WO2005042523A1 - A novel oxazolidinone derivative and manufacturing process thereof - Google Patents

A novel oxazolidinone derivative and manufacturing process thereof Download PDF

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WO2005042523A1
WO2005042523A1 PCT/KR2004/002805 KR2004002805W WO2005042523A1 WO 2005042523 A1 WO2005042523 A1 WO 2005042523A1 KR 2004002805 W KR2004002805 W KR 2004002805W WO 2005042523 A1 WO2005042523 A1 WO 2005042523A1
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formula
triazol
phenyl
fluoro
ylmethyl
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PCT/KR2004/002805
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French (fr)
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Jae-Hoon Kang
Chun-Ho Park
Jin-Sun Kwon
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Il-Dong Pharm. Co., Ltd.
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Priority claimed from KR1020040082328A external-priority patent/KR20050042446A/en
Application filed by Il-Dong Pharm. Co., Ltd. filed Critical Il-Dong Pharm. Co., Ltd.
Publication of WO2005042523A1 publication Critical patent/WO2005042523A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to triazDlylmethyl oxazDlidinone derivatives of formula I with antibacterial activity, their pharmaceutically acceptable salts, pharmaceutical compositions comprising the same, a preparation method thereof. [2] [3] Formula I [4]
  • one object of the present invention is to provide oxazolidinone derivatives of formula I and pharmaceutically acceptable salt thereof which can be used as an antibiotic exhibiting higher activities against multi-drug resistant strains (MRSA).
  • MRSA multi-drug resistant strains
  • the other object of the present invention is to provide a process for preparing such an oxazolidinone derivatives of formula I or its pharmaceutically acceptable salt.
  • R is hydrogen atom, ethylcarboxylate, amide, diethoxymethyl, aldehyde, hydroxyoxime or nitrile;
  • X is each and independently carbon or nitrogen atom;
  • the resultant sulfonate derivative is then reacted with sodium azide in DMF to provide the azide (2-3) analogue, which is then cyclized by refluxing vinyl acetate. And then triazole was deprotected by hydrogenation to afford key intermediate aniline (2-4).
  • the aniline (2-4) was condensed with 2,5-dimethoxy-3-tetrahydro&rancarboxaldehyde to yield the formylpyrrole (formula 1-3) which was exploited for the preparation of oximepyrrole (formula 1-4) via standard transformations. Dehydration of the oxime with trichloroacetyl chloride in dichloromethane yielded the 3-cyano analogue (formula 1-5).
  • the compound of formula 1-1-14 may be used in its native form or as pharam- ceutically acceptable salt. In cases where forming a stable nontoxic acid or base salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, alkali metal (for example, sodium or potassium) or alkaline earth metal (for example, calcium or magnesium) salts of carboxylic acids can be made. And reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion (for example, ammonium, tri- ethylamine, pyridine and N,N-dimethylethanolamine salt).
  • Siitable inorganic salts are formed, including hydrochloride, hydrobromide, sulfate and nitrate salts.
  • Organic acid addition salts may also be formed with acids which form a physiological acceptable anion, for example, formic acid, acetic acid, tartaric acid, citric acid, methylsulfonic acid, lactic acid, succinic acid and benzenesulfonic acid.
  • the compound of formula 1-1-14 show inhibitory activity against a broad spectrum of bacteria, but its antibacterial activity is excellent in vivo.
  • the compound of the present invention can exert potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganism, such as Bacteroides and Clostridia, and acid-resistant microorganism such as Mycobacterium tuberculosis and Mycobacterium avium.
  • the oxazolidinone antibacterial agents of the present invention have excellent activity against gram-positive bacterial infection, including MRS A strains.
  • the compounds are shown high stability as an antimicrobial medicament from LD 50 >4000mg/kg in oral routes. Accordingly, the compounds of the present invention can be used in the therapeutic treatment of human beings or animals infected with variety of gram-positive bacteria.
  • compositions comprising one or more of the compound I-l and their derivatives as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary.
  • the compositions may be formulated into various forms such as tablets, capsules, troche, suspension, solution, suppositories, ointment, cream, injection, which may contain conventional additives such as a dispersant, suspending agent, stabilizer and the like.
  • the compounds of formula I according to this invention are administered orally and parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration.
  • compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution.
  • a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection
  • Suitable buffering agents include, for example, -(+)-lysine, -(+)-arginine, N-methylglucamine, sodium citrate, sodium bicarbonate and trisodium orthophosphate to name but a few representative buffering agents.
  • Citric acid (leq) was added to a solution of I-l (30mg, 0.09mmol) in isopropylalcohol (1ml) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 31mg (65%).
  • Citric acid (leq) was added to a solution of 1-2 (30mg, 0.09mmol) in isopropylalcohol (1ml) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 29mg (62%).
  • Citric acid (leq) was added to a solution of 1-5 (30mg, 0.08mmol) in isopropylalcohol (1ml) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 29mg (62%).
  • the oxazolidinonoe derivatives of the general formula I have potent antibacterial activity against a broad spectrum of bacteria and their antibacterial activity is maintained high in vivo. Exerting potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganism such as Bacteroides and Clostridia, and acid-resistant microorganism such as Mycobacterium, the compounds of the present invention are therefore use&l as antibiotics.
