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Patent 2614105 Summary

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(12) Patent Application: (11) CA 2614105
(54) English Title: OXAZOLIDINONE CARBOXAMIDES CONTAINING AZETIDINE AND CYCLOBUTANE AS ANTIBACTERIAL AGENTS
(54) French Title: CARBOXAMIDES D'OXAZOLIDINONE CONTENANT DE L'AZETIDINE ET DU CYCLOBUTANE UTILISES EN TANT QU'AGENTS ANTIBACTERIENS
Status: Deemed Abandoned and Beyond the Period of Reinstatement - Pending Response to Notice of Disregarded Communication
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07D 413/10 (2006.01)
  • A61K 31/422 (2006.01)
(72) Inventors :
  • GORDEEV, MIKHAIL FEDOROVICH (United States of America)
  • JOSYULA, VARA PRASAD VENKATA NAGENDRA (United States of America)
  • RENSLO, ADAM ROBERT (United States of America)
(73) Owners :
  • PHARMACIA & UPJOHN COMPANY LLC
(71) Applicants :
  • PHARMACIA & UPJOHN COMPANY LLC (United States of America)
(74) Agent: MARKS & CLERK
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2006-06-26
(87) Open to Public Inspection: 2007-01-11
Examination requested: 2008-01-03
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/IB2006/001835
(87) International Publication Number: WO 2007004037
(85) National Entry: 2008-01-03

(30) Application Priority Data:
Application No. Country/Territory Date
60/696,735 (United States of America) 2005-07-06

Abstracts

English Abstract


The present invention provides a compound of formula (I), or a
pharmaceutically acceptable salt thereof as antibacterial agents.


French Abstract

L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, utilisés en tant qu'agents antibactériens.

Claims

Note: Claims are shown in the official language in which they were submitted.


CLAIMS
1. A compound of formula I
<IMG>
or a pharmaceutically acceptable salt thereof wherein:
W is O, or S;
Y1, Y2, Y3, Y4 are independently CH, or CF;
Z is CH, or N;
R1 and R2 are independently
(a) -H,
(b) halo,
(c) -CN,
(d) -C(=W)NR3R4
(e) -(C=O)C1-6alkyl,
(f) -(C=O)C3-8cycloalkyl,
(g) -COOH,
(h) -C1-6alkyl,
(i) -WC1-6alkyl,
(j) -C3-8cycloalkyl,
(k) -OC3-8cycloalkyl, or
(l) R1 and R2 taken together form =O, =N-OH, =N-OC1-4alkyl, =CH-CN;
R3 is -H, -C1-6alkyl, or -OC1-6alkyl;
at each occurrence, C1-6alkyl, or C3-8cycloalkyl is optionally substituted
with CF3, 1-3 halo,
OH, OC1-4alkyl, CN, N3, O(C=O)C1-4 alkyl, C3-6cycloalkyl, NH2, NHC(=O)C1-4
alkyl, or
C(=O)C1-4 alkyl; and
n is 0, 1, or 2.
2. A compound of claim 2 wherein Y1 and Y3 are independently CH or CF; and Y2
and
Y4 are CH.
3. A compound of claim 2 wherein R1 and R2 are independently H, F, OH, OC1-
2alkyl,
C1-2alkyl, or CF3.
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4. A compound of claim 2 wherein R3 is H or CH3.
5. A compound of claim 2 which is
(1) (5R)-3-[3,5-difluoro-4-(3-fluoroazetidin-1-yl)phenyl]-2-oxo-1,3-
oxazolidine-5-
carboxamide,
(2) (5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3,5-difluorophenyl]-2-oxo-1,3-
oxazolidine-5-
carboxamide,
(3) (5R)-3-[4-(3-methoxyazetidin-1-yl)-3,5-difluorophenyl]-2-oxo-1,3-
oxazolidine-5-
carboxamide,
(4) (5R)-3-{3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]phenyl}-
2-oxo-
1,3-oxazolidine-5-carboxamide,
(5) (5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-
oxazolidine-5-
carboxamide,
(6) (5R)-N-methyl-3-[4-(3,3-difluoroazetidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-
oxazolidine-5-carboxamide,
(7) (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-
carboxamide,
(8) (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-
carboxamide,
(9) (5R)-3-[4-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl)-3,5-
difluorophenyl]-2-
oxo-1,3-oxazolidine-5-carboxamide, or
(10) (5R)-3-[4-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl)-3,5-
difluorophenyl]-N-
methyl-2-oxo-1,3-oxazolidine-5-carboxamide.
6. A pharmaceutical composition comprising a compound of claim 1 or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier.
7. A method for treating bacteria infections comprising administering to a
mammal
being treated a pharmaceutically effective amount of the compound of claim 1.
8. The method of claim 7 wherein the compound of claim 1 is administered
orally.
9. The method of claim 7 wherein the compound of claim 1 is administered
parenterally, topically, rectally, or intranasally.
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10. The method of claim 7 wherein said compound is administered in an amount
of from
about 0.1 to about 100 mg/kg of body weight/day.
11. The method of claim 7 wherein said compound is administered in an amount
of from
about 1 to about 50 mg/kg of body weight/day.
12. The bacteria infection of claim 7 which is ear infections, eye infections,
respiratory
tract infections, skin and skin structure infections, bacterial endocarditis,
osteomyelitis, endocarditis or diabetic foot.
13. The bacteria infection of claim 7 which is caused by gram-positive
bacteria, gram
negative bacteria, anaerobic organisms, and acid-fast organisms.
14. The bacteria infection of claim 7 which is caused by bacteria comprising
staphylococci, streptococci, Enterococci, Haemophilus, Moraxella, bacteroides,
clostridia, Mycobacteria, or Chlamydia.
15. The bacteria of claim 14 wherein staphylococci is S. aureus and S.
epidermidis;
wherein streptococci is S. pneumoniae of S. pyogenes; wherein Enterococci is
E.
faecalis; wherein Haemophilus is H. influenzae; wherein Moraxella is M.
catarrhalis; and wherein Mycobacteria is M. tuberculosis; or Mycobacterium
avium.
16. The bacteria infections of claim 7 which is caused by multi-drug resistant
S. aureus.
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Description

Note: Descriptions are shown in the official language in which they were submitted.


