Dihydropyridine compounds and their use in reducing blood sugar

Blood-sugar-lowering dihydropyridines of the formula ##STR1## in which R.sup.1 represents phenyl, naphthyl, thienyl, pyridyl, chromenyl or thiochromenyl, it being possible for the radicals mentioned each to carry up to 2 identical or different substituents from the series comprising halogen, alkyl, alkoxy and alkylthio with in each case up to 6 carbon atoms, fluoroalkyl and fluoroalkoxy with in each case up to 3 carbon atoms and 3 fluorine atoms, nitro and cyano, PA0 R.sup.2 represents straight-chain, branched or cyclic alkyl which has up to 8 carbon atoms, can be interrupted in the alkyl chain by an oxygen or a sulphur atom and can be substituted by halogen, phenyl, cyano, hydroxyl, amino, alkylamino or dialkylamino with in each case up to 3 carbon atoms per alkyl group or by N-benzylmethylamino, PA0 R.sup.3 represents straight-chain, branched or cyclic alkyl which has up to 6 carbon atoms, can be interrupted in the alkyl chain by an oxygen atom and can be substituted by halogen, hydroxyl, amino, phenyl, morpholino, carboxy or alkoxycarbonyl with up to 4 carbon atoms and PA0 R.sup.4 and R.sup.5 each represent hydroxyl, or PA0 R.sup.4 and R.sup.5 together represent --O--, or a physiologically acceptable salt thereof.

The invention relates to dihydropyridine compounds, processes for their 
preparation and their use in medicaments, in particular medicaments which 
influence the blood sugar. 
The present invention relates to dihydropyridine compounds of the general 
formula (I) 
##STR2## 
in which R.sup.1 represents phenyl, naphthyl, thienyl, pyridyl, chromenyl 
or thiochromenyl, it being possible for the radicals mentioned each to 
carry up to 2 identical or different substituents from the series 
comprising halogen, alkyl, alkoxy and alkylthio with in each case up to 6 
carbon atoms, fluoroalkyl and fluoroalkoxy with in each case up to 3 
carbon atoms and 3 fluorine atoms, nitro and cyano, 
R.sup.2 represents straight-chain, branched or cyclic alkyl which has up to 
8 carbon atoms, can be interrupted in the alkyl chain by an oxygen or a 
sulphur atom and can be substituted by halogen, phenyl, cyano, hydroxyl, 
amino, alkylamino or dialkylamino with in each case up to 3 carbon atoms 
per alkyl group or by N-benzylmethylamino, 
R.sup.3 represents straight-chain, branched or cyclic alkyl which has up to 
6 carbon atoms, can be interrupted in the alkyl chain by an oxygen atom 
and can be substituted by halogen, hydroxyl, amino, phenyl, morpholino, 
carboxy or alkoxycarbonyl with up to 4 carbon atoms and 
R.sup.4 and R.sup.5 each represent hydroxyl, or 
R.sup.4 and R.sup.5 together represent --O--, 
in the form of their isomers, isomer mixtures, optical antipodes or 
racemates, and their physiologically acceptable salts. 
Preferred compounds of the general formula (I) which may be mentioned are 
those 
in which 
R.sup.1 represents phenyl or thienyl, it being possible for the radicals 
mentioned to carry up to 2 identical or different substituents from the 
series comprising fluorine, chlorine, alkyl, alkoxy with in each case up 
to 3 carbon atoms, trifluoromethyl, nitro and cyano, 
R.sup.2 represents straight-chain or branched alkyl which has up to 6 
carbon atoms, can be interrupted by an oxygen atom in the alkyl chain and 
can be substituted by fluorine, chlorine or phenyl, 
R.sup.3 represents straight-chain or branched alkyl which has up to 6 
carbon atoms and can be substituted by hydroxyl or alkoxycarbonyl with up 
to 2 carbon atoms and 
R.sup.4 and R.sup.5 each represent hydroxyl, or 
R.sup.4 and R.sup.5 together represent --O--, 
in the form of their isomers, isomer mixture, optical antipodes or 
racemates, and their physiologically acceptable salts. 
