.alpha.-(aminoalkylaminomethyl)phenylmethanols, composition containing them, and use thereof to treat certain heart and circulatory diseases

The present invention provides aminoalcohols of the general formula: ##STR1## wherein R.sub.1 and R.sub.2, which can be same or different, are hydrogen atoms, hydroxyl groups, C.sub.1 -C.sub.4 -alkoxy, benzyloxy, C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.1 -C.sub.4 -alkanesulphonylamino, C.sub.1 -C.sub.4 -alkanesulphinyl or C.sub.1 -C.sub.4 -alkanesulphonyl radicals, m is 2, 3 or 4, X and Y, which can be the same or different, are hydrogen atoms or benzyl radicals and R.sub.3 is a phenyl radical substituted twice by C.sub.1 -C.sub.6 -alkyl radicals, a nitrophenyl radical, an aminophenyl radical, a 1,3,5-tri-C.sub.1 -C.sub.6 -alkyl-2,4-dioxo-1H,3H-pyrimidin-6-yl radical, an indolyl radical, an indazolyl radical, a benzimidazolyl radical, a 1,4-di-C.sub.1 -C.sub.6 -alkylpyrazol-5-yl radical or a radical of the general formula: ##STR2## wherein R.sub.4 and R.sub.5, which can be the same or different, are C.sub.1 -C.sub.4 -alkyl radicals and R.sub.6 is a C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, phenyl or benzyl radical; and the pharmacologically acceptable salts there, as well as methods for making and using these compounds and compositions containing them. There are useful as cardiovascular medicaments.

The present invention is concerned with new aminoalcohols, processes for 
the preparation thereof and pharmaceutical compositions containing them. 
The compounds according to the present invention possess a significant 
action on the deformability of erythrocytes and improve the flowability of 
the blood. Therefore, they can be used especially for the treatment of 
peripheral, cerebral and coronary blood flow disturbances. Furthermore, 
they display a positive inotropic action. 
The new aminoalcohols according to the present invention are compounds of 
the general formula: 
##STR3## 
wherein R.sub.1 and R.sub.2, which can be the same or different, are 
hydrogen atoms, hydroxyl groups or C.sub.1 -C.sub.4 -alkoxy, benzyloxy, 
C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.1 -C.sub.4 -alkanesulphonamido, 
C.sub.1 -C.sub.4 -alkanesulphinyl or C.sub.1 -C.sub.4 -alkanesulphonyl 
radicals, m is 2, 3 or 4, X and Y, which can be the same or different, are 
hydrogen atoms or benzyl radicals and R.sub.3 is a phenyl radical 
substituted twice by C.sub.1 -C.sub.4 -alkyl radicals, a nitrophenyl 
radical, an aminophenyl radical, a 1,3,5-tri-C.sub.1 -C.sub.6 
-alkyl-2,4-dioxo-1H,3H-pyrimidin-6-yl radical, an indolyl radical, an 
indazolyl radical, a benzimidazolyl radical, a 1,4-di-C.sub.1 -C.sub.6 
-alkylpyrazol-5-yl radical or a radical of the general formula: 
##STR4## 
wherein R.sub.4 and R.sub.5, which can be the same or different, are 
C.sub.1 -C.sub.4 -alkyl radicals and R.sub.6 is a C.sub.1 -C.sub.6 -alkyl, 
C.sub.2 -C.sub.6 -alkenyl, phenyl or benzyl radical; as well as the 
pharmacologically acceptable salts thereof. 
Apart from the compounds mentioned hereinafter in the specific Examples, 
the present invention also provides all compounds which have every 
possible combination of the substituents mentioned in the Examples. 
The new compounds of general formula (I) according to the present invention 
can be prepared in known manner by reacting a compound of the general 
formula: 
##STR5## 
in which R.sub.1 and R.sub.2 have the above-given meaning, V is a reactive 
residue and U is a &gt;C.dbd.O or &gt;CH--Z group, Z being a hydroxyl group or, 
together with V, representing an oxygen atom, with a compound of the 
general formula: 
##STR6## 
in which X, Y, m and R.sub.3 have the above-given meanings, and, when U is 
a &gt;C.dbd.O group, the product obtained is subsequently reduced and when X 
and/or Y stands for a benzyl radical, this is, if desired, split off, a 
radical R.sub.1 or R.sub.2 is, if desired, changed into another radical 
R.sub.1 and R.sub.2 and the compound thus obtained is, if desired, 
converted into a pharmacologically acceptable salt. 
