(Substituted aralkyl) heterocyclic compounds

Abstract

A (substituted-aralkyl)heterocyclic compound of the formula I wherein R1 is an azido, carbamoyl, cyano, formyl, hydroxy or nitro radical, a 1-6C 1-hydroxyalkyl, alkoxy, alkylcarbamoyl, alkylthio, alkylsulphinyl or alkylsulphonyl radical, a 2-cyanoethyl radical, optionally bearing one to four 1-6C alkyl substituents, or a 2-6C alkanoyl, halogenoalkanoyl, alkanoyloxy, alkanoylamino, dialkylcarbamoyl or alkoxycarbonyl radical; R2 and R3, which may be the same or different, are each a hydrogen atom, a 1-6C alkyl, dueterioalkyl or halogenoalkyl radical, or a phenyl or phenyl(1-6C alkyl) radical, in each of which the phenyl may optionally bear one or more substituents; or R2 and R3, together with the carbon atom to which they are attached, may form a 3- to 6-membered ring; or R1R2R3C- is a 1,1-dicyanoethyl or trifluoromethylsulphonyl radical; R4 is a hydrogen or halogen atom, a cyano or nitro radical or a 1-6C alkyl or halogenoalkyl radical; R5 has any of the values defined above for the group R1R2R3C but is not necessarily the same as R1R2R3C, or has any of the values defined above for R4 but is not necesarily the same as R4, or is a carbamoyl, 1-pyrrolidinyl-carbonyl, piperidinocarbonyl, morpholinocarbonyl or nitro radical, a 1-6C alkoxy or halogenoalkoxy radical or a 2-6C alkanoyl or alkoxy-carbonyl radical; A is a methylene or ethylene radical optionally bearing one or more substituents selected from deuterium and halogen atoms, carbamoyl, cyano and hydroxy radicals, 1-6C alkyl and alkoxy radicals, and 2-6C alkanoyloxy radicals provided that when A is linked to R6 through a nitrogen atom thereof, it may not bear a hydroxy, alkoxy or alkanoyloxy substituent on the carbon atom adjacent to such nitrogen atoms; and R6 is a 1+E,uns H+EE -1,2,4-triazol-1-yl, 4+E,uns H+EE -1,2,4-triazol-4-yl, 1+E,uns H+EE -imidazol-1-yl, 5-cyano-1+E,uns H+EE -imidazol-1-yl, 3-pyridyl or 5-pyrimidinyl radical, or a 1+E,uns H+EE -imidazol-1-yl radical, bearing at the 5-position thereof a 1-6C alkyl substituent which is itself optionally substituted by one or more carbamoyl, cyano, hydroxy or 2-6C alkoxycarbonyl radicals; and provided that when R2, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is a 3-pyridyl radical, R1 is not a cyano, hydroxy or hydroxymethyl radical, and when R1 is a hydroxy radical, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is 3-pyridyl, R2 is not a methyl or a 2-chloro-1-methylethyl radical, and provided that when R1 is a methoxycarbonyl radical, R2, R3, R4 and R5 are hydrogen and A is a methylene radical, R1 is not a 1+E,uns H+EE -imidazol-1-yl radical; and the pharmaceutically acceptable acid addition salts thereof.

We claim: .[. 
     
