Note: Descriptions are shown in the official language in which they were submitted.
- 1i.247~
The present invention relates to 1-[3-(3,4,5-trimethoxy-
phenoxy)-2-hydroxypropyl]-4-aryl piperazine derivatives and to
a process for their production.
German Offenlegungsschrift l~o. 2,235,597 describes
blood-pressure-reducing compounds corresponding to the general
formula
u C1 -CH-CN - N ~ ~ +
in which A is a hydrogen atom or a hydroxyl group, X is a
hydrogen or a halogen atom, an alkyl, alkoxy, alkylthio, tri-
fluoromethyl, hydroxy, nitro, amino, acylamino or alkyl-
sulphonylamino group, and n is the number 0, 1 or 2, and their
salts.
The present invention provides compounds corresponding
to the general formula
.
: 20 CH30 ~ ~ ~ \ R2
CH3) ~ ' O-CH2-CH-cH2 N~ ,
: in which Rl is a hydrogen atom, a C2 to C6-alkanoyl radical,
3,4,5-trimethoxy benzoyl radical, a nicotinoyl radical or a
thienyl carbonyl radicaI and R2 represents a phenyl, napthyl
: or pyridyl radical which may be substituted by the radicals R3
and R4, the radicals R3 and R4 which may be the same or differ-
ent, each representing hydrogen, hydroxyl, fluorine, chlorine,
bromine, a nitro group, a trifluoromethyl group, a Cl to C6-
alkyl radical, a Cl to C6-alkoxy radical, a Cl to C6-alkyl thio
radical, a C2 to C6-alkanoyl radical, an amino group, a C2-C6
4~Y18
alkanoyl-amino group, a C2-C6-alkanoyl-oxy group, a benzoyl-oxy
group, a cyclohexylcarbonyl-oxy group or a thienyl-carbonyl-oxy
group.
The compounds are pharmaceodynamically active and show
for example, a pronounced anti-aggresive action together with
neuroleptic properties, anti-convulsive and hypnotic effects
being in evidence to a very limited extent only, if at all. In
addition, the compounds show fever-reducing and oedema-inhibiting
effects.
The alkanoyl and alkenoyl radicals may be linear or
branched. The alkanoyl radicals consist in particular of 2, 3
or 4 carbon atoms. The thienyl carbonyl radicals may be the
corresponding thienyl-(2)- or thienyl-(3)-carbonyl radical.
The alkyl, alkoxy and alkyl-thio radicals may each be
linear or branched in regard to the respective alkyl groups.
Examples of these radicals are methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.-butoxy,
methylthio, ethylthio, propylthio, butylthio, methyl sulphonyl,
ethyl sulphonyl, propyl sulphonyl. Examples of the acylamino
Zo group are the acetamino group and benzoylamino group. Where R2
is a naphthyl radical, it may be the
~ ~ 2 -
r~
. . ~ '
l~Z471~
naphthyl-tl)- or naphthyl-(2)-radical, this naphthyl radical
optionally being substituted in both rings by the radicals R3
and R4. ~owever, the naphthyl ring is preferably substituted
in the 6-ring which is not attached to the piperazine riny.
Where R2 is a pyridyl ring, this ring may be attached to the
piperazine ring in the 2-, 3- or 4-position.
Rl is preferably hydrogen or an alkanoyl group having
2, 3 or 4 carbon atoms.
In case R2 is a phenyl or pyridyl group the substi-
tuents Rl and/or R4 are preferably adjacent to the carbon atom
coupling R2 with the piperazine ring.
Preferably Rl is hydrogen and R is a Cl-C4-alkoxy-
phenyl group (for example, methoxyphenyl, ethoxyphenyl, propoxy-
phenyl, isopropoxyphenyl, butoxyphenyl), a hydroxyphenyl group, t
an aminophenyl group, a C2-C4-alkanoylaminophenyl group (for ~ :
example, acetylaminophenyl, propionylaminophenyl, butyrylamino-
phenyl) or a C2-C4-alkanoxyloxyphenyl group (for example, ace-
toxyphenyl, propionyloxyphenyl, butyryloxyphenyl) wherein these t
S
substituents are in the o- or p-position, particularly the o-
pOSition.
Accordingly, the object of the invention is to provide
compounds with favourable pharmacodynamic properties which may
be used as medicaments. ~ `
By contrast, the [3-(5,6,7,8-tetrahydronap~thyl-(1)-
oxypropyl]~piperazine derivatives described in German Offenle-
gungsschrift No. 2,235,597 show blood-pressure-reducing and hence
anti-hypertensive properties. Unlike these derivatives, the
compounds according to the invention show very little, if any,
blood-pressure-reducing activity.
The compounds according to the invention may be pro-
duced by reacting a compound corresponding to the formula
- 3 -
.. . .. . .
~124718
C 1~ 3~--OY I I
with a compound corresponding to the formula
~ 2
Z-N NR III
/
in which Y and Z are different from one another and one repre-
sents hydrogen, whilst the other represents the group
-CH2-C~(OR )-CH2-V where V represents chlorine, bromine or
iodine or, where Rl is a hydrogen atom, may also form an ethylene
oxide ring together with this hydroxy group, and when required,
reducing one or two nitro groups to amino groups and/or acylating
the compounds obtained with an acid or acid derivative corres- `
ponding to the radical Rl.
The process for producing the compounds according to F
the lnvention may be carried out in the presence or absence
of a solvent at a temperature in the range from 20 to 200C and
~20 preferably at a temperature in the range from 50 to 150C.
