Note: Descriptions are shown in the official language in which they were submitted.
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
DIAZEPINE OXAZOLIDINONES AS ANTIBACTERIAL AGENTS
FIELD OF INVENTION
The present invention relates to a new class of oxazolidinone derivatives, to
their use as antibacterial agents, to pharmaceutical compositions containing
these
compounds and to methods for their preparation.
BACKGROUND OF THE INVENTION
Antibacterial resistance is a global clinical and public health problem that
has
to emerged with alarming rapidity in recent years and undoubtedly will
increase in the
near future. Resistance is a problem in the community as well as in health
care
settings, where transmission of bacteria is greatly amplified. Because
multiple drug
resistance is a growing problem, physicians are now confronted with infections
for
which there is no effective therapy. As result, structurally novel
antibacterials with a
new mode of action have become increasingly important in the treatment of
bacterial
infections.
Among newer antibacterial agents, oxazolidinone compounds are the most
recent synthetic class of antimicrobials. This invention provides a new class
of
oxazolidinone derivatives containing a diazepine ring, which are active
against a
2o number of human and veterinary pathogens, including multiple resistant
strains of
bacteria.
INFORMATION DISCLOSURE
WO 9323384, WO 20028084, WO 2003072553, WO 2003072576,
WO 2003072575, WO 200142229, WO 200264575, WO 9615130, WO 200216960,
WO 200027830, WO 200146185, WO 200281469, WO 200281470, WO
2001080841, WO 2003084534, WO 2003093247, WO 200202095, WO 200230395,
WO 200272066, WO 2003063862, WO 2003072141, WO 2003072081, WO
2003119817, WO 2003008389, WO 2003007870, WO 200206278, WO 200032599,
WO 9924428, WO 2004014392, WO 2004002967, WO 2004009587, WO
2004018439, US Patent Application Publication No. US 2004/0044052, US Patent
No. 5547950, US Patent No. 5700799, DE 10034627 disclose oxazolidinone
compounds having antibacterial activity useful for treating microbial
infections.
-1-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
SUMNIARY OF THE 1NVENTION
The present invention provides a compound of formula I
R\N N~~ 1 ~--A-W
Y2=Y3
or a pharmaceutically acceptable salt thereof wherein:
A is a structure of the following formula i, ii, iii, or iv
0 0 0
N4 I ,N'kO O
iv
Wis
(a) CONHR2,
(b) CH2NHCO(NH)C1_6alkyl,
(c) CH2NHCOOCI-6alkyl
(d) CHZOH,
(e) CH(OH)-CH=CHR2,
(f) CH(OH)C - CRZ,
(g) CH2NH het,
(h) CH2O-het,
(i) CH2S-het, or
(j) CH2het;
Y' is CH, CF, or N;
Y2 and Y3 are independently CH, or CF;
Q is 0, or S;
R' is H, or Cl-6allcyl;
RZ is H, Cl-6 alkyl, or OCl-6allcyl;
each ". ...." is independently a bond or absence,
at each occurrence, Cl-6allcyl is optionally substituted with one or more CF3,
halo, OH,
OCl-4alkyl, CN, N3, O(C=O)Cl-4 alkyl, C3-6cycloallcyl, NH2, NHC(=O)C1.4 alkyl,
or
C(=O)Cl-4 alkyl; and
-2-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
het is a five- (5) or six-.(6).membered heterocyclic ring having.1-
4:heteroatoms
selected from the group consisting of oxygen, sulfur, and nitrogen within the
ring,
wherein each carbon atom in het is optionally substituted with one or more
CF3, halo,
OH, OCl_4allcyl, CN, N3, O(C=O)C1_4 alkyl, C3_6cycloalkyl, NHZ, NHC(=O)Cl-4
alkyl,
or C(=O)Cl-4 alkyl.
In another aspect, the present invention also provides:
a pharmaceutical composition which con-iprises a pharmaceutically acceptable
carrier and a compound of formula I,
a method for treating microbial infections in a mammal by administering to the
subject in need a therapeutically effective amount of a compound of formula I
or a
pharmaceutically acceptable salt thereof, and
a use of a compound of formula I or a pharmaceutically acceptable salt thereof
to prepare a medicament for treating microbial infections.
The invention may also provide novel intermediates and novel processes that
are useful for preparing compounds of forrnula I.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and
claims have the meanings given below:
The carbon atom content of various hydrocarbon-containing moieties is
indicated by a prefix designating the minimum and maximum number of carbon
atoms
in the moiety, i.e., the prefix C;; indicates a moiety of the integer "i" to
the integer "j"
carbon atoms, inclusive. Thus, for example, Cl-6 alkyl refers to alkyl of one
to six
carbon atoms, inclusive.
The term alkyl, or alkenyl, etc. refer to both straight and branched groups,
but
reference to an individual radical such as "propyl" embraces only the straight
chain
radical, a branched chain isomer such as "isopropyl" being specifically
referred to.
The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
The term "a pharma.ceutically acceptable salt" of a compound means a salt that
is
pharmaceutically acceptable and that possesses the desired pharmacological
activity of
the parent compound.
The term "het" is a five- (5) or six- (6) membered heterocyclic ring having 1-
4
heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen
within
-3-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
the ring. An.examples of het includes, but are not limited.to, azetidine,
pyrrole,
imidazole, pyrazole, 1,2,3-triazole, 1,3,4-triazole, oxazole, thiazole,
isoxazole,
isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole,
tetrazole, pyridine,
pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,
dihydroindole, indazole,
purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline,
quinazoline,
cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline,
isothiazole, phenazine, isoxazole, isoxazolinone, phenoxazine, phenothiazine,
imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide,
1,2,3,4-
tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole,
thiadiazole,
tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine,
thiomorpholine,
(also referred to as thiamorpholine), piperidine, pyrrolidine,
tetrahydrofuran, or the
like. Another example of het includes, but are not limited to, pyridine,
thiophene, furan,
pyrazole, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-
pyrimidinyl, 5-
pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-
imidazolyl,
4-imidazolyl, 3-isoxaz-olyl, 4-is-oxaz-olyl, 5-isoxaz-olyl, 3-pyrazolyl, 4-
pyrazolyl, 5-
pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-
oxathiazole,
1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-
thiazolyl, 4-
thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-
furanyl, 3-furanyl, 2-
thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-
isopyrrolyl,
1,2,3,-oxathiazole-l-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-
1,2,4-
oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-
5-yl, 3-
oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl,
1,2,3-
triazole-l-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazole-l-yl, 1,2,3,4-
tetrazol-5-yl,
5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-
oxadiazole, 4-oxo-
2-thiazolinyl, or 5-methyl- 1,3,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-
thiatriazole, or
1,2,4-dithiazolone.
The term "pharmaceutically acceptable carrier" means a carrier that is useful
in
preparing a pharmaceutical composition that is generally safe, non-toxic and
neither
biologically nor otherwise undesirable, and includes a carrier that is
acceptable for
veterinary use as well as human pharmaceutical use. "A pharmaceutically
acceptable
carrier" as used in the specification and claims includes both one and more
than one
such carrier.
-4-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
The term "mammal", refers to human or..warm blooded animals including .
livestock and companion animals. Livestock refers to animals suitable for
human meat
consumption. Examples include pigs, cattle, chickens, fish, turkeys, rabbits,
etc.
Companion animals refer to animals kept as pets such as dogs, cats, etc.
The terrn "optional" or "optionally" means that the subsequently described
event or circumstance may, but need not, occur, and that the description
includes
instances where the event or circumstance occurs and instances in which it
does not.
The term "treating" or "treatment" of a disease includes: (1) preventing the
disease, i.e. causing the clinical symptoms of the disease not to develop in a
matrunal
that may be exposed to or predisposed to the disease but does not yet
experience or
display symptoms of the disease; (2) inhibiting the disease, i.e., arresting
or reducing
the development of the disease or its clinical symptoms; or (3) relieving the
disease,
i.e., causing regression of the disease or its clinical symptoms.
The term "therapeutically effective amount" means the amount of a compound
that, when administered to a mammal for treating a disease, is sufficient to
effect such
treatment for the disease. The "therapeutically effective amount" will vary
depending
on the compound, the disease and its severity and the age, weight, etc., of
the mammal
to be treated.
The term "prodrug" refers to compounds that are rapidly transformed in vivo
to yield the parent compound of the above forrnulas, for example, by
hydrolysis in
blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-
drugs as
Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987.
The term "leaving group" has the meaning conventionally associated with it in
synthetic organic chemistry i.e., an atom or group capable of being displaced
by a
nucleophile and includes halogen, alkylsulfonyloxy, ester, or amino such as
chloro,
bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O-
dimethylhydroxyl-amino, and the like.
Compounds that have the same molecular formula but differ in the nature or
sequence of bonding of their atoms or the arrangement of their atoms in space
are
termed "isomers". Isomers that differ in the arrangement of their atoms in
space are
termed "stereoisomers".
-5-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
.- It will be appreciated by. those skilled in the art .that compounds, of the
invention having a chiral center may exist in and be isolated in optically
active and
racemic forms. Some compounds may exhibit polymorphism. It is to be understood
that the present invention encompasses any racemic, optically-active,
polymorphic,
tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the
invention, which possesses the useful properties described herein, it being
well known
in the art how to prepare optically active forms (for example, by resolution
of the
racemic form by recrystallization techniques, by synthesis from optically-
active starting
materials, by chiral synthesis, or by chromatographic separation using a
chiral
stationary phase) and how to determine antiviral activity using the standard
tests
described herein, or using other similar tests which are well known in the
art.
The compounds of the present invention are generally named according to the
IUPAC or CAS nomenclature system.
Abbreviations which are well known to one of ordinary skill in the art may be
used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for an hour
or hours
and "rt" for room temperature).
Specific and preferred values listed below for radicals, substituents, and
ranges,
are for illustration only; they do not exclude other defined values or other
values within
defined ranges for the radicals and substituents.
Specifically, alkyl denotes both straight and branched groups; but reference
to
an individual radical such as "propyl" embraces only the straight chain
radical, a
branched chain isomer such as "isopropyl" being specifically referred to.
Specifically, alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-
butyl,
and their isomeric forms thereof.
Specifically, alkenyl is vinyl, propenyl, allyl, butenyl, and their isomeric
forms
thereof.
Specifically, halo is fluoro (F), or chloro (Cl).
Specifically the present invention provides a compound of formula Ia
0
Ft~NI N~" ' ~ NAO
Y2-
W
Ia
-6-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
wherein Y' and.Y? are independently..CH.or_ CF; and W. is.CONHRZ or.
CHZNHCO(NH)Cl-6alkyl,
Specifically the present invention provides a compound of formula lb
0
R", N N~~ t\ N~O 2
/ Y2 NHR
O \-Y
O
Ib
wherein Y' and Y2 are independently CH or CF; R' is H or methyl; and R2 is H,
CH3,
or OCH3.
Examples of the present invention are:
(1) (5R)-3-[3-fluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-2-oxo-1,3-oxazolidine-
5-
carboxamide,
(2) (5R)-3-[3-fluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-N-methyl-2-oxo-1,3-
oxazolidine-5-carboxamide,
(3) (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-1-yl)phenyl]-2-oxo-1,3-
oxazolidine-5-carboxamide,
(4) 5R)-3-[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-1-yl)phenyl]-N-methyl-2-
oxo-1, 3 -oxazolidine- 5-carboxamide,
(5) (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-1,4-diazepan-1-yl)phenyl]-2-oxo-1,3-
oxazolidine-5-carboxamide,
(6) (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-1,4-diazepan-1-yl)phenyl]-N-methyl-
2-oxo-1,3-oxazolidine-5-carboxamide,
(7) (5R)-3-[3,5-difluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-2-oxo-1,3-
oxazolidine-5-carboxamide,
(8) (5R)-3-[3,5-difluoro-4-(5-oxo-l,4-diazepan-1-yl)phenyl]-N-methyl-2-oxo-1,3-
oxazolidine-5-carboxamide,
(9) 5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-1,4-diazepin-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxamide, or
(10) (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-1,4-diazepin-l-
yl)phenyl]-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide.
-7-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
Compounds ofthis invention can be prepared.in accordance with one or more
of the Schemes discussed below. All of the starting materials are either
commercially
available or can be prepared by procedures that would be well known to one of
ordinary skill in organic chemistry. The variables used in the Schemes are as
defined
below, or as in the summary of the invention or claims.
SCHEME I
t HO
JCN_)_NH2 Y2:Y3 Y2-Y3 jy
2 O
O
W,N~ Yl~ R~N~~ Y~~ ~
N-/ r-N O ~N-/ --N O H
Y2-Y3 ~O Q Y2:Y3 ~N-_FZ2
3 O 4 O
Scheme I describes the synthesis of the oxazolidinone ring with its C-5
1o carboxamide side chain, starting from commercially available aniline 1.
First, the
aniline 1 is reacted with an alkyl (2R)-epoxypropanoate and a Lewis acid such
as
ithium triflate (as described in US Patent Application Publication No. US
2004/0044052) to provide amino alcohol 2. Next the amino alcohol 2 is cyclized
to
give the aryl oxazolidinones 3 using methods known to one skilled in the art.
For
instance, treatment of intermediate 2 with 1;1'-carbonyldiimidazole in a
solvent such as
acetonitrile or tetrahydrofuran at an appropriate temperature, typically in a
range of 20
C to 80 C provides the oxazolidinone 3. Alternatively, reaction of 2 with
phosgene in
a solvent such as toluene or methylene chloride, or mixtures thereof, in the
presence of
a base such as triethylamine at an appropriate temperature, typically in a
range from -
10 C to 25 C, affords the oxazolidinone 3. The product may be used as
collected or
may first be purified using conventional techniques such as preparative TLC or
HPLC,
chromatography, precipitation, crystallization and the like.
Subsequent treatment of oxazolidinone ester 3 with ammonia or optionally
with substituted amines (R2NH2) in a suitable solvent such as methanol or
acetonitrile
affords amides 4(R2 = H or optionally substituted alkyl). Similarly, treatment
of ester
3 with O-alkylhydroxylamines provides hydroxamates (RZ = O-alkyl). The product
-8-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
may.be used as collected or.may.first.be.purified using conventional
techniques.such as
preparative TLC or HPLC, chromatography, precipitation, crystallization and
the like.
SCHEME II
H N"' Y~
H HN--~/ '~-NOZ --
O O Y2:Ys
5 6
~
R~N N~/ l~NO2 -- R\N N~~ 1-NH2
pikJ Y2=Y3 O/ Y2:Y3
7 8
Scheme II describes the synthesis of aniline intermediates 9 bearing the
diazepanone ring. The diazepanone 5 (for synthesis see Scheme III) is reacted
in a
nucleophilic aromatic substitution reaction with a fluoronitrobenzene (for
example,
Io with 3,4,-difluoronitrobenzene) to provide intermediates such as 6. Such
reactions are
well known those skilled in the art and review articles descnbing these
reactions are
available (see Zoltewicz in Top. Curr. Chem. 1975, vol. 59, pp. 33-64). These
transformations are generally performed at a temperature in a range from about
40 C
to about 90 C using polar aprotic solvents such as acetonitrile or
dimethylformamide
and in the presence of acid-scavenging bases such as triethylamine or N,N-
diisopropylethylamine. Intermediate 6 is then optionally alkylated on the
nitrogen
atom to form intermediate 7. For instance, reaction of 6 with methyl iodide
using
potassium hydroxide as a base and tetrabutylammonium bromide as a phase-
transfer
catalyst provides intermediate 7 where R1= methyl. Intermediate 7 is then
reduced to
provide the aniline intermediate 8. This reduction is generally accomplished
by
reacting 7 with reducing metals (for example with iron powder). The reaction
is
favorably carried out at temperatures in a range from about 60 C to about 90 C
in
mixtures of water and alcohol (methanol, ethanol, etc.) as solvent, and in the
presence
of ammonium chloride to buffer the reaction mixture. Optionally, reductions of
this
type are conducted by reaction with other metals such as tin or zinc or by
hydrogenation under palladium or platinum catalysis (see Rylander
Hydrogenation
Methods; Academic Press: New York, 1985, pp. 104-116). The product may be used
-9-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
as collected.or..may first be purified.using conventional,techniques such.as
preparative
TLC or HPLC, chromatography, precipitation, crystallization and the like.
Aniline
intermediates such as 9 can then be converted to oxazolidinone analogs as
described in
Scheme I.
SCHEME III.
Cbz HON~NCbz --~ HN' HN NH
0~~~~=' -=~ O~NCbz ' O--~
11 12 5
10 Scheme III describes the synthesis of the diazepanone heterocycle 5. This
compound may be prepared in three steps from commerically available piperidone
compounds such as benzyl 4-oxopiperidine-1-carboxylate (10, commercially
available)
or tert-butyl4-oxopiperidine-l-carboxylate. Reaction of 10 with hydroxylamine
in the
presence of molecular sieves (to remove water formed in the reaction) and in a
solvent
such as pyridine provides the oxime intermediate 11.
Next, intermediate 11 is converted to the protected diazepanone intermediate
12. This
reaction, known as the Beckmann rearrangement, is well known to those of
ordinary
skill in the art and may be accomplished under a variety of conditions (for a
review see
Gawley Organic Reactions, 1988, 35, pp 1-420). With intermediate 11, the
reaction is
favorably carried out with tosyl chloride to activate the oxime, and in
solvents such as
acetone, water, or mixtures thereof and in the presence of an acid scavenging
base
such as sodium carbonate. The product may be used as collected or may first be
purified using conventional techniques such as preparative TLC or HPLC,
chromatography, precipitation, crystallization and the like.
Finally, the protecting group (e.g., Cbz or Boc) is removed from intermediate
12 to provide the diazepanone 5. Removal of benzyl carbamate protection is
favorably
accomplished by hydrogenolysis, typically employing a palladium catalyst under
an
atmosphere of hydrogen gas and using solvents such as ethyl acetate, alcohols,
or
mixtures thereof. Cleavage of tert-butyl carbamates is typically accomplished
by
treatment with acids such as hydrochloric acid or trifluoroacetic acid. If
less harsh
conditions are required, treatement with trimethylsilyltrifluoromethane
sulfonate and
-10-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
2,6-lutidine. (as. described by Ohfune, Y. and Sakaitani,.M... J..Org. Chem.
_19.90, 55,
870-876) is also effective. The diazepanone 5 may then be employed in the
synthesis
of final analogs as outlined in Schemes I and II.
SCHEME IV
_
Y' HO Yi'
O~ JJ ~\ NHCbz s N\ NHCbz
v Y3 ~~~/// ~.3
13 14
HN'---\ Y'-
--~ N--CY NHCbz
3
R5\ /~
N \ Yi :/>-NHCbz R5\ N~ Y1-
QY3-~ J N-~\ NHz
Q Y~
16 17
Scheme IV outlines the synthesis of aniline intermediates bearing a
tetrahydrodiazepinone ring. The starting materials employed are
dihydropyridone
lo intermediates such as 13 (prepared as descnbed in the PCT publication
W02004/033449). Reaction of 13 with hydroxylamine as described above in Scheme
III provides the oxime intermediate 14. Next, oxime intermediate 14 is
converted to
the protected diazepanone intermediate 15 using a Beckmann rearrangement
reaction
as described above in Scheme III. Intermediate 15 is then optionally converted
to the
15 intermediate 16 in which the nitrogen atom of the heterocyclic ring has
been alkylated.
