WO2004004725A2 - Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases - Google Patents

Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases Download PDF

Info

Publication number
WO2004004725A2
WO2004004725A2 PCT/EP2003/006739 EP0306739W WO2004004725A2 WO 2004004725 A2 WO2004004725 A2 WO 2004004725A2 EP 0306739 W EP0306739 W EP 0306739W WO 2004004725 A2 WO2004004725 A2 WO 2004004725A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
optionally
amino
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2003/006739
Other languages
English (en)
French (fr)
Other versions
WO2004004725A3 (en
Inventor
Michel Pairet
Christopher John Montague Meade
Michael P. Pieper
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to EP03738089A priority Critical patent/EP1534282B1/en
Priority to DE60310730T priority patent/DE60310730T2/de
Priority to CA002492033A priority patent/CA2492033A1/en
Priority to AU2003245989A priority patent/AU2003245989A1/en
Priority to JP2004518584A priority patent/JP2005538066A/ja
Publication of WO2004004725A2 publication Critical patent/WO2004004725A2/en
Publication of WO2004004725A3 publication Critical patent/WO2004004725A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel pharmaceutical compositions based on novel anticholinergics and p38 kinase inhibitors, processes for preparing them and their use in the treatment of respiratory diseases.
  • the present invention relates to novel pharmaceutical compositions based on novel anticholinergics and p38 kinase inhibitors, processes for preparing them and their use in the treatment of respiratory diseases.
  • an unexpectedly beneficial therapeutic effect particularly a synergistic effect can be observed in the treatment of diseases of the upper or lower respiratory tract, particularly in the treatment of allergic or non-allergic rhinitis, if one or more, preferably one anticholinergic of general formula A is or are used together with one or more, preferably one, p38 kinase inhibitor B. Thanks to this synergistic effect the pharmaceutical combinations according to the invention can be used in lower doses than is the case when the individual compounds are used in monotherapy in the usual way.
  • anticholinergics A denotes compounds of formula
  • X denotes an anion (counter-ion), preferably an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methansulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.
  • X denotes an anion (counter-ion), preferably an anion selected from the group consisting of chloride, bromide, methansulphonate and p- toluenesulphonate, preferably bromide.
  • X denotes an anion (counter-ion), preferably an anion selected from the group consisting of chloride, bromide and methansulphonate, preferably bromide.
  • p38 kinase inhibitors applicable within the scope of the invention are known in the art.
  • the term p38 kinase inhibitors denotes compounds selected from the compounds that are disclosed for instance in US Patents 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, 5 US 5,593,991 , US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US
  • compositions according to the invention 5 are those p38 inhibitors B_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.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 1 as disclosed in WO 99/01131
  • Rl 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 4 alkyl, halogen, hydroxyl, d-4 alkoxy, C1-4 akylthio, d-4 aklylsulfinyl, CH 2 OR ⁇ 2) amino, mono and di- C ⁇ - 6 alkyl substituted amino, an N-heterocyclyl ring which ring has from
  • 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)NR R 17 , C(Z)OR ⁇ 6 , (CRioR2o) v CORi2, SR 5 , SOR5, ORi 2 , halo-substituted-C ⁇ -4 alkyl, d-4 alkyl, ZC(Z)R 12 , NR ⁇ oC(Z)R 16 , or (CR ⁇ 0 R2o) v NR ⁇ 0 R2o and which, for other positions of substitution, is halogen, cyano, C(Z)NR 13 Ri4, C(Z)OR
  • R 2 is -C(H) (A) (R 22 ); A is optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is substituted CM O alkyl; R22 is an optionally substituted C ⁇ - ⁇ 0 alkyl;
  • R a is aryl, arylC ⁇ -6 alkyl, heterocyclic, heterocyclylC ⁇ -6 alkyl, heteroaryl, heteroarylC ⁇ . 6 alkyl, wherein each of these moieties may be optionally substituted;
  • Rb is hydrogen, d- ⁇ alkyl, C 3 . 7 cycloalkyl, aryl, aryl C ⁇ -4 alkyl, heteroaryl, heteroarylC ⁇ -4 alkyl, heterocyclyl, or heterocyclylC ⁇ - 4 alkyl, wherein each of these moieties may be optionally substituted;
  • R 3 is heterocyclyl, heterocyclyl d-10 alkyl or R 8 ;
  • R 5 is hydrogen, d. 4 alkyl, C2-4 alkenyl, C 2- 4 alkynyl or NR 7 R 17 , excluding the moieties SR 5 being SNR 7 R ⁇ 7 and SOR 5 being SOH;
  • R 6 is hydrogen, a pharmaceutically acceptable cation, d- 10 alkyl, C 3-7 cycloalkyl, aryl, aryl C1. 4 alkyl, heteroaryl, heteroaryl d -4 alkyl, heterocyclyl, aryl, or d- 10 alkanoyl; R and R 17 is each independently selected from hydrogen or d.
  • R 8 is d- ⁇ o alkyl, halo-substituted d-10 alkyl, C 2- ⁇ o alkenyl, C-2-10 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, aryl C1-10 alkyl, heteroaryl, heteroaryl C 1-10 alkyl, (CRi 0 R 2 o)nORn, (CR ⁇ oR 2 o)nS(0) m R ⁇ 8 , (CR 10 R2o)nNHS(0) 2 Ri8,
  • R 9 is hydrogen, C(Z) Rn or optionally substituted d-10 alkyl, S(0) 2 R ⁇ 8 , optionally substituted aryl or optionally substituted aryl d -4 alkyl;
  • R1 0 and R2 0 is each independently selected from hydrogen or d -4 alkyl;
  • Rn is hydrogen, - 10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl d- 10 alkyl, aryl, arylC ⁇ - ⁇ 0 alkyl, heteroaryl or heteroaryl d-10 alkyl, wherein these moieties may be optionally substituted;
  • R 12 is hydrogen or R ⁇ 6 ⁇ R13 an Rn is each independently selected from hydrogen or optionally substituted
  • C 1 . 4 alkyl optionally substituted aryl or optionally substituted arylC ⁇ -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 g ;
  • R 5 is R10 or C(Z)-Ci- 4 alkyl;
  • R16 is C1-4 alkyl, halo-substituted-C ⁇ - 4 alkyl, or C 3-7 cycloalkyl;
  • R18 is d-10 alkyl, C 3- cycloalkyl, heterocyclyl, aryl, aryl 1-10 alkyl, heterocyclyl, heterocyclyl- C ⁇ - ⁇ oalkyl, heteroaryl or heteroary -io 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 1 - 1 0 alkyl moiety.
  • R 2 is a -C(AA ⁇ )(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 3-7 cycloalkyl, aryl, heteroaryl, or heterocyclic ring, or A is a substituted d-10 alkyl moiety.
  • the ring may be substituted independently one or more times, preferably, 1 to 3 times by d- 1 0 alkyl; halogen; halo substituted C ⁇ -10 alkyl such as CF 3 ; (CR ⁇ 0 R2o)tORn; (CR ⁇ 0 R2o)tNR ⁇ 2 Ri4, especially amino or mono-or di-C ⁇ .
  • t is 0, or an integer of 1 to 4.
  • A is an optionally substituted cycloalkyl it is as defined below with the R22 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 d- 10 alkyl, such as CF 3 ; C 3 .
  • A is a C 3- 7 cycloalkyl, or a C ⁇ -6 alkyl, more preferably a C 1 - 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 is a C M O alkyl
  • Rn is preferably hydrogen, aryl or arylalkyl; NR ⁇ 3 R ; OC(Z)Rn; C(Z)ORn.
  • A is substituted by ORn where Rn is hydrogen.
  • R 22 is a C 1 - 10 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 C1-10 alkyl; d-1 0 alkoxy, such as methoxy or ethoxy; hydroxy substituted C1-10 alkoxy; halosubstituted d- 10 alkoxy, such as OCF 2 CF 2 H; OR ; S(O) m R ⁇ 8 ; NR ⁇ 3 R 14 ; C(Z)NR ⁇ 3 R 14 ; S(0) m .NR ⁇ 3 Ru; NR 23 C(Z)Rn; NHS(0) 2 R ⁇ 8 ; C(Z)Rn; OC(Z)OR ⁇ ; C(Z)OR ⁇ ; C(Z)NRnOR ⁇ ; N(OR 6 )C(Z)NR ⁇ 3 R 14 ; N(OR 6 )C(
  • NR 23 C(Z)OR ⁇ o optionally substituted C 3 . 7 cycloalkyl; optionally substituted aryl, such as phenyl; optionally substituted heteroaryl; or an optionally substituted heterocyclic.
  • the 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 d- ⁇ unsubstituted or substituted alkyl group, such as a C 1 - 3 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(0)ORn; C(O)NR ⁇ 3 Ri4 or R 2 2 is an optionally substituted aryl group, such as a benzyl or phenethyl.
  • R 22 is C1. 6 unsubstituted or substituted alkyl group, more preferably a C ⁇ - alkylene chain, such as a methylene or ethylene moiety, more preferably methylene.
  • the alkyl chain is substituted by ORn, where Rn is preferably hydrogen, aryl or arylalkyl; S(O) m R ⁇ 8 , where m is 0 and R ⁇ 8 is a C 1 - 6 alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety.
  • R2 2 is phenyl, benzyl, CH 2 OH, or CH 2 -0-aryl.
  • one or both of A and R 22 contain hydroxy moieties, such as in
  • AA ! is the (R) side chain residue of an amino acid
  • it is a C 1 - 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 d-10 alkyl and R 22 is a d-10 alkyl or a hydroxy substituted C1-10 alkyl.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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; fra ⁇ s-1-(4-Hydroxycyclohexyl)-4-(4-fiuorophenyl)5-[(2-methoxy)pyrimidin-4- yl]imidazole;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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, -OOCR, -NROCR, RCO, -COOR, -CONR 2 , -S0 NR 2 , CN, CF 3 , and N0 , wherein 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 2 , S0 2 NR 2 , CN, CF3 or N0 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, -NROCR, RCO, -COOR, - CONR 2 , S0 2 NR 2 , CN, CF3, or N0 , wherein each R is independently H or alkyl (1-4C);