Suitable solvents or dispersants are, for example, aromatic
hydrocarbons such as, for example, benzene, toluene, xylene;
aliphatic ketones such as, for example, acetone, methylethyl
ketone; halogenated hydrocarbons such as, for example, chloro-
form, carbon tetrachloridine, chlorobenzene, methylene chloride;
aliphatic ethers such as, for example, butyl ether; cyclic r
ethers such as, for example, tetrahydrofuran, dioxane; sulphox-
ides such as, for example, dimethyl sulphoxide; tertiary acid
amides such as, for example, dimethyl formamide, N-methyl pyrro-
lidone; aliphatic alcohols, such as methanol, ethanol, isopro-
panol, amyl alcohol, tert.-butanol; cycloaliphatic hydrocarbons,
such as cyclohexane and the like. Mixtures of the above-mentioned
- 4 -
~1~47~8
solvents may also be used. In many cases, the reaction is
carried out at the reflux temperature of the solvent or disper- ~
sant used. In general, the reaction components are reacted in 5:
molar quantities. In some cases, however, it can be of advantage
to use the compound of formula III in excess (for example 0.5
mol) where Z is a hydrogen atom. The reaction may also be
carried out in the presence of an acid-binding agent, such as an
alkali metal carbonate (potash, soda), an alkali metal hydroxide
or a tertiary amine tfor example triethylamine). This applies
in particular when compounds in which V is a halogen atom are
used~
Where a compound of formula II in which Y is a hydrogen
atom is used as the starting substance, this compound may also
be used in the form of a metal salt, more especially an alkali
metal salt (for example the sodium or potassium salt). This
applies in particular when in the other reaction component III,
the symbol V in the group Z, which is -CH2-CH(ORl)-C~2V, is a F
halogen atom.
For carrying out the reaction, the ethylene oxide used
as the ethylene oxide starting compound may even be replaced
by the corresponding halohydrin or by a mixture of these two
compounds (crude synthesis product). `
In the products obtained, the amino and/or hydroxy
groups present and also the secondary hydroxy group in the cen-
tral position( introduction of the Rl-acyl radical) can be ob-
tained by acylation, i.e. by treatment with acids of the formula r
RlOH, in which Rl has any of the meanings defined except hydro-
gen or by treatment with the corresponding reactive acid deri-
vatives.
Corresponding acid derivatives are, in particular, F
compounds corresponding to the formula
.. .. . . . . .
R W IV
in which W represents chlorine,.bromine or iodine, the group
-N-N, a group of the formuLa -OR', -SR' or a group of the
formula -OS03H, -O-PO(OH)2, -OP(OR')2, -O-As(OR')2 or -OCO-R".
In these groups, R' represents an alkyl radical or even, in the
case of -OR' and -SR', for example a phenyl radical, a p-nitro-
phenyl radical, a cyanomethyl radical or a carboxymethyl radical;
R" may be a linear or branched alkyl radical, an alkoxy radical,
a phenoxy radical, a carbobenzoxy radical or even the radical Rl.
Aliphatic C2 to C6-ketenes may also be used as acylating agents.
Acid derivatives of formula IV in which W is chlorine or bromine
represent particularly appropriate acylating agents. Where R'
and R" represent alkyl radicals or alkoxy radicals, these
radicals are preferably of low molecular weight and consist of
1 to 6 carbon atoms.
.~ The acylation step may be carried out, for example, E
in an inert solvent or suspending agent such as water, a lower
aliphatic alcohol, a lower aliphatic ketone, dioxane, dimethyl
: ' formamide, benzene or toluene, at a temperature of from 0 to
:~ 20
200C. The acylation step is optionally carried out in the
. . .
presence of an acid-binding agent, such as an alkali metal
hydroxide, an alkali metal carbonate (potassium carbonate), an
.~ alkali metal hydrogen carbonate, an alkali metal acetate, an
alkaline earth metal carbonate, a tertiary amine ~or example
: trialkylamine, pyridine) or an alkali metal alcoholate (sodium
. ~
ethylate).
. It is also possible initially to convert the groups
to be acylated (hydroxy group, amino group) in the compound to
be reacted into the corresponding alkali metal compound by
reacting them with an alkali metal, an alkali metal hydride or F
an alkali metal amide (especially sodium or a sodium compound)
at a temperature of from 0 to 150C in an inert solvent, such
~Z47~8
as dioxane, dimethyl formamide, benzene or toluene, and subse-
quently addi~g the acylating ayent.
In cases where the free acid with the formula RlOH is
used, it has to be activated by the presence of a condensation
agent, such as dicyclohexyl carbodiimide, a sulphurous acid-bis-
alkyl amide-(for example SO[N(CH3)2]2), N,N'-carbonyl diimidazole
and so on (Organic ~eactions, Vol. 12, 1962, pages 205 and 239).
Instead of using the acylating agents mentioned above, F
it is also possible to use other chemically equivalent agents
10commonly encountered in chemistry (cf. for example L.F. and Mary
Fieser "Reagents for Organic Synthesis". John Wiley and Sons,
Inc. New York, 1967, Vol. 1, pages 1303-4 and Vol. 2, page 471).
Any acyl groups present in the compounds obtained may of course
also be split off again in known manner, for exampIe with aqueous
alkali or alcoholic alkali metal hydroxide (for example
methanolic KOH) or possibly even with mineral acids, such as
hydrochloric acid or sulphuric acid, in alcoholic or aqueous-
alcoholic solution at a temperature in the range from 20C to
100C.
For the reduction of one or even two nitro groups '.
there is particularly employed catalytic hydrogen. As catalysts
there can be used, for example, Raney-nickel, noble metals such
as palladium and platinum as well as their compounds, with or
without carriers, as for example barium sulphate, calcium sul- .
phate, etc. It is recommended to carry out the hydrogenation
of the nitro groups at temperatures between 20 and 80C and a
pressure of approximately 5-50 atmospheres absolute in a solvent,
for example, an alcohol, e.g., methyl alcohol, ethyl alcohol or
isopropyl alcohol, dioxane, tetrahydrofuran, etc. In many cases,
it is advantageous for the subsequent isolation of the reduced
compounds to add at the beginning to the hyydrogenating mixture
a drying agent such as anhydrous sodium sulphate or magnesium
-- 7 --
~i2~8
sulphate.
~lowever, the reaction can also be carried out with
nascent hydrogen, for example zinc/hydrochloric acid, tin/hydro-
chloric acid, iron/hydrochloric acid or with salts of hydrogen
sulphide and alcohol/water at about 70 to 120C or with acti-
vated aluminum 9n hydrated ether at 20 to 40C or with tin II
chloride/hydrochloric acid.
