Purine derivatives having phosphodiesterase iv inhibition activity

A method for selectively effecting PDE IV inhibition, compared to PDE III inhibition, in a patient suffering from a disease state selected from the group consisting of inflammation, depression, Alzheimer's disease, vascular dementia, and multi-in-farct demetia, said method comprising the administration of a compound of the formula (I):

• and pharmaceutically acceptable salts thereof,
• wherein R3, R6a, R6b, and R8 is selected from the group consisting of A and B,
• wherein A is selected from the group consisting of
• hydrogen;
• C1-10 alkyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-12 cycloalkoxy, halogen ═NOH, ═NOCONH2, CO2H, ↑O and benzyloxy;
• said benzyloxy optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy and C3-12 cycloalkoxy;
• C2-10 alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10 cycloalkyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C1-10alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10 cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-12cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• aryl which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, carbamyl, amido, C1-10 alkylamido, C1-10dialkylamido, C1-10 acylamino, C1-10 alkysulfonylamino, phenyl and benzyl;
• ar(C1-4)alkyl wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10 alkylcarboxy, halogen, hydroxy, hydroxy(C1-10) alkoxy, nitro, trihalocarbon benzyloxy, heterocyclyl, C1-10 cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10 alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy and C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy optionally substituted on a carbon with hydroxy and said heterocyclyl is optionally substituted with C1-10 alkyl;
• and wherein the alkyl moiety of said ar (C1-14)alkyl is optionally substituted with OH, halogen, C1-10 alkoxy or C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
• heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10 alkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, amido, C1-10 alkylamido, C1-10 dialkylamido, C1-10 acylamino, C1-10 alkylsulfonylamino, phenyl and benzyl;
• heterocycly(C1-C4)alkyl wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, carbamyl, amido, C1-10 alkylamido, C1-10 dialkylamido, C1-10 acylamino, C1-10 alkylsulfonylamino, phenyl and benzyl, and wherein said alkyl moiety is optionally substituted with OH, C1-10 alkoxy, C3-12 cycloalkoxy, C3-12 cycloalkyl, halogen or halo(C1-10)alkyl;
• heteroaryl, which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, halogen, nitro, CF3, C1-10 alkoxy and C3-12 cycloalkoxy;
• and
• heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, halogen, nitro trihalocarbon, C1-10 alkoxy and C3-12 cycloalkoxy;
• and
• B is selected from the group consisting of
• C1-10 alkyl which is unbranched or branched and is substituted with 1-3 substituents chosen from the group consisting of benzyloxy, methylenedioxybenzyloxy, methylenedioxyphenyl, pyridylmethoxy, thienylmethoxy and alkylamino;
• said substituents optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy and oxo;
• said substituted C1-10 alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-,2 cycloalkoxy, halogen, ═NOH, ═NOCONH2, CO2H, and ═O;
• C2-10 alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10 cycloalkyl which is substituted with 1-3 substituents chosen from the group consisting of C2-10 alkyl and C3-12 cycloalkyl;
• said substituted C3-10 cycloalkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-12 cycloalkoxy, halogen halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-12 cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, and C3-12 cycloalkyl;
• said substituted C3-12 cycloalkyl(C1-10)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-12 cycloalkoxy, ═NOH ═NOCONH2, and CO2H;
• aryl which is substituted with 1-3 substituents chosen from the group consisting of amido, C1-10 alkylamido, and C1-10 dialkylamido;
• said substituted aryl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, phenyl and benzyl;
