Lipopeptides as antibacterial agents
View Patent ↗The present invention relates to novel lipopeptide compounds. The invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial compounds. The invention also relates to methods of producing these novel lipopeptide compounds and intermediates used in producing these compounds.
1. A compound having the formula (I):
and salts thereof;
wherein R is:
wherein X′ and X″ are independently C═O, C═S, C═NH, C═NR X , S═O or SO 2 ;
wherein n is 0 or 1;
wherein R X is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B is X″R Y , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein R Y is hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A is H, NH 2 , NHR A , NR A R B , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein R A and R B are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein when n is 0, then A is additionally:
wherein each of R 50 -R 53 is independently C 1 -C 15 alkyl;
alternatively, wherein B and A together form a 5-7 membered heterocyclic or heteroaryl ring;
wherein R 1 is
wherein X′ and X′″ are independently C═O, C═S, C═NH, C═NR X′ , S═O or SO 2 ;
wherein m is 0 or 1;
wherein R X′ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteorcyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B′ is X′″R Y′ , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein R Y′ is hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A′ is unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aryloxy; or alkyl wherein one or more hydrogen atoms is replaced by a substituent group selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, oxo, guanidino, and formyl;
provided that when B′ is H then (X′) m -A′ is other than
(a) —C(O)(C 1 -C 16 unsubstituted alkyl)-NH 2 ;
(b) —C(O)(C 1 -C 10 unsubstituted alkyl)-NHC(O)R D , wherein R D is —C 1 -C 18 unsubstituted alkyl, or —C 1 -C 18 selected substituted alkyl wherein one proton is replaced by a hydroxyl, carboxyl or C 1 -C 3 alkoxy, or one to three protons is replaced by a halo substituent;
(c) —C(O)C 1 -C 18 unsubstituted alkyl;
(d) —C(O)C 4 -C 18 unsubstituted alkenyl;
wherein R 54 is selected from C 1 -C 17 -unsubstituted alkyl or C 2 -C 17 -unsubstituted alkenyl; wherein R 55 is selected from hyroxyethyl, hydroxymethyl, mercaptomethyl, mercaptoethyl, methylthioethyl, 2-thienyl, 3-indolemthyl, phenyl optionally substituted with a group selected from halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -unsubstituted alkoxy, C 1 -C 3 -unsubstituted alkylthio, carbamyl or C 1 -C 3 unsubstituted alkylcarbamyl; or benzyl optionally substituted with a group selected from halo, nitro, C 1 -C 3 -unsubstituted alkyl, hydroxy, C 1 -C 3 -unsubstituted alkoxy, C 1 -C 3 -unsubstituted alkylthio, carbamyl or C 1 -C 3 unsubstituted alkylcarbamyl; wherein t is 0 or 1 and wherein u is an integer from 1-3;
(f) —C(O)C 1 -C 18 selected unsubstituted alkyl wherein one proton is replaced by a hydroxyl, carboxyl or C 1 -C 3 alkoxy, or one to three protons is replaced by a halo substituent; and
(g) an amino protecting group; and
wherein when B′ is H and m is 0, then A′ is other than C 4 -C 14 unsubstituted alkyl;
wherein R 2 is
wherein K and K′ together form a C 3 -C 7 cycloalkyl or heterocyclyl ring or a C 5 -C 10 aryl or heteroaryl ring;
wherein J is hydrido, amino, NHR J , NR J R K , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
wherein each of R 24 , R 25 , and R 26 is independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R 24 and R 25 together form a 5-8 membered heterocyclyl ring;
wherein R J and R K are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
alternatively, wherein J together with R 17 , forms a 5-8 membered heterocyclyl or cycloalkyl ring; or
alternatively, wherein J, together with both R 17 and R 18 , forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and
wherein each of R 17 and R 18 is independently hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl or
wherein R 17 and R 18 taken together can form a ketal, thioketal,
wherein each of R 22 and R 23 is independently hydrido or alkyl.
