Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses

Abstract

Compounds having activity against production of an inflammatory cytokine of formula (I)′: A′ is pyrrole; R 1′ is phenyl or naphthyl; R 2′ is pyridyl or pyrimidinyl; R 3′ is (IIa)′, (IIb)′ or (IIc)′: m′ is 1; E′ is nitrogen; D′ is >C(R 5′ ), R 5′ is hydrogen, Substituent α′ or Substituent β′; B′ is nitrogen-containing 5-membered heterocyclic; R 4′ is 1 to 3 substituents from Substituent α′, Substituent β′ and Substituent γ′; R 1′ and R 3′ are bonded to two atoms of the pyrrole adjacent to the pyrrole atom bonded to R 2′ ; Substituent α′ is hydroxyl, nitro, cyano, halogen, alkoxy, halogeno alkoxy, alkylthio, halogeno alkylthio or —NR a′ R b′ ; R a′ and R b′ are hydrogen, alkyl, alkenyl, alkynyl, aralkyl or alkylsulfonyl, or R a′ and R b′ with the nitrogen atom form a heterocyclyl; Substituent β′ is alkyl, alkenyl, alkynyl, aralkyl or cycloalkyl; Substituent γ′is oxo, hydroxyimino, alkoxyimino, alkylene, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, aryl, aryloxy, alkylidenyl or aralkylidenyl.

1 . A compound of a formula (I), or a pharmacologically acceptable salt, ester or other derivative thereof:  
     
       
         
         
             
             
         
       
       wherein:  
       A represents a pyrrole ring;  
       R 1  is a phenyl or a naphthyl, which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α defined below, Substituent group β defined below, Substituent group γ defined below and Substituent group δ defined below;  
       R 2  represents a pyridyl or pyrimidinyl group, which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α defined below, Substituent group β defined below, Substituent group γ defined below and Substituent group δ defined below;  
       R 3  is a group of the following formula (II):  
       
         
           
           
               
               
           
         
       
       wherein:  
       m represents 0 or 1;  
       n represents 1 or 2;  
       R 5 , R 6 , R 7 , R 8  and R 9  may be the same or different from one another and each is selected from the group consisting of hydrogen atoms, Substituent group α, Substituent group β, Substituent group γ and Substituent group δ;  
       one of D and E represents a formula >NR 10 , wherein R 10  is selected from the group consisting of hydrogen atoms, Substituent group γ and Substituent group δ, and the other represents a formula >CR 11 R 12 , wherein R 11  and R 12  are the same or different from one another and each is selected from the group consisting of hydrogen atoms, Substituent group α, Substituent group β, Substituent group γ and Substituent group δ, or  
       R 6  may form, together with R 5  or R 7 , a single bond, and/or R 10  and R 11  together may form a straight or branched alkylene group having from 1 to 6 carbon atoms which is unsubstituted or is substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ; and  
       PROVIDED THAT said substituents R 1  and R 3  are bonded to the two atoms of said pyrrole ring which are adjacent to the atom of the pyrrole ring to which said substituent R 2  is bonded; and 
 in R 3 , one of R 5  and R 7  together with R 6  represents a single bond and the other represents a substituent selected from the group consisting of hydrogen atoms, Substituent group α, Substituent group γ and Substituent group δ; R 8 , R 9  and R 12  are the same or different from one another and each represents a substituent selected from the group consisting of hydrogen atoms, Substituent group α, Substituent group γ and Substituent group δ; and R 10  and R 11  are the same or different from one another and each represents a substituent selected from the group consisting of hydrogen atoms, Substituent group α, Substituent group γ and Substituent group δ; or R 10  and R 11  together form an alkylene group having from 1 to 6 carbon atoms which is unsubstituted or is substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ;  
 
