Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • 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
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • 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
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases where activation of CCR2 plays a causative role, especially pulmonary diseases like asthma and COPD, neurologic disease, especially of pain diseases, immune related diseases, especially diabetes mellitus including diabetes nephropathy, and cardiovascular diseases, especially
• the chemokines are a family of small, proinflammatory cytokines, with potent chemotatctic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation.
• ring R ⁇ is optionally substituted with one or more groups selected from among -Ci-C 6 -alkyl, -0-Ci-C 6 -alkyl, -C 5 -C 10 -aryl, -Cs-Cio-heteroaryl, -C 3 -C 8 -cycloalkyl,
• G and E are independently selected from among C or N;
• ring R ⁇ is optionally substituted with one or more groups selected from among -C 5 -C 10 -aryl, optionally being substituted by one or more groups selected from -CF 3 , and -OCF 3 , preferably selected from among -OCF 3 .
• R 7 is a ring selected from among-Cs-Cio-aryl, and -Cs-Cio-heteroaryl,
• -CF 3 -0-CF 3 , -CN, -Ci-C 6 -alkyl, and -halogen, preferably selected from among -halogen, -Ci-C 3 -alkyl -CF 3 , and -0-CF 3 , more preferred selected from among -CF 3 , and -0-CF 3 .
• Preferred compounds of formula (I) according to the invention are compounds with Ri, R 3 , R4, R5, 5, R7, R8, Li, E, G, and n as herein before or below defined,
• R 2 denotes -CH 3 .
• R 3 is selected from among -OCH 3 , -Ci-C 3 -alkyl, -CF 3 , and -H, preferably selected from among -H, and -methyl, more preferred wherein R 3 denotes -H.
• R 3 is selected from among -H, and -methyl, preferably wherein R 3 denotes -H.
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R4, R5, 5, R7, R8, Li, E, G, and n as herein before or below defined,
• R 3 denotes -H.
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R4, R5, 5, R7, R8, Li, E, G, and n as herein before or below defined,
• R 3 denotes -methyl
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R4, R5, 5, R7, R8, Li, E, G, and n as herein before or below defined,
• R 3 denotes -OCH 3 .
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R4, R5, 5, R7, R8, Li, E, G, and n as herein before or below defined,
• R 3 denotes -CF 3 .
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R 3 , R 5 , 5, R7, R8, Li, E, G, and n as herein before or below defined, wherein R4 denotes -H.
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R3, R4, R5, R5, R7, R8, Li, E, G, and n as herein before or below defined,
• R 5 denotes -H.
• G denotes N
• E is selected from among C, and N.
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R3, R4, R5, R5, R7, R8, Li, and n as herein before or below defined,
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R3, R4, R5, R5, R7, R8, Li, and n as herein before or below defined,
• Preferred compounds of formula (I) according to the invention are compounds with R l s R 2 , R3, R4, R5, R5, R7, R8, Li, and n as herein before or below defined,
• n 2
• such compounds as herein before or below defined could be used for making a medicament for the treatment of inflammatory diseases. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from inflammatory diseases of the respiratory tract. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from chronic obstructive pulmonary disease, asthma, and cystic fibrosis.
• such compounds as herein before or below defined could be used for making a medicament for the treatment of neurologic diseases, preferably for the treatment of pain diseases especially for the treatment of inflammatory and neuropathic pain disease, especially for the treatment of chronic pain. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of immune related diseases, preferably for the treatment of diabetes mellitus. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of cardiovascular diseases, preferably for the treatment of peripheral atherosclerotic disease. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of diabetic nephropathy.
• Present invention encloses compounds as herein before or below defined as medicaments.
• Present invention encloses compounds as herein before or below defined as medicaments for the treatment of inflammatory diseases.
• Present invention encloses compounds as herein before or below defined as medicaments for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from inflammatory diseases of the respiratory tract.
• Present invention encloses compounds as herein before or below defined as medicaments for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from chronic obstructive pulmonary disease, asthma, and cystic fibrosis.
• Present invention encloses compounds as herein before or below defined as medicaments for the treatment of neurologic diseases, preferably for the treatment of pain diseases especially for the treatment of inflammatory and neuropathic pain disease, especially for the treatment of chronic pain.
