U.S. patent application number 14/199212 was filed with the patent office on 2014-09-11 for steroid antibiotic conjugates.
This patent application is currently assigned to Allergan, Inc.. The applicant listed for this patent is Allergan, Inc.. Invention is credited to MAYSSA ATTAR, Ken Chow, MICHAEL E. GARST, Santosh C. Sinha, BRANDON D. SWIFT, LIMING WANG.
Application Number | 20140256694 14/199212 |
Document ID | / |
Family ID | 50382692 |
Filed Date | 2014-09-11 |
United States Patent
Application |
20140256694 |
Kind Code |
A1 |
Sinha; Santosh C. ; et
al. |
September 11, 2014 |
STEROID ANTIBIOTIC CONJUGATES
Abstract
The present invention describes steroid antibiotic conjugates.
These single drug entities are formed connecting a steroid moiety
and two same antibiotics moieties, or a steroid moiety and two
different antibiotics moieties. Upon topical application to the
eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic
cleavage to release the individual drugs.
Inventors: |
Sinha; Santosh C.; (Ladera
Ranch, CA) ; Chow; Ken; (Newport Coast, CA) ;
WANG; LIMING; (Irvine, CA) ; GARST; MICHAEL E.;
(Newport Beach, CA) ; ATTAR; MAYSSA; (Placentia,
CA) ; SWIFT; BRANDON D.; (Irvine, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
50382692 |
Appl. No.: |
14/199212 |
Filed: |
March 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61775216 |
Mar 8, 2013 |
|
|
|
Current U.S.
Class: |
514/175 ;
514/176; 540/110 |
Current CPC
Class: |
A61P 31/04 20180101;
A61K 47/55 20170801; A61P 27/14 20180101; A61P 29/00 20180101; A61K
9/0048 20130101; A61P 27/00 20180101; C07K 7/645 20130101; A61K
47/554 20170801; A61P 27/02 20180101; A61P 31/02 20180101; A61K
47/64 20170801; A61P 43/00 20180101 |
Class at
Publication: |
514/175 ;
540/110; 514/176 |
International
Class: |
A61K 47/48 20060101
A61K047/48; A61K 9/00 20060101 A61K009/00 |
Claims
1. A hybrid compound comprising a steroid and two antibiotic
moieties, or a pharmaceutical salt thereof, which are connected via
separate covalent bonds to at least one linker each such that said
covalent bond degrade in vivo to yield the respective two
antibiotics independently and the respective steroid drug.
2. The hybrid compound according to claim 1, wherein the two
antibiotics moieties are identical.
3. The hybrid compound according to claim 1, wherein the two
antibiotics moieties are different.
4. The hybrid compound according to claim 1, wherein a first
antibiotic moiety is directly linked to the steroid moiety and
further linked to the other antibiotic moiety via a linker.
5. The hybrid compound according to claim 1, wherein a first
antibiotic moiety is linked to the steroid moiety via a linker and
further linked to the other antibiotic moiety via another
linker.
6. The hybrid compound according to claim 1 wherein the two
antibiotic drug moieties are selected from the group consisting of:
gatifloxacin, moxifloxacin, chloramphenicol, tobramycin and
amikacin.
7. The hybrid compound according to claim 1 wherein the steroid
drug moiety is selected from the group consisting of: dexmethasone,
betamethasone, triamcinolone acetonide, prednisolone and
hydrocortisone.
8. The hybrid compound according to claim 1 wherein said linker
comprises an ester, a carboxylate, a carbonyl, a carbonate, an
amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol,
a polyethylene glycol moiety or an ethylene moiety.
9. A pharmaceutical composition comprising a therapeutically
effective amount of a hybrid compound, comprising two antibiotic
moieties and one steroid drug moiety, which are connected via
separate covalent bonds wherein said covalent bonds degrade in vivo
to yield the antibiotics and steroid drugs, and wherein said
pharmaceutical composition is formulated for topical ophthalmic
administration.
10. A method comprising administrating to an eye of a mammal a
pharmaceutical composition comprising a therapeutically effective
amount of a hybrid compound comprising two antibiotic moieties and
one steroid moiety, which are connected via separate covalent bonds
wherein said covalent bonds degrade in vivo to yield the
antibiotics and the steroid drugs, and wherein said method is
effective in the treatment of an inflammatory condition or
bacterial infection affecting said eye.
11. The method according to claim 10 wherein said hybrid compound
has topical antibiotic and anti-inflammatory activity upon a
surface of an eye, and wherein the hybrid compound degrades on said
surface into said active antibiotics and said steroid drug, which
are capable of penetrating beyond tissue of said surface eye.
12. The hybrid compound according to claim 1 comprising at least
one linker having at least two bonds, wherein said bonds are
asymmetrically degraded in vivo to release the antibiotic and
steroid drugs.
13. The hybrid compound according to claim 1, selected from:
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7--
(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]c-
arbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fl-
uoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-(4-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7--
(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]c-
arbonyl}oxy)methoxy]carbonyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-
-oxo-1,4-dihydroquinoline-3-carboxylate;
[({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10-
,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-c-
yclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4--
oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}carbonyl)oxy]methyl
rel-7-[(3S)-3-aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,-
4-dihydroquinoline-3-carboxylate;
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7--
{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo--
1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin--
1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7--
{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyri-
din-6-yl]-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl}oxy}methoxy)carbonyl]-3--
methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carb-
oxylate;
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R-
,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,-
7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-y-
l]-2-oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methy-
lpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1--
yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid;
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S-
,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10-
,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxo-
ethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperaz-
in-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fl-
uoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({2-[(10R,11S,13S,17R)-11-
,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecah-
ydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-m-
ethoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-ox-
o-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-
-1,4-dihydroquinoline-3-carboxylic acid;
rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R-
)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dod-
ecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy-
]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-di-
hydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]--
6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
rel-1-cyclopropyl-7-[1-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R-
)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dod-
ecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy-
]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-di-
hydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4--
b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid;
rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(4-{2-[(10R,11S,1-
3S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,-
17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutano-
yl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro--
8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-2--
methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carb-
oxylic acid;
({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpi-
perazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl-
}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-y-
l]carbonyl}oxy)methyl
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,1-
2,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
rel-butanedioate;
({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl
piperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbo-
nyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4--
dihydroquinolin-3-yl]carbonyl}oxy)methyl
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,1-
2,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
rel-butanedioate;
({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro--
6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy-
)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-meth-
oxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,1-
2,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
rel-butanedioate;
2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-
-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthr-
en-17-yl]-2-oxoethyl
2-[(9S,10R,11R,13R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-
-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthr-
en-17-yl]-2-oxoethyl
rel-7,7'-{(2-oxo-1,3-dioxole-4,5-diyl)bis[methanediyl(3-methylpiperazine--
4,1-diyl)]}bis(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-
-3-carboxylate);
2-[(8R,9S,10R,11R,13R,14R,16R,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trim-
ethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]ph-
enanthren-17-yl]-2-oxoethyl
rel-1-cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propanoyl]ox-
y}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dihydroqui-
noline-3-carboxylate;
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl
rel-1-cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propa-
noyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy-4-oxo-1,4-dih-
ydroquinoline-3-carboxylate;
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-o-
xo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl
2-[(8R,9S,10R,11R,13R,14R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trim-
ethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]ph-
enanthren-17-yl]-2-oxoethyl rel-benzene-1,4-dicarboxylate;
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-o-
xo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate;
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-o-
xo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,-
8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17--
yl]-2-oxoethyl rel-butanedioate;
1,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-
-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)car-
bonyl]oxy}propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate;
1,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)--
4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}oxy)propan-2--
yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,-
9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
-oxoethyl rel-butanedioate;
1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2--
oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl]-4-oxo-1,4-dihydroquinolin-3-yl)-
carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate;
1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-d-
ioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihyd-
roquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate; and
2-({2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,-
8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-
-2-oxoethoxy}carbonyl)propane-1,3-diyl
relbis(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,-
3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxyl-
ate).