2. A compound having the formula (I):
and salts thereof;
wherein R is:
wherein X and X′ are independently C═O, C═S, C═NH, C═NR X , S═O or SO 2 ;
wherein n is 0 or 1;
wherein R X is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B is X″R Y , H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein R Y is hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A is H, NH 2 , NHR A , NR A R B , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein R A and R B are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein when n is 0, then A is additionally:
wherein each of R 50 -R 53 is independently C 1 -C 15 alkyl;
alternatively, wherein B and A together form a 5-7 membered heterocyclic or heteroaryl ring;
wherein R 1 is
wherein X′ and X″′ are independently C═O, C═S, C═NH, C═NR X′ S═O or SO 2 ;
wherein m is 0 or 1;
wherein R X′ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteorcyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B′ and A′ together form a 5-7 membered heterocyclic or heteroaryl ring;
wherein R A′ and R B′ are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein R 2 is
wherein K and K′ together form a C 3 -C 7 cycloalkyl or heterocyclyl ring or a C 5 -C 10 aryl or heteroaryl ring;
wherein J is hydrido, amino, NHR J , NR J R K , alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
wherein each of R 24 , R 25 , and R 26 is independently alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 24 and R 25 together form a 5-8 membered heterocyclyl ring;
wherein R J and R K are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or
alternatively, wherein J, together with R 17 , forms a 5-8 membered heterocyclyl or cycloalkyl ring; or
alternatively, wherein J, together with both R 17 and R 18 , forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and
wherein each of R 17 and R 18 is of hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl or
wherein R 17 and R 18 taken together can form a ketal, thioketal,
wherein each of R 22 and R 23 is independently hydrido or alkyl.
3. The compound according to either of claims 1 or 2 , wherein R is
wherein each of R 3 , R 4 R 5 , and R 6 is independently hydrido, alkyl, aryl, heterocyclyl or heteroaryl, and wherein R 44 alkyl, aryl, heterocyclyl or heteroaryl.
4. The compound according to claim 3 , wherein R is
wherein R 4 is alkyl, aryl-substituted alkyl, substituted phenyl, heteroaryl, heterocyclyl, optionally substituted (C 8 -C 14 )-straight chain alkyl or
wherein R 7 is an alkyl group.
5. The compound according to claim 4 , wherein R is
wherein X 3 is chloro or trifluoromethyl and wherein q is 0 or 1.
6. The compound according to claim 1 , wherein R 1 is:
