Thiadiazolone derivatives and their use as AMPK agonists for the treatment of diabetes and related disorders
The invention relates to a compound of formula I, wherein: R 1 is as defined in the specification, or a pharmaceutically acceptable salt or solvate thereof, which compounds are useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, particularly as prodrugs.
1 . A compound of formula I,
wherein R 1 is selected from the group consisting of —C(O)—C 2 H 4 —CO 2 H and —PO 3 H 2 ,
or a pharmaceutically acceptable salt or solvate thereof.
2 . The compound according to claim 1 , wherein the compound of formula I is:
or a pharmaceutically acceptable salt or solvate thereof.
3 . The compound according to claim 1 , wherein the compound of formula I is:
or a pharmaceutically acceptable salt or solvate thereof.
4 . The compound according to claim 1 , wherein the pharmaceutically acceptable salt is an alkali metal salt, an alkaline earth metal salt or a quaternary ammonium salt of the compound of formula I.
5 . The compound according to claim 4 , wherein the pharmaceutically acceptable salt is a sodium or potassium salt of the compound of formula I.
6 . A pharmaceutical formulation comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
7 . The pharmaceutical formulation according to claim 6 , wherein the pharmaceutically acceptable excipient is a basic excipient.
8 . The pharmaceutical formulation according to claim 6 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of magnesium oxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate, or any combination thereof.
9 . The pharmaceutical formulation according to claim 6 , further comprising an enteric coating.
10 . A process for preparing a compound according to claim 1 , wherein the process comprises:
(i) reacting a compound of formula V,
with a suitable acid or acid anhydride; or
(ii) reacting a compound of formula VI,
with a suitable acid or suitable acid salt.
11 . A method of treating a disorder or condition ameliorated by the activation of AMPK in a subject in need thereof, wherein the disorder or condition is a cardiovascular disease, diabetic kidney disease, diabetes, insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, pain, opioid addiction, obesity, cancer, inflammation, an autoimmune disease, osteoporosis or an intestinal disease, the method comprising administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to the subject.
12 . The method according to claim 11 , wherein the cardiovascular disease is heart failure.
13 . The method according to claim 11 , wherein the disorder or condition ameliorated by the activation of AMPK is a condition associated with hyperinsulinemia selected from the group consisting of obesity and cardiovascular disease.
14 . The method according to claim 11 , wherein the compound is administered orally, subcutaneously or intramuscularly.
15 . The method according to claim 11 , wherein the inflammatory disorder or condition is a chronic inflammatory disease.
16 . The method according to claim 11 , wherein the disorder or condition is type 2 diabetes.
17 . The method according to claim 11 , wherein the disorder or condition is obesity.