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/775,216 filed Mar. 8, 2013, the
disclosure of which is hereby incorporated in its entirety by
reference.
FIELD OF THE INVENTION
[0002] The present invention describes steroid antibiotic
conjugates. These single drug entities are formed connecting a
steroid moiety and two same antibiotics moieties, or a steroid
moiety and two different antibiotics moieties. Upon topical
application to the eye, the conjugate hybrid would undergo
enzymatic and/or hydrolytic cleavage to release the individual
drugs.
SUMMARY OF THE INVENTION
[0003] The antibiotic moieties and the steroid moiety, of the
compounds disclosed herein are connected via two covalent bonds to
a linker such that said compound degrades in vivo to yield the
respective antibiotic and the respective steroids. Each bond is an
amide bond or an ester bond depending on the nature of the
compound. In other words, the single drug entity has one amide bond
connecting to the antibiotic and/or one ester bond connecting to
the other antibiotic and/or one ester bond connecting to the
steroid.
[0004] Degradation of the ester or amide bonds generally, but not
necessarily, yields the corresponding acid and alcohol or amine by
hydrolysis or a related reaction. A compound which degrades in vivo
to yield the antibiotic and steroid, produces the active drugs
belonging to distinct classes at some point in the metabolic
process of the claimed compound. In many cases, cleavage of the
first amide or ester bond will release one active, and cleavage of
the second amide or ester bond will release the second active and
then the third active will be released if it is the case.
DETAILED DESCRIPTION OF THE INVENTION
[0005] In one aspect, the present invention relates to a hybrid
compound comprising a steroid moiety and two same antibiotics
moieties, or a pharmaceutical salt thereof, which are connected via
two covalent bonds to a linker such that said compound degrades in
vivo to yield the respective two antibiotics independently and the
respective steroid drug, wherein each bond is an amide bond or an
ester bond.
[0006] In another aspect, the present invention relates to a
compound comprising a steroid moiety and two different antibiotics
moieties, or a pharmaceutical salt thereof, which are connected via
two covalent bonds to a linker such that said compound degrades in
vivo to yield the respective two antibiotics independently and the
respective steroid drug, wherein each bond is an amide bond or an
ester bond.
[0007] In another aspect, the present invention relates to a hybrid
compound comprising a steroid moiety and two antibiotics moieties,
which are connected via separate covalent bonds to at least one
linker each such that said covalent bond degrade in vivo to yield
the respective two antibiotics independently and the respective
steroid drug.
[0008] In another aspect, the present invention relates to a hybrid
compound wherein the two antibiotics moieties are identical.
[0009] In another aspect, the present invention relates to a hybrid
compound wherein the two antibiotics moieties are different.
[0010] In another aspect, the present invention relates to a hybrid
compound wherein a first antibiotic moiety is directly linked to
the steroid moiety and further linked to the other antibiotic
moiety via a linker.
[0011] In another aspect, the present invention relates to a hybrid
compound a first antibiotic moiety is linked to the steroid moiety
via a linker and further linked to the other antibiotic moiety via
another linker.
[0012] In another aspect, the present invention relates to a hybrid
compound wherein a first antibiotic moiety is linked to the steroid
moiety via a linker and further linked to the other antibiotic
moiety via another linker.
[0013] In another aspect, the present invention relates to a hybrid
compound wherein the two antibiotic drug moieties are selected from
the group consisting of: gatifloxacin, moxifloxacin,
chloramphenicol, tobramycin and amikacin.
[0014] In another aspect, the present invention relates to a hybrid
compound wherein the steroid drug moiety is selected from the group
consisting of: dexmethasone, betamethasone, triamcinolone
acetonide, prednisolone and hydrocortisone.
[0015] In another aspect, the present invention relates to a hybrid
compound wherein said linker comprises an ester, a carboxylate, a
carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino,
an oxo, an ethylene glycol, a polyethylene glycol moiety or an
ethylene moiety.
[0016] In another aspect, the present invention relates to a
pharmaceutical composition comprising a therapeutically effective
amount of a hybrid compound, comprising two antibiotic moieties and
one steroid drug moiety, which are connected via separate covalent
bonds such that said covalent bonds degrade in vivo to yield the
antibiotics and steroid drugs, and wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0017] In another aspect, the present invention relates to a method
comprising administrating to an eye of a mammal a pharmaceutical
composition comprising a therapeutically effective amount of a
hybrid compound comprising two antibiotic moieties and one steroid
moiety, which are connected via separate covalent bonds such that
said covalent bonds degrade in vivo to yield the antibiotics and
the steroid drugs, and wherein said method is effective in the
treatment of an inflammatory condition or bacterial infection
affecting said eye.
[0018] In another aspect, the present invention relates to a method
wherein said hybrid compound has topical antibiotic and
anti-inflammatory activity upon a surface of an eye, and wherein
the hybrid compound degrades on said surface into said active
antibiotics and said steroid drug, which are capable of penetrating
beyond tissue of said surface
[0019] In another aspect, the present invention relates to a hybrid
compound comprising at least one linker having at least two bonds,
wherein said bonds are asymmetrically degraded in vivo to release
the antibiotic and steroid drugs.
[0020] The hybrid compounds of the invention have both
antibacterial and anti-inflammatory activities and are very useful
compounds capable of producing the effect of an antibacterial drug
and anti-inflammatory drug in monotherapy.
[0021] In another aspect, the present invention relates to a
compound which is an active drug, which degrades in vivo into
active antibacterial(s) and anti-inflammatory drug(s).
[0022] The hybrid drugs of the invention provide a unique delivery
of an antibiotic and a steroid for the treatment of ophthalmic
bacterial infections and inflammation. A single drug entity is
advantageous for individual dosing of each drug because of the
ability for simultaneous dosing and elimination of washout concerns
when applying each drug separately.
[0023] The use of an antibiotic/anti-inflammatory hybrid drug is
indicated where the risk of infection is high or where there is an
expectation that potentially dangerous numbers of bacteria will be
present in the eye. The anti-inflammatory component of the
composition is useful in treating inflammation associated with
physical trauma to ophthalmic tissues, inflammation associated with
bacterial infections and inflammation resulting from surgical
procedures. The combination of an antibiotic and anti-inflammatory
is also useful in post-operative inflammation where there is an
increased chance of bacterial infection. The composition of the
invention may also be used prophylactically in connection with
various ophthalmic surgical procedures that create a risk of
bacterial infection. Other examples of ophthalmic conditions which
may be treated with the compositions of the present invention
include infective conditions associated with inflammation and where
the use of anti-inflammatory is acceptable. Such conditions may
include, but are not limited to conjunctivitis, keratitis,
blepharitis, endophthalmitis, dacyrocystitis, hordeolum, corneal
ulcers, red eye, hyperemia, anterior blepharitis, posterior
blepharitis, meibomian gland dysfunction, dry eye disease
(keratocojunctivitis sicca) ocular pain, ocular pain and
inflammation post-ocular surgery, bacterial conjunctivitis,
anterior uveitis, post-surgical inflammation, inflammatory
conditions of the palpebral and bulbar conjunctiva, cornea, and
anterior segment of the globe, such as allergic conjunctivitis,
ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction,
superficial punctate keratitis, herpes zoster keratitis, iritis,
cyclitis, selected infective conjunctivitis, corneal injury from
chemical radiation, or thermal burns, penetration of foreign
bodies, allergy, and combinations thereof.
[0024] The hybrid drugs disclosed herein comprise antibiotics
moieties belonging to distinct classes: fluoroquinolones,
cephalosporins, chloramphenicol, aminoglycosides, penicillins,
erythromycin, macrolide antibiotics and oxazolidionones.
[0025] Fluoroquinolones include, but are not limited to:
levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin,
trovafloxacin, ofloxacin, ciprofloxacin, sparfloxacin,
grepafloxacin, norfoxacin, enoxacin, lomefloxacin, fleroxacin,
tosufloxacin, prulifloxacin, pazufloxacin, clinafloxacin,
garenoxacin, and sitafloxacin.
