Patent Grant
9163043
1. Technical Field
The present invention relates to novel derivatives of oxazolidinone, preparation methods of the same, and pharmaceutical compositions comprising the same for use in an antibiotic.
2. Description of the Related Art
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), J. Med. Chem. 33, 2569 (1990), Tetrahedron, 45, 123 (1989), etc.
Pharmacia & Upjohn developed oxazolidinone derivatives of Formulas 3 and 4 (WO 93/23384, WO 95/14684 and WO 95/07271). Having succeeded in gaining the approval of the Food and Drug Administration (FDA) of U.S.A., the oxazolidinone derivative of Formula 3, by the name of ‘Zyvox’, has come into the market. However, these conventional synthetic oxazolidinone compounds were 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. Zyvox may be used restrictively as injection since the solubility of Zyvox against water is inadequate for use in injection, which is about 3 mg/ml.
Further, WO 93/09103 discloses derivatives of phenyl oxazolidinone, substituted with heterocyclics such as thiazole, indole, oxazole and quinole, as well as pyridine, at position 4 of the phenyl ring. However, these derivatives of oxazolidinone are known as providing insufficient medicinal effects because the heterocyclics bear simple substituents such as alkyl or amino groups.
In WO 01/94342, synthesizing derivatives of phenyl oxazolidinone, having with pyridine or derivatives of phenyl at position 4 of the phenyl ring was described. The compounds synthesized are potent in inhibitory activity against a broad spectrum of bacteria and are also superior antibiotic to Zyvox. However, The compounds are unable to be formulated as injection because solubility of the same is under 30 μg/ml.
Accordingly, 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 oxazolidinone derivatives as well as prodrugs thereof, wherein the prodrugs are prepared by reacting amino acid or phosphate with the oxazolidinone derivatives having hydroxyl group. Further, salts of the oxazolidinone derivatives prodruged were easily synthesized by using amine group of amino acid of the same to synthesize organic acid or inorganic acid and by using a hydroxyl group of phosphate and one selected from sodium and calcium. The oxazolidinone derivatives have excellent effects on antibiotic activity and the solubility of the same is greatly enhanced.
It is an object of the present invention to provide novel derivatives of oxazolidinone.
It is another object of the present invention to provide a method of preparing the above-mentioned derivatives.
It is still another object of the present invention to provide a pharmaceutical composition comprising the above-mentioned derivatives for use in an antibiotic.
The present invention provides novel derivatives of oxazolidinone corresponding to Formula 1 defined below.
In the Formula 1, X represents carbon or nitrogen.
R1 and R1′ respectively represent hydrogen or fluorine.
R2 represents —NR5R6, —OR7, triazol, fluorine, alkylphosphate, monophosphate or a metal salt of phosphate;
R5 and R6, which are the same or different, respectively represent hydrogen, C. sub. 1-4 alkyl group or acetyl; and
R7 is hydrogen, C. sub. 1-3 alkyl group or acylated amino acid. When the R7 is acylated amino acid, amino acid refers to alanine, glycine, proline, isoleucine, leucine, phenylalanine, β-alanine or valine.
Het, which is a heterocyclic ring or a hetero aromatic ring, refers to pyrrole, furan, piperazine, piperidine, imidazole, 1,2,4-triazol, 1,2,3-triazol, tetrazole, pyrazole, pyrrolidine, oxazole, isoxazole, oxadiazole, pyridin, pyrimidine, thiazole or pyrazine.
R3 and R4, which are the same or different, respectively refer to hydrogen, C. sub. 1-4 alkyl group that is substituted or unsubstituted with cyano, —(CH2)m-OR, (m represents 0, 1, 2, 3, 4) or ketone.
The derivatives of oxazolidinone corresponding to Formula 1 may be used for a pharmaceutically acceptable salt, it is preferably an acid addition salt prepared by using pharmaceutically acceptable free acid. The free acid may be inorganic or organic. The inorganic free acid may comprise hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. The organic free acid may include citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galuturonic acid, embonic acid, glutamic acid, aspartic acid, etc.
Preferred compounds of the oxazolidinone derivatives according to the present invention include the following compounds and their structures are described in Table 1.
In Table 1, ‘Ac’ represents acetyl and ‘TfOH’ refers to trifluoroacetic acid.
Further, the present invention provides a method of preparing the derivatives of oxazolidinone corresponding to Formula 1, as shown in Scheme 1 is defined below.
In the Scheme 1, Z represents C1-4 alkyl group, X, R1, R1′, R2, R3 and R4 are as defined in Formula 1 and Y represents halogen.
The method of preparing the derivatives of oxazolidinone according to the present invention comprises:
In the Step 1, the derivative (II) of hydroxymethyloxazolidinone may be synthesized by conventional methods. For example, a method may comprise substituting an amino group of anilin for a benzyloxycarbonyl group and reacting a substituted compound with glycidylbutylate in a state of strong bases thereby to form the derivative (II). The state may be prepared by adding a strong base; preferably the strong base may include n-butyllitium, sec-butyllitium, tert-butyllitium, etc., more preferably n-butyllitium. Further, it is preferable to subject the method at a temperature of about −78° C. in liquid nitrogen.
The Step 1 is subjected to substitute a hydrogen atom of phenyl group of the derivative (II) for a halogen atom, preferably for an iodine atom. When the hydrogen atom is substituted for the iodine atom, the substituted reaction may be subjected preferably by adding iodine monochloride (ICI) or trifluoroacetic acid silver salt (CF3COOAg) and adding iodine at room temperature.
The Step 2 is subjected the derivative (III) to react with hexamethylditin, hexabutylditin or tributyltin hydride by adding a catalyst of palladium to form the derivative (IV) of which iodine atom is substituted for a trimethylstannyl group or a tributylstannyl group. The catalyst of palladium may comprise dichlorobistriphenylphosphine palladium (II), tetrakistriphenylphosphine palladium (0), etc. It is preferred to carry out the Step 2 in a solvent of 1,4-dioxan, dimethylformamide, tetrahydrofuran, 1-methyl-2-pyrolidone, etc. at a temperature of about 90 to 150° C.
The Step 3 is carried out by reacting the derivative (IV) with a compound having hetero ring on phenyl or pyridine ring thereby to form the derivative (V). A catalyst of palladium added in the Step 3 may be identical to that of palladium in Step 2. It is preferred to carry out the Step 3 in a solvent of dimethylformamide, 1-methyl-2-pyrolidone, etc. at a temperature of about 100 to 120° C.
The Step 4 is performed by reacting the derivative (V) with amino acid that is protecting an amino group with t-butyloxycarbonyl, dicyclohexylcarbodiimide and 4-dimethylaminopyridine thereby to form the derivative (I) having amino group. The amino acid may include alanine, glycine, proline, isoleucine, leucine, phenylalanine, β-alanine, valine, etc. A solvent comprises dimethylformamide, 1-methyl-2-pyrolidone, etc. Preferably, a reaction by adding the derivative (V) with amino acid is carried out by stirring for about 5 hours above at room temperature.
