Note: Descriptions are shown in the official language in which they were submitted.
I
0.Z.0050/36243
Phenylpropanolam;nes, their preparation_ and their use
The present invention relates to novel phenylpro-
panolamines, processes for their preparation and their
use in the treatment of disorders.
The phenoxypropanolamine moiety is an essential
structural feature of conventional beta-receptor blockers,
such as toliprolol or bupranolol. Furthermore, USA Patent
2,695,919 discloses phenoxy-substituted phenylalkanolam;nes
which have local anesthetic and bronchodilatory actions.
We have found structurally modified compounds
which have a different action spectrum.
The present invention relates to phenylpropanol-
amine of the formula I
I OR ~H2~B5
where R1 is hydrogen or halogen, R2 is hydrogen, a
saturated or unsaturated hydrocarbon radical of not more
than 15 carbon atoms or phenol, R3 is hydrogen, a sat-
rated or unsaturated hydrocarbon radical of not more than
3 carbon atoms, C1-C4-acyl~ Bunnell, Cz-C4-carb-
alkoxy or a carboxamido group -C0-NHR6, where R6 is
C1-C4-aLkyl, R4 is hydrogen or halogen, R5 is
dimethylamino, piperidino or pyrrolidino and X is oxygen
or sulfur, and their salts with physiologically tolerated
acids.
In formula I, R1 and R4 are preferably each
fluorine, chlorine or bromide in the para-position, but
are each, in particular, hydrogen. R2 is preferably
hydrogen or C1-C4~alkyl, R3 is preferably hydrogen
or C1-C2-acyl and R5 is preferably dimethylamino.
Phenylpropanolamines of the formula I can be pro-
pared by a method in which a compound of the formula II
62!3~.
- z osseous
,f~.4
I
2 \=/ I I
CRY
where R1, R4, R5 and X have the above meanings,
a) is reduced, or
b) is reacted with an appropriately substituted organ-
metallic compound and if desired, the resulting compound is etherified
or esterified and/or converted to its salts -with phase-
logically tolerated acids.
The reduction a) of the compounds II is carried
out in a conventional manner with catalytically activated
hydrogen using, for example, a palladium/carbon catalyst
in an alcohol, or with a metal hydrae ego lithium alum-
nut hydrae d;borane or sodium bordered. This pro-
seedier gives the compounds of the formula I in which R2
and R3 are each hydrogen.
Reaction b) is preferably carried out using Grog-
nerd compounds of the formula R2MgHal or R2Li. This
procedure gives the compounds of the formula I in which
R2 is a hydrocarbon radical or phenol and R3 is hydra-
gent This reaction, like other conventional Grignard
reactions, us carried out in ether or tetrahydrofuran
at from 0 to 60C, the Grignard compound being used
in excess Ether the free bases or the salts of the
compounds of the formula II can be used in this reaction.
The resulting compound of the formula I, where
R3 us hydrogen, can be converted to its alkyd or azalea
derivatives on a conventional manner Reaction with azalea
halides or alkyd halides in a bipolar aprotic solvent, ego
preferably dimethylformamide, on the presence of a base,
ego sodium hydrides leads to the desired compounds of the
~LZ26Z9~
- 3 - OOZE
formula I on which R3 has the above meanings, with the
exception of hydrogen The carboxam;do compounds (R3
= CONNER) are obtained from the compounds I try
= OH) by reaction with an appropriate isocyanate in a
solvent, such as acetonitrile.
The compounds I contain 2 asymmetric carbon atoms,
and are therefore expected to occur as d;astereomers.
However, we have found that, as a result of asymmetric
induction, both the reduction and the action of organ-
metallic reagents on the compounds of the formula II juvenile one diastereomer, which can, if desired, be resolved
into the enantiomers in a conventional manner.
The starting materials of the formula II which
are required for preparation of the compounds I have not
been described to date. They can be prepared from the
corresponding phonics- or ~-thiophenoxyprop;ophenones
by reaction with N,N-substituted ~ethyleneimonium Shelley-
rides (cf. Anger. Chum. 88 t1976), 2161).
The substances according to the invention are
ZOO useful for treating psychological illnesses, on portico-
far depression.