Finally, the carbamate function of intermediate 16 is removed to provide the
desired
aniline intermediate 17. The reaction conditions for this step will depend
upon the type
of carbamate employed (for example, a benzyl carbamate is favorably removed by
hydrogenolysis as described above in Scheme III). Intermediate 17 may then be
used in
the synthesis of oxazolidinone analogs as described in Scheme I.
Schemes V-VIII describe the synthesis of aryl isoxazolinone, aryl isoxazoline
and aryl butyrolactone compounds bearing diazepanone and related heterocyclic
rings
of the type described in Schemes I-VII. The following schemes describe general
methods to prepare claimed structures in which A is (ii), (iii), or (iv). The
diazepanone
and related heterocycles may be prepared as described above in Schemes I-VII
but it
-11-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
will be understood by'.those of.ordinary. skill in the art.that suitable.
protecting groups
may be required to protect and later reveal sensitive functional groups.
Scheme V summarizes the synthesis of the requisite substituted benzaldehyde
intermediates. The general methods described in the previous Schemes are
applicable
but with the use of fluorinated benzonitrile (29) or benzoate ester starting
materials in
the place of fluorinated nitrobenzenes. The required starting materials (e.g.,
3,4,5-
trifluorobenzonitrile) are commercially available. Conversion of these
starting
materials to intermediate 30 is accomplished in a series of steps using the
same
methods described in Schemes II-IV for the preparation of aniline
intermediates.
lo Intermediate 30 is then converted to the benzaldehyde intermediate 31 using
methods
that are well known to those of ordinary skill in the art, for example by
reduction to
the imine with SnC12/HCl followed by hydrolysis (Stephen aldehyde synthesis).
SCHEME V
F\'~ '\ 3~
Y' Q~ Y Q Y
29 30 31
Scheme VI describes the preparation of aryl isoxazolinone analogs. The first
step involves reaction of benzaldehyde intermediate 31 with ethyl diazoacetate
(as
described by Mahmood et al. in J. Org. Chem., 1998, 63, 3333-3336) to provide
the
ester aldehyde intermediate 32. Reaction of this material with hydroxylamine,
followed by warming to reflux in aqueous methanol forms the isoxazolinone ring
and
intermediate 33. This intermediate is then converted to the corresponding
methylacetamide 34 by reaction with N-(hydroxymethyl)acetanude acetate
(prepared as
described by Barnes et al. in US Patent 5,284,863) in a polar aprotic solvent
such as
DMF.
-12-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
SCHEME VI
Yi ~O v~ Yi- O
Z1 ~Y3~ Z, O 30
31 H
32
O 0
Zl l Z2 \ Y
QA\_JZ' Y3) H o~ Z' ~Y3 / ~ 1 vN
33 O
34
Scheme VII describes a general method for preparing aryl isoxazoline
compounds bearing diazepanone or related heterocycles of the type described in
the
Schemes above. In the first step of Scheme X the benzaldehyde intermediate 31
is
reacted with hydroxylamine hydrochloride in a polar protic solvent, such as
methanol,
in the presence of a base, such as pyridine, to afford the oxime intermediate
35. The
oxime 35 is then oxidized with N-chlorosuccinimide (NCS) in an appropriate
solvent,
such as dichloromethane, to give the hydroximinoyl chloride intermediate 36.
This
material is then reacted with an alkene, for example with allyl alcohol, in
the presence
of a base such as triethylamine and in a solvent such as dichloromethane, to
provide the
hydroxymethyl-substituted isoxazoline 37. The hydroxymethyl function of 37 may
then
be converted to acetamidomethyl or related moieties (e.g. 38, where R' = Et,
OMe,
etc.) using established synthetic procedures (for example, as described in US
PCT
publication US2004/0127530) to provide 38. Alternatively, the hydroximinoyl
chloride 36 may be reacted with 1V-acetylallylamine to directly provide
acetamidomethyl-substituted isoxazoline products (38, W = 0 and R' = Me).
Optionally, the hydroximinoyl chloride intermediate may be formed in situ as
described
above and then directly treated with the alkenes to generate the isoxazoline
intermediates directly from 35.
-13-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
SCHEME. VII
Z2 Y' +_
O Zz~ Z2~ Y OH
/
QZ Y3 / -~ Z+ y3 ~ H-OH-' Q~Z+~Y3 / CI
35 36
Z ZZ~ Y+ / H
QZ+~OH Q"~'Z+~Y3~N R'
y
37 W
38
Scheme VIII describes the synthesis of aryl butyrolactone analogs such as 42.
The synthesis of the saturated (as in 41) and unsaturated (as in 42) 3-
arylbutyrolactone
ring system is described in the literature (for example, see Bioorganic &
Medicinal
Chemistry Letters, 1994, 4, 1925-1930). Aldehyde intermediate 31 is converted
to
phenyl acetic acid intermediate 39 using established procedures (for example
as
described by Hester, et al. in US Patent 5,708,169). The dianion of 39 is then
reacted
with R-benzyloxymethyloxirane in THF. The resulting hydroxyacid is cyclized
under
acid catalysis (for example, using p-toluenesulfonic acid) to provide lactone
40. The
benzyl group is then removed by hydrogenolysis and the resulting hydroxymethyl
function converted to acetamidomethyl or related moieties (e.g. 41, where R' =
Et,
OMe, etc.) using established synthetic procedures (for example, as described
in US
PCT publication US2004/0127530) to provide 41. Finally the butyrolactone is
oxidized using a two-step protocol involving bromination (using for example 1V-
bromosuccinimide) and subsequent elimination by treatment with a suitable base
such
as pyridine or DBU to provide 42.
SCHEME VIII
Q
Y+_ 0 ZZ Y+_ Z_/\ Y+_
Z+~Y~ Q~ZiYOH Q __I\Z+ OBn --
0
39 40
O O
Y+ Y_
Z2 Z~ +
Q~Z+Y H NyR, -s Q( -r~ ~ b N~R'
41 W ~ ~,42 W
-14-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
Medical and Veterinaa Uses
The compounds of the present invention may be used for the treatment of
infectious diseases caused by a variety of bacterial organisms.
Examples include gram-positive bacteria such as multiple resistant
staphylococci, for example S. aureus and S. epidermidis; multiple resistant
streptococci, for example S. pneumoniae and S. pyogenes; and multiple
resistant
Enterococci, for example E. faecalis; gram negative aerobic bacteria such as
Haemophilus, for exarnple H. influenzae and Moraxella, for example M.
catarrhalis; as
well as anaerobic organisms such as bacteroides and clostridia species, and
acid-fast
organisms such as Mycobacteria, for exainple M. tuberculosis; and/or
Mycobacterium
avium. Other examples include Escherichia, for example E. coli. intercellular
microbes, for example Chlanrydia and Rickettsiae.
Examples of infections that may be treated with the compounds of the present
invention include central nervous system infections, external ear infections,
infections
of the middle ear, such as acute otitis media, infections of the cranial
sinuses, eye
infections, infections of the oral cavity, such as infections of the teeth,
gums and
mucosa, upper respiratory tract infections, lower respiratory tract
infections,
genitourinary infections, gastrointestinal infections, gynecological
infections,
septicemia, bone and joint infections, skin and skin structure infections,
bacterial
2o endocarditis, burns, antibacterial prophylaxis of surgery, and
antibacterial prophylaxis
in immunosuppressed patients, such as patients receiving cancer chemotherapy,
or
organ transplant patients. Specifically, infectious diseases that may be
treated with the
compounds of the present invention are gram-positive infections such as
osteomyelitis,
endocarditis and diabetic foot.
Antibacterial activitv
The in vitro antibacterial activity of the compounds of the present invention
may be assessed by following procedures recommended in (1) National Committee
for
Clinical Laboratory Standards (Jan. 2003), Methods for dilution antimicrobial
tests
for bacteria that grow aerobically, Approved Standard (6Ih ed), M7-A6, NCCLS,
Wayne, PA; (2) National Committee for Clinical Laboratory Standards (Mar.
2001),
Methods for antimicrobial susceptibility testing of anaerobic bacteria,
Approved
Standard (5th ed), M11-A4, NCCLS, Wayne, PA; (3) National Committee for
Clinical
Laboratory Standards (Jan.2003), MIC testing supplemental tables, M100-S13
(for
-15-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
use with M7-A6), NCCLS, Wayne, PA; and (4) Murray PR, Baron EJ, Jorgensen JH,
et al. Manual of Clinical Microbiology (81" ed) Washington, DC: American
Society
for Microbiology Press, 2003. The antibacterial activity can be presented in
the form
of MIC value. The MIC value is the lowest concentration of drug which
prevented
macroscopically visible growth under the conditions of the test. The test
result is
shown in Table 1.
Table 1
(Minimum Inhibitorv concentrations ( /mLl
Example S. S. p,voeenes S. pneumoniae
aureus (C203) SV-1
(UC-76)
1 4 4 8
2 8 4 8
3 8 8 16
4 8 8 8
5 8 4 8
6 8 4 8
7 4 2 4
8 4 4 4
9 4 2 16
8 4 16
Pharmaceutical Salts
The compound of forrnula I may be used in its native form or as a salt. In
cases
where forming a stable nontoxic acid or base salt is' desired, administration
of the
compound as a pharmaceutically acceptable salt may be appropriate. Examples of
pharmaceutically acceptable salts of the present invention include inorganic
salts such
as hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, carbonate
salts, and
organic salts such as tosylate, methanesulfonate, acetate, citrate, malonate,
tartarate,
succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate.
Pharmaceutically acceptable salts may be obtained using standard procedures
well known in the art, for example, reacting a sufficiently basic compound
such as an
-16-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
amine with a suitable acid affording a physiologically.acceptable_ anion..
