WO2011098801A1 - Inflammatory disease treatment - Google Patents

Abstract

Compounds of formula (I) are useful in the treatment of inflammatory disease wherein at least 95% by weight of the said compound of formula (I) is in the stereoconfiguration shown in formula (IA) and less than 5% by weight is in the stereoconfiguration shown in formula (IB) in which formulae (I), (IA) and (IB): R is CH₃- or hydrogen; X¹ is -OR¹, -S(O)_nR² or -NR³R⁴ and X² is-OH; or X¹ and X² taken together represent a radical *-OC(O)NH-** or *-C(O)N(H)O-** wherein the bond marked * is attached to the carbon to which W and R are attached, and the bond marked ** is attached to the carbonyl carbon; R¹ and R² are independently C_1-6 alkyl optionally substituted with one or more halogen atoms; C_1-6 alkoxyalkyl; or aryl R³ and R⁴ are independently hydrogen; C_1-6 alkyl; aryl; a group -C(R^a)=C(R^b)-C(=O)-Ar^a wherein R^a and R^b are independently hydrogen or C_1-6 alkyl and Ar^a is aryl; or a group -Ar^b-C(=O)-Ar^c wherein Ar^b and Ar^c are aryl; or -C(=O)O-R^c wherein R^c is an aryl or C_1-6alkyl; or R³ and R⁴ taken together with the nitrogen to which they are attached form a saturated ring of 3 to 7 ring members or an unsaturated ring of 5 to 7 ring members; n is 0,1 or 2; W is a group which when linked to the -C(R)(X¹)C(=O)X² results in a compound (I) having PPARγ agonist activity.

Description

Inflammatory Disease Treatment

This invention relates to the use of certain compounds with Peroxisome Proliferation Receptor gamma receptor (PPARy) agonist activity, and having a defined

stereoconfiguration, for treatment of inflammatory diseases, such as inflammatory respiratory diseases.

Background to the invention Among the leading causes of mortality worldwide, including cardiovascular disease, stroke, cancer, and a variety of other diseases including respiratory diseases, many are, at least in part, caused by the body's own inflammatory response. Ischemic heart disease, for example, is the leading cause of death in the United States.

Approximately 1.5 million people in the U.S. alone suffer heart attacks, a common complication of ischemic disease, and approximately 1/3 of those individuals experience a fatal attack. Ischemic disease has been associated with elevated markers of inflammation, and certain pro-inflammatory molecules are proposed to play a role in development of the disease state: Cancer has also been associated with inflammation, particularly chronic inflammation. Stroke can be a result of inflammation of the blood vessel walls. Stroke is the third leading cause of death in the United States and the most common cause of disability in adults.

Inflammation occurs in many other conditions for example in inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, arthritis,

neuroinflammation, Alzheimer's, Parkinson's disease, pain, fever, fibrotic diseases, cardiovascular diseases, post -ischemic reperfusion injury and congestive heart failure, cardiomyopathy, atherosclerosis, reperfusion injury, renal reperfusion injury, brain edema, neurotrauma and brain trauma, neurodegenerative disorders, central nervous system disorders, liver disease, hepatitis and nephritis, gastrointestinal conditions, ulcerative diseases, Crohn's disease, ophthalmic diseases,

ophthalmological conditions, glaucoma, acute injury to the eye tissue and ocular traumas, diabetic nephropathy, skin-related conditions, myalgias due to infection, influenza, endotoxic shock, toxic shock syndrome, autoimmune disease, graft rejection, bone resorption diseases, multiple sclerosis, autoimmune

encephalomyelitis, psoriasis, dermatitis, eczema, diverticulitis, coeliac disease, disorders of the female reproductive system, pathological (but non -malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone, benign and malignant tumors/neoplasia, obesity-related

inflammation and infection.

Inflammation plays a major role in the development of many respiratory diseases including pulmonary artery hypertension, tuberculosis, lung cancer,

chronic or acute bronchoconstriction, bronchitis including infectious and eosinophilic bronchitis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoisosis, silicosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cryptogenic fibrosing alveolitis, respiratory failure, acute respiratory distress syndrome, emphysema, chronic bronchitis, tuberculosis, acute lung injury and bronchiectasis, allergic airway syndrome, cystic fibrosis, 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, 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 (prophylactic and therapeutic therapy), coronavirus (including SARS) and adenovirus, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, farmer's lung and related diseases; hypersensitivity

pneumonitis, respiratory failure, acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma (allergic, intrinsic, extrinsic, exercise- induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma), mild asthma, moderate asthma, severe asthma, steroid resistant asthma and other pulmonary disorders and diseases such as hyperoxic alveolar injury.

Current therapy for COPD and asthma focuses mainly on the reduction of symptoms using short and long acting bronchodilators either as monotherapies or combinations of long acting β₂ agonist bronchodilators with inhaled corticosteroids (ICS). Whilst in general, the treatment of asthma is well served by current therapy, the disappointing anti-inflammatory data for ICS either alone or in combination with β₂ agonists has intensified the search for an effective anti-inflammatory drug for COPD. COPD is a chronic inflammatory disorder that involves complex interactions between cells of the innate and acquired immune response both in the lung and potentially also systemically. One hypothesis under intense investigation is whether novel, demonstrably anti-inflammatory agents can halt or slow the functional decline characteristic of COPD. Reducing the frequency and severity of exacerbations has become an increasingly important target for COPD therapy as the prognosis for patients following exacerbations is poor. Anti-inflammatory therapy in COPD, as in asthma, is expected to reduce the frequency and severity of exacerbations. It is also desirable that decline in lung function and quality of life are also ameliorated with treatment.

Hence, new treatments for inflammatory diseases such as inflammatory respiratory diseases, including asthma, severe asthma and COPD are constantly sought.

Peroxisome Proliferation Receptor gamma receptor (PPARy) agonists are a class of drugs which increase sensitivity to glucose in diabetic patients. Physiological activation of PPARy is believed to increase the sensitivity of peripheral tissues to insulin, thus facilitating the clearance of glucose from the blood and producing the desired anti-diabetic effect.

Many PPARy agonists are known from the patent and other literature, but currently only two are approved for clinical use in diabetes; Rosiglitazone and Pioglitazone. See Campbell IW, Curr Mol Med. 2005 May; 5(3):349-63. Both of these compounds are thiazolidinediones ("TZDs" or "glitazones"), and are in practice administered by the oral route for systemic delivery.

In addition to its effect on glucose metabolism, a variety of reports have been published which demonstrate that rosiglitazone also exerts anti-inflammatory effects. For instance, (i) rosiglitazone has been reported to exert effects in diabetic patients consistent with an anti-inflammatory effect (Haffner et al., Circulation. 2002 Aug 6;106(6):679-84, Marx et al., Arterioscler. Thromb. Vase. Biol. 2003 Feb 1 ;23(2):283- 8); (ii) Rosiglitazone has been reported to exert anti-inflammatory effects in a range of animal models of inflammation, including: carageenan-induced paw oedema

(Cuzzocrea et al., Eur. J. Pharmacol. 2004 Jan 1 ;483(1 ):79-93), TNBS-induced colitis (Desreumanux et al., J. Exp. Med. 2001 Apr 2;193(7):827-38, Sanchez-Hidalgo et al., Biochem. Pharmacol. 2005 Jun 5;69( 12): 1733-44), experimental encephalomyelitis (Feinstein et al., Ann. Neurol. 2002 Jun;51 (6):694-702) collagen-induced (Cuzzocrea et al., Arthritis Rheum. 2003 Dec;48(12):3544-56) and adjuvant-induced arthritis (Shiojiri et al., Eur. J. Pharmacol. 2002 Jul 19;448(2-3):231-8), carageenan-induced pleurisy (Cuzzocrea et al., Eur. J. Pharmacol. 2004 Jan 1 ;483(1 ):79-93), ovalbumin- induced lung inflammation (Lee et al., FASEB J. 2005 Jun;19(8): 1033-5) and LPS- induced lung tissue neutrophilia (Birrell et al., Eur. Respir. J. 2004 Jul;24(1 ): 18-23) and (iii) rosiglitazone has been reported to exert anti-inflammatory effects in isolated cells, including iNOS expression in murine macrophages (Reddy et al., Am. J.

