U.S. patent application number 10/302247 was filed with the patent office on 2003-09-11 for antimicrobial 2-pyridones, their compositions and uses.
This patent application is currently assigned to The Procter & Gamble Company. Invention is credited to Flaim, Sean M., Ledoussal, Benoit.
Application Number | 20030171587 10/302247 |
Document ID | / |
Family ID | 22969188 |
Filed Date | 2003-09-11 |
United States Patent
Application |
20030171587 |
Kind Code |
A1 |
Ledoussal, Benoit ; et
al. |
September 11, 2003 |
Antimicrobial 2-pyridones, their compositions and uses
Abstract
Compounds having the general structure: 1 are effective
antimicrobial agents.
Inventors: |
Ledoussal, Benoit; (Mason,
OH) ; Flaim, Sean M.; (Toledo, OH) |
Correspondence
Address: |
THE PROCTER & GAMBLE COMPANY
INTELLECTUAL PROPERTY DIVISION
WINTON HILL TECHNICAL CENTER - BOX 161
6110 CENTER HILL AVENUE
CINCINNATI
OH
45224
US
|
Assignee: |
The Procter & Gamble
Company
|
Family ID: |
22969188 |
Appl. No.: |
10/302247 |
Filed: |
November 22, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10302247 |
Nov 22, 2002 |
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10020709 |
Dec 14, 2001 |
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6509349 |
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60255628 |
Dec 14, 2000 |
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Current U.S.
Class: |
546/136 |
Current CPC
Class: |
C07D 455/02 20130101;
A61P 31/00 20180101; A61P 31/04 20180101 |
Class at
Publication: |
546/136 ;
514/210.21; 514/306 |
International
Class: |
A61K 031/4745; C07D
455/02 |
Claims
What is claimed is:
1. A compound having a structure according to Formula (I)
108wherein: (A) (1) R.sup.1 is selected from C.sub.3 to about
C.sub.6 cycloalkyl, C.sub.4 to about C.sub.6 heterocycloalkyl,
C.sub.1 to about C.sub.6 alkyl, C.sub.2 to about C.sub.6 alkene, a
6-membered aryl, and a 6-membered heteroaryl; (2) R.sup.2 is
hydrogen; (3) R.sup.3 is selected from hydrogen and hydroxy; (4)
R.sup.5 is selected from hydrogen, hydroxy, amino, halo, C.sub.1 to
about C.sub.6 alkyl, C.sub.2 to about C.sub.6 alkene, and C.sub.1
to about C.sub.6 alkoxy; (5) R.sup.6 is selected from hydrogen,
hydroxy, aminocarbonyl, cyano, C.sub.1 to about C.sub.4 alkyl, and
C.sub.2 to about C.sub.4 alkene; all such alkyl and alkene moieties
being unsubstituted or substituted with from 1 to about 3 fluoro,
or in the case of methyl or ethyl, optionally substituted with one
hydroxy or one amino moiety; (6) R.sup.7 is selected from 109
wherein (a) R.sup.9 is (i) amino which is attached to a ring carbon
of R.sup.7 which is not adjacent to the ring nitrogen of R.sup.7,
the amino being unsubstituted or substituted with one or two
C.sub.1 to about C.sub.3 alkyl; or (ii) aminoalkyl which is
attached to any ring carbon of R.sup.7 and is C.sub.1 to about
C.sub.3 alkyl substituted with one amino, the amino being
unsubstituted or substituted with one or two C.sub.1 to about
C.sub.3 alkyl; and (b) R.sup.10 represents the moieties on R.sup.7
other than R.sup.9 and each R.sup.10 is independently selected from
hydrogen, C.sub.1 to about C.sub.4 alkyl, C.sub.2 to about C.sub.6
alkene, and a C.sub.3 to about C.sub.6 fused or spirocycle alkyl
ring; all alkyl, alkene and cyclic R.sup.10 moieties being
unsubstituted or substituted with one hydroxy or with from 1 to
about 3 fluoro moieties; and (7) R.sup.8 is selected from hydrogen,
halo, C.sub.1 to about C.sub.6 alkoxy, C.sub.1 to about C.sub.6
alkylthio, C.sub.1 to about C.sub.6 alkyl and C.sub.2 to about
C.sub.6 alkene; or (B) R.sup.8 and R.sup.1 can join to form a
6-membered heterocyclic ring, where R.sup.2, R.sup.3, R.sup.5,
R.sup.6 and R.sup.7 are as described in (A); or an optical isomer,
diastereomer or enantiomer thereof; or a
pharmaceutically-acceptable salt, hydrate, or biohydrolyzable
ester, amide or imide thereof.
2. A compound of claim 1 wherein R.sup.1 is selected from C.sub.3
to about C.sub.6 cycloalkyl, a 6-membered aryl, C.sub.1 to about
C.sub.2 alkyl, and C.sub.2 to about C.sub.3 alkene.
3. A compound of claim 2 wherein R.sup.1 is selected from
cyclopropyl, ethyl, 4-hydroxyphenyl, and 2,4-difluorophenyl.
4. A compound of claim 1 wherein R.sup.3 is hydroxy.
5. A compound of claim 1 wherein R.sup.5 is selected from hydrogen,
hydroxy, chloro, bromo, amino, methyl, monofluoromethyl,
difluoromethyl, and trifluoromethyl.
6. A compound of claim 1 wherein R.sup.6 is selected from hydrogen,
hydroxy, methyl, monofluoromethyl, difluoromethyl, and
trifluoromethyl.
7. A compound of claim 6 wherein R.sup.6 is hydrogen.
8. A compound of claim 1 wherein R.sup.8 is selected from chloro,
methyl, methoxy, methylthio, monofluoromethyl, difluoromethyl,
trifluoromethyl, monofluoromethoxy, difluoromethoxy, and
trifluoromethoxy.
9. A compound of claim 1 wherein R.sup.7 is selected from: 110
10. A compound of claim 1 wherein R.sup.1 and R.sup.8 do not join
together to form a heterocyclic ring.
11. A compound of claim 1 wherein R.sup.9 is amino, unsubstituted
or substituted with one or two alkyl moieties independently
selected from methyl and ethyl.
12. A compound of claim 11 wherein R.sup.9 is --NH.sub.2.
13. A compound of claim 1 wherein R.sup.9 is aminoalkyl, wherein
the alkyl is unsubstituted or substituted with one or more C.sub.1
to about C.sub.6 alkyl groups and the amino is unsubstituted or
substituted with one or two alkyl moieties independently selected
from methyl and ethyl.
14. A compound of claim 13 wherein R.sup.9 is selected from
aminomethyl, methylaminomethyl, 1-aminoethyl, 1-methylaminoethyl,
1-amino-1-methylethyl, and 1-methylamino-1-methylethyl.
15. A compound of claim 1 wherein each R.sup.10 is independently
selected from hydrogen and C.sub.1 to about C.sub.6 alkyl.
16. A compound of claim 15 wherein not more than one R.sup.10 is
other than hydrogen.
17. A compound having a structure according to the following
Formula (B): 111wherein (1) R.sup.2is hydrogen; (2) R.sup.3 is
selected from hydrogen and hydroxy; (3) R.sup.5 is selected from
hydrogen, hydroxy, amino, halo, C.sub.1 to about C.sub.6 alkyl,
C.sub.2 to about C.sub.6 alkene, and C.sub.1 to about C.sub.6
alkoxy; (4) R.sup.6 is selected from hydrogen, hydroxy,
aminocarbonyl, cyano, C.sub.1 to about C.sub.4 alkyl, and C.sub.2
to about C.sub.4 alkene; all such alkyl and alkene moieties being
unsubstituted or substituted with from 1 to about 3 fluoro, or in
the case of methyl or ethyl, optionally substituted with one
hydroxy or one amino moiety; (5) R.sup.7 is selected from 112
wherein (a) R.sup.9 is (i) amino which is attached to a ring carbon
of R.sup.7 which is not adjacent to the ring nitrogen of R.sup.7,
the amino being unsubstituted or substituted with one or two
C.sub.1 to about C.sub.3 alkyl; or (ii) aminoalkyl which is
attached to any ring carbon of R.sup.7 and is C.sub.1 to about
C.sub.3 alkyl substituted with one amino, the amino being
unsubstituted or substituted with one or two C.sub.1 to about
C.sub.3 alkyl; and (b) R.sup.10 represents the moieties on R.sup.7
other than R.sup.9 and each R.sup.10 is independently selected from
hydrogen, C.sub.1 to about C.sub.4 alkyl, C.sub.2 to about C.sub.6
alkene, and a C.sub.3 to about C.sub.6 fused or spirocycle alkyl
ring; all alkyl, alkene, and cyclic R.sup.10 moieties being
unsubstituted or substituted with one hydroxy or with from 1 to
about 3 fluoro moieties; (6) Y is selected substituted or
unsubstituted --C-- or --N--, or Y is --O--; (7) Z is selected from
--O--, --S--, substituted or unsubstituted --C--, and substituted
or unsubstituted --N--; and (8) R.sup.3 and R.sup.13' are
independently selected from hydrogen and C.sub.1 to about C.sub.6
alkyl; or an optical isomer, diastereomer or enantiomer thereof; a
pharmaceutically-acceptable salt, hydrate, or biohydrolyzable
ester, amide or imide thereof.
18. A pharmaceutical composition comprising: (a) a safe and
effective amount of a compound of claim 1; and (b) a
pharmaceutically-acceptable excipient.
19. A pharmaceutical composition comprising: (a) a safe and
effective amount of a compound of claim 10; and (b) a
pharmaceutically-acceptable excipient.
20. A method for treating microbial infection comprising
administering to a host in need of such a treatment a safe and
antimicrobially effective amount of a compound of claim 1.
21. A method for treating microbial infection comprising
administering to a host in need of such a treatment a safe and
antimicrobially effective amount of a compound of claim 10.
22. A method of using a compound having a structure according to
Formula (C) 113wherein R.sup.14 is selected from methoxy or methyl;
R.sup.15 is selected from ethyl or cyclopropyl; in the process of
making a compound according to Formula (I) 114
Description
CROSS REFERENCE
[0001] This application claims priority under Title 35, United
States Code 119(e) from Provisional application Serial No.
60/255,628, filed Dec. 14, 2000.
FIELD OF THE INVENTION
[0002] The subject invention relates to novel antimicrobial
compounds, their compositions and their uses.
BACKGROUND
[0003] The chemical and medical literature describes compounds that
are said to be antimicrobial, i.e., capable of destroying or
suppressing the growth or reproduction of microorganisms, such as
bacteria. For example, such antibacterials and other antimicrobials
are described in Antibiotics, Chemotherapeutics, and Antibacterial
Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale
et al., The Molecular Basis of Antibiotic Action 2d edition
(1981).
[0004] The mechanism of action of these antibacterials vary.
However, they are generally believed to function in one or more of
the following ways: by inhibiting cell wall synthesis or repair; by
altering cell wall permeability; by inhibiting protein synthesis;
or by inhibiting synthesis of nucleic acids. For example,
beta-lactam antibacterials act through inhibiting the essential
penicillin binding proteins (PBPs) in bacteria, which are
responsible for cell wall synthesis. As another example, quinolones
act, at least in part, by inhibiting synthesis of DNA, thus
preventing the cell from replicating.
