Title of Invention

A PHENYL OXAZOLIDINONE COMPOUND HAVING ANTI-BACTORIAL ACTIVITY

Abstract Bicyclic heterocyclic substituted phenyl oxazolidinone antibacterials, and related compositions and methods. Bicyclic heterocyclic substituted phenyl oxazolidinone compounds of the formula:wherein Y is a radical of Formulae II or III: in which the substituents have the meaning indicated in the description. These compounds are useful as antibacterial agents.
Full Text Bicyclic Heterocyclic Substituted Phenyl Oxazolidinone Antibacterials,
and Related Compositions and Methods
CROSS-RFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part to U.S. application Serial
Number 09/621,814 filed on July 21. 2000.
FIELD OF THE INVENTION
The present invention relates to the field of phenyl oxazolidinone
compounds having antibacterial activity against Gram-positive and Gram-
. ....
negative bacteria, pharmaceutical compositions containing the compounds,
and methods of treating bacterial infections with the compounds.
BACKGROUND OF THE INVENTION
Oxazolidinones have been identified, within the last twenty years, as a
new class of antibacterials which are active against numerous multidrug-
resistant gram positive organisms. Particularly problematic pathogens include
methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-
intermediate resistant Staphylococcus aureus (GISA), vancomycin-resistant
enterocci (VRE) and penicillin- and cephalosporin-resistant Streptococcus
pneumoniae. As a class, oxazolidinones exhibit a unique mechanism of
action. Studies have shown that these compounds selectively bind to the 50S
ribosomal subunit and inhibit bacterial translation at the initiation phase of
protein synthesis. Exemplary members of oxazolidinones are linezolid (see
WO 95/07271) and eperezolid.
U.S. Pat. No. 5,792,765 to Riedl et al. discloses a series of substituted
oxazolidinones (cyanoguanidine, cyanoamidines, and amidines) useful as
antibacterial medicaments.
U. S. Patent No. 5,910,504 to Hutchinson discloses a series of hetero-
aromatic ring substituted phenyl oxazolidinones, including indolyl substituted
compounds useful as antibacterial agents.
WO 98/54161 (Hester et al.) discloses amides, thioamides, ureas, and
thioureas which are antibacterial agents.
WO 95/07271 (Barbachyn et al.) discloses qxazine and thiazine
oxazolidinone derivatives such as linezolid and its analogs which are useful
antimicrobial agents, effective against a number of human and veterinary
pathogens, including gram-positive aerobic bacteria such as multiple-resistant
staphylococci, streptococci and enterococci as well as anaerobic organisms
such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms
such as Mycobacterium tuberculosis, Mycobacterium avium and
Mycobacterium spp.
WO 93/09103 (Barbachyn et al.) discloses substituted aryl- and
heteroaryjphenyloxazolidinones_which are useful as antibacterial agents.
SUMMARY OF THE INVENTION
The invention provides phenyl oxazolidinone compounds of Formula I:
wherein:
(i) R" is straight-chain or branched acyl having up to 6 carbon atoms or benzyl;
(ii) R" is straight-chain or branched alkyl, having up to 5 carbon atoms, phenyl
or tolyl; and
(iii) R"" and R"" are independently selected from the group consisting of H,
cycloalkyl having 3 to 6 carbon atoms, phenyl or tert-butoxycarbonyl,
fluorenyloxycarbonyl, benzyloxycarbonyl, straight-chain or branched alkyl
having up to 6 carbon atoms which is optionally substituted by cyano or
alkoxycarbonyl having up to 4 carbon atoms, -CO2-R1, -CO-R1, -CS-R1,
and -SO2-R4, in which
R1 is selected from the group consisting of H, cycloalkyl having 3 to 6
carbon atoms, trifluoromethyl or phenyl, benzyl or acyl having up to 5
carbon atoms, straight-chain or branched alkyl having up to 6 carbon
atoms, said alkyl optionally substituted by straight-chain or branched
alkoxycarbonyl having up to 5 carbon atoms, OH, cyano, up to 3 halogen
atoms, and -NR5 R6 in which R5 and R6 are identical or different and are
selected from H, phenyl or straight-chain or branched alkyl having up to 4
carbon atoms;
R4 is selected from straight-chain or branched alkyl having up to 4 carbon
atoms or phenyl and;
R4a is CN, COR4C, COOR4c, CONHR4c, CO-NR4c R4d, SO2R4C, or NO2;
R4b is H, alkyl, OR4c, SR4c, amino, NHR4c, NR4C,R4d;
R4c and R4d are independently selected from H, alkyl, aryl, or in the case of
any NR4cR4d group R4c and R4d taken together with the nitrogen atom to
which they are attached form a unsubstituted or substituted pyrrolidinyl,
piperidinyl or morpholinyl group;
X is 0 to 4 members independently selected from the group consisting of
halogen, OH, nitro, C1-8 alkoxy, C1-8 alkyl-amino, di(C1-8-alkyl-)amino,
carboxy, alkoxycarbonyl, C1-8 alkyl-CO-O-, C1-8 alkyl-CO-NH-, carboxamide,
CN, amine, C3-6 cycloalkyl, C1-8 alkyl optionally substituted with one or more
members selected from the group consisting of F, Cl, OH; and
R5, R6, R7, and R8, are each independently H, alkyl, CN, nitro, C1-8 alkyl,
halo-C1-8-alkyl, formyl, carboxy, alkoxycarbonyl, carboxamide, or R5 and
R6 and/or R7 and R8 together form an oxo group;
R9, and R10 are each independently H, halogen, alkyl, OH, CN, nitro, C1-8
alkyl, halo-C1-8-alkyl, C1-8 aikoxyl, amino, C1-8-alkyl-amino, di(C1-8-alkyl-
)amino, formyl, carboxy, alkoxycarbonyl, C1-8-alkyl-CO-O-, C1-8-alkyl-CO-
NH-, carboxamide, or amine ;
(ol
is a fused phenyl ring or a five- or six-membered heteroaromatic
ring having one to four members selected from the group consisting of S,
O, and N;
Z is halogen, alkyl, substituted-alkyl, aryl, substituted-aryl, heteroaryl,
substituted-heteroaryl, CN, CHO, COalkyl, amino, alkoxy, HNCO-(C1-8
C8alkyl), allyl, propargyl, allenyl, or N-alkylthiocarbamoyl;
and
m is 0 or 1,
and the pharmaceutically acceptable salts and esters thereof.
Compounds of the above formula are useful as antibacterial agents for
the treatment of bacterial infections in humans and animals.
The present invention is also directed to a method of treating a subject
having a condition caused by or contributed to by bacterial infection, which
comprises administering to said mammal a therapeutically effective amount of
the compound of Formula I.
The present invention is further directed to a method of preventing a
subject from suffering from a condition caused by or contributed to by
bacterial infection, which comprises administering to the subject a
prophylactically effective dose of the pharmaceutical composition of a
compound of Formula I.
Other objects and advantages will become apparent to those skilled in
the art from a review of the ensuing specification.
DETAILED DESCRIPTION
Relative to the above description of the phenyl oxazolidinone
compounds of the present invention, the following definitions apply.
Unless specified otherwise, the terms "alkyl", "alkenyl", and "alkynyl"
may be straight or branched groups with 1-8 carbon atoms.
"Substituted alkyl" may be a straight or branched-chain moiety with 1-8
carbon atoms having one or more substituents selected from the group
consisting of amino, diaikylarnino, cycloalky!, hydroxy, oxo, alkoxycarbonyl,
benzyloxy, arylthio, alkylthio, hydroxyalkylthio, alkylsulfinyl, alkylsulfonyl,
carboxy, phosphonooxy, dialkylphosphonooxy, dibenzylphosphonooxy,
cyano, halo, trialkylsilyl, dialkylphenylsilyl, aryl, heteroaryl, heterocyclo,
heterocyclomethyibenzoyloxy, dialkylaminomethylbenzoyloxy,
dialkylaminoalkylcarbonyloxy, benzyloxycarbonylaminoalkylcarbonyloxy, and
aminoalkylcarbonyloxy.
"Acyl" means an organic radical having the designated number of
carbon atoms, derived from an organic acid by the removal of a hydroxyl
group having the formula RCO, as in the case of acetyl where R is CH3.
"Aryl" is an unsubstituted carbocyclic aromatic group including, but not
limited to, phenyl, 1- or 2-naphthyl and the like. "Heteroaryl" refers to a cyclic
aromatic radical having from five to ten atoms in the ring; where one to three
ring atoms are independent heteroatoms such as S, O, and N, and the
remaining ring atoms are carbon, for example, a • pyridinyl, pyrazinyl,
pyrimidinyl, pyrroyi, pyrazolyl, imidazolyl, thiazoiyl, oxazolyl, isoxazolyl,
thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, or isoquinolinyl, radical
and the like.
"Substituted aryl" or "substituted heteroaryl" refers to an aryl or
heteroaryl substituted by independent replacement of 1-3 of the hydrogen
atoms thereon with halogen, OH, CN, mercapto, nitro, C1-8-alkyl, halo-C1-8-
alkyl, C1-8,alkoxy, thio-C1-8-alkyl, amino, C1-8-alkyl-amine, di(C1-C8-alkyl-
)amino, formyl, carboxy, alkoxycarbonyl, C1-8-alkyl-CO-O-, C1-8-alkyl-CO-NH-,
or carboxamide. Further, substituted-heteroaryl may be substituted with a
mono-oxo to give, for example, a 4-oxo-1-H-quinoline. Substituted-heteroaryl
may also be substituted with a substituted-aryl or a second substituted-
heteroaryl to give, for example, a 4-phenyl-imidazol-1-yl or a 3-pyridinyl-
imidazol-1-yl, and the like.
The terms "heterocycle," "heterocyclic," and "heterocyclo" refer to an
optionally substituted, fully saturated, partially saturated, or non-aromatic
cyclic group which is, for example, a 3- to 7-membered monocyclic, 7- to 11-
membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at
least one heteroatom in at least one carbon atom containing ring. Each ring
of the heterocyclic group containing a heteroatom may have 1, 2, or 3
heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms,
where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
The nitrogen atoms may optionally be quaternized. The heterocyclic group
may be attached at any heteroatom or carbon atom.
The term "halo" or "halogen" means fluoro, chloro, bromo and iodo.
(mono-, di-, tri-, and per-) halo-alkyl is an alkyl radical substituted by
independent replacement of the hydrogen atoms thereon with halogen. P
denotes phosphorus.
The compounds of the instant invention are asymmetric in the
oxazolidinone ring at the 5- position and thus exist as optical antipodes. As
such, all possible optical antipodes, enantiomers or diastereomers resulting
from additional asymmetric centers that may exist in optical antipodes,
racemates and racemic mixtures thereof are also part of this invention. The
antipodes can be separated by methods known to those skilled in the art such
as, for example, fractional recrystallization of diastereomeric salts of
enantiomerically pure acids. Alternatively, the antipodes can be separated by
chromatography on a Pirkle column.
The phrase "pharmaceutically acceptable salts" denotes salts of the
free base which possess the desired pharmacological activity of the free base
and which are neither biologically nor otherwise undesirable. These salts may
be derived from inorganic or organic acids. Examples of inorganic acids are
hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric
acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid,
lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
methyl sulfonic acid, salicyclic acid and the like. Suitable salts are
furthermore those of inorganic or organic bases, such as KOH, NaOH,
Ca(OH)2, AI(OH)3, piperidine, morpholine, ethylamine, triethylamine and the
like.
Also included within the scope of the invention are the hydrated forms
of the compounds which contain various amounts of water, for instance, the
hydrate, hemihydrate and sesquihydrate forms.
The term "subject" includes, without limitation, any animal or artificially
modified animal. In the preferred embodiment, the subject is a human.
The term "drug-resistant" or "drug-resistance" refers to the
characteristics of a microbe to survive in presence of a currently available
antimicrobial agent at its routine, effective concentration.
The compounds of the present invention possess antibacterial activity
against Gram-positive and certain Gram-negative bacteria. They are useful
as antibacterial agents for the treatment of bacterial infections in humans and
animals. Particularly, these compounds have antimicrobial activity against S.
aureus, S. epidermidis, S. pneumoniae, E. faecalis, E. faecium, Moraxella
catarrhalis, and H. influenzae. More particularly, these compounds are useful
against resistant bacteria such as MRSA and GISA, and have a low
susceptibility to acquired resistance mechanisms.
Compounds of Formula I which are preferred for such purposes are
those in which R is any of the following:
In addition Compounds of Formula I which are preferred for such
purposes are those in which Y is any of the following:
In addition, Compounds of Formula I which are preferred for such
purposes or those in which Z is any of the following: propargyl, allyl, allenyl,
N-alkylthiocarbamoyl, alkyl, heteroaryl, substituted-heteroaryl, or a substituted
alkyl having one or more substituents selected form the group consisting of
amino, dialkylamino, cycloalkyl, hydroxy, oxo, alkoxycarbonyl, benzyloxy,
arylthio, alkylthio, hydroxyalkylthio, alkylsulfinyl, alkylsulfonyl, carboxy,
phosphonooxy, dialkylphosphonooxy, dibenzylphosphonooxy, cyano, halo,
trialkylsilyl, dialkyiphenylsilyl, aryl, heteroaryl, heterocyclo,
heterocyclomethylbenzoyioxy, dialkyiaminomethylbenzoyloxy,
dialkylaminoalkylcarbonyloxy, benzyloxycarbonylaminoalkylcarbonyioxy, and
aminoalkylcarbonyloxy.
Particularly preferred Compounds of Formula I are those wherein Z is
selected from the group consisting of propargyl, ally!, allenyl, N-
alkylthiocarbamoyl, ethyl, isopropyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl,
2,2,2-trifluoroethyl, cyanomethyl, 2-cyanoethyl, cyclopropylmethyl, 2-
oxopropyl, methylthiomethyl, 2-methylthioethyl, methylsulfonylmethyl, 2-
methylsulfonylethyl, methylsulfinylmethyl, t-butoxycarbonylmethyl, 2-
carboxyethyl, 2-(di-t-butylphosphonooxy)ethyl,2-(dibenzylphosphonooxy)ethyl,
2-phosphonooxyethyl, 2-aminoethyl, 2-(diethylamino)ethyl, 2-
(dimethylamino)ethyl, 2-(4-morpholinyl)ethyl, 2-(4-thiomorpholinyl)ethyl,
trimethylsilylmethyl, dimethylphenylsilylmethyl, benzyloxymethyl, benzyl, 5-
tetrazolylmethyl, 3-pyridylmethyl, 2-pyridylmethyl, 2-oxiranylmethyl, 2-
oxooxazolidin-5-ylmethyl, 2,3-dihydroxypropyl, 2-hydroxy-3-(1 -
piperidinyl)propyl, 2-hydroxy-3-(4-morpholinyl)propyl, 2-hydroxy-3-
phenylthiopropyl, 2-hydroxy-3-ethylthiopropyl, 2-hydroxy-3-(2-
hydroxyethylthio)propyl, 3-[4-{1,1-dioxothiomorpholinyl)]-2-hydroxypropyl, 3-
ethylsulfinyl-2-hydroxypropyl, 2-[4-(4-morpholinylmethyl)benzoyloxy]ethyl, 2-
[4-(dimethylaminomethyl)benzoyloxy]ethyl, 2-[4-(4-methyl-1 -
piperazinylmethyl)benzoyioxy]ethyl, 2-(dimethylaminoacetoxy)ethyl, 2-[2-
(benzyloxycarbonylamino)-3-methylbutyryloxy]ethyl, 2-(2-amino-3-
methylbutyryloxy)ethyl, 2-pyridinyl, pyridazinyl, and 2-pyrimidinyl.
Particular examples of the present invention include the following
compounds:
A/-[[(5S)-3-[4-(1,3-Dihydro-2H-isoindol-2-yl)-3-fluorophenyl]-2-oxo-5-
oxazolidinyl]methyi]acetamide;
N-[[(5S)-3-[4-(1,3-Dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-3-
fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
A/-[[(5S)-3-[3-Fluoro-4-(5-oxido-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl]-2-
oxo-5-oxazolidinyl]methyl]acetamide;
A/-[[(5S)-3-[4-(5,7-dihydro-6/-/-pyrrolo[3,4-b]pyridin-6-yl)-3-f1uorophenyl]-
2-oxo-5-oxazolidinyl]methyl]acetamide;
A/-[[(5S)-3-[4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-3-fluorophenyl]-2-
oxo-5-oxazolidinyi]methyl]acetamide; and
(5R)-3-[4-(5,7-Dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-fluorophenyl]-
5-(hydroxymethyl)-2-oxazolidinone;
N-[[(5S)-3-[4-[2,6-dihydro-2-(2-hydroxyethyl)pyrrolo[3,4-c]pyrazol-
5(4H)-yi]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
N-[[(5S)-3-[4-[2,6-dihydro-2-[(2R)-2,3-dihydroxypropyl]pyrrolo[3,4-
c]pyrazol-5(4H)-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
N-[[(5S)-3-[4-[2,6-dihydro-2-[(2S)-2.3-dihydroxypropyl]pyrrolo[3,4-
c]pyrazoi-5(4H)-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
N-[[(5S)-3-[4-(2,6-dihydro-2-propargyipyrrolo[3,4-c]pyrazol-5(4H)-yl)-3-
fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
N-[[(5S)-3-[4-(2,6-dihydro-2-cyanomethylpyrrolo[3,4-c]pyrazol-5(4H)-
yl)-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
The compounds of Formula I that are the subject of this invention may be
prepared from readily available starting materials such as isoindole (Gawley
et al., J. Org. Chem., 1988, 53:5381), 6,7-dihydro-5H-pyrrolo[3,4-c]pyridine
and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (US Pat. No. 5,371,090 to Petersen
et al.) in accordance with synthetic methods well known in the art.
Representative procedures are outlined in Scheme I-V:
Scheme I
In accordance with Scheme I, bicyclic heterocycles of general formula IV are
treated with a substituted nitrobenzene derivative (L is an appropriate leaving
group such as a halogen of trifluoromethanesulfonyloxy) in a suitable base
and solvent, such as diisopropylamine and ethyl acetate, to give the
substituted nitrophenyl compound V.
The nitrobenzene derivative V is then reduced to the aniline by an
appropriate reaction, for instance by treatment with SnCI2 or by catalytic
hydrogenation in the presence of a suitable catalyst, such as palladium on
carbon. The aniline is then treated with benzyl or methyl chloroformate and
sodium bicarbonate to form the corresponding benzyl or methyl carbamate
derivative VI.
The Cbz aniline VI is then deprotonated with a lithium base such as n-
butyllithium and reacted with (R)- glycidyl butyrate to afford the oxazolidinone
VII. The hydroxymethyl group can then be converted to an amide as shown in
Scheme I by preparation of the mesylate, conversion to azide VIII, and
reduction to amine IX by an appropriate procedure such as hydrogenation.
Alternatively displacement of a mesylate (Scheme II) or appropiate leaving
group such as tosylate or chlorine with potassium phthalimide and removal of
the phthaloyl protecting group by hydrazinolysis would provide amine IX. The
amine IX can be converted to amide X by an acylation reaction using
techniques known in the art, such as treatment with acetic anhydride in the
presence of a base such as pyridine. Alternatively, amine IX can be
converted to a carbamate XI by treatment with methylchloroformate and
pyridine, or reacted with a sulfonyl chloride in an inert solvent in the presence
of an organic base like pyridine to form a sulfonamide XII
For the formation of oxazolidione in which R = O-Heteroaryl (XIII), the
oxazolidinone carbinol VII can be converted to the corresponding mesylate or
other appropriate leaving group and reacted with HO-Het (a suitible hydroxyl
containing heterocycle), either in the presence of base or with HO-Het as a
preformed alkoxide, in an appropriate solvent, for example DMF or acetonitrile
(Scheme III). Alternatively, Mitsunobu conditions can be used to couple VII
with HO-Heterocycle by treating with triphenylphosphine and diisopropyl
azodicarboxylate (DIAD) in an appropriate solvent, such as THF, at a suitable
temperature, preferably room temperature. Reaction conditions and leading
references can be found in Gravestock et al, WO99/64416.
Furthermore, by treating VII with a suitable, non-nucleophilic base, for
example NaH, the displacement of a leaving group (LG), such as chlorine or
bromine, can be effected from an appropriately reactive aza-heterocycle (LG-
Het)(Scheme III).
Compounds of structure XIV can be prepared as shown in Scheme IV.
Amine IX can be converted to various functionalized amidines by reaction with
activated imines, where Q is a leaving group such as methylthio or methoxy,
in a suitable solvent, for example toluene or methanol, with or without a
0
catalyst (such AgNO3) present at a temperature range of 0-110 C.
In accordance with Scheme V pyrrolidinone XV (prepared as in WO96/13502)
is first reacted with methoxy-bis(dimethylamine) or other activated
dimethylformamide reagent and, second, heated in a suitable solvent (for
example DMF and benzene) with either substituted amidines, to form
pyrrolopyrimidines oxazolidinones such as XVI, or substituted hydrazines, to
form pyrrolopyrazole oxazolidinones such as XVII. Formation of the
enamine, alkoxymethylene or alkoxycarbonyl derivatives of pyrrolidinone XV,
according to Brighty et al in US 5037834A, would also allow access to these
systems.
As shown in Scheme VI compounds with the structure XIX can be
achieved by oxidation of the various compounds, XVIII, using an appropriate
oxidant (for example manganese dioxide, peroxyacetic acid, DDQ or air) in a
suitable solvent such as methylene chloride.
Oxo-derivatives of structure XXII in Scheme VII, (X = O, Y = H2 or X =
H2, Y = O) can be constructed by reacting 1,2-aryl dicarboxaldehydes (where
XXI, U = H) with aniline XX (prepared as in WO96/23788) in the presence of
acids, such as acetic acid, in a suitable solvent such as methylene chloride.
The di-oxo-derivatives (structure XXII where X = Y = O) are prepared from the
reaction of aniline XX with selected 1,2-aryl dicarbonyl reagents with a
suitable leaving group (XXI where U = Cl, Br, etc).
Compounds of the structure XXIV and XVII can be prepared as shown
in Scheme VIII. Pyrazole XXIII can be converted to regioisomeric alkylated
pyrazoles by reaction with a base, such as potassium fert-butoxide , sodium
hydride, or cesium carbonate, and an afkyfating agent, such as an alkyl
halide.
Pyrazole XXV can be further functionalized (Scheme IX) by conversion
of the hydroxyl group to an appropriate leaving group, such as mesylate or
haiide, and displacement with nucieophiles, such as an amine, thiol, etc to
afford substituted pyrazoles such as XXVI where X represents nitrogen,
sulfur, etc.
Various derivatives [amino acid (XXVII), phosphate (XXVIII) and
substituted benzoic acid (XXIX)] with greater aqueous solubility can be
prepared as illustrated in Scheme X. Coupling of pyrazole XXV with an amino
acid derivative can be accomplished using a coupling reagent, such as EDCI
and DMAP. Following coupling, the amino acid protecting groups can be
remove (if so desired) by standard literature methods known to those skilled in
the art. Phosphate derivative XXVIII can be prepared by a three-step
procedure via reaction of pyrazole XXV with dialkyl(dialkylamino)phosphite
and tetrazole, oxidation of the phosphorous with mefa-chloroperoxybenzoic
acid and removal of tert-butyl protecting groups with acid, such as TFA in
methylene chloride. Water soluble benzoic acid derivative XXIX can be
prepared by initial coupling of pyrazole XXV with 2-(chloromethyl)benzoyl
chloride, utilizing triethyl amine as base, and then displacement of the halide
with an amine, such morpholine, dimethylamine and the like, employing
sodium iodide as a catalyst.
Substituted 2-hydroxy propyl pyrazoles can be prepared through attack
on the epoxide functionality of Compound XXX with various nucleophiles,
such an amine, thiol, etc. to provide pyrazoles such as XXXI where X
represents nitrogen, sulfur, etc (Scheme XI). The sulfur containing analogs,
represented by Compound XXXII where X represents an inert linking group
(Scheme XII), can be further functionalized by reaction with oxidizing agent,
such as mete-chloroperoxybenzoic acid or tetrabutylammonium oxone, to
provide sulfoxide or sulfone analogs, such as XXXIII.
Tetrazole XXXV can be prepared by reaction of nitrile XXXIV with
azidotrimethylsilane and catalytic dibutyltinoxide provides tetrazole (Scheme
XIII).
Definitions
All temperatures are in degrees Centigrade
Brine refers to an saturated aqueous sodium chloride solution
DMF refers to N,N-dimethylformamide
THF refers to tetrahydrofuran
Cbz refers to carbobenzyloxy
n-BuLi refers to n-butyl lithium
MS refers to mass spectrometry expressed as m/e or mass/charge unit
[M + H] refers to the positive ion of a parent plus a hydrogen atom
Ether refers to diethyl ether
RT refers to room temperature
Mp refers to melting point
CH2CI2 refers to methylene chloride
NaOH refers to sodium hydroxide
MeOH refers to methanol
EtOAc refers to ethyl acetate
ppt refers to a precipitate
These compounds have antimicrobial activity against susceptible and
drug resistant bacterial pathogens such as S. aureus, S. epidermidis, S.
pneumoniae, S. pyogenes, Enterococcus spp., Moraxella catarrhalis and H.
influenzae. These compounds are particularly useful against drug resistant
Gram-positive cocci such as methicillin-resistant S. aureus and vancomycin-
resistant enterococci. These compounds are useful in the treatment of
community-acquired pneumonia, upper and lower respiratory tract infections,
skin and soft tissue infections, hospital-acquired lung infections, bone and
joint infections, and other bacterial infections.
Minimal inhibitory concentration (MIC) has been an indicator of in vitro
antibacterial activity widely used in the art. The in vitro antimicrobial activity of
the compounds was determined by the microdilution broth method following
the test method from the National Committee for Laboratory Standards
(NCCLS). This method is described in the NCCLS Document M7-A4, Vol.17,
No.2, "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that
Grow Aerobically-Fourth Edition", which is incorporated herein by reference.
In this method two-fold serial dilutions of drug in cation adjusted
Mueller-Hinton broth are added to wells in microdilution trays. The test
organisms are prepared by adjusting the turbidity of actively growing broth
cultures so that the final concentration of test organism after it is added to the
wells is approximately 5 x 104 CFU/well.
Following inoculation of the microdilution trays, the trays are incubated
at 35°C for 16-20 hours and then read. The MIC is the lowest concentration of
test compound that completely inhibits growth of the test organism. The
amount of growth in the wells containing the test compound is compared with
the amount of growth in the growth-control wells (no test compound) used in
each tray. As set forth in Table 1, some compounds of the present invention
were tested against a variety of pathogenic bacteria resulting in a range of
activities, from 1 to =128 mg/mL depending on the organism tested. S. aureus
OC2878 is a MRSA and £. faecium OC3312 is a vancomycin resistant
enterococcus.
This invention further provides a method of treating bacterial infections,
or enhancing or potentiating the activity of other antibacterial agents, in a
subject having conditions caused by or contributed to by bacterial infection,
which comprises administering to the animals a compound of the invention
alone or in admixture with another antibacterial agent in the form of a
medicament according to the invention. The terms of "treating" and
"treatment" include administering, either simultaneously, separately or
sequentially, a pharmaceutically effective amount of a composition containing
one or more of the compounds disclosed herein to a subject that desires
inhibition of bacterial growth. The pharmaceutically effective amount of the
compound used to practice the present invention for treatment varies
depending on the manner of administration, the age, weight, and general
health of the subject treated, and ultimately will be decided by physicians or
veterinarians.
The compounds of the present invention may be administered to a
subject such as a human by any route appropriate to the condition to be
treated, suitable routes including oral, rectal, nasal, topical (including buccal
and sublingual), vaginal and parenteral (including subcutaneous,
intramuscular, intravenous, intradermal, intrathecal and epidural). The
preferred route may vary with, for example, the condition of the recipient as
well as the ease of preparation and administration.
When the compounds are employed for the above utility, they may be
combined with one or more pharmaceutically acceptable carriers, e.g.,
solvents, diluents, and the like, and may be administered orally in such forms
as tablets, capsules, dispersible powders, granules, or suspensions
containing for example, from about 0.5% to 5% of suspending agent, syrups
containing, for example, from about 10% to 50% of sugar, and elixirs
containing, for example, from about 20% to 50% ethanol, and the like, or
parenteraily in the form of sterile injectable solutions or suspensions
containing from about 0.5% to 5% suspending agent in an isotonic medium.
These pharmaceutical preparations may contain, for example, from about
0.5% up to about 90% of the active ingredient in combination with the carrier,
more usually between 5% and 60% by weight.
Compositions for topical application may take the form of liquids,
creams or gels, containing a therapeutically effective concentration of a
compound of the invention admixed with a dermatologically acceptable
carrier.
In preparing the compositions in oral dosage form, any of the usual
pharmaceutical media may be employed. Solid carriers include starch,
lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin,
while liquid carriers include sterile water, polyethylene glycols, non-ionic
surfactants and edible oils such as corn, peanut and sesame oils, as are
appropriate to the nature of the active ingredient and the particular form of
administration desired. Adjuvants customarily employed in the preparation of
pharmaceutical compositions may be advantageously included, such as
flavoring agents, coloring agents, preserving agents, and antioxidants, for
example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of
ease of preparation and administration are solid compositions, particularly
tablets and hard-filled or liquid-filled capsules. Oral administration of the
compounds is preferred. These active compounds may also be administered
parenterally or intraperitoneally. Solutions or suspensions of these active
compounds as a freebase or pharmacological acceptable salt can be
prepared in water suitably mixed with a surfactant such as hydroxypropyl-
cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of storage and
use, these preparations may contain a preservative to prevent the growth of
microorganisms.
The pharmaceutical forms suitable for injectable use include sterile
aqueous solutions or dispersions and sterile powders for the extemporaneous
preparation of sterile injectable solutions or dispersions. In all cases, the form
must be sterile and must be fluid to the extent that easy syringability exists. It
must be stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such as
bacteria and fungi. The carrier can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol
and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of administration
and the severity of the condition being treated. However, in general,
satisfactory results are obtained when the compounds of the invention are
administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of
animal body weight, preferably given in divided doses two to four times a day,
or in sustained release form. For most large mammals the total daily dosage
is from about 0.07 g to 7.0 g, preferably from about 100 mg to 1000 mg.
Dosage forms suitable for internal use comprise from about 100 mg to 500 mg
of the active compound in intimate admixture with a solid or liquid
pharmaceutically acceptable carrier. This dosage regimen may be adjusted
to provide the optimal therapeutic response. For example, several divided
doses may be administered daily or the dose may be proportionally reduced
as indicated by the exigencies of the therapeutic situation.
The production of the above-mentioned pharmaceutical compositions
and medicaments is carried out by any method known in the art, for example,
by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical
composition (e.g. a granulate) and then forming the composition into the
medicament (e.g. tablets).
The following examples describe in detail the chemical synthesis of
representative compounds of the present invention. The procedures are
illustrations, and the invention should not be construed as being limited by
chemical reactions and conditions they express. No attempt has been made
to optimize the yields obtained in these reactions, and it would be obvious to
one skilled in the art that variations in reaction times, temperatures, solvents,
and/or reagents could increase the yields.
Isoindoline was synthesized employing the method of R. E. Gawley, S. R.
Chemburkar, A. L. Smith, T. V. Anklekar J. Org. Chem. 1988, 53, 5381.
Step 1:
To 3,4-difluoronitrobenzene (3.02 mL, 27.3 mmols) in ethyl acetate at rt was
added diisopropylethylamine (5.03 mL, 28.9 mmols) and then isoindoline
(3.50 g, 29.4 mmols) and stirred overnight. A yellow precipitate (ppt) formed
and was collected on a filter, washed with water and ether and dried in a
To the above nitro compound (2.62 g, 10.2 mmols) in ethanol (100 m(_) was
added SnCl2 (9.84 g, 50.9mmols) and was refluxed for 16hrs. After cooling to
rt the reaction mixture was added to 10% aq. NaOH (300 mL) and extracted
with CH2CI2 (6x50 mL). The combined organic washings were washed with
brine (100 mL), dried over Na2SO4 and concentrated to give 2.63 g of an olive
green solid (aniline), which was used without further purification. To this
aniline in acetone (150 mL) and water (20 mL) was added NaHCO3 (1.84 g,
21.9 mmols) and then benzylchloroformate (1.68 mL, 11.8 mmols). After
stirring overnight the mixture was poured into ice water (100 mL) and the
resulting tan precipitate was collected on a filter, washed with water and dried
in a vacuum to give the Cbz aniline as a tan solid (3.50 g, 95% yield). Mp =
146-148°C. MS (M + 1) = 363 m/z.
Step 3:
To the above Cbz aniline (0.74 g, 2.04 mmols) in THF (10 mL) at -780C was
added n-BuLi (2.5 M, 0.82 mL, 2.05 mmols) dropwise. After stirring for 40
min, (R)-glycidyl butyrate (0.31 mL, 2.10 mmols) in THF (0.5 mL) was added
dropwise and the resulting mixture was allowed to warm to RT overnight. A
white precipitate had formed and was collected on a filter and washed with
water and ether. Chromatography on silica gel with 25% ethyl acetate/hexane
as eluent provided the product as a white solid (0.58 g, 87% yield). MS (M +
1) = 329 m/z.
Example 2
(5R)-3-[4-(1,3-Dihydro-1 -oxo-2H-isoindol-2-yl)-
3-fluorophenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-oxazolidinone
To the oxazolidinone carbinol from Example 1 (0.58 g, 1.78 mmols), in DMF
(10 mL) and acetonititile (10 mL) at 0°C was added triethylamine (0.74 ml ,
5.31 mmols) and. after 10 mtn, methanesulfnyl chloride (0.28 mL, 3.62
mmols). After allowing) the reaction mixture to warm to RT over an hour
starting material was still present so cooling and addition of triethyl amine
(0.37 mL, 2.65 mmole) and methanesulfonyl chloride (0.14 mL, 1.81 mmols)
was repeated. The mixture was poureo Into wate (50 ml..) and extracted with
CH2CI2 (6 X 20 mL), washed with brine (4 x 10mL), dried over Na2SO4,
concentrated to afford the crude product as a bowl oil (0.95 g). MS (M + 1)
= 407 m/z.
To the mesyiate from Example 2 (0.05 g, 1.7ti rnmols) in DMF (25 mL) was
added sodium a/Mo (0.47 g, 7.?J.i inmoS:] *i~ 0" hnated to 70°C for 16 hrs. After
cooling to rt wnUsi wan added and f!ie: snJ/iure extracted with ethyl acetate
(6X25 mL), we shed with brine (4x10 ml }, diied over Na2SO4, concentrated to
give 0.48 g oi" a (hu ^oEkJ. MS (M + 1} ¦¦ :;"". \ a".."z.
The azide from Example 3 in ethyl acetate (25 mL) was placed in a Paar flask
and nitrogen bubbled through for 15 min whereupon 10% Pd/C (0.15 g, 0.14
mmol) was added. The mixture was pressurized with 50 psi of H2 (g) and
shaken for 16 hrs whereupon an additional amount of 10% Pd/C (0.15 g, 1.4
mmols) was added and the mixture shaken for an additional 6 hrs (at this
point MS (M + 1) = 328 m/z). After placing the mixture under nitrogen,
pyridine (0.22 mL, 2.72 mmol) and then Ac2O (0.51 mL, 5.30 mmol) were
added and the mixture stirred for 2 hrs. The mixture was filtered through
celite, washing with ethyl acetate (100 mL), concentrated, and
chromatographed on silica (gradient elution 1%-5% MeOH/CH2CI2) and then
triturated with ethyl acetate (3X3 mL) to give 0.19 g of a white solid
(Compound 1, 29% yield for 4 steps). Mp = 240-242°C. MS (M + 1) = 370
m/z.
Example 5
6.7-Dihvdro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-blpyridine: To 6,7-
dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride salt (as described by
Petersen, et al. (Bayer) EP0520277A2)(42.8 g, 222 mmols) in DMF (1.2 L)
was added 2,4-difluoronitrobenzene (25 mL, 224 mmols). The mixture was
heated to 60°C and DIPEA (195 mL, 1.12 mols) was added dropwise from an
addition funnel over 2 hrs. After heating overnight the reaction mixture was
cooled to rt, poured into water (3 L), filtered and dried in a vacuum oven
(50°C) to provide a yellow-green solid (53.8 g, 94% yield). MS (M + 1) = 260
m/z.
Step 2:
6.7-Dihvdro-6-(2-fluoro-4-aminophenyl)-5H-pyrrolo[3.4-b]pvridine
To the above nitro compound (53.8 g, 208 mmol) in THF (175 mL) and
methanol (600 mL) was added ammonium formate (59.0 g, 907 mmol).
Nitrogen was bubbled through the reaction for approximately 30 minutes
whereupon 10% Pd/C (2.20 g, 21 mmols) was added. After stirring overnight
at rt under an atmosphere of nitrogen the reaction mixture was filtered through
a pad of Celite, washing thoroughly with methanol (400 mL), and
concentrated to a volume of ca. 200 mL. Water (300 mL) was added and the
mixture extracted with ethyl acetate (5X200 mL). The combined organic
layers were washed with brine, dried (Na2SO4), filtered, and utilized directly in
the next step without further purification. MS (M + 1) = 230 m/z.
Step 3:
6.7-Dihvdor-6-(2-fluoro-4-(Aminocarfaoxybenzyl)phenyl)-5H-5H-pyrrolo[3.4-
b]pvridine The above aniline (-208 mmols) in acetone (1 L) and water (160
mL) was cooled to 0°C whereupon sodium bicarbonate (37.4 g, 445 mmols)
was added followed by the dropwise addition of benzylchloroformate (34.2
mL, 228 mmols). The reaction mixture was allowed to warm to room
temperature and stirred overnight whereupon a ppt formed. The reaction was
poured into ice water (2 L) and the resulting precipitate was collected by
0
filtration. The solid was washed with water and dried in a vacuum oven (50 C)
to afford the Cbz derivative (73.0 g, 97% yield) as a salmon colored powder.
MS (M + 1) = 364 m/z.
Step 4:
(Compound 2). The above Cbz derivative (40.8 g, 112 mmols) in THF (1 L)

