Aminoalkylphenols, methods of using and making the same
View Patent ↗The present invention relates to Mannich base antimalarial aminoalkylphenol compounds and their use against protozoa of the genus Plasmodium , particularly emerging strains of drug-resistant Plasmodia. This invention further relates to compositions containing such compounds and a process for making the compounds. This and other aspects of the invention are realized upon review of the entire specification.
1. A method for the treatment of malaria which comprises administering to a patient in need of such treatment a compound of formula I:
wherein,
R 5 is hydrogen;
R 1a and R 1 independently are tert-butyl, halo, C 1-6 alkoxy, C 3-10 cycloalkyl, C 6-10 aryl, or trihalovinyl, wherein said aryl is optionally substituted with 1-3 groups of R a ;
each R 2 is hydrogen;
R 3 and R 3a are independently hydrogen, halo, C 1-6 alkyl, C 3-10 cycloalkyl, or C 6-10 aryl, wherein said aryl and alkyl optionally substituted with 1-3 groups of R a ;
R 4 is hydrogen;
R a represents C 1-6 alkoxy, C 1-6 alkyl, CF 3 , nitro, amino, cyano, C 1-6 alkylamino, or halogen; and
n represents 1-3;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.
2. A method according to claim 1 wherein the compound is selected from the group consisting of:
2-aminomethyl-5-tert-butyl-3-phenylphenol,
2-aminomethyl-5-tert-butyl-3-(4-methylphenyl)phenol,
2-(aminomethyl)-3,5-di-tert-butyiphenol,
2-(2-aminoethyl)-3,5-di-tert-butyiphenol,
2-(aminomethyl)-3,5-bis(trichlorovinyl)phenol,
2-(1-aminoethyl)-3,5-di-tert-butyiphenol,
and pharmaceutically acceptable salts thereof.
3. A method according to claim 1 wherein a second anti-malarial agent is administered and said second anti-malarial agent selected from the group consisting of Chloroquine, Fansidar, Amodiaquine, Quinine, Halofantrine, Mefloquine, Artemether/Artesunate and Malarone.
4. A method according to claim 1 , wherein in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a and R 1 independently are tert-butyl, 1,2,2-trichlorovinyl, or phenyl.
5. A method according to claim 1 , wherein in the compound of formula I or a pharmaceutically acceptable salt thereof, n is 1.
6. A method according to claim 1 , wherein in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a and R 1 independently are tert-butyl, 1,2,2-trichlorovinyl, or phenyl; and n is 1.
7. A method according to claim 6 , wherein in the compound of formula I or a pharmaceutically acceptable salt thereof, R 1a and R 1 are tert-butyl; and R 2 is hydrogen.
8. A method according to claim 7 , wherein the compound of formula I is 2-(aminomethyl)-3,5-di-tert-butylphenol or a pharmaceutically acceptable salt thereof.
9. A method according to claim 8 , wherein the compound of formula I is 2-(aminomethyl)-3,5-di-tert-butylphenol hydrochloride.
10. A method according to claim 8 , wherein a second anti-malarial agent is administered and said second anti-malarial agent selected from the group consisting of Chloroquine, Fansidar, Amodiaquine, Quinine, Halofantrine, Mefloquine, Artemether/Artesunate and Malarone.
11. A method according to claim 8 , wherein the compound or its pharmaceutically acceptable salt is a component in a pharmaceutical composition that also comprises a pharmaceutically acceptable carrier.
12. A method according to claim 1 , wherein the compound of formula I or its pharmaceutically acceptable salt is a component in a pharmaceutical composition that also comprises a pharmaceutically acceptable carrier.