Contraception in female primates without affecting the menstrual cycle

The invention relates to the use of aromatase inhibitors for contraception in female primates and to a method for contraception in female primates using such substances and to the use of those substances for the preparation of pharmaceutical compositions for contraception in female primates.

Pregnancy occurs in primates, including humans, when a fertilised egg has 
become implanted in the mucous coat of the uterus. In the course of the 
female cycle, under the control of the anterior pituitary hormones FSH and 
LH, follicle stimulation and ovulation occur, whereupon the ovum is 
released into the funnel of the fallopian tube. If a sperm cell meets the 
ovum, fertilisation occurs. The fertilised egg takes 3-4 days to pass 
through the fallopian tube and into the uterus. During that time, by a 
series of divisions, it develops into a blastocyst, which implants in the 
tissue of the uterus approximately 7 days after fertilisation. 
Conventional hormonal contraception (the "pill") relies on the inhibition 
of ovulation. The compositions used are a combination of synthetic 
gestagens and oestrogens which, by means of a negative feed-back 
mechanism, inhibit secretion of the gonadotropic hormones LH and FSH and 
thus inhibit follicle stimulation and ovulation. 
The so-called "minipill" consists of a low dose of gestagen. Contraceptives 
of that type do not have an inhibiting effect on the cycle, rather they 
stimulate the production of cervical mucus and alter its physical 
properties so that the sperm are not able to pass through it. This form of 
contraception relies exclusively on a mechanical barrier produced by 
physically altering the cervical mucus and is therefore less reliable than 
the ingestion of ovulation inhibitors, but on the other hand is associated 
with fewer risks (side effects). 
It would be very desirable to be able to combine the advantages of the 
"pill"--large degree of reliability--with those of the "minipill"--no 
effect on the female cycle. 
It has now been found that it is possible, surprisingly, by administering 
aromatase inhibitors to female primates, including humans, to effect 
reliable contraception without at the same time substantially affecting 
the menstrual cycle of the female primate. 
Substances that inhibit the enzyme aromatase are already known. 
Furthermore, aromatase inhibitors have already been proposed as 
anti-fertility agents for women of reproductive age (see, for example, 
EP-A-340 153, page 3, lines 5-6). In all of those cases, however, the 
aromatase inhibitor is intended to reduce the oestrogen level of the 
female mammal in such a manner that ovulation as well as implantation is 
suppressed. It goes without saying that, just as in the case of the 
conventional "pill", the female cycle is greatly affected by this. 
In contrast, the present invention relates to the use of aromatase 
inhibitors for contraception in female primates of reproductive age 
without substantially affecting the menstrual cycle of the female primate. 
The contraceptive action of the aromatase inhibitors is reversible, that 
is to say once their use has been discontinued pregnancy can occur in the 
treated primates as early as the next cycle. 
For the purpose of contraception, the maximum dose of aromatase inhibitor 
administered is one that has substantially no effect on the menstrual 
cycle of the female primate. 
The invention relates to the use of aromatase inhibitors for contraception 
in female primates of reproductive age in a dose at which the menstrual 
cycle of the female primate remains substantially unaffected. 
The absolute upper limit for the daily doses required for contraceptive 
action depends entirely on the type of aromatase inhibitor that is used. 
In the case of the highly active aromatase inhibitors that can be used 
according to the invention, the daily doses are generally from 
approximately 0.05 mg to approximately 30 mg, based on an individual 
having a body weight of approximately 60 kg, preference being given to the 
administration of individual doses of from approximately 0.01 mg to 
approximately 20 mg. In the case of less active aromatase inhibitors the 
daily doses can, however, be higher. 
The invention relates also to a method of contraception in female primates 
of reproductive age which comprises administering aromatase inhibitors to 
the female primate in a dose at which the menstrual cycle of the female 
primate remains substantially unaffected. 
The invention relates further to the use of aromatase inhibitors for the 
preparation of pharmaceutical compositions that comprise the aromatase 
inhibitors in a dose that prevents conception in female primates of 
reproductive age without substantially affecting the menstrual cycle of 
the female primate, which means that the menstrual cycle proceeds 
substantially as it would without the administration of the aromatase 
inhibitors. There is no substantial disruption of the cycle or delay in or 
bringing forward of menstruation caused by the administration of the 
aromatase inhibitor. 
In accordance with the customary definition, "primates" are to be 
understood as being prosimians, apes and humans. Female primates are 
distinguished by the fact that they all have a very similar reproductive 
endocrinology which is very different from that of other mammals, for 
example of rodents. 
The contraceptive action according to the invention of aromatase inhibitors 
in primates can be determined, for example, by means of the following 
experimental procedure: 
Female apes in the fertile phase of the cycle are cohabited with male 
members of the same species that have proved to be fertile. After 
ovulation the female animals are treated with an aromatase inhibitor. 
Under the same experimental conditions a control not treated with the test 
compound is carried out and the incidence of pregnancy in the treatment 
group is compared with that in the untreated control group. In order to 
assess the regularity of the cycle, suitable parameters, for example basal 
temperature, hormone levels, such as serum hormone levels, especially the 
serum progesterone level, and/or the onset of menstruation at the expected 
time are measured throughout the experiment. In addition, parameters of 
the subsequent cycle, for example the onset of menstruation, the length of 
the luteal phase and/or follicle function can be used to demonstrate that 
the menstrual cycle of the primates treated with an aromatase inhibitor 
used in accordance with the invention remains substantially unaffected. 
With the use according to the invention of the aromatase inhibitors, no 
pregnancy occurs in the treated primates, and the menstrual cycle proceeds 
with essentially the customary regularity (i.e. essentially as without the 
administration of aromatase inhibitors), which is evident, for example, 
from the fact that menstruation occurs at the expected time and that the 
length of the cycle, the length of the luteal phase, the progesterone 
profile and/or follicle function in the subsequent cycle remain 
substantially unaffected. 
The minimum effective dose of an aromatase inhibitor required for the use 
according to the invention can be determined experimentally, for example 
in apes, for example using the following experimental procedures: 
a) the overall dose of administered aromatase inhibitor is reduced until no 
contraceptive action is observed, i.e. until a significant proportion of 
the animals become pregnant; and/or 
b) the duration of treatment is reduced until no contraceptive action is 
observed, i.e. until a significant proportion of the animals or all the 
animals become pregnant. 
The minimum dose is defined as the lowest dose of active ingredient that 
leads to a significant reduction in the incidence of pregnancy as compared 
with the untreated control. 
Significant means significant in accordance with current statistical 
methods, for example Student's t-test. 
The duration of administration of the aromatase inhibitors used in 
accordance with the invention shall be selected so that the menstrual 
cycle of the female primate is substantially unaffected. For example, 
administration may begin after ovulation, for example two to three days 
after ovulation, and may continue for a period of from approximately five 
or six days to approximately the end of the cycle. 
By "aromatase inhibitors" there are to be understood substances that 
inhibit the enzyme aromatase (=oestrogen synthetase), which is responsible 
for converting androgens to oestrogens. Within the context of the present 
invention, preference is given to selective aromatase inhibitors, i.e. 
those that, apart from inhibiting aromatase, exhibit as few other, 
undesired inhibiting effects as possible on the biosynthesis of other 
steroid hormones, such as gestagens, androgens and gluco- and 
mineralo-corticoids, and that, for example, do not induce adrenal 
hypertrophy. 
Aromatase inhibitors may have a non-steroidal or a steroidal chemical 
structure. According to the present invention, both non-steroidal 
aromatase inhibitors and steroidal aromatase inhibitors can be used. 
By aromatase inhibitors there are to be understood especially those 
substances that in a determination of the in vitro inhibition of aromatase 
activity exhibit IC.sub.50 values of 10.sup.-5 M or lower, especially 
10.sup.-6 M or lower, preferably 10.sup.-7 M or lower and most especially 
10.sup.-8 M or lower. 
The in vitro inhibition of aromatase activity can be demonstrated, for 
example, using the methods described in J. Biol. Chem. 249, 5364 (1974) or 
in J. Enzyme Inhib. 4, 169 (1990). In addition, IC.sub.50 values for 
aromatase inhibition can be obtained, for example, in vitro by a direct 
product isolation method relating to inhibition of the conversion of 
4-.sup.14 C-androstenedione to 4-.sup.14 C-oestrone in human placental 
microsomes. 
By aromatase inhibitors there are to be understood most especially 
substances for which the minimum effective dose in the case of in vivo 
aromatase inhibition is 10 mg/kg or less, especially 1 mg/kg or less, 
preferably 0.1 mg/kg or less and most especially 0.01 mg/kg or less. 
In vivo aromatase inhibition can be determined, for example, by the 
following method [see J. Enzyme Inhib. 4, 179 (1990)]: androstenedione (30 
mg/kg subcutaneously) is administered on its own or together with a 
compound of the invention (orally or subcutaneously) to sexually immature 
female rats for a period of 4 days. After the fourth administration, the 
rats are sacrificed and the uteri are isolated and weighed. The aromatase 
inhibition is determined by the extent to which the hypertrophy of the 
uterus induced by the administration of androstenedione alone is 
suppressed or reduced by the simultaneous administration of the compound 
according to the invention. 
The following groups of compounds are listed as examples of aromatase 
inhibitors. Each individual group forms a group of aromatase inhibitors 
that can be used successfully in accordance with the present invention: 
(a) The compounds of formulae I and I* as defined in EP-A-165 904. These 
are especially the compounds of formula I 
##STR1## 
wherein R.sub.1 is hydrogen, lower alkyl; lower alkyl substituted by 
hydroxy, lower alkoxy, lower alkanoyloxy, lower alkanoyl, amino, lower 
alkylamino, di-lower alkylamino, halogen, sulfo, carboxy, lower 
alkoxycarbonyl, carbamoyl or by cyano; nitro, halogen, hydroxy, lower 
alkoxy, lower alkanoyloxy, phenylsulfonyloxy, lower alkylsulfonyloxy, 
mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower 
alkanoylthio, amino, lower alkylamino, di-lower alkylamino, lower 
alkyleneamino, N-morpholino, N-thiomorpholino, N-piperazino that is 
unsubstituted or lower alkyl-substituted in the 4-position, tri-lower 
alkylammonio, sulfo, lower alkoxysulfonyl, sulfamoyl, lower 
alkylsulfamoyl, di-lower alkylsulfamoyl, formyl; iminomethyl that is 
unsubstituted or substituted at the nitrogen atom by hydroxy, lower 
alkoxy, lower alkanoyloxy, lower alkyl, phenyl or by amino; C.sub.2 
-C.sub.7 alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl, carbamoyl, 
lower alkylcarbamoyl, di-lower alkylcarbamoyl, cyano, 5-tetrazolyl, 
unsubstituted or lower alkyl-substituted 4,5-dihydro-2-oxazolyl or 
hydroxycarbamoyl; and R.sub.2 is hydrogen, lower alkyl, phenyl-lower 
alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, halogen, 
hydroxy, lower alkoxy, lower alkanoyloxy, mercapto, lower alkylthio, 
phenyl-lower alkylthio, phenylthio, lower alkanoylthio, carboxy, lower 
alkoxycarbonyl or lower alkanoyl; the 7,8-dihydro derivatives thereof; and 
the compounds of formula I* 
##STR2## 
wherein n is 0, 1, 2, 3 or 4; and R.sub.1 and R.sub.2 are as defined above 
for formula I; it being possible for the phenyl ring in the radicals 
phenylsulfonyloxy, phenyliminomethyl, benzoyl, phenyl-lower alkyl, 
phenyl-lower alkylthio and phenylthio to be unsubstituted or substituted 
by lower alkyl, lower alkoxy or by halogen; it being possible in a 
compound of formula I* for the two substituents C.sub.6 H.sub.4 --R.sub.1 
and R.sub.2 to be linked to each of the saturated carbon atoms of the 
saturated ring, either both to the same carbon atom or both to different 
carbon atoms, and pharmaceutically acceptable salts thereof. 
