Functionalized vinyl azoles and methods of use

Pharmaceutical preparations comprising functionalized vinyl azoles of formula I ##STR1## wherein the substituents are as defined herein, including novel compounds, as well as methods of use and methods of their preparation, are provided.

SUMMARY OF THE INVENTION 
This invention relates to functionalized vinyl azoles of formula I 
##STR2## 
in which X means an N atom or a CH group, Y means an S atom or a CH=CH 
group, Z means a cyano group, a fluorine, chlorine or bromine atom and 
R.sup.1 or R.sup.2 means 
optionally esterified carboxyl group, 
an optionally substituted carboxylic acid amide group, 
an aldehyde group, 
an alkylketone or arylketone group, 
an optionally substituted sulfonamide group or a nitrile group 
and the respective other group R.sup.1 or R.sup.2 independently means 
a hydrogen atom, 
a lower-alkyl group or cycloalkyl group, 
an optionally substituted aryl group, 
an aralkyl group, 
an optionally esterified carboxyl group, 
an optionally substituted carboxylic acid amide group, 
an aldehyde group, 
an alkylketone or arylketone group as well as 
a nitrile group or 
R.sup.1 and R.sup.2 together with the carbon atom, on which they are bound, 
mean a 5-, 6- or 7-membered ring, which contains a ketone, ester, lactone, 
lactam or imide grouping placed so that at least one carbonyl group is 
conjugated with a vinyl double bond, and 
R.sup.3 means a hydrogen atom or R.sup.3 together with R.sup.2 means an 
--O--C.dbd.O grouping or an --N--C.dbd.O grouping optionally substituted 
on the N atom whose carbonyl group is conjugated with a vinyl double bond, 
as well as pharmaceutical preparations containing a pharmaceutically 
compatible vehicle, 
use of these vinyl azoles for the production of pharmaceutical agents, 
vinyl azoles themselves as well as process for their production. 
Substituent Z preferably stands for a fluorine atom or a cyano group. 
If R.sup.1 and/or R.sup.2 stands for an esterified carboxyl group 
(--COOR.sup.1 or --COOR.sup.2), the latter is esterified first with a 
straight-chain or branched-chain or cyclic O-alkyl radical with up to 10 
carbon atoms, with an O-aryl radical, and aryl is a phenyl or naphthyl 
radical optionally substituted up to three times by one or more 
lower-alkyl groups (1-4 carbon atoms) or halogen atoms (F, Cl, Br, I) or 
an O-aralkyl radical, and in the latter, the aryl and the alkyl fragments 
have the above-indicated meaning. In this case, the methoxy, ethoxy, 
propoxy, isopropoxy, isobutoxy, tert-butoxy, cyclohexyloxy, 
cyclopentyloxy, phenyloxy or 2,6-dichlorophenoxy radical is especially 
preferred. 
If R.sup.1 and/or R.sup.2 is a substituted carboxylic acid amide group 
(--CONH.sub.2), the carboxyl groups are as defined above, and are 
substituted with one or two, in the latter case same or different, 
radicals. These radicals can be straight-chain or branched-chain alkyl 
radicals with 1 to 10 carbon atoms, or aryl radicals with 6 to 10 carbon 
atoms optionally substituted up to three times by alkyl groups or halogen 
atoms as defined above. Further, the amidic nitrogen atom can also be part 
of a 5- to 8-membered heterocyclic ring, optionally containing one 
additional ring heteroatom N, O or S; if there is and additional N atom in 
the ring, it can be substituted by R.sup.6, wherein R.sup.6 is a hydrogen 
atom or a straight-chain or branched-chain alkyl group with 1 to 6 carbon 
atoms. 
Quite especially to be emphasized is the substitution of the carboxylic 
acid amide group with a methyl, ethyl, propyl, phenyl, benzyl radical, two 
methyl, ethyl, propyl radicals, a phenyl and a methyl, a phenyl and an 
ethyl, and a benzyl and a methyl radical or a pyrrolidine, piperidine, 
piperazine, N-methylpiperazine, morpholine or thiomorpholine ring formed 
together with the amidic nitrogen atom. 
The preferred substituents suitable for the substituted sulfonamide group 
are identical with the preferred N-substituents for the carboxylic acid 
amide group. First of all, R.sup.9 and R.sup.10 each mean an alkyl 
substituent with 1 to 10 carbon atoms. 
As alkylketone group R.sup.1 and/or R.sup.2, radical --CO--R.sup.7 is 
preferred, and R.sup.7 means a straight-chain or branched-chain alkyl 
radical with 1 to 10 carbon atoms or a cycloalkyl radical with 3 to 12 
carbon atoms, and as an arylketone group, radical -CO-R.sup.8 is 
preferred, and R.sup.8 means a phenyl, naphthyl or heteroaryl radical, 
each optionally substituted up to three times by one or more alkyl, 
halogen, hydroxy or alkoxy radicals, such as, e.g., a thiophene, furan, 
pyridine, thiazole, oxazole or diazine ring. 
