Substituted heterocyclylalkyl esters of 1,4-dihydropyridine-3,5-dicarboxylic acids

Dihydropyridine derivatives and acid addition salts thereof which are of use as prophylactic or/and therapeutic drugs for cardiovascular diseases, said dihydropyridine derivatives having the formula ##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and each is alkyl, cycloalkyl, cycloalkylalkyl or alkoxyalkyl; R.sup.4 and R.sup.5 are the same or different and each is hydrogen, halogen, nitro, trifluoromethyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio; R.sup.6 is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or a pyridyl; X is oxygen, sulfur, vinylene, azomethine or a group of the formula ##STR2## A is alkylene; Ar is aryl or a pyridyl; m is an integer of 1 to 3; n is an integer of 0 to 2.

It is known that several dihydropyridines having a skeletal structure 
similar to that of compounds of this invention have coronary artery 
dilating and antihypertensive activities. 
However, a broad field of synthetic chemistry remains yet to be explored 
for dihydropyridine derivatives and it is true, even the more, of 
pharmacologic investigations of such compounds. 
This invention relates to novel dihydropyridine derivatives having 
desirable pharmacological activities. 
More particularly, this invention provides dihydropyridine derivatives of 
formula (I) 
##STR3## 
[wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and each 
is alkyl, cycloalkyl or alkoxyalkyl; R.sup.4 and R.sup.5 are the same or 
different and each is hydrogen, halogen, nitro, trifluoromethyl, alkyl, 
cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkylthio; R.sup.6 is 
hydrogen, alkyl, cycloalkyl, aralkyl, aryl or a pyridyl; X is oxygen, 
sulfur, vinylene, azomethine or a group of the formula 
##STR4## 
A is alkylene; Ar is aryl or a pyridyl; m is an integer of 1 to 3; n is an 
integer of 0 to 2]and acid addition salts thereof, which derivatives and 
acid addition salts have strong and long-lasting antihypertensive, 
peripheral vasodilating, coronary artery dilating, cerebral vasodilating, 
renal vasodilating and other activities and, therefore, are of value as 
medicines. 
Referring to the above formula, the alkyls designated by R.sup.1, R.sup.2 
and R.sup.3 are preferably lower (C.sub.1-6) alkyls which may be either 
straight-chain or branched, such as methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 
etc., although C.sub.1-4 alkyls are particularly desirable. These alkyls 
may each terminate with a further lower (C.sub.3-6) cycloalkyl group (e.g. 
cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl). The cycloalkyl is 
preferably lower (C.sub.3 -C.sub.6) cycloalkyl, such as cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl, etc. The alkoxyalkyl preferably has a 
total of 3 to 7 carbon atoms and may for example be methoxyethyl, 
ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 
2-methoxy-1-methylethyl, 2-ethoxy-1-methylethyl or the like. 
The substituents designated by R.sup.4 and R.sup.5 may be the same or 
different, and be present in any optional position of the ring, although 
they are preferably located in 2- or/and 3-position with respect to the 
site of attachement to the dihydropyridine ring. The halogen as an example 
of such substituents may be fluorine, chlorine, bromine or iodine and is 
preferably fluorine or chlorine. The alkyl and cycloalkyl are preferably 
those mentioned for R.sup.1 through R.sup.3. The alkoxy and alkylthio are 
preferably those containing lower (C.sub.1-3) alkyls, thus being 
exemplified by methoxy, ethoxy, propoxy and isopropoxy and by methylthio, 
ethylthio, propylthio and isopropylthio, respectively. Examples of said 
alkoxycarbonyl include those containing 2 to 4 carbon atoms, such as 
methoxycarbonyl, ethoxycarbonyl, etc. 
The alkyl and cycloalkyl, as designated by R.sup.6, may be those mentioned 
for R.sup.1 through R.sup.3. The aralkyl may be phenyl C.sub.1-3 alkyls 
such as benzyl, .alpha.-phenylethyl, .beta.-phenylethyl, 
.gamma.-phenylpropyl, etc., and the aryl may be phenyl or naphthyl. The 
benzene ring thereof may have the same or different substituents in 
optional positions. Such substituents on the benzene ring may for example 
be those mentioned for R.sup.4 and R.sup.5. The pyridyl may be 2-pyridyl, 
3-pyridyl or 4-pyridyl, which may have the substituents mentioned for 
R.sup.4 and R.sup.5. 
