Note: Descriptions are shown in the official language in which they were submitted.
~0'7704'2
The new 4-hydroxy-aporphine derivatives according
to the present invention are compounds of the general formula:
R 2 0~ H R S
11 1 .
R30
OR4
wherein Rl R2, R3 and R4, which may be the same or different,
are methyl or ethyl radicals, R5 is a hydrogen atom or a
straight-chained, cyclic or branched alkyl radical containing
up to 5 carbon atoms and the symbol X or Y in the trans- pos-
ition to the 6a hydrogen atom represents a hydroxyl group while
the remaining X or Y symbol represents a hydrogen atom, with
the proviso that when R5 is a methyl radical, then at least
one of the substituents Rl, R2, R3 or R4 is an ethyl radical.
The pharmaceutically acceptable acid addition salts
are also encompassed by this invention.
The wavy line in the 6a-position of the formula
indicates an a- or ~-bonding of the hydrogen atom. When the
hydrogen atom has the ~- configuration, then X is a hydroxyl
group and Y is a hydrogen atom. When the hydrogen atom has the
~-configuration, Y is a hydroxyl group and X is a hydrogen atom.
When R5 is a straight-chained alkyl radical, it may
be a methyl, ethyl, n-propyl, n-butyl or n-pentyl radical.
Cyclic radicals include, for example cycloalkylalkyl radicals,
` ~07704Z
such as cyclopropylmethyl and cyclobutylmethyl radicals.
Branched-chain alkyl radicals include, for example, isopropyl,
isobutyl and isopentyl radicals.
Compounds of general formula (I) are preferred in
which Rl, R2, R3 and/or R4 is a methyl or ethyl radical and
R5 is a hydrogen atom or a methyl, ethyl or n-propyl radical.
Prior to our invention, only a limited number of
compounds with the aporphine structure according to general
formula (I) (with a hydroxyl group in the 4-position) have
been described. Besides the naturally-occuring (t)-cataline
( (~)-l-hydroxy-5-oxo-5H-pyrido l3~2a~1 phenoxazine-3-carboxylic
acid) isolated from Glaucium flavum Cr. var. vestitum Tetra~
hedron Letters, p. 2033/1972, (~)-cataline has recently been
synthesised by the oxidation of (t)-thaliporphine ((~)-5, 6,
6a, 7-tetrahydro-2, 9, 10-trimethoxy-6-methyl-4H-dibenzo [de,
g~ quinolin-l-ol) with lead tetraacetate in acetic acid yield-
ing (t)-4~-acetoxythaliporphine, which was then acid hydrolysed
with hydrochloric acid at ambient temperature to give (t)_4~_
hydroxythaliporphine which was, in turn, 0-methylated with
diazomethane (J.C.S. Chem. Comm., p. 306/1975).
Aporphine derivatives have also been prepared by the
intramolecular, non-phenolic oxidative coupling of tetrahydro-
isoquinolines (J.A.C.S., 95, 6861/1973). However, prior to our
invention, 4-hydroxy-aporphine derivatives have not been obtain-
able by this route. This coupling requires the cyclization of
laudanosine in a solvent mixture of fluorosulphinic acid,
methylene chloride and trifuloroacetic acid in a reaction solu-
tion of vanadyl trifluoride in trifluoroacetic acid. This pro-
cess yields glaucine which is unsubstituted in the 4-position.
1~77042
We have now found that the above-described reaction
can be directed in such a manner that there is formed a 4-hydro-
xy-substituted aporphine derivative of general formula (I) or
general formula ~I') when, instead of the solvent mixture of
methylene chloride and trifuloroacetic acid, there is used
trifluoroacetic acid without the admixture of organic solvents.
This finding is extradordinarily surprising, since
the hydroxylation effect according to our invention also in-
volves a remarkably high regio-and stero-selectivity. It is
also surprising that hydroxyaporphines are exclusively formed
which carry the hydroxyl function in the 4-position since the
aporphine system contains three reactive benzylic positions.
Since the l-position of general formula II contains a more
reactive hydrogen atom, it would be expected that a hydroxyl-
ation, if at all, would take place at this position, however,
under the conditions of the process according to the present
invention, the hydroxyl group enters preponderantly in the trans
4-position (referred to the 6a-hydrogen atom in general formula
(I) or (I'). A further characteristic feature of the present
invention is that the chiralic center in the tetrahydroisoquin-
oline (C-l) and in the aporphine ring system (C-6a) remains
intact under the reaction conditions, i.e. that when using the
optically-active tetrahydroisoquinolines of general formula
(II), the corresponding optically-active 4-hydroxyaporphine
of formula (I) or (I') are obtained.
