The cyclohexadiene derivatives are prepared by reaction of cyclohexanones with amines and subsequent dehydration. The compounds are suitable as active compounds in medicaments on account of their property of being selective modulators of calcium channel-dependent potassium channels.

The present invention relates to cyclohexadiene derivatives, a process for 
their preparation and their use as medicaments, in particular as 
cerebrally active agents. 
It is already known that 3,6-cyclohexadiene-2-phenyl-1,3-dicarboxylic acid 
esters have a muscle contraction-inhibiting action [cf. for this Chem. 
Pharm. Bull., 39 (11), 2915-23, 1991; GB 87-18906 870810/GB 87-19441 
870817]. 
The invention relates to cyclohexadiene derivatives of the general formulae 
(Ia and b), 
##STR1## 
in which A represents aryl having 6 to 10 carbon atoms or pyridyl, each of 
which is optionally substituted up to 3 times by identical or different 
substituents from the group consisting of nitro, cyano, cycloalkyl having 
3 to 7 carbon atoms, halogen and trifluoromethyl or straight-chain or 
branched alkylthio, alkyl or alkoxy in each case having up to 6 carbon 
atoms, 
R.sup.1 represents hydrogen or straight-chain or branched alkyl having up 
to 8 carbon atoms, 
R.sup.2 and R.sup.3 are identical or different and represent hydrogen or 
straight-chain or branched alkyl or acyl in each case having up to 6 
carbon atoms, 
D represents nitro or straight-chain or branched alkoxycarbonyl having up 
to 8 carbon atoms, 
and their salts. 
Preferred salts are physiologically acceptable salts. In general, these are 
salts of the compounds according to the invention with inorganic or 
organic acids. Preferred salts are those with inorganic acids such as, for 
example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric 
acid, or salts with organic carboxylic or sulphonic acids such as, for 
example acetic acid, malic acid, fumaric acid, malic acid, citric acid, 
tartaric acid, lactic acid, benzoic acid or methanesulphonic acid, 
ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or 
naphthalenedisulphonic acid. 
The compounds according to the invention can exist in stereoisomeric forms 
which behave either as image and mirror image (enantiomers) or which do 
not behave as image and mirror image (diastereomers). The invention 
relates both to the antipodes and to the racemic forms as well as the 
diastereomer mixtures. Like the diastereomers, the racemic forms can also 
be separated into the stereoisomerically uniform constituents in a known 
manner. 
Preferred compounds of the general formula (Ia or b) are those in which 
A represents phenyl, naphthyl or pyridyl, each of which is optionally 
substituted up to 3 times by identical or different substituents from the 
group consisting of nitro, cyano, fluorine, chlorine, bromine, iodine, 
cyclopentyl, cyclohexyl and trifluoromethyl or straight-chain or branched 
alkylthio, alkyl or alkoxy in each case having up to 4 carbon atoms, 
R.sup.1 represents hydrogen or straight-chain or branched alkyl having up 
to 6 carbon atoms, 
R.sup.2 and R.sup.3 are identical or different and represent hydrogen or 
straight-chain or branched alkyl or acyl in each case having up to 4 
carbon atoms, 
D represents straight-chain or branched alkoxycarbonyl having up to 6 
carbon atoms, 
and their salts. 
Particularly preferred compounds of the general formula (Ia or b) are those 
in which 
A represents phenyl or pyridyl, each of which is optionally substituted up 
to 3 times by identical or different substituents from the group 
consisting of nitro, cyano, fluorine, chlorine, bromine, iodine, 
trifluoromethyl, cyclohexyl, methyl and methoxy or methylthio, 
R.sup.1 represents hydrogen or straight-chain or branched alkyl having up 
to 4 carbon atoms, 
R.sup.2 and R.sup.3 are identical or different and represent hydrogen or 
straight-chain or branched alkyl or acyl in each case having up to 3 
carbon atoms, 
D represents straight-chain or branched alkoxycarbonyl having up to 4 
carbon atoms, 
and their salts. 
