U.S. patent number RE38,103 [Application Number 09/827,508] was granted by the patent office on 2003-04-29 for 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2.
This patent grant is currently assigned to Merck Frosst Canada & Co.. Invention is credited to Daniel Guay, Chun-Sing Li.
United States Patent |
RE38,103 |
Guay , et al. |
April 29, 2003 |
5-methanesulfonamido-1-indanones as an inhibitor of
cyclooxygenase-2
Abstract
The Compound of Formula I and pharmaceutically acceptable sales
thereof in the treatment of cyclooxygenase-2 mediated diseases are
disclosed. ##STR1##
Inventors: |
Guay; Daniel (Ile Perrot,
CA), Li; Chun-Sing (Dollard des Ormeaux,
CA) |
Assignee: |
Merck Frosst Canada & Co.
(Rairkland, CA)
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Family
ID: |
27364391 |
Appl.
No.: |
09/827,508 |
Filed: |
April 6, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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989286 |
Dec 11, 1992 |
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147804 |
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033397 |
Mar 19, 1993 |
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Reissue of: |
147804 |
Nov 4, 1993 |
05604260 |
Feb 18, 1997 |
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Current U.S.
Class: |
514/605; 514/601;
564/99 |
Current CPC
Class: |
C07C
311/08 (20130101); A61P 43/00 (20180101); C07C
323/49 (20130101); A61P 29/00 (20180101); C07C
2602/08 (20170501) |
Current International
Class: |
C07C
311/00 (20060101); C07C 311/08 (20060101); C07C
323/49 (20060101); C07C 323/00 (20060101); A61K
031/165 (); C07C 311/12 () |
Field of
Search: |
;514/605,601
;564/99 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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130870/86 |
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Jan 1986 |
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JP |
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242997/90 |
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Apr 1992 |
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JP |
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Other References
Boyce et al. Nueropharmacology. 1994. vol. 33, No. 12, pp.
1609-1611.* .
Wisenberg-Bottcher et al. Agents and Actions. 1989. vol. 26, pp.
240-242.* .
Lombardino et al. Arzneim.-Forsch. (Drug Res.) 1975. vol. 25, No.
10, pp. 1629-1635.* .
Lombardino. Nonsteroidal Antiinflammatory Drugs. 1985. pp.
114-130.* .
National Meeting of the American Chemical Society, Washington,
D.C., USA, Aug. 21-25, 1994. Abstracts of Papers American Chemical
Society. 208 (1-2), 1994 MEDI 272, ISSN: 0065-7727.* .
National Meeting of the American Chemical Society, Washington,
D.C., USA, Aug. 21-25, 1994. Abstracts of Papers American Chemical
Society. 208 (1-2), 1994 MEDI 116, ISSN: 0065-7727.* .
Chem Abstracts. 1983. vol. 100, No. 1, AB #6113u.* .
D.P. Carr, et al., Agents and Actions, vol. 19, 5/6 (1986) pp.
374-375, "Comparison of the systemic inhibition of thromboxane
synthesis, anti-inflammatory activity and gastro-intestinal
toxicity . . .".* .
Chem Abstracts. 1985. vol. 104, AB #107904r.* .
Chem Abstracts. 1990. vol. 113, AB #224303r.* .
Chem Abstracts. 1987. vol. 106, AB #60922u.* .
Chem Abstracts. 1989. vol. 110, AB #128249v.* .
Gans et al. Journal of Pharm. and Experim. Ther., 1990. vol. 254,
No. 1, pp. 180-187.* .
Hla et al. Proceedings of the National Academy of Sciences, USA.
1992. vol. 89, pp. 7384-7388.* .
Rufer et al. European Journal of Med. Chem. Chim. Ther. 1982. vol.
17, pp. 173-180..
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Primary Examiner: Myers; Carla J.
Attorney, Agent or Firm: Howrey Simon Arnold & White
LLP
Parent Case Text
This is a continuation-in-part of U.S. Ser. No. 07/989,286 filed
Dec. 11, 1992, now abandoned, and U.S. Ser. No. 08/033,397, filed
Mar. 19, 1993, now abandoned.
Claims
What is claimed is:
1. A compound of the formula I ##STR37##
or a pharmaceutically acceptable salt thereof.
2. A method of selectively inhibiting cyclooxygenase-2 comprising
administration to a patient in need of such treatment a non-toxic
therapeutically effective amount of a compound according to claim
1.
3. A method of treating a cyclooxygenase-2 mediated disease in
patients having a history of a gastro-intestinal disorder
comprising administration to a patient in need of such treatment a
non-toxic therapeutically effective amount of a compound according
to claim 1..[.
4. A method of selectively inhibiting cyclooxygenase-2 comprising
administration to a patient in need of such treatment a non-toxic
therapeutically effective amount of a compound according to claim
1..]..Iadd.
5. A method for selectively inhibiting cyclooxygenase-2activity in
a human host, comprising administering a non-steroidal compound
that selectively inhibits activity of the cyclooxygenase-2 gene
product to a human host in need of such treatment, wherein said
non-steroidal compound is a compound of the formula I ##STR38##
or a pharmaceutically acceptable salt thereof..Iaddend..Iadd.
6. The method of claim 5, wherein the compound of formula I is
administered at a dosage of from about 0.01 mg to about 140 mg per
kilogram of body weight per day..Iaddend..Iadd.
7. The method of claim 5, wherein the compound of formula I is
administered in an amount from about 1 mg to about 1000
mg..Iaddend.
Description
BACKGROUND OF THE INVENTION
This invention relates to compounds and pharmaceutical compositions
for the treatment of inflammation, particularly cyclooxygenase
mediated diseases and methods of treating thereof.
Non-steroidal, antiinflammatory drugs exert most of their
antiinflammatory, 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. Up until recently, only one form of
cyclooxygenase had been characterized, this corresponding to
cyclooxygenase-1 or the constitutive enzyme, as originally
identified in bovine seminal vesicles. Recently the gene for an
inducible form of cyclooxygenase (cyclooxygenase-2) has been
cloned, sequenced and characterized from chicken, mu-rine and human
sources. This enzyme is distinct from the cyclooxygenase-1 which
has now also been cloned, sequenced and characterized from sheep,
murine and human sources. The second form of cyclooxygenase,
cyclooxygenase-2, is rapidly and readily inducible by a number of
agents including mitogens, endotoxin, hormones, cytokines and
growth factors. As prostaglandins have physiological and
pathological roles, we have concluded that the constitutive enzyme,
cyclooxygenase-1, 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, cyclooxygenase-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 cyclooxygenase-2 will have similar antiinflammatory,
antipyretic and analgesic properties of a conventional
non-steroidal antiinflammatory drug (NSAID), and in addition would
inhibit hormone-induced uterine contractions and have potential
anti-cancer effects, but will have a diminished ability to induce
some of the mechanism-based side effects. In particular, such a
compound should have a reduced potential for gastrointestinal
toxicity, a reduced potential for renal side effects, a reduced
effect on bleeding times and a lessened ability to induce asthma
attacks in aspirin-sensitive asthmatic subjects.
