+

WO2010150014A1 - Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires - Google Patents

Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires Download PDF

Info

Publication number
WO2010150014A1
WO2010150014A1 PCT/GB2010/051044 GB2010051044W WO2010150014A1 WO 2010150014 A1 WO2010150014 A1 WO 2010150014A1 GB 2010051044 W GB2010051044 W GB 2010051044W WO 2010150014 A1 WO2010150014 A1 WO 2010150014A1
Authority
WO
WIPO (PCT)
Prior art keywords
deuterated
glitazone
pioglitazone
composition
salt
Prior art date
Application number
PCT/GB2010/051044
Other languages
English (en)
Inventor
Harry Finch
Mohammed Sajad
Andrew Forrest
Monique Bodil Van Niel
Original Assignee
Pulmagen Therapeutics (Inflammation) Limited
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
Priority claimed from GB0910944A external-priority patent/GB0910944D0/en
Priority claimed from GBGB1001903.2A external-priority patent/GB201001903D0/en
Application filed by Pulmagen Therapeutics (Inflammation) Limited filed Critical Pulmagen Therapeutics (Inflammation) Limited
Publication of WO2010150014A1 publication Critical patent/WO2010150014A1/fr

Links

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
    • A61K31/33—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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K9/0043—Nose
    • 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
    • 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
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to the substantially pure 5R enantiomers of the known glitazone drug class, such as the known pharmaceutical products pioglitazone and rosiglitazone, in which the hydrogen at position 5 of the thiazolidinone ring which characterises the glitazones is replaced by deuterium and to the use of these compounds for pulmonary administration by inhalation, for treatment of inflammatory respiratory diseases.
  • the known glitazone drug class such as the known pharmaceutical products pioglitazone and rosiglitazone
  • COPD chronic obstructive pulmonary disorder
  • asthma Respiratory diseases have a significant inflammatory component.
  • current therapy for COPD and severe asthma focuses mainly on the reduction of symptoms using short and long acting bronchodilators either as monotherapies or combinations of long acting ⁇ 2 agonist bronchodilators with inhaled corticosteroids (ICS).
  • ICS inhaled corticosteroids
  • COPD chronic inflammatory disorder that involves complex interactions between cells of the innate and acquired immune response both in the lung and potentially also systemically.
  • One hypothesis under intense investigation is whether novel, demonstrably anti-inflammatory agents can halt or slow function decline characteristic of COPD. Reducing the frequency and severity of exacerbations has become an increasingly important target for COPD therapy as the prognosis for patients following exacerbations is poor.
  • Antiinflammatory therapy in COPD, and in asthma, is expected to reduce the frequency and severity of exacerbations. It is also desirable that decline in lung function and quality of life are also improved with treatment.
  • inflammatory respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), allergic airway syndrome, bronchitis, cystic fibrosis and emphysema.
  • COPD chronic obstructive pulmonary disease
  • bronchitis cystic fibrosis
  • emphysema emphysema
  • Peroxisome Proliferation Receptor gamma receptor (PPAR ⁇ ) agonists are a class of drug which increase sensitivity to glucose in diabetic patients. Physiological activation of PPAR ⁇ is believed to increase the sensitivity of peripheral tissues to insulin, thus facilitating the clearance of glucose from the blood and producing the desired anti-diabetic effect.
  • PPAR ⁇ Peroxisome Proliferation Receptor gamma receptor
  • PPAR ⁇ agonists are known from the patent and other literature, but currently only two are approved for clinical use in diabetes; Rosigl ⁇ tazone and Pioglitazone. See Campbell IW, Curr MoI Med. 2005 May; 5(3):349-63. Both of these compounds are thiazolidinediones ("TZDs" or “glitazones”), and are in practice administered by the oral route for systemic delivery.
  • TZDs thiazolidinediones
  • rosiglitazone has been reported to exert effects in diabetic patients consistent with an anti-inflammatory effect (Haffner et al, Circulation. 2002 Aug 6; 106(6):679-84, Marx et al, Arterioscler Thromb Vase Biol. 2003 Feb 1 ;23(2):283-8);
  • Rosiglitazone has been reported to exert anti-inflammatory effects in a range of animal models of inflammation, including: carageenan-induced paw oedema (Cuzzocrea et al, Eur J Pharmacol.
  • PPAR ⁇ agonists have also been shown to be effective in models of pulmonary fibrosis (Milam et al., Am. J. Physiol. Lung Cell. MoI. Physiol, 2008, 294(5):L891-901 ) and pulmonary arterial hypertension (Crossno et al., Am. J.
  • PPAR ⁇ agonists also have unwanted cardiovascular effects, including haemodilution, peripheral and pulmonary oedema and congestive heart failure
  • PPAR ⁇ agonists disturb the normal maintenance of fluid balance via binding to the
  • PPAR ⁇ agonists by the oral route for systemic delivery is also associated with an unwanted increase in body weight.
  • COPD patients are known to be at a higher risk than other clinical populations from congestive heart failure (CHF) (Curkendali et al, Ann Epidemiol, 2006; 16: 63-70,
  • CHF congestive heart failure
  • Pioglitazone has structural formula (I)
  • Rosiglitazone has the structural formula (H) and can be named as 5-(4- ⁇ 2-[methyI (pyridin-2-yI)amino]ethoxy]benzyl ⁇ -1 ,3-thiazolidine-2,4-dione.
  • the 5S enantiomer of rosiglitazone has a higher binding affinity for the PPAR ⁇ receptor than the 5R enantiomer (30nm vs 2 ⁇ M, Parks et al, 1998, Bioorg Med Chem Lett. 8(24):3657-8).
  • Rivogiitazone the 5S enantiomer also has higher receptor binding affinity than the 5R enantiomer (see page 13 of WO2007100027).
  • pioglitazone and rosiglitazone are administered for treatment of diabetes as a mixture of 5R and 5S enantiomers (a 1 :1 racemic mixture) by the oral route for systemic delivery.
  • the individual enantiomers of these compounds, and the glitazone family generally, are known to equilibrate rapidly in vivo after oral administration (see for example J. CHn. Pharmacol. 2007, 47, 323-33; Rapid Commun. Mass Spectrum. 2005, 19, 1125-9; J. Chromatography, 835 (2006), 40-46; Biopharmaceutics and Drug Disposition 1997, 18 (4), 305-24; Chem. Pharm. Bull 1984, 32, (11 ) 4460-65; T. J. Med. Chem.
  • the glitazone class of PPAR ⁇ agonists as a whole is characterised by the presence in the molecule of a thiazolidin-2,4-dione radical (A), often as part of a (thiazolidin- 2,4,dione-5-yI)methylphenyl radical (B):
  • glitazone refers to a PPAR ⁇ agonist compound whose structure includes a thiazolidin-2,4-dione radical (A), or a (thiazolidin-2,4,dione » 5-yl)methylphenyl radical (B):
  • glitazones Besides the approved and marketed rosiglitazone and pioglitazone, there is a multitude of glitazones known from the patent and scientific literature. Known examples include the following:
  • any organic biologically active compounds one or more protons can be in principle be replaced by the hydrogen isotope deuterium.
  • deuteration usually changes one or more pharmacodynamic properties of the compound, for example absorption, distribution, metabolism and execretion (ADME) properties.
  • amphetamines are more readily transported into the brain in the deuterated form (Wenzel, 1989); halogenated anaesthetics, such as selvoflurane, when deuterated are no longer oxidized to toxic forms within the body (Baker et a/., 1993), and the deuterated forms of certain antimicrobial compounds [long-chain fatty acids (Abrahamson et a/., 1982) and D- fluorophenylalanine (Merck and Co., 1977)] are not oxidized by the affected microorganism arid hence are toxic for longer times.
  • halogenated anaesthetics such as selvoflurane
  • This invention is based on the finding that in an animal model of treatment of inflammatory respiratory disease by inhalation, the 5R-enantiomer of a glitazone, for example pioglitazone and rosiglitazone, in which the hydrogen at position 5 of the thiazolidinone ring is replaced by deuterium is active, whereas the corresponding 5S enantiomer is essentially inactive.
  • This finding leads to the conclusion that inhaled pulmonary administration of the 5-deuterated, 5R giitazone enantiomer allows the anti-inflammatory effect of the giitazone to be achieved more efficiently than by similar administration of the racemate, with all the concomitant reduced side effect benefits of lower systemic exposure than oral administration.
  • the invention also includes a particularly efficient method for the resolution of racemic 5-deuterated pioglitazone-ch ⁇ ral resolving agent salts.
  • Figure 1 is a bar graph (mean ⁇ SD) that illustrates the effect of intranasal administration to laboratory mice with vehicle (0.2% tween 80 in saline), 5S-5- deuterated pioglitazone (5S-D-Pio) (1 or 3 ⁇ g/kg) or 5R-5-deuterated pioglitazone (5R-D-Pio) (1 or 3 ⁇ g/kg) on the number of BAL cells induced by tobacco smoke for 4 days examined 24 hours post the finaf exposure.
  • 5S-D-Pio 5S-5- deuterated pioglitazone
  • 5R-D-Pio 5R-5-deuterated pioglitazone
  • Figure 2 is a bar graph (mean ⁇ SD) that illustrates the effect of intranasal administration to laboratory mice with vehicle (0.2% tween 80 in saline), 5S-5- deuterated pioglitazone (5S-D-Pio) (1 or 3 ⁇ g/kg) or 5R-5-deuterated pioglitazone (5S-D-Pio) (1 or 3 ⁇ g/kg) on the number of BAL neutrophils induced by tobacco smoke for 4 days examined 24 hours post the final exposure.
  • 5S-D-Pio 5S-5- deuterated pioglitazone
  • 5R-5-deuterated pioglitazone (1 or 3 ⁇ g/kg
  • Figure 3 is a bar graph (mean ⁇ SD) that illustrates the effect of intranasal administration to laboratory mice with vehicle (0.2% tween 80 in saline), 5S-5- deuterated rosiglitazone (5S-D-Rosi) (3 or 10 ⁇ g/kg), 5R-5-deuterated rosiglitazone (5R-D-Rosi) (3 or 10 ⁇ g/kg) or racemic 5-deuterated rosiglitazone (D-Rosi) (10 ⁇ g/kg) on the number of BAL cells induced by tobacco smoke for 4 days examined 24 hours post the final exposure.
  • 5S-D-Rosi 5S-5- deuterated rosiglitazone
  • 5R-D-Rosi 5R-5-deuterated rosiglitazone
  • D-Rosi racemic 5-deuterated rosiglitazone
  • Figure 4 is a bar graph (mean ⁇ SD) that illustrates the effect of intranasal administration to laboratory mice with vehicle (0.2% tween 80 in saline), 5S-5- deuterated rosiglitazone (5S-D-Pio) (3 or 10 ⁇ g/kg) or 5R-5-deuterated rosigiitazone (SR-D-Pio) (3 or 10 ⁇ g/kg) on the number of BAL neutrophils induced by tobacco smoke for 4 days examined 24 hours post the final exposure.
  • 5S-D-Pio 5S-5- deuterated rosiglitazone
  • SR-D-Pio 5R-5-deuterated rosigiitazone
  • glitazone has the meaning ascribed to it above, i.e., a PPAR ⁇ agonist compound whose structure includes a thiazolidin-2,4-dione radical (A), or a (thiazolidin-2,4,dione-5-yi)methylphenyl radical (B):
  • pioglitazone As used herein, the terms "pioglitazone”, “pioglitazone component”, “5H-pioglitazone” and “5-protonated pioglitazone” mean the compound of formula (I) above.
  • 5R-pioglitazone means the 5R enantiomer of the compound of formula (1) above.
  • 5S-pioglitazone means the 5S enantiomer of the compound of formula (I) above.
  • 5R-5-deuterated p ⁇ oglitazone mean the 5R-enantiorner of 5-deuterated pioglitazone.
  • 5S-5-deuterated pioglitazone and “5S-S- 2 H pioglitazone” mean the 5S-enantiorner of 5-deuterated pioglitazone.
  • rosiglitazone As used herein, the terms “rosiglitazone”, “rosiglitazone component”, “5H- rosiglitazone” and “5-protonated rosiglitazone” mean the compound of formula (II) above.
  • 5R-rosiglitazone means the 5R enantiomer of the compound of formula (H) above.
