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WO2010069979A1 - Dérivés de pyrane en tant que modulateurs du ccr3 - Google Patents

Dérivés de pyrane en tant que modulateurs du ccr3 Download PDF

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Publication number
WO2010069979A1
WO2010069979A1 PCT/EP2009/067247 EP2009067247W WO2010069979A1 WO 2010069979 A1 WO2010069979 A1 WO 2010069979A1 EP 2009067247 W EP2009067247 W EP 2009067247W WO 2010069979 A1 WO2010069979 A1 WO 2010069979A1
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Prior art keywords
compound
stereoisomer
pharmaceutically acceptable
compounds
acceptable salt
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Inventor
Thomas Martin
Wolf-Rüdiger Ulrich
Alexander Mann
Siegfried Schneider
Angelika Hoffmeyer
Rainer Boer
Michaela SCHÄFER
Frank SCHWÖBEL
Raimund KÜLZER
Armin Hatzelmann
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Takeda GmbH
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Nycomed GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the invention relates to novel pyran derivatives, processes for their preparation, pharmaceutical compositions comprising said pyran derivatives and the use thereof in the treatment or prophylaxis of diseases.
  • N-ureidoheterocycloalkyl-piperidines are described as modulators of CC chemokine receptor 3 (CCR3) activity, whereby the central heterocyclic ring can be inter alia an optionally substituted pyran ring.
  • CCR3 CC chemokine receptor 3
  • WO0035452 WO0198270 and WO2004110993 N-ureidocycloalkyl-piperidines are described as modulators of CC chemokine receptor 3 (CCR3) activity.
  • CCR3 CC chemokine receptor 3
  • the invention relates to compounds of formula (1 )
  • R1 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
  • R2 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, and
  • R3 is hydrogen, halogen, cyano, hydroxycarbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkylcarbonyl, 1-4C-alkoxy- carbonyl, 1-4C-alkylcarbonylamino, aminocarbonyl or mono- or di-1-4C-alkylamino- carbonyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • 1-4C-Alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • 1-4C-Alkoxy is a group which, in addition to the oxygen atom, contains a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
  • Alkoxy groups having 1 to 4 carbon atoms which may be mentioned in this context are, for example, the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy groups.
  • 1-4C-Alkoxy which is completely or predominantly substituted by fluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy and in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluorom ethoxy and the difluoromethoxy group, of which the difluoromethoxy group is preferred.
  • "Predominantly” in this connection means that more than half of the hydrogen atoms of the 1-4C-alkoxy group are replaced by fluorine atoms.
  • "Halogen" within the meaning of the present invention includes fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
  • 1-4C-Alkylcarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkyl group is bonded.
  • An example is the acetyl group [CH 3 C(O)-].
  • An 1-4C-Alkylcarbonylamino group is, for example, the propionylamino [C 3 H 7 C(O)NH-] and the acetylamino group [CH 3 C(O)NH-].
  • 1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy groups is bonded.
  • Examples are the methoxycarbonyl [CH 3 O-C(O)-], the ethoxycarbonyl [CH 3 CH 2 O-C(O)-] and the tert-butoxycarbonyl [(CH 3 ) 3 CO-C(O)-] group.
  • Mono- or Di-1-4C-alkylaminocarbonyl groups contain in addition to the carbonyl group one of the abovementioned mono- or di-1-4C-alkylamino groups. Examples which may be mentioned are the N-methyl- the N,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and the N-isopropyl- aminocarbonyl group.
  • the invention relates to compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R2 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine
  • R3 is hydrogen, halogen, cyano, hydroxycarbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkylcarbonyl, 1-4C-alkoxy- carbonyl, 1-4C-alkylcarbonylamino, aminocarbonyl or mono- or di-1-4C-alkylamino- carbonyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • the invention relates to compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
  • R2 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, and
  • R3 is hydrogen, halogen, cyano, hydroxycarbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy which is completely or predominantly substituted by fluorine, 1-4C-alkylcarbonyl, 1-4C-alkoxy- carbonyl, 1-4C-alkylcarbonylamino, aminocarbonyl or mono- or di-1-4C-alkylamino- carbonyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • the invention relates to compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 is fluorine, chlorine, methoxy or difluoromethoxy
  • R2 is hydrogen, fluorine, chlorine, methyl or difluoromethoxy
  • R3 is cyano, fluorine, methyl, methoxy, ethoxy, difluoromethoxy or acetyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • the invention relates to compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 is fluorine, chlorine, methoxy or difluoromethoxy
  • R2 is hydrogen, fluorine, chlorine, methyl or difluoromethoxy
  • R3 is cyano, fluorine, methyl, methoxy, ethoxy, difluoromethoxy or acetyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • the invention relates to compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 is 2-fluorine or 4-fluorine
  • R2 is hydrogen or 2-methyl
  • R3 is 3-cyano, 4-cyano, 3-fluorine, 4-fluorine, 3-methyl, 4-methyl, 3-methoxy, 4-methoxy, 3- difluoromethoxy, 4-difluoromethoxy, 3-acetyl or 4-acetyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • the invention relates to compounds of formula (1 ), wherein wherein the group -A-CH 2 -B- is selected from
  • R1 is 4-fluorine
  • R2 is hydrogen
  • R3 is 3-cyano, 4-cyano, 3-fluorine, 4-fluorine, 3-methyl, 4-methyl, 3-methoxy, 4-methoxy, 3- ethoxy, 4-ethoxy, 3-difluoromethoxy, 4-difluoromethoxy, 3-acetyl or 4-acetyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • the invention relates to compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 is 4-fluorine
  • R2 is hydrogen
  • R3 is 4-cyano, 4-fluorine, 4-methyl, 4-methoxy, 4-ethoxy, 4-difluoromethoxy, 3-acetyl or 4- acetyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • the invention relates to compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 is 4-fluorine
  • R2 is hydrogen
  • R3 is 3-methoxy, 4-methoxy, 3-ethoxy, 4-difluoromethoxy, 3-acetyl or 4-acetyl, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • a special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 , R2 and R3 are as defined above, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 , R2 and R3 are as defined above, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ) wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is and R1 , R2 and R3 are as defined above, the stereoisomers thereof, as well as the salts of these compounds and stereoisomers.
  • Salts of the compounds or stereoisomers according to the invention include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
  • acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, citrates, D-gluconates, benzoates, 2-(4-hydroxybenzoyl)- benzoates, butyrates, subsalicylates, maleates, laurates, malates, fumarates, succinates, oxalates, tartrates, stearates, toluenesulfonates, methanesulfonates, 3-hydroxy-2-naphthoat.es and trifluoroacetates.
  • salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • the compounds of the invention, the salts thereof, the stereoisomers of the compounds of the invention and the salts thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are therefore, all solvates of the compounds of the invention, of the salts thereof, of the stereoisomers of the compounds of the invention and of the salts of the stereoisomers. Hydrates are a preferred example of said solvates.
  • the compounds according to the invention and the salts thereof include stereoisomers.
  • stereogenic centers exist in the group -A-CH 2 -B-:
  • Preferred compounds of formula (1 ) are those wherein the group -A-CH 2 -B- shows one of the following stereochemistries:
  • One group of particularly preferred compounds of formula (1 ) are those wherein the group -A-CH 2 -B-ShOWs one of the following stereochemistries:
  • Another group of particularly preferred compounds of formula (1 ) are those wherein the group -A-CH 2 -B- shows one of the following stereochemistries:
  • a further group of particularly preferred compounds of formula (1 ) are those wherein the group -A-CH 2 -B- shows one of the following stereochemistries:
  • the invention includes each of the possible stereoisomers indicated above in pure form as well as any mixture of these stereoisomers independent of the ratio.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from and R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is and R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from and R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is selected from
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is and R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ), wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ) wherein the group -A-CH 2 -B- is selected from
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ) wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • a further special embodiment of the compounds of the present invention includes those compounds of formula (1 ) wherein the group -A-CH 2 -B- is
  • R1 , R2 and R3 are as defined above, and the salts of these compounds.
