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USOO8242146 B2

(12) United States Patent (10) Patent No.: US 8.242,146 B2 Klein et al. (45) Date of Patent: Aug. 14, 2012

(54) COMBINATION OF ANSAID AND A PDE-4 Wolda, S.L., “PDE4 inhibitors and chronic obstructive pulmonary INHIBITOR disease”, Emerging Drugs, vol. 5, No. 3, pp. 309-319, (2000). Silva, J.C.R. et al., “Effects of pentoxifylline and on the (75) Inventors: Thomas Klein, Constance (DE); serum levels of IL-1B and TNF C in rats with adjuvant arthritis', Hans-Peter Kley, Allensbach (DE) Inflammation Research, vol. 49, pp. 14-19, (2000). Kumar, A. et al., “ and anti-inflammatory effects of (73) Assignee: Nycomed GmbH, Constance (DE) phosphodiesterase inhibitors'. Indian Journal of Experimental Biol ogy, vol. 38, pp. 26-30. (2000). (*) Notice: Subject to any disclaimer, the term of this Reuter, B.K. et al., “Phosphodiesterase inhibitors prevent NSAID patent is extended or adjusted under 35 entreopathy independently of effects on TNF-C. release'. Am J U.S.C. 154(b) by 1207 days. Physiol, vol. 277, pp. G847-G854, (1999). Sivola, J. et al., “Effects of nonsteroidal anti-inflammatory drugs on (21) Appl. No.: 12/003,129 rat gastric mucosal phosphodiesterase activity'. Agents and Actions, vol. 12, No. 4, pp. 516-520, (1982). (22) Filed: Dec. 20, 2007 Salcedo, J. et al., “Phosphodiesterase 4 Inhibition, A New Mecha nism to Maintain and Promote Gastric and Intestinal Mucosal Integ (65) Prior Publication Data rity Against NSAID-Induced Injury in the Rat', Gastroenterology, US 2008/O255.209 A1 Oct. 16, 2008 vol. 114, No. 4, pp. G1126, Abstract. Tariq, M. et al., “Gastric Antiulcer and cytoprotective effects of Related U.S. Application Data Dipyridamole in rats'. J. Pharmacol. Exp. Ther. vol. 253, No. 3, pp. 944-949 (1990), Abstract 113:71071 American Chemical Society. (62) Division of application No. 10/489,920, filed as Bertrand, et al., “Increase in tumor necrosis factor-O production application No. PCT/EP02/10424 on Sep. 17, 2002, linked to the toxicity of indomethacin for the rat Small intestine'. now abandoned. British Journal of Pharmacology, vol. 124, pp. 1385-1394. (1998). Bouchier-Hayes, et al., “Comparison of the efficacy and tolerability (51) Int. Cl. of gel (Voltarol Emulgel) and gel (Traxam) in the A6 IK3I/44 (2006.01) treatment of soft tissue injuries'. BJCP, vol. 44, No. 8, pp. 319-320, (52) U.S. Cl...... S14/352 (1990). Diaz-Granados, et al., “Dextran Sulfate Sodium-Induced Colonic (58) Field of Classification Search ...... None Histopathology, but not Altered Epithelial Ion Transport, Is Reduced See application file for complete search history. by Inhibition of Phosphodiesterase Activity”, American Journal of Pathology, vol. 156, No. 6, pp. 2169-2177. (2000). (56) References Cited Ding, et al., “, tumor necrosis factor O. and neutrophils: causative relationship in indomethacin-induced stomach injuries'. U.S. PATENT DOCUMENTS European Journal of Pharmacology, vol. 348, pp. 257-263, (1998). 4,736,024 A 4, 1988 Della Valle et al. Gomez, et al., “Effect of Topical Diflumidone on Ultraviolet-Light 6,174,878 B1 1/2001 Gamache et al...... 514,211.12 Induced Erythema'. Dermatologica, vol. 162, pp. 175-182 (1981). 6.410,563 B1 6/2002 Deschenes et al. Häfner, et al., “Additive Effects of Phosphodiesterase-4 Inhibition on FOREIGN PATENT DOCUMENTS Effects of rSP-C Surfactant”, Am J Respir Crit Care Med, vol. 161, CA 2009.730 A1 8, 1990 pp. 1495-1500, (2000). WO 99.06404 A1 2, 1999 Hartmann, et al., “Specific Type IV Phosphodiesterase Inhibitor WO 99/23077 A1 5, 1999 Rolipram Mitigates Experimental Colitis in Mice'. The Journal of WO 01.00229 A1 1, 2001 Pharmacology and Experimental Therapeutics, vol. 292, No. 1, pp. WO O1? 13953 A2 3, 2001 22-30, (2000). WO O1/32127 A2 5, 2001 Hatzelmann, et al., “Anti-Inflammatory and Immunomodulatory WO Of 47880 A1 T 2001 Potential of the Novel PDE4 Inhibitor Roflumilast in Vitro’. The WO O1, 57.036 A1 8, 2001 Journal of Pharmacology and Experimental Therapeutics, vol. 297, WO 01,58441 A1 8, 2001 No. 1, pp. 267-279, (2001). WO 02/060896 A1 8, 2002 WO 02/064584 A1 8, 2002 Primary Examiner — Tracy Vivlemore OTHER PUBLICATIONS Assistant Examiner — Jennifer Berrios Bundschuh, D.S. et al., “In Vivo Efficacy in Airway Disease Models (74) Attorney, Agent, or Firm — The Nath Law Group; of Roflumilast, a Novel Orally Active PDE4 Inhibitor'. Journal of Sheldon M. McGee Pharmacology and Experimental Therapeutics, vol. 297, No. 1, pp. (57) ABSTRACT 280–290, (2001). Dyke, H.J., “Update on the therapeutic potential of PDE4 inhibitors'. The invention relates to the combined use of a PDE4 inhibitor Expert Opin. Investig. Drugs, vol. 11, No. 1, pp. 1-13, (2002). and a conventional NSAID in the treatment of an inflamma Germann, P. et al., “Experimental approaches for the treatment of the tory disease and/or an inflammation-associated disorder acute respiratory distress syndrome in a rat lung lavage model”. while minimizing gastrointestinal side effects, such as gastric Recent Res. Devel. Resp. Critical Care Med., vol. 1, pp. 161-179, (2001). erosions and ulcer, which are frequently associated with the Norman, P., “PDE4 inhibitors 2001. Patent and literature activity use of conventional NSAIDs. A preferred PDE4 inhibitor for 2000–Sep. 2001'. Expert Opin. Ther: Patents, vol. 12, No. 1, pp. this combination is roflumilast or a derivative thereof. A pre 93-111, (2002). ferred conventional NSAID for this combination is Suttorp, N. et al., “Phosphodiesterasen Inhibition und pulmonale diclofenac or a derivative thereof. Strombahn—ein neuer Therapieansatz?'. Altenwegs und Lungenkrankheiten, vol. 22, No. 11, pp. 560-566, (1996). 4 Claims, No Drawings US 8,242,146 B2 1. 2 COMBINATION OF ANSAID AND A PDE-4 The invention thus relates to the combined use of a PDE4 INHIBITOR inhibitor and a conventional NSAID in the treatment of an inflammatory disease and/or an inflammation-associated dis This application is a divisional of U.S. Ser. No. 10/489,920, order while minimizing gastrointestinal side effects, such as filed Mar. 18, 2004 now abandoned, which is a 371 of PCT/ 5 gastric erosions and ulcer, which are frequently associated EP02/10424 filed Sep. 17, 2002, and which claims benefit of with the use of conventional NSAIDs. priority to EP01000473.7 filed Sep. 19, 2001, the disclosure “Combined use” in the context of the invention means the of which is incorporated herein by reference in its entirety for simultaneous, sequential or separate ad-ministration of the all purposes. conventional NSAID on the one hand and of the PDE4 inhibi 10 tor on the other hand. FIELD OF APPLICATION OF THE INVENTION Simultaneous administration includes—aside from the simultaneous uptake of two separate dosage forms containing The invention relates to the combination of certain known the conventional NSAID in the one and the PDE4 inhibitor in active compounds for therapeutic purposes. the other dosage form pharmaceutical compositions con The Substances used in the combination according to the 15 invention are known active compounds from the PDE4-in taining both active ingredients in one single dosage form hibitor class and active compounds from the non-steroidal (fixed unit dose form). anti-inflammatory drug (NSAID) class. Simultaneous administration also includes the oral admin istration of the PDE4 inhibitor during i.v. administration (e.g. KNOWN TECHNICAL BACKGROUND by infusion) of the conventional NSAID, or shortly after intramuscular or intravenous injection of the conventional In the International Patent Application WO01/58441 the NSAID. treating of an inflammatory disease by administering a phos Sequential administration in the context of the invention phodiesterase 4 inhibitor in combination with an inhibitor of means the administration of the conventional NSAID on the prostaglandin synthesis, NSAIDS being exemplary, is dis 25 one hand and of the PDE4 inhibitor on the other hand in closed. separate dosage forms within less than 12 hours, more pref erably within less than one hour, most preferably within 5 DESCRIPTION OF THE INVENTION minutes or less, including regimen where the PDE4 inhibitor is administered first. The use of nonsteroidal anti-inflammatory drugs 30 Separate administration within the context of the invention (NSAIDs) is often associated with the development of gas means the administration of the conventional NSAID on the trointestinal (GI) side effects such as gastric erosions and one hand and of the PDE4 inhibitor on the other