Generation of 1,4-dihydropyridine derivatives

A 1,4-dihydropyridine derivative of the formula I: ##STR1## is provided in which: A is an azole moiety; PA1 R is a C.sub.1 -C.sub.4 alkyl group; PA1 X is --CH.sub.2 --, --S--, --SO-- or --SO.sub.2 --; PA1 n is 5, 6, 7 or 8; and PA1 Ph is a phenyl group substituted once or twice by NO.sub.2, CF.sub.3 or Cl groups.

FIELD OF THE INVENTION 
The present invention relates to novel 1,4-dihydropyridine compounds, to 
processes for their preparation and to their use primarily as 
cardiovascular regulating agents. 
BACKGROUND OF THE INVENTION 
It is well known that numerous 1,4-dihydropyridine derivatives exhibit 
calcium channel blocking (or antagonist) antihypertensive activity. 
Exemplary compounds of this type have been described in Japanese Patent 
60,226,876 [85,226,876](11, 1985); Japanese Patent 5978,185 [8478, 185](5, 
1984); Japanese Patent 6097,955 [8597, 955](5, 1985); French Patent 
2,511,370 (3, 1983) and EP 151,006 [8, 1985). 
Of particular interest is the disclosure of D. J. Tiggle et al. entitled 
"Dimeric 1,4-Dihydropyridines as Calcium Channel Antagonists" in J. Med. 
Chem. 1988, 31, 1489-1492. 
SUMMARY OF THE INVENTION 
The invention comprises a 1,4-dihydropyridine derivative of the formula I: 
##STR2## 
in which: A is an azole moiety, by an azole moiety is meant an aromatic 
five-membered heterocyclic ring having one or two heteratoms such as 
oxygen, nitrogen or sulphur. The azole moiety may be optionally 
substituted by a halogen group, or a C.sub.1 -C.sub.4 alkyl group. 
Preferably, the optional substituent would be selected from a CH.sub.3 
group, or CO.sub.2 R group, wherein R is a C.sub.1 -C.sub.4 alkyl group, 
or a CN group or a NO.sub.2 group; 
R is, more specifically, a C.sub.1 -C.sub.4 alkyl group; 
X is --CH.sub.2 --, --S--, --SO-- or --SO.sub.2 --; 
n is 5, 6, 7 or 8; and 
Ph is a phenyl group substituted once or twice by NO.sub.2, CF.sub.3 or Cl 
groups. 
In a first preferred embodiment there is provided a 1,4,dihydropyridine 
derivative of the formula II: 
##STR3## 
wherein: A is 3-methyl-5-isoxazolyl; 3,5-dimethyl-1-pyrazolyl, or 
4-methyl-2-thiazolyl; 
X is a --CH.sub.2 --, --S--, --SO-- or --SO.sub.2 ; 
n is 5, 6, 7 or 8; and 
Ph is a phenyl group substituted once or twice by NO.sub.2, CF.sub.3, or Cl 
groups. 
In a second preferred embodiment, the pharmaceutical compound has the 
structural formula II in which A is 4-methyl-2-thiazolyl; X is methylene; 
n is 6; and Ph is a phenyl group substituted once by NO.sub.2. 
In a third preferred embodiment the pharmaceutical compound has a 
structural formula II wherein A is 3-methyl-5-isoxazolyl; X is methylene; 
n is 6; and Ph is a phenyl group substituted once by NO.sub.2. 
In a fourth preferred embodiment, the pharmaceutical compound has the 
structural formula II wherein A is 4-methyl-2-thiazolyl; X is sulfone; n 
is 6; and Ph is a phenyl group substituted once by NO.sub.2. 
It has been found that physiologically acceptable compounds of the formulae 
I and II possess valuable pharmacological properties. More particularly, 
they exhibit specific calcium channel blocking activity. Advantageously, 
such compounds exhibit no effect, or in some instances, positive 
ionotropic effect on the heart muscle without altering the heart rate and 
produce a relaxation effect on smooth muscle. 
Furthermore, it has been discovered that such compounds exhibit angiotensin 
inhibitory activity in addition to their calcium channel blocking 
activity. That such compounds possess both of these properties together is 
not only most beneficial but also somewhat surprising because the 
controlling mechanisms for angiotensin inhibition and high blood pressure 
control are different. 
Also these compounds exhibit BradyKinine inhibitory, anti-inflammatory, and 
an anti-ulcer stressic effects. 
Thus, the compounds of the formulae I and II can be used as active 
compounds in medicaments. 
