N-bicycloheptyl-and n-bicycloheptenyl-imidazoles for affecting serum lipoproteins

N-Bicycloheptyl- and N-bicycloheptenyl-imidazoles of the formula I ##STR1## in which A, B, R.sup.1, R.sup.2 and n have the indicated meanings, and their physiologically tolerated salts, a process for the preparation of these compounds, pharmaceutical products based on these compounds, and their use as medicaments, in particular for the treatment of disturbances of the serum lipoprotein spectrum, are the subject-matter of the invention.

The invention relates to N-bicycloheptyl- and N-bicycloheptenyl-imidazoles, 
a process for their preparation, pharmaceutical products containing these 
compounds, and their use as medicaments, in particular for the treatment 
of hyperlipidemia. 
It has already been described that imidazoles which are substituted on the 
nitrogen atom by a straight-chain or branched alkyl radical or by the 
benzyl radical have a hypolipidemic effect (see J. Med. Chem. 18, 833 
(1975)). However, in order to achieve therapeutically satisfactory 
results, high doses of the compounds described in this publication are 
necessary. Imidazolmethylsubstituted bicycles having an antithromboembolic 
effect are described in German Offenlegungsschrift No. 2,944,663. Where 
the bicycles mentioned in this publication are bicycloheptanes, they are 
unsubstituted in the 7-position. 
It has been found, surprisingly, that N-bicycloheptyl- and 
N-bicycloheptenyl-imidazoles substituted in the 7-position have a much 
greater hypolipidemic effect than imidazole derivatives hitherto 
described. 
Thus the invention relates to new N-bicyclopheptyl- and 
N-bicycloheptenyl-imidazoles of the formula I 
##STR2## 
in which R.sup.1 and R.sup.2 are identical or different and denote alkyl 
having 1 to 10 carbon atoms, cycloalkyl having 4 to 10 carbon atoms, 
phenyl which is optionally mono- or disubstituted by halogen, (C.sub.1 
-C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, trifluoromethyl, hydroxyl, 
amino, (C.sub.1 -C.sub.4)-alkylamino or (C.sub.1 -C.sub.4)-dialkylamino, 
the substituents in the case of disubstitution being identical or 
different, naphthyl or phenylalkyl having 1 to 4 alkyl carbon atoms, or 
R.sup.1 and R.sup.2 together represent a (CH.sub.2).sub.m bridge which is 
optionally substituted by phenyl, m denoting a number from 3 to 10, 
A represents a single or double bond, 
B denotes a single bond or, if n represents 0 or 1, also the 
##STR3## 
group or, if n represents 1, the --CHOH-- group, and n represents 0, 1, 
2, 3 or 4, 
and to their physiologically tolerated acid addition salts. 
Alkyl is to be understood to be both straight-chain and branched alkyl. 
The wavy line in formula I and in the formulae which follow indicates that 
the substituents can be in either the endo- or exo-position on the 
bicycle. 
Preferred compounds of the formula I are those in which R.sup.1 and R.sup.2 
are identical or different and denote phenyl and phenyl which is 
monosubstituted by halogen, in particular fluorine or chlorine. A 
preferably represents a single bond, n particularly denotes 0 to 1, and B 
a single bond or the --CO-- group. 
The process for the preparation of compounds of the formula I and their 
salts comprises 
(a) converting an alcohol of the formula II 
##STR4## 
in which A, R.sup.1, R.sup.2 and n have the meanings indicated for formula 
I, by methods known per se into a compound of the formula III 
##STR5## 
in which A, R.sup.1, R.sup.2 and n have the meanings indicated for formula 
I, and Y denotes a leaving group, such as, for example, hydrogen, in 
particular chlorine or bromine, or a sulfonic acid derivative, such as 
(C.sub.1 -C.sub.4)-alkyl-SO.sub.2 --O--, 
##STR6## 
and reacting the latter with imidazole or an imidazole salt of the formula 
IV 
##STR7## 
in which Z denotes hydrogen or alkali metal, to give a compound of the 
formula I in which R.sup.1, R.sup.2, A and n have the meanings indicated, 
and B represents a single bond, and, where appropriate, hydrogenating the 
double bond in a resulting compound in which A represents a double bond, 
the hydrogenation being carried out either on an intermediate or on a 
compound of the formula I (A=double bond), or 
(b) reacting a halide of the formula V 
##STR8## 
in which A, R.sup.1 and R.sup.2 have the meanings indicated for formula I, 
n represents 0 or 1, and halogen represents bromine or chlorine, with 
imidazole or an imidazole salt of the formula IV, to give a compound of 
the formula I in which A, R.sup.1 and R.sup.2 have the meanings indicated, 
B is the 
##STR9## 
group, and n is 0 or 1, and, where appropriate, reducing the latter to 
give a compound in which B denotes the CHOH group and, if desired, 
converting with an acid the compounds obtained by (a) or (b) into the 
physiologically tolerated acid addition salts. 
In process (a), the alcohols of the formula II are converted into the 
halogen compound III (Y=halogen), for example with an inorganic halide, 
such as, for example, POCl.sub.3, PCl.sub.3, PBr.sub.3, P(C.sub.6 
H.sub.5).sub.3 /CCl.sub.4 or SOCl.sub.2, or they are converted into the 
sulfonic esters with a sulfonyl halide. Suitable sulfonyl halides are the 
customarily used halides, such as mesyl chloride, tosyl chloride or 
p-chlorobenzenesulfonyl chloride. The substitution of the halide or 
sulfonic ester is advantageously carried out with imidazole in the 
presence of an acid-binding additive, such as an aliphatic or aromatic 
amine, or with the sodium salt of imidazole, in a polar solvent, such as 
DMF, DMSO, THF or alcohol, at temperatures between 0.degree. and 
100.degree. C. 