hand in ulcer, which limit their widespread clinical use. separate dosage forms within 12 hours or more, including Investigations into the role of several NSAIDs in inhibiting administration regimen where the PDE4 inhibitor is admin the phosphodiesterase 4 and 5 in vitro showed that in partially 35 istered first, and including regimen where e.g. the conven purified or recombinant PDE4 and PDE5, NSAIDs with pref tional NSAID is administered twice or three times daily and erential COX-2 selectivity (for example, INN), the PDE4 inhibitor is administered once or twice daily. CGP28238 Research Code, L-745337 Research Code, Sequential and separate administration also include the and the highly selective drug (INN) possess PDE4 oral administration of the PDE4 inhibitor and the i.v. admin and PDE5 activity in the uM range, whereas conventional 40 istration (e.g. by infusion) or intramuscular or intravenous NSAIDs (for example, acetylsalicylic acid, diclofenac (INN) injection of the conventional NSAID. or (INN) show only minor effects. “Combined use” in the context of the invention also In isolated guinea pig Langendorffhearts, celecoxib selec includes a pharmaceutical product comprising both the con tively increased coronary heart flow at doses consistent with ventional NSAID and the PDE4 inhibitor as discrete separate its inhibitory potency on PDE4 and 5, but had no effect on left 45 dosage forms, in separate containers or e.g. in blisters con Ventricular pressure and heart rate, thereby excluding inhibi taining both types of drugs in discrete solid dosage units, tion of PDE3. preferably in a form in which the dosage units which have to In mice, diclofenac (3-100 mg/kg, p.o.) induced gas be taken together or which have to be taken within one day are trointestinal bleeding (EDs 56 mg/kg), assessed by spectro grouped together in a manner which is convenient for the photometric determination of fecal hemoglobin. Treatment 50 patient. Said pharmaceutical product itself or as a part of a kit with diclofenac (10-100 mg/kg, p.o. t-Oh) in the presence of may contain instructions for the simultaneous, sequential or the selective PDE5 inhibitor sildenafil (3-100 mg/kg, p.o. separate administration of the discrete separate dosage units, =-48 h to +7 h) demonstrated no protection from NSAID to a patient in need thereof. induced blood loss, whereas treatment in the presence of By the expression “PDE4 inhibitor is meant a phosphodi several selective PDE4 inhibitors significantly reduced the 55 esterase inhibitor, which selectively inhibits the type 4 phos amount of detectable hemoglobin. phodiesterase when compared to other known types of phos In summary, one can say that NSAIDs with preferential phodiesterase, e.g. type 1, 2, 3, 5 etc., whereby the compound COX-2 selectivity possess PDE4 and PDE5 inhibitory has a lower ICso (more potent) for the type 4 phosphodi potency on isolated , an effect which was confirmed esterase, such as where the ICs for PDE4 inhibition is about in the Langendorff heart by an increase in coronary flow. It 60 factor 100 lower compared to ICs for inhibition of other seems that the intrinsic PDE4—but not the intrinsic PDE5— known type of phosphodiesterase, e.g. type 1, 2, 3, 5 etc. inhibitory component of NSAIDs with preferential COX-2 By "conventional NSAID is meant a selectivity most likely contribute to the gastrointestinal safety inhibitor which inhibits both, the constitutive form (COX-1) of these drugs. Furthermore, gastrointestinal side effects of and the inducible form (COX-2) of the cyclooxygenase and conventional NSAIDs can be attentuated or even prevented, if 65 does not contain any of the following residues: —S(O)NH2, these class of compounds is applied in combination with a —S(O)CH, -S(O)N(H)C(O)CHCH and - N(H)–S compound from the class of selective PDE4 inhibitors. (O) CHs. US 8,242,146 B2 3 4 PDE4 inhibitors within the meaning of the present inven dro-5-(4-methoxybenzoyl)-1H pyrrolizine-1- tion are those which are named expressis verbis as an example INN: ANIROLAC. 2-4-(alpha,alpha,alpha-trifluoro-m- or described and/or claimed generically in the following tolyl)-1-piperazinylethyl-N-(7-trifluoromethyl-4-quinolyl) patent applications and patents: EP0428302, EP0731099, anthranilate INN: ), 5-(dimethylamino)-9- WO9212961, WO9319749, WO9402465, WO9500516, methyl-2-propyl-1H-pyrazolo 12-a 1.2.4benzo-triazine WO950.1338, WO9611690, WO9603399, WO9636625, 1.3(2H)-dione INN: ), WO9636626, WO9723457, WO9728131, WO9735854, 4-acetamidophenyl salicylate acetate INN: , WO9743288, WO9807715, WO9808841, WO9809946, 2-(8-methyl-10,11-dihydro-11-oxodibenzb.foxepin-2-yl) WO982.1207, WO9821209, WO98224.53, WO983.1674, (INN: BERMOPROFEN), 2-(1-benzyl-1H WO9905111, WO9905112, WO9905113, WO9931090, 10 indazol-3-yl)methoxy-2-methylpropionic acid INN: BIN WO9957 115, WO9964.414, WO0001695, WO0026208, DARIT), 2-amino-3-(p-bromobenzoyl)phenyl) WO0042017, WO0042018, WO0042019, WO0042020, INN: ), 3-(3-chloro-4-cyclohexylbenzoyl) WO0042034, WO0130766, WO0130777, WOO151470, propionic acid (INN: BUCLOXIC ACID), 5-butyl-1-cyclo WO0206239, WO0206270, WO0205616 and WO0206238 hexylbarbituric acid (INN: BUCOLOM), 4-butoxy-N-hy and additionally the following compounds identified by their 15 droxybenzeneacetamide INN: , research codes: CDC-998, D-4396, IC-485, CC-1088 and butylmalonic acid mono (1,2-diphenylhydrazide) INN: KW-4490. Substances having good oral availability are pre , alpha-ethyl-4-(2-methylpropyl) ferred here. acetic acid INN: BUTIBUFEN), 2-(4-biphenylyl)butyric Preferred PDE4 inhibitors which are selected from the acid, trans-4-phenylcyclohexylamine-salt (1:1) INN: above-defined PDE4 inhibitors are the compounds with the BUTIXIRATE), 2-(acetyloxy)-benzoic acid, calcium salt, research codes CDC-998, SH-636, D-4396, IC-485, compound with urea (1:1) (INN: CARBASALATE CAL CC-1088 and 3,5-dichloro-4-8-methoxy-2-(trifluorom CIUM), (plus/minus)-6-chloro-alpha-methylcarbazole-2- ethyl)cquinoline-5-ylcarboxamidolpyridine-1-oxide Re acetic acid (INN: ), 1-cinnamoyl-5-methoxy search Code: SCH351591), 3-3-(cyclopentyloxy)-4-meth 2-methylindole-3-acetic acid (INN: CINMETACIN), N-(2- oxybenzyl-6-(ethylamino)-8-isopropyl-3H-purine 25 pyridyl)-2-methyl-4-cinnamoyloxy-2H-1,2-benzothiazine Research-Code: V 11294A. N-9-methyl-4-oxo-1-phenyl 3-carboxamide-1,1-dioxide INN: CINNOXICAM), 3,4,6,7-tetrahydropyrrolo3.2,1-jk]1,4)benzo-diazepin-3 6-chloro-5-cyclohexyl-1-indancarboxylic acid INN: CLID (R)-ylpyridine-4-carboxamide Research-Code: CI-1018, ANAC. 2-4-(p-chlorophenyl)benzyloxy-2-methylpropi N-(3,5-dichloro-4-pyridinyl)-2-1-(4-fluorobenzyl)-5-hy onic acid (INN: CLOBUZARITI, 5-methoxy-2-methyl-3-in droxy-1H-indol-3-yl)-2-oxoacetamide Research-Code: 30 dolylacetohydroxamic acid (INN: DEBOXAMET, (S)-(+)- AWD-12-281, N-(3,5-dichloropyridin-4-yl)-2-5-fluoro-1- p-isobutylhydratropic acid (INN: ), (+)- (4-fluorobenzyl)-1H-indol-3-yl)-2-oxoacetamide Research (S)-m-benzoylhydratropic acid |INN: Code: AWD-12-343, 8-Amino-1,3-bis(cyclopropylmethyl) ), 2-(2,6-dichlorophenyl)aminoben Xanthine INN: CIPAMFYLLINE), Tetrahydro-5-4- Zeneacetic acid INN: DICLOFENAC), 2',4'-Difluoro-4-hy methoxy-3-(1S,2S.4R)-2-norbornyloxyphenyl-2(1H)- 35 droxy-3-biphenylcarboxylic acid (INN: ). pyrimidone INN: ATIZORAM, B-3-(Cyclopentyloxy)-4- 4-(2,6-dichloroanilino)-3-thiopheneacetic acid INN: ELTE methoxyphenyl-1,3-dihydro-1,3-dioxo-2H-isoindole-2- NAC), N-beta-phenethyl-anthranilic acid INN: ENFE propanamide Research-Code: CDC-801, Methanesulfonic NAMIC ACID acetate, with beta-hy acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan droxy p-acetophenetidide. INN: ETERSALATE), 1.8- 6-yl ester INN: LIRIMILAST, N-(3,5-dichloropyrid-4-yl)- 40 diethyl-1,3,4,9-tetrahydropyrano3,4-bindole-1-acetic acid 3-cyclopentyloxy-4-methoxybenzamide INN: PICLAMI INN: ), 2-3-(trifluoromethyl)phenylamino LAST, cis-4-Cyano-4-(3-cyclopentyloxy-4- benzoic acid 2-(2-hydroxyethoxy)-ethyl ester INN: ETOFE methoxyphenyl)cyclohexane-1-carboxylic acid INN: NAMATE). p-chlorobenzoic acid, ester with 4-butyl-4-(hy CILOMILAST and 3-Cyclopropylmethoxy-4-difluo droxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione INN: romethoxy-N-(3,5-dichloropyrid-4-yl)- INN: 45 FECLOBUZONE, 4-biphenylacetic acid (INN: FELBI ROFLUMILAST). NAC), 3-(4-biphenylylcarbonyl)propionic acid INN: FEN Particularly preferred PDE4-inhibitors are cis-4-Cyano BUFEN. Io-(2,4-dichlorophenoxy)phenyl)acetic acid INN: 4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-car ), (plus/minus)-m-phenoxyhydratropic boxylic acid (INN: CILOMILAST and 3-Cyclopropyl acid INN: ), 4-(p-chlorophenyl)-2-phenyl methoxy-4-difluoromethoxy-N-(3,5-di-chloropyrid-4-yl)- 50 5-thiazoleacetic acid INN: ), (plus/minus)-al benzamide INN: ROFLUMILAST. pha-(2-hydroxy-1,1-dimethylethyl)aminomethyl-benzyl Conventional NSAIDs within the meaning of the present (INN: FEPRADINOL), 4-(2',4'-difluorobiphenylyl)- invention are glycolic acid o-(2,6-dichloroanilino)phenyl 4-oxo-2-methylbutanoic acid INN: FLOBUFEN,N-(alpha, acetate(ester) INN: : 1-(4-chloroben alpha,alpha-trifluoro-m-tolyl)anthranilic acid INN: FLUFE Zoyl)-5-methoxy-2-methyl-1H--3-acetic acid car 55 NAMIC ACID), (plus)-2-(p-fluorophenyl)-alpha-methyl-5- boxymethyl ester INN: : 2-(acetyloxy) benzoxazoleacetic acid INN: , benzoic acid ACETYLSALICYLIC ACID, 2-fluoro-alpha-methyl-4-biphenylacetic acid INN: FLUR 2-methoxyphenyl-alpha-methyl-4-(isobutyl)phenylacetate BIPROFEN, (plus/minus)-2-(2-fluoro-4-biphenylyl)propi Research Code: AF-2259 (4-allyloxy-3-chlorophenyl)ace onic acid 1 (acetoxy)ethyl ester INN: tic acid INN: . p-(2-methylallyl)amino 60 AXETILI, 2-ethyl-2,3-dihydro-5-benzofuranacetic acid hydratropic acid (INN: ), 2-amino-3-ben INN: FUROFENAC. 