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 2 as disclosed in US 6,277,989 , wherein R 1 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the follwoing compounds disclosed US 6,277,989:
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 3a, 3b, 3c, or 3d as disclosed in US 6,340,685
  • R in the foregoing optional substituents is H or alkyl (1-6C);
  • X 1 is CO, SO, CHOH or S0 2 ; m is 1 ; Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; n is 0, 1 or 2;
  • Z3 is N; X 2 is CH or CH 2 ; and
  • Ar consists of one or two phenyl moieties directly coupled to X 2 , 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;
  • R3 is H, halo, N0 , 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the follwoing compounds disclosed US 6,340,685:
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 4 as disclosed in WO 00/43384
  • An is a heterocyclic group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and wherein An 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 one to three R groups;
  • L a linking group
  • a linking group is a Ci-TM saturated or unsaturated branched or unbranched carbon chain; wherein one or more methylene groups are optionally independently replaced by 0,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1 . 4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
  • Q is selected from the group consisting of:
  • 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, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C 1-3 alkyloxy which is optionally partially or fully hal
  • C 5 - 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;
  • R 2 is selected from the group consisting of: a C 1 - 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
  • C1- 5 alkyl-C(0)-C ⁇ - 4 branched or unbranched alkyl, an amino-C ⁇ . 5 alkyl, mono- or di-(Ci- 3 )alkylamino-Ci- 5 alkyl, R 9 -C ⁇ - 5 alkyl, R ⁇ 0 -C ⁇ - 5 alkoxy, Rii-C(0)-Ci- 5 alkyl, and R ⁇ 2 -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 Ci-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 may optionally be substituted with one to three C1-3 alkyl groups; and e) acetyl, aroyl, alkoxycarbonylalkyl or phenyls
  • R-i 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 1 -4 branched or unbranched alkyl which may optionally be partially or fully halogenated;
  • each R 4 , R 5 , R 6 , R 7 , R 9 , R10, Rn and R12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole;
  • X O or S and physiologically acceptable acids or salts thereof.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is a compound of the formula 4 wherein Ar 2 is naphthyl.
  • a yet more preferred subgeneric aspect of the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from 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 Ci-e saturated or unsaturated branched or unbranched carbon chain , wherein one or more methylene groups are optionally independently replaced by 0,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1 - 4 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 ⁇ - 3 alkyl groups;
  • R 3 is selected from the group consisting of C ⁇ - 4 alkyl branched or unbranched, cyclopropyl, phenyl, pyridinyl each being optionally substituted as described above, alkoxycarbonylalkyl; d- 6 alkyl branched or unbranched; cyclopropy
  • a yet further preferred subgeneric aspect of the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from compounds of the formula 4, as described in the immediate previous paragraph, wherein An is pyrazole.
  • a still yet further preferred subgeneric aspect of previous the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from compounds of the formula 4, as described in the immediate paragraph, wherein L is C ⁇ -5 saturated carbon chain wherein one or more methylene groups are optionally independently replaced by 0,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1 - 4 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the following compounds of formula 4 as disclosed in WO 00/43384:
  • Particularly preferred p38 kinase inhibitors B within the scope of the present invention are the following compounds of the formula 4 :
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 Ri, 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 groups;
  • X is: a) a C 5 . 8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C 1 - 4 branched or unbranched alkyl, d -4 alkoxy or C 1 - 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 1 - 4 branched or unbranched alkyl, C ⁇ - 4 alkoxy, hydroxy, nitrile, mono- or di-(C ⁇ . 3 alkyl)amino, C ⁇ -6 alkyl-S(0) m , or halogen;
  • 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 methylene groups are optionally replaced by O, NH, S(O), S(0) 2 or S and wherein Y is optionally independently substituted with 0-2 oxo groups and one or more C 1 . 4 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, d- ⁇ alkyl, C ⁇ - 6 alkoxy, hydroxy, mono- or di-(C ⁇ - 3 alkyl)amino, Ci -6 alkyl-S(0) m , COOH and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, d -6 alkyl and Ci-e alkoxy; b) tetrahydropyran, tetrahydrofuran, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4- dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, piperidine, piperidinone,
  • R is: a Ci- 6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C 1 - 4 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
  • alkyl groups e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) C 1 - 6 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 1 - 4 branched or unbranched alkyl optionally be partially or fully halogenated;
  • each R 4 , R 5 , Re, R 7 , R9, R10, Rn and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
  • n 0, 1 or 2;
  • W is O or S and pharmaceutically acceptable derivatives thereof.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein:
  • An is selected from thiophene and pyrazole
  • X is C 5 . 7 cycloalkyl or Cs ⁇ cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C1. 4 branched or unbranched alkyl, C1-4 alkoxy or C1-4 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, hydroxy, nitrile, mono- or di-(C ⁇ - 3 alkyl)amino, Ci-
  • Ri is C ⁇ -4 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 ⁇ - 4 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein:
  • X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with an oxo group or 0-3 C ⁇ - 4 branched or unbranched alkyl, C ⁇ - 4 alkoxy or Ci. 4 alkylamino; or X is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 0-3 C ⁇ -4 branched or unbranched alkyl, d -4 alkoxy, hydroxy, nitrile, mono- or di-(C ⁇ -3 alkyl)amino, C ⁇ - 6 alkyl-
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 d -5 alkoxyalkyl, 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(0) m and phenyl-S(0) 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.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein: An is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted by R 3 ; R 3 is C ⁇ -4 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein X is pyridinyl.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5 as disclosed in WO 00/55139 wherein the pyridinyl is attached to An via the 3-pyridinyl position.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5 as disclosed in WO 00/55139 that are mentioned below: 1-[5-t ⁇ rf-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(morpholin-4-yl)phenyl)naphthalen-1- yl]urea;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the following compounds of formula 5 :
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5a as disclosed in WO 00/55139
  • An is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; wherein An is optionally substituted by one or more R ⁇ , R 2 or R 3 ;
  • X is: a C 5 . 8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1.4 alkyl, C1.4 alkoxy or C 1 . 4 alkylamino chains each being branched or unbranched;
  • Ci- 6 alkyl-S(0) m or halogen is: a bond or a d -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(0) m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C 1 - 4 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,
  • 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) Ci -6 branched or unbranched alkoxycarbonyl, C 1 - 6 branched or unbranched alkylaminocarbonyl, Ci-e branched or unbranched alkylcarbonylamino-d- 3 -alkyl;
  • R 2 is: a C1. 6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile, or R 2 is acetyl, aroyl, C 1 -4 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
  • heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH 2 C(0), a mono- or di-(C ⁇ -3 )alkyl aminocarbonyl, C -5 alkyl-C(0)-C ⁇ -4 alkyl, amino-C ⁇ -5 alkyl, mono- or di-(Ci-3)alkylamino-Ci- 5 alkyl, amino-S(0) 2 , di-(C ⁇ -3)alkylamino-S(0) 2 , R4-C1.5 alkyl, R 5 -C1.5 alkoxy, R 6 -C(0)-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, cyclopentanoisoquino