In particular, R.sup.7 is a methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, pentyl, isopentyl, neopentyl, cyclopentyl or cyclohexyl radical 
and R.sup.8 is a phenyl, hydroxyphenyl, methoxyphenyl or chlorophenyl 
radical. 
If R.sup.1 and R.sup.2 together with the carbon atom, on which they are 
bound, form a cyclic system, which should contain at least one carbonyl 
group, the following ring systems are to be emphasized: 
##STR3## 
wherein n=2 or 3 and W means a hydrogen atom or an alkyl group with 1-10 C 
atoms. 
With the bridge formed from R.sup.2 and R.sup.3, the following partial 
structures result together with the aromatic ring containing Y: 
##STR4## 
If R.sup.1 and R.sup.2 in formula I are different, Z- and E-isomeric 
compounds are produced (except in the case of the cyclical structures 
above). The invention therefore also comprises the pure Z- or E-compounds 
as well as any mixtures of both. 
The separation of the isomers takes place with standard methods, such as 
crystallization or chromatography. 
The following compounds are preferred: 
3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acid methyl ester, 
3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester, 
E-3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acid, 
E-3- (4 -cyanophenyl) -3- (1-imidazolyl) -acrylic acid piperidide, 
E-3 - ( 4 -cyanophenyl ) -3- ( 1-imidazolyl ) -acrylic acid methylamide, 
3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylonitrile, 
4-[1-(1-imidazolyl)-3-oxo-l-butenyl]-benzonitrile, 
3-[(4-cyanophenyl)-(1-imidazolyl)-methylene]dihydro-2(3H)-furanone, 
3-(5-cyano-2-thienyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester, 
3-(5-cyano-2-thienyl)-3-(1-imidazolyl)-acrylonitrile, 
3-(4-cyanophenyl)-3-(1,2,4-triazol-l-yl)-acrylic acid-tert-butyl ester, 
3-(4-cyanophenyl)-3-(1,2,4-triazol-l-yl)-acrylonitrile, 
7-cyano-4-(1-imidazolyl)-coumarin, 
3-(4-fluorophenyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester, 
3-(4-chlorophenyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester, 
3-(4-bromophenyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester, and 
3-(4-fluorophenyl)-3-(1,2,4-triazol-l-yl)-acrylic acid-tert-butyl ester. 
The compounds of formula I are inhibitors of estrogen biosynthesis 
(aromatase inhibitors). Thus, they are suitable for the treatment of 
diseases which are caused by estrogens or are dependent on estrogens. 
Thus, they are suitable for the treatment of estrogen-induced or 
estrogen-stimulated tumors, such as, for example, breast cancer, 
endometrial carcinoma, melanoma or prostatic hyperplasia (The Lancet, 
1984, 1237-1239). 
Said compounds are also valuable for influencing fertility. Thus, male 
infertility which results from increased estrogen levels can be overcome 
with the new active ingredients. Further, the compounds can be used in 
females of child-bearing age as a means of birth control, to inhibit 
ovulation by removal of estrogen. Aromatase inhibitors are also suitable 
for preventing impending myocardial infarction, since increased estrogen 
levels in the male can precede a myocardial infarction (U.S. Pat. No. 
4,289,762). 
This invention therefore also relates to the use of compounds of formula I 
for the production of pharmaceutical agents for treating estrogen-induced 
and estrogendependent diseases. 
Phenylalkenones of general formula R.sup.8 C(O)CH.dbd.CR.sup.b R.sup.c, in 
which R.sup.a means an optionally substituted alkyl or cycloalkyl radical, 
R.sup.b means a 1,2,4-triazolyl or 1-imidazolyl radical and R.sup.c means 
a phenyl or naphthyl ring, which optionally can be substituted, among 
others, with a fluorine, chlorine or bromine atom or a cyano group, are 
disclosed in EP-A-0 003 884. These phenylalkenones are described as 
compounds having herbicidal activity. Other herbicidal 
1,2,4-triazolylvinyl and imidazolyl vinyl compounds, which, in geminal 
position in the heterocycle, have a phenyl ring chlorosubstituted in 
p-position, are disclosed in DE-A-27 38 640. 
DE-A 28 26 760 discloses 3-(4-chlorophenyl)-3-(1,2,4-triazolyl)-acrylic 
acid alkyl esters for use as fungicides and plant-growth regulators. 