Physiol. Lung Cell. Mol. Physiol. 2004 Mar;286(3):L613-9), TNF -induced MMP-9 activity in human bronchial epithelial cells (Hetzel et al., Thorax. 2003 Sep;58(9):778- 83), human airway smooth muscle cell proliferation (Ward et al., Br. J. Pharmacol. 2004 Feb; 141(3):517-25) and MMP-9 release by neutrophils (WO 2000/062766). PPARy agonists have also been shown to be effective in models of pulmonary fibrosis (Milam et al., Am. J. Physiol. Lung Cell. Mol. Physiol, 2008, 294(5):L891 -901 ) and pulmonary arterial hypertension (Crossno et al., Am. J. Physiol. Lung Cell. Mol. Physiol, 2007, 292(4):L885-897). Based on observations of anti-inflammatory activity in cells, for example cells relevant to the lung, the utility of other PPARy agonists has been suggested for the treatment of inflammatory respiratory disorders including asthma, COPD, cystic fibrosis and pulmonary fibrosis. See WO 2000/053601 , WO 2002/013812 and WO0062766. These suggestions include administration by both the systemic oral and pulmonary inhalation routes.

Unfortunately, PPARy agonists also have unwanted cardiovascular effects, including haemodilution, peripheral and pulmonary oedema and congestive heart failure (CHF). These effects are also believed to result from activation of PPARy. In particular, a significant effort has been devoted to investigating the hypothesis that PPARy agonists disturb the normal maintenance of fluid balance via binding to the PPARy receptor in the kidney. See Guan et al, Nat. Med. 2005; 1 1 (8):861-6 and Zhang et. al., Proc. Natl. Acad. Sci. USA. 2005 28;102(26):9406-1 1. Treatment with PPARy agonists by the oral route for systemic delivery is also associated with an unwanted increase in body weight.

Pioglitazone has structural formula (I)

and can be named as 5-{4-[2-(5-ethylpy din-2-yl)ethoxy]benzyl}-1 ,3-thiazolidine-2,4- dione. The carbon atom in the 5-position of the thiazolidine-dione ring of pioglitazone, indicated by an arrow in formula (I) above, is asymmetric, so pioglitazone has two enantiomers, the 5R and 5S enantiomers.

Rosiglitazone has the structural formula (II) and can be named as 5-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy]benzyl}-1 ,3-thiazolidine-2,4-dione. The carbon atom in the 5-position of the thiazolidine-dione ring of rosiglitazone, indicated by an arrow in formula (II) below, is also asymmetric, so rosiglitazone also has two enantiomers, the 5R and 5S enantiomers.

The 5S enantiomer of rosiglitazone has a higher binding affinity for the PPARy receptor than the 5R enantiomer (30nM vs 2μ , Parks et al, 1998, Bioorg. Med.

Chem. Lett. 8(24):3657-8). For another member of the glitazone class, Rivoglitazone, the 5S enantiomer also has higher receptor binding affinity than the 5R enantiomer (see page 13 of WO 2007/100027). In practice, pioglitazone and rosiglitazone are administered for treatment of diabetes as a mixture of 5R and 5S enantiomers (a 1 :1 racemic mixture) by the oral route for systemic delivery. The individual enantiomers of these compounds, and members of the glitazone family generally, are known to equilibrate rapidly in vivo after oral administration (see for example J.Clin. Pharmacol. 2007, 47, 323-33; Rapid

Commun. Mass Spectrom. 2005, 19, 1125-9; J. Chromatography, 835 (2006), 40-46; Biopharmaceutics and Drug Disposition 1997, 18 (4), 305-24; Chem. Pharm. Bull 1984, 32, (1 1 ) 4460-65; T. J. Med. Chem. 1991 , 34, 319-25) so there is no difference in practice between oral administration of either substantially pure isomer and oral administration of the racemic mixture. Specifically in relation to pioglitazone, it has been stated in a submission to the Federal Drug Administration (FDA) that there was no difference in activity following oral administration either of the racemate or the individual enantiomers in a rodent diabetes model

(www.fda.gov/medwatch/SAFETY/2007/Sep Pl/Actoplus Met Pl.pdf):

"(Pioglitazone) contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the

pharmacologic activity between the two enantiomers".

As used herein, the term "enantiomeric excess" or its abbreviation "e.e." is defined as the percentage:

((R-S)/(R+S)) x 100 percent where R and S are the respective weight fractions of the R and S enantiomers in a sample. Thus for a sample containing 95% by weight of the 5R enantiomer and 5% of the 5S enantiomer, the enantiomeric excess of R over S enantiomer is ((95- 5)/95+5)) x 100 = 90%.

Brief summary of the invention

This invention is based on the finding that, in the case of a class of PPARy agonist compounds defined herein having specific asymmetric centre, one of the

configurations at that centre is preferred over the other for treatment of inflammatory conditions, for example respiratory inflammatory conditions, and that preferred configuration is not that which the state of the art suggests is preferred for the PPARy agonist activity of the glitazones such as rosiglitazone. Proof of principle drives from an animal model of treatment of inflammatory respiratory disease, in which the compounds with which the invention is concerned, having the preferred

stereoconfiguration have been shown to be active without evidence of systemic side effects, whereas those with the opposite stereoconfiguration have some anti- inflammatory activity but also evidence of systemic side effects. This finding leads to the conclusion that compounds that have the preferred stereoconfiguration deliver a potent anti-inflammatory effect without the systemic side effects observed with compounds of the other stereoconfiguration. Brief description of the figures Figure 1 is a bar graph (mean ±SD) that illustrates the effect of oral administration to laboratory mice with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 1 (0.3 mg/kg), Compound 1 (1 mg/kg), Compound 1 (3 mg/kg) or Compound 1 (10 mg/kg), on the number of BAL cells induced by tobacco smoke for 4 days examined 24 hours post the final exposure.

Figure 2 is a bar graph (mean ±SD) that illustrates the effect of oral administration to laboratory mice with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 1 (0.3 mg/kg), Compound 1 (1 mg/kg), Compound 1 (3 mg/kg) or Compound 1 (10 mg/kg), on the change in body weight following treatment for 4 days examined 24 hours post the final exposure.

Figure 3 is a bar graph (mean ±SD) that illustrates the effect of oral administration to laboratory mice with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 2 (0.01 mg/kg), Compound 2 (0.1 mg/kg), Compound 2 (1 mg/kg) or Compound 2 (10 mg/kg), on the number of BAL cells induced by tobacco smoke for 4 days examined 24 hours post the final exposure. Figure 4 is a bar graph (mean ±SD) that illustrates the effect of oral administration to laboratory mice with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 2 (0.01 mg/kg), Compound 2 (0.1 mg/kg), Compound 2 (1 mg/kg) or Compound 2 (10 mg/kg), on the change in body weight following treatment for 4 days examined 24 hours post the final exposure.