  • alkyl-C(0)-Ci. 4 branched or unbranched alkyl, an amino-C ⁇ -5 alkyl, mono- or di-(C ⁇ - 3 )alkylamino-C ⁇ - 5 alkyl, R 9 -C ⁇ -5 alkyl, R10-C1-5 alkoxy, Rn -C(0)-C ⁇ - 5 alkyl and R 12 -C 1 - 5 alkyl(R 13 )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 1 - 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 1 . 3 alkyl groups; e) acetyl, aroyl, C ⁇ - 6 alkoxycarbonylC ⁇ -6 alkyl or phenylsulfonyl; or f) C 1 - 6 branched or unbranched alkyl optionally partially or fully halogenated;
  • R1 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 d -4 branched or unbranched alkyl optionally partially or fully halogenated;
  • each R 4 , R 5 , R 6 , R 7 , Rg, R1 0 , Rn and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5a wherein:
  • X is: a C 5 - 7 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1.
  • 4 alkyl, C1-4 alkoxy or C ⁇ -4 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 Ci- 4 alkyl, C ⁇ - 4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C ⁇ -3 alkyl)amino, mono- or di-(C ⁇ - 3 alkylamino)carbonyl, NH 2 C(0), Ci- 6 alkyl-S(0) m
  • 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 C1- 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 ⁇ - 6 alkyl, Ci-6 alkoxy, d -3 alkoxy-C ⁇ -3 alkyl, C ⁇ - 6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C ⁇ -3acyl, oxo, hydroxy, pyridinyl-C ⁇ -3 alkyl, imidazolyl-C ⁇ - 3 alkyl, tetrahydro
  • acyl d. 6 alkyl, C ⁇ - 5 lkoxyC ⁇ - 3 alkyl, pyridinylC ⁇ - 3 alkyl, tetrahydrafuranylC ⁇ - 3 alkyl, nitriled- 4 alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C ⁇ -3 alkyl)amino, or Z is C ⁇ . 6 alkyl branched or unbranched, d. 6 alkoxy or nitriled- aikyl;
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally partially or fully halogenated and optionally substituted with one to three C 1 - 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 1 - 3 alkyl groups;
  • R 2 is: a C 1 - 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, Ci-e branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl C 1 - 5 alkyl, naphthyl C1- 5 alkyl, halogen, hydroxy, oxo, nitrile, C 1 .
  • 3 alkoxy optionally be partially or fully halogenated, C ⁇ - 3 alkoxyC ⁇ . 5 alkyl, C ⁇ -3 thioalkyl, C ⁇ - 3 thioalkylC ⁇ . 5 alkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C ⁇ .
  • 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;
  • Ri 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 , R7, Rg, R10, Rn and R12 is independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole;
  • compositions containing A and B characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5a wherein:
  • X is: cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted with an oxo group or one to three d -4 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, Ci-e alkyl, C ⁇ - 6 alkoxy, C1-3 alkoxy-C ⁇ - 3 alkyl, Ci- 6 alkoxycarbonyl, aroyl, morpholinocarbonyl, C ⁇ - 3 acyl, oxo, hydroxy, pyridinyl-C ⁇ -3 alkyl, imidazoly
  • cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl optionally partially or fully halogenated and optionally substituted with one to three C1.
  • cyclopentenyl and cyclohexenyl optionally substituted with one to three C 1 - 3 alkyl groups;
  • R 2 is: a C 1 . 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 1 - 5 alkyl, halogen, hydroxy, oxo, nitrile, C 1 . 3 alkoxy optionally partially or fully halogenated, C ⁇ - 3 thioalkyl, C ⁇ . 3 thioalkylC ⁇ - 5 alkyl, amino, mono- or di-(C ⁇ - 3 )alkylamino, NH 2 C(0) or a mono- or di-(C ⁇ - 3 )alkyl aminocarbonyl,
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C 1 - 3 alkyl groups
  • compositions containing A and B characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5a wherein:
  • Y is -CH 2 -, -0-(CH 2 )o- 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 d -4 alkyl, CM alkoxy or CM alkylamino chains each being branched or unbranched;
  • phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C1- 2 alkyl, d. 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 1 .
  • C1- 6 alkyl or Ci- 6 alkoxy; or Z is hydroxy, hydroxyC ⁇ - 3 alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by d -3 alkyl, pyridinylCi- ⁇ alkyl, tetrahydrafuranylC ⁇ -2 alkyl, C ⁇ . 3 alkoxyC ⁇ - 3 alkyl, C ⁇ - 3 acyl, nitrileC ⁇ .
  • R 2 is: a C1- 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 ⁇ - 3 branched or unbranched alkyl which is optionally partially or fully halogenated, C ⁇ - 3 alkoxy which optionally partially or fully halogenated, C ⁇ - 3 thioalkyl, C ⁇ - 3 thioalkylC ⁇ - 5 alkyl, amino or NH 2 C(0);
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C ⁇ - 3 alkyl groups.
  • compositions containing A and B characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5a wherein:
  • X is: cyclohexenyl; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with 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 1 . 3 alkyl, C - 3 alkoxy, oxo , hydroxy or NH 2 C(0)-; or Z is hydroxyC ⁇ .
  • N atom is optionally independently mono- or di-substituted by pyridinylmethyl, tetrahydrafuranylmethyl, C ⁇ - 3 alkoxyC ⁇ - 3 alkyl, C ⁇ - 3 acyl or nitrileC ⁇ - 4 alkyl, or Z is nitrileC ⁇ - 4 alkyl;
  • 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 1 - 2 alkyl which is optionally partially or fully halogenated, C ⁇ - 2 alkoxy which optionally partially or fully halogenated, C ⁇ - 2 thioalkyl, Ci-
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C1- 3 alkyl groups.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5a wherein X is pyridinyl.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 5a wherein the pyridinyl is attached to An via the 3- pyridinyl position.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the following compounds of formula 5a:
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the following compounds of formula 5a:
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 6 as disclosed in WO 00/55139
  • G is : an aromatic C ⁇ -io 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 Ri, 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 ⁇ - ⁇ cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three CM alkyl, C ⁇ - 4 alkoxy or d- 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 d. 4 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(0) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C 1 . 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, Ci- 6 alkyl, C ⁇ - 6 alkoxy, hydroxy, amino, mono- or di- (C 1 .
  • each Ri is independently: C 1 - 10 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C 3- ⁇ ocycloalkanyl, 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 ⁇ -6 alkyl which is optionally partially or fully halogenated, C 3 .
  • phenyloxy or benzyloxy 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 ⁇ . 3 alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by
  • alkyloxy which is optionally partially or fully halogenated, NH 2 C(0), mono- or di(Ci. 3 alkyl)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 C1.3 alkyl groups;
  • silyl containing three CM 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 0, NH or S(0) 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 ⁇ -3 alkyl)amino optionally substituted by one or more halogen atoms;
  • each R 2 , R 4 , and R 5 is a C 1 - 6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, CM branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, nitrile, methoxycarbonyl, C 1 - 3 alkyl- S(0) m optionally partially or fully halogenated, or phenylsulfonyl;
  • mono- or di-(C ⁇ - alkyl)amino-S(0) 2 optionally partially or fully halogenated, or H 2 NS0 2 ;
  • 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
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1 . 3 alkyl groups;
  • OR ⁇ 8 or Ci-e alkyl optionally substituted with OR ⁇ 8 ;
  • R 19 amino or mono- or di-(C ⁇ - 5 alkyl)amino optionally substituted with R 19 ;
  • R 6 is a:
  • Ci-4 alkyl optionally partially or fully halogenated and optionally substituted with R 26 ;
  • each R 7 , R 8 , R 9 , R10, R12, R ⁇ 3 , R14, R15, R17, R19, R25 and R 26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C ⁇ -4alkyl)amino optionally partially or fully halogenated;
  • each Rn and R ⁇ 6 is independently: hydrogen or CM alkyl optionally partially or fully halogenated;
  • R ⁇ is independently: hydrogen or a d- 4 alkyl optionally independently substituted with oxo or R 25 ;
  • R 2 o is independently:
  • C 1 -10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
  • R 2 1 is independently: hydrogen or C 1 - 3 alkyl optionally partially or fully halogenated
  • each R22, R 23 and R 2 4 is independently: hydrogen, Ci-e 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-(d- 3 alkyl)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-(C ⁇ - 3 alkyl)amino; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 6 wherein
