U.S. patent application number 11/316050 was filed with the patent office on 2006-11-09 for imidazo[4,5-c]pyridine compound and method of antiviral treatment.
This patent application is currently assigned to GILEAD SCIENCES, INC.. Invention is credited to Steven S. Bondy, David A. Oare, Winston C. Tse.
Application Number | 20060252791 11/316050 |
Document ID | / |
Family ID | 36481451 |
Filed Date | 2006-11-09 |
United States Patent
Application |
20060252791 |
Kind Code |
A1 |
Bondy; Steven S. ; et
al. |
November 9, 2006 |
Imidazo[4,5-c]pyridine compound and method of antiviral
treatment
Abstract
The compound
5-((3-(2,4-trifluoromethyphenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)--
5H-imidazo[4,5-c]pyridine, together with the salts and solvates
thereof. Also provided are compositions comprising this compound
and pharmaceutically acceptable carriers, as well as the use of
such compositions in the treatment or prophylaxis of viral
infections.
Inventors: |
Bondy; Steven S.; (Danville,
CA) ; Oare; David A.; (Belmont, CA) ; Tse;
Winston C.; (San Mateo, CA) |
Correspondence
Address: |
Intellectual Property Department;Gilead Sciences, Inc.
333 Lakeside Drive
Foster City
CA
94404
US
|
Assignee: |
GILEAD SCIENCES, INC.
|
Family ID: |
36481451 |
Appl. No.: |
11/316050 |
Filed: |
December 21, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60638215 |
Dec 21, 2004 |
|
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|
Current U.S.
Class: |
514/303 ;
546/118 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
31/00 20180101; A61P 31/12 20180101; C07D 471/04 20130101; A61P
31/14 20180101 |
Class at
Publication: |
514/303 ;
546/118 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745; C07D 471/02 20060101 C07D471/02 |
Claims
1.
5-((3-(2,4-trifluoromethyphenyl)isoxazol-5-yl)methyl)-2-(2-fluoropheny-
l)-5H-imidazo[4,5-c]pyridine, and its salts and solvates.
2. A composition comprising the compound of claim 1 and at least
one pharmaceutically acceptable carrier.
3. A method for treatment or prophylaxis of a viral infection
comprising administering to a subject an antiviral amount of a
compound of claim 1.
4. The method of claim 3 wherein the viral infection is HCV.
5. The compound of claim 1 as the free base.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds useful in the
treatment or prophylaxis of viral infections, particularly those by
the Flaviviridae and Picornaviridae families including hepatitis C
virus (HCV).
BACKGROUND OF THE INVENTION
[0002] The Flaviviridae family consists of 3 genera, the
pestiviruses, the flaviviruses and the hepaciviruses. It also
contains the hepatitis G virus (HGV/GBV-C), which has not yet been
assigned to a genus. Pestiviruses such as the Classical Swine Fever
Virus (CSFV), the Bovine Viral Diarrhea Virus (BVDV) and the Border
Disease Virus (BDV) cause infections of domestic livestock
(respectively pigs, cattle and sheep) and are responsible for
significant economic losses world-wide. BVDV, the prototypic
representative of the pestivirus genus, is ubiquitous and causes a
range of clinical manifestations, including abortion,
teratogenesis, respiratory problems, chronic wasting disease,
immune system dysfunction, and predisposition to secondary viral
and bacterial infections.
[0003] Vaccines are used in some countries with varying degrees of
success to control pestivirus disease. In other countries, animal
culling and slaughter are used to contain pestivirus disease
outbreaks.
[0004] The World Health Organization estimates that world-wide 170
million people (3% of the world's population) are chronically
infected with HCV. These chronic carriers are at risk of developing
cirrhosis and/or liver cancer. In studies with a 10 to 20 year
follow-up, cirrhosis developed in 20-30% of the patients, 1 to 5%
of whom may develop liver cancer during the next ten years. The
only treatment option available today is the use of interferon
.alpha.-2 (or its pegylated from) either alone or combined with
ribavirin. However, sustained response is only observed in about
40% of the patients and treatment is associated with serious
adverse effects. There is thus an urgent need for potent and
selective inhibitors of HCV.