2-4-(2-furoyl)phenylpropionic acid Zoylphenylacetic acid INN: . (plus/minus)-4- INN: FURPROFEN), 2-2-1-(p-chlorobenzoyl)-5-meth (1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2- oxy-2-methylindol-3-ylacetamido)-2-deoxy-D-glucose benzothiazine-3-carboxamide ethylcarbonate (ester), 1,1- INN: GLUCAMETACIN), 2-(2-fluorobiphenyl-4-yl)propi dioxide INN: ), 2-methoxyphenyl-1- 65 onic acid 4-nitrooxybutylester Research Code: HCT-1026. methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate (p-isobutylphenyl)acetic acid INN: IBUFENAC), alpha-p- INN: AMTOLMETINGUACIL), (plus/minus)-2,3-dihy isobutylphenylpropionic acid INN: ), methyl US 8,242,146 B2 5 6 4-(3-thienyl)phenyl-alpha-methylacetate Research Code: 2-thiophenecarboxylic acid, ester with salicylic acid INN: IDPH-8261), (plus/minus)-2-p-(1-oxo-2-isoindolinyl)phe TENOSAL), 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno2. nylbutyric acid (INN: INDOBUFEN, 1-(4-chlorobenzoyl)- 3-e-1,2-thiazine-3-carboxamide INN: , 5-methoxy-2-methyl-1H-indole-3-acetic acid INN: 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N- INDOMETACIN), 1-(4-chlorobenzoyl)-5-methoxy-2-me methyl-1H-pyrazole-3-propionamide INN: TEPOXALINI, thyl-1H-indole-3-acetic acid, 3.7.11-trimethyl-2,6,10-dode alpha-(5-benzoyl-2-thienyl)propionic acid INN: TIAPRO catrienyl ester INN: INDOMETACIN FARNESIL), p-(1- FENIC ACID, 5-chloro-3-4-(2-hydroxyethyl)-1-piperazi oxo-2-isoindolinyl)hydratropic acid (INN: ), nylcarbonylmethyl-2-benzo-thiazolin one INN: TIARA 2-(10-methoxy-4H-benzo4.5-cyclohepta 1,2-bithiophen MIDE), 2-(2-methyl-5H-1 benzopyrano 2,3-bipyridin-7- 4-ylidene)-acetic acid Research Code: IX-207-887, m-ben 10 yl)-propionic acid N.N-dimethylcarbamoylmethyl ester Zoylhydratropic acid INN: ), (DL)-5-ben INN: TILNOPROFEN ARBAMEL), 1-Cyclohexyl-2-(2- Zoyl-3H-1,2-dihydropyrrolo 1,2-alpyrrole-1-carboxylic acid methyl-4-quinolyl)-3-(2-thiazolyl)guanidine INN: TIM INN: ), 2,3-dihydro-5-hydroxy-6-2-(hy EGADINE, 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno2. droxymethyl)cinnamylbenzofuran Research Code: 3-clpyridine INN: TINORIDINE, N-(3-chloro-o-tolyl) L-651896, N-(2-carboxyphenyl)-4-chloroanthranilic acid 15 anthranilic acid INN: ), 1-methyl-5- INN: LOBENZARIT), 3-(p-chlorophenyl)-1-phenylpyra (4-methylbenzoyl)-1H-pyrrole-2-acetic acid INN: Zole-4-acetic acid INN: . 6-chloro-4-hy ), hydroxybisalpha-methyl-4-(2-methylpropyl) droxy-2-methyl-N-2-pyridyl-2H-thieno-2,3-e-1,2-thiaz benzene acetato-O-aluminium Research Code: U-18573 ine-3-carboxamide 1,1-dioxide INN: , G. N-(3-trifluoromethylphenyl)-anthranilic acid n-butyl 2-4-(2-oxocyclopentan-1-yl-methyl)phenyl-propionate ester INN: UFENAMATE), 2-4-3-(hydroxyimino)cyclo INN: ), 2(R)-4-(3-methyl-2-thienyl)phe hexylphenylpropionic acid (INN; XIMOPROFEN), 2-(10, nylpropionic acid Research Code: M-5010, N-(2,3-xylyl) 11-dihydro-10-oxo-dibenzb.fthiepin-2-yl-propionic acid anthranilic acid (INN: ), 4-hydroxy-2- INN: and 2-4-(2-thiazolyloxy)phenyl methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3- propionic acid (INN: ZOLIPROFEN. carboxamide 1,1-dioxide INN: ), 25 Preferred conventional NSAIDs which are selected from 5-aminosalicylic acid INN: , (2,2-dim the above-defined group of conventional NSAIDs are ethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyr 2-(acetyloxy)benzoic acid (ACETYLSALICYLIC ACID, rolizin-5-yl)-acetic acid Research Code: ML-3000, 3,4-bis 2-(2,6-dichlorophenyl)amino-benzeneacetic acid INN: (4-methoxyphenyl)-5-isoxazoleacetic acid INN: DICLOFENAC), alpha-p-isobutylphenylpropionic acid ), 4-(6-methoxy-2-naphthyl)-2-butanone 30 INN: IBUPROFEN.), 1-(4-chlorobenzoyl)-5-methoxy-2- INN: NABUMETONE, (plus)-6-methoxy-alpha-methyl-2- methyl-1H-indole-3-acetic acid (INN: INDOMETACIN), naphthalineacetic acid INN: ), 2-3-(trifluo (plus)-6-meth-oxy-alpha-methyl-2-naphthalineacetic acid romethyl)anilinonicotinic acid (INN: ), INN: NAPROXEN and 4-hydroxy-2-methyl-N-2-pyridyl 5.5'-azodisalicylic acid INN: OLSALAZINE), alpha-me 2H-1,2-benzothiadiazin-3-carboxamide 1,1-dioxide INN: thyl-4-(2-oxocyclohexylidene)methylbenzene acetic acid 35 ). INN: PELUBIPROFEN), 2-(p-isobutylphenyl)propionic An particularly preferred conventional NSAID is 2-(2,6- acid 2-pyridyl-methyl ester INN; PIMEPROFEN), 4-(p- dichlorophenyl)aminobenzeneacetic acid INN: chlorophenyl)-1-(p-fluorophenyl)pyrazole-3-acetic acid DICLOFENAC. INN: PIRAZOLAC), 4-hydroxy-2-methyl-N-2-pyridyl-2H In the context of the present invention, unless otherwise 1,2-benzothiadiazin-3-carboxamide 1,1-dioxide INN: 40 stated, a pharmaceutically acceptable derivative of an active PIROXICAM, 3-chloro-4-(3-pyrrolin-1-yl)hydratropic acid ingredient means a pharmaceutically acceptable salt or Sol INN: ), 2-5H-(1)benzopyrano)2,3-bipyridin vate (e.g. hydrate), a pharmaceutically acceptable Solvate of 7-yl)propionic acid (INN: ), 2,6-di-tert-bu Such salt, a pharmaceutically acceptable N-oxide or a phar tyl-4-(2'-thenoyl)phenol (INN: PRIFELONE, alpha-cyano maceutically acceptable salt or solvate of the latter. 1-methyl-beta-oxopyrrole-2-propionanilide INN: 45 Suitable pharmacologically tolerable salts here are on the PRINOMIDE), 3-4-(2-hydroxyethyl)-1-piperazinyl-pro one hand in particular water-soluble and water-insoluble acid pyl-D.L-4-benzamido-N,N-dipropylglutaramat 1-(p-chlo addition salts with acids such as, for example, hydrochloric robenzoyl)-5-methoxy-2-methylindole-3-acetate (ester) acid, hydrobromic acid, phosphoric acid, nitric acid, Sulfuric INN: ), 7-methyl-1-(1-methylethyl)-4- acid, acetic acid, , D-gluconic acid, benzoic acid, phenyl-2(1H)quinazolinone (INN: ), 50 2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, Sulfosali 7-methoxy-alpha,10-dimethylphenothiazine-2-acetic acid cylic acid, , lauric acid, malic acid, , INN: PROTIZINIC ACID, 2-2-(p-chlorophenyl)-4-me Succinic acid, oxalic acid, tartaric acid, embonic acid, Stearic thyl-5-oxazolylmethoxy-2-methylpropionic acid INN: acid, toluenesulfonic acid, methanesulfonic acid or 1-hy ROMAZARITI, o-hydroxybenzamide ), droxy-2-naphthoic acid, the acids being employed in Salt 2-hydroxybenzoic acid SALICYLIC ACID, N-acetyl-L- 55 preparation—depending on whether it is a mono- or polyba salicylate (ester), acetate (ester) INN: SALM sic acid and depending on which salt is desired in an ISTEINE), N-acetyl-L-cysteine salicylate (ester) INN: equimolar quantitative ratio or one differing therefrom. Fur SALNACEDIN), 2-hydroxybenzoic acid 2-carboxyphenyl thermore, the active compounds mentioned can also be ester INN: , 4-1-(2-fluorobiphenyl-4-yl) present as pure enantiomers or as enantiomer mixtures in any ethyl-N-methylthiazole-2- Research Code: 60 mixing ratio. SM-8849, (Z)-5-fluoro-2-methyl-1-p-(methylsulfinyl)ben On the other hand, salts with bases are also suitable. Zylideneindene-3-acetic acid INN: ), p-2- Examples of salts with bases which may be mentioned are thenoylhydratropic acid INN: SUPROFEN2-(4-(3-methyl alkali metal (lithium, Sodium, potassium) or calcium, alumi 2-butenyl)phenyl)propionic acid Research Code: TA-60), num, magnesium, titanium, ammonium, meglumine or phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-toluidino)nico 65 guanidinium salts, where here too the bases are employed in tinate INN: TALNIFLUMATE), (Z)-5-chloro-3-(2- salt preparation in an equimolar quantitative ratio or one thenoyl)-2-oxoindole-1-carboxamide INN: ), differing therefrom. US 8,242,146 B2 7 8 Certain of the active ingredients used in the present inven methylpropyl)benzeneacetic acid INN: BUTIBUFEN), tion are capable of existing in Stereoisomeric forms. The 2-(4-biphenylyl)butyric acid, trans-4-phenylcyclohexy invention encompasses all stereoisomers of the active ingre lamine salt (1:1) (INN: BUTIXIRATE), 2-(acetyloxy)-ben dients and mixtures thereof including racemates. Tautomers Zoic acid, calcium salt, compound with urea (1:1) INN: and mixtures thereof of the active ingredients are also part of 5 ), (plus/minus)-6-chloro-al the present invention. pha-methylcarbazole-2-acetic acid (INN: CARPROFEN), In accordance with the present invention, there is provided 1-cinnamoyl-5-methoxy-2-methylindole-3-acetic acid INN: in a first aspect a pharmaceutical composition comprising, in CINMETACIN), N-(2-pyridyl)-2-methyl-4-cinnamoyloxy admixture, a first active ingredient which is a PDE4-inhibitor 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide INN: selected from CDC-998, SH-636, D-4396, IC-485, CC-1088 10 CINNOXICAM), 6-chloro-5-cyclohexyl-1-indancarboxylic and 3,5-dichloro-4-8-methoxy-2-(trifluoromethyl)cquino acid INN: CLIDANAC. 