  • G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 Ri, 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 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 CM saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(0) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C 1 - 4 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 ⁇ -3 alkyl, C ⁇ - 3 alkoxy, amino, mono- or di-(C ⁇ - 3 alky!)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 ⁇ - 3 alkyl, C ⁇ - 3 alkoxy, amino, mono- or di-
  • each Ri 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 ⁇ - 3 alkoxy which is optionally partially or fully halogenated;
  • R 2 is independently: halogen, C 1 - 3 alkoxy, C 1 - 3 alkyl-S(0) 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 1 - 5 alkyl, naphthyl C 1 - 5 alkyl, halogen, oxo, hydroxy, nitrile, C1-3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroary
  • OR ⁇ 8 or Ci-e alkyl optionally substituted with OR ⁇ 8 ;
  • R 20 C(O)N(R 2 ⁇ )-, R 22 0- ; R 23 R 24 NC(0)-; R 2 6CH 2 C(0)N(R 2 ⁇ )- or R 26 C(0)CH 2 N(R 2 ⁇ )-; C 2-4 alkenyl substituted by R 23 R 24 NC(0)-; 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 d-4 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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
  • Ar is naphthyl
  • X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C 1 - 4 alkyl, C ⁇ - 4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C 1-3 alkyl)amino, mono- or di-(C ⁇ - 3 alkylamino)carbonyl, NH 2 C(0), C ⁇ - 6 alkyl-S(0) 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 C1-2 alkyl or C ⁇ - 2 alkoxy;
  • tetrahydropyranyl morpholinyl, thiomorpholinyl, thiomorpholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl which are optionally substituted with one to two C ⁇ - 2 alkyl or d -2 alkoxy; or
  • each Ri is independently:
  • C 3 . 5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl substituted with zero to three halogen, C1- 3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or d. 3 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 ⁇ -3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC ⁇ -3 alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O; and
  • each R 2 is independently: bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile;
  • each R 3 is independently: phenyl, morpholino, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, 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 C1-3 alkyloxy optionally partially or fully halogenated;
  • Ci -3 alkyl or C 1 . 3 alkoxy each being optionally partially or fully halogenated or optionally substituted with R ⁇ 7 ;
  • ORi 8 or Ci- 3 alkyl optionally substituted with OR ⁇ 8 ; amino or mono- or di-(C ⁇ - 3 alkyl)amino optionally substituted with R ⁇ 9 ;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 Ri, R2 or R3;
  • Ar is 1 -naphthyl
  • X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
  • Y is: a bond or
  • each Ri is independently: C 3 . 5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl;
  • 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;
  • C 1 - 3 alkyl or C ⁇ - 3 alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino;
  • R 23 and R2 4 are H or R 23 and R 24 taken together optionally form morpholino; and R 26 is morpholino.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 6 G is phenyl, pyridinyl or naphthyl wherein G is substituted by one or more Ri, R 2 or
  • X is: imidazolyl or pyridinyl
  • Y is:
  • Z is morpholino
  • each Ri 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 pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 6 wherein X is pyridinyl.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 6 wherein the pyridinyl is attached to Ar via the 3-pyridinyl position.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the following compounds of formula 6
  • compositions containing A and B characterized in that the p38 kinase inhibitor B is selected from the following compounds of formula 6 :
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 7 as disclosed in WO 00/55139 wherein:
  • E is carbon or a heteroatom group chosen from -0-, -NH- and -S-;
  • G is : an aromatic C ⁇ -io carbocycle or a nonaromatic C 3- ⁇ ocarbocycle 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 C 5 . 8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C alkyl, C alkoxy or CM alkylamino chains each being branched or unbranched;
  • Y is: a bond or a CM 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(0) m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more CM 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-
  • each Ri is independently:
  • cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C ⁇ .
  • phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 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 1 - 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 one to five halogen, Ci-e alkyl which is optionally partially or fully halogenated, cyclop ropany I, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, d -3 alkyloxy which is optionally partially
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
  • silyl containing three C alkyl groups optionally partially or fully halogenated
  • each R , R4, and R 5 is a C1- 6 branched or unbranched alkyl optionally partially or fully halogenated, d- ⁇ acyl, aroyl, C M branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C 1 . 3 alkyl-S(0) m optionally partially or fully halogenated, or phenyl-S(0) m ;
  • N atom is optionally independently mono- or di- substituted by C ⁇ -6 alkyl or arylCo- 3 alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by d. 3 alkyl, arylC 0 - 3 alkyl, Ci. 6 acyl, Ci- 6 alkyl-S(0) m - 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 Ci- 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
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C ⁇ - 3 alkyl groups;
  • OR ⁇ s or Ci- 6 alkyl optionally substituted with OR ⁇ 8 ;
  • alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(0) 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 d- 4 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;
  • Re is a: Ci- alkyl optionally partially or fully halogenated and optionally substituted with R 26 ;
  • each R 7 , R 8 , R 9 , Rio, R12, R13, R14, R15, R17, R19, R25 and R 26 is independently: nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C ⁇ -4alkyl)amino optionally partially or fully halogenated;
  • each Rn and R ⁇ 6 is independently: hydrogen or d- alkyl optionally partially or fully halogenated;
  • R ⁇ s is independently: hydrogen or a d -4 alkyl optionally independently substituted with oxo or R 2 s;
  • R20 is independently: C1-10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
  • R 2 ⁇ 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 d. 6 alkyl is optionally interrupted by one or more O, N or S, said Ci- 6 alkyl also being independently optionally substituted by mono- or di-(C ⁇ . 3 alkyl)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-(C ⁇ - 3 alkyl)amino; or R 23 and R 2 4 taken together optionally form a heterocyclic or heteroaryl ring;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B is selected from the compounds of formula 7 wherein: E is -CH 2 -, -NH- or -0-; W is O; and G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 H-indolyl or indolinonyl, wherein G is optionally substituted by one
  • 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; each being optionally independently substituted with one to three CM alkyl, d.
  • Y is: a bond or a C ⁇ - 4 saturated or unsaturated carbon chain wherein one or more of the C atoms is optionally replaced by O, N, or S(0) m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more d. 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,
  • each Ri is independently:
  • R 2 is independently: a Ci- 5 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C M branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C 1 - 2 alkyl-S(0) m optionally partially or fully halogenated, or phenyl-S(0) m ;
  • N atom is optionally independently mono- or di- substituted by C ⁇ - 3 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 - 3 alkyl, C 1 -
  • R 3 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 Ci- 5 alkyl, naphthyl C1- 5 alkyl, halogen, oxo, hydroxy, nitrile, C1- 3 alkoxy optionally partially or fully halogenated, phenyloxy,
  • alkyl or d- 4 alkoxy each being optionally partially or fully halogenated or optionally substituted with R ⁇ 7 ;
  • R ⁇ 9 amino or mono- or di- (C 1 - 5 alkyl)amino optionally substituted with R ⁇ 9 ;
  • R 20 C(O)N(R 21 )-, R 22 0- ;
  • C 2 - 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;
  • R2 3 and R 24 taken together optionally form imidazolyl, piperidinyl, morpholino, piperazinyl or a pyridinyl ring.
  • the invention relates to pharmaceutical compositions containing A and B, characterized in that the p38 kinase inhibitor B 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 Ri, 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 d- 4 alkyl, C ⁇ . 4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C ⁇ -3 alkyl)amino, mono- or di-(Ci- 3 alkylamino)carbonyl, NH 2 C(0), C ⁇ - 6 alkyl-S(0) m or halogen;

