U.S. patent application number 10/043747 was filed with the patent office on 2003-09-11 for bicyclic heterocyclic substituted phenyl oxazolidinone antibacterials, and related compositions and methods.
Invention is credited to Hlasta, Dennis, Paget, Steven.
Application Number | 20030171366 10/043747 |
Document ID | / |
Family ID | 22526580 |
Filed Date | 2003-09-11 |
United States Patent
Application |
20030171366 |
Kind Code |
A1 |
Paget, Steven ; et
al. |
September 11, 2003 |
Bicyclic heterocyclic substituted phenyl oxazolidinone
antibacterials, and related compositions and methods
Abstract
Bicyclic heterocyclic substituted phenyl oxazolidinone compounds
of the formula: 1 wherein Y is a radical of the formulae II or III:
2 in which the substituents have the meaning indicated in the
description. These compounds are useful as antibacterial
agents.
Inventors: |
Paget, Steven; (Belle Mead,
NJ) ; Hlasta, Dennis; (Doylestown, PA) |
Correspondence
Address: |
AUDLEY A. CIAMPORCERO JR.
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
22526580 |
Appl. No.: |
10/043747 |
Filed: |
January 10, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10043747 |
Jan 10, 2002 |
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09621814 |
Jul 21, 2000 |
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6413981 |
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60148621 |
Aug 12, 1999 |
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Current U.S.
Class: |
514/224.2 ;
514/230.5; 514/234.2; 514/248; 514/249; 514/265.1; 514/300;
544/105; 544/117; 544/14; 544/236; 544/280; 544/349; 546/113 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 31/00 20180101; C07D 487/04 20130101; C07D 413/10 20130101;
A61P 31/04 20180101 |
Class at
Publication: |
514/224.2 ;
514/230.5; 514/234.2; 514/248; 514/249; 514/265.1; 514/300; 544/14;
544/105; 544/117; 544/280; 544/236; 544/349; 546/113 |
International
Class: |
A61K 031/542; A61K
031/538; A61K 031/5377; A61K 031/519; A61K 031/503; A61K 031/498;
C07D 487/02; C07D 498/02; C07D 491/02 |
Claims
We claim:
1. A compound of Formula I 72wherein: R is selected from the group
consisting of OH, O-Aryl, O-Heteroaryl, N.sub.3, OR', OSO.sub.2R",
--NR'"R"", or 73wherein: (i) R' is straight-chain or branched acyl
having up to 6 carbon atoms or benzyl; (ii) R" is straight-chain or
branched alkyl, having up to 5 carbon atoms, phenyl or tolyl; and
(iii) R'" and R"" are independently selected from the group
consisting of H, cycloalkyl having 3 to 6 carbon atoms, phenyl or
tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl,
straight-chain or branched alkyl having up to 6 carbon atoms which
is optionally substituted by cyano or alkoxycarbonyl having up to 4
carbon atoms, --CO.sub.2--R.sub.1, --CO--R.sub.1, --CO--SR.sub.1,
--CS--R.sub.1, P(O)(OR.sub.2)(OR.sub.3), and --SO.sub.2--R.sub.4,
in which R.sub.1 is selected from the group consisting of H,
cycloalkyl having 3 to 6 carbon atoms, trifluoromethyl or phenyl,
benzyl.backslash. or acyl having up to 5 carbon atoms,
straight-chain or branched alkyl having up to 6 carbon atoms, said
alkyl optionally substituted by straight-chain or branched
alkoxycarbonyl having up to 5 carbon atoms, OH, cyano, up to 3
halogen atoms, and --NR.sub.5R.sub.6 in which R.sub.5 and R.sub.6
are identical or different and are selected from H, phenyl or
straight-chain or branched alkyl having up to 4 carbon atoms;
R.sub.2 and R.sub.3 are identical or different and are selected
from hydrogen or straight-chain or branched alkyl having up to 4
carbon atoms; and R.sub.4 is selected from straight-chain or
branched alkyl having up to 4 carbon atoms or phenyl and; R.sub.4a
is CN, COR.sub.4c, COOR.sub.4c, CONHR.sub.4c,
CO--NR.sub.4cR.sub.4d, SO.sub.2R.sub.4c, SO.sub.2NHR.sub.4c,
SO.sub.2--NR.sub.4cR.sub.4d, or NO.sub.2; R.sub.4b is H, alkyl,
OR.sub.4c, SR.sub.4c, amino, NHR.sub.4c, NR.sub.4c,R.sub.4d,
(C1-C8), alkylaryl or mono-, di-, tri-, and per-halo(C1-C8) alkyl;
R.sub.4c and R.sub.4d are independently selected from H, alkyl,
aryl, or in the case of any NR.sub.4cR.sub.4d group R.sub.4c and
R.sub.4d taken together with the nitrogen atom to which they are
attached form a unsubstituted or substituted pyrrolidinyl,
piperidinyl or morpholinyl group; X is 0 to 4 members independently
selected from the group consisting of halogen, OH, mercapto, nitro,
halo-C.sub.1-8-alkyl, C.sub.1-8 alkoxy, thio-C.sub.1-8-alkyl,
C.sub.1-8 alkyl-amino, di(C.sub.1-8-alkyl-)amino, formyl, carboxy,
alkoxycarbonyl, C.sub.1-8 alkyl-CO--O--, C.sub.1-8 alkyl-CO--NH--,
carboxamide, aryl, substituted-aryl, heteroaryl,
substituted-heteroaryl, CN, amine, C.sub.3-6 cycloalkyl, C.sub.1-8
alkyl optionally substituted with one or more members selected from
the group consisting of F, Cl, OH, C.sub.1-8 alkoxyl and C.sub.1-8
acyloxy; and Y is a radical of Formulae II or III: 74wherein
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are each independently H,
alkyl, CN, nitro, C.sub.1-8 alkyl, halo-C.sub.1-8-alkyl, formyl,
carboxy, alkoxycarbonyl, carboxamide, aryl, substituted-aryl,
heteroaryl, or substituted-heteroaryl, or R.sub.5 and R.sub.6
and/or R.sub.7 and R.sub.8 together form an oxo group; R.sub.9, and
R.sub.10 are each independently H, halogen, alkyl, OH, CN,
mercapto, nitro, C.sub.1-8 alkyl, halo-C.sub.1-8-alkyl, C.sub.1-8
alkoxyl, thio-C.sub.1-8-alkyl, amino, C.sub.1-8-alkyl-amino,
di(C.sub.1-8-alkyl-)amino, formyl, carboxy, alkoxycarbonyl,
C.sub.1-8-alkyl-CO--O--, C.sub.1-8-alkyl-CO--NH--, carboxamide,
aryl, substituted-aryl, alkoxy, heteroaryl, substituted-heteroaryl,
or amine; A, B, C, and D are selected from C, S, O, and N to form
any five to ten membered aromatic or heteroaromatic ring, said
heteroaromatic ring having one to four members selected from the
group consisting of S, O, and N; Z is selected from halogen, alkyl,
aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, CN,
CHO, COalkyl, amine, (dialkylamino)alkyl where dialkylamino is
selected from dimethylamine, diethylamine, morpholinyl,
thiomorpholinyl, pyrroidinyl, or piperidinyl, or, alkoxy, or
NHCO--(C.sub.1-C.sub.8-alkyl); and m is 0 or 1, and the
pharmaceutically acceptable salts and esters thereof.
2. The compound of claim 1 wherein Y is selected from the group
consisting of 75
3. The compound of claim 1 wherein R is --NHCOCH.sub.3 or is
selected from the group consisting of 76
4. A compound of claim 1 having the formula: 77
5. A compound of claim 1 having the formula: 78
6. A compound of claim 1 having the formula: 79
7. A compound of claim 1 having the formula: 80
8. A compound of claim 1 having the formula: 81
9. A compound of claim 1 having the formula: 82
10. A compound of claim 1 having the formula: 83
11. A compound of claim 1 having the formula: 84
12. A compound of claim 1 having the formula: 85
13. A compound of claim 1 having the formula: 86
14. A compound of claim 1 having the formula: 87
15. A compound of claim 1 having the formula: 88
16. A compound of claim 1 having the formula: 89
17. A compound of claim 1 having the formula: 90
18. A compound of claim 1 having the formula: 91
19. A compound of claim 1 having the formula: 92
20. A compound of claim 1 having the formula: 93
21. A compound of claim 1 having the formula: 94
22. A compound of claim 1 having the formula: 95
23. A compound of claim 1 having the formula: 96
24. A compound of claim 1 having the formula: 97
25. A compound of claim 1 having the formula: 98
26. A compound of claim 1 having the formula: 99
27. A compound of claim 1 having the formula: 100
28. A compound of claim 1 having the formula: 101
29. A compound of claim 1 having the formula: 102
30. A compound of claim 1 having the formula: 103
31. A compound of claim 1 having the formula: 104
32. A compound of claim 1 having the formula: 105
33. A compound of claim 1 having the formula: 106
34. A compound of claim 1 having the formula: 107
35. A compound of claim 1 having the formula: 108
36. A compound of claim 1 having the formula: 109
37. A compound of claim 1 having the formula: 110
38. A compound of claim 1 having the formula: 111
39. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier.
40. A method of treating a subject having a condition caused by or
contributed to by bacterial infection, which comprises
administering to said mammal a therapeutically effective amount of
the compound according to claim 1.
41. A method of preventing a subject from suffering from a
condition caused by or contributed to by bacterial infection, which
comprises administering to the subject a prophylactically effective
dose of the pharmaceutical composition of a compound according to
claim 1.
42. The method of claim 40 or 41 wherein said condition is selected
from the group consisting of community-acquired pneumonia, upper
and lower respiratory tract infections, skin and soft tissue
infections, bone and joint infections and hospital-acquired lung
infections.
43. The method of claim 40 or 41 wherein said bacterium is selected
from the group consisting of S. aureus, S. epidermidis, S.
pneumoniae, S. pyogenes, Enterococcus spp., Moraxella catarrhalis
and H. influenzae.
44. The method of claim 40 or 41 wherein said bacterium is a
Gram-positive coccus.
45. The method of claim 44 wherein said Gram-positive coccus is
drug-resistant.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the field of phenyl
oxazolidinone compounds having antibacterial activity against
Gram-positive and Gram-negative bacteria, pharmaceutical
compositions containing the compounds, and methods of treating
bacterial infections with the compounds.
BACKGROUND OF THE INVENTION
[0002] Oxazolidinones have been identified, within the last twenty
years, as a new class of antibacterials which are active against
numerous multidrug-resistant gram positive organisms. Particularly
problematic pathogens include methicillin-resistant Staphylococcus
aureus (MRSA), glycopeptide-intermediate resistant Staphylococcus
aureus (GISA), vancomycin-resistant enterocci (VRE) and penicillin-
and cephalosporin-resistant Streptococcus pneumoniae. As a class,
oxazolidinones exhibit a unique mechanism of action. Studies have
shown that these compounds selectively bind to the 50S ribosomal
subunit and inhibit bacterial translation at the initiation phase
of protein synthesis. Exemplary members of oxazolidinones are
linezolid (see WO 95/07271) and eperezolid. 3
[0003] U.S. Pat. No. 5,792,765 to Riedl et al. discloses a series
of substituted oxazolidinones (cyanoguanidine, cyanoamidines, and
amidines) useful as antibacterial medicaments.
[0004] U.S. Pat. No. 5,910,504 to Hutchinson discloses a series of
heteroaromatic ring substituted phenyl oxazolidinones, including
indolyl substituted compounds useful as antibacterial agents.
[0005] WO 98/54161 (Hester et al.) discloses amides, thioamides,
ureas, and thioureas which are antibacterial agents.
[0006] WO 95/07271 (Barbachyn et al.) discloses oxazine and
thiazine oxazolidinone derivatives such as linezolid and its
analogs which are useful antimicrobial agents, effective against a
number of human and veterinary pathogens, including gram-positive
aerobic bacteria such as multiple-resistant staphylococci,
streptococci and enterococci as well as anaerobic organisms such as
Bacteroides spp. and Clostridia spp. species, and acid-fast
organisms such as Mycobacterium tuberculosis, Mycobacterium avium
and Mycobacterium spp.
[0007] WO 93/09103 (Barbachyn et al.) discloses substituted aryl-
and heteroarylphenyloxazolidinones which are useful as
antibacterial agents.
SUMMARY OF THE INVENTION
[0008] The invention provides phenyl oxazolidinone compounds of
Formula I: 4
[0009] wherein:
[0010] R is selected from the group consisting of OH, N.sub.3, OR',
O-Aryl, O-Heteroaryl OSO.sub.2R", --NR'"R"", or 5
[0011] wherein:
[0012] (i) R' is straight-chain or branched acyl having up to 6
carbon atoms or benzyl;
[0013] (ii) R" is straight-chain or branched alkyl, having up to 5
carbon atoms, phenyl or tolyl; and
[0014] (iii) R'" and R"" are independently selected from the group
consisting of H, cycloalkyl having 3 to 6 carbon atoms, phenyl or
tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl,
straight-chain or branched alkyl having up to 6 carbon atoms which
is optionally substituted by cyano or alkoxycarbonyl having up to 4
carbon atoms, --CO.sub.2--R.sub.1, --CO--R.sub.1, --CO--SR.sub.1,
--CS--R.sub.1, P(O)(OR.sub.2)(OR.sub.3), and --SO.sub.2--R.sub.4,
in which
[0015] R.sub.1 is selected from the group consisting of H,
cycloalkyl having 3 to 6 carbon atoms, trifluoromethyl or phenyl,
benzyl, or acyl each having up to 5 carbon atoms, straight-chain or
branched alkyl having up to 6 carbon atoms, said alkyl optionally
substituted by straight-chain or branched alkoxycarbonyl having up
to 5 carbon atoms, OH, cyano, up to 3 halogen atoms, and
--NR.sub.5R.sub.6 in which R.sub.5 and R.sub.6 are identical or
different and are selected from H, phenyl or straight-chain or
branched alkyl having up to 4 carbon atoms;
[0016] R.sub.2 and R.sub.3 are identical or different and are
selected from hydrogen or straight-chain or branched alkyl having
up to 4 carbon atoms; and
[0017] R.sub.4 is selected from straight-chain or branched alkyl
having up to 4 carbon atoms or phenyl and;
[0018] R.sub.4a is CN, COR.sub.4c, COOR.sub.4c, CONHR.sub.4c,
CO--NR.sub.4cR.sub.4d, SO.sub.2R.sub.4c, SO.sub.2NHR.sub.4c,
SO.sub.2--NR.sub.4cR.sub.4d, or NO.sub.2;
[0019] R.sub.4b is H, alkyl, OR.sub.4c, SR.sub.4c, amino,
NHR.sub.4c, NR.sub.4c,R.sub.4d, C1-C8-alkylaryl or mono-, di-,
tri-, and per-halo C1-C8-alkyl;
[0020] R.sub.4c and R.sub.4d are independently selected from H,
alkyl, aryl, or in the case of any NR.sub.4cR.sub.4d group R.sub.4c
and R.sub.4d taken together with the nitrogen atom to which they
are attached form a unsubstituted or substituted pyrrolidinyl,
piperidinyl or morpholinyl group;
[0021] X is 0 to 4 members independently selected from the group
consisting of halogen, OH, mercapto, nitro, halo-C.sub.1-8-alkyl,
C.sub.1-8 alkoxy, thio-C.sub.1-8-alkyl, C.sub.1-8 alkyl-amino,
di(C.sub.1-8-alkyl-)amino, formyl, carboxy, alkoxycarbonyl,
C.sub.1-8 alkyl-CO--O--, C.sub.1-8 alkyl-CO--NH--, carboxamide,
aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, CN,
amine, C.sub.3-6 cycloalkyl, C.sub.1-8 alkyl optionally substituted
with one or more members selected from the group consisting of F,
Cl, OH, C.sub.1-8 alkoxyl and C.sub.1-8 acyloxy; and
[0022] Y is a radical of Formulae II or III: 6
[0023] wherein
[0024] R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are each
independently H, alkyl, CN, nitro, C.sub.1-8 alkyl,
halo-C.sub.1-8-alkyl, formyl, carboxy, alkoxycarbonyl, carboxamide,
aryl, substituted-aryl, heteroaryl, substituted-heteroaryl, or
R.sub.5 and R.sub.6 and/or R.sub.7 and R.sub.8 together form an oxo
group;
[0025] R.sub.9, and R.sub.10 are each independently H, halogen,
alkyl, OH, CN, mercapto, nitro, C.sub.1-8 alkyl,
halo-C.sub.1-8-alkyl, C.sub.1-8 alkoxy, thio-C.sub.1-8-alkyl,
amino, C.sub.1-8-alkyl-amino, di(C.sub.1-8-alkyl-)amino, formyl,
carboxy, alkoxycarbonyl, C.sub.1-8-alkyl-CO--O--,
C.sub.1-8-alkyl-CO--NH--, carboxamide, aryl, substituted-aryl,
heteroaryl, substituted-heteroaryl, or amine;
[0026] A, B, C, and D are selected from C, S, O, and N to form any
five to ten membered aromatic or heteroaromatic ring, said
heteroaromatic ring having one to four members selected from the
group consisting of S, O, and N;
[0027] Z is selected from halogen, alkyl, aryl, substituted-aryl,
heteroaryl, substituted-heteroaryl, CN, CHO, COalkyl, amine,
(dialkylamino)alkyl, said dialkylamino consisting of straight-chain
or branched alkyl having up to 6 carbon atoms or phenyl or
constituting a ring of 2 to 5 carbons having 0 to 2 atoms selected
from S, O and N or alkoxy, or NHCO--(C.sub.1-C.sub.8-alkyl);
and
[0028] m is 0 or 1,
[0029] and the pharmaceutically acceptable salts and esters
thereof.
[0030] Compounds of the above formula are useful as antibacterial
agents for the treatment of bacterial infections in humans and
animals.
[0031] The present invention is also directed to a method of
treating a subject having a condition caused by or contributed to
by bacterial infection, which comprises administering to said
mammal a therapeutically effective amount of the compound of
Formula I.
[0032] The present invention is further directed to a method of
preventing a subject from suffering from a condition caused by or
contributed to by bacterial infection, which comprises
administering to the subject a prophylactically effective dose of
the pharmaceutical composition of a compound of Formula I.
[0033] Other objects and advantages will become apparent to those
skilled in the art from a review of the ensuing specification.
DETAILED DESCRIPTION
[0034] Relative to the above description of the phenyl
oxazolidinone compounds of the present invention, the following
definitions apply.
[0035] Unless specified otherwise, the terms "alkyl", "alkenyl",
and "alkynyl" may be straight or branched groups with 1-8 carbon
atoms.
[0036] "Acyl" means an organic radical having the designated number
of carbon atoms, derived from an organic acid by the removal of a
hydroxyl group having the formula RCO, as in the case of acetyl
where R is CH.sub.3.
[0037] "Aryl" is an unsubstituted carbocyclic aromatic group
including, but not limited to, phenyl, 1- or 2-naphthyl and the
like. "Heteroaryl" refers to a cyclic aromatic radical having from
five to ten atoms in the ring; where one to three ring atoms are
independent heteroatoms such as S, O, and N, and the remaining ring
atoms are carbon, for example, a pyridinyl, pyrazinyl, pyrimidinyl,
pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, or
isoquinolinyl, radical and the like.
