2-phenoxy- and 2-phenylsulfonamide derivatives with CCR3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders

1. A compound of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof:

wherein

X represents O or S;

R 1 represents hydrogen, halogen, hydroxy, nitro, cyano, C 1-6 alkoxy carbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkanoyl, phenyl, C 1-6 alkyl optionally substituted by mono-, di- or tri-halogen, or C 1-6 alkoxy optionally substituted by mono-, di- or tri-halogen;

R 2 represents hydrogen, halogen, hydroxy, nitro, cyano, C 1-6 alkoxy carbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkanoyl, phenyl, C 1-6 alkyl optionally substituted by mono-, di- or tri-halogen, or C 1-6 alkoxy optionally substituted by mono-, di- or tri-halogen;

R 3 represents hydrogen, halogen, hydroxy, nitro, cyano, amino, carboxy, tetrazolyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkanoyl, C 1-6 alkanoylamino, C 1-6 alkyl optionally substituted by mono-, di- or tri-halogen or hydroxy;

R 4 represents

wherein:

R 71 represents hydrogen, or C 1-6 alkyl optionally substituted by amino, hydroxy, carboxy, pyrrolidinyl or piperidinyl, wherein said pyrrolidinyl and piperidinyl are optionally substituted by mono- or di-oxo;

R 72 represents hydrogen, carboxy, C 1-6 alkanoyl, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, N-(C 1-6 alkyl)amino carbonyl, C 1-6 alkyl optionally substituted by hydroxy, carboxy, or mono-, di- or tri-halogen, C 1-6 alkoxy optionally substituted by mono-, di- or tri-halogen, pyrrolidinyl or piperidinyl, wherein said pyrrolidinyl and piperidinyl are optionally substituted by mono- or di-oxo; and

Z 1 represents —[CH 2 ] p —, wherein p is 2.

2. The compound of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 ,

wherein R 4 represents

wherein:

R 72 represents hydrogen, carboxy, C 1-6 alkanoyl, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, N—(C 1-6 alkyl)amino carbonyl, C 1-6 alkyl optionally substituted by hydroxy, carboxy, or mono-, di- or tri-halogen, C 1-6 alkoxy option substituted by mono-, di- or tri-halogen, pyrrolidinyl or piperidinyl wherein said pyrrolidinyl and piperidinyl are optionally substituted by mono- or di-oxo.

3. The compound of claim 1 , wherein the derivative is of the formula (I-b), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof:

wherein:

R 1 represents fluoro, chloro, bromo, iodo, or nitro;

R 2 represents fluoro, chloro, bromo, iodo, or nitro;

R 3 represents acetyl, cyano, or tetrazolyl;

R 4 represents

wherein:

R 71 represents hydrogen, or C 1-6 alkyl optionally substituted by amino, hydroxy, carboxy, pyrrolidinyl or piperidinyl, wherein said pyrrolidinyl and piperidinyl are optionally substituted by mono- or di-oxo;

R 72 represents hydrogen, carboxy, C 1-6 alkanoyl, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, N—(C 1-6 alkyl)amino carbonyl, C 1-6 alkyl optionally substituted by hydroxy, carboxy, or mono-, di- or tri-halogen, C 1-6 alkoxy optionally substituted by mono-, di- or tri-halogen, pyrrolidinyl or piperidinyl, wherein said pyrrolidinyl and piperidinyl are optionally substituted by mono- or di-oxo; and

Z 1 represents —[CH 2 ] p —, wherein p is 2.

4. The compound of claim 3 , its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof,

wherein:

R 1 represents fluoro, chloro or bromo;

R 2 represents fluoro, chloro or bromo;

R 3 represents cyano;

R 4 represents

wherein:

R 72 represents hydrogen, carboxy, C 1-6 alkanoyl, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, N—(C 1-6 alkyl)amino carbonyl, C 1-6 alkyl optionally substituted by hydroxy, carboxy, or mono-, di- or tri-halogen, C 1-6 alkoxy optionally substituted by mono-, di- or tri-halogen, pyrrolidinyl or piperidinyl wherein said pyrrolidinyl and piperidinyl are optionally substituted by mono- or di-oxo.

5. A compound of claim 1 , its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof, wherein said compound is selected from the group consisting of:

(R)-N-(1-Aza-bicyclo[2.2.2]oct-3-yl)-5-cyano-2-(3,5-dichloro-phenoxy)-benzenesulfonamide;

(S)-N-(1-Aza-bicyclo[2.2.2]oct-3-yl)-5-cyano-2-(3,5-dichloro-phenoxy)-benzenesulfonamide;

N-(1-aza-bicyclo[2.2.2]oct-3-yl)-2-(3,5-dichloro-phenylsulfanyl)-5-nitro-benzenesulfonamide; and

(R)-5-cyano-2-(3,5-dichlorophenoxy)-N-(2-(2,5-dioxopyrrolidin-1-yl)ethyl)-N-(1-aza-bicyclo[2.2.2]oct-3-yl)benzenesulfonamide.

6. A pharmaceutical composition comprising a compound of claim 1 , its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients.

7. A method of treating asthma, allergic rhinitis or lung granuloma, comprising administering a compound of claim 1 or its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.

8. The method of claim 7 , wherein said compound, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is formulated with one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition of claim 6 wherein the excipient is an inert substance selected from the group consisting of a carrier, a diluent, a flavoring agent, a sweetener, a lubricant, a solubilizer, a suspending agent, a binder, a tablet disintegrating agent and an encapsuling agent.

10. The method of claim 8 wherein the excipient is an inert substance selected from the group consisting of a carrier, a diluent, a flavoring agent, a sweetener, a lubricant, a solubilizer, a suspending agent, a binder, a tablet disintegrating agent and an encapsuling agent.