Compounds and methods for treating spasticity
Provided herein are methods of treating and preventing spasticity in a patient in need thereof. A particular method comprises administering an effective amount of an adaptor associated kinase 1 inhibitor of Formula (I):
1 . A method of treating or preventing cerebral spasticity, which comprises administering a therapeutically or prophylactically effective amount of an adaptor associated kinase 1 (AAK1) inhibitor to a patient in need thereof, wherein the AAK1 inhibitor is a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from
wherein “ ” denotes the point of attachment to B;
B is selected from
wherein “*” indicates the point of attachment to R 5 and “**” indicates the point of attachment to ring A;
R 1 is selected from hydrogen, amino, —CO 2 H, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methyl, —NHC(O)CH 3 , —NHCO 2 CH 3 , trifluoromethoxy, and trifluoromethyl;
R 2 is selected from hydrogen, cyano, —CH 2 OH, halo, and methyl;
R 3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy, trifluoromethyl, —CH 2 N(CH 3 ) 2 , and a five-membered aromatic ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur;
R 4 is selected from hydrogen, halo, and methyl;
R 5 is selected from
R 6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl; and
R 7 is methyl.
2 . The method of claim 1 , wherein the AAK1 inhibitor is a compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from
R 1 is selected from hydrogen, difluoromethyl, halo, methoxy, methyl, —NHC(O)CH 3 , —NHCO 2 CH 3 , and trifluoromethyl;
R 2 is selected from hydrogen, —CH 2 OH, and halo; and
R 3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, trifluoromethoxy, trifluoromethyl, and a five-membered aromatic ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur.
3 . The method of claim 2 , wherein A is
4 . The method of claim 2 , wherein B is
5 . The method of claim 1 , wherein the patient suffers from amyotrophic lateral sclerosis, cerebral palsy, multiple sclerosis, or stroke.
6 . A method of treating or preventing cerebral spasticity which comprises administering a therapeutically or prophylactically effective amount of an adaptor associated kinase 1 (AAK1) inhibitor to a patient in need thereof, wherein the AAK1 inhibitor is(S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine:
or a pharmaceutically acceptable salt thereof.
7 . The method of claim 6 , wherein the AAK1 inhibitor is ((S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate.
8 . The method of claim 7 , wherein the AAK1 inhibitor has a melting point of 184±2° C.
9 . The method of claim 6 , wherein the patient suffers from amyotrophic lateral sclerosis, cerebral palsy, multiple sclerosis, or stroke.
10 . The method of claim 6 , wherein the AAK1 inhibitor is administered orally.