The alkylene designated by A is preferably a group of C.sub.2-4 which may 
be straight-chain or branched, thus being exemplified by ethylene, 
trimethylene, propylene, tetramethylene, 1,2-dimethylethylene, etc. 
The aryl and pyridyl designated by Ar may be those mentioned for R.sup.6 
and may have substituents similar to those mentioned. When R.sup.6 is aryl 
or pyridyl, Ar may represent either the same aryl or pyridyl or different 
aryl or pyridyl group. 
Referring to m which is an integer of 1 to 3 and n which is an integer of 0 
to 2, the case in which n is 0 is that the nitrogen atom is directly 
attached to Ar. 
The ring 
##STR5## 
which is a substituent at the 4-position of the dihydropyridine ring is a 
benzene ring when X is vinylene (--CH.dbd.CH--) but means a heterocyclic 
ring or a fused heterocyclic ring in other cases. Thus, when X is oxygen 
or sulfur, the ring is furan or thiophene; when X is azomethine 
(--CH.dbd.N--), the ring is pyridine; when X is 
##STR6## 
the ring is 2,1,3-benzoxadiazole; and when X is 
##STR7## 
the ring is benzothiadiazole. These heterocyclic rings or fused 
heterocyclic rings may be attached in any optional position thereof to the 
4-position of the dihydropyridine ring but the cases in which X is 
adjacent to the site of attachement to the dihydropyridine ring are 
particularly desirable. Preferred examples of such heterocyclic or fused 
heterocyclic groups are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 
2,1,3-benzoxadiazol-4-yl, 2,1,3-benzothiadiazol-4-yl, etc. 
In the production of the dihydropyridine derivatives of formula (I) of this 
invention, 
##STR8## 
the starting material corresponding to a fragment which can constitute the 
dihydropyridine derivative (I) may be subjected to dehydration and 
cyclization reaction with the remaining fragment(s) in a manner 
conventional per se. 
The following are typical examples of the production of the compound (I). 
##STR9## 
In the above formulas, all symbols have the same meanings as defined 
hereinbefore. 
Each of these production processes will be described in detail below. 
PRODUCTION PROCESS A 
In this process, compounds (II), (III) and (IV) are reacted in a suitable 
solvent. This reaction is generally conducted at a temperature of about 
20.degree. C. to about 160.degree. C., preferably at about 50.degree. C. 
to about 130.degree. C., and most conveniently at the boiling point of the 
solvent used. The solvent may be any solvent that is inert to the 
reaction. Examples of the solvent include alkanols such as methanol, 
ethanol, propanol, isopropyl alcohol, butanol, sec-butanol, etc., ethers 
such as ethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl 
ether, ethylene glycol dimethyl ether, etc., acetic acid, pyridine, 
N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. The reaction 
goes to completion generally in 0.5 to 15 hours. The proportions of (II), 
(III) and (IV) are such that to each mole of any one of these compounds, 1 
to 1.5 moles each of the other two compounds are employed. The starting 
compound (II) is either a known compound or can be produced by a known 
production process [e.g. J. Am. Chem. Soc. 67, 1017 (1945)]. The compound 
(IV) can be produced by the following exemplary process. 
##STR10## 
Wherein R.sup.7 is lower alkyl; Y is halogen; and all other symbols have 
the same meanings as defined hereinbefore. 
In the first place (VII) is reacted with an epoxy compound having an 
alkylene group corresponding to A moiety (e.g. ethylene oxide, propylene 
oxide) or a halohydrin of formula (IX) to synthesize (VIII). The reaction 
of (VII) with said epoxy compound is generally conducted in an appropriate 
solvent (e.g. water, methanol, ethanol, dioxane, tetrahydrofuran, etc.) at 
20.degree. C. to 100.degree. C. The reaction of (VII) with (IX) to give 
(VIII) is preferably conducted in the presence of a base such as sodium 
carbonate, potassium carbonate, etc. As the solvent, acetone, methyl ethyl 
ketone, N,N-dimethylformamide, etc. may also be employed as well as those 
mentioned above, and the reaction may also be conducted at 20.degree. C. 
to 100.degree. C. The halogen Y in formula (IX) is chlorine, bromine or 
iodine, and when Y is chlorine or bromine, the reaction may be carried out 
in the presence of about 0.1 to 1 molar equivalents of sodium iodide, 
potassium iodide or the like per mole of (VII) so as to accelerate the 
reaction. 
