GluN2C/D subunit selective antagonists of the N-methyl-D-aspartate receptor
A compound according to Formula (I) or salts or prodrugs thereof and pharmaceutical formulations comprising the compound are provided herein for the treatment of neurological disorders. The disorders may include providing neuroprotection, preventing neurodegeneration, treating neuropathic pain or treating schizophrenia, psychoses or depression. Furthermore, the compounds may be used in combination with another active ingredient.
1. A compound of Formula (I) or a salt thereof,
wherein R 1 , R 5 , and R 7 , in each occurrence, are individually and independently a C1 to C3 alkyl, alkoxy, halogen, or trifluoroalkyl;
wherein R 2 , R 3 , R 2′ , and R 3′ are individually and independently H or a halogen;
wherein R 4 is an amino, hydroxyl, or C1 to C3 alkoxy;
wherein R 6 and R 6′ are individually and independently S, O, or absent;
wherein when R 6 is absent, the carbon connected to R 6 is —CH 2 —;
wherein Ring A is a 5 or 6 membered aryl or heteroaryl or absent;
wherein Ring B is thiophene or furan;
wherein Ring C is a monocyclic or bicyclic aryl or heteroaryl ring;
wherein the dashed bond represented by is a single bond or a double bond;
wherein when the dashed bond represented by is a double bond, R 3 and R 3′ are absent;
wherein n, in each occurrence, is individually and independently 0, 1, 2, or 3; and
wherein R 1 , R 2 , R 3 , R 2′ , R 3′ , R 4 , R 5 , and R 7 , in each occurrence, are, individually and independently, optionally substituted with R 10 , which is a halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
2. The compound of claim 1 , wherein R 4 is NH 2 , OH, OMe, or OEt.
3. The compound of claim 1 , wherein R 6′ is S or O when Ring C is a bicyclic aryl or heteroaryl ring or is absent when Ring C is a monocyclic aryl or heteroaryl ring.
4. The compound of claim 1 , wherein R 1 and R 5 , in each occurrence, are individually and independently chloro or fluoro.
5. The compound of claim 1 , wherein each of R 2 and R 3 is fluoro when each of R 2′ and R 3′ is H or wherein each of R 2 and R 3 is H when each of R 2′ and R 3′ is fluoro.
6. The compound of claim 1 , wherein Ring A is a phenyl, pyridine, pyrazine, or thiophene and Ring C is a phenyl or a quinolinone or quinolinethione ring system.
7. The compound of claim 1 , wherein Ring C is a bicyclic aryl or heteroaryl ring.
8. The compound of claim 1 , wherein R 6′ is O.
9. The compound of claim 1 , wherein the dashed bond represented by is a single bond.
10. The compound of claim 1 , wherein Ring A, when considered together with its R 5 substituent(s), is:
11. The compound of claim 1 , wherein Ring B, when considered together with its R 1 substituent(s), is
12. The compound of claim 1 , which is a compound of Formula (IE) or (IF), or a salt thereof;
wherein R 1 , R 2 , R 3 , R 2′ , R 3′ , R 4 , R 5 , R 6 , R 6′ , R 7 , and n are as defined in claim 1 ;
wherein Y, in each occurrence, is independently N or CH; and
wherein Z is S or O.
13. The compound of claim 1 , which is
or a salt thereof.
14. A composition comprising a compound of claim 1 , wherein the compound is a purified S enantiomer of Formula (I) as shown below:
or a salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of tablets, capsules, pills, gels, granules, aerosols, aqueous buffers, nanoparticle formulations, emulsions, or liposomes.
16. The pharmaceutical composition of claim 15 , further comprising one or more further active agents.
17. A method of treating a neurological disorder in a subject in need thereof, the method comprising administering an effective amount of a compound of claim 1 to the subject.
18. The method of claim 17 , wherein the treating of the neurological disorder comprises providing neuroprotection, preventing neurodegeneration, treating neuropathic pain, or treating schizophrenia, psychoses, or depression.
19. The method of claim 17 , wherein the compound is administered in combination with one or more further active agents.
20. The method of claim 17 , wherein the compound is administered orally.