  • the compounds according to the invention can be prepared as follows:
  • R1 , R2 and R3 have the abovementioned meanings can be prepared, for example, as shown in reaction Scheme 1.
  • R1 , R2 and R3 have the abovementioned meanings can be prepared, for example, as shown in reaction Scheme 2.
  • compounds of formula (1*) wherein R1 , R2 and R3 have the abovementioned meanings can be prepared by reaction of compounds of formula (3), wherein R1 and R2 have the abovementioned meanings with an isocyanate of formula (2), wherein R3 has the abovementioned meanings.
  • the reaction is preferably carried out in an anhydrous inert solvent, such as, for example, but not limited to dichloromethane, trichloromethane, tetrahydrofuran, dioxane, toluene, ethyl acetate or dimethylformamide at a temperature between O 0 C and the boiling point of the solvent being used, preferably between 20 and 3O 0 C.
  • the amino-compounds of formula (3) wherein R1 and R2 have the abovementioned meanings can be prepared from the corresponding azido-com pounds of formula (4) by a reduction process.
  • Suitable reduction systems are for example zinc in acetic acid, hydrogen over Pd/C in an inert solvent, P(OEt) 3 / HCI, Ph 3 P / H 2 O; preferably the conversion is carried out as a catalytic reduction with hydrogen over Pd/C in an inert solvent, such as for example, but not limited to methanol, ethanol or glacial acetic acid at room temperature.
  • the azido-compounds of formula (4), wherein R1 and R2 have the abovementioned meanings can be prepared by reaction of compounds of formula (6), wherein a suitable leaving group is attached to the 6-position, such as, for example TsO, MsO or iodine, with a benzyl-piperidine of formula (5), wherein R1 and R2 have the abovementioned meanings.
  • a suitable leaving group is attached to the 6-position
  • a benzyl-piperidine of formula (5) wherein R1 and R2 have the abovementioned meanings.
  • the leaving group is TsO.
  • the reaction is preferably carried out in an anhydrous inert solvent, such as, for example dimethylformamide, dimethylacetamide or N-m ethyl pyrrol idon at a temperature between O 0 C and the boiling point of the solvent being used.
  • Compounds of formula (6) with a suitable leaving group can be prepared from compounds of formula (7) wherein PG is a suitable hydroxyl protective group, such as, for example, tert- butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS) or dimethylthexylsilyl (TDS) by a PG cleavage/LG introduction reaction sequence.
  • TDMS tert- butyldimethylsilyl
  • TIPS triisopropylsilyl
  • TDS dimethylthexylsilyl
  • Reaction conditions for the cleavage of the suitable hydroxyl protective group and the introduction of the suitable leaving group depend on the particular hydroxyl protective group, respectively the particular leaving group; such reaction conditions are known to the person skilled in the art and can be found for example in Theodora V. Greene, Peter G. M.
  • the azido-group of the compounds of formula (7) wherein PG is a suitable hydroxyl protective group can be prepared from corresponding hydroxyl-com pounds of formula (8) by a nucleophilic substitution reaction.
  • the hydroxyl group of the compounds of formula (8) is activated by reaction with, for example, trifluoromethanesulfonic anhydride in the presence of a base, such as for example pyridine, triethylamine, ethyldiisopropylamine or lutidine in an inert anhydrous solvent like dichloromethane, trichloromethane, tetrahydrofuran or toluene at low temperatures between -5O 0 C and +1 O 0 C.
  • a base such as for example pyridine, triethylamine, ethyldiisopropylamine or lutidine in an inert anhydrous solvent like dichloromethane, trichloromethane, tetrahydro
  • the activated hydroxyl group is replaced in a nucleophilic substitution reaction by the azido-group;
  • the nucleophilic substitution reaction is carried out with sodium azide in an inert anhydrous solvent, such as, for example, dimethylformamide, dimethylacetamide or N-m ethyl pyrrol idon, preferably at temperatures between O 0 C and room temperature.
  • hydroxyl compounds of formula (8) wherein PG is a suitable hydroxyl protective group, such as, for example tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS) or dimethylthexylsilyl (TDS) can be prepared from the corresponding compounds of formula (9), wherein the primary hydroxyl group is unprotected.
  • Hydroxyl protective groups which are suitable to protect a primary hydroxyl group in the presence of a secondary hydroxyl group and the reaction conditions for their introduction are known to the person skilled in the art and can be found for example in Theodora V. Greene, Peter G. M. Wuts (eds.) Protective groups in Organic Synthesis 4rd ed 2007, John Wiley & Sons. Reaction conditions for the introduction of the TBDMS protective group are described in the experimental part of the present application.
  • R1 , R2 and R3 have the abovementioned meanings can be prepared, for example, as described in reaction scheme 4:
  • R1 , R2 and R3 have the abovementioned meanings can be prepared as described in reaction scheme 5.
  • the invention further relates to compounds of formulae (9), (15), (21 ) and (27) shown below, which are important intermediates in the process of preparing the compounds of formula (1 ) according to the invention as described above.
  • a further aspect of the present invention therefore is to provide novel intermediate compounds of formulae (9), (15), (21 ) and (27) as well as a process for their preparation.
  • the invention therefore also relates to a compound of formula (9)
  • the compound of formula (9) can be prepared as described in reaction scheme 6.
  • the invention as well relates to a compound of formula (15)
  • the compound of formula (15) can be prepared as described in reaction scheme 7.
  • the compound of formula (21 ) can be prepared as described in reaction scheme 8.
  • Salts of the compounds of formula (1 ) and the salts of the stereoisomers of the compounds of formula (1 ) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofurane or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as
  • the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds, which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • Pure stereoisomers of the compounds of formula (1 ) and the salts thereof according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
  • the pure stereoiomers of the invention are obtained by using chiral starting compounds in synthesis.
  • stereoisomeric mixtures can be split up into the pure stereoisomers by methods known to a person skilled in the art.
  • diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography.
  • Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent.
  • chiral auxiliary agents for example, chiral acids can be used to separate enantiomeric bases and chiral bases can be used to separate enantiomeric acids via formation of diastereomeric salts.
  • diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliary agents.
  • diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures.
  • enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
  • DIPEA N,N-Di-isopropylethylamine
  • reaction mixture is diluted with 250 ml aqueous HCI (1 M), the organic phase is separated and ex-tracted with a saturated aqueous solution of NaHCO 3 .
  • the combined organic phases are dried over Na 2 SO 4 and filtered.
  • To the filtrate 1140 ml (1.15 mol, 1 M solution in anhydrous THF) TBAF is added at O 0 C.
  • the reaction solution is diluted with 1000 ml water and extracted with 1000 ml dichloromethane (2 x).
  • the combined organic phases are dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the compounds of formula (1 ), the stereoisomers thereof, the salts of the compounds of formula (1 ) and the salts of the stereoisomers of the compounds of formula (1 ) are hereinafter referred to as compounds of the invention.
  • the compounds of the invention are pharmaceutically acceptable.
  • CCR3 modulators they are able to influence the physiological and pathophysiological function of various cells.
  • Those modulators are able to influence angiogenesis in vivo in animal eyes, particularly angiogenesis in mammals, e.g. mice or humans.
  • a certain form of angiogenesis comprises the invasion of the retina by choroidal neovascularisation (CNV).
  • a "ligand” is a molecule that binds to a receptor.
  • a “modulator” is a ligand that interacts with the receptor with the consequence to modulate the receptor activity or responsiveness to a ligand.
  • Modules as used herein is intended to encompass antagonists, agonists, partial antagonists, partial agonists, inverse agonists and/or co-agonists.
  • an "allosteric ligand” is a ligand that interacts with the receptor at a site distinct from the site recognized by an endogenous ligand, e. g. transmitter or hormone. On binding, the allosteric ligand can alter the constitutive activity of the receptor and can qualitatively or quantitatively influence the activity of orthosteric ligands in a non-competitive manner.