The above-named compounds, whose medicinal applicability was previously 
unknown, are encompassed by formula I. On the other hand, the compounds of 
formula Ia 
##STR5## 
in which X means an N atom or a CH group, 
Y means an S atom or a CH.dbd.CH group, 
Z.sup.a means a cyano group or a fluorine or bromine atom and 
R.sup.1a or R.sup.2a means 
an optionally esterified carboxyl group, 
an optionally substituted carboxylic acid amide group, 
an aldehyde group, 
an arylketone group, 
an optionally substituted sulfonamide group or a nitrile group 
and the respective other group R.sup.1a or R.sup.2a means 
a hydrogen atom, 
a lower-alkyl group or cycloalkyl group, 
an optionally substituted aryl group, 
an aralkyl group, 
an optionally esterified carboxyl group, 
an optionally substituted carboxylic acid amide group, 
an aldehyde group, 
an alkylketone group as well as 
a nitrile group or 
R.sup.1a and R.sup.2a together with the carbon atom, on which they are 
bound, mean a 5-, 6- or 7-membered ring, which contains a ketone, ester, 
lactone, lactam or imide grouping placed so that at least one carbonyl 
group is conjugated with a vinyl double bond, and 
R.sup.3 means a hydrogen atom or R.sup.3 together with R.sup.2a means an 
--O--C.dbd.O grouping or an --N--C.dbd.O grouping optionally substituted 
on an N atom whose carbonyl group is conjugated with a vinyl double bond, 
are new. 
The compounds of formula Ia therefore also are an object of this invention. 
The radicals possibly or preferably standing for substituents R.sup.1a, 
R.sup.2a and R.sup.3 in the compounds of formula Ia are the same as those 
of formula I mentioned as possibly or preferably standing for substituents 
R.sup.1, R.sup.2 and R.sup.3, with the difference that in the compounds of 
formula Ia, Z.sup.a is not chlorine and R.sup.1a and R.sup.2a are not an 
alkylketone group. 
Known substances exhibiting an aromatase-inhibiting effect are in addition 
to steroids also nonsteroidal substances, for example, the various 
nitrogen heterocycles described in European patent applications EP-A 
0165777 to 0165784, the substituted glutaric acid imides described in J. 
Med. Chem. 1986, 29, pages 1362-1369, the substituted imidazobenzenes 
described in European patent application EP 0165904, the substituted 
heterocyclicallysubstituted toluenenitriles described in European patent 
application EP-A 0236940 and the imidazo- and 
5,6,7,8tetrahydro-imidazo[1,5a]pyridines having an optionally substituted 
phenyl ring, seen from U.S. Pat. No. 4,728,465, from which in particular 
5-(p-cyanophenyl)5,6,7,8-tetrahydroimidazo-[1,5a]pyridine, hydrochloride 
stands out as a greatly effective aromatase inhibitor (Cancer Res. 48, pp. 
834-838, 1988). 
The compounds of formula I are distinguished relative to the previously 
known compounds in that they inhibit the enzyme system of the aromatase 
more strongly and at the same time more selectively. The selective 
activity is shown in that other enzyme systems are affected to a smaller 
extent. 
The concentrations in which the aromatase activity is inhibited in vitro by 
the compounds of formula I are in the range of 10.sup.-7 to 10.sup.-10 
mol/1. 
In comparison with the compounds of EP-A 0236940 that are structurally 
related, by the introduction of the double bond the compounds of formula I 
no longer have a chirality center on the carbon atom, on which both the 
cyanoaryl and the N-heteroaryl radical are present. An enantioselective 
synthesis or a difficult separation of enantiomers is avoided by the 
elimination of the chirality center. 
The amount of the compounds to be administered varies within a wide range 
and encompasses all effective amounts. As a function of the condition to 
be treated and the route of administration, the amount of the administered 
compounds is 0.0001-10 mg/kg of body weight, preferably 0.001-1 mg/kg of 
body weight daily. They can be administered analogously to the known 
aromatase inhibitors discussed above. 
For oral administration, capsules, pills, tablets, coated tablets, etc. are 
suitable. In addition to the active ingredient, the dosage units can 
contain a pharmaceutically compatible vehicle, such as, for example, 
starch, sugar, sorbitol, gelatin, lubricants, silicic acids, talc, etc. 
The individual dosage units for oral administration can contain, for 
example, 0.05-50 mg of the active ingredient (aromatase inhibitor). The 
compounds are customarily administered in amounts of from 0.1 to 4.0 g per 
patient per day. 
For parenteral administration, the active ingredients can be dissolved or 
suspended in a physiologically compatible diluent. As a diluent, very 
often oils are used with or without adding a solubilizer, a surfactant, a 
suspension mixture or an emulsifying mixture. As examples for oils used, 
there can be mentioned: olive oil, peanut oil, cottonseed oil, soybean 
oil, castor oil and sesame oil. 