Alkali metal
(for example, sodium, potassium or lithium) or alkaline earth metal (for
example
calcium) salts of carboxylic acids can also be made.
Routes of Administration
In therapeutic use for treating, or combating, bacterial infections in a
mammal
(i.e. human and animals), a compound of the present invention or its
pharmaceutical
compositions can be administered orally, parenterally, topically, rectally,
transmucosally, or intestinally.
Parenteral administrations include indirect injections to generate a systemic
effect or direct injections to the afflicted area. Examples of parenteral
administrations
are subcutaneous, intravenous, intramuscular, intradermal, intrathecal,
intraocular,
intranasal, intravetricular injections or infusions techniques.
Topical administrations include the treatment of infectious areas or organs
readily accessibly by local application, such as, for example, eyes, ears
including
external and middle ear infections, vaginal, open wound, skins including the
surface
skin and the underneath dermal structures, or other lower intestinal tract. It
also
includes transdermal delivery to generate a systemic effect.
The rectal administration includes the form of suppositories.
The transmucosal administration includes nasal aerosol or inhalation
applications.
The preferred routes of administration are oral and parenteral.
Composition/Formulation
Pharmaceutical compositions of the present invention may be manufactured by
processes well known in the art, e.g., by means of conventional mixing,
dissolving,
granulation, dragee-making, levigating, emulsifying, encapsulating,
entrapping,
lyophilizing processes or spray drying.
Pharmaceutical compositions for use in accordance with the present invention
may be forrnulated in conventional manner using one or more physiologically
acceptable carriers comprising excipients and auxiliaries which facilitate
processing of
the active compounds into preparations which can be used pharmaceutically.
Proper
formulation is dependent upon the route of administration chosen.
For oral administration, the compounds can be forrnulated by combining the
active compounds with pharmaceutically acceptable carriers well known in the
art.
-17-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
Such carriers enable the compou.nds. of theinvention to.be._formulated.as.
tablets, pills,
lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups,
slurries,
suspensions and the like, for oral ingestion by a patient. A carrier can be at
least one
substance which may also function as a diluent, flavoring agent, solubilizer,
lubricant,
suspending agent, binder, tablet disintegrating agent, and encapsulating
agent.
Examples of such carriers or excipients include, but are not limited to,
magnesium
carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin,
mannitol,
sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa
butter or
powder, polymers such as polyethylene glycols and other pharmaceutical
acceptable
materials.
Dragee cores are provided with suitable coatings. For this purpose,
concentrated sugar solutions may be used which may optionally contain gum
arabic,
talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide,
lacquer solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or
pigments may be added to the tablets or dragee coatings for identification or
to
characterize different combinations of active compound doses.
Pharmaceutical compositions which can be used orally include push-fit capsules
made of gelatin, as well as soft, sealed capsules made of gelatin and a
plasticizer, such
as glycerol or sorbitol. The push-fit capsules can contain the active
ingredients in
admixture with a filler such as lactose, a binder such as starch, and/or a
lubricant such
as talc or magnesium stearate and, optionally, stabilizers. In soft capsules,
the active
compounds may be dissolved or suspended in suitable liquids, such as fatty
oils, liquid
paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain
mono-,
di- or triglycerides. Stabilizers may be added in these formulations, also.
Liquid form compositions include solutions, suspensions and emulsions. For
example, there may be provided solutions of the compounds of this invention
dissolved
in water and water-propylene glycol and water-polyethylene glycol systems,
optionally
containing suitable conventional coloring agents, flavoring agents,
stabilizers and
thickening agents.
The compounds may also be formulated for parenteral administration, e.g., by
injections, bolus injection or continuous infusion. Formulations for
parenteral
-18-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
administration may.be presented in.unit dosage form, e.g.,.in ampoules or,in
multi-dose
containers, with an added preservative. The compositions may take such forms
as
suspensions, solutions or emulsions in oily or aqueous vehicles, and may
contain
formulating materials such as suspending, stabilizing and/or dispersing
agents.
For injection, the compounds of the invention may be formulated in aqueous
solution, preferably in physiologically compatible buffers or physiological
saline buffer.
Suitable buffering agents include trisodium orthophosphate, sodium
bicarbonate,
sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine.
Parenteral administrations also include aqueous solutions of a water soluble
1o form, such as, without limitation, a salt, of the active compound.
Additionally,
suspensions of the active compounds may be prepared in a lipophilic vehicle.
Suitable
lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty
acid esters such
as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous
injection
suspensions may contain substances which increase the viscosity of the
suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the
suspension may also contain suitable stabilizers and/or agents that increase
the
solubility of the compounds to allow for the preparation of highly
concentrated
solutions.
Alternatively, the active ingredient may be in powder form for constitution
with
a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For suppository administration, the compounds may also be formulated by mixing
the
agent with a suitable non-irritating excipient which is solid at room
temperature but
liquid at rectal temperature and therefore will melt in the rectum to release
the drug.
Such materials include cocoa butter, beeswax and other glycerides.
For administration by inhalation, compounds of the present invention can be
conveniently delivered through an aerosol spray in the form of solution, dry
powder, or
suspensions. The aerosol may use a pressurized pack or a nebulizer and a
suitable
propellant. In the case of a pressurized aerosol, the dosage unit may be
controlled by
providing a valve to deliver a metered amount. Capsules and cartridges of, for
example, gelatin for use in an inhaler may be forrnulated containing a power
base such
as lactose or starch.
For topical applications, the pharmaceutical composition may be formulated in
a suitable ointment containing the active component suspended or dissolved in
one or
-19-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
more carriers. Carriers for topical administration of the compounds of this
invention
include, but are not limited to, mineral oil, liquid petrolatum, white
petrolatum,
propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax
and
water. Alternatively, the pharmaceutical compositions can be formulated in a
suitable
lotion such as suspensions, emulsion, or cream containing the active
components
suspended or dissolved in one or more pharmaceutically acceptable carriers.
Suitable
carriers include, but are not limited to, mineral oil, sorbitan monostearate,
polysorbate
60, cetyl esters wax, ceteary alcohol, 2-octyldodecanol, benzyl alcohol and
water.
For ophthalmic and otitis uses, the pharmaceutical compositions may be
Io formulated as micronized suspensions in isotonic, pH adjusted sterile
saline, or
preferably, as solutions in isotonic, pH adjusted sterile saline, either with
or without a
preservative such as a benzylalkonium chloride. Alternatively, for ophthalmic
uses, the
pharmaceutical compositions may be forrnulated in an ointment such as
petrolatum.
In addition to the formulations described previously, the compounds may also
be formulated as depot preparations. Such long acting formulations may be in
the
form of implants. A compound of this invention may be formulated for this
route of
administration with suitable polymers, hydrophobic materials, or as a sparing
soluble
derivative such as, without limitation, a sparingly soluble salt.
Additionally, the compounds may be delivered using a sustained-release
system. Various sustained-release materials have been established and are well
known
by those skilled in the art. Sustained-release capsules may, depending on
their
chemical nature, release the compounds for 24 hours or for up to several days.
Dosage
Pharmaceutical compositions suitable for use in the present invention include
compositions wherein the active ingredients are contained in an amount
sufficient to
achieve the intended purpose, i.e., the treatment or prevent of infectious
diseases.
More specifically, a therapeutically effective amount means an amount of
compound
effective to prevent, alleviate or ameliorate symptoms of disease or prolong
the
survival of the subject being treated.
The quantity of active component, that is the compou.nd of this invention, in
the
pharmaceutical composition and unit dosage form thereof may be varied or
adjusted
widely depending upon the manner of administration, the potency of the
particular
compound and the desired concentration. Determination of a therapeutically
effective
-20-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
amount is-well within the capability of those-skilled in the art.
Generally,the quantity
of active component will range between 0.5% to 90% by weight of the
composition.
Generally, a therapeutically effective amount of dosage of active component
will be in the range of about 0.1 to about 400 mg/kg of body weight/day, more
preferably about 1.0 to about 50 mg/kg of body weight/day. It is to be
understood that
the dosages may vary depending upon the requirements of each subject and the
severity of the bacterial infection being treated. In average, the effective
amount of
active component is about 200 mg to 800 mg and preferable 600 mg per day.
The desired dose may conveniently be presented in a single dose or as divided
doses administered at appropriate intervals, for example, as two, three, four
or more
sub-doses per day. The sub-dose itself may be further divided, e.g., into a
number of
discrete loosely spaced administrations; such as multiple inhalations from an
insufflator
or by application of a plurality of drops into the eye.
Also, it is to be understood that the initial dosage administered may be
increased beyond the above upper level in order to rapidly achieve the desired
plasma
concentration. On the other hand, the initial dosage may be smaller than the
optimum
and the daily dosage may be progressively increased during the course of
treatment
depending on the particular situation. If desired, the daily dose may also be
divided
into multiple doses for administration, e.g., two to four times per day.
In cases of local administration or selective uptake, the effective local
concentration of the drug may not be related to plasma concentration and other
procedures know in the art may be used to determine the desired dosage amount.
