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WO2008087437A1 - Traitement de l'asthme résistant aux corticoïdes ou copd par inhibition de la map kinase p38 (par exemple sb2035809) - Google Patents

Traitement de l'asthme résistant aux corticoïdes ou copd par inhibition de la map kinase p38 (par exemple sb2035809) Download PDF

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Publication number
WO2008087437A1
WO2008087437A1 PCT/GB2008/000183 GB2008000183W WO2008087437A1 WO 2008087437 A1 WO2008087437 A1 WO 2008087437A1 GB 2008000183 W GB2008000183 W GB 2008000183W WO 2008087437 A1 WO2008087437 A1 WO 2008087437A1
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WO
WIPO (PCT)
Prior art keywords
urea
tert
pyridin
naphthalen
butyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2008/000183
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English (en)
Inventor
Pankaj Kumar Bhavsar
Kian Fan Chung
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ip2ipo Innovations Ltd
Original Assignee
Imperial Innovations Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Imperial Innovations Ltd filed Critical Imperial Innovations Ltd
Publication of WO2008087437A1 publication Critical patent/WO2008087437A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to the treatment of severe respiratory disease.
  • Corticosteroids are the most effective anti-inflammatory therapy for inflammatory diseases such as asthma
  • ICS inhaled corticosteroids
  • p 2 -agonists long-acting corticosteroids
  • these latter patients with severe (or uncontrolled) asthma suffer greater morbidity and face a greater risk of asthma-associated death despite taking high doses of ICS (sometimes together with oral corticosteroids).
  • Severe asthmatics do not display absolute resistance to the therapeutic effects of corticosteroids, as ceasing therapy exacerbates their symptoms. Instead the ⁇ - show a reduced responsiveness to corticosteroids, and as a result, high does of corticosteroid are required to adequately control their asthma. This is described as corticosteroid-dependcnf (CD) asthma.
  • CD corticosteroid-dependcnf
  • COPD chronic obstructive pulmonary disease
  • cytokine release has been shown to be distinctly resistant to the anti-infiammatoiy effects of corticosteroids in comparison with alveolar macrophages from smokers with normal lung function.
  • Lear tctr ⁇ administration o ⁇ ' orai cor ⁇ coRtcicids c ⁇ cyr ⁇ y effects the hyopo(b-ua!ru>- P'Uiitii.'-v-adren;.'! tixir. n - r,d m-: ' ciuis-.; side e rfcri.
  • corticosteroid therapy offers clear benefits to sufferers of severe asthma and COPD in the short term, the development of corticosteroid resistance is a very serious setback for these patients.
  • p38 MAP kinase inhibitors in the treatment of COPD has been disclosed as a means of reducing the inflammatory response mediated by cytokine release (WO 2005/018624 A2).
  • WO 2005/01 S624 A2 does not disclose the use of p38 MAP kinase inhibitors in conjunction with corticosteroids, or for reducing corticosteroid resistance, in patients with asthma or COPD.
  • US 2006/0018904 Al focuses on the inhibition of the P2X 7 receptor by a number of disclosed compounds that are co-administered with one or more of the compounds listed above.
  • the compounds at the centre of the invention in US 2006/0018904 Al are the inhibitors of the P2X 7 receptor.
  • the current invention provides the use of p38 MAP kinase inhibitor in cases of severe asthma and COPD where corticosteroid resistance is present.
  • This approach in considered to be particularly beneficial to the patient in: cases of corticosteroid resistance, where large doses of corticosteroids are required by the patient in these cases there is the poie ⁇ uai for the patient to suffer from the broad range of side effects caused by overuse of corticosteroids (listed above).