[0038] "Substituted aryl" or "substituted heteroaryl" refers to an
aryl or heteroaryl substituted by independent replacement of 1-3 of
the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro,
C.sub.1-8-alkyl, halo-C.sub.1-8-alkyl, C.sub.1-8-alkoxy,
thio-C.sub.1-8-alkyl, amino, C.sub.1-8-alkyl-amine,
di(C.sub.1-C.sub.8-alkyl-)amino, formyl, carboxy, alkoxycarbonyl,
C.sub.1-8-alkyl-CO--O--, C.sub.1-8-alkyl-CO--NH--, or carboxamide.
Further, substituted-heteroaryl may be substituted with a mono-oxo
to give, for example, a 4-oxo-1-H-quinoline. Substituted-heteroaryl
may also be substituted with a substituted-aryl or a second
substituted-heteroaryl to give, for example, a
4-phenyl-imidazol-1-yl or a 3-pyridinyl-imidazol-1-yl, and the
like.
[0039] The term "halo" or "halogen" means fluoro, chloro, bromo and
iodo. (mono-, di-, tri-, and per-) halo-alkyl is an alkyl radical
substituted by independent replacement of the hydrogen atoms
thereon with halogen. P denotes phosphorus.
[0040] The compounds of the instant invention are asymmetric in the
oxazolidinone ring at the 5- position and thus exist as optical
antipodes. As such, all possible optical antipodes, enantiomers or
diastereomers resulting from additional asymmetric centers that may
exist in optical antipodes, racemates and racemic mixtures thereof
are also part of this invention. The antipodes can be separated by
methods known to those skilled in the art such as, for example,
fractional recrystallization of diastereomeric salts of
enantiomerically pure acids. Alternatively, the antipodes can be
separated by chromatography on a Pirkle column.
[0041] The phrase "pharmaceutically acceptable salts" denotes salts
of the free base which possess the desired pharmacological activity
of the free base and which are neither biologically nor otherwise
undesirable. These salts may be derived from inorganic or organic
acids. Examples of inorganic acids are hydrochloric acid, nitric
acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples
of organic acids are acetic acid, propionic acid, glycolic acid,
lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid,
maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, methyl sulfonic acid,
salicyclic acid and the like. Suitable salts are furthermore those
of inorganic or organic bases, such as KOH, NaOH, Ca(OH).sub.2,
Al(OH).sub.3, piperidine, morpholine, ethylamine, triethylamine and
the like.
[0042] Also included within the scope of the invention are the
hydrated forms of the compounds which contain various amounts of
water, for instance, the hydrate, hemihydrate and sesquihydrate
forms.
[0043] The term "subject" includes, without limitation, any animal
or artificially modified animal. In the preferred embodiment, the
subject is a human.
[0044] The term "drug-resistant" or "drug-resistance" refers to the
characteristics of a microbe to survive in presence of a currently
available antimicrobial agent at its routine, effective
concentration.
[0045] The compounds of the present invention possess antibacterial
activity against Gram-positive and certain Gram-negative bacteria.
They are useful as antibacterial agents for the treatment of
bacterial infections in humans and animals. Particularly, these
compounds have antimicrobial activity against S. aureus, S.
epidermidis, S. pneumoniae, E. faecalis, E. faecium, Moraxella
catarrhalis, and H. influenzae. More particularly, these compounds
are useful against resistant bacteria such as MRSA and GISA, and
have a low susceptibility to acquired resistance mechanisms.
Compounds of Formula I which are most preferred for such purposes
are those in which R is any of the following: 7
[0046] In addition Compounds of Formula I which are most preferred
for such purposes are those in which Y is any of the following:
8
[0047] Particular examples of the present invention include the
following compounds:
[0048]
N-[[(5S)-3-[4-(1,3-Dihydro-2H-isoindol-2-yl)-3-fluorophenyl]-2-oxo--
5-oxazolidinyl]methyl]acetamide;
[0049]
N-[[(5S)-3-[4-(1,3-Dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-fluorop-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0050]
N-[[(5S)-3-[3-Fluoro-4-(5-oxido-2H-pyrrolo[3,4-c]pyridin-2-yl)pheny-
l]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0051]
N-[[(5S)-3-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorop-
henyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
[0052]
N-[[(5S)-3-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]--
2-oxo-5-oxazolidinyl]methyl]acetamide; and
[0053]
(5R)-3-[4-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluoropheny-
l]-5-(hydroxymethyl)-2-oxazolidinone.
[0054] The compounds of Formula I that are the subject of this
invention may be prepared from readily available starting materials
such as isoindole (Gawley et al., J. Org. Chem., 1988, 53:5381),
6,7-dihydro-5H-pyrrolo[3,4-c]pyridine and
6,7-dihydro-5H-pyrrolo[3,4-b]py- ridine (U.S. Pat. No. 5,371,090 to
Petersen et al.) in accordance with synthetic methods well known in
the art. Representative procedures are outlined in Scheme I-V:
9
[0055] In accordance with Scheme I, bicyclic heterocycles of
general formula IV are treated with a substituted nitrobenzene
derivative (L is an appropriate leaving group such as a halogen of
trifluoromethanesulfony- loxy) in a suitable base and solvent, such
as diisopropylamine and ethyl acetate, to give the substituted
nitrophenyl compound V.
[0056] The nitrobenzene derivative V is then reduced to the aniline
by an appropriate reaction, for instance by treatment with
SnCl.sub.2 or by catalytic hydrogenation in the presence of a
suitable catalyst, such as palladium on carbon. The aniline is then
treated with benzyl or methyl chloroformate and sodium bicarbonate
to form the corresponding benzyl or methyl carbamate derivative
VI.
[0057] The Cbz aniline VI is then deprotonated with a lithium base
such as n-butyllithium and reacted with (R)-glycidyl butyrate to
afford the oxazolidinone VII. The hydroxymethyl group can then be
converted to an amide as shown in Scheme I by preparation of the
mesylate, conversion to azide VIII, and reduction to amine IX by an
appropriate procedure such as hydrogenation. Alternatively
displacement of a mesylate (Scheme II) or appropiate leaving group
such as tosylate or chlorine with potassium phthalimide and removal
of the phthaloyl protecting group by hydrazinolysis would provide
amine IX. The amine IX can be converted to amide X by an acylation
reaction using techniques known in the art, such as treatment with
acetic anhydride in the presence of a base such as pyridine.
Alternatively, amine IX can be converted to a carbamate XI by
treatment with methylchloroformate and pyridine, or reacted with a
sulfonyl chloride in an inert solvent in the presence of an organic
base like pyridine to form a sulfonamide XII 10 11
[0058] For the formation of oxazolidione in which R=O-Heteroaryl
(XIII), the oxazolidinone carbinol VII can be converted to the
corresponding mesylate or other appropriate leaving group and
reacted with HO-Het (a suitible hydroxyl containing heterocycle),
either in the presence of base or with HO-Het as a preformed
alkoxide, in an appropriate solvent, for example DMF or
acetonitrile (Scheme III). Alternatively, Mitsunobu conditions can
be used to couple VII with HO-Heterocycle by treating with
triphenylphosphine and diisopropyl azodicarboxylate (DIAD) in an
appropriate solvent, such as THF, at a suitable temperature,
preferably room temperature. Reaction conditions and leading
references can be found in Gravestock et al, WO99/64416.
[0059] Furthermore, by treating VII with a suitable,
non-nucleophilic base, for example NaH, the displacement of a
leaving group (LG), such as chlorine or bromine, can be effected
from an appropriately reactive aza-heterocycle (LG-Het)(Scheme
III). 12
[0060] Compounds of structure XIV can be prepared as shown in
Scheme IV. Amine IX can be converted to various functionalized
amidines by reaction with activated imines, where Q is a leaving
group such as methylthio or methoxy, in a suitable solvent, for
example toluene or methanol, with or without a catalyst (such
AgNO.sub.3) present at a temperature range of 0-110.degree. C.
13
[0061] In accordance with Scheme V pyrrolidinone XV (prepared as in
WO96/13502) is first reacted with methoxy-bis(dimethylamine) or
other activated dimethylformamide reagent and, second, heated in a
suitable solvent (for example DMF and benzene) with either
substituted amidines, to form pyrrolopyrimidines oxazolidinones
such as XVI, or substituted hydrazines, to form pyrrolopyrazole
oxazolidinones such as XVII. Formation of the--enamine,
alkoxymethylene or alkoxycarbonyl derivatives of pyrrolidinone XV,
according to Brighty et al in U.S. Pat. No. 5,037,834A, would also
allow access to these systems. 14
[0062] As shown in Scheme VI compounds with the structure XIX can
be achieved by oxidation of the various compounds, XVIII, using an
appropriate oxidant (for example manganese dioxide, peroxyacetic
acid, DDQ or air) in a suitable solvent such as methylene chloride.
15
[0063] Oxo-derivatives of structure XXII in Scheme VII, (X=O,
Y=H.sub.2 or X=H.sub.2, Y=O) can be constructed by reacting
1,2-aryl dicarboxaldehydes (where XXI, U=H) with aniline XX
(prepared as in WO96/23788) in the presence of acids, such as
acetic acid, in a suitable solvent such as methylene chloride. The
di-oxo-derivatives (structure XXII where X=Y=O) are prepared from
the reaction of aniline XX with selected 1,2-aryl dicarbonyl
reagents with a suitable leaving group (XXI where U=Cl, Br,
etc).