Figure 5 is a bar graph (mean ±SD) that illustrates the effect of oral administration to laboratory mice with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 3 (0.1 mg/kg), Compound 3 (1 mg/kg), Compound 3 (10 mg/kg) or racemic Pioglitazone (10 mg/kg), on the number of BAL cells induced by tobacco smoke for 4 days examined 24 hours post the final exposure.

Figure 6 is a bar graph (mean ±SD) that illustrates the effect of oral administration to laboratory mice with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 4 (0.1 mg/kg), Compound 4 (1 mg/kg), Compound 4 (10 mg/kg) or Compound 3 (10 mg/kg), on the number of BAL cells induced by tobacco smoke for 4 days examined 24 hours post the final exposure. Detailed description of the invention

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory disease:

wherein at least 95% by weight of the said compound of formula (I) is in the stereoconfigu ration shown in formula (IA) and less than 5% by weight is in the stereoconfiguration shown in formula (IB):

in which formulae (I), (IA) and (IB): R is CH₃- or hydrogen;

X¹ is -OR¹, -S(0)_nR² or -NR³R⁴ and X² is-OH; or X and X² taken together represent a radical *-QC(0)NH-*^* or ^*-C(0)N(H)0-** wherein the bond marked * is attached to the carbon to which W and R are attached, and the bond marked ** is attached to the carbonyl carbon;

R and R² are independently C_1-6 alkyl optionally substituted with one or more halogen atoms; C-|.₆ alkoxyalkyl; or aryl; R³ and R⁴ are independently hydrogen; C_1-6 alkyl; aryl; a group -C(R^a)=C(R^b)-C(=0)- Ar^a wherein R^a and R^b are independently hydrogen or C_1-6 alkyl and Ar^a is aryl; or a group -Ar^b-C(=0)-Ar^c wherein Ar^b and Ar^c are aryl; or -C(=0)0-R^c wherein R^c is an aryl or C_1-6alkyl; or R³ and R⁴ taken together with the nitrogen to which they are attached form a saturated ring of 3 to 7 ring members or an unsaturated ring of 5 to 7 ring members; n is 0, 1 or 2;

W is a group which when linked to the -C(R)(X¹)C(=0)X² results in a compound (I) having PPARy agonist activity.

A preferred compound for use in accordance with the invention is 2-ethoxy-3-[2-(5- methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-propionic acid or

pharmaceutically acceptable salt thereof, wherein at least 95% by weight of the said compound is in the R stereoconfiguration and less than 5% by weight is in the S stereoconfiguration,

Another preferred compound for use in accordance with the invention is 2-ethoxy-3- {4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid wherein at least 95% by weight of the said compound is in the R stereoconfiguration and less than 5% by weight is in the S stereoconfiguration.

2-Ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid is a novel compound in its own right. Hence the invention includes the compound 2-ethoxy-3- {4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid or a pharmaceutically acceptable salt thereof, wherein the R enantiomer predominates by weight (i.e. constitutes more than 50% by weight) over the S enantiomer, especially where the R enantiomer constitutes at least 95% by weight and the S enantiomer less than 5% by weight.

In another aspect, the invention provides the use of a compound of formula (I) as defined above, including the two specific preferred compounds defined above, or a pharmaceutically acceptable salt of any of them, in the preparation of a medicament for the treatment of inflammatory disease.

In another aspect, the invention provides a method of treatment of inflammatory disease comprising administration of a therapeutically effective amount of a compound of formula (I) as defined above, including the two specific preferred compounds defined above, or a pharmaceutically acceptable salt of any of them, to a subject suffering such disease. In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, including the two specific preferred compounds defined above, or a pharmaceutically acceptable salt of any of them, and one or more pharmaceutically acceptable carriers and/or excipients.

In all aspects of the invention, the compound of formula (I) as defined above, including the two specific preferred compounds defined above, or a pharmaceutically acceptable salt of any of them may be administered by any convenient route orally, rectally, or parenterally. Administration by inhalation via the nose or the mouth for pulmonary delivery is often a preferred route. In the latter case, preferably it is inhaled via the mouth. However, oral administration will also often be preferred.

In all aspects of the invention, the compound of formula (I) as defined above, including the two specific preferred compounds defined above, should preferably contain as little of the compound with 5S stereoconfiguration as possible. For example, the compound with the stereoconfiguration shown in formula (IA) (ie the R enantiomer of the two preferred compounds defined above) may constitute at least 97%, or at least 98%, or at least 99% by weight of the compound (I) component.

In all aspects of the invention, the compound of formula (I) as defined above, including the two specific preferred compounds defined above, or a pharmaceutically acceptable salt of any of them, may be accompanied by, or administered sequentially or concurrently with, one or more inflammatory disorder treatment agents useful for the purpose of preventing and treating inflammatory disorders (including respiratory disorders), other than a PPARy agonist.

In all aspects of the invention, the inflammatory disease may be any of those conditions in which inflammation is a symptom, including: Inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, arthritis,

neuroinflammation, Alzheimer's, Parkinson's disease, pain, fever, fibrotic diseases, cardiovascular diseases, post -ischemic reperfusion injury and congestive heart failure, cardiomyopathy, atherosclerosis, reperfusion injury, renal reperfusion injury, brain edema, neurotrauma and brain trauma, neurodegenerative disorders, central nervous system disorders, liver disease, hepatitis and nephritis, gastrointestinal conditions, ulcerative diseases, Crohn's disease, ophthalmic diseases,

ophthalmological conditions, glaucoma, acute injury to the eye tissue and ocular traumas, diabetic nephropathy, skin-related conditions, myalgias due to infection, influenza, endotoxic shock, toxic shock syndrome, autoimmune disease, graft rejection, bone resorption diseases, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, dermatitis, eczema, diverticulitis, coeliac disease, disorders of the female reproductive system, pathological (but non -malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone, benign and malignant tumors/neoplasia, obesity-related

inflammation and infection.

In particular, the respiratory inflammatory disease to be treated in accordance with the invention may be selected from, for example, pulmonary artery hypertension, tuberculosis, lung cancer, chronic or acute bronchoconstriction, bronchitis including infectious and eosinophilic bronchitis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoisosis, silicosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cryptogenic fibrosing alveolitis, respiratory failure, acute respiratory distress syndrome, emphysema, chronic bronchitis, tuberculosis, acute lung injury and bronchiectasis, allergic airway syndrome, cystic fibrosis, 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, 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 (prophylactic and therapeutic therapy), coronavirus (including SARS) and adenovirus, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, farmer's lung and related diseases; hypersensitivity pneumonitis, respiratory failure, acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma (allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma), mild asthma, moderate asthma, severe asthma, steroid resistant asthma and other pulmonary disorders and diseases such as hyperoxic alveolar injury.

In the compound of formula (I) the group W is functionally defined as a group which when linked to the -C(R)(X¹)C(=0)X² radical results in a compound (I) having PPARy agonist activity. Methods for determining PPARy agonist activity are very well known in the art, since they have been used for the identification of the many known members of the glitazone class of compounds. Examples of such groups W are known in the art, for example as described in Miyachi, Expert Opin. Ther. Patents 2004, 14(5), 607-618; Rami and Smith, Expert Opin. Ther. Patents 2000, 10(5), 623- 634; Miyachi, Expert Opin. Ther. Patents 2005, 15(1 1 ), 1521-1530 and patent applications cited therein.

