WO2001013953A2 - Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist - Google Patents

Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist Download PDF

Info

Publication number
WO2001013953A2
WO2001013953A2 PCT/EP2000/007852 EP0007852W WO0113953A2 WO 2001013953 A2 WO2001013953 A2 WO 2001013953A2 EP 0007852 W EP0007852 W EP 0007852W WO 0113953 A2 WO0113953 A2 WO 0113953A2
Authority
WO
WIPO (PCT)
Prior art keywords
medicament
salt
adrenoceptor agonist
pde inhibitor
acid
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/EP2000/007852
Other languages
French (fr)
Other versions
WO2001013953A3 (en
Inventor
Ulrich Kilian
Rolf Beume
Daniela Bundschuh
Armin Hatzelmann
Christian Schudt
Christian Weimar
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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 to EA200200208A priority Critical patent/EA006685B1/en
Priority to HU0203098A priority patent/HU229439B1/en
Priority to MXPA02001830A priority patent/MXPA02001830A/en
Priority to SK255-2002A priority patent/SK287231B6/en
Priority to IL14768800A priority patent/IL147688A0/en
Priority to DE60026855T priority patent/DE60026855T2/en
Priority to SI200030862T priority patent/SI1212089T1/en
Priority to CA2381802A priority patent/CA2381802C/en
Priority to AU67016/00A priority patent/AU777012B2/en
Priority to EP00954625A priority patent/EP1212089B1/en
Priority to BRPI0013478A priority patent/BRPI0013478B8/en
Priority to HK02108936.8A priority patent/HK1047244B/en
Priority to PL356252A priority patent/PL200923B1/en
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Priority to HR20020158A priority patent/HRP20020158B1/en
Priority to JP2001518088A priority patent/JP5038568B2/en
Priority to US10/049,999 priority patent/US6624181B1/en
Priority to NZ517166A priority patent/NZ517166A/en
Publication of WO2001013953A2 publication Critical patent/WO2001013953A2/en
Publication of WO2001013953A3 publication Critical patent/WO2001013953A3/en
Priority to IL147688A priority patent/IL147688A/en
Priority to NO20020815A priority patent/NO328340B1/en
Anticipated expiration legal-status Critical
Priority to US10/437,005 priority patent/US7056936B2/en
Priority to US11/286,391 priority patent/US20060079539A1/en
Priority to US11/433,419 priority patent/US20060205806A1/en
Ceased legal-status Critical Current

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
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the combination of certain known active compounds for therapeutic purposes.
  • the substances used in the combination according to the invention are known active compounds from the PDE inhibitors class and active compounds from the ⁇ 2 adrenoceptor agonists class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.
  • the invention thus relates to the combined use of a PDE inhibitor which can be used as a respiratory tract therapeutic and a ⁇ 2 adrenoceptor agonist in the treatment of respiratory tract disorders.
  • PDE inhibitors which can be used as respiratory tract therapeutics in the sense of the present invention are those compounds which slow the breakdown of cyclic AMP (cAMP) or cyclic GMP (cGMP) by inhibition of the phosphodiesterases, which can lead to a relative increase in the intracellular concentration of cAMP or cGMP.
  • Possible PDE inhibitors within the meaning of the present invention are primarily those substances which are to be considered part of the PDE4 inhibitor class and those substances which can be designated as mixed types of PDE3/4 inhibitors.
  • PDE inhibitors may be mentioned which are described or claimed in the following patent applications and patents: DE 1545687, DE 2028869, DE 2123328, DE 2315801 , DE 2402908, DE 2413935, DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP 0163965, EP 0335386, EP 0389282, EP 0428302, EP 0435811 , EP 0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP 0527117, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474, EP 0685475, EP 0685479, EP 0736532, EP 0738715, EP 0748805, EP 0763534, EP 0816357, EP 0819688, EP 0819689, EP 0832886, EP 0834508, EP 0848000, JP 92234389, JP 94329652, JP 95010875
  • PDE inhibitors are shown on the following pages with the aid of their formulae: cl Xo ;
  • PDE inhibitors to be emphasized which are selected from the abovementioned compounds and which may be mentioned are the active compounds arofylline, atizoram, AWD-12-281, BAY-19-8004, benafentrine, BYK-33043, CC-3052, CDP-840, CM 018, cipamfylline, CP- 220629, CP-293121, D-22888, D-4396, D-4418, denbufylline, filaminast, GW-3600, ibudilast, KF-17625, KS-506-G, laprafylline, NA-0226A, NA-23063A, ORG-20241 , ORG-30029, PDB- 093, pentoxifylline, piclamilast, roflumilast, rolipram, RPR-117658, RPR-122818, RPR- 132294, RPR-132703, RS-17597, RS-25344-000, SB-207499
  • the compounds preferred from the group of the abovementioned PDE inhibitors are arofylline, cipamfylline, D-4418, filaminast, ibudilast, laprafylline, ORG-20241 , piclamilast, rolipram, SB-207499, tibenelast and V-11294A.
  • the compounds particularly preferred are BYK-33043 and in particular roflumilast.
  • ⁇ 2 adrenoceptor agonists which may particularly be mentioned are those selectively acting substances which only have a slight cardiac action and therefore are also employed in therapy, in particular in the oral therapy of respiratory tract disorders.
  • ⁇ 2 adrenoceptor agonists which may be mentioned are, for example: AR-C68397AA, broxaterol, CHF-1035, HOKU-81 , ibuterol, KUL-1248, soterenol, meluadrine, TA-2005, tiaramide, salbutamol, levosalbutamol, tulobuterol, terbutaline, carbuterol, pirbuterol, reproterol, clenbuterol, fenotero!, hexoprenaline, orciprenaline, isopre ⁇ aline, formoterol, salmeterol, rimiterol, procaterol, ba buterol, bitolterol and mabuterol.
  • ⁇ 2 adrenoceptor agonists such as clenbuterol, orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol and reproterol are preferred. Particularly preferred are the so-called long acting ⁇ 2 adrenoceptor agonists, such as salmeterol.
  • the PDE inhibitors and the ⁇ 2 adrenoceptor agonists can be present as such or in chemically bonded form. It is understood hereby that the active compounds mentioned can also be present, for example, in the form of their pharmacologically tolerable salts and/or as solvates (e.g. hydrates), and/or in the form of their N-oxides etc.
  • Suitable pharmacologically tolerable salts here are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)- benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tarta c acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom.
  • the active compounds mentioned can also be present as pure
  • Respiratory tract disorders which may be mentioned are in particular allergen- and inflammation-induced bronchial disorders (bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, COPD), which can be treated by the combination according to the invention also in the sense of a long-term therapy (if desired with appropriate adjustment of the dose of the individual components to the needs at the time, for example needs subject to seasonally related variations).
  • allergen- and inflammation-induced bronchial disorders bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, COPD
  • Combined use or “combination” within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament), more or less simultaneously (from separate pack units) or in succession (directly in succession or else alternatively at a relatively large time interval) in a manner which is known per se and customary.
  • ⁇ 2 adrenoceptor agonist is understood in particular as meaning topical application in inhalatory form.
  • the ⁇ 2 adrenoceptor agonist is preferably administered by inhalation in the form of an aerosol, the aerosol particles of solid, liquid or mixed composition having a diameter of 0.5 to 10 ⁇ m, advantageously of 2 to 6 ⁇ m.
  • Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic atomizers, but advantageously by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.
  • the active compounds are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the active compounds compared with the norm.
  • the ⁇ 2 adrenoceptor agonist (depending on potency) is administered in a dose of, for example, 0.002 to 2.0 mg per day on administration by inhalation.
  • the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen 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.
  • propellants e.g. Frigen in the case of metered aerosols
  • surface-active substances e.g. Frigen in the case of metered aerosols
  • emulsifiers emulsifiers
  • stabilizers emulsifiers
  • preservatives e.g., emulsifiers, stabilizers, preservatives
  • flavorings e.g. lactose in the case of powder inhalers
  • fillers e.g. lactose in the case of powder inhalers
  • the ⁇ 2 adrenoceptor agonist is administered in a daily dose of, for example, 0.05 to 60 mg.
  • the PDE inhibitors it is possible in the case of oral administration to vary the doses - depending on the active compound - within a wide range, it being possible, as bounds, to start from a dose of 1 - 2000 ⁇ g/kg of body weight.
  • the dose is in the range from 2 - 20 ⁇ g/kg of body weight.
  • the PDE inhibitors to be administered orally are formulated - if appropriate together with the ⁇ 2 adrenoceptor agonists - to give medicaments according to processes known per se and familiar to the person skilled in the art.
  • the pharmacologically active compounds are employed as medicaments, preferably in combination with suitable pharmaceutical excipients or vehicles, in the form of tablets, coated tablets, capsules, emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and, by the appropriate choice of the excipients and vehicles, it being possible to achieve a pharmaceutical administration form precisely tailored to the active compound(s) and/or to the desired onset of action (e.g. a sustained-release form or an enteric form).
  • oral administration of both active compounds according to the invention are oral administration forms, e.g. tablets or capsules, in which one part of the ⁇ 2 adrenoceptor agonist and the PDE inhibitor is present in non sustained- release form and a further, preferably larger part, of the ⁇ 2 adrenoceptor agonist is present in sustained-release form.
  • excipients or vehicles are suitable for the desired pharmaceutical formulations.
  • solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyclodextrins).
  • OVA ovalbumin
  • Sensitization was done by simultaneous injection of Bordetella pertussis suspension i.p. and OVAAHG suspension s.c. on day 1 , 14 and 21. 28 days after start of sensitization, conscious Brown-Norway rats were challenged by inhalation of the aerosolized OVA solution for 1 h ( ⁇ 20 ml/h). Non-challenged, only sensitized animals were used as baseline control.
  • the drugs were administered intratracheally (i.t.) as dry powders 1 h before OVA-challenge. 48h later, OVA-challenged or non-challenged animals were anaesthetized and bronchoalveolar lavage (BAL) was performed using 3x4 ml BAL buffer per animal. The number of total cells and eosinophils in the BAL fluid, and the concentration of protein in the cell-free BAL fluid were determined. Drug-induced relative changes were calculated and statistically analyzed by the Jonckheere Terpstra test.
  • the long-acting ⁇ 2-adrenergic receptor agonist Salmeterol given at a dose of 3 ⁇ mol/kg i.t exhibited inhibitory effects on total cell and eosinophil influx into alveolar space and protein levels in BAL fluid. However, the data failed to reach significance.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Seasonings (AREA)
  • Inorganic Insulating Materials (AREA)
  • Medicinal Preparation (AREA)
  • Dental Preparations (AREA)
  • Piezo-Electric Or Mechanical Vibrators, Or Delay Or Filter Circuits (AREA)
  • Lubricants (AREA)

Abstract

The invention relates to the combined administration of PDE inhibitors and beta 2 adrenoceptor agonists for the treatment of respiratory tract disorders.

