Novel compounds

Abstract

Novel 1, 4, 5- substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

What is claimed is:  
     
         1 . A compound of Formula (III)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted with one or two substituents each of which is independently selected from C 1-4  alkyl, halogen, hydroxyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfinyl, CH 2 OR 12 , NR 10 R 20 , or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 R 2  is C 1-10  alkyl N 3 , (CR 10 R 20 ) n′ OR 9 , heterocyclyl, heterocyclylC 1-10  alkyl, C 1-10 alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 3-7 cycloalkylC 1-10  alkyl, C 5-7  cycloalkenyl, C 5-7 cycloalkenyl-C 1-10 -alkyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroaryl-C 1-10 alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 , (CR 10 R 20 ) n NO 2 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n′ SO 2 R 18 , (CR 10 R 20 ) n S(O) m′ NR 13 R 14 , (CR 10 R 20 ) n C(Z)R 11 , (CR 10 R 20 ) n OC(Z)R 11 , (CR 10 R 20 ) n C(Z)OR 11 , (CR 10 R 20 ) n C(Z)NR 13 R 14 , (CR 10 R 20 ) n C(Z)NR 11 OR 9 , (CR 10 R 20 ) n NR 10 C(Z)R 11 , (CR 10 R 20 ) n NR 10 C(Z)NR 13 R 14 , (CR 10 R 20 ) n N(OR 6 )C(Z)NR 13 R 14 , (CR 10 R 20 ) n N(OR 6 )C(Z)R 11 , (CR 10 R 20 ) n C(═NOR 6 )R 11 , (CR 10 R 20 ) n NR 10 C(═NR 19 )NR 13 R 14 , (CR 10 R 20 ) n OC(Z)NR 13 R 14 , (CR 10 R 20 ) n NR 10 C(Z)NR 13 R 14 , (CR 10 R 20 ) n NR 10 C(Z)OR 10 , 5-(R 18 )-1,2,4-oxadizaol-3-yl or 4-(R 12 )-5-(R 18 R 19 )-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted;  
 R 3  is heterocyclyl, heterocyclylC 1-10  alkyl or R 8 ;  
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 7 R 17 , excluding the moeities SR 5  being SNR 7 R 17  and SOR 5  being SOH;  
 R 6  is hydrogen, a pharmaceutically acceptable cation, C 1-10  alkyl, C 3-7  cycloalkyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C 1-10  alkanoyl;  
 R 7  and R 17  is each independently selected from hydrogen or C 1-4  alkyl or R 7  and R 17  together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 R 8  is C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;  
 R 9  is hydrogen, C(Z)R 11  or optionally substituted C 1-10  alkyl, S(O) 2 R 18 , optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl;  
 R 10  and R 20  is each independently selected from hydrogen or C 1-4  alkyl;  
 R 11  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl or heteroarylC 1-10  alkyl;  
 R 12  is hydrogen or R 16 ;  
 R 13  and R 14  is each independently selected from hydrogen or optionally substituted C 1-4  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ;  
 R 15  is R 10  or C(Z)-C 1-4  alkyl;  
 R 16  is C 1-4  alkyl, halo-substituted-C 1-4  alkyl, or C 3-7  cycloalkyl;  
 R 18  is C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or heteroarylalkyl; and  
 R 19  is hydrogen, cyano, C 1-4  alkyl, C 3-7  cycloalkyl or aryl.  
 
     
     
         2 . The compound according to  claim 1  wherein R 2  is selected from C 1-10  alkyl, optionally substituted heterocylcyl, optionally substiuted heterocyclylC 1-10  alkyl, (CR 10 R 20 ) n NS(O) 2 R 18 , (CR 10 R 20 ) n S(O) m R 18 , arylC 1-10  alkyl, (CR 10 R 20 ) n NR 13 R 14 , optionally substituted C 3-7 cycloalkyl, or optionally substituted C 3-7 cycloalkyl C 1-10  alkyl.  
     
