IP Library › Granted Patent US 9,126,937

Granted Patent B2

US 9,126,937 · App. 14/388,175 · Granted Sep 8, 2015

Alkylated imino sugars exhibiting glucosidase inhibition and their method of use

Inventors: Yanming Du (Cheshire, CT); Xiaodong Xu (Doylestown, PA); Hong Ye (Lansdale, PA); Jinhong Chang (Chalfont, PA); Timothy M. Block (Doylestown, PA)

Assignees: Baruch S. Blumberg Institute; Drexel University

C07D211/46 C07D413/06 C07F9/591

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Quick Facts

Patent No.: US 9,126,937
App. No.: 14/388,175
Granted: Sep 8, 2015
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Pharmaceutical compositions of the invention comprise alkylated imino sugars derivatives having a disease-modifying action in the treatment of diseases associated with glucosidase activity that include Viral hemorrhagic fevers, and any other diseases involving glucosidase activity.

Claims (98)

1. The compound having formula (III):

Including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:

R 1 at each occurrence is independently selected from the group consisting of hydrogen and COR 4 ;

R 5 is selected from a group consisting of optionally substituted C 1-6 alkyl, optionally substituted branched C 1-6 alkyl, optionally substituted cyclic C 3-8 alkyl, optionally substituted C 5 -C 10 bicycloalkyl, optionally substituted aryl which may be substituted by 0-5 moieties, OR 5 ′ and NHR 6 ;

R 3 is selected from a group consisting of optionally substituted C 1-6 alkyl, optionally substituted branched C 1-6 alkyl, optionally substituted cyclic C 3-8 alkyl, 1-adamantyl, 2-adamantyl, optionally substituted C 5 -C 10 bicycloalkyl, and optionally substituted aryl which may be substituted by 0-5 moieties;

R 3 and R 5 are taken together with the atom to which they are bound to form an optionally substituted ring having 5 ring atoms;

R 3 and R 5 are taken together with the atom to which they are bound to form

R 4 at each occurrence is independently selected from the group consisting of optionally substituted C 1-6 alkyl and optionally substituted branched C 1-6 alkyl;

R 5 is selected from a group consisting of an optionally substituted C 1-6 alkyl, optionally substituted branched C 1-6 alkyl, optionally substituted cyclic C 3-8 alkyl, optionally substituted C 5 -C 10 bicycloalkyl, and optionally substituted aryl which may be substituted by 0-5 moieties;

R 6 is selected from a group consisting of hydrogen, an optionally substituted C 1-6 alkyl, optionally substituted branched C 1-6 alkyl, optionally substituted cyclic C 3-8 alkyl, optionally substituted C 5 -C 10 bicycloalkyl, and optionally substituted aryl which may be substituted by 0-5 moieties;

R 7a , R 7b , R 7c , and R 7d are each selected from a group consisting of hydrogen, optionally substituted C 1-6 alkyl, and optionally substituted aryl which may be substituted by 0-5 moieties;

R 8a , R 8b , R 8c , and R 8d are each selected from a group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted branched C 1-6 alkyl, and optionally substituted C 1-6 alkoxy.

2. The compound according to claim 1 having formula (VII):

Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

3. The compound according to claim 1 having formula (VIII):

Including hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof.

4. The compound according to claim 1 that is:

N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)benzamide;

(2R,3R,4R,5S)-2-((butyryloxy)methyl)-1-(6-(N-cyclohexylpivalamido) hexyl)piperidine-3,4,5-triyl tributyrate;

tert-butyl(2-methylcyclohexyl)(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)carbamate;

(2R,3R,4R,5S)-2-(hydroxymethyl)-1-(6-((2-ethylcyclohexyl)amino) hexyl)piperidine-3,4,5-triol;

N-(2-methylcyclohexyl)-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)pivalamide;

N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)acetamide;

tert-butyl (6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)carbamate;

N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)pivalamide;

N-(2,5-difluorophenyl)-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxyl methyl)piperidin-1-yl)hexyl)acetamide;

N-(2,4-difluorophenyl)-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxyl methyl)piperidin-1-yl)hexyl)acetamide;

N-(2,5-difluorophenyl)-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxyl methyl)piperidin-1-yl)hexyl)pivalamide;

N-(2,4-difluorophenyl)-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxyl methyl)piperidin-1-yl)hexyl)pivalamide;

N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)isobutyramide;

N-cyclohexyl-3,3-dimethyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)butanamide;

N-cyclopropyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxyl methyl)piperidin-1-yl)hexyl)pivalamide;

N-cyclobutyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)pivalamide;

N-cyclopentyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)pivalamide;

N-cycloheptyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)pivalamide;

N-cyclooctyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)pivalamide;

N-((1R,5R,7S)-adamantan-2-yl)-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)pivalamide;

N-((3S,5S,7S)-adamantan-1-yl)-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)pivalamide;

(S)-4-phenyl-3-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)oxazolidin-2-one;

(R)-4-phenyl-3-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)oxazolidin-2-one;

3-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)benzo[d]oxazol-2(3H)-one;

1-cyclohexyl-3-phenyl-1-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxyl methyl)piperidin-1-yl)hexyl)urea;

1-cyclohexyl-1-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)urea;

N-cyclohexyl-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl) piperidin-1-yl)hexyl)benzamide;

1-cyclohexyl-3-propyl-1-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)urea;

(2R,3R,4R,5S)-2-(acetoxymethyl)-1-(6-(N-cyclohexylpivalamido) hexyl)piperidine-3,4,5-triyl triacetate;

(2R,3R,4R,5S)-2-((butyryloxy)methyl)-1-(6-(N-cyclohexylmethyl sulfonamido)hexyl)piperidine-3,4,5-triyltributyrate;

(2R,3R,4R,5S)-2-(acetoxymethyl)-1-(6-(N-cyclohexylmethylsulfonamido) hexyl)piperidine-3,4,5-triyl triacetate;

(2R,3R,4R,5S)-1-(6-(dicyclohexylamino)hexyl)-2-(hydroxymethyl) piperidine-3,4,5-triol;

N-(3-(3-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)propyl)phenyl)pivalamide;

N-(4-(3-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)propyl)phenyl)pivalamide;

3-(tert-butyl)-1-cyclohexyl-1-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)urea;

N-cyclohexyl-2,4-difluoro-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)benzamide;

N-cyclohexyl-2,4,5-trifluoro-N-(6-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)hexyl)benzamide;

or a pharmaceutically acceptable form thereof.

5. A composition comprising an effective amount of at least one compound according to claim 1 .

6. The composition according to claim 5 , further comprising at least one excipient.

7. The composition according to claim 6 , wherein the at least one compound is at least one member selected from the group consisting of: