4,4-Disubstituted spiro-1,4-dihydropyridines and a process for their production

The invention relates to 4,4-disubstituted spiro-1,4-dihydropyridine compounds of formula (I). Also included in the invention are methods for producing the compounds of formula (I) by (a) cyclizing a compound of formula (II) in the presence of a base or (b) reducing a sulphinyl compound of formula (I) by means of Raney nickel. The compounds of formula I are intermediates and can be converted to sulphur-free compounds of formula (III) which are known to be useful for treating circulatory illnesses.

The present invention relates to certain new, 4,4-disubstituted 
spiro-1,4-dihydropyridine compounds and to a new and unobvious process for 
their production. The compounds can be used as intermediate products for 
the synthesis of pharmaceuticals. 
1,4-Dihydropyridines which are monosubstituted in the 4-position are 
readily accessible by the "Hantzsch synthesis" and are already known (see 
A Hantzsch Justus Lieb. Ann. Chem. 215, 1 (1882) and DT-OS (German 
Published Specification) 2,117,571). 
1,4-Dihydropyridine-3,5-dicarboxylic acid ester derivates which carry two 
substituents in the 4-position could not hitherto be prepared by known 
methods (see B. Loev and K. M. Snader, J. Org. Chem. 30, 1914 (1965)). It 
is also only possible to carry out the addition of organometallic 
compounds onto pyridine derivatives if the 4-position of the pyridine is 
not already substituted (see R. Lukes and J. Kuthan, Collect. Czech, Chem. 
Comm. 26, 1845 (1961); J. Palacek, K. Vondra and J. Kuthan, ibid. 34, 2991 
(1969) and J. F. Biellmann, H. J. Callot and M. P. Goeldner, Tetrahedron 
26, 4655 (1970)). 
According to the present invention there are provided compounds which are 
4,4-disubstituted spiro-1,4-dihydro-pyridines of the formula 
##STR1## 
in which A represents a carboxylic aryl radical (preferably a mono- or 
bi-cyclic carbocyclic aryl radical) or a heterocyclic radical selected 
from furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, 
pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, 
benzimidazolyl, quinazolyl and quinoxalyl, the said carbocyclic aryl 
radical or heterocyclic radical optionally containing 1, 2 or 3 identical 
or different substituents selected from phenyl, alkyl, alkenyl, alkinyl, 
alkoxy, alkylene, dioxyalkylene, halogen, trifluoromethyl, 
trifluoromethoxy, alkylamino, dialkylamino, nitro, cyano, azido and 
carboxamido, 
R.sup.3 and R.sup.4 are identical or different and each represent a 
hydrogen atom or an achiral straight-chain or branched alkyl radical, an 
aryl radical or an aralkyl radical, 
R.sup.2 and R.sup.5 are identical or different and each represent a 
straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon 
radical, which is optionally interrupted in the chain by hydrogen and is 
optionally substituted by halogen, pyridyl, phenyl or phenoxy, the phenyl 
or phenoxy group optionally being substituted by halogen, cyano, 
dialkylamino, alkoxy, alkyl, trifluoromethyl or nitro, 
R.sup.1 represents a straight-chain, branched or cyclic, saturated or 
unsaturated aliphatic hydrocarbon radical which is optionally interrupted 
in the chain by one oxygen and is optionally substituted by phenyl, 
phenoxy and pyridyl or amino, the phenyl, phenoxy or pyridine radicals 
optionally being substituted by halogen, cyano, dialkylamino, alkoxy, 
alkyl, trifluoromethyl or nitro, and the amino group optionally being 
substituted by two identical or different substituents selected from 
alkyl, alkoxy-alkyl, aryl and aralkyl, and 
n is 0, 1 or 2. 
As used herein and unless otherwise specified, the term "aryl" defines 
preferably mono- or bi-cyclic carbocyclic aryl and the term "aralkyl" 
defines preferably mono- or bi-cyclic carbocyclic aryl -C.sub.1 -C.sub.4 
-alkyl. Also, the terms "alkyl", "alkenyl", "alkinyl" and "alkoxy" 
preferably contain up to 8, particularly up to 4 carbon atoms, the term 
"alkylene" preferably contains up to 6 carbon atoms; the term 
"dioxy-alkylene" preferably contains 4 carbon atoms; the term "halogen" 
preferably includes chlorine, fluorine and bromine; the terms "alkylamino" 
and "dialkylamino" preferably contain up to 4 carbon atoms in each alkyl 
group. 
According to the present invention there is provided a process for the 
production of a compound of the present invention, in which 
(a) a pyridine of the general formula 
##STR2## 
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, n and A have the 
above-mentioned meanings, is cyclised at a temperature between 
-120.degree. C. and +30.degree. C. in the presence of a base and 
optionally in the presence of an inert organic solvent, to give a spiro 
compound of the general formula (I), and 
(b) if a compound of general formula (I) in which n is 0 is required and 
the product of reaction variant (a) is a sulphinyl compound (n is 1), that 
sulphinyl compound of formula (I) is reduced by means of Raney nickel. 
If 2,6-dimethyl-4-(2-methylsulphinyl-phenyl)pyridine-3,5-dicarboxylic acid 
dimethyl ester is used as the starting substance, the course of the 
reaction variant (a) for the production of compounds according to the 
present invention is illustrated by the following equation: 
##STR3## 
The pyridine compounds of the general formula (II) used as starting 
substances are novel, but they can be prepared from the corresponding 
1,4-dihydropyridines by known oxidation processes, such as, for example, 
oxidation with chloranil (see J. Am. Chem. Soc. 79, 3477 (1957)). The 
1,4-dihydropyridines are likewise prepared by known methods (see DT-OS 
(German Published Specification) No. 2,117,571 and U.S. Pat. No. 
3,799,934; and J. Med. Chem. 17, 956 (1974)). 
Preferred inert organic solvents which may be mentioned are ethers (such as 
diethyl ether, tetrahydrofuran or dioxane), and hydrocarbons, (such as 
benzine, petroleum ether, toluene or xylene). 
As preferred bases which can be used according to the invention there may 
be mentioned metal hydrides (such as sodium hydride or potassium hydride), 
amides (such as lithium-diethylamide or lithium-diisopropylamide) or 
alcoholates, particularly alkali metal alcoholates, (such as potassium 
t-butylate or sodium methylate). 
The process of reaction variant (a) according to the invention is 
preferably carried out in a temperature range from -100.degree. C. to 
+20.degree. C., in particular in a range between -90.degree. C. and 
-40.degree. C. 
The reaction variant (a) usually takes place under normal pressure, but can 
also be carried out under increased pressure. The base used for the 
cyclisation is preferably employed in at least equivalent amounts. A 2- to 
3-fold excess of base can be advantageous in some cases. 
With knowledge of the start of the art, it could not have been expected 
that the compounds of the formula (II) would be cyclised under the given 
process conditions to give 4,4-disubstituted 1,4-dihydropyridines, 
especially since it was known from the state of the art that it is not 
possible to substitute the 4-position a second time by addition of 
organometallic compounds onto pyridine derivatives. It is thus to be 
described as exceptionally surprising that these new compounds which were 
hitherto inaccessible can be prepared by such a simple process. 
Compounds of the present invention which are of particular interest are 
those in which 
A represents a phenyl, naphthyl, furyl, pyryl or pyridyl radical 
optionally containing 1, 2 or 3 identical or different substituents 
selected from phenyl, alkyl, alkenyl, alkinyl, alkoxy, alkylene, 
dioxyalkylene and alkylamino with in each case up to 4 carbon atoms, 
halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, azido and 
carboxamido, 
R.sup.3 and R.sup.4 are identical or different and each represent a 
hydrogen atom or an alkyl radical with up to 4 carbon atoms, a phenyl 
radical or a benzyl radical, 
R.sup.2 and R.sup.5 are identical or different and each represent a 
straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon 
radical which has up to 8 carbon atoms, which is optionally interrupted in 
the chain by oxygen and is optionally substituted by halogen, pyridyl, 
phenyl or phenoxy, the phenyl or phenoxy radicals optionally being 
substituted by halogen, cyano, nitro or trifluoromethyl, 
R.sup.1 represents a straight-chain, branched or cyclic, saturated or 
unsaturated aliphatic hydrocarbon radical which has up to 8 carbon atoms, 
which is optionally interrupted in the chain and is optionally substituted 
by phenyl, phenoxy, pyridyl or amino, the amino group optionally being 
substituted by two identical or different substituents selected from alkyl 
and alkoxyalkyl with in each case up to 4 carbon atoms, phenyl and benzyl, 
and the phenyl or phenoxy radical optionally being substituted by halogen, 
cyano, trifluoromethyl, nitro or alkyl, alkoxy or alkylamino with in each 
case 1 to 4 carbon atoms, and 
n is 0, 1 or 2. 