Individual compounds that may be given special mention here are: 
(1) 5-(p-cyanophenyl)imidazo[1,5-a]pyridine, 
(2) 5-(p-ethoxycarbonylphenyl)imidazo[1,5-a]pyridine, 
(3) 5-(p-carboxyphenyl )imidazo[1,5-a]pyridine, 
(4) 5-(p-tert-butylaminocarbonylphenyl)imidazo[1,5-a]pyridine, 
(5) 5-(p-ethoxycarbonylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(6) 5-(p-carboxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(7) 5-(p-carbamoylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(8) 5-(p-tolyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(9) 5-(p-hydroxymethylphenyl)imidazo[1,5-a]pyridine, 
(10) 5-(p-cyanophenyl)-7,8-dihydroimidazo[1,5-a]pyridine, 
(11) 5-(p-bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(12) 5-(p-hydroxymethylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(13) 5-(p-formylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(14) 
5-(p-cyanophenyl)-5-methylthio-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(15) 
5-(p-cyanophenyl)-5-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin 
e, 
(16) 5-(p-aminophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(17) 5-(p-formylphenyl)imidazo[1,5-a]pyridine, 
(18) 5-(p-carbamoylphenyl)imidazo[1,5-a]pyridine, 
(19) 
5H-5-(4-tert-butylaminocarbonylphenyl)-6,7-dihydropyrrolo[1,2-c]imidazole, 
(20) 5H-5-(4-cyanophenyl)-6,7-dihydropyrrolo[1,2-c]imidazole, 
(21) 5H-5-(4-cyanophenyl)-6,7,8,9-tetrahydroimidazo[1,5-a]azepine, 
(22) 
5-(4-cyanophenyl)-6-ethoxycarbonylmethyl-5,6,7,8-tetrahydroimidazo[1,5-a]p 
yridine, 
(23) 
5-(4-cyanophenyl)-6-carboxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine 
(24) 5-benzyl-5-(4-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(25) 7-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(26) 7-(p-carbamoylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(27) 5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine 
(=Fadrozol). 
(b) The compounds of formula I as defined in EP-A 236 940. These are 
especially the compounds of formula I 
##STR3## 
wherein R and R.sub.0, independently of one another, are each hydrogen or 
lower alkyl, or R and R.sub.0 at adjacent carbon atoms, together with the 
benzene ting to which they are bonded, form a naphthalene or 
tetrahydronaphthalene ring; wherein R.sub.1 is hydrogen, lower alkyl, 
aryl, aryl-lower alkyl or lower alkenyl; R.sub.2 is hydrogen, lower alkyl, 
aryl, aryl-lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio or 
lower alkenyl, or wherein R.sub.1 and R.sub.2 together are lower 
alkylidene or C.sub.4 -C.sub.6 alkylene; wherein W is 1-imidazolyl, 
1-(1,2,4 or 1,3,4)-triazolyl, 3-pyridyl or one of the mentioned 
heterocyclic radicals substituted by lower alkyl; and aryl within the 
context of the above definitions has the following meanings: phenyl that 
is unsubstituted or substituted by one or two substituents from the group 
lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino, 
halogen, trifluoromethyl, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, 
N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkanoyl, 
benzoyl, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl and 
N,N-di-lower alkylsulfamoyl; also thienyl, indolyl, pyridyl or furyl, or 
one of the four last-mentioned heterocyclic radicals monosubstituted by 
lower alkyl, lower alkoxy, cyano or by halogen; and pharmaceutically 
acceptable salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile, 
(2) 4-[alpha-(3-pyridyl )-1-imidazolylmethyl]-benzonitrile, 
(3) 4-[alpha-(4-cyanobenzyl)-1-imidazolylmethyl]-benzonitrile, 
(4) 1-(4-cyanophenyl)-1-(1-imidazolyl)-ethylene, 
(5) 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile, 
(6) 4-[alpha-(4-cyanophenyl)-3-pyridylmethyl]-benzonitrile. 
(c) The compounds of formula I as defined in EP-A-408 509. These are 
especially the compounds of formula I 
##STR4## 
wherein Tetr is 1- or 2-tetrazolyl that is unsubstituted or substituted in 
the 5-position by lower alkyl, phenyl-lower alkyl or by lower alkanoyl; 
R.sub. and R.sub.2, independently of one another, are each hydrogen; lower 
alkyl that is unsubstituted or substituted by hydroxy, lower alkoxy, 
halogen, carboxy, lower alkoxycarbonyl, (amino, lower alkylamino or 
di-lower alkylamino)-carbonyl or by cyano; lower alkenyl, aryl, 
heteroaryl, aryl-lower alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 
-C.sub.6 cycloalkyl-lower alkyl, lower alkylthio, arylthio or aryl-lower 
alkylthio; or R.sub.1 and R.sub.2 together are straight-chained C.sub.4 
-C.sub.6 alkylene that is unsubstituted or substituted by lower alkyl, or 
are a group --(CH.sub.2).sub.m -1,2-phenylene-(CH.sub.2).sub.n -- wherein 
m and n, independently of one another, are each 1 or 2 and 1,2-phenylene 
is unsubstituted or substituted in the same way as phenyl in the 
definition of aryl below, or are lower alkylidene that is unsubstituted or 
mono- or di-substituted by aryl; and R and R.sub.0, independently of one 
another, are each hydrogen or lower alkyl; or R and R.sub.0 together, 
located at adjacent carbon atoms of the benzene ring, are a benzo group 
that is unsubstituted or substituted in the same way as phenyl in the 
definition of aryl below; aryl in the above definitions being phenyl that 
is unsubstituted or substituted by one or more substituents from the group 
consisting of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, 
nitro, amino, halogen, trifluoromethyl, carboxy, lower alkoxycarbonyl, 
(amino, lower alkylamino or di-lower alkylamino)-carbonyl, cyano, lower 
alkanoyl, benzoyl, lower alkylsulfonyl and (amino, lower alkylamino or 
di-lower alkylamino)-sulfonyl; heteroaryl in the above definitions being 
an aromatic heterocyclic radical from the group consisting of pyrrolyl, 
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, 
isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, 
pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, indolyl, 
isoindolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, 
benzoxazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolyl 
and isoquinolyl that is unsubstituted or substituted in the same way as 
phenyl in the definition of aryl above; and pharmaceutically acceptable 
salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 4-(2-tetrazolyl)methyl-benzonitrile, 
(2) 4-[.alpha.-(4-cyanophenyl )-(2-tetrazolyl )methyl]-benzonitrile, 
(3) 1-cyano-4-(1-tetrazolyl)methyl-naphthalene, 
(4) 4-[.alpha.-(4-cyanophenyl)-(1-tetrazolyl)methyl]-benzonitrile. 
(d) The compounds of formula I as defined in European Patent Application 
No. 91810110.6. These are especially the compounds of formula I 
##STR5## 
wherein X is halogen, cyano, carbamoyl, N-lower alkylcarbamoyl, 
N-cycloalkyl-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, 
N-arylcarbamoyl, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy, 
wherein aryl is phenyl or naphthyl, each of which is unsubstituted or 
substituted by lower alkyl, hydroxy, lower alkoxy, halogen and/or by 
trifluoromethyl; Y is a group --CH.sub.2 --A wherein A is 1-imidazolyl, 
1-(1,2,4-triazolyl), 1-(1,3,4-triazolyl), 1-(1,2,3-triazolyl), 
1-(1,2,5-triazolyl), 1-tetrazolyl or 2-tetrazolyl, or Y is hydrogen, 
R.sub.1 and R.sub.2, independently of one another, are each hydrogen, 
lower alkyl or a group --CH.sub.2 --A as defined for Y, or R.sub.1 and 
R.sub.2 together are --(CH.sub.2).sub.n -- wherein n is 3, 4 or 5, with 
the proviso that one of the radicals Y, R.sub.1 and R.sub.2 is a group 
--CH.sub.2 --A, with the further proviso that in a group --CH.sub.2 --A as 
a meaning of R.sub.1 or R.sub.2, A is other than 1-imidazolyl when X is 
bromine, cyano or carbamoyl, and with the proviso that in a group 
--CH.sub.2 --A as a meaning of Y, A is other than 1-imidazolyl when X is 
halogen or lower alkoxy, R.sub.1 is hydrogen and R.sub.2 is hydrogen or 
lower alkyl, and pharmaceutically acceptable salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 7-cyano-4-[1-(1,2,4-triazolyl)methyl]-2,3-dimethylbenzofuran, 
(2) 7-cyano-4-(1-imidazolylmethyl)-2,3-dimethylbenzofuran, 
(3) 7-carbamoyl-4-(1-imidazolylmethyl)-2,3-dimethylbenzofuran, 
(4) 
7-N-(cyclohexylmethyl)carbamoyl-4-(1-imidazolylmethyl)-2,3-dimethylbenzofu 
ran. 
(e) The compounds of formula I as defined in Swiss Patent Application 
1339/90-7. These are especially the compounds of formula I 
##STR6## 
wherein the dotted line denotes an additional bond or no additional bond, 
Az is imidazolyl, triazolyl or tetrazolyl bonded via a ring nitrogen atom, 
each of those radicals being unsubstituted or substituted at carbon atoms 
by lower alkyl or by aryl-lower alkyl, Z is carboxy, lower alkoxycarbonyl, 
carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, 
N-arylcarbamoyl, cyano, halogen, hydroxy, lower alkoxy, aryl-lower alkoxy, 
aryloxy, lower alkyl, trifluoromethyl or aryl-lower alkyl, and R.sub.1 and 
R.sub.2, independently of one another, are each hydrogen, lower alkyl, 
lower alkoxy, hydroxy, halogen or trifluoromethyl; aryl being phenyl or 
naphthyl each of which is unsubstituted or substituted by one or two 
substituents from the group consisting of lower alkyl, lower alkoxy, 
hydroxy, halogen and trifluoromethyl; with the proviso that neither Z nor 
R.sub.2 is hydroxy in the 8-position, and pharmaceutically acceptable 
salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 6-cyano-1-(1-imidazolyl)-3,4-dihydronaphthalene, 
(2) 6-cyano-1-[1-(1,2,4-triazolyl)]-3,4-dihydronaphthalene, 
(3) 6-chloro-1-(1-imidazolyl)-3,4-dihydronaphthalene, 
(4) 6-bromo-1-(1-imidazolyl)-3,4-dihydronaphthalene. 
(f) The compounds of formula I as defined in Swiss Patent Application 
3014/90-0. These are especially the compounds of formula I 
##STR7## 
wherein Z is a five-membered nitrogen-containing heteroaromatic ting 
selected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl, 
5-oxazolyl, 5-(1,2,3-thiadiazolyl), 5-(1,2,3-oxadiazolyl), 
3-(1,2,5-thiadiazolyl), 3-(1,2,5-oxadiazolyl), 4-isothiazolyl, 
4-isoxazolyl, 4-(1,2,3-thiadiazolyl), 4-(1,2,3-oxadiazolyl), 
2-(1,3,4-thiadiazolyl), 2-(1,3,4-oxadiazolyl), 5-(1,2,4-thiadiazolyl) and 
5-(1,2,4-oxadiazolyl); R and R.sub.0 are hydrogen; or R and R.sub.0 
together are a benzo group that is unsubstituted or substituted by lower 
alkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; R.sub.1 is 
hydrogen, hydroxy, chlorine or fluorine; R.sub.3 is hydrogen; R.sub.2 is 
hydrogen, lower alkyl or phenyl that is unsubstituted or substituted by 
lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl or by cyano; 
or R.sub.1 and R.sub.2 together are methylidene; or R.sub.2 and R.sub.3 
together are --(CH.sub.2).sub.3 --; or R.sub.1 and R.sub.2 and R.sub.3 
together are a group .dbd.CH--(CH.sub.2).sub.2 -- wherein the single bone 
is linked to the benzene ring; X is cyano; and X may also be halogen when 
R.sub.2 and R.sub.3 together are --(CH.sub.2).sub.3 -- or R.sub.1 and 
R.sub.2 and R.sub.3 together are a group .dbd.CH--(CH.sub.2).sub.2 --; and 
pharmaceutically acceptable salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-hydroxy-5-isothiazolylmethyl]-benzonitr 
ile. 
(2) 4-[.alpha.-(4-cyanophenyl)-5-isothiazolylmethyl]-benzonitrile, 
(3) 4-[.alpha.-(4-cyanophenyl)-5-thiazolylmethyl]-benzonitrile, 
(4) 1-(4-cyanophenyl)-1-(5-thiazolyl)-ethylene, 
(5) 6-cyano-1-(5-isothiazolyl )-3,4-dihydronaphthalene, 
(6) 6-cyano-1-(5-thiazolyl)-3,4-dihydronaphthalene. 
