Omega-aminoalkylamides of r-2-aryl-propionic acids as inhibitors of the chemotaxis of polymorphonucleate and mononucleate cells

Abstract

(R)-2-Arylpropionamide compounds of formula (I) are described. The process for their preparation and pharmaceutical preparations thereof are also described. The 2-Arylpropionamides of the invention are useful in the prevention and treatment of tissue damage due to the exacerbate recruitment of polymorphonuclear leukocytes (leukocytes PMN) and of monocytes at the inflammatory sites. In particular, the invention relates to the R enantiomers of omega-aminoalkylamides of 2-aryl propionic acids, of formula (I), for use in the inhibition of the chemotaxis of neutrophils and monocytes induced by the C5a fraction of the complement and by other chemotactic proteins whose biological activity is associated with activation of a 7-TD receptor. Selected compounds of formula (I) are dual inhibitors of both the C5a-induced chemotaxis of neutrophils and monocytes and the IL-8-induced chemotaxis of PMN leukocytes. The compounds of the invention are used in the treatment of psoriasis, ulcerative cholitis, glomerular nephritis, acute respiratory insufficiency, idiopathic fibrosis, rheumatoid arthritis and in the prevention and the treatment of injury caused by ischemia and reperfusion.

1 . A method for treating psoriasis, pemphigus and pemphigoid, rheumatoid arthritis, intestinal chronic inflammatory pathologies including ulcerative colitis, acute respiratory distress syndrome, idiopathic fibrosis, cystic fibrosis, chronic obstructive pulmonary disease or glomerulonephritis, comprising administering to a patient in need thereof an effective amount of a (R)-2-Aryl-propionamide compound of formula (I):  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein  
       Ar represents a substituted or non-substituted aryl group;  
       R represents hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, optionally substituted by a CO 2 R 3  group, wherein R 3  represents hydrogen or a linear or branched C 1 -C 6  alkyl group or a linear or branched C 2 -C 6  alkenyl group;  
       X represents  
       a linear or branched C 1 -C 6  alkylene, C 4 -C 6  alkenylene, C 4 -C 6  alkynylene, optionally substituted by a CO 2 R 3  group or by a CONHR 4  group wherein R 4  represents hydrogen, linear or branched C 2 -C 6  alkyl or an OR 3  group, R 3  being defined as above;  
       a (CH 2 ) m —B—(CH 2 ) n , group, optionally substituted by a CO 2 R 3  or CONHR 4  group, as defined above, wherein B is an oxygen or sulfur atom, m is zero or an integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n is an integer from 2 to 3;  
       or X together with the nitrogen atom of the omega-amino group to which it is bound and with the R 1  group forms a non-aromatic nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring wherein the nitrogen atom has a substituent Rc, where Rc represents hydrogen, C 1 -C 4  alkyl, C 1 -C 4  hydroxylalkyl, C 1 -C 4  acyl, substituted or non-substituted phenyl, diphenylmethyl;  
       R 1  and R 2  are independently hydrogen, linear or branched C 1 -C 6  alkyl, optionally interrupted by an O or S atom, a C 3 -C 7  cycloalkyl, C 3 -C 6  alkenyl, C 3 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, hydroxy-C 2 -C 3 -alkyl group;  
       or R 1  and R 2  together with the N atom to which they are bound, form a nitrogen containing 3-7 membered heterocyclic ring of formula (II)  
       
         
           
           
               
               
           
         
       
       wherein Y represents a single bond, CH 2 , O, S, or a N-Rc group as defined above and p represents an integer from 0 to 3;  
       or, R 1  being as defined above, R 2  represents a group of formula (III):  
       
         
           
           
               
               
           
         
       
       wherein R a  is hydrogen and R b  is hydrogen, hydroxy, C 1 -C 4 -alkyl or an NR d R e  group wherein R d  and R e  are independently hydrogen, C 1 -C 4 -alkyl or phenyl;  
       or R a  and R b , together with the nitrogen atoms to which they are bound, form a 5-7 membered heterocyclic ring, monocyclic or fused with a benzene, pyridine or pyrimidine ring;  
       with the proviso that when Ar is 4-diphenyl and X is (CH 2 ) 2  or (CH 2 ) 3 , R 1  and R 2  are not ethyl;  
       with the further proviso that, when Ar is a 4-(2-fluoro)diphenyl residue, and X is butylene substituted by a CO 2 H group, R a  and R b  are not hydrogen;  
       and with the further proviso that, when Ar is phenyl and X is butylene, R 1  and R 2  together are not a N-(2-methoxy phenyl)piperazine.  
     