       Substituent group α is selected from the group consisting of hydroxyl groups, nitro groups, cyano groups, halogen atoms, lower alkoxy groups defined below, halogeno lower alkoxy groups defined below, lower alkylthio groups defined below, and halogeno lower alkylthio groups defined below;  
       Substituent group β is a formula —NR c R d , wherein R c  and R d  are the same or different from each other and each is independently selected from the group consisting of hydrogen atoms, lower alkyl groups defined below, lower alkenyl groups defined below, lower alkynyl groups defined below, aralkyl groups defined below and lower alkylsulfonyl groups, or  
       R c  and R d , together with the nitrogen atom to which R c  and R d  are bonded, form a heterocyclyl group defined below;  
       Substituent group γ is a lower alkyl group defined below which is substituted with the formula —NR c R d , wherein R c  and R d  are as defined above; and  
       Substituent group δ is a lower alkyl group defined below which is unsubstituted or substituted with at least one substituent selected from Substituent group α defined above, lower alkenyl groups defined below which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α defined above, lower alkynyl groups defined below which is unsubstituted or substituted with at least one substituent selected from Substituent group a defined above, aralkyl groups defined below and cycloalkyl groups defined below;  
       said cycloalkyl groups in the definition of Substituent group δ above are cycloalkyl groups having from 3 to 7 carbon atoms;  
       said lower alkyl groups in the definition of substituents R c  and R d  above, said lower alkyl groups which are unsubstituted or substituted with at least one substituent selected from Substituent group α in the definition of Substituent group δ above and said lower alkyl moiety of the lower alkyl groups substituted with the formula —NR c R d  in the definition of Substituent group γ above are straight or branched alkyl groups having from 1 to 6 carbon atoms;  
       said lower alkenyl groups in the definition of substituents R c  and R d  above and said lower alkenyl groups which are unsubstituted or substituted with at least one substituent selected from Substituent group α in the definition of Substituent group δ above are straight or branched alkenyl groups having from 2 to 6 carbon atoms;  
       said lower alkynyl groups in the definition of substituents R c  and R d  above and said lower alkynyl groups which are unsubstituted or substituted with at least one substituent selected from Substituent group a in the definition of Substituent group δ above are straight or branched alkynyl groups having from 2 to 6 carbon atoms;  
       said aralkyl groups in the definition of R c  and R d  above and in the definition of Substituent group δ above are lower alkyl groups as defined above which are substituted with at least one aryl group as defined above;  
       said lower alkylsulfonyl groups in the definition of substituents R c  and R d  are lower alkyl groups as defined above which are bonded to a sulfonyl group;  
       said heterocyclyl groups formed by substituents R c  and R d  together with the nitrogen atom to which they are bonded are 4- to 12-membered non-aromatic heterocyclic groups containing one nitrogen atom and optionally containing one further heteroatom selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms, said non-aromatic heterocyclic groups optionally being fused with another cyclic group selected from the group consisting of aryl groups as defined below and heteroaryl groups as defined below;  
       said aryl groups are aromatic hydrocarbon groups having from 6 to 14 carbon atoms in one or more rings, said aromatic hydrocarbon groups optionally being fused with a cycloalkyl group having from 3 to 10 carbon atoms;  
       said heteroaryl groups are 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 heteroatoms selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms, said aromatic heterocyclic groups optionally being fused with another cyclic group selected from the group consisting of aryl groups as defined above and cycloalkyl groups having from 3 to 10 carbon atoms;  
       said lower alkoxy groups in the definition of Substituent group α above are lower alkyl groups as defined above which are bonded to an oxygen atom;  
       said halogeno lower alkoxy groups in the definition of Substituent group α above are lower alkoxy groups as defined above which are substituted with at least one halogen atom;  
       said lower alkylthio groups in the definition of Substituent group a above are lower alkyl groups as defined above which are bonded to a sulfur atom; and  
       said halogeno lower alkylthio groups in the definition of Substituent group α above are lower alkylthio groups as defined above which are substituted with at least one halogen atom.  
     
