U.S. patent application number 15/057019 was filed with the patent office on 2016-09-29 for moenomycin analogs, methods of synthesis, and uses thereof.
This patent application is currently assigned to President and Fellows of Harvard College. The applicant listed for this patent is President and Fellows of Harvard College. Invention is credited to Daniel Evan Kahne, Suzanne Walker Kahne, Hirokazu Tsukamoto.
Application Number | 20160280732 15/057019 |
Document ID | / |
Family ID | 48142986 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160280732 |
Kind Code |
A1 |
Kahne; Daniel Evan ; et
al. |
September 29, 2016 |
MOENOMYCIN ANALOGS, METHODS OF SYNTHESIS, AND USES THEREOF
Abstract
The present invention provides compounds of Formula (I):
##STR00001## or a pharmaceutically acceptable form thereof; wherein
R.sup.1, R.sup.2, R.sup.3, R .sup.6, R.sup.7, R.sup.12, R.sup.XX,
R.sup.a, and R.sup.b are as defined herein, and G is a group of
Formula (a), (b), or (c): ##STR00002## wherein X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, Y, R.sup.c, R.sup.d,
R.sup.z, a, d, e, x, n, and m are as defined herein. The present
invention further provides pharmaceutical compositions comprising a
compound of Formula (I), kits comprising such compositions, methods
of use and treatment, and preparative methods.
Inventors: |
Kahne; Daniel Evan;
(Brookline, MA) ; Kahne; Suzanne Walker;
(Brookline, MA) ; Tsukamoto; Hirokazu; (Sendai,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
President and Fellows of Harvard College |
Cambridge |
MA |
US |
|
|
Assignee: |
President and Fellows of Harvard
College
Cambridge
MA
|
Family ID: |
48142986 |
Appl. No.: |
15/057019 |
Filed: |
February 29, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14390811 |
Oct 6, 2014 |
9273084 |
|
|
PCT/US2013/035416 |
Apr 5, 2013 |
|
|
|
15057019 |
|
|
|
|
61621161 |
Apr 6, 2012 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 9/65586 20130101;
C07H 1/00 20130101; C07H 5/06 20130101; C07H 13/12 20130101 |
International
Class: |
C07H 13/12 20060101
C07H013/12; C07H 1/00 20060101 C07H001/00 |
Goverment Interests
GOVERNMENT FUNDING
[0002] This invention was made with U.S. Government support under
grant GM066174 awarded by the National Institutes of Health. The
U.S. Government has certain rights in the invention.
Claims
1-24. (canceled)
25. A method of synthesizing a compound of Formula (II):
##STR00103## or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph
thereof; the method comprising the steps of: (i) providing
moenomycin A: ##STR00104## (ii) removing the phosphoglycerate
linker and moenocinol chain of moenomycin A, and optionally Rings A
and/or D, to provide a saccharide group of Formula (II-S1):
##STR00105## wherein: each of R.sup.1, R.sup.2, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, and R.sup.11 is hydrogen; each of
R.sup.3 and R.sup.4 is C(.dbd.O)CH.sub.3; R.sup.5 is hydrogen or
Ring A: ##STR00106## R.sup.12 K is hydrogen or Ring D: ##STR00107##
wherein R.sup.13, R.sup.14, R.sup.15.sub., and R.sup.16 are each
hydrogen; (iii) reacting (II-S1) with a phosphitylation agent to
provide a H-phosphonate diester of Formula (II-S2): ##STR00108##
wherein R.sup.a is hydrogen or a hydroxyl protecting group; and
(iv) coupling (II-S2) with a compound of Formula (P1): ##STR00109##
wherein: R.sup.b is hydrogen or a hydroxyl protecting group; and G
is a group of Formula (a), (b), or (c): ##STR00110## wherein a is
3, 4, or 5; ##STR00111## wherein: X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, X.sub.6, and X.sub.7 are each independently
hydrogen or halogen; d is an integer between 1 and 25, inclusive;
and e is an integer of between 2 and 25, inclusive; provided that
at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6, and X.sub.7 is halogen; and the sum of d and e is greater
than 16; or ##STR00112## wherein: Y is --S--, --S--, --NR.sup.Y --,
or an optionally substituted methylene group, wherein R.sup.Y is
hydrogen, optionally substituted aliphatic, or an amino protecting
group; each instance of R.sup.c is independently --F, --Br, --I,
--Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.e, --SR.sup.e,--NHR.sup.e, or
--N(R.sup.e).sub.2, wherein each instance of R.sup.e is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.e groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of R.sup.d is independently --F, --Br, --I, --Cl,
optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.f, --SR.sup.f, --NHR.sup.f, or
--N(R.sup.f).sub.2, wherein each instance of R.sup.f is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.f groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
R.sup.z is hydrogen, --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.g, --SR.sup.g, --NHR.sup.g, or --N(R.sup.g).sub.2, wherein
each instance of R.sup.g is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl or two R.sup.g groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; each instance of n is, independently,
0, 1, 2, 3, or 4; each instance of m is, independently, 0, 1, 2, 3,
or 4; and x is 1, 2, 3, 4, 5, or 6; to provide a compound of
Formula (II), or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph
thereof.
26. A method of synthesizing a compound of Formula (III):
##STR00113## or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph
thereof; the method comprising the steps of: (i) providing
moenomycin A: ##STR00114## (ii) removing the phosphoglycerate
linker, moenocinol chain, and Rings A and B of moenomycin A, and
optionally Ring D, to provide a saccharide group of Formula
(III-S1): ##STR00115## wherein: each of R.sup.1, R.sup.2, R.sup.6,
R.sup.7, and R.sup.8 is hydrogen; each of R.sup.3 and R.sup.4 is
--C(.dbd.O)CH.sub.3; R.sup.12 is hydrogen or Ring D: ##STR00116##
wherein R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are each
hydrogen; and R.sup.17 is hydrogen or a hydroxyl protecting group;
(iii) reacting (III-S1) with a phosphitylation agent to provide a
H-phosphonate diester of the formula (III-S2): ##STR00117## wherein
R.sup.a is hydrogen or a hydroxyl protecting group; and (iv)
coupling (III-S2) with a compound of Formula (P1): ##STR00118##
wherein: R.sup.b is hydrogen or a hydroxyl protecting group; and G
is a group of Formula (a), (b), or (c): ##STR00119## wherein a is
3, 4, or 5; ##STR00120## wherein: X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, X.sub.6, and X.sub.7 are each independently
hydrogen or halogen; d is an integer between 1 and 25, inclusive;
and e is an integer of between 2 and 25, inclusive; provided that
at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5,
X.sub.6, and X.sub.7 is halogen; and the sum of d and e is greater
than 16; or ##STR00121## wherein: Y is --O, --S , --NR.sup.Y--, or
an optionally substituted methylene group, wherein R.sup.Y is
hydrogen, optionally substituted aliphatic, or an amino protecting
group; each instance of R.sup.c is independently --F, --Br, --I,
--Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.e, --SR.sup.e, --NHR.sup.e, or
--N(R.sup.e).sub.2, wherein each instance of R.sup.e is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.e groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of R.sup.d is independently --F, --Br, --I, --Cl,
optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.f, --SR.sup.f, --NHR.sup.f, or
--N(R.sup.f).sub.2, wherein each instance of R.sup.f is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.f groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
R.sup.z is hydrogen, --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.g, --SR.sup.g, --NHR.sup.g, or --N(R.sup.g).sub.2, wherein
each instance of R.sup.g is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl or two R.sup.g groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; each instance of n is, independently,
0, 1, 2, 3, or 4; each instance of m is, independently, 0, 1, 2, 3,
or 4; and x is 1, 2, 3, 4, 5, or 6; to provide a compound of
Formula (III), or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph
thereof.
27. A method of synthesizing a compound of Formula (IV), comprising
the steps of: ##STR00122## or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or
polymorph thereof; the method comprising the steps of: (i)
providing moenomycin A: ##STR00123## (ii) removing the
phosphoglycerate linker, moenocinol chain, and Rings A, B and C of
moenomycin A, and optionally Ring D, to provide a saccharide group
of Formula (IV-S1): ##STR00124## wherein: each of R.sup.1, R.sup.2,
R.sup.6, and R.sup.7 is hydrogen; R.sup.3 is C(.dbd.O)CH.sub.3;
R.sup.12 is hydrogen or Ring D: ##STR00125## wherein R.sup.13,
R.sup.14, R.sup.15, and R and R.sup.16 are each hydrogen; and
R.sup.16 are each hydrogen; and R.sup.18 is hydrogen or a hydroxyl
protecting group; (iii) reacting (IV-S1) with a phosphitylation
agent to provide an H-phosphonate diester of Formula (IV-S2):
##STR00126## wherein R.sup.a is hydrogen or a hydroxyl protecting
group; and (iv) coupling (IV-S2) with a compound of Formula (P1):
##STR00127## wherein: R.sup.b is hydrogen or a hydroxyl protecting
group; and G is a group of Formula (a), (b), or (c): ##STR00128##
wherein a is 3, 4, or 5; ##STR00129## wherein: X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, X.sub.6, and X.sub.7 are each
independently hydrogen or halogen; d is an integer between 1 and
25, inclusive; and e is an integer of between 2 and 25, inclusive;
provided that at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, and X.sub.7 is halogen; and the sum of d and e is
greater than 16; or ##STR00130## wherein: Y is --O--, --S--,
--NR.sup.Y --, or an optionally substituted methylene group,
wherein R.sup.Y is hydrogen, optionally substituted aliphatic, or
an amino protecting group; each instance of R.sup.c is
independently --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.e, --SR.sup.e, --NHR.sup.e, or --N(R.sup.e).sub.2, wherein
each instance of R.sup.e is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl, or two R.sup.e groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; each instance of R.sup.d is
independently --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.f, --SR.sup.f, --NHR.sup.f, or --N(R.sup.f).sub.2, wherein
each instance of R.sup.f is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl, or two R.sup.f groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; R.sup.z is hydrogen, --F, --Br, --I,
--Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.g, --SR.sup.g, --NHR.sup.g, or
--N(R.sup.g).sub.2, wherein each instance of R.sup.g is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl or two
R.sup.g groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of n is, independently, 0, 1, 2, 3, or 4; each
instance of m is, independently, 0, 1, 2, 3, or 4; and x is 1, 2,
3, 4, 5, or 6; to provide a compound of Formula (IV), or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer,
isomer, enantiomer, diastereomer, or polymorph thereof.
28. The method of claim 25, wherein G is a group of formula
(a).
29. The method of claim 28, wherein the group of Formula (a) is:
##STR00131##
30. The method of claim 28, wherein the group of Formula (a) is:
##STR00132##
31. The method of claim 28, wherein the group of Formula (a) is:
##STR00133##
32. The method of claim 25, wherein G is a group of formula
(b).
33. The method of claim 32, wherein at least one of X.sub.1,
X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and X.sub.7 is
halogen.
34. The method of claim 33, wherein X.sub.1 and X.sub.2 are each
hydrogen, X.sub.3 and X.sub.4 are each fluoro, and X.sub.5,
X.sub.6, and X.sub.7 are each fluoro.
35. The method of claim 33, wherein the group of Formula (b) is
selected from the group consisting of: ##STR00134##
##STR00135##
36. The method of claim 33, wherein the group of Formula (b) is:
##STR00136##
37. The method of claim 25, wherein G is a group of Formula
(c).
38. The method of claim 37, wherein the group of Formula (c) is:
##STR00137## wherein: R.sup.c1 and R.sup.c2 are each independently
--F, --Br, --I, --Cl, optionally substituted aliphatic, optionally
substituted heteroaliphatic, optionally substituted carbocycyl,
optionally substituted heterocycyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.e, --SR.sup.e,
--NHR.sup.e, or --N(R.sup.e).sub.2, wherein each instance of
R.sup.e is independently hydrogen, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, or optionally substituted heteroaryl,
or two R.sup.e groups are joined to form a 5- to 6-membered
optionally substituted heterocycyl or optionally substituted
heteroaryl ring; R.sup.d1 and R.sup.d2 are each independently --F,
--Br, --I, --Cl, optionally substituted aliphatic, optionally
substituted heteroaliphatic, optionally substituted carbocycyl,
optionally substituted heterocycyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.f, --SR.sup.f,
--NHR.sup.f, or --N(R.sup.f).sub.2, wherein each instance of
R.sup.f is independently hydrogen, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, or optionally substituted heteroaryl,
or two R.sup.f groups are joined to form a 5- to 6-membered
optionally substituted heterocycyl or optionally substituted
heteroaryl ring; Y.sup.1 and Y.sup.2 are each independently
corresponds to --O, --S--, --NR.sup.Y --, or an optionally
substituted methylene group, wherein R.sup.Y is hydrogen,
optionally substituted aliphatic, or an amino protecting group; n1
and n2 are each independently 0, 1, 2, 3, or 4; and m1 and m2 are
each independently 0, 1, 2, 3, or 4.
39. The method of claim 37, wherein the group of Formula (c) is:
##STR00138## ##STR00139## wherein: R.sup.c1, R.sup.c2, R.sup.c3,
R.sup.c4, R.sup.c5, and R.sup.c6 are each independently --F, --Br,
--I, --Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.e, --SR.sup.e, --NHR.sup.e, or
--N(R.sup.e).sub.2, wherein each instance of R.sup.e is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.e groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.d4, R.sup.d5, and R.sup.d6 are
each independently --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.f, --SR.sup.f, --NHR.sup.f, or --N(R.sup.f).sub.2, wherein
each instance of R.sup.f is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl, or two R.sup.f groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4,
Y.sup.5, and Y.sup.6 are each independently corresponds to --O--,
--S--, --NR.sup.Y--, or an optionally substituted methylene group,
wherein R.sup.Y is hydrogen, optionally substituted aliphatic, or
an amino protecting group; n1, n2, n3, n4, n5, and n6 are each
independently 0, 1, 2, 3, or 4; and m1, m2, m3, m4, m5, and m6 are
each independently 0, 1, 2, 3, or 4.
40. The method of claim 38, wherein the group of Formula (c) is:
##STR00140##
41. The method of claim 25, wherein step (ii) comprises removing
the moenocinol chain, followed by removal of the phosphoglycerate
linker.
42. The method of claim 41, wherein step (ii) comprises removing
Ring A and Ring D of moenomycin A, followed by removing the
moenocinol chain, followed by removal of the phosphoglycerate
linker.
43. The method of claim 25, wherein step (ii) comprises removing
the moenocinol chain using a Lewis acid.
44. The method of claim 25, wherein step (ii) comprises removing
the phosphoglycerate linker using a base.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of and claims
priority under 35 U.S.C. .sctn.120 to U.S. patent application, U.S.
Ser. No. 14/390,811, filed Oct. 6, 2014, which is a national stage
filing under 35 U.S.C. .sctn.371 of international PCT application,
PCT/US2013/035416, filed Apr. 5, 2013, which claims priority under
35 U.S.C. .sctn.119(e) to U.S. provisional patent application, U.S.
Ser. No. 61/621,161, filed Apr. 6, 2012, which is incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0003] Bacteria have the ability to generate resistance to
antibiotics through lateral gene transfer, mutation of enzymes, or
the expression of enzymes which actively pump the antibiotic out of
the cell or break it down. Over the past 10 years, resistance to
existing antibiotics has become a significant problem in many
countries. Vancomycin is currently the drug of last resort to
combat multidrug-resistant Gram-positive bacteria. In many places
vancomycin-resistant Staphylococcus aureus and Enterococci (VRE)
have been discovered. There is thus a desperate need for a new
antibiotic drug to replace this drug of last resort.
[0004] There are a host of cytoplasmic targets for the development
of new antibacterials, such as gyrase inhibitors, protein synthesis
inhibitors, muramyl cascade inhibitors, and many more. The major
hurdle in designing such drugs is that in addition to enzyme based
activity these drugs need to cross the bacterial cell wall to exert
their antibacterial effect. On the other hand, enzymes involved in
synthesis of the bacterial cell wall exist on the cell wall
exterior, and therefore drugs inhibiting these enzymes can exert
their bactericidal or bacteriostatic effect without having to cross
the cell wall. For example, penicillins, cephalosporins, and
moenomycin are antibiotics that interact with bacterial
transpeptidase enzymes. Vancomycin does not interact with bacterial
transpeptidase enzymes but rather sequesters the substrate of the
enzyme.
[0005] Moenomycin is the only known natural product that directly
inhibits the synthesis of bacterial peptidoglycan (PG). The
biological activity of moenomycin is remarkable compared with that
of most other natural antibiotics: it is 10-1000 times more potent
than vancomycin against Gram-positive organisms. See, e.g., Ostash
and Walker, Curr. Opin. Chem. Biol. (2005) 9:459-466; Goldman et
al., Curr. Med. Chem. (2000) 7:801-820. Structure-activity
relationship studies of Moneomycin analogs conducted on the
saccharide portion of the molecule have revealed that moenomycins
with at least three carbohydrate units (C, E, and F) are active in
vivo against Gram-positive bacteria. See, e.g., Garneau et al.,
Bioorganic & Medicinal Chemistry (2004) 12:6473-6494.
Furthermore, while the phosporyl group and the carboxylate group of
the phosphoglycerate linker are now considered important for
bioactivity, the moenocinol chain is also considered to be an
important structural component of the molecule and probably
contributes to target binding both by direct interactions with the
hydrophobic funnel that leads to the membrane and by membrane
anchoring. See, e.g., Fuse et al., Chemical Biology (2010)
5:701-711. However, at the same time, the moenocinol chain is also
credited with poor pharmacokinetic properties and high serum
binding of meonomycin, e.g., its absorption upon oral
administration is relatively poor. See, e.g., van Heijenoort,
Glycobiology (2001) 11:25R-36R.
##STR00003##
SUMMARY OF THE INVENTION
[0006] Previous work established that, although C.sub.10 analogues
of the moenocinol chain are too short to retain biological
activity, the C.sub.25 moenocinol chain of Moenomycin A is longer
than required for activity. See, e.g., Ostash et al., Biochemistry
(2009) 48:8830-8841. The inventors evaluated groups of intermediate
length, structure, and hydrophobicity, e.g., C.sub.15-farnesyl, in
an effort to explore the structure activity relationship (SAR) of
the moenocinol chain. See, e.g., PCT Application Publication No. WO
2009/046314, incorporated herein by reference. The inventors now
believe that groups with lengths greater than C.sub.15-farnesyl,
chains substituted with halogen atoms, and chains comprising
multiple aryl moieties, will provide increasingly more potent
anti-bacterial compounds.
[0007] Thus, in one aspect, provided is a moenomycin A analog
wherein the moenocinol chain is replaced with a group G, e.g., of
the Formula (I),
##STR00004##
or a pharmaceutically acceptable form thereof; [0008] wherein Rings
A, B, C and D moenomycin A are optionally present, e.g., wherein
R.sup.XX is hydrogen, a hydroxyl protecting group, or a group of
Formula:
##STR00005##
[0008] and R is hydrogen, a hydroxyl protecting group, or the group
(D):
##STR00006##
and wherein G is a group of Formula (a), (b), or (c):
##STR00007##
wherein:
[0009] a is 3, 4, or 5;
[0010] X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and
X.sub.7 are each independently hydrogen or halogen;
[0011] d is an integer between 1 and 25, inclusive;
[0012] e is an integer of between 2 and 25, inclusive;
[0013] provided the sum of d and e is greater than 16;
[0014] Y is --O--, --S--, --NR.sup.Y--, or an optionally
substituted methylene group, wherein R.sup.Y is hydrogen,
optionally substituted aliphatic, or an amino protecting group;
[0015] each instance of R.sup.c is independently --F,--Br,
--I,--Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.e, --SR.sup.e, --NHR.sup.e, or
--N(R.sup.e).sub.2, wherein each instance of R.sup.e is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.e groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl
ring;
[0016] each instance of R.sup.d is independently --F, --Cl,
optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.f,--SR.sup.f, --NHR.sup.f, or
--N(R.sup.f).sub.2, wherein each instance of R.sup.f is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.f groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl
ring;
[0017] R.sup.z is hydrogen, --F, --Br, --I, --Cl, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.g, --SR.sup.g, --NHR.sup.g, or
--N(R.sup.g).sub.2, wherein each instance of R.sup.g is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl or two
R.sup.g groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl
ring;
[0018] each instance of n is, independently, 0, 1, 2, 3, or 4;
[0019] each instance of m is, independently, 0, 1, 2, 3, or 4;
and
[0020] x is 1, 2, 3, 4, 5, or 6;
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.13, R.sup.15,
R.sup.16, R.sup.17, R.sup.a, and R.sup.b are as defined herein.
[0021] For example, in one embodiment of Formula (I), provided is a
compound of Formula (II):
##STR00008##
or a pharmaceutically acceptable form thereof; wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.a, and R.sup.b are as
defined herein, and G is a group of Formula (a), (b), or (c) as
defined herein.
[0022] In another embodiment of Formula (I), provided is a compound
of Formula (III):
##STR00009##
or a pharmaceutically acceptable form thereof; wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.12, R.sup.17, R.sup.a, and R.sup.b are as defined herein, and
G is a group of Formula (a, (b), or (c) as defined herein.
[0023] In yet another embodiment of Formula (I), provided is a
compound of Formula (IV):
##STR00010##
or a pharmaceutically acceptable form hereof; wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.12, R.sup.17and R.sup.17, R.sup.a, and R.sup.b are as defined
herein, and G is a group of Formula (a), (b), or (c) as defined
herein.
[0024] The present invention further provides pharmaceutical
compositions comprising a compound of Formula (I), (II), (III), or
(IV), and kits comprising such compositions. The present invention
futher provides methods of use and treatment, and preparative
methods.
[0025] The details of one or more embodiments of the invention are
set forth in the Detailed Description of Certain Embodiments, as
described below. Other features, objects, and advantages of the
invention will be apparent from the Definitions, Examples, and
Claims.
