A (substituted-aralkyl)heterocyclic compound of the formula I ##STR1## wherein R.sup.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.sup.2 and R.sup.3, 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 R.sup.2 and R.sup.3, together with the carbon atom to which they are attached, may form a 3- to 6-membered ring; or R.sup.1 R.sup.2 R.sup.3 C- is a 1,1-dicyanoethyl or trifluoromethylsulphonyl radical; R.sup.4 is a hydrogen or halogen atom, a cyano or nitro radical or a 1-6C alkyl or halogenoalkyl radical; R.sup.5 has any of the values defined above for the group R.sup.1 R.sup.2 R.sup.3 C but is not necessarily the same as R.sup.1 R.sup.2 R.sup.3 C, or has any of the values defined above for R.sup.4 but is not necesarily the same as R.sup.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 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.sup.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.sup.6 is a 1H-1,2,4-triazol-1-yl, 4H-1,2,4-triazol-4-yl, 1H-imidazol-1-yl, 5-cyano-1H-imidazol-1-yl, 3-pyridyl or 5-pyrimidinyl radical, or a 1H-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 R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen, A is a methylene radical and R.sup.6 is a 3-pyridyl radical, R.sup.1 is not a cyano, hydroxy or hydroxymethyl radical, and when R.sup.1 is a hydroxy radical, R.sup.3, R.sup.4 and R.sup.5 are hydrogen, A is a methylene radical and R.sup.6 is 3-pyridyl, R.sup.2 is not a methyl or a 2-chloro-1-methylethyl radical, and provided that when R.sup.1 is a methoxycarbonyl radical, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen and A is a methylene radical, R.sub.1 is not a 1H-imidazol-1-yl radical; and the pharmaceutically acceptable acid addition salts thereof.

This invention relates to (substituted-aralkyl)heterocyclic compounds, and 
in particular relates to such compounds which are useful as inhibitors of 
the enzyme aromatase. 
Aromatase is an enzyme which effects aromatisation of ring A in the 
metabolic formation of various steroid hormones. Various cancers, for 
example breast cancer, are dependent upon circulating steroid hormones 
which have an aromatic ring A. Such cancers can be treated by removing the 
source of ring A aromatised steroid hormones, for example by the 
combination of oophorectomy and adrenalectomy. An alternative way of 
obtaining the same effect is by administering a chemical compound which 
inhibits the aromatisation of the steroid ring A, and the compounds of the 
invention are useful for this purpose. 
A variety of compounds possessing aromatase inhibitory activity is known, 
of which the most important clinically is aminoglutethimide. 
Aminoglutethimide, however, has the drawback that it affects other aspects 
of steroid metabolism, with the consequence that its use is often 
associated with undesirable side-effects. It is a particular object of the 
present invention to provide aromatase inhibitory compounds with fewer 
undesirable side effects than aminoglutethimide. 
According to the invention, there is provided a 
(substituted-aralkyl)heterocyclic compound of the formula I wherein 
R.sup.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.sup.2 and R.sup.3, which may be the same or different, are each a 
hydrogen atom, a 1-6C alkyl, deuterioalkyl 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 R.sup.2 and R.sup.3, together 
with the carbon atom to which they are attached, may form a 3- to 
6-membered ring; or R.sup.1 R.sup.2 R.sup.3 C-- is a 1,1-dicyanoethyl or 
trifluoromethylsulphonyl radical; R.sup.4 is a hydrogen or halogen atom, a 
cyano or nitro radical or a 1-6C alkyl or halogenoalkyl radical; R.sup.5 
has any of the values defined above for the group R.sup.1 R.sup.2 R.sup.3 
C but is not necessarily the same as R.sup.1 R.sup.2 R.sup.3 C, or has any 
of the values defined above for R.sup.4 but is not necessarily the same as 
R.sup.4, or is a carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 
morpholinocarbonyl or nitro radical, a 1-6C alkoxy or halogenoalkoxy 
radical or a 2-6C alkanoyl or alkoxycarbonyl 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 R.sup.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.sup.6 is a 1H-1,2,4-triazol-1 -yl, 
4H-1,2,4-triazol-4-yl, 1H-imidazol-1-yl, 5 cyano-1H-imidazol-1-yl, 
3-pyridyl or 5-pyrimidinyl radical, or a 1H-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 R.sup.2, R.sup.3, R.sup.4 
and R.sup.5 are hydrogen, A is a methylene radical and R.sup.6 is a 
3-pyridyl radical, R.sup.1 is not a cyano, hydroxy or hydroxymethyl 
radical, and when R.sup.1 is a hydroxy radical, R.sup.3, R.sup.4 and 
R.sup.5 are hydrogen, A is a methylene radical and R.sup.6 is 3-pyridyl, 
R.sup.2 is not a methyl or a 2-chloro-1-methylethyl radical, and provided 
that when R.sup.1 is a methoxycarbonyl radical, R.sup.2, R.sup.3, R.sup.4 
and R.sup.5 are hydrogen and A is a methylene radical, R.sup.1 is not a 
1H-imidazol-1-yl radical; and the pharmaceutically acceptable acid 
addition salts thereof. 
A suitable value for R.sup.1 when it is a hydroxyalkyl radical, or for a 
hydroxyalkyl radical in R.sup.5 when it is a group of the formula R.sup.1 
R.sup.2 R.sup.3 C is, for example, a hydroxymethyl, 1-hydroxyethyl, 
1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-1-methylpropyl, 
1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxypentyl or 
1-hydroxyhexyl radical. 
A suitable value for R.sup.1 or R.sup.5 when either is an alkoxy radical, 
or for an alkoxy radical in R.sup.5 when it is a group of the formula 
R.sup.1 R.sup.2 R.sup.3 C, or for an optional alkoxy substituent in A, is, 
for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 
sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy or hexyloxy radical. 
A suitable value for R.sup.1 when it is an alkylthio radical, or for an 
alkylthio radical in R.sup.5 when it is a group of the formula R.sup.1 
R.sup.2 R.sup.3 C, is, for example, a methylthio, ethylthio, propylthio, 
isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, 
pentylthio, neopentylthio or hexylthio radical. 
A suitable value for R.sup.1 when it is an alkylsulphinyl radical, or for 
an alkylsulphinyl radical in R.sup.5 when it is a group of the formula 
R.sup.1 R.sup.2 R.sup.3 C, is, for example, a methylsulphinyl, 
ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, butylsulphinyl, 
isobutylsulphinyl, sec-butylsulphinyl, tert-butylsulphinyl, 
pentylsulphinyl, neopentylsulphinyl or hexylsulphinyl radical. 
A suitable value for R.sup.1 when it is an alkylsulphonyl radical, or for 
an alkylsulphonyl radical in R.sup.5 when it is a group of the formula 
R.sup.1 R.sup.2 R.sup.3 C, is, for example, a methylsulphonyl, 
ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, butylsulphonyl, 
isobutylsulphonyl, sec-butylsulphonyl, tert-butylsulphonyl, 
pentylsulphonyl, neopentylsulphonyl or hexylsulphonyl radical. 
A suitable value for R.sup.1 or R.sup.5, when either is an alkanoyl 
radical, or for an alkanoyl radical in R.sup.5 when it is a group of the 
formula R.sup.1 R.sup.2 R.sup.3 C, is, for example, an acetyl, butyryl, 
isobutyryl, valeryl, isovaleryl, pivaloyl or hexanoyl radical. 
A suitable value for R.sup.1 when it is a halogenoalkanoyl radical, or for 
a halogenoalkanoyl radical in R.sup.5 when it is a group of the formula 
R.sup.1 R.sup.2 R.sup.3 C, is, for example, a 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 or 
5,5,5-trifluorohexanoyl radical. 
A suitable value for R.sup.1 when it is an alkanoyloxy radical, or for an 
alkanoyloxy radical in R.sup.5 when it is a group of the formula R.sup.1 
R.sup.2 R.sup.3 C, or for an optional alkanoyloxy substituent in A, is, 
for example, an acetoxy, propionyloxy, butyryloxy, isobutyryloxy, 
valeryloxy, isovaleryloxy, pivaloyloxy or hexanoyloxy radical. 
A suitable value for R.sup.1 when it is an alkanoylamino radical, or for an 
alkanoylamino radical in R.sup.5 when it is a group of the formula R.sup.1 
R.sup.2 R.sup.3, is, for example, an acetamido, propionamido, butyramido, 
isobutyramido, valeramido, isovaleramido, pivalamido or hexanamido 
radical. 
A suitable value for R.sup.1 or R.sup.5, when either is an alkoxycarbonyl 
radical, or for an alkoxycarbonyl radical in R.sup.5 when it is a group of 
the formula R.sup.1 R.sup.2 R.sup.3 C, is, for example, a methoxycarbonyl, 
ethoxycaronyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, 
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or 
pentyloxycarbonyl radical. 
A suitable value for R.sup.2, R.sup.3 or R.sup.4, when any is an alkyl 
radical, or for an optional alkyl substituent in A, is, for example a 
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 
pentyl, neopentyl or hexyl radical. 
A suitable value for R.sup.2 or R.sup.3, when either is a deuterioalkyl 
radical, is, for example, a trideuteriomethyl radical. 
A suitable value for R.sup.2, R.sup.3 or R.sup.4, when any is a 
halogenoalkyl radical, is, for example, a 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. 
When either of R.sup.2 and R.sup.3 is a substituted phenyl or 
phenyl(1-6C)alkyl) radical, the phenyl may bear one to five, preferably 
one or two, substituents selected from halogen atoms, for example 
fluorine, chlorine and bromine atoms, and cyano and 1-6C alkyl radicals. A 
suitable phenyl(1-6C)alkyl) radical is, for example, a benzyl, phenethyl, 
1-phenylethyl or 1-methyl-1-phenylethyl radical. 
A suitable value for R.sup.4 when it is a halogen atom is, for example, a 
fluorine, chlorine, bromine or iodine atom. 
A suitable value for R.sup.5 when it is a halogenoalkoxy radical is, for 
example, a mono-, di- or tri-chloromethoxy, mono-, di- or 
tri-fluoromethoxy, 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. 
Suitable values for A, when it is a substituted methylene or ethylene 
radical are, for example, an ethylidene, propylidene, butylidene, 1- or 
2-methylethylene, 1,2-dimethylethylene, dideuteriomethylene, 
difluoromethylene, hydroxymethylene, cyanomethylene, carbamoylmethylene 
and 1-hydroxyethylene (in which C-1 of the ethylene is linked to the 
benzene ring) radicals. 
Suitable pharmaceutically acceptable acid addition salts are, for example, 
hydrochlorides, hydrobromides, sulphates, nitrates, phosphates and 
toluene-p-sulphonates. 
It is to be understood that when A bears one or more substituents as 
defined above, one or both of the carbon atoms in A may be asymmetrically 
substituted, and that the carbon atom bearing substituents R.sup.1, 
R.sup.2 and R.sup.3 may also be asymmetrically substituted, so that the 
compounds of the invention may exist in racemic or optically active forms. 
It is common general knowledge how such optically active and meso forms 
may be synthesized or separated, and their respective aromatase inhibitory 
properties determined. 