Particularly preferred compounds of the general formula (I) which may be 
mentioned are those 
in which 
R.sup.1 represents phenyl, which can be substituted by up to 2 identical or 
different substituents from the group comprising chlorine, alkyl with up 
to 3 carbon atoms, trifluoromethyl or nitro, 
R.sup.2 represents straight-chain or branched alkyl which has up to 4 
carbon atoms and can be interrupted in the alkyl chain by an oxygen atom, 
R.sup.3 represents straight-chain or branched alkyl with up to 4 carbon 
atoms and 
R.sup.4 and R.sup.5 each represent hydroxyl, or 
R.sup.4 and R.sup.5 together represent --O--, 
in the form of their isomers, isomer mixtures, optical antipodes or 
racemates and their physiologically acceptable salts. 
The compounds according to the invention exist in stereoisomeric forms 
which either behave as mirror images (enantiomers) or do not behave as 
mirror images (diastereomers). The invention relates both to the antipodes 
and to the racemic forms as well as the diastereomer mixtures. The racemic 
forms, like the diastereomers, can be resolved into the stereoisomerically 
uniform constituents in a known manner (compare E. L. Eliel, 
Stereochemistry of Carbon Compounds, McGraw Hill, 1962). 
The dihydropyridinedicarboxylic anhydrides in the context of the general 
formula (I) correspond to the formula (Ia) 
##STR3## 
and the dihydropyridinedicarboxylic acids in the context of the general 
formula (I) correspond to the formula (Ib) 
##STR4## 
The compounds according to the invention can be in the form of their salts. 
Physiologically acceptable salts of the dihydropyridinedicarboxylic acid 
anhydrides are in general salts of the substances (Ia) according to the 
invention with inorganic or organic salts. Examples which may be mentioned 
are: hydrohalides, bisulphates, sulphates, hydrogen phosphates, acetates, 
maleates, citrates, fumarates, tartrates, lactates or benzoates. 
Physiologically acceptable salts of the dihydropyridinedicarboxylic acids 
(Ib) can be metal salts or ammonium salts of the substances according to 
the invention. Particularly preferred salts are, for example, the sodium, 
potassium, magnesium or calcium salts, and ammonium salts which are 
derived from ammonia or organic amines, such as, for example, ethylamine, 
di- or tri-ethylamine, di- or triethanolamine, dicyclohexylamine, 
dimethylaminoethanol, arginine or ethylenediamine. 
The dihydropyridinedicarboxylic acid anhydrides of the general formula (Ia) 
according to the invention can be prepared by a process in which 
dihydropyridine-lactols of the general formula (II) 
##STR5## 
in which R.sup.1, R.sup.2 and R.sup.3 have the meaning given, are oxidized 
in inert solvents. 
If ethyl 
4-(2-chlorophenyl)-1-ethyl-7-hydroxy-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro 
[3,4-b]pyridine-3-carboxylate is used as the starting substance, the 
reaction can be illustrated by the following equation: 
##STR6## 
The oxidation is in general carried out with dimethylsulphoxide as the 
oxidizing agent in the presence of an activating agent in suitable 
solvents. 
Activating agents which can be employed are carboxylic acid anhydrides, 
preferably acetic anhydride or trifluoroacetic anhydride, carboxylic acid 
halides, preferably oxalyl chloride, or 
dicyclohexylcarbodiimide/phosphoric acid, pyridinesulphurtrioxide-complex, 
phosphorus pentoxide or chlorosulphonyl isocyanate. 
Suitable solvents are the customary solvents which do not change under the 
reaction conditions. These include, preferably, hydrocarbons, such as 
benzene, toluene, xylene or hexane, or ethers, such as diethyl ether, 
dioxane or tetrahydrofuran, or halogenohydrocarbons, such as methylene 
chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane or 
1,2-dichloroethylene, or mixtures of the solvents mentioned. 
