquilo C3-6, heterociclilo, arilo, heteroarilo, alquilcarbonilo C1-6 que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, cicloalquil C3-6carbonilo, heterociclilcarbonilo, arilcarbonilo, heteroarilcarbonilo, alcoxicarbonilo C1-6 que puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, aminocarbonilo, N-alquil C1-6aminocarbonilo, donde la porción alquilo puede estar opcionalmente sustituida con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, N,N-di-(alquil C1-6)aminocarbonilo, donde las porciones alquilo pueden estar opcionalmente sustituidas con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, alcoxicarbonilo C1-6, ciano, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, N-alquil C1-6-N-cicloalquil C3-6aminocarbonilo, N-alquil C1-6-N-cicloalquil C3-6-alquil C1-6aminocarbonilo, aminotiocarbonilo, N-alquil C1-6aminotiocarbonilo, donde la porción alquilo puede estar opcionalmente sustituida con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, N,N-di-(alquil C1-6)aminotiocarbonilo, donde las porciones alquilo pueden estar opcionalmente sustituidas con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, alquilsulfonilo C1-6, donde la porción alquilo puede estar opcionalmente sustituida con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, C1-6alcoxi, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, cicloalquil C3-6sulfonilo, aminosulfonilo, N-alquil C1-6aminosulfonilo, donde la porción alquilo puede estar opcionalmente sustituida con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino, o N,N-di-(alquil C1-6)aminosulfonilo, donde las porciones alquilo pueden estar opcionalmente sustituidas con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alcoxi C1-6, amino, hidroxi, alquil C1-6amino, y di-(alquil C1-6)amino; R9 representa H, alquilo C1-6, o F; R10 representa H, alquilo C1-6, o F; R9 y R10 junto con el átomo de carbono al cual se encuentran unidos forman un anillo de entre 3 y 7 miembros que puede ser saturado o insaturado, donde el anillo opcionalmente puede contener uno o dos heteroátomos seleccionados entre azufre, oxigeno, y nitrógeno y donde el anillo puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alquilo C1-6, alcoxi C1-6, amino, hidroxi, ciano, acilo, alquil C1-6amino, di-(alquil C1-6)amino, alquil C1-6carbonilamino, y oxo; R11 representa H, alquilo C1-6, o cicloalquilo C3-6; R12 representa H, alquilo C1-6, o cicloalquilo C3-6; o R11 y R12 junto con el átomo de nitrógeno al cual están unidos forman un anillo de entre 3 y 7 miembros que puede ser saturado o insaturado, donde el anillo opcionalmente puede contener uno o dos heteroátomos seleccionados entre azufre, oxígeno, y nitrógeno y donde el anillo puede estar opcionalmente sustituido con uno o más sustituyentes seleccionados entre halógeno, trifluorometilo, trifluorometoxi, alquilo C1-6, alcoxi C1-6, amino, hidroxi, ciano, acilo, alquil C1-6amino, di(alquil C1-6)amino, alquil C1-6carbonilamino, y oxo; e isómeros ópticos, prodrogas, sales aceptables farmacéuticamente, hidratos, solvatos, y polimorfos del mismo; donde debe comprenderse que: si R1 y R2 junto con el átomo de carbono al cual se encuentran unidos forman un grupo carbonilo, luego R8 también puede representar H; R5 no puede representar tiazolilo opcionalmente sustituido; si R8 representa alquilo C1-6 no sustituido, luego R5 no representa fenilo opcionalmente sustituido; y el compuesto de fórmula (1) no puede representar: N-(2,4-difluorofenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, N-(2,4-dimetoxifenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, N-(2-fluorofenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, N-(3,5-dimetoxifenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, N-(3-metoxifenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, N-(4-fluorofenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, N-(4-metoxifenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, N-fenil-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina, 