Glycosidase inhibitors
Compounds of formula (I), wherein A, R, W, Q, n and m have the meaning according to the claims, can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
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′″″;
X 4 is N or CR 9 ;
R 9 is 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 , S(O)(NH), 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 ;
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 , S(O)(NH), 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 O, NR 3 , S, SO, SO 2 , S(O)(NH), 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 2 is CR 5 , CR 6 , or N;
Z 4 is N, CH, CON, or COCH;
Z 5 is S, O, NR 8 , SO 2 , or CHR 5 ;
Z 6 is CH 2 or CO;
s is 0 or 1;
T is N, CH, or CR 7 ;
R 3 ′ is H or a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups may be replaced by a group selected from SO 2 , CO, and O; and wherein 1 to 5 hydrogen atoms may be replaced by Hal;
R 3 ″ is a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH 2 -groups are replaced by a group selected from SO 2 , CO, and O; and
wherein 1 to 5 hydrogen atoms may be replaced by Hal;
R 5 , R 6 , R 7 are, independently, H, Hal, NR 3 R 4 , NO 2 , Ar, Het, Cyc, 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 , S(O)(NH), 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, Br, 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, O, 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 aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R 5 , OR 3 , and Hal;
Cyc is a saturated or an unsaturated 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, or any mixture thereof in any ratio.
2. A compound of formula Ia or Ib:
wherein A, R, W, and Q have the meaning 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 according to claim 1 , wherein R is methyl and/or W is N.
5. The compound according to claim 1 , wherein A is:
wherein R′ and R″ have the meaning given in claim 1 .
6. The compound according to claim 1 , wherein Q is:
wherein R 3 ′, R 7 and R 8 have the meaning given in claim 1 .
7. The compound according to claim 1 , wherein R 5 , R 6 , and R 7 are, independently H, Hal, NR 3 R 4 , NH 2 , N(CH 3 ) 2 , phenyl, 2-, 3- or 4-hydroxy or methoxyphenyl, alkyl, CF 3 , alkoxy, hydroxyalkylene, alkoxyalkylene, COOH, COOalkyl, CONHalkyl, CONH 2 , CON(CH 3 ) 2 , NHCOalkyl, NHalkyl, 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. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
Configuration
No
Structure
specification
1
racemic
2
racemic
3
racemic
4
racemic
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
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
175
176
177
178
179
180
181
182
183
214
215
216
217
231
S-enantiomer
232
S-enantiomer
233
S-enantiomer
234
S-enantiomer
235
S-enantiomer
236
S-enantiomer
237
S-enantiomer
238
S-enantiomer
239
S-enantiomer
240
S-enantiomer
241
S-enantiomer
242
S-enantiomer
243
S-enantiomer
244
S-enantiomer
245
S-enantiomer
246
S-enantiomer
247
S-enantiomer
248
S-enantiomer
249
S-enantiomer
250
S-enantiomer
251
S-enantiomer
252
S-enantiomer
253
S-enantiomer
254
S-enantiomer
255
S-enantiomer
256
S-enantiomer
257
S-enantiomer
258
S-enantiomer
259
S-enantiomer
260
S-enantiomer
261
S-enantiomer
262
S-enantiomer
263
S-enantiomer
264
S-enantiomer
265
S-enantiomer
266
S-enantiomer
267
S-enantiomer
268
S-enantiomer
269
S-enantiomer
270
S-enantiomer
271
S-enantiomer
272
S-enantiomer
273
S-enantiomer
274
S-enantiomer
275
S-enantiomer
276
S-enantiomer
277
S-enantiomer
278
S-enantiomer
279
S-enantiomer
280
S-enantiomer
281
S-enantiomer
282
S-enantiomer
283
S-enantiomer
284
S-enantiomer
285
S-enantiomer
286
S-enantiomer
287
S-enantiomer
or a solvate, salt, tautomer, enantiomer, racemate, or stereoisomer thereof, including mixtures thereof in any ratio.
9. A method for 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.
10. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 together with pharmaceutically tolerable adjuvants and/or excipients.
11. The pharmaceutical composition of claim 10 , further comprising one or more additional active ingredients.