A process for the preparation of the compounds of the general formula (Ia 
or b) according to the invention has been found, characterized in that 
compounds of the general formula (II) 
##STR2## 
in which A and D have the meaning specified, and 
R.sup.1' has the meaning specified for R.sup.1, but does not represent 
hydrogen, are first converted by reaction with amines of the general 
formula (III) 
EQU R.sup.2 R.sup.3 NH (III) 
in which 
R.sup.2 and R.sup.3 have the meaning specified above, 
in inert solvents and in the presence of an auxiliary into the compounds of 
the general formula (IV) 
##STR3## 
in which A, D, R.sup.1', R.sup.2 and R.sup.3 have the meaning specified 
above, 
and in a second step reacted in an inert solvent, if appropriate in the 
presence of a base, and in the presence of a dehydrating auxiliary, 
and the double bond isomers obtained in this process are separated by 
chromatography and/or crystallization, 
and if R.sup.1 =H, the esters are hydrolysed by customary methods, 
and if R.sup.2 and/or R.sup.3 .noteq.H, an alkylation or acylation is 
carried out. 
The process according to the invention can be illustrated by way of example 
by the following reaction scheme: 
##STR4## 
Suitable solvents for the two process steps are all inert organic solvents 
which do not change under the reaction conditions. These preferably 
include alcohols such as methanol, ethanol, propanol or isopropanol, or 
ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl 
ether or diethylene glycol dimethyl ether, acetonitrile, or amides such as 
hexamethylphosphoramide or dimethylformamide, or halogenated hydrocarbon 
such as methylene chloride or carbon tetrachloride, or hydrocarbons such 
as benzene or toluene, or pyridine. It is also possible to use mixtures of 
the solvents mentioned. Toluene is particularly preferred for the first 
step and pyridine for the second step. 
In general, the amine is employed in an amount from 1 mol to 5 mol, 
preferably from 1 mol to 2 mol, relative to 1 mol of the compounds of the 
general formula (II). 
Suitable auxiliaries for the reaction of the compounds of the general 
formula (II) are in general organic sulphonic acids, such as 
p-toluenesulphonic acid, or anhydrous mineral acid such as phosphoric acid 
or sulphuric acid. p-Toluenesulphonic acid hydrate is preferred. 
The auxiliary is employed in an amount from 0.1 mol to 1 mol, preferably 
from 0.1 mol to 0.2 mol, in each case relative to 1 mol of the compounds 
of the general formulae (III) and (II). 
The reaction with amines of the general formula (III) is in general carried 
out in a temperature range from 10.degree. C. to 150.degree. C., 
preferably from 40.degree. C. to 80.degree. C. 
The reactions can be carried out at normal pressure, but also at elevated 
or reduced pressure (e.g. 0.5 to 3 bar). In general, the reaction is 
carried out at normal pressure. 
Suitable auxiliaries for the reaction with the compounds of the formula 
(IV) are carbodiimides such as, for example, diisopropylcarbodiimide, 
dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide 
hydrochloride, or carbonyl compounds such as carbonyldiimidazole or 
1,2-oxazolium compounds such as 
2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphonic anhydride 
or isobutyl chloroformate or 
benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or 
diphenyl phosphoramidate or methanesulphonyl chloride or thionyl chloride, 
trifluoroacetic anhydride, if appropriate in the presence of bases such as 
triethylamine, pyridine or N-ethylmorpholine or N-methylpiperidine or 
dicyclohexylcarbodiimide and N-hydroxysuccinimide, 
alkoxycarbonylsulphonyltrialkylammonium hydroxides, acetic 
anhydride/NaOAc/phosphoric acid, mineral acids, such as, for example, 
sulphuric acid, or organic sulphonic acids such as, for example, 
p-toluenesulphonic acid. Thionyl chloride/pyridine is preferred. 
The reaction of the compounds of the general formula (IV) is in general 
carded out in a temperature range from 0.degree. C. to 150.degree. C., 
preferably from 30.degree. C. to 80.degree. C. 
