Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • 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
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics

Definitions

• the present invention relates to a combination of two or more pharmaceutically active substances for use in the treatment of respiratory diseases (for example chronic obstructive pulmonary disease (COPD) or asthma).
• respiratory diseases for example chronic obstructive pulmonary disease (COPD) or asthma.
• COPD chronic obstructive pulmonary disease
• Respiratory diseases include Acute Lung Injury, Acute Respiratory Distress Syndrome (ARDS), occupational lung disease, lung cancer, tuberculosis, fibrosis, pneumoconiosis, pneumonia, emphysema, Chronic Obstructive Pulmonary Disease (COPD) and asthma.
• ARDS Acute Respiratory Distress Syndrome
• COPD Chronic Obstructive Pulmonary Disease
• Asthma is generally defined as an inflammatory disorder of the airways with clinical symptoms arising from intermittent airflow obstruction. It is characterised clinically by paroxysms of wheezing, dyspnea and cough. It is a chronic disabling disorder that appears to be increasing in prevalence and severity. It is estimated that 15% of children and 5% of adults in the population of developed countries suffer from asthma. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.
• COPD is a term that refers to a large group of lung diseases which can interfere with normal breathing.
• Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible.
• the airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
• the most important contributory source of such particles and gases is tobacco smoke.
• COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells.
• the two most important conditions covered by COPD are chronic bronchitis and emphysema.
• Chronic bronchitis is a long-standing inflammation of the bronchi that causes increased production of mucous and other changes. The patients' symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.
• Emphysema is a chronic lung disease that affects the alveoli and/or the ends of the smallest bronchi.
• the lung loses its elasticity and therefore these areas of the lungs become enlarged. These enlarged areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood.
• the predominant symptom in patients with emphysema is shortness of breath.
• Corticosteroids also known as glucocorticosteroids or glucocorticoids
• glucocorticoids are potent antiinflammatory agents. Whilst their exact mechanism of action is not clear, the end result of corticosteroid treatment is a decrease in the number, activity and movement of
• Corticosteroids may also cause reduced shedding of bronchial epithelial lining, vascular permeability, and mucus secretion. Whilst corticosteroid treatment can yield important benefits, the efficacy of these agents is often far from satisfactory, particularly in COPD. Moreover, whilst the use of steroids may lead to therapeutic effects, it is desirable to be able to use steroids in low doses to minimise the occurrence and severity of undesirable side effects that may be associated with regular administration. Recent studies have also highlighted the problem of the acquisition of steroid resistance amongst patients suffering from respiratory diseases.
• bronchodilators may be used to alleviate symptoms of respiratory diseases by relaxing the bronchial smooth muscles, reducing airway obstruction, reducing lung hyperinflation and decreasing shortness of breath.
• Types of bronchodilators in clinical use include ⁇ 2 adrenoceptor agonists, muscarinic receptor antagonists and
• Bronchodilators are prescribed mainly for symptomatic relief and they are not considered to alter the natural history of respiratory diseases.
• Combination products comprising a ⁇ 2 adrenoceptor agonist and a corticosteroid are available.
• One such product is a combination of budesonide and formoterol fumarate dihydrate (marketed by AstraZeneca under the trade mark Symbicort ®), which has proven to be effective in controlling asthma and COPD, and improving quality of life in many patients.
• Symbicort ® formoterol fumarate dihydrate
• the present invention provides a new combination product comprising
• a pharmaceutical product comprising a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b- Fluoro- 1 - ⁇ [(fluoromethy l)sulfanyl] carbonyl ⁇ -7-(6-fluoropyridin-3 -yl)- 11 -hydroxy- 2,10a,12a-trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a pharmaceutically acceptable salt thereof; a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M3 receptor antagonist
• MABA compound a muscarinic antagonist
• a p38 kinase inhibitor a neutrophil elastase inhibitor
• a phosphodiesterase PDE4 inhibitor an IKK2 kinase inhibitor or a non-steroidal glucocorticoid receptor (GR receptor) agonist
• GR receptor non-steroidal glucocorticoid receptor
• a pharmaceutical product comprising a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b- Fluoro- 1 - ⁇ [(fluoromethy l)sulfanyl] carbonyl ⁇ -7-(6-fluoropyridin-3 -yl)- 11 -hydroxy- 2,10a,12a-trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a pharmaceutically acceptable salt thereof; a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M3 receptor antagonist, a muscarinic antagonist
• a pharmaceutical product comprising a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b- Fluoro- 1 - ⁇ [(fluoromethy l)sulfanyl] carbonyl ⁇ -7-(6-fluoropyridin-3 -yl)- 11 -hydroxy- 2,10a,12a-trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a pharmaceutically acceptable salt thereof; a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M3 receptor antagonist or a muscarinic antagonist
• a pharmaceutical product comprising a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b- Fluoro- 1 - ⁇ [(fluoromethy l)sulfanyl] carbonyl ⁇ -7-(6-fluoropyridin-3 -yl)- 11 -hydroxy- 2,10a,12a-trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist or a dual ⁇ 2 adrenoreceptor agonist/M3 receptor antagonist; and optionally one or more pharmaceutically acceptable excipients.