CA 02614105 2008-01-03
WO 2007/004037 PCT/IB2006/001835
OXAZOLIDINONE CARBOXAMIDES CONTAIlVING AZETIDINE AND
CYCLOBUTANE AS ANTIBACTERIAL AGENTS
FIELD OF INVENTION
The present invention relates to novel oxazolidinones carboxamide derivatives
bearing azetidine and cyclobutane rings, pharmaceutical compositions thereof,
methods for
their use, and methods for preparing these compounds. These compounds have
potent
activities against gram-positive and/or gram-negative bacteria.
BACKGROUND OF THE INVENTION
Antibacterial resistance is a global clinical and public health problem that
has
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 azetidine and
cyclobutane
derivatives of oxazolidinones as an inhibitors of bacterial protein synthesis
for the treatment
of serious infections caused by a number of human and veterinary pathogens,
including
multiple resistant strains of bacteria.
INFORMATION DISCLOSURE
DE10129725, JP11322729, US4705799, WO9613502, WO9710223, W09854161,
W09912914, WO200027830, WO200032599, W0200232857, W0200206278,
WO2003072553, WO2003008389, WO2003007870, WO2003006440, WO2004014392
disclose oxazolidinone compounds useful as antibacterial agents.
SUMMARY OF THE 1NVENTION
The present invention provides a compound of formula I
0
vi_Y2
Ri
~Z~/ N 0 N-ss
R2 Y3=Y4
w
I
or a pharmaceutically acceptable salt thereof wherein:
WisOorS;
Yl, Y2, Y3, Y4 are independently CH or CF;
Z is CH or N;
Rl and R2 are independently
(a) -H,
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(b) halo,
(c) -CN
(d) -C(=W)NR3Ra.
(e) -(C=0)C1_6alkyl
(f) -(C=O)C3_$cycloalkyl
(g) -COOH
(h) -C1_6alkyl,
(i) -WC1_6alkyl,
(j) -C3_$cycloalkyl,
(k) -OC3.8cycloalkyl, or
(1) R' and R2 taken together form =0, =N-OH, =N-OC1_~alkyl, =CH-CN;
R3 is -H, -C1_6alkyl, or -OC1.6alkyl;
at each occurrence, C1_6alkyl, or C3_8cycloalkyl is optionally substituted
with CF3, 1-3 halo,
OH, OC1_4alkyl, CN, N3, O(C=O)C1_4 alkyl, C3_6cycloalkyl, NH2, NHC(=O)Ci_4
alkyl, or
C(=O)C1_4 alkyl; and
nis0,1,or2.
In another aspect, the present invention also provides:
a pharmaceutical composition which comprises a pharmaceutically acceptable
carrier
and an effective amount of a compound of formula I,
a method for treating gram-positive 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 gram-positive or gram-negative microbial
infections.
The invention may also provide novel intermediates and novel processes that
are
useful for preparing compounds of formula 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; -j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive.
Thus, for example, C1_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.
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The term "C3_8cycloalkyl" or "C3_6cycloalkyl" refers to a cyclic saturated
monovalent
hydrocarbon group of three to eight or three to six carbon atoms, e.g.,
cyclopropyl,
cyclohexyl, and the like.
The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
The term "a pharmaceutically 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 "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.
The term "mammal" refers to human or warm-blooded animals including livestock
and companion animals.
The term "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.
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".
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 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 mammal
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
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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 "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.
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 is methyl or ethyl.
Specifically, halo is fluoro (F).
Specifically, R' and R2 are independently H, F, OH, OC1_2alkyl, Cl_Zalkyl, or
CF3.
Specifically, Y2 and Y4 are CH; and Yland Y3 are independently CH or CF.
Specifically, R3 is H or CH3.
Examples of the present invention are
(1) (5R)-3-[3,5-difluoro-4-(3-fluoroazetidin-1-yl)phenyl]-2-oxo-1,3-
oxazolidine-5-
carboxamide,
(2) (5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3,5-difluorophenyl]-2-oxo-1,3-
oxazolidine-5-
carboxamide,
(3) (5R)-3-[4-(3-methoxyazetidin-1-yl)-3,5-difluorophenyl]-2-oxo-
1,3oxazolidine-5-
carboxamide,
(4) (5R)-3-{ 3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidin-l-yl]phenyl
}-2-oxo-
1,3-oxazolidine-5-carboxamide,
(5) (5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-
oxazolidine-5-
carboxamide,
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(6) (5R)-N-methyl-3-[4-(3,3-difluoroazetidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-
oxazolidine-5-carboxamide,
(7) (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-
carboxamide,
(8) (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-
carboxamide,
(9) (5R)-3-[4-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl)-3,5-
difluorophenyl]-2-
oxo-1,3-oxazolidine-5-carboxamide, or
(10) (5R)-3-[4-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl)-3,5-
difluorophenyl]-N-
methyl-2-oxo-1,3-oxazolidine-5-carboxamide.
Compounds of this 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
Ri Y1 Ri Yl
H OH
!~Z--~/ Z~/ N~O RY33-NH 2 R2 Ya-
2 O
O 0
1 1
Rs~Z ~N O ' Ri~Z ' 1 O H
R2 Ya ~ R2 Y3 ~N'R3
3 O 4 O
Scheme I describes the synthesis of analogs bearing carboxamide substitution
at C-5
of the oxazolidinone. First, the aniline intermediate 1 is reacted with an
alkyl (2R)-
epoxypropanoate and a Lewis acid such as lithium triflate as described in US
Patent
Application Publication No. US 2004/0044052.
In step 2, 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
intennediate 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
-5-

