US 20060083714A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0083714 A1 Warner (43) Pub. Date: Apr. 20, 2006

(54) COMBINATION OF A PDE IV INHIBITOR Publication Classification AND A TNF-ALPHIA ANTAGONST (51) Int. Cl. A 6LX 39/395 (2006.01) (76) Inventor: James M. Warner, Webster Groves, A6II 38/16 (2006.01) MO (US) A6II 38/2 (2006.01) A 6LX 3L/S377 (2006.01) A6II 3/58 (2006.01) Correspondence Address: A6II 3 L/704 (2006.01) PHARMACA CORPORATION A61K 3 1/519 (2006.01) GLOBAL PATENT DEPARTMENT A61K 3 1/522 (2006.01) POST OFFICE BOX 1027 (52) U.S. Cl...... 424/85.6; 514/220; 514/235.5; 9 424/145.1: 514/454: 514/11; 514/6: 514/176; 514/323; 424/7 18: (21) Appl. No.: 10/500,266 424/725; 514/252.15; 514/266.3 (22) PCT Filed: Jan. 23, 2004 (57) ABSTRACT (86). PCT No.: PCT/BO4/OO616 The subject invention relates to therapeutic combinations and methods for the treatment of inflammatory conditions Related U.S. Application Data and diseases. Particularly the present invention relates to treatments and methods for PDE IV-related conditions and (60) Provisional application No. 60/442,881, filed on Jan. for TNF-alpha-related conditions using a combination of a 27, 2003. PDE IV inhibitor and a TNF-alpha antagonist. US 2006/0O83714 A1 Apr. 20, 2006

COMBINATION OF A PDE V INHIBITOR AND A inhibited, is the cAMP-specific type-4 PDE (PDE IV). TNF-ALPHIA ANTAGONST Within the category of the PDE IV isoform, there are 4 known subtypes. The PDE IV subtypes. A through D, are all BACKGROUND OF THE INVENTION specific for cyclic AMP, but differ in terms of their mRNA splicing and upstream conserved domains. However, all 4 0001) 1. Field of the Invention subtypes, A-D, are included within the scope of the term, 0002 This invention relates to therapeutic combinations “PDE IV, for purposes of the present invention. and methods for the treatment of inflammatory conditions 0010 PDE inhibitors like theophylline and pentoxyphyl and diseases. Particularly the present invention relates to line inhibit all or most PDE isozymes indiscriminately in all treatments and methods for PDE IV-related conditions and tissue. These compounds exhibit side effects, apparently for TNF-alpha-related conditions. because they nonselectively inhibit multiple PDE isozyme 0003 2. Description of Related Art classes in a variety of tissues. The target disease may be effectively treated by such compounds, but unwanted sec 0004 Tumor necrosis factor-alpha (TNF-alpha) is a ondary side effects may be exhibited which, if they could be proinflammatory cytokine and plays a role in inflammatory avoided or minimized, would increase the overall therapeu and immunological events. The major sources of TNF-alpha tic effect of this approach to treating certain diseases. See are mast cells, eosinphils, macrophages, and monocytes. PCT publication WO 01/60358A1. Examples of compounds TNF-alpha causes a broad spectrum of effects both in vitro that inhibit multiple isoforms, in addition to PDE IV, of the and in Vivo, including vascular thrombosis and tumor necro PDE enzyme include theophylline, quinazolines, ibudilast, sis, inflammation, activation of macrophages and neutro phils, leukocytosis, apoptosis, and shock. TNF-alpha has benafentrine Zardaverine, and pentoxyfyllin. been associated with a variety of disease states including 0011. The therapeutic use a of PDE IV inhibitor with a various forms of cancer, arthritis, psoriasis, endotoxic shock, PDE III inhibitor is described in PCT publication number sepsis, autoimmune diseases, infarctions, obesity, asthma, WO 00/66123. A method of treatment using a PDE IV COPD, cachexia, stroke, glaucoma, retinitis, atherosclerosis inhibitor and a corticosteroid is described in PCT publica and uveitis. tion number WO O1/32127 A2. 0005 TNF-alpha activity can be reduced by treatment 0012 Asthma affects about 10 million Americans, about with, for example, an anti-TNF antibody. Examples of a third of whom are under 18 years of age. In the United anti-TNF antibodies include, individually, etanercept or States alone billions of dollars are spent annually on asthma infliximab. An alternative therapy used to reduce TNF-alpha related health care. The episodic breathing difficulty that activity includes treating the patient with a glucocorticoid. characterizes asthma is brought about by a combination of Further individual therapies for the reduction of TNF-alpha three primary factors including 1) bronchospasm, i.e. Vari activity are described by K. J. Tracey et al., Annu. Rev. Med. able and reversible airway obstruction due to airway muscle 45: 491-503 1994. contraction, 2) inflammation of the airway lining, and 3) bronchial hyper-responsiveness that results in excessive 0006. The enzyme phosphodiesterase-IV (PDE IV), is mucus in the airways. Triggers of asthma attacks vary believed to be the predominant phosphodiesterase expressed among individuals, but common triggers include allergens within inflammatory cells. One of the primary activities of Such as dust mites and mold, environmental pollutants, viral PDE IV is to metabolize excess intracellular levels of the agents, and physical exertion or exercise. signal transduction molecule cyclic adenosine 3',5'-mono phosphate (cAMP). 0013 The Mayo Clinic reports that chronic obstructive pulmonary disease (COPD), mostly emphysema or chronic 0007. The molecule cAMP is a ubiquitous second mes bronchitis, kills 85,000 people a year in the United States. senger produced in cells in response to extracellular hor Chronic obstructive pulmonary disease actually refers col mones and several neurotransmitters. The synthesis and lectively to several chronic or progressive pulmonary dis release of proinflammatory mediators, cytokines (including eases including asthmatic bronchitis, chronic bronchitis TNF-alpha) and active oxygen species are inhibited where (with normal airflow), chronic obstructive bronchitis, there is an increased level of cAMP (Dal Piaz, Eur. J. Med. bullous disease, and emphysema, all involving inflamma Chem. 35: 463-480, 2000). tion. For example, chronic bronchitis involves an inflam 0008. In contrast, native PDE IV activity causes reduc mation and eventual scarring of the lining of the bronchial tion of intracellular cAMP and is associated with triggering tubes producing symptoms including chronic cough, the release of several inflammatory cellular mediators increase of mucus, frequent clearing of the throat and including histamine and several cytokines, thus resulting in shortness of breath. Emphysema results from the normal but the symptoms of inflammation. Chemical inhibition of PDE chronic inflammatory response of the airway lining to IV activity has been found to increase intracellular levels of chronic exposure to environmental pollutants such as ciga cAMP, which in turn, down-regulate the harmful activity of rette Smoke. inflammatory cells. 0014 Drug treatment for asthma and COPD includes 0009 Multiple isoforms of the phosphodiesterase intravenous, oral, Subcutaneous or inhaled administration of enzyme have been identified that differ in their substrate bronchodilators including beta-adrenergics, methyl Xan specificity, kinetic properties, responsiveness to endogenous thines, and anti-cholinergics, and also administration of regulators (Ca2+/calmodulin, cyclic GMP), and susceptibil corticosteroids, the mast cell mediator-release inhibitors ity to inhibition by various compounds. Phosphodiesterase known as Cromolyn and Tilade, or, more recently, anti isoforms include the phosphodiesterases 1-10. For purposes leukotrienes, for anti-inflammatory effects. However, the of the present invention, the preferred PDE isoform to be cellular and molecular mechanisms of inflammatory and US 2006/0O83714 A1 Apr. 20, 2006

immune processes that play a role in the pathogenesis and or bacterial infection especially infection with a “common progression of asthma and COPD are not yet well under cold virus, environmental pollutants such as chemical stood. fumes or Smoke, physical over exertion Such as during exercise, stress, or inhalation of cold air. The terms "chronic SUMMARY OF THE INVENTION obstructive pulmonary disease' and “COPD as used inter changeably herein refers to a chronic disorder or combina 00.15 Briefly, therefore, the present invention is directed tion of disorders characterised by, for example, reduced to a method for the treatment or prophylaxis of a PDE IV maximal expiratory flow and slow forced emptying of the or a TNF-alpha-related condition in a mammal in need of lungs that does not change markedly over several months Such treatment or prophylaxis, comprising administrating to and is not, or is only minimally, reversible with traditional the mammal an amount of a PDE IV inhibitor and an amount bronchodilators. Commonly, COPD involves a combination of a TNF-alpha antagonist wherein the amount of the PDE of chronic bronchitis, i.e. the presence of cough and sputum IV inhibitor and the amount of the TNF-alpha antagonist for more than three months for about two consecutive years, together comprise an effective therapy for the treatment or and emphysema, i.e. alveolar damage. However, COPD can prevention of a PDE IV- or a TNF-alpha-related condition. involve singly or in combination chronic bronchitis with 0016. The invention is further directed to a therapeutic normal airflow, chronic bronchitis with airway obstruction composition comprising an amount of a PDE IV inhibitor (chronic obstructive bronchitis), emphysema, asthmatic and an amount of a TNF-alpha antagonist and a pharma bronchitis, or bullous disease. ceutically acceptable excipient. 0023 The term “respiratory disease or condition” refers 0017 Another embodiment of the present invention pro to any one of several ailments that involve inflammation and vides a kit for the purpose of treatment or prophylaxis of a affect a component of the respiratory system including PDE IV- or a TNF-alpha-related condition in a mammal in especially the trachea, bronchi and lungs. Such ailments can need of Such treatment or prophylaxis, the kit comprising a include without limitation asthmatic conditions such as dosage form comprising a PDE IV inhibitor and a dosage allergen-induced asthma, exercise-induced asthma, pollu form comprising a TNF-alpha antagonist. tion-induced asthma, cold-induced asthma, stress-induced asthma and viral-induced-asthma, chronic obstructive pull 0018 Further scope of the applicability of the present monary diseases including chronic bronchitis with normal invention will become apparent from the detailed descrip airflow, chronic bronchitis with airway obstruction (chronic tion provided below. However, it should be understood that obstructive bronchitis), emphysema, asthmatic bronchitis, or the following detailed description and examples, while bullous disease. The term “respiratory disease or condition indicating preferred embodiments of the invention, are given can also include without limitation other pulmonary diseases by way of illustration only since various changes and involving inflammation including cystic fibrosis, pigeon modifications within the spirit and scope of the invention fancier's disease, farmer's lung, acute respiratory distress will become apparent to those skilled in the art from this syndrome, pneumonia, aspiration or inhalation injury, fat detailed description. embolism in the lung, acidosis inflammation of the lung, acute pulmonary edema, acute mountain sickness, post DETAILED DESCRIPTION OF THE cardiac Surgery, acute pulmonary hypertension, persistent PREFERRED EMBODIMENTS pulmonary hypertension of the newborn, perinatal aspiration 0019. The following detailed description is provided to syndrome, hyaline membrane disease, acute pulmonary aid those skilled in the art in practicing the present invention. thromboembolism, heparin-protamine reactions, sepsis, sta Even so, this detailed description should not be construed to tus asthmaticus and hypoxia. unduly limit the present invention as modifications and 0024. The terms “phosphodiestrease inhibitor” and “PDE variations in the embodiments discussed herein can be made inhibitor” as used interchangeably herein denote a com by those of ordinary skill in the art without departing from pound that reduces the physiological effect of a phosphod the spirit or scope of the present inventive discovery. isterase enzyme, for example slowing the degradation of 0020. The contents of each of the references cited herein, cyclic AMP (cAMP) or cyclic (cGMP). including the contents of the references cited within these 0.025 The term “PDE IV inhibitor” denotes a compound primary references, are herein incorporated by reference in that is capable of reducing the in vitro enzyme activity of the their entirety. PDE IV isoform of phosphodiesterase. a. Definitions 0026. A PDE IV inhibitor may show different in vitro 0021. The following definitions are provided in order to IC values with respect to different isoforms of PDE. The in aid the reader in understanding the detailed description of vitro ICs value exhibited by a compound for the inhibition the present invention: of another isoform of PDE (herein, “PDE Z) divided by the ICs value for the inhibition of PDE IVis referred to herein 0022. The term “asthma’ refers to a respiratory disorder as “inter-isoform selectivity” with respect to that other PDE characterized by episodic difficulty in breathing brought on isoform. by any one or a combination of three primary factors including: 1) bronchospasm, i.e. variable and reversible 0027. The term “inter-isoform selective PDE IV inhibi airway obstruction due to airway muscle contraction, 2) tor” refers to a PDE IV inhibitor for which its inter-isoform inflammation of the airway lining, and 3) bronchial hyper selectivity with respect to another PDE isoform is greater responsiveness resulting in excessive mucus in the airways, than one. which may be triggered by exposure to an allergen or 0028. It is believed that there are at least two binding combination of allergens Such as dust mites and mold, viral forms on human monocyte recombinant PDE IV (human US 2006/0O83714 A1 Apr. 20, 2006

