Note: Descriptions are shown in the official language in which they were submitted.
2180624
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TITLE OF THE INVENTION -
DIPHENYLr1,2,3-THIADIAZOLES AS ANTI-INFLAMMATORY
AGENTS
BACKGROUND OF THE INVENTION
This invention relates to methods of treating cyclooxygenase
mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, anti-inflammatory drugs exert most of their
anti-inflammatory, analgesic and antipyretic activity and inhibit hormone-
induced uterine contractions and certain types of cancer growth through
inhibition of prostaglandin G/H synthase, also known as cyclooxygenase.
Initially, only one form of cyclooxygenase was known, this
corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme,
as originally identified in bovine seminal vesicles. More recently the
gene for a second inducible form of cyclooxygenase, cyclooxygenase-2
(COX-2) has been cloned, sequenced and characterized initially from
chicken, murine and human sources. This enzyme is distinct from the
COX-1 which has been cloned, sequenced and characterized from various
sources including the sheep, the mouse and man. The second form of
cyclooxygenase, COX-2, is rapidly and readily inducible by a number of
agents including mitogens, endotoxin, hormones, cytokines and growth
factors. As prostaglandins have both physiological and pathological
roles, we have concluded that the constitutive enzyme, COX-l, is
responsible, in large part, for endogenous basal release of prostaglandins
and hence is important in their physiological functions such as the
maintenance of gastrointestinal integrity and renal blood flow. In
contrast, we have concluded that the inducible form, COX-2, is mainly
responsible for the pathological effects of prostaglandins where rapid
induction of the enzyme would occur in response to such agents as
inflammatory agents, hormones, growth factors, and cytokines. Thus, a
selective inhibitor of COX-2 will have similar anti-inflammatory,
antipyretic and analgesic properties to a conventional non-steroidal anti-
inflammatory drug, and in addition would inhibit hormone-induced
uterine contractions and have potential anti-cancer effects, but will have a
CA 02180624 2005-06-13
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diminished ability to induce some of the mechanism-based side c;ffects.
In particular, such a compound should have a reduced potential for
gastrointestinal toxicity, a reduced potential for renal side effect:>, a
reduced effect on bleeding times and possibly a lessened ability to induce
asthma attacks in aspirin-sensitive asthmatic subjects.
A brief description of the potential utilities of COX-2
inhibitors is given in an article by John Vane, Nature, Vol. 367, pp. 215-
216, 1994 and in an article in Drug News and Perspectives, Vol. 7, pp.
50I-512, 1994.
SUMMARY OF THE INVENTION
The invention encompasses the novel compound of Formula
I as well as a method of treating COX-2 mediated diseases comprising
administration to a patient in need of such treatment of a non-toxic
therapeutically effective amount of a compound of Formula I.
R'
The invention also encompasses certain pharmaceutical
compositions for treatment of COX-2 mediated diseases comprising
compounds of Formula I.
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DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses the novel compound of Formula
I as well as a method of treating COX-2 mediated diseases comprising
administration to a patient in need of such treatment of a non-toxic
therapeutically effective amount of a compound of Formula I.
R'
~3
I
or a pharmaceutically
acceptable salt
thereof
wherein:
RI is selected m the group consisting
fro of:
(a) S(O)2CH3,
(b) S(O)2NHR4,
(c) S(O)2NHCOCF3,
(d) S(O)(NH)CH3,
(e) S(O)(NH)NH2,
(f) S(O)(NH)NHCOCF3,
(g) P(O)(CH3)OH, and
(h) P(O)(CH3)NH2,
R2 and R3 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C 1 _(allcoxy,
(d) CI-6alkylthio,
(e) CN,
(f) CI-3fluoroalkyl,
CA 02180624 2005-06-13
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(g) Cl-6~Y1>
(h) N3,
(i) -C02H,
(j) -C02-C1_4alkyl,
(k) _C(R5)(R6)_OH~
(1) -C(RS)(R6)-O-C1-4~Yh ~d
(m) -C 1 _6alkyl-C02-R~;
R4 is selected from the group consisting of H, C1-6alkyl, phenyl and
benzyl;
R5, R6 and R7 are each independently selected from the group consisting
of:
(a) hydrogen, and
(b) C 1 _6alkyl.
As appreciated by those of skill in the art formula I is
intended to include, but not be limited to compounds of the following
formulae:
R3
1~1
S ~ /\ R2
N\'
N \
R'
IA or Is
Within the embodiment described above, there is a genus
of compounds wherein
R1 is selected from the group consisting of:
(a) S(O)2CH3,
(b) S(O)2NHR4,
(c) S(O)2NHCOCF3,
CA 02180624 2005-06-13
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(d)S(O)(NH)CH3,
(e)S(O)(Nfi)NH2~
(f)S(O)(NH)NHCOCF3,
R2 and R3 are each independently selected from the group con:>isting
of:
(a) hydrogen,
(b) halo,
(c) C1-4alkoxy,
(d) C 1 _4alkylthio,
(e) CN,
(f) C1-3fluoroalkyl,
(g) C1-4~Y1~
(h) -C(R5)(R6)-~H~
(i) -C(R5)(R6)-O-C1-4~Y1~ ~d
Cl) -C1-4~Y1-C02-R~;
R4 is selected
from the group
consisting
of hydrogen,
C1_4alkyl,
phenyl and benzyl;
R5, R6 and R~ each independently selected from the
are group
consisting of:
(a) hydrogen, and
(b) C1-q.alkyl.
Within this genus, there is a first class of compounds wherein:
R~ is selected from the group consisting of
(a)S(O)2CH3,
(b)S(O)2NHR4,
(c)S(O)ZNHCOCF3,
(d)S(O)(NH)CH3,
and
(e)S(O)~)~a
CA 02180624 2005-06-13
- Sa -
RZ and R3 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) Cl.~alkoxy,
(d) C,.~alkylthio,
(e) CN,
(f) C,_3fluoroalkyl,
(g) C,~,alkyl,
(k) -C(RS)(R~)-OH, and
(1) -C(RS)(R6)-O-Ci~alkyl, and
R~ is selected from the group consisting of hydrogen, C~_dalkyl, phenyl and
benzyl; and
RS and R6 are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C l.~alkyl.
