U.S. patent application number 14/459161 was filed with the patent office on 2014-11-27 for novel oxazolidinone derivatives.
The applicant listed for this patent is DONG-A ST CO., LTD.. Invention is credited to Chong Hwan CHO, Sung Hak CHOI, Weon Bin IM, Tae Ho LEE, Jae Keol RHEE.
Application Number | 20140350059 14/459161 |
Document ID | / |
Family ID | 36660051 |
Filed Date | 2014-11-27 |
United States Patent
Application |
20140350059 |
Kind Code |
A1 |
RHEE; Jae Keol ; et
al. |
November 27, 2014 |
NOVEL OXAZOLIDINONE DERIVATIVES
Abstract
The present invention relates to novel derivatives of
oxazolidinone, a method thereof and pharmaceutical compositions
comprising the derivatives for use in an antibiotic. 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
group with amino acid or phosphate, have an excellent efficiency on
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 oxazolidinone are used in an antibiotic.
Inventors: |
RHEE; Jae Keol; (Suwan,
KR) ; IM; Weon Bin; (Yongin-se, KR) ; CHO;
Chong Hwan; (Yongin-si, KR) ; CHOI; Sung Hak;
(Seongnam-si, KR) ; LEE; Tae Ho; (Yongin-so,
KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DONG-A ST CO., LTD. |
Seoul |
|
KR |
|
|
Family ID: |
36660051 |
Appl. No.: |
14/459161 |
Filed: |
August 13, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13863216 |
Apr 15, 2013 |
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14459161 |
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12211655 |
Sep 16, 2008 |
8420676 |
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13863216 |
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10596412 |
Jun 13, 2006 |
7816379 |
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PCT/KR04/03327 |
Jun 13, 2006 |
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12211655 |
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Current U.S.
Class: |
514/340 ;
514/365; 514/376; 546/271.4; 548/204; 548/229 |
Current CPC
Class: |
A61P 3/04 20180101; A61K
31/4439 20130101; C07D 413/14 20130101; C07D 417/10 20130101; A61P
31/00 20180101; A61K 31/675 20130101; C07D 263/32 20130101; C07D
417/14 20130101; C07F 9/65583 20130101; A61P 31/04 20180101; C07F
9/653 20130101 |
Class at
Publication: |
514/340 ;
546/271.4; 548/229; 514/376; 548/204; 514/365 |
International
Class: |
C07F 9/6558 20060101
C07F009/6558; C07D 417/10 20060101 C07D417/10; C07D 417/14 20060101
C07D417/14; C07D 413/14 20060101 C07D413/14 |
Claims
1. An oxazolidinone derivative of Formula I, or a pharmaceutically
acceptable salt thereof; ##STR00078## wherein, Het is pyrrolyl,
furanyl, piperazinyl, piperidinyl, imidazolyl, 1,2,4-triazolyl,
1,2,3-triazolyl, tetrazolyl, pyrazolyl, pyrrolidinyl, oxazolyl,
isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, thiazolyl or
pyrazinyl; ring A is unsubstituted or has at least one fluorine
substituent; R.sub.7 is H or a prodrug substituent; R.sub.3 is
hydrogen, or at least one C.sub.1-4 alkyl group that is
unsubstituted, or substituted with cyano, --(CH.sub.2)m-OR.sub.7 or
ketone; and m is 0, 1, 2, 3, or 4.
2. The oxazolidinone derivative of claim 1, wherein R.sub.7 is a
prodrug substituent, and wherein the oxazolidinone derivative has a
solubility of greater than 30 mg/mL.
3. The oxazolidinone derivative of claim 2, wherein the
oxazolidinone derivative has a solubility of greater than 50
mg/mL.
4. The oxazolidinone derivative of claim 1, wherein R.sub.7 is a
prodrug substituent, the prodrug substituent is PO(OH).sub.2 or
PO(O).sub.2.sup.-2(M.sup.+).sub.2, and M.sup.+ is a metal
cation.
5. The oxazolidinone derivative of claim 4, wherein M.sup.+ is
Na.sup.+.
6. An active metabolite of the oxazolidinone derivative of claim
1.
7. The oxazolidinone derivative of claim 1, wherein Het is
triazolyl.
8. An oxazolidinone derivative which is ##STR00079## or a
pharmaceutically acceptable salt thereof; wherein R.sub.1 and
R.sub.1' are each independently H or F; Het is pyrrolyl, furanyl,
piperazinyl, piperidinyl, imidazolyl, 1,2,4-triazolyl,
1,2,3-triazolyl, tetrazolyl, pyrazolyl, pyrrolidinyl, oxazolyl,
isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, thiazolyl or
pyrazinyl; R.sub.7 is H or a prodrug substituent; R.sub.3 is
hydrogen, or at least one C.sub.1-4 alkyl group that is
unsubstituted, or substituted with cyano, --(CH.sub.2)m-OR.sub.7 or
ketone; and m is 0, 1, 2, 3, or 4.
9. A pharmaceutical composition comprising the oxazolidinone
derivative of claim 1 and a pharmaceutically acceptable
carrier.
10. The pharmaceutical composition of claim 9, wherein the
pharmaceutical composition is an injectable composition.
11. A method of treating a bacterial infection in a subject,
comprising administering to the subject the oxazolidinone
derivative of claim 1.
