Novel benzofuran derivatives and therapeutic agents containing them

Benzofuran derivatives of the formula I ##STR1## where R.sup.1 to R.sup.5 and X have the meanings stated in the description, and therapeutic agents containing these derivatives.

The present invention relates to novel benzofuran derivatives of the 
formula I and therapeutic agents which contain these derivatives and are 
used for the treatment of cardiovascular disorders, coronary heart 
diseases, vasospasms and hypertension. 
German Laid-Open Applications DOS 2,235,941 and DOS 2,238,115 describe 
benzofuran derivatives which have a powerful in vitro calcium-antagonistic 
activity but have only weak enteral activity. 
We have found, surprisingly, that the benzofuran derivatives of the formula 
##STR2## 
where R.sup.1 and R.sup.2 independently of one another are each hydrogen, 
alkyl or phenylalkyl where alkyl in each case is of 1 to 4 carbon atoms, 
R.sup.3, R.sup.3' and R.sup.3" are each hydrogen, benzyloxy, fluorine, 
chlorine, bromine, hydroxyl or C.sub.1-6 -alkoxy, or are each amine which 
is monosubstituted or disubstituted by C.sub.1 -C.sub.4 -alkyl or C.sub.1 
-C.sub.4 -acyl, or are each nitro, hydroxymethyl or C.sub.1 -C.sub.4 
-alkyl, and two adjacent radicals R.sup.3 and R.sup.3' together may form 
the radical --CH.dbd.CH--NH--, R.sup.4 and R.sup.5 independently of one 
another are each hydrogen, C.sub.1 -C.sub.4 -alkyl or phenylalkyl where 
alkyl is of 1 to 4 carbon atoms and the phenyl nucleus may be 
monosubstituted or disubstituted by fluorine, chlorine, bromine, C.sub.1 
-C.sub.4 -alkoxy, unsubstituted or mono-or di-C.sub.1 -C.sub.4 
-alkyl-substituted amine or nitro, or R.sup.4 and R.sup.5 together form a 
3-membered to 6-membered chain which may contain an oxygen or nitrogen 
atom and may be bonded to a benzene ring which in turn may be substituted 
by fluorine, chlorine, bromine, C.sub.1 -C.sub.4 -alkoxy, unsubstituted or 
mono- or di-C.sub.1 -C.sub.4 -alkyl-substituted amine or nitro, X is 
--CO--CH.dbd.CH--, --CO--CH.sub.2 --CH.sub.2 -- or --CHOH--CH.sub.2 
--CH.sub.2 --, n is 2 or 3 and 
##STR3## 
is a single or double bond, with the proviso that if R.sup.1 and R.sup.2 
are simultaneously methyl, R.sup.4 can only be hydrogen or alkyl and 
R.sup.5 can only be unsubstituted or substituted phenylalkyl or R.sup.4 
and R.sup.5 together form a 3-membered to 6-membered chain which may 
contain an oxygen or nitrogen atom and is bonded to an unsubstituted or 
substituted benzene ring, have substantially higher oral availability 
while retaining the calcium-antagonistic activity. 
The novel compounds of the formula I can in principle be prepared by the 
processes as described in German Patent Application P 37 10 469.1. 
The compounds of the general formula I where X is --CO--CH.sub.2 CH.sub.2 
can be prepared from the compounds of the formula I in which X is 
--CO--CH.dbd.CH-- by catalytic hydrogenation of the double bond by methods 
known from the literature, as described in, for example, R. N. Rylander, 
Catalytic Hydrogenation over Pt Metals, Acad. Press, New York, page 282, 
1967. Particularly suitable catalysts are metal catalysts, such as 
palladium on carbon or Raney nickel in alcohol. 
The compounds of the general formula I in which X is --CH(OH)--CH.sub.2 
CH.sub.2 can be prepared by reduction of the compounds of the general 
formula I where X is --CO--CH.sub.2 CH.sub.2, with a metal hydride by a 
conventional method, as described in Houben-Weyl, Methoden der org. 