  • 5S-rosigiitazone means the 5S enantiomer of the compound of formula (II) above.
  • 5R-5-deuterated rosiglitazone and “5R-S- 2 H rosiglitazone” mean the 5R-enantiomer of 5-deuterated rosiglitazone.
  • 5S-5-deuterated rosiglitazone and “5S-S- 2 H rosiglitazone” mean the 5S-enantiomer of 5-deuterated rosiglitazone.
  • the symbols D and 2 H are interchangeable and refer to the deuterium isotope of hydrogen.
  • R and S are the respective weight fractions of the R and S enantiomers in a sample.
  • R and S are the respective weight fractions of the R and S enantiomers in a sample.
  • the glitazone component includes less than 3%, more preferably less than 1%, by weight in total of 5R-5-protonated glitazone, 5S-5-protonated glitazone and 5S-5-deuterated glitazone.
  • the composition of matter of the invention is a pharmaceutical composition adapted for pulmonary administration by inhalation.
  • the pharmaceutical composition may additionally comprise a bronchodiiator drug and/or another anti-inflammatory drug.
  • the invention also provides the use of a composition of matter comprising a 5R-5- deuterated glitazone or a salt thereof, in which composition the 5R-5 deuterated glitazone component includes less than 5% by weight in total of 5R-5-protonated glitazone, 5S-5-protonated glitazone and 5S-5-deuterated glitazone, for the treatment of inflammatory respiratory disease by pulmonary administration by inhalation, and the use of such composition of matter in the preparation of a medicament for the treatment of inflammatory respiratory disease by pulmonary administration by inhalation.
  • the invention also provides a method of treatment of inflammatory respiratory disease comprising pulmonary administration by inhalation to a subject of an effective amount of a composition of matter comprising a 5R-5-deuterated glitazone or a salt thereof, in which composition the glitazone component includes less than 5% by weight in total of 5R-5-protonated glitazone, 5S-5-protonated glitazone and 5S-5-deuterated glitazone.
  • the method of the invention may also include the step wherein the subject is additionally administered an amount of a bronchodilator drug and/or another anti- inflammatory drug wherein the amount of 5R-5-deuterated giitazone, or salt thereof and the amount of the conventional respiratory treatment agent together comprises a therapeutically effective amount.
  • the invention also includes a kit for treatment of respiratory disorders in a subject, the kit comprising one dosage form comprising 5R-5-deuterated glitazone or a salt thereof, in which composition the glitazone component includes less than 5% by weight in tota! of 5R-5-protonated glitazone, 5S-5-protonated glitazone and 5S-5- deuterated glitazone.
  • the 5R-5-deuterated glitazone component may be inhaled via the nose or the mouth. Preferably it is inhaled via the mouth.
  • the 5R-5-deuterated glitazone component may, in particular, be 5R-5-deuterated pioglitazone or 5R-5-deuterated rosiglitazone.
  • the 5R-5-deuterated glitazone component can be in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.
  • Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences.
  • Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, d ⁇ ethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolam ⁇ ne, ethylenediarnine, meglumine (N-methylglucam ⁇ ne) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzyIethyIenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrab
  • Illustrative pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, maiic, tartaric, (-)-dibenzoyl-L-tartaric, citric, nitric, ascorbic, glucuronic, fumaric, pyruvic, aspartic, glutamic, hydrochloric, deuterochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, anthranilic, mesylic, napadisyiate, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic
  • compositions of the invention are useful for treatment of inflammatory respiratory disorders, for example asthma (mild, moderate or severe), e.g., bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID- induced) and dust-induced asthma, steroid resistant asthma, smoking asthmatics, bronchitis including infectious and eosinophilic bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis including cryptogenic fibrosing alveolitis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, fibrosis complicating antineoplastic therapy and chronic infection, including tubercuSos ⁇ s and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension (including pulmonary arterial hypertension); antitussive activity including treatment of chronic cough associated with
  • the methods and compositions of the present invention encompass the prevention and treatment of the respiratory disorder, COPD.
  • COPD chronic obstructive pulmonary disease
  • COPD refers to a set of physiological symptoms including chronic bronchitis, chronic cough, expectoration, exertional dyspnea and a significant, progressive reduction in airflow that may or may not be partly reversible. Emphysema may also be present in the lungs. COPD is a disease characterized by a progressive airflow limitation caused by an abnormal inflammatory reaction to the chronic inhalation of particles.
  • COPD chronic obstructive bronchitis and emphysema.
  • compositions suitable for administration by inhalation via the mouth or the nose are known, and may include carriers and/or diluents that are known for use in such compositions.
  • the composition may contain 0.01-99% by weight of the 5R-5- deuterated glitazone component.
  • a unit dose comprises the 5R-5- deuterated glitazone component in an amount of 1 ⁇ g to 15 mg.
  • the most suitable dosage level may be determined by any suitable method known to one skilled in the art.
  • the specific amount for any particular patient will depend upon a variety of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment. Optimum dosages will be determined by clinical trial, as is required in the art.
  • compositions of the invention may be used in combination with other therapeutic agents that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which present compounds are useful.
  • Such other therapeutic agents may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the 5R-5-deuterated glitazone component.
  • a pharmaceutical composition containing such other therapeutic agents in addition to the glitazone component is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to the 5R-5-deuterated glitazone component.
  • Suitable therapeutic agents for a combination therapy with the 5R-5-deuterated glitazone compositions of the invention include one or more other therapeutic agents selected from anti-inflammatory agents, bronchodilators, mucolytic agents, antitussive agents, leukotriene inhibitors, and antibiotics.
  • Suitable therapeutic agents for a combination therapy with the 5R-5-deuterated glitazone compositions of the invention include: (1 ) a (1 ) a steroid drug such as a corticosteroid, for example beclomethasone, (e.g., as the mono or the dipropionate ester), flunisolide, fluticasone (e.g., as the propionate or furoate ester), ciclesonide, mometasone (e.g., as the furoate ester), mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methyl prednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone dipropionate, halometas
  • Steroid drugs can also additionally include next generation molecules in development with reduced side effect profiles such as selective glucocorticoid receptor agonists (SEGRAs), including ZK-216348 and compounds referred to in international patent applications WO-00032585, WO-QQQ21Q143, WQ-2Q05Q34939, WO-2005003098, WO-2005035518 and WO-2005035502 and functional equivalents and functional derivatives thereof; (2) a ⁇ 2-adrenoreceptor agonist, such as albuterol, bambuterol, terbutaline, fenoterol, formoterol, formoterol fumarate, salmeterol, salmeterol xinafoate, arformoterol, arfomoterol tartrate, indacaterol (QAB-149), carmoterol, picumeterol, BI 1744 CL, GSK159797, GSK59790, GSK159802, GSK642444, GSK67800
  • the invention provides for the use of inhaled administration of the 5R- 5-deuterated glitazone compositions of the invention in combination with other anti- inflammatory drugs and bronchodiiator drug combinations (i.e. triple combination product), including but not limited to salmeterol xinafoate/fluticasone propionate (Advair/Seretide®), formoterol fumarate/budesonide (Syrnbicort®), formoterol fumarate/mometasone furoate, formoterol fumarate/beclometasone dipropionate (Foster®), formoterol fumarate/fluticasone propionate (Flut ⁇ Form®), Indacateroi/mometasone furoate, lndacaterol/QAE-397, GSK159797/GSK 685698, GSK159802/GSK 685698, GSK642444/GSK 685698, formot
  • the invention provides for the use of inhaled administration of the 5R-5-deuterated glitazone compositions of the invention in combination with other bronchodiiator drug combinations, particularly B2 agonist/M3 antagonist combinations (i.e. triple combination product), including but not limited to salmeterol xinafoate/tiotropium bromide, formoterol fumarate/tiotropium bromide, BI 1744 CL/tiotropium bromide, indacaterol/NVA237, indacterol/QAT-370, formoterol/ LAS34273, GSK159797/GSK 573719, GSK159802/GSK 573719, GSK642444/GSK 573719, GSK159797/GSK 233705, GSK159802/GSK 233705, GSK642444/GSK 233705, and compounds which possess both B2 agonist and M3 antnagonist activity in the same molecule (dual functionality) such as GSK
  • the invention provides a kit for treatment of respiratory disorders in a subject, the kit comprising one dosage form comprising a composition adapted for pulmonary administration by inhalation, which composition comprises a 5R-5-deuterated glitazone, particularly 5R-5-deuterated pioglitazone or 5R-5- deuterated rosiglitazone, and one or more pharmaceutically acceptable carriers and/or excipients, wherein the 5R-5-deuterated glitazone content of the composition consists of at least 95% by weight of the 5R-5-duterated glitazone and less than 5% by weight in total of 5R-5-protonated glitazone, 5S-5-protonated glitazone and 5S-5- deuterated glitazone and a second dosage form comprising another therapeutic agent, for example as discussed above, selected from anti-inflammatory agents, bronchodilators, mucolytic agents, antitussive agents, leukotriene inhibitors, and antibiotics.
  • the active compound is preferably in the form of microparticles. These may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation. Following size reduction to produce microparticles, particle size distribution (PSD) of the compound is examined and generally described in the art by specifying d10, d50 and d90 values.
  • PSD particle size distribution
  • the average particle size i.e. the average equivalent diameter, is defined as the diameter where 50 mass-% (of the particles) of the powder have a larger equivalent diameter, and the other 50 mass-% have a smaller equivalent diameter. Hence the average particle size is denoted as equivalent d50.
  • a d50 of less than 10 microns, preferably less than 5 microns is desired.
  • a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI).
  • PMDI pressurised metered dose inhaler
  • Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI 2 F 2 ) and HFA-152 (CH 4 F 2 and isobutane).
  • the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation.
  • a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • Microparticles for delivery by inhalation may be formulated with excipients that aid delivery and release.
  • microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung.
  • Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 ⁇ m.
  • Aerosol generation can be carried out using, for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably using propellant-driven metered aerosols or propellant-free administration of rnicronized active compounds from, for example, inhalation capsules or other "dry powder" delivery systems.