The reaction can be carried out at normal pressure, but also at elevated or 
reduced pressure (e.g. 0.5 to 3 bar). In general the reaction is carried 
out at normal pressure. 
Suitable solvents for the alkylation am also customary organic solvents 
which do not change under the reaction conditions. These preferably 
include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol 
dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, 
cyclohexane or petroleum fractions, or halogenohydrocarbons such as 
dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, 
trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, 
pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, 
acetonitrile, acetone or nitromethane. It is also possible to use mixtures 
of the solvents mentioned. Dimethylformamide is preferred. 
Suitable bases are in general alkali metal hydrides or alkoxides, such as, 
for example, sodium hydride or potassium tert-butoxide, or cyclic amines, 
such as, for example, piperidine, dimethylaminopyridine or C.sub.1 
-C.sub.4 -alkylamines, such as, for example, triethylamine. Sodium hydride 
is preferred. 
The reaction temperatures can be varied within a relatively wide range. In 
general the reaction is carried out between +10.degree. C. and 
+150.degree. C., preferably between +20.degree. C. and +100.degree. C., in 
particular at room temperature. 
The alkylation is carried out in the abovementioned solvents at 
temperatures from 0.degree. C. to +150.degree. C., preferably at room 
temperatures to +100.degree. C. 
The reactions can be carried out at normal pressure, but also at elevated 
or reduced pressure (e.g. 0.5 to 3 bar). In general the reactions are 
carried out at normal pressure. 
The base is in general employed in an amount from 1 mol to 5 mol, 
preferably from 1 mol to 2 mol, in each case relative to 1 mol of the 
compounds to be alkylated. 
Suitable bases for the acylation are inorganic or organic bases. These 
preferably include alkali metal hydroxides such as e.g. sodium hydroxide 
or potassium hydroxide, alkaline earth metal hydroxides such as e.g. 
barium hydroxide, alkali metal carbonates such as sodium carbonate or 
potassium carbonate, alkaline earth metal carbonates such as calcium 
carbonate, or organic amines, e.g. trialkyl(C.sub.1 -C.sub.6)amines such 
as triethylamine, or heterocycles such as pyridine, methylpiperidine, 
piperidine or morpholine. Triethylamine is particularly preferred. 
Suitable solvents for the acylation are also customary organic solvents 
which do not change under the reaction conditions. These preferably 
include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol 
dimethyl ether, or hydrocarbons such as benzene, toluene, xylene, hexane, 
cyclohexane or petroleum fractions, or halogenohydrocarbons such as 
dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, 
trichloroethylene or chlorobenzene, or ethyl acetate, or triethylamine, 
pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, 
acetonitrile, acetone or nitromethane. It is also possible to use mixtures 
of the solvents mentioned or even to employ the respective acylating agent 
as a solvent. Acetic anhydride and pyridine are preferred. 
The acylation in general proceeds in a temperature range from 0.degree. C. 
to +120.degree. C., preferably at +30.degree. C. to +90.degree. C. and at 
normal pressure. 
The hydrolysis of the carboxylic acid esters is carried out by customary 
methods, by treating the esters in inert solvents with customary bases. 
Suitable bases for the hydrolysis are the customary inorganic bases. These 
preferably include alkali metal hydroxides or alkaline earth metal 
hydroxides such as, for example, sodium hydroxide, potassium hydroxide or 
barium hydroxide, or alkali metal carbonates such as sodium carbonate or 
potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or 
potassium hydroxide is particularly preferably employed. 
Suitable solvents for the hydrolysis are water or the organic solvents 
customary for hydrolysis. These preferably include alcohols such as 
methanol, ethanol, propanol, isopropanol or butanol, or ethers such as 
tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. 
Alcohols such as methanol, ethanol, propanol or isopropanol are 
particularly preferably used. It is also possible to employ mixtures of 
the solvents mentioned. 
The hydrolysis is in general carried out in a temperature range from 
0.degree. C. to +100.degree. C., preferably from +20.degree. C. to 
+80.degree. C. 
