US20100069392A1 - Combination of HMG-COA Reductase Inhibitors with Phosphodiesterase 4 Inhibitors for the Treatment of Inflammatory Pulmonary Disease - Google Patents

Combination of HMG-COA Reductase Inhibitors with Phosphodiesterase 4 Inhibitors for the Treatment of Inflammatory Pulmonary Disease Download PDF

Info

Publication number
US20100069392A1
US20100069392A1 US12/308,878 US30887807A US2010069392A1 US 20100069392 A1 US20100069392 A1 US 20100069392A1 US 30887807 A US30887807 A US 30887807A US 2010069392 A1 US2010069392 A1 US 2010069392A1
Authority
US
United States
Prior art keywords
pharmaceutically acceptable
acceptable salt
roflumilast
pde4 inhibitor
hmg
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.)
Abandoned
Application number
US12/308,878
Other languages
English (en)
Inventor
Stefan-Lutz Wollin
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
Nycomed Germany Holding GmbH
Original Assignee
Nycomed 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
Application filed by Nycomed GmbH filed Critical Nycomed GmbH
Assigned to NYCOMED GMBH reassignment NYCOMED GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRAUN, CLEMENS, WOHLSEN, ANDREA, MARX, DEGENHARD, WOLLIN, STEFAN-LUTZ
Publication of US20100069392A1 publication Critical patent/US20100069392A1/en
Assigned to TAKEDA GMBH reassignment TAKEDA GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: NYCOMED GMBH
Assigned to NYCOMED ASSET MANAGEMENT GMBH reassignment NYCOMED ASSET MANAGEMENT GMBH MERGER (SEE DOCUMENT FOR DETAILS). Assignors: TAKEDA GMBH
Assigned to TAKEDA GMBH reassignment TAKEDA GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: NYCOMED GERMANY HOLDING GMBH
Assigned to NYCOMED GERMANY HOLDING GMBH reassignment NYCOMED GERMANY HOLDING GMBH MERGER (SEE DOCUMENT FOR DETAILS). Assignors: NYCOMED ASSET MANAGEMENT GMBH
Abandoned legal-status Critical Current

