US2009011977A1PendingUtilityA1
Novel Lipopeptides as Antibacterial Agents
Est. expiryDec 15, 2019(expired)· nominal 20-yr term from priority
Inventors:Jason HillIan ParrMichael MorytkoJim SiedleckiXiang Y. YuJared SilvermanDennis KeithJohn FinnDale J. ChristensenTsvetelina LazarovaAlan D. WatsonYan Zhang
A61K 38/00C07K 7/08A61P 31/04C07K 7/00
70
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Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . 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, 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′ , heteroaryl, cycloalkyl or heterocyclyl;
wherein R A′ and R B′ are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein when m is 0, then A′ is additionally:
wherein each of R 50 -R 53 is independently C 1 -C 15 alkyl;
provided that when B′ is H and X′ is C═O, then A′ is other than
(a) a pyridinyl ring substituted with one substitutent NHC(O)R D or
(b) a C 5 -C 6 saturated cycloalkyl ring substituted with one substitutent NHC(O)R D ;
wherein R D is C 1 -C 17 unsubstituted alkyl or C 2 -C 17 unsubstituted alkenyl; and
when B′ is H and m=0, then A′ is not H;
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 independently hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl or
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 selected from:
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, 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 aryl;
provided that when B′ is H and X′ is C═O, then A′ is other than a phenyl ring substituted with substitutent NHC(O)R D , wherein R D is C 1 -C 17 unsubstituted alkyl or C 2 -C 17 unsubstituted alkenyl, wherein said phenyl ring may be further optionally substituted with 1-2 substituents independently selected from amino, nitro, C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkoxy, halo, mercapto, C 1 -C 3 alkylthio, carbamyl or C 1 -C 3 alkyl carbamyl;
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 selected from 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
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 is s alkyl, aryl, heterocyclyl or heteroaryl.
4 . The compound according to claim 3 , wherein R is
wherein R 4 ′ is s 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 either of claims 1 or 2 , wherein R 1 is
wherein each of R 10 and R 11 is independently hydrido, alkyl, aryl, heterocyclyl or heteroaryl; and
wherein R 13 is aryl.
7 . The compound according to claim 6 , wherein R 1 is
wherein each of R 10 and R 11 is independently hydrido or alkyl; and
wherein X 4 is fluoro or trifluoromethyl.
8 . The compound according to either of claims 1 or 2 , wherein J is hydrido, amino, azido or
wherein R 17 and R 18 taken together form a group selected from 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 R 2 is
wherein R 17 and R 18 taken together form
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 either of claims 1 or 2 wherein said compound is
Cpd #
R
R 1
R 2
1
NHCO(CH 2 ) 8 CH 3
2
NHCO(CH 2 ) 8 CH 3
3
NHCO(CH 2 ) 8 CH 3
NHSO 2 Ph
4
NHCO(CH 2 ) 8 CH 3
5
NHCO(CH 2 ) 8 CH 3
6
NHCO(CH 2 ) 8 CH 3
7
NHCO(CH 2 ) 8 CH 3
8
NHCO(CH 2 ) 8 CH 3
9
NHCO(CH 2 ) 8 CH 3
10
NHCO(CH 2 ) 8 CH 3
11
NHCO(CH 2 ) 8 CH 3
12
NHCO(CH 2 ) 8 CH 3
13
NHCO(CH 2 ) 8 CH 3
14
NHCO(CH 2 ) 8 CH 3
15
NHCO(CH 2 ) 8 CH 3
16
NHCO(CH 2 ) 8 CH 3
17
NHCO(CH 2 ) 8 CH 3
18
NHCO(CH 2 ) 8 CH 3
19
NHCO(CH 2 ) 8 CH 3
20
NHCO(CH 2 ) 8 CH 3
21
NHCO(CH 2 ) 8 CH 3
22
NHCO(CH 2 ) 8 CH 3
23
NHCO(CH 2 ) 8 CH 3
24
NHCO(CH 2 ) 8 CH 3
25
NHCO(CH 2 ) 8 CH 3
26
NHCO(CH 2 ) 8 CH 3
27
NHCO(CH 2 ) 8 CH 3
28
NHCO(CH 2 ) 8 CH 3
29
NHCO(CH 2 ) 8 CH 3
30
NHCO(CH 2 ) 8 CH 3
31
NHCO(CH 2 ) 8 CH 3
32
NHCO(CH 2 ) 8 CH 3
