Methods and compositions of novel triazine compounds
View Patent ↗The present invention relates to methods and compositions comprising compounds that treat pathophysiological conditions arising from inflammatory responses. In particular, the present invention is directed to compounds that inhibit or block glycated protein produced induction of the signaling-associated inflammatory response in endothelial cells. The present invention relates to compounds that inhibit smooth muscle proliferation. In particular, the present invention is directed to compounds that inhibit smooth muscle cell proliferation by modulating HSPGs such as Perlecan. The present invention further relates to the use of compounds to treat vascular occlusive conditions characterized by smooth muscle proliferation such as restenosis and atherosclerosis.
1. A compound of the formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein:
R 1 in each occurrence is selected independently from H; linear or branched alkyl with up to 10 carbon atoms; cycloalkyl with up to 10 carbon atoms; or (CH 2 ) x CN, wherein x is 0 or 1;
E is CH or N;
n is 0 or 1;
X 1 is selected from H, m-F, m-Cl, m-Br, m-I, m-SO 2 R 1 , m-SO 2 OR 1 , or m-NC(O)R 1 ;
X 2 is selected from H, o-R 1 , p-OR 1 , p-SR 1 , p-F, p-Cl, p-Br, p-CF 3 , p-C(O)OR 1 , p-NC(O)R 1 , p-(4-morpholinyl), or p-(4-methyl-1-piperazinyl);
A is NR 1 or O;
Y 1 is selected from cycloalkyl with up to 10 carbon atoms, cycloalkyl with up to 10 carbon atoms substituted with at least one substituent R 1 , linear or branched alkyl with up to 10 carbon atoms, CH 2 R 1 , (CHR 1 ) y OR 1 , wherein y is an integer from 1 to 3, or
or AY 1 is
wherein x is an integer from 3 to 5; and
D is NR 1 and Y 2 is selected from
cycloalkyl with up to 10 carbon atoms, cycloalkyl with up to 10 carbon atoms substituted with at least one substituent R 1 , linear or branched alkyl with up to 10 carbon atoms, CH 2 R 1 ,
wherein x is an integer from 3 to 5, or
or DY 2 is selected from
C(O)R 1 , C(O)OR 1 , pyridinyl, aryl,
and wherein q is an integer from 0 to 6.
2. A composition comprising a pharmaceutically acceptable carrier and one or more compounds of the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof; wherein:
R 1 in each occurrence is selected independently from H; linear or branched alkyl with up to 10 carbon atoms; cycloalkyl with up to 10 carbon atoms; or (CH 2 ) x CN, wherein x is 0 or 1;
E is CH or N;
n is 0 or 1;
X 1 is selected from H, m-F, m-Cl, m-Br, m-I, m-SO 2 R 1 , m-SO 2 OR 1 , or m-NC(O)R 1 ;
X 2 is selected from H, o-R 1 , p-OR 1 , p-SR 1 , p-F, p-Cl, p-Br, p-CF 3 , p-C(O)OR 1 , p-NC(O)R 1 , p-(4-morpholinyl), or p-(4-methyl-1-piperazinyl);
A is NR 1 or O;
Y 1 is selected from cycloalkyl with up to 10 carbon atoms, cycloalkyl with up to 10 carbon atoms substituted with at least one substituent R 1 , linear or branched alkyl with up to 10 carbon atoms, CH 2 R 1 , (CHR 1 ) y OR 1 , wherein y is an integer from 1 to 3, or
or AY 1 is
wherein x is an integer from 3 to 5; and
D is NR 1 and Y 2 is selected from
cycloalkyl with up to 10 carbon atoms, cycloalkyl with up to 10 carbon atoms substituted with at least one substituent R 1 , linear or branched alkyl with up to 10 carbon atoms, CH 2 R 1 ,
wherein x is an integer from 3 to 5, or
or DY 2 is selected from
C(O)R 1 , C(O)OR 1 , pyridinyl, aryl,
and wherein q is an integer from 0 to 6.
