WO2009142589A1 - Combinaison de: (a) un modulateur des récepteurs des glucocorticoïdes et (b) un antagoniste muscarinique - Google Patents

Combinaison de: (a) un modulateur des récepteurs des glucocorticoïdes et (b) un antagoniste muscarinique Download PDF

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Publication number
WO2009142589A1
WO2009142589A1 PCT/SE2009/050564 SE2009050564W WO2009142589A1 WO 2009142589 A1 WO2009142589 A1 WO 2009142589A1 SE 2009050564 W SE2009050564 W SE 2009050564W WO 2009142589 A1 WO2009142589 A1 WO 2009142589A1
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Prior art keywords
fluorophenyl
oxy
indazol
propan
alkyl
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PCT/SE2009/050564
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English (en)
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Tomas Eriksson
Thomas Hansson
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Astrazeneca Ab
Bayer Schering Pharma Ag
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Publication of WO2009142589A1 publication Critical patent/WO2009142589A1/fr

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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

Definitions

  • the present invention relates to a combination of (a) glucocorticoid receptor modulator and (b) a muscarinic antagonist.
  • the invention further relates to pharmaceutical compositions comprising said combination and to methods of treatment of airway diseases, such as chronic obstructive pulmonary disease (COPD) and asthma in mammals by administrating said combination.
  • COPD chronic obstructive pulmonary disease
  • the invention also relates to a kit comprising the combination and use of said kit in treatment of airway diseases.
  • Airway 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 which refers to a large group of lung diseases which can interfere with normal breathing. Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible.
  • the airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
  • the most important contributory source of such particles and gases is tobacco smoke.
  • COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells.
  • the two most important conditions covered by COPD are chronic bronchitis and emphysema.
  • Chronic bronchitis is a long-standing inflammation of the bronchi which causes increased production of mucous and other changes. The patients' symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.
  • Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi.
  • the lung loses its elasticity and therefore these areas of the lungs become enlarged. These enlarged areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood.
  • the predominant symptom in patients with emphysema is shortness of breath.
  • Sulphonamide derivatives are disclosed as antiinflammatories in WO 2004/019935 and WO 2004/050631.
  • Pharmaceutically active sulphonamides are also disclosed in Arch. Pharm. (1980) 313 166-173, J. Med. Chem. (2003) 46 64-73, J. Med. Chem (1997) 40 996- 1004, EP 0031954, EP 1190710 (WO 200124786), US 5861401, US 4948809, US3992441 and WO 99/33786. It is known that certain non-steroidal compounds interact with the glucocorticoid receptor (GR) and, as a result of this interaction, produce a suppression of inflammation (see, for example, US6323199).
  • GR glucocorticoid receptor
  • Such compounds can show a clear dissociation between antiinflammatory and metabolic actions making them superior to earlier reported steroidal and non-steroidal glucocorticoids.
  • the muscarinic receptors Ml, M2 and M3 are expressed in human lungs, M2 and M3 dominating in the airways and Ml found only in smaller peripheral airways. Most cell types in airways and lung including inflammatory cells express muscarinic receptors.
  • Acetylcholine (ACh) being the classical neurotransmitter of the parasympattic nervous system is the main endougenous ligand binding to the muscarinic receptors.
  • M3 receptors are expressed on airway smooth muscle cells and mediate bronchoconstriction leading to airway narrowing.
  • Ml receptors facilitate cholinergic neurotransmission and enhance airway bronchoconstriction.
  • the M2 receptor acts as a feedback autoreceptor inhibiting the release of ACh at the nerve endings.
  • activation of M2 receptors augment ACh-triggered smooth muscle contraction initiated by activation of M3 receptors, leading to bronchoconstriction and an overall reduced lung functional capacity being a hallmark of COPD.
  • M3 signalling mediates smooth muscle cell proliferation and accordingly contributes to the remodelling process in chronic inflammatory airways. M3 signalling enhances mucus production from airway goblet cells, contributing to plugging of small airways, leading to cough (bronchitis) and reduced lung function in COPD patients.
  • Muscarinic agonists such as ACh, act on airway tracheal epithelial cells and increase cell proliferation, release of inflammatory mediators from epithelial and inflammatory cells, which results in increased chemotactic activity of neutrophils and macrophages.