2-4-(p-chlorophenyl)benzyloxy line-5-ylcarboxamidolpyridine-1-oxide Research Code: 2-methylpropionic acid (INN: CLOBUZARITI, 5-methoxy SCH351591, 3-3-(cyclopentyloxy)-4-methoxybenzyl-6- 2-methyl-3-indolylacetohydroxamic acid INN: DEBOX (ethylamino)-8-isopropyl-3H-purine Research-Code: AMET, (S)-(+)-p-isobutylhydratropic acid INN: V-11294A. N-9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahy 15 DEXIBUPROFEN), (+)-(S)-m-benzoylhydratropic acid dropyrrolo3.2,1-jk]1,4)benzo-diazepin-3(R)-ylpyridine INN: DEXKETOPROFEN), 2-(2,6-dichlorophenyl) 4-carboxamide Research-Code: CI-1018, N-(3,5-dichloro aminobenzeneacetic acid INN: DICLOFENAC, 2',4'-Dif 4-pyridinyl)-2-1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3- luoro-4-hydroxy-3-biphenylcarboxylic acid INN: yl)-2-oxoacetamide Research-Code: AWD-12-281, N-(3.5- DIFLUNISAL), 4-(2,6-dichloroanilino)-3-thiopheneacetic dichloropyridin-4-yl)-2-5-fluoro-1-(4-fluorobenzyl)-1H acid INN: ELTENAC), N-beta-phenethyl-anthranilic acid indol-3-yl)-2-oxoacetamide Research-Code: AWD-12 INN: ENFENAMIC ACID salicylic acid acetate, ester with 343, 8-Amino-1,3-bis(cyclopropylmethyl)xanthine INN: beta-hydroxy p-acetophenetidide INN: ETERSALATE, CIPAMFYLLINE), Tetrahydro-5-4-methoxy-3-(S,2S,4R)- 1,8-diethyl-1,3,4,9-tetrahydropyrano3,4-bindole-1-acetic 2-norbornyloxyphenyl-2(1H)-pyrimidone INN: ATIZO acid (INN: ETODOLAC), 2-3-(trifluoromethyl)phenyl RAM, 3-3-(Cyclopentyloxy)-4-methoxyphenyl-1,3-dihy 25 aminobenzoic acid 2-(2-hydroxyethoxy)-ethyl ester INN: dro-1,3-dioxo-2H-isoindole-2-propanamide Research ), p-chlorobenzoic acid, ester with 4-butyl Code: CDC-801, Methanesulfonic acid 2-(2,4- 4-(hydroxymethyl)-1,2-diphenyl-3,5-pyrazolidinedione dichlorophenyl-carbonyl)-3-ureidobenzo-furan-6-yl ester INN: FECLOBUZONE, 4-biphenylacetic acid (INN: FEL INN: LIRIMILAST, N-(3,5-dichloropyrid-4-yl)-3-cyclo BINAC), 3-(4-biphenylylcarbonyl)propionic acid INN: pentyl-oxy-4-methoxybenzamide INN: PICLAMILAST). 30 . Io-(2,4-dichlorophenoxy)phenyl)acetic acid cis-4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-cy INN: FENCLOFENAC), (plus/minus)-m-phenoxyhydrat clohexane-1-carboxylic acid INN: CILOMILAST), 3-Cy ropic acid INN: FENOPROFEN), 4-(p-chlorophenyl)-2- clopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropy phenyl-5-thiazoleacetic acid INN: FENTIAZAC), (plus/mi rid-4-yl)-benzamide INN: ROFLUMILAST and their nus)-alpha-(2-hydroxy-1,1-dimethylethyl)aminomethyl pharmaceutically acceptable derivatives, and a second active 35 benzyl alcohol (INN: FEPRADINOL), 4-(2',4'- ingredient which is a conventional NSAID selected from difluorobiphenylyl)-4-oxo-2-methylbutanoic acid INN: glycolic acid o-(2,6-dichloroanilino)phenyl)acetate(ester) FLOBUFEN, N-(alpha,alpha,alpha-trifluoro-m-tolyl)an INN: ACECLOFENAC: 1-(4-chlorobenzoyl)-5-methoxy thranilic acid INN: ), (plus)-2-(p- 2-meth-yl-1H-indole-3-acetic acid carboxymethyl ester fluorophenyl)-alpha-methyl-5-benzoxazoleacetic acid INN: INN: ACEMETACIN: 2-(acetyloxy)benzoic acid ACE 40 FLUNOXAPROFEN), 2-fluoro-alpha-methyl-4-bipheny TYLSALICYLIC ACID, 2-methoxyphenyl-alpha-methyl lacetic acid INN: FLURBIPROFEN, (plus/minus)-2-(2- 4-(isobutyl)phenylacetate Research Code: AF-2259 (4-al fluoro-4-biphenylyl)propionic acid 1 (acetoxy)ethyl ester lyloxy-3-chlorophenyl)acetic acid INN: ALCLOFENAC), INN: FLURBIPROFEN AXETILI, 2-ethyl-2,3-dihydro-5- p-(2-methylallyl)aminohydratropic acid INN: ALMINO benzofuranacetic acid INN: FURCFENAC. 2-4-(2-fu PROFEN), 2-amino-3-benzoylphenylacetic acid INN: 45 royl)phenylpropionic acid (INN: FURPROFEN), 2-2-1- AMFENAC. (plus/minus)-4-(1-hydroxyethoxy)-2-methyl (p-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl) N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide ethylcar acetamido)-2-deoxy-D-glucose INN: GLUCAMETACIN). bonate (ester), 1,1-dioxide INN: AMPIROXICAM), 2-(2-fluorobiphenyl-4-yl)propionic acid 4-nitrooxybuty 2-methoxyphenyl-1-methyl-5-(p-methylbenzoyl)pyrrol-2- lester Research Code: HCT-1026, (p-isobutylphenyl)acetic acetamido-acetate (INN: AMTOLMETINGUACIL), (plus/ 50 acid INN: IBUFENAC), alpha-p-isobutylphenylpropionic minus)-2,3-dihydro-5-(4-methoxybenzoyl)-1H pyrrolizine acid INN: IBUPROFEN), methyl 4-(3-thienyl)phenyl-al 1-carboxylic acid INN: ANIROLAC. 2-4-(alpha,alpha, pha-methylacetate Research Code: IDPH-8261), (plus/mi alpha-trifluoro-m-tolyl)-1-piperazinyl-ethyl-N-(7- nus)-2-p-(1-oxo-2-isoindolinyl)phenylbutyric acid INN: trifluoromethyl-4-quinolyl)anthranilate INN: INDOBUFEN), 1-(4-chlorobenzoyl)-5-methoxy-2-methyl ANTRAFENINE), 5-(dimethylamino)-9-methyl-2-propyl 55 1H-indole-3-acetic acid (INN: INDOMETACIN), 1-(4-chlo 1H-pyrazolo 12-a 1,2,4-benzo-triazine-1,3(2H)-dione robenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, INN: AZAPROPAZONE, 4-acetamido-phenyl salicylate 3.7.11-trimethyl-2,6,10-dodecatrienyl ester INN: acetate INN: BENORILATE), 2-(8-methyl-10,11-dihydro INDOMETACIN. FARNESIL), p-(1-oxo-2-isoindolinyl)hy 11-oxodibenzb.foxepin-2-yl)propionic acid INN: BER dratropic acid INN: INDOPROFEN), 2-(10-methoxy-4H MOPROFEN), 2-(1-benzyl-1H-indazol-3-yl)methoxy-2- 60 benzo 4.5 cyclohepta 1.2-bithiophen-4-ylidene)-acetic acid methylpropionic acid INN: BINDARITI, 2-amino-3-(p- Research Code: IX-207-887, m-benzoyl-hydratropic acid bromobenzoyl)phenyl)acetic acid (INN: BROMFENAC), INN: KETOPROFEN), (DL)-5-benzoyl-3H-1,2-dihydropy 3-(3-chloro-4-cyclohexylbenzoyl)propionic acid INN: rrolo 1,2-alpyrrole-1-carboxylic acid INN: KETOROLAC), BUCLOXIC ACID), 5-butyl-1-cyclohexylbarbituric acid 2,3-dihydro-5-hydroxy-6-2-(hydroxymethyl)cinnamyl INN: BUCOLOM),4-butoxy-N-hydroxybenzeneacetamide 65 benzofuran Research Code: L-651896, N-(2-carboxyphe INN: BUFEXAMAC, butylmalonic acid mono (1,2-diphe nyl)-4-chloroanthranilic acid INN: LOBENZARIT), 3-(p- nylhydrazide) INN: BUMADIZONE), alpha-ethyl-4-(2- chlorophenyl)-1-phenylpyrazole-4-acetic acid INN: US 8,242,146 B2 9 10 LONAZOLAC), 6-chloro-4-hydroxy-2-methyl-N-2-py benzene acetato-O-aluminium Research Code: U-18573 ridyl-2H-thieno2,3-e-1,2-thiazine-3-carboxamide 1,1-di G. N-(3-trifluoromethylphenyl)-anthranilic acid n-butyl oxide INN: LORNOXICAM), 2-4-(2-oxocyclopentan-1- ester INN: UFENAMATE), 2-4-3-(hydroxyimino)cyclo ylmethyl)phenyl-propionate INN: LOXOPROFEN), 2(R)- hexylphenylpropionic acid (INN; XIMOPROFEN), 2-(10, 4-(3-methyl-2-thienyl)phenylpropionic acid Research 5 11-dihydro-10-oxo-dibenzb.fthiepin-2-yl-propionic acid Code: M-5010, N-(2,3-xylyl)anthranilic acid (INN: MEFE INN: ZALTOPROFEN), 2-4-(2-thiazolyloxy)phenyl-pro NAMIC ACID, 4-hydroxy-2-methyl-N-(5-methyl-2-thiaz pionic acid INN: ZOLIPROFEN and their pharmaceuti olyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide cally acceptable derivatives. INN: MELOXICAM), 5-aminosalicylic acid (INN: In a second aspect—which is an embodiment of the first MESALAZINE, (2,2-dimethyl-6-(4-chlorophenyl)-7-phe 10 aspect—there is provided a pharmaceutical composition nyl-2,3-dihydro-1H-pyrrolizin-5-yl)-acetic acid Research comprising, in admixture, a first active ingredient which is a Code: ML-3000, 3,4-bis(4-methoxyphenyl)-5-isox PDE4-inhibitor selected from cis-4-Cyano-4-(3-cyclopen azoleacetic acid INN: MOFEZOLAC, 4-(6-methoxy-2- tyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid naphthyl)-2-butanone INN: NABUMETONE, (plus)-6- INN: CILOMILAST), 3-Cyclopropylmethoxy-4-difluo methoxy-alpha-methyl-2-naphthalineacetic acid INN: 15 romethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide INN: NAPROXEN), 2-3-(trifluoromethyl)anilinonicotinic acid ROFLUMILAST and their pharmaceutically acceptable INN: NIFLUMIC ACID), 5,5'-azodisalicylic acid (INN: derivatives, and a second active ingredient which is a conven OLSALAZINE, alpha-methyl-4-(2-oxocyclohexylidene) tional NSAID selected from 2-(acetyloxy)benzoic acid methylbenzene acetic acid INN: PELUBIPROFEN), 2-(p- ACETYLSALICYLIC ACID, 2-(2,6-di-chlorophenyl) isobutylphenyl)propionic acid 2-pyridyl-methyl ester INN: aminobenzeneacetic acid INN: DICLOFENAC), alpha-p- PIMEPROFEN), 4-(p-chlorophenyl)-1-(p-fluorophenyl) isobutylphenylpropionic acid INN: IBUPROFEN.), 1-(4- pyrazole-3-acetic acid INN: PIRAZOLAC, 4-hydroxy-2'- chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide acid (INN: INDOMETACIN), (plus)-6-methoxy-alpha-me 1,1-dioxide INN: PIROXICAM), 3-chloro-4-(3-pyrrolin-1- thyl-2-naphthalineacetic acid INN: NAPROXEN), 4-hy yl)hydratropic acid INN: PIRPROFEN), 2-5H-(1)benzopy 25 droxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-car rano 2,3-bipyridin-7-yl)propionic acid INN: PRANOPRO boxamide 1,1-dioxide INN: PIROXICAM and their FEN), 2,6-di-tert-butyl-4-(2'-thenoyl)phenol INN: pharmaceutically acceptable derivatives. PRIFELONE, alpha-cyano-1-methyl-beta-oxopyrrole-2- In a third aspect—which is another embodiment of the first propionanilide INN: PRINOMIDE), 3-4-(2-hydroxyethyl)- aspect—there is provided a pharmaceutical composition 1-piperazinyl-propyl-D.L-4-benzamido-N,N-dipropylglut 30 comprising, in admixture, a first active ingredient which aramat 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3- selected from 3-Cyclopropylmethoxy-4-difluoromethoxy acetate (ester) (INN: PROGLUMETACIN), 7-methyl-1-(1- N-(3,5-dichloropyrid-4-yl)-benzamide INN: ROFLUMI methylethyl)-4-phenyl-2(1H)quinazolinone INN: LAST and its Pharmaceutically acceptable derivatives, and a PROQUAZONE), 7-methoxy-alpha,10-dimethylphenothi second active ingredient which is selected from 2-(2,6- azine-2-acetic acid (INN: PROTIZINIC ACID, 2-2-(p- 35 dichlorophenyl)aminobenzeneacetic acid INN: chlorophenyl)-4-methyl-5-oxazolylmethoxy-2-methylpro DICLOFENAC and its pharmaceutically acceptable deriva pionic acid INN: ROMAZARIT, o-hydroxybenzamide tives. SALICYLAMIDE), 2-hydroxy-1-benzoic acid SALI In a forth aspect the invention provides a pharmaceutical CYLIC ACID, N-acetyl-L-cysteine salicylate (ester), acetate product comprising, in combination, a preparation of a first (ester) INN: SALMISTEINE), N-acetyl-L-cysteine salicy 40 active ingredient which is a PDE4-inhibitor selected from late (ester) INN: SALNACEDIN), 2-hydroxybenzoic acid CDC-998, SH-636, D-4396, IC-485, CC-1088 and 3,5- 2-carboxyphenyl ester INN: SALSALATE, 4-1-(2-fluoro dichloro-4-8-methoxy-2-(trifluoromethyl)cquinoline-5-yl -4-yl)ethyl-N-methylthiazole-2-amine Research carboxamidopyridine-1-oxide Research Code: Code: SM-8849, (Z)-5-fluoro-2-methyl-1-p-(methylsulfi SCH351591, 3-3-(cyclopentyloxy)-4-methoxybenzyl-6- nyl)benzylideneindene-3-acetic acid INN: SULINDAC), 45 (ethylamino)-8-isopropyl-3H-purine Research-Code: p-2-thenoylhydratropic acid INN: 2-(4-(3- V-11294A. N-9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahy methyl-2-butenyl)phenyl)-propionic acid Research Code: dropyrrolo3.2,1-jk]1,4-benzo-diazepin-3(R)-ylpyridine TA-60), phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-tolui 4-carboxamide Research-Code: CI-1018, N-(3,5-dichloro dino)nicotinate (INN: TALNIFLUMATE), (Z)-5-chloro-3- 4-pyridinyl)-2-1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3- (2-thenoyl)-2-oxoindole-1-carboxamide INN: TENIDAP. 50 yl)-2-oxoacetamide Research-Code: AWD-12-281, N-(3.5- 2-thiophenecarboxylic acid, ester with salicylic acid INN: dichloropyridin-4-yl)-2-5-fluoro-1-(4-fluorobenzyl)-1H TENOSAL), 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno2. indol-3-yl)-2-oxoacetamide Research-Code: AWD-12 3-e-1,2-thiazine-3-carboxamide INN: TENOXICAM, 343, 8-Amino-1,3-bis(cyclopropylmethyl)xanthine INN: 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N- CIPAMFYLLINE), Tetrahydro-5-4-methoxy-3-(1S,2S, methyl-1H-pyrazole-3-propionamide INN: ), 55 4R)-2-norbornyloxyphenyl-2(1H)-pyrimidone INN: ATI alpha-(5-benzoyl-2-thienyl)propionic acid INN: TIAPRO ZORAM. B-3-(Cyclopentyloxy)-4-methoxyphenyl-1,3- FENIC ACID, 5-chloro-3-4-(2-hydroxyethyl)-1-piperazi dihydro-1,3-dioxo-2H-isoindole-2-propanamide Research nylcarbonyl-methyl-2-benzo-thiazolin one INN: TIARA Code: CDC-801, Methanesulfonic acid 2-(2,4- MIDE), 2-(2-methyl-5H-1 benzopyrano 2,3-bipyridin-7- dichlorophenylcarbonyl)-3-ureidobenzo-furan-6-yl ester yl)-propionic acid N.N-dimethylcarbamoylmethyl ester 60 INN: LIRIMILAST, N-(3,5-dichloropyrid-4-yl)-3-cyclo INN: TILNOPROFEN ARBAMEL), 1-Cyclohexyl-2-(2- pentyloxy-4-methoxybenzamide INN: PICLAMILAST. methyl-4-quinolyl)-3-(2-thiazolyl)guanidine INN: TIM cis-4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclo EGADINE, 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno2. hexane-1-carboxylic acid (INN: CILOMILAST), 3-Cyclo 3-clpyridine INN: TINORIDINE, N-(3-chloro-o-tolyl) propylmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4- anthranilic acid INN: TOLFENAMIC ACID), 1-methyl-5- 65 yl)-benzamide INN: ROFLUMILAST and their (4-methylbenzoyl)-1H-pyrrole-2-acetic acid INN: pharmaceutically acceptable derivatives, and a preparation of TOLMETIN), hydroxybisalpha-methyl-4-(2-methylpropyl) a second active ingredient which is a conventional NSAID

US 8,242,146 B2 13 14 INN: PROTIZINIC ACID, 2-2-(p-chlorophenyl)-4-me difluoromethoxy-N-(3,5-dichloropyrid-4-yl)-benzamide thyl-5-oxazolylmethoxy-2-methylpropionic acid INN: INN: ROFLUMILAST and its pharmaceutically acceptable ROMAZARITI, o-hydroxybenzamide SALICYLAMIDE), derivatives, and a preparation of a second active ingredient 2-hydroxybenzoic acid SALICYLIC ACID, N-acetyl-L- which is selected from 2-(2,6-dichlorophenyl)aminobenze cysteine salicylate (ester); acetate (ester) INN: SALM neacetic acid INN: DICLOFENAC and its pharmaceuti ISTEINE), N-acetyl-L-cysteine salicylate (ester) INN: cally acceptable derivatives, for simultaneous, sequential or SALNACEDIN), 2-hydroxybenzoic acid 2-carboxyphenyl separate use in therapy. ester INN: SALSALATE, 4-1-(2-fluorobiphenyl-4-yl) In a seventh aspect, the invention provides a kit comprising ethyl-N-methylthiazole-2-amine Research Code: a preparation of a first active ingredient which is a PDE4 SM-8849, (Z)-5-fluoro-2-methyl-1-p-(methylsulfinyl)ben 10 inhibitor selected from CDC-998, SH-636, D-4396, IC-485, Zylideneindene-3-acetic acid INN: SULINDAC), p-2- CC-1088 and 3,5-dichloro-4-8-methoxy-2-(trifluorom thenoylhydratropic acid INN: SUPROFEN2-(4-(3-methyl ethyl)cquinoline-5-ylcarboxamidolpyridine-1-oxide Re 2-butenyl)phenyl)propionic acid Research Code: TA-60), search Code: SCH351591, 3-3-(cyclopentyloxy)-4-meth phthalidyl 2-(alpha,alpha,alpha-trifluoro-m-toluidino)nico oxybenzyl-6-(ethylamino)-8-isopropyl-3H-purine tinate INN: TALNIFLUMATE), (Z)-5-chloro-3-(2- 15 Research-Code: V-11294A. N-9-methyl-4-oxo-1-phenyl thenoyl)-2-oxoinidole-1-carboxamide INN: TENIDAP), 3,4,6,7-tetrahydropyrrolo3.2,1-jk]1,4)benzodiazepin-3 2-thiophenecarboxylic acid, ester with salicylic acid INN: (R)-ylpyridine-4-carboxamide Research-Code: CI-1018, TENOSAL), 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno2. N-(3,5-dichloro-4-pyridinyl)-2-1-(4-fluorobenzyl)-5-hy 3-e-1,2-thiazine-3-carboxamide INN: TENOXICAM, droxy-1H-indol-3-yl)-2-oxoacetamide Research-Code: 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N- AWD-12-281, N-(3,5-di-chloropyridin-4-yl)-2-5-fluoro-1- methyl-1H-pyrazole-3-propionamide INN: TEPOXALIN), (4-fluorobenzyl)-1H-indol-3-yl)-2-oxoacetamide Research alpha-(5-benzoyl-2-thienyl)propionic acid INN: TIAPRO Code: AWD-12-343, 8-Amino-1,3-bis(cyclopropylmethyl) FENIC ACID, 5-chloro-3-4-(2-hydroxyethyl)-1-piperazi Xanthine INN: CIPAMFYLLINE), Tetrahydro-5-4- nylcarbonylmethyl-2-benzo-thiazolin one INN: TIARA methoxy-3-(1S,2S.4R)-2-norbornyloxyphenyl-2(1H)- MIDE), 2-(2-methyl-5H-1 benzopyrano 2,3-bipyridin-7- 25 pyrimidone INN: ATIZORAM, B-3-(Cyclopentyloxy)-4- yl)-propionic acid N.N-dimethylcarbamoylmethyl ester methoxyphenyl-1,3-dihydro-1,3-dioxo-2H-isoindole-2- INN: TILNOPROFEN ARBAMEL), 1-Cyclohexyl-2-(2- propanamide Research-Code: CDC-801, Methanesulfonic methyl-4-quinolyl)-3-(2-thiazolyl)guanidine INN: TIM acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan EGADINE, 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno2. 