wherein R 8 is a natural amino acid side chain or an amino acid side chain that is not naturally occurring;
wherein R 9 is hydrido, alkyl, aryl, heterocyclyl or heteroaryl;
wherein R 12 is heterocyclyl, heteroaryl, aryl, or alkyl
provided that R 12 is other than C 3 -C 13 unsubstituted alkyl; and
wherein R 13 is (C 1 -C 3 -alkyl) wherein one or more hydrogen atoms is replaced by a substituent group selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, oxo guanidino, and formyl.
7. The compound according to claim 6 , wherein R J is:
wherein R 8 is tryptophan side chain or lysine side chain;
wherein R 12 is imidazolyl, N-methylimidazolyl, indolyl, quinolinyl, benzyloxybenzyl, or benzylpiperidenylbenzyl.
8. The compound according to either of claims 1 or 4 , wherein J is hydrido, amino, azido or
wherein R 17 and R 18 taken together form a ketal,
or wherein R 17 is hydroxyl when R 18 is hydrido;
or wherein J, together with R 17 , forms a heterocyclyl ring.
9. The compound according to claim 8 , wherein
wherein R 17 and R 18 taken together form a
wherein R 22 is H or alkyl; and wherein R 19 is hydrido, amino, azido or
10. The compound according to claim 9 , wherein R 2 is
11. The compound according to claim 1 wherein said compound is
Cpd #
R
R 1
R 2
37
NHCO(CH 2 ) 8 CH 3
38
NHCO(CH 2 ) 8 CH 3
39
NHCO(CH 2 ) 8 CH 3
40
NHCO(CH 2 ) 8 CH 3
41
NHCO(CH 2 ) 8 CH 3
42
NHCO(CH 2 ) 8 CH 3
43
NHCO(CH 2 ) 8 CH 3
44
NHCO(CH 2 ) 8 CH 3
45
NHCO(CH 2 ) 8 CH 3
46
NHCO(CH 2 ) 8 CH 3
47
NHCO(CH 2 ) 8 CH 3
48
NHCO(CH 2 ) 8 CH 3
49
NHCO(CH 2 ) 8 CH 3
50
NHCO(CH 2 ) 8 CH 3
51
NHCO(CH 2 ) 8 CH 3
52
NHCO(CH 2 ) 8 CH 3
54
NHCO(CH 2 ) 8 CH 3
55
NHCO(CH 2 ) 8 CH 3
56
NHCO(CH 2 ) 8 CH 3
58
NHCO(CH 2 ) 8 CH 3
60
NHCO(CH 2 ) 8 CH 3
61
NHCO(CH 2 ) 8 CH 3
62
NHCO(CH 2 ) 8 CH 3
63
NHCO(CH 2 ) 8 CH 3
64
NHCO(CH 2 ) 8 CH 3
65
NHCO(CH 2 ) 8 CH 3
66
NHCO(CH 2 ) 8 CH 3
67
NHCO(CH 2 ) 8 CH 3
68
NHCO(CH 2 ) 8 CH 3
69
NHCO(CH 2 ) 8 CH 3
72
NHCO(CH 2 ) 8 CH 3
73
NHCO(CH 2 ) 8 CH 3
74
NHCO(CH 2 ) 8 CH 3
75
NHCO(CH 2 ) 8 CH 3
76
NHCO(CH 2 ) 8 CH 3
77
NHCO(CH 2 ) 8 CH 3
NH(CH 2 ) 2 OH
78
NHCO(CH 2 ) 8 CH 3
79
NHCO(CH 2 ) 8 CH 3
80
NHGO(CH 2 ) 8 CH 3
81
NHCO(CH 2 ) 8 CH 3
82
NHCO(CH 2 ) 8 CH 3
83
NHCO(CH 2 ) 8 CH 3
84
NHCO(CH 2 ) 8 CH 3
85
NHCO(CH 2 ) 8 CH 3
86
87
NHCO(CH 2 ) 8 CH 3
88
NHCO(CH 2 ) 8 CH 3
89
NHCO(CH 2 ) 8 CH 3
90
NHCO(CH 2 ) 8 CH 3
91
NHCO(CH 2 ) 8 CH 3
92
NHCO(CH 2 ) 8 CH 3
93
NHCO(CH 2 ) 8 CH 3
94
NHCO(CH 2 ) 8 CH 3
95
NHCO(CH 2 ) 8 CH 3
96
NHCO(CH 2 ) 8 CH 3
97
NHCO(CH 2 ) 8 CH 3
98
NHCO(CH 2 ) 8 CH 3
99
NHCO(CH 2 ) 8 CH 3
100
NHCO(CH 2 ) 8 CH 3
101
102
NHCO(CH 2 ) 11 CH 3
103
NHCO(CH 2 ) 8 CH 3
104
NHCO(CH 2 ) 8 CH 3
105
NHCO(CH 2 ) 8 CH 3
106
NHCO(CH 2 ) 8 CH 3
107
NHCO(CH 2 ) 8 CH 3
108
NHCO(CH 2 ) 8 CH 3