A preferred group of compounds of the invention comprises compounds wherein 
R.sup.1 is a cyano radical, R.sup.5 is a radical of the formula R.sup.1 
R.sup.2 R.sup.3 C wherein R.sup.1 is a cyano or hydroxy radical, and 
R.sup.6 is a 1H-imidazol-1-yl or 1H-1,2,4-triazol-1-yl radical, and 
especially preferred are such compounds wherein R.sup.2 and R.sup.3, both 
in the group R.sup.1 R.sup.2 R.sup.3 C and in R.sup.5, are methyl or 
trideuteriomethyl radicals and A is a methylene or dideuteriomethylene 
radical. 
Particular preferred compounds are the compounds described below as 
Examples 1, 9, 33, 53 and 54, that is respectively 2,2'-[5-( 
1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), 
2,2'-[5-(imidazol-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-trideut 
eriomethyl-3,3,3-trideuteriopropiononitrile) and 
2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylp 
ropiononitrile). 
The compounds of the invention may be manufactured by processes known per 
se for the manufacture of analogous compounds. Thus, the following 
processes are provided as further features of this invention, in which 
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and A have the 
meanings defined above, unless otherwise stated: 
(a) the reaction of a compound of the formula II, wherein X is a known 
displaceable leaving group, with a heterocyclic compound of the formula 
R.sup.6 H, or with a reactive metal derivative thereof, or with a 
protected derivative thereof wherein a nitrogen atom which is intended not 
to be involved in the reaction with the compound of the formula II is 
protected by a known nitrogen protecting group, whereafter the said 
protecting group is removed; or 
(b) for those compounds wherein A is a hydroxymethylene radical or an 
optionally-substituted 2-hydroxyethylene radical, in which C-1 of the 
ethyl radical is attached to the benzene ring, the reaction of an oxo 
compound of the formula III wherein Al is a direct bond or a methylene 
radical, optionally substituted as defined above and R.sup.7 is one of the 
optional substituents in A defined above, with an alkali metal derivative 
of a heterocyclic compound of the formula R.sup.6 H; or 
(c) for those compounds wherein A is a 1-hydroxyethylene radical, in which 
0-1 of the ethylene radical is attached to the benzene ring, the reaction 
of an epoxide of the formula IV, either as such or formed in situ in the 
reaction, with a heterocyclic compound of the formula R.sup.6 H; or 
(d) for those compounds wherein R.sup.6 is a 5-cyanoimidazol-1-yl radical, 
the reaction of the corresponding 5-oximino-imidazol-1-yl compound with a 
dehydrating agent; whereafter if desired 
(i) a compound of the invention in which R.sup.1, R.sup.4 or R.sup.5 is a 
cyano radical is hydrolysed with an acid to form a compound of the 
invention bearing a corresponding carbamoyl substituent; or 
(ii) a compound of the invention in which R.sup.1 or R.sup.5 is an 
alkoxycarbonyl radical is reacted with ammonia, pyrrolidine, piperidine or 
morpholine to form a compound of the invention wherein R.sup.1 or R.sup.5 
is a corresponding carbamoyl substituent, or R.sup.5 is a corresponding 
1-pyrrolidinylcarbonyl, piperidinocarbonyl or morpholinocarbonyl 
substituent; or 
(iii) a compound of the invention in which R.sup.1 or R.sup.5 is a 
carbamoyl radical is dehydrated with an acid anhydride to form a compound 
of the invention bearing a corresponding cyano substituent; or 
(iv) a compound of the invention in which R.sup.1 or R.sup.5 is an 
alkoxycarbonyl substituent is reduced to form a compound of the invention 
bearing a corresponding hydroxymethyl substituent; or 
(v) a compound of the invention in which R.sup.4 or R.sup.5 is a 
hydroxyalkyl radical is reacted with a halogenating agent to form a 
compound of the invention in which R.sup.4 or R.sup.5 is a corresponding 
halogenoalkyl substituent; or 
(vi) a compound of the invention in which R.sup.5 is a halogenoalkyl 
substituent is reacted with an alkali metal cyanide to form a compound of 
the invention wherein R.sup.5 is a group of the formula R.sup.1 R.sup.2 
R.sup.3 which is a cyanoalkyl substituent; or 
(vii) a compound of the invention in which R.sup.5 is a halogenoalkyl 
radical is reacted with an alkali metal alkylthiolate to form a compound 
of the invention wherein R.sup.5 is a group R.sup.1 R.sup.2 R.sup.3 C in 
which R.sup.1 is an alkylthio substituent; or 
(viii) a compound of the invention in which R.sup.5 is a group R.sup.1 
R.sup.2 R.sup.3 C wherein, R.sup.1 is an alkylthio radical is reacted with 
an oxidising agent to form a compound of the invention in which R.sup.5 is 
a group R.sup.1 R.sup.2 R.sup.3 C wherein R.sup.1 is an alkylsulphinyl or 
alkylsulphonyl radical; or 
(ix) a compound of the invention in which R.sup.1 or R.sup.5 is an 
alkoxycarbonyl radical is reacted with an alkylmagnesium halide to form a 
compound of the invention in which R.sup.1 or R.sup.5 is a corresponding 
hydroxyalkyl radical; or 
(x) a compound of the invention in which A bears a hydroxy substituent is 
reacted with a halogenating agent to form a corresponding compound of the 
invention in which A bears a halogen substituent; or 
(xi) a compound of the invention in which A bears a halogen substituent is 
hydrogenated to form a corresponding compound of the invention wherein A 
lacks the halogen substituent of the starting compound; or 
(xii) a compound of the invention in which R.sup.1 is a 1-hydroxyalkyl 
radical wherein C-1 bears a hydrogen atom, is oxidised to form a compound 
of the invention wherein R.sup.1 is an alkanoyl radical; or 
(xiii) a compound of the invention in which A is a 1-hydroxyethylene 
radical wherein C-1 of the ethylene radical is attached to the benzene 
ring, is converted to a compound of the invention in which A is an 
ethylene radical by successively reacting with a halogenating agent to 
form the corresponding 1-halogenoethylene compound, dehydrohalogenating 
the 1-halogenoethylene compound to the corresponding compound in which A 
is vinylene, and hydrogenating the compound in which A is vinylene; or 
(xiv) a compound of the invention in which R.sup.1 is a 2-6C alkanoyl 
radical is reduced to form a compound of the invention wherein R.sup.1 is 
a 1-hydroxyalkyl radical: or 
(xv) a compound of the invention in which R.sup.1 is a hydroxy radical is 
reacted with a trialkylsilane to form a compound of the invention wherein 
R.sup.4 is an alkyl radical; or 
(xvi) a compound of the invention in which R.sup.4 is a halogen atom is 
reacted with a metal cyanide to form a compound of the invention wherein 
R.sup.4 is a cyano radical. 
In process (a), a suitable value for the known displaceable leaving group X 
is, for example, a halogen atom, for example a chlorine or bromine atom, 
or an alkylsulphonyloxy or arylsulphonyloxy radical, for example a 
mesyloxy or tosyloxy radical or a hydroxy radical. When X is a hydroxy 
radical, the process is preferably carried out in trifluoroacetic acid. A 
suitable metal derivative of a heterocyclic compound of the formula 
R.sup.6 H is an alkali metal derivative, such as sodium 1H-1,2,4-triazole 
or 3-pyridyl-lithium A suitable known nitrogen protecting group for a 
nitrogen atom of R.sup.6 H which is intended not to be involved in the 
reaction with the compound of the formula II is, for example, a trityl 
radical. Such a trityl protecting group can be readily removed by acid 
treatment. Examples of the use of such a protected heterocyclic compound 
are Examples 5 and 6 hereafter, in which R.sup.6 H is 
4-methyl-1-tritylimidazole, leading to the desired 5-methyl-1-imidazolyl 
products rather than the undesired 4-methyl-1-imidazolyl isomers. 
The compound of the formula II wherein X is a bromine atom, which is used 
as starting material in process (a), may be obtained by standard, 
relatively simple processes involving bromination of an 
appropriately-substituted alkylbenzene. For example, 
3,5-bis(bromomethyl)toluene V was reacted with potassium cyanide to form 
3,5-bis(cyanomethyl)toluene VI, which was then alkylated with an 
iodoalkane R.sup.2 I or R.sup.3 I to form VII, which in turn was 
brominated with N bromosuccinimide to form the required starting material 
II, X=Br. 
Similarly, starting materials of the formula II wherein X is chlorine, 
alkylsulphonyloxy or arylsulphonyloxy may be obtained by conventional 
procedures. For example, methyl 3,5-dimethylbenzoate VIII was brominated 
with N bromosuccinimide to form the 3,5-bis(bromomethyl) compound IX, 
which was converted as described above to the corresponding dinitrile X 
and alkylated dinitrile XI. This compound XI was then reduced, for example 
with lithium borohydride, to the corresponding alcohol XII, which was then 
converted either to the starting material of the formula II in which X is 
chlorine by reaction with thionyl chloride or phosphoryl chloride, or to a 
starting material of the formula II in which X is an alkylsulphonyloxy or 
arylsulphonyloxy radical by reaction with an appropriate alkylsulphonyl 
chloride or arylsulphonyl chloride, for example mesyl chloride or tosyl 
chloride. Starting materials of the formula II bearing other of the 
defined substituents may be obtained by generally similar processes. 
Starting materials of the formula II wherein X is a hydroxy radical may 
similarly be made by conventional procedures, for example as described 
above for a compound of the formula XII. Corresponding starting materials 
wherein A is an alkylated methylene group may be obtained by reacting a 
methoxycarbonyl compound, such as for example compound XI, with a Grignard 
reagent, for example methylmagnesium chloride. 
In process (b), suitable alkali metal derivatives of a heterocyclic 
compound of the formula R.sup.6 H are those described above, under process 
(a). 
The oxo compound of the formula III used as starting material in process 
(b) may be obtained by oxidation of the corresponding hydroxyalkyl 
compound, (for example compound XIII), for example with pyridinium 
chlorochromate 
The epoxide of the formula IV, used in process (c), may be obtained by 
reacting an aldehyde of the formula III with trimethylsulphoxonium iodide 
in the presence of a base, for example potassium hydroxide. The epoxide 
may be isolated as such, and then reacted with a heterocyclic compound 
R.sup.6 H, or the epoxide may be formed in situ by reacting the aldehyde 
of the formula III, trimethylsulphoxonium iodide and the heterocyclic 
compound R.sup.6 H together in one reaction. 
In process (d), a suitable dehydrating agent is, for example, 
trifluoroacetic anhydride. 
In optional process (i), a suitable acid for use in the hydrolysis process 
is, for example, hydrochloric acid or sulphuric acid. 
In optional process (iii), a suitable acid anhydride is, for example, 
trifluoroacetic anhydride. 
The reduction in optional process (iv) may be carried out with, for 
example, a metal hydride reducing agent, for example lithium aluminium 
hydride or lithium borohydride. 
A suitable halogenating agent for use in optional processes (v), (x) and 
(xiii) is, for example, thionyl chloride or phosphoryl chloride. 