was cooled to -780 C under a nitrogen atmosphere. To this mixture was
added n-BuLi (2.5 M, 45.8 mL, 114.5 mmols) dropwise via syringe over fifteen
minutes. The reaction was warmed to room temperature and allowed to stir

for 45 minutes before again being cooled to -78 0C. At this point (R)-glycidyl
butyrate (17.2 mL, 117 mmols) was added and the reaction mixture allowed to
warm to rt overnight during which time a precipitate formed. The ppt was
collected, washed with several portions of ether (5X100 mL) and dried in a
vacuum oven (50 C) to afford 40.6 g of the ether solvate of the lithium
alkoxide as a tan fluffy powder. This material was then washed with several
o
portions of water (4X200 mL) and dried in a vacuum oven (50 C) to afford the
oxazolidinone alcohol (34.1 g, 92% yield) as a tan granular solid. Mp = 208-
212°C, decomp. MS (M + 1) = 330 m/z.
Oxazolidinone Mesvlate. The above oxazolidinone carbinol (from Example
4) (33.8 g, 103 mmols) was suspended in DMF (1.25 L, previously degassed
with nitrogen) at rt under a nitrogen atmosphere. Triethylamine (50 mL, 360
mmols) was added followed by the dropwise addition of methanesulfonyl
chloride (13.5 mL, 174 mmols). After stirring for 3 hrs the reaction mixture was
poured into water (200 mL) and methylene chloride (1 L) added. A ppt was