The compounds can also be used in the form of a depot injection or an 
implantation preparation, which can be formulated so that a delayed 
release of active ingredient is made possible. 
Implantations can contain as inert materials, for example, biodegradable 
polymers or synthetic silicones, such as, for example, silicone rubber. 
The active ingredients can further be worked into, for example, plasters 
for percutaneous administration. 
The compounds of this invention can also be administered in other 
pharmaceutically customary forms of application, including topically, for 
example, in solutions, powders, creams, sprays and ointments. These 
compositions can be formulated conventionally, e.g., as described in U.S. 
Pat. No. 4,006,243, Examples 81 and. 82, and having a concentration of 
active agent of, e.g., between 0.5 and 5% by weight. 
Without wishing to be bound by theory, the tumorinhibiting activity of 
imidazole derivatives is based on the inhibition of P-450-dependent enzyme 
systems (cf., e.g., J. P. Van Wanne and P. A. J. Janssen; J. Med. Chem. 32 
(1989) 2231). Also, the action of antifungal therapeutic agents of the 
series of imidazole-triazole derivatives is based on a blocking of 
P-450-dependent biochemical reactions (loc. cit.). Further, it is known 
from the patent literature that azole derivatives have both antifungal and 
tumor-inhibiting action at the same time (in this connection, cf. EPA 
0165777, Eli Lilly). The compounds according to the invention therefore 
also have antifungal activity against human-, animal- and plant-pathogenic 
organisms. 
The invention further relates to processes for the production of compounds 
of formula Ia as well as a process for the production of certain compounds 
of formula I, identified below as compounds of formula I'. 
For the production of the compounds of formula Ia, either 
a) a compound of formula II 
##STR6## 
in which 
R.sup.1a, R.sup.2a, Y and Z.sup.a have the meaning indicated in formula Ia 
and R.sup.3' means a hydrogen atom or R.sup.3' together with R.sup.2a 
forms a ring of the above-indicated partial structures, reacts with a 
compound of formula VII 
##STR7## 
in which 
X means an N atom or a CH group and 
A means a hydrogen atom, an alkali metal or a trialkylsilyl radical with 
the same or different straightchain or branched C.sub.1 -C.sub.8 alkyl 
groups, in an inert solvent at a temperature between room temperature and 
boiling temperature of the solvent or without solvent, optionally by 
adding a catalyst first to a compound of formula IIi 
##STR8## 
in which R.sup.1a, R.sup.2a, R.sup.3', X, Y and Z.sup.a have the meaning 
already indicated in formula II or VII, and the latter is allowed to 
further react by dehydration above 60.degree. C., optionally in a solvent 
and optionally by using a catalyst, to a compound of formula Ia, or 
ii) a compound of formula III 
##STR9## 
in which 
R.sup.1, R.sup.2 and Y have the meaning indicated in formula 1, R.sup.3' 
means a hydrogen atom or together with R.sup.2, forms a ring of the 
above-indicated partial structures, and Hal means halogen atoms, in 
particular one bromine atom each, reacts with a compound of formula VII 
according to conventional processes with or without adding a foreign base 
to a compound of formula I or 
iii) to an acetylene compound of formula V 
##STR10## 
in which Y and Z.sup.a have the meaning indicated in formula I and R.sup.1a 
means an esterified carboxyl group, 
an optionally substituted carboxylic acid amide group, 
an aldehyde group, 
an arylketone group, 
an optionally substituted sulfonamide group or 
a nitrile group, and the optionally possible substituents and the alkoxy 
radicals of the esterified carboxyl group correspond to the definitions 
already indicated in more detail, 
is added a compound of formula VII in a solvent between room temperature 
and boiling temperature of this solvent with forming a compound of formula 
Iiii 
##STR11## 
The production of the compounds of formula I according to the invention 
takes place according to variant i) starting from an epoxide of formula II 
and an azole of formula VII in a way known in the art. 
The addition of the azole is performed in an inert solvent, such as, for 
example, benzene, toluene, xylene, tetrahydrofuran, dioxane, acetonitrile 
or dimethylformamide, preferably at a temperature between 60.degree. C. 
and the boiling temperature of the solvent or without solvent, preferably 
between 60.degree. C. and 150.degree. C. If necessary, a catalyst, e.g., a 
metal salt, such as lithium, magnesium, sodium perchlorate, zinc chloride 
or calcium chloride, can be added (Tetrahedron Letters 31 (1990) 4661). 
