EP1494645A2 - Method of treating mucus hypersecretion - Google Patents

Method of treating mucus hypersecretion

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Publication number
EP1494645A2
EP1494645A2 EP03720407A EP03720407A EP1494645A2 EP 1494645 A2 EP1494645 A2 EP 1494645A2 EP 03720407 A EP03720407 A EP 03720407A EP 03720407 A EP03720407 A EP 03720407A EP 1494645 A2 EP1494645 A2 EP 1494645A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
phenyl
optionally
optionally substituted
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP03720407A
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German (de)
English (en)
French (fr)
Inventor
Birgit Jung
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to EP03720407A priority Critical patent/EP1494645A2/en
Publication of EP1494645A2 publication Critical patent/EP1494645A2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the use of p38 kinase inhibitors for the preparation of a pharmaceutical composition suitable for inhalation for the treatment of mucus hypersecretion. Furthermore the invention is directed to pharmaceutical compositions suitable for inhalation comprising p38 kinase inhibitors and to methods for the preparation thereof.
  • MAPK mitogen-activated protein kinases
  • p38 also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, was isolated from murine pre-B cells that were transfected with the lipopolysaccharide (LPS) receptor CD14 and induced with LPS.
  • LPS lipopolysaccharide
  • p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mouse.
  • Activation of p38 has been observed in cells stimulated by stresses, such as treatment of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF.
  • p38 along with other MAPKs, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia.
  • MAPKs such as p38
  • MAPKs have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders.
  • Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction.
  • the mucociliary system serves as the primary defence mechanism to move inhaled particles or infectious agents out of the airways in the lungs.
  • substances present in airway fluids serve to limit the toxicity of the particles and the inactivate infective agents.
  • the physical mechanism of coughing serves to expel the mucus from the airway passages (see e.g., "Foundation of Respiratory Care,” Pierson and Kacmarek, eds. (1992) Churchill Livingstone Inc. New York, New York; “Harrison's Principles of Internal Medicine", Fauci et al., eds. (1997) 14th Edition, McGraw Hill, New York, New York).
  • the mucociliary system consists of ciliated epitelial cells, epithelial goblet cells, and serous and mucous cells located in submucosal glands.
  • the cilia are surrounded by an aqueous layer (periciliary fluid) secreted into the lumen of the airway passage by the active transport of chloride and the passive movement of water across the epithelium.
  • the cilia make contact with the mucus floating on this aqueous layer, and via a unidirectional propelling motion provide for movement of mucus toward the glottis (see Pierson and Kacmarek).
  • Mucus is produced by the epithelial goblet cells and submucosal gland cells and is secreted into the lumen of the airway after degranulation.
  • Cystis fibrosis is an autosomal recessive diseases that causes the airway mucosal cell to become unresponsive to cyclic-AMP-dependent protein kinase activation of the membrane chloride ion channels (Pierson and Kacmarek). The subsequent electrolyte imbalance reduces the level of hydration of the airway mucus, thus resulting in highly viscous mucus in the lungs of an individual afflicted with cystic fibrosis. Hypersecretion obstructs the air passages of individuals with cystic fibrosis, further compromising lung function.
  • mucosal clearence is reduced.
  • Pathological agents such as bacteria, e.g. Pseudomonas aeruginosa, often establish colonies within the mucus, resulting in frequent lung infection.
  • Classical modalities of treating individuals afflicted with airway hypersecretion include antibiotic therapy, bronchodilators (e.g., methylxantines, sympathomimetics with strong ⁇ 2 adrenergic stimulating properties, anticholinergics), use of systemic or inhaled corticosteroids, liquefaction of the mucus by oral administration of expectorants, and aerosol delivery of "mucolytic" agents, e.g. water, hyperonic saline solution (see Harrison's, supra).
  • bronchodilators e.g., methylxantines, sympathomimetics with strong ⁇ 2 adrenergic stimulating properties, anticholinergics
  • systemic or inhaled corticosteroids liquefaction of the mucus by oral administration of expectorants
  • aerosol delivery of "mucolytic” agents e.g. water, hyperonic saline solution (see Harrison's, supra).
  • a newer therapy for cystic fibrosis is
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, in particular cystic fibrosis.
  • p38 kinase inhibitors applicable within the scope of the invention are known in the art. Suitable compounds are disclosed for instance in US Patents
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula ⁇ as disclosed in WO 99/01131
  • R-l is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, 1 ,2,4-triazin-5-yl, quinolyl, isoquinolinyl, or quinazolin-4-yl ring, which ring is substituted with Y-R a and optionally with an additional independent substituent selected from C - alkyl, halogen, hydroxyl, C 4 alkoxy, C,- 4 akylthio, C 4 aklylsulfinyl, CH 2 OR 12 , amino, mono and di- C 6 alkyl substituted amino, an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 1?
  • R4 is phenyl, naphth-1-yl or naphth — yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4naphth-1-yl, 5-naphth-2-yl or 6-naphth-2- yl substituent, is halogen, cyano, nitro, C(Z)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) V COR 12 , SR 5 , SOR 5 , OR 12 , halo-substituted-C M alkyl, C ⁇ alkyl,
  • R 22 is an optionally substituted C 1-10 alkyl;
  • R a is aryl, arylC,. 6 alkyl, heterocyclic, heterocyclylC., ⁇ alkyl, heteroaryl, heteroarylC ⁇ alkyl, wherein each of these moieties may be optionally substituted;
  • R b is hydrogen, C,. 6 alkyl, C 3 . 7 cycloalkyl, aryl, aryl C M alkyl, heteroaryl, heteroarylC ⁇ alkyl, heterocyclyl, or heterocyclylC, ⁇ alkyl, wherein each of these moieties may be optionally substituted;
  • R 3 is heterocyclyl, heterocyclyl C
  • R 5 is hydrogen, C ⁇ alkyl, C 2 alkenyl, C 2 alkynyl or NR 7 R 17 , excluding the moieties SR 5 being SNR 7 R 17 and SOR 5 being SOH;
  • R 6 is hydrogen, a pharmaceutically acceptable cation, C h alky!, C 3 .
