WO2011098801A1 - Traitement de maladies inflammatoires - Google Patents

Traitement de maladies inflammatoires Download PDF

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Publication number
WO2011098801A1
WO2011098801A1 PCT/GB2011/050226 GB2011050226W WO2011098801A1 WO 2011098801 A1 WO2011098801 A1 WO 2011098801A1 GB 2011050226 W GB2011050226 W GB 2011050226W WO 2011098801 A1 WO2011098801 A1 WO 2011098801A1
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compound
disease
inflammatory
pulmonary
treatment
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PCT/GB2011/050226
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English (en)
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Harry Finch
Craig Fox
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Pulmagen Therapeutics (Inflammation) Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy

Definitions

  • 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.
  • 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 plays a major role in the development of many respiratory diseases including pulmonary artery hypertension, tuberculosis, lung cancer,
  • 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
  • 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.
  • COPD chronic obstructive pulmonary disease
  • COPD corticosteroids
  • 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.
  • PPARy Peroxisome Proliferation Receptor gamma receptor
  • 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.
  • TZDs thiazolidinediones
  • 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
  • PPARy agonists have also been shown to be effective in models of pulmonary fibrosis (Milam 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.
  • 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.
  • CHF congestive heart failure
  • 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)
  • 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 2 ⁇ , Parks et al, 1998, Bioorg. Med.
  • (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
  • 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
  • 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.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory disease:
  • R is CH 3 - or hydrogen
  • X 1 is -OR 1 , -S(0) n R 2 or -NR 3 R 4 and X 2 is-OH; or X and X 2 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 R 2 are independently C 1-6 alkyl optionally substituted with one or more halogen atoms; C-
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of formula (I) as defined above 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.
  • oral administration will also often be preferred.
  • the compound of formula (I) as defined above should preferably contain as little of the compound with 5S stereoconfiguration as possible.
  • the compound with the stereoconfiguration shown in formula (IA) ie the R enantiomer of the two preferred compounds defined above
  • the compound of formula (I) as defined above 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.
  • 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
  • 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;
  • bronchitis including infectious and eosinophilic
  • 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;
  • 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.
  • COPD chronic obstructive pulmonary disease
  • 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.
  • W may be selected from groups of formulae (lla) - (llg):
  • B 1 is a heterocyclic ring, and Ar 2 , G, G 1 and m are as defined for formula (lla);
  • R 5 is selected from aryl, aryl-C ⁇ alkyl, aryloxyaryl-C 1-6 alkyl, and R 6 is C 6 alkyl or a hydrogen atom;
  • L 1 is O, S or -CH 2 -; L 2 is O or S or a bond; and Ar 2 , G and m are as described for formula (lla); Ar-G- (CH 2 ) m -G
  • B 2 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 Ar 2 , G, G 1 and m are as defined for formula (Ha);
  • L3 is -O- or -S(0) admir- wherein n is 0, 1 or 2 and Ar 2 , G, G 1 and m are as defined for formula (Ma);
  • (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.
  • a 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • radicals are thienyl, benzthienyl, fury I, benzfuryl, pyrrolyl, imidazolyl,
  • 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.
  • 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.
  • substituted as applied to any moiety herein means substituted with up to four compatible
  • substituents each of which independently may be, for example, (C C 6 )alkyl, (d- C 6 )alkoxy, hydroxy, hydroxy(C C 6 )alkyl, mercapto, mercapto(C -C 6 )alkyl, (CV
  • the compound with which the invention is concerned can be in the form of a pharmaceutically acceptable salt.
  • 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 diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; and quaternary ammonium cations.
  • bases include arginine, betaine, caffeine, choline, ⁇ , ⁇ -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, ⁇ -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
  • inflammatory disorders for example In
  • 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
  • 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;
  • the respiratory inflammatory disorder
  • 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.
  • COPD chronic obstructive pulmonary disease