12. The method of claim 11, wherein the bacterium is selected from
the group consisting of Staphylococcus, Enterococcus, and
Streptococcus.
13. The method of claim 12, wherein the bacterium is MRSA or
VRE.
14. A pharmaceutical composition comprising the oxazolidinone
derivative of claim 8 and a pharmaceutically acceptable
carrier.
15. The pharmaceutical composition of claim 14, wherein the
pharmaceutical composition is an injectable composition.
16. A method of treating a bacterial infection in a subject,
comprising administering to the subject the oxazolidinone
derivative of claim 8.
17. The method of claim 16, wherein the bacterium is selected from
the group consisting of Staphylococcus, Enterococcus, and
Streptococcus.
18. The method of claim 17, wherein the bacterium is MRSA or
VRE.
19. An active metabolite of the oxazolidinone derivative of claim
8.
20. The oxazolidinone derivative of claim 8, wherein Het is
triazolyl.
21. The oxazolidinone derivative of claim 20, wherein the compound
is selected from Compound 17, 22, 24 or 29.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. patent
application Ser. No. 13/863,216 filed on Apr. 15, 2013, which is a
Continuation of U.S. patent application Ser. No. 12/211,655 filed
on Sep. 16, 2008 (issued as U.S. Pat. No. 8,420,676), which is a
Divisional of U.S. patent application Ser. No. 10/596,412 filed on
Jun. 13, 2006 (issued as U.S. Pat. No. 7,816,379), which is a
National Phase application of PCT/KR04/03327, 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.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] 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.
[0004] 2. Description of the Related Art
[0005] 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.
##STR00001##
[0006] 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.
##STR00002##
[0007] 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.
[0008] 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 .mu.g/ml.
[0009] 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.
SUMMARY OF THE INVENTION
Disclosure of the Invention
Technical Problem
[0010] It is an object of the present invention to provide novel
derivatives of oxazolidinone.
[0011] It is another object of the present invention to provide a
method of preparing the above-mentioned derivatives.
[0012] It is still another object of the present invention to
provide a pharmaceutical composition comprising the above-mentioned
derivatives for use in an antibiotic.
Technical Solution
[0013] The present invention provides novel derivatives of
oxazolidinone corresponding to Formula 1 defined below.
##STR00003##
[0014] In the Formula 1, X represents carbon or nitrogen.
[0015] R.sub.1 and R.sub.1' respectively represent hydrogen or
fluorine.
[0016] R.sub.2 represents --NR.sub.5R.sub.6, --OR.sub.7, triazol,
fluorine, alkylphosphate, monophosphate or a metal salt of
phosphate;
[0017] R.sub.5 and R.sub.6, which are the same or different,
respectively represent hydrogen, C. sub. 1-4 alkyl group or acetyl;
and
[0018] R.sub.7 is hydrogen, C. sub. 1-3 alkyl group or acylated
amino acid. When the R.sub.7 is acylated amino acid, amino acid
refers to alanine, glycine, proline, isoleucine, leucine,
phenylalanine, .beta.-alanine or valine.
[0019] 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.
[0020] R.sub.3 and R.sub.4, which are the same or different,
respectively refer to hydrogen, C. sub. 1-4 alkyl group that is
substituted or unsubstituted with cyano, --(CH.sub.2)m-OR.sub.7 (m
represents 0, 1, 2, 3, 4) or ketone.
[0021] 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.
[0022] Preferred compounds of the oxazolidinone derivatives
according to the present invention include the following compounds
and their structures are described in Table 1. [0023] 1)
(S)-3-(4-(2-(2-oxo-4-glycyloxymethylpylolidin-1-yl)pyridin-5-yl)-3-fluoro-
phenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic acid,
[0024] 2)
(S)-3-(4-(2-(4-glycyloxymethyl-1,2,3-triazol-1-yl)pyridin-5-yl)-3-fluo-
rophenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic
acid, [0025] 3)
(S)-3-(4-(2-(5-glycyloxymethylisoxazol-3-yl)pyridin-5-yl)-3-flu-
orophenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic
acid, [0026] 4)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl-
)-5-([1,2,4]triazol-1-yl)methyl oxazolidin-2-on, [0027] 5)
(S)-3-(4-(2-(2-oxo-3-glycyloxypyrrolidine-1-yl)pyridin-5-yl)-3-fluorophen-
yl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic acid,
[0028] 6)
(S)-3-(4-(2-(5-glycyloxymethyl-[1,2,4]oxadiazole-3-yl)pyridin-5-yl)-3-flu-
orophenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic
acid, [0029] 7)
(S)-3-(4-(2-(5-glycyloxymethyl-4,5-dihydroisoxazole-3-yl)pyridi-
n-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide
trifluoroacetic acid, [0030] 8)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,-
3]triazol-2-yl)methyl oxazolidin-2-on, [0031] 9)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,-
3]triazol-1-yl)methyl oxazolidin-2-on, [0032] 10)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox-
ymethyl oxazolidin-2-on, [0033] 11)
(S)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxaz-
olidinylmethyl acetamide, [0034] 12)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on trifluoroacetic acid, [0035] 13)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-([1,2,3]triazol-1-yl)methyl oxazolidin-2-on, [0036] 14)
(R)-3-(4-(2-([1,2,4]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]-
triazol-1-yl)methyl oxazolidin-2-on, [0037] 15)
(S)-3-(4-(2-(4,5-dimethyloxazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo--
5-oxazolidinyl]methyl acetamide, [0038] 16)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-hydroxymethyl oxazolidin-2-on, [0039] 17)
(R)-3-(4-(2-[1,2,4]triazol-1-yl
pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on,
[0040] 18)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoro-
methyl oxazolidin-2-on, [0041] 19)
(S)-3-(4-(2-(imidazole-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-aminomethyl
oxazolidin-2-on hydrochloride, [0042] 20)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0043] 21)
(R)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymet-
hyl oxazolidin-2-on, [0044] 22)
(R)-3-(4-(2-([1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycylox-
ymethyl oxazolidin-2-on trifluoroacetic acid, [0045] 23)
(R)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxym-
ethyl oxazolidin-2-on trifluoroacetic acid, [0046] 24)
(R)-3-(4-(2-([1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxym-
ethyl oxazolidin-2-on, [0047] 25)
(S)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-ox-
azolidinylmethyl acetamide, [0048] 26)
(S)-3-(4-(4-(4(S)-hydroxymethyl-4,5-dihydroxazole-2-yl)phenyl)-3-fluoroph-
enyl)-2-oxo-5-oxazolidinylmethyl acetamide, [0049] 27)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazole-5-yl)pyridin-5-yl)-3-fluorophenyl-
)-5-glycyloxymethyl oxazolidin-2-on trifluoroacetic acid, [0050]
28)
(S)-3-(4-(4-(4-hydroxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5--
oxazolidinylmethyl acetamide, [0051] 29)
(R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxym-
ethyl oxazolidin-2-on, [0052] 30)
(S)-3-(4-(4-(4-glycyloxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo--
5-oxazolidinylmethyl acetamide trifluoroacetic acid, [0053] 31)
(S)-3-(4-(4-(4-cyanomethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl
acetamide, [0054] 32) (R)-3-(4-(4-(4-cyanomethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymethyl
oxazolidin-2-on, [0055] 33)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methox-
ymethyl oxazolidin-2-on, [0056] 34) (R)-3-(4-(4-(4-cyanomethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxymethyl
oxazolidin-2-on trifluoroacetic acid, [0057] 35)
(R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycylox-
ymethyl oxazolidin-2-on trifluoroacetic acid, [0058] 36)
(R)-3-(4-(4-(4-hydroxymethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl
oxazolidin-2-on, [0059] 37) (R)-3-(4-(4-(4-glycyloxymethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl
oxazolidin-2-on trifluoroacetic acid, [0060] 38)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hy-
droxymethyl oxazolidin-2-on, [0061] 39)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3,5-difluorophe-
nyl)-5-hydroxymethyl oxazolidin-2-on, [0062] 40)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N,N-d-
imethylaminomethyl)oxazolidin-2-on, [0063] 41)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N-met-
hylaminomethyl)oxazolidin-2-on, [0064] 42)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0065] 43)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on hydrochloride, [0066] 44)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on hydrochloride, [0067] 45)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on hydrochloride, [0068] 46)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-pro-
linyloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0069] 47)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-pro-
linyloxy)methyl oxazolidin-2-on hydrochloride, [0070] 48)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-glycyloxymethyl oxazolidin-2-on hydrochloride, [0071] 49)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0072] 50)
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on hydrochloride, [0073] 51)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0074]
52)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-alanyloxy)methyl oxazolidin-2-on hydrochloride, [0075] 53)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-valyloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0076]
54)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-valyloxy)methyl oxazolidin-2-on hydrochloride, [0077] 55)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-prolinyloxy)methyl oxazolidin-2-on trifluoroacetic acid,
[0078] 56)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-prolinyloxy)methyl oxazolidin-2-on hydrochloride, [0079] 57)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(.beta.-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid,
[0080] 58)
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophe-
nyl)-5-(.beta.-alanyloxy)methyl oxazolidin-2-on hydrochloride,
[0081] 59)
(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-
-oxazolidinyl]methyl disodiumphosphate, [0082] 60)
(R)-[3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl-
)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate, [0083] 61)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox-
ymethyl oxazolidin-2-on, [0084] 62)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on trifluoroacetic acid, [0085] 63)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on hydrochloride, [0086] 64)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0087] 65)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on hydrochloride, [0088] 66)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0089] 67)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on hydrochloride, [0090] 68)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid, [0091] 69)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on hydrochloride, [0092] 70)
(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-
-oxazolidinyl]methyl disodiumphosphate, [0093] 71)
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,-
3]triazol-1-yl)methyl oxazolidin-2-on, [0094] 72)
mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-
-oxo-5-oxazolidinyl]methyl]phosphate, and [0095] 73)
mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-
-oxo-5-oxazolidinyl]methyl]phosphate.