[0005] The pharmacological characteristics of antimicrobials, and
their suitability for any given clinical use, vary. For example,
the classes of antimicrobials (and members within a class) may vary
in 1) their relative efficacy against different types of
microorganisms, 2) their susceptibility to development of microbial
resistance and 3) their pharmacological characteristics, such as
their bioavailability and biodistribution. Accordingly, selection
of an appropriate antibacterial (or other antimicrobial) in a given
clinical situation requires analysis of many factors, including the
type of organism involved, the desired method of administration,
the location of the infection to be treated and other
considerations.
[0006] However, many such attempts to produce improved
antimicrobials yield equivocal results. Indeed, few antimicrobials
are produced that are truly clinically-acceptable in terms of their
spectrum of antimicrobial activity, avoidance of microbial
resistance, and pharmacology. Thus there is a continuing need for
broad spectrum antimicrobials, which are effective against
resistant microbes.
[0007] Some 1,4-dihydroquinolone, naphthyridine or related
heterocyclic moieties are known in the art to have antimicrobial
activity and are described in the following references: R.
Albrecht, Prog. Drug Research, Vol. 21, p. 9 (1977); J. Wolfson et
al., "The Fluoroquinolones: Structures, Mechanisms of Action and
Resistance, and Spectra of Activity In Vitro", Antimicrob. Agents
and Chemother., Vol. 28, p. 581 (1985); G. Klopman et al.,
Antimicrob. Agents and Chemother., Vol. 31, p. 1831 (1987); M. P.
Wentland et al., Ann. Rep. Med. Chem., Vol. 20, p. 145 (1986); J.
B. Cornett et al., Ann. Rep. Med. Chem., Vol. 21, p. 139 (1986); P.
B. Fernandes et al., Ann. Rep. Med. Chem., Vol. 22, p. 117 (1987);
A. Koga, et al., "Structure-Activity Relationships of Antibacterial
6,7- and 7,8-Disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoli-
ne-3-carboxylic Acids", J. Med. Chem., Vol. 23, pp. 1358-1363
(1980); J. M. Domagala et al., J. Med. Chem., Vol. 31, p. 991
(1988); T. Rosen et al., J. Med. Chem., Vol. 31, p. 1586 (1988); T.
Rosen et al., J. Med. Chem., Vol. 31, p. 1598 (1988); B. Ledoussal
et al., "Non 6-Fluoro Substituted Quinolone Antibacterials:
Structure and Activity", J. Med. Chem., Vol. 35, p. 198-200 (1992);
J. M. Domagala et al., "Quinolone Antibacterials Containing the New
7-[3-(1-Aminoethyl)-1-pyrrolidinyl] Side Chain: The Effects of the
1-Aminoethyl Moiety and Its Stereochemical Configurations on
Potency and in Vivo Efficacy", J. Med. Chem., Vol. 36, pp. 871-882
(1993); Hagen et al., "Synthesis and Antibacterial Activity of New
Quinolones Containing a 7-[3-(1-Amino-1-methylethyl)-1-pyrrolidiny-
l] Moiety. Gram Positive Agents with Excellent Oral Activity and
Low Side-Effect Potential", J. Med. Chem. Vol. 37, pp. 733-738
(1994); V. Cecchetti et al., "Studies on 6-Aminoquinolines:
Synthesis and Antibacterial Evaluation of
6-Amino-8-methylquinolones", J. Med. Chem., Vol. 39, pp. 436-445
(1996); V. Cecchetti et al., "Potent 6-Desfluoro-8-methylquinolones
as New Lead Compounds in Antibacterial Chemotherapy", J. Med.
Chem., Vol. 39, pp. 4952-4957 (1996); Hong et al., "Novel
5-Amino-6-methylquinolone Antibacterials: a New Class of
Non-6-fluoroquinolones", Bioorg. of Med. Chem. Let., Vol. 7, pp.
1875-1878 (1997); U.S. Pat. No. 4,844,902 to Grohe on Jul. 4, 1989;
U.S. Pat. No. 5,072,001 to Hagen & Suto on Dec. 10, 1991; U.S.
Pat No. 5,328,908 to Demuth & White on Jul. 12, 1994; U.S. Pat
No. 5,457,104 to Bartel et al. on Oct. 10, 1995; U.S. Pat. No.
5,556,979 to Philipps et al. on Sep. 17, 1996; European Patent
Appl. 572,259 of Ube Ind. pub. Dec. 1, 1993; European Patent Appl.
775,702 of Toyama Chem. Co. pub. May 28, 1997; Japanese Patent Pub.
62/255,482 of Kyorin Pharm. Co. pub. Mar. 1, 1995. Additionally,
there is a small body of literature describing 2-pyridones,
including: European Patent Application No. 308,019 to Heck James,
V. et al, Sep. 9, 1988; World Patent Application No. 99/07696 to
Tae Ho et al, Aug. 9, 1997; World Patent Application No. 91/16894
to Chu Daniel, T. et al, May 2, 1990; World Patent Application No.
95/10519 to Chu Daniel, T. et al, Oct 14, 1993; U.S. Pat. No.
5,599,816 to Chu Daniel, T. et al, Jun. 7, 1995; U.S. Pat. No.
5,726,182 to Chu Daniel, T. et al, Jun. 7, 1995; U.S. Pat. No.
5,580,872 to Chu Daniel, T. et al, Sep. 30, 1995; and J. Med.
Chem., Vol. 39, pp. 3070-3088 (1996), Qun et al., "Synthesis and
Structure-Activity Relationships of 2-Pyridones: A Novel series of
Potent DNA Gyrase Inhibitors as Antibacterial Agents."
[0008] Examples of bacterial infections resistant to antibiotic
therapy have been reported in the past; they are now a significant
threat to public health in the developed world. The development of
microbial resistance (perhaps as a result of the intense use of
antibacterials over extended periods of time) is of increasing
concern in medical science. "Resistance" can be defined as
existence of organisms, within a population of a given microbial
species, that are less susceptible to the action of a given
antimicrobial agent. This resistance is of particular concern in
environments such as hospitals and nursing homes, where relatively
high rates of infection and intense use of antibacterials are
common. See, e.g., W. Sanders, Jr. et al., "Inducible
Beta-lactamases: Clinical and Epidemiologic Implications for Use of
Newer Cephalosporins", Reviews of Infectious Diseases, p. 830
(1988).
[0009] Pathogenic bacteria are known to acquire resistance via
several distinct mechanisms including inactivation of the
antibiotic by bacterial enzymes (e.g., .beta.-lactamases
hydrolyzing penicillin and cephalosporins); removal of the
antibiotic using efflux pumps; modification of the target of the
antibiotic via mutation and genetic recombination (e.g.,
penicillin-resistance in Neiserria gonorrhoeae); and acquisition of
a readily transferable gene from an external source to create a
resistant target (e.g., methicillin-resistance in Staphylococcus
aureus). There are certain Gram positive pathogens, such as
vancomycin-resistant Enterococcus faecium, which are resistant to
virtually all commercially available antibiotics.
[0010] Hence, existing antibacterials have limited capacity in
overcoming the threat of resistance. Thus it would be advantageous
to provide compounds with useful properties that can be used
against resistant microbes.
SUMMARY OF THE INVENTION
[0011] Applicants have found a novel series of 2-pyridone compounds
that are effective against resistant microbes. In particular, the
invention relates to compounds having a structure according to
Formula (I) 2
[0012] wherein:
[0013] (A) (1) R.sup.1 is selected from C.sub.3 to about C.sub.6
cycloalkyl, C.sub.4 to about C.sub.6 heterocycloalkyl, lower alkyl,
lower alkene, a 6-membered aryl, and a 6-membered heteroaryl;
[0014] (2) R.sup.2 is hydrogen;
[0015] (3) R.sup.3 is selected from hydrogen and hydroxy;
[0016] (4) R.sup.5 is selected from hydrogen, hydroxy, amino, halo,
lower alkyl, lower alkene, and lower alkoxy;
[0017] (5) R.sup.6 is selected from hydrogen, hydroxy,
aminocarbonyl, cyano, C.sub.1 to about C.sub.4 alkyl, and C.sub.2
to about C.sub.4 alkene; all such alkyl and alkene moieties being
unsubstituted or substituted with from 1 to about 3 fluoro, or in
the case of methyl or ethyl, optionally substituted with one
hydroxy or one amino moiety;
[0018] (6) R.sup.7 is selected from 3
[0019] wherein
[0020] (a) R.sup.9 is (i) amino which is attached to a ring carbon
of R.sup.7 which is not adjacent to the ring nitrogen of R.sup.7,
the amino being unsubstituted or substituted with one or two
C.sub.1 to about C.sub.3 alkyl; or (ii) aminoalkyl which is
attached to any ring carbon of R.sup.7 and is C.sub.1 to about
C.sub.3 alkyl substituted with one amino, the amino being
unsubstituted or substituted with one or two C.sub.1 to about
C.sub.3 alkyl; and
[0021] (b) R.sup.10 represents the moieties on R.sup.7 other than
R.sup.9 and each R.sup.10 is independently selected from hydrogen,
C.sub.1 to about C.sub.4 alkyl, C.sub.2 to about C.sub.6 alkene,
and a C.sub.3 to about C.sub.6 fused or spirocycle alkyl ring; all
alkyl, alkene and cyclic R.sup.10 moieties being unsubstituted or
substituted with one hydroxy or with from 1 to about 3 fluoro
moieties; and
[0022] (7) R.sup.8 is selected from hydrogen, halo, C.sub.1 to
about C.sub.2 alkoxy, C.sub.1 to about C.sub.2 alkylthio, C.sub.2
to about C.sub.4 alkyl and lower alkene; or
[0023] (B) R.sup.8 and R.sup.1 can join to form a 6-membered
heterocyclic ring, where R.sup.2, R.sup.3, R.sup.5, R.sup.6 and
R.sup.7 are as described in (A);
[0024] or an optical isomer, diastereomer or enantiomer thereof; or
a pharmaceutically-acceptable salt, hydrate, or biohydrolyzable
ester, amide or imide thereof. In addition, compounds incorporating
the compounds of the invention, or the use of compounds of the
invention as starting materials for making other antimicrobial
compounds, are also contemplated in this invention.
DESCRIPTION OF THE INVENTION
[0025] I. Terms and Definitions
[0026] The following is a list of definitions for terms used
herein:
[0027] "Acyl" is a radical formed by removal of the hydroxy from a
carboxylic acid (i.e., R--C(.dbd.O)--). Preferred acyl groups
include (for example) acetyl, formyl, and propionyl.
[0028] "Alkyl" is a saturated hydrocarbon chain having 1 to 15
carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon
atoms. "Alkene" is a hydrocarbon chain having at least one
(preferably only one) carbon-carbon double bond and having 2 to 15
carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon
atoms. "Alkyne" is a hydrocarbon chain having at least one
(preferably only one) carbon-carbon triple bond and having 2 to 15
carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon
atoms. Alkyl, alkene and alkyne chains (referred to collectively as
"hydrocarbon chains") may be straight or branched and may be
unsubstituted or substituted. Preferred branched alkyl, alkene and
alkyne chains have one or two branches, preferably one branch.
Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon
chains each may be unsubstituted or substituted with from 1 to 4
substituents; when substituted, preferred chains are mono-, di-, or
tri-substituted. Alkyl, alkene and alkyne hydrocarbon chains each
may be substituted with halo, hydroxy, aryloxy (e.g., phenoxy),
heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, aryl (e.g.,
phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle,
amino, amido, acylamino, keto, thioketo, cyano, or any combination
thereof. Preferred hydrocarbon groups include methyl, ethyl,
propyl, isopropyl, butyl, vinyl, allyl, butenyl, and
exomethylenyl.
[0029] "Alkoxy" is an oxygen radical having a hydrocarbon chain
substituent, where the hydrocarbon chain is an alkyl or alkenyl
(i.e., --O-alkyl or --O-alkenyl). Preferred alkoxy groups include
(for example) methoxy, ethoxy, propoxy and allyloxy.
[0030] "Alkylthio" is a sulfur radical having a hydrocarbon chain
substituent, where the hydrocarbon chain is an alkyl (e.g.
--S--CH.sub.3) or alkenyl (e.g., --S--CH.sub.2CH.dbd.CH.sub.2).
[0031] "Amino" refers to a primary (--NH.sub.2), secondary
(--NH(alkyl), also referred to herein as "alkylamino") or tertiary
(--N(alkyl).sub.2,also referred to herein as "dialkylamino").
[0032] "Aminoalkyl" is an alkyl moiety substituted with an amino,
alkylamino or dialkylamino group (e.g., --CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3,
--CH.sub.2N(CH.sub.3).s- ub.2).
[0033] "Aryl" is an aromatic hydrocarbon ring. Aryl rings are
monocyclic or fused bicyclic ring systems. Monocyclic aryl rings
contain 6 carbon atoms in the ring. Monocyclic aryl rings are also
referred to as phenyl rings. Bicyclic aryl rings contain from 8 to
17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring.
Bicyclic aryl rings include ring systems wherein one ring is aryl
and the other ring is aryl, cycloalkyl, or heterocycloakyl.
Preferred bicyclic aryl rings comprise 5-, 6- or 7-membered rings
fused to 5-, 6-, or 7-membered rings. Aryl rings may be
unsubstituted or substituted with from 1 to 4 substituents on the
ring. Aryl may be substituted with halo, cyano, nitro, hydroxy,
carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl,
aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl,
methylenedioxy, heteroaryloxy, or any combination thereof.
Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl.
The most preferred aryl ring radical is phenyl.
[0034] "Aryloxy" is an oxygen radical having an aryl substituent
(i.e., --O-aryl). Preferred aryloxy groups include (for example)
phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.
[0035] "Biohydrolyzable amides" are aminoacyl, acylamino, or other
amides of the compounds of the invention, where the amide does not
essentially interfere, preferably does not interfere, with the
activity of the compound, or where the amide is readily converted
in vivo by a host to yield an active compound.
[0036] "Biohydrolyzable imides" are imides of compounds of the
invention, where the imide does not essentially interfere,
preferably does not interfere, with the activity of the compound,
or where the imide is readily converted in vivo by a host to yield
an active compound. Preferred imides are hydroxyimides.
[0037] "Biohydrolyzable esters" are esters of compounds of the
invention, where the ester does not essentially interfere,
preferably does not interfere, with the antimicrobial activity of
the compound, or where the ester is readily converted in a host to
yield an active compound. Many such esters are known in the art, as
described in U.S. Pat. No. 4,783,443, issued to Johnston and
Mobashery on Nov. 8, 1988 (incorporated by reference herein). Such
esters include lower alkyl esters, lower acyloxy-alkyl esters (such
as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl,
pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters
(such as phthalidyl and thiophthalidyl esters), lower
alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl,
ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters),
alkoxyalkyl esters, choline esters and alkylacylaminoalkyl esters
(such as acetamidomethyl esters).
[0038] "Carbocyclic ring" encompasses both cycloalkyl and aryl
moieties, as those terms are defined herein.
[0039] "Carbonyl" is --C(.dbd.O)--.
[0040] "Cycloalkyl" is a saturated or unsaturated hydrocarbon ring.
Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic,
or are fused, spiro, or bridged bicyclic ring systems. Monocyclic
cycloalkyl rings contain from about 3 to about 9 carbon atoms,
preferably from 3 to 7 carbon atoms, in the ring. Bicyclic
cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from
7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl
rings comprise 4-, 5-, 6- or 7-membered cycloalkyl rings fused to
5-, 6-, or 7-membered cycloalkyl rings. Cycloalkyl rings may be
unsubstituted or substituted with from 1 to 4 substituents on the
ring. Cycloalkyl may be substituted with halo, cyano, alkyl,
heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino,
acylamino, aryloxy, or heteroaryloxy, or any combination thereof.
Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and
cyclohexyl.
[0041] "Halo" or "halogen" is fluoro, chloro, bromo or iodo.
Preferred halo are fluoro, chloro and bromo; more preferred
typically are chloro and fluoro, especially fluoro.
[0042] "Haloalkyl" is a straight, branched, or cyclic hydrocarbon
substituted with one or more halo substituents. Preferred are
C.sub.1--C.sub.12 haloalkyls; more preferred are C.sub.1--C.sub.6
haloalkyls; still more preferred still are C.sub.1--C.sub.3
haloalkyls. Preferred halo substituents are fluoro and chloro. The
most preferred haloalkyl is trifluoromethyl.
[0043] "Heteroatom" is a nitrogen, sulfur, or oxygen atom. Groups
containing more than one heteroatom may contain different
heteroatoms.
[0044] "Heteroalkyl" is a saturated or unsaturated chain containing
carbon and at least one heteroatom, wherein no two heteroatoms are
adjacent. Heteroalkyl chains contain from 2 to 15 member atoms
(carbon and heteroatoms) in the chain, preferably 2 to 10, more
preferably 2 to 5. For example, alkoxy (i.e., --O-alkyl or
--O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl
chains may be straight or branched. Preferred branched heteroalkyl
have one or two branches, preferably one branch. Preferred
heteroalkyl are saturated. Unsaturated heteroalkyl have one or more
carbon-carbon double bonds and/or one or more carbon-carbon triple
bonds. Preferred unsaturated heteroalkyls have one or two double
bonds or one triple bond, more preferably one double bond.
Heteroalkyl chains may be unsubstituted or substituted with from 1
to 4 substituents. Preferred substituted heteroalkyl are mono-,
di-, or tri-substituted. Heteroalkyl may be substituted with lower
alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy,
carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
spirocycle, amino, acylamino, amido, keto, thioketo, or cyano, or
any combination thereof.
[0045] "Heteroaryl" is an aromatic ring containing carbon atoms and
from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are
monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl
rings contain from about 5 to about 9 member atoms (carbon and
heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic
heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to
12 member atoms, in the ring. Bicyclic heteroaryl rings include
ring systems wherein one ring is heteroaryl and the other ring is
aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Preferred
bicyclic heteroaryl ring systems comprise 5-, 6-or 7-membered rings
fused to 5-, 6-, or 7-membered rings. Heteroaryl rings may be
unsubstituted or substituted with from 1 to 4 substituents on the
ring. Heteroaryl may be substituted with halo, cyano, nitro,
hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl,
phenyl, alkoxy, aryloxy, or heteroaryloxy, or any combination
thereof. Preferred heteroaryl rings include, but are not limited
to, the following: 45
[0046] "Heteroaryloxy" is an oxygen radical having a heteroaryl
substituent (i.e., --O-heteroaryl). Preferred heteroaryloxy groups
include (for example) pyridyloxy, furanyloxy, (thiophene)oxy,
(oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy,
pyrazinyloxy, and benzothiazolyloxy.
[0047] "Heterocycloalkyl" is a saturated or unsaturated ring
containing carbon atoms and from 1 to about 4 (preferably 1 to 3)
heteroatoms in the ring. Heterocycloalkyl rings are not aromatic.
Heterocycloalkyl rings are monocyclic or bicyclic ring systems.
Monocyclic heterocycloalkyl rings contain from about 3 to about 9
member atoms (carbon and heteroatoms), preferably from 5 to 7
member atoms, in the ring. Bicyclic heterocycloalkyl rings contain
from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the
ring. Bicyclic heterocycloalkyl rings contain from about 7 to about
17 ring atoms, preferably from 7 to 12 ring atoms. Bicyclic
heterocycloalkyl rings may be fused, spiro, or bridged ring
systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6-
or 7-membered rings fused to 5-, 6-, or 7-membered rings.
Heterocycloalkyl rings may be unsubstituted or substituted with
from 1 to 4 substituents on the ring. Heterocycloalkyl may be
substituted with halo, cyano, hydroxy, carboxy, keto, thioketo,
amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl,
phenyl, alkoxy, or aryloxy, or any combination thereof. Preferred
substituents on heterocycloalkyl include halo and haloalkyl.
Preferred heterocycloalkyl rings include, but are not limited to,
the following: 6
[0048] "Heterocyclic ring" encompasses both hetercycloalkyl and
heteroaryl moieties, as those terms are defined herein.
[0049] "Host" is a substrate capable of sustaining a microbe,
typically it is a living organism, more typically an animal, more
typically a mammal, more typically still a human.
[0050] "Lower" alkoxy, alkylthio, alkyl, alkene or alkyne moiety
(e.g., "lower alkyl") is a chain comprised of 1 to 6, preferably
from 1 to 4, carbon atoms in the case of alkyl, alkoxy and
alkylthio, and 2 to 6, preferably 2 to 4, carbon atoms in the case
of alkene and alkyne.
[0051] The terms "optical isomer", "stereoisomer", and
"diastereomer" have the standard art recognized meanings (see,
e.g., Hawley's Condensed Chemical Dictionary, 11th Ed.). The
illustration of specific protected forms and other derivatives of
the compounds of the instant invention is not intended to be
limiting. The application of other useful protecting groups, salt
forms, etc. is within the ability of the skilled artisan.
[0052] The compounds of the invention may have one or more chiral
centers. As a result, one may selectively prepare one optical
isomer, including diastereomer and enantiomer, over another, for
example by use of chiral starting materials, catalysts or solvents,
one may prepare both stereoisomers or both optical isomers,
including diastereomers and enantiomers at once (a racemic
mixture). Since the compounds of the invention may exist as racemic
mixtures, mixtures of optical isomers, including diastereomers and
enantiomers, or stereoisomers, they may be separated using known
methods, such as chiral resolution, chiral chromatography and the
like.
[0053] In addition, it is recognized that one optical isomer,
including diastereomer and enantiomer, or stereoisomer may have
favorable properties over the other. Thus when disclosing and
claiming the invention, when one racemic mixture is disclosed, it
is clearly contemplated that both optical isomers, including
diastereomers and enantiomers, or stereoisomers substantially free
of the other are disclosed and claimed as well.
[0054] A "pharmaceutically-acceptable salt" is a cationic salt
formed at any acidic (e.g., carboxyl) group, or an anionic salt
formed at any basic (e.g., amino, alkylamino, dialkylamino,
morphylino, and the like) group on the compound of the invention.
Since many of the compounds of the invention are zwitterionic,
either salt is possible and acceptable. Many such salts are known
in the art. Preferred cationic salts include the alkali metal salts
(such as sodium and potassium), alkaline earth metal salts (such as
magnesium and calcium) and organic salts, such as ammonio.