Description

Synergistic combination
Field of application of the invention
The invention relates to the combination of certain known active compounds for therapeutic purposes.
The substances used in the combination according to the invention are known active compounds from the PDE inhibitors class and active compounds from the β2 adrenoceptor agonists class. Their combined use in the sense according to the invention for therapeutic purposes has not yet been described in the prior art.
Description of the invention
It is the object of the present invention to make available respiratory tract therapeutics which fulfill the following conditions:
Good antiinflammatory action
Marked bronchorelaxation and -dilatation
Good oral availability, at least with respect to the PDE inhibitor
Minor side effects
Good suitability for long-term therapy
Favorable influence on bronchial hyperreactivity.
It has now been found that the combined use of a PDE inhibitor which can be used as a respiratory tract therapeutic and of a β2 adrenoceptor agonist outstandingly fulfills the abovementioned conditions.
The invention thus relates to the combined use of a PDE inhibitor which can be used as a respiratory tract therapeutic and a β2 adrenoceptor agonist in the treatment of respiratory tract disorders.
PDE inhibitors which can be used as respiratory tract therapeutics in the sense of the present invention are those compounds which slow the breakdown of cyclic AMP (cAMP) or cyclic GMP (cGMP) by inhibition of the phosphodiesterases, which can lead to a relative increase in the intracellular concentration of cAMP or cGMP. Possible PDE inhibitors within the meaning of the present invention are primarily those substances which are to be considered part of the PDE4 inhibitor class and those substances which can be designated as mixed types of PDE3/4 inhibitors. By way of example, those PDE inhibitors may be mentioned which are described or claimed in the following patent applications and patents: DE 1545687, DE 2028869, DE 2123328, DE 2315801 , DE 2402908, DE 2413935, DE 3900233, EP 0103497, EP 0139464, EP 0158380, EP 0163965, EP 0335386, EP 0389282, EP 0428302, EP 0435811 , EP 0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP 0527117, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474, EP 0685475, EP 0685479, EP 0736532, EP 0738715, EP 0748805, EP 0763534, EP 0816357, EP 0819688, EP 0819689, EP 0832886, EP 0834508, EP 0848000, JP 92234389, JP 94329652, JP 95010875, JP 98072415, JP 98147585, US 5703098, US 5739144, WO 9117991 , WO 9200968, WO 9212961 , WO 9307146, WO 9315044, WO 9315045, WO 9318024, WO 9319068, WO 9319720, WO 9319747, WO 9319749, WO 9319751 , WO 9325517, WO 9402465, WO 9412461 , WO 9420455, WO 9422852, WO 9427947, WO 9501338, WO 9501980, WO 9503794, WO 9504045, WO 9504046, WO 9505386, WO 9508534, WO 9509623, WO 9509624, WO 9509627, WO 9509836, WO 9514667, WO 9514680, WO 9514681, WO 9517392, WO 9517399, WO 9519362, WO 9520578, WO 9522520, WO 9524381 , WO 9527692, WO 9535281 , WO 9535283, WO 9535284, WO 9600218, WO 9601825, WO 9606843, WO 9611690, WO 9611917, WO 9612720, WO 9631486, WO 9631487, WO 9635683, WO 9636595, WO 9636596, WO 9636611 , WO 9636625, WO 9636638, WO 9638150, WO 9639408, WO 9640636, WO 9703967, WO 9704779, WO 9705105, WO 9708143, WO 9709345, WO 9712895, WO 9718208, WO 9719078, WO 9720833, WO 9722585, WO 9722586, WO 9723457, WO 9723460, WO 9723461 , WO 9724117, WO 9724355, WO 9725312, WO 9728131 , WO 9730999, WO 9731000, WO 9732853, WO 9735854, WO 9736905, WO 9743288, WO 9744036, WO 9744322, WO 9747604, WO 9748697, WO 9804534, WO 9805327, WO 9806692, WO 9806704, WO 9807715, WO 9808828, WO 9808830, WO 9808841 , WO 9808844, WO 9809946, WO 9809961 , WO 9811113, WO 9814448, WO 9818796, WO 9821208, WO 9822453, WO 9845268, WO 9855481 , WO 9856756, WO 9905111 , WO 9905112, WO 9505113, WO 9906404 and WO 9918095. Those PDE inhibitors are to be emphasized which are claimed in the patent applications or patents EP 0393500, EP 0510562, EP 0553174, WO 9501338, WO 9603399, WO 9636625, WO 9636626, WO 9735854, WO 9821208, WO 9831674, WO 9840382, WO 9855481 , WO 9905111 , WO 9905112, WO 9905113, WO 9931071 and WO 9931090. Substances having good oral availability are preferred here.
Exemplary PDE inhibitors are shown on the following pages with the aid of their formulae: cl Xo;
Figure imgf000004_0002
Figure imgf000004_0001
Figure imgf000004_0003
Figure imgf000004_0004
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
BYK-33043
(Pumafentrin)
Figure imgf000014_0001
Roflumilast
Figure imgf000015_0002
Figure imgf000015_0001
Figure imgf000015_0003
Figure imgf000016_0001
Figure imgf000016_0002
No hydrogen atoms are indicated in the above formulae. -O is accordingly -OH, -N is NH2. Methyl groups, e.g. on the oxygen atoms, are indicated by lines.
PDE inhibitors to be emphasized which are selected from the abovementioned compounds and which may be mentioned are the active compounds arofylline, atizoram, AWD-12-281, BAY-19-8004, benafentrine, BYK-33043, CC-3052, CDP-840, CM 018, cipamfylline, CP- 220629, CP-293121, D-22888, D-4396, D-4418, denbufylline, filaminast, GW-3600, ibudilast, KF-17625, KS-506-G, laprafylline, NA-0226A, NA-23063A, ORG-20241 , ORG-30029, PDB- 093, pentoxifylline, piclamilast, roflumilast, rolipram, RPR-117658, RPR-122818, RPR- 132294, RPR-132703, RS-17597, RS-25344-000, SB-207499, SB-210667, SB-211572, SB- 211600, SB-212066, SB-212179, SDZ-ISQ-844, SDZ-MNS-949, SKF-107806, SQ-20006, T- 2585, T-440, tibenelast, tolafentrine, UCB-29646, V-11294A, YM-58997, YM-976 and zardaverine.
The compounds preferred from the group of the abovementioned PDE inhibitors are arofylline, cipamfylline, D-4418, filaminast, ibudilast, laprafylline, ORG-20241 , piclamilast, rolipram, SB-207499, tibenelast and V-11294A. The compounds particularly preferred are BYK-33043 and in particular roflumilast.
β2 adrenoceptor agonists which may particularly be mentioned are those selectively acting substances which only have a slight cardiac action and therefore are also employed in therapy, in particular in the oral therapy of respiratory tract disorders. β2 adrenoceptor agonists which may be mentioned are, for example: AR-C68397AA, broxaterol, CHF-1035, HOKU-81 , ibuterol, KUL-1248, soterenol, meluadrine, TA-2005, tiaramide, salbutamol, levosalbutamol, tulobuterol, terbutaline, carbuterol, pirbuterol, reproterol, clenbuterol, fenotero!, hexoprenaline, orciprenaline, isopreπaline, formoterol, salmeterol, rimiterol, procaterol, ba buterol, bitolterol and mabuterol. The orally readily available β2 adrenoceptor agonists such as clenbuterol, orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol and reproterol are preferred. Particularly preferred are the so-called long acting β2 adrenoceptor agonists, such as salmeterol.
The PDE inhibitors and the β2 adrenoceptor agonists can be present as such or in chemically bonded form. It is understood hereby that the active compounds mentioned can also be present, for example, in the form of their pharmacologically tolerable salts and/or as solvates (e.g. hydrates), and/or in the form of their N-oxides etc. Suitable pharmacologically tolerable salts here are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)- benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tarta c acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom. Furthermore, the active compounds mentioned can also be present as pure enantiomers or as enantiomer mixtures in any mixing ratio.
Respiratory tract disorders which may be mentioned are in particular allergen- and inflammation-induced bronchial disorders (bronchitis, obstructive bronchitis, spastic bronchitis, allergic bronchitis, allergic asthma, bronchial asthma, COPD), which can be treated by the combination according to the invention also in the sense of a long-term therapy (if desired with appropriate adjustment of the dose of the individual components to the needs at the time, for example needs subject to seasonally related variations).
"Combined use" or "combination" within the meaning of the present invention is to be understood as meaning that the individual components can be administered simultaneously (in the form of a combination medicament), more or less simultaneously (from separate pack units) or in succession (directly in succession or else alternatively at a relatively large time interval) in a manner which is known per se and customary.
Within the meaning of the present invention, "use" is preferably understood as meaning the oral administration of both active compounds. If only the PDE inhibitor is administered orally, "use" with respect to the β2 adrenoceptor agonist is understood in particular as meaning topical application in inhalatory form. For this, the β2 adrenoceptor agonist is preferably administered by inhalation in the form of an aerosol, the aerosol particles of solid, liquid or mixed composition having a diameter of 0.5 to 10 μm, advantageously of 2 to 6 μm.
Aerosol generation can be carried out, for example, by pressure-driven jet atomizers or ultrasonic atomizers, but advantageously by propellant-driven metered aerosols or propellant-free administration of micronized active compounds from inhalation capsules.
The active compounds are dosed in an order of magnitude customary for the individual dose, it more likely being possible, on account of the individual actions, which are mutually positively influencing and reinforcing, to reduce the respective doses on the combined administration of the active compounds compared with the norm. Customarily, the β2 adrenoceptor agonist (depending on potency) is administered in a dose of, for example, 0.002 to 2.0 mg per day on administration by inhalation.
Depending on the inhaler system used, in addition to the active compounds the administration forms additionally contain the required excipients, such as, for example, propellants (e.g. Frigen 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.
For the purposes of inhalation, a large number of apparatuses are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is as right as possible for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhaler described in European Patent Application EP 0 505 321), using which an optimal administration of active compound can be achieved.
In the case of the oral administration of the β2 adrenoceptor agonists together with the PDE inhibitor, which is the preferred administration form, the β2 adrenoceptor agonist is administered in a daily dose of, for example, 0.05 to 60 mg. For the PDE inhibitors, it is possible in the case of oral administration to vary the doses - depending on the active compound - within a wide range, it being possible, as bounds, to start from a dose of 1 - 2000 μg/kg of body weight. In the case of the administration of the preferred PDE inhibitor roflumilast, the dose is in the range from 2 - 20 μg/kg of body weight.
The PDE inhibitors to be administered orally are formulated - if appropriate together with the β2 adrenoceptor agonists - to give medicaments according to processes known per se and familiar to the person skilled in the art. The pharmacologically active compounds are employed as medicaments, preferably in combination with suitable pharmaceutical excipients or vehicles, in the form of tablets, coated tablets, capsules, emulsions, suspensions or solutions, the active compound content advantageously being between 0.1 and 95% and, by the appropriate choice of the excipients and vehicles, it being possible to achieve a pharmaceutical administration form precisely tailored to the active compound(s) and/or to the desired onset of action (e.g. a sustained-release form or an enteric form). Particularly worthy of mention within the meaning of the combined, oral administration of both active compounds according to the invention are oral administration forms, e.g. tablets or capsules, in which one part of the β2 adrenoceptor agonist and the PDE inhibitor is present in non sustained- release form and a further, preferably larger part, of theβ2 adrenoceptor agonist is present in sustained-release form.
The person skilled in the art is familiar on the basis of his/her expert knowledge with which excipients or vehicles are suitable for the desired pharmaceutical formulations. In addition to solvents, gel-forming agents, tablet excipients and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or permeation promoters and complexing agents (e.g. cyclodextrins).
Pharmacology
Model
Late Inflammatory Airway Reaction in the Ovalbumin-sensitized/-challenged Brown-Norway Rat
Anti-inflammatory activity of Roflumilast, Pumafentrine (BYK-33043), and Salmeterol was determined in ovalbumin (OVA)-sensitized and OVA-challenged Brown Norway rats. Sensitization was done by simultaneous injection of Bordetella pertussis suspension i.p. and OVAAHG suspension s.c. on day 1 , 14 and 21. 28 days after start of sensitization, conscious Brown-Norway rats were challenged by inhalation of the aerosolized OVA solution for 1 h (~20 ml/h). Non-challenged, only sensitized animals were used as baseline control. The drugs (thoroughly mixed with lactose) or the placebo control (lactose) were administered intratracheally (i.t.) as dry powders 1 h before OVA-challenge. 48h later, OVA-challenged or non-challenged animals were anaesthetized and bronchoalveolar lavage (BAL) was performed using 3x4 ml BAL buffer per animal. The number of total cells and eosinophils in the BAL fluid, and the concentration of protein in the cell-free BAL fluid were determined. Drug-induced relative changes were calculated and statistically analyzed by the Jonckheere Terpstra test.
Results
Figure imgf000020_0001
*p< 0.05, ** p< 0.01 v.s. untreated, OVA-challenged control groups
Summary
The PDE inhibitors Roflumilast (PDE4 inhibitor) and Pumafentrine (PDE3>4 inhibitor) administered at doses of 0.3 μmol/kg and 3 μmol/kg i.t., respectively, did not show any significant effects on cell infiltration and protein accumulation. The negative values obtained (trend: amplification of inflammation) fall into the range of biological variability of the model and therefore, no significance must be attached to these data. In contrast, the long-acting β2-adrenergic receptor agonist Salmeterol given at a dose of 3 μmol/kg i.t exhibited inhibitory effects on total cell and eosinophil influx into alveolar space and protein levels in BAL fluid. However, the data failed to reach significance.
Co-administration of the PDE inhibitor Roflumilast or Pumafentrine with Salmeterol resulted in synergistic effects compared to administration of every compound alone, i.e. both PDE inhibitors combined with the β2 agonist displayed a significant inhibition of eosinophilia and reduction of protein concentration in the BAL fluid. The combination of the PDE3/4 inhibitor Pumafentrine and Salmeterol was more efficacious on all parameters measured (difference was not significant), and additionally, showed a significant effect on inhibition of total cell influx into the alveolar space.

