Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF USING CYCLOOXYGENASS-2 INHIBITORS
IN THE TRFATMENT AND PREVENTION OF NEOPLASIA
Field of the invention
This invention is in the field of the prevention and
treatment of neoplasia. More specifically, this invention
relates to the use of cyclooxygenase-2 inhibitors or
derivatives thereof in preventing and treating neoplasia.
Background of the Invention
Prostaglandins play a major role in the inflammation
process and the inhibition of prostaglandin production,
especially production of PGG2, PGH2 and PGE2, has been a
common target of anti-inflammatory drug discovery.
However, common non-steroidal anti-inflammatory drugs
(NSAID's) that are active in reducing the prostaglandin-
induced pain and swelling associated with the inflammation
process are also active in affecting other prostaglandin-
regulated processes not associated with the inflammation
process. Thus, use of high doses of most common NSAID's
can produce severe side effects, including life
threatening ulcers, that limit their therapeutic
potential. An alternative to NSAID's is the use of
corticosteroids, which also produce adverse effects,
especially when long term therapy is involved.
NSAIDs have been found to prevent the
production of prostaglandins by inhibiting enzymes
in the human arachidonic acid/prostaglandin pathway,
including the enzyme cyclooxygenase (COX). The
recent discovery of an inducible enzyme associated
with inflammation (named "cyclooxygenase-2 (COX-2)"
or "prostaglandin G/H synthase II") provides a
viable target of inhibition which more effectively
reduces inflammation and produces fewer and less
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drastic side effects.
Compounds which selectively inhibit
cyclooxygenase-2 have been described in U.S. patents
5,380,738, 5,344,991, 5,393,790, 5,434,178,
5,474,995, 5, 510,368 and WO documents W096/06840,
W096/03388, W096/03387, W096/25405, W095/15316,
W094/15932, W094/27980, W095/00501, W094/13635,
W094/20480, and W094/26731.
Neoplastic disease states are serious and oftentimes
life-threatening conditions. These neoplastic diseases,
which are characterized by rapidly-proliferating cell
growth, continue to be the subject of worldwide research
efforts directed toward the identification of therapeutic
agents which are effective in the treatment thereof.
Effective therapeutic agents prolong the survivability of
the patient, inhibit the rapidly-proliferating cell growth
associated with the neoplasm, or effect a regression of
the neoplasm. Research in this area is primarily focused
toward identifying agents which would be therapeutically
effective in humans and other mammals.
Recently, the presence of COX-2 has been observed in
neoplastic disease. See Masanobu Oshima et al. (Cell, 87,
803-809 (1996); and Michelle Parret et al. (International
Journal of Oncology, 10, 503-507 (1997).
(Pyrazol-l-yl]benzenesulfonamides have been described
as inhibitors of cyclooxygenase-2 and have shown promise
in the treatment of inflammation, arthritis, and pain,
with minimal side effects in pre-clinical and clinical
trials. Their use for preventing colon cancer has been
described in U.S. Patent No. 5,466,823. However, their use
for treating colon cancer or for treating or preventing
other neoplasias has not been previously described.
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The present invention is directed to the use of
inhibitors of cyclooxygenase-2 for the treatment and
prevention of neoplasias. Conjunctive treatment of a
selective cyclooxygenase-2 inhibitor with other neoplastic
agents produces a synergistic effect, or alternatively
reduces the toxic side effects associated with
chemotherapy by reducing the concentration of the side
effect-causing agent needed for therapeutic efficacy.
Detailed Description of the invention
The present invention provides a method for treating
or preventing a neoplasia that produces a prostaglandin in
a subject in need of such treatment or prevention, the
method comprises treating the subject with a
therapeutically effective amount of a cyclooxygenase-2
inhibitor or derivative thereof.
The term "treatment" includes partial or total
inhibition of the neoplasia growth, spreading or
metastasis, as well as partial or total destruction of the
neoplasia cells.
The term "prevention" includes either preventing the
onset of clinically evident neoplasia altogether or
preventing the onset of a preclinically evident stage of
neoplasia in individuals at risk. Also intended to be
encompassed by this definition is the prevention of
initiation for malignant cells or to arrest or reverse the
progression of premalignant cells to malignant cells. This
includes prophylactic treatment of those at risk of
developing the neoplasia.
The phrase "therapeutically-effective" is intended to
qualify the amount of each agent which will achieve the
goal of improvement in disease severity and the frequency
of incidence over treatment of each agent by itself, while
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avoiding adverse side effects typically-associated with
alternative therapies.
The term "subject" for purposes of treatment includes
any human or mammal subject who has any one of the known
neoplasias, and preferably is a human subject. For methods
of prevention, the subject is any human or animal subject,
and preferably is a human subject who is at risk for
obtaining an epithelium cell-derived neoplasia. The
subject may be at risk due to exposure to carcinogenic
agents, being genetically predisposed to have the
neoplasia, and the like.
The term "neoplasia" includes neoplasia that produce
prostaglandins or express a cyclooxygenase, including both
benign and cancerous tumors, growths and polyps.
In the method above, the neoplasia that produce
prostaglandins include brain cancer, bone cancer, '
epithelial cell-derived neoplasia (epithelial carcinoma)
such as basal cell carcinoma, adenocarcinoma,
gastrointestinal cancer such as lip cancer, mouth cancer,
esophogeal cancer, small bowel cancer and stomach cancer,
colon cancer, liver cancer, bladder cancer, pancreas
cancer, ovary cancer, cervical cancer, lung cancer, breast
cancer and skin cancer, such as squamus cell and basal
cell cancers, prostate cancer, renal cell carcinoma, and
other known cancers that effect epithelial cells
throughout the body. Preferably, neoplasia is selected
from gastrointestinal cancer, liver cancer, bladder
cancer, pancreas cancer, ovary cancer, prostate cancer,
cervical cancer, lung cancer, breast cancer and skin
cancer, such as squamus cell and basal cell cancers. The
COX-2 inhibitors can also be used to treat the fibrosis
which occurs with radiation therapy. The method can be
used to treat subjects having adenomatous polyps,
including those with familial adenomatous polyposis (FAP).