[0005] The compound
3-[((2-dipropylamino)ethyl)thio]-5H-1,2,4-triazino[5,6-b]indole has
been reported to selectively inhibit the replication of BVDV and
other pestiviruses (Baginski S. G. et al., Proc. Natl. Acad. Sci.
U.S.A. 2000 Jul. 5, 1997 (14):7981-6). Currently, no pharmaceutical
strategy is available for controlling pestivirus infections.
[0006] Coxsackie viruses belong to the enteroviruses of the
Picornaviridae family. They cause a heterogeneous group of
infections including herpangina, aseptic meningitis, a
common-cold-like syndrome, a non-paralytic poliomyelitis-like
syndrome, epidemic pleurodynia (an acute, febrile, infectious
disease generally occurring in epidemics), hand-foot-mouth
syndrome, pediatric and adult pancreatitis and serious
myocarditis.
[0007] Currently only pleconaril
(3-13,5-dimethyl-4-[[3-methyl-5-isoxazolyl)propyl]phenyl]-5-(trifluoromet-
hyl-1,2,4-oxadiazole)) and enviroxime
(2-amino-1-(isopropylsulfonyl)-6-benzimidazole phenyl ketone oxime)
have been studied clinically for the treatment of infections with
enteroviruses. Pleconaril is a so called "capsid
function-inhibitor"; enviroxime prevents the formation of the RNA
replicative intermediate. Enviroxime resulted in only modest
clinical and virological benefit in some studies and no benefits in
others. Clinical response with pleconaril has been observed in some
studies, but the compound has not been approved by the Food and
Drug Administration (hearing of Mar. 18.sup.th, 2002).
[0008] Relevant disclosures include U.S. Pat. Nos. 4,914,108;
4,988,707; 4,990,518; 5,137,896; 5,208,242; 5,227,384; 5,302,601;
5,374,638; 5,405,964; 5,438,063; 5,486,525; 6,479,508; and U.S.
Patent Publication No. US2003/0108862 A1, Canadian Patent No.
2423800 A1, German Patent Nos. 4211474 A1, 4236026, 4309969,
4318813, European Patent Nos. EP 0 138 552 A2, EP 0 706 795 A2, EP
1 132 381 A1, Great Britain Patent No. 2158440 A, PCT Patent
Publication Nos. WO 00/20416, WO 00/39127, WO 00/40583, WO
03/007945 A1, WO 03/010140 A2, WO 03/010141 A2, WO 93/02080, WO
93/14072, WO 96/11192, WO 96/12703, WO 99/27929, PCT-US2004/43112,
PCT-BE2003/000117, PCT-US2005/26606, Akamatsu, et al., "New
Efficient Route for Solid-Phase Synthesis of Benzimidazole
Derivatives", 4:475-483, J. COMB. CHEM., 2002, Cleve et al.,
"Derivate des Imidazo[4.5-b]-und lmidazo[4.5-c]pyridins",
747:158-171, JUSTUS LIEBIGS ANNALEN DER CHEMICA, 1971, Kiyama, et
al., "Synthesis and Evaluation of Novel Nonpeptide Angiotensin II
Receptor Antagonists: Imidazo[4,5-c]pyridine Derivatives with an
Aromatic Substituent", 43(3):450-60, CHEM PHARM BULL, 1995,
Mederski et al., "Synthesis and Structural Assignment of Some
N-substituted Imidazopyridine Derivatives", 48(48):10549-58,
TETRAHEDRON, 1992, Yutilov et al., 23(1):56-9,
KHIMIKO-FARMATSEVTICHESKII ZHURNAL, 1989. The disclosures of all
citations set forth herein are expressly incorporated by reference
to the extent such disclosures are relevant to the contents
herein.
[0009] A need exists for compounds having therapeutic properties,
such as greater oral bioavailability, reduced toxicity, optimal
clearance, increased potency and the like against viruses belonging
to the family of Flaviviridae including hepatitis C virus, and
against viruses belonging to the family of Picornaviridae. These
and other objects of this invention will be apparent to one skilled
in the art from consideration of this specification as a whole.