1~7704Z
Consequently, the present invention also provides a
process for the preparation of compounds of the general formula:
X ' ~ , Y '
R' ~0~
R 2~;,N_Rl 5
I H (I ' )
R' 30~ ~
o R l 4
as well as of the salts thereof with organic and inorganic
: acids, wherein R'l, R'2, R'3 and R'4, which may be the same
or different, are methyl or ethyl radicals and R'5 is a hydro-
gen atom or a straight-chained, cyclic or branched alkyl radi-
cal containing up to 5 carbon atoms and the symbol X' or Y'
in the trans-position to the 6a-hydrogen atom represents a
hydroxyl group, while the remaining X' or Y' symbol represents
a hydrogen atom, by the cyclisation of a compound of the
general formula:
R ' 1 O~
R 2 ~ N-R 5
~ (II),
R ' 30 /[~
R l 4
107704Z
wherein R'l, R'2, R'3, R'4 and R'5 have the same meanings as
above, in trifluoroacetic acjd, by reaction with vanadyl tri-
fluoride. The reaction is carried out at a temperature of
from -50 to 10C, preferably from -15 to 0C., without the
admixture of an organic solvent. The vanadyl trifluoride used
in a molar excess and water being subsequently added. The
compound of general formula (I') is thus obtained and, if
desired, converted into an acid addition salt.
As starting materials for the process according to
the present invention, there can be used not only the racemic
but also the enantiomeric compounds of general formula (II).
Some of these starting materials are known, for example,
laudanosine (l-C(3,4-dimethoyxphenyl)methyl] -1,2,3,4-tetra-
hydro-6, 7-dimethoxy-2-methylisoquinoline) and N-ethyl- and
N-propyl-tetrahydropapaverine. They are preferably prepared
from the corresponding tetrahydroisoquinolines, for example
tetrahydropapaverine, by alkylation (J. Chem. Soc., p. 1481/
1962) or from the corresponding isoquinolines, for example,
papaverine (l-r(3,4-dimethoxyphenyl)methyl~-6,7-dimethoxyiso-
quinoline) by alkylation and subsequent reduction, preferably
by means of sodium borohydride (Ber. 90, 1997/1957).
For carrying out the reaction, the starting compounds
of general formula (II) are dissolved, while cooling, in tri-
fluoroacetic acid and mixed dropwise at -10 to -15C with an
excess amount of a vanadyl trifluoride trifluoroacetic acid
solution, the reaction mixture becoming a red-violet color.
It is generally preferable to use about a 2.5 mol excess of
vanadyl fluoride per mol of tetrahydroisoquinoline to assure
all the starting material is reacted.
After the addition of the vanadyl trifluoride solu-
tion, the reaction mixture is further stirred for about 3 to
-- 5 --
~07704'2
4 hours at -10 to -15C and thereafter allowed to rise to
ambient temperature. After stirring for one hour at ambient
temperature, the trifluoroacetic acid is removed in a vacuum
and the residue, after being rendered alkaline, is partitioned
between water and an organic solvent, for example, chloroform,
methylene chloride or diethyl ether.
The 4-hydroxyaporphine may be obtained from the
organic phase either by direct crystallization from an organic
solvent or from an organic solvent mixture or after previous
chromatographic separation on an inert carrier material, for
example, silica gel or basic aluminum oxide by removal of the
elution agent.
According to a preferred variant of the new process,
the amount of expensive trifluoroacetic acid needed for the
preparation of the vanadyl trifluoride solution (because of the
poor solubility of vanadyl trifluoride in trifluoroacetic acid,
relatively large volumes are necessary) is replaced by an inex-
pensive liquified sulphur dioxide. In this case, it is
preferable to place the vanadyl trifluoride in liquified
sulphur dioxide and to add dropwise a solution of the tetra-
hydroisoquinoline in trifluoroacetic acid at a temperature of
from -15 to -50C. Here, too, a coloration of the reaction
mixture towards red-violet is observed. At the end of the
dropwise addition, the reaction mixture is stirred for 4 - 5
hours at -10 to -15C. The sulphur dioxide is then allowed to
evaporate at ambient temperatures, the trifluoroacetic acid
is removed in a vacuum and the residue treated as described
above.