In process (vi), a suitable alkali metal cyanide is, for example, potassium 
cyanide or sodium cyanide. 
The oxidation in optional process (viii) may be carried out using, for 
example, a derivative of a peracid, for example sodium periodate, 
peracetic acid or m-chloroperbenzoic acid. 
In optional process (x), a suitable halogenating agent to obtain 
fluorine-substituted compound of the invention is, for example, 
diethylaminosulphur trifluoride 
In optional process (xi), the hydrogenation may be carried out over a metal 
catalyst, for example, palladium, platinum or nickel, at normal 
temperature and pressure 
The oxidation in optional process (xii) may be carried out, for example, 
with dimethylsulphoxide and oxalyl chloride, Jones's reagent or 
periodinane. 
In optional process (xiii), the dehydrohalogenation reaction may be carried 
out with a base, for example, sodium triazole, a sodium (lower alkoxide) 
or sodium hydroxide. 
In optional process (xiv), a suitable reducing agent is, for example, 
sodium borohydride. 
In optional process (xv), a suitable trialkylsilane is, for example, 
triethylsilane, in trifluoroacetic acid. 
In optional process (xvi), a suitable halogen substituent is, for example, 
a bromine atom, and a suitable metal cyanide is, for example, cuprous 
cyanide. 
The processes (a) to (d) of the invention, and optional subsequent 
processes (i) to (xiii) may be carried out as specified, and may be 
accelerated or completed by heating. 
As indicated above, the compounds of the invention of the formula I are 
useful as aromatase inhibitors. Aromatase inhibition may be demonstrated 
by the following tests: 
DEMONSTRATION OF ACTIVITY IN VITRO 
Aromatase inhibitory activity was measured using the enzyme present in the 
microsomal fraction of human term placenta, as described by Ryan, J. Biol, 
Chem. 234,268, 1959. Enzyme activity was determined by measuring the 
amount of tritiated water released from 0.5 micromolar 
(1.beta.,2.beta.-.sup.3 H)testosterone after 20 minutes incubation at 
37.degree.. The method used was essentially that described by Thomson and 
Siiteri, J. Biol. Chem. 249,5364,1974 except that testosterone was used in 
place of androstenedione Test compounds were dissolved in 
dimethylsulphoxide (DMSO) then diluted as appropriate to achieve final 
concentrations of 2, 0.2 or 0.02 .mu.g/ml. The reaction was started by the 
addition of 50 .mu.l of microsome suspension to 50 .mu.l of a solution 
containing substrate (testosterone) and cofactors (NADPH 
glucose-6-phosphate and glucose-6-phosphate dehydrogenase) and either DMSO 
alone or a DMSO solution of test compound Each concentration of test 
compound was tested in triplicate. The reaction was stopped by the 
addition of 200 .mu.l of 5% (w/v) suspension of charcoal in 0.5% (w/v) 
solution of Dextran T70 in water. After 1 hour the charcoal was 
precipitated by centrifugation and 150 .mu.l of supernatant removed and 
the amount of tritiated water present determined using a liquid 
scintillation counter. The number of counts in supernatant from 
incubations containing test compound expressed as a percentage of the 
counts in supernatant from incubations containing only DMSO was taken as 
the degree of enzyme inhibition achieved by the test compound 
DEMONSTRATION OF ACTIVITY IN VIVO 
Activity in vivo was demonstrated in terms of ovulation inhibition in 
female rats. Daily vaginal smears were taken from rats housed under 
controlled lighting (lights on 06.00 hr to 20.00 hr) and those having a 
vaginal smear pattern consistent with 4 day ovarian cycles were selected 
To these rats a single dose of test compound was given either at 16.00 hr 
on Day 2 of the cycle or at 12.00 hr on Day 3 of the cycle. The rats were 
then killed in the morning following Day 4 of the cycle--approximately 64 
hours after Day 2 treatments or approximately 46 hours after Day 3 
treatments--and the presence or absence of eggs in the fallopian tubes 
determined. The presence of eggs indicates that the rats have ovulated. 
Without treatment more than 95% of rats with 4-day ovarian cycles are found 
to have ovulated at the time of the post-mortem examination. At an 
effective dose, aromatase inhibitors prevent ovulation i.e. no eggs are 
found in the fallopian tubes. 
In the above tests, the compounds of formula I are active at less than 10 
.mu.g/ml (in vitro), and the preferred compounds of the formula I are 
active at below 0.1 .mu.g/ml (in vitro) and 1.0 mg/kg (in vivo), and no 
indication of any toxicity has been seen at these doses. 
Thus, according to a further feature of the invention there is provided a 
pharmaceutical or veterinary composition which comprises an effective 
amount of a compound of the formula I together with a pharmaceutically or 
veterinarily acceptable diluent or carrier. 
The composition of the invention may be in a conventional pharmaceutical 
form suitable for oral administration, for example a tablet, a capsule, an 
emulsion or an aqueous or oily solution or suspension. The composition may 
contain conventional pharmaceutical excipients, and may be manufactured by 
conventional pharmaceutical techniques. 
Preferred pharmaceutical or veterinary compositions of the invention are 
tablets and capsules containing from 0.1 to 100, preferably 0.25 to 25 mg. 
of a compound of the invention.

The invention is illustrated but not limited by the following Examples. 
Melting points are given in degrees Celsius. Flash column chromatography 
was carried out on silica gel (Merck Kieselgel 60H). 
EXAMPLE 1 
A mixture of 2,2'-(5-methyl-1,3-phenylene)di(2-methylpropiononitrile), 
(2.26 g), N-bromosuccinimide (1.78 g), benzoyl peroxide (0.05 g) and 
carbon tetrachloride (50 ml) was heated under reflux for 2 h, cooled and 
filtered, and the filtrate was evaporated to dryness under reduced 
pressure. The residue was dissolved in dimethylformamide (20 ml), sodium 
triazole (1.8 g) was added, and the mixture was stirred at room 
temperature for 18 h. Water (100 ml) was added, and the mixture was 
extracted twice with ethyl acetate. The extracts were combined, dried and 
evaporated to dryness under reduced pressure, and the residue was purified 
by flash column chromatography, eluting with ethyl acetate, to give 
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononit 
rile), mp 81.degree.-82.degree. after crystallisation from ethyl 
acetate/cyclohexane. 
The 5-methyl-1,3-phenylene compound used as starting material in the above 
process may be prepared as follows: 
A mixture of 3,5-bis(bromomethyl)toluene (30 g), tetrabutylammonium bromide 
(1 g), potassium cyanide (17.6 g), dichloromethane (100 ml) and water (30 
ml) was stirred vigorously and heated under reflux for 3 h. The mixture 
was cooled, diluted with water (100 ml) and extracted three times with 
ethyl acetate. The extracts were combined, dried and evaporated to 
dryness, and the residue was purified by flash column chromatography, 
eluting with petroleum ether (bp 60.degree.-80.degree.): ethyl acetate 
(3:1 by volume), to give 2,2'-(5-methyl-1,3-phenylene)diacetonitrile, mp 
73 74.degree. after crystallisation from carbon tetrachloride. 
A mixture of this diacetonitrile (11.5 g), iodomethane (42 g) and 
dimethylformamide (150 ml) was cooled in an ice bath and stirred while 
sodium hydride (50% dispersion in mineral oil, 15 g) was added in portions 
over 1 h. The mixture was then allowed to warm to room temperature and 
stirred for 2 h, then water (500 ml) was added, and the mixture was 
extracted twice with ethyl acetate. The extracts were combined, dried and 
evaporated to dryness under reduced pressure, and the residue was 
crystallised from carbon tetrachloride to give the required 
5-methyl-1,3-phenylene starting material, mp 126.degree.-127.degree.. 
EXAMPLES 2-4 
The process described in Example 1 was repeated, using the appropriate 
5-methyl-1,3-disubstituted phenylene compound as starting material, to 
give the following compounds: 
______________________________________ 
##STR2## 
Example 
R.sup.3 R.sup.4 Mp Footnotes 
______________________________________ 
2 CN C(CH.sub.3).sub.2 COCH.sub.3 
-- 1,2 
3 COCH.sub.3 
C(CH.sub.3).sub.2 COCH.sub.3 
73-75 2 
4 CN COOCH.sub.3 159-161 
3,4 
______________________________________ 
Footnotes 
1. Nmr in deuteriochloroform; .delta. 8.12(1H, s), 8.0(1H, s), 7.35(1H, 
m), 
7.25(1H, m), 7.1(1H, m), 5.37(2H, s), 1.92(3H, s), 1.70(6H, s), 
1.48(6H, s). 
2. The 2-methyl-2-[5-(1,1-dimethyl-2-oxopropyl)-3-tolyl]propiono- 
nitrile required as starting material for Example 2 and the 1,1'-(5- 
methyl-1,3-phenylene)di(1,1-dimethyl-2-propanone) required as the 
starting material for Example 3, were obtained as follows:- 
A solution of methylmagnesium chloride in tetrahydrofuran 
(3M, 1 ml) was added to a solution of 2,2'-(5-methyl-1,3- 
phenylene)di(2-methylpropiononitrile) (0.45 g) in tetrahydrofuran, 
and heated under reflux in an atomosphere of argon for 6 h. The 
mixture was cooled, treated with 2N aqueous hydrochloric acid 
(5 ml) and stirred at room temperature for 18 h. The mixture was 
then extracted twice with ethyl acetate, and the combined extracts 
were dried and evaporated to dryness under reduced pressure. 
The residue was purified by flash column chromatography. Elution 
with dichloromethane: cyclohexane (2:1 by volume) gave the 
required starting material for Example 2, mp 37-39.degree., and 
subsequent elution with dichloromethane gave the required 
starting material for Example 3, mp 81-82.degree.. 
3. Hydrochloride salt. 
4. The methyl 5-(1-cyano-1-methylethyl)-3-toluate starting 
material was obtained as follows:- 
A mixture of methyl 3,5-dimethylbenzoate (10 g), N- 
bromosuccinimide (11.94 g), benzoyl peroxide (0.1 g) and carbon 
tetrachloride (100 ml) was heated under reflux for 2 h, cooled and 
filtered, and the filtrate was evaporated to dryness under reduced 
pressure. The residue was purified by flash column chromatography, 
and elution with ethyl acetate:petroleum ether (bp 60-80.degree.), (3:97 
by 
volume) gave methyl 5-bromomethyl-3-toluate as an oil, which was then 
used in place of 3,5-bis(bromomethyl)toluene in the process described 
in the second part of Example 1 to give successively methyl 5- 
cyanomethyl-3-toluate, mp 56-57.degree. after crystallisation from 
cyclohexane, and the required starting material, methyl 5-(1-cyano- 
1-methylethyl)-3-toluate, mp. 50-51.degree. after crystallisation 
from hexane. 