Links

Images

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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • 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
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the combination of certain known therapeutic compounds for therapeutic purposes.
  • the substances used in the combinations according to the invention are known active agents from the phosphodiesterase 4 (PDE4) inhibitor class and active agents from the HMG-CoA-reductase inhibitor class.
  • PDE4 phosphodiesterase 4
  • Statins are widely used as cholesterol lowering therapeutic agents. They reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • the cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors.
  • LDL low-density lipoprotein
  • statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway including the cholesterol precursor mevalonate which is required as a precursor for the prenylation of a number of proteins leading to a change in function [Drugs of Today; 2004; 40: 975-990].
  • simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages [Veillard N R et al; Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages; Atherosclerosis; 2005 Nov. 28; Epub ahead of print].
  • Statins also have a potential role as antioxidants leading to downregulation of inflammation [Drugs of Today; 2004; 40: 975-990].
  • statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion [Timely Top Med Cardiovasc Dis; 2005; 9: E3]. Statins exhibit additional effects on inflammation by decreasing IL-6, IL-8, and MCP-1 synthesis in human vascular smooth muscle cells (VSMC) in vitro [Cardiovas Res; 2003; 59: 755-66].
  • VSMC vascular smooth muscle cells
  • Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts [Am J Respir Cell Mol. Biol. 2005; 32: 290-300]. Furthermore, statins increase bioavailability of nitric oxide. Cerivastatin increased eNOS expression a NO release in human endothelial cells [J Physiol Pharmacol. 2002; 53:585-95]. In vivo statins exert anti-inflammatory effects in many models of inflammatory airway diseases like asthma and COPD. Simvastatin was shown to inhibit pulmonary inflammatory cell accumulation and IL-4 and IL-5 release into the alveolar lumen after allergen challenge in mice [J Immunol. 2004; 172: 2903-8].
  • statin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs [Am J Respir Crit. Care Med. 2005; 172: 987-93]. Overall statins exhibit inhibitory properties on inflammation and modulation on the immune system.
  • Cyclic nucleotide phosphodiesterase (PDE) inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, for example in respiratory diseases, such as asthma and chronic obstructive pulmonary disease.
  • HMG-CoA reductase inhibitors by a route different from PDE4 inhibitors, are also useful in the treatment of inflammatory diseases.
  • a pharmaceutical composition comprising a pharmaceutical formulation including an amount of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof, an amount of a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise an effective amount for the preventive or curative treatment of an inflammatory pulmonary disease, and at least one pharmaceutically acceptable auxiliary.
  • the above-mentioned pharmaceutical composition provides for the administration of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof with a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof and is thus presented as a single formulation.
  • the PDE4 inhibitor or a pharmaceutically acceptable salt thereof and the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof may be presented as separate formulations, wherein at least one of those formulations comprises a PDE4 inhibitor or a pharmaceutically acceptable salt thereof and at least one comprises a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof.
  • a combination product comprising the components: (A) an amount of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof; (B) an amount of a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof; wherein the first and the second amount together comprise an effective amount for the preventive or curative treatment of an inflammatory pulmonary disease and wherein each of the components (A) and (B) is formulated in admixture with at least one pharmaceutically acceptable auxiliary.
  • a kit comprising the components: (A) a pharmaceutical formulation including an amount of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable auxiliary; (B) a pharmaceutical formulation including an amount of a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable auxiliary; wherein the first and the second amount together comprise an effective amount for the preventive or curative treatment of an inflammatory pulmonary disease.
  • the combinations according to the invention can be used for the preventive or curative treatment of inflammatory pulmonary diseases, such as, for example, asthma, COPD, sclerosis, alveolitis, sarcoidosis, idiopathic pulmonary fibrosis and pulmonary hypertension.
  • inflammatory pulmonary diseases such as, for example, asthma, COPD, sclerosis, alveolitis, sarcoidosis, idiopathic pulmonary fibrosis and pulmonary hypertension.
  • compositions, combination product or kit, as described in the preceding paragraphs, for use as a medicament for use as a medicament.
  • compositions, combination product or kit, as described in the preceding paragraphs, for the preventive or curative treatment of an inflammatory pulmonary disease for the preventive or curative treatment of an inflammatory pulmonary disease.
  • a PDE4 inhibitor or a pharmaceutically acceptable salt thereof and a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, in particular the pharmaceutical composition according to the invention, for the preventive or curative treatment of an inflammatory pulmonary disease.
  • Another aspect of the present invention is the use of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof and a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof for the manufacture of a sequential or separate co-administrable medicament, in particular the combination product or kit according to the invention, for the preventive or curative treatment of an inflammatory pulmonary disease.
  • Still another aspect of the present invention is a method for the preventive or curative treatment of an inflammatory pulmonary disease comprising administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutical formulation including an amount of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof, an amount of a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise an effective amount for the preventive or curative treatment of an inflammatory pulmonary disease, and at least one pharmaceutically acceptable auxiliary.
  • a further aspect of the present invention is a method for the preventive or curative treatment of an inflammatory pulmonary disease comprising administering to a patient in need thereof a combination product comprising the components:
  • each of the components (A) and (B) is formulated in admixture with at least one pharmaceutically acceptable auxiliary; and wherein the components (A) and (B) are administered simultaneously, sequentially or separately.
  • compositions according to the invention may be prepared by mixing the first active agent with the second active agent.
  • the first active agent and the second active agent can be any active agent and the second active agent.
  • a) in a first step be mixed as such, afterwards be processed with at least one pharmaceutically acceptable auxiliary and finally, for example, be pressed to tablets or caplets or b) in a first step separately be processed with at least one pharmaceutically acceptable auxiliary to give granules or pellets containing each only one of the two active agents; the pellets or granules for their part then can be mixed in an appropriate ratio and either pressed—optionally with further pharmaceutically acceptable auxiliaries—to give, for example tablets or caplets, or can be filled in loose form in capsules.
  • a process for the preparation of a pharmaceutical composition which comprises mixing a first active agent, which is a PDE4 inhibitor or a pharmaceutically acceptable salt thereof with a second active agent, which is a HMG CoA-reductase inhibitor or a pharmaceutically acceptable salt thereof.
  • Simultaneous administration of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof and a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof can be preferably accomplished, by administering to the patient in need of inflammatory pulmonary disease therapy the pharmaceutical composition according to the invention in one dosage form, such as for example in a single capsule, tablet or injection.
  • Components (A) and (B) of the combination product as well as of the kit may be administered sequentially or separately over the course of the preventive or curative treatment of an inflammatory pulmonary disease.
  • Sequential or separate administration of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof and a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof can be preferably accomplished, by administering to the patient in need of inflammatory pulmonary disease therapy components (A) and (B) of the combination product or the kit according to the invention in (multiple) separate dosage forms, such as for example, in separate capsules, tablets or injections.