• the first and second active ingredients are in admixture.
• the invention also provides a pharmaceutical product comprising a preparation
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist, a p38 kinase inhibitor, a neutrophil elastase inhibitor, a phosphodiesterase PDE4 inhibitor, an IKK2 kinase inhibitor or a non-steroidal
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist, a p38 kinase inhibitor, a neutrophil elastase inhibitor, a phosphodiesterase PDE4 inhibitor, an IKK2 kinase inhibitor or a non-steroidal
• glucocorticoid receptor (GR receptor) agonist wherein the preparations are for
• the invention also provides a pharmaceutical product comprising a preparation
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• the invention also provides a pharmaceutical product comprising a preparation
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• the invention also provides a pharmaceutical product comprising a preparation of a preparation of a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist or a muscarinic antagonist, wherein the preparations are for simultaneous, sequential or separate administration to a patient in need thereof.
• a pharmaceutical product comprising a preparation
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• the present invention further provides a kit comprising a preparation of a preparation of a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist or a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, wherein the preparations are for simultaneous, sequential or separate administration to a patient in need thereof.
• the present invention further provides a kit comprising a preparation of a preparation of a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist or a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, wherein the preparations are for simultaneous, sequential or separate administration to a patient in need thereof.
• the present invention further provides a kit comprising a preparation of a preparation of a preparation of a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist or a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, wherein the preparations are for simultaneous, sequential or separate administration to
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• the present invention further provides a kit comprising a preparation
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• the present invention further provides a kit comprising a preparation
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a
• the present invention further provides a kit comprising a preparation
• a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a
• a preparation of a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist or a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.
• “simultaneous” is meant that the preparations of the first and second active ingredients are administered at the same time.
• simultaneous is meant that the preparations of the first and second active ingredients are administered, in any order, one immediately after the other. They still have the desired effect if they are administered separately, but when administered in this manner they are generally administered less than 4 hours apart, conveniently less than two hours apart, more conveniently less than 30 minutes apart and most conveniently less than 20 minutes apart, for example less than 10 minutes but not one immediately after the other.
• pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated, as well as unsolvated forms, and the present invention encompasses all such solvated forms.
• any reference to any of the second active ingredients includes any active salt, solvate or derivative that may be formed from said active ingredient, or any enantiomer or mixture thereof.
• a p 2 -adrenoreceptor agonist is any compound or substance capable of stimulating the P 2 -receptors and acting as a bronchodilator.
• any reference to a ⁇ 2 - adrenoreceptor agonist includes an active salt, solvate or derivative that may be formed from said ⁇ 2 - adrenoreceptor agonist or any enantiomer or mixture thereof.
• Examples of possible salts or derivatives of a ⁇ 2 - adrenoreceptor agonist are (1) acid addition salts such as the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, l-hydroxy-2- naphthalenecarboxylic acid, maleic acid, and (2) pharmaceutically acceptable esters (e.g. Ci-C 6 alkyl esters).
• the 2 -adrenoreceptor agonists may also be in the form of solvates, e.g. hydrates.
• ⁇ 2 - adrenoreceptor agonists examples include:
• formoterol e.g. as fumarate or fumarate dihydrate
• salmeterol e.g. as xinafoate
• bitolterol e.g. as mesylate
• indacaterol (chemically identified as 5- ⁇ (lR)-2-[(5,6-diethyl-2,3-dihydro-lH-inden-2- yl)amino]-l-hydroxyethyl ⁇ -8-hydroxyquinolin-2(lH)-one, and which is commercially available).