The alcohols of the formula II are either described in the literature or 
are prepared in analogy to described methods. For the preparation of 
alcohols of the formula II in which n is 1, the procedure is 
advantageously as follows: 
Bicycloheptene derivatives are obtained from R.sup.1, R.sup.2 -substituted 
pentafulvenes and appropriately substituted olefins, such as, for example, 
acrylic acid, acrylic esters, acrylonitrile, .alpha.-chloroacrylonitrile, 
methyl vinyl ketone and other electron-poor olefins, without a solvent or 
in the presence of a solvent, at temperatures of, advantageously, 
20.degree.-80.degree. C., in accordance with the method indicated in Ann. 
566, pages 1 et seq. and 27 et seq. (1950). The bicycloheptene derivative 
of the formula VI 
##STR10## 
in which R.sup.1 and R.sup.2 have the meanings indicated, and X denotes 
hydrogen or a (C.sub.1 -C.sub.4)-alkyl group, is obtained by reaction with 
acrylic acid or an appropriate acrylic ester. The reaction is many times 
faster than indicated in Ann. 566, 1 et seq. The reaction time is usually 
between a few hours and some days. 
The fulvenes used to synthesize the bicycle are obtained by methods known 
from the literature (see Adv. in Alicyclic Chem. 2, 59 (1968)). 
The compounds of the formula VI are particularly suitable for procedure 
(a). They are converted into the corresponding alcohol using a reducing 
agent, for example a complex hydride, such as LiAlH.sub.4. 
An alcohol of the formula II in which n is 1 and A represents a single bond 
is obtained by hydrogenation by methods known per se. 
In the preparation of the alcohols of the formula II in which n represents 
O and A represents a single bond, the starting material used is, for 
example, a ketone of the formula VII 
##STR11## 
which is reduced, for example, with LiAlH.sub.4 to give the desired 
alcohol. 
Compounds of the formula VIII 
##STR12## 
in which X denotes the cation of an alkali metal or (C.sub.1 
-C.sub.4)-alkyl are obtained by reaction of the same ketone VII with 
organometallic reagents, such as (EtO).sub.2 POCHNaCOX, or with a Wittig 
reagent such as, for example, (C.sub.6 H.sub.5).sub.3 
P.dbd.CH--(CH.sub.2).sub.n-2 --COX. The reduction to give the alcohol is 
carried out as described above, for example. In the subsequent 
hydrogenation, only the double bond in the side-chain is hydrogenated. 
In principle, the hydrogenation of the endocyclic double bond (A=double 
bond) is possible at any stage of the synthetic sequence. However, it is 
preferably carried out at the stage of the cyclo adduct (compound of the 
formula VI) or on the imidazole derivative I itself. The procedure is 
known per se, the catalyst used being, for example 5% Pd on charcoal. In 
this way, compounds according to the invention, with A=single bond, are 
obtained. 
The preparation of compounds of the formula I which contain a keto or 
hydroxyl group in the imidazolesubstituted side-chain (B=CO or CHOH) is 
carried out by process (b). The halide of the formula V used as starting 
material is obtained by methods known from the literature. The methyl 
ketone which is described in Ann. 566, 27 (1950), which is preferably 
used, was converted under kinetic control into the silyl enol ether (see 
JOC 34, 2324 (1969)) and the latter was then brominated (see Synthesis 
1976, 194). 
The imidazole derivative according to the invention is obtained by reacting 
the corresponding halide, preferably in a polar organic solvent, such as 
DMF, DMSO, THF or low molecular weight alcohols, at a temperature between 
0.degree. and 100.degree. C., preferably room temperature, with at least 
twice the amount of imidazole or the Na salt of imidazole. The resulting 
keto imidazole derivative (B=CO) can, where appropriate, be reduced to the 
corresponding alcohol (B=CHOH). Complex hydrides such as, for example 
LiAlH.sub.4 or NaBH.sub.4, in a suitable solvent are most suitable for the 
reduction. 
Acid addition salts can be prepared from the imidazole derivatives of the 
general formula (I), which usually result as an oil. All acids which form 
physiologically tolerated salts are suitable for this. These include both 
inorganic acids such as, for example, hydrochloric acid, nitric acid and 
sulfuric acid and mono- and bifunctional organic acids, in particular 
carboxylic acids, such as acetic acid, succinic acid, tartaric acid etc. 
The compounds according to the invention, of the formula I, have valuable 
pharmacological properties, in particular they exhibit a very strong and 
favorable effect on the serum lipoproteins. Thus the invention also 
relates to pharmaceutical products based on these compounds, and to their 
use as medicaments, in particular for affecting the serum lipoproteins. 
It is generally accepted that hyperlipoproteinemia is an essential risk 
factor for the development of arteriosclerotic vascular changes, in 
particular coronary heart disease. Thus, extreme importance attaches to 
the reduction in raised serum lipoproteins for the prophylaxis and 
reduction of arteriosclerotic changes. However, very particular classes of 
serum lipoproteins are important in this context, since the low density 
(LDL) and very low density lipoproteins (VLDL) represent a risk factor for 
atherogenesis, while the high density lipoproteins (HDL) exert a 
protective function with respect to arteriosclerotic vascular changes. 