  • orthosteric ligand is a ligand that interacts with the receptor at a site that corresponds to or overlaps with the site recognized by the endogenous ligand.
  • Orthosteric ligands can compete with endogenous ligand for the receptor and can behave as agonists, inverse agonists or antagonists.
  • Antagonists are ligands with selective affinity for the active conformation of the receptor. Through stabilization of this active conformation, the agonists can promote induction of related intracellular responses.
  • Frull agonists as herein understood means agonists that are able to elicit a maximal response following receptor occupation and activation.
  • Partial agonists are agonists that can activate receptors but are unable to elicit the maximal response of the receptor system.
  • agonists or agonistic effects can be determined according to the "Eosinophil shape- change assay" disclosed in part "Biological Investigations” of this specification.
  • Antagonists interact with the receptor, and can thereby prevent binding of ligands, e. g. agonists.
  • the conformation of the receptor seems to be uninfluenced by the interaction.
  • antagonists exhibit affinity for the receptor but do not have intrinsic activity at the receptor and are neutral to any cellular action.
  • Antagonists that bind to the receptor in a manner that blocks essentially binding of agonists to the receptor are referred to as "competitive antagonists".
  • a key point about competitive antagonists is that like agonists, they bind in a reversible manner.
  • a ligand refers to its property to influence these responses differentially.
  • functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor.
  • a consequence of a functional selective agonism may be, for example, that a functional selective receptor internalizing agonist may result in functional inhibition of the receptor.
  • the compounds of the invention modulate CCR3 activity on cells that express the CCR3 receptor including eosinophils, basophils or endothelial cells, in particular choroidal endothelial cells (CECs), and sub-types of Th2 cells.
  • CECs choroidal endothelial cells
  • competitive antagonists inhibit the ligand-induced action of CCR3, including calcium-flux, receptor internalization, extracellular regulated kinase (ERK) activation and promotion of chemotaxis
  • CCR3 agonists activate one or more of these actions.
  • Partial antagonists inhibit the activity of an agonist while having intermediate to low intrinsic activity for one or more of these actions.
  • Inverse agonists downmodulate the constitutive and induced activity of CCR3 in unstimulated and stimulated cells.
  • Co-agonists provide an additive or synergistic effect to the effect of an agonist, e.g. by increasing the potency and/or the maximal efficacy of an agonist.
  • Co-agonists itself can have partial or full agonistic activity.
  • chemokines that act agonistic for CCR3 are induced at sites of a primary inflammatory response and build up a chemokine gradient that is used by CCR3 expressing cells to migrate towards the site of inflammation.
  • Prevention of the recruitment of CCR3 expressing cells by CCR3 modulators represents an important therapeutic target.
  • CNV choroidal neovascularisation
  • Compounds of the invention that contain a 4-piperidinyl substitution show on eosinophils at least partial agonistic effects when measured in functional eosinophil shape change assay, in the chemotaxis assay using transwell cell culture plates or in the CCR3 internalization assay.
  • a person skilled in the art is familiar with such assays, in particular it is known to a person skilled in the art how to establish, conduct and evaluate such assays.
  • the eosinophil shape change assay is disclosed in part "Biological investigations" of this specification.
  • Compounds of the invention that contain a 3-piperidinyl substitution show competitive antagonistic properties when measured in eosinophil shape change assay.
  • the compounds of the invention are distinguished by one or more valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half-life), absence of significant side effects, and further beneficial effects related with their therapeutic and pharmaceutical suitability.
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by modulation of the CC chemokine receptor 3 (CCR3) activity.
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases:
  • Respiratory diseases associated with inflammatory or allergic disorders including bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity, bronchial acute exacerbations, chronic bronchitis, acute respiratory distress syndrome, chronic obstuctive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis; • Inflammatory or allergic diseases, including allergic rhinitis and nasal polyposis;
  • Skin diseases associated with inflammatory or allergic disorders including pruritis, atopic dermatitis, eczema, psoriasis, dermatitis, erythema multiforma, scleroderma, hypersensitivity vasculitis, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus and pemphigus, pemphigus vulgaris and Hyper IgE syndrome; • Eye diseases associated with inflammatory or allergic disorders, including conjunctivitis;
  • Eye diseases associated with non-inflammatory disorders including angiogenetic disorders, which are comprising the invasion of the retina by choroidal neovascularisation (CNV), which are influenced by choroidal endothelial cells (CECs), e.g. age-related macular degeneration (AMD), in particular the so called wet form of AMD; • Intestinal diseases associated with inflammatory or allergic disorders, including inflammatory bowel disease, Crohn ' s disease, eosinophil-related disorders including eosinophilic esophagitis, eosinophilic gastroenteritis and eosinophilic pancreatitis;
  • CNV choroidal neovascularisation
  • AMD choroidal endothelial cells
  • AMD age-related macular degeneration
  • Intestinal diseases associated with inflammatory or allergic disorders including inflammatory bowel disease, Crohn ' s disease, eosinophil-related disorders including eosinophilic esophagitis, eosinophil
  • Systemic eosinophilic diseases including hypereosinophilia and Churg-Strauss-Syndrome; • Infections including HIV infection and influenza infection;
  • Cancer/leukemias including Hodgkin ' s disease, leukemia, lymphoproliferative disorder, renal cell carcinoma, colorectal cancer and cellular leiomyoma;
  • Autoimmune disease such as type I diabetes, thyroiditis, multiple sclerosis, vasculitic glomerulonephritis, rheumatic disease, osteoarthritis and atherosclerosis
  • Transplant rejection including rejection of cardiac allograft, skin allograft, lung transplants, liver transplant, corneal allograft, renal allograft and post-coronary artery bypass grafts;
  • Miscellaneous diseases including Kimura's disease, septic shock, parasitic disease, dementia, Alzheimer ' s disease, genital ulcer disease, encephalopathy, idiopathic inflammatory myopathies and drug-induced liver disease.
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of one or more of the following diseases: bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity, bronchial acute exacerbations, chronic bronchitis, acute respiratory distress syndrome, chronic obstuctive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis.
  • diseases bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity, bronchial acute exacerbations, chronic bronchitis, acute respiratory distress syndrome, chronic obstuctive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis.
  • COPD chronic obstuctive pulmonary disorder
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of allergic rhinitis.
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of skin diseases, such as, but not limited to atopic dermatitis, eczema, psoriasis and pruritis.
  • the invention relates to the compounds of the invention for use in the treatment and prophylaxis of intestinal diseases, such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis.
  • intestinal diseases such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis.
  • the compound of the invention for use in the treatment or prophylaxis of the abovementioned diseases is one of the examples or a pharmaceutically acceptable salt thereof.
  • the invention relates furthermore to the compounds for use in the treatment and prophylaxis of systemic eosinophilic diseases, such as, but not limited to hypereosinophilia and Churg-Strauss- Syndrome. Additionally, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of eye diseases, which are influenced by choroidal endothelial cells (CECs), e.g. wet age-related macular degeneration (AMD).
  • CECs choroidal endothelial cells
  • AMD wet age-related macular degeneration
  • the compounds of the invention are selected from one of the compounds that contain a 4-piperidinyl substitution.
  • Compounds that contain a 4-piperidinyl substitution and additionally a fluor substitution in 3-piperidinyl position are regarded as 4-piperidinyl substituted compounds in the herein presented invention, in particular these compounds can display an at least partial agonistic effect.
  • the 4-piperidinyl substituted compounds can comprise at least a partial agonistic effect on CC chemokine receptor 3.
  • these compounds comprise at least a partial CC chemokine receptor 3 internalizing effect.
  • the compounds are selected from one of the compounds that contain a 3-piperidinyl substitution.
  • the 3-piperidinyl substituted compounds comprise an antagonistic effect on CC chemokine receptor 3.
  • the invention also relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition modulating CC chemokine receptor 3 activity, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by modulation of the CC chemokine receptor 3 activity, preferably, a pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above.