DEFINITIONS
[0026] Definitions of specific functional groups and chemical terms
are described in more detail below. For purposes of this invention,
the chemical elements are identified in accordance with the
Periodic Table of the Elements, CAS version, Handbook of Chemistry
and Physics, 75.sup.th Ed., inside cover, and specific functional
groups are generally defined as described therein. Additionally,
general principles of organic chemistry, as well as specific
functional moieties and reactivity, are described in Organic
Chemistry, Thomas Sorrell, University Science Books, Sausalito,
1999; Smith and March March's Advanced Organic Chemistry, 5.sup.th
Edition, John Wiley & Sons, Inc., New York, 2001; Larock,
Comprehensive Organic Transformations, VCH Publishers, Inc., New
York, 1989; Carruthers Some Modern Methods of Organic Synthesis,
3.sup.rd Edition, Cambridge University Press, Cambridge, 1987; the
entire contents of each of which are incorporated herein by
reference.
[0027] The compounds of the present invention may exist in
particular geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the
racemic mixtures thereof, and other mixtures thereof, as falling
within the scope of the invention.
[0028] Where an isomer/enantiomer is preferred, it may, in some
embodiments, be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically enriched," as used herein, means that the compound is
made up of a significantly greater proportion of one enantiomer. In
certain embodiments the compound of the present invention is made
up of at least about 90% by weight of a preferred enantioiner. Tn
other embodiments the compound is made up of at least about 95%,
98%, or 99% by weight of a preferred enantiomer. Preferred
enantiomers may be isolated from racemic mixtures by any method
known to those skilled in the art, including chiral high pressure
liquid chromatography (HPLC) and the formation and crystallization
of chiral salts or prepared by asymmetric syntheses. See, for
example, Jacques, et al., Enantiomers, Racemates and Resolutions
(Wiley Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon
Compounds (McGraw-Hill, New York, 1962); Wilen, S. H. Tables of
Resolving Agents and Optical Relationship p. 268 (E. L. Eliel, Ed.,
Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
[0029] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example,
an "alkyl group having from 1 to 6 carbons" (also referred to
herein as "C.sub.1-6 alkyl") is intended to encompass 1 (C.sub.1
alkyl), 2 (C.sub.2 alkyl), 3 (C.sub.3 alkyl), 4 (C.sub.4 alkyl), 5
(C.sub.5 alkyl) and 6 (C.sub.6 alkyl) carbons, and a range of 1 to
6 (C.sub.1-6 alkyl), 1 to 5 (C.sub.1-5 alkyl), 1 to 4 (C.sub.1-4
alkyl), 1 to 3 (C.sub.1-2 alkyl), 1 to 2 (C.sub.1-2 alkyl), 2 to 6
(C.sub.2-6 alkyl), 2 to 5 (C.sub.2-5 alkyl), 2 to 4 (C.sub.2-4
alkyl), 2 to 3 (C.sub.2-3 alkyl), 3 to 6 (C.sub.3-6 alkyl), 3 to 5
(C.sub.3-5 alkyl), 3 to 4 (C.sub.3-4 alkyl), 4 to 6 (C.sub.4-6
alkyl), 4 to 5 (C.sub.4-5 alkyl), and 5 to 6 (C.sub.5-6 alkyl)
carbons.
[0030] The term "aliphatic," as used herein, refers to a
monoradical of a non-aromatic, saturated or unsaturated, unbranched
("straight-chain") or branched, substituted or unsubstituted,
acyclic hydrocarbon having 1-50 carbon atoms (i.e., C.sub.1-50
aliphatic). Thus, as used herein, the term "aliphatic" encompasses
the groups "alkyl", "alkynyl", and "alkenyl" as defined herein. In
certain embodiments, aliphatic refers to a C.sub.2-C.sub.30
aliphatic group. In certain embodiments, aliphatic refers to a
C.sub.5-C.sub.25 aliphatic group. In certain embodiments, aliphatic
refers to a C.sub.1-C.sub.10 aliphatic group. In certain
embodiments, aliphatic refers to a C.sub.10-C.sub.20 aliphatic
group. In certain embodiments, aliphatic refers to a
C.sub.11-C.sub.15 aliphatic group. Unless otherwise specified, each
instance of aliphatic is independently unsubstituted
("unsubstituted aliphatic") or substituted ("substituted
aliphatic") with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
substituents as described herein. Aliphatic group substituents
include, but are not limited to, any of the monovalent or divalent
substituents described herein, that result in the formation of a
stable moiety.
[0031] The term "alkyl," as used herein, refers to a monoradical of
a non-aromatic, saturated, unbranched ("straight-chain") or
branched, substituted or unsubstituted, acyclic hydrocarbon having
1-50 carbon atoms (i.e., C.sub.1-50 alkyl). In certain embodiments,
alkyl refers to a C.sub.2-C.sub.30 alkyl group. In certain
embodiments, alkyl refers to a C.sub.5-C.sub.2 alkyl group. In
certain embodiments, alkyl refers to a C.sub.10-C.sub.20 alkyl
group. In certain embodiments, alkyl refers to a C.sub.1-C.sub.10
alkyl group. In certain embodiments, alkyl refers to a
C.sub.11-C.sub.15 alkyl group. Exemplary alkyl groups include,
without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl,
iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl,
neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl,
n-undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,
heptadecyl, octadecyl, nonadecyl, eicosyl, and the like, which may
bear one or more sustitutents. Unless otherwise specified, each
instance of alkyl is independently unsubstituted ("unsubstituted
alkyl") or substituted ("substituted alkyl") with 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more substituents as described herein. Alkyl group
substituents include, but are not limited to, any of the monovalent
or divalent substituents described herein, that result in the
formation of a stable moiety.
[0032] "Methylene" refers to a divalent C.sub.1-alkyl group as
defined herein.
[0033] The term "fluoroalkyl,"as used herein, refers to an alkyl
group having from 1 to 50 carbon atoms wherein at least one
hydrogen is replaced with a fluorine atom ("C .sub.1-50
fluoroalkyl"). In certain embodiments, the fluoroalkyl group has 1
to 8 carbon atoms ("C.sub.1-50 fluoroalkyl"). In certain
embodiments, the fluoroalkyl group has 1 to 6 carbon atoms
("C.sub.1-6 fluoroalkyl"). In certain embodiments, the fluoroalkyl
group has 1 to 4 carbon atoms ("C.sub.1-4 fluoroalkyl"). In certain
embodiments, the fluoroalkyl group has 1 to 3 carbon atoms
("C.sub.1-3 fluoroalkyl"). In certain embodiments, the fluoroalkyl
group has 1 to 2 carbon atoms ("C.sub.1-2 fluoroalkyl"). In certain
embodiments, one hydrogen atom is replaced with a fluorine atom. In
certain embodiments, two hydrogen atoms are replaced with fluorine
atoms. In certain embodiments, three hydrogen atoms are replaced
with fluorine atoms. In certain embodiments, four hydrogen atoms
are replaced with fluorine atoms. In certain embodiments, five
hydrogen atoms are replaced with fluorine atoms. In certain
embodiments, all of the hydrogen atoms are replaced with fluorine
atoms (also referred to as a "perfluoroalkyl" group). Exemplary
fluoroalkyl groups include, but are not limited to, --CH.sub.2F,
--CF.sub.2H, --CF.sub.3, --CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CF.sub.2CF.sub.3,
--CF.sub.2CF.sub.2CF.sub.3, and the like.
[0034] The term "alkenyl," as used herein, refers to a monoradical
of a non-aromatic, unbranched ("straight-chain") or branched,
substituted or unsubstituted, acyclic hydrocarbon having at least
one carbon-carbon double bond, having zero carbon-carbon triple
bonds, and having 2-50 carbon atoms (i.e., C.sub.2-50 alkenyl). In
certain embodiments, alkenyl refers to a C.sub.5-C.sub.25 alkenyl
group. In certain embodiments, alkenyl refers to a
C.sub.10-C.sub.20 alkenyl group. In certain embodiments, alkenyl
refers to a C.sub.2-C.sub.10 alkenyl group. In certain embodiments,
alkenyl refers to a C.sub.11-C.sub.15 alkenyl group. Exemplary
alkenyl groups include, without limitation, ethenyl, propenyl,
butenyl, 1-methyl-2-buten-1-yl, and the like, which may bear one or
more substituents. Unless otherwise specified, each instance of
alkenyl is independently unsubstituted ("unsubstituted alkenyl") or
substituted ("substituted alkenyl") with 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, or more substituents as described herein. Alkenyl group
substituents include, but are not limited to, any of the monovalent
or divalent substituents described herein, that result in the
formation of a stable moiety.
[0035] The term "alkynyl," as used herein, refers to a monoradical
of a non-aromatic, unbranched ("straight-chain") or branched,
substituted or unsubstituted, acyclic hydrocarbon having at least
one carbon-carbon triple bond, optionally containing one or more
carbon-carbon double bonds, and having 2-50 carbon atoms (i.e.,
C.sub.2-50 alkynyl). In certain embodiments, alkynyl refers to a
C.sub.5-C.sub.25 alkynyl group. In certain embodiments, alkynyl
refers to a C.sub.2-C.sub.10 alkynyl group. In certain embodiments,
alkynyl refers to a C.sub.10-C.sub.20 alkynyl group. In certain
embodiments, alkynyl refers to a C.sub.11-C.sub.15 alkynyl group.
Exemplary alkynyl groups include, without limitation, ethynyl,
2-propynyl (propargyl), 1-propynyl, and the like, which may bear
one or more substituents. Unless otherwise specified, each instance
of alkynyl is independently unsubstituted ("unsubstituted alkynyl")
or substituted ("substituted alkynyl") with 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, or more substituents as described herein. Alkynyl group
substituents include, but are not limited to, any of the monovalent
or divalent substituents described herein, that result in the
formation of a stable moiety.
[0036] The term "heteroaliphatic," as used herein, refers to a
C.sub.1-50 aliphatic group wherein one, two or three methylene
units of the hydrocarbon chain are independently replaced with one
or more oxygen, sulfur or nitrogen atoms. Thus, as used herein, the
term "heteroaliphatic" encompasses the groups "heteroalkyl",
"heteroalkynyl", and "heteroalkenyl" as defined herein. Unless
otherwise specified, each instance of heteroaliphatic is
independently unsubstituted ("unsubstituted heteroaliphatic") or
substituted ("substituted heteroaliphatic") with 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more substituents as described herein.
Heteroaliphatic group substituents include, but are not limited to,
any of the monovalent or divalent substituents described herein,
that result in the formation of a stable moiety.
[0037] The term "heteroalkyl," as used herein, refers to a
C.sub.1-50 alkyl group wherein one, two or three methylene units of
the hydrocarbon chain are independently replaced with one or more
oxygen, sulfur or nitrogen atoms. Unless otherwise specified, each
instance of heteroalkyl is independently unsubstituted
("unsubstituted heteroalkyl") or substituted ("substituted
heteroalkyl") with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
substituents as described herein. Heteroalkyl group substituents
include, but are not limited to, any of the monovalent or divalent
substituents described herein, that result in the formation of a
stable moiety,
[0038] The term "heteroalkenyl," as used herein, refers to a
C.sub.2-50 alkenyl group wherein one, two or three methylene units
of the hydrocarbon chain are independently replaced with one or
more oxygen, sulfur or nitrogen atoms. Unless otherwise specified,
each instance of heteroalkenyl is independently unsubstituted
("unsubstituted heteroalkenyl") or substituted. ("substituted
heteroalkenyl") with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
substituents as described herein. Heteroalkenyl group substituents
include, but are not limited to, any of the monovalent or divalent
substituents described herein, that result in the formation of a
stable moiety.
[0039] The term "heteroalkynyl," as used herein, refers to a
C.sub.2-50 alkynyl group wherein one, two or three methylene units
of the hydrocarbon chain are independently replaced with one or
more oxygen, sulfur or nitrogen atoms. Unless otherwise specified,
each instance of heteroalkynyl is independently unsubstituted
("unsubstituted heteroalkynyl") or substituted. ("substituted
heteroalkynyl") with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
substituents as described herein. Heteroalkynyl group substituents
include, but are not limited to, any of the monovalent or divalent
substituents described herein, that result in the formation of a
stable moiety.
[0040] The terms "carbocyclic" or "carbocyclyl," as used herein,
refer to a monoradical of a non-aromatic cyclic hydrocarbon group
having from 3 to 10 ring carbon atoms ("C.sub.3-10 carbocyclyl")
and zero heteroatoms in the non-aromatic ring system. In some
embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms
("C.sub.3-8 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 5 to 10 ring carbon atoms ("C.sub.5-10 carbocyclyl"). Exemplary
C.sub.3-6 carbocyclyl groups include, without limitation,
cyclopropyl (C.sub.3), cyclopropenyl (C.sub.3), cyclobutyl
(C.sub.4), cyclobutenyl (C.sub.4), cyclopentyl (C.sub.5),
cyclopentenyl (C.sub.5), cyclohexyl (C.sub.6), cyclohexenyl
(C.sub.6), cyclohexadienyl (C.sub.6) and the like. Exemplary
C.sub.3-8 carbocyclyl groups include, without limitation, the
aforementioned C.sub.3-6 carbocyclyl groups as well as cycloheptyl
(C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl (C.sub.7),
cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8), cyclooctenyl
(C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7), bicyclo[2.2.2]octanyl
(C.sub.8), and the like. Exemplary C.sub.3-10 carbocyclyl groups
include, without limitation, the aforementioned C.sub.3-8
carbocyclyl groups as well as cyclononyl (C.sub.9), cyclononenyl
(C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl (C.sub.10),
octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl (C.sub.10),
spiro[4.5]decanyl (C.sub.10) and the like. As the foregoing
examples illustrate, in certain embodiments, the carbocyclyl group
is either monocyclic ("monocyclic carbocyclyl") or polycyclic
(e.g., containing a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic carbocyclyl") or tricyclic system
("tricyclic carbocyclyl")) and can be saturated or can contain one
or more carbon-carbon double or triple bonds. "Carbocyclyl" also
includes ring systems wherein the carbocyclyl ring, as defined
above, is fused with one or more aryl or heteroaryl groups, as
defined herein, wherein the point of attachment is on the
cathocyclyl ring; in such instances, the number of carbons
continues to designate the number of carbons in the carbocyclic
ring system. Unless otherwise specified, each instance of a
carbocyclyl group is independently unsubstituted ("unsubstituted
carbocyclyl") or substituted ("substituted carbocyclyl") with 2, 3,
4, 5, 6, 7, 8, 9, 10, or more substituents as described herein.
Carbocyclyl group substituents include, but are not limited to, any
of the monovalent or divalent substituents described herein, that
result in the formation of a stable moiety.
[0041] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 10 ring carbon atoms
("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Exemplary C.sub.5-6 cycloalkyl groups
include, without limitation, cyclopentyl (C.sub.5) and cyclohexyl
(C.sub.5). Exemplary C.sub.3-6 cycloalkyl groups include, without
limitation, the aforementioned C.sub.5-6 cycloalkyl groups as well
as cyclopropyl (C.sub.3) and cyclobutyl (C,.sub.4). Exemplary
C.sub.3-8 cycloalkyl groups include, without limitation, the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
("unsubstituted cycloalkyl") or substituted ("substituted
cycloalkyl") with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more
substituents as described herein. Cycloalkyl group substituents
include, but are not limited to, any of the monovalent or divalent
substituents described herein, that result in the formation of a
stable moiety.
[0042] The terms "heterocyclic" or "heterocyclyl," as used herein,
refer to a radical of a 3- to 14-membered non-aromatic ring system
having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur ("3-14-membered heterocyclyl"). In
heterocyclyl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. A heterocyclyl group can either be monocyclic ("monocyclic
heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring
system such as a bicyclic system ("bicyclic heterocyclyl") or
tricyclic system ("tricyclic heterocyclyl")), and can be saturated
or can contain one or more carbon-carbon double or triple bonds.
Heterocyclyl polycyclic ring systems can include one or more
heteroatoms in one or both rings. "Heterocyclyl" includes ring
systems wherein the heterocycyl ring, as defined above, is fused
with one or more carbocycyl groups wherein the point of attachment
is either on the carbocycyl or heterocyclyl ring; in such
instances, the number of ring members continues to designate the
number of ring members in the heterocyclyl ring system. Heterocycyl
also includes ring systems wherein the heterocyclyl ring, as
defined above, is fused with one or more aryl or heteroaryl groups,
wherein the point of attachment is on the heterocyclyl ring; in
such instances, the number of ring members continues to designate
the number of ring members in the heterocyclyl ring system. In some
embodiments, a heterocyclyl group is a 5-10-membered non-aromatic
ring system having ring carbon atoms and 1-4 ring heteroatoms,
wherein each heteroatom is independently selected from the group
consisting of nitrogen, oxygen and sulfur ("5-10-membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a
5-8-membered non-aromatic ring system having ring carbon atoms and
1-4 ring heteroatoms, wherein each heteroatom is independently
selected from the group consisting of nitrogen, oxygen and sulfur
("5-8-membered heterocyclyl"). In some embodiments, a heterocyclyl
group is a 5-6-membered non-aromatic ring system having ring carbon
atoms and 1-4 ring heteroatoms, wherein each heteroatom is
independently selected from the group consisting of nitrogen,
oxygen and sulfur ("5-6-membered heterocyclyl"). In some
embodiments, the 5-6-membered heterocyclyl has 1-3 ring heteroatoms
selected from the group consisting of nitrogen, oxygen and sulfur.
In some embodiments, the 5-6-membered heterocyclyl has 1-2 ring
heteroatoms selected from the group consisting of nitrogen, oxygen
and sulfur. In some embodiments, the 5-6-membered heterocyclyl has
1 ring heteroatom selected from the group consisting of nitrogen,
oxygen and sulfur. Exemplary 3-membered heterocyclyls containing 1
heteroatom include, without limitation, azirdinyl, oxiranyl,
thiorenyl. Exemplary 4-membered heterocyclyls containing 1
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclyls containing 1
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5dione. Exemplary
5-membered heterocyclyls containing 2 heteroatoms include, without
limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary
5-membered heterocyclyls containing 3 heteroatoms include, without
limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
Exemplary 6-membered heterocyclyl groups containing 1 heteroatom
include, without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing 2 heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered
heterocyclyl groups containing 2 heteroatoms include, without
limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups
containing 1 heteroatom include, without limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups
containing 1 heteroatom include, without limitation, azocanyl,
oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups
include, without limitation, indolinyl, isoindolinyl,
dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl,
tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroqunolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl,
decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl,
octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl,
naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl,
1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,
5,6-dihydro-4H-furo[3,2-b]pyrrolyl,
6,7-dihydro-5H-furo[3,2b]pyranyl,
5,7-dihydro-4-thieno[2,3c]pyranyl,
2,3dihydro-1H-pyrrolo[2,3-b]pyridinyl,
2,3-dihydrofuro[2,3b-]pyridinyl,
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,
4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,
4,5,6,7-tetrahydrothieno[3,2b]pyridinyl,
1,2,3,4tetrahydro-1,6-naphthyridinyl, and the like. Unless
otherwise specified, each instance of heterocyclyl is independently
unsubstituted ("unsubstituted heterocyclyl") or substituted
("substituted heterocyclyl") with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or
more substituents as described herein. Heterocyclyl group
substituents include, but are not limited to, any of the monovalent
or divalent substituents described herein, that result in the
formation of a stable moiety.
[0043] The term "aryl," as used herein, refers to a radical of a
monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic
ring system (e.g., having 6, 10 or 14.pi. electrons shared in a
cyclic array) having 6-14 ring carbon atoms and zero heteroatoms
provided in the aromatic ring system ("C.sub.6 14 aryl"). In some
embodiments, an aryl group has 6 ring carbon atoms ("C.sub.6aryl";
e.g., phenyl). In some embodiments, an aryl group has 10 ring
carbon atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl
and 2-naphthyl). In some embodiments, an aryl group has 14 ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring; in such
instances, the number of carbon atoms continues to designate the
number of carbon atoms in the aryl ring system. Unless otherwise
specified, each instance of an aryl group is independently
unsubstituted ("unsubstituted aryl") or substituted ("substituted
aryl") with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more substituents as
described herein. Aryl group substituents include, but are not
limited to, any of the monovalent substituents described herein,
that result in the formation of a stable moiety.
[0044] The terms "aralkyl" or "arylalkyl" are a subset of "alkyl"
and refer to an alkyl group, as defined herein, substituted by an
aryl group, as defined herein, wherein the point of attachment is
on the alkyl moiety.
[0045] The term "heteroaryl," as used herein, refers to a radical
of a 5-14-membered monocyclic or polycyclic (e.g., bicyclic or
tricyclic) aromatic ring system (e.g., having 6,10 or 14.pi.
electrons shared in acyclic array) having ring carbon atoms and 1-4
ring heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur ("5-14-membered heteroaryl"). In
heteroaryl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. Heteroaryl polycyclic ring systems can include one or more
heteroatoms in one or both rings. "Heteroaryl" includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more carbocycyl or heterocycyl groups wherein the point
of attachment is on the heteroaryl ring; in such instances, the
number of ring members continues to designate the number of ring
members in the heteroaryl ring system. "Heteroaryl" also includes
ring systems wherein the heteroaryl ring, as defined above, is
fused with one or more aryl groups wherein the point of attachment
is either on the aryl or on the heteroaryl ring; in such instances,
the number of ring members designates the number of ring members in
the fused polycyclic (aryl/heteroaryl) ring system. For example,
polycyclic heteroaryl groups wherein one ring does not contain a
heteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like) the
point of attachment can be on either ring, i.e., either the ring
bearing a heteroatom (e.g., 2-indolyl) or the ring that does not
contain a heteroatom (e.g., 5-indolyl). In some embodiments, a
heteroaryl group is a 5-10-membered aromatic ring system having
ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic
ring system, wherein each heteroatom is independently selected from
the group consisting of nitrogen, oxygen and sulfur ("5-10 membered
heteroaryl"). In some embodiments, a heteroaryl group is
a5-8-membered aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from the group consisting of
nitrogen, oxygen and sulfur ("5-8-membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6-membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from the group consisting of nitrogen,
oxygen and sulfur ("5-6-membered heteroaryl"). In some embodiments,
the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from
the group consisting of nitrogen, oxygen and sulfur. In some
embodiments, the 5-6-membered heteroaryl has 1-2 ring heteroatoms
selected from the group consisting of nitrogen, oxygen and sulfur.