SUMMARY OF THE INVENTION
The invention encompasses compounds of Formula I useful in the
treatment of inflammation such as cyclooxygenase mediated diseases,
particularly cyclooxygenase-2 mediated diseases. ##STR2##
The invention also encompasses methods of treating inflammation
including cyclooxygenase mediated diseases, particularly
cyclooxygenase-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. ##STR3##
The invention also encompasses certain pharmaceutical compositions
for treatment of inflammation including cyclooxygenase mediated
diseases, particularly cyclooxygenase-2 mediated diseases
comprising compounds of Formula I and a pharmaceutically acceptable
carrier.
The invention also encompasses the compound 12 ##STR4##
and pharmaceutically acceptable salts thereof which are useful in
the treatment of inflammation such as cyclooxygenase mediated
diseases, in particular cyclooxygenase-2 mediated diseases.
The invention also encompasses anti-inflammatory pharmaceutical
compositions such as those useful for inhibiting a cyclooxygenase
and for treating cyclooxygenase mediated diseases as disclosed
herein comprising a pharmaceutically acceptable carrier and a
non-toxic therapeutically effective amount of the compound of
Formula I as described herein.
The pharmaceutical compositions of the present invention comprise a
compound of Formulas 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 s 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 o 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,
methylgncamine, morpholine, piperazine, piperdine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine, and the like.
The invention also encompasses methods of inhibiting cyclooxygenase
and treating cyclooxygenase mediated diseases comprising:
administration to a patient in need of such treatment of a
non-toxic therapeutically effective amount of compound of Formula I
as disclosed herein.
It will be understood that in the discussion of methods of
treatment which follows, references to the compound of Formula I
are meant to also include the pharmaceutically acceptable
salts.
DETAILED DESCRIPTION OF THE INVENTION
The invention encompasses compounds of Formula I useful in the
treatment of inflammation such as cyclooxygenase mediated diseases,
particularly cyclooxygenase-2 mediated diseases ##STR5##
wherein Y is O, S, S(O), S(O).sub.2, --CH.sub.2 --, --NH--, CO or
##STR6##
X is H, halo, including Cl and Br, or C.sub.1-6 alkyl; and
Ar.sub.1 and Ar.sub.2 are as defined below in the following five
embodiments.
In one embodiment the invention encompasses compounds of Formula I
wherein Y is ##STR7##
wherein
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of (a) NHS(O).sub.2 C.sub.1-6 alkyl, (b) halo, including
Fluoro, (c) C.sub.1-6 alkyl, (d) S(O).sub.2 C.sub.1-6 alkyl, (e)
OC.sub.1-6 alkyl, and (f) hydrogen,
with the proviso that R.sub.1 and R.sub.2 are not simultaneously
the same.
In a second embodiment, the invention encompasses compounds of
Formula I wherein wherein Y is O, S, S(O), S(O).sub.2, --CH.sub.2
--, --NH-- or CO, preferably S or O; Ar.sub.1 is ##STR8## Ar.sub.2
is a group selected from the group consisting of: ##STR9##
wherein
R.sub.3 is NHS(O).sub.2 C.sub.1-6 alkyl, NHS(O).sub.2 CF.sub.3, or
N(CH.sub.3 CO)S(O).sub.2 CH.sub.3 ;
R.sub.4 is selected from the group consisting of (a) acyl such as
CO--C.sub.1-3 alkyl, (b) cyano, (c) carboxy; (d) carboxy C.sub.1-6
alkyl ester, (e) carboxamide, (f) C.sub.1-6 alkyl sulfinyl, (g)
C.sub.1-6 alkyl sulfonyl, and (h) nitro;
R.sub.5 is H, C.sub.1-3 alkyl, or R.sub.4 and R.sub.5 are joined
together to form a saturated monocyclic ring of five (5) carbons,
wherein one of the carbons is substituted with an oxo or oximino
group, or one of the carbons may be replaced by S(O).sub.2 ;
R.sub.6 and R.sub.7 are each independently selected from the group
consisting of hydrogen, C.sub.1-3 alkyl or halo, including
fluoro;
n is 0, 1, or 2; and
Z is O or S.
In a third embodiment the invention encompasses compounds of
formula I wherein
Y is O;
Ar.sub.1 is ##STR10##
R.sub.7 is a group such as
(a) NHS(O).sub.2 C.sub.1-6 alkyl,
(b) N(CH.sub.3 CO)S(O).sub.2 CH.sub.3, or
(c) NHS(O).sub.2 CF.sub.3 ; and
Ra and Rb are jointly oxo or oximino;
Ar.sub.2 is ##STR11##
wherein Rc and Rd are each independently selected from hydrogen or
halo, such as fluoro, Cl, Br, or Iodo.
With regard to the third embodiment Ar.sub.2 may alteratively be
tri substituted with substituents independently selected from:
(a) hydrogen,
(b) F, Cl, Br, or I,
(c) methyl or ethyl,
(d) --CF.sub.3,
(e) vinyl or --C.ident.CH,
(f) --OCH.sub.3 or --OCF.sub.3,
(g) SCH.sub.3 or SCF.sub.3,
(h) CN, or
(i) N.sub.3,
the substitutents residing at position 1, 3 and 5 of the
phenyl.
Thus one alternative to this third embodiment is the compounds of
Formula I ##STR12##
wherein
Ar.sub.1 is ##STR13##
Y is O or S; and
Ar.sub.2 is ##STR14##
wherein A, B and C are each independently selected from
(a) hydrogen,
(b) F, CI, Br, or I,
(c) methyl or ethyl,
(d) --CF.sub.3,
(e) vinyl or --C.ident.CH,
(f) --OCH.sub.3 or --OCF.sub.3,
(g) SCH.sub.3 or SCF.sub.3,
(h) CN, or
(i) N.sub.3.
In a fourth embodiment the invention encompasses compounds of
Formula I wherein
Y is O or S;
Ar.sub.1 is ##STR15##
wherein
R.sub.9 is a group such as R.sub.x S(O)2NR, wherein
R.sub.x is C.sub.1-3 alkyl or CF.sub.3, and
R is hydrogen or a pharmaceutically acceptable cation;
R.sub.8 is nitro or acyl, such as CO--C.sub.1-3 alkyl;
Ar.sub.2 is ##STR16## R.sub.6 and R.sub.7 are each independently
selected from the group consisting of hydrogen, C.sub.1-3 alkyl or
halo, including fluoro;
In a fifth embodiment the invention encompasses compounds of
Formula I wherein Ar.sub.1 is ##STR17## Re is C.sub.1-3 alkyl or
trifluoromethyl; Y is O, S, S(O), or S(O).sub.2 ; and Ar.sub.2 is
##STR18##
wherein
R.sub.6 and R.sub.7 are each independently selected from the group
consisting of hydrogen, Cl-3alkyl or halo, including fluoro; or
Ar.sub.2 is ##STR19##
wherein n is 0, 1, or 2.