filtered off, washed with water (3X200 mL) and dried in a vac oven (500C) to
afford the mesylate as a tan solid (28.1 g, 67%). The organic layer was dried
(Na2SO4), filtered and evaporated to also afford the mesylate (11.7 g, 28%
yield) as a tan solid. Both where characterized with MS (M + 1) = 408 m/z.
Oxazolidinone Azide. The above mesylate (from Example 5) (27.8 g, 68.2
mmols) and sodium azide (17.7 g, 271 mmols) in anhydrous DMF (1 L),
o
previously degassed with nitrogen, were heated 95 C for 6 hr under a nitrogen
atmosphere. After cooling, the mixture was poured into stirred ice water (2 L)
and formed a flocculant white ppt. The ppt was collected on a filter and
o
washed with water (4X200 mL), dried in a vac oven (50 C) to afford the azide
as a light beige solid (22.7 g, 94% yield). Mp = 175-1800C, decomp. MS (M +
1) = 355 m/z.
Oxazolidinone Acetamide. The above azide (from Example 6)(21.67 g, 61.16
mmol) dissolved in DMF (400 mL) and THF (500 mL) was degassed with
nitrogen for 30 minutes whereupon 10% Pd/C (4.74 g, 4.4 mmols) was added
and the reaction hydrogenated on a Parr apparatus (60 psi of hydrogen) for
14 hr. The reaction mixture was removed from the Parr apparatus and placed
under a nitrogen atmosphere whereupon pyridine (5.44 mL, 67.3 mmols) and
acetic anhydride (6.35 mL, 67.3 mmols) were added. After stirring for 1 hr the
reaction mixture was filtered through a pad of Celite, washing thoroughly with
methanol and then copious amounts of 50% MeOH/CH2CI2 (ca. 2 L). The
filtrate was evaporated to afford the crude acetamide in DMF. The mixture
was slowly added to water (2 L) and the ppt collected on a filter, washed with
o
water (5X400 mL) and dried in a vac oven (50 C) to provide the acetamide as
an analytically pure white solid (14.2 g, 63% yield). The combined filtrates
were extracted with methylene chloride (5X200 mL), dried over Na2SO4 and
concentrated. Water was added to the residue and the resulting ppt was
o
filtered off and dried in a vac oven (50 C) to afford a second crop of the
acetamide as a light tan, fluffy solid (5.61 g, 25%). For the analytically pure
material Mp = 229-230°C, decomp. MS (M + 1) = 371 m/z.
The above acetamide from Example 8 (2.51 g, 6.78 mmols) was taken up in
CH2CI2 and MnO2 added (23.9 g, 234 mmols). After stirring overnight the
reaction mixture was filtered through celite, concentrated and chromatography
on silica with 10% MeOH/CH2CL2 as eluent to afford the product as a light
Compound 5 was prepared as in Example 8 except (S)-glycidyl butyrate was
employed in the oxazolidinone formation. The product was isolated as a light
tan solid. Mp = 227-230°C decomp. MS (M + 1) = 371 m/z.
Compound 6 was prepared as in Example 9 and isolated as a light yellow
solid. Mp = 181-185 C decomp. MS (M + 1) = 369 m/z.
To 5-hydroxyisoxazole (prepared as in Chem Pharm Bull 1966, 74(11), 1277)
(0.174 g, 2.04 mmols) in DMF was added NaH (60% in oil)(0.105 g, 2.62
mmols). After stirring for 30 min the mesylate (from Example 6) (0.744g, 1.82
0
mmols) was added in one portion and the mixture stirred at 60 C overnight.
After cooling to rt water was added and a ppt was collected on a filter, air
dried and chromatographed on silica with 2.5% MeOH/CH2CI2 as eluent to
afford the product as a white solid (0.140 g, 19 % yield). Mp = 182-185°C.
MS (M + 1) = 397 m/z.
To the above oxazolidinone (from Example 12) (0.264 g, 6.66 mmols) was
taken up in CH2CI2 and MnO2 added (1.66 g, 16.2 mmols) in two portions over
two days. After stirring for two days the reaction mixture was filtered through
celite, concentrated and chromatographed on silica with 10% MeOH/CH2CI2
as eluent to afford the product as a light yellow solid (0.086 g, 32% yield). Mp
= 133-135°C. MS (M + 1) = 395 m/z.
To NaH (60% by wt in oil)(0.03 g, 0.76 mmol) in DMF (5 mL) was added
oxazolidinone carbinol (from Example 5) (0.23 g, 0.71 mmol) in four portions.
After stirring for 30 min 2-chloropyrazine (0.065 mL, 0.71 mmol) was added
via syringe and stirred overnight at rt. Water was added and a ppt was
collected on a filter, air dried and chromatographed on silica with 5%
MeOH/CH2CI2 as eluent to afford the product as a white solid (0.067 g, 23 %
yield). Mp = 225-230"C. MS (M + 1) = 408 m/z.
The above oxazolidinone (from Example 14) (0.024 g, 0.058 mmol) in CH2CI2
(5 mL) was added MnO2 (0.07 g, 0.7 mmol). After stirring overnight the
reaction mixture was filtered through Celite and concentrated to afford the
product as a very light yellow solid (0.015 g, 64% yield). Mp = 192-1940C.
MS(M + 1) = 406m/z.
To a suspension of the oxazolidinone carbinol (prepared in Example 5) (330
mg, 1.0 mmol), triphenylphosphine (260 mg, 1.1 mmols) and 4-hydroxy-1, 2,
5-thiadiazole (100 mg, 1.0 mmol) (as prepared in U.S Patent 3,391,150
[7/2/68]) in THF (8 mL) was added diisopropylazodicarboxylate (0.20 m
mmols). After stirring overnight at rt the reaction mixture was filtered, w;
with methanol, and air dried to afford a yellow crystalline solid (60 mg
yield). Mp = 185-187"c. MS (M + 1) = 414 m/z.
To the oxazolidinone (prepared in Example 16) (160 mg, 0.39 mmol)
suspended in CH2CI2 (1.0 ml_) was added MnC>2 (four additions of 150 mg
over four days). The reaction mixture was filtered through a plug of Celite,
washed with CH2CI2 (15 mL), and concentrated under reduced pressure to
afford the product as a white crystalline solid (63 mg, 40% yield). Mp = 185-
188°C. MS(M + 1) = 412m/z.
To the amine (as prepared in Example 8) (100 mg, 0.30 mmol) and potassium
carbonate (100 mg, 0.72 mmol) suspended in methanol (1.0 mL), was added
o
propionyl chloride (50 mg, 0.54 mmol). After stirring overnight at 80 C the
reaction mixture was cooled and water was added. A precipitate was filtered
off, washed with methanol and air dried to afford the product as a brown
crystalline solid (15 mg, 13 % yield). Mp = 110-112°C. MS (M + 1) = 385 m/z.
To the amide (prepared in Example 18) (15 mg, 0.04 mmol) suspended in
CH2CI2 (1.0 mL), was added MnO2 (200 mg) at rt. After stirring overnight, the
reaction mixture was filtered through a plug of Celite, washed with CH2CI2 (10
mL), and concentrated under reduced pressure to afford the product as an
light brown crystalline solid (1.6 mg, 8 % yield). MS (M + 1) = 383 m/z.
To the amine (as prepared in Example 8) (60 mg, 0.18 mmol) and potassium
acetate (60 mg, 0.61 mmol) suspended in methanol (1.0 mL), was added
cyclopropyl carbonyl chloride (120 mg, 1.15 mmols). After stirring at rt
overnight, the reaction mixture was filtered, rinsed with methanol, and then
concentrated to dryness under reduced pressure. The resulting solid residue
was triturated with water and filtered to afford the product as a brown
crystalline solid (36 mg, 50 % yield). Mp = 235-2400C. MS (M + 1) = 397 m/z.
To the amide (prepared in Example 20) (36 mg, 0.09 mmol) suspended in
CH2CI2 (1.0 mL), was added MnO2 (three portions of 100 mg over three days)
at rt. The reaction mixture was filtered through a plug of Celite, washed with
CH2CI2 (10 mL), and concentrated under reduced pressure to afford the
product as an off-white crystalline solid (3 mg, 8 % yield). MS (M + 1) = 395
m/z.
To the amine (prepared in Example 8) (60 mg, 0.18 mmol) and potassium
acetate (60 mg, 0.61 mmol) suspended in methanol (1.0 mL), was added
dropwise methyl chloroformate (120 mg, 1.27 mmols). After stirring for four
hours at rt, the reaction mixture was filtered, diluted with water, and
concentrated under reduced pressure to remove the methanol. The aqueous
solution was extracted with ethyl acetate (5X5 mL). The combined organics
were washed with water, dried over MgSO4, filtered, and concentrated to
provide an oil which was triturated with ether to afford a brown crystalline solid
(35 mg, 50% yield). MS (M + 1) = 387 m/z.
To the carbamate (prepared in Example 22) (33 mg, 0.08 mmol) suspended in
CH2CI2 (1.0 mL), was added MnO2 (150 mg). After stirring overnight at rt the
reaction mixture was filtered through a plug of Celite, washed with CH2CI2 (10
mL), and concentrated under reduced pressure to afford the product as a
yellow crystalline solid (6.0 mg, 18% yield). MS (M + 1) = 385 m/z.
To the amine (prepared in Example 8) (60 mg, 0.18 mmol) and potassium
acetate (60 mg, 0.61 mmol) suspended in methanol (1.0 mL) was added
dropwise ethyl chloroformate (0.1 mL, 1.04 mmols). After stirring overnight at
rt the reaction mixture was filtered, diluted with water, and concentrated under
reduced pressure to remove the methanol. The aqueous solution was
extracted with ethyl acetate (5X5 mL). The combined organics were washed
with water, dried over MgSO4, filtered, and concentrated. The resulting semi-
solid was treated with water, filtered and air-dried to afford a brown crystalline
solid (18 mg, 30% yield). MS (M + 1) = 401 m/z.
Example 25
To the amine (prepared in Example 8) (95 mg, 0.29 mmol) suspended in
pyridine (0.5 mL) was added methane sulfonylchloride (0.08 mL, 1.0 mmol).
After stirring overnight at rt the pyridine was removed under a stream of
nitrogen. The residue was treated with water, filtered and air-dried to afford a
brown solid (45 mg, 38% yield). Mp = 172-176°C. MS (M + 1) = 407 m/z.
Example 26
To the sulfonamide (prepared in Example 25) (10 mg, 0.02 mmol) suspended
in CH2CI2 (1.0 mL), was added MnO2 (100 mg, 10 mmols). After stirring
overnight the reaction mixture was filtered through a plug of Celite, washed
with CH2CI2 (10 mL), and concentrated under reduced pressure to afford the
product as a brown crystalline solid (0.5 mg, 5% yield). MS (M + 1) = 405 m/z.
To the amine (prepared in Example 8) (200 mg, 0.61 mmol) suspended in
toluene (8 mL), was added dimethyl-N-cyanodithioiminocarbonate (89 mg,
0.61 mmol). After stirring overnight at reflux the toluene was decanted and
the oily residue treated with methanol, filtered, and air-dried to afford a brown
crystalline solid (62 mg, 20% yield). Mp = 204-207"C. MS (M + 1) = 427 m/z.
A suspension of the thioimidate (from Example 27) (45 mg, 0.10 mmol) and
MnO2 (200 mg, 2.0 mmols) in CH2CI2 were stirred at rt for one day whereupon
a second addition of MnO2 (150 mg, 1.5 mmols) was added. After an
additional day of stirring the mixture was filtered through Celite, washed with
CH2CI2 (10 mL), concentrated to afford a yellow crystalline solid (20 mg, 45%
yield). MS (M + 1) = 426 m/z.
A suspension of the amine (prepared in Example 8) (165 mg, 0.5 mmol) and
2-methyl-1-nitro-2-thiopseudourea (94 mg, 0.70 mmol) (as prepared as in EP
0539204/1993) in methanol (2 mL) was refluxed for four hours. After cooling
to rt the reaction mixture was filtered and air dried to afford a yellow crystalline
solid (50 mg, 24% yield). Mp = 202-206°C. MS (M + 1) = 416 m/z.
To the nitroguanidine (prepared in Example 29) (35 mg, 0.08 mmol)
suspended in CH2CI2 (1.0 mL) was added MnO2 (three additions of 100 mg
over three days). The reaction mixture was filtered through a plug of Celite,
washed with CH2CI2 (10 mL), and concentrated under reduced pressure to
afford the product as a yellow crystalline solid (1.6 mg, 4% yield). MS (M + 1)
= 414 m/z.
The starting material 6,7-dihydro-5H-pyrrolo[3,4-c]pyridine was prepared as in
US Pat. No. 5,371,090 to Petersen et al. Compound 26 was then prepared as
in Example 8 except the acetamide was recrystallized from acetonitrile to give
a light tan solid. Mp = 182-190 C decomposition. MS (M + 1) = 371 m/z.
Compound 27
Compound 27 was isolated from the final step of Example 31 via
chromatography (5% MeOH/CH2CI2 as eluent) of the mother liquors collected
o
from recrystallization. Light yellow solid, Mp = 219-225 C decomp. MS (M +
1) = 385 m/z.
Compound 28 was prepared as in Example 9 except with 10% MeOH/CH2CI2
as eluent. Light yellow solid, Mp = 219-2250C decomposition. MS (M + 1) =
369 m/z.
Isothiazole (0.088 g, 0.87mmol)(prepared as in J Heterocyclic Chem 1971, 8,
591) was added portionwise at rt to a suspension of sodium hydride (0.036 g,
0.91 mmol, 60% in oil) in DMF (4 mL) under nitrogen. The mixture was stirred
for 30 minutes whereupon the mesylate from Example 31 (0.31 g, 0.76 mmol),
o
in DMF (10 mL),was added all at once. After stirring for 6 hours at 60 C the
reaction mixture was cooled to rt, diluted with water (50 mL), and extracted
with ethyl acetate (3x50 mL). The combined organics were washed several
times with water, then once with brine, dried over sodium sulfate,
concentrated, and chromatographed on silica with 5% MeOH/EtOAc as
eluent. Two products were isolated from the chromatography: 0.050g of
Compound 29; and 0.022 g of Compound 30. Overall yield, 30%.
Compound 29 MS (M+1) = 413.0
Compound 30 MS (M+1) = 411.1
To a suspension of sodium hydride (0.036 g, 0.91 mmol, 60% in oii) in DMF (4
mL) at rt under nitrogen was added portion wise 4-hydroxy-1, 2, 5-thiadiazole
(0.088 g, 0.87 mmol) (as prepared in U.S Patent 3,391,150 [7/2/68]). After
stirring for 30 min the mesylate from Example 31 (0.310 g, 0.76 mmol), in
DMF (10 mL), was added all at once. After stirring for 6 hours at 60 C the
reaction mixture was cooled to rt, diluted with water (50 mL), and extracted
with ethyl acetate (3x50 mL). The combined organics were washed several
times with water, then once with brine, dried over sodium sulfate,
concentrated, and chromatographed on silica with 2% MeOH/EtOAc as
eluent. Two products were isolated from the chromatography: 0.035 g of
Compound 31; and 0.0093 g of Compound 32. Overall yield, 14%.
Compound 31 MS (M+1) = 414.0
Compound 32 MS (M+1) = 412.1
To the mesylate from Example 31 (2.45 g, 6.01 mmol) dissolved in degassed
DMF (100 mL) under nitrogen was added potassium phthalimide (2.23 g, 12.0
0
mmols). After heating at 65 C for 3 hours the reaction mixture was cooled,
poured into water (300 mL), and extracted with methylene chloride (3x200
mL). The combined organics were washed with water (3x150 mL) dried over
sodium sulfate, concentrated to a tan solid. This solid was washed with water
o
and dried in a high vacuum oven at 50 C to afford 2.20 g (80%) of the
oxazolidinone phthalimide. MS=459.1 (M+1)
Step 2:
To the above phthalimide (0.97 g, 2.1 mmols) in degassed methanol (30 mL)
under nitrogen was added hydrazine monohydrate (0.2 mL, 4.3 mmols)
dropwise. After refluxing for 12 hours the reaction mixture was cooled to rt.
and concentrated, suspended CH2CI2 and filtered. The crude oxazolidinone
amine was concentrated and used without further purification.
Step 3:
Compound 33,
To the crude amine (0.14 g, 0.44 mmol) in CH2CI2 (5 mL) was added pyridine
(0.14 mL, 18 mmols) followed by propionyl chloride (0.76 mL, 0.88 mmol).
After stirring for 5 hrs at rt the solution was poured into water (20 mL) and
extracted with methylene chloride (3x10 mL). The combined extracts were
washed with water (10 mL) and 1 M NaOH (aq) (10 mL), dried over sodium
sulfate, concentrated and chromatographed using neat EtOAc as eluent to
afford the propionyl amide as a gold oil (0.020 g, 12% yield). MS= 385.2
(M+1)
To the crude amine (as prepared in Example 36) (0.144 g, 0.437 mmol) in
methylene chloride (5 mL) was added pyridine (0.14 mL, 1.7 mmols), followed
by cyclopropane carbonyl chloride (0.08 mL, 0.88 mmol). After stirring for 5
hrs at rt the solution was poured into water (20 mL) and extracted with
methylene chloride (3x10 mL). The combined extracts were washed with
water (10 mL) and 1 M NaOH (aq) (10 mL), dried over sodium sulfate,
concentrated and chromatographed using a gradient elution of 1 % to 5% to
10% MeOH/ EtOAc. The desired product eluted with 5% MeOH/ EtOAc and
To N-[(3-pyrrolidinone-3-fluorophenyl) 5-oxazolidinyl]methyl acetamide
(prepared according to W096/13502)(0.150 g, 0.447 mmols) was added
o
methoxy-bis(dimethyiamino)methane (1 mL). After heating at 50 C for 15 min
the reaction mixture was concentrated to provide the crude p-ketoenamine
which was used without further purification.
Step 2;
Compound 35
To ethanoiic NaOEt (made from 0.027 g Na in 3 mL EtOH) was added
acetamidine hydrochloride (0.113 g, 1.19 mmols) and the above b-
ketoenamine oxazolidinone acetamide. After refluxing for 3 hrs the reaction
mixture was cooled to rt, concentrated, taken up in chloroform, and washed
with water (3x8 mL). After drying over sodium sulfate the crude product was