In some embodiments, the 5-6-membered heteroaryl has 1 ring
heteroatom selected from the group consisting of nitrogen, oxygen
and sulfur. Exemplary 5-membered heteroaryls containing 1
heteroatom include, without limitation, pyrrolyl, furanyl and
thiophenyl. Exemplary 5-membered heteroaryls containing 2
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryls containing 3 heteroatoms include, without
limitation, triazolyl, oxadiazolyl, thiadiazolyl. Exemplary
5-membered heteroaryls containing 4 heteroatoms include, without
limitation, tetrazolyl. Exemplary 6-membered heteroaryls containing
1 heteroatom include, without limitation, pyridinyl. Exemplary
6-membered heteroaryls containing 2 heteroatoms include, without
limitation, pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary
6-membered heteroaryls containing 3 or 4 heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryls containing 1 heteroatom include,
without limitation, azepinyl, oxepinyl and thiepinyl. Exemplary
5,6-bicyclic heteroaryls include, without limitation, indolyl,
isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,
isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,
benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
Exemplary 6,6-bicyclic heteroaryls include, without limitation,
naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl,
quinoxalinyl, phthalazinyl and quinazolinyl. Exemplary tricyclic
heteroaryls include, without limitation, phenanthridinyl,
dibenzafuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl
and phenazinyl. Unless otherwise specified, each instance of a
heteroaryl group is independently unsubstituted ("unsubstituted
heteroaryl") or substituted ("substituted heteroaryl") 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, or more substituents as described herein.
Heteroaryl group substituents include, but are not limited to, any
of the monovalent substituents described herein, that result in the
formation of a stable moiety.
[0046] The terms "heteroarylalkyl" or "heteroaralkyl" are a subset
of "alkyl" and refer to an alkyl group, as defined herein,
substituted by a heteroaryl group, as defined herein, wherein the
point of attachment is on the alkyl moiety.
[0047] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond. The
term "partially unsaturated" is intended to encompass rings having
multiple sites of unsaturation, but is not intended to include
aromatic groups (e.g., aryl or heteroaryl moieties as defined
herein.
[0048] Unless otherwise specified, aliphatic (e.g., alkyl, alkenyl,
alkynyl), heteroaliphatic (e.g., heteroalkyl, heteroalkenyl,
heteroalkynyl), carbocyclyl, heterocyclyl, aryl and heteroaryl
groups, as defined herein, are optionally substituted (e.g.,
"substituted" or "unsubstituted" aliphatic, "substituted" or
"unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl,
"substituted" or "unsubstituted" alkynyl, "substituted" or
"unsubstituted" heteroaliphatic, "substituted" or "unsubstituted."
heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl,
"substituted" or "unsubstituted" heteroalkynyl, "substituted" or
"unsubstituted" carbocyclyl, "substituted" or "unsubstituted"
heterocyclyl, "substituted" or "unsubstituted" aryl, or
"substituted" or "unsubstituted" heteroaryl group). In general, the
term "substituted" means that at least one hydrogen present on a
group (e.g., a carbon or nitrogen atom etc.) is replaced with a
permissible substituent, e.g., a substituent which upon
substitution results in a stable compound, e.g., a compound which
does not spontaneously undergo transformation such as by
rearrangement, cyclization, elimination, or other reaction. Unless
otherwise indicated, a "substituted" group has a substituent at one
or more substitutable positions of the group, and when more than
one position in any given structure is substituted, the substituent
is either the same or different at each position.
[0049] Exemplary monovalent carbon atoms substituents include, but
are not limited to, halo/halogen. (i.e., --F, --Br, --Cl, --I),
--NC, --CN, --NO.sub.2, --N.sub.3, --CO.sub.2H, --CHO, --SO.sub.2H,
--SO.sub.3H, --S(.dbd.O)OH, acyl (e.g., --C(.dbd.O)R.sup.A,
--CO.sub.2R.sup.A, --C(.dbd.O)--O--C(.dbd.O)R.sup.A,
--C(.dbd.O)SR.sup.A, --C(.dbd.O)N(R.sub.2,
--C(.dbd.O)NR.sup.BSO.sub.2R.sup.A, --C(.dbd.NR.sup.B)R.sup.A,
--C(.dbd.NR.sup.B)OR.sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2,
--C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.A).sub.2,
--C(.dbd.S)SR.sup.A), amino (e.g., --NH.sub.2,
--N(OR.sup.B)R.sup.B, --N(R.sup.B).sub.2,
--NR.sup.BSO.sub.2R.sup.A, --NR .sup.BC(.dbd.O)R.sup.A,
--NR.sup.BCO.sub.2R.sup.A, --NR.sup.BC(.dbd.O)N(R.sup.B).sub.2,
--NR.sup.BC(.dbd.NR.sup.B)N(R.sup.B).sub.2), thio (e.g., --SH,
--SR.sup.A, --SSR.sup.B), oxy (e.g., --OH, --OR.sup.A,
--ON(R.sup.B).sub.2, --OSO.sub.2R.sup.A, --OS(.dbd.O)R.sup.A,
--OC(.dbd.O)R.sup.A, --OCO.sub.2R.sup.A,
--OC(.dbd.O)N(R.sup.B).sub.2, --OC(.dbd.NR.sup.B)R.sup.A,
--OC(.dbd.NR.sup.B)OR.sup.A, --OC(.dbd.NR.sup.B)N(R.sup.B).sub.2),
sulfonyl (e.g., SO.sub.2R.sup.A, --SO.sub.2OR.sup.A,
--SO.sub.2N(R.sup.B).sub.2), sulfinyl (e.g., --S(.dbd.O)R.sup.A),
silyl (e.g., --Si(R.sup.A).sub.3), C.sub.1-10 alkyl, C.sub.1-10
fluoroalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14-membered heterocyclyl, C.sub.6-14 aryl, and
5-14-membered heteroaryl, wherein each aliphatic, heteroaliphatic,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1., 2, 3, 4, or 5 R.sup.D groups;
[0050] each instance of R.sup.A is, independently, selected from
the group consisting of C.sub.1-10 alkyl, C.sub.1-10 fluoroalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl,
3-14-membered heterocyclyl, C.sub.6-14 aryl, and 5-14 membered
heteroaryl, wherein each aliphatic, heteroahphatic, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independent substituted with
0, 1, 2, 3, 4, or 5 R.sup.D groups;
[0051] each instance of R.sup.B is, independently, selected from
the group consisting of hydrogen, --OH, --OR.sup.A,
--N(R.sup.C).sub.2, --CN, --C(.dbd.O)R.sup.A,
--C(.dbd.O)N(R.sup.C).sub.2, --CO.sub.2R.sup.A,
--C(.dbd.NR.sup.C)OR.sup.A, --C(.dbd.NR.sup.C)N(R.sup.C).sub.2,
--SO.sub.2N(R.sup.C).sub.2, --SO.sub.2R.sup.C, --SO.sub.2OR.sup.C,
--SOR.sup.A, --C(.dbd.S)N(R.sup.C) .sub.2, --C(.dbd.O)SR.sup.C,
--C(.dbd.S)SR.sup.C, C.sub.1-10 alkyl, C.sub.1-10 fluoroalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl,
3-14-membered heterocyclyl, C,.sub.6-14 aryl, and 5-14-membered
heteroaryl, or two R.sup.B groups attached to an N atom are joined
to form a 3-14-membered heterocyclyl or 5-14 membered heteroaryl
ring, wherein each aliphatic, heteroaliphatic, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1., 2, 3, 4, or 5 R.sup.D groups;
[0052] each instance of R.sup.C is, independently, selected from
the group consisting of hydrogen, C.sub.1-10 alkyl, C.sub.1-10
fluoroalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.C groups attached to an N atom
are joined to form a 3-14-membered heterocyclyl or 5-14-membered
heteroaryl ring, wherein each aliphatic, heteroaliphatic,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2, 3, 4, or 5 R.sup.D groups; and
[0053] each instance of R.sup.D is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl.).sub.2,
--N(OC.sub.1-6 alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl),
--NH(OH), --SH, --SC .sub.1-6 alkyl), --SS(C.sub.1-6 alkyl)
--C(.dbd.O)(C.sub.1-6 alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6
alkyl), --OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6
alkyl), --C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6alkyl), --OC(.dbd.NH)OC.sub.1-6alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --S(.dbd.O)C.sub.1-6 alkyl, C.sub.1-6
alkyl, C.sub.1-6 fluoroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10-membered heteroaryl; or two geminal R.sup.D
substituents are joined to form.dbd.O, .dbd.S or .dbd.NR.sup.B.
[0054] Exemplary divalent carbon atom substituents include, but are
not limited to .dbd.O, .dbd.S, and .dbd.NR.sup.B, wherein R.sup.B
is as defined herein.
[0055] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include prima y, secondary, tertiary and
quartemary nitrogen atoms. Exemplary nitrogen atom substitutents
include, but are not limited to, .dbd.NR.sup.B, --CHO,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A, --NH.sub.2,
--N(OR.sup.B)R.sup.B, --N(R .sup.B.sub.2,
--NR.sup.BSO.sub.2R.sup.A, --NR.sup.BC(.dbd.O)R.sup.A,
--NR.sup.BCO.sub.2R.sup.A, --NR.sup.BC(.dbd.O)N(R.sup.B).sub.2,
--NR.sup.BC(.dbd.NR.sup.B)N(R.sup.B).sub.2, --OH, --OR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A), --Si(R.sup.A).sub.3, C.sub.1-10 alkyl,
C.sub.1-10 fluoroalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
C.sub.3-10 carbocyclyl, 3-14-membered heterocyclyl, C.sub.6-14
aryl, and 5-14-membered heteroaryl, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1., 2, 3, 4, or 5 R.sup.D
groups.
[0056] In certain embodiments, nitrogen atom substituents, as
described above, are also referred to as "amino protecting groups"
or "nitrogen protecting groups". Amino protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, the entirety
of which is incorporated herein by reference.
[0057] Exemplary amino protecting groups include, but are not
limited to, methyl carbamate, ethyl carbamante, acetyl
(--C(.dbd.O)CH.sub.3, --Ac), 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl
carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1(4-biphenylyl)ethyl carbamate (Bpoc),
1,-(3,5di-t-butylphenyl)-1methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl
carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl
carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl
carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate,
benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4,-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl
carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl
carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,
[2-(1.3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl
carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc),
2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl
carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate,
m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl
carbamate, 5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl
derivative, N' -p-toluenesulfonylaminocarbonyl derivative,
N'-phenylaminothiocarbonyl derivative, t-amyl carbamate, S-benzyl
thiocarbamate p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl
carbamate, o-(N,N-dimethylearboxamido)benzyl carbamate,
1,1.-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate, 1-methyl 1-(3,5
dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-,1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, 2,4,6,-trimethylbenzyl carbamate, formamide, acetamide,
chloroacetamide, trichloroacetamide, trifluoroacetamide,
phenylacetamide, 3-phenylpropanamide, picolinamide,
3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,
p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,
acetoacetamide, (N'-dithiobenzyloxycarbonylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-(o-nitrophenoxy)propanamide, 2-methyl 2
(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl 3
nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative,
o-nitrobenzamide, o-(benzoyloxymethyl)benzamide,
4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide
(Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,
N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),
5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,
5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2one,
1-substituted 3,5 dinitro-4-pyridone, N-methylamine, N-allylamine,
N-[2-(trimethylsilyl)ethoxy]methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N
5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-p-methoxybenzylideneamine,
N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,
N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine,
N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine,
amine N-oxide, diphenylphosphinamide (Dpp),
dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt),
dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl
phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide
(Nps), 2,4-dinitrobenzenesulfenamide,
pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,
triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys),
p-toluenesulfonamide (Ts), benzenesulfonamide,
2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr),
2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy
4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), .beta.-trimethylsilylethanesulfonamide
(SES), 9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0058] Exemplary oxygen substituents include, but are not limited
to, --C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A.sub.2, --C(.dbd.S)SR.sup.A, ,
--SO.sub.2R.sup.A, --SO.sub.2N(R.sup.B).sub.2, --S(.dbd.O)R.sup.A,
--Si(R.sup.A).sub.3, C.sub.1-10 alkyl, C.sub.1-10 fluoroalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.2-10 alkenyl,
C.sub.3-10 carbocyclyl, 3-14-membered heterocyclyl, C.sub.6-14
aryl, and 5-14-membered heteroaryl, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.D
groups.
[0059] In certain embodiments, oxygen atom substituents, as
described above, are also referred to as "hydroxyl protecting
groups" or "oxygen protecting groups". Hydroxyl protecting groups
are well known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, the entirety
of which is incorporated herein by reference.
[0060] Exemplary hydroxyl protecting groups include, but are not
limited to, acetyl (--C(.dbd.O)CH.sub.3, --Ac), methyl,
methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),
p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),
guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),
siloxymethyl, 2-methoxyethoxymethyl (MEM),
2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,
2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP),
3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP),
4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]4-methoxypiperidin-4-yl
(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido,
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl
(DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl (DPMS),
t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3,-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenythenzoate,
2,4,6-trimethylbenzoate (mesitoate), methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate,
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsily)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate,
vinyl carbonate, allyl carbonate, p-nitrophenyl carbonate, benzyl
carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl
carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate,
S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl
dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,
4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,
4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethy)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxycarbonyl)benzoate, .alpha.-naphthoate,
N,N,N',N'-tetramethylphosphorodiamidate, N-phenylcarbamate,
dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate, sulfate,
methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
For protecting 1,2- or 1,3-diols, the protecting groups include
methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal,
1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal,
2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene
ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene
acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene
ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal,
methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene
ortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine
ortho ester, 1,2-dimethoxyethylidene ortho ester,
.alpha.-methoxybenzylidene ortho ester,
1-(N,N-dimethylamino)ethylidene derivative,
.alpha.-(N,N'-dimethylamino)benzylidene derivative,
2-oxacyclopentylidene ortho ester, di-t-butylsilylene group (DTBS),
1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),
tetra-1-butoxydisiloxane-1,3-diylidene derivative (TBDS), cyclic
carbonates, cyclic boronates, ethyl boronate, and phenyl
boronate.
[0061] The term "pharmaceutically acceptable form thereof" as used
herein refers to pharmaceutically acceptable salts, solvates,
hydrates, prodrugs, tautomers, isomers, enantiomers, diastereomers,
and/or polymorphs of a compound of the present invention.
[0062] In certain embodiments, the pharmaceutically acceptable form
is a pharmaceutically acceptable salt. The term "pharmaceutically
acceptable salt" as used herein refers to those salts which are,
within the scope of sound medical judgment, suitable for use in
contact with the tissues of humans and lower animals without undue
toxicity, irritation, allergic response and the like, and are
commensurate with a reasonable benefit/risk ratio. Pharmaceutically
acceptable salts are well known in the art. For example, Berge et
al., describe pharmaceutically acceptable salts in detail in J.
Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by
reference. Pharmaceutically acceptable salts of the compounds of
this invention include those derived from suitable inorganic and
organic acids and bases. Examples of pharmaceutically acceptable,
nontoxic acid addition salts are salts of an amino group formed
with inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid or malonic acid or by using other
methods used in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C,.sub.1-4alkyl).sub.4 salts.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0063] In certain embodiments, the pharmaceutically acceptable form
is a hydrate or solvate. The term "hydrate" as used herein refers
to a compound non-covalently associated with one or more molecules
of water. Likewise, the term "solvate" refers to a compound
non-covalently associated with one or more molecules of an organic
solvent.
[0064] In certain embodiments, the pharmaceutically acceptable form
is a prodrug. The term "prodrug" as used herein refers to a
derivative of a parent compound that requires transformation within
the body in order to release the parent compound. In certain cases,
a prodrug has improved physical and/or delivery properties over the
parent compound. Prodrugs are typically designed to enhance
pharmaceutically and/or pharmacokinetically based properties
associated with the parent compound. The advantage of a prodrug can
lie in its physical properties, such as enhanced water solubility
for parenteral administration at physiological pH compared to the
parent compound, or it enhances absorption from the digestive
tract, or it may enhance drug stability for long-term storage. In
recent years several types of bioreversible derivatives have been
exploited for utilization in designing prodrugs. Using esters as a
prodrug type for compounds containing a carboxyl or hydroxyl
functionality is known in the art as described, for example, in The
Organic Chemistry of Drug Design and Drug Interaction by Richard
Silverman, published by Academic Press (1992).
[0065] In certain embodiments, the pharmaceutically acceptable form
is a tautomer. The term "tautomer" as used herein includes two or
more interconvertable compounds resulting from at least one formal
migration of a hydrogen atom and at least one change in valency
(e.g., a single bond to a double bond, a triple bond to a single
bond, or vice versa). The exact ratio of the tautomers depends on
several factors, including temperature, solvent, and pH.
Tautomerizations (i.e., the reaction providing a tautomeric pair)
may catalyzed by acid or base. Exemplary tautomerizations include
keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine;
and enamine-to-(a different) enamine tautomerizations.
[0066] In certain embodiments, the pharmaceutically acceptable form
is an isomer. The term "isomer" as used herein includes any and all
geometric isomers and stereoisomers (e.g., enantiomers,
diasteromers, etc.). For example, "isomer" include cis- and
trans-isomers, E- and Z-isomers, R- and S-enantiomers,
diastereotners, (D)isomers, (L)-isomers, racemic mixtures thereof,
and other mixtures thereof, as falling within the scope of the
invention. For instance, an isomer/enantiomer may, in some
embodiments, be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically enriched," as used herein, means that the compound is
made up of a significantly greater proportion of one enantiomer. In
certain embodiments the compound of the present invention is made
up of at least about 90% by weight of a preferred enantiomer. In
other embodiments the compound is made up of at least about 95%,
98%, or 99% by weight of a preferred enantiomer. Preferred
enantiomers may be isolated from racemic mixtures by any method
known to those skilled in the art, including chiral high pressure
liquid chromatography (HPLC) and the formation and crystallization
of chiral salts or prepared by asymmetric syntheses. See, for
example, Jacques, et al., Enantiotners, Racemates and Resolutions
(Wiley Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon
Compounds (McGraw-Hill, New York, 1962); Wilen, S. H. Tables of
Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed.,
Univ. of Notre Dome Press, Notre Dame, Ind. 1972).
[0067] In certain embodiments, the pharmaceutically acceptable form
is a polymorph. The term "polymorph" as used herein refers to a
crystalline compound existing in more than one crystalline
form/structure. When polymorphism exists as a result of difference
in crystal packing it is called packing polymorphism. Polymorphism
can also result from the existence of different conformers of the
same molecule in conformational polymorphism. In pseudopolymorphism
the different crystal types are the result of hydration or
solvation.
[0068] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g. infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult
or senior adult)) and/or other primates (e.g., cynomolgus monkeys,
rhesus monkeys); mammals, including commercially relevant mammals
such as cattle, pigs, horses, sheep, goats, cats, and/or dogs;
and/or birds, including commercially relevant birds such as
chickens, ducks, geese, and/or turkeys.
[0069] As used herein, the terms "treat," "treating" and
"treatment" refer to partially or completely halting, reducing,
delaying, or diminishing the severity of an infection or symptoms
related to an infection from which the subject is suffering.
[0070] As used herein, the terms "prevent," "preventing" and
"prevention" contemplate an action that occurs before a subject
begins to suffer an infection or symptoms related to an
infection.
[0071] As used herein "inhibition," "inhibiting," and "inhibit",
refer to the ability of a compound to reduce, slow, halt or prevent
activity of a particular biological process in a cell relative to
vehicle. In certain embodiments, the biological process is in vitro
(e.g., cellular assay). In certain embodiments, the biological
process is in vivo.
[0072] As used herein, and unless otherwise specified, an
"effective amount" refers to the minimal amount or concentration of
an inventive compound or pharmaceutical composition thereof that,
when administered, is sufficient in treating or preventin an
infection in the subject. In certain embodiments of the present
invention an "effective amount" of the inventive compound or
pharmaceutical composition thereof is that amount effective for
killing, inhibiting, or preventing, the growth of the causative
microbial organism (e.g., a bacterium, virus, parasite, or fungus).
In certain embodiments, an effective amount is the amount
administered to a subject to achieve a concentration at the site of
infection sufficient to inhibit the growth of the causative
microbial organism. In certain embodiments, an effective amount is
the amount administered to a subject to achieve the mean inhibitory
concentration at the site of infection for the causative microbial
organism.
[0073] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment of a
infection or to delay or minimize one or more symptoms associated
with the infection. A therapeutically effective amount of a
compound means an amount of therapeutic agent, alone or in
combination with other therapies, which provides a therapeutic
benefit in the treatment of the infection. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces or avoids symptoms or causes of
infection, or enhances the therapeutic efficacy of another
therapeutic agent.
[0074] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent an infection, or one or more symptoms
associated with the infection or prevent its recurrence. A
prophylactically effective amount of a compound means an amount of
a therapeutic agent, alone or in combination with other agents,
which provides a prophylactic benefit in the prevention of the
infection. The term "prophylactically effective amount" can
encompass an amount that improves overall prophylaxis or enhances
the prophylactic efficacy of another prophylactic agent.
[0075] As used herein, "infection" refers to a microbial infection
(i.e., a bacterial infection, a viral infection, a parasitic
infection, or a fungal infection). In certain embodiments, the
infection is a bacterial infection.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0076] Moenomycin A is a natural product that inhibits
peptidoglycan biosynthesis by binding to bacterial
transglycosylases. Moenomycin A is a thousand times more potent
than the antibiotic vancomycin, but poor pharmacokinetic properties
related to the lipid side chain have prevented its use in humans.
Removal of the natural lipid side chain completely abolishes
biological activities. A comprehensive study of the effect of
different side chains, optionally in combination with different
sugar portions, on the antibacterial activity compared to natural
moenomycin A, has been limited as most synthetic tranformations
employed in the removal of the natural lipid side chain and in the
addition of other different side chains have also altered other
structural features of the molecule. Recently, a mild,
semi-synthetic, methodology was disclosed which enabled SAR study
of new moenomycins; e.g., see PCT Application Publication No. WO
20091046314, incorporated herein by reference. In the '314
publication, the inventors explored groups of intermediate length
and hydrophobicity, e.g., C.sub.15-farnesyl, in an effort to
explore the optimal length for activity and bioavailability. The
inventors now believe that groups with lengths greater than
C.sub.15-farnesyl, chains substituted with halogen atoms, and
chains comprising multiple aryl moieties, will provide increasingly
more potent anti-bacterial compounds.