Accordingly, hypolipidemic agents should lower VLDL-cholesterol and 
LDL-cholesterol in the serum but, at the same time, where possible leave 
the HDL-cholesterol concentration unaffected or even raise it, so that the 
antiatherogenic index (HDL/LDL) increases. 
The compounds according to the invention have valuable therapeutic 
properties. Thus, they lower, in particular, the concentration of LDL and 
VLDL but they lower the HDL fraction only at excessive doses which have 
already reduced the LDL-cholesterol concentration by more than about 50%, 
so that the result in the therapeutically utilizable range is a great 
reduction in the LDL fraction without any effect on the HDL fraction. 
Thus, these compounds represent a considerable advance compared with the 
comparison compound clofibrate which, apart from LDL, always brings about 
a very great reduction in HDL, as is evident from the data described 
below. Thus they can be used for the prophylaxis and regression of 
arteriosclerotic changes since they eliminate a causal risk factor. 
This includes not only primary hyperlipidemia, but also certain types of 
secondary hyperlipidemia as occur with, for example, diabetes. The 
increase in the relative liver weight caused by the compounds at effective 
doses is zero or only slight, while clofibrate, which is used as a 
standard hypolipidemic agent, leads to a great increase in the relative 
liver weight. 
The effect of the compounds listed was investigated on the serum 
lipoproteins in male Wistar rats which were treated with the compounds 
listed, suspended in polyethylene glycol 400, by gavage for 7 days. In 
addition, a control group received only the solvent polyethylene glycol 
400, and, in most experiments, there was a group of rats which received 
the standard hypolipidemic agent clofibrate. As a rule, 10 animals were 
used in each group, their blood being sampled from the orbital plexus 
after shallow ether anesthesia at the end of the treatment. The serum 
lipoproteins from the rat serum obtained were fractionated into the 
following density classes in a preparative ultracentrifuge: 
EQU VLDL&lt;1.006; LDL 1.006 to 1.04; HDL 1.04 to 1.21 
Since, in contrast to humans, the serum lipoproteins of the rat contain 
about 4/5 HDL-cholesterol and only 1/5 LDL-cholesterol, and only very 
small amounts of VLDL (conversely, about 4/5 LDL and VLDL and only 1/5 HDL 
in humans), fractionation of the rat serum into lipoprotein classes is 
absolutely necessary for assessment of a hypolipidemic effect in the rat. 
This is because simply reducing the serum total cholesterol content in the 
rat would merely indicate the undesired reduction in the antiatherogenic 
HDL class which predominates in the rat. A desired reduction of LDL with, 
at the same time, a desired increase in HDL would, however, have no 
(substantial) effect on the total cholesterol content of rat serum. 
The cholesterol contained in the lipoprotein fractions isolated in the 
ultracentrifuge was determined completely enzymatically by the CHOD-PAP 
method using the Boehringer-Mannheim assay combination, and the figures 
have been converted into .mu.g/ml serum. Table I below shows the 
percentage change in the lipoprotein cholesterol in the treated group 
compared with a control group kept under the same conditions. As is 
evident from Table I, clofibrate brings about a greater reduction in the 
HDL than in the LDL fraction, while the new compounds exert a strong and 
selectively reducing effect on the atherogenic lipoprotein fractions (VLDL 
and LDL), and leave the protective HDL fraction essentially unaffected. 
TABLE I 
__________________________________________________________________________ 
Percentage changes in the Lipoproteins in rat serum after 
oral administration of the compounds for 7 days 
% change in cholesterol, relative to 
the control groups 
in the serum Lipo- 
% change in the 
Example 
Dose protein fractions 
relative liver 
No. mg/kg/day 
in serum 
VLDL 
LDL HDL HDL weight 
__________________________________________________________________________ 
17 30 -55 -88 -54 3.74 
+20 
12.5 -47 -82 -39 3.34 
+10 
5 -26 -43 -17 1.46 
+3 
3 +2 -26 +2 1.38 
+4 
1 -13 -60 -23 -11 1.16 
0.3 +6 +13 -26 -2 1.33 
-1 
15 30 -78 -74 -94 -95 0.93 
+31 
10 -96 -88 -100 
-98 +24 
3 -93 -63 -89 -96 0.35 
+24 
1 -80 0 -89 -83 1.49 
+19 
0.3 -53 +19 -69 -58 1.37 
+6 
0.1 -2 -20 -36 -9 1.43 
+1 
0.03 +1 -33 -21 -5 1.78 
-1 
7 3 -11 -18 -30 -4 1.36 
-1 
2 30 +7 -31 -37 +11 1.76 
+15 
22 10 -5 -57 -44 +4 1.85 
+10 
3 -5 -57 -29 0 1.42 
0 
4 10 -69 +50 -88 -74 2.13 
+10 
3 -36 -5 -53 -36 1.36 
0 
1 -15 +6 -36 -19 1.0 +1 
20 3 -46 0 -75 -50 2.6 +2 
0.3 -2 -9 -30 -9 1.30 
-4 
21 0.3 -18 -20 -25 -16 1.12 
0 
9 30 -12 -43 -40 -14 1.43 
+10 
14 3 -14 +32 -44 -9 0.97 
0 
12 0.3 -15 -10 -25 -14 1.16 
0 
13 0.3 -17 -10 -37 -17 1.33 
-2 
24 0.1 -49 -6 -68 -40 1.84 
+12 
25 3 -16 -17 -36 -11 1.39 
+2 
0.3 -2 +10 -16 +3 1.23 
+8 
Clofibrate 
100 -26 -10 -38 -23 1.18 
+29 
__________________________________________________________________________ 
Particularly suitable therapeutic preparations of the compounds of the 
formula I are tablets, coated tablets, capsules, suppositories and syrups. 