  • the components (A) and (B) of the combination product or the kit according to the invention can also be administered simultaneously, for example by swallowing the two tablets containing the both active agents at the same time, or by using an inhaler system, which contains both active agents in separate containers, but deliver them together.
  • one of the components (A) and (B) may be formulated as tablet or capsule and the other component may be formulated for administration, for example, by injection or inhalation.
  • Sequential administration encompasses a short time period between the administration of components (A) and (B) of the combination product or the kit according to the invention (for example, the time that is needed to swallow one tablet after the other).
  • Separate administration encompasses both relatively short and relatively long time periods between the administration of components (A) and (B) of the combination product or the kit according to the invention.
  • at least one of the components is administered while the other component is still having an effect on the patient being treated.
  • the effect on the patient being treated is a synergistic effect.
  • the combined administration of a PDE4 inhibitor or a pharmaceutically acceptable thereof and a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof shows a synergistic efficacy for treating an inflammatory pulmonary disease.
  • the term “synergistic” refers to the combination of a PDE4 inhibitor or a Pharmaceutically acceptable salt thereof with a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof either in form of the pharmaceutical composition, combination product or kit according to the invention having an efficacy for the preventive or curative treatment of an inflammatory pulmonary disease that is greater than would be expected from the sum of their individuals effects.
  • the synergistic effects of the embodiments of the present invention encompass additional unexpected advantages for the preventive or curative treatment of inflammatory pulmonary diseases.
  • Such additional advantages may include, but are not limited to, lowering the required dose of one or more of the active compounds of the combination, reducing the side effects of one or more of the active compounds of the combination or rendering one or more of the active compounds more tolerable to the patient in need of an inflammatory pulmonary disease therapy.
  • the combined administration of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof and a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof may also be useful for decreasing the required number of separate dosages, thus, potentially improving compliance of the patient in need of inflammatory pulmonary disease therapy.
  • the therapeutic effect of the combinations according to the invention may be also observed with regard to the fast decline in lung function that is a hallmark of COPD, and effects may be observed regarding the systemic inflammation that is also a characteristic of COPD.
  • the long-term effect of the combinations according to the invention will be the conservation of lung function and putatively less co-morbidity (based on effects on the systemic inflammation).
  • active compound refers to a compound useful in the preventive or curative treatment of a disease.
  • an effective amount refers to a therapeutically effective amount for treating an inflammatory pulmonary disease.
  • an effective amount refers to the sum of the amounts of the combination partners, which is therapeutically effective for the preventive or curative treatment of an inflammatory pulmonary disease.
  • patient includes both humans and other mammals. In a preferred embodiment of the invention the term “patient” stands for humans.
  • PDE4 inhibitor refers to an active compound that is capable of reducing the physiological effect of the PDE4 isoenzyme of phosphodiesterase preferentially over other isoenzyme of phosphodiesterase.
  • PDE4 inhibitors which may be usefully employed in the pharmaceutical compositions, combination products and kits according to the invention are listed in Table 1.
  • the PDE4 inhibitor is selected from the group consisting of ROFLUMILAST (CAS-No. 162401-32-3), ROFLUMILAST-N-Oxide (CAS-No. 292135-78-5), CILOMILAST (CAS-No. 153259-65-5), AWD-12-281 (CAS-No. 257892-33-4), TOFIMILAST (CAS-No. 185954-27-2), TETOMILAST (CAS-No. 145739-56-6), LIRIMILAST (CAS-No. 329306-27-6), L-869298 (CAS-No. 362718-73-8), OGLEMILAST (CAS-No.
  • the PDE4 inhibitor is selected from the group consisting of ROFLUMILAST, a pharmaceutically acceptable salt of ROFLUMILAST, ROFLUMILAST-N-oxide and a pharmaceutically acceptable salt of ROFLUMILAST-N-oxide.
  • the PDE4 inhibitor is ROFLUMILAST.
  • the PDE4 inhibitor is ROFLUMILAST-N-oxide.
  • the PDE4 inhibitor is CILOMILAST or a pharmaceutically acceptable salt thereof.
  • preferred pharmaceutically acceptable salts of CILOMILAST are the lithium, sodium, ethylene diamine and tromethamine salt of CILOMILAST.
  • a particularly preferred pharmaceutically acceptable salt of CILOMILAST is the sodium salt of CILOMILAST.
  • Another particularly preferred pharmaceutically acceptable salt of CILOMILAST is the lithium salt of CILOMILAST.
  • a hydrate of CILOMILAST may be mentioned the monohydrate of the lithium salt of CILOMILAST.
  • the PDE4 inhibitor is AWD-12-281 or a pharmaceutically acceptable salt thereof.
  • a preferred pharmaceutically acceptable salt of AWD-12-281 is the sodium salt of AWD-12-281.
  • the PDE4 inhibitor is TOFIMILAST or a pharmaceutically acceptable salt thereof.
  • the PDE4 inhibitor is TETOMILAST or a pharmaceutically acceptable salt thereof.
  • the PDE4 inhibitor is LIRIMILAST or a pharmaceutically acceptable salt thereof.
  • the PDE4 inhibitor is L-869298 or a pharmaceutically acceptable salt thereof.
  • the PDE4 inhibitor is OGLEMILAST or a pharmaceutically acceptable salt thereof.
  • preferred pharmaceutically acceptable salts of OGLEMILAST are the mono-sodium and the di-sodium salt of OGLEMILAST.
  • the PDE4 inhibitor is COMPOUND A or a pharmaceutically acceptable salt thereof.
  • ROFLUMILAST 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4- (difluoromethoxy)benzamide
  • N-oxide of ROFLUMI- Last ROFLUMI- LAST-N-oxide 3-(cyclopropylmethoxy)-N-(3,5-dichloro-1-oxidopyridin-4-yl)-4- (difluoromethoxy)benzamide
  • AWD-12-281 N-(3,5-dichloropyridin-4-yl )-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]- 2-oxoacetamide
  • HMG-CoA reductase inhibitor refers to competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis, thereby lowering levels of cholesterol and triglyceride in hyperlipidemic patients.
  • HMG-CoA reductase inhibitor refers to competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limiting step in cholesterol biosynthesis, thereby lowering levels of cholesterol and triglyceride in hyperlipidemic patients.
  • HMG-CoA reductase inhibitors which may be usefully employed in the pharmaceutical compositions, combination products and kits according to the invention are listed in Table 2.
  • the HMG-CoA reductase inhibitor is selected from the group consisting of LOVASTATIN (CAS-No. 75330-75-5), PRAVASTATIN (CAS-No. 081093-37-0), SIMVASTATIN (CAS-No. 079902-63-9), ATORVASTATIN (CAS-No. 134523-00-5), FLUVASTATIN (093957-54-1), ROSUVASTATIN (CAS-No. 287714-41-4), PITAVASTATIN (CAS-No. 147511-69-1), BERVASTATIN (CAS-No. 132017-01-7), DALVASTATIN (CAS-No. 132100-55-1), GLENVASTATIN (CAS-No. 122254-45-9) and the pharmaceutically acceptable salts of these compounds.
  • LOVASTATIN CAS-No. 75330-75-5
  • PRAVASTATIN CAS-No. 081093-37-0
  • SIMVASTATIN CAS-No. 079902-63-9
  • the HMG-CoA reductase inhibitor is LOVASTATIN or a pharmaceutically acceptable salt thereof.
  • the HMG-CoA reductase inhibitor is PRAVASTATIN or a pharmaceutically acceptable salt thereof.
  • preferred pharmaceutically acceptable salts of PRAVASTATIN are the potassium, lithium, sodium and hemi-calcium salt of PRAVASTATIN.
  • a particularly preferred pharmaceutically acceptable salt of PRAVASTATIN is the sodium salt of PRAVASTATIN.
  • the HMG-CoA reductase inhibitor is SIMVASTATIN or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of SIMVASTATIN is the sodium salt of SIMVASTATIN.
  • the HMG-CoA reductase inhibitor is ATORVASTATIN or a pharmaceutically acceptable salt thereof.
  • preferred pharmaceutically acceptable salts of ATORVASTATIN are the potassium, sodium and the hemi-calcium salt of ATORVASTATIN.
  • a particularly preferred pharmaceutically acceptable salt of ATORVASTATIN is the hemi-calcium salt of ATORVASTATIN.
  • a hydrate of ATORVASTATIN may be mentioned the trihydrate and the sesqui-hydrate of the hemi-calcium salt of ATORVASTATIN.
  • the HMG-CoA reductase inhibitor is FLUVASTATIN or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of FLUVASTATIN is the sodium salt of FLUVASTATIN.
  • the HMG-CoA reductase inhibitor is ROSUVASTATIN or a pharmaceutically acceptable salt thereof.
  • preferred pharmaceutically acceptable salts of ROSUVASTATIN are the potassium, lithium, sodium, hemi-magnesium and the hemi-calcium salt of ROSUVASTATIN.
  • a particularly preferred pharmaceutically acceptable salt of ROSUVASTATIN is the hemi-calcium salt of ROSUVASTATIN.
