Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-30
2003-03-11
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S376000, C544S137000, C548S229000, C548S232000
Reexamination Certificate
active
06531470
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to oxazolidinones; oxazolidinone compositions; oxazolidinone combinational libraries; and methods for their preparation and use.
BACKGROUND ART
Oxazolidinones are compounds where an amine group and a hydroxyl group on adjacent carbon atoms have been cyclized to form a 5-membered ring containing a carbonyl group. Certain oxazolidinones have been shown to exhibit a variety of biological activities. For example, some oxazolidinones are inhibitors of monoamine oxidase-B, an enzyme implicated in Parkinson's disease. See, for example, Ding et al.,
J Med. Chem.
36:3606-3610 (1993).
A a ten step synthesis of oxazolidinone antibiotics has been described. U.S. Pat. No. 5,547,950. A four step synthesis of the antibacterial compound U-100592 also has been reported. Schauss et al.,
Tetrahedron Letters,
37:7937-7940 (1996). A five step preparation of enantiomerically pure cis- and trans-N-(propionyl)hexahydrobenzoxazolidin-2-ones further was reported. De Parrodi et al.,
Tetrahedron: Asymmetry,
8:1075-1082 (1997).
Scientists have reported that certain oxazolidinone derivatives exhibit beneficial antibacterial effects. For instance, N-[3-[3-fluoro-4-(morpholin-4-yl)phenyl]2-oxooxazolidin-5(s)-ylmethyl] acetamide (below) has been reported to be useful for the treatment of bacterial infections. Lizondo et al.,
Drugs of the Future,
21:1116-1123 (1996).
The synthesis of the oxazolidinone antibacterial agent shown below has been reported. Wang et al,
Tetrahedron,
45:1323-1326 (1989). This oxazolidinone was made using a process that included the reaction of an aniline with glycidol to provide an amino alcohol, and the diethylcarbonate mediated cyclization of the amino alcohol to afford an oxazolidinone.
The synthesis of oxazolidinone antibacterial agents, including the compound shown below has been reported. U.S. Pat. No. 4,705,799. The process used to make the compound shown below included a metal mediated reduction of a sulfonyl chloride to provide a sulfide.
The synthesis of oxazolidinone antibacterial agents, including the pyridyl compound shown below has been reported. U.S. Pat. No. 4,948,801. The process used included an organometallic mediated coupling of an organotin compound and an aryl iodide.
Synthetic routes to oxazolidinones often allow a chemist to produce only one compound at a time. These laborious methods can provide a limited number of compounds for evaluation in a biological screen. These methods cannot, however, provide the number of compounds required to supply a high-throughput biological screen, an assay technique whereby the activity of thousands of drug candidates, for example, per week, may be analyzed. This limitation on compound production is of practical importance since high-throughput screens are desirable and efficient for the discovery of new drugs.
SUMMARY OF INVENTION
Provided are oxazolidinones and combinatorial libraries, compositions comprising oxazolidinones, as well as methods of their synthesis and use. Using the methods provided herein, one of skill in the art can rapidly produce the large number of compounds required for high-throughput screening.
In one embodiment, provided are methods for the solid phase synthesis of oxazolidinones.
In one embodiment, the method comprises attaching an olefin to a solid support, oxidizing the olefin to provide an epoxide functionality, opening the epoxide with an amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching an allylic amine to a solid support, oxidizing the olefin of the allylic amine to provide an epoxide, opening the epoxide with an amine, and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching allylamine to a solid support, oxidizing the olefin of allylamine to provide an epoxide, opening the epoxide with an amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to a solid support, oxidizing the olefin to provide an epoxide, opening the epoxide with an amino acid and cyclizing the resulting amino alcohol using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to a solid support, oxidizing the olefin to provide an epoxide, opening the epoxide with an aromatic amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
Methods also are provided for the synthesis of oxazolidinone combinatorial libraries.
In one embodiment, the method comprises attaching an olefin group to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amine units, and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching an allylic amine to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amine units and. cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching allyl amine to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amine units and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with amino acid units and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
In another embodiment, the method comprises attaching an olefin to an array of solid supports, oxidizing the individual olefin groups to provide an array of solid support bound epoxides, opening the epoxides with aromatic amine units and cyclizing the resulting array of amino alcohols using a phosgene equivalent.
Provided are a variety of oxazolidinones and combinatorial libraries thereof. In one embodiment, the oxazolidinones have the structure:
where R
1
is selected from the group consisting of alkyl, heteroalkyl aryl and heteroaryl; R
2
is selected from the group consisting of hydrogen, alkyl, heteroalkyl; aryl and heteroaryl; R
3
is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl; R
11
is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl; and R
12
is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, oxazolidinones and combinatorial libraries are provided wherein the oxazolidinones are of the structure 1b, wherein R
2
, R
3
, R
4
and R
5
are, independently, hydrogen, alkyl,
heteroalkyl, heteroaryl or an electron withdrawing group; R
6
is acyl or sulfonyl; and, R
1
is one of the following functional groups: C(O)NR
7
R
8
, wherein R
7
and R
8
are, independently, hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; C(O)OR
9
, wherein R
9
is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; C(O)R
10
, wherein R
10
is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; SR
11
, wherein R
11
is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; S(O)
2
R
11
, wherein R
11
is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; S(O)R
11
, wherein R
11
is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; NR
12
R
13
, wherein R
12
and R
13
are, independently, hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, aryl or heteroaryl; 2-oxazolyl, wherein R
14
is at the 4-position and R
15
is at the 5-position of the oxazolyl, and wherein R
14
and R
15
are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group; 2-aminothiazolyl, wherein R
16
is at the 4-position and R
17
is at the 5-position of the thiazole, and wherein R
16
and R
17
, are, ind
Gordeev Mikhail F.
Gordon Eric
Luehr Gary W.
Ni Zhi-Jie
Patel Dinesh V.
Gerstl Robert
O'Brien Jonathan P.
Pharmacia & Upjohn Company
Yang Lucy X.
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