• Present invention encloses compounds as herein before or below defined as medicaments for the treatment of immune related diseases, preferably for the treatment of diabetes mellitus.
• Present invention encloses compounds as herein before or below defined as medicaments for the treatment of cardiovascular diseases, preferably for the treatment of peripheral atherosclerotic disease.
• Present invention encloses compounds as herein before or below defined as medicaments for the treatment of diabetic nephropathy.
• such compounds as herein before or below defined could be used for the treatment of inflammatory diseases. It has been found that such compounds as herein before or below defined could be used for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from inflammatory diseases of the respiratory tract. It has been found that such compounds as herein before or below defined could be used for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from chronic obstructive pulmonary disease, asthma, and cystic fibrosis. It has been found that such compounds as herein before or below defined could be used for the treatment of neurologic diseases, preferably for the treatment of pain diseases especially for the treatment of inflammatory and neuropathic pain disease, especially for the treatment of chronic pain.
• Such compounds as herein before or below defined could be used for the treatment of immune related diseases, preferably for the treatment of diabetes mellitus. It has been found that such compounds as herein before or below defined could be used for the treatment of cardiovascular diseases, preferably for the treatment of peripheral atherosclerotic disease. It has been found that such compounds as herein before or below defined could be used for the treatment of diabetic nephropathy.
• -Ci-C6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• the last named subgroup is the radical attachment point, for example, the substituent
• aryl-Ci-C3-alkyl- means an aryl group which is bound to a Ci-C3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
• 3-carboxypropyl-group represents the following substituent: wherein the carboxy group is attached to the third carbon atom of the propyl group.
• 1-methylpropyl-", "2,2-dimethylpropyl-” or "cyclopropylmethyl-” group represent the following groups:
• the asterisk may be used in sub- formulas to indicate the bond which is connected to the core molecule as defined.
• Many of the follwings terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
• substituents may also be represented in the form of a structural formula.
• An asterisk (*) in the structural formula of the substituent is to be understood as being the linking point to the rest of the molecule.
• the atom of the substituent which follows the linking point is referred to as the atom in position number 1.
• the groups N-piperidinyl (Piperidin-A), 4-piperidinyl (Piperidin-B), 2-tolyl (Tolyl-C), 3-tolyl (Tolyl-D), and 4-tolyl (Tolyl-E) are shown as follows:
• Piperidinyl-A Piperidinyl-B, Tolyl-C, Tolyl-D, an Tolyl-E.
• each hydrogen atom may be removed from the substituent and the valency thus freed may act as a binding site to the rest of a molecule.
• (Tolyl-F) may represent 2-tolyl, 3-tolyl, 4-tolyl, and benzyl
• substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
• the above- mentioned group optionally substituted by a lower-molecular group.
• lower- molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds.
• the groups may comprise:
• Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may in turn be substituted by functional groups.
• Ci-C n -alkyl wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
• Ci-C 5 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-,
• metal By the term “methenylene” is meant a group with 1 carbon atom, provided that it is linked by a single bond as well as on the other side by a double bond.
• the asterisks (*) in the structural formula is to be understood as being the linking points to the rest of the molecule, whereas the valency of the rest of the molecule be freed thus a single and a double bond can be formed by replacement of further hydrogens at the binding site if applicable:
• C 2 -C n -alkenylene is used for a group as defined in the definition for
• Carbon-C n -alkylene with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
• C 2 -C8-alkenylene (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 8 carbon atoms and by the term
• C 2 -C 6 -alkenylene are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms.
• Ci-C 2 -alkenylene are meant alkenylene groups with 1 to 2 carbon atoms, provided that they have at least one double bond, whereas by the term “Ci-alkenylene” is meant “methenylene”.
• Examples for C 2 -Cs-alkenylenes include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1 , 1-dimethylethenylene,
• propenylene, butenylene, pentenylene and hexenylene include all the possible isomeric forms of the groups in question with the same number of carbons.
• propenyl also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1 , 1-dimethylethenylene, 1 ,2-dimethylethenylene.
