Claims
- 1. A compound represented by the formula I,
- 2. A compound according to claim 1, wherein Ar comprises a ring system selected from the group consisting of benzene, thiazole, furyl, pyranyl, 2H-pyrrolyl, thienyl, pyrollyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalizinyl, naphthyridinyl, quinazolinyl, cinnolinyl, isothiazolyl, quinoxalinyl indolizinyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, and chromenyl rings,
wherein Ar optionally may independently be substituted with up to two C1-C3 alkyl groups, or up to two halogen atoms, where halogen is selected from F, Cl, Br, and I.
- 3. The compound according to claim 1, wherein R contains 7-11 carbon atoms, wherein some or all of the hydrogen atoms on two carbon atoms optionally may be replaced with substituents independently selected from the group consisting of F, Cl, OH, OMe, and ═O.
- 4. The compound according to claim 1, wherein [linker] comprises an amide, ester, or thioester group.
- 5. The compound according to claim 3, wherein R comprises a moiety selected from the group consisting of adamantyl, 2-adamantyl, (1S,2S,3S,5R)-isopinocamphenyl, tricyclo[4.3.1.1(3,8)]undec-3-yl, (1S,2R,5S)-cis-myrtanyl, (1R,2R,4S)-isobornyl (1R,2R,3R,5S)-isopinocamphenyl, (1S,2S,5S)-trans-myrtanyl, (1R,2R,5R)-trans-myrtanyl, (1R,2S,4S)-bornyl, 1-adamantanemethyl, 3-noradamantyl, (1S,2S,3S,5R)-3-pinanemethyl, cyclooctyl, α,α-dimethylphenethyl, (S)-2-phenyl-1-propyl, cycloheptyl, 4-methyl-2-hexyl groups, 2,2,3,3,4,4, 4-heptafluorobutyl, 4-ketoadamantyl, 3-phenyl-2-methylpropyl, 3,5-dimethyladamantyl, trans-2-phenylcyclopropyl, 2-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 2-(o-methoxyphenyl)ethyl, 2-(1,2,3,4-tetrahydronaphthyl), 4-phenylbutyl, 2-methyl-2-phenylbutyl, 2-(m-fluorophenyl)ethyl, 2-(p-fluorophenyl)ethyl, 2-(3-hydroxy-3-phenyl)propyl, (S)-2-hydroxy-2-phenylethyl, (R)-2-hydroxy-2-phenylethyl, 2-(3-m-chlorophenyl-2-methyl)propyl, 2-(3-p-chlorophenyl-2-methyl)propyl, 4-tert-butyl-cyclohexyl, (S)-1-(cyclohexyl)ethyl, 2-(3-(3,4-dimethylphenyl)-2-methyl)propyl, 3,3-dimethylbutyl, 2-(5-methyl)hexyl, 1-myrtanyl, 2-bornyl, 3-pinanemethyl, 2,2,3,3,4,4,5,5-octafluoropentyl, p-fluoro-α,α-dimethylphenethyl, 2-naphthyl, 2-bornanyl, cyclohexylmethyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,4-dimethylcyclohexyl, 5-chloro-tricyclo[2.2.1]heptyl, o-α,α-dimethylphenethyl, 2-indanyl, 2-spiro[4.5]decyl, 2-phenylethyl, 1-adamantylethyl, 1-(1-bicyclo[2.2.1]hept-2-yl)ethyl, 2-(2-methyl-2-phenylpropyl), 2-(o-fluorophenyl)ethyl, 1-(cyclohexyl)ethyl, and cyclohexyl.
- 6. The compound according to claim 1, wherein Ar comprises a group having the formula
- 7. The compound according to claim 6, wherein X1 is N.
- 8. The compound according to claim 7, wherein X2 is N.
- 9. The compound according to claim 6, wherein X3 is N.
- 10. The compound according to claim 6, wherein X1 is CH and X2 is N.
- 11. The compound according to claim 1, wherein Ar is an optionally substituted 2-, 3-, or 4-pyridyl moiety.
- 12. The compound according to claim 1, wherein Ar is a 6-benzothiazolyl moiety.
- 13. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable diluent or excipient.
