Sulfoxyalkyl organonitro and related compounds and pharmaceutical compounds for use in medicine

Patent metadata

Field	Value
Publication number	US-11008287-B2
Application number	US-201716341538-A
Country	US
Kind code	B2
Filing date	Oct 13, 2017
Priority date	Oct 14, 2016
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Epicentrx Inc

Inventors

• Oronsky Bryan T
• Scicinski Jan

Classifications

• C07K5/0606

  the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr · CPC title

• C07K5/0215

  containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu · CPC title

• C07D205/04 Primary

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C07C2601/04

  with a four-membered ring · CPC title