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,
wherein at least one of X 1 , X 2 , and X 3 is F.
2. The compound of claim 1 of formula I:
or a pharmaceutically acceptable salt or solvate thereof.
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.
6. The compound of claim 5 , wherein X 6 is fluorine and one of X 1 , X 2 , and X 3 is fluorine.
7. A compound of claim 1 selected from
Com-
pound #
Chemical Structure
2A
3A
4A
10A
or a pharmaceutically acceptable salt or solvate thereof.
8. 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.
9. 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.
10. 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.
11. The method of claim 10 , wherein the disease is epilepsy.
12. The compound of claim 5 , wherein one of X 1 , X 2 , X 3 , and X 6 is 18F.
13. The compound of claim 12 , wherein at least one of X 1 , X 2 , and X 3 is 19F.
14. The compound of claim 12 , wherein X 6 is 19F or 18F.
15. The compound of claim 12 selected from
Com-
pound #
Chemical Structure
6A
9A
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising at least one compound according to claim 12 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier or excipient.
17. A method of imaging (1) the functional status of the KCNQ2/3 potassium channel, (2) the biodistribution of a compound according to claim 12 , 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 a compound according to claim 12 or a pharmaceutically acceptable salt thereof and imaging the subject using positron emission tomography.