Combination

Abstract

The invention relates to the combined administration of PDE4-inhibitors and NSAIDs for the treatment of an inflammatory disease and/or an inflammation associated disorder while minimizing gastrointesti-nal side effects, such as gastric erosions and ulcer, which are frequently associated with the use of NSAIDs.

1 . A pharmaceutical composition comprising, in admixture, a first active ingredient which is a PDE4 inhibitor selected from CDC-998, SH-636, D-4396, IC-485, CC-1088 and 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code: SCH351591], 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code: V11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk] [1,4]benzo-diazepin-3(R)yl]pyridine-4-carboxamide [Research-Code: C 1-1018 , N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research-Code: AWD-12-281], N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN: CIPAMFYLLINE], Tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2-(1H)-pyrimidone [ATIZORAM], B-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide [Research-Code: CDC-801], Methanesulfonic acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN: LIRIMILAST], N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN: PICLAMILAST], cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST], 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives,  
       and a second active ingredient which is a conventional NSAID selected from glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC]; 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylacetate [Research Code: AF2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN: ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN: ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC], (plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN: AMPIROXICAM], 2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate [INN: AMTOLMETINGUACIL], (plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H pyrrolizine-1-carboxylic acid [INN: ANIROLAC], 2-[4-(alpha,alpha,alpha-trifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthranilate [INN: ANTRAFENINE], 5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazolo[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE], 4-acetamidophenyl salicylate acetate [INN: BENORILATE], 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid [INN: BERMOPROFEN], 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropionic acid [INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid [INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid [INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN: BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC], butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE], alpha-ethyl-4-(2-methylpropyl)benzeneacetic acid [INN: BUTIBUFEN], 2-(4-bi-phenylyl)butyric acid, trans-4-phenylcyctohexylamine salt (1:1) [INN: BUTIXIRATE], 2-(acetyloxy)benzoic acid, calcium salt, compound with urea (1:1) [INN: CARBASALATE CALCIUM], (plus/minus)-6-chloro-alpha-methylcarbazole-2-acetic acid [INN: CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid [INN: CINMETACIN], N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM], 6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC], 2-[4(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN: CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN: DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN], (+)—(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], 2′,4′-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN: DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN: ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID] salicylic acid acetate, ester with beta-hydroxy p-acetophenetidide [INN: ETERSALATE], 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid [INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid 2-(2-hydroxyethoxy}ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic acid, ester with 4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN: FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC], 3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN], [o-(2,4-dichlorophenoxy)phenyl]acetic acid (NN: FENCLOFENAC], (plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN], 4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC], (plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl alcohol [INN: FEPRADINOL], 4-(2′,4′-difluorobiphenylyl)-4-oxo-2-methylbutanoic acid [INN: FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthranilic acid [INN: FLUFENAMIC ACID], (plus)-2-(p-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid [INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biphenylacetic acid [INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL], 2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC], 2-[4-(2′-furoyl)phenyl]propionic acid [INN: FURPROFEN], 2-[2-(1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic acid 4-nitrooxybutylester [Research Code: HCT-1026], (p-isobutylphenyl)acetic acid [INN: IBUFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl 4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261], (plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN: INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, 3,7,11-trimethyl-2,6,10-dodeca-trienyl ester [INN: INDOMETACIN FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN: INDOPROFEN], 2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic acid [INN: KETOPROFEN], (DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-carboxylic acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl)cinnamyl]benzofuran [Research Code: L-651896], N-(2-carboxyphenyl)-4chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1-phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN: LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN: MEFENAMIC ACID], 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN: MESALAZINE], (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-acetic acid [Research Code: ML-3000], 3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC], 4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE], (plus)-6-methoxyalpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN: NIFLUMIC ACID], 5,5′-azodisalicylic acid [INN: OLSALAZINE], alpha-methyl-4-((2oxocyclohexylidene)methyl]benzene acetic acid [INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid 2-pyridyl-methyl ester [INN: PIMEPROFEN], 4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN: PIRAZOLAC], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], 3-chloro-4-(3-pyrrolin-1-yl)hydratropic acid [INN: PIRPROFEN], 2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN: PRANOPROFEN], 2,6-di-tert-butyl-4-(2′-thenoyl)phenol [INN: PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide [INN: PRINOMIDE], 3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L-4-benzamido-N,N-dipropylglutaramat 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (ester) [INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-2(1H)quinazolinone [INN: PROQUAZONE], 7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid [INN: PROTIZINIC ACID], 2-[[2-(p-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT], o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid [SALICYLIC ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester) [INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN: SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN: SALSALATE], 4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine [Research Code: SM-8849], (Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]indene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid [INN: SUPROFEN], 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid [Research Code: TA-601], phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN: TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide [INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide [INN: TENOXICAM], 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propionamide {INN: TEPOXALIN], alpha-(5-benzoyl-2-thienyl)-propionic acid [INN: TIAPROFENIC ACID], 5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzo-thiazolinone [INN: TIARAMIDE], 2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7yl)-propionic acid N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL], 1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN: TIMEGADINE], 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine [INN: TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN: TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene acetato-O]-aluminium [Research Code: U-18573-G], N-(3-trifluoromethylphenyl)-anthranilic acid n-butyl ester [INN: UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl] propionic acid [INN: XIMOPROFEN], 2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid [INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]propionic acid [INN: ZOLIPROFEN] and their pharmaceutically acceptable derivatives.  
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein the first and/or second active ingredient is in the form of a pharmaceutically acceptable salt, solvate, ester, N-oxide, solvate of a salt, solvate of an ester or solvate of an N-oxide.  
     