Claims

Patent claims
1. A medicament comprising a PDE inhibitor, which is to be administered orally, from the PDE4 or PDE3/4 inhibitors group combined with a β2 adrenoceptor agonist in fixed or free combination.
2. The medicament as claimed in claim 1 , which is a fixed oral combination.
3. The medicament as claimed in claim 1 or 2 for use in the therapeutic treatment of respiratory tract disorders.
4. The medicament as claimed in claim 1 or 2, wherein the PDE inhibitor is a compound selected from the group consisting of arofylline, cipamfylline, D-4418, filaminast, ibudilast, laprafylline, ORG-20241 , piclamilast, rolipram, SB-207499, tibenelast and V- 11294A or a salt thereof.
5. The medicament as claimed in claim 1 or 2, wherein the PDE inhibitor is roflumilast, its salt and/or its N-oxide.
6. The medicament as claimed in claim 1 or 2, wherein the PDE inhibitor is BYK-33043, its salt and/or its N-oxide.
7. The medicament as claimed in claim 1 or 2, wherein the PDE inhibitor is roflumilast, its salt and/or its N-oxide and the β2 adrenoceptor agonist is salmeterol or a salt thereof.
8. The medicament as claimed in claim 1 or 2, wherein the PDE inhibitor is BYK-33043, its salt and/or its N-oxide and the β2 adrenoceptor agonist is salmeterol or a salt thereof.
9. The medicament as claimed in claim 1 or 2, wherein the β2 adrenoceptor agonist is clenbuterol, orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol or reproterol or a salt thereof.
10. The medicament as claimed in claim 1 or 2, wherein the PDE inhibitor is arofylline, cipamfylline, D-4418, filaminast, ibudilast, laprafylline, ORG-20241 , piclamilast, rolipram, SB-207499, tibenelast or V-11294A or a salt thereof, and the β2 adrenoceptor agonist is clenbuterol, orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol or reproterol or a salt thereof.
11. The medicament as claimed in claim 1 or 2, wherein the PDE inhibitor is roflumilast or BYK-33043, their salts and/or their N-oxides and the β2 adrenoceptor agonist is clenbuterol, orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol or reproterol or a salt thereof.
12. The use of a PDE inhibitor, which is to be administered orally, from the PDE4- or PDE3/4 inhibitors group in the combined use with a β2 adrenoceptor agonist in the therapeutic treatment of respiratory tract disorders.
PCT/EP2000/007852 1997-02-28 2000-08-11 Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist Ceased WO2001013953A2 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
PL356252A PL200923B1 (en) 1999-08-21 2000-08-11 SYNERGISTIC COMBINATION OF PDE INHIBITORS AND ß₂ ADRENOCEPTOR AGONIST
MXPA02001830A MXPA02001830A (en) 1999-08-21 2000-08-11 Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist.
SK255-2002A SK287231B6 (en) 1999-08-21 2000-08-11 Medicament comprising a PDE inhibitor and a beta2 adrenoreceptor agonist
IL14768800A IL147688A0 (en) 1999-08-21 2000-08-11 Synergistic combination
DE60026855T DE60026855T2 (en) 1999-08-21 2000-08-11 SYNERGISTIC COMBINATION OF ROFLUMILAST AND SALMETEROL
SI200030862T SI1212089T1 (en) 1999-08-21 2000-08-11 Synergistic combination of roflumilast and salmeterol
CA2381802A CA2381802C (en) 1999-08-21 2000-08-11 Synergistic combination of roflumilast and salmeterol
AU67016/00A AU777012B2 (en) 1999-08-21 2000-08-11 Synergistic combination of PDE inhibitors and beta 2 adrenoceptor agonist
HU0203098A HU229439B1 (en) 1999-08-21 2000-08-11 Synergistic combination roflumilast and salmeterol
BRPI0013478A BRPI0013478B8 (en) 1999-08-21 2000-08-11 medicament comprising pde inhibitor and use of roflumilast
HR20020158A HRP20020158B1 (en) 1999-08-21 2000-08-11 Action of synergistic combination
EA200200208A EA006685B1 (en) 1999-08-21 2000-08-11 Synergistic combination
EP00954625A EP1212089B1 (en) 1999-08-21 2000-08-11 Synergistic combination of roflumilast and salmeterol
HK02108936.8A HK1047244B (en) 1999-08-21 2000-08-11 Synergistic combination of roflumilast and salmeterol
JP2001518088A JP5038568B2 (en) 1999-08-21 2000-08-11 Combination of synergists
US10/049,999 US6624181B1 (en) 1997-02-28 2000-08-11 Synergistic combination
NZ517166A NZ517166A (en) 1999-08-21 2000-08-11 Synergistic combination of PDE inhibitors and beta 2 adrenoceptor agonists
IL147688A IL147688A (en) 1999-08-21 2002-01-17 Medicaments comprising roflumilast and uses thereof
NO20020815A NO328340B1 (en) 1999-08-21 2002-02-19 Synergistic combination drug of roflumilast and salmeterol and use thereof.
US10/437,005 US7056936B2 (en) 1998-02-24 2003-05-14 Synergistic combination
US11/286,391 US20060079539A1 (en) 1998-02-24 2005-11-25 Synergistic combination
US11/433,419 US20060205806A1 (en) 1998-02-24 2006-05-15 Synergistic combination

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP99116447.6 1999-08-21
EP99116447 1999-08-21

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
US09/367,850 Continuation-In-Part US6333354B1 (en) 1997-02-28 1998-02-24 Synergistic combination of PDE inhibitors and adenylate cyclase agonists or guanyl cyclyse agonists
PCT/EP1998/001047 Continuation-In-Part WO1998037894A1 (en) 1997-02-28 1998-02-24 Synergistic combination of pde inhibitors and adenylate cyclase agonists or guanyl cyclyse agonists
US09367850 Continuation-In-Part 1998-02-24

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US10049999 A-371-Of-International 2000-08-11
US10/049,999 A-371-Of-International US6624181B1 (en) 1997-02-28 2000-08-11 Synergistic combination
US10/437,005 Continuation US7056936B2 (en) 1998-02-24 2003-05-14 Synergistic combination

Publications (2)

Publication Number Publication Date
WO2001013953A2 true WO2001013953A2 (en) 2001-03-01
WO2001013953A3 WO2001013953A3 (en) 2001-09-20

Family

ID=8238828

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/007852 Ceased WO2001013953A2 (en) 1997-02-28 2000-08-11 Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist

Country Status (28)

Country Link
US (3) US7056936B2 (en)
EP (3) EP2193808A1 (en)
JP (1) JP5038568B2 (en)
KR (1) KR100701904B1 (en)
CN (1) CN1202865C (en)
AT (2) ATE320800T1 (en)
AU (1) AU777012B2 (en)
BR (1) BRPI0013478B8 (en)
CA (2) CA2715683A1 (en)
CZ (1) CZ302882B6 (en)
DE (2) DE60026855T2 (en)
DK (1) DK1212089T3 (en)
EA (1) EA006685B1 (en)
ES (1) ES2260043T3 (en)
HK (1) HK1047244B (en)
HR (1) HRP20020158B1 (en)
HU (1) HU229439B1 (en)
IL (2) IL147688A0 (en)
MX (1) MXPA02001830A (en)
NO (1) NO328340B1 (en)
NZ (1) NZ517166A (en)
PL (1) PL200923B1 (en)
PT (1) PT1212089E (en)
SI (1) SI1212089T1 (en)
SK (1) SK287231B6 (en)
TR (2) TR200909479T2 (en)
WO (1) WO2001013953A2 (en)
ZA (1) ZA200201389B (en)