The mechanism of action of a group of therapeutic
gaily frequently used antidepressants (erg. tr1cyclic anti-
depressants) comprises inhibition of the neuron Al uptake
of transmitter substances tnorepinephrine anger surety-
nun). This property is used in biological test models
for characterizing potential antidepressants. The follow-
in method was employed:
Inhibition of neurotransmitter uptake in rat brain sync
aptosomes
The hippo campus and cortex from rat brain were prepared, and homogenized in 0.32 M sucrose solution.
Synaptosomes were obtained by differential centrifuging,
and were suspended in buffer solution. The synaptosomes
are capable of actively taking up added neurotransmitter
substances leg. norepinephrine or serotonin) from the
surrounding medium. my means of uptake inhibitors, it
2629~
- - OOZE
us possible to antagonize this process as a function of
concentration. The synaptosomes were mixed with the jest
substances in various concentrations, and then incubated
with OH norepinephrine (hippo campus) or OH serotonin
(cortex) at 37C. The substrate concentration was about
10 no Uptake was terminated by dilution with ice-cold
buffer solution, after which the synaptosomes were sepal
rated off by centrifuging, and the OH activity in the
sediment was measured. A blank value was determined by
incubation at 0~.
The mean inhibitory concentration (ISSUE) was
calculated from the inhibitory values found for various
inhibitor concentrations in comparison with the control,
by a linear regression after--logit-log transformation.
In this test model, the standard antidepressant
imipramine (see Table 1) inhibited both the norepinephrine
uptake and the serotonin uptake in a low concentration
range, the inhibition o; norepinephrine uptake being clear-
lye predominant. On the other hand, the newly developed
ZOO antidepressant femoxetine (see Table 2) exhibits prefer en-
trial inhibition of the uptake of serotonin.
The novel substances can be divided into 3 dip-
fervent groups, based on the type of effect. A first
group exhibits preferential inhibition of the no repine-
shrine uptake and hence corresponds to the ;m;pramine
type, a second group exhibits preferential inhibition
of the serotonin uptake and hence corresponds to the
femoxetine type, and a third group inhibits the uptake
of the two neurotransmitters about equally.
The substances ox group 1 are shown in Table 1.
These include substances which in some cases are very
substantially superior (by a factor of 8 in Examples 1.6
and 5) to imipramine in their absolute potency in the
inhibition of the uptake of norepinephrine. The serotonin
uptake, too, is inhibited, although in substantially higher concentrations. This specific inhibition of the
norep;nephr;ne uptake is expressed by the quotient in
SLY
- 5 - OOZE
the last column of the Table. The higher this value,
the more specific is the inhibition of the norep;nephrine
uptake. All the quotients listed are greater than the
imipramine quotient, in some cases by a very substantial
amount.
Table shows the novel compounds in which the
inhibition of the serotonin uptake predominates. All
the examples listed are more effective by a factor as
high as 1Z~ than the comparative substance femoxetine.
The uptake of norepinephr;ne is also inhibited, although
substantially higher concentrations are required for this.
The spec;f;c;ty of the ;nh;bit;on of the certain uptake
us expressed by the quotient on the last column, a larger
quotient corresponding to greater specificity. Thus,
3 of the examples in the Table have a substantially higher
specificity than femoxet;ne~
The substances of group 3 inhibit the uptake of
the two transmitters equally. The results are summarized
in Table 3. The ISSUE values for the inhibition of the
uptake of norepinephrine and of serotonin are in a lower
concentration range in each case. However, the quotients
of the two ISSUE values are predominantly close to unity,
inducting equal ;nh;b;t;on for the two transmitters.
As a result, the substances differ substantially from,
on the one hand, imipram;ne where, with a quotation of
9~3, the inh;b;t;on of the norep;nephrine uptake is clear-
lye predominant, and, on the other hand, femoxetine where
the ;nh;b;tion of the serotonin uptake exceeds that of
the norepinephr;ne uptake by a factor of 10.
In a generally recognized working hypothesis
it is assumed that depression is caused by a disturbance
of the monoamine metabolism. More recent investigations
indicate the existence of different forms of depression,
in some of which a disturbance of the norepinephrine mote-
holism may predominate, uh;le on others a disturbance
of the serotonin metabolism may be more important. In
the majority of cases, both transmitter systems are pro-
~L~262~L
- 6 - OSSEOUS
badly affected.
On the basis of these clinical hypotheses, the
novel substances can be used in the treatment of depress
sion-related disturbances of these types. Thus, the sub-
stances of group 1 appear appropriate in the case of disk
turbances in the norepinephrine balance, the substances
of group 2 on the case of disturbances on the serotonin
balance and the substances of group 3 in the case of the
stated mixed forms.
