Glycosidase inhibitors
The disclosure relates to compounds of formula (I) useful in the treatment of tauopathies and Alzheimer's disease wherein A, R, W, Q, n, and m are described herein.
1. A compound of formula (I)
wherein
R is straight chain or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH;
W is CH or N;
A is:
X is N or CR′″;
X 1 , X 2 is N or CR′″;
X 3 is N or CR′″″;
Y is O, S, SO, or SO 2 ;
R′, R″ are, independently, H, Hal, or straight chain or branched alkyl having 1 to 12 carbon atoms;
R′″, R″″ are, independently, H, Hal, NR 3 R 4 , CHR 3 R 4 , OR 3 , CN, or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , CO, COO, OCO, CONR 3 , and NR 3 CO; and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , or NO 2 ;
R′″″ is H, Hal, NR 3 R 4 , CHR 3 R 4 , CN, or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from NR 3 , S, SO, SO 2 , CO, COO, OCO, CONR 3 , and NR 3 CO; and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , or NO 2 ;
R 3 , R 4 are, independently, H or a straight chain or branched alkyl group having 1 to 12 carbon atoms;
Q is:
Z 1 is S, O, or NR 3 ;
Z 2 , Z 3 are, independently, CR 5 , CR 6 , or N;
T is N, CH, or CR 7 ;
R 5 , R 6 , R 7 are, independently, H, Hal, NR 3 R 4 , NO 2 , Ar, Het, Cyc, or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , CO, COO, OCO, CONR 3 , and NR 3 CO; and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , NO 2 , OR 3 , Het, Ar, or Cyc;
R 8 is H, methyl, or straight chain or branched alkyl having 2 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from O, NR 3 , S, SO, SO 2 , CO, COO, OCO, CONR 3 , and NR 3 CO; and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR 3 R 4 , or NO 2 ;
Hal is F, Cl, or I;
Het is a saturated, unsaturated, or aromatic ring, being monocyclic or bicyclic or fused-bicyclic and having 3- to 8-members and containing 1 to 4 heteroatoms selected from N, Q and S, which may be substituted by 1 to 3 substituents selected from R 5 , Hal, and OR 3 ;
Ar is a 6-membered carbocyclic aromatic ring or a fused or non-fused bicyclic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R 5 , OR 3 , and Hal;
Cyc is a saturated carbocyclic ring having from 3 to 8 carbon atoms which is optionally substituted by 1 to 3 substituents independently selected from R 5 , Hal and OH;
or a solvate, salt, tautomer, enantiomer, racemate, stereoisomer, compound of formula (I) where one or more H atoms are replaced by deuterium, or any mixture thereof in any ratio.
2. A compound of formula Ia or Ib
wherein A, R, W, and Q have the meanings given in claim 1 .
3. A mixture comprising compounds (Ia) and (Ib) according to claim 2 , in equal or unequal amounts, wherein:
the A groups in (Ia) and (Ib) are identical; the R groups in (Ia) and (Ib) are identical;
the W groups in (Ia) and (Ib) are identical; and the Q groups in (Ia) and (Ib) are identical.
4. The compound of claim 1 , wherein R is methyl.
5. The compound of claim 1 , wherein A is:
wherein R′ and R″ have the meaning given in claim 1 .
6. The compound of claim 1 , wherein Q is:
wherein X, R′″, R″″, R 5 , R 6 , R 7 and R 8 have the meaning given in claim 1 .
7. The compound of claim 1 , wherein R 5 , R 6 , and R 7 are independently H, Hal, NR 3 R 4 , phenyl, 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, CF 3 , alkoxy, hydroxyalkylene, alkoxyalkylene, COOH, COOalkyl, CONHalkyl, CONH 2 , CON(CH 3 ) 2 , NHCOalkyl, CO—N-morpholinyl, CON(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , CO-1-piperidinyl, CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl, CH 2 —N-morpholinyl, CH 2 N(H)COCH 3 , CH 2 N(CH 3 )COCH 3 , substituted Cyc or Het, or unsubstituted Cyc or Het.
8. A compound selected from the group consisting of:
No
Structure
2
3
4
8
9
10
11
14
15
20
21
22
23
24
25
26
31
34
37
38
39
40
41
44
45
46
51
52
53
54
55
58
68
69
70
72
77
78
82
83
86
89
91
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
131
132
133
134
137
138
141
142
143
145
146
147
148
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
192
193
194
195
196
197
198
200
201
and
202
or a solvate, salt, tautomer, enantiomer, racemate, stereoisomer, or any mixture thereof in any ratio.
9. A method of treating a disease that is mediated or propagated by O-GlcNAcase activity, comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment.
10. A method of treating a neurodegenerative disease, diabetes, cancer, or stress, comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment.
11. The method of claim 10 , wherein the neurodegenerative disease is selected from the group consisting of one or more tauopathies, Alzheimer's disease, Dementia, Amyotrophic lateral sclerosis, Amyotrophic lateral sclerosis with cognitive impairment, Argyrophilic grain dementia, Bluit disease, Corticobasal degeneration, Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, Guadeloupean parkinsonism, Hallevorden-Spatz disease, Multiple system atrophy, Myotonic dystrophy, Niemann-Pick disease, Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick's disease, Postencephalitic parkinsonism, and a Prion disease.
12. A method of treating a tauopathy, comprising administering a therapeutically effective amount of a compound of claim 1 to a mammal in need of such treatment.
13. A method of inhibiting a glycosidase, comprising contacting a system expressing the glycosidase with a compound of claim 1 under in-vitro conditions such that the glycosidase is inhibited.
14. A pharmaceutical composition comprising one or more compounds of claim 1 , and one or more pharmaceutically tolerable adjuvants or excipients.
15. The compound of claim 1 , wherein W is N.
16. The method of claim 11 , wherein the Frontotemporal dementia is Frontotemporal dementia with parkinsonism linked to chromosome 17.
17. The method of claim 11 , wherein the Niemann-Pick disease is Niemann-Pick disease type C.
18. The method of claim 11 , wherein the Prion disease is Creutzfeldt-Jakob Disease, Variant Creutzfeldt-Jakob Disease, Fatal Familial Insomnia, Kuru, Progressive supercortical gliosis, Progressive supranuclear palsy, Steele-Richardson-Olszewski syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, Huntington's disease, or Parkinson's disease.
19. The method of claim 11 , wherein the neurodegenerative disease is Alzheimer's disease.
20. The pharmaceutical composition of claim 14 , further comprising one or more active ingredients.