AR046272A1 - DIPEPTIDIL PEPTIDASA IV INHIBITORS - Google Patents

DIPEPTIDIL PEPTIDASA IV INHIBITORS

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Publication number
AR046272A1
AR046272A1 ARP040103608A ARP040103608A AR046272A1 AR 046272 A1 AR046272 A1 AR 046272A1 AR P040103608 A ARP040103608 A AR P040103608A AR P040103608 A ARP040103608 A AR P040103608A AR 046272 A1 AR046272 A1 AR 046272A1
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AR
Argentina
Prior art keywords
alkyl
optionally substituted
ring
cycloalkyl
het1
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ARP040103608A
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Spanish (es)
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Astrazeneca Ab
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Publication of AR046272A1 publication Critical patent/AR046272A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Abstract

Los compuestos de la presente son valiosos en el tratamiento de los estados patológicos asociados con la actividad de la DPP-IV, como por ejemplo la diabetes mellitus. También se describen procesos para la preparación de los mencionados compuestos, los intermediarios utilizados en dichos procesos, composiciones farmacéuticas que contienen dichos compuestos o sales y el uso de dichos compuestos o sales. Reivindicación 1: Un compuesto de la fórmula (1) o una sal farmacéuticamente aceptable del mismo, en la cual Ar es fenilo optativamente sustituido con 1, 2, 3, 4 o 5 grupos independientemente seleccionados entre R9; R9 se selecciona entre halo, alquilo C1-6 (optativamente sustituido con halo 1-5), alcoxi C1-6 (optativamente sustituido con 1-5 halo) y ciano; R1 se selecciona entre H y alquilo C1-6, R2 se selecciona entre H, alquilo C1-6, cicloalquilo C3-8, bicicloalquilo C5-12, tricicloalquilo C6-12, AR1, HET1, -alquil C1-6AR1, -alquil C1-6AR2, -alquil C1-6-cicloalquilo C3-8, -alquil C1-6HET1, -alquil C1-6HET2, -alquil C1-6CO2alquilo C1-6, -alquil C1-6CO2cicloalquilo C3-8, -alquil C1-6CO2AR1, -alquil C1-6CO2HET1, -alquil C1-6OCOalquilo C1-6, -alquil C1-6OCOcicloalquilo C3-8, -alquil C1-6OCOAR1, -alquil C1-6OCOHET1, -alquil C1- 6COalquilo C1-6, -alquil C1-6COcicloalquilo C3-8, -alquil C1-6COAR1, -alquil C1-6COHET1, -alquil(C1-6)NHCOalquilo C1-6, -alquil C1-6NHCOcicloalquilo C3-8, -alquil C1-6NHCOAR1, -alquil C1-6CONHalquilo C1-6, -alquil C1-6CONHcicloalquilo C3-8, -alquil C1-6CON-dialquilo C1-6, -alquil C1-6CONHAR1, -alquil C1-6NHalquilo C1-6, -alquil C1-6N-dialquilo C1-6, -alquil C1-6NHAR1, -alquil C1-6NH(HET1), -alquil C1-6NHSO2alquilo C1-6, -alquil C1-6SO2NHalquilo C1-6, -alquil C1-6SO2alquilo C1-6, -SO2alquilo C1- 6 y -alquil C1-6SO2N-dialquilo C1-6; o R1 y R2, junto con el N al cual están unidos, forman un anillo definido por HET1 o HET3; donde un anillo que comprende R1 y R2 está optativamente sustituido con 1 o 2 sustituyentes independientemente seleccionados entre halo, alquilo C1-6, haloalquilo C1-6, alcoxi C1-6, ciano, carboxi, carboxialquilo C1-6, -COalquilo C1-6, -CO2alquilo C1-6, alquilamino C1-6, di-alquilamino C1-6-amino, -NHCOalquilo C1-6, -CONHalquilo C1-6, -CONdi-alquilo C1-6 y HET1; R3 y R4 se seleccionan independientemente entre H, alquilo C1-6, cicloalquilo C3-8, cicloalquenilo C3-8, bicicloalquilo C5-12, -alquil C1-6-cicloalquilo C3-8, -alquil C1-6-cicloalquenilo C3-8, AR1, AR2, HET1, HET2, -alquil C1-6AR1, -alquil C1- 