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US 6,958,328 B2Granted
Arylindenopyridines and related therapeutic and prophylactic methods
AssigneeOrtho-McNeil Pharmaceutical, Inc.
InventorsGeoffrey R. Heintzelman, Kristin M. Averill, John H. Dodd
Life of this patent
Estimating the term…
Abstract
This invention provides novel arylindenopyridines of the formula: , and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.
Claims35
A compound having the structure
- (a) R1 is selected from the group consisting of:
- (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
- wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, or aryl,;
- (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
- wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, or aryl;
- (iii) cyano;
- (iv) a lactone or lactam formed with R4;
- (v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, and aryl;
- wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, and aryl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,
- (b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclyl, wherein the heterocyclyl is 1,3-dioxolane heterocylyl is 1,3-dixolane, and optionally substituted C3-7 cycloalkyl, or R2 is
- (c) R3 is from one to four groups independently selected from the group consisting of:
- (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, and aryl;
- (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, or aryl;
- (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R31N(CH2)p—, R30R31NCO(CH2)p—, aryl, and arylalkyl, wherein R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,
- (d) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
- wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, and aryl;
- and
- (e) X is selected from S and O;
- with the proviso that when R4 is isopropyl, then R3 is not halogen, and that when R4 is C1-3 straight or branched chain alkyl, then X is not O, R3 is not H and R1 is not COO-methyl and R2 is not 2-methoxyphenyl, and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
16 more elements
A compound having the structure:
- wherein
- (a) R1 is selected from the group consisting of:
- (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
- wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, or aryl;
- (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;
- wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, or aryl;
- (iii) cyano;
- (iv) a lactone or lactam formed with R4;
- (v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, or aryl;
- wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;
- (b) R2 is —NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl;
- with the proviso that when R2 is NHR16, R1 is not —COOR6 where R6 is ethyl;
- (c) R3 is from one to four groups independently selected from the group consisting of:
- (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, or aryl;
- (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, or aryl;
- (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R31N(CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;
- (d) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
- wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, or aryl;
- and
- (e) X is selected from S and O;
- provided that when R4 is C1-3 straight or branched chain alkyl, then X is not O, R3 is not H and R1 is not COO— methyl and R2 is not 2-methoxyphenyl, and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
18 more elements
Dependencies are inferred from the claim text.