For example W may be selected from groups of formulae (lla) - (llg):

wherein m is 0-4; G is a bond, -0-, -S-, -NH- or group -N(C_1-6 alkyl)-; G¹ is -O- or -C(=0)- or a bond; and Ar² is a monocyclic or bicyclic or fused bicyclic ring system wherein each ring may be either saturated, partially saturated or aromatic and optionally containing heteroatoms selected from N, O or S.

wherein B¹ is a heterocyclic ring, and Ar², G, G¹ and m are as defined for formula (lla);

wherein R⁵ is selected from aryl, aryl-C^alkyl, aryloxyaryl-C_1-6 alkyl, and R⁶ is C ₆alkyl or a hydrogen atom;

wherein L¹ is O, S or -CH₂-; L² is O or S or a bond; and Ar², G and m are as described for formula (lla); Ar-G- (CH₂)_m-G

(lie)

wherein B² is a fused bicyclic ring system wherein each ring may be either saturated, partially saturated or aromatic and optionally containing heteroatoms selected from N, O or S and Ar², G, G¹ and m are as defined for formula (Ha);

wherein L3 is -O- or -S(0)„- wherein n is 0, 1 or 2 and Ar², G, G¹ and m are as defined for formula (Ma);

wherein R^c and R^d are C_1-6 alkyl or hydrogen, R^e is -C(=0)OC₁.₆ alkyl, -C(=0)Oaryl or arylalkyl, p is 1 or 2 and Ar², G, G¹ and m are as defined for formula ( I la);

As used herein, the term "(C_a-C_b)alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl. Alkyl groups may be optionally substituted.

As used herein the unqualified term "carbocyclic" refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.

As used herein the unqualified term "cycloalkyl" refers to a monocyclic saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein the unqualified term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and includes radicals having two monocyclic carbocyclic aromatic rings which are directly linked by a covalent bond. Illustrative of such radicals are phenyl, biphenyl and naphthyl.

As used herein the unqualified term "heteroaryl" refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are directly linked by a covalent bond. Illustrative of such radicals are thienyl, benzthienyl, fury I, benzfuryl, pyrrolyl, imidazolyl,

benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.

As used herein the unqualified term "heterocyclyl" or "heterocyclic" includes

"heteroaryl" as defined above, and in its non-aromatic meaning relates to a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups. Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with up to four compatible

substituents, each of which independently may be, for example, (C C₆)alkyl, (d- C₆)alkoxy, hydroxy, hydroxy(C C₆)alkyl, mercapto, mercapto(C -C₆)alkyl, (CV

C₆)alkylthio, phenyl, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, -COOH, -COOR^A, -COR^A, -S0₂R^A, -CONH_2> -S0₂NH₂, -CONHR^A, -S0₂NHR^A, -CONR^AR^B, -S0₂NR^AR^B, -NH₂, -NHR^A,

-NR^AR^B, -OCONH₂, -OCONHR^A , -OCONR^AR^B, -NHCOR^A, -NHCOOR^A,

-NR^BCOOR^A, -NHS0₂OR^A, -NR^BS0₂OH, -NR^BS0₂OR^A,-NHCONH₂, -NR^ACONH₂, -NHCONHR^B -NR^ACONHR^B, -NHCONR^AR^B or -NR^ACONR^AR^B wherein R^A and R^B are independently a (C₁-C₆)alkyl, (C₃-C₆) cycloalkyi , phenyl or monocyclic heteroaryl having 5 or 6 ring atoms. An "optional substituent" may be one of the foregoing substituent groups. Specific examples of groups of formula (I la) are;

Specific examples of groups of formula (lib) are;

pecific examples of groups of formula (lie) are;

Specific examples of groups of formula (llf) are;

Specific examples of groups of formula (llg) are;

Examples of the radical -C(R)(X¹)C(=0)X² in formula (I) include the following (drawn with the stereoconfiguration shown in formula (IA), and with W and R having the meanings defined for formula (I)):

As stated above, the compound with which the invention is concerned can be in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.

Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.

Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline,

diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; and quaternary ammonium cations. Examples of such bases include arginine, betaine, caffeine, choline, Ν,Ν-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Illustrative pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, xinafoic, tartaric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, napadisylate, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic,

benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids. Exemplary pharmaceutically acceptable salts include the salts of hydrochloric acid and hydrobromic acid.

Compositions of the invention are useful for treatment of inflammatory disorders, for example Inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, arthritis, neuroinflammation, Alzheimer's, Parkinson's disease, pain, fever, fibrotic diseases, cardiovascular diseases, post -ischemic reperfusion injury and congestive heart failure, cardiomyopathy, atherosclerosis, reperfusion injury, renal reperfusion injury, brain edema, neurotrauma and brain trauma, neurodegenerative disorders, central nervous system disorders, liver disease, hepatitis and nephritis, gastrointestinal conditions, ulcerative diseases, Crohn's disease, ophthalmic diseases, ophthalmological conditions, glaucoma, acute injury to the eye tissue and ocular traumas, diabetic nephropathy, skin-related conditions, myalgias due to infection, influenza, endotoxic shock, toxic shock syndrome, autoimmune disease, graft rejection, bone resorption diseases, multiple sclerosis, autoimmune

encephalomyelitis, psoriasis, dermatitis, eczema, diverticulitis, coeliac disease, disorders of the female reproductive system, pathological (but non -malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone, benign and malignant tumors/neoplasia, obesity-related

inflammation and infection.

In particular, the methods and compositions of the present invention encompass the prevention and treatment of the respiratory inflammatory disorder such as, for example, pulmonary artery hypertension, tuberculosis, lung cancer, chronic or acute bronchoconstriction, bronchitis including infectious and eosinophilic bronchitis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoisosis, silicosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cryptogenic fibrosing alveolitis, respiratory failure, acute respiratory distress syndrome, emphysema, chronic bronchitis, tuberculosis, acute lung injury and bronchiectasis, allergic airway syndrome, cystic fibrosis, 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, 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 (prophylactic and therapeutic therapy), coronavirus (including SARS) and

adenovirus, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, farmer's lung and related diseases; hypersensitivity

pneumonitis, respiratory failure, acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma (allergic, intrinsic, extrinsic, exercise- induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma), mild asthma, moderate asthma, severe asthma, steroid resistant asthma and other pulmonary disorders and diseases such as hyperoxic alveolar injury.

Any suitable route of administration may be employed for providing an effective dosage of a compound of the present invention. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route.

Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary. Compositions suitable for administration by the oral route are known, and may include carriers and/or diluents that are known for use in such compositions. The composition may contain 0.01-99% by weight of the compound (I) component.

Preferably, a unit dose comprises the compound (I) component in an amount of 1 pg to 500 mg.

Compositions suitable for administration by inhalation via the mouth or the nose are known, and may include carriers and/or diluents that are known for use in such compositions. The composition may contain 0.01-99% by weight of the compound (I) component. Preferably, a unit dose comprises the compound (I) component in an amount of 1 pg to 500 mg.

The most suitable dosage level may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific amount for any particular patient will depend upon a variety of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment. Optimum dosages will be determined by clinical trial, as is required in the art. Compositions of the invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the inflammatory diseases or conditions for which present compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the compound (I) component. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound (I) component is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to the compound (I) component.