Within the latter first class, there is a subclass of formula IA, hereinbefore
wherein:
R' is selected from the group consisting of:
(a) S(O)2CH3,
(b) S(O)2N~4~
(d) S(O)(NH)CH3, and
(e) s(O)(NH)NH2,
RZ and R3 are each independently selected from the group consisting of:
(a)hydrogen,
(b)halo,
(c)C,_3alkoxy,
(d)C~_3alkylthio,
(e)CN,
(f)C1_3fluoroalkyl,
(g)C, _3alkyl, and
(1)-C(RS)(R6)-O-C l.~alkyl,
and
CA 02180624 2005-06-13
-Sb-
R4 is selected from the group consisting of hydrogen, C,_3alkyl, phenyl and
benzyl; and
R5, R6 and R' are each independently selected from the group c~~nsisting
of:
(a) hydrogen, and
(b) C,.~alkyl.
Within the genus there is a second class of compounds wherein:
R1 is selected from the group consisting of:
(a) S(Q)2CH3~
(b) S(O)2NHR4~
(c) S(O)2NHCOCF3,
(d) S(O)(NH)CH3,
RZ and R3
are each
independently
selected
from the
group consisting
of:
(a) hydrogen,
(b) halo,
(c) C 1 _3alkoxy,
(d) C 1 _3alkylthio,
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(e) CN,
(fj C1-3fluoroalkyl,
(g) C1-3~Y1~
(h) -C(RS)(RS)-OH,
(i) -C(R~)(R6)-O-C1-3alkyl, and
R~ is selected from the group consisting of hydrogen, C 1-3alkyl, phenyl
and benzyl;
RS and R6 are each independently selected from the group con;>isting of:
(a) hydrogen, and
(b) C 1 _3alkyl.
Within this class there is a sub-class of compounds of
Formula Ia
R'
R3
IA
Within this sub-class there is a group of compounds wherein:
R1 is selected from the group consisting of:
(a) S(O)2CH3,
(b) S(C)2~R4,
(c) S(O)(NH)CH3,
(d) S(O)(NH)NH2,
R2 and R3 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C 1 _3alkoxy,
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i
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(d) C1_3alkylthio,
(e) CN,
(f) Cl_3fluoroaikyl,
(g) Cl-3~'1,
(h) -C(RS)(R6)-C-C1-4~'1> and
R~ is selected from the group consisting of hydrogen, C l~ alkyl, phenyl
and benzyl;
RS and R6 are each independently selected from the group consisting of:
(a) hydrogen, and
(b) Cl-3alkyl.
Within this group there is a sub-group of compounds
wherein:
R1 is selected from the group consisting of:
(a) S(O)2CH3,
(b) S(O)2NHR4,
(c) S(O)(NH)CH3,
R2 and R3 are each independently selected from the group consisting of:
(a) hydrogen,
(b) halo,
(c) C1_3alkoxy,
(d) C1_3alkylthio,
(e) CN,
(f) C1-2fluoroalkyl,
(g) C1-3~kY1>
R4 is selected from the group consisting of hydrogen, C 1-3alkyl, phenyl
and benzyI;
RS and R6 are each independently selected from the group consisting of:
(a) hydrogen, and
(b) C1_3alkyl.
Within this sub-group are the compounds wherein
R1 is selected from the group consisting of:
(a) S(O)2CH3,
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(b) S(~)2NH2,
R2 and R3 are each
independently
selected from
the group consisting
of:
(a) hydrogen,
(b) halo,
(c) C1_2alkoxy,
(d) C1-2alkylthio,
(e) CN,
(f) C 1-2fluoroalkyl, and
(g) methyl and ethyl.
The invention is illustrated by the compounds of the
examples as disclosed herein as well as the compounds of Tables I, II and
III.
For purposes of this specification, alkyl is defined to include
linear, branched, and cyclic structures, with CI-6alkyl including, but not
restricted to, methyl, ethyl, propyl, 2-propyl, n-, i-, s- and t-butyl,
pentyl,
hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl. Similarly, C1-(alkoxy is intended to include alkoxy groups
of from 1 to 6 carbon atoms of a straight, branched, or cyclic
configuration. EXamples of lower alkoxy groups include methoxy,
ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the
like. Likewise, C1-6alkylthio is intended to include alkylthio groups of
from 1 to 6 carbon atoms of a straight, branched or cyclic configuration.
Examples of lower alkylthio groups include methylthio, n-propylthio,
isopropylthio, cyclohexylthio, etc. By way of illustration, the propylthio
group signifies -SCH2CH2CH3. CI-(fluoroalkyl includes alkyl groups
of from 1 to 6 carbon atoms of a straight, branched or cyclic
configuration, in which one or more hydrogen is replaced by fluorine.
Examples are -CHF2, CH2F, -CF3, -CH2CF3, c-pr-F$, c-Hex-F11, and
the like. Halo includes F, Cl, Br, or L.
Exemplifying the invention are:
(a) 4-phenyl-5-(4-(methylsulfonyl)phenyl)-I-2-3-thiadiazole,
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(b) 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-1-2-3-
thiadiazole,
(c) 4-(3-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-1-2-3-
thiadiazole,
(d) 4-(3.4-difluorophenyl)-5-(4-(methylsulfonyl)phenyl)-1-2-3-
thiadiazole,
(e) 5-phenyl-4-(4-(methylsulfonyl)phenyl)-1-2-3-thiadiazole,
(f) 4-(3,5-difluorophenyl)-5-(4-(methylsulfonyl)phenyl)-1-2-3-
thiadiazole, and
(g) 4-(3-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)-1-2-3-
thiadiazole.