• the 2 -adrenoreceptor agonist is a long-acting ⁇ 2 - adrenoreceptor agonist (i.e. a 2 -adrenoreceptor agonist with activity that persists for more than 24 hours), examples of which include: indacaterol
• salmeterol e.g. as xinafoate
• formoterol e.g. as fumarate or fumarate dihydrate
• bambuterol e.g. as hydrochloride
• carmoterol (TA 2005, chemically identified as [R-(R*,R*)]-8-hydroxy-5-[l-hydroxy-2-[[2- (4-methoxy-phenyl)- 1 -methylethyl]-amino]ethyl]-2( 1 H)-quinolone monohydrochloride, also identified by Chemical Abstract Service Registry Number 137888-11-0 and disclosed in U.S. Patent No 4,579,854),
• an aryl aniline as disclosed in WO 2003/042164 or WO 2006/133942 (for example, N-[2- [4- [(3 -phenyl-4-methoxyphenyl)amino]phenyl] ethyl] -(R)-2-hydroxy-2-(8-hydroxy- 1,2- dihydro-2-oxoquinolin-5-yl)ethylamine),
• a formanilide as disclosed in WO 2004/011416, WO 2005/030678, or WO 2006/066907 for example, N-(2- [4-((R)-2-hydroxy-2-phenylethylamino)phenyl] ethyl)-(R)-2-hydroxy- 2-(3-formamido-4-hydroxyphenyl)ethylamine),
• GSK159797 (chemically identified as N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[2- [4-[[(2R)-2-hydroxy-2-phenyl-ethyl]amino]phenyl]ethylamino]ethyl]phenyl]formamide), GSK159802, GSK597901, GSK642444 (chemically identified as 4-[(lR)-2-[6-[2-[(2,6- dichlorophenyl)methoxy]ethoxy]hexylamino]-l-hydroxy-ethyl]-2-(hydroxymethyl)phenol) or GSK678007,
• the 2-adrenoreceptor agonist is selected from: N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3- benzothiazol-7-yl)ethyl] amino ⁇ ethyl)-3 - [2-( 1 -naphthyl)ethoxy]propanamide as disclosed in WO 2008/096111,
• the P2-adrenoreceptor agonist is formoterol (e.g. as fumarate or fumarate dihydrate).
• the P2-adrenoreceptor agonist is selected from N- [2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro- 1 ,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3-[2-(l-naphthyl)ethoxy]propanamide or indacaterol, or a pharmaceutically acceptable salt of any one thereof.
• the 2-adrenoreceptor agonist is indacaterol, or a pharmaceutically acceptable salt thereof (for example indacaterol 2(Z)-but-2-ene dioate).
• the 2-adrenoreceptor agonist is N-[2- (Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3 - [2-( 1 -naphthyl)ethoxy]propanamide, or a pharmaceutically acceptable salt thereof (for example N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2- oxo-2,3-dihydro- 1 ,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(l - naphthyl)ethoxy]propanamide hydrobromide) .
• the p 2 -adrenoreceptor agonist is selected from indacaterol 2(Z)-but-2-ene dioate or N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2- oxo-2,3-dihydro- 1 ,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(l - naphthyl)ethoxy]propanamide hydrobromide.
• the p 2 -adrenoreceptor agonist is selected from:
• the 2 -adrenoreceptor agonist is N-[2- (Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo-2,3-dihydro-l,3-benzothiazol-7- yl)ethyl] amino ⁇ ethyl)-3 - [2-( 1 -naphthy l)ethoxy]propanamide dihydrobromide.
• N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo- 2,3-dihydro- 1 ,3-benzothiazol-7-yl)ethyl]amino ⁇ ethyl)-3-[2-(l - naphthyl)ethoxy]propanamide is N-[2-(Diethylamino)ethyl]-N-(2- ⁇ [2-(4-hydroxy-2-oxo- 2,3 -dihydro- 1 ,3 -benzothiazol-7-yl)ethyl] amino ⁇ ethyl)-3 -(2 -naphthalene- 1 - ylethoxy)propanamide.
• the second active ingredient is a ⁇ 2 adrenoreceptor agonist, for example a long-acting 2 -adrenoreceptor agonist.
• the dual ⁇ 2 adrenoreceptor agonist/M3 receptor antagonist is also known as a MABA compound.