The oxidation is particularly preferably carried out with 
dimethylsulphoxide as the oxidizing agent in the presence of 
trifluoroacetic anhydride. It has proved advantageous here for 
dimethylsulphoxide to be simultaneously used as the solvent in a large 
excess. 
The oxidation can moreover also be carried out with oxidizing agents such 
as chromium(VI) compounds, preferably with chromium(VI) oxide in dilute 
sulphuric acid/acetone, acetic acid or pyridine, and sodium dichromate or 
potassium dichromate, manganese dioxide or potassium permanganate, such as 
is described in Houben-Weyl's "Methoden der organischen Chemie" ("Methods 
of Organic Chemistry") Volume IV/1a, 1b. 
The process according to the invention is in general carried out in a 
temperature range from -30.degree. C. to +60.degree. C., preferably from 
-10.degree. C. to +30.degree. C. 
The process according to the invention is in general carried out under 
normal pressure, but it is also possible for the process to be carried out 
under reduced pressure or under increased pressure. 
The process according to the invention can be carried out, for example, as 
follows: 
The dihydropyridine-lactol is dissolved in an excess of dimethylsulphoxide, 
and trifluoroacetic anhydride is added, with cooling. When the reaction is 
added, the mixture is worked up in the customary manner by extraction, 
chromatography and/or crystallization. 
The compounds of the general formula (Ib) according to the invention 
##STR7## 
can be prepared by a process in which dihydropyridinedicarboxylic acid 
anhydrides of the general formula (Ia) in which 
R.sup.1, R.sup.2 and R.sup.3 have the meaning given, are hydrolyzed and if 
appropriate the free acids are converted into their salts. 
If ethyl 
4-(2-chlorophenyl)-5,7-dioxo-1-ethyl-2-methyl-1,4,5,7-tetrahydrofuro[3,4-b 
]pyridine-3-carboxylate is used as the starting substance, the process can 
be illustrated by the following equation: 
##STR8## 
The hydrolysis is in general carried out with the aid of bases in suitable 
solvents. 
Suitable bases are the customary basic compounds. These include, 
preferably, alkali metal or alkaline earth metal hydroxides, such as 
sodium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal 
carbonates, such as sodium carbonate, sodium bicarbonate or potassium 
carbonate, or alkali metal alcoholates, such as sodium methanolate, 
potassium methanolate, sodium ethanolate, potassium ethanolate or 
potassium tert.-butylate, or ammonia or organie amines, such as 
triethylamine or diisopropylamine. 
Suitable solvents are the customary solvents which do not change under the 
reaction conditions. These include, preferably, water of alcohols, such as 
methanol, ethanol, propanol, isopropanol or butanol, or ethers, such as 
diethyl ether, dioxane or tetrahydrofuran, or dimethylformamide, 
hexamethylphosphoric acid triamide, acetone or acetonitrile. It is also 
possible to use mixtures of the solvents mentioned. 
The hydrolysis is particularly preferably carried out with aqueous alkali 
metal hydroxide solutions, such as, for example, potassium hydroxide 
solution or sodium hydroxide solution in alcohols, such as, for example, 
methanol, ethanol, propanol, isopropanol or butanol, as the solvent. 
The hydrolysis is carried out in a temperature range from 0.degree. C. to 
+100.degree. C., preferably from +20.degree. C. to +60.degree. C. 
The hydrolysis can be carried out under normal pressure, under increased 
pressure or under reduced pressure. It is in general carried out under 
normal pressure. 
The base is in general employed in an amount of 2 to 6 mols, preferably 2 
to 4 mols per mol of the dihydropyridinedicarboxylic acid anhydride. 
It has proved advantageous here to use the base in an amount of at least 2 
mols per mol of the dihydropyridinedicarboxylic acid anhydride and to 
prepare the corresponding salts in one step. 
The process can be carried out, for example, as follows: 
The dihydropyridinedicarboxylic acid anhydride is dissolved in a suitable 
solvent, and the corresponding base is added. Working up is effected in 
the customary manner. 