Some of the compounds described herein contain one or
more asymmetric centers and may thus give rise to diastereomers and
optical isomers. The present invention is meant to comprehend such
possible diastereomers as well as their racemic and resolved,
enantiomerically pure forms and pharmaceutically acceptable salts
thereof.
Some of the compounds described herein contain olefinic
double bonds, and unless specified otherwise, are meant to include both E
and Z geometric isomers.
In a second embodiment, the invention encompasses
pharmaceutical compositions for inhibiting cyclooxygenase and for
treating cyclooxygenase mediated diseases as disclosed herein
comprising a pharmaceutically acceptable carrier and a non-toxic
therapeutically effective amount of compound of Formula I as described
above.
Within this embodiment the invention encompasses
pharmaceutical compositions for inhibiting COX-2 and for treating COX-
2 mediated diseases as disclosed herein comprising a pharmaceutically
acceptable carrier and a non-toxic therapeutically effective amount of
compound of Formula I as described above.
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In a third embodiment, the invention encompasses a method
of inhibiting cyclooxygenase and treating cyclooxygenase mediated
diseases, advantageously treated by an active agent that selectively
inhibits COX-2 in preference to COX-1 as disclosed herein comprising:
administration to a patient in need of such treatment of a non-toxic
therapeutically effective amount of a compound of Formula I as discllosed
herein.
The pharmaceutical compositions of the present invention
comprise a compound of Formula I as an active ingredient or a
pharmaceutically acceptable salt, thereof, and may also contain a
pharmaceutically acceptable carrier and optionally other therapeutic
ingredients. The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases including
inorganic bases and organic bases. Salts derived from inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium,
magnesium, manganic salts, manganous, potassium, sodium, zinc, and the
like. Particularly preferred are the ammonium, calcium, magnesium,
potassium, and sodium salts. Salts derived from pharmaceutically
acceptable organic non-toxic bases include salts of primary, secondary,
and tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines, and basic ion exchange resins, such as
arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,
glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
It will be understood that in the discussion of methods of
treatment which follows, references to the compounds of Formula I are
meant to also include the pharmaceutically acceptable salts.
The Compound of Formula I is useful for the relief of pain,
fever and inflammation of a variety of conditions including rheumatic
fever, symptoms associated with influenza or other viral infections,
218062
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common cold, low back and neck pain, dysmenorrhea, headache,
toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis,
including rheumatoid arthritis, degenerative joint diseases (osteoarttuitis),
gout and ankylosing spondylitis, bursitis, burns, injuries, following
surgical and dental procedures. In addition, such a compound may inhibit
cellular neoplastic transformations and metastic tumor growth and hence
can be used in the treatment of cancer. Compound I may also be of use in
the treatment and/or prevention of cyclooxygenase-mediated proliferative
disorders such as may occur in diabetic retinopathy and tumour
angiogenesis.
Compound I will also inhibit prostanoid-induced smooth
muscle contraction by preventing the synthesis of contractile prostanoids
and hence may be of use in the treatment of dysmenorrhea, premature
labor, asthma and eosinophil related disorders. It will also be of use in
the treatment of Alzheimer's disease, and for the prevention of bone loss
(treatment of osteoporosis).
By virtue of its high inhibitory activity against COX-2
and/or its specificity for COX-2 over COX-1 Compound I will prove
useful as an alternative to conventional NSAID'S particularly where such
non-steroidal anti-inflammatory drugs may be contra-indicated such as in
patients with peptic ulcers, gastritis, regional enteritis, ulcerative
colitis,
diverticulitis or with a recurrent history of gastrointestinal lesions; Gl
bleeding, coagulation disorders including anemia such as
hypoprothrombinemia, haemophilia or other bleeding problems; kidney
disease; those prior to surgery or taking anticoagulants.
Similarly, Compound I, will be useful as a partial or
complete substitute for conventional NSAID'S in preparations wherein
they are presently co-administered with other agents or ingredients. Thus
in further aspects, the invention encompasses pharmaceutical
compositions for treating COX-2 mediated diseases as defined above
comprising a non-toxic therapeutically effective amount of the compound
of Formula I as defined above and one or more ingredients such as
another pain reliever including acetominophen or phenacetin; a
potentiator including caffeine; an H2-antagonist, aluminum or
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magnesium hydroxide, simethicone, a decongestant including
phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,
ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-
desoxyephedrine; an antiitussive including codeine, hydrocodone,
caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating
or non-sedating antihistamine. In addition the invention encompasses a
method of treating cyclooxygenase mediated diseases comprising:
administration to a patient in need of such treatment a non-toxic
therapeutically effect amount of the compound of Formula I, optionally
I O co-administered with one or more of such ingredients as listed
immediately above.
For the treatment of any of these cyclooxygenase mediated
diseases Compound I may be administered orally, topically, parenterally,
by inhalation spray or rectally in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable earners, adjuvants
and vehicles. The term parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrasternal injection or infusion
techniques. In addition to the treatment of warm-blooded animals such as
mice, rats, horses, cattle sheep, dogs, cats, etc., the compound of the
invention is effective in the treatment of humans.
As indicated above, pharmaceutical compositions for
treating COX-2 mediated diseases as defined may optionally include one
or more ingredients as listed above.