(g) The compounds of formula VI as defined in Swiss Patent Application 
3014/90-0. These are especially the compounds of formula VI 
##STR8## 
wherein Z is a five-membered nitrogen-containing heteroaromatic ring 
selected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl, 
5-oxazolyl, 5-(1,2,3-thiadiazolyl). 5-(1,2,3-oxadiazolyl) 
3-(1,2,5-thiadiazolyl), 3-(1,2,5-oxadiazolyl), 4-isothiazolyl. 
4-isoxazolyl, 4-(1,2,3-thiadiazolyl), 4-(1,2,3-oxadiazolyl), 
2-(1,3,4-thiadiazolyl), 2-(1,3,4-oxadiazolyl), 5-(1,2,4-thiadiazolyl) and 
5-(1,2,4-oxadiazolyl); R and R.sub.0 are each hydrogen; or R and R.sub.0 
together are a benzo group that is unsubstituted or substituted by lower 
alkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; R.sub.1 is 
hydrogen, hydroxy, chlorine or fluorine; R.sub.3 is hydrogen; R.sub. 2 is 
hydrogen, lower alkyl or phenyl that is unsubstituted or substituted by 
lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, aryl-lower 
alkoxy or by aryloxy; or R.sub.l and R.sub.2 together are methylidene, and 
W.sub.2 is halogen, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy; 
aryl in each case being phenyl that is unsubstituted or substituted by 
lower alkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; and 
pharmaceutically acceptable salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) bis(4,4'-bromophenyl)-(5-isothiazolyl)methanol, 
(2) bis(4,4'-bromophenyl)-(5-isothiazolyl)methane, 
(3) bis(4,4'-bromophenyl)-(5-thiazolyl)methanol, 
(4) bis(4,4'-bromophenyl)-(5-thiazolyl)methane, 
(h) The compounds of formula I as defined in Swiss Patent Application 
3923/90-4. These are especially the compounds of formula I 
##STR9## 
wherein Z is imidazolyl, triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, 
indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, 
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl. triazinyl, quinolinyl or 
isoquinolinyl, all those radicals being bonded via their heterocyclic 
rings and all those radicals being unsubstituted or substituted by lower 
alkyl, hydroxy, lower alkoxy, halogen or by trifluoromethyl: R.sub.l and 
R.sub.2, independently of one another, are each hydrogen or lower alkyl; 
or R.sub.1 and R.sub.2 together are C.sub.3 -C.sub.4 alkylene, or a benzo 
group that is unsubstituted or substituted as indicated below for aryl; R 
is hydrogen, lower alkyl, aryl or heteroaryl, and X is cyano, carbamoyl, 
N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-lower 
alkylenecarbamoyl; N,N-lower alkylenecarbamoyl interrupted by --O--, --S-- 
or --NR"--, wherein R" is hydrogen, lower alkyl or lower alkanoyl; 
N-cycloalkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)-carbamoyl, 
N-cycloalkyl-lower alkylcarbamoyl, N-(lower alkyl-substituted 
cycloalkyl)-lower alkylcarbamoyl, N-aryl-lower alkylcarbamoyl, 
N-arylcarbamoyl, N-hydroxycarbamoyl, hydroxy, lower alkoxy, aryl-lower 
alkoxy or aryloxy; and wherein X is also halogen when Z is imidazolyl, 
triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, indolyl, isoindolyl, 
benzimidazolyl, benzopyrazolyl or benzotriazolyl; 
wherein aryl is phenyl or naphthyl, these radicals being unsubstituted or 
substituted by from 1 to 4 substituents from the group consisting of lower 
alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two 
adjacent carbon atoms), C.sub.3 -C.sub.8 cycloalkyl, phenyl-lower alkyl, 
phenyl; lower alkyl that is substituted in turn by hydroxy, lower alkoxy, 
phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, 
di-lower alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower 
alkylsulfonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower 
alkylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano; hydroxy; 
lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy, phenoxy, lower 
alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy 
(linked to two adjacent carbon atoms), lower alkanoyloxy, phenyl-lower 
alkanoyloxy, phenylcarbonyloxy, mercapto, lower alkylthio, phenyl-lower 
alkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower alkylsulfinyl, 
phenylsulfinyl, lower alkylsulfonyl, phenyl-lower alkylsulfonyl, 
phenylsulfonyl, halogen, nitro, amino, lower alkylamino, C.sub.3 -C.sub.8 
cycloalkylamino, phenyl-lower alkylamino, phenylamino, di-lower 
alkylamino, N-lower alkyl-N-phenylamino, N-lower alkyl-N-phenyl-lower 
alkylamino; lower alkyleneamino or lower alkyleneamino interrupted by 
--O--, --S-- or --NR"-- (wherein R" is hydrogen, lower alkyl or lower 
alkanoyl); lower alkanoylamino, phenyl-lower alkanoylamino, 
phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl, 
phenylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower 
alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-lower alkylenecarbamoyl; 
N,N-lower alkylenecarbamoyl interrupted by --O--, --S-- or --NR"--, 
wherein R" is hydrogen, lower alkyl or lower alkanoyl; 
N-cycloalkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)-carbamoyl, 
N-cycloalkyl-lower alkylcarbamoyl, N-(lower alkyl-substituted 
cycloalkyl)-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenyl-lower 
alkylcarbamoyl, N-phenylcarbamoyl, cyano, sulfo, lower alkoxysulfonyl, 
sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl and 
N-phenylsulfamoyl; the phenyl groups occurring in the substituents of 
phenyl and naphthyl in turn being unsubstituted or substituted by lower 
alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; 
wherein heteroaryl is indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, 
benzotriazolyl, benzo[b]furanyl, benzo[b]thienyl, benzoxazolyl or 
benzothiazolyl, those radicals being unsubstituted or substituted by from 
1 to 3 identical or different substituents selected from lower alkyl, 
hydroxy, lower alkoxy, halogen, cyano and trifluoromethyl; and 
pharmaceutically acceptable salts thereof. 
Those compounds are especially the compounds of formula I whereto Z is 
1-imidazolyl, 1-(1,2,4-triazolyl), 1-(1,3,4-triazolyl), 
1-(1,2,3-triazolyl), 1-tetrazolyl, 2-tetrazolyl, 3-pyridyl, 4-pyridyl, 
4-pyrimidyl, 5-pyrimidinyl or 2-pyrazinyl; R.sub.1 and R.sub.2, 
independently of one another, are each hydrogen or lower alkyl; or R.sub.1 
and R.sub.2 together are 1,4-butylene or a benzo group; R is lower alkyl; 
phenyl that is unsubstituted or substituted by cyano, carbamoyl, halogen, 
lower alkyl, trifluoromethyl, hydroxy, lower alkoxy or by phenoxy; or 
benzotriazolyl or benzo[b]furanyl, the last two radicals being 
unsubstituted or substituted by from 1 to 3 identical or different 
substituents selected from lower alkyl, halogen and cyano; and X is cyano 
or carbamoyl; and wherein X is also halogen when Z is 1-imidazolyl, 
1-(1,2,4-triazolyl), 1-(1,3,4-triazolyl), 1-(1,2,3-triazolyl), 
1-tetrazolyl 2-tetrazolyl; and pharmaceutically acceptable salts thereof. 
Individual compounds that may be given special mention here are: 
(1) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methyl]-benzo 
nitrile, 
(2) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(2-tetrazolyl)methyl]-benzonitri 
le, 
(3) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(1-tetrazolyl)methyl]-benzonitri 
le, 
(4) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(1-imidazolyl)methyl]-benzonitri 
le, 
(5) 
1-methyl-6-[.alpha.-(4-chlorophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)met 
hyl]-benzotriazole, 
(6) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,3-triazolyl)methyl]-benzo 
nitrile, 
(7) 
7-cyano-4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methy 
l]-2,3-dimethylbenzo[b]furan, 
(8) 
4-[.alpha.-(4-bromophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methyl]-benzo 
nitrile, 
(9) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(5-pyrimidyl)methyl]-benzonitril 
e, 
(10) 
4-[.alpha.-(4-bromophenyl)-.alpha.-fluoro-(5-pyrimidyl)methyl]-benzonitril 
e, 
(11) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(3-pyridyl)methyl]-benzonitrile, 
(12) 
7-bromo-4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(1-imidazolyl)methyl]-2, 
3-dimethylbenzo[b]furan, 
(13) 
7-bromo-4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methy 
l]-2,3-dimethylbenzo[b]furan, 
(14) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(5-pyrimidyl)methyl]-benzonitril 
e, 
(15) 
4-[.alpha.-(4-bromophenyl)-.alpha.-fluoro-(5-pyrimidyl)methyl]-benzonitril 
e, 
(16) 4-[.alpha.-(4-cyanophenyl)-1-(1,2,3-triazolyl)methyl]-benzonitrile, 
(17) 
2,3-dimethyl-4-[.alpha.-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-7-cyano 
-benzo[b]furan, 
(18) 4-[.alpha.-(4-cyanophenyl)-(5-pyrimidyl)methyl]-benzonitrile, 
(19) 4-[.alpha.-(4-bromophenyl)-(5-pyrimidyl)methyl]-benzonitrile, 
(20) 
2,3-dimethyl-4-[.alpha.-(4-cyanophenyl)-(1-imidazolyl)methyl]-7-bromo-benz 
o[b]furan, 
(21) 
2,3-dimethyl-4-[.alpha.-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-7-bromo 
-benzo-[b]furan. 
(i) The compounds of formula I as defined in EP-A-114 033. These are 
especially the compounds of formula I 
##STR10## 
wherein R.sub.1 is hydrogen, R.sub.2 is hydrogen, sulfo, C.sub.1 -C.sub.7 
alkanoyl or C.sub.1 -C.sub.7 alkanesulfonyl and R.sub.3 is hydrogen, or 
wherein R.sub.1 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, 
C.sub.2 -C.sub.7 alkynyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.10 
cycloalkenyl, C.sub.3 -C.sub.6 cycloalkyl-C.sub.1 -C.sub.4 alkyl, C.sub.3 
-C.sub.6 cycloalkyl-C.sub.2 -C.sub.4 alkenyl or C.sub.3 -C.sub.6 
cycloalkenyl-C.sub.1 -C.sub.4 alkyl, R.sub.2 is hydrogen, C.sub.1 -C.sub.7 
alkyl, sulfo, C.sub.1 -C.sub.7 alkanoyl or C.sub.1 -C.sub.7 alkanesulfonyl 
and R.sub.3 is hydrogen or C.sub.1 -C.sub.7 alkyl, and salts of those 
compounds. 
Individual compounds from that group that may be given special mention are: 
(1) 1-(4-aminophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione, 
(2) 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.0]hexane-2,4-dione, 
(3) 1-(4-aminophenyl)-3-isobutyl-3-azabicyclo[3.1.0]hexane-2,4-dione, 
(4) 1-(4-aminophenyl)-3-n-heptyl-3-azabicyclo[3.1.0]hexane-2,4-dione, 
(5) 
1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.0]hexane-2,4-dione. 
(j) The compounds of formula I as defined in EP-A-166 692. These are 
especially the compounds of formula I 
##STR11## 
wherein R.sub.1 is hydrogen, alkyl having from 1 to 12 carbon atoms, 
alkenyl having from 2 to 12 carbon atoms, lower alkynyl, cycloalkyl or 
cycloalkenyl each having from 3 to 10 carbon atoms, cycloalkyl-lower alkyl 
having from 4 to 10 carbon atoms, cycloalkyl-lower alkenyl having from 5 
to 10 carbon atoms, cycloalkenyl-lower alkyl having from 4 to 10 carbon 
atoms, or aryl having from 6 to 12 carbon atoms or aryl-lower alkyl having 
from 7 to 15 carbon atoms, each of which is unsubstituted or substituted 
by lower alkyl, hydroxy, lower alkoxy, acyloxy, amino, lower alkylamino, 
di-lower alkylamino, acylamino amino or by halogen, R.sub.2 is hydrogen, 
lower alkyl, sulfo, lower alkanoyl or lower alkanesulfonyl, sulfonyl, 
R.sub.3 is hydrogen or lower alkyl and R.sub.4 is hydrogen, lower alkyl, 
phenyl or phenyl substituted by --N(R.sub.2)(R.sub.3), and salts thereof, 
radicals described as "lower" containing up to and including 7 carbon 
atoms. 