The compounds according to the invention are generally
obtained in the form of racemates. The optically active anti-
ln podes are obtained either by using optically active starting
materials or by racemate splitting via the salts of optically
active acids such as, for example, L-(+)-tartaric acid, D-(-)-
tartaric acid, (+)-O,O'-dibenzoyl-D-tartaric acid, (-)-O,O'-
dibenzoyl-L-tartaric acid, (-)-O,O'-di-_-toluoyl-L-tartaric
acid, (+)-O,O'-di-p-toluoyl-D-tartaric acid, (+)-camphor-10-
sulphonic acid and others.
The compounds corresponding to general formula I may
be converted into their pharmaceutically acceptable salts by
known methods. Suitable anions for these salts are the known
and therapeutically useable acid radicals. Examples of acids .
such as these are H2SO4, phosphoric acid, hydrohalic acids,
ethylene diamine tetraacetic acid, sulphamic acid, benzene
sulphonic acid, ~-toluene sulphonic acid, camphor sulphonic ~;
acid, methane sulphonic acid, guaiazulene sulphonic acid,
maleic acid, fumaric acid, succinic acid, tartaric acid, lactic
acid, ascorbic acid, glycolic acid, salicyclic acid, acetic F
acid, propionic acid, gluconic acid, benzoic acid, citric acid,
acetaminoacetic acid, oxyethane sulphonic acid.
The free bases may in turn be-produced from the salts
of the compounds in known manner, for example by treating a
solution in an organic solvent, such as an alcohol ~methanol),
with soda or sodium hydroxide.
1~24~8
The compounds according to the invention are suitable
for the production of pharmaceutical compositions and prepara-
tions. The pharmaceutical compositions or medicaments contain,
as active principle, one or more of the compounds according to
the invention, optionally in admixture with other pharmacologi-
cally or pharmaceutically active substances. The medicaments
may be prepared in known manner with the usual pharmaceutical
excipients, assistants, carriers and dilients.
As carriers and assistants, for example, are those
recommended in the following literature as adjuvants for
pharmacy, cosmetic and related fields such as in Ullmann's ~ -
Encyklop-adie der technischer Chemie, Vol. 4 (1953), pages 1 to
39; Journal of Pharmaceutical Sciences 52 (1963), pages 918
et seq.; N. v. Czetsch-Lindenwald, Hilftstoffe fùr Pharmazie
und angrenzende Gebiete; Pharm. Ind. 2 (1961), pages 72 et ~.; L
Dr. H.P. Fiedler, Lexicon der Hilftstoffe fur Pharmazie, Kosmetik
und angrenzende Gebiete, Cantor Kg. Aulendorf i. Wurtt (1971).
Examples of such materials include gelatin, natural
sugars such as sucrose or lactose, lecithin, pectin, starch (for
example cornstarch), alginic acid, tylose, talc, lycopodium
silica (or example colloidal silica~, glucose, cellulose, cel-
lulose ~erivatives for example cellulose ethers in which the cel-
lulose hydroxyl group are partially etherified with lower all-
phatic alcohols and/or lower saturated oxyalcohols (for example,
methyl hydroxypropyl cellulose, methyl cellulose, hydroxyethyl
cellulose), stearates, e.g~, methylstearate and glyceryl stear-
ate, magnesium and calcium salts of fatty acids with 12 to 22
carbon atoms, especially saturated acids (for example, calcium
stearate, calcium laurate, magnesium oleate, calcium palmitate,
calcium behenate and magnesium stearate), emulsifiers, oils and
fats, especially of plant origin (for example, peanut oil, corn
oil, wheat germ oil, sunflower seed oil, cod-liver oil), mono-,
g _
~i247~L8
di- and trlglycerides of saturated fatty acids lC12H2402 to
C18H36O2 and their mixtures), e.g., glyceryl monostearate, a
glyceryl distearate, glyceryl tristearate, glyceryl trilaurate),
pharmaceutically compatible mono- or polyvalent alcohols and
polyglycols such as glycerine, mannitol, sorbitol, pentaery-
thritol, ethyl alcohol, diethylene glycol, triethylene glycol,
ethylene glycol, propylene glycol, dipropylene glycol, poly-
ethylene glycol 400 and other polyethylene glycols, as well as
derivatives of such alcohols and polyglycols, esters of saturated
and unsaturated fatty acids (2 to 22 carbon atoms, especially
10 to 18 carbon atoms), with monohydric aliphatic alcohols (1 to
20 carbon atom alkanols) or polyhydric alcohols such as glycols,
glycerine, diethylene glycol, pentaerythritol, sorbitol, manni-
tol, ethyl alcohol, butyl alcohol, octadecyl alcohol, etc.,
e.g., glyceryl stearate, glyceryl palmitate, glycol distearate, L;
glycol dilaurate, glycol diacetate, monoacetin, triacetin, ~ -
glyceryl oleate, ethylene glycol stearate; such esters of poly- F
valent alcohols can in a given case also be etherified, benzyl
benzoate, dioxolane, glycerine formal, tetrahydrofurfuryl alco- t
hol, polyglycol ethers with 1 to 12 carbon atom alcohols,
dimethyl acetamide, lactamide, lactates, e.g., ethyl lactate,
ethyl carbonate, silicones (esp-cially middle vi5c09ity dimethyl
polysiloxane), magnesium aarbonate and the like. !'
For the production of solutions there can be used
water or physiologically compatible organic solvents, as for
example, ethanol, 1,2-propylene glycol, polyglycols, e.g.,
diethylene glycol, triethylene glycol and dipropylene glycol and
their derivatives, dimethyl sulfoxide, fatty alcohols, e.g.,
stearyl alcohol, cetyl alcohol, lauryl alcohol and oleyl alcohol,
triglycerides, e.g., glyceryl oleate, glyceryl stearate, glyceryl
palmitate, and glyceryl acetate, partial esters of glycerine,
e.g., monoacetic, diacetin, glyceryl monostearate, glyceryl
-- 10 --
;
112471~3
.,
glyceryl distearate, glyceryl monopalmitate, paraffins and the
like.