Chemie, 4th edition, G. Thieme Verlag Stuttgart 1984, volume 6/1b, page 
145. Examples of suitable metal hydrides are LiAlH.sub.4 in ethers and 
NaBH.sub.4 in alcohols, such as ethanol or isopropanol. 
These compounds can also be prepared from the compounds of the formula I 
where X is --CO--CH.dbd.CH-- by catalytic hydrogenation as described in 
Houben-Weyl, vol. 6/1b, page 61, or by reduction with a metal hydride, as 
described in Houben-Weyl, 4th edition, (1981), vol. 4/1d, page 297 and in 
German Laid-Open Application DOS 2,235,941. 
The compounds of the formula I where X is --CO--CH.dbd.CH-- are synthesized 
from the acetophenones of the formula III by condensation with aromatic 
aldehydes by known methods, as described in, for example, Org. Reactions 
vol. 16, page 1 et seq., John Wiley Publishers, New York 1968. Examples of 
suitable condensing agents are alkali metal hydroxides in aqueous 
alcoholic solution. 
The compounds of the formula III where R.sup.1 and R.sup.2 are each 
CH.sub.3 can be obtained by alkylation of the o-hydroxyacetophenone 
khellinone II (J. Amer. Chem. Soc. 72 (1950), 1613) with a haloalkylamine, 
as described in Chimie Therapeutique 4 (1973), 475 and German Patent 
Application P 37 10 469.1. The alkylation of II 
##STR4## 
can also be carried out with aminoalcohols under conditions of the 
Mitsunobu method (Synth. 1981, 1). 
The compounds of the formula III where R.sup.1 and R.sup.2 is not CH.sub.3 
can be prepared by alkylation of the hydroxyacetophenones IV 
##STR5## 
by a conventional method of phenol synthesis (Houben-Weyl vol. VI/3, page 
49 et seq.). For example, the alkylation can be carried out with an alkyl 
halide using an alkali metal carbonate as the base in acetone as a 
solvent, or using a metal hydride in an aprotic solvent, such as 
dimethylformamide or tetrahydrofuran. 
The compounds IV are obtainable via hydrogenolysis of the benzyl ether V by 
a known method (Houben-Weyl vol. 4/1c, page 385 et seq.). The 
debenzylation is preferably carried out at room temperature in order to 
avoid hydrogenation of the furan ring. 
The compounds V are synthesized from the hydroxyacetophenones VI by the 
process described for the preparation of III (where R.sup.1 and R.sup.2 
are each CH.sub.3). 
The hydroxyacetophenone VI is prepared by alkaline ring cleavage of the 
pyrone VII by the method described in German Patent Application P 37 10 
469.1. 
##STR6## 
The compounds of the general formula I in which the furan ring is 
hydrogenated are synthesized in a similar manner, a suitable intermediate, 
for example II, being converted into the corresponding dihydrobenzofuran 
derivative by a conventional method of catalytic hydrogenation. 
The hydrogenation is preferably carried out at slightly elevated 
temperatures of from 20.degree. to 100.degree. C. using Pd or Pt as 
catalyst. 
The novel compounds of the formula I in which X is CHOH--CH.sub.2 CH.sub.2 
possess a center of chirality and are obtained as racemates, which can be 
resolved into the optically active antipodes by a known method, for 
example by formation of diastereomeric salts with optically active acids 
or dibenzoyltartaric acid, camphor-10-sulfonic acid or ditolytartaric 
acid. 
If necessary, the resulting novel compounds can be converted into addition 
salts with a physiologically tolerated acid. A list of conventional 
physiologically tolerated acids is given in Fortschritte der 
Arzbneimittelforschung 1966, Birkhauser Verlag, vol. 10, pages 224-285, 
Germany, Switzerland. 