The salts of compounds of general formula (I) or
(I') can be obtained by neutralization of the free bases with
pharmacologically compatible inorganic or organic acids, for
example, hydrochloric acid, sulphuric acid, phosphoric acid,
-- 6 --
'1~7704Z
hydrobromic acid, acetic acid, tartaric acid, lactic acid,
citric acid, malic acid, salicyclic acid, ascorbic acid,
malonic acid, maleic acid or succinic acid.
The following examples are given for the purpose of
illustrating the present invention:
EXAMPLE 1
(t)-4-Hydroxy-1,2,9,10-tetramethoxyaporphine
Variant A:
2 9. (t)-laudanosine is dissolved in 25 ml. trifluoro-
acetic acid and mixed dropwise at -15C., while stirring and
with the exclusion of moisture, with a solution of 1.73 9.
vanadyl (V) fluoride in 50 ml. trifluoroacetic acid. The dark
red solution obtained is stirred for a total of 4 hours at
-15C., then warmed to about 0C. and the greater part of the
trifluoroacetic acid removed under slightly reduced pressure.
The residue is partitioned between water and chloroform. The
organic phase is treated with an aqueous solution of ammonia
and again washed with water. After drying in a vacuum, 2.1 9.
of a yellow syrup remains. Either by direct crystallization
2G (ethyl acetate/diethyl ether) or, after previous chromatography
on silica gel or a basic aluminium oxide, there is obtained
(t)-4-hydroxy-1,2,9,10-tetramethoxyaporphine; m.p. 152 - 153C.
The corresponding acetate melts at 169 - 170C. NMR spectrum
(60 MHz, CDCL3) ~ 2.54 (s,3H,N-CH3), 3.63 (s,3H,OCH3), 3.90
(s,3H,OCH3), 3.93 (s,6H,20CH3), 4.50 (m,lH,4-H), 6.77 (s,lH,
ArH), 6.90 (s,lH,ArH), 8.07 (s,lH,LL-H).
Variant B:
0.93 g. vanadyl fluoride is suspended in about 60 ml.
liquified sulphur dioxide. To the suspension is slowly added
dropwise at -45C. a solution of 1.07 9 (-)-laudanosine in 5 ml.
107704Z
trifluoroacetic acid; the reaction mixture becoming red-violet
colored. After stirring for 2 hours at -45C., a clear, deep
red solution is obtained. This solution is stirred for an
additional 4 hours at -15C. By warming to ambient temperature,
the sulphur dioxide is first evaporated off, ~ollowed by the
trifluoroacetic acid under a vacuum. The residue is mixed with
a aqueous solution of ammonia and extracted with chloroform.
Further working up is then carried out as described in Varient
A. Chromatography on silica gel with chloroform containing
0.1% triethylamine as elution agent gives 300 mg. (t) 4_
hydroxy-1,2,9,10-tetramethoxyaporphine, as well as 300 mg. of
the starting material, i.e. (~)-laudanosine.
EXAMPLE 2
(t)-4-HYdroxy-l~2~9~lo-tetramethoxyaporphine (cataline) and
(-)-4-hydroxy-1,2,9,10-tetramethoxyaporphine.
2 9. (~)-lauanosine (Eur. J. Med. Chem., 9, 237/1974)
is reacted, in the manner described in Example 1, with 1.73 9.
vanadyl (V) fluoride in trifluoroacetic acid. After analogous
working up and crystallisation from diethyl ether, there is
obtained (~)-4-hydroxy-1,2,9,10-tetramethoxyaporphine (cataline)
in the form of colourless crystals; m.p. 180-182C; ~7D = +
139.7 (1.04 in chloroform).
Analysis:
C21 H25N5
calc : C 67.91%;H 6.78%; N 3.77%
found : 68.16~;6.72%; 3.55%
UV: A EaOXH : 217 (39.500), 230 (sh 29.000), 272 (sh 12.000j,
218 (14.500), 301 (13.600), 312 (sh 12.000) nm
The corresponding acetate melts at 127C. after
recrystallisation from diethyl ether/petroleum ether.
.... ~ ', ~ ' ~ , .
~07704Z
In a corresponding manner, from (-~-laudanosine
there is obtained the enantiomeric (-)-4-hydroxy-1,2,9,10-
tetramethoxyaporphine, which melts at 179 - 180C.; L a_/
-147.7 (0.9 in chloroform).