6AR2, -alquil C1-6HET1 y -alquil C1-6HET2; o R3 y R4 juntos forman un anillo definido por cicloalquilo C3-8, AR2, HET1 o HET2, R5, R6, R7 y R8 se seleccionan independientemente entre H y alquilo C1-6, donde cualquier grupo alquilo C1-6 comprendido en cualquier definición de R1, R2, R3, R4, R5, R6, R7 o R8 está optativamente sustituido con 1 ó 2 sustituyentes independientemente seleccionados entre hidroxi y F; donde cualquier cicloalquilo C3-8, cicloalquenilo C3-8, bicicloalquilo C5-12 o tricicloalquilo C6-12 incluido en cualquier definición de R2, R3 o R4 está optativamente sustituido; AR1 es fenilo optativamente sustituido; AR2 es un anillo carbocíclico bicíclico de 8, 9 o 10 miembros insaturado, parcial o completamente saturado, optativamente sustituido; HET1 es un anillo heterocíclico monocíclico insaturado, parcial o completamente saturado de 3, 4 o 6 miembros, optativamente sustituido que contiene hasta 4 heteroátomos independientemente seleccionados entre O, N y S (aunque sin contenido alguno de enlaces O-O, O-S o S-S), ligado por medio de un átomo de C, o un átomo de N del anillo si el anillo no fuera así cuaternizado y donde cualquier átomo de C, S o N libre pueda oxidarse; HET2 es un anillo de heterociclilo bicíclico insaturado, parcial o completamente saturado de 8, 9 o 10 miembros, optativamente sustituido, que contiene hasta cuatro heteroátomos independientemente seleccionados entre O, N y S (aunque sin contenido de enlaces O-O, O-S o S-S), ligado por medio de un átomo de C del anillo en cualquiera de los anillos que comprende el sistema bicíclico; HET3 es un sistema de anillos saturados bicíclicos o tricíclicos ligado con N, que contiene hasta 12 átomos en el anillo, incluyendo el átomo de N ligante; donde los sustituyentes optativos adecuados en cicloalquilo C3-8, bicicloalquilo C5-12, tricicloalquilo C6-12, AR1, AR2, HET1 y HET2 son 1, 2, 3, 4 o 5 sustituyentes independientemente seleccionados entre fenilo (optativamente sustituido con halo, trifluorometilo, alquilo C1-4 o alcoxi C1-4), halo, alquilo C1-6, haloalquilo C1-6, dihaloalquilo C1-6, trifluormetilo, alcoxi C1-6, carboxialquilo C1-6, carboxialcoxi C1-6, hidroxi, amino, alquil C1-6-amino, dialquil C1-6- amino, -CONH2, -CONHalquilo C1-6, -CONdialquilo C1-6, -NHCOalquilo C1-6, -SO2alquilo C1-6, -S(O)2NH2, -SO2NHalquilo C1-6, -SO2Ndialquilo C1-6 y -NHSO2alquilo C1-6.The compounds herein are valuable in the treatment of the pathological conditions associated with the activity of DPP-IV, such as diabetes mellitus. Processes for the preparation of said compounds, the intermediates used in said processes, pharmaceutical compositions containing said compounds or salts and the use of said compounds or salts are also described. Claim 1: A compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R9; R9 is selected from halo, C1-6 alkyl (optionally substituted with halo 1-5), C1-6 alkoxy (optionally substituted with 1-5 halo) and cyano; R1 is selected from H and C1-6 alkyl, R2 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, C5-12 cycloalkyl, C6-12 tricycloalkyl, AR1, HET1, -C1-6AR1 alkyl, -C1 alkyl -6AR2, -C1-6 alkyl-C3-8 cycloalkyl, -C1-6HET1 alkyl, -C1-6HET2 alkyl, -C1-6CO2 alkyl C1-6 alkyl, -C1-6CO2 alkylC3-8 alkyl, -C1-6CO2AR1 alkyl, -C1-6CO2HET1 alkyl, -C1-6 alkyl-C1-6 alkyl, -C1-6 alkyl-C3-8 alkylcycloalkyl, C1-6 alkyl -COCO1, -C1-6 alkyl -COHET1, -C1-6 