   
   
       2 . The method of  claim 1  in which in the compound of the formula (I): 
 Ar represents a substituted or non-substituted aryl group;    R represents hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, optionally substituted by a CO 2 R 3  group, wherein R 3  represents hydrogen or a linear or branched C 1 -C 6  alkyl group or a linear or branched C 2 -C 6  alkenyl group;    X represents:    a linear or branched C 1 -C 6  alkylene, C 4 -C 6  alkenylene, C 4 -C 6  alkynylene, optionally substituted by a CO 2 R 3  group or by a CONHR 4  group wherein R 4  represents hydrogen, linear or branched C 2 -C 6  alkyl or an OR 3  group, R 3  being defined as in  claim 1;     a (CH 2 ) m —B—(CH 2 ) n , group, optionally substituted by a CO 2 R 3  or CONHR 4  group, as defined above, wherein B is an oxygen or sulfur atom, m is zero or an integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n is an integer from 2 to 3;    or X together with the nitrogen atom of the omega-amino group to which it is bound and with the R 1  group forms a non-aromatic nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring wherein the nitrogen atom has a substituent Rc, where Rc represents hydrogen, C 1 -C 4  alkyl, C 1 -C 4  hydroxylalkyl, C 1 -C 4  acyl, substituted or non-substituted phenyl, diphenylmethyl;    R 1  and R 2  are independently hydrogen, linear or branched C 1 -C 6  alkyl, optionally interrupted by an O or S atom, a C 3 -C 7  cycloalkyl, C 3 -C 6  alkenyl, C 3 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl or hydroxy-C 2 -C 3 -alkyl group;    or R 1  and R 2  together with the N atom to which they are bound, form a 3-7 membered nitrogen heterocyclic ring of formula (II)                          wherein Y represents a single bond, CH 2 , O, S, or a N-Rc group as defined above and p represents an integer from 0 to 3;    or, R 1  being as defined above, R 2  represents a group of formula (III):                          wherein R a  is hydrogen and R b  is hydrogen, hydroxy, C 1 -C 4 -alkyl or an NR d R e  group wherein R d  and R e , are each independently, hydrogen, C 1 -C 4 -alkyl or phenyl;    or R a  and R b , together with the nitrogen atoms to which they are bound, form a 5-7 membered heterocyclic ring, monocyclic or fused with a benzene, pyridine or pyrimidine ring;    said compound of the formula (I) having activity of inhibiting C5a-induced chemotaxis of polymorphonucleate leukocytes and monocytes.    
   