  • the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of one or more of the following diseases: bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity, bronchial acute exacerbations, chronic bronchitis, acute respiratory distress syndrome, chronic obstuctive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis.
  • diseases bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity
  • bronchial acute exacerbations chronic bronchitis
  • acute respiratory distress syndrome chronic obstuctive pulmonary disorder (COPD)
  • COPD chronic obstuctive pulmonary disorder
  • idiopathic pulmonary fibrosis idiopathic pulmonary fibrosis.
  • the invention relates also to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of allergic rhinitis.
  • the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of dermatological diseases, such as, but not limited to atopic dermatitis, eczema, psoriasis and pruritis. Additionally, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of intestinal diseases, such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis.
  • dermatological diseases such as, but not limited to atopic dermatitis, eczema, psoriasis and pruritis.
  • intestinal diseases such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis.
  • the invention relates furthermore to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of a systemic eosinophilic disease, such as, but not limited to hypereosinophilia and Churg-Strauss-Syndrome.
  • a systemic eosinophilic disease such as, but not limited to hypereosinophilia and Churg-Strauss-Syndrome.
  • the invention relates furthermore to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of eye disorders, which are comprising the invasion of the retina by choroidal neovascularisation (CNV), which are influenced by choroidal endothelial cells (CECs), e.g. wet age-related macular degeneration (AMD).
  • CNV choroidal neovascularisation
  • CECs choroidal endothelial cells
  • AMD wet age-related macular degeneration
  • a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of the abovementioned diseases is carried out with one of the examples or a pharmaceutically acceptable salt thereof according to the present invention.
  • the invention further relates to a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention relates to a method of treating or preventing one of the above mentioned diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention relates to a method of treating or preventing a disease, which is alleviated by modulation of the CC chemokine receptor 3 activity comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention relates to a method of treating or preventing one or more of the following diseases: bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity, bronchial acute exacerbations, chronic bronchitis, acute respiratory distress syndrome, chronic obstuctive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • COPD chronic obstuctive pulmonary disorder
  • idiopathic pulmonary fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention also relates to a method of treating or preventing allergic rhinitis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the invention preferably relates to a method of treating or preventing skin diseases, such as, but not limited to, atopic dermatitis, eczema, psoriasis and pruritis, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • skin diseases such as, but not limited to, atopic dermatitis, eczema, psoriasis and pruritis
  • the invention preferably relates to a method of treating or preventing intestinal diseases, such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • intestinal diseases such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis
  • the invention furthermore relates to a method of treating or preventing a systemic eosinophilic disease, such as, but not limited to, hypereosinophilia and Churg-Strauss-Syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • a systemic eosinophilic disease such as, but not limited to, hypereosinophilia and Churg-Strauss-Syndrome
  • the invention furthermore relates to a method of treating or preventing eye disorders, which are comprising the invasion of the retina by choroidal neovascularisation (CNV), which are influenced by choroidal endothelial cells (CECs), e.g. wet age-related macular degeneration (AMD).
  • CNV choroidal neovascularisation
  • CECs choroidal endothelial cells
  • AMD wet age-related macular degeneration
  • the patient is preferably a mammal, more preferably a human.
  • at least one of the compounds of the invention can be used.
  • one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
  • the above methods of treating or preventing one of the above mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one of the examples or a pharmaceutically acceptable salt thereof according to the present invention.
  • the invention furthermore relates to a pharmaceutical composition which comprises at least one of the compounds of the invention together with at least one pharmaceutically acceptable auxiliary.
  • the pharmaceutical composition comprises one or two of the compounds of the invention. More preferably, the pharmaceutical composition comprises one of the compounds of the invention. In a particularly preferred embodiment of the invention, the pharmaceutical composition comprises one of the examples or a pharmaceutically acceptable salt thereof according to the present invention together with at least one pharmaceutically acceptable auxiliary.
  • the invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, modulating the CC chemokine receptor 3 activity, especially for the treatment or prophylaxis of diseases alleviated by modulation of the CC chemokine receptor 3 activity, in particular for the treatment or prophylaxis of the diseases exemplified above.
  • the invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of one or more of the following diseases: bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity, bronchial acute exacerbations, chronic bronchitis, acute respiratory distress syndrome, chronic obstruc- tive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis.
  • diseases bronchial asthma, chronic asthmatic disorders with reduced lung function and airway hyperreactivity, bronchial acute exacerbations, chronic bronchitis, acute respiratory distress syndrome, chronic obstruc- tive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis.
  • COPD chronic obstruc- tive pulmonary disorder
  • the invention also relates to pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of allergic rhinitis.
  • the invention relates to pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of skin diseases, such as, but not limited to, atopic dermatitis, eczema, psoriasis and pruritis.
  • skin diseases such as, but not limited to, atopic dermatitis, eczema, psoriasis and pruritis.
  • the invention relates to pharmaceutical compositions according to the invention, as defined above, for the treatment and prophylaxis of intestinal diseases, such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis.
  • intestinal diseases such as, but not limited to inflammatory bowel disease, Crohn's disease, eosinophilic esophagitis and eosinophilic gastroenteritis.
  • the invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, for the treatment and prophylaxis of a systemic eosinophilic disease, such as, but not limited to, hypereosinophilia and Churg-Strauss-Syndrome.
  • a systemic eosinophilic disease such as, but not limited to, hypereosinophilia and Churg-Strauss-Syndrome.
  • the invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, for the treatment and prophylaxis of eye disorders, which are comprising the invasion of the retina by choroidal neovascularisation (CNV), which are influenced by choroidal endothelial cells (CECs), e.g. wet age-related macular degeneration (AMD).
  • CNV choroidal neovascularisation
  • CECs choroidal endothelial cells
  • AMD wet age-related macular degeneration
  • therapeutic agents which are normally administered to treat or prevent that disease, may optionally be co-administered with the compounds of the invention.
  • at least one of the compounds of the invention is co-administered with at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin antagonists, type 4 phosphodiesterase inhibitors, theophylline, immunosuppressants, immune modulators, cytokine inhibitors, vitamin D analogues, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics and angiogenesis inhibitors.
  • the "therapeutic agent” includes the corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5- lipoxygenase inhibitors, endothelin antagonists, type 4 phosphodiesterase inhibitors, theophylline, immunosuppressants, immune modulators, cytokine inhibitors, vitamin D analogues, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics and angiogenesis inhibitors in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives, N-oxides etc.), the solvates (hydrates) thereof and the stereoisomers of the compounds, salts, derivatives and solvates.
  • the pharmaceutically acceptable salts thereof e.g., but not limited to, ester derivatives, N-oxides etc.
  • the solvates hydrates
  • at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin antagonists, type
  • a "fixed combination” is defined as a combination wherein the compound of the invention and the therapeutic agent intended for co-administration are present in one dosing unit or in a single entity.
  • a fixed combination is a pharmaceutical composition wherein the compound of the invention and the therapeutic agent are present in admixture for simultaneous administration.
  • a fixed combination is a pharmaceutical composition wherein the compound of the invention and the therapeutic compound are present in one dosing unit without being in direct admixture (for example, in form of pellets, which are filled in a capsule, whereby a part of the pellets contains the compound of the invention and another part of the pellets contains the therapeutic agent).
  • a "non-fixed combination” or “kit of parts” is defined as a combination wherein the compound of the invention and the therapeutic agent are present in more than one dosing unit.
  • the compound of the invention and the therapeutic compound are provided as separate formulations. They might be packaged and presented together as separate components of a combination pack for simultaneous, sequential or separate use in combination therapy. Simultaneous or sequential administration of the compound of the invention and the therapeutic agent are preferred. In case of sequential or separate administration of the compound of the invention and the therapeutic agent, the compound of the invention can be administered before or after administration of the therapeutic agent.