• C 2 -C n -alkynyl is used for a group as defined in the definition for "Ci-C n -alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
• C 2 -C 6 -alkynyl (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term
• C 2 -C 4 -alkynyl are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond.
• Examples for C 2 -C 6 -alkynyls include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl, pentynyl and hexynyl include all the possible isomeric forms of the groups in question.
• propynyl includes 1 -propynyl and 2-propynyl
• butynyl includes 1-, 2-, and 3-butynyl, 1 -methyl- 1 -propynyl, l-methyl-2-propynyl etc.
• C 2 -C n -alkynylene is used for a group as defined in the definition for
• Carbon-C n -alkylene with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
• C 2 -C8-alkynylene (including those which are part of other groups) are meant branched and unbranched alkynylene groups with 2 to 8 carbon atoms and by the term
• C 2 -C 6 -alkynylene are meant branched and unbranched alkynylene groups with 2 to 6 carbon atoms.
• Examples of C2-C8-alkynylenes include: ethynylene, propynylene,
• hexynylene include all the possible isomeric forms of the groups in question with the same number of carbons.
• propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1, 1-dimethylethynylene, 1, 2-dimethylethynylene.
• carbocyclyl as used either alone or in combination with another radical, means a mono- bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms.
• carbocycle refers to fully saturated and aromatic ring systems and partially saturated ring systems.
• carbocycle encompasses fused, bridged and spirocyclic systems:
• ring carbocycles, which can be saturated, unsaturated or aromatic and which optionally can comprise one or more hetero atoms selected from N, O or S.
• heterocycle is intended to include all the possible isomeric forms.
• heterocyclyl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• -Cs-Cs-heterocyclyl are meant three-, four-, five-, six-, seven-, or eight- membered, saturated or unsaturated heterocyclic rings which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen, whereas carbon atoms be replaced by such heteroatoms.
• the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one.
• -Cs-Cs-heterocyclyl are meant five-, six-, seven-, or eight-membered, saturated or unsaturated heterocyclic rings which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one.
• Examples for Cs-heterocyclyl include:
• C6-heterocyclyl examples include:
• heterocyclic ring may be provided with a keto group.
• heterocycle may be provided with a keto group. Examples include:
• C 3 -C n -cycloalkyl wherein n is an integer from 3 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
• C 3 -Cy-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Cs-Cs-cycloalkyl (including those which are part of other groups) are meant cyclic alkyl groups with 3 to 8 carbon atoms.
• C 3 -C 6 -cycloalkyl are meant cyclic alkyl groups with 3 to 6 carbon atoms.
• Examples of C 3 -Cs-cycloalkyls include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
• the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.
• C3-C n -cycloalkenyl wherein n is an integer from 3 to n, either alone or in combination with another radical, denotes an cyclic, unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to n C atoms, at least two of which are bonded to each other by a double bond.
• C3-C7-cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl
• aryl including those which are part of other groups
• Cs-Cio-aryl including those which are part of other groups
• aromatic ring systems with 5 to 10 carbon atoms.
• Preferred are “C 6 -Cio-aryl” groups whereas aromatic rings are meant with 6 to 10 carbon atoms. Examples include: phenyl or naphthyl.
• Cs-Ce-aryl whereas aromatic rings are meant with 5 to 6 carbon atoms Unless otherwise stated, the aromatic ring systems may be substituted by one or more groups selected from among methyl, ethyl, z ' so-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
• heteroaryl is intended to include all the possible isomeric forms.
• heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• the compounds according to the invention may optionally occur as racemates, but they may also be obtained as pure enantiomers / diastereomers.
• Membranes were prepared from THP-1 cells. THP-1 cells were centrifuged at 300xg at 4°C for 10 min. The cell pellet was resuspendet in Phosphate Buffer Saline (PBS , including 10 ⁇ Pefabloc and a protease inhibitor mix 'complete', Boehringer Mannheim (1 tablet/ 50 ml)), to a concentration of 80 cells/ ml. The membrane preparation was performed by disrupting the cells by nitrogen decomposition (at 50 bar, for lh) in a "Nitrogen Bombe" (Parr Instrument). Cell debris was removed by centrifugation (800xg at 4°C, 1 min).