Particularly preferred compounds of the present invention which may be 
mentioned are those in which 
A represents a phenyl, furyl, pyrryl or pyridyl radical optionally 
containing 1 or 2 identical or different substituents selected from 
phenyl, alkyl, alkoxy and alkylamino, with in each case 1 to 4 carbon 
atoms in the alkyl or alkoxy radicals, halogen, trifluoromethyl, 
trifluoromethoxy, nitro, cyano and azido, 
R.sup.3 and R.sup.4 are identical or different and each represent a 
hydrogen atom, an alkyl radical with 1 to 4 carbon atoms or a phenyl or 
benzyl radical, 
R.sup.2 and R.sup.5 are identical or different and each represent an alkyl 
radical which has 1 to 6 carbon atoms, and which is optionally interrupted 
in the chain by oxygen or is optionally substituted by halogen or phenyl, 
R.sup.1 represents alkyl or alkinyl with up to 6 carbon atoms, the alkyl 
radical optionally being interrupted in the chain by one oxygen and 
optionally being substituted by phenyl, phenoxy or amino, and the amino 
group optionally being substituted by two identical or different 
substituents selected from alkyl with 1 to 4 carbon atoms, phenyl and 
benzyl, and 
n is 0 or 1. 
The compounds of the present invention can be converted into sulphur-free 
products of the formula (III) 
##STR4## 
in a simple manner by known methods, for example by treatment with Raney 
nickel. (See Org. React. 12, 356-529 (1962) and Chem. Rev. 62, 374-404 
(1962)). These 4,4-disubstituted 1,4-dihydropyridines of the formula (III) 
represent valuable pharmaceutically active compounds which can be used for 
the treatment of circulatory illnesses, preferrably as vasodilating, 
coronary, cerebral and blood pressure lowering agent (see U.S. Pat. Nos. 
3,799,934 and 3,488,359). 
The process according to the invention and the new compounds prepared in 
this way thus represent an advantageous route for the preparation of new 
pharmaceutically active substances.

The following Examples 1 to 6 relate to reaction variant (a) and Example 7 
to 9 relate to reaction variant (b) and the Examples merely illustrate the 
process according to the invention. 
EXAMPLE 1 
##STR5## 
150 mmoles of 
2,6-dimethyl-4-(2-methylsulphinylphenyl)-pyridine-3,5-dicarboxylic acid 
dimethyl ester were dissolved in 500 ml of anhydrous tetrahydrofuran, and 
300 mmoles of lithium diisopropylamide were added at -78.degree. C. 
Immediately thereafter, 50 ml of methanol, solid ammonium chloride and 1 
liter of water were added. The precipitate was filtered off, washed in 
water and dried at 100.degree. C. 
4,3'-Spiro[2,6-dimethyl-3,5-bis-methoxycarbonyl-1,4-dihydropyridine]-[2',3 
'-dihydro-1'-benzothiophene-1'-oxide] of melting point 286.degree. to 
289.degree. C. (decomposition) was obtained. Yield: 80% of theory. 
EXAMPLE 2 
##STR6## 
135 mmoles of 
2,6-dimethyl-4-(2-methylsulphinyl-5-nitrophenyl)-pyridine-3,5-dicarboxylic 
acid dimethyl ester were dissolved in diethyl ether and reacted with 270 
mmoles of potassium hydride at 20.degree. C. and protonated. The solvent 
was evaporated off in a rotary evaporator, the residue was taken up in 
methylene chloride and the mixture was dried and evaporated again in a 
rotary evaporator. The residue crystallised on trituration with ethyl 
acetate. 
4,3'-Spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-[5'-nit 
ro-2',3'-dihydro-1'-benzothiophene-1'-oxide] of melting point: 
257.degree.-259.degree. C. (decomposition) was obtained. 
Yield: 33% of theory. 
EXAMPLE 3 
##STR7## 
21 mmoles of 
2,3-dimethyl-4-(2-methylsulphinylpyrid-3-yl)-pyridine-3,5-dicarboxylic 
acid diethyl ester were dissolved in dioxane, and the reaction with 
lithium diethylamide and working up were carried out analogously to 
Example 1. 