PDE IV) at which inhibitors bind. One explanation for these Such as in a single capsule having a fixed ratio of active observations is that human PDE IV exists in two distinct ingredients or in multiple, separate capsules for each active forms. One binds rolipram with high affinity while the other ingredient. In addition, Such administration also encom binds rolipram with low affinity. Herein we distinguish these passes use of each type of therapeutic agent in a sequential forms by referring to them as the high affimity rolipram manner. In either case, the treatment regimen will provide binding form (HPDE IV) and the low affinity binding form beneficial effects of the drug combination in treating...the (LPDE IV). It has been reported that certain compounds condition. which potently compete for HPDE IV have more side effects 0037. The term “pharmaceutically-acceptable salt or more intense side effects than those which more potently embraces salts commonly used to form alkali metal salts and compete with LPDE IV (see, for example, U.S. Pat. No. to form addition salts of free acids or free bases. The nature 5.998.428, herein incorporated by reference). Further data of the salt is not critical, provided that it is pharmaceutically indicate that compounds can be targeted to the low affinity acceptable or compatible with a medical therapy. Pharma binding form of PDE IV and that this form is distinct from ceutically acceptable salts are particularly useful as products the binding form for which rolipram is a high affmity binder. of the methods of the present invention because of their Compounds that interact with LPDE IV are reported to have greater aqueous solubility relative to a corresponding parent anti-inflammatory activity, whereas those that interact with or neutral compound. Such salts must have a pharmaceuti the HPDE IV produce side effects or exhibit more intensely cally acceptable anion or cation. Suitable pharmaceutically those side effects. Rolipram binds to one catalytic site of one acceptable acid addition salts of compounds of the present form with a high affinity (HPDE IV), defined herein as invention may be prepared from inorganic acid or from an having a K, less than 10 nanomolar, and to the other form organic acid. Examples of Such inorganic acids are hydro with a low affinity (LPDE IV), defined here as having a K. chloric, hydrobromic, hydroiodic, nitric, carbonic, Sulfuric of greater than 100 nanomolar. U.S. Pat. No. 5,998,428 and phosphoric acid. Appropriate organic acids include from describes a method of measuring the in vitro ICso ratios for aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, a compound with respect to HPDE IV and LPDE IV. carboxylic and Sulfonic classes of organic acids, examples of 0029. As used herein, the term “intra-isoform selectivity” which are formic, acetic, propionic, succinic, glycolic, glu with respect to a particular compound refers to its in vitro conic, lactic, malic, tartaric, citric, ascorbic, glucoronic, IC with respect to HPDE IV divided by its in vitro ICs with maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, respect to LPDE IV. anthranilic, mesylic, Salicylic, p-hydroxybenzoic, pheny lacetic, mandelic, embonic (pamoic), methanesulfonic, eth 0030) The term “intra-isoform selective PDE IV inhibi ylsulfonic, benzenesulfonic, Sulfanilic, Stearic, cyclohexy tor” means a PDE IV inhibitor for which the intra-isoform laminosulfonic, algenic, or galacturonic acid. Suitable selectivity is about 0.1 or greater. pharmaceutically-acceptable base addition salts of com 0031. The terms “selective phosphodiesterase IV inhibi pounds of the present invention include metallic salts made tor” and “selective PDE IV inhibitor” denote a compound from aluminum, calcium, lithium, magnesium, potassium, which exhibits either an inter-isoform selective PDE IV sodium and Zinc or organic salts made from N,N'-dibenzyl inhibitor or an intra-isoform selective PDE IV inhibitor. ethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and 0032. The term “subject' as used herein refers to an procaine. Suitable pharmnaceutically acceptable acid addi animal, in one embodiment a mammal, and in an exemplary tion salts of the compounds of the present invention when embodiment particularly a human being, who is the object of possible include those derived from inorganic acids, such as treatment, observation or experiment. In another embodi hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, ment the mammal can be, for example, a companion animal phosphoric, metaphosphoric, nitric, carbonic (including car Such as a dog, a cat, or a horse. bonate and hydrogen carbonate anions), Sulfonic, and Sul 0033. The terms “dosing and “treatment’ as used herein furic acids, and organic acids such as acetic, benzene refer to any process, action, application, therapy or the like, Sulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, wherein a Subject, particularly a human being, is rendered glycolic, isothionic, lactic, lactobionic, maleic, malic, meth medical aid with the object of improving the subjects anesulfonic, trifluoromethanesulfonic, succinic, toluene condition, either directly or indirectly. sulfonic, tartaric, and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable phar 0034. The term “therapeutic compound as used herein maceutically acceptable base salts include ammonium salts, refers to a compound useful in the prophylaxis or treatment alkali metal salts such as Sodium and potassium salts, and of a disease or condition. alkaline earth salts such as magnesium and calcium salts. All 0035) The term “therapeutically effective” as used herein of these salts may be prepared by conventional means from refers to a characteristic of an amount of a therapeutic the corresponding conjugate base or conjugate acid of the compound, or a characteristic of amounts of combined compounds useful in the present invention by reacting, therapeutic compounds in combination therapy. The amount respectively, the appropriate acid or base with the conjugate or combined amounts achieve the goal of preventing, avoid base or conjugate acid of the compound. ing, reducing or eliminating the respiratory disease or con b. Detailed Description dition. 0038. In accordance with the present invention, there is 0036) “Combination therapy” means the administration now provided a method for the treatment or prophylaxis of of two or more therapeutic agents to treat a condition. Such a PDE IV- or a TNF-alpha-related condition in a mammal in administration encompasses co-administration of these need of Such treatment or prophylaxis comprising adminis therapeutic agents in a Substantially simultaneous manner, trating to the mammal an amount of a PDE IV inhibitor and US 2006/0O83714 A1 Apr. 20, 2006 an amount of a TNF-alpha antagonist wherein the amount of 50% inhibition of phosphodiesterase activity. A PDE IV the PDE IV inhibitor and the amount of the TNF-alpha selective inhibitor is any inhibitor for which the ratio of PDE antagonist together comprise an effective therapy for the Z ICsoto PDE IV ICso is greater than 1. In a preferred treatment or prevention of a PDE IV- or a TNF-alpha-related embodiment, this ratio is greater than 2, more preferably condition. Preferably the PDE IV inhibitor is a selective greater than 10, yet more preferably greater than 100, and PDE IV inhibitor. more preferably still greater than 1000. 0.039 For purposes of the present invention, the terms 0043. By way of example, in Hatzelmann, A., et al., J. “PDE IV inhibitor” refer to any compound that is known to Pharm. Exper. Therap., 297(1) 267-279 (2001), the ICs for inhibit the PDE IV enzyme or which is discovered to act as roflumilast activity on PDE IV was reported to be 0.0008 a PDE IV inhibitor (PDE IV antagonist). PDE IV inhibitors uM, while the ICs for roflumilast activity on PDE I was include any compound that is known or can be discovered to reported to be >10 uM. Accordingly, the selectivity of inhibit the PDE IV enzyme regardless of whether the com roflumilast for PDE IV as compared with PDE I would be pound also demonstrates inhibition of other isoforms of the >10/0.0008 or at least about 12,500. Likewise, the selectiv phosphodiesterase enzyme (PDE). ity of roflumilast for PDE IV as compared with PDE V 0040. It is preferred that the PDE IV inhibitor that is used would be 8/0,0008 or at least about 10,000. in the present invention is one that is a PDE IV selective 0044) Thus, preferred PDE IV selective inhibitors of the inhibitor. present invention have a PDE IV ICs of less than about 1 0041) To determine the inter-isoform selectivity of a PDE uM, more preferred of less than about 0.1 uM, even more IV inhibitor, the putative inhibitor compound is typically preferred of less than about 0.01 uM, and more preferred still incubated together with each individual isoform of phos of less than about 0.001 uM. Preferred PDE IV selective phodiesterase and simultaneously with Substrate cyclic inhibitors have a PDEZICso of greater than about 1 uM, and nucleotides. PDE inhibition is then determined by the pres more preferably of greater than 10 uM. ence or absence of Substrate degradation products. See e.g. 0045 An example of a selective PDE IV inhibitor that is Hatzelmann, A., et al., J. Pharm. Exper. Therap., particularly preferred for use in the present invention has 297(1):267-279 (2001). The relative ability of an inhibitory been recently described for use in treating pulmonary compound to slow or prevent the degradation of tritiated inflammation is the pyridyl benzamide derivative, roflumi cyclic nucleotides is one test that is indicative of how well last (3-cyclopropylmethloxy-4-difluoromnethoxy-N-3,5- the compound in question selects one or more of each dichloropyrid-4-yl)-benzamide), a novel, highly potent, and isoform to inhibit. Representative PDE isoform enzymes selective PDE4 inhibitor. See U.S. Pat. No. 5,712,298, and other reaction substrates can be obtained by isolation which in herein incorporated by reference. from appropriate tissues and their purchase has been reported. 0046) PDE IV inhibitors are classified into three main chemical classes 1) Catechol Ethers (in which are grouped 0042. In practice, the in vitro selectivity of a PDE IV a wide variety of flexible molecules of inhibitors structurally inhibitor may vary depending upon the condition under related to rolipram) 2) Quinazolinediones which are struc which the test is performed and on the inhibitors being turally related to NitraquaZone and 3) Xanthines, to which tested. However, for the purposes of this specification, the theophylline belongs. Inside this class, two Subclasses can selectivity of a PDE IV inhibitor can be measured as a ratio be distinguished quinazolindiones and Xanthines. of the in vitro ICs value for inhibition of any other isoform of the phosphodiesterase enzyme (Z) other than PDE IV. 0047 Preferably the PDE IV inhibitor is selected from divided by the ICs value for inhibition of PDE IV (PDE Z the group consisting of rolipram, roflumilast, cilomilast, and ICs/PDE IV ICs), where Z identifies any PDE other than ZK-1 17137, bamifylline, dyphylline, ibudilast, and Theo PDE IV. As used herein, the term “ICs” refers to the phylline. Further individual PDE IV inhibitors useful in the concentration of a compound that is required to produce present invention are individually listed in Table 1.

TABLE 1.