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Additionally, the method can be used to prevent polyps
from forming in patients at risk of FAP.
inhibitors of the cyclooxygenase pathway in the
5 metabolism of arachidonic acid used in the
prevention and treatment of epithelial cell derived
neoplasias may inhibit enzyme activity through a
variety of mechanisms. By the way of example, the
inhibitors used in the methods described herein may
block the enzyme activity directly by acting as a
substrate for the enzyme. The use of
cyclooxygenasse-2 selective inhibitors is highly
advantageous in that they minimize the gastric side
effects that can occur with non-selective NSAID's,
especially where prolonged prophylactic treatment is
expected.
The term "cyclooxygenase-2 inhibitor" denotes
a compound able to inhibit cyclooxygenase-2 without
significant inhibition of cyclooxygenase-1.
Preferably, it includes compounds which have a
cyclooxygenase-2 IC50 of less than about 0.2 pM, and
also have a selectivity ratio of cyclooxygenase-2
inhibition over cyclooxygenase-1 inhibition of at
least 50, and more preferably of at least 100. Even
more preferably, the compounds have a
cyclooxygenase-1 IC50 of greater than about 1 pM,
and more preferably of greater than 10 pM.
Pyrazoles can be prepared by methods described in
W095/15316, W095/15315 and W096/03385. Thiophene
analogs can be prepared by methods described in WO
95/00501 and W094/15932. Oxazoles can be prepared
by the methods described in PCT documents
W095/00501 and W094/27980. Isoxazoles can be
prepared by the methods described in W096/25405.
Imidazoles can be prepared by the methods described
in W096/03388 and W096/03387. Cyclopentene
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cyclooxygenase-2 inhibitors can be prepared by the
methods described in U.S. Patent No. 5,344,991 and
WO 95/005-01. Terphenyl compounds can be prepared by
the methods described in W096/16934. Thiazole
compounds can be prepared by the methods described
in W096/03392. Pyridine compounds can be prepared
by the methods described in W096/24584 and
W096/24585.
The method provided herein relates to the use of
cyclooxygenase-2 inhibitors or derivatives thereof in the
prevention and treatment of derived neoplasias. in the
preferred embodiments, the cycclooxygenase-2 compound is
selected from the compounds of Formula I
R~S L/ \ R
O A
\ R3
wherein A is a substituent selected from
-partially unsaturated or unsaturated heterocyclyl and
partially unsaturated or unsaturated carbocyclic
rings;
wherein R1 is at least one substituent selected
from heterocyclyl, cycloalkyl, cycloalkenyl and aryl,
wherein R1 is optionally substituted at a
substitutable position with one or more radicals
selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy,
amino, alkylamino, arylamino, nitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy and alkylthio;
wherein R2 is methyl or amino; and
wherein R3 is a radical selected from hydrido,
halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl,
cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio,
alkylcarbonyl, cycloalkyl, aryl, haloalkyl,
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heterocyclyl, cycloalkenyl, aralkyl,
heterocyclylalkyl, acyl, alkylthioalkyl,
hydroxyalkyl, alkoxycarbonyl, arylcarbonyl,
aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl,.aralkylthioalkyZ,
aralkoxyalkyl, alkoxyaralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminocarbonyl, N-
arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-
arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-
alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-
arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-
aralkylaminoalkyl, N-alky.l-N-arylaminoalkyl, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl,
alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-
arylaminosulfonyl, arylsulfonyl, N-alkyl-N-
arylaminosulfonyl; or a pharmaceutically-acceptable
salt thereof.
A preferred class of compounds which inhibit
cyclooxygenase-2 consists of compounds of Formula I
wherein A is selected from 5- or 6-member partially
unsaturated heterocyclyl, 5- or 6-member unsaturated
heterocyclyl, 9- or 10-member unsaturated condensed
heterocyclyl, lower cycloalkenyl and phenyl; wherein
R1 is selected from 5- and 6-membered heterocyclyl,
lower cycloalkyl, lower cycloalkenyl and aryl
selected from phenyl, biphenyl and naphthyl, wherein
RI is optionally substituted at a substitutable
position with one or more radicals selected from
lower alkyl, lower haloalkyl, cyano, carboxyl, lower
alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower
haloalkoxy, amino, lower alkylamino, phenylamino,
lower alkoxyalkyl, lower alkylsulfinyl, halo, lower
alkoxy and lower alkylthio; wherein R2 is methyl or
amino; and wherein R3 is a radical selected from
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hydrido, oxo, cyano, carboxyl, lower alkoxycarbonyl,
lower carboxyalkyl, lower cyanoalkyl, halo, lower
alkyl, lower alkyloxy, lower cycloalkyl, phenyl,
lower haloalkyl, 5- or 6-membered heterocyclyl, lower
hydroxylalkyl, lower aralkyl, acyl, phenylcarbonyl,
lower alkoxyalkyl, 5- or 6-membered heteroaryloxy,
aminocarbonyl, lower alkylaminocarbonyl, lower
alkylamino, lower aminoalkyl, lower alkylaminoalkyl,
phenyloxy, and lower aralkoxy; or a pharmaceutically-
acceptable salt thereof.
A more preferred class of compounds which
inhibit cyclooxygenase-2 consists of compounds of
Formula I wherein A is selected from oxazolyl,
isoxazolyl, furyl, thienyl, dihydrofuryl, pyrrolyl,
pyrazolyl, thiazolyl, imidazolyl, isothiazolyl,
benzofuryl, cyclopentenyl, cyclopentadienyl, phenyl,
and pyridyl; wherein R1 is selected from pyridyl
optionally substituted at a substitutable position
with one or more methyl radicals, and phenyl
optionally substituted at a substitutable position
with one or more radicals selected from methyl,
ethyl, isopropyl, butyl, tert-butyl, isobutyl,
pentyl, hexyl, fluoromethyl, difluoromethyl,
trifluoromethyl, cyano, carboxyl, methoxycarbonyl,
ethoxycarbonyl, hydroxyl,.hydroxymethyl,
trifluoromethoxy, amino, N-methylamino, N,N-
dimethylamino, N-ethylamino, N,N-dipropylamino, N-
butylamino, N-methyl-N-ethylamino, phenylamino,
methoxymethyl, methylsulfinyl, fluoro, chloro, bromo,
methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and
methylthio; wherein R2 is methyl or amino; and
wherein R3 is a radical selected from hydrido, oxo,
cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
carboxypropyl, carboxymethyl, carboxyethyl,
cyanomethyl, fluoro, chloro, bromo, methyl, ethyl,
isopropyl, butyl, tert-butyl, isobutyl, pentyl,
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hexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,
heptafluoropropyl, difluoroethyl, difluoropropyl, methoxy,
ethoxy, propoxy, n-butoxy, pentoxy, cyclohexyl, phenyl,
pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl,
hydroxylmethyl, hydroxylpropyl, benzyl, formyl,
phenylcarbonyl, methoxymethyl, furylmethyloxy,
aminocarbonyl, N-methylaminocarbonyl,
N,N-dimethylaminocarbonyl, N,N-dimethylamino, N-ethylamino,
N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino,
aminomethyl, N,N-dimethylaminomethyl, N-methyl-N-
ethylaminomethyl, benzyloxy, and phenyloxy; or a
pharmaceutically acceptable salt thereof.