109
NHCO(CH 2 ) 8 CH 3
110
NHCO(CH 2 ) 8 CH 3
111
NHCO(CH 2 ) 8 CH 3
112
NHCO(CH 2 ) 8 CH 3
113
NHCO(CH 2 ) 8 CH 3
114
NHCO(CH 2 ) 8 CH 3
115
NHCO(CH 2 ) 8 CH 3
116
NHCO(CH 2 ) 8 CH 3
117
NHCO(CH 2 ) 8 CH 3
118
NHCO(CH 2 ) 8 CH 3
119
NHCO(CH 2 ) 8 CH 3
120
NHCO(CH 2 ) 8 CH 3
121
NHCO(CH 2 ) 8 CH 3
122
NHCO(CH 2 ) 8 CH 3
123
NHCO(CH 2 ) 8 CH 3
124
NHCO(CH 2 ) 8 CH 3
125
NHCO(CH 2 ) 8 CH 3
126
NHCO(CH 2 ) 8 CH 3
127
NHCO(CH 2 ) 8 CH 3
128
NHCO(CH 2 ) 8 CH 3
129
NHCO(CH 2 ) 8 CH 3
130
NHCO(CH 2 ) 8 CH 3
131
NHCO(CH 2 ) 8 CH 3
132
NHCO(CH 2 ) 8 CH 3
133
NHCO(CH 2 ) 8 CH 3
134
NHCO(CH 2 ) 8 CH 3
135
NHCO(CH 2 ) 8 CH 3
136
NHCO(CH 2 ) 8 CH 3
137
NHCO(CH 2 ) 8 CH 3
138
NHCO(CH 2 ) 8 CH 3
139
NHCO(CH 2 ) 8 CH 3
140
NHCO(CH 2 ) 8 CH 3
141
NHCO(CH 2 ) 8 CH 3
142
NHCO(CH 2 ) 8 CH 3
143
NHCO(CH 2 ) 8 CH 3
144
NHCO(CH 2 ) 8 CH 3
145
NHCO(CH 2 ) 8 CH 3
146
NHCO(CH 2 ) 8 CH 3
147
NHCO(CH 2 ) 8 CH 3
148
NHCO(CH 2 ) 8 CH 3
149
NHCO(CH 2 ) 8 CH 3
150
NHCO(CH 2 ) 8 CH 3
151
NHCO(CH 2 ) 8 CH 3
152
NHCO(CH 2 ) 8 CH 3
153
NHCO(CH 2 ) 8 CH 3
154
NHCO(CH 2 ) 8 CH 3
155
NHCO(CH 2 ) 8 CH 3
156
NHCO(CH 2 ) 8 CH 3
157
NHCO(CH 2 ) 8 CH 3
158
NHCO(CH 2 ) 8 CH 3
159
NHCO(CH 2 ) 8 CH 3
160
NHCO(CH 2 ) 8 CH 3
161
NHCO(CH 2 ) 8 CH 3
162
NHCO(CH 2 ) 8 CH 3
163
NHCO(CH 2 ) 8 CH 3
164
NHCO(CH 2 ) 8 CH 3
165
NHCO(CH 2 ) 8 CH 3
166
NHCO(CH 2 ) 8 CH 3
167
NHCO(CH 2 ) 8 CH 3
168
NHCO(CH 2 ) 8 CH 3
169
NHCO(CH 2 ) 8 CH 3
171
NHCO(CH 2 ) 8 CH 3
172
NHCO(CH 2 ) 8 CH 3
173
NHCO(CH 2 ) 8 CH 3
174
NHCO(CH 2 ) 8 CH 3
175
NHCO(CH 2 ) 8 CH 3
176
NHCO(CH 2 ) 8 CH 3
177
NH 2
178
NHCO(CH 2 ) 8 CH 3
179
NHCO(CH 2 ) 8 CH 3
180
NHCO(CH 2 ) 8 CH 3
181
NHCONH(CH 2 ) 10 CH 3
182
NHCO(CH 2 ) 8 CH 3
183
NHCO(CH 2 ) 8 CH 3
184
NHCO(CH 2 ) 8 CH 3
185
NHCO(CH 2 ) 8 CH 3
186
NHCO(CH 2 ) 8 CH 3
187
NHCO(CH 2 ) 8 CH 3
192
NHCO(CH 2 ) 8 CH 3
193
NHCO(CH 2 ) 8 CH 3
194
NHCO(CH 2 ) 8 CH 3
195
NHCO(CH 2 ) 8 CH 3
196
NHCO(CH 2 ) 8 CH 3
197
NHCO(CH 2 ) 8 CH 3
198
NHCO(CH 2 ) 8 CH 3
199
NHCO(CH 2 ) 8 CH 3
200
NHCO(CH 2 ) 8 CH 3
201
NHCO(CH 2 ) 8 CH 3
202
NHCO(CH 2 ) 8 CH 3
203
NHCO(CH 2 ) 8 CH 3
204
NHCO(CH 2 ) 8 CH 3
205
NH(CH 2 ) 8 CH 3
206
NHCO(CH 2 ) 8 CO 2 Me
207
NHCO(CH 2 ) 6 CO 2 Me
208
NHCO(CH 2 ) 8 CH 3
209
NHCO(CH 2 ) 8 CH 3
210
NHCO(CH 2 ) 8 CH 3
211
NHCO(CH 2 ) 8 CH 3
212
NHCO(CH 2 ) 8 CH 3
213
NHCO(CH 2 ) 6 NHBoc
214
NHCO(CH 2 ) 7 NHBoc
215
NHCO(CH 2 ) 10 NHBoc
216
NHCO(CH 2 ) 11 NHBoc
217
NHCO(CH 2 ) 10 NH 2
218
NHCO(CH 2 ) 11 NH 2
219
NHCO(CH 2 ) 6 CH(CH 3 ) 2
220
NHCONH(CH 2 ) 11 CH 3
221
NHCO(CH 2 ) 8 CH 3
222
NHCO(CH 2 ) 8 CH 3
223
NHCO(CH 2 ) 8 CH 3
224
NHCO(CH 2 ) 8 CH 3
225
NHCO(CH 2 ) 8 CH 3
226
NHCO(CH 2 ) 8 CH 3
227
NHCO(CH 2 ) 8 CH 3
228
NHCO(CH 2 ) 8 CH 3
229
NHCO(CH 2 ) 8 CH 3
230
NHCO(CH 2 ) 8 CH 3
