Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
.
1331877
Aminopropanol derivatives of 3-(3-hvdroxYDhenyl~ ro~anone
compounds. process for preparina same. and pharmaceutical
com~ositions containina said com~ounds
Backaround of the Invention ~,
German Patent No. 2 001 431 discloses 2-(2'-hydroxy-3'-
alkylaminopropoxy)-B-phenyl-propiophenones of the general
for~3ula
.
1l OH N~-R
~
and their acid addltion salts. Although these compounds and
their salts constitute pharmaceuticals, only the n-propylamino
compound (propafenone) shows antiarrhythmic activity.
European patent publication EP-A-0 074 014 published on March
10 16, 1983 (patented on June 27, 1984) describes 2-t2'-hydroxy-
3'-(1,1-dimethylpropylamino)-propoxy]-~-phenyl-propiophenone
(diprafenone) and its acid addition salts. Diprafenone is an
antiarrhythmic.
European patent publication EP-A-0 075 207 published on
15 Narch 30, 1983 (patented on February 5, 1986) describes
aminopropanol derivatives of the general formula
.
~:
r.
f~3
... . . .
1331877
Il OH
4(n ~ R3
and its physiologically acceptable acid addition salts. Ty-
pical examples for R1-R4 include hydrogen atoms or alkyl
groups and n has a value of 1, 2 or 3. These compounds are
pharmaceuticals.
.
Summarv of the Invention
One object of the invention is to provide novel aminopropa-
nol derivatives of 3-(3-hydroxyphenyl)-1-propanone compounds - ~
of the general formula I and physiologically acceptable acid --
~10 addition salts which are distinguished by a substantially
improved antiarrhythmic activity than that of propafenone
and without a corresponding increase in toxicity. It is
another object of the invention to provide a process for
producing these compounds and acid addition salts. Finally, - -
it is an object of the invention to provide pharmaceutical
compositions for treating heart rhythm disorders which con-
tain those compounds or their physiologically acceptable
acid addition salts.
~ Detailed Description of the Invention
; 20 The invention relates to novel aminopropanol derivatives of 3-
(3-hydroxyphenyl)-1-propanone compounds of general formula I
CHz-CH2-CO ~ (I)
R ~ ~
4' ~ 1 2
O-CH2-fH-CH2-~R R
OH
~ .
.
1331877
and their acid addi~ion salts, and to a process for pre-
paring same. The invention also relates to pharmaceutical i
compositions containing a compound of general formula I or
acid addition salts thereof, preferably a physiologically
acceptable acid addition salt.
In general formula I, Rl and R2 are the same or different
and denote hydrogen atoms, alkyl, cycloalkyl, alkenyl, al-
kinyl or hydroxyalkyl groups with up to 6 carbon atoms each,
alkoxyalkyl, alkylthioalkyl or dialkylaminoalkyl groups with
up to 9 carbon atoms each, or phenylalkyl or phenoxyalkyl
groups having up to 6 carbon atoms in the alkyl portion, the
phenyl group optionally being substituted by an alkyl or
alkoxy group with respectively up to 3 carbon atoms, or Rl
and R2 form together with the nitrogen atom which connects
them a 5 to 7 membered, saturated heterocyclic ring, which
may optionally be substituted by one or two phenyl and/or
hydroxy groups and contain in the ring an oxygen or
n~trogen atom as a further heteroatom, with the additional
nltrogen atom optionally substituted by an alkyl group
w~th 1 to 3 carbon atoms, or by a phenyl group. R3
denotes a hydrogen atom, an
alkyl group having up to 3 carbon atoms, a fluorine, chlo-
rine or bromine atom, a hydroxyl or alkoxy group with up to
6 carbon atoms. R4 denotes a hydrogen atom, an alkyl group
having up to 3 carbon atoms, a fluorine, chlorine or bromine
atom, a h~droxyl group or an alkoxy group with up to 6 car-
bon atoms, or R4 together with the phenyl group bound to it
is part of an anellated aromatic system having up to 18 car-
bon atoms. n is an integer from 1 to 5.
, .
Preferred are compounds in which NRlR2 is a tert.-pen-
tylamino, n-propylamino, l,l-dimethylpropylamino, morpho-
lino~ isopropylamino, tert.-butylamino, pyrrolidino, piperi-
dino or cyclohexylamino group,
the R3 residue is hydrogen, or a methyl, methoxy or hydroxy
group,
133~877
R4 is hydrogen, or a methyl, methoxy or hydroxy group, or
together with the phenyl group attached thereto is a l-naph-
thyl group, 2-naphthyl group or 3-phenanthrenyl group, and
n has the value 1, 2 or 3.
Especially preferred are compounds in which NRlR2 is a
tert.-pentylamino, n-propylamino, isopropylamino, tert.-bu-
tylamino, piperidino or cyclohexylamino group,
the R3 residue is hydrogen, or a methoxy group in the 4-po-
sition,
R4is a methyl or methoxy group or together with the phenyl
group attached thereto is a 2-naphthyl group and
and n has the value 1, 2 or 3.
The most preferred compounds are
1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-
aminopropoxy)-phenyl]-l-propanone hydrochloride, (Example
8).
1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-tert.-bu-
tylamino-propoxy)-phenyl]-l-propanone hydrochloride,
(Example 17).
1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopropylamino-
propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride
(Example 23).
1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-cyclo- -
hexylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydrochlo-
ride, (Example 32).
1-(2-naphthyl)-3-[3'-(2-hydroxy-3-n-propylaminopropoxy)-4'-
methoxyphenyl]-l-propanone hydrochloride, (Example 48).
The invention also relates to a process for preparing the
compounds of general formula I and their acid addition salts
which is characterized by reacting a Phenol ether of general
formula II
' ~. . - . . ~. , ~ , -. . - :
... ... . - .. : ; - : ~
r~
r i: . i .- . ' ' ' . - ' , : ` ' '
- 1331877 -
~C~2 -CH2 -CO-~
o-CH2-C~-CH2 (II)
O
with an amine of general formula III
1 2
HNR R (III)
Rl, R2, R3, R4 and n have the above meaning.
If appropriate, the resulting compound of general formula I
may be converted with an acid into an acid addition salt.
The reaction may, for instance, follow the method described
in European Patent 0 074 014.
The reaction is carried out at temperatures ranging from 10-
to 120~C, that is at room temperature or at higher tempera-
tures, preferably at temperatures ranging from 50- to 120-C,
at atmospheric pressure or in a closed vessel at elevated
pressure.
The starting compounds of general formulae II and III can be
reacted without diluents or solvents. However, the reaction
is preferably carried out in the presence of an inert dil-
uent or solvent, such as a lower alcohol having 1 to 4 car-
bon atoms, as for instance methanol, ethanol or propanol,
preferably isopropanol or ethanol, a lower saturated dial-
kylether, dialkylglycol ethers or cyclic ethers, such as
diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or di-
oxane, a benzene hydrocarbon, such as benzene itself or an
alXyl benzene, in particular toluene or xylene, or an ali- ~-~
phatic hydrocarbon, such as hexane, heptane or octane, di-
,~:-; . . . - ' ,. ' . : :
--~`` 1331877
methylsulfoxide or in the presence of water or mixtures of
the mentioned solvents.
When used in excess, the amine of general formula III may
also be a suitable diluent or solvent.
The completeness of the reaction depends on the reaction
temperature and is in general achieved within 2 to 15 hours.
The reaction product can be obtained in a conventional man-
ner, for instance by filtration or distillation of the dilu-
ent from the reaction mixture. The compound obtained is pu-
rified in the usual manner, for instance by recrystalli-
zation from a solvent, conversion into an acid addition salt
or by column chromatography.
The phenyl ether of general formula II can be obtained by
alkylating 3-hydroxy-~-phenylpropiophenone having general
formula IV
R4 -
CH2-CH2-CO ~ (IV)
OH
with an epihalohydrin. R3, R4 and n have the above meaning.
Examples of epihalohydrins are epichlorohydrin, epibromo-
hydrin and epiiodohydrin.
The reaction of the compounds IV for preparing the starting -
compounds of general formula II is expediently carried out -
at temperatures ranging from 0- to 120C and normal pressure
or in a- closed vessel at elevated pressure. Suitable sol-
vents or diluents are a lower aliphatic ketone, such as ace-
tone, methylethyl ketone or methylisobutylketone, a lower
alcohol having 1 to 4 carbon atoms, such as methanol, etha-
nol, propanol or butanol, a lower aliphatic or cyclic ether,
such as diethylether, tetrahydrofuran or dioxane, a dialkyl-
~ 1331877
formamide, such as dimethylformamide or diethylformamide, or
dimethylsulfoxide or hexamethylphosphoric acid triamide or
an excess amount of the alkylating agent.
The reactions are preferably carried out in the presence of
a base as acid-binding agent. Suitable bases are alkali me-
tal carbonates, alkali metal bicarbonates, alkali metal hy-
droxides, alkali metal hydrides or alkali metal alcoholates,
in particular those of sodium and potassium, basic oxides,
such as aluminum oxide or calcium oxide, organic tertiary
bases, such as pyridine, lower trialkyl amines, such as tri-
methyl amine or triethyl amine, or piperidine. The bases
can be used in catalytic or stoichiometric amounts or in
slightly excess amounts with respect to the alkylating agent
used.