Analysis:
C21H25N5
calc. : C 67.91%;H 6.78%;N 3.77%
found : 67.56%;6.75%; 3.59%
U~: ~ mtaOxH :218 (39.300), 281 (14.500), 302 (13.600),
313 (12.1oo) nm
EXAMPLE 3
(~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-
dibenzo ~de, g]quinolin-4-ol
2.31 g (~)-diethoxy-1-(3',4'-diethoxybenzyl)-2-
methyl-1,2,3,4-tetrahydroisoquinoline (Ber., 99, 2873/1966) is
dissolved in 25 ml. trifluoroacetic acid and mixed dropwise
at -15C. with a solution of 1.73 9. vanadyl fluoride in
50 ml. trifluoroacetic acid. The red-violet solution obtained
is stirred for 4 hours at -15C. and for 1 hour at ambient
temperature. The reaction mixture is evaporated in a vacuum,
the residue mixed with ice water and 5% aqueous sodium bicar-
bonate solution and extracted with chloroform. The crude
product obtained after drying and removing the solvent is
chromatographed on silica gel with methylene chloride/methanol
(99:1 v/v) and the eluate obtained is evaporated to give 657 mg.
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-methyl-4H-
dibenzo ~de,~a quinoline, the hydrobromide of which, after
recrystallisation from ethanol/diethyl ether, melts at 198 - -
199C., together with 721 mg.(~)-5,6,6a,7-tetrahydro-1,2,9,10-
tetraethoxy-6-methyl-4H-dibenzo rde,g7quinolin-4-ol which,
g _
107704Z
after recrystallisation from diethyl ether/petroleum ether,
melts at 140 - 142C. NMR spectrum (CDC13) ~ 1.43 (m,12H,OCH2
CH3), 2.47 (s,3H,N-CH3), 4.0 (m, -OCH2CH3), 4.42 (m,lH,4-H),
6.69 (s,lH,ArH), 6.80 (s,lH,ArH), 8.01 (s,lH,ll-H).
EXAMPLE 4
(~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-
4H-dibeno [de,~ quinolin-4-ol.
11.95 9. (~)-10(3,4-dimethoxybenzyl)-6,7-dimethoxy-
2-n-propyl-1,2,3,4-tetrahydroisoquinoline (J. Chem. Soc., p.
1481/1962) is dissolved at 0C. in 50 ml. trifluoroacetic acid.
A solution of 9.6 9. vanadyl fluoride in 350 ml. trifluoroacetic
acid is added dropwise, with stirring, to this solution at
-15C. After the addition, the reaction mixture is stirred
for 2 hours at -15C. and for 2 hours at ambient temperature.
The reaction mixture is worked up in the manner described in
Example 1 and direct crystallisation of the crude product from
diethyl ether gives 2.6 9. (~)-5,6,6a,7-tetrahydro-1,2,9,10-
tetramethoxy-6-n-propyl-4H-dibenzo rde,~7 quinolin-4-ol, which
melts at 153 - 154C. By chromatography on basic aluminum oxide
(activity stage III) with methylene chloride/petroleum ether
(1:1 v/v) as elution agent, further amounts of thin layer
chromatographically pure product are obtained. NMR spectrum
(60MHz,CDC13), ~ 0.96 (m,3H,CH3), 1.6 (m,2H), 3.65 (s,3H,OCH3),
3.88 (s,9H,3xOCH3), 4.44 (m,lH,4-H), 6.77 (s,lH,Ar-H), 6.95
(s,lH,ArH), 8.02 (s,lH,ll-H).
- 10 ;.,
~0'7704Z
EXAMPLE 5
(4S,6aS)-(~)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-
propyl-4H-dibenzo Lde,g1 quinolin-4-ol.
14.8 9. (+)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-
n-propyl-1,2,3,4-tetrahydroisoquinoline (-)-dibenzoyltartrate
is converted into the base by treatment with ammonia and extra-
ction with chloroform. The solvent is removed in a vacuum and
the residue taken up in 35 ml. trifluoroacetic acid. A solu-
tion of 6.38 9 vanadyl fluoride in 250 ml. trifluoroacetic acid
is added dropwise to this solution at -15C., while stirring,
in the course of 30 minutes. After completion of the addition,
stirring is continued for 2 hours at -15 to -10C. and for 2
hours at ambient temperature, followed by working up in the
manner described in Example 1. Chromatography on basic aluminum
oxide with methylene chloride/petroleum ether (1:1 v/v) and
crystallization from diethyl ether gives (4S,6aS)-( )-5,6,6a,7-
tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-dibenzorde,g¦
quinolin-4-ol in the form of colorless crystals which melt at
152 - 153C-; r~]D ~ 132.5 (0.5 in chloroform). NMR spectrum
20 (60 MHz, CDC13), ~ 1.0 (m,3H), 1.6 (m,2H), 3.64 (s,3H,OCH3),
3.89 (s,9H,3xOCH3), 4.44 (m,lH,4-H), 6.75 (s,lH,ArH), 6.83
(s,lH,Ar-H), 8.02 (s,lH,ll-H).