  • gram-positive bacteria such as Staphylococi, Enterococci and Streptococi
  • anaerobic microorganism such as Bacteroides and Clostridia
  • acid-resistant microorganism such as Mycobacterium

Abstract

The present invention relates to novel oxazolidinone compound represented by general formula I or a their pharmaceutically acceptable salts and a process for the preparation thereof. The compounds of the present invention have wide antibacterial spectrum, superior antibacterial activity. Therefore, the compound of the present invention can be used as an antibacterial agent.

Description

Description A NOVEL OXAZOUDINONE DERIVATIVE AND MANUFACTURING PROCESS THEREOF Technical Field [1] The present invention relates to triazDlylmethyl oxazDlidinone derivatives of formula I with antibacterial activity, their pharmaceutically acceptable salts, pharmaceutical compositions comprising the same, a preparation method thereof. [2] [3] Formula I [4]
Figure imgf000002_0001
[5] wherein R is hydrogen atom, ethylcarboxylate, amide, diethoxymethyl, aldehyde, hydroxyoxime or nitrile; [6] X is each and independently carbon or nitrogen atom; and [7] is single bond or double bond. [8] Background Art [9] The oxazDlidinones developed in 1980s represent a new class of antibacterial agents which showed activity of wide spectrum against gram-positive bacterial infections, including those infections caused by strains resistant to other antibiotics. The oxazDlidinones are a relatively new class of orally active, totally synthetic antibacterial agents which have no cross-resistance with other antibiotics. [10] [11] In 1987, Dupont Co. reported first that Dup-721 (formula A), a compound of oxa- zolidinone derivative, showed good activities against gram-positive pathogens (including MRSA, MRSE), gram-negative anaerobes, and Mycobacterium tuberculosis. (EP 0312000, J. Med. Chem. 1989, 32, 1673). [12] Formula A
Figure imgf000003_0001
[14] [15] Subsequently, Pharmacia and Upjohn Co. reported two Mnds of potent oxa- zolidinone antibacterial agents, linezolid (formula B) and eperezolid (formula C). These compounds showed good activity against gram-positive bacterial infections, including the resistant strain of methicillin-resistant Staphylococcus aureus (MRS A), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant en- teroccocci (VRE). The compounds showed similar antimicrobial activity to vancomycin. However, oxazDlidinones generally show a very low activity against aerobic gram-negative organism.
[16] [17] Formula B [18]
Figure imgf000003_0002
O
[19] [20] Formula C [21]
Figure imgf000003_0003
[22] [23] Thus, the present inventors carried out an intensive study for new derivatives of oxazDlidinone antibacterial agents and at last found out the fact that the oxazolidinone derivatives of the general formula I have strong antimicrobial activity.
[24] [25] The oxazolidinone derivatives of the general formula I were not reported, have antimicrobial activities of wide spectrum and have excellent antimicrobial activities in vivo. [26] Disclosure of Invention Technical Problem
[27] Therefore, one object of the present invention is to provide oxazolidinone derivatives of formula I and pharmaceutically acceptable salt thereof which can be used as an antibiotic exhibiting higher activities against multi-drug resistant strains (MRSA).
[28] The other object of the present invention is to provide a process for preparing such an oxazolidinone derivatives of formula I or its pharmaceutically acceptable salt.
[29] Technical Solution
[30] There are provided oxazolidinone derivatives represented by the following general formula I and pharmaceutically acceptable salt thereof.
[31]
[32] Formula I
[33]
Figure imgf000004_0001
[34] wherein R is hydrogen atom, ethylcarboxylate, amide, diethoxymethyl, aldehyde, hydroxyoxime or nitrile; [35] X is each and independently carbon or nitrogen atom; and
[36] is single bond or double bond. [37] [38] Among the oxazolidinone derivatives of the general formula I, representative compounds are shown below. [39] [40] Formula I- 1
[41]
Figure imgf000004_0002
[43] Formula 1-2
[44]
Figure imgf000005_0001
[45]
[46] Formula 1-3
[47]
Figure imgf000005_0002
[48]
[49] Formula 1-4
[50]
Figure imgf000005_0003
[51]
[52] Formula 1-5
[53] o
Nc r^ ^ Ή F
[54]
[55] Formula 1-6
[56]
Figure imgf000005_0004
[57]
[58] Formula 1-7
[59]
Figure imgf000006_0001
[60]
[61] Formula 1-8
[62]
Figure imgf000006_0002
[63]
[64] Formula 1-9
[65]
Figure imgf000006_0003
[66] [67] Formula I- 10 [68]
Figure imgf000006_0004
[69] [70] Formula I- 11 [71]
Figure imgf000006_0005
[72]
[73] Formula 1-12
[74]
Figure imgf000006_0006
[75]
[76] Formula 1-13 [77]
Figure imgf000007_0001
[78]
[79] Formula 1-14
[80]
Figure imgf000007_0002
[81]
[82] Hereinafter, a preparation method of the compound represented by the general I will be described by the following schemes 1~3. [83]
[84] Scheme 1
[85]
Figure imgf000007_0003
N A V-N. I — - I.. N- N. i Γ F F 1-4 Formula I
[86] wherein R is the same defined in the general formula I.
