Geminally di-substituted NSAID derivatives as Aβ42 lowering agents
AssigneeMerck & Co., Inc.
InventorsBenito Munoz, Petpiboon Prasit, Nicholas Simon Stock
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Abstract
The present invention encompasses compounds of Formula I (I) or pharmaceutically acceptable salts thereof, wherein A is the base molecule of a propionic acid or acetic acid NSAID, or a derivative thereof, X is —CO2H, 1H-tetrazol-5-yl or 2H-tetrazol-5-yl and R1 and R2 are each independently selected from the group consisting of: C1-6alkyl and C3-6cycloalkyl, as well as pharmaceutical composition comprising said compounds and methods of using said compounds. The compounds of the present invention lower the level of Aβ42 and are therefore useful for preventing, delaying or reversing the progression of Alzheimer's Disease.
Claims7
A method for treating Alzheimer's Disease in a patient in need thereof comprising administering to said patient a compound of Formula I
- or a pharmaceutically acceptable salt thereof, wherein:
- X is —CO2H, 1H-tetrazol-5-yl or 2H-tetrazol-5-yl;
- each Ra may be substituted at any substitutable position on A and each Ra is independently selected from the group consisting of:
- fluoro, chloro, bromo, NH2, methyl, ethyl, methoxy and CF3;
- R1 and R2 are each independently selected from the group consisting of:
- C1-6alkyl and C3-6cycloalkyl;
- and
- A is selected from the group consisting of:
- wherein for 38) above Ra is substituted on A as shown and Z is selected from the group consisting of:
- phenyl, benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl,
- in amount that is effective for treating Alzheimer's Disease.
A method for treating Alzheimer's Disease in a patient in need thereof comprising administering to said patient a compound of Formula I′
- or a pharmaceutically acceptable salt thereof, wherein:
- Z is selected from the group consisting of:
- phenyl, benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofiuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl,
- X is —CO2H, 1H-tetrazol-5-yl or 2H-tetrazol-5-yl,
- R1 and R2 are each independently ethyl or methyl, and
- each Ra is independently selected from the group consisting of:
- fluoro, chloro, bromo, NH2, methyl, ethyl, methoxy and CF3,
- in amount that is effective for treating Alzheimer's Disease.
Dependencies are inferred from the claim text.