US2011152209A1PendingUtilityA1
Core 2 GlcNAc-T Inhibitors
Est. expiryDec 22, 2023(expired)· nominal 20-yr term from priority
Inventors:Rakesh Chibber
A61P 43/00A61P 35/02A61P 9/10A61P 35/00A61P 9/00A61P 3/10A61P 35/04A61P 27/02A61P 29/00A61P 13/10A61P 15/00A61P 19/02A61P 11/06C07H 3/00A61P 1/16A61P 1/00A61P 13/08A61P 1/04A61K 31/702A61P 11/00A61P 1/02
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Claims
Abstract
The present invention relates to the use of known and novel compounds as inhibitors of UDP-GlcNAc:Galβ1,3GalNAc-R (GlcNAc to GalNAc) β1,6-N-acetylglucosaminyl transferase (core 2 β1,6 N-acetylaminotransferase, core 2 GlcNAc-T-EC 2.4.1.102). Such inhibitors have applications in therapy for diseases associated with raised activity of core 2 GlcNAc-T, in particular inflammatory diseases, atherosclerosis, diabetic cardiomyopathy, cancers—including treatment or prevention of metastasis—or diabetic retinopathy.
Claims
exact text as granted — not AI-modified1 - 76 . (canceled)
77 . A method of treatment of a condition associated with raised activity of the enzyme core 2 GlcNAc-T comprising administration of an effective amount of a compound of the formula I to a patient in need thereof;
wherein R 1 is —OH, C 1-6 alkoxy, —NR 8 R 9 , or a monosaccharide of the formula IIa;
R 2 is —OH, C 1-6 alkoxy or a monosaccharide of the formula IIb:
R 3 is —OH, C 1-6 alkoxy or a monosaccharide of the formula IIc;
R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl;
R 5 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 alkoxy-C 1-6 -alkyl;
R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl;
R 7 is C 2-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl;
R 8 is H, C 1-6 alkyl or C 1-6 acyl;
R 9 is H, C 1-6 alkyl or C 1-6 acyl; and
Z is a steroid group;
or a pharmaceutically acceptable salt, ester or tautomeric form or derivative thereof.
78 . A method of treatment as described in claim 77 in which R 1 is a monosaccharide of the formula IIa.
79 . A method of treatment as described in claim 78 in which R 5 is C 1-6 alkyl or C 1-6 hydroxyalkyl.
80 . A method of treatment as described in claim 78 in which R 5 is —CH 3 , —C 2 H 5 , —CH 2 OH or —C 2 H 4 OH.
81 . A method of treatment as described in claim 77 in which R 3 is a monosaccharide of the formula IIc.
82 . A method of treatment as described in claim 81 in which R 7 is C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl.
83 . A method of treatment as described in claim 81 in which R 7 is —CH 2 OH or C 1-6 alkoxymethyl.
84 . A method of treatment as described in claim 81 in which R 7 is —CH 2 OH.
85 . A method of treatment as described in claim 77 in which the compound of the formula I is a compound of the formula III:
wherein:
R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl,
R 5 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl; and
R 7 is C 2-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl.
86 . A method of treatment as described in claim 85 in which R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl.
87 . A method of treatment as described in claim 85 in which R 4 is —CH 2 OH or —CH 3 .
88 . A method of treatment as described in claim 85 in which R 5 is C 1-6 alkyl, C 1-6 hydroxyalkyl.
89 . A method of treatment as described in claim 85 in which R 5 is —CH 3 , —C 2 H 5 , —CH 2 OH or —C 2 H 4 OH.
90 . A method of treatment as described in claim 85 in which R 7 is C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl.
91 . A method of treatment as described in claim 85 in which R 7 is —CH 2 OH or C 1-6 alkoxymethyl.
92 . A method of treatment as described in claim 85 in which R 7 is —CH 2 OH.
93 . A method as described in claim 85 wherein compounds of the formula III are compounds of the formula I wherein:
R 1 is rhamnose;
R 2 is —OH;
R 3 is glucose; and
R4 is CH 2 OH.
94 . A method as described in claim 85 wherein compounds of the formula III are compounds of the formula IV
95 . A method as described in claim 77 in which the compound of the formula I is a compound of the formula V:
wherein:
R 1 is OH, C 1-6 alkoxy or NR 8 R 9 , or a monosaccharide of the formula IIa:
R 4 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl;
R 5 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 alkyl;
R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl;
R 8 is H, C 1-6 alkyl or C 1-6 acyl;
R 9 is H, C 1-6 alkyl or C 1-6 acyl; and
Z is a steroid group.
96 . A method as described in claim 95 in which R 1 is OH, or NR 8 R 9 .
