U.S. patent application number 16/615232 was filed with the patent office on 2020-11-26 for glycopeptide derivative compounds and uses thereof.
This patent application is currently assigned to Insmed Incorporated. The applicant listed for this patent is Insmed Incorporated. Invention is credited to Ryan HECKLER, Donna KONICEK, Vladimir MALININ, Walter PERKINS, Adam PLAUNT.
Application Number | 20200368312 16/615232 |
Document ID | / |
Family ID | 1000005060764 |
Filed Date | 2020-11-26 |
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United States Patent
Application |
20200368312 |
Kind Code |
A1 |
HECKLER; Ryan ; et
al. |
November 26, 2020 |
GLYCOPEPTIDE DERIVATIVE COMPOUNDS AND USES THEREOF
Abstract
Provided herein are methods and compositions for the treatment
of Gram positive bacterial infections. The infection in some
embodiments, is a pulmonary infection. The method for treating the
bacterial infection, comprises in one embodiment, administering to
a patient in need thereof, a composition comprising an effective
amount of a compound a glycopeptide derivative of Formula (I) or
(II), or a pharmaceutically acceptable salt of Formula (I) or
(II).
Inventors: |
HECKLER; Ryan; (Bridgewater,
NJ) ; KONICEK; Donna; (Bridgewater, NJ) ;
PLAUNT; Adam; (Bridgewater, NJ) ; MALININ;
Vladimir; (Bridgewater, NJ) ; PERKINS; Walter;
(Bridgewater, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Insmed Incorporated |
Bridgewater |
NJ |
US |
|
|
Assignee: |
Insmed Incorporated
Bridgewater
NJ
|
Family ID: |
1000005060764 |
Appl. No.: |
16/615232 |
Filed: |
May 22, 2018 |
PCT Filed: |
May 22, 2018 |
PCT NO: |
PCT/US2018/033953 |
371 Date: |
November 20, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62509378 |
May 22, 2017 |
|
|
|
62518280 |
Jun 12, 2017 |
|
|
|
62560413 |
Sep 19, 2017 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/04 20180101;
A61K 38/14 20130101; A61K 9/0073 20130101 |
International
Class: |
A61K 38/14 20060101
A61K038/14; A61K 9/00 20060101 A61K009/00; A61P 31/04 20060101
A61P031/04 |
Claims
1. (canceled)
2. A method for treating a bacterial pulmonary infection in a
patient in need thereof, comprising administering to the lungs of a
patient via a nebulizer, metered dose inhaler or a dry powder
inhaler, a composition comprising an effective amount of a compound
of Formula (II), or a pharmaceutically acceptable salt thereof:
##STR00053## wherein: R.sup.1 is C.sub.1-C.sub.18 linear alkyl,
C.sub.1-C.sub.18 branched alkyl, R.sup.5--Y--R.sup.6--(Z).sub.n, or
##STR00054## R.sup.2 is --OH or --NH--(CH.sub.2).sub.q--R.sup.7;
R.sup.3 is H or ##STR00055## R.sup.4 is H or
CH.sub.2NH--CH.sub.2--PO.sub.3H.sub.2; n is 1 or 2; q is 1, 2, 3,
4, or 5; X is O, S, NH or H.sub.2; each Z is independently selected
from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and
heterocyclic; R.sup.5 and R.sup.6 are independently selected from
the group consisting of alkylene, alkenylene and alkynylene,
wherein the alkylene, alkenylene and alkynylene groups are
optionally substituted with from 1 to 3 substituents selected from
the group consisting of alkoxy, substituted alkoxy, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,
carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl R.sup.7 is --N(CH.sub.2).sub.2;
--N(CH.sub.2).sub.3; or ##STR00056## Y is independently selected
from the group consisting of oxygen, sulfur, --S--S--,
--NR.sup.8--, --S(O)--, --SO.sub.2--, --OSO.sub.2--,
--NR.sup.8SO.sub.2--, --SO.sub.2NR.sup.8--, --SO.sub.2O--,
--P(O)(OR.sup.8)O--, --P(O)(OR.sup.8)NR--, --OP(O)(OR.sup.8)O--,
--OP(O)(OR.sup.8)NR.sup.8--, --NR.sup.8C(O)NR.sup.8--, and
--NR.sup.8SO.sub.2NR.sup.8--; and each R.sup.8 is independently
selected from the group consisting of hydrogen, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, aryl, heteroaryl and heterocyclic.
3. The method of claim 2, wherein R.sup.3 is H.
4. The method of claim 2, wherein R.sup.3 is ##STR00057##
5. The method of claim 3, wherein R.sup.4 is H.
6. The method of claim 3, wherein R.sup.4 is
CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2.
7. The method of claim 1, wherein X is O.
8-12. (canceled)
13. The method of claim 1, wherein R.sup.1 is
R.sup.5--Y--R.sup.6--(Z).sub.n and Y is --NH--.
14. (canceled)
15. The method of claim 7, wherein R.sup.1 is
(CH.sub.2).sub.2--Y--R.sup.6--(Z).sub.n.
16-19. (canceled)
20. The method of claim 13, wherein R.sup.1 is
R.sup.5--Y--(CH.sub.2).sub.10--(Z).
21. The method of claim 20, wherein (Z).sub.n is H and R.sup.4 is
H.
22. The method of claim 1, wherein R.sup.2 is OH, R.sup.4 is H, Y
is --NH--, and (Z).sub.n is H.
23-24. (canceled)
25. The method of claim 1, wherein R.sup.1 is n-decyl.
26-39. (canceled)
40. The method of claim 1, wherein R.sup.1 is
(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3.
41-43. (canceled)
44. The method of claim 40, wherein R.sup.2 is OH.
45-80. (canceled)
81. The method of claim 1, wherein the bacterial infection is a
Gram positive bacterial pulmonary infection.
82-83. (canceled)
84. The method of claim 81, wherein the Gram-positive bacterial
pulmonary infection is a Staphylococcus pulmonary infection.
85-86. (canceled)
87. The method of claim 84, wherein the Staphylococcus pulmonary
infection is a Staphylococcus aureus (S. aureus) pulmonary
infection.
88. The method of claim 87, wherein the S. aureus pulmonary
infection is a methicillin-resistant S. aureus (MRSA) pulmonary
infection.
89. The method of claim 87, wherein the S. aureus pulmonary
infection is a methicillin-sensitive S. aureus (MSSA) pulmonary
infection.
90-117. (canceled)
118. The method of claim 1, wherein the patient is a cystic
fibrosis patient.
119-122. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Application Ser. No. 62/509,378, filed May 22, 2017; U.S.
Provisional Application Ser. No. 62/518,280, filed Jun. 12, 2017;
and U.S. Provisional Application Ser. No. 62/560,413, filed Sep.
19, 2017, the disclosures of each of which is incorporated by
reference herein in their entireties.
BACKGROUND OF THE INVENTION
[0002] The high frequency of multidrug resistant bacteria, and in
particular, Gram-positive bacteria, both in the hospital setting
and the community present a significant challenge for the
management of infections (Krause et al. (2008). Antimicrobial
Agents and Chemotherapy 52(7), pp. 2647-2652, incorporated by
reference herein in its entirety for all purposes).
[0003] The treatment of invasive Staphylococcus aureus (S. aureus)
infections has relied significantly on vancomycin. However, the
treatment and management of such infections is a therapeutic
challenge because certain S. aureus isolates, and in particular,
methicillin-resistant S. aureus isolates, have been shown to be
resistant to vancomycin (Shaw et al. (2005). Antimicrobial Agents
and Chemotherapy 49(1), pp. 195-201; Mendes et al. (2015).
Antimicrobial Agents and Chemotherapy 59(3), pp. 1811-1814, each of
which is incorporated by reference herein in its entirety for all
purposes).
[0004] Because of the resistance displayed by many Gram-positive
organisms to antibiotics, and the general lack of susceptibility to
existing antibiotics, there is a need for new therapeutic
strategies to combat infections due to these bacteria. The present
invention addresses this and other needs.
SUMMARY OF THE INVENTION
[0005] In one aspect of the invention, a method is provided for
treating a bacterial infection in a patient in need thereof. In one
aspect a method of the invention comprises administrating to the
patient a composition comprising an effective amount of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof:
##STR00001## [0006] wherein,
[0007] R.sup.1 is C.sub.1-C.sub.18 linear alkyl, C.sub.1-C.sub.18
branched alkyl, R.sup.5--Y--R.sup.6--(Z).sub.n, or
##STR00002##
[0008] R.sup.2 is --OH or --NH--(CH.sub.2).sub.q--R.sup.7;
[0009] R.sup.3 is H or
##STR00003##
[0010] R.sup.4 is H or CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2;
[0011] n is 1 or 2;
[0012] each q is independently 1, 2, 3, 4, or 5;
[0013] X is O, S, NH or H.sub.2;
[0014] each Z is independently selected from hydrogen, aryl,
cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
[0015] R.sup.5 and R.sup.6 are independently selected from the
group consisting of alkylene, alkenylene and alkynylene, wherein
the alkylene, alkenylene and alkynylene groups are optionally
substituted with from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,
carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl
[0016] R.sup.7 is --N(CH.sub.2).sub.2; --N.sup.+(CH.sub.2).sub.3;
or
##STR00004##
[0017] Y is independently selected from the group consisting of
oxygen, sulfur, --S--S--, --NR.sup.8--, --S(O)--, --SO.sub.2--,
--NR.sup.8C(O)--, --OSO.sub.2--, --OC(O)--, --NR.sup.8SO.sub.2--,
--C(O)NR.sup.8--, --C(O)O--, --SO.sub.2NR.sup.8--, --SO.sub.2O--,
--P(O)(OR.sup.8)O--, --P(O)(OR.sup.8)NR.sup.8--,
--OP(O)(OR.sup.8)O--, --OP(O)(OR.sup.8)NR.sup.8--, --OC(O)O--,
--NR.sup.8C(O)O--, --NR.sup.8C(O)NR.sup.8--, --OC(O)NR.sup.8-- and
--NR.sup.8SO.sub.2NR.sup.8--; and
[0018] each R.sup.8 is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl and heterocyclic.
[0019] In another aspect, a method of the invention comprises
administrating to the patient a composition comprising an effective
amount of a compound of Formula (II), a prodrug thereof, or a
pharmaceutically acceptable salt thereof:
##STR00005## [0020] wherein,
[0021] R.sup.1 is C.sub.1-C.sub.18 linear alkyl, C.sub.1-C.sub.18
branched alkyl, R.sup.5--Y--R.sup.6--(Z).sub.n, or
##STR00006##
[0022] R.sup.2 is --OH or --NH--(CH.sub.2).sub.q--R.sup.7;
[0023] R.sup.3 is H or
##STR00007##
[0024] R.sup.4 is H or CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2;
[0025] n is 1 or 2;
[0026] each q is independently 1, 2, 3, 4, or 5;
[0027] X is O, S, NH or H.sub.2;
[0028] each Z is independently selected from hydrogen, aryl,
cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
[0029] R.sup.5 and R.sup.6 are independently selected from the
group consisting of alkylene, alkenylene and alkynylene, wherein
the alkylene, alkenylene and alkynylene groups are optionally
substituted with from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,
carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl;
[0030] R.sup.7 is --N(CH.sub.2).sub.2; --N.sup.+(CH.sub.2).sub.3;
or
##STR00008##
[0031] Y is independently selected from the group consisting of
oxygen, sulfur, --S--S--, --NR.sup.8--, --S(O)--, --SO.sub.2--,
--OSO.sub.2--, --NR.sup.8SO.sub.2--, --SO.sub.2NR.sup.8--,
--SO.sub.2O--, --P(O)(OR.sup.8)O--, --P(O)(OR.sup.8)NR.sup.8--,
--OP(O)(OR.sup.8)O--, --OP(O)(OR.sup.8)NR.sup.8--,
--NR.sup.8C(O)NR.sup.8--, and --NR.sup.8SO.sub.2NR.sup.8--; and
[0032] each R.sup.8 is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl and heterocyclic.
[0033] In one embodiment of the method for treating a bacterial
infection, the composition comprises an effective amount of a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), wherein R.sup.1 is
C.sub.6 to C.sub.16 linear alkyl. In a further embodiment, R.sup.1
is C.sub.6, C.sub.10 or C.sub.16 alkyl. In even a further
embodiment, R is C.sub.10 alkyl. In a further embodiment, the
bacterial infection is a pulmonary bacterial infection. In even a
further embodiment, the administering comprises administering via
inhalation.
[0034] In one embodiment, the method for treating a bacterial
infection comprises administering to the patient in need thereof, a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), where R.sup.1 is
R.sup.5--Y--R.sup.6--(Z).sub.n. In a further embodiment, R.sup.5 is
--(CH.sub.2).sub.2--, R.sup.6 is --(CH.sub.2).sub.10--, X is O; Y
is NR.sup.8, Z is hydrogen and n is 1. In a further embodiment,
R.sup.8 is hydrogen. As such, one embodiment of the invention
includes a compound of Formula (I), Formula (II) or a
pharmaceutically acceptable salt thereof, where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3. In a further
embodiment, the bacterial infection is a pulmonary bacterial
infection. In even a further embodiment, the administering
comprises administering via inhalation.
[0035] In one embodiment, the method for treating a bacterial
infection comprises administering to the patient in need thereof, a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3 and R.sup.3 and
R.sup.4 are H. In a further embodiment, R.sup.2 is OH. In even a
further embodiment, the administering comprises administering via
the intravenous route. In a further embodiment, X is O.
[0036] In one embodiment, the method for treating a bacterial
infection comprises administering to the patient in need thereof, a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II) where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3, R.sup.2 is
--NH--(CH.sub.2).sub.q--R.sup.7, and R.sup.3 and R.sup.4 are H. In
a further embodiment, the administering comprises administering via
the intravenous or pulmonary route. In even a further embodiment, q
is 2 or 3 and R.sup.7 is --N(CH.sub.2).sub.2. In a further
embodiment, X is O.
[0037] In one embodiment of the methods provided herein, the
composition administered to the patient comprises an effective
amount of a compound of Formula (I) or Formula (II), where R.sup.1
is
##STR00009##
In a further embodiment, R.sup.2 is OH and R.sup.3 and R.sup.4 are
H. In even a further embodiment, the halogen is Cl and q is 1 or 2.
In a further embodiment, the administering comprises administering
via the pulmonary or intravenous route. In a further embodiment, X
is O and R.sup.1 is
##STR00010##
[0038] In one embodiment of the methods provided herein, the
composition administered to the patient comprises an effective
amount of a compound of Formula (I) or Formula (II), where R.sup.1
is
##STR00011##
R.sup.2 is OH and R.sup.3 is
##STR00012##
and R.sup.4 is H. In even a further embodiment, the halogen is Cl
and q is 1 or 2. In a further embodiment, the administering
comprises administering via the intravenous route. In a further
embodiment, X is O and R.sup.1 is
##STR00013##
[0039] In yet another embodiment, the bacterial infection is a
Gram-positive cocci infection and the composition administered to
the patient in need thereof comprises an effective amount of a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), wherein R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3. In a further
embodiment, the infection is a Gram-positive infection is a cocci
infection, and in a further embodiment, is a vancomycin-resistant
enterococci (VRE), methicillin-resistant Staphylococcus aureus
(MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE),
vancomycin resistant Enterococcus faecium also resistant to
teicoplanin (VRE Fm Van A), vancomycin resistant Enterococcus
faecium sensitive to teicoplanin (VRE Fm Van B), vancomycin
resistant Enterococcus faecalis also resistant to teicoplanin (VRE
Fs Van A), vancomycin resistant Enterococcus faecalis sensitive to
teicoplanin (VRE Fs Van B), or penicillin-resistant Streptococcus
pneumoniae (PRSP).
[0040] In even another embodiment, the bacterial infection is a
Gram-positive cocci infection and the composition administered to
the patient in need thereof comprises an effective amount of a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), wherein R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3. In a further
embodiment, the infection is erythromycin-resistant (erm.sup.R),
vancomycin-intermediate S. aureus (VISA) heterogenous
vancomycin-intermediate S. aureus (hVISA), S. epidermidis
coagulase-negative staphylococci (CoNS), penicillin-intermediate S.
pneumoniae (PISP), or penicillin-resistant S. pneumoniae
(PRSP).
[0041] In even another embodiment, R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3 and the
bacterial infection is Propionibacterium acnes (skin acne),
Eggerthella lenta (bacteremia) or Peptostreptococcus anaerobius
(gynecological infection). In a further embodiment, R.sup.2 is OH
and R.sup.3 and R.sup.4 are H.
[0042] In one embodiment, the bacterial infection is a
methicillin-resistant Staphylococcus aureus (MRSA) infection and
the composition administered to the patient in need thereof
comprises an effective amount of a compound of Formula (I), Formula
(II), or a pharmaceutically acceptable salt of Formula (I) or
Formula (II), wherein R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3. In a further
embodiment, the administration is conducted via a nebulizer or a
dry powder inhaler and the bacterial infection is a pulmonary
infection. In another embodiment, administration is intravenous,
R.sup.1 is --(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3;
R.sup.2 is OH and R.sup.3 and R.sup.4 are H. In a further
embodiment, X is O.
BRIEF DESCRIPTION OF THE FIGURES
[0043] FIG. 1, top shows the reductive amination of vancomycin to
arrive at a glycopeptide derivative. The reaction occurs at the
primary amine of vancomycin. FIG. 1, bottom, shows a synthesis
scheme for a chloroeremomycin derivative.
[0044] FIG. 2 shows synthesis schemes for making the glycopeptide
derivative RV40.
[0045] FIG. 3 shows a synthesis scheme for making the glycopeptide
derivative RV79.
[0046] FIG. 4 is a synthesis scheme for making alkyl vancomycin
derivatives.
[0047] FIG. 5 shows one synthesis scheme for making
decyl-vancomycin (Compound #5).
[0048] FIG. 6 is a bar graph showing the minimum inhibitory
concentration (MIC) (.mu.g antibiotic/mL) for various antibiotics
against 23 different S. aureus strains.
[0049] FIG. 7 is a scatter plot showing the minimum inhibitory
concentration (MIC) (.mu.g antibiotic/mL) for various antibiotics
against 23 different S. aureus strains. Data is plotted as
geometric mean with a 95% confidence interval.
[0050] FIG. 8 is a bar graph showing the minimum inhibitory
concentration (MIC) (.mu.g antibiotic/mL) for various antibiotics
against 12 different MRSA strains.
[0051] FIG. 9 is a scatter plot showing the minimum inhibitory
concentration (MIC) (.mu.g antibiotic/mL) for various antibiotics
against 12 different MRSA strains. Data is plotted as geometric
mean with a 95% confidence interval.
[0052] FIG. 10 is a graph showing the log reduction of in CFU/mL
biofilm as a function of antibiotic concentration (.mu.g/mL).
[0053] FIG. 11 is a graph showing the log reduction of in CFU/mL
biofilm as a function of antibiotic concentration (.mu.g/mL).
[0054] FIG. 12 is a graph showing bacterial burden in lung versus
control in animal model of pulmonary MRSA infection. Dose based on
body weight target. The geometric mean for control was 6.4
Log.sub.10 CFU/g lung versus 3.2 Log.sub.10 CFU/g lung for RV40
treatment. Error is 95% Cl of geometric mean. N=11 for control and
n=10 for RV40 treatment. P<0.0001, Mann-Whitney U-Test.
[0055] FIG. 13 is a graph showing the difference in log reduction
in CFU/g lung versus control treatment (nebulized inhaled saline)
for various antibiotics. Dose based on body weight target. Data
plotted as mean of log values and error is SEM. Vehicle and control
for RV40 and ORI was bicine buffer, pH 9.2. Vehicle and control for
Vancomycin treatments was saline. N=10 for RV40, n=11 for ORI, n=9
for VAN neb, and n=6 for VAN i.v.
[0056] FIG. 14 is a graph showing reduction in lung CFU for inhaled
RV40 targeted delivered dosed at 10, 5, 2, and 1 mg/kg vs control.
Drugs were administered via inhalation at 12 and 24 h after
intranasal bacterial challenge with MRSA (USA300, ATCC BAA-1556) in
neutropenic rats and CFUs were counted 36 h after challenge. Data
plotted is average of Log CFU/g (n=10 for 10 mg/kg, n=9 for 5 and 2
mg/kg, and n=11 for 1 mg/kg groups). Error is SEM.
[0057] FIG. 15 is a graph showing the difference in log reduction
in CFU/g lung versus control treatment (nebulized inhaled saline)
for prophylactic dosing of RV40. Prophylactic dosing of inhaled
RV40 reduces lung bacterial burden vs. control (inhaled saline) up
to 5 days before infection. Single doses of RV40 (10 mg/kg
delivered target) were administered by inhalation. Neutropenic rats
were infected with MRSA (USA300, ATCC BAA-1556) on Day 0 and CFUs
were counted 36 h after challenge. Data plotted as geometric mean
of CFU/g. Error bars are 95% confidence interval (CI). Statistics
based on one-way ANOVA (p=0.001) with post-hoc Bonferroni multiple
comparison test. N=11 for treatment groups on Days -7, -5, -3, -1,
n=10 for Day +0.5, and n=8 for control.
DETAILED DESCRIPTION OF THE INVENTION
[0058] The high frequency of multidrug resistant bacteria, and in
particular, Gram-positive bacteria, both in the healthcare setting
and the community present a significant challenge for the
management of infections (Krause et al. (2008). Antimicrobial
Agents and Chemotherapy 52(7), pp. 2647-2652, incorporated by
reference herein in its entirety for all purposes). Moreover,
methicillin resistant S. aureus (MRSA) infections in cystic
fibrosis (CF) patients is a concern, and there is a lack of
clinical data regarding approaches to eradicate such infections
(Goss and Muhlebach (2011). Journal of Cystic Fibrosis 10, pp.
298-306, incorporated by reference herein in its entirety for all
purposes).
[0059] The present invention addresses the need for new bacterial
infection treatment methods, and in particular, bacterial infection
treatment methods by delivering compounds of Formula (I), Formula
(II), or a pharmaceutically acceptable salt of Formula (I) or
Formula (II) to patients in need thereof, for example via the
pulmonary or intravenous route.
[0060] In one aspect, the present invention relates to methods for
treating bacterial infections, for example, Gram-positive bacterial
infections and in some embodiments, Gram-positive bacterial
pulmonary infections. The method, in one embodiment, comprises
administering to a patient in need thereof, a composition
comprising an effective amount of a compound of Formula (I),
Formula (II), or a pharmaceutically acceptable salt of Formula (I)
or Formula (II). The composition can be administered by any route.
In the case of a pulmonary infection, in one embodiment, the
composition is administered via a nebulizer, dry powder inhaler or
metered dose inhaler. In another embodiment, the composition is
administered intravenously.
[0061] The compounds for use in the bacterial infection treatment
methods, and the specific treatment methods, are discussed in
detail below.
[0062] An "effective amount" of a compound of Formula (I), Formula
(II), or a pharmaceutically acceptable salt of Formula (I) or
Formula (II), is an amount that can provide the desired therapeutic
response. The effective amount can refer to a single dose as part
of multiple doses during an administration period, or as the total
dosage of glycopeptide given during an administration period. A
treatment regimen can include substantially the same dose for each
glycopeptide administration, or can comprise at least one, at least
two or at least three different dosages.
[0063] The term "alkyl" refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 40 carbon
atoms, e.g., from 1 to 10 carbon atoms, or from 1 to 6 carbon
atoms. This term is exemplified by groups such as methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl,
tetradecyl, and the like. Both linear and branched alkyl groups are
encompassed by the term "alkyl".
[0064] The term "substituted alkyl" refers to an alkyl group as
defined above, having from 1 to 8 substituents, e.g., from 1 to 5
substituents or from 1 to 3 substituents, selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-- heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0065] The term "alkylene" refers to a diradical of a branched or
unbranched saturated hydrocarbon chain, for example, having from 1
to 40 carbon atoms, e.g., from 1 to 10 carbon atoms, or from 1 to 6
carbon atoms. This term is exemplified by groups such as methylene
(CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--), the propylene
isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CCH.sub.2--) and the like.
[0066] The term "substituted alkylene" refers to an alkylene group,
as defined above, having from 1 to 5 substituents, for example,
from 1 to 3 substituents, selected from the group consisting of
alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl,
thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,
thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,
heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl.
Additionally, such substituted alkylene groups include those where
2 substituents on the alkylene group are fused to form one or more
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the
alkylene group. Such fused groups can contain from 1 to 3 fused
ring structures. Additionally, the term substituted alkylene
includes alkylene groups in which from 1 to 5 of the alkylene
carbon atoms are replaced with oxygen, sulfur or NR-- where R is
hydrogen or alkyl. Examples of substituted alkylenes are
chloromethylene (--CH(Cl)--), aminoethylene
(--CH(NH.sub.2)CH.sub.2--), 2-carboxypropylene isomers
(--CH.sub.2CH(CO.sub.2H)CH.sub.2--), ethoxyethyl
(--CH.sub.2CH.sub.2--O--CH.sub.2CH.sub.2--) and the like.
[0067] The term "alkaryl" refers to the groups -alkylene-aryl and
substituted alkylene-aryl where alkylene, substituted alkylene and
aryl are defined herein. Such alkaryl groups are exemplified by
benzyl, phenethyl and the like.
[0068] The term "alkoxy" refers to the groups alkyl-O--,
alkenyl-O--, cycloalkyl-O-cycloalkenyl-O--, and alkynyl-O--, where
alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as
defined herein. Alkyl-O-- alkoxy groups include, e.g., methoxy,
ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
[0069] The term "substituted alkoxy" refers to the groups
substituted alkyl-O--, substituted alkenyl-O--, substituted
cycloalkyl-O--, substituted cycloalkenyl-O--, and substituted
alkynyl-O-- where substituted alkyl, substituted alkenyl,
substituted cycloalkyl, substituted cycloalkenyl and substituted
alkynyl are as defined herein.
[0070] The term "alkylalkoxy" refers to the groups
-alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted
alkylene-O-alkyl and substituted alkylene-O-substituted alkyl
wherein alkyl, substituted alkyl, alkylene and substituted alkylene
are as defined herein. Alkylalkoxy groups are also expressed as
alkylene-O-alkyl and include, by way of example, methylenemethoxy
(--CH.sub.2OCH.sub.3), ethylenemethoxy
(--CH.sub.2CH.sub.2OCH.sub.3), n-propylene-iso-propoxy
(--CH.sub.2CH.sub.2CH.sub.2OCH(CH.sub.3).sub.2), methylene-t-butoxy
(--CH.sub.2--O--C(CH.sub.3).sub.3) and the like.
[0071] The term "alkenyl" refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group having from 2 to 40 carbon
atoms, e.g., 2 to 10 carbon atoms or 2 to 6 carbon atoms, and
having at least 1 and in some embodiments, from 1-6 sites of vinyl
unsaturation. Alkenyl groups include ethenyl (--CH.dbd.CH.sub.2),
n-propenyl (--CH.sub.2CH.dbd.CH.sub.2), iso-propenyl
(--C(CH.sub.3).dbd.CH.sub.2), and the like.
[0072] The term "substituted alkenyl" refers to an alkenyl group as
defined above having from 1 to 5 substituents, and e.g., from 1 to
3 substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0073] The term "alkenylene" refers to a diradical of a branched or
unbranched unsaturated hydrocarbon group having from 2 to 40 carbon
atoms, for example from 2 to 10 carbon atoms or from 2 to 6 carbon
atoms and having at least 1 and for example, from 1-6 sites of
vinyl unsaturation. This term is exemplified by groups such as
ethenylene (--CH.dbd.CH--), the propenylene isomers (e.g.,
--CH.sub.2CH.dbd.CH-- and --C(CH.sub.3).dbd.CH--) and the like.
[0074] The term "substituted alkenylene" refers to an alkenylene
group as defined above having from 1 to 5 substituents, and for
example, from 1 to 3 substituents, selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,
carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-- heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Additionally, such substituted alkenylene
groups include those where 2 substituents on the alkenylene group
are fused to form one or more cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or
heteroaryl groups fused to the alkenylene group.
[0075] The term "alkynyl" refers to a monoradical of an unsaturated
hydrocarbon having from 2 to 40 carbon atoms, for example, from 2
to 20 carbon atoms, or from 2 to 6 carbon atoms and having at least
1 and in some embodiments from 1 to 6 sites of acetylene (triple
bond) unsaturation. Representative alkynyl groups include ethynyl
(--C.ident.CH), propargyl (--CH.sub.2C.ident.CH) and the like.
[0076] The term "substituted alkynyl" refers to an alkynyl group as
defined above having from 1 to 5 substituents, for example, from 1
to 3 substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl,
thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,
thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,
heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, --SO-alkyl, --SO-substituted alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, --SO.sub.2-substituted alkyl,
--SO.sub.2-aryl and --SO.sub.2-heteroaryl.
[0077] The term "alkynylene" refers to a diradical of an
unsaturated hydrocarbon having from 2 to 40 carbon atoms, for
example from 2 to 10 carbon atoms or 2 to 6 carbon atoms and having
at least 1 and in some embodiment, from 1-6 sites of acetylene
(triple bond) unsaturation. Representative alkynylene groups
include ethynylene (--C.ident.C--), propargylene
(--CH.sub.2C.ident.C--).
[0078] The term "substituted alkynylene" refers to an alkynylene
group as defined above having from 1 to 5 substituents, for
example, from 1 to 3 substituents, selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-- heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0079] The term "acyl" refers to the groups HC(O)--, alkyl-C(O)--,
substituted alkyl-C(O)--, cycloalkyl-C(O)--, substituted
cycloalkyl-C(O)--, cycloalkenyl-C(O)--, substituted
cycloalkenyl-C(O)--, aryl-C(O)--, heteroaryl-C(O)-- and
heterocyclic-C(O)-- where alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl and heterocyclic are as defined herein.
[0080] The term "acylamino" or "aminocarbonyl" refers to the group
--C(O)NRR where each R is independently hydrogen, alkyl,
substituted alkyl, aryl, heteroaryl, heterocyclic or where both R
groups are joined to form a heterocyclic group (e.g., morpholino)
wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic
are as defined herein.
[0081] The term "aminoacyl" refers to the group --NRC(O)R where
each R is independently hydrogen, alkyl, substituted alkyl, aryl,
heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl,
heteroaryl and heterocyclic are as defined herein.
[0082] The term "aminoacyloxy" or "alkoxycarbonylamino" refers to
the group --NRC(O)OR where each R is independently hydrogen, alkyl,
substituted alkyl aryl, heteroaryl, or heterocyclic.
[0083] The term "acyloxy" refers to the groups alkyl-C(O)O--,
substituted alkyl-C(O)O--, cycloalkyl-C(O)O--, substituted
cycloalkyl-C(O)O--, aryl-C(O)O--, heteroaryl-C(O)O--, and
heterocyclic-C(O)O-- wherein alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as
defined herein.
[0084] The term "aryl" refers to an unsaturated aromatic
carbocyclic group of from 6 to 20 carbon atoms having a single ring
(e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl
or anthryl). Representative aryls include phenyl, naphthyl and the
like. Unless otherwise constrained by the definition for the aryl
substituent, such aryl groups can optionally be substituted with
from 1 to 5 substituents, e.g., from 1 to 3 substituents, selected
from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl,
alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted
alkyl, substituted alkoxy, substituted alkenyl, substituted
alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino,
substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy,
azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy,
oxyacylamino, sulfonamide, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thioheteroaryloxy, --SO-alkyl, --SO-substituted alkyl,
--SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl,
--SO.sub.2-heteroaryl and trihalomethyl. In one embodiment, the
aryl substituent is alkyl, alkoxy, halo, cyano, nitro,
trihalomethyl, thioalkoxy or a combination thereof.
[0085] The term "aryloxy" refers to the group aryl-O-- wherein the
aryl group is as defined above including optionally substituted
aryl groups as also defined above.
[0086] The term "arylene" refers to the diradical derived from aryl
(including substituted aryl) as defined above and is exemplified by
1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and
the like.
[0087] The term "amino" refers to the group --NH.sub.2.
[0088] The term "substituted amino" refers to the group --NRR where
each R is independently selected from the group consisting of
hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted
cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted
cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and
heterocyclic provided that both R groups are not H.
[0089] "Amino acid" refers to any of the naturally occurring amino
acids, synthetic amino acids, and derivatives thereof .alpha.-Amino
acids comprise a carbon atom to which is bonded an amino group, a
carboxy group, a hydrogen atom, and a distinctive group referred to
as a "side chain". The side chains of naturally occurring amino
acids are well known in the art and include, for example, hydrogen
(e.g., glycine), alkyl (e.g., alanine, valine, leucine, isoleucine,
proline), substituted alkyl (e.g., as in threonine, serine,
methionine, cysteine, aspartic acid, asparagine, glutamic acid,
glutamine, arginine, and lysine), alkaryl (e.g., phenylalanine and
tryptophan), substituted arylalkyl (e.g., tyrosine), and
heteroarylalkyl (e.g., histidine).
[0090] The term "carboxyalkyl" or "alkoxycarbonyl" refers to the
groups "--C(O)O-alkyl", "--C(O)O-substituted alkyl",
"--C(O)O-cycloalkyl", "--C(O)O-substituted cycloalkyl", "--C(O)O--
alkenyl", "--C(O)O-substituted alkenyl", "--C(O)O-alkynyl" and
"--C(O)O-substituted alkynyl" where alkyl, substituted alkyl,
cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,
alkynyl and substituted alkynyl are as defined herein
[0091] The term "cycloalkyl" refers to cyclic alkyl groups of from
3 to 20 carbon atoms having a single cyclic ring or multiple
condensed rings. Such cycloalkyl groups include, by way of example,
single ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclooctyl, and the like, or multiple ring structures
such as adamantanyl, and the like.
[0092] The term "substituted cycloalkyl" refers to cycloalkyl
groups having from 1 to 5 substituents, and for example, from 1 to
3 substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0093] The term "cycloalkenyl" refers to cyclic alkenyl groups of
from 4 to 20 carbon atoms having a single cyclic ring and at least
one point of internal unsaturation. Examples of suitable
cycloalkenyl groups include, e.g., cyclobut-2-enyl,
cyclopent-3-enyl, cyclooct-3-enyl.
[0094] The term "substituted cycloalkenyl" refers to cycloalkenyl
groups having from 1 to 5 substituents, and for example, from 1 to
3 substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-substituted
alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl.
[0095] The term "halo" or "halogen" refers to fluoro, chloro, bromo
and/or iodo.
[0096] "Haloalkyl" refers to alkyl as defined herein substituted by
1-4 halo groups as defined herein, which may be the same or
different. Representative haloalkyl groups include, by way of
example, trifluoromethyl, 3-fluorododecyl,
12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl,
and the like.
[0097] The term "heteroaryl" refers to an aromatic group of from 1
to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen,
nitrogen and sulfur within at least one ring moiety.
[0098] Unless otherwise constrained by the definition for the
heteroaryl substituent, such heteroaryl groups can be optionally
substituted with 1 to 5 substituents, for example from 1 to 3
substituents, selected from the group consisting of acyloxy,
hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, substituted alkyl, substituted alkoxy, substituted
alkenyl, substituted alkynyl, substituted cycloalkyl, substituted
cycloalkenyl, amino, substituted amino, aminoacyl, acylamino,
alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano,
halo, nitro, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted
thioalkoxy, thioaryloxy, thioheteroaryloxy, SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl and trihalomethyl. Representative aryl
substituents include alkyl, alkoxy, halo, cyano, nitro,
trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a
single ring (e.g., pyridyl or furyl) or multiple condensed rings
(e.g., indolizinyl or benzothienyl). In one embodiment, the
heteroaryl is pyridyl, pyrrolyl or furyl. "Heteroarylalkyl" refers
to (heteroaryl)alkyl- where heteroaryl and alkyl are as defined
herein. Representative examples include 2-pyridylmethyl and the
like.
[0099] The term "heteroaryloxy" refers to the group
heteroaryl-O--.
[0100] The term "heteroarylene" refers to the diradical group
derived from heteroaryl (including substituted heteroaryl), as
defined above, and is exemplified by the groups 2,6-pyridylene,
2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene,
1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl and the
like.
[0101] The term "heterocycle" or "heterocyclic" refers to a
monoradical saturated unsaturated group having a single ring or
multiple condensed rings, from 1 to 40 carbon atoms and from 1 to
10 hetero atoms, for example from 1 to 4 heteroatoms, selected from
nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
[0102] Unless otherwise constrained by the definition for the
heterocyclic substituent, such heterocyclic groups can be
optionally substituted with 1 to 5, and for example, from 1 to 3
substituents, selected from the group consisting of alkoxy,
substituted alkoxy, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy,
amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl,
azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,
heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, SO-alkyl, --SO-substituted alkyl,
--SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
--SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Such heterocyclic groups can have a single
ring or multiple condensed rings. In one embodiment, the
heterocyclic is morpholino or piperidinyl.
[0103] Examples of nitrogen heterocycles and heteroaryls include,
but are not limited to, pyrrole, imidazole, pyrazole, pyridine,
pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,
indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,
phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,
indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like
as well as N-alkoxy-nitrogen containing heterocycles.
[0104] Another class of heterocyclics is known as "crown compounds"
which refers to a specific class of heterocyclic compounds having
one or more repeating units of the formula [(CH.sub.2--).sub.aA-]
where a is equal to or greater than 2, and A at each separate
occurrence can be 0, N, S or P. Examples of crown compounds
include, by way of example only, [--(CH.sub.2).sub.3--NH-]3,
[--((CH.sub.2).sub.2--O).sub.4--((CH.sub.2).sub.2--NH).sub.2] and
the like. In one embodiment, the crown compound has from 4 to 10
heteroatoms and 8 to 40 carbon atoms.
[0105] The term "heterocyclooxy" refers to the group
heterocyclic-O--.
[0106] The term "heterocyclene" refers to the diradical group
formed from a heterocycle, as defined herein, and is exemplified by
the groups 2,6-morpholino, 2,5-morpholino and the like.
[0107] The term "oxyacylamino" or "aminocarbonyloxy" refers to the
group --OC(O)NRR where each R is independently hydrogen, alkyl,
substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl,
substituted alkyl, aryl, heteroaryl and heterocyclic are as defined
herein.
[0108] The term "spiro-attached cycloalkyl group" refers to a
cycloalkyl group attached to another ring via one carbon atom
common to both rings.
[0109] The term "sulfonamide" refers to a group of the formula
--SO.sub.2NRR, where each R is independently hydrogen, alkyl,
substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl,
substituted alkyl, aryl, heteroaryl and heterocyclic are as defined
herein.
[0110] The term "thiol" refers to the group --SH.
[0111] The term "thioheteroaryloxy" refers to the group
heteroaryl-S-- wherein the heteroaryl group is as defined above
including optionally substituted aryl groups as also defined
above.
[0112] As to any of the above groups which contain one or more
substituents, it is understood that such groups do not contain any
substitution or substitution patterns which are sterically
impractical and/or synthetically non-feasible. In addition, the
compounds of this invention include all stereochemical isomers
arising from the substitution of these compounds.
[0113] "Glycopeptide" refers to heptapeptide antibiotics,
characterized by a multi-ring peptide core optionally substituted
with saccharide groups. Examples of glycopeptides included in this
definition may be found in "Glycopeptides Classification,
Occurrence, and Discovery", by Raymond C. Rao and Louise W.
Crandall, ("Drugs and the Pharmaceutical Sciences" Volume 63,
edited by Ramakrishnan Nagarajan, published by Marcal Dekker,
Inc.), which is hereby incorporated by reference in its entirety.
Representative glycopeptides include those identified as A477,
A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850,
A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin,
Azureomycin, Balhimycin, Chloroorientiein, Chloropolysporin,
Decaplanin, N-demethylvancomycin, Eremomycin, Galacardin,
Helvecardin, Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289,
MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270,
MM56597, MM56598, OA-7653, Orenticin, Parvodicin, Ristocetin,
Ristomycin, Synmonicin, Teicoplanin, Telavancin, UK-68597,
UK-69542, UK-72051, Vancomycin, and the like. The term
"glycopeptide" as used herein is also intended to include the
general class of peptides disclosed above on which the sugar moiety
is absent, i.e., the aglycone series of glycopeptides. For example,
removal of the disaccharide moiety appended to the phenol on
vancomycin by mild hydrolysis gives vancomycin aglycone. Also
within the scope of the invention are glycopeptides that have been
further appended with additional saccharide residues, especially
aminoglycosides, in a manner similar to vancosamine. In embodiments
described herein, one or more of the aforementioned glycopeoptides
can be used in combination with a compound of Formula (I), Formula
(II), or a pharmaceutically acceptable salt of Formula (I) or
(II).
[0114] "Pharmaceutically acceptable salt" includes both acid and
base addition salts. A pharmaceutically acceptable addition salt
refers to those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but are not limited to, hydrochloric acid (HCl),
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and
the like, and organic acids such as, but not limited to, acetic
acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic
acid, aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid (e.g., as lactate), lactobionic acid, lauric
acid, maleic acid, malic acid, malonic acid, mandelic acid,
methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic
acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic
acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic
acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic
acid, acetic acid (e.g., as acetate), tartaric acid, thiocyanic
acid, p-toluenesulfonic acid, trifluoroacetic acid (TFA),
undecylenic acid, and the like. In one embodiment, the
pharmaceutically acceptable salt is HCl, TFA, lactate or
acetate.
[0115] A pharmaceutically acceptable base addition salt retains the
biological effectiveness and properties of the free acids, which
are not biologically or otherwise undesirable. These salts are
prepared from addition of an inorganic base or an organic base to
the free acid. Salts derived from inorganic bases include, but are
not limited to, the sodium, potassium, lithium, ammonium, calcium,
magnesium, iron, zinc, copper, manganese, aluminum salts and the
like. Inorganic salts include the ammonium, sodium, potassium,
calcium, and magnesium salts. Salts derived from organic bases
include, but are not limited to, salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines and basic ion exchange resins,
such as ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, benethamine, benzathine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
triethanolamine, tromethamine, purines, piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Organic bases
that can be used to form a pharmaceutically acceptable salt include
isopropylamine, diethylamine, ethanolamine, trimethylamine,
dicyclohexylamine, choline and caffeine.
[0116] In one aspect of the invention, a method is provided for
treating a bacterial infection in a patient in need thereof. The
method comprises administrating to the patient a composition
comprising an effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
##STR00014## [0117] wherein,
[0118] R.sup.1 is C.sub.1-C.sub.18 linear alkyl, C.sub.1-C.sub.18
branched alkyl, R.sup.5--Y--R.sup.6--(Z).sub.n, or
##STR00015##
[0119] R.sup.2 is --OH or --NH--(CH.sub.2).sub.q--R.sup.7;
[0120] R.sup.3 is H or
##STR00016##
[0121] R.sup.4 is H or CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2;
[0122] n is 1 or 2;
[0123] each q is independently 1, 2, 3, 4, or 5;
[0124] X is O, S, NH or H.sub.2;
[0125] each Z is independently selected from hydrogen, aryl,
cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
[0126] R.sup.5 and R.sup.6 are independently selected from the
group consisting of alkylene, alkenylene and alkynylene, wherein
the alkylene, alkenylene and alkynylene groups are optionally
substituted with from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,
carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl
[0127] R.sup.7 is --N(CH.sub.2).sub.2; --N.sup.+(CH.sub.2).sub.3;
or
##STR00017##
Y is independently selected from the group consisting of oxygen,
sulfur, --S--S--, --NR.sup.8--, --S(O)--, --SO.sub.2--,
--NR.sup.8C(O)--, --OSO.sub.2--, --OC(O)--, --NR.sup.8SO.sub.2--,
--C(O)NR.sup.8--, --C(O)O--, --SO.sub.2NR.sup.8--, --SO.sub.2O--,
--P(O)(OR.sup.8)O--, --P(O)(OR.sup.8)NR.sup.8--,
--OP(O)(OR.sup.8)O--, --OP(O)(OR.sup.8)NR.sup.8--, --OC(O)O--,
--NR.sup.8C(O)O--, --NR.sup.8C(O)NR.sup.8--, --OC(O)NR.sup.8-- and
--NR.sup.8SO.sub.2NR.sup.8--; and
[0128] each R.sup.8 is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl and heterocyclic
[0129] Another aspect of the invention relates to a method of
treating a patient for a bacterial infection. The method comprises
administering a composition comprising an effective amount of a
compound of Formula (II), or a pharmaceutically acceptable salt
thereof, to the patient in need of treatment. Formula (II) is
defined as follows:
##STR00018## [0130] wherein,
[0131] R.sup.1 is C.sub.1-C.sub.18 linear alkyl, C.sub.1-C.sub.18
branched alkyl, R.sup.5--Y--R.sup.6--(Z).sub.n, or
##STR00019##
[0132] R.sup.2 is --OH or --NH--(CH.sub.2).sub.q--R.sup.7;
[0133] R.sup.3 is H or
##STR00020##
[0134] R.sup.4 is H or CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2;
[0135] n is 1 or 2;
[0136] each q is independently 1, 2, 3, 4, or 5;
[0137] X is O, S, NH or H.sub.2;
[0138] each Z is independently selected from hydrogen, aryl,
cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
[0139] R.sup.5 and R.sup.6 are independently selected from the
group consisting of alkylene, alkenylene and alkynylene, wherein
the alkylene, alkenylene and alkynylene groups are optionally
substituted with from 1 to 3 substituents selected from the group
consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
acylamino, acyloxy, amino, substituted amino, aminoacyl,
aminoacyloxy, oxy aminoacyl, azido, cyano, halogen, hydroxyl,
carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,
heterocyclooxy, hydroxyamino, alkoxyamino, nitro, --SO-alkyl,
--SO-substituted alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, --SO.sub.2-aryl and
--SO.sub.2-heteroaryl
[0140] R.sup.7 is --N(CH.sub.2).sub.2; --N.sup.+(CH.sub.2).sub.3;
or
##STR00021##
[0141] Y is independently selected from the group consisting of
oxygen, sulfur, --S--S--, --NR.sup.8--, --S(O)--, --SO.sub.2--,
--OSO.sub.2--, --NR.sup.8SO.sub.2--, --SO.sub.2NR.sup.8--,
--SO.sub.2O--, --P(O)(OR.sup.8)O--, --P(O)(OR.sup.8)NR.sup.8--,
--OP(O)(OR.sup.8)O--, --OP(O)(OR.sup.8)NR.sup.8--,
NR.sup.8C(O)NR.sup.1--, and --NR.sup.8SO.sub.2NR.sup.8--; and
[0142] each R.sup.8 is independently selected from the group
consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, heteroaryl and heterocyclic.
[0143] Compounds of Formula (I) and Formula (II) are synthesized,
in one embodiment, by the methods provided in U.S. Pat. Nos.
6,455,669 and/or 7,160,984, the disclosure of each of which is
incorporated by reference herein in their entireties. Further
synthesis methods are provided in the Example section, herein.
Other preparation steps and methods that can be employed are
disclosed in U.S. Pat. No. 6,392,012; U.S. Patent Application
Publication No. 2017/0152291; U.S. Patent Application Publication
No. 2016/0272682, each of which is hereby incorporated by reference
in their entirety for all purposes. Methods described in
International Publication No. WO 2018/08197, the disclosure of
which is incorporated by reference in its entirety, can also be
employed. Synthesis schemes are also provided at the Example
section, herein.
[0144] In one embodiment, compounds of Formula (I) and Formula
(II), e.g., where R.sup.1 is
##STR00022##
and R.sup.2 is OH, are synthesized according to the methods
provided in U.S. Patent Application Publication No. 2017/0152291,
the disclosure of which is incorporated by reference in its
entirety.
[0145] In embodiments, where R.sup.2 is
--NH--(CH.sub.2).sub.q--R.sup.7, the amide coupling can be carried
out as described in Yarlagadda et al. (2014). J. Med. Chem. 57, pp.
4558-4568, the disclosure of which is incorporated by reference
herein in its entirety for all purposes. For example, a solution of
vancomycin or other glycopeptide derivative (e.g., a compound of
Formula (I) or Formula (II), where R.sup.1 is
##STR00023##
and X is O) can be treated with a solution of
--NH--(CH.sub.2).sub.q--R.sup.7 (e.g., a solution of
--NH--(CH.sub.2).sub.3--N(CH.sub.2).sub.2,
--NH--(CH.sub.2).sub.3--N.sup.+(CH.sub.2).sub.3, or
##STR00024##
N-methylmorpholine and HBTU at 25.degree. C. The reaction mixture
can be stirred at 25.degree. C. for 5 min and quenched with the
addition of 50% MeOH in H.sub.2O at 25.degree. C. The mixture can
be purified by semi-preparative reverse-phase HPLC to afford the
compound as a white film.
[0146] In one embodiment, the method for treating a bacterial
infection comprises administering to the patient in need thereof, a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), where R.sup.1 does
not include a physiologically cleavable functional group. Stated
another way, the R.sup.1 group, in one embodiment, is not subject
to hydrolysis or enzymatic cleavage in vivo.
[0147] In another embodiment, the method for treating a bacterial
infection comprises administering to the patient in need thereof, a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), where R.sup.1 does
not include an amide or ester moiety.
[0148] In one embodiment, the method for treating a bacterial
infection comprises administering to the patient in need thereof, a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), where R.sup.1 is
R.sup.5--Y--R.sup.6--(Z).sub.n. In a further embodiment, R.sup.5 is
--(CH.sub.2).sub.2--, R.sup.6 is --(CH.sub.2).sub.10--, X is O, Y
is NR, Z is hydrogen and n is 1. In a further embodiment, R.sup.8
is hydrogen. As such, one embodiment of the method provided herein
includes delivering to a patient a composition comprising an
effective amount of a compound of Formula (I), Formula (II), or a
pharmaceutically acceptable salt of Formula (I) or Formula (II),
where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3. In a further
embodiment, X is O, R.sup.2 is OH and R.sup.3 and R.sup.4 are H. In
even a further embodiment, administration is via the intravenous or
pulmonary route.
[0149] In one embodiment of the method, a patient is administered a
composition comprising an effective amount of a compound of Formula
(I), Formula (II), or a pharmaceutically acceptable salt of Formula
(I) or Formula (II), where R.sup.1 is
--CH.sub.2--NH--(CH.sub.2).sub.10--CH.sub.3. In a further
embodiment, X is O, R.sup.2 is OH and R.sup.3 and R.sup.4 are H. In
even a further embodiment, administration is via the intravenous or
pulmonary route.
[0150] In one embodiment of the method, a patient is administered a
composition comprising an effective amount of a compound of Formula
(I), Formula (II), or a pharmaceutically acceptable salt of Formula
(I) or Formula (II), or a pharmaceutically acceptable salt thereof,
where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.10--CH.sub.3. In a further
embodiment, X is O, R.sup.2 is OH and R.sup.3 and R.sup.4 are H. In
even a further embodiment, administration is via the intravenous or
pulmonary route.
[0151] In one embodiment of the method, a patient is administered a
composition comprising an effective amount of a compound of Formula
(I), Formula (II), or a pharmaceutically acceptable salt of Formula
(I) or Formula (II), where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.11--CH.sub.3. In a further
embodiment, X is O, R.sup.2 is OH and R.sup.3 and R.sup.4 are H. In
even a further embodiment, administration is via the intravenous or
pulmonary route.
[0152] In another embodiment, a compound of Formula (I), Formula
(II), or a pharmaceutically acceptable salt of Formula (I) or
Formula (II), is administered to the patient in need thereof, where
R.sup.1 is
##STR00025##
X is O or H.sub.2; and R.sup.2 is --NH--(CH.sub.2).sub.q--R.sup.7.
In a further embodiment, R.sup.2 is
--NH--(CH.sub.2).sub.3--R.sup.7. In a further embodiment, R.sup.1
is
##STR00026##
and R.sup.7 is --N.sup.+(CH.sub.2).sub.3 or
--N(CH.sub.2).sub.2.
[0153] In yet another embodiment, R is C.sub.10-C.sub.16 alkyl. In
even a further embodiment, R.sup.1 is C.sub.10 alkyl.
[0154] In yet another embodiment, a composition comprising an
effective amount of a compound of Formula (I), Formula (II), or a
pharmaceutically acceptable salt of Formula (I) or Formula (II), is
delivered to the patient, where R.sup.2 is OH, R.sup.3 and R.sup.4
are H and X is O. In a further embodiment, R.sup.1 is
##STR00027##
or R.sup.5--Y--R.sup.6--(Z).sub.n. In even a further embodiment,
R.sup.1 is R.sup.5--Y--R.sup.6--(Z).sub.1, R.sup.5 is methylene,
ethylene or propylene; R.sup.6 is --(CH.sub.2).sub.9--,
--(CH.sub.2).sub.10--, --(CH.sub.2).sub.11--, or
--(CH.sub.2).sub.12--, Z is H and n is 1.
[0155] In yet another embodiment, of the bacterial infection
treatment methods, an effective amount of a compound of Formula
(I), Formula (II), or a pharmaceutically acceptable salt of Formula
(I) or Formula (II) is provided, wherein one or more hydrogen atoms
is replaced with a deuterium atom.
[0156] In one embodiment, the method for treating the bacterial
infection comprises administering to the patient in need thereof, a
compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), where R.sup.1 is
R.sup.5--Y--R.sup.6--(Z).sub.n. In a further embodiment, R.sup.5 is
--(CH.sub.2).sub.2--, R.sup.6 is --(CH.sub.2).sub.10--, Y is
NR.sup.8, Z is hydrogen and n is 1. In a further embodiment,
R.sup.8 is hydrogen.
[0157] In one embodiment of the methods provided herein, R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3.
[0158] Exemplary embodiments of the compound of Formula (I) or
Formula (II), for use in methods of treating bacterial infections,
are provided in Table 1, below. It should be noted that the
compound can also be provided as a pharmaceutically acceptable
salt. The compounds in Table 1 are identified by their respective
R.sup.1, R.sup.2 and X groups. Compounds of Table 1, in one
embodiment, are defined as having R.sup.3 and R.sup.4 as both H. In
another embodiment, a compound of Table 1 is administered, where
R.sup.3 is
##STR00028##
and R.sup.4 is H. In yet another embodiment, a compound of Table 1
is administered, where R.sup.3 is H and R.sup.4 is
CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2. In even another
embodiment, a compound of Table 1 is administered, where R.sup.3
is
##STR00029##
and R.sup.4 is CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2.
TABLE-US-00001 TABLE 1 Exemplary compounds of Formula (I) or
Formula (II) for use with the invention. Com- pound # R.sup.2 X
R.sup.1 1. OH O --(CH.sub.2).sub.5--CH.sub.3 (n-hexyl) 2. OH O
--(CH.sub.2).sub.6--CH.sub.3 (n-heptyl) 3. OH O
--(CH.sub.2).sub.7--CH.sub.3 (n-octyl) 4. OH O
--(CH.sub.2).sub.8--CH.sub.3 (n-nonyl) 5. OH O
--(CH.sub.2).sub.9--CH.sub.3 (n-decyl) 6. OH O
--(CH.sub.2).sub.10--CH.sub.3 (n-undecyl) 7. OH O
--(CH.sub.2).sub.11--CH.sub.3 (n-dodecyl) 8. OH O
--(CH.sub.2).sub.12--CH.sub.3 (n-tridecyl) 9. OH O
--(CH.sub.2).sub.13--CH.sub.3 (n-butadecyl) 10. OH O
--(CH.sub.2).sub.14--CH.sub.3 (n-pentadecyl) 11. OH O
--(CH.sub.2).sub.15--CH.sub.3 (n-hexadecyl) 12. OH O
--(CH.sub.2).sub.16--CH.sub.3 (n-heptadecyl) 13. OH O
--(CH.sub.2).sub.17--CH.sub.3 (n-octadecyl) 14. OH O
--CH.sub.2--NH--(CH.sub.2).sub.5--CH.sub.3 15. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.5--CH.sub.3 16. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.6--CH.sub.3 17. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.7--CH.sub.3 18. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.8--CH.sub.3 19. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.9--CH.sub.3 20. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.10--CH.sub.3 21. OH
O --(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.11--CH.sub.3 22.
OH O --(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.12--CH.sub.3
23. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.5--CH.sub.3
24. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.6--CH.sub.3
25. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.7--CH.sub.3
26. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.8--CH.sub.3
27. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.9--CH.sub.3
28. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.10--CH.sub.3
29. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.11--CH.sub.3
30. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.12--CH.sub.3
31. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.13--CH.sub.3
32. OH O --(CH.sub.2).sub.2--OSO.sub.2--(CH.sub.2).sub.14--CH.sub.3
33. OH O --(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2--CH.sub.3 34. OH
O --(CH.sub.2).sub.2--NH--(CH.sub.2).sub.3--CH.sub.3 35. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.4--CH.sub.3 36. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.5--CH.sub.3 37. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.6--CH.sub.3 38. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.7--CH.sub.3 39. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.8--CH.sub.3 40. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3 41. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.10--CH.sub.3 42. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.11--CH.sub.3 43. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.12--CH.sub.3 44. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.13--CH.sub.3 45. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.14--CH.sub.3 46. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.5--CH.sub.3 47. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.6--CH.sub.3 48. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.7--CH.sub.3 49. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.8--CH.sub.3 50. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.9--CH.sub.3 51. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.10--CH.sub.3 52. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.11--CH.sub.3 53. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.12--CH.sub.3 54. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.13--CH.sub.3 55. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.5--CH.sub.3 56. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.6--CH.sub.3 57. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.7--CH.sub.3 58. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.8--CH.sub.3 59. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.9--CH.sub.3 60. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.10--CH.sub.3 61. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.11--CH.sub.3 62. OH O
--(CH.sub.2).sub.2--C(O)O--(CH.sub.2).sub.12--CH.sub.3 63. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.5--CH.sub.3 64. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.6--CH.sub.3 65. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.7--CH.sub.3 66. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.8--CH.sub.3 67. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.9--CH.sub.3 68. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.10--CH.sub.3 69. OH
O --(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.11--CH.sub.3 70.
OH O --(CH.sub.2).sub.2--NHSO.sub.2--(CH.sub.2).sub.12--CH.sub.3
71. OH O --(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.5--CH.sub.3 72.
OH O --(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.6--CH.sub.3 73. OH
O --(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.7--CH.sub.3 74. OH O
--(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.8--CH.sub.3 75. OH O
--(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.9--CH.sub.3 76. OH O
--(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.10--CH.sub.3 77. OH O
--(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.11--CH.sub.3 78. OH O
--(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.12--CH.sub.3 79. OH O
##STR00030## 80. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.6--CH.sub.3 81. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.7--CH.sub.3 82. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.8--CH.sub.3 83. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.9--CH.sub.3 84. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.10--CH.sub.3 85. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.11--CH.sub.3 86. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.12--CH.sub.3 87. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.5--CH.sub.3 88. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.6--CH.sub.3 89. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.7--CH.sub.3 90. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.8--CH.sub.3 91. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.9--CH.sub.3 92. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.10--CH.sub.3 93. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.11--CH.sub.3 94. OH O
--(CH.sub.2).sub.2--C(O)NH--(CH.sub.2).sub.12--CH.sub.3 95. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.5--CH.sub.3 96. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.6--CH.sub.3 97. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.7--CH.sub.3 98. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.8--CH.sub.3 99. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.9--CH.sub.3 100. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.10--CH.sub.3 101. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.11--CH.sub.3 102. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.12--CH.sub.3 103. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.5--CH.sub.3 104. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.6--CH.sub.3 105. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.7--CH.sub.3 106. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.8--CH.sub.3 107. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.9--CH.sub.3 108. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.10--CH.sub.3 109. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.11--CH.sub.3 110. OH O
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.12--CH.sub.3 111. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.5--CH.sub.3 112. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.6--CH.sub.3 113. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.7--CH.sub.3 114. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.8--CH.sub.3 115. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.9--CH.sub.3 116. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.10--CH.sub.3 117. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.11--CH.sub.3 118. OH O
--(CH.sub.2).sub.4--NH--(CH.sub.2).sub.12--CH.sub.3 119. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.5--CH.sub.3 120. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.6--CH.sub.3 121. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.7--CH.sub.3 122. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.8--CH.sub.3 123. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.9--CH.sub.3 124. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.10--CH.sub.3 125. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.11--CH.sub.3 126. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.12--CH.sub.3 127. OH O
--(CH.sub.2).sub.2--N[(CH.sub.2).sub.9CH.sub.3].sub.2 128. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.5--CH(CH.sub.3).sub.2 129.
OH O --(CH.sub.2).sub.5--NH--(CH.sub.2).sub.6--CH(CH.sub.3).sub.2
130. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.7--CH(CH.sub.3).sub.2 131.
OH O --(CH.sub.2).sub.5--NH--(CH.sub.2).sub.8--CH(CH.sub.3).sub.2
132. OH O
--(CH.sub.2).sub.5--NH--(CH.sub.2).sub.9--CH(CH.sub.3).sub.2 133.
OH O --(CH.sub.2).sub.5--NH--(CH.sub.2).sub.10--CH(CH.sub.3).sub.2
134. OH O --(CH.sub.2).sub.2--NH--CH.sub.2--Ph 135. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2--Ph 136. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.3--Ph 137. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.4--Ph 138. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.5--Ph 139. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.6--Ph 140. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.7--Ph 141. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.8--Ph 142. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-
[(CH.sub.3).sub.2CHCH.sub.2--]Ph 143. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-(Ph--S--)Ph 144. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-(4-CF.sub.3--Ph)Ph 145. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-{4-
[CH.sub.3(CH.sub.2).sub.4O--]--Ph}--Ph 146. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-Cl--Ph 147. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2--4-Cl--Ph 148. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.3--4-Cl--Ph 149. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.4--4-Cl--Ph 150. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.5--4-Cl--Ph 151. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.6--4-Cl--Ph 152. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.7--4-Cl--Ph 153. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.8--4-Cl--Ph 154. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-Ph--Ph 155. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-(4-Cl--Ph)--Ph 156. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.2O---
]Ph 157. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.3O---
]Ph 158. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.4O---
]Ph 159. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.5O---
]Ph 160. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.6O---
]Ph 161. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.7O---
]Ph 162. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.8O---
]Ph 163. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.2--]-
Ph 164. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.3--]-
Ph 165. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.4--]-
Ph 166. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.5--]-
Ph 167. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.6--]-
Ph 168. OH O --(CH.sub.2).sub.2--NH--CH.sub.2--3-[Ph--S--]Ph 169.
OH O --(CH.sub.2).sub.2--NH--CH.sub.2--4-[Ph--O--]Ph 170. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3CH.sub.2Ph--O--]Ph
171. OH O --(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.2Ph--O--]Ph 172. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.3Ph--O--]Ph 173. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.4Ph--O--]Ph 174. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.5Ph--O--]Ph 175. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.6Ph--O--]Ph 176. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.7Ph--O--]Ph 177. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.8Ph--O--]Ph 178. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--
4-[CH.sub.3(CH.sub.2).sub.9Ph--O--]Ph 179. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--3-[Ph--S--]Ph 180. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[Ph--S--]Ph 181. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2-cyclopropyl 182. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2-cyclopropyl 183. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2-cyclopentyl 184. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2-cyclopentyl 185. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2-cyclohexyl 186. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2-cyclohexyl 187. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.8--CH.dbd.CH.sub.2 188. OH O
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.8--CH(OH)--CH.sub.3 189. OH
O --(CH.sub.2).sub.2--NH--(CH.sub.2).sub.3CH.dbd.CH(CH.sub.2).sub.-
4CH.sub.3 (trans) 190. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2CH.dbd.C(CH.sub.3)(CH.sub.2).sub-
.2-- CH.dbd.C(CH.sub.3).sub.2 (trans, trans) 191. OH O
--(CH.sub.2).sub.2--NHC(O)--(CH.sub.2).sub.6--CH(CH.sub.3)CH.sub-
.3 192. OH O --(CH.sub.2).sub.2--S--(CH.sub.2).sub.8Ph 193. OH O
--(CH.sub.2).sub.2NH--CH.sub.2--4-[(CH.sub.3).sub.3CO]--Ph 194. OH
O --(CH.sub.2).sub.2--S--(CHO).sub.3CH.ident.CH(CH.sub.2).sub.4CH.-
sub.3 (trans) 195. OH O
--(CH.sub.2).sub.2NH--CH.sub.2--3,4-di-(CH.sub.3CH.sub.2O)--Ph 196.
OH O
--(CH.sub.2).sub.2--S--CH.sub.2CH.sub.2(CF.sub.2).sub.5CF.sub.3
197. OH O
--(CH.sub.2).sub.2NH--CH.sub.2--4-[(CH.sub.3).sub.2CH]--Ph 198. OH
O --(CH.sub.2).sub.2--S--CH.sub.2--4-[(CH.sub.3).sub.2CHCH.sub.2---
]Ph 199. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[CH.sub.3(CH.sub.2).sub.3C.i-
dent.C]--Ph 200. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.11CH.sub.3 201. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[(CH.sub.3).sub.2CHO]--Ph 202.
OH O --(CH.sub.2).sub.2--S--(CH.sub.2)8CH.sub.3 203. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-(Ph--.ident.C)--Ph 204. OH O
--(CH.sub.2).sub.2--S--CH.sub.23,4-di(PhCH.sub.2O--)Ph 205. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[(CH.sub.3).sub.3C]--Ph 206. OH
O --(CH.sub.2).sub.3--S--(CH.sub.2).sub.8Ph 207. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--5-(PhC.ident.C)- thiophen-2-yl
208. OH O --(CH.sub.2).sub.3--S--(CH.sub.2).sub.8CH.sub.3
209. OH O --(CH.sub.2).sub.2--NH--CH.sub.2--4-(PhCH.ident.CH--)Ph
(trans) 210. OH O --(CH.sub.2).sub.3--S--(CH.sub.2).sub.9CH.sub.3
211. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--(CH.ident.CH).sub.4--CH.sub.3
(trans, trans, trans, trans) 212. OH O
--(CH.sub.2).sub.3--S--(CH.sub.2).sub.6Ph 213. OH O
--(CH.sub.2).sub.2--N(C(O)Ph)--(CH.sub.2).sub.9CH.sub.3 214. OH O
--(CH.sub.2).sub.4--S--(CH.sub.2).sub.7CH.sub.3 215. OH O
--(CH.sub.2).sub.2--NH--CH.sub.2--4-[4-(CH.sub.3).sub.3C-
thiozol-2-yl]--Ph 216. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.6Ph 217. OH O
--(CH.sub.2).sub.2--N[(CH.sub.2).sub.9CH.sub.3]--
C(O)CHrS-4-pyridyl 218. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.10Ph 219. OH O
--(CH.sub.2).sub.2--N[(CH.sub.2).sub.9CH.sub.3]--
C(O)-2-[PhCH(CH.sub.3)NHC(O)--]Ph (R isomer) 220. OH O
--(CH.sub.2).sub.3--S--CH.sub.2--
4-[(CH.sub.3).sub.2CHCH.sub.2--]Ph 221. OH O
--(CH.sub.2).sub.2--N[(CH.sub.2).sub.9CH.sub.3]--
C(O)-(1-PhCH.sub.2OC(O)--2- oxoimidazolidin-5-yl) (S isomer) 222.
OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.3CH.ident.CH(CH.sub.2).sub-
.4CH.sub.3 (trans) 223. OH O
--(CH.sub.2).sub.2--N[(CH.sub.2).sub.9CH.sub.3]--
C(O)-1-HO-cyclopropyl 224. OH O
--(CH.sub.2).sub.2--S--CH.sub.2-4-[3,4- di-Cl--PhCH.sub.2O--]Ph
225. OH O --(CH.sub.2).sub.2--N(C(O)CH.sub.2--
naphth-2-yl)--(CH.sub.2).sub.9CH 226. OH O
--(CH.sub.2).sub.3--S--CH.sub.2-4-[3,4- di-Cl--PhCH.sub.2O--]Ph
227. OH O
--(CH.sub.2).sub.2--N[C(O)(CH.sub.2).sub.9CH.sub.2OH]--(CH.sub.2-
).sub.9CH.sub.3 228. OH O --(CH.sub.2).sub.2--SO--4-(4-Cl--Ph)--Ph
229. OH O
--CH.sub.2CH.sub.2--N[C(O)CH.sub.2(OCH.sub.2CH.sub.2).sub.2
OCH.sub.3]--(CH.sub.2).sub.9CH.sub.3 230. OH O
--(CH.sub.2).sub.3--SO--4-(4-Cl--Ph)--Ph 231. OH O
--(CH.sub.2).sub.2--N[C(O)CH.sub.2CH(Ph).sub.2]--
(CH.sub.2).sub.9CH.sub.3 232. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.10CH.sub.3 233. OH O
--(CH.sub.2).sub.2--N(C(O)CH.sub.2--3-HO--Ph)--
(CH.sub.2).sub.9CH.sub.3 234. OH O
--(CH.sub.2).sub.3--S--(CH.sub.2).sub.10CH.sub.3 235. OH O
--(CH.sub.2).sub.2--N(C(O)CH.sub.2--NHC(O)--3-
CH.sub.3--Ph)--(CH.sub.2).sub.9CH.sub.3 236. OH O
--(CH.sub.2).sub.3--S--CH.sub.2-4-(CH.sub.3(CH.sub.2).sub.4O--]P- h
237. OH O --(CH.sub.2).sub.2--N(C(O)CH.sub.2CH.sub.2--O--Ph)--
(CH.sub.2).sub.9CH.sub.3 238. OH O
--(CH.sub.2).sub.3--S--CH.sub.2CH.ident.CH--CH.ident.
CH(CH.sub.2).sub.4CH.sub.3(trans, trans) 239. OH O
--(CH.sub.2).sub.2--N(C(O)CH.sub.2CH.sub.2--
3-pyridyl)--(CH.sub.2).sub.9CH.sub.3 240. OH O
--(CH.sub.2).sub.2--S--CHr4-[4-Cl--PhCH.sub.2O--]Ph 241. OH O
--(CH.sub.2).sub.2--N(C(O)(CH.sub.2).sub.3--
4-CH.sub.3O--Ph)--(CH.sub.2).sub.9CH.sub.3 242. OH O
--(CH.sub.2).sub.3--S--CH.sub.24-[4-Cl--PhCH.sub.2O--]Ph 243. OH O
--(CH.sub.2).sub.2--N(C(O)-indol-2- yl)-(CH.sub.2).sub.9CH.sub.3
244. OH O --(CH.sub.2).sub.3--S--CH.sub.2-4-(4-CF.sub.3--Ph--)Ph
245. OH O --(CH.sub.2).sub.2--N{C(O)-1-
[CH.sub.3COC(O)--]-pyrrolidin-2-yl}-(CH.sub.2).sub.9CH.sub.3 246.
OH O --(CH.sub.2).sub.3--S--CH.sub.2-4- (4-F--PhSO.sub.2NH--)Ph
247. OH O --(CH.sub.2).sub.2--N(C(O)CH.sub.2--NHC(O)--CH.dbd.CH-
furan-2-yl)-(CH.sub.2).sub.9CH.sub.3 (trans) 248. OH O
--(CH.sub.2).sub.3--S--(CH.sub.2).sub.8CH.sub.3 249. OH O
--(CH.sub.2).sub.2--N[C(O)-1-CH.sub.3CHr 7-CH.sub.3-4-oxo-
1,4-dihydro[1,8]naphthyridin-3-yl]-(CH.sub.2).sub.9CH.sub.3 250. OH
O --(CH.sub.2).sub.3--S(O)--(CH.sub.2).sub.6Ph 251. OH O
--(CH.sub.2).sub.2--N(C(O)-1,3-benzodioxol-5-yl)-
(CH.sub.2).sub.9CH.sub.3 252. OH O
--(CH.sub.2).sub.2--S(O)--(CH.sub.2).sub.8Ph 253. OH O
--(CH.sub.2).sub.2--N(C(O)CH.sub.2-4-oxo-2-
thiooxothiazolidin-.sub.3-yl)-(CH.sub.2).sub.9CH.sub.3 254. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2).sub.3-4-Cl--Ph 255. OH O
--(CH.sub.2).sub.2--N(C(O)-3,4,5-tri-HO-cyclohex-1-en-
1-yl)-(CH.sub.2).sub.9CH.sub.3 (R,S,R isomer) 256. OH O
--(CH.sub.2).sub.2--S--(CH.sub.2)c4-Cl--Ph 257. OH O
--(CH.sub.2).sub.2--N(C(O)CH.sub.2CH.sub.2C(O)NH.sub.2)--
(CH.sub.2).sub.9CH.sub.3 258. OH O
--(CH.sub.2).sub.2--SO.sub.2--(CH.sub.2).sub.9CH.sub.3 259. OH O
--(CH.sub.2).sub.2--N(C(O)(CH.sub.2)5--CH.sub.3-2,4-dioxo-
3,4-dihydropyrimidin-1-yl)-(CH.sub.2).sub.9CH.sub.3 260. OH O
--(CH.sub.2).sub.2--NHC(O)--CH.sub.2CH(CH.sub.2CH.sub.2Ph)--
{3-[4-(9H-flouren-9-ylCH.sub.2OC(O)NH(CH.sub.2).sub.4--]-
1,4-dioxohexahydro-1,2-.alpha.-pyrazin-2-yl} (S,S,S isomer) 261. OH
O --(CH.sub.2).sub.2--N(C(O)CH.ident.CH--imidazol-4-yl)-
(CH.sub.2).sub.9CH.sub.3 (trans) 262. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--4-(2-Cl--Ph)--Ph 263. OH O
--(CH.sub.2).sub.2--N[C(O)CH(CH.sub.2CH.sub.2C(O)NH.sub.2)--
NHC(O)O--CH.sub.2Ph]--(CH.sub.2).sub.9CH.sub.3(S isomer) 264. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--4-[4-(CH.sub.3).sub.3C--Ph]--Ph
265. OH O --(CH.sub.2).sub.2--N[C(O)CH(CH.sub.2OH)--
NHC(O)O--CH.sub.2Ph]--(CH.sub.2).sub.9CH.sub.3(S isomer) 266. OH O
--(CH.sub.2).sub.2--NHSO.sub.2--4-[4-(Ph)--Ph--]Ph 267. OH O
--(CH.sub.2).sub.2--N[C(O)CH[CH(OH)CH.sub.3]
NH--C(O)O--CH.sub.2Ph]--(CH.sub.2).sub.9CH.sub.3(S isomer) 268. OH
O --(CH.sub.2).sub.2--NH--4-(4-CF.sub.3--Ph)--Ph 269. OH O
--(CH.sub.2).sub.2--N(C(O)CH.sub.2NHSO.sub.2-4-
CH.sub.3--Ph)--(CH.sub.2).sub.9CH.sub.3(S isomer) 270. OH O
--(CH.sub.2).sub.2--N(C(O)CH(NH.sub.2)CHr.sub.3--
HO--Ph)--(CH.sub.2).sub.9CH.sub.3 271. OH O
--(CH.sub.2).sub.2--N(C(O)(CH.sub.2).sub.3--NH.sub.2)--(CH.sub.2-
).sub.9CH.sub.3 272. OH O
--(CH.sub.2).sub.2--N(C(O)CH(NH.sub.2)CH.sub.3)--
(CH.sub.2).sub.9CH.sub.3(R isomer) 273. OH O
--(CH.sub.2).sub.2--N(C(O)--pyrrolidin-2-yl)-
(CH.sub.2).sub.9CH.sub.3 274. OH O
--(CH.sub.2).sub.2--N[C(O)CH(CH.sub.2OH)NHC(O)--
CH.sub.3]--(CH.sub.2).sub.9CH.sub.3(S isomer) 275. OH O
--(CH.sub.2).sub.2--N(C(O)--pyrrolidin-2-yl)-
(CH.sub.2).sub.9CH.sub.3(R isomer) 276. OH O
--(CH.sub.2).sub.2--N[C(O)CH(NHC(O)CH.sub.3--
(CH.sub.2).sub.3--NHC(NH)NH.sub.2]--(CH.sub.2).sub.9CH.sub.3(S
isomer) 277. OH O
--(CH.sub.2).sub.2--N(C(O)CH(NH.sub.2)(CH.sub.2)4-
NH.sub.2)--(CH.sub.2).sub.9CH.sub.3(S isomer) 278. OH O
--(CH.sub.2).sub.2--N(C(O)CH.sub.2NHC(O)CH.sub.3)--
(CH.sub.2).sub.9CH.sub.3 279. OH O
--(CH.sub.2).sub.2--N(C(O)-5-oxopyrrolidin-2-yl)-
(CH.sub.2).sub.9CH.sub.3(R isomer) 280. OH O
--(CH.sub.2).sub.2--N(C(O)CH(CH.sub.3)OC(O)CH--
(NH.sub.2)(CH.sub.3)--(CH.sub.2).sub.9CH.sub.3(R,R isomer) 281.
--N(CH.sub.2).sub.2 O ##STR00031## 282. --N(CH.sub.2).sub.2 NH
##STR00032## 283. --N(CH.sub.2).sub.2 S ##STR00033## 284.
--N(CH.sub.2).sub.2 H.sub.2 ##STR00034## 285. ##STR00035## O
##STR00036## 286. ##STR00037## NH ##STR00038## 287. ##STR00039## S
##STR00040## 288. ##STR00041## H.sub.2 ##STR00042## 289.
--N.sup.+(CH.sub.2).sub.3 O ##STR00043## 290.
--N.sup.+(CH.sub.2).sub.3 NH ##STR00044## 291.
--N.sup.+(CH.sub.2).sub.3 S ##STR00045## 292.
--N.sup.+(CH.sub.2).sub.3 H.sub.2 ##STR00046## 293. OH O
##STR00047## 294. OH O
--(CH.sub.2).sub.2--OC(O)--(CH.sub.2).sub.5--CH.sub.3 Ph-
phenyl
[0159] In one embodiment, the compound is a prodrug of Formula (I)
or Formula (II), for example an alkyl ester prodrug. The alkyl
group in one embodiment is a straight chain C.sub.1-C.sub.20 alkyl
or a branched C.sub.1-C.sub.20 alkyl. The alkyl ester attachment
can be at any oxygen in the molecule, determined by the user of the
method.
[0160] In one embodiment of the invention, a compound of Formula
(I), Formula (II), or a pharmaceutically acceptable salt of Formula
(I) or Formula (II), is delivered to a patient in need thereof,
wherein, X is O, R.sup.1 is a C.sub.1-C.sub.18 linear alkyl,
R.sup.2 is OH, and R.sup.3 and R.sup.4 are H.
[0161] R.sup.1 in a further embodiment is a C.sub.7-C.sub.17 linear
alkyl; C.sub.7-C.sub.10 or C.sub.6-C.sub.10 linear alkyl.
[0162] In yet another embodiment, a compound of Formula (I),
Formula (II) a prodrug thereof, or a pharmaceutically acceptable
salt thereof, is delivered to a patient in need thereof, wherein, X
is O, R.sup.1 is R.sup.5--Y--R.sup.6--(Z).sub.n, R.sup.2 is OH, and
R.sup.3 and R.sup.4 are H.
[0163] In a further embodiment, R.sup.5 is --(CH.sub.2).sub.2--,
R.sup.6 is --(CH.sub.2).sub.10--, Y is NR, Z is hydrogen and n is
1. In a further embodiment, R.sup.8 is hydrogen and X is O. In even
a further embodiment, the administering is intravenous or via the
pulmonary route.
[0164] In one embodiment of the invention, a compound of Formula
(I), Formula (II) or a pharmaceutically acceptable salt thereof, is
delivered to a patient in need of bacterial infection treatment,
where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3, X is O, R.sup.2
is --NH--(CH.sub.2).sub.q--R.sup.7, and R.sup.3 and R.sup.4 are H.
In a further embodiment, q is 2 or 3 and R.sup.1 is
--N(CH.sub.2).sub.2.
[0165] In one embodiment of the invention, a compound of Formula
(I), Formula (II) or a pharmaceutically acceptable salt thereof, is
delivered to a patient in need of bacterial infection treatment,
where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3, X is O, R.sup.2
is OH, R.sup.3 is
##STR00048##
and R.sup.4 is H.
[0166] In one embodiment, a compound of Formula (I), Formula (II)
or a pharmaceutically acceptable salt thereof, is delivered to a
patient in need of bacterial infection treatment, where R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3, X is O, R.sup.2
is OH, and R.sup.3 is H and R.sup.4 is
CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2.
[0167] In yet another embodiment, a compound of Formula (I) or
Formula (II) is provided, wherein one or more hydrogen atoms is
replaced with a deuterium atom. In a further embodiment,
R.sup.2--Y--R.sup.3--(Z) is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3.
[0168] In one embodiment of the treatment methods provided herein,
the compound of Formula (I), Formula (II), or a pharmaceutically
acceptable salt of Formula (I) or Formula (II), is defined as
follows: R.sup.1 is
(CH.sub.2).sub.n1--Y--(CH.sub.2).sub.n2--CH.sub.3, R.sup.2 is OH,
R.sup.3 and R.sup.4 are H, n2 is an integer selected from 1 to 6
and n3 is an integer from 1 to 15. In a further embodiment, X is O.
In even a further embodiment, the administering is intravenous or
via the pulmonary route.
[0169] In one embodiment, a compound of Formula (I), Formula (II),
or a pharmaceutically acceptable salt of Formula (I) or Formula
(II), is delivered to a patient in need of bacterial infection
treatment, where R.sup.1 is
(CH.sub.2)--Y--(CH.sub.2).sub.n2--CH.sub.3, R.sup.2 is OH, R.sup.3
and R.sup.4 are H and X is O. In a further embodiment, Y is oxygen,
sulfur, --S--S--, --NH--, --S(O)-- or --SO.sub.2--. In a further
embodiment, Y is --NH--.
[0170] In one embodiment, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is delivered to a patient
in need of bacterial infection treatment, where R.sup.1 is
(CH.sub.2).sub.2--Y--(CH.sub.2).sub.n2--CH.sub.3, R.sup.2 is OH,
R.sup.3 and R.sup.4 are H and X is O. In a further embodiment, Y is
oxygen, sulfur, --S--S--, --NH--, --S(O)-- or --SO.sub.2--. In a
further embodiment, Y is --NH--.
[0171] In one embodiment, a compound of Formula (I), Formula (II),
or a pharmaceutically acceptable salt of Formula (I) or Formula
(II), is delivered to a patient in need of bacterial infection
treatment, where R.sup.1 is
(CH.sub.2).sub.3--Y--(CH.sub.2).sub.2--CH.sub.3, R.sup.2 is OH,
R.sup.3 and R.sup.4 are H and X is O. In a further embodiment, Y is
oxygen, sulfur, --S--S--, --NH--, --S(O)-- or --SO.sub.2--. In a
further embodiment, Y is --NH--.
[0172] In one embodiment, a compound of Formula (I), Formula (II),
or a pharmaceutically acceptable salt of Formula (I) or Formula
(II), is delivered to a patient in need of bacterial infection
treatment, where R.sup.1 is
(CH.sub.2).sub.1-3--Y--(CH.sub.2).sub.8--CH.sub.3, R.sup.2 is OH,
R.sup.3 and R.sup.4 are H and X is O. In a further embodiment, Y is
oxygen, sulfur, --S--S--, --NH--, --S(O)-- or --SO.sub.2--. In a
further embodiment, Y is --NH--.
[0173] In one embodiment, a compound of Formula (I), Formula (II),
or a pharmaceutically acceptable salt of Formula (I) or Formula
(II), is delivered to a patient in need of bacterial infection
treatment, where R.sup.1 is
(CH.sub.2).sub.1-3--Y--(CH.sub.2).sub.9--CH.sub.3, R.sup.2 is OH,
R.sup.3 and R.sup.4 are H and X is O. In a further embodiment, Y is
oxygen, sulfur, --S--S--, --NH--, --S(O)-- or --SO.sub.2--. In a
further embodiment, Y is --NH--.
[0174] In one embodiment, a compound of Formula (I), Formula (II),
or a pharmaceutically acceptable salt of Formula (I) or Formula
(II), is delivered to a patient in need of bacterial infection
treatment, where R.sup.1 is
(CH.sub.2).sub.2--Y--(CH.sub.2).sub.1--CH.sub.3, R.sup.2 is OH,
R.sup.3 and R.sup.4 are H and X is O. In a further embodiment, Y is
oxygen, sulfur, --S--S--, --NH--, --S(O)-- or --SO.sub.2--. In a
further embodiment, Y is --NH--.
[0175] Compositions provided herein can be in the form of a
solution, suspension or dry powder. Compositions can be
administered by techniques known in the art, including, but not
limited to intramuscular, intravenous, intratracheal, intranasal,
intraocular, intraperitoneal, subcutaneous, and transdermal routes.
In addition, as discussed throughout, the compositions can also be
administered via the pulmonary route, e.g., via inhalation with a
nebulizer or a dry powder inhaler.
[0176] In one embodiment, the composition provided herein comprises
a plurality of nanoparticles of the antibiotic of Formula (I),
Formula (II), or a pharmaceutically acceptable salt of Formula (I)
or Formula (II) in association with a polymer. The mean diameter of
the plurality of nanoparticles, in one embodiment, is from about 50
nm to about 900 nm, for example from about 10 nm to about 800 nm,
from about 100 nm to about 700 nm, from about 100 nm to about 600
nm or from about 100 nm to about 500 nm.
[0177] In one embodiment, the plurality of nanoparticles comprise a
biodegradable polymer and the antibiotic of Formula (I), Formula
(II), or a pharmaceutically acceptable salt of Formula (I) or
Formula (II). In a further embodiment, the biodegradable polymer is
poly(D,L-lactide), poly(lactic acid) (PLA), poly(D,L-glycolide)
(PLG), poly(lactide-co-glycolide) (PLGA), poly-(cyanoacrylate)
(PCA), or a combination thereof.
[0178] In even a further embodiment, the biodegradable polymer is
poly(lactic-co-glycolitic acid) (PLGA).
[0179] Nanoparticle compositions can be prepared according to
methods known to those of ordinary skill in the art. For example,
coacervation, solvent evaporation, emulsification, in situ
polymerization, or a combination thereof can be employed (see,
e.g., Soppimath et al. (2001). Journal of Controlled Release 70,
pp. 1-20, incorporated by reference herein in its entirety for all
purposes).
[0180] The amount of polymer in the composition can be adjusted,
for example, to adjust the release profile of the compound of
Formula from the composition.
[0181] In one embodiment, a dry powder composition disclosed in one
of U.S. Pat. Nos. 5,874,064, 5,855,913 and/or U.S. Patent
Application Publication No. 2008/0160092 is used to formulate one
of the glycopeptides of Formula (I), Formula (II), or a
pharmaceutically acceptable salt of Formula (I) or Formula (II).
The disclosures of U.S. Pat. Nos. 5,874,064, 5,855,913 and U.S.
Patent Application Publication No. 2008/0160092 are each
incorporated by reference herein in their entireties for all
purposes.
[0182] In one embodiment, the composition delivered via the methods
provided herein are spray dried, hollow and porous particulate
compositions. For example, the hollow and porous particulate
compositions as disclosed in WO 1999/16419, hereby incorporated in
its entirety by reference for all purposes, can be employed. Such
particulate compositions comprise particles having a relatively
thin porous wall defining a large internal void, although, other
void containing or perforated structures are contemplated as
well.
[0183] Compositions delivered via the methods provided herein, in
one embodiment, yield powders with bulk densities less than 0.5
g/cm.sup.3 or 0.3 g/cm.sup.3, for example, less 0.1 g/cm3, or less
than 0.05 g/cm.sup.3. By providing particles with very low bulk
density, the minimum powder mass that can be filled into a unit
dose container is reduced, which eliminates the need for carrier
particles. Moreover, the elimination of carrier particles, without
wishing to be bound by theory, can minimize throat deposition and
any "gag" effect, since the large lactose particles can impact the
throat and upper airways due to their size.
[0184] In some embodiments, the particulate compositions delivered
via the methods provided herein comprise a structural matrix that
exhibits, defines or comprises voids, pores, defects, hollows,
spaces, interstitial spaces, apertures, perforations or holes. The
particulate compositions in one embodiment, are provided in a "dry"
state. That is, the particulate composition possesses a moisture
content that allows the powder to remain chemically and physically
stable during storage at ambient temperature and easily
dispersible. As such, the moisture content of the microparticles is
typically less than 6% by weight, and for example, less 3% by
weight. In some embodiments, the moisture content is as low as 1%
by weight. The moisture content is, at least in part, dictated by
the formulation and is controlled by the process conditions
employed, e.g., inlet temperature, feed concentration, pump rate,
and blowing agent type, concentration and post drying.
[0185] Reduction in bound water can lead to improvements in the
dispersibility and flowability of phospholipid based powders,
leading to the potential for highly efficient delivery of powdered
lung surfactants or particulate composition comprising active agent
dispersed in the phospholipid.
[0186] The composition administered via the methods provided
herein, in one embodiment, is a particulate composition comprising
a compound of Formula (I) or Formula (II), a phospholipid and a
polyvalent cation. In particular, the compositions of the present
invention can employ polyvalent cations in phospholipid-containing,
dispersible particulate compositions for pulmonary administration
to the respiratory tract for local or systemic therapy via
aerosolization.
[0187] Without wishing to be bound by theory, it is thought that
the use of a polyvalent cation in the form of a hygroscopic salt
such as calcium chloride stabilizes a dry powder prone to moisture
induced stabilization. Without wishing to be bound by theory, it is
thought that such cations intercalate the phospholipid membrane,
thereby interacting directly with the negatively charged portion of
the zwitterionic headgroup. The result of this interaction is
increased dehydration of the headgroup area and condensation of the
acyl-chain packing, all of which leads to increased thermodynamic
stability of the phospholipids. Other benefits of such dry powder
compositions are provided in U.S. Pat. No. 7,442,388, the
disclosure of which is incorporated herein in its entirety for all
purposes.
[0188] The polyvalent cation for use in the present invention in
one embodiment, is a divalent cation. In a further embodiment, the
divalent cation is calcium, magnesium, zinc or iron. The polyvalent
cation is present in one embodiment, to increase the Tm of the
phospholipid such that the particulate composition exhibits a Tm
which is greater than its storage temperature Ts by at least
20.degree. C. The molar ratio of polyvalent cation to phospholipid
in one embodiment, is 0.05, e.g., from about 0.05 to about 2.0, or
from about 0.25 to about 1.0. In one embodiment, the molar ratio of
polyvalent cation to phospholipid is about 0.50. In one embodiment,
the polyvalent cation is calcium and is provided as calcium
chloride.
[0189] According to one embodiment, the phospholipid is a saturated
phospholipid. In a further embodiment, the saturated phospholipid
is a saturated phosphatidylcholine. Acyl chain lengths that can be
employed range from about C.sub.16 to C.sub.22. For example, in one
embodiment an acyl chain length of 16:0 or 18:0 (i.e., palmitoyl
and stearoyl) is employed. In one phospholipid embodiment, a
natural or synthetic lung surfactant is provided as the
phospholipid component. In this embodiment, the phospholipid can
make up to 90 to 99.9% w/w of the lung surfactant. Suitable
phospholipids according to this aspect of the invention include
natural or synthetic lung surfactants such as those commercially
available under the trademarks ExoSurf, InfaSurf.RTM. (Ony, Inc.),
Survanta, CuroSurf, and ALEC.
[0190] The Tm of the phospholipid-glycopeptide particles, in one
embodiment, is manipulated by varying the amount of polyvalent
cations in the composition.
[0191] Phospholipids from both natural and synthetic sources are
compatible with the compositions administered by the methods
provided herein, and may be used in varying concentrations to form
the structural matrix. Generally compatible phospholipids comprise
those that have a gel to liquid crystal phase transition greater
than about 40.degree. C. The incorporated phospholipids in one
embodiment, are relatively long chain (i.e., C.sub.16-C.sub.22)
saturated lipids and in a further embodiment, comprise saturated
phospholipids. In even a further embodiment, the saturated
phospholipid is a saturated phosphatidylcholine. In even a further
embodiment, the saturated phosphatidylcholine has an acyl chain
lengths of 16:0 or 18:0 (palmitoyl or stearoyl). Exemplary
phospholipids useful in the disclosed stabilized preparations
comprise, phosphoglycerides such as dipalmitoylphosphatidylcholine
(DPPC), disteroylphosphatidylcholine (DSPC),
diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine,
diphosphatidyl glycerol, short-chain phosphatidylcholines,
long-chain saturated phosphatidylethanolamines, long-chain
saturated phosphatidylserines, long-chain saturated
phosphatidylglycerols, long-chain saturated
phosphatidylinositols.
[0192] In addition to the phospholipid, a co-surfactant or
combinations of surfactants, including the use of one or more in
the liquid phase and one or more associated with the particulate
compositions can be used in the compositions delivered via the
methods provided herein. By "associated with or comprise" it is
meant that the particulate compositions may incorporate, adsorb,
absorb, be coated with or be formed by the surfactant. Surfactants
include fluorinated and nonfluorinated compounds and can include
saturated and unsaturated lipids, nonionic detergents, nonionic
block copolymers, ionic surfactants and combinations thereof. In
one embodiment comprising stabilized dispersions, nonfluorinated
surfactants are relatively insoluble in the suspension medium.
[0193] Compatible nonionic detergents suitable as co-surfactants in
the compositions provided herein include sorbitan esters including
sorbitan trioleate (Span.TM. 85), sorbitan sesquioleate, sorbitan
monooleate, sorbitan monolaurate, polyoxyethylene (20) (Brij.RTM.
S20), sorbitan monolaurate, and polyoxyethylene (20) sorbitan
monooleate, oleyl polyoxyethylene (2) ether, stearyl
polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether,
glycerol esters, and sucrose esters. Block copolymers include
diblock and triblock copolymers of polyoxyethylene and
polyoxypropylene, including poloxamer 188 (Pluronic.RTM. F-68),
poloxamer 407 (Pluronic.RTM. F-127), and poloxamer 338. Ionic
surfactants such as sodium sulfosuccinate, and fatty acid soaps may
also be utilized.
[0194] The phospholipid-glycopeptide particulate compositions can
include additional lipids such as a glycolipid, ganglioside GM1,
sphingomyelin, phosphatidic acid, cardiolipin; a lipid bearing a
polymer chain such as polyethylene glycol, chitin, hyaluronic acid,
or polyvinylpyrrolidone; a lipid bearing sulfonated mono-, di-, and
polysaccharides; a fatty acid such as palmitic acid, stearic acid,
and/or oleic acid; cholesterol, cholesterol esters, and cholesterol
hemisuccinate.
[0195] In addition to the phospholipid and polyvalent cation, the
particulate composition delivered via the methods provided herein
can also include a biocompatible, and in some embodiments,
biodegradable polymer, copolymer, or blend or other combination
thereof. The polymer in one embodiment is a polylactide,
polylactide-glycolide, cyclodextrin, polyacrylate, methylcellulose,
carboxymethylcellulose, polyvinyl alcohol, polyanhydride,
polylactam, polyvinyl pyrrolidone, polysaccharide (e.g., dextran,
starch, chitin, chitosan), hyaluronic acid, protein (e.g., albumin,
collagen, gelatin, etc.).
[0196] Besides the aforementioned polymer materials and
surfactants, other excipients can be added to a particulate
composition, for example, to improve particle rigidity, production
yield, emitted dose and deposition, shelf-life and/or patient
acceptance. Such optional excipients include, but are not limited
to: coloring agents, taste masking agents, buffers, hygroscopic
agents, antioxidants, and chemical stabilizers. Other excipients
may include, but are not limited to, carbohydrates including
monosaccharides, disaccharides and polysaccharides. For example,
monosaccharides such as dextrose (anhydrous and monohydrate),
galactose, mannitol, D-mannose, sorbitol, sorbose and the like;
disaccharides such as lactose, maltose, sucrose, trehalose, and the
like; trisaccharides such as raffinose and the like; and other
carbohydrates such as starches (hydroxyethylstarch), cyclodextrins
and maltodextrins. Mixtures of carbohydrates and amino acids are
further held to be within the scope of the present invention. The
inclusion of both inorganic (e.g., sodium chloride), organic acids
and their salts (e.g., carboxylic acids and their salts such as
sodium citrate, sodium ascorbate, magnesium gluconate, sodium
gluconate, tromethamine hydrochloride, etc.) and buffers can also
be undertaken. Salts and/or organic solids such as ammonium
carbonate, ammonium acetate, ammonium chloride or camphor can also
be employed.
[0197] According to one embodiment, the particulate compositions
may be used in the form of dry powders or in the form of stabilized
dispersions comprising a non-aqueous phase. The dispersions or
powders of the present invention may be used in conjunction with
metered dose inhalers (MDIs), dry powder inhalers (DPIs),
atomizers, or nebulizers to provide for pulmonary delivery.
[0198] While several procedures are generally compatible with
making certain dry powder compositions described herein, spray
drying is a particularly useful method. As is well known, spray
drying is a one-step process that converts a liquid feed to a dried
particulate form. With respect to pharmaceutical applications, it
will be appreciated that spray drying has been used to provide
powdered material for various administrative routes including
inhalation. See, for example, M. Sacchetti and M. M. Van Oort in:
Inhalation Aerosols: Physical and Biological Basis for Therapy, A.
J. Hickey, ed. Marcel Dekkar, New York, 1996, which is incorporated
herein by reference in its entirety for all purposes. In general,
spray drying consists of bringing together a highly dispersed
liquid, and a sufficient volume of hot air to produce evaporation
and drying of the liquid droplets. The preparation to be spray
dried or feed (or feed stock) can be any solution, suspension,
slurry, colloidal dispersion, or paste that may be atomized using
the selected spray drying apparatus. In one embodiment, the feed
stock comprises a colloidal system such as an emulsion, reverse
emulsion, microemulsion, multiple emulsion, particulate dispersion,
or slurry. Typically, the feed is sprayed into a current of warm
filtered air that evaporates the solvent and conveys the dried
product to a collector. The spent air is then exhausted with the
solvent.
[0199] It will further be appreciated that spray dryers, and
specifically their atomizers, may be modified or customized for
specialized applications, e.g., the simultaneous spraying of two
solutions using a double nozzle technique. More specifically, a
water-in-oil emulsion can be atomized from one nozzle and a
solution containing an anti-adherent such as mannitol can be
co-atomized from a second nozzle. In one embodiment, it may be
desirable to push the feed solution though a custom designed nozzle
using a high pressure liquid chromatography (HPLC) pump. Examples
of spray drying methods and systems suitable for making the dry
powders of the present invention are disclosed in U.S. Pat. Nos.
6,077,543, 6,051,256, 6,001,336, 5,985,248, and 5,976,574, each of
which is incorporated in their entirety by reference for all
purposes.
[0200] While the resulting spray-dried powdered particles typically
are approximately spherical in shape, nearly uniform in size and
frequently are hollow, there may be some degree of irregularity in
shape depending upon the incorporated glycopeptide of Formula (I)
or Formula (II) and the spray drying conditions. In one embodiment,
an inflating agent (or blowing agent) is used in the spray-dried
powder production, e.g., as disclosed in WO 99/16419, incorporated
by reference herein in its entirety for all purposes. Additionally,
an emulsion can be included with the inflating agent as the
disperse or continuous phase. The inflating agent can be dispersed
with a surfactant solution, using, for instance, a commercially
available microfluidizer at a pressure of about 5000 to 15,000 PSI.
This process forms an emulsion, and in some embodiments, an
emulsion stabilized by an incorporated surfactant, and can comprise
submicron droplets of water immiscible blowing agent dispersed in
an aqueous continuous phase. The blowing agent in one embodiment,
is a fluorinated compound (e.g., perfluorohexane, perfluorooctyl
bromide, perfluorooctyl ethane, perfluorodecalin, perfluorobutyl
ethane) which vaporizes during the spray-drying process, leaving
behind generally hollow, porous aerodynamically light microspheres.
Other suitable liquid blowing agents include nonfluorinated oils,
chloroform, Freons, ethyl acetate, alcohols and hydrocarbons.
Nitrogen and carbon dioxide gases are also contemplated as a
suitable blowing agent. Perfluorooctyl ethane is the blowing agent,
in one embodiment.
[0201] Whatever components are selected, the first step in
particulate production in one embodiment, comprises feed stock
preparation. The selected glycopeptide is dissolved in a solvent,
for example water, dimethylformamide (DMF), dimethyl sulfoxide
(DMSO), acetonitrile, ethanol, methanol, or combinations thereof,
to produce a concentrated solution. The polyvalent cation may be
added to the glycopeptide solution or may be added to the
phospholipid emulsion as discussed below. The glycopeptide may also
be dispersed directly in the emulsion, particularly in the case of
water insoluble agents. Alternatively, the glycopeptide is
incorporated in the form of a solid particulate dispersion. The
concentration of the glycopeptide used is dependent on the amount
of glycopeptide required in the final powder and the performance of
the delivery device employed (e.g., the fine particle dose for a
MDI or DPI). As needed, cosurfactants such as poloxamer 188 or span
80 may be dispersed into this annex solution. Additionally,
excipients such as sugars and starches can also be added.
[0202] In one embodiment, a polyvalent cation-containing
oil-in-water emulsion is then formed in a separate vessel. The oil
employed in one embodiment, is a fluorocarbon (e.g., perfluorooctyl
bromide, perfluorooctyl ethane, perfluorodecalin) which is
emulsified with a phospholipid. For example, polyvalent cation and
phospholipid may be homogenized in hot distilled water (e.g.,
60.degree. C.) using a suitable high shear mechanical mixer (e.g.,
Ultra-Turrax model T-25 mixer) at 8000 rpm for 2 to 5 minutes. In
one embodiment, 5 to 25 g of fluorocarbon is added dropwise to the
dispersed surfactant solution while mixing. The resulting
polyvalent cation-containing perfluorocarbon in water emulsion is
then processed using a high pressure homogenizer to reduce the
particle size. In one embodiment, the emulsion is processed at
12,000 to 18,000 PSI, 5 discrete passes and kept at 50 to
80.degree. C.
[0203] The glycopeptide solution (or suspension) and
perfluorocarbon emulsion are then combined and fed into the spray
dryer. In one embodiment, the two preparations are miscible. While
the glycopeptide is solubilized separately for the purposes of the
instant discussion it will be appreciated that, in other
embodiments, the glycopeptide may be solubilized (or dispersed)
directly in the emulsion. In such cases, the glycopeptide emulsion
is simply spray dried without combining a separate glycopeptide
preparation.
[0204] Operating conditions such as inlet and outlet temperature,
feed rate, atomization pressure, flow rate of the drying air, and
nozzle configuration can be adjusted in accordance with the
manufacturer's guidelines in order to produce the desired particle
size, and production yield of the resulting dry particles. The
selection of appropriate apparatus and processing conditions are
well within the purview of a skilled artisan. In one embodiment,
the particulate composition comprises hollow, porous spray dried
micro- or nano-particles.
[0205] Along with spray drying, particulate compositions useful in
the present invention may be formed by lyophilization. Those
skilled in the art will appreciate that lyophilization is a
freeze-drying process in which water is sublimed from the
composition after it is frozen. Methods for providing lyophilized
particulates are known to those of skill in the art. The
lyophilized cake containing a fine foam-like structure can be
micronized using techniques known in the art.
[0206] Besides the aforementioned techniques, the glycopeptide
particulate compositions or glycopeptide particles provided herein
may be formed using a method where a feed solution (either emulsion
or aqueous) containing wall forming agents is rapidly added to a
reservoir of heated oil (e.g., perflubron or other high boiling
FCs) under reduced pressure. The water and volatile solvents of the
feed solution rapidly boils and are evaporated. In one embodiment,
the wall forming agents are insoluble in the heated oil. The
resulting particles can then separated from the heated oil using a
filtering technique and then dried under vacuum.
[0207] In another embodiment, the particulate compositions of the
present invention may also be formed using a double emulsion
method. In the double emulsion method, the medicament is first
dispersed in a polymer dissolved in an organic solvent (e.g.,
methylene chloride, ethyl acetate) by sonication or homogenization.
This primary emulsion is then stabilized by forming a multiple
emulsion in a continuous aqueous phase containing an emulsifier
such as polyvinylalcohol. Evaporation or extraction using
conventional techniques and apparatus then removes the organic
solvent. The resulting particles are washed, filtered and dried
prior to combining them with an appropriate suspension medium.
[0208] In order to maximize dispersibility, dispersion stability
and optimize distribution upon administration, the mean geometric
particle size of the particulate compositions in one embodiment, is
from about 0.5-50 .mu.m, for example from about 0.5 .mu.m to about
10 .mu.m or from about 0.5 to about 5 .mu.m. In one embodiment, the
mean geometric particle size (or diameter) of the particulate
compositions is less than 20 .mu.m or less than 10 .mu.m. In a
further embodiment, the mean geometric diameter is .ltoreq.about 7
.mu.m or .ltoreq.5 .mu.m. In even a further embodiment, the mass
geometric diameter is .ltoreq.about 2.5 .mu.m. In one embodiment,
the particulate composition comprises a powder of dry, hollow,
porous spherical shells of from about 0.1 to about 10 .mu.m, e.g.,
from about 0.5 to about 5 .mu.m in diameter, with shell thicknesses
of approximately 0.1 .mu.m to about 0.5 .mu.m.
[0209] In addition to the glycopeptides of Formula (I), Formula
(II) or a pharmaceutically acceptable salt thereof, one or more
additional antiinfectives can be included in the composition
administered to the patient in need thereof, either in the same
composition, or a different composition. Additional antiinfectives
include an additional glycopeptide, for example, one of the
glycopeptides described herein. Other additional antiinfectives
include but are not limited to aminoglycosides (e.g., dibekacin,
K-4619, sisomicin, amikacin, dactimicin, isepamicin,
rhodestreptomycin, apramycin, etimicin, KA-5685, sorbistin,
arbekacin, framycetin, kanamycin, spectinomycin, astromicin,
gentamicin, neomycin, sporaricin, bekanamycin, H107, netilmicin,
streptomycin, boholmycin, hygromycin, paromomycin, tobramycin,
brulamycin, hygromycin B, plazomicin, verdamicin, capreomycin,
inosamycin, ribostamycin, vertilmicin), tetracyclines (e.g.,
chlortetracycline, oxytetracycline, methacycline, doxycycline,
minocycline), sulfonamides (e.g., sulfanilamide, sulfadiazine,
sulfamethaoxazole, sulfisoxazole, sulfacetamide), paraaminobenzoic
acid, diaminopyrimidines (e.g., trimethoprim), quinolones (e.g.,
nalidixic acid, cinoxacin, ciprofloxacin and norfloxacin),
penicillins (e.g., penicillin G, penicillin V, ampicillin,
amoxicillin, bacampicillin, carbenicillin, carbenicillin indanyl,
ticarcillin, azlocillin, mezlocillin, piperacillin), penicillinase
resistant penicillin (e.g., methicillin, oxacillin, cloxacillin,
dicloxacillin, nafcillin), first generation cephalosporins (e.g.,
cefadroxil, cephalexin, cephradine, cephalothin, cephapirin,
cefazolin), second generation cephalosporins (e.g., cefaclor,
cefamandole, cefonicid, cefoxitin, cefotetan, cefuroxime,
cefuroxime axetil; cefmetazole, cefprozil, loracarbef, ceforanide),
third generation cephalosporins (e.g., cefepime, cefoperazone,
cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefixime,
cefpodoxime, ceftibuten), other .beta.-lactams (e.g., imipenem,
meropenem, aztreonam, clavulanic acid, sulbactam, tazobactam, and
the like), betalactamase inhibitors (e.g., clavulanic acid),
chlorampheriicol, macrolides (e.g., erythromycin, azithromycin,
clarithromycin), lincomycin, clindamycin, spectinomycin, polymyxin
B, polymixins (e.g., polymyxin A, B, C, D, E1 (colistin A), or E2,
colistin B or C) colistin, vancomycin, telavancin, bacitracin,
isoniazid, rifampin, ethambutol, ethionamide, aminosalicylic acid,
cycloserine, capreomycin, sulfones (e.g., dapsone, sulfoxone
sodium, and the like), clofazimine, thalidomide.
[0210] In one embodiment, the compound of Formula (I) or (II), or
pharmaceutically acceptable salt of Formula (I) or (II), is
administered in combination with an aminoglycoside. In a further
embodiment, the compound is a compound of Formula (I) or Formula
(I) wherein R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3. The
aminoglycoside, in a further embodiment, is dibekacin, K-4619,
sisomicin, amikacin, dactimicin, isepamicin, rhodestreptomycin,
apramycin, etimicin, KA-5685, sorbistin, arbekacin, framycetin,
kanamycin, spectinomycin, astromicin, gentamicin, neomycin,
sporaricin, bekanamycin, H107, netilmicin, streptomycin,
boholmycin, hygromycin, paromomycin, tobramycin, brulamycin,
hygromycin B, plazomicin, verdamicin, capreomycin, inosamycin,
ribostamycin or vertilmicin. In a further embodiment, the
aminoglycoside is amikacin or gentamicin. In a further embodiment,
the aminoglycoside is gentamicin.
[0211] Methods for treating bacterial infections, e.g., those
caused by Gram-positive microorganisms, are provided. Without
wishing to be bound by a particular theory, it is believed that the
R.sup.1 groups conjugated to the glycopeptides provided herein
facilitate cellular uptake of the glycopeptide at the site of
infection, for example, macrophage uptake.
[0212] In one embodiment, the infection is a Gram-positive cocci
infection, for example, a Staphylococcus, Enterococcus or
Streptococcus infection. Streptococcus pneumoniae is treated, in
one embodiment, in a patient that has been diagnosed with
community-acquired pneumonia or purulent meningitis. An
Enterococcus infection is treated, in one embodiment, in a patient
that has been diagnosed with a urinary-catheter related infection.
A Staphylococcus infection, e.g., S. aureus is treated in one
embodiment, in a patient that has been diagnosed with mechanical
ventilation-associated pneumonia.
[0213] Over the past few decades, there has been a decrease in the
susceptibility of Gram-positive cocci to antibacterials for the
treatment of infection. See, e.g., Alvarez-Lerma et al. (2006)
Drugs 66, pp. 751-768, incorporated by reference herein in its
entirety for all purposes. As such, in one aspect, the present
invention addresses this need by providing a composition comprising
an effective amount of a compound of Formula (I), Formula (II) or a
pharmaceutically acceptable salt thereof, in a method for treating
a patient in need thereof for a Gram-positive cocci infection that
is resistant to a different antibacterial. For example, in one
embodiment, the Gram-positive cocci infection is a penicillin
resistant or a vancomycin resistant bacterial infection. In a
further embodiment, the resistant bacterial infection is a
methicillin-resistant Staphylococcus infection, e.g.,
methicillin-resistant S. aureus or a methicillin-resistant
Staphylococcus epidermidis infection. In another embodiment, the
resistant bacterial infection is an oxacillin-resistant
Staphylococcus (e.g., S. aureus) infection, a vancomycin-resistant
Enterococcus infection or a penicillin-resistant Streptococcus
(e.g., S. pneumoniae) infection. In yet another embodiment, the
Gram-positive cocci infection is a vancomycin-resistant enterococci
(VRE), methicillin-resistant Staphylococcus aureus (MRSA),
methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin
resistant Enterococcus faecium also resistant to teicoplanin (VRE
Fm Van A), vancomycin resistant Enterococcus faecium sensitive to
teicoplanin (VRE Fm Van B), vancomycin resistant Enterococcus
faecalis also resistant to teicoplanin (VRE Fs Van A), vancomycin
resistant Enterococcus faecalis sensitive to teicoplanin (VRE Fs
Van B), or penicillin-resistant Streptococcus pneumoniae
(PSRP).
[0214] According to one embodiment, a method is provided to treat
an infection due to a Gram-positive bacterium, including, but not
limited to, genera Staphylococcus, Streptococcus, Enlerococcus,
Bacillus, Corynebaclerium, Nocardia, Clostridium, and Listeria. In
one embodiment, the infection is due to a Gram-positive Cocci
bacterium. In a further embodiment, the infection is a pulmonary
infection. In another embodiment, the infection is a Clostridium
difficile infection.
[0215] In even another embodiment, the bacterial infection is
Propionibacterium acnes (skin acne), Eggerthella lenta (bacteremia)
or Peptostreptococcus anaerobius (gynecological infection). In a
further embodiment, the composition administered to the patient in
need thereof comprises a compound of Formula (I) or Formula (II)
wherein R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3 and X is O.
[0216] Staphylococcus is Gram positive non-motile bacteria that
colonizes skin and mucus membranes. Staphylococci are spherical and
occur in microscopic clusters resembling grapes. The natural
habitat of Staphylococcus is nose; it can be isolated in 50% of
normal individuals. 20% of people are skin carriers and 10% of
people harbor Staphylococcus in their intestines. Examples of
Staphylococci infections treatable with the methods and
compositions provided herein, include S. aureus, S. epidermidis, S.
auricularis, S. carnosus, S. haemolyticus, S. hyicus, S.
intermedius, S. lugdunensis, S. saprophytics, S. sciuri, S.
simulans, and S. warneri.
[0217] While there have been about 20 species of Staphylococcus
reported, only Staphylococcus aureus and Staphylococcus epidermis
are known to be significant in their interactions with humans.
[0218] In one embodiment, the Staphylococcus species is resistant
to a penicillin such as methicillin. In a further embodiment, the
Staphylococcus species is methicillin-resistant Staphylococcus
aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis
(MRSE). The Staphylococcus infection, in another embodiment, is a
methicillin-sensitive S. aureus (MSSA) infection, a
vancomycin-intermediate S. aureus (VISA) infection, or a
vancomycin-resistant S. aureus (VRSA) infection.
[0219] S. aureus colonizes mainly the nasal passages, but it may be
found regularly in most anatomical locales, including skin oral
cavity, and gastrointestinal tract. In one embodiment, a S. aureus
infection is treated with one of the methods and/or compositions
provided herein. In a further embodiment, the S. aureus infection
is a methicillin-resistant Staphylococcus aureus (MRSA) infection.
In another embodiment, the S. aureus infection is a S. aureus
(VISA) infection, or a vancomycin-resistant S. aureus (VRSA)
infection.
[0220] The S. aureus infection can be a healthcare associated,
i.e., acquired in a hospital or other healthcare setting, or
community-acquired.
[0221] In one embodiment, the Staphylococcal infection treated with
one of the methods and/or compositions provided herein, causes
endocarditis or septicemia (sepsis). As such, the patient in need
of treatment with one of the methods and/or compositions provided
herein, in one embodiment, is an endocarditis patient. In another
embodiment, the patient is a septicemia (sepsis) patient.
[0222] In one embodiment, the bacterial infection is
erythromycin-resistant (erm.sup.R), vancomycin-intermediate S.
aureus (VISA) heterogenous vancomycin-intermediate S. aureus
(hVISA), S. epidermidis coagulase-negative staphylococci (CoNS),
penicillin-intermediate S. pneumoniae (PISP), or
penicillin-resistant S. pneumoniae (PRSP). In even a further
embodiment, the administering comprises administering via
inhalation. In even a further embodiment, the compound of Formula
(I) or Formula (II) is a compound wherein R.sup.1 is
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.9--CH.sub.3 or
##STR00049##
[0223] Streptococci are Gram-positive, non-motile cocci that divide
in one plane, producing chains of cells. The primary pathogens
include S. pyrogenes and S. pneumoniae but other species can be
opportunistic. S. pyrogenes is the leading cause of bacterial
pharyngitis and tonsillitis. It can also produce sinusitis, otitis,
arthritis, and bone infections. Some strains prefer skin, producing
either superficial (impetigo) or deep (cellulitis) infections.
[0224] S. pneumoniae is the major cause of bacterial pneumonia in
adults, and in one embodiment, an infection due to S. pneumoniae is
treated via one of the methods and/or compositions provided herein.
Its virulence is dictated by its capsule. Toxins produced by
streptococci include: streptolysins (S & O), NADase,
hyaluronidase, streptokinase, DNAses, erythrogenic toxin (which
causes scarlet fever rash by producing damage to blood vessels;
requires that bacterial cells are lysogenized by phage that encodes
toxin). Examples of Streptococcus infections treatable with the
compositions and methods provided herein include, S. agalactiae, S.
anginosus, S. bovis, S. canis, S. constellatus, S. dysgalactiae, S.
equi, S. equinus, S. Mae, S. intermedins, S. mitis, S. mutans, S.
oralis, S. parasanguinis, S. peroris, S. pneumoniae, S. pyogenes,
S. ratti, S. salivarius, S. salivarius ssp. thermophilics, S.
sanguinis, S. sobrinus, S. suis, S. uteris, S. vestibularis, S.
viridans, and S. zooepidemicus.
[0225] The genus Enterococci consists of Gram-positive,
facultatively anaerobic organisms that are ovoid in shape and
appear on smear in short chains, in pairs, or as single cells.
Enterococci are human pathogens that are increasingly resistant to
antimicrobial agents. Examples of Enterococci treatable with the
methods and compositions provided herein are E. avium, E. durans,
E. faecalis, E. faecium, E. gallinarum, and E. solitarius.
[0226] In one embodiment of the methods provided herein, a patient
in need thereof is treated for an Enterococcus faecalis (E.
faecalis) infection. In a further embodiment, the infection is a
pulmonary infection. In another embodiment, a patient in need
thereof is treated for an Enterococcus faecium (E. faecium)
infection. In a further embodiment, the infection is a pulmonary
infection. In one embodiment, a patient in need thereof is treated
for an Enterococcus infection that is resistant or sensitive to
vancomycin or resistant or sensitive to penicillin. In a further
embodiment, the infection is a E. faecalis or E. faecium
infection.
[0227] Bacteria of the genus Bacillus are aerobic,
endospore-forming, Gram-positive rods, and infections due to such
bacteria are treatable via the methods and compositions provided
herein. Bacillus species can be found in soil, air, and water where
they are involved in a range of chemical transformations. In one
embodiment, a method is provided herein to treat a Bacillus
anthracis (B. anthracis) infection with a glycopeptide composition.
Bacillus anthracis, the infection that causes Anthrax, is acquired
via direct contact with infected herbivores or indirectly via their
products. The clinical forms include cutaneous anthrax, from
handling infected material, intestinal anthrax, from eating
infected meat, and pulmonary anthrax from inhaling spore-laden
dust. The route of administration of the glycopeptide will vary
depending on how the patient acquires the B. anthracis infection.
For example, in the case of pulmonary anthrax, the patient, in one
embodiment, is treated via a dry powder inhaler (DPI), nebulizer or
metered dose inhaler (MDI).
[0228] Several other Bacillus species, in particular, B. cereus, B.
subtilis and B. licheniformis, are associated periodically with
bacteremia/septicemia, endocarditis, meningitis, and infections of
wounds, the ears, eyes, respiratory tract, urinary tract, and
gastrointestinal tract, and are therefore treatable with the
methods and compositions provided herein. Examples of pathogenic
Bacillus species whose infection is treatable with the methods and
compositions provided herein, include, but are not limited to, B.
anthracis, B. cereus and B. coagulans.
[0229] Corynebacteria are small, generally non-motile,
Gram-positive, non sporalating, pleomorphic bacilli and infections
due to these bacteria are treatable via the methods provided
herein. Corynebacterium diphtheria is the etiological agent of
diphtheria, an upper respiratory disease mainly affecting children,
and is treatable via the methods provided herein. Examples of other
Corynebacteria species treatable with the methods and compositions
provided herein include Corynebacterium diphtheria, Corynebacterium
pseudotuberculosis, Corynebacterium tenuis, Corynebacterium
striatum, and Corynebacterium minutissimum.
[0230] The bacteria of the genus Nocardia are Gram-positive,
partially acid-fast rods, which grow slowly in branching chains
resembling fungal hyphae. Three species cause nearly all human
infections: N. asteroides, N. brasiliensis, and N. caviae, and
patients with such infections can be treated with the compositions
and methods provided herein. Infection is by inhalation of airborne
bacilli from an environmental source (soil or organic material).
Other Nocardial species treatable with the methods provided herein
include N. aerocolonigenes, N. africana, N. argentinensis, N.
asteroides, N. blackwellu, N. brasiliensis, N. brevicalena, N.
cornea, N. caviae, N. cerradoensis, N. corallina, N.
cyriacigeorgica, N. dassonvillei, N. elegans, N. farcinica, N.
nigiitansis, N. nova, N. opaca, N. otitidis-cavarium, N.
paucivorans, N. pseudobrasiliensis, N. rubra, N. transvelencesis,
N. unif ormis, N. vaccinii, and N. veterana.
[0231] Clostridia are spore-forming, Gram-positive anaerobes, and
infections due to such bacteria are treatable via the methods and
compositions provided herein. In one embodiment, one of the methods
provided herein are used to treat a Clostridium tetani (C. tetani)
infection, the etiological agent of tetanus. In another embodiment,
one of the methods provided herein is used to treat a Clostridium
botidinum (C. botidinum) infection, the etiological agent of
botulism. In yet another embodiment, one of the methods provided
herein is used to treat a C. perfringens infection, one of the
etiological agents of gas gangrene. Other Clostridium species
treatable with the methods of the present invention, include, C.
difficile, C. perfringens, and/or C. sordelii. In one embodiment,
the infection to be treated is a C. difficile infection.
[0232] Listeria are non spore-forming, nonbranching Gram-positive
rods that occur individually or form short chains. Listeria
monocytogenes (L. monocytogenes) is the causative agent of
listeriosis, and in one embodiment, a patient infected with L.
monocytogenes is treated with one of the methods and compositions
provided herein. Examples of Listeria species treatable with the
methods and compositions provided herein, include L. grayi, L.
innocua, L. ivanovii, L. monocytogenes, L. seeligeri, L. murrayi,
and L. welshimeri.
[0233] The bacterial infection in one embodiment, is a respiratory
tract infection. In a further embodiment, the infection is a
resistant bacterial infection, for example, one of the infections
provided above. The patient treatable by the methods provided
herein, in one embodiment, has been diagnosed with a
community-acquired respiratory tract infection, e.g., pneumonia. In
one embodiment, the bacterial infection treated in the pneumonia
patient is a S. pneumoniae infection. In another embodiment, the
bacterial infection treated in the pneumonia patient is Mycoplasma
pneumonia or a Legionella species. In another embodiment, the
bacterial infection in the pneumonia patient is penicillin
resistant, e.g., penicillin-resistant S. pneumoniae.
[0234] The bacterial infection, in one embodiment, is a hospital
acquired infection (HAI), or acquired in another health care
facility, e.g., a nursing home, rehabilitation facility, outpatient
clinic, etc. Such infections are also referred to as nosocomial
infections. In a further embodiment, the infection is a respiratory
tract infection or a skin infection. In one embodiment, the HAI is
pneumonia. In a further embodiment, the pneumonia is due to S.
aureus, e.g., MRSA.
[0235] The inhalation delivery device employed in embodiments of
the methods provided herein can be a nebulizer, dry powder inhaler
(DPI), or a metered dose inhaler (MDI), or any other suitable
inhalation delivery device known to one of ordinary skill in the
art. The device can contain and be used to deliver a single dose of
the composition or the device can contain and be used to deliver
multi-doses of the composition of the present invention.
[0236] According to one embodiment, a dry powder particulate
composition is delivered to a patient in need thereof via a metered
dose inhaler (MDI), dry powder inhaler (DPI), atomizer, nebulizer
or liquid dose instillation (LDI) technique to provide for
glycopeptide delivery. With respect to inhalation therapies, those
skilled in the art will appreciate that where a hollow and porous
microparticle composition is employed, the composition is
particularly amenable for delivery via a DPI. Conventional DPIs
comprise powdered formulations and devices where a predetermined
dose of medicament, either alone or in a blend with lactose carrier
particles, is delivered as an aerosol of dry powder for
inhalation.
[0237] The medicament is formulated in a way such that it readily
disperses into discrete particles with an MMD between 0.5 to 20
.mu.m, for example from 0.5-5 .mu.m, and are further characterized
by an aerosol particle size distribution less than about 10 .mu.m
mass median aerodynamic diameter (MMAD), and in some embodiments,
less than 5.0 .mu.m. The MMAD of the powders will
characteristically range from about 0.5-10 .mu.m, from about
0.5-5.0 .mu.m, or from about 0.5-4.0 .mu.m.
[0238] The powder is actuated either by inspiration or by some
external delivery force, such as pressurized air. Examples of DPIs
suitable for administration of the particulate compositions of the
present invention are disclosed in U.S. Pat. Nos. 5,740,794,
5,785,049, 5,673,686, and 4,995,385 and PCT application Nos.
00/72904, 00/21594, and 01/00263, the disclosure of each of which
is incorporated by reference in their entireties for all purposes.
DPI formulations are typically packaged in single dose units such
as those disclosed in the aforementioned patents or they employ
reservoir systems capable of metering multiple doses with manual
transfer of the dose to the device.
[0239] The compositions disclosed herein may also be administered
to the nasal or pulmonary air passages of a patient via
aerosolization, such as with a metered dose inhaler (MDI). Breath
activated MDIs are also compatible with the methods provided
herein.
[0240] Along with the aforementioned embodiments, the compositions
disclosed herein may be delivered to a patient in need thereof via
a nebulizer, e.g., a nebulizer disclosed in PCT WO 99/16420, the
disclosure of which is hereby incorporated in its entirety by
reference, in order to provide an aerosolized medicament that may
be administered to the pulmonary air passages of the patient. A
nebulizer type inhalation delivery device can contain the
compositions of the present invention as a solution, usually
aqueous, or a suspension. For example, the prostacyclin compound or
composition can be suspended in saline and loaded into the
inhalation delivery device. In generating the nebulized spray of
the compositions for inhalation, the nebulizer delivery device may
be driven ultrasonically, by compressed air, by other gases,
electronically or mechanically (e.g., vibrating mesh or aperture
plate). Vibrating mesh nebulizers generate fine particle, low
velocity aerosol, and nebulize therapeutic solutions and
suspensions at a faster rate than conventional jet or ultrasonic
nebulizers. Accordingly, the duration of treatment can be shortened
with a vibrating mesh nebulizer, as compared to a jet or ultrasonic
nebulizer. Vibrating mesh nebulizers amenable for use with the
methods described herein include the Philips Respironics
I-Neb.RTM., the Omron MicroAir, the Nektar Aeroneb.RTM., and the
Pari eFlow.RTM..
[0241] The nebulizer may be portable and hand held in design, and
may be equipped with a self contained electrical unit. The
nebulizer device may comprise a nozzle that has two coincident
outlet channels of defined aperture size through which the liquid
formulation can be accelerated. This results in impaction of the
two streams and atomization of the formulation. The nebulizer may
use a mechanical actuator to force the liquid formulation through a
multiorifice nozzle of defined aperture size(s) to produce an
aerosol of the formulation for inhalation. In the design of single
dose nebulizers, blister packs containing single doses of the
formulation may be employed.
[0242] In the present invention, the nebulizer may be employed to
ensure the sizing of particles is optimal for positioning of the
particle within, for example, the pulmonary membrane.
[0243] Upon nebulization, the nebulized composition (also referred
to as "aerosolized composition") is in the form of aerosolized
particles. The aerosolized composition can be characterized by the
particle size of the aerosol, for example, by measuring the "mass
median aerodynamic diameter" or "fine particle fraction" associated
with the aerosolized composition. "Mass median aerodynamic
diameter" or "MMAD" is normalized regarding the aerodynamic
separation of aqua aerosol droplets and is determined by impactor
measurements, e.g., the Andersen Cascade Impactor (ACI) or the Next
Generation Impactor (NGI). The gas flow rate, in one embodiment, is
8 Liter per minute for the ACI and 15 liters per minute for the
NGI.
[0244] "Geometric standard deviation" or "GSD" is a measure of the
spread of an aerodynamic particle size distribution. Low GSDs
characterize a narrow droplet size distribution (homogeneously
sized droplets), which is advantageous for targeting aerosol to the
respiratory system. The average droplet size of the nebulized
composition provided herein, in one embodiment is less than 5 .mu.m
or about 1 .mu.m to about 5 .mu.m, and has a GSD in a range of 1.0
to 2.2, or about 1.0 to about 2.2, or 1.5 to 2.2, or about 1.5 to
about 2.2.
[0245] "Fine particle fraction" or "FPF," as used herein, refers to
the fraction of the aerosol having a particle size less than 5
.mu.m in diameter, as measured by cascade impaction. FPF is usually
expressed as a percentage.
[0246] In one embodiment, the mass median aerodynamic diameter
(MMAD) of the nebulized composition is about 1 .mu.m to about 5
.mu.m, or about 1 .mu.m to about 4 .mu.m, or about 1 .mu.m to about
3 .mu.m or about 1 .mu.m to about 2 .mu.m, as measured by the
Anderson Cascade Impactor (ACI) or Next Generation Impactor (NGI).
In another embodiment, the MMAD of the nebulized composition is
about 5 .mu.m or less, about 4 .mu.m or less, about 3 .mu.m or
less, about 2 .mu.m or less, or about 1 .mu.m or less, as measured
by cascade impaction, for example, by the ACI or NGI.
[0247] In one embodiment, the MMAD of the aerosol of the
pharmaceutical composition is less than about 4.9 .mu.m, less than
about 4.5 .mu.m, less than about 4.3 .mu.m, less than about 4.2
.mu.m, less than about 4.1 .mu.m, less than about 4.0 .mu.m or less
than about 3.5 .mu.m, as measured by cascade impaction.
[0248] In one embodiment, the MMAD of the aerosol of the
pharmaceutical composition is about 1.0 .mu.m to about 5.0 .mu.m,
about 2.0 .mu.m to about 4.5 .mu.m, about 2.5 .mu.m to about 4.0
.mu.m, about 3.0 .mu.m to about 4.0 .mu.m or about 3.5 .mu.m to
about 4.5 .mu.m, as measured by cascade impaction (e.g., by the ACI
or NGI).
[0249] In one embodiment, the FPF of the aerosolized composition is
greater than or equal to about 50%, as measured by the ACI or NGI,
greater than or equal to about 60%, as measured by the ACI or NGI
or greater than or equal to about 70%, as measured by the ACI or
NGI. In another embodiment, the FPF of the aerosolized composition
is about 50% to about 80%, or about 50% to about 70% or about 50%
to about 60%, as measured by the NGI or ACI.
[0250] In one embodiment, a metered dose inhalator (MDI) is
employed as the inhalation delivery device for the compositions of
the present invention. In a further embodiment, the prostacyclin
compound is suspended in a propellant (e.g., hydrofluorocarbon)
prior to loading into the MDI. The basic structure of the MDI
comprises a metering valve, an actuator and a container. A
propellant is used to discharge the formulation from the device.
The composition may consist of particles of a defined size
suspended in the pressurized propellant(s) liquid, or the
composition can be in a solution or suspension of pressurized
liquid propellant(s). The propellants used are primarily
atmospheric friendly hydroflourocarbons (HFCs) such as 134a and
227. The device of the inhalation system may deliver a single dose
via, e.g., a blister pack, or it may be multi dose in design. The
pressurized metered dose inhalator of the inhalation system can be
breath actuated to deliver an accurate dose of the lipid-containing
formulation. To insure accuracy of dosing, the delivery of the
formulation may be programmed via a microprocessor to occur at a
certain point in the inhalation cycle. The MDI may be portable and
hand held.
[0251] In one embodiment, a dry powder inhaler (DPI) is employed as
the inhalation delivery device for the compositions of the present
invention.
[0252] In one embodiment, the DPI generates particles having an
MMAD of from about 1 .mu.m to about 10 .mu.m, or about 1 .mu.m to
about 9 .mu.m, or about 1 .mu.m to about 8 .mu.m, or about 1 .mu.m
to about 7 .mu.m, or about 1 .mu.m to about 6 .mu.m, or about 1
.mu.m to about 5 .mu.m, or about 1 .mu.m to about 4 .mu.m, or about
1 .mu.m to about 3 .mu.m, or about 1 .mu.m to about 2 .mu.m in
diameter, as measured by the NGI or AC. In another embodiment, the
DPI generates particles having an MMAD of from about 1 .mu.m to
about 10 .mu.m, or about 2 .mu.m to about 10 .mu.m, or about 3
.mu.m to about 10 .mu.m, or about 4 .mu.m to about 10 .mu.m, or
about 5 .mu.m to about 10 .mu.m, or about 6 .mu.m to about 10
.mu.m, or about 7 .mu.m to about 10 .mu.m, or about 8 .mu.m to
about 10 .mu.m, or about 9 .mu.m to about 10 .mu.m, as measured by
the NGI or ACI.
[0253] In one embodiment, the MMAD of the particles generated by
the DPI is about 1 .mu.m or less, about 9 .mu.m or less, about 8
.mu.m or less, about 7 .mu.m or less, 6 .mu.m or less, 5 .mu.m or
less, about 4 .mu.m or less, about 3 .mu.m or less, about 2 .mu.m
or less, or about 1 .mu.m or less, as measured by the NGI or
ACI.
[0254] In one embodiment, each administration comprises 1 to 5
doses (puffs) from a DPI, for example 1 dose (1 puff), 2 dose (2
puffs), 3 doses (3 puffs), 4 doses (4 puffs) or 5 doses (5 puffs).
The DPI, in one embodiment, is small and transportable by the
patient.
[0255] In one embodiment, the MMAD of the particles generated by
the DPI is less than about 9.9 .mu.m, less than about 9.5 .mu.m,
less than about 9.3 .mu.m, less than about 9.2 .mu.m, less than
about 9.1 .mu.m, less than about 9.0 .mu.m, less than about 8.5
.mu.m, less than about 8.3 .mu.m, less than about 8.2 .mu.m, less
than about 8.1 .mu.m, less than about 8.0 .mu.m, less than about
7.5 .mu.m, less than about 7.3 .mu.m, less than about 7.2 .mu.m,
less than about 7.1 .mu.m, less than about 7.0 .mu.m, less than
about 6.5 .mu.m, less than about 6.3 .mu.m, less than about 6.2
.mu.m, less than about 6.1 .mu.m, less than about 6.0 .mu.m, less
than about 5.5 .mu.m, less than about 5.3 .mu.m, less than about
5.2 .mu.m, less than about 5.1 .mu.m, less than about 5.0 .mu.m,
less than about 4.5 .mu.m, less than about 4.3 .mu.m, less than
about 4.2 .mu.m, less than about 4.1 .mu.m, less than about 4.0
.mu.m or less than about 3.5 .mu.m, as measured by the NGI or
ACI.
[0256] In one embodiment, the MMAD of the particles generated by
the DPI is about 1.0 .mu.m to about 10.0 .mu.m, about 2.0 .mu.m to
about 9.5 .mu.m, about 2.5 .mu.m to about 9.0 .mu.m, about 3.0
.mu.m to about 9.0 .mu.m, about 3.5 .mu.m to about 8.5 .mu.m or
about 4.0 .mu.m to about 8.0 .mu.m.
[0257] In one embodiment, the FPF of the prostacyclin particulate
composition generated by the DPI is greater than or equal to about
40%, as measured by the ACI or NGI, greater than or equal to about
50%, as measured by the ACI or NGI, greater than or equal to about
60%, as measured by the ACI or NGI, or greater than or equal to
about 70%, as measured by the ACI or NGI. In another embodiment,
the FPF of the aerosolized composition is about 40% to about 70%,
or about 50% to about 70% or about 40% to about 60%, as measured by
the NGI or ACI.
EXAMPLES
[0258] The present invention is further illustrated by reference to
the following Examples. However, it should be noted that these
Examples, like the embodiments described above, are illustrative
and are not to be construed as restricting the scope of the
invention in any way.
Example 1--Synthesis of Glycopeptide Derivative Via Reductive
Amination
[0259] Glycopeptide derivatives were prepared as follows. The
synthesis scheme is also provided at FIG. 1.
[0260] To a reactor vessel equipped with temperature control and
agitation was added anhydrous DMF and DIPEA. The resulting solution
was heated to 65.degree. C. with agitation and Vancomycin HCl or
telavancin HCl was added slowly in portions. Heating was continued
until all of vancomycin HCl or telavancin HCl had dissolved (5-10
min).
[0261] The beige colored solution was allowed to cool after which a
solution of the desired aldehyde dissolved in DMF was added over
5-10 min. The resulting solution was allowed to stir overnight,
typically producing a clear red-yellow solution. MeOH and TFA were
introduced and stirring was further continued for at least 2 h. At
the end of the stirring period, the imine forming reaction mixture
was analyzed by HPLC which was characteristically typical. Borane
tert-butylamine complex was added in portions and the reaction
mixture was stirred at ambient temperature for an additional 2 h
after which an in-process HPLC analysis of the reaction mixture
indicated a near quantitative reduction of the intermediate imine
group. After the reaction was over, the reaction mixture was
purified using reverse phase C18 column chromatography (Phenomenex
Luna 10 uM PREP C18(2) 250.times.21.2 mm column) using gradients of
water and acetonitrile, each containing 0.1% (v/v) of TFA.
Fractions were evaluated using HPLC and then pertinent fractions
containing the target product were pooled together for the
isolation of the product via lyophilization. Typical products were
isolated as fluffy white solids. The procedure is shown below in
Scheme 1 with vancomycin HCl as a representative starting
compound.
Example 2--Synthesis of Vancomycin Derivative RV40 (Compound
40)
[0262] General Synthesis:
[0263] To a temperature controlled reactor vessel equipped with an
overhead stirrer was added a suitable reaction solvent (DMF or DMA)
and an organic base (typically DIPEA). The temperature was
increased to approximately 60.degree. C. and vancomycin HCl was
added. The warm reaction mixture was agitated at elevated
temperature for approximately 20 minutes at which point all
vancomycin HCl had dissolved and the reaction mixture was returned
to room temperature. To the reaction mixture was then added
9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate
(N-Fmoc-N-decylaminoacetaldehyde) dissolved in a suitable reaction
solvent (DMF or DMA). The reaction mixture was agitated with an
overhead stirrer overnight at which point a suitable reducing
agent, acid catalyst (e.g., TFA), and a protic solvent (e.g., MeOH)
were added. The reaction mixture was agitated by an overhead
stirrer at room temperature for approximately two hours at which
point solvent volume was reduced by half via rotary evaporation. To
the concentrated reaction mixture was then added an organic base to
remove the FMOC protecting group and yield crude product (Compound
40, also referred to as "RV40", see also Table 1). Solvent was then
evaporated by rotary evaporation and the crude material was
dry-packed using C18 silica and purified via reverse phase C18
flash chromatography to isolate product with >97% purity.
Solvent was removed from the purified material using a combination
of techniques including rotary evaporation, lyophilization, and
spray drying to yield product (Compound 40 or RV40) as a white
powder, typically in 40-75% overall yield. Suitable solvents
include N,N-Dimethylacetamide, N,N-Dimethylformamide,
N,N-Dimethylacetamide or a combination thereof. Suitable organic
bases include N,N-diisopropylethylamine or trimethylamine. Suitable
reducing agents include NaBH.sub.4, NaBH.sub.3CN, Borane-pyridine
complex, or Borane-.sup.tertbutylamine complex. Suitable organic
bases for FMOC deprotection include piperidine, methylamine, and
.sup.tertbutylamine.
[0264] Salt Forms:
[0265] Control over the salt form and associated counter-ions for
alkyl-vancomycin derivatives was managed by altering the acid
species used during flash chromatography. Lactate, Acetate, HCl,
and TFA salts have been prepared. To isolate free base derivatives
of alkyl vancomycin derivatives the pH of purified material was
adjusted between 7-8 to induce precipitation; purified free base
material was then collected by filtration, rotary evaporation,
lyophilization, or spray drying.
[0266] One synthetic scheme for arriving at compound 40 (RV40) is
provided at FIG. 2 (top). Here, a jacketed 1 L reactor vessel was
equipped with an overhead stirrer and connected to a recirculating
water bath calibrated to 65.degree. C. To the warm reaction vessel
was added N,N-Dimethylformamide (75 mL) and DIPEA (640 .mu.L, 3.7
mmol, 2.0 equivalents). Solvent was allowed to stir for 20 minutes
and warmed to 65.degree. C., at which point vancomycin HCl (2.70 g,
1.8 mmol, 1.00 equivalents) was added to the reaction mixture. Once
all vancomycin HCl had dissolved the temperature was reduced to
25.degree. C. and 9H-fluoren-9-ylmethyl
N-decyl-N-(2-oxoethyl)carbamate (890 mg, 2.1 mmol, 1.15
equivalents) dissolved in N,N-Dimethylformamide (20 mL) was added.
The reaction mixture was allowed to stir at 25.degree. C. for 18
hrs. To the reaction mixture was then added NaBH.sub.3CN (330 mg,
5.3 mmol, 2.89 equivalents), MeOH (75 mL), and TFA (3.0 mL, 5.5
mmol, 3.00 equivalents). The reaction mixture was allowed to stir
for 3 hr at RT at which point solvent volume was reduced by half
via rotary evaporation. To the concentrated reaction mixture was
then added piperidine (360 .mu.L, 3.7 mmol, 2.00 equivalents) with
stirring. Reaction progress was monitored by HPLC. Once HPLC
analysis indicated complete deprotection, solvent was removed from
the reaction mixture under reduced pressure to yield crude product
(Compound 40) as an off-white solid. The crude material was
dry-packed using C18 silica and purified via reverse phase C18
flash chromatography to isolate product with >97% purity.
Example 3--Synthesis of Vancomycin Derivative RV40 (Compound
40)
[0267] General Synthesis:
[0268] To a temperature controlled reactor vessel equipped with an
overhead stirrer was added a suitable reaction solvent (DMF or DMA)
and an organic base (typically DIPEA). The temperature was
increased to approximately 60.degree. C. and vancomycin HCl was
added. The warm reaction mixture was agitated at elevated
temperature for approximately 20 minutes at which point all
vancomycin HCl had dissolved and the reaction mixture was returned
to room temperature. To the reaction mixture was then added
9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate
(N-Fmoc-N-decylaminoacetaldehyde) dissolved in a suitable reaction
solvent (DMF or DMA). The reaction mixture was agitated with an
overhead stirrer overnight. To the reaction mixture was added a
protic solvent (e.g., MeOH) and an acid catalyst (e.g., TFA) and
the reaction mixture was allowed to stir for 15 minutes prior to
addition of a suitable reducing agent (e.g., borane tertbutylamine
complex).
[0269] The reaction mixture was agitated by an overhead stirrer at
room temperature for approximately two hours at which point an
organic base (e.g., tertbutylamine) was added to remove the FMOC
protecting group. The temperature was increased to 55.degree. C.
and the mixture was allowed to stir for 2 h. Solvent was then
evaporated by rotary evaporation and the crude material was
dry-packed using C18 silica and purified via reverse phase C18
flash chromatography to isolate product with >97% purity.
Solvent was removed from the purified material using a combination
of techniques including rotary evaporation, lyophilization, and
spray drying to yield product (RV40) as a white powder, typically
in 75% overall yield. Suitable solvents include
N,N-Dimethylacetamide, N,N-Dimethylformamide, N,N-Dimethylacetamide
or a combination thereof. Suitable organic bases include
N,N-diisopropylethylamine or trimethylamine. Suitable reducing
agents include NaBH.sub.4, NaBH.sub.3CN, Borane-pyridine complex,
or Borane-.sup.tertbutylamine complex. Suitable organic bases for
FMOC deprotection include piperidine, methylamine, and
.sup.tertbutylamine.
[0270] Salt Forms:
[0271] Control over the salt form and associated counter-ions for
alkyl-vancomycin derivatives was managed by altering the acid
species used during flash chromatography. Lactate, Acetate, HCl,
and TFA salts have been prepared. To isolate free base derivatives
of the vancomycin derivative, the pH of purified material was
adjusted between 7-8 to induce precipitation; purified free base
material was then collected by filtration, rotary evaporation,
lyophilization, or spray drying.
[0272] One synthetic scheme for arriving at compound 40 (RV40) is
provided at FIG. 2, bottom, and is described in further detail
below. To a 400 mL reactor vessel equipped with an overhead
stirrer, a thermometer, and a pH meter was added DMF (50 mL) and
DIPEA (1.17 mL, 6.73 mmol, 2.00 equivalents). The reaction mixture
was heated to 55.degree. C. at which point vancomycin HCl (5.0 g,
3.37 mmol, 1.0 equivalents) were added. The mixture was stirred at
55.degree. C. for about 15 min., or until all of the vancomycin
dissolved, at which point the temperature was reduced to 25.degree.
C. To the reaction mixture was added a solution of
N-Fmoc-decylaminoacetaldehyde (1.63 g, 3.87 mmol, 1.15 equivalents)
dissolved in DMF (16.32 mL). The reaction mixture was allowed to
stir at 25.degree. C. for 18 h. To the reaction mixture was added
MeOH (14.0 mL) and TFA (1.03 mL, 13.46 mmol, 4.00 equivalent) and
the mixture was allowed to stir at 25.degree. C. for 15 min., at
which point Borane tert-butylamine complex (294 mg, 3.37 mmol, 1.0
equivalents) were added. The reaction mixture was allowed to stir
at 25.degree. C. for 2 h, at which point tert-butylamine (4.24 mL,
40.38 mmol, 12.0 equivalents) was added, and the temperature was
increased to 55.degree. C. The reaction mixture was allowed to stir
at 55.degree. C. for 2 h. C18 functionalized silica gel was then
added to the reaction mixture and solvent was removed under reduced
pressure. The dry-packed material was purified using reverse phase
C18 flash chromatography (Biotage.RTM. SNAP-KP-C18-HS column).
Example 4--Preparation of Monolactate Salt of RV40
[0273] A 3 L three-necked flask was equipped with a mechanical
stirrer, a nitrogen inlet, a condenser and an addition funnel.
Anhydrous DMF (900 mL) and DIPEA (21.06 mL, 0.12 mol) were charged.
The resulting solution was heated to 55-60.degree. C. and
vancomycin HCl (90.0 g, 0.06 mol) was added in portions. Heating
was continued until all of vancomycin HCl had dissolved (15-30
min). The beige colored solution was allowed to cool to ambient
temperature after which a solution of
N--FMOC--N-decylaminoacetaldehyde (29.34 g, 0.069 mol) and DMF
(293.4 mL) was added via the addition funnel over 5-10 min. The
resulting solution was allowed to stir overnight to give a clear
red-yellow solution. An in-process HPLC analysis of the reaction
mixture at the end of the stirring period was typical. MeOH (252
mL) and TFA (18.54 mL, 0.24 mol) were introduced and stirring was
further continued for at least 2 h. At the end of the stirring
period, the imine forming reaction mixture was analyzed by HPLC
which was characteristically typical. Borane tert-butylamine
complex (5.28 g, 0.61 mol) was added in portions and the reaction
mixture was stirred at ambient temperature for an additional 2 h
after which an in-process HPLC analysis of the reaction mixture
indicated a near quantitative reduction of the intermediate imine
group with less than 3% of the unreacted vancomycin remaining.
Tert-Butylamine (76.32 mL, 0.73 mol) was added via the addition
funnel and the resulting reaction was heated to 55.degree. C. The
stirring was continued at 55.degree. C. and progress of the FMOC
group deprotection reaction was monitored by HPLC.
[0274] After the reaction was over (about 2 h), heating was removed
and C18 silica gel (C-18 (Carbon 17%) 60A, 40-63 .mu.m, 270 g) was
added and the mixture was concentrated on a rotavap at 52.degree.
C./15 torr until free-flowing solids of C-18 silica adsorbed crude
RV40 were obtained (3-7 h). The C-18 silica adsorbed crude RV40
(compound 40) was divided into three equal parts and each part-lot
was purified by means of Biotage chromatography on a Biotage SNAP
ULTRA C18 1850 g Cartridge (Biotage HP-Sphere C18 25 .mu.m) using
gradients of water and acetonitrile, each containing 0.1% (v/v) of
an 85% L-(+)-Lactic acid solution in water, and collecting 240 mL
fractions. Each part lot required 50 liters of eluents. After each
Biotage run, the C-18 column was conditioned for the next run by
running through 60 liters of methanol. Fractions were evaluated
using HPLC and then pertinent fractions containing RV40 were pooled
together for the isolation of the product via lyophilization.
[0275] Lyophilization provided RV40 lactate salt as a white solid.
The lyophilized RV40 lactate at this point typically contained
excess lactic acid and also contained lactic acid related
impurities arising from its self-condensation reactions. The
isolated RV40 lactate from this run was combined with two other
batches of similarly isolated lyophilized RV40 lactate to form a
composite batch of RV40 lactate totaling 105 g (lot 637-140A). The
excess lactic acid and its related impurities present in the above
composite batch of RV40 lactate were removed via trituration with
THF and then the final triturated material (RV40 mono lactate
salts) was subjected to re-lyophilization to remove the trapped
residual THF; both steps are described below.
[0276] A 5 L three-necked flask was equipped with a mechanical
stirrer, a nitrogen inlet, and a condenser. RV40 lactate salts (105
g) and inhibitor-free anhydrous THF (1 L) were charged. The
resulting mixture was stirred under nitrogen. After stirring
overnight, the resulting mixture was filtered using a medium frit
Buchner filter funnel. The filtered cake was washed with THF (250
mL). The filtered cake was dried on the filter funnel by pulling
vacuum under nitrogen. After drying for 5 h the cake was analyzed
by 1H NMR for the residual levels of lactic acid which were
measured as 3.5 equivalents. The process of trituration with THF
was repeated two more times after which the isolated product was
determined to contain estimated 1 equivalent of lactic acid/lactate
and THF. The isolated material was re-lyophilized to remove the
residual THF as follows:
[0277] The above THF-triturated material was first dissolved in
aqueous acetonitrile (3:1 water:acetonitrile) at a concentration of
8.1 mL per gram and then lyophilized in batches using multiple
flasks. Typically, about 10-12 grams (maximum) of the material was
charged into each 2 L flask followed by aqueous acetonitrile (125
mL) to prepare a solution which was lyophilized. At the end of the
lyophilization and drying, product was analyzed by NMR for THF
levels to determine whether lyophilization was needed to be
repeated. In the current case, contents of each flask were
lyophilized once more (after re-dissolving in 125 mL of aqueous
acetonitrile) when no remaining THF could be detected by NMR. The
final lyophilized product at this point contained an average of 0.8
wt. % acetonitrile as estimated by NMR. The contents of each flask
were pulverized into smaller particles using spatula and then
placed on high vacuum pumps to remove acetonitrile. No further
reduction in acetonitrile levels was observed after 56-60 h on the
vacuum pumps. Contents of each flasks were combined to provide a
total of 74.3 g (35.5% yield based on the total conversion of 180 g
of vancomycin HCl) of a composite batch of RV40 mono lactate salts
as white solid which was found to be >99 area % pure by HPLC and
contained one equivalent of lactate as determined by 1HNMR
(DMSO-d6) analysis. The water content in the product was found at
5.6 wt. % as determined by K--F analysis.
Example 5--Synthesis of Vancomycin Derivative RV79
[0278] The synthesis scheme for arriving at the glycopeptide
derivative RV79 is described below, and also provided at FIG. 3. To
a 40 mL vial equipped a stir bar was added anhydrous DMF (20 mL)
and DIPEA (0.20 mL). The resulting solution was heated to
65.degree. C. on an incubated shaker and vancomycin HCl (700 mg,
0.462 mmol) was added slowly in portions. Heating was continued
until all of vancomycin HCl had dissolved (5-10 min). The beige
colored solution was allowed to cool to room temperature at which
point 4'-Chloro-biphenyl-4-carbaldehyde (0.1 g, 0.462 mmol) was
added to the reaction mixture. The reaction mixture was allowed to
stir overnight. MeOH (1.5 mL) and TFA (0.14 mL, 1.8 mmol) were
introduced and stirring was further continued for at least 2 h.
Borane tert-butylamine complex (40 mg, 0.46 mmol) was added in
portions and the reaction mixture was stirred at ambient
temperature for an additional 2 h. After the reaction completed,
the reaction mixture is purified using reverse phase C18 column
chromatography (Phenomenex Luna 10 uM PREP C18(2) 250.times.21.2 mm
column) using gradients of water and acetonitrile, each containing
0.1% (v/v) of TFA. Fractions were evaluated using HPLC and then
pertinent fractions containing RV79 were pooled together for
isolation of the product via lyophilization. The target compound,
RV79 (81.2 mg, 0.05 mmol, 10% overall yield), was obtained as a
white solid in >97% purity (by HPLC). The reaction scheme is
shown at FIG. 3.
Example 6--Synthesis of Alkyl-Vancomycin Derivatives
[0279] Alkyl vancomycin derivatives were prepared according to the
procedure disclosed in Nagarajan et al., with slight modifications
(Nagarajan et al. (1989). The Journal of Antibiotics 42(1), pp.
63-72, incorporated by reference herein in its entirety for all
purposes).
[0280] The general synthesis for alkyl vancomycin derivatives is
shown in FIG. 4. Briefly, to a temperature controlled reactor
vessel was added vancomycin HCl, a suitable reaction solvent, an
organic base, and the appropriate aldehyde. The reaction mixture
was agitated with an overhead stirrer at elevated temperature and
reaction progress was monitored via HPLC looking at consumption of
vancomycin and imine formation. To the reactor vessel was then
added a suitable reducing agent, acid catalyst (TFA), and a protic
solvent (MeOH). The reaction mixture was agitated by an overhead
stirrer for approximately 2 h. The reaction mixture was then either
poured into water to induce precipitation of the alkyl vancomycin
derivative, or solvent was removed under reduced pressure.
[0281] The crude material was dissolved in a suitable mobile phase
and purified via preparative chromatography. Solvent was removed
from the purified material using a combination of techniques
including rotary evaporation, lyophilization, and spray drying to
yield the vancomycin alkyl derivative as a white powder, typically
in 40-60% overall yield. Suitable solvents include either
N,N-Dimethylformamide or N,N-Dimethylacetamide. Suitable organic
bases include N,N-diisopropylethylamine or trimethylamine. Suitable
reducing agents include NaBH.sub.4, NaBH.sub.3CN, Borane-pyridine
complex, or Borane-.sup.tertbutylamine complex.
[0282] Synthesis of N-Decyl Vancomycin (Compound 5):
[0283] The synthetic route to Compound 5, decyl vancomycin, is
provided at FIG. 5. A jacketed 1 L reactor vessel was equipped with
an overhead stirrer and connected to a recirculating water bath
calibrated to 65.degree. C. To the warm reaction vessel was added
N,N-Dimethylacetamide (160 mL) and DIPEA (6.8 mL, 39.0 mmol, 2.92
equivalents), the solvents were allowed to stir for approximately
20 minutes. Once the solvent temperature had reached 65.degree. C.,
vancomycin HCl (19.8 g, 13.38 mmol, 1.00 equivalents) was added to
the reactor vessel. To the reactor vessel was added 1-Decanal (2.54
mL, 13.50 mmol, 1.01 equivalents) and the reaction mixture was
allowed to stir for 2 hours at 65 C.degree.. To the reaction
mixture was then added NaBH.sub.3CN (2.31 g, 36.77 mmol, 2.75
equivalents), MeOH (100 mL), and TFA (3.1 mL, 40.48 mmol, 3.03
equivalents). The reaction mixture was allowed to stir for 2 hours
while cooling to room temperature. The reaction mixture was then
poured into acetonitrile (1 L) to induce precipitation. The decant
was removed and the remaining off-white slurry was centrifuged and
decanted to remove excess solvent and produce a slurry containing
N-decyl vancomycin and unreacted vancomycin. Crude N-decyl
vancomycin as dissolved in 30:70 acetonitrile:H.sub.2O with 0.05%
HOAc and purified using reverse phase C18 preparative HPLC. Pure
fractions were subjected to rotary evaporation to remove organics
and the flash-frozen and lyophilized to isolate purified N-decyl
vancomycin as a fluffy white powder.
Example 7--Synthesis of Chloroeremomycin Derivative RV79
[0284] To a 20 mL scintillation vial equipped with a stir bar was
added chloroeremomycin and a solution of copper (II) acetate in
MeOH. The reaction mixture was stirred at room temperature until
the chloroeremomycin had dissolved. To the reaction mixture was
then added the appropriate aldehyde and sodium cyanoborohydride as
a 1M solution in THF. The reaction mixture was transferred to an
incubated shaker set to 45.degree. C. and reaction progress was
monitored by HPLC. In some instances, it was necessary to add an
additional aliquot of aldehyde reagent. The reaction mixture was
allowed to shake overnight at 45.degree. C. The reaction mixture
was cooled to RT and sodium borohydride was added to convert
residual aldehyde reagent to the corresponding alcohol. The pH was
adjusted to between 7-8 using either acetic acid or 0.1M NaOH and
volatile solvents were removed by blowing N.sub.2(g) with gentle
heat. To the reaction mixture was added acetonitrile to precipitate
the crude product as an off-white solid. The reaction mixture was
centrifuged and the liquid was decanted. The solid was dissolved in
10% MeCN/H.sub.2O containing 0.1% phosphoric acid to decomplex the
copper at which point the solution briefly turned purple and then
took on a yellow tinge. Preparatory HPLC was used to purify final
product and LCMS was used to confirm compound identity and
purity.
[0285] A diagram of the reaction is provided at FIG. 1, bottom.
Example 8--C-terminus Modification of Glyconentide Derivative
[0286] To a round bottom flask equipped with a stir bar was added a
LPGC derivative, a 1:1 solution of DMF:DMSO, and DIPEA. To the
reaction mixture was then added HBTU and the appropriate amine
(e.g., 3-(dimethylamino)-1-propylamine). Reaction progress was
monitored by HPLC. Once complete, the reaction was quenched upon
addition of 1:1 H.sub.2O:MeOH. The crude material was then purified
using reverse phase C18 preparatory HPLC. Purified fractions were
lyophilized to yield the target products, typically as a white
fluffy powder in modest yield and high purity.
Example 9--Resorcinol-Like Modification of Glycopeptide
Derivative
[0287] To a round bottom flask equipped with a stir bar was added
(Aminomethyl)phosphoric acid, water, and DIPEA. The reaction
mixture was allowed to stir for 15 minutes at room temperature. To
the reaction mixture was then added acetonitrile and formaldehyde,
37% solution in H.sub.2O. The reaction mixture was allowed to stir
for an additional 15 min. at which point a glycopeptide derivative
and additional DIPEA were added. Reaction progress was closely
monitored using HPLC. Once complete the reaction mixture was
purified using reverse phase C18 preparative HPLC. Purified
fractions were lyophilized to yield the target product as a white
fluffy powder.
Example 10--Minimum Inhibitory Concentration (MIC) of Glycopeptide
Derivatives
[0288] MIC Testing: Glycopeptide compounds were dissolved in 100%
DMSO. In vitro activities were determined using CLSI-guided broth
susceptibility testing to measure drug minimum inhibitory
concentrations (MICs) of the compounds against the quality control
strain ATCC 29213 (MSSA) and the MRSA isolate ATCC BAA-1556. The
minimal inhibitory concentrations MICs are summarized in Table 2.
Glycopeptides are defined as compounds of Formula (I), and their
respective R.sup.1, R.sup.2, R.sup.3 and R.sup.4 groups. X is --O--
for each compound in Table 2.
TABLE-US-00002 TABLE 2 MIC Values .mu.g/mL MRSA MRSA Glycopeptide
Structure (Formula (I)) CMPD 1556 29213 R.sup.1 R.sup.2 R.sup.3
R.sup.4 RV41 0.063 0.031 (CH.sub.2).sub.9CH.sub.3 H H H RV57 0.250
0.125 (CH.sub.2).sub.7CH.sub.3 H H H RV58 1.000 1.000
(CH.sub.2).sub.5CH.sub.3 H H H RV79 0.016 0.016 ##STR00050## H H H
RV84 1.000 1.000 (CH2).sub.2NH(CH.sub.2).sub.9CH.sub.3 H H
##STR00051## RV85 0.125 0.125 (CH.sub.2).sub.9CH.sub.3 H H
##STR00052## RV45 0.063 0.125
(CH.sub.2).sub.2NH(CH.sub.2).sub.9CH.sub.3 H
NH(CH.sub.2).sub.3N(CH.sub.3).sub.2 H Tela- 0.063 0.063
(CH.sub.2).sub.2NH(CH.sub.2).sub.9CH.sub.3
CH.sub.2--NH--CH.sub.2--PO.sub.3H.sub.2 H H vancin
Example 11--In Vitro Activity of Glycopeptide Agents Against Gram
Positive Bacteria
[0289] The susceptibility of a variety of Staphylococcus aureus,
including reference methicillin-resistant (MRSA) and
vancomycin-intermediate (VISA) isolates to various antibiotic
compounds was assessed.
[0290] Broth microdilution MIC testing was conducted in accordance
with guidelines from the Clinical and Laboratory Standards
Institute (CLSI; 1, 2) and included the comparators telavancin
(TLV), vancomycin (VAN), tigecycline (TGC), and linezolid (LNZ). In
addition, the susceptibility of other Gram-positive bacteria
(Enterococci, Streptococci, and Clostridium difficile) to the test
agents and comparators was also determined.
Materials and Methods
[0291] Test compounds. The 6 test agents and the comparators are
detailed in Table 3 below.
TABLE-US-00003 TABLE 3 Test compounds Stock Solution Compound
Solvent/Diluent .mu.g/mL Compound 5 DMSO 6400 Compound 40 (RV40)
DMSO 3200-6400 Telavancin (TLV) DMSO 800 Tigecycline (TGC) H.sub.2O
800-3200 Vancomycin (VAN) H.sub.2O 6400 Linezolid (LNZ) H.sub.2O
1600 Oritavancin (ORI) 0.002% P80 800 DMSO: Dimethyl sulfoxide
(Sigma, St. Louis, MO; Cat. No. 472301) P80: Polysorbate-80
(Spectrum, New Brunswick, NJ; Cat. No. P0138)
[0292] Isolates.
[0293] The test organisms were originally received from clinical
sources, the American Type Culture Collection (ATCC, Manassas,
Va.), and the Network on Antimicrobial Resistance in S. aureus
(NARSA; BEI Resources, Manassas, Va.). Upon receipt, the organisms
were sub-cultured onto an appropriate agar medium. Following
incubation, colonies were harvested from these plates and cell
suspensions prepared and frozen at -80.degree. C. with a
cryoprotectant. On the day prior to the assay, frozen stocks of
isolates were streaked onto Trypticase Soy Agar with 5% sheep blood
(Remel, Lenexa, Kans.; Lot No. 964323) and incubated overnight at
35.degree. C. in ambient atmosphere, with the exception of
Streptococci which were incubated overnight at 35.degree. C. in 5%
CO.sub.2, and C. difficile which was streaked onto Brucella Agar
(Becton Dickinson, Sparks, Md.; Lot No. 6168880) and incubated
anaerobically at 35.degree. C. for 48 h.
[0294] The following S. aureus isolates and associated phenotypes
were evaluated against the aforementioned antibiotics (Table
4).
TABLE-US-00004 TABLE 4 MIC (.mu.g/mL) Organism Isolate No.
Phenotype LNZ* VAN* TCG* ORI #5 TLV #40* S. aureus MMX MSSA 1.5 1
0.12 0.025 0.06 0.12 0.015 2490 S. aureus MMX MSSA 3 0.5 0.12 0.06
0.06 0.06 0.008 7907 S. aureus MMX MSSA 2 1 0.12 0.06 0.12 0.12
0.015 7908 S. aureus MMX MRSA 3 1 0.09 0.06 0.06 0.06 0.008 2010 S.
aureus MMX MRSA 2 1 0.12 0.03 0.12 0.06 0.008 2011ATCC BAA-1756 S.
aureus MMX MRSA 3 0.5 0.185 0.12 0.06 0.06 0.008 3982 S. aureus MMX
MRSA 1.5 1 0.12 0.06 0.06 0.06 0.008 4675ATCC BAA-1556 S. aureus
MMX MRSA 1 1 0.25 0.12 0.06 0.06 0.015 5717 ATCC 33591 S. aureus
MMX MRSA 2.5 0.5 0.185 0.03 0.06 0.06 0.008 5985 S. aureus MMX MRSA
1.5 0.5 0.12 0.12 0.06 0.06 0.008 5999 S. aureus MMX MRSA 1.5 0.5
0.12 0.12 0.06 0.06 0.008 7899 S. aureus MMX MRSA 2 0.5 0.185 0.12
0.12 0.06 0.008 7900 S. aureus MMX MRSA 2 0.5 0.12 0.5 0.06 0.03
0.008 7901 S. aureus MMX MRSA 2 1 0.12 0.5 0.25 0.06 0.015 7902 S.
aureus MMX MRSA 1.5 1 0.12 0.06 0.06 0.06 0.008 7903 S. aureus MMX
hVISA 1.5 4 0.25 0.5 0.5 0.25 0.03 4665 S. aureus MMX Mu3; hVISA
1.5 1 0.75 0.12 0.06 0.12 0.015 5989 S. aureus MMX Mu50; VISA 1.25
8 0.5 1 0.5 0.5 0.06 1723 S. aureus MMX VISA; 1.5 4 0.045 1 0.25
0.5 0.06 2124 DaptoNS S. aureus MMX VISA 1.5 4 0.12 0.25 0.5 0.12
0.03 4658 S. aureus MMX VISA 2.5 4 0.09 1 0.12 0.12 0.03 4660 S.
aureus MMX 100 MSSA 4 1 0.25 0.03 0.06 0.06 0.008 ATCC 29213 *LNZ
and TGC values are average MICs from n = 2 experiments; all others
are n = 1 experiment. **In Figure 4, strains listed here are
arranged left to right in the bar plots.
[0295] S. aureus ATCC 29213 was included during the testing of S.
aureus for purposes of quality control (Clinical and Laboratory
Standards Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing: Twenty-Seventh Informational Supplement.
CLSI document M100-S27. CLSI, 950 West Valley Road, Suite 2500,
Wayne, Pa. 19087 USA, 2017; CLSI. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically; Approved Standard-Tenth Edition. CLSI document
M07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa.
19087-1898 USA, 2015).
[0296] A summary of the subset of MRSA strains is also provided in
Table 5.
TABLE-US-00005 TABLE 5 MIC (.mu.g/mL) #40 Organism Isolate No.
Phenotype LNZ* VAN* TCG* ORI #5 TLV (RV40)* S. aureus MMX MRSA 3 1
0.09 0.06 0.06 0.06 0.008 2010 S. aureus MMX MRSA 2 1 0.12 0.03
0.12 0.06 0.008 2011ATCC BAA-1756 S. aureus MMX MRSA 3 0.5 0.185
0.12 0.06 0.06 0.008 3982 S. aureus MMX MRSA 1.5 1 0.12 0.06 0.06
0.06 0.008 4675ATCC BAA-1556 S. aureus MMX MRSA 1 1 0.25 0.12 0.06
0.06 0.015 5717 ATCC 33591 S. aureus MMX MRSA 2.5 0.5 0.185 0.03
0.06 0.06 0.008 5985 S. aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.06
0.008 5999 S. aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.06 0.008
7899 S. aureus MMX MRSA 2 0.5 0.185 0.12 0.12 0.06 0.008 7900 S.
aureus MMX MRSA 2 0.5 0.12 0.5 0.06 0.03 0.008 7901 S. aureus MMX
MRSA 2 1 0.12 0.5 0.25 0.06 0.015 7902 S. aureus MMX MRSA 1.5 1
0.12 0.06 0.06 0.06 0.008 7903 *LNZ and TGC values are average MICs
from n = 2 experiments; all others are n = 1 experiment. **In
Figure 6, strains listed here are arranged left to right in the bar
plots.
[0297] With respect to the MRSA strains (Table 5), Compound 40
(RV40) was found to be more active than the respective comparator
drug by the factors provided in Table 6.
TABLE-US-00006 TABLE 6 RV40 activity Comparator as compared Drug to
Comparator LNZ 214 .times. VAN 86 .times. TGC 16 .times. ORI 17
.times. Compound 5 9 .times. TLV 6 .times.
[0298] A summary of the subset of Gram Positive strains other than
those of the S. aureus species is provided below in Table 7. Blank
entries indicate that the respective antibiotic was not tested
against the respective organism.
TABLE-US-00007 TABLE 7 MIC Organism Isolate No. Type LNZ VAN TGC
ORI #5 TLV #40 S. epidermidis MMX 762 MRSE 2 2 0.06 0.25 0.12 0.12
0.008 (CoNS) S. epidermidis MMX 5145 MRSE 0.5 1 0.12 0.12 0.06 0.03
0.004 (CoNS) S. lugdenensis MMX 8724 -- 0.5 0.5 0.06 .ltoreq.0.008
0.03 0.06 0.004 (CoNS) S. haemolyticus MMX 529 -- 0.5 1 0.06 0.12
0.06 0.06 0.015 (CoNS) ATCC 29970 S. hominis MMX 667 -- 1 0.5 0.12
0.06 0.06 0.06 0.015 (CoNS) ATCC 27844 E. faecalis MMX 101 VSE 2 2
0.06 .ltoreq.0.008 0.06 0.12 0.015 ATCC 29212 E. faecalis MMX 4176
-- 4 1 0.12 0.03 -- 0.25 0.03 E. faecalis MMX 1086 VanA VRE 2
>64 0.12 1 0.06 1 0.5 E. faecium MMX 4204 -- 2 0.5 0.06 0.015 --
0.06 0.004 E. faecium MMX 851 VanA VRE 2 >64 0.06 0.12 2 2 1 E.
faecium MMX 173 VanB VRE 4 >64 0.06 .ltoreq.0.008 0.12 0.06
0.008 S. pneumoniae MMX 1195 PISP 1 0.25 0.06 .ltoreq.0.008 0.015
0.03 0.004 ATCC 49619 S. pneumoniae MMX 747 -- 1 0.12 0.03
.ltoreq.0.008 -- 0.015 0.004 S. pneumoniae MMX 432 PRSP 1 0.25 0.03
.ltoreq.0.008 -- 0.03 0.008 S. pyogenes MMX 404 -- 2 0.25 0.015 2
-- 0.06 0.06 ATCC 19615 S. pyogenes MMX 946 ermR 1 0.25 0.015 0.25
0.015 0.06 0.008 S. pyogenes MMX 8778 -- 1 0.25 0.03 1 -- 0.06
0.015 C. difficile MMX 4381 toxinAB- 1 0.25 0.18 1 0.06 0.12 0.06
ATCC 700057 negative C. difficile MMX 4994 ribotype 027 -- 0.25
0.03 0.5 0.06 0.12 0.06 ATCC BAA-1805 C. difficile MMX 5668
NAP1/027 -- 1 0.03 2 0.5 0.12 0.12 ATCC BAA-1870 S. agalactiae MMX
427 -- -- 0.25 -- 1 0.03 0.06 0.015 ATCC 13813 S. agalactiae MMX
4088 -- 1 0.25 0.03 0.12 0.015 0.06 0.008 S. agalactiae MMX 4115
erm.sup.R 1 0.25 0.03 0.25 0.015 0.06 0.008 S. dysgalactiae MMX
5121 -- 1 0.25 0.06 0.05 0.015 0.12 0.008 S. dysgalactiae MMX 5123
-- 1 0.5 0.015 2 0.03 0.25 0.12 S. dysgalactiae MMX 5124 -- 1 0.25
0.12 1 0.015 0.03 0.015 S. anginosus MMX 1201 -- 0.5 0.5 0.008 0.5
0.03 0.06 0.015 (AGS) ATCC 33397 S. constellatus MMX 5677 -- 0.5
0.25 0.03 .ltoreq.0.008 0.03 0.03 0.008 (AGS) S. mitis (MGS) MMX
1205 -- -- 0.5 -- 0.03 0.03 0.06 0.008 ATCC 49456 S. mitis (MGS)
MMX 5798 -- 0.5 0.25 0.03 0.25 0.015 -0.03 0.03 S. oralis (MGS) MMX
5821 -- 1 0.25 0.06 .ltoreq.0.008 0.03 0.06 0.015 C. perfringens
MMX 8351 -- -- 0.5 0.12 0.015 0.06 0.015 0.015 ATCC 13124 P. micros
MMX 3546 -- -- 0.5 0.015 0.03 0.12 0.06 0.015 P. anaerobius MMX
1208 -- -- 0.25 0.03 0.03 0.03 0.03 0.008 ATCC 27337 P. acnes MMX
7942 -- -- 0.25 0.03 .ltoreq.0.008 0.06 0.03 0.008 ATCC 6919 P.
acnes MMX 7946 -- -- 0.25 0.03 .ltoreq.0.008 0.06 0.015 0.008 ATCC
11827 E. lenta MMX 1287 -- -- -- 0.25 -- 0.12 -- -- ATCC 43055
[0299] Test Media.
[0300] The medium employed for the MIC assay was cation-adjusted
Mueller-Hinton Broth (MHBII; BD; Lot No. 6117994), excluding C.
difficile which were tested in supplemented Brucella Broth (SBB).
For Streptococcus isolates, the MHBII was supplemented with 3%
Laked Horse Blood (Cleveland Scientific; Bath, Ohio; Lot No.
333835). For testing C. difficile, Brucella Broth (BD; Lot No.
6155858) was supplemented with vitamin K (Sigma, St. Louis, Mo.;
Lot No. 108K1088), hemin (Sigma; Lot No. SLB14685V), and 5% Laked
Horse Blood. Test media was prepared fresh on each day of testing
and was supplemented with 0.002% polysorbate-80 (v/v) for the
testing of telavancin per CLSI (Clinical and Laboratory Standards
Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing: Twenty-Seventh Informational Supplement.
CLSI document M100-S27. CLSI, 950 West Valley Road, Suite 2500,
Wayne, Pa. 19087 USA, 2017; CLSI. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow
Aerobically; Approved Standard--Tenth Edition. CLSI document
M07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa.
19087-1898 USA, 2015) and for the testing of oritavancin, Compound
40 and Compound 5.
[0301] Test Procedure.
[0302] MIC values were determined using a broth microdilution
procedure described by CLSI (Clinical and Laboratory Standards
Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing: Twenty-Seventh Informational Supplement.
CLSI document M100-S27. CLSI, 950 West Valley Road, Suite 2500,
Wayne, Pa. 19087 USA, 2017). Automated liquid handlers (Multidrop
384, Labsystems, Helsinki, Finland; Biomek 2000 and Biomek FX,
Beckman Coulter, Fullerton Calif.) were used to conduct serial
dilutions and liquid transfers.
[0303] To prepare the drug mother plates, which would provide the
serial drug dilutions for the replicate daughter plates, the wells
of columns 2-12 of standard 96-well microdilution plates (Costar
3795) were filled with 150 .mu.L of the designated diluent for each
row of drug. The test articles and comparator compounds (300 .mu.L
at 100.times. the highest concentration to be tested) were
dispensed into the appropriate wells in column 1. The Biomek 2000
was then used to make 2-fold serial dilutions in the mother plates
from column 1 through column 11. The wells of Column 12 contained
no drug and served as the organism growth control wells for the
assay.
[0304] The daughter plates were loaded with 190 .mu.L per well of
the appropriate test medium containing 0.002% polysorbate-80 (v/v)
for telavancin, oritavancin, Compound 40, and Compound 5, using the
Multidrop 384. The daughter plates were prepared on the Biomek FX
instrument which transferred 2 .mu.L of drug solution from each
well of a mother plate to the corresponding well of each daughter
plate in a single step. The daughter plates for C. difficile were
placed in the anaerobe chamber and allowed to reduce for one hour
prior to inoculation.
[0305] A standardized inoculum of each organism was prepared per
CLSI methods (CLSI. Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically;
[0306] Approved Standard-Tenth Edition. CLSI document M07-A10.
CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa. 19087-1898 USA,
2015). Bacterial suspensions were prepared in MHBII (or in the case
of C. difficile SBB without blood) to equal the turbidity of a 0.5
McFarland standard. The 0.5 McFarland suspensions were further
diluted 1:20 (or in the case of C. difficile, 1:10) in the
appropriate test medium. The inoculum for each organism was
dispensed into sterile reservoirs (Beckman Coulter 372788), and the
Biomek 2000 was used to deliver 10 .mu.L of standardized inoculum
into each well resulting in a final test concentration of
approximately 5.times.10.sup.5 CFU/mL. Daughter plates were placed
on the Biomek 2000 work surface reversed so that inoculation took
place from low to high drug concentration. For C. difficile,
inoculum preparation and the inoculation of the daughter plates was
carried out by hand in the anaerobe chamber.
[0307] Plates were stacked 3 high, covered with a lid on the top
plate, placed in plastic bags, and incubated at 35.degree. C. in
ambient atmosphere for approximately 18-20 hr for telavancin,
Compound 40, Compound 5, oritavancin, linezolid, and tigecycline,
or 24 hr for vancomycin with the exception of C. difficile plates
which were incubated at 35.degree. C. anaerobically for 48 h.
Following incubation, the microplates were removed from the
incubator and viewed from the bottom using a plate viewer. For each
of the test compounds, an un-inoculated solubility control plate
for each test medium was observed for evidence of drug
precipitation. The MIC was read and recorded as the lowest
concentration of drug that inhibited visible growth. For linezolid,
pinpoint trailing was ignored when reading the MIC per CLSI (CLSI.
Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically; Approved Standard-Tenth Edition.
CLSI document M07-A10. CLSI, 950 West Valley Road, Suite 2500,
Wayne, Pa. 19087-1898 USA, 2015).
Results
[0308] No precipitation was observed for the comparators during the
assay with the un-inoculated solubility controls. Some
precipitation was noted for Compound 40 and Compound 5 at the top
concentration tested (64 .mu.g/mL) in MHBII with blood and
supplemented Brucella broth, and for Compound 40 (RV40) in HTM.
However, this precipitation did not interfere with the reading of
MICs. The MICs of comparators against ATCC quality control
organisms were within the established CLSI QC ranges (CLSI.
Performance Standards for Antimicrobial Susceptibility Testing;
Twenty-seventh Informational Supplement. CLSI document M100-S27.
CLSI, 940 West Valley Road, Suite 1400, Wayne, Pa. 19087-1898 USA,
2017.), thus validating the assay.
[0309] The observed MIC values for the S. aureus strains against
the various antibiotics is provided at Tables 3-5. These data are
also provided at FIGS. 6 and 7. Data for the 12 MRSA strains are
provided at Tables 4-5, and FIGS. 8 and 9.
[0310] The observed MIC values for the Gram positive strains other
than S. aureus against the various antibiotics is provided at Table
6. Compound 40 was the most potent compound across the evaluated
Streptococci, Enterococci, and C. difficile test isolates. The
activity observed with Compound 40 was 5-fold greater than that of
the telavancin, a trend consistent with the data observed with S.
aureus where Compound 40 was 3-fold great than that of telavancin
(Table 1). Both telavancin and Compound 40 had potent activity
against vancomycin-resistant enterococci (VRE) though MIC values
for VRE were elevated relative to vancomycin-susceptible
enterococci (VSE).
Example 12--MRSA 1556 Biofilm Eradication
[0311] Vancomycin (Vanc), telavancin (TLV), oritivancin (ORI) and
RV40 (compound of Formula (I) or (II) where R.sup.1 is
(CH.sub.2)--NH--(CH.sub.2).sub.9--CH.sub.3, R.sup.2 is OH, R.sup.3
and R.sup.4 are H and X is O) were tested for their ability to
eradicate MRSA 1556 biofilm.
[0312] For biofilm development, empty 96-well plates or cystic
fibrosis bronchial epithelial (CFBE) cells that were seeded in a
24-well plate were inoculated with MRSA 1556 overnight culture for
6 h followed by 16 h antibiotic treatment. After 16 h incubation,
planktonic bacteria were removed and biofilm was disrupted by
scrapping method and collected for CFU count. The results are
provided in FIG. 10 (plastic biofilm) and FIG. 11 (cell biofilm).
RV40 killed MRSA 1556 biofilm that formed on plastic significantly
at 0.3-10 .mu.g/ml compared to telavancin and vancomycin (FIG. 10).
RV40 was more potent to kill MRSA 1556 biofilm developed in a
co-culture with CFBE cells compared to vancomycin, telavancin and
oritavancin with >3 log CFU/ml reduction at 20 .mu.g/ml (FIG.
11).
Example 13--In Vivo Activity of Glycopeptide Agents Against MRSA
Organisms
[0313] Male Sprague Dawley rats (179-200 g) were rendered
neutropenic through a series of cyclophosphamide injections (IP) at
150 mg/kg (Day -4) and 100 mg/kg (Day -1). They were then
challenged with Methicillin-Resistant Staphylococcus aureus (MRSA)
(ATCC-BAA-1556; TPPS 1062) at 8 log 10 via intranasal (IN)
instillation on study Day 0.
[0314] Rats were treated with vehicle control (bicine; pH 9.2) or
RV40 (compound 40) (in bicine; pH 9.2) via nebulization using CH
Technologies 12 Port Module Oral-Nasal Aerosol and Respiratory
Exposure Systems (ONARES) connected to an Aeroneb Pro nebulizer at
12 h and 24 h post-challenge. At 36 hours, post-challenge lungs
were collected for CFU enumeration. The results are shown in FIG.
12.
[0315] For the data reported in FIG. 13, At 36 h, post-challenge
lungs were collected for CFU enumeration. Drugs that were nebulized
were done using the same procedures described for the data in FIG.
12. Results are listed as the .DELTA. Log reduction in lung CFU
versus control (FIG. 13).
[0316] The same animal model from FIG. 12 was used to acquire the
data in FIG. 14 regarding the dose response of inhaled RV40 in
reducing lung MRSA CFUs. Again, animals were treated with the drug
at 12 h and 24 h post-challenge. At 36 hours, post-challenge lungs
were collected for CFU enumeration. Here, animals were dosed with
RV40 at body-weight targets of 1, 2, 5, and 10 mg/kg using the same
nebulization procedures described for the data in FIG. 12. Results
are listed as the .DELTA. Log reduction in lung CFU versus control
(FIG. 14). Data is plotted as mean and error is SEM.
[0317] The same animal model from FIG. 12 was used to acquire the
data in FIG. 15 regarding prophylactic dosing of inhaled RV40 to
reduce lung MRSA CFUs. Here, animals were administered single doses
of nebulized inhaled RV40 (10 mg/kg body weight target) at 7, 5, 3,
and 1 days before bacterial challenge and at 0.5 days after
bacterial challenge. At 36 hours post-challenge lungs were
collected for CFU enumeration. Dosing was done using the same
nebulization procedures described for the data in FIG. 12. The
results are provided at FIG. 15. Data is plotted as geometric mean
with 95% CI. Statistics based on one-way ANOVA (p=0.001) with
post-hoc Bonferroni multiple comparison test. N=11 for treatment
groups on Days -7, -5, -3, -1, n=10 for Day +0.5, and n=8 for
control.
[0318] All, documents, patents, patent applications, publications,
product descriptions, and protocols which are cited throughout this
application are incorporated herein by reference in their
entireties for all purposes.
[0319] The embodiments illustrated and discussed in this
specification are intended only to teach those skilled in the art
the best way known to the inventors to make and use the invention.
Modifications and variation of the above-described embodiments of
the invention are possible without departing from the invention, as
appreciated by those skilled in the art in light of the above
teachings. It is therefore understood that, within the scope of the
claims and their equivalents, the invention may be practiced
otherwise than as specifically described.
* * * * *