In another embodiment, the present invention
provides a use of a compound of the formula
R6
O
-
O l~s ~ ~ N N R4
R
or a pharmaceutically acceptable salt thereof wherein
Rl is methyl;
R4 is (i) C1-C6 haloalkyl, (ii) phenyl optionally substituted
with one or more members independently selected from the
group consisting of C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano,
halogen, hydroxy, amino, C1-C6 alkylamino, and
di-C1-C6 alkylamino groups, or (iii) thienyl optionally
substituted with one or more members independently selected
from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, nitro,
cyano, halogen, hydroxy, amino, C1-C6 alkylamino, and
di (C1-C6) alkylamino groups; and
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- 9a -
R6 is phenyl optionally substituted at a substitutable
position with one or more radicals selected from the group
consisting of halo, C1-C6 alkylthio, C1-C6 alkylsulfonyl,
cyano, nitro, C1-C6 haloalkyl, C1-C6 alkyl, hydroxyl,
C1-C6 alkenyl, C1-C6 hydroxyalkyl, carboxyl, C1-C6 cycloalkyl,
C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl,
aminocarbonyl, C1-C6 alkoxy, C1-C6 haloalkoxy, sulfamyl, five
or six membered heterocyclic radicals, and amino,
for treating a neoplasia in a subject in need of such
treatment.
In a further embodiment, the present invention
provides a use of a compound of the formula
O
N, N
O l~s ~ ~ R8
R
R6
or a pharmaceutically acceptable salt thereof wherein
R' is methyl;
R6 is phenyl optionally substituted at a substitutable
position with one or more radicals selected from the group
consisting of halo, C1-C6 alkylthio, C1-C6 alkylsulfonyl,
cyano, nitro, C1-C6 haloalkyl, C1-C6 alkyl, hydroxyl,
C1.-C6 alkenyl, C1-C6 hydroxyalkyl, carboxyl, C1-C6 cycloalkyl,
C1-C6 alkylamino, C1-C6 dialkylamino, C1.-C6 alkoxycarbonyl,
aminocarbonyl, C1-C6 alkoxy, C1-C6 haloalkoxy, sulfamyl, five
or six membered heterocyclic radicals, and amino; and
R8 is hydrogen or C1-C6 haloalkyl,
for treating a neoplasia in a subject in need of such
treatment.
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A family of specific compounds of particular
interest within Formula I consists of compounds and
pharmaceutically-acceptable salts thereof as follows:
5- (4-fluorophenyl) -1- [4- (methylsulfonyl)phenyl] -3-
(trifluoromethyl)pyrazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-
(trifluoromethyl)pyrazole;
4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-
yl)benzenesulfonamide;
4-(3,5-bis(4-methylphenyl)-1H-pyrazol-l-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-phenyl-lH-pyrazol-l-
yl)benzenesulfonamide;
4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-l-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-l-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-l-
yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-l-
yl)benzenesulfonamide;
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4-(4-chloro-3,5-diphenyl-lH-pyrazol-l-
yl)benzenesulfonamide
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
5 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-l-
ylJbenzenesulfonamide;
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-
10 1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)--1H-
pyrazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-phenyl-lH-pyrazol-l-
yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-
pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-phenyl-lH-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide;
5-(4-fluorophenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-
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yl]benzenesulfonamide;
6-(4-fluorophenyl)-7-[4-
(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene;
5-(3-chloro-4-methoxyphenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
4-[6-(3-chloro-4-methoxyphenyl)spiro[2-4]hept-5-en-5-
yl]benzenesulfonamide;
5-(3,5-dichloro-4-methoxyphenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
5-(3-chloro-4-fluorophenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-
yl]benzenesulfonamide;
2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)thiazole;
2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-
methylsulfonylphenyl)thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-
methylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-
. trifluoromethylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-
thienyl)thiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-
benzylaminothiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-
propylamino)thiazole;
2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-
[4-(methylsulfonyl)phenyl]thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-
trifluoromethylthiazole;
2-methylsulfonyl-4-[1,1-dimethyl-4-(4-
fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene;
4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-
3-yl]benzenesulfonamide;
5-(4-fluorophenyl)-6-[4-
(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene;
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4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-
yl]benzenesulfonamide;
6-(4-fluorophenyl)-2-methoxy-5-[4-
(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;
2-bromo-6-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;
6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenylJ-2-
phenyl-pyridine-3-carbonitrile;
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-
imidazol-1-ylJbenzenesulfonamide;
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide;
4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-
imidazol-2-yl]pyridine;
2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-
imidazol-2-yl]pyridine;
2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-
(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-
(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-
imidazol-1-ylJbenzenesulfonamide;
2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenylJ-4-
(trifluoromethyl)-1H-imidazole;
4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-
1-ylJbenzenesulfonamide;
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
methyl-IH-imidazole;
2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-
phenyl-lH-imidazole;
2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-
(methylsulfonyl)phenylJ-lH-imidazole;
2-(3-fluoro-4-methoxyphenyl)-1-[4-
(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-
imidazole;
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1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-
trifluoromethyl-lH-imidazole;
2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-
trifluoromethyl-lH-imidazole;
4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide;
2-(3-fluoro-5-methylphenyl)-1-[4-
(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-
imidazole;