The intermediates obtained of the general formula: 
##STR7## 
in which R.sub.1, R.sub.2, m, X, Y and R.sub.3 have the above-given 
meanings, are also new and part of the subject matter of the present 
invention. 
The reactive residue V in compounds of general formula (II) can be a 
chlorine or bromine atom or a mesyloxy or tosyloxy radical. 
The process according to the present invention is preferably carried out in 
a solvent which is inert under the reaction conditions, for example, 
toluene, dioxan, tetrahydrofuran, ethylene glycol dimethyl ether, ethanol, 
butanol, acetone or dimethylformamide, possibly in the presence of an 
acid-binding agent. Mixtures of the above-mentioned solvents can also be 
used. 
The reduction possibly to be carried out when R stands for a &gt;C.dbd.O group 
can be carried out by means of complex metal hydrides, for example sodium 
borohydride, or by catalytic hydrogenation in the presence of noble metal 
catalysts. 
The splitting off of a benzyl radical X and Y is preferably carried out 
with the use of catalytically-activated hydrogen. 
A subsequent conversion of a radical R.sub.1 or R.sub.2 into another 
radical R.sub.1 and R.sub.2 can be, for example, a hydrogenolytic 
conversion of a benzyl radical into a hydroxyl group. 
The compounds of general formulae (II) and (III) are either known from the 
literature or can be prepared by known methods from materials known from 
the literature (cf. Federal Republic of Germany Patent Specifications Nos. 
30 23 369 and 31 31 146). 
For the conversion of compounds of general formula (I) into their 
pharmacologically acceptable salts, they are reacted, preferably in an 
organic solvent, with an inorganic or organic acid, for example 
hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, 
acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, 
benzoic acid or oxalic acid. 
The compounds of general formula (I) according to the present invention can 
be obtained in the form of a racemic mixture. The resolution of the 
racemate into the optically-active forms takes place in known manner via 
diastereomeric of optically-active acids, for example tartaric acid, malic 
acid or camphorsulphonic acid. 
For the preparation of pharmaceutical compositions, the compounds of 
general formula (I) are mixed in known manner with appropriate 
pharmaceutical carrier substances, aroma, flavouring and colouring 
materials and formed, for example, into tablets or dragees or, with the 
addition of appropriate adjuvants, suspended or dissolved in water or in 
an oil, for example olive oil. 
The new compounds of general formula (I) according to the present invention 
and the salts thereof can be administered enterally or parenterally. As 
injection medium, it is preferred to use water which contains the 
additives usual in the case of injection solutions, such as stabilising 
agents, solubilising agents or buffers. 
Such additives include, for example, tartrate and citrate buffers, ethanol, 
complex formers (such as ethylenediamine-tetraacetic acid and the 
non-toxic salts thereof) and high molecular weight polymers (such as 
liquid polyethylene oxide) for viscosity regulation. Solid carrier 
materials include, for example, starch, lactose, mannitol, methyl 
cellulose, talc, highly dispersed silicic acids, high molecular weight 
fatty acids (such as stearic acid), gelatine, agar-agar, calcium 
phosphate, magnesium stearate, animal and vegetable fats and solid high 
molecular weight polymers (such as polyethylene glycols). Compositions 
suitable for oral administration can, if desired, contain flavouring and 
sweetening agents. 
The dosage administered depends upon the age, state of health and weight of 
the recipient, the extent of the disease, the nature of possibly 
simultaneously carried out other treatments, the frequency of the 
treatment and the nature of the desired action. The daily dosage of the 
active compound is usually 0.1 to 50 mg./kg. of body weight. Normally, 0.5 
to 40 and preferably 1.0 to 20 mg./kg./day in one or more administrations 
are effective for obtaining the desired results. 