The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any
method lrnown to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, 'flavoring agents,
coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain the
active ingredient in admixture with non-toxic pharmaceutically
2180624
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acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be, for example, inert diluents, such as calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, for example, corn
starch, or alginic acid; binding agents, for example, starch, gelatin or
acacia, and lubricating agents, for example, magnesium stearate, stearic
acid or talc. The tablets may be uncoated or they may be coated by
known techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over a longer
period. For example, a time delay material such as glyceryl monostearate
or glyceryl distearate may be employed. They may also be coated by the
technique described in the U.S. Patent 4,256,108; 4,166,452; and
4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or
as soft gelatin capsules wherein the active ingredients is mixed with water
or miscible solvents such as propylene glycol, PEGS and ethanol, or an oil
medium, for example, peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example, sodium
carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose,
sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersnng or wetting agents may be a naturally-occurring phosphatide,
for example, lecithin, or condensation products of an alkylene oxide with
fatty acids, for example, polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation products
of ethylene oxide with partial esters derived from fatty acids and hexntol
anhydrides, for example, polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more preservatives, for example,
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- 14 - 19502
ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one
or more flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the
active ingredient in a vegetable oil, for example, arachis oiI, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The
oily suspensions may contain a thickening agent, for example, beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavoring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent, suspending
agent and one or more preservatives. Suitable dispersing or wetting
agents and suspending agents are exemplified by those akeady mentioned
above. Additional excipients, for example, sweetening, flavoring and
coloring agents, may also be present.
The pharmaceutical compositions of the invention may also
be in the form of an oil-in-water emulsions. The oily phase may be a
vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for
example, liquid paraffin or mixtures of these. Suitable emulsifying
agents may be naturally-occurring phosphatides, for example, soy bean,
lecithin, and esters or partial esters derived from fatty acids and hexicol
anhydrides, for example, sorbitan monooleate, and condensation products
of the said partial esters with ethylene oxide, for example, polyoxy-
ethylene sorbitan monooleate. The emulsions may also contain
sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening
agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and flavoring
and coloring agents. The pharmaceutical compositions may be in the
form of a sterile injectable aqueous or oleagenous suspension. This
suspension may be formulated according to the known art using those
2180624
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suitable dispersing or wetting agents and suspending agents which have
been mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic parenterally-
acceptable diluent or solvent, for example, as a solution in 1,3-butane
S diol. Among the acceptable vehicles and solvents that may be employed
are water, Ringer's solution and isotonic sodium chloride solution.
Cosolvents such as ethanol, propylene glycol or polyethylene glycols may
also be used. In addition, sterile, fixed oils are conventionally employed
as a solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of injectables.
Compound I may also be administered in the form of a
suppositories for rectal administration of the drug. These compositions
can be prepared by mixing the drug with a suitable non-irritating
excipient which is solid at ordinary temperatures but liquid at the recvtal
temperature and will therefore melt in the rectum to release the drug.
Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or
suspensions, etc., containing the compound of Formula I are employed.
(For purposes of this application, topical application shall include mouth
washes and gargles.) Topical formulations may generally be comprised
of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,
preservative system, and emollient.
Dosage levels of the order of from about 0.01 mg to about
140 mg/kg of body weight per day are useful in the treatment of the
above-indicated conditions, or alternatively about 0.5 mg to about 7 g per
patient per day. For example, inflammation may be effectively treated by
the administration of from about 0.01 to 50 mg of the compound per
kilogram of body weight per day, or alternatively about 0.5 mg to about
3.5 g per patient per day.
The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary depending
upon the host treated and the particular mode of administration. For
example, a formulation intended for the oral administration of humans
2180b24
- 16 - 1'9502
may contain from 0.5 mg to 5 g of active agent compounded with an
appropriate and convenient amount of carrier material which may vary
from about 5 to about 95 percent of the total composition. Dosage unit
forms will generally contain between from about 1 mg to about 500 mg
S of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg,
400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level
for any particular patient will depend upon a variety of factors including
the age, body weight, general health, sex, diet, time of administration,
route of administration, rate of excretion, drug combination and the
severity of the particular disease undergoing therapy.
The compounds of the present invention can be prepared
according to the following methods.
Method A
Compound I can be prepared from an appropriately
substituted 2-ethanone. Following the method of Hurd and Mori, the
ketones II were treated with an acyl hydrazine in refluxing toluene to
form acylhydrazones III. Treatment of these acylhyrazones with thiomyl
chloride gives the corresponding thiadiazoles. See Hurd, C. D. and Mori,
R.I. J. Am Chem. Soc. 1955, 77, 5359.
CA 02180624 2005-06-13
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METHOD A
EtOOC ~
NH ,
R, ~ \ /~-- R
O \ / N
H2NNHC02Et
PhCH3, a ~ ~ R2
':~ R
r3 R
R
II SOC12 III
N' ~ \ /~ R,
_" R2
R3
IA
As appreciated by those of skill in the art, the scheme is
equally applicable to compounds of formule IA and IB.
Tables I, II and III illustrate compounds of Formula I, which
are representative of the present invention.
Image
Image
CA 02180624 2005-11-09
- 20 - 19502
Table II
SOp Rla
IA
Example R1a R2 R3
Me 3-SMe H
Me 4-CF3 4-CN
NH2 4-Me H
11 NHMe 4-F H
12 NH2 4_F H
13 NH2 3-F 4-F
14 NH2 4-Cl H
NH2 3-F H
CA 02180624 2005-11-09
- 21 - 19502
Tab._ 1e III
R3
.S R
I
N
i
S02 Rlb
IB
Examples Rib R2 R3
16 Me 4-F H
17 Me 3-F H
18 Me 3-F 4-F
19 Me 3_C1 H
20 NH2 H H
21 NH2 4-F H
22 NH2 3-F H
CA 02180624 2005-06-13
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Assa'~s for detgrminin~ Biological Activity
The compound of Formula I can be tested using thf:
following assays to determine their COX-2 inhibiting activity.
INHIBITION OF CYCLO~XYGE~1ASE ACTIVITY
Compounds were tested as inhibitors of cyclooxyge;nase
activity in whole cell cyclooxygenase assays. Both of these assays
measured prostaglandin E2 synthesis in response to arachidonic acid,
using a radioimmunoassay. Cells used for these assays were human
osteosarcoma 143 cells (which specifically express COX-2) and human
U-937 cells (which specifically express COX-1). In these assays, 100%
activity is defined as the difference between prostaglandin E2 synthesis in
the absence and presence of arachidonate.