  • Treatment of COPD patients with inhaled Ml and M3 selective muscarinic antagonists targets cholinergic bronchoconstriction by opening narrowed airways resulting in sustained improvement in lung function, reduced mucus production, reduced exacerbation frequency, less activity-induced breathlessness, improved exercise endurance and an overall quality of life (QOL) improvement for these patients.
  • the present invention relates to a combination of a glucocorticoid receptor modulator with a muscarinic antagonist.
  • the combination of the present invention has a beneficial therapeutic effect in the treatment of airway diseases.
  • the combination according to the invention is considered to be particularly effective in reducing inflammatory cell influx into the lung.
  • the beneficial effect may be observed when the two active substances are administered simultaneously (either in a single pharmaceutical composition or in separate compositions), or sequentially or separately.
  • a pharmaceutical product comprising, in combination,
  • A is Ci- ⁇ alkyl, Ci- ⁇ hydroxyalkyl, Ci_ 6 alkoxy, C 3 - 7 cycloalkyl, Cs-yheterocycloalkyl, Ci_ ehaloalkyl, Ci_ 6 alkyl0Ci_ 6 alkyl, C ⁇ alkylOC ⁇ alkylOC ⁇ alkyl, Ci_ 6 alkylC(O)OCi_ 6 alkyl,
  • Ci_ 4 alkylOCi_ 4 alkyl and Ci_ 4 alkylS(O) 2 and R x is hydrogen, or
  • A forms together with R x a 5 membered azacyclic ring optionally having one or more further heteroatoms independently selected from O and N;
  • R 1 and R la are independently selected from hydrogen, Ci_ 4 alkyl, C ⁇ hydroxy alky 1, Ci_ 4 alkyl0Ci_ 4 alkyl and C ⁇ haloalkyl, or R 1 and R la together are oxo;
  • R 2 is hydrogen or Ci_ 4 alkyl
  • R 2 is hydrogen
  • R is C 5 _ioaryl, C 5 _ioarylCi_ 4 alkyl, Cs_ioarylO, Cs_ioarylOCi_ 4 alkyl or Cs_ioheteroaryl, which may be optionally substituted by one or more substituents independently selected from B;
  • B is hydroxy, Ci_ 4 alkyl, Ci_ 4 alkoxy, Ci_ 4 alkylCi_ 4 thioalkyl, Ci_ 4 thioalkyl, C 3 - 6 cycloalkylS,
  • Ci. 3 alkylS(O) n Ci. 4 alkyl, Ci_ 3 alkylS(O) n , Ci_ 4 haloalkyl or halo; n is 1 or 2;
  • R 4 is hydrogen
  • W is phenyl, Ci_ 4 alkyl, C 3 _ 7 Cycloalkyl, pyridinyl, pyridazinyl or pyrimidinyl all of which are optionally substituted by one or more substituents independently selected from Ci_ shydroxyalkyl, C 3 - 6 heterocycloalkylCi_ 4 alkyl, halo, Ci_ 4 alkylOC(O) and NR 10 R ⁇ Ci_ 4 alkyl;
  • X is O or S;
  • Y is hydrogen, halo or C 1-4 alkyl; Z is O or S;
  • R 5 , R 6 , R 10 and R 11 are independently selected from hydrogen, C 1-6 alkylC(O), NHR 7 C(O) and Ci_ 6 alkyl;
  • R 7 is hydrogen, d_ 6 alkyl, Ci_ 6 alkylOC(O)Ci_ 3 alkyl, C 5 _i 0 heteroarylCi_ 3 alkyl or C 3 . ⁇ cycloalkyl; or a pharmaceutically acceptable salt thereof, and (b) a second active ingredient, which is a muscarinic antagonist, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical product comprising, in combination, (a) a first active ingredient, which is glucocorticoid receptor modulator of formula (III), wherein:
  • A is Ci_ 3 hydroxyalkyl, C 3 _ 5 cycloalkyl, Ci_ 3 haloalkyl Or NR 5 R 6 C(O);
  • R 1 and R la are independently selected from hydrogen and Ci_ 3 alkyl
  • R 2 is hydrogen
  • R 3 is C 5 _ioaryl C 5 _ioarylOCi_ 2 alkyl or Cs-ioheteroaryl, which may be optionally substituted by one or more substituents independently selected from B;
  • B is Ci_ 3 alkoxy or Ci_ 3 alkylS(O) n ; n is 2;
  • R 4 is hydrogen; W is phenyl which is optionally substituted by one or more halo;
  • X is O
  • Y is hydrogen; Z is O;
  • R 5 and R 6 are independently selected from hydrogen and Ci_ 3 alkyl; and R x is hydrogen; or a pharmaceutically acceptable salt thereof.
