Oxazolidinone derivatives and a process for the preparation...

Details Oxazolidinone derivatives and a process for the preparation... Oxazolidinone derivatives and a process for the preparation...

2002-11-27

2004-02-10

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S121000, C544S131000, C544S295000, C544S364000, C546S194000, C546S256000, C546S269400, C546S271400

Reexamination Certificate

active

06689779

ABSTRACT:

This patent application claims a benefit of priority from Korean Patent Application No. 2000/30895 filed Jun. 5, 2000, Korean Patent Application No. 2000/30896 filed Jun. 5, 2000, Korean Patent Application No. 2000/56035 filed Sep. 23, 2000 and Korean Patent Application No. 2001/11691 filed Mar. 7, 2001; through PCT Application Serial No. PCT/KR01/00821 filed May 18, 2001, the contents of each of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to novel oxazolidinone derivatives of formula 1 with antibacterial activity, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same. Also, the present invention is concerned with a method for the preparation thereof.
BACKGROUND OF THE INVENTION
Used as orally administrable antibacterial agents, oxazolidinone compounds are not products of fermentation, but artificially synthesized ones, and various structures of their derivatives are known. For instance, 3-phenyl-2-oxazolidinone derivatives having one or two substituents are stated in U.S. Pat. Nos. 4,948,801, 4,461,773, 4,340,606, 4,476,136, 4,250,318 and 4,128,654. 3-[(Monosubstituted)phenyl]-2-oxazolidinone derivatives of formula 2 are disclosed in EP 0312000
, J. Med. Chem
. 32, 1673(1989), and
J. Med. Chem
. 33, 2569 (1990),
Tetrahedron
, 45, 123(1989).
Pharmcia & Upjohn developed oxazolidinone derivatives of formula 3 and 4 (WO 93/23384, WO 95/14684 and WO 95/07271). Having succeeded in gaining the approval of the FDA (Food and Drug Administration) of U.S.A., the oxazolidinone derivatives of formula 3 are going to come into the market. However, these conventional synthetic oxazolidinone compounds was found to suffer from the disadvantage of showing antibacterial activity against a narrow spectrum of bacteria, being toxic to humans, and being poor in therapeutic activity in vivo.
WO 93/09103 discloses oxazolidinone derivatives of formula 1, substituted with heterocyclics such as thiazole, indole, oxazole, and quinole as well as pyridine, at position 4 of the phenyl ring. However, these oxazolidinone derivatives do not provide sufficient medicinal effects because the heterocyclics bear simple substituents such as alkyl or amino groups.
SUMMARY OF THE INVENTION
Leading to the present invention, the intensive and thorough research on oxazolidinone derivatives, conducted by the present inventors aiming to overcome the above problems encountered in prior arts, resulted in the finding that oxazolidinone derivatives substituted with pyridine or pyrimidine derivatives at the 4 position of the phenyl ring have potent antibacterial activity against a broad spectrum of bacteria and their antibacterial activity is maintained high in vivo.
Therefore, it is an object of the present invention to provide oxazolidinone derivatives of formula 1, which potent in inhibitory activity against a broad spectrum of bacteria, and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide a process for preparing such an oxazolidinone derivative of formula 1, or its pharmaceutically acceptable salt.
It is a further object of the present invention to provide a pharmaceutical composition comprising such an oxazolidinone derivative of formula 1, or its pharmaceutically acceptable salt as a therapeutically effective ingredient.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with an aspect of the present invention, there is provided an oxazolidinone derivative of formula 1:
wherein,
R
1
is H, F, Cl or CF
3
;
R
2
is
where R
3
is
1) H,
2) C
1
-C
4
alkoxy, or piperazinyl optionally substituted with R
5
,
where R
5
is:
(a) H;
(b) Triphenylmethyl;
(c) substituted or unsubstituted acetyl, provided that the substituted acetyl is selected from the group consisting of benzyloxyacetyl, acetoxyacetyl, hydroxy acetyl, C
1
-C
3