     
         3 . A pharmaceutical composition according to  claim 1  which is a fixed oral combination.  
     
     
         4 . A pharmaceutical composition according to  claim 1  wherein the first active ingredient is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiic acid [INN: CILOMILAST] and 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second active ingredient is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].  
     
     
         5 . A pharmaceutical composition according to  claim 4 , wherein the first active ingredient is 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically acceptable salt, solvate, N-oxide, solvate of a salt or solvate of an N-oxide thereof.  
     
     
         6 . A pharmaceutical composition according to  claim 4 , wherein the second active ingredient is 2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or a pharmaceutically acceptable salt, ester, solvate, solvate of a salt or solvate of an ester thereof.  
     
     
         7 . A method of treating an inflammatory disease and/or an inflammation associated disorder in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to  claim 1 .  
     
     
         8 . A process for the preparation of a pharmaceutical composition as defined in  claim 1  which comprises mixing the first active ingredient with the second active ingredient.  
     
     
         9 - 14 . (Canceled)  
     
     
         15 . A kit comprising a preparation of a first active ingredient which is a PDE4 inhibitor selected from CDC-998, SH-636, D-4396, IC-485, CC-1088 and 3,5-dichloro-4-[8-methoxy-2-(trifluoromethyl)quinoline-5-ylcarboxamido]pyridine-1-oxide [Research Code: SCH351591], 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine [Research-Code: V11294A], N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk] [1,4]benzodiazepin-3(R)yl]pyridine-4-carboxamide [Research-Code: CI-1018, N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide [Research-Code: AWD-12-281], N-(3,5-dichloropyridin-4-yl)-2-[5-fluoro-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide [Research Code: AWD-12-343], 8-Amino-1,3-bis(cyclopropylmethyl)xanthine [INN: CIPAMFYLLINE], Tetra-hydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]-2-(1H)-pyrimidone [ATIZORAM], 1-[3-(Cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide [Research-Code: CDC-801], Methanesulfonic acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester [INN: LIRIMILAST], N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide [INN: PICLAMILAST], cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid [INN: CILOMILAST], 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] and their pharmaceutically acceptable derivatives,  
       a preparation of a second active ingredient which is a conventional NSAID selected from glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate(ester) [INN: ACECLOFENAC]; 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl ester [INN: ACEMETACIN]; 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylacetate [Research Code: AF2259], (4-allyloxy-3-chlorophenyl)acetic acid [INN: ALCLOFENAC], p-[(2-methylallyl)amino]hydratropic acid [INN: ALMINOPROFEN], 2-amino-3-benzoylphenylacetic acid [INN: AMFENAC], (plus/minus)-4-(1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide ethylcarbonate (ester), 1,1-dioxide [INN: AMPIROXICAM], 2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate [INN: AMTOLMETINGUACIL], (plus/minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H pyrrolizine-1-carboxylic acid [INN: ANIROLAC], 2-[4-(alpha,alpha,alpha-trifluoro-m-tolyl)-1-piperazinyl]ethyl-N-(7-trifluoromethyl-4-quinolyl)anthranilate [INN: ANTRAFENINE], 5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazolo[1,2-a][1,2,4]benzo-triazine-1,3(2H)-dione [INN: AZAPROPAZONE], 4-acetamidophenyl salicylate acetate [INN: BENORILATE], 