  • a second active ingredient which is a muscarinic antagonist, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical product as defined above comprising:
  • the second active ingredient is tiotropium bromide.
  • the present invention relates to a pharmaceutical product whereby the muscarinic antagonist is combined with any compound falling within the scope of compounds of formula (III) as defined above.
  • alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl.
  • Ci_ 4 alkyl having 1 to 4 carbon atoms and may be but are not limited to methyl, ethyl, n-propyl, i-propyl or tert-butyi.
  • alkoxy refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • alkoxy may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
  • cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
  • the term “Ci_ 6 cycloalkyl” may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • haloalkyl means an alkyl group as defined above, which is substituted with halogen as defined above.
  • C 1 - Cehaloalkyl may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl or bromopropyl.
  • Ci_ 3 haloalkylO may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
  • halophenyl may include, but is not limited to fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, dichlorophenyl or trichlorophenyl.
  • alkylcarbonyl or “alkoxycarbonyl” may include, but is not limited to an alkyl or alkoxy group as defined above, which is substituted with COOH.
  • alkylcarbonylamino may include, but is not limited to an alkyl group as defined above, which is substituted with NHCOOH.
  • hydroxyalkyl may include, but is not limited to an alkyl group as defined above, which is substituted with one or more hydroxyl groups.
  • the first active compound which is a glucocorticoid receptor modulator is selected from:
  • the compound of formula (III) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers of the compounds of formula (III) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. In one embodiment the optical isomers are the (S)-enantiomers.
  • the compounds of formula (III) may be used in the form of a pharmaceutically acceptable salt thereof, conceivably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, 2-fluorobenzoate, 2,6-difluorobenzoate, (hemi)fumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate, methanesulphonate, trifluoroacetate or/?-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, sulfphate, acetate, ascorbate, benzoate, 2-fluorobenzoate, 2,6-difluorobenzoate, (hemi)fumarate, furoate, succinate, maleate, tartrate, citrate, oxalate, xinafoate
  • Pharmaceutically acceptable salts may also be formed together with metals such as calcium, magnesium, sodium, potassium or zinc or bases such as piperazine, 2-aminoethanol, choline, diethylamine or diethanol amine.
  • the compounds of formula (III) may be used in the form of a pharmaceutically acceptable salt thereof, like an amino acid addition salt such as L- lysine, glycine, L-glutamine, L-asparagine or L-arganine
  • a pharmaceutically acceptable salt also includes internal salt (zwitterionic) forms. Any reference to compounds of formula (III) or salts thereof also encompasses solvates of such compounds and solvates of such salts (e.g. hydrates) as well as cocrystals.
  • the glucocorticoid receptor modulators mentioned above may be prepared according to the process desribed in patent application PCT/SE2007/001136.
  • the second active ingredient in the combination of the present invention is a muscarinic antagonist.
  • One embodiment of the invention relates to long acting muscarinic antagonists.
  • Another embodiment relates to short acting muscarinic antagonists.
  • Non-limiting examples of a muscarinic antagonist that may be used in the pharmaceutical product according to the present invention include ipratropium (e.g. as bromide), tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine, pirenzepine, telenzepine, glycopyrronium bromide (such as R,R-glycopyrronium bromide or a mixture of R,S- and S,R-glycopyrronium bromide); mepensolate (e.g.
  • bromide a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-l-(3-phenoxypropyl)-l- azonia-bicyclo[2.2.2]octane (e.g. as bromide) (Aclidinium bromide) or LAS35201; GSK 656398, GSK 961081 or GSK202405; QAT370; 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5- methyl-2,2-diphenylhexanamide (e.g. as hydrochloride); darotropium (e.g. as bromide) and trospium (e.g. as bromide), or a pharmaceutically acceptable salt thereof.
  • a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-l-(3-phenoxypropyl)-l- azonia
  • the present invention relates to a pharmaceutical product whereby any one of the compounds of formula (III) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), is combined with any one of the specific the muscarinic antagonist mentioned above.