Individual compounds from that group that may be given special mention are: 
(1) 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione, 
(2) 1-(4-aminophenyl)-3-methyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione, 
(3) 1-(4-aminophenyl)-3-n-decyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione, 
(4) 1-(4-aminophenyl)-3-cyclohexyl-3-azabicyclo[3.1.1 ]heptane-2,4-dione, 
(5) 1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.1 
]heptane-2,4-dione. 
(k) The compounds of formula I as defined in EP-A-356 673. These are 
especially the compounds of formula I 
##STR12## 
wherein W (.alpha.) is a 2-naphthyl or 1-anthryl radical, wherein each 
benzene ring is unsubstituted or substituted by a substituent selected 
from halogen, hydroxy, carboxy, cyano and nitro; or 
(.beta.) is 4-pyridyl, 2-pyrimidyl or 2-pyrazinyl, each of those radicals 
being unsubstituted or substituted by a substituent selected from halogen, 
cyano, nitro, C.sub.1 -C.sub.4 alkoxy and C.sub.2 -C.sub.5 alkoxycarbonyl; 
and pharmaceutically acceptable salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 5-(2'-naphthyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 
(2) 5-(4'-pyridyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. 
(1) The compounds of formula I or Ia as defined in EP-A-337 929. These are 
especially the compounds of formula I/Ia 
##STR13## 
wherein R.sub.1 is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, 
butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, 
cyclohexylmethyl or benzyl, R.sub.2 is benzyloxy, 3-bromo-, 4-bromo-, 
4-chloro-, 2,3-, 2,4-, 4,5- or 4,6-dichloro-benzyloxy, and R.sub.3 is 
cyano; C.sub.2 -C.sub.10 alkanoyl that is unsubstituted or mono- or 
poly-substituted by halogen, methoxy, amino, hydroxy and/or by cyano; 
benzoyl that is unsubstituted or substituted by one or more substituents 
from the group halogen, C.sub.1 -C.sub.4 alkyl, methoxy, amino, hydroxy 
and cyano; carboxy, (methoxy, ethoxy or butoxy)-carbonyl, carbamoyl, 
N-isopropylcarbamoyl, N-phenylcarbamoyl, N-pyrrolidylcarbonyl, nitro or 
amino; and salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 4-(2,4-dichlorobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzonitrile, 
(2) (4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl )-butyl]-phenyl pentyl ketone, 
(3) 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzanilide, 
(4) 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzoic acid, 
(5) 3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzonitrile, 
(6) 3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic acid 
methyl ester, 
(7) 3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic acid, 
(8) 3-(3-bromobenzyloxy)-4-[1-(1-imidazolyl )-butyl]-benzonitrile, 
(9) 4-(3-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzonitrile, 
(10) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic acid, 
(11) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzanilide, 
(12) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-phenyl pentyl ketone, 
(13) 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzonitrile, 
(14) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzonitrile, 
(15) 4-nitro-2-[1-(1-imidazolyl)-butyl]-phenyl-(2,4-dichlorobenzyl) ether, 
(16) 4-amino-2-[1-(1-imidazolyl)-butyl]-phenyl-(2,4-dichlorobenzyl) ether, 
(17) (2,4-dichlorobenzyl)-[2-(1-imidazolyl-methyl)-4-nitrophenyl]ether. 
(m) The compounds of formula I as defined in EP-A-337 928. These are 
especially the compounds of formula I 
##STR14## 
wherein R.sub.1 is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, 
butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, 
cyclohexylmethyl or benzyl, R.sub.2 is hydrogen, halogen, cyano, methyl, 
hydroxymethyl, cyanomethyl, methoxymethyl, pyrrolidinylmethyl, carboxy, 
(methoxy, ethoxy or butoxy)-carbonyl, carbamoyl, N-isopropylcarbamoyl, 
N-phenylcarbamoyl, N-pyrrolidylcarbonyl; C.sub.2 -C.sub.10 alkanoyl that 
is unsubstituted or mono- or poly-substituted by halogen, methoxy, ethoxy, 
amino, hydroxy and/or by cyano; or benzoyl that is unsubstituted or 
substituted by one or more substituents from the group halogen, C.sub.1 
-C.sub.4 alkyl, methoxy, ethoxy, amino, hydroxy and cyano, R.sub.3 is 
hydrogen, benzyloxy, 3-bromo-, 4-bromo-, 4-chloro-, 2,3-, 2,4-, 4,5- or 
4,6-dichlorobenzyloxy, and X is --CH.dbd.N--; --CH.dbd.N(--O)--or --S--; 
and salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 5-[1-(1-imidazolyl)-butyl]-thiophene-2-carbonitrile, 
(2) 2-[1-(1-imidazolyl)-butyl]-thiophene-4-carbonitrile, 
(3) 2-[1-(1-imidazolyl)-butyl]-4-bromo-thiophene, 
(4) 2-[1-(1-imidazolyl)-butyl]-5-bromo-thiophene, 
(5) 5-[1-(1-imidazolyl)-butyl]-2-thienyl pentyl ketone, 
(6) 5-[1-(1-imidazolyl)-butyl]-2-thienyl ethyl ketone, 
(7) 
5-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine-2-carbonitrile, 
(8) 3-(4-chlorobenzyloxy 
)-4-[1-(1-imidazolyl)-pentyl]-pyridine-2-carbonitrile, 
(9) 3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine-N-oxide, 
(10) 3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine. 
(n) The compounds of formula I as defined in EP-A-340 153. These are 
especially the compounds of formula I 
##STR15## 
wherein R.sub.1 is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl, 
butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, 
cyclohexylmethyl or benzyl, and R.sub.2 is a radical from the group 
methyl, ethyl, propyl, benzyl, phenyl and ethenyl that is substituted by 
hydroxy, cyano, methoxy, butoxy, phenoxy, amino, pyrrolidinyl, carboxy, 
lower alkoxycarbonyl or by carbamoyl; or R.sub.2 is formyl or derivatised 
formyl that can be obtained by reaction of the formyl group with an amine 
or amine derivative from the group hydroxylamine, O-methylhydroxylamine, 
O-ethylhydroxylamine, O-allylhydroxylamine, O-benzylhydroxylamine, 
O-4-nitrobenzyloxyhydroxylamine, 
O-2,3,4,5,6-pentafluorobenzyloxyhydroxylamine, semicarbazide, 
thiosemicarbazide, ethylamine and aniline; acetyl, propionyl, butyryl, 
valeryl, caproyl; benzoyl that is unsubstituted or substituted by one or 
more substituents from the group halogen, C.sub.1 -C.sub.4 -alkyl, 
methoxy, amino, hydroxy and cyano; carboxy, (methoxy, ethoxy or 
butoxy)carbonyl, carbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl or 
N-pyrrolidylcarbonyl; and salts thereof. 
Individual compounds from that group that may be given special mention are: 
(1) 4-(1-(1-imidazolyl)-butyl)-benzoic acid methyl ester, 
(2) 4-(1-(1-imidazolyl)-butyl)-benzoic acid butyl ester, 
(3) 4-(1-(1-imidazolyl)-butyl)-phenyl-acetonitrile, 
(4) 4-(1-(1-imidazolyl)-butyl)-benzaldehyde, 
(5) 4-(1-(1-imidazolyl)-butyl)-benzyl alcohol, 
(6) {4-[1-(1-imidazolyl)-butyl]-phenyl }-2-propyl ketone, 
(7) 4-[1-(1-imidazolyl)-butyl]-phenyl propyl ketone, 
(8) 4-[1-(1-imidazolyl)-butyl]-phenyl butyl ketone, 
(9) 4-[1-(1-imidazolyl)-butyl]-phenyl pentyl ketone, 
(10) 4-[1-(1-imidazolyl)-butyl]-phenyl hexyl ketone. 
(o) The compounds of formula I as defined in DE-A-4 014 006. These are 
especially the compounds of formula I 
##STR16## 
wherein A is an N-atom or a CH radical and W is a radical of the formula 
##STR17## 
wherein X is an oxygen or a sulfur atom or a --CH.dbd.CH-- group and Y is 
a methylene group, an oxygen or a sulfur atom and Z is a 
--(CH.sub.2).sub.n -- group wherein n=1, 2 or 3 and either 
a) R.sub.3 in W is a hydrogen atom and R.sub.1 and R.sub.2, independently 
of one another, are each a hydrogen atom, a C.sub.1 -- to C.sub.10 alkyl 
group or a C.sub.3 -- to C.sub.7 cycloalkyl group, or 
b) R.sub.2 is as defined under a) and R.sub.1 together with R.sub.3 forms a 
--(CH.sub.2).sub.m -- group wherein m=2,3,or4, 
and their pharmaceutically acceptable addition salts with acids. 
Individual compounds from that group that may be given special mention are: 
(1) 5-[1-(1-imidazolyl)-butyl]-1-indanone, 
(2) 7-[1-(1-imidazolyl)-butyl]-1-indanone, 
(3) 6-[1-(1-imidazolyl)-butyl]-1-indanone, 
(4) 6-(1-imidazolyl)-6,7,8,9-tetrahydro-1H-benz[e]inden-3(2H)-one, 
(5) 2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6-oxo-cyclopenta[b]-thiophene, 
(6) 6-[1-(1-imidazolyl)-butyl]-3,4-dihydro-2H-naphthalen-1-one, 
(7) 2-[1-(1-imidazolyl)-butyl]-6,7-dihydro-5H-benzo[b]thiophen-4-one, 
(8) 6-[1-(1-imidazolyl)-butyl]-2H-benzo[b]furan-3-one, 
(9) 5-[cyclohexyl-(1-imidazolyl)-methyl]-1-indanone, 
(10) 2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6H-benzo[b]thiophen-7-one, 
(11) 5-[1-(1-imidazolyl)-1-propyl-butyl]-1-indanone, 
(12) 2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6H-benzo[b ]thiophen-7-one, 
(13) 2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6-oxo-cyclopenta[b]-thiophene, 
(14) 5-(1-imidazolylmethyl)-1-indanone, 
(15) 5-[1-(1,2,4-triazolyl)-methyl]-1-indanone. 
(p) The compounds of formula I as disclosed in DE-A-3 926 365. These are 
especially the compounds of formula I 
##STR18## 
wherein W' is a cyclopentylidene, cyclohexylidene, cycloheptylidene or 
2-adamantylidene radical, X is the grouping --CH.dbd.CH--, an oxygen or a 
sulfur atom, and Y and Z, independently of one another, are each a methine 
group (CH) or a nitrogen atom, and their pharmaceutically acceptable 
addition salts with acids. 
Individual compounds from that group that may be given special mention are: 
(1) 4-[1-cyclohexylidene-1-(imidazolyl)-methyl]-benzonitrile, 
(2) 4-[1-cyclopentylidene-1-(imidazolyl)-methyl]-benzonitrile, 
(3) 4-[1-cycloheptylidene-1-(imidazolyl )-methyl]-benzonitrile, 
(4) 4-[2-adamantylidene-1-(imidazolyl)-methyl]-benzonitrile, 
(5) 4-[1-cyclohexylidene-1-(1,2,4-triazolyl)-methyl]-benzonitrile, 
(6) 4-[1-cyclopentylidene-1-(1,2,4-triazolyl)-methyl]-benzonitrile, 
(7) 4-[1-cycloheptylidene-1-(1,2,4-triazolyl)-methyl]-benzonitrile, 
(8) 4-[2-adamantylidene-1-(1,2,4-triazolyl )-methyl]-benzonitrile, 
(9) 4-[1-cyclohexylidene-1-(1,2,3-triazolyl)-methyl]-benzonitrile, 
(10) 4-[1-cyclopentylidene-1-(1,2,3-triazolyl)-methyl]-benzonitrile, 
(11) 5-[cyclohexylidene-1-imidazolylmethyl]-thiophene-2-carbonitrile. 
