Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 4. Multiply-substituted aryl derivatives

The oxazolidinones, exemplified by , 2) are a new class of synthetic antibacterial agents with activity against gram-positive bacteria. Pharmacia group found linezolid (2) 3) which was known to be the first candidate of effective oxazolidinones against serious gram-positive human pathogens caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) without severe toxicity.In our preceding paper, 1) we demonstrated from our SAR study that the antibacterial activity was greatly affected by the conversion of 5-substituent. (S)-N- phenyl]-2-oxo-5-oxazolidinyl]methyl] thiourea (3), which has a 5-thiourea group, was found to show more excellent in vitro antibacterial activity than linezolid against gram-positive bacteria including MRSA and VRE.Concerning a substituent on the benzene ring, on the other hand, Gregory et al. proposed earlier that the co-planarity between 4Ј-substituent and benzene ring is related to the antibacterial activity in case of 5-acetamide derivatives. 4) They also reported that there might be a small pocket around 3Ј-position on the benzene ring in the binding mode of 5-acetamide oxazolidinones.5) While considering their suggestions, we focused our attention on lipophilicity to further study 5-thiocarbonyl oxazolidinones. Partition coefficient (log P), which is well known as an index of lipophilicity, is an important physicochemical parameter in the development of antibacterial agent because it is known to be closely related to the permeation through a lipid coat of bacteria. Concerning the lipophilicity on oxazolidinones, it has been reported that the balance between 5-hydrophilic substituent and hydrophobic substituent on the aromatic ring is important for the antibacterial activity. 2,4) In this paper, we describe our SAR study, especially the relationship between lipophilicity and antibacterial activity, on (4Ј-cycloalkylamino)phenyl oxazolidinones bearing 5-thiocarbonyl groups.Chemistry 5-Thiourea oxazolidinones 4 and 5-dithiocarbamate oxazolidinones 5 were synthesized as shown in Chart 2. They were prepared from key intermediates 12, which were easily derived from 6 by the usual method.3b) The key intermediates 12 were treated with carbon disulfide followed by ethyl chloroformate to give isothiocyanates 13. Thiourea derivatives 4 were synthesized from 13 by treatment with ammonia (method A), or prepared from 14 (method B). Dithiocarbamate derivatives 5 were synthesized from the corresponding key intermediates 12 by treatment with carbon disulfide and iodomethane. The physicochemical data of compounds 4 and 5 are shown in the experimental April 2001 Chem. Pharm. Bull. 49(4) 353-360 (2001) 353 * To whom correspondence should be addressed. Research and Development Division, Hokuriku Seiyaku Co., Ltd., 37-1-1, Inokuchi, Katsuyama, Fukui 911-8555, Japan. Received July 21, 2000; accepted December 22, 2000 5-Thiourea and 5-dithiocarbamate oxazolidinones were synthesized as a continuation of research on 5-thiocarbonyl oxazolidinone antibacteria...

Section: -Fluoro-4-(4-methyl-1-piperidinyl)aniline (8d)mentioning

confidence: 99%

mentioning

confidence: 99%

Structure-Activity Relationship (SAR) Studies on Oxazolidinone Antibacterial Agents. 2. Relationship between Lipophilicity and Antibacterial Activity in 5-Thiocarbonyl Oxazolidinones.

Tokuyama

Takahashi

Tomita

et al. 2001

“…The acidic aqueous layer was washed with Et 2 O, neutralized with K 2 CO 3 , and then reextracted with Et 2 O. The ethereal extract was dried over anhydrous MgSO 4 and then evaporation of the solvent under reduced pressure afforded a solid material. This was treated with 10% methanolic HCl and concentrated under reduced pressure to give the crude product of 3.…”

Section: (Cooh)mentioning

confidence: 99%

“…4,5) These derivatives (3) are selected as the target heterocycles for one of the synthetic applications of the above unique amino acid b-aminoalanine derivatives (1) (Fig. 1).…”

mentioning

confidence: 99%

A Conventional Route for the Synthesis of New Oxazolidin-2-one Derivatives with .BETA.-Aminoalanines

Fujisaki

Abe

Sumoto

2004

“…5,6) This paper deals with the relative rates of ring closure by cyclization with diethyl carbonate (EtO) 2 CO from aminoalcohols as starting material. We report here two typical experimental results for the cyclization that has two possibilities as a function of the ring intramolecular cyclization by (EtO) 2 CO.1…”

mentioning

confidence: 99%

Preferential Intramolecular Ring Closure of Aminoalcohols with Diethyl Carbonate to Oxazolidinones

Fujisaki

Oishi

Sumoto

2007

In connection with our interest in the chemistry of baminoalanines, [1][2][3][4] we have reported the synthetic application of these materials as a synthon for the preparation of a 5-membered oxazolidinone ring system.2) Some of the oxazolidinone derivatives have attracted much attention not only as a synthetic target but also because of the importance of the related compounds in the biological activities. 5,6) This paper deals with the relative rates of ring closure by cyclization with diethyl carbonate (EtO) 2 CO from aminoalcohols as starting material. We report here two typical experimental results for the cyclization that has two possibilities as a function of the ring intramolecular cyclization by (EtO) 2 CO.1 Results and DiscussionsThe objective of this report is to explore the orientation of ring closure of aminoalcohol by (EtO) 2 CO. The compounds (1 7) and 6 8)) are selected as the starting aminoalcohols, which have two hydroxy groups and a basic secondary amine in the molecules, so that the cyclization of these compounds employing (EtO) 2 CO can lead to the corresponding heterocycles (e.g. compounds 2 and 3, respectively, in the case of aminoalcohol 1).Since the experiment using compound 1 under similar reaction conditions reported previously 2) resulted in a quite complex reaction mixture by TLC analysis, it is not used to determine conditions suitable for cyclization of this aminoalcohol (1). Then, we tried the cyclization of (1) under the conditions of this aminoalcohol (1) , 2b). Because a diastereomeric mixture of aminoalcohol (1) (cis : transϭca. 3/1) was used as the starting material (see Experimental), the 5-membered ring products (oxazolidinones) may generate the products 2 as a mixture of four diastereoisomers theoretically.We were able to isolate two cis-isomers (2a, b, a or bstereoisomers, respectively), and our repeated trials for separation of two pure trans-isomers were unsuccessful. However, NMR spectroscopic analysis showed the isolated sample 2c was a mixture of two stereoisomers (see Experimental). In this case, the preferential formation of a 5-membered oxazolidinone ring system apparently indicated that this process (5-Exo-Trig 9) ring closure) is more favorable than that of 6-membered ring derivative 3 by 6-Exo-Trig ring closure. The fact that the 6-membered ring system can be isolated easily in the reaction of a noncompetitive cyclization system, i.e., the formation of compound (5) 10) from the start- Preferential Intramolecular Ring Closure of Aminoalcohols with Diethyl Carbonate to OxazolidinonesFumiko FUJISAKI, Marumi OISHI, and Kunihiro SUMOTO* Science, Fukuoka University; Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Received January 19, 2007; accepted February 22, 2007 The closure by cyclization with diethyl carbonate (EtO) 2 CO from aminoalcohols 1 as starting material can lead to the oxazolidinones 2a, b and 2c, respectively. In the reaction of trans-isomer (6) and (EtO) 2 CO, isolated products were also only 5-membered oxazolidinone derivative (7), containing its deh...