The addition salts with acid are, as a rule, obtained in a conventional 
manner by mixing the free base or a solution thereof with the 
corresponding acid or a solution thereof in an organic solvent, for 
example a lower alcohol, such as methanol, ethanol or propanol, or a lower 
ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or 
an ether, such as diethyl ether, tetrahydrofuran or dioxane. To improve 
deposition of crystals, mixtures of the stated solvents may be used. 
Moreover, pharmaceutically acceptable aqueous solutions of acid addition 
compounds of the aminopropanol derivatives of the formula I can be 
prepared by dissolving the free bases in an aqueous acid solution. 
The novel compounds (of the general formula I) and their physiologically 
tolerated addition salts with acids have useful pharmacological 
properties. They are highly active Ca antagonists and consequently produce 
in vitro relaxation of the blood vessels. They also reduce the arterial 
blood pressure in normotonic and hypertensive experimental animals. They 
are furthermore capable of protecting the myocardium from the loss of 
high-energy phosphates (e.g. adenosine triphosphate, ATP) which occurs 
during anoxic respiration, i.e. they have a cardioprotective action. 
Because of the pronounced Ca-antagonistic action and the superior 
antihypertensive and cardioprotective action, the novel compounds are 
suitable for the enteral treatment of cardiovascular disorders, in 
particular coronary heart disease, and of vasospasms and hypertension. 
The dose depends on the age, condition and weight of the patient and on the 
route of administration. As a rule, the daily dose of active compound is 
about 10-1000 mg per patient. 
The novel compounds can be used in the conventional solid pharmaceutical 
enteral administration forms, for example as tablets, film tablets, 
capsules, powders, granules, coated tablets or suppositories. These are 
prepared in a conventional manner and to do so the active compounds can be 
mixed with the conventional pharmaceutical auxiliaries, such as tablet 
binders, fillers, preservatives, tablet disintegrators, flow regulators, 
plasticizers, wetting agents, dispersants, emulsifiers, solvents, 
retarding agents and antioxidants (cf. H. Sucker et al.: Pharmazeutische 
Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms 
thus obtained normally contain the active compound in an amount of from 1 
to 99% by weight. 
The following method is used to demonstrate the pharmacological activity: 
Antihypertensive action 
The substances are administered orally to spontaneously hypertensive male 
Okamoto rats (SHR) weighing 270-380 g (5-10 animals per dose). The 
systolic blood pressure is determined prior to administration and 2 hours 
afterwards non-invasively at the tail of the rat with the aid of 
piezoelectric crystal transducers by a plethysmographic method. The dose 
which reduces the systolic blood pressure by 20% is determined as the ED 
20%, the values for untreated control animals being taken into account. 
TABLE 
______________________________________ 
Blood pressure lowering doses (ED 20%, mg/kg) in 
conscious spontaneously hypertensive rats (SHR) 
Antihypertensive 
activity SHR p.o. 
Example ED 20% R.P.* 
______________________________________ 
1 5.0 17.2 
2 6.7 12.7 
3 21.5 4.0 
5 21.5 4.0 
7 5.5 15.6 
9 21.5 4.0 
18 13.1 6.5 
20 8.0 10.7 
21 12.6 6.8 
23 21.5 4.0 
25 25.7 3.3 
27 16.7 5.1 
Piprofurol 85.5 1 
______________________________________ 
*Relative potency; Piprofurol = 1.0 
The results show that the orally administered novel substances have good 
hypotensive and antihypertensive actions.

EXAMPLES FOR THE PREATION OF THE STARTING COMPOUNDS 
5-Acetyl-4,7-dimethoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)pr 
opoxy]-benzofuran 
39 g of 5-acetyl-6-hydroxy-4,7-dimethoxybenzofuran are refluxed with 40 g 
of 3-chloropropyl-(2-(3,4-dimethoxyphenyl)-ethyl)-methylamine in 250 ml of 
methyl ethyl ketone for 14 hours. The mixture is filtered, the solvent is 
stripped off and the oily residue is dissolved in dilute HCl. The aqueous 
phase is washed with ether, rendered alkaline with dilute sodium hydroxide 
solution and extracted with ether. Stripping off the solvent gives 45 g of 
crude oily product which is further reacted without purification. 
