U.S. patent application number 13/864779 was filed with the patent office on 2013-09-05 for aminiothiazoles and their uses.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Simon Bushell, Matthew J. Lamarche, Jennifer Leeds, Lewis Whitehead. Invention is credited to Simon Bushell, Matthew J. Lamarche, Jennifer Leeds, Lewis Whitehead.
Application Number | 20130231275 13/864779 |
Document ID | / |
Family ID | 40377437 |
Filed Date | 2013-09-05 |
United States Patent
Application |
20130231275 |
Kind Code |
A1 |
Bushell; Simon ; et
al. |
September 5, 2013 |
AMINIOTHIAZOLES AND THEIR USES
Abstract
The present application describes organic compounds that are
useful for the treatment, prevention and/or amelioration of
diseases particularly bacterial infections.
Inventors: |
Bushell; Simon; (Boston,
MA) ; Lamarche; Matthew J.; (Reading, MA) ;
Leeds; Jennifer; (Arlington, MA) ; Whitehead;
Lewis; (Swampscott, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bushell; Simon
Lamarche; Matthew J.
Leeds; Jennifer
Whitehead; Lewis |
Boston
Reading
Arlington
Swampscott |
MA
MA
MA
MA |
US
US
US
US |
|
|
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
40377437 |
Appl. No.: |
13/864779 |
Filed: |
April 17, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12333602 |
Dec 12, 2008 |
8426356 |
|
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13864779 |
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61024709 |
Jan 30, 2008 |
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61013122 |
Dec 12, 2007 |
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Current U.S.
Class: |
514/2.4 ;
540/492 |
Current CPC
Class: |
A61P 17/02 20180101;
A61K 38/05 20130101; A61P 43/00 20180101; C07D 417/04 20130101;
Y02A 50/473 20180101; C07K 5/06139 20130101; A61P 17/10 20180101;
A61K 38/00 20130101; A61P 31/04 20180101; A61P 31/00 20180101; A61K
45/06 20130101 |
Class at
Publication: |
514/2.4 ;
540/492 |
International
Class: |
A61K 38/05 20060101
A61K038/05; A61K 45/06 20060101 A61K045/06; C07K 5/078 20060101
C07K005/078 |
Claims
1. A compound of the formula I: ##STR00178## and pharmaceutically
acceptable salts, enantiomers, stereoisomers, rotamers, tautomers,
diastereomers, atropisomers or racemates thereof, including the
pyridine N-oxide thereof; wherein R.sup.1 is --Z--CO.sub.2H and
-A-Z--CO.sub.2H; R.sup.1a is hydrogen, --Z--CO.sub.2H, and
-A-Z--CO.sub.2H, wherein if R.sup.1a is hydrogen, then the Z
residue of R.sup.1 is substituted by at least two CO.sub.2H groups;
or R.sup.1 and R.sup.1a, taken in combination, form a saturated,
partially unsaturated or aromatic heterocycle having 4 to 7 ring
atoms and having 0-3 additional ring heteroatoms selected from N, O
and S, wherein the heterocycle is substituted by at least two
residues independently selected from CO.sub.2H, --Z--CO.sub.2H, and
-A-Z--CO.sub.2H; A is indepenendently selected at each occurrence
from the group consisting of a --C(O)--, --C(O)O--,
--C(O)N(R.sup.8a)--, --S(O).sub.2--, --S(O)--, --C(H).dbd.N--,
--S(O).sub.2N(R.sup.8a)--, and --S(O)N(R.sup.8a)--; Z is
C.sub.1-C.sub.10alkylene, C.sub.3-C.sub.8cycloalkylene,
C.sub.3-C.sub.8heterocycloalkylene, phenylene, or 5-6 membered
heteroarylene, each of which is optionally substituted with one or
more groups independently selected from C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, hydroxy, amino, mono- and
di-C.sub.1-C.sub.6alkylamino, C(O)OH, or halogen; R.sup.2a is
selected from the group consisting of H, substituted or
unsubstituted alkyl, OH, OR.sup.4a, OC(O)R.sup.4a,
OC(O)N(R.sup.8a).sub.2 and N(R.sup.8a).sub.2; R.sup.2b is selected
from the group consisting of absent, H and alkyl, or R.sup.2a and
R.sup.2b may together form .dbd.O or .dbd.NH; R.sup.3 an R.sup.12
are each, independently, selected from the group consisting of H,
halogen, OR.sup.4b, -A-J, and N(R.sup.8a).sub.2; R.sup.4a is
selected from the group consisting of H, and alkyl; R.sup.4b is
selected from the group consisting of alkyl and
--(CH.sub.2--CH.sub.2--O--).sub.n--R.sup.9, wherein n is an integer
of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000,
30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of
integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000,
5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000; R.sup.5
is selected from the group consisting of H, alkyl, and R.sup.4b; J
is selected from the group consisting of H, F, O-alkyl,
N(R.sup.8a).sub.2, N.sup.+(R.sup.8a).sub.3, N(R.sup.8a)C(O)alkyl,
CO.sub.2H, C(.dbd.O)N(R.sup.8a).sub.2, CO.sub.2-alkyl,
P(O)(OH).sub.2, P(O)(O-alkyl).sub.2, and a substituted
nitrogen-containing heterocycle; R.sup.8a is absent, or selected
from the group consisting of H, -(alkyl)-, -(cycloalkyl)-,
C(alkyl).sub.2-J, --R.sup.4b, wherein R.sup.8a can also cyclize
with the atom to which R.sup.8a is bonded to form a 3, 4, 5, 6 or
7-membered ring that is aromatic or non-aromatic and may contain
one or more heteroatoms, wherein the ring may be further
substituted one or more times with substitutents that are the same
or different; and R.sup.9 is selected from the group consisting of
H, alkyl and CH.sub.2CO.sub.2H.
2. The compound of claim 1, wherein R.sup.2b, R.sup.4b and R.sup.5
are H, and R.sup.4a is CH.sub.3.
3. The compound of claim 1, wherein R.sup.2b, R.sup.4b and R.sup.5
are H, R.sup.4a is CH.sub.3, and R.sup.12 is
CH.sub.2--O--CH.sub.3.
4. The compound of claim 1, wherein formula I is represented by a
compound of formula II: ##STR00179## and pharmaceutically
acceptable salts thereof.
5. The compound of claim 1, wherein formula I is represented by a
compound of formula III: ##STR00180## and pharmaceutically
acceptable salts, enantiomers, stereoisomers, rotamers, tautomers,
diastereomers, atropisomers or racemates thereof, including the
pyridine N-oxide thereof.
6. The compound of claim 5, wherein R.sup.2b, R.sup.4b and R.sup.5
are H, and R.sup.4a is CH.sub.3.
7. The compound of claim 5, wherein R.sup.2b, R.sup.4b and R.sup.5
are H, R.sup.4a is CH.sub.3, and R.sup.12 is
CH.sub.2--O--CH.sub.3.
8. The compound of claim 5, wherein formula III is represented by a
compound of formula IV: ##STR00181##
9. The compound of claim 8, wherein A is selected from the group
consisting of --C(O)O--, C(O)--NH--, --C(O)--, --S(O).sub.2--, and
--S(O).sub.2NH--; and Z is independently selected at each
occurrence from the group consisting of C.sub.1-C.sub.10alkylene,
##STR00182##
10. The compound of claim 1, wherein formula I is represented by a
compound of formula V: ##STR00183## and pharmaceutically acceptable
salts, enantiomers, stereoisomers, rotamers, tautomers,
diastereomers, atropisomers or racemates thereof, including the
pyridine N-oxide thereof, wherein D represents a five or six
membered heterocyclic ring which is saturated or aromatic, which
ring comprises 0-2 additional ring heteroatoms selected from N, O
or S.
11. The compound of claim 10, wherein R.sup.2b, R.sup.4b and
R.sup.5 are H, and R.sup.4a is CH.sub.3.
12. The compound of claim 10, wherein R.sup.2b, R.sup.4b and
R.sup.5 are H, R.sup.4a is CH.sub.3, and R.sup.12 is
CH.sub.2--O--CH.sub.3.
13. The compound of claim 10, wherein formula V is represented by a
compound of formula VI: ##STR00184##
14. The compound of claim 13, wherein A is selected from the group
consisting of --C(O)O--, C(O)--NH--, --C(O)--, --S(O).sub.2--, and
--S(O).sub.2NH--; and Z is independently selected at each
occurrence from the group consisting of C.sub.1-C.sub.10alkylene,
##STR00185##
15. The compound of claim 1, wherein R.sup.2a is OH or OAc.
16. The compound of claim 1, wherein the core pyridine
functionality is of the following N-oxide formula: ##STR00186##
17. A compound selected from the group consisting of: ##STR00187##
##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192##
##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197##
##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202##
##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207##
##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212##
##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217##
##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222##
##STR00223## ##STR00224## ##STR00225## ##STR00226##
##STR00227##
18. A compound of formula VII: ##STR00228## and pharmaceutically
acceptable salts, enantiomers, stereoisomers, rotamers, tautomers,
diastereomers, atropisomers or racemates thereof, including the
pyridine N-oxide thereof; wherein R.sup.1 is --Z--CO.sub.2H and
-A-Z--CO.sub.2H; R.sup.1a is hydrogen, --Z--CO.sub.2H, and
-A-Z--CO.sub.2H, wherein if R.sup.1a is hydrogen, then the Z
residue of R.sup.1 is substituted by at least two CO.sub.2H groups;
or R.sup.1 and R.sup.1a, taken in combination, form a saturated,
partially unsaturated or aromatic heterocycle having 4 to 7 ring
atoms and having 0-3 additional ring heteroatoms selected from N, O
and S, wherein the heterocycle is substituted by at least two
residues independently selected from CO.sub.2H, --Z--CO.sub.2H, and
-A-Z--CO.sub.2H; A is indepenendently selected at each occurrence
from the group consisting of a --C(O)--, --C(O)O--,
--C(O)N(R.sup.8a)--, --S(O).sub.2--, --S(O)--, --C(H).dbd.N--,
--S(O).sub.2N(R.sup.8a)--, and --S(O)N(R.sup.8a)--; Z is
C.sub.1-C.sub.10alkylene, C.sub.3-C.sub.8cycloalkylene,
C.sub.3-C.sub.8heterocycloalkylene, phenylene, or 5-6 membered
heteroarylene, each of which is optionally substituted with one or
more groups independently selected from C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, hydroxy, amino, mono- and
di-C.sub.1-C.sub.6alkylamino, C(O)OH, or halogen; R.sup.2 is
hydrogen, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkoxyC.sub.0-6alkyl, C.sub.3-7cycloalkylC.sub.0-4alkyl,
arylC.sub.0-4alkyl, or a residue of the formula: ##STR00229##
R.sup.2a is selected from the group consisting of H, substituted or
unsubstituted alkyl, OH, OR.sup.4a, OC(O)R.sup.4a,
OC(O)N(R.sup.8a).sub.2 and N(R.sup.8a).sub.2; R.sup.2b is selected
from the group consisting of absent, H and alkyl, or R.sup.2a and
R.sup.2b may together form .dbd.O or .dbd.NH; R.sup.3 an R.sup.12
are each, independently, selected from the group consisting of H,
halogen, OR.sup.4b, -A-J, and N(R.sup.8a).sub.2; R.sup.4a is
selected from the group consisting of H, and alkyl; R.sup.4b is
selected from the group consisting of alkyl and
--(CH.sub.2--CH.sub.2--O--).sub.n--R.sup.9, wherein n is an integer
of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000,
30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of
integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000,
5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000; R.sup.5
is selected from the group consisting of H, alkyl, and R.sup.4b; J
is selected from the group consisting of H, F, O-alkyl,
N(R.sup.8a).sub.2, N.sup.+(R.sup.8a).sub.3, N(R.sup.8a)C(O)alkyl,
CO.sub.2H, C(.dbd.O)N(R.sup.8a).sub.2, CO.sub.2-alkyl,
P(O)(OH).sub.2, P(O)(O-alkyl).sub.2, and a substituted
nitrogen-containing heterocycle; R.sup.8a is absent, or selected
from the group consisting of H, -(alkyl)-, -(cycloalkyl)-,
C(alkyl).sub.2-J, --R.sup.4b, wherein R.sup.8a can also cyclize
with the atom to which R.sup.8a is bonded to form a 3, 4, 5, 6 or
7-membered ring that is aromatic or non-aromatic and may contain
one or more heteroatoms, wherein the ring may be further
substituted one or more times with substitutents that are the same
or different; and R.sup.9 is selected from the group consisting of
H, alkyl and CH.sub.2CO.sub.2H.
19. A method of treating a bacterial infection comprising
administering to a subject in need thereof a pharmaceutically
acceptable amount of a compound of claim 1, such that the bacterial
infection is treated.
20. A method of treating an EF-Tu associated-state comprising
administering to a subject in need thereof a pharmaceutically
acceptable amount of a compound of claim 1, such that the EF-Tu
associated state is treated.
21. A method of treating, inhibiting or preventing the activity of
EF-Tu in a subject in need thereof, comprising administering to the
subject a pharmaceutically acceptable amount of a compound of claim
1.
22. The method of claim 20, wherein a bacterial infection is
treated in a subject in need thereof.
23. A method of treating, inhibiting or preventing the activity of
bacteria in a subject in need thereof, comprising administering to
the subject a pharmaceutically acceptable amount of a compound of
claim 1, wherein the compound interacts with any target in the life
cycle of the bacteria.
24. The method of claim 22, wherein the target is EF-Tu.
25. A method of treating a bacterial infection in a subject,
comprising administering to a subject in need thereof a
pharmaceutically acceptable amount of a compound of claim 1, and a
pharmaceutically acceptable carrier, such that the bacterial
infection is treated.
26. A method of treating a bacterial infection comprising
administering to a subject in need thereof a pharmaceutically
effective amount of a compound of claims 1, in combination with a
pharmaceutically effective amount of an additional therapeutic
agent, such that the bacterial infection is treated.
27. The method of claim 25, wherein the compound of 1 and the other
pharmaceutical agent are administered as part of the same
pharmaceutical composition.
28. The method of claim 25, wherein the compound of claim 1 and the
other therapeutic agent are administered as separate pharmaceutical
compositions, and the compound is administered prior to, at the
same time as, or following administration of the other agent.
29. A packaged bacterial infection treatment, comprising a compound
of claim 1, packaged with instructions for using an effective
amount of the compound to treat a bacterial infection.
30. A method of treating acne in subject in need thereof comprising
administering to the subject a pharmaceutically acceptable amount
of a compound of claim 1.
31. A pharmaceutical composition comprising a compound of claim 1,
and at least one pharmaceutically acceptable carrier or
diluent.
32. The compound of claim 1, or a salt thereof, which is selected
from the group consisting of ##STR00230## ##STR00231## ##STR00232##
##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237##
##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242##
##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247##
Description
BACKGROUND
[0001] Since the discovery of penicillin, pharmaceutical companies
have produced a number of antibacterial agents to combat a wide
variety of bacterial infections. In the past several years, there
has been rapid emergence of bacterial resistance to several of
these antibiotics. The multidrug resistance among these bacterial
pathogens may also be due to mutation leading to more virulent
clinical isolation. Perhaps the most disturbing occurrence has been
the acquisition of resistance to vancomycin, an antibiotic
generally regarded as the agent of last resort for serious
Gram-positive infections.
[0002] This is true especially of some Gram-positive pathogen
groups, such as staphylococci, pneumococci and enterococci (S. Ewig
et al.; Antibiotika-Resistenz bei Erregern ambulant erworbener
Atemwegsinfektionen (Antibiotic resistance in pathogens of
outpatient-acquired respiratory tract infections); Chemother. J.
2002, 11, 12-26; F. Tenover; Development and spread of bacterial
resistance to antimicrobial agents: an overview; Clin. Infect. Dis.
2001 Sep. 15, 33 Suppl. 3, 108-115) as well as Staphylococcus,
Streptococcus, Mycobacterium, Enterococcus, Corynebacterium,
Borrelia, Bacillus, Chlamydia, Mycoplasma, and the like.
[0003] A problem of equally large dimension is the increasing
incidence of the more virulent, methicillin-resistant
Staphylococcus aureas (MRSA) among clinical isolates found
worldwide. As with vancomycin resistant organisms, many MRSA
strains are resistant to most of the known antibiotics, but MRSA
strains have remained sensitive to vancomycin. However, in view of
the increasing reports of vancomycin resistant clinical isolates
and growing problem of bacterial resistance, there is an urgent
need for new molecular entities effective against the emerging and
currently problematic Gram-positive organisms.
[0004] This growing multidrug resistance has recently rekindled
interest in the search for new structural classes of antibiotics
that inhibit or kill these bacteria.
SUMMARY OF THE INVENTION
[0005] There remains a need for new treatments and therapies for
bacterial infections. There is also a need for compounds useful in
the treatment or prevention or amelioration of one or more symptoms
of bacterial infections. Furthermore, there is a need for methods
for modulating the activity of the elongation factor EF-Tu, using
the compounds provided herein.
[0006] In one aspect, the invention provides a compound of formula
I:
##STR00001##
[0007] In another aspect, the invention provides a method of
treating a bacterial infection wherein the treatment includes
administering to a subject in need thereof a pharmaceutically
acceptable amount of a compound of formula I, II, III, IV, V, or
VI, such that the bacterial infection is treated.
[0008] In another aspect, the invention provides a method of
treating an EF-Tu associated-state wherein the treatment includes
administering to a subject in need thereof a pharmaceutically
acceptable amount of a compound of formula I, II, III, IV, V, or
VI, such that the EF-Tu associated state is treated.
[0009] In still another aspect, the invention provides a method of
treating, inhibiting or preventing the activity of EF-Tu in a
subject in need thereof, which includes administering to the
subject a pharmaceutically acceptable amount of a compound of
formula I, II, III, IV, V, or VI. In one embodiment, a bacterial
infection is treated in a subject in need thereof.
[0010] In another aspect, the invention provides a method of
treating, inhibiting or preventing the activity of bacteria in a
subject in need thereof, which includes administering to the
subject a pharmaceutically acceptable amount of a compound of
formula I, II, III, IV, V, or VI, wherein the compound interacts
with any target in the life cycle of the bacteria. In one
embodiment, the target is EF-Tu.
[0011] In another aspect, the invention provides a method of
treating a bacterial infection in a subject, wherein the treatment
includes administering to a subject in need thereof a
pharmaceutically acceptable amount of a compound of the formula I,
II, III, IV, V, or VI, and a pharmaceutically acceptable carrier,
such that the bacterial infection is treated.
[0012] In still another aspect, the invention provides a method of
treating a bacterial infection wherein the treatment includes
administering to a subject in need thereof a pharmaceutically
effective amount of a compound of the formula I, II, III, IV, V, or
VI, in combination with a pharmaceutically effective amount of an
additional therapeutic agent, such that the bacterial infection is
treated. In one embodiment, the compound of the formula I, II, III,
IV, V, or VI and the other pharmaceutical agent are administered as
part of the same pharmaceutical composition. In another embodiment,
the compound of the formula I, II, III, IV, V, or VI and the other
therapeutic agent are administered as separate pharmaceutical
compositions, and the compound is administered prior to, at the
same time as, or following administration of the other agent.
[0013] In another aspect, the invention provides a packaged
bacterial infection treatment, comprised of formula I, II, III, IV,
V, or VI, packaged with instructions for using an effective amount
of the compound to treat a bacterial infection.
[0014] In another aspect, the invention provides a method of
treating acne in subject in need thereof, wherein the treatment
includes administering to the subject a pharmaceutically acceptable
amount of a compound of formula I, II, III, IV, V, or VI.
[0015] In yet another aspect, the invention provides a
pharmaceutical composition which includes a compound of formula I,
II, III, IV, V, or VI, and at least one pharmaceutically acceptable
carrier or diluent.
DETAILED DESCRIPTION OF THE INVENTION
[0016] This invention is directed to compounds, e.g., thiopeptide
compounds, and intermediates thereto, as well as pharmaceutical
compositions containing the compounds for use in treatment of
bacterial infection. This invention is also directed to the
compounds of the invention or compositions thereof as modulators of
the elongation factor EF-Tu. The compounds are particularly useful
in interfering with the life cycle of bacteria and in treating or
preventing a bacterial infection or physiological conditions
associated therewith. The present invention is also directed to
methods of combination therapy for inhibiting EF-Tu activity in
cells, or for treating or preventing a bacterial infection in
patients using the compounds of the invention or pharmaceutical
compositions, or kits thereof.