TABLE 1
Substance of Inhibition of the neurotransmitter uptake
Example No. in synaptosomes
Norepinephrine Serotonin Quotient
ISSUE ISSUE ISSUE Serotonin
t/umole/l) t,umole/l) ISSUE No repine-
shrine
_ _ . ,
1 0.0052 0.19 36.5
1.3 0.32 0.49 15.3
1.6 0.0017 0.065 38.Z
0.0017 Q~40 235.0
5.3 0.020 0.30 15.0
_
Imipram;ne 0.014 0 13 9.3
~26~
- 7 - OOZE
TABLE 2
Substance of Inhibition of the neurotransDI;tter uptake
Example No. in synaptosomes
Serotonin Norepinephrine Quotient
ISSUE ISSUE ISSUE No repine
_ - ~umole/l) t~mole/l) D Rhine
_ ISSUE Serotonin
1.2 OOZE 0.18 9.0
Z.6 0.0036 0.20 55.6
Z.7 0.0031 0.15 48.4
2.8 0.0038 0.16 4Z.1
Femoxetine 0.036 0.33 9.2
TABLE 3
Substance of Inhibition of the neurotransmitter uptake
Example No. in synaptosomes
Norepinephrine Serotonin Quotient
ISSUE IC50IC50 Serotonin
. (molehill) (~mole/L)phr;ne
1.4 0.017 00073 4.3
ZOO 2 0.011 OOZE 2.3
2.2 0.094 0.20 2.1
2.3 00094 Ooze 0.3
2.4 0.036 Oboe 1 ox
Z.5 0.013 0.037 Z.8
Z5 Z.9 Oboe 0.10 1.5
2.10 0.038 0.049 -1.3
2.11 0.50 0.30 0.6
2.12 0.10 0.069 0.7
6 0.017 0.056 3.3
- . _ _ _
Imipramine 0.014 d.13 9.3
Femoxetine 0.33 0 036 0.11
~L226Z~3~
- 8 - OOZE
The present invention therefore also notates to
drugs which contain a compound of the formula I, and to
their use on the treatment of disorders.
The compounds according to the invention can be
administered orally or parenter~lly in a conventional
manner.
The dosage 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 from about
0.1 to I mg/kg of body weight.
The novel compounds may be employed in the convent
tonal solid or liquid pharmaceutical forms, such as jab-
lets, film tablets, capsules, powders, granules, coated
tablets, suppositories, solutions, ointments, creams or
sprays. 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, dispel-
- 20 slants, emulsifiers, solvents, retarding agents and/or
antioxidant of H. Sucker et at: Pharmazeutische Tech-
neology Thieme-Verlag, Stuttgart, 1~78~. The resulting
forms for administration normally contain from 1 to 99%
by weight ox the active compound.
The novel substances can also be administered
in the form of their salts with physiologically tolerated
acids. Examples of such acids are hydrochloric acid,
sulfuric acid, phosphoric acid, tartaric acid, acetic
acid, succinic acid, lactic acid, citric acid and amino-
I sulfonic acid.
The Examples which follow illustrate the invention.
A. Preparation of the starting materials
a) 3-Dimethylam;no-2 phenoxymethyl-1-phenylpropan-1-one
hydrochloride
22.6 9 (0.1 mole) of ~-phenoxypropiophenone (pro-
pared by reacting ~-chloropropiophenone with phenol in
alkaline solution) and 10 9 of N,N-dimethylmethyleneimonium
Lowe
.
- 9 - OSSEOUS
chloride (prepared from bis-dimethylaminomethane and ace-
twill chloride) in 200 ml of dry acetonitrile were heated
at 65C for 3 hours, while stirring. The reaction mix-
lure was then poured into 1 1 of ether, and the precipi-
late was filtered off under suction and used in this form for the further reactions. Yield: 75%, my. 128-132C.
The compounds below were obtained by a similar
method, using substituted phenols, or thiophenol:
b)1-t4-Chlorophenyl)-3-dimethylamino-Z-phenoxymethylpro-
pan-1-one hydrochloride, my. 170-173~.