[0077] In particular, the present invention is directed to
moenomycin A analogs wherein the moenocinol chain is replaced with
a group G, e.g., of the Formula (I),
##STR00011##
or a pharmaceutically acceptable form thereof; [0078] wherein Rings
A, B, C and D of moenomycin A are optionally present, e.g., wherein
R.sup.XX is hydrogen, a hydroxyl protecting group, or a group of
Formula:
##STR00012##
[0078] and R.sup.12 is hydrogen, a hydroxyl protecting group, or
the group (D):
##STR00013##
and wherein G is group of Formula (a), (b), (c):
##STR00014##
wherein
[0079] a is 3, 4, or 5;
[0080] X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and
X.sub.7 are each independently hydrogen or halogen;
[0081] d is an integer between 1 and 25, inclusive;
[0082] e is an integer of between 2 and 25, inclusive;
[0083] provided the sum of d and e is greater than 16;
[0084] Y is --O--, --S--, --NR.sup.Y, or an optionally substituted
methylene group, wherein R.sup.Y is hydrogen, optionally
substituted aliphatic, or an amino protecting group; [0085] each
instance of R.sup.e is independently --F, --Br, --I, --Cl,
optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.e, --SR.sup.e, --NHR.sup.e, or
--N(R.sup.e).sub.2, wherein each instance of R.sup.e is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.e groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
[0086] each instance of R.sup.d is independently --F, --Br, --I,
--Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.f, --SR.sup.f, NHR.sup.f, or
--N(R.sup.f)2, wherein each instance of R.sup.f is independently
hydrogen, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, or optionally
substituted heteroaryl, or two R.sup.f groups are joined to form a
5- to 6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; [0087] R.sup.z is hydrogen, --F, --Br,
--I, --Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.g, --SR.sup.g, --NHR.sup.g, or
--N(R.sup.g).sub.2, wherein each instance of R.sup.g is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl or two
R.sup.f groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl
ring;
[0088] each instance of n is, independently, 0, 1, 2, 3, or 4;
[0089] each instance of m is, independently, 0, 1, 2, 3, or 4;
and
[0090] x is 1, 2, 3, 4, 5, or 6;
and wherein R.sup.1, .sub.R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.13,
R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.a, and R.sup.b are as
defined herein.
[0091] In certain embodiments, the present invention provides
compounds wherein the sugar portion comprising Rings C, E and F,
and optionally Rings A, B, and D, is derived from moenomycin A. In
certain embodiments, Rings A, B and/or D are enzymatically or
chemically cleaved to provide such compounds. In other embodiments,
intermediate moenomycin-like compounds (e.g., without Rings A, B,
and/or D) are generated from bacteria (e.g., wild type or
genetically engineered bacteria) and further sythetically modified
to provide compounds of the present invention.
[0092] Compounds encompassed by the present invention, e.g.,
compounds of the Formula (II), (III), and (IV), are described in
more detail herein.
Compounds of Formula (II)
[0093] The present invention further provides compounds of Formula
(II), as provided below, which include compounds comprising Rings
B, C, E and F, and optionally Rings A and D, of the moenomycin A
sugar scaffold.
[0094] In one aspect, the present invention provides a compound of
Formula (II):
##STR00015##
or a pharmaceutically acceptable form hereof; [0095] wherein:
[0096] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each
independently hydrogen or an amino protecting group;
[0097] R.sup.5 is hydrogen, an amino protecting group, or the group
(A):
##STR00016##
[0098] R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11
are each independently hydrogen or a hydroxyl protecting group;
[0099] R.sup.12 is hydrogen, a hydroxyl protecting group, or the
group (D):
##STR00017##
wherein R.sup.B, R.sup.14, R.sup.15, and R.sup.16 are each
independently hydrogen or a hydroxyl protecting group;
[0100] R.sup.a and R.sup.b are each independently hydrogen or a
hydroxyl protecting group; and wherein G is a group of Formula (a),
(b), or (c) as defined herein.
[0101] As generally defined above, R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are each independently hydrogen or an amino protecting
group. Amino protecting groups are defined herein, and include, but
are not limited to, --CHO, --C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)SR.sup.A, --C(.dbd.O)N(R.sup.B).sub.2,
--C(.dbd.O)NR.sup.BSO.sub.2R.sup.A, --C(.dbd.NR.sup.B)R.sup.A,
--C(.dbd.NR.sup.B)OR .sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2,
--C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.A).sub.2,
--C(.dbd.S)SR.sup.A, --NH.sub.2, --N(OR.sup.B)R.sup.B,
--N(R.sup.B).sub.2, --NR.sup.BSO.sub.2R.sup.A,
--NR.sup.BC(.dbd.O)R.sup.A, --NR.sup.BCO.sub.2R.sup.A,
--NR.sup.BC(.dbd.O)N(R.sup.B).sub.2,
NR.sup.BC(.dbd.NR.sup.B)N(R.sup.B).sub.2, --OH, --OR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A), --Si(R.sup.A).sub.3, C.sub.1-10 alkyl,
C.sub.1-10 fluoroalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
C.sub.3-10 carbocyclyl, 3-14-membered heterocyclyl, C.sub.6-14
aryl, and 5-14-membered heteroaryl, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.D groups,
wherein R.sup.A, R.sup.B, and R.sup.D are as defined herein.
[0102] In certain embodiments, R.sup.1 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A), or --Si(R.sup.A).sub.3, wherein R.sup.A and R
.sup.B are as defined herein. In certain embodiments, R .sup.1 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.1 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.1 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.1 is
hydrogen. In certain embodiments, R.sup.1 is
--C(.dbd.O)CH.sub.3.
[0103] In certain embodiments, R.sup.2 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, .dbd.SO.sub.2OR.sup.A,
--SO.sub.2N(R.sup.B).sub.2, --S(.dbd.O)R.sup.A), or
--Si(R.sup.A).sub.3, wherein R.sup.A and R.sup.b are as defined
herein. In certain embodiments, R.sup.2 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.Ais as defined herein. In certain
embodiments, R.sup.2 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-10 alkyl. In certain embodiments, R.sup.2 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-6 alkyl.
In certain embodiments, R.sup.2 is hydrogen or --C(.dbd.O)CH.sub.3.
In certain embodiments R.sup.2 is hydrogen. In certain embodiments,
R.sup.2 is --C(.dbd.O).sub.3.
[0104] In certain embodiments, R.sup.3 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR,.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B.sub.2,
--S(.dbd.O)R.sup.A), or --Si(R.sup.A).sub.3, wherein R.sup.Aand
R.sup.B are as defined herein. In certain embodiments, R.sup.3 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.3 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.3 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is
hydrogen or --C(.dbd.C)CH.sub.3. In certain embodiments, R.sup.3 is
hydrogen. In certain embodiments, R.sup.3 is
--C(.dbd.O)CH.sub.3.
[0105] In certain embodiments, R.sup.4 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A), and --Si(R.sub.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein. In certain embodiments, R.sup.4 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.4 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.4 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.4 is
hydrogen. In certain embodiments, R.sup.4 is
--C(.dbd.O)CH.sub.3.
[0106] As defined generally above, R.sup.5 is hydrogen, an amino
protecting group, or the group (A). Amino protecting groups are
defined herein, e.g., --CHO, --C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)SR.sup.A, --C(.dbd.O)N(R.sup.B).sub.2,
--C(.dbd.O)NR.sup.BSO.sub.2R.sup.A, --C(.dbd.NR.sup.B)R.sup.A,
--C(.dbd.NR.sup.B)OR.sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2,
--C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.A).sub.2,
--C(.dbd.S)SR.sup.A, --NH.sub.2, --N(OR.sup.B)R.sup.B,
--N(R).sup.B,.sub.2, --NR.sup.BSO.sub.2R.sup.A,
--NR.sup.BC(.dbd.O)R.sup.A, --NR.sup.BCO.sub.2R.sup.A,
--NR.sup.BC(.dbd.O)N(R.sup.B).sub.2,
--NR.sup.BC(.dbd.NR.sup.B)N(R.sup.B).sub.2, --OH, --OR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A), --Si(R.sup.A).sub.3, C.sub.1-10 alkyl,
C.sub.l-10 fluoroalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14
aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1 2, 3, 4, or 5 R.sup.D groups,
wherein R.sup.A, R.sup.B, and R.sup.D are as defined herein.
[0107] In certain embodiments, R.sup.5 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A), and ----Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein, or the group (A).
[0108] In certain embodiments, R.sup.5 is hydrogen or
--C(.dbd.O)R.sup.A wherein R.sup.A is as defined herein, or the
group (A).
[0109] In certain embodiments, R.sup.5 is hydrogen or the group
(A).
[0110] In certain embodiments, R.sup.5 is hydrogen.
[0111] In certain embodiments, R.sup.5 is the group (A).
[0112] As defined generally above, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, and R.sup.11 are each independently hydrogen or
a hydroxyl protecting group. Hydroxyl protecting groups are defined
herein, and include, but are not limited to, --C(.dbd.O)R.sup.A,
--CO.sub.2R.sup.A, --C(.dbd.O)--O--C(.dbd.O)R.sup.A,
--C(.dbd.O)SR.sup.A, --C(.dbd.O)N(R.sup.B).sub.2,
--C(.dbd.O)NR.sup.BSO.sub.2R.sup.A, --C(.dbd.NR.sup.B)R.sup.A,
--C(.dbd.NR.sup.B)OR,.sup.A --C(.dbd.NR.sup.B)N(R.sup.B).sub.2,
--C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.A).sub.2,
--C(.dbd.S)SR.sup.A, --SO.sub.2R.sup.A, --SO.sub.2OR.sup.A,
--SO.sub.2N(R.sup.B).sub.2, --S(.dbd.O)R.sup.A,
--Si(R.sup.A).sub.3, C.sub.1-10 alkyl, C.sub.1-10 fluoroalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl,
3-14-membered heterocyclyl, C.sub.6-14 aryl, and 5-14-membered
heteroaryl wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.D groups, wherein R.sup.A, R.sup.B,
and R.sup.D are as defined herein.
[0113] In certain embodiments, R.sup.6 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, and --Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein. In certain embodiments, R.sup.6 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.6 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.6 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.6 is
hydrogen. In certain embodiments, R.sup.6 is
--C(.dbd.O)CH.sub.3,
[0114] In certain embodiments, R.sup.7 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2,--C(.dbd.S)SR.sup.A, --SO.sub.2R.sup.A,
--SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2, --S(.dbd.O)R.sup.A,
or --Si(R.sup.A).sub.3, wherein R.sup.A and R.sup.B are as defined
herein. In certain embodiments, is R.sup.7 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is as defined herein. In
certain embodiments, R.sup.7 is hydrogen or --C(.dbd.O)R.sup.A,
wherein R.sup.A is C.sub.1-10 alkyl. In certain embodiments,
R.sup.7 is hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is
C.sub.1-6 alkyl. In certain embodiments, R .sup.7 is hydrogen or
--C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.7 is hydrogen.
In certain embodiments, R.sup.7 is --C(.dbd.O)CH.sub.3.
[0115] In certain embodiments, R.sup.8 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2OR.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, or --Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein. In certain embodiments, R.sup.8 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.8 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.8 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is (C.sub.1-6 alkyl. In certain embodiments, R.sup.8 is
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.8 is
hydrogen. In certain embodiments, R.sup.8 is
--C(.dbd.O)CH.sub.3.
[0116] In certain embodiments, R.sup.9 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A--SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, or --Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein. In certain embodiments, R.sup.9 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.9 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.9 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.9 is
hydrogen or --(.dbd.O)CH.sub.3. In certain embodiments, R.sup.9 is
hydrogen. In certain embodiments, R.sup.9 is
--C(.dbd.O)CH.sub.3.
[0117] In certain embodiments, R.sup.10 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR..sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.8).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, or --Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein. In certain embodiments, R.sup.10 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.10 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.10 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.10 is
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.10
is hydrogen. In certain embodiments, R.sup.10 is
--C(.dbd.O)CH.sub.3.
[0118] In certain embodiments, R.sup.11 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A, --C(.dbd.O)--O--C(.dbd.O)RA,
--C(.dbd.O)SR.sup.A, --C(.dbd.O)N(R.sup.B).sub.2,
--C(.dbd.O)NR.sup.BSO.sub.2R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--or --S(.dbd.O)R.sup.A).sub.3, wherein R.sup.A and R.sup.B are as
defined herein. In certain embodiments, R.sup.11 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is as defined herein. In
certain embodiments, R.sup.11 is hydrogen or --C(.dbd.O)R.sup.A,
wherein R.sup.A is C.sub.1-10 alkyl. In certain embodiments,
R.sup.11 is hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is
C.sub.1-6 alkyl. In certain embodiments, R.sup.11 hydrogen or
--C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.10 is hydrogen.
In certain embodiments, R.sup.11 is --C(.dbd.O)CH.sub.3.
[0119] In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
independently hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as
defined herein.
[0120] In certain embodiments, R.sup.1 and R.sup.2 are each
hydrogen.
[0121] In certain embodiments, R.sup.3 and R.sup.4 are each
--C(.dbd.O)R.sup.A, wherein R.sup.A is as defined herein. In
certain embodiments. R.sup.3 and R.sup.4 are each
--C(.dbd.O)CH.sub.3.
[0122] In certain embodiments, R.sup.6, R.sup.7, R.sup.8, R.sup.9,
R.sup.10 and R.sup.11 are each hydrogen.
[0123] As generally defined above, R.sup.12 is hydrogen, a hydroxyl
protecting group, or the group (D), wherein R.sup.B, R.sup.14,
R.sup.15, and R.sup.16 are each independently hydrogen or a
hydroxyl protecting group. Hydroxyl protecting groups are defined
herein, and include, but are not limited to, --C(.dbd.O)R.sup.A,
--CO.sub.2R.sup.A, --C(.dbd.O)--O--C(.dbd.O)R.sup.A,
--C(.dbd.O)SR.sup.A, --C(.dbd.O)N(R.sup.B).sub.2,
--C(.dbd.O)NR.sup.BSO.sub.2R.sup.A, --C(.dbd.NR.sup.B)R.sup.A,
--C(.dbd.NR.sup.B)OR.sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2,
--C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.A).sub.2,
--C(.dbd.S)SR.sup.A, --SO.sub.2R.sup.A, --SO.sub.2OR.sup.A,
--SO.sub.2N(R.sup.B).sub.2, --S(.dbd.O)R.sup.A,
--Si(R.sup.A).sub.3, C.sub.1-10 alkyl, C.sub.1-10 fluoroalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl,
3-14-membered heterocyclyl, C(,.sub.6-14 aryl, and 5-14 membered
heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.D groups, wherein R.sup.A, R.sup.B,
and R.sup.D are as defined herein.
[0124] In certain embodiments, R.sup.12 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, and --Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein, or the group (D), wherein
R.sup.1-13, R.sup.14, R.sup.15, and R.sup.16 are each independently
--C(.dbd.O)R.sup.A, --CO2R.sup.A, --C(.dbd.O)--O--C(.dbd.O)R.sup.A,
--C(.dbd.O)SR.sup.A, --C(.dbd.O)N(R.sup.B).sub.2,
--C(.dbd.O)NR.sup.BSO.sub.2R.sup.A, --C(.dbd.NR.sup.B)R.sup.A,
--C(.dbd.NR.sup.B)OR.sup.A, --C(.dbd.NR.sup.B)N(R.sup.B).sub.2,
--C(.dbd.S)R.sup.A, --C(.dbd.S)N(R.sup.A).sub.2,
--C(.dbd.S)SR.sup.A, --SO.sub.2R.sup.A, --SO.sub.2OR.sup.A,
--SO.sub.2N(R.sup.B).sub.2, --S(.dbd.O)R.sup.A, or
--Si(R.sup.A).sub.3, wherein R.sup.A and R.sup.B are as defined
herein.
[0125] In certain embodiments, R.sup.12 is hydrogen,
--C(.dbd.O)R.sup.A, or the group (D), wherein .sub.R.sup.B,
R.sup.14, R.sup.15, and R.sup.16 are each independently hydrogen or
--C(.dbd.O)R.sup.A, and wherein R.sup.A is as defined herein.
[0126] In certain embodiments, R.sup.12 is hydrogen,
--C(.dbd.O)CH.sub.3or the group (D), wherein R.sup.B, R.sup.14,
R.sup.15 and R.sup.16 are each independently hydrogen or
--C(.dbd.O)CH.sub.3.
[0127] In certain embodiments, R.sup.12 is hydrogen. In certain
embodiments, R.sup.12 is --C(.dbd.O)CH.sub.3.
[0128] In certain embodiments, R.sup.12 is the group (D), wherein
R.sup.B, R.sup.14, R.sup.15, and R.sup.16 are each independently
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.B,
R.sup.14, R.sup.15, and R.sup.16 are each hydrogen.
[0129] As generally defined above, R.sup.a and R.sup.b are each
independently hydrogen or a hydroxyl protecting group. Hydroxyl
protecting groups are defined herein, and include, but are not
limited to, --C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, --Si(R.sup.A).sub.3, C.sub.1-10 alkyl,
C.sub.1-10 fluoroalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
C.sub.3-10 carbocyclyl, 3-14-membered heterocyclyl, C.sub.6-14
aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.D groups,
wherein R.sup.A, R.sup.B, and R.sup.D are as defined herein.
[0130] In certain embodiments, R.sup.a and R.sup.b are each
independently hydrogen or C.sub.1-10 alkyl. In certain embodiments,
R.sup.a and R.sup.b are each independently hydrogen or C.sub.1-6
alkyl. In certain embodiments, R.sup.a and R.sup.b are each
independently hydrogen or --CH.sub.3. In certain embodiments,
R.sup.a is hydrogen. In certain embodiments, R.sup.b is hydrogen.
In certain embodiments, both R.sup.a and R.sup.b are hydrogen.
[0131] In certain embodiments, R.sup.a, R.sup.b, R.sub.1, R.sup.2,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
hydrogen, and R.sup.3 and R.sup.4 are each --C(.dbd.O)C.sub.3.
[0132] In certain embodiments, R.sup.a, R.sup.b, R.sup.1, R.sup.2,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each
hydrogen, R.sup.3 and R.sup.4 are each --C(.dbd.O)CH.sub.3, R.sup.5
is the group (A), and R.sup.12 is the group (D) wherein R.sup.B,
R.sup.14, R.sup.15, and R.sup.16 are each hydrogen.
[0133] Various sub-genera of Formula (II) are further described
herein. For example, in certain embodiments, the compound of
Formula (II) is a compound of Formula (II-a):
##STR00018##
or a pharmaceutically acceptable form thereof; wherein G, R.sup.5,
and R.sup.12 are as defined herein.
[0134] In certain embodiments the compound of Formula (II) is a
compound of Formula (II-b):
##STR00019##
or a pharmaceutically acceptable form hereof; wherein G is as
defined herein.
Compounds of Formula (III)
[0135] The present invention further provides compounds of Formula
(III), as provided below, which include compounds comprising Rings
C, E and F, and optionally Ring D, of the moenomycin A sugar
scaffold.
[0136] For example, in one aspect, the present invention provides a
compound of Formula (III):
##STR00020##
or a pharmaceutically acceptable form thereof; wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.12,
R.sup.a, and R.sup.b, are as defined above and herein; G is a group
of Formula (a), (b), or (c) as defined above and herein; and
R.sup.17 is hydrogen or a hydroxyl protecting group.
[0137] Hydroxyl protecting groups are defined herein, and include,
but are not limited to, --C(.dbd.O)R.sup.A,--CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2,
--C(.dbd.S)R.sup.A,--C(.dbd.S)N(R.sup.A).sub.2,
--C(.dbd.S)SR.sup.A, SO.sub.2R.sup.A, --SO.sub.2OR.sup.A,
--SO.sub.2N(R.sup.B).sub.2, --S(.dbd.O)R.sup.A,
--Si(R.sup.A).sub.3, C.sub.1-10 alkyl, C.sub.1-10 fluoroalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl,
3-14-membered heterocyclyl, C(.sub.6-14 aryl, and 5-14 membered
heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl
heterocyclyl aryl, and heteroaryl is independently substituted with
0, 1, 2, 3, 4, or 5 R.sup.D groups, wherein R.sup.A, R.sup.B, and
R.sup.D are as defined herein.
[0138] In certain embodiments, R.sup.17 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, or --Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B defined are as de herein. In certain embodiments, R.sup.17
is hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.17 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.17 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.17 is
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.17
is hydrogen. In certain embodiments, R.sup.17 is
--C(.dbd.O)CH.sub.3.
[0139] In certain embodiments R.sup.a, R.sup.b, R.sup.1, R.sup.2,
R.sup.6, R.sup.7, R.sup.8, and R.sup.17 are each hydrogen, and
R.sup.3 and R.sup.4 are each --C(.dbd.O)CH.sub.3.
[0140] In certain embodiments, R.sup.a, R.sup.b, R.sup.1, R.sup.2,
R.sup.6, R.sup.7, R.sup.8, and R.sup.17 are each hydrogen, R.sup.3
and R.sup.4 are each C(.dbd.O)CH.sub.3, and R.sup.12 is the group
(D) wherein R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are each
hydrogen.
[0141] Various sub-genera of Formula (III) are further described
below and herein. For example, in certain embodiments, the compound
of Formula (III) is of Formula (III-a):
##STR00021##
or a pharmaceutically acceptable form thereof; wherein R.sup.12 and
G are as defined herein.
[0142] In yet other embodiments, the compound of the Formula (III)
is of Formula (III-b):
##STR00022##
or a pharmaceutically acceptable form thereof; wherein G is as
defined herein.
Compounds of Formula (IV)
[0143] The present invention further provides compounds of Formula
(IV), as provided below, which include compounds comprising Rings E
and F, and optionally Ring D, of the moenomycin A sugar
scaffold.