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001090076A1 (en) * 2000-05-25 2001-11-29 Merck Frosst Canada & Co. Fluoroalkoxy-substituted benzamide dichloropyridinyl n-oxide pde4 inhibitor
WO2003030939A1 (en) * 2001-10-05 2003-04-17 Glaxo Group Limited Therapies for treating respiratory diseases
WO2003047578A1 (en) * 2001-12-07 2003-06-12 Pfizer Limited Combination of a selective pde4 inhibitor and an adrenergic beta-2 receptor agonist
WO2003024488A3 (en) * 2001-09-19 2003-09-04 Altana Pharma Ag Combination of a pde inhibitor and a leukotriene receptor antagonist
WO2003024489A3 (en) * 2001-09-19 2003-09-18 Altana Pharma Ag Combination of a nsaid and a pde-4 inhibitor
WO2004047829A1 (en) * 2002-11-27 2004-06-10 Altana Pharma Ag New synergistic combination comprising roflumilast and formoterol
WO2004047828A1 (en) * 2002-11-27 2004-06-10 Altana Pharma Ag Synergistic combination compresing roflumilas and (r.r) -formoterol
US6822114B1 (en) 2002-10-08 2004-11-23 Albemarle Corporation Process for production of fluoroalkoxy-substituted benzamides and their intermediates
WO2004062671A3 (en) * 2003-01-14 2005-01-27 Altana Pharma Ag Pde4 inhibitors for the treatment of neoplasms of lymphoid cells
US7045658B2 (en) 2001-03-22 2006-05-16 Glaxo Group Limited Formailide derivatives as beta2-adrenoreceptor agonists
WO2006056471A1 (en) 2004-11-29 2006-06-01 Novartis Ag 5-hydroxy-benzothiazole derivatives having beta-2-adrenorecptor agonist activity
US7105667B2 (en) 2001-05-01 2006-09-12 Bristol-Myers Squibb Co. Fused heterocyclic compounds and use thereof
US7135600B2 (en) 2001-02-14 2006-11-14 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
EP1389467A4 (en) * 2001-05-23 2007-01-10 Tanabe Seiyaku Co THERAPEUTIC COMPOSITIONS FOR REPAIRING CHONDROPATHY
EP1389468A4 (en) * 2001-05-23 2007-01-10 Tanabe Seiyaku Co COMPOSITIONS PROMOTING THE GUISON OF A BONE FRACTURE
WO2007071400A1 (en) 2005-12-22 2007-06-28 Novartis Ag Pyrazine derivatives as epithelial sodium channel blocker
US7271197B2 (en) 2002-04-25 2007-09-18 Glaxo Group Limited Phenethanolamine derivatives
WO2007121920A2 (en) 2006-04-21 2007-11-01 Novartis Ag Purine derivatives for use as adenosin a2a receptor agonists
US7294650B2 (en) 2003-12-17 2007-11-13 Glaxo Group Limited Benzothiophen and thiochrone containing phenethanolamine derivatives for the treatment of respiratory disorders
WO2008037477A1 (en) 2006-09-29 2008-04-03 Novartis Ag Pyrazolopyrimidines as p13k lipid kinase inhibitors
US7361787B2 (en) 2001-09-14 2008-04-22 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
WO2008052734A1 (en) 2006-10-30 2008-05-08 Novartis Ag Heterocyclic compounds as antiinflammatory agents
US7402598B2 (en) 2002-07-25 2008-07-22 Glaxo Group Limited Arylethanolamine β2-adrenoreceptor agonist compounds
US7442839B2 (en) 2002-10-28 2008-10-28 Glaxo Group Limited Phenethanolamine derivative for the treatment of respiratory diseases
US7538127B2 (en) 2003-02-14 2009-05-26 Glaxo Group Limited Medicinal compounds
WO2009087224A1 (en) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines as kinase inhibitors
EP1908463A3 (en) * 2001-12-14 2009-11-25 Merck Serono SA Methods of inducing ovulation using a non-polypeptide camp level modulator
WO2009150137A2 (en) 2008-06-10 2009-12-17 Novartis Ag Organic compounds
EP2206499A1 (en) 2004-11-02 2010-07-14 Novartis AG Quinuclidine derivatives and their use as muscarinic m3 receptor antagonists
WO2010088335A1 (en) 2009-01-29 2010-08-05 Novartis Ag Substituted benzimidazoles for the treatment of astrocytomas
EP2253612A1 (en) 2005-04-14 2010-11-24 Novartis AG Organic compounds
EP2270008A1 (en) 2005-05-20 2011-01-05 Novartis AG 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones as lipid kinase and/or pi3 kinases inhibitors
EP2279777A2 (en) 2007-01-10 2011-02-02 Irm Llc Compounds and compositions as channel activating protease inhibitors
EP2281819A1 (en) 2004-01-21 2011-02-09 Novartis AG Benzimidazolyl or benzoxazolyl derivatives
WO2011015652A1 (en) 2009-08-07 2011-02-10 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives as c-met tyrosine kinase modulators
WO2011018454A1 (en) 2009-08-12 2011-02-17 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
EP2286813A2 (en) 2006-01-31 2011-02-23 Novartis AG Use of naphthyridine derivatives as medicaments
WO2011022439A1 (en) 2009-08-17 2011-02-24 Intellikine, Inc. Heterocyclic compounds and uses thereof
WO2011020861A1 (en) 2009-08-20 2011-02-24 Novartis Ag Heterocyclic oxime compounds
EP2292619A1 (en) 2004-10-22 2011-03-09 Novartis AG Purine derivatives for use as adenonsin A-2A receptor agonists
WO2011050325A1 (en) 2009-10-22 2011-04-28 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
US7943658B2 (en) 2007-07-23 2011-05-17 Bristol-Myers Squibb Company Indole indane amide compounds useful as CB2 agonists and method
EP2332933A1 (en) 2007-05-07 2011-06-15 Novartis AG Epithelial sodium channel (ENaC) inhibitors
WO2011113894A1 (en) 2010-03-19 2011-09-22 Novartis Ag Pyridine and pyrazine derivative for the treatment of cf
WO2012034091A1 (en) 2010-09-09 2012-03-15 Irm Llc Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
WO2012035158A1 (en) 2010-09-17 2012-03-22 Novartis Ag Pyrazine derivatives as enac blockers
EP2436686A1 (en) 2005-03-25 2012-04-04 Glaxo Group Limited Pyrimidopyridine compound used as a CSBP/RK/p38 modulator
WO2012022796A3 (en) * 2010-08-20 2012-04-19 Boehringer Ingelheim International Gmbh Novel combinations
EP2444120A1 (en) 2007-12-10 2012-04-25 Novartis AG Spirocyclic amiloride analogues as ENac blockers
WO2012098495A1 (en) * 2011-01-19 2012-07-26 Glenmark Pharmaceuticals Sa Pharmaceutical composition that includes revamilast and a beta-2 agonist
WO2012107500A1 (en) 2011-02-10 2012-08-16 Novartis Ag [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
WO2012116217A1 (en) 2011-02-25 2012-08-30 Irm Llc Compounds and compositions as trk inhibitors
WO2012116237A2 (en) 2011-02-23 2012-08-30 Intellikine, Llc Heterocyclic compounds and uses thereof
EP2532677A1 (en) 2005-10-21 2012-12-12 Novartis AG Human antibodies against il13 and therapeutic uses
WO2013030802A1 (en) 2011-09-01 2013-03-07 Novartis Ag Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
WO2013038373A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
WO2013038378A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
WO2013038362A1 (en) 2011-09-15 2013-03-21 Novartis Ag 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
WO2013038390A1 (en) 2011-09-16 2013-03-21 Novartis Ag N-substituted heterocyclyl carboxamides
WO2013038381A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine/pyrazine amide derivatives
WO2013038386A1 (en) 2011-09-16 2013-03-21 Novartis Ag Heterocyclic compounds for the treatment of cystic fibrosis
WO2013077830A1 (en) * 2011-11-25 2013-05-30 Mahmut Bilgic Synergistilly active combinations of roflumilast and carmoterol
WO2013081565A1 (en) * 2011-11-21 2013-06-06 Mahmut Bilgic Pharmaceutical compositions comprising roflumilast and terbutaline
WO2013140319A1 (en) 2012-03-19 2013-09-26 Novartis Ag Crystalline form of a succinate salt
WO2013149581A1 (en) 2012-04-03 2013-10-10 Novartis Ag Combination products with tyrosine kinase inhibitors and their use
WO2014132220A1 (en) 2013-03-01 2014-09-04 Novartis Ag Solid forms of bicyclic heterocyclic derivatives as pdgf receptor mediators
WO2014151147A1 (en) 2013-03-15 2014-09-25 Intellikine, Llc Combination of kinase inhibitors and uses thereof
WO2015084804A1 (en) 2013-12-03 2015-06-11 Novartis Ag Combination of mdm2 inhibitor and braf inhibitor and their use
WO2015162461A1 (en) 2014-04-24 2015-10-29 Novartis Ag Pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors
WO2015162459A1 (en) 2014-04-24 2015-10-29 Novartis Ag Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors
WO2015162456A1 (en) 2014-04-24 2015-10-29 Novartis Ag Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors
US9174994B2 (en) 2011-11-23 2015-11-03 Intellikine, Llc Enhanced treatment regimens using mTor inhibitors
WO2016011956A1 (en) 2014-07-25 2016-01-28 Novartis Ag Combination therapy
WO2016016822A1 (en) 2014-07-31 2016-02-04 Novartis Ag Combination therapy
EP3603634A1 (en) 2004-05-18 2020-02-05 Novartis AG Pharmaceutical composition containing glycopyrrolate and a beta2 adrenoceptor agonist
WO2020250116A1 (en) 2019-06-10 2020-12-17 Novartis Ag Pyridine and pyrazine derivative for the treatment of cf, copd, and bronchiectasis
WO2021038426A1 (en) 2019-08-28 2021-03-04 Novartis Ag Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY140561A (en) 2002-02-20 2009-12-31 Nycomed Gmbh Dosage form containing pde 4 inhibitor as active ingredient
ES2335498T3 (en) 2003-03-10 2010-03-29 Nycomed Gmbh NEW PROCESS FOR THE PREPARATION OF REFLUMILAST.
JPWO2004087151A1 (en) * 2003-03-31 2006-06-29 協和醗酵工業株式会社 Pharmaceutical composition
EA009646B1 (en) * 2003-05-30 2008-02-28 Рэнбакси Лабораториз Лтд. Substituted pyrrole derivatives and their use thereof as hmg-coa inhibitors
WO2006094640A2 (en) * 2005-03-04 2006-09-14 F.Hoffmann-La Roche Ag Roflumilast and integrin inhibitor combination and method of treatment
US8663694B2 (en) * 2005-03-16 2014-03-04 Takeda Gmbh Taste masked dosage form containing roflumilast
JP2009514851A (en) * 2005-11-08 2009-04-09 ランバクシー ラボラトリーズ リミテッド (3R, 5R) -7- [2- (4-Fluorophenyl) -5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl] -pyrrol-1-yl] -3,5 -Preparation of dihydroxy-heptanoic acid hemi-calcium salt
TW200744583A (en) * 2006-03-14 2007-12-16 Ranbaxy Lab Ltd Statin stabilizing dosage formulations
US20100029681A1 (en) * 2006-05-26 2010-02-04 Hassan Pajouhesh Heterocyclic compounds as calcium channel blockers
TW200815054A (en) * 2006-06-19 2008-04-01 Otsuka Pharma Co Ltd Methods of using a thiazole derivative
BRPI0714361A2 (en) * 2006-07-14 2013-03-26 Ranbaxy Lab Ltd crystalline polymorph, pharmaceutical composition containing the same, method of preparation and method of treatment
CA2796826A1 (en) 2010-05-10 2011-11-17 Gilead Sciences, Inc. Bifunctional quinoline derivatives
UY33373A (en) 2010-05-10 2011-12-30 Gilead Sciences Inc ? Bifunctional pyrazolopyridine compounds, their use in therapy and compositions that comprise them ?.
CN103830236A (en) * 2012-11-21 2014-06-04 岳阳新华达制药有限公司 Bambuterol hydrochloride and roflumilast compound preparation and its preparation method
HUE052275T2 (en) * 2013-01-28 2021-04-28 Incozen Therapeutics Pvt Ltd Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast n-oxide
JOP20190219A1 (en) * 2017-05-09 2019-09-22 Cardix Therapeutics LLC Pharmaceutical compositions and methods of treating cardiovascular diseases
CA3161376A1 (en) 2019-12-18 2021-06-24 Anthony P. FORD Methods for improving neurological diseases and disorders
US20250051277A1 (en) 2021-10-29 2025-02-13 Sensorium Therapeutics, Inc. Delivery of therapeutic alkaloid compounds
WO2025188807A1 (en) * 2024-03-06 2025-09-12 Curasen Therapeutics, Inc. Combination compositions and methods of use