97 . A method as described in claim 95 in which R 1 is NR 8 R 9 ;
R 8 is H, C 1-6 alkyl or C 1-6 acyl; and
R 9 is H, C 1-6 alkyl or C 1-6 acyl.
98 . A method as described in claim 95 in which R 1 is NR 8 R 9 ;
R 8 is H; and
R 9 is H, C 1-6 alkyl or C 1-6 acyl.
99 . A method as described in claim 95 in which R 1 is NR 8 R 9
R 8 is H; and
R 9 is C 1-6 acyl.
100 . A method as described in claim 95 in which R 1 is NR 8 R 9 ;
R 8 is H; and
R 9 is —COCH 3 .
101 . A method as described in claim 95 in which the compound of formula IV is Galβ1->3(6-deoxy)GalNAcα-Z.
102 . A method according to claim 77 in which the steroid group is a group of the formula VII:
wherein:
R 12 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 13 is H, —OH, ═O, or C 1-6 alkyl;
R 14 is H, —OH or C 1-6 alkyl or R 14 and R 33 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 15 is H, or —OH, or R 15 and R 33 taken together are ═O;
R 16 is H, —OH or ═O;
R 17 is H, —OH or ═O;
R 18 is H, —OH, C 1-6 alkoxy or C 1-6 alkyl;
R 19 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 20 is H, —OH, C 1-6 alkoxy or C 1-6 alkyl;
R 21 is H, —OH, C 1-6 alkyl, C 1-6 alkoxy or is a group of the formula VIII:
R 22 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 23 is H, —OH, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 -alkoxy-C 1-6 -alkyl, ═CH 2 or ═CH—C 1-6 -alkyl;
R 24 is H, C 1-6 alkyl, C 1-6 acyl or a monosaccharide MS;
R 28 and R 29 are the same or different and are H or —OH;
R 32 is H, —OH or ═O;
R 33 is H, or R 33 and R 15 taken together are ═O, or R33 and R14 taken together represent the second bond of a double bond joining adjacent carbon atoms; MS is selected from a group consisting of rabinose, xylose, lyxose, ribose, glucose, mannose, galactose, allose, altrose, gulose, idose, talose, ribulose, xylulose, fructose, sorbose, tagatose, psicose, sedoheptulose, deoxyribose, fucose, rhamnose, 2-deoxy-glucose, quinovose, abequose, glucosamine, mannosamine, galactosamine, neurminic acid, muramic acid, N-acetyl-glucosannine, N-acetyl-mannosamine, N-acetyl-galactosmine, N-acetylneuraminic acid, N-acetylmuramic acid, O-acetylneuraminic acid, N-glycolylneuraminic acid, fructuronic acid, tagaturonic acid, glucuronic acid, mannuronic acid, galacturonic acid, iduronic acid, sialic acid and guluronic acid; and
Y is N or O.
103 . A method according to claim 102 in which Y is O.
104 . A method according to claim 102 in which R 21 is a group of the formula VIII.
105 . A method according to claim 104 in which R 24 is C 1-6 alkyl, C 1-6 acyl or a monosaccharide MS.
106 . A method according to claim 104 in which R 24 is C 1-6 acyl or a monosaccharide MS.
107 . A method according to claim 104 in which R 24 is a monosaccharide MS.
108 . A method according to claim 105 , in which MS is selected from the group consisting of glucose, galactose, mannose, fucose, N-acetyl-glucosamine, N-acetyl-galactosamine and sialic acid.
109 . A method according to claim 105 , in which MS is glucose.
110 . A method according to claim 104 in which R 23 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 -alkoxy-C 1-6 -alkyl, ═CH 2 or ═CH—C 1-6 -alkyl.
111 . A method according to claim 104 in which R 23 is C 1-6 alkyl, C 1-6 hydroxyalkyl or ═CH 2 .
112 . A method according to claim 104 in which R 23 is —C 2 H 4 OH, —CH 2 OH, C 1-6 alkyl, or ═CH 2 .
113 . A method according to claim 104 in which R 23 is —C 2 H 4 OH, —CH 2 OH, —C 2 H 5 , —CH 3 or ═CH 2 .
114 . A method according to claim 104 in which R 23 is —CH 3 .
115 . A method according to claim 104 in which R 23 is ═CH 2 .
116 . A method of claim 104 in which R 22 is H, —OH, or C 1-6 alkoxy.
117 . A method of claim 104 in which R 22 is H.
118 . A method of claim 102 in which R 19 is H, —OH, or C 1-6 alkyl.