3-hydroxy-~-phenylpropiophenone is preferably reacted with
epichlorohydrin or epibromohydrin in a polar, aprotic sol-
vent, in particular dimethylsulfoxide, at temperatures rang-
ing from O-to 50 C, in the presence of at least one mole
equivalent base, in particular sodium hydride, based on the
alkylating agent.
The starting compound of general formula IV, that is the 3-
hydroxy-~-phenylpropiophenone, and its preparation are
known.
The compound of formula I obtained according to the inven-
tion is optionally converted into an acid addition salt,
preferably into a salt of a physiologically acceptable acid.
Usual physiologically acceptable inorganic and organic acids
are for instance hydrochloric acid, hydrobromic acid, phos-
phoric acid, sulfuric acid, oxalic acid, maleic acid, fuma-
ric acid, lactic acid, tartaric acid, malic acid, citric
acid, salicylic acid, adipic acid and benzoic acid. Other
suitable acids are described for instance in Fortschritte
der Arzneimittelforschung, vol. 10, pp. 224-225, Birkhauser
. ., .: ~... . - :
. , . -.. ~. . . .~ .:. . -:
, ~ . ... . ...................... .. . ... .
, . . :- - . - - . .. ... : . , - .. , : . ,
.:' . . . : :: ':.: :::' ' .. ,-.-: . ':: : ' . -~ . :
1331877
publishers, Basle and stuttgart, 1966, and Journal of
Pharmaceutical sciences, vol. 66, pp. 1-5 (1977). Hydro-
chloric acid is preferred.
The acid addition salts are normally obtained in a conven-
tional manner by mixing the free base or its solutions with
the corresponding acid or its solutions in an organic sol-
vent, for instance a lower alcohol, such as methanol, etha-
nol, n-propanol or isopropanol, or a lower ketone. such as
acetone, methylethyl ketone or methyl-isobutyl ketone, or an
ether, such as diethyl ether, tetrahydrofuran or dioxane.
Mixtures of the mentioned solvents can also be used for bet-
ter crystal deposition. Moreover, pharmaceutically accept-
able aqueous solutions of acid addition salts of the com- `
pound of formula I can be prepared in an aqueous acid solu-
tion.
The acid addition salts of the compound of formula I can be
converted into the free base in a manner known per se, as
for instance with alkalis or ion exchangers. Further salts
can be obtained from the free base by reaction with inorga-
nic or organic acids, in particular with those which are
. .
suitable for the formation of therapeutically useful salts.
These and other salts of the new compound, such as the
picrate, can also lend themselves to the purification of the
free base wherein the free base is converted into a salt,
which is separated and the base is again liberated from the
salt.
The present invention also relates to pharmaceutical compo- ;-~
sitions for oral, rectal, intravenous or intramuscular ap-
plication, which apart from the usual carriers and diluents
contain the compound of formula I or its acid addition salt
as active ingredient. Furthermore it relates to the use of
the new compounds and their physiologically acceptable salts
in the treatment of heart rhythm disorders.
~, .... . ........ .......... ...... .. . .. . .
-` 1331877
The pharmaceutical compositions of the invention are pre-
pared in a conventional manner with the usual solid or
liquid carriers or diluents and the conventional pharmaceu-
tical adjuvants in a suitable dosage form in accordance with
the desired form of application. The preferred preparations
are compositions in dosage unit form for oral applications.
Such pharmaceutical forms are for instance tablets, film-
coated tablets, dragees, capsules, pills, powders, solutions
or suspensions or depot preparations.
Parenteral preparations, such as injection solutions, are of
course also suitable. Another pharmaceutical form to be
mentioned is, for instance, the suppositories.
Corresponding tablets can be obtained for instance by mixing
the active ingredient with known auxiliaries, or instance
with inert diluents, such as dextrose, sugar, sorbitol, man-
nitol, polyvinylpyrrolidone, disintegrating agents, such as
corn starch or alginic acid, binders, such as starch or
gelatine, lubricants, such as magnesium stearate or talcum
and/or agents for achieving a depot effect, such as carboxy-
polymethylene, carboxymethyl cellulose, cellulose ace-
tatephthalate or polyvinylacetate. The tablets may comprise
several layers.
Dragees can be prepared correspondingly by coating cores
which have been manufactured analogously to the tablets with
compositions commonly used in dragee coatings, such as poly-
vinylpyrrolidone or shellac, gum arabic, talcum, titanium
dioxide or sugar. The dragee shell may also consist of sev-
eral layers, wherein the auxiliaries mentianed above in
connection with the tablets may be used.
Solutions or suspensions comprising the inventive active in-
gredient may additionally contain flavoring agents, such as
saccharin, cyclamate or sugar and for instance aromatics,
such as vanillin or orange extract. Moreover, they may con-
! . . . ` `
.j:-`' :' ' ` '' ' ~' '
` ~ '`' ' : , ' ' : ~ ':
, ~, . ~ ,
,. ~ .