In the production of the preparations there can be
used known and customary solution aids or emulsifiers. As
solution aids and emulsifiers there can be used, for example,
polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbi- L
tan trioleate, lecithin, gum acadia, gum tragacanth, polyoxy-
ethylated sorbitan monoleate, polyoxyethylated fats, polyoxy-
ethylated oleotriglycerides, linolized oleotriglycerides, poly-
ethylene oxide-condensation products of fatty alcohols, alkyl-
phenols or fatty acids. As used herein polyoxyethylated means
that the materials in question contain polyoxyethylene chains
whose degree of polymerization generally is between 2 and 40,
particularly between 10 and 20.
Such polyoxyethylated materials for example can be
obtained by reaction of hydroxyl group containing compounds
- (for example, mono- or diglycerides) or unsaturated compounds
such as, for example, those containing the oleic acid radical
~ with ethylene oxide (for example, 40 moles of ethylene oxide ~A
per mole of glyceride).
Examples of oleotriglycerides are olive oil, peanut
oil, castor oil, sesame oil, cottonseed oil, corn oil (see
also Dr. H.P. Friedler, ~ , pages 191-195).
Furthermore, there can be added preservatives, stab-
ilizers, buffers, for example, calcium hydrogen phosphate,
colloidal aluminum hydroxide, taste correctives, antioxidants r
and complex formers (for example, ethylene diamine tetraacetic
acid) and the like. In a given case for stabilization of the
active molecule the pH is adjusted to about 3 to 7 with physio-
logically compatible acids or buffers. Generally, there is pre-
ferred as neutral as possible to wek acid (to pH 5) pH value.
As antioxidants there can be used for example sodium metal
-- 11 --
.
... . .. .
112~718
bisul~ite, ascorbic acid, gallic acid, alkyl gallates, e.g.,
methyl gallate and ethyl gallate, butyl hydroxyanisole, nordihy-
droguararetic acid, tocopherols as well as tocopherol and syner-
gists (materials which bind heavy metals by complex formation,
for example, lecithin, ascorbic acid, phosphoric acid). The
addition of synergists increases considerably the antioxidant
activity of tocopherol. AS preservatives there can be used
for example sorbic acid, p-hydroxybenzoic acid esters (for
example, lower alkyl esters such as the methyl ester and the
ethyl ester) benzoic acid, sodium benzoate, trichloroisobutyl
alcohol, phenul, cresol, benzethonium chloride and formalin
derivatives).
The pharmacological and galenical treatment of the
compounds of the invention takes place according to the usual
standard methods. For example, the active material or materials
and assistants or carriers are well mixed by stirring or homo-
genization (for example, by means of a colloid mill or ball
mill), wherein the operation is generally carried out at tempera- r -
tures between 20 and 80C, preferably 20 to 50C.
~`20 The application of active material or drug can take
place on the skin or mucous membrane or internally, for example,
orally, parenterally, pulmonarily, rectally, nasally, vaginally,
perlingually, intravenously, intraarterially, intracardially, l~
intramuscularly, intraperitoneally, intracutaneously or subcu- t
taneously.
The addition of other medicines is also possible or r
favorahle.
The compounds of the invention in the combat test,
mouse ( R.E. Tedeschi and coworkers, J. Pharmacol, Exp. Therap.,
~0 Vol. 125, page 28 (1959) or in the amphetamine group toxicity
test, mouse, H. Fujimori and coworkers, J. Pharmacol. Exp. Therap.,
Vol. 148, page 151 (1965) showed a good anxiolytic-anti-
- 12 -
1~%~718
aggressive or amphetamine-antagonistic ~neuroleptic property)
activity.
For example in the above-mentioned test methods at a
dosage of 2.0 m~/kg body weight mouse there occurred the anxio- `
lytic-anti-aggressive and amphetamine-antagonistic-activity.
This tranquilizing-neuroleptic activity is comparable with the
activity of the known medicines Diazepam and Chloropromazin. E
The lowest clearly effective dosage in the above-
mentioned animal experiments is, for example, 0.1 mg/kg orally;
0.01 mg/kg intravenously.
As the general dosage range for the above-mentioned
activities (animal experiments as above), there can be used, for
example, 0.1 to 20 mg~kg orally, particularly 1.0 to 10 mg/kg,
0.01 to 5.0 mg/kg intravenously, particularly 0.1 to 1.0 mg/kg.
The compounds of the invention are indicated for use
in excitement, internal tension, anxiety, psychoneurotic dis-
turbances, disturbances of sleep, psychoses, depression condi-
tions.
The pharmaceutical preparations generally contain
between 0.1 to 50 mg of the active component or components of
the invention.
The compounds can be delivered in the form of tablets, t
capsules, pills, dragees, plugs, salves, gels, suppositories,
ointments, jellies, creams, powders, dusts, aerosols or in
liquid form. As liquid forms there can be used for example
oily or alcoholic or aqueous solutions as well as suspension and r
emulsions. The preferred forms of use are tablets which contain
between 0.5 and 30 mg or solutions which contain between 0.1 and
5% of active material.
In individual doses, the amount of active component ;;
of the invention can be used for example in an amount of: F
a. in oral dispensation between 0.1 and 50 mg;
- 13 -
llZA7~8
b. in parenteral dispensation (for example intraven-
ously, intramuscularly) between 0.01 and 10 mg; h
c. in dispensation rectally or vaginally between 3
0.2 and 200 mg.
For example, there is recommended the use of 1 to 3
tablets containing 0.5 to 20 mg of active ingredient 3 times
daily or for example, intravenously the injection 1 to 6 times
daily of a 1 to 10 ml ampoule containing 0.01 to 5.0 mg of
active substance. In oral preparations the minimum daily dos-
age for example is 10 mg; the maximum daily dosage in oral ad-
ministration should not be over 10 grams. e
The dosages in each case are based on the free base.