[0144] For example, in one aspect, provided is a compound of
Formula (IV):
##STR00023##
or a are as pharmaceutically acceptable form thereof; wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7, R.sup.12, R.sup.a, and
R.sup.b are as defined above and herein; G is a group of Formula
(a), (b), or (c) as defined above and herein; and R.sup.18 is
hydrogen or a hydroxyl protecting group.
[0145] Hydroxyl protecting groups are defined herein, and include,
but are not limited to, --C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A,--SO.sub.2OR.sup.A,
--SO.sub.2N(R.sup.B).sub.2,--S(.dbd.O)R.sup.A, --Si(R.sup.A).sub.3,
C.sub.1-10 alkyl, C.sub.1-10 fluoroalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14-membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.D groups, wherein R.sup.A, R.sup.B, and R.sup.D are
as defined herein.
[0146] In certain embodiments, R .sup.18 is hydrogen,
--C(.dbd.O)R.sup.A, --CO.sub.2R.sup.A,
--C(.dbd.O)--O--C(.dbd.O)R.sup.A, --C(.dbd.O)SR.sup.A,
--C(.dbd.O)N(R.sup.B).sub.2, --C(.dbd.O)NR.sup.BSO.sub.2R.sup.A,
--C(.dbd.NR.sup.B)R.sup.A, --C(.dbd.NR.sup.B)OR.sup.A,
--C(.dbd.NR.sup.B)N(R.sup.B).sub.2, --C(.dbd.S)R.sup.A,
--C(.dbd.S)N(R.sup.A).sub.2, --C(.dbd.S)SR.sup.A,
--SO.sub.2R.sup.A, --SO.sub.2OR.sup.A, --SO.sub.2N(R.sup.B).sub.2,
--S(.dbd.O)R.sup.A, and --Si(R.sup.A).sub.3, wherein R.sup.A and
R.sup.B are as defined herein. In certain embodiments, R.sup.18 is
hydrogen or --C(.dbd.O)R.sup.A, wherein R.sup.A is as defined
herein. In certain embodiments, R.sup.18 is hydrogen or
--C(.dbd.O)R.sup.A, wherein R.sup.A is C.sub.1-10 alkyl. In certain
embodiments, R.sup.18 is hydrogen or --C(.dbd.O)R.sup.A, wherein
R.sup.A is C.sub.1-6 alkyl. In certain embodiments, R.sup.18 is
hydrogen or --C(.dbd.O)CH.sub.3. In certain embodiments, R.sup.18
is hydrogen. In certain embodiments, R.sup.18 is
--C(.dbd.O)CH.sub.3.
[0147] In certain embodiments R.sup.a, R.sup.b, R.sup.1, R.sup.2,
R.sup.6, R.sup.7, and R.sup.18 are each hydrogen, and R.sup.3 is
--C(.dbd.O)CH.sub.3.
[0148] In certain embodiments R.sup.a, R.sup.b, R.sup.1, R.sup.2,
R.sup.6, R.sup.7, and R.sup.18 are each hydrogen, R.sup.3 is
--C(.dbd.O)CH.sub.3, and R.sup.12 is the group (D) wherein
R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are each hydrogen.
[0149] Various sub-genera of Formula, (IV) are further described
herein.
[0150] For example, in certain embodiments, the compound of Formula
(IV) is a compound of Formula (IV-a):
##STR00024##
or a pharmaceutically acceptable form thereof; wherein R.sup.12 and
G are as defined herein.
[0151] In yet other embodiments the compound of Formula (IV) is of
Formula (IV-b):
##STR00025##
or a pharmaceutically acceptable form thereof; wherein G is as
defined herein.
Group G of Formula (a)
[0152] As generally described herein, in certain embodiments,
compounds of Formula (I), (II), (III), and (IV) include a group G
of Formula (a):
##STR00026##
wherein a is 3, 4, or 5.
[0153] For example, in certain embodiments, the group G a group
selected from the group consisting of:
##STR00027##
wherein a is 3;
##STR00028##
wherein a is 4; or
##STR00029##
wherein a is 5,
Group G Formula (b)
[0154] As generally described herein, in certain embodiments,
compounds of Formula (I), (II), (III), and (IV) include a group G
of Formula (b):
##STR00030##
wherein:
[0155] X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, and
X.sub.7 are each independently hydrogen or halogen;
[0156] d is an integer between 1 and 25, inclusive; and
[0157] e is an integer of between 2 and 25, inclusive;
[0158] provided the sum of d and e is greater than 16.
[0159] In certain embodiments, e is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 24, or 25. In
certain embodiments, d is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 24, or 25. Any
particular combination of e or d is contemplated, provided the sum
of d and e is greater than 16.
[0160] For example, in certain embodiments, e is 16 or an integer
greater than 16, and d is 1 or an integer greater than 1. In
certain embodiments, e is 15, and d is 2 or an integer greater than
2. In certain embodiments, e is 14, and d is 3 or an integer
greater than 3. In certain embodiments, e is 13, and d is 4 or an
integer greater than 4. In certain embodiments, e is 12, and d is 5
or an integer greater than 5. In certain embodiments, e is 11, and
d is 6 or an integer greater than 6. In certain embodiments, e is
10, and d is 7 or an integer greater than 7. In certain
embodiments, e is 9, and d is 8 or an integer greater than 8. In
certain embodiments, e is 8, and d is 9 or an integer greater than
9. In certain embodiments, e is 7, and d is 10 or an integer
greater than 10. In certain embodiments, e is 6, and d is 11 or an
integer greater than 11. In certain embodiments, e is 5, and d is
12 or an integer greater than 12. In certain embodiments, e is 4,
and d is 13 or an integer greater than 13. In certain embodiments,
e is 3, and d is 14 or an integer greater than 14. In certain
embodiments, e is 2, and d is 15 or an integer greater than 15.
[0161] In certain embodiments, e is 10, and d is 7 or an integer
greater than 7, e.g., d is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23 24, or 25. In certain embodiments, e is 10
and d is 7. In certain embodiments, e is 10 and d is 8. In certain
embodiments, e is 10 and d is 9. In certain embodiments, e is 10
and d is 10. In certain embodiments, e is 10 and d is 11. In
certain embodiments, e is 10 and d is 12. In certain embodiments, e
is 10 and d is 13. In certain embodiments, e is 10 and d is 14. In
certain embodiments, e is 10 and d is 15.
[0162] In certain embodiments, at least one of X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, X.sub.6, or X.sub.7 is halogen, e.g.,
fluoro. In certain embodiments, at least two of X.sub.1, X.sub.2,
X.sub.3, X.sub.4, X.sub.5, X.sub.6, or X.sub.7 is halogen. In
certain embodiments, at least three of X.sub.1, X.sub.2, X.sub.3,
X.sub.4, X.sub.5, X.sub.6, or X.sub.7 is halogen. In certain
embodiments, at least four of X.sub.1, X.sub.2, X.sub.3, X.sub.4,
X.sub.5, X.sub.6, or X.sub.7 is halogen. In certain embodiments, at
least five of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6,
or X.sub.7 is halogen. In certain embodiments, at least six of
X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, or X.sub.7 is
halogen.
[0163] In certain embodiments, each instance of X.sub.1 and X.sub.2
is hydrogen. In certain embodiments, each instance of X.sub.1 and
X2 is halogen, e.g., fluoro.
[0164] In certain embodiments, each instance of X.sub.3 and X.sub.4
is hydrogen. In certain embodiments, each instance of X.sub.3 and
X.sub.4 is halogen, e.g., fluoro.
[0165] In certain embodiments, each instance of X.sub.5, X.sub.6,
and X.sub.7 is hydrogen. In certain embodiments, each instance of
X.sub.5, X.sub.6, and X.sub.7 is halogen, e.g., fluoro.
[0166] In certain embodiments, each instance of X.sub.1 and X.sub.2
is fluoro, optionally wherein each instance of X.sub.3 and X.sub.4
is fluoro and/or each instance of X.sub.5, X.sub.6, and X.sub.7 is
fluoro. In certain embodiments, X.sub.1 and X.sub.2 are each
fluoro, X.sub.3 and X.sub.4 are each hydrogen, and X.sub.5,
X.sub.6, and X.sub.7 are each hydrogen. In certain embodiments,
X.sub.1 and X.sub.2 are each fluoro, X.sub.3 and X.sub.4 are each
fluoro, and X.sub.5, X.sub.6, and X.sub.7 are each hydrogen. In
certain embodiments, X.sub.1 and X.sub.2 are each fluoro, X.sub.3
and X.sub.4 are each hydrogen, and X.sub.5, X.sub.6, and X.sub.7
are each fluoro. In certain embodiments, X.sub.1 and X.sub.2, are
each fluoro, X.sub.3 and X.sub.4 are each fluoro, and X.sub.5,
X.sub.6, and X.sub.7 are each fluoro.
[0167] Alternatively, in certain embodiments, each instance of
X.sub.3 and X.sub.4 is fluoro, optionally wherein each instance of
X.sub.1 and X.sub.2 is fluoro and/or each instance of X.sub.5,
X.sub.6, and X.sub.7 is fluoro. In certain embodiments, X.sub.3 and
X.sub.4 are each fluoro, X.sub.1 and X.sub.2 are each hydrogen, and
X.sub.5, X.sub.6, and X.sub.7 are each hydrogen. In certain
embodiments, X.sub.3 and X.sub.4 are each fluoro, X.sub.1 and
X.sub.2 are each hydrogen, and X.sub.5, X.sub.6, and X.sub.7 are
each fluoro. In certain embodiments, X.sub.3 and X.sub.4 are each
fluoro, X.sub.1 and X.sub.2 are each fluoro, and X.sub.5, X.sub.6,
and X.sub.7 are each hydrogen. In certain embodiments, X.sub.3 and
X.sub.4 are each fluoro, X.sub.1 and X.sub.2 are each fluoro, and
X.sub.5, X.sub.6, and X.sub.7 are each fluoro.
[0168] Exemplary fluoroalkyl groups of formula (b), wherein X.sub.1
and X.sub.2 are hydrogen and X.sub.3, X.sub.4, X.sub.5, X.sub.6,
and X.sub.7 are each fluoro include, but are not limited to:
##STR00031##
wherein e is 10, and d is 7;
##STR00032##
wherein e is 10, and d is 8;
##STR00033##
wherein e is 10, and d is 9;
##STR00034##
wherein e is 10, and d is 10;
##STR00035##
wherein e is 10, and d is 11;
##STR00036##
wherein e is 10, and d is 12;
##STR00037##
wherein e is 10, and d is 13;
##STR00038##
wherein e is 10, and d 14: and
##STR00039##
wherein e is 10, and d is 15.
[0169] Exemplary fluoroalkyl groups of formula (b), wherein each
instance of X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6,
and X.sub.7 is fluoro, include hut are not limited to:
##STR00040##
wherein e is 10, and d is 7;
##STR00041##
wherein e is 10, and d is 8;
##STR00042##
wherein e is 10, and d is 9;
##STR00043##
wherein e is 10, and d is 10;
##STR00044##
wherein e is 10, and d is 11;
##STR00045##
wherein e is 10, and d is 12;
##STR00046##
wherein e is 10, and d is 13;
##STR00047##
wherein e is 10, and d is 14; and
##STR00048##
wherein c is 10, and d is 15.
Group G of Formula (c)
[0170] As generally described herein, in certain embodiments,
compounds of Formula (I), (II), (III), and (IV) include a group G
of Formula (c):
##STR00049##
wherein: [0171] Y is --O--, --S--, --NR.sup.Y--, or an optionally
substituted methylene group, wherein R.sup.Y is hydrogen,
optionally substituted aliphatic, or an amino protecting group;
[0172] each instance of R.sup.e is independently --F, --Br, --I,
--Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, and --N(R.sup.e).sub.2, wherein each
instance of R.sup.e is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl, or two R.sup.e groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring;
[0173] each instance of R.sup.d is independently --F, --Br, --I,
--Cl, optionally substituted aliphatic, optionally substituted
heteroaliphatic, optionally substituted carbocycyl, optionally
substituted heterocycyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.f, --SR.sup.f, --NHR.sup.f, or
--N(R.sup.f).sub.2, wherein each instance of R.sup.f is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.f groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl
ring;
[0174] R.sup.z is hydrogen, --F, --Br, --I, --Cl, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.g, --SR.sup.g, --NHR.sup.g, or
--N(R.sup.g).sub.2, wherein each instance of R.sup.g is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl or two
R.sup.g groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl
ring;
[0175] each instance of n is, independently, 0, 1, 2, 3, or 4;
[0176] each instance of m is, independently, 0, 1, 2, 3, or 4;
and
[0177] x is 1, 2, 3, 4, 5, or 6.
[0178] As generally defined above, Y --O--, --S--, --NR.sup.Y--, or
an optionally substituted methylene group, wherein R.sup.Y is
hydrogen, optionally substituted aliphatic, or an amino protecting
group. In certain embodiments, Y is --O--. In certain embodiments,
Y is --S--. In certain embodiments, Y is--NR.sup.Y--. In certain
embodiments, Y is an optionally substituted methylene group,
e.g.,--CH.sub.2--.
[0179] As generally defined above, each instance of R.sup.e is
independently --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.e, --SR.sup.e, --NHR.sup.e, or --N(R.sup.e).sub.2, wherein
each instance of R.sup.e is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl, or two
R.sup.e groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl ring;
and n is 0, 1, 2, 3, or 4.
[0180] In certain embodiments, each instance of R.sup.e is
independently --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.e, --SR.sup.e, --NHR.sup.e, or --N(R.sup.e).sub.2, wherein
each instance of R.sup.e is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl, or two R.sup.e groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; wherein each instance of aliphatic,
heteroaliphatic, carbocycyl, heterocycyl, aryl and heteroaryl is
independently unsubstituted or substituted with 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more substituents, as defined herein. In certain
embodiments, each instance of aliphatic, heteroaliphatic,
carbocycyl, heterocycyl, aryl and heteroaryl is independently
unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl or halogen.
[0181] In certain embodiments, each instance of R.sup.e is
independently --F, aliphatic, heteroalphatic, carbocycyl,
heterocycyl, aryl, or heteroaryl, wherein each instance of
aliphatic, heteroaliphatic, carbocycyl, heterocycyl, aryl and
heteroaryl is independently unsubstituted or substituted with
C.sub.1-6alkyl, C.sub.16fluoroalkyl or halogen.
[0182] In certain embodiments, each instance of R.sup.e is
independently --F or alkyl, wherein each instance of alkyl is
independently unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl or halogen.
[0183] In certain embodiments, n is 0 or 1. In certain embodiments,
n is 0. In certain embodiments, n is 1. In certain embodiments, n
is 2.
[0184] As generally defined above, each instance of R.sup.d is
independently --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.f, --SR.sup.f, --NHR.sup.f, or --N(R.sup.f).sub.2, wherein
each instance of R.sup.f is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl, or two R.sup.f groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; and m is 0, 1, 2, 3, or 4.
[0185] In certain embodiments, each instance of R.sup.d is
independently --F, --Br, --I, --Cl, optionally substituted
aliphatic, optionally substituted heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.f, --SR.sup.f, --NHR.sup.f, or --N(R.sup.f).sub.2, wherein
each instance of R.sup.f is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl, or two R.sup.f groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring; wherein each instance of aliphatic,
heteroaliphatic, carbocycyl, heterocycyl, aryl and heteroaryl is
independently unsubstituted or substituted with 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more substituents, as defined herein. In certain
embodiments, each instance of aliphatic, heteroaliphatic,
carbocycyl, heterocycyl, aryl and heteroaryl is independently
unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl or halogen.
[0186] In certain embodiments, each instance of R.sup.d is
independently aliphatic, heteroaliphatic, carbocycyl, heterocycyl,
aryl, or heteroaryl, wherein each instance of aliphatic,
heteroaliphatic, carbocycyl, heterocycyl, aryl, and heteroaryl is
independently unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl or halogen.
[0187] In certain embodiments, each instance of R.sup.d is
independently --F or alkyl, wherein each instance of alkyl is
independently unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl, or halogen.
[0188] In certain embodiments, in is 0 or 1. In certain
embodiments, m is 0. In certain embodiments, m is 1. In certain
embodiments, m is 2.
[0189] In certain embodiments, R.sup.z is an ortho, meta, or para
substituent to the --OCH--.sub.2--linking group. In certain
embodiments, R.sup.z is a meta substituent.
[0190] As generally defined above, R.sup.z is hydrogen, --F, --Br,
--I, --Cl, optionally substituted aliphatic, heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.g, --SR.sup.g, --NHR.sup.g, or
--N(R.sup.g).sub.2, wherein each instance of R.sup.g is
independently hydrogen, optionally substituted aliphatic,
optionally substituted heteroaliphatic, optionally substituted
carbocycyl, optionally substituted heterocycyl, optionally
substituted aryl, or optionally substituted heteroaryl or two
R.sup.g groups are joined to form a 5- to 6-membered optionally
substituted heterocycyl or optionally substituted heteroaryl
ring.
[0191] In certain embodiments, R.sup.z is hydrogen, --F --Br, --I,
--Cl, optionally substituted aliphatic, heteroaliphatic, optionally
substituted carbocycyl, optionally substituted heterocycyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.g, --SR.sup.g, --NHR.sup.g, or --N(R.sup.g).sub.2, wherein
each instance of R.sup.g is independently hydrogen, optionally
substituted aliphatic, optionally substituted heteroaliphatic,
optionally substituted carbocycyl, optionally substituted
heterocycyl, optionally substituted aryl, or optionally substituted
heteroaryl or two R.sup.g groups are joined to form a 5- to
6-membered optionally substituted heterocycyl or optionally
substituted heteroaryl ring, wherein each instance of aliphatic,
heteroaliphatic, carbocycyl, heterocycyl, aryl and heteroaryl is
independently unsubstituted or substituted with 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more substituents, as defined herein. In certain
embodiments, each instance of aliphatic, heteroaliphatic,
carbocycyl, heterocycyl, aryl and heteroaryl is independently
unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl or halogen.
[0192] In certain embodiments, R.sup.z is hydrogen, alkyl, alkenyl,
alkynyl, carbocycyl, heterocycyl, aryl, heteroaryl, --OR.sup.g,
--SR.sup.g, --NHR.sup.g, or --N(R.sup.g).sub.2, wherein each
instance of R.sup.g, is independently hydrogen, alkyl, alkenyl,
alkynyl, carbocycyl, heterocycyl, aryl, heteroaryl, or two R.sup.g
groups are joined to form a 5- to 6-membered heterocycyl or
heteroaryl ring, and wherein each instance of alkyl, alkenyl,
alkynyl, carbocycyl, heterocycyl, aryl, and heteroaryl, is
independently unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl or halogen.
[0193] In certain embodiments, R.sup.z is hydrogen or aryl, wherein
aryl is unsubstituted or substituted with C.sub.1-6alkyl,
C.sub.1-6fluoroalkyl or halogen.
[0194] As generally depicted above, x is 1, 2, 3, 4, 5, or 6. In
certain embodiments, x is 1 or 2. In certain embodiments, x is 1.
In certain embodiments, x is 2.
[0195] It is understood that each repeat unit of formula (c), when
x is greater than 1, can optionally differ from one another,
arising from differences in the independent variables Y, R.sup.c,
R.sup.d, n and m, as well as different substitution patterns on and
between each repeating unit. Thus, in further defining the
compounds of the present invention, it is also generally helpful to
further designate Y, R.sup.c, R.sup.d, n and m, with a sequential
number corresponding to the first, second, third, fourth, fifth or
sixth sequential group from which it is formally a member, e.g., Y,
R.sup.c, R.sup.d, n, m and x can also be referred to as Y.sup.1,
R.sup.c1, R.sup.d1, n1 and m1 for the first group in the sequence;
Y.sup.2, R.sup.c2, R.sup.d2, n2 and m2 for the second optional
repeating unit in the sequence; Y.sup.3, R.sup.c3, R.sup.d3, n3 and
m3 for the third optional repeating unit in the sequence; Y.sup.4
R.sup.c4 R.sup.d4, and n4 and m4 for the fourth optional repeating
unit in the sequence; Y.sup.5, R.sup.c5, R.sup.d5, n5 and m5 for
the fifth optional repeating unit in the sequence; and Y.sup.-, R
n6 and in6 for the sixth optional repeating unit in the
sequence.
[0196] For example, in certain embodiments, the group of Formula
(c) is of the formula:
##STR00050##
wherein x is 1;
##STR00051##
wherein x is 2;
##STR00052##
wherein x is 3;
##STR00053##
wherein is 4;
##STR00054##
wherein x is 5;
##STR00055##
wherein x is 6; [0197] wherein
[0198] R.sup.c1, R.sup.c2, R.sup.c3, R.sup.c4, R.sup.c5, and
R.sup.c6 each independently correspond to the definition and
various embodiments of R.sup.c;
[0199] R.sup.d1, R.sup.d2, R.sup.d3, R.sup.d5, and R.sup.d6 each
independently correspond to the definition and various embodiments
of R.sup.d;
[0200] n1, n2, n3, n4, n5, and n6 each independently correspond to
the definition and various embodiments of n;
[0201] m1, m2, m3, m4, m5, and m6 each independently correspond to
the definition and various embodiments of m;
[0202] Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, and Y.sup.6,
each independently correspond to the definition and various
embodiments of Y; and
[0203] R.sup.z is as defined herein.
[0204] In certain embodiments, the group of Formula (c) is of the
formula:
##STR00056##
wherein Y, R.sup.z, R.sup.c, R.sup.d, m, n, and x are as defined
herein.
[0205] In certain embodiments, the group of Formula (c) is:
##STR00057##
wherein x is 1;
##STR00058##
wherein x is 2;
##STR00059##
wherein x is 3;
##STR00060##
wherein x is 4;
##STR00061##
wherein x is 5;or
##STR00062##
wherein is 6; [0206] wherein:
[0207] R.sup.c1, R.sup.c2, R.sup.c3, R.sup.c4, .sup.c5, and
R.sup.c6 each independently correspond to the definition and
various embodiments of R.sup.c;
[0208] R.sup.d1, R.sup.d2, R.sup.d3, R.sup.d4, R.sup.d5, and
R.sup.d6 each independently correspond to the definition and
various embodiments of R.sup.d;
[0209] n1, n2, n3, n4, n5, and n6 each independently correspond to
the definition and various embodiments of n;
[0210] m1, m2, m3, m4, m5, and m6 each independently correspond to
the definition and various embodiments of m;
[0211] Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5, and Y.sup.6,
each independently correspond to the definition and various
embodiments of Y;
[0212] and R.sup.z is as defined herein.
