Thiazolidinedione analogues for the treatment of metabolic diseases
Inventors
Colca, Gerard R. • Gadwood, Robert C. • Parker, Tim
Assignees
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Publication Number
US-8067450-B2
Publication Date
2011-11-29
Expiration Date
Abstract
The present invention relates to thiazolidinedione analogues that are useful for treating hypertension, diabetes, and inflammatory diseases. Formula (I), wherein: each of R1 and R4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo; R2 is halo, hydroxy, or optionally substituted aliphatic, and R′2 is H, or R2 and R′2 together form oxo; R3 is H; and Ring A is a phenyl.
Core Innovation
The invention relates to thiazolidinedione analogs of Formula I and Formula II having a Ring A defined as phenyl. The analogs are designed to treat or prevent hypertension and diabetes, and to address inflammatory diseases, including inflammatory and autoimmune conditions.
The disclosed analogs are characterized by reduced PPARγ binding and/or activation, so that sodium reabsorption and related side effects are avoided relative to rosiglitazone and pioglitazone. The document compares activity to rosiglitazone and pioglitazone while maintaining the thiazolidinedione structure.
The invention provides a pharmaceutical composition that comprises the compound and a pharmaceutically acceptable carrier. The composition is described with oral administration, parenteral administration, rectal suppositories, vaginal administration, topical/transdermal formulations, sterile injectable formulations, and microencapsulated depot forms.
The description also includes combination-therapy rationale and incorporation of the pharmaceutical composition into coatings for implantable medical devices, including stents and catheters.
Claims Coverage
The independent claims cover three inventive features.
Pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.
Selected compound
5-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)benzyl)thiazolidine-2,4-dione.
Addition of selected cardiovascular and metabolic drug subclasses
The pharmaceutical composition further comprises selected diuretic, statin, angiotensin II receptor blocker, ACE inhibitor, and/or calcium channel blocker components chosen from the recited examples, including any combinations thereof.
Addition of selected glucocorticoid agonists
The pharmaceutical composition further comprises a glucocorticoid agonist selected from the recited glucocorticoid agents or any combination thereof.
Overall claim coverage is directed to the specified TZD analogs as pharmaceutical entities formulated with a pharmaceutically acceptable carrier, with dependent claim coverage further specifying optional inclusion of particular cardiovascular and metabolic drug subclasses and glucocorticoid agonists.
Stated Advantages
Avoid sodium reabsorption and related side effects by using TZD analogs with reduced PPARγ binding and/or activation relative to rosiglitazone and pioglitazone.
Reduced PPARγ activity.
Treating hypertension, diabetes, and inflammatory diseases.
Documented Applications
Treatment or prevention of hypertension and diabetes.
Treatment of inflammatory diseases, including inflammatory and autoimmune conditions.
Use in combination therapy with diuretics, RAAS modulators, and other listed cardiovascular and metabolic agents, as well as glucocorticoid agonists for inflammatory and autoimmune conditions.
Use in combination therapy.
Incorporation into coatings for implantable medical devices, including stents and catheters.
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