A mixture of the derivative (V) and amino acid reacts to a strong acid such as trifluoroacetic acid, etc. to eliminate a protecting group. The solvent is removed from the mixture and the mixture is crystallized thereby to provide a salt of the derivative of oxazolidinone corresponding to Formula 1. Preferably, a reaction by adding the derivative (V) with amino acid is carried out by stirring for about 2 hours above at room temperature.
The salt of the derivative of formula 1, prepared by using amino acid at position R3 or R4, in a method known similarly to the above method, may be gained. (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material in the method is known and the method is described in WO0194342.
Further, a phosphate metallic salt of the derivative (I) may be formed by adding sodiummethoxide, sodium hydroxide, etc. to a composition in a solvent such as methanol, ethanol etc., the composition is prepared by dissolving the derivative (V) in trimethylphosphate or triethylphosphate, adding phosphorous oxy chloride and stirring for about 12 hours at room temperature. The phosphate metallic salt may be produced by reacting the derivative (V) with tetrazole and derivates of amidite at room temperature, oxidizing a reacted compound, synthesizing a derivative of alkylphosphate, eliminating alkyl group using a strong acid thereby to form a derivative of phosphate acid, and converting the derivative of phosphate acid into the phosphate metallic salt by the above-mentioned method.
Further, the present invention provides a pharmaceutical composition comprising the derivatives of oxazolidinone corresponding to Formula 1 for use in an antibiotic.
The oxazolidinone derivatives of the present invention show inhibitory activity against a broad spectrum of bacteria, against methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE) and have excellent relatively antibiotic activity with a relatively low concentration thereof or in vivo.
Further, the derivatives of the present invention may exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganisms such as Bacteroides and Clostridia, and acid-resistant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium.
The derivatives of oxazolidinone, having hydroxyl, are reacted with amino acid or phosphate to form prodrugs thereof. The prodrugs have superior solubility to compounds that are not formed as prodrugs: the solubility of the prodrugs represents above 28 mg/ml and the solubility of the compound 10 mg/ml (compound 10). The prodrugs stabilize in water or acidic solution and change to hydroxylmethyl compounds by being reverted using esterase and phosphatase in a blood thereby to develop easy formulation for injection or oral administration.
The composition of the present invention may comprise at least one effective ingredient having functions similar to those of the derivatives of oxazolidinone.
For formulating a pharmaceutical composition, at least one specie of the compound of formula 1 may be admixed with at least one pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may include saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, malto-dextrin solution, glycerol, ethanol, etc. According to the user's necessity, the pharmaceutical composition may contain conventional expedient such as antioxidizing agent, buffer, soil cleaner, etc. Also, the compositions are admixed with diluents, disintegrants, surface active agents, binders, lubricants, aqueous solution, suspension, etc. to be formed for injection, powders, capsules, granules, tablet, etc. Preferably, the formulation is prepared using proper methods described in Remington's Pharmaceutical Science (the newest edition), Mack Publishing Company, Easton Pa., etc. according to diseases or ingredients.
The compound of the present invention may be administrated orally or parenterally, such as intravenously, hypodermically, intra-abdominally, topically, etc. The dosage of the compound may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. As used in accordance with invention, satisfactory results may be obtained when the compounds of the present invention are administered to the individual in need at a daily dosage of about 10 mg to about 25 mg per kilogram of body weight, preferably about 13 mg to about 20 mg per kilogram of body weight, more preferably administered each of divided doses to many times per day.
The Lethal Dose (LD50) of the oxazolidinone derivatives shows above 1 g/kg in test of acute toxicity so that the derivatives are found stable.
The oxazolidinone derivatives of the present invention show inhibitory activity against a broad spectrum of bacteria and lower toxicity. The prodrugs, prepared by reacting the compound having hydroxyl with amino acid or phosphate, have high solubility thereof against water.
Further, the derivatives of the present invention may exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganisms such as Bacteroides and Clostridia, and acid-resistant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium.
Accordingly, the compositions comprising the derivatives of oxazolidinone are used in an antibiotic.
The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
3-fluoroaniline 100 g was dissolved in 1 L of tetrahydrofuran (THE) and the solution was added with 150 g (1.8 mol) of sodium bicarbonate (NaHCO3). After being cooled to 0° C., the solution was slowly added with 154 ml of N-carbobenzyloxy chloride (CbzCl) for reaction. While the temperature was maintained at 0° C., the reaction mixture was let to react for 2 hours with stirring. Afterwards, the reaction was extracted with 0.5 L of ethyl acetate. The organic layer, after being separated, was washed with brine, dried over anhydrous magnesium sulfate (MgSO4) and concentrated in vacuo. The residue was washed twice with n-hexane to afford the title compound as white crystal. 132 g. Yield 85%.
132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (NH4Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.
1H NMR (DMSO-d6) δ 7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m, 1H), 4.02 (t, 1H), 3.80 (dd, 1H), 3.60 (br dd, 2H).
In 300 ml of acetonitryl was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF3COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.
1H NMR (DMSO-d6) δ 7.77 (t, 1H), 7.56 (dd, 1H), 7.20 (dd, 1H), 5.20 (m, 1H), 4.70 (m, 1H), 4.07 (t, 1H), 3.80 (m, 1H), 3.67 (m, 2H), 3.56 (m, 3H)
In 660 ml of 1,4-dioxan was dissolved 50 g of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 3, 52 g of hexabutylditin ((Bu3Sn)2) and 9.3 g of dichlorobistriphenylphosphinpalladium were added into the solution, and stirred for 2 hours. The solution was filtered using celite and concentrated in vacuo. The residue was purified by column chromatography and 45 g of the title compound was formed.
1H NMR (DMSO-d6) δ 7.74 (m, 3H), 5.20 (t, 1H), 4.71 (m, 1H), 4.08 (t, 1H), 3.82 (dd, 1H), 3.68 (m, 1H), 3.52 (m, 1H), 1.48 (m, 6H), 1.24 (m, 6H), 1.06 (m, 6H), 0.83 (t, 9H)
In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.
1H NMR(CDCl3) δ 8.76 (s, 1H), 7.98 (dd, 1H), 7.58 (dd, 1H)
10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammoniumchloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.
10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6 was dissolved in 100 ml of dimethylformamide. And then 6.5 g of sodiumhydroxide was added to the solution and 9.3 g of iodomethane was slowly added to the solution at the temperature of 0° C. The solution was stirred for 6 hours at room temperature, added with water, extracted with ethyl acetate. And then the organic layer was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to obtain 4 g of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine.