TABLE-US-00001 [0095] TABLE 1 Compound Structure 1 ##STR00004## 2
##STR00005## 3 ##STR00006## 4 ##STR00007## 5 ##STR00008## 6
##STR00009## 7 ##STR00010## 8 ##STR00011## 9 ##STR00012## 10
##STR00013## 11 ##STR00014## 12 ##STR00015## 13 ##STR00016## 14
##STR00017## 15 ##STR00018## 16 ##STR00019## 17 ##STR00020## 18
##STR00021## 19 ##STR00022## 20 ##STR00023## 21 ##STR00024## 22
##STR00025## 23 ##STR00026## 24 ##STR00027## 25 ##STR00028## 26
##STR00029## 27 ##STR00030## 28 ##STR00031## 29 ##STR00032## 30
##STR00033## 31 ##STR00034## 32 ##STR00035## 33 ##STR00036## 34
##STR00037## 35 ##STR00038## 36 ##STR00039## 37 ##STR00040## 38
##STR00041## 39 ##STR00042## 40 ##STR00043## 41 ##STR00044## 42
##STR00045## 43 ##STR00046## 44 ##STR00047## 45 ##STR00048## 46
##STR00049## 47 ##STR00050## 48 ##STR00051## 49 ##STR00052## 50
##STR00053## 51 ##STR00054## 52 ##STR00055## 53 ##STR00056## 54
##STR00057## 55 ##STR00058## 56 ##STR00059## 57 ##STR00060## 58
##STR00061## 59 ##STR00062## 60 ##STR00063## 61 ##STR00064## 62
##STR00065## 63 ##STR00066## 64 ##STR00067## 65 ##STR00068## 66
##STR00069## 67 ##STR00070## 68 ##STR00071## 69 ##STR00072## 70
##STR00073## 71 ##STR00074## 72 ##STR00075## 73 ##STR00076##
[0096] In Table 1, `Ac` represents acetyl and `TfOH` refers to
trifluoroacetic acid.
[0097] 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.
##STR00077##
[0098] In the Scheme 1, Z represents C.sub.1-4 alkyl group, X,
R.sub.1, R.sub.1', R.sub.2, R.sub.3 and R.sub.4 are as defined in
Formula 1 and Y represents halogen.
[0099] The method of preparing the derivatives of oxazolidinone
according to the present invention comprises: [0100] substituting a
halogen atom for a hydrogen atom on phenyl of a derivative (II) of
hydroxymethyloxazolidinone thereby to form a derivative (III) (Step
1); [0101] substituting stannyl for a halogen atom (Y) of the
derivative (III) to form a derivative (IV) (Step 2); [0102]
reacting the derivative (IV) with pyridine or phenyl derivative
that is substituted to bromine or iodine to form a derivative (V)
of oxazolidinone having pyridine ring or phenyl ring (Step 3); and
[0103] reacting the derivative (V) with amino acid having a
protecting group and then with acid thereby to eliminate the
protecting group and to form salts of the compounds corresponding
to Formula 1, or subjecting the derivative (V) to react with
phosphate and then with metallic salt thereby to form salts of the
compounds corresponding to Formula 1 (Step 4).
[0104] 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.degree. C. in liquid
nitrogen.
[0105] 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 (CF.sub.3COOAg) and adding iodine at room temperature.
[0106] 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.degree. C.
[0107] 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.degree. C.
[0108] 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, .beta.-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.
[0109] 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.
[0110] The salt of the derivative of formula 1, prepared by using
amino acid at position R.sub.3 or R.sub.4, 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.
[0111] 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.
[0112] Further, the present invention provides a pharmaceutical
composition comprising the derivatives of oxazolidinone
corresponding to Formula 1 for use in an antibiotic.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] The composition of the present invention may comprise at
least one effective ingredient having functions similar to those of
the derivatives of oxazolidinone.
[0117] 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.
[0118] 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.
[0119] The Lethal Dose (LD.sub.50) of the oxazolidinone derivatives
shows above 1 g/kg in test of acute toxicity so that the
derivatives are found stable.
(a) Advantageous Effects
[0120] 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.
[0121] 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.
[0122] Accordingly, the compositions comprising the derivatives of
oxazolidinone are used in an antibiotic.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
(b) Best Mode for Carrying Out the Invention
[0123] 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.
Preparation Example 1
Preparation of N-Carbobenzyloxy-3-fluoroaniline
[0124] 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 (NaHCO.sub.3). After being cooled to
0.degree. C., the solution was slowly added with 154 ml of
N-carbobenzyloxy chloride (CbzCl) for reaction. While the
temperature was maintained at 0.degree. 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 (MgSO.sub.4) and concentrated in vacuo.
The residue was washed twice with n-hexane to afford the title
compound as white crystal. 132 g. Yield 85%.
Preparation Example 2
Preparation of
(R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol
[0125] 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.degree. 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
(NH.sub.4Cl) 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%.
[0126] .sup.1H NMR (DMSO-d.sub.6) .delta. 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).
Preparation Example 3
Preparation of
(R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol
[0127] 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
(CF.sub.3COOAg) 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%.
[0128] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Preparation Example 4
Preparation of
(R)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol
[0129] 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
((Bu.sub.3Sn).sub.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.
[0130] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Preparation Example 5
Preparation of 2-cyano-5-bromopyridine
[0131] 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.degree. 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%.
[0132] .sup.1H NMR (CDCl.sub.3) .delta. 8.76 (s, 1H), 7.98 (dd,
1H), 7.58 (dd, 1H)
Preparation Example 6
Preparation of 2-(tetrazol-5-yl)-5-bromopyridine
[0133] 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.degree. 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%.
Preparation Example 7
Preparation of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and
2-(2-methyltetrazol-5-yl)-5-bromopyridine
[0134] 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.degree. 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.