The dehydration takes place thermally, preferably at temperatures between 
100.degree. C. and 200.degree. C. or the boiling temperature of an 
optionally used solvent, such as, e.g., toluene, chlorobenzene or xylene. 
As catalysts, inorganic or organic acids, such as, for example, sulfuric 
acid or p-toluenesulfonic acid are suitable. 
The dehydration can also be performed by using dehydrating agents such as 
thionyl chloride or phosphorus oxychloride with or without a solvent 
(e.g., dichloromethane, acetonitrile, tetrahydrofuran) at room temperature 
to boiling temperature of the solvent, preferably between 20.degree. C. 
and 50.degree. C. 
In the reaction of the dihalide of formula III with an azole of formula VII 
according to ii), methods familiar to one skilled in the art are also 
involved. The additional use of a foreign base (Heterocycles 15 (1981), 
961) can be useful in facilitating the reaction. 
First, the exchange of the halogen atom on the benzylic carbon atom takes 
place and then the elimination of the hydrogen halide. The 
intermediately-formed monohalogen compound is not isolated. 
The necessary initial compounds of formula II or formula III are prepared 
from the corresponding olefins in a way known in the art by epoxidation or 
halogenation, preferably bromation: the olefins in turn can be produced 
conventionally, for example, by Wittig or Knoevenagel reaction of the 
corresponding feedstocks. 
In the addition of an azole of formula VII to an acetylene compound of 
formula V to be performed in a way known in the art according to variant 
iii), compounds of formula Iiii are obtained with R.sup.2 .dbd.H as a 
Z-/E-isomeric mixture. The production of compounds of formula V is known 
(e.g., Chem. Ber. 94 (1961) 3005; J. Org. Chem. 30 (1965) 1915). The 
reaction of compounds of formula V with the optionally substituted azoles 
VII takes place preferably in solvents such as hydrocarbons (benzene, 
toluene), ethers (ethyl ether, dioxane, tetrahydrofuran), alcohols 
(tert-butanol) or halogenated hydrocarbons (dichloromethane, chloroform, 
1,2-dichloroethane) between room temperature and boiling temperature of 
the solvent. 
Compounds of formula I' 
##STR12## 
in which R.sup.1, X, Y and Z have the meaning indicated in formula I, 
R.sup.2' means a hydrogen atom or 
R.sup.1 and R.sup.2 together with the methylene carbon atom mean a 5-, 6- 
or 7-membered ring, which contains a ketone, ester, lactone, lactam or 
imide grouping placed so that at least one carbonyl group is conjugated 
with a vinyl double bond, are produced, by a compound of formula IV 
##STR13## 
in which X, Y and Z have the meaning indicated in formula I, being reacted 
with a phosphorane of formula VIII 
##STR14## 
in which 
L means a phenyl radical optionally substituted with 
lower-alkyl(C.sub.1-6), low-alkoxy(C.sub.1-6), or halogen or a 
straight-chain or branched lower-alkyl radical with 1 to 6 carbon atoms 
and R.sup.1 and R.sup.2' have the above-indicated meaning, in an inert 
solvent between room temperature and boiling temperature of the solvent 
used. 
By reaction of an acylazole of formula IV with a phosphorane of formula 
VIII, the last-mentioned process variant according to the invention 
results in the compounds of formula I' (Wittig reaction). As an inert 
solvent, for example, benzene, toluene, xylene, chlorobenzene, 
tetrahydrofuran, dioxane, acetonitrile, dimethylformamide or 
dimethylsulfoxide are used. The reaction temperature is preferably 
selected above 60.degree. C. 
That acylazoles react with a phosphorane in the manner of a Wittig reaction 
was not previously known. Rather, it is known that acylimidazoles 
(generally also acylazoles) are good acylation agents (Comprehensive 
Heterocyclic Chemistry (Eds. A. R. Katritzky, K. T. Potts) Pergamon Press 
1984, Volume 4A, page 451 ff). Accordingly, it was to be expected that a 
Wittig reagent (phosphorane) is acylated on the carbanion, as it is 
observed, e.g., in the reaction with acid chlorides: 
##STR15## 
For aliphatic acyl imidazolids, acylation of triphenyl methylene 
phosphorane is described in M. Miyano et al., J. Org. Chem. 40, 2840 
(1975). 
It was therefore unexpected and surprising that aromatic acylimidazoles or 
acylazoles enter into a normal Wittig reaction: 
##STR16## 
Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. 
In the foregoing and in the following examples, all temperatures are set 
forth uncorrected in degrees Celsius and unless otherwise indicated, all 
parts and percentages are by weight. 
The entire disclosures of all applications, patents and publications, cited 
above and below, and of corresponding German application P 40 39 559.6, 
filed Dec. 7, 1990, are hereby incorporated by reference.