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Otolaryngology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)
PCT/EP2003/006739 2002-07-09 2003-06-26 Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases Ceased WO2004004725A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP03738089A EP1534282B1 (en) 2002-07-09 2003-06-26 Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases
DE60310730T DE60310730T2 (de) 2002-07-09 2003-06-26 Pharmazeutische zusammensetzungen aus anticholinergica und p38 kinase hemmern zur behandlung von erkrankungen der atemwege
CA002492033A CA2492033A1 (en) 2002-07-09 2003-06-26 Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases
AU2003245989A AU2003245989A1 (en) 2002-07-09 2003-06-26 Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases
JP2004518584A JP2005538066A (ja) 2002-07-09 2003-06-26 新規な抗コリン作用薬及びｐ３８キナーゼ阻害剤を用いた新規な医薬組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02015231 2002-07-09
EP02015231.0 2002-07-09

Publications (2)

Publication Number Publication Date
WO2004004725A2 true WO2004004725A2 (en) 2004-01-15
WO2004004725A3 WO2004004725A3 (en) 2004-05-27

Family

ID=30011064

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/006739 Ceased WO2004004725A2 (en) 2002-07-09 2003-06-26 Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases

Country Status (8)

Country Link
EP (2) EP1707205A2 (https=)
JP (1) JP2005538066A (https=)
AT (1) ATE349210T1 (https=)
AU (1) AU2003245989A1 (https=)
CA (1) CA2492033A1 (https=)
DE (1) DE60310730T2 (https=)
ES (1) ES2278170T3 (https=)
WO (1) WO2004004725A2 (https=)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023761A2 (en) 2003-09-11 2005-03-17 Kemia, Inc. Cytokine inhibitors
WO2008142031A1 (en) 2007-05-18 2008-11-27 Institut Curie P38alpha as a therapeutic target in bladder carcinoma
US9096554B2 (en) 2011-11-02 2015-08-04 Universidad Autónoma de Madrid Drugs for inhibiting p38 and uses thereof
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2710039C (en) 2007-12-26 2018-07-03 Critical Outcome Technologies, Inc. Semicarbazones, thiosemicarbazones and related compounds and methods for treatment of cancer
EP2318406B1 (en) 2008-07-17 2016-01-27 Critical Outcome Technologies, Inc. Thiosemicarbazone inhibitor compounds and cancer treatment methods