[0017] In one aspect, the invention provides compounds of the
formula I:
##STR00002##
[0018] and pharmaceutically acceptable salts, enantiomers,
stereoisomers, rotamers, tautomers, diastereomers, atropisomers or
racemates thereof, including the pyridine N-oxide thereof;
[0019] wherein
[0020] R.sup.1 is --Z--CO.sub.2H and -A-Z--CO.sub.2H;
[0021] R.sup.1a is hydrogen, --Z--CO.sub.2H, and -A-Z--CO.sub.2H,
wherein if R.sup.1a is hydrogen, then the Z residue of R.sup.1 is
substituted by at least two CO.sub.2H groups; or
[0022] R.sup.1 and R.sup.1a, taken in combination, form a
saturated, partially unsaturated or aromatic heterocycle having 4
to 7 ring atoms and having 0-3 additional ring heteroatoms selected
from N, O and S, wherein the heterocycle is substituted by at least
two residues independently selected from CO.sub.2H, --Z--CO.sub.2H,
and -A-Z--CO.sub.2H;
[0023] A is independently selected at each occurrence from the
group consisting of a --C(O)--, --C(O)O--, --C(O)N(R.sup.8a)--,
--S(O).sub.2--, --S(O)--, --C(H).dbd.N--,
--S(O).sub.2N(R.sup.8a)--, and --S(O)N(R.sup.8a)--;
[0024] Z is C.sub.1-C.sub.10alkylene, C.sub.3-C.sub.8cycloalkylene,
C.sub.3-C.sub.8heterocycloalkylene, phenylene, or 5-6 membered
heteroarylene, each of which is optionally substituted with one or
more groups independently selected from C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, hydroxy, amino, mono- and
di-C.sub.1-C.sub.6alkylamino, C(O)0H, or halogen;
[0025] R.sup.2a is selected from the group consisting of H,
substituted or unsubstituted alkyl, OH, OR.sup.4a, OC(O)R.sup.4a,
OC(O)N(R.sup.8a).sub.2 and N(R.sup.8a).sub.2;
[0026] R.sup.2b is selected from the group consisting of absent, H
and alkyl, or R.sup.2a and R.sup.2b may together form .dbd.O or
.dbd.NH;
[0027] R.sup.3 an R.sup.12 are each, independently, selected from
the group consisting of H, halogen, OR.sup.4b, -A-J, and
N(R.sup.8a).sub.2;
[0028] R.sup.4a is selected from the group consisting of H, and
alkyl;
[0029] R.sup.4b is selected from the group consisting of alkyl and
--(CH.sub.2--CH.sub.2--O--).sub.n--R.sup.9, wherein n is an integer
of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000,
30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of
integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000,
5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
[0030] R.sup.5 is selected from the group consisting of H, alkyl,
and R.sup.4b;
[0031] J is selected from the group consisting of H, F, O-alkyl,
N(R.sup.8a).sub.2, N.sup.+(R.sup.8a).sub.3, N(R.sup.8a)C(O)alkyl,
CO.sub.2H, C(.dbd.O)N(R.sup.8a).sub.2, CO.sub.2-alkyl,
P(O)(OH).sub.2, P(O)(O-alkyl).sub.2, and a substituted
nitrogen-containing heterocycle;
[0032] R.sup.8a is absent, or selected from the group consisting of
H, -(alkyl)-, -(cycloalkyl)-, C(alkyl)-2-J, --R.sup.4b, wherein
R.sup.8a can also cyclize with the atom to which R.sup.8a is bonded
to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or
non-aromatic and may contain one or more heteroatoms, wherein the
ring may be further substituted one or more times with
substitutents that are the same or different; and
[0033] R.sup.9 is selected from the group consisting of H, alkyl
and CH.sub.2CO.sub.2H.
[0034] Certain compounds of formula I provided herein include
compounds of formula II and formula III:
##STR00003##
[0035] and pharmaceutically acceptable salts, enantiomers,
stereoisomers, rotamers, tautomers, diastereomers, atropisomers or
racemates thereof, including the pyridine N-oxide thereof.
[0036] Certain compounds of formula III include those compounds
represented by formula IV:
##STR00004##
[0037] Certain compounds of formula I include those compounds
represented by formula V:
##STR00005##
[0038] and pharmaceutically acceptable salts, enantiomers,
stereoisomers, rotamers, tautomers, diastereomers, atropisomers or
racemates thereof, including the pyridine N-oxide thereof,
wherein
[0039] D represents a five or six membered heterocyclic ring which
is saturated or aromatic, which ring comprises 0-2 additional ring
heteroatoms selected from N, O or S.
[0040] Certain compounds of formula IV include those compounds
represented by formula V-a:
##STR00006##
[0041] and pharmaceutically acceptable salts, enantiomers,
stereoisomers, rotamers, tautomers, diastereomers, atropisomers or
racemates thereof, including the pyridine N-oxide thereof,
wherein
[0042] D represents a five or six membered heterocyclic ring which
is saturated or aromatic, which ring comprises 0-2 additional ring
heteroatoms selected from N, O or S.
[0043] Certain preferred compounds of Formula I, III, or V include
those compounds in which R.sup.2b, R.sup.4b and R.sup.5 are H, and
R.sup.4a is CH.sub.3. Other preferred compounds of Formula I
include those compounds in which R.sup.2b, R.sup.4b and R.sup.5 are
H, R.sup.4a is CH.sub.3, and R.sup.12 is CH.sub.2--O--CH.sub.3.
[0044] Certain compounds of formula V include those compounds
represented by formula VI:
##STR00007##
[0045] Certain compounds of formula I include those compounds
represented by formula VI-a:
##STR00008##
[0046] and pharmaceutically acceptable salts, enantiomers,
stereoisomers, rotamers, tautomers, diastereomers, atropisomers or
racemates thereof, including the pyridine N-oxide thereof,
wherein
[0047] D represents a five or six membered heterocyclic ring which
is saturated or aromatic, which ring comprises 0-2 additional ring
heteroatoms selected from N, O or S.
[0048] Certain preferred compounds of Formula III, IV, V, V-a, VI,
VI-a include those compounds in which
[0049] A is selected from the group consisting of --C(O)O--,
C(O)--NH--, --C(O)--, --S(O).sub.2--, and --S(O).sub.2NH--; and
[0050] Z is independently selected at each occurrence from the
group consisting of C.sub.1-C.sub.10alkylene,
##STR00009##
[0051] Still other compounds of formula I provided herein include
those compounds in which R.sup.2a is OH or OAC.
[0052] Yet other compounds of formula I provided herein include
those compounds in which the core pyridine functionality is of the
following N-oxide formula:
##STR00010##
[0053] In yet another aspect, the invention provides compounds of
the formula VII:
##STR00011##
[0054] and pharmaceutically acceptable salts, enantiomers,
stereoisomers, rotamers, tautomers, diastereomers, atropisomers or
racemates thereof, including the pyridine N-oxide thereof;
[0055] wherein
[0056] R.sup.1 is --Z--CO.sub.2H and -A-Z--CO.sub.2H;
[0057] R.sup.1a is hydrogen, --Z--CO.sub.2H, and -A-Z--CO.sub.2H,
wherein if R.sup.1a is hydrogen, then the Z residue of R.sup.1 is
substituted by at least two CO.sub.2H groups; or
[0058] R.sup.1 and R.sup.1a, taken in combination, form a
saturated, partially unsaturated or aromatic heterocycle having 4
to 7 ring atoms and having 0-3 additional ring heteroatoms selected
from N, O and S, wherein the heterocycle is substituted by at least
two residues independently selected from CO.sub.2H, --Z--CO.sub.2H,
and -A-Z--CO.sub.2H;
[0059] A is indepenendently selected at each occurrence from the
group consisting of a --C(O)--, --C(O)O--, --C(O)N(R.sup.8a)--,
--S(O).sub.2--, --S(O)--, --C(H).dbd.N--,
--S(O).sub.2N(R.sup.8a)--, and --S(O)N(R.sup.8a)--;
[0060] Z is C.sub.1-C.sub.10alkylene, C.sub.3-C.sub.8cycloalkylene,
C.sub.3-C.sub.8heterocycloalkylene, phenylene, or 5-6 membered
heteroarylene, each of which is optionally substituted with one or
more groups independently selected from C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkoxy, hydroxy, amino, mono- and
di-C.sub.1-C.sub.6alkylamino, C(O)OH, or halogen;
[0061] R.sup.2 is hydrogen, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
C.sub.1-6alkoxyC.sub.0-6alkyl, C.sub.3-7cycloalkylC.sub.0-4alkyl,
arylC.sub.0-4alkyl, or a residue of the formula:
##STR00012##
[0062] R.sup.2a is selected from the group consisting of H,
substituted or unsubstituted alkyl, OH, OR.sup.4a, OC(O)R.sup.4a,
OC(O)N(R.sup.8a).sub.2 and N(R.sup.8a).sub.2;
[0063] R.sup.2b is selected from the group consisting of absent, H
and alkyl, or R.sup.2a and R.sup.2b may together form .dbd.O or
.dbd.NH;
[0064] R.sup.3 an R.sup.12 are each, independently, selected from
the group consisting of H, halogen, OR.sup.4b, -A-J, and
N(R.sup.8a).sub.2;
[0065] R.sup.4a is selected from the group consisting of H, and
alkyl;
[0066] R.sup.4b is selected from the group consisting of alkyl and
--(CH.sub.2--CH.sub.2-O--).sub.n--R.sup.9, wherein n is an integer
of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000,
30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of
integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000,
5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
[0067] R.sup.5 is selected from the group consisting of H, alkyl,
and R.sup.4b;
[0068] J is selected from the group consisting of H, F, O-alkyl,
N(R.sup.8a).sub.2, N.sup.+(R.sup.8a).sub.3, N(R.sup.8a)C(O)alkyl,
CO.sub.2H, C(.dbd.O)N(R.sup.8a).sub.2, CO.sub.2-alkyl,
P(O)(OH).sub.2, P(O)(O-alkyl).sub.2, and a substituted
nitrogen-containing heterocycle;
[0069] R.sup.8a is absent, or selected from the group consisting of
H, -(alkyl)-, -(cycloalkyl)-, C(alkyl)-2-J, --R.sup.4b, wherein
R.sup.8a can also cyclize with the atom to which R.sup.8a is bonded
to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or
non-aromatic and may contain one or more heteroatoms, wherein the
ring may be further substituted one or more times with
substitutents that are the same or different; and
[0070] R.sup.9 is selected from the group consisting of H, alkyl
and CH.sub.2CO.sub.2H.
[0071] Preferred embodiments of the compounds of the invention
(including pharmaceutically acceptable salts thereof, as well as
enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or
racemates thereof) are shown below in Table A and Table B, and are
also considered to be "compounds of the invention."
TABLE-US-00001 TABLE A 1. ##STR00013## 2. ##STR00014## 3.
##STR00015## 4. ##STR00016## 5. ##STR00017## 6. ##STR00018## 7.
##STR00019## 8. ##STR00020## 9. ##STR00021## 10. ##STR00022## 11.
##STR00023## 12. ##STR00024## 13. ##STR00025## 14. ##STR00026## 15.
##STR00027## 16. ##STR00028## 17. ##STR00029## 18. ##STR00030## 19.
##STR00031## 20. ##STR00032## 21. ##STR00033## 22. ##STR00034## 23.
##STR00035## 24. ##STR00036## 25. ##STR00037## 26. ##STR00038## 27.
##STR00039## 28. ##STR00040## 29. ##STR00041## 30. ##STR00042## 31.
##STR00043## 32. ##STR00044## 33. ##STR00045## 34. ##STR00046## 35.
##STR00047##
TABLE-US-00002 TABLE B ##STR00048## 36. ##STR00049## 37.
##STR00050## 38. ##STR00051## 39. ##STR00052## 40. ##STR00053## 41.
##STR00054## 42. ##STR00055## 43. ##STR00056## 44. ##STR00057## 45.
##STR00058## 46. ##STR00059## 47. ##STR00060## 48. ##STR00061## 49.
##STR00062## 50. ##STR00063## 51. ##STR00064## 52. ##STR00065## 53.
##STR00066## 54. ##STR00067## 55. ##STR00068## 56. ##STR00069## 57.
##STR00070## 58. ##STR00071## 59. ##STR00072## 60. ##STR00073## 61.
##STR00074## 62. ##STR00075## 63. ##STR00076## 64. ##STR00077## 65.
##STR00078## 66. ##STR00079## 67. ##STR00080## 68. ##STR00081## 69.
##STR00082## 70. ##STR00083## 71. ##STR00084## 72. ##STR00085## 73.
##STR00086## 74. ##STR00087## 75. ##STR00088## 76. ##STR00089## 77.
##STR00090## 78. ##STR00091## 79. ##STR00092## 80. ##STR00093## 81.
##STR00094## 82. ##STR00095## 83. ##STR00096## 84. ##STR00097## 85.
##STR00098## 86. ##STR00099## 87. ##STR00100## 88. ##STR00101## 89.
##STR00102## 90. ##STR00103## 91. ##STR00104## 92. ##STR00105## 93.
##STR00106## 94. ##STR00107## 95. ##STR00108## 96. ##STR00109## 97.
##STR00110## 98. ##STR00111## 99. ##STR00112## 100. ##STR00113##
101. ##STR00114## 102. ##STR00115## 103. ##STR00116## 104.
##STR00117## 105. ##STR00118## 106.
[0072] In certain embodiments, the compound of the present
invention is further characterized as a modulator of EF-Tu,
including a prokaryotic EF-Tu, and especially including a bacterial
EF-Tu. In a preferred embodiment, the compound of the invention is
an EF-Tu inhibitor.
[0073] As used herein, the term "bacterial infection(s)" includes,
but is not limited to, bacterial infections that occur in mammals,
fish and birds as well as disorders related to bacterial infections
that may be treated or prevented by administering antibiotics such
as the compounds of the present invention. In addition to treating
infections caused by multi-drug resistant strains of Staphyloccocus
aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis and
Enterococci, the compounds of the present invention are useful in
treating infections caused by other bacteria including, but not
limited to, Clostridium difficile, Propionibacterium acnes,
Bacteroides fagiles, Neisseria gonorrhoeae, Branhamella
catarrhalis, Haemophilus influenzae, E. coli, Pseudomonas
aeruginosa, Proteus vulgaris, Klebsiella pneumonia, and Chlamydia
trachomatis.
[0074] Such bacterial infections and disorders related to such
infections include, but are not limited to, the following: acne,
rosacea, skin infection, pneumonia, otitis media, sinusitus,
bronchitis, tonsillitis, and mastoiditis related to infection by
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis, Staphylococcus aureus, Peptostreptococcus spp. or
Pseudomonas spp.; pharynigitis, rheumatic fever, and
glomerulonephritis related to infection by Streptococcus pyogenes,
Groups C and G streptococci, Clostridium diptheriae, or
Actinobacillus haemolyticum; respiratory tract infections related
to infection by Mycoplasma pneumoniae, Legionella pneumophila,
Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia
pneumoniae; uncomplicated skin and soft tissue infections,
abscesses and osteomyelitis, and puerperal fever related to
infection by Staphylococcus aureus, coagulase-positive
staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), S.
pyogenes, S. agalactiae, Streptococcal groups C-F (minute-colony
streptococci), viridans streptococci, Corynebacterium spp.,
Clostridium spp., or Bartonella henselae; uncomplicated acute
urinary tract infections related to infection by S. saprophyticus
or Enterococcus spp.; urethritis and cervicitis; sexually
transmitted diseases related to infection by Chlamydia trachomatis,
Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or
Nesseria gonorrheae; toxin diseases related to infection by S.
aureus (food poisoning and Toxic shock syndrome), or Groups A, S,
and C streptococci; ulcers related to infection by Helicobacter
pylori; systemic febrile syndromes related to infection by Borrelia
recurrentis; Lyme disease related to infection by Borrelia
burgdorferi; conjunctivitis, keratitis, and dacrocystitis related
to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.
pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.;
disseminated Mycobacterium avium complex (MAC) disease related to
infection by Mycobacterium avium, or Mycobacterium intracellulare;
gastroenteritis related to infection by Campylobacter jejuni;
intestinal protozoa related to infection by Cryptosporidium spp.,
odontogenic infection related to infection by viridans
streptococci; persistent cough related to infection by Bordetella
pertussis; gas gangrene related to infection by Clostridium
perfringens or Bacteroides spp.; Skin infection by S. aureus,
Propionibacterium acne; atherosclerosis related to infection by
Helicobacter pylori or Chlamydia pneumoniae; or the like.
[0075] Further bacterial infections and disorders related to such
infections that may be treated or prevented in animals include, but
are not limited to, the following: bovine respiratory disease
related to infection by P. haemolytica., P. multocida, Mycoplasma
bovis, or Bordetella spp.; cow enteric disease related to infection
by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.),
dairy cow mastitis related to infection by S. aureus, S. uberis, S.
agalactiae, S. dysgalactiae, Klebsiella spp., Corynebacterium, or
Enterococcus spp.; swine respiratory disease related to infection
by A. pleuropneumoniae., P. multocida, or Mycoplasma spp.; swine
enteric disease related to infection by E. coli, Lawsonia
intracellularis, Salmonella spp., or Serpulina hyodyisinteriae; cow
footrot related to infection by Fusobacterium spp.; cow metritis
related to infection by E. coli; cow hairy warts related to
infection by Fusobacterium necrophorum or Bacteroides nodosus; cow
pink-eye related to infection by Moraxella bovis, cow premature
abortion related to infection by protozoa (i.e., neosporium);
urinary tract infection in dogs and cats related to infection by E.
coli; skin and soft tissue infections in dogs and cats related to
infection by S. epidermidis, S. intermedius, coagulase neg.
Staphylococcus or P. multocida; dental or mouth infections in dogs
and goats related to infection by Alcaligenes spp., Bacteroides
spp., Clostridium spp., Enterobacter spp., Eubacterium spp.,
Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,
Actinomyces spp., Erysipelothrix spp., Rhodococcus spp.,
Trypanosoma spp., Plasmodium spp., Babesia spp., Toxoplasma spp.,
Pneumocystis spp., Leishmania spp., Trichomonas spp. or Prevotella
spp. Other bacterial infections and disorders related to such
infections that may be treated or prevented in accord with the
method of the present invention are referred to in J. P. Sanford at
al., "The Sanford Guide To Antimicrobial Therapy," 26th Edition,
(Antimicrobial Therapy, Inc., 1996).
[0076] Further bacterial infections and disorders related to such
infections that may be treated or prevented in animals include, but
are not limited to, central nervous system infections, external ear
infections, infections of the middle ear, such as acute otitis
media, infections of the cranial sinuses, eye infections,
infections of the oral cavity, such as infections of the teeth,
gums and mucosa, upper respiratory tract infections, lower
respiratory tract infections, genitourinary infections,
gastrointestinal infections, gynecological infections, septicemia,
bone and joint infections, skin and skin structure infections,
bacterial endocarditis, burns, antibacterial prophylaxis of
surgery, antibacterial prophylaxis in immunosuppressed patients,
such as patients receiving cancer chemotherapy, or organ transplant
patients and chronic diseases caused by infectious organisms, e.g.,
arteriosclerosis.
[0077] Bacterial protein synthesis requires EF-Tu chaperone
proteins. EF-Tu is one of the most abundant proteins in bacteria,
as well as one of the most highly conserved, and in a number of
species the gene is duplicated with identical function. When bound
to GTP, EF-Tu can form a complex with most aminoacylated tRNAs,
loading the tRNA onto the ribosome. In one embodiment, the
bacterial infection is associated with the activity of EF-Tu.
Without being bound by theory, it is believed that the disruption
of EF-Tu protein activity by the compounds of the invention will
interfere with protein synthesis and thus bacterial function and/or
proliferation. Because EF-Tu is highly conserved across
Gram-positive and Gram-negative bacteria, the compounds of the
present invention are useful for treating infections of both
classes of bacteria.
[0078] As used herein, the term "EF-Tu-associated state" or
"EF-Tu-associated disorder" include disorders and states (e.g., a
disease state) that are associated with the activity of EF-Tu. A
non-limiting example of an EF-Tu associated disorder is a bacterial
infection in a subject.
[0079] The present invention includes treatment of bacterial
infections, as well as EF-Tu-associated disorders, as described
above, but the invention is not intended to be limited to the
manner by which the compound performs its intended function of
treatment of a disease. The present invention includes treatment of
diseases described herein in any manner that allows treatment to
occur, e.g., bacterial infection.
[0080] In certain embodiments, the invention provides a
pharmaceutical composition of any of the compounds of the present
invention. In a related embodiment, the invention provides a
pharmaceutical composition of any of the compounds of the present
invention and a pharmaceutically acceptable carrier or excipient of
any of these compounds. In certain embodiments, the invention
includes the compounds as novel chemical entities.
[0081] In one embodiment, the invention includes a packaged
bacterial infection treatment. The packaged treatment includes a
compound of the invention packaged with instructions for using an
effective amount of the compound of the invention for an intended
use.