:" ,': -: ' . . '
` - ~ ~ . : - .. ' :
~' ' .
~ 1331877
tain suspension auxiliaries, such as sodium carboxymethyl
cellulose or preservati~es, such as p-hydroxybenzoates.
Capsules containing the active ingredient can for instance
be prepared by mixing the active ingredient with an inert
carrier, such as lactose or sorbitol, and encapsulating it
in gelatine capsules.
Suitable suppositories can, for example, be prepared by mi-
xing the active ingredient with corresponding carriers, such
as neutral fats or polyethylene glycol or their derivatives.
In humans, the single dose is
from 0.5 - 5 mg/kg for oral application
from 0.05 - 2 mg/kg for intravenous application
from O.l - 3 mg/kg for intramuscular application
from 0.5 - 10 mg/kg for rectal application.
In particular, the antiarrhythmic and ~-sympatholytic pro-
perties of the compounds of the invention and their physio-
logically acceptable acid addition salts make them espe-
cially suitable for phar~acotherapy of heart rhythm disor-
ders, treatment of coronary heart disease, and prophylaxis
of sudden death from heart disease. The antiarrhythmic ef-
ficacy of the inventive compounds was established both by
electrophysiological studies on dog heart Purkinje fibers
and with the aid of ouabain-induced ventricular tachycardia
in dogs.
.;
In the following tables I and II the compounds of the inven-
tion are compared to propafenone (A).
,
The effect on the contractive strength of the heart was
tested on guinea pig papillary muscle. Hemodynamic studies
werè carried out on both healthy and acutely infarcted dogs.
One important criterion in table I which follows is the
safety factor (S.F.), which i8 calculated from the
relationship of the antiarrhythmic efficacy,
, .
` . ~ ~. ~ - ' : ' :
: . , , . :
~... . . ..
.: -.,,
-` 11 1331877
the negative inotropy and the specifically greater
efficacy at higher frequencies according to the formula
rate factor of Vmax x (C20CF/C20 Vmax). By way of
comparison it is noted that the currently leading
antiarrhythmics propafenone and flecainid have an S.F. of
1.5 and 1.7 respectively.
As a supplementary criterion the prematurity factor was
established. This characterizes the desired efficacy of
the inventive compounds in premature extrasystoles.
The high antiarrhythmic effect is not accompanied by a
significant increase in toxicity compared to propafenone
(A) as seen from a comparison of the LD50 values in rats
and mice which are summarized in table II.
.. .. .. ..
:, . ..
~ .
.. . . . . .
. ; - ~
., - , ~ :
.
~ 1331877
12
Table I
Example C20 CF C20 Vmax Rate Factor Prematurity S.F.
No. (~M) (~M) of Vmax Factor Vmax
____________________________________________________________
7 6.0 2.9 1.21 0.902.5
8 3.0 1.6 5.00 1.089.4
9 15.0 9.1 1.26 1.012.1
5.0 2.6 1.17 0.992.3
11 10.0 3.3 1.15 0.953.5
14 20.0 11.9 1.47 0.952.5
7.0 1.0 1.09 0.947.6
17 15.0 1.7 1.12 0.999.9
22 7.0 3.2 0.97 0.992.1
23 6.0 2.2 5.00 1.0514.0
6.0 2.4 1.21 1.013.0
27 15.0 3.5 1.25 1.055.4
28 6.0 1.4 1.16 1.015.0
5.0 2.5 1.13 1.012.3
31 5.0 1.4 1.15 0.974.1
32 9.0 1.1 1.25 1.0510.2
10.0 3.0 1.20 0.914.0
36 8.0 2.8 1.41 0.994.0
37 5.0 2.6 1.22 0.942.4
39 4.0 1.2 1.51 0.945.0
5.0 1.3 1.33 0.945.1
44 14.0 1.7 1.03 1.108.5
47 17.0 6.1 1.22 1.103.4
48 9.0 1.1 1.43 0.9011.7
49 14.0 12.1 4.00 0.504.6
A 5.3 3.7 1.08 0.971.5
_________
C20 CF: Concentration that reduces contractions of the
papillary muscle by 20%.
C20 Vmax: Concentration that reduces Vmax by 20% at a
basic cycle length of 1000 msec.
. - ... ~ . . : .: . :
,' : - . . , ~, -: - - . . ~ . , : -
. . i - ~ . , ~ .. -.. ,, ~ .. .
, .... : :::; - :. . -
13 1331877
Rate Factor (% control Vmax at a basic cycle length of
of Vmax: 2000 msec)/(% control Vmax at a basic cycle
length of 500 msec) at C20 Vmax.
Prematurity (% control Vmax at premature extrasystoles)/
Factor Vmax: (% control Vmax at a normal beat) at Vmax.