The dextrarotary 1-(3,4-dimethoxybenzyl)-6,7-dimeth-
oxy-2-n-propyl-1,2,3,4-tetrahydroisoquinoline used as starting
material was obtained as follows from the racemic compound
(J. Chem. Soc., p. 1481/1962); 16 9. of racemic hydrochloride
was converted into the base by treatment with ammonia. Extra-
ction with chloroform, drying and evaporating in a vacuum gives
the base in the form of a viscous oil which is taken up in
- ' ' ' .' ~
107704Z
!
ethanol and mixed with 14.30 9. (-) dibenzoyl-tartaric acid.
After seeding, the product is left to crystallize at ambient
temperature. The crystals obtained are then recrystallized
twice from hot isopropanol. The yield is 5 9. and the product
melts at 155 - 156C.; [~]C =~17.9 (1 in chloroform).
The base is liberated from the salt by treatment
with dilute aqueous ammonia solution. Extraction with chloro-
form, drying, evaporation and subsequent recrystallization
from aqueous ethanol gives crystalline (t)-1-(3,4-dimethoxy-
benzyl)-6,7-dimethoxy-2-n-propyl-1,2,3,4-tetrahydroisoquino-
line, which melts at 78 - 80C.; r~ ~D = f76.2 (1 in chloro-
form).
EXAMPLE 6
(4R,6aR-(-)-5,6,6a,7-Tetrahydro-1,2,9,10-tetramethoxy-6-n-
propyl-4H-dibenzo ~de,~ quinolin-4-ol.
11.35 9. (-)-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-
n-propyl-1,2,3,4-tetrahydroisoquinoline (t)-dibenzoyl-tartrate
is converted into the base by treatment with ammonia and extra-
cted with chloroform. The base, after freeing from solvent
and drying, is dissolved in 27 ml. trifluoroacetic acid and
mixed, within the course of 30 minutes, at -15C. with a solu-
tion of 4.89 9. vanadyl fluoride in 192 ml. trifluoroacetic
acid. after further proceeding in a manner analogous to that
described in Example 1, there is obtained, 5.02 9. of crude
product which, for further purification, was chromatographed
on 300 9. basic aluminium oxide (activity state III) with a
mixture of petroleum ether/chloroform (85.15 v/v) as elution
agent. The fractions containing the desired product are com- ;`
bined and evaporated in a vaccum and the residue is
1077042
crystallized from diethyl ether. There is obtained (4R,6aR)-
(-)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-n-propyl-4H-
dibenzo ~de,~ quinolin-4-ol in the form of colorless crystals
which melt at 151 - 153C.i ~D = -142.4 (0.5 in chloroform).
The NMR spectrum is identical with the spectrum of the enantio-
meric compound (see Example 5).
Laevorotary 1-(3,4-dimethylbenzyl)-6,7-dimethoxy-2-
n-propyl-1,2,3,4-tetrahydroisoquinoline was obtained, analog-
ously to the preparation of the dextrarotary enantiomer, from
the racemic compound (J. Chem. Soc., p. 1481/1962), as the
D-dibenzoyl-tartrate, which melts at 154 - 155C.; [ ~ D =
-18.2 (1 in chloroform). From the dibenzoyl-tartrate, the
free base is obtained by treatment analogous to that described
in Example 5. The free base melts at 78 - 79C.; [~]D =
-77.1 (1 in chloroform).
EXAMPLE 7
(t)-4-Hydroxy-1,2,9,10-tetramethoxy-N-noraporphine
2 9. (~)-Tetrahydropapaverine hydrochloride is con-
verted into the base by treatment with semi-concentrated aqueous
ammonia solution. It is extracted with chloroform, dried and
the solvent removed in a vacuum. The residue is dissolved in
20 ml. trifluoroacetic acid and mixed dropwise at -15 C., while
stirring, with a solution of 1.64 9. vanadyl fluoride in 100 ml.
trifluoroacetic acid within the course of 15 minutes. The
mixture becomes deep red colored. The reaction mixture is
further stirred for 1 hour at -15 to -10C. and for 4 hours at
ambient temperature, followed by working up in the manner des-
cribed in Example 1. The product obtained (2.11 9. of dark
brown foam) is, for further purification, chromatographed on
100 9. basic aluminium oxide (activity stage III) with chloro-
form/triethylamine (99:1 v/v) as elution agent. Besides
500 mg. (t)-N-norglaucine (yellow foam; hydrobromide m.p.