The compounds of formulae I and II can have an asymmetric carbon at the C4 
position of the 1,4-dihydropyridine ring. Thus they can exist as racemates 
in various optically active forms. 
In another aspect of the invention, there is provided a process for the 
preparation of the compounds of the formulae I and II. The process is 
characterized in that an aromatic five-membered heterocyclic alkyl 
acetoacetate, of the general formula III: 
EQU R.sub.3 --(CH.sub.2).sub.n --O--CO--CH.sub.2 --CO--CH.sub.3III 
in which R.sub.3 is 3-methyl-5-isoxazolyl, 3,5-dimethyl-1-pyrazolyl, or 
4-methyl-2-thiazolyl and n has a value of between 5 to 8, is reacted with 
methyl-.beta.-aminocrotonate and a mono or disubstituted benzaldehyde of 
the general formula IV: 
##STR4## 
in which R.sub.1 is a hydrogen, nitro, trifluoromethyl or chloro, R.sub.2 
is a hydrogen, nitro, trifluoromethyl or chloro, or R.sub.1 =R.sub.2 and 
is a chloro group. The reaction is carried out in a suitable solvent. 
The compounds of the general formula III may be prepared by reacting 
diketene, in an inert solvent, with a substituted aromatic five-membered 
heterocyclic .omega.-alkanol having the general formula V: 
EQU R.sub.3 --(CH.sub.2).sub.n --CH.sub.2 OH V 
in which R.sub.3 is 3-methyl-5-isoxazolyl, 3,5-dimethyl-1-pyrazolyl or 
4-methyl-2-thiazolyl and n has a value of between 4 to 7. 
The compounds having the general formula V may be prepared by reacting the 
appropriate lithium salt of the 3,5-dimethyl isoxazole, 
3,5-dimethylpyrazole or 2,4-dimethyl thiazole with 6-bromo-1-hexanol in an 
inert solvent, preferably at a temperature in the range of about 
-70.degree. C. 
The compounds having the general formula I and II, wherein X comprises 
sulfur, sulfoxide or sulfone, may be prepared by reacting a substituted 
aromatic five-membered heterocyclic mercapto, sulfoxy, or sulfonyl alkyl 
acetoacetate having the general formula VI: 
EQU R.sub.3 --X--(CH.sub.2).sub.n --OCOCH.sub.2 COCH.sub.3 VI 
in which R.sub.3 is 4-methyl-2-thiazolyl, X is sulfur, sulfoxy or sulfone, 
n has a value of 4 to 7, with methyl-.beta.-aminocrotonate and a mono or 
disubstituted benzaldehyde having the general formula IV in a suitable 
solvent. 
The compounds of general formula VI can be prepared by reacting diketene in 
an inert solvent with a substituted aromatic five-membered heterocyclic 
mercapto .omega.-alkanol having the general formula V: 
EQU R.sub.3 --X(CH.sub.2).sub.n --CH.sub.2 OH VII 
in which R.sub.3 is 4-methyl-2-thiazolyl, X is sulfur and n is between 4 to 
7 inclusive. 
The compounds having the general formula VII may be prepared by reacting an 
appropriate sodium salt of a mercapto derivative of a substituted aromatic 
five-membered heterocycle comprising 4-methyl-2-thiazolyl with 
6-bromo-1-hexanol in an inert solvent. The resultant thioether derivative 
of general formula VI is consecutively oxidized utilizing m-chlorobenzoic 
acid to the related sulfonyl and by potassium permanganate in acetic acid 
to the sulfonyl analogue. 
Broadly stated, the invention is a 1,4-dihydropyridine derivative of the 
formula I: 
##STR5## 
in which: A is an azole moiety; 
R is a C.sub.1 -C.sub.4 alkyl group; 
X is --CH.sub.2 --, --S--, --SO-- or --SO.sub.2 --; 
n is 5, 6, 7 or 8; and 
Ph is a phenyl group substituted once or twice by NO.sub.2, CF.sub.3 or Cl 
groups. 
Another broad aspect of the invention is a process for the preparation of 
the compounds of formula I or II comprising: reacting the compound of 
formula III in which R3 is 3-methyl-5-isoxazolyl, 
3,5-dimethyl-1-pyrazolyl, or 4-methyl-2-thiazolyl, and n has a value of 
between 5 to 8 with methyl-.beta.-aminocrotonate and a mono- or 
disubstituted benzaldehyde of the formula IV in which R.sub.1 is a 
hydrogen, nitro, trifluoromethyl, or chloro. R.sub.2 is a hydrogen or a 
nitro group, or a trifluoromethyl group or a chloro group, or R.sub.1 
=R.sub.2 and is a chloro group.