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)
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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Filing date
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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Abstract

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.

Description

Method of treating Mucus hypersecretion
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.
Background of the invention Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen-activated protein kinases (MAPK) have been discovered. Members of this family are Ser/Thr kinases that activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31 , pp. 289-98 (1996)]. MAPKs are themselves activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents.
One particularly interesting MAPK is p38. 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. 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.
Based upon this finding it is believed that 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. In addition, MAPKs, such as p38, 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.
In the conducting airways of the respiratory system, the mucociliary system serves as the primary defence mechanism to move inhaled particles or infectious agents out of the airways in the lungs. In addition, 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.
While mucus generally facilitates the clearence of inhaled particles or infectious agents, hypersecretion of mucus in the airways may cause progressive airway obstruction. In peripheral airways, cough is ineffective for clearing secretions. Futhermore, because of their small dimensions, small airways containing many goblet cells are especially vulnerable to airway plugging by mucus. Airway hypersecretion affects a substantial number of individuals.
Hypersecretion has for instance been implicated in cystic fibrosis, with is one of the most common, fatal, genetic diseases in the world. 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.
As a result of the high levels of mucus in the lungs of patients with hypersecretory pulmonary diseases, 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 β2 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). A newer therapy for cystic fibrosis is the administration of DNAse to target the DANN-rich mucus or sputum (Shak, et al. (1990) Proc. Natl. Acad. (USA) 87:9188-9192; Hubbard, R.C. et al. (1991) N. Engl. J. Med. 326:812). In addition, chest physical therapy consisting of percussion, vibration and drainage are also used to facilitate clearence of viscous mucus. Lung transplantation may be a final option for those with severe to target the mucosal secretions is needed. Specifically, there is a need for a specific modality that will reduce the formation of mucus secretions in the airways.
Description of the invention Suprisingly it has been found that p38 kinase inhibitors administered via inhalation are suitable for the reduction of mucus hypersecretion.
Accordingly, 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
5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991 , US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, and US 5,716,955 and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851 , WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941 , WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131 , WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121 , WO 99/58502, WO 99/58523, WO 99/57101 , WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441 , WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111 , WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991 , WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911 , WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791 , WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591 , WO 01/29041 , WO 01/29042, WO 01/62731 , WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751 , WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241 , WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921 , WO 01/27089, DE 19842833, and JP 2000 86657 whose disclosures are all incorporated herein by reference in their entirety.
Of particular interest for the use according to the invention are those p38 inhibitors disclosed in US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791 , WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921 , WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131 , WO 00/43384, WO 00/55152, WO 00/55139, and WO 01/36403.
In a preferred embodiment 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 Λ as disclosed in WO 99/01131
wherein
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-Ra and optionally with an additional independent substituent selected from C - alkyl, halogen, hydroxyl, C 4 alkoxy, C,-4 akylthio, C 4 aklylsulfinyl, CH2OR12, 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 NR1?, N(R10)C(O)Rb or NHRa; Y is oxygen or sulfur; 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)NR7R17, C(Z)OR16, (CR10R20)VCOR12, SR5, SOR5, OR12, halo-substituted-CM alkyl, C^ alkyl,
ZC(Z)R12, NR10C(Z)R16, or (CR10R20)VNR10R20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR13R14, C(Z)OR3, (CR10R20)m,.COR3, S(O)mR3, OR3, halo-substituted-C^ alkyl, C,.4 alkyl, (CR10R20)m,R10C(Z)R3, NR10S(O)m.R8, NR10S(O)m.NR7R17, ZC(Z)R3 or (CR10R20)m„NR13R14; Z is oxygen or sulfur; n is an integer having a value of 1 to 10; m is 0, or integer 1 or 2; m' is an integer having a value of 1 or 2; m" is 0, or an integer having a value of 1 to 5; v is 0, or an integer having a value of 1 to 2; R2 is -C(H) (A) (R22); A is optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is substituted
C1-10 alkyl; R22 is an optionally substituted C1-10 alkyl; Ra is aryl, arylC,.6 alkyl, heterocyclic, heterocyclylC.,^ alkyl, heteroaryl, heteroarylC^alkyl, wherein each of these moieties may be optionally substituted; Rb is hydrogen, C,.6 alkyl, C3.7 cycloalkyl, aryl, aryl CM alkyl, heteroaryl, heteroarylC^ alkyl, heterocyclyl, or heterocyclylC,^ alkyl, wherein each of these moieties may be optionally substituted;
R3 is heterocyclyl, heterocyclyl C|_10 alkyl or R8; R5 is hydrogen, C^ alkyl, C2 alkenyl, C2 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17and SOR5 being SOH; R6 is hydrogen, a pharmaceutically acceptable cation, Chalky!, C3.7 cycloalkyl, aryl, aryl C,^ alkyl, heteroaryl, heteroaryl C,^ alkyl, heterocyclyl, aryl, or C_._0 alkanoyl; R7 and R17 is each independently selected from hydrogen or C,^ alkyl or R7 and R17 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 NR15;
R8 is C,_10 alkyl, halo-substituted C,. alkyl, C2.10 alkenyl, C2-10 alkynyl, C3.7 cycloalkyl, C5.7 cycloalkenyl, aryl, aryl C,.10 alkyl, heteroaryl, heteroaryl C1-10 alkyl, (CR^R^OR^, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, C(Z) R^ or optionally substituted C__ 0 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl CM alkyl; R10 and R20 is each independently selected from hydrogen or CM alkyl;
R is hydrogen, C^Q alkyl, C3.7 cycloalkyl, heterocyclyl, heterocyclyl C,_10 alkyl, aryl, arylC.,_10 alkyl, heteroaryl or heteroaryl C^o alkyl, wherein these moieties may be optionally substituted; R12 is hydrogen or R16. R13an R14is each independently selected from hydrogen or optionally substituted
C_ alkyl, optionally substituted aryl or optionally substituted arylC1-4 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 NR9; R15 is R10 or C(Z)-C^ alkyl;
R16 is C.,.4 alkyl, halo-substituted-C,^ alkyl, or C3.7 cycloalkyl;
R18 is C^o alkyl, C3.7 cycloalkyl, heterocyclyl, aryl, aryl.,.10 alkyl, heterocyclyl, heterocyclyl- Chalky!, heteroaryl or heteroaryl1_10 alkyl; or a pharmaceutically acceptable salt thereof.
In the aforementioned compounds of formula 1_ R2is 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 R22 moiety and an A moiety, -C(H)(A)( R22). Both A and R22 may not be unsubstituted C,..10 alkyl moiety.
In a preferred embodiment, R2 is a -C(AA1)(A) moiety, wherein AA1 is the R22 moiety, but is specifically the side chain residue (R) of an amino acid, as is further described herein.
Suitably, A is an optionally substituted C13.7 cycloalkyl, aryl, heteroaryl, or heterocyclic ring, or A is a substituted C1-10 alkyl moiety.
When A is an aryl, heteroaryl and heterocyclic ring, the ring may be substituted independently one or more times, preferably, 1 to 3 times by C_._0 alkyl; halogen; halo substituted C1-10 alkyl such as CF3; (CR^R^ORn; (CR10R20)tNR12R14, especially amino or mono-or di-C^ alkylamino; (CR10R20),S(O)m R18, wherein m is 0, 1 or 2; SH; NR10C(Z)R3 (such NHCO(C1-10 alkyl)); or NR10S(O)m R8 (such as NHSO^o alkyl)).
Suitably, t is 0, or an integer of 1 to 4.
When A is an optionally substituted cycloalkyl it is as defined below with the R22 substitution. When A is an optionally substituted heterocyclil ring, the ring is preferably a morpholino, pyrrolidinyl, piperazinyl or a piperidinyl ring.
When A is an optionally substituted aryl moiety, it is preferably a phenyl ring. When A is an optionally substituted heteroaryl ring, it is as defined below in the definition section.
When A is a substituted C,.10 alkyl moiety, 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 CF3; C3.7cycloaklyl, C^^alkloxy, such as methoxy or ethoxy; hydroxy substituted C1-10 alkoxy; halosubstituted C.__0 alkoxy, such as OCF2CF2H; OR,,; S(O)mR18 (wherein m is 0, 1 or 2); NR13R14; C(Z)NR13R14; S(O)m.NR13R14; NR23C(Z)R11; NHS(O)2R18; C(Z)R11; OC(Z)R11; C(Z)OR11; C(Z)NR11OR9; N(OR6)C(Z)NR13R14; N(0R6)C(Z)R11 ; C(=N0R6)R11 ; NR23C(=NR19)NR13R14; OC(Z)NR13R14; NR23C(Z)NR13R14; or NR23C(Z)OR10.
Preferably A is a C3.7 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.
Preferably, when A is a C^0 alkyl, it is substituted by OR„ where R^ is preferably hydrogen, aryl or arylalkyl; NR13R14; OC(Z)R11; C(Z)OR11. More preferably, A is substituted by OR^ where R„ is hydrogen. Suitably, R22 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,.10 alkyl; C.,_10 alkoxy, such as methoxy or ethoxy; hydroxy substituted C,.10 alkoxy; halosubstituted C.,.10 alkoxy, such as OCF2CF2H; OR.,.,; S(O)mR18; NR13R14; C(Z)NR13R14; S(O)m.NR13R14; NR23C(Z)R11 ; NHS(O)2R18; C(Z)R11 ; OC(Z)OR1i ; C(Z)OR1i ; C(Z)NR11OR9; N(OR6)C(Z)NR13R14; N(0R6)C(Z)R11 ; C(=NOR6)R11; NR23C(=NR19)NR13R14; OC(Z)NR13R14; NR23C(Z)NR13R14; NR23C(Z)OR10; optionally substituted C3-7 cycloalkyl; optionally substituted aryl, such as phenyl; optionally substituted heteroaryl; or an optionally substituted heterocyclic. The optional substituents on these cycloalkyl, aryl, heteroaryl, and heterocyclic moieties are as defined herein below.
It is noted that those R22 substituent groups which contain carbon as the first connecting group, i.e. C(Z)OR.,.,; C(Z)NR11OR9, C(Z)R11, C(Z)NR13R14, and
C(=NOR6)R11, may be the sole carbon in alkyl chain. Therefore, the R22 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. Preferably R22 is a C,.6 unsubstituted or substituted 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)OR11; C(O)NR13R14 or R22is an optionally substituted aryl group, such as a benzyl or phenethyl. In other words, R22can be an optionally substituted alkyl group, or R22can be C(Z)OR11; C(Z)NR11OR9, C(Z)R11, C(Z)NR13R14, or C(=NOR6)R11.
Preferably R22is C,.6 unsubstituted or substituted alkyl group, more preferably a C,.2 alkylene chain, such as a methylene or ethylene moiety, more preferably methylene.
Preferably the alkyl chain is substituted by OR^, where R„ is preferably hydrogen, aryl or arylalkyl; S(O)mR18t where m is 0 and R18 is a C,_6 alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety. More preferably, R^ is phenyl, benzyl, CH2OH, or CH2-O-aryl.
Preferably, one or both of A and R22 contain hydroxy moieties, such as in C,.6 alkyl OR.,.,, wherein R^ is hydrogen, i.e. CH2CH2OH.
Suitably, when AA1 is the (R) side chain residue of an amino acid, it is a C,_6 alkyl group, which may be straight or branched. This means the R group of the core amino acid of the structure R-C(H)(COOH)(NH2). The R residue term is for example, CH3 for alanine, (CH3)2CH- for valine, (CH3)2CH-CH2-for leucine, phenyl- CH2- for phenylalanine, CH3-S-CH2-CH2- 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 β-alanine, Y-aminobutyric acid, homocysteine, homoserine, citrulline, ornithine, canavanine, djenkolic acid, and β-cyanoalanine, or other naturally occurring non-mammalian amino acids.
Preferably AA1 is the residue of phenylalanine, or alanine. Preferably A is a hydroxy substituted C,.10 alkyl and R22 is a Chalky! or a hydroxy substituted Chalky!.
In a further preferred embodiment 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- yφmidazole;
1-(4-Piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole; (4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-imidazole;
In yet another preferred embodiment 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
and the pharmaceutically acceptable salts thereof, wherein 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,
-OOCR, -NROCR, RCO, -COOR, -CONR2, -SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C); each R2 is independently alkyl (1-6C), halo, OR, SR, OOCR, NROCR, COOR, RCO, CONR , SO2NR2, CN, CF3 or NO2, 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, NR2, SR, -OOCR, -NROCR, RCO, -COOR, -
CONR , SO2NR2, CN, CF3, or NO2, wherein each R is independently H or alkyl (1-4C);
Preferably 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; R2 is halo, m is 0, 1 , or 2, and I is 1 or 2; Ar is 4-pyridyl.
In a particularily preferred embodiment 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:
2-phenyl-4-(4-pyridylamino)-quinazoline;
2-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-chlorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline;
2-(4-fluorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(3-methoxyanilyl)-4-(4-pyridylamino)-quinazoline;
2-(2,6-dichlorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2,6-dibromophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2,6-difluorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyri dylamino)-6,7-dimethoxyquinazoline; 2-(4-fluorophenyl)-4-(4-pyri dylamino)-6,7-dimethoxyquinazoline; 2-(2-fluorophenyl)-4-(4-pyri dylamino)-6-nitroquinazoline; 2-(2-fluorophenyl)-4-(4-pyri dylamino -6-aminoquinazoline; 2-(2-fluorophenyl)-4-(4-pyri dylamino)-7-aminoquinazoline; 2-(2-fluorophenyl)-4-(4-pyri dylamino)-6-(3-methoxybenzylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyri dylamino)-6-(4-methoxybenzylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyri dylamino)-6-(2-isobutylamino)-quinazoline; and 2-(2-fluorophenyl)-4-(4-pyri dylamino)-6-(4-methylmercaptobenzyIamino)-quina zoline; and the pharmaceutically acceptable salts thereof.
In yet another preferred embodiment 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
and the pharmaceutically acceptable salts thereof, wherein each of Z^ and Z2 is independently CR4 or N; where each R4 is independently selected from H and alkyl(1-6C); wherein said alkyl optionally includes one or more heteroatoms selected from O, S and N, and wherein said alkyl is optionally substituted by one or more substituents selected from halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, =O, a 5 or 6 membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a 6-membered aromatic ring optionally containing 1- 2 N heteroatoms, wherein R in the foregoing optional substituents is H or alkyl (1-6C);
R1 is
wherein χ1 is CO, SO, CHOH or SO2 ; m is 1 ;
Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; n is O, 1 or 2;
Z3 is N; X2 is CH or CH2 ; and
Ar consists of one or two phenyl moieties directly coupled to χ , said one or two phenyl moieties being optionally substituted by a substituent selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), CN, CF3, RCO, COOR, CONR2, NR2, 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, NR2, RCO, COOR,
CONR2, OOCR, NROCR, (where R in the foregoing is H or 1-6C alkyl) CN, =O, a 5 or 6 membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a 6-membered aromatic ring optionally containing 1-2 N heteroatoms; R3 is H, halo, NO2, alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (1 -6C).
In a particularily preferred embodiment 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:
4-(2,6-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(2,3-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(3,5-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-carboxymethyl benzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-methoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-trifluoromethoxybenzyI)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-methylbenzyl)-piperazinyl-benzimidazole-5arboxamide; 4-(2,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(3,4-dichlorobenzoylm)piperazinyl-benzinidazole-5-carboxamnide;
4-[trans-3-(trifluoromethyl)-cinnamoyl]-piperazinyl-benzimidazole-5-carboxm ide;
4-(4-chlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
4-benzomethylbenzoylpiperazyl-benzimidazole-5-carboxamide; 4-(2-trifluoromethylbenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-methxybenzoyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(3,4-dichlorophenyl)-piperazinyl-benzimnidazole-5-carboxamide;
4-(4-chlorobenzhydryl)-piperazinyl-benzimidazole-5-carboxamide;
4-trans-1 -cinnamyl piperazinyl-benzimidazole-5-carboxamide; 4-(4-chlorophenyl)-piperazinyl-benzimidazole-5-carboxamide;
4-[bis(4-fluorophenyl)-methyl]-piperazinyl-benzimidazole-5-carboxamide;
4-(4-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(2-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-benzylpiperazinyl-benzinudazole-5-carboxamnide;
4-(4-methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(3,4,5-trimethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(2-naphthylmethyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-diethylaminobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(biphenylmethyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-phenoxybenzyl)-piperazinyl-benzimidazoIe-5-carboxamide;
4-(4-quinolinylmethyl)-piperazinyl-benzimidazole-5-carboxamide;
4-(4-chlorobenzyl)-piperazinyl-1-(2-propyl)-indole-5-carboxamide;
4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide; 4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-5-carboxamide;
4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-6-carboxamide;
4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-5-carboxamide;
4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-6-carboxamide;
4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-5-carboxamide; and 4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-6-carboxamide.