The compound (VIII) is then reacted with diketene or a .beta.-keto ester of 
formula (X) to synthesize (IV). The reaction of (VIII) with diketene is 
generally carried out by heating a mixture of the reactants at a 
temperature of about 40.degree. C. to about 130.degree. C. This reaction 
may be conducted in the presence of a solvent inert to the reaction. This 
reaction gives rise to a compound (IV) in which R.sup.3 is methyl. 
Alternatively, (IV) may be produced by reacting (VIII) with a .beta.-keto 
ester of formula (X). This reaction may be conducted in the presence of a 
base such as sodium methoxide, sodium ethoxide, potassium t-butoxide, 
sodium hydride, sodium amide, sodium metal or the like, in the presence or 
absence of a suitable inert solvent, at a temperature of about 20.degree. 
C. to about 100.degree. C. 
##STR11## 
Wherein n' is an integer of 1 to 2; all other symbols have the same 
meanings as defined hereinbefore. 
This reaction process yields a starting compound (IV) in which n.noteq.O, 
i.e. a compound of formula (IV'). The reaction of (XI) with (XII) and the 
reaction of (VIII') with diketene or (X) may be conducted under the same 
conditions as the above-mentioned reaction (1) of (VII) with (IX) and the 
reaction (1) of (VIII) with diketene or (X), respectively. 
PRODUCTION PROCESS B 
This production process may be conducted substantially under the same 
conditions as Production Process A. The starting compound (VI) can be 
synthesized by permitting ammonia to react with the starting compound (IV) 
used in Production Process A. Thus, (IV) is dissolved in a suitable 
solvent (e.g. methanol, ethanol, ethyl ether, dioxane, tetrahydrofuran) 
and an excess of ammonia gas is bubbled into the reaction mixture at about 
0.degree. C. to about 60.degree. C. Or, a solution of ammonia in the 
above-mentioned solvent is added and the reaction is conducted in a closed 
vessel at about 0.degree. C. to about 60.degree. C. In either manner, (VI) 
can be easily synthesized. 
PRODUCTION PROCESS C 
In this production process, benzylidene .beta.-keto ester (VII) is reacted 
with compound (VI) to give the object compound (I). The reaction 
conditions of this process are also substantially identical with those of 
Production Process A. Thus, each mole of compound (VII) is reacted with 
0.8 to 1.5 moles of (VI). The starting benzylidene .beta.-keto ester (VII) 
is either a known compound or can be prepared from the aldehyde (III) and 
.beta.-keto ester (V) by the convention procedure [e.g. Organic Reactions 
15, 204-599 (1967)]. 
PRODUCTION PROCESS D 
In this production process, ammonia and compound (IV) are simultaneously 
reacted with (VII) instead of (VI) alone in Production Process C. It 
appears that in this system, ammonia reacts with (IV) in the first place 
to give (VI) which then reacts with (VII). Therefore, this process may be 
conducted substantially under the same conditions as Production Process C. 
The molar proportion of (IV) relative to each mole of (VII) is generally 
0.8 to 1.5 moles and that of ammonia is 1 to 5 moles on the same basis. 
PRODUCTION PROCESS E 
In this process, (II) and (VIII) are reacted substantially under the same 
conditions as in Production Process C. Like (VII), the starting 
benzylidene .beta.-keto ester (VIII) can be synthesized by reacting the 
aldehyde (III) with the .beta.-keto ester [e.g. Organic Reactions 15, 
204-599 (1967)]. Generally this reaction is conducted using 0.8 to 1.5 
moles of (II) to each mole of (VIII). 
PRODUCTION PROCESS F 
In this process, ammonia and (V) are simultaneously reacted with (VIII) 
instead of (II) alone in Production Process E. It appears that in this 
process, ammonia reacts with (V) in the first place to give (II) which 
then reacts with (VIII). Therefore, this reaction may be conducted 
substantially under the same conditions as in Production Process E. The 
molar proportion of (V) relative to each mole of (VIII) is generally 0.8 
to 1.5 moles and that of ammonia is 1 to 5 moles on the same basis. 