   
       3 . The method of  claim 1 , in which in the formula (I), Ar is selected from the group consisting of: 
 a) an Ara mono- or poly-substituted aryl group of (±)2-aryl-propionic acids selected from alminoprofen, benoxaprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, R-naproxen, pirprofen, dehydropirprofen, dihydropirprofen, pranoprofen, surprofen, tiaprofenic acid and zaltoprofen;    b) an aryl-hydroxymethyl-aryl group of formula (IVa), both as diastereoisomeric mixture and as single S′ and/or R′ diastereoisomers                          wherein, when Ar 2  is phenyl Ar 1  is selected from the group consisting of phenyl and thien-2-yl while when Ar 1  is phenyl, Ar 2  is selected from the group consisting of phenyl, 4-thienyl and pyridyl;    c) an aryl group of formula (IVb):      Φ-Ar b   (IV b)    wherein    Ar b  is phenyl that is mono- and poly-substituted by hydroxy, mercapto, C 1 -C 3 -alcoxy, C 1 -C 3 -alkylthio, chlorine, fluorine, trifluoromethyl, nitro, amino, C 1 -C 7 -acylamino optionally substituted; and Φ is hydrogen or a linear or branched C 1 -C 5  alkyl, C 2 -C 5 — alkenyl or C 2 -C 5 — alkynyl residue optionally substituted by C 1 -C 3 -alkoxycarbonyl, substituted or non-substituted phenyl, 2-, 3- or 4-pyridyl, quinolin-2-yl; a C 3 -C 6 -cycloalkyl; 2-furyl; 3-tetrahydrofuryl; 2-thiophenyl; 2-tetrahydrothiophenyl or a residue of formula (IVc)      Φ—(CH 2 ) q -  (IVc)    wherein A is a C 1 -C 5 -dialkylamino group, a C 1 -C 8 -(alkanoyl, cycloalkanoyl, arylalkanoyl)-C 1 -C 5 -alkylamino group; a nitrogen containing 5-7 membered monocyclic ring optionally containing one or two double bonds and optionally another heteroatom separated by at least 2 carbon atoms from the N atom, so as to form; or a residue of formula (IVd)                          wherein Rg is hydrogen, C 1 -C 3 -alkyl or the residue of a C 1 -C 3 -alkanoic acid;    q is zero or the integer 1,    d) 2-(phenylamino)-phenyl of formula (IV e):                          wherein the substituents P 1  and P 2  indicate that the two phenyl groups bear, each independently, mono- or poly-substitutions with C 1 -C 4 -alkyl, C 1 -C 3 -alkoxy groups, chlorine, fluorine and/or trifluoromethyl.    
   
   
       4 . The method according to  claim 1 , wherein in the compound of formula (I), Ar is selected from the group consisting of: 
 4-isobutylphenyl, 4-(2-methyl)allyl-phenyl, 3-phenoxyphenyl, 3-benzoyl-phenyl, 3-acetyl-phenyl, the single diastereoisomers (R),(S) and the diastereoisomeric mixture (R,S) of 3-C 6 H 5 —CH(OH)-phenyl, 3-CH 3 —CH(OH)-phenyl, 5-C 6 H 5 —CH(OH)-thienyl, 4-thienyl-CH(OH)-phenyl, 3-(pyrid-3-yl)-CH(OH)-phenyl, 5-benzoyl-thien-2-yl, 4 thienoyl-phenyl, 3-nicotinoyl-phenyl, 2-fluoro-4-phenyl, 6-methoxy-2-naphthyl, 5-benzoyl-2-acetoxy-phenyl and 5-benzoyl-2-hydroxy-phenyl.    
   
   
       5 . The method according to  claim 1 , wherein in the compound of formula (I), wherein Ar is phenyl 3-substituted by a group selected form: isoprop-1-en-1-yl, isopropyl, pent-2-en-3-yl, pent-3-yl, 1-phenylethylen-1-yl and α-methylbenzyl.  
   
   
       6 . The method according to  claim 1 , wherein in the compound of formula (I), the Ar group of formula IVc is selected from the group consisting of: 
 4-(pyrrolidin-1-yl)-methyl-phenyl, 3-chloro-4-(pyrrolidin-1-yl)-methyl-phenyl, 3-chloro-4-(2,5-dihydro-1-H-pyrrol-1-yl)-methyl-phenyl, 3 chloro-4-(thiomorpholin-4-yl)phenyl, 3-chloro-4-(piperidin-1-yl)-phenyl, 4-((N-ethyl-N-quinolin-2-yl-methylamino)-methyl)phenyl and 3-chloro-4-(morpholin-4-yl)-phenyl.    
   
   
       7 . The method according to  claim 1 , wherein in the compound of formula (I), the Ar group of formula IVe is selected from: 
 2-(2,6-dichloro-phenyl-amino)-phenyl, 2-(2,6-dichloro-phenyl-amino)-5-chloro-phenyl, 2-(2,6-dichloro-3-methyl-phenyl-amino)-phenyl and 2-(3-trifluoromethyl-phenyl-amino)-phenyl.    
   