In another preferred embodiment 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, 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„R2 or R3;
Ar2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R2 groups;
L, a linking group, 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:
a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5- b]pyridine and imidazo[4,5-ib]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, C,.6 alkyl, C^ alkoxy, hydroxy, mono- or di-(C^ alkyl)amino, C,_6 alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C^ alkyl and C,_
6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4- dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of C^ alkyl, C,^ alkoxy, hydroxy, mono- or di-(C,_3 alkyl)amino-C,..3 alkyl, phenylamino-C^ alkyl and C,_3 alkoxy-C^ alkyl; c) C^e alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl and C,..5alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C^ alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, C^ alkyl-S(O)r, phenyl-S(0)t, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C 6 alkoxy, hydroxy or mono- or d C^ alkyl)amino; R., is selected from the group consisting of:
(a) C3.10 branched or unbranched alkyl, which may optionally be 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, C 6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5^ cycloalkenyl, hydroxy, cyano, C^ alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C,.3)alkylaminocarbonyl;
(b) C3.7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which may optionally be partially or fully halogenated and which may optionally be 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 O, S, CHOH, >C=O, >C=S and NH; (c) C3.10 branched alkenyl which may optionally be partially or fully halogenated, and which is optionally substituted with one to three C,.5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from halogen, C,_6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C^ alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C,.3)alkylaminocarbonyl;
(d) C5.7 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;
(e) cyano; and,
(f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; R2 is selected from the group consisting of: a C,.6 branched or unbranched alkyl which may optionally be partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
R3 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, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a C,.6 branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C,_5 alkyl, naphthyl C,_5 alkyl, halo, hydroxy, cyano, G^ alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C,..3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di- (C1-3)alkyl aminocarbonyl, C^ alkyl-C(O)-C^ alkyl, amino-C^ alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, amino-S(O)2, di-(C1.3)alkylamino-S(O)2, R4- C1-5 alkyl, alkoxy, R6-C(O)-C,.5 alkyl and R7-C1.5 alkyl(R8)N; b) 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, cyclohexanoisoquinolihe, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, G,_6 branched or unbranched alkyl which is optionally partially or fully halogenated, halo, cyano, C,^ alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C,.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C alkyl-OC(O), C1-5 alkyl-C(O)-C1-4 branched or unbranched alkyl, an amino-C,.5 alkyl, mono- or di-(C,.3)alkylamino-C.,.5 alkyl, R9-C,..5 alkyl, R10-C1-5 alkoxy, 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) C5.7 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) C1-6 branched or unbranched alkyl which may optionally be partially or fully halogenated;
or R1 and R2 taken together may optionally form a fused phenyl or pyridinyl ring,
and wherein each R8, R13 is independently selected from the group consisting of: hydrogen and CM branched or unbranched alkyl which may optionally be partially or fully halogenated;
each R4, R5, R6, R7, R9, R10, R^ and R12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole; m = 0, 1 , 2; r = 0, 1 , 2; t = 0, 1 , 2;
X = O or S and physiologically acceptable acids or salts thereof.
In a preferred embodiment 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 Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl.
A more preferred subgeneric aspect of the invention comprises the use of compounds of the formula 4 wherein Ar2 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; Ar2 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; R1 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; R3 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 described above.
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 C1i4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
Particularly preferred embodiments of L are propoxy, ethoxy, methoxy, methyl, propyl, C3.5 acetylene or methylamino each being optionally substituted are described herein.
A more particularly preferred embodiment of L is ethoxy optionally substituted.
The following compounds are representative of the compounds of formula 4 and are of particular interest according to the invention:
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea;
1-[5-tetf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(c/s-2,6-dimethylmorpholin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-te/ -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(fraπs-2,6-dimethylmorpholin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-ter.-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-te/f-Butyl-2-p-tolyl-2H-pyrazol-3-yI]-3-[4-(2-(morpholin-4-yl)-2- oxoethoxy)naphthalen-1-yl]-urea;
1-[5-te/f-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2- methylethoxy)naphthalen-1 -yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-1- methylethoxy)naphthalen-1-yl]-ufea; 1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiomorpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4- yl)ethoxy)naphthalen-1 -yl]-urea;
1-[5-.et -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-3- methylnaphthalen-1 -yl]-urea;
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-piperidin-4-yl-ethoxy)naphthalen-1 - yl]-urea;
1-[5-tø/ -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-acetylpiperidin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiazolidin-3-yl-ethoxy)naphthalen-1- yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl- carbony!oxo)ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(tetrahydropyran-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(N-methyl-2- methoxyethylamino)ethoxy)naphthalen-1 -yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxo-tetrahydrothiophen-3- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-1- yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-methyl)naphthalen-1-yl]- urea;
1-[5-tet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-thiazolidin-3-yl-propyl)naphthalen-1- yl]-urea; 1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydopyran-2-yl- oxy)propyl)naphthalen-1-yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-1-yl]- urea;
1-[5-tert-Butyl-2-p-tolyI-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethenyl)naphthalen-1-yl]- urea;
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)propyn-1 - yl)naphthalen-1-yl]-urea;
1-[5-fe/ -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyn-1- yl)naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(methoxymethyloxy)propyn-1- yl)naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3-methylpropyn-1- yl)naphthalen-1-yl]-urea;
1-[5-tett-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3,3-dimethylpropyn- 1 -yl)naphthalen-1 -yl]-urea;
1 -[5-terf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)butyn-1 - yl)naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(furan-2-ylcarbonyloxy)propyn-1- yl)naphthalen-1 -yl]-urea;
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piperdin-1 -yl)propyn-1 -yl)naphthalen- 1-yl]-urea;
1-[5-.e f-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methoxymethylmorpholin-4- yl)propyn-1 -yl)naphthalen-1 -yl]-urea;
1-[5-.erf-Butyl-2-p-tolyl-2H-pyrazoI-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]- urea; 1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1-yl]- urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-1-yl]- urea;
1 -[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol-1 -yl-ethoxy)naphthalen-1 -yl]- urea;
1 -[5-terf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-benzimidazol-1 -yl-ethoxy)naphthalen- 1-yl]-urea;
1-[5-fet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)- ethoxy)naphthalen-1 -yl]-urea;
1-[5-tetτf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-1- yl]-urea;
1-[5-fet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-carbonylamino)naphthalen- 1-yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-acetamido)naphthalen- 1-yl]-urea;
1-[5-tetf-Butyl-2-p-tolyl-2H-pyrazoI-3-yI]-3-[4-(pyridin-3-yl-methylamino)naphthalen-1- yl]-urea;
1-[5-tet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-3-yl-carbonylamino)naphthalen- 1-yl]-urea;
1-[5-/so-PropyI-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen- 1-yl]-urea;
1-[5-(Tetrahydropyran-3-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-cyclohexyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen- 1-yl]-urea; 1-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1 -[5-(1 -methylcycloprop-1 -yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-ethoxycarbonyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-(1-methylcyclohex-1-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-fetf-butyI-2-methyl-2H-pyrazoI-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea;
1-[5-tert-butyl-2-benzyl-2H-pyrazoI-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea;
1-[5-terf-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-fe/t-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]- urea;
1-[5-fert-butyl-2-(ethoxycarbonylmethyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-te/τf-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yI]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(4-methyl-3-(2-ethoxycarbonylvinyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;
1-[5-ter.-butyl-2-(4-methyl-3-(morpholin-4-yl)methylphenyl)-2H-pyrazoI-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)naphthalen-1 -yl]-urea;
1-[5-fert-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)naphthaleή-1-yl]-urea; 1-[5-fer.-butyl-2-(3-(2-morpholin-4-yl-ethyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin- 4-yl-ethoxy)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(3-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)naphthalen-1 -yl]-urea;
1-[5-ferf-butyl-2-(3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4- yl-ethoxy)naphthalen-1-yl]-urea;
1-[5-fert-butyl-2-(4-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;
1-[5-fert-butyl-2-(4-(3-benzylureido)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-ter.-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-/er.-butyI-2-(2-methyipyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-.erf-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-te/ -butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-.et -butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-t5-tet -butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(^ans-2,6- dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-te/t-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyn- 1-yl)naphthalen-1-yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-dimethylaminomethylmorpholin-4- yl)ethoxy)naphthalen-1 -yl]-urea; ' 1-[5-terf-butyl-2-/so-propyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-.ert-butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-butyl-2-(thiophen-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-tørt-butyl-2-cyclopentyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthaIen-1 -yl]-urea;
1-[5-tert-butyl-2-/so-propyl-2H-pyrazol-3-yl]-3-[4-(tetrahyropyran-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-tett-butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(1-oxo-tetrahydrothiophen-3-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-fert-butyl-2-(thiophen-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridinyl-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-tet -butyl-2-cyclopentyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1- yl]-urea;
1 -[5-fet -Butyl-2-p-tolyl-2H-pyrazoI-3-yl]-3-[4-(3-(pyridin-4-yl)propyn-1 -yl)naphthalen- 1-yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methylaminopyridin-4-yl)propyn-1- yl)naphthalen-1-yl]-urea;
1-[5-tet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(1-oxo-tetrahydothiophen-3- yl)propyn-1-yl)naphthalen-1-yl]-urea;
1 -[5-te/ -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(thiazolidin-3-yl)propyn-1 - yl)naphthalen-1-yl]-urea;
1-[5-.ert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-4-yl)propyn-1- yl)naphthalen-1 -yl]-urea; 1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl- methoxy)naphthalen-1 -yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4- yl)ethoxy)naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tørf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-1- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-[1 ,8]naphthyridin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin- 5-yl)ethoxy)naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-pyridin-3-yl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl- methoxy)naphthalen-1-yl]-urea;
1 -[5-.erf-Butyl-2-(2-methylpyridin-5-yl) -2H-pyrazol-3-yl]-3-[4-(2-(2- methylaminopyrimidin-4-yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-terf-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4- methoxybenzimidazol-1 -yl)ethoxy)naphthalen-1 -yl]-urea;
1-[5-ter -Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4- methylaminobenzimidazol-1-yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-.et -Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5- b]pyridin-1-yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tø/τf-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-[1 ,8]naphthyridin-4- yl)ethoxy)naphthalen-1-yl]-urea; ' 1-[5-tet -Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H- pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tetf-Butyl-2-cyclopropyl -2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl- methoxy)naphthalen-1-yl]-urea;
1-[5-fert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1 -[5-tøtt-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-1 - yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tøtf-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-1- yl)ethoxy)naphthalen-1-yl]-urea;
1 -[5-tetτf-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-1 - yl)ethoxy)naphthalen-1 -yl]-urea;
1-[5-.e/ιf-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-[1 ,8]naphthyridin-4- yl)ethoxy)naphthalen-1 -yl]-urea;
1-[5-fert-Butyl-2-methyI-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3-b]pyridin- 5-yI)ethoxy)naphthalen-1-yl]-urea
and their physiologically acceptable acids or salts thereof.
In a particularily preferred embodiment 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:
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea;
1-[5-.erf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(c s-2,6-dimethylmorpholin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazόl-3-yl]-3-[4-(2-(.rans-2,6-dimethylmorpholin-4- yl)ethoxy)naphthalen-1-yl]-urea; 1-[5-.etf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2- oxoethoxy)naphthalen-1 -yl]-urea;
1-[5-tørf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2- methylethoxy)naphthalen-1-yl]-urea;
1-[5-fer.-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-1- methylethoxy)naphthalen-1-yl]-urea;
1-[5-fet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiomorpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-ferf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-.er.-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-3- methylnaphthalen-1 -yl]-urea;
1-[5-.erf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl- carbonyloxo)ethoxy)naphthalen-1-yl]-urea;
1-[5-.etιf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(tetrahydropyran-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-fet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxo-tetrahydrothiophen-3- yl)ethoxy)naphthalen-1 -yl]-urea;
1-[5-tørt-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-1- yl]-urea;
1 -[5-fer-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-methyl)naphthalen-1 -yl]- urea;
1-[5-tett-Butyl-2-p-tolyl-2H-pyrazόl-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-1-y - urea; 1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)propyn-1- yl)naphthalen-1 -yl]-urea;
1 -[5-fet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)propyn-1 - yl)naphthalen-1 -yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)butyn-1- yl)naphthalen-1 -yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piperdin-1-yl)propyn-1-yl)naphthalen- 1-yl]-urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methoxymethylmorpholin-4- yl)propyn-1 -yl)naphthalen-1 -yl]-urea;
1-[5-tørt-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-1-yl]- urea;
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-1 -yl]- urea;
1-[5-fert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-pyridin-4-yl-propoxy)naphthalen-1-yl]- urea;
1 -[5-.erf-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol-1 -yl-ethoxy)naphthalen-1 -yl]- urea;
1-[5-ter -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)- ethoxy)naphthalen-1-yl]-urea;
1-[5-ter.-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-1- yl]-urea;
1-[5-/so-Propyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen- 1-yl]-urea;
1-[5-cyclohexyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen- 1-yl]-urea; 1-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1 -[5-(1 -methylcycloprop-1 -yl)-2-p enyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1 -[5-(1 -methylcyclohex-1 -yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-tett-butyI-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea;
1-[5-ferf-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea;
1-[5-te/f-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yI-ethoxy)naphthalen-1-yl]- urea;
1-[5-tetf-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-ferf-butyl-2-(4-methyl-3-(morpholin-4-yl)methylphenyl)-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;
1-[5-.er.-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2- morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea;
1-[5-/ert-butyl-2-(3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4- yl-ethoxy)naphthalen-1-yl]-urea;
1-[5-terf-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-terf-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-tetf-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea; 1-[5--e/f-butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-.erf-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-.er.-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(frans-2,6- dimethylmorpholin-4-yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tør.-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyn- 1 -yl)naphthalen-1 -yl]-urea.
Particularly preferred compounds of the formula 4 are:
1-[5-fet -Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea;
1-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4- yl)ethoxy)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl- ethoxy)naphthalen-1 -yl]-urea;
1-[5-ferf-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen-1-yl]-urea or
1-[5-fe/t-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1- yl]-urea.
In another preferred embodiment 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:
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.,, R2 or R3;
Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three R2 groups;
X is: a) a C5.8 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-(C1^3 alkyl)amino, C,^ alkyI-S(O)m, or halogen;
Y is: a bond or a CM 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 CM 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,„6 alkyl, C,.6 alkoxy, hydroxy, mono- or di-(C1.3 alkyl)amino,
C1-6 alkyl-S(O)m , COOH and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C,.6 alkyl and C,.6 alkoxy; ' b) tetrahydropyran, tetrahydrofuran, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4- dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, C,.6 alkyl, C,_e alkoxy, hydroxy, mono- or di-(C,.3 alky!)amino-C,.3 alkyl, phenylamino-C1.3 alkyl and C,_3 alkoxy-C^ alkyl; c) C,_6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C,_3 alkyl, C^alkoxyalkyl, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, alkyl, phenylamino, wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C,.3 alkyl)amino, G,^ alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C^ alkoxy, hydroxy or mono- or di-(C,.3 alkyl)amino;
is : a) C3.10 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 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, C3.8 cycloalkyl, C5.8 cycloalkenyl, hydroxy, nitrile, C,.3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C,.3)alkylaminocarbonyl; b) C3.7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl each being optionally be partially or fully halogenated and optionally substituted with one to three C,^ 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, CHOH, >C=0, >C=S and NH; c) C3.10 branched alkenyl" optionally partially or fully halogenated and optionally substituted with one to three C,.5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C^ alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C1.3)alkylaminocarbonyl; d) a C5.7 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, C1-6 branched or unbranched alkylcarbonylamino-C^- alkyl;
R2 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;
R3 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 substituted with one to five groups selected from the group consisting of phenyl, naphthyl, 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 Cw alkyl, halogen, hydroxy, nitrile, C,.3 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-(C1.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1.3)alkyl aminocarbonyl, C,.5 alkyl-C(O)-C,.4 alkyl, amino-C,.5 alkyl, mono- or di-(C1.3)alkylamino-C1^ alkyl, amino-S(O)2, di- (C1.3)alkylamino-S(O)2, R4-C1.5 alkyl, alkoxy, R6-C(O)-C1.5 alkyl and R -C1-5 alkyl(R8)N, carboxy-mono- or di-(C1.5)-alkyl-amino; b) 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, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring 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,.3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl 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, NH2C(O), a mono- or di-(C,.3)aIkyl aminocarbonyl, ClJt alkyl-OC(O), C^ alkyl, mono- or alkyl, alkyl, R10-C1-5 alkoxy, R11 -C(0)-C1.5 alkyl, and R12-C^alkyl(R13)N; c) 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) C5.7 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, alkoxycarbonylalkyl or phenylsulfonyl; or f) C1-β branched or unbranched alkyl optionally partially or fully halogenated;
or R1 and R2 taken together may optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C^ branched or unbranched alkyl optionally be partially or fully halogenated;
each R4, R5, R6, R7, R9, R10 R„ and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2; W is O or S and pharmaceutically acceptable derivatives thereof.
In another preferred embodiment 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:
Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
In another preferred embodiment 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 C5.7cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C-,.4 branched or unbranched alkyl, C alkoxy or CM 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, C1-4alkoxy, hydroxy, nitrile, mono- or di-(C1.3 alkyl)amino, C,_6 a!kyl-S(O)m or halogen; R1 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; R3 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.
In yet another preferred embodiment 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 CM branched or unbranched alkyl, C^alkoxy or
C^alkylamino; 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-(C1-3 alky!)amino, G,.6 alkyl-S(O)m or halogen.
In yet still another preferred embodiment 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; and
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,.6 alkoxy, hydroxy or mono- or di-(C,.3 alkyl)amino, C14 alkyl-S(O)m and phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C^ alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino. In a further embodiment 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/ϊ-butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted by 3;
R3 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.
In another preferred embodiment 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.
In another preferred embodiment 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.
