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US 6,583,140 B2Granted
2-substituted thiazolidinones as beta-3 adrenergic receptor agonists
AssigneeWyeth
InventorBaihua Hu
Life of this patent
Estimating the term…
Abstract
This invention provides compounds of Formula I having the structure wherein: A, X, Y, Z, R1, R2, R3, R4, R5, and R6 are as defined hereinbefore or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Claims12
A compound of formula I having the structure
- wherein:
- A is aryl;
- X a bond;
- Y is piperidine;
- wherein the nitrogen of the piperidine is attached to the adjacent phenyl ring;
- Z is S;
- R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, or dihydroxyphosphorylamino, or two of the three R1, R2 or R3 substituents combine with the carbon to which each is attached to form a aryl fused cycloalkyl of 3-8 carbon atoms optionally substituted with an acylamino or hydroxy group;
- R4 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, carboxy, or halogen;
- R5 is hydrogen or alkyl of 1-6 carbon atoms;
- R6 is (i) SCH3 or NR7R8;
- (ii) an amino acid, wherein a nitrogen of the amino acid is attached to the adjacent thiazolidinone ring;
- (iii) an alkyl ester of an amino acid, wherein a nitrogen of the amino acid is attached to the adjacent thiazolidinone ring, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
- or (iv) NH(C═Q)NR7R8 or NHNH(C═Q)NR7R8;
- R7 and R8 are each, independently, hydrogen, aryl, Het, alkyl of 1-6 carbon atoms, arylalkyl in which the alkyl moiety has 1-6 carbon atoms, Hetalkyl in which the alkyl moiety has 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, dialkylaminoalkyl of 1-6 carbon atoms per alkyl group, hydroxy, alkoxy of 1-6 carbon atoms, benzyloxy, cyano, alkylamino of 1-6 carbon atoms, dialkylamino having 1-6 carbon atoms per alkyl group, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms;
- or R7 and R8 are taken together with the nitrogen to which each is attached to form a saturated, unsaturated, or partially unsaturated 3-8 membered heterocyclic ring optionally containing 1 to 3 additional heteroatoms selected from S, O and N, and optionally substituted with R9;
- Q is O, S, NH, NCN;
- or Q and one of R7 and R8 are taken together to form a partially unsaturated or unsaturated 3-8 membered heterocyclic ring optionally containing 1-2 additional heteroatoms selected from S, O, and N, and optionally substituted with R9;
- Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
- wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
- may be optionally fused to a phenyl ring, and may be optionally substituted with R9;
- R9 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl group, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, or dihydroxyphosphorylamino;
- or a pharmaceutically acceptable salt thereof.
19 more elements
A pharmaceutical composition which comprises a compound of formula I having the structure
- wherein:
- A is aryl;
- X is a bond;
- Y is piperidine;
- wherein the nitrogen of the piperidine is attached to the adjacent phenyl ring;
- Z is S;
- R1, R2, and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, or dihydroxyphosphorylamino, or two of the three R1, R2 or R3 substituents combine with the carbon to which each is attached to form an aryl fused cycloalkyl of 3-8 carbon atoms optionally substituted with an acylamino or hydroxy group;
- R4 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, carboxy, or halogen;
- R5 is hydrogen or alkyl of 1-6 carbon atoms;
- R6 is (I) SCH3 or NR7R8;
- (ii) an amino acid, wherein a nitrogen of the amino acid is attached to the adjacent thiazolidinone ring;
- (iii) an alkyl ester of an amino acid, wherein a nitrogen of the amino acid is attached to the adjacent thiazolidinone ring, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms;
- or (iv) NH(C═Q)NR7R8 or NHNH(C═Q)NR7R8;
- R7 and R8 are each, independently, hydrogen, aryl, Het, alkyl of 1-6 carbon atoms, arylalkyl in which the alkyl moiety has 1-6 carbon atoms, Hetalkyl in which the alkyl moiety has 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, dialkylaminoalkyl of 1-6 carbon atoms per alkyl group, hydroxy, alkoxy of 1-6 carbon atoms, benzyloxy, cyano, alkylamino of 1-6 carbon atoms, dialkylamino having 1-6 carbon atoms per alkyl group, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms;
- or R7 and R8 are taken together with the nitrogen to which each is attached to form a saturated, unsaturated, or partially unsaturated 3-8 membered heterocyclic ring optionally containing 1 to 3 additional heteroatoms selected from S, O and N, and optionally substituted with R9;
- Q is O, S, NH, NCN;
- or Q and one of R7 and R8 are taken together to form a partially unsaturated or unsaturated 3-8 membered heterocyclic ring optionally containing 1-2 additional heteroatoms selected from S, O, and N, and optionally substituted with R9;
- Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
- wherein the heterocycle may be saturated, unsaturated, or partially unsaturated;
- may be optionally fused to a phenyl ring, and may be optionally substituted with R9;
- R9 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl group, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, or dihydroxyphosphorylamino;
- or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.
19 more elements
Dependencies are inferred from the claim text.