  • compositions may be dosed as described depending on the inhaler system used.
  • the administration forms may additionally contain excipients, such as, for example, propellents (e.g. Fr ⁇ gen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.
  • Deuferated glitazones can be prepared, using pioglitazone (I) by way of example, as shown in Scheme 1.
  • a base (II) can be used to deprotonate the C-5 position of the glitazone.
  • Suitable bases include, but are not restricted to, 1 ,5- diazabicyclo[4.3.0]non-5-ene and more preferably to sodium deuteroxide.
  • Deuterated reagents (III), preferably deuterochloride can be used to incorporate the C-5 deuterium.
  • Deuterated glitazones can be separated using chiral HPLC (see for example Methods 1 , 7 and 10 below).
  • Chiral columns include CHIRALPAK AD, AD-H, AS-V, IA, IC, OD, OF, OG, OJ, OK, and OZ
  • Preferred chiral columns for HPLC are CHIRALPAK AD-H and CHSRALPAK IA using elution with ethanol and varying portions of TFA, preferably O 05-0 2% TFA alternatively heptane, ethanof and acetic acid in varying proportions, preferably 30% heptane, 70% ethanol and 0 2% acetic acid
  • a preferred set of chiral acid resolving agents for use in the present invention includes (-)-Q,O'-d ⁇ benzoyl-L-tarta ⁇ c acid (anhydrous), (-)-O,O'-d ⁇ benzoy!-L-tarta ⁇ c acid monohydrate, (-)-d ⁇ -O-p-toluoyl-L-tarta ⁇ c acid, L-(+)-tarta ⁇ c acid and (-)-d ⁇ -p- anisolyl-L-tartaric acid
  • the most preferred chiral acid resolving agent is (-)-O,Q'-d ⁇ benzoyI-L-tartar ⁇ c acid
  • Chiral acid resolving agents can be used in different stoichiometrics to effect resolutions
  • the above resolving agents can be used in a ratio of 1 part (I) to 10 parts of chiral acids (V), more preferably in a ratio of 1 part (I) to 5 parts of chiral acids (V), and most preferably in a ratio of 1 part (I) to 2 part of chiraf acids (V) Even more preferred is a ratio of 1 part (I) to 1 part of chirai acids (V)
  • solvents may be useful to form diastereomeric salts (Vl) with chiral acids (V)
  • Preferred solvents will include ethyl acetate, dichloromethane tetrahydrofuran, 1 ,4-d ⁇ oxane, acetone, acetonit ⁇ le, alcohols such as MeOH, EtOH, IPA, 1-propanol, 1-butanol, 2-butanol, t-butanol, and deuterated forms of such alcohols such as IvIeOD, d 4 -fvieOH, EtOD 1 1 ,2-dimethoxyethane, diethyl ether, dichloroethane, tert- butylmethyl ether, 2-butanone, toluene, cyclohexane, heptane, hexane, H2O, DIvIF, D 2 O, petroleum ethers and CHCI 3
  • Solvents may be used in combination with each other and preferred combinations include 10% HCI in H2 ⁇ , 10% H2O in DMF, 10% H2O in EtOH, 10% H2O in IPA, methanol or deuteromethanol and water or deuterium oxide in varying portions, methanol or deuteromethanol and water or deuterium oxide in varying portions with HCI or DCI 1 CHCI 3 and ethyl acetate in varying portions, EtOH or EtOD and water or deuterium oxide in varying portions, IPA and water in varying portions, 1-propanol and water in varying portions and CHCI 3 and dioxane in varying portions
  • More preferred solvent combinations include CHCi 3 and dioxane in varying portions, CHCI 3 and ethyl acetate in varying portions, methanol and water in varying portions with HCl and methanol and water in varying portions
  • Commonly used chiral amine resolving agents include, without limitation, 1- phenylethyl amine, cinchonidine, cinchonine, quinidine, codeine, morphine, strychnine, brucine, quinine, ephed ⁇ ne, ammo butanol, dehydroabiethylamine, 2- phenyl glycinol, 1 ,2-cyclohexyld ⁇ am ⁇ ne, 1-naphthylethylam ⁇ ne, 2-am ⁇ no-1- phenylpropane-1 ,3-d ⁇ ol, 4-chloro-1-pheny!amme, N-(4-methoxybenzyl)-1-pheny! ⁇ thyl amine, fenchylamine, N-benzyl-1-phenylethyl amine, N-(4-dimethylammobenzyl)-1- phenylethy!
  • amine 3-amino-2,2-dimethyl-3-phenylpropan-1-ol, sparteine, proline, serine, phenylalanine, lysine, threonine, valine, histidine, alanine, glutamic acid and glutamine, arginine, homo-arginine, N- ⁇ -acetyl lysine, N- ⁇ -acetyllys ⁇ ne and ornithine.
  • deuterated glitazones can be also be prepared and then resolved in the same flask, as exemplified in example 4.
  • compositions with which the invention is concerned are of high enantiomeric and deuterated purity.
  • the glitazone is pioglitazone
  • a method for the preparation of a salt of 5R-5-deuterated pioglitazone with a chiral acid resolving agent containing less than 5% by weight in total of the corresponding salt of 5R-5- protonated piogiitazone, 5S-5-protonated pioglitazone and 5S-5-deuterated pioglitazone. which method comprises:
  • step (b) forming a solution of the precipitate from step (a) in an alcohol solvent in the presence of an acid, and adding H 2 O or D 2 O to the resultant solution, thereby precipitating 5R-5-deuterated pioglitazone-chiral resolving agent salt, and recovering the precipitate.
  • Alcohol solvents have been discussed above, but a preferred alcohol for use in the pioglitazone resolution method is CH 3 OH or CH 3 OD.
  • the L-tartaric acid derivative resolving agent may be, for example, (-)-O,O'- dibenzoyl-L-tartaric acid (available as anhydrous or monohydrate), (-)-di-O-p-toluoyl- L-tartaric acid, L-(+)-tartaric acid or(-)-di-p-anisolyl-L-tartaric acid.
  • the most preferred chiral acid resolving agent is (-)-O,O'-dibenzoyl-L-tartaric acid (preferably anhydrous).
  • the acid whose presence is required in step (b) is preferably hydrochloric acid or deuteor hydrochloric acid, but other acids which may be used include sulphuric, hydrobromic, trifluoroacetic, citric, dibenzoyl tartatric, malic, maleic, ditoloyl and nitric acids, or deuterated forms of any of those acids.
  • the 5R-5-deuterated p ⁇ oglitazone-chira! resolving agent salt prepared according to this aspect of the invention may be converted by salt exchange to a pharmaceutically acceptable salt of 5R-5-deuterated pioglitazone, such as the hydrochloride or the hydrobromide.
  • NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5mm inverse detection triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 5mm inverse detection triple resonance TXI probe operating at 400MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5rnm dual frequency probe operating at 300MHz. Shifts are given in ppm relative to tetramethylsilane. Optical rotations were measured using an AA-10R automatic polarimeter with 5x25 mm jacketed sample cell.
  • CHIRALPAK IA 250 x 21 mm, 5 ⁇ m
  • EtOH elution with EtOH +0.05%TFA - flow rate 13 ml/min.
  • Detection -In-line LJV detection set at 250 nM wavelength.
  • CHIRALPAK IA 250 x 4.6 mm, 5 ⁇ M
  • Detection - In-line DAD set at 280 nM wavelength.
  • CHIRALPAK IA 250 x 21 mm, 5 ⁇ m
  • MS ionization method Electrospray (positive and negative ion).
  • CHIRALPAK IA 250 x 21 mm, 5 ⁇ m
  • Detection -In-line UV detection set at 254 nM wavelength. Desired fractions were concentrated with a few drops of TFA.
  • CHIRALPAK IA 250 x 4.6 mm, 5 ⁇ m
  • Detection -In-line UV detection set at 254 nM wavelength.
  • MS Detection MS, ELS 1 UV (100 ⁇ l split to MS with in-line UV DAD detector).
  • MS ionisation method Electrospray (positive/negative ion).
  • CHIRALPAK IA 250 x 4.6 mm, 5 ⁇ m
  • Detection -In-line UV detection set at 280 nM wavelength.
  • the title compound was prepared from 5- ⁇ 4-[(methyI-pyridin-2-yI-amino)-ethoxy]- benzyi ⁇ - ⁇ -thiazolidine-2,4-dione using the methods described in example 1a and 1 b.
  • Example 3 Contains 9.0% (5S)-5- ⁇ 4-[(methyl-pyridin-2-yl-amino)-ethoxy]-benzyl ⁇ - ⁇ -(5)- thiazo!idine-2,4-dione hydrochloride.
  • step c acid was included in the MeOH solvent for recrystallisation of the R-enantiomer as the chira! salt.
  • the following comparative Example shows that omission of the acid results in recovery of less than 1 :1 stoichiometry of the salt as 5 an enantiomeric mixture rather than the required R enant ⁇ omer of the chiral salt with > 90% d.e.:
  • Example 13 MeOD-D 2 O was used as solvent for recrystallisation of the R- enantiomer as the chiral salt
  • the following comparative Example shows that stirring in MeOD results in recovery of the free base as an enantiomeric mixture rather than the required R enantiomer of the chiral salt with enhanced d e
  • Protocols for the exposure of mice to TS, obtaining bronchoalveolar lavage (BAL), preparation of cytospin slides for differential ceil counts are as outlined below.
  • mice Exposure of mice to TS daily for 4 or 11 consecutive days
  • mice were exposed in groups of 5 in individual clear polycarbonate chambers (27 cm x 16 cm x 12 cm).
  • the TS from the cigarettes was allowed to enter the exposure chambers at a flow rate of 100 ml/min.
  • the exposure of the mice to TS was increased gradually over the exposure period to a maximum of 6 cigarettes.
  • the exposure schedule used for 4 days was as follows: Day 1 : 4 cigarettes (approximately 32 min exposure)
  • the exposure schedule used for 11 days exposure was as follows:
  • mice were exposed to air on a daily basis for equivalent lengths of time as controls (no TS exposure).
  • Bronchoalveolar lavage (BAL) analysis Bronchoalveolar lavage was performed as follows: the trachea was cannulated using a Portex nylon intravenous cannula (pink luer fitting) shortened to approximately 8 mrn. Phosphate buffered saline (PBS) was used as the lavage fluid. A volume of 0.4 ml was gently instilled and withdrawn 3 times using a 1 ml syringe and then placed in an Eppendorf tube and kept on ice prior to subsequent determinations.
  • PBS Phosphate buffered saline
  • Lavage fluid was separated from cells by centrifugation and the supernatant decanted and frozen for subsequent analysis.
  • the cell pellet was re-suspended in a known volume of PBS and total eel! numbers calculated by counting a stained (Turks stain) aliquot under a microscope using a haemocytometer.
  • the residual cell pellet was diluted to approximately 10 5 cells per ml. A volume of 500 ⁇ l was placed in the funnel of a cytospin slide and centrifuged for 8 min at 800 rpm. The slide was air dried and stained using 'Kwik-DifP solutions (Shandon) as per the proprietary instructions. When dried and cover-s ⁇ pped, differential cells were counted using light microscopy. Up to 400 cells were counted by unbiased operator using light microscopy. Cells were differentiated using standard morphometric techniques.
  • Rodents such as mice and rats are obligate nasal breathers thus oral delivery of test materials (such as therapeutic agents) for inhalation will not produce good lung exposure.
  • delivery of therapeutic agents to the lungs in rodents is generally achieved by intra-nasal, intra-tracheal or inhalation by whole body aerosol exposure in a chamber.
  • the chamber method utilises large amounts of test material and is generally reserved for inhalation toxicology studies rather than pharmacological efficacy studies.
  • Intra- tracheal administration is a very efficient delivery method as almost all of the test material is delivered to the lungs, but this is quite an invasive technique. For studies in the mouse particularly, it is also quite technically demanding as the diameter of the trachea is quite small.
  • the intranasal route is less invasive than the intra-tracheal route and so is particularly suitable for repeat dosing studies such as the 4-11 day mouse model described below. Following intranasal administration ⁇ 50% of the dose administered is delivered to the lungs (Eyles JE, Williamson ED and Alpar HO. 1999, In! J Pharm, 189(1):75-9).
  • the control group of mice received vehicle 1 hr prior to being exposed to air daily for a maximum of 50 minutes per day.
  • the control group of mice received vehicle 1 hr prior to being exposed to air daily for a maximum of 50 minutes per day.