231
NHCO(CH 2 ) 8 CH 3
232
NHCO(CH 2 ) 8 CH 3
233
NHCO(CH 2 ) 8 CH 3
234
NHCO(CH 2 ) 8 CH 3
235
NHCO(CH 2 ) 8 CH 3
236
NHCO(CH 2 ) 8 CH 3
237
NHCO(CH 2 ) 8 CH 3
238
NHCO(CH 2 ) 8 CH 3
239
NHCO(CH 2 ) 8 CH 3
240
NHCO(CH 2 ) 8 CH 3
241
NHCO(CH 2 ) 8 CH 3
242
NHCO(CH 2 ) 8 CH 3
243
NHCO(CH 2 ) 8 CH 3
244
NHCO(CH 2 ) 8 CH 3
245
NHCO(CH 2 ) 8 CH 3
246
247
248
249
250
251
252
NHCO(CH 2 ) 8 CH 3
253
NHCO(CH 2 ) 8 CH 3
264
265
NHCO(CH 2 ) 8 CH 3
266
NHCO(CH 2 ) 8 CH 3
267
NHCO(CH 2 ) 8 CH 3
268
NHCO(CH 2 ) 8 CH 3
269
270
NHCO(CH 2 ) 8 CH 3
271
NHCO(CH 2 ) 8 CH 3
272
NHCO(CH 2 ) 8 CH 3
273
NHCO(CH 2 ) 8 CH 3
274
NHCO(CH 2 ) 8 CH 3
275
NHCO(CH 2 ) 8 CH 3
276
NHCO(CH 2 ) 8 CH 3
277
NHCO(CH 2 ) 8 CH 3
278
NHCO(CH 2 ) 8 CH 3
279
NHCO(CH 2 ) 8 CH 3
280
NHCO(CH 2 ) 8 CH 3
281
NHCO(CH 2 ) 8 CH 3
282
NHCO(CH 2 ) 8 CH 3
283
NHCO(CH 2 ) 8 CH 3
284
NHCO(CH 2 ) 8 CH 3
285
NHCO(CH 2 ) 8 CH 3
286
NHCO(CH 2 ) 8 CH 3
287
NHCO(CH 2 ) 8 CH 3
288
NHCO(CH 2 ) 8 CH 3
289
NHCO(CH 2 ) 8 CH 3
290
NHCO(CH 2 ) 8 CH 3
291
NHCO(CH 2 ) 8 CH 3
295
NHCO(CH 2 ) 11 CH 3
296
NHCO(CH 2 ) 10 CH 3
297
NHCO(CH 2 ) 9 CH 3
298
NHCONH(CH 2 ) 7 CH 3
299
NHCONH(CH 2 ) 10 CH 3
300
NHCONH(CH 2 ) 11 CH 3
301
NHCO(CH 2 ) 11 CH 3
302
NHCO(CH 2 ) 10 CH 3
303
NHCO(CH 2 ) 9 CH 3
304
NHCONH(CH 2 ) 7 CH 3
305
NHCONH(CH 2 ) 10 CH 3
306
NHCONH(CH 2 ) 11 CH 3
307
NHCO(CH 2 ) 9 CH 3
308
NHCO(CH 2 ) 10 CH 3
309
NHCO(CH 2 ) 10 CH 3
310
NHCO(CH 2 ) 9 CH 3
311
NHCONH(CH 2 ) 7 CH 3
315
NHCONH(CH 2 ) 7 CH 3
316
NHCONH(CH 2 ) 7 CH 3
317
NHCONH(CH 2 ) 7 CH 3
318
NHCO(CH 2 ) 9 CH 3
319
NHCO(CH 2 ) 9 CH 3
320
NHCO(CH 2 ) 11 CH 3
321
NHCO(CH 2 ) 11 CH 3
322
NHCO(CH 2 ) 11 CH 3
323
NHCO(CH 2 ) 8 CH 3
324
NHCO(CH 2 ) 8 CH 3
325
NHCO(CH 2 ) 8 CH 3
326
NHCO(CH 2 ) 8 CH 3
327
NHCO(CH 2 ) 8 CH 3
328
NHCO(CH 2 ) 8 CH 3
329
NHCO(CH 2 ) 8 CH 3
330
NHCO(CH 2 ) 8 CH 3
331
NHCO(CH 2 ) 8 CH 3
332
NHCO(CH 2 ) 10 CH 3
333
NHCO(CH 2 ) 10 CH 3
334
NHCO(CH 2 ) 10 CH 3
335
NHCONH(CH 2 ) 11 CH 3
336
NHCONH(CH 2 ) 11 CH 3
337
NHCONH(CH 2 ) 11 CH 3
338
NHCO(CH 2 ) 12 CH 3
339
NHCO(CH 2 ) 12 CH 3
340
NHCO(CH 2 ) 12 CH 3
341
NHCO(CH 2 ) 12 CH 3
345
NHCO(CH 2 ) 12 CH 3
346
NHCO(CH 2 ) 12 CH 3
347
NHCO(CH 2 ) 7 CH 3
348
NHCO(CH 2 ) 7 CH 3
349
NHCO(CH 2 ) 7 CH 3
350
351
NHCO(CH 2 ) 11 CH 3
352
NHCONH(CH 2 ) 10 CH 3
355
NHCONH(CH 2 ) 10 CH 3
356
NHCONH(CH 2 ) 10 CH 3
358
NHCO(CH 2 ) 8 CH 3
359
NHCO(CH 2 ) 8 CH 3
360
NHCO(CH 2 ) 8 CH 3
361
NHCO(CH 2 ) 8 CH 3
362
NHCO(CH 2 ) 8 CH 3
363
NHCO(CH 2 ) 8 CH 3
364
NHCO(CH 2 ) 8 CH 3
365
NHCO(CH 2 ) 8 CH 3
366
NHCO(CH 2 ) 8 CH 3
367
NHCO(CH 2 ) 8 CH 3
368
NHCO(CH 2 ) 8 CH 3
369
NHCO(CH 2 ) 8 CH 3
370
NHCO(CH 2 ) 8 CH 3
371
NHCO(CH 2 ) 8 CH 3
372
NHCO(CH 2 ) 8 CH 3
373
NHCO(CH 2 ) 8 CH 3
374
NHCO(CH 2 ) 8 CH 3