       1.  A (substituted-aralkyl)heterocyclic compound of the formula I wherein R 1  is an azido, carbamoyl, cyano, formyl, hydroxy or nitro radical, a 1-6C 1-hydroxyalkyl, alkoxy, alkylcarbamoyl, alkylthio, alkylsulphinyl or alkylsulphonyl radical, a 2-cyanoethyl radical, optionally bearing one to four 1-6C alkyl substituents, or a 2-6C alkanoyl, halogenoalkanoyl, alkanoyloxy, alkanoylamino, dialkylcarbamoyl or alkoxycarbonyl radical; R 2  and R 3 , which may be the same or different, are each a 1-6C alkyl, deuterioalkyl or halogenoalkyl radical, or R 1  R 2  R 3  C-is a 1,1-dicyanoethyl or trifluoromethylsulphonyl radical; R 4  is a hydrogen or halogen atom, a cyano or nitro radical or a 1-6C alkyl or halogenoalkyl radical; R 5  has any of the values defined above for the group R 1  R 2  R 3  C, or has any of the values defined above for R 4 , or is a carbamoyl, 1-pyrrolidinyl-carbonyl, piperidinocarbonyl, morpholinocarbonyl or nitro radical, a 1-6C alkoxy or halogenoalkoxy radical or a 2 6C alkanoyl or alkoxy-carbonyl radical; A is a methylene or ethylene radical optionally bearing one or more substituents selected from the group consisting of deuterium and halogen atoms, carbamoyl, cyano and hydroxy radicals, 1-6C alkyl and alkoxy radicals, and 2 6C alkanoyloxy radicals provided that when A is linked to R 6  through a nitrogen atom thereof, it may not bear a hydroxy, alkoxy or alkanoyloxy substituent on the carbon atom adjacent to such nitrogen atoms; and R 6  is a 1H-1,2,4-triazol-1-yl or 4H-1,2,4-triazol-4 yl; and the pharmaceutically acceptable acid addition salts thereof..]..[.2. A compound as claimed in claim 1 wherein R 1  is an azido, carbamoyl, cyano, formyl, hydroxy, nitro, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-1-methylpropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxypentyl, 1-hydroxyhexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio, hexylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, butylsulphinyl, isobutylsulphinyl, sec-butylsulphinyl, tert-butylsulphinyl, pentylsulphinyl, neopentylsulphinyl, hexylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, isobutylsulphonyl, sec-butylsulphonyl, tert-butylsulphonyl, pentylsulphonyl, neopentylsulphonyl, hexylsulphonyl, acetyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, 2,2,2-trichloropropionyl, 2,2,2-trifluoropropionyl, 1,2,2-trifluoropropionyl, 1,2,2,2-tetrafluoropropionyl, perfluoropropionyl, 2,2,3,3,3-pentafluorobutyryl, 2,2-dichloro-3,3,3-trifluorobutyryl, 4,4,4-trifluorovaleryl, 5,5,5-trifluorohexanoyl, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, acetamido, propionamido, butyramido, isobutyramido, valeramido, isovaleramido, pivalamido, hexanamido, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or pentyloxycarbonyl radical; R 2  and R 3 , which may be the same or different, are each a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, trideuteriomethyl, mono-, di or tri-chloromethyl, mono-, di- or trifluoromethyl, 2,2,2-trichloro- or trifluoro-ethyl, 1,2,2-trichloro-or trifluoro-ethyl, pentafluoroethyl, 2,2,3,3,3-pentafluoropropyl, 2,2-dichloro-3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl or 6,6,6-trifluorohexyl radical, or R 1  R 2  R 3  C is a 1,1-dicyanoethyl or trifluoromethylsulphonyl radical; R 4  is a hydrogen atom, a cyano or nitro radical, or a 1-6C alkyl or halogenoalkyl radical as defined above; R 5  has any of the values defined above for the group R 1  R 2  R 3  C, or has any of the values defined above for R 4 , or is a 1-6C alkoxy or a 2 6C alkanoyl or alkoxycarbonyl radical as defined above, or a carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl or nitro radical, a fluorine, chlorine, bromine or iodine atom, or a mono-, di- or tri-chloromethoxy, mono-, di- or trifluoromethoxy, bromomethoxy, iodomethoxy, 2,2,2-trichloro- or trifluoro-ethoxy, 1,2,2-trichloro- or trifluoro-ethoxy, pentafluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2-dichloro-3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy or 6,6,6-trifluorohexyloxy radical; A is an ethylidene, propylidene, butylidene, 1- or 2-methylethylene, 1,2-dimethylethylene, dideuteriomethylene, difluoromethylene, hydroxymethylene, cyanomethylene or carbamoylmethylene radical, or a 1-hydroxyethylene radical (in which C-1 of the ethylene is linked to the benzene ring) radicals..]..[.3. A compound as claimed in claim 1 which is a hydrochloride, hydrobromide, sulphate, nitrate, phosphate or toluene-p-sulphonate..]..[.4. A compound as claimed in claim 1, 2 or 3 wherein R 1  is a carbamoyl, cyano, hydroxy, 1-hydroxyethyl, methylthio, methylsulphinyl, methylsulphonyl or acetyl radical R 2  and R 3 , which may be the same or different, are each a methyl, ethyl, trideuteriomethyl or fluoromethyl radical; R 4  is a hydrogen, fluorine or bromine atom or a cyano, nitro, isopropyl or chloromethyl radical; R 5  is a 1-cyano-1-methylethyl, 1,1-dimethyl-2-oxopropyl, 1-carbamoyl-1-methylethyl, 1-cyano-1-trideuteriomethyl-2,2,2-trideuterioethyl, 1-cyano-2-fluoro-1-(fluoromethyl)ethyl, 1-methyl-1-(methylsulphonyl)-ethyl, 1-cyano-1-ethylpropyl, carbamoyl, 1-piperidinocarbonyl, 1-morpholinocarbonyl, acetyl or methoxycarbonyl radical; A is a methylene, ethylene, ethylidene, isopropylidene, dideuteriomethylene, hydroxymethylene, cyanomethylene, fluoromethylene or difluoromethylene radical, or a 1-hydroxyethylene radical in which the carbon atom bearing the hydroxy substituent is bonded to the benzene ring; and R 6  is a 1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl..]..[.5. A compound as claimed in claim 1 wherein R 1  is a cyano radical, R 5  is a radical of the formula R 1  R 2  R 3  C wherein R 1  is a cyano or hydroxy radical, and R 6  is a 1H-1,2,4-triazol-1-yl radical..]..[.6. A compound as claimed in claim 5 wherein R 2  and R 3 , both in the group R 1  R 2  R 3  C and in R 5 , are methyl or trideuteriomethyl radicals, and A is a methylene or 
     