  • Another particularly preferred pharmaceutically acceptable salt of ROSUVASTATIN is the sodium salt of ROSUVASTATIN.
  • the HMG-CoA reductase inhibitor is PITAVASTATIN or a pharmaceutically acceptable salt thereof.
  • preferred pharmaceutically acceptable salts of PITAVASTATIN are the potassium, sodium and the hemi-calcium salt of PITAVASTATIN.
  • a particularly preferred pharmaceutically acceptable salt of PITAVASTATIN is the hemi-calcium salt of PITAVASTATIN.
  • the HMG-CoA reductase inhibitor is BERVASTATIN or a pharmaceutically acceptable salt thereof.
  • the HMG-CoA reductase inhibitor is DALVASTATIN or a pharmaceutically acceptable salt thereof.
  • the HMG-CoA reductase inhibitor is GLENVASTATIN or a pharmaceutically acceptable salt thereof.
  • LOVASTATIN (1S,3R,7S,8S,8aR)-8- ⁇ 2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2- yl]ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2- methylbutanoate
  • PRAVASTATIN (3S,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8- ⁇ [(2S)- 2-methylbutanoyl]oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]heptanoic acid
  • SIMVASTATIN (1R,3S,7R,8R,8aS)-8- ⁇ 2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2
  • HMG-CoA reductase inhibitors BERVASTATIN, DALVASTATIN, GLENVASTATIN and the pharmaceutically acceptable salts thereof can be found in the following patents/patent applications: EP0380392, WO8905639 and EP0307342.
  • Salts encompassed within the term “pharmaceutically acceptable salts” are not restricted to the specific examples given above.
  • the term refers to non-toxic salts of the PDE4 inhibitors or the HMG-CoA reductase inhibitors, which are generally prepared by reacting a free base with a suitable organic or inorganic acid (acid addition salt) or by reacting the free acid with a suitable organic or inorganic base.
  • Acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, citrates, D-gluconates, benzoates, 2-(4-hydroxybenzoyl)benzoates, butyrates, sulfosalicylates, maleates, laurates, malates, fumarates, succinates, oxalates, tartarates, stearates, toluenesulfonates, methanesulfonates, 3-hydroxy-2-naphthoates and trifluoroacetates.
  • salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
  • the PDE4 inhibitors, the HMG-CoA reductase inhibitors as well as their pharmaceutically acceptable salts can also be present in the form of their pharmaceutically acceptable solvates and in particular in the form of their pharmaceutically acceptable hydrates.
  • the combinations according to the invention may be administered by any suitable route, for example, by the oral, sublingual, buccal, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, topical, transdermal, intranasal, intraperitoneal, rectal or vaginal route, by inhalation or by insufflation.
  • Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration.
  • said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form.
  • Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the active compound to a biodegradable polymer.
  • Administration by inhalation is preferably made by using an aerosol.
  • the aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
  • the aerosol may be generated by means of aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers.
  • the aerosol-producing device can contain the active compound in form of a powder, a solution or a dispersion.
  • the powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers.
  • the solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings.
  • the dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings.
  • auxiliaries include, but are not limited to, saccharides, e.g. lactose and glucose.
  • propellants include, but are not limited to, fluorohydrocarbons, e.g. 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane.
  • the particle size of the aerosol particles is preferably less than 100 ⁇ m, more preferably it is in the range of from 0.5 to 10 ⁇ m, in particular in the range of from 2 to 6 ⁇ m (D50 value, measured by laser diffraction).
  • parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous and intraperitoneal administration, preferably solutions (e.g. sterile solutions, isotonic solutions) are used. They are preferably administered by injection or infusion techniques.
  • solutions e.g. sterile solutions, isotonic solutions
  • compositions (formulations) comprising the PDE4 inhibitor or a pharmaceutically acceptable salt thereof and/or the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • pharmaceutically acceptable auxiliaries any auxiliaries known to be suitable for preparing pharmaceutical compositions (formulations) can be used.
  • Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes.
  • auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
  • Roflumilast The most preferred mode of administration of Roflumilast, Roflumilast-N-oxide or a pharmaceutically acceptable salt of either is oral.
  • Roflumilast, Roflumilast-N-oxide or a pharmaceutically acceptable salt of either is administered by intravenous infusion or injection.
  • Roflumilast, Roflumilast-N-oxide or a pharmaceutically acceptable salt of either is administered by intramuscular or subcutaneous injection.
  • Other routes of administration are also contemplated, including for example intranasal and transdermal routes, and by inhalation.
  • the preferred mode of administration of the PDE4 inhibitors CILOMILAST, TETOMILAST, LIRIMILAST, L-869298, OGLEMILAST and COMPOUND A is oral, while the preferred mode of administration of the PDE4 inhibitors AWD-12-281 and TOFIMILAST is administration by inhalation.
  • HMG CoA reductase inhibitors LOVASTATIN, PRAVASTATIN; SIMVASTATIN; ATORVASTATIN, FLUVASTATIN, ROSUVASTATIN, PITAVASTATIN, BERVASTATIN, DALVASTATIN and GLENVASTATIN is oral.
  • a PDE4 inhibitor or a pharmaceutically acceptable salt thereof in combination with a HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof will necessarily depend on the potency and duration of action of the active compounds used, the nature and severity of the inflammatory pulmonary disease to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances.
  • the PDE4 inhibitor or a pharmaceutically acceptable salt thereof and the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof are dosed in an order of magnitude customary for the mono-therapy, 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 PDE4 inhibitor or a pharmaceutically acceptable salt thereof and the HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof with the norm.
  • the orally administered daily dosage (for an adult patient) of the PDE4 inhibitors or the pharmaceutically acceptable salts thereof will generally range from about 0.05 mg to about 200 mg; without intended to be limiting, the daily dosage (for an adult patient) of a PDE4 inhibitor or a pharmaceutically acceptable salt thereof for administration by inhalation will generally range from 0.05 mg to about 100 mg.
  • the daily dose (for an adult patient) for the mono-therapy is in the range from 50 to 1000 ⁇ g per day, preferably in the range of 50 to 500 ⁇ g per day, preferably by once daily administration.
  • the daily dose (for an adult patient) for the mono-therapy is in the range from 50 to 500 ⁇ g per day, preferably 150 to 300 ⁇ g per day.
  • the daily dose (for an adult patient) for the monotherapy is likely to be in the range from 10 to 40 mg per day, preferably from 20 to 30 mg per day, preferably by twice daily administration.
  • the daily dosage (for an adult patient) for the mono-therapy is likely to be in the range of 500 to 2000 ⁇ g per day.
  • the daily dosage (for an adult patient) for the monotherapy is likely to be in a range of 1 to 10 mg per day.
  • the daily dosage (for an adult patient) for the monotherapy is likely to be in the range of 1 to 10 mg per day.
  • the daily dosage (for an adult patient) for the monotherapy is likely to be in a range of 0.1 to 10 mg once daily, preferably 0.1 to 2 mg once daily.
  • the orally administered daily dosage (for an adult patient) of the HMG-CoA reductase inhibitors or the pharmaceutically acceptable salts thereof will generally range from about 0.01 mg to about 200 mg, preferably from 10 to 80 mg, more preferably from 5 to 40 mg; for administration by inhalation a dosage range of 0.001 mg to about 25 mg is preferred, even more preferable is a dosage from 0.1 to 25 mg.
  • Drugs were administered by gavage as a methocel/polyethylenglycol 400 suspension 1 h before intravenous administration of LPS (0.1 mg/kg). Euthanasia was induced 90 minutes later by injecting pentobarbital (48 mg/kg) and heparin (1,000 U/kg). Heparinized blood was obtained by heart puncture. Blood was centrifuged (21,000 ⁇ g, 4° C., 15 min), and plasma samples were kept frozen at ⁇ 80° C. until determination of TNF ⁇ levels by a commercially available ELISA kit (Quantakine®M, Rat TNF ⁇ immunoassay, R&D, MN, USA).
  • ATORVASTATIN hemi-calcium sesqui-hydrate is indicated simply as “ATORVASTATIN Ca”
  • FIG. 1 Inhibition of LPS-induced (systemic) TNF ⁇ release in rats by COMPOUND A
  • FIG. 2 Inhibition of LPS-induced (systemic) TNF ⁇ release in rats by ATORVASTATIN hemi-calcium sesqui-hydrate
  • FIG. 3 Inhibition of LPS-induced (systemic) TNF ⁇ release in rats by a combination of COMPOUND A and ATORVASTATIN hemi-calcium sesqui-hydrate