     
         3 . The compound according to  claim 2  wherein R 2  is morpholino propyl, piperidine, N-methylpiperidine, or N-benzylpiperidine.  
     
     
         4 . The compound according to  claim 1  wherein R 1  is an optionally substituted 4-pyridyl or 4-pyriminindyl.  
     
     
         5 . The compound according to  claim 4  wherein the optional substituent is methyl or amino.  
     
     
         6 . The compound according to  claim 1  which is: 
 Pyridine-4-carboxaldehyde [4-Morpholinylprop-3-yl]imine;  
 Pyridine-4-carboxaldehyde (3-Chloropropyl)imine;  
 Pyridine-4-carboxaldehyde-[2-(4-Morpholinyl)ethyl]imine;  
 Pyridine-4-carboxaldehyde 3-(N-methyl-N-benzylaminopropyl)imine;  
 Pyridine-4-carboxaldehdye (4-methylthiophenyl)imine;  
 Pyridine-4-carboxaldehdye (3-methylthiophenyl)imine;  
 Pyridine-4-carboxaldehdye (2-methylthiophenyl)imine;  
 Pyridine-4-carboxaldehyde [4-(4-morpholinyl)butyl]imine;  
 Pyridine-4-carboxaldehyde cyclopropylimine;  
 Pyridine-4-carboxaldehyde isopropylimine;  
 Pyridine-4-carboxaldehyde Cyclopropylmethylimine;  
 Pyridine-4-carboxaldehyde tert-butylimine;  
 Pyridine-4-carboxaldehyde 2,2-diethoxyethylimine;  
 2-Chloropyridine-4-carboxaldehyde [3-(4-morpholinyl)propyl]imine;  
 Pyridine-4-carboxaldehyde (4-carboxymethylbutyl)imine;  
 Pyridine-4-carboxaldehyde (3-carboxymethyl)ethyl irnine;  
 Pyridine-4-carboxaldehyde (1-benzylpiperidin-4-yl)imine;  
 2-Aminopyrimidine-4-carboxaldehyde [3-(4-Morpholinyl)propylimine;  
 2-Aminopyrimidine-4-carboxaldehyde (1-benzylpiperidin-4-yl)imine;  
 2-Aminopyrimidine-4-carboxaldehyde (2-propyl)imine;  
 2-Aminopyrimidine-4-carboxaldehyde (cyclopropylmethyl)imine;  
 2-Aminopyrimidine-4-carboxaldehyde (1-carboxyethyl-4-piperidinyl)imine;  
 2-Aminopyrimidine-4-carboxaldehyde (1-t-butoxycarbonyl-4-aminopiperidinyl)imine;  
 Quinoyl-4-carboxaldehyde [3-(4-Morpholinyl)propyl]imine;  
 2-Methylthiopyrimidine-4-carboxaldehyde [3-(4-morpholinyl)propyl]imine;  
 Pyridine-4-carboxaldehyde (2-propenyl)imine;  
 2-Methylpyridine-4-carboxaldehyde (cyclopropylmethyl)imine;  
 2-Aminopyrimidine-4-carboxaldehyde (ethyl 3-amino-2,2-dimethylpropionate)imine;  
 2-Aminopyrimidine-4-carboxaldehyde (1-methylpiperidin-4-yl)imine; or  
 2-Amninopyrimidine-4-carboxaldehyde [3-(4-Morpholinyl)-2,2-dimethylpropyl]imine.  
 
     
     
         7 . A process for making a compound of Formula (III) according to  claim 1  wherein R 1 CHO is reacted under appropriate conditions with R 2 NH 2  to yield a compound of Formula (III), and wherein R 1  and R 2  are as defined according to Formula (III).  
     
     
         8 . The process according to  claim 7  wherein the R 1 CHO is:  
       
         
           
           
               
               
           
         
       
       wherein X is hydrogen, or is defined as the optional substituent group on the R 1  moiety according to Formula (III).  
     
     
         9 . The process according to  claim 7  wherein the R 1 CHO is  
       
         
           
           
               
               
           
         
       
       wherein X and X 1  are hydrogen or defined as optional substituents group on the R 1  moiety according to Formula (III).  
     