Suitable therapeutic agents for a combination therapy with the compositions of the invention for respiratory diseases include: (1 ) a steroid drug such as a corticosteroid, for example beclomethasone, (e.g., as the mono or the dipropionate ester), flunisolide, fluticasone (e.g., as the propionate or furoate ester), ciclesonide, mometasone (e.g., as the furoate ester), mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methyl prednisolone, naflocort,

deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone,

desoxycorticosterone, etiprendnol dicloacetate and the like. Steroid drugs can additionally include steroids in clinical or pre-clinical development for respiratory diseases such as GW-685698, GW-799943, GSK 870086, QAE397, NCX-1010, NCX-1020, NO-dexamethasone, PL-2146, NS-126 (formerly ST-126) and

compounds referred to in international patent applications WO0212265,

WO0212266, WO02100879, WO03062259, WO03048181 and WO03042229.

Steroid drugs can also additionally include next generation molecules in development with reduced side effect profiles such as selective glucocorticoid receptor agonists (SEGRAs), including ZK-216348 and compounds referred to in international patent applications WO-00032585, WO-000210143, WO-2005034939, WO-2005003098, WO-2005035518 and WO-2005035502 and functional equivalents and functional derivatives thereof; (2) a 2-adrenoreceptor agonist, such as albuterol, bambuterol, terbutaline, fenoterol, formoterol, formoterol fumarate, salmeterol, salmeterol xinafoate, arformoterol, arfomoterol tartrate, indacaterol (QAB-149), carmoterol, picumeterol, Bl 1744 CL, GSK159797, GSK59790, GSK159802, GSK642444, GSK678007, GSK96108, clenbuterol, procaterol, bitolterol, and brodxaterol,TA-2005 and also compounds of EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651 , US2005/0133417, US2005/5159448, WO00/0751 14,

WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO02/76933,

WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204,

WO03/99764, WO04/16578, WO04/016601 , WO04/22547, WO04/32921 ,

WO04/33412, WO04/37768, WO04/37773, WO04/37807, WO0439762,

WO04/39766, WO04/45618, WO04/46083, WO04/71388, WO04/80964, EP1460064, WO04/087142, WO04/89892, EP01477167, US2004/0242622, US2004/0229904, WO04/108675, WO04/108676, WO05/033121 , WO05/040103, WO05/044787, WO04/071388, WO05/058299, WO05/058867, WO05/065650, WO05/066140, WO05/070908, WO05/092840, WO05/092841 , WO05/092860, WO05/092887, WO05/092861 , WO05/090288, WO05/092087, WO05/080324, WO05/080313, US20050182091 , US20050171 147, WO05/092870, WO05/077361 , DE10258695, WO05/1 11002, WO05/1 11005, WO05/1 10990, US2005/0272769 WO05/110359, WO05/12 065, US2006/0019991 , WO06/016245, WO06/014704, WO06/031556, WO06/032627, US2006/0106075, US2006/0106213, WO06/051373, WO06/056471 , WO08/0961 12, WO08/104790, WO08/0961 19, WO08/0961 12; (3) a leukotriene modulator, for example, montelukast or pranlukast; (4) anticholinergic agents, for example, selective muscarinic-3 (M3) receptor antagonists such as ipratropium bromide, tiotropium, tiotropium bromide (Spiriva®), glycopyrollate, NVA237,

LAS34273, GSK656398, GSK233705, GSK 573719, LAS35201 , QAT370 and oxytropium bromide; (5) phosphodiesterase-IV (PDE-IV) inhibitors, for example, roflumilast or cilomilast; (6) an antitussive agent, such as codeine or dextramorphan; (7) a non-steroidal anti-inflammatory agent (NSAID), for example, ibuprofen or ketoprofen; (8) a mucolytic, for example, N acetyl cysteine or fudostein; (9) a expectorant/mucokinetic modulator, for example, ambroxol, hypertonic solutions (e.g., saline or mannitol) or surfactant; (10) a peptide mucolytic, for example, recombinant human deoxyribonoclease I (dornase-alfa and rhDNase) or helicidin; (1 1 ) antibiotics, for example, azithromycin, tobramycin and aztreonam; and (12) p38 MAP kinase inhibitors such as GSK 856553 and GSK 681323.

In one aspect, the invention provides for the use of the compositions of the invention in combination with other anti-inflammatory drugs and bronchodilator drug

combinations including but not limited to salmeterol xinafoate/fluticasone propionate (Advair/Seretide®), formoterol fumarate/budesonide (Symbicort®), formoterol fumarate/mometasone furoate, formoterol fumarate/beclometasone dipropionate (Foster®), formoterol fumarate/fluticasone propionate (FlutiForm®),

Indacaterol/mometasone furoate, lndacaterol/QAE-397, GSK159797/GSK 685698, GSK 59802/GSK 685698, GSK642444/GSK 685698, formoterol

fumarate/ciclesonide, arformoterol tartrate/ciclesonide.

In another aspect, the invention provides for the use of the compositions of the invention in combination with other bronchodilator drug combinations, particularly B2 agonist/M3 antagonist combinations, including but not limited to salmeterol xinafoate/tiotropium bromide, formoterol fumarate/tiotropium bromide, Bl 1744 CL/tiotropium bromide, indacaterol/NVA237, indacterol/QAT-370, formoterol/ LAS34273, GSK159797/GSK 573719, GSK159802/GSK 573719, GSK642444/GSK 573719, GSK159797/GSK 233705, GSK 59802/GSK 233705, GSK642444/GSK 233705, and compounds which possess both β2 agonist and M3 antagonist activity in the same molecule (dual functionality) such as GSK 961081 .

Thus in another aspect, the invention provides a kit for treatment of inflammatory disorders in a subject, the kit comprising one dosage form comprising a composition adapted for oral administration, which composition comprises a compound with which the invention is concerned (including the two specific preferred compounds defined above), and one or more pharmaceutically acceptable carriers and/or excipients, and a second dosage form comprising another therapeutic agent, for example as discussed above, selected from anti-inflammatory agents, bronchodilators, mucolytic agents, antitussive agents, leukotriene inhibitors, and antibiotics. The following illustrate the preparation of enantiomers, and the biological results on which the present invention is based:

EXAMPLES

General Experimental Details

Abbreviations used in the experimental section: LCMS = liquid chromatography mass spectrometry; Rt = retention time; DCM = CH₂CI₂; H₂0 = water; EtOAc = ethyl acetate; THF = tetrahydrofuran; min = minutes; RT = room temperature; TFA = trifluoroacetic acid; c = concentration; h = hour; HPLC = high performance liquid chromatography; MeOH = methanol; DMSO = dimethyl sulphoxide; HCI = hydrogen chloride; EtOH = ethanol; IPA = isopropyl alcohol; NH₄CI = ammonium chloride; min = minutes; e.e. = enantiomeric excess; d.e. = diastereomeric excess; MgS0₄ = magnesium sulphate The nomenclature of structures was assigned using ACD Labs version 10.

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5mm inverse detection triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 5mm inverse detection triple resonance TXI probe operating at 400MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300MHz. Shifts are given in ppm relative to tetramethylsilane. Optical rotations were measured using an AA-10R automatic polarimeter with 5x25 mm jacketed sample cell.

All solvents and commercial reagents were used as received. All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.

The Liquid Chromatography Mass Spectroscopy (LC/MS) and Liquid

Chromatography systems used:

Method 1

Waters Micromass ZQ2000 with a Acquity BEH or Acquity BEH Shield RP18 1 .7uM 100 x 2.1 mm C18-reverse-phase column, elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 0.4 95 5

0.4 0.4 95 5

6.00 0.4 5 95

6.80 0.4 5 95

7.00 0.4 95 5

8.00 0.4 95 5

Detection - MS, ELS, UV PDA. MS ionisation method - Electrospray

(positive/negative ion)

NMR method 1

Compound (1 mg) and R(+)-1 -(1-naphthyl)-ethylamine (10mg) were dissolved in CDCI₃ and a NMR spectrum generated as described above. A triplet in the 6.28- 6.3ppm region of the spectrum was integrated and used to determine e.e.