[0026] Cephalosporins include, but are not limited to: loracarbef,
cephalexin, cefuroxime, ceftriaxone, ceftaxime, ceftizoxime,
ceftibuten, ceftazidime, cefprozil, cefpodoxime, cefoxitin,
cefotetan, cefotaxime, cefoperazone, cefixime, cefepime,
cefditoren, cefdinir, cefoperaxone, moxalactam, cefazolin,
cefamandole, cefadroxil, cefaclor, cephalothin, cephradine,
cephacetrile, and cephalothin.
[0027] Aminoglycosides include, but are not limited to: tobramycin,
streptomycin, gentamicin, kanamycin, amikacin and netilmicin.
[0028] Penicillins include, but are not limited to: penicillin G,
ticarcillin, methicillin, phenthicillin, cloxacillin,
dicloxacillin, nafcillin, oxacillin.
[0029] Macrolide antibiotics include, but are not limited to:
erythromycin and azithromycin.
[0030] Oxazolidinones include, but are not limited to:
linezolid.
[0031] Further, the compounds disclosed herein comprise a steroidal
drug selected from: dexmethasone, betamethasone, triamcinolone
acetonide, prednisolone and hydrocortisone.
[0032] In another embodiment the compounds disclosed herein
comprise at least one antibiotic drug selected from levofloxacin,
moxifloxacin, gatifloxacin, gemifloxacin, trovafloxacin, ofloxacin,
ciprofloxacin, sparfloxacin, grepafloxacin, norfoxacin, enoxacin,
lomefloxacin, fleroxacin, tosufloxacin, prulifloxacin,
pazufloxacin, clinafloxacin, garenoxacin, sitafloxacin, loracarbef,
cephalexin, cefuroxime, ceftriaxone, ceftaxime, ceftizoxime,
ceftibuten, ceftazidime, cefprozil, cefpodoxime, cefoxitin,
cefotetan, cefotaxime, cefoperazone, cefixime, cefepime,
cefditoren, cefdinir, cefoperaxone, moxalactam, cefazolin,
cefamandole, cefadroxil, cefaclor, cephalothin, cephradine,
cephacetrile, cephalothin, chloramphenicol, tobramycin,
streptomycin, gentamicin, kanamycin, amikacin, netilmicin,
penicillin g, ticarcillin, methicillin, phenthicillin, cloxacillin,
dicloxacillin, nafcillin and oxacillin.
[0033] In another embodiment the compounds disclosed herein
comprise at least one steroidal drug selected from: dexmethasone,
betamethasone, triamcinolone acetonide, prednisolone and
hydrocortisone.
[0034] Depending on the linking site, the hybrid compounds of the
invention can be represented by Schemes 1, wherein the antibiotic
moieties can be the same or different:
##STR00001##
##STR00002##
##STR00003##
##STR00004##
##STR00005##
##STR00006##
##STR00007##
##STR00008##
##STR00009##
[0035] In another aspect the invention provides compounds which may
comprise a linker moiety selected from, but not limited to, an
ester, a carboxylate, a carbonyl, a carbonate, an amido, a
carbamate, a ketone, an amino, an oxo, an ethylene glycol, a
polyethylene glycol, an ethylene.
[0036] In another aspect, the invention provides compounds which
may comprise a linker moiety comprising any combination of an
ester, a carboxylate, a carbonyl, a carbonate, an amido, a
carbamate, a ketone, an ethylene, an amino, an oxo, an ethylene
glycol and/or a polyethylene glycol. Such linker moieties are
exemplified below and linker structures are exemplified in Table
1.
[0037] Examples of ester moieties comprised in the linkers are:
##STR00010##
[0038] Examples of carboxylate moieties comprised in the linkers
are:
##STR00011##
[0039] Example of a carbonyl moiety comprised in the linkers is
##STR00012##
[0040] Example of a carbonate moiety comprised in the linkers
is:
##STR00013##
[0041] Examples of amido moieties comprised in the linkers are:
##STR00014##
[0042] Example of carbamate moiety comprised in the linkers is:
##STR00015##
[0043] Example of a ketone moiety comprised in the linkers is:
##STR00016##
[0044] Examples of amino moieties comprised in the linkers are:
##STR00017##
[0045] Example of an oxo moiety comprised in the linker is:
##STR00018##
[0046] Example of ethylene glycol moieties comprised in the linkers
are:
##STR00019##
[0047] Example of polyethylene glycol moiety comprised in the
linkers is:
##STR00020##
[0048] Further the compounds disclosed herein comprise a linker
selected from Table 1:
TABLE-US-00001 TABLE 1 Linker Number Linker Structure n = 0 n = 1 n
= 2 n = 3 ##STR00021## L2 L1 ##STR00022## L3 ##STR00023## L4
##STR00024## L35 L5 ##STR00025## L6 ##STR00026## L7 ##STR00027##
L14 ##STR00028## L15 ##STR00029## L16 ##STR00030## L46 ##STR00031##
L8 ##STR00032## L9 ##STR00033## L10 ##STR00034## L18 ##STR00035##
L11 ##STR00036## L19 ##STR00037## L12 ##STR00038## L13 ##STR00039##
L20 ##STR00040## L21 ##STR00041## L22 ##STR00042## L23 ##STR00043##
L24 ##STR00044## L25 ##STR00045## L26 ##STR00046## L27 ##STR00047##
L28 ##STR00048## L29 ##STR00049## L30 ##STR00050## L31 ##STR00051##
L32 ##STR00052## L33 ##STR00053## L34 ##STR00054## L35 ##STR00055##
L36 ##STR00056## L37 ##STR00057## L38 ##STR00058## L39 ##STR00059##
L40 ##STR00060## L41 ##STR00061## L42 ##STR00062## L43 ##STR00063##
L44 ##STR00064## L45 ##STR00065## L47 ##STR00066## L48 ##STR00067##
L49 ##STR00068## L50 ##STR00069## L51 ##STR00070## L52 ##STR00071##
L53 ##STR00072## L54 ##STR00073## L58 ##STR00074## L56 ##STR00075##
L57 ##STR00076## L59 ##STR00077## L60 ##STR00078## L61 ##STR00079##
L62 ##STR00080## L63 ##STR00081## L64 ##STR00082## L65 ##STR00083##
L66 ##STR00084## L67 ##STR00085## L68 L103 L104 ##STR00086## L69
##STR00087## L70 ##STR00088## L71 ##STR00089## L72 ##STR00090## L73
##STR00091## L74 ##STR00092## L75 ##STR00093## L76 ##STR00094## L77
##STR00095## L78 ##STR00096## L79 ##STR00097## L80 ##STR00098## L81
##STR00099## L82 ##STR00100## L83 ##STR00101## L84 ##STR00102## L85
L86 ##STR00103## L87 ##STR00104## L88 ##STR00105## L89 ##STR00106##
L90 ##STR00107## L91 ##STR00108## L92 ##STR00109## L93 ##STR00110##
L94 ##STR00111## L95 ##STR00112## L96 ##STR00113## L97 ##STR00114##
L98 ##STR00115## L99 ##STR00116## L100 L101 L102
[0049] Further the compounds disclosed herein comprise at least one
pro-drug moiety selected from Table 2:
TABLE-US-00002 TABLE 2 Prodrug Structure Prodrug Number
##STR00117## P1 ##STR00118## P2 ##STR00119## P3 ##STR00120## P4
##STR00121## P5 ##STR00122## P6 ##STR00123## P7 ##STR00124## P8
##STR00125## P9 ##STR00126## P10 ##STR00127## P11 ##STR00128## P12
##STR00129## P13 ##STR00130## P14 ##STR00131## P15
[0050] Compounds of the invention are shown in Table 3.