Family Cites Families (180)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1545687B2 (en) 1964-09-05 1975-09-04 Hoechst Ag, 6000 Frankfurt 1- (5'-Oxohexyl) -3,7-dimethylxanthine and process for its preparation
CA924721A (en) 1969-06-16 1973-04-17 Chasin Mark Hydrazines and hydrazones of pyrazolopyridine carboxylic acids and esters
GB1361441A (en) 1970-05-13 1974-07-24 Sandoz Ltd Benzonaphthyridine derivatives
BE791025A (en) * 1971-11-19 1973-05-07 Allen & Hanburys Ltd HETEROCYCLIC COMPOUNDS
JPS5229318B2 (en) 1972-03-30 1977-08-01
GB1457873A (en) * 1973-01-04 1976-12-08 Allen & Hanburys Ltd Imidazotriazines
DE2462367A1 (en) 1974-01-22 1976-11-11 Wuelfing J A Fa 7-(Oxo-alkyl)-1,3-dialkyl-xanthines - as agents for increasing blood flow in skeletal muscles
DE2413935A1 (en) 1974-03-20 1975-10-16 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE
FR2390164A1 (en) * 1977-05-13 1978-12-08 Blanie Paul Anti:asthmatic methyl-xanthine compsns. - synergised with beta-sympathomimetic agents
DE2847693A1 (en) 1978-11-03 1980-05-22 Hoechst Ag METHOD FOR PRODUCING PYRIMIDO- (6,1-A) -ISOCHINOLIN-2-ONES
FR2531085A1 (en) 1982-07-28 1984-02-03 Adir NOVEL XANTHINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING SAME
ZW6584A1 (en) * 1983-04-18 1985-04-17 Glaxo Group Ltd Phenethanolamine derivatives
US4552891A (en) 1983-09-13 1985-11-12 Eli Lilly And Company Benzothiophene derivatives
GB8406906D0 (en) 1984-03-16 1984-04-18 Akzo Nv Benzo-thiazole and benzothiophene derivatives
DK159431C (en) 1984-05-10 1991-03-18 Byk Gulden Lomberg Chem Fab 6-PHENYL-3 (2H) -PYRIDAZINONES, METHOD OF PREPARING THEREOF, PHARMACEUTICALS CONTAINING THESE AND USING THE COMPOUNDS FOR THE PREPARATION OF MEDICINAL PRODUCTS
GB8800397D0 (en) 1988-01-08 1988-02-10 Sandoz Ltd Improvements in/relating to organic compounds
US5142096A (en) 1988-03-31 1992-08-25 Kyowa Hakko Kogyo Co., Ltd. 2,4-dihydroxy-3,5,6-trimethylbenzoic acid compounds
GB8906792D0 (en) 1989-03-23 1989-05-10 Beecham Wuelfing Gmbh & Co Kg Treatment and compounds
DE59009351D1 (en) 1989-04-17 1995-08-03 Byk Gulden Lomberg Chem Fab NEW ARYLPYRIDAZINE, THEIR PRODUCTION, USE AND MEDICINAL PRODUCTS CONTAINING IT.
GB9413975D0 (en) 1994-07-11 1994-08-31 Fujisawa Pharmaceutical Co New heterobicyclic derivatives
RU2104306C1 (en) 1989-11-13 1998-02-10 Пфайзер Инк. Method of synthesis of optically active (2s)- or (2r)-endo-bicyclo-[2,2,1]-heptane-2-ol, method of synthesis of 5-(3-[(2r)-exo-bicyclo-[2,2,1]-hept-2-yloxy]-4-methoxyphenyl)- -3,4,5,6-tetrahydropyrimidine-2(1h)-one
GB8929208D0 (en) 1989-12-27 1990-02-28 Almirall Lab New xanthine derivatives
MY105344A (en) 1990-05-16 1994-09-30 Byk Gulden Lomberg Chemische Fabrik New sulphonyl compounds
ES2094772T3 (en) 1990-06-01 1997-02-01 Kyowa Hakko Kogyo Kk DERIVATIVES OF IMIDAZONAFTIRIDINAS.
MA22668A1 (en) 1990-07-10 1993-07-01 Smithkline Beecham Corp PROCESS FOR THE PREPARATION OF OXAMIDES.
US5124455A (en) 1990-08-08 1992-06-23 American Home Products Corporation Oxime-carbamates and oxime-carbonates as bronchodilators and anti-inflammatory agents
EP0553174B1 (en) 1990-10-16 1998-07-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Arylpyridazinones
GB9027055D0 (en) 1990-12-13 1991-02-06 Sandoz Ltd Organic compounds
JPH04234389A (en) 1990-12-28 1992-08-24 Sapporo Breweries Ltd Naphthyridine derivative and antiulcer agent containing the derivative as active component
IE71647B1 (en) 1991-01-28 1997-02-26 Rhone Poulenc Rorer Ltd Benzamide derivatives
AU650953B2 (en) 1991-03-21 1994-07-07 Novartis Ag Inhaler
IE73235B1 (en) 1991-03-25 1997-05-21 Akzo Nv 4-aryl-thiazole or imidazole derivatives
US5795564A (en) 1991-04-05 1998-08-18 Sepracor, Inc. Methods and compositions for treating pulmonary disorders using optically pure (R,R)-formoterol
WO1992019602A1 (en) 1991-04-26 1992-11-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Novel pyridazines
US5191084A (en) 1991-05-01 1993-03-02 American Home Products Corporation Phenyl pyrazolidinones as bronchodilators and anti-inflammatory agents
GB9116039D0 (en) 1991-07-25 1991-09-11 Ucb Sa Substituted cyclopropylamino-1,3,5-triazines
ZA927755B (en) 1991-10-09 1994-04-08 Syntex Inc Pyrido pyridazinone and pyridazinthione compounds
AU3481593A (en) 1992-01-29 1993-09-01 Smithkline Beecham Corporation N-(3-phenylpropyl)oxamic acid, oxamate, and oxamide derivatives
WO1993015044A1 (en) 1992-01-29 1993-08-05 Smithkline Beecham Corporation N-benzyloxamic acid, oxamate, and oxamide derivatives and their use as tnf and pde iv inhibitors
JP3042156B2 (en) 1992-02-20 2000-05-15 田辺製薬株式会社 Naphthalene derivative, its production method and its synthetic intermediate
GB9204808D0 (en) 1992-03-04 1992-04-15 Rhone Poulenc Rorer Ltd Novel compositions of matter
US5264437A (en) 1992-03-20 1993-11-23 Syntex (U.S.A.) Inc. Optionally substituted pyrido[2,3-d]pyridine-2,4(1H,3H)-diones and pyrido[2,]pyrimidine-2(1H,3H)-ones
JP3251587B2 (en) 1992-04-02 2002-01-28 スミスクライン・ビーチャム・コーポレイション Compounds useful for treating inflammatory diseases and inhibiting tumor necrosis factor production
WO1993019747A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
JP3199380B2 (en) 1992-04-02 2001-08-20 スミスクライン・ビーチャム・コーポレイション Compound
US5552438A (en) * 1992-04-02 1996-09-03 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
ES2102036T3 (en) 1992-06-15 1997-07-16 Celltech Therapeutics Ltd DERIVATIVES WITH GROUP PHENYL TRISUSTITUTED USED AS SELECTIVE INHIBITORS OF PHOSPHODIESTERASE IV.
CZ14795A3 (en) 1992-07-28 1996-07-17 Rhone Poulenc Rorer Ltd Benzene derivative containing phenyl group bound to aryl or heteroaryl fraction through an aliphatic or hetero atom containing group, process of its preparation and pharmaceutical composition containing thereof
NZ257955A (en) 1992-12-02 1996-05-28 Pfizer Catechol diethers pharmaceutical compositions
TW263495B (en) 1992-12-23 1995-11-21 Celltech Ltd
GB9304920D0 (en) 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
GB9304919D0 (en) 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
US5455252A (en) 1993-03-31 1995-10-03 Syntex (U.S.A.) Inc. Optionally substituted 6,8-quinolines
GB9309324D0 (en) 1993-05-06 1993-06-16 Bayer Ag Venzofuranyl-and-thiophenyl-alkanecarboxyclic acids derivatives
GB9311282D0 (en) 1993-06-01 1993-07-21 Rhone Poulenc Rorer Ltd New compositions of matter
JPH0710875A (en) 1993-06-21 1995-01-13 Green Cross Corp:The Selective phosphodiesterase IV inhibitors
DE59410119D1 (en) * 1993-07-02 2002-06-20 Byk Gulden Lomberg Chem Fab FLUORALKOXY SUBSTITUTED BENZAMIDES AND THEIR USE AS CYCLIC NUCLEOTIDE PHOSPHODIESTERASE INHIBITORS
HUT74170A (en) 1993-07-06 1996-11-28 Pfizer Bicyclic tetrahydro pyrazolopyridines
GB9315595D0 (en) 1993-07-28 1993-09-08 Res Inst Medicine Chem New compounds
JP3775685B2 (en) 1993-07-28 2006-05-17 ローン−プーラン・ロレ・リミテツド PDE IV and compounds as TNF inhibitors
WO1995003794A1 (en) 1993-07-30 1995-02-09 Smithkline Beecham Corporation 3-cyano-3-(3,4-disubstituted)phenylcyclohexyl-1-carboxylates
DE4495960D2 (en) 1993-08-19 1996-08-22 Block Medtech Gmbh Phoropter
EP0714397A1 (en) 1993-08-19 1996-06-05 Smithkline Beecham Corporation Phenethylamine compounds
US5665754A (en) 1993-09-20 1997-09-09 Glaxo Wellcome Inc. Substituted pyrrolidines
WO1995009836A1 (en) 1993-10-01 1995-04-13 Smithkline Beecham Corporation Cyanocyclohexane compounds, compositions, and uses thereof
EP0722322B1 (en) 1993-10-01 2001-11-14 Smithkline Beecham Corporation Compounds, compositions and treatment of allergies and inflammation therewith
EP0727990B1 (en) 1993-10-01 2001-06-13 Smithkline Beecham Corporation Compounds, compositions and treatment of allergies and inflammation
WO1995009623A1 (en) 1993-10-01 1995-04-13 Smithkline Beecham Corporation Anti-allergic, anti-inflammatory compounds, compositions and uses
GB9322828D0 (en) 1993-11-05 1993-12-22 Sandoz Ltd Organic compounds
JP2818820B2 (en) 1993-11-26 1998-10-30 ファイザー・インク． 3-Aryl-2-isoxazolines as anti-inflammatory agents
US5502072A (en) 1993-11-26 1996-03-26 Pfizer Inc. Substituted oxindoles
CN1046274C (en) 1993-11-26 1999-11-10 辉瑞大药厂 Isoxazoline compounds used as anti-inflammatory agents
EP0738268B1 (en) 1993-12-22 2004-03-03 Celltech R&amp;D Limited Trisubstituted phenyl derivatives, processes for their preparation and their use as phosphodiesterase (type iv) inhibitors
GB9326600D0 (en) 1993-12-22 1994-03-02 Celltech Ltd Chemical compounds
US5508300A (en) 1994-01-14 1996-04-16 Pfizer Inc. Dihydro pyrazolopyrroles, compositions and use
GB9401460D0 (en) 1994-01-26 1994-03-23 Rhone Poulenc Rorer Ltd Compositions of matter
EP0745063B1 (en) 1994-02-17 1999-03-24 American Home Products Corporation Substituted biphenyl derivatives as phosphodiesterase inhibitors
CA2143143A1 (en) 1994-03-08 1995-09-09 Toshihiko Tanaka 3-phenylpyrrolidine derivatives
GB9404706D0 (en) 1994-03-11 1994-04-27 Smithkline Beecham Corp Compounds
WO1995027692A1 (en) 1994-04-08 1995-10-19 Smithkline Beecham Corporation Subtituted biphenyl tnf inhibitors
GB9410877D0 (en) 1994-05-31 1994-07-20 Bayer Ag Heterocyclycarbonyl substituted benzoduranyl-and-thiophenyl-alkanecarboxyclic acid derivatives
ES2127966T3 (en) 1994-05-31 1999-05-01 Bayer Ag DERIVATIVES OF AMINO-BENZOFURILO AND -BENZOTIENILO.
HRP950288A2 (en) 1994-05-31 1997-08-31 Bayer Ag Oxalylamino-benzofuran- and benzothienyl-derivatives
US5786354A (en) 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
GB9412573D0 (en) 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
CA2193725A1 (en) 1994-06-24 1996-01-04 David Cavalla Aryl derivative compounds and uses to inhibit phosphodiesterase iv acti vity
DK0772610T3 (en) 1994-07-22 2001-01-29 Byk Gulden Lomberg Chem Fab dihydrobenzofuranes
WO1996006843A1 (en) 1994-08-29 1996-03-07 Yamanouchi Pharmaceutical Co., Ltd. Novel naphthyridine derivative and medicinal composition thereof
US5602110A (en) * 1994-08-31 1997-02-11 Case Western Reserve University Method and composition for treating cystic fibrosis
AU699489B2 (en) 1994-10-12 1998-12-03 Euro-Celtique S.A. Novel benzoxazoles
FR2725719B1 (en) 1994-10-14 1996-12-06 Jouveinal Inst Rech DIAZEPINO-INDOLES IV PHOSPHODIESTERASE INHIBITORS
KR970707124A (en) 1994-10-20 1997-12-01 스피겔 알렌 제이 Bicyclic tetrahydropyrazolopyridines and their use as medicaments (BICYCLIC TETRAHYDRO PYRAZOLOPYRIDINES AND THEIR USE AS MEDICAMENTS)