S.F.: Safety factor computed as Rate Factor of Vmax
(C20 CF/C20 Vmax).
Table II
LD50(mg/kg)
Test compound rat(i.v.) mouse (i.v.)
- A 17 18
Example 28 11 16 ,
31 13 18
36 10 18
The invention is illustrated by the examples.
A) Preparation of the starting compounds:
ExamDle I
1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-
l-propanone
:
100 g (0.3S mole) of 3,4-dimethoxy-~-3'-hydroxyphenylpro-
piophenone are heated under refluxing for 23 hrs with 300 ml
of epichlorohydin and 24.2 g (0.175 mole) of potassium car-
bonate and stirred. The resulting salt is filtered off, and
the remaining solution is evaporated under reduced pressure.
The residue is recrystallized from isopropanol. Yield:
109.8 g (91.9%) of the title compound, Fp. 81-84'C.
,,., ~, ~ ,.: - . ~ .
~ - . .
.~ . ...
' . ': .
1331877
14
The following compounds were prepared in the same manner:
1-(4-methoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phenyl]-1-
propanone
1-(3,4,5-trimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phe-
nyl]-l-propanone
1-(2,4,6-trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-phe-
nyl]-l-propanone
l-phenyl-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxyphenyl]-1-
propanone
1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-me-
thoxyphenyl]-l-propanone
1-(3,4,5-trimethoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-
methoxyphenyl]-l-propanone
1-(2-methoxyphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-
phenyl]-l-propanone
1-(4-methylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-
phenyl]-l-propanone
1-(2,4,6-trimethylphenyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-
methoxyphenyl]-l-propanone
Exam~le II
1-(2-naphthyl)-3-[3'-(1,2-epoxy-3-propoxy)-4'-methoxy-
phenyl]-l-propanone
13.1 g (0.04 mole) of 1-(2-naphthyl)-3-(3'-hydroxy-4'-me-
thoxyphenyl)-l-propanone are heated for 5 hrs under re-
fluxing with 26.3 ml of epichlorohydrin, 90 ml of isopropa-
nol and 1.6 g (0.04 mole) of sodium hydroxide. The resul-
ting salt is filtered off and the remaining solution is
evaporated under reduced pressure. The remaining oily resi-
due is-used without purification in the next step. Yield:
16.4 g (~ 100 %).
Example III
1-(3-phenanthrenyl)-3-~3'-(1,2-epoxy-3-propoxy)-phenyl]-1-
propanone
:~ . . - . :. - .
. . ~
~, ~ ,. -:
-` 1331877
61.6 g (0.18 mole) of 1-(3-phenanthrenyl)-3-(3'-hydroxy-
phenyl)-l-propanone are heated for 12 hrs under refluxing
with 105.6 ml of epichlorohydrin, 66 ml of methanol and
7.2 g (0.18 mole) of sodium hydroxide. The resulting salt
is filtered off and the remaining solution is evaporated un-
der reduced pressure. The residue is used without purifica-
tion in the next step. Yield: 6S.2 g (= 85.3 %).
B) Preparation of the inventive compounds:
Exam~le 1
1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-
aminopropoxy)-phenyl]-l-propanone hydrochloride
27.4 g (0.08 mole) of 1-(3,4-dimethoxyphenyl)-3-[3'-(1,2-
epoxy-3-propoxy)-phenyl]-1-propanone and 20.9 g (0.24 mole)
of tert.-pentylamine are dissolved in 300 ml of methanol and
heated for 4 hrs under refluxing. The solvent and the ex-
cess amount of amine are removed under reduced pressure.
The oily residue is taken up in methanol and concentrated
hydrochloric acid is added thereto. After heating and cool-
ing, crystals are obtained which are recrystallized from
acetone. Yield: 22.8 g (61.2~) of the title compound, Fp.
117-ll9-C.
The following compounds were prepared in the same manner
tExamPles 2 to 51):
2. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-pro-
pylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 146-
147-C.
3. 1-(3,4-dimethoxyphenyl)-3-t3'-(2-hydroxy-3-morpholino-
propoxy)-phenyl]-1-propanone hydrochloride, Fp. 148-149-C.
- -- - - . . : ~ : . ' ` - :
fi : ~ ~ ` . " .~
- 1331877
16
4. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopro-
pylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 175-
177-C.
5. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-butyl-
aminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 179-
181C.
6. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-piperidino-
propoxy)-phenyl]-l-propanone hydrochloride, Fp. 141-142-C.
7. 1-(4-methoxyphenyl)-3-t3'-(2-hydroxy-3-n-propylamino-
propoxy)-phenyl]-l-propanone hydrochloride, Fp. 128.5-
129.5-C.
8. 1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-tert.-
pentylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
160-161-C.