Exemplifying this aspect of the invention are the following
compounds: ##STR20##
as well as compound compound 12 mentioned above ##STR21##
and pharmaceutically acceptable salts thereof.
A is appreciated by thoses of skill in the art, compounds A to D
are known by the names Dup 697 (compound A), Flosulide (compound
B), Nimesulide (compound C), and NS 398 (compound D).
Illustrative of the pharmaceutically acceptable salts is the
formula ##STR22##
wherein Z.sup.+ is a pharmaceutically acceptable counterion. As is
well appreciated by those of skill in the an, the pharmaceutically
acceptable counterions include, aluminum, calcium, lithium,
magnesium, potassium, sodium, barium, zinc, ammonium, or an amino
acid such as glycine, alinine, valine, leucine, isoleucine, serine,
threonine, aspartic acid, asparagine, glutamic acid, lysine,
hydroxylsine, histidine, arginine, phenylalanine, tyrosine,
tryptophan, thyroxine, cystine, x s cysteine, methionine, proline,
hydroxyproline, ornithine, b-alanine, a-amino butyric acid,
sarcosine, betaine, homoserine, and citrulline, or mono, di, or
triC.sub.1-6 alkylamino.
The invention also encompasses anti-inflammatory pharmaceutical
compositions such as 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 cyclooxygenase-2 and for treating
cyclooxygenase-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.
The invention also encompasses a method of inflammation such as
inhibiting cyclooxygenase (e.g. cyclooxygenase-2) and treating
cyclooxygenase (e.g. cycloxygenase-2) mediated diseases as
disclosed herein comprising: administration to a patient in need of
such treatment of a non-toxic therapeutically effective amount of
compound of Formula I as described above.
Within this embodiment the invention encompasses a method of
selectively inhibiting cyclooxygenase-2 and selectively treating
cyclooxygenase-2 mediated diseases as disclosed herein comprising:
administration to a patient in need of such treatment of a
non-toxic therapeutically effective amount of compound of Formula I
as disclosed herein. For purpose of this specification a compound
that is selective for the inhibition of cyclooxygenase-2 or for
treatment of cyclooxygenase-2 mediated diseases is a compound that
demonstrates an in vitro or in vivo IC.sub.50 ratio for COX-1 to
COX-2 of approximately 1000 or greater.
As disclosed elsewhere in this specification in further detail,
these diseases include pain, fever and inflammation of a variety of
conditions including rheumatic fever, symptoms associated with
influenza or other viral infections, common cold, low back and neck
pain, dysmenorrhea, headache, toothache, sprains and strains,
myositis, neuralgia, synovitis, arthritis, including rheumatoid
arthritis degenerative joint diseases (osteoarthritis), gout and
ankylosing spondylitis, bursitis, burns, injuries.
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, common cold, low back and neck pain, dysmenorrhea,
headache, toothache, sprains and strains, myositis, neuralgia,
synovitis, arthritis, including rheumatoid arthritis degenerative
joint diseases (osteoarthritis), gout and ankylosing spondylitis,
bursiris, bums, 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. The compounds of Formula 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 and asthma.
Compounds of formula 1 may also be useful in the treatment of
Alzheimers disease and menentia.
By virtue of their high cyclooxygenase-2 (COX-2) activity and/or
their specificity for cyclooxygenase-2 over cyclooxygenase-1
(COX-1), the compound of Formula I will prove useful as
alternatives to conventional non-steroidal anti-inflammatory drugs
(NSAID'S) particularly where such non-steroidal anti-inflammatory
drugs may be contraindicated such as in patients with peptic
ulcers, gastritis, regional enteritis, ulcerative colitis,
diverticulitis or with a recurrent history of gastrointestinal
lesions; GI bleeding, coagulation disorders including anemia such
as hypoprothrombinemia, haemophilia or other bleeding problems;
kidney disease; those prior to surgery or taking
anticoagulants.
Similarly, the compound of Formula 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 cyclooxygenase-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
acetaminophen or phenacetin; a potentiator including caffeine; an
H2-antagonist, aluminum or magnesium hydroxide, simethicone, a
decongestant including phenylephrine, phenylpropanolamine, s
pseudophedrine, oxymetazoline, ephinephrine, naphazoline,
xylometazoline, propylhexedrine, or levo-desoxyephedrine; an
antitussive including codeine, hydrocodone, caramiphen,
carbetapentane, or dextramethorphan; a diuretic; a sedating or
nonsedating 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 effective amount of compound of Formula I,
optionally co-administered with one or more of such ingredients as
listed immediately above.
The compounds of the present invention is an inhibitor of
cyclooxygenase-2 and is thereby useful in the treatment of
cyclooxygenase-2 mediated diseases as enumerated above. This
activity is illustrated by it's ability to selectively inhibit
cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in one assay,
the ability of the compounds of this invention to treat
cyclooxygenase mediated diseases can be demonstrated by measuring
the amount of prostaglandin E.sub.2 (PGE.sub.2) synthesized in the
presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2
and a compound of formula I. The IC50 values represent the
concentration of inhibitor required to return PGE.sub.2 synthesis
to 50% of that obtained as compared to the uninhibited control.
Illustrating this aspect, is the a comparison is provided
hereinunder of the compound 12 with Flosulide: ##STR23##
This compound and it's method of preparation is disclosed in U.S.
Pat. No. 4,375,479, issued to Schroeder, et al., Mar. 1, 1983.
By way of comparison, Ibuprofen has an IC50 for COX-2 of 1 mM, and
Indomethacin has an IC.sub.50 for COX-2 of approximately 100
nM.
For the treatment of any of these cyclooxygenase mediated diseases
the compound of Formula I and pharmaceutically accetable salts
thereof may be administered orally, topically, parenterally, by
inhalation spray or rectally in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrastemal
injection or infusion techniques. In addition to the treatment of
warm-blooded animals such as mice, rats, horses, cattle, sheep,
dogs, cats, etc., the compounds of the invention are effective in
the treatment of humans.
As indicated above, pharmaceutical compositions for treating
cyclooxygenase-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 known to the an 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 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 techniques described in
U.S. Pat. Nos. 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 ingredient
is mixed with water or an oil medium, for example peanut oil,
liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with
excipients suitable for the manufacture of aqueous suspensions.