(q) The compounds of formula I as defined in DE-A-3 740 125. These are 
especially the compounds of formula I 
##STR19## 
wherein X is CH or N, R.sub.1 and R.sub.2 are identical or different and 
are each phenyl or halophenyl, and R.sub.3 is C.sub.1 -C.sub.4 alkyl; 
C.sub.1 -C.sub.4 alkyl substituted by CN, C.sub.1 -C.sub.4 alkoxy, 
benzyloxy or by C.sub.1 -C.sub.4 alkoxy-(mono-, di- or tri-)ethyleneoxy; 
C.sub.1 -C.sub.4 alkoxy, phenyl; phenyl that is substituted by halogen or 
by cyano; a C.sub.5 -C.sub.7 cycloalkyl group that is optionally condensed 
by benzene, or is thienyl, pyridyl or 2- or 3-indolyl; and acid addition 
salts thereof. 
An individual compound from that group that may be given special mention 
is: 
(1) 2,2-bis(4-chlorophenyl)-2-(1H-imidazol-1-yl)-1-(4-chlorobenzoyl-amino 
)ethane. 
(r) The compounds of formula I as defined in EP-A-293 978. These are 
especially the compounds of formula I 
##STR20## 
pharmaceutically acceptable salts and stereochemically isomeric forms 
thereof, wherein --A.sub.1 .dbd.A.sub.2 --A.sub.3 .dbd.A.sub.4 -- is a 
divalent radical selected from --CH.dbd.N--CH.dbd.CH--, 
--CH.dbd.N--CH.dbd.N-- and --CH.dbd.N--N.dbd.CH--, R is hydrogen or 
C.sub.1 -C.sub.6 alkyl; R.sub.1 is hydrogen, C.sub.1 -C.sub.10 alkyl, 
C.sub.3 -C.sub.7 cycloalkyl, Ar.sub.1, Ar.sub.2 -C.sub.1`-C.sub.6 alkyl, 
C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl: R.sub.2 is hydrogen; 
C.sub.1 -C.sub.10 alkyl that is unsubstituted or substituted by Ar.sub.1 ; 
C.sub.3 -C.sub.7 cycloalkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, Ar.sub.1, 
C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 
cycloalkyl, bicyclo[2.2.1]heptan-2-yl, 2,3-dihydro-1H-indenyl, 
1,2,3,4-tetrahydronaphthyl, hydroxy; C.sub.2 -C.sub.6 alkenyloxy that is 
unsubstituted or substituted by Ar.sub.2 ; C.sub.2 -C.sub.6 alkynyloxy; 
pyrimidyloxy; di(Ar.sub.2)methoxy, (1-C.sub.1 -C.sub.4 
alkyl-4-piperidinyl)oxy, C.sub.1 -C.sub.10 alkoxy; or C.sub.1 -C.sub.10 
alkoxy that is substituted by halogen, hydroxy, C.sub.1 -C.sub.6 alkyloxy, 
amino, mono- or di-(C.sub.1 -C.sub.6 alkyl)amino, trifluoromethyl, 
carboxy, C.sub.1 -C.sub.6 alkoxycarbonyl, Ar.sub.l, Ar.sub.2 --O--, 
Ar.sub.2 --S--, C.sub.3 -C.sub.7 cycloalkyl, 
2,3-dihydro-1,4-benzodioxinyl, 1H-benzimidazolyl, C.sub.1 -C.sub.4 
alkyl-substituted 1H-benzimidazolyl, (1,1'-biphenyl)-4-yl or by 
2,3-dihydro-2-oxo-1H-benzimidazolyl; and R.sub.3 is hydrogen, nitro, 
amino, mono- or di-(C.sub.1 -C.sub.6 alkyl)amino, halogen, C.sub.1 
-C.sub.6 alkyl, hydroxy or C.sub.1 -C.sub.6 alkoxy; wherein Ar.sub.1 is 
phenyl, substituted phenyl, naphthyl, pyridyl, aminopyridyl, imidazolyl, 
triazolyl, thienyl, halothienyl, furanyl, C.sub.1 -C.sub.6 alkylfuranyl, 
halofuranyl or thiazolyl; wherein Ar.sub.2 is phenyl, substituted phenyl 
or pyridyl; and wherein "substituted phenyl" is phenyl that is substituted 
by up to 3 substituents in each case selected independently of one another 
from the group consisting of halogen, hydroxy, hydroxymethyl, 
trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 
-C.sub.6 alkoxycarbonyl, carboxy, formyl, hydroxyiminomethyl, cyano, 
amino, mono- and di-(C.sub.1 -C.sub.6 alkyl)amino and nitro. 
Individual compounds from that group that may be given special mention are: 
(1) 6-[(1H-imidazol-1-yl)-phenylmethyl]-1-methyl-1H-benzotriazole, 
(2) 
6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazol 
e. 
(s) The compounds of formula II as defined in EP-A-250 198, especially 
(1) 2-(4-chlorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol, 
(2) 2-(4-fluorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol, 
(3) 
2-(2-fluoro-4-trifluoromethylphenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethan 
ol, 
(4) 2-(2,4-dichlorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol, 
(5) 2-(4-chlorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)-ethanol, 
(6) 2-(4-fluorophenyl)-1,1-di(1,2,4-triazol-1-yl-methyl)ethanol. 
(t) The compounds of formula I as defined in EP-A-281 283, especially 
(1) 
(1R*2R*)-6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-(1H-1,2,4-triazo 
l-1-yl-methyl)naphthalene, 
(2)(1 R *,2R * )-6-fluoro-2-(4-fluorophenyl 
)-1,2,3,4-tetrahydro-1-(1H-imidazolylmethyl)-naphthalene, 
(3) (1R*,2R*)- and 
(1R*,2S*)-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-1-(1H-1,2,4-triazol-1-ylme 
thyl)naphthalene-6-carbonitrile, 
(4) (1R*,2R*)- and 
(1R*,2S*)-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-1-(1H-imidazolylmethyl)nap 
hthalene-6-carbonitrile, 
(5) (1R*,2R*)- and 
(1R*,2S*)-1,2,3,4-tetrahydro-1-(1H-1,2,4-triazol-1-ylmethyl)-naphthalene-2 
,6-dicarbonitrile, 
(6) (1R*,2R*)- and 
(1R*,2S*)-1,2,3,4-tetrahydro-1-(1H-imidazol-1-ylmethyl)naphthalene-2,6-dic 
arbonitrile, 
(7) 
(1R*,2S*)-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-(5-methyl-1H-imidazolyl- 
methyl )naphthalene-6-carbonitrile. 
(u) The compounds of formula I as defined in EP-A-296 749, especially 
(1) 
2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononit 
rile), 
(2) 
2,2'-[5-(imidazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), ( 
3) 
2-[3-(1-hydroxy-1-methylethyl)-5-(5H-1,2,4-triazol-1-ylmethyl)phenyl]-2-me 
thylpropiononitrile, 
(4) 
2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-trideut 
eriomethyl-3,3,3-trideuteriopropiononitrile), 
(5) 
2,2'-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-3-phenylene]di(2methylprop 
iononitrile). 
(v) The compounds of formula I as defined in EP-A-299 683, especially 
(1) (Z)-.alpha.-(1,2,4-triazol-1-ylmethyl)stilbene-4,4'-dicarbonitrile, 
(2) 
(Z)-4'-chloro-.alpha.-(1,2,4-triazol-1-ylmethyl)stilbene-4-carbonitrile, 
(3) 
(Z)-.alpha.-(1,2,4-triazol-1-ylmethyl)-4'-(trifluoromethyl)stilbene-4-carb 
onitrile, 
(4) 
(E)-.beta.-fluoro-.alpha.-(1,2,4-triazol-1-ylmethyl)stilbene-4,4'-dicarbon 
itrile, 
(5) (Z)-4'-fluoro-.alpha.-(imidazol-1-ylmethyl)stilbene-4-carbonitrile, 
(6) (Z)-2', 
4'-dichloro-.alpha.-(imidazol-1-ylmethyl)stilbene-4-carbonitrile, 
(7) (Z)-4'-chloro-.alpha.-(imidazol-1-ylmethyl )stilbene-4-carbonitrile, 
(8) (Z)-.alpha.-(imidazol-1-ylmethyl)stilbene-4,4'dicarbonitrile, 
(9) (Z)-.alpha.-(5-methylimidazol-1-ylmethyl)stilbene-4,4'-dicarbonitrile, 
(10) (Z)-2-[2-(4-cyanophenyl 
)-3-(1,2,4-triazol-1-yl)propenyl]pyridine-5-carbonitrile. 
(w) The compounds of formula I as defined in EP-A-299 684, especially 
(1) 2-(4-chlorobenzyl)-2-fluoro-1,3-di(1,2,4-triazol-1-yl)propane, 
(2) 2-fluoro-2-(2-fluoro-4-chlorobenzyl)-1,3-di(1,2,4-triazol-1-yl)propane, 
(3) 
2-fluoro-2-(2-fluoro-4-trifluoromethylbenzyl)-1,3-di(1,2,4-triazol-1-yl)pr 
opane, 
(4) 
3-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-(1,2,4-triazol-1-ylmethyl)buta 
n-2-ol, 
(5) 
2-(4-chloro-.alpha.-fluorobenzyl)-1,3-di(1,2,4-triazol-1-yl)propan-2-ol, 
(6) 2-(4-chlorobenzyl)-1,3-bis(1,2,4-triazol-1-yl)propane, 
(7) 
4-[2-(4-chlorophenyl)-1,3-di(1,2,4-triazol-1-ylmethyl)ethoxymethyl]-benzon 
itrile, 
(8) 
1-(4-fluorobenzyl)-2-(2fluoro-4-trifluoromethylphenyl)-1,3-di(1,2,4-triazo 
l-1-yl)-propan-2-ol, 
(9) 
2-(4-chlorophenyl)-1-(4-fluorophenoxy)-1,3-di(1,2,4-triazol-1-yl)propan-2- 
ol, 
(10) 1-(4-cyanobenzyl )-2-(2,4-difluorophenyl)-1,3di(1,2,4-triazol-1-yl 
)propan-2-ol, 
(11) 2-(4-chlorophenyl)-1-phenyl-1,3-di(1,2,4-triazol-1-yl)propan-2-ol. 
(x) The compounds as defined in claim 1 of EP-A-316 097, especially 
(1) 1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b 
]furanone, 
(2) 1,2-dihydro 
1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]-furan-7-c 
arbonitrile, 
(3) 
1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1- 
b]-furan-7-carboxamide, 
(4) 1,2-dihydro-1,1-dimethyl-2-oxo-8-[di(1H-1,2,4-triazol-1-yl 
)methyl]naphtho[2,1-b]-furan-7-carbonitrile. 
(y) The compounds of formula I as defined in EP-A-354 689, especially 
(1) 4-[2-(4-cyanophenyl)-3-(1,2,4-triazol-1-yl)propyl]benzonitrile, 
(2) 4-[1-(4-chlorobenzyl)-2-(1,2,4-triazol-1-yl)ethyl]benzonitrile, 
(3) 
4-[2-(1,2,4-triazol-1-yl)-1-(4-[trifluoromethyl]benzyl)ethyl]benzonitrile, 
(4) 
4-[2-(1,2,4-triazol-1-yl)-1-(4-[trifluoromethoxy]benzyl)ethyl]benzonitrile 
. 
(z) The compounds of formula (1) as defined in EP-A-354 683, especially 
(1) 6-[2-(4-cyanophenyl)-3-(1,2,4-triazol-1-yl)-propyl]nicotinonitrile, 
(2) 
4-[1-(1,2,4-triazol-1-yl-methyl)-2-(5-[trifluoromethyl]pyrid-2-yl)ethyl]be 
nzonitrile. 
Examples of steroidal aromatase inhibitors that may be mentioned are: 
(aa) The compounds of formula I as defined in EP-A-181 287. These are 
especially the compounds of formula I 
##STR21## 
wherein R is hydrogen, acetyl, heptanoyl or benzoyl. An individual 
compound from that group that may be given special mention is: 
(1) 4-hydroxy-4-androstene-3,17-dione. 
(ab) The compounds as defined in the claims of U.S. Pat. No. 4,322,416, 
especially 
10-(2-propynyl )-oestr-4-ene-3,17-dione. 
(ac) The compounds as defined in the claims of DE-A-3 622 841, especially 
6-methyleneandrosta-1,4-diene-3,17-dione. 
(ad) The compounds as defined in the claims of GB-A-2 17 1100, especially 
4-amino-androsta-1,4,6-triene-3,17-dione. 
Also: (ae) androsta-1,4,6-triene-3,17-dione. 