[0082] The compounds of the present invention are suitable as
active agents in pharmaceutical compositions that are efficacious
particularly for treating bacterial infections. The pharmaceutical
composition in various embodiments has a pharmaceutically effective
amount of the present active agent along with other
pharmaceutically acceptable excipients, carriers, fillers, diluents
and the like. The phrase, "pharmaceutically effective amount" as
used herein indicates an amount necessary to administer to a host,
or to a cell, issue, or organ of a host, to achieve a therapeutic
result, especially an anti-bacterial infection effect, e.g.,
inhibition of proliferation of a bacterium, or of any other
bacterial infection.
[0083] In other embodiments, the present invention provides a
method for inhibiting the activity of an EF-Tu protein. The method
includes contacting a cell with any of the compounds of the present
invention. In a related embodiment, the method further provides
that the compound is present in an amount effective to selectively
inhibit the activity of an EF-Tu protein.
[0084] In other embodiments, the present invention provides a use
of any of the compounds of the invention for manufacture of a
medicament to treat a bacterial infection in a subject.
[0085] In other embodiments, the invention provides a method of
manufacture of a medicament, including formulating any of the
compounds of the present invention for treatment of a subject.
DEFINITIONS
[0086] The term "treat," "treated," "treating" or "treatment"
includes the diminishment or alleviation of at least one symptom
associated or caused by the state, disorder or disease being
treated. In certain embodiments, the treatment comprises the
induction of a bacterial infection, followed by the activation of
the compound of the invention, which would in turn diminish or
alleviate at least one symptom associated or caused by the
bacterial infection being treated. For example, treatment can be
diminishment of one or several symptoms of a disorder or complete
eradication of a disorder.
[0087] The term "subject" is intended to include organisms, e.g.,
prokaryotes and eukaryotes, which are capable of suffering from or
afflicted with a bacterial infection. Examples of subjects include
mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats,
cats, mice, rabbits, rats, and transgenic non-human animals. In
certain embodiments, the subject is a human, e.g., a human
suffering from, at risk of suffering from, or potentially capable
of suffering from a bacterial infection, and for diseases or
conditions described herein. In another embodiment, the subject is
a cell.
[0088] The language "EF-Tu-modulating compound," "modulator of
EF-Tu" or "EF-Tu inhibitor" refers to compounds that modulate,
e.g., inhibit, or otherwise alter, the activity of EF-Tu. Examples
of EF-Tu-modulating compounds include compounds of formula I, II,
III, IV and V, as well as Table A and Table B (including
pharmaceutically acceptable salts thereof, as well as enantiomers,
stereoisomers, rotamers, tautomers, diastereomers, atropisomers or
racemates thereof).
[0089] Additionally, a method of the invention includes
administering to a subject an effective amount of an
EF-Tu-modulating compound of the invention, e.g., EF-Tu-modulating
compounds of Formula I, II, III, IV and V, as well as Table A and
Table B (including pharmaceutically acceptable salts thereof, as
well as enantiomers, stereoisomers, rotamers, tautomers,
diastereomers, atropisomers or racemates thereof).
[0090] The term "alkyl" includes saturated aliphatic groups,
including straight-chain alkyl groups (e.g., methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.),
branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl,
etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl
groups, and cycloalkyl substituted alkyl groups. The term "alkyl"
also includes alkenyl groups and alkynyl groups. Furthermore, the
expression "C.sub.x-C.sub.y-alkyl", wherein x is 1-5 and y is 2-10
indicates a particular alkyl group (straight- or branched-chain) of
a particular range of carbons. For example, the expression
C.sub.1-C.sub.4-alkyl includes, but is not limited to, methyl,
ethyl, propyl, butyl, isopropyl, tert-butyl, isobutyl and
sec-butyl. Moreover, the term C.sub.3-6-cycloalkyl includes, but is
not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. As
discussed below, these alkyl groups, as well as cycloalkyl groups,
may be further substituted. "C.sub.0-C.sub.nalkyl" refers to a
single covalent bond (C.sub.0) or an alkyl group having from 1 to n
carbon atoms; for example "C.sub.0-C.sub.4alkyl" refers to a single
covalent bond or a C.sub.1-C.sub.4alkyl group;
"C.sub.0-C.sub.8alkyl" refers to a single covalent bond or a
C.sub.1-C.sub.8alkyl group. In some instances, a substituent of an
alkyl group is specifically indicated. For example,
"C.sub.1-C.sub.4hydroxyalkyl" refers to a C.sub.1-C.sub.4alkyl
group that has at least one hydroxy substituent.
[0091] "Alkylene" refers to a divalent alkyl group, as defined
above. C.sub.0-C.sub.4alkylene is a single covalent bond or an
alkylene group having from 1 to 4 carbon atoms; and
C.sub.0-C.sub.6alkylene is a single covalent bond or an alkylene
group having from 1 to 6 carbon atoms. "Alkenylene" and
"Alkynylene" refer to divalent alkenyl and alkynyl groups
respsectively, as defined above.
[0092] A "cycloalkyl" is a group that comprises one or more
saturated and/or partially saturated rings in which all ring
members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, adamantyl,
decahydro-naphthalenyl, octahydro-indenyl, and partially saturated
variants of the foregoing, such as cyclohexenyl. Cycloalkyl groups
do not comprise an aromatic ring or a heterocyclic ring. Certain
cycloalkyl groups are C.sub.3-C.sub.8cycloalkyl, in which the group
contains a single ring with from 3 to 8 ring members. A
"(C.sub.3-C.sub.8cycloalkyl)C.sub.0-C.sub.4alkyl" is a
C.sub.3-C.sub.8cycloalkyl group linked via a single covalent bond
or a C.sub.1-C.sub.4alkylene group. In certain aspects,
C.sub.3-6-cycloalkyl groups are substituted one or more times (or
preferably between one and five times) with substitutents
independently selected from a halogen atom, aryl, heteroaryl,
trihalomethyl, C.sub.1-4-alkoxy or C.sub.1-4-alkyl.
[0093] Moreover, alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl,
hexyl, etc.) include both "unsubstituted alkyl" and "substituted
alkyl", the latter of which refers to alkyl moieties having
substituents replacing a hydrogen on one or more carbons of the
hydrocarbon backbone, which allow the molecule to perform its
intended function.
[0094] The term "substituted" is intended to describe moieties
having substituents replacing a hydrogen on one or more atoms, e.g.
C, O or N, of a molecule. Such substituents can include, for
example, oxo, alkyl, alkoxy, alkenyl, alkynyl, halogen, hydroxyl,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, morpholino, phenol, benzyl, phenyl,
piperizine, cyclopentane, cyclohexane, pyridine, 5H-tetrazole,
triazole, piperidine, or an aromatic or heteroaromatic moiety, and
any combination thereof.
[0095] Further examples of substituents of the invention, which are
not intended to be limiting, include moieties selected from
straight or branched alkyl (preferably C.sub.1-C.sub.5), cycloalkyl
(preferably C.sub.3-C.sub.8), alkoxy (preferably C.sub.1-C.sub.6),
thioalkyl (preferably C.sub.1-C.sub.6), alkenyl (preferably
C.sub.2-C.sub.6), alkynyl (preferably C.sub.2-C.sub.6),
heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g.,
phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g.,
phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl,
alkylcarbonyl and arylcarbonyl or other such acyl group,
heteroarylcarbonyl, or heteroaryl group, (CR'R'').sub.0-3NR'R''
(e.g., --NH.sub.2), (CR'R'').sub.0-3CN (e.g., --CN), --NO.sub.2,
halogen (e.g., --F, --Cl, --Br, or --I),
(CR'R'').sub.0-3C(halogen).sub.3 (e.g., --CF.sub.3),
(CR'R'').sub.0-3CH(halogen).sub.2,
(CR'R'').sub.0-3CH.sub.2(halogen), (CR'R'').sub.0-3CONR'R'',
(CR'R'').sub.0-3(CNH)NR'R'', (CR'R'').sub.0-3S(O).sub.1-2NR'R'',
(CR'R'').sub.0-3CHO, (CR'R'').sub.0-3O(CR'R'').sub.0-3H,
(CR'R'').sub.0-3S(O).sub.0-3R' (e.g., --SO.sub.3H, --OSO.sub.3H),
(CR'R'').sub.0-3O(CR'R'').sub.0-3H (e.g., --CH.sub.2OCH.sub.3 and
--OCH.sub.3), (CR'R'').sub.0-3S(CR'R'').sub.0-3H (e.g., --SH and
--SCH.sub.3), (CR'R'').sub.0-3OH (e.g., --OH),
(CR'R'').sub.0-3COR', (CR'R'').sub.0-3 (substituted or
unsubstituted phenyl), (CR'R'').sub.0-3(C.sub.3-C.sub.8
cycloalkyl), (CR'R'').sub.0-3CO.sub.2R' (e.g., --CO.sub.2H), or
(CR'R'').sub.0-3OR' group, or the side chain of any naturally
occurring amino acid; wherein R' and R'' are each independently
hydrogen, a C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl,
C.sub.2-C.sub.5 alkynyl, or aryl group. Such substituents can
include, for example, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino,
diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, oxime, sulfhydryl, alkylthio, arylthio,
thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido,
nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic
or heteroaromatic moiety, and any combination thereof. In certain
embodiments, a carbonyl moiety (C.dbd.O) may be further derivatized
with an oxime moiety, e.g., an aldehyde moiety may be derivatized
as its oxime (--C.dbd.N--OH) analog. It will be understood by those
skilled in the art that the moieties substituted on the hydrocarbon
chain can themselves be substituted, if appropriate. Cycloalkyls
can be further substituted, e.g., with the substituents described
above. An "aralkyl" moiety is an alkyl substituted with an aryl
(e.g., phenylmethyl (i.e., benzyl)).
[0096] The term "alkenyl" includes unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but which contain at least one double bond.
[0097] For example, the term "alkenyl" includes straight-chain
alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl,
hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain
alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or
alkenyl substituted cycloalkenyl groups, and cycloalkyl or
cycloalkenyl substituted alkenyl groups. The term alkenyl further
includes alkenyl groups that include oxygen, nitrogen, sulfur or
phosphorous atoms replacing one or more carbons of the hydrocarbon
backbone. In certain embodiments, a straight chain or branched
chain alkenyl group has 6 or fewer carbon atoms in its backbone
(e.g., C.sub.2-C.sub.6 for straight chain, C.sub.3-C.sub.6 for
branched chain). Likewise, cycloalkenyl groups may have from 3-8
carbon atoms in their ring structure, and more preferably have 5 or
6 carbons in the ring structure. The term C.sub.2-C.sub.6 includes
alkenyl groups containing 2 to 6 carbon atoms.
[0098] Moreover, the term alkenyl includes both "unsubstituted
alkenyls" and "substituted alkenyls", the latter of which refers to
alkenyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0099] The term "alkynyl" includes unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but which contain at least one triple bond.
[0100] For example, the term "alkynyl" includes straight-chain
alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl,
hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain
alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl
groups. The term alkynyl further includes alkynyl groups that
include oxygen, nitrogen, sulfur or phosphorous atoms replacing one
or more carbons of the hydrocarbon backbone. In certain
embodiments, a straight chain or branched chain alkynyl group has 6
or fewer carbon atoms in its backbone (e.g., C.sub.2-C.sub.6 for
straight chain, C.sub.3-C.sub.6 for branched chain). The term
C.sub.2-C.sub.6 includes alkynyl groups containing 2 to 6 carbon
atoms.
[0101] Moreover, the term alkynyl includes both "unsubstituted
alkynyls" and "substituted alkynyls", the latter of which refers to
alkynyl moieties having substituents replacing a hydrogen on one or
more carbons of the hydrocarbon backbone. Such substituents can
include, for example, alkyl groups, alkynyl groups, halogens,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0102] The term "amine" or "amino" should be understood as being
broadly applied to both a molecule, or a moiety or functional
group, as generally understood in the art, and may be primary,
secondary, or tertiary. The term "amine" or "amino" includes
compounds where a nitrogen atom is covalently bonded to at least
one carbon, hydrogen or heteroatom. The terms include, for example,
but are not limited to, "alkylamino," "arylamino," "diarylamino,"
"alkylarylamino," "alkylaminoaryl," "arylaminoalkyl,"
"alkaminoalkyl," "amide," "amido," and "aminocarbonyl." The term
"alkyl amino" comprises groups and compounds wherein the nitrogen
is bound to at least one additional alkyl group. The term "dialkyl
amino" includes groups wherein the nitrogen atom is bound to at
least two additional alkyl groups. The term "arylamino" and
"diarylamino" include groups wherein the nitrogen is bound to at
least one or two aryl groups, respectively. The term
"alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl" refers to an
amino group which is bound to at least one alkyl group and at least
one aryl group. The term "alkaminoalkyl" refers to an alkyl,
alkenyl, or alkynyl group bound to a nitrogen atom which is also
bound to an alkyl group.
[0103] The term "amide," "amido" or "aminocarbonyl" includes
compounds or moieties which contain a nitrogen atom which is bound
to the carbon of a carbonyl or a thiocarbonyl group. The term
includes "alkaminocarbonyl" or "alkylaminocarbonyl" groups which
include alkyl, alkenyl, aryl or alkynyl groups bound to an amino
group bound to a carbonyl group. It includes arylaminocarbonyl and
arylcarbonylamino groups which include aryl or heteroaryl moieties
bound to an amino group which is bound to the carbon of a carbonyl
or thiocarbonyl group. The terms "alkylaminocarbonyl,"
"alkenylaminocarbonyl," "alkynylaminocarbonyl,"
"arylaminocarbonyl," "alkylcarbonylamino," "alkenylcarbonylamino,"
"alkynylcarbonylamino," and "arylcarbonylamino" are included in
term "amide." Amides also include urea groups (aminocarbonylamino)
and carbamates (oxycarbonylamino)
[0104] The term "aryl" includes groups, including 5- and 6-membered
single-ring aromatic groups that may include from zero to four
heteroatoms, for example, phenyl, pyrrole, furan, thiophene,
thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole,
oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine,
and the like. Furthermore, the term "aryl" includes multicyclic
aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,
benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,
benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,
anthryl, phenanthryl, napthridine, indole, benzofuran, purine,
benzofuran, deazapurine, or indolizine. Those aryl groups having
heteroatoms in the ring structure may also be referred to as "aryl
heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics."
The aromatic ring can be substituted at one or more ring positions
with such substituents as described above, as for example, alkyl,
halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
Aryl groups can also be fused or bridged with alicyclic or
heterocyclic rings which are not aromatic so as to form a polycycle
(e.g., tetralin).
[0105] The term heteroaryl, as used herein, represents a stable
monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein
at least one ring is aromatic and contains from 1 to 4 heteroatoms
selected from the group consisting of O, N and S. Heteroaryl groups
within the scope of this definition include but are not limited to:
acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl,
indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,
benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl,
indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
tetrahydroquinoline. As with the definition of heterocycle below,
"heteroaryl" is also understood to include the N-oxide derivative
of any nitrogen-containing heteroaryl. In cases where the
heteroaryl substituent is bicyclic and one ring is non-aromatic or
contains no heteroatoms, it is understood that attachment is via
the aromatic ring or via the heteroatom containing ring,
respectively.
[0106] The term "heterocycle" or "heterocyclyl" as used herein is
intended to mean a 5- to 10-membered aromatic or nonaromatic
heterocycle containing from 1 to 4 heteroatoms selected from the
group consisting of O, N and S, and includes bicyclic groups.
"Heterocyclyl" therefore includes the above mentioned heteroaryls,
as well as dihydro and tetrathydro analogs thereof. Further
examples of "heterocyclyl" include, but are not limited to the
following: benzoimidazolyl, benzofuranyl, benzofurazanyl,
benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,
carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,
indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,
isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl,
oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,
pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,
tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,
thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,
hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,
pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,
dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,
dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,
dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl,
dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl,
dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl,
dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl,
dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and
tetrahydrothienyl, and N-oxides thereof. Attachment of a
heterocyclyl substituent can occur via a carbon atom or via a
heteroatom.
[0107] The term "acyl" includes compounds and moieties which
contain the acyl radical (CH.sub.3CO--) or a carbonyl group. The
term "substituted acyl" includes acyl groups where one or more of
the hydrogen atoms are replaced by for example, alkyl groups,
alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,
alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino,
diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an
aromatic or heteroaromatic moiety.
[0108] The term "acylamino" includes moieties wherein an acyl
moiety is bonded to an amino group. For example, the term includes
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido
groups.
[0109] The term "alkoxy" includes substituted and unsubstituted
alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen
atom. Examples of alkoxy groups include methoxy, ethoxy,
isopropyloxy, propoxy, butoxy, and pentoxy groups and may include
cyclic groups such as cyclopentoxy. Examples of substituted alkoxy
groups include halogenated alkoxy groups. The alkoxy groups can be
substituted with groups such as alkenyl, alkynyl, halogen,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,
phosphonato, phosphinato, cyano, amino (including alkyl amino,
dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
Examples of halogen substituted alkoxy groups include, but are not
limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
chloromethoxy, dichloromethoxy, trichloromethoxy, etc.
[0110] The term "carbonyl" or "carboxy" includes compounds and
moieties which contain a carbon connected with a double bond to an
oxygen atom, and tautomeric forms thereof. Examples of moieties
that contain a carbonyl include aldehydes, ketones, carboxylic
acids, amides, esters, anhydrides, etc. The term "carboxy moiety"
or "carbonyl moiety" refers to groups such as "alkylcarbonyl"
groups wherein an alkyl group is covalently bound to a carbonyl
group, "alkenylcarbonyl" groups wherein an alkenyl group is
covalently bound to a carbonyl group, "alkynylcarbonyl" groups
wherein an alkynyl group is covalently bound to a carbonyl group,
"arylcarbonyl" groups wherein an aryl group is covalently attached
to the carbonyl group. Furthermore, the term also refers to groups
wherein one or more heteroatoms are covalently bonded to the
carbonyl moiety. For example, the term includes moieties such as,
for example, aminocarbonyl moieties, (wherein a nitrogen atom is
bound to the carbon of the carbonyl group, e.g., an amide),
aminocarbonyloxy moieties, wherein an oxygen and a nitrogen atom
are both bond to the carbon of the carbonyl group (e.g., also
referred to as a "carbamate"). Furthermore, aminocarbonylamino
groups (e.g., ureas) are also include as well as other combinations
of carbonyl groups bound to heteroatoms (e.g., nitrogen, oxygen,
sulfur, etc. as well as carbon atoms). Furthermore, the heteroatom
can be further substituted with one or more alkyl, alkenyl,
alkynyl, aryl, aralkyl, acyl, etc. moieties.
[0111] The term "thiocarbonyl" or "thiocarboxy" includes compounds
and moieties which contain a carbon connected with a double bond to
a sulfur atom. The term "thiocarbonyl moiety" includes moieties
that are analogous to carbonyl moieties. For example,
"thiocarbonyl" moieties include aminothiocarbonyl, wherein an amino
group is bound to the carbon atom of the thiocarbonyl group,
furthermore other thiocarbonyl moieties include, oxythiocarbonyls
(oxygen bound to the carbon atom), aminothiocarbonylamino groups,
etc.
[0112] The term "ether" includes compounds or moieties that contain
an oxygen bonded to two different carbon atoms or heteroatoms. For
example, the term includes "alkoxyalkyl" which refers to an alkyl,
alkenyl, or alkynyl group covalently bonded to an oxygen atom that
is covalently bonded to another alkyl group.
[0113] The term "ester" includes compounds and moieties that
contain a carbon or a heteroatom bound to an oxygen atom that is
bonded to the carbon of a carbonyl group. The term "ester" includes
alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl,
alkenyl, or alkynyl groups are as defined above.
[0114] The term "thioether" includes compounds and moieties which
contain a sulfur atom bonded to two different carbon or hetero
atoms. Examples of thioethers include, but are not limited to
alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term
"alkthioalkyls" include compounds with an alkyl, alkenyl, or
alkynyl group bonded to a sulfur atom that is bonded to an alkyl
group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls"
refer to compounds or moieties wherein an alkyl, alkenyl, or
alkynyl group is bonded to a sulfur atom which is covalently bonded
to an alkynyl group.
[0115] The term "hydroxy" or "hydroxyl" includes groups with an
--OH or --O.sup.-.
[0116] The term "halogen" includes fluorine, bromine, chlorine,
iodine, etc. The term "perhalogenated" generally refers to a moiety
wherein all hydrogens are replaced by halogen atoms.
[0117] The terms "polycyclyl" or "polycyclic radical" include
moieties with two or more rings (e.g., cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls and/or heterocyclyls) in which two or more
carbons are common to two adjoining rings, e.g., the rings are
"fused rings". Rings that are joined through non-adjacent atoms are
termed "bridged" rings. Each of the rings of the polycycle can be
substituted with such substituents as described above, as for
example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl,
alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,
alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl,
phosphate, phosphonato, phosphinato, cyano, amino (including alkyl
amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato,
sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,
heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic
moiety.