EXAMPLE 5 
A mixture of methyl 3-bromomethyl-5-(1-cyano-1-methylethyl)benzoate (0.7 
g), 4-methyl-1-tritylimidazole (0.8 g) and acetonitrile (2 ml) was heated 
under reflux for 48 h, then evaporated to dryness. The residue of 
3-[3-(1-cyano-1-methylethyl)-5-methoxycarbonylbenzyl]-4-methyl-1-tritylimi 
dazolium bromide was washed with diethyl ether (2.times.10 ml), and the 
residue was treated with glacial acetic acid (4 ml) and water (1 ml) and 
heated at 90.degree. for 15 minutes. The mixture was diluted with water 
(20 ml), and washed with diethyl ether, and the aqueous phase was basified 
with 10N aqueous sodium hdroxide and extracted three times with ethyl 
acetate. The extracts were combined and evaporated to dryness, and the 
residue was purified by flash column chromatography, eluting with 
methanol:chloroform (1:49 by volume), to give methyl 
5-(1-cyano-1-methylethyl)-3-(5-methylimidazol-1-ylmethyl)benzoate, mp 
101.degree.-104.degree.. 
The 4-methyl-1-tritylimidazole used in the above process was prepared as 
follows: 
A mixture of trityl chloride (17 g), triethylamine (8.5 ml), 
4-methylimidazole (5 g) and toluene (40 ml) was stirred at 80.degree. for 
4 h and filtered, and the solid material was washed with toluene. It was 
then partitioned between water and chloroform, and the chloroform solution 
was separated, dried and combined with the dried toluene filtrate. The 
combined organic solutions were evaporated to dryness under reduced 
pressure, and the residue was triturated with diethyl ether to give 
4-methyl-1-tritylimidazole, mp. 214.degree.-216.degree.. 
EXAMPLE 6 
The process described in Example 5 was repeated, using 
2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropiononitrile) as the 
starting material, to obtain 
2,2'-[5-(5-methylimidazol-1-yl)-1,3-phenylene]di(2-methylpropiononitrile), 
mp. of hydrochloride salt, 183.degree.-185.degree., crystallised from 
ethyl acetate. 
EXAMPLE 7 
A mixture of 
2,2'-[5-(1-chloroethyl)-1,3-phenylene)di(2-methylpropiononitrile), (0.35 
g), sodium triazole (0.25 g) and dimethylformamide (3 ml) was stirred at 
room temperature for 18 h, then water (20 ml) was added and the mixture 
was extracted twice with ethyl acetate. The extracts were combined and 
evaporated to dryness, and the residue was purified by flash column 
chromatography, eluting with ethyl acetate, to give 
2,2'-[5-(1-[1H-1,2,4-triazol-1-yl]ethyl)-1,3-phenylene]di(2-methylpropiono 
nitrile), crystallised as the hydrochloride from acetone, mp. 
168.degree.-170.degree.. 
The 5-(1-chloroethyl)-1,3-phenylene derivative used as starting material in 
the above process may be prepared as follows: 
A solution of 
2,2'-(5-hydroxymethyl-1,3-phenylene)di(2-methylpropiononitrile), (1.9 g), 
in dichloromethane (20 ml) was treated with pyridinium chlorochromate 
(2.15 g) and stirred at room temperature for 1.5 h. The reaction mixture 
was subjected to flash column chromatography, eluting with 
dichloromethane, to give 2,2'-(5-formyl- 
1,3-phenylene)di(2-methylpropiononitrile), mp. 145.degree.-147.degree.. 
This compound (0.48 g) was dissolved in tetrahydrofuran (5 ml), and the 
solution was stirred at 0.degree. under an atmosphere of argon while a 
solution of methylmagnesium chloride in tetrahydrofuran (3M, 0.7 ml) was 
added over 5 minutes. The mixture was stirred for 0.5 h, then a saturated 
aqueous solution of ammonium chloride was added, and the mixture was 
extracted twice with diethyl ether. The extracts were combined, dried and 
evaporated to dryness under reduced pressure to give 
2,2'-[5-(1-hydroxyethyl)-1,3-phenylene]di(2-methylpropiononitrile), which 
was used without further purification. This was dissolved in 
dichloromethane (5 ml). and ice-cooled while pyridine (0.16 g) was added, 
followed by thionyl chloride (0.36 g) dropwise. The mixture was kept at 
room temperature for 2 h, then evaporated to dryness. The residue was 
partitioned between diethyl ether and water, and the ether phase was 
separated, dried and evaporated to dryness under reduced pressure to give 
the required 
2,2'-[5-(1-chloroethyl)-1,3-phenylene]di(2-methylpropiononitrile), which 
was used without further purification. 
EXAMPLE 8 
A solution of 
2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), (0.23 g), 
and 1H-1,2,4-triazole (0.35 g) in acetonitrile (2 ml) was heated under 
reflux for 18 h, then evaporated to dryness. The residue was partitioned 
between 1N aqueous potassium hydrogen carbonate solution and ethyl 
acetate, the organic phase was separated, dried and evaporated to dryness 
under reduced pressure, and the residue was purified by flash column 
chromatography. Elution with methanol:chloroform (1:49 by volume), gave 
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononit 
rile), identical with the product of Example 1, and further elution with 
methanol:chloroform (2:23 by volume, gave 
2,2'-[5-(4H-1,2,4-triazol-4-ylmethyl)-1,3-phenylene]di(2-methylpropiononit 
rile), mp. 158.degree.-161.degree.. 
The chloromethyl compound used as starting material in the above process 
may be prepared as follows: 
A mixture of methyl 3,5-dimethylbenzoate (6 g), N-bromosuccinimide (13 g), 
benzoyl peroxide (50 mg) and carbon tetrachloride (150 ml) was heated 
under reflux for 1 h. The mixture was then cooled and filtered, the 
filtrate was evaporated to dryness under reduced pressure, and the residue 
was crystallised from cyclohexane to give methyl 
3,5-bis(bromomethyl)benzoate mp. 99.degree.-101.degree.. 
The methyl 3,5-bis(bromomethyl)benzoate was treated with potassium cyanide 
in a similar manner to that described in the second part of Example I to 
give methyl 3,5-bis(cyanomethyl)benzoate mp. 90.degree.-92.degree., which 
was then alkylated with methyl iodide as also described in the latter part 
of Example I, to give methyl 3,5-bis(1-cyano-1-methyl ethyl)benzoate, mp. 
83.degree.-85.degree.. 
A mixture of methyl 3,5-bis(1-cyano-1-methyl ethyl)benzoate (5.6 g), 
lithium borohydride (0.44 g) and tetrahydrofuran (30 ml) was heated under 
reflux for 2 h. The mixture was cooled and stirred while 2N aqueous 
hydrochloric acid was added dropwise until the solution remained acidic, 
and then the mixture was extracted twice with ethyl acetate. The combined 
extracts were washed with 1N aqueous potasium bicarbonate solution and 
then dried and evaporated to dryness under reduced pressure to give 
2,2'-(5-hydroxymethyl-1,3-phenylene)di(2-methylpropiononitrile), mp. 
151.degree.-153.degree., which was used without further purification. 
A solution of 
2,2'-(5-hydroxymethyl-1,3-phenylene)di-(2-methylpropiononitrile), (3.8 g) 
and pyridine (1.58 g) in dichloromethane (10 ml) was stirred, and cooled 
in an ice bath, while thionyl chloride (3 g) was added over 10 minutes. 
The solution was kept at room temperature for 2 h and then heated under 
reflux for 1 h and evaporated to dryness under reduced pressure The 
residue was partitioned between water and ethyl acetate and the organic 
phase was separated, dried and evaporated to dryness under reduced 
pressure to give 
2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), which was 
used without further purification. 
EXAMPLES 9-16 
The process described in Example 8 was repeated, using the appropriate 
chloromethyl or bromomethyl derivative and the appropriate heterocyclic 
starting materials, to give the following compounds: 
__________________________________________________________________________ 
##STR3## 
Position Foot- 
Ex R.sup.5 
R.sup.4 R of R Mp Notes 
__________________________________________________________________________ 
9 1 .sub.--H-1-I* 
C(CH.sub.3).sub.2 CN 
C(CH.sub.3).sub.2 CN 
3 125-127 
1 
10 1 .sub.--H-1-I 
H C(CH.sub.3).sub.2 CN 
3 62-65 
11 1 .sub.--H-1-T* 
H C(CH.sub.3).sub.2 CN 
3 2 
12 4 .sub.--H-4-T 
H C(CH.sub.3).sub.2 CN 
3 3 
13 1 .sub.--H-1-I 
H C(CH.sub.3).sub.2 CN 
4 65-66 
14 1 .sub.--H-1-T 
H C(CH.sub.3).sub.2 CN 
4 4 
15 1 .sub.--H-1-I 
H CH.sub.2 CN 
3 146-147 
5 
16 1 .sub.--H-1-I 
COOCH.sub.3 
C(CH.sub.3).sub.2 CN 
3 69-70 
__________________________________________________________________________ 
*I = imidazolyl; T = 1,2,4triazolyl 
Footnotes 
1. Crystallised from toluene/petroleum ether, (bp 60-80.degree.). 
2. Nmr in deuteriochloroform; .delta. 8.12(1H, s), 7.98(1H, s), 7.35- 
7.6(3H, m), 7.2(1H, m), 5.39(2H, s), 1.72(6H, s). 
3. Nmr in deuteriochloroform; .delta. 8.2(2H, s), 7.25-7.55(3H, m), 
7.1(1H, m), 5.2(2H, s), 1.7(6H, s). 
4. Nmr in deuteriochloroform; .delta. 8.12(1H, s), 8.0(1H, s), 7.5(2H, 
d), 
7.3(2H, d), 5.4(2H, s), 1.72(6H, s). 
5. Hydrochloride salt. 
The compound of Example 9 was prepared from the chloromethyl starting 
material described in Example 8; and the compounds of Examples 10-16 were 
prepared from the corresponding bromomethyl starting materials, made by 
the sequence of reactions described in the second part of Example 1, and 
used without further purification. 
EXAMPLE 17 
The process described in Example 8 was repeated, using imidazole in place 
of 1,2,4-triazole, and 
2,2'-[5-(1-chloroethyl)-1,3-phenylene]di(2-methylpropiononitrile), 
(obtained as described in the second part of Example 7), as the starting 
materials, to give 
2,2'-[5-(1-[imidazol-1-yl]ethyl)-1,3-phenylene]di(2-methylpropiononitrile) 
, mp. 77.degree.-80.degree.. 
EXAMPLE 18 
A solution of 2-methyl-2-[3-(imidazol-1-ylmethyl)phenyl]-propiononitrile, 
obtained as described in Example 10, (0.2 g) in concentrated sulphuric 
acid (0.5 ml) was kept at room temperature for 18 h, diluted to 5 ml with 
ice water, neutralised with concentrated aqueous ammonia, and extracted 
three times with ethyl acetate. The extracts were combined, dried and 
evaporated to dryness under reduced pressure, and the residue was purified 
by flash column chromatography, eluting with methanol:chloroform (2:23 by 
volume), to give 2-methyl-2-[3-(imidazol-1-ylmethyl)phenyl]propionamide, 
mp. 79.degree.-82.degree.. 