2-((2,4-difluorofenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 2-((2,4-dimetoxifenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 2-((2,5-dimetoxifenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 2-((2-metoxifenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 2-((3,5-dimetoxifenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 2-((3-metoxifenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 2-((4-fluorofenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 2-((4-metoxifenil)amino)-7,8-dihidropirido[4,3-d]pirimidin-6(5H)-carboxilato de tert-butilo, 1-(4-(5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-ilamino)fenil)etanona, o N-(4-fenoxifenil)-5,6,7,8-tetrahidropirido[4,3-d]pirimidin-2-amina.Claim 1: A compound characterized in that it is selected from those of the formula (1), wherein X represents CR6 (C = O) R7 or NR8; R1 represents H, C1-6 alkyl, or F; R2 represents H, C1-6 alkyl, or F; or R1 and R2 together with the carbon atom to which they are attached form a carbonyl group; or R1 and R2 together with the carbon atom to which they are attached form a ring of between 3 and 7 members that can be saturated or unsaturated, where the ring can optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and where the ring may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, acyl, C1-6 alkyl, di- (C1-6 alkyl ) amino, C 1-6 alkylcarbonylamino, and oxo; R3 represents H, C1-6 alkyl, or F; R4 represents H, C1-6 alkyl, or F; or R3 and R4 together with the carbon atom to which they are attached form a ring of between 3 and 7 members that can be saturated or unsaturated, where the ring can optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and where the ring may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, acyl, C1-6 alkyl, di- (C1-6 alkyl ) amino, C 1-6 alkylcarbonylamino, and oxo; R5 represents a monocyclic portion selected from aryl, heteroaryl, C3-6 cycloalkyl, and heterocyclyl; R 6 represents H, C 1-6 alkyl which may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkoxy, amino, hydroxy, C 1-6 alkyl, and di- (C 1-6 alkyl) amino , or F; R 7 represents C 1-6 alkyl, which may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkoxy, amino, hydroxy, C 1-6 alkyl, and di (C 1-6 alkyl) amino, cycloalkyl C3-6, heterocyclyl, or NR11R12; or R6 and R7 together with the carbon atoms to which they are attached form a ring of between 3 and 7 members that can be saturated or unsaturated, where the ring can optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and where the ring may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, acyl, C1-6 alkyl, di- (C1- alkyl 6) amino, C 1-6 alkylcarbonylamino, and oxo; R 8 represents C 1-6 alkyl which may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C 1-6 alkoxy, amino, hydroxy, C 1-6 alkyl, and di- (C 1-6 alkyl) amino, cycloalkyl C3-6, heterocyclyl, aryl, heteroaryl, C1-6 alkylcarbonyl which may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkoxy, amino, hydroxy, C1-6amino alkyl, and di- ( C1-6 alkyl) amino, C3-6cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C1-6 alkoxycarbonyl which may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkoxy, amino, hydroxy, alkyl C1-6amino, and di- (C1-6 alkyl) amino, aminocarbonyl, N-C1-6aminocarbonyl, where the alkyl portion may be optionally substituted with one or more substituents selected from halogen, tr ifluoromethyl, trifluoromethoxy, C1-6 alkoxy, amino, hydroxy, C1-6 alkyl, and di- (C1-6 alkyl) amino, N, N-di- (C1-6 alkyl) aminocarbonyl, where the alkyl portions may optionally be substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkoxy, C1-6 alkoxycarbonyl, cyano, amino, hydroxy, C1-6 amino alkyl, and di- (C1-6 alkyl) amino, N-C1 alkyl -6-N-C3-6aminocarbonyl, N-C1-6-N-cycloalkyl C3-6-C1-6alkylcarbonyl, aminothiocarbonyl, N-C1-6-aminothiocarbonyl, where the alkyl portion