Preferred anionic salts include halides, sulfonates, carboxylates,
phosphates, and the like. Clearly contemplated in such salts are
addition salts that may provide an optical center, where there
previously were none. For example, a chiral tartrate salt may be
prepared from the compounds of the invention, and this definition
includes such chiral salts. Salts contemplated are nontoxic in the
amounts administered to the patient-animal, mammal or human.
[0055] The compounds of the invention are sufficiently basic to
form acid-addition salts. The compounds are useful both in the free
base form and the form of acid-addition salts, and both forms are
within the purview of the invention. The acid-addition salts are in
some cases a more convenient form for use. In practice, the use of
the salt form inherently amounts to the use of the base form of the
active. Acids used to prepare acid-addition salts include
preferably those which produce, when combined with the free base,
medicinally acceptable salts. These salts have anions that are
relatively innocuous to the animal organism, such as a mammal, in
medicinal doses of the salts so that the beneficial property
inherent in the free base are not vitiated by any side effects
ascribable to the acid's anions.
[0056] Examples of appropriate acid-addition salts include, but are
not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate,
hydrogensulfate, acetate, trifluoroacetate, nitrate, citrate,
fumarate, formate, stearate, succinate, maleate, malonate, adipate,
glutarate, lactate, propionate, butyrate, tartrate,
methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate,
dodecyl sulfate, cyclohexanesulfamate, and the like. However, other
appropriate medicinally acceptable salts within the scope of the
invention are those derived from other mineral acids and organic
acids. The acid-addition salts of the basic compounds are prepared
by several methods. For example, the free base can be dissolved in
an aqueous alcohol solution containing the appropriate acid and the
salt is isolated by evaporation of the solution. Alternatively,
they may be prepared by reacting the free base with an acid in an
organic solvent so that the salt separates directly. Where
separation of the salt is difficult, it can be precipitated with a
second organic solvent, or can be obtained by concentration of the
solution.
[0057] Although medicinally acceptable salts of the basic compounds
are preferred, all acid-addition salts are within the scope of the
present invention. All acid-addition salts are useful as sources of
the free base form, even if the particular salt per se is desired
only as an intermediate product. For example, when the salt is
formed only for purposes of purification or identification, or when
it is used as an intermediate in preparing a medicinally acceptable
salt by ion exchange procedures, these salts are clearly
contemplated to be a part of this invention.
[0058] Such salts are well understood by the skilled artisan, and
the skilled artisan is able to prepare any number of salts given
the knowledge in the art. Furthermore, it is recognized that the
skilled artisan may prefer one salt over another for reasons of
solubility, stability, formulation ease and the like. Determination
and optimization of such salts is within the purview of the skilled
artisan's practice.
[0059] A "solvate" is a complex formed by the combination of a
solute (e.g., a 2-pyridone) and a solvent (e.g., water). See J.
Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953).
Pharmaceutically-acceptable solvents used according to this
invention include those that do not interfere with the biological
activity of the 2-pyridone or 2-pyridone derivative (e.g., water,
ethanol, acetic acid, N,N-dimethylformamide and others known or
readily determined by the skilled artisan).
[0060] "Spirocycle" is an alkyl or heteroalkyl diradical
substituent of alkyl or heteroalkyl wherein said diradical
substituent is attached geminally and wherein said diradical
substituent forms a ring, said ring containing 4 to 8 member atoms
(carbon or heteroatom), preferably 5 or 6 member atoms.
[0061] While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl
groups may be substituted with hydroxy, amino, and amido groups as
stated above, the following are not envisioned in the
invention:
[0062] 1. Enols (OH attached to an alkene carbon).
[0063] 2. Amino groups attached to a carbon bearing a double bond
(except for vinylogous amides).
[0064] 3. More than one hydroxy, amino, or amido attached to a
single carbon (except where two nitrogen atoms are attached to a
single carbon atom and all three atoms are member atoms within a
heterocycloalkyl ring).
[0065] 4. Hydroxy, amino, or amido attached to a carbon that also
has a heteroatom attached to it.
[0066] 5. Hydroxy, amino, or amido attached to a carbon that also
has a halogen attached to it.
[0067] The illustration of specific protected forms and other
derivatives of the Formula (I) compounds is not intended to be
limiting. The application of other useful protecting groups, salt
forms, etc. is within the ability of the skilled artisan.
[0068] As used herein, a 2-pyridone derivative includes prodrugs of
a 2-pyridone, or an active drug made from a 2-pyridone. Preferably,
such derivatives include lactams (e.g., cephems, carbacephems,
penems, monolactams, etc.) covalently linked to the 2-pyridone
optionally via a spacer. Such derivatives and methods to make and
use them are apparent to the skilled artisan, given the teachings
of this specification.
[0069] II. Compounds
[0070] The subject invention involves compounds of Formula (I):
7
[0071] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7
and R.sup.8 are as defined in the Summary of the Invention section
above.
[0072] With reference to Formula (I), the description above
indicates that in one embodiment (defined in sub-part (A)), the
nucleus of the compounds will include only two fused rings as
depicted. Alternatively, the nucleus will include three fused
rings, as defined in sub-part (B) which is depicted as Formula (B)
below.
[0073] With respect to each of the preferred embodiments described,
a non-limiting list of preferred compounds is also set forth in
tabular form. It will be recognized that for purification,
administration and the like, salts and other derivatives of the
above compounds are often used. Thus, a pharmaceutically-acceptable
salt, hydrate, or biohydrolyzable ester, amide or imide thereof is
contemplated as part of the subject invention and is meant to be
included in the tables.
[0074] Table I contains a non-limiting list of preferred compounds
of Formula (I) where R.sup.1 and R.sup.8 do not join to form a
third fused ring (i.e., compounds of sub-part (A)).
1TABLE I R.sup.1 R.sup.2 R.sup.3 R.sup.5 R.sup.6 R.sup.7 R.sup.8 Et
H OH H H 8 OMe Et H OH H H 9 OMe Et H OH H H 10 OMe Et H OH H H 11
OMe Et H OH H H 12 OMe 13 H OH H H 14 OMe 15 H OH H H 16 OMe 17 H
OH H H 18 OMe 19 H OH H H 20 OMe 21 H OH H H 22 OMe 23 H OH H H 24
OMe 25 H OH H H 26 OMe 27 H OH H H 28 OMe 29 H OH H H 30 OMe 31 H
OH H H 32 OMe Et H OH H H 33 Me Et H OH H H 34 Me Et H OH H H 35 Me
Et H OH H H 36 Me Et H OH H H 37 Me 38 H OH H H 39 Me 40 H OH H H
41 Me 42 H OH H H 43 Me 44 H OH H H 45 Me 46 H OH H H 47 Me 48 H OH
H H 49 Me 50 H OH H H 51 Me 52 H OH H H 53 Me 54 H OH H H 55 Me 56
H OH H H 57 Me Et H OH H H 58 Cl Et H OH H H 59 Cl Et H OH H H 60
Cl Et H OH H H 61 Cl Et H OH H H 62 Cl 63 H OH H H 64 Cl 65 H OH H
H 66 Cl 67 H OH H H 68 Cl 69 H OH H H 70 Cl 71 H OH H H 72 Cl 73 H
OH H H 74 Cl 75 H OH H H 76 Cl 77 H OH H H 78 Cl 79 H OH H H 80 Cl
81 H OH H H 82 Cl
[0075] With regard to Formula (B), the compounds have a structure
according to the following structure: 83
[0076] where R.sup.1 and R.sup.8 of Formula (I) join to form a
6-membered heterocycloalkyl, and where Y is substituted or
unsubstituted --C-- or --N-- or Y is --O--; R.sup.13 and R.sup.13'
are independently selected from hydrogen and lower alkyl; and Z is
selected from --O--, --S--, substituted or unsubstituted --C-- and
substituted or unsubstituted --N--. Preferred for Y is --O--.
Preferred for Z is --CH.sub.2--. Preferred is where R.sup.13 is
hydrogen and R.sup.13' is lower alkyl, preferably methyl.
[0077] Table B contains a non-limiting list of preferred compounds
of Formula (B).
2TABLE B R.sup.2 R.sup.3 R.sup.5 R.sup.6 R.sup.7 Y Z R.sup.13
R.sup.13' H OH H H 84 O CH.sub.2 H Me H OH H H 85 O CH.sub.2 H Me H
OH H H 86 O CH.sub.2 H Me H OH H H 87 O CH.sub.2 H Me H OH H H 88 O
CH.sub.2 H Me H OH H H 89 S CH.sub.2 H Me H OH H H 90 S CH.sub.2 H
Me H OH H H 91 S CH.sub.2 H Me H OH H H 92 S CH.sub.2 H Me H OH H H
93 S CH.sub.2 H Me (Stereochemistry at the carbon atom bearing
R.sup.13 and R.sup.13' is preferably the S-configuration)
[0078] The preferred compounds of the present invention are those
where R.sup.8 and R.sup.1 do not join to form a ring.
[0079] The following provides a description of particularly
preferred moieties with respect to each of Formulas (I) and (B),
but is not intended to limit the scope of the claims.
[0080] R.sup.1 is selected from C.sub.3 to about C.sub.6
cycloalkyl, C.sub.4 to about C.sub.6 heterocycloalkyl, lower alkyl,
lower alkene, a 6-membered aryl, and a 6-membered heteroaryl.
Preferred is where R.sup.1 is C.sub.3 to about C.sub.6 cycloalkyl,
C.sub.4 to about C.sub.6 heterocycloalkyl, lower alkyl or lower
alkene. Most preferred is C.sub.3 to about C.sub.6 cycloalkyl and
lower alkyl. When R.sup.1 is cycloalkyl, preferred are rings having
from about 3 to about 5 ring carbon atoms, more preferably 3 ring
carbon atoms. R.sup.1 cycloalkyl moieties are preferably saturated
or unsaturated with one double bond; more preferably cycloalkyl
that is saturated. When R.sup.1 is linear lower alkyl, preferred is
where R.sup.1 contains from 1 to about 2 carbon atoms; methyl and
ethyl are preferred, most preferred is ethyl. When R.sup.1 is lower
linear alkene, preferred is where R.sup.1 contains from 2 to about
3 carbon atoms; ethenyl is preferred. When R.sup.1 is branched
lower alkyl or lower alkene, preferred is where R.sup.1 contains
from 3 to about 4 carbon atoms; branched lower alkyl is preferred;
t-butyl is particularly preferred. All of the R.sup.1 moieties
mentioned in this paragraph are unsubstituted or substituted. When
R.sup.1 is substituted, preferred is with one or more fluorine
atoms. When R.sup.1 is a 6-membered aryl or a 6-membered heteroaryl
aryl, the ring is unsubstituted or substituted with from 1 to about
3 fluorine atoms, one amino group (preferably at the 3-position of
the ring), one hydroxy group (preferably in the 4-position of the
ring), or a combination of these substituents; substituted phenyl
are preferred. Most preferred R.sup.1 moieties are selected from
cyclopropyl, ethyl, phenyl substituted with 1 to 3 fluoro, and
4-hydroxyphenyl; more preferred is 2,4-difluorophenyl, and
especially cyclopropyl or ethyl.
[0081] R.sup.2 is hydrogen.