4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-
imidazol-1-yl]benzenesulfonamide;
2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-
trifluoromethyl-lH-imidazole;
4-[2-(3-methylphenyl)-4-trifluoromethyl-lH-imidazol-l-
yl]benzenesulfonamide;
1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-
trifluoromethyl-lH-imidazole;
4-[2-(3-chlorophenyl)-4-trifluoromethyl-lH-imidazol-l-
yl]benzenesulfonamide;
4-[2-phenyl-4-trifluoromethyl-lH-imidazol-l-
yl]benzenesulfonamide;
4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-lH-
imidazol-1-yl]benzenesulfonamide;
1-allyl-4-(4-fluorophenyl)-3-[4-
(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-
pyrazole;
4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-
pyrazol-3-yl]benzenesulfonamide;
N-phenyl-[4-(4-luorophenyl)-3-[4-
(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-
pyrazol-1-yl]acetamide;
ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-
5-(trifluoromethyl)-1H-pyrazol-].-yl]acetate;
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-
phenylethyl)-ZH-pyrazole;
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-
phenylethyl)-5-(trifluoromethyl)pyrazole;
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14
i-ethyl-4-(4-fluorophenyl)-3-[4-
(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-
pyrazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-
trifluoromethyl-lH-imidazole;
4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-
(trifluoromethyl)-1H-imidazole;
5-(4-fluorophenyl)-2-methoxy-4-[4-
(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
2-ethoxy-5-(4-fluorophenyl)-4-[4-
(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-
propynyloxy)-6-(trifluoromethyl)pyridine;
2-bromo-5-(4-fluorophenyl)-4-[4-
(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
4-[2-(3-chloro-4-methoxyphenyl)-4,5-
difluorophenyl]benzenesulfonamide;
1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-
phenylisoxazole;
4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-difluoromethyl-3-phenylisoxazol-4-
yl]benzenesulfonamide;
4-[5-hydroxymethyl-3-phenylisoxazol-4-
yl]benzenesulfonamide;
4-[S-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;
1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
1-[2-(2,4-dichlorophenyl)cyclopenten-l-yl]-4-
(methylsulfonyl)benzene;
1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
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1-[2-(4-methylthiophenyl)cyclopenten-1=y1]-4-
(methylsulfonyl)benzene;
1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten--1-yi]-4-
(methylsulfonyl)benzene;
5 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-l-
yl]benzenesulfonamide;
1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-l-
10 yl]benzenesulfonamide;
4-[2-(4-fluorophenyl)cyclopenten-l-
yl]benzenesulfonamide;
4-[2-(4-chlorophenyl)cyclopenten-l-
yl]benzenesulfonamide;
15 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
1-[2-(2,3-difluorophenyl)cyclopenten-1-y1]-4-
(methylsulfonyl)benzene;
4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-l-
yl3benzenesulfonamide;
1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-
(methylsulfonyl)benzene;
4-[2-(3-chloro-4-fluorophenyl)cyclopenten-l-
yl]benzenesulfonamide;
4-[2-(2-methylpyridin-5-yl)cyclopenten-l-
yl]benzenesulfonamide;
ethyl 2-{4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]oxazol-2-yl]-2-benzyl-acetate;
2-[4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid;
2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-
(methylsulfonyl)phenyl]oxazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-
phenyloxazole;
4-(4-fluorophenyl)-2-methyl-5-[4-
(methylsulfonyl)phenyl]oxazole; and
4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-
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16
oxazolyl]benzenesulfonamide.
A family of specific compounds of more
particular interest within Formula I consists of
compounds and pharmaceutically-acceptable salts
thereof as follows:
4-{5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-
1-yl)benzenesulfonamide;
4-I5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-
1H-pyrazol-l-yl]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-lH-
imidazol-2-yl)pyridine;
2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-
trifluoromethyl-lH-imidazol-2-yl]pyridine;
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-
imidazol-l-yl]benzenesulfonamide;
4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-hydroxymethyl-3-phenylisoxazol-4-
yl]benzenesulfonamide;
[2-trifluoromethyl-5-(3,4-difluorophenyl)-4-
oxazolyl]benzenesulfonamide;
4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide;
and
4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-
oxazolyl]benzenesulfonamide.
A subclass of cyclooxygenase-2 inhibitors is selected
from compounds of W095/15316. Preferably, the
cyclooxygenase-2 inhibitor is selected from compounds of
Formula II
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17
R6
R
H2N
OlS N II
0 N~-- 4
R
wherein R4 is lower haloalkyl; wherein R5 is hydrido;
and wherein R6 is phenyl optionally substituted at a
substitutable position with one or more radicals selected
from halo, lower alkylthio, lower alkylsulfonyl, cyano,
nitro, lower haloalkyl, lower alkyl, hydroxyl, lower
alkenyl, lower hydroxyalkyl, carboxyl, lower cycloalkyl,
lower alkylamino, lower dialkylamino, lower
alkoxycarbonyl, aminocarbonyl, lower alkoxy, lower
haloalkoxy, sulfamyl, five or six membered heterocyclic
and amino; or a pharmaceutically-acceptable salt or
derivative thereof.
A family of specific compounds of particular interest
within Formula'II consists of compounds, pharmaceutically-
~acceptable salts and derivatives thereof as follows:
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-l-
yljbenzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
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18
4-[3-(difluoromethyl)-5-phenyl-lH-pyrazol-l-
yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-
pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide; and
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide.
A family of specific compounds of more particular
interest within Formula II consists of compounds and
pharmaceutically-acceptable salts or derivatives thereof
as follows:
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide; and
4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide.
Derivatives are intended to encompass any compounds
which are structurally related to the cyclooxygenase-2
inhibitors or which possess the substantially equivalent
biologic activity. By way of example, such inhibitors may
include, but are not limited to, prodrugs thereof.
The compounds utilized in the methods of the present
invention may be present in the form of free bases or
pharmaceutically acceptable acid addition salts thereof.