• a MABA compound is a compound having dual activity as both a muscarinic antagonist and as a 2 -adrenoreceptor agonist, examples of which are disclosed in WO 2004/089892, WO 2004/106333, US 2004/0167167, WO 2005/111004, WO 2005/051946, US 2005/0256114, WO 2006/023457, WO 2006/023460, US 2006/0223858,
• MABA compounds include:
• the dual ⁇ 2 adrenoreceptor agonist/M3 receptor antagonist is 7-[-2-[2-[2-fluoro-5-[[8-(2-isopropylthiazole-4-carbonyl)-l l-oxa-3,8- diazaspiro [5.5 ]undecan-3 -yl]methyl]phenyl]ethylamino] - 1 -hydroxy-ethyl] -4-hydroxy-3H- l,3-benzothiazol-2-one, or a pharmaceutically acceptable salt thereof.
• the dual ⁇ 2 adrenoreceptor agonist/M3 receptor antagonist is 7-[( 1 R)-2- [2- [2-fluoro-5 - [ [8-(2-isopropylthiazole-4-carbonyl)- 11 -oxa-3 ,8- diazaspiro [5.5 ]undecan-3 -yl]methyl]phenyl]ethylamino] - 1 -hydroxy-ethyl] -4-hydroxy-3H- l,3-benzothiazol-2-one, or a pharmaceutically acceptable salt thereof.
• the second active ingredient is a dual ⁇ 2
• adrenoreceptor agonist/M 3 receptor antagonist adrenoreceptor agonist/M 3 receptor antagonist.
• muscarinic antagonists also known as LAMA compounds
• examples of muscarinic antagonists include:
• glycopyrrolate such as R,R-, R,S-, S,R-, or S,S-glycopyrronium bromide
• oxitropium bromide such as R,R-, R,S-, S,R-, or S,S-glycopyrronium bromide
• darotropium ((1R, 3R, 5S)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8- azoniabicyclo[3 ,2, 1 Joctane bromide), 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-l-(3-phenoxypropyl)-l- azoniabicyclo[2.2.2]octane bromide (see WO 01/04118),
• quaternary ammonium salts such as [2-((S)-Cyclohexyl-hydroxy-phenyl-methyl)- oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium salt, [2-((R)-Cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5 -ylmethyl] -dimethyl-(3 -phenoxy-propyl)-ammonium salt, [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5 -ylmethyl] -dimethyl-(2- phenethyloxy-ethyl)-ammonium salt, [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol- 5-ylmethyl]-[3-(3,4-dichloro-phenoxy)-propyl] dimethyl-ammonium salt, [2-(
• the muscarinic antagonist is selected from ((i?)-3-(l -phenyl- cycloheptanecarbonyloxy))- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane salt (particularly the bromide salt) or tiotropium (particularly tiotropium bromide).
• the muscarinic antagonist is ((i?)-3-(l -phenyl- cycloheptanecarbonyloxy))- 1 -(pyridin-2-ylcarbamoylmethyl)- 1 -azonia- bicyclo[2.2.2]octane salt, particularly ((i?)-3-(l-phenyl-cycloheptanecarbonyloxy))-l- (pyridin-2-ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane bromide.
• the muscarinic antagonist is 3-(l-phenyl- cycloheptanecarbonyloxy)-l-(pyridin-2-ylcarbamoylmethyl)-l-azonia-bicyclo[2.2.2]octane salt, particularly 3-(l -phenyl-cycloheptanecarbonyloxy)- 1 -(pyridin-2-ylcarbamoylmethyl)- l-azonia-bicyclo[2.2.2]octane bromide.
• the muscarinic antagonist is tiotropium (particularly tiotropium bromide).
• An alternative chemical name for ((R)-3 -( 1 -phenyl-cycloheptanecarbonyloxy))- 1 -(pyridin- 2-ylcarbamoylmethyl)- 1 -azonia-bicyclo[2.2.2]octane is (3R)- 1 -[2-oxo-2-(pyridin-2- ylamino)ethyl]-3- ⁇ [(l-phenylcycloheptyl)carbonyl]oxy ⁇ -l-azoniabicyclo[2.2.2]octane.
• Tiotropium is chemically identified as (li?,2i?,45',55',75)-7- ⁇ [hydroxy(dithiophen-2- yl)acetyl]oxy ⁇ -9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2 ' 4 ]nonane.
• the second active ingredient is a muscarinic antagonist.
• p38 Kinase inhibitors are known, for example, from WO 2009/001 132.
• One such compound described in WO 2009/001 132 is N-cyclopropyl-3-fiuoro-4-methyl-5-[3-[[l-[2- [2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-l(2H)-pyrazinyl]-benzamide and pharmaceutically acceptable salts thereof.