No. Structure I.D. Structure Structure Name Reference

1. cilomilast O 4-cyano-4-3- Dal Piaz, V., Arifo SB- cyclopentyloxy)-4- et. al., Eur. J. 2O7499 CAS w methoxy phenyl Med. Chem. RN: 153259- Ns s OH cyclohexane carboxylic 35 (2000) 463-480 65-5 Co., acid

H3C No US 2006/0O83714 A1 Apr. 20, 2006

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference rofumilast 3-(cyclopropylmethoxy)- Souness, J., et al., BY-217 CAS N-(3,5-dichloropyridin Immunopharmacology RN: 1624O1-32-3 4-yl)-4- 47 (2000) 127-162 (difluoromethoxy) benzamide

Pumafentrin 4-(9-Ethoxy-8-methoxy Norman P., BYK-33O43 2-methyl Expert Opin. BY-343 CAS 1,2,3,4,4a,10b Ther. Patents RN: 207993-12-2 hexahydro-benzo (2002) c1.6 napthyridin-6- 12(1):93-111 yl)-N,N-diisopropyl benzamide

L-869298 2-4-1-34 Norman P., CT-2450 bis(difluoromethoxy) Expert Opin. Analogue: phenyl-2-(1- Ther. Patents CT-2820 CT oxidopyridin-4- (2002) 12(1):93-111 3883 L-826141 yl)ethylphenyl Analogue: L 1,1,1,3,3,3- 791943 CT5210 hexafluoropropan-2-ol CAS RN: 225919-29-9

L-791943

ZK-1171.37 Chiral 5-(4-methoxy-3- US 2002fO10310 SH-636 propoxyphenyl)-5- 6A1 Trade Name: methyl-1,3-oxazolidin Mesopram CAS 2-one RN: 1899.40-24-7

rolipram ME 4-(3-cyclopentyloxy Dal Piaz, V., 3.167 ZK 4-methoxy-phenyl)- et. al., Eur. J. 62711 CAS pyrrolidan-2-one Med. Chem. RN: 61413-54-5 35 (2000) 463-480

US 2006/0O83714 A1 Apr. 20, 2006

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference

1S. D-22888 9-ethyl-2-methoxy-7- Dal Piaz, V., Analogue: O -CH3 methyl-5- et. al., Eur. J. AWD-12-232 propylimidazol-5- Med. Chem. CAS RN: apyrido3.2-epyrazin 35 (2000) 463-480 182282-60-6 H3C N N 6(5H)-one / N 2 N

3C O

16. YM-58977 C 4-(3-bromophenyl)-1,7- Dal Piaz, V., diethylpyrido 2,3- et. al., Eur. J. r dpyrimidin-2(1H)-one Med. Chem. N N O 35 (2000) 463-480 C n Y

Br

17. Theophylline O 3,7-Dihydro-1,3- Dal Piaz, V., CAS RN: 58-55-9 dimethyl-1H-purine-2,6- et. al., Eur. J. dione Med. Chem. NH 1. 35 (2000) 463-480 CH

18. Cipamfylline 8-amino-1,3-bis Dal Piaz, V., HEP-688 cyclopropylmethyl-3,7- et. al., Eur. J. BRL-61063 dihydro-purine-2,6- Med. Chem. CAS RN: dione 35 (2000) 463-480 13221O-43-6 O N

N Aulu),NH O

19. Arofylline O 3-(4-chlorophenyl)-1- Dal Piaz, V., LAS-31025 propyl-3,7-dihydro-1H et. al., Eur. J. CAS RN: HC NH purine-2,6-dione Med. Chem. 136145-07-8 N 35 (2000) 463-480

O ul-2N N

C US 2006/0O83714 A1 Apr. 20, 2006

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference

20. V-11294A 3-(3-cyclopentyloxy-4- Dal Piaz, V., CAS RN: CH3 methoxybenzyl-8-8- et. al., Eur. J. 162278-09-3 isopropyl-3H-purin-6-yl Med. Chem. N CH ethylamine 35 (2000) 463-480 hydrochloride

N CH3

HCI

21. RPR-132294 N-(3,5- Dal Piaz, V., Analogue: dimethylisoxazol-4-yl)- et. al., Eur. J. RPR-132703 4-methoxy-3- Med. Chem. (tetrahydrofuran-3- 35 (2000) 463-480 yloxy)benzamide

22. IBMCX CAS 3-isobutyl-1-methyl-3,7- Dal Piaz, V., RN: 28822 dihydro-1H-purine-2,6- et. al., Eur. J. 58-4 dione Med. Chem. 35 (2000) 463-480

23. Isbufylline 7-isobutyl-1,3-dimethyl Dal Piaz, V., CAS RN: O 3,7-dihydro-1H-purine et. al., Eur. J. 90.162-60-0 2,6-dione Med. Chem. N X 35 (2000) 463-480 es ^

24. Doxofylline 7-(1,3-dioxolan-2- Dal Piaz, V., Trade Names: ylmethyl)-1,3-dimethyl et. al., Eur. J. Ansimar Maxivent 3,7-dihydro-1H-purine Med. Chem. CAS RN: C 2,6-dione 35 (2000) 463-480 69975-86-6 US 2006/0O83714 A1 Apr. 20, 2006 10

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference

25. Dyphylline O 7-(2,3-dihydroxypropyl)- Dal Piaz, V., CAS RN: / 1,3-dimethyl-3,7- et. al., Eur. J. 479-18-5 dihydro-1H-purine-2,6- Med. Chem. N N. ÖH OH dione 35 (2000) 463-480

26. Verofylline O 1,8-dimethyl-3-(2- Dal Piaz, V., CAS RN: methylbutyl)-3,7- et. al., Eur. J. 65O29-11-0 N N dihydro-1H-purine-2,6- Med. Chem. N dione 35 (2000) 463-480 1. N

27. Bamifylline 7-2-ethyl(hydroxy- Dal Piaz, V., CAS RN: methyl)aminoethyl-1,3- et. al., Eur. J. 2016-63-9 dimethyl-8-phenyl-3,7- Med. Chem. 1N dihydro-1H-purine-2,6- 35 (2000) 463-480 OH dione

O

N N (s N

28. Pentoxifylline O 3,7-dimethyl-1-(5- Dal Piaz, V., CAS RN: / oxohexyl)-3,7-dihydro- et. al., Eur. J. 6493-05-6 1H-purine-2,6-dione Med. Chem. 35 (2000) 463-480

29. Enprofylline O 3-propyl-3,7-dihydro- Dal Piaz, V., CAS RN: 1H-purine-2,6-dione et. al., Eur. J. 41 O78-02-8 Med. Chem. 35 (2000) 463-480 US 2006/0O83714 A1 Apr. 20, 2006 11

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference

30. Denbufylline 1,3-dibutyl-7-(2- Dal Piaz, V., CAS RN: Oxopropyl)-3,7-dihydro et. al., Eur. J. 57076-71-8 1H-purine-2,6-dione Med. Chem. 35 (2000) 463-480

31. Chiroscience 3-(3-methoxyphenyl)-1- Dal Piaz, V., 245412 phenyl-3,7-dihydro-1H et. al., Eur. J. purine-2,6-dione Med. Chem. 35 (2000) 463-480

32. ICI 63197 2-amino-4-propyl-3a,4- Dal Piaz, V., CAS RN: dihydro1,2,4-triazolo 1,5- et. al., Eur. J. 27277-00-5 a 1.3.5 triazin-5(1H)- Med. Chem. Ole 35 (2000) 463-480

33. SCA 40 6-bromo-8- Dal Piaz, V., ethylimidazol-2- et. al., Eur. J. apyrazin-2-amine Med. Chem. 35 (2000) 463-480

34. Ibudilast 1-(2-isopropyl Dal Piaz, V., CAS RN: pyrazolo 1,5- et. al., Eur. J. SO847-11-5 apyridin-3-yl)-2- Med. Chem. methylpropan-1-one 35 (2000) 463-480

US 2006/0O83714 A1 Apr. 20, 2006

TABLE 1-continued

No. Structure I.D. Structure Name Reference

49. Filaminast Ethanone, 1-(3- Souness, J., et al., WAYPDA-641 (cyclopentyloxy)-4- Immunopharmacology CAS RN: methoxyphenyl)-O- 47 (2000) 127-162 141184-34-1 (aminocarbonyl) oxime, (E)

SO. Piclaimilast N Benzamide, 3 Dal Piaz, V., RP 73401 (cyclopentyloxy)-N-(3,5- et. al., Eur. J. RPR 73401 dichloro-4-pyridinyl)-4- Med. Chem. CAS RN: methoxy 35 (2000) 463-480 144035-83-6 C HN

S1. Tibenelast Sodium 5,6- Souness, J., et al., Sodium LY diethoxybenzo(b)-thioph Immunopharmacology 1866SS CAS RN: ene-2-carboxylate 47 (2000) 127-162 105102-18-9

52. CDP 840 Pyridine, 4-(2R)-2-3- Souness, J., et al., CAS RN: (cyclopentyloxy)-4- Immunopharmacology 1625.42-90-7 methoxyphenyl-2- 47 (2000) 127-162 phenylethyl

53. GW 3600 1-Pyrrollidinecarboxylic US 2002fO10310 GL 1936OOX acid, 3-acetyl-4-3- 6A1 CAS RN: (cyclopentyloxy)-4- 173258-94-1 methoxyphenyl-3- methyl-, methyl ester, (3R4R)

54. NCS 613 9H-Purin-6-amine, 9 US 2002fO10310 CAS RN: (2-fluorophenyl)methyl 6A1 190377-71-0 N-methyl-2- (trifluoromethyl)-

55. PDB 093 No Structure US 2002fO10310 CAS RN: 6A1 444657-05-0 US 2006/0O83714 A1 Apr. 20, 2006 16

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference

56. RO 20-172 O H 2-Imidazolidinone, 4- US 2002fO10310 CAS RN: N (3-butoxy-4- 6A1 29925-17-5 methoxyphenyl)methyl HN / O y

57. RS 25344- N Pyrido 2,3-dipyrimidine- Dal Piaz, V., OOO CAS 2.4(1H,3H)-dione, 1-(3- et. al., Eur, J. RN: 152814-89-6 nitrophenyl)-3-(4- Med. Chem. 21 O 2N pyridinylmethyl) 35 (2000) 463-480 N

S N NN O O

S8. SKF 107806 No Structure US 2002fO10310 CAS RN: 6A1 444615-76-3

59. XT-44 CAS HN-V 1-n-butyl-3-n- Waki, Y., et al., RN: 135462-05-4 \ propylxanthine Jpn. J Pharmacol O N 79(4): 477-83 (1999) n-n- O l

60. tollafentrine Benzenesulfonamide, US 2002fO10310 N-4-(4aR1ObS)- 1,2,3,4,4a,10b-hexahydro 8,9-dimethoxy-2- methylbenzoc1,6- naphthyridin-6-ylphenyl 4-methyl

61. Zardaverine 3(2H)-Pyridazinone, 6 Souness, J., et al., 4-(difluoromethoxy)-3- Immunopharmacology methoxyphenyl 47 (2000) 127-162

US 2006/0O83714 A1 Apr. 20, 2006 19

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference

74. WAY No structure US 2002fO10310 12612O 6A1

75. WAY. CH3 1-(3-Cyclopentoxy-4- US 2002fO10310 122331 methoxy-phenyl)-7,8- 6A1 CH dimethyl-3-Oxa-1-aza spiro4.5 dec-7-en-2-one

O

HN O y-d CH O

76. WAY. -O 3-(3-Cyclopentyloxy-4- US 2002fO10310 127093B HC CH O methoxy-phenyl)-2- 6A1 N ls pyrazolidine-1-methyl-5-oxo O YN N 21 N carboxylic acid (pyridin H 3-ylmethyl)-amide: compound with but-2- O N enedioic acid 21 OH