  • the use of the current invention is considered to allow reduction of the dose of corticosteroids needed for a therapeutic effect and thus reduce side effects. This 5 may save a great deal of morbidity associated with severe asthma and COPD and may even reduce mortality associated with these diseases.
  • asthma any disease of the respirator ⁇ ' tract that is brought about by a chronic inflammatory disorder of the airways associated with
  • bronchial hyperresponsiveness that leads to loss of control of symptoms of recuiient wheezing, brealhlessness.
  • chest tightness and coughing despite utilising reliever and controller medications thai include corticosteroids.
  • COPD chronic obstructive pulmonary disease
  • coi LiGCsl ⁇ joid is often ww ⁇ .. and may be used i ⁇ f;; -:>.
  • glucocorticoid is often used when describing the use of these compounds in the context of the laboratory for in vitro analysis and may also be used herein.
  • a first aspect of the invention provides the use of a p38 MAP kinase inhibitor in the manufacture of a medicament for the treatment of severe or corticosteroid- resistant asthma or chronic obstructive pulmonary disease (COPD). It is considered that such a use may be able to decrease or potentially even reverse corticosteroid resistance in patients. This may lower the dose of corticosteroid required, and thus reduce the unwanted side effects associated with taking said corticosteroid over prolonged periods of time.
  • COPD chronic obstructive pulmonary disease
  • the patient is selected on the basis of inadequate control of the asthma or COPD (with either recurrent symptoms or recurrent exacerbations) at a corticosteroid dose of 2000 ⁇ g or more of inhaled beclomethasone or equivalent corticosteroid per day, with or without the use of systemic corticosteroid therap ⁇ ' (usually administered orally) such as prednisolone.
  • systemic corticosteroid therap ⁇ ' usually administered orally
  • prednisolone systemic corticosteroid therap ⁇ '
  • this would be suitable particularly if the patient is experiencing significant side-effects from the corticosteroid therapy.
  • any patient who requires any dose of corticosteroid for the treatment of severe asthma or COPD will benefit from die use of the invention.
  • the benefits of the invention may be more marked in patients requiring said dose of corticosteroid.
  • a further aspect of the invention provides a method of treating severe or corticosteroid-resistant asthma or COPD. comprising administering to the patient a therapeutically effective amount of a p38 MAP kinase inhibitor.
  • the therapeutically effective dose of p38 MAP kinase inhibitor for a particular patient ma ⁇ ' be determined by the medical practitioner.
  • a desired end point in clinical treatment may be improvement in symptoms and lung function and quality of ⁇ fe, with the possibility of a rs ⁇ i ⁇ xtion in the dosage of corticosteroid required bv the patient.
  • a y ⁇ t further aspect of the invention provides thai said medicament comprises, along with said p3S MAP kinase inhibitor, a corticosteroid.
  • a corticosteroid as well as a p3S MAP kinase inhibitor is also intended to be an aspect of said method of treating a patient with either severe asthma or COPD.
  • the p3S MAP kinase inhibitor of said use and/or method is selected from, but not limited to. any of the following compounds:
  • IyIJ -urea l-[4-(6-Morpholin-4-yknetl'iyl-pyridin-3-yl)-naphthalen-l-yl]-3-naphthaien-2-yl- urea; l-[4-(6-Morpholin-4-ylmethyl-pyridir!-3-yl)-naphthaien-l- ⁇ l]-3-pben3'l-urea;
  • the corticosteroid (or glucocorticoid) of the invention is selected from any one or more of hydrocortisone, prednisolone, ro ⁇ thylprednisolo ⁇ e. 5 triamcinolone, dexamethasone. beclomethasone. budesonide. fluticasone, ciclesonide, mometasone. and any derivative or form thereof. It is particularly preferred mat said corticosteroid is dexamethasone.