3. The composition as claimed in claim 2 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative; and
optionally, a pharmaceutically acceptable excipient.
4. The composition as claimed in claim 2 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
5. A compound of the formula Ib:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
R 1b is selected from
R 2b is selected from
R 3b is selected from
R 4b is selected from —H, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ;
R 5b is selected from
R 6b is selected from
and
R 7b is selected from
6. A composition comprising a pharmaceutically acceptable carrier and one or more compounds of the formula Ib:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, wherein:
R 1b is selected from
R 2b is selected from
R 3b is selected from
R 4b is selected from —H, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ;
R 5b is selected from
R 6b is selected from
and
R 7b is selected from
7. The composition as claimed in claim 6 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative; and
optionally, a pharmaceutically acceptable excipient.
8. The composition as claimed in claim 6 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
9. A compound having the following formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
wherein R 1b is selected from
R 6b is selected from
10. A compound according to claim 9 , wherein the compound has the following formula:
11. A compound according to claim 9 , wherein the compound has the following formula:
wherein R 1b is selected from
12. A compound according to claim 9 , wherein R 6b is selected from >NH, >NCH 3 , >NCH 2 CH 3 , or >NC≡N.
13. A compound according to claim 9 , wherein the compound has the following formula:
wherein R 1b is selected from
14. A compound according to claim 9 , wherein the compound has the following formula:
wherein R 1b is selected from
15. A composition comprising a pharmaceutically acceptable carrier and one or more compounds having the following formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
wherein R 1b is selected from
R 6b is selected from
16. The composition as claimed in claim 15 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative; and
optionally, a pharmaceutically acceptable excipient.
17. The composition as claimed in claim 15 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
18. A compound having the following formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
wherein R 1b is selected from
R 3b is selected from
19. A compound according to claim 18 , wherein the compound has the following formula:
20. A compound according to claim 18 , wherein the compound has the following formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
wherein R 1b is selected from
21. A composition comprising a pharmaceutically acceptable carrier and one or more compounds having the following formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
wherein R 1b is selected from
R 3b is selected from
22. The composition as claimed in claim 21 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative; and
optionally, a pharmaceutically acceptable excipient.
23. The composition as claimed in claim 21 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
24. A compound having the following formula:
wherein:
R 1b is selected from
R 2b is selected from
R 3b is selected from
25. A compound according to claim 24 , wherein R 2b is selected from
26. A composition comprising a pharmaceutically acceptable carrier and one or more compounds having the following formula:
wherein:
R 3b is selected from
27. The composition as claimed in claim 26 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative; and
optionally, a pharmaceutically acceptable excipient.
28. The composition as claimed in claim 26 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
29. A compound of the formula Ib:
wherein:
R 1b is selected from
R 2b is
R 3b is
R 4b is —H;
R 5b is selected from
R 7b is selected from
30. A compound according to claim 29 , wherein R 7b is
31. A compound according to claim 29 , wherein:
R 5b is selected from
32. A compound according to claim 29 , wherein R 7b is selected from
33. A composition comprising a pharmaceutically acceptable carrier and one or more compounds having the following formula:
wherein:
R 1b is selected from
R 4b is
R 4b is —H;
R 5b is selected from
R 7b is selected from
34. The composition as claimed in claim 33 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative; and
optionally, a pharmaceutically acceptable excipient.
35. The composition as claimed in claim 33 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
36. A compound having the following formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
wherein R 1b is selected from
R 4b is selected from —H, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 .
37. A composition comprising a pharmaceutically acceptable carrier and one or more compounds having the following formula:
or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof;
wherein R 1b is selected from
R 4b is selected from —H, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 .
38. The composition as claimed in claim 37 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative; and
optionally, a pharmaceutically acceptable excipient.
39. The composition as claimed in claim 37 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.