O HO O

77. PDB-093 No structure US 2002fO10310 6A1

78. CDC-8O1 3-(3-Cyclopentyloxy-4- US 2002fO10310 methoxy-phenyl)-3-(1.3- 6A1 -CH3 dioxo-1,3-dihydro O isoindol-2-yl)- propionamide O

O O

N NH2

O

79. CC-7085 No structure US 2002fO10310 6A1 80. CDC-998 No structure US 2002fO10310 6A1 81. CH-3697 No structure US 2002fO10310 6A1 82 CH-3442 No structure US 2002fO10310 6A1 83. CH-287.4 No structure US 2002fO10310 6A1 84 CH-4139 No structure US 2002fO10310 US 2006/0O83714 A1 Apr. 20, 2006 20

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference 85. RPR 5-Methoxy-1-oxy-4- US 2002fO10310 C 2 O 114597 (tetrahydro-furan-3- 6A1 yloxy)-pyridine-2- aN r carboxylic acid (3,5- 21 N N dicloro-1-oxy-pyridin-4- H yl) amide HCN, N C

86. RPR 3-3(3,4-Dimethoxy US 2002fO10310 12281.8 bemzenesulfonyl)-2- 6A1 methyl-7-phenyl heptanoic acid hydroxamide

87. KF-19514 5-Phenyl-3-pyridin-3- US 2002fO10310 ylmethyl-3,5-dihydro 6A1 1,3,5,6-tetraaza cyclopentaa naphthalene-A-one

88. CH-422 No structure US 2002fO10310 6A1 89. CH-673 No structure US 2002fO10310 6A1 90. CH-928 No structure US 2002fO10310 6A1 91. KW-4490 No structure US 2002fO10310 6A1 92. Org 20241 4-(3,4-Dimethoxy US 2002fO10310 phenyl)-N-hydroxy 6A1 thiazole-2- carboxamidine

93. Org 30029 N-Hydroxy-5,6- US 2002fO10310 dimethoxy-benzob 6A1 thiopene-2carboxamidine; compound with a O HN-OH generic inorganic neutral component 94. VMX SS4 No Structure New Drugs for VMX 565 Respiratory Diseases, 5" International Conference, San Diego, CA, USA, July 3–5, 2002

US 2006/0O83714 A1 Apr. 20, 2006 22

TABLE 1-continued

No. Structure I.D. Structure Structure Name Reference 100. Oxagrelate 6-Phthalazinecarboxylic US 6,333,354 acid, 3,4-dihydro-1- B1 OH (hydroxymethyl)-5,7- dimethyl-4-oxo-, ethyl ester

0048. In one embodiment the PDE IV inhibitor is a Zardaverine, T-2585, SDZ-ISQ-844, SB 207499, RPR catechol ether selected from the group consisting of cilomi 117658A, L-787258, E-4021, GF-248, IPL-4088, last, roflumilast, pumafentrin, L-869298, ZK-1 17137, and CP-353164, CP-146523, CP-293321, T-611, WAY-126120, rolipram. In a preferred embodiment the PDE IV inhibitor is WAY-122331, WAY-127093B, PDB-093, CDC-801, cilomilast. In another preferred embodiment the PDE IV CC-7085, CDC-998, CH-3697, CH-3442, CH-2874, inhibitor is roflumilast. In another preferred embodiment the CH-4139, RPR-114597, RPR-122818, KF-19514, CH-422, PDE IV inhibitor is rolipram. CH-673, CH-928, KW-4490, Org 20241, Org 30029, VMX 0049. In another embodiment the PDE IV inhibitor is a 554, VMX 565, benafentrine, trequinsin, EMD 54622, RS quinazolidione or related compound selected from the group 17597, NitraquaZone, oxagrelate, T-440. consisting of YM-976, Sch-351591, IC-485, Sch-365351, 0052. In the present invention the TNFalpha anagonist is PD-189659, CP-77059, RS-14203 e, AWD-12-281, an agent, compound, or molecule or a composition contain D-22888, and YM-58977. ing an agent, compound or molecule, including analogs, 0050. In another embodiment the PDE IV inhibitor is a isomers, homologues, fragments or variants thereof, which Xanthine or related compound selected from the group antagonizes, inhibits, inactivates, reduces, Suppresses, and/ consisting of Theophylline, cipamfylline, arofylline, or limits the release, synthesis, or production from cells of V-11294A, RPR-132294, IBMX, isbufylline, doxofylline, TNF alpha. dyphylline, verofylline, bamifylline, pentoxiylline, 0053 Preferably the TNF-alpha antagonist is selected enprofylline, denbufylline, Chiroscience 245412, ICI from the group consisting of a TNF-alpha antibody, a 63197, SCA-40, ibudilast, N-cyclopentyl-8-cyclopropyl-3- metalloproteinase inhibitor, a corticosteroid, a tetracycline propyl-3H-purin-6-amine, and 8-cyclopropyl-N,3-diethyl TNF-alpha antagonist, a fluoroquinolone TNF-alpha antago 3H-purin-6-amine. In a preferred embodiment the PDE IV nist, and a quinolone TNF-alpha antagonist. inhibitor is theophylline. In another preferred embodiment the PDE IV inhibitor is arofylline. In another preferred 0054. In one embodiment the TNF-alpha antagonist is a embodiment the PDE IV inhibitor is doxofylline. In another TNF-alpha antibody. Preferably the TNF-alpha antibody is preferred embodiment the PDE IV inhibitor is dyphylline. In selected from the group consisting of infliximab, etanercept, another preferred embodiment the PDE IV inhibitor is CytoFAb, AGT-1, afelimomab, PassTNF, and CDP-870. bamifylline. In another preferred embodiment the PDE IV 0055. In another embodiment the TNF-alpha antagonist inhibitor is ibudilast. is a metalloproteinase inhibitor. Even more preferably the 0051. In another embodiment the PDE IV inhibitor is a metalloproteinase inhibitor is a matrix metalloproteinase benzofuran, benzopyran or related compound selected from inhibitor. the group consisting of lirimilast, (4-chlorophenyl)3-(3.3- dihydroxybutyl)-6-hydroxy-1-benzofuran-2-yl)methanone, 0056. In another embodiment the TNF-alpha antagonist 1-3-(dimethylamino)-4-(dimethylamino)methyl-7-hy is a corticosteroid. Preferably the corticosteroid is selected droxy-5,6-dimethyl-1-benzofuran-2-yl)ethanone, N-(3.5- from the group consisting of mometaSone, fluticaSone, dichloropyridin-4-yl)-8-methoxy-2,2-dimethylchromane-5- ciclesonide, budesonide, beclomethasone, beconase, carboxamide, and 2-acetyl-N-benzyl-7-methoxy-1- flunisolide, deflazacort, betamethasone, methyl-predniso benzofuran-4-sulfonamide. In another embodiment the PDE lone, dexamethasone, prednisolone, hydrocortisone, corti IV inhibitor is selected from the group consisting of 1-cy Sol, triamcinolone, cortisone, corticosterone, dihydroxycor clopentyl-N-(3,5-dichloropyridin-4-yl)-3-ethyl-1H-inda tisone, beclomethasone dipropionate, and prednisone. Zole-6-carboxamide, 1-cyclopentyl-3-ethyl-6-(2-methylphe 0057. In another embodiment the TNF-alpha antagonist nyl)-13a,4,5,6,7a-hexahydro-7H-pyrazolo 3,4-cpyridin-7- is a tetracycline TNF-alpha antagonist. Preferably the tetra one, N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro1.4diazepino.6, cycline TNF-alpha antagonist is selected from the group. 7, 1-hiindol-3-yl)-1H-indole-2-carboxamide, CI-1118, 4-4- consisting of doxycycline, minocycline, oxytetracycline, cyclopropyl-6-(cyclopropylamino)-1,3,5-triazin-2-yl)- tetracycline, lymecycline, and 4-hydroxy-4-dimethylami lambda-4-,4-thiazinane-1,1-diol, N-cyclopropyl-4-(2- notetracycline. methylcyclopropyl)-6-(2-methylmorpholin-4-yl)-1,3,5- triazin-2-amine, and atizoram, filaminast, piclaimilast, 0058. In another embodiment the TNF-alpha antagonist tibenelast, CDP 840, GW 3600, NCS 613, PDB 093, Ro is a fluoroquinolone TNF-alpha antagonist. Preferably the 20-1724, RS 25344-000, SKF 107806, XT44, tolafentrine, fluoroquinolone TNF-alpha antagonist is selected from the US 2006/0O83714 A1 Apr. 20, 2006 group consisting of norfloxacin, ofloxacin, ciprofloxacin, pharmaceutically elegant and palatable preparations. Tablets lomefloxacin, gatifloxacin, perfloxacin, and temafloxacin. can contain the active ingredient in admixture with non 0059. In another embodiment the TNF-alpha antagonist toxic pharmaceutically acceptable excipients which are Suit is a quinolone TNF-alpha antagonist. Preferably the qui able for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, nolone TNF-alpha antagonist is selected from the group Sodium carbonate, lactose, calcium phosphate or sodium consisting of Vesnarinone and amrinone. phosphate, granulating and disintegrating agents, for 0060. In another embodiment the TNF-alpha antagonist example, maize starch, or alginic acid, binding agents, for is selected from the group consisting of thalidomide, Oner example starch, gelatin or acacia, and lubricating agents, for cept, PegSunercept, interferon-gamma, interleukin-1, pen example magnesium Stearate, Stearic acid, or talc. The toxyphylline, pimobeddan, lactoferrin, melatonin, nitrogen tablets may be uncoated or they may be coated by known oxide, napthopyridine, a lazaroid, hydrazine Sulfate, keto techniques to delay disintegration and absorption in the tifen, tenidap, a cyclosporin, peptide T. SulfaSalazine, thora gastrointestinal tract and thereby provide a Sustained action Zine, an antioxidant, a cannabinoid, glycyrrhizin, sho-Saiko over a longer period. For example, a time delay material to, and L-camitine. Such as glyceryl monostearate or glyceryl distearate may be 0061 The present invention provides for a therapeutic employed. composition for the treatment or prophylaxis of a PDE IV 0067 Formulations for oral use may also be presented as or a TNF-alpha-related condition in a mammal in need of hard gelatin capsules wherein the active ingredients are Such treatment or prophylaxis comprising administrating to mixed with an inert Solid diluent, for example, calcium the mammal an amount of a PDE IV inhibitor and an amount carbonate, calcium phosphate or kaolin, or as Soft gelatin of a TNF-alpha antagonist wherein the amount of the PDE capsules wherein the active ingredients are present as such, IV inhibitor and the amount of the TNF-alpha antagonist or mixed with water or an oil medium, for example, peanut together comprise an effective treatment or prevention of a oil, liquid paraffm, or olive oil. PDE IV- or a TNF-alpha-related condition. 0068 Aqueous suspensions can be produced that contain 0062) The therapeutic composition of the present inven the active materials in admixture with excipients suitable for tion comprises an amount of a PDE IV inhibitor and an the manufacture of aqueous Suspensions. Such excipients amount of a TNF alpha antagonist. include Suspending agents, for example sodium carboxym 0063. The present invention also provides for a kit for the ethylcellulose, methylcellulose, hydroxypropylmethyl-cel purpose of treatment or prophylaxis of a PDE IV- or a lulose, Sodium alginate, polyvinylpyrrolidone gum traga TNF-alpha-related condition in a mammal in need of such canth and gum acacia. Dispersing or wetting agents may be treatment or prophylaxis, the kit comprising a dosage form naturally-occurring phosphatides, for example lecithin, or comprising a PDE IV inhibitor and a dosage form compris condensation products of an alkylene oxide with fatty acids, ing a TNF-alpha antagonist. for example polyoxyethylene Stearate, or condensation prod ucts of ethylene oxide with long chain aliphatic alcohols, for Dosage Forms and Delivery System. example heptadecaethyleneoxycetanol, or condensation 0064. The PDE IV inhibitor, the TNFalpha antagonist, or products of ethylene oxide with partial esters derived from pharmaceutical compositions comprising them may be fatty acids and a hexitol Such as polyoxyethylene Sorbitol administered enterally and parenterally. Oral (intra-gastric) monooleate, or condensation products of ethylene oxide is a preferred route of administration. The compounds useful with partial esters derived from fatty acids and hexitol in the present inventioncan be administered, for example, in anhydrides, for example polyoxyethylene Sorbitan Solid dosage forms for the methods of the present invention, monooleate. Another useful excipient is polyethylene oxide which include tablets, capsules, pills, and granules, which (PEG). can be prepared with coatings and shells, such as enteric 0069. The aqueous suspensions may also contain one or coatings and others well known in the art. Liquid dosage more preservatives, for example, ethyl or n-propyl p-hy forms for oral administration include pharmaceutically droxybenzoate, one or more coloring agents, one or more acceptable emulsions, solutions, Suspensions, syrups, and flavoring agents, or one or more Sweetening agents, such as elixirs. Topical dosage forms for administration of this Sucrose or saccharin. invention include ointments, powders, sprays, inhalants, creams, jellies, collyriums, Solutions or Suspensions. 0070 Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable 0065 Parenteral administration includes subcutaneous, oil, for example, arachis oil, olive oil, Sesame oil or coconut intramuscular, intradermal, intramammary, intravenous, and oil, or in a mineral oil Such as liquid paraffin. The oily other administrative methods known in the art. Enteral Suspensions may contain a thickening agent, for example administration includes solution, tablets, Sustained release beeswax, hard paraffin or cetyl alcohol. capsules, enteric coated capsules, and syrups. When admin istered, the pharmaceutical composition may be at or near 0071 Sweetening agents, such as those set forth above, body temperature. and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by 0.066 Compositions intended for oral use may be pre pared according to any method known in the art for the the addition of an antioxidant such as ascorbic acid. manufacture of pharmaceutical compositions and Such com 0072 Dispersible powders and granules suitable for positions may contain one or more agents selected from the preparation of an aqueous Suspension by the addition of group consisting of Sweetening agents, flavoring agents, water provide the active ingredient in admixture with a coloring agents and preserving agents in order to provide dispersing or Wetting agent, a Suspending agent and one or US 2006/0O83714 A1 Apr. 20, 2006 24 more preservatives. Suitable dispersing or wetting agents particles smaller than about 0.5 microns are inhaled to the and Suspending agents are exemplified by those already alveolae and then exhaled without significant deposition in mentioned above. Additional excipients, for example Sweet the lungs. An alternative device for inhalant therapy is a dry ening, flavoring and coloring agents, may also be present. powder inhaler using, for example, lactose or glucose pow der to carry the therapeutic compound. For all forms of 0073 Syrups and elixirs containing the PDE IV inhibitor inhalant therapy, factors other than particle size and type of and/or the TNF alpha antagonist may be formulated with device also influence the amount of deposition in the lungs, Sweetening agents, for example glycerol, Sorbitol, or including tidal Volume, rate of breathing and breath holding. Sucrose. Such formulations may also contain a demulcent, a Therefore, an individual being instructed in inhalation preservative and flavoring and coloring agents. therapy according to the methods of current invention 0074 The subject method of prescribing a PDE IV should also be instructed to take slow deep breaths and hold inhibitor and a TNF alpha antagonist can also be adminis each breath for several seconds, and preferably for about tered parenterally, either Subcutaneously, or intravenously, 5-10 seconds. Typically, the total daily dose of the thera or intramuscularly, or intrasternally, or by infusion tech peutic compounds according to the methods of the present niques, in the form of sterile injectable aqueous or olagenous invention will be administered as 1-4 puffs on a b.i.d-q.i.d. Suspensions. Such suspensions may be formulated according basis (i.e. twice-a-day, three times per day or four times a to the known art using those Suitable dispersing of wetting day), and as needed, or Solely on an as-needed basis. agents and Suspending agents which have been mentioned PDE IV Inhibitor Dosage Amount above, or other acceptable agents. The sterile injectable 0076 Daily dosages can vary within wide limits and will preparation may also be a sterile injectable solution or be adjusted to the individual requirements in each particular Suspension in a non-toxic parenterally-acceptable diluent or case. In general, for administration to adults, an appropriate Solvent, for example as a solution in 1,3-butanediol. Among daily dosage has been described below, although the limits the acceptable vehicles and solvents that may be employed that were identified as being preferred may be exceeded if are water, Ringer's solution and isotonic sodium chloride expedient. The daily dosage can be administered as a single Solution. In addition, sterile, fixed oils are conventionally dosage or in divided dosages. Various delivery systems employed as a solvent or Suspending medium. For this include capsules, tablets, food, and gelatin capsules, for purpose, any bland fixed oil may be employed, including example.