   
   
       2 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 1  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α 1  defined below, Substituent group β 1  defined below, Substituent group γ 1  defined below and Substituent group 5 defined below; 
 said Substituent group α 1  is selected from the group consisting of halogen atoms, lower alkoxy groups as defined in  claim 1  and halogeno lower alkoxy groups as defined in  claim 1;     said Substituent group β 1  is the formula —NR c R d , wherein one of R c  and R d  is selected from the group consisting of hydrogen atoms and lower alkyl groups as defined in  claim 1  and the other is selected from the group consisting of hydrogen atoms, lower alkyl groups as defined in  claim 1  and aralkyl groups as defined in  claim 1;     said Substituent group γ 1  is selected from the group consisting of lower alkyl groups as defined in  claim 1  which are substituted with a substituent selected from the group consisting of amino groups, amino groups substituted with one or two lower alkyl groups as defined in  claim 1  and amino groups substituted with an aralkyl group as defined in  claim 1;  and    said Substituent group δ 1  is selected from the group consisting of lower alkyl groups as defined in  claim 1 , halogeno lower alkyl groups wherein the lower alkyl groups therein are defined in  claim 1  and which are substituted with at least one halogen atom, hydroxy lower alkyl groups comprising lower alkyl groups as defined in  claim 1  which are substituted with at least one hydroxy group and nitro lower alkyl groups wherein the lower alkyl groups therein are defined in  claim 1  and which are substituted with at least one nitro group.    
   
   
       3 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 1  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups comprising lower alkyl groups as defined in  claim 1  which are substituted with at least one halogen atom and halogeno lower alkoxy groups as defined in  claim 1 .  
   
   
       4 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 1  is selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups.  
   
   
       5 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 2  is a 4-pyridyl or 4-pyrimidinyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ.  
   
   
       6 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 2  is a 4-pyridyl or 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ.  
   
   
       7 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 2  is a 4-pyridyl or 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino and α-methylbenzylamino groups.  
   
   
       8 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein in R 3 , m is 1 and n is 1.  
   
   
       9 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein in R 3 , E represents the formula >NR 10  and D represents the formula >CR 11 R 12 .  
   
   
       10 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein in R 3 , R 10  and R 11  together form a straight chain alkylene group having 3 or 4 carbon atoms which is unsubstituted or is substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ.  
   
   
       11 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein in R 3 , each of R 7 , R 8  and R 9  is a hydrogen atom, and R 10  and R 11  together form a straight chain alkylene group having 3 or 4 carbon atoms which is unsubstituted or is substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ.  
   
   
       12 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein said compound of the formula (I) is a compound of a formula (I-1) or (I-3) below:  
     
       
         
         
             
             
         
       
     
   
   
       13 . A compound according to  claim 1  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 1  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α 1  defined below, Substituent group β 1  defined below, Substituent group γ 1  defined below and Substituent group δ 1  defined below;    R 2  is a 4-pyridyl or 4-pyrimidinyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ; and    R 3  is the formula (II) as defined in  claim 1  wherein m is 1 and n is 1;    said Substituent group α 1  comprises halogen atoms, lower alkoxy groups as defined in  claim 1  and halogeno lower alkoxy groups as defined in  claim 1;     said Substituent group β 1  is the formula —NR c R d , wherein one of R c  and R d  is selected from the group consisting of hydrogen atoms and lower alkyl groups as defined in  claim 1  and the other is selected from the group consisting of hydrogen atoms, lower alkyl groups as defined in  claim 1  and aralkyl groups as defined in  claim 1;     said Substituent group γ 1  comprises lower alkyl groups as defined in  claim 1  which are substituted with a substituent selected from the group consisting of amino groups, amino groups substituted with one or two lower alkyl groups as defined in  claim 1  and amino groups substituted with an aralkyl group as defined in  claim 1;  and    said Substituent group δ 1  comprises lower alkyl groups as defined in  claim 1 , halogeno lower alkyl groups wherein the lower alkyl groups therein are defined in  claim 1  and which are substituted with at least one halogen atom, hydroxy lower alkyl groups comprising lower alkyl groups as defined in  claim 1  and which are substituted with at least one hydroxy group and nitro lower alkyl groups wherein the lower alkyl groups therein are defined in  claim 1  and which are substituted with at least one nitro group.    
   