• (2H)-pyrazinyl]-benzamide is, for example, a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate,
• ethanesulphonate malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, 2- furoate, 3-furoate, napadisylate (naphthalene- 1 , 5 -disulfonate or naphthalene- 1 -(sulfonic acid)-5-sulfonate), edisylate (ethane- 1 ,2-disulfonate or ethane- 1 -(sulfonic acid)-2- sulfonate), isethionate (2-hydroxyethylsulfonate), 2-mesitylenesulphonate, 2- naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate, L-
• Another known p38 Kinase inhibitor is N-cyclopropyl-4-methyl-3- ⁇ 3-[(l- ⁇ 2-[2- (methylamino)ethoxy]phenyl ⁇ cyclopropyl)amino]-2-oxopyrazin- 1 (2H)-yl ⁇ benzamide (as disclosed in WO 2009/001132) and pharmaceutically acceptable salts thereof.
• the p38 Kinase inhibitor is selected from N-cyclopropyl-3-fluoro-4- methyl-5 -[3 - [[ 1 - [2- [2-(methylamino)ethoxy]phenyl] cyclopropyl] amino] -2-oxo- 1 (2H - pyrazinylj-benzamide and N-cyclopropyl-4-methyl-3- ⁇ 3-[(l- ⁇ 2-[2-
• the p38 Kinase inhibitor is N-cyclopropyl-3-fluoro-4-methyl-5-[3- [[ 1 -[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo- 1 (2H)-pyrazinyl]- benzamide, or a pharmaceutically acceptable salt thereof.
• the p38 Kinase inhibitor is N-cyclopropyl-4-methyl-3- ⁇ 3-[(l- ⁇ 2- [2-(methylamino)ethoxy]phenyl ⁇ cyclopropyl)amino]-2-oxopyrazin- 1 (2H)-yl ⁇ benzamide, or a pharmaceutically acceptable salt thereof.
• the second active ingredient is a p38 kinase inhibitor.
• a neutrophil elastase inhibitor is, for example, 6-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-5- methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic acid ethylamide (WO 2007/129963).
• the second active ingredient is a neutrophil elastase inhibitor.
• Phosphodiesterase PDE4 inhibitors are known in the art and include, for example, 6- fluoro-N-((ls,4s)-4-(6-fluoro-2,4-dioxo-l-(4'-(piperazin-l-ylmethyl)-biphenyl-3-yl)-l,2- dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)cyclohexyl)imidazo[ 1 ,2-a]pyridine-2- carboxamide (as disclosed in WO 2008/084223), or a pharmaceutically acceptable salt thereof, for example, a (l S)-(+)-10-camphorsulfonic acid or trihydrochloride salt; and 6- Fluoro-N-(( 1 s,4s)-4-(6-fluoro-2,4-dioxo- 1 -(4'-(piperazin- 1 -ylmethyl)-biphenyl-3-yl)-
• the second active ingredient is a phosphodiesterase PDE4 inhibitor.
• IKK2 kinase inhibitor is, for example, 2- ⁇ [2-(2-Methylamino-pyrimidin-4-yl)-lH- indole-5-carbonyl]-amino ⁇ -3-(phenyl-pyridin-2-yl-amino)-propionic acid or a compound as disclosed in WO 01/58890, WO 03/010158, WO 03/010163, WO 04/063185 or WO 04/063186.
• the second active ingredient is an IKK2 kinase inhibitor.
• a non-steroidal glucocorticoid receptor (GR) agonist is, for example, a compound disclosed in WO 2008/076048, for example 2,2,2-trifluoro-N-[(lR,2S)-l-[l-(4- fluorophenyl)indazol-5-yl]oxy-l-(3-methoxyphenyl)propan-2-yl]acetamide, N-[(1R,2S)-1- [ 1 -(4-fluorophenyl)indazol-5 -yl]oxy- 1 -(4-methylsulfonylphenyl)propan-2-yl] -2-hydroxy- acetamide, N- [( 1 R* ,2S *)- 1 - [ 1 -(4-fluorophenyl)indazol-5 -yl]oxy- 1 -(6-methoxypyr
• the second active ingredient is a non-steroidal glucocorticoid receptor agonist.