375
NHCO(CH 2 ) 8 CH 3
376
NHCO(CH 2 ) 8 CH 3
377
NHCO(CH 2 ) 8 CH 3
378
NHCO(CH 2 ) 8 CH 3
379
NHCO(CH 2 ) 8 CH 3
380
NHCO(CH 2 ) 8 CH 3
381
NHCO(CH 2 ) 8 CH 3
382
NHCO(CH 2 ) 8 CH 3
383
NHCO(CH 2 ) 8 CH 3
384
NHCO(CH 2 ) 8 CH 3
385
NHCO(CH 2 ) 8 CH 3
386
NHCO(CH 2 ) 8 CH 3
387
NHCO(CH 2 ) 8 CH 3
388
NHCO(CH 2 ) 8 CH 3
389
NHCO(CH 2 ) 8 CH 3
390
NHCO(CH 2 ) 8 CH 3
391
NHCO(CH 2 ) 8 CH 3
392
NHCO(CH 2 ) 8 CH 3
393
NHCO(CH 2 ) 8 CH 3
394
NHCO(CH 2 ) 8 CH 3
395
NHCO(CH 2 ) 8 CH 3
398
NHCO(CH 2 ) 8 CH 3
399
NHCO(CH 2 ) 8 CH 3
400
NHCO(CH 2 ) 8 CH 3
401
NHCO(CH 2 ) 8 CH 3
402
NHCO(CH 2 ) 8 CH 3
403
NHCO(CH 2 ) 8 CH 3
404
NHCO(CH 2 ) 8 CH 3
405
NHCO(CH 2 ) 8 CH 3
406
NHCO(CH 2 ) 8 CH 3
407
NHCO(CH 2 ) 8 CH 3
408
NHCO(CH 2 ) 8 CH 3
409
NHCO(CH 2 ) 8 CH 3
410
NHCO(CH 2 ) 8 CH 3
12. The compound according to claim 11 wherein the compound is
Cpd #
R
R 1
R 2
45
NHCO(CH 2 ) 8 CH 3
54
NHCO(CH 2 ) 8 CH 3
76
NHCO(CH 2 ) 8 CH 3
81
NHCO(CH 2 ) 8 CH 3
85
NHCO(CH 2 ) 8 CH 3
102
NHCO(CH 2 ) 11 CH 3
209
NHCO(CH 2 ) 8 CH 3
212
NHCO(CH 2 ) 8 CH 3
253
NHCO(CH 2 ) 8 CH 3
282
NHCO(CH 2 ) 8 CH 3
285
NHCO(CH 2 ) 8 CH 3
319
NHCO(CH 2 ) 9 CH 3
322
NHCO(CH 2 ) 11 CH 3
333
NHCO(CH 2 ) 10 CH 3
334
NHCO(CH 2 ) 10 CH 3
335
NHCOKH(CH 2 ) 11 CH 3
336
NHCONH(CH 2 ) 11 CH 3
355
NHCOKH(CH 2 ) 10 CH 3
13. A compound of formula (I) according to claim 1 , wherein R is NHCO-[(C 6 -C 14 )-alkyl]-CH 3 , and R 1 and R 2 are selected from:
R 1
R 2
NH(CH 2 ) 2 OH
14. The compound according to claim 13 , wherein R is NHCO-[(CH 2 ) 6-14 ]-CH 3 .
15. A pharmaceutical composition comprising the compound according to either-one of claims 1 or 2 and a pharmaceutically acceptable carrier.
16. A method of treating a bacterial infection in a subject, comprising the step of administering the pharmaceutical composition according to claim 15 to a subject in need thereof for a time and under conditions effective to ameliorate said bacterial infection.
17. The method according to claim 16 , wherein said subject is a human, an animal, a cell culture or a plant.
18. The method according to claim 16 , wherein said bacterial infection is caused by a gram-positive bacteria.
19. The method according to claim 18 , wherein said bacterial is an antibiotic-resistant bacteria that is resistant to an antibiotic that is not included within the scope of Formula (I).
20. The method according to claim 19 , wherein said antibiotic-resistant bacteria are resistant to vancomycin, methicillin, glycopeptide antibiotics, penicillin or daptomycin.
21. The method according to claim 16 , further comprising the step of co-administering more than one compound of Formula (I) according to either of claims 3 or 4 to a subject in need thereof.