SUMMARY OF THE INVENTION
[0010] In accordance with the objects, the novel compound
5-((3-(2,4-trifluoromethyphenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)--
5H-imidazo[4,5-c]pyridine ##STR1## and its salts and solvates. Also
provided are compositions comprising the compound of this invention
together with pharmaceutically acceptable carriers, as well as the
use of such compositions in the treatment or prophylaxis of viral,
especially HCV, infections.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The compound of this invention is employed for the treatment
or prophylaxis of flaviviral or picornaviral infections, in
particular HCV and BVDV.
[0012] The therapeutic compound of this invention is administered
to a subject mammal (including a human) by any means well known in
the art, i.e. orally, intranasally, subcutaneously,
intramuscularly, intradermally, intravenously, intra-arterially,
parenterally or by catheterization in a therapeutically effective
amount, i.e., a flaviviral or picornaviral growth inhibiting amount
or a flaviviral or picornaviral replication inhibiting amount. This
amount is believed to be an amount that ensures a plasma level of
between about 1 .mu.g/ml and 100 mg/ml, optionally of 10 mg/ml.
This optionally is achieved by administration of a dosage of in the
range of 0.001 mg to 60 mg, preferably 0.01 mg to 10 mg, preferably
about 0.5 mg to 1.5 mg per day per kg bodyweight for humans.
Dosages of 1, 3, 6, 10, 20, 30 and 60 mg/kg are suitable for
conducting toxicity studies in dogs and for extrapolating to
suitable doses in humans. The optimal dosage of the compound of
this invention will depend upon many factors known to the artisan,
including bioavailability of the compound, its metabolism and
distribution in the subject, its toxicity and its potency, among
others. Proper dosing typically is determined in the preclinical
and clinical settings, and is well within the skill of the ordinary
artisan. The therapeutically effective amount of the compound of
this invention optionally is divided into several sub-units per day
or is administered daily or in more than one day intervals,
depending upon the nature of the infection, the patient's general
condition and the nature of the compound of this invention.
Generally, the compound is administered daily.
[0013] The compound of this invention is employed in concert with
other agents effective against Picornaviral or Flaviviral
infections. Such agents include, for instance, interferon alpha,
ribavirin, and/or compounds falling within the disclosures of
EP1162196, WO 03/010141, WO 03/007945 WO 00/204425 and/or WO
03/010140 (and other filings within their patent families). Such
other agents are used in conventional amounts, although if the
efficacy of the compound of this invention and the other compound
is additive then the amounts of each active agent optionally are
commensurately reduced, and more so if the agents act
synergistically. In general, however, the agents are used in their
ordinary active amounts in the compositions.
[0014] Co-administered agents generally are formulated into unitary
compositions with the compound of this invention so long as they
are chemically compatible and are intended to be administered by
the same route. If not, then they optionally are provided in the
form of a medical kit or package containing the two agents in
separate repositories or compartments.
[0015] The present invention further provides veterinary
compositions comprising at least one compound of this invention
together with a veterinary carrier therefor, for example in the
treatment of BVDV. Veterinary carriers are materials useful for the
purpose of administering the composition and are excipients which
are otherwise inert or acceptable in the veterinary art and are
compatible with the compound of this invention. These veterinary
compositions are administered orally, parenterally or by any other
desired route.
[0016] The compound of this invention is provided as the free base
or as a salt. Salts typically are prepared by acid addition of
certain organic and inorganic acids to the free base. Examples
include (1) inorganic acids such as hydrohalogen acids, e.g.
hydrochloric or hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid and sulfamic acids; or (2) organic acids such as
acetic, propanoic, hydroxyacetic, benzoic, 2-hydroxypropanoic,
2-oxopropanoic, lactic, fumaric, tartaric, pyruvic, maleic,
malonic, malic, salicylic (e.g. 2-hydroxybenzoic),
p-aminosalicylic, isethionic, lactobionic, succinic, oxalic and
citric acids; organic sulfonic acids, such as methanesulfonic,
ethanesulfonic, benzenesulfonic, p-toluenesulfonic, C1-C6
alkylsulfonic, benzenesulfonic, p-toluenesulfonic, and
cyclohexanesulfamic acids. Also included within the scope of this
invention are the salts of the compound of this invention with one
or more amino acids, typically naturally-occuring amino acids such
as one of the amino acids found in proteins. The acidic counterion
desirably is physiologically innocuous and non-toxic or otherwise
pharmaceutically acceptable, unless the salt is being used as an
intermediate in preparation of the compounds whereupon toxicity is
not relevant. While the free base is preferred, suitable salts
include mesylate (methanesulfonic acid) and HCl.