  • R 7 and R 17 is each independently selected from hydrogen or C, ⁇ alkyl or R 7 and R 17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;
  • R 8 is C,_ 10 alkyl, halo-substituted C,. alkyl, C 2 . 10 alkenyl, C 2-10 alkynyl, C 3 . 7 cycloalkyl, C 5 . 7 cycloalkenyl, aryl, aryl C,.
  • R is hydrogen, C ⁇ Q alkyl, C 3 . 7 cycloalkyl, heterocyclyl, heterocyclyl C,_ 10 alkyl, aryl, arylC.,_ 10 alkyl, heteroaryl or heteroaryl C ⁇ o alkyl, wherein these moieties may be optionally substituted;
  • R 12 is hydrogen or R 16 .
  • R 13 an R 14 is each independently selected from hydrogen or optionally substituted
  • C_ alkyl optionally substituted aryl or optionally substituted arylC 1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ;
  • R 15 is R 10 or C(Z)-C ⁇ alkyl;
  • R 16 is C.,. 4 alkyl, halo-substituted-C, ⁇ alkyl, or C 3 . 7 cycloalkyl;
  • R 18 is C ⁇ o alkyl, C 3 . 7 cycloalkyl, heterocyclyl, aryl, aryl.,. 10 alkyl, heterocyclyl, heterocyclyl- C h alky!, heteroaryl or heteroaryl 1 _ 10 alkyl; or a pharmaceutically acceptable salt thereof.
  • R 2 is a substituted alkyl derivative. It is recognised that the first methylene carbon in this chain is a tertiary carbon, and it will contain one hydrogen moiety. This ethylene group has two additional substituents, an R 22 moiety and an A moiety, -C(H)(A)( R 22 ). Both A and R 22 may not be unsubstituted C,.. 10 alkyl moiety.
  • R 2 is a -C(AA 1 )(A) moiety, wherein AA 1 is the R 22 moiety, but is specifically the side chain residue (R) of an amino acid, as is further described herein.
  • A is an optionally substituted C 13 . 7 cycloalkyl, aryl, heteroaryl, or heterocyclic ring, or A is a substituted C 1-10 alkyl moiety.
  • the ring may be substituted independently one or more times, preferably, 1 to 3 times by C_._ 0 alkyl; halogen; halo substituted C 1-10 alkyl such as CF 3 ; (CR ⁇ R ⁇ ORn; (CR 10 R 20 ) t NR 12 R 14 , especially amino or mono-or di-C ⁇ alkylamino; (CR 10 R 20 ),S(O)m R 18 , wherein m is 0, 1 or 2; SH; NR 10 C(Z)R 3 (such NHCO(C 1-10 alkyl)); or NR 10 S(O)m R 8 (such as NHSO ⁇ o alkyl)).
  • C_._ 0 alkyl halogen; halo substituted C 1-10 alkyl such as CF 3 ; (CR ⁇ R ⁇ ORn; (CR 10 R 20 ) t NR 12 R 14 , especially amino or mono-or di-C ⁇ alkylamino; (CR 10 R 20 ),S(O)m R 18
  • t is 0, or an integer of 1 to 4.
  • A is an optionally substituted cycloalkyl it is as defined below with the R 22 substitution.
  • the ring is preferably a morpholino, pyrrolidinyl, piperazinyl or a piperidinyl ring.
  • A is an optionally substituted aryl moiety, it is preferably a phenyl ring.
  • A is an optionally substituted heteroaryl ring, it is as defined below in the definition section.
  • the alkyl chain may be straight or branched.
  • the chain is substituted independently 1 or more times, preferably 1 to 3 times by halogen, such as fluorine, chlorine, bromine or iodine; halosubstituted C,. ⁇ alkyl, such as CF 3 ; C 3.7 cycloaklyl, C ⁇ alkloxy, such as methoxy or ethoxy; hydroxy substituted C 1-10 alkoxy; halosubstituted C .
  • A is a C 3 . 7 cycloalkyl, or a C,. 6 alkyl, more preferably a C,_ 2 alkyl, i.e. a methylene or ethylene moiety, more preferably a methylene moiety which is substituted by one of the above noted groups.
  • A when A is a C ⁇ 0 alkyl, it is substituted by ORvenue where R ⁇ is preferably hydrogen, aryl or arylalkyl; NR 13 R 14 ; OC(Z)R 11 ; C(Z)OR 11 . More preferably, A is substituted by OR ⁇ where Rêt is hydrogen.
  • R 22 is a C,_., 0 alkyl chain, which chain may be straight or branched and which may be optionally substituted independently, one or more times, preferably 1 to 3 times, by halogen, such as fluorine, chlorine or iodine; halo substituted C,.
  • R 22 substituent groups which contain carbon as the first connecting group i.e. C(Z)OR.,.,; C(Z)NR 11 OR 9 , C(Z)R 11 , C(Z)NR 13 R 14 , and
  • R 22 group may, for instance, be a carboxy, an aldehyde, or an amide, as well as being a substituent of a methylene unit, such as carbamoylmethyl, or acetamidomethyl.
  • R 22 is a C,.
  • alkyl group such as a C ⁇ alkylene such as methyl, ethyl or isopropyl, or a methylene or ethylene moiety substituted by one of the above noted moieties, or as noted above those substituent groups which contain a carbon may substituent for the first methylene unit of the alkyl chain, such as carboxy, C(O)OR 11 ; C(O)NR 13 R 14 or R 22 is an optionally substituted aryl group, such as a benzyl or phenethyl.
  • R 22 is C,. 6 unsubstituted or substituted alkyl group, more preferably a C,. 2 alkylene chain, such as a methylene or ethylene moiety, more preferably methylene.
  • the alkyl chain is substituted by OR ⁇ , where R relieve is preferably hydrogen, aryl or arylalkyl; S(O) m R 18t where m is 0 and R 18 is a C,_ 6 alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety. More preferably, R ⁇ is phenyl, benzyl, CH 2 OH, or CH 2 -O-aryl.