I3-Dimethylamino-1-(4-fluorophenyl)-2-phenoxymethylpro-
pan-1 one hydrochloride, my. kiwi
d)Z-(4-Chlorophenoxymethyl)-3-dimethylaminophenylproopen-
1-one hydrochloride, my. 153-155C.
e)2-(4-Bromophenoxymethyl)-3-dimethylamino-1-phenylppropane
1-one hydrochloride, my. 150-152C.
f)3-Dimethylamino-1-phenyl-Z-thiophenoxymethylpropann-1-
one hydrochloride, my. 136-138C.
g)2-(2-Chlorophenoxymethyl)-3-dimethylamino-1-phenylpro-
pan-1-one hydrochloride, mop 138-140C.
h)2-(4-Chlorothiophenoxymethyl)-3-dimethylamino-1-phHoneywell-
propan-1-one hydrochloride, my. 156-158C.
The compounds below were obtained using piperidine-
and pyrrolidinemethyleneimonium chloride (prepared from
dipiperidinomethane or dipyrrolidinomethane and acutely
chloride):
i)1-Phenyl-3-piperidinyl-Z-thiophenoxymethylpropan-11-one
hydrochloride, my 161-163C.
k)2-Phenoxymethyl-1-phenyl-3-piperidinylpropan-1-onee
hydrochloride, my. kiwi
1)2-Phenoxymethyl-1-phenyl-3-pyrrolidinylpropan-1-onno
hydrochloride, impure oily substance.
B. Preparation of the end products
EXAMPLE 1
46 9 (0.17 mole) of 3-dimethylamino~2-phenoxy-
methyl-1-phenylpropan-1-one liberated from the hydrochlo-
ride obtained as described in Ala) were dissolved in
~2Z6~
- 10 - OOZE
Z00 ml of absolute tetrahydrofuran, and were added drop-
Sue, at the bowl, to a suspension of 10 9 of lithium
aluminum hydrides in 100 ml of absolute tetrahydrofuran
in the course of 45 minutes. The stirred mixture was
reflexed for 2 hours, after which it was decomposed with
water and dilute sodium hydroxide solution and then lit-
toned under suction, the residue was evaporated down and
the product obtained was recrystallized from 2 parts of
isopropanol. Z0.3 9 (45%) of 1-dimethylamino-2-phenoxy-
methyl-3-phenylpropan-3-ol t1.1) of melting point 107-
109C were obtained.,
The following compounds were obtained by the same
procedure:
1.2)2-(4-Chlorophenoxymethyl)-1-dimethylamino-3-phenyll-
propano3-ol, my. 98-100C.
1.3)1-Dimethylamino-3-~4-fluorophenyl)-2-phenoxymethyll-
propan-3-ol hydrochloride, my. 146-150C.
1.4)2-(4-Bromophenoxymethyl)-1-dimethylamino-3-phenylppro-
pinwheel hydrochloride, my. 199-200C.
1.5)3-(4~Chlorophenyl)-1-dimethylamino-2-phenoxymethyll-
propan-3-ol hydrochloride, my. 170-173C.
I1-Dimethylamino-3-phenyl-2-thiophenoxymethylpropann-
oily, my. 88-90C.
1.7)2-(2-Chlorophenoxymethyl)-1-dimethylamino-3-phenyll-
Z5 propan-3-ol hydrochloride, my. 188-190C.
1.8~ 2-(4-Chlorothiophenoxymethyl)-1-dimethylamino-3-
phenylpropan-3-ol, my. 108-110C.
1.9)3-Phenyl-1-piperidinyl-2-thiophenoxymethylpropan-33-
of hydrochloride, my. 201-203C.
1.10) 2-Phenoxymethyl-3-phenyl-1-piperidinylpropan-3-ol
hydrochloride, my. SKYE.
1.11)2-Phenoxymethyl-3-phenyl-1-pyrrol;dinylpropan-3-oll,
my. 100-103~C.
- EXAMPLE 2
20 9 (0.063 mole) of 3 dimethylam;no-2-phenoxy-
methyl-1-phenylpropan-1-one hydrochloride, obtained as
described in Example a), were added, a little at a time,
~L2~6~
- 11 - OOZED
to the Grignard solution prepared prom 20.5 9 (0.188 mole)
of ethyl bromide and 4.5 9 ox magnesium in 300 ml of
ether, and the mixture WAS stirred for 5 hours at room
temperature. Decomposition was then effected using sat-
rated ammonium chloride solution, the solution was dried and1-dimethylamino-3-phenyl-Z-phenoxymethylpentan-3-oof
hydrochloride (2.1) was precipitated by passing in hydra-
gun chloride gas. The product was recrystallized from
isopropanol. Yield: 12 9 (55X), my. 211-212C.