TABLE 2 PDE IV Dosage Inhibitor Amount REFERENCE Ariflo 20–30 mg per day Souness, J., et al., Immunopharmacology, 47: 127-162 (2000) Rollipram 0.5–2 mg/kg per day Teixeira, M., et al., Memorias do Instituto Oswaldo Cruz, 92(II): 193-196 (1997); Souness, J., et al., Immunopharmacology, 47: 127–162 (2000) Arofylline mg per day Souness, J., et al., Immunopharmacology, 47: 127-162 (2000) Ibudilast mg per day Souness, J., et al., Immunopharmacology, 47: 127-162 (2000) Tibenalast 150 mg per day Souness, J., et al., Immunopharmacology, 47: 127-162 (2000) Piclaimilast 0.2-0.8 mg per day Souness, J., et al., Immunopharmacology, 47: 127-162 (2000) CDP-840 mg per day Souness, J., et al., Immunopharmacology, 47: 127-162 (2000) RP 73401 mg/kg per day Teixeira, M., et al., Memorias do Instituto Oswaldo Cruz, 92(II): 193-196 (1997) NVP- 0.1–3 mg/kg per day Trifilieff, A., et al., J. Pharmacol. Exp. Ther., 301 (1): ABE171 241-248 (2002) synthetic mono- or diglycerides. In addition, n-3 polyun 0077. The exact dosage and regimen for administering a saturated fatty acids may find use in the preparation of PDE IV inhibitor will necessarily depend upon the potency injectables. and duration of action of the compounds used, the nature and 0075 Also, administration can be delivered by inhala severity of the illness to be treated, as well as the sex, age, tion, whether oral or nasal inhalation, according to the weight, general health and individual responsiveness of the methods of the present invention can include formulations as patient to be treated, and other relevant circumstances. are well known in the art, that are capable of being aero While not intended to be limiting, an example of the solized for delivery by inhalation. A metered dose inhaler or normally prescribed dosage for the PDE IV inhibitor, rof a nebulizer provides aerosol delivery. Both devices are lumilast, has been reported to be about 0.5 mg once daily for capable of providing delivery of a range of particle sizes human rhinitis treatment. See Schmidt, M. et al., J. Allergy including particles in the preferred range of about 1 micron Clin. Immunol. 108(4):530-536 (2001). In humans, roflumi to about 5 microns. Particles larger than about 10 microns last has been reported as effective when dosed at between are deposited primarily in the mouth and oropharynx, while about 0.01 and 0.5 mg/kg of body weight for inhalation and US 2006/0O83714 A1 Apr. 20, 2006 between about 0.05 and 2 mg/kg of body weight per day for TNF Alpha Antagonist Dosage Amount systemic therapies. See U.S. Pat. No. 5,712,298. 0081 Etanercept is known to those in the art. For adult 0078. Other examples of recommended PDE IV dosages patients the recommended dose of etanercept is 25 mg are include in Table 2. administered as a Subcutaneous injection given twice a week Table 2 at least 72-96 hours apart. Physician Desk Reference, 2002. For pediatric patients ages 4-17 years, the recommended 0079 Therefore, for purposes of the present invention, it dose of etanercept is 0.4/mg/kg (up to a maximum of 25 mg is preferred to dose the PDE IV inhibitor in an amount Sufficient to provide a steroid-sparing benefit when given as per dose) administered as a Subcutaneous injection given a combination therapy to a subject in need of such treatment, twice a week at least 72-96 hours apart. Id. wherein the amount of the PDE IV inhibitor which is 0082 Infliximab is know to those skilled in the art. The administered and the amount of the corticosteroid which is recommended dose of infliximab is 5 mg/kg administered as administered together comprise a therapeutically effective an intravenous infusion. Id. Infliximab is also administered amount of the combination. in combination with methotrexzte. The recommended dose 0080 More preferred is to dose the PDE IV inhibitor to of infliximab in combination with methotrexate is 3 mg/kg a subject in need of such therapy between about 0.001 mg/kg administered as an intravenous infusion followed with addi and 10 mg/kg of body weight per day. More preferred, the tional similar doses at 2 and 6 weeks after the first infusion PDE IV inhibitor should be dosed to the subject between then every 8 weeks thereafter. Id. about 0.01 and 5 mg/kg per day. Even more preferred still, the PDE IV inhibitor should be dosed to the subject between 0083) Other examples of recommended TNF alpha about 0.1 and 2.0 mg/kg per day. antagonist dosages are include in Table 3.

TABLE 3

TNF ALPHA ANTAGONIST DOSAGE AND ROUTE OF ADMINISTRATION Remicade (Inflixbimab) Dose of 3 mg/kg given as an intravenous infusion anti-tumor necrosis factor followed w additional similar doses at 2 and 6 weeks (TNF) monoclonal antibody after the first infusion and then every 8 weeks thereafter Embrel 25 mg dose given twice weekly as a subcutaneous (Etanercept) injection 72-96 hours apart. soluble TNF receptor fusion protein Methylprenisolone 4-160 mg/day - Suspension Doxycycline Oral & IV: 200 mg/day in adults on the first day, and thereafter 100 mg/day: 100 mg q 12 h for the entire course of therapy has also been used. In children 8 yr & older 4 mg/kg/day on the first day, and thereafter 2 mg/kg/day; 4 mg/kg/day for the entire course has also been used. Minocycline Oral & IV: 200 mg followed by 100 mg q 12 h in adults and in children 8 yrs & older 4 mg/kg followed by 2 mg/kg q. 12 h. Oxytetracycline Oral: 250–500 mg q6 h to adults and 25–50 mg/kg/day in children 8 yr & older. IV: 250–500 mg q 12 h to adults and 10–25 mg/kg/day in children 8 yr & older. Tetracycline Oral: 250–500 mg q6 h to adults and 25–50 mg/kg/day in children 8 yr & older. IV: 250–500 mg q 12 h to adults and 10–25 mg/kg/day in children 8 yr & older. Norfloxacin Oral: 400 mg bid Ofloxacin Oral & IV: 200–400 mg bid Ciprofloxacin Oral: 250–750 mg bid IV: 200–400 mg q 12 h. Gatifloxacin Oral: 200 mg & 400 mg tablets IV: 20 mL (200 mg) & 40 mL (400 mg) single use vials Amrinone Loading dose: 40 mg IVP over 3 minutes (0.75 mg/kg) Maintenance dose: 250-900 mcg.min (5-10 mcg/kg/min) Interferon-gamma Interferon gamma 1b (Actimmune) injection 100 mcg (2 Million IU) Thalidomide Oral—100–400 mg per day Pentoxyphylline Oral-Controlled Release 400 mg tid Melatonin Oral - 3–10 mg per day Reference: Physicians' Desk Reference, 56" Edition, 2002. US 2006/0O83714 A1 Apr. 20, 2006 26