   
       14 . A compound of the formula (I) according to  claim 1  or a pharmacologically acceptable salt or ester thereof, wherein: 
 R 1  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α 1  defined below, Substituent group β 1  defined below, Substituent group γ 1  defined below and Substituent group δ 1  defined below;    R 2  is a 4-pyridyl or 4-pyrimidinyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ; and    in R 3 , E represents the formula >NR 10 , wherein R 10  is as defined in  claim 1  and D represents the formula >CR 11 R 12 , wherein R 11  and R 12  are as defined in  claim 1;     said Substituent group α 1  is selected from the group consisting of halogen atoms, lower alkoxy groups as defined in  claim 1  and halogeno lower alkoxy groups as defined in  claim 1;     said Substituent group β 1  is the formula —NR c R d , wherein one of R c  and R d  is selected from the group consisting of hydrogen atoms and lower alkyl groups as defined in  claim 1  and the other is selected from the group consisting of hydrogen atoms, lower alkyl groups as defined in  claim 1  and aralkyl groups as defined in  claim 1;     said Substituent group γ 1  is a lower alkyl group as defined in  claim 1  which is substituted with a substituent selected from the group consisting of unsubstituted amino groups, amino groups substituted with one or two lower alkyl groups as defined in  claim 1  and amino groups substituted with an aralkyl group as defined in  claim 1;  and    said Substituent group δ 1  is selected from the group consisting of lower alkyl groups as defined in  claim 1 , halogeno lower alkyl groups wherein the lower alkyl groups therein are defined in  claim 1  and which are substituted with at least one halogen atom, hydroxy lower alkyl groups wherein the lower alkyl groups therein are defined in  claim 1  which are substituted with at least one hydroxy group and nitro lower alkyl groups wherein the lower alkyl groups therein are defined in  claim 1  and which are substituted with at least one nitro group.    
   
   
       15 . A compound of the formula (I) according to  claim 1  or a pharmacologically acceptable salt or ester thereof, wherein: 
 R 1  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups comprising lower alkyl groups as defined in  claim 1  which are substituted with at least one halogen atom and halogeno lower alkoxy groups as defined in  claim 1;     R 2  is a 4-pyridyl or 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ; and    in R 3 , E represents the formula >NR 10  and D represents the formula >CR 11 R 12 .    
   
   
       16 . A compound of the formula (I) according to  claim 1  or a pharmacologically acceptable salt or ester thereof, wherein: 
 R 1  is selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;    R 2  is a 4-pyridyl or 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino and α-methylbenzylamino groups; and    in R 3 , each of R 7 , R 8  and R 9  is a hydrogen atom; and R 10  and R 11  together form a straight chain alkylene group having 3 or 4 carbon atoms which is unsubstituted or is substituted with at least one substituent selected from the group consisting of Substituent group α, Substituent group β, Substituent group γ and Substituent group δ.    
   
   
       17 . A compound of the formula (I) according to  claim 1  or a pharmacologically acceptable salt or ester thereof, wherein said compound of the formula (I) is a compound of a formula (I-1) or (I-3) below:  
     
       
         
         
             
             
         
       
     
   
   
       18 . A compound selected from the group consisting of 
 4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-3-(pyridin-4-yl)-4-(1,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(1,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(1,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(1-ethyl-6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(1-ethyl-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(6-allyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(2-allyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(6-benzyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(2-benzyl-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(6-methyl-1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(2-methyl-1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1,3,4,6,7,9a-hexahydro-2H-quinolizin-8-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1,3,4,6,9,9a-hexahydro-2H-quinolizin-8-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-3-(2-methylaminopyrimidin-4-yl)-1H-pyrrole,    2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(2-methylaminopyrimidin-4-yl)-1H-pyrrole,    2-(3,4-difluorophenyl)-4-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(3,4-difluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,    4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-2-(3-trifluoromethylphenyl)-1H-pyrrole,    2-(3-fluorophenyl)-4-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(3-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(3-chlorophenyl)-4-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    2-(3-chlorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole,    4-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-2-phenyl-3-(pyridin-4-yl)-1H-pyrrole, and    4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-2-phenyl-3-(pyridin-4-yl)-1H-pyrrole,    or a pharmacologically acceptable salt or ester thereof.    
   