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Otolaryngology (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US12/308,878 2006-07-05 2007-07-03 Combination of HMG-COA Reductase Inhibitors with Phosphodiesterase 4 Inhibitors for the Treatment of Inflammatory Pulmonary Disease Abandoned US20100069392A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06116625.2 2006-07-05
EP06116625 2006-07-05
PCT/EP2007/056683 WO2008003701A2 (en) 2006-07-05 2007-07-03 Combination of hmg-coa reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/056683 A-371-Of-International WO2008003701A2 (en) 2006-07-05 2007-07-03 Combination of hmg-coa reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/719,948 Continuation US9713614B2 (en) 2006-07-05 2015-05-22 Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases

Publications (1)

Publication Number Publication Date
US20100069392A1 true US20100069392A1 (en) 2010-03-18

Family

ID=37311957

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/308,878 Abandoned US20100069392A1 (en) 2006-07-05 2007-07-03 Combination of HMG-COA Reductase Inhibitors with Phosphodiesterase 4 Inhibitors for the Treatment of Inflammatory Pulmonary Disease
US14/719,948 Expired - Fee Related US9713614B2 (en) 2006-07-05 2015-05-22 Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases

Family Applications After (1)

Application Number Title Priority Date Filing Date
US14/719,948 Expired - Fee Related US9713614B2 (en) 2006-07-05 2015-05-22 Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases

Country Status (26)

Country Link
US (2) US20100069392A1 (ja)
EP (3) EP2359826B1 (ja)
JP (3) JP5349302B2 (ja)
KR (1) KR101433394B1 (ja)
CN (3) CN102764440A (ja)
AT (1) ATE535244T1 (ja)
AU (1) AU2007271186C1 (ja)
BR (1) BRPI0713768A2 (ja)
CA (1) CA2656366A1 (ja)
CY (2) CY1114742T1 (ja)
DK (2) DK2359826T3 (ja)
EA (2) EA032476B1 (ja)
ES (3) ES2489265T3 (ja)
HR (2) HRP20140073T1 (ja)
IL (3) IL195433A (ja)
ME (2) ME01901B (ja)
MX (1) MX2008016123A (ja)
NO (1) NO342590B1 (ja)
NZ (3) NZ573378A (ja)
PL (2) PL2359826T3 (ja)
PT (2) PT2363130E (ja)
RS (2) RS53084B (ja)
SI (2) SI2359826T1 (ja)
UA (3) UA101556C2 (ja)
WO (1) WO2008003701A2 (ja)
ZA (1) ZA200809905B (ja)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019147824A1 (en) 2018-01-26 2019-08-01 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a pde4 inhibitor
WO2020106754A1 (en) 2018-11-19 2020-05-28 Progenity, Inc. Methods and devices for treating a disease with biotherapeutics
WO2021119482A1 (en) 2019-12-13 2021-06-17 Progenity, Inc. Ingestible device for delivery of therapeutic agent to the gastrointestinal tract

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0909288A2 (pt) * 2008-03-14 2015-08-18 Otsuka Pharma Co Ltd Inibidores da mmp-2 e/ou da mmp-9
CN102671198A (zh) * 2011-12-17 2012-09-19 东莞达信生物技术有限公司 一种降压降脂复方药及其制备方法
US10508307B2 (en) 2014-06-05 2019-12-17 Transgenion—International Institute for Regenerative Translational Medicine GmbH Methods of diagnosing chronic obstructive pulmonary disease (COPD) using novel molecular biomarkers
JP6755240B2 (ja) * 2014-06-05 2020-09-16 トランスゲニオン−インターナショナル インスティテュート フォー リジェネレイティヴ トランスレイショナル メディシン ゲーエムベーハー 新規分子バイオマーカーを使用して慢性閉塞性肺疾患（ｃｏｐｄ）を診断する方法
WO2015185658A2 (en) 2014-06-05 2015-12-10 Medizinische Universität Wien Methods of diagnosing chronic obstructive pulmonary disease (copd) using novel molecular biomarkers
WO2021218988A1 (zh) * 2020-04-30 2021-11-04 中国科学院上海药物研究所 Prdx1激动剂及其用途
CN117504071A (zh) * 2022-08-03 2024-02-06 奇斯药制品公司 干粉吸入器