Landscapes

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

Abstract

L'invention porte sur une composition comprenant un glitazone 5R-5-deutéré ou un sel de celui-ci, dans laquelle composition le constituant glitazone 5R-5-deutéré représente moins de 5 % en poids du total de glitazone 5R-5-protoné, de glitazone 5S-5-protoné et de glitazone 5S-5-deutéré. Le glitazone peut être du rosiglitazone ou du pioglitazone. Les compositions peuvent être destinées à une inhalation pulmonaire pour le traitement d'une maladie inflammatoire pulmonaire.
PCT/GB2010/051044 2009-06-24 2010-06-24 Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires WO2010150014A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0910944A GB0910944D0 (en) 2009-06-24 2009-06-24 Respiratory disease treatment
GB0910944.8 2009-06-24
GBGB1001903.2A GB201001903D0 (en) 2010-02-05 2010-02-05 Respiratory disease treatment
GB1001903.2 2010-02-05

Publications (1)

Publication Number Publication Date
WO2010150014A1 true WO2010150014A1 (fr) 2010-12-29

Family

ID=42542817

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2010/051044 WO2010150014A1 (fr) 2009-06-24 2010-06-24 Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires

Country Status (1)

Country Link
WO (1) WO2010150014A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2477540A (en) * 2010-02-05 2011-08-10 Argenta Therapeutics Ltd Respiratory disease treatment
GB2477743A (en) * 2010-02-10 2011-08-17 Argenta Therapeutics Ltd Enantiomers of 5-methyl-thiazolidine-2,4-dione glitazone compounds
WO2014121036A1 (fr) * 2013-02-01 2014-08-07 Deuterx, Llc Dérivés de 5-deutéro-2,4-thiazolidinedione et 5-deutéro-2,4-oxazolidinedione, compositions les comprenant et leur procédés d'utilisation
WO2014152843A1 (fr) * 2013-03-14 2014-09-25 Deuterx, Llc 2,4-thiazolidinediones enrichies en deutérium et méthodes de traitement
WO2015109037A1 (fr) * 2014-01-15 2015-07-23 Deuterx, Llc Méthodes de traitement de troubles neurologiques, métaboliques et autres à l'aide de pioglitazone énantiopure enrichie en deutérium
WO2011098799A3 (fr) * 2010-02-10 2015-09-11 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
WO2016153948A1 (fr) * 2015-03-20 2016-09-29 Deuterx, Llc Polythérapie utilisant des 5-(benzyl)-5-deutéro-thiazolidine-2,4-diones oxy-substituées énantiopures, enrichies en deutérium pour le traitement de troubles médicaux
WO2016153952A1 (fr) * 2015-03-20 2016-09-29 Deuterx, Llc Méthodes de traitement d'infections bactériennes et d'infections fongiques à l'aide de pioglitazone enrichie en deutérium énantiopure
WO2016153949A1 (fr) * 2015-03-20 2016-09-29 Deuterx, Llc Composés 5-deutéro-thiazolidine-2,4-dione et procédés de traitement de troubles médicaux les utilisant
US9925175B2 (en) 2007-09-26 2018-03-27 Deuterx, Llc Deuterium-enriched pioglitazone
US11319313B2 (en) 2020-06-30 2022-05-03 Poxel Sa Crystalline forms of deuterium-enriched pioglitazone
CN116390725A (zh) * 2020-04-30 2023-07-04 米尼奥尔克斯治疗有限公司 用于治疗肺部炎症和间质性肺病的羟基吡格列酮
US11767317B1 (en) 2020-06-30 2023-09-26 Poxel Sa Methods of synthesizing enantiopure deuterium-enriched pioglitazone