In general, the hydrolysis is carried out at normal pressure. However, it 
is also possible to work at reduced pressure or at elevated pressure (e.g. 
from 0.5 to 5 bar). 
Enantiomerically pure forms are obtained e.g. by separating diastereomer 
mixtures of the compounds of the general formula (Ia or b) in which 
R.sup.1 is an optically active ester radical, by a customary method, then 
either directly transesterifying or first preparing the chiral carboxylic 
acids and then preparing the enantiomerically pure compounds by 
esterification. 
The separation of the diastereomers is in general carried out either by 
fractional crystallization, by column chromatography or by countercurrent 
distribution. Which is the optimum process must be decided from case to 
case; sometimes it is also expedient to use combinations of the individual 
processes. Separation by crystallization or countercurrent distribution or 
a combination of both processes is particularly suitable. 
The enantiomerically pure compounds are also accessible by chromatography 
of the racemic esters on chiral phases. 
The amines of the general formula (III) are known. 
The compounds of the general formula (IV) are known or can be prepared, for 
example, as described above. 
The compounds of the general formula (II) are known or can be prepared, for 
example, by reacting aldehydes of the general formula (V) 
EQU A--CHO (V) 
in which 
A has the meaning specified above, with two equivalents of the compounds of 
the general formula (VI) 
EQU H.sub.3 C--CO--CH.sub.2 --CO.sub.2 R.sup.1' (VI) 
in which 
R.sup.1' has the meaning specified above, 
in an organic solvent and in the presence of a base. 
Suitable solvents are all inert organic solvents which do not change under 
the reaction conditions. These preferably include alcohols such as 
methanol, ethanol, propanol or isopropanol, or ethers such as diethyl 
ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene 
glycol dimethyl ether, acetonitrile, or amides such as 
hexamethylphosphoramide or dimethylformamide, or acetic acid or 
halogenated hydrocarbons such as methylene chloride, carbon tetrachloride 
or hydrocarbons such as benzene or toluene. It is also possible to use 
mixtures of the solvents mentioned. Ethanol and methanol are particularly 
preferred. 
Suitable bases are in general alkaline metal hydrides or alkoxides, such 
as, for example, sodium hydride or potassium tert-butoxide, or cyclic 
amines, such as, for example, piperidine, dimethylaminopyridine or C.sub.1 
-C.sub.4 -alkylamines, such as, for example, triethylamine. Piperidine is 
preferred. 
The reactions can be carried out at normal pressure, but also at elevated 
or reduced pressure (e.g. 0.5 to 3 bar). In general the reactions are 
carried out at normal pressure. 
The reaction temperatures can be varied within a relatively wide range. In 
general the reaction is carded out between +10.degree. C. and +150.degree. 
C., preferably between +20.degree. C. and 100.degree. C., in particular at 
the boiling temperature of the respective solvent. 
The compounds of the general formulae (V) and (VI) are known per se or can 
be prepared by customary methods. 
The compounds of the general formula (Ia or b) according to the invention 
show an unforeseeable, useful spectrum of pharmacological action. 
They are modulators having selectivity for calcium-dependent potassium 
channels of high conductivity (BK(Ca) channels), in particular of the 
central nervous system. 
On account of their pharmacological properties, they can be employed for 
the production of medicaments for the treatment of degenerative central 
nervous system disorders, on occurrence of dementias such as multiinfarct 
dementia (MID), primary degenerative dementia (PDD), presenile and senile 
dementia of the Alzheimer's disease type, HIV dementia and other forms of 
dementia, for the treatment of Parkinson's disease, amyotropic lateral 
sclerosis and also multiple sclerosis and sickle cell anemia. 
The active compounds are furthermore suitable for the treatment of brain 
function disorders in old age, of organic brain syndrome (OBS) and of 
age-related memory disorders (age-associated memory impairment, AAMI). 