The content of the patent applications mentioned under (a) to (z) and (aa) 
to (ad), especially the subgroups of compounds disclosed therein and the 
individual compounds disclosed therein as examples, have been incorporated 
by reference into the disclosure of the present application. 
The general terms used hereinbefore and hereinafter to define the compounds 
have the following meanings: 
Organic radicals designated by the term "lower" contain up to and including 
7, preferably up to and including 4, carbon atoms. 
Acyl is especially lower alkanoyl. 
Aryl is, for example, phenyl or 1- or 2-naphthyl, each of which is 
unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, lower 
alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, lower 
alkanoylamino or by halogen. 
Pharmaceutically acceptable salts of the above-mentioned compounds are, for 
example, pharmaceutically acceptable acid addition salts or 
pharmaceutically acceptable metal or ammonium salts. 
Pharmaceutically acceptable acid addition salts are especially those with 
suitable inorganic or organic acids, for example strong mineral acids, 
such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic 
acids, especially aliphatic or aromatic carboxylic or sulfonic acids, for 
example formic, acetic, propionic, succinic, glycolic, lactic, 
hydroxysuccinic, tartaric, citric, maleic, fumaric, hydroxymaleic, 
pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 
4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, gluconic, 
nicotinic, methanesulfonic, ethanesulfonic, halobenzenesulfonic, 
p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic 
acid; or with other acidic organic substances, for example ascorbic acid. 
Pharmaceutically acceptable salts may also be formed, for example, with 
amino acids, such as arginine or lysine. 
Compounds containing acid groups, for example a free carboxy or sulfo 
group, can also form pharmaceutically acceptable metal or ammonium salts, 
such as alkali metal or alkaline earth metal salts, for example sodium, 
potassium, magnesium or calcium salts, also ammonium salts derived from 
ammonia or suitable organic amines. Them come into consideration 
especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or 
araliphatic primary, secondary or tertiary mono-, di- or poly-amines, such 
as lower alkylamines, for example di- or tri-ethylamine, hydroxy-lower 
alkylamines, for example 2-hydroxyethylamine, bis(2-hydroxyethyl)amine or 
tris(2-hydroxyethyl)amine, basic aliphatic esters or carboxylic acids, for 
example 4-aminobenzoic acid 2-diethylaminoethyl ester, lower 
alkyleneamines, for example 1-ethylpiperidine, cycloalkylamines, for 
example dicyclohexylamine, benzylamines, for example 
N,N'-dibenzylethylenediamine; also heterocyclic bases, for example of the 
pyridine type, for example pyridine, collidine or quinoline. If several 
acidic or basic groups are present, mono- or poly-salts can be formed. 
Compounds according to the invention having an acidic and a basic group 
may also be in the form of internal salts, i.e. in the form of zwitterions 
and another part of the molecule in the form of a normal salt. 
In the case of the above-mentioned individual compounds the 
pharmaceutically acceptable salts are included in each case insofar as the 
individual compound is capable of salt formation. 
The compounds listed, including the individual compounds mentioned, both in 
free form and in salt form, may also be in the form of hydrates, or their 
crystals may include, for example, the solvent used for crystallisation. 
The present invention relates also to all those forms. 
Many of the above-mentioned compounds, including the individual compounds 
mentioned, contain at least one asymmetric carbon atom. They can therefore 
occur in the form of R- or S-enantiomers and as enantiomeric mixtures 
thereof, for example in the form of a racemate. The present invention 
relates to the use of all those forms and to the use of all further 
isomers, and of mixtures of at least 2 isomers, for example mixtures of 
diastereoisomers or enantiomers which can occur when there are one or more 
further asymmetric centres in the molecule. Also included are, for 
example, all geometric isomers, for example cis- and trans-isomers, that 
can occur when the compounds contain one or more double bonds. 
The invention relates most especially to the use of 
5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (=Fadrozol), or 
of a pharmaceutically acceptable acid addition salt thereof, for the 
purpose of contraception in female primates of reproductive age, without 
substantially affecting the menstrual cycle of the female primate, and to 
a method for such contraception in female primates using such compounds, 
and to the use of those compounds for the preparation of compositions for 
such contraception in female primates. 
The invention relates further to the use of the optical antipodes of the 
above-mentioned compound, (a) 
(-)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and (b) 
(+)-5-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, especially 
the (-) antipode (a), or of a pharmaceutically acceptable acid addition 
salt thereof for contraception in female primates of reproductive age 
without substantially affecting the menstrual cycle of the female primate, 
and to a method for such contraception in female primates using such 
compounds, and to the use of those compounds for the preparation of 
compositions for such contraception in female primates. 
The invention relates further to the use of 
-4-[.alpha.-(4-cyanophenyl)-5-isothiazolylmethyl]-benzonitrile, 
-4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methyl]-benzo 
nitrile, 
-4-[a-(4-cyanophenyl-1-(1,2,4-triazolyl)methyl]-benzonitrile, 
-4-[.alpha.-(4-cyanophenyl)-(2-tetrazolyl)methyl]-benzonitrile, 
-4-[.alpha.-(4-cyanophenyl)-1-(1,2,3-triazolyl)methyl]-benzonitrile, 
-4-[.alpha.-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile, 
or of a pharmaceutically acceptable salt thereof for contraception in 
female primates of reproductive age in a dose at which the menstrual cycle 
of the female primate remains substantially unaffected, and to a method 
for such contraception in female primates using such compounds, and to the 
use of those compounds for the preparation of compositions for such 
contraception in female primates. 
As explained hereinbefore, aromatase inhibitors can be used to prepare 
pharmaceutical compositions for the inhibition of fertilisation or 
implantation in female primates without the female cycle being 
substantially affected thereby. 
The pharmaceutical compositions that can be prepared according to the 
invention are compositions for enteral, such as peroral or rectal, 
administration, also for transdermal or sublingual administration, and for 
parenteral, for example intravenous, subcutaneous and intramuscular, 
administration. Suitable unit dose forms, especially for peroral and/or 
sublingual administration, for example dragees, tablets or capsules, 
comprise preferably from approximately 0.01 mg to approximately 20 mg, 
especially from approximately 0.1 mg to approximately 10 mg, of one of the 
above-mentioned compounds or of a pharmaceutically acceptable salt 
thereof, together with pharmaceutically acceptable carriers. The 
proportion of active ingredient in such pharmaceutical compositions is 
from approximately 0.001% to approximately 60%, preferably from 
approximately 0.1% to approximately 20%. 
Suitable excipients for pharmaceutical compositions for oral administration 
are especially fillers, such as sugars, for example lactose, saccharose, 
mannitol or sorbitol, cellulose preparations and/or calcium phosphates, 
for example tricalcium phosphate or calcium hydrogen phosphate, and 
binders, such as starches, for example corn, wheat, rice or potato starch, 
gelatin, tragacanth, methylcellulose and/or hydroxypropylcellulose, 
disintegrators, such as the above-mentioned starches, also carboxymethyl 
starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt 
thereof, such as sodium alginate, and/or cellulose, for example in the 
form of crystals, especially in the form of microcrystals, and/or flow 
regulators and lubricants, for example silicic acid, talc, stearic acid or 
salts thereof, such as magnesium or calcium stearate, cellulose and/or 
polyethylene glycol. 
Dragee cores can be provided with suitable, optionally enteric, coatings, 
there being used inter alia concentrated sugar solutions which may 
comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol 
and/or titanium dioxide, or coating solutions in suitable solvents or 
solvent mixtures, or, for the preparation of enteric coatings, solutions 
of suitable cellulose preparations, such as acetylcellulose phthalate or 
hydroxypropylmethylcellulose phthalate. 
Other orally administrable pharmaceutical compositions are dry-filled 
capsules consisting of gelatin, and also soft sealed capsules consisting 
of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled 
capsules may contain the active ingredient in the form of granules, for 
example in admixture with fillers, such as lactose, binders, such as 
starches, and/or glidants, such as talc or magnesium stearate, and, if 
desired, stabilisers. In soft capsules, the active ingredient is 
preferably dissolved or suspended in suitable oily excipients, such as 
fatty oils, paraffin oil or liquid polyethylene glycols, to which 
stabilisers and/or anti-bacterial agents may also be added. There may also 
be used capsules that are easily bitten through, in order to achieve by 
means of the sublingual ingestion of the active ingredient that takes 
place as rapid an action as possible. 
Suitable rectally administrable pharmaceutical compositions are, for 
example, suppositories that consist of a combination of the active 
ingredient with a suppository base. Suitable suppository bases are, for 
example, natural or synthetic triglycerides, paraffin hydrocarbons, 
polyethylene glycols or higher alkanols. There may also be used gelatin 
rectal capsules, which contain a combination of the active ingredient with 
a base material. Suitable base materials are, for example, liquid 
triglycerides, polyethylene glycols or paraffin hydrocarbons. 
Suitable formulations for transdermal administration comprise the active 
ingredient together with a carrier. Advantageous carriers include 
absorbable pharmacologically acceptable solvents that serve to facilitate 
the passage through the skin of the host. Transdermal systems are usually 
in the form of a bandage that comprises a support, a supply container 
containing the active ingredient, if necessary together with carriers, 
optionally a separating device that releases the active ingredient onto 
the skin of the host at a controlled and established rate over a 
relatively long period of time, and means for securing the system to the 
skin. 
Suitable for parenteral administration are especially aqueous solutions of 
an active ingredient in water-soluble form, for example in the form of a 
water-soluble salt, and also suspensions of active ingredient, such as 
corresponding oily injection suspensions, there being used suitable 
lipophilic solvents or vehicles, such as fatty oils, for example sesame 
oil, or synthetic fatty acid esters, for example ethyl oleate, or 
triglycerides, or aqueous injection suspensions that comprise 
viscosity-increasing substances, for example sodium 
carboxymethylcellulose, sorbitol and/or dextran, and, optionally, 
stabilisers. 
Dyes or pigments may be added to the pharmaceutical compositions, 
especially to the tablets or dragee coatings, for example for 
identification purposes or to indicate different doses of active 
ingredient. 
The pharmaceutical compositions of the present invention can be prepared in 
a manner known per se, for example by means of conventional mixing, 
granulating, confectioning, dissolving or lyophilising processes. For 
example, pharmaceutical compositions for oral administration can be 
obtained by combining the active ingredient with solid carriers, 
optionally granulating a resulting mixture, and processing the mixture or 
granules, if desired or necessary after the addition of suitable 
excipients, to form tablets or dragee cores.

The invention that is claimed is described in detail in the following 
Examples which are intended merely to illustrate the invention and in no 
way represent a limitation thereof. 
Temperatures are in degrees Celsius. The following abbreviations are used: 
ether=diethyl ether; ethyl acetate=acetic acid ethyl ester; 
THF=tetrahydrofuran; hexane=n-hexane; DMSO=dimethylsulfoxide; 
DMF=dimethylformamide; 
N-fluoro-dimethylsaccharinsultam=N-fluoro-3,3-dimethyl-2,3-dihydro-1,2-ben 
zothiazole-1,1-dioxide; TLC=thin-layer chromatography; RT=room temperature; 
MS(FAB)=mass spectrum ("Fast Atom Bombardment"). 
EXAMPLE 1 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methyl]-benzon 
itrile 
A solution of 0.8 mmol of potassium hexamethyldisilazane in 1.6 ml of 
toluene is diluted with 5 ml of THF and, after cooling to -78.degree., a 
solution of 190 mg of 
4-[.alpha.-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile (see 
EP-A-236 940, Ex. 20a) in 3 ml of THF is added thereto. After stirring for 
1 hour at the same temperature, there are added dropwise to the dark-red 
solution 301 mg of N-fluoro-dimethylsaccharinsultam in 3 ml of THF. After 
a further 1.5 hours at -78.degree., the reaction mixture is heated to RT 
in the course of 1 hour and poured onto a saturated solution of ammonium 
chloride in water and then extracted with methylene chloride. Drying over 
magnesium chloride and concentration of the solution by evaporation yield 
the crude product, which is purified by flash chromatography (SiO.sub.2, 
hexane/ethyl acetate 9:1, 4:1 to 1:1). TLC (SiO.sub.2, CHCl.sub.3 
/methanol 9:1, Rf=0.85); IR (KBr): 2220 cm.sup.-1 ; .sup.1 H-NMR 
(CDCl.sub.3): .delta.(ppm)=7.46 and 7.76 (8H,m), 8.07 (1H,s), 8.16 (1H,s). 