[0064] Definitions
[0065] All temperatures are in degrees Centigrade
[0066] Brine refers to an aqueous saturated sodium chloride
solution
[0067] DMF refers to N,N-dimethylformamide
[0068] THF refers to tetrahydrofuran
[0069] Cbz refers to carbobenzyloxy
[0070] n-BuLi refers to n-butyl lithium
[0071] MS refers to mass spectrometry expressed as m/e or
mass/charge unit
[0072] [M+H] refers to the positive ion of a parent plus a hydrogen
atom
[0073] Ether refers to diethyl ether
[0074] rt refers to room temperature
[0075] Mp refers to melting point
[0076] CH.sub.2Cl.sub.2 refers to methylene chloride
[0077] NaOH refers to sodium hydroxide
[0078] MeOH refers to methanol
[0079] EtOAc refers to ethyl acetate
[0080] ppt refers to a precipitate
[0081] These compounds have antimicrobial activity against
susceptible and drug resistant bacterial pathogens such as S.
aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococcus
spp., Moraxella catarrhalis and H. influenzae. These compounds are
particularly useful against drug resistant Gram-positive cocci such
as methicillin-resistant S. aureus and vancomycin-resistant
enterococci. These compounds are useful in the treatment of
community-acquired pneumonia, upper and lower respiratory tract
infections, skin and soft tissue infections, hospital-acquired lung
infections, bone and joint infections, and other bacterial
infections.
[0082] Minimal inhibitory concentration (MIC) has been an indicator
of in vitro antibacterial activity widely used in the art. The in
vitro antimicrobial activity of the compounds was determined by the
microdilution broth method following the test method from the
National Committee for Laboratory Standards (NCCLS). This method is
described in the NCCLS Document M7-A4, Vol.17, No.2, "Methods for
Dilution Antimicrobial Susceptibility Test for Bacteria that Grow
Aerobically--Fourth Edition", which is incorporated herein by
reference.
[0083] In this method two-fold serial dilutions of drug in cation
adjusted Mueller-Hinton broth are added to wells in microdilution
trays. The test organisms are prepared by adjusting the turbidity
of actively growing broth cultures so that the final concentration
of test organism after it is added to the wells is approximately
5.times.10.sup.4 CFU/well.
[0084] Following inoculation of the microdilution trays, the trays
are incubated at 35.degree. C. for 16-20 hours and then read. The
MIC is the lowest concentration of test compound that completely
inhibits growth of the test organism. The amount of growth in the
wells containing the test compound is compared with the amount of
growth in the growth-control wells (no test compound) used in each
tray. As set forth in Table 1, some compounds of the present
invention were tested against a variety of pathogenic bacteria
resulting in a range of activities, from 1 to .gtoreq.128 .mu.g/mL
depending on the organism tested. S. aureus OC2878 is a MRSA and E.
faecium OC3312 is a vancomycin resistant enterococcus.
1TABLE 1 MIC Values of Some Compounds of Formula I MIC (mg/mL) in
Test Strains Compound S. aureus S. aureus E. faecium No. OC4172
OC2878 OC3312 1 2 2 2 2 2 1 4 3 0.5 0.25 0.5 4 1 0.5 1 5 >32
>32 >32 6 64 32 32 7 >32 8 16 8 8 4 8 9 >32 >32
>32 10 >32 8 64 11 2 1 2 12 8 2 4 13 2 1 2 14 32 16 16 15 2 2
2 16 8 8 8 17 4 2 2 18 16 16 16 19 8 4 8 20 4 2 4 21 >64 >64
>64 22 2 2 2 23 8 8 8 24 8 8 8 25 64 >128 32 26 1 0.5 1 27 8
4 8 28 0.5 0.5 0.5 29 >32 8 16 30 >128 >128 >128 31
>16 >16 >16 32 4 2 2 33 32 32 32 34 8 2 4 35 0.5 0.25 2 36
1 0.5 1 37 1 1 0.5 38 2 2 1 39 1 2 1 40 1 1 1 41 2 2 2 42 2 2 2 43
1 1 1 44 1 1 1 45 4 4 4 46 4 4 8 47 32 16 32 48 8 8 8 49 16 4 8
[0085] This invention further provides a method of treating
bacterial infections, or enhancing or potentiating the activity of
other antibacterial agents, in a subject having conditions caused
by or contributed to by bacterial infection, which comprises
administering to the animals a compound of the invention alone or
in admixture with another antibacterial agent in the form of a
medicament according to the invention. The terms of "treating" and
"treatment" include administering, either simultaneously,
separately or sequentially, a pharmaceutically effective amount of
a composition containing one or more of the compounds disclosed
herein to a subject that desires inhibition of bacterial growth.
The pharmaceutically effective amount of the compound used to
practice the present invention for treatment varies depending on
the manner of administration, the age, weight, and general health
of the subject treated, and ultimately will be decided by
physicians or veterinarians.
[0086] The compounds of the present invention may be administered
to a subject such as a human by any route appropriate to the
condition to be treated, suitable routes including oral, rectal,
nasal, topical (including buccal and sublingual), vaginal and
parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, intrathecal and epidural). The preferred route may
vary with, for example, the condition of the recipient as well as
the ease of preparation and administration.
[0087] When the compounds are employed for the above utility, they
may be combined with one or more pharmaceutically acceptable
carriers, e.g., solvents, diluents, and the like, and may be
administered orally in such forms as tablets, capsules, dispersible
powders, granules, or suspensions containing for example, from
about 0.5% to 5% of suspending agent, syrups containing, for
example, from about 10% to 50% of sugar, and elixirs containing,
for example, from about 20% to 50% ethanol, and the like, or
parenterally in the form of sterile injectable solutions or
suspensions containing from about 0.5% to 5% suspending agent in an
isotonic medium. These pharmaceutical preparations may contain, for
example, from about 0.5% up to about 90% of the active ingredient
in combination with the carrier, more usually between 5% and 60% by
weight.
[0088] Compositions for topical application may take the form of
liquids, creams or gels, containing a therapeutically effective
concentration of a compound of the invention admixed with a
dermatologically acceptable carrier.
[0089] In preparing the compositions in oral dosage form, any of
the usual pharmaceutical media may be employed. Solid carriers
include starch, lactose, dicalcium phosphate, microcrystalline
cellulose, sucrose and kaolin, while liquid carriers include
sterile water, polyethylene glycols, non-ionic surfactants and
edible oils such as corn, peanut and sesame oils, as are
appropriate to the nature of the active ingredient and the
particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions may be
advantageously included, such as flavoring agents, coloring agents,
preserving agents, and antioxidants, for example, vitamin E,
ascorbic acid, BHT and BHA.
[0090] The preferred pharmaceutical compositions from the
standpoint of ease of preparation and administration are solid
compositions, particularly tablets and hard-filled or liquid-filled
capsules. Oral administration of the compounds is preferred. These
active compounds may also be administered parenterally or
intraperitoneally. Solutions or suspensions of these active
compounds as a free base or pharmacological acceptable salt can be
prepared in water suitably mixed with a surfactant such as
hydroxypropyl-cellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols and mixtures thereof in oils.
Under ordinary conditions of storage and use, these preparations
may contain a preservative to prevent the growth of
microorganisms.
[0091] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0092] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration and the severity of the condition being treated.
However, in general, satisfactory results are obtained when the
compounds of the invention are administered at a daily dosage of
from about 0.1 mg/kg to about 400 mg/kg of animal body weight,
preferably given in divided doses two to four times a day, or in
sustained release form. For most large mammals the total daily
dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg
to 1000 mg. Dosage forms suitable for internal use comprise from
about 100 mg to 500 mg of the active compound in intimate admixture
with a solid or liquid pharmaceutically acceptable carrier. This
dosage regimen may be adjusted to provide the optimal therapeutic
response. For example, several divided doses may be administered
daily or the dose may be proportionally reduced as indicated by the
exigencies of the therapeutic situation.
[0093] The production of the above-mentioned pharmaceutical
compositions and medicaments is carried out by any method known in
the art, for example, by mixing the active ingredients(s) with the
diluent(s) to form a pharmaceutical composition (e.g. a granulate)
and then forming the composition into the medicament (e.g.
tablets).
[0094] The following examples describe in detail the chemical
synthesis of representative compounds of the present ivention. The
procedures are illustrations, and the invention should not be
construed as being limited by chemical reactions and conditions
they express. No attempt has been made to optimize the yields
obtained in these reactions, and it would be obvious to one skilled
in the art that variations in reaction times, temperatures,
solvents, and/or reagents could increase the yields.
EXAMPLE 1
(5R)-3-[4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]-5-(hydroxym-
ethyl)-2-oxazolidinone
[0095] 16
[0096] Isoindoline was synthesized employing the method of R. E.
Gawley, S. R. Chemburkar, A. L. Smith, T. V. Anklekar J. Org. Chem.
1988, 53, 5381. 17
[0097] To 3,4-difluoronitrobenzene (3.02 mL, 27.3 mmols) in ethyl
acetate at rt was added diisopropylethylamine (5.03 mL, 28.9 mmols)
and then isoindoline (3.50 g, 29.4 mmols) and stirred overnight. A
yellow precipitate (ppt) formed and was collected on a filter,
washed with water and ether and dried in a vacuum oven (30.degree.
