Sulfoxyalkyl organonitro and related compounds and pharmaceutical compounds for use in medicine
The invention provides sulfoxyalkyl organonitro and related compounds, compositions containing such compounds, and methods for using such compounds and compositions to treat medical disorders, such as a neurodegenerative disorder, autoimmune disease, infection, or cancer in a patient. Exemplary sulfoxyalkyl organonitro compounds described herein include ((2-(3,3-dinitroaze-tidin-1-yl)-2-oxoethyl)sulfinyl)-D-alanine and variants thereof.
1. A compound of Formula I or II, wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —N(R 5 )— or —C(R 2 )(R 3 )—;
A 2 is —C(O)— or —(C(R 6 ) 2 ) x C(O)(C(R 6 ) 2 ) x —;
R 1 is C 1 -C 5 alkyl or C 3 -C 7 cycloalkyl;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a carbocyclic ring;
R 4 is C 1 -C 5 alkyl substituted with one X 1 group and one X 2 group; wherein X 1 is —N(R 7 )(R 8 ), —N(R 7 )C(O) k —C 1 -C 5 alkyl, —N(R 7 )C(O) k —C 3 -C 7 cycloalkyl, —N(R 7 )C(O) k -aryl, —N(R 7 )C(O) k -aralkyl, or —N(R 7 )C(O)—(C 1 -C 5 alkylene)—C(H)[N(R 7 )(R 8 )]—CO 2 R 9 ; and X 2 is —CO 2 R 10 or —C(O)N(R 7 )—(C 1 -C 5 alkylene)—CO 2 R 10 ;
R 5 is hydrogen or C 1 -C 5 alkyl;
R 6 represents independently for each occurrence C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, aryl, or aralkyl;
R 7 and R 8 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl; or R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;
R 9 and R 10 each represent independently hydrogen, C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl, aryl, or aralkyl;
k and w are independently 1 or 2;
n, p, and t are independently 1, 2, or 3; and
m and x each represent independently for each occurrence 0, 1, 2, 3, or 4;
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —N(R 5 )- or —C(R 2 )(R 3 )—;
A 2 is —C(O)— or —(C(R 6 ) 2 ) x C(O)(C(R 6 ) 2 ) x —;
R 1 is C 1 -C 5 alkyl or C 3 -C 7 cycloalkyl;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl; or
R 2 and R 3 are taken together with the carbon atom to which they are attached to form a carbocyclic ring;
R 4 is C 1 -C 5 alkyl substituted with one X 1 group and one X 2 group; wherein X 1 is —N(R 7 )(R 8 ), —N(R 7 )C(O) k —C 1 -C 5 alkyl, —N(R 7 )C(O) k —C 3 -C 7 cycloalkyl, —N(R 7 )C(O) k -aryl, —N(R 7 )C(O) k -aralkyl, or —N(R 7 )C(O)—(C 1 -C 5 alkylene)-C(H)[N(R 7 )(R 8 )]-CO 2 R 9 ; and X 2 is —CO 2 R 10 or —C(O)N(R 7 )-(C 1 -C 5 alkylene)—CO 2 R 10 ;
R 5 is hydrogen or C 1 -C 5 alkyl;
R 6 represents independently for each occurrence C 1 -C 5 alkyl, C 1 -C 5 haloalkyl, aryl, or aralkyl;
R 7 and R 8 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl; or
R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;
R 9 and R 10 each represent independently hydrogen, C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl, aryl, or aralkyl;
k and w are independently 1 or 2;
t and v are independently 1, 2, or 3; and
x represents independently for each occurrence 0, 1, 2, 3, or 4.
2. The compound of claim 1 , wherein the organonitro compound is a compound of Formula I.
3. The compound of claim 2 , wherein A 1 is N.
4. The compound of claim 2 , wherein A 2 is —C(O)—.
5. The compound of claim 2 , wherein R 2 and R 3 are hydrogen.
6. The compound of claim 2 , wherein m is 0.
7. The compound of claim 2 , wherein n is 2.
8. The compound of claim 2 , wherein t is 1.
9. The compound of claim 2 , wherein p is 1.
10. The compound of claim 2 , wherein R 4 is —CH 2 C(H)(X 1 )X 2 .
11. The compound of claim 2 , wherein X 1 is —NH 2 , —N(H)C(O)CH 3 , or —N(H)C(O)CH 2 CH 2 C(H)(NH 2 )—CO 2 H; and X 2 is —CO 2 H, —CO 2 Me, or —C(O)N(H)CH 2 CO 2 H.
12. The compound of claim 2 , wherein R 4 is
13. The compound of claim 2 , wherein w is 1.
14. The compound of claim 2 , wherein w is 2.
15. The compound of claim 1 , wherein the compound is a compound of Formula I-A:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is N or C(H);
R 1 represents independently for each occurrence hydrogen or methyl;
R 4 is C 1 -C 5 alkyl substituted with one X 1 group and one X 2 group; wherein X 1 is —NH 2 , —N(H)C(O)—C 1 -C 5 alkyl, or —N(H)C(O)-(C 1 -C 5 alkylene)-C(H)(NH 2 )—CO 2 H; and X 2 is —CO 2 H, —CO 2 - C 1 -C 5 alkyl, or —C(O)N(H)CH 2 CO 2 H;
p represents independently for each occurrence 1 or 2; and
w is 1 or 2.
16. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is a compound of Formula II.
19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.