Family Cites Families (146)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4570630A (en) 1983-08-03 1986-02-18 Miles Laboratories, Inc. Medicament inhalation device
DE3682457D1 (de) 1985-07-30 1991-12-19 Glaxo Group Ltd Geraet zur verabreichung von medikamenten an patienten.
SE453566B (sv) 1986-03-07 1988-02-15 Draco Ab Anordning vid pulverinhalatorer
SG45171A1 (en) 1990-03-21 1998-01-16 Boehringer Ingelheim Int Atomising devices and methods
WO1992012154A1 (en) 1990-12-31 1992-07-23 Fujisawa Pharmaceutical Co., Ltd. Imidazotriazine derivatives
GB9816837D0 (en) 1998-08-04 1998-09-30 Zeneca Ltd Amide derivatives
MX9300141A (es) 1992-01-13 1994-07-29 Smithkline Beecham Corp Compuestos de imidazol novedosos, procedimiento para su preparacion y composiciones farmaceuticas que lo contienen.
US5716972A (en) 1993-01-13 1998-02-10 Smithkline Beecham Corporation Pyridyl substituted imidazoles
US5656644A (en) 1994-07-20 1997-08-12 Smithkline Beecham Corporation Pyridyl imidazoles
IL107120A (en) 1992-09-29 1997-09-30 Boehringer Ingelheim Int Atomising nozzle and filter and spray generating device
GB9303993D0 (en) 1993-02-26 1993-04-14 Fujisawa Pharmaceutical Co New heterocyclic derivatives
DE4318455A1 (de) 1993-06-03 1994-12-08 Boehringer Ingelheim Kg Kapselhalterung
US5593992A (en) 1993-07-16 1997-01-14 Smithkline Beecham Corporation Compounds
US5670527A (en) 1993-07-16 1997-09-23 Smithkline Beecham Corporation Pyridyl imidazole compounds and compositions
US5593991A (en) 1993-07-16 1997-01-14 Adams; Jerry L. Imidazole compounds, use and process of making
WO1995009851A1 (en) 1993-10-01 1995-04-13 Ciba-Geigy Ag Pharmacologically active pyrimidineamine derivatives and processes for the preparation thereof
JPH08503971A (ja) 1993-10-01 1996-04-30 チバ−ガイギー アクチェンゲゼルシャフト ピリミジンアミン誘導体及びその調製のための方法
KR100330553B1 (ko) 1993-10-01 2002-11-27 노파르티스 아게 약물학적활성피리딘유도체및그의제조방법
US5543520A (en) 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives
US5559137A (en) 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds
IL118544A (en) 1995-06-07 2001-08-08 Smithkline Beecham Corp History of imidazole, the process for their preparation and the pharmaceutical preparations containing them
US5739143A (en) 1995-06-07 1998-04-14 Smithkline Beecham Corporation Imidazole compounds and compositions
DE19536903C2 (de) 1995-10-04 1998-09-10 Boehringer Ingelheim Int Vorrichtung zum Haltern eines fluidischen Bauteils
DE19536902A1 (de) 1995-10-04 1997-04-10 Boehringer Ingelheim Int Vorrichtung zur Hochdruckerzeugung in einem Fluid in Miniaturausführung
PL184819B1 (pl) 1995-10-06 2002-12-31 Merck & Co Inc Podstawione związki imidazolilowe oraz zawierające je kompozycje farmaceutyczne
EP0859771A4 (en) 1995-10-31 2000-03-15 Merck & Co Inc SUBSTITUTED PYRIDYLPYRROLE, PREPARATIONS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE USE THEREOF
WO1997016441A1 (en) 1995-10-31 1997-05-09 Merck & Co., Inc. Substituted aryl pyrroles, compositions containing such compounds and methods of use
DE19545226C1 (de) 1995-12-05 1997-06-19 Boehringer Ingelheim Int Sperrspannwerk für einen federbetätigten Abtrieb
PL187516B1 (pl) 1996-01-11 2004-07-30 Smithkline Beecham Corp Nowe podstawione pochodne imidazolu, sposób ich wytwarzania oraz kompozycja farmaceutyczna zawierająca te związki
WO1997025047A1 (en) 1996-01-11 1997-07-17 Smithkline Beecham Corporation Novel cycloalkyl substituded imidazoles
ZA97175B (en) 1996-01-11 1997-11-04 Smithkline Beecham Corp Novel substituted imidazole compounds.
AP9700912A0 (en) 1996-01-11 1997-01-31 Smithkline Beecham Corp Novel cycloalkyl substituted imidazoles
US6096748A (en) 1996-03-13 2000-08-01 Smithkline Beecham Corporation Pyrimidine compounds useful in treating cytokine mediated diseases
JP2000507558A (ja) 1996-03-25 2000-06-20 スミスクライン・ビーチャム・コーポレイション Ｃｎｓ損傷についての新規な治療
US6235760B1 (en) 1996-03-25 2001-05-22 Smithkline Beecham Corporation Treatment for CNS injuries
CA2250232A1 (en) 1996-04-03 1997-10-09 Allen I. Oliff A method of treating cancer
EP0906307B1 (en) 1996-06-10 2005-04-27 Merck & Co., Inc. Substituted imidazoles having cytokine inhibitory activity
EP0922042A1 (en) 1996-08-09 1999-06-16 Smithkline Beecham Corporation Novel piperazine containing compounds
DE19633640C2 (de) 1996-08-21 1999-05-06 Ford Global Tech Inc Vorrichtung zur Winkelverstellung einer Welle gegenüber einem Antriebsrad
WO1998007425A1 (en) 1996-08-21 1998-02-26 Smithkline Beecham Corporation Imidazole compounds, compositions and use
DE69728688T2 (de) 1996-11-19 2004-08-19 Amgen Inc., Thousand Oaks Aryl und heteroaryl substituierte kondensierte pyrrole als entzündunghemmende mittel
WO1998022109A1 (en) 1996-11-20 1998-05-28 Merck & Co., Inc. Triaryl substituted imidazoles as glucagon antagonists
AR038955A1 (es) 1996-12-05 2005-02-02 Amgen Inc Compuestos de pirimidinona y piridona sustituidos y metodos para su uso
IL130181A0 (en) 1996-12-05 2000-06-01 Amgen Inc Substituted pyrimidone and pyridone compounds and methods of use
ZA9711092B (en) 1996-12-11 1999-07-22 Smithkline Beecham Corp Novel compounds.
US6147080A (en) 1996-12-18 2000-11-14 Vertex Pharmaceuticals Incorporated Inhibitors of p38
WO1998028292A1 (en) 1996-12-23 1998-07-02 Smithkline Beecham Corporation Novel piperidine containing compounds
PT1270565E (pt) 1997-01-29 2004-09-30 Pfizer Furano-2-sulfonamida 4-substituida e sua utilizacao na preparacao de derivados de sulfonilureia
RU2222534C2 (ru) 1997-04-24 2004-01-27 Орто-Макнейл Фармасьютикал, Инк. Замещенные имидазолы, способ их получения, фармацевтическая композиция на их основе, способы лечения цитокин-опосредованных заболеваний
AU7132998A (en) 1997-04-24 1998-11-13 Ortho-Mcneil Corporation, Inc. Substituted pyrrolopyridines useful in the treatment of inflammatory diseases
EP0984930B1 (en) 1997-05-07 2005-04-06 Sugen, Inc. 2-indolinone derivatives as modulators of protein kinase activity
PL337020A1 (en) 1997-05-22 2000-07-31 Searle & Co Substituted pyrazoles as kinase p38 inhibitors
EP0983260A2 (en) 1997-05-22 2000-03-08 G.D. Searle & Co. 3(5)-HETEROARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
AU7726898A (en) 1997-05-22 1998-12-11 G.D. Searle & Co. Pyrazole derivatives as p38 kinase inhibitors
ATE399007T1 (de) 1997-05-23 2008-07-15 Bayer Pharmaceuticals Corp Raf kinase hemmer
WO1998052558A1 (en) 1997-05-23 1998-11-26 Bayer Corporation INHIBITION OF p38 KINASE ACTIVITY BY ARYL UREAS
KR100704059B1 (ko) 1997-06-12 2007-04-05 롱프랑 로라 리미티드 이미다졸릴-사이클릭 아세탈
CA2294057A1 (en) 1997-06-13 1998-12-17 Smithkline Beecham Corporation Novel pyrazole and pyrazoline substituted compounds
US6093742A (en) 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
GB9713726D0 (en) 1997-06-30 1997-09-03 Ciba Geigy Ag Organic compounds
EP0994858A1 (en) 1997-06-30 2000-04-26 Ortho-McNeil Pharmaceutical, Inc. 2-substituted imidazoles useful in the treatment of inflammatory diseases
US5939421A (en) 1997-07-01 1999-08-17 Signal Pharmaceuticals, Inc. Quinazoline analogs and related compounds and methods for treating inflammatory conditions
AR016294A1 (es) * 1997-07-02 2001-07-04 Smithkline Beecham Corp Compuesto de imidazol sustituido, composicion farmaceutica que la contiene, su uso en la fabricacion de un medicamento y procedimiento para supreparacion
TW517055B (en) 1997-07-02 2003-01-11 Smithkline Beecham Corp Novel substituted imidazole compounds
WO1999001452A1 (en) 1997-07-02 1999-01-14 Smithkline Beecham Corporation Novel cycloalkyl substituted imidazoles
US5981710A (en) 1997-07-21 1999-11-09 Baxter International, Inc. Therapeutic hemoglobin composition having isotropically increased size
AU739066B2 (en) 1997-09-23 2001-10-04 Astrazeneca Ab Amide derivatives for the treatment of diseases mediated by cytokines
US5975738A (en) 1997-09-30 1999-11-02 Lsi Logic Corporation Method for detecting failure in redundant controllers using a private LUN
WO1999017776A1 (en) 1997-10-08 1999-04-15 Smithkline Beecham Corporation Novel cycloalkenyl substituted compounds
HUP0004947A2 (hu) 1997-11-14 2002-03-28 Sankyo Co., Ltd. Piridilpirrol-származékok
WO1999032121A1 (en) 1997-12-19 1999-07-01 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
MXPA00006233A (es) 1997-12-22 2002-09-18 Bayer Ag Inhibicion de la actividad de la cinasa p38 utilizando ureas heterociclicas sustituidas.
JP3887769B2 (ja) 1997-12-22 2007-02-28 バイエル コーポレイション 対称および非対称ジフェニル尿素を用いるｐ３８キナーゼの阻害
DE69836563T2 (de) 1997-12-22 2007-05-16 Bayer Pharmaceuticals Corp., West Haven INHIBIERUNG DER p38 KINASE-AKTIVITÄT DURCH DIE VERWENDUNG VON ARYL- UND HETEROARYL-SUBSTITUIERTEN HARNSTOFFEN
DE69917005T2 (de) 1998-02-26 2005-03-24 Ortho-Mcneil Pharmaceutical, Inc. Substituierte pyrrolobenzimidazolderivate zur entzündungshemmung
CN1305846C (zh) 1998-03-26 2007-03-21 参天制药株式会社 脲衍生物