Preferred compounds according to the present invention, apart from those 
described in the following Examples, include the following: 
2-hydroxy-5-{1-hydroxy-2-[2-(2,6-dimethylphenylamino)-ethylamino]-ethyl}-be 
nzenesulphonamide 
N-[2-hydroxy-5-{1-hydroxy-2-[2-(2,6-dimethylphenylamino)-ethylamino]-ethyl} 
-phenyl]-methanesulphonamide 
4-hydroxy-3-methylsulphinyl-.alpha.-{[2-(2,6-dimethylphenylamino)-ethyl]-am 
inomethyl}-phenylmethanol 
4-hydroxy-3-methylsulphonyl-.alpha.-{[2-(2,6-dimethylphenylamino)-ethyl]-am 
inomethyl}-phenylmethanol 
3-hydroxy-.alpha.-{[2-(3-nitrophenylamino)-ethyl]-aminomethyl}-phenylmethan 
ol 
4-hydroxy-.alpha.-{[2-(3-nitrophenylamino)-ethyl]-aminomethyl}-phenylmethan 
ol 
3-hydroxy-.alpha.-{[2-(2,4-dioxo-1,3,5-trimethyl-1H,3H-pyrimidin-6-ylamino) 
-ethyl]-aminomethyl}-phenylmethanol 
.alpha.-{[2-(1-allyl-3,5-dimethylpyrazol-4-ylamino)-ethyl]-aminomethyl}-phe 
nylmethanol 
3-hydroxy-.alpha.-{[2-(1-allyl-3,5-dimethylpyrazol-4-ylamino)-ethyl]-aminom 
ethyl}-phenylmethanol 
4-hydroxy-.alpha.-{[2-(1-allyl-3,5-dimethylpyrazol-4-ylamino)-ethyl]-aminom 
ethyl}-phenylmethanol 
.alpha.-{[2-(1-phenyl-3,5-dimethylpyrazol-4-ylamino)-ethyl]-aminomethyl}-ph 
enylmethanol 
.alpha.-{[2-(1-benzyl-3,5-dimethylpyrazol-4-ylamino)-ethyl]-aminomethyl}-ph 
enylmethanol.

The following Examples are given for the purpose of illustrating the 
present invention: 
EXAMPLE 1 
.alpha.-{[2-(3-Nitrophenylamino)-ethyl]-aminomethyl}-phenylmethanol 
A mixture of 3.0 g. (25 mMole) styrene oxide, 9.0 g. (50 mMole) 
N-(3-nitrophenyl)-1,2-diaminoethane and 25 ml. n-butanol is stirred at 
ambient temperature for 3 hours. The reaction mixture is mixed with 100 
ml. diethyl ether and the precipitate is filtered off and recrystallised 
from ethyl acetate. There are obtained 3.9 g. (52% of theory) 
.alpha.-{[2-(3-nitrophenylamino)-ethyl]-aminomethyl}-phenylmethanol; m.p. 
141.degree.-142.degree. C. 
EXAMPLE 2 
The following compounds are obtained in the form of oils in a manner 
analogous to that described in Example 1: 
______________________________________ 
yield 
designation % 
______________________________________ 
(a) 2-benzyloxy-.alpha.-{[2-(2,6-dimethyl- 
59 
phenylamino)-ethyl]-aminomethyl}- 
phenylmethanol from 
2-benzyloxystyrene oxide and N-- 
(2,6-dimethylphenyl)-1,2-diamino- 
ethane 
(b) 2-methoxy-.alpha.-{[2-(2,6-dimethyl- 
29 
phenylamino)-ethyl]-N--benzylamino- 
methyl}-phenylmethanol from 
2-methoxystyrene oxide and N--[2- 
(2,6-dimethylphenylamino)-ethyl]- 
benzylamine 
______________________________________ 
EXAMPLE 3 
4-Benzyloxy-.alpha.-{[2-(2,6-dimethylphenylamino)-ethyl]-aminomethyl}-pheny 
lmethanol 
9.6 g. (0.24 mole) sodium borohydride are added at 0.degree. C., within the 
course of 10 minutes, to a solution of 33.8 g. (80 mMole) 
1-(4-benzyloxyphenyl)-2-[2-(2,6dimethylphenylamino)-ethylamino]-ethane in 
600 ml. ethanol. The reaction mixture is further stirred for 1 hour at 
0.degree. C., poured on to ice, acidified with dilute acetic acid, mixed 
with excess sodium hydrogen carbonate solution and extracted with 
dichloromethane. After evaporation of the extracts, there are obtained 
28.9 g. (87% of theory) 
4-benzyloxy-.alpha.-{[2-(2,6-dimethylphenylamino)-ethyl]-aminomethyl}-phen 
ylmethanol in the form of an oil. 