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WO 2007/004037 PCT/IB2006/001835
product may be used as collected or may first be purifed 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 (RNH2) in a suitable solvent such as methanol or
acetonitrile affords
amides 4 (R = H or optionally substituted alkyl). Similarly, treatment of
ester 3 with 0-
alkylhydoxylamines or hydrazines gives the hydroxamate (R = 0-alkyl) or the
hydrazide (R =
NH2) respectively. The product may be used as collected or may first be
purifed using
conventional techniques such as preparative TLC or HPLC, chromatography,
precipitation,
crystallization and the like.
Scheme II
F
HO-CNH + F /~ NO2 -~ HO--~N O_NO2
F F
2
3
F F
R2N / ~ N02 R ~N / ~ NH2
F F
4 5
Intermediates bearing azetidine substitution are conveniently prepared by the
nucleophilic aromatic substitution reaction of 3-hydroxyazetidine with
fluorinated nitro
aromatic compounds. Such reactions are well known those skilled in the art and
review
articles describing these reactions are available (see Zoltewicz in Top. Curr.
Chem. 1975, vol.
59, pp. 33-64). These transformations are generally performed at 40 C to 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. The 3-
hydroxyazetidine 1 is prepared by hydrogenolysis (for example with Pd/C in
methanol) of 1-
benzyl-3-trimethylsilyloxyazetidine (prepared as described by Higgins, R. H.
J. Heterocyclic
Chem. 1987, 24, 1489).. The product may be used as collected or may first be
purifed using
conventional techniques such as preparative TLC or HPLC, chromatography,
precipitation,
crystallization and the like.
Step 2 of Scheme 4 represents one or more steps required for the protection,
oxidation, or otherwise conversion of the hydroxyazetidine ring to a more
highly
functionalized state. A person of ordinary skill in organic chemistry will be
well acquainted
with the various reactions that will be required for this functionalization.
This may involve,
for example, protection as a silyl ether, fluorination, oxidation to the
azetidinone, olefination
of the azetidione thus obtained, reaction of the azetidinone thus obtained
with nucleophiles,
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or activation of the hydroxy group and substitution with nucleophiles. The
products may be
used as collected or may first be purifed using conventional techniques such
as preparative
TLC or HPLC, chromatography, precipitation, crystallization and the like.
Finally, step 3 involves reduction of the nitro group to provide the aniline
intermediate 5. This reduction is generally accomplished by reacting the nitro
intermediate 4
with iron metal. The reaction is carried out at temperatures between 60 C and
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 as collected or may
first be
purifed using conventional techniques such as preparative TLC or HPLC,
chromatography,
precipitation, crystallization and the like.
Scheme III
O~ }Br --' Oo s~NHCbz-- --~ 3 j-NHCbz
Y3 Y ~~ Y -/
2 3
Y1 R1 Y1
-> 0==<>-0 NHCbz ~NHCbV
Y3- R2 Y3-
4 5
Scheme III describes the synthesis of intermediates bearing a cyclobutane
ring. The
intermediate 2 can be prepared in a single step involving the transition metal
catalyzed
reaction of a 4-bromo benzaldehyde starting material (1) with an alkyl
carbamate, for
example benzyl carbamate. Reactions of this type are well known to those
skilled in the art
(see for example Buchwald et.al. J. Am. Chem. Soc. 2002, 124, 7421-7428) and
are typically
carried out with palladium or copper catalysts and employing ligands such as
BINAP or
related phosphine or arsine ligands. The reaction is favorably carried out in
solvents such as
toluene or benzene and at temperatures of about 50 C up to 110 C. The
product may be
used as collected or may first be purifed using conventional techniques such
as preparative
TLC or HPLC, chromatography, precipitation, crystallization and the like.
Step 2 of Scheme 5 involves the conversion of benzaldehyde intermediate 2 to
the
styrene 3. Olefination of 2 is accomplished under conditions well-known to
those of ordinary
skill in organic chemistry, for example by reaction of the aldehyde with a
phophorus ylide
(generated by the reaction of a methyltriphenylphosphonium salt with a base
such as sodium
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hydride or potassium bis(trimethylsilyl)amide). The reaction is typically
carried out in
solvents such as THF or DMF and at temperatures of about -50 C up to 25 C.
The product
may be used as collected or may first be purifed using conventional techniques
such as
preparative TLC or HPLC, chromatography, precipitation, crystallization and
the like.
In step 3 of Scheme 5, the cyclobutanone ring is formed by the reaction of the
styrene intermediate 3 with dichlorocarbene followed by a dechlorination step
to provide 4.
The generation and [2-1-2] cycloaddition of dichlorocarbene with olefins is
well known and
review articles describing these reactions are available (for example, see
Brady, W. T.
Tetrahedron 1981, 17, 2949-2966). The dichlorocyclobutanone intermediate
formed in the
cycloaddition reaction is then dechlorinated by reaction with reducing metals
(for example
with Zn-Cu couple) to form the desired cyclobutanone intermediate. Such
reduction reactions
are well known and are discussed in review articles, including that referenced
above. The
products of these reactions may be used as collected or may first be purifed
using
conventional techniques such as preparative TLC or HPLC, chromatography,
precipitation,
crystallization and the like.
Step 4 of Scheme 5 represents one or more steps required for the protection,
reduction, or otherwise conversion of the azetidinone ring to a more highly
functionalized
state. This may involve, for example, reduction, protection of the alcohol
thus formed as a
silyl ether, fluorination, olefination reactions, oxime formation, or reaction
with nucleophiles.
The product may be used as collected or may first be purifed using
conventional techniques