[0213] In certain embodiments, each of n, n1, n2, n3, n4, n5, and
n6 is 0.
[0214] In certain embodiments, each of m, m1, m2, m3, m4, m5, and
m6 is 0.
[0215] In certain embodiments, each of Y, Y.sup.1, Y.sup.2,
Y.sup.3, Y.sup.4, Y.sup.5, and Y.sup.6 is --O--.
Specifically Contemplated Embodiments
[0216] Compounds of the present invention specifically contemplated
include, but are not limited to, compounds having the following
structure:
##STR00063##
or a pharmaceutically acceptable form thereof; [0217] wherein G is
selected from the group consisting of
##STR00064##
[0217] Pharmaceutical Compositions
[0218] The present invention also provides pharmaceutical
compositions comprising an effective amount of a compound of
Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable
form thereof, and, optionally, a pharmaceutically acceptable
excipient.
[0219] Pharmaceutically acceptable excipients include any and all
solvents, diluents or other liquid vehicles, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired. General
considerations in formulation and/or manufacture of pharmaceutical
compositions agents can be found, for example, in Remington's
Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack
Publishing Co., Easton, Pa., 1980), and Remington: The Science and
Practice of Pharmacy, 21st Edition (Lippincott Williams &
Wilkins, 2005).
[0220] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the compound of
the present invention (the "active ingredient") into association
with a carrier and/or one or more other accessory ingredients, and
then, if necessary and/or desirable, shaping and/or packaging the
product into a desired single- or multidose unit.
[0221] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is discrete
amount of the pharmaceutical composition comprising a predetermined
amount of the active ingredient. The amount of the active
ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a. dosage such as, for example,
one-half or one-third of such a dosage.
[0222] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0223] Pharmaceutically acceptable excipients used in the
manufacture of provided pharmaceutical compositions include inert
diluents, dispersing and/or granulating agents, surface active
agents and/or emulsifiers, disintegrating agents, binding agents,
preservatives, buffering agents, lubricating agents, and/or oils.
Excipients such as cocoa butter and suppository waxes, coloring
agents, coating agents, sweetening, flavoring, and perfuming agents
may also be present in the composition.
[0224] Exemplary diluents include calcium carbonate, sodium
carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate,
calcium hydrogen phosphate, sodium phosphate lactose, sucrose,
cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium chloride, dry starch, cornstarch, powdered sugar,
etc., and combinations thereof.
[0225] Exemplary granulating and/or dispersing agents include
potato starch, corn starch, tapioca starch, sodium starch
glycolate, clays, alginic acid, guar gum, citrus pulp, agar,
bentonite, cellulose and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(Veegum), sodium lauryl sulfate, quaternary ammonium compounds,
etc., and combinations thereof.
[0226] Exemplary surface active agents and/or emulsifiers include
natural emulsifiers (e.g. acacia, agar, alginic acid, sodium
alginate, tragacanth, chondrux, cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and
lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and
Veegum (magnesium aluminum silicate)), long chain amino acid
derivatives, high molecular weight alcohols (e.g. stearyl alcohol,
cetyl alcohol, oleyl alcohol, triacctin monostearate, ethylene
glycol distearate, glyceryl monostearate, and propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g. carboxy
polymethylene, polyacrylic acid, acrylic acid polymer, and
carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene
sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween
60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan
monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan
tristearate (Span 65), glyceryl monooleate, sorbitan monooleate
(Span 80)), polyoxyethylene esters (e.g. polyoxyethylene
monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,
polyethoxylated castor oil, polyoxymethylene stearate, and
Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid
esters (e.g. Cremophor), polyoxyethylene ethers, (e.g.
polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone),
diethylene glycol monolaurate, triethanolamine oleate, sodium
oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate,
sodium lauryl sulfate, Pluronic F-68, Poloxamer P188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, etc. and/or combinations thereof.
[0227] Exemplary binding agents include starch(e.g. cornstarch and
starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose,
dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and
synthetic gums (e.g. acacia, sodium alginate, extract of Irish
moss, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate,
poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and
larch arabogalactan), alginates, polyethylene oxide, polyethylene
glycol, inorganic calcium salts, silicic acid, polymethacrylates,
waxes, water, alcohol, etc., and/or combinations thereof.
[0228] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives.
[0229] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and sodium sulfite.
[0230] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA) and salts and hydrates
thereof (e.g., sodium edetate, disodium edetate, trisodium edetate,
calcium disodium edetate, dipotassium edetate, and the like),
citric acid and salts and hydrates thereof (e.g., citric acid
monohydrate), fumaric acid and salts and hydrates thereof, malic
acid and salts and hydrates thereof, phosphoric acid and salts and
hydrates thereof, and tartaric acid and salts and hydrates thereof.
Exemplary antimicrobial preservatives include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium. chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and thimerosal.
[0231] Exemplary antifungal preservatives include butyl paraben,
methyl paraben, ethyl paraben, propyl paraben, benzoic acid,
hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, and sorbic acid.
[0232] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0233] Exemplary acidic preservatives include vitamin A, vitamin C,
vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic
acid, ascorbic acid, sorbic acid, and phytic acid.
[0234] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115,
Germaben Neolone, Kathon, and Euxyl. In certain embodiments, the
preservative is an anti-oxidant. In other embodiments, the
preservative is a chelating agent.
[0235] Exemplary buffering agents include citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free
water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and
combinations thereof.
[0236] Exemplary lubricating agents include magnesium stearate,
calcium stearate, stearic acid, silica, talc, malt, glyceryl
behanate, hydrogenated vegetable oils, polyethylene glycol, sodium
benzoate, sodium acetate, sodium chloride, leucine, magnesium
lauryl sulfate, sodium lauryl sulfate, etc., and combinations
thereof.
[0237] Exemplary natural oils include almond, apricot kernel,
avocado, babassu, bergamot, black current seed, borage, cade,
camomile, canola, caraway, carnauba, castor, cinnamon, cocoa
butter, coconut, cod liver, coffee, corn, cotton seed, emu,
eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd,
grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui
nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary synthetic oils include, but are not
limited to, butyl stearate, caprylic triglyceride, capric
triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,
isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,
silicone oil, and combinations thereof.
[0238] Liquid dosage forms for oral and parenteral administration
include pharmaceutically acceptable emulsions, microemulsions,
solutions, suspensions, syrups and elixirs. In addition to the
active ingredients, the liquid dosage forms may comprise inert
diluents 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,
dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ,
olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions
can include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents. In
certain embodiments for parenteral administration, the conjugates
of the invention are mixed with solubilizing agents such as
Cremophor, alcohols, oils, modified oils, glycols, polysorbates,
cyclodextrins, polymers, and combinations thereof.
[0239] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0240] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0241] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This can be accomplished by the use of a
liquid suspension of crystalline or amorphous material with 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.
[0242] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
conjugates of this invention with suitable nonirritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active ingredient.
[0243] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active ingredient is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may comprise buffering agents.
[0244] Solid compositions of a similar type can be employed as
fillers in soft and hard filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally comprise opacifying agents and can be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes. Solid compositions of a
similar type can be employed as fillers in soft and hardfilled
gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polethylene glycols and the like.
[0245] The active ingredients can be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active ingredient can be admixed with at least one inert diluent
such as sucrose, lactose or starch. Such dosage forms may comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may comprise
buffering agents. They may optionally comprise opacifying agents
and can be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[0246] Dosage forms for topical and/or transdermal administration
of a compound of this invention may include ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants and/or
patches. Generally, the active ingredient is admixed under sterile
conditions with a pharmaceutically acceptable carrier and/or any
needed preservatives and/or buffers as can be required.
Additionally, the present invention contemplates the use of
transdermal patches, which often have the added advantage of
providing controlled delivery of an active ingredient to the body.
Such dosage forms can be prepared, for example, by dissolving
and/or dispensing the active ingredient in the proper medium.
Alternatively or additionally, the rate can be controlled by either
providing a rate controlling membrane and/or by dispersing the
active ingredient in a polymer matrix and/or gel.
[0247] Suitable devices for use in delivering intradermal
pharmaceutical compositions described herein include short needle
devices such as those described in U.S. Pat. Nos. 4,886,499;
5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496;
and 5,417,662. Intradermal compositions can be administered by
devices which limit the effective penetration length of a needle
into the skin, such as those described in PCT publication WO
99/34850 and functional equivalents thereof. Jet injection devices
which deliver liquid vaccines to the dermis via a liquid jet
injector and/or via a needle which pierces the stratum corneum and
produces a jet which reaches the dermis are suitable. Jet injection
devices are described, for example, in U.S. Pat. Nos. 5,480,381;
5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;
5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627;
5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460;
and PCT publications WO 97/37705 and WO 97/13537. Ballistic
powder/particle delivery devices which use compressed gas to
accelerate vaccine in powder form through the outer layers of the
skin to the dermis are suitable. Alternatively or additionally,
conventional syringes can be used in the classical mantoux method
of intradermal administration.
[0248] Formulations suitable for topical administration include,
but are not limited to, liquid and/or semi liquid preparations such
as liniments, lotions, oil in water and/or water in oil emulsions
such as creams, ointments and/or pastes, and/or solutions and/or
suspensions. Topically-administrable formulations may, for example,
comprise from about 1% to about 10% (w/w) active ingredient,
although the concentration of the active ingredient can be as high
as the solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0249] A pharmaceutical composition of the invention can be
prepared, packaged, and/or sold in a formulation suitable for
pulmonary administration via the buccal cavity. Such a formulation
may comprise dry particles which comprise the active ingredient and
which have a diameter in the range from about 0.5 to about 7
nanometers or from about 1 to about 6 nanometers. Such compositions
are conveniently in the form of dry powders for administration
using a device comprising a dry powder reservoir to which a stream
of propellant can be directed to disperse the powder and/or using a
self propelling solvent/powder dispensing container such as a
device comprising the active ingredient dissolved and/or suspended
in a low-boiling propellant in a sealed container. Such powders
comprise particles wherein at least 98% of the particles by weight
have a diameter greater than 0.5 nanometers and at least 95% of the
particles by number have a diameter less than 7 nanometers.
Alternatively, at least 95% of the particles by weight have a
diameter greater than 1 nanometer and at least 90% of the particles
by number have a diameter less than 6 nanometers. Dry powder
compositions may include a solid fine powder diluent such as sugar
and are conveniently provided in a unit dose form.
[0250] Low boiling propellants generally include liquid propellants
having a boiling point of below 65.degree. F. at atmospheric
pressure. Generally the propellant may constitute 50 to 99.9% (w/w)
of the composition, and the active ingredient may constitute 0.1 to
20% (w/w) of the composition. The propellant may further comprise
additional ingredients such as a liquid non-ionic and/or solid
anionic surfactant and/or a solid diluent (which may have a
particle size of the same order as particles comprising the active
ingredient).
[0251] Pharmaceutical compositions of the invention formulated for
pulmonary delivery may provide the active ingredient in the form of
droplets of a solution and/or suspension. Such formulations can be
prepared, packaged, and/or sold as aqueous and/or dilute alcoholic
solutions and/or suspensions, optionally sterile, comprising the
active ingredient, and may conveniently be administered using any
nebulization and/or atomization device. Such formulations may
further comprise one or more additional ingredients including, but
not limited to, a flavoring agent such as saccharin sodium, a
volatile oil, a buffering agent, a surface active agent, and/or a
preservative such as methylhydroxybenzoate. The droplets provided
by this route of administration may have an average diameter in the
range from about 0.1 to about 200 nanometers.
[0252] Formulations described herein as being useful for pulmonary
delivery are useful for intranasal delivery of a pharmaceutical
composition of the invention. Another formulation suitable for
intranasal administration is a coarse powder comprising the active
ingredient and having an average particle from about 0.2 to 500
micrometers. Such a formulation is administered by rapid inhalation
through the nasal passage from a container of the powder held close
to the nares.
[0253] Formulations for nasal administration may, for example,
comprise from about as little as 0.1% (w/w) and as much as 100%
(w/w) of the active ingredient, and may comprise one or more of the
additional ingredients described herein. A pharmaceutical
composition of the invention can be prepared, packaged, and/or sold
in a formulation for buccal administration. Such formulations may,
for example, be in the form of tablets and/or lozenges made using
conventional methods, and may contain, for example, 0.1 to 20%
(w/w) active ingredient, the balance comprising an orally
dissolvable and/or degradable composition and, optionally, one or
more of the additional ingredients described herein. Alternately,
formulations for buccal administration may comprise a powder and/or
an aerosolized and/or atomized solution and/or suspension
comprising the active ingredient. Such powdered, aerosolized,
and/or aerosolized formulations, when dispersed, may have an
average particle and/or droplet size in the range from about 0.1 to
about 200 nanometers, and may further comprise one or more of the
additional ingredients described herein.
[0254] A pharmaceutical composition of the invention can be
prepared, packaged, and/or sold in a formulation for ophthalmic
administration. Such formulations may, for example, be in the form
of eye drops including, for example, a 0.1/1.0% (w/w) solution
and/or suspension of the active ingredient in an aqueous or oily
liquid carrier. Such drops may further comprise buffering agents,
salts, and/or one or more other of the additional ingredients
described herein. Other opthalmically-administrable formulations
which are useful include those which comprise the active ingredient
in microcrystalline form and/or in a liposomal preparation. Ear
drops and/or eye drops are contemplated as being within the scope
of this invention.
[0255] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
[0256] Still further encompassed by the invention are kits (e.g.,
pharmaceutical packs). The kits provided may comprise an inventive
pharmaceutical composition or compound and a container (e.g., a
vial, ampule, bottle, syringe, and/or dispenser package, or other
suitable container). In some embodiments, provided kits may
optionally further include a second container comprising a
pharmaceutical excipient for dilution or suspension of an inventive
pharmaceutical composition or compound. In some embodiments, the
inventive pharmaceutical composition or compound provided in the
container and the second container are combined to form one unit
dosage form,
[0257] Optionally, a single container may comprise one or more
compartments for containing an inventive pharmaceutical composition
or compound, and/or a pharmaceutically acceptable excipient for
suspension or dilution. In some embodiments, a single container can
be appropriate for modification such that the container may receive
a physical modification so as to allow combination of compartments
and/or components of individual compartments. For example, a foil
or plastic bag may comprise two or more compartments separated by a
perforated seal which can be broken so as to allow combination of
contents of two individual compartments once the signal to break
the seal is generated. A kit may thus comprise such
multi-compartment containers providing an inventive pharmaceutical
composition or compound and one or more pharmaceutically acceptable
excipients.
[0258] Optionally, instructions for use are additionally provided
in such kits of the invention. Such instructions may provide,
generally, for example, instructions for dosage and administration.
In other embodiments, instructions may further provide additional
detail relating to specialized instructions for particular
containers and/or systems for administration. Still further,
instructions may provide specialized instructions for use in
conjunction and/or in combination with an additional therapeutic
agent.
Methods of Use and Treatment
[0259] The present invention also provides methods of treating or
preventing an infection comprising administering to a subject an
effective amount a compound of Formula (I), (II), (III), or (IV),
or a pharmaceutically acceptable form thereof. In certain
embodiments, the infection is a bacterial infection. In certain
embodiments, the bacterial infection is caused by a Gram-positive
bacterium. In certain embodiments, the bacterial infection is
caused by a Gram-negative bacterium.
[0260] The present invention also provides methods of inhibiting
microbial growth, e.g., bacterial, viral, parasitic, or fungal
growth, comprising contacting a microbial organism, e.g., a
bacterium, a virus, a parasite, or a fungus, with an effective
amount of a compound of Formula (I), (II), (III), or (IV), or a
pharmaceutically acceptable form thereof. In certain embodiments,
the method is an in vitro or in situ method. In certain
embodiments, the microbial organism is a bacterium. In certain
embodiments, the bacterium is a Gram-positive bacterium. In certain
embodiments, the bacterium is a Gram-negative bacterium.
[0261] In certain embodiments, the bacterial infection being
treated or prevented is caused by Gram-negative bacteria. Exemplary
Gram-negative bacteria include, but are not limited to, Escherichia
coli, Salmonella (e.g., Salmonella enteritidis, and Salmonella
typhi), Hemophilus influenzae, Klebsiella pneumoniae, Legionella
pneumophila, Pseudomonas aeruginosa, Proteus mirabilis,
Enterobacter cloacae, Serratia marcescens, Helicobacter pylori,
Pseudomonas, Moraxella (e.g., Moraxella catarrhalis), Helicobacter,
Stenotrophomonas, Bdellovibrio, acetic acid bacteria, Legionella,
and Neisseria (e.g., Neisseria gonorrhoeae, Neisseria
meningitidis).
[0262] In certain embodiments, the infection being treated or
prevented is caused by Gram-positive bacteria. Exemplary
Gram-positive bacteria include, but are not limited to,
Streptococci bacteria such as Streptococcus Group A, Streptococcus
Group B, Streptococcus Group G (e.g., Streptococcus anginosus,
Streptococcus pneumoniae), Streptococcus viridans, Streptococcus
pyogenes (e.g., ATCC8668); Staphylococci bacteria such as
Staphylococcus aureaus (e.g., Staphylococcus aureus (e.g.,
ATCC29213), Staphylococcus aureus (e.g., ATCC43300) MSA), and
Staphylococcus saprophyticus; Micrococcus bacteria such as
Micrococcus luteus (e.g., ATCC272); and Enterococcus bacteria such
as Enterococcus faecalis (e.g., ATCC29212) and Enterococcus
faecalis (e.g., ATCC51299).
[0263] In certain embodiments, the bacterial infection being
treated or prevented is caused by vancomycin-resistant bacteria In
certain embodiments, the bacterial infection is caused by
vancomycin-resistant Gram-negative or Gram-positive bacteria. In
certain embodiments, the bacterial infection is caused by
vancomycin-resistant Gram-positive bacteria. In certain
embodiments, the bacterial infection is caused by
vancomycin-resistant Staphylococcus aureus. In certain embodiments,
the bacterial infection is caused by vancomycin-resistant
Gram-positive enterococci (VRE). In certain embodiments, the
bacterial infection is caused by methicillin-resistant bacteria. In
certain embodiments, the bacterial infection is caused by
methicillin-resistant Staphylococcus aureus (MRSA).
[0264] The compounds and pharmaceutical compositions described
herein may be used to treat any infection including, but not
limited to, anthrax, bacterial meningitis, botulism, brucellosis,
campylobacteriosis, cholera, diphtheria, gonorrhea, impetigo,
legionellosis, leprosy (Hansen's disease), leptospirosis,
listeriosis, lyme disease, melioidosis, MRSA infection,
nocardiosis, pertussis (whooping cough), plague, pneumococcal
pneumonia, psittacosis, Q fever, rocky mountain spotted fever
(RMSF), scarlet fever, shigellosis, syphilis, tetanus, trachoma,
tuberculosis, tularemia, typhoid fever, typhus, urinary tract
infection (UTI), skin infections, gastrointestinal infections,
genito-urinary infections, and systemic infections.
[0265] Particularly useful compounds of the present invention
include those with biological activity. In certain embodiments, the
compounds of the invention exhibit antibacterial activity. For
example, the compound may have a mean inhibitory concentration,
with respect to a particular bacteria, of less than 50 .mu.g/mL,
less than 25 .mu.g/mL, less than 5 .mu.g/mL, or less than 1
.mu.g/mL.
[0266] A method for treating an infection is provided comprising
administering an effective amount of an inventive compound, or a
pharmaceutical composition thereof, to a subject in need thereof,
in such amounts and for such time as is necessary to achieve the
desired result.
[0267] The compounds and compositions for use in methods of the
present invention may be administered in such amounts, time, and
route deemed necessary in order to achieve the desired result. The
exact amount required will vary from subject to subject, depending
on the species, age, and general condition of the subject, the
severity of the infection, the particular compound, its mode of
administration, its mode of activity, and the like. The compounds
of the invention are preferably formulated in dosage unit form for
ease of administration and uniformity of dosage. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
subject will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well known in the medical arts.
[0268] In some embodiments, an effective amount of an inventive
compound is delivered to the subject prior to, simultaneously with,
and/or after diagnosis of an infection. In some embodiments, a
therapeutic amount of an inventive composition is delivered to the
subjet prior to, simultaneously with, and/or after onset of
symptoms associated with an infection. In some embodiments, the
amount of inventive compound is sufficient to treat, alleviate,
ameliorate, relieve, delay onset of, inhibit progression of, reduce
severity of, and/or reduce incidence of one or more symptoms or
features associated with the infection.
[0269] The inventive compounds and compositions of the present
invention may be administered by any route. In some embodiments,
the inventive compounds and compositions are administered via a
variety of routes, including oral, intravenous, intramuscular,
intra-arterial, intramedullary, intrathecal, subcutaneous,
intraventricular, transdermal, interdermal, rectal, intravaginal,
intraperitoneal, topical (as by powders, ointments, creams, and/or
drops), mucosal, nasal, bucal, enteral, sublingual; by
intratracheal instillation, bronchial instillation, and/or
inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
Specifically contemplated routes are systemic intravenous
injection, regional administration via blood and/or lymph supply,
and/or direct administration to an affected site. In general the
most appropriate route of administration will depend upon a variety
of factors including the nature of the agent (e.g., its stability
in the environment of the gastrointestinal tract), the condition of
the subject (e.g., whether the subject is able to tolerate oral
administration), etc. At present the oral and/or nasal spray and/or
aerosol route is most commonly used to deliver therapeutic agents
directly to the lungs and/or respiratory system. However, the
invention encompasses the delivery of the inventive pharmaceutical
composition by any appropriate route taking into consideration
likely advances in the sciences of drug delivery.