[0135] 1) 2-(1-methyltetrazol-5-yl)-5-bromopyridine
[0136] .sup.1H NMR (CDCl.sub.3) .delta. 8.77 (t, 1H), 8.23 (dd,
1H), 8.04 (dd, 1H), 4.46 (s, 3H)
[0137] 2) 2-(2-methyltetrazol-5-yl)-5-bromopyridine
[0138] .sup.1H NMR (CDCl.sub.3) .delta. 8.80 (t, 1H), 8.13 (dd,
1H), 7.98 (dd, 1H), 4.42 (s, 3H)
Preparation Example 8
Preparation of
2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine
[0139] 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%.
[0140] .sup.1H NMR (CDCl.sub.3) .delta. 7.99 (t, 1H), 7.40 (dd,
1H), 7.27 (dd, 1H), 1.83 (s, 3H)
Preparation Example 9
Preparation of 2-([1,2,3]triazol-1-yl)-5-bromopyridine and
2-([1,2,3]triazol-2-yl)-5-bromopyridine
[0141] 20 g of 2,5-dibromopyridine was dissolved in 200 ml of
1-methyl-2-pyrrolidone. The solution was added with 35 g of
potasiumcarbonate and stirred for 10 hours at the temperature of
100.degree. 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.
[0142] 1) 2-([1,2,3]triazol-1-yl)-5-bromopyridine
[0143] .sup.1H NMR (CDCl.sub.3) .delta. 8.53 (dd, 2H), 8.10 (d,
1H), 8.03 (dd, 1H), 7.82 (s, 1H)
[0144] 2) 2-([1,2,3]triazol-2-yl)-5-bromopyridine
[0145] .sup.1H NMR (CDCl.sub.3) .delta. 8.60 (t, 1H), 7.97 (s, 2H),
7.87 (s, 2H)
Example 1
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox-
ymethyl oxazolidin-2-on (compound 10)
[0146] 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 dichlorobistriphenylphosphine palladium (II)
at room temperature and then stirred at the temperature of
120.degree. 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%.
[0147] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 2
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-hydroxymethyl oxazolidin-2-on (compound 16)
[0148] 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.
[0149] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 3
Preparation of
(R)-3-(4-(2-([1,2,4]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxym-
ethyl oxazolidin-2-on (compound 17)
[0150] 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%).
Example 4
Preparation of
(R)-3-(4-(4-(4,5-dimethyloxzol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymeth-
yl oxazolidin-2-on (compound 21)
[0151] 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%).
[0152] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 5
Preparation of
(R)-3-(4-(2-([1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxym-
ethyloxazolidin-2-on (compound 24)
[0153] 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.
[0154] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 6
Preparation of
(R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxym-
ethyl oxazolidin-2-on (compound 29)
[0155] 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.
[0156] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 7
Preparation of (R)-3-(4-(4-(4-cyanomethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-hydroxymethyl
oxazolidin-2-on (compound 32)
[0157] 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.
[0158] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 8
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hy-
droxymethyl oxazolidin-2-on (compound 38)
[0159] 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-oxazolidinylmethano-
l as a starting material, to prepare the title compound.
[0160] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 9
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3,4-difluorophe-
nyl)-5-hydroxymethyl oxazolidin-2-on (compound 39)
[0161] The same procedure as in Example 1 was conducted by using
(R)-3-(4-trimethylstannyl-3,4-difluorophenyl)-2-oxo-5-oxazolidinylmethano-
l and 2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridine as a
starting material, to prepare the title compound.
[0162] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 10
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on trifluoroacetic acid (compound 12)
[0163] In 25 ml of dimethylformamide was dissolved 4 g of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox-
ymethyl 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%.
[0164] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 11
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound 20)
[0165] The title compound was prepared in a method similar to that
of Example 10 using BOC-valline, instead of BOC-glycine.
[0166] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 12
Preparation of (R)-3-(4-(2-[1,2,3]triazol-1-yl
pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl oxazolidin-2-on
trifluoroacetic acid (compound 22)
[0167] The title compound was prepared in a method similar to that
of Example 10 using compound 24.
[0168] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 13
Preparation of
(R)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxym-
ethyl oxazolidin-2-on trifluoroacetic acid (compound 23)
[0169] The title compound was prepared in a method similar to that
of Example 10 using compound 21.
[0170] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 14
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-glycyloxymethyl oxazolidin-2-on trifluoroacetic acid (compound
27)
[0171] The title compound was prepared in a method similar to that
of Example 10 using compound 16.
[0172] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 15
Preparation of (R)-3-(4-(4-(4-cyanomethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-glycyloxymethyl
oxazolidin-2-on trifluoroacetic acid (compound 34)
[0173] The title compound was prepared in a method similar to that
of Example 10 using compound 32.
[0174] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 16
Preparation of
(R)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycylox-
ymethyl oxazolidin-2-on trifluoroacetic acid (compound 35)
[0175] The title compound was prepared in a method similar to that
of Example 10 using compound 29.
[0176] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 17
Preparation of
(S)-3-(4-(2-(2-oxo-4-glycyloxymethylpyrrolidin-1-yl)pyridin-5-yl)-3-fluor-
ophenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic acid
(compound 1)
[0177] 1. The Primary Step
[0178] 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.degree. 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-fluorop-
henyl)-2-oxo-5-oxazolidinylmethyl acetamide 410 mg. Yield 21%.
[0179] 2. The Secondary Step
[0180] 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.