     
         10 . A compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein p is 0, 1 or 2; 
 Ar is an optionally substituted phenyl or napthyl group;  
 R4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substitiuent, is halogen, cyano, nitro, C(Z)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) m COR 12 , SR 5 , SOR 5 , OR 12 , halo-substitutedC 1-4  alkyl, C 1-4  alkyl, ZC(Z)R 12 , NR 10 C (Z)R 16,  or (CR 10 R 20 ) m NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, C(Z)NR 13 R 14 , C(Z)OR 3 , (CR 10 R 20 ) m COR 3 , S(O) m R 3 , OR 3 , halo-substitutedC 1-4  alkyl, C 1-4  alkyl, (CR 10 R 20 ) m NR 10 C(Z)R 3 , NR10S(O) m R 8 , NR 10 S(O) m′ NR 7 R 17 , ZC(Z)R 3  or (CR 10 R 20 ) m NR 13 R 14 ;  
 n is an integer having a value of 1 to 10;  
 m is 0, or the integer 1 or 2;  
 m′ is 1 or 2,  
 Z is oxygen or sulfur;  
 R 3  is heterocyclyl, heterocyclylC 1-10  alkyl or R 8 ;  
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 7 R 17 , excluding the moeities SR 5  being SNR 7 R 17  and SOR 5  being SOH;  
 R 7  and R 17  is each independently selected from hydrogen or C 1-4  alkyl or R 7  and R 17  together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 R 8  is C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted by halogen; hydroxy; hydroxy substituted C 1-10 alkyl; C 1-10  alkoxy; S(O)m alkyl; NR 7 R 17 ; C 1-10  alkyl, cycloalkyl, cycloalkyl alkyl group; halosubstituted C 1-10  alkyl; optionally substituted aryl; or optionally substituted arylalkyl, and wherein the optionally substituted aryl or arylalkyl moieties may be substituted one or two times by halogen; hydroxy; hydroxy substituted alkyl; C 1-10  alkoxy; S(O) m  alkyl; NR 7 R 17 ; alkyl, or CF 3 ;  
 R 9  is hydrogen, C(Z)R 11  or optionally substituted C 1-10  alkyl, S(O) 2 R 18 , optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl, and wherein the optional substituents for the alkyl, aryl and aryl alkyl groups are halogen; hydroxy; hydroxy substituted C 1-10 alkyl; C 1-10  alkoxy; S(O)m alkyl; NR 7 R 17 ; C 1-10  alkyl, cycloalkyl, cycloalkyl alkyl group; halosubstituted C 1-10  alkyl; optionally substituted aryl, or optionally substituted arylalkyl, wherein the optionally substituted aryl or arylalkyl moieties may be substituted one or two times by halogen; hydroxy; hydroxy substituted alkyl; C 1-10  alkoxy; S(O) m  alkyl; NR 7 R 17 ; alkyl, or CF 3 ;  
 R 10  and R 20  is each independently selected from hydrogen or C 1-4  alkyl;  
 R 11  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl or heteroarylC 1-10  alkyl;  
 R 12  is hydrogen or R 16 ;  
 R 13  and R 14  is each independently selected from hydrogen or optionally substituted C 1-4  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ; and wherein the optional substituents for the alkyl, aryl and aryl alkyl groups are halogen; hydroxy; hydroxy substituted C 1-10  alkyl; C 1-10  alkoxy; S(O)m alkyl; NR 7 R 17 ; C 1-10  alkyl, cycloalkyl, cycloalkyl alkyl group; halosubstituted C 1-10  alkyl; optionally substituted aryl, or optionally substituted arylalkyl, and wherein the optionally substituted aryl or arylalkyl moieties may be substituted one or two times by halogen; hydroxy; hydroxy substituted alkyl; C 1-10  alkoxy; S(O) m  alkyl; NR 7 R 17  group; alkyl; or CF 3 ;  
 R 15  is R 10  or C(Z)-C 1-4  alkyl;  
 R 16  is C 1-4  alkyl, halo-substituted-C 1-4  alkyl, or C 3-7  cycloalkyl;  
 R 18  is C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or heteroarylalkyl;  
 provided that when ArS(O)p is tosyl, R 4  is not unsubstituted phenyl.  
 