22. The method according to claim 16 , further comprising the step of co-administering a second antimicrobial agent wherein said second antimicrobial agent is not included within the scope of Formula (I).
23. The method according to claim 22 , wherein said antimicrobial agent is penicillins, carbapenems, cephalosporins, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, fusidate sodium, lincomycin, clindamycin, macrolides, novobiocin, polymyxins, rifamycins, spectinomycin, tetracyclines, vancomycin, teicoplanin, streptogramins, anti-folate agents, trimethoprim, pyrimethamine, nitroimidazoles, quinolones, fluoroquinolones, isoniazid, ethambutol, pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, prothionamide, thiacetazone, viomycin, everninomicin, glycopeptide, glycylcycline, ketolides, -oxazolidinones, imipenen, amikacin, netilmicin, fosfonycin, gentamicin, ceftriaxone, ZIRACIN (56-deacetyl-57-demethyl-45-O-de(2-methyl-1-oxopropyl)-12-O-(2,3,6-trideoxy-3-C-methyl-4-O-methyl-3-nitro-alpha-L-arabino-hexopyranosyl)flambamycin), LY333328 (oritavancin), linezolid (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide), SYNERCID (dalfopristin-quinupristin), aztreonam (2-[[(Z)-[1-(2-amino-4-thiazolyl)-2-[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methyl-propanoic acid), metonidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol), epiroprim (5-[[3,5-diethoxy-4-(1H-pyrrol-1-yl)phenyl]methyl]-2,4-pyrimidinediamine), OCA-983 (1-[[(2S)-2-amino-3-methyl-1-oxobutyl]amino]-2,5-anhydro-3-S-[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol), GV-143253 (trinem), sanfetrinem ((1S, 5S,8aS, 8bR)-1, 2, 5, 6, 7, 8, 8a, 8b-octahydro-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-azeto[2,1-a]isoindole-4-carboxylic acid), CS-83 ((4R,5S, 6S)-6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3R)-5-oxo-3-pyrrolidinyl]thio]-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester), biapenem (6[[(4R,5S,6S)-2-carboxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio]-6, 7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium inner salt), KA 159 (stipiamide), dynemicin A ((1S,4R,4aR, 14S,14aS,18Z)-1,4,7,12,13 14-hexahydro-6,8,11-trihydroxy-3-methoxy-1-methyl-7,12-dioxo-4a,14a-epoxy-4,14-[3]hexene[1,5]diynonaphtho[2,3-c]phenanthridine-2-carboxylic acid), DX8739 ((4R,5S,6S)-3-[[(3S,5S)-5-[[4-[(2S)-5-amino-2-hydroxy-1-oxopentyl]-1-piperazinyl]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), DU 6681 ((4R,5S,6S)-3-[[(6S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl]thio]-6-(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid), cefluprenam ((2E)-N-(2-amino-2-oxoethyl)-3-[[(6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)[(fluoro methoxy)imino]acetyl] amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]-N-ethyl-N-methyl-2-propen-1-aminium inner salt), ER 35786 ((4R, 5S,6S)-6[(1R)-1-hydroxyethyl]-3-[[(3S,5S)-5-[(R)-hydroxy(3R)-3-pyrrolidinylmethy]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrochloride), cefoselis ((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxy imino)acetyl]amino]-3-[[2,3-dihydro-2-(2-hydroxyethyl)-3-imino-1H-pyrazol-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid), sanfetrinem celexetil ((1S5S,8aS,8bR)-1,2,5,6,7,8,8a,8b-octahydro-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-azeto[2,1-a]isoindole-4-carboxylic acid 1-[(cyclohexyloxy)carbonyl] oxy]ethyl ester), cefpirome (1-[[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-6,7-dihydro-5H-cyclopenta[b]pyridinium inner salt), HMR-3647 (3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy]-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl[[4-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]imino]]-erythromycin), RU-59863 (C-7 catechol substituted cephalosporin), KP 736 ((6R,7R)-7-[[2Z)-(2-amino-4-thiazolyl)[[(1,4-dihydro-1,5-dihyroxy-4-oxo-2-pyridinyl)methoxy] imino]acetyl]amino]-8-oxo-3[(1,2,3-thiadiazol-5-ylthio)methyl]-5-this-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium slat), Rifalazil (1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[4-(2-methylpropyl)-1-piperazinyl]-1-oxo-rifamycin VII, MEN 10700 ((5R,6S)-3-[[2-amino-2-oxoethyl)methylamino]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), lenapenem ((4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[3S,5S)-5-[(1R)-1-hydroxy-3-(methylamino)propyl]-3-pyrrolidinyl]thio]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), BO 2502A ((4R,5S,6S)-3-[(2S,3′S,4S)-[2,3′-bipyrrolidin[-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), NE-1530 (3+-sialyl]acto-N-neotetraose), K130 (5-[[4-[3-[[4-[(4-aminophenyl)sulfonyl]phenyl]amino]propoxy]-3,5-dimethoxyphenyl] methyl]-2,4-pyrimidinediarnine), PD 138312 ((R)-7-[3-(1-amino-1-methylethyl)-1-pyrrolidinyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid), PD 140248 (7-[(3R)-3-[(1S)-1-aminoethyl]-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid), CP 111905 (5-deoxy-5-[[(2E)-3-[3-hydroxy-4-(2-propenyloxy)phenyl]-2-methyl-1-oxo-2-propenyl]amino]-1,2-O-methylene-D-neo-inositol), sulopenem ((5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[[(1R,3S)-tetrahydro-1-oxido-3-thienyl]thio]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid), ritipenam acoxyl ((5R,6R)-3-[]aminocarbonyl)oxy]methyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (acetyloxy)methyl ester), RO-65-5788 ((6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadianol-3-yl)(hydroxyimino)acetyl]amino]-3-[(E)-[(3′R)-1′-[[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl]-2-oxo[1,3′-bipyrrolidinyl]-3-ylidene]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosoidum salt), Sch-40832 (N-[[48-[1-[[2,6-dideoxy-3-O-(2,6-dideoxy-D-arabino-hexopyranosyl)-D-arabino-hexopyranosyl]oxy]ethyl]-15-ethylidene-1,3a,4,510,11,12, 13,14,15,19,20,21,22,28,29,41,42-octadecahydro-41-hydroxy-12,45-bis(1-hydroxyethyl)-1-(hydroxymethyl)-22-(1-hydroxy-1-methylpropyl)-36-methyl-51,54,57-tris(methylene)-3-(methylthio)-10,13,20,27,38,49,52,55,58-nonaoxo-18H,27H-5a,29-(iminoethaniminoethanimino ethaniminoethanimino[7,2]quinolinomethanoxy methano)-9,6:19,16:26,23:33,30-tetranitrilo-16H,33aH-imidazo(1′,5′:1,6 pyrido [3,2-m][1,11,17,24,4,7,20,27]tetrathiatetraazacyclotriacontin-1-yl]carbonyl]-2,3-didehydroalanyl-2,3-didehydro-alanine methyl ester stereoisomer), micacocidin A((OC-6-26-A)-[(4S)-2-[(2S)-2-[(2R,4R)-2-[(4R)-4,5-dihydro-2-[2-(hydroxy-.kappa.O)-6-pentylphenyl]-4-thiazolyl-.kappa.N3]-3-methyl-4-thiaolidinyl-.kappa.N3]-2-(hydroxy-.kappa.N3, .kappa.O4]-Zinc), SR-15402 ((1S,5S,8aS,8bR)-1,2,5,6,7,8,8a,8b-octahydro-1-[(1R)-1-hydroxyethyl]-2-oxo-5-[(3S)-3-pyrrolidinylthio]-azeto[2,1-a]isoindole-4-carboxylic acid), TOC 39 (1-(2-amino-2-oxoethyl)-4-[[(1E)-2-[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl) (hydroxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]ethenyl]thio]-pyridinium inner salt), carurnonam ([[(Z)-[2-[[(2S,3S)-2-[[(aminocarbonyl)oxy]methyl]-4-oxo-1-sulfo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-acetic acid), cefozopran (1-[[(6R,7R)-7-[[(2Z)-(5-amino-1,2,4-thiadiazol-3-yl)(methoxy imino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-imidazo[1,2-b]pyridazinium inner salt), cefetamet pivoxil ((6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)(methoxy imino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester), and T 3811 (des-F(6)-quinolone).
24. The method according to claim 22 , wherein said antimicrobial agent is selected from the group consisting of imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, teicoplanin, ZIRACIN, LY333348, CL331022, HMR3647, linezolid, SYNERCID, aztreonam and metronidazole.
25. The method according to claim 17 , wherein said subject is selected from a human or an animal.
26. The method according to claim 25 , wherein said subject is a human.
27. The compound of claim 1 having the formula (III):
wherein R 15 is hydrido or a carbamate amino protecting group; wherein R 16 is
and, wherein, R 20 is an amino acid side chain.
28. The compound according to claim 27 selected from:
Com-
pound
#
R 16
45
54
79
80
81
82
84
139
158
146
212
85
174
78
150
130
138
168
274
317
280
275
283
285
50
38
115
105
76
147
164
210
107
111
103
253
227
372
386
29. The compound according to claim 2 wherein said compound is
Cpd
#
R
R 1
R 2
189
NHCO(CH2)8CH3
30. A compound of formula (I) according to claim 2 , wherein R is NHCO-[(C 6 -C 14 )-alkyl]-CH 3 , and R 1 and R 2 are:
R 1
R 2