EXAMPLES 
EXAMPLE 1 
3-(4-Cyanopheny1)-3-(1-imidazoly1)-acrylic acid methyl ester 
2.85 g of 4-cyanobenzoyl chloride, dissolved in 20 ml of ether, is 
instilled in a solution of 2.4 g of imidazole in 25 ml of tetrahydrofuran 
and 50 ml of ether. After 10 minutes at room temperature, it is filtered 
with exclusion of air and the filtrate is concentrated by evaporation in a 
vacuum. The residue is dissolved in 20 ml of tetrahydrofuran and refluxed 
with 5.7 g of methoxycarbonylmethylene-triphenylphosphorane for 5 hours. 
It is added to water extracted with ethyl acetate and the ethyl acetate 
phase is washed with water. Then, the ethyl acetate phase is extracted 
three times with 2M hydrochloric acid. The hydrochloric acid phase is 
alkalized with potassium carbonate and extracted with ethyl acetate. After 
drying the ethyl acetate phase with sodium sulfate and concentration by 
evaporation, an oil remains, which thoroughly crystallizes. After 
suctioning off the crystals with ether, 3.5 g (81%) of a Z-/E-mixture of 
the title compound is obtained. By recrystallization of ethanol, the 
E-compound is obtained pure. Mp: 144.degree.-147.degree. C. 
EXAMPLE 2 
3-(4-Cyanophenyl)-3-(1-imidazolyl)-acrylic acid-tertbutyl ester 
Analogously to example 1, with use of 
tert-butoxycarbonylmethylenetriphenylphosphorane. Yield 37%. After 
chromatography on silica gel (eluant ethyl acetate) and crystallization 
from ether, the E-isomer melts at 151.degree.-153.degree. C. 
EXAMPLE 3 
E-3-(4-Cyanophenyl)-3-(1-imidazolyl)-acrylic acid 
100 mg of the E-compound of example 1 is dissolved in 1.5 ml of 10% 
methanolic potassium hydroxide and left for 15 minutes at room 
temperature. 
Then, it is concentrated by evaporation in a vacuum at 30.degree. C. and 
the residue is dissolved in 2 ml of water. By adding 1M hydrochloric acid 
and later 10% acetic acid, it is adjusted to a pH of 5 and extracted with 
ethyl acetate. After concentration by evaporation of the solvent, 38 mg of 
the title compound is obtained. 
Mp: 230.degree.-246.degree. C. 
The hydrochloride of the title compound is obtained as follows: 
200 mg of the E-tert-butyl ester of example 2 is stirred with 20 ml of 6 M 
hydrochloric acid for 2 hours at room temperature. It is concentrated by 
evaporation in a vacuum, distilled twice more each with toluene and 
methylene chloride and 195 mg (100%) of 
E-3-(4-cyanophenyl)-3-(1-imidazolyl)-acrylic acid, hydrochloride, is 
obtained. 
EXAMPLE 4 
E-3-(4-Cyanophenyl)-3-(1-imidazolyl)-acrylic acid piperidide 
190 mg of the hydrochloride of example 3, 196 mg of 
2-chloro-l-methylpyridinium iodide, 57 mg of piperidine, 290 mg of 
tributylamine and 12 ml of methylene chloride are refluxed for 20 hours. 
The acid phase is separated and saturated with potassium carbonate. It is 
extracted with ethyl acetate, the ethyl acetate phase is concentrated by 
evaporation and the low-boiling material is distilled off from the residue 
at 100.degree. C. and 0.01 mbar. The residue is chromatographed on silica 
gel. With methylene chloride/isopropanol (0.5-4% isopropanol), 52 mg of 
crystalline product is obtained with a melting point of 
160.degree.-165.degree. C. 
EXAMPLE 5 
E-3-(4-Cyanophenyl)-3-(1-imidazolyl)-acrylic acid methylamide 
1.35 g of methylammonium chloride in 10 ml of toluene is mixed under argon 
with 7.5 ml of trimethylaluminum in 10 ml of toluene by instillation and 
stirred for 2 hours at room temperature. 50 mg of the E-methyl ester of 
example 1 is mixed in 2 ml of toluene with 2 ml of the above-produced 
reagent. It is stirred for 6 hours at 80.degree. C., then mixed at room 
temperature with 1M hydrochloric acid and extracted with ether. The acid 
phase is alkalized with potassium carbonate and extracted with ethyl 
acetate. After washing with water and drying, the ethyl acetate phase is 
concentrated by evaporation. 30 mg of the title compound (50%) remains; 
melting range: 172.degree.-180.degree. C. 