EXAMPLE 4 
The following compounds are obtained in the form of oils in a manner 
analogous to that described in Example 3. 
______________________________________ 
yield 
designation % 
______________________________________ 
(a) 3-benzyloxy-.alpha.-{[2-(2,6-dimethyl- 
45 
phenylamino)-ethyl]-aminomethyl}- 
phenylmethanol from 
1-(3-benzyloxyphenyl)-2-[2-(2,6- 
dimethylphenylamino)-ethylamino]- 
ethanone 
(b) .alpha.-{[2-(2,6-dimethylphenylamino)- 
84 
ethyl]-N--benzylaminomethyl}-phenyl- 
methanol from 
2-[2-(2,6-dimethylphenylamino)- 
ethyl-N--benzylamino]-1-phenyl- 
ethanone 
(c) 4-benzyloxy-3-methoxy-.alpha.-{[2-(2,6- 
71 
dimethylphenylamino)-ethyl]-N-- 
benzylaminomethyl}-phenylmethanol 
from 
1-(4-benzyloxy-3-methoxyphenyl)-2- 
[2-(2,6-dimethylphenylamino)-ethyl- 
N--benzylamino]-ethanone 
(d) 3,5-dibenzyloxy-.alpha.-{[2-(2,6- 
55 
dimethylphenylamino)-ethyl]-N-- 
benzylaminomethyl}-phenylmethanol 
from 
1-(3,5-dibenzyloxyphenyl)-2-[2- 
(2,6-dimethylphenylamino)-ethyl-N-- 
benzylamino-ethanone 
(e) .alpha.-{[3-(2,6-dimethylphenylamino)- 
76 
propyl]-N--benzylaminomethyl}- 
phenylmethanol from 
2-[3-(2,6-dimethylphenylamino)- 
propyl-N--benzylamino]-1-phenyl- 
ethanone 
(f) 4-benzyloxy-.alpha.-{[3-(2,6-dimethyl- 
68 
phenylamino)-propyl]-N--benzylamino- 
methyl}-phenylmethanol from 
1-(4-benzyloxyphenyl)-2-[3-(2,6- 
dimethylphenylamino)-propyl-N-- 
benzylamino]-ethanone 
(g) 3-benzyloxy-.alpha.-[{2-(1,3,5-trimethyl- 
62 
pyrazol-4-yl)-N--benzylamino]-ethyl}- 
N--benzylaminomethyl]-phenylmethanol 
from 
1-(3-benzyloxyphenyl)-2-{2-[1,3,5- 
trimethylpyrazol-4-yl)-N--benzyl- 
amino]-ethyl-N--benzylamino}-ethanone 
(h) 4-benzyloxy-.alpha.-[{2-[(1,3,5-trimethyl- 
55 
pyrazol-4-yl)-N--benzylamino]-ethyl}- 
N--benzylaminomethyl]-phenylmethanol 
from 
1-(4-benzyloxyphenyl)-2-{2-[(1,3,5- 
trimethylpyrazol-4-yl)-N--benzyl- 
amino]-ethyl-N--benzylamino}-ethanone 
(i) .alpha.-[{2-[(1,3,5-trimethylpyrazol-4-yl)- 
45 
N--benzylamino]-ethyl}-N--benzylamino- 
methyl]-phenylmethanol from 
1-phenyl-2-{2-[(1,3,5-trimethyl- 
pyrazol-4-yl)-N--benzylamino]-ethyl- 
N--benzylamino}-ethanone 
(j) 3-benzyloxy-.alpha.-{[2-(1,4-dimethyl- 
38 
pyrazol-5-ylamino)-ethyl]-N--benzyl- 
aminomethyl}-phenylmethanol from 
1-(3-benzyloxyphenyl)-2-[2-(1,4- 
dimethylpyrazol-5-ylamino)-ethyl- 
N--benzylamino]-ethanone 
(k) 4-benzyloxy-.alpha.-{[2-(1.4-dimethyl- 
43 
pyrazol-5-ylamino)-ethyl]-N-- 
benzylaminomethyl}-phenylmethanol 
from 
1-(4-benzyloxyphenyl)-2-[2-(1,4- 
dimethylpyrazol-5-ylamino)-ethyl- 
N--benzylamino]-ethanone 
(l) 3-benzyloxy-.alpha.-{[2-(indazol-4-yl- 
35 
amino)-ethyl]-aminomethyl}-phenyl- 
methanol from 
1-(3-benzyloxyphenyl)-2-[2- 
(indazol-4-ylamino)-ethylamino]- 
ethanone 