  • One embodiment relates to a pharmaceutical product whereby the compound 2,2,2- trifluoro-N- [( 1 R,2S)- 1 - [ 1 -(4-fluorophenyl)indazol-5 -yl]oxy- 1 -(3 -methoxyphenyl)propan- 2-yl]acetamide or a pharmaceutically acceptable salt thereof, is combined with a muscarinic antagonist selected from ipratropium (e.g. as bromide), tiotropium (e.g. as bromide), oxitropium (e.g.
  • bromide as bromide
  • tolterodine pirenzepine
  • telenzepine glycopyrronium bromide
  • glycopyrronium bromide such as R,R- glycopyrronium bromide or a mixture of R,S- and S,R-glycopyrronium bromide
  • mepensolate e.g. as bromide
  • a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2- dithien-2-ylacetoxy)-l-(3-phenoxypropyl)-l-azonia-bicyclo[2.2.2]octane (e.g.
  • bromide (Aclidinium bromide) or LAS35201; GSK 656398, GSK 961081 or GSK202405; QAT370; 5-[3-(3-hydroxyphenoxy)azetidin- 1 -yl]-5-methyl-2,2-diphenylhexanamide (e.g. as hydrochloride); darotropium (e.g. as bromide) and trospium (e.g. as bromide), or a pharmaceutically acceptable salt thereof.
  • the active ingredients of the present invention may be administered by oral or parenteral (e.g. intravenous, subcutaneous, intramuscular or intraarticular) administration using conventional systemic dosage forms, such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions and sterile injectable aqueous or oily solutions or suspensions.
  • the active ingredients may also be administered topically (e.g. to the lung and/or airways) in the form of solutions, suspensions, aerosols and dry powder compositions.
  • These dosage forms will usually include one or more pharmaceutically acceptable ingredients which may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • pharmaceutically acceptable ingredients may be selected, for example, from adjuvants, carriers, binders, lubricants, diluents, stabilising agents, buffering agents, emulsifying agents, viscosity-regulating agents, surfactants, preservatives, flavourings and colorants.
  • the most appropriate method of administering the active ingredients is dependent on a number of factors.
  • One embodiment relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, in admixture, a first active ingredient which is a compounds of formula (III) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above) or a pharmaceutically acceptable salt thereof, and a second active ingredient which is a muscarinic antagonist mentioned above, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • a first active ingredient which is a compounds of formula (III) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above) or a pharmaceutically acceptable salt thereof
  • a second active ingredient which is a muscarinic antagonist mentioned above
  • the active ingredients are administered via separate pharmaceutical compositions.
  • the present invention provides a kit comprising a composition of a first active ingredient, which is a compounds of formula (III) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above) and a composition of a second active ingredient, which is a muscarinic antagonist mentioned above, and optionally instructions for the simultaneous, sequential or separate administration of the compositions to a patient in need thereof.
  • the pharmaceutical compositions of the present invention may be prepared by mixing the first active ingredient and the second active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for the preparation of a pharmaceutical composition which comprises mixing a compounds of formula (III) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), with a second active ingredient as defined above, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a compounds of formula (III) i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above
  • 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 and second active ingredients of the present invention are each administered by inhalation.
  • the active ingredients may be inhaled simultaneously.
  • the active ingredients may be inhaled sequentially.
  • the active ingredients may be inhaled separately.
  • the active ingredients are conveniently administered via inhalation (e.g. topically to the lung and/or airways) in the form of solutions, suspensions, aerosols or dry powder compositions. Administration may be by inhalation, orally or intranasally.
  • the active ingredients are preferably adapted to be administered, either together or individually, from a dry powder inhaler, pressurised metered dose inhaler, or a nebuliser.
  • the active ingredients may be used in admixture with one or more pharmaceutically acceptable additives, diluents or carriers.
  • suitable diluents or carriers include lactose (e.g. the monohydrate), dextran, mannitol or glucose.
  • Metered dose inhaler devices may be used to administer the active ingredients, dispersed in a suitable propellant and with or without additional excipients such as ethanol, a surfactant, a lubricant, an anti-oxidant or a stabilising agent.
  • Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P 134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • Nebulised aqueous suspensions, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose compositions.
  • Dry powder inhalers may be used to administer the active ingredients, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • the active ingredients When the active ingredients are adapted to be administered, either together or individually, via a nebuliser they may be in the form of a nebulised aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a single dose or multidose device.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compounds of formula (III) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), and a second active ingredient, which is muscarinic antagonist, wherein each active ingredient is formulated for inhaled administration.