Whole Cell Assays
T
For cyclooxygenase assays, osteosarcoma cells are cultured
in 1 mL of media in 24-well multidishes (Nunclon) until confluent ( 1-2 x
105 cells/well). U-937 cells are grown in spinner flasks and resuspended
to a final density of 1.5 x 106 cells/mL in 24-well multidishes (Nunclon)TM
Following washing and resuspension of osteosarcoma and U-937 cells in
1 mL of HBSS, 1 ~L of a DMSO solution of test compound or D:MSO
vehicle is added, and samples gently mixed. All assays are perfo~:-med in
triplicate. Samples are then incubated for 5 or 15 minutes at 37°C:,
prior
to the addition of arachidonic acid. Arachidonac acid (peroxide-free,
Cayman Chemical) is prepared as a 10 mM stock solution in ethanol and
further diluted 10-fold in HBSS. An aliquot of 10 p.L of this diluted
solution is added to the cells to give a final arachidonic acid concentration
of 10 ~M. Control samples are incubated with ethanol vehicle instead of
arachidonic acid. Samples are again gently mixed and incubated f or a
further 10 min at 37°C. For osteosarcoma cells, reactions are then
stopped by the addition of 100 pL of 1N HCl with mixing and by the
rapid removal of the solution from cell monolayers. For U-937 cells,
reactions are stopped by the addition of 100 p.L of 1 N HCl with mixing.
CA 02180624 2005-06-13
- 23 - 19502
Samples are then neutralized by the addition of 100 ~L of 1 N NaOH and
PGE2 levels measured by radioimmunoassay.
Assa~r of fox-1 Activit'r from U937 microsomes
U937 cell are pelleted by centrifuhation at 500 x g for 5 min
and washed once with phosphate-buffered saline and repelleted. Cells are
resuspended in homogenization buffer consisting of 0.1 M Tris-HCI, pH
7.4., 10 mM EDTA, 2 ~,g/ml leupeptin, 2 ~g/ml soybean trypsin inhibitor,
2 ~g/ml aprotinin and 1 mM phenyl methyl sulfinyl fluoride. The cell
suspension is sonicated 4 times for 10 sec and is centrifuged at 10,000 x g
for 10 min at 4 °C. The suspension is centrifuged at 100,000 x gv for 1
hr
at 4 °C. The 100,000 x g microsomal pellet is resuspended in 0. l M
Tris-
HCI, pH 7.4, 10 mM EDTA to approximately 7 mg protein/ml arid stored
at -80 °C.
Microsomal preparations are thawed immediately prior to
use, subjected to a brief sonication, and then diluted to a protein
concentration of 125 ~g/ml in 0.1 M Tris-HCl buffer, pH 7.4 containing
10 rnM EDTA, 0.5 mM phenol, 1 mM reduced glutathione and 1 p,M
hematin. Assays are performed in duplicate in a final volume of 250 p.1.
Initally, 5 ~l of DMSO vehicle or drug in DMSO are added to 20 p.1 of
0.1 M Tris-HCI buffer, pH 7.4 containing 10 mM EDTA in wells of 96-
deepwell polypropylene titre plate. 200 ~l of the microsomal preparation
are then added and pre-incubated for 15 min at room temperature before
addition of 25 ~1 of arachidinic acid in 0.1 M Tris-HCl and 10 mP~I
EDTA, pH 7.4. Samples are incubated for 40 min at roam temperature
and the reaction is stopped by the addition of 25 p,1 of 1 N HCL. ;samples
are neutralized with 25 ~1 1 N NaOH prior to quantitation of PGE,~
content by radioimmunoassay (Dupont-NENTor Amershani assay kits).
Cyclooxygenase activity is defined as the difference betwEen PGE;2
levels in the samples incubated in the presence of aracidonic acid and
ethanol vehicle.
Assa3r of the activity of purified human COX-2
2180624
- 24 - 19$02
The enzyme activity is measured using a chromogenic assay
based on the oxidation of N,N,N',N'-tetramethyl-p-phenylenediamine
(TMPD) during the reduction of PGG2 to PGH2 by COX-2. See
Copeland et al (1994) Proc. Natl. Acad. Sci. 91, 11202-11206).
Recombinant COX-2 is purified from S~ cells as previausly
described (Percival et al (1994) Arch. Biochem. Biophys. I5. I I I-I 18).
The assay mixyure (180 1t1) contains 100 mM sodium phosphate, pH 6.5,
2mM genapol X-100, 1pM hematin, 1 mg/ml gelatin, 80-100 units of
purified enzyme (one unit of enzyme is defined as the amount of enzyme
required to produce an O.D. change of 0.001/min at 610 nm) and 4 p1 of
the test compound in DMSO. The enzyme is pre-incubated at room
temperature (22 °C) for 15 min prior to initiation of the enzymatic
reaction by the addition of 20 ~1 of a sonicated solution of 1 mM
arachidonic acid (AA) and 1 mM TMPD in assay buffer (without enzyme
or hematin). The enzyme activity is measured by estimation of the initial
velocity of TMPD oxidation over the first 36 sec of the reaction. A non-
specific rate of oxidation is observed in the absence of enzyme (0.007-
0.010 O.D./min) and is subtracted before the calculation of the percent
inhibition. IC50 values are derived from 4-paramater least squares non
linear regression analysis of the log-dose vs percent inhibition plot.