In another preferred embodiment 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:
1-[5-ferf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl)phenyl)naphthalen-1- yl]urea;
1-[5-fert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]urea;
1-[5-fer.-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4- yl)ethyl)phenyl)naphthalen-1-yl]urea;
1-[5-fert-butyl-2-p-tolyl-2H-pyrazόl-3-yl]-3-[4-(4-dimethylaminophenyl)naphthalen-1- yl]urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)ρhenyl)naphthalen-1- yl]urea;
1-[5-fert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl- methyl)phenyl)naphthalen-1 -yl]urea;
1-[5-fetιf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)naphthalen-1 -yl]urea;
1-[5-tet -butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2- yl)naphthalen-1 -yl]urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-fur-2- yl)naphthalen-1 -yl]urea;
1-[5-fe/ιf-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)naphthalen-1-yl]urea;
1-[5-tenf-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)naphthalen-1-yl]urea;
1-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-piperdin-1-ylmethyl- phenyl)naphthalen-1 -yl]urea;
1 -[5-terf-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-(4-methylpiperazin-1 - yl)methylphenyl)naphthalen-1-yl]urea;
1-[5-fer.-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-di(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]urea;
1-[5-.e/f-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-pyridin-4-ylmethyl- pyridin-3-yl)naphthalen-1-yl]urea;
1-[5-.etτf-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin- 4-ylmethyl)pyridin-3-yl)naphthalen-1 -yl]urea;
1-[5-.erf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4- ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea; 1-[5-tet -butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-tetrahydropyran-4- ylmethyi-pyridin-3-yl)naphthalen-1-yl]urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo- tetrahydrothiophen-3-ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
1-[5-te/f-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(imidazol-1- ylmethyl)pyridin-3-yl)naphthalen-1-yl]urea;
1-[2-(3-dimethylaminomethylphenyl)-5-(1-methyl-cyclohexyl)-2H-pyrazol-3-yl]-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
1-[2-(5-(1-methyl-cyclohexyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1-yl]urea;
1-[5-tøt -butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5- yl)naphthalen-1-yl]urea;
1-[5-.er.-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-methoxy-5-(2- morpholin-4-yl-ethoxy)phenyl)naphthalen-1 -yl]urea;
1-[5-fer.-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-yl- ethoxy)phenyl)naphthalen-1-yl]urea;
1-[5-tett-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3- (dimethylamino)phenyI)naphthalen-1-yl]urea;
1-[5-fe/t-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3- (methylsulfonyl)phenyl)naphthalen-1-yl]urea;
5-fet -butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1- yl]ureido}thiophene-2-carboxylic acid methyl ester;
5-tett-butyl-3-{3-[4-(6-morpholin-4-ylmethyI-pyridin-3-yl)naphthalen-1- yl]ureido}thiophene-2-carboxylic acid methylamide;
5-fert-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1- yl]ureido}-1 H-pyrrole-2-carboxylic acid methyl ester; 5-tett-butyl-1-methyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen-1- yl]ureido}-1 H-pyrrole-2-carboxylic acid methylamide;
2-acetylamino N-(5-tert-butyl-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)naphthalen- 1-yl]ureido}thiophen-2-ylmethyl)acetamide;
1-[5-fetτf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohex-1- enyl)naphthalen-1 -yl]urea;
1 -[5-tett-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyIohept-1 - enyl)naphthalen-1 -yl]urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-morpholin-4-yl- ethylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-ter.-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-cyclohept-1- enyl)naphthalen-1 -yl]urea;
1-[5-tørf-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-4-yl- methylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-te/f-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3- (dimethylaminoethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
1-[5-fer.-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yI]-3-[4-(3-(pyridin-3-yl- methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
1-[5-fe/f-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(phenyl- methylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2- phenylethylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-fert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(furan-2-yl- methylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-te/f-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pyridin-2-yl- ethylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea; 1-[5-fer,-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-piperdin-1-yl- ethylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-fetf-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-imidazol-4-yl- ethylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-fert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-2-yl- methylamino)cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-ter.-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(4- methoxyphenyl)ethylamino)cyclohex-1-enyl)naphthalen-1-yl]urea;
1-[5-fetf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-ylmethyl-3-oxo-cyclohex- 1-enyl)naphthalen-1-yl]urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-tetrahydrothiophen-3- ylmethyl)-3-oxo-cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-ferf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(1-oxo-thiomorpholin-4-ylmethyl)-3- oxo-cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1-[5-terf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperazin-1-ylmethyl)-3-oxo- cyclohex-1 -enyl)naphthalen-1 -yl]urea;
1 -[5-terf-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazoI-3-yl]-3-[4-{6-oxo-1 -(tetrahydro- pyran-4-ylmethyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl}naphthalen-1-yl]urea;
1-[5-fert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-oxo-1-pyridin-4- ylmethyl-piperdin-4-yl)naphthalen-1-yl]urea;
1 -[5-fert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1 -pyridin-4-yl-1 ,2,3,6-tetrahydro- pyridin-4-yl)naphthalen-1-yl]urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-oxo-1-pyridin-4-yl- 1 ,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1 -yl]urea;
5-tetϊ-butyl-3-{3-[4-(6-oxo-1 -pyridin-4-yl-1 ,2,3,6-tetrahydro-pyridin-4-yl)naphthalen-1 - yl]ureido}thiophene-2-carboxylic acid methyl ester; 5-te/f-butyl-1 -methyl-3-{3-[4-(6-oxo-1 -pyridin-4-yl-1 ,2,3,6-tetrahydro-pyridin-4- yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl ester;
5-tetf-butyl-1 -methyl-3-{3-[4-(6-oxo-1 -pyridin-4-yl-1 ,2,3,6-tetrahydro-pyridin-4- yl)naphthalen-1-yl]ureido}pyrrole-2-carboxylic acid methyl amide;
5-fert-butyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1- yl]ureido}thiophene-2-carboxylic acid methyl ester;
5-te/f-butyl-1-methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1-enyl)naphthalen-1- yl]ureido}pyrrole-2-carboxylic acid methyl ester; and
5-terf-butyl~1 -methyl-3-{3-[4-(3-morpholin-4-yl-cyclohex-1 -enyl)naphthalen-1 - yl]ureido}pyrrole-2-carboxylic acid methyl amide and
the pharmaceutically acceptable derivatives thereof.
Preferably 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 :
1-[5-ferf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- methyl)phenyl)naphthalen-1 -yl]urea;
1-[5-fert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(morpholin-4- yl)ethyl)phenyl)naphthalen-1-yl]urea;
1-[5-fert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]urea;
1-[5-tør.-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)naphthalen-1-yl]urea;
1-[5-fett-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-pyridin-2- yl)naphthalen-1 -yl]urea; 1-[5-ter.-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-ylmethyl-fur-2- yl)naphthalen-1 -yl]urea;
1-[5-ter.-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)naphthalen-1 -yl]urea;
1-[5-fert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)naphthalen-1-yl]urea and
the pharmaceutically acceptable derivatives thereof.
In another embodiment 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
wherein:
Ar, is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein A is optionally substituted by one or more R.,, R2 or R3;
Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole each being optionally substituted with zero to three R2 groups;
X is: a C5.8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C,^ alkyl, C^ alkoxy or C1-4 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 CM alkyl, C^alkoxy, hydroxy, nitrile, amino, mono- or di-(C1.3 alkyl)amino, mono- or di-(C1.3 alkylamino)carbonyl, NH2C(O), C,.6 alkyl-S(O)m or halogen;
Y is: a bond or a C1-4 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, tetrahydrofuranyl, 1 ,3-dioxolanonyI, 1 ,3-dioxanonyl, 1 ,4- dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C,„6 alkyl, C,_6 alkoxy, C^ alkoxy-C,^ alkyl, C,.6 alkoxycarbonyl, aroyl, heteroaroyl, heterocycleC^acyl wherein the heteroaryl and heterocycle are as defined hereinabove in this paragraph, C,.3acyl, oxo, hydroxy, pyridinyl- C|.3 alkyl, imidazolyl-C,_3 alkyl, alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, amino-S(O)m, C14 alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1.3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C^ alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC,.6alkyl, C,.3alkyl, arylC0.3alkyl, C^alkoxyC,.;, alkyl, G^ alkoxy, aroyl, C,.3acyl, C1.3alkyl-S(O)m- or arylC0.3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C,.6 alkyl, C,^ alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino; 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,.6 alkyl or C,_6 alkoxy; or Z is hydroxy, hydroxyC^alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C^alkyl, aminoC,_6alkyl, arylC^alkyl, C^alkoxyC^ alkyl, Cw alkoxy, aroyl, C^acyl. C^alkyl-S(0)m- , arylC0.3alkyl-S(O)m- , nitrileC^alkyl or C^alkoxyC^alkyl, 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-(C1.3 alkyl)amino, C,_6 alkoxyheteroarylC0^alkyl, heteroarylC0.3alkyl or heterocycyleC0.3alkyl wherein the heteroaryl and heterocycle is hereinabove described in this paragraph, or Z is C,.6alkyl branched or unbranched, C,.6alkoxy, C^acylamino, nitriieC1_4alkyl, C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C1^3 alkyl)amino;
is : a) 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, C3.8 cycloalkyl, C5.8 cycloalkenyl, hydroxy, nitrile, C^ alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C1.3)alkylaminocarbonyl; b) C3.7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each 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, CHOH, >C=O, >C=S and NH; c) C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C,_5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C1.3)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;
R2 is: a C,_6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile, or R2 is acetyl, aroyl, C^ branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl;
R3 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 substituted with one to five groups selected from the group consisting of a phenyl; naphthyl, 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^ alkyl, naphthyl C^ alkyl, halogen, hydroxy, oxo, nitrile, C,.3 alkoxy optionally 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-(C1.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or dKC^alkyl aminocarbonyl, C,_5 alkyl, mono- or alkyl, amino-S(O)2, di-(C1.3)alkylamino-S(O)2, R4-C..5 alkyl, R6-C(O)-C1.5 alkyl and R7-C1.5 alkyl(R8)N, carboxy-mono- or di-(C,.5 )-alkyl-amino; 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, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring 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, nitro, amino, mono- or di-(C1.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C,.3)alkyl aminocarbonyl, CM alkyl-OC(O), C.,_5 alkyl-C(O)-CM branched or unbranched alkyl, an amino-C.,.5 alkyl, mono- or di-(C1_3)alkylamino-C1_5 alkyl, alkyl and R12-C,.5 alkyl(R13)N; 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,.3 alkyl groups; e) acetyl, aroyl, C^alkoxycarbonylC^alkyl or phenylsulfonyl; or f) C,.6 branched or unbranched alkyl optionally partially or fully halogenated;
or R1 and R2 taken together optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C,^ branched or unbranched alkyl optionally partially or fully halogenated;
each R4, R5, R6, R7, R9, R10, R-n and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2; W is O or S; wherein X is directly attached to one or two -Y-Z, and pharmaceutically acceptable derivatives thereof.
In another embodiment 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: Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
In another embodiment 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 R1; R2 or R3; X is: a C5-7 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three CM alkyl, CM 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
G,_4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1.3 alkyl)amino, mono- or di-(C,_3 alkylamino)carbonyl, NH2C(O), C,_6 alkyl-S(O)m or halogen;
Y is: a bond or a C1.4 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, C1-6 alkyl, C1-6 alkoxy, C,.3 alkoxy-C,^ alkyl, C,.6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C^acyl, oxo, hydroxy, pyridinyl-C^ alkyl, imidazolyl-C1-3 alkyl, alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, amino-S(O)m, alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy, halogen or mono- or di-(C1.3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C^ alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC^alkyl, C^alkyl, arylC0^alkyl, C^alkoxyC^ alkyl, C,.g alkoxy, aroyl, C^acyl, C1-3alkyl-S(O)m- or arylC0.3alkyl-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 C1-6 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, C1-6 alkyl or C,.6 alkoxy; or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by aroyl, C,.3acyl, C,.6alkyl, C^alkoxyC^ alkyl, pyridinylC^alkyl, tetrahydrafuranylC^alkyl, nitrileC1_4alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, or Z is Chalky! branched or unbranched, C^alkoxy or nitrileClJ(alkyl;
R., is:
C,_4 branched or unbranched alkyl optionally partially or fully halogenated;
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;
C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C,_5 branched or unbranched alkyl;
cyclopentenyl and cyclohexenyl optionally substituted with one to three C^ alkyl groups;
R2 is: a C,.6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
R3 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^alkoxyC^alkyl, C1-3thioalkyI, C,. phenyloxy, naphthyloxy, heteraryloxy wherein the 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, NH2C(O), a mono- or di-(C1.3)alkyl aminocarbonyl, alkyl, alkyl, mono- or di-(C1.3)alkylamino-C1.5 alkyl, amino-S(O)2, di-(C1.3)alkylamino-S(O)2, R4-C1.5alkyl, R5-C^ alkoxy, R6-C(O)-C1.5 alkyl and R7-C1.5 alkyl(R8)N, carboxy-mono- or di-(C1.5)-alkyl-amino; 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 paragraph, nitro, amino, mono- or di-(C1.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1.3)alkyl aminocarbonyl, C,^ alkyl-OC(O), C,.5 alkyl-C(0)-CM branched or unbranched alkyl,, an alkyl, mono- or di-(C1.3)alkylamino-C1.5 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;
C.,.6alkoxycarbonylC.,.6alkyl;
or R., and R2 taken together optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C,^ branched or unbranched alkyl optionally partially or fully halogenated; and each R4, R5, R6, R7, R9, R10ι RΉ and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
wherein X is directly attached to one -Y-Z.
In another embodiment 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 CM 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,. 2alkoxy, 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,.3 alkyl, C|_6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C^acyl, oxo, hydroxy, pyridinyl-C^a alkyl, imidazolyl-C^ alkyl, tetrahydrofuranyl-C^ alkyl, nitrile-C^ alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C^ alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, amino-S(O)m, C,.6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C^ alkoxy, hydroxy, halogen or mono- or di-(C,_3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C^ alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C,.3alkyi, arylC0.3alkyl, C^alkoxyC^ alkyl, C^ alkoxy, aroyl, C,.3acyl, C1.3alkyl-S(O)m-, pyridinylC0.3alkyl, tetrahydrafuranylC0.3alkyl, or arylC0. 3alkyI-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C,.6 alkyl or C1-6 alkoxy; or Z is hydroxy, hydroxyC,.3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C,.6alkyl, pyridinylC0.3alkyl, tetrahydrafuranylC0.3alkyl, C^alkoxyC.,^ alkyl, C^acyl, nitrileC^alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, or Z is C,.6alkyl branched or unbranched, C,_6alkoxy or nitrileC^alkyl;
R1 is:
CM branched or unbranched alkyl optionally partially or fully halogenated;
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;
C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C^ branched or unbranched alkyl;
cyclopentenyl and cyclohexenyl optionally substituted with one to three C,_3 alkyl groups;
R2 is: a C,.6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
R3 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.,. athioalkylC^alkyl, amino, mono- or di-(C.,..3)alkylamino, NH2C(O) or a mono- or di-(C1.3)alkyl aminocarbonyl, or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C^ alkyl groups
or R1 and R2 taken together optionally form a fused phenyl or pyridinyl ring.
In another embodiment 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 -CH2-, -O-(CH2)0.3-, -CH2CH2-, -CH2NH-, -CH2CH2-NH-, NH-CH2CH2-,
-CH2-NH-CH2-, -NH-, -NH-C(O)-, -C(O)-, -CH(OH)-, -CH2(CH2CH3)- or a bond; X is: cyclohexenyl optionally substituted with an oxo group or one to three CM 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,_2alkoxy, 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,.6 alkyl, G,^ alkoxy, C^ alkoxy-C^ alkyl, C,.6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C,.3acyl, oxo, hydroxy, pyridinyl-C^ alkyl, alkyl, tetrahydrofuranyl-C^ alkyl, nitrile-C,.3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, amino-S(O)m, C,.6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy, halogen or mono- or di-(G,_3 alkyl)amino; or Z is optionally substituted with one to three amino or aminocarbonyl wherein the N atom is optionally independently mono- or di-substituted by aminoC,.6alkyl, C,.3alkyl, arylC0.3alkyl, C,.5 alkoxyC,.3 alkyl, C,_g alkoxy, aroyl, C^acyl, C,_3alkyl- S(O)m- or arylC0.3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C,_6 alkyl or C,.6 alkoxy; or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C^alkyl, pyridinylC^alkyl, tetrahydrafuranylC1-2alkyl, C1-3 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-(C1.3 alkyl)amino, or Z is C^alkyl branched or unbranched, C^alkoxy or nitrileC^alkyl;
R, is:
Cw branched or unbranched alkyl optionally partially or fully halogenated;
R2 is: a C1-3 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
R3 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 C1-3 branched or unbranched alkyl which is optionally partially or fully halogenated, C1-3 alkoxy which optionally partially or fully halogenated, C 3thioalkyl, C1.3thioalkylC1.5alkyl, amino or NH2C(O);
C^alkoxycarbonyl;
or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C,^ alkyl groups.
In a further embodiment 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 R2 or R3; X is: cyclohexenyl; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with C,„2alkoxy 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,„3 alkyl, C,.3 alkoxy, oxo , hydroxy or NH2C(O)-; or Z is hydroxyC,.3alkyl, amino wherein the N atom is optionally independently mono- or di-substituted by pyridinylmethyl, tetrahydrafuranylmethyl, C,^ alkoxyC,.3 alkyl, C1-3acyl or nitrileC^alkyl, or Z is nitrileC^alkyl;
R3 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,_ 2thioalkylC,.3alkyl, amino or NH2C(O);
C,_3alkoxycarbonyl;
or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C,_3 alkyl groups.
In a still further embodiment 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.
In a yet still further embodiment 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.