   
       19 . A pharmaceutical composition comprising a pharmaceutically effective amount of a pharmacologically active compound together with a carrier therefor, wherein said pharmacologically active compound is a compound of the formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof according to  claim 1 .  
   
   
       20 . A method for the treatment of a disease which is treatable by inhibiting the production of an inflammatory cytokine in a human which comprises administering to a human in need thereof an effective amount for the treatment of a disease which is treatable by inhibiting the production of an inflammatory cytokine in a human of a compound of the formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof according to  claim 1 .  
   
   
       21 . A method for inhibiting bone absorption, relieving pain or pyrexia, treating or preventing an inflammatory disease, a viral disease, chronic rheumatoid arthritis, osteoarthritis, hepatitis, an allergic disease, septicemia, psoriasis, osteoporosis, ulcerative colitis, diabetes, nephritis, ischemic heart disease, Alzheimer's disease or arteriosclerosis which comprises administering to a human in need thereof a pharmaceutically effective amount of a compound of the formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof according to  claim 1 .  
   
   
       22 . A method of inhibiting the production of an inflammatory cytokine in a human which comprises administering to a human in need thereof a pharmaceutically effective amount of a compound as defined in  claim 1 .  
   
   
       23 . A compound of a formula (I)′, or a pharmacologically acceptable salt, ester or other derivative thereof:  
     
       
         
         
             
             
         
       
     
     wherein: 
 A′ represents a pyrrole ring;  
 R 1′  is an aryl group selected from the group consisting of phenyl and naphthyl, which are unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α′ defined below and Substituent group β′ defined below;  
 R 2′  is a pyrimidinyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α′ defined below and Substituent group β′ defined below; and  
 R 3′  represents a formula (IIa)′, (IIb)′ or (IIc)′ shown below:  
                     