[0181] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 18
Preparation of
(S)-3-(4-(2-(4-glycyloxymethyl-[1,2,3]triazol-1-yl)pyridin-5-yl)-3-fluoro-
phenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic acid
(compound 2)
[0182] 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.
[0183] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 19
Preparation of
(S)-3-(4-(2-(5-glycyloxymethylisoxazol-3-yl)pyridin-5-yl)-3-fluorophenyl)-
-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic acid
(compound 3)
[0184] 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.
[0185] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 20
Preparation of
(S)-3-(4-(2-(2-oxo-3-glycyloxypyrrolidin-1-yl)pyridin-5-yl)-3-fluoropheny-
l)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic acid
(compound 5)
[0186] 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.
[0187] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 21
Preparation of
(S)-3-(4-(2-(5-glycyloxymethyl-[1,2,4]oxadiazol-3-yl)pyridin-5-yl)-3-fluo-
rophenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic acid
(compound 6)
[0188] 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.
[0189] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 22
Preparation of
(S)-3-(4-(2-(5-glycyloxymethyl-4,5-dihydroisoxazol-3-yl)pyridin-5-yl)-3-f-
luorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide trifluoroacetic
acid (compound 7)
[0190] 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.
[0191] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 23
Preparation of
(S)-3-(4-(4-(4-glycyloxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo--
5-oxazolidinylmethyl acetamide trifluoroacetic acid (compound
30)
[0192] 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.
[0193] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 24
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,-
4]triazol-1-yl)methyl oxazolidin-2-on (compound 4)
[0194] 1. The Primary Step
[0195] In 14 ml of methylenechloride was dissolved 1 g of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox-
ymethyl oxazolidin-2-on (compound 10). The solution was added with
0.46 g of methanesulfonylchloride 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-methan-
esulfonyloxymethyl oxazolidin-2-on 1 g. Yield 82%.
[0196] 2. The Secondary Step
[0197] 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%.
[0198] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 25
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,-
3]triazol-2-yl)methyl oxazolidin-2-on (compound 8) and
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,-
3]triazol-1-yl)methyl oxazolidin-2-on (compound 9)
[0199] 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.
[0200] (compound 8) .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
[0201] (compound 9) .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 26
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-([1,2,3]triazol-1-yl)methyl oxazolidin-2-on (compound 13)
[0202] 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.
[0203] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 27
Preparation of
(R)-3-(4-(2-([1,2,4]triazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,3]-
triazol-1-yl)methyl oxazolidin-2-on (compound 14)
[0204] 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.
[0205] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 28
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoro-
methyl oxazolidin-2-on (compound 18)
[0206] In 5 ml of methylenechloride was dissolved 100 mg of the
compound 10. The solution was added with 43 mg of
diethylaminosulfurtrifluoride (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%.
[0207] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 29
Preparation of
(S)-3-(4-(2-(imidazol-1-yl)pyridin-5-yl)-3-fluorophenyl)-5-aminomethyl
oxazolidin-2-on hydrochloride (compound 19)
[0208] 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-oxazolid-
inylmethyl acetamide. The solution was added with 2.36 g of
hydroxylamine at room temperature and stirred for 10 hours at the
temperature 100.degree. 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.
Example 30
Preparation of
(S)-3-(4-(4-(4,5-dimethyloxazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxaz-
olidinylmethyl acetamide (compound 11)
[0209] 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.
[0210] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 31
Preparation of
(S)-3-(4-(2-(4,5-dimethyloxazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo--
5-oxazolidinylmethyl acetamide (compound 15)
[0211] 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.
[0212] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 32
Preparation of
(S)-3-(4-(2-([1,2,3]triazol-2-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-ox-
azolidinylmethyl acetamide (compound 25)
[0213] 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.
[0214] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 33
Preparation of
(S)-3-(4-(4-(4(S)-hydroxymethyl-4,5-dihydrooxazol-2-yl)phenyl)-3-fluoroph-
enyl)-2-oxo-5-oxazolidinylmethyl acetamide (compound 26)
[0215] 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.
[0216] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 34
Preparation of (S)-3-(4-(4-(4-cyanomethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl
acetamide (compound 31)
[0217] 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.
[0218] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 35
Preparation of (R)-3-(4-(4-(4-hydroxymethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl
oxazolidin-2-on (compound 36)
[0219] 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.
[0220] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 36
Preparation of (R)-3-(4-(4-(4-glycyloxymethyl
thiazol-2-yl)phenyl)-3-fluorophenyl)-5-([1,2,3]triazol-1-yl)methyl
oxazolidin-2-on trifluoroacetic acid (compound 37)
[0221] 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.
[0222] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 37
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methox-
ymethyl oxazolidin-2-on (compound 33)
[0223] In 10 ml of methanol was dissolved 400 mg of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methan-
esulfonyloxymethyl oxazolidin-2-on prepared in the secondary step
of the Example 24. The solution was added with 90 mg of
sodiummethoxide 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%.
[0224] .sup.1H NMR (CDCl.sub.3) .delta. 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)
Example 38
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N,N-d-
imethylaminomethyl)oxazolidin-2-on (compound 40)
[0225] In 5 ml of dimethylformamide was dissolved 100 mg of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methan-
esulfonyloxymethyl 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.degree. 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%.