1H NMR (CDCl3) δ 8.77 (t, 1H), 8.23 (dd, 1H), 8.04 (dd, 1H), 4.46 (s, 3H)
1H NMR (CDCl3) δ 8.80 (t, 1H), 8.13 (dd, 1H), 7.98 (dd, 1H), 4.42 (s, 3H)
In 130 ml of acetic anhydride was dissolved 8.6 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6. And then the solution was added with 15 ml of pyridine and stirred for 3 hours for reaction. The reaction mixture was added with ethyl acetate and extracted to separate organic layer. And then the organic layer was washed with water and brine. The organic layer was dehydrated, filtrated and concentrated in vacuo to give 7.3 g of the title compound. Yield 80%.
1H NMR (CDCl3) δ 7.99 (t, 1H), 7.40 (dd, 1H), 7.27 (dd, 1H), 1.83 (s, 3H)
20 g of 2,5-dibromopyridine was dissolved in 200 ml of 1-methyl-2-pyrrolidone. The solution was added with 35 g of potassium carbonate and stirred for 10 hours at the temperature of 100° C. The reaction mixture was added with ethyl acetate and the organic layer, thus obtained was washed with water and brine. The organic layer was dried, filtered and concentrated in vacuo to provide 6 g of 2-([1,2,3]triazol-1-yl)-5-bromopyridine, 4 g of 2-([1,2,3]triazol-2-yl)-5-bromopyridine.
1H NMR (CDCl3) δ 8.53 (dd, 2H), 8.10 (d, 1H), 8.03 (dd, 1H), 7.82 (s, 1H)
1H NMR (CDCl3) δ 8.60 (t, 1H), 7.97 (s, 2H), 7.87 (s, 2H)
In 150 ml of 1-methyl-2-pyrrolidone was dissolved 37 g of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol. The solution was added with 19.7 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 10.44 g of lithium chloride and 2.9 g of dichlorobistriphenylphospine palladium (II) at room temperature and then stirred at the temperature of 120° C. for 4 hours. The reaction mixture was added with water and then extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to provide 8 g of the title compound. Yield 26%.
1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.18 (m, 2H), 7.70 (m, 2H), 7.49 (dd, 1H), 5.25 (t, 1H), 4.74 (m, 1H), 4.46 (s, 3H), 4.14 (t, 1H), 3.88 (dd, 1H), 3.68 (m, 1H), 3.58 (m, 1H)
The title compound 6.6 g (yield 30%) was prepared in a method similar to that of Example 1, except that, 14.3 g of 2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine, instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, was used as a starting material.
1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.21 (s, 2H), 7.71 (m, 2H), 7.50 (dd, 1H), 5.25 (t, 1H), 4.74 (m, 1H), 4.14 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H), 2.64 (s, 3H)
The same procedure as in Example 1 was conducted, except for using, instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 200 mg of 2-([1,2,4]triazol-1-yl)-5-bromopyridine as a starting material, to prepare the title compound 150 mg (yield 48%).
The same procedure as in Example 1 was conducted, except for using, instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 1 g of 4-(4,5-dimethyloxazol-2-yl)bromobenzene as a starting material, to prepare the title compound 780 mg (yield 76%).
1H NMR (DMSO-d6) δ 7.96 (s, 1H), 7.94 (s, 1H), 7.63 (m, 4H), 7.44 (dd, 1H), 5.23 (t, 1H), 4.72 (m, 1H), 4.12 (t, 1H), 3.87 (dd, 1H), 3.68 (m, 1H), 3.56 (m, 1H), 2.32 (s, 3H), 2.10 (s, 3H)
The same procedure as in Example 1 was conducted, except for using, instead of 2 (2-methyltetrazol-5-yl)-5-bromopyridine, 2 g of 2-([1,2,3]triazol-1-yl)-5-bromopyridine as a starting material, to prepare the title compound 1.2 g.
1H NMR (DMSO-d6) δ 8.88 (s, 1H), 8.76 (s, 1H), 8.28 (d, 1H), 8.21 (d, 1H), 8.01 (s, 1H), 7.70 (m, 2H), 7.51 (dd, 1H), 5.26 (t, 1H), 4.75 (m, 1H), 4.14 (t, 1H), 3.90 (dd, 1H), 3.68 (m, 1H), 3.58 (m, 1H)
The same procedure as in Example 1 was conducted, except for using, instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 1 g of 2-([1,2,3]triazol-2-yl)-5-bromopyridine as a starting material, to prepare the title compound 0.7 g.
1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.25 (dd, 1H), 8.23 (s, 1H), 8.11 (d, 1H), 7.69 (m, 3H), 7.49 (dd, 1H), 5.24 (t, 1H), 4.75 (m, 1H), 4.14 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H)
The same procedure as in Example 1 was conducted, except for using, instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 1 g of 4-(4-cyanomethyl thiazol-2-yl)bromobenzene as a starting material, to prepare the title compound 520 mg.
1H NMR (DMSO-d6) δ 8.04 (s, 1H), 8.00 (s, 1H), 7.65 (m, 5H), 7.47 (dd, 1H), 5.24 (t, 1H), 4.74 (m, 1H), 4.23 (s, 2H), 4.13 (t, 1H), 3.88 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H)
The same procedure as in Example 1 was conducted, except for using, instead of (R)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol, (R)-3-(4-trimethylstannyl-3,4-difluorophenyl)-2-oxo-5-oxazolidinylmethanol as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.81 (s, 1H), 8.25 (d, 1H), 8.10 (d, 1H), 7.54 (d, 2H), 5.25 (t, 1H), 4.77 (m, 1H), 4.47 (s, 3H), 4.13 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.57 (m, 1H)
The same procedure as in Example 1 was conducted by using (R)-3-(4-trimethylstannyl-3,4-difluorophenyl)-2-oxo-5-oxazolidinylmethanol and 2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.83 (s, 1H), 8.25 (d, 1H), 8.15 (d, 1H), 7.55 (d, 2H), 5.25 (t, 1H), 4.77 (m, 1H), 4.13 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H), 2.63 (s, 3H)
In 25 ml of dimethylformamide was dissolved 4 g of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10). The solution was added 3.34 g of 1,3-dicyclohexylcarbodiimide, 2.36 g of BOC-glycine and 0.2 g of 4-dimethylaminopyridine at room temperature and then stirred for 10 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtered, concentrated in vacuo and purified by column chromatography. A residue, thus resulted in concentrating in vacuo, was dissolved in 70 ml of methylenechloride, added with 30 ml of trifluoroacetic acid, and stirred for 2 hours at room temperature. The residue was washed with ethanol and ethyl ether and concentrated in vacuo to obtain the title compound 4.47 g. Yield 76%.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.19 (s, 3H), 8.17 (m, 2H), 7.77 (t, 1H), 7.69 (dd, 1H), 7.49 (dd, 1H), 5.00 (m, 1H), 4.46 (m, 2H), 4.47 (s, 3H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.90 (s, 2H)
The title compound was prepared in a method similar to that of Example 10 using BOC-valline, instead of BOC-glycine.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.40 (s, 3H), 8.21 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.63 (dd, 1H), 4.47 (s, 3H), 4.43 (dd, 1H), 4.28 (t, 1H), 4.01 (d, 1H), 3.93 (dd, 1H), 2.14 (m, 1H), 0.98 (d, 3H), 0.95 (d, 3H)
The title compound was prepared in a method similar to that of Example 10 using compound 24.