EXAMPLES 19-20 
The process described in Example 18 was repeated, using as starting 
material the product of Example 1, to give 
2-[3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-meth 
ylpropionamide, (eluted from the flash chromatography column with 
methanol:ethylacetate, 1:3 by volume), mp. 134 135.degree.; and 
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropionamid 
e), mp. 51.degree.-53.degree., eluted from the flash chromatography column 
with methanol:ethyl acetate, (1:2 by volume). 
EXAMPLE 21 
The product from Example 16 (0.12 g) and concentrated aqueous ammonia (3 
ml) were stirred together at room temperature for 72 h. The insoluble 
product was filtered off, washed with water and dried to give 
3-(1-cyano-1-methylethyl)-5-(imidazol-1-ylmethyl)benzamide, mp. 
149.degree.-150.degree.. 
EXAMPLE 22 
The process described in Example 21 was repeated, using the product of 
Example 4 as the starting material, to give 
3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl) benzamide, mp. 
144.degree.-145.degree.. 
EXAMPLE 23 
A mixture of the product from Example 22 (0.41 g), pyridine (0.25 ml) and 
1,4-dioxan (5 ml) was stirred while trifluoroacetic anhydride (0.24 ml) 
was added dropwise The resulting solution was kept at room temperature for 
18 h, diluted with water (10 ml), made basic with sodium hydrogen 
carbonate and extracted three times with ethyl acetate. The extracts were 
combined, dried and evaporated to dryness, and the residue was purified by 
flash column chromatography, eluting with methanol:chloroform (3:97 by 
volume) to give 
3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)benzonitrile, mp. 
90.degree.-92.degree.. 
EXAMPLE 24 
The process described in Example 23 was repeated, using the product of 
Example 21 as the starting material, to give 
3-(1-cyano-1-methylethyl)-5-(imidazol-1-ylmethyl) benzonitrile, mp. 
89.degree.-92.degree.. 
EXAMPLE 25 
The process described in Example 22 was repeated, using piperidine in place 
of aqueous ammonia, and heating at 80.degree. for 72 h to give 
2-methyl-2-[3-piperidinocarbonyl-5-(1H-1,2,4-triazol-1-ylmethyl]propiononi 
trile. Nmr in deuteriochloroform, .delta. 8.2(1H,s), 8.0(1H,s), 7.48(1H,m), 
7.44(1H,m), 7.2(1H,m), 5.4(2H,s), 3.68(2H,m), 3.27(2H,m), 1.4 1.8(12H,m). 
EXAMPLE 26 
The process described in Example 25 was repeated, using morpholine in place 
of piperidine, to give 
2-methyl-2-[3-morpholinocarbonyl-5-(1H-1,2,4-triazol-1-ylmethyl]-propionon 
itrile. Nmr in deuteriochloroform, .delta. 8.18(1H,s), 8.0(1H,s), 
7.5(1H,m), 7.45(1H,m), 7.2(1H,m), 5.4(2H,s), 3.5-3.9(8H,m), 1.72(6H,s). 
EXAMPLE 27 
A mixture of the product of Example 4 (1.5 g), lithium borohydride (0.23 g) 
and tetrahydrofuran (5 ml) was heated under reflux for 1 h, then cooled 
and stirred while 2N aqueous hydrochloric acid was added dropwise until 
the solution remained acidic, then stirred at room temperature for 1 h and 
basified by the addition of sodium hydrogen carbonate. The mixture was 
extracted three times with ethyl acetate, the combined extracts were dried 
and evaporated to dryness under reduced pressure, and the residue was 
purified by flash column chromatography, eluting with methanol:chloroform 
(1:24 by volume), to give 
2-[3-hydroxymethyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiono 
nitrile, mp. 111.degree.-113.degree.. 
EXAMPLE 28 
A solution of the product from Example 27 (1 g) and thionyl chloride (0.4 
ml) in dichloromethane (5 ml) was heated under reflux for 0.5 h, then 
evaporated to dryness under reduced pressure, to give 
2-[3-chloromethyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropionon 
itrile hydrochloride, mp. 189.degree.-190.degree. after trituration with 
ethyl acetate. 
EXAMPLE 29 
A mixture of the product from Example 28 (0.73 g), tetrabutylammonium 
bromide (0.01 g), potassium cyanide (0.52 g), dichloromethane (2 ml) and 
water (2 ml) was heated under reflux for 3 h. It was then cooled, water 
(20 ml) was added, and the mixture was extracted three times with ethyl 
acetate. The extracts were combined, dried and evaporated to dryness under 
reduced pressure, and the residue was purified by flash column 
chromatography, eluting with methanol:ethyl acetate (3:97 by volume), to 
give 
3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenylacetonitril 
e. Nmr in deuteriochloroform: .delta. 8.18(1H,s), 8.0(1H,s), 7.42(1H,m), 
7.38(1H,m), 7.18(1H,m), 5.4(2H,s), 3.78(2H,s), 1.72(6H,s). 
EXAMPLE 30 
A mixture of the product from Example 28 (0.6 g), S-methylthiouronium 
sulphate (0.56 g), 10N aqueous sodium hydroxide (1 ml) and 
dimethylformamide (5 ml) was stirred at room temperature for 18 h, diluted 
with water (20 ml) and extracted twice with dichloromethane. The extracts 
were combined, dried and evaporated to dryness under reduced pressure, and 
the residue was purified by flash column chromatography, eluting with 
methanol:ethyl acetate (1:49 by volume) to give 
2-methyl-2-[3-methylthiomethyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-prop 
iononitrile. Nmr in deuteriochloroform: .delta. 8.12(1H,s), 8.0(1H,s), 
7.4(1H,m), 7.27(1H,m), 7.15(1H,m), 5.38(2H,s), 3.66(2H,s), 2.0(3H,s), 
1.72(6H,s). 
EXAMPLE 31 
A solution of the product of Example 30 (0.16 g) in methanol (0.5 ml) and 
tetrahydrofuran (5 ml) was stirred while a solution of sodium periodate 
(0.15 g) in water (0.5 ml) was added, and was then stirred at room 
temperature for a further 18 h. Water (5 ml) was added and the mixture was 
extracted six times with dichloromethane. The extracts were combined, 
dried and evaporated to dryness, and the residue was purified by flash 
column chromatography, eluting with methanol:ethyl acetate (1:9 by volume) 
to give 
2-methyl-2-[3-methylsulphinylmethyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl] 
-propiononitrile. Nmr in deuteriochloroform; .delta. 8.16(1H,s), 8.0(1H,s), 
7.38(1H,m), 7.27(1H,m), 7.15(1H,m), 5.4(2H,s), 3.98(1H,d), 3.88(1H,d), 
2.5(3H,s), 1.72(6H,s). 
EXAMPLE 32 
A solution of the product of Example 5 (0.25 g) in tetrahydrofuran (5 ml) 
was cooled to 0.degree. and stirred under an atmosphere of argon while a 
solution of methylmagnesium chloride in tetrahydrofuran (3M, 0.5 ml) was 
added over 5 minutes. The solution was stirred for a further 0.5 h, then 
treated with saturated aqueous ammonium chloride solution and extracted 
twice with ethyl acetate. The extracts were combined, dried and evaporated 
to dryness under reduced pressure, and the residue was purified by flash 
column chromatography, eluting with methanol:ethyl acetate (1:19 by 
volume) to give 
2-[3-(1-hydroxy-1-methylethyl)-5-(5-methylimidazol-1-ylmethyl)phenyl]-2-me 
thylpropiononitrile, mp. 128.degree.-131.degree. after trituration with 
pentane. 
EXAMPLE 33 
The process described in Example 32 was repeated, using the product from 
Example 4 as the starting material, to give 
2-[3-(1-hydroxy-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-me 
thylpropiononitrile, mp. 152.degree.-154.degree., after crystallisation 
from diethyl ether. 
EXAMPLE 34 
A solution of 3-bromopyridine (0.31 g) in diethyl ether was stirred and 
cooled to -70.degree. while a solution of n-butyl-lithium in hexane (1.6M, 
1.33 ml) was added, followed by 2,2'-(5 
formyl-1,3-phenylene)di(2-methylpropiononitrile), (0.48 g). The mixture 
was allowed to warm to room temperature and was then extracted with 2N 
aqueous hydrochloric acid (10 ml). The acid extract was separated, 
basified with 10N aqueous sodium hydroxide solution and extracted twice 
with ethyl acetate. The extracts were combined, dried and evaporated to 
dryness under reduced pressure, and the residue was purified by flash 
column chromatography, eluting with ethyl acetate, to give 
2,2'-[5-(1-hydroxy-1-(3-pyridyl]methyl)-1,3-phenylene]di(2-methyl 
propiononitrile), mp. 117.degree.-120.degree.. 
EXAMPLE 35 
A solution of the product from Example 34 (50 mg) in dichloromethane (2 ml) 
and thionyl chloride (0.1 ml) was heated under reflux for 1 h, then 
evaporated to dryness under reduced pressure. The residue was dissolved in 
ethanol, 10% palladium-on-carbon catalyst was added, and the mixture was 
shaken in an atomosphere of hydrogen at room temperature and atmospheric 
pressure for 1 h. The mixture was filtered, the filtrate was evaporated to 
dryness under reduced pressure, and the residue was partitioned between 
aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl 
acetate phase was separated, dried and evaporated to dryness under reduced 
pressure, and the residue was purified by flash column chromatography, 
eluting with ethyl acetate, to give 2,2'-[5-(3-pyridylmethyl)-1,3 
-phenylene]di(2-methylpropiononitrile), mp 82.degree.-84.degree.. 
EXAMPLE 36 
A mixture of 2,2'-(5 formyl-1,3-phenylene)di(2-methylpropiononitrile (0.48 
g), trimethylsulphoxonium iodide (0.53 g), powdered potassium hydroxide 
(0.27 g), 1H-1,2,4-triazole (0.16 g) and tert-butyl alcohol (5 ml) was 
stirred at 80.degree. for 1 h, then cooled, diluted with water (10 ml) and 
extracted three times with ethyl acetate. The combined extracts were dried 
and evaporated to dryness under reduced pressure, and the residue was 
purified by flash column chromatography, eluting with methanol:ethyl 
acetate (1:49 by volume) to give 
2,2'-[5-(1-hydroxy-2-(1H-1,2,4-triazol-1-yl]ethyl)-1,3-phenylene]di(2-meth 
ylpropiononitrile, mp 131.degree.-134.degree.. 
EXAMPLE 37 
A mixture of 
2,2'-[5-(E-2-[1H-1,2,4-triazol-1-yl]vinyl)-1,3-phenylene]di(2-methylpropio 
nonitrile), (25 mg), 10% palladium-on-carbon catalyst (10 mg) and ethyl 
acetate (2 ml) was stirred in an atmosphere of hydrogen at room 
temperature and atmospheric pressure for 1 h. The mixture was filtered, 
and the filtrate was evaporated to dryness under reduced pressure to give 
2,2'-[5-(2 
[1H-1,2,4-triazol-1-ylmethyl]ethyl)-1,3-phenylene]di(2-methylpropiononitri 
le), mp 102.degree.-104.degree.. 