  • Sequential administration encompasses a short time period between the administration of the compound of the invention and the therapeutic agent or vice versa (for example, the time that is needed to swallow one tablet after the other).
  • Separate administration encompasses longer time periods between the administration of the compound of the invention and the therapeutic agent.
  • the compound of the invention is administered while the therapeutic agent (or vice versa) still has an therapeutic effect on the patient being treated.
  • at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenas
  • the type of formulation of the compound of the invention and the therapeutic agent of a non-fixed combination or a kit of parts can be identical, similar, i.e. both, the compound of the invention and the therapeutic agent are formulated in separate tablets or capsules, or can be different, i.e. suited for different administration forms, such as e.g. the compound of the invention is formulated as tablet or capsule and the therapeutic agent is formulated as powder, solution or suspension.
  • the invention additionally relates to a fixed combination, a non-fixed combination or kit of parts comprising at least one of the compounds of the invention, at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin antagonists, type 4 phosphodiesterase inhibitors, theophylline, immunosuppressants, immune modulators, cytokine inhibitors, vitamin D analogues, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics and angiogenesis inhibitors, and at least one pharmaceutically acceptable auxiliary.
  • at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endo
  • a compound of the invention and a therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin antagonists, type 4 phosphodiesterase inhibitors, theophylline, immune modulators, cytokine inhibitors, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics and angiogenesis inhibitors are particulary useful for the treatment or prophylaxis of inflammatory and allergic airway disorders, such as, but not limited to bronchial asthma, COPD and allergic rhinitis. Others are partcularly useful for the treatment or prophylaxis of dermatological diseases, such as, but not limited to, psoriasis and atopic dermatitis.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a corticosteroid and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and budesonide, a compound of the invention and fluticasone, a compound of the invention and beclometasone, a compound of the invention and mometasone, a compound of the invention and fluocinolone, preferably f I uocinolone acetonide, a compound of the invention and triamcinolone acetonide, or a compound of the invention and ciclesonide, and at least one pharmaceutically acceptable auxiliary.
  • the pharmaceutically acceptable derivative of fluticasone is fluticasone- 17-propionate.
  • the pharmaceutically acceptable derivative of beclometasone is beclometasone 17, 21-dipropionate ester.
  • the pharmaceutically acceptable derivative of mometasone is mometasone furoate.
  • the combination comprising a compound of the invention and a corticosteroid preferably is for the treatment and prophylaxis of bronchial asthma, COPD, allergic rhinitis, eosinophilic esophagitis, wet AMD or a dermatological disease, such as for example atopic dermatitis.
  • a dermatological disease such as for example atopic dermatitis.
  • the corticosteroid is used for intranasal, inhaled or (in case of a dermatological disease) transdermal ad- ministration; in severe cases, the corticosteroid may also be used orally.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), an anticholinergic and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and glycopyrronium bromide, a compound of the invention and aclidinium bromide, a compound of the invention and tiotropium bromide, or a compound of the invention and ipratropium bromide, and at least one pharmaceutically acceptable auxiliary.
  • the stereoisomer of glycopyrronium bromide is (R,R)-glycopyrronium bromide.
  • tiotropium bromide is used in form of its monohydrate.
  • the anticholinergic is for inhaled administration.
  • the combination comprising a compound of the invention and an anticholinergic is preferably for the treatment or prophylaxis of COPD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a ⁇ 2 -adrenoreceptor agonist and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and salbutamol, a compound of the invention and milveterol, a compound of the invention and indacaterol, a compound of the invention and carmoterol, a compound of the invention and salmeterol, a compound of the invention and formoterol, and at least one pharmaceutically acceptable auxiliary.
  • the pharmaceutically acceptable salt of salbutamol is salbutamol sul- fate.
  • the pharmaceutically acceptable salt of milveterol is milveterol hydrochloride.
  • the pharmaceutically acceptable salt of carmoterol is carmoterol hydrochloride.
  • the pharmaceutically acceptable salt of salmeterol is salmeterol xinafoate.
  • the pharmaceutically acceptable salt of formoterol is formoterol hemifumarate monohydrate.
  • the stereoisomer of formoterol is R,R-formoterol.
  • the pharmaceutically acceptable salt of R,R-formoterol is R,R-formoterol L-tartrate.
  • the ⁇ 2-adrenoreceptor agonist is a long-acting ⁇ 2-adrenoreceptor agonist; particularly preferred in this respect are those ⁇ 2-adrenoreceptor agonists having a therapeutic effect over a 12-24 hours period.
  • the combination comprising a compound of the invention and a ⁇ 2-adrenoreceptor agonist is for the treatment or prophylaxis of bronchial asthma and COPD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention), a H1 receptor antagonist and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non- fixed combination or kit of parts comprise: a compound of the invention and azelastine, a compound of the invention and olopatadine, a compound of the invention and loratadine, a compound of the invention and desloratadine, or a compound of the invention and cetirizine, and at least one pharmaceutically acceptable auxiliary.
  • the pharmaceutically acceptable salt of azelastine is is azelastine hydrochloride.
  • the pharmaceutically acceptable salt of olapatadine is ola- patadine hydrochloride.
  • the pharmaceutically acceptable salt of cetirizine is cetirizine dihydrochloride.
  • the stereoisomer of cetirizine is levo- cetirizine.
  • the pharmaceutically acceptable salt of levocetirizine is levocetirizine dihydrochloride.
  • the combination comprising a compound of the invention and a H1 receptor agonist or antagonist is preferably for the treatment or prophylaxis of allergic rhinitis or bronchial asthma.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention), a leukotriene receptor antagonist and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and montelukast, a compound of the invention and pranlukast, or a compound of the invention and zafirlukast, and at least one pharmaceutically acceptable auxiliary.
  • the pharmaceutically acceptable salt of montelukast is montelukast sodium.
  • pranlukast is used in form of its monohydrate.
  • the combination comprising a compound of the invention and a leukotriene receptor antagonist is preferably for the treatment or prophylaxis of bronchial asthma or allergic rhinitis.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a 5-lipoxygenase inhibitor and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and zileuton, and at least one pharmaceutically acceptable auxiliary.
  • the combination comprising a compound of the invention and a 5-lipoxygenase inhibitor is preferably for the treatment or prophylaxis of bronchial asthma.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), an endothelin antagonist and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and bosentan, a compound of the invention and ambrisentan, a compound of the invention and atrasentan, a compound of the invention and darusentan, a compound of the invention and clazosentan, or a compound of the invention and avosentan, and at least one pharmaceutically acceptable auxiliary.
  • bosentan is used in form of its monohydrate.
  • pharmaceutically acceptable salt of clazosentan is the disodium salt of clazosentan.
  • pharmaceutically acceptable salts of atrasentan are atrasentan hydrochloride or the sodium salt of atrasentan.
  • R-enantiomer of atrasentan is used.
  • S-enantiomer of darusentan is used.
  • the combination comprising a compound of the invention and an endothelin antagonist is preferably for the treatment or prophylaxis of bronchial asthma.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a type 4 phosphodi- esterase inhibitor and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and roflumilast, a compound of the invention and roflumilast-N-oxide, a compound of the invention and oglemilast, a compound of the invention and tipelukast, and at least one pharmaceutically acceptable auxiliary.
  • the combination comprising a compound of the invention and a type 4 phosphodiesterase inhibitor is preferably for the treatment or prophylaxis of bronchial asthma, COPD and wet AMD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), theophylline and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and theophylline, and at least one pharmaceutically acceptable auxiliary.
  • the combination comprising a compound of the invention and theophylline is preferably for the treatment or prophylaxis of bronchial asthma and COPD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), an immune modulator and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and omalizumab, or a compound of the invention and lumiliximab, and at least one pharmaceutically acceptable auxiliary.
  • the combination comprising a compound of the invention and one of the abovementioned immune modulators is preferably for the treatment or prophylaxis of bronchial asthma or eosinophilic esophagitis.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a cytokine inhibitor and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and suplatast, a compound of the invention and mepolizumab, a compound of the invention and etanercept, or a compound of the invention and maraviroc, and at least one pharmaceutically acceptable auxiliary.