[0270] The exact amount of a compound required to achieve an
effective amount at a desired site in the subject will vary from
subject to subject, depending on species, age, and general
condition of a subject, severity of the side effects or disorder,
identity of the particular compound(s), mode of administration, and
the like. In certain embodiments of the present invention, an
effective amount of an inventive compound for administration one or
more times a day to a 70 kg adult human may comprise about 0.001
mg/kg to about 100 mg/kg of an inventive compound per unit dosage
form. It will be appreciated that dose ranges as described herein
provide guidance for the administration of inventive pharmaceutical
compositions to an adult. The amount to be administered to, for
example, a child or an adolescent can be determined by a medical
practitioner or person skilled in the art and can be lower or the
same as that administered to an adult.
[0271] In certain embodiments, the compounds of the invention may
be administered at dosage levels sufficient to deliver from about
0.001 mg/kg to about 100 mg/kg, from about 0.01. mg/kg to about 50
mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg
to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from
about 0.1 mg/kg to about 10 mg/kg, and from about 1 mg/kg to about
25 mg/kg, of subject body weight per day, one or more times a day,
to obtain the desired therapeutic effect. The desired dosage may be
delivered three times a day, two times a day, once a day, every
other day, every third day, every week, every two weeks, every
three weeks, or every four weeks. In certain embodiments, the
desired dosage may be delivered using multiple administrations
(e.g., two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, or more administrations).
[0272] It will be also appreciated that an inventive compound or
composition thereof, as described above and herein, can be
administered in combination with one or more additional
therapeutically active agents ("agent"). By "in combination with,"
it is not intended to imply that the compound and agent must be
administered at the same time and/or formulated for delivery
together, although these methods of delivery are within the scope
of the invention. The inventive compound can be administered
concurrently with, prior to, or subsequent to, the administration
an agent. In general, each compound or agent used in combination
will be administered at a dose and/or on a time schedule determined
for that compound or agent.
[0273] In will further be appreciated that the additional
therapeutically active agent utilized in this combination may be
administered together in a single composition or administered
separately in different compositions.
[0274] In general, it is expected that additional therapeutically
active agents utilized in combination be utilized at levels that do
not exceed the levels at which they are utilized individually. In
some embodiments, the levels utilized in combination will be lower
than those utilized individually.
[0275] The particular combination to employ in a regimen will take
into account compatibility of the inventive compound with the
additional therapeutically active agent and/or the desired
therapeutic effect to be achieved.
[0276] It will also be appreciated that the therapy employed may
achieve a desired effect for the same disorder (for example, an
inventive compound may be administered in combination with another
antibacterial agent), and/or they may achieve different effects
(e.g., control of any adverse effects). For example, an agent may
improve the bioavailability, reduce and/or modify the metabolism,
inhibit the excretion, and/or modify the distribution of the
inventive compound within the body of the subject.
[0277] Therapeutically active agents include, but are not limited
to, organic molecules that are drug compounds, peptides, proteins,
carbohydrates, monosaccharides, oligosaccharides, polysaccharides,
nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides
or proteins, small molecules linked to proteins, glycoproteins,
steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides,
oligonucleotides, antisense oligonucleotides, lipids, hormones, and
vitamins. Therapeutically active agents include any substance used
as a medicine for treatment, prevention, delay, reduction or
amelioration of a disease, condition, or disorder, and refers to a
substance that is useful for therapy, including prophylactic and
therapeutic treatment. A therapeutically active agent also includes
a compound that increases the effect or effectiveness of another
compound, for example, by enhancing potency or reducing adverse
effects of the other compound.
[0278] For example, in certain embodiments, an additional
therapeutically active agent is another antibacterial agent.
Exemplary antibacterial agents include, but are not limited to,
aminoglycosides, glycoproteins (e.g. vancomycin, teicoplanin),
penicillins, cephalosporins, carbapenems (e.g., imipenem, cilastin,
ertapenem), chloramphenicol, macrolides (e.g., erythromycin),
lincosamides (e.g., lincomycin, clindamycin), fusidic acid,
tetracyclines, streptogramins, quinolones fluoroquinolones,
ciprofloxacin, levofloxacin), rifampicin, nitrofurans, polymyxins,
daptomycin, sulphonamides, diaminopyrimidines etc.
Methods of Synthesis
[0279] As generally described above, the present invention provides
compounds of Formula (I), (II), (III), and (IV), wherein the sugar
portion comprising Rings E and F, and optionally Rings A, B, C, and
D, is derived from moenomycin A. Thus, in certain embodiments, the
present invention provides methods of synthesis of these compounds
from the natural product moenomycin A. The methods described herein
include the use of synthetic methods (i.e., building up, adding
groups as well as degradative methods (Le., breaking down, removing
groups) to arrive at compounds of the present invention. For
example, Rings A, B, C and/or D of moenomycin A may optionally be
cleaved using one or more degradative steps. The degraded compound
may then be further synthetically modified (e.g., using a
combination of degradative and synthetic steps) to provide a
compound of Formula (I), (II), (III), or (IV).
[0280] In one aspect, the present invention provides a method of
synthesizing a compound of Formula (II) comprising the steps of:
[0281] (i) providing moenomycin A; [0282] (ii) removing the
phosphoglycerate linker and moenocinol chain of moenomycin A, and
optionally Rings A and/or D, to provide a saccharide group of
Formula (II-S1):
##STR00065##
[0282] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are as defined herein; [0283] (iii) reacting (II-S1) with
a phosphitylation agent to provide a H-phosphonate diester of
Formula (II-S2):
##STR00066##
[0283] wherein R.sup.a is as defined herein; and [0284] (iv)
coupling (II-S2) with a compound of Formula (P1):
##STR00067##
[0284] wherein R.sup.b and G are as defined herein, to provide a
compound of Formula (II) or a pharmaceutically acceptable form
thereof.
[0285] In another aspect, the present invention provides a method
of synthesizing a compound of Formula (III) comprising the steps
of: [0286] (i)
[0287] providing moenomycin A; [0288] (ii) removing the
phosphoglycerate linker, moenocinol chain, and Rings A and B
moenomycin A, and optionally Ring D, to provide a saccharide group
of Formula (III-S1):
##STR00068##
[0288] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6,
R.sup.7, R.sup.8, R.sup.17, and R.sup.12 are as defined herein;
[0289] (iii) reacting (III-S1) with a phosphitylation agent to
provide a H-phosphonate diester of the formula (III-S2):
##STR00069##
[0289] wherein R.sup.a is as defined herein; and [0290] (iv)
coupling (III-S2) with a compound of Formula (P1):
##STR00070##
[0290] wherein R.sup.b and G are as defined herein, to provide a
compound of Formula (III), or a pharmaceutically acceptable form
thereof.
[0291] In yet another aspect, the present invention provides a
method of synthesizing a compound of Formula (IV) comprising the
steps of: [0292] (i) providing moenomycin A; [0293] (ii) removing
the phosphoglycerate linker, moenocinol chain, and Rings A, B and C
of moenomycin A, and optionally Ring D, to provide a saccharide
group of Formula (IV-S1):
##STR00071##
[0293] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7,
R.sup.18, and R.sup.12 are as defined herein; [0294] (iii) reacting
(IV-S1) with a phosphitylation agent to provide an H-phosphonate
diester of Formula (IV-S2):
##STR00072##
[0294] wherein R.sup.a is as defined herein; and [0295] (iv)
coupling (IV-S2) with a compound of Formula (P1):
##STR00073##
[0295] wherein R.sup.b and G are as defined herein, to provide a
compound of Formula (IV), or a pharmaceutically acceptable form
thereof.
[0296] In certain embodiments, step (ii) of the any of the above
methods comprises removing the moenocinol chain, followed by
removal of the phosphoglycerate linker.
[0297] In certain embodiments, step (ii) comprises removing the
moenocinol chain using a Lewis acid. Exemplary Lewis acids include,
but are not limited to, AlCl.sub.3, BF.sub.3OEt.sub.3, and
TMSOTf.
[0298] In certain embodiments, step (ii) comprises removing the
phosphoglycerate linker using abuse. In certain embodiments, the
base is an inorganic base. Exemplary inorganic bases include, but
are not limited to, NaOH, KOH, LiOH, Ca(OH).sub.2, Mg(OH).sub.2,
Na.sub.2CO.sub.3, NaHCO.sub.3, K.sub.2CO.sub.3 and KHCO.sub.3.
[0299] Phosphitylation agents are well-known reagents in the art;
see Garegg et al., Chem. Scr. (1985) 25:280-282 and Westerduin et
al., Tel. Lett. (1986) 27:6271-6274, incorporated herein by
reference. Exemplary phosphitylation agents include, but are not
limited to, 2-benzo[d]-1,2-oxaphosphophepin-2,5-dione compounds
(e.g., 2-methoxybenzo[d]-1,3,2-dioxaphosphorin-4-one,
2-chloro-benzo[d]-1,3,2-dioxaphosphorin-4-one,
2-R-benzo[d]-1,3,2-dioxaphosphorin-4-one), and
tris(1,1,1,3,3,3-hexafluoro-2-propyl) phosphite.
[0300] In certain embodiments, step (ii) of any of the above
methods comprises removing Rings A, B, C and/or D of moenomycin A.
In certain embodiments, step (ii) of the above methods comprises
first removing Rings A, B, C and/or D of moenomycin A, followed by
removing the moenocinol chain, followed by removal of the
phosphoglycerate linker. In certain embodiments, the step of
removing Rings A, B, C and/or D comprises one or more enzymatic
degradative reactions. In certain embodiments, the step of removing
Rings A, B, C and/or D comprises a combination of enzymatic
degradative and enzymatic synthetic reactions.
[0301] Examples of enzymatic degradative reactions are well known
in the art; see for example, U.S. Pat. Nos. 5,206,405; 5,260,206;
5,315,038; and 5,506,140, each of which is incorporated herein by
reference. For example, the enzymatic degradative step may be
catalyzed by an enzyme (e.g., lipase, esterase, transferase, etc.).
The enzymatic degradative step may be accomplished using an enzyme,
a cell lysate, a cell, a cell culture, or the like. The cell or
enzyme may be a wild-type or genetically engineered cell or
enzyme.
[0302] Examples of enzymatic synthetic reactions useful in
preparing the inventive compounds are also known in the art; see
for example, WO 2008/021367, incorporated herein by reference. For
example, the enzymatic synthetic step may be catalyzed by an enzyme
(e.g., lipase, esterase, ligase, synthase, transferase, epimerase,
etc.). The enzymatic synthetic step may be accomplished using an
enzyme, using a cell lysate, using a cell, using a cell culture, or
the like. The cell or enzyme may be a wild-type or genetically
engineered cell or enzyme.
[0303] In certain embodiments, step (iv) of any of the above
methods comprises coupling a H-phosphonate diester with a compound
of the formula (P1). In certain embodiments, the method comprises
use of a coupling agent used in H-phosphate chemistry; e.g., see
Stawinski, In Handbook of Organophosphorus Chemistry, R. Engel
(Ed.), pp. 377-434, Marcel Dekker, New York (1992), and Kraszewski
and Stawinski, Trends Org. Chem. (2003) 10:1, incorporated herein
by reference. Exemplary coupling reagents include, but are not
limited to, adamantanecarbonyl chloride and
1,3-dimethyl-2-chloro-imidazolinium chloride (DMCI).
EXAMPLES
[0304] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
Synthetic Methods
Preparation of 2,5-Di--O--Alkyl-D-Mannitol
[0305] To a stirred suspension of 60% NaH (3 equiv.), washed twice
with petroleum ether, in anhydrous DMF (8 mL/mmol-starting material
(SM)) was added 1,3:4,6-di-O,O-(4-methoxybenzylidene)-D-mannitol (1
equiv., SM) at room temperature. After being stirred for 30 min,
the mixture was treated with a 1.2 M solution of alkylating
reagents (2.4 equiv., Br, Cl, and methane-or p-toluene-sulfonate
for R=ally, benzyl, and n-alkyl groups, respectively) in anhydrous
DMF and a catalytic amount of tetrabutylammonium iodide for
allyl-Br, bromide for benzyl-Cl, or 15-Crown-5for n-alkyl
sulfonates. The resulting mixture was stirred for 18 h at rt for
allyl-Br and benzyl-Cl or 70.degree. C. for n-alkyl sulfonates, and
then poured into sat. aq. NH.sub.4Cl (8 mL/mmol-SM). The immiscible
mixture was extracted twice with Et.sub.2O and the combined organic
phases were washed with water, brine, dried over MgSO.sub.4, and
then concentrated in vacuo. The crude ether was used for the next
reaction without further purification.
[0306] For allyl and benzyl derivatives, a stirred solution of the
residue in THF-H.sub.2O(4:1, 8 mL/mmol-SM) was treated with AcOH
(170 equiv.) at room temperature. After being stirred at 55.degree.
C. for 2 d, the mixture was cooled to 0.degree. C. and basified
with 4M aq. K.sub.2CO.sub.3 (90 equiv.). The immiscible mixture was
extracted twice with CHCl.sub.3 and the combined organic phases
were washed with brine, dried over MgSO.sub.4, and then
concentrated in vacuo. The residue was purified by silica gel
chromatography (petroleum ether:EtOAc=1:3 to 0:1) to give
2,5-di-O-allyl or benzyl-D-mannitol.
[0307] For n-alkyl derivatives, a stirred solution of the residue
in EtOH (12 mL/mmol-SM) was treated with 3 M aq. HCl (12 equiv.) at
room temperature. After being stirred at 70.degree. C. for 3 h, the
mixture was cooled to room temperature and basified with 4 M aq.
K.sub.2CO.sub.3 (16 equiv.). The immiscible mixture was extracted
twice with CHCl.sub.3 and the combined organic phases were washed
with brine, dried over MgSO.sub.4, and then concentrated in vacuo.
The residue was purified by recrystallization from Et.sub.2O/EtOAc
to give 2,5-di-O-n-alkyl-D-mannitol.
Preparation of Methyl 2-O-Alkyl-D-Glycerate
[0308] To a 5.5 M solution of 2,5-di-O-alkyl-D-mannitol (1 equiv.,
SM) in THF-H.sub.2O (9:1) was added NaIO.sub.4 (1.2 equiv.) at room
temperature and the mixture was stirred at 50.degree. C. for 1 h.
The resulting inorganic salt was removed by filtration through a
pad of silica gel and washed with EtOAc. The filtrate was
concentrated in vacuo and the crude aldehyde was used for the next
reaction.
[0309] To a stirred solution of the residue in t-BuOH (20
mL/mmol-SM) were added 2-methyl-2-butene (100 equiv.) and a
solution of 80% NaClO.sub.2 (12 equiv.) and
NaH.sub.2PO.sub.4.H.sub.2O (10 equiv.) in H.sub.2O (8 mL/mmol-SM)
at 0.degree. C. successively. The resulting yellow mixture was
allowed to warm to room temperature for 6 h, during which it turned
into clear. Then, the mixture was cooled to 0.degree. C. again and
treated with 2.5 M aq. Na.sub.2SO.sub.3 (25 equiv.) to reduce an
excess of NaClO.sub.2. The mixture was acidified with 10% aq.
citric acid (10 mL/mmol-SM) and extracted twice with CHCl.sub.3 and
the combined organic phases were washed with brine, dried over
MgSO.sub.4, and then concentrated in vacuo. The crude acid was used
for the next reaction without further purification.
[0310] To a stirred solution of the residue in anhydrous THF-MeOH
(1:1, 10 mL/mmol-SM) was treated with 2 M TMSCHN.sub.2 solution in
hexanes (3.2 equiv.) at 0.degree. C. After being stirred for 10
min, the resulting yellow mixture was decolorized by an addition of
AcOH (3.2 equiv.) to consume an excess of TMSCHN.sub.2. The mixture
was concentrated in vacuo and the residue was purified by silica
gel chromatography (petroleum ether:EtOAc=4:1 to 3:2) to give
methyl 2-O-alkyl-D-glycerate.
Preparation Methyl 2--O-Fluoroalkyl-D-Glycerate
[0311] To a stirred 0.9 M solution of methyl
2-O-(9-decenyl)-D-glycerate (1 equiv., SM), prepared from
1,3:4,6-di-O,O-(4-methoxybenzylidene)-D-mannitol and 9-decenyl
p-toluenesulfonate in the above-mentioned 5 steps, in hexane were
added perfluorooctyl iodide (1.2 equiv.)and 1 M Et.sub.3B solution
in hexanes (0.2 equiv.) at room temperature under air. The reaction
mixture was stirred at the same temperature for 1.5 h, then
perfluorooctyl iodide (0.3 equiv.) and 1 M Et.sub.3B solution in
hexanes (0.1 equiv.) were added again. After being stirred for 30
min, the solution was diluted with Et.sub.2O and poured into a
mixture of sat. aq. NaHCO.sub.3 and 10% aq.
Na.sub.2S.sub.2O.sub.3.5H.sub.2 O. The mixture was extracted twice
with Et.sub.2O and the combined organic phases were washed with
brine, dried over MgSO.sub.4, and then concentrated in vacuo. The
crude iodide was used for the next reaction without further
purification.
[0312] To a solution of the residue in MeOH (10 mL/mmol-SM) were
added NaHCO.sub.3 (1.5 equiv.) and 10% Pd/C (mg/mg-SM), The
resulting mixture was stirred at room temperature for 13 h under
H.sub.2 atmosphere (1 atm). Pd/C was removed by filtration through
a pad of Celite and washed with EtOAc. The filtrate was
concentrated in vacuo and the residue was purified by silica gel
chromatography (petroleum ether:EtOAc=3:1 to 7:3) to give methyl
2-O-fluoroalkyl-D-glycerate.
Preparation of 0.2 M Phosphoramidite Solution
[0313] To a 0.2 M solution of methyl 2-O-alkyl-D-glycerate (1
equiv.) in anhydrous CH.sub.3CN were added
N,N-diisopropylethylamine (1.5 equiv.) and CIP(OCE)Ni--Pr.sub.2
(1.2 equiv.) at room temperature successively. The reaction mixture
was stirred for 1 h and directly used for the next coupling
reaction.
Preparation of Nonaacetyl Moenomycin A Pentasaccharide
Phosphate
[0314] To a mixture of nonaacetyl moenomycin A pentasaccharide
lactol (1 equiv., SM), azeotropically dried from toluene, and
flame-dried MS-3A (2.8 g/mmol-SM) was added 0.34 M 1H-tetrazole
solution in CH.sub.3CN (6 equiv.) at room temperature. After being
stirred for 15 min to remove a trace amount of water, the
suspension was cooled to 0.degree. C. and treated with 0.2 M
phosphoramidite solution in CH.sub.3CN (2 equiv.). The reaction
mixture was allowed to warm to room temperature for 1 h, cooled to
0.degree. C. again, and then treated with 5.5 M t-BuO.sub.2H
solution in decane (12 equiv.) to oxidize the resulting phosphite
intermediate into the corresponding phosphate. After being stirred
below 10.degree. C. for 1 h, the mixture was treated with
P(OMe).sub.3 (12 equiv.) to reduce an excess of t-BuO.sub.2H. Then,
MS-3A was removed by filtration through a pad of Celite and washed
with MeOH. The filtrate was concentrated in vacuo and the residue
was roughly purified by silica gel chromatography (EtOAc:MeOH
containing 0.5% AcOH , 7:1 to 4:1) to give nonaacetyl moenomycin A
pentasaccharide phosphate.
Moenomycin A Lipid Analogues, Ammonium Salt
[0315] To a stirred 6 mM solution of nonaacetyl moenomycin A
pentasaccharide phosphate (1 equiv.) in THF-MeOH--H.sub.2O (3:1:1)
was added 1 M aq. LiOH.H.sub.2O (12 equiv.) at 0.degree. C. The
reaction mixture was allowed to warm to room temperature for 2.5 h,
and then neutralized with DOWEX 50W.times.2-100 (NH.sub.4 form, 120
equiv.). The resin was removed by filtration with sintered glass
funnel and washed with MeOH. The filtrate was concentrated in vacuo
and the residue was purified by reversed-phase HPLC (Agilent
Technologies 1200 series HPLC instrument (flow-rate:1.5 mL/min)
using a Phenamenex Luna 5 mm C18 column (250.times.10.0 mm)) to
give moenomycin A lipid analogues as a white solid.
##STR00074##
[0316]
N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl--
(1.fwdarw.4).beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido-2-deoxy-.bet-
a.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O--{[R)-2-carboxy-2-((2Z-
,6E,10E)-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraen-1-yloxy)ethoxy]h-
ydroxyphosphoryl}-4-C-methyl-.alpha.-D-glucopyranuronamide,
Ammonium salt (1b)
[0317] Retention time: 28.9 min (1.5 mL/min, gradient 0-60%
CH.sub.3CN/0.1 wt % aq.NH.sub.4HCO.sub.3 over 30 min). .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 5.95 (m, 1H), 5.40 (t, J=6.4Hz, 1H),
5.12-5.08 (m, 4H), 4.55-4.40 (m, 5 H), 4.30-4.11 (m, 8 H),
3.92-3.90 (m, 2H), 3.77-3.43 (m, 14 H), 3.36-3.22 (m, 2H), 2.54 (s,
4H), 2.10-1.94 (m, 18H), 1.77 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H),
1.59 (2s, 6H), 1.43 (d, J=5.9Hz, 3H), 1.24 (s, 3H). .sup.13C NMR
(125 MHz, D.sub.2O): .delta. 199.8, 174.7, 174.3, 172.7, 169.9,
158.3, 142.4, 135.8, 135.0, 131.3 124.6, 124.5, 124.0, 120.7,
110.6, 103.3, 103.1, 102.4, 101.4, 94.6, 83.0, 79.5, 77.7, 76.4,
76.3, 76.0, 74.9, 73.7, 73.2, 73.1, 72.6, 72.4, 72.2, 71.4, 70.7,
69.9, 69.2, 68,6, 66.7, 61.0, 55.9, 55.2, 39.7, 32.0, 30.3, 29.8,
26.7, 26.6, 25.6, 23.4, 22.7, 17.5, 17.0, 15.9, 15.8, 15.2.