6-yl ester INN: LIRIMILAST, N-(3,5-dichloropyrid-4-yl)- 3-clpyridine INN: TINORIDINE, N-(3-chloro-o-tolyl) 30 3-cyclopentyloxy-4-methoxybenzamide INN: PICLAMI anthranilic acid INN: TOLFENAMIC ACID), 1-methyl-5- LAST, cis-4-Cyano-4-(3-cyclopentyloxy-4- (4-methylbenzoyl)-1H-pyrrole-2-acetic acid |INN: methoxyphenyl)cyclohexane-1-carboxylic acid INN: TOLMETIN), hydroxybisalpha-methyl-4-(2-methylpropyl) CILOMILAST), 3-Cyclopropylethoxy-4-difluoromethoxy benzene acetato-O-aluminium Research Code: U-18573 N-(3,5-dichloropyrid-4-yl)-benzamide INN: ROFLUMI G., N-(3-trifluoromethylphenyl)-anthranilic acid n-butyl 35 LAST and their pharmaceutically acceptable derivatives, a ester INN: UFENAMATE), 2-4-3-(hydroxyimino)cyclo preparation of a second active ingredient which is a conven hexylphenylpropionic acid (INN; XIMOPROFEN), 2-(10, tional NSAID selected from glycolic acido-(2,6-dichloroa 11-dihydro-10-oxo-dibenzb.fthiepin-2-yl-propionic acid nilino)phenyl)acetate(ester) INN: ACECLOFENAC: 1-(4- INN: ZALTOPROFEN), 2-4-(2-thiazolyloxy)phenyl-pro chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic pionic acid INN: ZOLIPROFEN and their pharmaceuti 40 acid carboxymethyl ester INN: ACEMETACIN: 2-(acety cally acceptable derivatives, for simultaneous, sequential or loxy)benzoic acid (ACETYLSALICYLIC ACID, 2-meth separate use in therapy. oxyphenyl-alpha-methyl-4-(isobutyl)phenylacetate Re In a fifth aspect which is an embodiment of the forth search Code: AF-2259 (4-allyloxy-3-chlorophenyl)acetic aspect—the invention provides a pharmaceutical product acid INN: ALCLOFENAC), p-(2-methylallyl)aminohy comprising, in combination, a preparation of a first active 45 dratropic acid INN: ALMINOPROFEN), 2-amino-3-ben ingredient which is a PDE4-inhibitor selected from cis-4- Zoylphenylacetic acid INN: AMFENAC. (plus/minus)-4- Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex (1-hydroxyethoxy)-2-methyl-N-2-pyridyl-2H-1,2- ane-1-carboxylic acid INN: CILOMILAST, 3-Cyclopropy benzothiazine-3-carboxamide ethylcarbonate (ester), 1,1- lmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)- dioxide INN: AMPIROXICAM), 2-methoxyphenyl-1- benzamide INN: ROFLUMILAST and their 50 methyl-5-(p-methylbenzoyl)pyrrol-2-acetamido-acetate pharmaceutically acceptable derivatives, and a preparation of INN: AMTOLMETINGUACIL), (plus/minus)-2,3-dihy a second active ingredient which is a conventional NSAID dro-5-(4-methoxybenzoyl)-1H pyrrolizine-1-carboxylic acid selected from 2-(acetyloxy)benzoic acid (ACETYLSALI INN: ANIROLAC. 2-4-(alpha,alpha,alpha-trifluoro-m- CYLIC ACID, 2-(2,6-dichlorophenyl)aminobenzeneace tolyl)-1-piperazinylethyl-N-(7-trifluoromethyl-4-quinolyl) tic acid INN: DICLOFENAC, alpha-p-isobutylphenylpro 55 anthranilate INN: ANTRAFENINE), 5-(dimethylamino)-9- pionic acid INN: IBUPROFEN.), 1-(4-chlorobenzoyl)-5- methyl-2-propyl-1H-pyrazolo 12-a 1.2.4benzo-triazine methoxy-2-methyl-1H-indole-3-acetic acid INN: 1.3(2H)-dione INN: AZAPROPAZONE), INDOMETACIN), (plus)-6-methoxy-alpha-methyl-2-naph 4-acetamidophenyl salicylate acetate INN: BENORILATE, thalineacetic acid (INN: NAPROXEN), 4-hydroxy-2-me 2-(8-methyl-10,11-dihydro-11-oxodibenzb.foxepin-2-yl) thyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide 60 propionic acid (INN: BERMOPROFEN), 2-(1-benzyl-1H 1,1-dioxide INN: PIROXICAM) and their pharmaceutically indazol-3-yl)methoxy-2-methylpropionic acid INN: BIN acceptable derivatives, for simultaneous, sequential or sepa DARIT), 2-amino-3-(p-bromobenzoyl)phenyl)acetic acid rate use in therapy. INN: BROMFENAC), 3-(3-chloro-4-cyclohexylbenzoyl) In a sixth aspect—which is another embodiment of the propionic acid (INN: BUCLOXIC ACID), 5-butyl-1-cyclo forth aspect—the invention provides a pharmaceutical prod 65 hexylbarbituric acid (INN: BUCOLOM), 4-butoxy-N-hy uct comprising, in combination, a preparation of a first active droxybenzeneacetamide INN: BUFEXAMAC); ingredient which is selected from 3-Cyclopropylmethoxy-4- butylmalonic acid mono (1,2-diphenylhydrazide) INN:

US 8,242,146 B2 17 18 TOLMETIN), hydroxybisalpha-methyl-4-(2-methylpropyl) Therefore, in a tenth aspect of the present invention, there benzene acetato-O-aluminium Research Code: U-18573 is provided a process for the preparation of a pharmaceutical G., N-(3-trifluoromethylphenyl)-anthranilic acid n-butyl composition which comprises mixing a first active ingredient ester INN: UFENAMATE), 2-4-3-(hydroxyimino)cyclo which is a PDE4-inhibitor selected from CDC-998, SH-636, hexyl-phenylpropionic acid (INN:XIMOPROFEN), 2-(10, D-4396, IC-485, CC-1088 and 3,5-dichloro-4-8-methoxy 11-dihydro-10-oxo-dibenzb.fthiopin-2-yl-propionic acid 2-(trifluoromethyl)cquinoline-5-ylcarboxamidolpyridine-1- INN: ZALTOPROFEN), 2-4-(2-thiazolyloxy)phenyl-pro oxide Research Code: SCH351591, 3-3-(cyclopentyloxy)- pionic acid INN: ZOLIPROFEN and their pharmaceuti 4-methoxybenzyl-6-(ethylamino)-8-isopropyl-3H-purine cally acceptable derivatives, and instructions for the simulta Research-Code: V-11294A. N-9-methyl-4-oxo-1-phenyl 10 3,4,6,7-tetrahydropyrrolo3.2,1-jk]1,4)benzo-diazepin-3 neous, sequential or separate administration of the (R)-ylpyridine-4-carboxamide Research-Code: CI-1018, preparations to a patient in need thereof. N-(3,5-dichloro-4-pyridinyl)-2-1-(4-fluorobenzyl)-5-hy Ina eighth aspect—which is an embodiment of the seventh droxy-1H-indol-3-yl)-2-oxoacetamide Research-Code: aspect—the invention provides a kit comprising a preparation AWD-12-281, N-(3,5-dichloropyridin-4-yl)-2-5-fluoro-1- of a first active ingredient which is a PDE4-inhibitor selected 15 (4-fluorobenzyl)-1H-indol-3-yl)-2-oxoacetamide Research from cis-4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) Code: AWD-12-343, 8-Amino-1,3-bis(cyclopropylmethyl) cyclohexane-1-carboxylic acid INN: CILOMILAST, 3-Cy Xanthine INN: CIPAMFYLLINE), Tetrahydro-5-4- clopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropy methoxy-3-(1S,2S.4R)-2-norbornyloxyphenyl-2(1H)- rid-4-yl)-benzamide INN: ROFLUMILAST and their pyrimidone INN: ATIZORAM, B-3-(Cyclopentyloxy)-4- pharmaceutically acceptable derivatives, a preparation of a methoxyphenyl-1,3-dihydro-1,3-dioxo-2H-isoindole-2- second active ingredient which is conventional NSAID propanamide Research-Code: CDC-801, Methanesulfonic selected from 2-(acetyloxy)benzoic acid (ACETYLSALI acid 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzo-furan CYLIC ACID, 2-(2,6-dichlorophenyl)aminobenzeneace 6-yl ester INN: LIRIMILAST, N-(3,5-dichloropyrid-4-yl)- tic acid INN: DICLOFENAC, alpha-p-isobutylphenylpro 3-cyclopentyloxy-4-methoxybenzamide INN: PICLAMI pionic acid INN: IBUPROFEN.), 1-(4-chlorobenzoyl)-5- 25 LAST, cis-4-Cyano-4-(3-cyclopentyloxy-4-methoxy methoxy-2-methyl-1H-indole-3-acetic acid INN: phenyl)cyclohexane-1-carboxylic acid INN: CILOMI INDOMETACIN), (plus)-6-methoxy-alpha-methyl-2-naph LAST, 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3.5- thalineacetic acid (INN: NAPROXEN), 4-hydroxy-2-me dichloropyrid-4-yl)-benzamide INN: ROFLUMILAST and thyl-N-2-pyridyl-2H-1,2-benzothiadiazin-3-carboxamide their pharmaceutically acceptable derivatives, with a second 1,1-dioxide INN: PIROXICAM) and their pharmaceutically 30 active ingredient which is a conventional NSAID selected acceptable derivatives, and instructions for the simultaneous, from glycolic acid o-(2,6-dichloroanilino)phenyl)acetate sequential or separate administration of the preparations to a (ester) INN: ACECLOFENAC: 1-(4-chlorobenzoyl)-5- patient in need thereof. methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl In a ninth aspect—which is another embodiment of the ester INN: ACEMETACIN: 2-(acetyloxy)benzoic acid seventh aspect—the invention provides a kit comprising a 35 ACETYLSALICYLIC ACID, 2-methoxyphenyl-alpha preparation of a first active ingredient which is selected from methyl-4-(isobutyl)phenylacetate Research Code: 3-Cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichlo AF-2259 (4-allyloxy-3-chlorophenyl)acetic acid INN: ropyrid-4-yl)-benzamide INN: ROFLUMILAST and its ALCLOFENAC), p-(2-methylallyl)amino-hydratropic pharmaceutically acceptable derivatives, a preparation of a acid INN: ALMINOPROFEN), 2-amino-3-benzoylpheny second active ingredient which is selected from 2-(2,6- 40 lacetic acid INN: AMFENAC), (plus/minus)-4-(1-hydroxy dichlorophenyl)aminobenzeneacetic acid INN: ethoxy)-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-car DICLOFENAC and its pharmaceutically acceptable deriva boxamide ethylcarbonate (ester), 1,1-dioxide INN: tives, and instructions for the simultaneous, sequential or AMPIROXICAM), 2-methoxyphenyl-1-methyl-5-(p-meth separate administration of the preparations to a patient in ylbenzoyl)pyrrol-2-acetamido-acetate INN: AMTOL need thereof. 