US6316466B1 (en) 1998-05-05 2001-11-13 Syntex (U.S.A.) Llc Pyrazole derivatives P-38 MAP kinase inhibitors
CA2329065A1 (en) 1998-05-05 1999-11-11 Francisco Xavier Talamas Pyrazole derivatives as p-38 map kinase inhibitors
MY132496A (en) 1998-05-11 2007-10-31 Vertex Pharma Inhibitors of p38
WO1999058523A1 (en) 1998-05-14 1999-11-18 G.D. Searle & Co. 1,5-DIARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
PT1077930E (pt) 1998-05-15 2005-03-31 Astrazeneca Ab Derivados de benzamida para o tratamento de doencas mediadas por citocinas
CA2328927C (en) 1998-05-15 2008-02-19 Astrazeneca Ab Benzamide derivatives for the treatment of diseases mediated by cytokines
CN1548436A (zh) 1998-05-22 2004-11-24 ʷ��˿�������ȳ�ķ���޹�˾ 新的2-烷基取代咪唑化合物
US6589954B1 (en) 1998-05-22 2003-07-08 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
ATE316961T1 (de) 1998-05-22 2006-02-15 Scios Inc Heterozyclische derivate für die behandlung von herzversagen und andere erkrankungen
US6340685B1 (en) 1998-05-22 2002-01-22 Scios, Inc. Compounds and methods to treat cardiac failure and other disorders
WO1999061440A1 (en) 1998-05-26 1999-12-02 Smithkline Beecham Corporation Novel substituted imidazole compounds
JP2002517486A (ja) 1998-06-12 2002-06-18 バーテックス ファーマシューティカルズ インコーポレイテッド ｐ３８のインヒビター
WO2000001688A1 (en) 1998-07-02 2000-01-13 Sankyo Company, Limited Five-membered heteroaryl compounds
US6207687B1 (en) 1998-07-31 2001-03-27 Merck & Co., Inc. Substituted imidazoles having cytokine inhibitory activity
CA2338121A1 (en) 1998-08-04 2000-02-17 Astrazeneca Ab Amide derivatives useful as inhibitors of the production of cytokines
CN1147469C (zh) 1998-08-05 2004-04-28 参天制药株式会社 带有芳香族含氮杂环的新型脲衍生物
JP2003525201A (ja) 1998-08-20 2003-08-26 スミスクライン・ビーチャム・コーポレイション 新規な置換トリアゾール化合物
CA2342251A1 (en) 1998-08-28 2000-03-09 Scios Inc. Use of piperidines and/or piperazines as inhibitors of p38-alpha kinase
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
JP4191825B2 (ja) 1998-09-10 2008-12-03 あすか製薬株式会社 ５−アミノイソキサゾール誘導体
AR023659A1 (es) 1998-09-18 2002-09-04 Vertex Pharma Un compuesto inhibidor de p38, una composicion farmaceutica que lo comprende y el uso de dicha composicion en el tratamiento y prevencion de estados patologicos
DE19842833B4 (de) 1998-09-18 2005-04-14 Merckle Gmbh 2-Arylalkylthio-imidazole, 2-Arylalkenylthio-imidazole und 2-Arylalkinylthio-imidazole als Entzündungs-Hemmstoffe und Hemmstoffe der Cytokin-Freisetzung
WO2000017175A1 (en) 1998-09-18 2000-03-30 Vertex Pharmaceuticals Incorporated INHIBITORS OF p38
EP1115707B1 (en) 1998-09-25 2003-11-12 AstraZeneca AB Benzamide derivatives and ther use as cytokine inhibitors
ATE232205T1 (de) 1998-10-01 2003-02-15 Astrazeneca Ab Chinolin- und chinazolin derivate und ihre verwendung als inhibitoren von krankheiten, bei denen cytokine beteiligt wird
DE19847968A1 (de) 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Verschlußkappe und Behälter als Zweikammer-Kartusche für Vernebler zur Erzeugung von Aerosolen
AU1127700A (en) 1998-10-20 2000-05-08 Omeros Medical Systems, Inc. Irrigation solution containing mapk inhibitors and their use for treating pain and inflammation
AU6476599A (en) 1998-11-03 2000-05-22 Novartis Ag Anti-inflammatory 4-phenyl-5-pyrimidinyl-imidazoles
WO2000025791A1 (en) 1998-11-04 2000-05-11 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US6350744B1 (en) 1998-11-20 2002-02-26 Merck & Co., Inc. Compounds having cytokine inhibitory activity
US6143892A (en) 1998-11-20 2000-11-07 G. D. Searle & Co. Process for making 5-substituted pyrazoles
WO2000035911A1 (en) 1998-12-16 2000-06-22 Aventis Pharma Limited Heteroaryl-cyclic acetals
AU3114600A (en) 1998-12-16 2000-07-03 Vertex Pharmaceuticals Incorporated Crystallized p38 complexes
AU765492B2 (en) 1998-12-25 2003-09-18 Teikoku Hormone Mfg. Co., Ltd. Aminopyrazole derivatives
ATE538794T1 (de) 1999-01-13 2012-01-15 Bayer Healthcare Llc Gamma carboxyarylsubstituierte diphenylharnstoffverbindungen als p38 kinasehemmer
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
WO2000055152A1 (en) 1999-03-12 2000-09-21 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
NZ528846A (en) 1999-03-12 2005-05-27 Boehringer Ingelheim Pharma Compounds useful as anti-inflammatory agents
AU761291B2 (en) 1999-03-17 2003-05-29 Astrazeneca Ab Amide derivatives
RU2260007C2 (ru) 1999-03-17 2005-09-10 Астразенека Аб Производные амида, способ их получения (варианты), фармацевтическая композиция, способ ингибирования
GB9906566D0 (en) 1999-03-23 1999-05-19 Zeneca Ltd Chemical compounds
CO5170501A1 (es) 1999-04-14 2002-06-27 Novartis Ag AZOLES SUSTITUIDOS UTILES PARA EL TRATAMIENTO DE ENFERMEDADES MEDIADAS POR TNFa eIL-1 Y ENFERMEDADES DEL METABOLISMO OSEO
US6492516B1 (en) 1999-05-14 2002-12-10 Merck & Co., Inc. Compounds having cytokine inhibitory activity
JP2003500403A (ja) 1999-05-21 2003-01-07 サイオス，インコーポレーテッド ｐ３８キナーゼのインヒビターとしてのインドール型誘導体
US6403596B1 (en) 1999-06-28 2002-06-11 Merck & Co., Inc. Substituted pyridones having cytokine inhibitory activity
EP1210325B1 (en) 1999-07-16 2004-10-06 Leo Pharma A/S Aminobenzophenones as inhibitors of il-1beta and tnf-alpha
AU768473B2 (en) 1999-07-16 2003-12-11 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Novel aminobenzophenones
ATE277889T1 (de) 1999-07-16 2004-10-15 Leo Pharma As Aminobenzophenone als inhibitoren von il-1beta und tnf-alpha
ES2228555T3 (es) 1999-07-16 2005-04-16 Leo Pharma A/S Aminobenzofenonas con inhibidores de la il-1beta y tnf-alfa.
RU2240995C2 (ru) 1999-07-16 2004-11-27 Лео Фармасьютикал Продактс Лтд.А/С (Левенс Кемиске Фабрик Продукционсактиесельскаб) Аминобензофеноны в качестве ингибиторов интерлейкина il-1бета и фактора некроза опухолей tnf-альфа
AU7584500A (en) * 1999-09-17 2001-04-17 Smithkline Beecham Corporation Use of csaids in rhinovirus infection
GB9924092D0 (en) 1999-10-13 1999-12-15 Zeneca Ltd Pyrimidine derivatives
AU7269600A (en) 1999-10-13 2001-04-23 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) A method of screening for substances acting on MSK1
KR100537241B1 (ko) 1999-10-21 2005-12-19 에프. 호프만-라 로슈 아게 Ｐ38 단백질 키나제의 억제제로서의 알킬아미노 치환된이중고리 질소 헤테로고리 화합물
DE60033307T2 (de) 1999-10-21 2007-07-12 F. Hoffmann-La Roche Ag Heteroalkylamino-substituierte bicyclische stickstoffheterocyclen als p38-proteinkinase-inhibitoren
DE60018037T2 (de) 1999-11-10 2006-01-12 Ortho-Mcneil Pharmaceutical, Inc. Substituierte 2-aryl-3-(heteroaryl)-imidazo[1,2-alpha]pyrimidine und ihren verwandten arzneimittel und verfahren
WO2001036403A1 (en) 1999-11-16 2001-05-25 Boehringer Ingelheim Pharmaceuticals, Inc. Urea derivatives as anti-inflammatory agents
EP1233951B1 (en) 1999-11-23 2005-06-01 SmithKline Beecham Corporation 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors
AU1781601A (en) 1999-11-23 2001-06-04 Smithkline Beecham Corporation 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors
ATE305787T1 (de) 1999-11-23 2005-10-15 Smithkline Beecham Corp 3,4-dihydro-(1h)chinazolin-2-on-verbindungen als csbp/p39-kinase-inhibitoren
EP1248624A4 (en) 1999-11-23 2003-01-22 Smithkline Beecham Corp 3,4-DIHYDRO- (1H) -CHIRAZOLINE-2-ONES AND THE USE THEREOF AS CSBP / P38 KINASE INHIBITORS
MXPA02005604A (es) 1999-12-06 2004-09-10 Leo Pharma As Aminobenzofenonas como inhibidores de il-1beta y tnf-alfa.
US6602872B1 (en) 1999-12-13 2003-08-05 Merck & Co., Inc. Substituted pyridazines having cytokine inhibitory activity
CA2394727A1 (en) 1999-12-28 2001-07-05 Pharmacopeia, Inc. Pyrimidine and triazine kinase inhibitors
US6537996B2 (en) 2000-02-23 2003-03-25 Iconix Pharmaceuticals, Inc. Modulators of p38 MAP kinase
AU2001241927A1 (en) 2000-02-28 2001-09-12 Scios Inc. Inhibitors of p38-alpha kinase
AU2001260081B2 (en) * 2000-05-22 2005-07-28 Leo Pharma A/S Benzophenones as inhibitors of il-1beta and tnf-alpha
DE10050994A1 (de) * 2000-10-14 2002-04-18 Boehringer Ingelheim Pharma Neue als Arneimittel einsetzbare Anticholinergika sowie Verfahren zu deren Herstellung
US20030225089A1 (en) * 2002-04-10 2003-12-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023761A2 (en) 2003-09-11 2005-03-17 Kemia, Inc. Cytokine inhibitors
US7749999B2 (en) 2003-09-11 2010-07-06 Itherx Pharmaceuticals, Inc. Alpha-ketoamides and derivatives thereof
US7897599B2 (en) 2003-09-11 2011-03-01 iTherX Pharmaceuticals Inc. Cytokine inhibitors
US7919617B2 (en) 2003-09-11 2011-04-05 iTherX Pharmaceuticals Inc. Cytokine inhibitors
WO2008142031A1 (en) 2007-05-18 2008-11-27 Institut Curie P38alpha as a therapeutic target in bladder carcinoma
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9096554B2 (en) 2011-11-02 2015-08-04 Universidad Autónoma de Madrid Drugs for inhibiting p38 and uses thereof
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4