The novel dihydropyridine derivative (I) produced in the manners described 
above can be isolated in a desired purity by the per se conventional 
separation and purification procedures such as concentration, extraction, 
chromatography, reprecipitation, recrystallization, etc. Since (I) 
contains a basic group, it can be converted to an acid addition salt by 
the known procedure. The salt is preferably a pharmaceutically acceptable 
non-toxic salt such as salts with mineral acids (hydrochloride, 
hydrobromide, phosphate, sulfate, etc.) and salts with organic acids 
(acetate, succinate, maleate, fumarate, malate, tartarate, 
methanesulfonate, etc.). 
The compound (I) and its salt according to this invention have low toxicity 
and display strong and long-lasting antihypertensive, peripheral 
vasodilating, coronary artery dilating, cerebral vasodilating, renal 
vasodilating and other activities in mammalian animals (e.g. mouse, rat, 
rabbit, dog, cat, man), and are of value in the prevention and treatment 
of cardiovascular diseases such as hypertension, ischemic heart disease 
(angina pectoris, myocardial infarction, etc.), cerebral and peripheral 
circulatory disorder (cerebral infarction, transient cerebral ischemic 
attack, renal artery stenosis, etc.), for instance. The present compound 
is very useful in that it is superior to the known dihydropyridine 
derivatives (e.g. nifedipine, nicardipine) in the intensity and duration 
of action and has the distinct property of dilating the renal blood 
vessels to increase the renal blood flow which is not found in the known 
compounds. When used as a prophylactic or therapeutic drug for 
hypertension, for instance, the compound of this invention produces a 
stable antihypertensive effect in a less frequent administration regimen 
(e.g. 1 to 2 doses per day). The increase of renal blood flow due to its 
renal vessel dilating activity promotes excretion of excess sodium and 
suppresses retention of sodium in the body. That is to say, the retention 
of sodium in the body due to an excessive intake of sodium chloride and 
the depressed sodium excreting function in hypertensive patients are 
improved, leading to an excellent antihypertensive effect. Moreover, since 
it is known that excessive sodium chloride intakes not only cause 
hypertension but also provoke onset of cerebral apoplexy, a mild diuretic 
action via an increase of renal blood flow appears to be useful for the 
prevention of hypertensive vascular disorders such as cerebral apoplexy. 
Furthermore, a decreased renal blood flow promotes release of renin (an 
enzyme which produces angiotensin which is a vasopressor substance) from 
the kidney. Therefore, the renal hemodynamics improving action of the 
compounds of this invention may be pressumed to supress secretion of renin 
and the compound (I) and salt thereof are of use as antihypertensive 
drugs. 
In the use of the compound (I) or its salt, it can be administered orally 
or otherwise in such dosage forms as powders, granules, tablets, capsules, 
injections, etc. which may be prepared by mixing the compound (I) or salt 
thereof with a pharmaceutically acceptable carrier, excipient or diluent. 
The dosage should vary with such factors as the route of administration, 
the condition, body weight and age of the patient, etc. but for oral 
administration to an adult patient with hypertension, for instance, 0.05 
to 20 mg/kg body weight/day or preferably 0.1 to 4 mg/kg body weight/day 
is administered divided into 1 to several times a day. 
The following are the results of pharmacological tests indicating the 
utility of compounds (I) according to this invention and the acute 
toxicity test data. 
1. Antihypertensive action 
[Procedure] 
Male spontaneously hypertensive rats aged 10 to 11 weeks were used (in 
groups of 3 to 6 individuals). The blood pressures were about 200 mmHg at 
the systolic blood pressures. To determine the blood pressure, an 
automatic blood pressure meter of Ueda Medical Co., Ltd. (USM-105R) was 
used to measure the systolic blood pressure in the caudal artery of each 
rat. 
Each test compound was suspended in a 5% solution of gum arabic and orally 
administered. The dosage was 10 mg/kg for all compounds. Animals in a 
control group was given the above solution of gum arabic only. Blood 
pressure measurements were made 1, 5, 8 and 24 hours after administration 
of each test compound. 
[Results] 
The antihypertensive effects (blood pressure after medication minus blood 
pressure before medication) of compounds of this invention are shown in 
Table 1. 
TABLE 1 
______________________________________ 
Antihypertensive Effects 
Change in blood pressure 
(mmHg) Duration of 
1 hr. 5 hrs. antihyper- 
Compound after after tensive 
(Example No.) 
treatment treatment effect (in hrs.) 