C.) to provide the product as a bright yellow solid (6.69 g, 95%
yield). Mp=200-202.degree. C. MS (M+1)=327 m/z. 18
[0098] To the above nitro compound (2.62 g, 10.2 mmols) in ethanol
(100 mL) was added SnCl.sub.2 (9.84 g, 50.9 mmols) and was refluxed
for 16 hrs. After cooling to rt the reaction mixture was added to
10% aq. NaOH (300 mL) and extracted with CH.sub.2Cl.sub.2
(6.times.50 mL). The combined organic washings were washed with
brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated to
give 2.63 g of an olive green solid (aniline), which was used
without further purification. To this aniline in acetone (150 mL)
and water (20 mL) was added NaHCO.sub.3 (1.84 g, 21.9 mmols) and
then benzylchloroformate (1.68 mL, 11.8 mmols). After stirring
overnight the mixture was poured into ice water (100 mL) and the
resulting tan precipitate was collected on a filter, washed with
water and dried in a vacuum to give the Cbz aniline as a tan solid
(3.50 g, 95% yield). Mp=146-148.degree. C. MS (M+1)=363 m/z.
[0099] Step 3:
[0100] To the above Cbz aniline (0.74 g, 2.04 mmols) in THF (10 mL)
at -78.degree. C. was added n-BuLi (2.5 M, 0.82 mL, 2.05 mmols)
dropwise. After stirring for 40 min, (R)-glycidyl butyrate (0.31
mL, 2.10 mmols) in THF (0.5 mL) was added dropwise and the
resulting mixture was allowed to warm to RT overnight. A white
precipitate had formed and was collected on a filter and washed
with water and ether. Chromatography on silica gel with 25% ethyl
acetate/hexane as eluent provided the product as a white solid
(0.58 g, 87% yield). MS (M+1)=329 m/z.
EXAMPLE 2
(5R)-3-[4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]-5-[[(methyl-
sulfonyl)oxy]methyl]-2-oxazolidinone
[0101] 19
[0102] To the oxazolidinone carbinol from Example 1 (0.58 g, 1.78
mmols), in DMF (10 mL) and acetonitrile (10 mL) at 0.degree. C. was
added triethylamine (0.74 mL, 5.31 mmols) and, after 10 min,
methanesulfonyl chloride (0.28 mL, 3.62 mmols). After allowing the
reaction mixture to warm to RT over an hour starting material was
still present so cooling and addition of triethyl amine (0.37 mL,
2.65 mmols) and methanesulfonyl chloride (0.14 mL, 1.81 mmols) was
repeated. The mixture was poured into water (50 mL) and extracted
with CH.sub.2Cl.sub.2 (6.times.20 mL), washed with brine
(4.times.10 mL), dried over Na.sub.2SO.sub.4, concentrated to
afford the crude product as a brown oil (0.95 g). MS (M+1)=407
m/z.
EXAMPLE 3
(5R)-5-(Azidomethyl)-3-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophe-
nyl]-2-oxazolidinone
[0103] 20
[0104] To the mesylate from Example 2 (0.95 g, 1.78 mmols) in DMF
(25 mL) was added sodium azide (0.47 g, 7.23 mmols) and heated to
70.degree. C. for 16 hrs. After cooling to rt water was added and
the mixture extracted with ethyl acetate (6.times.25 mL), washed
with brine (4.times.10 mL), dried over Na.sub.2SO.sub.4,
concentrated to give 0.48 g of a tan solid. MS (M+1)=354 m/z.
EXAMPLE 4
N-[[(5S)-3-[4-(1,3-Dihydro-2H-isoindol-2-yl)-3-fluorophenyl]-2-oxo-5-oxazo-
lidinyl]methyl]acetamide
[0105] 21
[0106] The azide from Example 3 in ethyl acetate (25 mL) was placed
in a Paar flask and nitrogen bubbled through for 15 min whereupon
10% Pd/C (0.15 g, 0.14 mmol) was added. The mixture was pressurized
with 50 psi of H.sub.2 (g) and shaken for 16 hrs whereupon an
additional amount of 10% Pd/C (0.15 g, 1.4 mmols) was added and the
mixture shaken for an additional 6 hrs (at this point MS (M+1)=328
m/z). After placing the mixture under nitrogen, pyridine (0.22 mL,
2.72 mmol) and then Ac.sub.2O (0.51 mL, 5.30 mmol) were added and
the mixture stirred for 2 hrs. The mixture was filtered through
celite, washing with ethyl acetate (100 mL), concentrated, and
chromatographed on silica (gradient elution 1%-5%
MeOH/CH.sub.2Cl.sub.2) and then triturated with ethyl acetate
(3.times.3 mL) to give 0.19 g of a white solid (Compound 1, 29%
yield for 4 steps). Mp=240-242.degree. C. MS (M+1)=370 m/z.
EXAMPLE 5
[0107] 22
[0108]
6.7-Dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine:
To 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride salt (as
described by Petersen, et al. (Bayer) EP0520277A2)(42.8 g, 222
mmols) in DMF (1.2 L) was added 2,4-difluoronitrobenzene (25 mL,
224 mmols). The mixture was heated to 60.degree. C. and DIPEA (195
mL, 1.12 mols) was added dropwise from an addition funnel over 2
hrs. After heating overnight the reaction mixture was cooled to rt,
poured into water (3 L), filtered and dried in a vacuum oven
(50.degree. C.) to provide a yellow-green solid (53.8 g, 94%
yield). MS (M+1)=260 m/z. 23
6,7-Dihydro-6-(2-fluoro-4-aminophenyl)-5H-pyrrolo[3,4-b]pyridine
[0109] To the above nitro compound (53.8 g, 208 mmol) in THF (175
mL) and methanol (600 mL) was added ammonium formate (59.0 g, 907
mmol). Nitrogen was bubbled through the reaction for approximately
30 minutes whereupon 10% Pd/C (2.20 g, 21 mmols) was added. After
stirring overnight at rt under an atmosphere of nitrogen the
reaction mixture was filtered through a pad of Celite, washing
thoroughly with methanol (400 mL), and concentrated to a volume of
ca. 200 mL. Water (300 mL) was added and the mixture extracted with
ethyl acetate (5.times.200 mL). The combined organic layers were
washed with brine, dried (Na.sub.2SO.sub.4), filtered, and utilized
directly in the next step without further purification. MS
(M+1)=230 m/z. 24
[0110]
6.7-Dihydor-6-(2-fluoro-4-(Aminocarboxybenzyl)phenyl)-5H-pyrrolo[3,-
4-b]pyridine The above aniline (.about.208 mmols) in acetone (1 L)
and water (160 mL) was cooled to 0.degree. C. whereupon sodium
bicarbonate (37.4 g, 445 mmols) was added followed by the dropwise
addition of benzylchloroformate (34.2 mL, 228 mmols). The reaction
mixture was allowed to warm to room temperature and stirred
overnight whereupon a ppt formed. The reaction was poured into ice
water (2 L) and the resulting precipitate was collected by
filtration. The solid was washed with water and dried in a vacuum
oven (50.degree. C.) to afford the Cbz derivative (73.0 g, 97%
yield) as a salmon colored powder. MS (M+1)=364 m/z.
[0111] Step 4:
[0112] (Compound 2). The above Cbz derivative (40.8 g, 112 mmols)
in THF (1 L) was cooled to -78.degree. C. under a nitrogen
atmosphere. To this mixture was added n-BuLi (2.5 M, 45.8 mL, 114.5
mmols) dropwise via syringe over fifteen minutes. The reaction was
warmed to room temperature and allowed to stir for 45 minutes
before again being cooled to -78.degree. C. At this point
(R)-glycidyl butyrate (17.2 mL, 117 mmols) was added and the
reaction mixture allowed to warm to rt overnight during which time
a precipitate formed. The ppt was collected, washed with several
portions of ether (5.times.100 mL) and dried in a vacuum oven
(50.degree. C.) to afford 40.6 g of the ether solvate of the
lithium alkoxide as a tan fluffy powder. This material was then
washed with several portions of water (4.times.200 mL) and dried in
a vacuum oven (50.degree. C.) to afford the oxazolidinone alcohol
(34.1 g, 92% yield) as a tan granular solid. Mp=208-212.degree. C.,
decomp. MS (M+1)=330 m/z.
EXAMPLE 6
[0113] 25
[0114] Oxazolidinone Mesylate. The above oxazolidinone carbinol
(from Example 4) (33.8 g, 103 mmols) was suspended in DMF (1.25 L,
previously degassed with nitrogen) at rt under a nitrogen
atmosphere. Triethylamine (50 mL, 360 mmols) was added followed by
the dropwise addition of methanesulfonyl chloride (13.5 mL, 174
mmols). After stirring for 3 hrs the reaction mixture was poured
into water (200 mL) and methylene chloride (1 L) added. A ppt was
filtered off, washed with water (3.times.200 mL) and dried in a vac
oven (50.degree. C.) to afford the mesylate as a tan solid (28.1 g,
67%). The organic layer was dried (Na.sub.2SO.sub.4), filtered and
evaporated to also afford the mesylate (11.7 g, 28% yield) as a tan
solid. Both where characterized with MS (M+1)=408 m/z.
EXAMPLE 7
[0115] 26
[0116] Oxazolidinone Azide. The above mesylate (from Example 5)
(27.8 g, 68.2 mmols) and sodium azide (17.7 g, 271 mmols) in
anhydrous DMF (1 L), previously degassed with nitrogen, were heated
95.degree. C. for 6 hr under a nitrogen atmosphere. After cooling,
the mixture was poured into stirred ice water (2 L) and formed a
flocculant white ppt. The ppt was collected on a filter and washed
with water (4.times.200 mL), dried in a vac oven (50.degree. C.) to
afford the azide as a light beige solid (22.7 g, 94% yield).
Mp=175-180.degree. C., decomp. MS (M+1)=355 m/z.