TABLE-US-00003 TABLE 3 Compound number IUPAC NAME 10
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-
cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-
(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-
dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}
octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-
4-oxo-1,4-dihydroquinoline-3-carboxylate 11
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-
cyclopropyl-7-(4-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-
(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-
dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-3-
methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylate 12
[({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)-
11,17-dihydroxy-10,13-dimethyl-3-oxo-
2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-
fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-
methylpiperazin-1-yl}carbonyl)oxy]methyl rel-7-[(3S)-3-
aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-
1,4-dihydroquinoline-3-carboxylate 13
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-
cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-
methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]
piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]
oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-
8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 14
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-
cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-
7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-
6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-
yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-
fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 15
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-
[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,
16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-
yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]
methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid 16
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-
[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,
16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
oxoethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-
7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]
methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid 17
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({2-
[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-
fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-
methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxo1-4-yl]
methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid 18
rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(4-{2-
[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-
oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-
6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-
yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-
6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid 19
rel-1-cyclopropyl-7[1-({[({1-cyclopropyl-7[4-({[(4-{2-
[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-
oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-
6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-
yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-
b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid 20
rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(4-{2-
[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-
oxobutanoyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-
b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-
3-yl}carbonyl)oxy]methoxy}carbonyl)-2-methylpiperazin-
1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline- 3-carboxylic
acid 21
({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-
(2-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]
carbonyl}oxy)methoxy]carbonyl}-6-fluoro-8-methoxy-4-oxo-
1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl}carbonyl}
oxy)methyl 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 22
({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-
7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-
yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-
b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-
3-yl]carbony}oxy)methyl 2-[(10R,11S,13S,17R)-11,17-
dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,
16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]- 2-oxoethyl
rel-butanedioate 23
({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-
(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-
dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}
octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-
4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl 2-
[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-
3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 24
2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-
10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-
[(9S,10R,11R,13R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,
16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
re1-7,7'-{(2-oxo-1,3-dioxole-4,5-diyl)bis[methanediyl(3-
methylpiperazine-4,1-diyl)]}bis(1-cyclopropyl-6-fluoro-8-
methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate) 25
2-[(8R,9S,10R,11R,13R,14R,16R,17S)-9-fluoro-11,17-
dihydroxy-10,13,16-trimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-cyclopropyl-
6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propanoyl]
oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy-
4-oxo-1,4-dihydroquinoline-3-carboxylate 26
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-1-
cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-
yl)propanoyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-
8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 27
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]
carbonyl}oxy)propan-2-yl 2-[(8R,9S,10R,11R,13R,14R,16S,
17S)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta
[a]phenanthren-17-yl]-2-oxoethyl rel-benzene-1,4-dicarboxylate 28
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]
carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-
11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,
15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]- 2-oxoethyl
rel-butanedioate 29
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]
carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-11,
17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,
15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-
2-oxoethyl rel-butanedioate 30
1,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-
methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-
1,4-dihydroquinolin-3-yl)carbonyl]oxy}propan-2-yl 2-
[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-
3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 31
1,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-
methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]
carbonyl}oxy)methoxy]carbonyl}oxy)propan-2-yl 2-
[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 32
1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-
[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-
1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}
propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-
10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-
dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2- oxoethyl
rel-butanedioate 33
1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-
2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]
pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]
oxy}methoxy)carbonyl]oxy}propan-2-yl 2-
[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 34
2-({2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-
dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-
3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)
propane-1,3-diyl relbis(1-cyclopropyl-6-fluoro-8-methoxy-
7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]
piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate)
[0051] In another embodiment the compounds disclosed herein
comprise one steroid moiety and two antibiotic moieties.
[0052] In another embodiment the compounds disclosed herein
comprise one steroid moiety and two antibiotic moieties and at
least one linker selected from Table 1.
[0053] In another embodiment the compounds disclosed herein
comprise one steroid moiety and two antibiotic moieties and at
least one linker selected from Table 1 and one pro-drug moiety
selected from Table 2.
[0054] In another embodiment the compounds disclosed herein
comprise one steroid moiety and two antibiotic moieties and two
linkers selected from Table 1 and two pro-drug moieties selected
from Table 2.
[0055] In another embodiment the compounds disclosed herein
comprise steroid moiety and two antibiotic moieties and least two
linkers selected from Table 1 and one pro-drug moiety selected from
Table 2.
[0056] In another embodiment the compounds disclosed herein
comprise steroid moiety and two antibiotic moieties and one linker
selected from Table 1 and two pro-drug moieties selected from Table
2.
[0057] In another embodiment the compounds disclosed herein
comprise one prednisolone moiety and two moxifloxacin moieties,
such as: [0058]
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7--
(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]c-
arbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fl-
uoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate; [0059]
({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro--
6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy-
)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-meth-
oxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,1-
2,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
rel-butanedioate.
[0060] In another embodiment the compounds disclosed herein
comprise one prednisolone moiety and one moxifloxacin moiety and
one gatifloxacin moiety such as: [0061]
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-(4-{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-
-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]-
carbonyl}oxy)methoxy]carbonyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy--
4-oxo-1,4-dihydroquinoline-3-carboxylate; [0062]
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7--
{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyri-
din-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3--
methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carb-
oxylate; [0063]
rel-1-cyclopropyl-7-[1-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R-
)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dod-
ecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy-
]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-di-
hydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4--
b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid; [0064]
rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(4-{2-[(10R,11S,13S,17R-
)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dod-
ecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy-
]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-meth-
oxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-2-methyl-
piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid; [0065]
({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpi-
perazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl-
}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dih-
ydroquinolin-3-yl]carbonyl}oxy)methyl
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,1-
2,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
rel-butanedioate.
[0066] In another embodiment the compounds disclosed herein
comprise one prednisolone moiety and two gatifloxacin moieties such
as: [0067]
({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpi-
perazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl-
}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-y-
l]carbonyl}oxy)methyl
2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,1-
2,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl
rel-butanedioate; [0068]
rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(4-{2-[(10R,11S,13S,17R-
)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dod-
ecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-4-oxobutanoyl)oxy-
]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-di-
hydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]--
6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;
[0069]
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({2-[(10R,11S,13S,17R)-11-
,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecah-
ydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-m-
ethoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-ox-
o-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-
-1,4-dihydroquinoline-3-carboxylic acid; [0070]
2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8-
,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]--
2-oxoethyl
rel-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7--
{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo--
1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin--
1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;
[0071]
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-o-
xo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate; [0072]
1,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-
-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)car-
bonyl]oxy}propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate.
[0073] In another embodiment the compounds disclosed herein
comprise one hydrocortisone moiety and one besifloxacin moiety and
one gatifloxacin moiety such as: [0074]
[({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10-
,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-c-
yclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4--
oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}carbonyl)oxy]methyl
rel-7-[(3S)-3-aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,-
4-dihydroquinoline-3-carboxylate.
[0075] In another embodiment the compounds disclosed herein
comprise one dexamethasone and two gatifloxacin moieties such as:
[0076]
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S-
,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10-
,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxo-
ethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperaz-
in-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fl-
uoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; [0077]
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-o-
xo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl
2-[(8R,9S,10R,11R,13R,14R,16S,17S)-9-fluoro-11,17-dihydroxy-10,13,16-trim-
ethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]ph-
enanthren-17-yl]-2-oxoethyl rel-benzene-1,4-dicarboxylate.
[0078] In another embodiment the compounds disclosed herein
comprise one bethasone and two gatifloxacin moieties such as:
[0079]
rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({2-[(9R,10S,11S-
,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10-
,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxo-
ethoxy}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperaz-
in-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fl-
uoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
[0080] In another embodiment the compounds disclosed herein
comprise one hydrocortisone and two gatifloxacin moieties such as:
[0081]
1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-o-
xo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,-
8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17--
yl]-2-oxoethyl rel-butanedioate; [0082]
1,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)--
4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}oxy)propan-2--
yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,-
9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-
-oxoethyl rel-butanedioate; [0083]
1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2--
oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)-
carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate.