   
       8 . The method according to  claim 1 , wherein in the compound of formula (I), 
 R is hydrogen,    X is: 
 a linear alkylene optionally substituted at C 1  by a —CO 2 R 3  group as defined above;  
 a linear alkylene optionally substituted at C 1  by a —CONHR 4  group wherein R 4  is OH;  
 2-butynylene, cis-2-butenylene, trans-2-butenylene;  
 3-oxa-pentylene, 3-thio-pentylene, 3-oxa-hexylene, 3-thio-hexylene;  
 (CH 2 ) m —CO—NH—(CH 2 ) n — wherein m and n are each independently an integer from 2 to 3;  
 (CHR′)—CONH—(CH 2 ) n  wherein n is an integer from 2 to 3 and R″ is a methyl, in absolute configuration R or S;  
 or X, together with the N atom of the omega-amino group, forms a nitrogen containing cycloaliphatic ring selected from 1-methyl-piperidin-4-yl and 1,5-tropan-3-yl.  
   
   
   
       9 . The method according to  claim 1 , wherein in the compound of formula (I), NR 1 R 2  represents an NH 2  group, dimethylamino, diethylamino, diisopropylamino, 1-piperidinyl, 4-morpholyl, 4-thiomorpholyl or, R 1  and R 2  together form a residue of guanidine, aminoguanidine, hydroxyguanidine, 2-amino-3,4,5,6-tetrahydropyrimidyl or 2-amino-3,5-dihydro-imidazolyl.  
   
   
       10 . The method according to  claim 1 , wherein the compound of formula (I) is one selected from the group consisting of 
 (R)-2-[(4-isobutyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;    (R)-2-[(4-isobutyl)phenyl]-N-(4-dimethylaminobutyl)-propionamide hydrochloride;    (R)-2-[(4-isobutyl)phenyl]-N-(3-N-morpholinylpropyl)propionamide;    (R)-2-[(4-isobutyl)phenyl]-N-(2-dimethylaminoethyl)propionamide;    (R)-2-[(4-isobutyl)phenyl)-propionyl]-N-[2-(4-methyl-piperazin-1-yl)ethyl]propionamide; 
 (R)—N-(exo-8-methyl-8-aza-bicyclo[3,2,1]oct-3-yl)-2-[(4-isobutylphenyl)-propionamide;  
   (R)-2-[(4-isobutyl)phenyl]-N-(3-N-thiomorpholinylpropyl)propionamide;    (R)-2-[(4-isobutyl)phenyl]-N-[4-(N′-methyl)piperidinyl]propionamide hydrochloride; 
 (R),(S′)-2-[(4-isobutyl)phenyl]-N-(1-carboxy-2-dimethylaminoethyl)-propionamide;  
 (R),(S′)-2-[(4-isobutyl)phenyl]-N-[(1-carboxy-4-piperidin-1-yl)butyl]propionamide;  
 (R),(S′)-2-[(4-isobutyl)phenyl]-N-(1-carboxy-4-aminobutyl)propionamide;  
   (R)-2-(4-isobutyl)phenyl-N-[2-(dimethylaminoethyl)aminocarbonylmethyl)]propionamide hydrochloride;    2-(2,6-dichlorophenylamino)-phenyl-N-(3-dimethylaminopropyl)propionamide;    (R),(R′,S′)-3-[3-α-methyl)benzyl]phenyl-N-(3-dimethylaminopropyl)-propionamide;    (R)-2-[(3-isopropyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;    (R)-2-[3-(pent-3-yl)phenyl]-N-(3-dimethylaminopropyl)propionamide;    (R)-2-[(4-isobutyl)phenyl]-N-(3-guanidylpropyl)propionamide;    (R)-2-[(4-isobutyl)phenyl]-N-[(3-hydroxy-guanidyl)propyl]propionamide;    (R)-2-[(4-isobutyl)phenyl]-N-[(3-amino-guanidyl)propyl]propionamide;    (R)-2-[(4-isobutyl)phenyl]-N-[3-(2-amino-2-imidazoline) propyl]propionamide;    (R)-2-[(4-isobutyl)phenyl]-N—[N-methyl-N-(2-hydroxyethyl)aminoethoxy]propionamide and    (R),(S′)-2-[(4-isobutyl)phenyl]-N-[1-carboxy-5-aminopentyl]propionamide.    
   