such as preparative TLC or HPLC, chromatography, precipitation,
crystallization and the
like.
Medical and Veterinary Uses
The compounds of the present invention may be used for the treatment of
infectious,
Gram-positive bacterial infections caused by a variety of bacterial organisms,
including those
that require long-term therapy (>28 days).
Examples of the bacterial organisms 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 example 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
example M. tuberculosis; and/or Mycobacterium avium. Other examples include
Escherichia, for example E. coli. intercellular microbes, for example
Chlamydia and
Rickettsiae.
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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 endocarditis, bums,
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 Activities
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), Metlaods for dilution antimicrobial tests
for bacteria that
grow aerobically, Approved Standard (6"' 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 (5'" ed), M11-
A4, NCCLS,
Wayne, PA; (3) National Committee for Clinical Laboratory Standards
(Jan.2003), MIC
testing supplemental tables, M100-S13 (for use with M7-A6), NCCLS, Wayne, PA;
and (4)
Murray PR, Baron EJ, Jorgensen JH, et al. Manual of Clinical Microbiology (8'h
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
antibacterial activities are shown in Table 1.
Table I
Results of in vitro antibacterial activity MIC40 ( g/mL)
Example No. S. aureus S. pneumoniae E.faecalis
UC-76 SA-1 SV 1 SP-3 MGH-2 EF 1-1
1 8 8 8
2 4 8 16
Pharmaceutical Salts
The compound of formula 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
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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 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) an oxazolidinone prodrug 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 formulated 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.
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For oral administration, the compounds can be formulated by combining the
active
compounds with pharmaceutically acceptable carriers well known in the art.
Such carriers
enable the compounds of the invention 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 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.
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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
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 formulated 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 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.
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For ophthalmic and otitis uses, the pharmaceutical compositions may be
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 formulated 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.
DosaLye
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 compound 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 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
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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
bd = broad doublet
bs = broad singlet
bt = broad triplet
br = broad signal
CDI = 1,1 (a-carbodiimidazole
d = doublet
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)-IH-1,2,3-triazolo-[4,5-b]pyridin-
1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate N-oxide
LG = leaving group
m = multiplet
M = molar
M Io = mole percent
max = maximum
meq = milliequivalent
mg = milligram
mL = milliliter
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mm - millimeter
mmol = 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
HC1 - 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
m/z = mass to charge ratio
min = minutes
Boc - tert-butoxycarbonyl
CBZ = benzyloxycarbonyl
DCC = 1,3-dicyclohexylcarbodiimide
PyBop - benzotriazole-1-yl-oxy-trispyrrolidinophosphonium
hexafluorophosphate
Example 1 Preparation of (5R)-3-[3,5-difluoro-4-(3-fluoroazetidin-1-yl)phenyl]-
2-oxo-
1,3-oxazolidine-5-carboxamide
F
yNH2
F
O
1,1'-Carbonyldiimidazole (0.163 g, 0.98 mmol) is added to a solution of methyl
(2R)-
3-{[3,5-difluoro-4-(3-fluoroazetidin-l-yl)phenyl]amino}-2-hydroxypropanoate
(0.150 g, 0.49
mmol) in acetonitrile (8 mL) and the solution heated to 50 C for three days.
After cooling,
ethyl acetate is added and the solution washed with dilute citric acid, twice
with dilute
NaHCO3, brine, and dried (MgSO4), filtered and concentrated to provide methyl
(5R)-3-[3,5-
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difluoro-4-(3-fluoroazetidin-1-yl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate
which is used
without further purification.
Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a
solution
of methyl (5R)-3-[3,5-difluoro-4-(3-fluoroazetidin-1-yl)phenyl]-2-oxo-1,3-
oxazolidine-5-
carboxylate (0.160 g, 0.49 mmol) in 3 mL of methanol. After 90 minutes, the
solution is
concentrated and the residue purified by preparative TLC (5% MeOH-
dichloromethane) to
afford the title compound.
MS (m/z): [M+H]+ = 316
'H NMR (300 MHz, CD3CN): 3.96 (dd, J = 9, 6 Hz, 1H), 4.18 (m, 3H), 4.42 (m,
2H),
4.93 (dd, J = 10, 6 Hz, 1H), 5.22- 5.42 (dm, J = 58 Hz, 1H), 6.17 (br s, 1H),
6.70 (br s, 1H),
7.12 (dd, J = 10, 2 Hz, 2H)
Intermediates for the synthesis of example 1 are prepared as follows.
I. Preparation of methyl (2R)-3-{[3,5-difluoro-4-(3-fluoroazetidin-l-
yl)phenyl]amino}-
2-hydroxypropanoate
A solution of 1-(2,6-difluoro-4-nitrophenyl)-3-fluoroazetidine (0.36 g, 1.5
mmol) in 2
mL of methanol containing 10% Pd/C (0.04 g) is stirred under an atmosphere of
hydrogen.
After 18 hours, the solution is filtered through celite with the aid of
methanol and the filtrate
concentrated to provide 1-(4-amino-2,6-difluorophenyl)-3-fluoroazetidine which
is used
directly in the next step.
A solution of 1-(4-amino-2,6-difluorophenyl)-3-fluoroazetidine (1.5 mmol) in
acetonitrile (5 mL) is treated with (R)-methyl glycidate (0.18 g, 1.8 mmol)