  • any suitable route of administration may be employed for providing an effective dosage of a compound of the present invention.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical composition containing such other drugs in addition to the compound (I) component is preferred.
  • 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,
  • 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
  • deflazacort halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone,
  • 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
  • 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,
  • phosphodiesterase-IV (PDE-IV) inhibitors for example, roflumilast or cilomilast
  • an antitussive agent such as codeine or dextramorphan
  • NSAID non-steroidal anti-inflammatory agent
  • ibuprofen or ketoprofen a mucolytic, for example, N acetyl cysteine or fudostein
  • a expectorant/mucokinetic modulator for example, ambroxol, hypertonic solutions (e.g., saline or mannitol) or surfactant
  • a peptide mucolytic for example, recombinant human deoxyribonoclease I (dornase-alfa and rhDNase) or helicidin;
  • the invention provides for the use of the compositions of the invention in combination with other anti-inflammatory drugs and bronchodilator drug
  • fumarate/ciclesonide arformoterol tartrate/ciclesonide.
  • 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 ⁇ 2 agonist and M3 antagonist activity in the same molecule (dual functionality) such as GSK 961081 .
  • B2 agonist/M3 antagonist combinations including but not limited to salmeterol xinaf
  • 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.
  • a therapeutic agent for example as discussed above, selected from anti-inflammatory agents, bronchodilators, mucolytic agents, antitussive agents, leukotriene inhibitors, and antibiotics.
  • LCMS liquid chromatography mass spectrometry
  • Rt retention time
  • DCM CH 2 CI 2
  • H 2 0 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
  • NH 4 CI ammonium chloride
  • MgS0 4 magnesium sulphate
  • 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.
  • 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).
  • mice Exposure of mice to TS daily for 4 or 11 consecutive days
  • 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.
  • 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:
  • the exposure schedule used for 1 1 days exposure was as follows:
  • mice were exposed to air on a daily basis for equivalent lengths of time as controls (no TS exposure).
  • 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.
  • PBS Phosphate buffered saline
  • 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 10 5 cells per ml. A volume of 500 ⁇ 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention porte sur des composés de formule (I) qui sont utiles dans le traitement d'une maladie inflammatoire, au moins 95 % en poids dudit composé de formule (I) étant dans la configuration stéréochimique représentée dans la formule (IA) et moins de 5 % en poids étant dans la configuration stéréochimique représentée dans la formule (IB), dans lesquelles formules (I), (IA) et (IB) : R représente CH3- ou l'hydrogène ; X1 représente -OR1, -S(O)nR2 ou -NR3R4 et X2 représente -OH ; ou X1 et X2 pris ensemble représentent un radical *-OC(O)NH-** ou *-C(O)N(H)O-**, la liaison marquée par * étant attachée au carbone auquel W et R sont attachés et la liaison marquée par ** étant attachée au carbone du carbonyle ; R1 et R2 représentent chacun indépendamment un alkyle en C1-6 éventuellement substitué par un ou plusieurs atomes d'halogène ; un alcoxyalkyle en C1-6 ; ou un aryle ; R3 et R4 représentent chacun indépendamment l'hydrogène ; un alkyle en C1-6 ; un aryle ; un groupe -C(Ra)=C(Rb)-C(=O)-Ara, où Ra et Rb représentent chacun indépendamment l'hydrogène ou un alkyle en C1-6 et Ara représente un aryle ; ou un groupe -Arb-C(=O)-Arc, où Arb et Arc représentent un aryle ; ou -C(=O)O-Rc, où Rc représente un aryle ou un alkyle en C1-6 ; ou R3 et R4 pris ensembles avec l'azote auquel ils sont attachés forment un noyau saturé de 3 à 7 chaînons ou un noyau insaturé de 5 à 7 chaînons ; n représente 0, 1 ou 2 ; W représente un groupe qui lorsqu'il est lié au -C(R)(X1)C(=O)X2 résulte en un composé (I) ayant une activité d'agoniste du PPARγ.
PCT/GB2011/050226 2010-02-10 2011-02-09 Traitement de maladies inflammatoires WO2011098801A1 (fr)

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RU2483743C1 (ru) * 2012-06-13 2013-06-10 Зухра Фаниловна Эделева Способ лечения ринита
US8969581B2 (en) 2013-03-14 2015-03-03 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US9925175B2 (en) 2007-09-26 2018-03-27 Deuterx, Llc Deuterium-enriched pioglitazone
US10143703B2 (en) * 2014-01-02 2018-12-04 Massachusetts Eye And Ear Infirmary Treating ocular neovascularization
US10188639B2 (en) 2014-01-15 2019-01-29 Deuterx, Llc Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
RU2712235C1 (ru) * 2019-05-16 2020-01-27 Закрытое акционерное общество "Санкт-Петербургский институт фармации" Средство с гликозилированным полипептидом и способ его получения
US11319313B2 (en) 2020-06-30 2022-05-03 Poxel Sa Crystalline forms of deuterium-enriched pioglitazone
US11767317B1 (en) 2020-06-30 2023-09-26 Poxel Sa Methods of synthesizing enantiopure deuterium-enriched pioglitazone

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