The dihydropyridine-lactols of the general formula (II) employed as 
starting substances can be prepared by a process in which 
[A] formyl compounds of the general formula (III) 
##STR9## 
in which R.sup.1, R.sup.2 and R.sup.3 have the meaning given and 
R.sup.6 represents straight-chain or branched alkyl with up to 8 carbon 
atoms, 
are reacted first with a base and then with an acid in suitable solvents, 
or by a process in which 
[B] dihydropyridine-lactones of the general formula (IV) 
##STR10## 
in which R.sup.1, R.sup.2 and R.sup.3 have the meaning given, are 
brominated in suitable solvents, if appropriate in the presence of a base, 
and then hydrolyzed, or hydroxylated directly. 
The preparation by process A or B of the starting substances (II) used 
according to the invention can be illustrated by the following equations, 
depending on the nature of the starting substances (III) and (IV) used: 
##STR11## 
Process A: 
Suitable solvents are water and all the organic solvents which do not 
change under the reaction conditions. These include, preferably, alcohols, 
such as methanol, ethanol, propanol, isopropanol or butanol, or ethers, 
such as diethyl ether, dioxane, tetrahydrofuran or glycol mono- or 
dimethyl ether, or acetonitrile, pyridine, dimethylformamide, 
dimethylsulphoxide or hexamethylphosphoric acid triamide. It is also 
possible to use mixtures of the solvents mentioned. 
Suitable bases are the customary inorganic or organic bases. These include, 
preferably, alkali metal hydroxides, such as sodium hydroxide or potassium 
hydroxide, or alkali metal alcoholates, such as sodium methylate, sodium 
ethylate, potassium methylate, potassium ethylate or potassium 
tert.-butylate, or alkali metals, such as sodium, or alkali metal 
hydrides, such as sodium hydride or potassium hydride, or alkali metal 
amides, such as sodium amide or lithium diisopropylamide. 
Possible acids are the customary organic or inorganic acids. These include, 
preferably, mineral acids, such as hydrochloric acid, hydrobromic acid, 
sulphuric acid or phosphoric acid, or organic carboxylic acids, such as 
acetic acid. 
The procedure is carried out by first reacting the formyl compounds of the 
formula (III) with 100 to 5 mols, preferably with 50 to 10 mols, of base 
per mol of formyl compound in suitable solvents and then treating the 
reaction mixture with acids. The mixture is worked up in the customary 
manner. 
The reaction is in general carried out at temperatures from 0.degree. C. to 
+150.degree. C., preferably from +20.degree. C. to +100.degree. C. 
The reaction can be carried out under normal pressure or under increased or 
reduced pressure. It is in general carried out under normal pressure. 
The formyl compounds of the general formula (III) employed as starting 
compounds are known or can be prepared by known methods [DOS (German 
Published Specification) No. 2,629,892]. 
Process B: 
The bromination is carried out with the customary brominating agents, such 
as N-bromosuccinimide or bromine, preferably with bromine. 
Suitable bases here are the customary basic compounds. These include, 
preferably, alkali metals, such as sodium or potassium, alkali metals 
hydrides, such as sodium hydride or potassium hydride, alkali metal 
amides, such as sodium amide or lithium diisopropylamide, or 
organometallic compounds, such as phenyllithium, n-butyllithium, 
sec.-butyllithium or tert.-butyllithium, or alcoholates, such as sodium 
ethanolate, sodium ethanolate, potassium methanolate, potassium ethanolate 
or potassium tert.-butanolate. 
Suitable solvents are all the organic solvents which do not change under 
the reaction conditions. These include, preferably, ethers, such as 
diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons, such as 
benzene, toluene, xylene, hexane or cyclohexane, or petroleum fractions. 
It is also possible to use mixtures of the solvents mentioned. 
The bromination is carried out in a temperature range from -120.degree. C. 
to +100.degree. C., preferably from -80.degree. C. to +50.degree. C. 