[0118] The term "heteroatom" includes atoms of any element other
than carbon or hydrogen. Preferred heteroatoms are nitrogen,
oxygen, sulfur and phosphorus.
[0119] Additionally, the phrase "any combination thereof" implies
that any number of the listed functional groups and molecules may
be combined to create a larger molecular architecture. For example,
the terms "phenyl," "carbonyl" (or "=0"), "--O--," "--OH," and
C.sub.1-6 (i.e., --CH.sub.3 and --CH.sub.2CH.sub.2CH.sub.2--) can
be combined to form a 3-methoxy-4-propoxybenzoic acid substituent.
It is to be understood that when combining functional groups and
molecules to create a larger molecular architecture, hydrogens can
be removed or added, as required to satisfy the valence of each
atom.
[0120] It is to be understood that all of the compounds of the
invention described above will further include bonds between
adjacent atoms and/or hydrogens as required to satisfy the valence
of each atom. That is, bonds and/or hydrogen atoms are added to
provide the following number of total bonds to each of the
following types of atoms: carbon: four bonds; nitrogen: three
bonds; oxygen: two bonds; and sulfur: two-six bonds.
[0121] It will be noted that the structures of some of the
compounds of this invention include asymmetric carbon atoms. It is
to be understood accordingly that the isomers arising from such
asymmetry (e.g., all enantiomers, stereoisomers, rotamers,
tautomers, diastereomers, or racemates) are included within the
scope of this invention. Such isomers can be obtained in
substantially pure form by classical separation techniques and by
stereochemically controlled synthesis. Furthermore, the structures
and other compounds and moieties discussed in this application also
include all tautomers thereof. Compounds described herein may be
obtained through art recognized synthesis strategies.
[0122] It will also be noted that the substituents of some of the
compounds of this invention include isomeric cyclic structures. It
is to be understood accordingly that constitutional isomers of
particular substituents are included within the scope of this
invention, unless indicated otherwise. For example, the term
"tetrazole" includes tetrazole, 2H-tetrazole, 3H-tetrazole,
4H-tetrazole and 5H-tetrazole.
Use in Bacterial Infection
[0123] The compounds of the present invention have valuable
pharmacological properties and are useful in the treatment of
diseases. In certain embodiments, compounds of the invention are
useful in the treatment of bacterial infections.
[0124] The term "use" includes any one or more of the following
embodiments of the invention, respectively: the use in the
treatment of bacterial infections; the use for the manufacture of
pharmaceutical compositions for use in the treatment of these
diseases, e.g., in the manufacture of a medicament; methods of use
of compounds of the invention in the treatment of these diseases;
pharmaceutical preparations having compounds of the invention for
the treatment of these diseases; and compounds of the invention for
use in the treatment of these diseases; as appropriate and
expedient, if not stated otherwise. In particular, diseases to be
treated and are thus preferred for use of a compound of the present
invention are selected from bacterial infections, as well as those
diseases that depend on the activity of EF-Tu. The term "use"
further includes embodiments of compositions herein which bind to
an EF-Tu protein sufficiently to serve as tracers or labels, so
that when coupled to a fluor or tag, or made radioactive, can be
used as a research reagent or as a diagnostic or an imaging
agent.
[0125] In certain embodiments, a compound of the present invention
is used for treating EF-Tu-associated diseases, and use of the
compound of the present invention as an inhibitor of any one or
more EF-Tu proteins. It is envisioned that a use can be a treatment
of inhibiting one or more isoforms of EF-Tu.
Assays
[0126] The inhibition of antibacterial activity by the compounds of
the invention may be measured using a number of assays available in
the art. An example of such an assay is the standard minimum
inhibitory concentration (MIC) test conducted according to CSLI
guidelines.
Pharmaceutical Compositions
[0127] The language "effective amount" of the compound is that
amount necessary or sufficient to treat or prevent a bacterial
infection, e.g. prevent the various morphological and somatic
symptoms of a bacterial infection, and/or a disease or condition
described herein. In an example, an effective amount of the
compound of the invention is the amount sufficient to treat a
bacterial infection in a subject. The effective amount can vary
depending on such factors as the size and weight of the subject,
the type of illness, or the particular compound of the invention.
For example, the choice of the compound of the invention can affect
what constitutes an "effective amount." One of ordinary skill in
the art would be able to study the factors contained herein and
make the determination regarding the effective amount of the
compounds of the invention without undue experimentation.
[0128] The regimen of administration can affect what constitutes an
effective amount. The compound of the invention can be administered
to the subject either prior to or after the onset of a bacterial
infection. Further, several divided dosages, as well as staggered
dosages, can be administered daily or sequentially, or the dose can
be continuously infused, or can be a bolus injection. Further, the
dosages of the compound(s) of the invention can be proportionally
increased or decreased as indicated by the exigencies of the
therapeutic or prophylactic situation.
[0129] Compounds of the invention may be used in the treatment of
states, disorders or diseases as described herein, or for the
manufacture of pharmaceutical compositions for use in the treatment
of these diseases. Methods of use of compounds of the present
invention in the treatment of these diseases, or pharmaceutical
preparations having compounds of the present invention for the
treatment of these diseases.
[0130] The language "pharmaceutical composition" includes
preparations suitable for administration to mammals, e.g., humans.
When the compounds of the present invention are administered as
pharmaceuticals to mammals, e.g., humans, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99.5% (more preferably, 0.5 to 90%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0131] The phrase "pharmaceutically acceptable carrier" is art
recognized and includes a pharmaceutically acceptable material,
composition or vehicle, suitable for administering compounds of the
present invention to mammals. The carriers include liquid or solid
filler, diluent, excipient, solvent or encapsulating material,
involved in carrying or transporting the subject agent from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
injurious to the patient. Some examples of materials which can
serve as pharmaceutically acceptable carriers include: sugars, such
as lactose, glucose and sucrose; starches, such as corn starch and
potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter and suppository waxes; oils, such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol; polyols, such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer
solutions; and other non-toxic compatible substances employed in
pharmaceutical formulations.
[0132] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0133] Examples of pharmaceutically acceptable antioxidants
include: water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, .alpha.-tocopherol,
and the like; and metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0134] Formulations of the present invention include those suitable
for oral, nasal, topical, buccal, sublingual, rectal, vaginal
and/or parenteral administration. The formulations may conveniently
be presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. The amount of active ingredient
that can be combined with a carrier material to produce a single
dosage form will generally be that amount of the compound that
produces a therapeutic effect. Generally, out of one hundred
percent, this amount will range from about 1 percent to about
ninety-nine percent of active ingredient, preferably from about 5
percent to about 70 percent, most preferably from about 10 percent
to about 30 percent.
[0135] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0136] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouth washes and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste.
[0137] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingredient is mixed with one or
more pharmaceutically acceptable carriers, such as sodium citrate
or dicalcium phosphate, and/or any of the following: fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; humectants, such as glycerol; disintegrating
agents, such as agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate;
solution retarding agents, such as paraffin; absorption
accelerators, such as quaternary ammonium compounds; wetting
agents, such as, for example, cetyl alcohol and glycerol
monostearate; absorbents, such as kaolin and bentonite clay;
lubricants, such a talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and coloring agents. In the case of capsules, tablets and
pills, the pharmaceutical compositions may also comprise buffering
agents. Solid compositions of a similar type may also be employed
as fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
[0138] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0139] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions that
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions that can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0140] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluent commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0141] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0142] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0143] Formulations of the pharmaceutical compositions of the
invention for rectal or vaginal administration may be presented as
a suppository, which may be prepared by mixing one or more
compounds of the invention with one or more suitable nonirritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the rectum or vaginal cavity and release
the active compound.
[0144] Formulations of the present invention which are suitable for
vaginal administration also include pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing such carriers
as are known in the art to be appropriate.
[0145] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants that may be required.
[0146] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0147] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0148] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
compound in the proper medium. Absorption enhancers can also be
used to increase the flux of the compound across the skin. The rate
of such flux can be controlled by either providing a rate
controlling membrane or dispersing the active compound in a polymer
matrix or gel.
[0149] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0150] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more pharmaceutically
acceptable sterile isotonic aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, or sterile powders which may
be reconstituted into sterile injectable solutions or dispersions
just prior to use, which may contain antioxidants, buffers,
bacteriostats, solutes which render the formulation isotonic with
the blood of the intended recipient or suspending or thickening
agents.
[0151] Examples of suitable aqueous and nonaqueous carriers that
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0152] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents that delay
absorption such as aluminum monostearate and gelatin.
[0153] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0154] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions that are
compatible with body tissue.
[0155] The preparations of the present invention may be given
orally, parenterally, topically, or rectally. They are of course
given by forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, etc., administration
by injection, infusion or inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral and/or IV
administration is preferred.
[0156] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0157] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0158] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0159] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically acceptable
dosage forms by conventional methods known to those of skill in the
art.
[0160] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0161] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion of the particular compound being employed, the
duration of the treatment, other drugs, compounds and/or materials
used in combination with the particular compound employed, the age,
sex, weight, condition, general health and prior medical history of
the patient being treated, and like factors well known in the
medical arts.
[0162] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0163] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound that is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, intravenous and subcutaneous doses of the compounds of
this invention for a patient, when used for the indicated analgesic
effects, will range from about 0.0001 to about 100 mg per kilogram
of body weight per day, more preferably from about 0.01 to about 50
mg per kg per day, and still more preferably from about 1.0 to
about 100 mg per kg per day. An effective amount is that amount
treats a bacterial infection.
[0164] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms.
[0165] While it is possible for a compound of the present invention
to be administered alone, it is preferable to administer the
compound as a pharmaceutical composition.
Synthetic Procedure
[0166] Compounds of the present invention are prepared from
commonly available compounds using procedures known to those
skilled in the art, including any one or more of the following
conditions without limitation:
[0167] Within the scope of this text, only a readily removable
group that is not a constituent of the particular desired end
product of the compounds of the present invention is designated a
"protecting group," unless the context indicates otherwise. The
protection of functional groups by such protecting groups, the
protecting groups themselves, and their cleavage reactions are
described for example in standard reference works, such as e.g.,
Science of Synthesis: Houben-Weyl Methods of Molecular
Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005.
41627 pp. (URL: http://www.science-of-synthesis.com (Electronic
Version, 48 Volumes)); J. F. W. McOmie, "Protective Groups in
Organic Chemistry", Plenum Press, London and New York 1973, in T.
W. Greene and P. G. M. Wuts, "Protective Groups in Organic
Synthesis", Third edition, Wiley, New York 1999, in "The Peptides";
Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press,
London and New York 1981, in "Methoden der organischen Chemie"
(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume
15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H.
Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides,
Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel
1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate:
Monosaccharide and Derivate" (Chemistry of Carbohydrates:
Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart
1974. A characteristic of protecting groups is that they can be
removed readily (i.e., without the occurrence of undesired
secondary reactions) for example by solvolysis, reduction,
photolysis or alternatively under physiological conditions (e.g.,
by enzymatic cleavage).
[0168] Salts of compounds of the present invention having at least
one salt-forming group may be prepared in a manner known per se.
For example, salts of compounds of the present invention having
acid groups may be formed, for example, by treating the compounds
with metal compounds, such as alkali metal salts of suitable
organic carboxylic acids, e.g., the sodium salt of 2-ethylhexanoic
acid, with organic alkali metal or alkaline earth metal compounds,
such as the corresponding hydroxides, carbonates or hydrogen
carbonates, such as sodium or potassium hydroxide, carbonate or
hydrogen carbonate, with corresponding calcium compounds or with
ammonia or a suitable organic amine, stoichiometric amounts or only
a small excess of the salt-forming agent preferably being used.
Acid addition salts of compounds of the present invention are
obtained in customary manner, e.g., by treating the compounds with
an acid or a suitable anion exchange reagent. Internal salts of
compounds of the present invention containing acid and basic
salt-forming groups, e.g., a free carboxy group and a free amino
group, may be formed, e.g., by the neutralisation of salts, such as
acid addition salts, to the isoelectric point, e.g., with weak
bases, or by treatment with ion exchangers.
[0169] Salts can be converted in customary manner into the free
compounds; metal and ammonium salts can be converted, for example,
by treatment with suitable acids, and acid addition salts, for
example, by treatment with a suitable basic agent.
[0170] Mixtures of isomers obtainable according to the invention
can be separated in a manner known per se into the individual
isomers; diastereoisomers can be separated, for example, by
partitioning between polyphasic solvent mixtures, recrystallisation
and/or chromatographic separation, for example over silica gel or
by, e.g., medium pressure liquid chromatography over a reversed
phase column, and racemates can be separated, for example, by the
formation of salts with optically pure salt-forming reagents and
separation of the mixture of diastereoisomers so obtainable, for
example by means of fractional crystallisation, or by
chromatography over optically active column materials.
[0171] Intermediates and final products can be worked up and/or
purified according to standard methods, e.g., using chromatographic
methods, distribution methods, (re-) crystallization, and the
like.
General Process Conditions
[0172] The following applies in general to all processes mentioned
throughout this disclosure.
[0173] The process steps to synthesize the compounds of the
invention can be carried out under reaction conditions that are
known per se, including those mentioned specifically, in the
absence or, customarily, in the presence of solvents or diluents,
including, for example, solvents or diluents that are inert towards
the reagents used and dissolve them, in the absence or presence of
catalysts, condensation or neutralizing agents, for example ion
exchangers, such as cation exchangers, e.g., in the H.sup.+ form,
depending on the nature of the reaction and/or of the reactants at
reduced, normal or elevated temperature, for example in a
temperature range of from about -100.degree. C. to about
190.degree. C., including, for example, from approximately
-80.degree. C. to approximately 150.degree. C., for example at from
-80 to -60.degree. C., at room temperature, at from -20 to
40.degree. C. or at reflux temperature, under atmospheric pressure
or in a closed vessel, where appropriate under pressure, and/or in
an inert atmosphere, for example under an argon or nitrogen
atmosphere.
[0174] At all stages of the reactions, mixtures of isomers that are
formed can be separated into the individual isomers, for example
diastereoisomers or enantiomers, or into any desired mixtures of
isomers, for example racemates or mixtures of diastereoisomers, for
example analogously to the methods described in Science of
Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg
Thieme Verlag, Stuttgart, Germany. 2005.
[0175] The solvents from which those solvents that are suitable for
any particular reaction may be selected include those mentioned
specifically or, for example, water, esters, such as lower
alkyl-lower alkanoates, for example ethyl acetate, ethers, such as
aliphatic ethers, for example diethyl ether, or cyclic ethers, for
example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons,
such as benzene or toluene, alcohols, such as methanol, ethanol or
1- or 2-propanol, nitriles, such as acetonitrile, halogenated
hydrocarbons, such as methylene chloride or chloroform, acid
amides, such as dimethylformamide or dimethyl acetamide, bases,
such as heterocyclic nitrogen bases, for example pyridine or
N-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower
alkanoic acid anhydrides, for example acetic anhydride, cyclic,
linear or branched hydrocarbons, such as cyclohexane, hexane or
isopentane, or mixtures of those solvents, for example aqueous
solutions, unless otherwise indicated in the description of the
processes. Such solvent mixtures may also be used in working up,
for example by chromatography or partitioning.
[0176] The compounds, including their salts, may also be obtained
in the form of hydrates, or their crystals may, for example,
include the solvent used for crystallization. Different crystalline
forms may be present.
[0177] The invention relates also to those forms of the process in
which a compound obtainable as an intermediate at any stage of the
process is used as starting material and the remaining process
steps are carried out, or in which a starting material is formed
under the reaction conditions or is used in the form of a
derivative, for example in a protected form or in the form of a
salt, or a compound obtainable by the process according to the
invention is produced under the process conditions and processed
further in situ.
Prodrugs
[0178] This invention also encompasses pharmaceutical compositions
containing, and methods of treating bacterial infections through
administering, pharmaceutically acceptable prodrugs of compounds of
the compounds of the invention. For example, compounds of the
invention having free amino, amido, hydroxy or carboxylic groups
can be converted into prodrugs. Prodrugs include compounds wherein
an amino acid residue, or a polypeptide chain of two or more (e.g.,
two, three or four) amino acid residues is covalently joined
through an amide or ester bond to a free amino, hydroxy or
carboxylic acid group of compounds of the invention. The amino acid
residues include but are not limited to the 20 naturally occurring
amino acids commonly designated by three letter symbols and also
includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,
3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,
citrulline homocysteine, homoserine, ornithine and methionine
sulfone. Additional types of prodrugs are also encompassed. For
instance, free carboxyl groups can be derivatized as amides or
alkyl esters. Free hydroxy groups may be derivatized using groups
including but not limited to hemisuccinates, phosphate esters,
dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
Carbamate prodrugs of hydroxy and amino groups are also included,
as are carbonate prodrugs, sulfonate esters and sulfate esters of
hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl
and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl
ester, optionally substituted with groups including but not limited
to ether, amine and carboxylic acid functionalities, or where the
acyl group is an amino acid ester as described above, are also
encompassed. Prodrugs of this type are described in J. Med. Chem.
1996, 39, 10. Free amines can also be derivatized as amides,
sulfonamides or phosphonamides. All of these prodrug moieties may
incorporate groups including but not limited to ether, amine and
carboxylic acid functionalities.
[0179] Any reference to a compound of the present invention is
therefore to be understood as referring also to the corresponding
pro-drugs of the compound of the present invention, as appropriate
and expedient.
Combinations
[0180] A compound of the present invention may also be used in
combination with other agents, e.g., an additional antibacterial
compound that is or is not a compound of the invention, for
treatment of a bacterial infection in a subject.
[0181] By the term "combination" is meant either a fixed
combination in one dosage unit form, or a kit of parts for the
combined administration where a compound of the present invention
and a combination partner may be administered independently at the
same time or separately within time intervals that especially allow
that the combination partners show a cooperative, e.g.,
synergistic, effect, or any combination thereof.
[0182] A compound of the present invention may be used in
combination with another antibacterial agent. The term
"antibacterial agent" refers to any substance that is either
bactericidal or bacteriostatic, i.e., capable of killing or
inhibiting the growth of bacterial cells. Antibacterial agents
include antibiotics, biocides, antimicrobials, and bacteriostatic
agents. The known types of antibiotics include, e.g., cell wall
synthesis inhibitors, cell membrane inhibitors, protein synthesis
inhibitors and inhibitors that bind to or affect the synthesis of
DNA or RNA. Numerous antibiotic agents suitable for use in the
treatment of bacteria-related diseases and disorders, are known and
disclosed, e.g. in The Physician's Desk Reference (PDR), Medical
Economics Company (Montvale, N.J.), (53.sup.rd Ed.), 1999; Mayo
Medical Center Formulary, Unabridged Version, Mayo Clinic
(Rochester, Minn.), January 1998; Merck Index: An Encyclopedia of
Chemicals, Drugs and Biologicals, (11.sup.th Ed.), Merck & Co.,
Inc. (Rahway, N.J.), 1989; University of Wisconsin Antimicrobial
Use Guide, http://www.medsch.wisc.edu/clinsci/5amcg/amcg.html;
Introduction on the Use of the Antibiotics Guideline, of Specific
Antibiotic Classes, Thomas Jefferson University,
http://jeffiine.tju.edu/CWIS/OAC/antibiotics_guide/intro.html; and
references cited therein.
[0183] Examples of antibiotics for use in combination with the
compounds of the invention include, but are not limited to,
quinolone, macrolide, glycopeptide, oxazolidinone, .beta.-lactams
(including amoxicillin, ampicillin, bacampicillin, carbenicillin,
cloxacillin, dicloxacillin, flucloxacillin, methicillin,
mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V,
piperacillin, pivampicillin, pivmecillinam, ticarcillin, sulbactam,
tazobactam, clavulanate), cephalosporins (cefaclor, cefadroxil,
cefamandole, cefazolin, cefdinir, cefditoren, cefepime, cefixime,
cefonicid, cefoperazone, cefotaxime, cefotetan, cefoxitin,
cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,
ceftriaxone, cefuroxime, cephalexin, cephalothin, cephapirin,
cephradine), aminoglycosides (including gentamycin, streptomycin,
amikacin, kanamycin, viomycin, capreomycin), ethionamide,
prothionamide, cycloserine, dapsone, clofazimine, tetracyclines
(tetracycline, doxycycline, chlortetracycline, oxytetracycline,
minocycline demeclocycline), oxazolidinones (linezolid,
eperezolid), metronidazole, rifabutin, isoniazonid, ethambutol, and
combinations thereof.