Oral Efficacy
EXAMPLES
In the discussion above and in the examples below, the following abbreviations
have the following meanings. If an abbreviation is not defined, it has its
generally
accepted meaning.
bm = broad multiplet
BOC = tert-butoxycarbonyl
bd = broad doublet
bs = broad singlet
bt = broad triplet
CDI = 1, 1 0-carbodiimidazole
d = doublet
-21-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
dd = . doublet of doublets
dq = doublet of quartets
dt = doublet of triplets
dm = doublet of multiplets
DMF = dimethylformamide
DMAP = dimethylaminopyridine
DIEA = diisopropylethylamine
DMSO = dimethyl sulfoxide
eq. = equivalents
g = grams
h = hours
HPLC = high pressure liquid chromatography
HATU = N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-
1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate N-oxide
LG = leaving group
m = multiplet
M = molar
M% = mole percent
max = maximum
meq = milliequivalent
mg = milligram
mL = milliliter
mm = millimeter
nirnol = millimol
q = quartet
s = singlet
t or tr = triplet
TBS = tributylsilyl
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
p-TLC = preparative thin layer chromatography
L = microliter
N = normality
MeOH = methanol
DCM = dichloromethane
HCl = hydrochloric acid
ACN = acetonitrile
MS = mass spectrometry
rt = room temperature
EtOAc = ethyl acetate
EtO = ethoxy
Ac = acetate
NMP = 1 -methyl-2-pyrrolidinone
L = microliter
J = coupling constant
NMR = Nuclear magnetic resonance
MHz = megahertz
Hz = hertz
-22-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
rn/z = mass to charge ratio
min = minutes
Boc = tert-butoxycarbonyl
CBZ = benzyloxycarbonyl
DCC = 1,3-dicyclohexylcarbodiimide
PyBop = benzotriazole-l-yl-oxy-trispyrrolidinophosphonium
hexafluorophosphate
Example 1 Preparation of (5R)-3-[3-fluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-2-
oxo-1,3-oxazolidine-5-carboxamide
0
H0+-b NHZ
To a suspension of methyl (5R)-3-[3-fluoro-4-(5-oxo-1,4-diazepan-1-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (0.14 g, 0.40 nunol) in
methanol (5
mL) at 23 C is added methanolic ammonia solution (5.0 mL, 2.0 M). The
suspension is
stirred at the same temperature for lh, concentrated, and purified by
preparative TLC
(6% MeOH-CHZCl2), to afford the title compound.
HPLC (SYIVIlVIETRY C18 3.5 M, 4.6 x 30 mm column; gradient elution 2%-
98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.39 min
1H NMR (300 MHz, DMSO-d6): 2.59 (m, 2H), 3.09 (m, 4H), 3.25 (m, 2H),
3.95 (m, 1 H), 4.22 (t, J=9.3 Hz, 1H), 5.0 (m, 1H), 7.09 (t, J=9.0 Hz, 1 H),
7.20 (d,
J=8.7 Hz 1H), 7.48 (d, J=14.9 Hz, 1H), 7.60 (s, 1H), 7.67 (m, 1H), 7.84 (s,
1H).
Intermediates for the preparation of example 1 are synthesized as follows.
I. Preparation of tert-butyl4-(hydroxyimino)piperidine-l-carboxylate
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (50 g, 251 mmol) in
pyridine (500 mL) is added molecular sieves (50 g) and the mixture is stirred
at room
temperature for 10 minutes, followed by the addition of NH2OH.HCI (30.25 g,
427
ntmol). The resulting reaction is stirred at room temperature overnight, and
the
reaction mixture filtered through a pad of celite to remove the molecular
sieves. The
filtrate is diluted with water, the layers separated and the aqueous phase
extracted with
more ethyl acetate. The combined organic phases are washed with brine, dried
over
- 23 -
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
MgSO4, filtered, and concentrated in vacuo to provide the title compound..This
material is used in the next step without further purification.
1H NMR (300 MHz, DMSO-d6): 1.52 (s, 9H), 2.36 (t, J=6.0 Hz, 2H), 2.58 (t,
J=6.0 Hz, 2H), 3.50-3.58 (m, 4H).
II. Preparation of tert-butyl 5-oxo-1,4-diazepane-l-carboxylate
To a solution of tert-butyl4-(hydroxyimino)piperidine-l-carboxylate (1.0 g,
4.67 mmol) in acetone (20 mL) is added a solution of Na2CO3 (1.48 g, 14 mmol)
in
water (20 mL), and the mixture is stirred for 5 minutes, then a solution of p-
toluenesulfonyl chloride (1.33 g, 7 mmol) in acetone (5 mL) is added slowly.
The
reaction is stirred at room temperature for 3h, then the acetone is removed in
vacuo,
water is added, and the solution extracted with dichloromethane. The organic
layer is
dried over MgSO4, filtered, concentrated in vacuo, and purified by
chromatography
(6% MeOH in dichloromethane) to afford the title compound.
'H NMR (300 MHz, DMSO-d6): 1.41 (s, 9H), 2.40 (m, 2H), 3.09 (m, 2H),
3.39-3.44 (m, 4H), 7.62 (m, 1H).
III. Preparation of 1,4-diazepan-5-one
A solution of HCl (20 mL, 2M in dioxane) is added to tert-butyl 5-oxo-1,4-
diazepane-l-carboxylate (1.0 g, 4.67 mmol) and the reaction mixture is stirred
at room
temperature for 2h. The solvent is removed in vacuo to afford the title
compound as
the hydrochloride salt, which is used without further purification in the next
step.
1H NMR (300 MHz, DMSO-d6): 2.36 (m, 2H), 2.65-2.72 (m, 4H), 3.05 (m,
2H), 3.17 (s, 1H), 7.47 (s, 1H).
IV. Preparation of 1-(2-fluoro-4-nitrophenyl)-1,4-diazepan-5-one
To a solution of 1,4-diazepan-5-one (3.25 g, 28.5 mmol) in acetonitrile (30
mL) is added N,N-diisopropylethylamine (24.8 mL, 142 mmol), followed by 3,4-
difluoronitrobenzene (3.5 mL, 31.3 mmol). The reaction mixture is heated to 70
C
overnight, cooled to room temperature, and the solvent removed in vacuo. Then
dichloromethane is added and the solution washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo to afford the title compound. This
material is used
directly in the next step without fiurther purification.
'H NMR (300 MHz, DMSO-d6): 2.62 (m, 2H), 3.30 (m, 2H), 3.47-3.55 (m,
4H), 7.08-7.14 (m, 1H), 7.67 (m, 1H), 7.94-8.02 (m, 2H).
V. Preparation of 1-(4-amino-2-fluorophenyl)-1,4-diazepan-5-one
-24-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
..To a solution of 1-(2-fluoro-4-nitrophenyl)-1,4-diazepan-5-one,(6.5_g, 25.7
mmol) and NHaCI powder (13.7 g, 257 mmol) in EtOH:H20 (2:1,200 mL) is heated
to 95 C, and treated with iron powder (4.3 g, 77 mmol) in portions over one
hour.
The reaction mixture is then stirred at 95 C for 2.5 hours, cooled to room
temperature, and filtered through a pad of celite with the aid of
dichloromethane. The
filtrate is concentrated, and the residue taken into dichloromethane and
water. The
layers are separated and the organic layer is dried over MgSO4i filtered, and
concentrated to afford the title compound which is used directly in the next
step
without further purification.
'H NMR (300 MHz, DMSO-d6): 2.52 (m, 2H), 2.88-2.91 (m, 4H), 3.18 (m,
211), 5.07 (s, 211), 6.25-6.34 (m, 2H), 6.79 (m, 1 H), 7.63 (m, 1 H).
VI. Preparation of methyl (2R)-3-{[3-fluoro-4-(5-oxo-1,4-diazepan-l-
yl) phenyl] amino } -2-hydroxypropano ate
To a solution of 1-(4-amino-2-fluorophenyl)-1,4-diazepan-5-one (500 mg, 2.24
mtnol) in acetonitrile (5 mL) at 23 C is added Lithium triflate (380 mg, 2.46
mmol),
followed by (R)-methyl glycidate (0.22 mL, 2.46 mmol). The reaction mixture is
then
stirred at 60 C for 20h and treated with additional (R)-methyl glycidate (0.06
mL, 0.67
mmol). After another day at 60 C, the reaction mixture is cooled to 23 C,
concentrated, and the residue purified by chromatography on a silica gel
column,
eluting with a gradient increasing in polarity from 2% to 5% MeOH in
dichloromethane. Relevant fractions are combined and concentrated to afford
the title
compound.
'H NMR (300 MHz, DMSO-d6): 2.51 (m, 211), 2.89-2.93 (m, 4H), 3.12-3.19
(m, 3H), 3.61 (s, 3H), 4.09 (m, 1H), 4.17 (m, 1H), 5.61 (m, 1H), 5.68 (d, c, 1
H),
6.25-6.43 (m, 2H), 6.79-6.89 (m, 1 H), 7.63 (m, 1 H).
VII. Preparation of methyl (5R)-3-[3-fluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-
2-
oxo-1, 3 -oxazolidine-5 -carboxylate
To a mixture of methyl (2R)-3-{[3-fluoro-4-(5-oxo-1,4-diazepan-l-
yl)phenyl]amino}-2-hydroxypropanoate (0.40 g, 1.23 mmol) and 1,1'-
carbonyldiimidazole (0.31 g, 1.84 mmol) at 23 C is added acetonitrile (15 mL).
The
resulting mixture is stirred at 50 C overnight and then cooled to 23 C and
concentrated. The residue is taken into ethyl acetate (300 mL), washed with
0.5 M
aqueous HCI, brine, and dried (Na2SO4), filtered, concentrated. The residue is
purified
- 25 -
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
by chromatography on a silica gel column, eluting. with a gradient increasing
in polarity
from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined to
afford
the title compound.
'H NMR (300 MHz, DMSO-d6): 2.57 (m, 2H), 3.06 (m, 4H), 3.27 (m, 2H),
3.75 (s, 3H), 4.12 (m, 1H), 4.32 (t, J=9.6 Hz, 1H), 5.30 (m, 1H), 7.09 (t,
J=9.0 Hz,
1 H), 7.20 (m, 1H), 7.43-7.48 (m, 1 H), 7.66 (m, IH).
Example 2 Preparation of (5R)-3-[3-fluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-N-
methyl-2-oxo-1,3-oxazolidine-5-carboxamide
O N,
*b-z H
O
Following the procedure in Example 1 and under analogous conditions, methyl
(5R)-3-[3-fluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-2-oxo-1,3-oxazolidine-5-
carboxylate (0.14 g, 0.40 mmol) is treated with methanolic methylamine
solution (5.0
mL, 2.0 M). The suspension is stirred at the same temperature for lh,
concentrated,
and the residue purified by preparative TLC (6% MeOH/CH2C12) to afford the
title
compound.