 wherein  
 m′ represents 1,  
 E′ represents a nitrogen atom and D′ represents a formula >C(R 5′ )—, wherein R 5′  is selected from the group consisting of hydrogen atoms, Substituent group α′ defined below and Substituent group β′ defined below,  
 B′ represents a 5-membered heterocyclic ring which has one ring nitrogen atom, said heterocyclic ring being saturated or unsaturated, and is unfused or fused with a group selected from the group consisting of aryl groups defined below, heteroaryl groups defined below, cycloalkyl groups defined below and heterocyclyl groups defined below, and  
 R 4′  represents from 1 to 3 substituents which are independently selected from the group consisting of Substituent group α′ defined below, Substituent group β′ defined below and Substituent group γ′ defined below, or  
 when B′ is a heterocyclic ring which is fused to an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group, R 4′  may be a hydrogen atom;  
 provided that said substituents R 1′  and R 3′  are bonded to the two atoms of said pyrrole ring which are adjacent to the atom of the pyrrole ring to which said substituent R 2′  is bonded;  
 Substituent group α′ is selected from the group consisting of hydroxyl groups, nitro groups, cyano groups, halogen atoms, lower alkoxy groups defined below, halogeno lower alkoxy groups defined below, lower alkylthio groups defined below, halogeno lower alkylthio groups defined below and a formula —NR a′ R b′ , wherein R a′  and R b′  are the same or different from each other and each is independently selected from the group consisting of hydrogen atoms, lower alkyl groups defined below, lower alkenyl groups defined below, lower alkynyl groups defined below, aralkyl groups defined below and lower alkylsulfonyl groups defined below, or R a′  and R b′ , taken together with the nitrogen atom to which they are attached, form a heterocyclyl group;  
 Substituent group β′ is selected from the group consiting of lower alkyl groups defined below which are unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group a defined above, lower alkenyl groups defined below which are unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α′ defined above, lower alkynyl groups defined below which are unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α′ defined above, aralkyl groups defined below and cycloalkyl groups defined below;  
 Substituents group γ′ is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups defined below, lower alkylene groups defined below, lower alkylenedioxy groups defined below, lower alkylsulfinyl groups defined below, lower alkylsulfonyl groups defined below, aryl groups defined below which are unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α′ defined above and Substituent group β′ defined above, aryloxy groups defined below which are unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α′ defined above, Substituent group β′ defined above, lower alkylidenyl groups and aralkylidenyl groups;  
 said aryl groups in the definitions of ring B′ and Substituent group γ′ above are aromatic hydrocarbon groups having from 6 to 14 carbon atoms in one or more rings, said aryl groups being unfused or fused with a cycloalkyl group having from 3 to 10 carbon atoms;  
 said heteroaryl groups in the definition of ring B′ above are 5- to 7-membered aromatic heterocyclic groups containing from 1 to 3 heteroatoms selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms, said heteroaryl groups being unfused or fused with another cyclic group selected from the group consisting of aryl groups defined above and cycloalkyl groups having from 3 to 10 carbon atoms;  
 said lower alkyl groups in the definitions of R a′ , R b′  and Substituent group β′ above, and the lower alkyl moiety of said lower alkyl groups which are unsubstituted or substituted with at least one substituent selected from Substituent group α′ in the definition of Substituent group β′ above are straight or branched alkyl groups having from 1 to 6 carbon atoms;  
 said lower alkenyl groups in the definitions of R a′ , R b′  and Substituent group β′ above, and the lower alkenyl moiety of said lower alkenyl groups which are unsubstituted or substituted with at least one substituent selected from Substituent group α′ in the definition of Substituent group β′ above are straight or branched alkenyl groups having from 2 to 6 carbon atoms;  
 said lower alkynyl groups in the definitions of R a′ , R b′  and Substituent group β′ above, and the lower alkynyl moiety of said lower alkynyl groups which are unsubstituted or substituted with at least one substituent selected from Substituent group α′ in the definition of Substituent group β′ above are straight or branched alkynyl groups having from 2 to 6 carbon atoms;  
 said aralkyl groups in the definitions of R a′ , R b′  and Substituent group β′ above are lower alkyl groups as defined above which are substituted with at least one aryl group as defined above which are unsubstituted or substituted with from 1 to 3  
 substituents selected from the group consisting of Substituent group α′ defined above and Substituent group β′ defined above;  
 said lower alkylsulfonyl groups in the definitions of R a′ , R b′  and Substituent γ′ above are lower alkyl groups as defined above which are bonded to a sulfonyl group;  
 wherein ring B′ is fused with a heterocyclyl group, said heterocyclyl groups are 4- to 7-membered heterocyclyl groups which contain from 1 to 3 ring heteroatoms selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms;  
 wherein R a′  and R b′  together with the nitrogen atom to which they are attached represent a heterocyclyl group, said heterocyclyl groups are 4- to 7-membered heterocyclyl groups which contain one nitrogen atom and which do not contain any further heteroatoms or contain one further heteroatom selected from the group consisting of oxygen atoms, sulfur atoms and nitrogen atoms, said heterocyclyl groups being unfused or fused with another cyclic group selected from the group consisting of aryl groups defined above and heteroaryl groups defined above;  
 said lower alkoxy groups in the definition of Substituent group α′ above are groups in which an oxygen atom is bonded to a lower alkyl group as defined above;  
 said halogeno lower alkoxy groups in the definition of Substituent group α′ above are groups in which a lower alkoxy group as defined above is substituted with at least one halogen atom;  
 said lower alkylthio groups in the definition of Substituent group α′ above are groups in which a sulfur atom is bonded to a lower alkyl group as defined above;  
 said halogeno lower alkylthio groups in the definition of Substituent group α′ above are groups in which a lower alkylthio group as defined above is substituted with at least one halogen atom;  
 said cycloalkyl groups in the definitions of Substituent group β′ and ring B′ are cycloalkyl groups having from 3 to 7 carbon atoms;  
 said lower alkoxyimino groups in the definition of Substituent group γ′ above are groups wherein the hydrogen atom of a hydroxyimino group is replaced by a lower alkyl group as defined above;  
 said lower alkylene groups in the definition of Substituent group γ′ above are alkylene groups having from 2 to 6 carbon atoms;  
 said lower alkylenedioxy groups in the definition of Substituent group γ′ above are groups wherein an alkylene moiety, which is a straight or branched chain alkylene group having from 1 to 6 carbon atoms, is subsitituted with 2 oxy groups;  
 said lower alkylsulfinyl groups in the definition of Substituent group γ′ above are groups in which a lower alkyl group as defined above is bonded to a sulfinyl group;  
 said lower alkylidenyl groups in the definition of Substituent group γ′ above are straight or branched alkylidenyl groups having from 1 to 6 carbon atoms;  
 said aralkylidenyl groups in the definition of Substituent group γ′ above are lower alkylidenyl groups as defined above which are substituted with 1 or more aryl groups as defined above;  
 said unsubstituted or substituted aryloxy groups in the definition of Substituent group γ′ above are groups in which an oxygen atom is attached to an aryl group as defined above.  
 