[0017] The compound of this invention includes the solvates formed
with the compound of this invention or their salts, such as for
example hydrates, alcoholates and the like.
[0018] The compound of this invention optionally is formulated with
conventional pharmaceutical carriers and excipients, which will be
selected in accord with ordinary practice. Tablets will contain
excipients, glidants, fillers, binders and the like. Aqueous
formulations are prepared in sterile form, and when intended for
delivery by other than oral administration generally will be
isotonic. Formulations optionally contain excipients such as those
set forth in the "Handbook of Pharmaceutical Excipients" (1986) and
include ascorbic acid and other antioxidants, chelating agents such
as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose,
hydroxyalkylmethylcellulose and stearic acid.
[0019] The term "pharmaceutically acceptable carrier" as used
herein means any material or substance with which the active
ingredient is formulated in order to facilitate its preparation
and/or its application or dissemination to the site to be treated.
Suitable pharmaceutical carriers for use in the compositions of
this invention are well known to those skilled in the art. They
include additives such as wetting agents, dispersing agents,
adhesives, emulsifying agents, solvents, glidants, coatings,
antibacterial and antifungal agents (for example phenol, sorbic
acid, chlorobutanol), isotonic agents (such as sugars or sodium
chloride), provided that the same are consistent with
pharmaceutical practice, i.e. they are not toxic to mammals.
[0020] The pharmaceutical compositions of the present invention are
prepared in any known manner, for instance by homogeneously mixing,
coating and/or grinding the active ingredients in a one-step or
multi-step procedure, with the selected carrier material and, where
appropriate, other additives such as surface-active agents.
Compositions containing the compound of this invention formulated
into microspheres (usually having a diameter of about 1 to 10 gm)
are useful as controlled or sustained release formulations.
[0021] Suitable surface-active agents, also known as emulgents or
emulsifiers, are useful in the pharmaceutical compositions of the
present invention. They are non-ionic, cationic and/or anionic
materials having suitable emulsifying, dispersing and/or wetting
properties. Suitable anionic surfactants include both water-soluble
soaps and water-soluble synthetic surface-active agents. Suitable
soaps are alkaline or alkaline-earth metal salts, unsubstituted or
substituted ammonium salts of higher fatty acids
(C.sub.10-C.sub.22), e.g. the sodium or potassium salts of oleic or
stearic acid, or of natural fatty acid mixtures obtainable from
coconut oil or tallow oil. Synthetic surfactants include sodium or
calcium salts of polyacrylic acids; fatty sulphonates and
sulphates; sulphonated benzimidazole derivatives and
alkylarylsulphonates. Fatty sulphonates or sulphates are usually in
the form of alkaline or alkaline-earth metal salts, unsubstituted
ammonium salts or ammonium salts substituted with an alkyl or acyl
radical having from 8 to 22 carbon atoms, e.g. the sodium or
calcium salt of lignosulphonic acid or dodecylsulphonic acid or a
mixture of fatty alcohol sulphates obtained from natural fatty
acids, alkaline or alkaline-earth metal salts of sulphuric or
sulphonic acid esters (such as sodium lauryl sulphate) and
sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable
sulphonated benzimidazole derivatives preferably contain 8 to 22
carbon atoms. Examples of alkylarylsulphonates are the sodium,
calcium or alcoholamine salts of dodecylbenzene sulphonic acid or
dibutyl-naphthalenesulphonic acid or a naphthalene-sulphonic
acid/formaldehyde condensation product. Also suitable are the
corresponding phosphates, e.g. salts of phosphoric acid ester and
an adduct of p-nonylphenol with ethylene and/or propylene oxide, or
phospholipids. Suitable phospholipids for this purpose are the
natural (originating from animal or plant cells) or synthetic
phospholipids of the cephalin or lecithin type such as e.g.
phosphatidylethanolamine, phosphatidylserine,
phosphatidylglycerine, lysolecithin, cardiolipin,
dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl-choline and
their mixtures.