[0184] Examples of anti-viral agents for use in combination with
the compounds of the invention include, but are not limited to,
zidovudine, lamivudine, didanosine, zalcitabine, stavudine,
abacavir, nevirapine, delavirdine, emtricitabine, efavirenz,
saquinavir, ritonavir, indinavir, nelfinavir, amprenavir,
tenofovir, adefovir, atazanavir, fosamprenavir, hydroxyurea,
AL-721, ampligen, butylated hydroxytoluene; polymannoacetate,
castanospermine; contracan; creme pharmatex, CS-87, penciclovir,
famciclovir, acyclovir, cytofovir, ganciclovir, dextran sulfate,
D-penicillamine trisodium phosphonoformate, fusidic acid, HPA-23,
eflornithine, nonoxynol, pentamidine isethionate, peptide T,
phenyloin, isoniazid, ribavirin, rifabutin, ansamycin,
trimetrexate, SK-818, suramin, UA001, enfuvirtide, gp41-derived
peptides, antibodies to CD4, soluble CD4, CD4-containing molecules,
CD4-IgG2, and combinations thereof.
[0185] Further examples of agents the compounds of the present
invention can be used in combination with include, but are not
limited to, free radical scavengers, ascorbic acid, Vitamin C,
anti-cancer agents, chemotherapeutic agents, non-steroidal
anti-inflammatory drugs, steroidal anti-inflammatory drugs,
anti-fungal agents, detoxifying agents, analgesics,
bronchodilators, drugs for the treatment of vascular ischemia
anti-body monoclonal agent, minoxidil for topical application for
hair growth, diuretics, immunosuppressants, lymphokynes,
.alpha.-and-.beta.-interferon and combinations thereof.
[0186] The compound of the invention and any additional agent may
be formulated in separate dosage forms. Alternatively, to decrease
the number of dosage forms administered to a patient, the compound
of the invention and any additional agent may be formulated
together in any combination. For example, the compound of the
invention inhibitor may be formulated in one dosage form and the
additional agent may be formulated together in another dosage form.
Any separate dosage forms may be administered at the same time or
different times.
[0187] Alternatively, a composition of this invention comprises an
additional agent as described herein. Each component may be present
in individual compositions, combination compositions, or in a
single composition.
Exemplification of the Invention
[0188] The invention is further illustrated by the following
examples, which should not be construed as further limiting. The
practice of the present invention will employ, unless otherwise
indicated, conventional techniques of cell biology, cell culture,
molecular biology, transgenic biology, microbiology and immunology,
which are within the skill of the art.
General Synthesis Methods
[0189] All starting materials, building blocks, reagents, acids,
bases, dehydrating agents, solvents, and catalysts utilized to
synthesize the compounds of the present invention are either
commercially available or can be produced by organic synthesis
methods known to one of ordinary skill in the art (Houben-Weyl 4th
Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Further, the compounds of the present invention can be produced by
organic synthesis methods known to one of ordinary skill in the art
as shown in the following examples.
EXAMPLES
Definitions
[0190] A, .ANG. Ankstrom [0191] ACN acetonitrile [0192] AcOH acetic
acid [0193] aq aqueous [0194] bnBr benzylbromide [0195] boc
tert-butoxycarbonyl [0196] C Celsius [0197] cat. catalytic [0198]
CDI cabonyldiimidazole [0199] CSA camphorsulfonic acid [0200] conc.
concentrated [0201] C.sub.2CO.sub.3 cesium carbonate [0202] Da
Daltons [0203] deg degrees [0204] DIBAL, DIBAL-H diisobutylaluminum
hydride [0205] DIPEA diisopropylethylamine [0206] DIPC
N,N'-diisopropylcarbodiimide [0207] DMF N,N-dimethylformamide
[0208] DMI 1,3 dimethyl-2-imidazolidinone [0209] DMP Dess-Martin
periodinane [0210] DCC N,N-dicyclohexylcarbodiimide [0211] DCE
dichloroethane [0212] DCM dichloromethane [0213] DMAP
4-dimethylaminopyridine [0214] DMSO dimethylsulfoxide [0215] EtOAc
ethyl acetate [0216] EtOH ethanol [0217] eq equivalents [0218] g
gas [0219] Grubbs II
1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophenylmeth-
ylene)(tricyclohexyl phosphine)ruthenium [0220] h hours [0221] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0222] HMPA hexamethlphosphoramide [0223] hep
heptane [0224] HCl hydrochloric acid [0225] inh. inhibition [0226]
imid. Imidazole [0227] K Kelvin [0228] KHMDS potassium
hexamethyldisilylazide [0229] K.sub.2CO.sub.3 potassium carbonate
[0230] LDA lithiumdiisopropylamine [0231] LiBH.sub.4 lithium
borohydride [0232] LHMDS lithiumhexamethyldisilylazide [0233] LC
liquid chromatography [0234] LC/MS liquid chromatography mass
spectrum [0235] M molar [0236] MeCN acetonitrile [0237] MeOH
methanol [0238] MgSO.sub.4 magnesium sulfate [0239] MHz megahertz
[0240] min minutes [0241] mol. sieves molecular sieves [0242]
NaBH.sub.4 sodium borohydride [0243] N normal [0244] NMR nuclear
magnetic resonance [0245] Pd/C palladium on carbon [0246] PEG(750)
O-(2-aminoethyl)-O'-methyl polyethylene glycol 750;
NH.sub.2(CH.sub.2CH.sub.2O).sub.nCH.sub.3; CAS#[80506-64-5]; Fluka
07964; AVERAGE MW=750 [0247] PS polystyrene [0248] Py pyridine
[0249] PPM parts per million [0250] RP reverse phase [0251] RT room
temperature [0252] R.sub.t retention time [0253] s solid [0254]
sat. saturated [0255] TBS tert-butyldimethylsilyl [0256] TMS
trimethylsilyl [0257] TBAF tetrabutylammonum fluoride [0258] TBTU
O-benzotriazol-1-yl-N,N, N,N'-tetramethyluronium tetrafluoroborate
[0259] TLC thin-layer chromatography [0260] TEA triethylamine
[0261] TFA trifluoroacetic acid [0262] THF tetrahydrofuran [0263] h
hours [0264] min minutes [0265] m/z mass to charge [0266] MS mass
spectrum [0267] HRMS high resolution mass spectrum [0268] NMR
nuclear magnetic resonance
Analytical Methods
[0269] NMR: proton spectra are recorded on a Bruker 400 MHz
ultrashield spectrometer unless otherwise noted. Chemical shifts
are reported in ppm relative to methanol (.delta. 3.31), dimethyl
sulfoxide (.delta. 2.50), or chloroform (.delta. 7.26).
LC/MS:
[0270] Method 1: compounds are analyzed on an Inertsil ODS-3 column
(C18, 50.times.4.6 mm, 3 .mu.m) with a 2 min gradient elution
(20-80% acetonitrile/H.sub.2O/5 mM ammonium formate) and a flow
rate of 4 mL/min. Method 5: GENERAL LC/MS method with acid mobile
phase (0.1% formic acid) and fast gradient. Electrospray mass
spectra (+) and (-), DAD-UV chromatogram 200-400 nm, scan range
120-1500 Da. Gradient: 20-80% MeCN/H.sub.2O in 2 min (2 mL/min), 2
.mu.L injection. Column: Inertsil ODS3 C-18, 3 cm.times.33
mm.times.3.0 .mu.m, 40 deg C. Method 6: GENERAL LC/MS method with
neutral mobile phase (5 mM NH.sub.4.sup.+HCOO.sup.-) and fast
(20-80%) gradient. Electrospray mass spectra (+) and (-), DAD-UV
chromatogram 200-400 nm, scan range 120-1500 Da. Gradient: 20-80%
MeCN/H.sub.2O in 2 min (2 mL/min), 2 .mu.L injection. Column.
Inertsil ODS3 C-18, 3 cm.times.33 mm.times.3.0 .mu.m, 40 deg C.
Method 7: LC/MS method for NON-POLAR (greasy) compounds with acid
mobile phase (0.1% formic acid) and fast (40-90%) gradient.
Electrospray mass spectra (+) and (-), DAD-UV chromatogram 200-400
nm, scan range 120-1500 Da. Gradient: 40-90% MeCN/H.sub.2O in 2 min
(2 mL/min), 2 .mu.L injection. Column. Inertsil C8-3, 3 cm.times.33
mm.times.3.0 .mu.m, 40 deg C. Method 8: LC/MS method for NON-POLAR
(greasy) compounds with neutral mobile phase (5 mM
NH.sub.4.sup.+HCOO.sup.-) and fast (40-90%) gradient. Electrospray
mass spectra (+) and (-), DAD-UV chromatogram 200-400 nm, scan
range 120-1500 Da. Gradient: 40-90% MeCN/H.sub.2O in 2 min (2
mL/min), 2 .mu.L injection. Column: Inertsil C8-3, 3.0 cm.times.33
mm.times.3.0 .mu.m, 40 deg C. Method 9: LC/MS method with broad
range (5-95%) gradient with acid mobile phase (0.1% Formic Acid).
Electrospray mass spectra (+) and (-), DAD-UV chromatogram 200-400
nm, scan range 120-1500 Da. Gradient: 5-95% MeCN/H.sub.2O in 2 min
(2 mL/min), 2 .mu.L injection. Column: Inertsil C8-3, 3.0
cm.times.33 mm.times.3.0 .mu.m, 40 deg C. Method 10: LC/MS method
with broad range (5-95%) gradient with neutral mobile phase (5 mM
NH.sub.4.sup.+HCOO.sub.-). Electrospray mass spectra (+) and (-),
DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da. Gradient:
5-95% MeCN/H.sub.2O in 2 min (2 mL/min), 2 .mu.L injection. Column:
Inertsil C8-3, 3 cm.times.433 mm.times.3.0 .mu.m, 40 deg C. Method
11: LC/MS method for POLAR compounds with acid mobile phase (0.1%
formic acid) and slow (0-100%) gradient. Electrospray mass spectra
(+) and (-), DAD-UV chromatogram 200-400 nm, scan range 120-1500
Da. Gradient: 0-100% MeCN/H.sub.2O in 2 min (2 mL/min), 2 .mu.L
injection. Column: Inertsil ODS3 (C-18, 3 cm.times.33 mm.times.3.0
.mu.m, 40 degree C.) Method 12: LC/MS method for POLAR compounds
with neutral mobile phase (5 mM NH.sub.4.sup.+HCOO.sup.-) and slow
(0-100%) gradient. Electrospray mass spectra (+) and (-), DAD-UV
chromatogram 200-400 nm, scan range 120-1500 Da. Gradient: 0-100%
MeCN/H.sub.2O in 2 min (2 mL/min), 2 .mu.L injection. Column:
Inertsil ODS-3 (C-18, 3 cm.times.33 mm.times.3.0 .mu.m, 40 deg C.
Method 13: Compounds are analyzed on an Inertsil ODS-3 column (C8,
30 mm.times.3.0 mm, 3.0 um) with a 2 min gradient elution (5-90%
acetonitrile/H.sub.2O/5 mM ammonium formate) and a flow rate of 2
mL/min. Method 14: Compounds are analyzed on an Inertsil ODS-3
column (C8, 30 mm.times.3.0 mm, 3.0 um) with a 2 min gradient
elution (5-90% acetonitrile/H.sub.2O/0.1% formic acid) and a flow
rate of 2 mL/min. HPLC purification utilizes a C8 or C18 column
(30.times.100 mm, 5 um, brand: Sunfire or XTerra) and is performed
with an appropriate gradient using two methods (unless otherwise
noted). Method 1 consists of 0.1% TFA in 5%-95% ACN in H.sub.2O.
Method 2 consists of 10 mM NH.sub.4OH in 5%-95% ACN in H.sub.2O. LC
analysis utilizes a liquid chromatography-UV detection (LC-UV)
using a Agilent 1100 liquid chromatograph. LC conditions are as
follows: column: Atlantis C18 (Waters, Inc.), 15 cm.times.4.6
mm.times.5 .mu.m; column temperature: ambient; flow rate: 1.4
mL/min; injection volume: 3.0 .mu.L; gradient: A=0.1%
trifluoroacetic acid (TFA) in water, B=0.05% trifluoroacetic Acid
(TFA) in acetonitrile, 0-95% B in 19.0 min, 1.8 min hold.
##STR00119## ##STR00120## ##STR00121## ##STR00122##
##STR00123##
The compound of general formula (I) may be prepared via synthetic
methods well known to those skilled in the art, or alternatively
isolated from a fermentation broth. See, for example, U.S. Pat. No.
5,202,241. The compound of general structural formula (II) may be
prepared by process A by the acid or base mediated rearrangement of
compound (i) in the presence of water and a suitable acid or base.
The compound of general formula (iii) may be prepared in process B
from (ii) directly via reaction with azide or alternatively through
a multi step process which includes removal of the ester
functionality through hydrolysis with a suitable base or acid,
activation of the carboxylic acid moiety using a suitable
activation agent, and reaction with a suitable reagent such as
azide. Azides represented by formula (iii) are known in the art and
are readily synthesized by standard procedures commonly employed in
the art. The compound of general formula (Iv) may be prepared by
reaction of the azide (iii) with a nucleophile, alcohol, amine, or
protecting group (X.sub.1). A suitable protecting group can be
selected by those skilled in the art. Protecting groups are
selected so that they are suitable for the depicted transformations
and can be removed following the synthesis with little or no loss
of yield. The introduction and selective removal of protecting
groups are taught in Greene and Wuts, "Protective Groups in Organic
Synthesis", John Wiley & Sons (1991). The compound of general
structural formula (v) may be prepared by reacting compound (iv)
with a reactive reagent such as an electrophile, alkylating agent,
acylating agent, or protecting group (X.sub.2) to afford compound
(v). The compound of general structure (vi) can be prepared by
reacting compound (v) with acid, base, a nucleophile, or
electrophile to remove the protecting group (X.sub.1). The compound
of general structure (vii) can be prepared by reacting compound
(vi) with a suitable electrophile, alkylating agent, or acylating
agent (X.sub.3). The compound of general structure (viii) can be
prepared by reacting compound (vii) with a suitable electrophile,
alkylating agent, or acylating agent (X.sub.4). The compound of
general structure (ix) can be prepared by reacting compound (viii)
with acid, base, a nucleophile, or electrophile to remove any
remaining protecting groups. Alternatively, any of these steps
(A-H) may be performed in a different order, or with some steps
removed or slightly altered, which is obvious to those skilled in
the art.
##STR00124## ##STR00125##
Intermediate vi can also be cyclized to form a heterocycle or
heteroaromatic ring according to process J through an alkylation,
acyation, cyclization, transition metal-mediated coupling, or
condensation which may be acid or base catalyzed to form x.
Compound x can be further derivitized through alkylation,
acylation, transition metal-mediated coupling, etc. and the
protecting groups removed through process K to provide xi.
Example 1
Preparation of Diacid 3 of Table A
##STR00126##
##STR00127##
[0271] Steps 1-3:
[0272] To a solution of XII (3.1 g, 2.4 mmol) in (CH.sub.3).sub.2CO
(350 mL) and H.sub.2O (40 mL), is added NaOH crystals (0.192 g, 4.8
mmol). The reaction mixture is sonicated and stirred at 22.degree.
C. for 1 hour (LC/MS: m/z [M+H].sup.+ 1125, R.sub.t=1.12 min,
method 1). The reaction mixture is then cooled to 0.degree. C. and
EtOCOCl (17.8 mL, 192 mmol) is added via syringe. After stirring
reaction mixture at 0.degree. C. for 1.5 hours, the reaction shows
the acyl carbonate intermediate (MS m/z 1197 [M+H].sup.+).
NaN.sub.3 solid (6.3 g, 96 mmol) is added to the reaction mixture
and is stirred at 22.degree. C. for 12 hours. 15 g of SiO.sub.2 is
added and all solvents are evaporated in vacuo. The solid is
purified by flash chromatography, eluting with 100% EtOAc to
provide 3.4 g (quant yield), of a cream solid, XIII. MS m/z 1167
(M+H.sub.2O).
Step 4:
[0273] To a solution of the acid sodium salt (8 g, 63 mmol) in DMF
(100 mL) is added MeI (7.9 mL, 126 mmol) and reaction mixture is
stirred for 5 days at 22.degree. C. The excess solvents are removed
under reduced pressure. The residue is diluted with EtOAc and
washed with aqueous brine solution. The organic layers are combined
and dried over Na.sub.2SO.sub.4, filtered and concentrated to
provide 6.2 g (83%) of a yellow oil, 4-hydroxy-butyric acid methyl
ester.
Step 5:
[0274] To a solution of XIII (3 g, 2.6 mmol) in PhMe (100 mL) is
added 4-hydroxy-butyric acid methyl ester (1.2 g, 10.4 mmol) and
the reaction mixture is stirred at 75.degree. C. for 12 hours. 7 g
of SiO.sub.2 is added to the mix and the solvents are concentrated
under reduced pressure. The solid is purified by flash
chromatography, eluting with 100% EtOAc to provide 3.82 g (quant.
yield), of a yellow solid, XIV. MS m/z 1240 (M+H).sup.+.
Step 6:
[0275] To a solution of XIV (1.8 g, 0.15 mmol) in DMF (50 mL), is
added 4-bromo-butyric acid methyl ester (1 g, 0.87 mmol) and
Cs.sub.2CO.sub.3 (800 mg, 0.48 mmol). The reaction is stirred at
22.degree. C. for 48 hours. 5 g SiO.sub.2 is added and all solvents
are evaporated in vacuo. The solid is purified by flash
chromatography, eluting with MeOH/DCM (0-10%) to provide 1.5 g
(75%), of a yellow solid. MS m/z 1357 (M+H.sub.2O).
Step 7:
[0276] To a solution of the diester (250 mg, 0.187 mmol) in MeOH
(10 mL) and H.sub.2O (2 mL) is added NaOH crystals (37 mg, 0.933
mmol) and the reaction mixture is stirred for 72 hours at
22.degree. C. 6 g of SiO.sub.2 is added and the solvents are
concentrated under reduced pressure. The solid is purified by flash
chromatography, eluting with MeOH/DCM (5-10%) then to 10% MeOH/DCM
with 1% AcOH to provide 0.2 g of a yellow oil. The yellow oil is
purified by Gilson HPLC eluting with ACN/H.sub.2O (5-50%) with 3%
n-propanol. Lypholization for 12 h provides 4 mg (16%) of a white
solid, 3. LC/MS: m/z 1329 [M+H.sub.2O].sup.+, method 1. LC:
R.sub.t=8.84 min, HRMS (ES.sup.+)
C.sub.56H.sub.57N.sub.13O.sub.13S.sub.6: Calc.: 1312.2601
[M+H].sup.+; Found: 1312.2637. .sup.1H NMR (DMSO-d6, 600 MHz, 300
K) .delta. 9.047 (d, 1H), 8.698 (d, 1H), 8.683 (d, 1H), 8.605 (s,
1H), 8.459 (dd, 1H), 8.381 (d, 1H), 8.265 (s, 1H), 8.238 (d, 1H),
7.758 (s, 1H), 7.388 (m, 1H), 7.361 (s, 1H), 7.321 (m, 1H), 7.289
(m, 1H), 7.239 (m, 1H), 6.06 (b, 1H), 5.295 (m, 1H), 5.237 (t, 1H),
5.211 (dd, 1H), 4.998 (d, 1H), 4.979 (s, 2H), 4.272-3.787 (dd, 2H),
4.163 (t, 2H), 4.007 (b, 2H), 3.391 (s, 3H), 2.717-1.298 (dd, 2H),
2.589 (s, 3H), 2.479 (d, 3H), 2.336 (t, 2H), 2.303 (t, 2H), 2.169
(m, 1H), 1.900 (m, 2H), 1.878 (m, 2H), 0.881-0.846 (d, 3H).
Example 2
Preparation of Diacid 4 of Table A
##STR00128##
[0277] Step 1:
[0278] To a suspension of acylazide (XIII, 0.600 g, 0.522 mmol) in
toluene (20 mL) is added trans-4-hydroxy-cyclohexane carboxylic
acid ethyl ester (0.134 g, 0.778 mmol) and the mixture is stirred
at 80.degree. C. for 5 h. The reaction is concentrated in vacuo and
the crude product is purified by flash chromatography (MeOH/DCM) to
yield 0.236 g (0.182 mmol, 35%) of the ester.
Step 2:
[0279] To a solution of the ester (125 mg, 0.098 mmol) in DMF (0.8
mL), is added methyl 4-bromobutyrate (67 uL, 0.588 mmol) and
Cs.sub.2CO.sub.3 (112 mg, 0.341 mmol). The reaction is stirred at
rt for 18 hours. The reaction mixture is concentrated, and the
residue is purified by flash chromatography, eluting with MeOH/DCM
(0-10%) to provide 100 mg (74.2%), of a yellow solid, the diester.