The compounds below were prepared by the same procedure:
2.2)1-D;methylamino-3,3-diphenyl-2-phenoxymethylpropann-
oily, my. 105-108C.
2.3) 2-t4-Chlorophenoxymethyl)-1-dimethylamino-3,3-di-
phenylpropan-3 of, my. 92-94C.
2.4)1-Dimethylamino-2-phenoxymethyl-3-phenylbut3n-3-oll
hyd;ochlor;de, my. 188-190C.
2.5)1-D;methylamino-2-phenoxymethyl-3-phenylhexan-3-oll
hydrochloride my. 183-185C.
Z.6)2-~4-Chlorophenoxymethyl)-1-dimethylamino-3-phenyll-
Texan oily hydrochloride, my. 159-161C.
2 no)2-t4-Chlorophenoxymethyl)-1-dimethylamino-3-phenyll-
pentan-3-ol hydrochloride, my. 225C.
2.8)2-(4-Chlorophenoxymethyl)-1-d;methylamino-3-phenyll-
buttonhole hydrochloride, my. 194-196C.
2.9)Z-(4-Chlorophenoxymethyl)-1-dimethylamino-3-phenyll-
pentan-3-ol hydrochloride, my. 184-186C.
2010)1-Dimethylamino-Z-phenoxymethyl-3-phenylundecan-3--
of tpuri~ied by chromatography over silica gel, using
ethylene chloride).
2.11)1-Dimethylamino-2-phenoxymethyl-3-phenylpentadecann-
oily, my. 54-57C.
2.12)1-Dimethylamino-2-phenoxymethyl-3-phenylpent-4-en--
oily hydrochloride, my kiwi
2.13) 3-Cyclopropyl-1-dimethylamino 2-phenoxymethyl-3-
phenylpropan-3-ol hydrochloride, my. 185-188C.
2.14)1-Dimethylamino-3-phenyl-2-(thiophenoxymethyl)-penn-
tunnel hydrochloride, my. 207-210C.
36;~
- 12 - OSSEOUS
2.15) 2-Phenoxymethyl-3-phenyl-1-p;perid;nylpentan-3-ol
hydrochloride, my. Z06-208C.
EXAMPLE 3
When the Grignard compound used in Example Z was
replaced by 0.188 mole of a lithium acetylide/ethylenedia-
mine complex in 300 ml of tetrahydrofuran, and 3-dimethyl-
amino-2-phenoxymethyl-1-phenylpropan-1-one hydrochloride
was replaced by the free base, the procedure described
in Example 2, followed by chromatography over silica gel
using ethylene chloride, gave 11 9 (50X) of 1-dimethyl-
amino~2-phenoxymethyl-3-phenylpent-4-yn-3-ol oxalate of
melting point 123-125C.
EXAMPLE 4
10.7 9 ~0.037 mole) of 1-dime~hylamino-2-phenoxy-
3-phenylmethyLpentan-3-ol obtained as described in En-
ample 2) and 14.06 9 (0.037 mole) of L-~-)-diben20yltar-
tang acid MindWrite were dissolved in 75 ml of swooper-
panel, and 400 my of ether were added. After some time
crystals were precipitated these crystals were recrystal-
lived twice, after which they had a constant angle of rotation ~]D20 = 69.8 (ethanol, 10 mg/ml). The levy-
rotatory base (4.1) liberated from this product gave an
angle of rotation C~]20 = -27.1, and the hydrochloride
gave ~D20 - -15~5. The melting point was 226-227C.
4.2) The optical antipope was obtained in a similar
manner, using D-(~)-dibenzoyltartaric acid: C~0 =
~26.6, hydrochloride: C~]D2O = ~15.9, my. 226-227.
All the angles of rotation were measured in ethanol at
a concentration c = 10 mg/ml.
EXAMPLE 5
A solution of 8.5 9 (0.03 mole) of 1-dimethyl-
am;no-2-phenoxymethyl-3-phenylpropan-3-ol (obtained as
described in Example 1) in 25 ml of dimethylformamide
was slowly added drops to a solution of 0.8 9 ~0.033
mole) of sodium hydrides in 50 ml of absolute dimethylform-
aside at room temperature. Thereafter 6 9 (0.06 mole)
ox acetic android in 25 ml of dimethylformamide were
isle
- 13 - OOZE 0050/36232
added drops, Chile the temperature increased to 40C,
and stirring was continued for a further 2 hours at room
temperature.