1H NMR (DMSO-d6) δ 8.87 (s, 1H), 8.76 (s, 1H), 8.33 (s, 3H), 8.29 (d, 1H), 8.00 (s, 1H), 7.77 (t, 1H), 7.76 (t, 1H), 7.67 (dd, 1H), 7.47 (dd, 1H), 5.02 (m, 1H), 4.49 (m, 2H), 4.23 (t, 1H), 3.93 (m, 3H)
The title compound was prepared in a method similar to that of Example 10 using compound 21.
1H NMR (DMSO-d6) δ 8.31 (s, 3H), 7.97 (d, 2H), 7.64 (m, 4H), 7.45 (dd, 1H), 5.01 (m, 1H), 4.47 (m, 2H), 4.25 (t, 1H), 3.94 (dd, 1H), 3.90 (s, 2H)
The title compound was prepared in a method similar to that of Example 10 using compound 16.
1H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.31 (s, 3H), 8.22 (s, 2H), 7.76 (t, 1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 5.04 (m, 1H), 4.50 (m, 2H), 4.25 (t, 1H), 3.94 (dd, 1H), 3.91 (s, 2H), 2.63 (s, 3H)
The title compound was prepared in a method similar to that of Example 10 using compound 32.
1H NMR (DMSO-d6) δ 8.25 (s, 3H), 8.03 (d, 2H), 7.68 (m, 5H), 7.44 (dd, 1H), 5.01 (m, 1H), 4.48 (m, 2H), 4.25 (m, 3H), 3.92 (m, 3H)
The title compound was prepared in a method similar to that of Example 10 using compound 29.
1H NMR (DMSO-d6) δ 8.78 (s, 1H), 8.23 (m, 2H), 8.22 (s, 3H), 8.20 (s, 1H), 8.12 (d, 1H), 7.75 (t, 1H), 7.67 (dd, 1H), 7.48 (dd, 1H), 5.01 (m, 1H), 4.49 (m, 2H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.89 (s, 2H)
1. The Primary Step
In 14 ml of 1-methyl-2-pyrrolidon was dissolved 1.8 g of (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide. The solution was added 1.03 g of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 0.55 g of lithium chloride and 0.15 g of dichlorobistriphenylphosphine palladium (II) at room temperature and then stirred at the temperature of 110° C. for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. After being washed with brine, the organic layer, thus separated, was dehydrated, filtered, concentrated in vacuo and purified by column chromatography thereby to obtain (S)-3-(4-(2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide 410 mg. Yield 21%.
2. The Secondary Step
In dimethylformamide 2.3 ml was dissolved 50 mg of the compound prepared in the primary step. The solution was added with 35 mg of 1,3-dicyclohexylcarbodiamide, 25 mg of BOC-glycine and 2.1 mg of 4-dimethylaminopyridin at room temperature and then stirred for 10 hours. The reaction mixture was added with water and extracted with ethyl acetate. After being washed with brine, the organic layer, thus separated, was dehydrated, filtrated, concentrated in vacuo and purified by column chromatography. A residue, provided by concentrating, was dissolved in 2 ml of methylenechloride, added with 1 ml of trifluoroacetic acid and then stirred for 2 hours at room temperature. The residue was washed with ethanol and ethyl ether, evaporated in vacuo to obtain the title compound 140 mg.
1H NMR (DMSO-d6) δ 8.60 (s, 1H), 8.40 (d, 1H), 8.28 (s, 3H), 8.25 (m, 1H), 8.08 (dd, 1H), 7.63 (m, 2H), 7.42 (dd, 1H), 4.76 (m, 1H), 4.27 (s, 2H), 4.16 (q, 2H), 3.87 (s, 2H), 3.80 (m, 2H), 3.42 (m, 2H), 2.62 (m, 1H), 2.11 (m, 1H), 1.83 (s, 3H)
The same procedure as in Example 17 was conducted, except for using, instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 2-(4-hydroxymethyl-[1,2,3]triazol-1-yl)-5-bromopyridine as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.89 (s, 1H), 8.22 (m, 6H), 7.74 (t, 1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.42 (s, 2H), 4.78 (m, 1H), 4.19 (t, 1H), 3.91 (s, 2H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.83 (s, 3H)
The same procedure as in Example 17 was conducted, except for using, instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 2-(5-hydroxymethylisoxazol)-5-bromopyridine as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.89 (s, 1H), 8.26 (s, 3H), 8.12 (m, 2H), 7.72 (t, 1H), 7.64 (dd, 1H), 7.48 (dd, 1H), 7.21 (s, 1H), 5.49 (s, 2H), 4.77 (m, 1H), 4.17 (t, 1H), 3.98 (s, 2H), 3.79 (m, 1H), 3.43 (m, 2H), 1.83 (s, 3H)
The same procedure as in Example 17 was conducted, except for using, instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 2-(2-oxo-3-hydroxypyrrolidin-1-yl)-5-bromopyridine as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.60 (s, 1H), 8.33 (d, 1H), 8.28 (s, 3H), 8.25 (m, 1H), 8.05 (d, 1H), 7.63 (m, 2H), 7.42 (dd, 1H), 5.78 (t, 1H), 4.78 (m, 1H), 4.16 (q, 2H), 3.98 (s, 2H), 3.85 (m, 1H), 3.78 (m, 1H), 3.43 (m, 2H), 2.62 (m, 1H), 2.12 (m, 1H), 1.83 (s, 3H)
The same procedure as in Example 17 was conducted, except for using, instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 2-(5-hydroxymethyl-[1,2,4]oxadiazol-3-yl)-5-bromopyridine as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.32 (s, 3H), 8.21 (m, 3H), 7.75 (t, 1H), 7.65 (dd, 1H), 7.47 (d, 1H) 5.67 (s, 1H), 4.78 (m, 1H), 4.18 (t, 1H), 4.05 (s, 2H), 3.80 (m, 1H), 3.43 (m, 2H), 1.83 (s, 3H)
The same procedure as in Example 17 was conducted, except for using, instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 2-(5-hydroxymethyl-4,5-dihydroisoxazol-1-yl)-5-bromopyridine as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.81 (s, 1H), 8.27 (t, 1H), 8.24 (s, 3H), 8.05 (m, 2H), 7.69 (m, 2H), 7.44 (d, 1H) 5.04 (m, 1H), 4.76 (m, 1H), 4.41 (dd, 1H), 4.32 (m, 1H), 4.17 (t, 1H), 3.86 (s, 2H), 3.77 (m, 1H), 3.60 (m, 1H), 3.44 (m, 2H), 1.83 (s, 3H)
The same procedure as in Example 17 was conducted, except for using, instead of 2-(2-oxo-4-hydroxymethylpyrrolidin-1-yl)-5-bromopyridine, 4-(4-hydroxymethyl thiazol-2-yl)-bromobenzene as a starting material, to prepare the title compound.