In veterinary medicine the compounds of the invention
can be used in treating dogs and cats. The individual dosages
in general orally are between approximately 0.1 and 20 mg/kg k
body weight; the parenteral dosage approximately between 0.01
- and 5.0 mg/kg body weight.
For the treatment of horses and cattle, the individual
oral dosages are general between about 0.1 and 20 mg/ky; the
individual parenteral dosages between about 0.01 and 20 mg/kg
body weight.
The acute ~oxicity of the compounds of the invention
in the mouse (expressed by the ~D50 mg~kg method of Miller and ~;
Tainter, Proc. Soc. Exper. Biol. and Med. 57 (1944), pages 261
et seq.) in oral application is between 100 mg/kg and 5000 mg/kg,
in some cases even above 5000 mg/kg. F
Starting compounds of formula III, in which Z repre-
sents the group -CH2-CH(OH)-CH2-V, may be obtained for exarnple
in the usual way by reacting epichlorohydrin or epibromohydrin jj
with the corresponding piperazine, which contains the radical F
R2 in the 4-position, at 10C in an alcohol, preerably methanol,
with approximately 5% of water added. The reaction time amounts
- 14 -
~2~7~8
for example to 30 minutes. The reaction mixture is then heated
to 30 to 40C and stirred for 5 hours.
The ratio of piperazine to the hydrin amounts for
example to from 1:1 to 1:5 and preferably to from 1:1 to 1:2.
The water content may be -rom 1 to 10% and is preferably from
2 to 6%.
In the compounds thus obtained, the radical Rl may be
introduced by acylation with a compound RlW under the conditions
specified above. Rl may also be introduced in the same way into
starting compounds of formula II in which Y represents the group
-CH2-CH(OH)-CH2-V.
The other starting compounds are known.
The invention is illustrated by the following Examples.
EXAMPLE 1
(+)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-
methoxyphenyl)-piperazine. ¦
a) 12 g (0.05 mole) of 3,4,5-trimethoxyphenoxy glycidyl F
; ether and 9.6 g (0.05 mole) of 1-(2-methoxyphenyl)-piperazine
are boiled under reflux for 5 hours in 100 ml of isopropanol.
Most of the solvent is then distilled off, the residue is
treated with excess lsopropanolic HCl and the dihydrochloride of
the 1-13-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl]-4-(2-
methoxyphenyl)-piperazine is precipitated by the addition of ~
diethyl ether, giving 18.4 g (73~ of the theoretical) of a t
colourless crystalline substance. M.p. of the dihydrochloride:
196-197C.
The 3,4,5-trimethoxyphenoxy glycidyl ether is produced
for example as follows:
In a suitable reaction vessel fitted with an attachment
for the azeotropic separation of water, 18.4 g (0.1 mole~ of
3,4,5-trimethoxyphenol are brought to the boil with 37 g (0.4 F
mole) of epichlorohydrin, followed by the dropwise addition over
-- 15 --
:
~1247~L8
a period of 30 minutes of 10 g (0.1 mole) of 40~ sodium hydroxide,
the water being simultaneously removed azeotropically from the
circuit. After the sodium hydroxide has been added, the mixture
is left to react for 1 hour at boiling temperature, subsequently
diluted with approximately 100 ml of toluene and the NaCl preci-
pitated is filtered off. The filtrate is fractionated first
under normal pressure and then in vacuo. The 3,4,5-trimethoxy-
phenoxy glycidyl ether is obtained as a colourless oil at b.p.
1.0 = 175-180C. Yield: 19.2 g, corresponding to 80~ of the
theoretical, based on trimethoxyphenol.
The process for producing the end product may also be
carried out as follows;
0.05 mole of sodium-(3,4,5-trimethoxy)-phenolate and
0.05 mole of 1-(3-chloro-2-hydroxypropyl)-4-(2-methoxyphenyl)-
piperazine (produced by reacting l-(2-methoxyphenyl)-piperazine
with epichlorohydrin) are boiled under reflux for 8 hours in 50
ml of dioxane. After cooling, the ~aCl precipitated is fil-
tered off and the filtrate is concentrated. The residue is
treated with isopropanolic hydrochloric acid and ether and the
crystalline solid is recrystallised from methanol, giving 8.2 g
(32% of the theoretical) of the above-mentioned compound in the
form of its dihydrochloride melting at 194-196C.
Another way of carrying out the process is as follows: k
A mixture of 0.05 mole of 3-(3,4,5-trimethoxyphenoxy)-
2-hydroxypropyl bromide, 0.05 mole of 1-(2-methoxyphenyl)-piper-
azine and 0.06 mole of triethlamine is boiled under reflux for 5
hours in 100 ml of toluene. Thç triethyl ammonium bromide preci-
pitated is then filtered off and the filtrate is concentrated. ~
The residue is taken up in a little isopropanol and the dihydro- L
chloride of the above-mentioned compound is precipitated with Y
isopropanolic hydrochloric acid and ether. Recrystallisation
from methanol gives 10.1 g of end product (40% of the theoretical)
- 16 -
~11247~8
melting at 195-1~7C.
The compounds listed in Table 1 corresponding to the t
formula
CH30~ F
CH30. _ ~ _ O - CH2 - CH(OH) - CH2 ~ N N - R
CH30.. . ~
are obtained in the same way as described in the first paragraph
of ~xample 1 from 0.05 mole of 3,4,5-trimethoxyphenoxy glycidyl
ether and 0.05 mole of a compound corresponding to formula III:
' .
'~ :
-
~:~ 20 ~
.~ ~
!
: , .; ~.
, ~ .
l~Z47~8
~ t ~ ~ ~ co o~ N ~r ~r ~ ~ CO O .--1 ~0 ~1 CJ~ ~1 1` ~1 11~
.,1
~ ~0 .
_ I .