The term "pharmaceutically-acceptable salts" embraces
salts commonly used to form alkali metal salts and to form
addition salts of free acids or free bases. The nature of
the salt is not critical, provided that it is
pharmaceutically-acceptable. Suitable pharmaceutically-
CA 02372912 2002-03-11
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19
acceptable acid addition salts of compounds of Formula I
may be prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and
phosphoric acid. Appropriate organic acids may be selected
from aliphatic, cycloaliphatic, aromatic, araliphatic,
heterocyclic, carboxylic and sulfonic classes of organic
acids, example of which are formic, acetic, propionic,
succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, 4-
hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic,
pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,
sulfanilic, cyclohexylaminosulfonic, stearic, algenic, (i-
hydroxybutyric, salicylic, galactaric and galacturonic
acid. Suitable pharmaceutically-acceptable base addition
salts of compounds of Formula I include metallic salts
made from aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc or organic salts made from
chloroprocaine., choline, N,N'-dibenzylethylenediamine,
diethanolamine, ethylenediamine, meglumine (N-
methylglucamine) and procaine. All of these salts may be
prepared by conventional means from the corresponding
compound of Formula I by reacting, for example, the
appropriate acid or base with the compound of Formula I.
Biological Evaluation
The efficacy of cyclooxygenase-2 inhibitors as
antineoplasia agents was determined in the following
models:
Murine Lewis luna Carcinoma Model.
Lewis lung carcinomas were implanted sub-cutaneously
into the foot pad of male C57BL/6 mice. The mice were
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WO 98/16227 PCT/US97/18670
subsequently treated with 4-[5-(4 -chlorophenyl)-3-
(difluoromethyl)-1H-pyrazol-l-yllbenzenesulfonamide. The
drug was supplied in the drinking water at 6 mg/kg/day.
Also a non-selective COX-1/COX-2 inhibitor indomethacin
5 was tested in this model. The drug was supplied in the
drinking water at the maximum tolerated dose of 2
mg/kg/day. A total of 10 mice/compound were tested.
Tumor volume was determined twice a week using a
plethysmometer. The efficacy of these compounds on tumor
10 growth was measured at day 32 after cancer cell injection,
as indicated in Table 1. The % inhibition value is
calculated by calculating the difference in tumor size
compared with the control group.
15 Table 1.
Tumor Volume (Day 32)
Treatment % Inhibition
Vehicle/control 0.00
COX-2 inhibitor 70.86
indomethacin 62.90
Human vrostate cancer cell tumors
Two human prostate cancer cell lines (PC-3 and LNCaP)
20 were obtained (ATCC) to determine the efficacy of
cyclooxygenase-2 inhibitors to inhibit tumor growth in a
therapeutic model. In addition, the LNCaP cell line
secretes prostate serum antigen (PSA) when grown in nude
mice.
PC-3
PC-3 cells (106 cells/0.2 ml of 30% matrigel) in RPMI
1640 medium was injected on the back of nude mice. At day
28, a COX-2 inhibitor 4-[5-(4-chlorophenyl)-3-
(difluoromethyl)-1H-pyrazol-l-ylJbenzenesulfonamide (20
mg/kg/day in water) was administered. After 45 days, PGEZ
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21
and TXB2 were measured. The COX-2 inhibitor inhibited
tumor growth by 55%. PGEZ and TXBZ levels were reduced by
80-90% in the animals treated with the COX-2 inhibitor.
LNCaP
Similar to the results in PC-3, a COX-2 inhibitor 4-
[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-l-
yl]benzenesulfonamide at a dose equivalent to 6 mg/kg/day
in the drinking water inhibited the growth of the tumor by
55% at day 58. PSA level was reduced to approximately 50%
as judged by western blotting.
Others
Cell lines: The following cell :Lines can be used:
classic small cell lung cancer (SCLC) cell lines NCI-H209,
NCI-H345, and NCI-H510; variant SCLC cell lines NCI-N417
and NCI-H82; large cell carcinoma cell line NCI-H1155;
adeno carcinoma cell line NCI-H23; and bronchioalveolear
carcinoma cell line A549, breast cancer cell line MCF-7
(American Type Tissue Culture Rockville MD; ATCC) and
colon cancer cell lines such as NCI-H630 (ATCC), HT 29,
SW948, HCA-7 and others that can be tested in vivo or in
vitro. All cells can be grown in RPMI-1640, supplemented
with 5% fetal bovine serum (FBS), penicillin and
streptomycin (Gibco, Grand Island, NY), and be maintained
in a 5% COzatmosphere at 37 C. All cell lines are free of
mycoplasma contamination.
Growth studies: A modification (Promega Ce1lTiter
96 , Promega Madison, WI) of the semiautomated
colorimetric assay, MTT [Nakanishi, et al. Exper. Cell
Biol., 56, 74-85 (1988)], which quantitates cell numbers
based on reduction of a tetrazolium compound by tumor
cells as determined by a spectrophotometer (540 nm) is
used. All assays are performed in RPMI-1640 media
supplemented with transfertin -10 g/ml, insulin -5 g/ml
and selenium (Sigma Chemicals, St. Louis, MO). Seeding
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22
densities are -2x104 cells/well, and cells are grown for 5
days. Each experiment is reported as mean optical density
corrected for background +/- standard deviation. The
cyclooxygenasse-2 inhibitors should be active, at a dose
of 20 mg/kg, in inhibiting growth of the cancerous cell
lines.
A mouse urinary bladder tumor model is.performed with
materials, reagents and procedures essentially as
described by Grubbs et al, [Anticancer Res., 13, 33-36
(1993)]. A COX-2 inhibitor should be active at a dose of
mg/kg.
A rat mammary tumor model is performed with
15 materials, reagents and procedures essentially as
described by Grubbs et al., [Anticancer Res., 15, 709-16
(1995)). A COX-2 inhibitor should be active at a dose of
20 mg/kg.
20 A mouse cervical and vaginal carcinogenesis model is
performed with materials, reagents and procedures
essentially as described by Arbeit et al., [Proc. Acad.
Sci. USA., 93, 2930-35 (1996)]. A COX-2 inhibitor should
be active at a dose of 20 mg/kg.
A colon adenocarcinoma cell model is performed with
materials, reagents and procedures essentially as
described by Shiff et al., [J. Clin. invest., 96, 491-503
(1995)]. A COX-2 inhibitor should be active at a dose of
20 mg/kg. See also Masahiko Tsujii et al. (Proc. Natl.
Acad. Sci. USA 94:3336-3340, 1997).