  • fnc medicament is a combination of a p3S IvLAP kinase0 inhibitor and a corticosteroid as ced above used for treatment of corticosteroid resistant severe asthma and COPD.
  • the use of said combination is for the manufacture of a medicament to reduce the side effects associated with the use of high dosages of corticosteroids used in the treatment of corticosteroid resistant severe asthma and COPD.
  • the synergistic action of said5 combination is of particular benefit to the patient. It is therefore an. aspect of the invention to provide the use of a p38 MAP kinase inhibitor, as defined above, in the manufacture of a medicament to reduce the side effects associated with the treatment of corticosteroid resistant severe asthma and COPD and moderate to severe asthma.
  • Jt is ⁇ No preferred that a possible aspect of the invention provides the use of a p3.
  • c : h A P kir,a?e. inhibitor, as dofi-xv] nbove, in the marmiactui o of a medicament Io overcome corticosteroid irisensitivity in the treatment of severe asthma . and COPD. It is envisaged that over a period of time, the- use of the invention will lead to a decrease in the patient's resistance to corticosteroids (in instances of corticosteroid resistance).
  • the patient be a mammalian patient It is preferred that said mammalian patient be a human, but said patient can also be any one of, but not limited to, a dog. cat. horse, cow, rai, mouse ; ape or monkey.
  • FIG. 1 A) Suppression of Lipopolysaccharide (LPS)-induced IL-6 release from peripheral blood mononuclear monocytes (PBMCs) from severe asthmatics by p38 MAP kinase inhibitor (p38i) SB203580 (SB) and dexamethasone (Dex) compared to dexamethasone alone.
  • Figure 2 A) Suppression of LPS-induced IL-6 release from PBMCs from patients with COPD by p38 inhibitor SB2035S0 and dexamethasoneccompared to dexamethasone alope. B) Comparison of IL -6 suppression between SB/Dex 1 0 -6 M and SB/Dex 10 -7 M. The percentage suppression of IL-6 release is shown at increasing concentrations of SB203580 on a log scale.
  • Example t Isolation and Stimtiktikm of Peripheral Blood Mononuclear Monocytes (PBMCs).
  • Venous blood (SO ml) was diluted 1 :! with Hanks buffered saline solution (HBSS) and layered on Ficoll-Hypaqu ⁇ -Plus (Amersham, UK). Following cent ⁇ fugation (30 minutes; LlOO x g: IS 0 C). PBMCs were collected, washed and centrifuged
  • PBMCs were re-suspended in culture media and counted using Kimura dy ⁇ . They were plated (7.5 x 10 " cclls ⁇ vell) and stimulated with lipopolysaccaride (LPS, 10 ⁇ g/rnl) alone or pre-trcated for 30 ⁇ v ⁇ n with dexamethasone (10 "6 M to 10 "10 M) and/or the p38 MAPK inhibitor SB203580 (10 ⁇ 6 M to 10 "!0 M) before stimulation with LPS. Sup ⁇ rnatants were removed 18 i -" hours later and analysed for IL-6 by ELlSA.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur l'utilisation d'un inhibiteur de la MAP kinase P38, par exemple SB 203580, dans le traitement d'un asthme résistant aux corticoïdes grave et/ou d'une maladie pulmonaire obstructive chronique. Le traitement peut être destiné à réduire les effets secondaires et la morbidité associés à une utilisation prolongée de corticostéroïdes et à réduire l'insensibilité du patient aux corticoïdes en améliorent les effets thérapeutiques des corticostéroïdes.
PCT/GB2008/000183 2007-01-18 2008-01-18 Traitement de l'asthme résistant aux corticoïdes ou copd par inhibition de la map kinase p38 (par exemple sb2035809) Ceased WO2008087437A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0700972.3A GB0700972D0 (en) 2007-01-18 2007-01-18 Treatment of inflammatory disease
GB0700972.3 2007-01-18

