Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity
AssigneeNorthwestern University
InventorsDimitri Krainc, Richard B. Silverman, Jianbin Zheng
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Abstract
Disclosed are new small molecules having a substituted quinazoline core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules or activated glucocerebrosidase conjugated to the small molecules, which compositions may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including neurological diseases and disorders such as Gaucher's disease and Parkinson's disease.
Claims20
A method for treating a disease or disorder that is associated with glucocerebrosidase activity in a subject in need thereof, wherein the disease or disorder is selected from Gaucher's disease and Parkinson's disease, and the method comprises administering to the subject a pharmaceutical composition comprising a pharmaceutical carrier and a compound or a salt or solvate thereof of a Formula I:
- wherein:
- R1 is hydrogen or C1-C10 alkyl;
- n is 0, 1, 2, 3, or 4;
- and
- R2 is hydrogen with the proviso that not both of R1 and R2 are hydrogen, or R2 is a C1-C10 alkyl group which may be straight chain or branched, a C3-C8 cycloalkyl group, a saturated or unsaturated carbon homocycle or heterocycle group comprising one 5- or 6-membered ring or comprising two or three fused 5- or 6-membered rings, a phenoxy group, a C1-C6-branched or straight chain alkyl-phenoxy group, a 2,3-dihydro-1H-indenyl group, a 1,2,3,4-tetrahydro-naphthalenyl group, a C2-C10 straight chain or branched alkenyl group, a C2-C10 straight chain or branched alkynyl group, a polyethylene oxide group, a pyridinoxy group, an indoloxy group, a benzofuranoxy group, or R2 has a formula selected from
- wherein R8 is hydrogen, C1-C8 alkoxy, C1-C8 alkyl, halo, or R8 has a formula selected from
- p is 1-10 and R9 is amino or R9 has a formula selected from
- wherein R10 is H, C1-C6 straight chain or branched alkyl, or a succinimidyl group;
- R2 optionally is substituted at one or more positions with a C1-C8 alkyl group, a C1-C8 alkoxy group, a halo group, a phenyl group, a benzyl group, an amino group, a hydroxyl group, a tert-butyloxycarbonyl (BOC) group, a sulfonylmethylphenyl group, a 2,3-dihydro-1,4-benzodioxine-2-carbaldehyde group, a 2,3-dihydromethyl-1,4-benzodioxin group, an imidazole group, a piperazinyl group, a 1-methylpiperazinyl group, a 4-piperazin-1-yl-benzaldehyde group, a 4-(4-methylpiperazin-1-yl)benzaldehyde group, or an azide group;
- or
- optionally where n is 0, R1 and R2 together form a heterocycle comprising one, two, or three 5- or 6-membered rings;
- and
- R3 is pyridinyl, phenyl, thiophenyl, halo, furanyl, or pyrimidinyl, and R3 optionally is substituted at one or more positions with C1-C8 alkyl, halo, amino, or R3 has a formula,
- wherein R4 is amino, or R4 has a formula
- wherein R5 is —CH2— or —O—CH2—CH2—, and m is 0-4, R6 is H or R6 has a formula
- wherein R7 is H, —OH, C1-C8 alkyl, or C1-C8 alkoxy.
A conjugate comprising a compound of a Formula I covalently attached to glucocerebrosidase:
- wherein:
- R1 is hydrogen or C1-C10 alkyl;
- n is 0, 1, 2, 3, or 4;
- and
- R2 is hydrogen with the proviso that not both of R1 and R2 are hydrogen, or R2 is a C1-C10 alkyl group which may be straight chain or branched, a C3-C8 cycloalkyl group, a saturated or unsaturated carbon homocycle or heterocycle group comprising one 5- or 6-membered ring or comprising two or three fused 5- or 6-membered rings, a phenoxy group, a C1-C6-branched or straight chain alkyl-phenoxy group, a 2,3-dihydro-1H-indenyl group, a 1,2,3,4-tetrahydro-naphthalenyl group, a C2-C10 straight chain or branched alkenyl group, a C2-C10 straight chain or branched alkynyl group, a polyethylene oxide group, a pyridinoxy group, an indoloxy group, a benzofuranoxy group, or R2 has a formula selected from
- wherein R8 is hydrogen, C1-C8 alkoxy, C1-C8 alkyl, halo, or R8 has a formula selected from
- p is 1-10 and R9 is amino or R9 has a formula selected from
- wherein R10 is H, C1-C6 straight chain or branched alkyl, or a succinimidyl group;
- R2 optionally is substituted at one or more positions with a C1-C8 alkyl group, a C1-C8 alkoxy group, a halo group, a phenyl group, a benzyl group, an amino group, a hydroxyl group, a tert-butyloxycarbonyl (BOC) group, a sulfonylmethylphenyl group, a 2,3-dihydro-1,4-benzodioxine-2-carbaldehyde group, a 2,3 -dihydromethyl- 1,4-benzodioxin group, an imidazole group, a piperazinyl group, a 1-methylpiperazinyl group, a 4-piperazin-1-yl-benzaldehyde group, a 4-(4-methylpiperazin-1-yl)benzaldehyde group, or an azide group;
- or
- optionally wherein n is 0, R1 and R2 together form a heterocycle comprising one, two, or three 5-or 6-membered rings;
- and
- R3 is pyridinyl, phenyl, thiophenyl, halo, furanyl, or pyrimidinyl, and R3 optionally is substituted at one or more positions with C1-C8 alkyl, halo, amino, or R3 has a formula,
- wherein R4 is amino, or R4 has a formula
- wherein R5 is —CH2— or —O—CH2—CH2—, and m is 0-4, R6 is H or R6 has a formula
- wherein R7 is H, —OH, C1-C8 alkyl, or C1-C8 alkoxy.
Dependencies are inferred from the claim text.