1H NMR (DMSO-d6) δ 8.25 (s, 3H), 8.00 (d, 2H), 7.85 (s, 1H), 7.69 (m, 4H), 7.44 (dd, 1H), 5.63 (s, 2H), 4.76 (m, 1H), 4.16 (t, 1H), 3.93 (s, 2H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.83 (s, 3H)
1. The Primary Step
In 14 ml of methylenechloride was dissolved 1 g of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10). The solution was added with 0.46 g of methansulfonylchloride 0.46 g and 0.75 ml of triethylamine at room temperature and stirred at the same temperature for 30 minutes. Water and brine were added to the reaction mixture for washing, followed by extraction. The organic layer was dehydrated, filtrated and concentrated in vacuo thereby to provide (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on 1 g. Yield 82%.
2. The Secondary Step
In 15 ml of dimethylformamide was dissolved the compound prepared in the primary step. The solution was added with 300 mg of 1,2,4-triazol 300 mg and 100 mg of sodiumhydride (60%) at room temperature and stirred for 2 days. The reaction mixture was extracted with ethyl acetate and then the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered and concentrated in vacuo. The residue, prepared by concentrating, was purified by column chromatography to provide the title compound 400 mg. Yield 43%.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.57 (s, 1H), 8.19 (m, 2H), 7.74 (t, 1H), 7.58 (dd, 1H), 7.42 (dd, 1H), 5.13 (m, 1H), 4.64 (m, 2H), 4.46 (s, 3H), 4.28 (t, 1H), 3.99 (dd, 1H)
The same procedure as in Example 24 was conducted, except for adding, instead of 1,2,4-triazol, 1,2,3-triazol, to obtain compound 8 and compound 9, and then the compounds were divided by column chromatography.
(compound 8) 1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.19 (m, 2H), 7.82 (s, 2H), 7.71 (t, 1H), 7.59 (dd, 1H) 7.41 (dd, 1H), 5.22 (m, 1H), 4.86 (m, 2H), 4.46 (s, 3H), 4.30 (t, 1H), 3.98 (dd, 1H)
(compound 9) 1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.18 (m, 3H), 7.75 (s, 1H), 7.72 (t, 1H), 7.59 (dd, 1H) 7.42 (dd, 1H), 5.22 (m, 1H), 4.86 (m, 2H), 4.46 (s, 3H), 4.30 (t, 1H), 3.98 (dd, 1H)
The same procedure as in Example 24 was conducted, except for adding 1,2,3-triazo and using the compound 16 as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.20 (s, 2H), 8.17 (s, 1H), 7.75 (s, 1H), 7.73 (t, 1H), 7.61 (dd, 1H) 7.43 (dd, 1H), 5.18 (m, 1H), 4.85 (m, 2H), 4.29 (t, 1H), 3.96 (dd, 1H), 2.62 (s, 3H)
The same procedure as in Example 24 was conducted, except for adding 1,2,3-triazol and using the compound 17 as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 9.40 (s, 1H), 8.70 (s, 1H), 8.32 (s, 2H), 8.25 (d, 1H), 8.17 (s, 1H), 7.96 (d, 1H), 7.75 (s, 1H), 7.71 (t, 1H), 7.60 (dd, 1H) 7.42 (dd, 1H), 5.18 (m, 1H), 4.86 (m, 2H), 4.29 (t, 1H), 3.96 (dd, 1H)
In 5 ml of methylenechloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.19 (m, 2H), 7.74 (t, 1H), 7.66 (dd, 1H) 7.49 (dd, 1H), 5.06 (m, 1H), 4.89 (m, 2H), 4.46 (s, 3H), 4.23 (t, 1H), 3.95 (dd, 1H)
In 3.4 ml of ethanol and 30.6 ml of pyridin was dissolved 2.5 g of (S)-3-(4-(2-(imidazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide. The solution was added with 2.36 g of hydroxylamine at room temperature and stirred for 10 hours at the temperature 100° C. The reaction mixture was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered and concentrated in vacuo. The residue, obtained by concentrating, was purified by column chromatography and then dissolved in tetrahydrofuran solution, saturated hydrochloric acid, and stirred for 10 minutes. The solid, prepared by the above reaction, was recrystallized to provide the title compound 1 g.
The same procedure as in Example 1 was conducted, except for adding 4-(4,5-dimethyloxazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.24 (m, 1H), 7.96 (m, 2H), 7.62 (m, 4H), 7.45 (dd, 1H), 4.78 (m, 1H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.41 (m, 2H), 2.32 (s, 3H), 2.10 (s, 3H), 1.83 (s, 3H)
The same procedure as in Example 1 was conducted, except for adding 4-(4,5-dimethyloxazol-2-yl)-5-bromopyridine and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.81 (s, 1H), 8.24 (t, 1H), 8.07 (m, 2H), 7.77 (t, 1H), 7.62 (dd, 1H), 7.45 (dd, 1H), 4.78 (m, 1H), 4.18 (t, 1H), 3.79 (dd, 1H), 3.42 (m, 2H), 2.35 (s, 3H), 2.12 (s, 3H), 1.84 (s, 3H)
The same procedure as in Example 1 was conducted, except for adding 2-([1,2,3]triazol-2-yl)-5-bromopyridine and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.24 (m, 2H), 8.19 (s, 2H), 8.11 (d, 1H), 7.72 (t, 1H), 7.64 (dd, 1H), 7.45 (dd, 1H), 4.79 (m, 1H), 4.18 (t, 1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.84 (s, 3H)
The same procedure as in Example 1 was conducted, except for adding 4-(4 (S)-hydroxymethyl-4,5-dihydro oxazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.23 (t, 1H), 7.91 (d, 2H), 7.62 (m, 4H), 7.42 (dd, 1H), 4.82 (t, 1H), 4.78 (m, 1H), 4.41 (t, 1H), 4.28 (m, 2H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.61 (m, 1H), 3.48 (m, 1H), 3.43 (m, 2H), 1.84 (s, 3H)
The same procedure as in Example 1 was conducted, except for adding 4-(4-cyanomethyl thiazol-2-yl)-bromobenzene and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.25 (t, 1H), 8.00 (d, 2H), 7.67 (m, 4H), 7.44 (dd, 1H), 4.79 (m, 1H), 4.23 (s, 2H), 4.14 (t, 1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.83 (s, 3H)
The same procedure as in Example 1 was conducted, except for adding 4-(4-hydroxymethyl thiazol-2-yl)-bromobenzene and using (R)-3-(4-trimethylstannyl-3-fluorophenyl)-5-[1,2,3]triazol-1-yl oxazolidin-2-on as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.16 (s, 1H), 8.00 (d, 2H), 7.75 (s, 1H), 7.64 (dd, 2H), 7.62 (t, 1H), 7.52 (dd, 1H), 7.48 (s, 1H), 7.36 (dd, 1H), 5.40 (t, 1H), 5.18 (m, 1H), 4.85 (d, 2H), 4.62 (d, 2H), 4.28 (t, 1H), 3.95 (dd, 1H)
The same procedure as in Example 10 was conducted, except for using (R)-3-(4-(4-(4-hydroxymethyl thiazol-2-yl)phenyl)-3-fluorophenyl)-5-[1,2,3]triazol-1-ylmethyl oxazolidin-2-on as a starting material, to obtain the title compound.