MS, m/z 1381 (M+H).sup.+.
Step 3:
[0280] To a solution of the diester (180 mg, 0.130 mmol) in MeOH
(3.6 mL) and THF (0.9 mL) is added 3 N NaOH (0.45 mL, 1.30 mmol)
and the reaction mixture is stirred for 7 hours at rt. The reaction
mixture is neutralized with solid NH.sub.4Cl (70 mg, 1.30 mmol).
The mixture is then concentrated under reduced pressure. The yellow
solid is purified by Gilson HPLC eluting with ACN/H.sub.2O with
0.1% TFA (gradient elution: 30-80%). Lyophylization for 12 h
provides 54 mg of light yellow solid, 4. LC: R.sub.t=11.68 min;
HRMS (ES.sup.+) C.sub.59H.sub.61N.sub.13O.sub.13S.sub.6: Calc.:
1352.2914 [M+H].sup.+; Found: 1352.2878.
Example 3
Preparation of Diacid 5 of Table A
##STR00129##
[0281] Step 1:
[0282] To a solution of the cyclohexyl ester (Example 2, step 1,
300 mg, 0.234 mmol) in DMF (2.1 mL), is added ethyl
7-bromo-heptanoate (282 uL, 1.40 mmol) and Cs.sub.2CO.sub.3 (267
mg, 0.819 mmol). The reaction is stirred at rt for 18 hours. The
reaction mixture is concentrated, and the residue is purified by
flash chromatography, eluting with MeOH/DCM (0-10%) to provide 210
mg of diester. MS m/z 1437 (M+H).sup.+.
Step 2:
[0283] To a solution of the diester (210 mg, 0.146 mmol) in MeOH
(4.5 mL) and THF (1.5 mL) is added 3N NaOH (0.49 mL, 1.46 mmol) and
the reaction mixture is stirred for 18 hours at rt. The reaction
mixture is neutralized with solid NH.sub.4Cl (81 mg, 1.50 mmol),
and is concentrated under reduced pressure. The yellow solid is
purified by Gilson HPLC eluting with ACN/H.sub.2O with 0.1% TFA
(30-80%). Lyophylization for 12 h provides 86 mg of light yellow
solid, 5. LC: R.sub.t=12.82 min, HRMS (ES.sup.+)
C.sub.62H.sub.67N.sub.13O.sub.13S.sub.6: Calc.:1394.3384
[M+H].sup.+; Found: 1394.3356.
Example 4
Preparation of Diacid 6 of Table A
##STR00130##
[0284] Compound 6 is prepared according to example 1 and scheme
3.
Step 1:
[0285] To a solution of XIII (1 g, 0.87 mmol) in dioxane (80 mL) is
added trans-4-hydroxy cyclohexane carboxylic acid methyl ester
(0.46 g, 2.9 mmol) and the reaction mixture is stirred at
80.degree. C. for 4 h. SiO.sub.2 is added to the mix and the
solvents are concentrated under reduced pressure. The solid is
purified by flash chromatography, eluting with 10% DCM/MeOH to
provide 530 mg (47.7% yield), of a yellow solid, the urethane. MS
m/z 1280 (M+H).sup.+.
Step 2:
[0286] To a solution of the urethane (300 mg, 0.234 mmol) and
Cs.sub.2CO.sub.3 (267 mg, 0.820 mmol) in DMF (2 mL), is added
methyl 5-bromovalerate (0.20 mL, 1.404 mmol). The reaction is
stirred at rt for 12 h, filtered and concentrated. The residue is
purified by flash chromatography, eluting with MeOH/DCM (gradient:
0-10%) to provide 270 mg (82.5%), of a yellow solid. MS m/z 1395
(M+H).sup.+.
Step 3:
[0287] To a solution of the diester (270 mg, 0.194 mmol) in MeOH
(6.5 mL) and THF (2.5 mL) is added 3 N NaOH (0.65 mg, 1.94 mmol)
and the reaction mixture is stirred for 12 h at rt. The reaction is
neutralized with NH.sub.4Cl until pH=6-7. The reaction is
concentrated under vacuum. The residue is dissolved in
DMF/H.sub.2O, purified with HPLC (gradient elution MeCN/H.sub.2O,
0.1% TFA modifier), and lypholized for 12 h to provide 98.5 mg
(37.2%) of a light yellow solid, 6. HRMS (ES.sup.+)
C.sub.60H.sub.63N.sub.13O.sub.13S.sub.6: Calc.: 1366.3071
[M+H].sup.+; Found: 1366.3009. LC/MS: m/z [M+2H].sup.+ 1367,
R.sub.t=1.41 min (method 14). .sup.1H NMR: (600 MHz, DMSO-d6)
.delta. 9.132 (d, 1H), 8.707 (d, 1H), 8.681 (d, 1H), 8.604 (s, 1H),
8.465 (dd, 1H), 8.387 (d, 1H), 8.257 (s, 1H), 8.217 (d, 1H), 7.713
(s, 1H), 7.394 (m, 1H), 7.354 (s, 1H), 7.322 (d, 2H), 7.285 (t,
2H), 7.235 (t, 1H), 6.175 (b, 1H), 5.294 (m, 1H), 5.239 (t, 1H),
5.213 (dd, 1H), 5.007 (d, 1H), 4.983 (d, 2H), 4.666 (m, 1H),
4.287-3.796 (dd, 2H), 3.982 (b, 2H), 3.392 (s, 3H), 2.794-1.285
(dd, 2H), 2.592 (s, 3H), 2.479 (d, 3H), 2.277 (t, 2H), 2.256 (m,
1H), 2.170 (m, 1H), 2.010-1.476 (m, 4H), 1.931-1.476 (m, 4H), 1.686
(m, 2H), 1.575 (m, 2H), 0.885 (d, 3H), 0.848 (d, 3H).
Example 5
Preparation of Diacid 7 of Table A
##STR00131##
[0288] Compound 7 is prepared according to the procedures described
in example 2. LC/MS: m/z [M+2H].sup.+ 1381, R.sub.t=1.43 min
(method 14).
Example 6
Preparation of Diacid 8 of Table A
##STR00132##
[0289] Compound 8 is prepared according to the procedures described
in example 8. LC/MS: m/z [M+H].sup.+ 1310, R.sub.t=1.2 min (method
5). .sup.1H NMR (DMSO-d6, 400 MHz) .delta. ppm 0.78-0.94 (m, 6H)
1.22-1.32 (br, 1H), 1.40-1.60 (br, 4H), 1.70-1.85 (br, 2H),
2.10-2.37 (m, 7H), 2.48 (s, 3H), 2.59 (s, 3H), 2.65-2.78 (m, 1H),
3.39 (s, 3H), 3.69-3.85 (m, 3H), 4.21-4.35 (m, 1H), 4.96-5.03 (br,
3H), 5.17-5.35 (m, 3H), 6.00-6.12 (br, 1H), 7.22-7.44 (m, 7H), 7.96
(s, 1H), 8.20-8.31 (m, 2H), 8.36-8.43 (m, 1H), 8.43-8.51 (m, 1H),
8.61 (s, 1H), 8.64-8.76 (m, 2H), 9.05 (d, J=7.71 Hz, 1H),
11.87-12.22 (br, 2H).
Example 7
Preparation of Diacid 9 of Table A
##STR00133##
[0290] Compound 9 is prepared according to the procedures described
in example 2. LC/MS: m/z [M+H].sup.+ 1338, R.sub.t=1.3 (method
5).
Example 8
Preparation of Diacid 10 of Table A
##STR00134##
##STR00135## ##STR00136##
[0291] Step 1:
[0292] A suspension of acyl-azide (XIII, 920 mg) is heated
(80.degree. C.) in t-BuOH (100 g). After 2 h complete dissolution
occurrs and after 12 h the reaction appears complete by LC/MS. The
solution is concentrated directly onto SiO.sub.2 and
chromatographed (gradient elution: 50-70% EtOAc/hexanes) which
affords 600 mg of the boc-amine, a white solid. LC/MS: m/z
[M+H].sup.+ 1196, R.sub.t=1.72 min, (method 1).
Step 2:
[0293] To a solution of the boc-amine (540 mg, 0.451 mmol) in DCM
(250 mL) is added acetic anhydride (0.100 mL, 0.979 mmol), pyridine
(1.0 mL, 12.4 mmol) and DMAP (20 mg, 0.169 mmol). The reaction is
stirred for 3 h, concentrated directly onto SiO.sub.2 and
chromatographed (gradient elution: 50-70% EtOAc/hexanes) which
provides 465 mg of boc-amine-acetate. LC/MS (method 1):
R.sub.t=1.81 min, [M+H].sup.+ 1238.
Step 3:
[0294] To a solution of the boc-amine-acetate (1 g, 0.836 mmol) in
DMF (10 mL) is added cesium carbonate (>10 fold excess). The
reaction is stirred for 12 h and concentrated onto SiO.sub.2. The
crude material is purified by flash column chromatography (gradient
elution: 0-10% MeOH in DCM) to afford 700 mg of the alkylated
product (with the acetate removed).
Step 4:
[0295] To a solution of the alkylated boc-amine (100 mg, 0.076
mmol) in DCM (15 mL) is added HCl (g) via a stream. After 10 min,
the reaction appeared complete by LC/MS and the reaction is
concentrated 3.times. from DCM.
Step 5-6:
[0296] To a solution of the amine salt in DCM (15 mL) is added
excess TBTU (>10 equivalents) 50 uL of pyridine, and 50 uL of
the diacid. The reaction is stirred for 12 h and NaOH (100 mg), 10
mL of MeOH, and 1 mL H.sub.2O are added. The reaction stirred 24 h
and is concentrated and purified by HPLC (gradient elution, 20-40%
MeCN in H.sub.2O+5% isopropanol). LC/MS: m/z [M+H].sup.+ 1322,
R.sub.t=1.2 (method 10).
Example 9
Preparation of Diacid 21 of Table A
##STR00137##
##STR00138## ##STR00139##
[0297] Step 1:
[0298] To a solution of azide (100 mg, 0.087 mmol) in toluene (5
mL) is added methyl isonipecotinate hydrochloride (17.2 mg, 0.096
mmol) and molecular sieves at ambient temperature. The mixture is
then heated to 70.degree. C. and stirs for 12 h. The reaction is
cooled to ambient temperature, concentrated and purified by flash
chromatography (gradient elution: 0-10% MeOH/DCM) which affords 90
mg of methyl ester. LC/MS: m/z [M+H].sup.+ 1265.6, R.sub.t=1.49 min
(method 10).
Step 2:
[0299] To a solution of methyl ester (60 mg, 0.047 mmol) in DMF (2
mL) is added methyl bromovalerate (28 mg, 0.142 mmol) and cesium
carbonate (46 mg, 0.142 mmol) at ambient temperature. The mixture
stirs at ambient temperature for 4 days. Water is added to quench
the reaction, the aqueous phase is extracted with 5% MeOH/DCM three
times. Organic phases are combined and dried over sodium sulfate,
filtered, concentrated and purified by flash chromatography
(gradient elution: 0-10% MeOH/DCM) which affords 20 mg of dimethyl
ester. LC/MS: m/z [M+2H].sup.2+ 691, R.sub.t=1.58 min (method
10).
Step 3:
[0300] To a solution of the dimethyl ester (20 mg, 0.015 mmol) in
THF (2 mL)/water (0.4 mL) is added LiOH (0.6 mL, 0.06 mmol, 0.1 M).
The reaction is stirred at ambient temperature for 4 h. 0.6 mL 0.1
M HCl is added to quench the reaction, the mixture is concentrated
and diluted with MeOH, the residue is purified by HPLC (10-60%
acetonitrile in H.sub.2O+0.1% ammonium hydroxide) furnishing 4.3 mg
compound 21. LC/MS: m/z [M+2H].sup.2+676, R.sub.t=1.35 min (method
10).
Example 10
Preparation of Diacid 11 of Table A
##STR00140##
[0301] Compound 11 is prepared according to the procedures
described in example 9. LC/MS: m/z [M+H].sup.+ 1353, R.sub.t=1.3
min (method 10). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.73 (d, J=13.14 Hz, 1H), 0.87 (dd, J=12.38, 6.82 Hz, 6H),
1.28-1.57 (m, 8H), 1.88 (d, J=11.87 Hz, 1H), 2.12-2.23 (m, 1H),
2.24-2.40 (m, 7H), 2.60 (s, 3H), 2.65-2.83 (m, 2H), 3.40 (s, 3H),
3.80 (dd, J=16.80, 3.92 Hz, 1H), 4.17-4.37 (m, 3H), 4.96-5.07 (m,
3H), 5.17-5.35 (m, 3H), 6.11 (br s, 1H), 7.19-7.35 (m, 5H), 7.37
(s, 1H), 7.38-7.47 (m, 1H), 7.59 (s, 1H), 8.20 (d, J=8.08 Hz, 1H),
8.25 (s, 1H), 8.40 (d, J=8.08 Hz, 1H), 8.42-8.49 (m, 1H), 8.60 (s,
1H), 8.69 (d, J=8.34 Hz, 2H), 9.01-9.10 (m, 1H), 9.84 (s, 1H).
Example 11
Preparation of Diacid 12 of Table A
##STR00141##
[0302] Compound 12 is prepared according to the procedures
described in example 8. LC/MS: m/z [M+2H].sup.+ 1325, R.sub.t=1.3
min (method 10).
Example 12
Preparation of Diacid 13 of Table A
##STR00142##
[0303] Compound 13 is prepared according to the procedures
described in example 2. LC/MS: m/z [M+H].sup.+ 1375, R.sub.t=0.64
min (method 10).
Example 13
Preparation of Diacid 14 of Table A
##STR00143##
[0304] Compound 14 is prepared according to the procedures
described in example 8. LC/MS: m/z [M+2H].sup.+ 1332, R.sub.t=1.18
min (method 10).
Example 14
Preparation of Diacid 15 of Table A
##STR00144##
[0305] Compound 15 is prepared according to the procedures
described in example 8. LC/MS: [M+2H].sup.+ 1351, R.sub.t=1.31 min
(method 10).
Example 15
Preparation of Diacid 16 of Table A
##STR00145##
[0306] Compound 16 is prepared according to the procedures
described in example 8. LC/MS: m/z [M+2H].sup.+ 1351, R.sub.t=1.22
min (method 10).
Example 16
Preparation of Diacid 17 of Table A
##STR00146##
[0307] Compound 17 is prepared according to the procedures
described in example 8. LC/MS: m/z [M+2H].sup.+ 1365, R.sub.t=1.31
min (method 10).
Example 17
Preparation of Diacid 18 of Table A
##STR00147##
[0308] Compound 18 is prepared according to the procedures
described in example 9. LC/MS: m/z [M+2F1].sup.+ 1366, R.sub.t=1.48
min (method 10).
Example 18
Preparation of Diacid 19 of Table A
##STR00148##
[0309] Compound 19 is prepared according to the procedures
described in example 2. LC/MS: m/z [M+H].sup.+ 1350, R.sub.t=1. 3
min (method 5).
Example 19
Preparation of Diacid 20 of Table A
##STR00149##
[0310] Compound 20 is prepared according to the procedures
described in example 2. LC/MS: m/z [M+H].sup.+ 1382, R.sub.t=1.2
min (method 5).
Example 20
Preparation of Diacid 22 of Table A
##STR00150##
[0311] Compound 22 is prepared according to the procedures
described in example 9. LC/MS: m/z [M+2H].sup.2+ 656, R.sub.t=1. 34
min (method 10).
Example 21
Preparation of Diacid 23 of Table A
##STR00151##
[0312] Compound 23 is prepared according to the procedures
described in example 9. LC/MS: m/z [M+2H].sup.+ 1352, R.sub.t=1. 47
min (method 10).
Example 22
Preparation of Diacid 24 of Table A
##STR00152##
[0313] Compound 24 is prepared according to the procedures
described in example 2. LC/MS: m/z [M+2H].sup.+ 1368, R.sub.t=1. 28
min (method 5). .sup.1H NMR (DMSO-d6, 400 MHz) .delta. ppm
0.78-0.98 (m, 6H), 1.21-1.36 (br, 1H), 1.39-1.55 (br, 4H),
1.85-2.08 (br, 4H), 2.09-2.21 (m, 1H), 2.22-2.30 (br, 1H), 2.47 (s,
3H), 2.60 (s, 3H), 2.68-2.76 (br, 1H), 3.39 (s, 3H), 3.71-3.85 (m,
3H), 4.06 (s, 2H), 4.12-4.20 (br, 2H), 4.22-4.33 (m, 1H), 4.61-4.71
(br, 1H), 4.94-5.03 (m, 3H), 5.17-5.34 (m, 3H), 5.96-6.10 (br, 1H),
7.18-7.43 (m, 7H), 7.72 (s, 1H), 8.19-8.29 (m, 2H), 8.36-8.41 (m,
1H), 8.42-8.48 (m, 1H), 8.60 (s, 1H), 8.69 (t, J=7.8, 7.8 Hz, 2H),
9.04 (d, J=7.70 Hz, 1H), 12.04-12.81 (br, 2H).
Example 23
Preparation of Diacid 25 of Table A
##STR00153##
[0314] Compound 25 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 6.
LC/MS: m/z [M+H].sup.+ 1480, R.sub.t=1.39 min (method 6).
##STR00154##
Step 1:
[0315] Chloro (1,1-dimethylethyl)dimethylsilane (1.10 g, 71 mmol)
is added in portions over 5 min. to a solution of the alcohol (1.0
g, 6.30 mmol), imidazole (959 mg, 14.08 mmol) and DMF (4.2 mL) and
the mixture is stirred under an atmosphere of N.sub.2 for 3 h. The
reaction mixture is then poured into 10% citric acid (18 mL) and
extracted with ethyl acetate. The organic extracts are washed with
water, brine, and then dried (Na.sub.2SO.sub.4) and purified by
flash chromatography (eluent: ethyl acetate/heptane, gradient) to
afford the TBS ether (quant.). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.61 (s, 3H), 2.20 (m, 1H), 1.85 (m, 4H), 1.50-1.20 (m,
4H), 0.83 (s, 9H), 0.00 (s, 6H).
Step 2:
[0316] To a solution of LDA (367 uL, 0.734 mmol, 2 M in
heptane/THF/ethyl benzene) in THF (1 mL) cooled to -70.degree. C.,
the TBS ether (100 mg, 0.367 mmol) is added in THF (1 mL). After 1
h at -70.degree. C., allyl iodide (101 uL, 1.10 mmol) is added and
the solution is allowed to warm to room temperature and stirred for
2 h. It is then partitioned between ammonium chloride and ethyl
acetate. The organic layer is dried (Na.sub.2SO.sub.4) and purified
by flash chromatography (eluent: ethyl acetate/heptane, gradient)
to afford the olefin (100 mg, 87%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.70 (m, 1H), 4.98 (m, 2H), 3.63 (s, 3H), 3.45
(m, 1H), 2.17 (m, 2H), 1.58-1.10 (m, 7H), 0.84 (s, 9H), 0.00 (s,
6H).
Step 3:
[0317] To a solution of Grubbs II (11 mg, 0.013 mmol) in DCM (1.5
mL) are added simultaneously via syringe methyl-3-butenoate (139
uL, 1.29 mmol) and the olefin (81 mg, 0.26 mmol). The reaction
mixture is heated to 40.degree. C. and is stirred for 12 h. The
solvent is concentrated and purified by flash chromatography
(eluent: ethyl acetate/heptane, gradient) to afford the diester (75
mg, 75%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.50-5.35 (m,
2H), 3.64 (s, 6H), 3.50 (m, 1H), 3.00 (d, 2H), 2.15 (br, 4H),
1.80-1.10 (m, 6H), 0.85 (s, 9H), 0.00 (s, 6H).
Step 4:
[0318] To a solution of the diester (200 mg, 0.52 mmol) in ethyl
acetate (2.5 mL) is added Pd/C (80 mg) under N.sub.2 atmosphere.
The reaction mixture is charged with H.sub.2 (balloon) and stirred
for 2 h after which the reaction mixture is filtered through celite
and concentrated to afford saturated diester (172 mg, 86%). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 3.63 (d, 6H), 3.50 (m, 1H), 3.50
(m, 1H), 2.24 (t, 2H), 2.15 (d, 2H), 1.70-1.10 (m, 8H), 0.85 (s,
9H), 0.00 (s, 6H).
Step 5:
[0319] To a solution of saturated diester (172 mg, 0.45 mmol) in
THF (2 mL) is added TBAF (890 mL, 0.89 mmol, 1 M solution in THF)
and heated to 60.degree. C. for 5 h. The reaction mixture is then
concentrated and purified by flash chromatography (eluent: ethyl
acetate/heptane, gradient) to afford the alcohol (90 mg). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 3.62 (s, 3H), 3.60 (s, 3H), 3.50
(m, 1H), 2.18 (m, 4H), 1.8 (br, 2H), 1.80-1.10 (m, 10H).