concentrated, dissolved in 5% MeOH/ EtOAc, and filtered to afford the
was concentration to afford the product as a white powder (0.012 g, 7% yield).
MS= 397.2 (M+1)
To N-[(3-pyrrolidinone-3-fluorophenyl) 5-oxazolidinyl]methyl acetamide
(prepared according to W096/13502)(0.099 g, 0.29 mmol) was added
o
methoxy-bis(dimethy!amino)methane (1.0 mL). After heating at 50 C for 2 hrs
the reaction mixture was concentrated to provide the crude p-ketoenamine.
To this mixture was added benzene (5 mL), DMF (1 mL) and formamidine
o
acetate (0.55 g, 5.3 mmols). After heating overnight at 95 C the reaction
mixture was cooled to rt and water (8 mL) was added. A ppt formed and was
o
collected by filtration, dried in a vacuum oven (50 C), and chromatographed
on silica with 5% MeOH/CH2CI2 as eluent to afford the product as a white
powder (0.037 g, 34% yield). Mp = 230-232°C. MS (M + 1) = 372 m/z.
o
product as an off-white solid (0.052 g, 45% yield). Mp = 234 C, decomp. MS
=385.9 (M+1)
The above acetamide from Example 39 (0.020 mg, 0.054 mmol) was taken up
in CH2CI2 (5 mL) and MnO2 added (0.10 g, 0.98 mmol). After stirring
overnight at rt the reaction mixture was filtered through Celite and
concentrated to afford the product as a light yellow solid (0.016 g, 80% yield).
Mp = 164-166°C. MS (M + 1) = 370 m/z.
Compound 38
To the b-ketoenamine (prepared as in Example 39) was added benzene (5
mL), DMF (1 mL) and pyrazine-2-carboxamidine hydrochloride (0.62 g, 3.9
o
mmols). After heating overnight at 95 C the reaction mixture was cooled to rt
and water (8 mL) was added. A ppt formed and was collected by filtration,
0
dried in a vacuum oven (50 C), and chromatographed on silica with 5%
MeOH/CH2CI2 as eluent to afford the product as a light yellow solid (0.0026 g,
2% yield). Mp = 212-214°C. MS (M + 1) = 450 m/z.
The above acetamide from Example 39 (0.040 g, 0.088 mmols) was taken up
in CH2CI2 (10 mL) and MnO2 (0.36 g, 3.5 mmols) added in three portions over
three days. After stirring for three days the reaction mixture was filtered
through Celite, concentrated and chromatography on silica with 7%
MeOH/CH2CI2 as eluent. Two products were isolated from the
chromatography: 0.001 g of Compound 39 as a light yellow solid (4% yield);
and 0.002 g of Compound 40 as a yellow solid (4% yield).
Compound 39: MS (M + 1) = 448 m/z.
Compound 40: MS (M + 1) = 464 m/z.
Compound 41
To the p-ketoenamine (prepared as in Example 39) was added benzene (5
mL), DMF (1 mL) and 4-amidinopyridine hydrochloride (0.81 g, 5.2 mmols).
o
After heating overnight at 95 C the reaction mixture was cooled to rt and water
(8 mL) was added. A ppt formed and was collected by filtration, dried in a
o
vacuum oven (50 C), and chromatographed on silica with 5% MeOH/CH2CI2
as eluent to afford the product as a light yellow solid (0.072 g, 55% yield). Mp
= 245-250°C, decomp. MS (M + 1) = 449 m/z. --
Compound 42
To the p-ketoenamine (prepared as in Example 39) was added benzene (5
mL), DMF (1 mL) and 2-amidinopyridine hydrochloride (0.61 g, 3.9 mmols).
O
After heating overnight at 95 C the reaction mixture was cooled to rt and water
(8 mL) was added. A ppt formed and was collected by filtration, dried in a
o
vacuum oven (50 C), and chromatographed on silica with 5% MeOH/CH2CI2
as eluent to afford the product as a yellow powder (0.054 g, 40% yield). Mp =
216-220°C. MS (M + 1) = 449 m/z.
To the P-ketoenamine (prepared as in Example 39) was added benzene (5
mL), DMF (2 mL) and 3-amidinopyridine hydrochloride (0.49 g, 3.1 mmols).
0
After heating overnight at 95 C the reaction mixture was cooled to rt and water
(8 mL) was added. A ppt formed and was collected by filtration, dried in a
0
vacuum oven (50 C), and chromatographed on silica with 5% MeOH/CH2CI2
as eluent to afford the product as a light purple, crystalline solid (0.044 g, 33%
yield). Mp = 265-270°C, decomp. MS (M + 1) = 449 m/z.
Compound 44
To the p-ketoenamine (prepared as in Example 39) was added benzene (5
mL), DMF (2 mL) and hydrazine hydrochloride (0.22 g, 3.2 mmols). After
o
heating overnight at 95 C the reaction mixture was cooled to rt and water (8
mL) was added. A ppt formed and was collected by filtration, dried in a
o
vacuum oven (50 C), and chromatographed on silica with 5% MeOH/CH2CI2
as eluent to afford the product as off-white powder (0.022 g, 21% yield). Mp =
244-247°C, decomp. MS (M + 1) = 360 m/z.
Compound 45
To the p-ketoenamine (prepared as in Example 39) was added benzene (5
mL), DMF (2 mL) and n-propylhydrazine oxalate (0.87 g, 5.3 mmols). After
heating overnight at 95 C the reaction mixture was cooled to rt and water (8
mL) was added. A ppt formed and was collected by filtration, dried in a
0
vacuum oven (50 C), and chromatographed on silica with 5% MeOH/CH2Cl2
as eluent to afford the product as a light yellow solid (0.081 g, 55% yield). Mp
= 204-208°C. MS (M + 1) = 402 m/z.
The starting material aniline (N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-5-
oxazolidinyl]methyl]-acetamide) was prepared as in World Patent WO
96/23788. To phthalic dicarboxaldehyde (0.0522 g, 0.378 mmol) in
acetonitrile (1 mL) was added glacial acetic acid (0.05 mL, 0.87 mmol) and
then the above aniline (0.0955 g, 0.357 mmol) in acetonitrile (5 mL) dropwise.
After 4 hrs water (10 mL) was added and a precipitate was collected on a filter
and washed with water and ether to provide Compound 46 as a light green
solid (0.0655g, 48%). Mp = 211-214°C. MS (M + 1) = 384 m/z.
Example 49
To starting material aniline (N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-5-
oxazolidinyl]methyl]-acetamide)(0.095 g, 0.36 mmol)(as prepared in World
Patent WO 96/23788) in CH2CI2 (5 mL) was added triethylamine (0.15 mL, 1.1
mmols) and phthaloyl dichloride (0.056 mL, 0.39 mmol). After stirring
overnight a solid was collected on a filter, washed with water (10 mL) and
o
dried in vacuum oven (50 C) to afford the product as a off-white solid (0.060,
42%). Mp = 240-242°C. MS (M + 1) = 398 m/z.
To starting material aniline (N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-5-
oxazolidinyl]methyl]-acetamide)(0.20 g, 0.75 mmol)(as prepared in World
Patent WO 96/23788) in acetonitrile (5 mL) was added 2,3-pyridine
dicarboxaldehyde (0.10 g, 6.6 mmols) and glacial acetic acid (0.050 mL, 0.87
mmol). After stirring for 5hrs the reaction mixture was concentrated and
chromatographed on silica with 2.5% MeOH/CH2CI2 as eluent to afford the two
products: 0.035 g of Compound 52 (12%) as a yellow solid; and 0.011 g of
Compound 53 (4%) as a yellow solid.
Compound 48: Mp = 230-232°C. MS (M + 1) = 385 m/z.
To the crude p-ketoenamine from Example 38 (-0.276 mmol) was
added benzene (5 ml_), DMF (2 ml_), methylhydrazine (0.15 mL, 2.8 mmols)
and HCI in ether (2.75 mL, 1.0 M). After heating overnight at 90°C the
reaction mixture was cooled to rt and water (8 mL) was added. A ppt formed
and was collected on a filter, dried in a vacuum oven (50°C), and
chromatographed on silica with 10% MeOH/CHgCb as eluent to afford the
product as a light yellow solid (0.0285 g, 28% yield). Mp = 211-213°C. MS
(M + 1) = 374m/z.
To the crude p-ketoenamine from Example 38 (0.282 mmol) was added
benzene (3 mL), DMF (2 mL), 2-hydrazinopyridine (0.3214 g, 2.8 mmols) and
HCI in ether (2.85 mL, 1.0 M). After heating overnight at 90°C the reaction
mixture was cooled to rt and water (8 mL) was added. A ppt formed and was
collected on a filter, dried in a vacuum oven (50°C), and chromatographed on
silica with 10% MeOH/CH2Cl2 as eluent to afford the product as a tan solid
(0.0046 g, 4% yield). Mp = 259-261°C, decomp. MS (M + 1) = 437 m/z.
Example 53
To the crude p-ketoenamine from Example 38 (0.2481 mmol) was added
benzene (3 mL), DMF (2 mL), and tert-butylhydrazine hydrochloride (0.3090
g, 2.48 mmols). After heating overnight at 90°C the reaction mixture was
cooled to RT and water (8 mL) was added. A ppt formed and was collected
on a filter, dried in a vacuum oven (50°C), and triturated with 10%
MeOH/CH2CI2 to afford the product as a light yellow glassy solid (0.0570 g,
55% yield). Mp = 155-157°C. MS (M + 1) = 416 m/z.
Example 54
To the crude p-ketoenamine from Example 38 (-0.298 mmol) was added
benzene (3 mL), DMF (2 mL), 2-hydroxyethylhydrazine (0.23 mL, 3.4 mmols)
and HCI in ether (3.00 mL, 1.0 M). After heating overnight at 90°C the
reaction mixture was cooled to RT and water (8 mL) was added. A ppt
formed and was collected on a filter, dried in a vacuum oven (50°C), and,
To Compound 44 (0.0481 g, 0.134 mmol) in DMF at RT was added
sodium hydride (60% in oil)(0.008 g, 0.2 mmol) and the mixture stirred for 20
min. To this mixture was added 2-(diethyiamino)ethyl chloride (0.16 mL, 1.0
M in benzene) and the mixture was stirred at 40°C overnight. The mixture
was treated with sat. aqueous NH4CI (10 mL) and water (5 mL). The mixture
was extracted with EtOAc (10X20 mL), dried over Na2SO4, concentrated and
chromatographed on silica with 10% MeOH/CH2Cl2 as eluent to afford the two
products. The isomer that eluted first was identified as Compound 54 and
was isolated as a light yellow oil (0.0054 g, 9%). The slower eluting isomer,
Compound 55, was isolated as a light yellow solid (0.0107 g, 17% yield).
Both: MS(M + 1) = 459m/z.
chromatographed on silica with 10% MeOH/CH2CI2 as eluent to afford the
product as a light yellow solid (0.0517 g, 43% yield). Mp = 163-165°C. MS
(M + 1) = 404 m/z.
Example 55
To Compound 44 (0.1098 g, 0.306 mmol) in DMF (4 mL) at RT was added
sodium hydride (60% in oil) (0.018 g, 0.45 mmol) and the mixture stirred for
30 min whereupon Mel (23.0 m.L, 0.369 mmol) was added. The mixture of
regioisomers (as shown by 1H NMR) was stirred for 2 h and then poured into
ice water. A ppt formed and was collected on a filter, dried in a vacuum oven
(50°C), and chromatographed on silica with 2.5% MeOH/CH2Cl2 as eluent to
afford the product as a white solid (0.0215 g, 19%). Mp = 234-238°C. MS (M
+ 1) = 374m/z.
To Compound 44 (0.0701 g, 0.195 mmol) in DMF (3 mL) at RT was added
sodium hydride (60% in oil) (0.014 g, 0.34 mmol) and the mixture stirred for
30 min whereupon chloroacetonitrile (17.5 mL, 0.276 mmol) was added. The
mixture was stirred for 2 h and then poured into ice water. A ppt formed and
was collected on a filter, dried in a vacuum oven (50°C), and recrystallized
from methanol to provide the product as a tan solid (0.0102 g, 13%). MS (M +
1) = 399 m/z.
Compound 58
To Compound 44 (0.0744 g, 0.207 mmol) in DMF (3 mL) at RT was added
sodium hydride (60% in oil) (0.015 g, 0.37 mmol) and the mixture stirred for
30 min whereupon chloropyrazine (26.5 ml, 0.299 mmol) was added. The
mixture was stirred overnight and then poured into ice water. A ppt formed
and was collected on a filter, dried in a vacuum oven (50°C), and triturated
with methanol to provide the product as a tan solid (0.0418 g, 46%). MS (M +
1) = 438 m/z.
To Compound 44 (0.0676 g, 0.188 mmol) in DMF (3 mL) at RT was added
sodium hydride (60% in oil) (0.018 g, 0.45 mmol) and the mixture stirred for
30 min whereupon 2-chloropyrimidine (0.0391 g, 0.324 mmol) was added.
The mixture was stirred overnight and then poured into ice water. A ppt
formed and was collected on a filter, dried in a vacuum oven (50°C), and
To Compound 44 (0.0712 g, 0.198 mmol) in DMF (3 mL) at RT was added
KOtBu (in THF) (0.26 mL, 1.0 M) and the mixture stirred for 30 min
whereupon 2-(methylamino)ethyl chloride (in benzene) (0.24 mL, 1.0 M) was
added. The mixture was stirred overnight and then poured into ice water.
The mixture was extracted with EtOAc (10X20 mL), dried over Na2SO4,
concentrated and chromatographed on silica with 10% MeOH/CH2CI2 as
eluent to afford two products. The isomer that eluted first was identified as
Compound 60 and was isolated as a light yellow glass (0.0074 g, 9%). The
slower eluting isomer (Compound 61) was isolated as a light yellow glass
(0.0269 g, 32% yield). Both: MS (M + 1) = 431 m/z.
triturated with methanol to provide the product as a tan solid (0.0214 g, 26%).
MS(M + 1) = 438 m/z.
To Compound 44 (0.989 g, 0.275 mmol) in DMF (4 mL) at RT was. added
KOtBu (in THF) (0.36 mL, 1.0 M) and the mixture stirred for 30 min
whereupon Etl (26.4mL, 0.330 mmol) was added. The mixture was stirred for
2 h and then poured into ice water. A ppt formed, and was collected on a filter
and dried in a vacuum oven (50°C). The mixture of regioisomers (as shown
by 1H NMR) was chromatographed on silica with 2.5% MeOH/CH2CI2 as
eluent to afford the product as a white solid (0.0016 g, 2%). MS (M + 1) = 388
m/z.
To Compound 44 (0.1120 g, 0.312 mmol) in DMF (3 mL) at RT was added
KOtBu (in THF) (0.40 mL, 1.0 M) and the mixture stirred for 30 min
whereupon 4-(2-chloroethyl)morpholine (in benzene) (0.37 mL, 1.0 M) was
added. The mixture was stirred overnight and then poured into ice water.
The mixture was extracted with EtOAc (10X20 mL), dried over Na2SO4,
concentrated and chromatographed on silica with 5->10% MeOH/CH2Cl2 as
eluent to afford the two products. The isomer that eluted first was identified
as Compound 63 and was isolated as a light yellow glass (0.0102 g, 7%).
The slower eluting isomer (Compound 64) was isolated as a light yellow solid
(0.0518 g, 35% yield), Mp = 180-190°C, decomp. Both: MS (M + 1) = 473
m/z.
To Compound 44 (0.0793 g, 0.221 mmol) in DMF (2.5 mL) at RT was added
CS2CO3 (0.71 g, 2.2 mmols) and the mixture stirred for 15 min whereupon 2-
chloroethanol (20 mL, 0.30 mmol) was added. The mixture was stirred
overnight and then poured into ice water. A ppt formed and was collected on
a filter and dried in a vacuum oven (50°C) to provide the product as a light
yellow solid (0.0632 g, 70%). Mp = 232-242°C, decomp. MS (M + 1) = 404
m/z.
To Compound 44 (0.1546 g, 0.430 mmpl) in DMF (3 mL) at RT was added
CS2CO3 (1.62 g, 5.0 mmols) and the mixture stirred for 15 min whereupon (R)-
(-)-3-chloro-1,2-propanediol (45 mL, 0.54 mmol) was added. The mixture was
stirred overnight and then poured into ice water. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C) to provide the product
as a light yellow solid (0.1316 g, 70%). Mp = 188-191°C. MS (M + 1) = 434
m/z.
To Compound 44 (0.1524 g, 0.424 mmol) in DMF (3 mL) at RT was added
KOtBu (in THF) (0.55 mL, 1.0 M) and the mixture stirred for 30 min
whereupon propargyl bromide (80% in toluene) (0.06 mL, 0.54 mmol) was
added. The mixture was stirred overnight at RT and then poured into ice
water. A ppt formed and was collected on a filter and dried in a vacuum oven
(50°C) to provide 0.1483 g of a mixture of regioisomers (as shown by 1H
NMR). A portion of the crude material was chromatographed (40 mg in 0.5
mL DMSO) on reverse-phase HPLC with 5-30% acetonitrile/water containing
0.1 %TFA as eluent. Pooled fractions containing Compound 67 were treated
with 10% K2CO3 and the acetonitrile removed on a rotovap. A ppt formed and
was collected on a filter and dried in a vacuum oven (50°C) to provide the
product as a white solid (0.0096 g, est. 21% yield). MS (M + 1) = 398 m/z.
To Compound 44 (0.1460 g, 0.406 mmol) in DMF (3 mL) at RT was added
CS2CO3 (1.26 g, 3.87 mmols) and the mixture stirred for 15 min whereupon 3-
chloropropanol (45 mL, 0.54 mmol) was added. The mixture was stirred
overnight and then poured into ice water. A ppt formed and was collected on
a filter and dried in a vacuum oven (50°C) to provide the product as a light
yellow solid (0.1526 g, 90%). Mp = 171-173°C. MS (M + 1) = 418 m/z.
To Compound 44 (0.3523 g, 0.352 mmol) in DMF (3 mL) at RT was added
CS2CO3 (1.26 g, 3.87 mmols) and the mixture stirred for 15 min whereupon
(S)-(+)-3-chloro-1,2-propanediol (37 mL, 0.44 mmol) was added. The mixture
was stirred overnight and then poured into ice water. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C) to provide the product
as a light brown solid (0.0862 g, 90%). Mp = 184-188°C. MS (M + 1) = 434
m/z.
To Compound 44 (0.1070 g, 0.298 mmol) in DMF (2 mL) at RT was added
CS2CO3 (0.97 g, 3.0 mmols) and the mixture stirred for 15 min whereupon 2-
iodo-1,1,1-trifluoroethane (37 mL, 0.38 rnmol) was added. The mixture was
stirred three days whereupon an additional amount of 2-iodo-1,1,1-
trifluoroethane (37 mL, 0.38 mmol) was added. After two days the mixture