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4346227A (en) * 1980-06-06 1982-08-24 Sankyo Company, Limited ML-236B Derivatives and their preparation
US20020103226A1 (en) * 1999-12-22 2002-08-01 Denis Deschenes Substituted 8-arylquinoline phosphodiesterase-4 inhibitors
WO2002064584A1 (en) * 2001-02-15 2002-08-22 Altana Pharma Ag Phthalayinone-piperidino-derivatives as pde4 inhibitors
US20020143032A1 (en) * 2000-12-20 2002-10-03 Macdonald Dwight Substituted 8-arylquinoline phosphodiesterase-4 inhibitors
US20020198136A1 (en) * 2001-03-06 2002-12-26 Cellegy Pharmaceuticals, Inc. Compounds and methods for the treatment of urogenital disorders
US20030096829A1 (en) * 2001-05-24 2003-05-22 Chun Li 1-biaryl-1,8-naphthyridin-4-one phosphodiesterase-4 inhibitors
US20040162314A1 (en) * 2001-06-27 2004-08-19 Daniel Dube Substituted 8-arylquinolune pde4 inhibitors
US20040167199A1 (en) * 2002-11-18 2004-08-26 Celgene Corporation Methods of using and compositions comprising (-)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide
US20040254238A1 (en) * 2003-04-07 2004-12-16 Osteoscreen Bone growth stimulation with NO/statin and other NO modulating combinations
US20050119330A1 (en) * 2003-03-17 2005-06-02 Kao Peter N. Use of antiproliferative agents in the treatment and prevention of pulmonary proliferative vascular diseases
US20050234068A1 (en) * 2004-04-19 2005-10-20 Baldwin Dalton D Composition and method of decreasing renal ischemic damage
US20060004056A1 (en) * 2002-07-02 2006-01-05 Bernard Cote Di-aryl-substituted-ethan pyridone pde4 inhibitors
US20060094723A1 (en) * 2003-05-22 2006-05-04 Torsten Dunkern Composition comprising a pde4 inhibitor and a pde5 inhibitor
US20060148721A1 (en) * 2003-06-06 2006-07-06 Erondu Ngozi E Combination therapy for the treatment of dyslipidemia
US20060160834A1 (en) * 2003-06-06 2006-07-20 Fong Tung M Combination therapy for the treatment of hypertension
US20060223850A1 (en) * 2003-04-30 2006-10-05 Daniel Dube 8-(3-Biaryl)phenylquinoline phosphodiesterase-4 inhibitors
US7178910B2 (en) * 2002-07-23 2007-02-20 Brother Kogyo Kabushiki Kaisha Ink cartridge
US20070208029A1 (en) * 2005-10-21 2007-09-06 Braincells, Inc. Modulation of neurogenesis by pde inhibition
US20080070940A1 (en) * 2005-10-27 2008-03-20 Daniel Dube 4-Oxo-1-(3-substituted phenyl-1,4-dihydro-1,8-naphthyridine-3-carboxamide phosphodiesterase-4 inhibitor and a method of preparing same
US20080103105A1 (en) * 2006-09-22 2008-05-01 Braincells, Inc. HMG CoA REDUCTASE MEDIATED MODULATION OF NEUROGENESIS

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR69216B (ja) 1979-06-15 1982-05-07 Merck & Co Inc
AU548996B2 (en) 1980-02-04 1986-01-09 Merck & Co., Inc. Tetrahydro-2h-pyran-2-one derivatives
AU570021B2 (en) 1982-11-22 1988-03-03 Novartis Ag Analogs of mevalolactone
US4681893A (en) 1986-05-30 1987-07-21 Warner-Lambert Company Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
FI90236C (fi) 1987-07-10 1994-01-10 Hoechst Ag Menetelmä terapeuttisesti käyttökelpoisten 3-desmetyylimevalonihappojohdannaisten valmistamiseksi
CA1336714C (en) 1987-08-20 1995-08-15 Yoshihiro Fujikawa Quinoline type mevalonolactone inhibitors of cholesterol biosynthesis
US4863957A (en) 1987-12-21 1989-09-05 Rorer Pharmaceutical Corporation Novel HMG-CoA reductase inhibitors
FR2642065B1 (fr) 1989-01-24 1991-05-24 Lipha Derives d'acides benzocycloalcenyl dihydroxy alcanoiques, procede de preparation et medicaments les contenant
DE69132006T2 (de) 1990-11-30 2000-08-03 Otsuka Pharma Co Ltd Thiazolederivate als inhibitoren von aktivem sauerstoff
JP2648897B2 (ja) 1991-07-01 1997-09-03 塩野義製薬株式会社 ピリミジン誘導体
DE69332987T2 (de) * 1992-04-02 2004-05-19 Smithkline Beecham Corp. Verbindungen verwendbar für die Behandlung von Allergien und Entzündungskrankheiten
NZ251092A (en) 1992-04-02 1996-12-20 Smithkline Beecham Corp 4-cyano-cyclohexane derivatives; medicaments; used in treating asthma
CA2165192C (en) * 1993-07-02 2001-04-24 Hermann Amschler Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors
GB9504460D0 (en) 1995-03-06 1995-04-26 Bayer Ag N-(3-Benzofuranyl)urea-derivatives
SK282167B6 (sk) 1995-06-06 2001-11-06 Pfizer Inc. Tricyklické 5,6-dihydro-9h-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a] pyridíny a farmaceutický prostriedok na ich báze
DE19636150A1 (de) 1996-09-06 1998-03-12 Asta Medica Ag N-substituierte Indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender Wirkung
ES2262072T3 (es) 1998-04-28 2006-11-16 Elbion Ag Derivados de indol y su utilizacion como inhibidores de la fosfodiesterasa 4.
US20010006656A1 (en) 1999-02-17 2001-07-05 University Of Washington Methods and compositions for inhibiting inflammation associated with pulmonary disease
DE19944161A1 (de) 1999-09-15 2001-03-22 Bayer Ag Neue Kombination zur Behandlung von sexueller Dysfunktion
MY134008A (en) 1999-12-22 2007-11-30 Merck Frosst Canada Inc Subtituted 8-arylquinoline phospohodiestrase-4 inhibitors
US20030018040A1 (en) 2000-02-10 2003-01-23 Yasuo Sugiyama Tnf-alpha inhibitors
JP2001294526A (ja) * 2000-02-10 2001-10-23 Takeda Chem Ind Ltd ＴＮＦ−α抑制剤
MY123585A (en) 2000-03-23 2006-05-31 Merck Canada Inc Tri-aryl-substituted-ethane pde4 inhibitors.
US20050102317A1 (en) * 2000-07-21 2005-05-12 Ali Kamarei System and method for event calendaring using a customizable rules subset
CA2422820A1 (en) * 2000-09-19 2002-03-28 Novimmune S.A. Use of statins (hmg-coa reductase inhibitors) for the preparation of medicament as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent
US20030114469A1 (en) 2001-09-27 2003-06-19 Cohen David Saul Combinations
MY140561A (en) 2002-02-20 2009-12-31 Nycomed Gmbh Dosage form containing pde 4 inhibitor as active ingredient
IS7839A (is) 2002-11-22 2004-05-23 Merck Frosst Canada Ltd. 4-oxó-1-(3-setið fenýl-1,4-díhýdró-1,8-naftýridín-3-karboxamíð fosfódíesterasa-4 hindrar
RS51081B (sr) * 2002-11-27 2010-10-31 Nycomed Gmbh. Nova sinergistička kombinacija koja uključuje roflumilast i formoterol
BRPI0409747A (pt) 2003-04-11 2006-05-09 Glenmark Pharmaceuticals Sa novos compostos heterocìclicos úteis para tratamento de distúrbios inflamatórios e alérgicos, processo para sua preparação e composições farmacêuticas contendo estes
WO2004098578A2 (en) * 2003-05-12 2004-11-18 Altana Pharma Ag Composition comprising a pde4 inhibitor and a tnf-alfa antagonist selected from infliximab, adalimumab, cdp870 and cdp517
DE10348646A1 (de) 2003-10-15 2005-05-25 Gkn Driveline International Gmbh Rollbalg mit großem Krümmungsradius
JP2007533760A (ja) * 2004-04-23 2007-11-22 セルジーン・コーポレーション 肺高血圧症を治療し管理するための、ｐｄｅ４モジュレーターの使用方法及びｐｄｅ４モジュレーターを含む組成物
ES2257152B1 (es) * 2004-05-31 2007-07-01 Laboratorios Almirall S.A. Combinaciones que comprenden agentes antimuscarinicos y agonistas beta-adrenergicos.
GB0415789D0 (en) * 2004-07-15 2004-08-18 Astrazeneca Ab Novel combination
DE102004046236A1 (de) 2004-09-22 2006-03-30 Altana Pharma Ag Arzneimittelzubereitung
GB0508924D0 (en) 2005-04-30 2005-06-08 Astrazeneca Ab New use
GB0510207D0 (en) 2005-05-19 2005-06-22 Astrazeneca Ab Novel combination
PL1894576T3 (pl) 2005-06-08 2011-10-31 Kowa Co Nowy środek do obniżania poziomu triglicerydów
US8026377B2 (en) 2005-11-08 2011-09-27 Ranbaxy Laboratories, Limited Process for (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt

Patent Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4346227A (en) * 1980-06-06 1982-08-24 Sankyo Company, Limited ML-236B Derivatives and their preparation
US20020103226A1 (en) * 1999-12-22 2002-08-01 Denis Deschenes Substituted 8-arylquinoline phosphodiesterase-4 inhibitors
US20020143032A1 (en) * 2000-12-20 2002-10-03 Macdonald Dwight Substituted 8-arylquinoline phosphodiesterase-4 inhibitors
US6953853B2 (en) * 2001-02-15 2005-10-11 Altana Pharma Ag Phthalazinone-piperidino-derivatives as PDE4 inhibitors
WO2002064584A1 (en) * 2001-02-15 2002-08-22 Altana Pharma Ag Phthalayinone-piperidino-derivatives as pde4 inhibitors
US7531540B2 (en) * 2001-02-15 2009-05-12 Nycomed Gmbh Phthalazinone-piperidino-derivatives as PDE4 inhibitors
US20020198136A1 (en) * 2001-03-06 2002-12-26 Cellegy Pharmaceuticals, Inc. Compounds and methods for the treatment of urogenital disorders
US20030096829A1 (en) * 2001-05-24 2003-05-22 Chun Li 1-biaryl-1,8-naphthyridin-4-one phosphodiesterase-4 inhibitors
US20040162314A1 (en) * 2001-06-27 2004-08-19 Daniel Dube Substituted 8-arylquinolune pde4 inhibitors
US20060004056A1 (en) * 2002-07-02 2006-01-05 Bernard Cote Di-aryl-substituted-ethan pyridone pde4 inhibitors
US7178910B2 (en) * 2002-07-23 2007-02-20 Brother Kogyo Kabushiki Kaisha Ink cartridge
US20040167199A1 (en) * 2002-11-18 2004-08-26 Celgene Corporation Methods of using and compositions comprising (-)-3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide
US20050119330A1 (en) * 2003-03-17 2005-06-02 Kao Peter N. Use of antiproliferative agents in the treatment and prevention of pulmonary proliferative vascular diseases
US20040254238A1 (en) * 2003-04-07 2004-12-16 Osteoscreen Bone growth stimulation with NO/statin and other NO modulating combinations
US20060223850A1 (en) * 2003-04-30 2006-10-05 Daniel Dube 8-(3-Biaryl)phenylquinoline phosphodiesterase-4 inhibitors
US20060094723A1 (en) * 2003-05-22 2006-05-04 Torsten Dunkern Composition comprising a pde4 inhibitor and a pde5 inhibitor
US20060148721A1 (en) * 2003-06-06 2006-07-06 Erondu Ngozi E Combination therapy for the treatment of dyslipidemia
US20060160834A1 (en) * 2003-06-06 2006-07-20 Fong Tung M Combination therapy for the treatment of hypertension
US20050234068A1 (en) * 2004-04-19 2005-10-20 Baldwin Dalton D Composition and method of decreasing renal ischemic damage
US20070208029A1 (en) * 2005-10-21 2007-09-06 Braincells, Inc. Modulation of neurogenesis by pde inhibition
US20080070940A1 (en) * 2005-10-27 2008-03-20 Daniel Dube 4-Oxo-1-(3-substituted phenyl-1,4-dihydro-1,8-naphthyridine-3-carboxamide phosphodiesterase-4 inhibitor and a method of preparing same
US20080103105A1 (en) * 2006-09-22 2008-05-01 Braincells, Inc. HMG CoA REDUCTASE MEDIATED MODULATION OF NEUROGENESIS