- 14. A method of making a compound according to claim 4, comprising reacting a compound containing an activated carboxylic acid group with a compound containing an amine, hydroxyl, or thiol group.
- 15. A method of inhibiting activation of an mGluR Group I receptor, comprising treating a cell containing said receptor with an effective amount of a compound-according to claim 1.
- 16. A method of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, comprising treating neurons with an effective amount of a compound according to claim 1.
- 17. A method of treating a disease associated with glutamate-induced neuronal damage, comprising administering to a patient suffering from said disease an effective amount of a composition according to claim 13.
- 18. The compound according to claim 1, wherein said compound is selected from the group consisting of N-[6-(2-Methylquinolyl)]-1-adamantanecarboxamide, N-(6-Quinolyl)-1-adamantanecarboxamide, N-(2-Quinolyl)-1-adamantanecarboxamide, N-(3-Quinolyl)-1-adamantane-carboxamide, 6-Quinolyl-1-adamantanecarboxylate, 1-Adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,5,5-Octafluoro-1-pentyl-6-quinolinecarboxylate, 1-Adamantanemethyl-6-quinolinecarboxylate, 1-Adamantyl-2-quinoxalinecarboxylate, N-(1-Adamantyl)-3-quinoline-carboxamide, N-(1-Adamantyl)-2-quinolinecarboxamide, N-(2-Adamantyl)-2-quinoxalinecarboxamide, N-[(1R,2R,3R,5S)-3-Pinanemethyl]-2-quinoxaline-carboxamide, N-(1-Adamantyl)-2-quinoxalinecarboxamide, N-(1-Adamantyl)-6-quinolinecarboxamide, N-(exo-2-Norbornanyl)-2-quinoxalinecarboxamide, N-[(1R,2S,4S)-Bornyl]-2-quinoxalinecarboxamide, N-(3-Noradamantyl)-2-quinoxalinecarboxamide, N-[(1R,2R, 3R,5S)Iso-pinocamphenyl]-2-quinoxalinecarboxamide, N-[(1S,2S ,3S,5R)-Isopinocamphenyl]-2-quinoxaline-carboxamide, N-(5-Chloro-[2.2.1.0]tricyclo-2,6-hepta-3-yl)-2-quinoxalinecarboxamide, N-([4.3.1.1)Tricyclo-3,8-undeca-3-yl)-2-quinoxalinecarboxamide, N-[(1S,2R,5S)-cis-Myrtanyl]-2-quinoxalinecarboxamide, N-[(1R,2R,4S)Isobornyl]-2-quinoxalinecarboxamide, N-[endo-(±)-2-Norbornanyl]-2-quinoxalinecarboxamide, N-[(R)-2-Phenyl-1 propyl]-2-quinoxalinecarboxamide, N-[(S)-2-Phenyl-1-propyl]-2-quinoxalinecarboxamide, N-(2-Indanyl)-2-quinoxalinecarboxamide, 1-Adamantanemethyl 6-quinolyl ether, 1-Adamantyl-3-quinolinecarboxylate, N-(α,α-Dimethylphenethyl)-2-quinoxalinecarboxamide, N-(α,α-Dimethyl-2-chlorophenethyl)-2-quinoxalinecarboxamide, N-(α,α-Dimethyl-4-fluorophenethyl)-2-quinoxalinecarboxamide, N-(β-Methylphenethyl)-2-quinoxalinecarboxamide, N-(3-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(2,3-Dimethylcyclohexyl)-2-quinoxalinecarboxamide, N-[(1S,2S,3S,5R)-3-Pinanemethyl]-2-quinoxaline-carboxamide, N-(1-Adamantanemethyl)-2-quinoxaline-carboxamide, N-(4-Methylcyclohexyl)-2-quinoxaline-carboxamide, N-[(1S,2S ,5S)-trans-Myrtanyl]-2-quinoxaline-carboxamide, and N-[(1R,2R,5R)-trans-Myrtanyl]-2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
