WO2008002246A1 - A pharmaceutical composition comprising an ikk2 inhibitor and a second active ingrdient. - Google Patents

Abstract

The present invention provides pharmaceutical compositions comprising an IKK2 inhibitor and a second active ingredient, and their use in therapy.

Description

A pharmaceutical composition comprising an IKK2 inhibitor and a second active ingrdient.

Field of the Invention

The present invention relates to combinations of pharmaceutically active substances for use in the treatment of inflammatory disorders, particularly respiratory disorders, especially chronic obstructive pulmonary disease (COPD) and asthma.

Background of the Invention

The essential function of the lungs requires a fragile structure with enormous exposure to the environment, including pollutants, microbes, allergens, and carcinogens. Host factors, resulting from interactions of lifestyle choices and genetic composition, influence the response to this exposure. Damage or infection to the lungs can give rise to a wide range of diseases of the respiratory system (or respiratory diseases). A number of these diseases are of great public health importance. Respiratory diseases include Acute Lung Injury, Acute Respiratory Distress Syndrome (ARDS), occupational lung disease, lung cancer, tuberculosis, fibrosis, pneumoconiosis, pneumonia, emphysema, Chronic Obstructive Pulmonary Disease (COPD) and asthma.

Among the most common respiratory diseases is asthma. Asthma is generally defined as an inflammatory disorder of the airways with clinical symptoms arising from intermittent airflow obstruction. It is characterised clinically by paroxysms of wheezing, dyspnea and cough. It is a chronic disabling disorder that appears to be increasing in prevalence and severity. It is estimated that 15% of children and 5% of adults in the population of developed countries suffer from asthma. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.

COPD is a term which refers to a large group of lung diseases which can interfere with normal breathing. Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases. The most important contributory source of such particles and gases, at least in the western world, is tobacco smoke. COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells. The two most important conditions covered by COPD are chronic bronchitis and emphysema.

Chronic bronchitis is a long-standing inflammation of the bronchi which causes increased production of mucous and other changes. The patients' symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.

Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi. The lung loses its elasticity and therefore these areas of the lungs become enlarged. These enlarged areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood. The predominant symptom in patients with emphysema is shortness of breath.

Various therapeutic agents are used in the treatment of respiratory diseases. Whilst treatment with many of these agents can yield important benefits, the efficacy of these agents is often far from satisfactory, particularly in COPD. Moreover, it is desirable to be able to use these agents in low doses so as to minimise the occurrence and severity of undesirable side effects that may be associated with regular administration. Hence there is a pressing medical need for new therapies against respiratory diseases such as COPD and asthma, in particular for therapies with disease modifying potential.

WO 01/58890, WO 03/010158, WO 03/010163, WO 04/063185 and WO 04/063186 disclose compounds having activity as pharmaceuticals, in particular as inhibitors of IKK2, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy. O 02/024679 and WO 02/044153 disclose pyridine derivatives, for example,

as IKK2 inhibitors.

WO 04/092167 andUS20050239781 disclose beta-carboline derivatives, for example,

for treating IKK2-mediated diseases.

WO 02/30353, WO 03/02942 and WO 04/053087 disclose thiophene derivatives having IKK2 inhibitory activity.

WO 04/022553 discloses indole and benzimidazole derivatives, for example,

as IKK2 inhibitors.

WO 04/106293 and WO 05/011609 disclose fused tricyclic compounds, for example,

having IKK2 inhibitory activity.

IKB kinase 2 (IKK2) is a serine-threonine kinase which is a key regulator of the activity and function of NF-κB. NF-κB is a key regulator of inflammatory genes and plays a critical role in the pathogenesis of a number of human disorders, particularly those with an inflammatory component. A large number of the mediators known to be involved in the inflammatory response in COPD are regulated by NF-κB and in addition Phospho-IκBα and activity of NF-κB is increased in lung tissue of COPD patients compared to non- COPD patients. Moreover, inflammatory cells (for example, neutrophils and monocytes/macrophages) contribute to the pathogenesis of respiratory diseases such as COPD by secretion of proteolytic enzymes, oxidants and pharmacologic mediators. These cells are dependent on the function of IKK2/NF-κB for recruitment and activation in lung tissue.

It has now been found that an unexpectedly beneficial therapeutic effect may be observed in the treatment of inflammatory diseases, particularly respiratory diseases, if an IKK2 inhibitor is used in combination with one or more other active agents. For example, the combinations according to the invention are considered to be particularly effective in reducing inflammatory cell influx into the lung. The beneficial effect may be observed when the two or more active substances are administered simultaneously (either in a single pharmaceutical preparation or via separate preparations), or sequentially or separately via separate pharmaceutical preparations. Disclosure of the Invention

Thus, according to the present invention, there is provided a pharmaceutical product comprising, in combination,

(a) a first active ingredient which is an inhibitor of IKK2; and

(b) a second active ingredient.

Inhibitors of IKK2 may be detected using a suitable in vitro assay such as the SPA kinase assay disclosed herein.

The first active ingredient may be, for example, any of the compounds disclosed in WO 01/58890, WO 03/010158, WO 03/010163, WO 04/063185 and WO 04/063186, the contents of which are incorporated herein in their entirety.

Alternatively, the first active ingredient may be any compound previously disclosed in the art as having IKK2 inhibitory activity including, for example, compounds disclosed in WO 02/024679, WO 02/044153, WO 04/092167, US20050239781, WO 02/30353, WO 03/02942, WO 04/053087, WO 04/022553, WO 04/106293 and WO 05/011609.

In one embodiment, the first active ingredient is a compound of formula (I)

in which: R represents NH2 or R represents a methyl group optionally substituted by one or more groups selected independently from Cj-C₄ alkyl, C₃-Cg cycloalkyl, halogen, hydroxyl,

C₁-C₄ alkoxy, S(O)_VCH₃ andNR⁴R⁵;

X represents O or S;

R represents hydrogen, halogen, cyano, nitro, -NR R , -CONR R , -COOR , -NR⁶COR⁷, -S(O)_1nR⁶, -SO₂NR⁶R⁷, -NR⁶SO₂ R⁷, Ci-C₂ alkyl, trifluoromethyl, C2-C3 alkenyl, C2-C3 alkynyl, trifluoromethoxy, Cj-C₂ alkoxy or Ci-C₂ alkanoyl;

A represents a phenyl ring or a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, nitro, -NR⁸R⁹, -CONR⁸R⁹, -COOR⁸, -NR⁸COR⁹, -S(O)₅R⁸, o Q o q i n 1 1

-SO₂NR R , -NR SO₂R , Ci-C₆ alkyl, trifluoromethyl, -(CH₂)_tR , -0(CH₂)_tR or-

OR¹²;

3 n represents an integer 1 or 2; and when n represents 2, each R group may be selected independently;

R represents a group -W-Y-Z wherein:

W represents O, S(O)₁, NR¹³, CH₂, -CH₂-O- or a bond;

Y represents a bond or a group -(CH2)_p-T-(CH₂)q- wherein p and q independently

14 15 represent an integer 0, 1 or 2; and T represents O, -CO- or CR R ; 14 15

R and R independently represent H, CH3 or F;

14 15 or R represents H or CH3 and R represents hydroxyl or OCH3;

14 15 or the group CR R together represents a C3-C6 cycloalkyl ring;

Z represents:

(a) a phenyl ring or a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, -KR¹⁶R¹⁷, -CONR¹⁶R¹⁷, -COOR¹⁶, -COR¹⁶ -NR¹⁶COR¹⁷, -S(O)₁₁R¹⁶, -SO₂NR¹V⁷, -NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl and C₁-C₆ alkoxy; said alkyl or alkoxy group being optionally further substituted by one or

18 19 more groups selected from halogen, cyano, hydroxyl, C1-C4 alkoxy and NR R ; or

(b) a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group; said ring system being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR¹⁶R¹⁷, -CONR¹⁶R¹⁷, -COOR¹⁶, -COR¹⁶, -NR¹⁶COR¹⁷, -S(O)_nR¹⁶, -SO₂NR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁷ hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl,

C3-C₆ cycloalkyl and C₁-C₆ alkoxy; said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano, hydroxyl,

18 19 C3-C₆ cycloalkyl, C i-C^ alkoxy and NR R ; provided that said saturated monocyclic ring Z is not bonded to Y through nitrogen if the group -W-Y- represents -(CH₂)₂_4~ or -O-(CH₂)₂_4— when the saturated ring Z is also unsubstituted; or (c) if W represents O, then Z may also represent hydroxyl, OCH3, CF3, CHF2 or CH2F, provided that the group -Y-Z does not thereby represent -O-(CH2)2-4~OCH3;

10 11 20 21 20 21 R and R independently represent NR R where R and R are independently

20 21 hydrogen or Ci-Cβ alkyl optionally substituted by C1-C4 alkoxy; or the group NR R represents a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S

22 22 10 11 or NR group; where R is hydrogen or Ci-Cg alkyl; or R and R independently represent Cj-Cg alkoxy;

4 5 4 5

R and R independently represent H or Cj -C4 alkyl; or the group NR R represents a

23 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR

23 group; where R is hydrogen or C1-C4 alkyl;

independently represent H or C1-C2 alkyl;

8 9 12

R , R and R independently represent H or Cj-Cg alkyl;

13 R represents H or C1-C4 alkyl;

R and R independently represent H or Ci-Cg alkyl optionally substituted by OH,

C1-C4 alkoxy or one or more fluoro atoms; or the group

represents a 5- or 6-

24 membered saturated azacyclic ring optionally containing a further O, S or NR group;

24 where R is hydrogen or Ci-Cg alkyl optionally substituted by OH, C1-C4 alkoxy or one or more fluoro atoms; R and R independently represent H or C 1-C4 alkyl; or the group NR R represents a

25 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR

25 group; where R is hydrogen or C1-C4 alkyl;

m, r, s, u and v independently represent an integer 0, 1 or 2;

t represents an integer 2, 3 or 4;

or a pharmaceutically acceptable salt thereof.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.

In one embodiment, the invention provides compounds of formula (I) wherein Z represents:

(a) a phenyl ring or a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR¹⁶R¹⁷, -CONR¹⁶R¹⁷, -COOR¹⁶, -COR¹⁶ -NR¹⁶COR¹⁷, -S(O)_UR¹⁶, -SO₂NR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl and C]₁-C₆ alkoxy; said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano, hydroxyl, C1-C4 alkoxy and NR R ; or

(b) a saturated 3- to 7-membered ring optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group; said saturated ring being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR¹⁶R¹⁷, -CONR¹⁶R¹⁷, -COOR¹⁶, -COR¹⁶, -NR¹⁶COR¹⁷, -S(O)₁₁R¹⁶, -SO₂NR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁷, hydroxy!, C₂-C₆ alkenyl,

C₂-C₆ alkynyl, Ci-C₆ alkyl and CJ-C₆ alkoxy; said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano, hydroxyl, C 1-C4 alkoxy and NR R ; provided that said saturated ring Z is not bonded to Y through nitrogen if the group -W-Y- represents -(CH₂)₂_4- or -O-(CH₂)₂_4~ when the saturated ring Z is also unsubstituted; or

(c) if W represents O, then Z may also represent hydroxyl, OCH3, CF3, CHF₂ or CH₂F, provided that the group -Y-Z does not thereby represent — O-(CH₂)₂_4-OCH3; and all other substituents are as defined above.

In one embodiment, X in formula (I) represents oxygen.

In another embodiment, R in formula (I) represents NH₂.

Suitably the group A in formula (I) is a phenyl group or a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more

8 9 8 9 substituents selected independently from halogen, cyano, nitro, -NR R , -CONR R ,

-COOR⁸, -NR⁸COR⁹, -S(O)₈R⁸, -SO₂NR⁸R⁹, -NR⁸SO₂R⁹, C₁-C₆ alkyl, trifluoromethyl,

-(CH₂)tR , -O(CH₂)tR or -OR . In one embodiment, A represents optionally substituted phenyl. In another embodiment, A represents an optionally substituted pyridyl.

2 In one embodiment, the group R in formula (I) represents H, halogen or

₂ Cj-C₂ alkyl. In another embodiment, the group R represents H or methyl. In another

2 embodiment, the group R in formula (I) represents H. In another embodiment, W in formula (I) represents O, CH2 or a bond.

In another embodiment, Y in formula (I) represents -CH2— CH2- or a bond.

In another embodiment, Z in formula (I) represents a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group; said ring system being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR R , -CONR R , -COOR¹⁶, -COR¹⁶, -NR¹⁶COR¹⁷, -S(O)_UR¹⁶, -SO₂NR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁷, hydroxyl,

C₂-Cg alkenyl, C₂-Cg alkynyl, Cχ-C6 alkyl, C3-C6 cycloalkyl and Ci-Cg alkoxy; said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano, hydroxyl, C3-Q; cycloalkyl, C1-C4 alkoxy and NR R ; provided that said saturated monocyclic ring Z is not bonded to Y through nitrogen if the group -W-Y- represents — (CH₂)₂-4~ or — O-(CH2)₂-4~ when the saturated ring Z is also unsubstituted.

In another embodiment, Z in formula (I) represents a phenyl ring or a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more

16 17 16 17 substitαents selected independently from halogen, cyano, -NR R , -CONR R , -COOR¹⁶, -COR¹⁶ -NR¹⁶COR¹⁷, -S(O)₁₁R¹⁶, -SO₂NR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁷, hydroxyl,

C₂-Cg alkenyl, C₂-Cg alkynyl, Ci-Cg alkyl and Ci-Cg alkoxy; said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano,

18 19 hydroxyl, C1-C4 alkoxy and NR R .

In one embodiment, n has the value 1. In another embodiment, the first active ingredient is a compound that is specifically exemplified in WO 03/010158, namely a compound selected from:

2-[(aminocarbonyl)amino]-4-methyl-5-(4-biphenyl)-3-thiophenecarboxamide; 2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl)-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(4-chlorophenyl)methoxy]phenyl)-3- thiophenecarboxamide;

2- [(aminocarbonyl)amino] -4-methyl-5-(4- [(5 -chlorothien-2-yl)methoxy]phenyl)-3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-4-methyl-5-{4-[2-(2,2,6,6-tetramethylpiperidin-l- yl)ethoxy]phenyl}-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(thiazol-4-yl)methoxy]phenyl)-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(l,2,5-thiadiazol-3-yl)methoxy]phenyl)-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(l-methylperhydroazepin-3-yl)oxy]phenyl)-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[6-(pyrrolidin-l-yl)pyridin-3-yl]-3-thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-[6-(2_:,2-difluoroethoxy)pyridin-3-yl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[6-(piperidin-l-yl)pyridin-3-yl]-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[6-(cyclopentyloxy)pyridin-3-yl]-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[6-(4-ethanesulfonylpiperazm-l-yl)pyridin-3-yl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[6-[(tetrahydrofuran-2-yl)methoxy]pyridin-3-yl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(furan-2-ylmethoxy)]-pyridme}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{3-[6-(4-acetyl)piρerazin-l-yl]-pyridine}-3- thiophenecarboxamide; (7?)-2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]-pyridine}--3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(l-isopropyl-pyrrolidin-3-yloxy)]-pyridine}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{3-[6-(l-^-butyloxycarbonyl-piperidin-4-yloxy)]-pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5- {3-[6-(piperidin-4-yloxy)]-pyridine} -3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(l-(2-methoxyethyl)-piperidin-4-yloxy)]-pyridine}-3- thiophenecarboxamide;

