Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-27
2002-04-02
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S207000
Reexamination Certificate
active
06365612
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel benzosultam oxazolidinones, specifically relates to N-substituted bicyclic benzosultam oxazolidinones; and their preparations. These compounds have potent antibacterial activities.
BACKGROUND OF THE INVENTION
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, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. The benzosultam oxazolidinones of the present invention may also possess activities against gram-negative organisms such as Haemophilus influenza and Moraxella catarrhalis.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,164,510 discloses 5′-indolinyloxazolidin-2-ones which are useful as antibacterial agents.
U.S. Pat. Nos. 5,036,092; 5,036,093; 5,039,690; 5,032,605 and 4,965,268 disclose aminomethyl oxazolidinyl aza cycloalkylbenzene derivatives useful as antibacterial agents.
U.S. Pat. Nos. 5,792,765 and 5,684,023 disclose substituted oxazolidinones useful as antibacterial agents.
PCT International Publications WO 98/32438, WO 98/34929, WO 99/36069, WO 9911264, discloses sultam derivatives useful in the treatment of disease states mediated by the chemokine, interleukin-8.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
or a pharmaceutically acceptable salt thereof wherein:
R
1
is H, NH
2
, NHC
1-4
alkyl, C
1-4
alkenyl, OC
1-4
alkyl, SC
1-4
alkyl, (CH
2
)
i
—C
3-6
cycloalkyl, or C
1-4
alkyl, optionally substituted with 1-3 F, 1-2 Cl or CN;
R
2
is H, C
1-12
alkyl optionally substituted with phenyl or CN, or C
2-12
alkyl substituted with OH, SH, NH
2
, —OC
1-6
alkyl, —NHC
1-6
alkyl, —NHCOC
1-6
alkyl, —NHSO
2
C
1-6
alkyl, —S(O)
i
C
1-6
alkyl, or one to three halo;
Y is O or S;
M is —(CH
2
)
n
—, wherein n is 1 or 2 and i is 0, 1, or 2.
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 carrier,
a method for treating microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof,
the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating microbial infections in humans or other warm-blooded animals, and
The invention also contains novel intermediates and processes that are useful for preparing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described.
The term alkyl, alkenyl, etc. refer to 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.
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.
Warm-blooded animals refer to farm animal, companion animal or other type of animal.
The term “halo” refers to fluoro, chloro, bromo, or iodo
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).
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.
A specific value for R
1
is NH
2
, —OCH
3
, or C
1-4
alkyl.
A specific value for R
1
is methyl, ethyl, or isopropyl.
A specific value for R
1
is methyl.
A specific value for R
1
is ethyl.
A specific value for R
2
is C
1-6
alkyl.
A specific value for R
2
is C
1-6
alkyl substituted with CN.
A specific value for R
2
is benzyl.
A specific value for R
2
is C
2-6
alkyl substituted with OH, SH, NH
2
, F, —OC
1-6
alkyl, —NHC
1-6
alkyl, —NHCOC
1-6
alkyl, —NHSO
2
C
1-6
alkyl, —S(O)
i
C
1-6
alkyl, or one to three halo.
A specific value for R
2
is methyl or methyl substituted with CN.
A specific value for R
2
is ethyl substituted with fluoro or methoxy.
A specific value for R
2
is —CH
2
CH
2
F.
A specific value for Y is sulfur.
A specific value for Y is oxygen.
A specific value for n is 1.
These absolute configurations are called (S)-configuration according to the Cahn-Ingold-Prelog nomenclature system. It will be appreciated by those skilled in the art that compounds of the present invention may have additional chiral centers and be isolated in optically active or racemic form. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention. It is well known in the art how to prepare the optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity using the standard tests described herein, or using other similar tests which are well known in the art.
Examples of the present invention are:
(1) N-{[(5S)-3-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide, (PNU-252307)
(2) N-({(5S)-3-[1-(2-Fluoroethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, (PNU-254380)
(3) N-({(5S)-3-[1-(2-Nitriloethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, (PNU-274919)
(4) N-({(5S)-3-[1-(2-Methoxyethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, and (PNU-276461)
(5) N-({(5S)-3-[1-(2-Fluoroethyl)-2,2-dioxo-2,3-dihydro-1H-2,1-benzisothiazol-5-yl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethiomide. (PNU-254646)
The following describes the preparation of compounds of the present invention. All of the starting materials are prepared by procedures described herein or by procedures that would be well known to one of ordinary skill in organic chemistry.
As shown in CHART I, nitrobenzosultam 1, (can be obtained according to the methods described in J. Het. Chem. 1986, 23, 1645), is first converted to a sodium salt by treatment with a suitable base such as sodium bicarbonate. The nitrogen at the 1-position can then be alkylated by treatment with a variety of alkylating agents including alkyl halides and heating in a suitable solvent such as DMF. These compounds of general structure 2 can be reduced by catalytic hydrogenation in the presence of a suitable catalyst such as palladium on carbon in a suitable solvent such as ethyl acetate, THF, methanol or combinations thereof to afford 5-aminobenzosultams 3. When 3 are treated with magnesium triflate and N-[(2S)oxiranylmethyl] acetamide, prepared by the method of Schaus and Jacobsen (Tetrahedron Lett. 1996, 37, 7937), in a suitable solvent, preferably acetonitrile, the chiral alcohols 4 can be obtained. These compounds can be cyclized to the desired oxazolidinones 5 by reaction with a carbonyl equivalent such as carbonyl diimidazole or preferably N,N′-disuccinimidyl carbonate with an app
Ciske Fred L.
Genin Michael J.
Pharmacia & Upjohn Company
Stockton Laura L.
Yang Lucy X.
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