EXAMPLE 8
[0117] 27
[0118] Oxazolidinone Acetamide. The above azide (from Example
6)(21.67 g, 61.16 mmol) dissolved in DMF (400 mL) and THF (500 mL)
was degassed with nitrogen for 30 minutes whereupon 10% Pd/C (4.74
g, 4.4 mmols) was added and the reaction hydrogenated on a Parr
apparatus (60 psi of hydrogen) for 14 hr. The reaction mixture was
removed from the Parr apparatus and placed under a nitrogen
atmosphere whereupon pyridine (5.44 mL, 67.3 mmols) and acetic
anhydride (6.35 mL, 67.3 mmols) were added. After stirring for 1 hr
the reaction mixture was filtered through a pad of Celite, washing
thoroughly with methanol and then copious amounts of 50%
MeOH/CH.sub.2Cl.sub.2 (ca. 2 L). The filtrate was evaporated to
afford the crude acetamide in DMF. The mixture was slowly added to
water (2 L) and the ppt collected on a filter, washed with water
(5.times.400 mL) and dried in a vac oven (50.degree. C.) to provide
the acetamide as an analytically pure white solid (14.2 g, 63%
yield). The combined filtrates were extracted with methylene
chloride (5.times.200 mL), dried over Na.sub.2SO.sub.4 and
concentrated. Water was added to the residue and the resulting ppt
was filtered off and dried in a vac oven (50.degree. C.) to afford
a second crop of the acetamide as a light tan, fluffy solid (5.61
g, 25%). For the analytically pure material Mp=229-230.degree. C.,
decomp. MS (M+1)=371 m/z.
EXAMPLE 9
[0119] 28
[0120] The above acetamide from Example 8 (2.51 g, 6.78 mmols) was
taken up in CH.sub.2Cl.sub.2 and MnO.sub.2 added (23.9 g, 234
mmols). After stirring overnight the reaction mixture was filtered
through celite, concentrated and chromatography on silica with 10%
MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as a light
yellow solid (0.48 g, 19% yield). Mp=220-225.degree. C. decomp. MS
(M+1)=369 m/z.
EXAMPLE 10
[0121] 29
[0122] Compound 5 was prepared as in Example 8 except (S)-glycidyl
butyrate was employed in the oxazolidinone formation. The product
was isolated as a light tan solid. Mp=227-230.degree. C. decomp. MS
(M+1)=371 m/z.
EXAMPLE 11
[0123] 30
[0124] Compound 6 was prepared as in Example 9 and isolated as a
light yellow solid. Mp=181-185.degree. C. decomp. MS (M+1)=369
m/z.
EXAMPLE 12
[0125] 31
[0126] To 5-hydroxyisoxazole (prepared as in Chem Pharm Bull 1966,
14(11), 1277) (0.174 g, 2.04 mmols) in DMF was added NaH (60% in
oil)(0.105 g, 2.62 mmols). After stirring for 30 min the mesylate
(from Example 6) (0.744 g, 1.82 mmols) was added in one portion and
the mixture stirred at 60.degree. C. overnight. After cooling to rt
water was added and a ppt was collected on a filter, air dried and
chromatographed on silica with 2.5% MeOH/CH.sub.2Cl.sub.2 as eluent
to afford the product as a white solid (0.140 g, 19% yield).
Mp=182-185.degree. C. MS (M+1)=397m/z.
EXAMPLE 13
[0127] 32
[0128] To the above oxazolidinone (from Example 12) (0.264 g, 6.66
mmols) was taken up in CH.sub.2Cl.sub.2 and MnO.sub.2 added (1.66
g, 16.2 mmols) in two portions over two days. After stirring for
two days the reaction mixture was filtered through celite,
concentrated and chromatographed on silica with 10%
MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as a light
yellow solid (0.086 g, 32% yield). Mp=133-135.degree. C. MS
(M+1)=395 m/z.
EXAMPLE 14
[0129] 33
[0130] To NaH (60% by wt in oil)(0.03 g, 0.76 mmol) in DMF (5 mL)
was added oxazolidinone carbinol (from Example 5) (0.23 g, 0.71
mmol) in four portions. After stirring for 30 min 2-chloropyrazine
(0.065 mL, 0.71 mmol) was added via syringe and stirred overnight
at rt. Water was added and a ppt was collected on a filter, air
dried and chromatographed on silica with 5% MeOH/CH.sub.2Cl.sub.2
as eluent to afford the product as a white solid (0.067 g, 23%
yield). Mp=225-230.degree. C. MS (M+1)=408 m/z.
EXAMPLE 15
[0131] 34
[0132] The above oxazolidinone (from Example 14) (0.024 g, 0.058
mmol) in CH.sub.2Cl.sub.2 (5 mL) was added MnO.sub.2 (0.07 g, 0.7
mmol). After stirring overnight the reaction mixture was filtered
through Celite and concentrated to afford the product as a very
light yellow solid (0.015 g, 64% yield). Mp=192-194.degree. C. MS
(M+1)=406 m/z.
EXAMPLE 16
[0133] 35
[0134] To a suspension of the oxazolidinone carbinol (prepared in
Example 5) (330 mg, 1.0 mmol), triphenylphosphine (260 mg, 1.1
mmols) and 4-hydroxy-1,2,5-thiadiazole (100 mg, 1.0 mmol) (as
prepared in U.S Pat. No. 3,391,150 [Jul. 2, 1968]) in THF (8 mL)
was added diisopropylazodicarboxylate (0.20 mL, 1.1 mmols). After
stirring overnight at rt the reaction mixture was filtered, washed
with methanol, and air dried to afford a yellow crystalline solid
(60 mg, 15% yield). Mp=185-187.degree. C. MS (M+1)=414 m/z.
EXAMPLE 17
[0135] 36
[0136] To the oxazolidinone (prepared in Example 16) (160 mg, 0.39
mmol) suspended in CH.sub.2Cl.sub.2 (1.0 mL) was added MnO.sub.2
(four additions of 150 mg over four days). The reaction mixture was
filtered through a plug of Celite, washed with CH.sub.2Cl.sub.2 (15
mL), and concentrated under reduced pressure to afford the product
as a white crystalline solid (63 mg, 40% yield). Mp=185-188.degree.
C. MS (M+1)=412 m/z.
EXAMPLE 18
[0137] 37
[0138] To the amine (as prepared in Example 8) (100 mg, 0.30 mmol)
and potassium carbonate (100 mg, 0.72 mmol) suspended in methanol
(1.0 mL), was added propionyl chloride (50 mg, 0.54 mmol). After
stirring overnight at 80.degree. C. the reaction mixture was cooled
and water was added. A precipitate was filtered off, washed with
methanol and air dried to afford the product as a brown crystalline
solid (15 mg, 13% yield). Mp=110-112.degree. C. MS (M+1)=385
m/z.
EXAMPLE 19
[0139] 38
[0140] To the amide (prepared in Example 18) (15 mg, 0.04 mmol)
suspended in CH.sub.2Cl.sub.2 (1.0 mL), was added MnO.sub.2 (200
mg) at rt. After stirring overnight, the reaction mixture was
filtered through a plug of Celite, washed with CH.sub.2Cl.sub.2 (10
mL), and concentrated under reduced pressure to afford the product
as an light brown crystalline solid (1.6 mg, 8% yield). MS
(M+1)=383 m/z.
EXAMPLE 20
[0141] 39
[0142] To the amine (as prepared in Example 8) (60 mg, 0.18 mmol)
and potassium acetate (60 mg, 0.61 mmol) suspended in methanol (1.0
mL), was added cyclopropyl carbonyl chloride (120 mg, 1.15 mmols).
After stirring at rt overnight, the reaction mixture was filtered,
rinsed with methanol, and then concentrated to dryness under
reduced pressure. The resulting solid residue was triturated with
water and filtered to afford the product as a brown crystalline
solid (36 mg, 50% yield). Mp=235-240.degree. C. MS (M+1)=397
m/z.
EXAMPLE 21
[0143] 40
[0144] To the amide (prepared in Example 20) (36 mg, 0.09 mmol)
suspended in CH.sub.2Cl.sub.2 (1.0 mL), was added MnO.sub.2 (three
portions of 100 mg over three days) at rt. The reaction mixture was
filtered through a plug of Celite, washed with CH.sub.2Cl.sub.2 (10
mL), and concentrated under reduced pressure to afford the product
as an off-white crystalline solid (3 mg, 8% yield). MS (M+1)=395
m/z.
EXAMPLE 22
[0145] 41
[0146] To the amine (prepared in Example 8) (60 mg, 0.18 mmol) and
potassium acetate (60 mg, 0.61 mmol) suspended in methanol (1.0
mL), was added dropwise methyl chloroformate (120 mg, 1.27 mmols).
After stirring for four hours at rt, the reaction mixture was
filtered, diluted with water, and concentrated under reduced
pressure to remove the methanol. The aqueous solution was extracted
with ethyl acetate (5.times.5 mL). The combined organics were
washed with water, dried over MgSO.sub.4, filtered, and
concentrated to provide an oil which was triturated with ether to
afford a brown crystalline solid (35 mg, 50% yield). MS (M+1)=387
m/z.
EXAMPLE 23
[0147] 42
[0148] To the carbamate (prepared in Example 22) (33 mg, 0.08 mmol)
suspended in CH.sub.2Cl.sub.2 (1.0 mL), was added MnO.sub.2 (150
mg). After stirring overnight at rt the reaction mixture was
filtered through a plug of Celite, washed with CH.sub.2Cl.sub.2 (10
mL), and concentrated under reduced pressure to afford the product
as a yellow crystalline solid (6.0 mg, 18% yield). MS (M+1)=385
m/z.