[0082] R.sup.3 is selected from hydrogen and hydroxy. Preferred is
hydroxy. When R.sup.3 is hydroxy, it and the carbonyl to which it
is attached form a carboxylic acid moiety. As such, it is a
potential point of formation for the subject compounds of
pharmaceutically-acceptable salts, and biohydrolizable esters,
aminoacyls, and amides, as described herein. Compounds having any
such variations at the R.sup.3 position are included in the subject
invention.
[0083] R.sup.5 is selected from hydrogen, hydroxy, amino, halo,
lower alkyl, lower alkene and lower alkoxy. When R.sup.5 is lower
alkyl, preferred is where R.sup.5 has 1 to about 2 carbon atoms,
preferably 1 carbon atom. When R.sup.5 is lower alkene preferred is
where R.sup.5 contains from 2 to about 3 carbon atoms, more
preferred is where R.sup.5 has 2 carbon atoms. When R.sup.5 is
lower alkoxy, preferred is where R.sup.5 has 1 to about 2 carbon
atoms, preferably 1 carbon atom. All R.sup.5 alkyl, alkene and
lower alkoxy moieties are unsubstituted or substituted with fluoro
moieties. Preferred R.sup.5 is selected from hydrogen, hydroxy,
chloro, bromo, amino (preferably --NH.sub.2), methyl,
monofluoromethyl, difluoromethyl and trifluoromethyl. More
preferred R.sup.5 is selected from hydrogen, hydroxy, amino, and
methyl; most preferred is hydrogen.
[0084] R.sup.6 is selected from hydrogen, hydroxy, aminocarbonyl,
cyano, C.sub.1 to about C.sub.4 alkyl, and C.sub.2 to about C.sub.4
alkene, all such alkyl and alkene moieties being unsubstituted or
substituted with from 1 to about 3 fluoro, or in the case of methyl
or ethyl, optionally substituted with one hydroxy or one amino
moiety. R.sup.6 alkyl moieties preferably have from 1 to about 2
carbon atoms; preferred are methyl and ethyl; more preferred is
methyl. R.sup.6 alkenyl moieties have from 2 to about 4 carbon
atoms, preferably 2 carbon atoms, with one double bond; ethenyl is
preferred. All R.sup.6 alkyl moieties are unsubstituted or
substituted with from 1 to about 3 fluoro. R.sup.6 methyl or ethyl
moieties are optionally substituted with one hydroxy moiety or one
amino moiety. Preferred R.sup.6 is selected from hydrogen, hydroxy,
methyl, monofluoromethyl, difluoromethyl, and trifluoromethyl. More
preferred R.sup.6 is hydrogen.
[0085] R.sup.7is selected from 94
[0086] Preferred R.sup.7 moieties are pyrrolidinyl and piperidinyl
rings.
[0087] With respect to R.sup.7, R.sup.9 is (i) amino which is
attached to a ring carbon of R.sup.7 which is not adjacent to the
ring nitrogen of R.sup.7, the amino being unsubstituted or
substituted with one or two C.sub.1 to about C.sub.3 alkyl; or (ii)
aminoalkyl which is attached to any ring carbon of R.sup.7 and is
C.sub.1 to about C.sub.3 alkyl substituted with one amino, the
amino being unsubstituted or substituted with one or two C.sub.1 to
about C.sub.3 alkyl.
[0088] When R.sup.9 is amino, it is unsubstituted or substituted
with one or two alkyl moieties having from 1 to about 3 carbon
atoms, preferably methyl or ethyl, more preferably methyl;
preferred amino is unsubstituted or substituted with one such alkyl
moiety. When R.sup.7 is a piperidinyl ring, R.sup.9 is preferably
an unsubstituted or substituted amino moiety, more preferably at
the 3-position. More preferred R.sup.9, especially when R.sup.7 is
a piperidinyl ring, is --NH.sub.2.
[0089] When R.sup.9 is aminoalkyl, the alkyl has from 1 to about 3
carbon atoms, and preferably is methyl, ethyl, or isopropyl. The
alkyl is substituted with one amino, such amino being unsubstituted
or substituted with 1 or 2, preferably 1, alkyl group having from 1
to about 3 carbon atoms, preferably ethyl or especially methyl.
Such aminoalkyl can be attached to any carbon of the ring of
R.sup.7; preferably it is attached to a carbon not adjacent to the
ring nitrogen atom.
[0090] R.sup.9is preferably aminoalkyl if R.sup.7is a pyrrolidinyl
ring. Preferred R.sup.9, especially when R.sup.7 is a pyrrolidinyl
ring, is selected from aminomethyl, methylaminomethyl,
1-aminoethyl, 1-methylaminoethyl, 1-amino-1-methylethyl, and
1-methylamino-1-methylethy- l; such moieties are preferably
attached at the 3-position of the pyrrolidinyl ring.
[0091] The amino moiety of R.sup.9 is a potential point of
formation for the subject compounds of a
pharmaceutically-acceptable anionic salt; such salts are included
in the subject invention compounds. Preferred salts are acid
addition salts with, for example, HCl, CH.sub.3SO.sub.3H, HCOOH, or
CF.sub.3COOH.
[0092] R.sup.10 represents the moieties on R.sup.7 other than
R.sup.9 and each R.sup.10 is independently selected from hydrogen,
C.sub.1 to about C.sub.4 alkyl, C.sub.2 to about C.sub.6 alkene,
and a C.sub.3 to about C.sub.6 fused or spirocycle alkyl ring.
Alkyl R.sup.10 may be mono- or disubstituents on each ring carbon
atom to which R.sup.9 is not attached or mono-substituents on the
ring carbon to which R.sup.9 is attached (i.e., each ring carbon of
R.sup.7 may have two hydrogens, one hydrogen and R.sup.9, one
hydrogen and one alkyl, one alkyl and R.sup.9, or two alkyls bonded
to it). Preferably no more than two ring carbons have alkyl
R.sup.10 substituents; more preferably only one ring carbon has
alkyl R.sup.10 substituents; also preferably all R.sup.10 are
hydrogen. A non-hydrogen, non-alkyl R.sup.10 (aryl, heteroaryl,
hydroxy or alkoxy) may optionally be a mono-substituent on a ring
carbon to which R.sup.9 is not attached. Preferably there is no
more than one non-hydrogen, non-alkyl R.sup.10 for a subject
compound; more preferably there are none.
[0093] Non-hydrogen R.sup.10 includes C.sub.3 to about C.sub.6
carbocycloalkyl and linear or branched alkyl, preferably linear,
having from 1 to about 4 carbon atoms; methyl and ethyl are
preferred; methyl is more preferred. Non-hydrogen R.sup.10 also
includes linear or branched alkenyl, preferably linear, having from
2 to about 6 carbon atoms, preferably from 2 to about 4 carbon
atoms; ethenyl is preferred. Non-hydrogen R.sup.10 includes hydroxy
and linear or branched alkoxy having from 1 to about 4 carbon
atoms, preferably methoxy or ethoxy. Non-hydrogen R.sup.10 includes
aryl, preferably phenyl; and heteroaryl, preferably having 5 or 6
ring atoms with one or two, preferably one, heteroatom that is
preferably oxygen or sulfur. Preferred are thienyl and furyl.
[0094] Alkyl R.sup.10, especially dialkyl R.sup.10, are preferably
attached to a carbon of the ring of R.sup.7 which is adjacent to
the ring nitrogen atom, especially when R.sup.7 is a pyrrolidinyl
ring. A non-hydrogen, non-alkyl R.sup.10 is preferably attached to
a carbon of the ring of R.sup.7 which is not adjacent to the ring
nitrogen atom. Also preferred, when R.sup.7 comprises the
piperidinyl ring and R.sup.9 is attached to the 3-carbon of the
ring, is for one non-hydrogen R.sup.9 to be attached to the
4-carbon of the ring.
[0095] Two alkyl R.sup.9 moieties can be attached together thus
forming a fused or a spirocycle alkyl ring with the N-containing
ring of R.sup.7, the fused or spirocycle ring having from about 3
to about 6 carbon atoms. Such a fused or spirocycle alkyl ring is
preferably saturated or unsaturated with one double bond, more
preferably saturated. A spirocyclopropyl ring is particularly
preferred.
[0096] All alkyl and aryl portions of R.sup.10 moieties are
unsubstituted or substituted with one hydroxy moiety or with from 1
to about 3 fluoro moieties, preferably unsubstituted.
[0097] More preferred R.sup.10 is selected from hydrogen, methyl,
dimethyl, spirocyclopropyl, and ethyl; more preferred are ethyl,
dimethyl, and spirocyclopropyl; and especially hydrogen.
[0098] Optionally, an alkyl R.sup.10 can be connected to R.sup.9
thus forming a fused or a spirocycle ring with the N-containing
ring of R.sup.7, the fused or spirocycle ring having from 2 to
about 5 ring carbon atoms and 0 or 1 ring nitrogen atom (from
R.sup.9). Such fused or spirocycle ring may be a hydrocarbon ring
with an amino or aminoalkyl substituent, the amino being from
R.sup.9; or it may be a heterocyclic ring with the R.sup.9 amino
nitrogen being a ring nitrogen. Such ring may have one or two
alkanyl substituents. Such fused or spirocycle ring is preferably
saturated or unsaturated with one double bond; more preferably it
is saturated.
[0099] Subject compounds having R.sup.9 or R.sup.10 spirocycles are
named according to the following numbering system: the numbering
starts at the smaller ring, completing around the larger ring which
forms a spiro junction, e.g., at carbon 3 when the smaller ring is
cyclopropyl as for the following example: 95
[0100] The aza nomenclature used herein follows the conventional
nomenclature and is the position where the ring nitrogen is
attached to the quinolone nucleus.
[0101] R.sup.8 is selected from hydrogen, halo, lower alkoxy, lower
alkylthio, lower alkyl and lower alkenyl. When R.sup.8 is lower
alkyl, preferred is where R.sup.8 has from 1 to about 2 carbon
atoms; methyl is preferred. When R.sup.8 is lower alkene, preferred
R.sup.8 will have from 2 to about 4 carbon atoms; ethenyl is
preferred. All R.sup.8 alkyl and alkene moieties are unsubstituted
or substituted with fluoro. When R.sup.8 is lower alkoxy, preferred
is where R.sup.8 has 1 to about 4 carbon atoms. When R.sup.8 is
lower alkylthio, preferred is where R.sup.8 has 1 to about 4 carbon
atoms. Preferred R.sup.8 is selected from chloro, methyl, inethoxy,
methylthio, monofluoromethyl, difluoromethyl, trifluoromethyl,
monofluoromethoxy, difluoromethoxy, and trifluoromethoxy. More
preferred R.sup.8 is selected from methyl substituted with from 1
to 3 fluoro, methoxy, methylthio, and chloro; especially methoxy,
methylthio and chloro.
[0102] As used herein, any radical is independently selected each
time it is used (e.g., R.sup.1 and R.sup.5 need not be the same in
all occurrences in defining a given compound of this
invention).
[0103] The compounds of the invention may contain chiral center(s),
thus any such compound includes and contemplates each optical
isomer, diastereomer or enantiomer thereof, in purified or
substantially purified form, and mixtures thereof, including
racemic mixtures.
[0104] The following exemplary compounds are made using the
procedures described herein and variations thereof which are within
the purview of the skilled artisan's practice. The examples below
do not limit the invention, but rather serve to illustrate some of
the embodiments of the invention.