[0022] Suitable non-ionic surfactants include polyethoxylated and
polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty
acids, aliphatic amines or amides containing at least 12 carbon
atoms in the molecule, alkylarenesulphonates and
dialkylsulphosuccinates, such as polyglycol ether derivatives of
aliphatic and cycloaliphatic alcohols, saturated and unsaturated
fatty acids and alkylphenols, said derivatives preferably
containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in
the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the
alkyl moiety of the alkylphenol. Further suitable non-ionic
surfactants are water-soluble adducts of polyethylene oxide with
poylypropylene glycol, ethylenediaminopolypropylene glycol
containing 1 to 10 carbon atoms in the alkyl chain, which adducts
contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100
propyleneglycol ether groups. Such compounds usually contain from I
to 5 ethyleneglycol units per propyleneglycol unit. Representative
examples of non-ionic surfactants are
nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers,
polypropylene/polyethylene oxide adducts,
tributylphenoxypolyethoxyethanol, polyethyleneglycol and
octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene
sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol,
sorbitan, sucrose and pentaerythritol are also suitable non-ionic
surfactants.
[0023] Suitable cationic surfactants include quaternary ammonium
salts, particularly halides, having 4 hydrocarbon radicals
optionally substituted with halo, phenyl, substituted phenyl or
hydroxy; for instance quaternary ammonium salts containing as
N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl,
palmityl, myristyl and oleyl) and, as further substituents,
unsubstituted or halogenated lower alkyl, benzyl and/or
hydroxy-lower alkyl radicals.
[0024] A more detailed description of surface-active agents
suitable for this purpose is found in "McCutcheon's Detergents and
Emulsifiers Annual" (MC Publishing Crop., Ridgewood, N.J., 1981),
"Tensid-Taschenbucw", 2nd ed. (Hanser Verlag, Vienna, 1981) and
"Encyclopaedia of Surfactants," (Chemical Publishing Co., New York,
1981).
[0025] The compound of this invention is administered by any route
appropriate to the condition to be treated, such as oral, rectal,
nasal, topical (including ocular, buccal and sublingual), vaginal
and parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, intrathecal and epidural). The preferred route of
administration may vary with for example the condition of the
recipient, but is generally oral.
[0026] Formulations of the compound of this invention for oral
administration usually are presented as discrete units such as
capsules, cachets or tablets each containing a predetermined amount
of the active ingredient; as a powder or granular form; as a
solution or suspension in an aqueous liquid or a non-aqueous
liquid; or as an oil-in-water liquid emulsion or a water-in-oil
liquid emulsion. The compound of this invention optionally is
presented as a bolus, electuary or paste.
[0027] A tablet is made by compression or molding, optionally with
one or more accessory ingredients. Compressed tablets are prepared
by compressing in a suitable machine the compound of the invention
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active and/or dispersing agent. Molded tablets typically
are made by molding in a suitable machine a mixture of the powdered
compound moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and may be formulated so as to
provide slow or controlled release of the active ingredient
therein.
[0028] For infections of the eye or other external tissues e.g.
mouth and skin, the formulations are optionally applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w (including active
ingredient(s) in a range between 0.1% and 20% in increments of 0.1%
w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and
most preferably 0.5 to 10% w/w. When formulated in an ointment, the
compound is employed with a paraffinic or a water-miscible ointment
base. Alternatively, the compound is formulated in a cream with an
oil-in-water cream base. If desired, the aqueous phase of the cream
base may include, for example, at least 30% w/w of a polyhydric
alcohol, i.e. an alcohol having two or more hydroxyl groups such as
propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs.
[0029] The oily phase of the emulsions of this invention is
constituted from known ingredients in a known manner. While this
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Optionally, a hydrophilic emulsifier is included together with a
lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0030] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties. Thus the cream
should optionally be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be
used, the last three being preferred esters. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0031] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is optionally
present in such formulations in a concentration of 0.5 to 20%,
advantageously 0.5 to 10% particularly about 1.5% w/w.
[0032] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0033] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate. Formulations suitable for nasal
administration wherein the carrier is a solid include a coarse
powder having a particle size for example in the range 20 to 500
microns (including particle sizes in a range between 20 and 500
microns in increments of 5 microns such as 30 microns, 35 microns,
etc), which is administered by aerosol or powder inhalers, of which
numerous examples are available. Suitable formulations wherein the
carrier is a liquid, for administration as for example a nasal
spray or as nasal drops, include aqueous or oily solutions of the
active ingredient.