EXAMPLE 6 
3-(4-Cyanophenyl)-3-(1-imidazolyl)-acrylonitrile 
Analogously to example 1, the title compound is obtained with use of 
cyanomethylenetriphenylphosphorane. The E-isomer is obtained pure from 
ethanol; mp: 188.degree.-193.degree. C. 
EXAMPLE 7 
4-[1-(1-Imidazolyl)-3-oxo-1-butenyl]-benzonitrile 
a) Analogously to example 1, with use of 
acetonylidine-triphenylphosphorane. A Z-/E-mixture of the title compound 
is obtained. 
b) By stirring 3.02 g of 4-cyanobenzaldehyde and 7.32 g of 
acetonylidene-triphenylphosphorane in 50 ml of dichloromethane and then 
recrystallizing from isopropanol, 3.15 g (80%) of 
4-(3-oxobutenyl)-benzonitrile is obtained. 1.71 g of it is mixed in 20 ml 
of dichloromethane with 20 ml of a 0.5 M solution of bromine in 
dichloromethane. After decolorization, the solvent is drawn off in a 
vacuum. The remaining oil is refluxed with 0.95 g of imidazole and 7 ml of 
triethylamine in 40 ml of toluene for 2 hours. A precipitate is filtered 
off, the filtrate is distributed in ethyl acetate-2M hydrochloric acid, 
the hydrochloric acid phase is alkalized with potassium carbonate and 
extracted with ethyl acetate. 1.2 g of a crude product is obtained, which, 
after recrystallization from isopropanol, yields the Z-isomer with mp. 
131.degree.-135.degree. C. After chromatography of the mother liquor on 
silica gel (eluant ethyl acetate), the E-isomer is obtained from ethyl 
acetate/ether as crystals of mp: 123.degree.-126.degree. C. 
EXAMPLE 8 
3-[(4-Cyanophenyl)-(1-imidazolyl)-methylene)-dihydro-2(3H)-furanone 
Analogously to example 1, with use of 
3-(triphenylphosphoranylidine)-dihydro-2(3H)-furanone in the solvent 
toluene under reflux (20 hours). Chromatography of the crude product on 
silica gel (eluant dichloromethane/ methanol 99:1) and recrystallization 
from isopropanol produces the title compound in E-form with mp: 
194.degree.-197.degree. C. 
EXAMPLE 9 
3-(5-Cyano-2-thienyl)-3-(1-imidazolyl)-acrylic acid tert-butyl ester 
The acid chloride is produced from 2 g of 5-cyanophiophene-2-carboxylic 
acid by boiling with thionyl chloride and distilling off excess thionyl 
chloride. The acid chloride is dissolved in 10 ml of ether and mixed with 
1.9 ml of N-trimethylsilylimidazole. It is concentrated by evaporation in 
a vacuum, dissolved in a mixture of 150 ml of tetrahydrofuran and 50 ml of 
acetonitrile and mixed with 4.9 g of 
tert-butoxycarbonylmethylenetriphenylphosphorane. It is refluxed for 20 
hours and worked up as in example 1. The crude product is chromatographed 
on silica gel using dichloromethane with 1-2% isopropanol. 2.4 g (63%) of 
the title compound is obtained as a Z-/E-mixture. The E-isomer is obtained 
pure by recrystallization from isopropanol; mp: 90.degree.-91.degree. C. 
EXAMPLE 10 
3-(5-Cyano-2-thienyl)-3-(1-imidazolyl)-acrylonitrile 
Analogously to example 9, with use of cyanomethylenetriphenylphosphorane, a 
Z-/E-mixture of the title compound is obtained. The E-isomer is obtained 
pure from ethanol; mp: 129.degree.-133.degree. C. 
EXAMPLE 11 
3-(4-Cyanophenyl)-3-(1,2,4-triazol-1-yl)-acrylic acid-tert-butyl ester 
Analogously to example 9, with use of 1-trimethylsilyl-1,2,4-triazole and 
tert-butoxycarbonylmethylenetriphenylphosphorane 
Z-isomer: mp: 132.degree.-133.degree. C. 
E-isomer: mp: 83.degree.-85.degree. C. 
EXAMPLE 12 
3-(4-Cyanopheny1)-3-(1,2,4-triazo1-1-y1)-acrylonitrile 
Analogously to example 9, with use of 1-trimethylsilyl-1,2,4-triazole and 
cyanomethylene-triphenylphosphorane. 
EXAMPLE 13 
7-Cyano-4-(1-imidazolyl)-coumarin 
5 g of 7-hydroxycoumarin in 25 ml of pyridine is mixed by instillation 
under argon at 0.degree. C. with a mixture of 8.1 ml of 
trifluoromethanesulfonic acid anhydride and 65 ml of pyridine. It is 
stirred for 20 more hours at room temperature, poured on 400 ml of 
ice-cold, semiconcentrated hydrochloric acid and extracted with ethyl 
acetate. After washing the ethyl acetate phase with semiconcentrated 
hydrochloric acid, water and potassium bicarbonate solution in succession, 
it is dried and concentrated by evaporation. 6.9 g of 
7-hydroxycoumarintrifluoromethanesulfonic acid ester is obtained; mp: 
75.degree.-76.degree. C. 