• the second active ingredient is selected from:
• the second active ingredient is selected from:
• the second active ingredient is selected from:
• the second active ingredient is selected from:
• the second active ingredient is selected from:
• the second active ingredient is selected from:
• the second active ingredient is selected from:
• the second active ingredient is selected from:
• All the above second et seq active ingredients may be in the form of solvates, for example hydrates.
• the active ingredients may be delivered to the lung and/or airways via oral administration in the form of a solution, suspension, aerosol or dry powder formulation.
• dosage forms will usually include one or more pharmaceutically acceptable excipients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings or colorants. Examples of such excipients are described in the Handbook of Pharmaceutical Excipients (Fifth Edition, 2005, edited by Ray C. Rowe, Paul J. Sheskey and Sian C. Owen, published by the American Pharmaceutical Association and the Pharmaceutical Press).
• the active ingredients of the present invention may also be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
• oral or parenteral e.g. intravenous, subcutaneous, intramuscular or intraarticular
• conventional systemic dosage forms such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
• the therapeutic dose of each active ingredient administered in accordance with the present invention will vary depending upon the particular active ingredient employed, the mode by which the active ingredient is to be administered, and the condition or disorder to be treated.
• the first active ingredient is administered via inhalation.
• the dose of the first active ingredient will generally be in the range of from 0.1 microgram ⁇ g) to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ , 0.1 to 100 ⁇ , 0.1 to 50 ⁇ , 0.1 to 5 ⁇ , 5 to 5000 ⁇ , 5 to 1000 ⁇ , 5 to 500 ⁇ , 5 to 100 ⁇ , 5 to 50 ⁇ g, 5 to 10 ⁇ , 10 to 5000 ⁇ , 10 to 1000 ⁇ , 10 to 500 ⁇ , 10 to 100 ⁇ , 10 to 50 ⁇ , 20 to 5000 ⁇ , 20 to 1000 ⁇ , 20 to 500 ⁇ , 20 to 100 ⁇ , 20 to 50 ⁇ , 50 to 5000 ⁇ , 50 to 1000 ⁇ , 50 to 500 ⁇ , 50 to 100 ⁇ , 100 to 5000 ⁇ , 100 to 1000 ⁇ g or 100 to 500 ⁇ g.
• the dose will generally be administered from 1 to 4 times a day, conveniently once or twice a day, and most conveniently once a day.
• the second active ingredient is administered by inhalation.
• the dose of the second active ingredient will generally be in the range of from 0.1 microgram ⁇ g) to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ , 0.1 to 100 ⁇ , 0.1 to 50 ⁇ , 0.1 to 5 ⁇ , 5 to 5000 ⁇ , 5 to 1000 ⁇ , 5 to 500 ⁇ , 5 to 100 ⁇ , 5 to 50 ⁇ 3 ⁇ 4 5 to 10 ⁇ , 10 to 5000 ⁇ , 10 to 1000 ⁇ , 10 to 500 ⁇ , 10 to 100 ⁇ , 10 to 50 ⁇ , 20 to 5000 ⁇ , 20 to 1000 ⁇ , 20 to 500 ⁇ , 20 to 100 ⁇ , 20 to 50 ⁇ , 50 to 5000 ⁇ , 50 to 1000 ⁇ , 50 to 500 ⁇ , 50 to 100 ⁇ , 100 to 5000 ⁇ , 100
• the present invention provides a pharmaceutical product wherein the molar ratio of first active ingredient to second active ingredient is from 1 : 1000 to
• 1000:1 such as from 1 : 100 to 100: 1, for example from 1 :50 to 50: 1, for example 1 :20 to 20:1.
• the pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 -
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist, a p38 kinase inhibitor, a neutrophil elastase inhibitor, a
• phosphodiesterase PDE4 inhibitor an IKK2 kinase inhibitor or a non-steroidal glucocorticoid receptor agonist; and optionally one or more pharmaceutically acceptable excipients, is formulated for inhaled administration.
• the pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 - ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist or a p38 kinase inhibitor; and optionally one or more
• the pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 - ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist or a muscarinic antagonist; and optionally one or more pharmaceutically acceptable excipients, is formulated for inhaled administration.
• the pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 - ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• the preparations of the first and second active ingredients for simultaneous, sequential or separate administration are each formulated for inhaled administration.
• Administration by inhalation may be via the oral or nasal route using a pressurised metered dose inhaler (pMDI), a nebuliser or a dry powder inhaler.
• a pMDI pressurised metered dose inhaler
• the first and/or second active ingredient(s) may be dispersed in a suitable propellant optionally together with an additional excipient such as an alcohol (e. ethanol), a surfactant, a lubricant or a stabilising agent.