• PBS Phosphate Buffer Saline
• the present invention provides a method for modulating or treating at least one MCP-1 related disease, in a cell, tissue, organ, animal, or patient, as known in the art or as described herein, using at least one CCR2 antagonist of the present invention.
• the present invention also provides a method for modulating or treating at least one MCP-1 related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of malignant disease, metabolic disease, an immune or
• Such conditions are selected from, but not limited to, diseases or conditions mediated by cell adhesion and/or angiogenesis.
• diseases or conditions include an immune disorder or disease, a cardiovascular disorder or disease, an infectious, malignant, and/or neurologic disorder or disease, or other known or specified MCP-1 related conditions.
• the CCR2 antagonists are useful for the treatment of diseases that involve inflammation such as COPD, angiogenesis such as disease of the eye and neoplastic disease, tissue remodeling such as restenosis, and proliferation of certain cells types particularly epithelial and squamous cell carcinomas.
• the present invention provides a method for modulating or treating at least one CCR2 related disease, in a cell, tissue, organ, animal, or patient, as known in the art or as described herein, using at least one CCR2 antagonist of the present invention. Particular indications are discussed below: Pulmonary Diseases
• the present invention also provides a method for modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: pneumonia; lung abscess; occupational lung diseases caused be agents in the form or dusts, gases, or mists; asthma, bronchiolitis fibrosa obliterans, respiratory failure, hypersensitivity diseases of the lungs iricludeing hypersensitivity pneumonitis (extrinsic allergic alveolitis), allergic bronchopulmonary aspergillosis, and drug reactions; adult respiratory distress syndrome (ARDS), Goodpasture's Syndrome, chronic obstructive airway disorders (COPD), idiopathic interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis, desquamative interstitial pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, idiopathic bronchiolitis obliterans with organizing pneumonia, lymphocytic interstitial pneu
• the present invention also provides a method for modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chromic myelocytic leukemia
• CML chronic lymphocytic leukemia
• CLL chronic lymphocytic leukemia
• MDS myelodyplastic syndrome
• a lymphoma Hodgkin's disease, a malignant lymphoma, non- hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma,
• colorectal carcinoma pancreatic carcinoma
• renal cell carcinoma breast cancer
• nasopharyngeal carcinoma malignant histiocytosis, paraneoplastic
• the present invention also provides a method for modulating or treating at least one immune related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospho lipid syndrome, iridocyclitisluveitisloptic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/ admireer's granulomatosis, sarcoidosis, orchitislvasectomy reversal procedures, allergiclatopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumoni
• the present invention also provides a method for modulating or treating at least one cardiovascular disease in a cell, tissue, organ, animal, or patient, including, but not limited to, at least one of cardiac 25 stun syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis, restenosis, diabetic ateriosclerotic disease, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis of the cardiovascular system, heart failure, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter, atrial fibrillation (sustained or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammation response, chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specific arrythrnias, ventricular fibrillation, His bundle arrythmias,
• the present invention also provides a method for modulating or treating at least one neurologic disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: Inflammatory pain, chronic pain, Neuropathic pain such as low back pain, hip pain, leg pain, non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve injury-induced pain, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma, toxin and chemotherapy caused nerve injuries, phantom limb pain, multiple sclerosis, root avulsions, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury, post surgical pain, carpal tunnel syndrome, trigeminal neuralgia, post mastectomy syndrome, postthoracotomy syndrome, stump pain, repetitive motion pain, neuropathic pain associated hyperalgesia and allodynia, alcoholism and other drug-induced pain; neurodegenerative diseases, multiple sclerosis,
• the present invention also provides a method for modulating or treating at least one wound, trauma or tissue injury or chronic condition resulting from or related thereto, in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: bodily injury or a trauma associated with surgery including thoracic, abdominal, cranial, or oral surgery; or wherein the wound is selected from the group consisting of aseptic wounds, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, infarctions and subcutaneous wounds; or wherein the wound is selected from the group consisting of ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns and donor site wounds; or wherein the wound is an aphthous wound, a traumatic wound or a herpes associated wound.
• Donor site wounds are wounds which e.g. occur in connection with removal of hard tissue from one part of the body to another part of the body e.g. in connection with transplantation.