(m) 4-benzyloxy-.alpha.-{[2-(indazol-4-yl- 
88 
amino)-ethyl]-N--benzylaminomethyl}- 
phenylmethanol from 
1-(4-benzyloxyphenyl)-2-[2- 
indazol-4-ylamino)-ethyl-N--benzyl- 
amino]-ethanone 
______________________________________ 
EXAMPLE 5 
.alpha.-{[2-(2,6-Dimethylphenylamino)-ethyl]-aminomethyl}-2-hydroxyphenylme 
thanol 
A solution of 6.8 g. (18 mMole) 
2-benzyloxy-.alpha.-{[2-(2,6-dimethylphenylamino)-ethyl]-aminomethyl}-phen 
ylmethanol (compound of Example 2a)) in 100 ml. ethanol and 10 ml. water is 
hydrogenated at ambient temperature and 1 bar hydrogen pressure in the 
presence of 1 g. 10% palladium-charcoal. The reaction mixture is then 
filtered, the filtrate is evaporated and the residue is taken up in 
acetone and mixed with the calculated amount of oxalic acid. After 
recrystallisation from acetone, there are obtained 5.4 g. of the oxalate 
of .alpha.-{[2-(2,6-dimethylphenylamino)-ethyl]-aminomethyl}-2-hydroxyphen 
ylmethanol; m.p. 112.degree.-113.degree. C. 
EXAMPLE 6 
The following compounds are obtained in a manner analogous to that 
described in Example 5: 
______________________________________ 
melting 
yield point 
designation % (solvent) 
______________________________________ 
(a) .alpha.-{[2-(2,6-dimethylphenyl- 
83 oxalate 
amino)-ethyl]-aminomethyl}- 186-188.degree. C. 
2-methoxyphenylmethanol (2-propanol) 
from the compound of 
Example 2 b 
(b) .alpha.-{[2-(2,6-dimethylphenyl- 
54 159-160.degree. C. 
amino)-ethyl]-aminomethyl}- (diethyl 
4-hydroxy-phenylmethanol ether) 
from the compound of Example 3 
(c) .alpha.-{[2-(2,6-dimethylphenyl- 
65 oxalate 
amino)-ethyl]-aminomethyl}- 85-90.degree. C. 
3-hydroxyphenylmethanol from 
(amorphous) 
the compound of Example 4 a 
(d) .alpha.-{[2-(2,6-dimethylphenyl- 
43 88-90.degree.C. 
amino)-ethyl]-aminomethyl}- (2-propanol) 
phenylmethanol from the 
compound of Example 4 b 
(e) .alpha.-{[2-(2,6-dimethylphenyl- 
56 hydro- 
amino)-ethyl]-aminomethyl}- chloride 
4-hydroxy-3-methoxyphenyl- 168-170.degree. C. 
methanol from the compound (ethanol) 
of Example 4 c 
(f) 3,5-dihydroxy-.alpha.-{[2-(2,6- 
75 hydro- 
dimethylphenylamino)-ethyl]- 
chloride 
aminomethyl}-phenylmethanol 100-110.degree. C. 
from the compound of Example 
(amorphous) 
4 d (ethyl 
acetate) 
(g) .alpha.-{[ 3-(2,6-dimethylphenyl- 
85 93-94.degree. C. 
amino)-propyl]-aminomethyl}- 
(2-propanol) 
phenylmethanol from the 
compound of Example 4 e 
(h) .alpha.{[3-(2,6-dimethylphenyl- 
76 148-150.degree. C. 
amino)-propyl]-aminomethyl}- 
(2-propanol) 
4-hydroxyphenylmethanol from 
the compound of Example 4 f 
(i) 3-hydroxy-.alpha.-{[2-(1,3,5- 
48 hydro- 
trimethylpyrazol-4-ylamino)- 
chloride 
ethyl]-aminomethyl}-phenyl- 65-70.degree. C. 