2[(aminocarbonyl)amino] -5 - {3-[6-(N-methanesulphonyl)-piperidin-4-yloxy]-pyridine} -3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(4,4-difluoropiperidin-l-yl)pyridine}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{3-[6-(pyrrolidin-l-yl)-5-methyl]pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5- {3-[6-(thien-2-ylmethoxy)]pyridine} -3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(cyclopentylmethoxy)]pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[3-(6-benzyloxy)pyridine]-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydroruran-3-yloxy)]pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-ylmethoxy)]pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(cyclopropylmethoxy)]pyridine}-3- thiophenecarboxamide; fSJ-2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]pyridine}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydropyran-4-yloxy)]pyridine}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{3-[6-(tetraαydiothiopyran-3-yloxy)]pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(l-isopropylazetidin-3-yloxy)]pyridme}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5- {3-[6-(benzyloxy-2-ethoxy)]pyridine} -3- thiophenecarboxamide;

2-[(aniinocarbonyl)amino]-5-{3-[6-(N-methylpiperidin-3-yloxy)]pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(2-(l-pyrrolidin-2-one)ethoxy)]pyridine}-3- thiophenecarboxamide;

2-[(ammocarbonyl)amino]-5-[3-(6-(moφholin-4-yl))pyridine]-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{3-[6-(4-methylpiperazin-l-yl)]pyridine}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(4-[l,3,4-oxadiazol-2-yl]-2-phenyl )-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(4-cyclopropylmethoxyphenyl )-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[3-(l,3-thiazol-4-ylmethoxy)phenyl]thiophene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide; 2-[(aminocarbonyl)amino]-5-(5-[2-(N-morpholinyl)]pyrimidinyl)-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(5-[2-(N-piperidinyl)]pyrimidinyl)-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(5-[2-(N-pyrrolidinyl)]pyrimidinyl)-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(5-[2-{4-(t-butyloxycarbonyl)piperazin-l-yl}]pyrimidinyl)-3- thiophenecarboxamide;

2-[(arninocarbonyl)amino]-5-(-5-[2- {4H-piperazin- 1 -yl} ]pyrimidinyl)-3 - thiophenecarboxamide;

2-[(aminocarbonyl)ammo]-5-(5-[2-{4-me1iιylpiperazin-l-yl}]pyrirnidinyl)-3- thiophenecarboxamide; 2-[(ammocarbonyl)ammo]-5-(5-[2-(3-dimethylaminopyrrolidin-l-yl)]pyrimidinyl)-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-(5-[2-{2()S)--aminocarbonylpyrrolidin-l-yl}]pyrimidinyl)-3-

.thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(5-[2-{4-acetylpiperazm-l-yl}]pyrimidinyl)-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-(5-{2-[4,4-difluoropiperidin-l-yl]}pyrimidinyl)-3- thiophenecarboxamide;

2-[(aminocarbonyl)amiQo]-5-(5-{2-[3,3-difluoropyrrolidin-l-yl]}pyriniidmyl)-3- thiophenecarboxamide;

2- [(arninocarbonyl)amino] -5 - {2-(5 -iV-morpholinomethyl)thienyl} -3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-ben2yloxyphenyl}-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5- {2-(4-fluorophenylmethoxy)phenyl} -3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-(2-[4-fluorophenyl]ethoxy)phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5- {2-(2-[4-chlorophenyl]ethoxy)phenyl } -3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-(2-phenylethoxy)phenyl}-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{4-chlorophenylmethoxy)phenyl}-3-thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5- {2-[2-(iV-moφholinyl)]ethylthio)phenyl} -3- thiophenecarboxamide;

2-[(ammocarbonyl)amino]-5-{2-[2-(Λ^r-pyrrolidmyl)]ethylthio)phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[2-(iV-piperidinyl)]ethylthio)phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[4-(pyrrolidinyl)phenyl]-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[4-(piperidinyl)phenyl]-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[4-(N-imidazolyl)phenyl]-3-thiophenecarboxamide;

2-[(ammocarbonyl)ammo]-5-[6-{(l-methylpyrrolidin-2-on-4-yl)methoxy}pyridin-3-yl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5{4-[2-(2-methoxyethoxy)ethoxy]-phenyl}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{4-[2-(cyclopropylmethoxy)ethoxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[6-(2,2-dimethyl-3-pyrrolidinylpropoxy)pyridin-3-yl]-3- thiophenecarboxamide; 2-[(ammocarbonyl)amino]-5-{3-chloro-4-(tetrahydrofuran-2-ylmethoxy)phenyl}-3- thiophenecarboxamide;

2- [(aminocarbonyl) amino] -5- {4-(tetrahydronαran-2-ylmethoxy)phenyl} -3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[(6-cyclopropylmethylthio)pyridm-3-yl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5{4-[2-(2-metlioxyethoxy)ethoxy]-3-methylphenyl}-3- thiophenecarboxamide;

2- [(aminocarbonyl)amino] -5- {3 -chloro-4- [2-(2-methoxyethoxy)ethoxy]phenyl} -3 - thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-[2-(4-methylpiperazinylmethyl)phenyl]-3- thiophenecarboxamide;

2- [(aminocarbonyl)amino] -5 - [2-(4-isopropylpiperazinylmethyl)phenyl] -3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[2-(4-t-butyloxycarbonylpiperazinylmethyl)phenyl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[4-(pyrrolidmyhnethyl)phenyl]thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[2-(2-(4,4-difluoropiperidin-l-yl)ethoxy)phenyl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[2-(2-(3,3-difluoropyrrolidin-l-yl)ethoxy)phenyl]-3- thiophenecarboxamide;

3-[(aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide;

3-[(aminocarbonyl)amino]-5-[4-(cz5'-2,6-dimethymiorpholin-4-ylmethyl)phenyl]thiophene-

2-carboxamide;

2-[(aminocarbonyl)amino]-5-[4-(cis-2,6-dimethylmorpholin-4-ylmethyl)phenyl]thiophene- 3-carboxamide;

2-[(aminocarbonyl)amino]-5-[(6-{4-morpholino}methyl)pyridin-3-yl]thiophene-3- carboxamide; 2-[(aminocarbonyl)amino]-5-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3- ylmethyl)phenyl]thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[3-(morpholin-4-ylmethyl)-4-isobutoxyphenyl]thiophene-3- carboxamide; 2-[(aminocarbonyl)amino]-5-[3-(morpliolm-4-ylmethyl)phenyl]thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-(4-{[2-(methoxymethyl)morpholin-4- yl]methyl} phenyl)thiophene-3 -carboxamide;

2-[(aminocarbonyl)amino]-5-[3-fluoro-4-(morpholiii-4-ylmetb.yl)phenyl]tb.iophene-3- carboxamide; 2- [(aminocarbonyl) amino]-5 -[3 -chloro-4-(morpholin-4-ylmethyl)pb.enyl]thiophene-3 - carboxamide;

2-[(arninocarbonyl)amino]-5-{4-[(4,4-difluoropiperidin-l-yl)methyl]plienyl}thiophene-3- carboxamide;

2-[(ammocarbonyl)amino]-5-[4-(l - {piperidin-1 -yl} ethyl)phenyl]thiophene-3-carboxamide; 2-[(aminocarbonyl)amino]-5-{4-[(li?)-l-morpholin-4-ylethyl]phenyl}thiophene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-(4-{[4-(2-metlioxyethyl)piperazin-l- yl]methyl}phenyl)thiophene-3-carboxamide;

2-[(ammocarbonyl)amino]-5-[4-(piperidin-l-ylmethyl)pb.enyl]thiopb.ene-3-carboxamide; 2-[(aminocarbonyl)arnino]-5-{4-[(liS',4»S)-2-oxa-5-azabicyclo[2.2.1]liept-5- ylmethyl]phenyl}thiophene-3-carboxamide;

5-{4-[(4-acetylpiρerazin-l-yl)methyl]phenyl}-2-[(aminocarbonyl)amino]thiophene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-[4-(l,4-oxazepan-4-ylmethyl)phenyl]thiophene-3- carboxamide;

(lS)-2-((aminocarbonyl)amino)-5-(4-(l-{moφb.olin-4-yl}ethyl)pr₁enyl)thiopliene-3- carboxamide; ' 2-((aminocarbonyl)amino)-5 -(4-(I -methyl- 1 - {morpholin-4-yl} ethyl)phenyl)thiophene-3 - carboxamide; 2-[(aminocarbonyl)amino]-5-[4-((4-methylpiperazin-l-yl)metliyl)pb.enyl]tliiophene-3- carboxamide; 2-[(aminocarbonyl)amino]-5-[4-((2-ethoxycarbonylpiperidin-l- yl)methyl)phenyl]thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[4-((3-diethylaminocarbonylpiperidin-l-yl)methyl)phenyl]- thiophene-3 -carboxamide; 2-[(aminocarbonyl)amino]-5-[4-((3-hydroxypyrrolidin-l-yl)methyl)phenyl]thiophene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-[4-({(2-hydroxyethyl)piperazin-l- yl}methyl)phenyl]thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-4-methyl-5-{4-[4-morpholino]methylphenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[4-((4-b.ydroxypiperidin-l-yl)methyl)phenyl]thiophene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-(2-piperazin-l-ylphenyl)thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[2-(4-rnethylpiperazin-l-yl)phenyl]thiopliene-3-carboxamide; 2-[(arMnocarbonyl)amino]-5-{2-[3-methylamino)pyrrolidijQ-l-yl]phenyl}ib.iophene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-[4-(cyclopentyloxy)-2-(2-{piperidin-l-yl}ethoxy)phenyl] thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[2-(2- {piperidin- 1 -yl} ethoxy)-4-pyrrolidin- 1 - ylphenyl]thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[4-piperidin-l-yl-2-(2-{piperidin-l- yl} ethoxy)phenyl]thiophene-3 -carboxamide;

2-[(aminocarbonyl)amrno]-5-[4-(rnorpholm-4-ylmetriyl)-2-(2-{piperidiii-l- yl}ethoxy)phenyl]tm^'ophene-3-carboxamide; 2-[(aminocarbonyl)amino]-5-[4-(2-methoxyethoxy)-2-(2-piperidin-l- ylethoxy)phenyl]thiophene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[4-morpholin-4-yl-2-(2-piperidin-l- ylethoxy)phenyl]thiopb.ene-3-carboxamide;

2-[(aminocarbonyl)amino]-5-[2-(2-hydroxyethoxy)phenyl]thiopriene-3-carboxamide; (3i?j-2-[(aminocarbonyl)amino]-5- {2-[tetrahydrofuran-3-yloxy]phenyl} -3- thiophenecarboxamide; (3ii}-2-[(aminocarbonyl)ammo]-5-{2-[tetrahydrofuran-3-yloxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(tetrahydropyran-4-yloxy]phenyl}-3- thiophenecarboxamide; 2- [(aminocarbonyl)amino]-5 - {2- [cyclopropylmethoxyjphenyl} -3 -thiophenecarboxamide;

2-[(aininocarbonyl)ammo]-5-{2-[cyclopentyloxy]phenyl}-3-thiophenecarboxainide;

2-[(aminocarbonyl)amino]-5-{2-[(l-isopropylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-ethylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecaxboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-tert-butyloxycarbonyl-3-pyrrolidinyl)oxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[2-(pyrrolidin-3-yloxy)phenyl]-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-methylpiperidin-2-yl)methoxy]phenyl}-3- thiophenecarboxamide;

(2iS)-2- [(aminocarbonyl)amino] -5 -(2- { [ 1 -methylpyrrolidin-2-yl]methoxy } phenyl)-3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(2-{[l-(2-methoxyethyl)pyrrolidin-3-yl]oxy}phenyl)-3- thiophenecarboxamide; (2i?)-2-[(aminocarbonyl)amino]-5-(2-{[l-methylpyrrolidin-2-yl]methoxy}phenyl)-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[2-(2-(2,2,6-trimethylpiperidin-l-yl)ethoxy)phenyl]-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{5-chloro-2-[(l-isopropylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{4-fluoro-2-[(l-isopropylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{4,5-difluoro-2-[(l-isopropylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{2-[(l-isopropylpyrrolidin-3-yl)oxy]-5-methylphenyl}-3- thiophenecarboxamide; 2-[(aminocarbonyl)amino]-5-{5-cyano-2-[(l-isopropylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-isopropylpyrrolidin-3-yl)oxy]-5-methoxyphenyl}-3- thiophenecarboxamide; s 2-[(aminocarbonyl)amino]-5-{3,5-difluoro-2-[(l-isoρropylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-isopropylpyrrolidin-3-yl)oxy]-3-methoxyphenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-isopropylpyrrolidin-3-yl)oxy]-5-o trifluoromethylphenyll-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-isopropylpyrrolidin-3-yl)oxy]-4- trifluoromethylphenyl} -3 -thiophenecarboxamide;

2- [(amiαocarbonyl)amino] -5-{2-[(l -isopropylpyrrolidin-3 -yl)oxy] -4-methoxyphenyl} -3 - thiophenecarboxamide; s 2- [(aminocarbonyl)amino] -5 - { 5 -fluoro-2-[( 1 -isopropylρyrrolidin-3 -yl)oxy]phenyl} -3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-isopropylpyrrolidin-3-yl)oxy]-3-(morpholin-4- ylmethyl)phenyl}-3-thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-(2-{[(l-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}phenyl)-3-Q thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2- [(l-cycloproρylpyrrolidin-3-yl)oxy]ρhenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(2-(4-fluoropiperidin-l-yl)ethoxy]phenyl}-3- thiophenecarboxamide; 5 2- [(aminocarbonyl)amino]-5 - {2- [( 1 -methylpiperidin-4-yl)oxy]phenyl} -3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(l-methylpyrrolidin-3-yl)oxy]phenyl}-3- thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[4-(2-{morpholin-4-yl}acetyl)phenyl33-0 thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-[2-{2-(4-hydroxy-l-piperidinyl)ethoxy}phenyl]-3- thiophenecarboxamide; 2- [(aminocarbonyl)amino] -5 - [2-(2-(2,2, 6,6-tetramethylpiperidin- 1 -yl)ethoxy)phenyl] -3 - thiophenecarboxamide;

2-[(aminocarbonyl)amino]-5-{2-[2-(3-pyrτolin-l-yl)ethoxy]phenyl} thiophene-3- carboxatnide; cis/trans-2-[(aminocarbonyl)amino]-5-{2-[2-(2,5-dimetb.yl-3-pyrrolin-l- yl)ethoxy]phenylthiophene-3-carboxamide;

(2S)-2-[(aminocarbonyl)amino]-5-[4-(2-methoxymethylpyrrolidin-l-ylmethyl)phenyl] thiophene-3 -carboxamide;

2-[(arainocarbonyl)amino]-5-[4-(4-aminocarbonylpiperidin-l-ylmethyl)pb.enylthiophene- 3-carboxamide;

2-[(aminocarbonyl)amino]-5-[4-(3-hydioxymetb.ylpiperidin-l-ylmethyl)phenyl]thiopliene-

3-carboxamide;

2-[(aminocarbonyl)ammo]-5-[4-(4-hydroxymethylpiperidin-l-ylmethyl)phenyl]thiophene-

3-carboxamide; 2-[(amrnocarbonyl)amino]-5-[2-(3-{morpholin-4-yl}pyrrolidin-l-yl)prienyl]thiopliene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-{2-[4-(2-methoxyethyl)piperazin-l-yl]phenyl}thiophene-3- carboxamide;

2-[(aminocarbonyl)amino]-5-{2-[(7_iS^f, <£S)-2,5-diazabicyclobicyclo[2.2.1]hept-2- yljphenyl} thiophene-3-carboxamide; or a pharmaceutically acceptable salt of any one thereof.