Such excipients are suspending agents, for example sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing 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 heptadecaethyleneoxycertanol, 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 hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example 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 oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. s 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
already 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 oil-in-water emulsions. The oil 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 gums, for example gum acacia or
gum tragacanth, naturally-occurring phosphatides, for example soy
bean, lecithin, and esters or partial esters derived from fatty
acids and hexitol anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene
oxide, for example polyoxyethylene sorbitan monooleate. The
emulsions may also contain sweetening and flavoring 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 an using those 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 diol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. 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, fattyacids such as oleic acid find use in the preparation
of injectables.
The compound of Formula (I) and pharmaceutically acceptable salts
thereof may also be administered in the form of 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
rectal 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, jellies, 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.)
Dosage levels of the order of from about 0.01 mg to about 140 mg
per kilogram 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 1.0 g per patient per day. A
typical dosage range is 100 or 200 mg to about 1000 mg. An upper
ranges of 500 or 2000 mg is also be regarded as typical.
The amount of active ingredient that may be combined with the
carder 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 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 1000 mg 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 activity of the specific compound employed, 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.
Compounds of the instant invention are conveniently prepared using
the procedures described in the methods below. Additional relevant
chemistry is described in U.S. Pat. No. 4,375,479, issued to
Schroeder, et al., Mar. 1, 1983 which is hereby incorporated by
reference.
METHOD A
5-Aminoindane II is acetylated, followed by bromination to give the
5-acetylamino-6-bromoindane III. Oxidation with chromium trioxide
in aqueous acetic acid, followed by acidic hydrolysis gives the
5-amino-6-bromo-1-indanone IV. The amino group is converted to the
nitro group by diazotization followed by treatment of the
corresponding diazonium salt with sodium nitrite in the presence of
copper powder. Subsequent protection of the carbonyl as a dioxolane
provides 5-nitro-6-bromo-1-indanone ethylene ketal V. Coupling with
an appropriate s nucleophile proceeds under basic conditions with
or without the presence of a copper salt. Reduction of the nitro
group with iron powder or tin(II) chloride in aqueous ethanol with
concomitant hydrolysis of the ketal group leads to amino indanone
VI. Sulfonylation with excess methanesulfonyl chloride in the
presence of trimetylamine yields the corresponding bissulfonamide,
which upon subsequent hydrolysis with sodium hydroxide yields the
title compound I'. ##STR24##
METHOD B
4-Chloro-3-nitrobenzaldehyde is coupled with an appropriate
nucleophile under basic conditions to give VII. Reduction of the
nitro groups with iron powder of tin/II chloride in aqueous ethanol
gives the corresponding aniline, which is converted to the
bissulfonamide with excess methanesulfonyl chloride in the presence
of triethylamine. Basic hydrolysis of the bissulfonamide then
yields IX. A two carbon elongation step with triethyl
phosphonoacetate anion (prepared from treatment with sodium
hydride) or (carbethoxymetylene)triphenylphosphorane provides an
.alpha., .beta.-unsaturated ester. Reduction of the double bond
with 10% palladium on charocoal under hydrogen atmosphere followed
by ester hydrolysis affords acid X. The acid X is converted to the
acid chloride and then treated with aluminum chloride or other
standard Friedel-Crafts Lewis acid catalysts to give the title
compound I'. ##STR25##
ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY
The compound of Formula I were tested using the following assays to
determine their cyclooxygenase-2 inhibiting activity.
INHIBITION OF CYCLOOXYGENASE ACTIVITY
Compounds were tested as inhibitors of cyclooxygenase activity in
whole cell and microsomal cyclooxygenase assays. Both of these
assays measured prostaglandin E.sub.2 synthesis in response to
arachidonic acid, using a radioimmunoassay. Cells used for whole
cell assays, and from which microsomes were prepared for microsomal
assays, were human osteosarcoma 143 cells (which specifically
express cyclooxygenase-2) and human U-937 cells (which specifically
express cyclooxygenase-1). In these assays, 100% activity is
defined as the difference between prostaglandin E.sub.2 synthesis
in the absence and presence of arachidonate addition.
RAT PAW EDEMA ASSAY--PROTOCOL
Male Sprague-Dawley rats (150-200 g) were fasted overnight and were
given po either vehicle (1% methocel) 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 (V.sub.O) was measured using a
plethysmometer (Ugo-Basile, Italy) based on the principle of water
displacement.
The animals were then injected subplantarly with 50 .mu.l of 1%
carrageenan solution in saline (FMC Corp, Maine) into the paw using
an insulin syringe with a 25 -gauge needle (i.e. 500 .mu.g
carrageenan per paw). Three hr later, the paw volume (V.sub.3) was
measured and the increases in paw volume (V.sub.3 -V.sub.0) were
calculated. The animals were sacrificed by CO.sub.2 aphyxiation and
the absence or presence of stomach lesions scored. Data were
compared with the vehicle-control values and percent inhibition
calculated. Since a maximum of 60-70% inhibition (paw edema) was
obtained with standard NSAIDs, ED.sub.30 values were used for
comparison and at at least 3 different concentrations. At least 6
animals were used at each concentration All treatment groups were
coded to eliminate observer bias.
REPRESENTATIVE BIOLOGICAL DATA
The compounds of the present invention are inhibitors of
cyclooxygenase-2 and are thereby useful in the treatment of
inflammation such cyclooxygenase-2 mediated diseases as enumerated
above. The activities of the compound against cyclooxygenase may be
seen in the representative results shown below. In the assay,
inhibition is determined by measuring the amount of prostaglandin
E.sub.2 (PGE.sub.2) synthesized in the presence of arachidonic
acid, cyclooxygenase-1 or cyclooxygenase-2 and a putative
inhibitor. The IC.sub.50 values represent the concentration of
putative inhibitor required to return PGE.sub.2 synthesis to 50% of
that obtained as compared to the uninhibited control.
The results for inhibition of PGE.sub.2 production may be seen in
the following Table.