Therapeutic Uses 0089. After preincubation for 5 min at 37° C., the reac tion isstarted by the addition of substrate (cAMP or cGMP) 0084. The present invention encompasses the therapeutic and the assays are incubated for further 15 min at 37° C. treatment of several inflammatory-related disorders. For Then 50 ul of 0.2N HCl is added to stop the reaction and example, the methods of the present invention are useful for the assays are left on ice for about 10 min. Following the treatment of pulmonary inflammatory disorders, pulmo incubation with 25 ug of 5'-nucleotidase (Crotalus atrox nary hypertension, asthma, exercised induced asthma, pol snake venom) for 10 min at 37°C., the assays areloaded on lution induced asthma, allergy induced asthma, COPD, QAE Sephadex A-25 (1 ml of bed volume in Poly-Prep osteoarthritis, adult respiratory distress syndrom, infant res chromatography columns: Bio-Rad, München, Germany). piratory distress syndrom, retinitis, uveitis, glaucoma, ret The columns are elutedwith 2 ml of 30 mM ammonium inopathy, diabetic angiopathy, edema formation, arthritis, formate (pH 6.0) and the eluate is counted for radioactivity. rheumatoid arthritis, multiple Sclerosis and Crohn's disease, Results are corrected for blank values (measured in the chronic bronchitis, eosinophilic granuloma, psoriasis and presence of denatured protein) that are below 5% of total other benign or malignant proliferative skin diseases, endot radioactivity. The amount of cyclic nucleotides hydrolyzed oxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, reperfusion does not exceed 30% of the original substrate concentration. injury of the myocardium and brain, osteoporosis, chronic 0090 PDE1 from bovine brain is assayed in the presence glomerulonephritis, atopic dermatitis, urticaria, adult respi of Ca" (1 mM) and calmodulin (100 nM) using coMP as ratory distress syndrome, infant respiratory distress Syn substrate. Ablank value is measured in the presence of EGTA drome, chronic obstructive pulmonary disease, diabetes (1 mM) is subtracted from all values. PDE2 from rat heart insipidus, rhinitis (including allergic rhinitis), allergic con is chromatographically purified and is assayed in the pres junctivitis, Vernal conjunctivitis, arterial restenosis, athero ence of c(GMP (5 uM) using cAMP as substrate. PDE3 and Sclerosis, neurogenic inflammation, pain, cough, ankylosing PDE5 are assayed in the cytosol of human platelets using spondylitis, transplant rejection and graft versus host dis cAMP and coMP respectively, as substrate. PDE4 is tested ease, hypersecretion of gastric acid, bacterial, fungal or viral in the cytosol of human neutrophils using cAMP as sub induced sepsis or septic shock, inflammation and cytokine strate. The PDE3-specific inhibitor motapizone (1 uM) is mediated chronic tissue degeneration, cancer, cachexia, con included to suppress PDE3 activity originating from con junctivitis, dermatitis, muscle wasting, depression, inflam taminatingplatelets. See Hatzelmann, A., et al., J. Pharm. matory bowel disease, allergic responses to insect and Exper. Therap., 297(1):267-279 (2001). arthropod bites, memory impairment, monopolar depres TNFC. Assay Sion, acute and chronic neurodegenerative disorders with 0.091 Cells areincubated in 96-well plates (Primaria inflammatory components, Parkinson disease, Alzheimer's 3872) at a density of 5x10 cells/well in a total assay volume disease, spinal cord trauma, head injury, joint injury, mul of 200 ul (RPMI 1640 medium containing 10% AB-serum tiple Sclerosis, tumor growth, and cancerous invasion of for monocytes and macrophages, and Iscove’s modified normal tissues, including any other disorders that are ame Dulbecco's medium containing 10% FBS for dendritic nable to amelioration through inhibition of the PDE IV cells). Compounds (10 ul) are added 30 min before stimu isoenzyme and the resulting elevated cAMP levels via lation of the cells with “LPS working solution’ (10 ul): a administration to a patient in need of Such treatment of an stock solution ofLPS (1 mg/ml, w/v) is prepared in 0.1% effective amount of the compounds referred to in the meth (v/v) hydroxylamine in PBS; after sonication for 5 min, 1-ml ods of the present invention. aliquots are stored at -20°C. Before starting the experiment, 0085. In view of the above, it will be seen that the several this solution is fivther diluted in the corresponding cell advantages of the invention are achieved and other advan specific culture medium to get the LPS working solution. tageous results obtained. The appropriate cell-specific submaximal final LPS concen trations are determined in preliminary experiments and are 0.086 As various changes could be made in the above 1 ng/ml for monocytes and 100 ng/ml for macrophages and methods and compositions without departing from the scope dendritic cells. In the macrophage experiments, PGE (10 of the invention, it is intended that all matter contained in the nM) is added as a cAMP trigger to provideresponsiveness of above description shall be interpreted as illustrative and not the cells for PDE inhibitors. in a limiting sense. 0092 Stock solutions of the compounds are diluted 1:50 c. Assays and Screens (v/v) in medium; subsequent dilutions are made in 2% (v/v) DMSO/medium to achieve the final drug concentrations in Inhibition of PDE Isoenzymes the assays at a DMSO concentration of 0.1% (v/v), which by itself does not affect TNFC. synthesis. Starting from a 10 0087. The assay mixture contains 50 mM Tris (pH 7.4), mM stock solution in DMSO, motapizone's further diluted 5 mM MgCl, 0.5 M cAMP or cGMP and HIcAMP or in medium so that the resulting DMSO concentration at the HcGMP (about 30,000 cpm/assay), the indicated concen final compound concentration (1 LM) could be neglected. tration of the inhibitor and an aliquot of the enzyme solution at a final assay volume of 200 ul. 0093. After overnight culture (about 13 h) in the case of monocytes and macrophages or 24h in the case of dendritic 0088 Stock solutions of the compounds are diluted 1:100 cells, supernatants (about 180 ul) are removed and stored at (v/v) in the Tris buffer mentioned above; appropriate dilu -20° C. before TNFL measurement by a commercially tions are prepared in 1% (v/v) DMSO/Tris buffer, which are available enzymimmunoassay from Immunotech (Hamburg, diluted 1:2 (v/v) in the assays to obtain the desired fimal Germany) performed essentially according to the manufac concentrations of the inhibitors at a DMSO concentration of turer's instructions. See Hatzelmann, A., et al., J. Pharm. 0.5% (v/v). DMSO itself affects none of the PDE activities. Exper. Therap., 297(1):267-279 (2001). US 2006/0O83714 A1 Apr. 20, 2006 27

Lung Function/Capacity 0094. The degree and severity of asthma and COPD can TABLE 4-continued be determined by measuring lung expiratory flow Volume Example and expiratory flow rates. Measurement can accomplished Number PDE IV Inhibitor TNF alpha Inhibitor with, for example, a spirometer, flow volume loop, or 12 arofylline & fluticaSone pneumotach, before and after each of the treatments. Use of 13 arofylline & ketotifen spirometry is a standard test for determining the efficacy of 14 arofylline & onercept PDE IV inhibitors and corticosteroids after administration to 15 arofylline & pentoxifylline 16 arofylline & halidomide a patient Suffering from a pulmonary inflammatory disorder. 17 arofylline & prednisone A device called a spirometer is used to measure how much 18 arofylline & triamcinolone air the lungs can hold and how well the respiratory system 19 arofylline & ciclesonide 2O arofylline & PegSunercept is able to move air into and out of the lungs. 21 izoram & nfliximab 0.095 Spirometry is a medical test that measures the 22 izoram & Etanercept 23 izoram & CytoFAb physical volume of air an individual forcibly inhales or 24 izoram & Afelimomab exhales into a device. The objective of spirometry is to 25 izoram & PassTNF assess ventilatory function. An estimate of flow rate, or the 26 izoram & CDP-870 rate at which the Volume is changing as a function of time 27 izoram & beclomethasone 28 izoram & (CO8Se. can also be calculated with spirometery. See SPIROMETRY 29 izoram & budesonide The Measurement and Inteipretation of Ventilatory Function 30 izoram & deflazacort in Clinical Practice, Rob Pierce and David P. Johns, The 31 izoram & flunisolide 32 izoram & fluticaSone Thoracic Society of Australia and New Zealand (1995). 33 izoram & ketotifen Thus, with the methods of the present invention, spirometric 34 izoram & onercept comparisons of pulmonary airflow before and after treat 35 izoram & pentoxifylline ment will elucidate similarities and differences that enable 36 izoram & halidomide one of skill to determine the effectiveness of the treatment 37 izoram & prednisone 38 izoram & triamcinolone methods. 39 izoram & ciclesonide 40 izoram & PegSunercept 0.096 Common parameters that spirometry measures are 41 AWD-12-28 nfliximab Forced Vital Capacity (FVC)—the maximum volume of air, 42 AWD-12-28 Etanercept measured in liters that can be forcibly and rapidly exhaled. 43 AWD-12-28 CytoFAb Another parameter is Forced Expiratory Volume (FEV1)— 44 AWD-12-28 Afelimomab 45 AWD-12-28 PassTNF the volume of air expelled in the first second of a forced 46 AWD-12-28 CDP-870 expiration. Normal parameters for a patient not suffering 47 AWD-12-28 beclomethasone from an inflammatory disorder such as asthma or COPD is: 48 AWD-12-28 (CO8Se. Tidal volume—5 to 7 milliliters per kilogram of body 49 AWD-12-28 budesonide 50 AWD-12-28 deflazacort weight; Expiratory reserve volume 25% of vital capacity: 51 AWD-12-28 flunisolide Inspiratory capacity—75% of vital capacity forced expira 52 AWD-12-28 fluticaSone tory volume 75% of vital capacity after 1 second, 94% 53 AWD-12-28 ketotifen after 2 seconds, and 97% after 3 seconds. Spirometry results S4 AWD-12-28 onercept 55 AWD-12-28 pentoxifylline are expressed as a percentage, and are considered abnormal 56 AWD-12-28 halidomide if less than 80% of the normal predicted value. An abnormal 57 AWD-12-28 prednisone result usually indicates the presence of some degree of 58 AWD-12-28 triamcinolone 59 AWD-12-28 ciclesonide obstructive lung disease such as COPD and chronic bron 60 AWD-12-28 PegSunercept chitis, or restrictive lung disease such as pulmonary fibrosis 61 ine & nfliximab or asthma. 62 ine & Etanercept 63 ine & CytoFAb EXAMPLE 1. 64 ine & Afelimomab 65 ine & PassTNF 66 ine & CDP-870 0097 table of Preferred Combinations 67 ine & beclomethasone 68 ine & (CO8Se. TABLE 4 69 ine & budesonide 70 ine & deflazacort Example 71 ine & flunisolide Number PDE IV Inhibitor TNF alpha Inhibitor 72 ine & fluticaSone 73 ine & ketotifen 1 arofylline & Infliximab 74 ine & onercept 2 arofylline & Etanercept 75 ine & pentoxifylline 3 arofylline & CytoFAb 76 ine & halidomide 4 arofylline & Afelimomab 77 ine & prednisone 5 arofylline & PassTNF 78 ine & triamcinolone 6 arofylline & CDP-870 79 ine & ciclesonide 7 arofylline & beclomethasone 8O bamifylline & PegSunercept 8 arofylline & beconase 81 CDC-801 & nfliximab 9 arofylline & budesonide 82 CDC-801 & Etanercept 10 arofylline & deflazacort 83 CDC-801 & CytoFAb 11 arofylline & flunisolide 84 CDC-801 & Afelimomab US 2006/0O83714 A1 Apr. 20, 2006 28