[87]
[88] The general preparation involved nucleophilic aromatic substitution reaction between the pyrrolidine or pyrrole and 3,4-difluoronitrobenzene (1-1) to give the 3-fluoro-4-azolylnitrobenzene intermediates. Reduction of the nitro group by hy- drogenation in the presence of palladium on carbon catalyst and Cbz protection of the resulting aniline gave intermediates (1-2). Deprotonation with base (n-BuLi) followed by treatment with (R)-(-)-glycidyl butyrate afforded oxazoldinones (1-3). The hy- droxymethyl side chain was then elaborated to the azide analogue (1-4') via standard transformations. Formation of the azide followed by 1,3-dipolar cycloaddition in refluxing vinyl acetate gave triazolylmethyl oxazolidinone (Formula 1-1).
[89] 4-Substituted pyrrole were synthesized in using similar method and also, 4-pyrazole analogues were synthesized utilizing the ethyl 4-pyrazolecarboxylate analogue. This material was prepared in a regioselective manner. The arylhydrazine was synthesized and condensed with the known (ethoxycarbonyl)malondialdehyde to give the ethyl 4-pyrazolecarboxylate.
[90]
[91] Scheme2
[92]
Figure imgf000008_0001
2_ ; 2-4 Formula 1
[93] wherein R is the same defined in the general formula I.
[94]
[95] And also, treatment of an acetonitrile solution of 3,4-difluoronitrobenzene (1-1) with benzylamine in the presence of triethylamine afforded in high yield. The nitro group of structure is then reduced by hydrogenation in the presence of platinum catalyst in a suitable solvent such as THF or Methanol is to give compound (2-1). The aniline (2-1) is then converted to its Cbz intermediate and then deprotonated by n-BuLi in THF to give a lithiated intermediate which is then treated with commercially available (R)-(-)-glycidyl butyrate. Warming to ambient temperature affords the compound (2-2). This alcohol (2-2) is then converted to the corresponding mesylate. The resultant sulfonate derivative is then reacted with sodium azide in DMF to provide the azide (2-3) analogue, which is then cyclized by refluxing vinyl acetate. And then triazole was deprotected by hydrogenation to afford key intermediate aniline (2-4). The aniline (2-4) was condensed with 2,5-dimethoxy-3-tetrahydro&rancarboxaldehyde to yield the formylpyrrole (formula 1-3) which was exploited for the preparation of oximepyrrole (formula 1-4) via standard transformations. Dehydration of the oxime with trichloroacetyl chloride in dichloromethane yielded the 3-cyano analogue (formula 1-5).
[96]
[97] Scheme3
[98]
Figure imgf000009_0001
Formula I
[99] wherein R is the same defined in the general formula I.
[100]
[101] The amine (2-4) is then reacted with sodium nitrite, sodium azide and sodium acetate in hydrochloride to provide the azide analogue (3-1) which is then cyclized by refluxing vinyl acetate or propiolaldehyde diethylacetal to afforded triazolylmethyl ox- azoldinones (formula 1-6 or formular 1-8). Deprotection of the diethylacetal with triflu- oroacetic acid afforded the 4-carbaldehydetriazole (formular 1-8), which was exploited for the preparation of 4-oximepyrrole (formular 1-9) via standard transformations. Dehydration of the oxime (formular I- 10) with trichloroacetyl chloride in dichloromethane yielded the 4-cyano analogue (formula I-l 1). And also reaction of the amine (2-4) with triethyl orthoformate and sodium azide afforded the tetrazole oxazolidinone (formula 1-7).
[102]
[103] The compound of formula 1-1-14 may be used in its native form or as pharam- ceutically acceptable salt. In cases where forming a stable nontoxic acid or base salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, alkali metal (for example, sodium or potassium) or alkaline earth metal (for example, calcium or magnesium) salts of carboxylic acids can be made. And reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion (for example, ammonium, tri- ethylamine, pyridine and N,N-dimethylethanolamine salt). Siitable inorganic salts are formed, including hydrochloride, hydrobromide, sulfate and nitrate salts. Organic acid addition salts may also be formed with acids which form a physiological acceptable anion, for example, formic acid, acetic acid, tartaric acid, citric acid, methylsulfonic acid, lactic acid, succinic acid and benzenesulfonic acid. Advantageous Effects
[104] It is found that not only does the compound of formula 1-1-14 show inhibitory activity against a broad spectrum of bacteria, but its antibacterial activity is excellent in vivo. For example, the compound of the present invention can exert potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganism, such as Bacteroides and Clostridia, and acid-resistant microorganism such as Mycobacterium tuberculosis and Mycobacterium avium.
[105] Best Mode for Carrying Out the Invention
[106] Experimental example 1 [107] MIC Test Method [108] The in vitro Minimum Inhibitory Concentration (MIC: βg/M) of test compounds were determined by a standard agar dilution method. {Chemotheraphy, 1981, 29 (1), 76). Linezolid is included in the assay and serves as a comparator and quality control compound of test compounds. The activity of compounds of this invention is shown in Table 1 and Table 2.
[109] [110] Table 1 [111]
Figure imgf000010_0001
[112] [113] Table 2 [114]
Figure imgf000011_0001
LZD: Linezolid
[115] [116] As can be seen from Tables 1 and 2, the oxazolidinone antibacterial agents of the present invention have excellent activity against gram-positive bacterial infection, including MRS A strains.
[117] [118] Experimental example 2 [119] Acute toxicity studies [120] In order to illustrate use&lness of the compounds of the present invention, acute toxicity test of the compounds synthesized in the Examples were carried out. Each dose of the compounds dissolved in 50% PIG (Polyethylene glycol) was determined in mice using oral route of administration. Mortalities of the animals were recorded 2 weeks later, the results of the acute toxicity studies are shown in Table 3.