Citations (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505321A2 (fr) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhalateur
JPH0525045A (ja) 1991-07-18 1993-02-02 Tanabe Seiyaku Co Ltd 経皮吸収製剤
WO1993018007A1 (fr) 1992-03-13 1993-09-16 Tokyo Tanabe Company Limited Nouveau derive de carbostyrile
WO1999064035A1 (fr) 1998-06-08 1999-12-16 Advanced Medicine, Inc. AGONISTES DU RECEPTEUR β2-ADRENERGIQUE
WO2000032585A1 (fr) 1998-12-02 2000-06-08 Lek Pharmaceutical And Chemical Company D.D. Procede de preparation de simvastatine et d'analogues de celle-ci
WO2000053601A1 (fr) 1999-03-08 2000-09-14 The University Of Mississippi Derives de 1,2-dithiolane
WO2000062766A2 (fr) 1999-04-15 2000-10-26 Smithkline Beecham Plc Nouveau procede de traitement
WO2000075114A1 (fr) 1999-06-04 2000-12-14 Novartis Ag Agonistes du recepteur beta 2-adrenergique
WO2001042193A1 (fr) 1999-12-08 2001-06-14 Theravance, Inc. Agonistes des recepteurs adrenergiques du beta 2
WO2001082980A1 (fr) * 2000-05-01 2001-11-08 Aeropharm Technology, Inc. Formulation d'aerosol medicinal
WO2001082873A2 (fr) * 2000-05-01 2001-11-08 Aeropharm Technology, Inc. Formulation medicamenteuse pour aerosol
WO2001083462A1 (fr) 2000-04-27 2001-11-08 Boehringer Ingelheim Pharma Kg Nouveaux beta-mimetiques a action lente, leurs procedes de production et leur utilisation comme medicament
WO2002010143A1 (fr) 2000-07-28 2002-02-07 Schering Aktiengesellschaft Anti-inflammatoires non steroidiens
WO2002012265A1 (fr) 2000-08-05 2002-02-14 Glaxo Group Limited 6.ALPHA., 9.ALPHA.-DIFLUORO-17.ALPHA.-`(2-FURANYLCARBOXYLE) OXY!-11.BETA.-HYDROXY-16.ALPHA.-METHYLE-3-OXO-ANDROST-1,4,-DIENE-17-ACIDE CARBOTHIOIQUE S-FLUOROMETHYLE ESTER UTILISE COMME AGENT ANTI INFLAMMATOIRE
WO2002013812A1 (fr) 2000-08-17 2002-02-21 Pershadsingh Harrihar A Traitements de maladies inflammatoires
US20020055651A1 (en) 1999-06-02 2002-05-09 Moran Edmund J. Beta2-adrenergic receptor agonists
WO2002066422A1 (fr) 2001-02-14 2002-08-29 Glaxo Group Limited Derives de phenethanolamine pour le traitement de maladies respiratoires
WO2002070490A1 (fr) 2001-03-08 2002-09-12 Glaxo Group Limited Agonistes de beta-adrenocepteurs
WO2002076933A1 (fr) 2001-03-22 2002-10-03 Glaxo Group Limited Derives formanilides utilises en tant qu'agonistes de l'adrenorecepteur beta2
WO2002100879A1 (fr) 2001-06-12 2002-12-19 Glaxo Group Limited 17 alpha esters heterocycliques anti-inflammatoires de derives de 17 beta carbothioate androstane
WO2003024439A1 (fr) 2001-09-14 2003-03-27 Glaxo Group Limited Derives de phenethanolamine destines au traitement de maladies respiratoires
WO2003042160A1 (fr) 2001-11-13 2003-05-22 Theravance, Inc. Agonistes de recepteur d'aryl aniline beta-2 adrenergique
WO2003042229A1 (fr) 2001-11-12 2003-05-22 Glaxo Group Limited Esters heterocycliques non aromatiques de furan-2-one esters de 17 $g(b) carboxyl ou 17 $g(b) carbothio glucocorticoides
WO2003042164A1 (fr) 2001-11-13 2003-05-22 Theravance, Inc Agonistes arylaniline des recepteurs adrenergiques $g(b)2
WO2003048181A1 (fr) 2001-12-01 2003-06-12 Glaxo Group Limited 17.alpha.-esters cycliques de 16-methylpregnan-3,20-dione en tant qu'agents anti-inflammatoires
WO2003062259A2 (fr) 2002-01-21 2003-07-31 Glaxo Group Limited Nouveaux composes
WO2003072539A1 (fr) 2002-02-28 2003-09-04 Glaxo Group Limited Derives de phenethanolamine pour traiter des maladies respiratoires
WO2003091204A1 (fr) 2002-04-25 2003-11-06 Glaxo Group Limited Derives de la phenethanolamine
WO2003099764A1 (fr) 2002-05-28 2003-12-04 Theravance, Inc. Agonistes du recepteur adrenergique $g(b)2 alcoxy aryle
WO2004016601A1 (fr) 2002-08-09 2004-02-26 Novartis Ag Derives de benzothiazole ayant une activite d'agoniste du beta-2-adrenorecepteur
WO2004016578A2 (fr) 2002-07-25 2004-02-26 Glaxo Group Limited Composes medicamenteux
WO2004022547A1 (fr) 2002-09-06 2004-03-18 Glaxo Group Limited Derives de phenethanolamine, et leur utilisation pour le traitement des maladies respiratoires
WO2004032921A1 (fr) 2002-10-11 2004-04-22 Pfizer Limited Derives d'indole utilises comme agonistes beta-2
WO2004033412A1 (fr) 2002-10-04 2004-04-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux betamimetiques a duree d'action prolongee, procedes de production et d'utilisation comme medicaments
WO2004037773A1 (fr) 2002-10-28 2004-05-06 Glaxo Group Limited Derive de phenethanolamine utilise dans le traitement de maladies respiratoires
WO2004037807A2 (fr) 2002-10-22 2004-05-06 Glaxo Group Limited Composes medicinaux
WO2004037768A2 (fr) 2002-10-28 2004-05-06 Glaxo Group Limited Composes a usage medicinal
WO2004039766A1 (fr) 2002-11-01 2004-05-13 Glaxo Group Limited Derives de phenylethanolamine pour le traitement de maladies respiratoires
WO2004039762A1 (fr) 2002-11-01 2004-05-13 Glaxo Group Limited Derives de phenethanolamine permettant de traiter des maladies des voies respiratoires
WO2004046083A1 (fr) 2002-11-15 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux derives de dihydroxymethylphenyle, procedes pour leur preparation, et utilisation desdits derives comme medicament
WO2004045618A2 (fr) 2002-11-15 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux medicaments destines au traitement de la bronchopneumopathie chronique obstructive
DE10258695A1 (de) 2002-12-16 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neuer, langwirksamer Beta-agonist, Verfahren zu dessen Herstellung und dessen Verwendung als Arzneimittel
EP1440966A1 (fr) 2003-01-10 2004-07-28 Pfizer Limited Dérivés d'indole utilisables pour traiter des maladies
WO2004071388A2 (fr) 2003-02-14 2004-08-26 Glaxo Group Limited Composés médicinaux
EP1460064A1 (fr) 2003-03-14 2004-09-22 Pfizer Limited Derivés de Indole-2-carboxamide comme beta-2 agonistes
WO2004087142A1 (fr) 2003-04-04 2004-10-14 Novartis Ag Derives de quinoline-2-one permettant de traiter des maladies des voies respiratoires
WO2004089892A2 (fr) 2003-04-01 2004-10-21 Theravance, Inc. Diarylmethyle et composes apparentes
EP1477167A1 (fr) 2003-05-15 2004-11-17 Pfizer Limited Dérivés de [(2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino)-propyl] phenyl come agonistes de beta2
US20040229904A1 (en) 2003-05-15 2004-11-18 Pfizer Inc Compounds useful for the treatment of diseases
US20040242622A1 (en) 2003-05-28 2004-12-02 Mathai Mammen Azabicycloalkane compounds
WO2004108676A1 (fr) 2003-06-04 2004-12-16 Pfizer Limited Derives de 2-(6-amino-pyridine-3-yl)-2-hydroxyethylamine utilises comme agonistes des recepteurs beta 2-adrenergiques
WO2004108675A1 (fr) 2003-06-04 2004-12-16 Pfizer Limited Derives de 2-amino-pyridine utiles comme agonistes de recepteurs beta-2 adrenergiques
WO2005003098A1 (fr) 2003-07-01 2005-01-13 Schering Aktiengesellschaft Derives de pentanol substitues par un heterocycle, procede de production de ces composes et leur utilisation comme agents anti-inflammatoires
WO2005033121A2 (fr) 2003-10-03 2005-04-14 King Pharmaceuticals Research & Development, Inc. Synthese de 2-aralkyloxyadenosines, 2-alkoxyadenosines, et leurs analogues
WO2005035502A1 (fr) 2003-10-06 2005-04-21 Schering Aktiengesellschaft Pentan-2-oles substitues en 1-(quinoleine-amino) et 1-(isoquinoleine-amino), un procede de production de ces composes, et leur utilisation en tant qu'anti-inflammatoires
WO2005034939A1 (fr) 2003-10-08 2005-04-21 Schering Aktiengesellschaft Derives de tetrahydronaphtalene a substitution 1-amino-2-oxy, procedes pour leur production et leur utilisation en tant qu'anti-inflammatoires
WO2005035518A1 (fr) 2003-10-08 2005-04-21 Schering Aktiengesellschaft Pentanols rearranges, un procede pour leur production et leur utilisation en tant qu'anti-inflammatoires
WO2005040103A1 (fr) 2003-10-22 2005-05-06 Glaxo Group Limited Composes medicaux
WO2005044787A1 (fr) 2003-10-24 2005-05-19 Glaxo Group Limited Derives de phenetanolamine
US20050133417A1 (en) 2003-12-19 2005-06-23 Bhan Opinder K. Systems, methods, and catalysts for producing a crude product
WO2005058299A1 (fr) 2003-12-09 2005-06-30 Glaxo Group Limited Derives de phenethanolamine destines au traitement de maladies respiratoires
WO2005058867A1 (fr) 2003-12-17 2005-06-30 Glaxo Group Limited Benzothiophene- et benzothiochromene- comprenant des derives de phenethanolamine pour traitements
WO2005066140A1 (fr) 2004-01-09 2005-07-21 Boehringer Ingelheim International Gmbh Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires
US20050159448A1 (en) 2004-01-12 2005-07-21 Theravance, Inc. Aryl aniline derivatives as beta2 adrenergic receptor agonists
WO2005065650A2 (fr) 2003-10-09 2005-07-21 Glaxo Group Limited Formulations
US20050171147A1 (en) 2004-01-22 2005-08-04 Brown Alan D. Sulfonamide derivatives for the treatment of diseases
WO2005070908A1 (fr) 2004-01-23 2005-08-04 Boehringer Ingelheim International Gmbh Nouveaux beta-2 agonistes a effet prolonge et leur utilisation comme medicaments
US20050182091A1 (en) 2004-01-22 2005-08-18 Brown Alan D. Sulfonamide derivatives for the treatment of diseases
WO2005077361A1 (fr) 2004-02-14 2005-08-25 Boehringer Ingelheim International Gmbh Nouveaux beta-2-agonistes a action longue duree et leur utilisation comme medicaments
WO2005090288A1 (fr) 2004-03-17 2005-09-29 Pfizer Limited Derives de phenylaminoethanol utilises comme agonistes du recepteur beta 2
WO2005092887A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Composes pour le traitement de maladies
WO2005092840A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Derives de formamide utiles comme recepteurs adrenergiques
WO2005092860A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Composes servant au traitement de maladies
WO2005092861A1 (fr) 2004-03-11 2005-10-06 Pfizer Limited Derives de quinolinone compositions pharmaceutiques contenant ces derives et utilisation de celles-ci
WO2005092870A1 (fr) 2004-03-17 2005-10-06 Boehringer Ingelheim International Gmbh Nouveaux derives de benzoxazinone utilises comme beta-mimetiques dans le traitement des affections des voies respiratoires
WO2005092841A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Composes presentant une activite beta-agoniste
WO2005092087A2 (fr) 2004-03-22 2005-10-06 Mars Incorporated Articles a macher pour animaux
WO2005111002A2 (fr) 2004-05-13 2005-11-24 Boehringer Ingelheim International Gmbh Derives de cycloalkyle substitues, leur procede de production et leur utilisation comme medicaments
WO2005111005A1 (fr) 2004-05-14 2005-11-24 Boehringer Ingelheim International Gmbh Nouveaux beta-agonistes enantiomeriquement purs, leur procede de production et leur utilisation comme medicament
WO2005110990A1 (fr) 2004-05-13 2005-11-24 Boehringer Ingelheim International Gmbh Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires
WO2005110359A1 (fr) 2004-05-14 2005-11-24 Boehringer Ingelheim International Gmbh Formulations pulverulentes a inhaler contenant des beta-agonistes enantiomeriquement purs
US20050272769A1 (en) 2004-06-03 2005-12-08 Theravance, Inc. Diamine beta2 adrenergic receptor agonists
US20060019991A1 (en) 2004-07-21 2006-01-26 Theravance, Inc. Diaryl ether beta2 adrenergic receptor agonists
WO2006016245A1 (fr) 2004-08-05 2006-02-16 Ranbaxy Laboratories Limited Antagonistes des récepteurs muscariniques
WO2006031556A2 (fr) 2004-09-10 2006-03-23 Theravance. Inc. Composes d'arylaniline a substitution amidine
WO2006032627A1 (fr) 2004-09-21 2006-03-30 Boehringer Ingelheim International Gmbh Composes heteroaryle en tant que betamimetiques pour traiter des maladies des voies respiratoires
US20060106213A1 (en) 2002-11-15 2006-05-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg New Medicaments for the Treatment of Chronic Obstructive Pulmonary Disease
WO2006051373A1 (fr) 2004-11-12 2006-05-18 Pfizer Limited Composes permettant de traiter de maladies
WO2006056471A1 (fr) 2004-11-29 2006-06-01 Novartis Ag Derives de 5-hydroxy-benzothiazole presentant une activite agoniste de l'adrenorecepteur beta-2
WO2007100027A1 (fr) 2006-03-02 2007-09-07 Daiichi Sankyo Company, Limited Derive de thiazolidinedione optiquement actif
WO2008096112A1 (fr) 2007-02-08 2008-08-14 Astrazeneca Ab Sels 668
WO2008096119A1 (fr) 2007-02-08 2008-08-14 Astrazeneca Ab Sels 669
WO2008104790A1 (fr) 2007-03-01 2008-09-04 Astrazeneca Ab Sels d'un agoniste de l'adrénorécepteur bêta-2 sélectif
US20090076093A1 (en) * 2007-09-14 2009-03-19 Protia, Llc Deuterium-enriched rosiglitazone
US20090082405A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched pioglitazone