• the wounds resulting from such operations are very painful and an improved healing is therefore most valuable.
• Wound fibrosis is also amenable to CCR2 antagonist therapy as the first cells to invade the wound area are neutrophils followed by monocytes which are activated by macrophages.
• Macrophages are believed to be essential for efficient wound healing in that they also are responsible for phagocytosis of pathogenic organisms and a clearing up of tissue debris. Furthermore, they release numerous factors involved in subsequent events of the healing process.
• the macrophages attract fibroblasts which start the production of collagen.
• the CCR2 antagonist of the invention can be used in methods for modulating, treating or preventing such sequelae of wound healing.
• the present invention also provides a method for modulating or treating at least one infectious disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HIV infection, HIV neuropathy, meningitis, hepatitis (A,B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, e.
• acute or chronic bacterial infection including acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HIV infection, HIV neuropathy, meningitis, hepatitis (A,B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, e.
• coli 0157:h7 hemolytic uremic syndrome/thrombo lytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitislepidydimitis, legionella, lyme disease, influenza a, epstein-barr virus, vital-associated hemaphagocytic syndrome, vital encephalitisiaseptic meningitis, and the like.
• Any method of the present invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one CCR2 antagonist to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.
• a composition or pharmaceutical composition comprising at least one CCR2 antagonist to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.
• these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
• B2-adrenoceptor-agonists short and lon-acting betamimetics
• anti-cholinergics short and lon-acting
• anti-inflammatory steroids oral and topical corticosteroids
• cromoglycate methylxanthine, dissociated-glucocorticoidmimetics
• PDE3 inhibitors PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors
• Lipoxygenase (5-LO) inhibitors Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors, non-steroidal antiinflammatory drugs (NSAIDs) including COX-2 inhibitors, CRTH2 antagonists, DPI -receptor modulators, Thromboxane receptor antagonists, CCR1 antagonists, CCR4 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR10 antagonists, CCR11 antagonists, CXCR1 antagonists, CXCR2 antagonists, CXCR3 antagonists, CXCR4 antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR1 antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1 -Phosphate receptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulators as
• Bradykinin (BK1, BK2) antagonists TACE inhibitors, PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-Co A reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonist, ENaC-inhibitors, Melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNFalpha antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL- 13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, compounds a
• the invention also encompasses combinations of three active substances, each selected from one of the above- mentioned categories of compounds. Said list is not considered to have a limiting character.
• the betamimetics used are preferably compounds selected from among albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol, tiaramide, terbutaline, tolubuterol, CHF- 1035, HOKU-81, KUL-1248, 3-(4- ⁇ 6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)- ethylamino]-hex
• the beta mimetics are selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tolubuterol, 3-(4- ⁇ 6-[2-hydroxy-2-(4-hydroxy-3- hydro xymethyl-phenyl)-ethylamino]-hexyloxy ⁇ -butyl)-benzenesulphonamide, 5-[2-(5,6- diethyl-indan-2-ylamino)- 1 -hydro xy-ethyl]-8-hydro xy- lH-quinolin-2-one , 4-hydroxy-7-[2- ⁇ [2- ⁇ [3 -(2-phenylethoxy)propyl] sulphonyl ⁇ ethyl]
• betamimetics are selected from among fenoterol, formoterol, salmeterol, 3-(4- ⁇ 6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]- hexyloxy ⁇ -butyl)-benzenesulphonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)- 1 -hydro xy- ethyl] -8-hydroxy- 1 H-quino lin-2-one, 1 - [3 -(4-methoxybenzyl-amino)-4-hydroxyphenyl] -2- [4- (1 -benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H- 1 ,4- benzoxazin-8-yl] -2- [3 -(4-N,N-dimethylaminophenyl)-2-methyl-2-prop
• betamimetics those which are particularly preferred according to the invention are formoterol, salmeterol, 3-(4- (6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)- ethylamino]-hexyloxy ⁇ -butyl)-benzenesulphonamide, 6-hydroxy-8- ⁇ 1 -hydro xy-2-[2-(4- methoxy-phenyl)- 1 , 1 -dimethyl-ethylamino]-ethyl ⁇ -4H-benzo[ 1 ,4]oxazin-3-one, 6-hydroxy-8- ⁇ 1 -hydro xy-2-[2-( ethyl 4-phenoxy-acetate)- 1 , 1 -dimethyl-ethylamino]-ethyl ⁇ -4H- benzo[ 1 ,4]oxazin-3-one, 6-hydroxy-8- ⁇ 1 -hydro xy-2-[2-(4-phenoxy-acetic
• the acid addition salts of the betamimetics are preferably selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydroiumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonat, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydroiumarate and hydromethanesulphonate.