[121] [122] Table 3 [123]
Figure imgf000012_0001
* Mouse Male ICR strain, 4 weeks
[124] [125] The compounds are shown high stability as an antimicrobial medicament from LD 50 >4000mg/kg in oral routes. Accordingly, the compounds of the present invention can be used in the therapeutic treatment of human beings or animals infected with variety of gram-positive bacteria.
[126] [127] The present invention includes within its scope pharmaceutical compositions comprising one or more of the compound I-l and their derivatives as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary. The compositions may be formulated into various forms such as tablets, capsules, troche, suspension, solution, suppositories, ointment, cream, injection, which may contain conventional additives such as a dispersant, suspending agent, stabilizer and the like. The compounds of formula I according to this invention are administered orally and parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution. Suitable buffering agents include, for example, -(+)-lysine, -(+)-arginine, N-methylglucamine, sodium citrate, sodium bicarbonate and trisodium orthophosphate to name but a few representative buffering agents.
[128] [129] Formulation examples are described below. [130] [131] Formulation example 1
[132]
[133] Excipient Amount
[134] The compound of prepared Example 1 400.0mg
[135] Corn starch 40.0mg
[136] Microcrystalline cellulose (intragranular) lό.Omg
[137] hydroxypropylcellulose (binder solution) 2.08mg
[138] Microcrystalline cellulose (extragranular) 70.0mg
[139] Croscarmellose sodium 30.0mg
[140] Magnesium stearate 5.6mg
[141] Water purified
[142]
[143] Film coating phase
[144] Opadry white YS-1-18202-A 16.8mg
[145] Water purified 129.2mg
[146]
[147] Polisher
[148] Carnauba wax 0.0224mg
[149]
[150] The following preparative examples are provided to further illustrate this invention but they do not limit the scope of the present invention. [151]
[152] Example 1
[ 153] 3-(3-Fluoro-4-pynolidin- 1 -yl-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one (I-l):
[154]
Figure imgf000013_0001
[155] Vinylacetate 3.5ml and 5-azidomethyl-3-(3-fluoro-4-pynolidin- 1 -yl-phenyl)-oxazolidin-2-one (50mg, O.lόmmol) [Chem. Pharm. Bull. 2001, 49, 353-360] were heated to 110°C for 30h, followed by cooling and concentration in vacuo. The residue was purified by silica gel column chromatography (ethylacetate/hexane = 10/1) to afford the title compound (40mg) in a yield of 74%. [156] 1H NMR (CDC1 ) δ ppm: 7.78 (2H, dd), 7.27 (IH, dd), 6.88 (IH, dd), 6.58 (IH, dd), 5.01 (IH, m), 4.77 (2H, dd), 4.10 (IH, dd), 3.83 (IH, dd), 3.33 (4H, dd), 2.01 (4H, dd)
[157]
[158] Example 2
[159] 3-(3-Fluoro-4-pynol- 1 -yl-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one (1-2):
[160]
Figure imgf000014_0001
[161] Vinylacetate 12.5ml and 5-azidomethyl-3-(3-fluoro-4-pynol- 1 -yl-phenyl)-oxazolidin-2-one ( 176mg, 0.585mmol) [J. Med. Chem. 2000, 43, 953-970] were heated to 110°C for 30h, followed by cooling and concentration in vacuo. The residue was purified by silica gel column chromatography (ethylacetate/hexane = 10/1) to afford the title compound (148mg) in a yield of 77%.
[162] 1H NMR (DMSO-d ) δ ppm: 8.18 (IH, dd), 7.76 (IH, dd), 7.56 (2H, dd), 7.36 (IH, dd), 7.10 (2H, dd), 6.25 (2H, dd), 5.17 (IH, m), 4.85 (2H, dd), 4.27 (IH, dd), 3.92 (IH, dd)
[163]
[164] Example 3
[ 165] Benzyl- [2-fluoro-4-(2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-phenyl]-car bamic acid benzyl ester
[166]
Figure imgf000014_0002
[167] Vinylacetate 8.3ml and [4-(5-azidomethyl-2-oxo-oxazDlidin-3-yl)-2-fluoro-phenyl] - benzyl-carbamic acid benzyl ester (185mg, 0.39mmol) were heated to 110°C for 30h, followed by cooling and concentration in vacuo. The residue was purified by silica gel column chromatography (ethylacetate/hexane = 3/1) to afford the title compound (150mg) in a yield of 77%.
[168] 1H NMR (CDC1 ) δ ppm: 7.45-6.50 (13H, m), 4.95 (IH, m), 4.92 (2H, dd), 4.73 3 (2H, dd), 4.67 (2H, dd), 4.28 (2H, dd), 4.01 (IH, dd), 3.78 (IH, dd) [169]
[170] Example 4
[171] 3-(4- Amino-3-fluoro-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one:
[172]
Figure imgf000015_0001
[173] A solution of benzyl-[2-fluoro-4-(2-oxo-5-[l,2,3] triazol- l-ylmethyl-oxazDlidin-3-yl)-phenyl]-carbamic acid benzyl ester (150mg, 0.3mmol) in ethanol (9.3ml) was added 62mg of 10% Pd C catalyst. The mixture was placed on a Parr hydrogenator for 7.5h. There was then added an additional 6.1mg of 10% Pd C catalyst and the reaction was allowed to continue. After an additional 15.5h the catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo to afford the title compound (69mg) in a yield of 83%.