[0084] In another embodiment the compounds disclosed herein
comprise one hydrocortisone and two moxifloxacin moieties such as:
[0085]
1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-d-
ioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihyd-
roquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl
2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,-
10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-o-
xoethyl rel-butanedioate; [0086]
2-({2-[(8R,10S,11R,13R,14R,17S)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,-
8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-
-2-oxoethoxy}carbonyl)propane-1,3-diyl
relbis(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,-
3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxyl-
ate).
[0087] In another embodiment the invention provides a hybrid
compound comprising two antibiotic moieties and a steroid drug
moiety, or a pharmaceutical salt thereof, which are connected via
three separate covalent bonds to a linker such that said covalent
bonds degrade in vivo to yield independently the antibiotics and
steroid drugs.
[0088] In another embodiment the invention provides a hybrid
compound comprising two different antibiotic moieties and a steroid
drug moiety, or a pharmaceutical salt thereof, which are connected
via three separate covalent bonds to a linker such that said
covalent bonds degrade in vivo to yield independently the
antibiotics and steroid drugs.
[0089] In another embodiment the invention provides a hybrid
compound comprising two identical antibiotic moieties and a steroid
drug moiety, or a pharmaceutical salt thereof, which are connected
via three separate covalent bonds to a linker such that said
covalent bonds degrade in vivo to yield independently the
antibiotics and steroid drugs.
[0090] In another embodiment the invention provides a hybrid
compound comprising two different antibiotic moieties and a steroid
drug moiety, or a pharmaceutical salt thereof, wherein the steroid
is directly linked to one antibiotic which is connected via a
linker to the other antibiotic and wherein the bonds degrade in
vivo to yield independently the antibiotics and steroid drugs.
[0091] In another embodiment the invention provides a hybrid
compound comprising two identical antibiotic moieties and a steroid
drug moiety, or a pharmaceutical salt thereof, which are connected
via four separate covalent bonds to two different linkers such that
said covalent bonds degrade in vivo to yield independently the
antibiotics and steroid drugs.
[0092] In another embodiment the invention provides a hybrid
compound comprising two identical antibiotic moieties and a steroid
drug moiety, or a pharmaceutical salt thereof, which are connected
via four separate covalent bonds to two identical linkers such that
said covalent bonds degrade in vivo to yield independently the
antibiotics and steroid drugs.
[0093] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two antibiotic moieties and a steroid moiety, which are connected
via three separate covalent bonds to a linker such that said
covalent bonds degrade in vivo to yield the antibiotics and the
steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0094] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two antibiotic moieties and a steroid moiety, which are connected
via four separate covalent bonds to two linkers such that said
covalent bonds degrade in vivo to yield the antibiotics and the
steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0095] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two identical antibiotic moieties and a steroid moiety, which are
connected via three separate covalent bonds to a linker such that
said covalent bonds degrade in vivo to yield the antibiotics and
the steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0096] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two different antibiotic moieties and a steroid moiety, which are
connected via three separate covalent bonds to a linker such that
said covalent bonds degrade in vivo to yield the antibiotics and
the steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0097] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two antibiotic moieties and a steroid moiety, which are connected
via four separate covalent bonds to two linkers such that said
covalent bonds degrade in vivo to yield the antibiotics and the
steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0098] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two identical antibiotic moieties and a steroid moiety, which are
connected via four separate covalent bonds to two linkers such that
said covalent bonds degrade in vivo to yield the antibiotics and
the steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0099] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two different antibiotic moieties and a steroid moiety, which are
connected via four separate covalent bonds to two linkers such that
said covalent bonds degrade in vivo to yield the antibiotics and
the steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0100] In another embodiment the invention provides a
pharmaceutical composition comprising a hybrid compound comprising
two different antibiotic moieties and a steroid moiety, which are
connected via three separate covalent bonds to one linker such that
said covalent bonds degrade in vivo to yield the antibiotics and
the steroid drugs, wherein each bond is an ester bond or an amide
depending on the nature of the linker, wherein said pharmaceutical
composition is formulated for topical ophthalmic
administration.
[0101] In another embodiment the invention provides a hybrid
compound comprising two linkers having four bonds, wherein said
bonds are asymmetrically degraded in vivo to release the three
active drugs.
[0102] Some compounds of the invention have at least one
stereogenic center in their structure. This stereogenic center may
be present in an R or S configuration, said R and S notation is
used in correspondence with the rules described in Pure Appli.
Chem. (1976), 45, 11-13.
[0103] The term "pharmaceutically acceptable salts" refers to salts
or complexes that retain the desired biological activity of the
above identified compounds and exhibit minimal or no undesired
toxicological effects. The "pharmaceutically acceptable salts"
according to the invention include therapeutically active,
non-toxic base or acid salt forms, which the compounds of the
invention are able to form.
[0104] The acid addition salt form of a compound of the invention
that occurs in its free form as a base can be obtained by treating
the free base with an appropriate acid such as an inorganic acid,
for example, hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, nitric acid and the like; or an organic acid such
as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic,
malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid,
succinic acid, malic acid, ascorbic acid, benzoic acid, tannic
acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,
benzenesulfonic, formic acid and the like (Handbook of
Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth
(Eds), Verlag Helvetica Chimica Acta-Zurich, 2002, 329-345).
[0105] The base addition salt form of a compound of the invention
that occurs in its acid form can be obtained by treating the acid
with an appropriate base such as an inorganic base, for example,
sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium
hydroxide, ammonia and the like; or an organic base such as for
example, L-Arginine, ethanolamine, betaine, benzathine, morpholine
and the like. (Handbook of Pharmaceutical Salts, P. Heinrich Stahl
& Camille G. Wermuth (Eds), Verlag Helvetica Chimica
Acta-Zurich, 2002, 329-345).
[0106] Compounds of the invention and their salts can be in the
form of a solvate, which is included within the scope of the
present invention. Such solvates include for example hydrates,
alcoholates and the like.
[0107] In still another embodiment of the invention, there are
provided methods for treating or preventing eye conditions such as:
conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum,
corneal ulcers, anterior blepharitis, posterior blepharitis,
meibomian gland dysfunction, dry eye disease (keratocojunctivitis
sicca) ocular pain, ocular pain and inflammation post-ocular
surgery, bacterial conjunctivitis, anterior uveitis, in a patient
suffering thereof. Such methods can be performed, for example, by
administering to a subject in need thereof a therapeutically
effective amount of at least one compound of the invention, or any
combination thereof, or pharmaceutically acceptable salts,
hydrates, solvates, crystal forms thereof.
[0108] The present invention concerns the use of a compound of the
invention or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of conjunctivitis,
keratitis, blepharitis, endophthalmitis, red eye, hyperemia,
dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis,
posterior blepharitis, meibomian gland dysfunction, dry eye disease
(keratocojunctivitis sicca) ocular pain, ocular pain and
inflammation post-ocular surgery, bacterial conjunctivitis,
anterior uveitis.
[0109] The actual amount of the compound to be administered in any
given case will be determined by a physician taking into account
the relevant circumstances, such as the severity of the condition,
the age and weight of the patient, the patient's general physical
condition, the cause of the condition, and the route of
administration.
[0110] The patient will be administered the compound orally in any
acceptable form, such as a tablet, liquid, capsule, powder and the
like, or other routes may be desirable or necessary, particularly
if the patient suffers from nausea. Such other routes may include,
without exception, transdermal, parenteral, subcutaneous,
intranasal, via an implant stent, intrathecal, intravitreal,
topical to the eye, back to the eye, intramuscular, intravenous,
and intrarectal modes of delivery. Additionally, the formulations
may be designed to delay release of the active compound over a
given period of time, or to carefully control the amount of drug
released at a given time during the course of therapy.