Unless otherwise indicated, the term "Ci-Cg alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. The terms

"C1-C2 alkyl" and "C1-C4 alkyl" are to be interpreted analogously.

Unless otherwise indicated, the term "C2-C3 alkenyl" referred to herein denotes a straight or branched chain alkyl group having 2 or 3 carbon atoms incorporating at least one carbon-carbon double bond. Examples of such groups include ethenyl and propenyl. The term "C2-C6 alkenyl" is to be interpreted analogously. Unless otherwise indicated, the term "C2-C3 alkynyl" referred to herein denotes a straight chain alkyl group having 2 or 3 carbon atoms incorporating one carbon-carbon triple bond. Examples of such groups include ethynyl and propynyl. The term "C2-Cg alkynyl" is to be interpreted analogously.

Unless otherwise indicated, the term "C3-C6 cycloalkyl" referred to herein denotes a saturated carbocyclic ring having from 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.

Unless otherwise indicated, the term "C1-C4 alkoxy" referred to herein denotes a straight or branched chain alkoxy group having 1 to 4 carbon atoms. Examples of such groups include methoxy, ethoxy and isopropoxy. The terms "C1-C2 alkoxy" and "Ci -Cg alkoxy" are to be interpreted analogously,

Unless otherwise indicated, the term "C₁-C₂ alkanoyl" referred to herein denotes a formyl or acetyl group.

Unless otherwise indicated, the term "halogen" referred to herein denotes fluoro, chloro, bromo and iodo.

Examples of a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, pyridine, pyridazine, pyrimidine and pyrazine.

Examples of a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group include cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuran, tetrahydropyran, pyrrolidine, 3-pyrroline, piperidine, piperazine, 8-oxa-3-azabicyclo[3.2.1]octane, pyrrolidone, 2-oxa-5-azabicyclo[2.2.1 ]heptane, 1 ,4-oxazepane, 2,5-diazabicyclo[2.2.1 ]heptane, piperidone and morpholine.

Examples of a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR group include pyrrolidine, piperidine, piperazine and morpholine.

Both general and specific processes for the preparation of compounds of formula (I) are disclosed in WO 03/010158.

The second active ingredient in the combination of the present invention may be a non-steroidal anti-inflammatory agent (hereinafter NSAID) including non-selective cyclo- oxygenase COX-I / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The second active ingredient in the combination of the present invention may alternatively be a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-I); interleukins (IL) including ILl to 23, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.

The second active ingredient in the combination of the present invention may alternatively be a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA- aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).

The second active ingredient in the combination of the present invention may alternatively be a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CRl for the C-X₃-C family.

The second active ingredient in the combination of the present invention may alternatively be an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO)₃ and stromelysin-3 (MMP-Il) and MMP-9 and MMP- 12, including agents such as doxycycline.

The second active ingredient in the combination of the present invention may alternatively be a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; aN-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di- tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substiτuted 2-cyanonaphthalene compound such as L- 739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The second active ingredient in the combination of the present invention may alternatively be a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4. selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamid.es such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The second active ingredient in the combination of the present invention may alternatively be a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The second active ingredient in the combination of the present invention may alternatively be a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.

The second active ingredient in the combination of the present invention may alternatively be a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The second active ingredient in the combination of the present invention may alternatively be an antagonist of the histamine type 4 receptor.

The second active ingredient in the combination of the present invention may alternatively be an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The second active ingredient in the combination of the present invention may alternatively be an anticholinergic agents including muscarinic receptor (Ml, M2, andM3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The second active ingredient in the combination of the present invention may alternatively be a heta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, indacaterol or pirbuterol, or a chiral enantiomer thereof.

The second active ingredient in the combination of the present invention may alternatively be a chromone, such as sodium cromoglycate or nedocromil sodium.

The second active ingredient in the combination of the present invention may alternatively be a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, fluticasone furoate, ciclesonide or mometasone furoate.

The second active ingredient in the combination of the present invention may alternatively be an agent that modulates a nuclear hormone receptor such as PPARs.

The second active ingredient in the combination of the present invention may alternatively be an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).

The second active ingredient in the combination of the present invention may alternatively be another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The second active ingredient in the combination of the present invention may alternatively be a combination of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide. The second active ingredient in the combination of the present invention may alternatively be an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta- lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The second active ingredient in the combination of the present invention may alternatively be a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.

The second active ingredient in the combination of the present invention may alternatively be a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti- Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.

The second active ingredient in the combination of the present invention may alternatively be an agent for the treatment of acute or chronic pain, such as a centrally or peripherally- acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a nonsteroidal anti-inflammatory agent. The second active ingredient in the combination of the present invention may alternatively be a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.

The second active ingredient in the combination of the present invention may alternatively be an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.

The second active ingredient in the combination of the present invention may alternatively be a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) MPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin- B.subl. - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFβ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK.subl. or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS. The second active ingredient in the combination of the present invention may alternatively be an existing therapeutic agent for the treatment of cancer, for example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycm or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin); (ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5oc-reductase such as finasteride;

(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function); (iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab

[C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholrnopropoxy)qumazolin-4-amine (geiϊtinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;

(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin αvβ3 function or an angiostatin);

(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213; (vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or (ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

In one embodiment, the second active ingredient in the combination of the present invention is selected from: a) a PDE4 inhibitor including an inhibitor of the isoform PDE4D; b) a β-adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol; c) a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; d) a modulator of chemokine receptor function (such as a CCRl or CCR8 receptor antagonist); e) an inhibitor of p38 kinase function; f) a glucocorticoid receptor ligand; g) a glucocorticoid; h) a statin; i) a MMP inhibitor (such as a MMP12 or MMP9 inhibitor); j) an epidermal growth factor inhibitor; k) a neutrophil elastase inhibitor; or 1) a histamine type 1 receptor antagonist;

In the context of the present specification, unless otherwise indicated any reference to a second active ingredient includes all active salts, solvates or derivatives thereof.

The pharmaceutical product of the present invention may, for example, be a pharmaceutical composition comprising the first and second active ingredients in admixture. Alternatively, the pharmaceutical product may, for example, be a kit comprising a preparation of the first active ingredient and a preparation of the second active ingredient and, optionally, instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.

The combinations of the present invention can be used in the treatment of inflammatory conditions.

The combinations of the present invention can be used in the treatment of diseases of the respiratory tract such as obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus.

The combinations of the present invention can also be used in the treatment of diseases of bone and joints such as arthritides associated with or including steoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection- related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle- Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies. The combinations of the present invention can also be used in the treatment of pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example, sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis).

The combinations of the present invention can also be used in the treatment of diseases of skin such as psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions.

The combinations of the present invention can also be used in the treatment of diseases of the eye such as blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial.