EXAMPLE 2: 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(2-tetrazolyl)methyl]-benzonitril 
e 
Analogously to Example 
1,4-[.alpha.-(4-cyanophenyl)-(2-tetrazolyl)methyl]-benzonitrile (see 
EP-A-408 509, Ex. 7 and 2) is converted using 
N-fluoro-dimethylsaccharinsultam into the title compound; m.p. 
145.degree.-146.degree.. 
EXAMPLE 3 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(1-tetrazolyl)methyl]-benzonitril 
e 
Analogously to Example 1, 
4-[.alpha.-(4-cyanophenyl)-(1-tetrazolyl)methyl]-benzonitrile (see 
EP-A-408 509, Ex. 7) is converted using N-fluoro-dimethylsaccharinsultam 
into the title compound. 
EXAMPLE 4 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(1-imidazolyl)methyl]-benzonitril 
e 
Analogously to Example 1, 1.075 g of 
4-[.alpha.-(4-cyanophenyl)-(1-imidazolyl)methyl]benzonitrile (see EP-A-236 
940, Ex. 2a, 3, 4 and 23) is converted using 930 mg of potassium 
hexamethyldisilazane and 1.7 g of N-fluoro-dimethylsaccharinsultam into 
the title compound; m.p. 133.degree., MS(FAB): (M+H).sup.+ =303, TLC 
(methylene chloride/methanol 9:1): Rf=0.7. 
EXAMPLE 5 
1-methyl-6-[.alpha.-(4-chlorophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)-met 
hyl]-benzotriazole 
Analogously to Example 1, 
1-methyl-6-[.alpha.-(4-chlorophenyl)-1-(1,2,4-triazolyl)methyl]benzotriazo 
le (see EP-A-293 978, e.g. Example 20) is convened using 
N-fluoro-dimethylsaccharinsultam into the title compound. 
EXAMPLE 6 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,3-triazolyl)methyl]-benzon 
itrile 
Analogously to Example 1, 
4-[.alpha.-(4-cyanophenyl)-1-(1,2,3-triazolyl)methyl]-benzonitrile is 
convened using N-fluoro-dimethylsaccharinsultam into the title compound; 
m.p. 138.degree.-140.degree.. 
The starting material is prepared as follows: 
(a) 4-[.alpha.-(4-cyanophenyl)-1-(1,2,3-triazolyl)methyl]-benzonitrile 
At constant temperature (25.degree.-26.5.degree.), a solution of 640 mg of 
4-[1-(1,2,3-triazolyl)methyl]-benzonitrile in 5 ml of DMF is added 
dropwise over the course of 30 minutes to a mixture of 1.07 g of potassium 
tert-butoxide in 5 ml of DMF. After a further 30 minutes 20.degree., a 
solution of 525 mg of 4-fluorobenzonitrile in 5 ml of DMF is added to the 
reaction mixture, which is then stirred for 1.5 hours at room temperature. 
The reaction mixture is then cooled to 0.degree., diluted with CH.sub.2 
Cl.sub.2 and neutralised with 6N HCl. The reaction mixture is concentrated 
and taken up in water/CH.sub.2 Cl.sub.2 and the aqueous phase is separated 
off. The organic phase is washed with brine, dried over sodium sulfate and 
concentrated. The crude product is purified by column chromatography 
(SiO.sub.2, toluene to toluene/ethyl acetate 3:1) and crystallised from 
CH.sub.2 Cl.sub.2 /ethanol/hexane, to yield starting material (a), m.p. 
&gt;230.degree.; IR (CH.sub.2 Cl.sub.2): 2230, 1605, 1500, 1160 cm.sup.-1. 
The precursor for the preparation of starting material (a) is prepared as 
follows: 
(1) 4-[1-(1,2,3-triazolyl)methyl]-benzonitrile 8 g of 1,2,3-triazole, 10.67 
g of potassium carbonate and 750 mg of potassium iodide are added in 
succession to a solution of 15.13 g of 4-bromomethylbenzonitrile in 375 ml 
of acetone. The reaction mixture is then stirred for 7.5 hours at 
55.degree. and then cooled and concentrated. The residue is dissolved in 
CH.sub.2 Cl.sub.2 and washed in succession with water and brine. After 
drying over sodium sulfate, the solution is concentrated and the resulting 
crude product is purified by column chromatography (SiO.sub.2, 
toluene/ethyl acetate 3:19), yielding precursor (1), IR (CH.sub.2 
Cl.sub.2): 2230, 1615, 1225, 1075 cm.sup.-1. 
EXAMPLE 7 
7-cyano-4-[.alpha.-(4-cyanophenyl )-.alpha.-fluoro-1-(1,2,4-triazolyl 
)methyl]-2,3-dimethylbenzo[b]furan 
Analogously to Example 1, 
7-cyano-4-[.alpha.-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-2,3-dimethyl 
benzol[b]furan is convened using N-fluoro-dimethylsaccharinsultam into the 
title compound. 
The starting material is prepared as follows: 
(a) 7-cyano-4-[.alpha.-(4-cyanophenyl 
)-1-(1,2,4-triazolyl)methyl]-2,3-dimethylbenzo[b]furan 
Analogously to Example 6(a), 252 mg of 
7-cyano-4-[1-(1,2,4-triazolyl)methyl]-2,3-dimethylbenzol[b]furan (see 
EP-A-445 073, Ex. 2 and 1) are converted using 308 mg of potassium 
tert-butoxide and 152 mg of 4-fluorobenzonitrile in DMF into starting 
material (a), m.p. (ether/hexane): 200.degree.-202.degree.; IR (CH.sub.2 
Cl.sub.2): 3051, 1613, 1499, 1351, 1104 cm.sup.-1. 
EXAMPLE 8 
4-[.alpha.-(4-bromophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methyl]-benzon 
itrile 
Analogously to Example 1, 
4-[.alpha.-(4-bromophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile is 
converted using N-fluoro-dimethylsaccharinsultam into the title compound. 
The starting material is prepared as follows: 
(a) 4-[.alpha.-(4-bromophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile 
Analogously to Example 6(a), 190 mg of 1-(4-bromobenzyl)-1,2,4-triazole are 
converted using 188 mg of potassium tert-butoxide and 106 mg of 
4-fluorobenzonitrile into starting material (a); .sup.1 H-NMR 
(CDCl.sub.3): .delta.=6.73 (1H,s), 7.05 and 7.55 (4H,m), 7.2 and 
7.68(4H,m), 8.02 (1H,s), 8.05 (1H,s). 
The precursor for the preparation of starting material (a) is prepared as 
follows: 
(1) 1-(4-bromobenzyl)-1,2,4-triazole 
A mixture of 1 g of 4-bromobenzyl bromide, 0.41 g of 1,2,4-triazole, 0.55 g 
of potassium carbonate and 33 mg of potassium iodide in 30 ml of acetone 
is stirred for 20 hours at 50.degree.. The solid material is removed by 
filtration and the solution is concentrated by evaporation. The resulting 
crude precursor (1) is purified by column chromatography (SiO.sub.2, 
hexane/ethyl acetate 1:1) and crystallised from ether; m.p. 
77.degree.-79.degree.; .sup.1 H-NMR (CDCl.sub.3): .delta.=5.3 (2H,s), 7.15 
and 7.5 (4H,m), 7.95 (1H,s), 8.08 (1H,m). 
EXAMPLE 9 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(5-pyrimidyl)methyl]-benzonitrile 
Analogously to Example 1, 
4-[.alpha.-(4-cyanophenyl)-(5-pyrimidyl)methyl]-benzonitrile is converted 
using N-fluoro-dimethylsaccharinsultam into the title compound. 
The starting material is prepared as follows: 
(a) 4-[.alpha.-(4-cyanophenyl)-(5-pyrimidyl)methyl]-benzonitrile 
1.25 g (5.53 mmol) of tin(II) chloride dihydrate and 3.2 ml of cone. HCl 
are added to a solution of 863 mg (2.76 mmol) of 
4-[.alpha.-(4-cyanophenyl)-.alpha.-hydroxy-(5-pyrimidyl)methyl]-benzonitri 
le [Example 15(b2)] in 10 ml of glacial acetic acid and the reaction 
mixture is boiled under reflux for 2 hours. After cooling, the reaction 
mixture is poured onto a large amount of water. The precipitate is 
filtered off with suction, washed with water, dried and dissolved in 4 ml 
of THF. 0.23 ml of pyridine is added to that solution, which is then 
stirred for 3 hours at room temperature and filtered and the filtrate is 
concentrated by evaporation. The resulting oily residue is purified by 
column chromatography (100 g of silica gel/ethyl acetate ) and corresponds 
to the title compound, m.p. 140.degree.-141.degree. (from ether/petroleum 
ether); Rf value: 0.25 (silica gel/ethyl acetate); IR (CH.sub.2 Cl.sub.2): 
2223 cm.sup.-1 ; .sup.1 H-NMR (CDCl.sub.3): .delta.=5.53 (s, 1H); 7.24 
(d,4H); 7.68 (d,4H); 8.48 (s, 2H); 9.18 (s, 1H). 
EXAMPLE 10 
4-[.alpha.-(4-bromophenyl)-.alpha.-fluoro-(5-pyrimidyl)methyl]-benzonitrile 
Analogously to Example 1, 
4-[.alpha.-(4-bromophenyl)-(5-pyrimidyl)methyl]-benzonitrile is converted 
using N-fluoro-dimethylsaccharinsultam into the title compound. 
The starting material is prepared as follows: 
(a) 4-[.alpha.-(4-bromophenyl)-(5-pyrimidyl)methyl]-benzonitrile 
Analogously to Example 9a, 
4-[.alpha.-(4-bromophenyl)-.alpha.-hydroxy-(5-pyrimidyl)methyl]benzonitril 
e [Example 15(b 1)] is reduced in glacial acetic acid with tin(II) chloride 
dihydrate and conc. HCl. 
EXAMPLE 11 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(3-pyridyl)methyl]-benzonitrile 
Analogously to Example 1, 
4-[.alpha.-(4-cyanophenyl)-(3-pyridyl)methyl]-benzonitrile (see EP-A-236 
940, Ex. 21) is converted using N-fluoro-dimethylsaccharinsultam into the 
title compound. 
EXAMPLE 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methyl]-benzon 
itrile 
10 ml of THF are cooled to -30.degree.. First 0.17 ml (1.2 mmol) of 
diisopropylamine and then 0.75 ml (1.2 mmol) of a 1.6M solution of 
n-butyllithium in hexane is added and the reaction mixture is cooled to 
-70 .degree.. 285 mg(1 mmol) of 
4-[.alpha.-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile (see 
EP-A-236 940, 20a), dissolved in 4 ml of THF, are slowly added dropwise 
and the reaction mixture is stirred for 3 hours at -70.degree.. Then 346.8 
mg(1.2 mmol) of 
N-fluoro-2,4,6-trimethylpyridinium-trifluoromethylsulfonate are added, 
whereupon the previously dark-red solution slowly loses its colour. The 
reaction mixture is allowed to warm to RT and is then poured onto a 
saturated aqueous ammonium chloride solution and extracted with methylene 
chloride. The organic extracts are dried over magnesium chloride and 
concentrated by evaporation, yielding the crude product which is purified 
by flash chromatography (SiO.sub.2, hexane/ethyl acetate 9:1, 4:1 to 1:1). 
TLC (SiO.sub.2, CHCl.sub.3 /methanol 9:1): Rf=0.85; IR (KBr): 2220 
cm.sup.-1 ; .sup.1 H-NMR (CDCl.sub.3): .delta.=7.46 and 7.76 (8H, m); 8.07 
(1H, s), 8.16 (1H, s). 
EXAMPLE 13 
7-bromo-4-[.alpha.-(4-cyanophenyl)-.alpha.fluoro-(1-imidazolyl)methyl]-2,3- 
dimethylbenzo[b]furan 
Analogously to Example 1, 
7-bromo-4-[.alpha.-(4-cyanophenyl)-(1-imidazolyl)methyl]-2,3-dimethylbenzo 
[b]furan is converted using N-fluoro-dimethylsaccharinsultam into the title 
compound. 
