Bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
New bicyclic compounds, their preparation, and their use as antibacterial agents, either alone or in combination with an antibiotic for the treatment of infections caused by β-lactamase-producing pathogenic bacteria, are described.
1. A compound of Formula (I):
wherein;
M is hydrogen or a pharmaceutically acceptable salt forming cation, and
R 1 is a radical selected from any of the following groups (1)-(6):
(1) C 1-6 straight or branched chain alkyl which is optionally substituted;
(2) C 3-7 cycloalkyl which is optionally substituted;
(3) C 4-7 saturated heterocycle containing at least one nitrogen, wherein the free ring N atom may optionally take a substituent;
(4) Heterocyclyl (C 1-6 ) alkyl wherein the heterocycle contains at least one heteroatom selected from O, N and S, wherein the heterocycle is optionally substituted, wherein the ring S is optionally oxidized to S(O) or S(O) 2 , and wherein the free ring N atom may optionally take a substituent;
(5) C 5-7 membered saturated N-containing heterocycle which is optionally fused with a C 3-7 membered cycloalkyl group to form a bicyclic ring system, wherein each ring of the bicyclic ring system is optionally substituted;
(6) C 5-7 membered heteroarylalkyl which is optionally substituted; and
and pharmaceutically acceptable salts of such compounds, and deuterated compounds of such compounds and salts.
2. The compound of claim 1 , wherein the compound falls within R 1 radical group (1) and the compound is selected from the group consisting of:
3. The compound of claim 1 , wherein the compound falls within R 1 radical group (2) and the compound is selected from the group consisting of:
4. The compound of claim 1 , wherein the compound falls within R 1 radical group (3) and the compound is selected from the group consisting of:
5. The compound of claim 1 , wherein the compound falls within R 1 radical group (4) and the compound is selected from the group consisting of:
6. The compound of claim 1 , wherein the compound falls within R 1 radical group (5) and the compound is:
7. The compound of claim 1 , wherein the compound falls within R 1 radical group (6) and the compound is selected from the group consisting of:
8. A compound selected from the group consisting of the compounds 156-198:
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Structure
Name
156
(2S,5R)-2-((2-(methylamino)ethoxy)carbamoyl)-7- oxo-1,6-diazabicyclo[3.2.]octan-6-yl hydrogen sulfate
157
(2S,5R)-2-((2-(methylamino)propoxy)carbamoyl)-7- oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
158
(2S,5R)-2-((2-amino-2-methylpropoxy)carbamoyl)-7- oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
159
(2S,5R)-2-((2-methyl-2-(methylamino)propoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
160
(2S,5R)-2-(((1-aminocyclopropyl)methoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
161
(2S,5R)-2-(((1-(methylamino)cyclopropyl)methoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
162
(2S,5R)-2-((2-aminobutoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
163
(2S,5R)-2-((2-aminobutoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
164
(2S,5R)-2-((2-amino-3-methylbutoxy)carbamoyl)-7- oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
165
(2S,5R)-2-((3-methyl-2-(methylamino)butoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
166
(2S,5R)-2-((2-amino-3,3-dimethylbutoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
167
(2S,5R)-2-((3-methyl-2-(methylamino)butoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
168
(2S,5R)-2-(((1-(aminomethyl)cyclopropyl)methoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
169
(2S,5R)-2-(((1-((methylamino)methyl)cyclopropyl) methoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
170
(2S,5R)-2-((2-(isopropylamino)propoxy)carbamoyl)- 7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
171
(2S,5R)-2-((2-(methylamino)cyclopropoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
172
(2S,5R)-2-(((2-(methylamino)cyclopentyl)oxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
173
(2S,5R)-2-((2-amino-2-phenylethoxy)carbamoyl)-7- oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
174
(2S,5R)-2-((2-amino-2-cyclohexylethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
175
(2S,5R)-2-((2-amino-2-cyclopentylethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
176
(2S,5R)-2-((2-amino-2-cyclopropylethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
177
(2S,5R)-2-((2-amino-2-cyclobutylethoxy)carbamoyl)- 7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