[0111] In another embodiment of the invention, there are provided
pharmaceutical compositions including at least one compound of the
invention in a pharmaceutically acceptable carrier thereof. The
phrase "pharmaceutically acceptable" means the carrier, diluent or
excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
[0112] Pharmaceutical compositions of the present invention can be
used in the form of a solid, a solution, an emulsion, a dispersion,
a patch, a micelle, a liposome, and the like, wherein the resulting
composition contains one or more compounds of the present
invention, as an active ingredient, in admixture with an organic or
inorganic carrier or excipient suitable for enteral or parenteral
applications. Invention compounds may be combined, for example,
with the usual non-toxic, pharmaceutically acceptable carriers for
tablets, pellets, capsules, suppositories, solutions, emulsions,
suspensions, and any other form suitable for use. The carriers
which can be used include glucose, lactose, gum acacia, gelatin,
mannitol, starch paste, magnesium trisilicate, talc, corn starch,
keratin, colloidal silica, potato starch, urea, medium chain length
triglycerides, dextrans, and other carriers suitable for use in
manufacturing preparations, in solid, semisolid, or liquid form. In
addition auxiliary, stabilizing, thickening and coloring agents and
perfumes may be used. Invention compounds are included in the
pharmaceutical composition in an amount sufficient to produce the
desired effect upon the process or disease condition.
[0113] Pharmaceutical compositions containing invention compounds
may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsions, hard or soft capsules, or syrups or
elixirs. Compositions intended for oral use may be prepared
according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of a sweetening
agent such as sucrose, lactose, or saccharin, flavoring agents such
as peppermint, oil of wintergreen or cherry, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets containing invention compounds in
admixture with non-toxic pharmaceutically acceptable excipients may
also be manufactured by known methods. The excipients used may be,
for example, (1) inert diluents such as calcium carbonate, lactose,
calcium phosphate or sodium phosphate; (2) granulating and
disintegrating agents such as corn starch, potato starch or alginic
acid; (3) binding agents such as gum tragacanth, corn starch,
gelatin or acacia, and (4) lubricating agents such as magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they
may be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate may
be employed.
[0114] In some cases, formulations for oral use may be in the form
of hard gelatin capsules wherein the invention compounds are mixed
with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin. They may also be in the form of soft
gelatin capsules wherein the invention compounds are mixed with
water or an oil medium, for example, peanut oil, liquid paraffin or
olive oil.
[0115] The pharmaceutical compositions may be in the form of a
sterile injectable suspension. This suspension may be formulated
according to known methods using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides, fatty acids (including oleic acid),
naturally occurring vegetable oils like sesame oil, coconut oil,
peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like
ethyl oleate or the like. Buffers, preservatives, antioxidants, and
the like can be incorporated as required.
[0116] The compounds of the invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions may be prepared by mixing the invention
compounds with a suitable non-irritating excipient, such as cocoa
butter, synthetic glyceride esters of polyethylene glycols, which
are solid at ordinary temperatures, but liquefy and/or dissolve in
the rectal cavity to release the drug.
[0117] The compounds of the invention may also be administered as
pharmaceutical compositions in a form suitable for topical use, for
example, as oily suspensions, as solutions or suspensions in
aqueous liquids or nonaqueous liquids, or as oil-in-water or
water-in-oil liquid emulsions.
[0118] Pharmaceutical compositions may be prepared by combining a
therapeutically effective amount of at least one compound according
to the present invention, or a pharmaceutically acceptable salt
thereof, as an active ingredient with conventional ophthalmically
acceptable pharmaceutical excipients and by preparation of unit
dosage suitable for topical ocular use. The therapeutically
efficient amount typically is between about 0.001 and about 5%
(w/v), preferably about 0.001 to about 2.0% (w/v) in liquid
formulations.
[0119] For ophthalmic application, preferably solutions are
prepared using a physiological saline solution as a major vehicle.
The pH of such ophthalmic solutions should preferably be maintained
between 4.5 and 8.0 with an appropriate buffer system, a neutral pH
being preferred but not essential. The formulations may also
contain conventional pharmaceutically acceptable preservatives,
stabilizers and surfactants.
[0120] Preferred preservatives that may be used in the
pharmaceutical compositions of the present invention include, but
are not limited to, benzalkonium chloride, chlorobutanol,
thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
[0121] A preferred surfactant is, for example, Tween 80. Likewise,
various preferred vehicles may be used in the ophthalmic
preparations of the present invention. These vehicles include, but
are not limited to, polyvinyl alcohol, povidone, hydroxypropyl
methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl
cellulose cyclodextrin and purified water.
[0122] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0123] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable.
Accordingly, buffers include acetate buffers, citrate buffers,
phosphate buffers and borate buffers. Acids or bases may be used to
adjust the pH of these formulations as needed.
[0124] In a similar manner an ophthalmically acceptable antioxidant
for use in the present invention includes, but is not limited to,
sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated
hydroxyanisole and butylated hydroxytoluene.
[0125] Other excipient components which may be included in the
ophthalmic preparations are chelating agents. The preferred
chelating agent is edentate disodium, although other chelating
agents may also be used in place of or in conjunction with it.
The ingredients are usually used in the following amounts:
TABLE-US-00004 Ingredient Amount (% w/v) active ingredient about
0.001 to about 5 preservative 0-0.10 vehicle 0-40 tonicity adjustor
0-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.8 antioxidant as
needed surfactant as needed purified water to make 100%
[0126] The actual dose of the active compounds of the present
invention depends on the specific compound, and on the condition to
be treated; the selection of the appropriate dose is well within
the knowledge of the skilled artisan.
[0127] The ophthalmic formulations of the present invention are
conveniently packaged in forms suitable for metered application,
such as in containers equipped with a dropper, to facilitate
application to the eye. Containers suitable for dropwise
application are usually made of suitable inert, non-toxic plastic
material, and generally contain between about 0.5 and about 15 ml
solution. One package may contain one or more unit doses.
Especially preservative-free solutions are often formulated in
non-resealable containers containing up to about ten, preferably up
to about five units doses, where a typical unit dose is from one to
about 8 drops, preferably one to about 3 drops. The volume of one
drop usually is about 20-35 .mu.l.
[0128] Since individual subjects may present a wide variation in
severity of symptoms and each drug has its unique therapeutic
characteristics, the precise mode of administration and dosage
employed for each subject is left to the discretion of the
practitioner.
[0129] The compounds and pharmaceutical compositions described
herein are useful as medicaments in mammals, including humans, for
treatment of diseases and/or alleviations of conditions such as
conjunctivitis, keratitis, blepharitis, endophthalmitis, red eye,
hyperemia, dacyrocystitis, hordeolum, corneal ulcers, anterior
blepharitis, posterior blepharitis, meibomian gland dysfunction,
dry eye disease (keratocojunctivitis sicca) ocular pain, ocular
pain and inflammation post-ocular surgery, bacterial
conjunctivitis, anterior uveitis, post-surgical inflammation,
inflammatory conditions of the palpebral and bulbar conjunctiva,
cornea, and anterior segment of the globe, such as allergic
conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian
gland dysfunction, superficial punctate keratitis, herpes zoster
keratitis, iritis, cyclitis, selected infective conjunctivitis,
corneal injury from chemical radiation, or thermal burns,
penetration of foreign bodies, allergy, and combinations
thereof.
[0130] Thus, in further embodiments of the invention, there are
provided methods for treating conjunctivitis, keratitis,
blepharitis, dacyrocystitis, endophthalmitis, red eye, hyperemia,
hordeolum, corneal ulcers, anterior blepharitis, posterior
blepharitis, meibomian gland dysfunction, dry eye disease
(keratocojunctivitis sicca) ocular pain, ocular pain and
inflammation post-ocular surgery, bacterial conjunctivitis,
anterior uveitis, post-surgical inflammation, inflammatory
conditions of the palpebral and bulbar conjunctiva, cornea, and
anterior segment of the globe, such as allergic conjunctivitis,
ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction,
superficial punctate keratitis, herpes zoster keratitis, iritis,
cyclitis, selected infective conjunctivitis, corneal injury from
chemical radiation, or thermal burns, penetration of foreign
bodies, allergy, and combinations thereof.
[0131] Such methods can be performed, for example, by administering
to a subject in need thereof a pharmaceutical composition
containing a therapeutically effective amount of at least one
invention compound. As used herein, the term "therapeutically
effective amount" means the amount of the pharmaceutical
composition that will elicit the biological or medical response of
a subject in need thereof that is being sought by the researcher,
veterinarian, medical doctor or other clinician. In some
embodiments, the subject in need thereof is a mammal. In some
embodiments, the mammal is human.