The starting material is prepared as follows: 
(a) 
7-bromo-4-[.alpha.-(4-cyanophenyl)-(1-imidazolyl)methyl]-2,3-dimethylbenzo 
[b]furan 
Analogously to Example 6(a), 610 mg of 
7-bromo-4-(1-imidazolylmethyl)-2,3-dimethylbenzo[b]furan (see EP-A-445 
073, Ex. 3) are converted using 617 mg of potassium tert-butoxide and 303 
mg of 4-fluorobenzonitrile in DMF into starting material (a) and 
crystallised from ether; m.p. 220.degree.-223.degree.; IR (CH.sub.2 
Cl.sub.2): 2231, 1674, 1629, 1490, 1199, 1109 cm.sup.-1. 
EXAMPLE 14 
7-bromo-4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,4-triazolyl)methyl 
]-2,3-dimethylbenzo[b]furan 
Analogously to Example 1, 
7-bromo-4-[.alpha.-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-2,3-dimethyl 
benzo[b]furan is converted using N-fluoro-dimethylsaccharinsultam into the 
title compound. 
The starting material is prepared as follows: 
(a) 
7-bromo-4-[.alpha.-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-2,3-dimethyl 
benzo[b]furan 
Analogously to Example 6(a), 612 mg of 
7-bromo-4-[1-(1,2,4-triazolyl)methyl]2,3-dimethylbenzo[b]furan (see 
EP-A-445 073, Ex. 1) are converted using 617 mg of potassium tert-butoxide 
and 303 mg of 4-fluorobenzonitrile in DMF into starting material (a) and 
crystallised from ether/acetate, m.p. 198.degree.-200.degree., IR 
(CH.sub.2 Cl.sub.2): 2231, 1629, 1498, 1347, 1254, 1200, 1015 cm.sup.-1. 
EXAMPLE 15 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(5-pyrimidyl 
)methyl]-benzonitrile 
0.35 g (2.0 mmol) of piperidino-sulfur trifluoride is added to a solution 
of 0.62 g (2.0 mmol) of 
4-[.alpha.-(4-cyanophenyl)-.alpha.-hydroxy-(5-pyrimidyl)methyl]-benzonitri 
le in 10 ml of 1,2-dichloroethane and the reaction mixture is stirred for 
48 hours at 50.degree. and then washed with water, with a saturated sodium 
hydrogen carbonate solution and again with water, dried over magnesium 
sulfate and concentrated by evaporation. The oily residue is purified by 
column chromatography (100 g of silica gel/ethyl acetate) and corresponds 
to the title compound, IR (CH.sub.2 C.sub.2): 2220 cm.sup.-1 ; .sup.1 
H-NMR (CDCl.sub.3): .delta.=7.20 (d,4H),7.66 (d,4H), 8.43 (s,2H), 9.15 (s, 
1H). 
The starting material is prepared as follows: 
(a) .alpha.,.alpha.-bis(4-bromophenyl)-5-pyrimidinemethanol 
With stirring and with the exclusion of moisture, a solution of 20 ml of 
1.6N n-butyllithium in hexane is added dropwise in the course of 30 
minutes to a solution, cooled to -75.degree., of 5.2 g (33 mmol) of 
5-bromopyrimidine and 10.7 g (31.2 mmol) of 4,4'-dibromobenzophenone in 
130 ml of THF. The reaction mixture is stirred for a further 0.5 hours at 
-75.degree. and then for 16 hours at room temperature; then, while cooling 
with ice, it is hydrolysed by the addition of 20 ml of water. The organic 
phase is separated off and diluted with ethyl acetate. The solution is 
washed with 2N HCl and a semi-saturated sodium chloride solution, dried 
over sodium sulfate, filtered and concentrated by evaporation. The residue 
is purified by column chromatography (400 g of silica gel, methylene 
chloride/ethyl acetate 85:15) and recrystallised from ethyl acetate, m.p. 
89.degree.-90.degree., R.sub.f value=0.11 (silica gel, methylene 
chloride/ethyl acetate 85:15). 
(b1) 
4-[.alpha.-(4-bromophenyl)-.alpha.-hydroxy-(5-pyrimidyl)methyl]-benzonitri 
le and 
(b2) 
4-[.alpha.-(4-cyanophenyl)-.alpha.-hydroxy-(5-pyrimidyl)methyl]-benzonitri 
le 
A mixture of 3.7 g (8.8 mmol) of 
.alpha.,.alpha.-bis(4-bromophenyl)-5-pyrimidinemethanol and 2.4 g (26.4 
mmol) of copper(I) cyanide in 8 ml of DMF is stirred under argon for 4 
hours at 160.degree.. The reaction mixture is then cooled to 70.degree., a 
solution of 6.4 g (39.6 mmol) of iron(III) chloride in 20 ml of 2N HCl is 
added dropwise thereto and the reaction mixture is stirred thoroughly for 
20 minutes at that temperature. After cooling, the reaction mixture is 
extracted with ethyl acetate. The organic phase is washed with a 
semi-saturated sodium chloride solution, dried over sodium-sulfate and 
concentrated by evaporation. The residue is purified by column 
chromatography (200 g of silica gel, hexane/ethyl acetate 1:2) and 
separated into compounds (b1) and (b2), yielding 
4-[.alpha.-(4-bromophenyl)-.alpha.-hydroxy(5-pyrimidyl)methyl]-benzonitril 
e in the form of a pale yellow amorphous product, IR (CH.sub.2 Cl.sub.2): 
2190, 3530 cm.sup.-1, R.sub.f value=0.27 (silica gel, hexane/ethyl acetate 
1:2), and 
4-[.alpha.-(4-cyanophenyl)-.alpha.-hydroxy-(5-pyrimidyl)methyl]-benzonitri 
le, m.p. 228.degree.-230.degree.(from ethyl acetate), IR (Nujol): 2225, 
3150 (broad) cm.sup.-1, R.sub.f value: 0.14; .sup.1 H-NMR (DMSO-d.sub.6): 
.delta.=7.42 (s, 1H); 7.55 (d, 4H); 7.86 (d, 4H); 8.67 (s, 2H); 9.16 (s, 
1H). 
EXAMPLE 16 
4-[.alpha.-(4-bromophenyl)-.alpha.-fluoro-(5-pyrimidyl)methyl]-benzonitrile 
Analogously to Example 15, 
4-[.alpha.-(4-bromophenyl)-.alpha.-hydroxy-(5-pyrimidyl)methyl]benzonitril 
e [Example 15(b1)] in 1,2-dichloroethane is reacted with piperidino-sulfur 
trifluoride. 
EXAMPLE 17 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-(2-tetrazolyl)methyl]-benzonitril 
e 
At -5 .degree., 399 mg of potassium hexamethyldisilazane are dissolved in 4 
ml of abs. toluene and diluted with 12 ml of abs. THF. The solution is 
cooled to -75.degree. and in the course of 10 minutes a solution of 475 mg 
of 4-[.alpha.-(4-cyanophenyl)-(2-tetrazolyl)methyl]-benzonitrile (see 
EP-A-408 509, Ex. 7 and 2) in 7.5 ml of abs. THF is added dropwise 
thereto. The dark-red reaction mixture is stirred for a further 1 hour at 
the same temperature and then in the course of 15 minutes a solution of 
0.75 g of N-fluoro-dimethylsaccharinsultam in 7.5 ml of abs. THF is added 
thereto; stirring is continued for 1.5 hours and then the reaction mixture 
is heated to RT in the course of 1 hour. The solution is poured onto 50 ml 
of a saturated aqueous sodium chloride solution and extracted with 
methylene chloride. The organic phase is washed with brine and, after 
drying, concentrated over sodium sulfate. The resulting crude product is 
stirred three times with ether, purified by column chromatography (silica 
gel, ethyl acetate/hexane 1:1) and crystallised from hexane; m.p. 
145.degree.-146.degree., MS(FAB): (M+H).sup.+ =305, TLC (ethyl 
acetate/hexane 1:1): Rf=0.5. 
EXAMPLE 18 
4-[.alpha.-(4-cyanophenyl)-.alpha.-fluoro-1-(1,2,3-triazolyl)methyl]-benzon 
itrile 
A solution, cooled to -5.degree., of 798 mg of potassium 
hexamethyldisilazane in 8 ml of abs. toluene is diluted with 25 ml of abs. 
THF, cooled to -75.degree. and, in the course of 15 minutes, a solution of 
950 mg of 
4-[.alpha.-(4-cyanophenyl)-1-(1,2,3-triazolyl)methyl]-benzonitrile (Ex. 
6a) in 15 ml of abs. THF and 1 ml of abs. DMF is added thereto. After 
stirring for 1 hour at -75.degree., a solution of 1.5 g of 
N-fluoro-dimethylsaccharinsultam in 15 ml of THF is added. After stirring 
for a further 1.5 hours, the cooling bath is removed and the reaction 
mixture warms to RT in the course of 1 hour. The reaction mixture is 
poured onto 100 ml of a saturated aqueous ammonium chloride solution and 
extracted with methylene chloride. The organic phase is washed with brine, 
dried over sodium sulfate and concentrated. The resulting crude product is 
stirred twice with ether and purified by column chromatography (silica 
gel, ethyl acetate/hexane 1:1); m.p. 138-140.degree., MS(FAB): (M+H).sup.+ 
=304, TLC (ethyl acetate/hexane 1:1): Rf =0.41. 
EXAMPLE 19 
Contraceptive action of Fadrozol hydrochloride without substantial effect 
on the menstrual cycle 
A group of five female bonnet-monkeys (M. Radiata) are cohabited in the 
fertile phase of the cycle (day 9-13; preovulatory and ovulatory phase) 
with male members of the same species that have proved to be fertile. 
After 4 days (day 13 of the cycle), the males are removed. On the evening 
of the 13th day of the cycle, the female animals are fitted with mini 
Alzet pumps that release 500 .mu.g of Fadrozol hydrochloride 
(5-(p-cyanophenyl)5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride) 
per day continuously. Towards the end of the cycle (day 26), the Alzet 
pumps are removed. This procedure is repeated during the next three 
cycles. Under the same experimental conditions, a control group, likewise 
of five bonnet-monkeys, that is not treated with Fadrozol hydrochloride is 
conducted. In order to assess the regularity of the cycles, the serum 
oestradiol and progesterone levels are measured throughout the experiment. 
In addition, the onset of menstruation at the expected time is monitored. 
Under these experimental conditions, 80% of the untreated control animals 
become pregnant, whereas in the case of the animals treated with Fadrozol 
hydrochloride, pregnancy does not occur in a single case over three 
treated cycles. All the animals treated with Fadrozol hydrochloride have 
normal cycles; this is monitored using the serum hormone values and the 
occurrence of menstruation at the expected time. Treatment with Fadrozol 
hydrochloride has substantially no effect on the cycle and the length of 
the luteal phase, the progesterone profile and follicle function in the 
subsequent cycle. The contraceptive action of Fadrozol hydrochloride is 
reversible, since only a short time after cohabitation the animals 
originally treated become pregnant. 
EXAMPLE 20 
100 00 100 mg tablets, each comprising 0.2 mg of active ingredient, are 
prepared: 
______________________________________ 
Composition: 
______________________________________ 
5-(p-cyanophenyl)-5,6,7,8-tetrahydro- 
2.00 g 
imidazo[1,5-a]pyridine hydrochloride 
silica, colloidal 2.00 g 
cellulose, microcrystalline 
100.00 g 
lactose, spray-dried 836.00 g 
magnesium stearate 10.00 g 
sodium carboxymethylcellulose 
50.00 g 
1000.00 g 
______________________________________ 
All the constituents of the tablet core are mixed together. As soon as a 
homogeneous mixture is obtained, it is compressed to form tablet cores. 
EXAMPLE 21 
10 000 100 mg tablets, each comprising 1 mg of active ingredient, are 
prepared: 
______________________________________ 
Composition: 
______________________________________ 
(-)-5-(p-cyanophenyl)-5,6,7,8-tetrahydro- 
10.00 g 
imidazo[1,5-a]pyridine hydrochloride 
lactose, crystalline 740.00 g 
cellulose, microcrystalline 
230.00 g 
silica, colloidal 10.00 g 
magnesium stearate 10.00 g 
1000.00 g 
______________________________________ 
All the constituents of the tablet core are mixed together. As soon as a 
homogeneous mixture is obtained, it is compressed to form tablet cores.