In summary, COX-2 inhibitors reduce tumor growth in
several animal cancer models.
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wo 98n6227 PCT/US97n8670
23
Combination Theraoy of a COX-2 inhibitor and other
antineoplastic aQents
Lewis Lung carcinoma cells (2.5 x 106 cells) prepared
from a brei carried in C57BL/6 mice were injected sub-
cutaneously into the hind legs of mice. A COX-2
inhibitor, 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-
pyrazol-l-yllbenzenesulfonamide was given by gavage twice
a week to groups of 10 mice at doses of 6 and 20 mg/kg.
Cyclophosphamide (CTX) was injected to mice on days 5,7
and 9 after the implantation of the tumor at a dose of 50
mg/kg. Tumor volume was determined during the study.
Animals were sacrificed at day 26 and the results of this
experiments are summarized in Table 2. The % inhibition
was calculated as above.
Table 2.
Tumor Volume (Day 22)
Treatment % Inhibition
Vehicle 0
COX-2 inhibitor (6 mg/kg) 0
COX-2 inhibitor (20 mg/kg) 54
CTX (50 mg/kg) 57
CTX+COX-2 inhibitor (6 mg/kg) 69
CTx+COX-2 inhibitor (20 mg/kg) 77
The results,of this experiment indicate that the
combination of a COX-2 inhibitor and a cytotoxic agent
produced an additive effect on their individual capacity
to inhibit tumor growth.
The active compounds of the present invention may be
administered by any suitable route known to those skilled
in the art, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose
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WO 98/16227 PCT/US97118670
24
effective for the treatment intended. The active
compounds and composition may, for example, be
administered orally, intravascularly, intraperitoneally,
intranasal, intrabronchial, subcutaneously, intra-
muscularly or topically (including aerosol).
The administration of the present invention may be
for either prevention or treatment purposes. The methods
and compositions used herein may be used alone or in
conjunction with additional therapies known to those
skilled in the art in the prevention or treatment of
neoplasia. Alternatively, the methods and compositions
described herein may be used as conjunctive therapy. By
way of example, the cyclooxygenase-2 inhibitor may be
administered alone or in conjunction with other
.antineoplastic agents or other growth inhibiting agents or
other drugs or nutrients.
There are large numbers of antineoplastic agents
available in commercial use, in clinical evaluation and in
pre-clinical development, which could be selected for
treatment of neoplasia bycombination drug chemotherapy.
Such antineoplastic agents fall into several major
categories, namely, antibiotic-type agents, alkylating
agents, antimetabolite agents, hormonal agents,
immunological agents, interferon-type agents and a
category of miscellaneous agents. Alternatively, other
anti-neoplastic agents , such as metallomatrix proteases
(MMP), SOD mimics or ocõp, inhibitors may be used.
A first family of antineoplastic agents which may be
used in combination with a selective cyclooxygenase-2
inhibitor consists of antimetabolite-type antineoplastic
agents. Suitable antimetabolite antineoplastic agents may
be selected from the group consisting of 5-FU-fibrinogen,
acanthifolic acid, aminothiadiazole, brequinar sodium,
carmofur, Ciba-Geigy CGP-30694TMcyclop.entyl cytosine,
CA 02372912 2002-03-11
WO 98Ji6Zt7 PCT/US97/18670
cytarabine phosphate stearate, cytarabine conjugates,
Lilly DATHF,--Merrel Dow DDFC, dezaguanine, TM
dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,
doxifluridine, Wellcome EHI~TA Merck & Co. EX-015,
5-fazarabine, floxuridine, fludarabine phosphate, 5-
fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi
TM_ Seiyaku FO-152 isopropyl pyrrolizine, Lilly LY-188011,
Lilly LY-264618, methobenzaprim, methotrexate, Welicome
MZPES; norspermidine, NCI NSC-1277161-NCI NSC-~64880,-NCI
10 NSC-39661-; - NCI NSC-612567- - Warner-Lam'bert PALA,
pentostatin,.piritrexim, plicamycin, Asahi Chemical PhLM-AC~
Takeda TAC-788T,"thioguanine, tiazofurin, Erbamont TIF,
trimetrexate, tyrosine kinase inhibitors, tyrosine protein
kinase inhibitors, Taiho UFTTMand uricytin.
A second family of antineoplastic agents which may be
used in combination with a selective cyclooxygenase-2
inhibitor consists of alkylating-type antineoplastic
agents. Suitable alkylating-type antineoplastic agents
may be selected from the group consisting of Shionogi 254-
5~-_aldo-phosphamide analogues, altretamine, anaxirone,
Boehringer Mannheim BBR-220T;-bestrabucil, budotitane
Wakunaga C~ 02_carboplatin, carmustine, Chinoin-139,
Chinoin-153, chlorambucil, cisplatin, cyclophosphamide,
American Cyanamid CL-286558, Sanofi CY-233~,2lcyplatate,
Degussa D-19-384~ Sumimoto DACHP(Myr)~;
diphenylspiromustirie, diplatinum cytostatic, Erb~
distamycin derivatives, Chuga~DWA-2114K;"ITI E09~
elmustine, Erbamont FCE-24517, estramustine phosphate
sodium, fotemustine, Unimed G-6-M;'Chinoin GYKI-1723 6;'
hepsul-fam, ifosfamide, iproplatin, lomustine,
mafosfamide, mitolactol, Nippon Kayaku NK-121';"NCI NSC-
264395r:NCI NSC-3422151'oxaliplatin, Upjohn PCNU~
prednimustine, Proter PTT-219~ranimustine ~ emustine,
SmithKline SK&F-101772;'Yakult Honsha SN-22, spiromus-
tine, Tanabe Seiyaku TA=077~ tauromustine, temozolomide,,
teroxirone, tetraplatin and trimelamol.