In these, the new compounds can be used either alone or mixed with 
pharmacologically acceptable vehicles. An oral administration form is 
preferred. For this purpose, the active compounds are preferably mixed 
with auxiliaries known per se, and converted, by methods known per se, 
into suitable administration forms, such as tablets, hard gelatine 
capsules, aqueous or oily suspensions or aqueous or oily solutions. 
Examples of inert vehicles which can be used are magnesium carbonate, 
lactose or corn starch, with the addition of other substances such as, for 
example, magnesium stearate. This can entail the preparation being carried 
out as dry or as moist granules. Particularly suitable oily vehicles or 
solvents are vegetable and animal oils such as, for example, sunflower oil 
or fish liver oil. A suitable daily dose is about 20 mg to 1 g, preferably 
50 to 100 mg. A dosage unit preferably contains 10 to 25 mg. 
For the treatment of disturbances of lipid metabolism, apart from the 
customary fillers and vehicles, the formulations can also contain an 
antihypertensive agent such as, for example, a saluretic, reserpine, 
hydralazine, guanethidine, .alpha.-methyldopa, clonidine or a 
.beta.-sympathicolytic agent, a compound having antithrombotic activity, 
such as, for example, acetylsalicylic acid, sulfinpyrazone, ticlopidine 
and heparinoids, or an agent having antihyperuricemic activity, an oral 
antidiabetic, a geriatric agent or an agent effecting an increase in blood 
flow.

The examples which follow illustrate the preparation of the compounds: 
Unless otherwise specified, the NMR spectra were recorded in DCCl.sub.3. 
The chemical shifts are expressed in .delta. values. 
EXAMPLE 1 
exo,endo-2-(1-Imidazolomethyl)-7-isopentylidenebicyclo[2.2.1]heptane 
(a) Methyl exo,endo-7-isopentylidenebicyclo[2.2.1]-hept-5-ene-2-carboxylate 
23.3 g (0.175 mol) of 6,6-diethylfulvene are mixed with 2.4 g (0.280 mol) 
of methyl acrylate, a spatula tip of hydroquinone is added, and the 
mixture is heated at 60.degree. C. for 30 h. After removal of the excess 
acrylate in vacuo, 30.7 g of methyl 
exo,endo-7-isopentylidenebicyclo[2.2.1]hept-5-ene-2-carboxylate are 
obtained as an oil. 
NMR: 6.0-6.5, m, 2H; 3.6 and 3.7 s, exo and endo CO.sub.2 CH.sub.3 ; 
1.2-3.5 m, 9H; 0.9, t, 2CH.sub.3 
(b) Methyl exo,endo-7-isopentylidenebicyclo[2.2.1]heptane-2-carboxylate 
30.6 g (0.138 mol) of ester from (a) are dissolved in 100 ml of THF. After 
addition of 2 g of Pd/C, hydrogenation is carried out at room temperature 
and under atmospheric pressure until one equivalent of hydrogen has been 
absorbed. After filtering off the catalyst with suction, the filtrate is 
distilled at 0.2 mm. 20.1 g of methyl 
exo,endo-7-isopentylidenebicyclo[2.2.1]heptane-2-carboxylate of boiling 
point 76.degree. C. are obtained. 
NMR: 3.6 and 3.7, s, exo and endo CO.sub.2 CH.sub.3 ; 0.7-3.0, m, 19H. 
(c) exo,endo-2-Hydroxymethyl-7-isopentylidenebicyclo[2.2.1]heptane 
1.9 g (50 mmol) of LiAlH.sub.4 in 100 ml of absolute ether are initially 
introduced. Then, under gentle reflux, 20.0 g (90 mmol) of ester from (b) 
in 50 ml of absolute ether are added dropwise, and the mixture is then 
stirred under reflux for one hour. It is hydrolyzed with dilute 
hydrochloric acid, and the ether phase is separated off, washed with water 
and dried over sodium sulfate. After removal of the ether in vacuo, 15.7 g 
of the alcohol remain as an oil. 
NMR: 3.6 and 3.2 d, exo and endo CH.sub.2 OH; 1.2-2.8, m, 13H; 0.9, t, 
2CH.sub.3. 
(d) 
exo,endo-7-Isopentylidenebicyclo[2.2.1]heptane-2-methyl(p-chlorophenyl)sul 
fonate 
9.0 g (90 mmol) of triethylamine are added dropwise to 15.6 g (81 mmol) of 
alcohol from (c) and 18.8 g (89 mmol) of p-chlorobenzenesulfonyl chloride 
in 100 ml of methylene chloride at room temperature. After 16 hours, water 
is added, and the organic phase is separated off, washed once with water 
and dried. After evaporation in a rotary evaporator, 26.6 g of 
exo,endo-7-isopentylidenebicyclo[2.2.1]heptane-2-methyl(p-chlorophenyl)sul 
fonate remain as an oil. 