9. 1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-isopro-
pylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
119.5-120.5-C.
10. 1-(3,4,5-trimethoxyphenyl)-3-t3'-(2-hydroxy-3-tert.-
butylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
158-159-C.
11. 1-(2,4,6-trimethylphenyl)-3-[3'(2-hydroxy-3-tert.-pen-
tylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 103-
105-C.
12. 1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-piperi-
dinopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 158-
159.5'C.
.~.`` `
D ~ e~ ~ ~ 5
`-" 1331877
13. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-morpho-
linopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 170-
171-C.
14. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-t~rt.-bu-
tylaminopropoxy)-phenyl]-l-propanone hydrochloride, Fp. 129-
131-C.
15. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-isopro-
pylaminopropoxy)-phenyl]-l-propanone semi-oxalate, Fp. 146-
148-C.
16. 1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-n-pro-
pylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp. 84-
85-C.
17. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-bu-
tylaminopropoxy)-phenyl]-1-propanone hydrochloride, Fp.
123.5-125.5-C.
18. 1-phenyl-3-t3'-(2-hydroxy-3-tert.-pentylaminopropoxy)-
4'-methoxyphenyl]-1-propanone semi-oxalate, Fp. 162-164-C.
19. 1-phenyl-3-t3'-(2-hydroxy-3-isopropylaminopropoxy)-4'-
methoxyphenyl]-1-propanone hydrochloride, Fp. 157-158-C.
20. 1-phenyl-3-[3'-(2-hydroxy-3-tert.-butylaminopropoxy)-
4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 158-159-C.
21. 1-phenyl-3-[3'-(2-hydroxy-3-piperidinopropoxy)-4'-me-
thoxyphenyl]-l-propanone hydrochloride, Fp. 115-117-C.
22. 1-(3,4-dimethoxypheny].)-3-[3'-(2-hydroxy-3-n-pro-
pylamino-propoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 115-116.5-C.
- -- 1331877
18
23. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-iso-
propylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 128-131-C.
24. 1-(3,4-dimethoxyphenyl)-3-t3'-(2-hydroxy-3-morpholino-
propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
158-161C.
25. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-bu-
tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 168-170-C.
26. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-cyclo-
hexylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 117.5-120.5-C.
27. 1-(3,4-dimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pen-
tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 147-148-C.
28. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-
pentylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 126-129 C.
29. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-n-pro-
pylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 103.5-106-C.
30. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroxy-3-isopro-
pylàminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 115-116C.
31.` l-(3,4,5-trimethoxyphenyl)-3-~3'-(2-hydroxy-3-tert.-bu-
tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 150.5-152C.
` ~ -- ` :
1`' ,
- 1331~77
~ . 19
32. 1-(3,4,5-trimethoxyphenyl)-3-[3'-(2-hydroXy-3-CyClo-
hexylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 136.5-138.5-C.
33. 1-(2-methoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-pen-
tylaminopropoxy)-4'-methoxyphenyl]-1-propanone acetate, Fp.
119-120-C.
34. 1-(2-methoxyphenyl)-3-t3'-(2-hydroxy-3-n-propylamino-
propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
141.5-143-C.
35. 1-(2-methoxyphenyl)-3-[3'-(2-hydroxy-3-tert.-bu-
tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 166.5-167-C.
36. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert.-pentyl-
aminopropoxy)-4'- methoxyphenyl]-1-propanone hydrochloride,
Fp. 107.5-109.5-C.
37. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-n-propylaminopro-
poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 108-
llOC.
38. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-morpholinopro-
poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 117-
119 . S C .
39. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert.-butylamino-
propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
117-ll9 C.
40. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-piperidinopro-
po~y)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
138.5-140'C. -~
- ~ ~
,; : .
C
;- ~: -.
~ 1331877
41. 1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-cyclohexylamino-
propoxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp.
134-136-C.
42. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-tert.-pen-
tylaminopropoxy)-4'-methoxyphenyl]-1-propanone hydro-
chloride, Fp. 117-118-C.
43. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-piperi-
dinopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride,
Fp. 119-120-C.
44. 1-(2,4,6-trimethylphenyl)-3-t3'-(2-hydroxy-3-n-propyl-
aminopropoxy)-4'-methoxyphenyl]-1-propanone oxalate, Fp.
121-122-C.
45. 1-(2,4,6-trimethylphenyl)-3-~3'-(2-hydroxy-3-isopropyl-
aminopropoxy)-4'-methoxyphenyl~-1-propanone hydrochloride,
Fp. llO-lll-C.
46. 1-(2,4,6-trimethylphenyl)-3-[3'-(2-hydroxy-3-morpho-
linopropoxy)-4'-methoxyphenyl]-1-propanone hydrochloride,
Fp. 154-lSS-C.