  • one or both of A and R 22 contain hydroxy moieties, such as in C,. 6 alkyl OR.,.,, wherein R ⁇ is hydrogen, i.e. CH 2 CH 2 OH.
  • AA 1 is the (R) side chain residue of an amino acid
  • it is a C,_ 6 alkyl group, which may be straight or branched.
  • the R residue term is for example, CH 3 for alanine, (CH 3 ) 2 CH- for valine, (CH 3 ) 2 CH-CH 2 -for leucine, phenyl- CH 2 - for phenylalanine, CH 3 -S-CH 2 -CH 2 - for methionine, etc.
  • All generally recognised primary amino acids are included in this groups, such as but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, hydroxylysine, methylhistidine, and other naturally accurring amino acids not found in proteins, such as ⁇ -alanine, Y-aminobutyric acid, homocysteine, homoserine, citrulline, ornithine, canavanine, djenkolic acid, and ⁇ -cyanoalanine, or other naturally occurring non-mammalian amino acids.
  • AA 1 is the residue of phenylalanine, or alanine.
  • A is a hydroxy substituted C,. 10 alkyl and R 22 is a C h alky! or a hydroxy substituted C h alky!.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds disclosed in WO 99/01131 : 1-(1 ,3-Dihydroxyprop-2-yl)-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; frat?s-1-(4-Hydroxycyclohexyl)-4-(4-fluorophenyl)5-[(2-methoxy)pyrimidin-4- y ⁇ midazole;
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 2 as disclosed in US 6,277,989
  • R1 is H, alkyl(1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR2, SR,
  • each R is independently H or lower alkyl (1-4C); each R 2 is independently alkyl (1-6C), halo, OR, SR, OOCR, NROCR, COOR, RCO, CONR , SO 2 NR 2 , CN, CF3 or NO 2 , wherein each R is independently H or lower alkyl (1-4C); each of I, m, and n is independently 0, 1 or 2; and Ar is phenyl, 2-, 3- or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, or benzimidazolyl, each optionally substituted with optionally substituted alkyl, alkenyl, alkynyl, aryl, N- aryl, NH-aroyl, halo, OR, NR 2 , SR, -OOCR
  • each R is independently H or alkyl (1-4C);
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 2 as disclosed in US 6,277,989 , wherein R1 is H; R 2 is halo, m is 0, 1 , or 2, and I is 1 or 2; Ar is 4-pyridyl.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the follwoing compounds disclosed US 6,277,989:
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 3a, 3b, 3c, or 3d as disclosed in US 6,340,685
  • Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; n is O, 1 or 2;
  • Z 3 is N; X 2 is CH or CH 2 ; and
  • Ar consists of one or two phenyl moieties directly coupled to ⁇ , said one or two phenyl moieties being optionally substituted by a substituent selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), CN, CF 3 , RCO, COOR, CONR 2 , NR 2 , OR, SR, OOCR, NROCR, (wherein R in the foregoing is H or 1-6C alkyl), and phenyl, itself optionally substituted by the foregoing substituents; R is selected from H, and alkyl (1-6C); wherein said alkyl optionally includes one or more heteroatoms which are selected from O, S and N, and wherein said alkyl is optionally substituted by one or more substituents selected from halo, OR, SR, NR 2 , RCO, COOR,
  • R3 is H, halo, NO 2 , alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR 2 , RCO, COOR, CONR 2 , OOCR, or NROCR where R is H or alkyl (1 -6C).
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the follwoing compounds disclosed US 6,340,685:
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 4 as disclosed in WO 00/43384
  • Ar is a heterocyclic group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and wherein Ar, may be substituted by one or more R perpetratR 2 or R 3 ;
  • Ar 2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R 2 groups;
  • L a linking group
  • L is a C,. 10 saturated or unsaturated branched or unbranched carbon chain; wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C,. 4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
  • Q is selected from the group consisting of:
  • R. is selected from the group consisting of:
  • cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C,. 3 alkyl groups;
  • R 2 is selected from the group consisting of: a C,. 6 branched or unbranched alkyl which may optionally be partially or fully halogenated, acetyl, aroyl, C 1-4 branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
  • R 3 is selected from the group consisting of: a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein such phenyl, naphthy
  • heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di- (C 1-3 )alkyl aminocarbonyl, C ⁇ alkyl-C(O)-C ⁇ alkyl, amino-C ⁇ alkyl, mono- or di-(C 1-3 )alkylamino-C 1-5 alkyl, amino-S(O) 2 , di-(C 1 . 3 )alkylamino-S(O) 2 , R 4 - C 1-5 alkyl, alkoxy, R 6 -C(O)-C,.
  • heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(C 1-3 )alkyl aminocarbonyl, C alkyl-OC(O), C 1-5 alkyl-C(O)-C 1-4 branched or unbranched alkyl, an amino-C,. 5 alkyl, mono- or di-(C,. 3 )alkylamino-C.,. 5 alkyl, R 9 -C,..
  • cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which the cycloalkyl may optionally be partially or fully halogenated and which may optionally be substituted with one to three C ⁇ alkyl groups; d) C 5 .
  • cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C, ⁇ alkyl groups; and e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; f) C 1-6 branched or unbranched alkyl which may optionally be partially or fully halogenated;
  • R 1 and R 2 taken together may optionally form a fused phenyl or pyridinyl ring,
  • each R 8 , R 13 is independently selected from the group consisting of: hydrogen and C M branched or unbranched alkyl which may optionally be partially or fully halogenated;
  • X O or S and physiologically acceptable acids or salts thereof.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 4 as disclosed in WO 00/43384 wherein Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl.
  • a more preferred subgeneric aspect of the invention comprises the use of compounds of the formula 4 wherein Ar 2 is naphthyl.