~ 1t t~ _ lC
O co ~ In (~ .-1 ~ o o~ ~ oo o oo u~
co O a~ 1--o o ~ o ~ ~o ~ cs~ oo ~ ~ O r~
~1 ~ ~ ~1 ~ (~ ~ ~ U~ ~ ~ ~ ~ '`J ~ ~D /~ ~ '`J Q ^
3 ~
~ ~ o ~ l ~ o o ~ o ~ ~,,,,
__ _
.0 ~ C~
h S ~--I ~ ~
O ~ ~:
'g~ C ~1
~ O) (v OJ 0) ~c s a~ s l OJ Q) ~1 ;~ a) 8 0 1~1 rc c
s s s ~ ~ P~S a~ O
.~: ooox~ 00~ 5
~ O O O O .C C O ~C; .C ,r~ U S 1c ~ ~ ~ ~ ~ ~ lJ r ~ v ~ r~
.~ c ~ r ~ ~ a~ S-~
aJ ~ E ~ ~ ~ f~ ~ ~ ~ s~ S C
~ ~ C ~ I I
____ ,................. ~
H ~
:: H ~ C C
1--1 ~ rl N N
I -~ O ~ ~1 N 11~ nl
E~ ~
~1 ~ N N rl~
o a~
C C C C~ rl ~1 C ~ ~ W ~ h ~ I I rl
~ rl N N rl I r~ C lu 11) ~rl ~ ~ N
~1 N N N N Id (lJ N ~ N rl ~ N ~1 ~1 W ~ rl
O ~ Id h h (~N " rl nl ~ ~ ~ ~ h N
h h ~1 1.1 Q\ ~ h ~ Q. h C~ 1
~1 W O W ~ Q~ O h I I o ~1 W N N Q- h
~ ~ ~ ~4 n.-,~ ,1 P, ~u ~ a~ ~--~ Q. S .C (~1 N ~1
W rl ~1 Q,~l ~1 -rl ~ Q~ h 0 1:1
s:: Q. ~ ~ ~ I I Q. ~ ~-~ h I ~rl
o a~ I I I I ^_ I o I ~ ~
0~ ~ ^ ~ ^ ^ 'I 'I ~~ ~ ^ I Q) W-- ~ ~ rl ~ ~ I
~ ,~ 1 ~ ~ s ~
O N ~ ~ ~ C ~ 1 r-l
U 0 ~ C C ~ ~ ~ C U C C ~ ~1 C ~ e ~
h a) Ql W ~J .C C W ~ W W :~ ~ W O O :~1 S C
W S 1~ S Q. ~S o ~ ~c: C .C ~ h I :~ ~ Q~
~ ~ e ~ o o~, ~s
.,1 ~1 0 0 0 0 ~ X ~ ~ ~1_ x ~
h O O O O S S Xo ,~ e ~ ~,--~ ~ o o
0 ,, ~,,~,,~~ ~ .~-~1~ 1 ~a~
~ ~ rC~u~ e e ~ e ~ h~-~ s C
~IIIIIII III~I II~II
Q~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 ~ 1 N
-
,~ o~ o~
a) ~ z
.
E~
~ - --
-- 18 --
.. . . . . ..
.
11247~8
EX~MPLE 22
(+)-1-[3-~3,4,5-trimethoxyphenoxy)-2-(nicotinoyloxy)-propyl]-4- 3
(2-methoxyphenyl)-piperazine
13.0 ~ (0.03) mole) of (+)-1-[3-(3,4,5-trimethoxyphen-
oxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine and 3.34
g of triethylamine (0.003 mole) are dissolved in 80 ml of anhy-
drous benzene, followed by the addition over a period of 30
minutes of a solution of 4.67 g (0.003 mole) of nicotinic acid
chloride in 50 ml of anhydrous benzene. After stirring for
another 2 hours at room temperature, the mixture is finally
heated for 1 hour to 70 to 80C. After cooling, the mixture
is repeatedly extracted by shaking with water, washed with
aqueous NaHC03 and water and the benzene phase is dried with
magnesium sulphate and concentrated. The solid residue is taken
up in dioxane. After the addition of excess isopropanolic
hydrochloric acid and ether, 13.0 g (67% of the theoretical) of
the above-mentioned compound are obtaine~ in the form of its
trii~ydrochloride (colourless crystals). r,l.p. 187 - 192C
(decor,lposition). t
EX~PLE 23
(+)-1-[2-(3,4,5-trimethoxyphenoxy]-2-[(3,4,5-trimethoxy)-benzoyl-
oxy]-propyl]-4-(2-methoxyphenyl-piperazine t
(+)-1-l3-(3,4,S-Trimethoxyphenyl)-2-hydroxypropyl]-4-
(2-methoxyphenyl)-piperazine is reacted with 3,4,5-trimethoxy-
benzoyl chloride in the presence of triethylamine as in Example
20. The reaction product is obtained in the form of the dihydro-
chloride meltin~ at 193 - 195C (decomposition). Yield: 38%.
xample of resolution
i
(+)-1-[3-(3,4,5-trimethoxyphenoxy)-2-hydroxypropyl~-4-(2-methoxy-
phenyl)-piperazine (base = compound la) and (-)-1-[3-(3,4,5-tri-
methoxyphenoxy)-2-hydroxypropyl]-4-(2-methoxyphenyl)-piperazine
(base - compound lb).
-- 19 --
; .~ . .
~L124718
4.32 g (0.005 mole) of the racemic compound produced
in accordance with Example 1 are dissolved in 80 ml of warm
butylacetate, followed by the addition in portions with thorough
stirring at 80C of 4.04 g (0.005 mole) of (-)-di-p-toluoyl-L-
tartaric acid hydrate, the levo-rotatory diastereomeric salt pair
actually being precipitated. After heating for 10 minutes to
110C, the mixture is left to cool to 80C and the deposit is
filtered off. The salt pair is recrystallised from acetone-
dimethyl formamide-petrol ([a]20 - 48.6; 1% in dimethyl forma-
mide), and is subsequently split by treatment with concentrated
ammonia. The base is e~tracted with ether and the extract is
concentrated. The solid residue is recrystallised from isopro-
panol: la-base colourless crystals, m.p. 103 - 104C; [a]D +
7.2 (concentration 2% in CH30H). Dissolution of the base in
methanol, followed by the addition of isopropanolic hydrochloric
acid and ether gives the dihydrochloride of compound la in the
form of colourless crystals melting at 189 - 193C; [~]D ~ 11.4
(concentration = 2% in CH301~). t'
The filtrate obtained after precipitation of the salt
~0 pair, which contains the dextrorotatory diastereomeric salt pair,
is concentrated in a rotary evaporator, the viscous residue is
suspended in water, concentrated ammonia is added and the base t~
extracted with ether. The etherial solution is dried and con-
centrated and the solid residue is recrystalllsed from isopro- . i
- panol: lb-base, colourless crystals, m.p. 100 - 101C; la]20 - ~
5.8 (concentration = 2% in CH30~). r
Dissolution of the base in methanol and treatment with
isopropanolic hydrochloric acid and ether gives the dihydro-
chloride of compound lb in the form of colourless crystals
melting at 182 - 187C; ~a]D + 11.0 (concentration = 2% in
CH30H).