The bromination can be carried out, for example, by first producing an 
anion with 5 to 1 mol, preferably with 2 to 1 mol and particularly 
preferably with 1 mol, of base per mol of the starting compound (IV) and 
converting this anion into the bromide by means of bromine. Subsequent 
conversion of the bromine compound into the corresponding hydroxy compound 
of the general formula (II) is advantageously carried out without 
isolation of the bromine compound. The hydrolysis is carried out by water, 
if appropriate in the presence of traces of an acid, such as, for example, 
hydrochloric acid or sulphuric acid, in a manner which is known per se. 
Process B can be carried out either under normal or under increased or 
reduced pressure. It is in general carried out under normal pressure. 
However, the conversion of the compound (IV) into the compounds (II) can 
also be carried out by other methods which are known from the literature 
and is not limited to the processes described. 
The hydroxylation can likewise be carried out by 2-sulphonyloxaziridine, 
with molybdenum peroxide/pyridine/phosphate or with oxygen/phosphite, in 
each case in the presence of bases in inert organic solvents, such as is 
described, for example, by E. Vedejs in J. Am. Chem. Soc. 96, 5944 (1974) 
or J. Org. Chem. 43, 188 (1978) or by J. M. Billmers, J. Finn in J. Org. 
Chem. 49, 3243 (1984) or by H. H. Wassermann, B. H. Lipschutz in 
Tetrahedron Letters 1975, 1731. 
The lactones of the general formula (IV) used as starting compounds are 
known or can be prepared by known methods [DOS (German Published 
Specification) No. 3,410,645]. 
The compounds of the general formula (I) according to the invention exhibit 
a useful pharmacological action spectrum. 
The hypoglycaemic action of the substances to be investigated was tested on 
male Wistar rats weighing between 140 and 190 g. For this purpose, the 
rats were fasted for 18 hours before administration of the substances. The 
substances to be investigated were dissolved in pure dimethylsulphoxide 
directly before administration. Pure dimethylsulphoxide (control animals) 
and the substances dissolved in dimethylsulphoxide were administered 
intravenously into the tail veins of the rats. 
Blood was withdrawn from each rat from the retroorbital venus plexus 30, 60 
and 120 minutes after the administration. 30 .mu.l portions of blood were 
withdrawn with an automatic diluter and deproteinated with 0.3 ml of 
uranyl acetate (0.16%). After centrifugation, the glucose in the 
supernatant was determined photometrically on a Gemsaec Fast Analyzer by 
the glucose oxidase method using 4-amino-phenazone as the colour reagent. 
The results were evaluated by the Student t-test, and p&lt;0.05 was chosen as 
the significance limit. 
Substances which effected a significant reduction in the blood glucose 
concentration of at least 10% at a point in time in the rats, compared 
with the control group which only received dimethylsulphoxide 
intravenously, were described as active. 
The following Table 1 contains the changes found in the blood glucose 
concentrations as a percentage of the control. 
TABLE 1 
______________________________________ 
Decrease in blood glucose 
concentration in % of the 
Substance control 
(Example No.) 
1 mg/kg of body weight i.v. 
______________________________________ 
2 22 
3 23 
______________________________________ 
The present invention includes pharmaceutical formulations which, in 
addition to non-toxic inert pharmaceutically suitable excipients, contain 
one or more compounds according to the invention or consist of one or more 
active compounds according to the invention and also includes processes 
for the preparation of these formulations. 
The present invention also includes pharmaceutical formulations in dosage 
units. This means that the formulations are in the form of individual 
parts, for example tablets, dragees, capsules, pills, suppositories and 
ampules,. the active compound content of which corresponds to a fraction 
or a multiple of an individual dose. The dosage units can contain, for 
example, 1, 2, 3 or 4 individual doses or 1/2, 1/3, or 1/4 of an 
individual dose. An individual dose preferably contains the amount of 
active compound which is given in one administration and which usually 
corresponds to a whole or one half, one third or one quarter of a daily 
dose. 
By non-toxic inert pharmaceutically suitable excipients there are to be 
understood solid, semi-solid or liquid diluents, fillers for formulation 
auxiliaries of all types. 
