Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-14
2004-11-30
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...
C548S243000
Reexamination Certificate
active
06825225
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel bicyclic isoxazolinones compounds and their preparations. These compounds are useful 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.
INFORMATION DISCLOSURE
PCT publications, WO 99/64416, WO99/64417, and WO 00/21960 disclose isoxazolinone derivatives useful as antibacterial agents.
PCT publication, WO 00/10566 discloses isoxazolinones useful as antibacterial agents.
U.S. patent application Ser. No. 09/57216 discloses novel bicyclic isoxazolinones as antibacterial agents.
U.S. Pat. No. 5,164,510 discloses 5′-indolinyloxazolidin-2-ones of formula XI
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 isoxazolinones useful as antibacterial agents.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
or a pharmaceutically acceptable salt thereof wherein
Y is
a) —NHC(═W)R
2
, or
b) —O-het, —S-het, or —NH-het;
W is
a) O, or
b) S;
X is
a) —S(═O)
m
—, or
b) —CHR
3
—;
R
1
is
a) C
1-8
alkyl,
b) —C(═O)R
4
, or
c) —C(═S)NHC
1-4
alkyl;
R
2
is
a) H,
b) C
1-6
alkyl,
c) cyclopropyl,
d) —OC
1-4
alkyl,
e) —NH
2
,
f) —NHC
1-6
alkyl, or
g) —N(C
1-6
alkyl)
2
;
R
3
is H, or C
1-4
alkyl;
R
4
is
a) H,
b) C
1-6
alkyl,
c) —CH
2
OC(═O)C
1-4
alkyl;
at each occurrence above, alkyl is optionally substituted with one or more R
5
;
R
5
is
a) halo,
b) CN,
c) NO
2
,
d) C
1-6
alkyl,
e) phenyl,
f) OR
6
,
g) C(═O)R
6
,
h) OC(═O)R
6
,
i) C(═O)OR
6
,
j) S(═O)
m
R
6
,
k) S(═O)
m
NR
6
R
6
,
l) NHC(═O)R
6
,
m) C(═O)NR
6
R
6
,
n) NR
6
R
6
,
R
6
is independently H, C
1-6
alkyl, phenyl, or het;
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; wherein het is optionally substituted with one or more halo, CN, NO
2
, C
1-6
alkyl, OR
6
, phenyl, S(═O)
m
R
6
, C(═O)R
6
, OC(═O)R
6
,OC═O)R
6
, NHC(═O)R
6
, or NR
6
R
6
, oxo, or oxime;
m is 0, 1 or 2; and n is 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 excipient (the composition preferably comprises a therapeutically effective amount of the compound or salt),
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,
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 disclosed herein that are useful for preparing compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described.
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.
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).
It will be appreciated by those skilled in the art that compounds of the present invention may have a or more chiral centers and be isolated in optically active or racemic form. The present invention encompasses any racemic, optically-active (such as enantiomers, diastereomers), tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention.
The term halo refers to fluoro, chloro, bromo, or iodo.
The term alkyl refers 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 term “het” refers to a 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. Examples of unsaturated “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-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzisoxazole, 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.
Examples of saturated “het” include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, hydantoin, oxathiolane, oxazolidine, dioxolane, or imidazolidine.
At each occurrence, bet may be substituted with one or more group as defined in the summary of the invention or in claims.
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, C
1-6
alkyl and C
1-8
alkyl can be an alkyl group having one to four, one to six, or one to eight carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomeric forms thereof;
A specific value for Y is —NHC(═W)R
2
.
A specific value for W is oxygen atom.
A specific value for W is sulfur atom
A specific value for R
2
is alkyl.
A specific value for R
2
is methyl.
A specific value for R
2
is ethyl, dichloromethyl, dichloroethyl, or NH
2
.
A specific value for R
1
is 2-fluoroethyl, glycolyl, methoxyacetyl, oxoethylacetate, or methylaminocarbothioyl.
A specific value for R
1
is formyl, oracetyl.
A specific value for X is —CHR
3
—, wherein R
3
is H or C
1-4
alkyl.
A specific value for X is —SO
2
—.
A specific value for Y is —O-het, —S-het, —NH-het.
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-thiadiaz
Barbachyn Michael Robert
Ciske Fred L.
Genin Michael J.
Hester, Jr. Jackson B.
Johnson Paul D.
Engelmann John H.
Pharmacia & Upjohn Company
Stockton Laura L.
Yang Lucy X.
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