  • suplatast is used in form of its tosilate salt.
  • the combination comprising a compound of the invention and one of the abovementioned cytokine inhibitors may be preferably used for the treatment or prophylaxis of bronchial asthma, allergic rhinitis, eosinophilic esophagitis or wet AMD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a HMG-CoA reductase inhibitor and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and lovastatin, a compound of the invention and pravastatin, a compound of the invention and simvastatin, a compound of the invention and atorvastatin, a compound of the invention and fluvastatin, a compound of the invention and rosuvastatin, a compound of the invention and pravastatin, a compound of the invention and bervastatin, a compound of the invention and dalvastatin, or a compound of the invention and glenvastatin, and at least one pharmaceutically acceptable auxiliary.
  • the pharmaceutically acceptable salts of pravastatin are the potassium, lithium, sodium and hemi-calcium salt of pravastatin.
  • a particularly preferred pharmaceutically acceptable salt of pravastatin is the sodium salt of pravastatin.
  • the phar- maceutically acceptable salt of simvastatin is the sodium salt of simvastatin.
  • the pharmaceutically acceptable salts of atorvastatin are the potassium, sodium and the hemi-calcium salt of atorvastatin.
  • a particularly preferred pharmaceutically acceptable salt of atorvastatin is the hemi-calcium salt of atorvastatin.
  • a hydrate of atorvastatin may be mentioned the trihydrate and the sesqui-hydrate of the hemi-calcium salt of atorvastatin.
  • the pharmaceutically acceptable salt of fluvastatin is the sodium salt of flu- vastatin.
  • the pharmaceutically acceptable salts of rosuvastatin are the potassium, lithium, sodium, hemi-magnesium and the hemi-calcium salt of rosuvastatin.
  • a particularly preferred pharmaceutically acceptable salt of rosuvastatin is the hemi-calcium salt of rosuvas- tatin.
  • Another particularly preferred pharmaceutically acceptable salt of rosuvastatin is the sodium salt of rosuvastatin.
  • the pharmaceutically acceptable salts of pitavas- tatin are the potassium, sodium and the hemi-calcium salt of pitavastatin.
  • a particularly preferred pharmaceutically acceptable salt of pitavastatin is the hemi-calcium salt of pitavastatin.
  • the combination comprising a compound of the invention and a HMG-CoA reductase inhibitor is preferably for the treatment or prophylaxis of COPD or wet AMD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention), a lung surfactant and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and lusupultide, a compound of the invention and poracant alfa, a compound of the invention and sinapultide, a compound of the invention and beracant, a compound of the invention and bovacant, a compound of the invention and colfosceril palmitate, a compound of the invention and surfactant-TA, or a compound of the invention and calfacant, and at least one pharmaceutically acceptable auxiliary.
  • the combination comprising a compound of the invention and a lung surfactant is preferably for the treatment or prophylaxis of bronchial asthma or COPD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), an antibiotic and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and amoxicillin, a compound of the invention and ampicillin, a compound of the invention and levofloxacin, a compound of the invention and clarithromycin, a compound of the invention and ciprofloxacin, a compound of the invention and telithromycin, or a compound of the invention and azithromycin, and at least one pharmaceutically acceptable auxiliary.
  • amoxicillin is used in form of its trihydrate.
  • ampicillin is used in form of its trihydrate.
  • the pharmaceutically acceptable salt of ampicillin is ampicillin natrium.
  • levofloxacin is used in form of its hemi hydrate.
  • the pharmaceutically acceptable salt of ciprofloxacin is ciprofloxacin hydrochloride monohydrate.
  • azithromycin is used in form of its monohydrate.
  • the combination comprising a compound of the invention and an antibiotic is preferably for the treatment or prophylaxis of exacerbations associated with bronchial asthma, COPD or wet AMD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), an angiogenesis in- hibitor and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and Pegaptanib, preferably Pegaptanib octasodium, a compound of the invention and Anecortave, preferably Anecortave acetate a compound of the invention and Ranibizumab, a compound of the invention and Aflibercept, a compound of the invention and Bevacizumab, a compound of the invention and Everolimus, a compound of the invention and Pazopanib, preferably Pazopanib hydrochloride, a compound of the invention and Vatalanib, preferably Vatalanib succinate, a compound of the invention and Sonepcizumab, or a compound of the invention and AGN 211745, and at least one pharmaceutically acceptable auxiliary.
  • the combination comprising a compound of the invention and an angiogenesis inhibitor is preferably for the treatment or prophylaxis of wet AMD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), an the following compounds and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and AL-8309B, a compound of the invention and Zinc compounds, preferably Zinc-monocysteine, a compound of the invention and Mecamylamine, preferably Mecamylamine hydrochloride, a compound of the invention and Brimonidine, preferably Brimonidine tartrate, or a compound of the invention and Sirolimus, and at least one pharmaceutically acceptable auxiliary.
  • the combination comprising a compound of the invention and AL-8309B, Zinc compounds, preferably Zinc-monocysteine, Mecamylamine, preferably Mecamylamine hydrochloride, Brimonidine, preferably Brimonidine tartrate, or Sirolimus is preferably for the treatment or prophylaxis of wet AMD.
  • Zinc compounds preferably Zinc-monocysteine, Mecamylamine, preferably Mecamylamine hydrochloride, Brimonidine, preferably Brimonidine tartrate, or Sirolimus is preferably for the treatment or prophylaxis of wet AMD.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a corticosteroid, a ⁇ 2 - adrenoceptor agonist and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention, budesonide and salbutamol, a compound of the invention, budesonide and milveterol, a compound of the invention, budesonide and indacaterol, a compound of the invention, budesonide and carmoterol, a compound of the invention, budesonide and salmeterol, a compound of the invention, budesonide and formoterol, a compound of the invention, fluticasone and salbutamol, a compound of the invention, fluticasone and milveterol, a compound of the invention, fluticasone and indacaterol, a compound of the invention, fluticasone and carmoterol, a compound of the invention, fluticasone and salmeterol, a compound of the invention, fluticasone and formoterol, a compound of the invention, beclometa
  • the pharmaceutically acceptable salt of salbutamol is salbutamol sulfate.
  • the pharmaceutically acceptable salt of milveterol is milveterol hydrochloride.
  • the pharmaceutically acceptable salt of carmoterol is carmoterol hydrochloride.
  • the pharmaceutically acceptable salt of sal- meterol is salmeterol xinafoate.
  • the pharmaceutically acceptable salt of formoterol is formoterol hemifumarate monohydrate.
  • the stereoisomer of formoterol is R,R-formoterol.
  • the pharmaceutically acceptable salt of R,R-formoterol is R,R-formoterol L-tartrate.
  • the pharmaceutically acceptable salt of fluticasone is fluticasone-17-propionate.
  • the pharmaceutically acceptable salt of beclometasone is beclometasone dipropion- ate.
  • the pharmaceutically acceptable salt of mometasone is mometasone furoate.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a ⁇ 2 -adrenoceptor agonist, an anticholinergic and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention, salbutamol and glycopyrronium bromide, a compound of the invention, salbutamol and aclidinium bromide, a compound of the invention, salbutamol and tiotropium bromide, a compound of the invention, salbutamol and ipratropium bromide, a compound of the invention, milveterol and glycopyrronium bromide, a compound of the invention, milveterol and aclidinium bromide, a compound of the invention, milveterol and tiotropium bromide, a compound of the invention, milveterol and ipratropium bromide, a compound of the invention, salmeterol and glycopyrronium bromide, a compound of the invention, salmeterol and aclidinium bromide, a compound of the invention, salmeterol and tio
  • the pharmaceutically acceptable salt of salbutamol is salbutamol sulfate.
  • the pharmaceutically acceptable salt of milveterol is milveterol hydrochloride.
