Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-01
2002-07-16
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S003000
Reexamination Certificate
active
06420360
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention provides sultam and sultone derived oxazolidinones, and more specifically, provides compounds of formula (I) described herein below. These compounds are useful as antibiotic agents.
The oxazolidinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, gram-negative aerobic bacteria such as
H. influenzae
and
M. catarrhalis,
as well as anaerobic organisms such as bacteroides and clostridia species, acid-fast organisms such as
Mycobacterium tuberculosis
and
Mycobacterium avium.
INFORMATION DISCLOSURE
International Publication No. WO 97/09328 discloses phenyloxazolidinones having a C—C bond to 4-8 membered heterocyclic rings useful as antimicrobial agents.
U.S. Pat. No. 4,709,026 discloses ketosultams useful as sensitizers or dyes.
J. Org. Chem. 1991, 56, 3549-3556 discloses vinyl sulfonyl esters and amides in the synthesis of substituted &dgr;-sultams and &dgr;-sultones.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I:
or a pharmaceutically acceptable salt thereof wherein
W is a structure i or ii;
R
1
is
(a) H,
(b) C
1-8
alkyl, optionally substituted with one to three F, Cl, OH, OC(═O)C
1
-
4
alkyl, or OC
1
-
4
alkyl,
(c) C
3
-
6
cycloalkyl,
(d) amino,
(e) C
1
-
8
alkylamino,
(f) C
1
-
8
dialkylamino, or
(g) OC
1
-
8
alkyl;
R
2
is H or F;
X is O or NR
3
;
R
3
is
(a) H,
(b) C
1-8
alkyl, optionally substituted with one to three F, Cl, OH, CN, NH
2
, OC(═O)C
1
-
4
alkyl, or OC
1
-
4
alkyl,
(c) C
3-8
alkene, or
(d) C(═O)NR
4
R
5
;
R
4
and R
5
are independently
(a) H, or
(b) C
1-8
alkyl, optionally substituted with one to three F, Cl, OH, CN, or NH
2
;
Y is O or S; and n is 0 or 1.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises an effective amount of the compound or salt),
a method of treating or preventing microbial infections in a mammal including skin and eye infections, comprising administering to said mammal in need of such treatment, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and
a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical treatment (e.g. the treatment or prevention of a microbial infection), and
The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours and “rt” for room temperature).
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C
i-j
indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, C
1-7
alkyl refers to alkyl of one to seven carbon atoms, inclusive.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
The following definitions are used, unless otherwise described.
Alkyl denotes both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to. Specifically, C
1-8
alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl and their isomeric forms thereof. Specifically, C
1-4
alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, and their isomeric forms thereof.
Alkene denotes both straight and branched groups having at least one double bond. Specifically, C
3-8
alkene can be allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and their isomeric forms thereof.
C
3-6
cycloalkyl denotes a cycloalkyl having three to six carbon atoms. Specifically, C
3-6
cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Mammal denotes human and other warm blooded animals.
Pharmaceutically acceptable salts denotes those salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate, methanesulfonic acid salt and etc.
Compounds of the present invention may be in a form of pharmaceutically acceptable salts.
It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof.
A specific value for R
1
is H.
A specific value for R
1
is C
1-8
alkyl, optionally substituted with one to three F, Cl, OH, OC(═O)C
1
-
4
alkyl, or OC
1
-
4
alkyl.
A specific value for R
1
is C
3
-
6
cycloalkyl.
A specific value for R
1
is amino, C
1
-
8
alkylamino, C
1
-
8
dialkylamino.
A specific value for R
1
is OC
1
-
8
alkyl.
A preferred value for R
1
is methyl.
A specific value for R
2
is F.
A specific value for X is O.
A specific value for X is NR
3
; wherein R
3
is H.
A specific value for X is NR
3
; wherein R
3
is C
1-8
alkyl, optionally substituted with one to three F, Cl, OH, CN, NH
2
, OC(═O)C
1
-
4
alkyl, or OC
1
-
4
alkyl.
A specific value for X is NR
3
; wherein R
3
is C
3-8
alkene.
A specific value for X is NR
3
; wherein R
3
is C(═O)NR
4
R
5
; wherein R
4
and R
5
are independently H or C
1-8
alkyl, optionally substituted with one to three F, Cl, OH, CN, or NH
2
;
A preferred value for X is O.
Another preferred value for X is NH.
Another preferred value for X is NCH
3
.
A specific value for Y is O.
A specific value for Y is S.
A specific value for n is 0 or 1.
A preferred value for n is 1.
A preferred structure is structure I-A
Examples of the present invention includes:
a) N-[[(5S)-3-[3-fluoro-4-[tetrahydro-1,1-dioxido-2-(2-propenyl)-2H-1,2-thiazin-4-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
b) N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
c) N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
d) N-[[(5S)-3-[-fluoro-4-(tetrahydro-2-methyl-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
e) N-[[(5S)-3-[4-(2,2-dioxido-1,2-oxathian-5-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide,
f) N-[[(5S)-3-[4-(1,1-dioxido-4-isothiazolidinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide, or
g) N-[[(5S)-3-[3-fluoro-4-(tetrahydro-2-methyl-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
The following Schemes describe the preparation of compounds of the present invention. All of the starting materials are commercially available or prepared by procedures described in these schemes or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the Schemes are as defined above or as in the claims.
The 6-membered ring sultams (n=1, X=NR
3
, R
3
is the same as defined above) may be prepared as outlined in Scheme 1. Also see Morris et al.,
J.
Anderson David John
Hester, Jr. Jackson B.
Balasubramanian Venkataraman
O'Brien Jonathan P.
Pharmacia & Upjohn Company
Shah Mukund J.
Yang Lucy X.
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