4-Benzyloxy-9-methoxy-7-methylfuro[3,2-g]chromone 
95 g of 4-hydroxy-9-methoxy-7-methfuro[3,2-g]chromone in 1000 ml of methyl 
ethyl ketone are refluxed with 100 g of benzyl bromide and 210 g of 
K.sub.2 CO.sub.3 for 15 hours. 1000 ml of CH.sub.2 Cl.sub.2 are added to 
the mixture, which is then filtered, and the solvent is distilled off. 
After treatment with petroleum ether, the residue gives 123 g of VII 
(where R.sup.1 is CH.sub.3) as a yellowish oil. 
5-Acetyl-4-benzyloxy-6-hydroxy-7-methoxybenzofuran 
113 g of VII (where R.sup.1 is CH.sub.3) are added a little at a time to a 
solution of 67 g of KOH in 1000 ml of water at 75.degree. C. The mixture 
is refluxed for 3 hours and then cooled and filtered. The filtrate is 
acidified with 110 ml of concentrated hydrochloric acid, and the 
precipitated residue is filtered off under suction and dried to give 115 g 
of V (where R.sup.1 is CH.sub.3). 
5-Acetyl-4-benzyloxy-7-methoxy-6-(2-N-piperidinoethoxy)-benzofuran 
50 g of VI (where R.sup.1 is CH.sub.3) in 400 ml of methyl ethyl ketone are 
refluxed with 35 g of chloroethylpiperidine and 90 g of K.sub.2 CO.sub.3 
for 5 hours. The mixture is filtered and the filtrate is evaporated down. 
The residue is partitioned between water and ether. 69 g of V (where 
R.sup.1 is CH.sub.3) are obtained as a yellowish oil. 
5-Acetyl-4-hydroxy-7-methoxy-6-(2-N-piperidinoethoxy)-benzofuran 
18.5 g of V (where R.sup.1 is CH.sub.3 and R.sup.3 and R.sup.4 together are 
pentamethylene) are dissolved in 150 ml of ethyl acetate and the solution 
is stirred with 1 g of Pd/C under atmospheric pressure at room temperature 
in a hydrogenation apparatus until the absorption of hydrogen has ended. 
The catalyst is filtered off and the filtrate is evaporated down. The 
residue gives 16 g of the desired product. 
5-Acetyl-4-ethoxy-7-methoxy-(2-piperidinoethoxy)-benzofuran 
3.3 g 5-Acetyl-4-hydroxy-7-methoxy-6-(2-piperidinoethoxy)-benzofuran in 2 
ml of dimethylformamide are added dropwise to a suspension of 0.4 g of NaH 
(55% strength in liquid paraffin) in 10 ml of dimethylformamide at room 
temperature. The mixture is stirred for 30 minutes, after which 2.1 g of 
ethyl iodide are added. Stirring is continued overnight and the mixture is 
poured onto ice and extracted with ether. The ether phase is washed with 
water and evaporated down. The residue is partitioned between CH.sub.2 
Cl.sub.2 and 1N HCl. The organic phase is dried and evaporated down to 
give 2.0 g of the hydrochloride and evaporated down to give 2.0 g of the 
hydrochloride of the desired compound. 