COMPARISON OF SELECTED COMPOUNDS WITH FLOSULIDE Rat Paw Rat Plasma
Monkey t1/2 CONC COX-2 COX-1 EDEMA Levels @ 1 hr C.sub.max Monkey
(n = 2) (nM) % INHB % INHB ED.sub.30 (mpk) (.mu.g/ml) (.mu.g/ml)
(Estimated) INDOMETHACIN IC.sub.50 50 nM 10 nM 1.1 .+-. .3
##STR26## IC.sub.50 50 nM Inactive at 50 .mu.M 1.1 .+-. .4 48 @ 20
mpk 17 @ 10 mpk <4 hr ##STR27## 10 100 1000 43 87 91 Inactive at
10 .mu.M 0.3 .+-. .1 70 @ 10 mpk 35 @ 5 mpk >9 hr ##STR28##
IC.sub.50 8 nM Inactive at 100 .mu.M 0.22 ##STR29## IC.sub.50 7 nM
0.1
BIOLOGICAL ACTIVITIES OF PREPARED EXAMPLES Com- COX-2 COX-1 pound
IC.sub.50 IC.sub.50 # (nM) (nM) Rat Paw Edema ED.sub.50 (mpk) 1 30
Schering U.S. Pat. No. 4,244,960 2 9 3 50 >50,000 0.62 Schering
U.S. Pat. No. 4,375,479 (Flo- sulide) 4 8 >100,000 0.22 5 100 6
50 >100,000 0.16 7 100 8 100 9 100 10 8 >10,000 3.0 11 10 12
50 >10,000 0.3 13 100 14 13 15 10 16 11 17 7 18 60 >100,000
19 100 20 50 21 100 22 50 23 300 24 100 25 1,000
NMR DATA FOR EXAMPLES Com- pound # X A B C NMR .delta. (ppm) 1 O H
H H See U.S. Pat. No. 4,244,960 2 O H Br H (CDCl.sub.3) 7.73(s,
1H), 7.53(d, 2H), 7.29(m, 1H), 7.14(s, 1H), 6.94(d, 2H), 3.16(s,
3H), 3.13(t, 2H), 2.70(t, 2H). 3 O F F H See U.S. Pat. No.
4,375,479 4 O Cl Cl H (CDCl.sub.3) 7.73(s, 1H), 7.50(s, 1H),
7.32(m, 2H), 7.08(d, 1H), 6.90(s, 1H), 3.14(s, 3H), 3.10(t, 2H),
2.68(t, 2H). 5 O H SMe H (Acetone-d.sub.6) 8.65(brs, 1H), 7.79(s,
1H), 7.38(d, 2H), 7.08(d, 2H), 7.01(s, 1H), 3.20(s, 3H), 3.14(t,
2H), 2.62(t, 2H), 2.50(s, 3H). 6 S H H H (CDCl.sub.3) 8.08(s, 1H),
7.85(s, 1H), 7.80(s, 1H), 7.32-7.10(m, 5H), 3.20(t, 2H), 2.78(s,
3H), 2.74(t, 2H). 7 S F H H (CDCl.sub.3) 8.02(s, 1H), 7.97(brs,
1H), 7.28(m, 1H) 7.15(t, 1H), 7.08(m, 2H), 3.13(t, 2H), 2.97(s,
3H), 2.70(t, 2H). 8 S H F H (CDCl.sub.3) 8.00(s, 1H), 7.80(s, 1H),
7.76(s, 1H) 7.16(t, 2H), 6.98(t, 2H), 3.16(t, 2H), 2.88(s, 3H),
2.72(t, 2H). 9 S H Cl H (CDCl.sub.3) 8.04(s, 1H), 7.82(brs, 2H),
7.25(d, 2H), 7.08(d, 2H), 3.20(t, 2H), 2.92(s, 3H), 2.75(t, 2H). 10
S H Br H (Acetone-d.sub.6) 9.15(brs, 1H), 7.75(s, 1H), 7.65(s, 1H),
7.54(d, 2H), 7.22(d, 2H), 3.18(t, 2H), 3.10(s, 3H), 2.65(t, 2H). 11
S H I H (CDCl.sub.3) 8.03(s, 1H), 7.78(brs, 2H), 7.56(d, 2H),
6.82(d, 2H), 3.18(t, 2H), 2.88(s, 3H), 2.71(t, 2H). 12 S F F H
(CDCl.sub.3) 8.05(s, 1H), 7.98(s, 1H), 7.78(s, 1H), 7.30(m, 1H),
6.88(m, 2H), 3.16(t, 2H), 3.06(s, 3H), 2.70(t, 2H). 13 S F H F
(CDCl.sub.3) 8.22(brs, 1H), 8.03(s, 1H), 7.72(s, 1H), 7.32(m, 1H),
6.96(m, 2H), 3.11(t, 2H), 3.05(s, 3H), 2.65(t, 2H). 14 S F Cl H
(CDCl.sub.3) 7.97(s, 1H), 7.92(bs, 1H), 7.75(s, 1H) 7.08(m, 3H),
3.14(t, 2H), 3.30(s, 3H), 2.70(t, 2H). 15 S F Br H (CDCl.sub.3)
7.97(s, 1H), 7.91(brs, 1H), 7.77(s, 1H) 7.23(m, 2H), 7.00(t, 1H),
3.13(t, 2H), 3.03(s, 3H) 2.70(t, 2H). 16 S Cl F H (CDCl.sub.3)
7.97(s, 1H), 7.82(brs, 1H), 7.78(s, 1H), 7.19(m, 1H), 6.88(d, 2H),
3.18(t, 2H), 3.00(s, 3H), 2.71(t, 2H). 17 S Cl Cl H (CDCl.sub.3)
8.00(s, 1H), 7.82(s, 1H), 7.78(s, 1H), 7.46(d, 1H), 7.10(dd, 1H),
6.68(d, 1H), 3.20(t, 2H), 3.02(s, 3H), 2.78(t, 3H). 18 S F Br F
(CDCl.sub.3) 8.18(brs, 1H), 8.03(s, 1H), 7.74(s, 1H), 7.16(d, 2H),
3.14(t, 2H), 3.11(s, 3H), 2.69(t, 2H). 19 S CH.sub.3 H H
(CDCl.sub.3) 7.97(s, 1H), 7.82(s, 1H), 7.68(brs, 1H), 7.23(d, 1H),
7.15(t, 1H), 7.05(t, 1H), 6.76(d, 1H), 3.18(t, 2H), 2.82(s, 3H),
2.75(t, 2H). 20 S H CH.sub.3 H (CDCl.sub.3) 8.04(s, 1H), 7.82(s,
1H), 7.78(s, 1H), 7.10(s, 4H), 3.16(t, 2H), 2.78(s, 3H), 2.72(t,
H), 2.30(s, 3H). 21 S CF.sub.3 H H (CDCl.sub.3) 8.05(s, 1H),
7.81(s, 1H), 7.74(s, 1H), 7.70(d, 1H), 7.30(m, 2H), 6.92(d, 1H),
3.18(t, 2H), 2.86(s, 3H), 2.73(t, 2H). 22 S H CF.sub.3 H
(CDCl.sub.3) 8.06(s, 1H), 7.85(s, 1H), 7.80(brs, 1H), 7.52(d, 2H),
7.16(d, 2H), 3.23(t, 2H), 2.97(s, 3H), 2.78(t, 2H). 23 S H
OCH.sub.3 H (CDCl.sub.3) 7.98(s, 1H), 7.80(brs, 1H), 7.72(s, 1H),
7.20(d, 2H), 6.72(d, 2H), 3.76(s, 3H), 3.13(t, 2H), 2.79(s, 3H),
2.69(t, 2H). 24 S H CH.dbd.CH.sub.2 H (CDCl.sub.3) 8.06(s, 1H),
7.84(s, 1H), 7.82(s, 1H), 7.31(m, 2H), 7.12(m, 2H), 6.65(q, 1H),
5.72(d, 1H), 5.28(d, 1H), 3.18(t, 2H), 2.80(s, 3H), 2.75(t, 2H). 25
S H Et H (CDCl.sub.3) 8.04(s, 1H), 7.80(brs, 1H), 7.77(s, 1H),
7.12(s, 4H), 3.18(t, 2H), 2.77(s, 3H), 2.73(t, 2H), 2.61(q, 2H),
1.19(t, 3H).