   
       11 . The method according to  claim 1 , wherein the compound of formula (I) is (R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide hydrochloride.  
   
   
       12 . The method according to  claim 1 , wherein the compound of formula (I), is (R)-2-(4-isobutylphenyl)-N-3-(1-piperidinylpropyl)propionamide hydrochloride.  
   
   
       13 . The method according to  claim 1 , wherein in the compound of formula (I), R 1  and R 2  are groups different from hydrogen.  
   
   
       14 . The method according to  claim 13 , wherein in the compound of formula (I), X is linear C 2 -C 4  alkylene.  
   
   
       15 . A method for preventing or treating of injury caused by ischemia and reperfusion comprising administering a compound administering to a patient in need thereof an effective amount of a (R)-2-Aryl-propionamide compound of formula (I):  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein  
       Ar represents a substituted or non-substituted aryl group;  
       R represents hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, optionally substituted by a CO 2 R 3  group, wherein R 3  represents hydrogen or a linear or branched C 1 -C 6  alkyl group or a linear or branched C 2 -C 6  alkenyl group;  
       X represents:  
       a linear or branched C 1 -C 6  alkylene, C 4 -C 6  alkenylene, C 4 -C 6  alkynylene, optionally substituted by a CO 2 R 3  group or by a CONHR 4  group wherein R 4  represents hydrogen, linear or branched C 2 -C 6  alkyl or an OR 3  group, R 3  being defined as in  claim 1;   
       a (CH 2 ) m —B—(CH 2 ) n , group, optionally substituted by a CO 2 R 3  or CONHR 4  group, as defined above, wherein B is an oxygen or sulfur atom, m is zero or an integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n is an integer from 2 to 3;  
       or X together with the nitrogen atom of the omega-amino group to which it is bound and with the R 1  group forms a non-aromatic nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring wherein the nitrogen atom has a substituent Rc, where Rc represents hydrogen, C 1 -C 4  alkyl, C 1 -C 4  hydroxylalkyl, C 1 -C 4  acyl, substituted or non-substituted phenyl, diphenylmethyl;  
       R 1  and R 2  are independently hydrogen, linear or branched C 1 -C 6  alkyl, optionally interrupted by an O or S atom, a C 3 -C 7  cycloalkyl, C 3 -C 6  alkenyl, C 3 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl or hydroxy-C 2 -C 3 -alkyl group;  
       or R 1  and R 2  together with the N atom to which they are bound, form a 3-7 membered nitrogen heterocyclic ring of formula (II)  
       
         
           
           
               
               
           
         
       
       wherein Y represents a single bond, CH 2 , O, S, or a N-Rc group as defined above and p represents an integer from 0 to 3;  
       or, R 1  being as defined above, R 2  represents a group of formula (III):  
       
         
           
           
               
               
           
         
       
       wherein R a  is hydrogen and R b  is hydrogen, hydroxy, C 1 -C 4 -alkyl or an NR d R e  group wherein R d  and R e , are each independently, hydrogen, C 1 -C 4 -alkyl or phenyl;  
       or R a  and R b , together with the nitrogen atoms to which they are bound, form a 5-7 membered heterocyclic ring, monocyclic or fused with a benzene, pyridine or pyrimidine ring;  
       said compound of the formula (I) having activity of inhibiting C5a-induced chemotaxis of polymorphonucleate leukocytes and monocytes.  
     
   
   
       16 . The method according to  claim 15 , wherein in the compound of formula (I), R 1  and R 2  are groups different from hydrogen.  
   