- 13 -
~077042
252 - 253C.), 720 mg. 4-hydroxy-N-norglaucine is obtained
which, after recrystallization from diethyl ether, melts at
143 - 146C. NMR spectrum (60 MHz, CDC13) ~ 3.66 (s,3H,OCH3),
3.92 (s,9H,3xOCH3), 4.52 (m,lH,4-H), 6.73 (s,lH,ArH), 6.89
(s,lH,ArH), 8.10 (s,lH,ll-H).
The following compounds are prepared in an analogous
manner:
(t)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-isobutyl-
4H-dibenzo rde,g1 quinolin-4-ol;
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetraethoxy-6-n-pentyl-
4H-dibenzo ~de,~ quinolin-4-ol;
(t)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-isopropyl-
4H-dibenzo rde,g7quinolin-4-ol;
(~)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-cyclopropyl-
methyl-4H-dibenzo Lde,~7quinolin-4-ol;
(~)-5,6,6_,7-tetrahydro-1,2-diethoxy-9,10-dimethoxy-6-
cyclobutylmethyl-4H-dibenzo rde,~7 quinolin-4-ol.
The preceding Examples are summarised in the follow-
ing Table:
- 14 -
1~7704Z
__~ ~ 7~ t~ ~ t ~ t ~ 1
I I I _ Q O ~
~ ~ O I ~ ~ O Q_ ~ .
~_ O ~ O
C~l C~l C~l ~ ~ ~ , S _ S
~ I T I I I I O Q O ~ ~ (.) ~
1~ ~ ~ c~ ~_) ~ ~ ~_) ~ 'I ~ ~ ~
_
t~) N ~ ~) ~ ~ ~') C~l
I I I I T I I I I I I
~ ~ ~ ~ C~ ~ C~ ~ L,~ t~ ~ ~ ~
_ I _ _ _
~ ~ C" ~ C~l ~ ~ ~ ~ ~ ~ ~ ~ ~
O I I I T I I I I I T I
~ _ ~ ~_) ~ ~.) ~ ~ ~ ~ ~ t_~ ~ ~ C~
I_ ~ ~ ~ I _ _ ~ I I
I I I ` I I -r I I I I I I
_ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
_ ~ _ _ _ T _ T
,: I ~ ~ ~
C~ ~ ~ t~) t~ ~') ~ N (~) ~ N
I I I ' I I I I I I I I
N ~ ~) C~ C,~ ~ ~.) C_~ ~ ~ ~ <_~
L, . ' ~L~ L ' ' ~
. ., E ~ c~l ~ d- In ~D I~ ~ I~ I~ I~ ~
o X ~,,,,, ., .i,__ __ . l
_ 1 5
,,: , ,' . ,
~077~4Z
Some of the 4-hydroxyaporphines of general formula
(I) obtained by the process according to the present invention
are valuable intermediates for the preparation of pharmacolog-
ically-effective products and some of them themselves possess
interesting pharmacological properties. In particular, they
have a remarkable action on the cardiovascular system.
Thus, they lower the blood pressure of hyper- and
normotensive subjects. Therefore, those compounds not merely
used as intermediates may also be used for the treatment of
cardiovascular diseases which are to be attributed to hyper-
tension.
The compounds of general formula (I) according to
the present invention can be administered orally or parenter-
ally in liquid or solid form. As injection solution, it is
especially preferred to use water which contains the additives
usual in the case of injection solutions, such as stabilizing
agents, solubilizing agents or buffers.
Additives of this type include, for example, tartrate
and citrate buffers, ethanol, complex-forming agents (such as
ethylenediamine-tetraacetic acid and the non-toxic salts there-
of), as well as 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 acid, 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 flavoring and/or
sweeting agents.
- 16 -
~077042
Thus, the present invention also provides pharma-
ceutical compositions containing at least one of the new
compounds according to the present invention, in admixture
with a solid or liquid pharmaceutical diluent or carrier.
; . ' :