[0105] The subject invention compounds above are also useful
precursors for compounds of formula P-L-B, wherein P is a compound
of Formula (I), L is a linking moiety, and B is a lactam containing
moiety. This formula includes optical isomers, disatereomers or
enantiomers thereof; pharmaceutically-acceptable salts, hydrates,
or biohydrolyzable esters, amides and imides thereof. Compounds
wherein a quinolone is linked to a lactam and their uses are
disclosed in U.S. Pat. No. 5,180,719 issued Jan. 19, 1993; U.S.
Pat. No. 5,387,748 issued Feb. 7, 1995; U.S. Pat. No. 5,491,139
issued Feb. 13, 1996; U.S. Pat. No. 5,530,116 issued Jun. 25, 1996;
and EPO publications 0366189 published May 2, 1990 and 0366640
published May 2, 1990, all incorporated herein by reference. The
skilled artisan will recognize that the 2-pyridone compounds of the
present invention can be substituted for the quinolones disclosed
in these references. For compositions and methods of use, the
compounds of formula P-L-B are useful in the same way as compounds
of Formula (I). Thus, they can be interchanged in the composition
examples herein.
[0106] Biological activities of the invention compounds can be
compared to ciprofloxacin and the other known antimicrobial
compounds. Compounds of the subject invention provide better
antibacterial properties against certain quinolone resistant
bacteria compared to ciprofloxacin and certain other prior art
compounds. When tested against quinolone-resistant bacteria such as
S. aureus, S. saprophyticus, E. faecalis, S. pyogenes, S.
pneumoniae, S. viridans, E. coli, P. aeruginosa, P. mirabilis, K.
pneumoniae, E. cloacae, certain compounds of the subject invention
have been found to have MIC values (.mu.g/ml) that are up to about
500 times lower than ciprofloxacin.
[0107] III. General Reaction Schemes for Compound Preparation
[0108] In making the compounds of the invention, the order of
synthetic steps may be varied to increase yield of desired product.
In addition, the skilled artisan will also recognize the judicious
choice of reactants, solvents, and temperatures is an important
component in successful synthesis. While the determination of
optimal conditions, etc. is routine, it will be understood that a
variety of compounds can be generated in a similar fashion, using
the guidance of the scheme below. Specific synthetic examples are
set forth for a variety of compounds in Section VI.
[0109] The starting materials used in preparing the compounds of
the invention are known, made by known methods, or are commercially
available as a starting material.
[0110] It is recognized that the skilled artisan in the art of
organic chemistry can readily carry out standard manipulations of
organic compounds without further direction; that is, it is well
within the scope and practice of the skilled artisan to carry out
such manipulations. These include, but are not limited to,
reduction of carbonyl compounds to their corresponding alcohols,
oxidations, acylations, aromatic substitutions, both electrophilic
and nucleophilic, etherifications, esterification and
saponification and the like. Examples of these manipulations are
discussed in standard texts such as March, Advanced Organic
Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry
(Vol. 2), Fieser & Feiser, Reagents for Organic Synthesis (16
volumes), L. Paquette, Encyclopedia of Reagents for Organic
Synthesis (8 volumes), Frost & Fleming, Comprehensive Organic
Synthesis (9 volumes) and the like.
[0111] The skilled artisan will readily appreciate that certain
reactions are best carried out when other functionality is masked
or protected in the molecule, thus avoiding any undesirable side
reactions and/or increasing the yield of the reaction. Often the
skilled artisan utilizes protecting groups to accomplish such
increased yields or to avoid the undesired reactions. These
reactions are found in the literature and are also well within the
scope of the skilled artisan. Examples of many of these
manipulations can be found for example in T. Greene, Protecting
Groups in Organic Synthesis. Of course, amino acids used as
starting materials with reactive side chains are preferably blocked
to prevent undesired side reactions.
[0112] General procedures for preparing 2-pyridone moieties useful
in making the compounds of the subject invention are described in
the following references, all incorporated by reference herein
(including articles listed within these references): European
Patent Application No. 308,019 to Heck James, V. et al, Sep. 9,
1988; World Patent Application No. 99/07696 to Tae Ho et al, Aug.
9, 1997; World Patent Application No. 91/16894 to Chu Daniel, T. et
al, May 2, 1990; World Patent Application No. 95/10519 to Chu
Daniel, T. et al, Oct. 14, 1993; U.S. Pat. No. No. 5,599,816 to Chu
Daniel, T. et al, Jun. 7, 1995; U.S. Pat. No. 5,726,182 to Chu
Daniel, T. et al, Jun. 7, 1995; U.S. Pat. No. 5,580,872 to Chu
Daniel, T. et al, Sep. 30, 1995; and J. Med. Chem., Vol. 39, pp.
3070-3088 (1996), Qun et al., "Synthesis and Structure-Activity
Relationships of 2-Pyridones: A Novel series of Potent DNA Gyrase
Inhibitors as Antibacterial Agents." One methodology for providing
the compounds of the invention is shown in Reaction Scheme below:
96
[0113] In this reaction scheme, the pyridone nucleus is typically
obtained from the corresponding substituted pyridine containing a
leaving group at the 4-position for subsequent introduction of the
desired side chain.
[0114] IV. Compositions
[0115] The compositions of this invention comprise:
[0116] (a) a safe and effective amount of the compound of the
invention; and
[0117] (b) a pharmaceutically-acceptable excipient.
[0118] It may also optionally comprise other antimicrobials or
other actives, which may or may not act synergystically with the
invention.
[0119] A "safe and effective amount" of a 2-pyridone is an amount
that is effective, to inhibit microbial growth at the site of an
infection to be treated in a host, without undue adverse side
effects (such as toxicity, irritation, or allergic response),
commensurate with a reasonable benefit/risk ratio when used in the
manner of this invention. The specific "safe and effective amount"
will vary with such factors as the particular condition being
treated, the physical condition of the patient, the duration of
treatment, the nature of concurrent therapy (if any), the specific
dosage form to be used, the excipient employed, the solubility of
the 2-pyridone therein, and the dosage regimen desired for the
composition.
[0120] The compositions of this invention are preferably provided
in unit dosage form. As used herein, a "unit dosage form" is a
composition of this invention containing an amount of a 2-pyridone
that is suitable for administration to a human or lower animal
subject, in a single dose, according to good medical practice.
These compositions preferably contain from about 30 mg, more
preferably from about 50 mg, more preferably still from about 100
mg, preferably to about 20,000 mg, more preferably to about 7,000
mg, more preferably still to about 1,000 mg, most preferably to
about 500 mg, of a 2-pyridone.
[0121] The compositions of this invention may be in any of a
variety of forms, suitable (for example) for oral, rectal, topical
or parenteral administration. Depending upon the particular route
of administration desired, a variety of pharmaceutically-acceptable
excipients well-known in the art may be used. These include solid
or liquid fillers, diluents, hydrotropes, surface-active agents,
and encapsulating substances. Optional pharmaceutically-active
materials may be included, which do not substantially interfere
with the antimicrobial activity of the 2-pyridone. The amount of
excipient employed in conjunction with the 2-pyridone is sufficient
to provide a practical quantity of material for administration per
unit dose of the 2-pyridone. Techniques and compositions for making
dosage forms useful in the methods of this invention are described
in the following references, all incorporated by reference herein:
Modern Pharmaceutics, Vol. 7, Chapters 9 and 10 (Banker &
Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage
Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical
Dosage Forms 2d Edition (1976).
[0122] In particular, pharmaceutically-acceptable excipients for
systemic administration include sugars, starches, cellulose and its
derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils,
synthetic oils, polyols, alginic acid, phosphate buffer solutions,
emulsifiers, isotonic saline, and pyrogen-free water. Preferred
excipients for parenteral administration include propylene glycol,
ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the
pharmaceutically-acceptable excipient, in compositions for
parenteral administration, comprises at least about 90% by weight
by the total composition.
[0123] In addition, dosages for injection may be prepared in dried
or lyophilized form. Such forms can be reconstituted with water or
saline solution, depending on the preparation of the dosage form.
Such forms may be packaged as individual dosages or multiple
dosages for easier handling. Where lyophilized or dried dosages are
used, the reconstituted dosage form is preferably isotonic, and at
a physiologically compatible pH.
[0124] Various oral dosage forms can be used, including such solid
forms as tablets, capsules, granules and bulk powders. These oral
forms comprise a safe and effective amount, usually at least about
5%, and preferably from about 25% to about 50%, of the 2-pyridone.
Tablets can be compressed, tablet triturates, enteric-coated,
sugar-coated, film-coated, or multiple-compressed, containing
suitable binders, lubricants, diluents, disintegrating agents,
coloring agents, flavoring agents, flow-inducing agents, and
melting agents. Liquid oral dosage forms include aqueous solutions,
emulsions, suspensions, solutions and/or suspensions reconstituted
from non-effervescent granules, and effervescent preparations
reconstituted from effervescent granules, containing suitable
solvents, preservatives, emulsifying agents, suspending agents,
diluents, sweeteners, melting agents, coloring agents and flavoring
agents, such are well known to the skilled artisan. Preferred
excipients for oral administration include gelatin, propylene
glycol, cottonseed oil and sesame oil.
[0125] The compositions of this invention can also be administered
topically to a subject, i.e., by the direct laying on or spreading
of the composition on the epidermal or epithelial tissue of the
subject. Such compositions include, for example, lotions, creams,
solutions, gels and solids. These topical compositions preferably
comprise a safe and effective amount, usually at least about 0.1%,
and preferably from about 1% to about 5%, of the 2-pyridone.
Suitable excipients for topical administration preferably remain in
place on the skin as a continuous film, and resist being removed by
perspiration or immersion in water. Generally, the excipient is
organic in nature and capable of having dispersed or dissolved
therein the 2-pyridone. The excipient may include
pharmaceutically-acceptable emolients, emulsifiers, thickening
agents, and solvents and the like; these are well known to the
skilled artisan.
[0126] V. Methods of Using the Compounds
[0127] This invention also provides methods of treating an
infectious disorder in a human or other animal subject, by
administering a safe and effective amount of a 2-pyridone to said
subject. As used herein, an "infectious disorder" is any disorder
characterized by the presence of a microbial infection. Preferred
methods of this invention are for the treatment of bacterial
infections. Such infectious disorders include (for example) central
nervous system infections, external ear infections, infections of
the middle ear (such as acute otitis media), infections of the
cranial sinuses, eye infections, infections of the oral cavity
(such as infections of the teeth, gums and mucosa), upper
respiratory tract infections, lower respiratory tract infections,
including pneumonia, genitourinary infections, gastrointestinal
infections, gynecological infections, septicemia, sepsis,
peritonitis, bone and joint infections, skin and skin structure
infections, bacterial endocarditis, burns, antibacterial
prophylaxis of surgery, and antibacterial prophylaxis in
post-operative patients or in immunosuppressed patients (such as
patients receiving cancer chemotherapy, or organ transplant
patients).