119 . A method of claim 102 in which:
R 12 is H, —OH
R 13 is H or —OH;
R 14 is H, or —OH or R 14 and R 33 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 15 is H, or R 15 and R 33 taken together are ═O;
R 18 is H, —OH or C 1-6 alkoxy;
R 19 is C 1-6 alkyl;
R 20 is H, —OH or C 1-6 alkoxy;
R 32 is H, —OH or ═O; and
R 33 is H, or R 33 and R 15 taken together are ═O, or R 33 and R 14 taken together represent the second bond of a double bond joining adjacent carbon atoms.
120 . A method of claim 102 in which:
R 16 is H or ═O;
R 17 is H or —OH;
R 18 is H or —OH; and
R 20 is —OH or C 1-6 alkoxy.
121 . A method of claim 102 in which the steroid group is selected from a group consisting of:
wherein:
R 18 is H or —OH;
R 20 is —OH or C 1-6 alkoxy;
R 24 is glucose or C 1-6 acyl; and
R 29 is H or —OH.
122 . A method of claim 77 in which the compound of the formula I is selected from the group consisting of
trigoneoside IVa which is (3β,25S)-26-(β3-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl-O-α-L-rhamnopyranosyl-(I->2)-O-
[β-D-glucopyranosyl-(1->4)]-β-D-glucopyranoside, glycoside F which is (3β)-26-(β-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl-O-α-L-rhanmopyranosyl-(1->2)-O-[β-D-glucopyranosyl-(1->4)]-β-D-glucopyranoside, shatavarin 1, compound 3, pardarinnoside C.
123 . A method according to claim 77 in which the steroid group is a group of the formula VIII:
wherein:
R 12 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 13 is H, —OH, ═O, or C 1-6 alkyl;
R 14 is H, —OH or C 1-6 alkyl or R 14 and R 33 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 15 is H, or —OH, or R 15 and R 33 taken together are ═O;
R 16 is H, —OH or ═O;
R 17 is H, —OH or ═O;
R 18 is H, —OH, C 1-6 alkoxy or C 1-6 alkyl;
R 19 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 20 is H, —OH, C 1-6 alkoxy or C 1-6 alkyl;
R 27 is H, —OH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 hydroxyalkyl;
R 28 and R 29 are the same or different and are H or —OH;
R 32 is H, —OH or ═O; and
R 33 is H, or R 33 and R 15 taken together are ═O, or R 33 and R 14 taken together represent the second bond of a double bond joining adjacent carbon atoms.
124 . A method of claim 123 in which R 27 is H, C 1-6 alkyl, or C 1-6 alkoxy.
125 . A method of claim 123 in which R 27 is H, or C 1-6 alkyl.
126 . A method of claim 123 in which R 19 is H, —OH, or C 1-6 alkyl.
127 . A method of claim 123 in which R 20 is —OH or C 1-6 alkoxy.
128 . A method of claim 123 in which
R 12 is H or —OH
R 13 is H or —OH;
R 14 is H, or —OH or R 14 and R 33 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 15 is H, or R 15 and R 33 taken together are ═O;
R 16 is H, —OH or ═O;
R 17 is H, —OH or ═O;
R 18 is H, —OH or C 1-6 alkoxy
R 19 is C 1-6 alkyl;
R 32 is H, —OH or ═O; and
R 33 is H, or R 33 and R 15 taken together are ═O, or R 33 and R 14 taken together represent the second bond of a double bond joining adjacent carbon atoms.
129 . A method of claim 123 in which the compound of the steroid group is a compound of the formula IXa
130 . A method of claim 123 in which the compound of the formula I is a compound of the formula:
131 . A method of claim 77 in which the steroid group is of the formula XI:
wherein:
R 12 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 13 is H, —OH, ═O, or C 1-6 alkyl;
R 14 is H, —OH or C 1-6 alkyl or R 14 and R 33 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 15 is H, or —OH, or R 15 and R 33 taken together are ═O;
R 16 is H, —OH or ═O;
R 17 is H, —OH or ═O;
R 18 is H, —OH, C 1-6 alkoxy or C 1-6 alkyl;
R 19 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 25 is H, —OH, C 1-6 alkyl or C 1-6 alkoxy;
R 26 is H, —OH, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 -alkoxy-C 1-6 -alkyl, ═CH 2 or ═CH—C 1-6 -alkyl;
R 28 and R 29 are the same or different and are H or —OH;
R 31 is H or —OH;
R 32 is H, —OH or ═O;
R 33 is H, or R 33 and R 15 taken together are ═O, or R 33 and R 14 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 34 is H or —OH; and
X is O, S or NH.
132 . A method of claim 131 in which X is O or NH;
133 . A method of claim 131 in which X is O;
134 . A method of claim 131 wherein R 26 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 -alkoxy-C 1-6 -alkyl, ═CH 2 or ═CH—C 1-6 -alkyl.