methanol from the compound of 
(amorphous) 
Example 4 g (2-propanol) 
(j) 4-hydroxy-.alpha.{[2-(1,3,5- 
45 162-164.degree. C. 
trimethylpyrazol-4-ylamino)- 
(diethyl 
ethyl]-aminomethyl}-phenyl- ether) 
methanol from the compound of 
Example 4 h 
(k) .alpha.-{[2-(1,3,5-trimethylpyrazol- 
51 dihydro- 
4-ylamino)-ethyl]-aminomethyl}- 
chloride 
phenylmethanol from the 75-80.degree. C. 
compound of Example 4 i (amorphous) 
(l) .alpha.-{[2-(1,4-dimethylpyrazol-5- 
60 dimaleate 
ylamino)-ethyl]-aminomethyl}- 
146-149.degree. C. 
3-hydroxyphenylmethanol from 
(acetone) 
the compound of Example 4 j 
(m) .alpha.-{[2-(1,4-dimethylpyrazol-5- 
77 dimaleate 
ylamino)-ethyl]-aminomethyl}- 
142-144.degree. C. 
4-hydroxyphenylmethanol from 
(acetone) 
the compound of Example 4 k 
(n) 3-hydroxy-.alpha. -{[2-(indazol-4- 
93 90-95.degree. C. 
ylamino)-ethyl]-aminomethyl}- 
(amorphous) 
phenylmethanol from the (diethyl 
compound of Example 4 l ether) 
(o) 4-hydroxy-.alpha.-{[2-(indazol-4- 
82 89-90.degree. C. 
ylamino)-ethyl]-aminomethyl}- 
(amorphous) 
phenylmethanol from the (diethyl 
compound of Example 4 m ether) 
______________________________________ 
EXAMPLE 7 
The 
1-(4-benzyloxyphenyl)-2-[2-(2,6-dimethylphenylamino)-ethylaminoe]-ethanone 
used as intermediate in Example 3 can be prepared in the following manner: 
A mixture of 6.6 g. (40 mMole) 2-(2,6-dimethylphenylamino)-ethylamine, 12.2 
g. (40 mMole) 4-benzyloxyphenacyl bromide, 150 ml. tetrahydrofuran and 5.1 
g. triethylamine is stirred at ambient temperature for 3 hours. The 
reaction mixture is then filtered and the filtrate is evaporated to give 
15.3 g. (99% of theory) 
1-(4-benzyloxyphenyl)-2-[2-(2,6-dimethylphenylamino)-ethylamino]-ethanone 
in the form of an oil. 
EXAMPLE 8 
The following compounds are obtained in the form of oils in a manner 
analogous to that described in Example 7: 
______________________________________ 
yield 
designation % 
______________________________________ 
(a) 1-(3-benzyloxyphenyl)-2-[2-(2,6- 
96 
dimethylphenylamino)-ethylamino]- 
ethanone from 
2-(2,6-dimethylphenylamino)- 
ethylamine and 3-benzyloxyphenacyl 
bromide 
(b) 2-[2-(2,6-dimethylphenylamino)- 
97 
ethyl-N--benzylamino]-1-phenyl- 
ethanone from 
N--[2-(2,6-dimethylphenylamino)- 
ethyl]-benzylamine and phenacyl 
bromide 
(c) 1-(4-benzyloxy-3-methoxyphenyl)- 
98 
2-[2-(2,6-dimethylphenylamino)- 
ethyl-N--benzylamino]-ethanone 
from 
N--[2-(2,6-dimethylphenylamino)- 
ethyl]-benzylamine and 4- 
benzyloxy-3-methoxyphenacyl 
bromide 
(d) 1-(3,5-dibenzyloxyphenyl)-2-[2- 
95 
(2,6-dimethylphenylamino)-ethyl- 
N--benzylamino]-ethanone from 
N--[2-(2,6-dimethylphenylamino)- 
ethyl]-benzylamine and 3,5- 
dibenzyloxyphenacyl bromide 
(e) 2-[3-(2,6-dimethylphenylamino)- 
100 
propyl-N--benzylamino]-1-phenyl- 
ethanone from 
N--[3-(2,6-dimethylphenylamino)- 
propyl]-benzylamine and phenacyl 
bromide 
(f) 1-(4-benzyloxyphenyl)-2-[3-(2,6- 
95 
dimethylphenylamino)-propyl-N-- 
benzylamino]-ethanone from 
N--[3-(2,6-dimethylphenylamino)- 
propyl]-benzylamine and 4- 
benzyloxyphenacyl bromide 
(g) 1-(3-benzyloxyphenyl)-2-{2-[(1,3,5- 
95 
trimethylpyrazol-4-yl)-N--benzyl- 
amino]-ethyl-N--benzylamino}- 
ethanone from 
N--{2-[(1,3,5-trimethylpyrazol-4-yl)- 
N--benzylamino]-ethyl}-benzylamine 