- 20 -
,
..... . . . ..
~.
~11247~L8
Examples of Pharmaceutical Preparations
EXAMPLE 27
Injection Solution
For a mixture of 100 liters
there are needed:
Compound according to Example 1
(dihydrochloride) 0.25 kg
Sodium chloride ' 0.775 kg
Water for purpose of injection 98.975 kg e
100.00 kg
Production:
The active material together with sodium chloride is
dissolved with stirring in the water for purpose of injection.
The solution is filtered and is filled into 2 ml ampoules of
colorless glass. The ampoules after being closed by melting are
sterilized for 20 minutes at 120C in superheated steam.
EXAMPLE 28
Suppositories
Production:
5 g of the compound of Example 7 (dihydrochloride) is t
worked into 1995 g of molten suppository composition (for example, ,`
hard fat DAB 7, a mixture of mono-, di- and triglycerides of L
saturated fatty acids C12H24O2 to C18H36O2) and in known manner
poured out in forms for 2.0 g suppositor1es.
1 suppository contains 5 mg of active material
EXAMPLE 29
Capsules
To prepare 100,000 capsules there are required the
following raw materials:
Compound according to
Example 7 (dihydrochloride') 0.125 kg
'.0 i~
Lactose 7.200 kg
Microcrystalline cellulose 4.800 kg
Magnesium stearate 0.375 kg
12.500 kg
- 21 -
gLiL2A~7~L8
r
To produce gelatin capsules (size 4) which are necessary
for production of the capsule composition the previously set
forth raw materials are passed through a sieve having a mesh
width of 1.5 mm and then mixed for 1 hour at 10 revolutions per
minute in a Turbula mixer. This composition is called the capsule
filling composition.
This capsule filling composition is filled into gelatin
capsules of size 2. Amount of filling per capsule : 125 mg.
` SUPPLEMENTARY DISCLOSURE
Example 30
Preparation of the compound of ~xample 1
(+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-
4-(2-methoxy-phenyl)piperazine
3-[~-(2-methoxy-phenyl)-piperazino]-1,2-epoxy-propane
obtained from 1.92 g of 1-(2-methoxy-phenyl)piperazine and 1.36 g
of epibromohydrin in 10 ml of methanol by allowing the mixture
to stand for 72 hours at room temperature is mixed with 3 g of
3,4,5-trimethoxy-phenol potassium salt without isolation. After
boiling the reaction mixture for 6 hours with reflux it is mixed
with 400 ml of ether, filtered and acidified with isopropanolic
hydrochloric acid. The precipitated dihydrochloride is purified
by column chromatography.
(eluant: CHC13 (90 parts)/CH3OH (5 parts)/acetic acid (5 parts))
and by subsequent crystallization from isopropanolic hydrochloric
acid; m.p. of the dihydrochloride 196 to 197 C, yield: 0.5 g.
Example 31
(+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl]-4-
(2-acetamido-phenyl)piperazine
4 g of (+)-1-[3-(3,4,5-trimethoxy-phenoxy-2-hydroxy-
propyl]-4 (2-amino-phenyl)piperazine(monohydrochloride) are dis-
solved in 200 ml of dioxane and mixed with 10 ml of triethylamine,
whereupon 0.9 ml of acetyl chloride is added dropwise at
- 22 -
7~8
-5C while stirring. A~ter two hours of post-reaction at room
temperature the solution is filtered and the solvent is removed
under reduced pressure. By dry-column chromatography on silica
gel.
(eluant: ether:acetic acid = 1:1) the desired compound is
isolated and recrystallized from acetone-ether. Yield: 50%,
m.p. = 128 to 130C. (+)-l-r3,4,5--trimethoxy-phenoxy)-2-
acetoxy-propyl]-4-(2-acetamldo-phenyl) piperazine is obtained
as a less polar by-product, which can become the main product
by increasing the amount of acetyl chloride. m.p. = 54C
Example 32
(+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-
4-(2-acetoxy-phenyl)piperazine
6 g (0.0143 mole) of (+)-1-[3-(3,4,5-trimethoxy-phenoxy)-
2-hydroxy-propyl]-4-(2-hydroxy-phenyl)piperazine and 2.9 g
(0.0286 mole) of triethylamine are dissolved in 80 ml of absolute
methylene chloride and mixed dropwise with a solution of 2.24 g
(0.0286 mole) of acetyl chloride in 20 ml of absolute methylene
chloride at 0C. The reaction mixture is stirred for two hours
at room temperature and the precipitated triethylamine hydro-
chloride is filtered off. The solvent is then distilled off in
vacuo and the residue is recrystallized from ether/petroleum
ether.
Yield: 57%, m.p. = 70C.
Example 33
(+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-hydroxy-propyl~-
4-(2-aminophenyl)piperazine
6 g (0.0124 mole) of (+)-1-~3-(3,4,5-trimethoxy-phenoxy)-
2-hydroxy-propyl]-4-(2-nitro-phenyl)piperazine are dissolved in
300 ml of methanol and hydrogenated in the presence of 0.5 g of
a 10% Pd-C at room temperature. After filtering off the catalyst
and removing the solvent in vacuo the residue is recrystallized
- 23 -
~1247~8
from ethanol in vacuo.