[0128] The term "treatment" is used herein to mean that, at a
minimum, administration of a compound of the present invention
mitigates a disease associated an infectious disorder in a host,
preferably in a mammalian subject, more preferably in humans. Thus,
the term "treatment" includes: preventing an infectious disorder
from occurring in a host, particularly when the host is predisposed
to acquiring the disease, but has not yet been diagnosed with the
disease; inhibiting the infectious disorder; and/or alleviating or
reversing the infectious disorder. Insofar as the methods of the
present invention are directed to preventing infectious disorders,
it is understood that the term "prevent" does not require that the
disease state be completely thwarted. (See Webster's Ninth
Collegiate Dictionary.) Rather, as used herein, the term preventing
refers to the ability of the skilled artisan to identify a
population that is susceptible to infectious disorders, such that
administration of the compounds of the present invention may occur
prior to onset of infection. The term does not imply that the
disease state need be completely avoided.
[0129] The 2-pyridone derivatives and compositions of this
invention can be administered topically or systemically. Systemic
application includes any method of introducing the 2-pyridone into
the tissues of the body, e.g., intrathecal, epidural,
intramuscular, transdermal, intravenous, intraperitoneal,
subcutaneous, sublingual, rectal, and oral administration. The
specific dosage of antimicrobial to be administered, as well as the
duration of treatment, are mutually dependent. The dosage and
treatment regimen will also depend upon such factors as the
specific 2-pyridone used, the resistance pattern of the infecting
organism to the 2-pyridone used, the ability of the 2-pyridone to
reach minimum inhibitory concentrations at the site of the
infection, the nature and extent of other infections (if any), the
personal attributes of the subject (such as weight), compliance
with the treatment regimen, the age and health status of the
patient, and the presence and severity of any side effects of the
treatment.
[0130] Typically, for a human adult (weighing approximately 70
kilograms), from about 75 mg, more preferably from about 200 mg,
most preferably from about 500 mg to about 30,000 mg, more
preferably to about 10,000 mg, most preferably to about 3,500 mg,
of 2-pyridone is administered per day. Treatment regimens
preferably extend from about 1, preferably from about 3 to about 56
days, preferably to about 20 days, in duration. Prophylactic
regimens (such as avoidance of opportunistic infections in
immuno-compromised patients) may extend 6 months, or longer,
according to good medical practice.
[0131] A preferred method of parenteral administration is through
intravenous injection. As is known and practiced in the art, all
formulations for parenteral administration must be sterile. For
mammals, especially humans, (assuming an approximate body weight of
70 kilograms) individual doses of from about 100 mg, preferably
from about 500 mg to about 7,000 mg, more preferably to about 3,500
mg, is acceptable.
[0132] In some cases, such as generalized, systemic infections or
in immune-compromised patients, the invention may be dosed
intravenously. The dosage form is generally isotonic and at
physiological pH. The dosage amount will depend on the patient and
severity of condition, as well as other commonly considered
parameters. Determination of such doses is well within the scope of
practice for the skilled practitioner using the guidance given in
the specification.
[0133] A preferred method of systemic administration is oral
administration. Individual doses of from about 20 mg, more
preferably from about 100 mg to about 2,500 mg, more preferably to
about 500 mg.
[0134] Topical administration can be used to deliver the 2-pyridone
systemically, or to treat a local infection. The amounts of
2-pyridone to be topically administered depends upon such factors
as skin sensitivity, type and location of the tissue to be treated,
the composition and excipient (if any) to be administered, the
particular 2-pyridone to be administered, as well as the particular
disorder to be treated and the extent to which systemic (as
distinguished from local) effects are desired.
VI. EXAMPLES
[0135] Compound Preparation
[0136] The following abbreviations are used herein:
[0137] THF: Tetrahydrofuran
[0138] LDA: Lithium diisopropylamide
[0139] DIBAL: Diisobutyl aluminium hydride
[0140] a. Precursor Preparation--Nuclei 97
[0141] 3-Methoxy-2-Methyl-1,4-Pyrone
[0142] 3-hydroxy-2-methyl-1,4-pyrone (100.3 g) is dissolved in 500
ml of a 10% solution of KOH in water. Dimethyl sulfate (76 ml) is
then added over a period of 30 min, while keeping the temperature
around 25.degree. C. The reaction is then concentrated to one
quarter of the original volume and acidified by addition of
hydrochloric acid. This phase is extracted 3 times with ethyl
acetate, the organic phase dried over sodium sulfate and the
solvent evaporated to yield the desired product.
[0143] 3-Methoxy-2-Methyl-1,4-Pyridone
[0144] 3-Methoxy-2-methyl-1,4-pyrone (64.14 g) is mixed with a 28%
aqueous solution of ammonia (750 ml) in a glass lined steel bomb
and the mixture is stirred at 120.degree. C. for 24 hours. The
excess of water and ammonia is evaporated and the residue
triturated in a mixture of ethanol and ethyl acetate; the solid is
filtered and dried to afford the desired product.
[0145] 4-Chloro-3-Methoxy-2-Methyl-Pyridine
[0146] 3-Methoxy-2-methyl-1,4-pyridone (11.29 g) is mixed in
phosphorous oxychloride (100 ml) and refluxed for 10 hours. The
excess of reagent is evaporated and the residue is redissolved in
toluene (100 ml) and evaporated. Water (100 ml) is added to the
residue and the pH adjusted to 11 by addition of potassium
carbonate, then extracted with methylene chloride. The organic
phased is dried over sodium sulfate and evaporated to afford the
desired product.
[0147] 4- Chloro-3-Methoxy-2-Bromomethyl-Pyridine
[0148] 4-Chloro-3-methoxy-2-methyl-pyridine (6.12 g) is dissolved
in carbon tetrachloride (80 ml) then N-bromo-succinimide (7.12 g)
and benzoyl peroxide (1 g) are added. The reaction mixture is
refluxed under UV irradiation for 1.5 hour. The solid is filtered
after cooling and the solvent evaporated. The desired product is
purified by chromatography on silica gel.
[0149] 2-(4-Chloro-3-Methoxy-2-Pyridinyl)-Acetonitrile
[0150] 4-Chloro-3-methoxy-2-bromomethyl-pyridine (4.69 g) and
sodium cyanide (5.11 g) are added to 20 ml of a 1/1 mixture of
water and ethanol. The reaction is stirred at 60.degree. C. for 3
hours. The ethanol is evaporated and the residue diluted in water
and extracted with methylene chloride. The desired product is
obtained by chromatography using hexane/ethyl acetate (9/1) as
solvent.
[0151] 2-(4-Chloro-3-Methoxy-2-Pyridinyl)-Butyronitrile
[0152] 2-(4-Chloro-3-methoxy-2-pyridinyl)-acetonitrile (7.06 g) is
dissolved in THF (40 ml) and 60% sodium hydride (1.62 g) is added
followed by 3.25 ml of ethyl iodide. The reaction is allowed to
stir at 45.degree. C. for 1.5 hour then the reaction mixture is
diluted with water and extracted with ethyl acetate. The desired
product is purified by chromatography using hexane/ethyl acetate
4/1 as solvent.
[0153] 2-(4-Chloro-3-Methoxy-2-Pyridinyl)-Butanal
[0154] 2-(4-Chloro-3-methoxy-2-pyridinyl)-butyronitrile (2.78 g) is
dissolved in diethyl ether (150 ml), the solution is cooled to
-74.degree. C. and DIBAL (29 ml 1.0M) is added over a 30 min
period. The solution is allowed to stir at -74.degree. C. for an
hour then at 0.degree. C. for another hour. The reaction is
quenched by addition of 5% sulfuric acid (25 ml), keeping the
temperature around 0.degree. C. The phases are separated and the
organic phase washed with a solution of sodium bicarbonate, dried
and evaporated to afford the desired product.
[0155]
Ethyl-4-(4-Chloro-3-Methoxy-2-Pyridinyl)-2-Carboxyethyl-Hexen-2-Oat-
e
[0156] 2-(4-Chloro-3-methoxy-2-pyridinyl)-butanal (1.081 g) is
dissolved in 40 ml of ethanol. Piperidine (1.2 ml), acetic acid
(1.2 ml), and diethyl malonate are then added sequentially. The
reaction is stirred at 40.degree. C. overnight and the volatiles
removed, the residue is redissolved in ether, washed with water,
brine, and evaporated. The desired product is purified by
chromatography using hexane/ethyl acetate 4/1 as solvent.
[0157]
Ethyl-8-Chloro-1-Ethyl-9-Methoxy-4-Oxo-4H-Quinolizine-3-Carboxylate
(Precursor A)
[0158]
Ethyl-4-(4-Chloro-3-methoxy-2-pyridinyl)-2-carboxyethyl-hexen-2-oat-
e (0.624 g) is dissolved in 25 ml of Dowtherm.TM. and heated at
200.degree. C. for 4 hours. The desired product is purified by
chromatography using hexane then ethyl acetate as solvent. 98
[0159] 4-Chloro-3-Methoxy-2-(Cyclopropyl)-Methyl Pyridine
[0160] Cyclopropyl bromide (0.5 ml) is dissolved in 5 ml of THF and
magnesium (0.15 g) is added and heat is applied to initiate the
reaction. Once the reaction is completed, the solution is cooled to
-45.degree. C. and cuprous iodide (0.5 g) is added. The reaction is
allowed to stir for 30 minutes and
4-Chloro-3-methoxy-2-bromomethyl-pyridine (0.154 g) is added. The
reaction is stirred at -45.degree. C. for one hour and allowed to
warm at room temperature before being quenched by 5 ml of28%
ammonium hydroxide. The reaction is extracted with ether and the
desired product purified by chromatography using hexane/ethyl
acetate 9/1 as solvent.
[0161]
Ethyl-4-(4-Chloro-3-Methoxy-2-Pyridinyl)-4-Cyclopropyl-2-Carboxyeth-
yl-Buten-2-Oate
[0162] A solution of LDA (2.0M, 0.8 ml) is dissolved in 2 ml of THF
and the solution cooled at -60.degree. C. A solution of
4-Chloro-3-methoxy-2-(cyclopropyl)-methyl pyridine (0.36 g) in THF
(1 ml) is added dropwise, keeping the temperature at -60.degree. C.
and the reaction is stirred at the same temperature for one hour.
Diethyl (ethoxymethylene)malonate is added and the solution is
slowly allowed to warm at room temperature. Water is added and the
reaction is extracted with dichloromethane. The desired product is
purified by chromatography using hexane ethyl acetate 4/1 as
solvent.
[0163]
Ethyl-8-Chloro-1-Cyclopropyl-9-Methoxy-4-Oxo-4H-Quinolizine-3-Carbo-
xylate (Prec. B)
[0164]
Ethyl-4-(4-Chloro-3-methoxy-2-pyridinyl)-4-cyclopropyl-2-carboxyeth-
yl-buten-2-oate (0.28 g) is dissolved in 12 ml of Dowtherm.TM. and
heated at 200.degree. C. for 4 hours. The desired product is
purified by chromatography using hexane then ethyl acetate as
solvent. 99
[0165] 4-Chloro-3-Methyl-Pyridine
[0166] To a solution of LDA (2.0 M, 50 ml) in THF (100 ml) at
-70.degree. C. is added 4-chloropyridine (11.3 g) in solution in
THF (20 ml) keeping the temperature below -65.degree. C. The
reaction is allowed to stir for 4 hours at -70.degree. C. and
methyl iodide (15 g) is added keeping the temperature below
-65.degree. C. The reaction is then allowed to warm at room
temperature and water is added. The aqueous phase is extracted with
ether and the desired compound is obtained by distillation under
reduced pressure after removal of the solvent.