- 19. The compound according to claim 1, wherein said compound is selected from the group consisting of N-(1-Adamantyl)-3-quinolinecarboxamide, N-(1-Adamantyl)-2-quinolinecarboxamide, N-(2-Adamantyl)-2-quinoxaline-carboxamide, N-[(1R,2R,3R,5S)-3-Pinanemethyl]-2-quinoxaline-carboxamide, N-(1-Adamantyl)-2-quinoxaline-carboxamide, N-(1-Adamantyl)-6-quinolinecarboxamide, N-(exo-2-Norbornanyl)-2-quinoxaline-carboxamide, N-[(1R,2S,4S)-Bornyl]-2-quinoxaline-carboxamide, N-(3-Noradamantyl)-2-quinoxaline-carboxamide, N-[(1R,2R,3R,5S)-Isopinocamphenyl]-2-quinoxaline-carboxamide, N-[(1S,2S,3S,5R)-Isopinocamphenyl]-2-quinoxaline-carboxamide, N-(5-Chloro-[2.2.1.0]tricyclo-2,6-hepta-3-yl)-2-quinoxaline-carboxamide, N-([4.3.1.1]Tricyclo-3,8-undeca-3-yl)-2-quinoxaline-carboxamide, N-[(1S,2R,5S)-cis-Myrtanyl]-2-quinoxaline-carboxamide, N-[(1R,2R,4S)Isobornyl)-2-quinoxaline-carboxamide, N-[endo-(±)-2-Norbornanyl]-2-quinoxaline-carboxamide, N-[(1S,2S,3S,5R)-3-Pinanemethyl]-2-quinoxalinecarboxamide, N-(1-Adamantanemethyl)-2-quinoxalinecarboxamide, N-[(1S,2S,5S)-trans-Myrtanyl]-2-quinoxalinecarboxamide, and N-[(1R,2R,5R)-trans-Myrtanyl]-2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
- 20. The compound according to claim 1, wherein said compound is selected from the group consisting of N-[6-(2-Methylquinolyl)]-1-adamantanecarboxamide, N-(6-Quinolyl)-1-adamantanecarboxamide, N-(2-Quinolyl)-1-adamantanecarboxamide, and N-(3-Quinolyl)-1-adamantanecarboxamide, and pharmaceutically acceptable salts thereof
- 21. The compound according to claim 1, wherein said compound is selected from the group consisting of N-(3-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(2,3-Dimethylcyclohexyl)-2-quinoxalinecarboxamide, N-[(1S,2S,3S ,5R)-3-Pinanemethyl]-2-quinoxalinecarboxamide, N-(1-Adamantanemethyl)-2-quinoxalinecarboxamide, and N-(4-Methylcyclohexyl)-2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
- 22. The compound according to claim 1, wherein said compound is selected from the group consisting of N-[(R)-2-Phenyl-1-propyl-2-quinoxalinecarboxamide, N-[(S)-2-Phenyl-1-propyl]-2-quinoxalinecarboxamide, N-(2-Indanyl)-2-quinoxalinecarboxanride, N-(α-α-Dimethylphenethyl)-2-quinoxalinecarboxamide, N-(α,α-Dimethyl-2-chlorophenethyl)-2-quinoxalinecarboxamide, N-(α,α-Dimethyl-4-fluorophenethyl)-2-quinoxaline-carboxamide, and N-(β-Methylphenethyl)-2-quinoxaline-carboxamide, and pharmaceutically acceptable salts thereof.
- 23. The compound according to claim 1, wherein said compound is 1-Adamantanemethyl 6-quinolyl ether, or a pharmaceutically acceptable salt thereof.
- 24. The compound according to claim 1, wherein said compound is selected from the group consisting of 6-Quinolyl-1-adamantanecarboxylate, 1-Adamantyl-6-quinolinecarboxylate, 2,2,3,3,4,4,5,5-Octafluoro-1-pentyl 6-quinolinecarboxylate, 1-Adamantanemethyl 6-quinolinecarboxylate, 1-Adamantyl-2-quinoxalinecarboxylate, and 1-Adamantyl-3-quinolinecarboxylate, and pharmaceutically acceptable salts thereof.
