Substituted triazoles and methods relating thereto
Substituted 1,2,3-triazole compounds are disclosed which have utility in the treatment of a variety of neurological disorders. The compounds provided herein have the general structure: wherein R 1 , R 2 , R 3 and n are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound provided herein in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for treating neurological disorders in a subject in need thereof.
1. A pharmaceutical composition comprising a compound having the following structure (A):
or a solvate, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent, wherein:
(i):
R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, —C(═O)OR 4 , —C(═O)—C 1-6 alkanediyl-NH 2 , —C(═O)NR 5 R 5 , or —C(═O)R 6 , wherein said C 1-6 alkanediyl is optionally substituted with a group selected from —NH—C(═NH)NH 2 , —CO 2 H, —CO 2 CH 3 , —SH, —C(═O)NH 2 , —NH 2 , —SCH 3 , phenyl, —OH, —OC 1-4 alkyl, 4 -hydroxy-phenyl, imidazolyl, cyclohexyl, and indolyl;
R 3 at each occurrence is Cl, F, C 1-4 alkyl, —OC 1-4 alkyl or trifluoromethyl;
R 4 at each occurrence is C 1-4 alkyl;
R 5 at each occurrence is independently H or C 1-4 alkyl;
R 6 is C 2-4 alkyl, 5-6 member nonaromatic heterocycle, or 5-6 member heterocycleC 1-4 alkyl wherein 5-6 member heterocycleC 1-4 alkyl is optionally substituted with OH, Cl, F, C 1-4 alkyl, —OC 1-4 alkyl or trifluoromethyl; and
n is 0-3; or
(ii):
R 1 and R 2 taken together with the N to which they are attached are a 5-6 member nonaromatic heterocycle substituted with 0-3 R 4 ;
R 3 at each occurrence is Cl, F, C 1-4 alkyl, —OC 1-4 alkyl or trifluoromethyl;
R 4 at each occurrence is C 1-4 alkyl; and
n is 1-3.
2. The pharmaceutical composition of claim 1 , wherein n is 1 or 2.
3. The pharmaceutical composition of claim 2 , wherein R 3 is F.
4. The pharmaceutical composition of claim 1 , wherein R 1 is H.
5. The pharmaceutical composition of claim 1 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
6. The pharmaceutical composition of claim 1 , wherein R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, —C(═O)OR 4 , —C(═O)NR 5 R 5 , or —C(═O)R 6 .
7. The pharmaceutical composition of claim 1 , wherein R 2 is —C(═O)—C 1-6 alkanediyl—NH 2 , wherein the C 1-6 alkanediyl is optionally substituted with a group selected from —NH—C(═NH)NH 2 , —CO 2 H, —CO 2 CH 3 , —SH, —C(═O)NH 2 , —NH 2 , —SCH 3 , phenyl, —OH, —OC 1-4 alkyl, 4-hydroxy-phenyl, cyclohexyl, imidazolyl, and indolyl.
8. The pharmaceutical composition of claim 1 , wherein R 1 and R 2 are both methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
9. The pharmaceutical composition of claim 1 , wherein R 3 is Cl, F, or trifluoromethyl.
10. The pharmaceutical composition of claim 1 , wherein R 3 is C 1-4 alkyl or —OC 1-4 alkyl.
11. The pharmaceutical composition of claim 1 , wherein R 6 is a 5 - 6 member nonaromatic heterocycle, or R 6 is a 5-6 member heterocycleC 1-4 alkyl which is optionally substituted with OH, Cl, F, C 1-4 alkyl, —OC 1-4 alkyl, or trifluoromethyl.
12. The pharmaceutical composition of claim 1 , wherein:
R 1 and R 2 taken together with the N to which they are attached are a 5-6 member nonaromatic heterocycle substituted with 0-3 R 4 ;
R 3 at each occurrence is Cl, F, C 1-4 alkyl, —OC 1-4 alkyl, or trifluoromethyl;
R 4 at each occurrence is C 1-4 alkyl; and
n is 1-3.
13. The pharmaceutical composition of claim 12 , wherein n is 1 or 2.
14. The pharmaceutical composition of claim 13 , wherein R 3 is F.
15. The pharmaceutical composition of claim 12 , wherein R 3 is C 1-4 alkyl, —OC 1-4 alkyl, trifluoromethyl, or Cl.
16. The pharmaceutical composition of claim 12 , wherein R 1 and R 2 taken together with the N to which they are attached are piperidine, morpholine, piperazine, oxazolidine, or pyrrolidine, each substituted with 0-3 R 4 .
17. The pharmaceutical composition of claim 12 , wherein R 4 is methyl or ethyl.
18. A pharmaceutical composition comprising one of the following compounds:
or a solvate or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
19. The pharmaceutical composition of claim 18 , wherein the compound is
or a solvate or pharmaceutically acceptable salt thereof.
20. A method for treating a neurological condition of a subject having said neurological condition, wherein the neurological condition is essential tremor, epilepsy, status epilepticus, or nerve agent exposure, comprising administering to the subject an effective amount of a pharmaceutical composition of claim 1 .