NMR method 2

Compound (1 mg) and R(+)-1 -(1 -naphthyl)-ethylamine (10mg) were dissolved in CDCI₃ and a NMR spectrum generated as described above. A triplet in the 0.8- 1.Oppm region of the spectrum was integrated and used to determine e.e. Compound 1

(S)-2-Ethoxy-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]- propionic acid

The title compound was prepared as described in J.Med.Chem., 1996, 39, 3897- 3907. The absolute configuration of the title compound is derived by the chiral auxiliary synthetic procedure adopted in the publication and as initially described by Evans (ref 23; Evans D. A. J.Am. Chem.Soc. 1981 , 103, 2127-29). LCMS (Method 1 ): Rt 5.23 min (99.12%), m/z 406 [M+H]\ H NMR (400 MHz, CDCI₃): 5 1.15 (3H, t, J 8 Hz), 2.36 (3H, s), 3.05 (1 H, dd, 8, 16 Hz), 3.21 (1 H, dd, J 4, 8 Hz), 3.41-3.59 (2H, m), 4.01 (2H, s), 4.09 (1 H, dd, J 4, 8 Hz), 6.42-6.43 ( H, m), 7.08 (1 H, dd, J 4, 8 Hz), 7.31-7.34 (2H, m), 7.39-7.45 (3H, m) 7.96-8.01 (2H, m). (NMR method 1 ) e.e. >99%. [a]_D ²² -1 1 .9° (c 1.01 , CDCI₃).

Compound 2

(R)-2-Ethoxy-3-[2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]- propionic acid

The title compound was prepared as described in J.Med.Chem., 1996, 39, 3897- 3907 and its absolute configuration is derived by using the same chiral auxiliary procedure for Compound 1 . LCMS (Method 1 ): Rt 5.23 min (>99%), m/z 406 [M+H]⁺. [a]_D ²³ +16° (c 1.0, CDCI₃). ¹H NMR (400 MHz, CDCI₃): δ 1.15 (3H, t, J 8 Hz), 2.36 (3H, s), 3.05 (1 H, dd, 8, 16 Hz), 3.21 (1 H, dd, J A, 8 Hz), 3.41-3.59 (2H, m), 4.01 (2H, s), 4.09 (1 H, dd, J 4, 8 Hz), 6.42-6.43 (1 H, m), 7.08 (1 H, dd, J 4, 8 Hz), 7.31-7.34 (2H, m), 7.39-7.45 (3H, m) 7.96-8.01 (2H, m). (NMR method 1 ) e.e. >99%. Compound 3

(S)-2-Ethoxy-3- 4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid

The title compound was prepared in a similar manner to that described for

Compound 1 and its absolute configuration is derived by using the same chiral auxiliary procedure. ¹H NMR (400 MHz, CDCI₃): 5 1 .19 (3H, t, J 6.9 hz), 1.24 (3H, t, J 7.6 Hz), 2.64 (2H, q, J 7.6 Hz), 2.98 (1 H, dd, J 13.9, 7.0 Hz), 3.06 (1 H, dd, J 13.9, 5.1 hz), 3.20 (2H, t, J 6.6 Hz), 3.47 (1 H, m), 3.65 (1 H, m), 4.04 (1 H, bm), 4.22 (2H, t, J 6.6 Hz), 6.81 (2H, d, J 8.3 Hz), 7.17 (2H, d, J 8.3 Hz), 7.23 (1 H, d, J 8.0 Hz), 7.51 (1 H, dd, J 8.0, 2.0 Hz), 8.43 (1 H, d, J 8.0, 2.0 Hz). LCMS (Method 1 ): Rt 2.88 min, m/z 344 [M+H]⁺. (NMR method 2) e.e. >99%. [a]_D ²² -4° (c 1.0, CDCI₃).

Compound 4

(R)-2-Ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid

The title compound was prepared in a similar manner to that described for Compound 2 and its absolute configuration is derived by using the same chiral auxiliary procedure. H NMR (400 MHz, CDCI₃): δ 1.18 (3H, t, J 6.9 Hz), 1.25 (3H, t,

J 7.6 Hz), 2.67 (2H, q, J 7.6 Hz), 3.01 (2H, dd, J 13.9, 7.0 Hz), 3.28 (2H, t, J 8 Hz), 3.39-3.49 (1 H, m), 3.59-3.69 (1 H, m), 4.01-4.06 (1 H, m), 4.24 (2H, t, J 8 Hz), 6.79 (2H, d, J 8 Hz), 7.16 (2H, d, J 8 Hz), 7.33 (1 H, d, J 8.0 Hz), 7.60-7.65 (1 H, m), 8.44 (1 H, s). LCMS (Method 1 ): Rt 2.87 min, m/z 344 [M+H]⁺. (NMR method 2) e.e. 97.0%. [<X]D² +8° (c 1.0, CDCIg).

Additional support for the absolute configuration assignments comes from Haigh D., Assymetry, 1999,10, 1335-51 which describe three related alkoxy acids whose (S)- enantiomers have -ve signs for the rotation of polarised light [ ]_D and +ve sign of rotation for the corresponding (R)-enantiomers.

Biological Results: Pre-clinical mouse model of COPD inflammation - Tobacco smoke induced pulmonary inflammation. Previous studies have established that the number of inflammatory cells recovered in the bronchoalveolar lavage (BAL) is significantly elevated 24 h following the final Tobacco Smoke (TS) exposure of 4 or 1 1 consecutive daily TS exposures, this time point was used in the studies reported here. Protocols for the exposure of mice to TS, obtaining bronchoalveolar lavage (BAL), preparation of cytospin slides for differential cell counts are as outlined below.

Exposure of mice to TS daily for 4 or 11 consecutive days

In this exposure protocol, mice were exposed in groups of 5 in individual clear polycarbonate chambers (27 cm x 16 cm x 12 cm). The TS from the cigarettes was allowed to enter the exposure chambers at a flow rate of 100 ml/min. In order to minimise any potential problems caused by repeated exposure to a high level of TS (6 cigarettes), the exposure of the mice to TS was increased gradually over the exposure period to a maximum of 6 cigarettes. The exposure schedule used for 4 days was as follows:

Day 1 4 cigarettes (approximately 32 min exposure)

Day 2 4 cigarettes (approximately 32 min exposure)

Day 3 6 cigarettes (approximately 48 min exposure)

Day 4 6 cigarettes (approximately 48 min exposure)

The exposure schedule used for 1 1 days exposure was as follows:

Day 1 2 cigarettes (approximately 16 min exposure)

Day 2 3 cigarettes (approximately 24 min exposure)

Day 3 4 cigarettes (approximately 32 min exposure)

Day 4 5 cigarettes (approximately 40 min exposure)

Day 5 to 1 1 : 6 cigarettes (approximately 48 min exposure)

A further group of mice were exposed to air on a daily basis for equivalent lengths of time as controls (no TS exposure).

Bronchoalveolar lavage (BAL) analysis

Bronchoalveolar lavage was performed as follows: the trachea was cannulated using a Portex nylon intravenous cannula (pink luer fitting) shortened to approximately 8 mm. Phosphate buffered saline (PBS) was used as the lavage fluid. A volume of 0.4 ml was gently instilled and withdrawn 3 times using a 1 ml syringe and then placed in an Eppendorf tube and kept on ice prior to subsequent determinations.