• a suitable propellant includes a hydrocarbon, chlorofluorocarbon or a hydrofluoroalkane (e.g. heptafluoroalkane) propellant, or a mixture of any such propellants.
• Preferred propellants are PI 34a and P227, each of which may be used alone or in combination with other another propellant and/or surfactant and/or other excipient.
• the first and/or second active ingredient(s) will typically be formulated as an aqueous suspension or, preferably, solution, with or without suitable pH and/or tonicity adjustment.
• a dry powder inhaler may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier (such as lactose), in the latter case either as a finely divided powder or as an ordered mixture.
• the dry powder inhaler may be "passive" or breath-actuated, or "active” where the powder is dispersed by some mechanism other than the patient's inhalation, for instance, an internal supply of compressed air.
• passive dry powder inhalers are available: single-dose, multiple unit dose or multidose (reservoir) inhalers. In single-dose devices, individual doses are provided, usually in capsules, and have to be loaded into the inhaler
• Turbuhaler (AstraZeneca), Easyhaler (Orion), Novolizer (ASTA Medica),
• the present invention further provides a dry powder inhaler, in particular a multiple unit dose dry powder inhaler, containing a pharmaceutical product as hereinbefore described.
• the pharmaceutical product of the present invention may be used to treat diseases of the respiratory tract such as obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
• COPD chronic obstructive pulmonary disease
• lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus.
• SARS coronavirus
• the present invention further provides a pharmaceutical product as hereinbefore defined for use in therapy.
• Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
• Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
• the present invention further provides the use of first and second active ingredients, wherein the first active ingredient is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a
• a ⁇ 2 adrenoreceptor agonist a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist, a p38 kinase inhibitor, a neutrophil elastase inhibitor, a
• phosphodiesterase PDE4 inhibitor an IKK2 kinase inhibitor or a non-steroidal glucocorticoid receptor agonist, in the manufacture of a medicament or pharmaceutical product for the treatment of a respiratory disease, in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention further provides the use of first and second active ingredients, wherein the first active ingredient is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(f uoromethyl)sulfanyl]carbonyl ⁇ -7-(6-f uoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention provides the use of first and second active ingredients, wherein the first active ingredient is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)- 1 Ob-Fluoro- 1 - ⁇ [(f uoromethyl)sulfanyl] carbonyl ⁇ -7-(6-fluoropyridin-3 -yl)- 11 -hydroxy- 2,10a,12a-trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention provides the use of first and second active ingredients, wherein the first active ingredient is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)- 1 Ob-Fluoro- 1 - ⁇ [(f uoromethyl)sulfanyl] carbonyl ⁇ -7-(6-fluoropyridin-3 -yl)- 11 -hydroxy- 2,10a,12a-trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention further provides a pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 - ⁇ [(f uoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist, a p38 kinase inhibitor, a neutrophil elastase inhibitor, a
• phosphodiesterase PDE4 inhibitor an IKK2 kinase inhibitor or a non-steroidal glucocorticoid receptor agonist, for use in treating a respiratory disease, in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention further provides a pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 - ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 1 Oa, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist or a p38 kinase inhibitor, for use in treating a respiratory disease, in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention further provides a pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 -
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist or a muscarinic antagonist, for use in treating a respiratory disease, in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention further provides a pharmaceutical product comprising a first active ingredient which is (1 R,2R,3aS,3bS, 1 OaS, 1 ObR, 11 S, 12aS)- 1 Ob-Fluoro- 1 -
• a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention further provides a pharmaceutical product comprising a preparation of a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-fJindazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist, a p38 kinase inhibitor, a neutrophil elastase inhibitor, a
• glucocorticoid receptor agonist for use in treating a respiratory disease, in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention further provides a pharmaceutical product comprising a preparation of a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-10b-Fluoro-l- ⁇ [(fluoromethyl)sulfanyl]carbonyl ⁇ -7-(6-fluoropyridin-3-yl)- 11 -hydroxy-2, 10a, 12a- trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a second active ingredient selected from a ⁇ 2 adrenoreceptor agonist, a dual ⁇ 2 adrenoreceptor agonist/M 3 receptor antagonist, a muscarinic antagonist or a p38 kinase inhibitor, for use in treating a respiratory disease, in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention provides a pharmaceutical product comprising a preparation of a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)-
• a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention provides a pharmaceutical product comprising a preparation of a first active ingredient which is (lR,2R,3aS,3bS,10aS,10bR,l lS,12aS)- 1 Ob-Fluoro- 1 - ⁇ [(fluoromethyl)sulfanyl] carbonyl ⁇ -7-(6-fluoropyridin-3 -yl)- 11 -hydroxy- 2,10a,12a-trimethyl-l,2,3,3a,3b,4,5,7,10,10a,10b,l 1,12,12a- tetradecahydrocyclopenta[5,6]naphtho[l ,2-f]indazol-l-yl methoxyacetate or a
• a respiratory disease in particular chronic obstructive pulmonary disease, asthma, rhinitis, emphysema or bronchitis.