The combinations of the present invention can also be used in the treatment of diseases of the gastrointestinal tract such as glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, non- inflammatory diarrhoea, and food-related allergies which may have effects remote from the gut (for example, migraine, rhinitis or eczema). The combinations of the present invention can also be used in the treatment of diseases of the cardiovascular system such as atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins.

The combinations of the present invention can also be used in oncology such as in the treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumours and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non- Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes.

In particular, the combinations of the present invention may be used in the treatment of adult respiratory distress syndrome (ARDS), cystic fibrosis, pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, asthma, rhinitis, ischemia-reperiusion injury, rheumatoid arthritis, osteoarthritis, cancer, atherosclerosis and gastric mucosal injury.

More particularly, the combinations of the present invention may be used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and rhinitis.

Even more particularly, the combinations of the present invention may be used in the treatment of chronic obstructive pulmonary disease (COPD).

The combinations of the present invention may demonstrate anti-inflammatory activity at dose levels where either component alone does not significantly affect inflammation. The combinations of the present invention may exhibit an anti-inflammatory activity that is greater than that expected from the additive effect of the two ingredients. Such a synergistic effect observed when combining the ingredients could be used, for example, to lower the therapeutic dose of one active ingredient, or at the same dose, to achieve an enhanced efficacy on inflammation in comparison to the use of the single active ingredient alone.

The pharmaceutical product of the present invention may further optionally comprise a third active ingredient. The third active ingredient may be chosen from the same list as for the second active ingredient.

The inhibitor of IKK2 (first active ingredient), second active ingredient and optionally third active ingredient of the present invention may be administered simultaneously, sequentially or separately to treat respiratory diseases. By sequential it is meant that the active ingredients are administered, in any order, one immediately after the other. They still have the desired effect if they are administered separately, but when administered in this manner they are generally administered less than 4 hours apart, more conveniently less than two hours apart, more conveniently less than 30 minutes apart and most conveniently less than 10 minutes apart.

The active ingredients of the present invention may be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions. The active ingredients may also be administered topically (to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations. These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity- regulating agents, surfactants, preservatives, flavourings and colorants. As will be understood by those skilled in the art, the most appropriate method of administering the active ingredients is dependent on a number of factors. In one embodiment of the present invention the active ingredients are administered via separate pharmaceutical preparations.

Therefore, in one aspect, the present invention provides a kit comprising a preparation of a first active ingredient which is an inhibitor of IKK2 or a pharmaceutically acceptable salt thereof, and a preparation of a second active ingredient, and optionally instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof. The kit may further optionally comprise a preparation of a third active ingredient.

In another embodiment the active ingredients may be administered via a single pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising, in admixture, a first active ingredient which is an inhibitor of IKK2 or pharmaceutically acceptable salt thereof, and a second active ingredient. The pharmaceutical composition may further optionally comprise a third active ingredient. The present invention also provides a process for the preparation of a pharmaceutical composition which comprises mixing the first active ingredient with the second active ingredient and optionally with the third active ingredient.

The pharmaceutical compositions of the present invention may be prepared by mixing the first active ingredient and the second active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier, and, optionally, the third active ingredient. Therefore, in a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical composition, which comprises mixing an inhibitor of IKK2 or a pharmaceutically acceptable salt thereof, with a second active ingredient, and a pharmaceutically acceptable adjuvant, diluent or carrier, and, optionally, a third active ingredient.

It will be understood that the therapeutic dose of each active ingredient administered in accordance with the present invention will vary depending upon the particular active ingredient employed, the mode by which the active ingredient is to be administered, and the condition or disorder to be treated.

In one embodiment of the present invention, the first, second (and when present, the third) active ingredients of the present invention are each administered by inhalation. In this aspect, the active ingredients are inhaled simultaneously, sequentially or separately.

Throughout the specification, the amount of the active ingredients used relate to inhaled unit doses unless explicitly defined differently.

When administered via inhalation the dose of the first active ingredient (an inhibitor of IKK2 or a pharmaceutically acceptable salt thereof), will generally be in the range of from 0.1 μg to 10000 μg, 0.1 to 5000 μg, 0.1 to 1000 μg, 0.1 to 500 μg, 0.1 to 200 μg, 0.1 to 200 μg, 0.1 to 100 μg, 0.1 to 50 μg, 5 μg to 5000 μg, 5 to 1000 μg, 5 to 500 μg, 5 to 200 μg, 5 to 100 μg, 5 to 50 μg, 10 to 5000 μg, 10 to 1000 μg, 10 to 500 μg, 10 to 200 μg, 10 to 100 μg, 10 to 50 μg, 20 to 5000 μg, 20 to 1000 μg, 20 to 500 μg, 20 to 200 μg, 20 to 100 μg, 20 to 50 μg, 50 to 5000 μg, 50 to 1000 μg, 50 to 500 μg, 50 to 200 μg, 50 to 100 μg, 100 to 5000 μg, 100 to 1000 μg or 100 to 500 μg.

When administered via inhalation the dose of the second active ingredient will generally be in the range of from 0.1 microgram (μg) to 1000 μg, 0.1 to 500 μg, 0.1 to 200 μg, 0.1 to 100 μg, 0.1 to 50 μg, 0.1 to 5 μg, 5 to 1000 μg, 5 to 500 μg, 5 to 200 μg, 5 to 50 μg, 5 to 10 μg, 10 to 1000 μg, 10 to 500 μg, 10 to 200 μg, 10 to 100 μg, 10 to 50 μg, 20 to 1000 μg, 20 to 500 μg, 20 to 200 μg, 20 to 100 μg, 20 to 50 μg, 50 to 1000 μg, 50 to 500 μg, 50 to 200 μg, 50 to 100 μg, 100 to 1000 μg, or 100 to 500 μg.

In one embodiment, the amount of the first active agent used is in the range 1 μg to 200 μg, and that of the second agent in the range 1 μg to 200 μg. The molar ratio of the second active ingredient to the first active ingredient in a dose may typically be in the range of 1 : 10 to 10:1. Preferably the ratio is in the range 1 : 1 to 10: 1 , and preferably still, in the range 5:1 to 20:1.

When present, the third active ingredient may conveniently be administered by inhalation at a dose generally in the range of from 0.1 to 100 μg, 0.1 to 50 μg, 0.1 to 40 μg, 0.1 to 30 μg, 0.1 to 20 μg, 0.1 to 10 μg; 5 to 100 μg, 5 to 50 μg, 5 to 40 μg, 5 to 30 μg, 5 to 20 μg, 5 to 10 μg, 10 to 100 μg, 10 to 50 μg, 10 to 40 μg, 10 to 30 μg, or 10 to 20 μg. In an embodiment of the present invention, the dose of the third active ingredient is in the range 1 to 30 μg.

The doses of the first and second (and where present the third) active ingredients will generally be administered from 1 to 4 times a day, conveniently once or twice a day, and most conveniently once a day.

In one embodiment, the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a an inhibitor of IKX2 or a pharmaceutically acceptable salt thereof, and a second active ingredient, and optionally a third active ingredient, wherein each active ingredient is formulated for inhaled administration.

The active ingredients are conveniently administered via inhalation (e.g. topically to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations. Administration may be by inhalation orally or intranasally. The active ingredients are preferably adapted to be administered, either together or individually, from a dry powder inhaler, pressurised metered dose inhaler, or a nebuliser.

The active ingredients may be used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers. Examples of suitable diluents or carriers include lactose (e.g. the monohydrate), dextran, mannitrol or glucose. Metered dose inhaler devices may be used to administer the active ingredients, dispersed in a suitable propellant and with or without additional excipients such as ethanol, a surfactants, a lubricant, an anti-oxidant or a stabilising agent. Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants. Preferred propellants are P134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients. Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.