Example 24
Preparation of Triacid 26 of Table A
##STR00155##
[0320] Compound 26 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 7.
LC/MS: m/z [M+H.sub.2O].sup.+ 1443, R.sub.t=1.14 min (method
6).
##STR00156##
Step 1:
[0321] To a solution of 2-nitrocyclohexanone (2.0 g, 18.97 mmol) in
MeOH (28 mL) is added methyl acrylate (1.4 mL, 15.37 mmol) and a
catalytic amount of Ph.sub.3P (10%). After stirring at room
temperature for 12 h, an alcoholic solution (209 mL) of KOH (20.9
mmol) is added and the solution is heated at reflux for 8 h. After
cooling to 0.degree. C., an aqueous solution (209 mL) of KMnO.sub.4
(16.70 mmol) and MgSO.sub.4 (20.95 mmol) is slowly added, and after
the complete addition, the reaction mixture is stirred for 18 h at
room temperature, and then filtered through celite. After
extraction with ethyl acetate, the organic phase is dried,
evaporated and the crude product is purified by flash
chromatography (eluent: ethyl acetate/heptane, gradient) to afford
1.37 g of the ketone: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.69 (s, 3H), 3.67 (s, 3H), 2.72 (m, 2H), 2.59 (m, 2H), 2.48 (br,
2H), 2.33 (br, 2H), 1.63 (m, 4H).
Step 2:
[0322] To a solution of the ketone dimethylester (500 mg, 2.17
mmol) in MeOH (11 mL) is added NaBH.sub.4 (41 mg, 1.08 mmol) at
0.degree. C. The reaction temperature is warmed to room temperature
and stirred for 30 min. TLC (EtOAc/heptane, 6:4) showed complete
conversion. The reaction mixture is concentrated and purified by
flash chromatography (eluent: EtOAc/heptane, gradient) to afford
the alcohol (444 mg, 88%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.42 (m, 1H), 3.60 (s, 6H), 1.81 (m, 4H), 1.75-1.43 (m,
8H).
Example 25
Preparation of Diacid 27 of Table A
##STR00157##
[0323] Compound 27 is prepared according to the procedures
described in example 2. LC/MS: m/z [M+2H].sup.+ 1339, R.sub.t=1.28
min (method 5).
Example 26
Preparation of Triacid 28 of Table A
##STR00158##
##STR00159##
[0324] Step 1:
[0325] To a solution of diisopropylamine (3.46 mL, 24.54 mmol) in
THF (110 mL), is added n-BuLi (15.22 mL, 24.35 mmol) at 0.degree.
C. under nitrogen. The resulting mixture is stirred for 15 mins at
0.degree. C. To this solution at -78.degree. C. is added dropwise a
solution of dimethyl glutarate in THF (9 mL), and the resulting
mixture is stirred for 5 min. A solution of 1,4-dibromobutene in
THF (9 mL) and HMPA (9 mL) is then added at -78.degree. C., and the
stirring is continued for 2 h at -78.degree. C. The reaction is
quenched with 30 mL saturated aq NH.sub.4Cl aqueous solution. The
THF is removed, and the material extracted with DCM (3.times.50
mL). The combined organic layers are concentrated, and the residue
is purified by flash chromatography, eluting with hepatane/EtOAc to
afford 600 mg of the bromide. LC/MS: m/z [M+H].sup.+ 293,
R.sub.t=1.12 min (method 5).
##STR00160## ##STR00161##
Step 2:
[0326] To a solution of 101 (416 mg, 0.325 mmol) and
Cs.sub.2CO.sub.3 (371 mg, 1.137 mmol) in DMF (4.2 mL), is added the
bromide (616 mg, 2.094 mmol). The reaction is stirred at rt for 12
h, filtered (Cs.sub.2CO.sub.3), and concentrated. The residue is
purified by flash chromatography, eluting with DCM/MeOH (gradient:
0-10%) to provide 290 mg (60%) of 102 as a yellow solid. LC/MS: m/z
[M+H].sup.+ 1492, R.sub.t=1.73 min (method 5).
Step 3:
[0327] To a solution of 102 (290 mg, 0.194 mmol) in DCM (5 mL) and
MeOH (16 mL), is added 10% Pd/C (82 mg, 0.078 mmol), degassed and
hydrogenated at 50 psi for 12 h. The reaction is filtered, and
additional 10% Pd/C (82 mg, 0.078 mmol) and ammonium formate (240
mg, 3.82 mmol) are added. The reaction stirred at reflux for two
days and is filtered and purified by flash chromatography, then
purified by HPLC (gradient elution, MeCN/H.sub.2O, 0.1% TFA) to
afford 50 mg of 103. LC/MS: m/z [M+H].sup.+ 1494, R.sub.t=1.75 min
(method 5).
Step 4:
[0328] To a solution of 103 (50 mg, 0.033 mmol) in THF (0.5 mL) and
H.sub.2O (0.3 mL) is added 2 N LiOH (0.188 mL, 0.377 mmol) and the
reaction mixture is stirred at rt for 25 h. The reaction is
neutralized with NH.sub.4Cl until pH=6-7. The reaction mixture is
concentrated under vacuum. The residue is dissolved in
DMF/H.sub.2O, purified with HPLC (0.1% TFA modified), and
lyophilized for 12 h to provide 15 mg (30%) of 104, a light yellow
solid. LC/MS: m/z [M+2H].sup.+ 1453, R.sub.t=1.29 min (method
5).
Example 27
Preparation of Triacid 29 of Table A
##STR00162##
[0329] Compound 29 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 10.
LC/MS: m/z [M+H].sup.+ 1466, R.sub.t=1.18 min (method 6).
##STR00163##
Step 1:
[0330] To a solution of oxalyl chloride (2.92 mL, 33.4 mmol) in DCM
(139 mL) at -78.degree. C. is added DMSO (4.74 mL, 66.8 mmol) and
the mixture is stirred for 30 minutes. A solution of alcohol (4.4
g, 27.8 mmol) in DCM (5 mL) is then added and the mixture is
stirred for an additional 45 minutes. Finally, Et.sub.3N (18.61 mL,
134 mmol) is added and the white solution is allowed to stir at
-78.degree. C. for 30 minutes before being warmed to 0.degree. C.
over 30 minutes. Saturated aqueous NH.sub.4Cl is added to quench
the reaction and the resulting mixture is extracted with DCM
(3.times.100 mL). The combined organic extracts are dried
(MgSO.sub.4), filtered, and concentrated and the residue is
purified by flash chromatography (gradient elution: 0-50%
EtOAc/heptane) furnishing 4.1 g of the ketone. .sup.1H NMR (400
MHz; CDCl.sub.3) .delta. 3.85 (s, 3H), 2.90 (m, 1H), 2.64-2.57 (m,
2H), 2.52-2.44 (m, 2H), 2.37-2.32 (m, 2H), 2.20-2.10 (m, 2H).
Step 2:
[0331] To a solution of ketone (3.8 g, 24.3 mmol) in THF (57.9 mL)
at -78.degree. C. is added HMPA (23.2 mL), followed by KHMDS (51.1
mL, 25.5 mmol, 0.5 M solution in toluene) and the resulting yellow
solution is stirred for 30 minutes. Allyl iodide (2.45 mL, 26.8
mmol) is added dropwise and the reaction mixture is allowed to stir
at -78.degree. C. for 30 minutes before being warmed to room
temperature over 10 minutes. Saturated aqueous NaHCO.sub.3 is added
to quench the reaction and the resulting mixture is extracted with
EtOAc (3.times.100 mL). The combined organic extracts are washed
with brine, dried (MgSO.sub.4), filtered and concentrated and the
residue is purified by flash chromatography (gradient elution:
0-50% EtOAc/heptane) furnishing 3.3 g of the olefin, .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta. 5.81-5.70 (m, 1H), 5.11-5.02 (m, 2H),
3.76 (s, 3H), 2.84 (t, 4.8 Hz, 1H), 2.61-2.30 (m, 6H), 2.07-1.93
(m, 2H), 1.73-1.66 (ddd, 13.8, 10.4, 4.7 Hz, 1H), followed by 985
mg of the isomer: .sup.1H NMR (400 MHz; CDCl.sub.3) .delta.
5.81-5.73 (m, 1H), 5.07-5.02 (m, 2H), 3.71 (s, 3H), 2.82 (t, 4.8
Hz, 1 H), 2.61-2.30 (m, 6H), 2.09-1.81 (m, 2H), 1.61-1.50 (m,
1H).
Step 3:
[0332] To a solution of the olefin (310 mg, 1.58 mmol) and
methyl-3-butenoate (843 .mu.L, 7.90 mmol) in DCM (10 mL) at reflux
is added a solution of Grubb's II (67 mg, 5 mol %) and the
resulting red mixture is stirred for 3 hours. The solvent is
evaporated and the residue is purified by flash chromatography
(gradient elution: 0-50% EtOAc/heptane) furnishing 315 mg of the
diester. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 5.66-5.47 (m,
2H), 3.75 (s, 3H), 3.68 (s, 3H), 3.04 (d, 5.8 Hz, 2H), 2.86 (qd,
4.6 Hz, 1H), 2.60-2.30 (m, 6H), 2.13-1.88 (m, 2H), 1.74-1.60 (m,
1H).
Step 4:
[0333] A solution of the diester (260 mg, 0.97 mmol) in EtOH (10
mL) is purged with N.sub.2, and 10% Pd/C (26 mg, 10% w/w) is added.
The mixture is again purged with N.sub.2, followed by H.sub.2 and
then maintained under an atmosphere of H.sub.2 (balloon) for 1
hour. The reaction mixture is purged with N.sub.2, filtered through
a pad of celite and the filtrate concentrated to furnish 261 mg of
the saturated diester, which is used without further
purification.
Step 5:
[0334] To a solution of the saturated diester (261 mg, 0.97 mmol)
in MeOH (10 mL) at 0.degree. C. is added NaBH.sub.4 (18 mg, 0.49
mmol) and the resulting mixture is allowed to stir for 30 minutes.
Saturated aqueous NH.sub.4Cl is added to quench the reaction and
the resulting mixture is extracted with EtOAc (3.times.100 mL). The
combined organic extracts are washed with brine, dried
(MgSO.sub.4), filtered and concentrated and the residue is purified
by flash chromatography (gradient elution: 0-50% EtOAc/heptane)
furnishing 200 mg of the alcohol. .sup.1H NMR (400 MHz; CDCl.sub.3)
.delta. 3.86-3.80 (m, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 2.58 (t, 4.8
Hz, 1H), 2.37-2.28 (m, 2H), 1.96-1.83 (m, 1H), 1.76-1.22 (m,
13H).
Example 28
Preparation of Triacid 30 of Table A
##STR00164##
[0335] Compound 30 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 11.
LC/MS: m/z [M+H].sup.2+ 714, R.sub.t=1.18 min (method 6). .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 9.05 (d, J=7.8 Hz, 1H), 8.69 (t,
J=7.8 Hz, 2H), 8.61 (s, 1 H), 8.50-8.44 (m, 1H), 8.39 (d, 8.0 Hz,
1H), 8.27 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.43-7.24
(m, 7H), 5.35-5.20 (m, 3H), 4.98 (br s, 3H), 4.33-3.75 (br m, 8H),
3.39 (s, 3H), 2.79-2.66 (m, 1H), 2.59 (s, 3H), 2.28 (t, J=7.0 Hz,
3H), 2.19 (t, J=7.0 Hz, 3H), 2.19-2.12 (m, 1H), 1.94-1.85 (m, 1H),
1.83-1.73 (m, 1H), 1.73-1.62 (m, 3H), 1.62-1.40 (m, 8H), 1.34-1.11
(m, 4H), 0.89 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H).
##STR00165##
Step 1:
[0336] To a solution of .gamma.-butyrolactone (10 g, 116 mmol) in
THF (200 mL) at -78.degree. C. is added LiHMDS (122 mL, 122 mmol,
1.0 M solution in THF). After stirring for 30 minutes
1,3-dimethyl-2-imidazolidinone (15.1 mL, 139 mmol), followed by
allyl bromide (11.1 mL, 128 mmol) are added and the resulting
mixture is allowed to stir for 1 hour. Saturated aqueous NH.sub.4Cl
is added to quench the reaction and the resulting mixture is
extracted with EtOAc (3.times.100 mL). The combined organic
extracts are washed with brine, dried (MgSO.sub.4), filtered and
concentrated and the residue is purified by flash chromatography
(gradient elution: 0-50% EtOAc/heptane) furnishing 14.6 g of the
olefin.
Step 2:
[0337] To a solution of the olefin (14.6 g, 116 mmol) in MeOH (100
mL) at room temperature is added KOH (13.0 g, 232 mmol) and the
resulting mixture is stirred for 3 hours. The solvent is removed
from the reaction and the residue is partitioned between H.sub.2O
and Et.sub.2O. The layers are separated and the aqueous phase is
extracted with Et.sub.2O (2.times.50 mL). The aqueous phase is then
acidified to pH 3 with HCl (1 M) and extracted with EtOAc
(3.times.100 mL). The combined organic extracts are washed with
brine, dried (MgSO.sub.4), filtered and concentrated furnishing
16.6 g of the acid which is used without further purification.
Step 3:
[0338] To a solution of the acid (16.6 g, 116 mmol) in MeOH (200
mL) and Et.sub.2O (500 mL) at 0.degree. C. is added
(trimethylsilyl)diazomethane (76 mL, 151 mmol, 2.0 M solution in
Et.sub.2O, enough to maintain a yellow color in the reaction
mixture). The solvent is removed from the reaction mixture and the
residue is purified by flash chromatography (gradient elution:
0-60% EtOAc/heptane) furnishing 18.3 g of the ester.
Step 4:
[0339] To a solution of the ester (18.3 g, 116 mmol) in DMF (150
mL) at room temperature is added imidazole (9.49 g, 139 mmol),
followed by TBSCl (19.3 g, 128 mmol) and the resulting mixture is
stirred for 8 hours. The reaction mixture is diluted with H.sub.2O,
extracted with Et.sub.2O (3.times.100 mL) and the combined extracts
are washed with H.sub.2O (2.times.100 mL), saturated aqueous
NaHCO.sub.3 and brine, then dried (MgSO.sub.4), filtered and
concentrated. The residue is purified by flash chromatography
(gradient elution: 0-30% EtOAc/heptane) furnishing 30.6 g of the
TBS ether. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 5.82-5.63 (m,
1H), 5.14-4.94 (m, 2H), 3.67 (s, 3H), 3.67-3.58 (m, 2H), 2.73-2.57
(m, 1H), 2.38-2.18 (m, 2H), 1.96-1.79 (m, 1H), 1.79-1.58 (m, 1H),
0.89 (s, 9H), -0.04 (s, 6H).
Step 5:
[0340] The olefin is prepared in an identical manner to that
described previously for example 27 and purified by flash
chromatography (gradient elution: 0-30% EtOAc/heptane) furnishing
420 mg. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 5.65-5.43 (m,
2H), 3.68 (s, 3H), 3.66 (s, 3H), 3.66-3.54 (m, 2H), 3.04 (d, 6.6
Hz, 2H), 2.68-2.57 (m, 1H), 2.41-2.21 (m, 2H), 1.94-1.81 (m, 1H),
1.74-1.51 (m, 1H), 0.89 (s, 9H), -0.03 (s, 6H).
Step 6:
[0341] The saturated diester is prepared in an identical manner to
that described previously for example 27 and purified by flash
chromatography (gradient elution: 0-30% EtOAc/heptane) furnishing
340 mg. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 3.67 (s, 6H),
3.65-3.54 (m, 2H), 2.59-2.48 (m, 1H), 2.30 (t, 7.5 Hz, 2H),
1.92-1.80 (m, 1H), 1.71-1.43 (m, 3H), 1.39-1.19 (m, 4H), 0.89 (s,
9H), -0.04 (s, 6H).
Step 7:
[0342] To a solution of the saturated diester (289 mg, 0.83 mmol)
in DCM (8 mL) and MeOH (8 mL) at -10.degree. C. is added CSA (213
mg, 0.92 mmol) and the resulting mixture is stirred for 1 hour.
Saturated aqueous NaHCO.sub.3 is added to quench the reaction and
the resulting mixture is extracted with DCM (3.times.20 mL). The
combined organic extracts are washed with saturated aqueous
NaHCO.sub.3, brine, dried (MgSO.sub.4), filtered and concentrated
and the residue is purified by flash chromatography (gradient
elution: 0-80% EtOAc/heptane) furnishing 190 mg of the alcohol.
.sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 3.69 (s, 3H), 3.69-3.63
(m, 2H), 3.66 (s, 3H), 2.61-2.48 (m, 1H), 2.30 (t, 7.5 Hz, 2H),
1.95-1.80 (m, 1H), 1.80-1.56 (m, 4H), 1.56-1.39 (m, 1H), 1.39-1.17
(m, 2H).
Example 29
Preparation of Triacid 31 of Table A
##STR00166##
[0343] Compound 31 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 12.
LC/MS: m/z [M+2H].sup.+ 1495, R.sub.t=1.44 (method 5).
##STR00167##
Step 1:
[0344] To a solution of valerolactone (contaning 25% polymer, 5 g,
37.5 mmol) in THF (100 mL) at -78.degree. C., is added LHMDS (52.4
mL) over 20 min. The solution is stirred for 0.5 h, then
1,3-dimethyl-2-imidazolidinone (6.84 g, 59.9 mmol) and allyl
idodide (5.02 mL, 54.9 mmol) is added, and the reaction is stirred
for 1 h. The reaction is quenched with saturated NH.sub.4Cl aqueous
solution (50 mL). The mixture is extracted by EtOAc (250 mL),
washed with saturated NaHCO.sub.3 and brine. The EtOAc layer is
concentrated and the residue is purified by flash chromatography,
eluting with heptane/EtOAc to afford 3.4 g (64.8% yield) of the
olefin.
Step 2:
[0345] To a solution of the olefin (1.1 g, 7.854 mmol) and
5-hexenoic acid methylester (5.03 g, 39.226 mmol) in DCM (110 mL)
at reflux is added a solution of Grubbs II (332 mg, 0.392 mmol) in
DCM (11 mL) and the resulting mixture is stirred for 1 hour at
reflux. The residue is purified with flash chromatography, eluting
with hepatane/EtOAc to afford 1.227 g (65% yield) of the
lactone.
Step 3:
[0346] The lactone (1.227 g, 5.11 mmol) and 10% Pd/C(0.893 g, 0.842
mmol) are mixed in MeOH (60 mL). The reaction is degassed and
hydrogenated for 2 h. TLC showed disappearance of starting
material. The reaction is filtered and concentrated to afford 1.2 g
of crude diester-alcohol.
Step 4:
[0347] The diester-alcohol (300 mg, 1.093 mmol) and Ph.sub.3P (315
mg, 1.203 mmol) are dissolved in CH.sub.2Cl.sub.2 (13 mL), and
cooled in an ice bath. CBr.sub.4 (363 mg, 1.083 mmol) is added with
stirring. The mixture is allowed to warm to rt and is stirred for
12 h. The reaction mixture is concentrated and purified with flash
chromatography, eluting by heptane/EtOAc to afford 220 mg (60%
yield) of the bromide. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
1.30 (broad, 6H) 1.45 (broad, 1H) 1.63 (broad, 5H) 1.85 (m, 2H)
2.30 (t, 2H) 2.35 (m, 1H) 3.40 (t, 2H) 3.67 (s, 6H).
Example 30
Preparation of Triacid 32 of Table A
##STR00168##
[0348] Compound 32 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 13.
LC/MS: m/z [M+H].sup.+ 1426, R.sub.t=1.05 min (method 6).
##STR00169##
Step 1:
[0349] To a solution of the ester (1.0 g, 3.7 mmol) in THF (20 mL)
at -10.degree. C. is added DIBAL-H (8.44 mL, 8.4 mmol, 1.0 M
solution in hexanes) dropwise and the resulting mixture is stirred
for 1 hour. MeOH (10 mL), Rochelle's Salt (100 mL) and EtOAc (100
mL) are added and the biphase is stirred vigorously for 3 h. The
layers are separated and the aqueous phase is extracted with EtOAc
(3.times.100 mL). The combined extracts are washed with brine,
dried (MgSO.sub.4), filtered and concentrated furnishing 895 mg of
the alcohol, which is used without further purification. .sup.1H
NMR (400 MHz; CDCl.sub.3) .delta. 5.86-5.71 (m, 1H), 5.09-4.98 (m,
2H), 3.78 (ddd, 10.4, 6.2, 4.0 Hz, 1H), 3.71-3.57 (m, 2H),
3.52-3.43 (m, 1H), 3.11-2.82 (br s, 1H), 2.18-1.97 (m, 2H),
1.82-1.63 (m, 2H), 1.59-1.47 (m, 1H), 0.91 (s, 9H), 0.08 (s,
6H).