Also Published As

Publication number Publication date
WO2004004725A3 (en) 2004-05-27
EP1534282B1 (en) 2006-12-27
ES2278170T3 (es) 2007-08-01
AU2003245989A8 (en) 2004-01-23
DE60310730D1 (de) 2007-02-08
CA2492033A1 (en) 2004-01-15
DE60310730T2 (de) 2007-05-16
JP2005538066A (ja) 2005-12-15
EP1534282A2 (en) 2005-06-01
AU2003245989A1 (en) 2004-01-23
EP1707205A2 (en) 2006-10-04
ATE349210T1 (de) 2007-01-15

Similar Documents

Publication Publication Date Title
US20030225089A1 (en) Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors
US20090017036A1 (en) Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
US20040044020A1 (en) Pharmaceutical compositions based on novel anticholinergics and p38 kinase inhibitors
AU2004266719A1 (en) Methods of treating COPD and pulmonary hypertension
US20040110755A1 (en) Combination therapy with p38 MAP kinase inhibitors and their pharmaceutical compositions
EP1494645A2 (en) Method of treating mucus hypersecretion
US20030220336A1 (en) Method of treating mucus hypersecretion
EP1534282B1 (en) Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases
US7276491B2 (en) Anticoagulant and fibrinolytic therapy using p38 MAP kinase inhibitors
KR20070035466A (ko) Ｃｏｐｄ 및 폐고혈압 치료 방법
HK1080738A (en) New pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

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

Ref document number: 2003738089

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2492033

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2004518584

Country of ref document: JP

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWP Wipo information: published in national office

Ref document number: 2003738089

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 2003738089

Country of ref document: EP