US5703098A (en) 1994-12-30 1997-12-30 Celgene Corporation Immunotherapeutic imides/amides
DE19510965A1 (en) 1995-03-24 1996-09-26 Asta Medica Ag New pyrido / 3,2-e / pyrazinone with anti-asthmatic activity and process for their preparation
TW424087B (en) 1995-04-06 2001-03-01 Janssen Pharmaceutica Nv 1,3-dihydro-1-(phenylalkenyl)-2H-imidazol-2-one derivatives
TW375612B (en) 1995-04-06 1999-12-01 Janssen Pharmaceutica Nv 1,3-dihydro-2H-imidazol-2-one derivatives for the treatment of disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase type IV, preparation thereof and pharmaceutical composition containing the same
DE19514568A1 (en) 1995-04-20 1996-10-24 Merck Patent Gmbh Arylalkyl pyridazinones
WO1996035683A1 (en) 1995-05-09 1996-11-14 Nippon Kayaku Kabushiki Kaisha Novel physiologically active na23063 analogues, process for producing the same and use of the same
DK0828727T3 (en) 1995-05-18 2003-04-22 Altana Pharma Ag Cyclohexyldihydrobenzofurans
ATE231501T1 (en) 1995-05-18 2003-02-15 Altana Pharma Ag PHENYLDIHYDROBENZOFURANES
WO1996036595A1 (en) 1995-05-19 1996-11-21 Chiroscience Limited 3,4-disubstituted-phenylsulphonamides and their therapeutic use
AU5772196A (en) 1995-05-19 1996-11-29 Chiroscience Limited 3,4-disubstituted-phenylsulphonamides and their therapeutic use
JPH10147585A (en) 1996-11-19 1998-06-02 Kyowa Hakko Kogyo Co Ltd Oxygen-containing heterocyclic compound
AU5772396A (en) 1995-05-19 1996-11-29 Chiroscience Limited 3,4-disubstituted-phenylsulphonamides and their therapeutic use
AU692104B2 (en) 1995-05-19 1998-05-28 Darwin Discovery Limited Xanthines and their therapeutic use
AR004471A1 (en) 1995-05-31 1998-12-16 Smithkline Beecham Corp CYCLOHEXAN-1-OL-4,4-DISSTITUTED COMPOUNDS, USEFUL IN THE TREATMENT OF ALLERGIC AND INFLAMMATORY DISEASES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM
ES2172583T3 (en) 1995-06-06 2002-10-01 Pfizer 5,6-DIHIDRO-9H-PIRAZOL (3,4-C) -1,2,4-TRIAZOL (4,3-ALPHA) TRICICLIC PYRIDINS.
ATE237589T1 (en) 1995-06-07 2003-05-15 Pfizer CATECHOL DIETHER DERIVATIVES USABLE AS PHARMACEUTICAL AGENTS
IL118469A (en) 1995-06-15 2000-08-13 Tanabe Seiyaku Co Naphthalene derivatives their preparation and intermediates thereof
AU6526896A (en) 1995-07-22 1997-02-18 Rhone-Poulenc Rorer Limited Substituted aromatic compounds and their pharmaceutical use
CA2227237C (en) 1995-07-26 2005-12-13 Pfizer Inc. N-(aroyl)glycine hydroxamic acid derivatives and related compounds
PT841929E (en) 1995-08-02 2003-09-30 Darwin Discovery Ltd QUINOLONES AND THEIR THERAPEUTIC UTILIZATION
US5728845A (en) 1995-08-29 1998-03-17 Celgene Corporation Immunotherapeutic nitriles
US5728844A (en) 1995-08-29 1998-03-17 Celgene Corporation Immunotherapeutic agents
AU7154596A (en) 1995-09-08 1997-03-27 St. Jude Children's Research Hospital Virus protein purification from virosomes
DE19533975A1 (en) 1995-09-14 1997-03-20 Merck Patent Gmbh Arylalkyl diazinones
DE69625326T2 (en) 1995-09-29 2003-09-18 Japan Science And Technology Corp., Kawaguchi ANTHRACYCLINE DERIVATIVES AND MEDICAL PREPARATIONS CONTAINING THEM
GB9523267D0 (en) 1995-11-14 1996-01-17 Sandoz Ltd Organic compounds
NZ322197A (en) 1995-11-21 1999-02-25 Yamanouchi Pharma Co Ltd Pyrido[2,3-d] pyrimidine derivatives and pharmaceutical compositions thereof
CZ292443B6 (en) 1995-12-05 2003-09-17 Darwin Discovery Limited Benzofuran sulfonamide pharmaceutical preparation containing thereof and its use
WO1997022586A1 (en) 1995-12-15 1997-06-26 Merck Frosst Canada Inc. Tri-aryl ethane derivatives as pde iv inhibitors
GB9603723D0 (en) 1996-02-22 1996-04-24 Merck & Co Inc Diphenyl pyridyl derivatives as pde iv inhibitors
GB9526246D0 (en) 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9526245D0 (en) 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9526558D0 (en) 1995-12-27 1996-02-28 Fujisawa Pharmaceutical Co Heterobicyclic derivatives
PT871439E (en) 1996-01-02 2004-08-31 Aventis Pharma Inc SUBSTITUTED HYDROXYLIC ACID COMPOUNDS (ARYLETHYLETHYLRENE ARYLMETHYL OR HETEROYARMETHYL)
DE19601938A1 (en) 1996-01-12 1997-07-17 Schering Ag New phosphodiesterase inhibitors
BR9707233A (en) 1996-01-31 1999-07-20 Byk Gulden Lomberg Chem Fab Phenanthridines
CA2241891A1 (en) 1996-02-21 1997-08-21 Darwin Discovery Limited Quinolones and their therapeutic use
WO1997030999A1 (en) 1996-02-21 1997-08-28 Darwin Discovery Limited Quinolones and their therapeutic use
GB9604926D0 (en) 1996-03-08 1996-05-08 Sandoz Ltd Organic compounds
SI0889886T1 (en) 1996-03-26 2003-02-28 Altana Pharma Ag Novel phenanthridines substituted in the 6 position
FR2746800B1 (en) 1996-03-29 1998-06-05 Jouveinal Inst Rech DIAZEPINO-INDOLES PHOSPHODIESTERASE INHIBITORS 4
FR2754260B1 (en) 1996-10-04 1998-10-30 Adir NOVEL SUBSTITUTED DERIVATIVES OF BIPHENYL OR PHENYLPYRIDINE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
ES2187775T3 (en) 1996-05-15 2003-06-16 Altana Pharma Ag IMIDAZOPIRIDINS.
AU722662B2 (en) 1996-05-20 2000-08-10 Darwin Discovery Limited Quinoline sulfonamides as TNF inhibitors and as PDE-IV inhibitors
CZ296163B6 (en) 1996-05-20 2006-01-11 TNF and/or PDE-IV inhibiting quinoline carboxamides
JP4017214B2 (en) 1996-06-11 2007-12-05 興和創薬株式会社 5-Phenyl-3-pyridazinone derivatives
JP4373497B2 (en) 1996-06-19 2009-11-25 ローン−プーラン・ロレ・リミテツド Substituted azabicyclo compounds and their use as inhibitors of TNF and cyclic AMP phosphodiesterase production
JPH1072415A (en) 1996-06-26 1998-03-17 Nikken Chem Co Ltd 3-anilino-2-cycloalkenone derivatives
EP0816357B1 (en) 1996-06-27 2002-01-09 Pfizer Inc. Substituted indazole derivatives
DE19628621A1 (en) 1996-07-16 1998-01-22 Byk Gulden Lomberg Chem Fab New 4-substituted benzofuran compounds are phosphodiesterase IV inhibitors
DE19628622A1 (en) 1996-07-16 1998-01-22 Byk Gulden Lomberg Chem Fab New chromene derivatives useful as phosphodiesterase IV inhibitors
DE69730980T2 (en) 1996-07-31 2006-02-23 Nikken Chemicals Co., Ltd. 6-PHENYLTETRAHYDRO-1,3-OXAZIN-2-ON DERIVATIVES AND MEDICAL COMPOSITIONS CONTAINING THEY
AU3899097A (en) 1996-08-05 1998-02-25 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted aromatic compounds
NZ334148A (en) 1996-08-12 2001-12-21 Celgene Corp 3-Substituted phenyl-ethyl or ethenyl derivatives terminated with a nitrile, alkane, carboxyl or carbamoyl group useful to reduce cytokine levels
DE19632549A1 (en) 1996-08-13 1998-02-19 Merck Patent Gmbh Arylalkanoylpyridazines
JP4309475B2 (en) 1996-08-19 2009-08-05 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング New benzofuran-4-carboxamide
AU4298997A (en) 1996-08-26 1998-03-19 Byk Gulden Lomberg Chemische Fabrik Gmbh Thiazole derivatives useful as selective inhibitors of pde-iv
PT920426E (en) 1996-08-26 2004-02-27 Altana Pharma Ag NEW TIAZOLE DERIVATIVES WITH PHOSPHODIESTERASE INHIBITOR EFFECT
AU4015497A (en) 1996-08-26 1998-03-19 Byk Gulden Lomberg Chemische Fabrik Gmbh Thiazole derivatives useful as selective inhibitors of pde-iv
EP0924204A4 (en) 1996-08-27 2002-10-23 Nikken Chemicals Co Ltd 2-PHENYLMORPHOLIN-5-ONE DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
EA002113B1 (en) 1996-09-04 2001-12-24 Пфайзер Инк. Indazole derivatives and their use as inhibitors of phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf)
DE19636150A1 (en) 1996-09-06 1998-03-12 Asta Medica Ag N-substituted indole-3-glyoxylamides with antiasthmatic, antiallergic and immunosuppressive / immunomodulating effects
US5744473A (en) 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
FR2753969B1 (en) 1996-09-27 1998-10-30 Adir NOVEL FLAVON DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
ATE229527T1 (en) 1996-10-04 2002-12-15 Kyorin Seiyaku Kk PYRAZOLOPYRIDYLPYRAZINONE DERIVATIVES AND A METHOD FOR THE PRODUCTION THEREOF
GB9622386D0 (en) 1996-10-28 1997-01-08 Sandoz Ltd Organic compounds
PL189641B1 (en) * 1996-11-11 2005-09-30 Altana Pharma Ag Benzonaphtyridines useful in particular in treating bronchial diseases
US6054475A (en) 1996-11-20 2000-04-25 Byk Gulden Lomberg Chemische Fabrik Gmbh Substituted dihydrobenzofuran-based phosphodiesterase 4 inhibitors useful for treating airway disorders
ID19155A (en) 1996-12-13 1998-06-18 Tanabe Seiyaku Co PYRIDINES, THEIR PRODUCTS AND THE INTERMEDIETS FOR THE PRODUCTION
BR9806752A (en) 1997-01-15 2000-03-14 Byk Gulden Lomberg Chem Fab Phthalazinones.
ES2302350T3 (en) * 1997-02-28 2008-07-01 Nycomed Gmbh SYNERGIC COMBINATION OF PDE INHIBITORS AND ADENYLATOCICLASS AGONISTS OR GUANILILCICLASA AGONISTS.
SI0968211T1 (en) 1997-03-07 2004-02-29 Altana Pharma Ag Tetrazole derivatives
AU738037B2 (en) 1997-04-04 2001-09-06 Pfizer Products Inc. Nicotinamide derivatives
ES2193539T3 (en) 1997-06-03 2003-11-01 Altana Pharma Ag BENZONAFTIRIDINS.
KR19990001101A (en) 1997-06-12 1999-01-15 손경식 Catechol amino acid derivatives, preparation methods thereof and pharmaceutical compositions containing the same
WO1999005112A1 (en) 1997-07-25 1999-02-04 Byk Gulden Lomberg Chemische Fabrik Gmbh Substituted 6-alkylphenanthridines
PT998460E (en) 1997-07-25 2004-07-30 Altana Pharma Ag NEW TETRAZOLE DERIVATIVES
JP2001510827A (en) 1997-07-25 2001-08-07 ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング Substituted 6-phenylphenanthridine
ES2137113B1 (en) 1997-07-29 2000-09-16 Almirall Prodesfarma Sa NEW DERIVATIVES OF TRIAZOLO-PIRIDAZINAS HETEROCICLICOS.
US6254882B1 (en) * 1997-09-16 2001-07-03 Sepracor Inc. Methods and compositions for treating pulmonary disorders using optically pure (S)—salmeterol
US6020339A (en) 1997-10-03 2000-02-01 Merck & Co., Inc. Aryl furan derivatives as PDE IV inhibitors
ATE432078T1 (en) * 1997-11-13 2009-06-15 Mowycal Lending Llc SMALL PEPTIDES AND METHODS FOR TREATING ASTHMA AND INFLAMMATION
AU1760399A (en) 1997-12-15 1999-07-05 Byk Gulden Lomberg Chemische Fabrik Gmbh New phthalazinones
WO1999031090A1 (en) 1997-12-15 1999-06-24 Byk Gulden Lomberg Chemische Fabrik Gmbh Dihydrobenzofurans
DK1075477T3 (en) * 1998-05-05 2003-06-30 Altana Pharma Ag New benzonaphthyridine N-oxides
BR9913152A (en) 1998-08-26 2001-05-15 Smithkline Beecham Corp Therapies for the treatment of lung diseases
US6303145B2 (en) 1999-05-10 2001-10-16 Sepracor Inc. (S,R) formoterol methods and compositions

