Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-06
2001-08-28
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255010, C544S367000, C544S369000, C544S374000, C544S121000
Reexamination Certificate
active
06281210
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel benzoic acid esters of oxazolidinones having a hydroxyacetylpiperazine substituent and their preparations. These compounds have potent activities against gram positive and gram-negative bacteria.
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.
However, oxazolidinones generally do not demonstrate an activity at a useful level against aerobic gram-negative organisms. Thus, the use of these oxazolidinone antibacterial agents is limited to infectious states due to gram-positive bacteria. Accordingly, it is among the objects of the present invention to provide pharmaceutical compounds, which have broader antibacterial activity including the activity against aerobic gram-negative organisms. We have now discovered that the oxazolidinones of the present invention increase the spectrum of activity to include gram-negative organisms such as
Haemophilus influenza
and
Moraxella catarrhalis
. In addition, the compounds of the present invention are excellent water soluble agents, which makes them particularly useful for IV and oral administration for the treatment of microbial infections.
INFORMATION DISCLOSURE
U.S. Pat. No. 5,652,238 discloses carboxylic and phosphate esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones.
PCT International Publication WO 98/54161 discloses oxazolidinone antibacterial agents having a thiocarbonyl functionality.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
or a pharmaceutically acceptable salt thereof wherein:
A is a structure i, ii, iii, or iv
W is
a) NHC(═X)R
1
,
b) —O—het, —S—het, or —NH—het; provided that when A is a structure iv, W is not the section b);
X is O, or S;
R
1
is
(a) H,
(b) NH
2
,
(c) NHC
1-4
alkyl,
(d) C
1-4
alkyl, optionally substituted by one or more F, Cl, or CN,
(e) C
2-4
alkenyl,
(f) OC
1-4
alkyl,
(g) SC
1-4
alkyl, or
(h) (CH
2
)
n
C
3-6
cycloalkyl;
R
2
and R
3
are independently H, F, Cl or C
1-2
alkyl;
R
4
is positioned at either C-3 or C-4 and is:
R
5
is H, or CH
3
;
R
6
is H, or C
1-4
alkyl, optionally substituted by OH, SH, SCH
3
, NH
2
or NHC(=NH)NH
2
;
R
7
and R
8
are independently H, C
1-4
alkyl, or R
7
and R
8
together with the nitrogen to which they are attached to form a saturated 5-, 6-, or 7-membered heterocyclic ring which may have additional heteroatoms selected from the group consisting of O, S(O)
n
, or N—R
5
; het is a C-linked five- (5) or six- (6) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring; at each occurrence, het is optionally substituted with one or more halo, OH, CF
3
, OC
1-6
alkyl, CN, C
1-6
alkyl, S(═O)
i
R
9
, C(═X)R
10
, OC(═O)R
10
, NHC(═O)R
10
, or NR
10
R
10
, oxo, or oxime; wherein R
9
is C
1-6
alkyl, aryl, or NR
7
R
8
; R
10
is H, C
1-6
alkyl, aryl, or NR
7
R
8
; n is 0, 1, or 2; and with the proviso that when X is O, R
4
is not the subsection (a).
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 gram-positive 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, and
a method for treating gram-negative 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 invention also provides some 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.
Mammal refers to human or animals.
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, “O” for oxygen atom, “S” for sulfur atom, “N” for nitrogen atom, “h” for hour or hours and “rt” for room temperature).
The term “het” refers to a C-linked five- (5) or six- (6) membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring.
Examples of “het” include pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole, or 1,2,4-dithiazolone.
At each occurrence, het may be substituted with one or more group as defined in the summary of the invention or in claims.
A specific value for het is isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl, 1,2,4-thiadiazol-3-yl or 1,2,5-thiadiazol-3-yl.
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.
Specifically, C
1-4
alkyl, can be an alkyl group having one to four carbon atoms such as, for example, methyl, ethyl, propyl, butyl, and their isomeric forms thereof; C
2-4
alkenyl can be vinyl, propenyl, allyl, butenyl, and their isomeric forms thereof; C
3-6
cycloalkyl can cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their isomeric forms thereof.
A specific value for A is structure ii as defined above.
A specific value for X is sulfur atom.
A specific value for X is oxygen atom.
A specific value for R
1
is C
1-4
alkyl.
A more specific value for R
1
is ethyl.
A specific value for R
1
is cyclopropyl.
A specific value for R
1
is NH
2
.
A specific value for R
2
and R
3
are independently H or F.
A specific value for R
2
and R
3
are that one of them is H, the other one is F.
A specific value for R
4
is —CH
D'Souza Andrea M.
Lambkin Deborah C.
Pharmacia & Upjohn Company
Yang Lucy X.
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