Tablets, dragees, capsules, pills, granules, suppositories, solutions, 
suspensions and emulsions, pastes, ointments, gels, creams, lotions, 
powders and sprays may be mentioned as preferred pharmaceutical 
formulations. 
Tablets, dragees, capsules, pills and granules can contain the active 
compound or compounds alongside the customary excipients, such as (a) 
fillers and extenders, for example starch, lactose, sucrose, glucose, 
mannitol and silicic acid, (b) binders, for example 
carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) 
humectants, for example glycerol, (d) disintegrating agents, for example 
agar-agar, calcium carbonate and sodium carbonate, (e) solution retarders, 
for example paraffin, and (f) absorption accelerators, for example 
quaternary ammonium compounds, (g) wetting agents, for example cetyl 
alcohol or glycerol monostearate, (h) adsorbents, for example kaolin and 
bentonite, and (i) lubricants, for example talc, calcium stearate, 
magnesium stearate and solid polyethylene glycols, or mixtures of the 
substances listed under (a) to (i). 
The active compound or compounds, if appropriate with one or more of the 
abovementioned excipients, can also be in microencapsulated form. 
Suppositories can contain, alongside the active compound or compounds, the 
customary water-soluble or water-insoluble excipients, for example 
polyethylene glycols, fats, for example cacao fat, and higher esters (for 
example C.sub.14 -alcohol with C.sub.16 -fatty acid), or mixtures of these 
substances. 
Solutions and emulsions can contain, alongside the active compound or 
compounds, the customary excipients, such as solvents, solubilizing agents 
and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, 
ethyl carbonate, ethyl acetate, benzyl alcohol, dimethylformamide, oils, 
in particular cottonseed oil, groundnut oil, maize germ oil, olive oil, 
castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl 
alcohol, polyethylene glycols and fatty acid esters of sorbitan, or 
mixtures of these substances. 
For parenteral administration, the solutions and emulsions can also be in a 
sterile form which is isotonic with blood. 
Suspensions can contain, alongside the active compound or compounds, the 
customary excipients, such as liquid diluents, for example water, ethyl 
alcohol or propylene glycol, or suspending agents, for example ethoxylated 
isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, 
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar 
and tragacanth, or mixtures of these substances. 
The formulation forms mentioned can also contain colouring agents, 
preservatives and smell- and taste-improved additives, for example 
peppermint oil and eucalyptus oil, and sweeteners, for example saccharin. 
The therapeutically active compounds should preferably be present in the 
abovementioned pharmaceutical formulations in a concentration of about 0.1 
to 99.5, preferably about 0.5 to 95 percent by weight of the total 
mixture. 
The abovementioned pharmaceutical formulations can also contain other 
pharmaceutical active compounds in addition to the compounds according to 
the invention. 
The abovementioned pharmaceutical formulations are prepared in the 
customary manner by known methods, for example by mixing the active 
compound or compounds with the excipient or excipients. 
The present invention also includes the use of the compounds of the general 
formula (I) and/or salts thereof, and pharmaceutical formulations thereof 
which contain the compounds of the formula (I) and/or salts thereof in 
human and veterinary medicine for the prevention, alleviation and/or cure 
of the abovementioned diseases. 
In general, it has proved advantageous both in human medicine and in 
veterinary medicine in administer the active compound or compounds 
according to the invention in total amounts of about 0.5 to 500, 
preferably 50 to 100 mg/kg of body weight every 24 hours, if appropriate 
in the form of several individual doses, in order to achieve the desired 
results. An individual dose preferably contains the active compound or 
compounds according to the invention in amounts of about 1 to about 80, in 
particular 3 to 30 mg/kg of body weight. However, it may be necessary to 
deviate from the dosages mentioned, and in particular to do so as a 
function of the nature and body weight of the subject to be treated, the 
nature and severity of the disease, the nature of the formulation and of 
the administration of the medicament and the period or interval within 
which administration takes place. 
