Substituted heteroarylalkanoic acids
View Patent ↗Disclosed are substituted heteroarylalkanoic acids acids of the following formula D-A-C(O)R′, where D, A, and R′ are defined herein. These compounds are useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as well as methods for their synthesis.
1. A compound of the formula
D-A-C(O)R′
or a pharmaceutically acceptable salt thereof wherein
D represents
where
Y is -Z-Ar where
Z is a bond, O, S, C(O)NH, or C 1 -C 6 alkylene optionally substituted with C 1 -C 2 alkyl; and
Ar represents benzothiazolyl or benzothiazolyl(C 1 -C 6 )alkyl, where the benzothiazolyl portion is optionally substituted by one, two or three groups independently selected from
(1) halogen, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 27 , SR 27 , S(O)R 27 , S(O) 2 R 27 and N(R 27 ) 2 wherein each R 27 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy; and
(2) phenyl, pyridyl, furyl, and thienyl, each of which is optionally substituted with one, two, or three groups independently selected from halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 37 , SR 37 , S(O) R 37 , S(O)2R 37 and N(R 37 ) 2 wherein each R 37 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy;
R 3 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, aryl, —SR 15 or —OR 15 , where R 15 is (C 1 -C 6 )alkyl, aryl, or aryl(C 1 -C 6 )alkyl where each aryl is optionally mono-, di-, or trisubstituted with halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7 , and N(R 7 ) 2 ,
R 5 represents hydrogen, halogen, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy, amino, mono or di(C 1 -C 6 )alkylamino, or aryl where aryl is optionally substituted with up to three groups independently selected from halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7 and N(R 7 ) 2 ;
each R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy;
A is a C 1 -C 4 alkylene group optionally substituted with C 1 -C 2 alkyl or mono- or disubstituted with halogen; and
R′ is hydroxy, benzyloxy, di(C 1 -C 6 )alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-yl methyl, or (C 1 -C 6 )alkoxy optionally substituted by N-morpholino or di(C 1 -C 6 )alkylamino.
2. A compound according to claim 1 , wherein Z is (C 1 -C 6 )alkylene and Ar is a substituted benzothiazole of Formula III
wherein R 11 , R 12 , R 13 and R 14 are independently hydrogen, halogen, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7 or N(R 7 ).
3. A compound according to claim 2 , wherein R 11 , R 12 , R 13 and R 14 are independently hydrogen, hydroxy, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )haloalkyl, cyano, nitro, or N(R 7 ) 2 wherein each R 7 is independently hydrogen or C 1 -C 6 alkyl.
4. A compound according to claim 3 , wherein R 11 , R 12 , R 13 and R 14 are independently hydrogen, fluorine, chlorine, bromine, trifluoromethyl or nitro.
5. A compound according to claim 3 , wherein Z is (C 1 -C 3 )alkylene.
6. A compound according to claim 5 , wherein A and Z are both methylene.
7. A compound according to claim 6 , wherein R′ is hydroxy or C 1 -C 6 alkoxy.
8. A compound according to claim 7 where each R 3 is independently hydrogen, C 1 -C 6 alkyl, or phenyl(C 1 -C 6 )alkyl where the phenyl portion is optionally substituted with one, two or three groups independently selected from halogen, hydroxy, C 1 -C 6 alkyl, amino, (C 1 -C 6 )alkylamino, and di(C 1 -C 6 )alkylamino.
9. A compound according to claim 7 , where D is
where each R 5 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, mono- or di(C 1 -C 6 )alkylamino, or phenyl(C 1 -C 6 )alkyl, phenoxy or phenyl where each phenyl portion is optionally mono, di, or trisubstituted with independently selected hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, or mono- or di(C 1 -C 6 )alkylamino groups.
10. A compound according to claim 9 , wherein D is
where R 5 and R 5 ′ independently represent hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or phenyl(C 1 -C 6 )alkyl, phenoxy or phenyl where each phenyl portion is optionally substituted with one or two independently selected hydroxy, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy groups.
11. A compound according to claim 5 , wherein R 11 , R 12 , R 13 and R 14 are independently hydrogen, hydroxy, (C 1 -C 2 )alkoxy, trifluoromethyl, (C 1 -C 3 )alkyl, fluoro, chloro, bromo, nitro, amino, mono(C 1 -C 2 )alkylamino or di(C 1 -C 2 )alkylamino.
12. A compound according to claim 5 , wherein R 11 , R 12 , R 13 and R 14 are independently hydrogen, hydroxy, fluoro, chloro, nitro, or amino.
13. A compound according to claim 5 , wherein three of R 11 , R 12 , R 13 and R 14 are fluoro and the other is hydrogen.
14. A compound according to claim 5 where at least one of R 11 , R 12 , R 13 , and R 14 is trifluoromethyl.
15. A compound according to claim 10 , wherein R 12 is trifluoromethyl.
16. A compound according to claim 7 , wherein R 11 , R 12 , and R 14 represent fluorine and R 13 is hydrogen.
17. A compound according to claim 14 , wherein R 11 , R 12 , and R 14 represent fluorine and R 13 is hydrogen.
18. A compound according to claim 5 , wherein R′ is hydroxy.
19. A compound according to claim 5 , wherein R′ is C 1 -C 6 alkoxy.
20. A compound according to claim 1 , which is
[2,6-Dimethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
21. A compound according to claim 1 , which is
[2,6-Diethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
22. A compound according to claim 1 , which is
[2,6-Diphenyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
23. A compound according to claim 1 , which is
[2,6-Dipropyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
24. A compound according to claim 1 , which is
[5-(4,5,7-Trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
25. A compound according to claim 1 , which is
[2,4,6-Trimethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
26. A compound according to claim 1 , which is
[4-Ethyl-2,6-dimethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
27. A compound according to claim 1 , which is
[2-Ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
28. A compound according to claim 1 , which is
[2-Benzyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
29. A compound according to claim 1 , which is
[2-Phenyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
30. A compound according to claim 1 , which is
[6-Ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
31. A compound according to claim 1 , which is
[6-Phenyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
32. A compound according to claim 1 , which is
[6-Benzyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
33. A compound according to claim 1 , which is
[2-Phenoxy-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]-acetic acid.
34. A method of alleviating chronic complications arising from diabetes mellitus, where the chronic complications are selected from the group consisting of diabetic cataracts, retinopathy, nephropathy and neuropathy, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1 .
35. A method for reducing serum uric acid levels, wherein the method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .
36. A method for treating gout, wherein the method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .