U.S. patent application number 12/124896 was filed with the patent office on 2008-09-11 for anti-cancer and anti-microbial oxazolidinones.
This patent application is currently assigned to NEREUS PHARMACEUTICALS, INC.. Invention is credited to Kin Sing Lam, Venkata Rami Reddy Macherla, Benjamin Nicholson.
Application Number | 20080221182 12/124896 |
Document ID | / |
Family ID | 36580024 |
Filed Date | 2008-09-11 |
United States Patent
Application |
20080221182 |
Kind Code |
A1 |
Macherla; Venkata Rami Reddy ;
et al. |
September 11, 2008 |
ANTI-CANCER AND ANTI-MICROBIAL OXAZOLIDINONES
Abstract
Disclosed herein are various novel oxazolidinone,
imidazolidinone, and thiazolidinone analogs and methods of treating
cancer and/or microbial infection using these analogs. Particular
4-oxazolidinone compounds are shown to have anti-cancer and
anti-microbial activity.
Inventors: |
Macherla; Venkata Rami Reddy;
(San Diego, CA) ; Nicholson; Benjamin; (Narberth,
PA) ; Lam; Kin Sing; (San Diego, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET, FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Assignee: |
NEREUS PHARMACEUTICALS,
INC.
San Diego
CA
|
Family ID: |
36580024 |
Appl. No.: |
12/124896 |
Filed: |
May 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11358961 |
Feb 21, 2006 |
7378530 |
|
|
12124896 |
|
|
|
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60655605 |
Feb 22, 2005 |
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Current U.S.
Class: |
514/376 ;
514/563; 548/232; 562/560 |
Current CPC
Class: |
C07D 263/40 20130101;
A61P 31/14 20180101; C07C 257/06 20130101; A61P 31/04 20180101;
A61P 35/00 20180101; C12P 17/14 20130101 |
Class at
Publication: |
514/376 ;
548/232; 562/560; 514/563 |
International
Class: |
A61K 31/421 20060101
A61K031/421; C07D 263/38 20060101 C07D263/38; C07C 229/30 20060101
C07C229/30; A61K 31/195 20060101 A61K031/195 |
Claims
1. A compound having the structure of formula I or Ia: ##STR00024##
and pharmaceutically acceptable salts or prodrugs thereof, wherein:
R.sup.1 and R.sup.2 are separately selected, wherein one of R.sup.1
and R.sup.2 is a molecular fragment having the structure of formula
(II), ##STR00025## Z is selected from the group consisting of O, S,
and NR.sup.5; R.sup.6 and R.sup.7 are separately selected from the
group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; R.sup.8 and
R.sup.9 are separately selected from the group consisting of
hydrogen; halogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl;
alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy;
nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl;
carboxy; and halogenated alkyl including polyhalogenated alkyl; or
are separately absent; R.sup.10 and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or are
separately absent; and the remaining substituent of R.sup.1 and
R.sup.2 is selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; heteroaryl; ester; arylalkoxy
carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide;
aminocarbonyloxy; nitro; azido; hydroxy; alkylthio; arylthio;
oxysulfonyl; carboxy; cyano; and halogenated alkyl including
polyhalogenated alkyl; R.sup.3 is .dbd.O; R.sup.1' is selected from
the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or are
separately absent; R.sup.2' is selected from the group consisting
of hydrogen; halogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
heteroaryl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino;
aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; hydroxy;
alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated
alkyl including polyhalogenated alkyl; or are separately absent; Y
is separately selected from the group consisting of O, S, and
NR.sup.5; R.sup.4 and each R.sup.5 are separately selected from the
group consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl, or are separately
absent, provided that R.sup.4 is not absent in a compound of
formula Ia; any bond represented by a dashed and solid line
represents a bond selected from the group consisting of a single
bond and a double bond; any bond represented by a single dashed
line is a single bond or is absent; and any carbon-carbon double
bond has a configuration selected from the group consisting of cis
and trans.
2. The compound of claim 1, wherein Y is O.
3. The compound of claim 1, wherein Z is O.
4. The compound of claim 1, wherein R.sup.4 is H.
5. The compound of claim 1, wherein R.sup.4 is absent.
6. The compound of claim 1, wherein R.sup.8, R.sup.9, R.sup.10, and
R.sup.11 are separately hydrogen or absent.
7. The compound of claim 1, wherein R.sup.2 is a mono-substituted,
poly-substituted, or unsubstituted variant of C.sub.1-C.sub.24
alkyl.
8. The compound of claim 1, wherein R.sup.6 and R.sup.7 are
separately mono-substituted, poly-substituted, or unsubstituted
variants of C.sub.1-C.sub.24 alkyl.
9. A compound having the structure of formula III or IIIa:
##STR00026## and pharmaceutically acceptable salts or prodrugs
thereof, wherein: Y is selected from the group consisting of O, S,
and NR.sup.5; R.sup.2, R.sup.6, and R.sup.7 are separately selected
from the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; R.sup.2' is
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or is
absent; R.sup.4 and R.sup.5 are separately selected from the group
consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl or are separately
absent, provided that R.sup.4 is not absent in a compound of
formula IIIa; R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
separately selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or are
separately absent; any bond represented by a dashed and solid line
represents a bond selected from the group consisting of a single
bond and a double bond; any bond represented by a single dashed
line is a single bond or is absent; and any carbon-carbon double
bond has a configuration selected from the group consisting of cis
and trans.
10. The compound of claim 9, wherein Y is O.
11. The compound of claim 9, wherein R.sup.2 is a mono-substituted,
poly-substituted, or unsubstituted variant of C.sub.1-C.sub.24
alkyl.
12. The compound of claim 9, wherein R.sup.6 and R.sup.7 are
separately mono-substituted, poly-substituted, or unsubstituted
variants of straight chain C.sub.1-C.sub.24 alkyl.
13. The compound of claim 9, wherein R.sup.4 is H.
14. The compound of claim 9, wherein R.sup.4 is absent.
15. The compound of claim 9, wherein R.sup.2' is H.
16. The compound of claim 9, wherein R.sup.2' is absent.
17. The compound of claim 9, wherein R.sup.8, R.sup.9, R.sup.10,
and R.sup.11 are separately hydrogen or absent.
18. A compound having the structure of formula IV or IVa:
##STR00027## and pharmaceutically acceptable salts or prodrugs
thereof, wherein: R.sup.2, R.sup.6, and R.sup.7 are separately
selected from the group consisting of mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; R.sup.2' is
selected from the group consisting of hydrogen and
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl;
R.sup.4 is selected from the group consisting of hydrogen,
straight- or branched-chain C.sub.1-6 alkyl, straight- or
branched-chain C.sub.2-6 alkenyl, and straight- or branched-chain
C.sub.2-6 alkynyl, or is absent, provided that R.sup.4 is not
absent in a compound of formula IVa; any bond represented by a
dashed and solid line represents a bond selected from the group
consisting of a single bond and a double bond with the proviso that
such bonds in the compound of formula IV may not both be double
bonds; and any carbon-carbon double bond has a configuration
selected from the group consisting of cis and trans.
19. A compound having the structure of formula V or Va:
##STR00028## and pharmaceutically acceptable salts or prodrugs
thereof, wherein: Y is selected from the group consisting of O and
NR.sup.5; Z is selected from the group consisting of O, S, and
NR.sup.5; R.sup.2, R.sup.7, and R.sup.6 are separately selected
from the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; R.sup.2' is selected from the
group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or is absent; R.sup.4 and each
R.sup.5 are separately selected from the group consisting of
hydrogen; mono-substituted, poly-substituted or unsubstituted,
straight or branched chain variants of the following residues:
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.2-6
heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl, C.sub.1-6
alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8 cycloalkyl;
--C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl or halo;
C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6 cycloalkyl; and
C.sub.5-6 heterocycloalkyl or are separately absent, provided that
R.sup.4 is not absent in a compound of formula Va; R.sup.8 and
R.sup.9 are separately selected from the group consisting of
hydrogen; halogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; and
halogenated alkyl including polyhalogenated alkyl; or are
separately absent; R.sup.10 and R.sup.11 are separately selected
from the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or are
separately absent; R.sup.6 and R.sup.8 are optionally bound
together to form an optionally substituted ring; any bond
represented by a dashed and solid line represents a bond selected
from the group consisting of a single bond and a double bond; any
bond represented by a single dashed line is a single bond or is
absent; and any carbon-carbon double bond has a configuration
selected from the group consisting of cis and trans.
20. The compound of claim 19, having the structure:
##STR00029##
21. A compound having the structure of formula V or Va:
##STR00030## and pharmaceutically acceptable salts or prodrugs
thereof, wherein: Y is selected from the group consisting of O, S,
and NR.sup.5; Z is selected from the group consisting of O, S, and
NR.sup.5; R.sup.2, R.sup.6, and R.sup.7 are separately selected
from the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; R.sup.2' is selected from the
group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or is absent; R.sup.4 and each
R.sup.5 are separately selected from the group consisting of
hydrogen; mono-substituted, poly-substituted or unsubstituted,
straight or branched chain variants of the following residues:
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.2-6
heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl, C.sub.1-6
alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8 cycloalkyl;
--C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl or halo;
C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6 cycloalkyl; and
C.sub.5-6 heterocycloalkyl or are separately absent, provided that
R.sup.4 is not absent in a compound of formula Va; R.sup.8 and
R.sup.9 are separately selected from the group consisting of
hydrogen; halogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; and
halogenated alkyl including polyhalogenated alkyl; or are
separately absent; R.sup.10 and R.sup.11 are separately selected
from the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or are
separately absent; R.sup.6 and R.sup.8 are optionally bound
together to form an optionally substituted ring, provided that if
R.sup.6 and R.sup.8 together form an aryl, then at least one of
R.sup.2, R.sup.4, and R.sup.11 is not hydrogen; any bond
represented by a dashed and solid line represents a bond selected
from the group consisting of a single bond and a double bond; any
bond represented by a single dashed line is a single bond or is
absent; and any carbon-carbon double bond has a configuration
selected from the group consisting of cis and trans.
22. The compound of claim 21, having the structure:
##STR00031##
23. A pharmaceutical composition, comprising a compound of claim 1
and a physiologically acceptable surface active agent, carrier,
diluent, excipient, smoothing agent, suspension agent, film forming
substance, or coating assistant, or a combination thereof.
24. A pharmaceutical composition, comprising a compound of claim 9
and a physiologically acceptable surface active agent, carrier,
diluent, excipient, smoothing agent, suspension agent, film forming
substance, or coating assistant, or a combination thereof.
25. A pharmaceutical composition, comprising a compound of claim 18
and a physiologically acceptable surface active agent, carrier,
diluent, excipient, smoothing agent, suspension agent, film forming
substance, or coating assistant, or a combination thereof.
26. A pharmaceutical composition, comprising a compound of claim 19
and a physiologically acceptable surface active agent, carrier,
diluent, excipient, smoothing agent, suspension agent, film forming
substance, or coating assistant, or a combination thereof.
27. A pharmaceutical composition, comprising a compound of claim 21
and a physiologically acceptable surface active agent, carrier,
diluent, excipient, smoothing agent, suspension agent, film forming
substance, or coating assistant, or a combination thereof.
28. A pharmaceutical composition, comprising a compound having the
structure of formula VI, VII, VIII, or IX: ##STR00032## and a
physiologically acceptable surface active agent, carrier, diluent,
excipient, smoothing agent, suspension agent, film forming
substance, or coating assistant, or a combination thereof.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/358,961, filed Feb. 21, 2006, which claims the benefit of
U.S. Provisional Application No. 60/655,605, filed on Feb. 22,
2005, both of which are incorporated herein by reference in their
entirety.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present invention relates to the fields of chemistry and
medicine. More particularly, the present invention relates to
certain oxazolidinone, imidazolidinone, and thiazolidonone analogs
and use of those analogs in anti-cancer and anti-microbial
pharmaceuticals.
[0004] 2. Description of the Related Art
[0005] Cancer is a leading cause of death in the United States.
Despite significant efforts to find new approaches for treating
cancer, the primary treatment options remain surgery, chemotherapy
and radiation therapy, either alone or in combination. Surgery and
radiation therapy, however, are generally useful only for fairly
defined types of cancer, and are of limited use for treating
patients with disseminated disease. Chemotherapy is the method that
is generally useful in treating patients with metastatic cancer or
diffuse cancers such as leukemias. Although chemotherapy can
provide a therapeutic benefit, it often fails to result in cure of
the disease due to the patient's cancer cells becoming resistant to
the chemotherapeutic agent. Due, in part, to the likelihood of
cancer cells becoming resistant to a chemotherapeutic agent, such
agents are commonly used in combination to treat patients.
[0006] Similarly, infectious diseases caused, for example, by
bacteria are becoming increasingly difficult to treat and cure. For
example, more and more microorganisms, such as bacteria, are
developing resistance to current antibiotics and chemotherapeutic
agents. Examples of such bacteria include both gram positive and
gram negative bacteria, including Staphylococcus, Streptococcus,
Mycobacterium, Enterococcus, Corynebacterium, Borrelia, Bacillus,
Chlamidia, Mycoplasma, and the like. Examples of Fungi include
Aspergillus, Candida, Trichoderma, and the like. Examples of
protozoa include Plasmodium and Acanthamoeba.
[0007] Therefore, a need exists for additional chemotherapeutics
and antimicrobial agents to treat cancer and infectious disease. A
continuing effort is being made by individual investigators,
academia and companies to identify new, potentially useful
chemotherapeutic and antimicrobial agents.
[0008] Marine-derived natural products are a rich source of
potential new anti-cancer agents and anti-microbial agents. The
oceans are massively complex and house a diverse assemblage of
microbes that occur in environments of extreme variations in
pressure, salinity, and temperature. Marine microorganisms have
therefore developed unique metabolic and physiological capabilities
that not only ensure survival in extreme and varied habitats, but
also offer the potential to produce metabolites that would not be
observed from terrestrial microorganisms (Okami, Y. 1993 J Mar
Biotechnol 1:59). Representative structural classes of such
metabolites include terpenes, peptides, polyketides, and compounds
with mixed biosynthetic origins. Many of these molecules have
demonstrable anti-tumor, anti-bacterial, anti-fungal,
anti-inflammatory or immunosuppressive activities (Bull, A. T. et
al. 2000 Microbiol Mol Biol Rev 64:573; Cragg, G. M. & D. J.
Newman 2002 Trends Pharmacol Sci 23:404; Kerr, R. G. & S. S.
Kerr 1999 Exp Opin Ther Patents 9:1207; Frenz, J. L., Kohl, A. C.
& R. G. Kerr 2004 Exp Opin Ther Patents 14:17; Moore, B. S 1999
Nat Prod Rep 16:653; Faulkner, D. J. 2001 Nat Prod Rep 18:1; Mayer,
A. M. & V. K. Lehmann 2001 Anticancer Res 21:2489), validating
the utility of this source for isolating invaluable therapeutic
agents. Further, the isolation of novel anti-cancer and
anti-microbial agents that represent alternative mechanistic
classes to those currently on the market will help to address
resistance concerns, including any mechanism-based resistance that
may have been engineered into pathogens for bioterrorism
purposes.
SUMMARY OF CERTAIN EMBODIMENTS
[0009] One aspect of the invention is a compound having the
structure of formula I or Ia:
##STR00001##
[0010] and pharmaceutically acceptable salts or prodrugs thereof,
wherein:
[0011] R.sup.1 and R.sup.2 are separately selected, wherein one of
R.sup.1 and R.sup.2 is a molecular fragment having the structure of
formula (II),
##STR00002##
[0012] Z is selected from the group consisting of O, S, and
NR.sup.5;
[0013] R.sup.1 and R.sup.7 are separately selected from the group
consisting of hydrogen; halogen; mono-substituted, poly-substituted
or unsubstituted, straight or branched chain variants of the
following residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24
alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl; acyloxy;
alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;
alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;
arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl;
[0014] R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or are
separately absent; and the remaining substituent of R.sup.1 and
R.sup.2 is selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl;
[0015] R.sup.3 is .dbd.O;
[0016] R.sup.1' and R.sup.2' are separately selected from the group
consisting of hydrogen; halogen; mono-substituted, poly-substituted
or unsubstituted, straight or branched chain variants of the
following residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24
alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl; acyloxy;
alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;
alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;
arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or are separately absent;
[0017] Y is selected from the group consisting of O, S, and
NR.sup.5;
[0018] R.sup.4 and each R.sup.5 are separately selected from the
group consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl, or are separately
absent, provided that R.sup.4 is not absent in a compound of
formula Ia;
[0019] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond;
[0020] any bond represented by a single dashed line is a single
bond or is absent; and
[0021] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0022] Another aspect of the invention is a compound having the
structure of formula III or IIIa:
##STR00003##
[0023] and pharmaceutically acceptable salts or prodrugs thereof,
wherein:
[0024] Y is selected from the group consisting of O, S, and
NR.sup.5;
[0025] R.sup.2, R.sup.6, and R.sup.7 are separately selected from
the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl;
[0026] R.sup.2' is selected from the group consisting of hydrogen;
halogen; mono-substituted, poly-substituted or unsubstituted,
straight or branched chain variants of the following residues:
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl;
alkoxy carbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy;
nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl;
carboxy; cyano; and halogenated alkyl including polyhalogenated
alkyl; or is absent;
[0027] R.sup.4 and R.sup.5 are separately selected from the group
consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl or are separately
absent, provided that R.sup.4 is not absent in a compound of
formula IIIa;
[0028] R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or are
separately absent;
[0029] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond;
[0030] any bond represented by a single dashed line is a single
bond or is absent; and
[0031] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0032] Another aspect of the invention is a compound having the
structure of formula IV or IVa:
##STR00004##
[0033] and pharmaceutically acceptable salts or prodrugs thereof,
wherein:
[0034] R.sup.2, R.sup.6, and R.sup.7 are separately selected from
the group consisting of mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl;
[0035] R.sup.2' is selected from the group consisting of hydrogen
and mono-substituted, poly-substituted or unsubstituted, straight
or branched chain variants of the following residues:
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl;
[0036] R.sup.4 is selected from the group consisting of hydrogen,
straight- or branched-chain C.sub.1-6 alkyl, straight- or
branched-chain C.sub.2-6 alkenyl, and straight- or branched-chain
C.sub.2-6 alkynyl, or is absent, provided that R.sup.4 is not
absent in a compound of formula IVa;
[0037] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond with the proviso that such bonds in the compound of
formula IV may not both be double bonds; and
[0038] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0039] Another aspect of the invention is a compound having the
structure of formula V or Va:
##STR00005##
[0040] and pharmaceutically acceptable salts or prodrugs thereof,
wherein:
[0041] Y is selected from the group consisting of O and
NR.sup.5;
[0042] Z is selected from the group consisting of O, S, and
NR.sup.5;
[0043] R.sup.2, R.sup.6, and R.sup.7 are separately selected from
the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl;
[0044] R.sup.2' is selected from the group consisting of hydrogen;
halogen; mono-substituted, poly-substituted or unsubstituted,
straight or branched chain variants of the following residues:
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or is
absent;
[0045] R.sup.4 and each R.sup.5 are separately selected from the
group consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl or are separately
absent, provided that R.sup.4 is not absent in a compound of
formula Va;
[0046] R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or are separately absent;
[0047] R.sup.6 and R.sup.8 are optionally bound together to form an
optionally substituted ring;
[0048] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond;
[0049] any bond represented by a single dashed line is a single
bond or is absent; and
[0050] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0051] Another aspect of the invention is a compound having the
structure of formula V or Va:
##STR00006##
and pharmaceutically acceptable salts or prodrugs thereof,
wherein:
[0052] Y is selected from the group consisting of O, S, and
NR.sup.5;
[0053] Z is selected from the group consisting of O, S, and
NR.sup.5;
[0054] R.sup.2, R.sup.6, and R.sup.7 are separately selected from
the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl;
[0055] R.sup.2' is selected from the group consisting of hydrogen;
halogen; mono-substituted, poly-substituted or unsubstituted,
straight or branched chain variants of the following residues:
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or is
absent;
[0056] R.sup.4 and each R.sup.5 are separately selected from the
group consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl or are separately
absent, provided that R.sup.4 is not absent in a compound of
formula Va;
[0057] R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or are separately absent;
[0058] R.sup.6 and R.sup.8 are optionally bound together to form an
optionally substituted ring, provided that if R.sup.6 and R.sup.8
together form an aryl, then at least one of R.sup.2, R.sup.4, and
R.sup.11 is not hydrogen;
[0059] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond;
[0060] any bond represented by a single dashed line is a single
bond or is absent; and
[0061] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0062] Another aspect of the invention is a method of treating an
individual infected with a bacterium, comprising: administering to
the individual a compound selected from the group consisting of the
compounds of formulas I, Ia, III, IIIa, IV, IVa, V, and Va.
[0063] Another aspect of the invention is a method of treating an
individual with cancer, comprising: administering to the individual
a compound selected from the group consisting of the compounds of
formulas I, Ia, III, IIIa, IV, IVa, V, and Va.
[0064] Another aspect of the invention is a method of treating
cancer comprising the step of contacting a cancer cell with a
compound selected from the group consisting of the compounds of
formulas I, Ia, III, IIIa, IV, IVa, V, and Va.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0065] In one embodiment, compounds having the structure of formula
I are provided:
##STR00007##
[0066] wherein R.sup.1 and R.sup.2 are separately selected, and
wherein one of R.sup.1 and R.sup.2 is a molecular fragment having
the structure of formula (II),
##STR00008##
[0067] Z is selected from the group consisting of O, S, and
NR.sup.5;
[0068] R.sup.6 and R.sup.7 are separately selected from the group
consisting of hydrogen; halogen; mono-substituted, poly-substituted
or unsubstituted, straight or branched chain variants of the
following residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24
alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl; acyloxy;
alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;
alkoxy; cycloalkoxy; aryl; heteroaryl; arylalkoxy carbonyl; alkoxy
carbonylacyl; ester; amino; aminocarbonyl; amide; aminocarbonyloxy;
nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl;
carboxy; cyano; and halogenated alkyl including polyhalogenated
alkyl;
[0069] R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; arylalkoxy
carbonyl; alkoxy carbonylacyl; ester; amino; aminocarbonyl; amide;
aminocarboyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or are separately absent; any bond
represented by a dashed and solid line represents a bond selected
from the group consisting of a single bond and a double bond;
[0070] and the remaining substituent of R.sup.1 and R.sup.2 is
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl, ester; arylalkoxy carbonyl; alkoxy carbonylacyl;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl;
[0071] R.sup.3 is .dbd.O;
[0072] R.sup.1' and R.sup.2' are separately selected from the group
consisting of hydrogen; halogen; mono-substituted, poly-substituted
or unsubstituted, straight or branched chain variants of the
following residues: C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24
alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl; acyloxy;
alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;
alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl, ester;
arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or are separately absent;
[0073] Y is selected from the group consisting of O, S, and
NR.sup.5;
[0074] R.sup.4 and each R.sup.5 are separately selected from the
group consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, straight C.sub.2-6
alkynyl, heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl; or are separately
absent;
[0075] any bond represented by a single dashed line is a single
bond or is absent; and
[0076] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0077] It will be appreciated that when a bond represented by a
dashed and solid line in the compound of formula I is a double
bond, some substituents on the atoms involved in the double bond
will be absent and/or other bonds connected to the atoms will be
single bonds so that the proper valency of the atoms are not
violated. Thus, for example, when the dashed and solid line
connected to R.sup.1 is a double bond, R.sup.1' will be absent and
the bond between the nitrogen atom and the carbon atom involved in
double bonding with R.sup.1 will be a single bond.
[0078] In one embodiment, Y and/or Z in the compound of formula I
is O. In one embodiment, R.sup.4 in the compound of formula I is H.
In another embodiment, R.sup.4 in the compound of formula I is
absent, such as to accommodate a double bond to the nitrogen atom.
In some embodiments, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
separately hydrogen or are separately absent when necessary to
accommodate double bonds. In some embodiments, R.sup.2 is a
mono-substituted, poly-substituted, or unsubstituted variant of
C.sub.1-C.sub.24 alkyl. In some embodiments, R.sup.6 and R.sup.7
are separately mono-substituted, poly-substituted, or unsubstituted
variants of C.sub.1-C.sub.24 alkyl.
[0079] In one embodiment, the compound of formula I may be
subjected to a ring opening reaction to produce the compound of
formula Ia:
##STR00009## [0080] (Ia) where the substituents are as defined
above for formula I, with the proviso that R.sup.4 is not
absent.
[0081] In another embodiment, compounds having the structure of
formula III are provided:
##STR00010##
[0082] wherein Y is selected from the group consisting of O, S, and
NR.sup.5;
[0083] R.sup.2, R.sup.6, and R.sup.7 are separately selected from
the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;
heterocycloalkyl; arylalkoxy carbonyl; alkoxy carbonylacyl; ester;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl;
[0084] R.sup.2' is selected from the group consisting of hydrogen;
halogen; mono-substituted, poly-substituted or unsubstituted,
straight or branched chain variants of the following residues:
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; arylalkoxy carbonyl; alkoxy carbonylacyl; ester;
amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;
phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano;
and halogenated alkyl including polyhalogenated alkyl; or is
absent; R.sup.4 and R.sup.5 are separately selected from the group
consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl; or are separately
absent;
[0085] R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; arylalkoxy
carbonyl; alkoxy carbonylacyl; ester; amino; aminocarbonyl; amide;
aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or are separately absent;
[0086] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond; any bond represented by a single dashed line is a
single bond or is absent; and
[0087] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0088] It will be appreciated that when a bond represented by a
dashed and solid line in the compound of formula III is a double
bond, some substituents on the atoms involved in the double bond
will be absent and/or other bonds connected to the atoms will be
single bonds so that the proper valency of the atoms are not
violated. Thus, for example, when the dashed and solid line
connected to R.sup.2 is a double bond, R.sup.2' will be absent.
[0089] In one embodiment, Y is O in the compound of formula III. In
one embodiment, R.sup.2 in the compound of formula III is a
mono-substituted, poly-substituted, or unsubstituted variant of
C.sub.1-C.sub.24 alkyl. In one embodiment, R.sup.6 and R.sup.7 in
the compound of formula III are separately mono-substituted,
poly-substituted, or unsubstituted variants of straight chain
C.sub.1-C.sub.24 alkyl. In one embodiment, R.sup.4 in the compound
of formula III is H. In another embodiment, R.sup.4 in the compound
of formula III is absent, such as to accommodate a double bond to
the nitrogen atom. In one embodiment R.sup.2' in the compound of
formula III is H. In another embodiment, R.sup.2' in the compound
of formula III is absent, such as to accommodate a double bond. In
some embodiments, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
separately hydrogen or are separately absent when necessary to
accommodate double bonds.
[0090] In one embodiment, the compound of formula III may be
subjected to a ring opening reaction to produce the compound of
formula IIIa:
##STR00011##
where the substituents are as defined above for formula III, with
the proviso that R.sup.4 is not absent.
[0091] In another embodiment, a 4-oxazolidinone compound having the
structure of formula IV is provided:
##STR00012##
[0092] wherein R.sup.2, R.sup.6, and R.sup.7 are separately
selected from the group consisting of mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl;
[0093] R.sup.2' is selected from the group consisting of hydrogen
and mono-substituted, poly-substituted or unsubstituted, straight
or branched chain variants of the following residues:
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl;
[0094] R.sup.4 is selected from the group consisting of hydrogen,
straight- or branched-chain C.sub.1-6 alkyl, straight- or
branched-chain C.sub.2-6 alkenyl, and straight- or branched-chain
C.sub.2-6 alkynyl, or is absent;
[0095] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond with the proviso that such bonds in the compound of
formula IV may not both be double bonds; and
[0096] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0097] It will be appreciated that when a bond represented by a
dashed and solid line in the compound of formula IV is a double
bond, some substituents on the atoms involved in the double bond
will be absent and/or other bonds connected to the atoms will be
single bonds so that the proper valency of the atoms are not
violated.
[0098] In one embodiment, the compound of formula IV may be
subjected to a ring opening reaction to produce the compound of
formula IVa:
##STR00013##
[0099] where the substituents are as defined above for formula IV,
with the proviso that R.sup.4 is not absent.
[0100] In one embodiment, R.sup.2 in the compound of formula IV is
a mono-substituted, poly-substituted, or unsubstituted variant of
C.sub.1-C.sub.24 alkyl. In one embodiment, R.sup.6 and R.sup.7 in
the compound of formula IV are separately mono-substituted,
poly-substituted, or unsubstituted variants of straight chain
C.sub.1-C.sub.24 alkyl. In one embodiment, R.sup.4 in the compound
of formula IV is H. In another embodiment, R.sup.4 in the compound
of formula IV is absent, such as to accommodate a double bond to
the nitrogen atom. In one embodiment R.sup.2' in the compound of
formula IV is H. In another embodiment, R.sup.2' in the compound of
formula IV is absent, such as to accommodate a double bond.
[0101] In another embodiment, compounds having the structure of
formula V are provided:
##STR00014##
[0102] wherein Y is selected from the group consisting of O, S, and
NR.sup.5;
[0103] Z is selected from the group consisting of O, S, and
NR.sup.5;
[0104] R.sup.2, R.sup.6, and R.sup.7 are separately selected from
the group consisting of hydrogen; halogen; mono-substituted,
poly-substituted or unsubstituted, straight or branched chain
variants of the following residues: C.sub.1-C.sub.24 alkyl,
C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; ester;
arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy;
nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl;
carboxy; cyano; and halogenated alkyl including polyhalogenated
alkyl;
[0105] R.sup.2' is selected from the group consisting of hydrogen;
halogen; mono-substituted, poly-substituted or unsubstituted,
straight or branched chain variants of the following residues:
C.sub.1-C.sub.24 alkyl, C.sub.2-C.sub.24 alkenyl, or
C.sub.2-C.sub.24 alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;
aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy;
aryl; heteroaryl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;
amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;
arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl
including polyhalogenated alkyl; or is absent;
[0106] R.sup.4 and each R.sup.5 are separately selected from the
group consisting of hydrogen; mono-substituted, poly-substituted or
unsubstituted, straight or branched chain variants of the following
residues: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.2-6 heteroalkyl, C.sub.2-6 aminoalkyl, C.sub.2-6 haloalkyl,
C.sub.1-6 alkoxycarbonyl, and C.sub.2-6 hydroxyalkyl; C.sub.3-8
cycloalkyl; --C(O)--C.sub.5-6 aryl substituted with C.sub.1-3 alkyl
or halo; C.sub.5-6 aryl; C.sub.5-6 heteroaryl; C.sub.5-6
cycloalkyl; and C.sub.5-6 heterocycloalkyl or are separately
absent;
[0107] R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are separately
selected from the group consisting of hydrogen; halogen;
mono-substituted, poly-substituted or unsubstituted, straight or
branched chain variants of the following residues: C.sub.1-C.sub.24
alkyl, C.sub.2-C.sub.24 alkenyl, or C.sub.2-C.sub.24 alkynyl; acyl;
acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;
cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; ester;
arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy;
nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl;
carboxy; cyano; and halogenated alkyl including polyhalogenated
alkyl; or are separately absent;
[0108] R.sup.6 and R.sup.8 are optionally bound together to form an
optionally substituted ring;
[0109] any bond represented by a dashed and solid line represents a
bond selected from the group consisting of a single bond and a
double bond;
[0110] any bond represented by a single dashed line is a single
bond or is absent; and
[0111] any carbon-carbon double bond has a configuration selected
from the group consisting of cis and trans.
[0112] In some embodiments, of the compound of formula V, Y is not
S. In other embodiments of the compound of formula V, when R.sup.6
and R.sup.8 together form an aryl, at least one of R.sup.2,
R.sup.4, and R.sup.11 is not hydrogen.
[0113] It will be appreciated that when a bond represented by a
dashed and solid line in the compound of formula V is a double
bond, some substituents on the atoms involved in the double bond
will be absent and/or other bonds connected to the atoms will be
single bonds so that the proper valency of the atoms are not
violated. Thus, for example, when the dashed and solid line
connected to R.sup.2 is a double bond, R.sup.2' will be absent.
[0114] In one embodiment, Y is O in the compound of formula V. In
one embodiment, Z is O in the compound of formula V. In one
embodiment, R.sup.2 in the compound of formula V is a
mono-substituted, poly-substituted, or unsubstituted variant of
C.sub.1-C.sub.24 alkyl. In one embodiment, R.sup.6 and R.sup.7 in
the compound of formula V are separately mono-substituted,
poly-substituted, or unsubstituted variants of straight chain
C.sub.1-C.sub.24 alkyl. In one embodiment, R.sup.4 in the compound
of formula V is H. In another embodiment, R.sup.4 in the compound
of formula V is absent, such as to accommodate a double bond to the
nitrogen atom. In one embodiment R.sup.2' in the compound of
formula V is H. In another embodiment, R.sup.2' in the compound of
formula V is absent, such as to accommodate a double bond. In some
embodiments, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are
separately hydrogen or are separately absent when necessary to
accommodate double bonds.
[0115] In one embodiment, R.sup.6 and R.sup.8 in the compound of
formula V are bound together to form an optionally substituted
aryl. In one such embodiment, the compound of formula V has the
structure:
##STR00015##
where R.sup.2, R.sup.2', R.sup.4, R.sup.7, R.sup.10, and R.sup.11
are as defined above.
[0116] In one embodiment, the compound of formula V may be
subjected to a ring opening reaction to produce the compound of
formula Va:
##STR00016##
[0117] where the substituents are as defined above for formula V,
with the proviso that R.sup.4 is not absent. [0027] In one
embodiment, the compound of formulas I, III, IV, or V has the
structure of formula VI:
##STR00017##
wherein the crossed double bond indicates that the double bond may
have either a trans or cis geometry.
[0118] In another embodiment, the compound of formulas I, III, IV,
or V has the structure formula VII:
##STR00018##
wherein the crossed double bond indicates that the double bond may
have either a trans or cis geometry.
[0119] In another embodiment, the compound of formulas I, III, IV,
or V has the structure of formula VIII:
##STR00019##
wherein the crossed double bond indicates that the double bond may
have either a trans or cis geometry.
[0120] In some embodiments, tautomers of the compounds of formulas
VI, VII, or VIII are provided. For example, the tautomer of the
compound of formula VI having the structure:
##STR00020##
is provided.
[0121] In one embodiment, the compound of formulas Ia, IIIa, IVa,
or Va has the structure of formula IX:
##STR00021##
[0122] In some embodiments, prodrugs, metabolites, stereoisomers,
and pharmaceutically acceptable salts of the compounds disclosed
herein are provided.
[0123] A "prodrug" refers to an agent that is converted into the
parent drug in vivo. Prodrugs are often useful because, in some
situations, they may be easier to administer than the parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent is not. The prodrug may also have improved
solubility in pharmaceutical compositions over the parent drug. An
example, without limitation, of a prodrug would be a compound which
is administered as an ester (the "prodrug") to facilitate
transmittal across a cell membrane where water solubility is
detrimental to mobility but which then is metabolically hydrolyzed
to the carboxylic acid, the active entity, once inside the cell
where water-solubility is beneficial. A further example of a
prodrug might be a short peptide (polyaminoacid) bonded to an acid
group where the peptide is metabolized to reveal the active moiety.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in Design
of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby
incorporated herein by reference in its entirety.
[0124] The term "pro-drug ester" refers to derivatives of the
compounds disclosed herein formed by the addition of any of several
ester-forming groups that are hydrolyzed under physiological
conditions. Examples of pro-drug ester groups include
pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and
methoxymethyl, as well as other such groups known in the art,
including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group. Other
examples of pro-drug ester groups can be found in, for example, T.
Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems",
Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975);
and "Bioreversible Carriers in Drug Design: Theory and
Application", edited by E. B. Roche, Pergamon Press: New York,
14-21 (1987) (providing examples of esters useful as prodrugs for
compounds containing carboxyl groups). Each of the above-mentioned
references is herein incorporated by reference in their
entirety.
[0125] Metabolites of the compounds disclosed herein include active
species that are produced upon introduction of the compounds into
the biological milieu.
[0126] Where the compounds disclosed herein have at least one
chiral center, they may exist as a racemate or as enantiomers. It
should be noted that all such isomers and mixtures thereof are
included in the scope of the present invention. Furthermore, some
of the crystalline forms for the compounds of disclosed herein may
exist as polymorphs. Such polymorphs are included in one embodiment
of the present invention. In addition, some of the compounds of the
present invention may form solvates with water (i.e., hydrates) or
common organic solvents. Such solvates are included in one
embodiment of the present invention.
[0127] The term "pharmaceutically acceptable salt" refers to a salt
of a compound that does not cause significant irritation to an
organism to which it is administered and does not abrogate the
biological activity and properties of the compound. In some
embodiments, the salt is an acid addition salt of the compound.
Pharmaceutical salts can be obtained by reacting a compound with
inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or
hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and
the like. Pharmaceutical salts can also be obtained by reacting a
compound with an organic acid such as aliphatic or aromatic
carboxylic or sulfonic acids, for example acetic, succinic, lactic,
malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,
ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic
acid. Pharmaceutical salts can also be obtained by reacting a
compound with a base to form a salt such as an ammonium salt, an
alkali metal salt, such as a sodium or a potassium salt, an
alkaline earth metal salt, such as a calcium or a magnesium salt, a
salt of organic bases such as dicyclohexylamine,
N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
C.sub.1-C.sub.7 alkylamine, cyclohexylamine, triethanolamine,
ethylenediamine, and salts with amino acids such as arginine,
lysine, and the like.
[0128] If the manufacture of pharmaceutical formulations involves
intimate mixing of the pharmaceutical excipients and the active
ingredient in its salt form, then it may be desirable to use
pharmaceutical excipients which are non-basic, that is, either
acidic or neutral excipients.
[0129] In various embodiments, the compounds disclosed herein can
be used alone, in combination with other compounds disclosed
herein, or in combination with one or more other agents active in
the therapeutic areas described herein.
[0130] The term "halogen atom," as used herein, means any one of
the radio-stable atoms of column 7 of the Periodic Table of the
Elements, e.g., fluorine, chlorine, bromine, or iodine, with
fluorine and chlorine being preferred.
[0131] The term "ester" refers to a chemical moiety with formula
--(R).sub.n--COOR', where R and R' are independently selected from
the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded
through a ring carbon) and heteroalicyclic (bonded through a ring
carbon), and where n is 0 or 1.
[0132] An "amide" is a chemical moiety with formula
--(R).sub.n--C(O)NHR', --(R).sub.n--NHC(O)R',
--(R).sub.n--C(O)NR'R'', or --(R).sub.n--R'NC(O)R'', where R, R',
and R'' are independently selected from the group consisting of
alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon)
and heteroalicyclic (bonded through a ring carbon), and where n is
0 or 1. An amide may be an amino acid or a peptide molecule
attached to a molecule of the present invention, thereby forming a
prodrug.
[0133] Any amine, hydroxy, or carboxyl side chain on the compounds
of the present invention can be esterified or amidified. The
procedures and specific groups to be used to achieve this end are
known to those of skill in the art and can readily be found in
reference sources such as Greene and Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York,
N.Y., 1999, which is incorporated herein in its entirety.
[0134] The term "aromatic" refers to an aromatic group which has at
least one ring having a conjugated pi electron system and includes
both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups
(e.g., pyridine). The term includes monocyclic or fused-ring
polycyclic (i.e., rings which share adjacent pairs of carbon atoms)
groups. The term "carbocyclic" refers to a compound which contains
one or more covalently closed ring structures, and that the atoms
forming the backbone of the ring are all carbon atoms. The term
thus distinguishes carbocyclic from heterocyclic rings in which the
ring backbone contains at least one atom which is different from
carbon. The term "heteroaromatic" refers to an aromatic group which
contains at least one heterocyclic ring.
[0135] The term "alkyl," as used herein, means any unbranched or
branched, substituted or unsubstituted, saturated hydrocarbon. The
alkyl moiety, may be branched, straight chain, or cyclic. The alkyl
group may have 1 to 20 carbon atoms (whenever it appears herein, a
numerical range such as "1 to 20" refers to each integer in the
given range; e.g., "1 to 20 carbon atoms" means that the alkyl
group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,
etc., up to and including 20 carbon atoms, although the present
definition also covers the occurrence of the term "alkyl" where no
numerical range is designated). The alkyl group may also be a
medium size alkyl having 1 to 10 carbon atoms. The alkyl group
could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl
group may be designated as "C.sub.1-C.sub.4 alkyl" or similar
designations. By way of example only, "C.sub.1-C.sub.4 alkyl"
indicates that there are one to four carbon atoms in the alkyl
chain, i.e., the alkyl chain is selected from the group consisting
of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, and t-butyl.
[0136] The alkyl group may be substituted or unsubstituted. When
substituted, the substituent group(s) is(are) one or more group(s)
individually and independently selected from substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
cylcloalkenyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroaryloxy, heterocyclyl, heterocyclooxy, heteroalicyclyl,
hydroxy, substituted or unsubstituted alkoxy, substituted or
unsubstituted aryloxy, acyl, thiol, substituted or unsubstituted
thioalkoxy, alkylthio, arylthio, cyano, halo, carbonyl,
thiocarbonyl, acylalkyl, acylamino, acyloxy, aminoacyl,
aminoacyloxy, oxyacylamino, keto, thioketo, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,
N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,
isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and
substituted or unsubstituted amino, including mono- and
di-substituted amino groups, and the protected derivatives thereof,
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. Typical alkyl groups include, but are in no
way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Wherever a substituent is described as being "optionally
substituted" that substitutent may be substituted with one of the
above substituents.
[0137] In the present context, the term "cycloalkyl" is intended to
cover three-, four-, five-, six-, seven-, and eight- or more
membered rings comprising carbon atoms only. A cycloalkyl can
optionally contain one or more unsaturated bonds situated in such a
way, however, that an aromatic pi-electron system does not arise.
Some examples of "cycloalkyl" are the carbocycles cyclopropane,
cyclobutane, cyclopentane, cyclopentene, cyclopentadiene,
cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene,
cycloheptane, or cycloheptene.
[0138] An "alkenyl" moiety refers to a group consisting of at least
two carbon atoms and at least one carbon-carbon double bond. An
alkenyl may be unbranched or branched, substituted or
unsubstituted, unsaturated hydrocarbon including polyunsaturated
hydrocarbons. In some embodiments, the alkenyl is a C.sub.1-C.sub.6
unbranched, mono-unsaturated or di-unsaturated, unsubstituted
hydrocarbons. The term "cycloalkenyl" refers to any non-aromatic
hydrocarbon ring, preferably having five to twelve atoms comprising
the ring.
[0139] An "alkyne" moiety refers to a group consisting of at least
two carbon atoms and at least one carbon-carbon triple bond.
[0140] The substituent "R", "R'", or "R''" appearing by itself and
without a number designation refers to a substituent selected from
the group consisting of hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heteroalicyclyl
(bonded through a ring carbon).
[0141] The term "alkoxy" refers to any unbranched, or branched,
substituted or unsubstituted, saturated or unsaturated ether, with
C.sub.1-C.sub.6 unbranched, saturated, unsubstituted ethers being
preferred, with methoxy being preferred, and also, with dimethyl,
diethyl, methyl-isobutyl, and methyl-tert-butyl ethers also being
preferred. The term "cycloalkoxy" refers to any non-aromatic
hydrocarbon ring, preferably having five to twelve atoms comprising
the ring.
[0142] An "O-carboxy" group refers to a RC(.dbd.O)O-- group, where
R is as defined herein.
[0143] A "C-carboxy" group refers to a --C(.dbd.O)OR groups where R
is as defined herein.
[0144] An "acetyl" group refers to a --C(.dbd.O)CH.sub.3,
group.
[0145] A "trihalomethanesulfonyl" group refers to a
X.sub.3CS(.dbd.O).sub.2-- group where X is a halogen.
[0146] A "cyano" group refers to a --CN group.
[0147] An "isocyanato" group refers to a --NCO group.
[0148] A "thiocyanato" group refers to a --SCN group.
[0149] An "isothiocyanato" group refers to a --NCS group.
[0150] A "sulfinyl" group refers to a --S(.dbd.O)--R group, with R
as defined herein.
[0151] A "S-sulfonamido" group refers to a --S(.dbd.O).sub.2NR,
group, with R as defined herein.
[0152] A "N-sulfonamido" group refers to a RS(.dbd.O).sub.2NH--
group with R as defined herein.
[0153] A "trihalomethanesulfonamido" group refers to a
X.sub.3CS(.dbd.O).sub.2NR-- group with X and R as defined
herein.
[0154] An "O-carbamyl" group refers to a --OC(.dbd.O)--NR, group
with R as defined herein.
[0155] An "N-carbamyl" group refers to a ROC(.dbd.O)NH-- group,
with R as defined herein.
[0156] An "O-thiocarbamyl" group refers to a --OC(.dbd.S)--NR,
group with R as defined herein.
[0157] An "N-thiocarbamyl" group refers to an ROC(.dbd.S)NH--
group, with R as defined herein.
[0158] A "C-amido" group refers to a --C(.dbd.O)--NR.sub.2 group
with R as defined herein.
[0159] An "N-amido" group refers to a RC(.dbd.O)NR'-- group, with R
and R' as defined herein.
[0160] The term "perhaloalkyl" refers to an alkyl group where all
of the hydrogen atoms are replaced by halogen atoms.
[0161] The term "acylalkyl" refers to a RC(.dbd.O)R-- group, with R
as defined herein, and R' being a diradical alkylene group.
Examples of acylalkyl, without limitation, may include
CH.sub.3C(.dbd.O)CH.sub.2--, CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3CH.sub.2C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2CH.sub.2--, and the like.
[0162] The term "acyloxy" refers to a RC(.dbd.O)O-- group, with R
as defined herein.
[0163] The term "alkyloxycarbonyloxy" refers to an
alkyl-O--C(.dbd.O)O-- group.
[0164] The term "aryloxycarbonyloxy" refers to an
aryl-OC(.dbd.O)O-- group.
[0165] The term "arylalkoxy carbonyl" refers to an
aryl-alkoxy(C.dbd.O)-- group.
[0166] The term "aminocarbonyl" refers to an amino(C.dbd.O)--
group.
[0167] The term "aminocarbonyloxy" refers to an amino(C.dbd.O)O--
group.
[0168] Unless otherwise indicated, when a substituent is deemed to
be "optionally substituted," it is meant that the substitutent is a
group that may be substituted with one or more group(s)
individually and independently selected from cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,
alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl,
O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,
N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,
isocyanato, thiocyanato, isothiocyanato, nitro, silyl,
trihalomethanesulfonyl, and amino, including mono- and
di-substituted amino groups, and the protected derivatives thereof.
The protecting groups that may form the protective derivatives of
the above substituents are known to those of skill in the art and
may be found in references such as Greene and Wuts, above.
[0169] The term "heterocyclyl" is intended to mean three-, four-,
five-, six-, seven-, and eight- or more membered rings wherein
carbon atoms together with from 1 to 3 heteroatoms constitute said
ring. A heterocyclyl can optionally contain one or more unsaturated
bonds situated in such a way, however, that an aromatic pi-electron
system does not arise. The heteroatoms are independently selected
from oxygen, sulfur, and nitrogen.
[0170] A heterocyclyl can further contain one or more carbonyl or
thiocarbonyl functionalities, so as to make the definition include
oxo-systems and thio-systems such as lactams, lactones, cyclic
imides, cyclic thioimides, cyclic carbamates, and the like.
[0171] Heterocyclyl rings can optionally also be fused to aryl
rings, such that the definition includes bicyclic structures.
Typically such fused heterocyclyl groups share one bond with an
optionally substituted benzene ring. Examples of benzo-fused
heterocyclyl groups include, but are not limited to,
benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene
ring structures.
[0172] Some examples of "heterocyclyls" include, but are not
limited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,
piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,
piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,
imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole,
1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.
Binding to the heterocycle can be at the position of a heteroatom
or via a carbon atom of the heterocycle, or, for benzo-fused
derivatives, via a carbon of the benzenoid ring.
[0173] In the present context the term "aryl" is intended to mean a
carbocyclic aromatic ring or ring system. Moreover, the term "aryl"
includes fused ring systems wherein at least two aryl rings, or at
least one aryl and at least one C.sub.3-8-cycloalkyl share at least
one chemical bond. Some examples of "aryl" rings include optionally
substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl,
tetralinyl, fluorenyl, indenyl, and indanyl. The term "aryl"
relates to aromatic, including, for example, benzenoid groups,
connected via one of the ring-forming carbon atoms, and optionally
carrying one or more substituents selected from heterocyclyl,
heteroaryl, halo, hydroxy, amino, cyano, nitro, alkylamido, acyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl,
C.sub.1-6 aminoalkyl, C.sub.1-6 alkylamino, alkylsulfenyl,
alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. The
aryl group can be substituted at the para and/or meta positions. In
other embodiments, the aryl group can be substituted at the ortho
position. Representative examples of aryl groups include, but are
not limited to, phenyl, 3-halophenyl, 4-halophenyl,
3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl,
3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
4-trifluoromethoxyphenyl 3-cyanophenyl, 4-cyanophenyl,
dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl,
trifluoromethylphenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl,
4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and
4-(2-oxopyrrolidin-1-yl)phenyl.
[0174] In the present context, the term "heteroaryl" is intended to
mean a heterocyclic aromatic group where one or more carbon atoms
in an aromatic ring have been replaced with one or more heteroatoms
selected from the group comprising nitrogen, sulfur, phosphorous,
and oxygen.
[0175] Furthermore, in the present context, the term "heteroaryl"
comprises fused ring systems wherein at least one aryl ring and at
least one heteroaryl ring, at least two heteroaryl rings, at least
one heteroaryl ring and at least one heterocyclyl ring, or at least
one heteroaryl ring and at least one cycloalkyl ring share at least
one chemical bond.
[0176] The term "heteroaryl" is understood to relate to aromatic,
C.sub.3-8 cyclic groups further containing one oxygen or sulfur
atom or up to four nitrogen atoms, or a combination of one oxygen
or sulfur atom with up to two nitrogen atoms, and their substituted
as well as benzo- and pyrido-fused derivatives, for example,
connected via one of the ring-forming carbon atoms. Heteroaryl
groups can carry one or more substituents, selected from halo,
hydroxy, amino, cyano, nitro, alkylamido, acyl, C.sub.1-6-alkoxy,
C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl, C.sub.1-6-aminoalkyl,
C.sub.1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl,
sulfamoyl, or trifluoromethyl. In some embodiments, heteroaryl
groups can be five- and six-membered aromatic heterocyclic systems
carrying 0, 1, or 2 substituents, which can be the same as or
different from one another, selected from the list above.
Representative examples of heteroaryl groups include, but are not
limited to, unsubstituted and mono- or di-substituted derivatives
of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,
indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole,
benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole,
indazole, tetrazole, quionoline, isoquinoline, pyridazine,
pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole,
1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole,
pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine,
cinnoline, phthalazine, quinazoline, and quinoxaline. In some
embodiments, the substituents are halo, hydroxy, cyano,
O--C.sub.1-6-alkyl, C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, and
amino-C.sub.1-6-alkyl.
[0177] The terms "purified," "substantially purified," and
"isolated" as used herein refer to compounds disclosed herein being
free of other, dissimilar compounds with which the compounds of the
invention are normally associated in their natural state, so that
the compounds of the invention comprise at least 0.5%, 1%, 5%, 10%,
or 20%, and most preferably at least 50% or 75% of the mass, by
weight, of a given sample.
Methods of Preparation
[0178] Compounds disclosed herein may be obtained by fermentation
of a strain of a marine actinomycete a strain isolated from a
marine sediment sample collected at Cocos Lagoon, Guam, a culture
of which (also identified as "NPS008920") was deposited on Jan. 19,
2005 with the American Type Culture Collection (ATCC) in Rockville,
Md. and assigned the ATCC patent deposition number PTA-6527. The
ATCC deposit meets all of the requirements of the Budapest treaty.
The culture is also maintained at and available from Nereus
Pharmaceutical Culture Collection at 10480 Wateridge Circle, San
Diego, Calif. 92121. In addition to the specific microorganism
described herein, it should be understood that mutants, such as
those produced by the use of chemical or physical mutagens
including X-rays, etc. and organisms whose genetic makeup has been
modified by molecular biology techniques, may also be cultivated to
produce compounds described herein. Compounds produced by this
strain may then be purified.
[0179] The production of compounds disclosed herein may be carried
out by cultivating the above-identified strain in a suitable
nutrient medium under conditions described herein, preferably under
submerged aerobic conditions, until a substantial amount of
compounds are detected in the fermentation; harvesting by
extracting the active components from the mycelial growth with a
suitable solvent; concentrating the solution containing the desired
components; then subjecting the concentrated material to
chromatographic separation to isolate the compounds from other
metabolites also present in the cultivation medium.
[0180] Production of compounds can be achieved at temperature
conducive to satisfactory growth of the producing organism, e.g.
from 16 degree C. to 40 degree C., but it is preferable to conduct
the fermentation at 22 degree C. to 32 degree C. The aqueous medium
can be incubated for a period of time necessary to complete the
production of compounds as monitored by high pressure liquid
chromatography (HPLC), preferably for a period of about 2 to 10
days, on a rotary shaker operating at about 50 rpm to 300 rpm,
preferably at 150 rpm to 250 rpm, for example.
[0181] Growth of the microorganisms may be achieved by one of
ordinary skill of the art by the use of appropriate medium.
Broadly, the sources of carbon include glucose, fructose, mannose,
maltose, galactose, mannitol and glycerol, other sugars and sugar
alcohols, starches and other carbohydrates, or carbohydrate
derivatives such as dextran, cerelose, as well as complex nutrients
such as oat flour, corn meal, millet, corn, and the like. The exact
quantity of the carbon source that is utilized in the medium will
depend in part, upon the other ingredients in the medium, but an
amount of carbohydrate between 0.5 to 25 percent by weight of the
medium can be satisfactorily used, for example. These carbon
sources can be used individually or several such carbon sources may
be combined in the same medium, for example. Certain carbon sources
are preferred as hereinafter set forth.
[0182] The sources of nitrogen include amino acids such as glycine,
arginine, threonine, methionine and the like, ammonium salt, as
well as complex sources such as yeast extracts, corn steep liquors,
distiller solubles, soybean meal, cotttonseed meal, fish meal,
peptone, and the like. The various sources of nitrogen can be used
alone or in combination in amounts ranging from 0.5 to 25 percent
by weight of the medium, for example.
[0183] Among the nutrient inorganic salts, which can be
incorporated in the culture media, are the customary salts capable
of yielding sodium, potassium, magnesium, calcium, phosphate,
sulfate, chloride, carbonate, and like ions. Also included are
trace metals such as cobalt, manganese, iron, molybdenum, zinc,
cadmium, and the like.
[0184] Those of skill in the art will recognize many suitable
techniques of fermentation and purification for use in producing
compounds disclosed herein. Compounds obtained in this manner may
be further modified to generate compounds disclosed herein by
semi-synthetic routes. For example, in some embodiments, compounds
of formulas Ia, IIIa, IVa, or Va are produced by subjecting
compounds of formulas I, III, IV, or V to a suitable ring opening
reaction such as by adjusting the pH to a suitable level (e.g.,
approximately 7.4).
[0185] The compounds disclosed herein may also be synthesized by
methods described below, or by modification of these methods. Ways
of modifying the methodology include, among others, temperature,
solvent, reagents etc., and will be obvious to those skilled in the
art. In general, during any of the processes for preparation of the
compounds disclosed herein, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and Greene
& Wuts, Protective Groups in Organic Synthesis, John Wiley
& Sons, 1991, which are both hereby incorporated herein by
reference in their entirety. The protecting groups may be removed
at a convenient subsequent stage using methods known from the art.
Synthetic chemistry transformations useful in synthesizing
applicable compounds are known in the art and include e.g. those
described in R. Larock, Comprehensive Organic Transformations, VCH
Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for
Organic Synthesis, John Wiley and Sons, 1995, which are both hereby
incorporated herein by reference in their entirety.
[0186] Compounds described herein can be synthesized by the
synthetic scheme A:
##STR00022##
[0187] In Scheme A, R.sup.2, R.sup.2', R.sup.6, R.sup.7, Y, and Z
are as described above for formulas I, III, and IV. R may be
hydrogen or a strait or branched chain C.sub.1-6 alkyl.
[0188] Where the processes for the preparation of the compounds
disclosed herein give rise mixtures of stereoisomers, such isomers
may be separated by conventional techniques such as preparative
chiral chromatography. The compounds may be prepared in racemic
form or individual enantiomers may be prepared by stereoselective
synthesis or by resolution. The compounds may be resolved into
their component enantiomers by standard techniques, such as the
formation of diastereomeric pairs by salt formation with an
optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid
and/or (+)-di-p-toluoyl-1-tartaric acid, followed by fractional
crystallization and regeneration of the free base. The compounds
may also be resolved using a chiral auxiliary by formation of
diastereomeric derivatives such as esters, amides or ketals
followed by chromatographic separation and removal of the chiral
auxiliary.
Methods of Use
[0189] In some embodiments, the compounds described herein can be
used for the treatment of cancer and/or microbial infection. Thus,
for example, the compounds described herein can be used to treat,
prevent the formation of, slow the growth of, or kill cancer cells.
In some embodiments, the compounds described herein are
administered to a subject suffering from cancer. In one embodiment,
the subject is a human. In some embodiments, cancer cells are
contacted with one or more of the compounds described herein. In
one embodiment, the cancer is a melanoma.
[0190] In some embodiments, the compounds described herein can be
used to treat a bacterial infection. In some embodiments, the
compounds prevent the formation of, slow the growth of, or kill
bacteria. In some embodiments, the compounds described herein are
administered to a subject suffering from a bacterial infection. In
one embodiment, the subject is a human. In some embodiments,
bacteria are contacted with one or more compounds described herein.
In some embodiments, the bacteria are Gram-positive bacteria. In
one embodiment, the bacteria is Staphylococcus aureus (methicillin
sensitive), Staphylococcus aureus (methicillin resistant),
Streptococcus pneumonia (penicillin sensitive), Streptococcus
pneumonia (penicillin resistant), Staphylococcus epidermis
(multiple drug resistant), Enterococcus faecalis (vancomycin
sensitive), or Enterococcus faecium (vancomycin resistant). In some
embodiments, the Gram-negative bacteria is Haemophilus
influenzae.
Pharmaceutical Compositions
[0191] In another aspect, the present disclosure relates to a
pharmaceutical composition comprising a physiologically acceptable
surface active agents, carriers, diluents, excipients, smoothing
agents, suspension agents, film forming substances, and coating
assistants, or a combination thereof; and a compound disclosed
herein. Acceptable carriers or diluents for therapeutic use are
well known in the pharmaceutical art, and are described, for
example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack
Publishing Co., Easton, Pa. (1990), which is incorporated herein by
reference in its entirety. Preservatives, stabilizers, dyes,
sweeteners, fragrances, flavoring agents, and the like may be
provided in the pharmaceutical composition. For example, sodium
benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be
added as preservatives. In addition, antioxidants and suspending
agents may be used. In various embodiments, alcohols, esters,
sulfated aliphatic alcohols, and the like may be used as surface
active agents; sucrose, glucose, lactose, starch, crystallized
cellulose, mannitol, light anhydrous silicate, magnesium aluminate,
magnesium methasilicate aluminate, synthetic aluminum silicate,
calcium carbonate, sodium acid carbonate, calcium hydrogen
phosphate, calcium carboxymethyl cellulose, and the like may be
used as excipients; magnesium stearate, talc, hardened oil and the
like may be used as smoothing agents; coconut oil, olive oil,
sesame oil, peanut oil, soya may be used as suspension agents or
lubricants; cellulose acetate phthalate as a derivative of a
carbohydrate such as cellulose or sugar, or
methylacetate-methacrylate copolymer as a derivative of polyvinyl
may be used as suspension agents; and plasticizers such as ester
phthalates and the like may be used as suspension agents.
[0192] The term "pharmaceutical composition" refers to a mixture of
a compound disclosed herein with other chemical components, such as
diluents or carriers. The pharmaceutical composition facilitates
administration of the compound to an organism. Multiple techniques
of administering a compound exist in the art including, but not
limited to, oral, injection, aerosol, parenteral, and topical
administration. Pharmaceutical compositions can also be obtained by
reacting compounds with inorganic or organic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid and the like.
[0193] The term "carrier" defines a chemical compound that
facilitates the incorporation of a compound into cells or tissues.
For example dimethyl sulfoxide (DMSO) is a commonly utilized
carrier as it facilitates the uptake of many organic compounds into
the cells or tissues of an organism.
[0194] The term "diluent" defines chemical compounds diluted in
water that will dissolve the compound of interest as well as
stabilize the biologically active form of the compound. Salts
dissolved in buffered solutions are utilized as diluents in the
art. One commonly used buffered solution is phosphate buffered
saline because it mimics the salt conditions of human blood. Since
buffer salts can control the pH of a solution at low
concentrations, a buffered diluent rarely modifies the biological
activity of a compound.
[0195] The term "physiologically acceptable" defines a carrier or
diluent that does not abrogate the biological activity and
properties of the compound.
[0196] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical
compositions where they are mixed with other active ingredients, as
in combination therapy, or suitable carriers or excipient(s).
Techniques for formulation and administration of the compounds of
the instant application may be found in "Remington's Pharmaceutical
Sciences," Mack Publishing Co., Easton, Pa., 18th edition,
1990.
[0197] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, topical, or intestinal administration;
parenteral delivery, including intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intranasal, or
intraocular injections. The compounds can also be administered in
sustained or controlled release dosage forms, including depot
injections, osmotic pumps, pills, transdermal (including
electrotransport) patches, and the like, for prolonged and/or
timed, pulsed administration at a predetermined rate.
[0198] The pharmaceutical compositions of the present invention may
be manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tabletting
processes.
[0199] Pharmaceutical compositions for use in accordance with the
present invention thus may be formulated in conventional manner
using one or more physiologically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen. Any of the well-known techniques, carriers,
and excipients may be used as suitable and as understood in the
art; e.g., in Remington's Pharmaceutical Sciences, above.
[0200] Injectables can be prepared in conventional forms, either as
liquid solutions or suspensions, solid forms suitable for solution
or suspension in liquid prior to injection, or as emulsions.
Suitable excipients are, for example, water, saline, dextrose,
mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine
hydrochloride, and the like. In addition, if desired, the
injectable pharmaceutical compositions may contain minor amounts of
nontoxic auxiliary substances, such as wetting agents, pH buffering
agents, and the like. Physiologically compatible buffers include,
but are not limited to, Hanks's solution, Ringer's solution, or
physiological saline buffer. If desired, absorption enhancing
preparations (for example, liposomes), may be utilized.
[0201] For transmucosal administration, penetrants appropriate to
the barrier to be permeated may be used in the formulation.
[0202] Pharmaceutical formulations for parenteral administration,
e.g., by bolus injection or continuous infusion, include aqueous
solutions of the active compounds in water-soluble form.
Additionally, suspensions of the active compounds may be prepared
as appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles include fatty oils such as sesame oil, or
other organic oils such as soybean, grapefruit or almond oils, or
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
or liposomes. Aqueous injection suspensions may contain substances
which increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. Optionally, the
suspension may also contain suitable stabilizers or agents that
increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions. Formulations for
injection may be presented in unit dosage form, e.g., in ampoules
or in multi-dose containers, with an added preservative. The
compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulatory
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0203] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by
combining the active compounds with solid excipient, optionally
grinding a resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents may be added, such as the
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. Dragee cores are provided with
suitable coatings. For this purpose, concentrated sugar solutions
may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solutions, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments may be added to the
tablets or dragee coatings for identification or to characterize
different combinations of active compound doses. For this purpose,
concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be added to the tablets or dragee coatings for
identification or to characterize different combinations of active
compound doses.
[0204] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0205] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0206] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of, e.g., gelatin for use in an inhaler or insufflator
may be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0207] Further disclosed herein are various pharmaceutical
compositions well known in the pharmaceutical art for uses that
include intraocular, intranasal, and intraauricular delivery.
Suitable penetrants for these uses are generally known in the art.
Pharmaceutical compositions for intraocular delivery include
aqueous ophthalmic solutions of the active compounds in
water-soluble form, such as eyedrops, or in gellan gum (Shedden et
al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al.,
Opthalmologica, 210(2):101-3 (1996)); ophthalmic ointments;
ophthalmic suspensions, such as microparticulates, drug-containing
small polymeric particles that are suspended in a liquid carrier
medium (Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)),
lipid-soluble formulations (Alm et al., Prog. Clin. Biol. Res.,
312:447-58 (1989)), and microspheres (Mordenti, Toxicol. Sci.,
52(1):101-6 (1999)); and ocular inserts. All of the above-mentioned
references, are incorporated herein by reference in their
entireties. Such suitable pharmaceutical formulations are most
often and preferably formulated to be sterile, isotonic and
buffered for stability and comfort. Pharmaceutical compositions for
intranasal delivery may also include drops and sprays often
prepared to simulate in many respects nasal secretions to ensure
maintenance of normal ciliary action. As disclosed in Remington's
Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.
(1990), which is incorporated herein by reference in its entirety,
and well-known to those skilled in the art, suitable formulations
are most often and preferably isotonic, slightly buffered to
maintain a pH of 5.5 to 6.5, and most often and preferably include
antimicrobial preservatives and appropriate drug stabilizers.
Pharmaceutical formulations for intraauricular delivery include
suspensions and ointments for topical application in the ear.
Common solvents for such aural formulations include glycerin and
water.
[0208] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0209] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds may be formulated with
suitable polymeric or hydrophobic materials (for example as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0210] For hydrophobic compounds, a suitable pharmaceutical carrier
may be a cosolvent system comprising benzyl alcohol, a nonpolar
surfactant, a water-miscible organic polymer, and an aqueous phase.
A common cosolvent system used is the VPD co-solvent system, which
is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant Polysorbate 80.TM., and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. Naturally, the proportions
of a co-solvent system may be varied considerably without
destroying its solubility and toxicity characteristics.
Furthermore, the identity of the co-solvent components may be
varied: for example, other low-toxicity nonpolar surfactants may be
used instead of POLYSORBATE 80.TM.; the fraction size of
polyethylene glycol may be varied; other biocompatible polymers may
replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other
sugars or polysaccharides may substitute for dextrose.
[0211] Alternatively, other delivery systems for hydrophobic
pharmaceutical compounds may be employed. Liposomes and emulsions
are well known examples of delivery vehicles or carriers for
hydrophobic drugs. Certain organic solvents such as
dimethylsulfoxide also may be employed, although usually at the
cost of greater toxicity. Additionally, the compounds may be
delivered using a sustained-release system, such as semipermeable
matrices of solid hydrophobic polymers containing the therapeutic
agent. Various sustained-release materials have been established
and are well known by those skilled in the art. Sustained-release
capsules may, depending on their chemical nature, release the
compounds for a few weeks up to over 100 days. Depending on the
chemical nature and the biological stability of the therapeutic
reagent, additional strategies for protein stabilization may be
employed.
[0212] Agents intended to be administered intracellularly may be
administered using techniques well known to those of ordinary skill
in the art. For example, such agents may be encapsulated into
liposomes. All molecules present in an aqueous solution at the time
of liposome formation are incorporated into the aqueous interior.
The liposomal contents are both protected from the external
micro-environment and, because liposomes fuse with cell membranes,
are efficiently delivered into the cell cytoplasm. The liposome may
be coated with a tissue-specific antibody. The liposomes will be
targeted to and taken up selectively by the desired organ.
Alternatively, small hydrophobic organic molecules may be directly
administered intracellularly.
[0213] Additional therapeutic or diagnostic agents may be
incorporated into the pharmaceutical compositions. Alternatively or
additionally, pharmaceutical compositions may be combined with
other compositions that contain other therapeutic or diagnostic
agents.
Methods of Administration
[0214] The compounds or pharmaceutical compositions may be
administered to the patient by any suitable means. Non-limiting
examples of methods of administration include, among others, (a)
administration though oral pathways, which administration includes
administration in capsule, tablet, granule, spray, syrup, or other
such forms; (b) administration through non-oral pathways such as
rectal, vaginal, intraurethral, intraocular, intranasal, or
intraauricular, which administration includes administration as an
aqueous suspension, an oily preparation or the like or as a drip,
spray, suppository, salve, ointment or the like; (c) administration
via injection, subcutaneously, intraperitoneally, intravenously,
intramuscularly, intradermally, intraorbitally, intracapsularly,
intraspinally, intrasternally, or the like, including infusion pump
delivery; (d) administration locally such as by injection directly
in the renal or cardiac area, e.g., by depot implantation; as well
as (e) administration topically; as deemed appropriate by those of
skill in the art for bringing the compound of the invention into
contact with living tissue.
[0215] Pharmaceutical compositions suitable for administration
include compositions where the active ingredients are contained in
an amount effective to achieve its intended purpose. The
therapeutically effective amount of the compounds disclosed herein
required as a dose will depend on the route of administration, the
type of animal, including human, being treated, and the physical
characteristics of the specific animal under consideration. The
dose can be tailored to achieve a desired effect, but will depend
on such factors as weight, diet, concurrent medication and other
factors which those skilled in the medical arts will recognize.
More specifically, a therapeutically effective amount means an
amount of compound effective to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being
treated. Determination of a therapeutically effective amount is
well within the capability of those skilled in the art, especially
in light of the detailed disclosure provided herein.
[0216] As will be readily apparent to one skilled in the art, the
useful in vivo dosage to be administered and the particular mode of
administration will vary depending upon the age, weight and
mammalian species treated, the particular compounds employed, and
the specific use for which these compounds are employed. The
determination of effective dosage levels, that is the dosage levels
necessary to achieve the desired result, can be accomplished by one
skilled in the art using routine pharmacological methods.
Typically, human clinical applications of products are commenced at
lower dosage levels, with dosage level being increased until the
desired effect is achieved. Alternatively, acceptable in vitro
studies can be used to establish useful doses and routes of
administration of the compositions identified by the present
methods using established pharmacological methods.
[0217] In non-human animal studies, applications of potential
products are commenced at higher dosage levels, with dosage being
decreased until the desired effect is no longer achieved or adverse
side effects disappear. The dosage may range broadly, depending
upon the desired affects and the therapeutic indication. Typically,
dosages may be between about 10 microgram/kg and 100 mg/kg body
weight, preferably between about 100 microgram/kg and 10 mg/kg body
weight. Alternatively dosages may be based and calculated upon the
surface area of the patient, as understood by those of skill in the
art.
[0218] The exact formulation, route of administration and dosage
for the pharmaceutical compositions of the present invention can be
chosen by the individual physician in view of the patient's
condition. (See e.g., Fingl et al. 1975, in "The Pharmacological
Basis of Therapeutics", which is hereby incorporated herein by
reference in its entirety, with particular reference to Ch. 1, p.
1). Typically, the dose range of the composition administered to
the patient can be from about 0.5 to 1000 mg/kg of the patient's
body weight. The dosage may be a single one or a series of two or
more given in the course of one or more days, as is needed by the
patient. In instances where human dosages for compounds have been
established for at least some condition, the present invention will
use those same dosages, or dosages that are between about 0.1% and
500%, more preferably between about 25% and 250% of the established
human dosage. Where no human dosage is established, as will be the
case for newly-discovered pharmaceutical compounds, a suitable
human dosage can be inferred from ED.sub.50 or ID.sub.50 values, or
other appropriate values derived from in vitro or in vivo studies,
as qualified by toxicity studies and efficacy studies in
animals.
[0219] It should be noted that the attending physician would know
how to and when to terminate, interrupt, or adjust administration
due to toxicity or organ dysfunctions. Conversely, the attending
physician would also know to adjust treatment to higher levels if
the clinical response were not adequate (precluding toxicity). The
magnitude of an administrated dose in the management of the
disorder of interest will vary with the severity of the condition
to be treated and to the route of administration. The severity of
the condition may, for example, be evaluated, in part, by standard
prognostic evaluation methods. Further, the dose and perhaps dose
frequency, will also vary according to the age, body weight, and
response of the individual patient. A program comparable to that
discussed above may be used in veterinary medicine.
[0220] Although the exact dosage will be determined on a
drug-by-drug basis, in most cases, some generalizations regarding
the dosage can be made. The daily dosage regimen for an adult human
patient may be, for example, an oral dose of between 0.1 mg and
2000 mg of each active ingredient, preferably between 1 mg and 500
mg, e.g. 5 to 200 mg. In other embodiments, an intravenous,
subcutaneous, or intramuscular dose of each active ingredient of
between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg,
e.g. 1 to 40 mg is used. In cases of administration of a
pharmaceutically acceptable salt, dosages may be calculated as the
free base. In some embodiments, the composition is administered 1
to 4 times per day. Alternatively the compositions of the invention
may be administered by continuous intravenous infusion, preferably
at a dose of each active ingredient up to 1000 mg per day. As will
be understood by those of skill in the art, in certain situations
it may be necessary to administer the compounds disclosed herein in
amounts that exceed, or even far exceed, the above-stated,
preferred dosage range in order to effectively and aggressively
treat particularly aggressive diseases or infections. In some
embodiments, the compounds will be administered for a period of
continuous therapy, for example for a week or more, or for months
or years.
[0221] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety which are sufficient to
maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will
depend on individual characteristics and route of administration.
However, HPLC assays or bioassays can be used to determine plasma
concentrations.
[0222] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, preferably
between 30-90% and most preferably between 50-90%.
[0223] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0224] The amount of composition administered will, of course, be
dependent on the subject being treated, on the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician.
[0225] Compounds disclosed herein can be evaluated for efficacy and
toxicity using known methods. For example, the toxicology of a
particular compound, or of a subset of the compounds, sharing
certain chemical moieties, may be established by determining in
vitro toxicity towards a cell line, such as a mammalian, and
preferably human, cell line. The results of such studies are often
predictive of toxicity in animals, such as mammals, or more
specifically, humans. Alternatively, the toxicity of particular
compounds in an animal model, such as mice, rats, rabbits, or
monkeys, may be determined using known methods. The efficacy of a
particular compound may be established using several recognized
methods, such as in vitro methods, animal models, or human clinical
trials. Recognized in vitro models exist for nearly every class of
condition, including but not limited to cancer, cardiovascular
disease, and various immune dysfunction. Similarly, acceptable
animal models may be used to establish efficacy of chemicals to
treat such conditions. When selecting a model to determine
efficacy, the skilled artisan can be guided by the state of the art
to choose an appropriate model, dose, and route of administration,
and regime. Of course, human clinical trials can also be used to
determine the efficacy of a compound in humans.
[0226] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions comprising a
compound of the invention formulated in a compatible pharmaceutical
carrier may also be prepared, placed in an appropriate container,
and labeled for treatment of an indicated condition.
EXAMPLES
Example 1
Fermentation of NPS-008920
[0227] Strain NPS008920 was grown in a 40 ml tube containing 10 ml
of seed medium consisting of the following per liter of sea water:
starch, 10 g; yeast extract, 4 g; and peptone, 2 g. The culture was
allowed to incubate for 3 days at 28 degree C. on a rotary shaker
operating at 250 rpm. The vegetative culture was mixed with 2 ml of
cryoprotective solution consisting of 500 g glycerol per liter of
deionized water. 1.5 ml portions of this mixture were transferred
to sterile cryogenic tube (1.8 ml capacity). The vegetative
cultures so obtained were frozen and stored at -80 degree C.
[0228] Seed culture was prepared by transferring two 1.5 ml of the
cryopreservative cultures to a 100 ml flask containing 100 ml of
sterile seed medium having the same composition as the above. The
seed culture was incubated at 28 degrees C. for 4 days on a rotary
shaker operating at 250 rpm. Five ml of this seed culture was
inoculated into nine 500 ml flasks each containing 100 ml of the
seed medium. The second seed cultures were incubated at 28 degrees
C. for 2 days on a rotary shaker operating at 250 rpm. Five to six
ml each of the second seed culture was inoculated into the
production medium having the same composition of the seed medium.
The production culture was incubated at 28 degree C. for 5 days on
a rotary shaker operating at 250 rpm. The culture broth (5 L) was
extracted with 5 liters of ethyl acetate. The extract was dried in
vacuo.
Example 2
Purification to Obtain Compounds of Formulae VI and VII
[0229] The crude extract (0.38 g) of NPS008920 obtained as
described in Example 1 was dissolved in MeOH (19 ml) and injected
in 950 .mu.l aliquots (19 mg each) on preparative reversed phase
HPLC using the following conditions: [0230] Column: Ace 5 um C18-HL
[0231] Dimensions: 15 cm.times.21 mm ID [0232] Flow rate: 14.5
ml/min [0233] Detection: UV DAD [0234] Solvent: 20% ACN/H.sub.2O to
80% ACN/H.sub.2O in 12 min; 80% to 100% ACN/H.sub.2O in 1 min then
9 min at 100% ACN
[0235] Two compounds were well separated using the above
conditions. One compound (identified as the compound of formula VI)
eluted at 21 minutes. The second compound (identified as the
compound of formula VII) eluted at 23 minutes. These compounds were
further purified by reversed phase semi-preparative HPLC using the
following conditions: [0236] Column: Hamilton 10 um PRP-1
(Polymeric Reversed Phase) [0237] Dimensions: 25 cm.times.10 mm ID
[0238] Flow rate: 3 ml/min [0239] Detection: UV DAD [0240] Solvent:
Gradient of 40% ACN/H.sub.2O to 80% ACN/H.sub.2O in 8 min; 80% to
100% ACN in 1 min then 15 min at 100% ACN.
Example 3
Fermentation of NPS-008920
[0241] Strain NPS008920 was grown in a 100 ml flask containing 100
ml of seed medium consisting of the following per liter of sea
water: starch, 10 g; yeast extract, 4 g; and peptone, 2 g. The
culture was allowed to incubate for 6 days at 28 degree C. on a
rotary shaker operating at 250 rpm. The vegetative culture was
mixed with cryoprotective solution consisting of 500 g glycerol per
liter of deionized water to yield a final glycerol concentration of
10%. 1.5 ml portions of this mixture were transferred to sterile
cryogenic tube (1.8 ml capacity). The vegetative cultures so
obtained were frozen and stored at -80 degree C.
[0242] Seed culture was prepared by transferring two 1.5 ml of the
cryopreservative cultures to a 100 ml flask containing 100 ml of
sterile seed medium having the same composition as the above. The
seed culture was incubated at 28 degrees C. for 3 days on a rotary
shaker operating at 250 rpm. Five ml of this seed culture was
inoculated into nine 500 ml flasks each containing 100 ml of the
seed medium. The second seed cultures were incubated at 28 degrees
C. for 2 days on a rotary shaker operating at 250 rpm. Five to six
ml each of the second seed culture was inoculated into the
production medium having the same composition of the seed medium.
The production culture was incubated at 28 degree C. for 5 days on
a rotary shaker operating at 250 rpm. The culture broth (10 L) was
extracted with 10 liters of ethyl acetate. The extract was dried in
vacuo.
Example 4
Purification to Obtain the Compound of Formula VIII
[0243] The crude extract (1.2 g) of NPS008920 obtained as described
in Example 3 was dissolved in water (100 mL) and extracted with
hexane (3.times.100 mL). The combined organic layer was
concentrated to yield about 570 mg of Formula VI enriched material
which was purified by preparative scale reversed phase HPLC using
the following conditions (50 mg per injection). [0244] Column: Ace
5 um C18-HL
[0245] Dimensions: 15 cm.times.21 mm ID [0246] Flow rate: 14.5
ml/min [0247] Detection: UV DAD [0248] Solvent: 50% ACN/H.sub.2O to
100% ACN in 12 min; then 13 min at 100% ACN
[0249] The compound of formula VIII eluted at about 18 min as a
minor compound. This compound was further purified by reversed
phase preparative HPLC using the following conditions with
different solvent system: [0250] Column: Ace 5 um C18-HL [0251]
Dimensions: 15 cm.times.21 mm ID [0252] Flow rate: 14.5 ml/min
[0253] Detection: UV DAD [0254] Solvent: 20% MeOH/H.sub.2O to 80%
MeOH/H.sub.2O in 12 min; 80% to 100% MeOH/H.sub.2O in 1 min then 9
min at 100% MeOH
[0255] The pure compound of formula VIII was eluted at about 18.5
min.
Example 5
Preparation of the Compound of Formula IX
[0256] The compound of formula IX was obtained by adding pH 7.4
buffer (2 mL) into a solution of the compound of formula XIII (4.2
mg) in acetonitrile and letting it stand at room temperature for
about 4 days. The acetonitrile was removed by rotavap and the
remaining aqueous layer was extracted with methyle chloride
(3.times.20 mL). The combined organic layer was concentrated to
yield the compound of formula IX (3.2 mg).
Example 6
Structural Characterization
[0257] The compounds of Formulas VI, VII, VIII, and IX were
characterized as follows:
[0258] Formula VI: [.alpha.].sup.21.2.sub.D-30.99 (c 0.0002, MeOH);
UV (MeOH) .lamda..sub.max 310 (.epsilon. 22,700), 253 (9,100) nm;
UV (Acetonitrile/H.sub.2O) .lamda..sub.max 310, 255 nm. HRESIMS m/z
322.2372 [M+H] .DELTA..sub.calc C.sub.19H.sub.32NO.sub.3
(322.2382)=3.3 ppm.
[0259] Formula VII: UV (Acetonitrile/H.sub.2O) .lamda..sub.max 310,
255 nm. HRESIMS m/z 336.2527 [M+H] .DELTA..sub.calc
C.sub.20H.sub.34NO.sub.3 (336.2539)=3.5 ppm.
[0260] Formula VIII: UV (Acetonitrile/H.sub.2O) .lamda..sub.max
310, 255 nm. HRESIMS m/z 308.2234 [M+H] .DELTA..sub.calc
C.sub.18H.sub.30NO.sub.3 (308.2226)=2.8 ppm.
[0261] Formula IX: UV (Acetonitrile/H.sub.2O) .lamda..sub.max 245
nm. LRESIMS m/z 340 [M+H].
[0262] .sup.1H-NMR and .sup.13C-NMR was conducted in order to
elucidate the structures of the four compounds. The results are
indicated in Tables 1-4 and the assignments were made as
illustrated in the following structures:
##STR00023##
The double bond geometry of C-1' to C-2 was not established for
Formulae VI, VII and VIII.
TABLE-US-00001 TABLE 1 .sup.1H NMR Assignments. Formula VII Formula
VI CDCl.sub.3 DMSO-d6 CDCl.sub.3 **.delta..sub.H int., Pos
*.delta..sub.H int., mult, J (Hz) **.delta..sub.H int., mult, J
(Hz) mult, J (Hz) 5 4.88 1H, dd, 4.7, 6.6 4.59 1H, dd, 4.4, 7.0
4.58 1H, dd, 4.4, 7.0 1' 5.28 1H, s 5.18 1H, s 5.17 1H, s 3' 5.98
1H, br s 5.87 1H, br s 5.86 1H, br s 5' 2.08 2H, br t, 7.5 2.10 3H,
br t, 7.6 2.09 2H, br t, 7.6 6' 1.43 2H, m 1.44 2H, m 1.44 2H, m 7'
1.25 2H, ca 1.26 2H, m 1.26 2H, m 8' 1.25 2H, ca 1.26 2H, m 1.26
2H, m 9' 1.25 2H, ca 1.23 2H, m 1.23 2H, m 10' 1.28 2H, ca 1.26 2H,
m 1.26 2H, m 11' 0.86 3H, t, 6.6 0.87 3H, t, 7.0 0.85 3H, t, 7.0
12' 2.11 3H, br s 2.15 3H, br s 2.14 3H, br s 1'' 1.71 1H, m 1.79
1H, m 1.77 1H, m 1.84 1H, m 1.96 1H, m 1.94 1H, m 2'' 1.31 2H, ca
1.40 2H, m 1.42 2H, m 3'' 1.30 2H, ca 1.36 2H, m 1.28 2H, m 4''
0.87 3H, t, 6.6 0.90 3H, t, 7.0 1.28 2H, m 5'' -- -- 0.86 3H, t,
7.0 *.delta..sub.H values referenced to internal solvent for
DMSO-d.sub.6 at 2.50 ppm **.delta..sub.H values referenced to
internal solvent for CDCl.sub.3 at 7.24 ppm
TABLE-US-00002 TABLE 2 .sup.1H NMR Assignments. Formula VIII
Formula IX CDCl.sub.3 CDCl.sub.3 Pos *.delta..sub.H int., mult, J
(Hz) *.delta..sub.H int., mult, J (Hz) 5 4.59 1H, dd, 4.4, 7.0 5.24
1H, dd, 3.8, 8.5 1' 5.18 1H, s 3.56 1H, d, 16.4 3.67 1H, d, 16.4 3'
5.87 1H, br s 6.02 1H, br s 5' 2.10 3H, br t, 7.6 2.15 2H, br t,
7.6 6' 1.44 2H, m 1.46 2H, m 7' 1.28 2H, m 1.26 2H, m 8' 1.24 2H, m
1.26 2H, m 9' 1.27 2H, m 1.23 2H, m 10' 0.86 3H, t, 7.0 1.26 2H, m
11' -- 0.87 3H, t, 7.0 12' 2.15 3H, br s 2.15 3H, br s 1'' 1.79 1H,
m 1.82 1H, m 1.96 1H, m 1.96 1H, m 2'' 1.41 2H, m 1.34 2H, m 3''
1.35 2H, m 1.31 2H, m 4'' 0.90 3H, t, 7.0 0.88 3H, t, 7.0
*.delta..sub.H values referenced to internal solvent for CDCl.sub.3
at 7.24 ppm
TABLE-US-00003 TABLE 3 .sup.13C NMR Assignments. Formula VI Formula
VII .delta..sub.C* mult in .delta..sub.C** mult in .delta..sub.C**
mult in Pos DMSO CDCl.sub.3 CDCl.sub.3 2 165.3 s 166.7 s 166.5 s 4
173.8 s 173.7 s 173.6 s 5 77.6 d 78.6 d 78.6 d 1' 83.6 d 84.0 d
84.0 d 2' 187.9 s 189.4 s 189.4 s 3' 124.6 d 124.3 d 124.3 d 4'
155.4 s 157.7 s 157.7 s 5' 40.4 t 41.5 t 41.4 t 6' 27.0 t 27.6 t
27.6 t 7' 28.4 t 29.1 t.sup.e 29.1 t.sup.d 8' 28.6 t 29.2 t.sup.e
29.7 t.sup.d 9' 31.1 t 31.8 t 31.7 t 10' 22.0 t 22.6 t 22.6 t 11'
13.9 q 14.1 q 14.0 q 12' 18.4 q 19.2 q 19.1 q 1'' 29.9 t 30.8 t
31.0 t 2'' 25.6 t 26.2 t 23.7 t 3'' 21.6 t 22.2 t 31.2 t 4'' 13.6 q
13.7 t 22.3 t 5'' -- -- 13.9 q *.delta..sub.C values referenced to
internal solvent for DMSO-d.sub.6 at 39.50 ppm **.delta..sub.C
values referenced to internal solvent for CDCl.sub.3 at 77.00 ppm
(some values obtained through HMBC and HMQC) .sup.d,emay be
interchangeable
TABLE-US-00004 TABLE 4 .sup.13C NMR Assignments. Formula VIII
Formula IX .delta..sub.C** mult in .delta..sub.C** mult in Pos
CDCl.sub.3 CDCl.sub.3 2 166.6 s 166.6 s 4 173.7 s 172.8 s 5 78.6 d
74.3 d 1' 84.1 d 50.3 t 2' 189.4 s 193.5 s 3' 124.3 d 121.5 d 4'
157.7 s 164.9 s 5' 41.5 t 41.5 t 6' 27.6 t 27.5 t 7' 28.9 t 29.0
t.sup.a 8' 31.7 t 29.2 t.sup.a 9' 22.5 t 31.7 t 10' 14.0 q 22.6 t
11' -- 14.0 q.sup.b 12' 19.1 q 20.0 q 1'' 30.8 t 31.2 t 2'' 26.1 t
27.2 t 3'' 22.2 t 22.3 t 4'' 13.7 q 13.9 q.sup.b **.delta..sub.C
values referenced to internal solvent for CDCl.sub.3 at 77.00 ppm
.sup.a,bmay be interchangeable
Example 7
Growth Inhibition of Murine Melanoma B16-F10 Cells
[0263] B16-F10 (ATCC; CRL-6475) a murine melanoma cell line was
maintained in complete Dulbecco's Modification of Eagle's Medium
(DMEM) (DMEM supplemented with 10% (v/v) Fetal bovine serum, 2 mM
glutamine, 10 mM HEPES and Penicillin/Streptomycin at 100 IU/ml and
100 .mu.g/ml respectively). The cells were cultured in an incubator
at 37.degree. C. in 5% CO.sub.2 and 95% humidified air.
[0264] For cell growth inhibition assays, B16-F10 cells were seeded
at 1.25.times.10.sup.3 cells/well in 90 .mu.l complete media into
Corning 3904 black-walled, clear-bottom tissue culture plates and
the plates were incubated overnight to allow cells to establish and
enter log phase growth. 20 mM stock solutions of formula VI were
prepared in 100% DMSO. 10.times. concentrated serial dilutions of
formula VI were prepared in complete media. Ten .mu.l volumes of
the serial dilutions were added to the test wells in triplicate
resulting in final concentrations ranging from 20 .mu.M to 6.32 nM.
The plates were returned to the incubator for 48 hours. The final
concentration of DMSO was 0.25% in all samples.
[0265] Following 48 hours of drug exposure, 10 .mu.l of 0.2 mg/ml
resazurin (obtained from Sigma-Aldrich Chemical Co.) in Mg.sup.2+,
Ca.sup.2+ free phosphate buffered saline was added to each well and
the plates were returned to the incubator for 3-6 hours. Since
living cells metabolize Resazurin, the fluorescence of the
reduction product of Resazurin was measured using a Fusion
microplate fluorometer (Packard Bioscience) with .lamda..sub.ex=535
nm and .lamda..sub.em=590 nm filters. Resazurin dye in medium
without cells was used to determine the background, which was
subtracted from the data for all experimental wells. The data were
normalized to the average fluorescence of the cells treated with
media+0.25% DMSO (100% cell growth) and EC.sub.50 values (the drug
concentration at which 50% of the maximal observed growth
inhibition is established) were determined using a standard
sigmoidal dose response curve fitting algorithm (XLfit 3.0, ID
Business Solutions Ltd).
[0266] The data in Table 5 summarize the mean growth inhibitory
effects of the compound of formula VI against the murine melanoma,
B16-F10 cell line.
TABLE-US-00005 TABLE 5 EC.sub.50 values of formula V against
B16-F10 cells. FORMULA VI B16-F10 EC.sub.50 (.mu.M) 6.0 .+-. 2.6*
*data presented as mean .+-. standard deviation of three
independent experiments
[0267] The EC.sub.50 value indicates that the compound of formula
VI inhibits the growth of B16-F10 tumor cells.
Example 8
Antimicrobial Assays
[0268] Minimum inhibitory concentrations (MICs) were determined
according to the National Committee for Clinical Laboratory
Standards (NCCLS) susceptibility test guideline M7-A5 (Ferraro, M.
2001 Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria that Grow Aerobically; Approved Standard (NCCLS). National
Committee for Clinical Laboratory Standards (NCCLS), Villanova,
which is incorporated herein by reference in its entirety). The
compound of formula VI was tested in DMSO while the compound of
formula VII was tested in aqueous MeOH. Antimicrobial data for the
compounds of formulae VI and VII are shown in Table 6. The compound
of formulae VIII and IX were tested in DMSO. Antimicrobial data for
the compounds of formulae VIII and IX are shown in Table 7.
TABLE-US-00006 TABLE 6 Antimicrobial data. MIC (.mu.g/ml) Organism
Formula VI Formula VII Staphylococcus aureus - MSSA 0.88 6
Staphylococcus aureus - MRSA 1.04 1.5 S. epi. 700578 0.54 1.25 S.
epi. 700582 0.54 0.75 PSSP 2.58 8 PRSP 4.67 6 VSE 3.67 3 VRE 1.83
1.5 E. c. imp >32 >32 E. c. MCR106 >32 >32 E. c. 25922
>32 >32 H. inf. 49247 12 12 H. inf. 49766 12 16 Candida
albicans >32 >32
TABLE-US-00007 TABLE 7 Antimicrobial data. MIC (.mu.g/ml) Organism
Formula VIII Formula IX Staphylococcus aureus - MSSA 4 24
Staphylococcus aureus - MRSA 3 >32 PSSP 10 >32 H. inf. 49247
16 >32 H. inf. 49766 5 >32
[0269] The compounds of formulas VI, VII, and VIII were shown to
possess anti-bacterial activity versus the Gram-positive
microorganisms tested and were also weakly active against the
Gram-negative microorganism Haemophilus influenzae.
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