EXAMPLES
The invention is illustrated by the following non-limiting
examples. Unless stated otherwide it is to be understood that (i)
all operations were carried out at room or ambient temperature,
that is, at a temperature in the range 18.degree.-25.degree. C.;
(ii) evaporation of solvent was carded out using a rotary
evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg)
with a bath temperature of up to 60.degree. C.; (iii) the course of
reactions was followed by thin layer chromatography (TLC) and
reaction times are given for 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; (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 (d) values for major diagnostic protons, given in pans per
million (ppm) relative to tetramethylsilane (TMS) as internal
standard, determined at 300 MHz or 400 MHz using the indicated
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; and (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
(milligram(s)), mol (moles), mmol (millimoles), eq
(equivalent(s)).
PREPARATION EXAMPLE FOR METHOD A (COMPOUND 12)
5-Methanesulfonamido-6-(2,4-difluorophenylthio)- 1-indanone
Step 1: 5-Acethylamninoindane
To a solution of 5 -aminoindane (10.0 g, 7.5 mmol) in CH.sub.2
Cl.sub.2 (100 mL) was added dropwise acetic anhydride (9.2 g, 9.0
mmol) over a period of 15 min. After further stirring for 30 min,
the mixture was quenched with 1M aqueous NaOH (100 mL). The
CH.sub.2 Cl.sub.2 layer was separated, washed successively with 1M
aqueous HCl, brine, and was then dried over anhydrous MgSO.sub.4
and concentrated in vacuo. Chromatography over silica gel, eluting
with ethyl acetate-:hexanes (1:1) afforded 12.2 g (85%) of the
title compound as a light brown powder. .sup.1 H NMR (CDCl.sub.3):
.delta.7.44 (1H, s), 7.12 (3H, three overlapping s), 2.88 (4H, m),
2.15 (3H, s), 2.06 (2H, m).
Step 2: 5-Acetylamino-6-bromoindane
To a solution of 5-acetylaminoindane (53.0 g, 0.30 mol) in glacial
acetic acid (1 L) at 10.degree. C. was added dropwise over a period
of 1 h a solution of bromine (19.0 mL, 0.37 mol). The mixture was
further stirred at 10.degree. C. for 15 min, and was then diluted
with water until no more precipitate formed. The precipitate was
collected, washed with water and dried under vacuum to give 61 g
(80%) of the title compound.
.sup.1 H NMR (CDCl.sub.3): .delta.5 8.14 (1H, s), 7.50 (1H, s),
7.38 (1H, s), 7.38 (4H, m), 2.20 (3H, s), 2.08 (2H, m).
Step 3: 5-Acetylamino-6-bromo-1-indanone
To a solution of 5-acetylamino-6-bromoindane (43.0 g, 0.17 mol) in
glacial acetic acid (400 mL) at 50.degree.-55.degree. C. was added
dropwise a solution of chromium trioxide (70.0 g, 0,7 mol) in 50%
aqueous acetic acid (400 mL) over a period of 30 min. After further
stirring for 15 min, the mixture was cooled to 0.degree. C. and
quenched with 2-propanol (100 mL). Solvent was removed in vacuo.
The residue was diluted with water (1 L) and extracted with ethyl
acetate (2.times.500 mL). The combined ethyl acetate layer was
washed with 0.5M aqueous NaOH (1 L), brine, dried over anhydrous
MgSO.sub.4 and concentrated to give 36 g (80%) of the title
compound as a light brown solid which was contaminated with about
10% of 5-bromo-6-acetylamino- 1-indanone. .sup.1 H NMR
(CDCl.sub.3); .delta.8.60 (1H, s), 7.90 (1H, s), 7.90 (1H, s), 3.10
(2H, t), 2.70 (2H, t), 2.30 (3H, s).
Step 4: 5-Amino-6-bromo-1-indanone
A mixture of 5-acetylamino-6-bromo-1-indanone (36.0 g, 0.13 mol)
and 6M aqueous hydrochloric acid (800 mL) was refluxed for 1 h. The
homogenous solution was then cooled to 0.degree. C. and adjusted to
pH 8 with 10M aqueous NaOH (-480 mL). The precipitate formed was
collected, washed with water and dried under vacuum to afford 30.0
g (quantitative) of the title compound as a light brown powder.
.sup.1 H NMR (acetone-d.sub.6): .delta.7.65 (1H, s), 6.90 (1H, s),
5.80 (2H, br s), 2.95 (2H, t), 2.50 (2H, t).
Step 5: 5-Nitro-6-bromo-1-indanone
To a suspension of 5-amino-6-bromo-1-indanone (30.0 g, 0.13 mol) in
20% aqueous fluoroboric acid (120 mL) at 0.degree. C. was added
dropwise 4M aqueous NaNO.sub.2 (50 mL, 0.20 mol) over a period of
30 min. The mixture was stirred for 30 min after completion of
addition. The resulting foamy suspension was added portionwise to a
vigorously stirred mixture of copper powder (40 g, 0.62 mol) and
sodium nitrite (120 g, 1.74 mol) in water (240 mL) at room
temperature over a period of 15 min. During the addition, excessive
foaming was broken up by the addition of small amounts of diethyl
ether. After further stirring for 30 min, the mixture was filtered
through celite, washed with ethyl acetate (5'300 mL). The ethyl
acetate layer was separated, washed with brine, dried over
anhydrous MgSO.sub.4 and concentrated in vacuo. Chromatography over
silica gel, eluting with CH.sub.2 Cl.sub.2, yielded 17.5 g (51%) of
the title compound as a pale yellow solid.
.sup.1 H NMR (CDCl.sub.3); .delta.8.10 (1H, s), 7.85 (1H, s), 3.20
(2H, t), 2.85 (2H, t); mass spectrum (DCI, CH.sub.4) m/e 256
(M.sup.+.sub.+ H). Step 6: 5-Nitro-6-bromo-1-indanone ethylene
ketal.