1H NMR (DMSO-d6) δ 8.29 (s, 3H), 8.17 (s, 1H), 8.00 (d, 2H), 7.85 (s, 1H), 7.75 (s, 1H), 7.69 (dd, 2H), 7.67 (t, 1H), 7.55 (dd, 1H), 7.43 (dd, 1H), 5.36 (s, 2H), 5.19 (m, 1H), 4.86 (d, 2H), 4.28 (t, 1H), 4.28 (t, 1H)
In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 90 mg of sodium methoxide at room temperature and then stirred for one day at room temperature. The solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered, concentrated in vacuo and purified by column chromatography to provide the title compound 200 mg. Yield 58%.
1H NMR (CDCl3) δ 8.90 (s, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.61 (dd, 1H), 7.58 (t, 1H), 7.38 (dd, 1H), 4.80 (m, 1H), 4.45 (s, 3H), 4.08 (t, 1H), 3.96 (dd, 1H), 3.67 (m, 2H), 3.43 (s, 3H)
In 5 ml of dimethylformamid was dissolved 100 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 30 mg of dimethylamine hydrochloride at room temperature. The solution was stirred for 30 hours at the temperature of 60° C. And then the solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The residue, prepared by dehydrating, filtering and concentrating the organic layer, was purified by column chromatography to provide the title compound 70 mg. Yield 76%.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.19 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.63 (s, 3H), 4.27 (m, 3H), 3.94 (dd, 1H), 2.79 (s, 3H), 2.74 (s, 3H)
In 7 ml of dimethylformamid was dissolved 200 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on, prepared in the primary step of the Example 24. The solution was added with 100 mg of methylamine hydrochloride and 240 mg of potassium carbonate at room temperature. The solution was stirred for 30 hours at the temperature of 80° C. The solution was added with ethyl acetate and then the organic layer, thus separated, was washed with water and brine. The residue, prepared by dehydrating, filtering and concentrating the organic layer, was purified by column chromatography to obtain the title compound 80 mg. Yield 45%.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.18 (m, 2H), 7.73 (t, 1H), 7.66 (dd, 1H), 7.47 (dd, 1H), 7.17 (m, 1H), 4.94 (m, 1H), 4.46 (s, 3H), 4.25 (m, 3H), 3.85 (dd, 1H), 2.49 (d, 3H)
The same procedure as in Example 10 was carried out to provide the title compound using BOC-L-alanine instead of BOC-glycine.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.42 (s, 3H), 8.20 (m, 2H), 7.75 (t, 1H), 7.67 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.61 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 4.18 (m, 1H), 3.96 (dd, 1H), 1.36 (d, 3H)
500 mg of compound 20, prepared in Example 11, was dissolved in water. The solution was controlled to pH 5 with the addition of sodium bicarbonate aqueous solution. The aqueous layer was extracted with ethyl acetate and then the organic layer was slowly added with ether solution saturating of hydrochloric acid. The solid prepared by the above method was filtered and concentrated in vacuo to provide the title compound 200 mg. Yield 46%.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.54 (bs, 3H), 8.20 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.58 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 3.95 (m, 2H), 2.17 (m, 1H), 0.97 (d, 3H), 0.94 (d, 3H)
With the exception of using compound 42, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.52 (bs, 3H), 8.20 (m, 2H), 7.75 (t, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.60 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 4.18 (m, 1H), 4.00 (dd, 1H), 1.37 (d, 3H)
With the exception of using the compound 12, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.48 (bs, 3H), 8.18 (m, 2H), 7.75 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.03 (m, 1H), 4.48 (m, 2H), 4.46 (s, 3H), 4.24 (t, 1H), 3.99 (dd, 1H), 3.86 (m, 2H)
With the exception of using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material and 4-(4-hydroxymethylthiazol-2-yl)-bromobenzene, the same procedure as in Example 1 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.24 (t, 1H), 7.98 (d, 2H), 7.65 (m, 2H), 7.59 (m, 2H), 7.43 (s, 1H), 7.41 (dd, 1H), 5.40 (t, 1H), 4.79 (m, 1H), 4.63 (d, 2H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.84 (s, 3H)
With the exception of using BOC-L-proline, instead of BOC-glycine, the same procedure as in Example 10 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 9.25 (bs, 2H), 8.91 (s, 1H), 8.20 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.57 (dd, 1H), 4.45 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 3.96 (dd, 1H), 3.23 (m, 2H), 2.21 (m, 1H), 1.92 (m, 3H)
With the exception of using the compound 46, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 9.11 (bs, 2H), 8.91 (s, 1H), 8.20 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.55 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.25 (t, 1H), 4.01 (dd, 1H), 3.36 (m, 2H), 2.07 (m, 1H), 1.89 (m, 3H)
With the exception of using the compound 27, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.48 (s, 3H), 8.21 (s, 2H), 7.76 (t, 1H), 7.66 (dd, 1H), 7.48 (dd, 1H), 5.04 (m, 1H), 4.47 (m, 2H), 4.23 (t, 1H), 3.94 (m, 1H), 3.84 (d, 2H), 2.62 (s, 3H)
With the exception of using BOC-β-alanine, instead of BOC-glycine, the same procedure as in Example 10 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.20 (m, 2H), 7.75 (t, 1H), 7.73 (bs, 3H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.46 (s, 3H), 4.36 (m, 2H), 4.26 (t, 1H), 3.93 (dd, 1H), 3.02 (m, 2H), 2.70 (t, 2H)
With the exception of using the compound 49, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.22 (m, 2H), 8.11 (bs, 3H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.46 (s, 3H), 4.36 (m, 2H), 4.23 (t, 1H), 3.95 (m, 1H), 3.00 (m, 2H), 2.74 (t, 2H)
With the exception of using the compound 16 and BOC-L-alanine, the same procedure as in Example 10 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.39 (bs, 3H), 8.21 (s, 2H), 7.76 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.61 (dd, 1H), 4.40 (dd, 1H), 4.28 (t, 1H), 4.18 (dd, 1H), 3.95 (dd, 1H), 2.62 (s, 3H), 1.36 (d, 3H)