     
     
         11 . A compound of the Formula (II) according to  claim 10  wherein p is 0.  
     
     
         12 . A compound of the Formula (II) according to  claim 10  wherein p is 2.  
     
     
         13 . The compound according to  claim 10  wherein the R 4  is a substituted phenyl.  
     
     
         14 . The compound according to  claim 13  wherein the phenyl is monosubstituted in the 3-, or 4-position, or is disubstituted in the 3,4-position.  
     
     
         15 . The compound according to  claim 13  wherein the phenyl is substituted by halogen, trifluromethyl, SR 5  or S(O)R 5 .  
     
     
         16 . The compound according to  claim 15  wherein R 5  is a C 1-2  alkyl.  
     
     
         17 . The compound according to  claim 13  wherein the phenyl is substituted by CF 3 .  
     
     
         18 . The compound according to  claim 13  wherein the phenyl is substituted by chloro or fluoro.  
     
     
         19 . The compound according to  claim 10  which is: 
 4-fluorophenyl-t tolylthiomethylisocyanide;  
 3-methylthiophenyl-(tolylthio)methylisocyanide;  
 4-Fluorophenyl-tosylmethylisocyanide;  
 3-chlorophenyl-tolylthiomethylisocyanide;  
 4-trifluoromethylphenyl-tolylthiomethylsocyanide;  
 3-trifluoromethylphenyl-tolylthiomethylisocyanide;  
 3,4-dichlorophenyl-tolylthiomethylisocyanide; or  
 3,5-bistrifluoromethylphenyl-tolylthiomethylisocyanide.  
 
     
     
         20 . A process for producing a compound of Formula (II) according to  claim 10  which process comprises dehydrating a compound of Formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein Ar, R 4  and p are as defined above for Formula (II), to produce a compound of Formula (II).  
     
     
         21 . The process according to  claim 20  which process produces: 
 4-fluorophenyl-t tolylthiomethylisocyanide;  
 3-methylthiophenyl-(tolylthio)methylisocyanide;  
 4-Fluorophenyl-tosylmethylisocyanide;  
 3-chlorophenyl-tolylthiomethylisocyanide;  
 4-trifluoromethylphenyl-tolylthiomethylisocyanide;  
 3-trifluoromethylphenyl-tolylthiomethylisocyanide;  
 3,4-dichlorophenyl-tolylthiomethylisocyanide; or  
 3,5-bistrifluoromethylphenyl-tolylthiomethylisocyanide.  
 
     
     
         22 . The process according to  claim 20  wherein the compound of Formula (IV) is: 
 4-fluorophenyl-tolylthiomethylformamide;  
 N-[3-methylthiophenyl-(tolylthio)methyl]formamide;  
 4-Fluorophenyl-tosylmethylformamide;  
 3-chlorophenyl-tolylthiomethylformamide;  
 4-trifluoromethylphenyl-tolylthiomethylformamide;  
 3-trifluoromethylphenyl-tolylthiomethylformamide;  
 3,4-dichlorophenyl-tolylthiomethylformamide; or  
 3,5-bistrifluoromethylphenyl-tolylthiomethylformamide.  
 
     
     
         23 . A process for producing a compound according to  claim 20 , wherein p is 2 which process comprises reacting in the presence of a strong base a compound of the formula  
       R 4 CH 2 NC 
       wherein R 4  is as defined for Formula (II), with a compound of the formula ArSO 2 L 1  wherein R 4  and Ar are as defined for Formula (II), and L 1  is a leaving group  
     
     
         24 . The process according to  claim 23  wherein the strong base is an alkyl lithium reagent.  
     