The following are prepared in a similar manner: 
5-acetyl-4-ethoxy-7-methoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylami 
no)-propoxy]-benzofuran, oil 
5-acetyl-4,7-dimethoxy-6-[3-((2-(3-methoxyphenyl)-ethylmethylamino)-propoxy 
]-benzofuran, oil 
5-acetyl-4-ethoxy-7-methoxy-6-[3-((2-(3-methoxyphenyl)-ethyl)-methylamino)- 
propoxy]-benzofuran, oil 
5-acetyl-4,7-dimethoxy-6-[3-(4-(2-methoxyphenyl)-piperazinyl)-propoxy]-benz 
ofuran, oil 
5-acetyl-4,7-dimethoxy-6-[3-(4-phenylpiperidinyl)-propoxy]-benzofuran, oil 
5-acetyl-2,3-dihydro-6-hydroxy-4,7-dimethoxybenzofuran 
10 g of 5-acetyl-6-hydroxy-4,7-dimethoxybenzofuran in 100 ml of methanol 
are hydrogenated using 2 g of Pd/C (10%) at room temperature and under 
slightly superatmospheric pressure. When the absorption of hydrogen is 
complete, the mixture is filtered and the solvent is distilled off. 9.7 g 
of the desired product of melting point 100.degree.-101.degree. C. are 
obtained. 
Examples of the preparation of the novel compounds: 
EXAMPLE 1 
1-[4,7-Dimethoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propoxy 
]-benzofuran-5-yl]-3-(4-hydroxyphenyl)-propenone 
8 g of 
acetyl-4,7-dimethoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-pr 
opoxy]-benzofuran and 4 g of 4-hydroxybenzaldehyde in 60 ml of ethanol and 
20 g of concentrated sodium hydroxide solution were stirred overnight at 
room temperature. The mixture was poured onto ice, neutralized with dilute 
hydrochloric acid and extracted with CH.sub.2 Cl.sub.2. The organic phase 
was washed again with water, dried and evaporated down. The residue was 
dissolved in CH.sub.2 Cl.sub.2 using an equimolar amount of oxalic acid. 
The product was precipitated as the oxalate by adding ether. 
Yield: 2.8 g, m.p. 60.degree. C. 
Examples 2 to 20 in Table 1 were synthesized in a similar manner. The 
structure of all compounds were ascertained by NMR spectroscopy. 
EXAMPLE 21 
1-[4-Ethoxy-7-methoxy-6-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-pr 
opoxy)-benzofuran-5-yl]-3-(4-hydroxyphenyl)-propanone 
15 of the chalkone from Example 2 in 200 ml of methanol were hydrogenated 
at room temperature using 1.5 g of Pd/C until the calculated amount of 
hydrogen had been absorbed. The solvent was distilled off and the residue 
was purified by chromatography. 2.1 g of oily product were obtained. 
Examples 22 to 24 in Table 2 were synthesized in a similar manner. 
EXAMPLE 25 
1-(4-Ethoxy-7-methoxy-6-(2-N-piperidinoethoxy)benzofuran-5-yl)-3-(4-hydroxy 
phenyl)-propan-1-ol 
3.7 g of NaBH.sub.4 were added to 9 g of 
1-(4-ethoxy-7-methoxy-6-(2-N-piperidinoethoxy)-benzofuran-5-yl)-3-(4-hydro 
xyphenyl)-propenone in 40 ml of ethanol and 7 g of pyridine at room 
temperature, and the mixture was refluxed for 5 hours. It was then poured 
onto iced water, neutralized with dilute HCl and extracted with CH.sub.2 
Cl.sub.2. The organic phase was dried, the solvent was distilled off and 
the residue was chromatographed over silica gel (8:1 CH.sub.2 Cl.sub.2 
/CH.sub.3 OH). 
3.7 g of product of melting point 132.degree. C. were obtained. 
The compounds in Table 3 were prepared in a similar manner. 
TABLE 1 
__________________________________________________________________________ 
##STR7## 
Example 
R.sup.1 
R.sup.2 
n NR.sup.4 R.sup.5 R.sup.3 R.sup.3' 
R.sup.3" 
Mp. [.degree.C.] 