______________________________________ 
Control group 
+2 -2 0 
(given gum arabic) 
1 -89* -91* &gt;24 
2 -99* -101* 8-24 
6 -30* -33* 8-24 
7 -59* -79* &gt;24 
8 -96* -98* &gt;24 
9 -96* -98* &gt;24 
10 -88* -57* 8-24 
12 -85* -87* &gt;24 
13 -34* -31* 8-24 
15 -38* -18* 5-8 
16 -51* -45* 8-24 
17 -77* -46* 8-24 
18 -68* -43* 8-24 
22 -97* -83* 8-24 
23 -59* -66* 8-24 
24 -49* -30* ca. 8 
28 -93* -75* 8-24 
30 -48* -31* 8-24 
31 -77* -77* 8-24 
32 -46* -48* 8-24 
33 -51* -60* 8-24 
37 -63* -30* ca. 8 
38 -50* -42* 8-24 
41 -55* -67* ca. 24 
42 -25* -35* 8-24 
43 -54* -44* 8-24 
44 -44* -22* 8-24 
45 -57* -42* 8-24 
46 -44* -43* 8-24 
50 -58* -37* 8-24 
51 -69* -54* 8-24 
52 -54* -14* ca. 8 
53 -60* -34* ca. 8 
57 -85* -69* 8-24 
58 -27* -39* 8-24 
60 -98* -90* 8-24 
Nifedipine.sup.(1) 
-45* -3 &lt;5 
Nicardipine.HCl.sup.(2) 
-38* +2 &lt;5 
______________________________________ 
*P &lt; 0.05 (compared with control group) 
##STR12## 
##STR13## 
It will be apparent from Table 1 that compounds of this invention are at 
least equivalent or superior to the known dihydropyridine derivatives 
(nifedipine and nicardipine) in the intensity of action and show much more 
long-lasting action as compound with the latter compounds. 
2. Renal blood flow increasing effect (renal circulation improving effect) 
[Procedure] 
Male spontaneously hypertensive rats aged 10 to 11 weeks (3 to 6 animals 
per group) were anesthetized with pentobarbital and used. After 
laparotomy, an electromagnetic flowmeter probe (Narco) was fitted to the 
left renal artery and the renal blood flow was continuously recorded on a 
polygraph (Sanei Sokki K.K.). The renal blood flows before medication were 
about 6.5 ml per min. 
Each test compound was dissolved in polyethylene glycol 400 to prepare a 
stock solution. This stock solution was diluted five-fold with 
physiological saline and the dilution was intravenously administered to 
rats in a volume of 0.5 ml/kg body weight. The dosage was 0.01 mg/kg for 
all test compounds. The renal blood flow was measured over a period of 40 
minutes following the medication. 
[Results] 
The effects of compounds of this invention on renal blood flow are shown in 
Table 2. The values shown are: 
##EQU1## 
TABLE 2 
______________________________________ 
Renal blood flow increasing effects 
Change in renal blood flow (%) 
Compound 1 Minute 20 Minutes 
40 Minutes 
(Example No.) 
after after after 
Control group 
medication medication 
medication 
(solvent vehicle only) 
2.4 2.9 3.4 
______________________________________ 
1 10.4* 13.4* 12.8* 
6 4.5* 7.5* 6.0* 
8 5.7* 6.4* 9.7* 
10 6.9* 8.3* 6.8* 
15 4.2* 4.2* 2.9* 
18 8.8* 4.2* 5.0* 
22 7.5* 7.8* 9.6* 
23 6.7* 9.7* 10.9* 
31 3.3 4.3* 1.8 
37 8.5* 10.8* 11.3* 
Nifedipine 3.0 3.1 2.2 
Nicardipine.HCl 
-15.0* -1.9 0.3 
______________________________________ 
*: P &lt; 0.05 (compared with control group) 
3. Acute toxicity 
[Procedure] 
2-(4-Benzhydryl-1-piperazinyl)ethyl methyl 
2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 
dihydrochloride was suspended in a 5% solution of gum arabic and orally 
administered to male and female Wistar rats aged 5 weeks (body weight 105 
to 139 g) in a dose of 62.5, 125, 250, 500 and 1000 mg/kg (in groups of 4 
to 8) and each animal so treated was observed over a period of 7 days. 
[Results] 
The acute toxicity test data are shown in Table 3. 
TABLE 3 
______________________________________ 
Acute toxicity (LD50, mg/kg) 
______________________________________ 
Rat .male. 
250 &lt; LD50 &lt; 500 
.female. 
250 &lt; LD50 &lt; 500 
______________________________________