Substituted xanthine derivatives
This invention relates to novel deuterated compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. In particular, this invention relates to novel substituted xanthine derivatives that are deuterated derivatives of a pentoxifylline metabolite. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed deuterated compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial. The compounds of the invention are represented by the following structural formula: wherein the values of R 1 , R 2 , R 3 , R 4 , R 5 , Y 1 and Y 2 are described herein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 and R 2 is —CH 3 ;
R 3 is —CD 3 ;
R 4 is † CD 2 (CH 2 ) 3 , wherein “†” represents the portion of the R 4 moiety bound to C(Y 1 )(Y 2 ) in the compound;
Y 1 is OH; and
Y 2 is hydrogen, wherein the isotopic enrichment factor for each designated deuterium atom is at least 5000.
2. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
3. The compound of claim 1 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.
4. The compound of claim 1 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.
5. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.
6. A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 2 , wherein the disease is selected from diabetic nephropathy and hypertensive nephropathy.
7. A method of treating diabetic nephropathy in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 2 .
8. A method of treating chronic kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 2 , wherein the chronic kidney disease is glomerulonephritis, focal segmental glomerulosclerosis, nephrotic syndrome, reflux uropathy, or polycystic kidney disease.
9. 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 compound of claim 2 , 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.
10. 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 compound of claim 2 , wherein the disease or condition is selected from insulin resistance, retinopathy, diabetic ulcers, radiation-associated necrosis, acute kidney failure or drug-induced nephrotoxicity.
11. A compound of Formula A:
or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 and R 2 is independently selected from —CH 3 or —CD 3 ;
R 3 is —CD 3 ;
R 4 is † CD 2 (CH 2 ) 3 , wherein “†” represents the portion of the R 4 moiety bound to C(Y 1 )(Y 2 ) in the compound;
R 5 is H or D;
Y 1 is OH; and
Y 2 is hydrogen, wherein the isotopic enrichment factor for each designated deuterium atom is at least 5000.
12. The compound of claim 11 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
13. The compound of claim 11 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6000.
14. The compound of claim 11 , wherein isotopic enrichment factor for each designated deuterium atom is at least 6600.
15. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier.
16. A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 12 wherein the disease is selected from diabetic nephropathy and hypertensive nephropathy.
17. A method of treating diabetic nephropathy in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 12 .
18. A method of treating chronic kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 12 , wherein the chronic kidney disease is glomerulonephritis, focal segmental glomerulosclerosis, nephrotic syndrome, reflux uropathy, or polycystic kidney disease.
19. 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 compound of claim 12 , 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.
20. 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 compound of claim 12 , wherein the disease or condition is selected from insulin resistance, retinopathy, diabetic ulcers, radiation-associated necrosis, acute kidney failure or drug-induced nephrotoxicity.
21. A racemic mixture comprising i) the S-enantiomer of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and ii) the R-enantiomer of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
22. A racemic mixture comprising i) the S-enantiomer of the compound of claim 11 or a pharmaceutically acceptable salt thereof; and ii) the R-enantiomer of the compound of claim 11 or a pharmaceutically acceptable salt thereof.