CA2372912C - Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia - Google Patents
Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia Download PDFInfo
- Publication number
- CA2372912C CA2372912C CA002372912A CA2372912A CA2372912C CA 2372912 C CA2372912 C CA 2372912C CA 002372912 A CA002372912 A CA 002372912A CA 2372912 A CA2372912 A CA 2372912A CA 2372912 C CA2372912 C CA 2372912C
- Authority
- CA
- Canada
- Prior art keywords
- cancer
- neoplasia
- alkylamino
- benzenesulfonamide
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating neoplasia. In particular, the invention describes the method of preventing and treating epithelial cell neoplasia in a subject, said method comprising treating the subject with a therapeutically--effective amount of a compound of Formula I. (see formula I) wherein A, R2 and R3 are as described in the specification.
Description
WO 99/16227 PCT/US97n8670 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 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.
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 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.
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 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).
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 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, 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 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, 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 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 - 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
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.
- 9b -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;
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-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;
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 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).
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 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, 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 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, 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 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 - 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
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.
- 9b -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;
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-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;
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;
WO 98/16227 PcT/US97/18670 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;
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;
WO 98/16227 PcT/US97/18670 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;
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;
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;
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;
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-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
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-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
R
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;
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;
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-= WO 98/16227 PCT/[7S97/18670 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 ,. ~
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 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
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-= WO 98/16227 PCT/[7S97/18670 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 ,. ~
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 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
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 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.
wo 98n6227 PCT/US97n8670 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 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, 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.
WO 98n6227 PCT/US97/18670 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.
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' 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 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 WO 98/16227 PC'I'/OS97/18670 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 Wo 98J162Z7 PCT/US97/18670 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 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.
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 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.
wo 98n6227 PCT/US97n8670 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 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, 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.
WO 98n6227 PCT/US97/18670 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.
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' 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 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 WO 98/16227 PC'I'/OS97/18670 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 Wo 98J162Z7 PCT/US97/18670 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 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.
Claims (8)
1. Use of a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1 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 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.
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 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.
2. The use according to claim 1, wherein the neoplasia is selected from the group consisting of colorectal cancer, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer and skin cancer.
3. The use according to claim 1, wherein the neoplasia is adenomatous polyps.
4. Use of a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1 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.
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.
5. A pharmaceutical composition for treating a neoplasia in a subject in need of such treatment, which pharmaceutical composition comprises:
a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1 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 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 at least one pharmaceutically acceptable carrier, adjuvant or diluent.
a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1 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 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 at least one pharmaceutically acceptable carrier, adjuvant or diluent.
6. The pharmaceutical composition according to claim 5, wherein the neoplasia is selected from the group consisting of colorectal cancer, gastrointestinal cancer, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer and skin cancer.
7. The pharmaceutical composition according to claim 5, wherein the neoplasia is adenomatous polyps.
8. A pharmaceutical composition for treating a neoplasia in a subject in need of such treatment, which pharmaceutical composition comprises:
a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1 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; and at least one pharmaceutically acceptable carrier, adjuvant or diluent.
a compound of the formula or a pharmaceutically acceptable salt thereof wherein R1 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; and at least one pharmaceutically acceptable carrier, adjuvant or diluent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002267186A CA2267186C (en) | 1996-10-15 | 1997-10-14 | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002267186A Division CA2267186C (en) | 1996-10-15 | 1997-10-14 | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2372912A1 CA2372912A1 (en) | 1998-04-23 |
| CA2372912C true CA2372912C (en) | 2008-12-02 |
Family
ID=4163412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002372912A Expired - Fee Related CA2372912C (en) | 1997-10-14 | 1997-10-14 | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2372912C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030100594A1 (en) * | 2001-08-10 | 2003-05-29 | Pharmacia Corporation | Carbonic anhydrase inhibitor |
| US20050227929A1 (en) * | 2003-11-13 | 2005-10-13 | Masferrer Jaime L | Combination therapy comprising a Cox-2 inhibitor and an antineoplastic agent |
| NL2000351C2 (en) | 2005-12-22 | 2007-09-11 | Pfizer Prod Inc | Estrogen modulators. |
-
1997
- 1997-10-14 CA CA002372912A patent/CA2372912C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2372912A1 (en) | 1998-04-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2267186C (en) | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia | |
| US6469040B2 (en) | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia | |
| WO1998016227A9 (en) | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia | |
| US6025353A (en) | Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents | |
| CA2270469C (en) | Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents | |
| CA2372912C (en) | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia | |
| NZ517374A (en) | Method of using cycloozygenase-2 inhibitors to prevent a neoplasia that produces a prostaglandin | |
| IL154502A (en) | Use of cyclooxygenase-2 inhibitors in the preparation of medicaments for treating angiogenesis-related disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20141014 |