  • a first active ingredient which is a compounds of formula (III) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above)
  • a second active ingredient which is muscarinic antagonist
  • the first active ingredient which is a compound of formula (III)) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), may be formulated for oral administration and the second active ingredient(s) , which is a muscarinic antagonist, as defined above, may be formulated for inhaled administration.
  • the second active ingredient(s) which is a muscarinic antagonist, as defined above
  • the first active ingredient which is a compound of formula (III)) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), may be formulated for inhaled administration and the second active ingredient(s), which is a muscarinic antagonist, as defined above, may be formulated for oral administration.
  • the second active ingredient(s) which is a muscarinic antagonist, as defined above
  • the first active ingredient which is a compound of formula (III)) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), and the second active ingredient(s), which is a muscarinic antagonist, as defined above, wherein each active ingredient is formulated for oral administration.
  • the use of compounds of formula (III) are contemplated to demonstrate particular effects when used in combination with a muscarinic antagonist, and in particular in combination with tiotropium.
  • a combination of a muscarinic antagonist and a compound of formula (III) at dose levels where neither component alone significantly affects lung inflammation, in combination give significant reduction of inflammatory cell influx.
  • the reduction in cell influx for the combination is contemplated to be greater than that expected from the additive effect of the two ingredients.
  • This synergistic effect when combining the ingredients could be used, for example, to lower the therapeutic dose of muscarinic antagonist, or at the same dose, achieve enhanced efficacy on inflammation in comparison to the use of the muscarinic antagonist alone.
  • the synergistic effect can be particularly advantageous where lower doses of the muscarinic antagonist are desirable, for example in individuals that have acquired resistance to such a muscarinic antagonist.
  • COPD chronic obstructive pulmonary disease
  • asthma such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g.
  • bronchitis acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia.
  • the compound of formula (III), or a pharmaceutically acceptable salt thereof, (first active ingredient) and the muscarinic antagonist or a pharmaceutically acceptable salt thereof, (second active ingredient) may be administered simultaneously, sequentially or separately to treat airway diseases.
  • sequential it is meant that the active ingredients are administered, in any order, one immediately after the other. They still have the desired effect if they are administered separately, but when administered in this manner they are generally administerted less than 4 hours apart, more conveniently less than two hours apart, more conveniently less than 30 minutes apart and most conveniently less than 10 minutes apart.
  • the amount of the active ingredients used relate to unit doses unless explicitly defined differently.
  • the dose of the first active ingredient (compound of formula (III) or a pharmaceutically acceptable salt thereof), will generally be in the range of from 0.1 ⁇ g to 10000 ⁇ g, 0.1 to 5000 ⁇ g, 0.1 to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 5 ⁇ g to 5000 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 200 ⁇ g, 5 to 100 ⁇ g, 5 to 50 ⁇ g, 10 to 5000 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 200 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 5000 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 200 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 5000 ⁇ g, 50 to 1000 ⁇ g, 50 to 1000 ⁇ g
  • the amount of the first active ctive ingredient used is in the range of from 1 ⁇ g to 200 ⁇ g, and that of the second active ingredient is in the range of from 1 ⁇ g to 200 ⁇ g.
  • the dose of the second active ingredient will generally be in the range of from 0.1 microgram ( ⁇ g) to 1000 ⁇ g, 0.1 to 500 ⁇ g, 0.1 to 200 ⁇ g, 0.1 to 100 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 5 ⁇ g, 5 to 1000 ⁇ g, 5 to 500 ⁇ g, 5 to 200 ⁇ g, 5 to 50 ⁇ g, 5 to 10 ⁇ g, 10 to 1000 ⁇ g, 10 to 500 ⁇ g, 10 to 200 ⁇ g, 10 to 100 ⁇ g, 10 to 50 ⁇ g, 20 to 1000 ⁇ g, 20 to 500 ⁇ g, 20 to 200 ⁇ g, 20 to 100 ⁇ g, 20 to 50 ⁇ g, 50 to 1000 ⁇ g, 50 to 500 ⁇ g, 50 to 200 ⁇ g, 50 to 100 ⁇ g, 100 to 1000 ⁇ g, or 100 to 500 ⁇ g.