Cited By (114)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001090076A1 (en) * 2000-05-25 2001-11-29 Merck Frosst Canada & Co. Fluoroalkoxy-substituted benzamide dichloropyridinyl n-oxide pde4 inhibitor
US7442836B2 (en) 2001-02-14 2008-10-28 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
US7442837B2 (en) 2001-02-14 2008-10-28 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
US7442719B2 (en) 2001-02-14 2008-10-28 Glaxo Group Limited Methods using phenethanolamine derivatives for treatment of respiratory diseases
US7135600B2 (en) 2001-02-14 2006-11-14 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
US7045658B2 (en) 2001-03-22 2006-05-16 Glaxo Group Limited Formailide derivatives as beta2-adrenoreceptor agonists
US7105667B2 (en) 2001-05-01 2006-09-12 Bristol-Myers Squibb Co. Fused heterocyclic compounds and use thereof
EP1389468A4 (en) * 2001-05-23 2007-01-10 Tanabe Seiyaku Co COMPOSITIONS PROMOTING THE GUISON OF A BONE FRACTURE
EP1389467A4 (en) * 2001-05-23 2007-01-10 Tanabe Seiyaku Co THERAPEUTIC COMPOSITIONS FOR REPAIRING CHONDROPATHY
US7776895B2 (en) 2001-09-14 2010-08-17 Glaxo Group Limited Inhalation devices for delivering phenethanolamine derivatives for the treatment of respiratory diseases
US7439393B2 (en) 2001-09-14 2008-10-21 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
US8198483B2 (en) 2001-09-14 2012-06-12 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
USRE44874E1 (en) 2001-09-14 2014-04-29 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
EP2042168A1 (en) 2001-09-14 2009-04-01 Glaxo Group Limited Inhalation device comprising phenethanolamine derivatives for treatment of respiratory diseases
US7982067B2 (en) 2001-09-14 2011-07-19 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
US7361787B2 (en) 2001-09-14 2008-04-22 Glaxo Group Limited Phenethanolamine derivatives for treatment of respiratory diseases
CN100496607C (en) * 2001-09-19 2009-06-10 尼科梅德有限责任公司 Combination of a NSAID and a PDE-4 inhibitor
EA007736B1 (en) * 2001-09-19 2006-12-29 Алтана Фарма Аг Combination of a pde inhibitor and leukotriene receptor antagonists
EA008108B1 (en) * 2001-09-19 2007-04-27 Алтана Фарма Аг Combination of a nsaid and a pde-4 inhibitors
US8242146B2 (en) 2001-09-19 2012-08-14 Nycomed Gmbh Combination of a NSAID and a PDE-4 inhibitor
WO2003024489A3 (en) * 2001-09-19 2003-09-18 Altana Pharma Ag Combination of a nsaid and a pde-4 inhibitor
WO2003024488A3 (en) * 2001-09-19 2003-09-04 Altana Pharma Ag Combination of a pde inhibitor and a leukotriene receptor antagonist
WO2003030939A1 (en) * 2001-10-05 2003-04-17 Glaxo Group Limited Therapies for treating respiratory diseases
WO2003047578A1 (en) * 2001-12-07 2003-06-12 Pfizer Limited Combination of a selective pde4 inhibitor and an adrenergic beta-2 receptor agonist
EP1908463A3 (en) * 2001-12-14 2009-11-25 Merck Serono SA Methods of inducing ovulation using a non-polypeptide camp level modulator
US7271197B2 (en) 2002-04-25 2007-09-18 Glaxo Group Limited Phenethanolamine derivatives
US7402598B2 (en) 2002-07-25 2008-07-22 Glaxo Group Limited Arylethanolamine β2-adrenoreceptor agonist compounds
US6822114B1 (en) 2002-10-08 2004-11-23 Albemarle Corporation Process for production of fluoroalkoxy-substituted benzamides and their intermediates
US7442839B2 (en) 2002-10-28 2008-10-28 Glaxo Group Limited Phenethanolamine derivative for the treatment of respiratory diseases
HRP20050579B1 (en) * 2002-11-27 2014-01-31 Takeda Gmbh New synergistic combination comprising roflumilast and formoterol
AU2003288169B8 (en) * 2002-11-27 2010-08-26 Astrazeneca Ab Synergistic combination comprising roflumilast and (R,R) -formoterol
EA009935B1 (en) * 2002-11-27 2008-04-28 Никомед Гмбх New synergistic combination comprising roflumilast and formoterol
EA009990B1 (en) * 2002-11-27 2008-04-28 Никомед Гмбх Synergistic combination comprising roflumilast and (r,r) -formoterol
WO2004047829A1 (en) * 2002-11-27 2004-06-10 Altana Pharma Ag New synergistic combination comprising roflumilast and formoterol
WO2004047828A1 (en) * 2002-11-27 2004-06-10 Altana Pharma Ag Synergistic combination compresing roflumilas and (r.r) -formoterol
KR101071798B1 (en) * 2002-11-27 2011-10-11 니코메드 게엠베하 New synergistic combination comprising roflumilast and formoterol
HRP20050580B1 (en) * 2002-11-27 2014-04-11 Takeda Gmbh THE SYNERGISTIC EFFECT OF ROFLUMILAST AND (R, R) -FORMOTEROL COMBINATION
NO334148B1 (en) * 2002-11-27 2013-12-16 Takeda Gmbh Synergistic combination including roflumilast and (R, R) formoterol
NO334247B1 (en) * 2002-11-27 2014-01-20 Takeda Gmbh Medication comprising roflumilast in combination with formoterol
JP2006508994A (en) * 2002-11-27 2006-03-16 アルタナ　ファルマ　アクチエンゲゼルシャフト A novel synergistic combination containing roflumilast and formoterol
AU2003288169B2 (en) * 2002-11-27 2010-01-07 Astrazeneca Ab Synergistic combination comprising roflumilast and (R,R) -formoterol
AU2003292120B2 (en) * 2002-11-27 2010-01-21 Astrazeneca Ab New synergistic combination comprising roflumilast and formoterol
JP2006508993A (en) * 2002-11-27 2006-03-16 アルタナ　ファルマ　アクチエンゲゼルシャフト Novel synergistic combination containing roflumilast and (R, R) -formoterol
WO2004062671A3 (en) * 2003-01-14 2005-01-27 Altana Pharma Ag Pde4 inhibitors for the treatment of neoplasms of lymphoid cells
US7538127B2 (en) 2003-02-14 2009-05-26 Glaxo Group Limited Medicinal compounds
US7294650B2 (en) 2003-12-17 2007-11-13 Glaxo Group Limited Benzothiophen and thiochrone containing phenethanolamine derivatives for the treatment of respiratory disorders
EP2281819A1 (en) 2004-01-21 2011-02-09 Novartis AG Benzimidazolyl or benzoxazolyl derivatives
EP3603634A1 (en) 2004-05-18 2020-02-05 Novartis AG Pharmaceutical composition containing glycopyrrolate and a beta2 adrenoceptor agonist
EP2292619A1 (en) 2004-10-22 2011-03-09 Novartis AG Purine derivatives for use as adenonsin A-2A receptor agonists
EP2206499A1 (en) 2004-11-02 2010-07-14 Novartis AG Quinuclidine derivatives and their use as muscarinic m3 receptor antagonists
EP2305659A1 (en) 2004-11-29 2011-04-06 Novartis AG 5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
WO2006056471A1 (en) 2004-11-29 2006-06-01 Novartis Ag 5-hydroxy-benzothiazole derivatives having beta-2-adrenorecptor agonist activity
EP2447266A1 (en) 2005-03-25 2012-05-02 Glaxo Group Limited Pyrimidopyridine compound used as a CSBP/RK/p38 modulator
EP2436686A1 (en) 2005-03-25 2012-04-04 Glaxo Group Limited Pyrimidopyridine compound used as a CSBP/RK/p38 modulator
EP2253612A1 (en) 2005-04-14 2010-11-24 Novartis AG Organic compounds
EP2270008A1 (en) 2005-05-20 2011-01-05 Novartis AG 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones as lipid kinase and/or pi3 kinases inhibitors
EP2292617A1 (en) 2005-05-20 2011-03-09 Novartis AG 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones as lipid kinase and/or pi3 kinase inhibitors
EP2532679A1 (en) 2005-10-21 2012-12-12 Novartis AG Human antibodies against il13 and therapeutic uses
EP2532677A1 (en) 2005-10-21 2012-12-12 Novartis AG Human antibodies against il13 and therapeutic uses
WO2007071400A1 (en) 2005-12-22 2007-06-28 Novartis Ag Pyrazine derivatives as epithelial sodium channel blocker
EP2286813A2 (en) 2006-01-31 2011-02-23 Novartis AG Use of naphthyridine derivatives as medicaments
WO2007121920A2 (en) 2006-04-21 2007-11-01 Novartis Ag Purine derivatives for use as adenosin a2a receptor agonists
EP2322525A1 (en) 2006-04-21 2011-05-18 Novartis AG Purine derivatives for use as adenosin A2A receptor agonists
WO2008037477A1 (en) 2006-09-29 2008-04-03 Novartis Ag Pyrazolopyrimidines as p13k lipid kinase inhibitors
WO2008052734A1 (en) 2006-10-30 2008-05-08 Novartis Ag Heterocyclic compounds as antiinflammatory agents
EP2279777A2 (en) 2007-01-10 2011-02-02 Irm Llc Compounds and compositions as channel activating protease inhibitors
EP2332933A1 (en) 2007-05-07 2011-06-15 Novartis AG Epithelial sodium channel (ENaC) inhibitors
US7943658B2 (en) 2007-07-23 2011-05-17 Bristol-Myers Squibb Company Indole indane amide compounds useful as CB2 agonists and method
EP2520574A1 (en) 2007-12-10 2012-11-07 Novartis AG Amiloride analogues substituted on the cyclic guanidine moiety as ENaC blockers for treating respiratory diseases
EP2444120A1 (en) 2007-12-10 2012-04-25 Novartis AG Spirocyclic amiloride analogues as ENac blockers
WO2009087224A1 (en) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines as kinase inhibitors
WO2009150137A2 (en) 2008-06-10 2009-12-17 Novartis Ag Organic compounds
WO2010088335A1 (en) 2009-01-29 2010-08-05 Novartis Ag Substituted benzimidazoles for the treatment of astrocytomas
WO2011015652A1 (en) 2009-08-07 2011-02-10 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives as c-met tyrosine kinase modulators
WO2011018454A1 (en) 2009-08-12 2011-02-17 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
WO2011022439A1 (en) 2009-08-17 2011-02-24 Intellikine, Inc. Heterocyclic compounds and uses thereof
WO2011020861A1 (en) 2009-08-20 2011-02-24 Novartis Ag Heterocyclic oxime compounds
EP2813227A1 (en) 2009-10-22 2014-12-17 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
WO2011050325A1 (en) 2009-10-22 2011-04-28 Vertex Pharmaceuticals Incorporated Compositions for treatment of cystic fibrosis and other chronic diseases
EP2845593A1 (en) 2010-03-19 2015-03-11 Novartis AG Pyridine and pyrazine derivative for the treatment of chronic obstructive pulmonary disease
WO2011113894A1 (en) 2010-03-19 2011-09-22 Novartis Ag Pyridine and pyrazine derivative for the treatment of cf
WO2012022796A3 (en) * 2010-08-20 2012-04-19 Boehringer Ingelheim International Gmbh Novel combinations
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
WO2012034091A1 (en) 2010-09-09 2012-03-15 Irm Llc Imidazo [1, 2] pyridazin compounds and compositions as trk inhibitors
WO2012035158A1 (en) 2010-09-17 2012-03-22 Novartis Ag Pyrazine derivatives as enac blockers
WO2012098495A1 (en) * 2011-01-19 2012-07-26 Glenmark Pharmaceuticals Sa Pharmaceutical composition that includes revamilast and a beta-2 agonist
WO2012107500A1 (en) 2011-02-10 2012-08-16 Novartis Ag [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
US9127000B2 (en) 2011-02-23 2015-09-08 Intellikine, LLC. Heterocyclic compounds and uses thereof
WO2012116237A2 (en) 2011-02-23 2012-08-30 Intellikine, Llc Heterocyclic compounds and uses thereof
WO2012116217A1 (en) 2011-02-25 2012-08-30 Irm Llc Compounds and compositions as trk inhibitors
WO2013030802A1 (en) 2011-09-01 2013-03-07 Novartis Ag Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
WO2013038362A1 (en) 2011-09-15 2013-03-21 Novartis Ag 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
WO2013038373A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
WO2013038386A1 (en) 2011-09-16 2013-03-21 Novartis Ag Heterocyclic compounds for the treatment of cystic fibrosis
WO2013038381A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine/pyrazine amide derivatives
WO2013038378A1 (en) 2011-09-16 2013-03-21 Novartis Ag Pyridine amide derivatives
WO2013038390A1 (en) 2011-09-16 2013-03-21 Novartis Ag N-substituted heterocyclyl carboxamides
WO2013081565A1 (en) * 2011-11-21 2013-06-06 Mahmut Bilgic Pharmaceutical compositions comprising roflumilast and terbutaline
US9669032B2 (en) 2011-11-23 2017-06-06 Intellikine Llc Enhanced treatment regimens using mTOR inhibitors
US9174994B2 (en) 2011-11-23 2015-11-03 Intellikine, Llc Enhanced treatment regimens using mTor inhibitors
WO2013077830A1 (en) * 2011-11-25 2013-05-30 Mahmut Bilgic Synergistilly active combinations of roflumilast and carmoterol
WO2013140319A1 (en) 2012-03-19 2013-09-26 Novartis Ag Crystalline form of a succinate salt
EP3964513A1 (en) 2012-04-03 2022-03-09 Novartis AG Combination products with tyrosine kinase inhibitors and their use
WO2013149581A1 (en) 2012-04-03 2013-10-10 Novartis Ag Combination products with tyrosine kinase inhibitors and their use
WO2014132220A1 (en) 2013-03-01 2014-09-04 Novartis Ag Solid forms of bicyclic heterocyclic derivatives as pdgf receptor mediators
WO2014151147A1 (en) 2013-03-15 2014-09-25 Intellikine, Llc Combination of kinase inhibitors and uses thereof
WO2015084804A1 (en) 2013-12-03 2015-06-11 Novartis Ag Combination of mdm2 inhibitor and braf inhibitor and their use
WO2015162456A1 (en) 2014-04-24 2015-10-29 Novartis Ag Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors
WO2015162459A1 (en) 2014-04-24 2015-10-29 Novartis Ag Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors
WO2015162461A1 (en) 2014-04-24 2015-10-29 Novartis Ag Pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors
WO2016011956A1 (en) 2014-07-25 2016-01-28 Novartis Ag Combination therapy
WO2016016822A1 (en) 2014-07-31 2016-02-04 Novartis Ag Combination therapy
WO2020250116A1 (en) 2019-06-10 2020-12-17 Novartis Ag Pyridine and pyrazine derivative for the treatment of cf, copd, and bronchiectasis
WO2021038426A1 (en) 2019-08-28 2021-03-04 Novartis Ag Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease

Also Published As

Publication number Publication date
PL356252A1 (en) 2004-06-28
US7056936B2 (en) 2006-06-06
US20040034087A1 (en) 2004-02-19
EA200200208A1 (en) 2002-08-29
DK1212089T3 (en) 2006-07-24
EP1212089B1 (en) 2006-03-22
DE60026855T2 (en) 2006-12-07
NZ517166A (en) 2004-01-30
SK287231B6 (en) 2010-04-07
CA2381802C (en) 2010-12-07
JP5038568B2 (en) 2012-10-03
AU6701600A (en) 2001-03-19
IL147688A0 (en) 2002-08-14
NO20020815L (en) 2002-02-19
SK2552002A3 (en) 2002-06-04
ATE447952T1 (en) 2009-11-15
EP1212089A2 (en) 2002-06-12
ZA200201389B (en) 2002-08-21
NO328340B1 (en) 2010-02-01
EP1671651A1 (en) 2006-06-21
DE60026855D1 (en) 2006-05-11
HRP20020158A2 (en) 2004-02-29
HUP0203098A2 (en) 2003-01-28
HU229439B1 (en) 2013-12-30
PT1212089E (en) 2006-08-31
EA006685B1 (en) 2006-02-24
MXPA02001830A (en) 2002-08-12
WO2001013953A3 (en) 2001-09-20
HK1047244B (en) 2006-10-27
BR0013478A (en) 2002-04-30
CA2715683A1 (en) 2001-03-01
SI1212089T1 (en) 2006-08-31
CA2381802A1 (en) 2001-03-01
CN1202865C (en) 2005-05-25
EP1671651B1 (en) 2009-11-11
US20060079539A1 (en) 2006-04-13
ES2260043T3 (en) 2006-11-01
HUP0203098A3 (en) 2006-07-28
KR100701904B1 (en) 2007-04-02
HK1047244A1 (en) 2003-02-14
TR200201317T2 (en) 2002-11-21
KR20020020275A (en) 2002-03-14
TR200909479T2 (en) 2012-02-21
HRP20020158B1 (en) 2007-08-31
PL200923B1 (en) 2009-02-27
IL147688A (en) 2007-09-20
BRPI0013478B8 (en) 2016-12-27
DE60043318D1 (en) 2010-01-14
EP2193808A1 (en) 2010-06-09
CN1370081A (en) 2002-09-18
JP2003507435A (en) 2003-02-25
ATE320800T1 (en) 2006-04-15
CZ302882B6 (en) 2012-01-04
BRPI0013478B1 (en) 2016-12-06
NO20020815D0 (en) 2002-02-19
CZ2002641A3 (en) 2002-08-14
US20060205806A1 (en) 2006-09-14
AU777012B2 (en) 2004-09-30

Similar Documents

Publication Publication Date Title
CA2381802C (en) Synergistic combination of roflumilast and salmeterol
US6624181B1 (en) Synergistic combination
KR20040029323A (en) Composition Comprising a PDE-4 Inhibitor and H1-Receptor Antagonist and the Use Thereof for the Manufacture of a Medicament for the Treatment of Repiratory Diseases
EP1482938B1 (en) Pharmaceutical composition of a pde4 or a pde3/4 inhibitor and a histamine receptor antagonist
KR101071798B1 (en) New synergistic combination comprising roflumilast and formoterol
EP1429843A2 (en) Combination of a pde inhibitor and a leukotriene receptor antagonist
HK1071308B (en) Pharmaceutical composition of a pde4 or a pde3/4 inhibitor and a histamine receptor antagonist
HK1081861B (en) New synergistic combination comprising roflumilast and formoterol
AU2002333851A1 (en) Combination of a PDE inhibitor and a leukotriene receptor antagonist

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AL AU BA BG BR CA CN CZ EE GE HR HU ID IL IN JP KR LT LV MK MX NO NZ PL RO SG SI SK TR UA US VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AL AU BA BG BR CA CN CZ EE GE HR HU ID IL IN JP KR LT LV MK MX NO NZ PL RO SG SI SK TR UA US VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 147688

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: IN/PCT/2002/00066/MU

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 67016/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2000954625

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2381802

Country of ref document: CA

Ref document number: 517166

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1020027002143

Country of ref document: KR

Ref document number: 200201389

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: P20020158A

Country of ref document: HR

Ref document number: 10049999

Country of ref document: US

Ref document number: 008118493

Country of ref document: CN

Ref document number: 2552002

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: PV2002-641

Country of ref document: CZ

Ref document number: PA/a/2002/001830

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 200200208

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 1020027002143

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2002/01317

Country of ref document: TR

WWP Wipo information: published in national office

Ref document number: 2000954625

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV2002-641

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 517166

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 517166

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 67016/00

Country of ref document: AU

WWG Wipo information: grant in national office

Ref document number: 2000954625

Country of ref document: EP

ENP Entry into the national phase

Ref country code: SK

Ref document number: SK A

WWE Wipo information: entry into national phase

Ref document number: PV2010-577

Country of ref document: CZ