The required starting material for use in the above process may be 
manufactured as follows: 
A solution of the product from Example 36 (0.25 g), thionyl chloride (0.2 
ml) and dichloromethane (2 ml) was heated under reflux for 1 h, then 
evaporated to dryness. The residue was triturated with ethyl acetate to 
give 2,2'-[5-(1-chloro-2 
[1H-1,2,4-triazol-1-yl]ethyl)-1,3-phenylene]di(2-methyl-propiononitrile) 
hydrochloride, mp 190.degree.-192.degree.. 
A mixture of this material (70 mg), sodium 1H-1,2,4-triazole (100 mg) and 
dimethylformamide (1 ml) was heated at 90.degree. for 2 h, then diluted 
with water (10 ml) and extracted with ethyl acetate. The extract was dried 
and evaporated to dryness under reduced pressure, and the residue was 
purified by flash column chromatography, eluting with ethyl 
acetate:n-pentane (3:1 by volume) to give the required starting material, 
mp 108.degree.-109.degree.. 
EXAMPLE 38 
A solution of oxalyl chloride (0.12 ml) in dichloromethane (2 ml) was 
stirred and cooled to 70.degree. while dimethyl sulphoxide (0.12 ml) was 
added dropwise. The solution was stirred for 2 minutes, then 
2-[3-(1-hydroxyethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropi 
ononitrile, (0.18 g), was added, and the temperature was kept at 
-70.degree. for 10 minutes. Triethylamine (0.2 ml) was added, and the 
mixture was allowed to warm to room temperature. Water (15 ml) was added, 
and the mixture was extracted three times with dichloromethane. The 
extracts were combined, dried and evaporated to dryness, and the residue 
was purified by flash column chromatography, eluting with 
methanol:chloroform (1:99 by volume) to give 2-[3 
acetyl-5-(1H-1,2,4-triazol-1 ylmethyl)phenyl]-2-methylpropiononitrile. Nmr 
in deuteriochloroform; .delta. 8.2(1H,s), 8.02(2H,m), 7.8(1H,m), 
7.64(1H,m), 5.45(2H,s), 2.6 (3H,s), 1.75(6H,s). 
The 1-hydroxyethyl starting material used in the above process may be 
manufactured as follows: 
The product from Example 27 was oxidised by the process described in the 
first part of this Example to the corresponding 3-formyl compound. 
The formyl compound (0.2 g) was dissolved in tetrahydrofuran ml), stirred 
and cooled to 70.degree. under an atmosphere of argon, and a solution of 
methylmagnesium chloride in tetrahydrofuran (3 m, 0.32 ml) was added. The 
mixture was stirred at 70.degree. for 0.5 h and allowed to warm to room 
temperature, then saturated aqueous ammonium chloride solution (10 ml) was 
added. The mixture was extracted three times with dichloromethane, and the 
extracts were combined, dried and evaporated to dryness under reduced 
pressure to give the required 1-hydroxyethyl starting material, which was 
used without further purification. 
EXAMPLES 39-48 
The process described in Example 1 was repeated, using the appropriate 
5-methyl-1,3-disubstituted phenylene compound as starting material, to 
give the following compounds: 
______________________________________ 
##STR4## 
Ex. R.sup.1 = R.sup.2 
R.sup.4 Mp. Footnotes 
______________________________________ 
39 CH.sub.3 CH.sub.3 79-81 1 
40 CH.sub.3 C(CH.sub.3)(C.sub.2 H.sub.5).CN 
-- 2,3 
41 CH.sub.3 C(C.sub.2 H.sub.5).sub.2.CN 
-- 4,5 
42 CH.sub.3 
##STR5## 45-48 6 
43 CH.sub.3 
##STR6## 68-69 7 
44 CH.sub.3 
##STR7## -- 8,9 
45 CD.sub.3 C(CD.sub.3).sub.2.CN 
82-83 10 
46 CH.sub.3 C(CH.sub.2 F).sub.2.CN 
-- 11,12 
47 CH.sub.3 Br 156-158 
13,14 
48 CH.sub.3 C(CH.sub.3).sub.2.SO.sub.2 CH.sub.3 
105-107 
15 
______________________________________ 
Footnotes 
1. The required starting material was prepared as follows:- 
A mixture of 3,5-dimethylbenzyl bromide (25 g), tetrabutylammonium 
bromide (1.2 g), potassium cyanide (12.3 g), dichloromethane (25 ml) 
and water (20 ml) was stirred vigorously and heated under reflux for 
2 h. The mixture was cooled and diluted with dichloromethane, and 
the organic phase was separated, dried and evaporated to dryness 
under reduced pressure. The residue was purified by flash column 
chromatography, eluting with petroleum ether (bp 60-80.degree.): ethyl 
acetate (19:1 by volume), to give 3,5-dimethylphenylacetonitrile, m.p. 
42-44.degree.. 
A mixture of this nitrile (12.5 g) and sodium hydride (80% 
dispersion in mineral oil, 6.45 g) was cooled in ice and stirred under 
an atmosphere of argon, while a solution of iodomethane (25 ml) in 
dimethylformamide (50 ml) was added dropwise over 0.5 h. The 
mixture was allowed to warm to room temperature, stirred at room 
temperature for a further 0.5 h, then added cautiously to ice-water 
(500 ml). The mixture was extracted three times with diethyl ether, 
and the extracts were combined and evaporated to dryness. 
The residue was purified by flash column chromatography, 
eluting with petroleum ether (bp 60-80.degree.): 
ethyl acetate (19:1 by volume), to give the required starting 
isothiuronium sulphate (1.39 g), dimethylformamide (10 ml) and 10N 
aqueous sodium hyroxide (2 ml). The mixture was stirred for 1 h, 
diluted with water and extracted with diethyl ether, the extract was 
dried and evaporated to dryness under reduced pressure, and the 
residue was purified by flash chromatography, eluting with ethyl 
acetate (5% by volume) in pentane, to give 2-methyl-2-[3-methyl-5- 
(methylthiomethyl)phenyl]propiononitrile. 
A solution of this nitrile (0.63 g) in dichloromethane (20 ml) 
was treated with m-chloroperbenzoic acid (1.2 g), added in portions 
over 10 minutes, then the mixture was stirred for 0.5 h. The mixture 
was then washed twice with 2N aqueous sodium hydroxide, dried and 
evaporated to dryness, to give 2-methyl-2-[3-methyl-5-(methyl- 
sulphonylmethyl)phenyl]propiononitrile, which was used without 
purification. 
A mixture of this nitrile (0.25 g), iodomethane (0.35 g), 
sodium hyride (80% dispersion in oil, 0.12 g) and dimethylformamide 
(5 ml) was stired under an atmosphere of argon at room temperature 
for 18 h. The mixture was treated with water and extracted twice 
with ethyl acetate, and the extracts were combined and evaporated 
to dryness. The residue was then triturated with tetrachloromethane 
to give 2-methyl-2-[3-methyl-5-(1-methylsulphonyl-1-methylethyl)- 
phenyl]propiononitrile, m.p. 129-131.degree.. 
EXAMPLES 49-52 
The process described in Example, 1 was repeated, using the appropriate 2- 
or 4-substituted 2,2-(5-methyl-1,3-phenylene)di(2-methylpropiononitrile) 
as starting material, to give the following compounds: 
______________________________________ 
##STR8## 
Position of 
Ex R.sup.4 
substitution Mp. Footnote 
______________________________________ 
49 NO.sub.2 
4 -- 1,2 
50 Br 4 83-86 3 
51 Br 2 128-131 
3 
52 CN 4 35-37 4 
______________________________________ 
Footnotes 
1. Nmr in deuteriochloroform: .delta. 8.18(1H, s), 8.0(1H, s), 
7.82(1H, d), 7.46(1H, d), 5.34(2H, s), 1.86(6H, s), 1.72(6H, s). 
2. The required starting material was prepared as follows:- 
2,2'-(5-methyl-1,3-phenylene)di(2-methylpropiononitrile), 
(0.23 g) was added to a 0.5M solution of nitronium tetrafluoroborate 
in sulpholane (2 ml), and the mixture was stirred at 55.degree. for 24 h. 
The 
cooled mixture was treated with water and extracted with ether. The 
ether extract was dried and evaporated to dryness under reduced 
pressure, and the residue was purified by flash chromatography using 
ethylacetate (15% by volume) in petroleum ether as eluant to give 
2,2'-(5-methyl-4-nitro-1,3-phenylene)di(2-methylpropiononitrile) mp 
82-85.degree.. 
3. The required starting material was prepared as follows:- 
A mixture of 2,2'-(5-methyl-1,3-phenylene)di(2-methyl- 
propiononitrile), (1.13 g), dichloromethane (10 ml) and silver tri- 
fluoromethanesulphonate (1.55 g) was stirred in the dark while adding 
a solution of bromine (0.88 g) in dichloromethane (2 ml) dropwise 
over 5 minutes The mixture was stirred for a further 1 h, then treated 
with dilute aqueous potassium bicarbonate and ethyl acetate. The 
mixture was filtered through a pad of kieselguhr ("Celite" -trade 
mark), and the organic phase was separated, dried and evaporated to 
dryness. The residue was subjected to flash chromatography eluting 
with ethyl acetate(15% by volume) in pentane to give 2,2'-(4-bromo- 
5- methyl-1,3-phenylene)di(2-methylpropiononitrile) mp 121-122.degree.. 
Further elution with ethyl acetate (25% by volume) in 
pentane gave 2,2'-(2-bromo-5-methyl-1,3-phenylene)di(2-methyl- 
propiononitrile) mp 141-149.degree.. 
4. The required starting material was prepared as follows:- 
A mixture of 2,2'-(4-bromo-5-methyl-1,3-phenylene)di(2- 
methylpropionontitrile), (0.2 g), cuprous cyanide (0.09 g) and di- 
methylformide (0.5 ml) was stirred under reflux for 4 h. A further 
0.09 g of cuprous cyanide was added, and the mixture was heated for 
a further 18 h. The mixture was cooled, treated with warm aqueous 
sodium cyanide solution and extracted with ethyl acetate. The 
extract was dried and evaporated to dryness under reduced pressure, 
and the residue was purified by flash chromatography, eluting with 
ethyl acetate (20% by volume) in petroleum ether (bp 60-80.degree.) to 
give 
2,2'-(4-cyano-5-methyl-1,3-phenylene)di(2-methylpropiono- nitrile) mp 
84-86.degree.. 
EXAMPLE 53 
A mixture of 
2,2'-(5-chlorodideuteriomethyl-1,3-phenylene)-di(2-trideuteriomethyl-3,3,3 
-trideuteriopropiononitrile) (0.65 g), dimethylformamide (5 ml) and sodium 
triazole (0.45 g) was stirred at room temperature for 18 h. The mixture 
was diluted with water (30 ml) and extracted with ethyl acetate, and the 
extract was dried and evaporated to dryness under reduced pressure. The 
residue was purified by flash chromatography, using ethyl acetate as 
eluant, to give 
2,2'-[5-dideuterio-(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]-di(2-tride 
uteriomethyl-3,3,3-trideuteriopropiononitrile), mp 82.degree.-83.degree. 
after crystallisation from ethyl acetate/cyclohexane. 