[174] 1H NMR (CD OD) δ ppm: 8.02 (IH, s), 7.73 (IH, s), 7.15 (IH, dd), 6.80 (2H, dd), 3 5.09 (IH, m), 4.82 (2H, dd), 4.18 (IH, dd), 3.87 (IH, dd) [175]
[176] Example 5
[ 177] 1 - [2-Fluoro-4-(2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-phenyl]- lH-pyn ole-3-carbaldehyde (1-3):
[178]
Figure imgf000015_0002
[179] A solution of 3-(4-amino-3-fluoro-phenyl)-5-[ 1,2,3] triazol- l-ylmethyl-oxazDlidin-2-one (48mg, 0.17mmol) and 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (34 fd, 0.24mmol) in acetic acid (1.2ml) was refluxed for 2h. The solution was cooled and the solvent removed under high vacuum, azeothroping the residue with toluene to remove the last traces of acetic acid. The residue was chromatographed (ethylacetate/hexane/methanol = 4/4/1) to afford the title compound (45mg) in a yield of 73%.
[180] 1H NMR (CD OD) δ ppm: 9.85 (IH, s), 7.79-6.80 (8H, dd), 5.12 (IH, m), 4.83 (2H, dd), 4.18 (2H, dd) [181]
[182] Example 6
[ 183] 1 - [2-Fluoro-4-(2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-phenyl]- lH-pyn ole-3-carbaldehyde oxime (T4):
[184]
[ 185] 1 - [2-Fluoro-4-(2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-phenyl]- lH-pyn ole-3-carbaldehyde (74mg, 0.21mmol), hydroxylamine hydrochloride (lOmg, 0.15mmol) and potassium carbonate (15mg, O.llmmol) were stined in methanol/ dichloromethane (1:1) (0.5ml/0.5ml) for overnight. And then the resulting precipitate was collected, washed with water and dried under vacuum to yield 48mg (63%) of title compound.
[186] 1H NMR (DMSO-d ) δ ppm: 10.58 (IH, s), 8.17-6.47 (8H, dd), 5.17 (IH, m), 4.84 (2H, dd), 4.27 (IH, dd), 3.95 (IH, dd)
[187]
[188] Example 7
[ 189] 1 - [2-Fluoro-4-(2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-phenyl]- lH-pyn ole-3-carbonitrile (1-5):
[190]
Figure imgf000016_0002
[191] To a stined solution of the l-[2-fluoro-4-(2-oxo-5-[l,2,3] triazol- l-ylmethyl-oxazDlidin-3-yl)-phenyl]-lH-pynole-3-carbaldehyde oxime (78mg, 0.22mmol) and triethylamine (60 fd, 0.43mmol) in dichloromethane (1ml), a solution of trichloroacetyl chloride (24.7 fd, 0.22mmol) in dichloromethane (1ml) is added dropwise at 5~10°C. The mixture is allowed to reach room temperature and is stined for 24h. The mixture was diluted with dichloromethane and washed with water. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (dichloromethane/methanol = 9/1) to afford the title compound (34mg) in a yield of 45%.
[192] 1H NMR (DMSO-d ) δ ppm: 7.97-6.60 (8H, dd), 5.18 (IH, m), 4.88 (2H, dd), 4.29 6 (IH, dd), 4.01 (IH, dd) [193]
[194] Example 8
[195] 3-(4-Azido-3-fluoro-phenyl)-5-[l,2,3]triazDl-l-ylmethyl-oxazolidin-2-one:
[196]
Figure imgf000017_0001
[ 197] 3-(4- Amino-3-fluoro-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one (6 lmg, 0.22mmol) was dissolved in concentrated hydrochloride 0.5ml and water 0.5ml and cooled to 0°C. Sodium nitrite (17mg, 0.24mmol) was added and the yellow solution was stined at 0°C for 2h. A solution of sodium azide (29mg, 0.44mmol)) and sodium acetate (360mg, 4.39mmol) was added dropwise. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (magnesium sulfate). Removal of solvent gave product as a tan solid. This was crystallized from ethyl acetate/hexane to give 45mg in a yield of 67%.
[198] 1H NMR (DMSO-d ) δ ppm: 8.15 (IH, s), 7.75 (IH, s), 7.54 (IH, dd), 7.30 (2H, dd), 5.13 (IH, m), 4.82 (2H, dd), 4.21 (IH, dd), 3.87 (IH, dd)
[199]
[200] Example 9
[201 ] 3-(3-Fluoro-4-[ 1 ,2,3]triazol- 1 -yl-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2- one (T6):
[202]
Figure imgf000017_0002
[203] Vinylacetate 2.6ml and 3-(4-azido-3-fluoro-phenyl)-5-[ 1 ,2,3] triazol- l-ylmethyl-oxazDlidin-2-one (36mg, 0.12mmol) were heated to 110°C for 30h, followed by cooling and concentration in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (40mg) in a yield of 99%.
[204] 1H NMR (CDC1 ) δ ppm: 8.22 (IH, s), 8.00 (IH, s), 7.86 (2H, dd), 7.75 (2H, dd), 3 7.35 (IH, dd), 5.20 (IH, m), 4.92 (2H, dd), 4.33 (IH, dd), 4.06 (IH, dd)
[205] [206] Example 10
[207] 3-(3-Ruoro-4-tetrazol-2-yl-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one (1-7): [208]
Figure imgf000018_0001
[209] A slurry of 3-(4-amino-3-fluoro-phenyl)-5-[l,2,3] triazol- l-ylmethyl-oxazDlidin-2-one (36mg, 0.13mmol), sodium azide (13mg, 0.19mmol) and triethyl orthoformate (34 fd, 0.2mmol) in acetic acid (0.68ml) was refluxed for 4h. The mixture was cooled and added to ice water (1.4ml). After setting at ambient temperature for 48h, the precipitated product was collected by filtration and washed with cold methanol to yield 27mg (63%).