and lithium triflate
(0.28 g, 1.8 mmol), heated to 70 C for 3 hours and then cooled and
concentrated. The
residue is purified by preparative TLC (2% MeOH-dichloromethane) to afford the
title
compound.
'H NMR (300 MHz, CDC13): 3.04 (br s, 1H), 3.35-3.48 (m, 2H), 3.81 (s, 3H),
3.91
(br s, IH), 4.06-4.17 (m, 2H), 4.31-4.50 (m, 3H), 5.19-5.39 (dm, J= 58 Hz,
1H), 6.16 (dd, J=
10, 2 Hz, 2H)
Example 2 Preparation of (5R)-3-[4-(3,3-difluoroazetidin-l-yl)-3,5-
difluorophenyl]-2-
oxo-1,3-oxazolidine-5-carboxamide
>C3YNH2
O
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1,1'-Carbonyldiimidazole (0.155 g, 0.93 mmol) is added to a solution of methyl
(2R)-
3-{ [4-(3,3-difluoroazetidin-1-yl)-3,5-difluorophenyl]amino}-2-
hydroxypropanoate (0.10 g,
0.31 mmol) in acetonitrile (4.0 mL) and the solution heated to 50 C for three
days. After
cooling, ethyl acetate is added and the solution washed with dilute citric
acid, twice with
dilute NaHCO3, brine, and dried (MgSO4), filtered and concentrated to provide
methyl (5R)-
3-[4-(3,3-difluoroazetidin-1-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidine-5-
carboxylate
which is used without further purification.
Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a
solution
of methyl (5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3,5-difluorophenyl]-2-oxo-1,3-
oxazolidine-5-
carboxylate (0.107 g, 0.31 mmol) in 3 mL of methanol. After 90 minutes, the
solution is
concentrated and the residue purified by preparative TLC (5% MeOH-
dichloromethane) to
afford the title compound.
MS (m/z): [M+H]} = 334
iH NMR (300 MHz, CD3CN): 3.96 (m, 1H), 4.18 (m, 1H), 4.40-4.52 (m, 4H), 4.93
(dd, J = 10, 6 Hz, 1H), 6.16 (br s, 1H), 6.70 (br s, 1H), 7.17 (dd, J= 10, 2
Hz, 2H)
Intermediates for the synthesis of example 2 are prepared as follows.
1. Preparation of methyl (2R)-3-{ [4-(3,3-difluoroazetidin-1-yl)-3,5-
difluorophenyl] amino } -2-hydroxypropanoate
F \ / NH OMe
A solution of 1-(2,6-difluoro-4-nitrophenyl)-3,3-difluoroazetidine (0.25 g,
1.0 mmol)
in 2 mL of methanol containing 10% Pd/C (0.050 g) is stirred under an
atmosphere of
hydrogen. After 2.5 hours, the solution is filtered through celite with the
aid of methanol and
the filtrate concentrated to provide 4-(3,3-difluoroazetidin-1-yl)-3,5-
difluoroaniline which is
used directly in the next step.
A solution of 4-(3,3-difluoroazetidin-1-yl)-3,5-difluoroaniline (1.0 mmol) in
acetonitrile (4 mL) is treated with (R)-methyl glycidate (0.185 g, 1.2 mmol)
and lithium
triflate (0.236 g, 1.5 mmol), heated to 70 C for 3 hours and then cooled and
concentrated.
The residue is purified by preparative TLC (2% MeOH-dichloromethane) to afford
the title
compound.
'H NMR (300 MHz, CDC13): 3.17 (br s, 1H), 3.30-3.45 (m, 2H), 3.81 (s, 311),
3.91
(br s, 1 H), 4.39 (m, 5 H), 6.16 (dd, J = 10, 2 Hz, 2H)
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Example 3 Preparation of (5R)-3-[4-(3-methoxyazetidin-l-yl)-3,5-
difluorophenyl]-2-
oxo-1,3-oxazolidine-5-carboxamide
P--<~ NH2
n-Butyllithium solution (2.1 mL of a 1.6 M hexanes solution, 3.32 mmol) is
added to
a cooled (-78 C) solution of benzy13,5-difluoro-4-(3-methoxyazetidin-1-
yl)phenylcarbamate
(0.77 g, 2.21 mmol) in THF (11 mL). After 10 minutes, ethyl (2R)-2,3-
epoxypropanoate
(0.77 g, 6.63 mmol) is added and the solution allowed to warm to room
temperature and
stirred for 18 h. Saturated aqueous ammonium chloride is added to the reaction
mixture and
extracted with dichloromethane. The aqueous phase is acidified to pH 1 with 1N
HCl and
extracted with dichloromethane twice. The combined organic phases are then
dried
(MgSO4), filtered and concentrated to provide crude (5R)-3-[4-(3-
methoxyazetidin-1-yl)-3,5-
difluorophenyl]-2-oxo-1,3-oxazolidine-5-carboxylic acid that is used directly
in the next
reaction.
(Trimethylsilyl)diazomethane solution (0.24 mL of a 2M diethylether solution,
0.48
mmol) is added to a solution of (5R)-3-[4-(3-methoxyazetidin-1-yl)-3,5-
difluorophenyl]-2-
oxo-1,3-oxazolidine-5-carboxylic acid (0.24 mmol) in MeOH (0.5 mL). After
stirring at room
temperature for 2 hours, the reaction mixture is concentrated and treated with
methanolic
ammonia (1.0 mL of a 2.0 M solution, 2.0 mmol). After 24 hours, the solution
is concentrated
and the residue purified by preparative TLC (5% MeOH-dichloromethane) to
afford the title
compound.
MS (m/z): [M+H]+ = 328
'H NMR (300 MHz, d6-DMSO): 3.20 (s, 3H), 3.84-3.95 (m, 3H), 4.14-4.27 (m, 4H),
4.98 (m, 1H), 7.22 (dd, J = 9, 2 Hz, 2H), 7.60 (br s, 1H), 7.83 (br s, 1H)
Example 4 Preparation of (5R)-3-{3,5-difluoro-4-[3-hydroxy-3-
(trifluoromethyl)azetidin-1-yl]phenyl } -2-oxo-1,3-oxazolidine-5-carboxamide
F
F3 -
HO NH2
F
1,1'-Carbonyldiimidazole (0.018 g, 0.108 mmol) is added to a solution of
methyl
(2R)-3-( { 3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]phenyl }
amino)-2-
hydroxypropanoate (0.020 g, 0.054 mmol) in acetonitrile (0.8 mL) and the
solution heated to
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50 C for three days. After cooling, ethyl acetate is added and the solution
washed with
dilute citric acid, twice with dilute NaHCO3, brine, and dried (MgSO4),
filtered and
concentrated to provide (5R)-3-{3,5-difluoro-4-[3-hydroxy-3-
(trifluoromethyl)azetidin-l-
yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxylate which is used without further
purification.
Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a
solution of methyl
(5R)-3-{ 3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidin-l-yl]phenyl }-2-
oxo-1,3-
oxazolidine-5-carboxylate (0.021 g, 0.054 mmol) in 0.5 mL of methanol. After
90 minutes,
the solution is concentrated and the residue purified by preparative TLC (5%
MeOH-
dichloromethane) to afford the title compound.
MS (m/z): [M-H]- = 380
1H NMR (300 MHz, CD3CN): 3.96 (dd, J= 9, 6 Hz, IH), 4.18 (m, 3H), 4.42 (m,
2H),
4.80 (s, 111), 4.93 (dd, J= 10, 6 Hz, 1H), 6.16 (br s, IH), 6.70 (br s, 1H),
7.12 (dd, J= 10, 2
Hz, 2H)
Intermediates for the synthesis of example 4 are prepared as follows.
I. Preparation of 1-(2,6-difluoro-4-nitrophenyl)azetidin-3-one