and 3-benzyloxyphenacyl bromide 
(h) 1-(4-benzyloxyphenyl)-2-{2-[(1,3,5- 
95 
trimethylpyrazol-4-yl)-N--benzyl- 
amino]-ethyl-N--benzylamino}- 
ethanone from 
N--{2-[(1,3,5-trimethylpyrazol-4-yl)- 
N--benzylamino] -ethyl}-benzylamine 
and 4-benzyloxyphenacyl bromide 
(i) 1-phenyl-2-{2-[(1,3,5-trimethyl- 
98 
pyrazol-4-yl)-N--benzylamino]- 
ethyl-N--benzylamino}-ethanone from 
N--{2-[(1,3,5-trimethylpyrazol-4-yl)- 
N--benzylamino]-ethyl}-benzylamine 
and phenyacyl bromide 
(j) 1-(3-benzyloxyphenyl)-2-[2-(1,4- 
100 
dimethylpyrazol-5-ylamino)-ethyl- 
N--benzylamino]-ethanone from 
N--[2-(1,4-dimethylpyrazol-5-yl- 
amino)-ethyl]-benzylamine and 3- 
benzyloxyphenacyl bromide 
(k) 1-(4-benzyloxyphenyl)-2-[2-(1,4- 
92 
dimethylpyrazol-5-ylamino)-ethyl- 
N--benzylamino]-ethanone from 
N--[2-(1,4-dimethylpyrazol-5-yl- 
amino)-ethyl]-benzylamine and 4- 
benzyloxyphenacyl bromide 
(l) 1-(3-benzyloxyphenyl)-2-[2- 
94 
(indazol-4-ylamino)-ethylamino]- 
ethanone from 
2-(indazol-4-ylamino)-ethylamine 
and 3-benzyloxyphenacyl bromide 
(m) 1-(4-benzyloxyphenyl)-2-[2- 
85 
indazol-4-ylamino)-ethyl-N--benzyl- 
amino]-ethanone from 
N--[2-(indazol-4-ylamino)-ethyl]- 
benzylamine and 4-benzyloxyphenacyl 
bromide 
______________________________________ 
EXAMPLE 9 
Tablets are produced, each of which contains 10 g. 
.alpha.-{[2-(3-nitrophenylamino)-ethyl]-aminomethyl}-phenylmethanol. The 
tablets are produced with the following formulation: 
______________________________________ 
.alpha.-{[2-(3-nitrophenylamino)-ethyl]- 
10 g. 
aminomethyl}-phenylmethanol 
lactose 80 g. 
starch 29 g. 
magnesium stearate 1 g. 
______________________________________ 
The above-mentioned active compound is finely pulverised and mixed with the 
lactose and starch. The mixture is then granulated in conventional manner. 
The magnesium stearate is added to the granulate and the mixture is 
pressed to give 1000 tablets, each having a weight of 0.12 g. 
A test of the inotropic effect of the compounds according to the invention 
was made by way of the measurement of hemodynamics. The haemorheological 
effect was also determined. 
HEMODYNAMICS 
For the investigations mixed-bred dogs of both sexes were used which in a 
preparatory operation under aseptic conditions had been implanted with 
catheters in the A. and V. femoralis and through the myocardium in the 
left ventricle. Not before 10 days after this operation, when the animals 
were once again in a clinically healthy state, were the tests begun. 
During the entire test, the animals were in the conscious state. The 
arterial blood pressure was recorded continually through the catheter with 
an electromechanical pressure transducer. In addition, by means of a 
pressure recorder (tipmanometer) which was introduced into the ventricle 
catheter and pushed right up to the heart, the pressure in the left 
ventricle was continually measured and from it, by differentiation with 
respect to time (dp/dt.sub.max) the heart output was determined. The heart 
rate was calculated by counting the heart action with rapid paper advance 
over a predetermined time of measurement. Through puncture electrodes, the 
ECG for recognizing arrhythmias and extrasystoles was obtained. All 
parameters were recorded on a direct recorder (made by Schwarzer). 