They are suitable for the prophylaxis and control of the sequelae of 
cerebral circulatory disorders such as cerebral ischaemias, strokes, 
craniocerebral traumata and subarachnoid haemorrhages. 
They are useful for the treatment of depressions and psychoses, e.g. 
schizophrenia. They are additionally suitable for the treatment of 
disorders of neuroendocrine secretion and of neurotransmitter secretion 
and health disorders connected therewith such as mania, alcoholism, drag 
abuse, dependence or abnormal eating behaviour. Other application areas 
are the treatment of migraine, sleep disorders and of neuropathy. They are 
moreover suitable as analgesics. 
The active compounds are furthermore suitable for the treatment of 
disorders of the immune system, in particular of T-lymphocyte 
proliferation and for affecting the smooth musculature, in particular of 
uterus, urinary bladder and bronchial tract and for the treatment of 
diseases connected therewith such as e.g. asthma and urinary incontinence 
and for the treatment of high blood pressure, arrhythmia, angina and 
diabetes. 
.sup.86 Rubidium Efflux from C6-BU1 Glioma Cells 
The experiments were carried out with slight changes according to the 
method described by Tas et al. (Neurosci. Lett. 94, 279-284, (1988). Rat 
C6-BU1 glioma cells are used for this. 
From the data collected by liquid scintillation, the increase in the efflux 
produced by ionomycin above the basal efflux is calculated and set as 
100%. The stimulations in the presence of test substances are then related 
to this value. 
The present invention also includes pharmaceutical preparations which, in 
addition to inert, non-toxic, pharmaceutically suitable auxiliaries and 
excipients, contain one or more compounds of the general formula (I), or 
which consist of one or more active compounds of the formula (I), and 
processes for the production of these preparations. 
The active compounds of the formula (I) should be present in these 
preparations in a concentration from 0.1 to 99.5% by weight, preferably 
from 0.5 to 95% by weight of the total mixture. 
In addition to the active compounds of the formula (I), the pharmaceutical 
preparations can also contain other pharmaceutical active compounds. 
The abovementioned pharmaceutical preparations can be prepared in a 
customary manner by known methods, for example using the auxiliary(ies) or 
excipient(s). 
In general, it has proven advantageous to administer the active compound(s) 
of the formula (I) in total amounts of about 0.01 to about 100 mg/kg, 
preferably in total amounts of about 1 mg/kg to 50 mg/kg of body weight 
every 24 hours, if appropriate in the form of several individual doses, to 
achieve the desired result. 
However, if appropriate it may be advantageous to deviate from the amounts 
mentioned, namely depending on the nature and the body weight of the 
subject treated, on individual behaviour towards the medicament, the 
nature and severity of the disorder, the type of preparation and 
administration, and the time or interval at which administration takes 
place. 
______________________________________ 
Mobile phase mixtures: 
______________________________________ 
a Methylene chloride/AcOEt 10 + 1 
b Methylene chloride/MeOH 10 + 1 
c PE/AcOEt 7 + 3 
d PE/AcOEt 1 + 1 
______________________________________

STARTING COMPOUNDS 
Example I 
Diethyl 
4-hydroxy-4-methyl-2-(3-nitrophenyl)-6-oxo-cyclohexane-1,3-dicarboxylate 
##STR5## 
45.3 g (0.3 mol) of 3-nitrobenzaldehyde and 78 g (0.6 mol) of ethyl 
acetoacetate are dissolved in 300 ml of ethanol and treated with 6 ml of 
piperidine. The mixture is then stirred at 40.degree. C. for 24 h. The 
precipitated solid is filtered off with suction and recrystallized from 
ethanol. 85.4 g of the title compound (72% yield) are obtained. 