With the exception of using the compound 51, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.61 (bs, 3H), 8.21 (s, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.58 (dd, 1H), 4.39 (dd, 1H), 4.25 (t, 1H), 4.12 (m, 1H), 4.00 (dd, 1H), 2.62 (s, 3H), 1.36 (d, 3H)
With the exception of using the compound 16 and BOC-L-valline, the same procedure as in Example 10 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.40 (bs, 3H), 8.21 (s, 2H), 7.75 (t, 1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.04 (m, 1H), 4.62 (dd, 1H), 4.40 (dd, 1H), 4.26 (t, 1H), 3.99 (d, 1H), 3.92 (dd, 1H), 2.62 (s, 3H), 2.12 (m, 1H), 0.97 (d, 3H), 0.94 (d, 3H)
With the exception of using the compound 53, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.60 (bs, 3H), 8.21 (s, 2H), 7.75 (t, 1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.58 (dd, 1H), 4.42 (dd, 1H), 4.26 (t, 1H), 3.92 (m, 1H), 2.62 (s, 3H), 2.12 (m, 1H), 0.97 (d, 3H), 0.94 (d, 3H)
With the exception of using the compound 16 and BOC-L-prroline, the same procedure as in Example 10 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 9.20 (bs, 2H), 8.93 (s, 1H), 8.21 (s, 2H), 7.77 (t, 1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 5.04 (m, 1H), 4.59 (dd, 1H), 4.43 (m, 2H), 4.26 (t, 1H), 3.96 (dd, 1H), 3.21 (m, 2H), 2.62 (s, 3H), 2.21 (m, 1H), 1.95 (m, 1H), 1.89 (m, 2H)
With the exception of using the compound 55, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 9.18 (bs, 2H), 8.93 (s, 1H), 8.21 (s, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.57 (dd, 1H), 4.43 (m, 2H), 4.26 (t, 1H), 4.00 (dd, 1H), 3.21 (m, 2H), 2.62 (s, 3H), 2.21 (m, 1H), 1.95 (m, 1H), 1.89 (m, 2H)
With the exception of using the compound 16 and BOC-β-allanine, the same procedure as in Example 10 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.21 (s, 2H), 7.88 (bs, 3H), 7.76 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.36 (m, 2H), 4.25 (t, 1H), 3.94 (dd, 1H), 3.03 (m, 2H), 2.70 (t, 2H), 2.62 (s, 3H)
With the exception of using the compound 57, the same procedure as in Example 41 was conducted to prepare the title compound.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.21 (s, 2H), 8.08 (bs, 3H), 7.76 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.36 (m, 2H), 4.25 (t, 1H), 3.96 (dd, 1H), 3.00 (m, 2H), 2.71 (t, 2H), 2.62 (s, 3H)
1. The Primary Step
In 10 ml of mixture solvent (tetrahydrofuran:methylenechloride=1:1) was dissolved 1 g of compound 10. The solution was added with 0.6 g of tetrazole and 2.3 g of di-tetrabuthyl diisoprophylphosphoamidite and stirred for 15 hours at room temperature. The reaction mixture was refrigerated to −78° C., added with 0.7 g of metachloroperbenzoic acid and stirred for 2 hours. After being cooling to −78° C., the reaction mixture was added with metachloroperbenzoic acid (0.7 g). When the reaction mixture was stirred for 2 hours, the temperature of the reaction mixture was raised to room temperature. The reaction mixture was then added with ethyl acetate. The organic layer, thus separated, was washed with sodiumbisulfate, sodiumbicarbonate and brine, dehydrated, filtered and concentrated in vacuo, followed by purification with column chromatography thereby to provide (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid ditetrabuthylester (0.71 g, 71%).
1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.18 (m, 2H), 7.74 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.46 (s, 3H), 4.23 (t, 1H), 4.18 (m, 1H), 4.09 (m, 1H), 3.89 (dd, 1H), 1.39 (s, 9H), 1.38 (s, 9H)
The crystal prepared the above method was dissolved in a mixture of methanol and chloroform. And then the solution added with 3.4 ml of sodiummethoxide (0.3M methanol solution) at the room temperature and stirred for 10 hours. The reaction mixture was concentrated to prepare the residue. The residue was crystallized and filtered thereby to obtain the title compound (compound 59) 300 mg.
1H NMR (D2O) δ 8.27 (s, 1H), 7.56 (dd, 2H), 7.06 (m, 2H), 6.90 (m, 1H), 4.79 (m, 1H), 4.63 (s, 3H), 3.90 (m, 4H)
2. The Secondary Step
In 30 ml of methylenechloride was dissolved the compound (0.7 g) in the Primary Step. The solution was added with 15 ml of trifluoroacetic acid and then stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to prepare the residue. The residue was crystallized with ethanol and ethyl ether to obtain mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) 400 mg.
1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.20 (m, 2H), 7.74 (t, 1H), 7.66 (dd, 1H), 7.500 (dd, 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (dd, 1H)
Using the compound 16, the title compound was prepared in a manner similar to that of the Example 58.
1H NMR (D2O) δ 8.33 (s, 1H), 7.65 (dd, 2H), 7.17 (m, 2H), 6.90 (m, 1H), 4.79 (m, 1H), 4.63 (s, 3H), 3.94 (t, 1H), 3.78 (m, 3H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 1.
1H NMR (DMSO-d6) δ 8.98 (s, 1H), 8.30 (m, 2H), 7.75 (m, 2H), 7.53 (dd, 1H), 5.25 (t, 1H), 4.76 (m, 1H), 4.44 (s, 3H), 4.14 (t, 1H), 3.89 (dd, 1H), 3.69 (m, 1H), 3.58 (m, 1H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 10.
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.20 (s, 3H), 8.19 (m, 2H), 7.80 (t, 1H), 7.69 (dd, 1H), 7.49 (dd, 1H), 5.00 (m, 1H), 4.46 (m, 2H), 4.45 (s, 3H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.90 (s, 2H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 43.
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.50 (bs, 3H), 8.21 (m, 2H), 7.80 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.03 (m, 1H), 4.48 (m, 2H), 4.43 (s, 3H), 4.24 (t, 1H), 3.99 (dd, 1H), 3.86 (m, 2H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 40.
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.43 (s, 3H), 8.25 (m, 2H), 7.77 (t, 1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.63 (dd, 1H), 4.44 (s, 3H), 4.42 (dd, 1H), 4.24 (t, 1H), 4.18 (m, 1H), 3.98 (dd, 1H), 1.36 (d, 3H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 42.
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.53 (bs, 3H), 8.24 (m, 2H), 7.77 (t, 1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.60 (dd, 1H), 4.43 (s, 3H), 4.42 (dd, 1H), 4.26 (t, 1H), 4.20 (m, 1H), 4.00 (dd, 1H), 1.37 (d, 3H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 11.