alkylaminoacetoxyacetyl, acetyl substituted with halogen, morpholi-4-nylacetyl, imidazol-1-ylcarbonyloxy acetyl, C
1
-C
3
alkoxycarbonylmethylaminoacetyl, C
1
-C
3
alkoxyacetyl, t-butyl acetyl, phenyl acetyl optionally substituted with C
1
-C
3
alkoxy, and C
1
-C
3
alkoxyoxoacetyl;
(d) substituted or unsubstituted benzoyl, provided that the substituted benzoyl is selected from the group consisting of C
1
-C
4
selected from the group consisting of C
1
-C
4
alkoxybenzoyl, trihalomethylbenzoyl and nitrobenzoyl;
(e) substituted or unsubstituted carbonyl, provided that the substituted carbonyl is selected from the group consisting of C
1
-C
4
haloalkylcarbonyl, phenoxycarbony, and benzyloxycarbonyl;
(f) C
1
-C
3
alkoxyphenyl of;
(g) acryloyl optionally substituted with C
1
-C
3
alkyl;
(h) nicotinoyl;
(i) pivaloyl;
(j) crotonyl, or
(k) n-valeryl,
R
4
is: H; azido; —(C═O)
1
—R
6
; —NR
7
R
8
; —(CH
2
)
m
—R
9
; or —OR
10
,
wherein R
6
is: H; C
1
-C
3
alkoxy; amino; C
1
-C
3
alkylamino; or C
1
-C
3
hydroxyalkylamino,
l is an integer of 1 or 2,
R
7
and R
8
, which may be the same or different, represent,
(a) H;
(b) C
1
-C
4
alkyl optionally substituted with one or more phenyl groups, or C
1
-C
4
alkenyl substituted with C
1
-C
3
alkylamino;
(c) substituted or unsubstituted acetyl, provided that the substituted acetyl is selected from the group consisting of acetoxyacetyl, hydroxyacetyl, C
1
-C
3
alkylaminoacetoxyacetyl, C
1
-C
3
alkoxyacetyl, aminoacetyl, azidoacetyl, acetylaminoacetyl, C
1
-C
3
alkylaminoacetyl, aminopropionyl, and hydroxylpropionyl; or
(d) nicotinoyl,
R
9
is: H; azido; hydroxy; C
1
-C
3
alkylaminoacetoxy; acetylthio, mercapto, cyano, a halogen atom, or a 5- or 6-membered heterocycle,
m is an integer of 1-4,
R
10
is: H; C
1
-C
3
alkyl; acetyl; alkoxyalkyl; methanesulfonyl; or Heterocylic rings selected from the group consisting of
a) 5- or 6-membered heteroring containing one or more N or O as ring members, preferably represented by the following formula:
b) a 5-membered heterocyclic ring containing at least one nitrogen or oxygen atom or both of them, as ring members, in which any one carbon atom is saturated with two hydrogen atoms or forms a double bond with oxygen (ketone), nitrogen (imino) or sulfur (thioketone), preferably of the following formula:
 wherein A, B, and D, which may be the same or different, each represents a carbon, an oxygen or a nitrogen atom, and E represents two hydrogen atoms, an oxygen, a sulfur, or a nitrogen atom, and more preferably of the following formula:
c) 5- or 6-membered hetero aromatic ring containing C, N, O or S as ring members and preferably one or two N or O, or at least one nitrogen and at least one oxygen atom together, as ring members of the following formula:
wherein R
11
and R
12
, which are the same or different, each represents:
(i) H, F, Cl, Br or I;
(ii) C
1
-C
4
alkyl substituted optionally with at least one substituent, provided that the substituted alkyl is selected from the group consisting of hydroxyalkyl, alkoxycarbonylalkyl, trihaloalkyl, acetoxyalkyl, alkylaminoalkyl, alkoxyalkyl, and methanesulfonyloxyalkyl;
(iii) substituted or unsubstituted acetyl, provided that the substituted acetyl is selected from the group consisting of acetoxyacetyl, hydroxyacetyl, C
1
-C
3
alkylamino acetoxyacetyl, C
1
-C
3
alkoxyacetyl, aminoacetyl, azidoacetyl, acetylaminoacetyl, C
1
-C
3
alkylaminoacetyl, aminopropionyl, and hydroxypropionyl;
(iv) azido, hydroxy, mercapto, cyano, ketone, or amino;
(v) substituted or unsubstituted imino, provided that the substituted imino is selected from the group consisting of hydroxyimino, alkylimino, alkoxyimino or methanesulfonyloxyimino;
(vi) hydrozino optionally substituted with alkoxycarbonyl;
(vii) —OR
13
, where R
13
is H, C
1
-C
3
alkyl, acetyl, alkoxyalkyl, hydroxyacetyl or methanesulfonyl;
(viii) —NR
14
R
15
, wherein R
14
and R
15
represent independently H, C
1
-C
3
alkyl, acetyl, alkoxylalkyl, hydroxyacetyl or methansulfonyl;
(ix) —(C═O)—(R
16
)
n
—,
wherein R
16
is:
 1) C
1
-C
6
alkyl, or alkenyl optionally substituted with C
1
-C
3
alkyl;
 2) alkoxycarbonyl;
 3) acetoxymethyl, benzyloxymethyl

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