  • a yet more preferred subgeneric aspect of the invention comprises the use of compounds of the formula 4, as described in the immediate previous paragraph, wherein: A is thiophene or pyrazole; Ar 2 is 1 -naphthyl;
  • L is saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C, ⁇ branched or unbranched alkyl which may be substituted by one or more halogen atoms;
  • R 1 is selected from the group consisting of C ⁇ alkyl branched or unbranched, cyclopropyl and cyclohexyl which may optionally be partially or fully halogenated and which may optionally be substituted with one to three C ⁇ alkyl groups;
  • R 3 is selected from the group consisting of C ⁇ alkyl branched or unbranched, cyclopropyl, phenyl, pyridinyl each being optionally substituted as described above, alkoxycarbonylalkyl; C ⁇ alkyl branched or unbranched; cyclopropyl or cyclopentyl optionally substituted as
  • a yet further preferred subgeneric aspect of the invention comprises the use of compounds of the formula 4, as described in the immediate previous paragraph, wherein Ar, is pyrazole.
  • a still yet further preferred subgeneric aspect of previous the invention comprises the use of compounds of the formula 4, as described in the immediate paragraph, wherein L is carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1i4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
  • L is propoxy, ethoxy, methoxy, methyl, propyl, C 3 . 5 acetylene or methylamino each being optionally substituted are described herein.
  • a more particularly preferred embodiment of L is ethoxy optionally substituted.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the follwoing compounds of formula 4 as disclosed in WO 00/43384:
  • Particularly preferred compounds of the formula 4 are:
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139
  • An is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein A may be substituted by one or more R.,, R 2 or R 3 ;
  • Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three R 2 groups;
  • X is: a) a C 5 . 8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C, ⁇ branched or unbranched alkyl, C, ⁇ alkoxy or C, ⁇ alkylamino chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 0-3 C, ⁇ branched or unbranched alkyl, C ⁇ alkoxy, hydroxy, nitrile, mono- or di-(C 1 ⁇ 3 alkyl)amino, C, ⁇ alkyI-S(O) m , or halogen;
  • Y is: a bond or a C M saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O) 2 or S and wherein Y is optionally independently substituted with 0-2 oxo groups and one or more C M branched or unbranched alkyl which may be substituted by one or more halogen atoms;
  • Z is: a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan, thiophene, pyran, which are optionally substituted with one to three groups consisting of halogen, C, favor 6 alkyl, C,. 6 alkoxy, hydroxy, mono- or di-(C 1 . 3 alkyl)amino,
  • branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen, G, ⁇ branched or unbranched alkyl which is optionally partially or fully halogenated, C 3 .
  • cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyi, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three G, ⁇ alkyl groups; e) nitrile; or f) branched or unbranched alkoxycarbonyl, C,_ 6 branched or unbranched alkylaminocarbonyl, C 1-6 branched or unbranched alkylcarbonylamino-C ⁇ - alkyl;
  • R 2 is: a C,_ 6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C, ⁇ branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl;
  • R 3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally
  • alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1 . 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C 1 . 3 )alkyl aminocarbonyl, C,. 5 alkyl-C(O)-C,. 4 alkyl, amino-C,.
  • a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclohexanoindole,
  • cycloalkyl selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C,. 3 alkyl groups; d) C 5 .
  • cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C, ⁇ alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) C 1- ⁇ branched or unbranched alkyl optionally partially or fully halogenated;
  • R 1 and R 2 taken together may optionally form a fused phenyl or pyridinyl ring;
  • each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C ⁇ branched or unbranched alkyl optionally be partially or fully halogenated;
  • each R 4 , R 5 , R 6 , R 7 , R 9 , R 10 R Formula and R 12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein:
  • Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein: Ar, is selected from thiophene and pyrazole;
  • X is Cg_ 7 cycloalkyl or C 5 . 7 cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C-,. 4 branched or unbranched alkyl, C alkoxy or C M alkylamino; or X is phenyl, pyridine, tetrahydropyridine, pyrimidine, furan or thiophene each being optionally independently substituted with 0-3 C,. 4 branched or unbranched alkyl, C 1-4 alkoxy, hydroxy, nitrile, mono- or di-(C 1 .
  • R 1 is C ⁇ alkyl branched or unbranched, cyclopropyl or cyclohexyl optionally partially or fully halogenated and optionally substituted with one to three C, .3 alkyl groups
  • R 3 is C ⁇ alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl or pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein:
  • Ar is pyrazole
  • X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with an oxo group or 0-3 C M branched or unbranched alkyl, C ⁇ alkoxy or
  • X is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 0-3 C,_ 4 branched or unbranched alkyl, C ⁇ alkoxy, hydroxy, nitrile, mono- or di-(C 1-3 alky!)amino, G,. 6 alkyl-S(O) m or halogen.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein:
  • Y is -CH2-, -CH2CH2-, -CH2NH-, -CH2CH2NH- or a bond;
  • Z is phenyl, imidazole, furan, piperazine, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, pyridine, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C,_ 3 alkyl and phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C,.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein: Ar, is 5-te/ ⁇ -butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted by 3 ;
  • R 3 is C ⁇ alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl, pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein X is pyridinyl.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein the pyridinyl is attached to Ar, via the 3-pyridinyl position.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 as disclosed in WO 00/55139 that are mentioned below:
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5 :
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a as disclosed in WO 00/55139
  • Ar is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein A is optionally substituted by one or more R.,, R 2 or R 3 ;
  • Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole each being optionally substituted with zero to three R 2 groups;
  • X is: a C 5 . 8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C, ⁇ alkyl, C ⁇ alkoxy or C 1-4 alkylamino chains each being branched or unbranched; phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C M alkyl, C ⁇ alkoxy, hydroxy, nitrile, amino, mono- or di-(
  • Y is: a bond or a C 1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C, ⁇ alkyl optionally substituted by one or more halogen atoms;
  • Z is: aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, t
  • each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C,_e alkyl, C ⁇ alkoxy, hydroxy or mono- or di-(C 1 . 3 alkyl)amino, C,_ 6 alkoxyheteroarylC 0 ⁇ alkyl, heteroarylC 0 . 3 alkyl or heterocycyleC 0 . 3 alkyl wherein the heteroaryl and heterocycle is hereinabove described in this paragraph, or Z is C,. 6 alkyl branched or unbranched, C,.