   
   
       24 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 1′  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α 1′  defined below and Substituent group β 1′  defined below; 
 said Substituent group α 1′  is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and the formula —NR a′ R b′ , wherein one of R a′  and R b′  represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;    said Substituent group β 1′  is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups.    
   
   
       25 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 1′  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups.  
   
   
       26 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 1′  is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups.  
   
   
       27 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′.  
   
   
       28 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α′ and said Substituent group β 2 .  
   
   
       29 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α-methylbenzylamino groups.  
   
   
       30 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein B′ optionally has one further ring heteroatom or ring group selected from the group consisting of a nitrogen atom, oxygen atom, sulfur atom, >SO and >SO 2 , said ring is saturated or unsaturated and optionally is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.  
   
   
       31 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein B′ is saturated or unsaturated and optionally is fused with an aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclyl group.  
   
   
       32 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein B′ is a pyrrolidinyl ring or a pyrrolinyl ring.  
   
   
       33 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 3′  is the formula (IIa)′ or the formula (IIb)′.  
   
   
       34 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 3′  is the formula (IIa)′.  
   
   
       35 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 4′  is 1 or 2 substituents which are selected independently from the group consisting of said Substituent group α, said Substituent group β′ and Substituent group γ 1′ , wherein said Substituent group γ 1′  is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′.  
   
   
       36 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 4′  is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′, said Substituent group β′, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.  
   
   
       37 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 4′  is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′ as defined in  claim 23 .  
   
   
       38 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 4′  is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.  
   
   
       39 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 4′  is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′, said Substituent group β′, alkylidene groups and aralkylidene groups.  
   
   
       40 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein R 4′  is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.  
   
   
       41 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein said compound of the formula (I)′ is represented by the formula (I-1)′ or (I-3)′ shown below:  
     
       
         
         
             
             
         
       
     
   
   
       42 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein the compound of the formula (I)′ is represented by the formula (I-1)′ below:  
     
       
         
         
             
             
         
       
     
   
   
       43 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 3′  is the formula (IIa)′ or the formula (IIb)′; and    R 4′  is 1 or 2 substituents which are selected independently from the group consisting of said Substituent group α′, said Substituent group β′ and Substituent group γ 1′ , wherein said Substituent group γ 1′  is selected from the group consisting of oxo groups, hydroxyimino groups, lower alkoxyimino groups, lower alkylene groups, lower alkylenedioxy groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups and aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′.    
   
   
       44 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 3′  is the formula (IIa)′ or the formula (IIb)′; and    R 4′  is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′, said Substituent group β′, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.    
   
   
       45 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 1′  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α 1′  defined below and Substituent group β 1′  defined below;    said Substituent group α 1′  is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and the formula —NR a′ R b′ , wherein one of R a′  and R b′  represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group;    said Substituent group β 1′  is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;    R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′;    R 3′  is the formula (IIa)′ or the formula (IIb)′; and    R 4′  is a substituent selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups, lower alkylthio groups, halogeno lower alkoxy groups, lower alkyl groups, halogeno lower alkyl groups, oxo groups, aryl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′, said Substituent group β′, lower alkylenedioxy groups, lower alkylene groups and lower alkylsulfonyl groups.    
   