  • the pharmaceutically acceptable salt of carmoterol is carmoterol hydrochloride.
  • the pharmaceutically acceptable salt of salmeterol is salmeterol xinafoate.
  • the pharmaceutically acceptable salt of formoterol is formoterol hemifumarate monohydrate.
  • the stereoisomer of formoterol is R,R-formoterol.
  • the pharmaceuti- cally acceptable salt of R,R-formoterol is R,R-formoterol L-tartrate.
  • the stereoisomer of glycopyrronium bromide is (R,R)-glycopyrronium bromide.
  • tiotropium bromide is used in form of its monohydrate.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a corticosteroid, an anticholinergic and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned fixed combination, non-fixed combination or kit of parts com- prise: a compound of the invention, budesonide and glycopyrronium bromide, a compound of the invention, budesonide and aclidinium bromide, a compound of the invention, budesonide and tiotropium bromide, a compound of the invention, budesonide and ipratropium bromide, a compound of the invention, fluticasone and glycopyrronium bromide, a compound of the invention, fluticasone and aclidinium bromide, a compound of the invention, fluticasone and tiotropium bromide, a compound of the invention, fluticasone and ipratropium bromide, a compound of the invention, beclometasone and glycopyrronium bromide, a compound of the invention, beclometasone and aclidinium bromide, a compound of the invention, beclometasone and
  • the pharmaceutically acceptable salt of fluticasone is fluticasone-17- propionate.
  • the pharmaceutically acceptable salt of beclometasone is beclometasone dipropionate.
  • the pharmaceutically acceptable salt of mometasone is mometasone furoate.
  • the stereoisomer of glycopyrronium bromide is (R,R)-glycopyrronium bromide.
  • tiotropium bromide is used in form of its monohydrate.
  • the abovementioned triple combinations may preferably be used in the treatment or prophylaxis of bronchial asthma or COPD.
  • Exemplary combinations in particular for transdermal administration (for example versus atopic dermatitis or psoriasis), may include a compound of the invention and an immunosuppressant, for example a calcineurin inhibitor, such as pimecrolimus or tacrolimus.
  • an immunosuppressant for example a calcineurin inhibitor, such as pimecrolimus or tacrolimus.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), an immunosuppressant and at least one pharmaceutically acceptable auxiliary.
  • the above mentioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and pimecrolimus, a compound of the invention and tacrolimus, a compound of the invention and methotrexate, a compound of the invention and ascomycin, or a compound of the invention and cyclosporin A, and at least one pharmaceutically acceptable auxiliary.
  • the externally topically (transdermal) administrable immunosuppressant can be administered or administrable in an external-topical composition separately from the compound of the invention (non-fixed combination or kit of parts) or it can be contained with the compound of the invention in a combined externally-topically administrable composition (fixed combination).
  • the externally topically administrable composition is a cream containing pimecrolimus at ca. 1 % w/w concentration.
  • the externally topically administrable composition is an ointment containing tacrolimus at from about 0.03% to about 0.1 % w/w concentration).
  • combinations for external topical adminstration in particular for the treatment or prophylaxis of atopic dermatitis and psoriasis, may include a compound of the invention and a corticosteroid. Beside the corticosteroid combinations mentioned above also the following corticosteroid combinations may be useful.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a corticosteroid and at least one pharmaceutically acceptable auxiliary.
  • the above mentioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and prednisolone, a compound of the invention and dexamethasone, a compound of the invention and clobetasol, a compound of the invention and betamethasone, or a compound of the invention and hydrocortisone, and at least one pharmaceutically acceptable auxiliary.
  • the abovementioned corticosteroids are used in form of an ester, such as, for example, prednisolone valerate acetate, hydrocortisone butyrate, hydrocortisone ace- tate, dexamethasone valerate, dexamethasone propionate, dexamethasone dipropionate, betamethasone butyrate propionate or prednisolone valerate acetate.
  • the pharmaceutically acceptable derivative of clobetasol is clobetasol propionate.
  • Further combinations for external topical (transdermal) administration in particular for the treatment of psoriasis, may include a compound of the invention and a vitamin D analogue.
  • the abovementioned fixed combination, non-fixed combination or kit of parts comprise a compound of the invention (in particular the compound of the invention is one of the examples of the invention or a pharmaceutically acceptable salt thereof), a vitamin D analogue and at least one pharmaceutically acceptable auxiliary.
  • the above mentioned fixed combination, non-fixed combination or kit of parts comprise: a compound of the invention and calcitriol, a compound of the invention and calcipotriol, or a compound of the invention and tacalcitol, and at least one pharmaceutically acceptable auxiliary.
  • compositions according to the invention if not indicated otherwise explicitly - preferably contain the compound or compounds of the invention in a total amount of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%.
  • the total amount of said therapeutic agent or therapeutic agents in the pharmaceutical compositions is - if not indicated otherwise explicitly - preferably in the range of from 0.1 to
  • auxiliaries any auxiliaries known to be suitable for preparing pharmaceutical compositions/formulations can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes.
  • auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
  • compositions/formulations can be formulated, for example, into tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions, for example eye drops), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
  • the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which the compound of the invention is coupled to monoclonal antibodies and systems in which the compound of the invention is coupled to polymers (e.g., but not limited to, soluble or biodegradable polymers).
  • compositions/formulations can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the selected formulation depends inter alia on the route of administering the pharmaceutical composition.
  • the pharmaceutical compositions/formulations of the invention can be administered by any suitable route, for example, by the oral, sublingual, buccal, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, topical, transdermal, intranasal, intraocular, intravitrial, intraperitoneal, intrasternal, intracoronary, transurethral, rectal or vaginal route, by inhalation or by insufflation. Oral administration of the compounds of the invention is preferred.
  • the compound of the invention and the therapeutic agent may be administered by the same route, e.g., without limitation, orally, or by different routes
  • compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin antagonists, type 4 phosphodiesterase inhibitors, theophylline, immunosuppressants, immune modulators, cytokine inhibitors, vitamin D analogues, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics, angiogenesis inhibitors, AL-8309B, Zinc compounds, preferably Zinc-monocysteine, Mecamylamine, preferably Mecamylamine hydrochloride, Brimonidine, preferably Brimonidine tartrate, or Sirolimus, the compound of the invention and the therapeutic agent may be formulated together into the same dosage form (e.g., but not limited to, tablets), separately into the same dosage form
  • Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration.
  • said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form.
  • Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the compound of the invention to a biodegradable polymer.
  • the aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
  • the aerosol may be generated by means of aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers.
  • the aerosol-producing device can contain the compound in form of a powder, a solution or a dispersion.
  • the powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers.
  • the solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings.
  • the dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings.
  • carriers include, but are not limited to, saccharides, e.g. lactose and glucose.
  • propellants include, but are not limited to, fluorohydrocarbons, e.g. 1 ,1 ,1 ,2- tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the particle size of the aerosol particles is preferably less than 100 ⁇ m, more preferably it is in the range of from 0.5 to 10 ⁇ m, in particular in the range of from 2 to 6 ⁇ m (D50 value, measured by laser diffraction).
  • Aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Novolizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers.
  • the aerosol- producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
  • suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
  • parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, intraperitoneal and intrasternal administration
  • solutions e.g., but not limited to, sterile solutions, isotonic solutions
  • they are preferably administered by injection or infusion techniques.
  • sprays and solutions to be applied in drop form are preferred formulations.
  • solutions to be applied in drop form, gels and ointments are exemplified formulations.
  • at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin antagonists, type 4 phosphodiesterase inhibitors, theophylline, immunosuppressants, immune modulators, cytokine inhibitors, vitamin D analogues, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics, angiogenesis inhibitors, AL-8309B, Zinc compounds, preferably Zi nc- monocysteine, Mecamylamine, preferably Mecamylamine hydrochloride, Brimonidine, preferably Brimonidine tartrate, or Sirolimus, in form of a fixed combination, non
  • the pharmaceutical compositions according to the invention can be administered such that the dose of the compound of the invention is in the range customary for CC chemokine receptor 3 modulators.