33
NHCO(CH 2 ) 8 CH 3
34
NHCO(CH 2 ) 8 CH 3
35
NHCO(CH 2 ) 8 CH 3
36
NHCO(CH 2 ) 8 CH 3
57
NHCO(CH 2 ) 8 CH 3
70
NHCO(CH 2 ) 8 CH 3
182
NHCO(CH 2 ) 8 CH 3
190
NHCO(CH 2 ) 8 CH 3
193
NHCO(CH 2 ) 8 CH 3
221
NHCO(CH 2 ) 8 CH 3
254
NHCO(CH 2 ) 7 CH 3
255
NHCO(CH 2 ) 9 CH 3
256
NHCO(CH 2 ) 10 CH 3
257
NHCO(CH 2 ) 11 CH 3
258
NHCO(CH 2 ) 12 CH 3
259
NHCO(CH 2 ) 8 CH 3
260
NHCO(CH 2 ) 9 CH 3
261
NHCO(CH 2 ) 11 CH 3
262
NHCO(CH 2 ) 12 CH 3
263
270
NHCO(CH 2 ) 8 CH 3
292
293
NHCO(CH 2 ) 10 CH 3
294
NHCO(CH 2 ) 7 CH 3
312
NHCONH(CH 2 ) 7 CH 3
313
NHCONH(CH 2 ) 7 CH 3
314
NHCONH(CH 2 ) 10 CH 3
342
NHCO(CH 2 ) 9 CH 3
343
NHCO(CH 2 ) 10 CH 3
344
NHCO(CH 2 ) 12 CH 3
350
351
NHCO(CH 2 ) 11 CH 3
352
NHCONH(CH 2 ) 10 CH 3
12 . The compound according to claim 11 wherein the compound is
Cpd #
R
R 1
R 2
260
NHCO(CH 2 ) 9 CH 3
262
NHCO(CH 2 ) 12 CH 3
344
NHCO(CH 2 ) 12 CH 3
13 . A compound of formula (I) according to either of claim 1 or claim 2 , wherein R is NHCO—[(C 6 -C 14 )-alkyl]-CH 3 , and R 1 and R 2 are selected from:
R 1
R 2
NHSO 2 Ph
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 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 bacteria is an antibiotic-resistant bacteria.
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 1 or 2 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, fosfomycin, 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), metronidazole (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-834 ((4R,5S,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-4-a,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-pyrrolidinylmethyl]-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 ((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 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-dihydroxy-4-oxo-2-pyridinyl)methoxy]imino]acetyl]amino]-8-oxo-3-[(1,2,3-thiadiazol-5-ylthio)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt), Rifalazil (1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[4-(2-methylpropyl)-1-piperazinyl]-1-oxo-rifamycin VIII, 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′-sialyllacto-N-neotetraose), K130 (5-[[4-[3-[[4-[(4-aminophenyl)sulfonyl]phenyl]amino]propoxy]-3,5-dimethoxyphenyl]methyl]-2,4-pyrimidinediamine), 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-thiadiazol-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′-bipyrrolidin]-3-ylidene]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt), Sch-40832 (N-[[[48-[1-[[2,6-d]deoxy-3-O-(2,6-dideoxy-D-arabino-hexopyranosyl)-D-arabino-hexopyranosyl]oxy]ethyl]-15-ethylidene-1,3a,4,5,10,11,12,13,14,15,19,20,21,22,28,29,41,42-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-thiazolidinyl-.kappa.N3]-2-(hydroxy-.kappa.O)-1,1-dimethylethyl]-4,5-dihydro-4-methyl-4-thiazolecarboxylato(2-)-.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), carumonam ([[(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), or T 3811 (des-F(6)-quinolone).
24 . The method according to claim 22 , wherein said second antimicrobial agent is imipenen, amikacin, netilmicin, fosfomycin, gentamicin, ceftriaxone, teicoplanin, Ziracin, LY333328, CL331022, HMR3647, Linezolid, Synercid, Aztreonam or Metronidazole.
25 . The method according to claim 17 , wherein said subject is 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; and wherein R 16 is
28 . The compound of claim 2 having the formula (III):
wherein R 15 is hydrido or a carbamate amino protecting group; wherein R 16 is
and wherein R 57 is a halo or halo substituted alkyl group.
29 . The compound according to either of claim 27 or 28 wherein said compound is
Compound #
R 16
2
10
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