Dry powder inhalers may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture. The dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.

When the active ingredients are adapted to be administered, either together or individually, via a nebuliser they may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a single dose or multidose device.

Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.

In an embodiment of the present invention, the inhibitor of IKK2 or pharmaceutically salt thereof may be administered orally and the other active ingredient(s) administered by inhalation.

The present invention further provides a pharmaceutical product, kit or pharmaceutical composition according to the invention for simultaneous, sequential or separate use in therapy. The present invention further provides the use of a pharmaceutical product, kit or pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of a respiratory disease, in particular chronic obstructive pulmonary disease or asthma.

The present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering:

(a) a (therapeutically effective) dose of a first active ingredient which is an inhibitor ofo IKK2 or a pharmaceutically acceptable salt thereof; and

(b) a (therapeutically effective) dose of a second active ingredient; and optionally

(c) a (therapeutically effective) dose of a third active ingredient; to a patient in need thereof. s In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the condition or disorder in question.0 Persons at risk of developing a particular condition or disorder generally include those having a family history of the condition or disorder, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition or disorder. s The present invention will now be further understood by reference to the following illustrative examples.

Human IKK2 SPA Kinase Assay

Compounds were tested for inhibition of human IKK2 using a Scintillation Proximityo Assay (SPA) kinase assay. The test compounds were dissolved to 10 mM in dimethylsulphoxide (DMSO). The compounds were then serial diluted 1 to 5 with DMSO. One μL of diluted test compounds was added to wells of 96-well assay plates (Corning #3604; white, flat with clear bottom). Duplicates were added on separate assay plates. Controls were added to assay plate columns 1 and 12. As 0% control 1 μL DMSO was used and as 100 % control 1 μL 400 μM AZl 1705240 was used (around 1000*IC₅₀ as final concentration in the assay).

Human full length FLAG-IKK2-6His, stably expressed in baculovirus transfected insect cells and purified on Ni-NTA column, was used in the kinase assay. The IKK2 protein was diluted in ice-cold Assay Buffer consisting of 50 mM Tris (pH 7.4), 10 mM magnesium acetate, 0.1 mM Na₃VO₄ (added fresh and newly heated), 0.1 mM NaF, 1 mM dithiotreitol (added fresh), 0.01% Triton X-100 and 5% glycerol, together with the kinase peptide substrate (AnaSpec #60213-1 CA95131; biotin-DRHDSGLDSMKD-NH₂). Thirty μL of the IKK2 (45 ng protein/well)/peptide substrate solution was added to each well of the assay plates and preincubated for 15 minutes at room temperature (RT). The kinase reaction was started by the addition of 10 μL ATP solution (RT) consisting of ATP and [γ-

P]ATP (Amersham #AH9960) diluted in Assay Buffer. The final concentration during phosphorylation of biotin-DRHDSGLDSMKD-NH₂ was 3 μM and 0.5 μM of ATP (around Km, 0.045 μCi [γ-³³P]ATP). The kinase reaction was stopped after 60 minutes (linear phosphorylation) incubation at room temperature by adding 200 μL SPA stop solution, consisting of 1 mg streptavidin-coated SPA beads/200 μL (Amersham #RPNQ0007) in 50 mM Tris (pH 7.4), 0.01% Triton X-100 and 40 mM EDTA. The assay plates were sealed with plastic foil and left for 60 minutes to allow the substrate to bind to the SPA beads. After centrifugation at 2500 rpm for 5 minutes on a Hettig Rotanta 460 R centrifuge, the assay plates were analyzed on a plate-based liquid scintillation counter (Wallac Microbeta 1450 Trilux).

The IC₅Q values were calculated using XLfit 4.1.1. Inflammatory cell influx experiment in LPS-challenged rats

The effect of an IKK2 inhibitor and a second active ingredient, and their combination, on inflammatory cell influx may be assayed by monitoring the effect on total cell number and neutrophils specifically in broncholalveolar lavage (BAL) fluid of rats challenged intra- tracheally (i.t.) with Lipopolyaccharide (LPS) [N = 8 rats per treatment group].

Methodology

LPS instillation: Rats were anaesthetized with Efrane and put in a supine position, head up, on a board tilted at 30°. LPS (Lipopolysaccharide B.E.coli 026:B6) (2.5 μg/ml) dissolved in saline (0.9% NaCl), or saline alone (negative control) in a volume of 200 μl was administered intratracheally using a modified metal cannula.

Preparation of solutions: The first and second active ingredients are separately dissolved in appropriate vehicles (for example, ethanol) and then mixed with 3.66 mM citric acid 1- hydrate and 15.85 mM sodium hydrogen phosphate, pH: 6.5 solution to give a suitable final concentration depending on the activity of the particular compound. Combination formulations were prepared similarly.

Treatments: Animals were intratracheally instilled with solutions (1 ml/kg) of the combination, or of the first active ingredient alone, or of the second active ingredient alone, or with saline (negative and positive control animals). The treatments were carried out under light anaesthesia (Efrane) to secure that the solution reached the lungs. The drugs were administrated 30min before the LPS instillation.

Termination: 4 hours after the LPS challenge, rats were intraperitoneally injected with the mixture (0.3 ml) of pentobarbital (60 mg/mL Apoteksbolaget, Sweden) and PBS (1:1) for 1 — 2 min. Bronchoalveolar lavage: After termination, BAL was performed twice with PBS. The BAL fluid was centrifuged and the cell pellet was resuspended in PBS. The total numbers of BAL cells were counted in a SYSMEX cell counter. Differential cell counts were obtained from May-Grunwald-stained cytospin (Shandon, UK) slides and the proportion of neutrophils, lymphocytes, eosinophils, and large mononuclear cells were determined. The amount of TNF-α in the supernatant of BAL was measured by a commercially available ELISA kit (R&D Systems Inc., Minneapolis, MN, USA).

Inhibition of TNFα stimulated IL-8 release by NHBE cells The effect of test compounds on nuclear factor kappa B (NFKB) activation in cells was assessed by measuring inhibition of Interleukin-8 (IL-8) production by Normal Human Bronchial Epithelial (NHBE) cells stimulated with tumour necrosis factor alpha (TNFα). Primary NHBE cells (Clonetics, San-Diego, CA, USA) were obtained from In Vitro Sweden AB (Stockholm, Sweden). The cells were cultured in Bronchial Epithelial cell Growth Medium (BEGM) according to the manufacturer's instructions (Clonetics, catalogue # CC-3170). BEGM consisted of basal medium (BEBM) supplemented with bovine pituitary extract (52 mg/mL), hydrocortisone (0.5 mg/mL), HEGF (0.5 ng/mL), epinephrine (0.5 mg/mL), transferrin (10 mg/mL), insulin (5 mg/mL), retinoic acid (0.1 ng/mL) and triiodothyronine (6.5 ng/mL), all supplied by Clonetics. Cultures were maintained at 37 °C in a humidified atmosphere of 5% CO2 in air. Cells were sub-cultured using the methods and reagents provided by Clonetics (catalogue # CC-5034). AU experiments were performed on cells at passages 2, 3, 4 and 5. During experiments the cells were grown in incomplete BEGM medium, lacking hydrocortisone, retinoic acid and epinephrine, hereafter referred to as -BEGM medium. Cells were seeded in non-coated 24-well plates (Costar, Cambridge, MA, USA) and grown in BEGM until ± 60% confluency. Experiments were started by starving the cells in -BEGM medium for 24 h, where after 10 μg/mL human recombinant TNFα (R&D Systems, Minneapolis, MN, USA) was added in the presence or absence of the IKK2 inhibitor and/or the second active agent. Test compounds were dissolved in DMSO to 10 mM and diluted 1 : 10 in DMSO to obtain the correct "stock" dilutions. These "stock" dilutions contained a 1000 times higher concentration than the final concentration in the cells, since 1 μl of each "stock" dilution in DMSO was added to the wells containing cells in 1 ml medium. DMSO concentrations up to 0.3% have been tested and shown to not interfere with the read-out. Cells were treated for 24 h and the experiment was ended by centrifuging the plates for 10 minutes at 1000 rpm, 4 °C. Each exposure was performed in duplicate and supernatants stored at -70 ⁰C until use. DNA content was measured to correct for the number of cells present in each well. Experiments were repeated several times with different batches of NHBE cells at different passage numbers. The amount of DNA was measured according to the modified method of Blaheta et al., J Immunol Methods (1991), 142, 199-206. After centrifugation and collection of the supernatants as described above, the 24-well plates were kept on ice, and 600 μL PBS was added to each well followed by the addition of 400 μL 10 μg/mL H33342 (Sigma, catalogue # B2261)/PBS. A standard curve was generated by using aliquots of calf thymus DNA (Sigma, catalogue # D1501) diluted in PBS. The plates were covered with foil and incubated for 30 minutes at room temperature. The fluorescence was measured and DNA amounts were calculated in μg/mL.