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.42 (s, 3H), 8.25 (m, 2H), 7.79 (t, 1H), 7.70 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.64 (dd, 1H), 4.44 (s, 3H), 4.43 (dd, 1H), 4.30 (t, 1H), 4.01 (d, 1H), 3.93 (dd, 1H), 2.14 (m, 1H), 0.98 (d, 3H), 0.95 (d, 3H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 41.
1H NMR (DMSO-d6) δ 8.94 (s, 1H), 8.57 (bs, 3H), 8.22 (m, 2H), 7.79 (t, 1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.59 (dd, 1H), 4.43 (s, 3H), 4.41 (dd, 1H), 4.27 (t, 1H), 3.99 (m, 2H), 2.17 (m, 1H), 0.97 (d, 3H), 0.94 (d, 3H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 48.
1H NMR (DMSO-d6) δ 8.94 (s, 1H), 8.24 (m, 2H), 7.77 (t, 1H), 7.73 (bs, 3H), 7.70 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.44 (s, 3H), 4.36 (m, 2H), 4.27 (t, 1H), 3.93 (dd, 1H), 3.05 (m, 2H), 2.70 (t, 2H)
Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title compound was prepared in a manner similar to that of the Example 49.
1H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.25 (m, 2H), 8.13 (bs, 3H), 7.79 (t, 1H), 7.66 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.43 (s, 3H), 4.36 (m, 2H), 4.25 (t, 1H), 3.97 (m, 1H), 3.01 (m, 2H), 2.74 (t, 2H)
1. The Primary Step
Using the compound 61, (R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid ditetrabuthylester was prepared in a manner similar to that of the Example 58.
1H NMR (DMSO-d6) δ 8.94 (s, 1H), 8.20 (m, 2H), 7.78 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.44 (s, 3H), 4.21 (t, 1H), 4.18 (m, 1H), 4.10 (m, 1H), 3.89 (dd, 1H), 1.39 (s, 9H), 1.38 (s, 9H)
2. The Secondary Step
Using the compound provided in the Primary Step, 400 mg of mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 73) was prepared in a manner similar to that of the Example 58
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.23 (m, 2H), 7.76 (t, 1H), 7.66 (dd, 1H), 7.500 (dd, 1H), 4.95 (m, 1H), 4.44 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (dd, 1H)
The title compound (compound 70) was obtained in a manner similar to that of the Example 58.
1H NMR (D2O) δ 8.29 (s, 1H), 7.60 (dd, 2H), 7.10 (m, 2H), 6.90 (m, 1H), 4.79 (m, 1H), 4.60 (s, 3H), 3.90 (m, 4H)
Using the compound 61, the title compound was prepared in a manner similar to that of the Example 24.
1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.21 (m, 3H), 7.77 (s, 1H), 7.75 (t, 1H), 7.59 (dd, 1H) 7.42 (dd, 1H), 5.22 (m, 1H), 4.86 (m, 2H), 4.44 (s, 3H), 4.31 (t, 1H), 3.98 (dd, 1H)
To test an antibacterial activity of the derivatives of oxazolidinone, the antibacterial activity, including methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE), was represented as Minimum Inhibitory Concentration (MIC50, μg/ml) using agar dilution described in a art (Chemotherapy, 29(1), 76, (1981)). Zyvox of Pharmacia & Upjohn Inc, corresponding to Formula 3, was used as control. The results are shown in Table 2.
As illustrated in Table 2, the derivatives of the present invention had sufficient efficiency on antibacterial activity against Staphylococcus aureus (MRSA) and Enterococci (VRE) in spite of using lower concentration of the derivatives than that of the Zyvox. Accordingly, the compounds of the present invention may be useful as antibiotics.
To test a solubility of the derivatives of the present invention, an experiment was carried out below. The derivatives of the present invention were added to 200 μl of distilled water and then the solution was stirred for 2 minutes. The turbidity of the solution was watched through naked eye.
When the derivatives were not dissolved completely, sofa of distilled water was added to the solution and then the turbidity of the solution was assayed in the above manner to find a point of becoming transparent solution.
When 2 mg of the derivatives was first added to distilled water and completely dissolved so that the solution became transparent, 2 mg of the derivatives was added more to the solution and then state of the solution was watched. The derivatives of the present invention were added to the five times and then solubility of the solution was assayed for. The assay for solubility was carried out the three times repeatedly in the above method and the results were averaged. The averages were shown in Table 3.
As shown in table 3, the solubility of the compound 42 (>50 mg/ml) that is prodruged, of the derivatives was enhanced as compared with those of Zyvox (3 mg/ml) and the compound 10 (10 μg/ml).
Accordingly, when the derivatives of the present invention were formulated for oral administration, absorption of the derivatives may be enhanced. When the derivatives were formulated as injection, various formations of the derivatives may be obtained.
To test acute toxicity of the compounds of the present invention, the following experiment was carried out.
A mixture of 1% hydroxyprophylmethylcellulose and 200 mg of one selected from the group consisting of the compounds 10, 12, 16, 17, 20, 22, 24 and 27 was administrated to 5 ICR mice (5-Week old males, 20 g±2 g by weight). And then lethality for 2 weeks, weight, symptoms etc. was watched to determine Minimum Lethal Dose (MLD, mg/kg). Zyvox of Pharmacia & Upjohn Inc was used as control. The results were represented in Table 4.
Observation of survival, change in weight, tests in blood, and toxicity syndrome, etc. proved that administration of the composition of the present invention has no toxic effects
The compounds of the present invention have excellent efficiency on antibacterial activity without any toxicity present according to Table 4.
Preparation as Powder
The above materials were mixed and then the mixture was filled into a closed pack to prepare as powder.
Preparation as Tablet
The above materials were mixed and then the mixture was tableted by the known method to prepare as tablet.
3. Preparation of Capsule
The above materials were mixed and the mixture was filled into gelatin capsule by the known method to prepare as capsule.
4. Preparation of Injection
The derivative of oxazolidine, salt of sodium citrate, citratic acid and dextrose were filled in 20 ml of vial, sterilized, for injection and then sealed off using aluminum cap. The mixture was dissolved in distilled water for injection and then diluted in distilled water solution, having appropriate volume, for injection.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2003-0093342 | Dec 2003 | KR | national |
| 10-2004-0058809 | Jul 2004 | KR | national |
This application is a Continuation of U.S. patent application Ser. No. 12/211,655 filed on Sep. 16, 2008, which is a Divisional of U.S. patent application Ser. No. 10/596,412 filed on Jun. 13, 2006, which is a National Phase application of PCT/KR04/03327 (issued as U.S. Pat. No. 7,816,379), which claims priority to KR10-2003-0093342 and KR10-2004-0058809, the full disclosure of each of these documents is incorporated by reference in their entirety herein.
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| Number | Date | Country | |
|---|---|---|---|
| 20130281492 A1 | Oct 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10596412 | US | |
| Child | 12211655 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12211655 | Sep 2008 | US |
| Child | 13863216 | US |