2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic acid [INN: BERMOPROFEN], 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropionic acid [INN: BINDARIT], [2-amino-3-(p-bromobenzoyl)phenyl]acetic acid [INN: BROMFENAC], 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid [INN: BUCLOXIC ACID], 5-butyl-1-cyclohexylbarbituric acid [INN: BUCOLOM], 4-butoxy-N-hydroxybenzeneacetamide [INN: BUFEXAMAC], butylmalonic acid mono(1,2-diphenylhydrazide) [INN: BUMADIZONE], alpha-ethyl-4-(2-methylpropyl)benzeneacetic acid [INN: BUTIBUFEN], 2-(4-bi-phenylyl)butyric acid, trans-4-phenylcyctohexylamine salt (1:1) [INN: BUTIXIRATE], 2-(acetyloxy)benzoic acid, calcium salt, compound with urea (1:1) [INN: CARBASALATE CALCIUM], (plus/minus)-6-chloro-alpha-methylcarbazole-2-acetic acid [INN: CARPROFEN], 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid [INN: CINMETACIN], N-(2-pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide [INN: CINNOXICAM], 6-chloro-5-cyclohexyl-1-indancarboxylic acid [INN: CLIDANAC], 2-[4(p-chlorophenyl)benzyloxy]-2-methylpropionic acid [INN: CLOBUZARIT], 5-methoxy-2-methyl-3-indolylacetohydroxamic acid [INN: DEBOXAMET], (S)-(+)-p-isobutylhydratropic acid [INN: DEXIBUPROFEN], (+)—(S)-m-benzoylhydratropic acid [INN: DEXKETOPROFEN], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], 2′,4′-Difluoro-4-hydroxy-3-biphenylcarboxylic acid [INN: DIFLUNISAL], 4-(2,6-dichloroanilino)-3-thiopheneacetic acid [INN: ELTENAC], N-beta-phenethyl-anthranilic acid [INN: ENFENAMIC ACID] salicylic acid acetate, ester with betahydroxy p-acetophenetidide [INN: ETERSALATE], 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid [INN: ETODOLAC], 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid 2-(2-hydroxyethoxy}ethyl ester [INN: ETOFENAMATE], p-chlorobenzoic acid, ester with 4-butyl-4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione [INN: FECLOBUZONE], 4-biphenylacetic acid [INN: FELBINAC], 3-(4-biphenylylcarbonyl)propionic acid [INN: FENBUFEN], [o-(2,4-dichlorophenoxy)phenyl]acetic acid (NN: FENCLOFENAC], (plus/minus)-m-phenoxyhydratropic acid [INN: FENOPROFEN], 4-(p-chlorophenyl)-2-phenyl-5-thiazoleacetic acid [INN: FENTIAZAC], (plus/minus)-alpha-[[(2-hydroxy-1,1-dimethylethyl)amino]methyl]-benzyl alcohol [INN: FEPRADINOL], 4-(2′,4′-difluorobiphenylyl)-4-oxo-2-methylbutanoic acid [INN: FLOBUFEN], N-(alpha,alpha,alpha-trifluoro-m-tolyl)anthranilic acid [INN: FLUFENAMIC ACID], (plus)-2-(p-fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid [INN: FLUNOXAPROFEN], 2-fluoro-alpha-methyl-4-biphenylacetic acid [INN: FLURBIPROFEN], (plus/minus)-2-(2-fluoro-4-biphenylyl)propionic acid 1 (acetoxy)ethyl ester [INN: FLURBIPROFEN AXETIL], 2-ethyl-2,3-dihydro-5-benzofuranacetic acid [INN: FUROFENAC], 2-[4-(2′-furoyl)phenyl]propionic acid [INN: FURPROFEN], 2-[2-(1-(p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetamido]-2-deoxy-D-glucose [INN: GLUCAMETACIN], 2-(2-fluorobiphenyl-4-yl)propionic acid 4-nitrooxybutylester [Research Code: HCT-1026], (p-isobutylphenyl)acetic acid [INN: IBUFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], methyl 4-(3-thienyl)phenyl-alpha-methylacetate [Research Code: IDPH-8261], (plus/minus)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid [INN: INDOBUFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, 3,7,11-trimethyl-2,6,10-dodecatrienyl ester [INN: INDOMETACIN FARNESIL], p-(1-oxo-2-isoindolinyl)hydratropic acid [INN: INDOPROFEN], 2-(10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-acetic acid [Research Code: IX-207-887], m-benzoylhydratropic acid [INN: KETOPROFEN], (DL)-5-benzoyl-3H-1,2-dihydropyrrolo[1,2-a]pyrrole-1-carboxylic acid [INN: KETOROLAC], 2,3-dihydro-5-hydroxy-6-[2-(hydroxymethyl)cinnamyl]benzofuran [Research Code: L-651896], N-(2-carboxyphenyl)-4chloroanthranilic acid [INN: LOBENZARIT], 3-(p-chlorophenyl)-1-phenylpyrazole-4-acetic acid [INN: LONAZOLAC], 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide [INN: LORNOXICAM], 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]-propionate [INN: LOXOPROFEN], 2(R)-[4-(3-methyl-2-thienyl)phenyl]propionic acid [Research Code: M-5010], N-(2,3-xylyl)anthranilic acid [INN: MEFENAMIC ACID], 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide [INN: MELOXICAM], 5-aminosalicylic acid [INN: MESALAZINE], (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-acetic acid [Research Code: ML-3000], 3,4-bis(4-methoxyphenyl)-5-isoxazoleacetic acid [INN: MOFEZOLAC], 4-(6-methoxy-2-naphthyl)-2-butanone [INN: NABUMETONE], (plus)-6-methoxyalpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN], 2-[3-(trifluoromethyl)anilino]nicotinic acid [INN: NIFLUMIC ACID], 5,5′-azodisalicylic acid [INN: OLSALAZINE], alpha-methyl-4-((2oxocyclohexylidene)methyl]benzene acetic acid [INN: PELUBIPROFEN], 2-(p-isobutylphenyl)propionic acid 2-pyridyl-methyl ester [INN: PIMEPROFEN], 4-(p-chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid [INN: PIRAZOLAC], 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM], 3-chloro-4-(3-pyrrolin-1-yl)hydratropic acid [INN: PIRPROFEN], 2-[5H-(1)benzopyrano]2,3-b]pyridin-7-yl]propionic acid [INN: PRANOPROFEN], 2,6-di-tert-butyl-4-(2′-thenoyl)phenol [INN: PRIFELONE], alpha-cyano-1-methyl-beta-oxopyrrole-2-propionanilide [INN: PRINOMIDE], 3-[4-(2-hydroxyethyl)-1-piperazinyl]-propyl-D,L-4-benzamido-N,N-dipropylglutaramat 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (ester) [INN: PROGLUMETACIN], 7-methyl-1-(1-methylethyl)-4-phenyl-2(1H)quinazolinone [INN: PROQUAZONE], 7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid [INN: PROTIZINIC ACID], 2-[[2-(p-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid [INN: ROMAZARIT], o-hydroxybenzamide [SALICYLAMIDE], 2-hydroxybenzoic acid (SALICYLIC ACID], N-acetyl-L-cysteine salicylate (ester), acetate (ester) [INN: SALMISTEINE], N-acetyl-L-cysteine salicylate (ester) [INN: SALNACEDIN], 2-hydroxybenzoic acid 2-carboxyphenyl ester [INN: SALSALATE], 4-[1-(2-fluorobiphenyl-4-yl)ethyl]-N-methylthiazole-2-amine [Research Code: SM-8849], (Z)-5-fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]indene-3-acetic acid [INN: SULINDAC], p-2-thenoylhydratropic acid [INN: SUPROFEN], 2-(4-(3-methyl-2-butenyl)phenyl)propionic acid [Research Code: TA-601], phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-toluidino)nicotinate [INN: TALNIFLUMATE], (Z)-5-chloro-3-(2-thenoyl)-2-oxoindole-1-carboxamide [INN: TENIDAP], 2-thiophenecarboxylic acid, ester with salicylic acid [INN: TENOSAL], 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide [INN: TENOXICAM], 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propionamide {INN: TEPOXALIN], alpha-(5-benzoyl-2-thienyl)-propionic acid [INN: TIAPROFENIC ACID], 5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl-2-benzothiazolinone [INN: TIARAMIDE], 2-(2-methyl-5H-[1]benzopyrano[2,3-b]pyridin-7yl)-propionic acid N,N-dimethylcarbamoylmethyl ester [INN: TILNOPROFEN ARBAMEL], 1-Cyclohexyl-2-(2-methyl-4-quinolyl)-3-(2-thiazolyl)guanidine [INN: TIMEGADINE], 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine [INN: TINORIDINE], N-(3-chloro-o-tolyl)anthranilic acid [INN: TOLFENAMIC ACID], 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid [INN: TOLMETIN], hydroxybis[alpha-methyl-4-(2-methylpropyl)benzene acetato-O]-aluminium [Research Code: U-18573-G], N-(3-trifluoromethylphenyl)-anthranilic acid n-butyl ester [INN: UFENAMATE], 2-[4-[3-(hydroxyimino)cyclohexyl]phenyl] propionic acid [INN: XIMOPROFEN], 2-(10,11-dihydro-10-oxo-dibenz[b,f]thiepin-2-yl-propionic acid [INN: ZALTOPROFEN], 2-[4-(2-thiazolyloxy)phenyl]propionic acid [INN: ZOLIPROFEN] and their pharmaceutically acceptable derivatives, and instructions for simultaneous, sequential or separate administration to the patient in need thereof.  
     