• the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.
• the anticholinergics used are preferably compounds selected from among the tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, tropenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide, tropenol 2-fluoro-2,2- diphenylacetate methobromide, tropenol 3,3',4,4'-tetrafluorobenzilate methobromide, scopine 3,3',4,4'-tetrafluorobenzilate methobromide, tropenol 4,4'-difluorobenzilate methobromide, scopine 4,4'-difluorobenzilate methobromide, tropenol 3,3'-difluorobenzilate
• the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active ingredients.
• the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate,
• tiotropium bromide In the case of tiotropium bromide the pharmaceutical combinations according to the invention preferably contain it in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, it is preferable to use anhydrous crystalline tiotropium bromide, which is known from WO 03/000265.
• Corticosteroids used here are preferably compounds selected from among prednisolone, prednisone, butixocortpropionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, defiazacort, RPR-106541, NS-126, (S)-fiuoromethyl 6,9-difluoro- 17-[(2- furanylcarbonyl)oxy]- 11 -hydroxy- 16-methyl-3-oxo-androsta- 1 ,4-diene- 17-carbothionate and (S)-(2-oxo-tetrahydro-furan-3 S-yl) 6,9-difluoro- 11 -hydroxy- 16-methyl-3-oxo- 17- propionyloxy-androsta-l,4-diene-l 7-carbothionate
• the steroid selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide,
• steroid selected from among budesonide, fluticasone,
• the PDE4-inhibitor used are preferably compounds selected from among enprofyllin, roflumilast, ariflo (cilomilast), arofyUin, atizoram, AWD-12-281 (GW-842470), T-440, T- 2585, PD-168787, V-l 1294A, Cl-1018, CDC-801, D-22888, YM-58997, Z-15370, N-(3,5- dichloro- 1 -oxo-pyridin-4-yl)-4-difluoromethoxy-3 -cyclopropylmethoxybenzamide, cis[4- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-carboxylic acid], 2- carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-l- one, cis[4-cyano
• LTD4-antagonists which may be used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM- 1507), VUF-5078, VUF-K-8707, L-733321, l-(((R)-(3-(2-(6,7-difiuoro-2- quino linyl)ethenyl)phenyl)-3 -(2-(2- hydro xy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, l-(((l(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(l- hydroxy- l-methylethyl)phenyl)propyl)thio)methyl)cyclo propane
• the LTD4-antagonist is selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L- 733321, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
• hydromethanesulphonate hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydroiumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydro fumarate and hydromethanesulphonate.
• salts or derivatives which the LTD4-antagonists may be capable of forming are meant, for example: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
• alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
• the EGFR-inhibitors are selected from among 4-[(3-chloro-4- fluorophenyl)amino]-6- ⁇ [4-(morpholin-4-yl)- 1 -oxo-2-buten- 1 -yl] amino ⁇ -7- cyclopropylmethoxy-quinazoline, 4-[(R)-(l-phenyl-ethyl)amino]-6- ⁇ [4-(morpholin-4-yl)- 1 -oxo-2-buten- 1 -yl] amino ⁇ -7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro- phenyl)amino]-6- ⁇ [4-((R)-6-methyl-2-oxo-morpholin-4-yl)- 1 -oxo-2-buten- 1 -yljamino ⁇ -7- [(S)-(tetrahydrofuran-3-yl)
• acid addition salts with pharmacologically acceptable acids which the EGFR-inhibitors may be capable of forming are meant, for example, salts selected from among the
• hydrochloride hydrobromide, hydroiodide, hydrosulphate, hydrophosphate
• hydromethanesulphonate hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydroiumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydroiumarate and hydromethanesulphonate.