Cell counts:

Lavage fluid was separated from cells by centrifugation and the supernatant decanted and frozen for subsequent analysis. The cell pellet was re-suspended in a known volume of PBS and total cell numbers calculated by counting a stained (Turks stain) aliquot under a microscope using a haemocytometer. Differential cell counts were performed as follows:

The residual cell pellet was diluted to approximately 10⁵ cells per ml. A volume of 500 μΙ was placed in the funnel of a cytospin slide and centrifuged for 8 min at 800 rpm. The slide was air dried and stained using 'Kwik-Diff' solutions (Shandon) as per the proprietary instructions. When dried and cover-slipped, differential cells were counted using light microscopy. Up to 400 cells were counted by unbiased operator using light microscopy. Cells were differentiated using standard morphometric techniques.

Drug Treatment Four separate studies were conducted, each examining one of the four test compounds (Compound 1 , Compound 2, Compound 3, Compound 4).

Study 1

Mice were dosed orally once daily with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 1 (0.3 mg/kg), Compound 1 (1 mg/kg), Compound 1 (3 mg/kg) or Compound 1 (10 mg/kg), 1 hr prior to TS exposure. The control group of mice received vehicle 1 hr prior to being exposed to air daily for a maximum of 50 minutes per day. TS exposure was conducted for 4 days. BAL was performed 24 h following the final TS exposure. Body weights were determined prior to the first compound dose and 24 hrs after the final TS exposure (i.e. following 4 daily doses for either compound or vehicle).

Study 2

Mice were dosed orally once daily with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 2 (0.01 mg/kg), Compound 2 (0.1 mg/kg), Compound 2 (1 mg/kg) or Compound 2 (10 mg/kg), 1 hr prior to TS exposure. The control group of mice received vehicle 1 hr prior to being exposed to air daily for a maximum of 50 minutes per day. TS exposure was conducted for 4 days. BAL was performed 24 h following the final TS exposure. Body weights were determined prior to the first compound dose and 24 hrs after the final TS exposure (i.e. following 4 daily doses for either compound or vehicle).

Study 3

Mice were dosed orally once daily with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 3 (0.1 mg/kg), Compound 3 (1 mg/kg), Compound 3 (10 mg/kg) or racemic Pioglitazone (10 mg/kg), 1 hr prior to TS exposure. The control group of mice received vehicle 1 hr prior to being exposed to air daily for a maximum of 50 minutes per day. TS exposure was conducted for 4 days. BAL was performed 24 h following the final TS exposure. Body weights were determined prior to the first compound dose and 24 hrs after the final TS exposure (i.e. following 4 daily doses for either compound or vehicle).

Study 4

Mice were dosed orally once daily with vehicle (0.5% Carboxymethylcellulose in deionised water), Compound 4 (0.1 mg/kg), Compound 4 (1 mg/kg), Compound 4 (10 mg/kg) or Compound 3 (10 mg/kg), 1 hr prior to TS exposure. The control group of mice received vehicle 1 hr prior to being exposed to air daily for a maximum of 50 minutes per day. TS exposure was conducted for 4 days. BAL was performed 24 h following the final TS exposure. Body weights were determined prior to the first compound dose and 24 hrs after the final TS exposure (i.e. following 4 daily doses for either compound or vehicle).

Data management and statistical analysis

All results are presented as individual data points for each animal and the mean value was calculated for each group. Since tests for normality were positive, the data were subjected to a one way analysis of variance test (ANOVA), followed by a Bonferroni correction for multiple comparisons in order to test for significance between treatment groups. A "p" value of < 0.05 was considered to be statistically significant. Percentage inhibitions were automatically calculated within the Excel spreadsheets for the cell data using the formula below:

f Treatment group result - sham group result

% Inhibition = 1 - x 100

TS vehicle group result ~ sham group result J Inhibition data for other parameters were calculated manually using the above formula.

Results

As illustrated in Figure 1 , Compound 1 significantly inhibited BAL cell influx following TS exposure when administered at doses of 1 mg/kg or higher. At least 3 mg/kg of Compound 1 was required to inhibit BAL cell inflammation by >50%. At 0.3 mg/kg, no inhibition of BAL cell influx was observed. As shown in Figure 2, all doses of Compound 1 caused significant weight gain (p<0.001 ) in the mice when administered over the 4 day treatment period.

As illustrated in Figure 3, Compound 2 significantly inhibited BAL cell influx following TS exposure at all doses administered (0.01 to 10 mg/kg) with all doses resulting in >50% inhibition. In contrast with the effects of Compound 1 , Compound 2 did not cause significant weight gain in the mice at any of the doses examined when administered over the 4 day treatment period.

These data suggest both stereoconfigurations are able to deliver anti-inflammatory activity with Compound 2 (R enantiomer) being the more potent.

These data also suggest however, that whilst Compound 1 can deliver antiinflammatory activity it is accompanied by systemic side effects that are observed in the therapeutic dose range suggesting a minimal therapeutic index and thus minimal therapeutic utility for the treatment of inflammation. In contrast, Compound 2 delivers significant anti-inflammatory activity with a much greater therapeutic index than Compound 1 as the systemic side effects (weight gain) were not observed at therapeutic doses. These data identify Compound 2 as the superior compound for the treatment of inflammatory diseases including inflammatory respiratory diseases. The activity of Compound 1 and Compound 2 has been examined in a mouse model of diabetes previously (Hulin et al.J.Med. Chem., 1996, 39, 3897-3907). It is well known in the art that PPARy agonists have utility in metabolic diseases including diabetes. In this mouse model, significant normalisation of blood glucose was observed with Compound 1 at 0.1 and 0.01 mg/kg when administered in the same fashion as in the mouse lung inflammation model detailed herein. Therefore, Hulin et al, identify the S enantiomer as the enantiomer that is particularly active for the treatment of diseases where PPAR agonists are useful. When data from both mouse models are taken together, these data suggest Compound 1 has more potent antidiabetic activity than anti-inflammatory activity.

In contrast, Compound 2 did not significantly normalise blood glucose at 0.1 or 0.01 mg kg with a dose of 1 mg/kg being required to see significant anti-diabetic activity. It is therefore surprising that the anti-inflammatory profile of Compounds 1 and 2 contrasts with their anti-diabetic profile and the prior art teaches away from the therapeutic utility of Compound 2 as compared with Compound 1. Furthermore, (unlike Compound 1), systemic side effects are not observed with therapeutic anti- inflammatory doses of Compound 2.

Therefore, whilst it is not surprising that one enantiomer has greater activity than the other, based on the data provided by Hulin et al which favours the S enantiomer, it is surprising that the R enantiomer rather than the S enantiomer has the more potent anti-inflammatory activity. Furthermore, the R enantiomer is also devoid of the side effect (weight gain) observed with the S enantiomer at therapeutic doses.

As illustrated in Figure 5, Compound 3 significantly inhibited BAL cell influx following TS exposure when administered at a doses of 10 mg/kg although the inhibition was not > 50%. This effect was less than that observed with Racemic Pioglitazone at the same dose (41% vs. 62% inhibition). At 0.1 or 1 mg/kg mg/kg, no inhibition of BAL cell influx was observed. No significant changes in body weight were observed in the mice when administered over the 4 day treatment period. As illustrated in Figure 6, Compound 4 significantly inhibited BAL cell influx following TS exposure at all doses administered (0.1 to 10 mg kg) with all doses resulting in >50% inhibition. In contrast, Compound 3 at 10 mg/kg inhibited the BAL cell influx by less than 50% (32%). No significant changes in body weight were observed in the mice with either compound when administered over the 4 day treatment period.