Preferably 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:
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl-methylphenyl)- naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[3-(4-morpholin-4-yl-methylphenyl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-morpholin-4-yl-methylfuran-2-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl-methyl)cyclohexenyl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-morpholin-4-yl)ethylphenyl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminomethylphenyl)- naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(morpholin-4- yl)ethylamino)cyclohexenyl)-naphthaIen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3,4-(morpholin-4-yl-methyl)phenyl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-methylpiperzin-1-yl-methyl)phenyl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(piperdin-1-yl-methyl)phenyl)- naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridin-2- yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(pyridin-4- yl)ethylaminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl- methylaminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3,4- dimethoxyphenylmethyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-1 ,6-dihydro-pyridin-3- yl)naphthalen-1-yi]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- methyl)imidazol-1-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yI-methyl)imidazol-1- yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-3-yl-methyl)-3- hydroxyphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4- hydroxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methyl)- 3-hydroxyphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4- yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(imidazol-2-yl-methyl)- 3-hydroxyphenyl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hydroxymorpholin- 4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-2-methoxyethy-N- methylaminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymorpholin- 4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl- methyl)cyclohexenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetrahydrofuran-3-yl- methyl)-3-hydroxyphenyl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2- methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3- cyanopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl- methyl-piperdinyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2- cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(1-morpholin-4-yl-indan-5-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3- hydroxyphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiomorpholin-4-yl- methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3- carboxamidomorpholin-4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo- piperzin-1 -yl-methyl)phenyl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4- hydroxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea;
1 -[3-tert-butyl-1 Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3- methoxyphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin- 4carbonyl)pyrazin-2-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran- 4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- " methyl)pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6- dimethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morphoIin-4-yI- methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-oxo-1 ,6-dihydropyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4- yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4- carbonyl)pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(3-carbamylphenyl)naphthalen-1 -yl]- urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (pyridin-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyI)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;
1 -[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1 -morpholin-4-yl- propyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3- methoxypropyl)amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3-methoxypropyl)- N-methylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1 -[3-tert-butyl-1 '-methyl-1 Η-[1 ,4']bipyrazol-5-y|]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-N-di-(2- cyanoethyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(4-carbamylphenyl)naphthalen-1-yl]- urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo- tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl- amino)pyridin-3-yl)-naphthalen-1-yI]-urea;
1 -[3-tert-butyl-1 '-(3-cyanopropyI)-1 Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methanesulfinylphenyl)naphthalen-1- yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-methanesulfonylphenyl)naphthalen-1- yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-sulfonamidophenyl)naphthalen-1-yl]- urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4- yl)carbonylphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothiopyran- 4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6- (methylcarbonylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4-carbonyl)phenyl)- naphthalen-1 -yl]-urea;
1-[3-tert-butyl-1 '-(3-methylsulfanylpropyl)-1 Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(morpholin- 4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-carbonyl)pyridin-3-yl)- naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl- methyl)pyrazin-2-yl)-naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-aminopyridin-3- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-methylpiperdin-4- yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo- piperzin-1 -yl-methyl)pyridin-3-yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- carbonyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N,N-di-(2- methoxyethyl)aminomethyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1 -[5-tert-butyl-2-(2-methylpyrimid in-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-( 1-oxo- thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4- yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl- methyl)pyrazin-2-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperzin-1-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-oxy)pyridin-3- yl)naphthalen-1 -yl]-urea
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-amino)pyridin-3- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-carbamylpyridin-3-yl)naphthalen-1-yl]- urea;
1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]-urea;
1-[3-tert-butyl-1 '-methyl-1 Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-cyclopropylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(pyridin-3-yl-amino)pyrimidin-5- yl)naphthalen-1-yl]-urea;
1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1 -oxo-tetrahydrothiopyran-4-yl- amino)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-methyl)pyridin-3- yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-amino-4-carbamylphenyl)naphthalen- 1-yl]-urea;
1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1 -oxo-thiomorpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(hydroxy-pyridin-3-yl-methyl)pyridin-3- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl- methyl)pyrimidin-5-yl)naphthalen-1-yl]-urea; and the pharmaceutically acceptable derivatives thereof.
In another embodiment 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:
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(morpholin-4-yl-methyl)pyridin-2-yl)- naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-methyI)pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridin-2- yl)ethylamino)cyclohexenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl- methylaminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4- hydroxybutylamino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4- yl-methyl)pyridin-3-yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3-hydroxypiperidin-1- yl-methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymorpholin- 4-yl-methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl- methyl)cyclohexenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(tetrahydrofuran-3-yl- methyl)-3-hydroxyphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2- methoxyethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(3- cyanopropoxy)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-morpholin-4-yl- methyl-piperdinyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2- cyanoethyl)aminomethyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3- hydroxyphenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(thiomorpholin-4-yl- methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3- carboxamidopiperidin-1-yl-methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo- piperzin-1 -yl-methyl)phenyl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4- hydroxybutyloxy)pyridin-3-yl)-naphthalen-1-yl]-urea;
1 -[3-tert-butyl-1 Η-[1 ,4,]bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl-methyl)pyridin-3- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran- 4-yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yI]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6- dimethylmorpholin-4-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl-4- carbonyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)-4-methoxypyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1-morpholin-4-yl- propyl)pyridin-3-yl)-naphthalen-1-yl]-urea;
1 -[3-tert-butyl-1 '-methyl-1 Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1 -[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1 -oxo- tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4yl- amino)pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothiopyran- 4yl-amino)pyrazin-2-yl)-naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6- (methylcarbonylamino)pyridin-3-yl)-naphthalen-1 -yl]-urea;
1 -[3-tert-butyI-1 '-(3-methylsulfanylpropyl)-1 Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(morpholin- 4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1 -[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(1 -oxo- thiomorpholin-4-yl-methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4- yl-amino)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(morpholin-4-yI- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1 -[3-tert-butyl-1 '-methyl-1 Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(morpholin-4-yl- methyl)phenyl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-tetrahydrothiopyran-4-yl- amino)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomorpholin-4-yl-methyl)pyridin-3- yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-carbonyl)pyrimidin-5- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl-methyl)pyrimidin-5- yl)naphthalen-1 -yl]-urea;
1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(1-oxo-thiomorpholin-4-yl- methyl)pyridin-3-yl)naphthalen-1-yl]-urea;
1-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl- methyl)pyrimidin-5-yl)naphthalen-1 -yl]-urea and
the pharmaceutically acceptable derivatives thereof.
In another preferred embodiment 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
wherein:
G is : an aromatic C6-10 carbocycle or a nonaromatic C3.10 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.,, R2 or R3;
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 R4 or R5;
X is: a C5.8 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 CM 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,.6 alkyl-S(O)m, CN, CONH2, COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C,_6 alkyl or C,.6 alkoxy; tetrahydropyranyl, tetrahydrofuranyl, 1 ,3-dioxolanonyl, 1 ,3-dioxanonyl, 1 ,4- dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, C,.β alkyl, C,.6 alkoxy, hydroxy, amino, mono- or di-(G,_3 alkyl)amino-C,..3 alkyl, CONH2, phenylamino-C,.3 alkyl or C^ alkoxy-C.,.3 alkyl; halogen, C,.4 alkyl, nitrile, amino, hydroxy, C1-6 alkoxy, NH2C(O), mono- or di(C1.3alkyl) aminocarbonyl, mono- or di(C1.6alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C,„5 alkoxyalkyl, pyridinyl-C1-3 alkyl, imidazolyl-C,_3 alkyl, tetrahydrofuranyl-C^ alkyl, nitrile-C1-3 alkyl, carboxamide-C1-3 alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, C,.6 alkyl-S(O)m, or phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy, halogen or mono- or di-(C,.3 alkyl)amino;
C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, G,.β alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino;
each R1 is independently:
C,.10 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C3.10 cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C^ alkyl which is optionally partially or fully halogenated, C3.8 cycloalkanyl, C5.8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated or NH2C(O), mono- or d C^alky amino, and mono- or di(C.,_3alkyl)arninocarbonyl;
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,.3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH; phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C^ alkyl groups optionally partially or fully halogenated, CN, hydroxyC^alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by 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^ alkyl groups optionally partially or fully halogenated, CN, hydroxyC,.3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH;
C3.10 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,.6 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, NH2C(O), mono- or di(C1^alkyl)aminocarbonyl; the C3.10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and
S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
nitrile, halogen;
methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated;
C3.6 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 CM 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 R2, R4, and R5 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;
alkoxy, hydroxy, amino, or mono- or di-(C1.4 alkyl)amino, nitrile, halogen;
OR8;
nitro; or
mono- or di-(C,.4 alkyl)amino-S(O)2 optionally partially or fully halogenated, or H2NSO2;
each R3 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 or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C^ branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C,_g alkyl, naphthyl C^ alkyl, halogen, hydroxy, oxo, nitrile, C.,_3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1. 3alkyl)amino, phenylamino", naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C,.3alkyl) aminocarbonyl, alkyl-C(O)- C^ alkyl, amino-C1-5 alkyl, mono- or di-(C1_3alkyl)amino-C1.5 alkyl, amino-S(O)2, dl-(Cwalkyl)amino-S(0)2. R7-C^ alkyl, R8-C,.5 alkoxy, R9-C(O)-C1-5 alkyl, R^-C^ g alky R^N, carboxy-mono- or di-(C,.5alkyl)-amino;
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, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C,.6 alkyl which is optionally partially or fully halogenated, halogen, nitrile, C^ alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C,_ 3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C,.3alkyl)aminocarbonyl, C,^ alkyl- OC(O), C1-5 alkyl-C(O)-C alkyl, amino-CLs alkyl, mono- or di-(C1.3)alkylamino- C^ alkyl, R^-C^ alkyl, R^-C^ alkoxy, R14-C(O)-C1.5 alkyl or R^-C^ alkyI(R16)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,.3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH; cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C,.3 alkyl groups;
CM alkyl-phenyl-C(O)-C alkyl-, CM alkyl-C(0)-CM alkyl- or C14 alkyl-phenyl- S(O)m-C1 alkyl-;
C1-6 alkyl or branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(C.,_5aIkyl)amino optionally substituted with R19;
R20C(O)N(R21)-, R22O- or R23R24NC(O)-; R26(CH2)mC(O)N(R21)- or
R26C(O)(CH2)mN(R21)-;
C2.6alkenyl substituted by R23R24NC(O)-;
C2_g 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(CM alkyl)amino optionally substituted by one or more halogen atoms; or
aroyl;
RR is a:
C^ alkyl optionally partially or fully halogenated and optionally substituted with
each R7, R8, R9, R10, R12, R13ι R14, R15, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C1^alkyl)amino optionally partially or fully halogenated; each R^ and R16 is independently: hydrogen or C_ alkyl optionally partially or fully halogenated;
R18 is independently: hydrogen or a C^ alkyl optionally independently substituted with oxo or R25;
R20 is independently:
C^o alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
R21 is independently: hydrogen or C,.3 alkyl optionally partially or fully halogenated;
each R22, R23 and R24 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-(C1.3alkyl)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-(C1.3alkyl)amino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m = 0, 1 or 2;
W is O or S and pharmaceutically acceptable derivatives thereof.
In another preferred embodiment 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;
pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydroben'zofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1 ,4]oxazin-3-onyl, benzodioxolyl, benzo[1 ,3]dioxol-2- onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one or more R.,, R2 or R3;
In a further preferred embodiment 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^ R2 or R3;
Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5 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-(C1.3 a!kyl)amino, CONH2 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,.3 alkyl, C,_3 alkoxy, amino, mono- or di- (C-L3 alkyl)amino, CONH2, or OH; nitrile, G,_6 alkyl-S(O)m, halogen, hydroxy, C alkoxy, amino, mono- or di-(C1.6 alkyl)amino, mono- or di-(C1.3 alkyl)aminocarbonyl or NH2C(O);
each R1 is independently:
C3.6 alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3.6cycloalkyl, 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;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC^alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH; or
silyl containing three C,^ alkyl groups optionally partially or fully halogenated;
R2 is independently: halogen, C,.3 alkoxy, C^ alkyl-S(O)m optionally partially or fully halogenated, phenylsulfonyl or nitrile;
R3 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,.5 alkyl, naphthyl C,. g alkyl, halogen, oxo, hydroxy, nitrile, C^ alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1.3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1.3alkyl)aminocarbonyl, alkyl-C(O)-CM alkyl, mono- or di-(C1_ 3alkyl)amino, mono- or di-(C1^)alkylamino-C1^ alkyl, mono- or di-(C,. 3alkyl)amino-S(O)2, alkyl, alkyl(R.,.|)N, carboxy-mono- or di-(C,.5)-alkyl-amino;
C^ alkyl or CM alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or G,.6 alkyl optionally substituted with OR18;
amino or mono- or di- (C 5 alkyl)amino optionally substituted with R1g;
R20C(O)N(R21)-, R220- ; R23R24NC(O)-; R26CH2C(O)N(R21)- or R26C(O)CH2N(R21)-; C2-4alkenyl substituted by R23R24NC(O)-; or
C2-4 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 CM alkyl optionally substituted by one or more halogen atoms; and
R23 and R24 taken together optionally form imidazolyl, piperidinyl, morpholinyl, piperazinyl or a pyridinyl ring.
In yet another preferred embodiment 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^ R2 or R3;
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-(C1.3 alkylamino)carbonyl, NH2C(O), C,.6 alkyl-S(O)m or halogen;
Y is: a bond or a C1-4 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,„2 alkyl or C^ alkoxy; or
C1-3 alkoxy;
each R1 is independently:
C3_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,.3alkoxy which is optionally partially or fully halogenated; cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C^ alkyl groups optionally partially or fully halogenated, CN, hydroxyC^alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O; and
silyl containing three C,.2 independently alkyl groups optionally partially or fully halogenated;
each R2 is independently: bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile;
each R3 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;
C_.z alkyl or C1-3 alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or G,_3 alkyl optionally substituted with OR18; amino or mono- or di-(C1-3 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)-, R22O- ; R23R24NC(O)-; R26CH2C(O)N(R21)- or R26C(O)CH2N(R21)-;
C2.4 alkenyl substituted by R23R24NC(O)-; or
C2 alkynyl substituted with pyrroldinyl or pyrrolyl; and >
R23 and R24 taken together optionally form morpholino.
In yet another preferred embodiment 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 R1 ( R2 or R3;
Ar is 1 -naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
Y is: a bond or
-CH2-, -CH2CH2-, -C(O)-, -O-, -S-, -NH-CH2CH2CH2-, -N(CH3)-, or -NH-;
each R1 is independently:
C3.5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl;
cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, CN, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or trimethyl silyl;
each R3 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;
C^ alkyl or C,^ alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino;
OR18 or C,.3 alkyl optionally substituted with OR18;
amino or mono- or di-(C,.3 alkyl)amino optionally substituted with R19; CH3C(O)NH-, R22O- ; R23R24NC(O)-; R26CH2C(O)N(R21)- or R26C(O)CH2N(R21)-;
C^alkenyl substituted by R23R24NC(O)-; or
C2.4 alkynyl substituted with pyrroldinyl or pyrrolyl;
R23 and R24 are H or R23 and R24 taken together optionally form morpholino; and R26 is morpholino.
In a further preferred embodiment 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.,, R2 or
R3;
X is: imidazolyl or pyridinyl;
Y is:
-CH2., -NH-CH2CH2CH2- or -NH-;
Z is morpholino;
each R1 is independently: tert-butyl, sec-butyl, tert-amyl or phenyl;
R2 is chloro;
R3 is independently: methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, morpholino or morpholinocarbonyl.
In yet a further preferred embodiment 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. In yet a still further preferred embodiment 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.
Preferably 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
1-(3-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1-(3-Fluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(3,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1 -(3-lodo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-m-tolyl-urea
1-(4-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(3-Chloro-4-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1 -(4-Chloro-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 - yl]-urea
1-(2,5-DichIoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea 1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-2-yl-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-phenyl-urea
1-(3-Chloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2,4,6-trichloro-phenyl)- urea
1-(2-Methyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(4-Methyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1 -(2,3-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]- urea
1-(2-Methoxy-5-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1-(2-Chloro-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1-(2,4-Dichloro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-(4- ethyl-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1 -(2,4-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]- urea
1-(2,3-Dimethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea 1-(4-Cyano-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3,4,5-trimethoxy- phenyl)-urea
1-Biphenyl-4-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1-(2,5-Difluoro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-(3-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1-(2-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(4-Benzyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yI]- urea
1-(2-Methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(4-Fluoro-3-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1 -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-3-(2,4,5-trimethyl-phenyI)- urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethyl- phenyl)-urea
1-(3-Methylsulfanyl-phenyl)-3-[4-(6-morphoIin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea 1-(2-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yr]-urea
1-(4-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1-(2-Fluoro-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(4-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1 -(2,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]- urea
1-(4,5-Dimethyl-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1-(5-Chloro-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)-naphthalen- 1-yl]-urea
1-(2-lsopropyl-6-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(2-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1 -(4-lsopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]- urea
1-(4-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-(3-Ethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1-(2-Ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea 1-(4-Butoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
4-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid ethyl ester
1-(4-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyI-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(3-Methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4- trifluoromethylsulfanyl-phenyl)-urea
5-{3-[4-(6-MorphoIin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-isophthalic acid dimethyl ester
1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
3-{3-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-benzoic acid ethyl ester
1-(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-pentyloxy-biphenyl-3- yl)-urea 4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}- benzoic acid methyl ester
1-(2,5-Diethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-Benzothiazol-6-yl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
N-(2,5-Diethoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- ureido}-phenyl)-benzamide
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-phenoxy-phenyl)- urea
1-(5-Ethanesulfonyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
4-Methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-N- phenyl-benzamide
1 -(2-Methyl-1 ,3-dioxo-2,3-dihydro-1 H-isoindol-5-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea
1-(2,3-Dimethyl-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
N-Butyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- ureido}-benzenesulfonamide
1-[3-(2-Methyl-[1 ,3]dioxolan-2-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(2,4-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea 1-(2-Methyl-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(2-Methoxy-4-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(4-Chloro-2-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)-naphthalen-1- yl]-urea
1-(5-Chloro-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea
1-(3,5-Dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy- phenyl)-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3- trifluoromethylsulfanyl-phenyl)-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-phenoxy-phenyl)- urea
1 -(2-Methoxy-5-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 - yl]-urea
1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(3,5-Bis-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)- naphthalen-1 -yl]-urea
1-(2-tert-ButyI-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-yImethyl-pyridin-3-yl)-naphthalen-1- yl]-urea 1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-yImethyl-pyridin-3-yl)-naphthalen-1-yl]- urea
1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morphoIin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea
1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(5-lsopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)- naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea .
1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3- yl}-naphthalen-1 -yl)-urea
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1-yl)- naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]- naphthalen-1 -yl}-urea 1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea
1 -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-3-(3-trifluoromethyl- phenyl)-urea
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy- phenyl)-urea
1-[5-(1 ,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea
1-[5-tert-Butyl-2-(1 H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea
1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea
1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea
1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-acetamide
and the pharmaceutically acceptable derivatives thereof. 1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
1-(3-tert-Butyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]-urea;
1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea;
1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- urea;
1 -(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 - yl]-urea;
1-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-lsopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomorpholin-4-ylmethyl-phenyl)- naphthalen-1 -yl]-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-phenyl)-naphthalen-1- yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetrahydro-pyran-4-ylamino)-phenyl]- naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3- yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3- yl}-naphthalen-1 -yl)-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-imidazol-1-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-phenyI)-naphthalen-1- yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]- naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-morpholin-4-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomorpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea; 1-[2-Methoxy-5-(1-methyl-cyclopropyl)-phenyl]-3-[4-(2-morpholin-4-ylmethyl- pyrimidin-5-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-trifluoromethyl- phenyl)-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(4-trifluoromethoxy- phenyl)-urea;
1-[5-(1 ,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomorpholin-4-ylmethyl- phenyl)-naphthalen-1 -yl]-urea;
1-[5-(1 ,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea;
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-morpholin-4-ylmethyl- pyrimidin-5-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(1 H-pyrazol-4-yI)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-[5-tert-ButyI-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(5-pyridin-4-ylmethyl-pyridin-2- yl)-naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-(3-morpholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yI)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1 -yl]-urea;
2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin-3-yl]-naphthalen- 1-yl}-ureido)-phenoxy]-acetamide; 3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-benzamide;
4-tert-Butyl-2-{3-[4-(2-chloro-4-morpholin-4-ylmethyl-phenyl)-naphthalen-1-yl]- ureido}-benzamide;
and the pharmaceutically acceptable derivatives thereof.
More preferably 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
1-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(3-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yI)-naphthalen-1-yl]- urea;
1-(4-Methyl-biphenyl-3-yl)-3-[4-(6-morpholin-4-yImethyl-pyridin-3-yl)-naphthalen-1-yl]- urea;
1-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
1-(5-lsopropyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3- yl}-naphthalen-1 -yl)-urea; 1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-[5-(1 ,1-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-2-(1 H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(morpholine-4-carbonyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1 -yl]-urea;
N-(5-tert-Buty!-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-acetamide
and the pharmaceutically acceptable derivatives thereof.
In another preferred embodiment 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
wherein:
E is carbon or a heteroatom group chosen from -O-, -NH- and -S-; G is : an aromatic C6.10 carbocycle or a nonaromatic C3.10carbocycle saturated or unsaturated;
a 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing 1 or more heteroatoms chosen from O, N and S;
a 6-8 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 optionally substituted by one or more R.,, R2 or R3;
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 R4 or R5;
X is: a Cg.8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C alkyl, C1-4 alkoxy or CM 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, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(G,_3 alkyl)amino, mono- or di-
(C1-3 alkylamino)carbonyl, NH2C(O), C,.6 alkyl-S(O)m or halogen;
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-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1 ,3-dioxolanonyl, 1 ,3-dioxanonyl, 1 ,4- dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C,.6 alkyl, C,.6 alkoxy, C^ alkoxy-C,^ alkyl, C,_6 alkoxycarbonyl, aroyl, C^acyl, oxo, hydroxy, pyridinyl-C,_3 alkyl, imidazolyl-C^ alkyl, alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C^ alkyl)amino, C,.6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy, halogen or mono- or di-(C,.3 alkyl)amino; or Z is optionally substituted with one to three amino or amino-C,.3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC,.
6alkyl, C^alkyl, arylC0.3alkyl, C^alkoxyC^ alkyl, C^ alkoxy, aroyl, C^acyl, G,_ 3alkyl-S(O)m- or arylC0.3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C,.6 alkyl or C,.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,.6 alkyl or C,_6 alkoxy; or Z is hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C,.3acyl, C,.6alkyl or C^alkoxyC^alkyl, C,.6alkyl branched or unbranched, C^alkoxy,
CLgacylamino, nitrileC1_4alkyI, C,_6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C,.3 alkyl)amino;
each R., is independently:
C1-10 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 C3.10 cycloalkyl, hydroxy, oxo^ phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C,.6 alkyl which is optionally partially or fully halogenated, C3.8 cycloalkanyl, C5.8 cycloalkenyl, hydroxy, nitrile, C,.3 alkoxy which is optionally partially or fully halogenated or
NH2C(O), mono- or di(C1.3alkyl)amino, and mono- or d C^alky aminocarbonyl;
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy 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^alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=O, >C=S or NH;
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.,.3alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C,_3 alkyl optionally partially or fully halogenated, nitrile, hydroxyC,_3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH;
C3.10 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,.6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C^ alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C,..3alkyl)aminocarbonyl; the C3.10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(0)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C,.3 alkyl groups;
oxo, nitrile, halogen;
silyl containing three C1 alkyl groups optionally partially or fully halogenated; or
C3.6 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 CM 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 R2, R4, and R5 is a C,.6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6acyl, 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;
OR6ι C,.6 alkoxy, hydroxy, nitrile, nitro, halogen;
or amino-S(O)m- wherein the N atom is optionally independently mono- or di- substituted by C,.6alkyl or arylC0.3alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C,.3alkyl, arylC0^alkyl, C,. 6acyl, C1.6alkyl-S(O)rπ- or arylC0.3alkyl-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 R3 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, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl alkyl, naphthyl C^ alkyl, halogen, hydroxy, oxo, nitrile, C,^ alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(G,_ 3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C,„3alkyl) aminocarbonyl, C,.5 alkyl-C(O)- C,_4 alkyl, amino-C,_5 alkyl, mono- or di-(C1.5alkyl)amino, mono- or di-(C1. 3alkyl)amino-C.,..5 alkyl, amino-S(O)2, di-(C,.3alkyl)amino-S(O)2, R7-C,.5 alkyl, Ra- C,_g alkoxy, alkyl(R11)N, carboxy-mono- or di-(C,_ 5alkyl)-amino;
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, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C,.6 alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1. 3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C,.3alkyl)anrιinocarbonyl, C,^ alkyl- OC(O), alkyl-C(O)-C1-4 alkyl, amino-C,_5 alkyl, mono- or di-(C,. 3)alkylamino-C1-5 alkyl, R12-C1-5 alkyl, alkoxy, R14-C(O)-C1.5 alkyl or R15-
C^alky R N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C,_3 alkyl groups;
C, alkyl-phenyl-C(O)-C1-4 alkyl-, C1-4 alkyl-C(0)-CM alkyl- or CM alkyl-phenyl- S(O)m-C^ alkyl-;
C,_6 alkyl or C,.6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C,^ alkyl optionally substituted with OR18;
amino or mono- or optionally substituted with R19;
R20C(O)N(R21)-, R22O- or R23R24NC(O)-; R26(CH2)mC(O)N(R21)-, R^N^O)-^. 3alkoxy or R26C(O)(CH2)mN(R21)-;
C2.6alkenyl substituted by R23R24NC(O)-;
C2.6 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 CM alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(CM alkyl)amino optionally substituted by one or more halogen atoms;
C,.6acyl or aroyl;
R6 is a:
C1 alkyl optionally partially or fully halogenated and optionally substituted with R2e; .
each R7, R8, R9, R10, R12, R13 R14, R15, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C1.4alkyl)amino optionally partially or fully halogenated;
each R„ and R16 is independently: hydrogen or C1-4 alkyl optionally partially or fully halogenated;
R18 is independently: hydrogen or a C,.4 alkyl optionally independently substituted with oxo or R25;
R20 is independently:
C^o alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
R21 is independently: hydrogen or C1-3 alkyl optionally partially or fully halogenated;
each R22, R23 and R24 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-(C1^alkyl)aminocarbonyl, phenyl, pyridinyl, aminό or mono- or d C^alky amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(G,.3alkyl)amino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m = 0, 1 or 2;
W is O or S and pharmaceutically acceptable derivatives thereof. In a preferred embodiment 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 -CH2-, -NH- or -O-; W is O; and G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1 ,4]oxazin-3-onyl, benzodioxolyl, benzo[1 ,3]dioxol-2- onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1 H- indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromoyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is optionally substituted by one or more R1 ( R2 or R3.
In yet another preferred embodiment 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-1H-indolyl or indolinonyl, wherein G is optionally substituted by one or more R R2 or R3; Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5 groups;
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 C1-4 alkyl, C^alkoxy, hydroxy, nitrile, amino, mono- or di-(C1.3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(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 C1 alkyl optionally substituted by one or more halogen atoms;
Z is: phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl, heterocycle selected from 2- oxa-5-aza-bicyclo[2.2.1]heptanyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1 ,3-dioxolanonyl, 1 ,3-dioxanonyl, 1 ,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyrrolidinyl and dioxolanyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C^ alkoxy, amino, mono- or di-(C,^ alkyl)amino, CONH2 or OH; or Z is optionally substituted by phenyl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C,.3 alkyl or C,.3 alkoxy; or Z is nitrile, nitriteC^ alkyl, G,^ alkyl-S(O)m, halogen, hydroxy, C^ alkyl, C,_3 acylamino, C,^ alkoxy, amino, mono- or di-(C1-3 alkyl)aminocarbonyl, or amino mono or di-substituted by aminoC,.6 alkyl or C^alkoxyC^alkyl;
each R, is independently: C,.6 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 G,.,, alkyl is optionally substituted with one to three C3.6cycloalkyl, oxo, phenyl, dioxolanyl, pyrrolidinyl, 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 and C^alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C^ alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH;
oxo;
C3.6 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, C,^ alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1.3alkyl)amino optionally substituted by one or more halogen atoms;
or silyl containing three C_ alkyl groups optionally partially or fully halogenated;
R2 is independently: a C,.5 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, 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;
C,_3 alkoxy, hydroxy, nitrile, nitro, halogen; or amino-S(O)m- wherein the N atom is optionally independently mono- or di- substituted by C1-3alkyl or arylC0^alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C^alkyl, arylC0.3alkyl, C,_ 3acyl, CMalkyl-S(O)m- or arylC0.3alkyl-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^ alkyl or C^ alkoxy;
R3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, [1 ,3,4]oxadiazol, pyrazolyl, each is 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, naphthyl C,_ 5alkyl, halogen, oxo, hydroxy, nitrile, C^ alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or dKC^alky amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C,.3alkyl)aminocarbonyl, alkyl, mono- or di-(C,. 3alkyl)amino, mono 3alkyl)amino-S(O)2, alkyl(R.,.,)N, carboxy-mono- or d C^-alkyl-amino;
C 3 alkyl or Λ alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or alkyl optionally substituted with OR18;
amino or mono- or di- (Cr5 alkyl)amino optionally substituted with R19;
R20C(O)N(R21)-, R22O- ; R23R24NC(O)-; R26CH2C(O)N(R21)-, R23R24NC(O)-C1.2alkoxy or R26C(O)CH2N(R21)-;
C2-4alkenyl substituted by R23R24NC(O)-; or
C2-4 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated wherein one of the methylene groups is optionally replaced by O, and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C alkyl optionally substituted by one or . more halogen atoms;
G^acyl; and
R23 and R24 taken together optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or a pyridinyl ring.
In yet another preferred embodiment 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:
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 3,4- dihydro-2H-benzo[1 ,4]oxazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is optionally substituted by one or more R17 R2 or R3;
Ar is naphthyl;
X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three CM alkyl, C^alkoxy, hydroxy, nitrile, amino, mono- or di-(C,.3 alkyl)amino, mono- or di-(G,.3 alkylamino)carbonyl, NH2C(O), C^ alkyl-S(O)m or halogen;
Y is: a bond or a CM saturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with nitrile or oxo;
Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl, pyrrolidinyl, phenylpiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl, 2-oxa-5-aza- bicyclo[2.2.1]heptanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl each of which are optionally substituted with one to two C^ alkyl or C,.2 alkoxy; or Z is hydroxy, C^ alkyl, C^ alkoxy, C1-3 acylamino, C1-3 alkylsulfonyl, nitrile C,.3 alkyl or amino mono or di-substituted by C^ alkoxyC,^ alkyl;
each R1 is independently:
C1-5 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,.g alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl each optionally substituted with one to three halogen, C,_3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile and C,_ 3alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, 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,.3aIkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O;
oxo;
C2.4 alkynyl optionally partially or fully halogenated wherein one or more methylene groups are optionally replaced by O, and optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, C 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;
or silyl containing three C,.2 alkyl groups optionally partially or fully halogenated;
each R2 is independently: a C,^ alkyl optionally partially or fully halogenated, CM alkoxy optionally partially or fully halogenated, bromo, chloro, fluoro, methoxycarbonyl, methyl-S(O)m , ethyl-S(O)m each optionally partially or fully halogenated or phenyl-S(O)m; or R2 is mono- or di-C^acylamino, amino-S(O)m or S(O)mamino wherein the N atom is mono- or di-substituted by C^alkyl or phenyl, nitrile, nitro or amino;
each R3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1 ,3,4]oxadiazol, pyrazolyl, each of the aforementioned is optionally substituted with one to three C,_3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C,^ alkoxy optionally partially or fully halogenated;
C,.3 alkyl or C,_3 alkoxy optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C,.3 alkyl optionally substituted with OR18; amino or mono- or di-(C,-3alkyl)amino optionally substituted with R19;
R20C(O)N(R21)-, R22O- ; R23R24NC(O)-; R26CH2C(O)N(R21)-, NH2C(O)methoxy or R26C(O)CH2N(R21)-;
CM alkenyl substituted by R23R24NC(O)-; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
C^acyl and
R23 and R24 taken together optionally form morpholino.
In another preferred embodiment 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:
G is phenyl, pyridinyl, pyridonyl, ^naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-
8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1 H-indol-5- yl, indolinyl, indolonyl, or indolinonyl , wherein G is optionally substituted by one or more R1 ( R2 or R3; Ar is 1 -naphthyl;
X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
Y is: a bond or
-CH2-, -CH2CH2-, -C(O)-, -O-, -S-, -NH-CH2CH2CH2- , -N(CH3)-, CH2(CN)CH2-NH-CH2 or -NH-;
Z is morpholino, dioxolanyl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza- bicyclo[2.2.1]heptanyl, C^galkoxyphenylpiperazinyl, hydroxy, C,.3alkyl, N.N-diC^alkoxyC^alkylamino, C^acylamino, C,_3alkylsulfonyl or nitrileC^alkyl;
each R1 is independently:
C,_5 alkyl optionally partially or fully halogenated wherein one or more C atoms are optionally independently replaced by O or N, and wherein said C,_5 alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl optionally substituted by C1.3alkoxy;
cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, nitrile, hydroxymethyl or phenyl; or 2-tetrahydrofuranyl substituted by methyl; or trimethyl silyl;
propynyl substituted hydroxy or tetrahydropyran-2-yloxy;
R, is is mono- or di-C^acylamino, amino-S(O)m or S(O)m amino wherein the N atom is mono- or di-substituted by C1-3alkyl or phenyl, bromo, chloro, fluoro, nitrile, nitro, amino, methylsulfonyl optionally partially or fully halogenated or phenylsulfonyl;
each R3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, [1 ,3,4]oxadiazol or pyrazolyl, each is optionally substituted with CΛ.__ alkyl which is optionally partially or fully halogenated; β C^ alkyl or C^ alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino;
OR18 or alkyl optionally substituted with OR18;
amino or mono- or di-(G,.3 alkyl)amino optionally substituted with R19;
CH3C(O)NH-, R22O- ; R23R24NC(O)-; R26CH2C(O)N(R21)-, NH2C(O)methoxy or R26C(O)CH2N(R21)-;
C2-4alkenyl substituted by R23R24NC(O)-; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
C1-2acyl; and
R23 and R24 are H or R23 and R24 taken together optionally form morpholino; and
R26 is morpholino.
In another preferred embodiment 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:
G is phenyl, pyridinyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1 H-indol-5-yl or 2- naphthyl wherein G is optionally substituted by one or more R^ R2 or R3;
X is: imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl;
Y is: a bond, CH2(CN)CH2-NH-CH2, -CH2-, -NH-CH2CH2CH2- or -NH-; Z is morpholin-4yl, dioxolan-2yl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-aza- bicyclo[2.2.1]hept-5yl, methoxyphenylpiperazinyl, hydroxy, methyl, N,N- dimethoxyethylamino, acetylamino, methylsulfonyl or cyanoethyl;
each R1 is independently: tert-butyl, sec-butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropynyl, hydroxypropynyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl;
R2 is chloro, nitro, amino, nitrile, methylsulfonylamino, diacetylamino, phenylsulfonylamino, N,N-di(methylsulfonyl)amino, methylsulfonyl or trihalomethylsulfonyl;
R3 is independently: methyl, C,.3 alkoxy, methoxymethyl, hydroxypropyl, dimethylamino, C,. 4alkylamino, NH2C(O)methoxy, acetyl, pyrrolidinyl, imidazolyl, pyrazolyl, morpholino or morpholinocarbonyl.
In yet another preferred embodiment 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 X is pyridinyl.
In still another preferred embodiment 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 the pyridinyl is attached to Ar via the 3-pyridinyl position.