The doses were i.v. administered cumulatively in a range between 1 and 256 
mcg/kg. 10 minutes after each administration of the compound, 
dp/dt.sub.max, the heart frequency and the mean blood pressure were 
determined. 
For the determination of the effect of the substance, the regression line 
was computed from the logarithm of the dose and dp/dt.sub.max. From it, 
the dose at which the starting values increased 50% was interpolated. 
To exemplify the inventive compounds the effects of representative 
inventive compounds were measured and the results entered in Table 1. As a 
rule the heart frequency rose while the blood pressure dropped. 
RHEOLOGY 
The rheology investigations were carried out in vitro with the following 
three methods. The flow shear stress was determined with the erythrocyte 
stasis apparatus (1). Using a selecting erythrocyte rigidometer (SER), on 
a membrane with a single hole, the erythrocyte passage time was measured 
(2). As a measure of the aggregation tendency of the erythrocytes, the 
erythrocyte aggregation index was determined by means of an aggregometer 
(3). All investigations were conducted with the blood of patients with 
peripheral circulatory disorders (stage 2 according to Fontaine). Two 
erythrocyte suspensions were prepared with a hematocrit of 45%. One 
contained only the corresponding volume in solvent, while the other 
contained the inventive compound to be tested. The compound concentration 
was 10.sup.-8 mol/l for each test. After 30 minutes of incubation, the 
rheological investigations were conducted. 
The results of this testing is presented in Table 2. It shows that without 
appreciably changing the erythrocyte aggregation index the flow shear 
stress and the erythrocyte rigidity are reduced by the inventive 
compounds. 
Therefore, the inventive compounds are not only positively inotropic, but 
they also reduce the blood viscosity, which expresses itself in a reduced 
flow shear stress. A parameter responsible for these effects is 
erythrocyte deformability. Our results therefor show that the rigidity of 
the erythrocytes of the patients is reduced. But since the aggregation 
tendency remains unchanged, the improvement of erythrocyte deformability 
appears to be responsible for the reduction of the flow shear stress. 
LITERATURE 
1. H. Radtke: 
Determination of the flow shear stress of blood and erythrocyte suspension 
in a capillary viscosimeter with y-shaped branching. Dissertation at the 
RWTH Aachen, West Germany (1982). 
2. H. G. Roogenkamp: F. Jung; H. Kiesewetter: 
Apparatus for the electrical measurement of the deformability of 
erythrocytes. Biomed. Tech. 28, 100-104 (1983) 
3. H. Kiesewetter: H. Radtke; R. Schneider; K. Mussler; A. Scheffler; H. 
Schmidt-Schonbein: 
The Mini erythrocyte aggregometer: A new device for rapid quantification of 
the extent of erythrocyte aggregation. Biomed. Tech. 27, 209-213 (1982). 
TABLE 1 
______________________________________ 
PHARMACOLOGICAL DATA 
DE.sub.150% = required dose to increase dp/dt.sub.max 50% relative to 
the starting value 
Compound Example 
DE.sub.150% (mcg/kg) 
______________________________________ 
(6j) 1.36 
(6n) 11.5 
(6c) 15.9 
(5) 28.9 
(6a) 275.9 
(6b) 3.8 
______________________________________ 
TABLE 2 
__________________________________________________________________________ 
RHEOLOGICAL DATA 
Mean value .+-. standard decrease (of 3 patients) 
Flow shear stress (mPa) 
Mean passage time (msec) 
Aggregation index 
control 
Example 6c) 
Example 6c) 
control 
Example 6c 
Example 6c 
control 
Example 
Example 
__________________________________________________________________________ 
6c 
0.3 .+-. 0.08 
0.04 .+-. 0.08 
0.09 .+-. 0.08 
18.8 .+-. 3.5 
14.8 .+-. 1.6 
16.2 .+-. 4.1 
14.8 .+-. 3.2 
14.4 .+-. 3.6 
15.5 .+-. 
__________________________________________________________________________ 
2.7 
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.