[0226] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 39
Preparation of
(S)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-N-meth-
ylaminomethyl oxazolidin-2-on (compound 41)
[0227] In 7 ml of dimethylformamide was dissolved 200 mg of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methan-
esulfonyloxymethyl 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 potasiumcarbonate at room temperature.
The solution was stirred for 30 hours at the temperature of
80.degree. 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%.
[0228] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 40
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound
42)
[0229] The same procedure as in Example 10 was carried out to
provide the title compound using BOC-L-alanine instead of
BOC-glycine.
[0230] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 41
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on hydrochloride (compound 43)
[0231] 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%.
[0232] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 42
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on hydrochloride (compound 44)
[0233] With the exception of using compound 42, the same procedure
as in Example 41 was conducted to prepare the title compound.
[0234] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 43
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on hydrochloride (compound 45)
[0235] With the exception of using the compound 12, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0236] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 44
Preparation of
(S)-3-(4-(4-(4-hydroxymethylthiazol-2-yl)phenyl)-3-fluorophenyl)-2-oxo-5--
oxazolidinylmethyl acetamide (compound 28)
[0237] 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.
[0238] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 45
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prol-
inyloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound
46)
[0239] 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.
[0240] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 46
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-pro-
linyloxy)methyl oxazolidin-2-on hydrochloride (compound 47)
[0241] With the exception of using the compound 46, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0242] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 47
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-glycyloxymethyl oxazolidin-2-on hydrochloride (compound 48)
[0243] With the exception of using the compound 27, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0244] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 48
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound
49)
[0245] With the exception of using BOC-.beta.-alanine, instead of
BOC-glycine, the same procedure as in Example 10 was conducted to
prepare the title compound.
[0246] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 49
Preparation of
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on hydrochloride (compound 50)
[0247] With the exception of using the compound 49, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0248] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 50
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid
(compound 51)
[0249] 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.
[0250] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 51
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-alanyloxy)methyl oxazolidin-2-on hydrochloride (compound
52)
[0251] With the exception of using the compound 51, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0252] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 52
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-valyloxy)methyl oxazolidin-2-on trifluoroacetic acid
(compound 53)
[0253] 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.
[0254] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 53
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-valyloxy)methyl oxazolidin-2-on hydrochloride (compound
54)
[0255] With the exception of using the compound 53, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0256] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 54
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-prolinyloxy)methyl oxazolidin-2-on trifluoroacetic acid
(compound 55)
[0257] With the exception of using the compound 16 and
BOC-L-pyrroline, the same procedure as in Example 10 was conducted
to prepare the title compound.
[0258] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 55
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(L-prolinyloxy)methyl oxazolidin-2-on hydrochloride (compound
56)
[0259] With the exception of using the compound 55, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0260] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 56
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(.beta.-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid
(compound 57)
[0261] With the exception of using the compound 16 and
BOC-.beta.-allanine, the same procedure as in Example 10 was
conducted to prepare the title compound.
[0262] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 57
Preparation of
(R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-
-5-(.beta.-alanyloxy)methyl oxazolidin-2-on hydrochloride (compound
58)
[0263] With the exception of using the compound 57, the same
procedure as in Example 41 was conducted to prepare the title
compound.
[0264] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 58
Preparation of
mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-
-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) and
(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-
-oxazolidinyl]methyl disodiumphosphate (compound 59)
[0265] 1. The Primary Step
[0266] 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.degree. C., added with 0.7 g of metachloroperbenzoic acid and
stirred for 2 hours. After being cooling to -78.degree. 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%).
[0267] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
[0268] 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.
[0269] .sup.1H NMR (D.sub.2O) .delta. 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)
[0270] 2. The Secondary Step
[0271] 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.
[0272] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 59
Preparation of
(R)-[3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl-
)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 60)
[0273] Using the compound 16, the title compound was prepared in a
manner similar to that of the Example 58.
[0274] .sup.1H NMR (D.sub.2O) .delta. 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)
Example 60
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox-
ymethyl oxazolidin-2-on (compound 61)
[0275] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
1.
[0276] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 61
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on trifluoroacetic acid (compound 62)
[0277] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
10.
[0278] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 62
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl-
oxymethyl oxazolidin-2-on hydrochloride (compound 63)
[0279] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
43.
[0280] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 63
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound
64)
[0281] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
40.
[0282] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 64
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala-
nyloxy)methyl oxazolidin-2-on hydrochloride (compound 65)
[0283] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
42.
[0284] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 65
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound 66)
[0285] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
11.
[0286] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 66
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val-
yloxy)methyl oxazolidin-2-on hydrochloride (compound 67)
[0287] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
41.
[0288] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 67
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on trifluoroacetic acid (compound
68)
[0289] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
48.
[0290] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 68
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta-
.-alanyloxy)methyl oxazolidin-2-on hydrochloride (compound 69)
[0291] Using 2-(1-methyltetrazol-5-yl)-5-bromopyridine, the title
compound was prepared in a manner similar to that of the Example
49.
[0292] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Example 69
Preparation of
mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-
-oxo-5-oxazolidinyl]methyl]phosphate (compound 73) and
(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-
-oxazolidinyl]methyl disodiumphosphate (compound 70)
[0293] 1. The Primary Step
[0294] 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.
[0295] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
[0296] 2. The Secondary Step
[0297] 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
[0298] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
[0299] The title compound (compound 70) was obtained in a manner
similar to that of the Example 58.