47. 1-(2-naphthyl)-3-t3'-(2-hydroxy-3-tert.-pentylaminopro-
poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 130-
132-C.
48. 1-(2-naphthyl)-3-t3'-(2-hydroxy-3-n-propylaminopro-
poxy)-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 142-
143-C.
49. 1-(2-naphthyl)-3-[3'-(2-hydroxy-3-isopropylaminopro-
poxy~-4'-methoxyphenyl]-1-propanone hydrochloride, Fp. 133-
135-C.
.,, :.~ .
~Y .
. ~
., ~ . ~ .
--` 133187~
21
50. 1-(3-phenanthrenyl) -3-[3'-(2-hydroxy-3-isopropylamino-
propoxy)-phenyl]-1-propanone hydrochloride, Fp. 140-142'C.
51. 1-(3-phenanthrenyl) -3-[3'-(2-hydroxy-3-n-propylamino-
propoxy)-phenyl]-1-propanone hydrochloride, Fp. 149-152-C.
2 x a m p l e 5 2
Manufacturing Process for Tablets
a) Ingredients
Compound of Example 1 75.00 g
Microcrystalline cellulose
(powder, 50 ~m) 15.75 g
Poly-(1-vinyl-2-pyrrolidone) 5.00 g
Hydroxypropylmethyl cellulose 2910 3.75 g
Magnesium stearate 0.50 g
lO0.00 g
b) Mixing and Granulating
The compound of Example l is optionally screened. All ma-
terials except for magnesium stearate are then mixed in a
mixer where they are moistened with a suitable amount of
granulation liquid (for instance water or isopropanol-di-
chloromethane l:l). The moist mixture is passed through a
suitable sieve, dried in a drying cabinet and screened
again. The dried granulate is mixed with the magnesium
stearate in the mixer.
c) Pressing of Tablets
The mixture prepared according to (a) is pressed in a
tablet press into tablets weighing from 40 to 400 mg. The
pressing force and the tablet diameter are so selected ~ ~
that the disintegration time in the testing device ~ -
according to the Eur. Pharm. is less than 15 minutes and
the tablets are sufficiently stable mechanically.
-: '. ' ' ' - . ., ,.- : . . .: :
. -, - . . : . : : :' '
- `
22
133187~
E x a m ~ l e 5 3
Manufacturing Process for Film-coated Tablets
A. Ingredients
a) Tablet
(see manufacturing process for tablets, Example 52).
b) Film coating
The total amount applied is 5-20% of the tablet weight
and
consists of:
~ydroxypropylmethyl cellulose 2910 77 %
Macrogol~R) 6000 (plasticizer) 23 %
B. Preparation of the Tablets
(see manufacturing process for tablets, Example S2).
C. Preparation of the Film-coated Tablets
The ingredients of the film coating are dissolved in a suit-
able solvent (for instance water or ethanol/water 70:30).
The tablets are sprayed in a film coating apparatus with the
solution containing the film former and plasticizer and are
dried in a hot air stream. The film-coated tablets are fur-
ther dried in a drying cabinet.
E x a m ~ 1 e 5 4
Manufacturing Process for Dragees
A. Ingredients
a) Dragee core .
(see manufacturing process for tablets)
b) Dragee shell
the total amount applied is 25-100% of the core weight
and consists of:
Ç~``` - ' '' .
~,, - : :
`~ ' ' ' -
.
1331877
- 23
Saccharose 51.4 %
Talcum 24.0 %
Calcium sulfate hemihydrate 10.3 %
Starch syrup 5.0 %
Gum arabic 3.9 %
Macroqol(R) 6000 2.9 %
Titanium (IV) oxide 1.6 %
Finely dispersed silica 0.8 %
Sodium dodecylsulfate 0.1 %
100. 0 %
B. Preparation of the Dragee Cores
(see manufacturing process for tablets)
C. Preparation of the Dragees
Composition of the dragee solution used,
Precoating composition and dragee~coatin~ suspension
a) Dragee solution
Saccharose 47.6 %
Starch syrup 19.1 %
Gum arabic 3.8 %
Distilled water 29.5 %
100.0 %
-
b) Precoating Composition
Talcum 70,0%
Calcium sulfate hemihydrate 26.7%
Finely dispersed silica 3.3%
100.0%
~-, .'' `' ' ' `'' ` .,' ` '' ' ~
~, ,.: .,' ." ,` , . `.`: ,~ ,, ~', ' ' ` ` ' . . `
23a
1331877
c) Coating suspension for Dragees
Saccharose 47.8%
Talcum 9.6%
Calcium sulfate hemihydrate 4.8%
Gum arabic 3.6~
Starch syrup 3.2%
Macrogol (R) 6000 2.9%
Titanium (IV) oxide 1.6%
Sodium dodecylsulfate 0.1%
Distilled water 26.4%
100 . O %
Coating of Dragee Cores
The dragee cores are first moistened in a rotating vessel
with dragee solution and then powdered with sufficient
precoating composition for them to roll freely again.