178
(2S,5R)-2-((2-amino-2-(tetrahydro-2H-pyran-4- yl)ethoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
179
(2S,5R)-2-((2-aminocyclobutoxy)carbamoyl)-7-oxo- 1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
180
(2S,5R)-2-((2-(methylamino)cyclobutoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
181
(2S,5R)-2-((2-amino-2-(piperidin-4-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
182
(2S,5R)-2-((2-amino-2-(1,1-dioxidotetrahydro-2H- thiopyran-4-yl)ethoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
183
(2S,5R)-2-((2-amino-2-(pyridin-3-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
184
(2S,5R)-2-((2-amino-2-(pyridin-2-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
185
(2S,5R)-2-((2-amino-2-(thiophen-2-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
186
(2S,5R)-2-((2-amino-2-(furan-2-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
187
(2S,5R)-2-(((2-azabicyclo[3.1.0]hexan-3-yl)methoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
188
(2S,5R)-2-(((6-methyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazin-1-yl)methoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
189
(2S,5R)-2-((((5R)-5-(hydroxymethyl)pyrrolidin-3- yl)oxy)carbamoyl)-7-oxo-l,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
190
(2S,5R)-2-((((5S)-5-methylpyrrolidin-3-yl)oxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
191
(2S,5R)-2-((2-amino-2-(thiazol-2-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
192
(2S,5R)-2-((2-amino-2-(2-aminothiazol-4-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
193
(2S,5R)-2-((2-amino-2-(1-methyl-1H-imidazol-2- yl)ethoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
194
(2S,5R)-2-((2-amino-2-(1-methyl-1H-imidazol-5- yl)ethoxy)carbamoyl)-7-oxo-1,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
195
(2S,5R)-2-((2-amino-2-(thiazol-5-yl)ethoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
196
(2S,5R)-2-(((3-aminooxetan-3-yl)methoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
197
(2S,5R)-2-(((3-aminotetrahydrofuran-3-yl)methoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate
198
(2S,5R)-2-(((3-aminopyrrolidin-3-yl)methoxy) carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate.
9. A pharmaceutical composition comprising, as an active ingredient, at least one compound as recited in claim 1 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising, as an active ingredient, (i) at least one compound as recited in claim 1 and (ii) at least one β-lactam antibiotic, at least one salt of a β-lactam antibiotic, at least one hydrate of a β-lactam antibiotic, or at least one prodrug of a β-lactam antibiotic, and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising, as an active ingredient, (i) at least one compound as recited in claim 1 and (ii) at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic, or at least one prodrug of an antibiotic, and a pharmaceutically acceptable carrier.
12. A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as recited in claim 1 .
13. A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof a combination of (i) a therapeutically effective amount of a compound as recited in claim 1 and (ii) a therapeutically effective amount of at least one β-lactam antibiotic, at least one salt of a β-lactam antibiotic, at least one hydrate of a β-lactam antibiotic, or at least one prodrug of a β-lactam antibiotic.
14. A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof a combination of (i) a therapeutically effective amount of a compound as recited in claim 1 and (ii) a therapeutically effective amount of at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic.
15. The method as recited in claim 13 , wherein (i) and (ii) are administered simultaneously, sequentially, or separated in time.
16. The method as recited in claim 14 , wherein (i) and (ii) are administered simultaneously, sequentially, or separated in time.
17. A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof a pharmaceutical composition as recited in claim 10 in an amount sufficient to inhibit a bacterial β-lactamase.
18. The method of claim 13 , wherein the subject is a human.
19. The pharmaceutical composition as recited in claim 10 , wherein the ratio of the weight of (i) to the weight of (ii) is in the range of from about 1:20 to about 20:1.
20. The pharmaceutical composition as recited in claim 11 , wherein the ratio of the weight of (i) to the weight of (ii) is in the range of from about 1:20 to about 20:1.