  • C,_ 10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle, selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, G, ⁇ branched or unbranched alkyl which is optionally partially or fully halogenated, C 3 .
  • alkylaminocarbonyl 3 )alkylaminocarbonyl; d) a Cg_ 7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C ⁇ alkyl groups; e) nitrile; or f) C ⁇ e branched or unbranched alkoxycarbonyl, G,. 6 branched or unbranched alkylaminocarbonyl, C,. 6 branched or unbranched alkylcarbonylamino-C,.. 3 - . alkyl;
  • R 2 is: a C,_ 6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile, or R 2 is acetyl, aroyl, C ⁇ branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl;
  • R 3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally
  • heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1.3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or dKC ⁇ alkyl aminocarbonyl, C,_ 5 alkyl, mono- or alkyl, amino-S(O) 2 , di-(C 1 .
  • a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclohexanoindole,
  • alkyl aminocarbonyl C M alkyl-OC(O), C.,_ 5 alkyl-C(O)-C M branched or unbranched alkyl, an amino-C.,. 5 alkyl, mono- or di-(C 1 _ 3 )alkylamino-C 1 _ 5 alkyl, alkyl and R 12 -C,.
  • cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C ⁇ alkyl groups; d) Cg_ 7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C,.
  • alkyl groups e) acetyl, aroyl, C ⁇ alkoxycarbonylC ⁇ alkyl or phenylsulfonyl; or f) C,. 6 branched or unbranched alkyl optionally partially or fully halogenated;
  • R 1 and R 2 taken together optionally form a fused phenyl or pyridinyl ring;
  • each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C, ⁇ branched or unbranched alkyl optionally partially or fully halogenated;
  • each R 4 , R 5 , R 6 , R 7 , R 9 , R 10, R-n and R 12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: A is thiophene or pyrazole each substituted independently by one to three R 1; R 2 or R 3 ; X is: a C 5-7 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C M alkyl, C M alkoxy or C, ⁇ alkylamino chains each being branched or unbranched;
  • phenyl indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl, tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperdinyl, benzimidazole or piperazinyl; each being optionally independently substituted with one to three
  • Y is: a bond or a C 1 . 4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O or N, and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C,_ 4 alkyl optionally substituted by one or more halogen atoms;
  • Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl and thienyl, heterocycle selected from piperazinyl, 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, morpholino, thiomorpholino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C 1-6 alkyl, C 1-6 alkoxy, C,. 3 alkoxy-C, ⁇ alkyl, C,.
  • 3 alkyl-S(O) m - each of the aforementioned alkyl and aryl attached to the amino group are optionally substituted with one to two halogen, C ⁇ alkyl or C 1-6 alkoxy; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C 1-6 alkyl or C,. 6 alkoxy; or Z is hydroxy, hydroxyC 1-3 alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by aroyl, C,. 3 acyl, C,.
  • R. is:
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally partially or fully halogenated and optionally substituted with one to three C,. 3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH;
  • R 2 is: a C,. 6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
  • R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C, .6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C,_ 5 alkyl, naphthyl C ⁇ alkyl, halogen, hydroxy, oxo, nitrile, C ⁇ alkoxy optionally be partially or fully halogenated, C ⁇ alk
  • heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C,. 3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C 1 . 3 )alkyl aminocarbonyl, alkyl, alkyl, mono- or di-(C 1 . 3 )alkylamino-C 1 . 5 alkyl, amino-S(O) 2 , di-(C 1 .
  • a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl; wherein the fused aryl is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C,_ 6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C, ⁇ alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this
  • heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(O), a mono- or di-(C 1 . 3 )alkyl aminocarbonyl, C, ⁇ alkyl-OC(O), C,. 5 alkyl-C(0)-C M branched or unbranched alkyl,, an alkyl, mono- or di-(C 1 . 3 )alkylamino-C 1 . 5 alkyl,
  • cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C,. 3 alkyl groups;
  • R., and R 2 taken together optionally form a fused phenyl or pyridinyl ring;
  • each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C, ⁇ branched or unbranched alkyl optionally partially or fully halogenated; and each R 4 , R 5 , R 6 , R 7 , R 9 , R 10 ⁇ R ⁇ and R 12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: Ar, is pyrazole; X is: cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted with an oxo group or one to three C M alkyl, C ⁇ alkoxy or C alkylamino chains each being branched or unbranched;
  • phenyl, furanyl, thienyl, pyridinyl, pyrazinyl piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C,. 2 alkyl, C,. 2 alkoxy, hydroxy or halogen;
  • Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C ⁇ alkyl, G, ⁇ alkoxy, C ⁇ alkoxy-C,.
  • R 1 is:
  • cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl optionally partially or fully halogenated and optionally substituted with one to three C,_ 3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH;
  • cyclopentenyl and cyclohexenyl optionally substituted with one to three C,_ 3 alkyl groups;
  • R 2 is: a C,. 6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
  • R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C,. 6 branched or unbranched alkyl which is optionally partially or fully halogenated, phenyl C, .5 alkyl, halogen, hydroxy, oxo, nitrile, C,_ 3 alkoxy optionally partially or fully halogenated, C ⁇ thioalkyl, C., .
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C ⁇ alkyl groups
  • R 1 and R 2 taken together optionally form a fused phenyl or pyridinyl ring.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: Y is -CH 2 -, -O-(CH 2 ) 0 . 3 -, -CH 2 CH 2 -, -CH 2 NH-, -CH 2 CH 2 -NH-, NH-CH 2 CH 2 -,
  • X is: cyclohexenyl optionally substituted with an oxo group or one to three C M alkyl, C alkoxy or C_ alkylamino chains each being branched or unbranched;
  • phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C,. 2 alkyl, G,_ 2 alkoxy, hydroxy or halogen;
  • Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, thiomorpholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C,.