After the cores are dried, this process is repeated. The
cores are then dried in a drying cabinet. The cores are
then layerwise coated with the dragee coating suspension
until the desired final weight is achieved. The cores
must be dried after application of each layer.
E x a m ~ 1 e 5 5
Manufacturing Process for Capsules
A. Dosage of the active ingredient of 75 mg and more
1. Ingredients
Compound of Example 2 75.00 g
Microcrystalline cellulose
(powder, S0 ~m) 16.25 g
Poly-(l-vinyl-2-pyrrolidone.)5.00 g
Hyd~oxypropylmethyl cellulose 2910 3.75 q
lOo.oo g
,
:` :
-:
~' :
:`
.
24 1331877
Saccharose 51.4 %
Talcum 24.0 %
Calcium sulfate hemihydrate 10.3 %
Starch syrup 5.0 %
Gum arabic 3.9 %
Macrogol(R) 6000 2.9 %
Titanium (IV) oxide 1.6 %
Finely dispersed silica0.8 %
Sodium dodecylsulfate0.1 %
100. 0 %
B. Preparation of the Dragee Cores
(see manufacturing process for tablets)
C. Preparation of the Dragees
Composition of the dragee solution used,
Precoating composition and dragee suspension
a) Dragee solution
Saccharose 47.6 %
Starch syrup 19.1 %
Gum arabic 3.8 %
Distilled water 29.5 %
100. 0 %
E x a m p 1 e 5 5
Manufacturing Process for Capsules
A. Dosage of the active ingredient of 75 mg and more ~:
1. Ingredients
Compound of Example 275.00 g ;:
Microcrystalline cellulose
(powder, 50 ~m) 16.25 g ~ :
Poly-(l-vinyl-2-pyrrolidone)5.00 g
Hydroxypropylmethyl cellulose 2910 3.75 g
100.00 g : : :
.~ ; -- ~ . ::
. - .. . . . .
- - . . , ,:
-- 1331877
2. Mixing and granulating acording to Example 52b)
3. Filling the Granulate into Capsules
The granulate is filled by means of a capsulating machine
into hard gelatine capsules of size 3, 2, 1 or 0, the amount
filled into each capsule depending on the desired dosage of
the active ingredient.
B. Dosage of the active ingredient 30-7S mg
1. Ingredients
Compound of Example 3 30.00 - 75.00 g
Microcrystalline cellulose
(powder, S0 ~m) 61.2S - 16.2S g
Poly-(l-vinyl-2-pyrrolidone) S.00 g
Hydroxypropylmethyl cellulose 2910 3.7S q
100.00 g
The sum of the amounts of active ingredient and micro-
crystalline cellulose should always be 91.2S g. The amount
of active ingredient is a thousand times the amount of the
single dose.
2. Mixing and granulating according to Example S2b)
3. Filling the Granulate into Capsules
100 mg each of granulate are filled into hard gelatine cap-
sules of size 3 or 2 with the aid of a capsulating machine.
E x a m D 1 e S 6
Manufacturing Process for ~mpoules
1. Ingredients
Compound of Example 6 1.5 g
Water for injection purposes ad: 100.0 ml
.... . ..
",~ , .
'
~ . . .. . .
.~ . .
-~ 13318~
26
2. Preparation of the Solution
90% of the water necessary for the batch selected is placed
into the reaction vessel. The active ingredient is dis-
solved in said water under heat. The final volume is
achieved by adding the necessary amount to the solution af-
ter cooling.
3. Filling the Solution into Ampoules
The finished solution is filled into glass ampoules, the
amount filled in depending on the dosage desired. The glass
ampoules are then sealed by fusion.
4. Sterilization
The ampoules are vapor-sterilized for 20 minutes at 120C.
E x a m ~ 1 e 5 7
Manufacturing Process for Suppositories
a. Ingredients
Compound of Example 50 30 - 200 mg
Hard fat (melting point 35-36.5C) ad: 2000 mg
:: :
b. Preparation of the Melt containing the Active Substance
The amount of hard fat necessary for a specific number of
suppositories is melted in a water bath at 40-C. The active
ingredient is pressed through an 0.8 mm sieve and mixed into
the melt to give a suspension.
::
c. Preparation of the Suppositories
The melt is allowed to cool down to 37-38C and filled under
steady stirring into suppository forms in such amounts that --
the weight of one suppository is 2000 mg. The suppository
form is sealed after solidification of the melt.
, .. . .... , .. . .. . , ~ . . -
`' ` . ? - : :: : : : ': : ' ' : : -
~. ... ,, ... , - ~