To a suspension of 5-nitro-6-bromo-1-indanone (11.0 g, 43 mmol) and
bis(trhnethylsilyloxy)ethane (22.0 mL, 90 mmol) in CH.sub.2
Cl.sub.2 (90 mL) at room temperature was added trimethylsilyl
trifluoromethanesulfonate (100 .mu.L). The mixture was stirred for
2 h and the homogeneous solution was quenched with saturated
aqueous NaHCO.sub.3 (100 mL). The CH.sub.2 Cl.sub.2 layer was
separated, washed with brine, dried over anhydrous MgSO.sub.4 and
concentrated in vacuo. Chromatography over silica gel, eluting with
ethyl acetate:hexanes (2:5), furnished 10.2 g (79%) of the title
compound as a pale yellow solid. .sup.1 H NMR (CDCl.sub.3):
.delta.7.70 (1H, s), 7.68 (1H, s), 4.15 (4H, m), 2.98 (2H, t), 2.38
(2H, t)
Step 7: 5-Nitro-6-(2,4-difluorophenylthio)-1-indanone ethylene
ketal
To a mixture of 5-nitro-6-bromo-1-indanone ethylene ketal (600 mg,
2.0 mmol) and 2,4-difluorothiophenol (F. Klages and K. Bott Chem.
Ber. 97,735 (1964)) (440 mg, 3.0 mmol) in pyridine (4.0 mL) was
added a solution of 8M aqueous potassium hydroxide (375 .mu.L, 3.0
mmol) at room temperature. The mixture was stirred for 2 h, diluted
with water and extracted with ethyl acetate. The ethyl acetate
extract was washed successively with 1M aqueous NaOH (2x),0.5M
aqueous HCl (1x), brine, dried over anhydrous MgSO.sub.4 and
concentrated in vacuo. Chromatography over silica gel and eluted
with toluene: ethyl acetate (10:1) afforded the title compound (590
mg, 81%) as a pale yellow solid.
.sup.1 H NMR (CDCl.sub.3).delta.8.12 (s,1H), 7.60 (m, 1H), 7.00 (m,
2H), 6.70 (s, 1H), 4.10-3.90 (m 4H), 2.95 (t, 2H), 2.30 (t,
2H).
Step 8: 5-Amino-6-(2,4-difluorophenylthio)-1-indanone
A mixture of 5-nitro-6-(2,4-difluorophenylthio)-1-indanone ethylene
ketal (580 mg, 1.59 mmol), iron powder (500 mg, 8.9 mmol) and
ammonium chloride (50 mg, 0.93 mmol) in 30 mL of ethanol:water
(2:1) was refluxed for 1 h. The hot mixture was filtered through
celite. The solvente was evaporated in vacuo. The residue was
diluted with water and extracted with ethyl acetate. The ethyl
acetate extract was dried over anhydrous MgSO.sub.4 and
concentrated to give the title compound (410 mg, 81%) as a light
brown solid. .sup.1 H NMR (CDCl.sub.3) .delta.7.95 (s, 1H), 7.00
(m, 1H), 6.80 (m, 2H), 6.72 (s, 1H), 4.95 (br s, 2h), 3.05 (t, 2H),
2.65 (t, 2H).
Step 9:
5-Methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone
A mixture of 5-amino-6-(2,4-difluorophenylthio)-1-indanone (400 mg,
1.25 mmol), triethylamine (1.0 mL, 7.2 mmol) and methanesulfonyl
chloride (300 .mu.L, 3.9 mmol) in methylene chloride (10 mL) was
stirred at room temperature for 1 h. After dilution with more
methylene chloride (20 mL), the mixture was washed successively
with saturated aqueous sodium bicarbonate, 1M aqueous HC1 and
brine. The methylene chloride layer was separated, dried over
anhydrous MgSO.sub.4 and concentrated to give a dark solid
residue.
To a solution of the above residue in MeOH:THF (2:1, 24 mL) at room
temperature was added 10M aqueous NaOH (375 .mu.L, 3.75 mmol). The
mixture was stirred at room temprature for 30 min and then
acidified with 3M aqueous HCl (1.5 mL). The volatile solvents were
evaporated in vacuo. The residue was diluted with water, and
extracted with ethyl acetate. The ethyl acetate layer was
separated, washed with brine, dried over anhydrous MgSO.sub.4 and
concentrated. Chromatography over silica gel and elution with
hexanes: ethyl acetate (1:1) yielded the title compound (350 mg,
76%) as a light brown solid. .sup.1 H NMR (CDCl.sub.3) .delta.8.05
(s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.30 (m, 1H), 6.88 (m, 2H),
3.16 (t, 2H), 3.06 (s, 3H), 2.70 (t, 2H).
PREPARATION EXAMPLE FOR METHOD B (COMPOUND 17)
4-(2,4-dichlorophenoxy)-3-nitrobenzaldehyde ##STR30##
To powdered potassium hydroxide (9.0 g, 0.12 mol) at 110.degree. C.
was added 2,4-dichlorophenol (19.0 g, 0.12 mol) in one portion. The
mixture was stirred for 15 min. and a homogenous solution resulted.
4-Chloro-3-nitrobenzaldehyde (20.0 g, 0.11 mol) was added and the
thick mixture was stirred at 110.degree. C. for 1 h. After cooling
to room temperature, the mixture was partitioned between 2M aqueous
sodium hydroxide and ethyl acetate. The organic layer was
separated, washed with brine and dried over magnesium sulfate.
Evaporation of solvent and recrystallization from ethanol afforded
27.0 g (80%) of the title compound as a pale yellow solid. .sup.1 H
NMR (CDCl.sub.3) .delta.9.80 (s, 1H), 8.48 (s, 1H), 7.90 (d, 1H),
7.53 (s, 1H), 7.35 (d, 1H), 7.16 (d, 1H), 6.88 (d, 1H).
3-Amino-4-(2,4-dichlorophenoxy)benzaldehyde ##STR31##
A mixture of 4-(2,4-dichlorophenoxy)-3-nitrobenzaldehyde (19.0 g,
0.006 mol), iron powder (13.0 g, 0.23 mol) and ammonium chloride
(saturated aqueous solution, 50 ml) in 600 mL of ethanol:water
(2:1) was refluxed for 1.5 h. The hot mixture was filtered through
celite. Solvent was evaporated in vacuo. The residue was
partitioned between dichloromethane and water. The organic layer
was separated, dried over anhydrous magnesium sulfate and
concentrated. Chromatography over silica gel and elution with
hexanes:ethyl acetate (2:1) gave the title compound (10.0g, 60%) as
a white solid. .sup.1 H NMR (CDCl.sub.3).delta.9.83 (s, 1H), 7.50
(s, 1H), 7.33 (s, 1H), 7.25 (d, 1H), 7.15 (d, 1H), 7.00 (d, 1H),
6.68 (d, 1H), 4.1 (brs, 2H).
