RU2003103097A - PIPERIDINE DERIVATIVES INTENDED FOR USE AS CCR-3 INHIBITORS - Google Patents

Claims (12)

1. The compound of the formula

in free form or in salt form, where Ar ¹ is phenyl substituted with one or more halogen atoms, Ar ² is phenyl or naphthyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ alkoxy or C ₁ -C ₈ alkoxycarbonyl, R ¹ is hydrogen or C ₁ -C ₈ alkyl optionally substituted with hydroxy, C ₁ -C ₈ alkoxy, acyloxy, -N (R ² ) R ³ , halogen, carboxy, C ₁ -C ₈ alkoxycarbonyl, -CON ( R ⁴ ) R ⁵ or a monovalent cyclic organic group, R ² and R ^{3 are} each independently hydrogen or C ₁ -C ₈ alkyl, or R ² is hydrogen and R ³ is acyl or —SO ₂ R ⁶ , or R ² and R ³ together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocyclic group, R ⁴ and R ⁵ each independently of one another is hydrogen or C ₁ -C ₈ alkyl, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group, R ⁶ is C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or phenyl optionally substituted with C ₁ -C ₈ alkyl, and n is 1, 2, 3 or 4, with the proviso that when Ar ¹ is para-chlorophenyl and R ¹ is hydrogen, then Ar ^{2 is} not phenyl or para-nitrophenyl. 2. The compound according to claim 1, where Ar ² denotes monosubstituted phenyl, the substituent of which is halogen, cyano, nitro or C ₁ -C ₄ alkoxygroup; or disubstituted phenyl, the substituents of which are selected from the group consisting of halogen, cyano, hydroxy, nitro, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl; or trisubstituted phenyl, the substituents of which are selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkoxycarbonyl; or pentasubstituted phenyl, the substituents of which are halogen atoms. 3. The compound according to claim 1, where R ¹ is C ₁ -C ₄ alkyl, optionally optionally substituted with hydroxy, C ₁ -C ₈ alkoxy, acyloxy, halogen, carboxy, C ₁ -C ₈ alkoxycarbonyl, - CON (R ⁴ ) R ⁵ or a monovalent cyclic organic group. 4. The compound according to claim 1, where Ar ¹ is phenyl substituted with fluorine or chlorine in the para position relative to the specified carbonyl group and optionally further substituted with halogen in the ortho position relative to the specified carbonyl group, Ar ² is phenyl monosubstituted with a substituent selected from the group consisting of halogen, cyano, nitro and C ₁ -C ₄ alkoxy, phenyl substituted with two substituents, which may be the same or different, selected from the group consisting of halogen, cyano, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl and nitro or phenyl substituted with three substituents, which may be the same or different, selected from the group consisting of halogen, hydroxy, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkoxycarbonyl, R ¹ is hydrogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyl substituted with a hydroxy group, C ₃ -C ₈ cycloalkyl, phenyl, phenyl, substituted with a C ₁ -C ₄ alkylsulfonylamino group, or a 5 or 6 membered heterocyclic aromatic a group carrying one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and n is 1 or 2. 5. The compound according to claim 1, where Ar ¹ denotes phenyl substituted by fluorine or chlorine in the para position relative to the specified carbonyl group, Ar ² is phenyl substituted in the ortho position relative to the indicated —CH═CH group with a C ₁ -C ₄ alkoxy group and in the para position relative to the C ₁ -C ₄ alkoxy group by a cyano group, halogen or a C ₁ -C ₄ alkoxy group, R ¹ is C ₁ -C ₄ alkyl substituted with a hydroxy group, phenyl, phenyl substituted with a C ₁ -C ₄ alkylsulfonylamino group, or a 5 or 6 membered heterocyclic aromatic group carrying one or two ring heteroatoms selected from nitrogen, oxygen and sulfur , and n is 1. 6. The compound of the formula

in free or salt form, where Ra ’is hydrogen and Ra, Rb, Rc, Rd, Re, Rf and Rf have the meanings indicated in the following table

or where Ra and Ra ’are fluorine, Rb, Rd, Re and Rg are hydrogen, Rc is methoxy and Rf is bromo. 7. The compound according to any one of the preceding paragraphs in combination with an anti-inflammatory, bronchodilator or antihistamine drug. 8. The compound according to any one of the preceding paragraphs, intended for use as a pharmaceutical agent. 9. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 7, optionally in combination with a pharmaceutically acceptable diluent or carrier. 10. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of a condition mediated by CCR-3. 11. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of an inflammatory or allergic condition, especially an inflammatory or obstructive airway disease. 12. A method of obtaining compounds of formula I, comprising (I) (A) the interaction of the compounds of formula

with a compound of the formula

or with its amide-forming derivative, where Ar ¹ , Ar ² , R ¹ and n are as defined above, or (B) reacting a compound of formula III or an amide derivative thereof with a compound of formula

where Ar ¹ , R ¹ and n are as defined above and Z is a solid phase substrate chemically bonded to said nitrogen atom and the cleavage of the resulting product from the substrate to replace Z with hydrogen; and (Ii) isolating the product in free or salt form.