NMR: 7.4-8.1, m, 4H; 4.0, q and 3.6, d, exo and endo 
##STR13## 
(e) exo,endo-2-(1-Imidazolomethyl)-7-isopentylidenebicyclo[2.2.1]heptane 
6.4 g (72 mmol) of sodium imidazolide in 80 ml of DMF are initially 
introduced, and 25.2 g (71 mmol) of sulfonic ester from (d) in 50 ml of 
DMF are added dropwise at room temperature. The reaction mixture is 
stirred at 60.degree. C. for 16 h, then cooled and water is added. The 
mixture is extracted three times with 150 ml of methylene chloride each 
time, and the organic phase is dried and evaporated. After purification of 
the residue by column chromatography on silica gel using cyclohexane/ethyl 
acetate (2:1), 6 g of the title compound are obtained as a pale yellow, 
solidifying oil. Formula: 
##STR14## 
NMR: 7.4, s, 1H; 6.9, d, 2H; 3.9, d and 3.6, q, exo and endo CH.sub.2 
-imidazole; 0.5-2.7 m, 19H. 
EXAMPLE 2 
endo-2-(1-Imidazolomethyl)-7-cyclohexylidenebicyclo[2.2.1]heptane 
4 g (15.8 mmol) of 
endo-2-(1-imidazolomethyl)-7-cyclohexylidenebicyclo[2.2.1]hept-5-ene 
(prepared in analogy of Example 1(a), (c), (d), (e) from 
6,6-pentamethylenefulvene, methyl acrylate and sodium imidazolide; melting 
point 48.degree. C., see Example 10) are hydrogenated in 50 ml of THF at 
room temperature and under atmospheric pressure, in the presence of 0.5 g 
of Pd/c (5%), until one equivalent of hydrogen has been absorbed. The 
catalyst is then filtered off, the solution is evaporated, and the residue 
is recrystallized from isopropyl ether. 3.3 g of imidazole derivative of 
melting point 95.degree. C. are obtained. Formula: 
##STR15## 
NMR: 7.5, s, 1H; 6.9, d, 2H; 3.9, d and 3.6, q, exo and endo CH.sub.2 
-imidazole; 0.5-2.7, m, 19H. 
EXAMPLE 3 
exo-2-(1-Imidazolomethyl)-7-diphenylmethylenebicyclo[2.2.1]heptane 
(a) exo and endo 7-Diphenylmethylenebicyclo[2.2.1]hept-5-ene-2-carboxylic 
acid 
50 g (0.218 mol) of 6,6-diphenylfulvene and 31.3 g (0.435 mol) of acrylic 
acid are intimately mixed and allowed to stand at room temperature for 14 
days until decolorized. By fractional recrystallization of the solid white 
crude product with ethanol, first 35.3 g of the endo acid of melting point 
190.degree. C. are obtained. Evaporation of the mother liquor and 
recrystallization of the residue from cyclohexane provides 8.4 g of the 
exo acid of melting point 146.degree. C. 
NMR: (endo acid): 7.4-7.0, m, 10H; 6.48, q, 1H, 6.28, q, 1H; 3.7-3.9, m, 
1H; 3.35-3.55, m, 1H; 3.2, dt, 1H, 2.22 o, 1H; 1.64, q, 1H. 
NMR (exo acid): 7.0-7.4, m, 10H; 6.42 t, 2H; 3.54-3.64, m, 1H; 3.40-3.52, 
m, 1H; 2.20-2.55, m, 2H; 1.60, q, 1H. 
(b) Methyl exo-7-diphenylmethylenebicyclo[2.2.1]hept-5-ene-2-carboxylate 
7.4 g (24.3 mmol) of the exo acid from (a) are dissolved in 50 ml of 
absolute methanol, and 0.5 g of concentrated sulfuric acid is added. The 
mixture is stirred at 40.degree. C. for 2 hours, allowed to stand at room 
temperature overnight, then water is added and the mixture is extracted 
with methylene chloride. After drying and evaporation of the organic 
phase, 7.8 g of methyl ester remain as a yellowish oil. 
NMR: 6.9-7.4, m, 10H; 6.2-6.4, m, 2H; 3.2-3.8, m, 2H; 3.4, s, 3H of 
CO.sub.2 CH.sub.3 ; 2.1-2.6, m, 2H; 1.2-1.8, m, 1H. 
(c) Methyl exo-7-diphenylmethylenebicyclo[2.2.1]heptane-2-carboxylate 
7.4 (23.3 mmol) of ester from (b) are dissolved in 100 ml of THF, and 
hydrogenation is carried out at room temperature and under atmospheric 
pressure, in the presence of 5% Pd on charcoal, until one equivalent of 
hydrogen has been absorbed. The catalyst is filtered off, and the solution 
is evaporated. 8.2 g of methyl 
exo-7-diphenylmethylenebicyclo[2.2.1]heptane-2-carboxylate remain as an 
oily residue. 
NMR: 7.0-7.5, m, 10H; 3.4, s, 3H of CO.sub.2 CH.sub.3 ; 1.0-2.8, m, 9H. 