- 25. The compound according to claim 1, wherein said compound is selected from the group consisting of 3-(1-Adamantanemethoxy)-2-chloroquinoxaline, 2-(1-Adamantanemethoxy)-3-methylquinoxaline, 3-(1-Adamantanemethoxy)-2-fluoroquinoxaline, 2-(1-Adamantanemethoxy)-3-trifluoromethylquinoxaline, N-[2-(4-Phenylthiazolyl)]-1-adamantanecarboxamide, N-[2-(5-Methyl-4-phenylthiazolyl)]-1-adamantanecarboxamide, 1-(1-Adamantyl)-2-(benzothiazol-2-ylsulfanyl)ethanone, N-(1-Adamantyl)-2-chloroquinoxaline-3-carboxamide, N-(1-Adamantyl)-3-methylquinoxaline-2-carboxamide, and N-(1-Adamantyl)-1-oxyquinoxaline-3-carboxamide, and pharmaceutically acceptable salts thereof.
- 26. The compound according to claim 1, wherein said compound is selected from the group consisting of 4-Chlorophenyl 3-coumarincarboxylate, 2-(1-Adamantanemethylsulfanyl)quinoxaline, 3-(1-Adamantanemethoxy)-2-chloropyrazine, 1-(1-Adamantyl)-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-anisylsulfanyl)ethanone, 3-(1-Adamantanemethoxy)-1H-quinoxalin-2-one, 1-(1-Adamantyl)-2-(3-anisylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(4-anisylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(4-chlorophenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-naphthylsulfanyl)ethanone, N-(2-[6-(1-Piperidinyl)pyrazinyl])-1-adamantanecarboxamide, N-(2-[6-(1-Piperidinyl)pyrazinyl])adamantan-1-ylmethylcarboxamide, 1-(1-Adamantyl)-2-(1-naphthylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(8-quinolylsulfanyl)ethanone hydrochloride, 1-(1-Adamantyl)-2-(4-6trifluoromethoxyphenoxy)ethanone, 2-(1-Adamantanemethoxy)quinoxaline, N-(trans-4-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(cis-4-Methylcyclohexyl)-2-quinoxalinecarboxamide, N-(trans-4-Methylcyclohexyl)-2-quinolinecarboxamide, N-(trans-4-Methylcyclohexyl)-3-quinolinecarboxamide, and N-(trans-4-Methylcyclohexyl)-6-quinolinecarboxamide, and pharmaceutically acceptable salts thereof.
- 27. The compound according to claim 1, wherein said compound is selected from the group consisting of 2-(1-Adamantanemethylsulfinyl)benzothiazole, N-(4-Phenylbutyl)-2-quinoxalinecarboxamide, 1-(1-Adamantyl)-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)ethanol, 1-(1-Adamantyl)-2-(3-chloroquinoxal-2-yl)ethanone, 2-(1-Adamantanemethylsulfanyl)-3-methylquinoxaline, N-(1-Adamantyl)-2-anisamide, N-(1-Adamantanemethyl)-2-anisamide, 1-(1-Adamantyl)-2-(4-chlorophenylsulfanyl)ethanone, 2-(1-Adamantanemethylsulfonyl)-3-methylquinoxaline, 1-(1-Adamantyl)-2-(4-fluorophenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(3-fluorophenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-methoxyphenoxy)ethanone, 1-(4-Anisylsulfanyl)butan-2-one, 1-(1-Adamantyl)-2-(4-anisidinyl)ethanone hydrochloride, 3, 3-Dimethyl-1-(4-anisylsulfanyl)butan-2-one, 1-(4-Biphenyl)-2-(4-anisylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-trifluoromethoxyphenylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(3-methylquinoxal-2-ylsulfanyl)ethanone, 1-(1-Adamantyl)-2-(2-anisidinyl)ethanone hydrochloride, 1-(1-Adamantyl)-2-(4-trifluoromethoxyphenylamino)ethanone hydrochloride, 1-(1-Adamantyl)-2-(N-methyl-4-anisidinyl)ethanone hydrochloride, N-(1-Adamantyl)-7-trifluoromethylquinoline-3-carboxamide, N-(1-Adamantyl)-2-(1-piperizinyl)quinoxaline-3-carboxamide, N-(1-Adamantyl)-2-(2-aminoethylamino)quinoxaline-3-carboxamide, Methyl N-(3-quinolyl)-3-carboxyadamantane-1-carboxamide, 1-(1-Adamantyl)-2-[(R)-1-(1-naphthyl)ethan-1-ylamino]ethanone, N-(1-Adamantyl)-2-methoxyquinoxaline-3-carboxamide, Ethyl N-(1-adamantyl)-2-(3-propanoylamino)quinoxaline-3-carboxamide, N-(4-Chlorophenyl)-2,3-dimethylquinoxaline-6-carboxamide, N-(1-Adamantyl)-6,7-dimethylquinoxaline-2-carboxamide, N-((S)-1-Tetralinyl)-2-quinoxalinecarboxamide, N-(4-Chlorophenethyl)-2-quinoxalinecarboxamide, N-(6-Quinolyl)-2-quinoxalinecarboxamide, N-(1-Tetralinmethyl)-2-quinoxalinecarboxamide, N-(1-Indanmethyl)-2-quinoxalinecarboxamide, N-(4,4-Dimethylcyclohexyl)-2-quinoxalinecarboxamide, and pharmaceutically acceptable salts thereof.