HPLC (SY1V11VD?TRY C18 3.5 M, 4.6 x 30 mm column; gradient elution 2%-
98% MeCN with 0.1 % TFA over 5 min; 2 mL/min rate): retention time = 1.48 min
1H NMR (300 MHz, DMSO-d6): 2.56 (m, 2H), 2.64 (d, J=4.8 Hz, 3H), 3.09
(m, 4H), 3.25 (m, 2H), 3.96 (m, 1 H), 4.23 (t, .1=9.3 Hz, 1 H), 5.04 (m, 1 H),
7.09 (t,
J=9.3 Hz, 1H), 7.20 (d, J=8.7 Hz 1H), 7.45-7.51 (m, 1H), 7.67 (m, 1H), 8.36
(s, 1H).
Example 3 Preparation of (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxamide
~
O b NH2
O
-26-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
To a suspension of methyl (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (0.15 g, 0.41 mmol) in methanol
(4
mL) at 23 C is added methanolic ammonia solution (4.0 mL, 2.0 M). The
suspension is
stirred at the same temperature for 2h, concentrated, and the residue purified
by
preparative TLC (6% MeOH/CH2C12) to afford the title compound.
HPLC (SYMMETRY C18 3.5 M, 4.6 x 30 nun column; gradient elution 2%-
98% MeCN with 0.1 lo TFA over 5 min; 2 mL/min rate): retention time = 1.53 min
'H NMR (300 MHz, DMSO-d6): 2.66 (m, 2H), 2.88 (s, 3H), 3.06-3.13 (m,
4H), 3.56 (m, 2H), 3.96 (m, IH), 4.22 (t, .7=9.6 Hz, 1 H), 5.0 (m, 1 H), 7.08
(t, J=8.7
1 o Hz, 1 H), 7.19-7.22 (m, 1 H), 7.46-7.52 (m, 1 H), 7.60 (s, 1H), 7.94 (s, 1
H).
Intermediates for the preparation of example 3 are synthesized as follows: -
1. Preparation of 1-(2-fluoro-4-nitrophenyl)-4-methyl-1,4-diazepan-5-one
To a mixture of powdered KOH (1.16 g, 20.7 mmol) and tetrabutylammonium
bromide (0.91 g, 2.76 mmol) in THF (250 mL) is added a solution of 1-(2-fluoro-
4-
nitrophenyl)-1,4-diazepan-5-one (3.5 g, 13.8 nunol) and methyl iodide (1.3 mL,
20.7
mmol) in THF (40 mL). The resulting reaction mixture is kept at room
temperature
overnight, diluted with ethyl acetate, and washed with water and brine, and
dried
(MgSOa), filtered, and concentrated. The residue is purified by column
chromatography (2% MeOH in dichloromethane) to afford the title compound.
'H NMR (300 MHz, DMSO-d6): 2.74 (m, 2H), 2.85 (s, 3H), 3.46-3.52 (m,
4H), 3.61 (m, 2H), 7.07-7.13 (m, 1H), 7.95-8.02 (m, 2H).
II. Preparation of 1-(4-amino-2-fluorophenyl)-4-methyl-1,4-diazepan-5-one
A solution of 1-(2-fluoro-4-nitrophenyl)-4-methyl-1,4-diazepan-5-one (1.75 g,
6.55 mmol) and NHaC1(3.5 g, 65.5 mmol) in ethanol-HZO (2:1, 125 mL) is heated
to
95 C, and then treated with iron powder (1. l g, 19.6 mmol) in portions over
one
hour. The reaction mixture is stirred at 95 C for 4h, cooled to room
temperature, and
filtered through a pad of celite, with the aid of dichloromethane. The solvent
is
removed in vacuo, and dichloromethane and water are added. The layers are
separated
3o and the organic layer is dried over MgSOa, filtered, and concentrated in
vacuo to
afford the title compound. This material is used directly in the next step
without
further purification.
-27-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
.1H NMR.(300 . MHz,. DMSO-d6): -2.59-2.63 (m, 211), 2.86..(s, 3H),..2.89-2.94
(m, 4H), 3.50 (m, 2H), 5.04 (s, 2H), 6.25-6.33 (m, 2H), 6.79 (t, J=9.9 Hz,
1H).
III. Preparation of methyl (2R)-3-{[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl] amino } -2-hydroxypropanoate
To a solution of 1-(4-amino-2-fluorophenyl)-4-methyl-1,4-diazepan-5-one
(1.47 g, 6.19 mmol) in acetonitrile (15 mL) at 23 C is added Lithium triflate
(1.16 g,
7.43 mmol), followed by (R)-methyl glycidate (0.65 mL, 7.43 mmol). The
reaction
mixture is stirred at 65 C for 2 days, cooled to 23 C, concentrated, and
purified by
chromatography on a silica gel column, eluting with a gradient increasing in
polarity
lo from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and
concentrated to afford the title compound.
MS (m/z): [M+Na]+ = 362.3
IV. Preparation of methyl (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate
To a mixture of methyl (2R)-3-{[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl]amino}-2-hydroxypropanoate (1.0 g, 2.95 mmol) and 1,1'-
carbonyldiimidazole (0.74 g, 4.42 mmol) is added acetonitrile (20 mL). The
resulting
mixture is stirred at 50 C overnight, cooled to 23 C, and concentrated in
vacuo. The
residue is taken into ethyl acetate (300 mL), washed with 0.5 M aqueous HCI,
brine,
and dried (NaZS04), filtered, and concentrated. The residue is purified by
chromatography on a silica gel colurrm, eluting with a gradient increasing in
polarity
from 2% to 5% MeOH in dichloromethane. Relevant fractions are combined and
concentrated to afford the title compound.
'H N1VIR (300 MHz, DMSO-d6): 2.66 (m, 2H), 2.88 (s, 3H), 3.07-3.15 (m,
4H), 3.56 (m, 2H), 3.75 (s, 3H), 4.13 (m, 1H), 4.32 (t, J=9.6 Hz, 1H), 5.30
(m, 1H),
7.09 (t, J=9.0 Hz, 1H), 7.19-7.23 (m, 1H), 7.43-7.49 (m, 1H).
Example 4 Preparation of (5R)-3-[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl] -N-methyl-2-oxo-1,3 -oxazolidine-5-carboxamide
o~ N.
0
-28-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
Following the procedure in_Example 3 and under_analogous conditions, methyl
(5R)-3-[3-fluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-yl)phenyl]-2-oxo-l,3-
oxazolidine-
5-carboxylate (0.15 g, 0.41 mmol) is treated with methanolic methylamine
solution
(4.0 mL, 2.0 M. The suspension is stirred at the same temperature for 2h,
concentrated, and purified by preparative TLC (6% MeOH-CHZCl2), to afford the
title
compound.
HPLC (SYIVIMI?TRY C18 3.5 M, 4.6 x 30 nun column; gradient elution 2%-
98% MeCN with 0.1 % TFA over 5 min; 2 mL/min rate): retention time = 1.64 min
'H NMR (300 MHz, DMSO-d6): 2.64 (d, J=4.5 Hz, 3H), 2.68 (m, 2H), 2.87
(s, 3H), 3.06-3.13 (m, 4H), 3.56 (m, 2H), 3.97 (m, 1H), 4.23 (t, J=9.3 Hz,
1H), 5.03
(m, 1H), 7.07 (t, J=9.0 Hz, 1H), 7.19-7.23 (m, IH), 7.46-7.51 (m, 1H), 8.38
(m, IH).
Example 5 Preparation of (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxamide
~ - ~
0~ NH2
To a suspension of methyl (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-1,4-
diazepan-l-yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (0.14 g, 0.40 mmol)
in
methanol (5 mL) at 23 C is added methanolic ammonia solution (5.0 mL, 2.0 M).
The
suspension is stirred at the same temperature for lh, concentrated, and
purified by
preparative TLC (6% MeOH/CH2C12) to afford the title compound.
HPLC (SYIVIlVII;TRY C18 3.5 M, 4.6 x 30 mm colunm; gradient elution 2%-
98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.69 min
'H NMR (300 MHz, DMSO-d6): 2.63 (m, 2H), 2.88 (s, 3H), 3.07-3.14 (m,
4H), 3.52 (m, 2H), 3.97 (m, 1 H), 4.22 (t, J=9.6 Hz, 111), 5.01 (m, 1 H), 7.32
(m, 2H),
7.62 (s, 1H), 7.86 (s, 1H).
Intermediates for the preparation of example 5 are synthesized as follows:
1. Preparation of 1-(2,6-difluoro-4-nitrophenyl)-1,4-diazepan-5-one
-29-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
To a solution of 1,4-diazepan-5-one hydrochloride (7.0 g, 46.7 mmol) in
acetonitrile (60 mL) is added N,N-diisopropylethylamine (50 mL, 280 mmol),
followed
by 3,4,5-trifluoronitrobenzene (6.1 mL, 51 n-imol). The reaction mixture is
heated to
70 C overnight, cooled to room temperature, and the solvent removed in vacuo.
Dichloromethane is added and the solution is washed with brine, dried over
MgSO4,
filtered, and concentrated in vacuo. The resulting residue is purified by
column
chromatography (0-3% MeOH-dichloromethane) to afford the title compound.
'H NMR (300 MHz, DMSO-d6): 2.58 (m, 2H), 3.27 (m, 2H), 3.36 (m, 4H),
7.70 (br tr, 1 H), 8.04 (d, J= 10 Hz, 2H).