[210] 1H NMR (DMSO-d ) δ ppm: 9.91 (IH, s), 8.17 (IH, dd), 7.91-7.50 (4H, m), 5.19 (IH, m), 4.85 (2H, dd), 4.31 (IH, dd), 3.98 (IH, dd)
[211]
[212] Example 11
[213] 3-(3-Fluoro-4-pynolidin- 1 -yl-phenyl)-5-[ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one hydrochloride:
[214] Etheral hydrochloride (3ml) was added dropwise to a solution of I-l (32mg, O.lOmmol) in chloroform (1ml) and was concentrated in vacuo. The residue was treated with water (3ml) and the suspended solid was removed by filtration and washed with additional water. The combined filtrates were freezedried to yield 28mg (79%).
[215]
[216] Example 12
[217] 3-(3-Fluoro-4-pynol- 1 -yl-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one hydrochloride:
[218] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-2 (30mg, 0.09mmol) in chloroform (1ml) and was concentrated in vacuo. The residue was treated with water (3ml) and the suspended solid was removed by filtration and washed with additional water. The combined filtrates were freezedried to yield 31mg (94%).
[219]
[220] Example 13 [221 ] 1 - [2-Fluoro-4-(2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-phenyl]- lH-pyn ole-3-carbonitrile hydrochloride:
[222] Etheral hydrochloride (3ml) was added dropwise to a solution of 1-5 (32mg, 0.09mmol) in chloroform (1ml) and was concentrated in vacuo. The residue was treated with water (3ml) and the suspended solid was removed by filtration and washed with additional water. The combined filtrates were freezedried to yield 30mg (86%).
[223]
[224] Example 14
[225] 3-(3-Fluoro-4-pynolidin- 1 -yl-phenyl)-5-[ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one sul&ric acid:
[226] Sul&ric acid (1ml) was added to a solution of I-l (30mg, 0.09mmol) in iso- propylalcohol (1ml) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 32mg (82%)
[227]
[228] Example 15
[229] 3-(3-Fluoro-4-pynol- 1 -yl-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one sul&ric acid:
[230] Sul&ric acid (1ml) was added to a solution of 1-2 (32mg, O.lmmol) in isopropylalcohol (1ml) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 36mg (87%)
[231]
[232] Example 16
[233] l-[2-Ruoro-4-(2-oxo-5-[l,2,3]triazol-l-ylmethyl-oxazolidin-3-yl)-phenyl]-lH-pyn ole-3-carbonitrile sul&ric acid:
[234] Sul&ric acid (1ml) was added to a solution of 1-5 (31mg, 0.09mmol) in isopropylalcohol (1ml) and was concentrated in vacuo afforded a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 31mg (79%)
[235]
[236] Example 17
[237] 3-(3-Fluoro-4-pynolidin- 1 -yl-phenyl)-5-[ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one citric acid:
[238] Citric acid (leq) was added to a solution of I-l (30mg, 0.09mmol) in isopropylalcohol (1ml) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 31mg (65%). [239]
[240] Example 18
[241 ] 3-(3-Fluoro-4-pynol- 1 -yl-phenyl)-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-2-one citric acid:
[242] Citric acid (leq) was added to a solution of 1-2 (30mg, 0.09mmol) in isopropylalcohol (1ml) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 29mg (62%).
[243]
[244] Example 19
[245] 1 - [2-Fluoro-4-(2-oxo-5- [ 1 ,2,3]triazol- 1 -ylmethyl-oxazolidin-3-yl)-phenyl]- lH-pyn ole-3-carbonitrile citric acid:
[246] Citric acid (leq) was added to a solution of 1-5 (30mg, 0.08mmol) in isopropylalcohol (1ml) and was concentrated in vacuo afford a solid which was re- crystallized from boiling isopropylalcohol to afford title compound 29mg (62%).
[247]
[248] Example 20
[249] (R)-5-((lH- 1 ,2,3-triazol- l-yl)methyl)-3-(4-(4-(diethoxymethyl)-lH- 1 ,2,3-triazol- 1- yl)-3-fluorophenyl)oxazDlidin-2-one(I-8)
[250]
Figure imgf000020_0001
[251] A solution of propiolaldehyde diethylacetal 333 fd and 3-(4-azido-3-fluoro-phenyl)-5-[l,2,3]triazDl-l-ylmethyl-oxazDlidin-2-one (320mg, 1.15mmol) in beznene (3ml) were refluxed for 30h. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (266mg) in a yield of 58%.