__________________________________________________________________________ 
2 C.sub.2 H.sub.3 
CH.sub.3 
3 
##STR8## 4-OH H H oil 
3 CH.sub.3 
CH.sub.3 
3 
##STR9## 4-OH H H oil 
4 CH.sub.3 
CH.sub.3 
3 
##STR10## 4-F H H oil 
5 CH.sub.3 
CH.sub.3 
3 
##STR11## H H H oil 
6 CH.sub.3 
CH.sub.3 
3 
##STR12## 4-OH H H 67 
7 C.sub.2 H.sub.5 
CH.sub.3 
3 
##STR13## 4-OH H H oil 
8 CH.sub.3 
CH.sub.3 
3 
##STR14## 
##STR15## 
H H oil 
9 CH.sub.3 
CH.sub.3 
3 
##STR16## 
##STR17## 
H H oil 
10 C.sub.3 H.sub.7 
CH.sub.3 
3 
##STR18## 4-OH H H oil 
11 CH.sub.3 
CH.sub.3 
3 
##STR19## 4-OH, 3-OCH.sub.3 
H oil 
12 CH.sub.3 
CH.sub.3 
3 
##STR20## 3-OH H H oil 
13 CH.sub.3 
CH.sub.3 
3 
##STR21## 4-NHCOCH.sub.3 
H H oil 
14 CH.sub.3 
CH.sub.3 
3 
##STR22## 4-OH H H 158 
15 CH.sub.3 
CH.sub.3 
3 
##STR23## 4-OH H H 170 
16 CH.sub.3 
CH.sub.3 
3 
##STR24## 4-OH H H 160 
17 CH.sub.3 
CH.sub.3 
3 
##STR25## 3-Cl 5-Cl 4-OH 
185 
18 CH.sub.3 
CH.sub.3 
3 
##STR26## 4-NHCHCH-3 (fused pyrrole) 
H 70 
19 CH.sub.3 
CH.sub.3 
3 
##STR27## 4-OH, 3-CH.sub.2 OH 
H 89 
20 
##STR28## oil 
__________________________________________________________________________ 
TABLE 2 
__________________________________________________________________________ 
##STR29## 
Example 
R.sup.1 
R.sup.2 
n NR.sup.4 R.sup.5 R.sup.3 
Mp. [.degree.C.] 
__________________________________________________________________________ 
22 CH.sub.3 
CH.sub.3 
3 
##STR30## 4-OH 
oil 
23 C.sub.2 H.sub.5 
CH.sub.3 
3 
##STR31## 4-OH 
oil 
24 CH.sub.3 
CH.sub.3 
3 
##STR32## H oil 
__________________________________________________________________________ 
TABLE 3 
__________________________________________________________________________ 
##STR33## 
Example 
R.sup.1 
R.sup.2 
n NR.sup.4 R.sup.5 R.sup.3 
Mp. [.degree.C.] 
__________________________________________________________________________ 
25 C.sub.2 H.sub.5 
CH.sub.3 
2 
##STR34## 4-OH 132 
26 C.sub.6 H.sub.5 CH.sub.2 
CH.sub.3 
2 
##STR35## 4-OH 140 
27 CH.sub.3 
CH.sub.3 
3 
##STR36## H oil 
28 C.sub.2 H.sub.5 
CH.sub.3 
2 
##STR37## 4-N(CH.sub.3).sub.2 
139 (fumarate) 
29 C.sub.3 H.sub.7 
CH.sub.3 
2 
##STR38## 4-OH 122 
30 CH.sub.3 
CH.sub.3 
3 
##STR39## 4-OH oil 
31 CH.sub.3 
CH.sub.3 
3 
##STR40## H oil 
32 CH.sub.3 
CH.sub.3 
3 
##STR41## 4-OH oil 
33 CH.sub.3 
CH.sub.3 
3 
##STR42## 4-F oil 
__________________________________________________________________________