was poured into ice water. A ppt formed and was collected on a filter, dried in
a vacuum oven (50°C), and chromatographed on silica with 2.5->5%
MeOH/CH2CI2 as eluent to afford the product as a light yellow solid (0.0161 g,
12%). Mp = 170-172°C. MS (M + 1) = 442 m/z.
To Compound 44 (0.0530 g, 0.148 mmol) in DMF (1 mL) at RT was added
KOtBu (in THF) (0.20 mL, 1.0 M) and the mixture stirred for 30 min
whereupon benzylbromide (21 mL, 0.18 mmol) was added. The mixture was
stirred overnight and then poured into ice water. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C) to provide 0.0521 g of
a mixture of regioisomers (as shown by 1H NMR). The crude material was
chromatographed on reverse-phase HPLC with 5-30% acetonitrile/water
containing 0.1 %TFA as eluent. Pooled fractions containing Compound 71
were treated with 10% K2CO3 and the acetonitrile removed on a rotovap. A
ppt formed and was collected on a filter and dried in a vacuum oven (50°C) to
provide the product as a yellow solid (0.0111 g, 17% yield). MS (M + 1) = 450
m/z.
To Compound 44 (0.1065 g, 0.296 mmol) in DMF (2 mL) at RT was added
KOtBu (in THF) (0.40 mL, 1.0 M) and the mixture stirred for 30 min
whereupon (chloromethyl)cyclopropane (33 mL, 0.35 mmol) was added. The
mixture was stirred overnight and then poured into ice water. A ppt formed
and was collected on a filter and dried in a vacuum oven (50°C) to provide
0.0868 g of a mixture of regioisomers. The crude material was
chromatographed on silica with 5% MeOH/CH2Cl2 as eluent and then
chromatographed (in 0.5 mL DMSO) on reverse-phase HPLC with 15-25%
acetonitrile/water containing 0.1 %TFA as eluent. Pooled fractions were
treated with 10% K2CO3 and the acetonitrile removed on a rotovap. A ppt
formed and was collected on a filter and dried in a vacuum oven (50°C). The
earlier eluting compound was identified as Compound 72 (0.0026 g, 2%
yield). The later eluting compound was identified as Compound 73 (0.0082 g,
7%), a white solid Mp = 234-236°C. Both: MS (M + 1) = 414 m/z.
To Compound 44 (0.0.45 g, 0.125 mmol) in DMF (2 mL) at RT was added
KOfBu (in THF) (0.16 mL, 1.0 M) and the mixture stirred for 30 min
whereupon chloroacetone (13 mL, 0.16 mmol) was added. The mixture was
stirred for seven days and resubjected to base and alkylating agent as before
[KO/Bu (in THF) (0.16 mL, 1.0 M) and chloroacetone (13 mL, 0.16 mmol)].
After two more days the mixture was poured into ice water. A ppt formed and
was collected on a filter, dried in a vacuum oven (50°C), and
chromatographed on silica with 5% MeOH/CH2CI2 as eluent to afford the
product as a white solid (0.0087 g, 17%). MS (M + 1) = 416 m/z.
To Compound 44 (0.1018 g, 0.283 mmol) in DMF (2 mL) at RT was added
CS2CO3 (0.92 g, 2.8 mmols) and the mixture stirred for 30 min whereupon 5-
chloromethyl-2-oxazolidinone (0.0511 g, 0.378 mmol) was added. The
mixture was stirred at 60°C for six days and then poured into ice water. A ppt
formed and was collected on a filter and dried in a vacuum oven (5°C) to
provide 0.0429 g of a crude mixture. The crude material was
chromatographed on reverse-phase HPLC with 5-30% acetonitrile/water
containing 0.1 %TFA as eluent. Pooled fractions were treated with 10%
K2CO3 and the acetonitrile removed on a rotovap. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C)) to provide a white
solid as a mixture of diastereomers (as indicated) (0.0054 g, 4%). MS (M + 1)
= 459 m/z.
To Compound 44 (0.4566 g, 1.27 mmol) in DMF (10 mL) at RT was added
KOtBu (in THF) (2.54 mL, 1.0 M) and the mixture stirred for 30 min
whereupon tert-butyl bromoacetate (0.38 mL, 2.6 mmol) was added. The
mixture was stirred overnight at 35°C and then poured into ice water. A ppt
formed and was collected on a filter and dried in a vacuum oven (50°C) to
provide 0.4404 g of a mixture of regioisomers. The crude material (200mg)
was chromatographed on reverse-phase HPLC with 5-20% acetonitrile/water
containing 0.1 %TFA as eluent. Pooled fractions were treated with 10%
K2CO3 and the acetonitrile removed on a rotovap. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C). The earlier eluting
compound was identified as Compound 76 (0.0032 g, 1%), a white solid Mp =
85-90°C. The later eiuting compound was identified as Compound 77 (0.0505
g, 18% yield) a white solid Mp = 136-138°C. Both: MS (M + 1) = 474 m/z.
To Compound 44 (0.2689 g, 0.748 mmol) in DMF (6 mL) at 35°C was added
KOfBu (in THF) (1.50 mL, 1.0 M) and the mixture stirred for 15 min
whereupon propargyl bromide (80% in toluene) (0.17 mL, 1.5 mmol) was
added. The mixture was stirred overnight at 35°C and then poured into ice
water. A ppt formed and was collected on a filter and dried in a vacuum oven
(50°C). The crude material was chromatographed on reverse-phase HPLC
with 5-25% acetonitrile/water containing 0.1 %TFAas eluent. Pooled fractions
were treated with 10% K2CO3 and the acetonitrile removed on a rotovap. A
ppt formed and was collected on a filter and dried in a vacuum oven (50°C).
Four compounds were separable in the following order, earlier to later eluting:
the first compound was identified as Compound 78 (0.0082 g, 3%), a white
solid Mp = 140-142°C; the second compound was identified as the previous
synthesized Compound 67 (0.0734 g, 25%), a white solid; the third
compound was identified as Compound 79 (0.0101 g, 3%), a white solid Mp =
180-182°C; the fourth compound was identified as Compound 80 (0.0062 g,
3%), a white solid Mp = 183-186°C. All: MS (M + 1) = 398 m/z.
To Compound 44 (0.0766 g, 0.213 mmol) in DMF (1.5 mL) at RT was added
KOtBu (in THF) (0.43 mL, 1.0 M) and the mixture stirred for 30 min
whereupon chloromethyltrimethylsilane (61 m.L, 0.44 mmol) was added. The
mixture was stirred overnight at RT and then poured into ice water. A ppt
formed and was collected on a filter, dried in a vacuum oven (50°C), and
chromatographed on reverse-phase HPLC with 5-50% acetonitriie/water
containing 0.1 %TFA as eluent. Pooled fractions were treated with 10%
K2CO3 and the acetonitrile removed on a rotovap. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C). The earlier eluting
compound was identified as Compound 81 (0.0148 g, 16%), a white solid Mp
= 148-150°C. The later eluting compound was identified as Compound 82
(0.0217 g, 23% yield) a white solid Mp = 151-153°C. Both: MS (M + 1) = 446
m/z.
To Compound 44 (0.1050 g, 0.292 mmol) in DMF (2 mL) at RT was added
KOtBu (in THF) (0.58 mL, 1.0 M) and the mixture stirred for 30 min
whereupon (chloromethyl)dimethylphenylsilane (0.12 mL, 0.66 mmol) was
added. The mixture was stirred overnight at RT and then poured into ice
water. The mixture was extracted with EtOAc (6X16 mL), dried over Na2SO4l
and concentrated. The crude material was chromatographed on reverse-
phase HPLC with 5-50% acetonitrile/water containing 0.1 %TFA as eluent.
Pooled fractions were treated with 10% K2CO3 and the acetonitrile removed
on a rotovap. A ppt formed and was collected on a filter and dried in a
vacuum oven (50°C). The earlier eluting compound was identified as
Compound 83 (0.0026 g, 2%), a white solid. The later eluting compound was
identified as Compound 84 (0.0064 g, 4% yield) a white solid. Both: MS (M +
1) = 508 m/z.
To Compound 44 (0.0998 g, 0.278 mmol) in DMF (1.5 mL) at RT was added
KOtBu (in THF) (0.42 mL, 1.0 M) and the mixture stirred for 30 min
whereupon benzyl chloromethyl ether (62.1 ml, 0.417 mmol) was added. The
mixture was stirred overnight at 35°C and then poured into ice water. A ppt
formed and was collected on a filter and dried in a vacuum oven (50°C) to
provide 0.1157 g of a mixture of regioisomers. The crude material was
chromatographed on reverse-phase HPLC with 5-30% acetonitrile/water
containing 0.1 %TFA as eluent. Pooled fractions were treated with 10%
K2CO3 and the acetonitrile removed on a rotovap. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C). The earlier eiuting
compound was identified as Compound 85 (0.0120 g, 9%), a white solid Mp =
127-130°C. The later eiuting compound was identified as Compound 86
(0.0262 g, 20% yield) a white solid Mp = 156-159°C. Both: MS (M + 1) = 480
m/z.
Compound 87
To Compound 44 (0.2983 g, 0.830 mmol) in DMF (9 mL) at RT was added
KOtBu (in THF) (1.0 mL, 1.0 M) and the mixture stirred for 30 min whereupon
methyl isothiocyanate (0.11 mL, 1.6 mmol) was added. The mixture was
stirred overnight at RT and then poured into ice water. A ppt formed and was
collected on a filter and dried in a vacuum oven (50°C) to provide 0.2903 g of
crude material. A portion of the material (100 mg) was chromatographed on
reverse-phase HPLC with 5-25% acetonitrile/water containing 0.1 %TFA as
eluent. Pooled fractions were treated with 10% K2CO3 and the acetonitrile
removed on a rotovap. A ppt formed and was collected on a filter and dried in
a vacuum oven (50°C). Compound 87 was isolated as a tan solid (0.0162 g,
13% yield). Mp = 246-249°C. MS (M + 1) = 433 m/z.
To Compound 57 from Example 57 (0.0955g, 0.240 mmol) in DMF (1 mL) at
RT was added dibutyltin oxide (0.0065 g, 0.03 mmol) and then
azidotrimethylsilane (64 uL, 0.48 mmol). The mixture was stirred overnight at
100°C and then poured into ice water. A ppt formed and was collected on a
filter, dried in a vacuum oven (50°C), and chromatographed on silica with 10
MeOH/CH2CI2 containing 1% acetic acid as eluent. The product was isolated
as a tan solid (0.0379 g, 36% yield). MS (M + 1) = 442 m/z.
Example 80
To Compound 44 (0.110 g, 0.306 mmol), and Cs2CO3 (1.03 g, 3.03 mmol) in
DMF (15 mL) was added 3-picolyl chloride hydrochloride. After stirring at RT
for 20 hr the reaction was poured into water and extracted with EtOAc (3 x 30
mL). The organic phases were washed with water and brine, dried over
Na2SO4, and concentrated in vacuo to an orange film. The mixture was
purified by column chromatography on silica using 5% methanol/ethyl acetate
to afford a mixture of regioisomers (as shown by 1H NMR). Compound 89
could be purified by preparative reverse-phase HPLC and was isolated as a
white powder (7%). MS = 451 (M+H)
The two regioisomers were synthesized by the above procedure, using 2-
picolyl chloride hydrochloride. After preparative reverse-phase HPLC
purification, Compound 90 was isolated as a yellow solid (6%) and Compound
5 91 was isolated as a yellow film (2%). Both MS = 451 (M+H)
To Compound 44 (0.051 g, 0.143 mmol), in DMF (5 mL) was added KOf-Bu
(0.17 mL, 1 M in THF). The reaction was stirred at RT for 10 min, and then
allyi bromide (0.014 mL, 0.16 mmol) was added. After 20 minutes the
reaction was poured into water, and extracted with EtOAc (3 x 50 mL). The
combined organics were washed with water, brine, and then dried over
MgSO4. The mixture of regioisomers (as shown by 1H NMR) was
concentrated in vacuo to a yellow residue, and purified by preparative
reverse-phase HPLC to give a colorless film to provide Compound 92 (3%).
MS= 438 (K+)
To Compound 44 (1.15 g, 3.20 mmol), in DMF (10 mL) was added (S)-
epichlorohydrin (0.28 mL, 3.5 mmol), followed by the dropwise addition of
KOt-Bu (3.84 mL, 1.0 M in THF) at RT. After 3 hr, the reaction was poured
into water (40 mL) and a fine, white powder precipitated from solution. The
powder was collected by filtration, washed with water, and dried in vacuo at
50°C to give the product as a single stereoisomer in 63% yield. MS= 454 (K+)
To Compound 44 (0.050 g, 0.139 mmol), in DMF (5 mL) was added (R)-
epichlorohydrin (0.01 mL, 0.2 mmol), followed by the dropwise addition of
KOt-Bu (0.17 mL, 1.0 M in THF) at RT. After 3 hr, the reaction was poured
into water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined
organics were washed with water, then brine and dried over MgSo4. The
filtrate was concentrated in vacuo to provide the crude product as a yellow
solid. The solid was chromatographed on silica using 3% methanol/
methylene chloride to elute the product as a single stereoisomer. Compound
94 was isolated as a yellow powder (37%). MS= 416 (M+H), 438 (Na+)
To Compound 44 (0.048 g, 0.13 mmol), in DMF (1 mL) was added K2CO3
(0.074 g, 0.54 mmol) and bromopropionitrile (0.013 mL, 0.16 mmol) and the
5 reaction was heated to 50°C for 40 minutes. Upon cooling, the reaction was
added to water (6 mL) and extracted with EtOAc (3x10 mL). The extracts
were washed with water, then brine and dried over MgSO4. The filtrate was
concentrated in vacuo. The crude product was chromatographed on silica
with 4% methanol/ ethyl acetate as eluent to provide Compound 95 (18%).
MS=413(M+H), 435 (Na+)
Compound 93 (0.050 g, 0.120 mmol) was dissolved in excess piperdine (1
mL) and refluxed for 20 hr. The reaction mixture was concentrated in vacuo
and the resulting residue was extracted with EtOAc (3x10 mL). The organics
were washed with water and brine, and dried over Na2SO4. The filtrate was
concentrated in vacuo to an orange oil that was purified by silica gel column
chromatography. The product eluted with 10% methanol/ methylene chloride
to give a white solid in 20% yield. MS = 501. (M+H), 523 (Na+)
Compound 93 (0.052 g, 0.124 mmol) was dissolved in excess morpholine (1
mL) and refluxed for 20 hr. The reaction mixture was concentrated in vacuo
and the resulting residue was extracted with EtOAc (3x10 mL). The organics
were washed with water and brine, and dried over Na2SO4. The filtrate was
concentrated in vacuo to an orange oil that was purified by silica gel column
chromatography. The product eluted with 5% methanol/ methylene chloride
to give Compound 97 as a white solid in 20% yield. MS= 503.3 (M+H), 525.3
(Na+)
The sodium salt of benzenethiol (0.0456 g, 0.345 mmol) was added to a
solution of Compound 93 (0.120 g, 0.288 mmol) in DMF (10 mL) RT. Upon
completion of the reaction as judged by thin layer chromatography, the
reaction mixture was poured into water and extracted with EtOAc (3x10 mL).
The extracts were washed with water, then brine, and dried over MgSO4 The
filtrate was concentrated in vacuo to afford an off-white solid In 7% yield. MS
= 526 (M+H), 548 (Na+)
Example 89
ethanethiol (0.02 mL, 0.295 mmol). After stirring for 3 hr at RT water (15 mL)
was added and the reaction mixture was extracted with EtOAc (3x10 mL).
The combined organic extracts were washed with water, then brine, and dried
over MgSO4. The filtrate was concentrated in vacuo to give the crude product
as a yellow film. Trituration with methylene chloride/ hexanes gave the
product as a goid solid (3%). MS = 478 (M+H), 500 (Na+)
Compound 100
To a solution of Compound 94 (0.0921 g, 0.222 mmol) in DMF (4 mL) was
added Cs2CO3 (0.722 g, 2.22 mmol) followed by the dropwise addition of
mercaptoethanol (0.02 mL, 0.266 mmol). The reaction mixture was stirred RT
for 20 hr. Water (15 mL) was poured into the reaction and the resulting
mixture was. extracted with EtOAc (3x10 mL). The combined extracts were
washed with water, then brine, and dried over MgSO4. The filtrate was
concentrated in vacuo and purified by silica gel column chromatography,
using 10% methanol/ methyiene chloride to elute the product (3%). MS = 516
(Na+)
Compound 101
To a DMSO(3 ml) solution of Compound 44 (0.123 g, 0.343 mmol), was
added 2-propyl bromide (0.04 mL, 0.411 mmol), followed by dropwise addition
of KOt-Bu (0.41 mL, 0.411 mmol, 1 M in THF). The reaction mixture was
stirred at RT for 20 hr, poured into water (15 mL) and extracted with EtOAc (3
x 15 mL). The combined organics were washed with water, then brine and
dried over Na2SO4. The filtrate was concentrated in vacuo to give a mixture of
starting material and the desired product as a yellow oil. These two
compounds were separated by preparative reverse-phase HPLC to give
Compound 101 (2%). MS= 440 (K+)
Compound 102
Mesylate formation:
To a suspension of Compound 65 (0.0521 g, 0.129 mmol) in DMF (5 mL) was
added triethylamine (0.04 mL, 0.3 mmol) followed by methanesulfonyl chloride
(0.01 mL, 0.2 mmol). The reaction was stirred at RT for 2 hr. At this time, the
reaction was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL).
The combined organics were washed with water, then brine and dried over
MgSO4. The filtrate was concentrated in vacuo to give a gold residue. The
mesylate was used in the next reaction without further purification.
Phthalimide formation:
To a DMF (10 mL) solution of the above compound (0.060 g, 0.12 mmol) was
added potassium phthalimide (0.046 g, 0.25 mmol) and the reaction was
heated to 60°C. After heating for 20 hr the solution was cooled to RT and
poured into water (40 mL), extracted with EtOAc (3 x 20 mL), and the
organics were washed with water and brine. After drying over MgSO4, the
organics were concentrated to an orange solid, then purified by silica gel
column chromatography. The desired phthalimide was eluted from the
column with 5% methanol/ methylene chloride in 14% yield.
Amine formation:
To a methanol solution containing the phthalimide compound from above
(0.0095 g, 0.018 mmol) was added hydrazine monohydrate (0.010 mL, 0.036
mmol) and the reaction mixture was heated to reflux for 10 hr. The methanol
was removed in vacuo and the reaction was dissolved in EtOAc (10 mL),
washed with water, and then brine. The organics were then dried over
MgSO4l and the filtrate was concentrated to a gold film. The residue was
. triturated with 5% methanol/ethyl acetate to remove impurities and provide the
product as a pale yellow film (20%). MS= 403 (M+H), 425 (Na+)
To a solution of Compound 93 (0.147 g, 0.353 mmol) in DMF (5 mL) at 60°C .
was added thiomorpholine (0.18 mL, 1.76 mmol) and the reaction was heated
to 85°C for five hours. After cooling to RT, water (15 mL) was added and an
off-white precipitate formed which was collected by vacuum filtration and
discarded. The filtrate was extracted with EtOAc (3 x 40 mL) and the extracts
were washed repeatedly with water to remove residual DMF. The organic
portion was dried over Na2SO4 and the filtrate was concentrated in vacuo to a
yellow film. The sulfide was isolated in 30% yield and used without further
purification.
Formation of the sulfone:
The compound from above (0.053 g, 0.03 mmol) was taken up in methylene
chloride (5 mL) and m-CPBA (77% peroxide) (0.069 g, 0.31 mmol) was added
to the solution at RT. After 3 hr the reaction was quenched with aqueous
NaHCO3, and a white precipitate formed. The solid was collected by vacuum
filtration and dried to recover the sulfone (7%). MS= 573 (Na+)
To Compound 93 (0.130 g, 0.313 mmol) in DMF (7 mL) was added Cs2CO3
(0.510 g, 1.56 mmo!) followed by ethanethiol (0.03 mL, 0.4 mmol) at RT and
the reaction was stirred for 3 hr. The reaction mixture was diluted with water
and the aqueous portion was extracted with EtOAc (3 x 20 mL). The
combined organics were dried over MgSO4 and the filtrate was concentrated
to give a white film. The crude product was purified using silica gel column
chromatography, eluting the pure product (23%) with 5% methanol/ ethyl
acetate.
Formation of the sulfoxide:
The sulfide from above (0.0162 g, 0.0340 mmol) was dissolved in methylene
chloride (2 mL) and (Polystyrylmethyl) trimethylammonium metaperiodate
(0.0283 g, 2.40 mmol/g) (Novabiochem®) was added. The reaction was
stirred gently for 20 hr at RT. The resin was removed by filtration, and
washed with methylene chloride. The filtrate was concentrated in vacuo to
give a crude mixture of products. The sulfoxide was purified by silica gel
. column chromatography, eluting with 10% methanol/ EtOAc. The resulting
product was a diastereomeric mixture of sulfoxides. MS = 494 (M+H), 516
(Na+)
Compound 105
A suspension of Compound 65 (0.4468 g, 1.11 mmols) in THF (2 ml) was
cooled to -78°C and LDA (0.72 mL, 2.0 M in THF) was added dropwise. After
15 min, tetrabenzylpyrophosphate (0.7753 g, 1.44 mmol) was added and the
mixture was stirred for 30 min at -78°C. The reaction mixture was allowed to
warm to RT and was then stirred for 24 hr. The crude product was
chromatographed on silica and the product (40%) eluted with 2% methanol/
methylene chloride. MS = 664 (M+H), 686 (Na+)
Compound 106
To the crude mesylate from Example 92 (0.087 g, 0.181 mmol) in DMF (10
mL) was added thiomorpholine (0.055 mL, 0.543 mmol) and the reaction was
heated to 80°C for 20 hr. Upon cooling the reaction mixture was poured into
water and extracted with EtOAc (3 x 40 mL). The combined organics were
washed with water, brine, and then dried over MgSO4. The mixture was
filtered and concentrated in vacuo to give a gold oil. The oil was purified
using silica gel column chromatography eluting with 10% methanol/ ethyl
acetate gave Compound 106 in 9% yield. MS = 489 (M+H), 511 (Na+)
To a DMF (20 mL) solution of Compound 44 (0.4126 g, 1.148 mmols), at 37°C
was added KOt-Bu (2.3 mL, 1.0 M in THF) and the reaction mixture was
stirred for 20 min. To this mixture was added chloromethyl methyl sulfide
(0.15 mL, 1.7 mmols) and the reaction was stirred for 20 hr. The reaction
mixture was poured into water and a precipitate formed. The solid was
collected by vacuum filtration and dried for several hours under vacuum at
50°C. The two regioisomers were separated by preparative reverse-phase
HPLC to give Compound 107 in a 6% yield and Compound 108 in a 12%
yield. MS= 420 (M+H), 442 (Na+)
To Compound 108 (0.0540 g, 0.1289 mmol) in methylene chloride (5 mL) was
added tetrabutylammonium oxone (0.3517 g, 0.3866 mmol). The solution
was stirred at RT for 20 hr. The reaction mixture was diluted with methylene
chloride and washed with water. The organic solution was dried over Na2SO4,
filtered and concentrated to a yellow solid. Silica gel column chromatography
was used to purify the product with 3% methanol/ methylene chloride as the
eluent. The Compound 109 was isolated, after trituration with EtOAc, as a
white solid in 12% yield. MS = 452 (M+H), 474 (Na+)
To a suspension of Compound 65 (0.1185 g, 0.294 mmol) in DMF (5 mL) was
added triethylamine (0.090 mL, 0.65 mmol) followed by methanesulfonyl
chloride (0.03 mL, 0.4 mmol). After stirring at RT for 30 min sodium
thiomethoxide (0.0247 g, 0.352 mmol) was added directly to the reaction
mixture which was heated to 50°C for 3 hours. The mixture was poured into
water (20 mL) and extracted with EtOAc (3x10 mL). The combined organics
were washed with water, then brine and dried over Na2SO4. The filtrate was
concentrated in vacuo to afford an orange oil in approximately 38% yield,
which was used without further purification in the next reaction. MS= 434
(M+H), 456 (Na+)
The crude oil from Example 99 (0.0982 g, 0.226 mmol) was dissolved in
methylene chloride (10 mL) and tetrabutylammonium oxone (0.2321 g, 0.680
mmol) was added. The reaction mixture was stirred at RT for 5 hr and then
diluted with methylene chloride. The organic portion was washed with water
several times, and dried over Na2SO4. The organic solution was concentrated
to a yellow solid and purified by silica gel column chromatography. The
product was eluted with 3% methanol/ methylene chloride to provide the
product in 2% yield. MS = 466 (M+H), 488 (Na+)
Compound 113
A methylene chloride (15 mL) solution of Compound 108 (0.0758 g, 0.181
mmol) was cooled to -78°C before adding m-CPBA (0.0405 g, 0.181 mmol) as
a methylene chloride solution, dropwise, over 20 min. The reaction mixture
was stirred for another 30 min at -78°C, then warmed to room temperature.
The mixture was washed with aqueous sodium bicarbonate, brine, and then
dried over sodium sulfate. The filtrate was concentrated in vacuo to a yellow
solid, and then purified by HPLC to give the separate diastereomeric sulfoxide
products of undetermined stereochemistry, 12 % overall yield. MS= 436
(M+H), 458 (Na+)
Compound 114
Di-t-butyl N.N-diethylphosphoramidite (0.13 mL, 0.45 mmol) was added
dropwise to a stirred suspension of Compound 65 (0.1134 g, 0.281 mmol) in
THF and 1H-tetrazole (0.1969 g, 2.81 mmol) at RT under nitrogen. The
reaction was stirred at RT for 2.5 hr. After cooling the reaction mixture to -
78°C, m-CPBA (0.0631 g, 0.281 mmol) was added in several portions. The
mixture was stirred for 1 hr at -78°C, then warmed to RT for another hour.
The reaction mixture was diluted with EtOAc and washed successively with
10% aqueous sodium bisulfite, saturated aqueous NaHCO3, and water. The
combined organics were dried over MgSO4) filtered, and concentrated to a tan
oii. The crude oil was chromatographed on silica and Compound 114 was
eluted with 5% methanol/ EtOAc and concentrated to provide a pale yellow
film (7%). MS = 596 (M+H), 618 (Na+)
Benzyl chloride formation:
To Compound 65 (0.0594 g, 0.147 mmol) suspended in a 2:1 solution of
methylene chloride/ acetonitrile was added triethylamine (0.10 mL, 0.74
mmol), followed by (4-chloromethyl)benzoyl chloride (0.035 g, 0.18 mmol).
The reaction mixture was stirred at RT for 3 hr. The solvent was removed and
water was added to precipitate a yellow solid. The solid was collected by
filtration and dried to a pale yellow powder. The product was used without
further purification.
Final product:
To a mixture of the benzyl chloride, described above, (0.040 g, 0.074 mmol) in
DMF (5 mL) was added Nal (0.005 g) and morpholine (0.050 mL, 0.56 mmol)
at 50°C for 20 hr. The reaction mixture was poured into water, and extracted
with methylene chloride (3x15 mL) and the combined organics were washed
with water, then brine, and dried over MgSO4. The organic layer was filtered
and concentrated in vacuo to a yellow solid. Compound 115 was purified by
silica gel column chromatography and eluted with 5% methanol/ methyiene
chloride as a white film (27%). MS = 607 (M+H)
To a mixture of the benzyl chloride (prepared as in Example 103) (0.1280 g,
0.230 mmol) in DMF (10 mL) was added Na| (0.005 g) and dimethylamine
(0.92 mL, 2.0 M in MeOH,), at 50°C for 1 hr. Methanol was removed in
vacuo, and the reaction mixture was diluted with? methylene chloride before
being washed with water and brine. The combined organics were dried over
MgSO4, and concentrated in vacuo to a yellow waxy solid. The crude product
was purified by silica gel column chromatography eluting with 2% methanol/
methyiene chloride. Further purification was achieved by preparative reverse
phase HPLC to provide Compound 116 as a white powder (3%). MS= 565
(M+H)
Example 105
To a mixture of the benzyl chloride (as prepared in Example 103)(0.1330 g,
0.239 mmol) in DMF (10 mL) was added Nal (0.010 g) and N-methyl
piperdine (0.13 mL, 1.2 mmol) at 50°C for 2 hr. The reaction mixture was
poured into water and extracted with EtOAc (3 x 15 mL). The combined
organics were washed with water, brine, and dried over MgSO4. The organic
layer was filtered and concentrated in vacuo to a yellow film. Compound 117
was purified by silica gel column chromatography and eluted with 10%
methanol/ methylene chloride as a yellow film (2%). MS = 620 (M+H)
A slurry of DCC (0.5033 g, 0.496 mmol), N.N-dimethyiglycine (0.1020 g, 0.992
mmol), and DMAP (0.0606 g, 0.496 mmol) in methylene chloride was stirred
for 5 min at RT before adding Compound 65. The reaction mixture was
stirred at RT for 24 h, diluted with methylene chloride and washed with water.
The organics were dried over MgSO4 and concentrated to a yellow oil. The oil
was triturated with EtOAc to give a white solid which was collected by
filtration. The filtrate was concentrated to a yellow oil, and purified by silica
gel column chromatography, eluting with 2% methanol/ methylene chloride
(2%). MS = 489 (M+H), 511 (Na+)
Compound 119
A mixture of EDCI (0.950 g, 4.96 mmol), DMAP (0.121 g, 0.992 mmol) and
carbobenzyloxy-L-valine was stirred for 15 min at RT in 20 mL methylene
chloride. Compound 65 (0.400 g, 0.992 mmol) was added and the reaction
mixture was stirred at RT for several hours. The mixture was diluted with
water and extracted with methylene chloride (3 x 30 mL). The combined
extracts were washed with water, brine, and then dried over Na2SO4. The
crude product was concentrated to a yellow oil, and purified by silica gel
column chromatography using 3% methanol/ methylene chloride. A yellow
foam was recovered as the product (43%). MS = 637 (M+H), 659 (Na+)
Compound 120
A solution of Compound 119 (0.134 g, 0.210 mmol) in MeOH (5 mL), THF (2.5
!5 mL) and water (1 mL) was added to 0.67 mL of 0.5 N aqueous HCI and 0.014
g 10 % Pd on C. The mixture was shaken under an initial pressure of 50 psi
H2 at RT for 18 hr. At this time, the reaction mixture was filtered through
Celite, eluting the product with methanol. .The filtrates were concentrated in
vacuo to give an off-white foam. This product was purified by preparative
reverse-phase HPLC using 0.1% AcOH as an additive. The diacetate salt was
isolated as a white powder (0.060 g, 43%). MS= 503 (M+H), 525 (Na+)
The invention has been described in detail with particular reference to
the above embodiments thereof. The above embodiments and examples are
given to illustrate the scope and spirit of the present invention. These
embodiments and examples will make apparent, to those skilled in the art,
other embodiments and examples. These other embodiments and examples
are within the contemplation of the present invention. It will be understood
that variations and modifications can be effected within the spirit and scope of
the invention; therefore, the instant invention should be limited only by the
appended claims.
To a solution of Compound 114 in CH2CI2 is added TFA. The reaction mixture
is stirred for 30 min and the solvent is removed on a rotavap. The product is
isolated by triturating with ether to give a solid. (M+H) = 484
We claim:
1. A compound of Formula I
wherein:
R is selected from the group consisting of OH, O-Aryl, Q-Heteroaryl, N3, OR",
OSO2R", -NR""R"", or
wherein:
(i) R" is straight-chain or branched acyl having up to 6 carbon atoms or benzyl;
(ii) R" is straight-chain or branched alkyl, having up to 5 carbon atoms, phenyl
or tolyl; and
(iii) R"" and R"" are independently selected from the group consisting of H,
cycloalkyl having 3 to 6 carbon atoms, phenyl or tert-butoxycarbonyl,
fluorenyloxycarbonyl, benzyloxycarbonyl, straight-chain or branched alkyl
having up to 6 carbon atoms which is optionally substituted by cyano or
alkoxycarbonyl having up to 4 carbon atoms, -CO2-R1, -CO-R1, -CS-R1,
and -SO2-R4, in which
R1 is selected from the group consisting of H, cycloalkyl having 3 to 6
carbon atoms, trifluoromethyl or phenyl, benzyl or acyl having up to 5
carbon atoms, straight-chain or branched alkyl having up to 6 carbon
atoms, said alkyl optionally substituted by straight-chain or branched
alkoxycarbonyl having up to 5 carbon atoms, OH, cyano, up to 3 halogen
atoms, and -NR5 R6 in which R5 and R6 are identical or different and are
selected from H, phenyl or straight-chain or branched alkyl having up to 4
carbon atoms;
R4 is selected from straight-chain or branched alkyl having up to 4 carbon
atoms or phenyl and;
R4a is CN, COR4c. COOR4c, CONHR4c, CO-NR4c R4d, SO2R4c, or NO2;
R4b is H, alkyl, OR4c, SR4c, amino, NHR4C, NR4c,R4d;
R4c and R4d are independently selected from H, alkyl, aryl, or in the case of
any NR4cR4d group R4c and R4d taken together with the nitrogen atom to
which they are attached form a unsubstituted or substituted pyrrolidinyl,
piperidinyl or morpholinyl group;
X is 0 to 4 members independently selected from the group consisting of
halogen, OH, nitro, C1-8 alkoxy, C1-8 alkyl-amino, di(C1-8-aIkyl-)amino,
carboxy, alkoxycarbonyl, C1-8 alkyl-CO-O-, C1-8 alkyl-CO-NH-, carboxamide,
CN, amine, C1-8 cycloalkyl, C1-8 alkyl optionally substituted with one or more
members selected from the group consisting of F, Cl, OH; and
R5, R6, R7, and R8 are each independently H, alkyl, CN, nitro, C1-8 alkyl,
halo-C1-8-alkyl, formyl, carboxy, alkoxycarbonyl, carboxamide, or R5 and
R6 and/or R7 and R8 together form an oxo group;
R9, and R10 are each independently H, halogen, alkyl, OH, CN, nitro, C1-8
alkyl, halo-C1-8-alkyl, C1-8 alkoxyl, amino, C1-8-alkyl-amino, di(C1-8-alkyl-
)amino, formyl, carboxy, alkoxycarbonyl, C1-8-alkyl-CO-O-, C1-8-alkyl-CO-
NH-, carboxamide, or amine ;
®
— is a fused phenyl ring or a five- or six-membered heteroaromatic
ring having one to four members selected from the group consisting of S,
O,and N;
Z is halogen, aikyl, substituted-alkyl, aryl, substituted-aryi, heteroaryl,
substituted-heteroaryl, CN, CHO, COalkyl, amino, alkoxy, HNCO-(d-
C8alkyl), allyl, propargyl, allenyl, or N-alkylthiocarbamoyl;
and
m is 0 or 1,
and the pharmaceutically acceptable salts and esters thereof.