[252] 1H NMR (CDC1 ) δ ppm: 8.08 (IH, dd), 7.90 (IH, dd), 7.82 (IH, dd), 7.76 (IH, dd), 7.63 (IH, dd), 7.21 (IH, dd), 5.80 (2H, dd), 5.15 (IH, m), 4.84 (2H, dd), 4.25 (IH, dd), 4.10 (IH, dd), 3.70 (4H, dd), 1.28 (6H, dd)
[253]
[254] Example 21
[255] l-(4-((R)-5-((lH-l,2,3-triazol-l-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)- lH-l,2,3-triazole-4-carbaldehyde(I-9)
[256]
Figure imgf000021_0001
[257] 3- [4-(4-Diethoxymethyl- [ 1 ,2,3]triazol- 1 -yl)-3-fluoro-phenyl]-5- [ 1 ,2,3]triazol- 1 -ylm ethyl-oxazDlidin-2-one (75mg, 0.17mmol) was dissolved in chloroform 1.0ml and cooled to 0°C. 50% aqueous trifluoroacetic acid (350 fd, 4.5mmol) was added and the solution was stined at 0°C for 90min. The mixture was extracted with methylene chloride, water and aq.NaHCO . Drying (magnesium sulfate) and concentration in 3 vacuo, the residue was purified by silica gel column chromatography (ethylacetate/hexane/methanol = 4/4/1) to afford the title compound (26mg) in a yield of 42%. [258] 1H NMR (DMSO-d ) δ ppm: 10.13 (IH, dd), 9.34 (IH, dd), 8.19 (IH, dd), 7.75 (3H, dd), 7.50 (IH, dd), 5.21 (IH, m), 4.87 (2H, dd), 4.31 (IH, dd), 3.97 (IH, dd) [259]
[260] Example 22
[261 ] 1 -(4-((R)-5-(( IH- 1 ,2,3-triazol- 1 -yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)- 1H- 1 ,2,3-triazole-4-carbaldehyde oxime(I- 10) [262]
Figure imgf000021_0002
[263] l-[2-Fluoro-4-(2-oxo-5-[ 1 ,2,3]triazol- l-ylmethyl-oxazolidin-3-yl)-phenyl]- lH-[ 1 ,2, 3]triazole-4-carbaldehyde (55mg, 0.15mmol), hydroxylamine hydrochloride (15mg, 0.23mmol) and potassium carbonate (32mg, 0.23mmol) were stined in methanol/ dichloromethane (1:1) (2ml/2ml) for overnight. And then the resulting precipitate was collected, washed with water and dried under vacuum to yield 45mg (80%) of title compound.
[264] 1H NMR (DMSO-d ) δ ppm: 10.11 (IH, dd), 9.34 (IH, dd), 8.18 (IH, dd), 7.89 (IH, dd), 7.75 (2H, dd), 7.51 (IH, dd), 5.21 (IH, m), 4.87 (2H, dd), 4.31 (IH, dd), 3.97 (IH, dd)
[265]
[266] Example 23
[267] l-(4-((R)-5-((lH-l,2,3-triazol-l-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)- 1H- 1 ,2,3-triazole-4-carbonitrile(I- 11 ) [268]
Figure imgf000022_0001
[269] To a solution of the l-[2-Fluoro-4-(2-oxo-5-[l,2,3] triazol- l-ylmethyl-oxazDlidin-3-yl)-phenyl]-lH-[l,2,3]triazole-4-carbaldehyde oxime (45mg, 0.12mmol) and triethylamine 04 fd, 0.24mmol) in dichloromethane (1ml), a solution of trichloroacetyl chloride (14 fd, 0.13mmol) in dichloromethane (1ml) is added dropwise at 5~10°C. The mixture is allowed to reach room temperature and is stined for 24h. The mixture was diluted with dichloromethane and washed with water. Drying (magnesium sulfate) and concentration in vacuo, the residue was purified by silica gel column chromatography (ethylacetate/hexane/methanol = 4/4/1) to afford the title compound (9mg) in a yield of 20%.
[270] 1H NMR (DMSO-d ) δ ppm: 9.55 (IH, dd), 8.18 (IH, dd), 7.89 (IH, dd), 7.79 (2H, dd), 7.53 (IH, dd), 5.21 (IH, m), 4.86 (2H, dd), 4.31 (IH, dd), 3.97 (IH, dd)
[271]
[272] Example 24
[273] ethyl l-(4-((R)-5-((lH-l,2,3-triazol-l-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)-lH -pyrazole-4-carboxylate(I- 12)
[274]
Figure imgf000022_0002
[275] Vinylacetate 12ml and ethyl l-(4-((R)-5-(azidomethyl)-2-oxooxazDlidin-3-yl)-2-fluorophenyl)-lH-pyrazDle-4-carb oxylate (200mg, 0.53mmol) were heated to 110°C for 30h, followed by cooling and concentration in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 6/6/1) to afford the title compound (184mg) in a yield of 86%.
[276] 1H NMR (CDC1 ) δ 7.97-7.20 (7H, dd), 5.10 (IH, m), 4.72 (2H, dd), 4.69 (2H, q), 4.40 (IH, dd), 4.05 (IH, dd), 1.42 (3H, t)
[277]
[278] Example 25
[279] l-(4-((R)-5-((lH-l,2,3-triazol-l-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)- 1 H-pyrazDle-4-carboxamide(I- 13) [280]
Figure imgf000023_0001
[281] A solution of the ethyl l-(4-((R)-5-((lH-l,2,3-triazol-l-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)-lH -pyrazole-4-carboxylate (184mg, 0.46mmol) and KCN (7.5mg, 0.115mmol) in saturated methanolic ammonia was heated in a sealed tube at 50°C. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol = 4/4/1) to afford the title compound (72mg) in a yield of 42%.