CA 02372912 2002-03-11
WO 98n6227 PCT/US97/18670
26
A third family of antineoplastic agents which may be
used in combination with a selective cyclooxygenase-2
inhibitor consists of antibiotic-type antineoplastic
agents. Suitable antibiotic-type antineoplastic agents
TM.
may be selected from the group consisting of Taiho 4181-K;
-
aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-
456~aeroplysinin derivativ~,e~,Aj inomoto AN-201-II~
Ajinomoto AN-3;- Nippon Soda anisomycins, anthracycline,
azino-mycin-A, bisucaberin, Bristol-Myers BL-6859,
Bristol-Myers BMY-25067-;-Bristol-Myers BMY-25551 Bristol-
Myers B~ 6605;-Bristol-Myers BMY-27557, Bristol-Myers TM
BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027,
calichemycin, chroTmMoximycin, dactinomy_cin, daunorubicin,
Kyowa Hakko DC-102,~Kyowa Hakko DC-79T,MKyowa Hakko DC-88A,
.Kyowa Hakko DC89-A1, Kyowa Hakko DC92-BT,M ditrisarubicin B,
Shionogi DOB-41~ doxorubicin, doxorubicin-fibrinogen,
elsamicin-A; epirubicin, erbstatin, esorubicin, TM
esperamicin-A1~esperamicin-Alb, Erbamont FCE-21954,
Fujisawa FK-973, fostriecin, Fujisawa FR-900482,
glidobactin, gregatin-A, grincamycin, herbimycin,
idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa
Hakko KM-553 J;_Kirin Brewery KRN-8602~Kyowa 5432T,M Kyowa Hakko KT-5594~
Kyowa Hakko KT-6149TMAmerican
Cyanamid LL-D49194_Meiji Seika ME 2303~ menogaril,
mitomycin, mitoxantrone, SmithRline M-TAG";'-neoenactin,
Nippon Kayaku NK-313;' Nippon Kayaku NKT-01 SRI
International NSC-357704;-oxalysine, oxaunomycin,
peplomycin, pilatin, pirarubicin, porothramycin,
pyrindamycin A, Tobishi RA-I;-rapamycin, rhizoxin,
rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887;
Snow Brand SN-700"Snow Brand SN-0T sorangicin-A,
sparsomycin, SS Pharmaceutical SS-21020~SS Pharmaceutical
SS-7313B;-SS Pharmaceutical SS-9816B~ steffimycin B, Taiho
4181-2~ talisomycin, Takeda TAN-868~ terpentecin,
thrazine, tricrozarin A,.Upjohn U-73975;"Kyowa Hakko UCN-
10028A;4 Fujisawa WF-3405;' Yoshitomi Y-25024-And zorubicin.
CA 02372912 2004-10-13
27
A fourth family of antineoplastic agents which may beused in combination with
the selective cyclooxygenase-2
inhibitor consists of a'miscellaneous family of
antineoplastic agents selected from the'group consisting
of alpha-car.otene, alpha-difluorometh-yl-argf~ine,
acitretin, Biotec AD-S,-Ryorin AHC-52,~Ialstoninqt,
amonaf.ide, amphethinile, amsacrini, AngiostaiM
10' ankinomycin, anti-neoplaston A10, antineoplaston A2,
antineoplaston A3, antineoplaston AS, antineoplaston AS2-
1, Henkel APII;aphidicolin glycinate, asparaginase, Avaror;'baccharin, batra
lin; benfluron, benzotript,
Ipsen-Beaufour BIM-2301bisantrene, Bristo-Myers BMY-
40481','Vestar ~ oa-lv;' bromofosfamide, Wellcoae BII-SOT; '
Wellcotae BW-773, caracemide, carmethizole hydrochloride,
A3inomoto CDiAi~chlorsulfaquinoxalone~Chemes C~c-a0537
Chemex CHX-100;"Warner-Lambert CI-92Warner-Lambert CI-
937~Warner-Lambert CI-94r;' Warner-Lambert CI-958~
clanfenur, claviridenona, ICN compound.1251;-ICN cowqp ovad
47111, ContracanT", Yakult Honsha CPT-111 (irinotecan), crisnatol=
curaderm, cytochalasin B, cytarabine, cytocytin,.Merz D-
609~DABIB maleate;'dacarbazine, datelliptinium, didem:tin-
B, dihaenmatoporphyrin ether, dihydrolenperone, dinaline,
distamycin, Toyo Pharmar nlri-341,~IToyo Pharmar nl4-75; -
Daiichi Seiyaku DN-96937elliprabin, elliptinium acetate,
Tsumura EPMC74ergotamine, etoposide, etretinate,
fenretinide, Fujisawa FR-577~0M4-', gallium nitrate,
genkwadaphnin, Chugai GLA-43, Glaxo GR-63178M, grifolan
NII4F-5N, hexadecylphosphocholine, Green Cross W-221,
homoharringtonine, hydro3yurea, BTG ICRF-~18'T' ilmofosine,
isoglutamine, isotretinoin,.Otsuka JI-36, Ramot 1C-477;"
Otsuak R-76COON4
'Rureha Chemical R-AM; MBCT Corp,RI-8110T
American Cyanamid ~L-623~leukoregulin, lonidamine~ ;
.35 Lundbeck LQ-23-112,'Lilly LY-186641TMNCI (US) MAP,
marycin, Merrel Dow 1rIDL-2704p, Medco MEDR-340;' merbarone,
merocyanine derivatives, methylanilinoacridine, Molecular'
CA 02372912 2002-03-11
WO 98/16227 PCT/US97/18670
28
TM
Genetics MGI-136, minactivin, mitonafide, mitoquidone,
mopidamol, motretinide, Zenyaku Kogyo MST-16, N-
(retinoyl)amino acids, Nisshin Flour Milling N-0211,~ N-
acylated-dehydroalanines, nafazal~tMrom, Taisho NCU-190~
nocodazole derivative, Normosang, NCI NSC-145813; NCI NSC-
361456; - NCI NSC-60478Z';' NCI NSC-9558~"; ' octreotide, Ono
ONO-112-;-oquizanocine, Akzo Org-10172-pancratistatin,
pazelliptine, Warner-Lambert PD-111707-Warner-Lambert PD-
_TM
=115934-;-Warner-Lambert PD-131141~, Pierre Fabre PE-1001T'M
ICRT peptide D~piroxantrone, polyhaematoporphyrin,
polypreic acid, Efamor_porphyrin, probimane, procarba~ne,
proglumide, Invitron protease nle~xin I, Tobis'hi RA-700,
razoxane, Sapporo Breweries RBS, restrictin-P,
retelliptine, retinoic acid, Rhone-Poulenc RP-49532'
Rhone-Poulenc RP-56976~ SmithKline SK&F-104864~ Sumitomo
SM-108';-Kuraray SMANCS~SeaPhaxm SP-10094, spatol,
spirocyclopropane derivatives, spirogermanium, Unimed~SS
Pharmaceutical SS-554!_strypoldinone, Stypoldione~Suntory
SUN 023 7, Suntory ~ 2071T,Msuperoxide dismu~tase, Toyama
T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,
thaliblastine, Eastman Kodak TJB-2p, tocotrienol,
Topostin~Teijin TT-82';'Kyowa Hakko UCN-01~ Kyowa Hakko
UCN-1028TMukrain, Eastman Kodak USB-00vinblastine
sulfate, vincristine, vindesine, vinestramide,
vinorelbine, vintriptol, vinzolidine, withanolides and
Yamanouchi YM-534~
Examples of radioprotective agents which may be used
in the combination chemotherapy of this invention are AD-
5, adchnon, amifostine analogues, detox, dimesna, ~ 02,
MM-159, N-acylated-dehydroalanines, TGF- Genentech,
tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen
transdermal, nabumetone, su~peroxide dismutase (Chiron~ and
superoxide dismutase Enzon.