2. The compound as claimed in claim 1 wherein Y is selected from the group consisting
of
isoindolone-;
3. The compound as claimed in claim 1 wherein R is selected from the group consisting
of
4.A compound as clamed inClaim 1 wherein Z is propargyl, allyl, allenyl, N-
alkylthiocarbamoyl, heteroaryl, substituted-heteroaryl, alkyl, or a substituted
alkyl having one or more substituents selected form the group consisting of
amino, dialkylamino, cycloalkyl, hydroxy, oxo, alkoxycarbonyl, benzyloxy,
arylthio, alkylthio, hydroxyalkylthio, alkylsulfinyl, alkylsulfonyl, carboxy,
phosphonooxy, dialkylphosphonooxy, dibenzylphosphonooxy, cyano, halo,
trialkylsilyl, dialkylphenylsilyl, aryl, heteroaryl, heterocyclo,
heterocyclomethylbenzoyloxy, dialkylaminomethylbenzoyloxy,
dialkylaminoalkylcarbonyloxy, benzyloxycarbonylaminoalkylcarbonyloxy, and
aminoalkylcarbonyloxy.
5. The compound as claimed inciaim 4 wherein Z is selected from the group consisting
of propargyi, allyl, allenyl, N-alkyithiocarbamoyl, ethyl, isopropyl, t-butyl, 2-
hydroxyethyl, 3-hydroxypropyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-cyanoethyl,
cyclopropylmethyl, 2-oxopropyl, methylthiomethyl, 2-methylthioethyl,
methylsulfonylmethyl, 2-methylsulfonylethyl, methylsulfinylmethyl, t-
butoxycarbonylmethyl, 2-carboxyethyl, 2-(di-t-butylphosphonooxy)ethyl,2-
(dibenzylphosphonooxy)ethyl, 2-phosphonooxyethyl, 2-aminoethyi, 2-
(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-(4-morpholinyl)ethyl, 2-(4-
thiomorpholinyl)ethyl, trimethylsilylmethyl, dimethylphenylsilylmethyl,
benzyloxymethyl, benzyl, 5-tetrazolylmethyl, 3-pyridylmethyl, 2-pyridylmethyl,
2-oxiranylmethyl, 2-oxooxazolidin-5-ylmethyl, 2,3-dihydroxypropyl, 2-hydroxy-
3-(1 -piperidinyl)propyl, 2-hydroxy-3-(4-morpholinyl)propyl, 2-hydroxy-3-
phenylthiopropyl, 2-hydroxy-3-ethylthiopropyl, 2-hydroxy-3-(2-
hydroxyethylthio)propyl, 3-[4-(1 .i-dioxothiomorpholinyOl^-hydroxypropyl, 3-
ethylsulfinyl-2-hydroxypropyl, 2-[4-(4-morpholinylmethyl)benzoyloxy]ethyl, 2-
[4-(dimethylaminomethyl)benzoyloxy]ethyl, 2-[4-(4-methyl-1 -
piperazinylmethyl)benzoyloxy]ethyl, 2-(dimethylaminoacetoxy)ethyl, 2-[2-
(benzyloxycarbonylamino)-3-methylbutyryloxy]ethyl, 2-(2-amino-3-
methylbutyryloxy)ethyl, 2-pyridinyl, pyridazinyl, and 2-pyrimidinyl.
A phenyl oxazolidinone compound having anti-bacterial activity
Bicyclic heterocyclic substituted phenyl oxazolidinone compounds of the
formula:
wherein Y is a radical of formula II or III:
in which the substituents have the meaning indicated in the description.
These compounds are useful as antibacterial agents.