(d) exo-2-Hydroxymethyl-7-diphenylmethylenebicyclo[2.2.1]heptane 
7.9 g (24.8 mmol) of ester from (c) in 50 ml of dry ether are added 
dropwise to 1.0 g (27.1 mmol) of lithium aluminum hydride in 35 ml of dry 
ether. The mixture is stirred under reflux for 2 hours, then dilute 
hydrochloric acid is added, and the organic phase is separated off, washed 
once with water, dried and the solvent is removed under waterpump vacuum. 
7.1 g of the alcohol are obtained as an oil. 
NMR: 6.7-7.4, m, 10H; 3.3, q, 2H, CH.sub.2 OH; 0.9-2.5, m, 9H. 
(e) 
exo-7-Diphenylmethylenebicyclo[2.2.1]heptane-2-methyl(p-chlorophenyl)sulfo 
nate 
7.0 g (24.1 mmol) of alcohol from (d) and 5.7 g (26.6 mmol) of 
p-chlorobenzenesulfonyl chloride in 50 ml of methylene chloride are 
initially introduced. 2.7 g (26.6 mmol) of triethylamine are added 
dropwise to this at room temperature. After standing overnight, water is 
added, and the organic phase is separated off, washed once with water, 
dried and evaporated. 11.8 g of sulfonic ester remain as an oil. 
NMR: 6.9-7.9, m, 14H; 3.8, q, 2H, 
##STR16## 
0.9-2.5, m, 9H. (f) 
exo-2-(1-Imidazolomethyl)-7-diphenylmethylenebicyclo[2.2.1]heptane 
10.9 g (23.5 mmol) of sulfonic ester from (e) in 25 ml of DMF are added to 
2.3 g (25.8 mmol) of sodium imidazolide in 50 ml of DMF. The mixture is 
stirred at 50.degree. C. for 5 hours, allowed to stand overnight, then 
water is added and the mixture is extracted three times with 150 ml of 
methylene chloride each time. The methylene chloride phase is washed once 
with water, dried and evaporated. The residue (7.2 g) is induced to 
crystallize with cyclohexane/ethyl acetate. 3.0 g of imidazole derivative 
of melting point 170.degree. C. are obtained. Formula: 
##STR17## 
NMR: 7.1-7.5, m, 10H; 6.8, d, 2H; 6.4, s, 1H; 3.9, q, 2H; 1.0-2.6, m, 9H. 
EXAMPLE 4 
endo-2-(.alpha.-Keto-.beta.-imidazoloethyl)-7-diphenylmethylenebicyclo[2.2. 
1]heptane 
13.3 g (35 mmol) of 
endo-2-(bromoacetyl)-7-diphenylmethylenebicyclo[2.2.1]heptane (prepared in 
analogy to Ann. 566, 27 and Synthesis 1976, 194; the resulting crude 
product is used for the subsequent reaction) in 30 ml of DMF are added 
dropwise to 6.0 g (88 mmol) of imidazole in 150 ml of DMF, and the mixture 
is stirred at room temperature for 10 hours. Water is added, the mixture 
is extracted with methylene chloride, and the organic phase is washed once 
with water, dried and the solvent is removed in vacuo. 4.2 g of imidazole 
derivative are obtained as a pale yellow oil from the residue by column 
chromatography on silica gel. Formula: 
##STR18## 
NMR: 6.0-7.4, m, 1H; 6.6, d, 2H, 4.5, s, 2H; 1.0-3.0, m, 9H. 
EXAMPLE 5 
exo,endo-2-(1-Imidazolyl)-7-diphenylmethylenebicyclo[2.2.1]heptane 
(a) exo,endo-2-Chloro-2-cyano-7-diphenylmethylenebicyclo[2.2.1]hept-5-ene 
46 g (0.2 mol) of 6,6-diphenylfulvene and 17.6 g (0.2 mol) of 
.alpha.-chloroacrylonitrile are dissolved in 120 ml of toluene, and the 
solution is stirred at 80.degree. C. for 20 hours. The solvent is removed 
under waterpump vacuum, and the residue is recrystallized from 
isopropanol. 37.2 g of 
exo,endo-2-chloro-2-cyano-7-diphenylmethylenebicyclo-[2.2.1]hept-5-ene are 
obtained as colorless crystals of melting point 135.degree. C. 
NMR: 7.0-7.4, m, 10H; 6.3-6.8, m, 2H; 3.8-4.0, m, 1H; 3.4-3.7, m, 1H; 2.9, 
q, 1H; 1.8, d, 1H. 
(b) exo,endo-2-Chloro-2-cyano-7-diphenylmethylenebicyclo[2.2.1]heptane 
17.5 g (55 mmol) of the bicycloheptene derivative from (a) are hydrogenated 
in the presence of 1 g of Pd/C, at room temperature and under atmospheric 
pressure, until 1235 ml of hydrogen have been absorbed. After filtering 
off the catalyst and removal of the solvent, 17.6 g of bicycloheptane 
derivative remain as a solid of melting point 84.degree.-87.degree. C. 
NMR: 7.0-7.4, m, 10H; 1.3-3.2, m, 8H. 
(c) 7-Diphenylmethylenebicyclo[2.2.1]heptan-2-one 
17.5 g (55 mmol) of the bicycloheptane derivative from (b) are dissolved in 
170 ml of DMSO. 7.8 g (139.3 mmol) of KOH in 30 ml of water are added to 
this. The mixture is then stirred at room temperature for 3 hours. After 
addition of 800 ml of water, the mixture is extracted with methylene 
chloride, and the organic phase is dried and evaporated. The residue is 
recrystallized from isopropyl ether. 13.7 g of ketone of melting point 
88.degree. C. are obtained. 