After dilution of the collected supernatant samples, IL-8 levels were detected by enzyme- linked immunosorbent assay (ELISA), using human IL-8 Quantikine ELISA kit (R&D Systems, Minneapolis, MN, USA, catalogue # D8000C). The ELISA was performed as described by the manufacturer. The amount of IL-8 in each sample was calculated from the standard curve, determined in pg/mL culture medium, and related to the DNA content in the corresponding well. All samples were analysed in duplicate. The absorbance at 450 nm was measured by spectrophotometry.

Claims

C L A I M S

1. A pharmaceutical product comprising, in combination,

(a) a first active ingredient which is an inhibitor of IKK2 or a pharmaceutically acceptable salt thereof; and (b) a second active ingredient.

2. A product according to claim 1, wherein the first active ingredient is a compound of formula (I)

(R³)n

in which:

R represents NH2 or R represents a methyl group optionally substituted by one or more groups selected independently from C1-C4 alkyl, C3-C6 cycloalkyl, halogen, hydroxyl, Ci-C₄ alkoxy, S(O)_VCH₃ and NR⁴R⁵;

X represents O or S;

-COO , -NR⁶COR⁷, -S(O)_1nR⁶, -SO₂NR⁶R⁷, -NR⁶SO₂ R⁷, Ci-C₂ alkyl, trifluoromethyl, C2-C3 alkenyl, C2-C3 alkynyl, trifluoromethoxy, C]₁-C₂ alkoxy or C1-C2 alkanoyl;

A represents a phenyl ring or a 5- to 7-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, nitro, -NR⁸R⁹, -CONR⁸R⁹, -COOR⁸, -NR⁸COR⁹, -S(O)₈R⁸,

O Q O Q | Λ 1 1

-SO₂NR R , -NR SO₂R , Ci-C₆ alkyl, trifluoromethyl, -(CH₂)_tR , -0(CH₂)_tR or- OR¹²;

3 n represents an integer 1 or 2; and when n represents 2, each R group may be selected independently;

3 R represents a group -W-Y-Z wherein:

W represents O, S(O)₁, NR¹³, CH₂, -CH₂-O- or a bond;

Y represents a bond or a group -(CH₂)p-T-(CH₂)q- wherein p and q independently

14 15 represent an integer O, 1 or 2; and T represents O, -CO- or CR R ;

14 15 R and R independently represent H, CH3 or F;

14 15 or R represents H or CH3 and R represents hydroxyl or OCH3;

14 15 or the group CR R together represents a C3-C6 cycloalkyl ring;

Z represents: (a) a phenyl ring or a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S; said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR¹⁶R¹⁷, -CONR¹⁶R¹⁷, -COOR¹⁶, -COR¹⁶ -NR¹⁶COR¹⁷, -S(O)₁₁R¹⁶, -SO₂NR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ alkyl and

Ci-C₆ alkoxy; said alkyl or alkoxy group being optionally further substituted by one or

18 19 more groups selected from halogen, cyano, hydroxyl, C1-C4 alkoxy and NR R ; or

(b) a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from

O₃ N and S, and optionally incorporating a carbonyl group; said ring system being optionally substituted by one or more substituents selected independently from halogen, cyano, -NR¹⁶R¹⁷, -CONR¹⁶R¹⁷, -COOR¹⁶, -COR¹⁶, -NR¹⁶COR¹⁷, -S(O)_UR¹⁶, -SO₂NR¹⁶R¹⁷, -NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ alkyl, C3-Q cycloalkyl and Ci-C₆ alkoxy; said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano, hydroxyl, C3"C₆ cycloalkyl, C1-C4 alkoxy and NR R ; provided that said saturated monocyclic ring Z is not bonded to Y through nitrogen if the group -W-Y- represents -(CH₂)₂_4~ or — O-(CH₂)₂_4- when the saturated ring Z is also unsubstituted; or

(c) if W represents O, then Z may also represent hydroxyl, OCH3, CF3, CHF₂ or CH₂F, provided that the group -Y-Z does not thereby represent -O-(CH2)₂_4-OCH3;

R and R independently represent NR R where R and R are independently

20 21 hydrogen or Ci-C₆ alkyl optionally substituted by C1-C4 alkoxy; or the group NR R represents a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S 22 22 10 11 or NR group; where R is hydrogen or Ci-Cg alkyl; or R and R independently

represent Cj-Cg alkoxy;

4 5 4 5

R and R independently represent H or C1-C4 alkyl; or the group NR R represents a

23 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR

23 group; where R is hydrogen or C1-C4 alkyl;

R and R independently represent H or C1-C2 alkyl;

8 9 12 R ₅ R and R independently represent H or C^-Cg alkyl;

R represents H or C1-C4 alkyl;

independently represent H or Q-Cg alkyl optionally substituted by OH,

C1-C4 alkoxy or one or more fluoro atoms; or the group NR R represents a 5- or 6-

24 membered saturated azacyclic ring optionally containing a further O, S or NR group;

24 where R is hydrogen or Ci-Cg alkyl optionally substituted by OH, C1-C4 alkoxy or one or more fluoro atoms;

18 19 18 19 R and R independently represent H or C1-C4 alkyl; or the group NR R represents a

25 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR

25 group; where R is hydrogen or C1-C4 alkyl;

m, r, s, u and v independently represent an integer 0, 1 or 2;

t represents an integer 2, 3 or 4; or a pharmaceutically acceptable salt thereof.

3. A product according to claim 1 or claim 2, wherein the second active ingredient is selected from: s a) a PDE4 inhibitor including an inhibitor of the isoform PDE4D; b) a β-adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol; o c) a muscarinic receptor antagonist (for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist) such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine; d) a modulator of chemokine receptor function (such as a CCRl or CCR8 receptor antagonist); 5 e) an inhibitor of p38 kinase function; f) a glucocorticoid receptor ligand; g) a glucocorticoid; h) a statin; i) a MMP inhibitor (such as a MMP 12 or MMP9 inhibitor); 0 j) an epidermal growth factor inhibitor; k) a neutrophil elastase inhibitor; or 1) a histamine type 1 receptor antagonist; or an active salt, solvate or derivative thereof.

5 4. A product according to any preceding claim, which is in a form suitable for administration by inhalation.

5. Use of a product according to any preceding claim, in the manufacture of a medicament for the treatment of a respiratory disease. 0

6. Use according to claim 5, wherein the respiratory disease is chronic obstructive pulmonary disease.

7. Use according to claim 5, wherein the respiratory disease is asthma.