   
       46 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 1′  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;    R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′;    R 3′  is the formula (IIa)′; and    R 4′  is a substituent selected from the group consisting of hydroxy groups, fluorine atoms, chlorine atoms, methoxy groups, ethoxy groups, propoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′.    
   
   
       47 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 1′  is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;    R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α-methylbenzylamino groups;    R 3′  is the formula (IIa)′; and    R 4′  is a substituent selected from the group consisting of methoxy groups, methyl groups, ethyl groups, propyl groups and phenyl groups.    
   
   
       48 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 3′  is the formula (IIa)′ or the formula (IIb)′; and    R 4′  is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′, said Substituent group β′, alkylidene groups and aralkylidene groups.    
   
   
       49 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 1′  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of Substituent group α 1′  defined below and Substituent group β 1′  defined below,    said Substituent group α 1′  is selected from the group consisting of halogen atoms, lower alkoxy groups, halogeno lower alkoxy groups and the formula —NR a′ R b′ , wherein one of R a′  and R b′  represents a hydrogen atom or a lower alkyl group, and the other represents a hydrogen atom, a lower alkyl group or an aralkyl group, and    said Substituent group β 1′  is selected from the group consisting of lower alkyl groups, halogeno lower alkyl groups, hydroxyl lower alkyl groups, nitro lower alkyl groups, amino lower alkyl groups, lower alkylamino lower alkyl groups, di(lower alkyl)amino lower alkyl groups and aralkylamino lower alkyl groups;    R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′;    R 3′  is the formula (IIa)′ or the formula (IIb)′; and    R 4′  is a substituent selected from the group consisting of aryloxy groups which are unsubstituted or substituted with at least one substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′, alkylidene groups and aralkylidene groups.    
   
   
       50 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 1′  is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, halogeno lower alkyl groups and halogeno lower alkoxy groups;    R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of said Substituent group α′ and said Substituent group β′;    R 3′  is the formula (IIa)′, and    R 4′  is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.    
   
   
       51 . A compound according to  claim 23  or a pharmacologically acceptable salt, ester or other derivative thereof, wherein: 
 R 1′  is a substituent selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-difluoromethoxyphenyl and 3-trifluoromethylphenyl groups;    R 2′  is a 4-pyrimidinyl group which is unsubstituted or substituted at the 2-position thereof with a substituent selected from the group consisting of methoxy, amino, methylamino, benzylamino, and α-methylbenzylamino groups;    R 3′  is the formula (IIa)′, and    R 4′  is a substituent selected from the group consisting of phenoxy, methylidene, ethylidene, propylidene and benzylidene groups.    
   
   
       52 . A pharmaceutical composition comprising a pharmaceutically effective amount of a pharmacologically active compound together with a carrier therefor, wherein said pharmacologically active compound is a compound of the formula (I)′ or a pharmacologically acceptable salt, ester or other derivative thereof according to  claim 23 .  
   
   
       53 . A method for the treatment or prophylaxis of a disease treatable or preventable by inhibiting the production of an inflammatory cytokine in a human which comprises administering to said human in need thereof a pharmaceutically effective amount of a compound of the formula (I)′ or a pharmacologically acceptable salt, ester or other derivative thereof according to  claim 23 .  
   
   
       54 . A method for inhibiting bone resporption, relieving inflammation, treating or preventing a viral disease, relieving pain or pyrexia, treating or preventing chronic rheumatoid arthritis, treating or preventing osteoarthritis, treating or preventing cancer, treating or preventing septicemia, or treating or preventing hepatitis comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of the formula (I)′ or a pharmaceutically acceptable salt, ester or other derivative thereof according to  claim 23 .  
   
   
       55 . A method for the treatment or prophylaxis of a disease selected from the group consisting of an allergic disease, psoriasis, degenerative arthritis, Crohn's disease, systemic lupus erythematosus, osteoporosis, ulcerative colitis, diabetes, nephritis, ischemic heart disease, Alzheimer's disease and arteriosclerosis comprising administering to a human in need thereof a pharmaceutically effective amount of a compound of the formula (I)′ or a pharmacologically acceptable salt, ester or other derivative thereof according to  claim 23.