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Ascer et al. in Atherosclerosis 177 (2004) 161 - 166 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019147824A1 (en) 2018-01-26 2019-08-01 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with a pde4 inhibitor
WO2020106754A1 (en) 2018-11-19 2020-05-28 Progenity, Inc. Methods and devices for treating a disease with biotherapeutics
WO2020106704A2 (en) 2018-11-19 2020-05-28 Progenity, Inc. Ingestible device for delivery of therapeutic agent to the gastrointestinal tract
WO2020106750A1 (en) 2018-11-19 2020-05-28 Progenity, Inc. Methods and devices for treating a disease with biotherapeutics
WO2020106757A1 (en) 2018-11-19 2020-05-28 Progenity, Inc. Ingestible device for delivery of therapeutic agent to the gastrointestinal tract
WO2021119482A1 (en) 2019-12-13 2021-06-17 Progenity, Inc. Ingestible device for delivery of therapeutic agent to the gastrointestinal tract
EP4309722A2 (en) 2019-12-13 2024-01-24 Biora Therapeutics, Inc. Ingestible device for delivery of therapeutic agent to the gastrointestinal tract

Also Published As

Publication number Publication date
DK2363130T3 (da) 2014-07-21
CN102764440A (zh) 2012-11-07
CN102772411A (zh) 2012-11-14
UA106422C2 (uk) 2014-08-26
AU2007271186C1 (en) 2013-08-15
NZ573378A (en) 2012-03-30
KR101433394B1 (ko) 2014-08-26
UA98466C2 (uk) 2012-05-25
ES2443342T3 (es) 2014-02-19
US9713614B2 (en) 2017-07-25
ME01901B (me) 2014-12-20
NZ603207A (en) 2013-12-20
EP2040707B1 (en) 2011-11-30
EP2359826A1 (en) 2011-08-24
JP2013035871A (ja) 2013-02-21
SI2359826T1 (sl) 2014-02-28
JP5349302B2 (ja) 2013-11-20
CY1115462T1 (el) 2017-01-04
MX2008016123A (es) 2009-01-15
ATE535244T1 (de) 2011-12-15
EP2359826B1 (en) 2013-10-30
EP2363130B1 (en) 2014-05-07
PT2363130E (pt) 2014-06-25
RS53084B (en) 2014-06-30
ES2378281T3 (es) 2012-04-10
UA101556C2 (uk) 2013-04-10
NO20090370L (no) 2009-02-04
US20150272949A1 (en) 2015-10-01
CN101484166B (zh) 2012-09-05
KR20090025368A (ko) 2009-03-10
IL221307A (en) 2014-08-31
HRP20140073T1 (hr) 2014-02-28
IL195433A0 (en) 2009-08-03
EA201401042A1 (ru) 2016-05-31
JP2009541459A (ja) 2009-11-26
CN101484166A (zh) 2009-07-15
PL2359826T3 (pl) 2014-04-30
DK2359826T3 (da) 2014-01-20
WO2008003701A3 (en) 2008-03-13
IL221309A (en) 2014-12-31
ES2489265T3 (es) 2014-09-01
EA021461B1 (ru) 2015-06-30
AU2007271186B2 (en) 2013-01-17
BRPI0713768A2 (pt) 2012-10-30
IL221307A0 (en) 2012-09-24
NO342590B1 (no) 2018-06-18
SI2363130T1 (sl) 2014-09-30
ZA200809905B (en) 2009-11-25
WO2008003701A2 (en) 2008-01-10
CA2656366A1 (en) 2008-01-10
AU2007271186A1 (en) 2008-01-10
EP2363130A1 (en) 2011-09-07
ME01648B (me) 2014-09-20
PT2359826E (pt) 2014-01-20
EP2040707A2 (en) 2009-04-01
PL2363130T3 (pl) 2014-09-30
CY1114742T1 (el) 2016-12-14
NZ594369A (en) 2013-10-25
JP2013035870A (ja) 2013-02-21
EA200900073A1 (ru) 2009-06-30
HRP20140707T1 (hr) 2014-09-12
IL195433A (en) 2013-02-28
EA032476B1 (ru) 2019-06-28
RS53461B (en) 2014-12-31

Similar Documents

Publication Publication Date Title
US9713614B2 (en) Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases
US20150272944A1 (en) Novel triglyceride reducing agent
CA2372850C (en) Synergistic combination comprising roflumilast and a pde-3 inhibitor
US20050014762A1 (en) Combination
US20050182036A1 (en) Medicinal composition containing an HMG-CoA reductase inhibitor
AU2013203070B2 (en) Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases
AU2002333851A1 (en) Combination of a PDE inhibitor and a leukotriene receptor antagonist

Legal Events

Date Code Title Description
AS Assignment

Owner name: NYCOMED GMBH,GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WOLLIN, STEFAN-LUTZ;WOHLSEN, ANDREA;BRAUN, CLEMENS;AND OTHERS;SIGNING DATES FROM 20081120 TO 20081124;REEL/FRAME:022059/0669

AS Assignment

Owner name: TAKEDA GMBH, GERMANY

Free format text: CHANGE OF NAME;ASSIGNOR:NYCOMED GMBH;REEL/FRAME:030062/0599

Effective date: 20121114

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: NYCOMED ASSET MANAGEMENT GMBH, GERMANY

Free format text: MERGER;ASSIGNOR:TAKEDA GMBH;REEL/FRAME:036193/0224

Effective date: 20121025

AS Assignment

Owner name: TAKEDA GMBH, GERMANY

Free format text: CHANGE OF NAME;ASSIGNOR:NYCOMED GERMANY HOLDING GMBH;REEL/FRAME:036205/0179

Effective date: 20141020

AS Assignment

Owner name: NYCOMED GERMANY HOLDING GMBH, GERMANY

Free format text: MERGER;ASSIGNOR:NYCOMED ASSET MANAGEMENT GMBH;REEL/FRAME:036395/0576

Effective date: 20141020