[0034] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0035] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents. The
formulations are presented in unit-dose or multi-dose containers,
for example sealed ampoules and vials, and may be stored in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example water for injections,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[0036] The compound of this invention is formulated into controlled
release compositions in which the release of the compound is
controlled and regulated to allow less frequency dosing or to
improve the pharmacokinetic or toxicity profile of the invention
compound. Controlled release compositions are prepared in accord
with known methods, many of which involve formulating the active
compound with one or more polymer carriers such a polyester,
polyamino acid, polyvinyl pyrrolidone, ethylene-vinyl acetate
copolymer, methylcellulose, carboxymethylcellulose and/or protamine
sulfate. The rate of drug release and duration of action optionally
is controlled by incorporating the active ingredient into
particles, e.g. microcapsules, of a polymeric substance such as
hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl
methacrylate and the other above-described polymers. Also suitable
are colloid drug delivery systems such as liposomes, microspheres,
microemulsions, nanoparticles, nanocapsules and so on. Depending on
the route of administration, the pharmaceutical composition, e.g.,
tablets, may require protective coatings.
EXAMPLE 1
5-((3-(2,4-trifluoromethyphenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5-
H-imidazo[4,5-c]pyridine
2,4-(bis-trifluoromethyl)benzaldoxime
[0037] To aromatic aldehyde (0.021 mol) suspended in EtOH/H.sub.2O
(1:2, 230 mL, 0.09 M) was added hydroxylamine hydrochloride (1.58
g, 0.023 mol) and cooled to 4.degree. C. To this solution was added
aqueous NaOH 50% w/w (4.13 mL, 0.052 mol) dropwise. After stirring
for 1.5 h at room temperature, the reaction mixture was acidified
with 2N aqueous HCl and extracted with CH.sub.2Cl.sub.2 (3.times.50
mL). The organic solution was washed with saturated aqueous NaCl
and dried over sodium sulfate. Removal of solvent gave crude oxime
(5.3 g, quant.) that was used directly in the next step.
3-(2,4-(bis-trifluoromethyl)phenyl)-5-(chloromethyl) isoxazole
[0038] 2,4-(bis-trifluoromethyl)benzaldoxime (9.75 g, 0.038 mol)
was suspended in CH.sub.2Cl.sub.2 (45 mL, 0.85 M) and cooled to
4.degree. C. Propargyl chloride (2.72 mL, 0.038 mol) was added to
the reaction solution followed by dropwise addition of NaOCl
(10-13% free chlorine, 37.6 mL, 0.061 mol). The reaction mixture
was stirred at 4.degree. C. for 15 min then heated to reflux for 3
h. After cooling to room temperature, the reaction was partitioned
between CH.sub.2Cl.sub.2 and H.sub.2O. The organic layer was
separated, washed with saturated aqueous NaCl, and dried over
sodium sulfate. After removal of solvent, the crude product
chloromethylisoxazole was purified by column chromatography on
silica (10% CH.sub.2Cl.sub.2/hexanes)(6.5 g ,0.020 mol).
5-((3-(2,4-trifluoromethyphenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-
-5H-imidazo[4,5-c]pyridine
[0039] To imidazopyridine (14.28 g, 0.067 mol) suspended in DMF (40
mL) was added aqueous NaOH 10% w/w (32.2 mL, 0.080 mol) dropwise
followed by addition of the chloromethyl isoxazole from the
previous step (26.3 g, 0.080 mol) in DMF (16 mL). After stirring
for 12 h at room temperature, solvents were evaporated to give
crude product as a tan solid. The crude solid was triturated with
H.sub.2O (7.times.) and crystallized (2.times.) from MeOH/H.sub.2O
(2:1) to provide pure title product. NMR; 300 Mhz D.sub.6MSO
Chemical shift, multiplicity, # of protons: [0040] 6.1, s, 2 [0041]
7.0, s, 1 [0042] 7.3, t, 2 [0043] 7.4-7.5, m, 1 [0044] 7.8-7.9, d,
1 [0045] 7.9-8.0, d, 1 [0046] 8.2-8.4, m, 4 [0047] 9.2, s, 1
* * * * *