4,3'-Spiro[2,6-dimethyl-3,5-bisethoxycarbonyl-1,4-dihydropyridine]-[2',3'-d 
ihydro-thieno-[2.3-b]pyridine-1'-oxide] of melting point 
253.degree.-256.degree. C. was obtained. Yield: 27% of theory. 
EXAMPLE 4 
##STR8## 
Analogously to Example 1, 125 mmoles of 
2,6-dimethyl-4-(2-ethylsulphinylphenyl)-pyridine-3,5-dicarboxylic acid 
dimethyl ester were reacted with lithium diisopropylamide at -100.degree. 
C. and protonated. The solvent was evaporated off in a rotary evaporator, 
the residue was extracted with methylene chloride and the mixture was 
dried over Na.sub.2 SO.sub.4 and evaporated in a rotary evaporator. The 
residue was dissolved in acetone and the product was precipitated with 
ether. 
4,4'-Spiro-[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydro-pyridine]-[2'- 
methyl-2',3'-dihydro-1'-benzothiophene-1'-oxide] was obtained as a 
diastereomer mixture with a melting point of 200.degree.-206.degree. C. 
Yield: 41% of theory. 
EXAMPLE 5 
##STR9## 
61 mmoles of 
2,6-dimethyl-4-(2-propylsulphinylphenyl)-pyridine-3,5-dicarboxylic acid 
dimethyl ester were dissolved in toluene and reacted analogously to 
Example 1. 
4,3'-Spiro[2,6-dimethyl-3,5-bismethoxy-carbonyl-1,4-dihydropyridine]-[2'-p 
ropyl-2',3'-dihydro-1'-benzothiophene-1'-oxide] of melting point: 
225.degree.-229.degree. C. remained. 
Yield: 52% of theory. 
EXAMPLE 6 
##STR10## 
50 mmoles of 
2,6-dimethyl-4-(2-methylsulphinyl-5-chloro-phenyl)-pyridine-3,5-dicarboxyl 
ic acid methyl ethyl ester were reacted analogously to Example 1. 
4,3'-Spiro[2,6-dimethyl-3-methoxycarbonyl-5-ethoxy-carbonyl-1,4-dihydropyr 
idine]-[5'-chloro-2',3'-dihydro-1'-benzothiophene-1'-oxide] of melting 
point 210.degree.-215.degree. C. was obtained. 
Yield: 44% of theory. 
EXAMPLE 7 
##STR11## 
28 mmoles of 
4,3'-spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-[2',3' 
-dihydro-1'-benzothiophene-1'-oxide] (obtained as described in Example 1) 
were dissolved in 500 ml of acetone and the solution was boiled under 
reflux with 100 g of Raney nickel (suspended in H.sub.2 O) for 45 minutes. 
After cooling, the mixture was filtered, the filtrate was evaporated in a 
rotary evaporator and the residue was recrystallised from diethyl ether. 
4,3'-Spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-[2',3' 
-dihydro-1'-benzothiophene] with a melting point of 167.degree.-168.degree. 
C. was obtained. 
Yield: 81% of theory. 
EXAMPLE 8 
##STR12## 
13 mmoles of 
4,3'-spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-[2'-me 
thyl-2',3'-dihydro-1'-benzothiophene-1'-oxide] (obtained as described in 
Example 4) in 150 ml of acetone were boiled under reflux together with 50 
g of Raney nickel (suspended in H.sub.2 O) for 30 minutes, the mixture was 
filtered, the filtrate was concentrated and ether was added to the 
residue. 4,3'-Spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridin 
e]-[2'-methyl-2',3'-dihydro-1'-benzothiophene] with a melting point of 
130.degree.-131.degree. C. was obtained. 
Yield: 10% of theory. 
EXAMPLE 9 
##STR13## 
10 mmoles of 
4,3'-spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-[2'-pr 
opyl-2',3'-dihydro-1'-benzothiophene-1'-oxide] (obtained as described in 
Example 5) in 200 ml of acetone were boiled under reflux together with 40 
g of Raney nickel for 1.5 hours, the mixture was filtered, the filtrate 
was concentrated, the residue was chromatographed on silica gel using 
ethyl acetate (R.sub.F =0.86) and the crystals were washed with a little 
ether. 
4,3'-Spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-[2'-pr 
opyl-2',3'-dihydro-1'-benzothiophene] with a melting point of 
160.degree.-164.degree. C. was obtained. 
Yield: 41% of theory.