45 METINGUACIL); (plus/minus)-2,3-dihydro-5-(4-methoxy It has been found that the choice of active ingredients benzoyl)-1H pyrrolizine-1-carboxylic acid INN: according to the invention is advantageous because it results ANIROLAC. 2-4-(alpha,alpha,alpha-trifluoro-m-tolyl)-1- in a beneficial antiinflammatory effect while simultaneously piperazinylethyl-N-(7-trifluoromethyl-4-quinolyl)anthra minimizing gastrointestinal side effects which are inevitably nilate INN: ANTRAFENINE), 5-(dimethylamino)-9-me associated with the use of the conventional NSAIDs. 50 thyl-2-propyl-1H-pyrazolo 1,2-a 1.2.4 benzo-triazine-1,3 The pharmaceutical composition of the present invention (2H)-dione INN: AZAPROPAZONE, 4-acetamidophenyl may be prepared by mixing the first active ingredient with the salicylate acetate (INN: BENORILATE), 2-(8-methyl-10,11 second active ingredient. dihydro-11-oxodibenzb.foxepin-2-yl)propionic acid INN: In the above-mentioned mixing process the first active BERMOPROFEN), 2-(1-benzyl-1H-indazol-3-yl)meth ingredient and the second active ingredient can 55 oxy-2-methylpropionic acid INN: BINDARITI, 2-amino a) in a first step be mixed as such, afterwards be processed 3-(p-bromobenzoyl)phenyl)acetic acid INN: BRO with pharmaceutically acceptable auxiliaries and/or MFENAC), 3-(3-chloro-4-cyclohexylbenzoyl)propionic excipients and finally pressed to tablets or caplets or acid INN: BUCLOXIC ACID), 5-butyl-1-cyclohexylbarbi b) in a first step separately be processed with pharmaceuti turic acid INN: BUCOLOM),4-butoxy-N-hydroxybenzene cally acceptable auxiliaries and/or excipients to give gran 60 acetamide INN: BUFEXAMAC, butylmalonic acid mono ules or pellets containing each only one of the two active (1,2-diphenylhydrazide) INN: BUMADIZONE), alpha ingredients; the pellets or granules for their part then can be ethyl-4-(2-methylpropyl)benzeneacetic acid INN: mixed in an appropriate ratio and either be pressed—op BUTIBUFEN), 2-(4-biphenylyl)butyric acid, trans-4-phe tionally with further pharmaceutically acceptable auxilia nylcyclohexylamine salt (1:1) (INN: BUTIXIRATE), ries and/or excipients—to give for example, tablets or 65 2-(acetyloxy)-benzoic acid, calcium salt, compound with caplets, or can be filled in more or less loose form in urea (1:1) (INN: CARBASALATE CALCIUM), (plus/mi capsules. nus)-6-chloro-alpha-methylcarbazole-2-acetic acid INN:

US 8,242,146 B2 21 22 INN: ZALTOPROFEN), 2-4-(2-thiazolyloxy)phenyl-pro said methods include a pharmaceutical product or kit contain pionic acid INN: ZOLIPROFEN and their pharmaceuti ing a PDE4 inhibitor and a written description which dis cally acceptable derivatives. closes that said PDE4 inhibitor can be administered together In an eleventh aspect—which is an embodiment of the with a conventional NSAID (a) for the treatment of an inflam tenth aspect—there is provided a process for the preparation matory disease and/or an inflammation associated disorder of a pharmaceutical composition which comprises mixing a while minimizing gastrointestinal side effects or (b) for the first active ingredient which is a PDE4-inhibitor selected attenuation of gastrointestinal side effects frequently associ from cis-4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) ated with the use of conventional NSAIDs. cyclohexane-1-carboxylic acid INN: CILOMILAST, 3-Cy “Inflammatory diseases” which may be mentioned in par clopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloropy 10 rid-4-yl)-benzamide INN: ROFLUMILAST and their ticular are arthritis, including but not limited to rheumatoid pharmaceutically acceptable derivatives, with a second active arthritis, , systemic lupus erythematosus and ingredient which is a conventional NSAID selected from juvenile arthritis; gastrointestinal conditions such as inflam 2-(acetyloxy)benzoic acid (ACETYLSALICYLIC ACID), matory bowel disease, Crohn's disease, irritable bowel syn 2-(2,6-dichlorophenyl)aminobenzeneacetic acid INN: 15 drome and ulcerative colitis; asthma, bronchitis and skin DICLOFENAC), alpha-p-isobutylphenylpropionic acid related disorders such as psoriasis, eczema, burns and derma INN: IBUPROFEN, 1-(4-chlorobenzoyl)-5-methoxy-2- titis. methyl-1H-indole-3-acetic acid (INN: INDOMETACIN), “Inflammation associated disorders” which may be men (plus)-6-methoxy-alpha-methyl-2-naphthalineacetic acid tioned are, for example, pain, migraine, fever and . INN: NAPROXEN), 4-hydroxy-2-methyl-N-2-pyridyl-2H The active ingredients may, and indeed will, as part of the 1,2-benzothiadiazin-3-carboxamide 1,1-dioxide INN: pharmaceutical composition, the pharmaceutical product or PIROXICAM and their pharmaceutically acceptable deriva preparation, be used in admixture with one or more pharma tives. ceutically acceptable auxiliaries and/or excipients. In an twelfth aspect—which is another embodiment of the The person skilled in the art is familiar on the basis of tenth aspect—there is provided a process for the preparation 25 his/her expert knowledge with which excipients or auxiliaries of a pharmaceutical composition which comprises mixing a are Suitable for the desired pharmaceutical composition, first active ingredient which is selected from 3-Cyclopropy product or preparation. In addition to Solvents, gel-forming lmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)- agents, tablet excipients and other active compound carriers, benzamide INN: ROFLUMILAST and its pharmaceuti it is possible to use, for example, antioxidants, dispersants, cally acceptable derivatives, with a second active ingredient 30 emulsifiers, antifoams, flavor corrigents, preservatives, solu which is selected from 2-(2,6-dichlorophenyl)aminobenze bilizers, colorants or permeation promoters and complexing neacetic acid INN: DICLOFENAC and its pharmaceuti agents (e.g. cyclodextrins). cally acceptable derivatives. Within the meaning of the present invention, “combined The present invention further provides the use of a phar use' is preferably understood as meaning the oral adminis maceutical composition, or pharmaceutical product accord 35 tration of both active ingredients. Further methods of admin ing to the invention in the manufacture of a medicament for istration, which may be mentioned are the parenteral (for the treatment of an inflammatory disease and/or an inflam example intravenous injection or infusion or intramuscular or mation associated disorder. intraarticular injection) and the topical administration of the In a further aspect the present invention provides a method active ingredients. of an effective treatment of an inflammatory disease and/oran 40 For oral administration the pharmaceutical compositions inflammation associated disorder which can be treated with a or products according to the invention are preferably in the conventional NSAID while minimizing gastrointestinal side form of tablets, coated tablets, chewing tablets, lemonade effects comprising the simultaneous, sequential or separate tablets, dragees, capsules, caplets, suppositories, emulsions, administration of i) a first amount of a conventional NSAID or (sterile parenteral) Suspensions or solutions, the active ingre a pharmaceutically acceptable derivative thereof, and ii) a 45 dient content advantageously being between 0.1 and 95% and second amount of a PDE4 inhibitor or a pharmaceutically by appropriate choice of the excipients and the auxiliaries, it acceptable derivative thereof, wherein the sum of the first and being possible to achieve a pharmaceutical administration the second amount is a therapeutically effective amount, to a form precisely tailored to the active ingredient(s) and/or to the patient in need thereof. desired onset of action (e.g. a Sustained release form or an In a still further aspect the present invention provides a 50 enteric form). method of minimizing gastrointestinal side effects frequently For the treatment of diseases of the arthritic type or skin associated with the use of conventional NSAIDs comprising related disorders, the compounds according to the invention the simultaneous, sequential or separate administration of i) a also can be used in form of pharmaceutical compositions or first amount of a conventional NSAID or a