II. Preparation of 1-(2,6-difluoro-4-nitrophenyl)-4-methyl-1,4-diazepan-5-one
To a mixture of powdered KOH (0.79 g, 14 mmol) and tetrabutylammonium
bromide (0.60 g, 1.87 mmol) in THF (60 mL) is added a solution of 1-(2,6-
difluoro-4-
nitrophenyl)-1,4-diazepan-5-one (2.55 g, 9.4 mmol) and methyl iodide (0.88 mL,
14
mmol) in THF (40 mL). The resulting reaction mixture is kept at room
temperature
overnight, diluted with ethyl acetate, and washed with water and brine, and
dried
(MgSO4), filtered, and concentrated. The residue is purified by column
chromatography (2% MeOH in dichloromethane) to afford the title compound.
1H NMR (300 MHz, DMSO-d6): 2.70 (m, 2H), 2.87 (s, 3H), 3.32-3.43 (m,
4H), 3.58 (m, 2H), 7.99 (d, J= 10 Hz, 2H).
III. Preparation of 1-(4-amino-2,6-difluorophenyl)-4-methyl-1,4-diazepan-5-one
A solution of 1-(2,6-difluoro-4-nitrophenyl)-4-methyl-1,4-diazepan-5-one (2.2
g, 7.5 mmol) and NH4C1(4.1 g, 75 mmol) in ethanol-H20 (2:1, 90 mL) is heated
to 95
C, and treated with iron powder (1.25 g, 23 mmol) in portions over one hour.
The
reaction mixture is then stirred at 95 C for 3 hours, cooled to room
temperature, and
filtered through a pad of celite with the aid of dichloromethane. The solvent
is
removed in vacuo, and the residue taken into ethyl acetate and water. The
layers are
separated and the organic layer is dried over MgSOa, filtered, and
concentrated to
afford the title compound which is used directly in the next step without
further
purification.
MS (m/z): [M+H]+ = 256.2
IV. Preparation o f methyl (2R)-3-{[3,5-difluoro-4-(4-methyl-5-oxo-1,4-
diazepan-
1-yl)phenyl] amino } -2-hydroxypropanoate
-30-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
To a solution of 1-(4-amino-2,6-difluorophenyl)-4-methyl-1,4-diazepan-5-one
(1 g, 3.92 mmol) in acetonitrile (20 mL) at 23 C is added Lithium triflate
(0.73 g, 4.7
mmol), followed by (R)-methyl glycidate (0.41 mL, 4.7 mmol). The reaction
mixture is
stirred at 95 C for 20h and then treated with additional R-methyl glycidate
(0.1 mL,
1.17 mmol). After another day at 95 C, the reaction mixture is cooled to 23 C,
concentrated, and purified by chromatography on a silica gel column, eluting
with a
gradient increasing in polarity from 2% to 5% MeOH in dichloromethane.
Relevant
fractions are combined and concentrated to afford the title compound.
MS (m/z): [M+Na]+ = 380.1
HPLC (SYNIlVIETRY C18 3.5 M, 4.6 x 30 mm column; gradient elution 2%-
98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.85 min.
V. Preparation ofinethyl (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-1,4-diazepan-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate
To a mixture ofinethyl (2R)-3-{[3,5-difluoro-4-(4-methyl-5-oxo-1,4-diazepan-
1-yl)phenyl]amino}-2-hydroxypropanoate (0.60 g, 1.68 mmol) and 1,1'-
carbonyldiimidazole (0.42 g, 2.52 mmol) at 23 C is added acetonitrile (15 mL).
The
resulting mixture is stirred at 75 C for 2 days, cooled to 23 C, and
concentrated in
vacuo. The residue is taken into ethyl acetate (300 mL), washed with 0.5 M HCl
aqueous, brine, and dried (Na2SO4), filtered, and concentrated in vacuo. The
residue is
purified by chromatography on a silica gel column, eluting with a gradient
increasing in
polarity from 2% to 5% MeOH in dichloromethane. Relevant fractions are
combined
and concentrated to afford the title compound.
MS (m/z): [M+H]+ = 452.2
HPLC (SYMMETRY C18 3.5 M, 4.6 x 30 mm column; gradient elution 2%-
98% MeCN with 0.1 % TFA over 5 min; 2 mL/min rate): retention time = 2.12 min.
-31-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
Example 6 Preparation of (5R)-3-[3,5-difluoro-4-(4-methyl-5-oxo-1,4-diazepan-
1=
yl)phenyl]-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide
~
o~ - ~N,,
0
Following the procedure in Example 1 and under analogous conditions, methyl
(5R)-3-[3, 5-difluoro-4-(4-methyl-5-oxo-1,4-diazepan-1-yl)phenyl]-2-oxo-1,3 -
oxazolidine-5-carboxylate (0.15 g, 0.39 mmol) is treated with methanolic
methylamine
solution (4.0 mL, 2.0 M). The suspension is stirred at the same temperature
for 2h,
concentrated, and purified by preparative TLC (6% MeOH/CHZCl2) to afford the
title
lo compound.
HPLC (SYMIlVIETRY C18 3.5 M, 4.6 x 30 mm colurrm; gradient elution 2%-
98% MeCN with 0.1 % TFA over 5 min; 2 mL/min rate): retention time = 1.78 min
1H NMR (300 MHz, DMSO-d6): 2.63-2.65 (m, 5H), 2.88 (s, 3H), 3.07-3.14
(m, 4H), 3.53 (m, 2H), 3.98 (m, 1H), 4.22 (t, J=9.3 Hz, 1H), 5.05 (m, 1H),
7.31 (m,
2H), 8.38 (m, 1H).
Example 7 Preparation of (5R)-3-[3,5-difluoro-4-(5-oxo-1,4-diazepan-l-
yl)phenyl] -2-oxo-1, 3 -oxazolidine- 5-carboxamide
H
~ NH2
F
To a suspension of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-1,4-diazepan-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (0.20 g, 0.54 mmol) in methanol
(2
mL) at 23 C is added methanolic ammonia solution (3.0 mL, 2.0 M). The
suspension is
stirred at the same temperature for lh, concentrated, and purified by
preparative TLC
(3% MeOH-dichloromethane) to afford the title compound.
HPLC (SYIVNMTRY C18 3.5 M, 4.6 x 30 mm column; gradient elution 2%-
98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.54 min
-32-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
'H NMR (300 MHz, DMSO-d6): 2.53 (m, 2H), 3.09 (m, 4H), 3.22 (m, 2H),
3.97 (dd, J= 9, 6 Hz, 1 H), 4.22 (tr, J= 9 Hz, 1 H), 5.01 (dd, J 9, 6 Hz, 1
H), 7.32 (d,
J= 11 Hz, 2H), 7.62, (s, 1 H), 7.67 (tr, J= 5 Hz, 1 H), 7.86 (s, 1 H).
Intermediates for the synthesis of example 7 are prepared as follows:
I. Preparation of 1-(4-ami.no-2,6-difluorophenyl)-1,4-diazepan-5-one
A solution of 1-(2,6-difluoro-4-nitrophenyl)-1,4-diazepan-5-one (4.0 g, 14.7
mmol) and NH4C1(7.8 g, 147 mmol) in ethanol-H20 (2:1, 90 mL) is heated to 95
C,
and treated with iron powder (2.5 g, 44 mmol) in portions over one hour. The
reaction
mixture is stirred at 95 C for 6 hours, cooled to room tenrperature, and
filtered
through a pad of celite with the aid of dichloromethane. The filtrate is
concentrated in
vacuo, and the residue taken into ethyl acetate and water. The layers are
separated and
the organic layer is dried over MgSO4, filtered, and concentrated to afford
the title
compound which is used directly in the next step without further purification.
MS (m/z): [M + Na]+ = 264.0
II. Preparation of methyl (2R)-3-{[3,5-difluoro-4-(5-oxo-1,4-diazepan-l-
yl)phenyl] amino } -2-hydroxypropanoate
To a solution of 1-(4-amino-2,6-difluorophenyl)-1,4-diazepan-5-one (3.42 g,
14.2 mmol) in acetonitrile (80 mL) at 23 C is added Lithium triflate (2.43 g,
15.6
mmol), followed by (R)-methyl glycidate (1.36 mL, 15.6 mmol). The reaction
mixture
is then stirred at 80 C for 20h and treated with additional (R)-methyl
glycidate (0.62
mL, 7 mmol) and Lithium triflate (1.11 g, 7.1 mmol). After another 2 days at
60 C, the
reaction mixture is cooled to 23 C, concentrated, and taken into ethyl acetate
and
water. The layers are separated and the organic phase washed with brine, dried
(MgSO4), filtered, and concentrated. The crude residue is purified by
chromatography
on a silica gel column, eluting with a gradient increasing in polarity from 0%
to 10%
MeOH in dichloromethane. Relevant fractions are combined and concentrated to
afford the title compound.
1H NMR (300 MHz, DMSO-d6): 2.48 (m, 2H), 2.97 (m, 4H), 3.18 (m, 3H),
3.27 (m, 1 H), 3.62 (s, 3H), 4.17 (m, 1 H), 5.73 (tr, J= 7 Hz, 1H), 6.10 (tr,
J= 5 Hz,
1 H), 6.24 (d, J= 12 Hz, 2H), 7.61 (tr, J= 5 Hz, 1 H).
III. Preparation of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-1,4-diazepan-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate
-33-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
. To a mixture of methyl (2R)-3-{[3,5-difluoro-4-(5-oxo-1,4-diazepan-l-
yl)phenyl]amino}-2-hydroxypropanoate (3.97 g, 11.6 rrimol) and 1,1'-
carbonyldiimidazole (5.6 g, 34.7 mmol) at 23 C is added acetonitrile (70 mL).