Thus in some cases it may be sufficient to manage with less than the 
abovementioned amount of active compound, whilst in other cases the 
abovementioned amount of active compound must be exceeded. The particular 
optimum dosage and mode of administration required for the active 
compounds can easily be specified by any expert on the basis of his expert 
knowledge.

PREATION EXAMPLES 
I. Starting substance 
Example 1 
Isopropyl 
4-(2-chlorophenyl)-1-ethyl-7-hydroxy-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro 
[3,4-b]pyridine-3-carboxylate 
##STR12## 
Process A: 
5 mmol of 3-methyl 5-isopropyl 
4-(2-chlorophenyl)-1-ethyl-2-formyl-6-methyl-1,4-dihydropyridine-3,5-dicar 
boxylate are taken in 40 mmol of 2N KOH and the mixture is warmed briefly 
at 40.degree. C. in a waterbath. It is then subsequently stirred at room 
temperature for one hour. The solution is clarified with active charcoal 
and acidified with hydrochloric acid and the precipitate is filtered off 
with suction. 
Yield: 30% of theory. 
Melting point: 145.degree.-147.degree. C. 
Process B: 
60 mmol of diisopropylamine are taken in 100 ml of tetrahydrofuran. 50 mmol 
of butyllithium are added at a temperature of 0.degree. C. under a stream 
of nitrogen. The mixture is then cooled to -78.degree. C. and a solution 
of 50 ml of isopropyl 
4-(2-chlorophenyl)-1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyr 
idine-3-carboxylate (dissolved in tetrahydrofuran) is added dropwise. The 
mixture is stirred at -78.degree. C. for 15 minutes, and this solution is 
pumped into a solution of 50 mmol of Br.sub.2 and 50 ml of tetrahydrofuran 
with the aid of nitrogen, 50 mmol of cyclohexane are then immediately 
added, the mixture is allowed to warm to room temperature and is 
concentrated, the residue is dissolved in dimethylsulphoxide and water is 
added until the solution starts to become cloudy. The mixture is left to 
stand for 2 hours and the product is precipitated with water, filtered off 
with suction and separated with CHCl.sub.3 /MeOH 9:1 on silica gel. 
Yield: 30% of theory. 
Melting point: 145.degree.-147.degree. C. 
II. End product 
Example 2 
Isopropyl 
4-(2-chlorophenyl)-5,7-dioxo-1-ethyl-2-methyl-1,4,5,7-tetrahydrofuro[3,4-b 
]pyridine-3-carboxylate 
##STR13## 
3.9 g (10 mmol) of isopropyl 
4-(2-chlorophenyl)-1-ethyl-7-hydroxy-2-metthyl-5-oxo-1,4,5,7-tetrahydrofur 
o[3,4-b]pyridine-3-carboxylate are dissolved in 6 ml of absolute 
dimethylsulphoxide, 3 ml of trifluoroacetic anhydride are added, with 
cooling, and the mixture is stirred at room temperature for 1 hour. It is 
chromatographed rapidly on silica gel (toluene:ethyl acetate=88:2) and the 
yellow spot is isolated. After concentration, the residue is crystallized 
with a little methanol and the product is immediately filtered off with 
suction and dried. 
Yield: 1.65 g (42.3% of theory). 
Melting point: 87.degree.-90.degree. C. 
Example 3 
Disodium 3-isopropyl 
4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarboxyl 
ate 
##STR14## 
120 mg of isopropyl 
4-(2-chlorophenyl)-5,7-dioxo-1-ethyl-2-methyl-1,4,5,7-tetrahydrofuro[3,4-b 
]pyridine-3-carboxylate are dissolved in 20 ml of tert.-butanol under the 
influence of heat and 2 equivalents of 0.2N aqueous sodium hydroxide 
solution are immediately added. The mixture is frozen and the product 
freeze-dried. 
Yield: 120 mg. 
Melting point: amorphous. 
It will be understood that the specification and examples are illustrative 
but not limitative of the present invention and that other embodiments 
within the spirit and scope of the invention will suggest themselves to 
those skilled in the art.