Preferably 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 7 :
1 -(4-tert-Butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]- urea;
1-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1-yl)- naphthalen-1-yl]-urea; 1-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(4-Difluoromethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea;
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
1 -[2-Methoxy-5-(1 -methyl-1 -phenyl-ethyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
(5-tert-ButyI-2-methyl-phenyl)-carbamic acid 3-(5-{4-[3-(5-tert-butyl-2-methyl-phenyl)- ureido]-naphthalen-1-yl}-pyridin-2-ylamino)-propyl ester;
1-(6-tert-Butyl-benzo[1 ,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-acetamide;
1 ,3-Bis-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1 -[5-tert-Butyl-3-(2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl)-2-hydroxy-phenyl]-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,3-Dimethyl-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(2-p-tolyloxy-5- trifluoromethyl-phenyl)-urea; 1-[2-(2-Methoxy-phenoxy)-5-trifluoromethyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-naphthalen-1-yl-urea;
1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-{5-tert-Butyl-2-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6-morpholin- 4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-Hydroxymethyl-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(2-Methoxy-dibenzofuran-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(2,5-Di-tert-butyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
1 -[3-(4-Bromo-1 -methyl- 1 H-pyrazol-3-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3-oxazol-5-yl-phenyl)- urea;
1 -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-3-(3-[1 ,3,4]oxadiazol-2-yl- phenyl)-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
Furan-2-carboxylic acid (4-tert-butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-ureido}-phenyl)-amide;
1-(2-Methoxy-4-phenylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-(5-Methoxy-2-methyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea;
1-(3-Hydroxy-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea;
N,N-Diethyl-4-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]- ureidoj-benzenesulfonamide;
1 -(2,2-Difluoro-benzo[1 ,3]dioxol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-(1 ,1-Dimethyl-propyl)-2-phenoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1-yl]-urea;
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1 -yl]-urea;
2-Chloro-5-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}- benzoic acid isopropyl ester;
1-(4-Amino-3,5-dibromo-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1 -[5-tert-Butyl-3-(3-hydroxy-prop-1 -ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1 ,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen- 1-yl]-urea;
1 -(5-tert-Butyl-2-pyrrolidin-1 -yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin- 3-yl]-naphthalen-1 -yl}-urea;
2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-acetamide;
1-(2-Methoxy-5-phenoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1 H-indol-7-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-1-ylmethyl)-pyridin- 3-yl]-naphthalen-1 -yl}-urea;
1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-7-yl)-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yI]-urea;
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-ureido}-phenyl)-acetamide; -
1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-[6-tert-Butyl-4-(2-morpholin-4-yl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8- yl]-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-imidazol-1-yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-4-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-methanesuIfonamide;
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1 -yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-bis(methanesulfon)amide;
1 -[5-tert-Butyl-2-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyI-pyridin-3- yl)-naphthalen-1 -yl]-urea;
1-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea;
1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert- butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-dimethylamino-pyrrolidin-1-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2- ylmethyl)-pyrrolidin-3-yl]-acetamide;
1 -(1 -Acetyl-3,3-dimethyl-2,3-dihydro-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-propionamide;
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3- trifluoromethanesulfonyl-phenyI)-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}- phenoxy)-acetamide;
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1 -[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-3-(1 ,3,3-trimethyl-2,3- dihydro-1 H-indol-5-yl)-urea;
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-benzenesulfonamide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-morpholin-4-ylmethyl-piperidin-1 -yl)- naphthalen-1 -yl]-urea;
1 -[5-tert-Butyl-2-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-3-[4-(4-morphoIin-4-ylmethyl- piperidin-1 -yl)-naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-mo"rpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)- methanesulfonamide;
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert- butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3- yl]-naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyI)-3-{4-[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin- 3-yl]-naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)- pyridin-3-yl]-naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]- naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2- ylmethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-morpholin-4-yl-ethylamino)-methyl]- pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2- ylmethyl)-piperidine-3-carboxylic acid amide;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2- ylmethyl)-piperidine-4-carboxylic acid amide;
1 -(5-tert-Butyl-2-methoxy-phenyI)-3-{4-[6-(1 -oxo-1 l4-thiomorpholin-4-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1 -ylmethyl)-pyridin-3-yl]- naphthalen-1 -yl}-urea;
1 -{4-[6-(4-Acetyl-piperazin-1 -ylmethyl)-pyridin-3-yl]-naphthalen-1 -yl}-3-(5-tert-butyl-2- methoxy-phenyl)-u rea ;
4-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2- ylmethyl)-piperazine-1 -carboxylic acid ethyl ester;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-methyl]-pyridin- 3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]- pyridin-3-yl}-naphthalen-1 -yl)-urea; ,
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]- methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyl-ethylamino)-methyl]- pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin- 3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-1-yl-ethylamino)-methyl]- pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yl-piperazin-1-yImethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperazin-1-ylmethyl)-pyridin- 3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1- ylmethyI]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]- naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)- naphthalen-1 -yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)- acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yI]-ureido}-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1- yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-ylamino)-pyridin-3-yl]-naphthalen- 1-yl}-urea;
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-carbamic acid 3-tert-butyl- phenyl ester;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-methanesulfonamide and
and the pharmaceutically acceptable derivatives thereof.
In another preferred embodiment 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 7
1-(3-Methyl-naphthalen-2-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-acetamide;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2,3-Dimethyl-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl]-urea;
1-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-phenyl}-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1-yl]-urea; 1-[5-tert-Butyl-3-(3-hydroxy-prop-1-ynyl)-2-methyl-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-2-(3-hydroxy-prop-1-ynyl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,2-dimethyl-[1 ,3]dioxolan-4-ylmethyl)-2-methoxy-phenyl]-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[5-(1-Cyano-cyclopropyl)-2-methoxy-phenyI]-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1 -yl]-urea;
1-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[1 ,3]dioxolan-2-yl-pyridin-3-yl)-naphthalen- 1-yl]-urea;
1 -(5-tert-Butyl-2-pyrrolidin-1 -yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin- 3-yl]-naphthalen-1 -yl}-urea; 1-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1- yl]-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-ureido}-phenyI)-acetamide;
1-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-3-[4-(6- morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1 -(5-tert-Butyl-2-imidazol-1 -yl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-bis(methanesulfon)amide;
1 -[5-tert-Butyl-2-(1 -methyl-1 H-pyrazol-4-yl)-phenyl]-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1 -yl]-urea;
1-(2-Methanesulfinyl-5-trifluoromethyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1 -yl]-urea; 1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert- butyl-2-methoxy-phenyl)-urea;
N-[1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2- yImethyl)-pyrrolidin-3-yl]-acetamide;
1-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-propionamide;
1-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-3-(3- trifluoromethanesulfonyl-phenyl)-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}- phenoxy)-acetamide;
1-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-benzenesulfonamide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3- yl)-naphthalen-1-yl]-ureido}-phenyl)-amide; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-morpholin-4-ylmethyl-pyrimidin-5-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
1-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-ureido}-phenyl)-amide;
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)- methanesulfonamide;
1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert- butyl-2-methoxy-phenyl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3- yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomorpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1-yl]-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-1 -yl methyl )-py rid in- 3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1-oxo-tetrahydro-thiopyran-4-ylamino)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-yl]- naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetrahydro-furan-2- ylmethyl)-amino]-methyl}-pyridin-3-yI)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-morpholin-4-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea; 1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-1-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2- ylmethyl)-piperidine-3-carboxylic acid amide;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(1 -oxo-1 l4-thiomorpholin-4-ylmethyl)- pyridin-3-y[]-naphthalen-1-yl}-urea;
1-(3,3-Dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-3-[4-(6-morpholin-4-ylmethyl- pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-oxo-piperazin-1-yImethyl)-pyridin-3-yl]- naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetrahydro-furan-3-ylamino)-methyl]- pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyI)-pyridin-3-ylmethyl-amino]- methyl}-pyridin-3-yl)-naphthalen-1-yl]-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)- pyridin-3-yl]-naphthalen-1-yl}-urea;
1-(5-tert-ButyI-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-morpholin-4-ylmethyl)-pyridin- 3-yl]-naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-1- ylmethyl]-pyridin-3-yl}-naphthalen-1-yl)-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]- naphthalen-1 -yl}-urea;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-morpholin-4-ylmethyl-pyrazin-2-yl)- naphthalen-1 -yl]-urea;
1-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-3-[4-(6-morpholin-4- ylmethyl-pyridin-3-yl)-naphthalen-1-yl]-urea; 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -yl]-urea;
N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)- acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;
1-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-1- yl}-urea;
[4-(6-Morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1 -yl]-carbamic acid 3-tert-butyl- phenyl ester;
N-(5-tert-ButyI-2-methoxy-3-{3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-naphthalen-1- yl]-ureido}-phenyl)-methanesulfonamide and
and the pharmaceutically acceptable derivatives thereof.
Particularily preferred according to the invention is 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:
Example 1 :
Example 2:
Example 3:
Example 4:
Example 5:
Example 6:
Example 7:
and the pharmaceutically acceptable derivatives thereof.
The invention includes the use of pharmaceutically acceptable derivatives of the compounds of formula 1, 2, 3a, 3b, 3c, 3d, 4, 5, 5a, 6, and 7. A "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formulas 1 , 2, 3a, 3b, 3c, 3d, 4, 5, 5a, 6, and 7.
Pharmaceutically acceptable salts of the compounds mentioned hereinbefore include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(Cj-C4 alkyl)4+ salts.
Within the scope of the present invention references to the term physiologically acceptable salts are to be understood as references to the term pharmaceutically acceptable salts.
In another aspect the present invention relates to pharmaceutical preparations suitable for inhalation containing at least one p38 kinase inhibitor in a therapeutically effective amount for treating mucus hypersecretion.
Inhalable preparations according to the invention include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the p38 kinase inhibitors optionally mixed with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
In the inhalable pharmaceutical compositions the p38 kinase inhibitor may be present in such an amount that per single dose about 100 to 10000 μg, preferably 1000 to 9000 μg, more preferably 1500 to 8000μg of the p 38 kinase inhibitor are applied. Preferred pharmaceutical compositions within the scope of the invention provide for the administration of about 2000 to about 7000 μg, more preferably 2500 to 6000 μg of the p38 kinase inhibitor per single dose. Preferably about 3000 to about 5500 μg p38 kinase inhibitor are administered once or twice daily to the patient in need thereof.
A) Inhalable powder: The inhalable powders which may be used according to the invention may contain the p38 kinase inhibitor either on its own or in admixture with suitable physiologically acceptable excipients.
If the p38 kinase inhibitor is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol),. salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250μm, preferably between 10 and 150μm, most preferably between 15 and 80μm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9μm to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active the p38 kinase inhibitor, preferably with an average particle size of 0.5 to 10μm, more preferably from 1 to 6μm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally mixing the ingredients together are known from the prior art.
Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to the p38 kinase inhibitor may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A. The inhalable powders according to the invention which contain the p38 kinase inhibitor optionally in conjunction with a physiologically acceptable excipient may be administered for example using an inhaler known by the name Turbuhaler® or using inhalers as disclosed for example in EP 237507 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to the p38 kinase inhibitor are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
A particularly preferred inhaler for administering the pharmaceutical combination according to the invention in capsules is shown in Figure 1.
This inhaler (Handyhaler) is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, a mouthpiece 12 which is connected to the housing 1 , the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut and three holes 13 with diameters below 1 mm in the central region around the capsule chamber 6 and underneath the screen housing 4 and screen 5.
The main air flow enters the inhaler between deck 3 and base 1 near to the hinge. The deck has in this range a reduced width, which forms the entrance slit for the air. Then the flow reverses and enters the capsule chamber 6 through the inlet tube. The flow is then further conducted through the filter and filter holder to the mouthpiece. A small portion of the flow enters the device between mouthpiece and deck and flows then between filterholder and deck into the main stream. Due to production tolerances there is some uncertainty in this flow because of the actual width of the slit between filterholder and deck. In case of new or reworked tools the flow resistance of the inhaler may therefore be a little off the target value. To correct this deviation the deck has in the central region around the capsule chamber 6 and underneath the screen housing 4 and screen 5 three holes 13 with diameters below 1 mm. Through these holes 13 flows air from the base into the main air stream and reduces such slightly the flow resistance of the inhaler. The actual diameter of these holes 13 can be chosen by proper inserts in the tools so that the mean flow resistance can be made equal to the target value.
If the inhalable powders according to the invention are packed into capsules (inhalers) for the preferred use described above, the quantities packed into each capsule should be 1 to 50mg, preferably 3 to 45mg, more particularly 5 to 40mg of inhalable powder per capsule. These capsules contain, according to the invention, either together or separately, the doses of the p38 kinase inhibitor mentioned hereinbefore for each single dose. B) Propellant gas-driven inhalation aerosols:
Inhalation aerosols containing propellant gas which may be used according to the invention may contain the p38 kinase inhibitor dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1 ,1 ,1 ,2- tetrafluoroethane), TG227 (1,1,1 , 2,3,3, 3-heptafluoropropane) and mixtures thereof.
The propellant-driven inhalation aerosols which may be used according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
The propellant-driven inhalation aerosols which may be used according to the invention may contain up to 5 wt.% of the p38 kinase inhibitor. The propellant-driven inhalation aerosols which may be used according to the invention contain, for example, 0.002 to 5 wt.%, 0.01 to 3 wt.%, 0.015 to 2 wt.% of the p38 kinase inhibitor.
If the p38 kinase inhibitors are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10μm, preferably from 0.1 to 5μm, more preferably from 1 to 5μm.
The propellant-driven inhalation aerosols according to the invention which may be used according to the invention may be administered using inhalers known in the art (MDIs = metered dose inhalers). Accordingly, in another aspect, the present invention relates to the use of the p38 kinase inhibitor according to the invention to prepare pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols.
In addition, the present invention relates to the use of the p38 kinase inhibitors according to the invention to prepare cartridges which when fitted with a suitable valve can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.
C) Propellant-free inhalable solutions: It is particularly preferred to use the p38 kinase inhibitors according to the invention to prepare propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing the p38 kinase inhibitor are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than 100mg/100ml, preferably less than 50mg/100 ml, more preferably less than 20mg/100 ml. Generally, inhalable solutions in which the content of sodium edetate is from 0 to 10mg/100ml are preferred.
Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions which may be used according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvmylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50mg/100ml, more preferably between 5 and 20mg/100ml.
Preferred formulations contain, in addition to the solvent water and the p38 kinase inhibitor, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present.
The propellant-free inhalable solutions which may be used within the scope of the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which a quantity of less than 100μl_, preferably less than 50μl_, more preferably between 10 and 30μL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20μm, preferably less than 10μm, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective quantity. An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 6a and 6b). The nebulisers (devices) described therein are also known by the name Respimat®.
This nebuliser (Respimat®) can advantageously be used to produce the inhalable aerosols according to the invention containing the p38 kinase inhibitors. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at all times by the patient. The nebuliser sprays a defined volume of pharmaceutical formulation using high pressures through small nozzles so as to produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterised by
- a pump housing which is secured in the upper housing part and which comprises at one end a nozzle body with the nozzle or nozzle arrangement, - a hollow plunger with valve body,
- a power takeoff flange in which the hollow plunger is secured and which is located in the upper housing part,
- a locking mechanism situated in the upper housing part,
- a spring housing with the spring contained therein, which is rotatably mounted on the upper housing part by means of a rotary bearing,
- a lower housing part which is fitted onto the spring housing in the axial direction.
The hollow plunger with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is axially movable within the cylinder. Reference is made in particular to Figures 1 to 4, especially Figure 3, and the relevant parts of the description. The hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active substance solution, at its high pressure end at the moment when the spring is actuated. Volumes of 10 to 50 microlitres are preferred, while volumes of 10 to 20 microlitres are particularly preferred and a volume of 15 microlitres per spray is most particularly preferred. The valve body is preferably mounted at the end of the hollow plunger facing the valve body.
The nozzle in the nozzle body is preferably microstructured, i.e. produced by microtechnology. Microstructured valve bodies are disclosed for example in WO-94/07607; reference is hereby made to the contents of this specification, particularly Figure 1 therein and the associated description.
The valve body consists for example of two sheets of glass and/or silicon firmly joined together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns while the length is preferably 7 to 9 microns. In the case of a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may extend parallel to one another or may be inclined relative to one another in the direction of the nozzle opening. In a nozzle body with at least two nozzle openings at the outlet end the directions of spraying may be at an angle of 20 to 160° to one another, preferably 60 to 150°, most preferably 80 to 100°. The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of 50 microns are most preferred. The directions of spraying will therefore meet in the vicinity of the nozzle openings.
The liquid pharmaceutical preparation strikes the nozzle body with an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an inhalable aerosol through the nozzle openings. The preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
The locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy. The spring acts on the power takeoff flange as an actuating member the movement of which is determined by the position of a locking member. The travel of the power takeoff flange is precisely limited by an upper and lower stop. The spring is preferably biased, via a power step-up gear, e.g. a helical thrust gear, by an external torque which is produced when the upper housing part is rotated counter to the spring housing in the lower housing part. In this case, the upper housing part and the power takeoff flange have a single or multiple V-shaped gear. The locking member with engaging locking surfaces is arranged in a ring around the power takeoff flange. It consists, for example, of a ring of plastic or metal which is inherently radially elastically deformable. The ring is arranged in a plane at right angles to the atomiser axis. After the biasing of the spring, the locking surfaces of the locking member move into the path of the power takeoff flange and prevent the spring from relaxing. The locking member is actuated by means of a button. The actuating button is connected or coupled to the locking member. In order to actuate the locking mechanism, the actuating button is moved parallel to the annular plane, preferably into the atomiser; this causes the deformable ring to deform in the annual plane. Details of the construction of the locking mechanism are given in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers the mounting, the drive of the spindle and the storage container for the fluid.
When the atomiser is actuated the upper housing part is rotated relative to the lower housing part, the lower housing part taking the spring housing with it. The spring is thereby compressed and biased by means of the helical thrust gear and the locking mechanism engages automatically. The angle of rotation is preferably a whole- number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is biased, the power takeoff part in the upper housing part is moved along by a given distance, the hollow plunger is withdrawn inside the cylinder in the pump housing, as a result of which some of the fluid is sucked out of the storage container and into the high pressure chamber in front of the nozzle.
