Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Reexamination Certificate
2000-12-15
2004-09-21
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C514S011400, C514S014800, C530S327000, C530S332000
Reexamination Certificate
active
06794490
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel lipopeptide compounds. The invention also relates to pharmaceutical compositions of these compounds and methods of using these compounds as antibacterial compounds. The invention also relates to methods of producing these novel lipopeptide compounds and intermediates used in producing these compounds.
BACKGROUND OF THE INVENTION
The rapid increase in the incidence of gram-positive infections—including those caused by resistant bacteria—has sparked renewed interest in the development of novel classes of antibiotics. A class of compounds which have shown potential as useful antibiotics includes the A-21978C lipopeptides described in, for example, U.S. Pat. Nos. RE 32,333; RE 32,455; RE 32,311; RE 32,310; U.S. Pat. Nos. 4,482,487; 4,537,717; and 5,912,226. Daptomycin, a member of this class, has potent bactericidal activity in vitro and in vivo against clinically relevant gram-positive bacteria that cause serious and life-threatening diseases. These bacteria include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant
Staphylococcus aureus
(NRSA), glycopeptide intermediate susceptible
Staphylococcus aureus
(GISA), coagulase-negative staphylococci (CNS), and penicillin-resistant
eptococcus pneumoniae
(PRSP), for which there are few therapeutic alternatives. See, e.g., Tally et al., 1999
, Exp. Opin. Invest. Drugs
8:1223-1238.
Despite the promise that antibacterial agents such as daptomycin offer, the need for novel antibiotics continues. Many pathogens have been repeatedly exposed to commonly-used antibiotics This exposure has led to the selection of variant antibacterial strains resistant to a broad spectrum of antibiotics. The loss of potency and effectiveness of an antibiotic caused by resistant mechanisms renders the antibiotic ineffective and consequently can lead to life-threatening infections that are virtually untreatable. As new antibiotics come to market pathogens may develop resistance or intermediate resistance to these new drugs, effectively creating a need for a stream of new antibacterial agents to combat these emerging strains. In addition compounds that exhibit bacteriacidal activity would offer advantages over present bacteriastatic compounds. Thus, novel synthetic antibacterial agents would be expected to be useful to treat not only “natural” pathogens, but also intermediate drug resistant and drug resistant pathogens because the pathogen has never been exposed to the novel antibacterial agent. Additionally, new antibacterial agents may exhibit differential effectiveness against different types of pathogens.
SUMMARY OF THE INVENTION
The present invention addresses this problem by providing novel lipopeptide compounds which have antibacterial activity against a broad spectrum of bacteria, including drug-resistant bacteria. Further, the compounds of the present invention exhibit bacteriacidal activity.
The present invention comprises, in one aspect, antibacterial compounds of Formula I:
and salts thereof,
wherein R and R
1
are independently:
wherein X and X′ are independently selected from C═O, C═S, C═NH, C═NR
X
, S═O or SO
2
;
wherein n is 0 or 1;
wherein R
X
is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, alkoxy, carboxy or carboalkoxy;
wherein B is X′R
Y
, H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
wherein R
Y
is selected from hydrido, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or hydroxyl;
wherein A is H, NH
2
, NHR
A
, NR
A
R
B
, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl;
wherein R
A
and R
B
are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or carboalkoxy;
wherein when n is 0, then A is additionally selected from:
wherein each of R
50
-R
53
is independently selected from C
1
-C
15
alkyl;
alternatively, B and A together form a 5-7 membered heterocyclic or heteroaryl ring.
Wherein R
2
is
wherein K and K′ together form a C
3
-C
7
cycloalkyl or heterocyclyl ring or a C
5
-C
10
aryl or heteroaryl ring;
wherein J is selected from the group consisting of hydrido, amino, NHR
J
, NR
J
R
K
, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylamino, hydroxyl, thio, alkylthio, alkenylthio, sulfinyl, sulfonyl, azido, cyano, halo,
wherein each of R
24
, R
25
, and R
26
is independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R
24
and R
25
together form a 5-8 membered heterocyclyl ring;
wherein R
J
and R
K
are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl; or
alternatively, wherein J, together with R
17
, forms a 5-8 membered heterocyclyl or cycloalkyl ring; or
alternatively, wherein J, together with both R
17
and R
18
, forms a 5-8 membered aryl, cycloalkyl, heterocyclyl or heteroaryl ring; and
wherein each of R
17
and R
18
is independently selected from the group consisting of hydrido, halo, hydroxyl, alkoxy, amino, thio, sulfinyl, sulfonyl and
or
wherein R
17
and R
18
taken together can form a group consisting of ketal, thioketal,
wherein each of R
22
and R
23
is independently selected from the group consisting of hydrido and alkyl;
provided that when K and K′ together form a phenyl ring and R
17
and R
18
taken together form C═O, then J is not NH
2
, C
4
-C
14
alkylidenyl, or NHR
Q
, wherein R
Q
is C
4
-C
14
unsubstituted alkyl, substituted or unsubstituted C
2
-C
19
alkanoyl, unsubstituted C
5
-C
19
alkenoyl, or a carboalkoxy.
In another embodiment, the invention also provides pharmaceutical compositions comprising compounds of Formula I and methods of use thereof.
In a further embodiment, the invention provides methods of making compounds of Formula I and pharmaceutical compositions thereof.
In a further embodiment, the invention provides compounds useful as intermediates for the preparation of compounds of Formula I.
In a still further embodiment, the invention provides methods of use of the compounds of Formula I to treat bacterial infections in humans.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Molecular terms, when used in this application, have their common meaning unless otherwise specified.
The term “hydrido” denotes a single hydrogen atom (H).
The term “acyl” is defined as a carbonyl radical attached to an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycyl, aryl or heteroaryl group, examples including, without limitation, such radicals as acetyl and benzoyl.
The term “amino” denotes a nitrogen radical containing two substituents independently selected from the group consisting of hydrido, alkyl, cycloalkyl, carboalkoxy, heterocyclyl, aryl, heteroaryl and sulfonyl. Subsets of the term amino are (1) the term “unsubstituted amino” which denotes an NH
2
radical, (2) the term “mono substituted amino” which is defined as a nitrogen radical containing a hydrido group and a substituent group selected from alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and (3) the term “disubstituted amino” which is defined as a nitrogen radical containing two substituent groups independently selected from, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferred mono substituted amino radicals are “lower mono substituted amino” radicals, whereby the substituent group is a lower alkyl group. Preferred disubstituted amino radicals are “lower disubstituted amino” radicals, whereby the substituent groups are lower alkyl.
The term “acyloxy” denotes an oxygen radical adjacent to an acyl group.
The term “acylamino” denotes a nitrogen radical adjacent to an acyl group.
The term “carboalkoxy” is defined as a carbonyl radical adjacent to an alkoxy or aryloxy group.
The term “carboxyamido” denotes a carbonyl radical adjacent to an amino group.
The term “halo” is defined as a bromo, chloro, fluoro or iodo radical.
The term “thio” denotes a radical
Christensen Dale
Finn John
Hill Jason
Keith Dennis
Lazarova Tsvetelina
Cubist Pharmaceuticals, Inc.
Douros Timothy J.
Low Christopher S. F.
Lukton David
Mandelblatt Jill M.N.
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