These data suggest that whilst both stereoconfigurations are able to deliver antiinflammatory activity, activity of Compound 4 (R enantiomer) is more potent than Compound 3. Furthermore, Compound 3 also appears to be less potent than racemic Pioglitazone.

In summary, the above data demonstrates that for compounds of formula (I), the stereoconfiguration shown in formula (IA) provides potent anti-inflammatory activity with the absence of significant side effects at therapeutic doses. This is a surprising finding based on the prior art which teaches that for compounds of formula (I), the stereoconfiguration shown in formula (IB) rather than formula (IA) delivers potent anti-diabetic activity and teaches away from the therapeutic utility of formula (IA).

Claims

Claims:

A compound of formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of inflammatory disease:

wherein at least 95% by weight of the said compound of formula (I) is in the stereoconfiguration shown in formula (IA) and less than 5% by weight is in the stereoconfiguration shown in formula (IB):

in which formulae (I), (IA) and (IB): R is CH₃- or hydrogen;

X¹ is -OR¹, -S(0)_nR² or -NR³R⁴ and X² is-OH; or X¹ and X² taken together represent a radical ^*-OC(0)NH-^** or ^*-C(0)N(H)0-^** wherein the bond marked * is attached to the carbon to which W and R are attached, and the bond marked ** is attached to the carbonyl carbon;

R¹ and R² are independently C_1-6 alkyl optionally substituted with one or more halogen atoms; Ci_₆ alkoxyalkyl; or aryl; R³ and R⁴ are independently hydrogen; C_1-6 alkyl; aryl; a group -C(R^a)=C(R^b)-C(=0)- Ar^a wherein R^a and R^b are independently hydrogen or C^e alkyl and Ar^a is aryl; or a group -Ar -C(=0)-Ar° wherein Ar^b and Ar° are aryl; or -C(=0)0-R^c wherein R° is an aryl or C_1-6alkyl; or R³ and R⁴ taken together with the nitrogen to which they are attached form a saturated ring of 3 to 7 ring members or an unsaturated ring of 5 to 7 ring members; n is 0,1 or 2;

W is a group which when linked to the -C(R)(X¹)C(=0)X² results in a compound (I) having PPARy agonist activity.

2. A compound for use as claimed in claim 1 which is selected from 2-ethoxy-3- [2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-benzofuran-5-yl]-propionic acid and 2- ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid and

pharmaceutically acceptable salts of either, wherein at least 95% by weight of the said compound is in the R stereoconfiguration and less than 5% by weight is in the S stereoconfiguration.

3. A compound for use as claimed in claim 1 or claim 2 wherein the use is for the treatment of inflammatory disease by oral administration.

4. The use of a compound of formula (i) as defined in claim 1 or a compound as defined in claim 2, or a pharmaceutically acceptable salt of any of them, in the preparation of a medicament for the treatment of inflammatory disease.

5. A method of treatment of inflammatory disease comprising administration of a therapeutically effective amount of a compound of formula (I) as defined in claim 1 , or a compound as defined in claim 2, or a pharmaceutically acceptable salt of any of them, to a subject suffering such disease.

6. A compound for use as claimed in any of claims 1 to 3, a use as claimed in claim 4, or a method of treatment as claimed in claim 5, wherein the said

inflammatory disease is selected from inflammatory bowel disease, irritable bowel syndrome, colitis, ulcerative colitis, arthritis, neuroinflammation, Alzheimer's,

Parkinson's disease, pain, fever, fibrotic diseases, cardiovascular diseases, post - ischemic reperfusion injury and congestive heart failure, cardiomyopathy,

atherosclerosis, reperfusion injury, renal reperfusion injury, brain edema,

neurotrauma and brain trauma, neurodegenerative disorders, central nervous system disorders, liver disease, hepatitis and nephritis, gastrointestinal conditions, ulcerative diseases, Crohn's disease, ophthalmic diseases, ophthalmological conditions, glaucoma, acute injury to the eye tissue and ocular traumas, diabetic nephropathy, skin-related conditions, myalgias due to infection, influenza, endotoxic shock, toxic shock syndrome, autoimmune disease, graft rejection, bone resorption diseases, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, dermatitis, eczema, diverticulitis, coeliac disease, disorders of the female reproductive system, pathological (but non-malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone, benign and malignant

tumors/neoplasia, obesity-related inflammation and infection.

7. A compound for use as claimed in any of claims 1 to 3, a use as claimed in claim 4, or a method of treatment as claimed in claim 5 or claim 6, wherein the compound is administered by the oral route.

8. A compound for use as claimed in any of claims 1 to 3, a use as claimed in claim 4, or a method of treatment as claimed in claim 5, wherein the said

inflammatory disease is an inflammatory respiratory disease.

9. A compound for use as claimed in any of claims 1 to 3, a use as claimed in claim 4, or a method of treatment as claimed in claim 5, wherein the said

inflammatory disease is an inflammatory respiratory disease selected from pulmonary artery hypertension, tuberculosis, lung cancer, chronic or acute bronchoconstriction, bronchitis including infectious and eosinophilic bronchitis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoisosis, silicosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis), cryptogenic fibrosing alveolitis, respiratory failure, acute respiratory distress syndrome, emphysema, chronic bronchitis, tuberculosis, acute lung injury and bronchiectasis, allergic airway syndrome, cystic fibrosis, 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, 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 (prophylactic and therapeutic therapy), coronavirus (including SARS) and adenovirus, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, farmer's lung and related diseases; hypersensitivity pneumonitis, respiratory failure, acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma (allergic, intrinsic, extrinsic, exercise- induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma), mild asthma, moderate asthma, severe asthma, steroid resistant asthma and other pulmonary disorders and diseases such as hyperoxic alveolar injury.

10. A compound for use as claimed in any of claims 1 to 3, a use as claimed in claim 4, or a method of treatment as claimed in claim 8 or claim 9, wherein the compound is administered by inhalation for pulmonary delivery.

1 1. A method as claimed in any of claims 5 to 10 wherein the subject is additionally administered an amount of another anti-inflammatory drug wherein the amount of the said compound of formula (I) and the amount of the other antiinflammatory drug together comprises a therapeutically effective amount.

12. A pharmaceutical composition which comprises a compound of formula (I) as defined in claim 1 , or a compound as defined in claim 2, and one or more

pharmaceutically acceptable carriers and/or excipients.

13. A pharmaceutical composition as claimed in claim 9 which is adapted for oral administration.

14. A kit for treatment of inflammatory disorders in a subject, the kit comprising one dosage form comprising a composition adapted for oral administration, which composition comprises a compound as defined in claim 1 or claim 2, and one or more pharmaceutically acceptable carriers and/or excipients, and a second dosage form comprising another therapeutic agent.

15. A kit as claimed in claim 14 wherein the other therapeutic agent selected from anti-inflammatory agents, bronchodilators, mucolytic agents, antitussive agents, leukotriene inhibitors, and antibiotics.

16. The compound 2-ethoxy-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}- propionic acid or a pharmaceutically acceptable salt thereof, wherein the R enantiomer predominates by weight over the S enantiomer.

17. The compound as claimed in claim 16 wherein the R enantiomer constitutes at least 95% by weight and the S enantiomer less than 5% by weight of the compound.