Selective glycosidase inhibitors and uses thereof
AssigneesMerck Sharp & Dohme Corp., Alectos Therapeutics Inc.
InventorsRamesh KAUL, Ernest J. MCEACHERN, Changwei MU, Harold G. SELNICK, David J. VOCADLO, Yaode WANG, Zhongyong WEI, Yuanxi ZHOU, Yongbao ZHU
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Abstract
The invention provides compounds with enhanced permeability for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc.
Claims27
A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 and R2 are H, or R1 is H and R2 is F, or R is F and R2 is H, or R1 is OR3 and R2 is H;
- each R3 is independently H or C1-6 acyl;
- R4 is H and R5 is OR3, or R4 is OR3 and R5 is H;
- R6 is H, F, or OR3;
- each R7 is independently H or F;
- each R8 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H;
- and
- with the proviso that either R1 or R6 is other than OR3.
A compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 and R2 are H and R6 is F;
- or R1 is H and R2 is F and R6 is H, F, or OR3;
- or R1 is F and R2 is H and R6 is H, F or OR3;
- or R1 is OR3 and R2 is H and R6 is F;
- each R3 is independently H or C1-6 acyl;
- each R7 is independently H or F;
- each R8 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H.
A method of selectively inhibiting an O-GlcNAcase in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 and R2 are H, or R is H and R2 is F, or R1 is F and R2 is H, or R is OR3 and R2 is H;
- each R3 is independently H or C1-6 acyl;
- R4 is H and R5 is OR3, or R4 is OR3 and R5 is H;
- R6 is H, F, or OR3;
- each R7 is independently H or F;
- each R5 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H;
- and
- with the proviso that either R1 or R6 is other than OR3.
A method of elevating the level of O-GlcNAc in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 and R2 are H, or R1 is H and R2 is F, or R1 is F and R2 is H, or R1 is OR3 and R2 is H;
- each R3 is independently H or C1-6 acyl;
- R4 is H and R5 is OR3, or R4 is OR3 and R5 is H;
- R6 is H, F, or OR3;
- each R7 is independently H or F;
- each R8 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H;
- and
- with the proviso that either R1 or R6 is other than OR3.
A method of treating a condition that is modulated by an O-GlcNAcase, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 and R2 are H, or R1 is H and R2 is F, or R1 is F and R2 is H, or R1 is OR3 and R2 is H;
- each R3 is independently H or C1-6 acyl;
- R4 is H and R5 is OR3, or R4 is OR3 and R5 is H;
- R6 is H, F, or OR3;
- each R7 is independently H or F;
- each R8 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H;
- and
- with the proviso that either R1 or R6 is other than OR3.
A method of treating a condition selected from the group consisting of a neurodegenerative disease, a tauopathy, cancer and stress, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 and R2 are H, or R1 is H and R2 is F, or R1 is F and R2 is H, or R1 is OR3 and R2 is H;
- each R3 is independently H or C1-6 acyl;
- R4 is H and R5 is OR3, or R4 is OR3 and R5 is H;
- R6 is H, F, or OR3;
- each R7 is independently H or F;
- each R8 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H;
- and
- with the proviso that either R1 or R6 is other than OR3.
Use of a compound of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein
- R1 and R2 are H, or R1 is II and R2 is F, or R1 is F and R2 is H, or R1 is OR3 and R2 is H;
- each R3 is independently H or C1-6 acyl;
- R4 is H and R5 is OR3, or R4 is OR3 and R5 is H;
- R6 is H, F, or OR3;
- each R7 is independently H or F;
- each R8 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H;
- and
- with the proviso that either R1 or R6 is other than OR3, in the preparation of a medicament.
A method for screening for a selective inhibitor of an O-GlcNAcase, the method comprising:
- a) contacting a first sample with a test compound;
- b) contacting a second sample with a compound of Formula (I)
- wherein
- R1 and R2 are H, or R1 is H and R2 is F, or R1 is F and R2 is H, or R1 is OR3 and R2 is H;
- each R3 is independently H or C1-6 acyl;
- R4 is H and R5 is OR3, or R4 is OR3 and R5 is H;
- R6 is H, F, or OR3;
- each R7 is independently H or F;
- each R8 is independently selected from the group consisting of:
- H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and C1-6 alkoxy, wherein the C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, or C1-6 alkoxy are optionally substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl, or
- the two R8 groups are connected together with the nitrogen atom to which they are attached to form a ring, said ring optionally independently substituted from one up to the maximum number of substituents with one or more of fluoro, OH, or methyl,
- with the proviso that when R6 is OR3, each R7 is H;
- and
- with the proviso that either R1 or R6 is other than OR3;
- c) determining the level of inhibition of the O-GlcNAcase in the first and second samples, wherein the test compound is a selective inhibitor of a O-GlcNAcase if the test compound exhibits the same or greater inhibition of the O-GlcNAcase when compared to the compound of Formula (I).
Dependencies are inferred from the claim text.