TABLE 4-continued TABLE 4-continued Example Example Number PDE IV Inhibitor TNF alpha Inhibitor Number PDE IV Inhibitor TNF alpha Inhibitor 85 DC-80 PassTNF 58 cipamfylline & triamcinolone 86 DC-80 CDP-870 59 cipamfylline & ciclesonide 87 DC-80 beclomethasone 60 cipamfylline & PegSunercept 88 DC-80 (CO8Se. 61 D-4418 & nfliximab 89 DC-80 budesonide 62 D-4418 & Etanercept 90 DC-80 deflazacort 63 D-4418 & CytoFAb 91 DC-80 flunisolide 64 D-4418 & Afelimomab 92 DC-80 fluticaSone 65 D-4418 & PassTNF 93 DC-80 ketotifen 66 D-4418 & CDP-870 94 DC-80 onercept 67 D-4418 & beclomethasone 95 DC-80 pentoxifylline 68 D-4418 & (CO8Se. 96 DC-80 halidomide 69 D-4418 & budesonide 97 DC-80 prednisone 70 D-4418 & deflazacort 98 DC-80 triamcinolone 71 D-4418 & flunisolide 99 DC-80 ciclesonide 72 D-4418 & fluticaSone OO DC-80 PegSumercept 73 D-4418 & ketotifen O1 P 840 & nfliximab 74 D-4418 & onercept O2 P 840 & Etanercept 75 D-4418 & pentoxifylline O3 P 840 & CytoFAb 76 D-4418 & halidomide O4 P 840 & Afelimomab 77 D-4418 & prednisone 05 P 840 & PassTNF 78 D-4418 & triamcinolone O6 P 840 & CDP-870 79 D-4418 & ciclesonide O7 P 840 & beclomethasone 8O D-4418 & PegSunercept O8 P 840 & (CO8Se. 81 oxofvline & nfliximab 09 P 840 & budesonide 82 oxofvline & Etanercept 10 P 840 & deflazacort 83 oxofvline & CytoFAb 11 P 840 & flunisolide 84 oxofvline & Afelimomab 12 P 840 & fluticaSone 85 oxofvline & PassTNF 13 P 840 & ketotifen 86 oxofvline & CDP-870 14 P 840 & onercept 87 oxofvline & beclomethasone 15 P 840 & pentoxifylline 88 oxofvline & (CO8Se. 16 P 840 & halidomide 89 oxofvline & budesonide 17 P 840 & prednisone 90 oxofvline & deflazacort 18 P 840 & triamcinolone 91 oxofvline & flunisolide 19 P 840 & ciclesonide 92 oxofvline & fluticaSone 2O P 840 & PegSumercept 93 oxofvline & ketotifen 21 nfliximab 94 oxofvline & onercept 22 Etanercept 95 oxofvline & pentoxifylline 23 CytoFAb 96 oxofvline & halidomide 24 Afelimomab 97 oxofvline & prednisone 25 PassTNF 98 oxofvline & triamcinolone 26 CDP-870 99 oxofvline & ciclesonide 27 beclomethasone 200 oxofvline & PegSunercept 28 (CO8Se. 2O1 hylline & nfliximab 29 budesonide 2O2 hylline & Etanercept 30 deflazacort 2O3 hylline & CytoFAb 31 flunisolide 204 hylline & Afelimomab 32 fluticaSone 205 hylline & PassTNF 33 ketotifen 2O6 hylline & CDP-870 34 onercept 2O7 hylline & beclomethasone 35 pentoxifylline 208 hylline & (CO8Se. 36 halidomide 209 hylline & budesonide 37 prednisone 210 hylline & deflazacort 38 triamcinolone 211 hylline & flunisolide 39 ciclesonide 212 hylline & fluticaSone 40 PegSumercept 213 hylline & ketotifen 41 ine & nfliximab 214 hylline & onercept 42 ine & Etanercept 215 hylline & pentoxifylline 43 ine & CytoFAb 216 hylline & halidomide ine & Afelimomab 217 hylline & prednisone 45 ine & PassTNF 218 hylline & triamcinolone 46 ine & CDP-870 219 hylline & ciclesonide 47 ine & beclomethasone 220 hylline & PegSunercept 48 ine & (CO8Se. 221 ilast & nfliximab 49 ine & budesonide 222 ilast & Etanercept 50 ine & deflazacort 223 ilast & CytoFAb 51 ine & flunisolide 224 ilast & Afelimomab 52 ine & fluticaSone 225 ilast & PassTNF 53 ine & ketotifen 226 ilast & CDP-870 S4 ine & onercept 227 ilast & beclomethasone 55 ine & pentoxifylline 228 ilast & (CO8Se. 56 ine & halidomide 229 ilast & budesonide 57 ine & prednisone 230 b l ilast & deflazacort US 2006/0O83714 A1 Apr. 20, 2006 29

TABLE 4-continued TABLE 4-continued Example Example Number PDE IV Inhibitor TNF alpha Inhibitor Number PDE IV Inhibitor TNF alpha Inhibitor 231 ibudilast & flunisolide 304 ONO-6126 & Afelimomab 232 ibudilast & fluticaSone 305 ONO-6126 & PassTNF 233 ibudilast & ketotifen 306 ONO-6126 & CDP-870 234 ibudilast & onercept 307 ONO-6126 & beclomethasone 235 ibudilast & pentoxifylline 3O8 ONO-6126 & (CO8Se. 236 ibudilast & halidomide 309 ONO-6126 & budesonide 237 ibudilast & prednisone 310 ONO-6126 & deflazacort 238 ibudilast & triamcinolone 311 ONO-6126 & flunisolide 239 ibudilast & ciclesonide 312 ONO-6126 & fluticaSone 240 ibudilast & PegSumercept 313 ONO-6126 & ketotifen 241 KW 4490 & nfliximab 314 ONO-6126 & onercept 242 KW 4490 & Etanercept 315 ONO-6126 & pentoxifylline 243 KW 4490 & CytoFAb 316 ONO-6126 & halidomide 244 KW 4490 & Afelimomab 317 ONO-6126 & prednisone 245 KW 4490 & PassTNF 3.18 ONO-6126 & triamcinolone 246 KW 4490 & CDP-870 319 ONO-6126 & ciclesonide 247 KW 4490 & beclomethasone 320 ONO-6126 & PegSunercept 248 KW 4490 & (CO8Se. 321 D-189659 & nfliximab 249 KW 4490 & budesonide 322 D-189659 & Etanercept 250 KW 4490 & deflazacort 323 D-189659 & CytoFAb 251 KW 4490 & flunisolide 324 D-189659 & Afelimomab 252 KW 4490 & fluticaSone 325 D-189659 & PassTNF 253 KW 4490 & ketotifen 326 D-189659 & CDP-870 254 KW 4490 & onercept 327 D-189659 & beclomethasone 255 KW 4490 & pentoxifylline 328 D-189659 & (CO8Se. 256 KW 4490 & halidomide 329 D-189659 & budesonide 257 KW 4490 & prednisone 330 D-189659 & deflazacort 258 KW 4490 & triamcinolone 331 D-189659 & flunisolide 259 KW 4490 & ciclesonide 332 D-189659 & fluticaSone 260 KW 4490 & PegSunercept 333 D-189659 & ketotifen 261 L-791943 & nfliximab 334 D-189659 & onercept 262 L-791943 & Etanercept 335 D-189659 & pentoxifylline 263 L-791943 & CytoFAb 336 D-189659 & halidomide 264 L-791943 & Afelimomab 337 D-189659 & prednisone 26S L-791943 & PassTNF 338 D-189659 & triamcinolone 266 L-791943 & CDP-870 339 D-189659 & ciclesonide 267 L-791943 & beclomethasone 340 D-189659 & PegSunercept 268 L-791943 & (CO8Se. 341 pentoxifylline & nfliximab 269 L-791943 & budesonide 342 pentoxifylline & Etanercept 270 L-791943 & deflazacort 343 pentoxifylline & CytoFAb 271 L-791943 & flunisolide 344 pentoxifylline & Afelimomab 272 L-791943 & fluticaSone 345 pentoxifylline & PassTNF 273 L-791943 & ketotifen 346 pentoxifylline & CDP-870 274 L-791943 & onercept 347 pentoxifylline & beclomethasone 275 L-791943 & pentoxifylline 348 pentoxifylline & (CO8Se. 276 L-791943 & halidomide 349 pentoxifylline & budesonide 277 L-791943 & prednisone 350 pentoxifylline & deflazacort 278 L-791943 & triamcinolone 351 pentoxifylline & flunisolide 279 L-791943 & ciclesonide 352 pentoxifylline & fluticaSone 28O L-791943 & PegSumercept 353 pentoxifylline & ketotifen 281 irimilas nfliximab 3S4 pentoxifylline & onercept 282 irimilas Etanercept 355 pentoxifylline & halidomide 283 irimilas CytoFAb 356 pentoxifylline & prednisone 284 irimilas Afelimomab 357 pentoxifylline & triamcinolone 285 irimilas PassTNF 358 pentoxifylline & ciclesonide 286 irimilas CDP-870 359 pentoxifylline & PegSunercept 287 irimilas beclomethasone 360 piclaimilas nfliximab 288 irimilas (CO8Se. 361 piclaimilas Etanercept 289 irimilas budesonide 362 piclaimilas CytoFAb 290 irimilas deflazacort 363 piclaimilas Afelimomab 291 irimilas flunisolide 364 piclaimilas PassTNF 292 irimilas fluticaSone 365 piclaimilas CDP-870 293 irimilas ketotifen 366 piclaimilas beclomethasone 294 irimilas onercept 367 piclaimilas (CO8Se. 295 irimilas pentoxifylline 368 piclaimilas budesonide 296 irimilas halidomide 369 piclaimilas deflazacort 297 irimilas prednisone 370 piclaimilas flunisolide 298 irimilas triamcinolone 371 piclaimilas fluticaSone 299 irimilas ciclesonide 372 piclaimilas ketotifen 300 irimilas PegSumercept 373 piclaimilas onercept 301 ONO-6126 & nfliximab 374 piclaimilas pentoxifylline 3O2 ONO-6126 & Etanercept 375 piclaimilas halidomide 303 ONO-6126 & CytoFAb 376 piclaimilas prednisone US 2006/0O83714 A1 Apr. 20, 2006 30