  • Z is hydroxy, hydroxyC 1-3 alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C ⁇ alkyl, pyridinylC ⁇ alkyl, tetrahydrafuranylC 1-2 alkyl, C 1-3 alkoxyC ⁇ alkyl, C ⁇ acyl, nitrileC ⁇ alkyl, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, alkoxy, hydroxy or mono- or di-(C 1 . 3 alkyl)amino, or Z is C ⁇ alkyl branched or unbranched, C ⁇ alkoxy or nitrileC ⁇ alkyl;
  • R is:
  • R 2 is: a C 1-3 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
  • R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of C 1-3 branched or unbranched alkyl which is optionally partially or fully halogenated, C 1-3 alkoxy which optionally partially or fully halogenated, C 3 thioalkyl, C 1 . 3 thioalkylC 1 . 5 alkyl, amino or NH 2 C(O);
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C, ⁇ alkyl groups.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein: Ar, is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring is substituted independently by one to two R 2 or R 3 ; X is: cyclohexenyl; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with C, quest 2 alkoxy or hydroxy;
  • Z is: phenyl, heteroaryl selected from pyridinyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl, morpholino, thiomorpholino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three C, favor 3 alkyl, C,. 3 alkoxy, oxo , hydroxy or NH 2 C(O)-; or Z is hydroxyC,.
  • R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to two groups selected from the group consisting of C ⁇ alkyl which is optionally partially or fully halogenated, C ⁇ alkoxy which optionally partially or fully halogenated, C ⁇ thioalkyl, C,_ 2 thioalkylC,. 3 alkyl, amino or NH 2 C(O);
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C,_ 3 alkyl groups.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein X is pyridinyl.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a wherein the pyridinyl is attached to Ar., via the 3-pyridinyl position.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 5a:
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 5a:
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 as disclosed in WO 00/55139
  • G is : an aromatic C 6-10 carbocycle or a nonaromatic C 3 . 10 carbocycle saturated or unsaturated; a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from O, N and S; a 5-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; or an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S; wherein G is substituted by one or more R.,, R 2 or R 3 ;
  • Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or R 5 ;
  • X is: a C 5 . 8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C ⁇ alkyl, C ⁇ alkoxy or C_ alkylamino chains;
  • phenyl furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl;
  • Y is: a bond or a C M saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C,_ 4 alkyl optionally substituted by one or more halogen atoms;
  • Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl each being optionally substituted with one to three halogen, C ⁇ alkyl, C,. 6 alkoxy, hydroxy, amino, mono- or di- (C, .3 alkyl)amino, C,.
  • alkyl C,. 6 alkoxy, hydroxy, amino, mono- or di-(G,_ 3 alkyl)amino-C,.. 3 alkyl, CONH 2 , phenylamino-C,. 3 alkyl or C ⁇ alkoxy-C.,. 3 alkyl; halogen, C,. 4 alkyl, nitrile, amino, hydroxy, C 1-6 alkoxy, NH 2 C(O), mono- or di(C 1.3 alkyl) aminocarbonyl, mono- or di(C 1 .
  • each R 1 is independently:
  • C,. 10 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C 3 .
  • cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three G, ⁇ alkyl groups optionally partially or fully halogenated, CN, hydroxyC,.
  • C 3 . 10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally be substituted with one to three C,. 5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with zero to five halogen, C,.
  • alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C,. 3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(O), mono- or di(C 1 ⁇ alkyl)aminocarbonyl; the C 3 . 10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C 1-3 alkyl groups;
  • alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O) m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrrolidinyl, pyrrolyl, one or more C M alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C ⁇ alkyl)amino optionally substituted by one or more halogen atoms;
  • each R 2 , R 4 , and R 5 is a branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, nitrile, methoxycarbonyl, C,. 3 alkyl-
  • S(O) m optionally partially or fully halogenated, or phenylsulfonyl
  • each R 3 is independently: phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl
  • a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoi
  • alkyl)aminocarbonyl C, ⁇ alkyl- OC(O), C 1-5 alkyl-C(O)-C alkyl, amino-C L s alkyl, mono- or di-(C 1 . 3 )alkylamino- C ⁇ alkyl, R ⁇ -C ⁇ alkyl, R ⁇ -C ⁇ alkoxy, R 14 -C(O)-C 1 . 5 alkyl or R ⁇ -C ⁇ alkyI(R 16 )N;
  • cyclopropanyl cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C,.
  • R 20 C(O)N(R 21 )-, R 22 O- or R 23 R 24 NC(O)-; R 26 (CH 2 ) m C(O)N(R 21 )- or
  • alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O) m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C, ⁇ alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C M alkyl)amino optionally substituted by one or more halogen atoms; or
  • R R is a:
  • each R 7 , R 8 , R 9 , R 10 , R 12 , R 13 ⁇ R 14 , R 15 , R 17 , R 19 , R 25 and R 26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C 1 ⁇ alkyl)amino optionally partially or fully halogenated; each R ⁇ and R 16 is independently: hydrogen or C_ alkyl optionally partially or fully halogenated;
  • R 18 is independently: hydrogen or a C ⁇ alkyl optionally independently substituted with oxo or R 25 ;
  • R 20 is independently:
  • C ⁇ o alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
  • R 21 is independently: hydrogen or C,. 3 alkyl optionally partially or fully halogenated
  • each R 22 , R 23 and R 24 is independently: hydrogen, C,. 6 alkyl optionally partially or fully halogenated, said C,. 6 alkyl is optionally interrupted by one or more O, N or S, said C,. 6 alkyl also being independently optionally substituted by mono- or di-(C 1 . 3 alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or dKC ⁇ alkyOamino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C 1 . 3 alkyl)amino; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring;
  • n 0, 1 or 2;
  • W is O or S and pharmaceutically acceptable derivatives thereof.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein
  • G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein
  • G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R ⁇ R 2 or R 3 ;
  • Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or R 5 groups;
  • X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl
  • Y is: a bond or a C__ 4 saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C ⁇ alkyl optionally substituted by one or more halogen atoms;
  • Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C ⁇ alkyl, C,. 3 alkoxy, amino, mono- or di-(C 1 . 3 a!kyl)amino, CONH 2 or OH;
  • tetrahydropyranyl tetrahydrofuranyl, 1 ,3-dioxolanonyl, 1 ,3-dioxanonyl, 1 ,4- dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C,.