A solution of DMSO (0.84 mL, 12 mmol) in dichloromethane (10 mL) is added to a
cooled (-65 C) solution of oxallyl chloride (3.0 mL, 6.0 mmol) in
dichloromethane (20 mL).
After stirring for 25 minutes, a solution of 1-(2,6-difluoro-4-
nitrophenyl)azetidin-3-ol (1.25 g,
5.4 mmol) in 20 mL of 5% DMSO-dichloromethane is added dropwise. The reaction
mixture
is stirred for 30 minutes at -60 C and then treated with triethylamine (3.7
mL, 27 mmol) and
allowed to warm to room temperature. After stirring for 4 hours, the reaction
mixture is
poured into water, the layers separated and the aqueous phase extracted with
more
dichloromethane. The combined organic phases washed with saturated NaHCO3,
brine, and
dried (MgSO4), filtered and concentrated. The residue is purified by column
chromatography
(0-30% ethyl acetate-hexane) to provide the title compound.
'H NMR (300 MHz, CDCl3): 5.17 (tr, J= 1 Hz, 4H), 7.80 (dd, J = 8, 2 Hz, 2H)
II. Preparation of 1-(2,6-difluoro-4-nitrophenyl)-3-(trifluoromethyl)azetidin-
3-ol
(Trifluoromethyl)trimethylsilane (0.11 mL, 0.75 mmol) and then
tetrabutylammonium fluoride (0.028 mL of a 1.0 M solution, 0.028 mmol) is
added to a THF
(3.5 mL) solution of 1-(2,6-difluoro-4-nitrophenyl)azetidin-3-one (0.16 g,
0.70 mmol) cooled
to 0 C. After warming to room temperature and stirring for 5 hours, saturated
ammonium
chloride solution (1.2 mL) and tetrabutylammonium fluoride (l.l mL of a 1.0 M
solution, 1.1
mmol) are added and the reaction mixture stirred for another hour. Ethyl
acetate and water
are then added, the layers separated, and the aqueous phase extracted with
more ethyl acetate.
Combined organic phases are washed with water, brine, and dried (MgSO4),
filtered and
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CA 02614105 2008-01-03
WO 2007/004037 PCT/IB2006/001835
concentrated. The crude residue is purified by preparative TLC (20% ethyl
acetate-hexane)
to afford the title compound.
'H NMR (300 MHz, CDCl3): 2.84 (s, 1H), 4.40 (d, J = 10 Hz, 2H), 4.68 (d, J =
10
Hz, 2H), 7.74 (dd, J = 8, 2 Hz, 2H)
IIT. Preparation of methyl (2R)-3-({3,5-difluoro-4-[3-hydroxy-3-
(trifluoromethyl)azetidin-1-yl]phenyl } amino)-2-hydroxypropanoate
A solution of 1-(2,6-difluoro-4-nitrophenyl)-3-(trifluoromethyl)azetidin-3-ol
(0.027
g, 0.091 mmol) in 2 mL of methanol containing 10% Pd/C (0.020 g) is stirred
under an
atmosphere of hydrogen. After 2.5 hours, the solution is filtered through
celite with the aid
of methanol and the filtrate concentrated to provide 1-(4-amino-2,6-
difluorophenyl)-3-
(trifluoromethyl)azetidin-3-ol which is used directly in the next step.
A solution of 1-(4-amino-2,6-difluorophenyl)-3-(trifluoromethyl)azetidin-3-ol
(0.091
mmol) in acetonitrile (0.3 mL) is treated with (R)-methyl glycidate (0.014 g,
0.14 mmol) and
lithium triflate (0.022 g, 0.14 mmol), heated to 70 C for 3 hours and then
cooled and
concentrated. The residue is purified by preparative TLC (5% MeOH-
dichloromethane) to
afford the title compound.
'H NMR (300 MHz, CDC13): 2.78 (br s, 1H), 3.04 (br s, 1H), 3.30-3.45 (m, 2H),
3.81
(s, 3H), 3.91 (br s, 1H), 4.06 (d, J = 10 Hz, 2H), 4.38 (app d, J= 10 Hz, 3H),
6.16 (dd, J = 10,
2 Hz, 2H)
Example 5 Preparation of (5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3-fluorophenyl]-
2-oxo-
1,3-oxazolidine-5-carboxamide
~ \ l NH2
1,1'-Carbonyldiimidazole (0.14 g, 0.83 mmol) is added to a solution of methyl
(2R)-
3-{[4-(3,3-difluoroazetidin-l-yl)-3-fluorophenyl]amino}-2-hydroxypropanoate
(0.13 g, 0.43
mmol) in acetonitrile (5 mL) and the solution heated to 50 C for three days.
After cooling,
ethyl acetate is added and the solution washed with dilute citric acid, twice
with dilute
NaHCO3, brine, and dried (MgSO4), filtered and concentrated to provide methyl
(5R)-3-[4-
(3,3-difluoroazetidin-I-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-
carboxylate which is
used without further purification.
Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to a
solution
of methyl (5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-
oxazolidine-5-
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CA 02614105 2008-01-03
WO 2007/004037 PCT/IB2006/001835
carboxylate (0.10 g, 0.31 mmol) in 3 mL of methanol. After 90 minutes, the
solution is
concentrated and the residue purified by preparative TLC (5% MeOH-
dichlorometliane) to
afford the title compound.
MS (m/z): [M+H7+ = 316
'H NMR (300 MHz, CD3CN): 4.02 (dd, J= 9, 6 Hz, 1H), 4.17-4.32 (m, 5H), 4.93
(dd, J = 10, 6 Hz, 1H), 6.17 (br s, 1H), 6.63 (m, 1H), 6.70 (br s, 1H), 7.12
(m, 111), 7.42 (dd, J
= 15, 3 Hz, 1H)
Intermediates for the synthesis of example 5 are prepared as follows.
I. Preparation of methyl (2R)-3-{[4-(3,3-difluoroazetidin-l-yl)-3-
fluorophenyl]amino}-
2-hydroxypropanoate
A solution 1-(2-fluoro-4-nitrophenyl)-3,3-difluoroazetidine (0.19 g, 0.84
mmol) in 10
mL of methanol containing 10% Pd/C (0.020 g) is stirred under an atmosphere of
hydrogen.
After 2.5 hours, the solution is filtered through celite with the aid of
methanol and the filtrate
concentrated to provide 1-(4-amino-2-fluorophenyl)-3,3-difluoroazetidine which
is used
directly in the next step.
A solution 1-(4-amino-2-fluorophenyl)-3,3-difluoroazetidine (0.84 mmol) in
acetonitrile (5 mL) is treated with (R)-methyl glycidate (0.13 g, 1.3 mmol)
and lithium triflate
(0.21 g, 1.3 mmol), heated to 70 C for 3 hours and then cooled and
concentrated. The
residue is purified by preparative TLC (2% MeOH-dichloromethane) to afford the
title
compound.
'H NMR (300 MHz, CDC13): 3.25-3.50 (m, 4H), 3.78 (s, 3H), 4.18 (m, 4H), 4.36
(m,
1H), 6.43 (m, 3H)
Example 6 Preparation of (5R)-N-methyl-3-[4-(3,3-difluoroazetidin-1-yl)-3-
fluorophenyl]-2-oxo-1,3-oxazolidine-5-carboxamide
H
p N-1
D
Methylamine (1.0 mL of a 2.0 M solution, 2.0 mmol) is added to a solution of
methyl
(5R)-3-[4-(3,3-difluoroazetidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-
carboxylate
(0.030 g, 0.091 mmol) in 0.5 mL of methanol. After 90 minutes, the solution is
concentrated