EXAMPLE 24
[0149] 43
[0150] To the amine (prepared in Example 8) (60 mg, 0.18 mmol) and
potassium acetate (60 mg, 0.61 mmol) suspended in methanol (1.0 mL)
was added dropwise ethyl chloroformate (0.1 mL, 1.04 mmols). After
stirring overnight at rt the reaction mixture was filtered, diluted
with water, and concentrated under reduced pressure to remove the
methanol. The aqueous solution was extracted with ethyl acetate
(5.times.5 mL). The combined organics were washed with water, dried
over MgSO.sub.4, filtered, and concentrated. The resulting
semi-solid was treated with water, filtered and air-dried to afford
a brown crystalline solid (18 mg, 30% yield). MS (M+1)=401 m/z.
EXAMPLE 25
[0151] 44
[0152] To the amine (prepared in Example 8) (95 mg, 0.29 mmol)
suspended in pyridine (0.5 mL) was added methane sulfonylchloride
(0.08 mL, 1.0 mmol). After stirring overnight at rt the pyridine
was removed under a stream of nitrogen. The residue was treated
with water, filtered and air-dried to afford a brown solid (45 mg,
38% yield). Mp=172-176.degree. C. MS (M+1)=407 m/z.
EXAMPLE 26
[0153] 45
[0154] To the sulfonamide (prepared in Example 25) (10 mg, 0.02
mmol) suspended in CH.sub.2Cl.sub.2 (1.0 mL), was added MnO.sub.2
(100 mg, 10 mmols). After stirring overnight the reaction mixture
was filtered through a plug of Celite, washed with CH.sub.2Cl.sub.2
(10 mL), and concentrated under reduced pressure to afford the
product as a brown crystalline solid (0.5 mg, 5% yield). MS
(M+1)=405 m/z.
EXAMPLE 27
[0155] 46
[0156] To the amine (prepared in Example 8) (200 mg, 0.61 mmol)
suspended in toluene (8 mL), was added
dimethyl-N-cyanodithioiminocarbonate (89 mg, 0.61 mmol). After
stirring overnight at reflux the toluene was decanted and the oily
residue treated with methanol, filtered, and air-dried to afford a
brown crystalline solid (62 mg, 20% yield). Mp=204-207.degree. C.
MS (M+1)=427 m/z.
EXAMPLE 28
[0157] 47
[0158] A suspension of the thioimidate (from Example 27) (45 mg,
0.10 mmol) and MnO.sub.2 (200 mg, 2.0 mmols) in CH.sub.2Cl.sub.2
were stirred at rt for one day whereupon a second addition of
MnO.sub.2 (150 mg, 1.5 mmols) was added. After an additional day of
stirring the mixture was filtered through Celite, washed with
CH.sub.2Cl.sub.2 (10 mL), concentrated to afford a yellow
crystalline solid (20 mg, 45% yield). MS (M+1)=426 m/z.
EXAMPLE 29
[0159] 48
[0160] A suspension of the amine (prepared in Example 8) (165 mg,
0.5 mmol) and 2-methyl-1-nitro-2-thiopseudourea (94 mg, 0.70 mmol)
(as prepared as in EP 0539204/1993) in methanol (2 mL) was refluxed
for four hours. After cooling to rt the reaction mixture was
filtered and air dried to afford a yellow crystalline solid (50 mg,
24% yield). Mp=202-206.degree. C. MS (M+1)=416 m/z.
EXAMPLE 30
[0161] 49
[0162] To the nitroguanidine (prepared in Example 29) (35 mg, 0.08
mmol) suspended in CH.sub.2Cl.sub.2 (1.0 mL) was added MnO.sub.2
(three additions of 100 mg over three days). The reaction mixture
was filtered through a plug of Celite, washed with CH.sub.2Cl.sub.2
(10 mL), and concentrated under reduced pressure to afford the
product as a yellow crystalline solid (1.6 mg, 4% yield). MS
(M+1)=414 m/z.
EXAMPLE 31
[0163] 50
[0164] The starting material 6,7-dihydro-5H-pyrrolo[3,4-c]pyridine
was prepared as in U.S. Pat. No. 5,371,090 to Petersen et al.
Compound 26 was then prepared as in Example 8 except the acetamide
was recrystallized from acetonitrile to give a light tan solid.
Mp=182-190.degree. C. decomposition. MS (M+1)=371 m/z.
EXAMPLE 32
[0165] 51
[0166] Compound 27 was isolated from the final step of Example 31
via chromatography (5% MeOH/CH.sub.2Cl.sub.2 as eluent) of the
mother liquors collected from recrystallization. Light yellow
solid, Mp=219-225.degree. C. decomp. MS (M+1)=385 m/z.
EXAMPLE 33
[0167] 52
[0168] Compound 28 was prepared as in Example 9 except with 10%
MeOH/CH.sub.2Cl.sub.2 as eluent. Light yellow solid,
Mp=219-225.degree. C. decomposition. MS (M+1)=369 m/z.
EXAMPLE 34
[0169] 53 54
[0170] Isothiazole (0.088 g, 0.87 mmol)(prepared as in J
Heterocyclic Chem 1971, 8, 591) was added portionwise at rt to a
suspension of sodium hydride (0.036 g, 0.91 mmol, 60% in oil) in
DMF (4 mL) under nitrogen. The mixture was stirred for 30 minutes
whereupon the mesylate from Example 31 (0.31 g, 0.76 mmol), in DMF
(10 mL), was added all at once. After stirring for 6 hours at
60.degree. C. the reaction mixture was cooled to rt, diluted with
water (50 mL), and extracted with ethyl acetate (3.times.50 mL).
The combined organics were washed several times with water, then
once with brine, dried over sodium sulfate, concentrated, and
chromatographed on silica with 5% MeOH/EtOAc as eluent. Two
products were isolated from the chromatography: 0.050 g of Compound
29; and 0.022 g of Compound 30. Overall yield, 30%.
[0171] Compound 29 MS (M+1)=413.0
[0172] Compound 30 MS (M+1)=411.1
EXAMPLE 35
[0173] 55
[0174] To a suspension of sodium hydride (0.036 g, 0.91 mmol, 60%
in oil) in DMF (4 mL) at rt under nitrogen was added portion wise
4-hydroxy-1,2,5-thiadiazole (0.088 g, 0.87 mmol) (as prepared in
U.S. Pat. No. 3,391,150 [Jul. 2, 1968]). After stirring for 30 min
the mesylate from Example 31 (0.310 g, 0.76 mmol), in DMF (10 mL),
was added all at once. After stirring for 6 hours at 60 C. the
reaction mixture was cooled to rt, diluted with water (50 mL), and
extracted with ethyl acetate (3.times.50 mL). The combined organics
were washed several times with water, then once with brine, dried
over sodium sulfate, concentrated, and chromatographed on silica
with 2% MeOH/EtOAc as eluent. Two products were isolated from the
chromatography: 0.035 g of Compound 31; and 0.0093 g of Compound
32. Overall yield, 14%.
[0175] Compound 31 MS (M+1)=414.0
[0176] Compound 32 MS (M+1)=412.1
EXAMPLE 36
[0177] 56
[0178] To the mesylate from Example 31 (2.45 g, 6.01 mmol)
dissolved in degassed DMF (100 mL) under nitrogen was added
potassium phthalimide (2.23 g, 12.0 mmols). After heating at
65.degree. C. for 3 hours the reaction mixture was cooled, poured
into water (300 mL), and extracted with methylene chloride
(3.times.200 mL). The combined organics were washed with water
(3.times.150 mL) dried over sodium sulfate, concentrated to a tan
solid. This solid was washed with water and dried in a high vacuum
oven at 50.degree. C. to afford 2.20 g (80%) of the oxazolidinone
phthalimide. MS=459.1 (M+1) 57
[0179] To the above phthalimide (0.97 g, 2.1 mmols) in degassed
methanol (30 mL) under nitrogen was added hydrazine monohydrate
(0.2 mL, 4.3 mmols) dropwise. After refluxing for 12 hours the
reaction mixture was cooled to rt, and concentrated, suspended
CH.sub.2Cl.sub.2 and filtered. The crude oxazolidinone amine was
concentrated and used without further purification.
[0180] Step 3:
[0181] Compound 33,
[0182] To the crude amine (0.14 g, 0.44 mmol) in CH.sub.2Cl.sub.2
(5 mL) was added pyridine (0.14 mL, 18 mmols) followed by propionyl
chloride (0.76 mL, 0.88 mmol).
[0183] After stirring for 5 hrs at rt the solution was poured into
water (20 mL) and extracted with methylene chloride (3.times.10
mL). The combined extracts were washed with water (10 mL) and 1 M
NaOH (aq)(10 mL), dried over sodium sulfate, concentrated and
chromatographed using neat EtOAc as eluent to afford the propionyl
amide as a gold oil (0.020 g, 12% yield). MS=385.2 (M+1)
EXAMPLE 37
[0184] 58
[0185] To the crude amine (as prepared in Example 36) (0.144 g,
0.437 mmol) in methylene chloride (5 mL) was added pyridine (0.14
mL, 1.7 mmols), followed by cyclopropane carbonyl chloride (0.08
mL, 0.88 mmol). After stirring for 5 hrs at rt the solution was
poured into water (20 mL) and extracted with methylene chloride
(3.times.10 mL). The combined extracts were washed with water (10
mL) and 1 M NaOH (aq) (10 mL), dried over sodium sulfate,
concentrated and chromatographed using a gradient elution of 1% to
5% to 10% MeOH/EtOAc. The desired product eluted with 5% MeOH/EtOAc
and was concentration to afford the product as a white powder
(0.012 g, 7% yield). MS=397.2 (M+1)
EXAMPLE 38
[0186] 59
[0187] To N-[(3-pyrrolidinone-3-fluorophenyl) 5-oxazolidinyl]methyl
acetamide (prepared according to W096/13502)(0.150 g, 0.447 mmols)
was added methoxy-bis(dimethylamino)methane (1 mL). After heating
at 50.degree. C. for 15 min the reaction mixture was concentrated
to provide the crude .beta.-ketoenamine which was used without
further purification.