[0132] The following examples are for illustrative purposes only
and are not intended, nor should they be construed as limiting the
invention in any manner. Those skilled in the art will appreciate
that variations and modifications of the following examples can be
made without exceeding the spirit or scope of the invention.
[0133] The present invention concerns also processes for preparing
the compounds of the invention. The compounds according to the
invention can be prepared analogously to conventional methods as
understood by the person skilled in the art of synthetic organic
chemistry. Schemes A, B, C, D and E set forth below, illustrate how
the compounds according to the invention can be made.
[0134] It should be noted that the brief description on each of the
arrows for each conversion has been added for illustration purpose
sonly and should not be regarded as limiting with respect to the
sequence of each individual step.
[0135] The following abbreviations are used in the examples: [0136]
CH.sub.2Cl.sub.2 dichloromethane [0137] EtOH ethanol [0138]
Na.sub.2SO.sub.4 sodium sulfate [0139] DMF N,N dimethylformamide
[0140] EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide [0141]
THF tetrahydrofuran [0142] BOO tert-butyl carbamate [0143]
BOC.sub.2O di-tert-butyl pyrocarbonate [0144] NaOH sodium hydroxide
[0145] HCl hydrochlorique acid [0146] DMAP 4-Dimethylaminopyridine
[0147] NaHCO.sub.3 sodium bicarbonate [0148] CHCl.sub.3 chloroform
[0149] Na.sub.2CO.sub.3 sodium carbonate [0150]
(n-Bu).sub.4NHSO.sub.4 tetrabutylammonium hydrogen sulfate
[0151] In Scheme A BOO protected gatifloxacin reacted with
prednisolone to form a directly coupled steroid antibiotic hybrid
compound, which was couple to a linker further coupled with a
molecule of moxifloxacin. Scheme A is representative of a Scheme 1C
hybrid compound.
##STR00132## ##STR00133##
[0152] In Scheme B BOO a gatifloxacin molecule was coupled with
linker and further coupled with a prednisolone molecule, which was
further coupled with a molecule of moxifloxacin via a linker.
Scheme B is representative of a Scheme 1D hybrid compound.
##STR00134## ##STR00135##
[0153] Scheme C shows the formation of a hybrid compound according
to Scheme 1 G.
##STR00136## ##STR00137##
[0154] Scheme D shows the formation of a hybrid compound according
to Scheme 1G with a pro-drug moiety.
##STR00138## ##STR00139##
[0155] Scheme E shows the formation of a hybrid compound according
to Scheme 1 E.
##STR00140## ##STR00141##
[0156] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention
claimed. As used herein, the use of the singular includes the
plural unless specifically stated otherwise.
[0157] It will be readily apparent to those skilled in the art that
some of the compounds of the invention may contain one or more
asymmetric centers, such that the compounds may exist in
enantiomeric as well as in diastereisomeric forms. Unless it is
specifically noted otherwise, the scope of the present invention
includes all enantiomers, diastereisomers and racemic mixtures.
Some of the compounds of the invention may form salts with
pharmaceutically acceptable acids or bases, and such
pharmaceutically acceptable salts of the compounds described herein
are also within the scope of the invention.
[0158] The present invention includes all pharmaceutically
acceptable isotopically enriched compounds. Any compound of the
invention may contain one or more isotopic atoms enriched or
different than the natural ratio such as deuterium .sup.2H (or D)
in place of hydrogen .sup.1H (or H) or use of .sup.13C enriched
material in place of .sup.12C and the like. Similar substitutions
can be employed for N, O and S. The use of isotopes may assist in
analytical as well as therapeutic aspects of the invention. For
example, use of deuterium may increase the in vivo half-life by
altering the metabolism (rate) of the compounds of the invention.
These compounds can be prepared in accord with the preparations
described by use of isotopically enriched reagents.
[0159] The following examples are for illustrative purposes only
and are not intended, nor should they be construed as limiting the
invention in any manner. Those skilled in the art will appreciate
that variations and modifications of the following examples can be
made without exceeding the spirit or scope of the invention.
[0160] As will be evident to those skilled in the art, individual
isomeric forms can be obtained by separation of mixtures thereof in
conventional manner. For example, in the case of diasteroisomeric
isomers, chromatographic separation may be employed.
[0161] Compound names were generated with ACDLabs version 12.5 or
ChemBioDraw Ultra version 12.0.2.
[0162] In general, characterization of the compounds is performed
according to the following methods. Proton nuclear magnetic
resonance (.sup.1H NMR) and carbon nuclear magnetic resonance
(.sup.13C NMR) spectra were recorded on a Varian 300 or 600 MHz
spectrometer in deuterated solvent. Chemical shifts were reported
as .delta. (delta) values in parts per million (ppm) relative to
tetramethylsilane (TMS) as an internal standard (0.00 ppm) and
multiplicities were reported as s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. Data were reported in the
following format: chemical shift (multiplicity, coupling
constant(s) J in hertz (Hz), integrated intensity). The mass
spectrometry data were determined on a Shimadzu LCMS-IT-TOF
instrument.
[0163] The formation of the hybrid compounds was checked by
.sup.1H-NMR, comparing the chemical shifts of the protons from the
CH.sub.2 group identified in the schemes shown below, and
identified as "CH.sub.2.sup.c" for the starting material and as
"CH.sub.2.sup.c*" or "c*" for of the corresponding protons on the
newly formed hybrid molecule wherein "*" indicates the hybrid
compound. Applicants have marked with arrows the location of these
protons and the reaction site of the pro-drug moiety, where
available. Each scheme shows the formation of the new hybrid drug.
Each table describes the results for the new hybrid drug and the
linker number, where existing. The linker and pro-drug moiety
numbers are as described in Table 1 and 2 respectively.
[0164] It is to be understood that the embodiments of the invention
disclosed herein are illustrative of the principles of the present
invention. Other modifications that may be employed are within the
scope of the invention. Thus, by way of example, but not of
limitation, alternative configurations of the present invention may
be utilized in accordance with the teachings herein. Accordingly,
the present invention is not limited to that precisely as shown and
described.
Examples of Compounds
[0165] Prednisolone reacted with two molecules of Moxifloxacin to
form the following hybrid compounds as shown in Scheme 1 with the
results described in Table 4; and as shown in Scheme 2 with the
results described in Table 5.
##STR00142##
TABLE-US-00005 TABLE 4 * Comp. No. Linker Structure CH.sub.2c* Mass
10 L46 ##STR00143## 5.12 (dd) 1201 (MH.sup.+)
##STR00144##
TABLE-US-00006 TABLE 5 * Comp. No. Linker1 Linker2 Structure
CH.sub.2.sup.c* Mass 23 L.sub.147 L.sub.246 ##STR00145## 4.88 (in
DMSO)
[0166] Prednisolone reacted with one molecule of Gatifloxacin and
one molecule of Moxifloxacin to form the following hybrid compounds
as shown in Scheme 3 with the results described in Table 6; and as
shown in Scheme 4 with the results described in Table 7; and as
shown in Scheme 5 with the results described in Table 8; and as
shown in Scheme 6 with the results described in Table 9; and as
shown in Scheme 7 with the results described in Table 10.