Patent Citations (102)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505321A2 (fr) 1991-03-21 1992-09-23 Ciba-Geigy Ag Inhalateur
JPH0525045A (ja) 1991-07-18 1993-02-02 Tanabe Seiyaku Co Ltd 経皮吸収製剤
WO1993018007A1 (fr) 1992-03-13 1993-09-16 Tokyo Tanabe Company Limited Nouveau derive de carbostyrile
WO1999064035A1 (fr) 1998-06-08 1999-12-16 Advanced Medicine, Inc. AGONISTES DU RECEPTEUR β2-ADRENERGIQUE
WO2000032585A1 (fr) 1998-12-02 2000-06-08 Lek Pharmaceutical And Chemical Company D.D. Procede de preparation de simvastatine et d'analogues de celle-ci
WO2000053601A1 (fr) 1999-03-08 2000-09-14 The University Of Mississippi Derives de 1,2-dithiolane
WO2000062766A2 (fr) 1999-04-15 2000-10-26 Smithkline Beecham Plc Nouveau procede de traitement
US20020055651A1 (en) 1999-06-02 2002-05-09 Moran Edmund J. Beta2-adrenergic receptor agonists
WO2000075114A1 (fr) 1999-06-04 2000-12-14 Novartis Ag Agonistes du recepteur beta 2-adrenergique
WO2001042193A1 (fr) 1999-12-08 2001-06-14 Theravance, Inc. Agonistes des recepteurs adrenergiques du beta 2
WO2001083462A1 (fr) 2000-04-27 2001-11-08 Boehringer Ingelheim Pharma Kg Nouveaux beta-mimetiques a action lente, leurs procedes de production et leur utilisation comme medicament
WO2001082980A1 (fr) * 2000-05-01 2001-11-08 Aeropharm Technology, Inc. Formulation d'aerosol medicinal
WO2001082873A2 (fr) * 2000-05-01 2001-11-08 Aeropharm Technology, Inc. Formulation medicamenteuse pour aerosol
WO2002010143A1 (fr) 2000-07-28 2002-02-07 Schering Aktiengesellschaft Anti-inflammatoires non steroidiens
WO2002012265A1 (fr) 2000-08-05 2002-02-14 Glaxo Group Limited 6.ALPHA., 9.ALPHA.-DIFLUORO-17.ALPHA.-`(2-FURANYLCARBOXYLE) OXY!-11.BETA.-HYDROXY-16.ALPHA.-METHYLE-3-OXO-ANDROST-1,4,-DIENE-17-ACIDE CARBOTHIOIQUE S-FLUOROMETHYLE ESTER UTILISE COMME AGENT ANTI INFLAMMATOIRE
WO2002012266A1 (fr) 2000-08-05 2002-02-14 Glaxo Group Limited Derives de 17-beta-carbothioate-17-alpha-arylcarbonyloxyloxy androstane utilises comme anti-inflammatoires
WO2002013812A1 (fr) 2000-08-17 2002-02-21 Pershadsingh Harrihar A Traitements de maladies inflammatoires
WO2002066422A1 (fr) 2001-02-14 2002-08-29 Glaxo Group Limited Derives de phenethanolamine pour le traitement de maladies respiratoires
WO2002070490A1 (fr) 2001-03-08 2002-09-12 Glaxo Group Limited Agonistes de beta-adrenocepteurs
WO2002076933A1 (fr) 2001-03-22 2002-10-03 Glaxo Group Limited Derives formanilides utilises en tant qu'agonistes de l'adrenorecepteur beta2
WO2002100879A1 (fr) 2001-06-12 2002-12-19 Glaxo Group Limited 17 alpha esters heterocycliques anti-inflammatoires de derives de 17 beta carbothioate androstane
WO2003024439A1 (fr) 2001-09-14 2003-03-27 Glaxo Group Limited Derives de phenethanolamine destines au traitement de maladies respiratoires
WO2003042229A1 (fr) 2001-11-12 2003-05-22 Glaxo Group Limited Esters heterocycliques non aromatiques de furan-2-one esters de 17 $g(b) carboxyl ou 17 $g(b) carbothio glucocorticoides
WO2003042164A1 (fr) 2001-11-13 2003-05-22 Theravance, Inc Agonistes arylaniline des recepteurs adrenergiques $g(b)2
WO2003042160A1 (fr) 2001-11-13 2003-05-22 Theravance, Inc. Agonistes de recepteur d'aryl aniline beta-2 adrenergique
WO2003048181A1 (fr) 2001-12-01 2003-06-12 Glaxo Group Limited 17.alpha.-esters cycliques de 16-methylpregnan-3,20-dione en tant qu'agents anti-inflammatoires
WO2003062259A2 (fr) 2002-01-21 2003-07-31 Glaxo Group Limited Nouveaux composes
WO2003072539A1 (fr) 2002-02-28 2003-09-04 Glaxo Group Limited Derives de phenethanolamine pour traiter des maladies respiratoires
WO2003091204A1 (fr) 2002-04-25 2003-11-06 Glaxo Group Limited Derives de la phenethanolamine
WO2003099764A1 (fr) 2002-05-28 2003-12-04 Theravance, Inc. Agonistes du recepteur adrenergique $g(b)2 alcoxy aryle
WO2004016578A2 (fr) 2002-07-25 2004-02-26 Glaxo Group Limited Composes medicamenteux
US20060106075A1 (en) 2002-08-09 2006-05-18 Bernard Cuenoud Benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
WO2004016601A1 (fr) 2002-08-09 2004-02-26 Novartis Ag Derives de benzothiazole ayant une activite d'agoniste du beta-2-adrenorecepteur
WO2004022547A1 (fr) 2002-09-06 2004-03-18 Glaxo Group Limited Derives de phenethanolamine, et leur utilisation pour le traitement des maladies respiratoires
WO2004033412A1 (fr) 2002-10-04 2004-04-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux betamimetiques a duree d'action prolongee, procedes de production et d'utilisation comme medicaments
WO2004032921A1 (fr) 2002-10-11 2004-04-22 Pfizer Limited Derives d'indole utilises comme agonistes beta-2
WO2004037807A2 (fr) 2002-10-22 2004-05-06 Glaxo Group Limited Composes medicinaux
WO2004037768A2 (fr) 2002-10-28 2004-05-06 Glaxo Group Limited Composes a usage medicinal
WO2004037773A1 (fr) 2002-10-28 2004-05-06 Glaxo Group Limited Derive de phenethanolamine utilise dans le traitement de maladies respiratoires
WO2004039766A1 (fr) 2002-11-01 2004-05-13 Glaxo Group Limited Derives de phenylethanolamine pour le traitement de maladies respiratoires
WO2004039762A1 (fr) 2002-11-01 2004-05-13 Glaxo Group Limited Derives de phenethanolamine permettant de traiter des maladies des voies respiratoires
US20060106213A1 (en) 2002-11-15 2006-05-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg New Medicaments for the Treatment of Chronic Obstructive Pulmonary Disease
WO2004046083A1 (fr) 2002-11-15 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux derives de dihydroxymethylphenyle, procedes pour leur preparation, et utilisation desdits derives comme medicament
WO2004045618A2 (fr) 2002-11-15 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux medicaments destines au traitement de la bronchopneumopathie chronique obstructive
DE10258695A1 (de) 2002-12-16 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neuer, langwirksamer Beta-agonist, Verfahren zu dessen Herstellung und dessen Verwendung als Arzneimittel
EP1440966A1 (fr) 2003-01-10 2004-07-28 Pfizer Limited Dérivés d'indole utilisables pour traiter des maladies
WO2004071388A2 (fr) 2003-02-14 2004-08-26 Glaxo Group Limited Composés médicinaux
WO2004080964A1 (fr) 2003-03-14 2004-09-23 Pfizer Limited Derives d'indole utiles pour traiter des maladies
EP1460064A1 (fr) 2003-03-14 2004-09-22 Pfizer Limited Derivés de Indole-2-carboxamide comme beta-2 agonistes
WO2004089892A2 (fr) 2003-04-01 2004-10-21 Theravance, Inc. Diarylmethyle et composes apparentes
WO2004087142A1 (fr) 2003-04-04 2004-10-14 Novartis Ag Derives de quinoline-2-one permettant de traiter des maladies des voies respiratoires
US20040229904A1 (en) 2003-05-15 2004-11-18 Pfizer Inc Compounds useful for the treatment of diseases