The content of the flask was poured unto 300 ml
S of water,. the mixture was extracted with 3 times 100 ml
of ether, and 3-acetoxy-1-dime~hylamino-2-phenoxymethyl-
3-phenylpropane hydrochloride to 1) was precipitated from
the ether solution by passing in hydrogen chloride gas.
The product was then recrystallized from isopropanol.
Yield: 7.1 9 ~65X~, my. 215-217C.
The compounds below were obtained by a similar
method:
5.2) 3-Eenzoyloxy-1-dimethylamino-2-phenoxymethyl-3-
phenyLpropane, my. 124-127C.
5.3)1-D;methylamino-3-ethoxycarbonyloxy-2-phenoxymethyyule-
phenylpropane hydrochloride, my. 183-186C.
5.433-Acetoxy-1-dimethylamino-2-phenoxymethyl-3-phenyll-
pontoon hydrochloride, my. 173-174C.
5.5) 3-Acetoxy-1-dimethylamino-3-phenyl-2-thiophenoxy-
methyl propane hydrochloride, my. 185 187~.
5.6)3-Acetoxy-Z-phenoxymethyl-3-phenyl~1~piperidinylprno-
pane hydrochloride, mop SKYE.
EXAMPLE 6
When the process of Example 5 was used, and acetic
Z5 android was replaced with an equimolar amount of ally
bromide, 3-allyloxy-1-dimethylamino-2-phenoxymethyl-3-
phenylpropane (o 1) was obtained Yield: 11.8 9 (95%).
Oxalate: my. 140-143C.
The compound below was prepared by the same pro-
seedier:
6.2)1-Dimethylamino-3-methoxy-2-phenoxymethyl-3-phenyll-
propane oxalate, my. 145-148C.
EXAMPLE 7
104 9 (0.005 mole) of 1-dimethylamino-2 phonics-
methyl-3-phenylpropan-3-ol, obtained as described in En-
ample 1.1, were reflexed for 3 hours with 1.0 9 (0.01
mole) of bottle ;socyanate in 25 ml of acetonitrile. The
~Z6Z~
- 14 - O~Z.OOS0/36Z43
oil obtained after the solvent had been distilled off
was converted to the hydrochloride with a solution of
hydrogen chloride in ether. 1.0 9 ~48X) of 3-~butylamino-
carbonyloxy)-1-dimethylamino-Z-phenoxymethyl-3-pheenylpro-
pane hydrochloride (7.1) of melting point 137-14QC
was obtained.
The compound below was obtained by the same pro-
seedier:
7.2)1~Dimethylamino-3-tethylaminocarbonyloxy)-2-phenoxmy-
I methyl-3-phenylpropane hydrochloride, my. 169-171C.
EXAMPLE I
A mixture of the following composition was tab-
feted in a conventional manner on a tabulating press:
10.00 my of 1-dimethylamino-2-phenoxymethyl-3-phenyl-
pentan-3-ol hydrochloride
50.00 my of corn starch,
4.50 my of gelatin,
15~00 my of lactose,
7.50 my of talc,
0.75 my of Aerosol (chemically pure silica in the
form of submicroscopic particles), and
Z.25 my of potato starch (as a 6% strength paste)
EXAMPLE II
Coated tablets having the following composition
Z5 were produced in a conventional manner:
10.00 my of 1-dimethylam;no~2-phenoxymethyl-3-phenyl-
pentan-3-ol hydrochloride,
50~00 my of core material, and
4û.00 my of sugar-coating material.
The core material consisted of 9 parts of corn
starch, 3 parts of lactose and 1 part of Luviskol(R)
VA 64 (60:40 copolymer of vinylpyrrolidone and vinyl ace-
ate, of Harm. In. 1962~ 586).
The sugar-coating material consisted of 5 parts
of sucrose, 2 parts of corn starch, 2 parts of calcium
carbonate and 1 part of talc. The coated tablets thus
prepared were then provided with a shell which is nests-
~Z~6;~
- 15.- OOZE
lent to gastric fluid.
EXAMPLE III
5 9 of 1-dimethylamino-2-phenoxymethyl-3-phenyl-
pontoon of hydrochloride were dissolved in 2.0 l of
water, and the solution was brought to pi 6, made isotonic
with sodium chloride and then introduced on a sterile
manner into 2 ml ampules.