Documents:

1195-kolnp-2004-granted-abstract.pdf

1195-kolnp-2004-granted-assignment.pdf

1195-kolnp-2004-granted-claims.pdf

1195-kolnp-2004-granted-correspondence.pdf

1195-kolnp-2004-granted-description (complete).pdf

1195-kolnp-2004-granted-form 1.pdf

1195-kolnp-2004-granted-form 18.pdf

1195-kolnp-2004-granted-form 2.pdf

1195-kolnp-2004-granted-form 26.pdf

1195-kolnp-2004-granted-form 3.pdf

1195-kolnp-2004-granted-form 5.pdf

1195-kolnp-2004-granted-letter patent.pdf

1195-kolnp-2004-granted-reply to examination report.pdf

1195-kolnp-2004-granted-specification.pdf


Patent Number 217424
Indian Patent Application Number 01195/KOLNP/2004
PG Journal Number 13/2008
Publication Date 28-Mar-2008
Grant Date 26-Mar-2008
Date of Filing 17-Aug-2004
Name of Patentee ORTHO-MCNEIL PHARMACEUTICAL INC.
Applicant Address 202, RARITAN NJ 08869-0602 USA.
Inventors:
# Inventor's Name Inventor's Address
1 PAGET STEVEN ,D CAMDEN ROAD HILLSBOROUGH NJ 08844 USA.
2 HLASTA DENNIS J. 5008 DAVIS DRIVE DOYLESTOWN PA18901 USA.
PCT International Classification Number C07D413/10
PCT International Application Number PCT/US03/01673
PCT International Filing date 2003-01-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/058, 841 2002-01-28 U.S.A.