FLUORINATED 2-AMINO-4-(BENZYLAMINO)PHENYLCARBAMATE DERIVATIVES
The invention relates to fluorinated compounds and their use as anti-epileptic, muscle-relaxing, fever-reducing and peripherally analgesically acting medications and as imaging agents. Novel fluorinated 2-amino-4-(benzylamino)phenyl carbamate derivatives of ezogabine and pharmaceutically acceptable salts or solvates thereof and their use are described.
1 . A compound of formula A:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are each independently selected from hydrogen, deuterium, and F;
X 9 and X 10 are each independently selected from hydrogen and deuterium; and
n is 1, 2, or 3,
provided that when X 6 is F, then X 1 , X 2 , X 3 , X 4 , X 5 , X 7 and X 8 are not all hydrogen.
2 . The compound of claim 1 of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from hydrogen, deuterium, and F, wherein at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 is F, provided that when X 6 is F, then X 1 , X 2 , X 3 , X 4 , X 5 , X 7 and X 8 are not all hydrogen.
3 . The compound of claim 2 , wherein two of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are F.
4 . The compound of claim 2 , wherein three of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are F.
5 . The compound of claim 1 of formula IV:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X 1 , X 2 , X 3 , and X 6 are each independently selected from hydrogen, deuterium, and F, provided that when X 6 is F, then X 1 , X 2 , and X 3 are not all hydrogen.
6 . The compound of claim 5 , wherein at least one of X 1 , X 2 , and X 3 is fluorine.
7 . The compound of claim 5 , wherein X 6 is fluorine and one of X 1 , X 2 , and X 3 is fluorine.
8 . A compound of claim 1 selected from
Compound #
Chemical Structure
2A
3A
4A
and
10A
or a pharmaceutically acceptable salt or solvate thereof.
9 . A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carrier or excipient.
10 . A method of treating a subject suffering from or susceptible to conditions ameliorated by KCNQ2/3 potassium channel opening, comprising administering to the subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.
11 . A method of treating or preventing a disease or disorder selected from epilepsy, neurodegenerative disorder, cognitive disorder, cancer, inflammatory disease, ophthalmic disease, migraine, bipolar disorder, unipolar depression, functional bowel disorder, or tinnitus in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.
12 . The method of claim 11 , wherein the disease is epilepsy.
13 . An 18F compound of formula V:
or a pharmaceutically acceptable salt thereof, wherein:
A is N or C—X 3 ;
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are each independently selected from hydrogen, 19F and 18F; and
n is 2 or 3,
provided that one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is 18F.
14 . The 18F compound of claim 13 , wherein at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is 19F.
15 . The 18F compound of claim 13 of formula VII:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 2 , X 3 , and X 6 are each independently selected from hydrogen, 18F, and 19F, provided that one of X 1 , X 2 , X 3 , and X 6 is 18F.
16 . The 18F compound of claim 15 , wherein at least one of X 1 , X 2 , and X 3 is 19F.
17 . The 18F compound of claim 15 , wherein X 6 is 19F or 18F.
18 . The 18F compound of claim 13 selected from
Compound #
Chemical Structure
5A
6A
7A
8A
and
9A
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising at least one 18F compound according to claim 13 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or excipient.
20 . A method of imaging (1) the functional status of the KCNQ2/3 potassium channel, (2) the biodistribution of an 18F compound according to claim 13 , or (3) a disorder or disease selected from a neurotransmission disorder, CNS disorder, cognitive disorder, and neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of an 18F compound according to claim 13 or a pharmaceutically acceptable salt thereof and imaging the subject using positron emission tomography.