BAT PAW EDEMA ASSAY
Protocol
Male Sprague-Dawley rats (150 - 200 g) were fasted
overnight and were given, po, either vehicle (1% methocel or 5% Tween
80), or a test compound. One hr later, a line was drawn using a
permanent marker at the level above the ankle in one hind paw to define
the area of the paw to be monitored. The paw volume (Vp) was
measured using a plethysmometer (Ugo-Basile, Italy) based on the
principle of water displacement. The animals were then injected
subplantarly with 50 p1 of 1% carrageenan solution in saline (FMC Corp,
Maine) into the paw using an insulin syringe with a 25-gauge needle (i.e.,
2180624
- 25 - 19502
500 ~g carrageenan per paw). Three hr later, the paw volume (V3) was
measured and the increases in paw volume (V3-VO) were calculated. The
animals were sacrificed by C02 asphyxiation and the absence or presence
of stomach lesions scored. Data were compared with the vehicle-control
values and percent inhibition calculated. EDSO values were used for
comparison. All treatment groups were coded to eliminate observer bias.
Rationale
The major side effect of conventional NSAIDs is their ability
to produce gastric lesions in man. This action is believed to be caused by
inhibition of COX-I in the gastrointestinal tract. Rats are particularly
sensitive to the actions of NSAIDS. In fact, rat models have been used
commonly in the past to evaluate the gastrointestinal side effects of
current conventional NSAIDs. In the present assay, NSAID-induced
gastrointestinal damage is observed by measuring fecal SICr excretion
after systemic injection of SICr-labeled red blood cells. Fecal SlCr
excretion is a well-established and sensitive technique to detect
gastrointestinal integrity in animals and man.
Male Sprague Dawley rats ( I50 - 200 g) are administered
orally a test compound, either once (acute dosing) or b.i.d. for 5 days
(chronic dosing). Immediately after the administration of the last dose,
the rats are injected via a tail vein with 0.5 mL of SICr-labeled red blood
cells from a donor rat. The animals are placed individually in metabolism
cages with food and water ad lib. Feces are collected for a 48 h period
and SlCr fecal excretion is calculated as a percent of total injected dose.
SlCr-labeled red blood cells are prepared using the
following procedures. Ten mL of blood is collected in heparinized tubes
via the vena cava from a donor rat. Plasma is removed by centrifugation
and replenished with equal volume of HBSS. The red blood cells are
incubated with 400 ~Ci of sodium Slchromate for 30 min at 37°C. At the
2 ~ aa~24
26 - 19502
end of the incubation, the red blood cells are washed twice with 20 mL
HBSS to remove free sodium Slchromate. The red blood cells are finally
reconstituted in 10 mL HBSS and 0.5 mL of the solution (about 20 ItCi)
is injected per rat.
PROTEIN-LOSING GASTROPATHY IN SQUIRREL MONKEYS
at
Protein-losing gastropathy (manifested as appearance of
cirulating cells and plasma proteins in the GI tract) is a significant and
dose-limiting adverse response to standard NSAIDs. This can be
quantitatively assessed by intravenous administration of SlCrCl3
solution. This isotopic ion can avidly bind to cell and serum globins and
cell endoplasmic reticulum. Measurement of radioactivity appearing in
feces collected for 24 h after administration of the isotope thus provides a
sensitive and quantitative index of protein-losing gastropathy.
IV~thods
Groups of male squirrel monkeys (0.8 to 1.4 kg) are treated
by gavage with either 1% methocel or 5% Tween 80 in H20 vehicles, (3
mLlkg b.i.d.) or test compounds at doses from 1 - 100 mg/kg b.i.d. for 5
days. Intravenous SlCr (5 ~Ci/kg in 1 ml/kg PBS) is administered 1 h
after the last drug/vehicle dose, and feces collected for 24 h in a
metabolism cage and assessed for excreted 51 Cr by gamma-counting.
Venous blood is sampled 1 h and 8 h after the last drug dose, and plasma
concentrations of drug measured by RP-HPLC.
HUMAN WHOLE BLOOD ASSAY
Rationale
Human whole blood provides a protein and cell-rich milieu
appropriate for the study of biochemical efficacy of anti-inflammatory
compounds such as selective COX-2 inhibitors. Studies have shown that
normal human blood does not contain the COX-2 enzyme. This is
2180b24
- 27 - 1'9502
consistent with the observation that COX-2 inhibitors have no effect on
PGE2 production in normal blood. These inhibitors are active only after
incubation of human whole blood with LPS which induces COX-2. This
assay can be used to evaluate the inhibitory effect of selective COX-2
inhibitors on PGE2 production. As well, platelets in whole blood contain
a large amount of the COX-1 enzyme. Immediately following blood
clotting, platelets are activated through a thrombin-mediated mechanism.
This reaction results in the production of thromboxane B2 (TxB2) via
activation of COX-1. Thus, the effect of test compounds on TxB2 levels
levels following blood clotting can be examined and used as an index for
COX-1 activity. Therefore, the degree of selectivity by the test
compound can be determined by measuring the levels of PGE2 after LPS
induction (COX-2) and TxB2 following blood clotting (COX-1) in the
same assay.
2~8D~2~
- 28 - 19502
A. COX-2 (LPS-induced PGE~~roduction)
Fresh blood was collected in heparinized tubes by
venipuncture from both male and female volunteers. The subjects had no
apparent inflammatory conditions and had not taken any NSAIDs for at
least 7 days prior to blood collection. Plasma was immediately obtained
from a 2 mL blood aliquot to use as blank (basal levels of PGE2). The
remaining blood was incubated with LPS (100 pg/ml final concentration,
Sigma Chem, #L-2630 from ~ ~; diluted in 0.1% BSA-Phosphate
buffered saline) for 5 minutes at room temperature. Five hundred ltL,
aliquots of blood were incubated with either 2 pL vehicle (DMSO) or 2
~tL of a test compound at final concentrations varying from 10 nM to 30
~tM for 24 hours at 37°C. At the end of the incubation, the blood was
IS centrifuged at 12,000 x g for 5 minutes to obtain plasma. A 100 pL
aliquot of plasma was mixed with 4001tL of methanol for protein
precipitation. The supernatant was obtained and was assayed for PGE2
using a radioimmunoassay kit (Amersham, RPA#530} after conversion of
PGE2 to its methyl oximate derivative according to the manufacturer's
procedure.