Example II 
Diethyl 
6-hydroxy-6-methyl-4-methylamino-2-(3-nitrophenyl)-cyclohex-3-ene-1,3-dica 
rboxylate 
##STR6## 
Variant A 
19.7 g (50 mmol) of the compound from Example I are dissolved in 200 ml of 
ethanol and treated with 30 ml of a 11N methanolic methylamine solution 
and 1 g of TsOH hydrate. The mixture is then stirred at 
60.degree.-65.degree. C. for 2 h. After concentrating the reaction 
mixture, the residue is chromatographically purified (methylene chloride) 
on 100 g of silica gel. The eluate is concentrated and recrystallized from 
diisopropyl ether. 17.0 g (84% of theory) of the title compound are 
obtained. M.p.: 112.degree. C. (diisopropyl ether). 
PREATION EXAMPLES 
Example 1 
Diethyl 
4-methyl-6-methylamino-2-(3-nitrophenyl)cyclohexa-3,6-diene-1,3-dicarboxyl 
ate 
##STR7## 
2.5 g (6.2 mmol) of the compound from Example II are initially introduced 
into 30 ml of pyridine, heated to 80.degree. C. and treated with 0.95 g 
(80 mmol) of thionyl chloride. The mixture is kept at this temperature for 
20 min and heated at reflux for a further 20 min. It is then concentrated 
and the residue is taken up in methylene chloride/water. The organic phase 
is separated off, dried over MgSO.sub.4 and concentrated. Chromatographic 
purification on silica gel (methylene chloride:ethyl acetate 20+1) and 
recrystallization from isopropanol/n-heptane yield 0.8 g of the title 
compound (33% of theory). 
The double bond isomers in each case obtained in this process are separated 
by chromatography and/or crystallization. The yields specified relate to 
isolated products. 
Examples 2 and 3 
Dimethyl 
4-methyl-6-methylamino-2-(4-trifluoromethyl-phenyl)cyclohexa-3,6-diene-1,3 
dicarboxylate (2) 
Dimethyl 
6-methyl-4-methylamino-2-(4-trifluoromethyl-phenyl)cyclohexa-3,5-diene-1,3 
-dicarboxylate (3) 
##STR8## 
10.0 g (25 mmol) of dimethyl 
6-hydroxy-6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohex-3-en 
e-1,3-dicarboxylate (preparation analogous to Example II) are heated to 
60.degree. C. in 100 ml of pyridine and treated with 2.5 ml of thionyl 
chloride. The mixture is stirred at 60.degree. C. for 10 minutes and 
concentrated, and the residue is taken up in methylene chloride, washed 
three times with water, dried and concentrated. The residue is grossly 
purified on 200 g of silica gel (petroleum ether/AcOEt=3:1) and then 
separated by MPLC (methylene chloride/AcOEt=30:1). Two fractions are 
obtained. 224 mg (2.3%) of dimethyl 
4-methyl-6-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,6-diene-1,3 
-dicarboxylate (non-polar isomer (2)) crystallize from ether/petroleum 
ether. From the 2nd fraction, 2.29 g (22%) of the polar isomer, dimethyl 
6-methyl-4-methylamino-2-(4-trifluoromethylphenyl)-cyclohexa-3,5-diene-1,3 
-dicarboxylate (3) are precipitated from AcOEt as the hydrochloride 
(R.sub.f =0.47 (c)). 
The compounds mentioned in Tables 1 and 2 are prepared in analogy to the 
preparation procedures mentioned above. 
TABLE 1 
______________________________________ 
##STR9## 
Yield 
Ex. No. 
D R.sup.1 R.sub.f * 
(% of theory) 
X 
______________________________________ 
4 CO.sub.2 CH.sub.3 
CH.sub.3 
0.36 (c) 
7% 3-NO.sub.2 
5 CO.sub.2 CH.sub.3 
CH.sub.3 
0.34 (c) 
10% 4-NO.sub.2 
______________________________________ 
TABLE 2 
______________________________________ 
##STR10## 
Yield 
Ex. No. L T R.sub.f * 
(% of theory) 
______________________________________ 
6 3-NO.sub.2 
H 0.33 (c) 
17 
7 4-Cl H 0.44 (c) 
9 
8 2-Cl 3-Cl 0.40 (c) 
25 
9 4-NO.sub.2 
H 0.31 (c) 
15 
______________________________________