EP1477167A1 (fr) 2003-05-15 2004-11-17 Pfizer Limited Dérivés de [(2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)-ethylamino)-propyl] phenyl come agonistes de beta2
US20040242622A1 (en) 2003-05-28 2004-12-02 Mathai Mammen Azabicycloalkane compounds
WO2004108675A1 (fr) 2003-06-04 2004-12-16 Pfizer Limited Derives de 2-amino-pyridine utiles comme agonistes de recepteurs beta-2 adrenergiques
WO2004108676A1 (fr) 2003-06-04 2004-12-16 Pfizer Limited Derives de 2-(6-amino-pyridine-3-yl)-2-hydroxyethylamine utilises comme agonistes des recepteurs beta 2-adrenergiques
WO2005003098A1 (fr) 2003-07-01 2005-01-13 Schering Aktiengesellschaft Derives de pentanol substitues par un heterocycle, procede de production de ces composes et leur utilisation comme agents anti-inflammatoires
WO2005033121A2 (fr) 2003-10-03 2005-04-14 King Pharmaceuticals Research & Development, Inc. Synthese de 2-aralkyloxyadenosines, 2-alkoxyadenosines, et leurs analogues
WO2005035502A1 (fr) 2003-10-06 2005-04-21 Schering Aktiengesellschaft Pentan-2-oles substitues en 1-(quinoleine-amino) et 1-(isoquinoleine-amino), un procede de production de ces composes, et leur utilisation en tant qu'anti-inflammatoires
WO2005035518A1 (fr) 2003-10-08 2005-04-21 Schering Aktiengesellschaft Pentanols rearranges, un procede pour leur production et leur utilisation en tant qu'anti-inflammatoires
WO2005034939A1 (fr) 2003-10-08 2005-04-21 Schering Aktiengesellschaft Derives de tetrahydronaphtalene a substitution 1-amino-2-oxy, procedes pour leur production et leur utilisation en tant qu'anti-inflammatoires
WO2005065650A2 (fr) 2003-10-09 2005-07-21 Glaxo Group Limited Formulations
WO2005040103A1 (fr) 2003-10-22 2005-05-06 Glaxo Group Limited Composes medicaux
WO2005044787A1 (fr) 2003-10-24 2005-05-19 Glaxo Group Limited Derives de phenetanolamine
WO2005058299A1 (fr) 2003-12-09 2005-06-30 Glaxo Group Limited Derives de phenethanolamine destines au traitement de maladies respiratoires
WO2005058867A1 (fr) 2003-12-17 2005-06-30 Glaxo Group Limited Benzothiophene- et benzothiochromene- comprenant des derives de phenethanolamine pour traitements
US20050133417A1 (en) 2003-12-19 2005-06-23 Bhan Opinder K. Systems, methods, and catalysts for producing a crude product
WO2005066140A1 (fr) 2004-01-09 2005-07-21 Boehringer Ingelheim International Gmbh Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires
US20050159448A1 (en) 2004-01-12 2005-07-21 Theravance, Inc. Aryl aniline derivatives as beta2 adrenergic receptor agonists
US20050182091A1 (en) 2004-01-22 2005-08-18 Brown Alan D. Sulfonamide derivatives for the treatment of diseases
WO2005080313A2 (fr) 2004-01-22 2005-09-01 Pfizer Limited Derives de sulfonamides utilises dans le traitement de maladies
WO2005080324A1 (fr) 2004-01-22 2005-09-01 Pfizer Limited Derives de sulfamides pour traitements medicaux
US20050171147A1 (en) 2004-01-22 2005-08-04 Brown Alan D. Sulfonamide derivatives for the treatment of diseases
WO2005070908A1 (fr) 2004-01-23 2005-08-04 Boehringer Ingelheim International Gmbh Nouveaux beta-2 agonistes a effet prolonge et leur utilisation comme medicaments
WO2005077361A1 (fr) 2004-02-14 2005-08-25 Boehringer Ingelheim International Gmbh Nouveaux beta-2-agonistes a action longue duree et leur utilisation comme medicaments
WO2005092861A1 (fr) 2004-03-11 2005-10-06 Pfizer Limited Derives de quinolinone compositions pharmaceutiques contenant ces derives et utilisation de celles-ci
WO2005090288A1 (fr) 2004-03-17 2005-09-29 Pfizer Limited Derives de phenylaminoethanol utilises comme agonistes du recepteur beta 2
WO2005092870A1 (fr) 2004-03-17 2005-10-06 Boehringer Ingelheim International Gmbh Nouveaux derives de benzoxazinone utilises comme beta-mimetiques dans le traitement des affections des voies respiratoires
WO2005092087A2 (fr) 2004-03-22 2005-10-06 Mars Incorporated Articles a macher pour animaux
WO2005092840A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Derives de formamide utiles comme recepteurs adrenergiques
WO2005092860A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Composes servant au traitement de maladies
WO2005092841A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Composes presentant une activite beta-agoniste
WO2005092887A1 (fr) 2004-03-23 2005-10-06 Pfizer Limited Composes pour le traitement de maladies
WO2005111002A2 (fr) 2004-05-13 2005-11-24 Boehringer Ingelheim International Gmbh Derives de cycloalkyle substitues, leur procede de production et leur utilisation comme medicaments
WO2005110990A1 (fr) 2004-05-13 2005-11-24 Boehringer Ingelheim International Gmbh Heterocycles benzocondenses substitues par hydroxy utilises comme beta-agonistes pour le traitement de maladies respiratoires
WO2005111005A1 (fr) 2004-05-14 2005-11-24 Boehringer Ingelheim International Gmbh Nouveaux beta-agonistes enantiomeriquement purs, leur procede de production et leur utilisation comme medicament
WO2005110359A1 (fr) 2004-05-14 2005-11-24 Boehringer Ingelheim International Gmbh Formulations pulverulentes a inhaler contenant des beta-agonistes enantiomeriquement purs
US20050272769A1 (en) 2004-06-03 2005-12-08 Theravance, Inc. Diamine beta2 adrenergic receptor agonists
WO2005121065A2 (fr) 2004-06-03 2005-12-22 Theravance, Inc. Agonistes des recepteurs $g(b)2-adrenergiques diaminiques
US20060019991A1 (en) 2004-07-21 2006-01-26 Theravance, Inc. Diaryl ether beta2 adrenergic receptor agonists
WO2006014704A1 (fr) 2004-07-21 2006-02-09 Theravance, Inc. AGONISTES DES RÉCEPTEURS β2-ADRÉNERGIQUES DÉRIVÉS D'ÉTHERS DE DIARYLE
WO2006016245A1 (fr) 2004-08-05 2006-02-16 Ranbaxy Laboratories Limited Antagonistes des récepteurs muscariniques
WO2006031556A2 (fr) 2004-09-10 2006-03-23 Theravance. Inc. Composes d'arylaniline a substitution amidine
WO2006032627A1 (fr) 2004-09-21 2006-03-30 Boehringer Ingelheim International Gmbh Composes heteroaryle en tant que betamimetiques pour traiter des maladies des voies respiratoires
WO2006051373A1 (fr) 2004-11-12 2006-05-18 Pfizer Limited Composes permettant de traiter de maladies
WO2006056471A1 (fr) 2004-11-29 2006-06-01 Novartis Ag Derives de 5-hydroxy-benzothiazole presentant une activite agoniste de l'adrenorecepteur beta-2
WO2007100027A1 (fr) 2006-03-02 2007-09-07 Daiichi Sankyo Company, Limited Derive de thiazolidinedione optiquement actif
WO2008096112A1 (fr) 2007-02-08 2008-08-14 Astrazeneca Ab Sels 668
WO2008096119A1 (fr) 2007-02-08 2008-08-14 Astrazeneca Ab Sels 669
WO2008104790A1 (fr) 2007-03-01 2008-09-04 Astrazeneca Ab Sels d'un agoniste de l'adrénorécepteur bêta-2 sélectif
US20090076093A1 (en) * 2007-09-14 2009-03-19 Protia, Llc Deuterium-enriched rosiglitazone
US20090082405A1 (en) * 2007-09-26 2009-03-26 Protia, Llc Deuterium-enriched pioglitazone