     
        dideuteriomethylene radical..].7. A compound .[.as claimed in claim 1 which is.]. .Iadd.selected from the group consisting of .Iaddend.2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), .[.2-[3-(1-hydroxy-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitrile,.]. 2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)-methyl-1,3-phenylene]di(2-trideu teriomethyl-3,3,3-trideuteriopropiononitrile) .[.or.]. .Iadd.and .Iaddend.2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylpropiononitrile).Iadd., or a pharmaceutically acceptable acid 
     
     
        addition salt thereof.Iaddend.. 8. A pharmaceutical or veterinary composition which comprises an effective amount of a compound as claimed in claim .[.1.]. .Iadd.7 .Iaddend.together with a pharmaceutically or 
     
     
        veterinarily acceptable diluent or carrier. 9. A method of treating steroid hormone-dependent tumours which comprises administering to a host in need of such treatment an effective amount of a compound as claimed in 
     
     
        claim .[.1.]. .Iadd.7.Iaddend.. .Iadd.10.  A compound of claim 7 which is 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile)..Iaddend..Iadd.11. A composition of claim 8 wherein the compound is 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)1,3-phenylene]di(2-methylpropiononitrile)..Iaddend..Iadd.12. The method of claim 9 wherein the compound is 2,2'-[5- (1H-1,2,4-triazol-1-ylmethyl)1,3-phenylene]di(2-methylpropiononitrile)..Iaddend..Iadd.13. A compound of claim 7 which is 2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-trideuteriomethyl-3,3,3-trideuteriopropiononitrile)..Iaddend..Iadd.14. A compound of claim 7 which is 2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylp 
     
     
       ropiononitrile)..Iaddend..Iadd.15.  A compound as claimed in claim 7 which is a hydrocholoride, hydrobromide, sulphate, nitrate, phosphate or toluene-p-sulphonate..Iaddend..Iadd.16. A compound selected from the group consisting of 2,2'-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), 2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-trideuteriomethyl-3,3,3-trideuteriopropiononitrile) and 2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylpropiononitrile)..Iaddend.