NMR: 7.0-7.4, m, 10H; 3.1-3.4, m, 2H; 1.5-2.5, m, 6H. 
(d) exo,endo-7-Diphenylmethylenebicyclo[2.2.1]heptan-2-ol 
12.0 g (44 mmol) of the ketone from (c) are dissolved in a mixture of 50 ml 
of ethanol and 30 ml of tetrahydrofuran, and reduced with 1.2 g (33 mmol) 
of NaBH.sub.4 at room temperature for 5 hours. After addition of water, 
the mixture is extracted with methylene chloride. The organic phase is 
dried and evaporated. 11.8 g of the alcohol are obtained as an oil. 
NMR: 7.0-7.4, m, 10H; 3.5-4.5, m, exo- and endo-2-H; 1.0-2.8, m, 8H. 
(e) exo,endo-7-Diphenylmethylenebicyclo[2.2.1]heptan-2-methanesulfonate 
4.8 g (48.0 mmol) of triethylamine are slowly added to 11.5 g (42.8 mmol) 
of the alcohol from (d) and 5.4 g (47.0 mmol) of methanesulfonyl chloride 
in 100 ml of methylene chloride, and the mixture is stirred at room 
temperature for 16 h. After addition of 500 ml of water, the organic phase 
is separated off, dried and evaporated. 14.7 g of sulfonic ester are 
obtained as an oil. 
NMR: 7.0-7.4, m, 10H; 4.8-5.2, m, exo- and endo-2-H; 2.9, s, CH.sub.3 ; 
1.0-3.1, m, 8H. 
(f) exo,endo-2-(1-Imidazolyl)-7-diphenylmethylenebicyclo[2.2.1]heptane 
A solution of Na imidazolide in 50 ml of DMF is prepared from 3.1 g (45.7 
mmol) of imidazole and 1.4 g (45.7 mmol) of 80% sodium hydride. 14.7 g 
(41.5 mmol) of the sulfonic ester from (e) in 50 ml of DMF is added 
dropwise to this solution, and the mixture is stirred at 100.degree. C. 
for 7 days. After addition of water, the mixture is extracted with 
methylene chloride. The organic phase is dried and evaporated. The oily 
residue (12.7 g) is chromatographed on silica gel (mobile phase: 
cyclohexane ethyl acetate, 3:1). 1.2 g of the desired imidazole derivative 
is eluted as an oil from which, with hydrogen chloride in ether, 1.0 g of 
the corresponding salt, of melting point 160.degree. C., is obtained. 
Formula: 
##STR19## 
NMR: 8.8-9.0, s, 1H; 6.5-7.5, m, 13H; 5.4-5.7, m, 1H; 1.0-2.8, m, 8H. 
The following compounds of the formula I are prepared in an analogous 
manner (Examples 6 to 23). 
__________________________________________________________________________ 
No R.sup.1 R.sup.2 A B Config. 
n phys. data 
__________________________________________________________________________ 
6 CH.sub.3 
CH.sub.3 
= -- exo/endo 
1 158.degree. C. (+HCl) 
7 CH.sub.3 
CH.sub.3 
-- 
-- exo/endo 
1 Oil, NMR: 7.4,s,1H;6.9,d,2H;3.9u,3.6 
d, exo and endo-CH.sub.2Imidazole; 
0.7-2.8,m,9H;2.7,s CH.sub.3 ;2.6,d,CH.sub. 
3 
8 (CH.sub.2).sub.4 
= -- exo/endo 
1 Oil, NMR: 7.4,s,1H;6.9,d,2H;6.0-6.5, 
m,2H;3.5-4.0,m,exo and endo- 
CH.sub.2Imidazole;0.5-3.1,m,13H 
9 (CH.sub.2).sub.4 
-- 
-- exo/endo 
1 Oil, NMR: 7.4,s,1H;6.9,d,2H;3.4-4.0, 
m,exo and endo-CH.sub.2Imidazole; 
0.5-2.5,m,17H 
10 (CH.sub.2).sub.5 
= -- endo 1 48.degree. C. 
11 
##STR20## = -- endo 1 161.degree. C. 
12 
##STR21## -- 
-- endo 1 130.degree. C. 
13 
##STR22## 
##STR23## 
-- 
-- endo 0 160.degree. C. (+HCl) 
14 
##STR24## 
##STR25## 
= -- endo 1 140.degree. C. 
15 
##STR26## 
##STR27## 
-- 
-- endo 1 146.degree. C. 
16 
##STR28## 
##STR29## 
-- 
-- endo 1 165.degree. C. (.times.HCl) 
17 
##STR30## 
##STR31## 
-- 
-- exo 1 162.degree. C. (+HCl) 
18* 
##STR32## 
##STR33## 
-- 
CHOH 
endo 1 160.degree. C. (+HCl) 
19 
##STR34## 
##STR35## 
-- 
-- exo 1 210.degree. C. (+HCl) 
20 
##STR36## 
##STR37## 
-- 
-- endo 1 144.degree. C. 
21 
##STR38## 
##STR39## 
-- 
-- endo 1 152.degree. C. 