~. COX-1 (Clotting-induced TxB~ produ non)
Fresh blood was collected into vacutainers containing no
anticoagulants. Aliquots of S00 p,L were immediately transferred to
siliconized microcentrifuge tubes preloaded with 2 ~tL of either DMSO or
a test compound at final concentrations varying from 10 nM to 30 ~M.
The tubes were vortexed and incubated at 37°C for 1 hour to allow
blood
to clot. At the end of incubation, serum was obtained by centrifugation
(12,000 x g for 5 min). A 100 ~L aliquot of serum was mixed with 400
~,L of methanol for protein precipitation. The supernatant was obtained
and was assayed for TxB2 using a enzyme immunoassay kit (Cayman,
#5I9031) according to the manufacturer's instruction.
2180b24
- 29 - 19502
REp~F.SENTATIVE >31OI~OGICAT_. DATA
Compounds of the present invention are inhibitors of COX-2
and are thereby useful in the treatment of COX-2 mediated diseases as
enumerated above. The activities of the compounds against
cyclooxygenase may be seen in the representative results shown below.
In the assay, inhibition is determined by measuring the amount of
prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid,
COX-1 ~ COX-2 and a putative inhibitor. The ICSp values represent the
IO concentration of putative inhibitor required to return PGE2 synthesis to
50% of that obtained as compared to the uninhibited control.
The results for inhibition of PGE2 production in whole blood
and edema inhibition in rat paw may be seen in Table IV. For comparison
purposes, the Table also contains data for the conventional NSAID
indomethacin.
Me0 H
0
N
'0
CI ~ Indomethacin
T V
Example COX-lICgO COX-2ICgp ED,~p(mg/kg)
(1tM)
2 20 2.8 0.5
3 63 1.3
Indomethacin 0.2 0.2 2
The following abbreviations have t_he 'ndic ted meanings
2180624
- 30 - 1 X502
Ac - acetyl
AIBN - 2.2-azobisisobutyronitrile
Bn - benzyl
DMAP - 4-(dimethylamino)pyridine
DMF - N,N-dimethylformamide
DMSO - dimethyl sulfoxide
Et3N - triethylamine
Fur - furandiyl
HBSS - Hanks balanced salt solution
HWB - human whole blood
KHMDS - potassium hexamethyldisilazane
LDA - lithium diisopropylamide
LPS - lipopolysaccharide
Ms - methanesulfonyl = mesyl
Ms0 - methanesulfonate = mesylate
NBS - N-bromosuccinimide
NCS - N-chlorosuccinimide
NIS - N-iodosuccinimide
NSAID - non-steroidal anti-inflammatory
drug
PCC - pyridinium chlorochromate
PDC - pyridinium dichromate
Ph - phenyl
Phe - benzenediyl
Pye - pyridinediyl
r.t. - room temperature
rac. - racemic
Tf - trifluoromethanesulfonyl = triflyl
Tf0 - trifluoromethanesulfonate = triflate
Th - 2- or 3-thienyl
THF - tetrahydrofuran
Thi - thiophenediyl
TLC - thin layer chromatography
Ts - p-toluenesulfonyl = tosyl
Ts0 - p-toluenesulfonate = tosylate
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Tz - 1H (or 2H)-tetrazoI-5-yl
C3H5 - allyl
SOZMe - methyl sulfone
S02NH2 - sulfonamide
Alk~group abbreviations
Me - methyl
Et - ethyl
n-Pr - normal propyl
i-Pr - isopropyl
n-Bu - normal butyl
i-Bu - isobutyl
s-Bu - secondary butyl
t-Bu - tertiary butyl
c-Pr - cyclopropyl
c-Bu - cyclobutyl
c-Pen - cyclopentyl
c-Hex - cyclohexyl
The invention will now be illustrated by the following non-
limiting examples in which, unless stated otherwise:
(i) all operations were carried out at room or ambient
temperature, that is, at a temperature in the range 18-25°C;
(ii) evaporation of solvent was carried out using a rotary
evaporator under reduced pressure (600-4000 pascals: 4..5-
mm Hg) with a bath temperature of up to 60°C;
(iii) the course of reactions was followed by thin layer
chromatography (TLC) and reaction times are given for
30 illustration only; (iv) melting points are uncorrected and'd'
indicates decomposition; the melting points given are those
obtained for the materials prepared as described;
polymorphism may result in isolation of materials with
different melting points in some preparations;
2180624
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(v) the structure and purity of all final products were assured by
at least one of the following techniques: TLC, mass
spectrometry, nuclear magnetic resonance (NMR)
spectrometry or microanalytical data;
(vi) yields are given for illustration only;
(vii) when given, NMR data is in the form of delta (8) values for
major diagnostic protons, given in parts per million (ppm)
relative to tetramethylsilane ('TMS) as internal standard,
determined at 300 MHz or 400 MHz using the indicated
1d solvent; conventional abbreviations used for signal shape
are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad;
etc.: in addition "Ar" signifies an aromatic signal;
(viii) chemical symbols have their usual meanings; the following
abbreviations have also been used v (volume), w (weight),
b.p. (boiling point), m.p. (melting point), L (liter(s)), mL
(milliliters), g (gram(s)), mg (milligrams(s)), mol (moles),
mmol (millimoles), eq (equivalent(s)).
2780b24
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EXAMPLE 1
4-Phen~'4-(methvlsulfon~)phenyl-1 2 3-thiad'a~ole
Steal 1-Phenyl-2-(4-lmethvl hio~yl)etha_none
To a cold (0 °C) solution of N-methoxy-N-methylbenzamide
(409 mg, 2.27 mmol) in THF (22mL) was added a THF solution (5.0 mL,
0.5 M) of 4-(methylthio)benzylmagnesium chloride (J.Org. Chem. ~,
1914, 1977). The mixture was stirred at 0 °C for 3 h, NH40Ac was added
and the mixture was extracted with EtOAc. The EtOAc extracts were
washed with brine, dried over MgS04, filtered and concentrated to an oil.