Publications (1)

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WO2008087437A1 true WO2008087437A1 (fr) 2008-07-24

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WO (1) WO2008087437A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012047674A3 (fr) * 2010-09-27 2012-05-24 Microdose Therapeutx, Inc. Procédés et compositions pour le traitement de maladie en utilisant l'inhalation
WO2014181213A1 (fr) * 2013-05-10 2014-11-13 Pfizer Inc. Forme cristalline de (sa)-(-)-3-(3-bromo-4-((2,4-difluorobenzyl)oxy)-6-methyl-2-oxopyridin-1 (2h)-yl)-n,4-dimethylbenzamide
WO2015011245A1 (fr) * 2013-07-25 2015-01-29 Almirall, S.A. Combinaisons comprenant des composés maba et des corticostéroïdes
US9119777B2 (en) 2008-05-30 2015-09-01 Microdose Therapeutx, Inc. Methods and compositions for administration of oxybutynin
US9518050B2 (en) 2012-12-18 2016-12-13 Almirall, S.A. Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity
US9549934B2 (en) 2011-11-11 2017-01-24 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9562039B2 (en) 2013-02-27 2017-02-07 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities
US9579316B2 (en) 2013-07-25 2017-02-28 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both muscarinic receptor antagonist and β2 adrenergic receptor agonist activities
US9643961B2 (en) 2010-05-13 2017-05-09 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005018624A2 (fr) * 2003-08-22 2005-03-03 Boehringer Ingelheim Pharmaceuticals, Inc. Procedes pour traiter la bronchopneumopathie chronique obstructive et l'hypertension pulmonaire

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2005018624A2 (fr) * 2003-08-22 2005-03-03 Boehringer Ingelheim Pharmaceuticals, Inc. Procedes pour traiter la bronchopneumopathie chronique obstructive et l'hypertension pulmonaire

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HEW MARK ET AL: "Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 174, no. 2, July 2006 (2006-07-01), pages 134 - 141, XP002474332, ISSN: 1073-449X *
IRUSEN ELVIS ET AL: "p38 mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 109, no. 4, April 2002 (2002-04-01), pages 649 - 657, XP002474333, ISSN: 0091-6749 *
PETER J. BARNES: "Corticosteroid Resistance in Airway Disease", PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY, vol. 1, 2004, pages 264 - 268, XP007904384 *
WULSTER-RADCLIFFE M C ET AL: "Adiponectin differentially regulates cytokines in porcine macrophages", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 316, no. 3, 9 April 2004 (2004-04-09), pages 924 - 929, XP004495977, ISSN: 0006-291X *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9119777B2 (en) 2008-05-30 2015-09-01 Microdose Therapeutx, Inc. Methods and compositions for administration of oxybutynin
US9643961B2 (en) 2010-05-13 2017-05-09 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic antagonist and M3 muscarinic antagonist activities
WO2012047674A3 (fr) * 2010-09-27 2012-05-24 Microdose Therapeutx, Inc. Procédés et compositions pour le traitement de maladie en utilisant l'inhalation
US9757383B2 (en) 2011-11-11 2017-09-12 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9549934B2 (en) 2011-11-11 2017-01-24 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US10300072B2 (en) 2011-11-11 2019-05-28 Almirall, S.A. Cyclohexylamine derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
US9518050B2 (en) 2012-12-18 2016-12-13 Almirall, S.A. Cyclohexyl and quinuclidinyl carbamate derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activity
US9562039B2 (en) 2013-02-27 2017-02-07 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities
WO2014181213A1 (fr) * 2013-05-10 2014-11-13 Pfizer Inc. Forme cristalline de (sa)-(-)-3-(3-bromo-4-((2,4-difluorobenzyl)oxy)-6-methyl-2-oxopyridin-1 (2h)-yl)-n,4-dimethylbenzamide
US9579316B2 (en) 2013-07-25 2017-02-28 Almirall, S.A. Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both muscarinic receptor antagonist and β2 adrenergic receptor agonist activities
WO2015011245A1 (fr) * 2013-07-25 2015-01-29 Almirall, S.A. Combinaisons comprenant des composés maba et des corticostéroïdes
US10456390B2 (en) 2013-07-25 2019-10-29 Almirall, S.A. Combinations comprising MABA compounds and corticosteroids
US10005771B2 (en) 2014-09-26 2018-06-26 Almirall, S.A. Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities

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Publication number Publication date
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