TABLE 4-continued TABLE 4-continued Example Example Number PDE IV Inhibitor TNF alpha Inhibitor Number PDE IV Inhibitor TNF alpha Inhibitor 377 piclaimilast & triamcinolone 450 SCH-3S1591 & flunisolide 378 piclaimilast & ciclesonide 451 SCH-3S1591 & fluticaSone 379 piclaimilast & PegSumercept 452 SCH-3S1591 & ketotifen 380 pumafentrin & nfliximab 453 SCH-3S1591 & onercept 381 pumafentrin & Etanercept 454 SCH-3S1591 & pentoxifylline 382 pumafentrin & CytoFAb 455 SCH-3S1591 & halidomide 383 pumafentrin & Afelimomab 456 SCH-3S1591 & prednisone 384 pumafentrin & PassTNF 457 SCH-3S1591 & triamcinolone 385 pumafentrin & CDP-870 458 SCH-3S1591 & ciclesonide 386 pumafentrin & beclomethasone 459 SCH-3S1591 & PegSunercept 387 pumafentrin & (CO8Se. 460 T-440 & nfliximab 388 pumafentrin & budesonide 461 T-440 & Etanercept 389 pumafentrin & deflazacort 462 T-440 & CytoFAb 390 pumafentrin & flunisolide 463 T-440 & Afelimomab 391 pumafentrin & fluticaSone 464 T-440 & PassTNF 392 pumafentrin & ketotifen 465 T-440 & CDP-870 393 pumafentrin & onercept 466 T-440 & beclomethasone 394 pumafentrin & pentoxifylline 467 T-440 & (CO8Se. 395 pumafentrin & halidomide 468 T-440 & budesonide 396 pumafentrin & prednisone 469 T-440 & deflazacort 397 pumafentrin & triamcinolone 470 T-440 & flunisolide 398 pumafentrin & ciclesonide 471 T-440 & fluticaSone 399 pumafentrin & PegSumercept 472 T-440 & ketotifen 400 rofumilas nfliximab 473 T-440 & onercept 401 rofumilas Etanercept 474 T-440 & pentoxifylline 402 rofumilas CytoFAb 475 T-440 & halidomide 403 rofumilas Afelimomab 476 T-440 & prednisone 404 rofumilas PassTNF 477 T-440 & triamcinolone 40S rofumilas CDP-870 478 T-440 & ciclesonide 406 rofumilas beclomethasone 479 T-440 & PegSunercept 407 rofumilas (CO8Se. 480 Theophylline & nfliximab 408 rofumilas budesonide 481 heophylline & Etanercept 409 rofumilas deflazacort 482 heophylline & CytoFAb 410 rofumilas flunisolide 483 heophylline & Afelimomab 411 rofumilas fluticaSone 484 heophylline & PassTNF 412 rofumilas ketotifen 485 heophylline & CDP-870 413 rofumilas onercept 486 heophylline & beclomethasone 414 rofumilas pentoxifylline 487 heophylline & (CO8Se. 415 rofumilas halidomide 488 heophylline & budesonide 416 rofumilas prednisone 489 heophylline & deflazacort 417 rofumilas triamcinolone 490 heophylline & flunisolide 418 rofumilas ciclesonide 491 heophylline & fluticaSone 419 rofumilas PegSumercept 492 heophylline & ketotifen 420 rolipram & nfliximab 493 heophylline & onercept 421 rolipram & Etanercept 494 heophylline & pentoxifylline 422 rolipram & CytoFAb 495 heophylline & halidomide 423 rolipram & Afelimomab 496 heophylline & prednisone 424 rolipram & PassTNF 497 heophylline & triamcinolone 425 rolipram & CDP-870 498 heophylline & ciclesonide 426 rolipram & beclomethasone 499 Theophylline & PegSunercept 427 rolipram & (CO8Se. 500 V-11294A & nfliximab 428 rolipram & budesonide 5O1 V-11294A & Etanercept 429 rolipram & deflazacort 502 V-11294A & CytoFAb 430 rolipram & flunisolide 503 V-11294A & Afelimomab 431 rolipram & fluticaSone SO4 V-11294A & PassTNF 432 rolipram & ketotifen 505 V-11294A & CDP-870 433 rolipram & onercept SO6 V-11294A & beclomethasone 434 rolipram & pentoxifylline 507 V-11294A & (CO8Se. 435 rolipram & halidomide SO8 V-11294A & budesonide 436 rolipram & prednisone 509 V-11294A & deflazacort 437 rolipram & triamcinolone 510 V-11294A & flunisolide 438 rolipram & ciclesonide 511 V-11294A & fluticaSone 439 pram & PegSumercept 512 V-11294A & ketotifen 440 SCH-3S1591 & nfliximab 513 V-11294A & onercept 441 SCH-3S1591 & Etanercept S14 V-11294A & pentoxifylline 442 SCH-3S1591 & CytoFAb 515 V-11294A & halidomide 443 SCH-3S1591 & Afelimomab S16 V-11294A & prednisone 444 SCH-3S1591 & PassTNF 517 V-11294A & triamcinolone 445 SCH-3S1591 & CDP-870 S18 V-11294A & ciclesonide 446 SCH-3S1591 & beclomethasone 519 V-11294A & PegSunercept 447 SCH-3S1591 & (CO8Se. 52O YM-976 & nfliximab 448 SCH-3S1591 & budesonide 521 YM-976 & Etanercept 449 SCH-3S1591 & deflazacort 522 YM-976 & CytoFAb US 2006/0O83714 A1 Apr. 20, 2006 31

CP-146523, CP-293321, T-611, WAY-126120, WAY TABLE 4-continued 122331, WAY-127093B, PDB-093, CDC-801, CC-7085, CDC-998, CH-3697, CH-3442, CH-2874, CH-4139, RPR Example 114597, RPR-122818, KF-19514, CH-422, CH-673, Number PDE IV Inhibitor TNF alpha Inhibitor CH-928, KW-4490, Org 20241, Org 30029.VMX 554, 523 YM-976 & Afelimomab VMX565, benafentrine, trequinsin, EMD 54622, RS 17597, 524 YM-976 & PassTNF NitraduaZone, oxagrelate, T-440. 525 YM-976 & CDP-870 526 YM-976 & beclomethasone 6. The method of claim 2, wherein the TNF-alpha antago 527 YM-976 & (CO8Se. nist is a TNF-alpha antibody. 528 YM-976 & budesonide 7. The method of claim 6, wherein the TNF-alpha anti 529 YM-976 & deflazacort body is selected from the group consisting of infliximab, 530 YM-976 & flunisolide etanercept, CytoFAb, AGT-1, afelimomab, PassTNF, and 531 YM-976 & fluticaSone CDP-870. 532 YM-976 & ketotifen 533 YM-976 & onercept 8. The method of claim 2, wherein the TNF-alpha antago 534 YM-976 & pentoxifylline nist is selected from the group consisting of thalidomide, 535 YM-976 & halidomide Onercept, PegSunercept, interferon-gamma, interleukin-1, 536 YM-976 & prednisone pentoxyphylline, pimobeddan, lactoferrin, melatonin, nitro 537 YM-976 & triamcinolone gen oxide, napthopyridine, a lazaroid, hydrazine Sulfate, 538 YM-976 & ciclesonide ketotifen, tenidap, a cyclosporin, peptide T. Sulfasalazine, 539 YM-976 & PegSumercept thorazine, an antioxidant, a cannabinoid, glycyrrhizin, sho saiko-to, and L-camitine. 9. A therapeutic composition comprising an amount of a 0098. The inventionbeing thus described, it is apparent PDE IV inhibitor and an amount of a TNF-alpha antagonist that the same can be varied in many ways. Such variations and a pharmaceutically acceptable excipient. are not to be regarded as a departure from the spirit and 10. The therapeutic composition of claim 9, wherein the Scope of the present invention, and all Such modifications PDE IV inhibitor is selected from the group consisting of and equivalents as would be obvious to one skilled in the art roflumilast, cilomilast, ZK- 117137, bamifylline, dyphyl are intended to be included within the scope of the following line, ibudilast, and theophylline. clims. 11. The therapeutic composition of claim 9, wherein the PDE IV inhibitor is selected from the group consisting of a What is claimed is: catechol ether PDE IV inhibitor, a quinazolinedione PDE IV 1. A method for the treatment or prophylaxis of a PDE IV inhibitor, a xanthine PDE IV inhibitor, and a benzamide or a TNF-alpha-related condition in a mammal in need of PDE IV inhibitor. Such treatment or prophylaxis comprising administrating to 12. The therapeutic composition of claim 11, wherein the the mammal an amount of a PDE IV inhibitor and an amount PDE IV inhibitor is selected from the group consisting of of a TNF-alpha antagonist wherein the amount of the PDE 1-cyclopentyl-N-(3,5-dichloropyridin-4-yl)-3-ethyl-1H-in IV inhibitor and the amount of the TNF-alpha antagonist dazole-6-carboxamide, 1 -cyclopentyl-3-ethyl-6-(2-meth together comprise a therapy effective for the treatment or ylphenyl)-13a,4,5,6,7a-hexahydro-7H-pyrazolo 3,4-cpyri prophylaxis of a PDE IV- or a TNF-alpha-related condition. din-7-one, N-(4-oxo-1-phenyl-3,4,6,7-tetrahydro1.4 2. The method of claim 1, wherein the TNF-alpha antago diazepino.6.7.1-hiindol-3-yl)-1H-indole-2-carboxamide, nist is selected from the group consisting of a metallopro CI-1118, 4-4-cyclopropyl-6-(cyclopropylamino)-1,3,5-tri teinase inhibitor, a tetracycline TNF-alpha antagonist, a azin-2-yl-lambda-4-,4-thiazinane-1,1-diol, and N-cyclo fluoroquinolone TNF-alpha antagonist, and a quinolone propyl-4-(2-methylcyclopropyl)-6-(2-methylmorpholin-4- TNF-alpha antagonist. yl)-1,3,5-triazin-2-amine, atizoram, filaminast, piclamilast, 3. The method of claim 1, wherein the PDE IV inhibitor tibenelast, CDP 840, GW 3600, NCS 613, PDB 093, Ro is selected from the group consisting of roflumilast, cilomi 20-1724, RS 25344-000, SKF 107806, XT-44, tolafentrine, last, ZK-1 17137, bamifylline, dyphylline, ibudilast, and Zardaverine, T-2585, SDZ-ISQ-844, SB 207499, RPR theophylline. 117658A, L-787258, E-4021, GF-248, IPL-4088, 4. The method of claim 1, wherein the PDE IV inhibitor CP-353164, CP-146523, CP-293321, T-611, WAY-126120, is selected from the group consisting of a quinazolinedione WAY-122331, WAY-127093B, PDB-093, CDC-801, PDE IV inhibitor, a xanthine PDE IV inhibitor, and a CC-7085, CDC-998, CH-3697, CH-3442, CH-2874, benzamide PDE IV inhibitor. CH-4139, RPR-114597, RPR-122818, KF-19514, CH422, 5. The method of claim 4, wherein the PDE IV inhibitor CH-673, CH-928, KW-4490, Org 20241, Org 30029, VMX is selected from the group consisting of 1-cyclopentyl-N- 554, VMX 565, benafentrine, trequinsin, EMD 54622, RS (3,5-dichloropyridin-4-yl)-3-ethyl-1H-indazole-6-carboxa 17597, NitraquaZone, oxagrelate, T-440. mide, 1-cyclopentyl-3-ethyl-6-(2-methylphenyl)-13a,4,5,6, 13. The therapeutic composition of claim 9, wherein the 7a-hexahydro-7H-pyrazolo 3,4-cpyridin-7-one, N-(4-oxo TNF-alpha antagonist is a TNF-alpha antibody. 1-phenyl-3,4,6,7-tetrahydro1.4diazepino.6.7.1-hiindol-3- 14. The therapeutic composition of claim 13, wherein the yl)-1H-indole-2-carboxamide, CI-1118, 4-4-cyclopropyl-6- TNF-alpha antibody is selected from the group consisting of (cyclopropylamino)-1,3,5-triazin-2-yl-lambda-4-4- infliximab, etanercept, CytoFAb, AGT-1, afelimomab, thiazinane-1,1-diol, and N-cyclopropyl-4-(2- PassTNF, and CDP-870. methylcyclopropyl)-6-(2-methylmorpholin-4-yl)-1,3,5- 15. A kit for the purpose of treatment or prophylaxis of a PDE IV- or a TNF-alpha-related condition in a mammal in triazin-2-amine, atizoram, filaminast, piclamilast, tibenelast, need of Such treatment or prophylaxis, the kit comprising a CDP 840, GW 3600, NCS 613, PDB 093, Ro 20-1724, RS dosage form comprising a PDE IV inhibitor and a dosage 25344-000, SKF 107806, XT-44, tolafentrine, Zardaverine, form comprising a TNF-alpha antagonist. T-2585, SDZ-ISQ-844, SB 207499, RPR-117658A, L-787258, E-4021, GF-248, IPL-4088, CP-353164, k k k k k