Methods for preparation of the antineoplastic agents
described above may be found in the literature. Methods
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29
for preparation of doxorubicin, for example, are described
in U.S. Patents No. 3,590,028 and No. 4,012,448. Methods
for preparing metallomatrix protease inhibitors are
described in EP 780386. Methods for preparing SOD mimics
are described in EP 524,101. Methods for preparing a(3,
inhibitors are described in W097/08174.
The phrase "conjunctive therapy" (or "combination
therapy ), in defining use of a cyclooxygenase-2 inhibitor
agent and another pharmaceutical agent, is intended to
embrace administration of each agent in a sequential
manner in a regimen that will provide beneficial effects
of the drug combination, and is intended as well to
embrace co-administration of these agents in a
substantially simultaneous manner, such as in a single
formulation having a fixed ratio of these active agents,
or in multiple, separate formulations for each agent. The
present invention also comprises a pharmaceutical
composition for the prevention and treatment of neoplasia,
comprising a therapeutically-effective amount of a
compound o.f Formula I in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent
(collectively referred to herein as "carrier" materials)
and, other antineoplastic agents or other growth
inhibiting agents or other drugs or nutrients.
For oral administration, the pharmaceutical
composition may be in the form of, for example, a tablet,
capsule, suspension or liquid. The pharmaceutical
composition is preferably made in the form of a dosage
unit containing a particular amount of the active
ingredient. Examples of such dosage units are capsules,
tablets, powders, granules or a suspension, with
conventional additives such as lactose, mannitol; corn
starch or potato starch; with binders such as crystalline
cellulose, cellulose derivatives, acacia, corn starch or
gelatins; with disintegratorssuch as corn starch, potato
CA 02372912 2002-03-11
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starch or sodium carboxymethyl-cellulose; and with
lubricants such as talc or magnesium stearate. The active
ingredient may also be administered by injection as a
composition wherein, for example, saline, dextrose or
5 water may be used as a suitable carrier.
For intravenous, intramuscular, subcutaneous, or
intraperitoneal administration, the compound may be
combined with a sterile aqueous solution which is
10 preferably isotonic with the blood of the recipient. Such
formulations may be prepared by dissolving solid active
ingredient in water containing physiologically compatible
substances such as sodium chloride, glycine, and the like,
and having a buffered pH compatible with physiological
15 conditions to produce an aqueous solution, and rendering
said solution sterile. The formulations may be present in
unit or multi-dose containers such as sealed ampoules or
vials.
20 if the neoplasia is localized in the G.I. tract, the
compound may be formulated with acid-stable, base-labile
coatings known in the art which begin to dissolve in the
high pH small intestine. Formulation to enhance local
pharmacologic effects and reduce systemic uptake are
25 preferred.
Formulations suitable for parenteral administration
conveniently comprise a sterile aqueous preparation of the
active compound which is preferably made isotonic.
30 Preparations for injections may also be formulated by
suspending or emulsifying the compounds in non-aqueous
solvent, such as vegetable oil, synthetic aliphatic acid
glycerides, esters of higher aliphatic acids or propylene
glycol.
Formulations for topical use include known gels,
creams, oils, and the like. For aerosol delivery, th.e
CA 02372912 2002-03-11
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31
compounds may be formulated with known aerosol exipients,
such as saline, and administered using commercially
available nebulizers. Formulation in a fatty acid source
may be used to enhance biocompatibility. Aerosol delivery
is the preferred method of delivery for epithelial
neoplasias of the lung for prevention application.
For rectal administration, the active ingredient may
be formulated into suppositories using bases which are
solid at room temperature and melt or dissolve at body
temperature. Commonly used bases include cocoa butter,
glycerinated gelatin, hydrogenated vegetable oil,
polyethylene glycols of various molecular weights, and
fatty esters of polyethylene stearate.
The dosage form and amount can be readily established
by reference to known neoplasia treatment or prophylactic
regiments. The amount of therapeutically active compound
that is administered and the dosage regimen for treating a
disease condition with the compounds and/or compositions
of this invention depends on a variety of factors,
including the age, weight, sex and medical condition of
the subject, the severity of the disease, the route and
frequency of administration, and the particular compound
employed, the location of the neoplasia, as well as the
pharmacokinetic properties,of the individual treated, and
thus may vary widely. The dosage will generally be lower
if the compounds are administered locally rather than
systemically, and for prevention rather than for
treatment. Such treatments may be administered as often as
necessary and for the period of time judged necessary by
the treating physician. One of skill in the art will
appreciate that the dosage regime or therapeutically
effective amount of the inhibitor to be administrated may
need to be optimized for each individual. The
pharmaceutical compositions may contain active ingredient
in the range of about 0.1 to 2000 mg, preferably in the
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32
range of about 0.5 to 500 mg and most preferably between
about 1 and 200 mg. A daily dose of about 0.01 to 100
mg/kg body weight, preferably between about 0.1 and about
50 mg/kg body weight, may be appropriate. The daily dose
can be administered in one to four doses per day.
Although this invention has been described with
respect to specific embodiments, the details of these
embodiments are not to be construed as limitations.