  • the molar ratio of the second active ingredient to the first active ingredient in a dose may typically be in the range of from 300: 1 to 1 :300. In one embodiment the ratio is in the range of from 100:1 to 1 :100. In another embodiment the ratio is in the range of from 50:1 to 1 :50. In a further embodiment the ratio is in the range of from 10:1 to 1 :10. In yet another embodiment the ratio is in the range of from 5:1 to 1 :5.
  • the ratio is in the range of 1 : 10 to 1 :50. In another embodiment the ratio is in the range of 1 : 15 to 1 :40.
  • the M3 antagonists are likely to have a lower molecular weight but may be as potent at their receptor as the glucocorticoid receptor modulators.
  • the doses of the first and second active ingredients will generally be administered from 1 to 4 times a day, conveniently once or twice a day, and most conveniently once a day.
  • the present invention further provides a pharmaceutical product, kit or pharmaceutical composition comprising the combination according to the present invention for simultaneous, sequential or separate use in therapy.
  • the present invention further provides the use of a pharmaceutical product, kit or pharmaceutical composition, which comprises:
  • a (therapeutically effective) dose of a first active ingredient which is a compound of formula (III)) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above) or a pharmaceutically acceptable salt thereof; and
  • the present invention further provides the use of a pharmaceutical product, kit or pharmaceutical composition, which comprises:
  • a (therapeutically effective) dose of a first active ingredient which is a compound of formula (III)) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), or a pharmaceutically acceptable salt thereof; and (b) a (therapeutically effective) dose of a second active ingredient, which is a muscarinic antagonist, or a pharmaceutically acceptable salt thereof as defined above, in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease or asthma, or any other disorder mentioned above.
  • a first active ingredient which is a compound of formula (III)
  • a second active ingredient which is a muscarinic antagonist, or a pharmaceutically acceptable salt thereof as defined above
  • the present invention still further provides a method of treating airway diseases, or chronic obstructive pulmonary disease or asthma, or any other disorder mentioned above which comprises simultaneously, sequentially or separately administering:
  • a (therapeutically effective) dose of a first active ingredient which is a compound of formula (III)) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above) or a pharmaceutically acceptable salt thereof; and (b) a (therapeutically effective) dose of a second active ingredient, which is a muscarinic antagonist, or a pharmaceutically acceptable salt thereof as defined above, to a patient in need thereof.
  • One embodiment relates to the uses and methods described above wherein the first active ingredient is a compound of formula (III)) (i.e. any one of the compounds falling within the scope of formula (III) as defined above or any one of the compounds or salts of compounds of formula (III) mentioned above), and
  • a second active ingredient is ipratropium (e.g. as bromide), tiotropium (e.g. as bromide), oxitropium (e.g. as bromide), tolterodine, pirenzepine, telenzepine, glycopyrronium bromide (such as R,R-glycopyrronium bromide or a mixture of R,S- and S,R-glycopyrronium bromide); mepensolate (e.g.
  • a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)- 1 -(3-phenoxypropyl)- 1 -azonia- bicyclo[2.2.2]octane (e.g. as bromide) (Aclidinium bromide) or LAS35201; GSK 656398, GSK 961081 or GSK202405; QAT370; 5-[3-(3-hydroxyphenoxy)azetidin-l-yl]-5-methyl- 2,2-diphenylhexanamide (e.g. as hydrochloride); darotropium (e.g. as bromide) and trospium (e.g.
  • phospodiesterase (PDE) inhibitors as well as glucocorticoid receptor agonists are excluded from the combination of the invention.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly. Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the condition or disorder in question. Persons at risk of developing a particular condition or disorder generally include those having a family history of the condition or disorder, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition or disorder.
  • the term “disease”, unless stated otherwise, has the same meaning as the terms “condition” and “disorder” and are used interchangeably throughout the description and claims.
  • agent and “ingredient” means the compounds comprised in the combination of the present invention, i.e. glucocorticoid receptor modulators or a muscarinic antagonist.
  • glucocorticoid receptor modulator referred to here as Compound A
  • Compound B a muscarinic antagonist
  • BAL bronchoalveolar lavage
  • Compound A/CompoundB mixed formulations are made by mixing 0.002 or 0.02 ⁇ g/ml Compound A in Vehicle and 0.2 ⁇ g/ml Compound B in Vehicle to the final concentrations of 0.001/0.1 ⁇ g/mL Compound A/Compound B and 0.01/0.1 ⁇ g/mL Compound A/Compound B.