The
resulting mixture is stirred at 60 C overnight and then cooled to 23 C and
concentrated. The residue is purified by chromatography on a silica gel
column, eluting
with a gradient increasing in polarity from 0% to 3% MeOH in dichloromethane.
Relevant fractions are combined and concentrated to afford the title compound.
1H NMR (300 MHz, DMSO-d6): 2.53 (m, 2H), 3.1 (m, 4H), 3.21 (m, 2H),
3.75 (s, 3H), 4.13 (dd, J= 10, 5 Hz, 1 H), 4.31 (tr, J= 10 Hz, 1 H), 5.32 (dd,
J= 10, 5
lo Hz, 114), 7.29 (d, J= 11 Hz, 2H), 7.66 (tr, J= 5 Hz, 1 H).
Example 8 Preparation of (5R)-3-[3,5-difluoro-4-(5-oxo-1,4-diazepan-l-
yl)phenyl]-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide
H H
O KI
F
Following the procedure in Example 7 and under analogous conditions, methyl
(5R)-3-[3,5-difluoro-4-(5-oxo-1,4-diazepan-1-yl)phenyl]-2-oxo-1,3-oxazolidine-
5-
carboxylate (0.20 g, 0.54 mmol) is treated with methanolic methylaniine
solution (3.0
mL, 2.0 M). The suspension is stirred at the same temperature for lh,
concentrated,
and the residue purified by preparative TLC (3% MeOH-dichloromethane ) to
afford
the title compound.
MS (m/z): [M+H]+ = 369.3
HPLC (SYIVIlvIETRY C18 3.5 M, 4.6 x 30 nun column; gradient elution 2%-
98% MeCN with 0.1% TFA over 5 min; 2 mL/min rate): retention time = 1.64 min.
1H NMR (300 MHz, DMSO-d6): 2.55 (m, 2H), 2.64 (d, J = 4 Hz, 3H), 3.09
(m, 4H), 3.22 (m, 2H), 3.98 (dd, J= 9, 6 Hz, 1 H), 4.22 (tr, J= 9 Hz, 1 H),
5.05 (dd, J
= 10, 6 Hz, 1 H), 7.31 (d, J= 12 Hz, 2H), 7.67 (tr, J= 5 Hz, 1 H), 8.38 (q, J=
4 Hz,
1H).
-34-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
Example 9 Preparation of (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-
1,4-diazepin-1-yl)phenyl]-2-oxo-1,3=oxazolidine-5-carboxamide
H
0 - NH2
F
Methanolic ammonia (2.5 mL of a 2.0 M solution) is added to a solution of
methyl (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-1,4-diazepin-1-
yl)phenyl]-2-oxo-l,3-oxazolidine-5-carboxylate (0.11 g, 0.3 mmol) in methanol
(4
mL). The reaction mixture is stirred at 23 C for 2h, concentrated, and the
residue
purified by column chromatography (0- 6% MeOH in dichloromethane), and
1 o lyophilized to afford the title compound.
'H NMR (300 MHz, DMSO-d6): 3.35 (m, 2H), 3.62 (m, 2H), 4.02 (m, 1H),
4.25 (t, J= 10 Hz, 1 H), 4.48 (dd, J= 9, 2 Hz, 1 H), 5.04 (m, 1 H), 6.42 (d,
J= 10 Hz,
1H), 7.42-7.48 (m, 3H), 7.63 (s, 1H), 7.89 (s, 1H).
Intermediates for the synthesis of example 9 are prepared as follows.
1. Preparation of benzy13,5-difluoro-4-[4-(hydroxyimino)-3,4-dihydropyridin-
1(2H)-yl]phenylcarbama.te
Hydroxylamine hydrochloride (3.96 g, 55.8 mmol) was added to a solution of
benzyl 3,5-difluoro-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)phenylcarbamate (8.0
g,
22.3 mmol, prepared as described in WO 2004/033449) in pyridine (80 mL)
containing
molecular sieves (40 g). The reaction was stirred at room temperature
overnight, and
the reaction mixture filtered through celite with the aid of ethyl acetate.
The filtrate
was washed with water, dried over MgSO4, filtered, and concentrated in vacuo
to
afford the title compound as mixtures of isomers. The crude residue was used
in the
next step without further purification.
II. Preparation of benzy13,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-1,4-
diazepin-1-yl)phenylcarbamate.
To a solution of benzyl 3,5-difluoro-4-[4-(hydroxyimino)-3,4-dihydropyridin-
1(2H)-yl]phenylcarbamate (1.2 g, 3.21 mmol) in acetone (20 mL) was added a
solution
of Na2CO3 (1.36 g, 12.8 mmol) in water (20 mL). The mixture was stirred for 5
minutes, and then a solution of p-toluenesulfonyl chloride (1.33 g, 7.0 mmol)
in
acetone (10 mL) was added slowly. The reaction was stirred at room temperature
-35-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
overnight, and. then the acetone was removed in vacuo, water was added, and
the
solution extracted with dichloromethane. The organic phases were dried over
MgSO4,
filtered, concentrated in vacuo, and purified by silica gel flash
chromatography (6%
MeOH in dichloromethane) to afford the title compound.
'H NMR (300 MHz, DMSO-d6): 3.34 (m, 2H), 3.59 (m, 2H), 4.45 (dd, J=
2.1, 8.1 Hz, 1H), 5.16 (s, 2H), 6.38 (d, J= 10.2 Hz, 1H), 7.24 (m, 2H), 7.32-
7.43 (m,
6H), 10.24 (s, 1 H).
III. Preparation of 1-(4-amino-2,6-difluorophenyl)-1,2,3,4-tetrahydro-5H-1,4-
diazepin-5-one
Palladium catalyst (20% Pd(OH)2 on carbon, 0.5 g) is added to a solution of
benzy13,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-1 H-1,4-diazepin-l-
yl)phenylcarbamate (1.25 g, 3.35 mmol) in ethyl acetate (200 mL) and the
mixture
stirred under an atmosphere of hydrogen gas. After 16 hours, the reaction
mixture is
filtered through celite and the filtrate concentrated to provide the title
compound,
which is used directly in the next step without further purification.
'H NMR (300 MHz, DMSO-d6) 3.33 (m, 2H), 3.51 (m, 211), 4.34 (dd, J= 2.1,
8.1 Hz, 1 H), 5.79 (s, 2H), 6.19-6.25 (m, 1H), 6.28 (d, J= 10.2 Hz, 2H), 8.30
(m, 1H)
N. Preparation of methyl (2R)-3-{[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-
1,4-diazepin-1-yl)phenyl]amino} -2-hydroxypropanoate
Lithium triflate (0.68 g, 4.35 mmol) and then (R)-methyl glycidate (0.38 mL,
4.35 mmol) are added to a solution of 1-(4-amino-2,6-difluorophenyl)-1,2,3,4-
tetrahydro-5H-1,4-diazepin-5-one (0.8 g, 3.34 mmol) in acetonitrile (10 mL).
The
reaction mixture is stirred at 95 C for 16 hours, cooled to 23 C,
concentrated, and
purified by flash chromatography (0-5% methanol in dichloromethane) to afford
the
title compound.
'H NMR (300 MHz, DMSO-d6): 3.22 (m, 1H), 3.34 (m, 2H), 3.52 (m, 2H),
3.63 (s, 3H), 4.08 (m, 2H), 4.18 (m, i H), 4.36 (dd, J= 2.1, 8.1 Hz, 1 H),
5.75 (d, J=
6.9 Hz, 1H), 6.29-6.39 (m, 3H), 7.31 (m, 1H).
V. Preparation of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-
1,4-diazepin-1-yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate
-36-
CA 02589250 2007-05-28
WO 2006/056877 PCT/IB2005/003559
H IV~~ F
O OMe
F 0
A mixture of methyl (2R)-3-{[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-
1,4-diazepin-1-yl)phenyl]amino}-2-hydroxypropanoate (0.85 g, 2.49 mmol) and
1,1'-
carbonyldiimidazole (0.83 g, 5.0 mmol) at 23 C is suspended in acetonitrile
(30 mL).
The reaction mixture is stirred at 75 C overnight, then cooled to 23 C and
concentrated in vacuo. The residue is purified by silica gel flash
chromatography (0-
5% MeOH in dichloromethane) to afford the title compound.
1H NMR (300 MHz, DMSO-d6): 3.35 (m, 2H), 3.61 (m, 2H), 3.75 (s, 3H),
4.17 (m, 1 H), 4.3 7(t, J= 9.6 Hz, 1 H), 4.48 (dd, J= 2.4, 8.1 Hz, 1 H), 5. 3
6(m, 1 H),
6.42 (d, J= 10.5 Hz, 1H), 7.44 (m, 3H).
Example 10 Preparation of (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-
1,4-diazepin-1-yl)phenyl]-N-methyl-2-oxo-1,3-oxazolidine-5-carboxamide
H H
O N-,
F
Methanolic methylamine (2.5 mL of a 2.0 M solution) is added to a solution
of methyl (5R)-3-[3,5-difluoro-4-(5-oxo-2,3,4,5-tetrahydro-lH-1,4-diazepin-l-
yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (0.11 g, 0.3 mmol) in methanol
(4
mL). The reaction mixture is stirred at 23 C for 4 hours, concentrated, and
the
residue purified by column chromatography (0-6% MeOH in dichloromethane), and
lyophilized to afford the title compound.
'H NMR (300 MHz, DMSO-d6): 2.64 (d, J= 4.8 Hz, 3H), 3.35 (m, 2H), 3.62
(m, 2H), 4.02 (m, 1 H), 4.25 (t, J= 9.6 Hz, 1 H), 4.48 (d, J= 10. 5 Hz, 1 H),
5.09 (m,
l H), 6.42 (d, J= 10. 5 Hz, 1 H), 7.44-7.48 (m, 3H), 8.42 (m, 1 H).
-37-