Step 2:
[0350] To a solution of the alcohol (895 mg, 3.7 mmol) in DMF (12
mL) at room temperature is added NaH (220 mg, 5.5 mmol). After
stirring for 30 minutes, benzyl bromide (524 .mu.L, 4.4 mmol) and
tetrabutylammonium iodide (678 mg, 1.8 mmol) are added and the
resulting mixture is allowed to stir 12 h. Saturated aqueous
NH.sub.4Cl is added to quench the reaction and the resulting
mixture is diluted with EtOAc (100 mL). The layers are separated
and the organic phase is washed with H.sub.2O (3.times.30 mL),
brine, then dried (MgSO.sub.4), filtered and concentrated and the
residue is purified by flash chromatography (gradient elution:
0-30% EtOAc/heptane) furnishing 1.22 g of the benzyl ether. .sup.1H
NMR (400 MHz; CDCl.sub.3) .delta. 7.43-7.24 (m, 5H), 5.86-5.70 (m,
1H), 5.11-4.96 (m, 2H), 4.50 (s, 2H), 3.73-3.61 (m, 1H), 3.61-3.45
(m, 1H), 3.45-3.34 (m, 1H), 2.28-2.00 (m, 2H), 1.95-1.83 (m, 1H),
1.77-1.49 (m, 3H), 0.90 (s, 9H), 0.05 (s, 6H).
Step 3:
[0351] To a solution of the benzyl ether (1.32 g, 4.0 mmol) in THF
(20 mL) at 0.degree. C. is added TBAF (5.92 mL, 5.9 mmol, 1.0 M
solution in THF) and the resulting mixture is allowed to warm to
room temperature and stirred for 2 hours. Saturated aqueous
NH.sub.4Cl is added to quench the reaction and the resulting
mixture is diluted with EtOAc (50 mL). The layers are separated and
the aqueous phase is extracted with EtOAc (3.times.30 mL). The
combined organic extracts are washed with brine, then dried
(MgSO.sub.4), filtered and concentrated and the residue is purified
by flash chromatography (gradient elution: 0-80% EtOAc/heptane)
furnishing 865 mg of the alcohol. .sup.1H NMR (400 MHz; CDCl.sub.3)
.delta. 7.41-7.24 (m, 5H), 5.84-5.68 (m, 1H), 5.09-4.94 (m, 2H),
4.53 (s, 2H), 3.76-3.58 (m, 2H), 3.49 (dd, 9.2, 7.2 Hz, 1 H), 3.37
(dd, 9.2, 7.2 Hz, 1H), 2.56 (br s, 1H), 2.21-2.01 (m, 2H),
1.98-1.84 (m, 1H), 1.79-1.65 (m, 1H), 1.65-1.52 (m, 1H).
Step 4:
[0352] To a solution of the alcohol (600 mg, 2.7 mmol) in DCM (14
mL) at room temperature is added Dess-Martin periodinane (1.4 g,
3.3 mmol) and the resulting mixture is stirred for 1 hour. The
reaction mixture is diluted with Et.sub.2O (50 mL) and a solution
of Na.sub.2S.sub.2O.sub.3 (5.5 g) in saturated aqueous
Na.sub.2CO.sub.3 (10 mL) is added and the biphase is stirred until
clear. The layers are separated and the organic phase is washed
with saturated aqueous Na.sub.2CO.sub.3, brine, then dried
(MgSO.sub.4), filtered and concentrated and the residue is purified
by flash chromatography (gradient elution: 0-30% EtOAc/heptane)
furnishing 535 mg of the aldehyde. .sup.1H NMR (400 MHz;
CDCl.sub.3) .delta. 9.77 (s, 1H), 7.38-7.27 (m, 5H), 5.80-5.69 (m,
1 H), 5.10-5.03 (m, 2H), 4.48 (s, 2H), 3.49 (dd, 9.2, 4.7 Hz, 1H),
3.33 (dd, 9.2, 6.7 Hz, 1H), 2.51-2.37 (m, 2H), 2.32-2.16 (m, 1H),
2.12-2.02 (m, 1H), 1.33-1.22 (m, 1H).
Step 5:
[0353] To a solution of the aldehyde (535 mg, 2.5 mmol) and
2-methyl-2-butene (2.6 mL, 24.5 mmol) in H.sub.2O (6 mL) and
tert-butanol (6 mL) at room temperature is added a solution of
NaH.sub.2PO.sub.4 (1.47 g, 12.3 mmol) in H.sub.2O (500 .mu.L)
followed by a solution of NaClO.sub.2 (665 mg, 7.4 mmol) in
H.sub.2O (500 .mu.L). The resulting mixture is allowed to stir for
15 minutes, then brine (10 mL) is added and the mixture is
extracted with CHCl.sub.3 (3.times.15 mL). The combined organic
extracts are dried (Na.sub.2SO.sub.4), filtered and concentrated
furnishing 574 mg of the acid which is used without further
purification.
Step 6:
[0354] The ester is prepared in an identical manner to that
described previously for example 28 and purified by flash
chromatography (gradient elution: 0-30% EtOAc/heptane) furnishing
470 mg. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 7.37-7.26 (m,
5H), 5.81-5.70 (m, 1H), 5.09-5.01 (m, 2H), 4.49 (s, 2H), 3.69 (s,
3H), 3.46 (dd, 9.3 5.1 Hz, 1H), 3.38 (dd, 9.3, 6.3 Hz, 1H),
2.45-2.18 (m, 3H), 2.13-2.08 (m, 1H), 1.35-1.24 (m, 1H).
Step 7:
[0355] The olefin metathesis product is prepared in an identical
manner to that described previously for example 27 and purified by
flash chromatography (gradient elution: 0-30% EtOAc/heptane)
furnishing 500 mg. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta.
7.37-7.26 (m, 5H), 5.62-5.43 (m, 2H), 4.52-4.43 (m, 2H), 3.68 (s,
3H), 3.63 (s, 3H), 3.43 (dd, 9.2, 4.8 Hz, 1 H), 3.36 (dd, 9.2, 5.9
Hz, 1H), 2.43-2.06 (m, 7H).
Step 8:
[0356] The alcohol is prepared in an identical manner to that
described previously in example 27 and purified by flash
chromatography (gradient elution: 0-80% EtOAc/heptane) furnishing
200 mg. .sup.1H NMR (400 MHz; C.sub.6D.sub.6) .delta. 3.37 (dd,
10.6, 4.5 Hz, 1H), 3.35 (s, 3H), 3.33 (s, 3H), 3.25 (dd, 10.6, 6.3
Hz, 1H), 2.29 (dd, 15.7, 7.6 Hz, 1H), 2.12 (dd, 15.7, 5.8 Hz, 1H),
2.05 (t, 7.5 Hz, 2H), 1.92-1.85 (m, 1H), 1.49-1.36 (m, 3H),
1.19-1.02 (m, 3H).
Example 31
Preparation of Triacid 33 of Table A
##STR00170##
[0357] Compound 33 is prepared according to the procedures
described in example 23, using the following deprotection
conditions (MgI.sub.2).
[0358] To the suspension of the triester (24 mg, 0.016 mmol) in
toluene is added magnesium iodide (27 mg, 0.095 mmol) and the
reaction mixture is heated to 100.degree. C. for 12 h. The reaction
mixture is concentrated and re-dissolved in DMF and filtered,
purified by HPLC (40 to 80% CAN in water, 0.1% TFA). The fractions
are collected and lyophilized to afford 33 (1.3 mg). LC/MS: m/z
[M+2H].sup.+ 1467, R.sub.t=1.05 min (method 6). .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 9.10 (d, 2H), 8.54 (t, 2H), 8.52 (s, 3H),
8.49 (m, 1H), 8.47 (d, 1H), 8.25 (s, 1H), 8.2 (d. 1H), 7.75 (s,
1H), 7.4-7.2 (m, 7H), 6.05 (s, 1H), 5.35-5.15 (m, 3H), 4.9 (m, 3H),
4.65 (s, 1H), 4.25 (m, 1H), 3.9 (s, 1H), 3.8 (d, 1H), 3.35 (s, 3H),
2.65 (m, 1H), 2.6 (s, 3H), 2.35-1.75 (m, 10H), 1.70-1.10 (m, 16H),
0.85 (m, 6H).
Example 32
Preparation of Triacid 34 of Table A
##STR00171##
[0359] Compound 34 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 14.
LC/MS: m/z [M+H].sup.+ 1467, R.sub.t=1.45 min (method 6).
##STR00172##
Step 1:
[0360] To a solution of oxalyl chloride in DCM (120 mL) at
-70.degree. C. is added DMSO (5.60 mL, 79 mmol). Then to the
mixture, a solution of the alcohol (5.0 g, 31.6 mmol) in DCM (940
mL) is added dropwise within 2 min. The mixture is stirred for 15
min. at -70.degree. C. After addition of i-Pr.sub.2EtN, the mixture
is allowed to reach room temperature and poured in to water (300
mL). The aqueous phase is extracted with DCM (30 mL). The combined
extracts are dried over Na.sub.2SO.sub.4, filtered, concentrated
and then purified by flash chromatography (eluent: EtOAc/heptane,
gradient) to afford the ketone (2.8 g). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.80 (s, 3H), 2.84 (m, 1H), 2.53 (m, 2H), 2.45
(m, 2H), 2.31 (m, 2H), 2.15 (m, 2H).
Step 2:
[0361] A solution of the ketone (500 mg, 3.20 mmol) in THF (20 mL)
is cooled to -50.degree. C. and allyl magnesium bromide (3.2 mL,
3.20 mmol) is added and the reaction stirred for 30 min. To the
reaction mixture is added sat. aq NH.sub.4Cl and the product is
extracted with ethyl acetate, dried over Na.sub.2SO.sub.4, and
purified by flash chromatography (eluent: EtOAc/heptane, gradient)
to afford the alcohol (150 mg). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 5.89 (m, 1H), 5.19 (m, 2H), 3.70 (s, 3H), 2.47 (m, 1H),
2.29 (d, 2H), 1.74 (m, 3H), 1.51-1.40 (m, 3H).
Step 3:
[0362] The diester is synthesized according to the procedure
described in example 27. Obtained 122 mg, .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.67 (m, 2H), 3.71 (s, 3H), 3.17 (d, 2H), 2.30
(m, 1H), 2.29 (d, 2H), 1.91 (m, 2H), 1.69 (m, 3H), 1.47 (m,
2H).
Step 4:
[0363] The saturated diester-alcohol is synthesized according to
the procedure described in example 27. Obtained 120 mg: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 3.61 (s, 6H), 2.35 (m, 1H), 2.25 (m,
4H), 1.8 (m, 2H), 1.80-1.10 (m, 10H).
Example 33
Preparation of Diacid 35 of Table A
##STR00173##
[0364] Compound 35 is prepared according to the procedures
described in example 2, using the alcohol prepared in scheme 11.
LC/MS: m/z [M+H].sup.+ 1326, R.sub.t=1.04 min (method 6).
Example 34
Preparation of Diacid 2 of Table A
##STR00174##
##STR00175## ##STR00176##
[0365] Step 1:
[0366] To a solution of the diester-acid (1 g, 4.6 mmol) in DCM (20
mL) is added oxalyl chloride (1.9 mL, 22.2 mmol), followed by 20
.mu.L of DMF. The reaction is stirred for 90 min at 22.degree. C.
Reaction proceeds to a clear solution after 60 min. Volatiles are
removed by concentration with DCM to afford 1.08 g (4.6 mmol,
quant.) of a pale yellow solid that is used without further
handling.
Step 2:
[0367] Hydrochloric acid is bubbled through a solution of acetate
protected boc-amine (as prepared in example 8, scheme 4; 1.4 g, 1.1
mmol) in DCM (20 mL) for thirty min. The reaction mixture is then
tightly capped and stirred for thirty minutes after which the
reaction mixture is sparged with nitrogen. The mixture loses its
gel like appearance. DCM (5 mL) is added to the solution, and HCl
gas is bubbled through it for an additional 20 min, followed by
nitrogen for 30 min. Crude product (1.32 g) is obtained after
concentration as a bright orange solid, and taken on to the next
step with no further purification. LC/MS: m/z [M+H].sup.+ 1138,
R.sub.t=1.5 min (method 1).
Step 3:
[0368] To a solution of the amine (1.24 g, 1.1 mmol) in DCM (120
mL), is added pyridine (445 .mu.L, 5.5 mmol), followed by the acid
chloride (0.510 g, 2.2 mmol). The reaction is stirred at 22.degree.
C. for 20 minutes. Subsequently, SiO.sub.2 is added, and the
resulting mix is concentrated to afford a slurry. Purification
using flash column chromatography (elution with 500 mL of 50%
EtOAc/heptane, 500 mL 75% EtOAc/heptane, to 1 L 100% EtOAc) affords
1.29 g (0.97 mmol, 88% yield) of a pale yellow solid that is used
without further modification.
Step 4:
[0369] To a solution of the diester (0.42 g, 0.31 mmol) in MeOH (30
mL) and H.sub.2O (10 mL) is added NaOH crystals (53 mg, 1.3 mmol)
and this mixture is stirred at 22.degree. C. for 24 hrs. The
mixture is then concentrated to dryness. HPLC purification (30-100%
ACN/H.sub.2O in 0.1% TFA, 10 min) then lypholization affords 300 mg
(0.24 mmol, 77%) as a pale yellow solid, LC: R.sub.t=10.24 min.
.sup.1H NMR (DMSO-d6, 400 MHz) .delta. (ppm) 11.15 (s, 2H), 9.12
(s, 1 H), 8.69 (d, 1H), 8.68 (d, 1H), 8.65 (d, 1H), 8.59 (s, 1H),
8.43 (d, 1H), 8.37 (d, 1H), 8.25 (s, 1H), 8.16 (d, 1H), 7.82 (s,
1H), 7.46 (s, 1H), 7.37 (s, 1H), 7.32 (d, 1H), 7.29 (t, 1H), 7.24
(t, 1H), 6.36 (s, 1H), 5.30 (m, 1H), 5.24 (t, 1H), 5.21 (dd, 1H),
5.01 (d, 1H), 4.98 (s, 2H), 4.28 (dd, 1H), 3.80 (dd, 1H), 3.39 (s,
3H), 2.78 (m, 1H), 2.71 (m, 2H), 2.70 (m, 1H), 2.59 (s, 3H), 2.49
(d, 3H), 2.45 (m, 1H), 2.32 (m, 2H), 2.17 (m, 1H), 1.95 (m, 1H),
1.64 (m, 1H), 1.37 (m, 1H), 0.88 (d, 3H), 0.86 (d, 3H). HRMS (ES+)
for C.sub.54H.sub.53N.sub.13O.sub.12S.sub.6: Calc: [M+2H].sup.2+
634.6198; Found: 634.6197.
Example 35
Preparation of Diacid 1 of Table A
##STR00177##
[0370] Compound 1 is prepared according to the procedures described
in example 34. LC: R.sub.t=10.05 min. .sup.1H NMR (DMSO-d6, 400
MHz) .delta. (ppm) 13.5 (s, 2H), 9.24 (s, 1H), 8.73 (d, 1 H), 8.68
(d, 1H), 8.65 (d, 1H), 8.59 (s, 1H), 8.43 (d, 1H), 8.37 (d, 1H),
8.23 (s, 1H), 8.16 (d, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.37 (s,
1H), 7.32 (d, 1H), 7.29 (t, 1H), 7.24 (t, 1H), 6.36 (s, 1H), 5.30
(m, 1H), 5.25 (t, 1H), 5.21 (dd, 1H), 5.01 (d, 1H), 4.98 (s, 2H),
4.28 (dd, 1H), 3.81 (dd, 1H), 3.39 (s, 3H), 2.78 (m, 1H), 2.71 (m,
2H), 2.70 (m, 1H), 2.59 (s, 3H), 2.49 (d, 3H), 2.45 (m, 1H), 2.32
(m, 2H), 2.17 (m, 1H), 2.09 (m, 1H), 1.75 (m, 1H), 1.31 (m, 1H),
0.88 (d, 3H), 0.86 (d, 3H). HRMS (ES+) for
C.sub.54H.sub.53N.sub.13O.sub.12S.sub.6: Calc:
[M+2H].sup.2+=634.6198; Found: 634.6197.
Biological Results:
[0371] Using the standard MIC test described above with the
bacteria Enterococcus faecalis, Enterococcus faecium or
Staphylococcus aureus, compounds 1-35 demonstrate a minimum
inhibitory concentration ranging from 0.0010 .mu.g/mL to 128
.mu.g/mL.
[0372] In vitro assay for inhibition of prokaryotic
transcription-translation [as described in the following
references: 1. Zubay, G. (1973) In vitro synthesis of protein in
microbial systems. Annu. Rev. Genet. 7, 267.87. 2. Zubay, G. (1980)
The isolation and properties of CAP, the catabolite gene activator.
Meth. Enzymol. 65, 856.77]. Antibiotic and compound dilutions:
stock solutions of compound to be assayed at 2 .mu.M are 80 .mu.M
in 40% DMSO. Stock solutions of compounds to be assayed at 10 .mu.M
are 400 .mu.M in 40% DMSO.
[0373] Assay setup and protocol for Promega E. coli S30 Extract
System
TABLE-US-00003 TABLE 1 E. coli S30 Extract system master mix
Component Final volume (16 .mu.l) "Methionine minus" amino acid mix
1.0 .mu.l "Cysteine minus" amino acid mix 1.0 .mu.l S30 premix 8.0
.mu.l S30 extract 6.0 .mu.l
TABLE-US-00004 TABLE 2 E. coli S30 Extract system assay components
Final volume Components/Reagents (20 .mu.l total volume) Template
(pBESTluc .TM.) 286 ng/.mu.l 3.5 .mu.l Compound (40x final
concentration) 0.5 .mu.l in 40% DMSO Master mix (see table 1) 16
.mu.l
[0374] The assay is performed as follows: pipet 3.5 p. 1 of 286
ng/.mu.l template DNA (pBESTluc.TM.) into assay wells. Negative
control wells receive sdH.sub.2O only. Transfer 0.5 .mu.l of
40.times. compound stock solution to assay wells. Positive control
wells (no compound) receive 0.5 .mu.l 40% DMSO sdH.sub.2O. Pipet 16
.mu.l of master mix into assay wells. Incubate plate for two hours
at 37.degree. C. Rapidly chill the assay plate on ice for five
minutes to stop the reaction. Add an equal volume (20 p. 1) of room
temperature Steady-Glo.RTM. Luciferase assay reagent to all assay
wells. Incubate 20 minutes and read light emitted with luminometer.
Results are reported as % inhibition @ 2 .mu.M or 10 .mu.M.
TABLE-US-00005 TABLE 2 (1) % inh. @ (2) % inh. @ (3) % inh. @ 2 uM
= 65.4 2 uM = 72.8 2 uM = 67.8 (4) % inh. @ (5) % inh. @ (6) % inh.
@ 2 uM = 85.3 2 uM = 78.5 2 uM = 86.8 (7) % inh. @ (8) % inh. @ (9)
% inh. @ 2 uM = 86.0 2 uM = 59.7 2 uM = 67.1 (10) % inh. @ (11) %
inh. @ (12) % inh. @ 2 uM = 2.0 2 uM = 92.3 2 uM = 82.4 (13) % inh.
@ (14) % inh. @ (15) % inh. @ 2 uM = 74.9 2 uM = 55.5 2 uM = 64.5
(16) % inh. @ (17) % inh. @ (18) % inh. @ 2 uM = 64.3 2 uM = 63.9 2
uM = 52.7 (19) % inh. @ (20) % inh. @ (21) % inh. @ 2 uM = 76.4 2
uM = 80.6 2 uM = 37.4 (22) % inh. @ (23) % inh. @ (24) % inh. @ 2
uM = 79.8 2 uM = 79.8 2 uM = 70.3 (25) % inh. @ (26) % inh. @ (27)
% inh. @ 2 uM = 83.7 2 uM = 68.2 2 uM = 81.9 (28) % inh. @ (29) %
inh. @ (30) % inh. @ 2 uM = 77.0 2 uM = 79.6 2 uM = 83.93 (31) %
inh. @ (32) % inh. @ (33) % inh. @ 2 uM = 79.4 2 uM = 78.0 2 uM =
46.8 (34) % inh. @ (35) % inh. @ 2 uM = 63.1 2 uM = 87.0
EQUIVALENTS
[0375] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments and methods described
herein. Such equivalents are intended to be encompassed by the
scope of the following claims.
* * * * *
References