[0167] 2-Propyl-4-Chloro-3-Methyl-Pyridine
[0168] To a solution of propyl iodide (12.7 g) in THF (10 ml) is
added lithium (0.45 g) and the reaction is allowed to stir at room
temperature until complete dissolution of the lithium.
4-Chloro-3-methyl-pyridine (9.5 g) is then added and the mixture
allowed to stir at 40.degree. C. for 4 hours. After cooling at room
temperature, ether is added and the organic phase washed with
water. After removal of the solvent the desired product is obtained
by chromatography using hexane/ether 9/1 as solvent.
[0169]
Ethyl-4-(4-Chloro-3-Methyl-2-Pyridinyl)-2-Carboxyethyl-Hexen-2-Oate
[0170] A solution of LDA (2.0M, 5 ml) is dissolved in 20 ml of THF
and the solution cooled at -60.degree. C. A solution of
2-propyl-4-chloro-3-methy- l-pyridine (1.7 g) in THF (5 ml) is
added dropwise, keeping the temperature at -60.degree. C. and the
reaction is stirred at the same temperature for one hour. Diethyl
(ethoxymethylene)malonate is added and the solution is slowly
allowed to warm at room temperature. Water is added and the
reaction is extracted with dichloromethane. The desired product is
purified by chromatography using hexane/ethyl acetate 4/1 as
solvent.
[0171]
Ethyl-8-Chloro-1-Ethyl-9-Methyl-4-Oxo-4H-Quinolizine-3-Carboxylate
(Precursor C)
[0172]
Ethyl-4-(4-Chloro-3-methyl-2-pyridinyl)-2-carboxyethyl-hexen-2-oate
(0.72 g) is dissolved in 20 ml of Dowtherm.TM. and heated at
200.degree. C. for 4 hours. The desired product is purified by
chromatography using hexane then ethyl acetate as solvent.
[0173] b. Precursor Preparation--7-Position Moiety 100
[0174] 3-(N-boc-aminoethyl)pyrrolidine (Precursor D) is prepared
according to Chem. Pharm. Bull. 42(7) 1442-1454 (1994) and
references cited therein.
Precursor Example E
[0175] 101
[0176] 3-S-aminopiperidine dihydrochloride (Precursor E) is
prepared according to J. Chem soc Dalton Trans. 1127-1132
(1987).
[0177] c. Final Product Preparation 102
[0178]
8-[3-(N-Boc-Aminoethyl)Pyrrolidinyl]-1-Ethyl-9-Methoxy-4-Oxo-4H-Qui-
nolizine-3-Carboxylic Acid Ethyl Ester
[0179]
Ethyl-8-chloro-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate
(Precursor A) (0.151 g) and triethylamine (0.5 ml) are dissolved in
acetonitrile (6 ml). To this solution
3-(N-boc-aminoethyl)pyrrolidine (Precursor D) (0.215 g) is added
and the solution stirred at 40.degree. C. for 18 hours. The solvent
is evaporated and the residue dissolved in dichloromethane, washed
with 1N hydrochloric acid and dried over sodium sulfate. The
desired product is obtained by evaporation of the solvent.
[0180]
8-[3-(N-Boc-Aminoethyl)Pyrrolidinyl]-1-Ethyl-9-Methoxy-4-Oxo-4H-Qui-
nolizine-3-Carboxylic Acid
[0181]
8-[3-(Nboc-aminoethyl)pyrrolidinyl]-1-ethyl-9-methoxy-4-oxo-4H-quin-
olizine-3-carboxylic acid ethyl ester (0.234 g) is suspended in a
mixture of water/THF (60 ml 5/1) and lithium hydroxide (0.215 g) is
added. The reaction is stirred at 60.degree. C. for 36 hours then
cooled, acidified to pH 2 by addition of hydrochloric acid and the
solution is extracted with dichloromethane. The extracts are dried
over sodium sulfate and the solvent evaporated to afford the
desired product.
[0182]
8-[3-Aminoethyl-Pyrrolidinyl]-1-Ethyl-9-Methoxy-4-Oxo-4H-Quinolizin-
e-3-Carboxylic Acid
[0183]
8-[3-(N-boc-aminoethyl)pyrrolidinyl]-1-ethyl-9-methoxy-4-oxo-4H-qui-
nolizine-3-carboxylic acid (0.12 g) is dissolved in dry
dichloromethane (3 ml) and iodotrimethylsilane (0.0534 g) is added.
The solution is allowed to stir 5 minutes and ethanol (5 ml) is
added. The solution is partially concentrated and the precipitate
filtered to afford the title compound.
Example 2
[0184] 103
[0185]
8-(3-Aminopiperidinyl)-1-Ethyl-9-Methoxy-4-Oxo-4H-Quinolizine-3-Car-
boxylic Acid, Ethyl Ester
[0186]
Ethyl-8-chloro-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate
(Precursor A) (0.05 g) is dissolved in acetonitrile (3 ml) and
triethylamine (0.3 ml). To this solution is added
3-S-aminopiperidine dihydrochloride (Precursor E) (0.055 g) and the
mixture is stirred at 40.degree. C. for five days. The reaction
mixture is evaporated and the desired product obtained by
recrystallization in isopropyl alcohol.
[0187]
8-(3-Aminopiperidinyl)-1-Ethyl-9-Methoxy-4-Oxo-4H-Quinolizine-3-Car-
boxylic Acid
[0188]
8-(3-aminopiperidinyl)-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-car-
boxylic acid, ethyl ester (0.028 g) is dissolved in 9 ml of a 2/1
mixture of water and THF and lithium hydroxide (0.035 g) is added.
The resulting solution is stirred at 60.degree. C. for 4 days and
the solution adjusted to pH 7.2 by addition of acetic acid. The
title compound is collected by filtration of the precipitate.
Example 3
[0189] 104
[0190]
8-[3-Aminoethyl-Pyrrolidinyl]-1-Cyclopropyl-9-Methoxy-4-Oxo-4H-Quin-
olizine-3-Carboxylic Acid
[0191] A series of procedures similar to Example 1 above is carried
out, using
Ethyl-8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carbo-
xylate (Precursor B) and 3-(N-boc-aminoethyl)pyrrolidine (Precursor
D) as the starting materials.
Example 4
[0192] 105
[0193]
8-(3-Aminopiperidinyl)-1-Cyclopropyl-9-Methoxy-4-Oxo-4H-Quinolizine-
-3-Carboxylic Acid
[0194] A series of procedures similar to Example 2 above is used
using
Ethyl-8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate
(Precursor B) and 3-S-aminopiperidine dihydrochloride (Precursor E)
as the starting materials.
Example 5
[0195] 106
[0196] A series of procedures similar to Example 1 above is used
using
Ethyl-8-chloro-1-ethyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate
(Precursor C) and 3-(N-boc-aminoethyl)pyrrolidine (Precursor D) as
the starting materials.
Example 6
[0197] 107
[0198] A series of procedures similar to Example 2 above is used
using
Ethyl-8-chloro-1-ethyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate
(Precursor C) and 3-S-aminopiperidine dihydrochloride (Precursor E)
as the starting materials.
[0199] VII. Examples--Compositions and Methods of Use
[0200] The following non-limiting examples illustrate the
compositions and methods of use of the present invention.
Example 7
[0201] A tablet composition for oral administration, according to
the present invention, is made comprising:
3 Component Amount Compound of Example 1 150 mg Lactose 120 mg
Maize Starch 70 mg Talc 4 mg Magnesium Stearate 1 mg
[0202] Other compounds having a structure according to Formula (I)
are used with substantially similar results.
Example 8
[0203] A capsule containing 200 mg of active for oral
administration, according to the present invention, is made
comprising:
4 Component Amount (% w/w) Compound of Example 4 15% Hydrous
Lactose 43% Microcrystalline Cellulose 33% Crosspovidone 3.3%
Magnesium Stearate 5.7%
[0204] Other compounds having a structure according to Formula (I)
are used with substantially similar results.
Example 9
[0205] A saline-based composition for ocular administration,
according to the present invention, is made comprising:
5 Component Amount (% w/w) Compound of Example 2 10% Saline 90%
[0206] Other compounds having a structure according to Formula (I)
are used with substantially similar results.
Example 10
[0207] An intranasal composition for local administration,
according to the present invention, is made comprising:
6 Component Composition (% w/v) Compound of Example 5 0.20
Benzalkonium chloride 0.02 EDTA 0.05 Glycerin 2.0 PEG 1450 2.0
Aromatics 0.075 Purified water q.s.
[0208] Other compounds having a structure according to Formula (I)
are used with substantially similar results.
Example 11
[0209] An inhalation aerosol composition, according to the present
invention, is made comprising:
7 Component Composition (% w/v) Compound of Example 3 5.0 Ascorbic
acid 0.1 Menthol 0.1 Sodium Saccharin 0.2 Propellant (F12, F114)
q.s.
[0210] Other compounds having a structure according to Formula (I)
are used with substantially similar results.
Example 12
[0211] A topical opthalmic composition, according to the present
invention, is made comprising:
8 Component Composition (% w/v) Compound of Example 1 0.10
Benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethylcellulose 0.5
Acetic acid 0.20 Sodium metabisulfite 0.10 Sodium chloride (0.9%)
q.s.
[0212] Other compounds having a structure according to Formula (I)
are used with substantially similar results.
Example 13
[0213] An antimicrobial composition for parenteral administration,
according to this invention, is made comprising:
9 Component Amount Compound of Example 2 30 mg/ml excipient
Excipient: 50 mm phosphate buffer pH 5 buffer with lecithin 0.48%
carboxymethylcellulose 0.53 povidone 0.50 methyl paraben 0.11
propyl paraben 0.011
[0214] The above ingredients are mixed, forming a suspension.
Approximately 2.0 ml of the suspension is systemically
administered, via intramuscular injection, to a human subject
suffering from a lower respiratory tract infection, with
Streptococcus pneumoniae present. This dosage is repeated twice
daily, for approximately 14 days. After 4 days, symptoms of the
disease subside, indicating that the pathogen has been
substantially eradicated. Other compounds having a structure
according to Formula (I) are used with substantially similar
results.
Example 14
[0215] An enteric coated antimicrobial composition for oral
administration, according to this invention, is made comprising the
following core tablet:
10 Component Amount (mg) Compound of Example 6 350.0 Maltodextrine
30.0 Magnesium Stearate 5.0 Microcrystalline Cellulose 100.0
Colloidal Silicon Dioxide 2.5 Povidone 12.5
[0216] The components are admixed into a bulk mixture. Compressed
tablets are formed, using tabletting methods known in the art. The
tablet is then coated with a suspension of methacrylic
acid/methacrylic acid ester polymer in isopropanol/acetone. A human
subject, having a urinary tract infection with Escherichia coli
present, is orally administered two of the tablets, every 8 hours,
for 4 days. Symptoms of the disease then subside, indicating
substantial eradication of the pathogen. Other compounds having a
structure according to Formula (I) are used with substantially
similar results.
[0217] All references described herein are hereby incorporated by
reference.
[0218] While particular embodiments of the subject invention have
been described, it will be obvious to those skilled in the art that
various changes and modifications of the subject invention can be
made without departing from the spirit and scope of the invention.
It is intended to cover, in the appended claims, all such
modifications that are within the scope of this invention.
* * * * *