The starting material from the above process may be prepared as follows: 
The process used to prepare methyl 3,5-bis(1-cyano-1-methylethyl)benzoate, 
described in the later part of Example 8, was repeated, using 
trideuterioiodomethane instead of iodomethane, to give methyl 
3,5-bis[1-cyano-2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]-benzoate, 
m.p. 83.degree.-84.degree.. 
A solution of this methyl ester (7.7 g) in tetrahydrofuran (100 ml) was 
stirred at -50.degree. under an atmosphere of argon, while lithium 
aluminium deuteride (0.63 g) was added in portions over 10 minutes at 
-40.degree. to -50.degree.. The solution was then allowed to warm to room 
temperature, and kept at room temperature for 0.5 h. The solution was then 
treated with ethyl acetate (5 ml), cautiously acidified with 2N aqueous 
hydrochloric acid, and filtered through a pad of kieselguhr ("Celite"), 
washing the pad with ethyl acetate (2.times.50 ml). The organic phase was 
separated, dried and evaporated to dryness under reduced pressure, to give 
2,2'-[5-dideuterio(hydroxy)methyl)-1,3-phenylene]di[3,3,3-trideuterio-2-(d 
ideuteriomethyl)propiononitrile], mp 152.degree.-154.degree.. 
An ice-cooled solution of this compound (6.8 g) in dichloromethane (30 ml) 
and thionyl chloride (3 ml) was stirred while pyridine (2.35 g) was added 
dropwise over 15 minutes. The mixture was stirred at room temperature for 
a further 2 h, and then evaporated to dryness under reduced pressure. The 
residue was partitioned between ethyl acetate and water, and the ethyl 
acetate phase was separated, dried and evaporated to dryness under reduced 
pressure, to give 
2,2'-[5-(chlorodideuteriomethyl)-1,3-phenylene]di[3,3,3-trideuterio-2-(tri 
deuteriomethyl)propiononitrile] mp 119.degree.-121.degree.. 
EXAMPLES 54-57 
The process described in Example 53 was repeated, using the appropriate 
chloromethyl or chlorodideuteriomethyl starting material, to give the 
following compounds: 
__________________________________________________________________________ 
##STR9## 
Position of Position of 
Ex R.sup.4 
substitution 
R.sup.5 substitution 
A Mp Footnote 
__________________________________________________________________________ 
54 -- -- C(CH.sub.3).sub.2 CN 
3 CD.sub.2 
82-83 
1 
55 -- -- C(CH.sub.3).sub.2 CN 
4 CH.sub.2 
95-98 
2 
56 Br 2 -- -- CH.sub.2 
-- 3,4 
57 F 2 C(CH.sub.3).sub.2 CN 
3 CH.sub.2 
-- 5,6 
__________________________________________________________________________ 
Footnotes 
1. Starting material was prepared from 2,2'-(5-methyl-1,3- 
phenylene)di(2-methylpropiononitrile) by reduction with lithium 
aluminium deuteride followed by chlorination with thionyl chloride, as 
described in the latter part of Example 53, to give 2,2'-(5-chlorodi- 
deuteriomethyl-1,3-phenylene)di(2-methylpropiononitrile), mp 
119-121.degree.. 
2. The starting material was prepared by the process described 
in the latter part of Example 8, using methyl 2,5-dimethylbenzoate in 
place of methyl 3,5-dimethylbenaozte. 
3. Nmr in deuteriochloroform: .delta. 8.14(1H, s), 7.98(1H, s), 
7.65(1H, d), 7.48(1H, d), 7.06(1H, dd), 5.35(2H, s), 1.86(6H, s). 
4. The starting material was prepared by the process described 
in the latter part of Example 8, using methyl 4-bromo-3-methylbenzoate 
in place of methyl 3,5-dimethylbenzoate. 
5. Nmr in deuteriochloroform: .delta. 8.18(1H, s), 8.0(1H, s), 7.44 
(2H, d), 5.36(2H, s), 1.8(6H, s). 
6. The starting material was prepared as follows:- 
2-Fluoro-m-xylene (5 g) was added dropwise to a stirred 
solution of aluminium chloride (6.4 g) and acetyl chloride (2.7 ml) in 
dichloroethane (20 ml), and the mixture was stirred at room temperature 
for 1.5 h. The mixture was treated with cold 1N aqueous hydrochloric 
acid (100 ml), the organic layer was separated and the aqueous phase 
was further extracted with dichloromethane. The combined extracts 
were dried and evaporated to dryness under reduced pressure, and the 
residue was purified by flash chromatography using ethyl acetate (10% 
by volume) in petroleum ether (bp 60-80.degree.) as eluant, to give 
4-fluoro- 
3,5-dimethylacetophenone. 
A mixture of this acetophenone (4 g), methanol (40 ml) and 
socium hypochlorite solution (60 ml) was stirred at reflux for 0.5 h. 
The cooled reaction mixture was diluted to 500 ml with water, and 
stirred while sodium sulphite (10 g) was added. The solution was 
washed with ethyl acetate, and the aqueous phase was acidified with 
concentrated hydrochloric acid and then extracted three times with 
ethyl acetate. The combined extracts were dried and evaporated to 
dryness to give 4-fluoro-3,5-dimethylbenzoic acid, mp 165-167.degree.. 
A mixture of this acid (6.7 g), methanol (100 ml) and 
concentrated sulphuric acid (4 ml) was heated under reflux for 2 h. 
The methanol was evaporated under reduced pressure, and the residue 
was washed with water (200 ml), then extracted twice with ethyl 
acetate. The combined ehtyl acetate extracts were washed with 2N- 
aqueous sodium hydroxide, dried and evaporated to dryness under 
reduced pressure, to give methyl 4-fluoro-3,5-dimethylbenzoate which 
was used without further purification. 
The methyl 4-fluoro-3,5-dimethylbenzoate was used in place 
of methyl 3,5-dimethylbenzoate in the processes described in the 
latter part of Example 8, to give 2,2'-(5-chloromethyl-2-fluoro-1,3- 
phenylene)di(2-methylpropiononitrile), mp 118- 120.degree.. 
EXAMPLE 58 
A mixture of 
2,2'-[5-(5-formylimidazol-1-yl)-1,3-phenylene]-di(2-methylpropiononitrile) 
, (0.17 g), ethanol (3 ml), sodium acetate (0.21 g), hydroxylamine 
hydrochloride (0.17 g), and water (2 ml) was heated under reflux for 1 h. 
The mixture was diluted with water (10 ml) and extracted twice with ethyl 
acetate, and the combined extracts were dried and evaporated to dryness 
under reduced pressure. 
A solution of the residue and pyridine (0.08 ml) in dioxan (2 ml) was 
stirred and cooled in an ice bath while trifluoroacetic anhydride (0.08 
ml) was added, and the mixture was kept at room temperature for 18 h. The 
mixture was treated with saturated sodium hydrogen carbonate solution (10 
ml) and extracted three times with dichloromethane, and the combined 
extracts were dried and evaporated to dryness under reduced pressure. The 
residue was purified by flash chromatography using methanol (2% by volume) 
in chloroform as eluant, to give 
2,2'-[5-(5-cyanoimidazol-1-yl)-1,3-phenylene]di(2-methylpropiononitrile), 
mp 88.degree.-90.degree.. 
The starting material for the above process was obtained as follows: 
A suspension of ethyl imidazole-4-carboxylate (1.4 g), triethylamine (1.2 
g) and chloroform (20 ml) was stirred at room temperature while trityl 
chloride (3.06 g) was added, and the mixture was stirred at room 
temperature for 1 h. The resulting solution was washed with water, dried 
and evaporated to dryness under reduced pressure, and the residue was 
crystallised from a mixture of ethyl acetate and cyclohexane, to give 
ethyl 1-tritylimidazole-4-carboxylate, mp 163.degree.-164.degree.. 
A solution of this ethyl ester (1 g) in dichloromethane (10 ml) under an 
atmosphere of argon at 70.degree. was stirred while a 1M solution of 
di-isobutylaluminium hydride in dichloromethane (5.3 ml) was added 
dropwise, and the mixture was then stirred at -70.degree. for a further 
0.5 h. Ethyl acetate (1 ml) was added dropwise, followed by a saturated 
aqueous solution of ammonium chloride (15 ml), the mixture was filtered 
and the filtrate was diluted with ethyl acetate. The organic phase was 
separated, dried and then evaporated to dryness to give 
4-formyl-1-tritylimidazole, mp 176.degree.-179.degree.. 
A mixture of 4-formyl-1-tritylimidazole (0.5 g), 
2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropiononitrile) and 
acetonitrile (2 ml) was heated under reflux for 30 h. The reaction mixture 
was treated with acetic acid (8 ml) and water (2 ml) and the mixture was 
then heated at 90.degree. for 1 h. The mixture was diluted with water (20 
ml) and washed with ether, the aqueous phase was basified with sodium 
carbonate, and the mixture was extracted three times with ethyl acetate. 
The combined extracts were dried and evaporated to dryness, and the 
residue was purified by flash chromatography using methanol (2% by volume) 
in chloroform as eluant, to give 
2,2'-[5-(5-formylimidazol-1-yl)-1,3-phenylene]di(2-methylpropiononitrile), 
mp 108.degree.-111.degree.. 
EXAMPLE 59 
A solution of 1,2,4-triazole (0.69 g) in trifluoroacetic acid (3.12 ml) was 
added to 
2,2'-[5-(1-hydroxy-1-methylethyl)-1,3-phenylene]-di(2-methylpropiononitril 
e), (0.27 g), and the resulting solution was stirred at room temperature 
for 18 hr and then evaporated to dryness. The residue was treated with 
aqueous sodium hydrogen carbonate solution and the mixture was extracted 
with ethyl acetate. The extract was dried and evaporated to dryness under 
reduced pressure, and the residue was purified by flash chromatography 
using methanol (1% by volume) in dichloromethane as eluant, to give 
2,2'-(5-[1-methyl-1-(1H-1,2,4-triazol-1-yl)ethyl]-1,3-phenylene)di(2-methy 
lpropiononitrile), which was characterised as the hydrochloride salt, mp 
185.degree.-188.degree.. 
The starting material for the above example may be prepared as follows: 
A 3M solution of methylmagnesium chloride in tetrahydrofuran (3 ml) was 
added over 5 minutes to a stirred solution of methyl 
3,5-bis-(1-cyano-1-methylethyl)benzoate (1.35 g) in tetrahydrofuran (20 
ml) at -60.degree. under an atmosphere of argon. The mixture was allowed 
to warm to room temperature and kept at room temperature for 0.5 h, then 
treated with 1N aqueous hydrochloric acid solution (20 ml). The mixture 
was extracted twice with ethyl acetate and the combined extracts were 
dried and evaporated to dryness under reduced pressure, to give 
2,2'-[5-(1-hydroxy-1-methylethyl)-1,3-phenylene]di(2-methylpropiononitrile 
) which was used without further purification. 