  • each R 1 is independently:
  • C 3 . 6 alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3 . 6 cycloalkyl, phenyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to three groups selected from halogen, C,. 3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or C ⁇ alkoxy which is optionally partially or fully halogenated;
  • R 2 is independently: halogen, C,. 3 alkoxy, C ⁇ alkyl-S(O) m optionally partially or fully halogenated, phenylsulfonyl or nitrile;
  • R 3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolylidinyl, imidazolyl, pyrazolyl, each being optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C,. 6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C,.
  • alkyl aminocarbonyl, alkyl-C(O)-C M alkyl, mono- or di-(C 1 _ 3 alkyl)amino, mono- or di-(C 1 ⁇ )alkylamino-C 1 ⁇ alkyl, mono- or di-(C,. 3 alkyl)amino-S(O) 2 , alkyl, alkyl(R.,.
  • R 20 C(O)N(R 21 )-, R 22 0- ; R 23 R 24 NC(O)-; R 26 CH 2 C(O)N(R 21 )- or R 26 C(O)CH 2 N(R 21 )-; C 2-4 alkenyl substituted by R 23 R 24 NC(O)-; or
  • C 2-4 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C M alkyl optionally substituted by one or more halogen atoms; and
  • R 23 and R 24 taken together optionally form imidazolyl, piperidinyl, morpholinyl, piperazinyl or a pyridinyl ring.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of ah inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein:
  • G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R ⁇ R 2 or R 3 ;
  • Ar is naphthyl;
  • X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C,_ 4 alkyl, C ⁇ alkoxy, hydroxy, nitrile, amino, mono- or di-(C,. 3 alkyl)amino, mono- or di-(C 1 . 3 alkylamino)carbonyl, NH 2 C(O), C,. 6 alkyl-S(O) m or halogen;
  • Y is: a bond or a C 1-4 saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group;
  • Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinyl which are optionally substituted with one to two C ⁇ alkyl or C ⁇ alkoxy;
  • tetrahydropyranyl morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl which are optionally substituted with one to two C, prison 2 alkyl or C ⁇ alkoxy; or
  • each R 1 is independently:
  • C 3 _g alkyl optionally partially or fully halogenated, and optionally substituted with phenyl substituted with zero to three halogen, C,. 3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or C,.
  • each R 2 is independently: bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile;
  • each R 3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolyl id inyl, 2,5-pyrrolidin-dionyl, imidazolyl, pyrazolyl, each of the aforementioned is optionally substituted with one to three C ⁇ alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C ⁇ alkyloxy optionally partially or fully halogenated;
  • OR 18 or G,_ 3 alkyl optionally substituted with OR 18 ; amino or mono- or di-(C 1 - 3 alkyl)amino optionally substituted with R 19 ;
  • R 20 C(O)N(R 21 )-, R 22 O- ; R 23 R 24 NC(O)-; R 26 CH 2 C(O)N(R 21 )- or R 26 C(O)CH 2 N(R 21 )-;
  • the invention relates to the use of p38 kinase inhibitors for the preparation of ah inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein
  • G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one or more R 1 ( R 2 or R 3 ;
  • Ar is 1 -naphthyl
  • X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
  • Y is: a bond or
  • each R 1 is independently:
  • each R 3 is independently: phenyl, morpholinyl, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl or pyrazolyl, wherein any of the aforementioned is optionally substituted with C,. 2 alkyl which is optionally partially or fully halogenated;
  • R 19 amino or mono- or di-(C,. 3 alkyl)amino optionally substituted with R 19 ; CH 3 C(O)NH-, R 22 O- ; R 23 R 24 NC(O)-; R 26 CH 2 C(O)N(R 21 )- or R 26 C(O)CH 2 N(R 21 )-;
  • R 23 and R 24 are H or R 23 and R 24 taken together optionally form morpholino; and R 26 is morpholino.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 G is phenyl, pyridinyl or naphthyl wherein G is substituted by one or more R.,, R 2 or
  • X is: imidazolyl or pyridinyl
  • Y is:
  • Z is morpholino
  • each R 1 is independently: tert-butyl, sec-butyl, tert-amyl or phenyl;
  • R 2 is chloro
  • R 3 is independently: methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, morpholino or morpholinocarbonyl.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein X is pyridinyl.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 6 wherein the pyridinyl is attached to Ar via the 3-pyridinyl position.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 6
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the following compounds of formula 6
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 as disclosed in WO 00/55139
  • E is carbon or a heteroatom group chosen from -O-, -NH- and -S-;
  • G is : an aromatic C 6 . 10 carbocycle or a nonaromatic C 3 . 10 carbocycle saturated or unsaturated;
  • Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R 4 or R 5 ;
  • X is: a Cg. 8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C alkyl, C 1-4 alkoxy or C M alkylamino chains each being branched or unbranched;
  • aryl furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C ⁇ alkyl, C 1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(G,_ 3 alkyl)amino, mono- or di-
  • Y is: a bond or a C, ⁇ saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C, ⁇ alkyl optionally substituted by one or more halogen atoms;
  • Z is: aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-
  • each R. is independently:
  • C 1-10 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O) m , and wherein said C,. 10 alkyl is optionally substituted with one to three C 3 .
  • phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C,. 3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC.,. 3 alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
  • C 3 . 10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally substituted with one to three C, ⁇ branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with one to five halogen, C,.