.sup.31P NMR (162 MHz, CD.sub.3OD): .delta. -1.52. HRMS (ESI) calcd
for C.sub.64H.sub.99N.sub.5O.sub.34P) [M-NH.sub.4].sup.+ 1512.5915,
found 1512.5899.
##STR00075##
[0318]
N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide-]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl-
-(1.fwdarw.4)[.beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido-2-deoxy-.b-
eta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O--{[(R)-2-carboxy-2-(-
(2Z,6E)-3,7,11-trimethyl-dodeca-2,6,10-trien-1-yloxy)ethoxy]hydroxyphospho-
ryl}-4-C-methyl-.alpha.-D-glucopyranuronamide, Ammonium salt (1c).
Retention time: 28.6 min (1.5 mL/min, gradient 0-45% CH.sub.3CN/0.1
wt % aq. NH.sub.4HCO.sub.3 over 30 min). .sup.1H NMR (400 MHz,
D.sub.2O): .delta. 5.79 (m,1H), 5.42 (m, 1H), 5.16 (m, 2 H), 5.03
(d, J=10.2Hz, 1H), 4.65-4.44 (m, 5H), 4.32-4.11 (m, 8H), 3.95-3.48
(m, 16H), 3.43-3.29 (m, 2H), 2.45 (s, 4H), 2.15-2.02 (m, 14H), 1.78
(s, 3H), 1.69 (s, 3H), 1.62 (2s, 6H) 1.41 (d, J=5.5Hz, 3H), 1.23
(s, 3H). .sup.13C NMR (125 MHz, D.sub.2O): .delta. 199.8, 175.4,
174.7, 174.4, 172.9, 169.9, 158.3, 143.6, 137.0, 133.5, 124.6,
124.1, 120.3, 110.6, 103.3, 103.0, 102.4, 101.4, 94.6, 83.3, 79.9,
78.1, 76.6, 76.2. 76.0, 75.1, 74.9, 73.7, 73.31, 73.26, 73.0, 72.6,
72.4, 72.2, 71.4, 70.8, 69.9, 69.1, 68.8, 66.7, 66.5, 60.9, 55.9,
55.2, 39.0, 31.5, 30.2, 26.1, 26.0, 25.1, 23.0, 22.6, 22.5, 17.3,
16.9, 15.5, 14.9. .sup.31P NMR (162 MHz, D.sub.2O): .delta. -1.08.
HRMS (ESI) calcd for C.sub.59H.sub.91N.sub.5O.sub.34P
[M-NH.sub.4].sup.+ 1444.5289, found 1444.5257.
##STR00076##
[0319] N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D
galactopyranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluo-
pyranosyl-(1.fwdarw.4)-[.beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido--
2-deoxy-(.beta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O--{[(R)-2--
carboxy-2-(eicosan-1-yloxy)ethoxy]hydroxyphosphoryl}-4-C-methyl-.alpha.-D--
glucopyranuronamide, Ammonium salt (1d). Retention time: 27.8 min
(1.5 mL/min, gradient 0-80% CH.sub.3CN/0.1 wt % aq.
NH.sub.4HCO.sub.3 over 30 min). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 5.95 (m, 1H), 5.10 (d, =10.2Hz, 1H), 4.55-4.04 (m, 13H),
3.93-3.90 (m, 2H), 3.75-3.24 (m, 16H), 2.54 (s, 4H), 2.05 (s, 3H),
2.03 (s, 3H), 1.64-1.62 (m, 2H), 1.43 (d, J=6.2Hz, 3H), 1.41-1.28
(m, 34H), 1.24 (s, 3H), 0.89 (t, J=6,8Hz, 3H). .sup.13C NMR (125
MHz, D.sub.2O): .delta. 199.6, 174.6, 174.4, 172.6, 169.8, 158.3,
110.7, 103.2, 103.1, 102.5, 101.4, 94.7, 82.9, 79,5, 79,1, 76.3,
76.1, 75.0, 73.6, 73.2, 72.4, 72.3, 71.3, 70.7, 69.9, 69.2, 68.5,
66.5, 61.0, 55.9, 55.2, 32.2, 30.1, 30.0, 29.7, 29.3, 26.0, 22.9,
22.7, 17.1, 15.3, 14.2. .sup.31P NMR (162 MHz, CD.sub.3OD): .delta.
-1.30. HRMS (ESI) calcd for C.sub.64H.sub.107N.sub.5O.sub.34P
[M-NH.sub.4].sup.+ 1520.6541, found 1520.5525.
##STR00077##
[0320]
N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl--
(1.fwdarw.4)-[.beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido-2-deoxy-.b-
eta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O-{[(R)-2-carboxy-2-(o-
ctadecan-1-yloxy)ethoxy]hydroxyphosphoryl}-4-C-methyl-.alpha.-D-glucopyran-
uronamide, Ammonium salt (1e). Retention time: 28.8 min (1.5
mL/min, gradient 0-70% CH.sub.3CN/0.1 wt % aq. NH.sub.4HCO.sub.3
over 30 min). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 5.99 (m
1H), 5.09 (d, J=10.2 Hz, 1H), 4.55-4.12 (m, 13H), 3.92-3.89 (m,
2H), 3.80-3.23 (m, 16H), 2.54 (s, 4H), 2.05 (s, 3H), 2.00 (s, 3H),
1.65-1.60 (m, 2H), 1.43 (d, J=5.9Hz, 3H), 1.38-1.28 (m, 30H), 1.24
(s, 3H), 0.89 (t, J=6.8 Hz, 3H). .sup.13C NMR (125 MHz, D.sub.2O):
.delta. 200.0, 174.9, 174.7, 174.4, 172.6, 169.8, 158.3, 110.5,
103.2, 103.1, 102.5, 101.4, 94.7, 83.1, 79.4, 79.2, 76.3, 76.1,
74.9, 73.7, 73.2, 72.4, 72.2, 71.4, 71.2, 70.7, 69.9, 69.2, 68.5,
66.5, 61.0, 55.9, 55.1, 32.2, 30.4, 30.1, 30.0, 29.7, 29.3, 25.9,
22.9, 22.7, 17.0, 15.2, 14.2, .sup.31P NMR (162 MHz, CD.sub.3OD):
.delta. -1.45. HRMS (ESI) calcd for
C.sub.62H.sub.103N.sub.5O.sub.34P[M-NH.sub.4].sup.+ 1492.6228,
found 1492.5222.
##STR00078##
[0321]
N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl--
(1.fwdarw.4)-[.beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido-2-deoxy-.b-
eta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O--{[(R)-2-carboxy-2-(-
11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,18-heptadecafluoro-octadec-
an-1-yloxy)ethoxy]hydroxyphosphoryl}-4-C-methyl-.alpha.-D-glucopyranuronam-
ide, Ammonium salt (1f). Retention time: 32.3 min (1.5 mL/min,
gradient 0-70% CH.sub.3CN/0.1 wt % aq. NH.sub.4HCO.sub.3 over 35
min). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 5.87 (dd, J=6.0,
3.5 Hz, 1H), 5.06 (d, J=10.6 Hz, 1H), 4.56-4.45 (m, 5H), 4,28-4.06
(m, 8H), 3.92-3.90 (m, 2H), 3.77-3.22 (m, 16H), 2.39 (s, 4H),
2.19-2.05 (m, 2H), 2.03 (s, 3H), 2.01 (s, 3H), 1.66-1.55 (m, 4H),
1.42 (d, J=5.9Hz, 3H), 1.32-1.28 (m, 12H), 1.24 (s, 3H). .sup.19F
NMR (376 MHz, D.sub.2O): .delta. -83.2 (3F), -115.8 (2F), -123.2
(2F), -123.5 (4F), -124.4 (2F), -124.9 (2F), -128.1 (2F). .sup.31P
NMR (162 MHz, CD.sub.3OD): .delta. -1.06. HRMS (ESI) calcd for
C.sub.62H.sub.86 F.sub.17N.sub.5O.sub.34P [M-NH.sub.4].sup.+
1798.4626, found 1798.4622.
##STR00079##
[0322]
N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl--
(1.fwdarw.4)-[.beta.-D-glucopyranosyl-(1.fwdarw.6)
]-2-acetamido-2-deoxy-.beta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-
-1-O--{[(R)-2-carboxy-2-(hexadecan-1-yloxy)ethoxy]hydroxyphosphoryl}-4-C-m-
ethyl-.alpha.-D-glucopyranuronamide, Ammonium salt (1g). Retention
time: 30.2 min (1.5 mL/min, gradient 0-60% CH.sub.3CN/0.1 wt % aq.
NH.sub.4HCO.sub.3 over 30 min). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 5.97 (m, 1H), 5.09 (d, J=10.6 Hz, 1H), 4.53-4.12 (m, 13H),
3.92-3.89 (m, 2H), 3.77-3.24 (m, 16H), 2.54 (s, 4H), 2.05 (s, 3H),
2.00 (s, 3H), 1.63-1.62 (m, 2H), 1.43 (d, J=6.2 Hz, 3H), 1.40-1.28
(m, 26H), 1.24 (s, 3H), 0.89 (t, J=6.8 Hz, 3H). .sup.13C NMR (125
MHz, D.sub.2O): .delta. 199.7, 175.0, 174.6, 174.4, 172.6, 169.8,
158.3, 110.6, 103.2, 103.1, 102.5, 101.4, 94.7, 83.0, 79.5, 79.3,
76.4, 76.3, 76.1, 75.0, 73.7, 73.2, 73.1, 72.5, 72.4, 72.2, 71.4,
71.2, 70.7, 69.8, 69.2, 68.5, 66.5, 60.9, 55.9, 55.2, 32.1, 30.3,
30.0, 29.9, 29.6, 29.2, 25.9, 22.8, 22.7, 17.0, 15.2, 14.2..sup.31P
NMR (162 MHz, CD.sub.3OD): .delta. -1.54. HRMS (ESI) calcd for
C.sub.60 H.sub.99N.sub.5O.sub.34P [M-NH.sub.4].sup.+ 1464.5915,
found 1464.5903.
##STR00080##
[0323]
N.sub.l-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl--
(1.fwdarw.4)-[.beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido-2-deoxy-.b-
eta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O--{[(R)-2-carboxy-2-(-
3-((3'-([1,1'-biphenyl]-3-ylmethoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenylme-
than-1-yloxy)ethoxy]hydroxyphosphoryl}-4-C-methyl-.alpha.-D-glucopyranuron-
amide, Ammonium salt (1h). Retention time: 33.3 min (1.5 mL/min,
gradient 0-60% CH.sub.3CN/0.1 wt % aq. NH.sub.4HCO.sub.3 over 35
min). .sup.1H NMR (400 MHz, D.sub.2O): .delta. 7.31-6.29 (m, 21H),
5.79 (m, 1H), 5.04 (m, 1H), 4.80-3.32 (m, 35H), 2.36 (s, 4H), 2.07
(s, 3H), 2.05 (s, 3H), 1.39 (m , 3H), 1.23 (s, 3H). .sup.13C NMR
(125 MHz, D.sub.2O): .delta. 200.2, 174.6, 174.4, 172.5, 169.8,
158.7, 158.3, 156.0, 141.7, 140.6, 140.2, 139.9, 137.5, 137.3,
130.1129.4, 128.7, 126.6, 125.8, 121.4, 119.6, 113.7, 113.3, 113.0,
112.3, 110.4, 103.2, 103.0, 102.4, 101.4, 94.5, 83.1, 79.4, 78.7,
76.2, 76.0, 74.9, 73.6, 73.2, 72.3, 72.2, 71.3, 70.7, 69.8, 69.1,
68.5, 66.7, 60.9, 55.8, 55.1, 30.4, 22.7, 17.0, 15.2. .sup.31P NMR
(162 MHz, D.sub.2O): .delta. -1.07. HRMS (ESI) calcd for
C.sub.77H.sub.93N.sub.5O.sub.36P [M-NH.sub.4].sup.30 1694.5343,
found 1694.5324.
##STR00081##
[0324]
N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl--
(1.fwdarw.4)-[.beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido-2-deoxy-.b-
eta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O--{[(R)-2-carboxy-2-(-
3-((3'-(benzyloxy)-[1,1'-biphenyl]-3-yl)methoxy)phenylmethan-1-yloxy)ethox-
y]hydroxyphosphoryl}-4-C-methyl-.alpha.-D-glucopyranuronamide,
Ammonium salt (1i). Retention time: 27.8 min (1.5 mL/min, gradient
0-60% CH.sub.3CN/0.1 wt % aq. NH.sub.4HCO.sub.3 over 30 min).
.sup.1H NMR (400 MHz, (CD.sub.3OD): .delta. 7.62-7.19 (m, 14H),
7.02-6.96 (m, 3H), 5.90 (dd, J=6.2, 3.3 Hz, 1H), 5.17 (s, 2H), 5.14
(s, 2H), 5.07 (d, J=10.6 Hz, 1H), 4.87-4.09 (m, 13H), 3.91-3.88 (m,
2H), 3.73-3.21 (m, 16H), 2.35 (s, 4H), 2.01 (s, 3H), 1.99 (s, 3H),
1.36 (d, J=6.2 Hz, 3H), 1.24 (s, 3H). .sup.13C NMR (125 MHz,
D.sub.2O): .delta. 200.5, 175.0, 174.6, 174.4, 172.5, 169.9, 158.7,
158.3, 156.1, 141.7, 140.3, 137.6, 136.6, 130.2, 129.4, 128.5,
127.9, 127.4, 126.6, 126.4, 125.9, 125.5, 121.4, 119.7, 113.6,
112.5, 110.3, 103.2, 103.1, 102.4, 101.4, 94.5, 83.2, 79.5, 78.9,
76.4, 76.2, 76.0, 75.0, 74.9, 73.7, 73.2, 73.1, 72.5, 72.4, 72.2,
71.3, 70.8, 69.8, 69.6, 69.1, 68.5, 67.1, 66.8, 60.9, 55.8, 55.2,
30.4, 30.2, 16.9, 15.1. .sup.31P NMR (162 MHz,CD.sub.3OD): .delta.
-0.98. HRMS (ESI) calcd for C.sub.71H.sub.89N.sub.5O.sub.36P
[M-NH.sub.4].sup.+ 1618.5030, found 1618.5003.
##STR00082##
[0325]
N.sub.1-[(2-Hydroxy-5-oxo-cyclopenten-1-yl)-(5S)-.beta.-D-galactopy-
ranuronamide]-(1.fwdarw.4)-2-acetamide-2,6-dideoxy-.beta.-D-gluopyranosyl--
(1.fwdarw.4)[.beta.-D-glucopyranosyl-(1.fwdarw.6)]-2-acetamido-2-deoxy-.be-
ta.-D-glucopyranosyl)-(1.fwdarw.2)-3-O-carbamoyl-1-O--{[(R)-2-carboxy-2-(3-
-((3'-methyl-{1,'-biphenyl]-3-yl)methoxy)phenylmethan-1-yloxy)ethoxy]hydro-
xyphosphoryl}-4-C-methyl-.alpha.-D-glucopyranuronamide, Ammonium
salt (1j). Retention time: 28.1 min (1.5 mL/min, gradient 0-50%
CH.sub.3CN/0.1 wt % aq. NH.sub.4HCO.sub.3 over 30 min).
Example 1
[0326] A 96 well plate with 100 .mu.L test medium in all wells was
prepared by handheld multipipettor. A stock solution of the
antibiotic or compound in DMSO (0.05.about.10 mg/mL, 5 .mu.L) and
the same medium (95 .mu.L) were put together into column one, where
the compound concentration doubled the highest one to be tested.
Two columns were necessary for each compound to check the
reproducibility. The compound was diluted by adding 100 .mu.L from
column one to column two with 50% volume mix done three times;
diluting serially across the plate was continued.
[0327] The day before the assay was scheduled to be run, strains
were suspended in the test media (Brain Heart Infusion (BHI)
containing 0.1% casamino a.cids for S. aureus, S. epidermidis, and
E. faecalis. Trypticase Soy Broth (TSB) containing 5% sheep blood
for S. pneumoniae, and Lysogeny Broth (LB) for E. coli) and
incubated overnight at 35-37.degree. C. The suspension was diluted
with the same media to 1%, 100 .mu.L of which was added to each
well of the MIC plate. The MIC plate was incubated at 35-37.degree.
C. for 20 h. A thiazolyl blue tetrazolium bromide (MTT) solution (1
mg/mL-water, 50 .mu.L) was added into each well and the resulting
MIC plate was incubated at 35-37 .degree. C. for a few hours to
stain wells in which cell proliferated. Growth is also visible as
any turbidity in wells. MIC was defined as the lowest antibiotic
concentration that resulted in no growth after the incubation. See
Table 1.
Example 2
[0328] Curtailing the tail portion of Moenomycin A (MmA) led to
shorter half-life. Following IV (2 mpk) and SC (10 mpk)
administration, significant systemic exposure to CB-186295
(Moenomycin A) was observed. The compound exhibited biphasic
kinetics with distribution phase followed by elimination phase. The
% SC bioavailability was 89%. The half-life following IV and SC
administration were 8.7 and 7.5 days, respectively (NCA analysis).
The clearance following IV administration was very low leading
higher exposure (3 mL/hr/kg) and volume of distribution (Vss) was
0.5 L/kg. See Table 2.
TABLE-US-00001 TABLE 1 S. aureus 13709 S. epidermidis E. faecalis
S. pneumoniae E. coli 25923 1228 29212 6303 MG1655 29213 700562
33186 #1629 NR698 Vancomycin.cndot.HCl 3.9 2.0 3.9 0.49 250 3.9 3.9
2.0 0.49 0.49 2.0 ##STR00083## 0.16 0.16 0.078 0.16 0.16 0.16 0.16
1.3 1.3 31 0.0098 ##STR00084## 3.9 3.9 2.0 2.0 2.0 3.9 3.9 2.0 3.9
63 0.061 ##STR00085## >250 >250 250 >250 >250 250
>250 63 31 >250 0.98 ##STR00086## 1.3 0.63 0.63 0.63 1.3 0.63
0.63 2.0 3.1 7.8 0.0049 ##STR00087## 2.0 0.98 0.98 0.49 0.49 0.49
0.98 3.9 3.9 63 0.0024 ##STR00088## 3.9 2.0 2.0 0.98 2.0 0.98 2.0
2.0 0.98 250 >0.16 ##STR00089## 16 16 16 16 31 31 16 16 16 250
0.16 ##STR00090## 0.39 0.20 0.20 0.20 0.20 0.39 0.78 0.98 2.0 125
0.039 ##STR00091## 7.8 7.8 7.8 3.9 7.8 16 32 3.9 7.8 >250 0.49
##STR00092## >250 >250 >250 125 >250 >250 >250 16
16 >250 0.98
TABLE-US-00002 TABLE 2 ##STR00093## Half- MIC MIC Dose AUC.sub.last
AUC.sub.int DN_AUG.sub.int C.sub.0 C.sub.max T.sub.max life MRT
Clearance V.sub.z V.sub.ss Sa42 Sa399 R= (mg/kg) (ug*hr/mL)
(ug*hr/mL) (ug*hr/mL)/(mg/kg) (ug/mL) (ug/mL) (hr) (hr) (hr)
(mL/min/kg) (L/kg) (L/kg) ug/ml ug/ml ##STR00094## 1a MmA 1.44
366.79 491.94 341.94 24.70 19.13 1.00 32.33 42.94 0.05 0.14 0.13
0.25 0.25 ##STR00095## 1b 1.7 234 241 141 10.2 8.64 1 47 0.12 0.48
0.34 2.5-3.1 5-6.3 ##STR00096## 1c 1.16 28 35 27 9.5 6.67 1 2.5
0.61 0.14 0.12 >50 >50 ##STR00097## 1d 2* 16.8 28.2* 14.1**
0.8 0.717 1 42.3** 71.5 1.18 4.33 5.07 6.3 12.5 ##STR00098## 1e 2*
35.1 41.7 20.8 1.49 1.4 1 21.1 34.9 0.8 1.46 1.67 >10 12.5
##STR00099## 1f 1.56 109.71 135.41 86.80 8.52 6.04 1.00 26.16 38.58
0.19 0.43 0.44 4 8 ##STR00100## 1g 2* 58.4 79.7 39.8 1.71 1.7 1
38.3 53 0.418 1.39 1.33 ND >10 ##STR00101## 1h 1.78 255.21
265.07 148.92 15.34 12.05 1.00 15.26 21.67 0.11 0.15 0.15 4 8
##STR00102## 1i 1.3 190.09 312.48 240.37 14.15 13.77 1.00 16.13
24.24 0.07 0.10 0.10 2 4 *does solution not analyzed to determine
exact dose **R.sup.2 > 0.9 for elimination rate constant
EQUIVALENTS AND SCOPE
[0329] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims.
[0330] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0331] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim.
[0332] Where elements are presented as lists, e.g., in Markush
group format, each subgroup of the elements is also disclosed, and
any element(s) can be removed from the group. It should it be
understood that, in general, where the invention, or aspects of the
invention, is/are referred to as comprising particular elements
and/or features, certain embodiments of the invention or aspects of
the invention consist, or consist essentially of, such elements
and/or features. For purposes of simplicity, those embodiments have
not been specifically set forth in haec verba herein. It is also
noted that the terms "comprising" and "containing" are intended to
be open and permits the inclusion of additional elements or
steps.
[0333] Where ranges are given, endpoints are included. Furthermore,
unless otherwise indicated or otherwise evident from the context
and understanding of one of ordinary skill in the art, values that
are expressed as ranges can assume any specific value or sub-range
within the stated ranges in different embodiments of the invention,
to the tenth of the unit of the lower limit of the range, unless
the context clearly dictates otherwise.
[0334] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control.
[0335] In addition, any particular embodiment of the present
invention that falls within the prior art may be explicitly
excluded from any one or more of the claims. Because such
embodiments are deemed to be known to one of ordinary skill in the
art, they may be excluded even if the exclusion is not set forth
explicitly herein. Any particular embodiment of the invention can
be excluded from any claim, for any reason, whether or not related
to the existence of prior art.
[0336] The foregoing has been a description of certain non-limiting
embodiments of the invention. Those of ordinary skill in the art
will appreciate that various changes and modifications to this
description may be made without departing from the spirit or scope
of the present invention, as defined in the following claims.
* * * * *