EXAMPLE 60 
The process described in Example 34 was repeated, using 5-bromopyrimidine 
instead of 3-bromopyridine, and a reaction temperature of -110.degree., to 
give 
2,2'-[5-hydroxy(5-pyrimidinyl)methyl]-1,3-phenylene]di(2-methylpropiononit 
rile), mp 129.degree.-130.degree.. 
EXAMPLE 61 
A solution of 
2,2'-[5-(1-hydroxy-1-(3-pyridyl)methyl)-1,3-phenylene]di(2-methylpropionon 
itrile) in dichloromethane (2 ml) was stirred under an atmosphere of argon 
at 70.degree. while diethylaminosulphurtrifluoride (0.07 ml) was added 
over 5 minutes. The solution was allowed to warm to room temperature over 
0.5 h, then treated with aqueous sodium hydrogen carbonate solution, and 
the mixture was extracted twice with ethyl acetate. The combined extracts 
were dried and evaporated to dryness under reduced pressure, and the 
residue was purified by flash chromatography using 2:1 (by volume) ethyl 
acetate: pentane as eluant to give 2,2'-[5 
fluoro(3-pyridyl)methyl-1,3-phenylene]di(2-methylpropiononitrile). Nmr in 
deuteriochloroform: .delta. 8.65 (2H, m), 7.7 (1H, d), 7.56 (1H, m), 7.42 
(2H, m), 7.38 (1H, m), 6.56 (1H, d), 1.75 (12H, s). 
EXAMPLE 62 
The process described in Example 61 was repeated, using 
2,2'-[5-(1-hydroxy-1-(5-pyrimidinyl)methyl)-1,3-phenylene]di(2-methylpropi 
ononitrile as starting material, to give 
2,2'-[5-fluoro(5-pyrimidinyl)methyl-1,3-phenylene]di(2-methylpropiononitri 
le, mp 72.degree.-74.degree.. 
EXAMPLE 63 
A solution of 2,2'-[5-nicotinoyl-1,3-phenylene)di(2-methylpropiononitrile) 
(80 mg) in dichloromethane (1 ml), at 70.degree. under an atmosphere of 
argon, was treated with diethylaminosulphurtrifluoride (0.3 ml) and the 
mixture was kept at room temperature for 3 days. The mixture was treated 
with aqueous sodium hydrogen carbonate solution and extracted twice with 
diethyl ether. The ether extracts were dried and evaporated to dryness 
under reduced pressure, and the residue was purified by flash 
chromatography, using ethyl acetate (40% by volume) in pentane as eluant, 
to give 
2,2'-[5-(1,1-difluoro-1-(3-pyridyl)-methyl)-1,3-phenylene]di(2-methylpropi 
ononitrile). Nmr in d.sub.6 -dimethylsulphoxide: .delta. 8.85 (1H, d), 8.75 
(1H, d), 8.05 (1H, d), 7.8 (1H, s), 7.68 (2H, s), 7.56 (1H, dd), 1.74 
(12H, s). 
The nicotinoyl compound used as starting material in the above process was 
obtained as follows: 
A mixture of 
2,2'-[5-hydroxy(3-pyridyl)methyl-1,3-phenylene]di(2-methylpropiononitrile) 
(0.1 g), dichloromethane (3 ml) and pyridinium chlorochromate (0.1 g) was 
stirred at room temperature for 1 h. The reaction mixture was purified by 
flash chromatography using ethyl acetate (20% by volume) in 
dichloromethane as eluant to give 
2,2'-[5-nicotinoyl-1,3-phenylene)di(2-methylpropiononitrile), mp 
87.degree.-89.degree.. 
EXAMPLE 64 
Sodium borohydride (20 mg) was added to a solution of 
2-[3-(2-oxo-1,1-dimethylpropyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-m 
ethylpropiononitrile (prepared as described in Example 2--40 mg) in ethanol 
(2 ml) and the mixture was stirred at room temperature for 18 h. The 
mixture was diluted with water and extracted with ethyl acetate, and the 
extract was dried and evaporated to dryness under reduced pressure. The 
residue was purified by flash chromatography, using methanol (1% by 
volume) in ethyl acetate as eluant, to give 
2-[3-(2-hydroxy-1,1-dimethylpropyl)-5-(1H-1,2,4-triazol-1-yl-methyl)phenyl 
]-2-methylpropiononitrile, mp 83.degree.-84.degree.. 
EXAMPLE 65 
A solution of 
2-[3-(1-hydroxy-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-me 
thylpropiononitrile (0.06 g) in trifluoroacetic acid (1 ml) was treated 
with triethylsilane (50 mg) and the solution kept at room temperature for 
18 h and then evaporated to dryness under reduced pressure. The residue 
was treated with aqueous sodium hydrogen carbonate solution and the 
mixture was extracted twice with ethyl acetate. The combined extracts were 
dried and evaporated to dryness under reduced pressure, and the residue 
was purified by flash chromatography, using ethyl acetate as eluant, to 
give 
2-[3-isopropyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitr 
ile. Nmr in deuteriochloroform: .delta. 8.1 (1H, s), 8.0 (1H, s), 7.32 (1H, 
m), 7.18 (1H, m), 7.05 (1H, m), 5.35 (2H, s), 2.92 (1H, m), 1.7 (6H, s), 
1.24 (6H, d). 
EXAMPLE 66 
A mixture of 
2-[2-bromo-5-(1H-1,2,4-triazol-1-ylmethyl)-phenyl]-2-methylpropiononitrile 
(0.15 g), dimethylformamide (2 ml) and cuprous cyanide (0.09 g) was 
stirred and heated under reflux for 8 h. The cooled mixture was treated 
with aqueous potassium cyanide solution (10 ml) and the mixture was 
stirred for 10 minutes, then extracted three times with dichloromethane. 
The combined extracts were dried and evaporated to dryness under reduced 
pressure, and the residue was purified by flash chromatography, using 
methanol (2% by volume) in chloroform as eluant, to give 
2-[2-cyano-5-(1H-1,2,4-triazol-yl methyl)phenyl]-2-methylpropiononitrile, 
characterised as the hydrochloride salt mp 159.degree.-166.degree.. 
A mixture of 
2,2'-[5-bromocyanomethyl-1,3-phenylene]di(2-methylpropiononitrile) (0.33 
g), 1,2,4-triazole (0.34 g) and dimethylformamide (2 ml) was stirred at 
50.degree. for 24 h. The mixture was treated with water (20 ml), and 
extracted with ethyl acetate, and the extract was dried and evaporated to 
dryness under reduced pressure. The residue was purified by flash 
chromatography, using methanol (3% by volume) in dichloromethane as 
eluant, to give 
2,2'-[5-cyano(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-methylpropio 
no-nitrile), characterised as the hydrochloride salt, mp 
148.degree.-151.degree.. 
The starting material for the above process was obtained as follows: 
A mixture of 
2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), (3.4 g), 
tetraethylammonium cyanide (3 g), and dichloromethane (10 ml) was stirred 
at room temperature for 1 h. The reaction mixture was washed three times 
with water, dried and evaporated to dryness under reduced pressure, and 
the residue was recrystallised from ethanol to give 
2,2'-[5-cyanomethyl-1,3-phenylene)di(2-methylpropiononitrile), mp 
72.degree.-73.degree.. 
A mixture of this cyanomethyl compound (1 g), 1,2-dichloroethane (1 ml) and 
bromine (0.23 ml) was heated under reflux for 12 h. The reaction mixture 
was dissolved in dichloromethane (40 ml) and the solution was washed with 
water, dried and evaporated to dryness under reduced pressure. The residue 
was purified by flash chromatography using ethyl acetate (20% by volume) 
in petroleum ether (bp 60.degree.-80.degree.) as eluant, to give 
2,2'-[5-bromocyanomethyl-1,3-phenylene]di(2-methylpropiononitrile), np 
108.degree.-111.degree.. 
EXAMPLE 68 
The process described in Example 67 was repeated, using imidazole instead 
of 1,2,4-triazole, to give 
2,2'-[5-cyano(imidazol-1-yl)methyl-1,3-phenylene]di(2-methylpropiononitril 
e), mp 136.degree.-138.degree.. 
EXAMPLE 69 
A 20% (w/v) solution of sodium nitrite in water was added dropwise in a 
stirred mixture of 4 amino-1-[3,5-bis 
(1-cyano-1-methylethyl)benzyl]-1H-1,2,4-triazolium bromide and 2N aqueous 
hydrochloric acid (10 ml), until a slight excess of nitrite was present. 
The solution was washed with ether, neutralised with sodium hydrogen 
carbonate, and extracted twice with ethyl acetate. The combined ethyl 
acetate extracts were dried and evaporated to dryness and the residue was 
recrystallised from a mixture of ethyl acetate and cyclohexane to give 
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene)di(2-methylpropiononit 
rile, mp 81.degree.-82.degree.. 
The starting material for the above example was obtained as follows: 
A mixture of 2,2'-(5-bromomethyl-1,3-phenylene)di(2-methylpropiononitrile), 
(3.05 g), 4 amino-1H-1,2,4-triazole (1.68 g) and acetonitrile (5 ml) was 
stirred at 50.degree. for 18 h. The mixture was diluted with ethyl acetate 
(5 ml) and cooled, and the solid which crystallised was filtered off, to 
give 4 amino-1-[3,5-bis(1-cyano-1-methylethyl)benzyl-1H-1,2,4-triazolium 
bromide, mp 195.degree.-197.degree.. 
EXAMPLE 70 
A mixture of 
2,2'-[5-(1-chloro-1-(pyrimidin-5-yl)methyl)-1,3-phenylene]di(2-methylpropi 
ononitrile), (0.55 g), triethylamine (0.25 ml), 5% palladium-on-carbon 
(0.02 g) and ethanol (10 ml) was stirred under hydrogen at room 
temperature and atmospheric pressure for 10 minutes and then filtered. The 
filtrate was diluted with ethyl acetate (25 ml), and the solution washed 
with aqueous sodium hydrogen carbonate, dried and evaporated to dryness. 
The residue was purified by flash chromatography using 1% by volume of 
methanol in dichloromethane as eluant to give 
2,2'-[5-(pyrimidin-5-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), 
mp 132.degree.-134.degree.. 
The starting material for the above process was obtained as follows: 
A solution of 
2,2'-[5-hydroxy-.1-(pyrimidin-5-yl)methyl-1,3-phenylene]di(2-methylpropion 
onitrile), (0.32 g), in dichloromethane (5 ml) was treated with thionyl 
chloride (0.11 ml) and the mixture was heated under reflux for 0.5 h. The 
cooled solution was treated with aqueous sodium hydrogen carbonate 
solution, and the mixture was stirred for 15 minutes. The organic phase 
was separated, dried and evaporated to dryness, and the residue was 
purified by flash chromatography, eluting with 1% by volume of methanol in 
dichloromethane, to give 
2,2'-(5-[1-chloro-1-(pyrimidin-5-yl)methyl]-1,3-phenylene)di(2-methylpropi 
ononitrile), mp 118.degree.-121.degree.. 
##STR10##