alkyl-C1-6 alkyl, -C1-6 alkyl C3-8, -C1-6COAR1 alkyl, -C1-6COHET1 alkyl, -C1-6 alkyl NHCOC1-6 alkyl, -C1-6 alkylC3-8 alkylcycloalkyl, C1-6NHCOAR1 alkyl, -C1-6CON alkylC1 alkyl 6, -C1-6CON alkylC3-8cycloalkyl, -C1-6 alkyl-C1-6 dialkyl, -C1-6 alkylCONHAR1, -C1-6N alkylC1-6 alkyl, -C1-6N alkyl-C1-6 dialkyl, -alkyl C1-6NHAR1, -C1-6NH alkyl (HET1), -C1-6NHSO2 alkyl C1-6 alkyl, -C1-6SO2 alkylC1-6 alkyl, -C1-6SO2 alkyl, C1-6 alkyl, -SO2C1-6 alkyl and -C1 alkyl 6SO2N-d C1-6 alkyl; or R1 and R2, together with the N to which they are attached, form a ring defined by HET1 or HET3; wherein a ring comprising R1 and R2 is optionally substituted with 1 or 2 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, cyano, carboxy, C1-6 carboxy alkyl, -C1-6 alkyl , -CO2C1-6 alkyl, C1-6 alkylamino, di- C1-6 alkylamino, -NHCOC1-6 alkyl, -CONC1-6 alkyl, -CONdi-C1-6 alkyl and HET1; R3 and R4 are independently selected from H, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C5-12 cycloalkyl, C1-6 alkyl C3-8 cycloalkyl, C1-6 alkyl C3-8 cycloalkenyl , AR1, AR2, HET1, HET2, - C1-6AR1 alkyl, - C1-6AR2 alkyl, - C1-6HET1 alkyl and - C1-6HET2 alkyl; or R3 and R4 together form a ring defined by C3-8 cycloalkyl, AR2, HET1 or HET2, R5, R6, R7 and R8 are independently selected from H and C1-6 alkyl, wherein any C1-6 alkyl group comprised in any definition of R1, R2, R3, R4, R5, R6, R7 or R8 is optionally substituted with 1 or 2 substituents independently selected from hydroxy and F; wherein any C3-8 cycloalkyl, C3-8 cycloalkenyl, C5-12 bicycloalkyl or C6-12 tricycloalkyl included in any definition of R2, R3 or R4 is optionally substituted; AR1 is optionally substituted phenyl; AR2 is an unsaturated, partially or fully saturated bicyclic carbocyclic ring of 8, 9 or 10 members, optionally substituted; HET1 is an unsaturated, partially or completely saturated monocyclic heterocyclic ring of 3, 4 or 6 members, optionally substituted containing up to 4 heteroatoms independently selected from O, N and S (although without any content of OO, OS or SS links), bound by means of a C atom, or an N atom of the ring if the ring were not quaternized and where any free C, S or N atom can oxidize; HET2 is an unsaturated, partially or fully saturated bicyclic heterocyclyl ring of 8, 9 or 10 members, optionally substituted, containing up to four heteroatoms independently selected from O, N and S (although without OO, OS or SS link content), linked by means of a C atom of the ring in any of the rings comprising the bicyclic system; HET3 is a N-linked bicyclic or tricyclic saturated ring system, containing up to 12 ring atoms, including the N-binding atom; wherein suitable optional substituents on C3-8 cycloalkyl, C5-12 bicycloalkyl, C6-12 tricycloalkyl, AR1, AR2, HET1 and HET2 are 1, 2, 3, 4 or 5 substituents independently selected from phenyl (optionally substituted with halo, trifluoromethyl , C1-4 alkyl or C1-4 alkoxy), halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 dihaloalkyl, trifluoromethyl, C1-6 alkoxy, C1-6 carboxyalkyl, C1-6 carboxyalkoxy, hydroxy, amino, C1-6-amino alkyl, C1-6 dialkyl-amino, -CONH2, -CONH1-6 alkyl, -CON-C1-6 alkyl, -NHCO C1-6 alkyl, -SO2C1-6 alkyl, -S (O) 2NH2, -SO2NHalkyl C1-6, -SO2N1-6alkyl and -NHSO2C1-6alkyl.

ARP040103608A 2003-10-16 2004-10-05 DIPEPTIDIL PEPTIDASA IV INHIBITORS AR046272A1 (en)

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