##STR00146##
TABLE-US-00007 TABLE 6 * Comp. No. Linker1 Linker2 Structure
CH.sub.2.sup.c* Mass 19 L.sub.152 L.sub.246 ##STR00147## 4.98 (dd)
1371 (MNa.sup.+)
##STR00148##
TABLE-US-00008 TABLE 7 * Comp. No. Linker 1 Linker2 Structure
CH.sub.2.sup.c* Mass 20 L.sub.152 L.sub.246 ##STR00149## 5.00 1371
(MNa.sup.+)
##STR00150##
TABLE-US-00009 TABLE 8 * Comp. No. Linker 1 Linker2 Structure
CH.sub.2.sup.c* Mass 22 L.sub.152 L.sub.246 ##STR00151## 4.88 (in
DMSO)
##STR00152##
TABLE-US-00010 TABLE 9 * Comp. No. Linker Structure CH.sub.2.sup.c*
Mass 11 L46 ##STR00153## 5.16 (dd) 1176 (MH.sup.+)
##STR00154##
TABLE-US-00011 TABLE 10 * Comp. No. Linker Prodrug Structure
CH.sub.2.sup.c* Mass 14 L46 P3 ##STR00155## 5.07 1309
(MH.sup.+)
[0167] Prednisolone reacted with two molecules Gatifloxacin to form
the following hybrid compounds as shown in Scheme 8 with the
results described in Table 11 and as shown in Scheme 9 with the
results described in Table 12 and as shown in Scheme 10 with the
results described in Table 13 and as shown in Scheme 11 with the
results described in Table 14 and as shown in Scheme 12 with the
results described in Table 15 and as shown in Scheme 13 with the
results described in Table 16.
##STR00156##
TABLE-US-00012 TABLE 11 * Comp. No. Linker 1 Linker2 Structure
CH.sub.2.sup.c* Mass 21 L.sub.156 L.sub.27 ##STR00157## 4.98 (dd)
1301 (MNa.sup.+)
##STR00158##
TABLE-US-00013 TABLE 12 * Comp. No. Linker 1 Linker2 Structure
CH.sub.2.sup.c* Mass 18 L.sub.152 L.sub.29 ##STR00159## 5.01 (dd)
134 (MNa.sup.+)
##STR00160##
TABLE-US-00014 TABLE 13 * Comp. No. Linker Structure
CH.sub.2.sup.c* Mass 17 L12 ##STR00161## 5.10 (dd) 1225
(MH.sup.+)
##STR00162##
TABLE-US-00015 TABLE 14 * Comp. No. Linker Prodrug Structure
CH.sub.2.sup.c* Mass 13 L46 P3 ##STR00163## 5.08 1283
(MH.sup.+)
##STR00164##
TABLE-US-00016 TABLE 15 * Comp. No. Linker Structure
CH.sub.2.sup.c* Mass 28 L50 ##STR00165## 5.02- 4.73.sub. (m) 1249
(MH.sup.+)
##STR00166##
TABLE-US-00017 TABLE 16 * Comp. No. Linker Prodrug Structure
CH.sub.2.sup.c* Mass 30 L50 P3 ##STR00167## 5.26-4.81 (m) 1495
(MH.sup.+)
[0168] Hydrocortisone reacted with Gatifloxacin and with
Besifloxacin to form the following hybrid compounds as shown in
Scheme 14 with the results described in Table 17.
##STR00168##
TABLE-US-00018 TABLE 17 * Comp. No. Linker Structure
CH.sub.2.sup.c* Mass 12 L46 ##STR00169## 5.13 (dd) 1167
(MH.sup.+)
[0169] Dexmethasone reacted with two molecules of Gatifloxacin to
form the following hybrid compounds as shown in Scheme 15 with the
results described in Table 18 and as shown in Scheme 16 with the
results described in Table 19.
##STR00170##
TABLE-US-00019 TABLE 18 * Comp. No. Linker Structure
CH.sub.2.sup.c* Mass 15 L12 ##STR00171## 5.07 (dd) 1257
(MNa.sup.+)
##STR00172##
TABLE-US-00020 TABLE 19 * Comp. No. Linker Structure
CH.sub.2.sup.c* Mass 27 L51 ##STR00173## 5.22 (dd) 1329
(MH.sup.+)
[0170] Betamethasone reacted with two molecules of Gatifloxacin to
form the following hybrid compounds as shown in Scheme 17 with the
results described in Table 20.
##STR00174##
TABLE-US-00021 TABLE 20 * Comp. No. Linker Structure
CH.sub.2.sup.c* Mass 16 L12 ##STR00175## 5.00 (dd) 1257
(MNa.sup.+)
[0171] Hydrocortisone reacted with two molecules of Gatifloxacin to
form the following hybrid compounds as shown in Scheme 18 with the
results described in Table 21 and as shown in Scheme 19 with the
results described in Table 22.
##STR00176##
TABLE-US-00022 TABLE 21 * Comp. No. Linker Structure
CH.sub.2.sup.c* Mass 31 L48 ##STR00177## 5.03 (dd) 1398 (MH.sup.+)
29 L50 ##STR00178## 5.06- 4.77 (m) 1273 (MH.sup.+)
##STR00179##
TABLE-US-00023 TABLE 22 * Comp. No. Linker Prodrug Structure
CH.sub.2.sup.c* Mass 32 L48 P3 ##STR00180## 5.01 (dd) 1642.8
(MH.sup.+)
[0172] Hydrocortisone reacted with two molecules of Moxifloxacin to
form the following hybrid compounds as shown in Scheme 20 with the
results described in Table 23.
##STR00181##
TABLE-US-00024 TABLE 23 * Comp. No. Linker Prodrug Structure
CH.sub.2.sup.c* Mass 34 L49 P3 ##STR00182## 5.10 (dd) 1401
(MH.sup.+) 33 L48 P3 ##STR00183## 4.98 (dd) 1695 (MH.sup.+)
In vitro Metabolic Stability in Human Recombinant
Carboxylesterases
[0173] Human recombinant carboxylesterases were purchased from a
commercial vendor (BD Gentest.TM., Bedford, Massachusettes). All
metabolic stability experiments were performed in triplicate in
96-well plate format. The final incubation mixture contained 1
.mu.M test compound, 0.3 mg/mL corneal protein homogenate or 0.1
mg/mL human recombinant carboxylesterase mixture in a final volume
of 0.5 mL 0.1 M potassium phosphate buffer (pH=6.0). The final
percentage of solvent in the incubation was less than 1.0% to
prevent inhibition of enzymatic activity. Following a
pre-incubation at 37.degree. C., test article was added to initiate
the reaction. At designated time points (typically less than 60
minutes to capture the linear range of metabolite formation), 0.05
mL aliquots were removed from the incubation mixtures using a clean
pipet tip and immediately placed in organic solvent to stop any
esterase activity. The hydrolysis to the metabolites was confirmed
to be due to esterase activity and not chemical lability.
[0174] The samples were analyzed by liquid chromatography with mass
spectrometry (LC-MS/MS) detection to determine the metabolite
concentrations resulting from the metabolism of the hybrid
compounds. Internal standards were used to compensate for
variability from sample processing, chromatographic elution, mass
spectrometer response and ion suppression by matrix components.
[0175] Results
[0176] Table 24 lists the rate of metabolite formation in human
recombinant carboxylesterases.
TABLE-US-00025 TABLE 24 Rate of Rate of Rate of formation formation
formation *Comp. Metabolite 1 Metabolite 2 Metabolite 3 No.
(nM/min/mg) (nM/min/mg) (nM/min/mg) 28 13.9 .+-. 1.1 55.9 .+-. 4.4
N/A Gatifloxacin Prednisolone 10 13.8 .+-. 1.5 14.6 .+-. 1.1 N/A
Moxifloxacin Prednisolone 11 256 .+-. 29 35.4 .+-. 5.0 69.7 .+-.
14.2 Prednisolone Gatifloxacin Moxifloxacin 12 155 .+-. 31 54.9
.+-. 8.1 91.0 .+-. 22.2 Prednisolone Gatifloxacin Besifloxacin 30
41.8 .+-. 10.2 6.16 .+-. 1.36 N/A Prednisolone Gatifloxacin 18 81.2
.+-. 9.0 107 .+-. 9 N/A Prednisolone Gatifloxacin N/A = Not
applicable
[0177] The data demonstrate that linkage of a fluoroquinolone (e.g.
gatifloxacin, moxifloxacin, and besifloxacin) and a steroid (e.g.
prednisolone) as a single hybrid compound was hydrolyzed
enzymatically in human recombinant carboxylesterases to their
respective individual antibiotic and steroid drugs.
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