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US 2003/0225083 A1Published application
Antidiabetic agents
AssigneeWarner-Lambert Company
InventorsStephen A. Fakhoury, Helen Lee, Robert Schaum, Karen Sexton
Life of this patent
Estimating the term…
Abstract
Compounds of formula I: 1 wherein X, E, and R′ have any of the values defined in the specification, and their pharmaceutically acceptable salts, lower blood glucose levels and are useful for treating diseases in mammals such as Non-Insulin Dependent Diabetes Mellitus. Also disclosed are pharmaceutical compositions, processes for preparing compounds of formula (I) and intermediates useful for preparing compounds of formula I.
Claims13
A compound of formula (I)
- 57
- or a pharmaceutically acceptable salt thereof, wherein:
- X is a tether 2 to 5 atoms in length,
- wherein 0, 1, 2, or 3 of the atoms of the tether are O, S, or NR1,
- wherein R1 is H or (C1-C6)alkyl, and wherein the other atoms are CR2R3, CR4═CR5, or C≡C, wherein R2 and R3 taken together are ═O, or R2-R5 are each independently H or (C1-C6)alkyl;
- E is COR6, wherein R6 is (C1-C6)alkyl, OH, (C1-C6)alkoxy, NR7R8,
- wherein R7 and R8 are each independently H or (C1-C6)alkyl, or
- one of R7 and R8 is H or (C1-C6)alkyl and the other is SO2R9,
- wherein R8 is H or (C1-C6)alkyl, or E is substituted heteroaryl or
- 58
- R′ is H,
- C1-C7 alkyl and substituted alkyl,
- C2-C7 alkenyl and substituted alkenyl,
- C2-C7 alkynyl and substituted alkynyl,
- C3-C7 cycloalkyl and substituted cycloalkyl,
- aryl and substituted aryl,
- heterocyclic and substituted heterocyclic,
- heteroaryl and substituted heteroaryl,
- halo,
- NO2,
- NO,
- CN,
- ORa,
- 59
- wherein
- Ra is H,
- C1-C7 alkyl and substituted alkyl,
- C2-C7 alkenyl and substituted alkenyl,
- C3-C7 cycloalkyl and substituted cycloalkyl,
- aryl and substituted aryl,
- heteroaryl and substituted heteroaryl, or
- heterocycloalkyl and substituted heterocycloalkyl.
29 more elements
A compound of formula (II):
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- or a pharmaceutically acceptable salt thereof, wherein:
- E is COR6, wherein R6 is (C1-C6)alkyl, OH, (C1-C6)alkoxy, NR7R8,
- wherein R7 and R8 are each independently H or (C1-C6)alkyl, or
- one of R7 and R8 is H or (C1-C6)alkyl and the other is SO2R9,
- wherein R9 is H or (C1-C6)alkyl, or E is substituted heteroaryl or
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- R′ is H,
- C1-C7 alkyl and substituted alkyl,
- C2-C7 alkenyl and substituted alkenyl,
- C2-C7 alkynyl and substituted alkynyl,
- C3-C7 cycloalkyl and substituted cycloalkyl,
- aryl and substituted aryl,
- heterocyclic and substituted heterocyclic,
- heteroaryl and substituted heteroaryl,
- halo,
- NO2,
- NO,
- CN,
- ORa,
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- wherein
- Ra is H,
- C1-C7 alkyl and substituted alkyl,
- C2-C7 alkenyl and substituted alkenyl,
- C3-C7 cycloalkyl and substituted cycloalkyl,
- aryl and substituted aryl,
- heteroaryl and substituted heteroaryl, or
- heterocycloalkyl and substituted heterocycloalkyl.
26 more elements
A compound which is:
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(hydroxy)-phenyl]-propionic acid;
- 69
- 3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester;
- 70
- 3-{2-Hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid ethyl ester;
- 71
- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-3-ylmethoxy)- phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(methoxy)-phenyl]-propionic acid;
- 73
- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(phenyloxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(phenethyloxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(cyclohexyloxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(cyclohexylmethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(cyclopentylmethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(cyclopropylmethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyrrolidine-1-ylethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(morpholine-1-ylethoxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(allyloxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(propoxy)-phenyl]-propionic acid;
- 85
- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(propargyloxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyrid-2-yloxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyridin-3-yloxy)-phenyl]-propionic acid;
- 88
- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(pyrid-4-yloxy)-phenyl]-propionic acid;
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-[3-(4-methylpiperazin-1-yl)-propoxy]-phenyl]-propionic acid;
- or
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- 3-[4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-(3-morpholine-4-ylpropoxy)-phenyl]-propionic acid.
46 more elements
A method of treating a patient suffering from abnormal insulin and/or evidence of glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone, comprising administering to the patient a therapeutically effective amount of a compound of formula I.
A process for preparing a compound of formula I
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- or a pharmaceutically acceptable salt thereof, wherein:
- X is a tether 2 to 5 atoms in length,
- wherein 0, 1, 2, or 3 of the atoms of the tether are O, S, or NR1,
- wherein R1 is H or (C1-C6)alkyl, and wherein the other atoms are CR2R3, CR4═CR5, or C≡C, wherein R2 and R3 taken together are ═O, or R2—R5 are each independently H or (C1-C6)alkyl;
- E is COR6, wherein R6 is (C1-C6)alkyl, OH, (C1-C6)alkoxy, NR7R8,
- wherein R7 and R8 are each independently H or (C1-C6)alkyl, or
- one of R7 and R8 is H or (C1-C6)alkyl and the other is SO2R9,
- wherein R9 is H or (C1-C6)alkyl, or E is substituted heteroaryl or
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- R′ is H,
- C1-C7 alkyl and substituted alkyl,
- C2-C7 alkenyl and substituted alkenyl,
- C2-C7 alkynyl and substituted alkynyl,
- C3-C7 cycloalkyl and substituted cycloalkyl,
- aryl and substituted aryl,
- heterocyclic and substituted heterocyclic,
- heteroaryl and substituted heteroaryl,
- halo,
- NO2,
- NO,
- CN,
- ORa,
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- wherein
- Ra is H,
- C1-C7 alkyl and substituted alkyl,
- C2-C7 alkenyl and substituted alkenyl,
- C3-C7 cycloalkyl and substituted cycloalkyl,
- aryl and substituted aryl,
- heteroaryl and substituted heteroaryl, or
- heterocycloalkyl and substituted heterocycloalkyl.
- invention,
- comprising:
- (a) formation of the a,o unsaturated ester from the aldehyde;
- (b) hydrogenation of the double bond in the α,β unsaturated ester;
- (c) saponification of the ester with base to provide the acid;
- (d) O-alkylation at the phenoxy moiety to provide an invention compound.
- 94
36 more elements
Dependencies are inferred from the claim text.