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US 2009/0270451 A1Published application
Piperdine Glycine Transporter Inhibitors
AssigneesMerck & Co., Inc., Merck Sharp & Dohme Corp.
InventorsDavid Hallett, Craig W. Lindsley, Elizabeth M. Naylor, Zhijian Zhao, Cory R. Theberge, Scott E. Wolkenberg, M. Brad Nolt
Life of this patent
Estimating the term…
Abstract
The present invention is directed to piperidine compounds that inhibit the glycine transporter GlyT1 and which are useful in the treatment of neurological and psychiatric disorders associated with glycinergic or glutamatergic neurotransmission dysfunction and diseases in which the glycine transporter GlyT1 is involved.
Claims18
1-20. (canceled)
A compound of the formula I:
- wherein:
- R1 is —(CH2)n—R1a, wherein n is independently 0-6, and R1a is selected from the group consisting of:
- (1) C1-6alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, phenyl substituted with R2a, R2b and R2c, or heterocycle substituted with R2a, R2b and R2c,
- (2) C3-6cycloalkyl, which is unsubstituted or substituted with C1-6alkyl, 1-6 halogen, hydroxy or —NR10R11,
- (3) piperidinyl, which is unsubstituted or substituted with C1-6alkyl, 1-6 halogen, hydroxy,
- —O—C1-6alkyl, or —NR10R11,
- (4) piperazinyl, which is unsubstituted or substituted with C1-6alkyl, 1-6 halogen, hydroxy,
- —O—C1-6alkyl, or —NR10R11,
- (5) tetrahydropyranyl or tetrahydrofuranyl, which is unsubstituted or substituted with
- C1-6alkyl, 1-6 halogen, hydroxy, —O—C1-6alkyl, or —NR10R11,
- (6) morpholinyl, which is unsubstituted or substituted with C1-6alkyl, 1-6 halogen, hydroxy,
- —O—C1-6alkyl, or —NR10R11,
- (7) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or
- —NR10R11,
- (8) —CO2R9,
- wherein R9 is independently selected from:
- (a) hydrogen,
- (b) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
- (c) benzyl, and
- (d) phenyl,
- (9) —NR10R11,
- wherein R10 and R11 are independently selected from:
- (a) hydrogen,
- (b) —C1-6alkyl, which is unsubstituted or substituted with hydroxy, 1-6 fluoro or
- —NR12R13, where R12 and R13 are independently selected from hydrogen and
- —C1-6alkyl,
- (c) —C3-6cycloalkyl, which is unsubstituted or substituted with hydroxy, 1-6 fluoro or —NR12R13,
- (d) benzyl,
- (e) phenyl, and
- (10) —CONR10R11;
- R2 is selected from the group consisting of:
- (1) phenyl, which is substituted with R2a, R2b and R2c,
- (2) heterocycle, which is substituted with R2a, R2b and R2c,
- (3) C1-8alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, —NR10R11, phenyl or heterocycle, where the phenyl or heterocycle is substituted with R2a, R2b and R2c,
- (4) C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or
- —NR10R11, and
- (5) —C1-6alkyl-(C3-6cycloalkyl), which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR10R11;
- R2a, R2b and R2c are independently selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C1-6alkyl, which is unsubstituted or substituted with:
- (a) 1-6 halogen,
- (b) phenyl,
- (c) C3-6cycloalkyl, or
- (d) —NR10R11,
- (4) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halogen,
- (5) —O-phenyl,
- (6) hydroxy,
- (7) —SCF3,
- (8) —SCHF2,
- (9) —SCH3,
- (10) —CO2R9,
- (11) —CN,
- (12) —SO2R9,
- (13) —SO2—NR10R11,
- (14) —NR10R11,
- (15) —CONR10R11, and
- (16) —NO2;
- R3 is selected from the group consisting of:
- (1) C1-6alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl, —NR10R11,
- (2) C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl or
- —NR10R11,
- (3) —C1-6alkyl-(C3-6cycloalkyl), which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR10R11, and
- (4) —NR10R11;
- with the proviso that if R1 is —CH2-cyclopropyl, then R3 is —NR10R11 or —C1-6alkyl-(C3-6cycloalkyl), which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR10R11;
- R4 and R5 are independently selected from the group consisting of:
- (1) hydrogen, and
- (2) C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,
- or R4 and R5 taken together form a C3-6cycloalkyl ring;
- A is selected from the group consisting of:
- (1) —O—, and
- (2) —NR10—;
- m is zero or one, whereby when m is zero, R2 is attached directly to the carbonyl;
- and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
71 more elements
A compound which is selected from the group consisting of:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.