     
         16 . A kit according to  claim 15 , wherein the first and/or second active ingredient is in the form of a pharmaceutically acceptable salt, solvate, ester, N-oxide, solvate of a salt, solvate of an ester or solvate of an N-oxide.  
     
     
         17 . A kit according to  claim 15  wherein the first active ingredient is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiic acid [INN: CILOMILAST] and 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second active ingredient is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].  
     
     
         18 . A kit according to  claim 17 , wherein the first active ingredient is 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically acceptable salt, solvate, N-oxide, solvate of a salt or solvate of an N-oxide thereof.  
     
     
         19 . A kit according to  claim 17 , wherein the second active ingredient is 2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or a pharmaceutically acceptable salt, ester, solvate, solvate of a salt or solvate of an ester thereof.  
     
     
         20 . A method of treating an inflammatory disease and/or an inflammation associated disorder which can be treated with a conventional NSAID while minimizing gastrointestinal side effects comprising the simultaneous, sequential or separate administration of 
 i) a first amount of a conventional NSAID or a pharmaceutically acceptable derivative thereof; and    ii) a second amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative thereof,    wherein the sum of the first and the second amount is a therapeutically effective amount, to a patient in need thereof.    
     
     
         21 . A method according to  claim 20  wherein the inflammatory disease is inflammatory bowel disease, Crohn's disease, irritable bowel syndrome or ulcerative colitis.  
     
     
         22 . A method of minimizing gastrointestinal side effects frequently associated with the use of conventional NSAIDs comprising the simultaneous, sequential or separate administration of 
 i) a first amount of a conventional NSAID or a pharmaceutically acceptable derivative thereof; and    ii) a second amount of a PDE4 inhibitor or a pharmaceutically acceptable derivative thereof,    wherein the sum of the first and the second amount is a therapeutically effective amount, to a patient in need thereof.    
     
     
         23 - 24 . (Canceled)  
     
     
         25 . A pharmaceutical composition according to  claim 2  which is a fixed oral combination.  
     
     
         26 . A pharmaceutical composition according to  claim 2  wherein the first active ingredient is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiic acid [INN: CILOMILAST] and 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second active ingredient is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].  
     
     
         27 . A pharmaceutical composition according to  claim 26 , wherein the first active ingredient is 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically acceptable salt, solvate, N-oxide, solvate of a salt or solvate of an N-oxide thereof.  
     
     
         28 . A pharmaceutical composition according to  claim 26 , wherein the second active ingredient is 2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or a pharmaceutically acceptable salt, ester, solvate, solvate of a salt of solvate of an ester thereof.  
     
     
         29 . A pharmaceutical composition according to  claim 3  wherein the first active ingredient is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxyiic acid [INN: CILOMILAST] and 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second active ingredient is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].  
     
     
         30 . A pharmaceutical composition according to  claim 29 , wherein the first active ingredient is 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically acceptable salt, solvate, N-oxide, solvate of a salt or solvate of an N-oxide thereof.  
     
     
         31 . A pharmaceutical composition according to  claim 29 , wherein the second active ingredient is 2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or a pharmaceutically acceptable salt, ester, solvate, solvate of a salt of solvate of an ester thereof.  
     
     
         32 . A method of treating an inflammatory disease and/or an inflammation associated disorder in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition according to  claim 2 .  
     
     
         33 . A kit according to  claim 16  wherein the first active ingredient is a PDE4-inhibitor selected from cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1—carboxyiic acid [INN: CILOMILAST] and 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST], and the second active ingredient is a conventional NSAID selected from 2-(acetyloxy)benzoic acid [ACETYLSALICYLIC ACID], 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC], alpha-p-isobutylphenylpropionic acid [INN: IBUPROFEN], 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid [INN: INDOMETACIN], (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid [INN: NAPROXEN] and 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide [INN: PIROXICAM].  
     
     
         34 . A kit according to  claim 33 , wherein the first active ingredient is 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide [INN: ROFLUMILAST] or a pharmaceutically acceptable salt, solvate, N-oxide, solvate of a salt or solvate of an N-oxide thereof.  
     
     
         35 . A kit according to  claim 33 , wherein the second active ingredient is 2-(2,6-dichlorophenyl)amino]benzeneacetic acid [INN: DICLOFENAC] or a pharmaceutically acceptable salt, ester, solvate, solvate of a salt of solvate of an ester thereof.