135 . A method of claim 131 wherein R 26 is C 1-6 alkyl, C 1-6 hydroxyalkyl or ═CH 2 .
136 . A method of claim 131 wherein R 26 is —C 2 H 4 OH, —CH 2 OH, C 1-6 alkyl, or ═CH 2 .
137 . A method of claim 131 wherein R 26 is —C 2 H 4 OH, —CH 2 OH, —C 2 H 5 , —CH 3 or ═CH 2 .
138 . A method of claim 131 wherein R 26 is —CH 3 or ═CH 2 .
139 . A method of claim 131 wherein R 19 is H, —OH, C 1-6 alkyl.
140 . A method of claim 131 wherein R 19 is C 1-6 alkyl.
141 . A method of claim 131 wherein:
R 12 is H, or —OH;
R 13 is H, or —OH;
R 14 is H or R 14 and R 33 taken together represent the second bond of a double bond joining adjacent carbon atoms;
R 15 is H, or R 15 and R 33 taken together are ═O;
R 18 is H or —OH;
R 25 is H or —OH;
R 28 and R 29 are H;
R 31 is H or —OH;
R 33 is H, or R 33 and R 15 taken together are ═O, or R 33 and R 14 taken together represent the second bond of a double bond joining adjacent carbon atoms; and
R 34 is H or —OH.
142 . A method of claim 131 wherein:
R 15 is H;
R 16 is H or —OH;
R 17 is H or —OH;
R 32 is H or —OH; and
R 33 is H, or R 33 and R 14 taken together represent the second bond of a double bond joining adjacent carbon atoms.
143 . A method of claim 131 in which the steroid group of the formula XI is selected from the group consisting of:
144 . A method of claim 131 in which the steroid group of the formula XI is selected from the group consisting of diosgenin, yamogenin, tigogenin, neotigogenin, sarsasapogenin, smilagenin, hecogenin, solasodine or tomatidine.
145 . A method of claim 77 in which the compounds of the formula I are selected from the group consisting of:
Shatavarin IV which is sarsasapogenin 3-O-α-L-rhamnopyranosyl-(1->2)-O-[β-D-glucopyranosyl-(1->4)]-β-D-glucopyranoside,
Compound 12 which is solasodine 3-O-α-L-rhamnopyranosyl-(1->2)-O-[β-D-glucopyranosyl-(1->4)]-(3-D-glucopyranoside,
Deltonin which is (3β,25R)-spirost-5-en-3-yl-O-α-L-rhamnopyranosyl-(1->2)-O-[β-D-glucopyranosyl-(1->4)]-β-D-Glucopyranoside, and
Balanitin VI is (3β,25S)-spirost-5-en-3-yl-O-α-L-rhamnopyranosyl-(1->2)-O-[β-D-glucopyranosyl-(1->4)]-β-D-Glucopyranoside.
146 . The method of claim 77 in which the condition is an inflammatory disease, asthma, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, diabetic cardiomyopathy, myocardial dysfunction, cancer, cancer metastasis or diabetic retinopathy.
147 . The method of claim 77 in which the condition is leukaemia, oral cavity carcinomas, pulmonary cancers such as pulmonary adenocarcinoma, colorectal cancer, bladder carcinoma, liver tumours, stomach tumours colon tumours, prostate cancer, testicular tumour, mammary cancer, lung tumours oral cavity carcinomas and any cancers where core 2 GlcNAc-T expression is raised above normal levels for that tissue type.
148 . The use of a compound disclosed in the method of claim 77 in the manufacture of a medicament for the treatment of a condition associated with raised activity of the enzyme core 2 GlcNAc-T.
149 . Use as described in claim 148 in which the condition is an inflammatory disease, asthma, rheumatoid arthritis, atherosclerosis inflammatory bowel disease, diabetic cardiomyopathy, myocardial dysfunction, cancer, cancer metastasis or diabetic retinopathy.
150 . Use as described in claim 145 in which the condition is leukaemia, oral cavity carcinomas, pulmonary cancers such as pulmonary adenocarcinoma, colorectal cancer, bladder carcinoma, liver tumours, stomach tumours colon tumours, prostate cancer, testicular tumour, mammary cancer, lung tumours oral cavity carcinomas and any cancers where core 2 GlcNAc-T expression is raised above normal levels for that tissue type.
151 . A pharmaceutical composition comprising a compound disclosed in the method of claim 77 .
152 . A compound of the formula:
153 . Use of the compound of the formula XII as described in claim 152 in therapy.Join the waitlist — get patent alerts
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