may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkoxy, amino, hydroxy, C1-6 alkyl, and di- (C1-6 alkyl) amino, N, N-di- (C1-6 alkyl) aminothiocarbonyl, where alkyl portions may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1- alkoxy 6, amino, hydroxy, C1-6 alkyl, and di- (C1-6 alkyl) amino, C1-6 alkylsulfonyl, where the alkyl portion may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1- 6alkoxy, amino, hydroxy, C1-6 alkyl, and di- (C1-6 alkyl) amino, C3-6 cycloalkyl sulfonyl, aminosulfonyl, N-C1-6 amino-sulfonyl alkyl, where the alkyl portion may be optionally substituted with one or more substituents selected between halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkoxy, amino, hydroxy, C1-6 alkyl, and di- (C1-6 alkyl) amino, or N, N-di- (C1-6 alkyl) aminosulfonyl, where the portions alkyl may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkoxy, amino, hydroxy, C1-6 alkyl, and di- (C1-6 alkyl) amino; R9 represents H, C1-6 alkyl, or F; R10 represents H, C1-6 alkyl, or F; R9 and R10 together with the carbon atom to which they are attached form a ring of between 3 and 7 members that can be saturated or unsaturated, where the ring can optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and where the ring may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, acyl, C1-6 alkyl, di- (C1-6 alkyl) amino, C 1-6 alkylcarbonylamino, and oxo; R 11 represents H, C 1-6 alkyl, or C 3-6 cycloalkyl; R12 represents H, C1-6 alkyl, or C3-6 cycloalkyl; or R11 and R12 together with the nitrogen atom to which they are attached form a ring of between 3 and 7 members that can be saturated or unsaturated, where the ring can optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and where the ring may be optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy, amino, hydroxy, cyano, acyl, C1-6 alkyl, di (C1-6 alkyl) amino , C1-6 alkylcarbonylamino, and oxo; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; where it should be understood that: if R1 and R2 together with the carbon atom to which they are attached form a carbonyl group, then R8 can also represent H; R5 cannot represent optionally substituted thiazolyl; if R8 represents unsubstituted C1-6 alkyl, then R5 does not represent optionally substituted phenyl; and the compound of formula (1) cannot represent: N- (2,4-difluorophenyl) -5,6,7,8-tetrahydropylido [4,3-d] pyrimidin-2-amine, N- (2,4 -dimethoxyphenyl) -5,6,7,8-tetrahydropyrid [4,3-d] pyrimidin-2-amine, N- (2-fluorophenyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-amine, N- (3,5-dimethoxyphenyl) -5,6,7,8-tetrahydropylido [4,3-d] pyrimidin-2-amine, N- (3-methoxyphenyl) -5,6, 7,8-tetrahydropyrid [4,3-d] pyrimidin-2-amine, N- (4-fluorophenyl) -5,6,7,8-tetrahydropylido [4,3-d] pyrimidin-2-amine, N- (4-Methoxyphenyl) -5,6,7,8-tetrahydropyrid [4,3-d] pyrimidin-2-amine, N-phenyl-5,6,7,8-tetrahydropyl [4,3-d] pyrimidin- 2-amine, 2 - ((2,4-difluorophenyl) amino) -7,8-dihydropylido [4,3-d] pyrimidin-6 (5H) -tert-butyl carboxylate, 2 - ((2,4- dimethoxyphenyl) amino) -7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -carboxylate tert-butyl, 2- ((2,5-dimethoxyphenyl) amino) -7,8-dihydropyrido [4 , 3-d] pyrimidin-6 (5H) -tert-butyl carboxylate, 2 - ((2-methoxyphenyl) amino) -7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -carboxylate tert-butyl, 2 - ((3,5-dimethoxy enyl) amino) -7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -tert-butyl carboxylate, 2 - ((3-methoxyphenyl) amino) -7,8-dihydropyrido [4,3 -d] pyrimidin-6 (5H) -tert-butyl carboxylate, 2 - ((4-fluorophenyl) amino) -7,8-dihydropyrido [4,3-d] pyrimidin-6 (5H) -tert-carboxylate butyl, 2 - ((4-methoxyphenyl) amino) -7,8-dihydropylido [4,3-d] pyrimidin-6 (5H) tert-butyl carboxylate, 1- (4- (5,6,7, 8-tetrahydropyl [4,3-d] pyrimidin-2-ylamino) phenyl) ethanone, or N- (4-phenoxyphenyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-amine .

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