22 
##STR40## 
##STR41## 
-- 
-- endo 1 198.degree. C. (+HCl) 
23 
##STR42## 
##STR43## 
-- 
-- exo 1 Amorphous, NMR: 6.8-7.5,10H;6.4,s, 
1H;3.5,q,2H,exo-CH.sub.2Imidazole; 
0.7-2.8,m,9H. 
__________________________________________________________________________ 
*was obtained by reduction of the compound from Example 4 with NaBH in a 
manner known per se. 
For compounds 16, 17, 19 and 20, it is also possible for R.sup.2 to be 
unsubstituted and R.sup.1 to be phenylsubstituted by chlorine or fluorine. 
EXAMPLE 24 
exo-2-Carbonylimidazolyl-7-diphenylmethylenebicyclo[2.2.1]heptane 
(a) exo-7-Diphenylmethylenebicyclo[2.2.1]heptane-2-carboxylic acid 
8 (26.5 mmol) of 
exo-7-diphenylmethylenebicyclo[2.2.1]hept-5-ene-2-carboxylic acid were 
dissolved in 80 ml of tetrahydrofuran and hydrogenated under atmospheric 
pressure and at room temperature, in the presence of 1 g of Pd/C, until 
one equivalent of hydrogen had been absorbed. After filtering off the 
catalyst and evaporation of the solution, 8.1 g of the hydrogenated acid 
remained as an oil. 
NMR: 11.2, 1H; 6.9-7.4, m, 10H; 3.5-3.8, m, 2H; 1.0-3.2, m, 7H. 
(b) exo-2-Carbonylimidazolyl-7-diphenylmethylenebicyclo[2.2.1]heptane 
8.1 g (26.5 mmol) of the acid from (a) in 60 ml of tetrahydrofuran were 
initially introduced. 2 drops of pyridine were added, and 5.5 g (46 mmol) 
of thionyl chloride were added dropwise. The mixture was heated to reflux 
for two hours, the solvent was removed in vacuo, and 9.4 g of crude acid 
chloride were obtained. This was dissolved again in 50 ml of 
tetrahydrofuran and, at 0.degree.-5.degree. C., 6.9 g (102 mmol) of 
imidazole in tetrahydrofuran were added dropwise, and the mixture was 
stirred at room temperature for 24 hours and worked up with water and 
methylene chloride. 8.8 g of oil were obtained and distilled in a 
Kugelrohr (250.degree. C., 0.3 mbar). 4.5 g of pure imidazole derivative 
were thus obtained. Formula: 
##STR44## 
NMR: 8.1, s, 1H; 6.8-7.5, m, 10H; 3.2-3.8, m, 1H; 1.0-3.0, m, 8H. 
EXAMPLE 25 
exo,endo-2-(1-Imidazoloethyl)-7-diphenylmethylenebicyclo[2.2.1]heptane 
(a) Ethyl 
E,Z-7-diphenylmethylenebicyclo[2.2.1]heptane-2-methylenecarboxylate 
3.0 g (0.1 mol) of 80% sodium hydride in 250 ml of dimethoxyethane were 
initially introduced, and 22.5 g (0.1 mol) of triethyl phosphonoacetate in 
dimethoxyethane were added dropwise. After one hour, 27.5 g (0.1 mol) of 
ketone obtained according to Example 5(c), in dimethoxyethane, were added 
dropwise, and the mixture was then stirred at 50.degree. C. for 3 hours 
and worked up with water/methylene chloride. 35 g of product were obtained 
as an oil. 
NMR: 7.0-7.4, m, 10H; 5.6 and 5.8, m, 1H; 4.2, q, 2H; 3.3, m, 1H; 1.0-3.0, 
m, 7H; 1.3, t, 3H. 
(b) E,Z-7-Diphenylmethylenebicyclo[2.2.1]heptane-2-(ethyliden-2-ol) 
23 g (0.067 mol) of ester from (a), in THF were added dropwise to 3.8 g 
(0.1 mol) of lithium aluminum hydride in 100 ml of THF, and the mixture 
was stirred at 70.degree. C. for 8 hours and worked up with dilute 
hydrochloric acid/methylene chloride. After removal of the solvent, 21.6 g 
of crude product remained, from which 12.5 g of alcohol were isolated by 
column chromatography (silica gel, cyclohexane/ethyl acetate=5:1). 
NMR: 7.0-7.4, m, 10H; 5.4-5.6, m, 1H; 4.1, d, 2H; 3.2, m, 1H; 2.9, m, 1H; 
1.1-2.6, m, 6H. 
(c) exo,endo-7-Diphenylmethylenebicyclo[2.2.1]heptane-2-(ethyl-2-ol) 
6.8 g (22.5 mmol) of alcohol from (b) were dissolved in 100 ml of THF and 
hydrogenated in the presence of 1 g of Pd/C, at room temperature and under 
atmospheric pressure, until one equivalent of hydrogen had been absorbed. 
After filtering off the catalyst and removal of the solvent, 6.7 g of oil 
remained. 
NMR: 6.9-7.4, m, 10H; 3.3-3.8, m, 1H; 0.5-3.1, m, 12H. 
The alcohol from 25 (c) was reacted further to give the imidazole 
derivative in analogy to Example 3 e,f. 0.8 g of a colorless oil was 
obtained. 
Formula: 
##STR45## 
NMR: 6.6-7.5, m, 13H; 3.6-4.0, m, 2H; 0.6-2.8, m, 11H.