     
         25 . The process according to  claim 24  wherein the alkyl lithium reagent is butyl lithium or lithium diisopropylamide.  
     
     
         26 . A formamide compound of Formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein p is 0, 1 or 2; 
 R 4  is phenyl, naphth-1-yl or naphth-2-yl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) m COR 12 , SR 5 , SOR 5 , OR 12 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, ZC(Z)R 12 , NR 10 C(Z)R 16 , or (CR 10 R 20 ) m NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, C(Z)NR 13 R 14 , C(Z)OR 3 , (CR 10 R 20 ) m COR 3 , S(O) m R 3 , OR 3 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, (CR 10 R 20 ) m NR 10 C(Z)R 3 , NR 10 S(O) m R 8 , NR 10 S(O) m′ NR 7 R 17 , ZC(Z)R 3  or (CR 10 R 20 ) m NR 13 R 14 ;  
 Z is oxygen or sulfur;  
 n is an integer having a value of 1 to 10;  
 m is 0, or the integer 1 or 2;  
 m′ is 1 or 2,  
 R 3  is heterocyclyl, heterocyclylC 1-10  alkyl or R 8 ;  
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 7 R 17 , excluding the moeities —SR 5  being —SNR 7 R 17  and —SOR 5  being —SOH;  
 R 7  and R 17  is each independently selected from hydrogen or C 1-4  alkyl or R 7  and R 17  together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 ;  
 R 8  is C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, (CR 10 R 20 ) n OR 11 , (CR10R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18 , (CR 10 R 20 ) n NR 13 R 14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;  
 R 9  is hydrogen, —C(Z)R 11  or optionally substituted C 1-10  alkyl, S(O) 2 R 18 , optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl;  
 R 10  and R 20  is each independently selected from hydrogen or C 1-4 alkyl;  
 R 11  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl or heteroarylC 1-10  alkyl;  
 R 12  is hydrogen or R 16 ;  
 R 13  and R 14  is each independently selected from hydrogen or optionally substituted C 1-4  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9 ;  
 R 15  is R 10  or C(Z)-C 1-4  alkyl;  
 R 16  is C 1-4  alkyl, halo-substituted-C 1-4  alkyl, or C 3-7  cycloalkyl;  
 R 18  is C 1-10 alkyl, C 3-7  cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or heteroarylalkyl;  
 Ar is an optionally substituted phenyl or napthyl;  
 provided that when ArS(O) p  is tosyl, R 4  is not an unsubstituted phenyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         27 . The compound according to  claim 26  wherein p is 0.  
     
     
         28 . The compound according to  claim 26  wherein p is 2.  
     
     
         29 . The compound according to  claim 26  wherein R 4  is a phenyl substituted by fluorine.  
     
     
         30 . The compound according to  claim 29  wherein the phenyl is substituted in the 4-position.  
     
     
         31 . The compound according to  claim 26  wherein R 4  is a phenyl substituted by SR 5  or S(O)R 5 .  
     
     
         32 . The compound according to  claim 31  wherein wherein R 5  is a C 1- 2  alkyl  
     
     
         33 . The compound according to  claim 32  wherein R 4  is a phenyl substituted in the 4-position.  
     
     
         34 . The compound according to  claim 33  wherein R 4  is a phenyl substituted by CF 3 .  
     
     
         35 . The compound according to  claim 34  wherein the phenyl is substituted in the 4-position.  
     
     
         36 . The compound according to  claim 26  which is 
 4-fluorophenyl-tolylthiomethylformamide;  
 N-[3-methylthiophenyl-(tolylthio)methyl]formamide;  
 4-Fluorophenyl-tosylmethylformamide;  
 3-chlorophenyl-tolylthiomethylformamide;  
 4-trifluoromethylphenyl-tolylthiomethylformamide;  
 3-trifluoromethylphenyl-tolylthiomethylformamide;  
 3,4-dichlorophenyl-tolylthiomethylformamide; or  
 3,5-bistrifluoromethylphenyl-tolylthiomethylformamide.