Immunosuppressive effects of administration of a cyclooxygenase-2 inhibitor, a leukotriene B4 receptor inhibitor and a cyclosporin

• US 20040106668A1
• Filed: 07/10/2003
• Published: 06/03/2004
• Est. Priority Date: 02/13/1996
• Status: Active Grant

• Current Assignee: Pharmacia Corporation (Pfizer Inc.)
• Original Assignee: Pharmacia Corporation (Pfizer Inc.)
• Inventors: Anderson, Gary, Isakson, Peter C., Gregory, Susan A.
• Granted Patent: US 7,141,599 B2
• Time in Patent Office: Days
• US Class Current: 514/406
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/10 Sulfides; Sulfoxides; Sulfones
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/02 Local antiseptics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics

Abstract

Treatment with a cyclooxygenase-2 inhibitor and a leukotriene B₄ receptor antagonist is described as being useful in reducing recipient rejection of transplanted organs and for treatment of autoimmune diseases.

Claims

1. A combination comprising a therapeutically-effective amount of a cyclooxygenase-2 inhibitor, a leukotriene B₄ receptor antagonist and an immunosuppressive drug, wherein the immunosuppressive drug is selected from the group consisting of antiproliferative agents, antiinflammatory-acting compounds and inhibitors of leukocyte activation.

2. The combination of claim 1 wherein the cyclooxygenase-2 inhibitor is selected from Dupont Dup-697, Taisho NS-398, meloxicam, flosulide or compounds of Formula I

3. The combination of claim 1 wherein the leukotriene B₄ receptor antagonist is selected from the group consisting of calcitriol, ontazolast, Bayer Bay-x-1005, Ciba-Geigy CGS-25019C, ebselen, Leo Denmark ETH-615, Lilly LY-293111, Ono ONO-4057, Terumo TMK-688, Boehringer Ingleheim BI-RM-270, Lilly LY 213024, Lilly LY 264086, Lilly LY 292728, Ono ONO LB457, Pfizer 105696, Perdue Frederick PF 10042, Rhone-Poulenc Rorer RP 66153, SmithKline Beecham SB-201146, SmithKline Beecham SB-201993, SmithKline Beecham SB-209247, Searle SC-53228, Shionogi S-2472, Searle SC-52798, Leo Denmark SR-2566, Tanabe T-757, Sumitamo SM 15178, and American Home Products WAY 121006.

4. The combination of claim 3 wherein the leukotriene B₄ receptor antagonist is selected from the group consisting of calcitriol, ontazolast, Bayer Bay-x-1005, Ciba-Geigy CGS-25019C, ebselen, Leo Denmark ETH-615, Lilly LY-293111, Ono ONO-4057, SmithKline Beecham SB-201993, SmithKline Beecham SB-209247, Warner-Lambert BPC-15, Pfizer 105696, Shionogi S-2472, Searle SC-52798, Leo Denmark SR-2566, Tanabe T-757, and Terumo TMK-688.

5. The combination of claim 2 wherein the cyclooxygenase-2 inhibitor is selected from compounds of Formula I.

6. The combination of claim 5 wherein A is selected from the group consisting of oxazolyl, isoxazolyl, thienyl, dihydrofuryl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazolyl, cyclopentenyl, phenyl, and pyridyl;

wherein R¹ is selected from the group consisting of 5- and 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl, wherein the aryl is selected from the group consisting of phenyl, biphenyl and naphthyl, wherein R¹ is optionally substituted at a substitutable position with one or more radicals selected from the group consisting of lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;

wherein R² is selected from the group consisting of lower alkyl and amino; and

wherein R³ is a radical selected from the group consisting of halo, lower alkyl, oxo, cyano, carboxyl, lower cyanoalkyl, heteroaryloxy, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, lower hydroxylalkyl, lower aralkyl, acyl, phenylcarbonyl, lower alkoxyalkyl, heteroaryloxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, aminoalkyl, alkylaminoalkyl, aryloxy, and aralkoxy;

or a pharmaceutically-acceptable salt thereof.

7. The combination of claim 6 wherein A is selected from the group consisting of oxazolyl, isoxazolyl, dihydrofuryl, imidazolyl, and pyrazolyl;

wherein R¹ is selected from the group consisting of 5- and 6-membered heterocyclo, and aryl, wherein aryl is selected from the group consisting of phenyl, biphenyl and naphthyl, wherein R¹ is optionally substituted at a substitutable position with one or more radicals selected from the group consisting of lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl., lower alkylsulfinyl, halo, lower alkoxy and lower alkylthio;

wherein R² is amino; and

wherein R³ is a radical selected from the group consisting of oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, halo, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower haloalkyl, 5- or 6-membered heterocyclo, 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.

8. The combination of claim 7 wherein A is selected from the group consisting of oxazolyl, isoxazolyl, imidazolyl, and pyrazolyl;

wherein R¹ is phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy, ethoxy, propoxy, n-butoxy, pentoxy, and methylthio;

wherein. R² is amino; and

wherein R³ is a radical selected from the group consisting of oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethyl, carboxyethyl, cyanomethyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, fluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichlorbpropyl, 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.

9. The combination of claim 8 wherein the cyclooxygenase-2 inhibitor is selected from compounds, their prodrugs and their pharmaceutically-acceptable salts, of the group consisting of

3-(3,4-difluorophenyl)-4-(4-methylsulfonylphenyl)-2-(5H)-furanone;

3-phenyl-4-4-methylsulfonylphenyl)-2-(5H)-furanone;

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;

3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;

4-[5-hydroxyethyl-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.

10. The composition of claim 1 wherein the leukocyte activation inhibitor is a cyclosporin.

11. The composition of claim 10 wherein the cyclosporin is cyclosporin A.

12. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a leukotriene B₄ receptor antagonist, a cyclosporin and a cyclooxygenase-2 inhibitor selected from Dupont Dup 697, Taisho NS-398, meloxicam, flosulide or compounds of Formula I

13. The combination of claim 12 wherein the cyclooxygenase-2 inhibitor is selected from compounds of Formula I.