[0188] Step 2;
[0189] Compound 35
[0190] To ethanolic NaOEt (made from 0.027 g Na in 3 mL EtOH) was
added acetamidine hydrochloride (0.113 g, 1.19 mmols) and the above
.beta.-ketoenamine oxazolidinone acetamide. After refluxing for 3
hrs the reaction mixture was cooled to rt, concentrated, taken up
in chloroform, and washed with water (3.times.8 mL). After drying
over sodium sulfate the crude product was concentrated, dissolved
in 5% MeOH/EtOAc, and filtered to afford the product as an
off-white solid (0.052 g, 45% yield). Mp=234.degree. C., decomp.
MS=385.9 (M+1)
EXAMPLE 39
[0191] 60
[0192] To N-[(3-pyrrolidinone-3-fluorophenyl) 5-oxazolidinyl]methyl
acetamide (prepared according to W096/13502)(0.099 g, 0.29 mmol)
was added methoxy-bis(dimethylamino)methane (1.0 mL). After heating
at 50.degree. C. for 2 hrs the reaction mixture was concentrated to
provide the crude .beta.-ketoenamine. To this mixture was added
benzene (5 mL), DMF (1 mL) and formamidine acetate (0.55 g, 5.3
mmols). After heating overnight at 95.degree. C. the reaction
mixture was cooled to rt and water (8 mL) was added. A ppt formed
and was collected by filtration, dried in a vacuum oven (50.degree.
C.), and chromatographed on silica with 5% MeOH/CH.sub.2Cl.sub.2 as
eluent to afford the product as a white powder (0.037 g, 34%
yield). Mp=230-232.degree. C. MS (M+1)=372 m/z.
EXAMPLE 40
[0193] 61
[0194] The above acetamide from Example 39 (0.020 mg, 0.054 mmol)
was taken up in CH.sub.2Cl.sub.2 (5 mL) and MnO.sub.2 added (0.10
g, 0.98 mmol). After stirring overnight at rt the reaction mixture
was filtered through Celite and concentrated to afford the product
as a light yellow solid (0.016 g, 80% yield). Mp=164-166.degree. C.
MS (M+1)=370 m/z.
EXAMPLE 41
[0195] 62
[0196] To the .beta.-ketoenamine (prepared as in Example 39) was
added benzene (5 mL), DMF (1 mL) and pyrazine-2-carboxamidine
hydrochloride (0.62 g, 3.9 mmols). After heating overnight at
95.degree. C. the reaction mixture was cooled to rt and water (8
mL) was added. A ppt formed and was collected by filtration, dried
in a vacuum oven (50.degree. C.), and chromatographed on silica
with 5% MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as a
light yellow solid (0.0026 g, 2% yield). Mp=212-214.degree. C. MS
(M+1)=450 m/z.
EXAMPLE 42
[0197] 63
[0198] The above acetamide from Example 39 (0.040 g, 0.088 mmols)
was taken up in CH.sub.2Cl.sub.2 (10 mL) and MnO.sub.2 (0.36 g, 3.5
mmols) added in three portions over three days. After stirring for
three days the reaction mixture was filtered through Celite,
concentrated and chromatography on silica with 7%
MeOH/CH.sub.2Cl.sub.2 as eluent. Two products were isolated from
the chromatography: 0.001 g of Compound 39 as a light yellow solid
(4% yield); and 0.002 g of Compound 40 as a yellow solid (4%
yield).
[0199] Compound 39: MS (M+1)=448 m/z.
[0200] Compound 40: MS (M+1)=464 m/z.
EXAMPLE 43
[0201] 64
[0202] To the .beta.-ketoenamine (prepared as in Example 39) was
added benzene (5 mL), DMF (1 mL) and 4-amidinopyridine
hydrochloride (0.81 g, 5.2 mmols). After heating overnight at
95.degree. C. the reaction mixture was cooled to rt and water (8
mL) was added. A ppt formed and was collected by filtration, dried
in a vacuum oven (50.degree. C.), and chromatographed on silica
with 5% MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as a
light yellow solid (0.072 g, 55% yield). Mp=245-250.degree. C.,
decomp. MS (M+1)=449 m/z.
EXAMPLE 44
[0203] 65
[0204] Compounf 42
[0205] To the .beta.-ketoenamine (prepared as in Example 39) was
added benzene (5 mL), DMF (1 mL) and 2-amidinopyridine
hydrochloride (0.61 g, 3.9 mmols). After heating overnight at
95.degree. C. the reaction mixture was cooled to rt and water (8
mL) was added. A ppt formed and was collected by filtration, dried
in a vacuum oven (50.degree. C.), and chromatographed on silica
with 5% MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as a
yellow powder (0.054 g, 40% yield). Mp=216-220.degree. C. MS
(M+1)=449 m/z.
EXAMPLE 45
[0206] 66
[0207] Compound 43
[0208] To the .beta.-ketoenamine (prepared as in Example 39) was
added benzene (5 mL), DMF (2 mL) and 3-amidinopyridine
hydrochloride (0.49 g, 3.1 mmols). After heating overnight at
95.degree. C. the reaction mixture was cooled to rt and water (8
mL) was added. A ppt formed and was collected by filtration, dried
in a vacuum oven (50.degree. C.), and chromatographed on silica
with 5% MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as a
light purple, crystalline solid (0.044 g, 33% yield).
Mp=265-270.degree. C., decomp. MS (M+1)=449 m/z.
EXAMPLE 46
[0209] 67
[0210] To the .beta.-ketoenamine (prepared as in Example 39) was
added benzene (5 mL), DMF (2 mL) and hydrazine hydrochloride (0.22
g, 3.2 mmols). After heating overnight at 95.degree. C. the
reaction mixture was cooled to rt and water (8 mL) was added. A ppt
formed and was collected by filtration, dried in a vacuum oven
(50.degree. C.), and chromatographed on silica with 5%
MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as off-white
powder (0.022 g, 21% yield). Mp=244-247.degree. C., decomp. MS
(M+1)=360 m/z.
EXAMPLE 47
[0211] 68
[0212] To the .beta.-ketoenamine (prepared as in Example 39) was
added benzene (5 mL), DMF (2 mL) and n-propylhydrazine oxalate
(0.87 g, 5.3 mmols). After heating overnight at 95.degree. C. the
reaction mixture was cooled to rt and water (8 mL) was added. A ppt
formed and was collected by filtration, dried in a vacuum oven
(50.degree. C.), and chromatographed on silica with 5%
MeOH/CH.sub.2Cl.sub.2 as eluent to afford the product as a light
yellow solid (0.081 g, 55% yield). Mp=204-208.degree. C. MS
(M+1)=402 m/z.
EXAMPLE 48
[0213] 69
[0214] The starting material aniline
(N-[[(5S)-3-(4-amino-3-fluorophenyl)--
2-oxo-5-oxazolidinyl]methyl]-acetamide) was prepared as in World
Patent WO 96/23788. To phthalic dicarboxaldehyde (0.0522 g, 0.378
mmol) in acetonitrile (1 mL) was added glacial acetic acid (0.05
mL, 0.87 mmol) and then the above aniline (0.0955 g, 0.357 mmol) in
acetonitrile (5 mL) dropwise. After 4 hrs water (10 mL) was added
and a precipitate was collected on a filter and washed with water
and ether to provide Compound 46 as a light green solid (0.0655 g,
48%). Mp=211-214.degree. C. MS (M+1)=384 m/z.
EXAMPLE 49
[0215] 70
[0216] To starting material aniline
(N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-
-oxo-5-oxazolidinyl]methyl]-acetamide)(0.095 g, 0.36 mmol)(as
prepared in World Patent WO 96/23788) in CH.sub.2Cl.sub.2 (5 mL)
was added triethylamine (0.15 mL, 1.1 mmols) and phthaloyl
dichloride (0.056 mL, 0.39 mmol). After stirring overnight a solid
was collected on a filter, washed with water (10 mL) and dried in
vacuum oven (50.degree. C.) to afford the product as a off-white
solid (0.060, 42%). Mp=240-242.degree. C. MS (M+1)=398 m/z.
EXAMPLE 50
[0217] 71
[0218] To starting material aniline
(N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-
-oxo-5-oxazolidinyl]methyl]-acetamide)(0.20 g, 0.75 mmol)(as
prepared in World Patent WO 96/23788) in acetonitrile (5 mL) was
added 2,3-pyridine dicarboxaldehyde (0.10 g, 6.6 mmols) and glacial
acetic acid (0.050 mL, 0.87 mmol). After stirring for 5 hrs the
reaction mixture was concentrated and chromatographed on silica
with 2.5% MeOH/CH.sub.2Cl.sub.2 as eluent to afford the two
products: 0.035 g of Compound 52 (12%) as a yellow solid; and 0.011
g of Compound 53 (4%) as a yellow solid.
[0219] Compound 48: Mp=230-232.degree. C. MS (M+1)=385 m/z.
[0220] Compound 49: Mp=207-209.degree. C. MS (M+1)=385 m/z.
[0221] The invention has been described in detail with particular
reference to the above embodiments thereof. The above embodiments
and examples are given to illustrate the scope and spirit of the
present invention. These embodiments and examples will make
apparent, to those skilled in the art, other embodiments and
examples. These other embodiments and examples are within the
contemplation of the present invention. It will be understood that
variations and modifications can be effected within the spirit and
scope of the invention; therefore, the instant invention should be
limited only by the appended claims.
* * * * *