3 g of it is refluxed with 960 mg of potassium cyanide, 2.4 g of 
tetrakis-(triphenylphosphine)-palladium(O) and 30 mg of 
1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) in 180 ml of 
tetrahydrofuran for 5 hours. It is diluted with water, extracted with 
ethyl acetate and the ethyl acetate phase is washed in succession with 1M 
sodium hydroxide solution, water and common salt solution. After 
concentration by evaporation in a vacuum, it is recrystallized from 
ethanol and 975 mg of 7-cyanocoumarin is obtained; mp: 
217.degree.-225.degree. C. 
This material is dissolved in 95 ml of dichloromethane, mixed with 10 ml of 
bromine and stirred under action of light (100 W) for 4 days. Then, it is 
concentrated by evaporation in a vacuum. The crystals are suctioned off 
with ether. 1.2 g of 3,4-dibromo-7-cyano 2-chromanone is obtained; mp: 
220.degree.-230.degree. C. 
The dibromo compound is refluxed with 372 mg of imidazole and 2.52 ml of 
triethylamine in 20 ml of toluene for 7 hours. The solution is distributed 
between 1M hydrochloric acid and ether, the acid water phase is separated 
and it is alkalized with potassium carbonate. After extraction with ethyl 
acetate and concentration of the solvent by evaporation, the remaining 
crystals are suctioned off with ether, dried at 50.degree. C. in a vacuum 
and 140 mg of the title compound of melting point 260.degree.-268.degree. 
C. is thus obtained. 
EXAMPLE 14 
3-(4-Cyanophenyl)-3-(1-imidazolyl)-acrylic acid methyl ester 
4-Cyanophenyl-propiolic acid methyl ester is obtained from 10 g of 
4-cyanobenzoyl chloride and 40 g of 
methoxy-carbonylmethylene-triphenylphosphorane (yield 5.5 g; mp: 
103.degree.-106.degree. C.) analogously to Chem. Ber. 94 (1961) 3005 and 
further reacted as follows: 
a) 185 mg of the ester and 75 mg of imidazole are 10 refluxed in 5 ml of 
tetrahydrofuran for 20 hours. It is distributed between 1M hydrochloric 
acid and ether, the acid water phase is separated, it is alkalized with 
potassium carbonate and then extracted with ethyl acetate. After drying 
and concentration by evaporation, 150 mg of crystals, which represent a 
Z:E mixture in the ratio 5.2:1 of the product produced in example 1, is 
obtained. 
b) 185 mg of the ester, 75 mg of imidazole and 0.07 mg of triethylamine in 
5 ml of tetrahydrofuran are reacted and worked up as in a). 150 mg of 
product is obtained; Z:E =6.5:1. 
c) 185 mg of ester and 155 mg of N-trimethylsilylimidazole in 5 ml of 
tetrahydrofuran are treated as in a). 100 mg of product is obtained; Z:E 
=4:1. 
EXAMPLE 16 
3-(4-Fluorophenyl)-S-(1-imidazoly1)-acrylic acidtert-butyl ester 
Analogously to example 9, with use of 4-fluorobenzoic acid, a Z-/E-mixture 
of the title compound is obtained. After chromatography and 
recrystallization, the E-isomer is obtained pure. 
Mp: 90.degree.-93.degree. C. 
EXAMPLE 16 
3-(4-Chlorophenyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester 
Analogously to example 9, with use of 4-chlorobenzoic acid. The E-isomer 
melts at 114.degree.-121.degree. C. (from cyclohexane). 
EXAMPLE 17 
3-(4-Bromophenyl)-3-(1-imidazolyl)-acrylic acidtert-butyl ester 
Analogously to example 9, with use of 4-bromobenzoic acid. The E-isomer 
melts at 131.degree.-132.degree. C. (from isopropanol). 
EXAMPLE 18 
3-(4-Fluorophenyl)-3-(1,2,4-triazol-1-yl)-acrylic acid-tert-butyl ester 
Analogously to example 9, with use of 4-fluorobenzoic acid and 
1-trimethylsilyl-l,2,4-triazole. The E-isomer melts at 
72.degree.-74.degree. C. 
The preceding examples can be repeated with similar success by substituting 
the generically or specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily ascertain 
the essential characteristics of this invention, and without departing 
from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various usages and 
conditions.