[282] 1H NMR (CDC1 ) δ 7.97-7.20 (7H, dd), 5.05 (IH, m), 4.70 (2H, dd), 4.32 (IH, dd), 3 4.09 (IH, dd) [283]
[284] Example 26
[285] l-(4-((R)-5-((lH-l,2,3-triazol-l-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)- 1 H-pyrazDle-4-carbonitrile(I- 14) [286]
Figure imgf000023_0002
[287] l-(4-((R)-5-((lH-l,2,3-triazol-l-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)- lH-pyrazDle-4-carboxamide (72mg, 0.19mmol) was placed in dry DMF 2.2ml and cooled to 0°C under N . SOCl (21 fd, 0.28mmol) was added dropwise and the reaction 2 2 was stined at room temperature for 30min. More SOCl (21 fd, 0.28mmol) was added 2 and stirring was continued another 30min. The mixture was extracted with methylene chloride, water and aq.NaHCO . Drying (magnesium sulfate) and concentration in 3 vacuo, the residue was purified by silica gel column chromatography (ethylacetate/hexane/methanol = 4/4/1) to afford the title compound (46mg) in a yield of 68%. [288] 1H NMR (CDC1 ) δ 7.97-7.20 (7H, dd), 5.07 (IH, m), 4.74 (2H, dd), 4.34 (IH, dd), 3 4.05 (IH, dd)
[289] Industrial Applicability As described hereinbefore, the oxazolidinonoe derivatives of the general formula I have potent antibacterial activity against a broad spectrum of bacteria and their antibacterial activity is maintained high in vivo. Exerting potent antibacterial activity versus various human and animal pathogens, including gram-positive bacteria such as Staphylococi, Enterococci and Streptococi, anaerobic microorganism such as Bacteroides and Clostridia, and acid-resistant microorganism such as Mycobacterium, the compounds of the present invention are therefore use&l as antibiotics.

Claims

Claims
[1] Derivatives of oxazolidinone of formula I, and pharmaceutically acceptable salt thereof: [Formula I]
Figure imgf000025_0001
wherein R is hydrogen atom, ethylcarboxylate, amide, diethoxymethyl, aldehyde, hydroxyoxime or nitrile; X is each and independently carbon or nitrogen atom; and is single bond or double bond. [2] A method for preparing an oxazolidinone derivative of the general formula I which comprises reacting a compound of formula 1-4 with vinylacetate, using or without using a solvent. [Formula 1-4]
Figure imgf000025_0002
[Formula I]
Figure imgf000025_0003
and pharamceutically acceptale salt thereof. wherein R is hydrogen atom, ethylcarboxylate, amide, diethoxymethyl, aldehyde, hydroxyoxime or nitrile; X is each and independently carbon or nitrogen atom; and is single bond or double bond. [3] A method for preparing an oxazolidinone derivative of the general formula I which comprises reacting a compound of formula 2-4 with 2,5-dimethoxy-3-tetrahydro&rancarboxaldehyde using acetic acid, with sodium azide using triethylorthoformate and also with sodium azide and vinylacetate. [Formula 2-4]
Figure imgf000026_0001
[Formula I]
Figure imgf000026_0002
and pharamceutically acceptale salt thereof. wherein R is hydrogen atom, ethylcarboxylate, amide, diethoxymethyl, aldehyde, hydroxyoxime or nitrile; X is each and independently carbon or nitrogen atom; and
is single bond or double bond.
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Cited By (2)

* Cited by examiner, † Cited by third party
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WO2008143649A2 (en) * 2006-12-04 2008-11-27 Dr. Reddy's Laboratories Limited Novel oxazolidinone compounds as antiinfective agents
CN113661163A (en) * 2019-02-28 2021-11-16 国立大学法人大阪大学 Molecules for modifying proteins and/or peptides

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WO2001081350A1 (en) * 2000-04-25 2001-11-01 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
WO2003006447A2 (en) * 2001-07-09 2003-01-23 Pharmacia Italia Spa Interaction inhibitors of tcf-4 with beta-catenin
WO2003072575A1 (en) * 2002-02-28 2003-09-04 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring) methyl-oxazolidinone derivatives and their use as antibacterial agents
WO2003072576A2 (en) * 2002-02-28 2003-09-04 Astrazeneca Ab Oxazolidinone derivatives, processes for their preparation, and pharmaceutical compositions containing them

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Publication number Priority date Publication date Assignee Title
WO2001081350A1 (en) * 2000-04-25 2001-11-01 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
WO2003006447A2 (en) * 2001-07-09 2003-01-23 Pharmacia Italia Spa Interaction inhibitors of tcf-4 with beta-catenin
WO2003072575A1 (en) * 2002-02-28 2003-09-04 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring) methyl-oxazolidinone derivatives and their use as antibacterial agents
WO2003072576A2 (en) * 2002-02-28 2003-09-04 Astrazeneca Ab Oxazolidinone derivatives, processes for their preparation, and pharmaceutical compositions containing them

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008143649A2 (en) * 2006-12-04 2008-11-27 Dr. Reddy's Laboratories Limited Novel oxazolidinone compounds as antiinfective agents
WO2008143649A3 (en) * 2006-12-04 2009-01-15 Reddys Lab Ltd Dr Novel oxazolidinone compounds as antiinfective agents
CN113661163A (en) * 2019-02-28 2021-11-16 国立大学法人大阪大学 Molecules for modifying proteins and/or peptides
EP3932912A4 (en) * 2019-02-28 2022-09-07 Osaka University Protein and/or peptide modification molecule

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