4-(2,4-Dichlorophenoxy)-3-methanesulfonamido-benzaldehyde
##STR32##
A mixture of 3-amino-4-(2,4-dichlorophenoxy)benzaldehyde (8.0 g,
0.028 mol), trietylamine (15.8 mL, 0.11 mol) and methanesulfonyl
chloride (9.75 g, 0.085 mol) in dichloromethane (200 mL) was
stirred at 0.degree. C. for 1 h. The mixture was then washed with
saturated aqueous sodium bicarbonate, dried over anhydrous
magnesium sulfate and concentrated to give a dark solid
residue.
To a solution of the above residue in MeOH:THF (2:1,150 mL) at
0.degree. C. was added 2M aqueous sodium hydroxide (42 mL, 84
mmol). The mixture was stirred at room temperature for 1 h and then
acidified with 1M aqueous hydrochloric acid. Most of the organic
solvents-were evaporated in vacuo. The residue was extracted with
ethyl acetate, washed with brine, dried over anhydrous magnesium
sulfate and concentrated. The solid residue was suspended in
ethanol and filtered to give the title compound. The filtrate was
concentrated and chromatographed over silica gel with
hexanes-:ethyl acetate (2:1) to give the title compound (14.0 g,
92% combined yield) as a white solid. .sup.1 H NMR (CDCl.sub.3)
.delta.9.90 (s, 1H), 8.13 (s, 1H), 7.58 (d, 1H), 7.53 (s, 1H), 7.35
(d,1H), 7.11 (d, 1H), 7.03 (brs, 1H), 6.68 (d, 1H), 3.12 (s,
3H).
Ethyl 4-(2,4-dichlorophenoxy)-3-methanesulfonamido-cinnamate
##STR33##
To a suspension of sodium hydride (500 mg, 16.7 mmol) in
tetrahydrofuran (15 mL) was added dropwise triethylphosphonoacetate
(1.87 g, 8.3 mmol) at 0.degree. C. The mixture was stirred at
0.degree. C. for 15 min. and a homogeneous solution resulted. A
solution of
4-(2,4-dichlorophenoxy)-3-methanesulfonamido-benzaldehyde (2.5 g,
6.94 mmol) in tetrahydrofuran (20 mL) was added slowly. After
stirring at room x s temperature for 2 h, the mixture was quenched
with acetic acid (1mL). Solvent was evaporated in vacuo. The
residue was diluted with water and extracted with ethyl acetate.
The ethyl acetate layer was separated, washed with water, brine,
dried over anhydrous magnesium sulfate and concentrated.
Chromatography over silica gel and elution with hexanes:ethyl
acetate (3:1) yielded the title compound (2.57 g, 86%) as a solid.
.sup.1 H NMR (CDCl.sub.3).delta.7.82 (s, 1H), 7.60 (d, 1H), 7.50
(s, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.89 (s, 1H),
6.60 (d, 1H), 6.36 (d, 1H), 4.25 (q, 2H) 3.08 (s, 3H), 1.30 (t,
3H).
Ethyl 3-[4-(2,4-dichlorophenoxy)-3-methanesulfonamido]
phenylpropionate ##STR34##
A mixture of ethyl
4-(2,4-dichlorophenoxy)-3-methanesulfonamido-cinnamate (2.2 g, 5.1
mmol) and 10% palladium on Charcoal (850 mg) in ethyl acetate (75
mL) was hydrogenated at room temperature under 30 psi of hydrogen
atmosphere for 2 h. The catalyst was filtered off and the tiltrate
was concentrated to give the title compound (2.1 g, quantitative
yield). .sup.1 H NMR (CDCl.sub.3) .delta.7.40 (s, 2H), 7.22 (d,
1H), 6.95 (d, 1H), 6.90 (d, 1H), 6.82 (brs, 1H), 6.59 (d, 1H), 4.08
(q, 2H), 3.0 (s, 3H), 2.90 (t, 2H), 2.59 (t, 2H), 1.22 (t, 3H).
3-[4-(2,4-Dichlorophenoxy)-3-methanesulfonamido]phenylpropionic
acid ##STR35##
To a solution of ethyl
3-[4-(2,4-dichlorophenoxy-3methanesulfonamido]phenylpropionate (2.1
g, 5.0 mmol) in ethanol (70 mL) was added an aqueous solution of 2
M sodium hydroxide (6.0 mL, 12 mmol). The mixture was stirred at
45.degree. C. for 2 h and acidified with acetic acid. Solvent was
removed in vacuo. The residue was diluted with water and extracted
with ethyl acetate. The ethyl acetate layer was separated, washed
successively with water, brine, dried over anhydrous magnesium
sulfate and concentrated. Chromatography over silica gel and
elution with hexanes:ethyl acetate (3:1) with 2% acetic acid
yielded the title compound (1.7 g, 84%) as a white solid. .sup.1 H
NMR (CDCl.sub.3) .delta.7.51 (s, 1H), 7.48 (s, 1H), 7.24 (d, 1H),
6.96 (d, 1H), 6.92 (d, 1H), 6.78 (brs, 1H), 6.60 (d, 1H), 3.02 (s,
3H), 2.93 (t, 2H), 2.68 (t, 2H).
5-Methanesulfonamido-6-(2,4-dichlorophenoxy)-1-indanone
##STR36##
To a mixture of
3-[4-(2,4-dichlorophenoxy)-3-methanesulfonamido]phenylpropionic
acid (1.2 g, 3.0 mmol) and N,N-dimethylformamide (1 drop) in
dichloromethane (12 mL) at 0.degree. C. was added dropwise oxalyl
chloride (785 mg, 6.2 mmol). The mixture was stirred for 30 min.
and solvent was evaporated in vacuo to give a foam.
The above foam residue was dissolved in anhydrous
1,2-dichloroethane (10 mL). Aluminum trichloride anhydrous (1.2 g,
9.0 mmol) was added portionwise at 0.degree. C. The mixture was
stirred at room temperature for 30 min. and 1M aqueous hydrochloric
acid was added. The whole mixture was extracted twice with
dichloromethane. The combined organic extracts were washed
successively with water, brine, dried over anhydrous magnesium
sulfate and concentrated. Chromatography over silica gel and
elution with hexanes-:ethyl acetate (2:1) afforded a solid residue.
Recrystallization from ethanol yielded the title compound (870 mg,
75%) as white needles. .sup.1 H NMR (CDCl.sub.3) .delta.7.73 (s,
1H), 7.50 (s, 1H), 7.32 (m, 2H), 7.08 (d, 1H), 6.90 (s, 1H), 3.14
(s, 3H), 3.10 (t, 2H), 2.68 (t, 2H).
* * * * *