   
       17 . A method for inhibiting both the Cfa-induced chemotaxis of polymorphonucleate leukocytes and monocytes, and the interleukin 8-induced chemotaxis of polymorphonucleate leukocytes, comprising administering comprising administering to a patient in need thereof an effective amount of a (R)-2-Aryl-propionamide compound of formula (I):  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof,  
       wherein  
       Ar represents a substituted or non-substituted aryl group;  
       R represents hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, optionally substituted by a CO 2 R 3  group, wherein R 3  represents hydrogen or a linear or branched C 1 -C 6  alkyl group or a linear or branched C 2 -C 6  alkenyl group;  
       X represents  
       a linear or branched C 1 -C 6  alkylene, C 4 -C 6  alkenylene, C 4 -C 6  alkynylene, optionally substituted by a CO 2 R 3  group or by a CONHR 4  group wherein R 4  represents hydrogen, linear or branched C 2 -C 6  alkyl or an OR 3  group, R 3  being defined as above;  
       a (CH 2 ) m —B—(CH 2 ) n , group, optionally substituted by a CO 2 R 3  or CONHR 4  group, as defined above, wherein B is an oxygen or sulfur atom, m is zero or an integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO, SO or CONH group, m is an integer from 1 to 3 and n is an integer from 2 to 3;  
       or X together with the nitrogen atom of the omega-amino group to which it is bound and with the R 1  group forms a non-aromatic nitrogen containing 3-7 membered heterocyclic, monocyclic or polycyclic ring wherein the nitrogen atom has a substituent Rc, where Rc represents hydrogen, C 1 -C 4  alkyl, C 1 -C 4  hydroxylalkyl, C 1 -C 4  acyl, substituted or non-substituted phenyl, diphenylmethyl;  
       R 1  and R 2  are independently linear or branched C 1 -C 6  alkyl, optionally interrupted by an O or S atom, a C 3 -C 7  cycloalkyl, C 3 -C 6  alkenyl, C 3 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, hydroxy-C 2 -C 3 -alkyl group;  
       or R 1  and R 2  together with the N atom to which they are bound, form a nitrogen containing 3-7 membered heterocyclic ring of formula (II)  
       
         
           
           
               
               
           
         
       
       wherein Y represents a single bond, CH 2 , O, S, or a N-Rc group as defined above and p represents an integer from 0 to 3;  
       or, R 1  being as defined above, R 2  represents a group of formula (III):  
       
         
           
           
               
               
           
         
       
       wherein R a  is hydrogen and R b  is hydrogen, hydroxy, C 1 -C 4 -alkyl or an NR d R e  group wherein R d  and R e  are independently hydrogen, C 1 -C 4 -alkyl or phenyl;  
       or R a  and R b , together with the nitrogen atoms to which they are bound, form a 5-7 membered heterocyclic ring, monocyclic or fused with a benzene, pyridine or pyrimidine ring;  
       with the proviso that when Ar is 4-diphenyl and X is (CH 2 ) 2  or (CH 2 ) 3 , R 1  and R 2  are not ethyl;  
       with the further proviso that, when Ar is a 4-(2-fluoro)diphenyl residue, and X is butylene substituted by a CO 2 H group, R a  and R b  are not hydrogen;  
       and with the further proviso that, when Ar is phenyl and X is butylene, R 1  and R 2  together are not a N-(2-methoxy phenyl)piperazine.  
     
   
   
       18 . The method of  claim 17 , in which in the compound of the formula (I), X is a linear C 2 -C 4  alkylene.  
   
   
       19 . The method of  claim 1 , in which in the compound of the formula (I), Ar b  has the formula IV(c) in which A is selected from the group consisting of dimethylamino, diethylamino, methyl-N-ethyl-amino, acetyl-N-methyl-amino and pivaloyl-N-ethyl-amino.  
   
   
       20 . The method of  claim 1 , in which in the compound of the formula (I), Ar b  has the formula IV(c) in which A is selected from the group consisting of a 1-pyrrolidino, 2,5-dihydro-pyrrol-1-yl, 1-pyrrol, 1-piperidino, 1-piperazino-4-non-substituted or 4-substituted (methyl, ethyl, 2-hydroxyethyl, benzyl, benzyhydril or phenyl), 4-morpholino, 4-3,5-dimethyl-morpholino, 4-thiomorpholino group.