• dopamine agonists which may be used preferably include compounds selected from among bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride and viozan.
• Any reference to the above- mentioned dopamine agonists within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts and optionally hydrates thereof which may exist.
• physiologically acceptable acid addition salts which may be formed by the above-mentioned dopamine agonists are meant, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
• HI -antihistamines preferably include compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine.
• HI -antihistamines within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts which may exist.
• PAF-antagonists preferably include compounds selected from among 4-(2- chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-l-yl]-6H-thieno-[3,2-fJ- [l,2,4]triazolo[4,3-a][l,4]diazepines, 6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[(4- morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepines.
• MRP4-inhibitors are preferably selected from among N-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-S-glutathione, estradiol 3, 17- disulphate, flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen,
• MRP4-inhibitors are selected from among dehydroepiandrosterone 3- sulphate, estradiol 3, 17-disulphate, flurbiprofen, indomethacin, indoprofen, MK571 , taurocholate, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof.
• the separation of enantiomers from the racemates can be carried out using methods known from the art (e.g. chromatography on chiral phases, etc.) .
• acid addition salts with pharmacologically acceptable acids are meant, for example, salts selected from among the hydrochlorides, hydrobromides, hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates,
• the invention further relates to pharmaceutical preparations which contain a triple combination of the CCR2 inhibitors, MRP4-inhibitors and another active substance according to the invention, such as, for example, an anticholinergic, a steroid, an LTD4-antagonist or a betamimetic, and the preparation thereof and the use thereof for treating respiratory complaints.
• a triple combination of the CCR2 inhibitors, MRP4-inhibitors and another active substance according to the invention such as, for example, an anticholinergic, a steroid, an LTD4-antagonist or a betamimetic, and the preparation thereof and the use thereof for treating respiratory complaints.
• the iNOS-inhibitors used are preferably compounds selected from among: S-(2- aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT, L-canavanine, 2- iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea, S- methyltiocitrulline, S-ethylthiocitrulline, L-NA (N co -nitro-L-arginine), L-NAME (TNP-nitro-L- arginine methylester), L-NMMA (N G -monomethyl-L-arginine), L-NIO (N co -iminoethyl-L- ornithine), L-NIL (N co -iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino-hexanoic
• Compounds which may be used as SYK- inhibitors are preferably compounds selected from among: R343 or R788.
• MAP kinase inhibitors as for example p38, ER l, ERK2, JNK1, JNK2, JNK3 or SAP, which may be mentioned include SCIO-323, SX-011, SD-282, SD-169, NPC-037282, SX-004, VX-702, GSK-681323, GSK-856553, ARRY-614, ARRY-797, ARRY-438162, ARRY-p38-002, ARRY-371797, AS-602801, AS-601245, AS-602183, CEP- 1347, KC706, TA-5493, RO-6226, Ro-1487, SC-409, CBS-3595, VGX-1027, PH-797804, BMS-582949, TA-5493 and BIRB-796 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• IKK2 kinase inhibitors examples include: MD-1041, MLN-041 und AVE-0547 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• Leukotriene biosynthesis inhibitors as for example 5 -Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 hydrolase inhibitors oder FLAP inhibitors, which may be mentioned include zileuton, tipelukast, licofelone, darapladib, TA- 270, IDEA-033, IDEA-070, NIK-639, ABT-761, fenleuton, tepoxalin, AM- 103, AM-803, Abbott-79175, Abbott-85761, PLT-3514, CMI-903, PEP-03, CMI-977, MLN-977, CMI-947, LDP-977, efipladib, PLA-695, veliflapon, MK-591, MK-886 und BAYxl005 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salt
• acetic acid derivatives indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac
• fenamic acid derivatives meclofenamic acid, mefenamic acid
• diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• CCRl antagonists examples include AZD-4818, CCX- 354, MLN-3701, MLN-3897, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• CCR5 antagonists examples include maraviroc, INCB- 15050.