[0300] .sup.1H NMR (D.sub.2O) .delta. 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)
Example 70
Preparation of
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-([1,2,-
3]triazol-1-yl)methyl oxazolidin-2-on (compound 71)
[0301] Using the compound 61, the title compound was prepared in a
manner similar to that of the Example 24.
[0302] .sup.1H NMR (DMSO-d.sub.6) .delta. 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)
Experimental Example 1
Assay for In Vitro Antibacterial Activity
[0303] 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 (MIC.sub.50, .mu.g/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.
TABLE-US-00002 TABLE 2 Minimum Inhibitory Concentration
(MIC.sub.50, .mu.g/ml) Compound MRSA VRE Zyvox 2 2 1 1 0.25 2 0.5
0.125 3 0.25 0.25 4 2 2 5 0.5 0.25 6 NA NA 7 0.5 0.5 8 16 16 9 0.25
0.125 10 0.5 0.25 11 0.5 0.25 12 0.5 0.25 13 0.25 0.25 14 0.25 0.25
15 1 1 16 0.5 1 17 1 1 18 1 2 19 32 32 20 0.5 0.25 21 1 1 22 1 1 23
2 2 24 0.5 0.5 25 0.25 0.125 26 0.5 0.5 27 0.5 1 28 0.5 0.5 29 0.5
1 30 0.5 0.5 31 0.5 0.5 32 0.5 1 33 2 2 34 1 1 35 1 1 36 0.5 0.5 37
0.5 0.5 38 0.5 1 39 1 1 40 4 8 41 4 8 42 0.5 0.25 43 0.5 0.25 44
0.5 0.25 45 0.5 0.25 46 0.5 0.25 47 0.5 0.25 48 0.5 1 49 0.5 0.25
50 0.5 0.25 51 0.5 1 52 0.5 1 53 0.5 1 54 0.5 1 55 0.5 1 56 0.5 1
57 0.5 1 58 0.5 1 59 0.5 0.25 60 0.5 1 61 0.5 0.25 62 0.5 0.25 63
0.5 0.25 64 0.5 0.25 65 0.5 0.25 66 0.5 0.25 67 0.5 0.25 68 0.5
0.25 69 0.5 0.25 70 0.5 0.25 71 0.5 0.125 72 32 32 73 32 32 NA: Not
determined MRSA: methicillin resistant Staphylococcus aureus VRE:
vancomycin resistant Enterococci
[0304] 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.
(i) Experimental Example 2
Assay for Solubility
[0305] 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 .mu.l of distilled water
and then the solution was stirred for 2 minutes. The turbidity of
the solution was watched through naked eye.
[0306] When the derivatives were not dissolved completely, 50 .mu.l
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.
[0307] 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.
TABLE-US-00003 TABLE 3 Compound Solubility Zyvox 3 mg/ml 10 10
.mu.g/ml 12 28 mg/ml 16 20 .mu.g/ml 20 4.7 mg/ml 27 >50 mg/ml 42
>50 mg/ml 43 4.2 mg/ml 44 >50 mg/ml 45 12 mg/ml 46 <1.63
mg/ml 47 2 mg/ml 48 >50 mg/ml 49 2.6 mg/ml 50 20.4 mg/ml 51
>50 mg/ml 52 >50 mg/ml 53 30.3 mg/ml 54 2.9 mg/ml 55 7.2
mg/ml 56 >50 mg/ml 57 >50 mg/ml 58 5.5 mg/ml 59 >50 mg/ml
60 >50 mg/ml 62 28 mg/ml 64 >50 mg/ml 66 4.7 mg/ml 68 2.6
mg/ml 70 >50 mg/ml
[0308] 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
.mu.g/ml).
[0309] 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.
Experimental Example 3
Test of Acute Toxicity by Oral Administrating the Derivatives to
Mouse
[0310] To test acute toxicity of the compounds of the present
invention, the following experiment was carried out.
[0311] A mixture of 1% hydroxypropylmethylcellulose 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.
TABLE-US-00004 TABLE 4 Compound Minimum Lethal Dose (MLD, mg/kg)
Zyvox >1000 10 >1000 12 >1000 16 >1000 17 >1000 20
>1000 22 >1000 24 >1000 27 >1000
[0312] 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
[0313] The compounds of the present invention have excellent
efficiency on antibacterial activity without any toxicity present
according to Table 4.
Example Formulation
Preparation of Pharmaceutical Composition
Preparation as Powder
TABLE-US-00005 [0314] Derivative of oxazolidinone 2 g Lactose 1
g
[0315] The above materials were mixed and then the mixture was
filled into a closed pack to prepare as powder.
Preparation as Tablet
TABLE-US-00006 [0316] Derivative of oxazolidinone 500 mg Corn
starch 100 mg Lactose 100 mg Magneisuim stearate 2 mg
[0317] The above materials were mixed and then the mixture was
tableted by the known method to prepare as tablet.
[0318] 3. Preparation of Capsule
TABLE-US-00007 Derivative of oxazolidinone 500 mg Corn starch 100
mg Lactose 100 mg Magneisuim stearate 2 mg
[0319] The above materials were mixed and the mixture was filled
into gelatin capsule by the known method to prepare as capsule.
[0320] 4. Preparation of Injection
TABLE-US-00008 Derivative of oxazolidinone 500 mg Citrate buffer
maintaining of pH 3.5 Dextrose isotonicity
[0321] 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.
* * * * *