SUBSTITUTED XANTHINE DERIVATIVES
This invention relates to novel compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. For example, this invention relates to novel substituted xanthine derivatives that are derivatives of pentoxifylline. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial.
1 . A compound of Formula C:
or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from —CH 3 and —CD 3 ;
R 2 is selected from —CH 3 and —CD 3 ; one of Y 1 and Y 2 is —OH; and the other of Y 1 and Y 2 is deuterium or hydrogen,
provided that if R 1 is CD 3 and R 2 is CH 3 , then Y 2 is —OH.
2 . The compound of claim 1 , wherein R 1 is —CH 3 .
3 . The compound of claim 1 , wherein R 1 is —CD 3 .
4 . The compound of claim 1 , wherein R 2 is —CH 3 .
5 . The compound of claim 1 , wherein R 2 is —CD 3 .
6 . The compound of claim 1 , wherein R 1 is —CH 3 and R 2 is —CH 3 .
7 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 7 , wherein Y 1 is deuterium.
9 . The compound of claim 7 , wherein Y 1 is hydrogen.
10 . The compound of claim 1 , wherein the compound has the structure:
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 10 , wherein Y 1 is deuterium.
12 . The compound of claim 10 , wherein Y 1 is hydrogen.
13 . The compound of claim 1 , wherein the compound is selected from the group consisting of the following compounds
or a pharmaceutically acceptable salt thereof.
14 . A compound of Formula D:
or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from —CH 3 and —CD 3 ; R 2 is selected from —CH 3 and —CD 3 ; one of Y 1 and Y 2 is —OH; and the other of Y 1 and Y 2 is deuterium or hydrogen;
with the proviso that
(i) if either one of Y 1 and Y 2 is deuterium, then R 2 is CD 3 ; and
(ii) if either one of Y 1 and Y 2 is hydrogen, then R 1 is CH 3 .
15 . The compound of claim 14 , wherein R 1 is —CH 3 .
16 . The compound of claim 14 , wherein R 1 is —CD 3 .
17 . The compound of claim 14 , wherein R 2 is —CH 3 .
18 . The compound of claim 14 , wherein R 2 is —CD 3 .
19 . The compound of claim 14 , wherein R 1 is —CH 3 and R 2 is —CH 3 .
20 . The compound of claim 14 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 20 , wherein Y 1 is deuterium.
22 . The compound of claim 20 , wherein Y 1 is hydrogen.
23 . The compound of claim 14 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 23 , wherein Y 2 is deuterium.
25 . The compound of claim 23 , Y 2 is hydrogen.
26 . The compound of claim 14 , wherein the compound is selected from the group consisting of the following compounds:
or a pharmaceutically acceptable salt thereof.
27 . The compound of claim 1 , wherein any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
28 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
29 . A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 , wherein the disease is selected from diabetic nephropathy, hypertensive nephropathy or intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.
30 . A method of treating chronic kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 .
31 . The method of claim 30 wherein the chronic kidney disease is glomerulonephritis, focal segmental glomerulosclerosis, nephrotic syndrome, reflux uropathy, or polycystic kidney disease.
32 . A method of treating chronic disease of the liver in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 .
33 . The method of claim 32 wherein the chronic disease of the liver is nonalcoholic steatohepatitis, fatty liver degeneration or other diet-induced high fat or alcohol-induced tissue-degenerative conditions, cirrhosis, liver failure, or alcoholic hepatitis.
34 . A method of treating a diabetes-related disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 , wherein the disease or condition is selected from insulin resistance, retinopathy, diabetic ulcers, radiation-associated necrosis, acute kidney failure or drug-induced nephrotoxicity.
35 . A method of treating intermittent claudication in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 .
36 . A method of treating chronic kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 .
37 . A method of treating a disease or condition in a patient in need thereof, wherein the disease or condition is selected from insulin dependent diabetes; non-insulin dependent diabetes; metabolic syndrome; obesity; insulin resistance; dyslipidemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout; and hypercoagulability, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 .
38 . A method of treating a disease or condition in a patient in need thereof, wherein the disease or condition is selected from anemia, Graves disease, retinal vein occlusion, lupus nephritis, macular degeneration, myelodysplasia, pruritis of HIV origin, pulmonary hypertension, retinal artery occlusion, intestinal inflammation, ischemic optic neuropathy, acute pancreatitis, sickle cell anemia and beta thalassemia, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 28 .