  • a dose in the range of from 0.05 to 500 mg, preferably 0.1 to 200 mg of the compound of the invention per day is preferred for an average adult patient having a body weight of 70 kg.
  • the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination.
  • the pharmaceutical composition can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day.
  • a single dose unit of the pharmaceutical composition can contain e.g. from 0.05 mg to 500 mg, preferably 0.1 mg to 200 mg, more preferably 0.1 to 100 mg, most preferably 0.1 to 10 mg, of the compound of the invention.
  • At least one compound of the invention and at least one therapeutic compound selected from the group consisting of corticosteroids, anticholinergics, ⁇ 2 -adrenoreceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, endothelin antagonists, type 4 phosphodiesterase inhibitors, theophylline, immunosuppressants, immune modulators, cytokine inhibitors, vitamin D analogues, HMG-CoA reductase-inhibitors, lung surfactants, antibiotics, angiogenesis inhibitors, AL-8309B, Zinc compounds, preferably Zinc-monocysteine, Mecamylamine, preferably Mecamylamine hydrochloride, Brimonidine, preferably Brimonidine tartrate, or Sirolimus, in form of a fixed combination, a non-fixed combination or a kit of parts a single dose unit of the respective pharmaceutical composition/formulation can contain e.g.
  • the at least one compound of the invention and the at least one therapeutic agent are present in the pharmaceutical compositions/formulations in a weight ratio of from 1000:1 to 1 :1000, more preferably in a weight ratio of from 100:1 to 1 :100, even more preferably in a weight ratio of from 25:1 to 1 :25.
  • the pharmaceutical composition may be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using the compound of the invention in form of a sparingly soluble salt or by using the compound of the invention coupled to a polymer.
  • an implant e.g. a subcutaneous or intramuscular implant
  • the compound of the invention in form of a sparingly soluble salt or by using the compound of the invention coupled to a polymer.
  • Isolated human peripheral blood polymorphnuclear granulocytes were resuspended in assay buffer [PBS (Dulbecco); 10 mM HEPES, 10 mM Glucose, 0.1% BSA (pH7.4)] to a concentration of 1x10Exp7/ml.
  • assay buffer PBS (Dulbecco); 10 mM HEPES, 10 mM Glucose, 0.1% BSA (pH7.4)
  • concentration of 1x10Exp7/ml In a 96-well plate 1 ⁇ l test compound in 10 different concentrations was mixed with 100 ⁇ l assay buffer. 10 ⁇ l of the diluted compound was added to 50 ⁇ l 18nM eotaxin coupled to AlexaFluor647 (Dictagene, Swiss, now available by ALMAC Biosciences, UK; Cat. No.
  • Percent control binding was assessed by substracting the unspecific binding from each well and then expressing the number of fluorescent units associated with the compound treated sample as a percent of the control binding in the absence of compound addition. IC50 values have been calculated by GraphPad Prism 4.0 Software. The assay was performed 4 times with cells of 4 different donors each in duplicates.
  • Examples 1 to 32 showed, when tested in the above-described assay system, an inhibition of the eotaxin binding on eosinophils [measured as -loglC 50 (mol/l)] in the range from 6.6 to 8.9.
  • Examples 4, 6, 17 and 18 were in the range from 7.3 to 7.8.
  • agonistic activity An increase of cell shape change of at least about 20 %, induced by a certain compound compared to the maximal cell shape change induced by eotaxin, was considered as "agonistic activity”.
  • a maximal increase below the treshold of about 20 % cell shape change was considered as "no agonistic activity”.
  • the samples were analysed on a FACS Array (BD Biosciences) by absorption of laser light in the forward scatter of at least 1000 gated autofluorescent eosinophiles from which the median value was used.
  • the control sample that contains DMSO without eotaxin was set to 100% inhbition and the sample containing DMSO with eotaxin as 0% inhibition.
  • Examples 4, 6, 17 and 18 were in the range of 40 % to 100 %.
  • Examples 4, 17 and 18 were used in a maximal concentration of 10 nM, example 6 in a maximal concentration of 100 nM, respectively, which means that those compounds displayed agonistic activity.
  • Eosinophilia is established by intraperitoneal stimulation with recombinant mouse Eotaxin (in saline for injection + 0.25% HSA + 1 % Carboxymethylcellulose (CMC, low viscosity, BDH, VWR Interna- tional Ltd., Poole, England), [10ml/kg]) in transgenic mice harbouring the coding sequence of human CCR3 instead of the murine CCR3 coding sequence.
  • 1.5 mg/kg body weight eotaxin solution is injected into the peritoneal cavity in a volume of 10ml/kg.
  • Test substances are administered per os 1 h before eotaxin stimulation. 6 h after eotaxin stimulation animals are euthanized by cervical dislocation.
  • Peritoneal lavage is performed by injection of 4 ml PBS (containing 2mM EDTA) and retrival of the lavage fluid with 14 G plastic cannulae.
  • the lavages are analysed by cellular differentiation of eosinophils and determination of total eosinophil number using an automated hematology analyzer (Sysmex XT-2000iV).
  • Ovalbumin (OVA) sensitisation and challenge with aerolised Ovalbumin results in eosinophilia in bronchoalveolar lavage.
  • Ovalbumin induced eosinophilia is established in transgenic mice harbouring the coding sequence of human CCR3 instead of the murine CCR3 coding sequence by sensitisation with 10 ⁇ g OVA/lmject Alum (i.p. at day 1 , 14, 21 ) and a challenge with aerolised OVA at day 26 and 27 for 1 hour.
  • Test substances are administered 1 h before and 5 h after each chal- lenge at day 26 and 27.
  • animals are euthanized by i.v. Narcoren/Heparin [60/17 mg/kg] injection.
  • a midline skin incision over the sternum and a small incision between two trachea rings is performed.
  • a 2OG plastic cannulae reduced to a length of 1 cm is introduced into the trachea.
  • the broncho-alveolar lavage is performed by two injections of 0.8 ml 0.9% NaCI into the trachea and retrival of the lavage fluid.
  • the lavages are analysed by cellular differentiation of eosinophils and determination of total eosinophil number using an automated hematology analyzer (Sysmex XT-2000iV).

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Abstract

La présente invention concerne des composés de formule (1) dans laquelle A, B, R1, R2 et R3 ont les significations telles que données dans la description, leurs stéréo-isomères ainsi que les sels de leurs stéréo-isomères qui sont des modulateurs efficaces du CCR3.
PCT/EP2009/067247 2008-12-16 2009-12-16 Dérivés de pyrane en tant que modulateurs du ccr3 Ceased WO2010069979A1 (fr)

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US20160081998A1 (en) * 2012-04-03 2016-03-24 Boehringer Ingelheim International Gmbh Use of ccr3-inhibitors
EP3050574A1 (fr) 2015-01-28 2016-08-03 Universite De Bordeaux Nouvelles compositions et méthodes de traitement et/ou de prévention d'une maladie pulmonaire obstructive chronique

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160081998A1 (en) * 2012-04-03 2016-03-24 Boehringer Ingelheim International Gmbh Use of ccr3-inhibitors
AU2013245027B2 (en) * 2012-04-03 2017-10-12 Alkahest, Inc. Use of CCR3-inhibitors
WO2014075124A1 (fr) * 2012-11-15 2014-05-22 Victoria University Procédés et compositions pour le traitement et/ou la prévention de troubles intestinaux
EP3050574A1 (fr) 2015-01-28 2016-08-03 Universite De Bordeaux Nouvelles compositions et méthodes de traitement et/ou de prévention d'une maladie pulmonaire obstructive chronique
EP3613435A1 (fr) 2015-01-28 2020-02-26 Universite De Bordeaux Inhibiteurs du recepteur cxcr4 pour le traitement et/ou la prévention d'une maladie pulmonaire obstructive chronique

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