and the residue purified by preparative TLC (3% MeOH-dichloromethane) to
afford the title
compound.
MS (m/z): [M+H]+ = 330
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CA 02614105 2008-01-03
WO 2007/004037 PCT/IB2006/001835
'H NMR (300 MHz, CD3CN): 2.73 (d, J= 3 Hz, 3H), 3.98 (m, IH), 4.16-4.32 (m,
5H), 4.93 (dd, J = 10, 6 Hz, 1H), 6.63 (m, 1H), 6.96 (br s, 1H), 7.14 (m, 1H),
7.43 (dd, J
15,3 Hz, 1H)
Example 7 Preparation of (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl)-2-oxo-
1,3-
oxazolidine-5-carboxamide
F
HO-0- NH2
Methanolic ammonia (2.0 mL of a 2.0 M solution, 4.0 mmol) is added to methyl
(5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-
carboxylate (0.12
g, 0.39 mmol) and stirred at room temperature. After an hour, the solution is
concentrated
and the residue purified by preparative TLC (5% MeOH-dichloromethane) to
afford the title
compound.
MS (m/z): [M+H]+ = 295
1H NMR (300 MHz, d6-DMSO): 1.82-1.92 (m, 2H), 2.55-2.61 (m, 2H), 2.98 (m, 1H),
3.95-4.08 (m, 2H), 4.24 (tr, J= 9 Hz, 1H), 4.98-5.03 (m, 1H), 5.11 (d, J= 6
Hz, 1H), 7.30-
7.35 (m, 2H), 7.42 (d, J = 12 Hz, 1H) 7.60 (s, 1H), 7.84 (s, 1H)
Intermediates for the synthesis of example 7 are prepared as follows.
I. Preparation of 3-fluoro-4-(3-{tert-butyldimethylsilyloxy}-
cyclobutyl)aniline
A solution of benzyl3-fluoro-4-(3-{tert-butyldimethylsilyloxy}-
cyclobutyl)phenylcarbamate (1.2 g, 2.79 mmol) in 25 mL of methanol containing
20%
Pd(OH)2/C (0.3 g) is stirred under an atmosphere of hydrogen. After 4 hours,
the solution is
filtered through celite with the aid of methanol and the filtrate concentrated
to provide the
title compound, which is used directly in the next step.
MS (m/z): [M+H]+ = 296
'H NMR (300 MHz, CDC13): 0.067 (s, 6H), 0.89 (s, 9H), 1.94-2.01 (m, 2H), 2.58-
2.63 (m, 2H), 2.94 (m, 1H), 3.45 (s, 2H), 4.19 (m, 1H), 6.29 (dd, J= 12, 2 Hz,
1H), 6.40 (dd,
J= 9, 2 Hz, 1H) 6.99 (tr, J= 9 Hz, 1H)
IC. Preparation of methyl (5R)-3-[3-fluoro-4-(3-{tert-butyldimethylsilyloxy}-
cyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate
A solution of 3-fluoro-4-(3-{tert-butyldimethylsilyloxy}-cyclobutyl)aniline
(0.83 g,
2.8 mmol) in acetonitrile (10.0 mL) is treated with (R)-methyl glycidate (0.43
g, 4.2 mmol)
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CA 02614105 2008-01-03
WO 2007/004037 PCT/IB2006/001835
and lithium triflate (0.66 g, 4.2 mmol), heated to 60 C for 16 hours and then
cooled and
concentrated to provide methyl (2R)-3-{[3-fluoro-4-(3-{tert-
butyldimethylsilyloxy}-
cyclobutyl)phenyl]amino }-2-hydroxypropanoate that is used in the next step
without further
purification.
1,1'-Carbonyldiimidazole (0.9 g, 5.6 mmol) is added to a solution of methyl
(2R)-3-
{ [3-fluoro-4-(3-{ tert-butyldimethylsilyloxy }-cyclobutyl)phenyl]amino } -2-
hydroxypropanoate (1.1 g, 2.8 mmol) in acetonitrile (28 mL) and the solution
heated to 65 C
for 16 hours. After cooling, ethyl acetate is added and the solution washed
with dilute citric
acid, saturated NaHCO3a brine, and dried (MgSO4), filtered and concentrated.
Column
chromatography (0-4% MeOH-dichloromethane) afforded the title compound.
MS (m/z): [M+H] " = 424
'H NMR (300 MHz, CDC13): 0.043 (s, 6H), 0.87 (s, 9H), 1.93-2.03 (m, 2H), 2.61-
2.69 (m, 2H), 3.03 (m, 1H), 3.84 (s, 3H), 4.06-4.11 (m, 1H), 4.21-4.28 (m,
2H), 5.02-5.07 (m,
1H), 7.11 (dd, J = 9, 2 Hz, 1H), 7.22 (tr, J = 9 Hz, 1H), 7.33 (dd, J = 12, 2
Hz, 1H)
III. Preparation of methyl (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-
oxo-1,3-
oxazolidine-5-carboxylate
Hydrogen fluoride triethylamine complex (0.58 mL, 3.54 mmol) is added to a THF
(12.0 mL) solution of methyl (5R)-3-[3-fluoro-4-(3-{tert-
butyldimethylsilyloxy}-
cyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (0.5 g, 1.18 mmol) at
room
temperature. After 5 hours, the solution is treated with dilute NaHCO3
dropwise and
extracted with dichloromethane. The organic extracts are washed with brine,
dried (MgSO4),
filtered, and concentrated. Purification by column chromatography (0-4% MeOH-
dichloromethane) afforded the title compound.
MS (m/z): [M+H]+ = 310
1H NMR (300 MHz, CDC13): 1.93-2.03 (m, 2H), 2.70-2.79 (m, 2H), 3.04-3.08 (m,
1H), 3.85 (m, 3H), 4.06-4.11 (m, 1H), 4.21-4.32 (m, 2H), 5.02-5.07 (m, 1H),
7.11-7.20 (m,
2H), 7.33 (dd, J= 12, 2 Hz, 1H)
Example 8 Preparation of (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-
1,3-
oxazolidine-5-carboxamide
O
NH2
O
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CA 02614105 2008-01-03
WO 2007/004037 PCT/IB2006/001835
Methanolic ammonia (1.0 mL of a 2.0 M solution, 2.0 mmol) is added to methyl
(5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-1,3-oxazolidine-5-
carboxylate (0.08
g, 0.25 mmol) and stirred at room temperature. After an hour, the solution is
concentrated to
afford the title compound.
MS (m/z): [M+H]+ = 309
'H NMR (300 MHz, CDC13): 1.93-2.02 (m, 2H), 2.67-2.73 (m, 2H), 3.15 (m, 1H),
3.25 (s, 3H), 3.87 (m, 1H), 4.17-4.29 (m, 2H), 4.94-4.99 (m, 1H), 5.61 (s,
1H), 6.55 (s, 1H),
7.10-7.22 (m, 2H), 7.36 (dd, J= 12, 2 Hz, 1H)
Synthesis of example 8 is prepared as follows.
I. Preparation of methyl (5R)-3-[3-fluoro-4-(3-methoxycyclobutyl)phenyl]-2-oxo-
1,3-oxazolidine-5-carboxylate
II.
, O
O
Trimethyloxonium tetrafluoroborate (0.077 g, 0.52 mmol) is added to a cooled
(0 C)
solution of methyl (5R)-3-[3-fluoro-4-(3-hydroxycyclobutyl)phenyl]-2-oxo-1,3-
oxazolidine-
5-carboxylate (0.16 g, 0.52 mmol) and 2,6-di-tert-butyl-4-methyl pyridine
(0.21 g, 1.0 mmol)
in dicloromethane (3.25 mL). After stirring at 4 C for 16 h, the reaction
mixture is diluted
with dichloromethane, washed with saturated NaHCO3 and brine, and dried
(MgSO4), filtered
and concentrated. The crude residue is purified by pTLC (4% MeOH-
dichloromethane) to
provide the title compound.
MS (m/z): [M+H]+ = 324
'H NMR (300 MHz, CDC13): 1.92-2.02 (m, 2H), 2.64-2.72 (m, 211), 3.11-3.18 (m,
1H), 3.24 (s, 3H), 3.81-3.89 (m, 4H), 4.06-4.11 (m, 1H), 4.24 (tr, J= 9 Hz,
1H), 5.02-5.06 (m,
IH), 7.11 (dd, J = 9, 2 Hz, 1H), 7.21 (tr, J = 6 Hz, 1H), 7.34 (dd, J = 12, 2
Hz, 1H)
-24-