• ar(C1-4)alkyl wherein the aryl moiety is substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10 alkylcarboxy, hydroxy(C1-10)alkoxy, nitro, benzyloxy, heterocyclyl, C1-10 cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10 alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10 alkoxy and C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy substituted on a carbon with hydroxy and said heterocyclyl is optionally substituted with C1-10 alkyl and wherein the alkyl moiety of said ar(C1-4)alkyl is optionally substituted with OH, halogen, C1-10 alkoxy or C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
• and said substituted ar(C1-4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of halogen, hydroxy, trihalocarbon, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy and C3-12 cycloalkoxy;
• heterocyclyl which is substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of carbamyl, C1-10 acylamino and C1-10 alkylsulfonylamino;
• said substituted heterocyclyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, amido, C1-10 alkylamido, C1-10 dialkylamido, phenyl and benzyl;
• heterocyclyl(C1-C4)alkyl wherein said heterocyclyl moiety is substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10acylamino, C1-10 alkylsulfonylamino, and C1-10 alkyl, said C1-10 alkyl substituted with OH, C1-10 alkoxy, C3-12 cycloalkoxy, C3-12 cycloalkyl, halogen or halo(C1-10)alkyl;
• said substituted heterocyclyl(C1-C4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, amido, C1-10 alkylamido and C1-10 dialkylamido;
• heteroaryl is optionally substituted with 1-3 substitutents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, halogen, nitro, CF3, C1-10 alkoxy and C3-12 cycloalkoxy and
• heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is substituted with nitro;
• said heteroaryl(C1-4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, halogen, trihalocarbon, C1-10 alkoxy and C3-12 cycloalkoxy;
• and
• provided that at least one of R3, R6a, R6b and R8 is B.

A pharmaceutical composition comprising a compound of the formula (I):

• and pharmaceutically acceptable salts thereof,
• wherein R3, R6a, R6b, and R8 is selected from the group consisting of A and B,
• wherein A is selected from the group consisting of
• hydrogen;
• C1-10 alkyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-12 cycloalkoxy, halogen ═NOH, ═NOCONH2, CO2H, ═O and benzyloxy;
• said benzyloxy optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy and C3-12 cycloalkoxy;
• C2-10 alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10 cycloalkyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10 cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-12 cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• aryl which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, carbamyl, amido, C1-10 alkylamido, C1-10 dialkylamido, C1-10 acylamino, C1-10alkysulfonylamino, phenyl and benzyl;
• ar(C1-4)alkyl wherein the aryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10 alkylcarboxy, halogen, hydroxy, hydroxy(C1-10)alkoxy, nitro, trihalocarbon, benzyloxy, heterocyclyl, C1-10 cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10 alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy and C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy optionally substituted on a carbon with hydroxy and said heterocyclyl is optionally substituted with C1-10 alkyl;
• and wherein the alkyl moiety of said ar(C1-4)alkyl is optionally substituted with OH, halogen, C1-10 alkoxy or C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
• heterocyclyl which is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10 alkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, amido, C1-10 alkylamido, C1-10 dialkylamido, C1-10 acylamino, C1-10 alkylsulfonylamino, phenyl and benzyl;
• heterocycly(C1-C4)alkyl wherein said heterocyclyl moiety is optionally substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 C1-10 dialkylamino, carbamyl, amido, C1-10 alkylamido, C1-10 dialkylamido, C1-10 acylamino, C1-10 alkylsulfonylamino, phenyl and benzyl, and wherein said alkyl moiety is optionally substituted with OH, C1-10 alkoxy, C3-12 cycloalkoxy, C3-12 cycloalkyl, halogen or halo(C1-10)alkyl;
• heteroaryl, which is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, halogen, nitro, CF3, C1-10 alkoxy and C3-12 cycloalkoxy;
• and
• heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, halogen, nitro trihalocarbon, C1-10 alkoxy and C3-12 cycloalkoxy;
• and
• B is selected from the group consisting of
• C1-10 alkyl which is unbranched or branched and is substituted with 1-3 substituents chosen from the group consisting of benzyloxy, methylenedioxybenzyloxy, methyl enedioxyphenyl, pyridylmethoxy, thienylmethoxy and alkylamino;
• said substituents optionally substituted with 1-3 substituents chosen from the group consisting of halogen, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy and oxo;
• said substituted C1-10 alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, ═NOH, ═NOCONH2, CO2H, and ═O;
• C2-10 alkenyl which is unbranched or branched and is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10 cycloalkyl which is substituted with 1-3 substituents chosen from the group consisting of C2-10 alkyl and C3-12 cycloalkyl;
• said substituted C3-10 cycloalkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-12 cycloalkoxy, halogen halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-10 cycloalkenyl which is optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy, C3-12 cycloalkoxy, halogen, halo(C1-10)alkyl, ═NOH, ═NOCONH2, CO2H and ═O;
• C3-12 cycloalkyl(C1-10)alkyl wherein the cycloalkyl portion is substituted with 1-3, substituents chosen from the group consisting of C1-10 alkyl, and C3-12 cycloalkyl;
• said substituted C3-12 cycloalkyl(C1-10)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of OH, C1-10 alkoxy, C3-12 cycloalkoxy, ═NOH, ═NOCONH2, and CO2H;
• aryl which is substituted with 1-3 substituents chosen from the group consisting of amido, C1-10 alkylamido, and C1-10 dialkylamido;
• said substituted aryl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, phenyl and benzyl;
• ar(C1-4)alkyl wherein the aryl moiety is substituted with 1-3 substituents chosen from the group consisting of carboxy, C1-10 alkylcarboxy, hydroxy(C1-10)alkoxy, nitro, benzyloxy, heterocyclyl, C1-10 cycloalkyl(C3-12)alkyloxy, ar(C1-10)alkyloxy, aryloxy, amino(C1-10)alkoxy, C1-10 alkylamino(C1-10)alkoxy, heteroaryloxy, heteroar(C1-10)alkyloxy, heterocyclyloxy, C1-10 alkoxy and C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy substituted on a carbon with hydroxy and said heterocyclyl is optionally substituted with C1-10 alkyl and wherein the alkyl moiety of said ar (C1-4)alkyl is optionally substituted with OH, halogen, C1-10 alkoxy or C3-12 cycloalkoxy;
• said alkoxy and cycloalkoxy being optionally substituted in one position at the alkyl moiety with hydroxy;
• and said substituted ar(C1-4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of halogen, hydroxy, trihalocarbon, C1-10 alkyl, C3-12 cycloalkyl, C1-10 alkoxy and C3-12 cycloalkoxy;
• heterocyclyl which is substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of carbamyl, C1-10 acylamino and C1-10 alkylsulfonylamino;
• said substituted heterocyclyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, amido, C1-10 alkylamido, C1-10 dialkylamido, phenyl and benzyl;
• heterocyclyl(C1-C4)alkyl wherein said heterocyclyl moiety is substituted on the carbons or nitrogens of the ring with 1-3 substituents chosen from the group consisting of C1-10 acylamino, C1-10 alkylsulfonylamino, and C1-10 alkyl, said C1-10 alkyl substituted with OH, C1-10 alkoxy, C3-12 cycloalkoxy, C3-12 cycloalkyl, halogen or halo(C1-10)alkyl;
• said substituted heterocyclyl(C1-C4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, OH, halogen, C1-10 alkoxy, C3-12 cycloalkoxy, NH2, C1-10 alkylamino, C1-10 dialkylamino, amido, C1-10 alkylamido and C1-10 dialkylamido;
• heteroaryl is optionally substituted with 1-3 substitutents chosen from the group consisting of C1-10 alkyl, C3-12 cycloalkyl, halogen, nitro, CF3, C1-10 alkoxy and C3-12 cycloalkoxy;
• and
• heteroaryl(C1-4)alkyl, wherein the heteroaryl moiety is substituted with nitro;
• said heteroaryl(C1-4)alkyl further optionally substituted with 1-3 substituents chosen from the group consisting of C1-10 alkyl C3-12 cycloalkyl, halogen, trihalocarbon, C1-10 alkoxy and C3-12 cycloalkoxy;
• and
• provided that at least one of R3, R6a, R6b and R8 is B;
• and a pharmaceutically acceptable excipient.