• the present invention still further provides a method of treating a respiratory disease which comprises simultaneously, sequentially or separately administering to a patient in need thereof:
• Figure 1 shows a graph of % inhibition against concentration for Compound A in combination with compound B
• Figure 2 shows a graph of % inhibition against concentration for Compound
• Figure 3 shows a graph of % inhibition against concentration for Compound A in combination with compound D
• Figure 4 shows a graph of % inhibition against concentration for Compound A in combination with compound E
• Figure 5 shows a graph of % inhibition against concentration for Compound A in combination with compound F
• Figure 6 shows a graph of % inhibition against concentration for Compound A in combination with compound G
• Figure 7 shows a graph of % inhibition against concentration for Compound
• the aqueous phase was collected, and the organic phase was extracted with an additional 40 ml of 2M NaOH.
• the combined aqueous phases were diluted with water (50 ml), washed with Et 2 0 (50 ml) and acidified with 4M HC1 (90 ml).
• the product was extracted with EtOAc (2x150 ml), and the combined organic phases were washed with brine (100 ml) and dried over Na 2 S0 4 .
• intermediate 4 In a 100 mL round-bottomed flask was dissolved intermediate 4 (8.7 g, 17.62 mmol) in DMF (20 mL) and di(lH-imidazol-l-yl)methanone (CDI, 5.71 g, 35.23 mmol) was added at room temperature. After the gas evolution had ceased, the mixture was stirred in a sealed flask overnight. Hydrogen sulfide (H 2 S) was subsequently bubbled through the solution for 10 minutes and the resulting solution was allowed to stir for another 10 minutes. The solution was added to 200 ml 1M HCl in a separation funnel and the mixture was extracted with EtOAc (2x150 ml).
• CDI di(lH-imidazol-l-yl)methanone
• intermediate 5 In a 250 mL round-bottomed flask was dissolved intermediate 5 (8.8 g, 17.07 mmol) in DCM (80 mL) and triethylamine (5.91 mL, 42.67 mmol) was added. To the stirred mixture was added 2-methoxyacetyl chloride (3.89 g, 35.84 mmol), whilst cooling in a water bath, and the mixture was stirred for 10 minutes.
• Ni-ethyl-N2,N2-dimethylethane-l ,2-diamine (3.48 mL, 22.19 mmol) was added and the mixture was stirred for another 10 minutes A solution of 60% bromofluoromethane (4.82 g, 25.60 mmol) in DMF was added, followed by triethyl amine (2 ml) and the reaction was allowed to stir for an additional 30 minutes. The resulting mixture was concentrated in vacuo and partitioned between EtOAc (150 ml) and 1M HC1 (150 ml).
• MABA compound a muscarinic antagonist or a p38 kinase inhibitor.
• LPS 5ng/mL
• the total assay volume was 200 ⁇ .
• 10 of the culture supernatant diluted 1 :5 was analysed to quantify the TNFa released using AlphaLISA (PerkinElmer). The fluorescence was detected on an EnVision Alphareader. Inhibition curves were fitted using a 4-parameter logistic equation in a non-linear curve fitting routine and activity was expressed as pIC50.

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• 2010
  • 2010-10-07 GB GBGB1016912.6A patent/GB201016912D0/en not_active Ceased
• 2011
  • 2011-10-05 BR BR112013008362A patent/BR112013008362A2/pt not_active Application Discontinuation
  • 2011-10-05 CN CN2011800589330A patent/CN103249418A/zh active Pending
  • 2011-10-05 RU RU2013115103/15A patent/RU2013115103A/ru not_active Application Discontinuation
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  • 2011-10-05 KR KR1020137008725A patent/KR20130126595A/ko not_active Application Discontinuation
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