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

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Event History

Description Date
Application Not Reinstated by Deadline 2010-06-28
Time Limit for Reversal Expired 2010-06-28
Deemed Abandoned - Failure to Respond to Maintenance Fee Notice 2009-06-26
Inactive: Cover page published 2008-03-27
Inactive: Acknowledgment of national entry - RFE 2008-03-25
Letter Sent 2008-03-25
Inactive: First IPC assigned 2008-01-26
Application Received - PCT 2008-01-25
National Entry Requirements Determined Compliant 2008-01-03
Request for Examination Requirements Determined Compliant 2008-01-03
All Requirements for Examination Determined Compliant 2008-01-03
Application Published (Open to Public Inspection) 2007-01-11

Abandonment History

Abandonment Date Reason Reinstatement Date
2009-06-26

Maintenance Fee

The last payment was received on 2008-01-03

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Fee History

Fee Type Anniversary Year Due Date Paid Date
Basic national fee - standard 2008-01-03
Request for examination - standard 2008-01-03
MF (application, 2nd anniv.) - standard 02 2008-06-26 2008-01-03
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
PHARMACIA & UPJOHN COMPANY LLC
Past Owners on Record
ADAM ROBERT RENSLO
MIKHAIL FEDOROVICH GORDEEV
VARA PRASAD VENKATA NAGENDRA JOSYULA
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Description 2008-01-03 24 1,297
Representative drawing 2008-01-03 1 2
Claims 2008-01-03 3 93
Abstract 2008-01-03 1 56
Cover Page 2008-03-27 1 31
Acknowledgement of Request for Examination 2008-03-25 1 177
Notice of National Entry 2008-03-25 1 204
Courtesy - Abandonment Letter (Maintenance Fee) 2009-08-24 1 174
PCT 2008-01-03 4 151