pharmaceutically products which are suitable for topical application. For the acceptable derivative thereof, and ii) a second amount of a 55 production of those pharmaceutical compositions or prod PDE4 inhibitor or a pharmaceutically acceptable derivative ucts, the compounds according to the invention (active thereof, wherein the sum of the first and the second amount is ingredients) are preferably mixed with suitable pharmaceuti a therapeutically effective amount, to a patient in need cal excipients and further processed to give Suitable pharma thereof. ceutical formulations. Suitable pharmaceutical formulations Said methods also include a pharmaceutical product or kit 60 which may be mentioned in this connection are, for example, containing a conventional NSAID and a written description ointments, fatty ointments, creams, pastes or gels. The phar which discloses that said conventional NSAID can be admin maceutical compositions or products for topical application istered together with a PDE4 inhibitor (a) for the treatment of can preferably also be in form of a patch (e.g. as TTS). an inflammatory disease and/or an inflammation associated For the above-mentioned therapeutic uses the dosages disorder while minimizing gastrointestinal side effects or (b) 65 administered will, of course, vary with the first and second for the attenuation of gastrointestinal side effects frequently active ingredients employed, the mode of administration, the associated with the use of conventional NSAIDs. Likewise, treatment desired and the disorder indicated. US 8,242,146 B2 23 24 However, in general, satisfactory results will be obtained from 1-100 mg/kg p.o. Preventive treatment: Diclofenac was when the total daily dosage of first active ingredient(s), the given at time point 0h. At time points -24, -16. Oh, +7 hone PDE4 inhibitor(s), when taken oral is in the range from of the selective PDE4 inhibitors was administered. Curative 1-2000 ug/kg of body weight. In the case of the especially treatment: Diclofenac was given at time point 0 h. At time preferred PDE4 inhibitor ROFLUMILAST, the daily dosage 5 points +1 hand +7 hone of the selective PDE4 inhibitors was is in a range from 2-20 ug/kg of body weight. administered. The drugs used were dissolved in 4% aqueous The total daily dosage of the second active ingredient(s), methyl cellulose. The animals were food reduced 24 h prior the conventional NSAIDs also can vary within a wide range. diclofenac administration. For each experiment 5 animals In the case of the especially preferred NSAIDs Diclofenac the were used for one experimental point. Following 24h admin daily doses are in a range from 100-200 ug/kg. " istration of drugs animals were weighted and stool was col Pharmacology lected quantitatively and homogenized as described below: Detection of Hemoglobin in Feces Investigations into the role of several NSAIDs in inhibiting The modified method of Welch (Clin. Chem. 29/12, 2022 the phosphodiesterase 4 and 5 in vitro (Table 1 below) showed is 2025, 1983) was used. The amount of hemoglobin was deter that in partially purified or recombinant PDE4 and PDE5. mined by the heme catalyzed oxidation of tolidine in the NSAIDs with preferential COX-2 selectivity (for example, presence of hydrogen peroxide. Feces was homogenized in nimeSulide INN, CGP28238 Research Code, L-745337 destined water in a concentration with 1 g feces/6.6 ml H20 Research Code, and the highly selective drug celecoxib with an ultra-turrax (IKA-Werke, Germany). 500 ul aliquots INN) possess PDE4 and PDE5 activity in the uM range, 20 from two different areas of the stool were taken to minimize whereas conventional NSAIDs (for example, acetylsalicylic error due to inhomogenous distribution of blood in the feces acid, diclofenac (INN or indometacin (INN) show only and heated 10 min at 95°C. to inactivate peroxidases and than minor effects: diluted with 500 ulofacetic acid/H20 (30/70 vol/vol). Hemo TABLE 1. ICso. IIM ASS Diclofenac Indometacin NimeSulide CGP28238 L-745337 Celecoxib

PDE4 -100 >100 -1OO 58 23 31 6 PDE5 >100 >100 62 25 14 24 12

ASS, acetylsalicylic acid; diclofenac, 2-(2,6-dichlorophe- globin was extracted in 2.5 ml of acetic acid/H20 (30/70 nyl)aminobenzeneacetic acid; indomethacin, 1-(4-chlo- vol/vol) by the addition of 4.5 ml ethyl acetate. The sample robenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid; was rigorously shacked and the Supernatant was used follow nimeSulide, 4'-nitro-2'-phenoxymethanSulfonamide: ing a centrifugation step for optical detection of hemoglobin. CGP28238, 6-(2,4-difluorophenoxy)-5-methylsulfony- Tolidine was prepared freshly from a stock solution (0.4g lamino-1-indanone; L-745337 5-methanesulfonamido-6-(2, tolidine in 10 ml ) by mixing equal Volumes of stock 4-difluorophenylthio)-1-indanone); celecoxib, (4-5-(4-me- a solution, H20 and acetic acid and equilibrated at room tem thylphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl) perature. 20 ul of extracted supernatant was diluted to 100 ul benzenesulfonamide. ethyl acetate in a 96er crystal plate and incubated with 50 ul In isolated guinea pig Langendorffhearts, celecoxib selec- of the working solution. The reaction was initiated by the tively increased coronary heart flow at doses consistent with injection of 25ul hydrogen peroxide (6%) in a Wallac Victor its inhibitory potency on PDE4 and 5, but had no effect on left 45 spectro-photometer (Turku, Finnland). The increase of OD Ventricular pressure and heart rate, thereby excluding inhibi- 690 was monitored by a kinetic analysis and expressed as tion of PDE3. AOD690/min. In mice, diclofenac (3-100 mg/kg, p.o.) induced gas trointestinal bleeding (EDs 56 mg/kg), assessed by spectro Results photometric determination of fecal hemoglobin. Treatment 50 Table 2 shows the % reduction of the AOD/min when a with diclofenac (10-100 mg/kg, p.o. t-Oh) in the presence of PDE4 inhibitor was administered (preventive or curative) the selective PDE5 inhibitor sildenafil (3-100 mg/kg, p.o. compared to the AODoo/min obtained without the adminis =-48 h to +7 h) demonstrated no protection from NSAID- tration of a PDE4-inhibitor. induced blood loss, whereas treatment in the presence of several selective PDE4 inhibitors significantly reduced the 55 TABLE 2 amount of detectable hemoglobin. % reduction of AOD Influence of PDE4 Inhibition on Diclofenac Induced Blood % reduction O 500 ill Loss in Mice NSAID: 100 mg/kg NSAID: 30 mg/kg Methods diclofenac indomethacin In Vivo Experiments 60 0. Male NMRI mice (Charles River Laboratories, Sulzfeld, Rene mg/kg 90% Germany) weighting 23-25 g were housed in groups of 5 Rolipram 10 mg/kg 82% understandard conditions at a temperature of 22°C.+/-2°C. (curative) 0. and a 12 h light-dark cycle. If not otherwise Stated animals it. 10 mg/kg 95% had free access to tap water and standard food pellets. 65 Ro?iumilast 3 mg/kg 95% Diclofenac was administrated at doses from 1-100 mg/kg (curative) p.o. rolipram, roflumliast and RP73401 were given at doses US 8,242,146 B2 25 26 TABLE 2-continued (ii) a second amount of 3-Cyclopropylmethoxy-4-difluoro methoxy-N-(3,5-dichloro pyrid-4- yl)-benzamide % reduction of AODaon/min INN: ROFLUMILAST or a pharmaceutically accept NSAID: 100 mg/kg NSAID: 30 mg/kg able salt, solvate, N-oxide, solvate of a salt, or solvate of diclofenac indomethacin 5 an N-oxide thereof; wherein the sum of the first and second amounts is a thera Rolipram 100 mg/kg 65% (curative) peutically effective amount. RP73401 100 mg/kg 96% 2. The method according to claim 1 wherein (i) and (ii) are (curative) administered (A) simultaneously as a fixed dosage form, or 10 (B) simultaneously, sequentially, or separately as discrete separate dosage forms. The invention claimed is: 3. The method according to claim 1 wherein the method is 1. A method of minimizing gastrointestinal side effects used in the treatment of an inflammatory disease. frequently associated with the use of conventional NSAIDs 4. The method according to claim3 wherein the inflamma comprising the simultaneous, sequential or separate admin 15 tory disease is rheumatoid arthritis, osteoarthritis, systemic istration to a patient in need thereof of lupus erythematosus, juvenile diabetes, inflammatory bowel (i) a first amount of 2-(2,6-dichlorophenyl)aminobenze disease, Crohn's disease, irritable bowel syndrome, or ulcer neacetic acid INN: DICLOFENAC or a pharmaceuti ative colitis. cally acceptable salt, ester, solvate, Solvate of a salt, or solvate of an ester thereof; and