Chromatography of the oil on silica gel (eluted with 2.5 %
EtOAc/toluene) gave 501 mg of the title compound .
Step 2 1-Phenyl-2-l4-(meth sulfonyllDhenyl)ethanone
To a suspension of the product of step 2 (59 g, 243 mmol) in
a mixture of CH2Cl2 (300 mL), MeOH (1 L), t-BuOH (350 mL) was
added a suspension of Oxone?M (248 g, 403 mmol) in 700 mL of H2O.
The mixture was stirred for 1 h. Saturated NaHC03 was added slowly
until all solid dissolved. The resulting mixture was extracted with Et20.
The ether extracts were dried (Na2S04) and concentrated to give 39.3 g
of the title compound.
Ste~3_: Ethyl-1-l(4-(meth lsulfo 1)v nhenvl me y1
((phenyl)methvlidene)hvdrazinocarbox, la a
A mixture of the product of step 2 (1.37 g, 5 mmol), ethyl
carbazate (572 mg, 5.5 mmol), and p-toluenesulfonic acid (20 m,g) in
toluene (30 mL) was refluxed with concomitant removal of water fon 5 h.
The mixture was cooled to r.t. and the crystallised product was filtered
and washed with toluene yielding 1.54 g of the title compound.
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Step 4: 4-Phenyl-5-l4-(methylsulfonyl~phenvl-1.2.3-thiadiazole
To the product of step 3 (800 mg, 2.23 mmol} at 0°C was
added SOCl2 (6 mL). The mixture was refluxed for 2h. Excess SOCIx was
removed under vaccum. The residue was chromatographed on silica gel,
eluted with 40% EtOAc in hexane to give 300 mg of the title compound;
m.p. 145-146°C. ~HNMR (CD3COCD3): 8 3.18 (s, 3H),7.46 (m, 3H),
7.72 (m, 2H), 7.73 (d, 2H, J = 8.2 Hz), 8.03 (d, 2H, J = 8.2 Hz)
EXAMPLE 2
4-(4-Fluorophenyl)-5-(4-(methvlsulfon 1)nhenvl-1 2 3-thiadiazole
Following the same procedure as described in Example l,
the title compound was obtained; IHNMR (CD3COCD3): 8 3.18 (s, 3H),
7.22 (m, 2H), 7.67 (m, 2H), 7.74 (d, 2H, J = 8.6 Hz), 8.04 (d, 2H, J = 8.6
Hz).
EXAMPLE 3
4-(3-FluoronhenvI)-5-(4-(methvlsulfonvl)nhenvl-1.2.3-thiadiazole
Following the same procedure as described in Example 1,
the title compound was obtained; ~HNMR (CD3COCD3): 8 3.10 (s, 3H),
7.14 (m, 1 H), 7.45 (m, 3H), 7.55 (d, 2H, J = 8.5 Hz), 7.98 (d, 2H, J = 8.5
Hz).
EX
4-13.4-Di<fluoronhen~)-5-(4-(meth lsulfonvl'iphenvl-1 2 3-thiadiazole
2180624
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Following the same procedure as described in Example 1,
the title compound was obtained; m.p. 110-111 °C. ' H1VMR
(CD3COCD3): 8 3.18 (s, 3H), 7.41 (m, 2H), 7.61 (m, 2H), 7.77 (d, 2H, J=
8.4 Hz), 8.05 (d, 2H, J= 8.4 Hz).
4-~3-Chlorophe~ 1~~1-5-(4-(meth lsy ulfonyl)phenyI-1 2 3-thiadiazole
Following the same procedure as described in Example 1,
the title compound was obtained; m.p. 130-131 °C. ' HNMR
(CD3COCD3): 8 3.18 (s, 3H), 7.49 (m, 3H), 7.70 (m, 1H), 7.76 (d, 2H, J=
8.6 Hz), 8.05 (d, 2H, J = 8.6 Hz).
EXAMPLE 6
4-(3.5-Difluoronhenvll-5-f4-~methylsulfoQ llnhenvl-1 2 3-thiadiazole
Following the same procedure as described in Example 1,
the title compound is obtained; m.p. 112-113°C. IHNIvIR (CD3COCD3): 8
3.20 (s, 3H), 7.15 (m, 1H), 7.25 (m, 2H), 7.80 (d, 2H, J= 8.3 Hz), 8.08
(d, 2H, J = 8.3 Hz).
30 4-l4-(Methvlsulfonyl)phenvl- -(phenYl_)-1 2 3-thiadiazole
Steal 1-f4-Methylthiopher~ 1y 1-2-p enyl-etha_none
To a cold (0 °C) solution of phenylacetyl chloride (92.8 ,g,
0.6 mot) in CHC13 (1.2 L) was added A1C13 (80 g, 0.6 mol) in portions.
2180624
- 36 - 19502
Thioanisole (62.I g, 0.5 mol) was then added dropwise. The resulting
mixture was stirred at r.t. for L5 h. The mixture was poured into 4 L of
ice and water and extracted with CHC13. The combined organic extracts
were dried over MgS04, filtered and concentrated. The residue was
slurried in 300 mL of 20 % EtOAc/hexane, filtered and washed with
hexane to give 78 g of the title compound.
Step 2 Starting from the product of step I, following the same
procedure as described in step 2-4 of Example 1, the title compound was
IO obtained; m.p. 154-155°C.'HNMR (CD3COCD3): 83.17 (s, 3H),7.49
(m,
SH), 7.89 (d, 2H, J = 8.6 Hz), 8.0 (d, 2H, J = 8.6 Hz)