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C,. 3 alkyl groups;
  • silyl containing three C 1 alkyl groups optionally partially or fully halogenated;
  • alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O) m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C M alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di ⁇ alky amino optionally substituted by one or more halogen atoms;
  • each R 2 , R 4 , and R 5 is a C,. 6 branched or unbranched alkyl optionally partially or fully halogenated, C 1-6 acyl, aroyl, C, ⁇ branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C, ⁇ alkyl-S(O) m optionally partially or fully halogenated, or phenyl-S(O) m ;
  • N atom is optionally independently mono- or di- substituted by C,. 6 alkyl or arylC 0.3 alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C,. 3 alkyl, arylC 0 ⁇ alkyl, C,. 6 acyl, C 1 . 6 alkyl-S(O) r ⁇ - or arylC 0 . 3 alkyl-S(O) m -, each of the aforementioned alkyl and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C,. 6 alkyl or C,_ 6 alkoxy;
  • each R 3 is independently: phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1 ,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, qui
  • a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoi
  • alkyl)anr ⁇ inocarbonyl C, ⁇ alkyl- OC(O), alkyl-C(O)-C 1-4 alkyl, amino-C,_ 5 alkyl, mono- or di-(C,. 3 )alkylamino-C 1-5 alkyl, R 12 -C 1-5 alkyl, alkoxy, R 14 -C(O)-C 1 . 5 alkyl or R 15 -
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C,_ 3 alkyl groups;
  • R 20 C(O)N(R 21 )-, R 22 O- or R 23 R 24 NC(O)-;
  • R 26 (CH 2 ) m C(O)N(R 21 )-, R ⁇ N ⁇ O)- ⁇ . 3 alkoxy or R 26 C(O)(CH 2 ) m N(R 21 )-;
  • alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O) m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C M alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C M alkyl)amino optionally substituted by one or more halogen atoms;
  • R 6 is a:
  • each R 7 , R 8 , R 9 , R 10 , R 12 , R 13 R 14 , R 15 , R 17 , R 19 , R 25 and R 26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C 1 . 4 alkyl)amino optionally partially or fully halogenated;
  • each R restroom and R 16 is independently: hydrogen or C 1-4 alkyl optionally partially or fully halogenated;
  • R 18 is independently: hydrogen or a C,. 4 alkyl optionally independently substituted with oxo or R 25 ;
  • R 20 is independently:
  • C ⁇ o alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
  • R 21 is independently: hydrogen or C 1-3 alkyl optionally partially or fully halogenated
  • each R 22 , R 23 and R 24 is independently: hydrogen, C,.. 6 alkyl optionally partially or fully halogenated, said C ⁇ alkyl is optionally interrupted by one or more O, N or S, said C, ⁇ alkyl also being independently optionally substituted by mono- or di-(C 1 ⁇ alkyl)aminocarbonyl, phenyl, pyridinyl, amin ⁇ or mono- or d C ⁇ alky amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(G,. 3 alkyl)amino; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring;
  • n 0, 1 or 2;
  • W is O or S and pharmaceutically acceptable derivatives thereof.
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 wherein: E is -CH 2 -, -NH- or -O-; W is O; and G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
  • the invention relates to the use of p38 kinase inhibitors for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion, characterized in that the p38 kinase inhibitor is selected from the compounds of formula 7 wherein: E is -NH-; G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, indanyl, indenyl, indolyl, indolinyl, indolonyl, 2,3-dihydro-1
  • X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C 1-4 alkyl, C ⁇ alkoxy, hydroxy, nitrile, amino, mono- or di-(C 1 . 3 alkyl)amino, mono- or di-(C 1-3 alkylamino)carbonyl, NH 2 C(O), alkyl-S(O) m or halogen;
  • Y is: a bond or a C saturated or unsaturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C 1 alkyl optionally substituted by one or more halogen atoms;

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  • Pulmonology (AREA)
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EP03720407A 2002-04-05 2003-04-02 Method of treating mucus hypersecretion Ceased EP1494645A2 (en)

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EP02007699 2002-04-05
EP02007699 2002-04-05
EP03720407A EP1494645A2 (en) 2002-04-05 2003-04-02 Method of treating mucus hypersecretion
PCT/EP2003/003434 WO2003084503A2 (en) 2002-04-05 2003-04-02 P38 kinase inhibitors for treating mucus hypersecretion_

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US20070010529A1 (en) * 2003-05-19 2007-01-11 Kanji Takahashi Nitrogenous heterocyclic compounds and medical use thereof
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
WO2006137421A1 (ja) * 2005-06-21 2006-12-28 Kyowa Hakko Kogyo Co., Ltd. 局所投与剤
FR2903774B1 (fr) * 2006-07-17 2008-09-05 Renault Sas Procede de validation d'un diagnostic de fontionnement d'un dispositif.
PE20110598A1 (es) 2008-10-02 2011-08-31 Respivert Ltd Inhibidores de las enzimas de proteina cinasa activadas por mitogeno p38
GB0818033D0 (en) 2008-10-02 2008-11-05 Respivert Ltd Novel compound
MX2011006220A (es) 2008-12-11 2011-06-28 Respivert Ltd Inhibidores de la proteina cinasa activada por el mitogeno p38.
GB0905955D0 (en) 2009-04-06 2009-05-20 Respivert Ltd Novel compounds
PT3691620T (pt) 2017-10-05 2022-10-06 Fulcrum Therapeutics Inc Os inibidores da quinase p38 reduzem a expressão de dux4 e genes a jusante para o tratamento de fshd
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD

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ID30176A (id) * 1999-03-12 2001-11-08 Boehringer Ingelheim Pharma Senyawa-senyawa yang bermanfaat sebagai zat anti-inflamasi
WO2000071535A1 (en) * 1999-05-21 2000-11-30 Scios Inc. INDOLE-TYPE DERIVATIVES AS INHIBITORS OF p38 KINASE
NZ517578A (en) * 1999-08-19 2004-02-27 Signal Pharm Inc Pyrazoloanthrone and derivatives thereof as JNK inhibitors and their compositions
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PL372963A1 (en) 2005-08-08
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IL163737A0 (en) 2005-12-18
CA2479520A1 (en) 2003-10-16
WO2003084503A2 (en) 2003-10-16
RU2004132847A (ru) 2006-08-20
ZA200406910B (en) 2006-06-28
WO2003084503A3 (en) 2004-04-08
CN1658834A (zh) 2005-08-24
NZ536278A (en) 2007-05-31
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AU2003224025A1 (en) 2003-10-20
MXPA04009605A (es) 2005-01-11

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