If desired, a number of exchangeable storage containers which contain the fluid to be atomised may be pushed into the atomiser one after another and used in succession. The storage container contains the aqueous aerosol preparation according to the invention.
The atomising process is initiated by pressing gently on the actuating button. As a result, the locking mechanism opens up the path for the power takeoff member. The biased spring pushes the plunger into the cylinder of the pump housing. The fluid leaves the nozzle of the atomiser in atomised form.
Further details of construction are disclosed in PCT Applications WO 97/12683 and WO 97/20590, to which reference is hereby made. The components of the atomiser (nebuliser) are made of a material which is suitable for its purpose. The housing of the atomiser and - if its operation permits - other parts as well are preferably made of plastics, e.g. by injection moulding. For medicinal purposes, physiologically safe materials are used.
Figures 2a/b attached to this patent application, which are identical to Figures 6a/b of WO 97/12687, show the nebuliser (Respimat®) which can advantageously be used for inhaling the aqueous aerosol preparations according to the invention.
Figure 2a shows a longitudinal section through the atomiser with the spring biased while Figure 2b shows a longitudinal section through the atomiser with the spring relaxed.
The upper housing part (51 ) contains the pump housing (52) on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow plunger (57) fixed in the power takeoff flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end the hollow plunger carries the valve body (58). The hollow plunger is sealed off by means of the seal (59). Inside the upper housing part is the stop (60) on which the power takeoff flange abuts when the spring is relaxed. On the power takeoff flange is the stop (61 ) on which the power takeoff flange abuts when the spring is biased. After the biasing of the spring the locking member (62) moves between the stop (61) and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is sealed off by means of the protective cover (66) which can be placed thereon.
The spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-in lugs (69) and rotary bearing. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the exchangeable storage container (71 ) for the fluid (72) which is to be atomised. The storage container is sealed off by the stopper (73) through which the hollow plunger projects into the storage container and is immersed at its end in the fluid (supply of active substance solution).
The spindle (74) for the mechanical counter is mounted in the covering of the spring housing. At the end of the spindle facing the upper housing part is the drive pinion (75). The slider (76) sits on the spindle. The nebuliser described above is suitable for nebulising the aerosol preparations which may be used according to the invention to produce an aerosol suitable for inhalation.
If the propellant-free inhalable solutions which may be used according to the invention are nebulised using the method described above (Respimat®) the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations). Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of formulation are delivered as a defined mass on each actuation.
However, the propellant-free inhalable solutions which may be used according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet stream inhalers or other stationary nebulisers.
Accordingly, in a further aspect, the invention relates to the use according to the invention of the p38 kinase inhibitor for preparing a pharmaceutical formulation in the form of propellant-free inhalable solutions or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respimat®. Preferably, the invention relates to the use according to the invention of the p38 kinase inhibitors for preparing propellant-free inhalable solutions or suspensions characterised in that they contain the p38 kinase inhibitors in conjunction with the device known by the name Respimat®. In addition, the present invention relates to the use according to the invention of the above-mentioned devices for inhalation, preferably the Respimat®, characterised in that they contain the propellant-free inhalable solutions or suspensions according to the invention as described hereinbefore.
The propellant-free inhalable solutions or suspensions which may be used within the scope of the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat®. Formulations ready for use may be produced from the concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles. Accordingly, in another aspect, the present invention relates to the use according to the invention of the p38 kinase inhibitor in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable for administering these solutions, characterised in that the device is an energy- operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods.
The Examples which follow serve to illustrate the present invention in more detail without restricting the scope of the invention to the following embodiments by way of example.
Examples of Formulations
Inhalable powders (filled in capsules):
1 )
2)
3)
4)
5)
6)
7)
8)
9)
0)

Claims

Patent Claims
1 ) Use of a p38 kinase inhibitor for the preparation of an inhalable pharmaceutical composition for the treatment of mucus hypersecretion.
2) Use according to claim 1 , chacterized in that the mucus hypersecretion is associated with cystic fibrosis.
3) Use according to claim 1 or 2, characterized in that the p38 kinase inhibitor is selected from the group of compounds disclosed in US Patents
5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991 , US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, and US 5,716,955 and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851 , WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO
97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441 , WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO - 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941 , WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO
98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131 , WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121 , WO 99/58502, WO 99/58523, WO 99/57101 , WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441 , WO 99/01449, WO 99/03484, WO 99/15164, WO 99/321 0, WO 99/32111 , WO
99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991 , WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911 , WO 00/39116, WO 00/43384, WO
00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791 , WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591 , WO 01/29041 , WO 01/29042, WO 01/62731 , WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751 , WO
01/27315, WO 01/42189, WO 01/00208, WO 01/42241 , WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921 , WO 01/27089, DE 19842833, and JP 2000 86657. 4) Use according to claim 3, characterized in that the p38 kinase inhibitor is selected from the group of compounds disclosed in US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO
01/64676, WO 99/61426, WO 00/10563, WO 00/25791 , WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921 , WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131 , WO 00/43384, WO 00/55152, WO 00/55139, and WO 01/36403.
5) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 1
wherein
R-j 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-Ra and optionally with an additional independent substituent selected from C,-4 alkyl, halogen, hydroxyl, C,-4 alkoxy, C,-4 akylthio, C,-4 aklylsulfinyl, CH2OR12, 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 NR15, N(R10)C(O)Rb or NHRa; Y is oxygen or sulfur; 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)NR7R17, C(Z)OR16, (CR10R20)VCOR12, SR5, SOR5, OR12, halo-substituted-C^ alkyl, C 4 alkyl, ZC(Z)R12, NR10C(Z)R16, or (CR10R20)VNR10R20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR13R14, C(Z)OR3, (CR10R20)m„COR3, S(O)mR3, OR3, halo-substituted-CM alkyl, C1-4 alkyl, (CR10R20)m ,.R10C(Z)R3, NR10S(O)m,R8, NR10S(O)m,NR7R17, ZC(Z)R3 or (CR10R20)m..NR13R14; Z is oxygen or sulfur; n is an integer having a value of 1 to 10; m is 0, or integer 1 or 2; m' is an integer having a value of 1 or 2; m" is 0, or an integer having a value of 1 to 5; v is 0, or an integer having a value of 1 to 2; R2 is -C(H) (A) (R22);
A is optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is substituted
C1-10 alkyl; R22 is an optionally substituted C1-10 alkyl;
Ra is aryl, arylC^e alkyl, heterocyclic, heterocyclylC,..6 alkyl, heteroaryl, heteroarylC|..6alkyl, wherein each of these moieties may be optionally substituted; Rb is hydrogen, C1-6 alkyl, C3.7 cycloalkyl, aryl, aryl C,^ alkyl, heteroaryl, heteroarylC,^ alkyl, heterocyclyl, or heterocyclylC,^ alkyl, wherein each of these moieties may be optionally substituted; R3 is heterocyclyl, heterocyclyl C1-10 alkyl or R8;
R5 is hydrogen, C,^ alkyl, C2.4 alkenyl, C2.4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17and SOR5 being SOH; R6 is hydrogen, a pharmaceutically acceptable cation, C^o alkyl, C3-7 cycloalkyl, aryl, aryl C,^ alkyl, heteroaryl, heteroaryl C,^ alkyl, heterocyclyl, aryl, or C,_10 alkanoyl;
R7 and R17 is each independently selected from hydrogen or CM alkyl or R7 and R17 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 NR15; R8 is C.,.™ alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2.10 alkynyl, C3.7 cycloalkyl, C5.7 cycloalkenyl, aryl, aryl C,.10 alkyl, heteroaryl, heteroaryl C,.10 alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18,
(CR10R20)nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; Rg is hydrogen, C(Z) R„ or optionally substituted C,.^ alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl ClJt alkyl; R10 and R20 is each independently selected from hydrogen or C alkyl; R^ is hydrogen, C,_10 alkyl, C3.7 cycloalkyl, heterocyclyl, heterocyclyl C.,_10 alkyl, aryl, arylC^o alkyl, heteroaryl or heteroaryl C,_10 alkyl, wherein these moieties may be optionally substituted;
R12 is hydrogen or R16. R13an R14is each independently selected from hydrogen or optionally substituted
C,^ alkyl, optionally substituted aryl or optionally substituted arylC1-4 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 NR9; R15 is R10 or C(Z)-C1.4 alkyl;
R16 is C.,.4 alkyl, halo-substituted-C,^ alkyl, or C3.7 cycloalkyl; R18 is C,_10 alkyl, C3.7 cycloalkyl, heterocyclyl, aryl, aryl^o alkyl, heterocyclyl, heterocyclyl- C,„.,0alkyl, heteroaryl or heteroaryl.,.^ alkyl; or a pharmaceutically acceptable salt thereof.
6) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formul
wherein
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, -OOCR, -NROCR, RCO, -COOR, -CONR2, -SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C); each R2 is independently alkyl (1-6C), halo, OR, SR, OOCR, NROCR, COOR, RCO, CONR2, SO2NR2, CN, CF3 or NO2, 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, NR2, SR, -OOCR, -NROCR, RCO, -COOR, - CONR2, SO2NR2, CN, CF3, or NO2, wherein each R is independently H or alkyl (1-4C), or the pharmaceutically acceptable salts thereof. 7) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 3a, 3b, 3c, or 3d
and the pharmaceutically acceptable salts thereof, wherein each of Z^ and Z2 is independently CR4 or N; where each R4 is independently selected from H and alkyl(1-6C); wherein said alkyl optionally includes one or more heteroatoms selected from O, S and N, and wherein said alkyl is optionally substituted by one or more substituents selected from halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, NROCR, CN, =O, a 5 or 6 membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a 6-membered aromatic ring optionally containing 1- 2 N heteroatoms, wherein R in the foregoing optional substituents is H or alkyl
(1-6C);
R1 is
wherein X1 is CO, SO, CHOH or SO2 ; m is 1 ;
Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; n is O, 1 or 2; Z3 is N;
X2 is CH or CH2 ; and
Ar consists of one or two phenyl moieties directly coupled to X2, said one or two phenyl moieties being optionally substituted by a substituent selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), CN, CF3, RCO, COOR, CONR2, NR2, OR, SR, OOCR, NROCR, (wherein R in the foregoing is H or 1-6C alkyl), and phenyl, itself optionally substituted by the foregoing substituents; R2 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, NR2, RCO, COOR, CONR2, OOCR, NROCR, (where R in the foregoing is H or 1-6C alkyl) CN, =O, a 5 or 6 membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a 6-membered aromatic ring optionally containing 1-2 N heteroatoms;
R3 is H, halo, NO2, alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (1-6C).
8) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 4
wherein
Ar, is a heterocyclic group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and wherein A may be substituted by one or more R1;R2 or R3;
Ar2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three
R2 groups;
L, a linking group, is a
C_._0 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;
Q is selected from the group consisting of: d) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5- b]pyridine and imidazo[4,5-έ>]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen,
C,.6 alkyl, C,.6 alkoxy, hydroxy, mono- or di-(C1.3 alkyl)amino, C^e alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C,.6 alkyl and C,_ 6 alkoxy; e) tetrahydropyran, tetrahydrofuran, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4- dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of C,_6 alkyl, C_.β alkoxy, hydroxy, mono- or di-(C,.3 alkylJamino-C^ alkyl, phenylamino-C^ alkyl and C,^ alkoxy-C,^ alkyl; f) C,.6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C^ alkyl and C^alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C,.6 alkoxy, hydroxy or mono- or di-(C,_3 alkyl)amino, C,_6 alkyl-S(O)r, phenyl-S(O)t, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C,_6 alkoxy, hydroxy or mono- or di-(C^ alkyl)amino;
is selected from the group consisting of:
(g) C3.10 branched or unbranched alkyl, which may optionally be 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, C^ branched or unbranched alkyl which is optionally partially or fully halogenated, C3.8 cycloalkyl, C5.8 cycloalkenyl, hydroxy, cyano, C^ alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C1.3)alkylaminocarbonyl; (h) C3.7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which may optionally be partially or fully halogenated and which may optionally be 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 O, S, CHOH, >C=O, >C=S and NH; (i) C3.10 branched alkenyl which may optionally be partially or fully . halogenated, and which is optionally substituted with one to three C^ branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from halogen, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C,.3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or d C^alkylaminocarbonyl;
(j) C5.7 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; (k) cyano; and,
(I) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
R2 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_ branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
R3 is selected from the group consisting of: g) 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 substituted with one to five groups selected from the group consisting of a C,.6 branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C,.5 alkyl, naphthyl C,_5 alkyl, halo, hydroxy, cyano, C,^ alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described, nitro, amino, mono- or d C^alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-
(C^)alkyl aminocarbonyl, C,^ alkyl-C(O)-C alkyl, amino-C.,.5 alkyl, mono- or di-(C1_3)alkylamino-C1..5 alkyl, amino-S(O)2, di-(C1.3)alkylamino-S(O)2, R4- alkyl, alkoxy, R6-C(O)-C1.5 alkyl and R7-C1.5 alkyl(R8)N; 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, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from 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, halo, cyano, C,.3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C1.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C1.3)alkyl aminocarbonyl, C,^ alkyl-OC(O), C,_5 alkyl, mono- or R10-C,.5 alkoxy, R11-C(O)-C1.5 alkyl, and R12-C,.5alkyl(R13)N; i) 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; j) C5.7 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; and k) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl;
I) C,.6 branched or unbranched alkyl which may optionally be partially or fully halogenated;
or R1 and R2 taken together may optionally form a fused phenyl or pyridinyl ring,
and wherein each R8, R13 is independently selected from the group consisting of: hydrogen and C branched or unbranched alkyl which may optionally be partially or fully halogenated;
each R4, R5, R6, R7, Rg, R10, R^ and R12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole;
m = 0, 1 , 2; r = 0, 1 , 2; t = 0, 1 , 2; X = O or S and physiologically acceptable acids or salts thereof. 9) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula
wherein:
Ar, is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ar, may be substituted by one or more R R2 or R3;
Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three R2 groups;
X is: a) a C5.8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C branched or unbranched alkyl, C_ alkoxy or C1-4 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, CMaIkoxy, hydroxy, nitrile, mono- or di-(C1-3 alkyl)amino, C,.6 alkyl-S(O)m, or halogen;
Y is: a bond or a C_A 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 C1 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, C1-6 alkyl, C^ alkoxy, hydroxy, mono- or di-(C1.3 alkyl)amino, C,_6 alkyl-S(O)m , COOH and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, alkyl and C,_6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4- dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, C1-6 alkyl, C,.6 alkoxy, hydroxy, mono- or di-(C,.3 alky amino-C^ alkyl, phenylamino-C^ alkyl and C^ alkoxy-C,„3 alkyl; c) C,.6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C,^ alkyl, alkyl, phenylamino, wherein the phenyl ring is optionally substituted with one to two halogen, C,„6 alkoxy, hydroxy or mono- or di-(C,.3 alkyl)amino, C,_6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, G,^ alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino;
is : a) C3.10 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 in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3.8 cycloalkyl, C5.8 cycloalkenyl, hydroxy, nitrile, C,„3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C,.3)alkylaminocarbonyl; b) C3.7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl each being optionally be 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, CHOH, >C=O, >C=S and NH; c) C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C^ branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C,^ branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C,.3 alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C.,_3)alkylaminocarbonyl; d) a C5_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,.3 alkyl groups; e) nitrile; or f) C,.6 branched or unbranched alkoxycarbonyl, C,.6 branched or unbranched alkylaminocarbonyl, C,.6 branched or unbranched alkylcarbonylamino-C1-3- alkyl;
R2 is: a C1-6 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;
R3 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 substituted with one to five groups selected from the group consisting of phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C^ branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C^ alkyl, naphthyl C,.5 alkyl, halogen, hydroxy, nitrile, C,.3 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-(C1^)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C,_3)alkyl aminocarbonyl, alkyl, amino-C,_g alkyl, mono- or di-(C1-3)alkylamino-C,_5 alkyl, amino-S(O)2, di- (C1.3)alkylamino-S(O)2, R4-C1.5alkyl, R6-C(O)-C1.5 alkyl and alkyl(R8)N, carboxy-mono- or di-(C,.5)-alkyl-amino; 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, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring 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,_3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1_3)alkyl aminocarbonyl, C_ alkyl-OC(O), C,.5 alkyl-C(O)-C1-4 branched or unbranched alkyl, an amino-C,^ alkyl, mono- or alkyl, R10-C,.5 alkoxy, R,rC(0)-Cw alkyl, and R12-C,.galkyl(R13)N; c) 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^ alkyl groups; d) C5.7 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,.3 alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) C,_6 branched or unbranched alkyl optionally partially or fully halogenated;
or R1 and R2 taken together may optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C1 branched or unbranched alkyl optionally be partially or fully halogenated;
each R4, R5, R6, R7, Rg, R10 R^ and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2;
W is O or S and pharmaceutically acceptable derivatives thereof.
10) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound
wherein:
A is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein Ar, is optionally substituted by one or more Rn, R2 or R3;
Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole each being optionally substituted with zero to three R2 groups;
X is: a C5.8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C^ alkyl, C^ alkoxy or C_ 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^ alkyl, C^alkoxy, hydroxy, nitrile, amino, mono- or di-(C^ alkyl)amino, mono- or di-(C^ alkylamino)carbonyl, NH2C(O), C,.e alkyl-S(O)m or halogen;
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, 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, tetrahydrofuranyl, 1 ,3-dioxolanonyl, 1 ,3-dioxanonyl, 1 ,4- dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C,.6 alkyl, C1-8 alkoxy, C1-3 alkoxy-C,„3 alkyl, C^ alkoxycarbonyl, aroyl, heteroaroyl, heterocycleC,.3acyl wherein the heteroaryl and heterocycle are as defined hereinabove in this paragraph, C^acyl, oxo, hydroxy, pyridinyl- C^ alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C,^ alkyl, nitrile-C^ alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C^ alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, amino-S(O)m, C,.6 alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy, halogen or mono- or di-(C^ alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by alkoxy, aroyl,
C^acyl, C,_3alkyl-S(O)m- or arylC0.3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl, C,.6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino; 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,_6 alkyl or C1-6 alkoxy; or Z is hydroxy, hydroxyC,.3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C,.6alkyl, arylCMalkyl, C^alkoxyC^ alkyl, C^ alkoxy, aroyl, C^acyl, C1.3alkyl-S(O)m- , arylC0^alkyl-S(O)m- , nitrileC1.4alkyl or C^alkoxyC^alkyl, each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C,.6 alkyl, C,.6 alkoxy, hydroxy or mono- or di-(C1.3 alkyI)amino, C,.6 alkoxyheteroarylC0.3alkyl, heteroarylC0.3alkyl or heterocycyleC0.3alkyl wherein the heteroaryl and heterocycle is hereinabove described in this paragraph, or Z is C,.galkyl branched or unbranched, C,.6alkoxy, C,.3acylamino, C,.6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C^ alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino;
is : a) C^o 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, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3.8 cycloalkyl, C5.8 cycloalkenyl, hydroxy, nitrile, C^ alkyloxy which is optionally partially or fully halogenated, NH2C(O) and d C^alkylaminocarbonyl; b) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each 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, CHOH, >C=O, >C=S and NH; c) C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C^ branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C,^ alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C1^)a!kylaminocarbonyl; d) a C5.7 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,_3 alkyl groups; e) nitrile; or f) C1-6 branched or unbranched alkoxycarbonyl, C^ branched or unbranched alkylaminocarbonyl, C1-6 branched or unbranched alkylcarbonylamino-C,.3- alkyl;
is: a C,_6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile, or R2 is acetyl, aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl;
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 substituted with one to five groups selected from the group consisting of a phenyl, naphthyl, 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^ alkyl, naphthyl C^ alkyl, halogen, hydroxy, oxo, nitrile, C,_3 alkoxy optionally 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-(C1.3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C,.3)alkyl aminocarbonyl, C,.5 alkyl-C(O)-CM alkyl, alkyl, mono- or alkyl, amino-S(O)2, di-(C1.3)alkylamino-S(O)2, R4-C1.g alkyl, alkyl(R8)N, carboxy-mono- or d\-(C._5 )-alkyl-amino; b) 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, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring 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, C1-6 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, nitro, amino, mono- or di-(C1.3)alky!amino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C1^)alkyl aminocarbonyl, alkyl-C(O)-C1-4 branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(C1^)alkylamino-C1^ alkyl, R9-C1-5 alkyl, R10-C1-5 alkoxy, R^ -CζOJ-C^ alkyl and R12-C1^ alkyl(R13)N; 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,.3 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|_3 alkyl groups; e) acetyl, aroyl, C,_6alkoxycarbonylC,.6alkyl or phenylsulfonyl; or f) C,.6 branched or unbranched alkyl optionally partially or fully halogenated;
or R., and R2 taken together optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C,^ branched or unbranched alkyl optionally partially or fully halogenated;
each R4, R5, R6, R7, R9, R10 R„ and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2; W is O or S; wherein X is directly attached to one or two -Y-Z, and pharmaceutically acceptable derivatives thereof.
11) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 6
wherein:
G is : an aromatic C6.10 carbocycle or a nonaromatic C3.10 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.,, R2 or R3;
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 R4 or R5;
X is: a C5.8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C^ alkyl, C1 alkoxy or C1-4 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 CM 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 CM 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,.6 alkyl, C,_6 alkoxy, hydroxy, amino, mono- or di- alkyl)amino, C,.6 alkyl-S(O)m, CN, CONH2, COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C^ alkyl or C,.6 alkoxy; tetrahydropyranyl, tetrahydrofuranyl, 1 ,3-dioxolanonyl, 1 ,3-dioxanonyl, 1 ,4- dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, C,.β alkyl, C,.6 alkoxy, hydroxy, amino, mono- or di-(C,.3 alky amino-C^ alkyl, CONH2, phenylamino-C,..3 alkyl or C.,.3 aIkoxy-C,.3 alkyl; halogen, C^ alkyl, nitrile, amino, hydroxy, C,.6 alkoxy, NH2C(O), mono- or di(C1_3a!kyl) aminocarbonyl, mono- or di(C,.6alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C^ alkyl or C^ alkoxyalkyl, pyridinyl-C^ alkyl, imidazolyl-C,..3 alkyl, tetrahydrofuranyl-C^ alkyl, nitrile-C.,_3 alkyl, carboxamide-C,^ alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C^ alkyl)amino, C,_6 alkyl-S(O)m, or phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1_3 alkyl)amino;
C.,.6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
each R., is independently:
Ci. alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C3.10cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1-6 alkyl which is optionally partially or fully halogenated, C3.8 cycloalkanyl, C5.8 cycloalkenyl, hydroxy, nitrile, C,^ alkoxy which is optionally partially or fully halogenated or NH2C(O), mono- or di(C1-3alkyl)amino, and mono- or di(C,.3alkyl)aminocarbonyl;
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C^ alkyl groups optionally partially or fully halogenated, CN, hydroxyC,.3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(0)m, CHOH, >C=O, >C=S or NH;
phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C^ alkyl groups optionally partially or fully halogenated, CN, hydroxyC^alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by 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,^ alkyl groups optionally partially or fully halogenated, CN, hydroxyC.,_3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH;
C3.10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally be substituted with one to three 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,.β alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C1.3alkyl)aminocarbonyl; the C3.10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(0)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C,.3 alkyl groups;
nitrile, halogen;
methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated;
C3.6 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,^ alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C,_3alkyl)amino optionally substituted by one or more halogen atoms;
each R2, R4, and R5 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;
C.,.6 alkoxy, hydroxy, amino, or mono- or di-(C^ alkyl)amino, nitrile, halogen;
OR6;
nitro; or
mono- or di-(C^ alkyl)amino-S(O)2 optionally partially or fully halogenated, or H2NSO2;
each R3 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 or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C,.6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl alkyl, naphthyl C^ alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C,_ 3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1_3alkyl) aminocarbonyl, C,.5 alkyl-C(O)- alkyl, mono- or di-(C1_3alkyl)amino-C1.5 alkyl, amino-S(O)2, di-(C1.3alkyl)amino-S(O)2, R7-C.,..5 alkyl, R8-C,.5 alkoxy, g alkyl(R11)N, carboxy-mono- or di-(C1.5alkyl)-amino;
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, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, G,^ alkyl which is optionally partially or fully halogenated, halogen, nitrile, C,.3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1. 3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C1.3alkyl)aminocarbonyl, C alkyl- OC(O), alkyl-C(0)-CM alkyl, amino-C,_g alkyl, mono- or di-(C,.3)alkylamino- C^ alkyl, R12-C^ alkyl, R13-Cw alkoxy, R14-C(0)-C^ alkyl or R1tf-C^ alkyl(R16)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,^ alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C_ alkyl-phenyI-C(O)-C^ alkyl-, C^ alkyl-C(O)-C^ alkyl- or C^ alkyl-phenyl- S(O)m-C^ alkyl-;
C,.6 alkyl or C^ branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C,.6 alkyl optionally substituted with OR18;
amino or mono- or di-(C,.galkyl)amino optionally substituted with R19;
R20C(O)N(R21)-, R22O- or R23R24NC(O)-; R26(CH2)mC(O)N(R21)- or R26C(O)(CH2)mN(R21)-;
C2.6alkenyl substituted by R23R24NC(O)-;
C2.g 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,.4 alkyl)amino optionally substituted by one or more halogen atoms; or
aroyl;
Rfi is a:
C,.4 alkyl optionally partially or fully halogenated and optionally substituted with R x 2,6>
each R7, R8, R9, R10, R12, R13ι R14, R15, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C1.4alkyl)amino optionally partially or fully halogenated;
each R^ and R16 is independently: hydrogen or C_ alkyl optionally partially or fully halogenated;
R18 is independently: hydrogen or a C alkyl optionally independently substituted with oxo or R25;
R20 is independently:
C,_10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
R21 is independently: hydrogen or C1-3 alkyl optionally partially or fully halogenated;
each R22, R23 and R24 is independently: hydrogen, C,^ 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-(C1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C,.4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C1.3alkyI)amino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m = 0, 1 or 2; W is O or S and pharmaceutically acceptable derivatives thereof. 12) Use according to claim 4, characterized in that the p38 kinase inhibitor is a compound of formula 7
wherein:
E is carbon or a heteroatom group chosen from -O-, -NH- and -S-;
G is : an aromatic C6.10 carbocycle or a nonaromatic C3.10carbocycle saturated or unsaturated;
a 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing 1 or more heteroatoms chosen from O, N and S;
a 6-8 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 optionally substituted by one or more R1( R2 or R3;
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 R4 or R5;
X is: a Cg.s cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three CM alkyl, C^ alkoxy or C. 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, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di- (C1-3 alkylamino)carbonyl, NH2C(O), C,.6 alkyl-S(O)m or halogen;
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-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1 ,3-dioxolanonyl, 1 ,3-dioxanonyl, 1 ,4- dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, alkoxy-C1-3 alkyl, C,.6 alkoxycarbonyl, aroyl, C,.3acyl, oxo, hydroxy, pyridinyl-C.,.3 alkyl, imidazolyl-C,..3 alkyl, tetrahydrofuranyl-C^ alkyl, nitrile-C,_3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1.3 alkyl)amino, C|_6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, alkoxy, hydroxy, halogen or mono- or di-(C1.3 alkyl)amino; or Z is optionally substituted with one to three amino or amino-C,..3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC,.
6alkyl, C^alkyl, arylC0.3alkyl, C,.5 alkoxyC^ alkyl, C^ alkoxy, aroyl, C,.3acyl, C,. 3alkyl-S(O)m- or arylC0.3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C,.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,_6 alkyl or C,.6 alkoxy; or Z is hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C^acyl, C,_6alkyl or C^alkoxyC^alkyl, C^alkyl branched or unbranched, C^alkoxy, CLaacylamino, nitrileC^alkyl, C,.6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C,.6 alkoxy, hydroxy or mono- or di-(C,_3 alkyl)amino;
each R., is independently:
C,.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 C3.10 cycloalkyl, hydroxy, oxo^^ phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C^ alkyl which is optionally partially or fully halogenated, C3.8 cycloalkanyl, C5.8 cycloalkenyl, hydroxy, nitrile, C^ alkoxy which is optionally partially or fully halogenated or
NH2C(O), mono- or di(C1-3alkyl)amino, and mono- or di(C.,.3alkyI)aminocarbonyl; or R, is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C,.3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH;
phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C,^ alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC,.3alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C,^ alkyl optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH; C3.10 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,.6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or d C^alky aminocarbonyl; the C3.10 branched or unbranced alkenyl being a optionally interrupted by one or more heteroatoms chosen from O, N and S(0)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C,.3 alkyl groups;
oxo, nitrile, halogen;
silyl containing three C^ alkyl groups optionally partially or fully halogenated; or
C3-6 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 C1^alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1.3alkyl)amino optionally substituted by one or more halogen atoms;
each R2, R4, and R5 is a C,.6 branched or unbranched alkyl optionally partially or fully halogenated, C,.6acyl, aroyl, C1-4 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;
OR6 C,_6 alkoxy, hydroxy, nitrile, nitro, halogen; or amino-S(O)m- wherein the N atom is optionally independently mono- or di- substituted by C,.6alkyl or arylC0.3alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C,.3alkyl, arylC0.3alkyl, C,. 6acyl, C1.6alkyl-S(O)m- or arylC0.3alkyl-S(O)rn-, 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 C1-6 alkoxy;
each R3 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, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C,_6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C,_5 alkyl, naphthyl C,„g alkyl, halogen, hydroxy, oxo, nitrile, C,.3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C|. 3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)- C_ alkyl, amino-C,„5 alkyl, mono- or di-(C1.5alkyI)amino, mono- or di-(C,_ R7-C,.g alkyl, R8- carboxy-mono- or di-(C,. 5alkyl)-amino;
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, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C.,.β alkyl which is optionally partially or fully halogenated, halogen, nitrile, C,.3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1.
3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or C1 alkyl- OC(O), C,_g alkyl-C(O)-C alkyl, amino-C^ alkyl, mono- or di-^. 3)alkylamino-C.,.5 alkyl, R12-C,.g alkyl, R^-C^ alkoxy, R14-C(O)-C,..5 alkyl or R15-
C1-5alkyl(R16)N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be 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 independently replaced by O, S, CHOH, >C=O, >C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C,.3 alkyl groups;
C, alkyl-phenyl-C(O)-C^ alkyl-, C_ alkyl-C(O)-C alkyl- or C1 alkyl-phenyl- S(O)m-C alkyl-;
alkyl or C,.6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
OR18 or Cw alkyl optionally substituted with OR18;
amino or mono- or di-(C1.5alkyl)amino optionally substituted with R19; R20C(O)N(R21)-, R22O- or R23R24NC(O)-; R26(CH2)mC(O)N(R21)-, R23R24NC(0)-C1. 3alkoxy or R26C(O)(CH2)mN(R21)-;
C2.6alkenyl substituted by R23R24NC(O)-;
C2.6 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 C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-4 alkyl)amino optionally substituted by one or more halogen atoms;
C^acyl or aroyl;
R6 is a:
C_ alkyl optionally partially or fully halogenated and optionally substituted with
each R7, R8, R9, R10, R12, R13ι R14, R15, R17, R19, R25 and R26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(CMalkyl)amino optionally partially or fully halogenated;
each R„ and R16 is independently: hydrogen or C1 alkyl optionally partially or fully halogenated;
R18 is independently: hydrogen or a Ci alkyl optionally independently substituted with oxo or R25;
R20 is independently:
Ci. alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
R21 is independently: hydrogen or C,.3 alkyl optionally partially or fully halogenated;
each R22, R23 and R24 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 alkyl also being independently optionally substituted by mono- or di-(C1.3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C1 alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C.,_3alkyl)anrιino; or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
m = 0, 1 or 2; W is O or S and pharmaceutically acceptable derivatives thereof.
13) Pharmaceutical preparations suitable for inhalation containing at least one p38 kinase inhibitor in a therapeutically effective amount for treating mucus hypersecretion.
14) Pharmaceutical composition according to claim 13, characterised in that a single administration corresponds to a dose of the p38 kinase inhibitor of 100 to 10000μg.
15) Pharmaceutical composition according to claim 13 or 14, characterised in that it is a formulation selected from among inhalable powders, propellant-containing metering aerosols and propellant-free inhalable solutions or suspensions.
16) Pharmaceutical composition according to claim 13, 14 or 15, characterised in that it is an inhalable powder which contains the p38 kinase inhibitor in admixture with suitable physiologically acceptable excipients selected from among the monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients with one another.
17) Inhalable powder according to claim 16, characterised in that the excipient has a maximum average particle size of up to 250μm, preferably between 10 and 150μm.
18) Capsules, characterised in that they contain an inhalable powder according to claim 16 or 17. 19) Pharmaceutical composition according to claim 15, characterised in that it is an inhalable powder which contains only the p38 kinase inhibitor as its ingredients.
20) Pharmaceutical composition according to claim 15, characterised in that it is a propellant-free inhalable solution or suspension which contains water, ethanol or a mixture of water and ethanol as solvent.
21) Pharmaceutical composition according to one of claims 13 to 20, characterised in that the p38 kinase inhibitor is selected from the group of compounds disclosed in US Patents 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992,
US 5,593,991 , US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, and US 5,716,955 and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851 , WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO
97/16441 , WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941 , WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO
99/01452, WO 99/01131 , WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121 , WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441 , WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111 , WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO
99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991 , WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO 00/31065, WO 00/35911 , WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO
00/59904, WO 00/71535, WO 00/10563, WO 00/25791 , WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591 , WO 01/29041 , WO 01/29042, WO 01/62731 , WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751 , WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241 , WO 01/34605, WO
01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921 , WO 01/27089, DE 19842833, and JP 2000 86657. 22) Pharmaceutical composition according to claim 21 , characterised in that the p38 kinase inhibitor is selected from the group of compounds disclosed in US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791 , WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO 01/47921 , WO
99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131 , WO 00/43384, WO 00/55152, WO 00/55139, and WO 01/36403.
23) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 1_
wherein R-j , R2, and R4 may have the meanings given in claim 5.
24) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a
wherein R1 , R2, Ar, m, n, and I may have the meanings given in claim 6.
25) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 3a, 3b, 3c, or 3d
wherein Ri , R2, R , Z^ , and Z2, have the meanings given in claim 7.
26) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a
wherein Ar.,, Ar2, X, L and Q may have the meanings given in claim 8.
27) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a
wherein Ar1; Ar2, W, X, Y and Z may have the meanings given in claim 9. 28) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a
wherein Ar1? Ar2, W, X, Y and Z may have the meanings given in claim 10.
29) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a compound of formula 6
wherein Ar, W, G, X, Y and Z may have the meanings given in claim 11.
30) Pharmaceutical composition according to claim 22, characterised in that the p38 kinase inhibitor is a
wherein Ar, W, G, E, X, Y and Z may have the meanings given in claim 12.
EP03720407A 2002-04-05 2003-04-02 Method of treating mucus hypersecretion Ceased EP1494645A2 (en)

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PCT/EP2003/003434 WO2003084503A2 (en) 2002-04-05 2003-04-02 P38 kinase inhibitors for treating mucus hypersecretion_
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