  • LPS Lipopolysaccharide B. E.coli 026:B6 is dissolved in saline to a final concentration of 2.5 ⁇ g/ml
  • Rats are anaesthetized with Isofluran and put in a supine position, head up, on a board tilted at 30°. Animals are intratracheally instilled with solutions (1 ml/kg) of Compound A/Compound B (0.001/ 0.1 ⁇ g/kg), Compound A/Compound B (0.01/0.1 ⁇ g/kg), Compound A (0.001 or 0.01 ⁇ g/kg) alone, Compound B (0.1 ⁇ g/kg) alone, or with Saline (negative and positive control animals). Rats remain in this position until regaining consciousness. The drugs are administrated 30 min before LPS instillation.
  • Rats are anaesthetized with Isofluran and put in a supine position, head up, on a board tilted at 30°. LPS or saline alone (negative control) in a volume of 200 ⁇ l is administered i.t. using a modified metal cannula. Rats remain in this position until regaining consciousness.
  • rats are intraperitoneally injected with 2 mL of a mixture of pentobarbital (60 mg/ml, Apoteksbolaget, Sweden) and PBS (1 : 1) for 1 - 2 min.
  • Broncho alveolar lavage After termination, collection of BAL fluid is performed twice with PBS. The BAL fluid is centrifuged and the cell pellet is resuspended in PBS. The total numbers of BAL cells are counted in a SYSMEX cell counter.
  • patients that receive a combination treatment containing both a muscarinic antagonist and a glucocorticoid receptor modulator will need to be treated with less amount of both active ingredients, compared to patients that are on single treatment.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une combinaison de: (a) un modulateur des récepteurs des glucocorticoïdes et (b) un antagoniste muscarinique. L'invention concerne également des compositions pharmaceutiques comprenant ladite combinaison ainsi que des méthodes de traitement de maladies des voies respiratoires, telles que la bronchopneumopathie chronique obstructive (BPCO) et l'asthme chez des mammifères par administration de ladite combinaison. L'invention concerne en outre un kit comprenant la combinaison, ainsi que l'utilisation dudit kit dans le traitement de maladies des voies respiratoires.
PCT/SE2009/050564 2008-05-20 2009-05-19 Combinaison de: (a) un modulateur des récepteurs des glucocorticoïdes et (b) un antagoniste muscarinique WO2009142589A1 (fr)

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US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
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US10543192B2 (en) 2013-02-28 2020-01-28 Dermira, Inc. Glycopyrrolate salts
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WO2008076048A1 (fr) * 2006-12-21 2008-06-26 Astrazeneca Ab Dérivés d'amide et d'ester d'indazolyle pour traiter des troubles médiés par le récepteur de glucocorticoïde

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WO2007046747A1 (fr) * 2005-10-20 2007-04-26 Astrazeneca Ab Sulfonamides bicycliques innovants utilisables en tant que modulateurs du recepteur des glucocorticoides dans le traitement des maladies inflammatoires
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8367829B2 (en) 2010-05-10 2013-02-05 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
US8394829B2 (en) 2010-05-10 2013-03-12 Gilead Sciences, Inc. Bi-functional quinoline analogs
US8450490B2 (en) 2010-05-10 2013-05-28 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
US9539248B2 (en) 2012-03-14 2017-01-10 Ltt Bio-Pharma Co., Ltd. Agent for ameliorating chronic obstructive pulmonary disease
JPWO2013137009A1 (ja) * 2012-03-14 2015-08-03 株式会社Ｌｔｔバイオファーマ 慢性閉塞性肺疾患改善剤
WO2013137009A1 (fr) * 2012-03-14 2013-09-19 株式会社Ｌｔｔバイオファーマ Agent pour faire régresser les maladies pulmonaires obstructives chroniques
US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
US8859610B2 (en) 2013-02-28 2014-10-14 Dermira, Inc. Crystalline glycopyrrolate tosylate
US9006461B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Crystalline glycopyrrolate tosylate
US10543192B2 (en) 2013-02-28 2020-01-28 Dermira, Inc. Glycopyrrolate salts
US10548875B2 (en) 2013-02-28 2020-02-04 Dermira, Inc. Glycopyrrolate salts
US11291652B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
US11291651B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
WO2016113216A1 (fr) * 2015-01-12 2016-07-21 Glaxosmithkline Intellectual Property Development Limited Combinaison pharmaceutique

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