Non-Patent Citations (31)

* Cited by examiner, † Cited by third party
Title
BIOPHARMACEUTICS AND DRUG DISPOSITION, vol. 18, no. 4, 1997, pages 305 - 24
BIRRELL ET AL., EUR RESPIR J., vol. 24, no. 1, July 2004 (2004-07-01), pages 18 - 23
CAMPBELL IW, CURR MOL MED., vol. 5, no. 3, May 2005 (2005-05-01), pages 349 - 63
CHEM. PHARM. BULL, vol. 32, no. 11, 1984, pages 4460 - 65
CLARK, J. MED. CHEM., vol. 34, 1991, pages 319 - 325
CROSSNO ET AL., AM. J. PHYSIOL. LUNG CELL. MOL. PHYSIOL, vol. 292, no. 4, 2007, pages L885 - 897
CURKENDALL ET AL., ANN EPIDEMIOL, vol. 16, 2006, pages 63 - 70
CUZZOCREA ET AL., ARTHRITIS RHEUM., vol. 48, no. 12, December 2003 (2003-12-01), pages 3544 - 56
CUZZOCREA ET AL., EUR J PHARMACOL., vol. 483, no. 1, 1 January 2004 (2004-01-01), pages 79 - 93
DESREUMANUX ET AL., J EXP MED., vol. 193, no. 7, 2 April 2001 (2001-04-02), pages 827 - 38
E. FOGASSY, TETRAHEDRON: ASYMMETRY, vol. 19, 2008, pages 519 - 536
EYLES JE; WILLIAMSON ED; ALPAR HO., INT J PHARM, vol. 189, no. 1, 1999, pages 75 - 9
FEINSTEIN ET AL., ANN NEUROL., vol. 51, no. 6, June 2002 (2002-06-01), pages 694 - 702
GUAN, NAT MED., vol. 11, no. 8, 2005, pages 861 - 6
HAFFNER ET AL., CIRCULATION, vol. 106, no. 6, 6 August 2002 (2002-08-06), pages 679 - 84
HETZEL ET AL., THORAX, vol. 58, no. 9, September 2003 (2003-09-01), pages 778 - 83
J. CHROMATOGRAPHY, vol. 835, 2006, pages 40 - 46
J.CLIN. PHARMACOL., vol. 47, 2007, pages 323 - 33
LEE ET AL., FASEB J., vol. 19, no. 8, June 2005 (2005-06-01), pages 1033 - 5
MARX ET AL., ARTERIOSCLER THROMB VASC BIOL., vol. 23, no. 2, 1 February 2003 (2003-02-01), pages 283 - 8
MILAM ET AL., AM. J. PHYSIOL. LUNG CELL. MOL. PHYSIOL, vol. 294, no. 5, 2008, pages L891 - 901
P.NEWMAN, OPTICAL RESOLUTION PROCEDURES OF CHIRAL COMPOUNDS 1-3, RESOLUTION INFORMATION CENTER, 1978
PADELETTI M ET AL., INT J CARDIOL., vol. 125, no. 2, 2008, pages 209 - 15
PARKS ET AL., BIOORG MED CHEM LETT., vol. 8, no. 24, 1998, pages 3657 - 8
RAPID COMMUN. MASS SPECTRUM., vol. 19, 2005, pages 1125 - 9
REDDY ET AL., AM J PHYSIOL LUNG CELL MOL PHYSIOL., vol. 286, no. 3, March 2004 (2004-03-01), pages L613 - 9
SANCHEZ-HIDALGO ET AL., BIOCHEM PHARMACOL., vol. 69, no. 12, 15 June 2005 (2005-06-15), pages 1733 - 44
SHIOJIRI ET AL., EUR J PHARMACOL., vol. 448, no. 2-3, 19 July 2002 (2002-07-19), pages 231 - 8
T. J. MED. CHEM., vol. 34, 1991, pages 319 - 25
WARD ET AL., BR J PHARMACOL., vol. 141, no. 3, February 2004 (2004-02-01), pages 517 - 25
ZHANG ET AL., PROC NATL ACAD SCI USA., vol. 102, no. 26, 2005, pages 9406 - 11

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9925175B2 (en) 2007-09-26 2018-03-27 Deuterx, Llc Deuterium-enriched pioglitazone
US11918567B2 (en) 2007-09-26 2024-03-05 Poxel Sa Deuterium-enriched pioglitazone
US10940143B2 (en) 2007-09-26 2021-03-09 Poxel Sa Deuterium-enriched pioglitazone
US10576071B2 (en) 2007-09-26 2020-03-03 Poxel Sa Deuterium-enriched pioglitazone
GB2477540A (en) * 2010-02-05 2011-08-10 Argenta Therapeutics Ltd Respiratory disease treatment
GB2477743A (en) * 2010-02-10 2011-08-17 Argenta Therapeutics Ltd Enantiomers of 5-methyl-thiazolidine-2,4-dione glitazone compounds
WO2011098799A3 (fr) * 2010-02-10 2015-09-11 Pulmagen Therapeutics (Inflammation) Limited Traitement de maladie respiratoire
WO2014121036A1 (fr) * 2013-02-01 2014-08-07 Deuterx, Llc Dérivés de 5-deutéro-2,4-thiazolidinedione et 5-deutéro-2,4-oxazolidinedione, compositions les comprenant et leur procédés d'utilisation
US10265305B2 (en) 2013-03-14 2019-04-23 Poxel Sa 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
JP2019142957A (ja) * 2013-03-14 2019-08-29 ポクセル・ソシエテ・アノニムＰｏｘｅｌ ＳＡ 重水素化２，４−チアゾリジンジオン及び治療方法
US11918569B2 (en) 2013-03-14 2024-03-05 Poxel Sa 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
WO2014152843A1 (fr) * 2013-03-14 2014-09-25 Deuterx, Llc 2,4-thiazolidinediones enrichies en deutérium et méthodes de traitement
US9833445B2 (en) 2013-03-14 2017-12-05 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US11123336B2 (en) 2013-03-14 2021-09-21 Poxel Sa 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US9416117B2 (en) 2013-03-14 2016-08-16 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
US8969581B2 (en) 2013-03-14 2015-03-03 Deuterx, Llc 5-deutero-2,4-thiazolidinedione derivatives and compositions comprising and methods of using the same
JP2016513719A (ja) * 2013-03-14 2016-05-16 デュートルクス・リミテッド・ライアビリティ・カンパニーＤｅｕｔｅＲｘ， ＬＬＣ 重水素化２，４−チアゾリジンジオン及び治療方法
EP3666273A2 (fr) 2014-01-15 2020-06-17 Poxel SA Procédés de traitement de troubles neurologiques, métaboliques et d'autres troubles utilisant de la pioglitazone enrichie en deutérium énantiopur
US11141411B2 (en) 2014-01-15 2021-10-12 Poxel Sa Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
WO2015109037A1 (fr) * 2014-01-15 2015-07-23 Deuterx, Llc Méthodes de traitement de troubles neurologiques, métaboliques et autres à l'aide de pioglitazone énantiopure enrichie en deutérium
EP3094328A4 (fr) * 2014-01-15 2017-12-13 Deuterx, LLC Méthodes de traitement de troubles neurologiques, métaboliques et autres à l'aide de pioglitazone énantiopure enrichie en deutérium
EP3666273A3 (fr) * 2014-01-15 2020-10-28 Poxel SA Procédés de traitement de troubles neurologiques, métaboliques et d'autres troubles utilisant de la pioglitazone enrichie en deutérium énantiopur
US10188639B2 (en) 2014-01-15 2019-01-29 Deuterx, Llc Methods of treating neurological, metabolic, and other disorders using enantiopure deuterium-enriched pioglitazone
US20200253937A1 (en) * 2015-03-20 2020-08-13 Poxel Sa 5-deutero-thiazolidine-2,4-dione compounds and methods of treating medical disorders using same
WO2016153948A1 (fr) * 2015-03-20 2016-09-29 Deuterx, Llc Polythérapie utilisant des 5-(benzyl)-5-deutéro-thiazolidine-2,4-diones oxy-substituées énantiopures, enrichies en deutérium pour le traitement de troubles médicaux
US20230218595A1 (en) * 2015-03-20 2023-07-13 Deuterx, Llc Combination therapy using enantiopure, oxy-substituted, deuterium-enriched 5-(benzyl)-5-deutero-thiazolidine-2,4-diones for treatment of medical disorders
WO2016153949A1 (fr) * 2015-03-20 2016-09-29 Deuterx, Llc Composés 5-deutéro-thiazolidine-2,4-dione et procédés de traitement de troubles médicaux les utilisant
WO2016153952A1 (fr) * 2015-03-20 2016-09-29 Deuterx, Llc Méthodes de traitement d'infections bactériennes et d'infections fongiques à l'aide de pioglitazone enrichie en deutérium énantiopure
CN116390725A (zh) * 2020-04-30 2023-07-04 米尼奥尔克斯治疗有限公司 用于治疗肺部炎症和间质性肺病的羟基吡格列酮
US11319313B2 (en) 2020-06-30 2022-05-03 Poxel Sa Crystalline forms of deuterium-enriched pioglitazone
CN116018330A (zh) * 2020-06-30 2023-04-25 博希尔公司 氘富集的吡格列酮的晶型
US11767317B1 (en) 2020-06-30 2023-09-26 Poxel Sa Methods of synthesizing enantiopure deuterium-enriched pioglitazone

Similar Documents

Publication Publication Date Title
EP2222272B1 (fr) Traitement de maladie respiratoires
WO2010150014A1 (fr) Glitazones 5r-5–deutérés pour le traitement de maladies respiratoires
US8236786B2 (en) Respiratory disease treatment
EP2600830B1 (fr) Formulation de poudre sèche comprenant un inhibiteur de phosphodiestérase
WO2011098746A1 (fr) Sels d'addition acide cristallins de l'énantiomère (5r) de la pioglitazone
US20050154013A1 (en) Pressurised metered dose inhalers containing solutions of beta-2 agonists
WO2011098801A1 (fr) Traitement de maladies inflammatoires
WO2009019598A2 (fr) Thérapie par inhalation pour des troubles respiratoires
WO2011098799A2 (fr) Traitement de maladie respiratoire
US20110166149A1 (en) Pteridine derivatives for treating respiratory disease
WO2004096274A1 (fr) Medicament administre par voie orale
JP5555255B2 (ja) 呼吸器疾患の治療のためのスルホンアミド化合物
GB2477540A (en) Respiratory disease treatment
US20060199789A1 (en) medical composition

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10734809

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10734809

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载