- 28. A compound according to claim 1 selected from the group consisting of N-[2-(2-fluorophenyl)propyl]quinoxaline-2-carboxamide, N-(pentyl)quinoxaline-2-carboxamide, N-(trans-4-phenylcyclohexyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)indole-5-carboxamide, N-(6-quinolinyl)-4-methylcyclohexane-1-carboxamide, N-(1-methyl-4-phenylcyclohexyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)benzothiaphene-2-carboxamide, N-(trans-4-methylcyclohexyl)benzofuran-2-carboxamide, N-(3-quinolinyl)quinoxaline-2-carboxamide hydrochloride, N-(trans-4-methylcyclohexyl)-6-bromopicolinamide, N-(adamantyl)-5-(1-piperidine)nicotinamide, N-(trans-4-methylcyclohexyl)-2-carboxamidebenzothiazole, N-[2-(2,6-difluorophenyl)ethyl]quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-6-methoxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-7-methoxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-5-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-7-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-8-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6,7-methylenedioxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6,7-ethylenedioxyquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6,8-difluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6-methoxy-7-fluoroquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-7-trifluoromethylquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-8-trifluoromethylquinoline-3-carboxamide, N-(trans-4-methylcyclohexyl)-6-fluoroquinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-5-fluoroquinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-6-trifluoromethylquinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-6-methoxyquinoxaline-2-carboxamide, and N-(trans-4-methylcyclohexyl)-6,7-methylenedioxyquinoxaline-2-carboxamide, and pharmaceutically acceptable salts thereof.
- 29. A compound according to claim 1 selected from the group consisting of N-(1-adamantyl)-2-quinoxalin carboxamide, N-(α,α-dimethylphenethyl)-2-quinoxalinecarboxamide, N-(3-noradamantyl)-2-quinoxalinecarboxamide, N-[(1S,2R,5S)-cis-myrtanyl]-2-quinoxalinecarboxamide, (1-adamantylmethyl)-2-(3-chloro)quinoxalylether, (1-adamantylmethyl)-2-(3-methyl)quinoxalylether, N-(6-quinolinyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)-2-quinoxalinecarboxamide, N-(4,4-dimethylcyclohexyl)quinoxaline-2-carboxamide, N-(trans-4-methylcyclohexyl)quinoline-2-carboxamide, N-(trans-4-methylcyclohexyl)quinoline-3-carboxamide, and N-(trans-4-methylcyclohexyl)quinoline-6-carboxamide, and pharmaceutically acceptable salts thereof.
- 30. A compound according to claim 1 having the structure
Parent Case Info
[0001] This application is a continuation-in-part of PCT International Application No. PCT/US98/24833, filed Nov. 20, 1998, which was a continuation-in-part of U.S. Provisional Application Serial No 60/066,758, filed Nov. 21, 1997, and is a continuation-in-part of U.S. Provisional Application Serial No. 60/137,272, filed Jun. 2, 1999, the specifications of which are hereby incorporated by reference in their entirety.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60137272 |
Jun 1999 |
US |
|
60066758 |
Nov 1997 |
US |
Divisions (1)
|
Number |
Date |
Country |
Parent |
09573347 |
May 2000 |
US |
Child |
10211523 |
Aug 2002 |
US |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
PCT/US98/24833 |
Nov 1998 |
US |
Child |
09573347 |
May 2000 |
US |