• Examples of preferred CXCRl or CXCR2 antagonists which may be mentioned include SCH- 527123 and SB-656933 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• NK1 or NK2 antagonists examples include Saredutant, Nepadutant, PRX-96026 und Figopitant optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• preferred purinergic receptor modulators including P2X7 inhibitors, which may be mentioned include AZD-9056 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• TLR Toll- like receptor
• Resiquimod Resiquimod
• PF-3512676 AVE-0675
• Heplisav IMO-2055
• CpG-28 CpG-28
• TAK-242 SAR-21609
• RC-52743198 and 852 A optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• VLA4 antagonists which may be mentioned include Natalizumab, Valategrast, TBC-4746, CDP-323 andTL-1102 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
• Examples of preferred Antiviral drugs which may be mentioned include acyclovir, tenovir, pleconaril, peramivir, pocosanol.
• Examples of preferred Antibiotic drugs like gentamicin, streptomycin, geldanamycin, doripenem, cephalexin, cefaclor, ceftazichine, cefepime, erythromycin, vancomycin, aztreonam, amoxicillin, bacitracin, enoxacin, mafenide, doxycycline, chloramphenicol.
• Examples of preferred opiate receptor agonists are selected from among morphine, propoxyphene (Darvon), tramadol , buprenorphin.
• Targets such as but not limited to CD-4, CTLA-4, LFA-1, IL-6, ICAM-1, C5 and Natalizumab.
• IL-1 receptor antagonists such as but not limited to Kineret
• Sodium channel blockers carbamazepine, mexiletine, lamotrigine, tectin, lacosamide
• Examples of preferred N-type calcium channel blockers are selected from among Ziconotide.
• Serotonergic and noradrenergic modulators such as but not limited to paroxetine, duloxetine, clonidine, amitriptyline, citalopram;
• Histamine HI receptor antagonists such as but not limited to bromophtniramint, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiJazine,
• promethazine trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, deslo- ratadine, fexofenadine and levocetirizine.
• Histamine H2 receptor antagonists such as but not limited to cimetidine, famotidine and ranitidine.
• preferred proton pump inhibitors such as but not limited to omeprazole, pantoprazole and esomeprazole.
• Leukotriene antagonists and 5 -lipoxygenase inhibitors such as but not limited to zafirlukast, montelukast, pranlukast and zileuton.
• Examples of preferred local anesthetics such as but not limited to ambroxol, lidocaine.
• preferred potassium channel modulators such as but not limited to retigabine.
• Examples of preferred GABA modulators such as but not limited to lacosamide, pregabalin, gabapentin.
• Examples of preferred anti-migraine drugs such as but not limited to sumatriptan,
• Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols.
• the content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.
• the preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension.
• a tablet e.g. a powder
• a capsule e.g. a hard gelatine capsule
• the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.
• Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core may also consist of a number of layers.
• the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
• Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as /?-hydroxybenzoates.
• a sweetener such as saccharine, cyclamate, glycerol or sugar
• a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
• suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as /?-hydroxybenzoates.
• Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
• Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and
• paraffins e.g. petroleum fractions
• vegetable oils e.g. groundnut or sesame oil
• mono- or polyfunctional alcohols e.g. ethanol or glycerol
• carriers such as e.g. natural mineral powders (e.g. kaolins, clays, tal
• polyvinylpyrrolidone polyvinylpyrrolidone
• lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
• the compounds of formula (I) are administered by inhalation, particularly preferably if they are administered once or twice a day.
• the compounds of formula (I) have to be made available in forms suitable for inhalation.
• Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients.
• propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions.
• the preparations which may be used according to the invention are described in more detail in the next part of the specification.
• lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates.
• lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
• the propellant-containing inhalable aerosols which may be used according to the invention may contain the active substances of formula (I) dissolved in the propellant gas or in dispersed form.
• the propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halo hydro carbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• the propellant gases mentioned above may be used on their own or in mixtures thereof.
• these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect.
• the excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates,
• polyvinylpyrrolidone other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art.
• the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
• the preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens.
• Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
• ready-to-use packs of a medicament for the treatment of respiratory complaints are provided, containing an enclosed description including for example the words respiratory disease, COPD or asthma, a pteridine and one or more combination partners selected from those described above.
• Carrier gas Helium, 1 ml/min costant flow

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