Yield: 94%, m.p. of the monohydrochloride = 181 to 183C.
Example 34
(+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(hydroxy-
`propyl]-4-(2-acetoxy~phenyl)piperazine
CH30~0-CH2-CH(OH)-CH2-lr\N ~
CH30 OC0-CH3
0.03 mole of 1-(2-acetoxy-phenyl)piperazine (crude
product) and 7.2 g (0.03 mole) of 3,4,5-trimethoxy-phenoxy
glycide ether are heated in 150 ml of isopropanol with reflux
until the reaction is complete as determined by thin layer
chromatography. After distilling off the solvent the hydro-
chloride is obtained by treatment with isopropanolic hydro-
chloric acid and is purified by recrystallization from isopropanol.
Yield: 18%, m.p. = 189 to 191C.
The 1-[2-acetyl-oxy-phenyl]piperazine used as the
starting material is obtained in the following manner:
192.8 g (1 mole) of 2-methoxy-phenyl piperazine, 130
ml (1.1 moles) of benzyl chloride and 150 g (1.10 moles) of
potassium carbonate are heated in 800 ml af xylene with re1ux
until the reaction is complete according to DC examination ~i.e.
examination, by thin layer chromatography). The solution is
filtered and the solvent is removed in vacuo. By treatment
with isopropanolic hydrochloric acid in the usual manner the
hydrochloride is then obtained (yield: 70%).
60 g (0.2 mole) of the hydrochloride thus obtained
are heated in 800 ml of a 63% a~ueous hydrobromic acid with
reflux until the ether cleavage is complete ~DC examination).
The solvent is then removed in vacuo and the crystalline resi-
due obtained is washed with ether (yield 70%). The free base
- 24 -
llZ4718
is liberated from the dihydro bromide with dilute aqueous
ammonia in the usual manner.
10 g (0.029 mole) of the free base thus obtained and
l~ ml of triethyl amine are cooled in 50 ml of dioxane to 5C
and mixed dropwise with 0.032 mole of acetyl chloride at a
temper~ture not higher than 10C. After stirring for one hour
at 10C the precipitated triethylamine hydrochloride is filtered
witll suction and the solvent is distilled off in vacuo. In the
oily free base obtained the benzyl group is hydrogenated off
without any further purification in the following manner: 0.4
mole of the free base is dissolved in 150 ml of methanol and
hydrogenated in the presence of 2 g of a 10% Pd/C at 50~C and
5 bars. After completed water absorption the catalyst is
filtered off and the solvent is removed in vacuo. The 1-(2-
acetoxy-phenyl)piperazine thus obtained can be further reacted
directly without any further purification.
Examples 35 and 36
In a manner analogously to that of Example 34 the
compounds listed in Table 2 are obtained from 0.03 mole of 3,4,5-
trimethoxy-phenoxy glycide ether and 0.03 mole of the corres-
ponding piperazine compound. The starting piperazine compound
is obtained in an analogous manner as the starting compound o
the preceding example and instead of using the acetyl chloride
in the acylating step the corresponding other acid chloride
(benzoyl chloride, cyclohexane carboxylic chloride) is used.
TAsLE 2
Starting Piperazine R2 in Formula 1 Melting Point Yield in % Example
Compound Rl = H (hydrochloride) of the ~o.
theoreti-
cal yield
1-(2-benzoyloxy 2-benzoyl-oxy-phenyl 194-196C 31% 35
-phenyl)piperazine
1-(2-cyclohexyl- 2-cyclohexyl carbonyl 151-152 C 22% 36
carbonyl-oxy- -oxy-phenyl
phenyl)piperazine
- - 25 -
11;;~47i~8
Example 37
(+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-acetoxy-propyl]-
4-(2-methoxy-phenyl)piperazine
10 g (0.023 mole) of (+)-1[3-(3,4,5-trimethoxy-phenoxy)-
2-hydroxy-propyl]-4-(2-methoxy-phenyl)piperazine are suspended in
100 ml of xylene and 10 ml of triethylamine are added, whereupon
9 ml of acetyl chloride are slowly added dropwise at room
temperature. The solutioniisleft at room temperature for 2
hours. The triethyl ammonium chloride is then filtered off and
the solvent is distilled off in vacuo. The crude product
obtained is purified by dry column chromatography on silica gel
~eluant chloroform/methanol 98:2). The hydrochloride is obtained
in the usual manner by treatment with isopropanolic hydrochloric
acid and recrystallized from isopropanol.
Yield: 80%, m.p. of the hydrochloride _ 178 to 179C.
CH30
CH30~ OCOCH3
Example 38
:
t+)-1-[3-(3,4,5-trimethoxy-phenoxy)-2-(thienyl-(2-
carbonyl-oxy)propyl]-4-(2-methoxy-phenyl)piperaæine
CH30 \ OCH3
CH30 ~ 0-CH2-CH-CH2- 3 N
CH30 CO ~
15 g (0.0319 mole) of (+)-1-[3-(3,4,5-trimethoxy-
phenoxy)-2-hydroxy-propyl]-4-(2-methoxy-phenyl)-piperazine
dihydrochloride and 3.3 g of triethylamine are suspended in
100 ml of xylene, whereupon 4.7 g (0.0319 mole) of thiophene-
2-carboxylic chloride are added dropwise at room temperature
while stirring. Stirring is then continued for
- 26 -
. ~
4718
one hour at room temperature. The precipitated triethyl
ammonium hydrochloride is then filtered off and the solution
concentrated under reduced pressure. The residue is taken up
in ether and mixed with isopropanolic HCl. The dihydrochloride
obtained is recrystallized from isopropanol. ~elting point of
the dihydrochloride 198 to 199C. (The substance contains
1 mole of isopropanol as the crystal solvent).
Yield: 42%.
Example 39
The corresponding thienyl-(3) compound is produced
analogously as in Example 38. Melting point of the dihydro-
chloride 193 to 194C.
Yield: 48% --
Example 40
(+)-1-~3-(3,4,5-trimethoxy-phenoxy)-2-~thienyl-(2)-
carbonyl-oxy)-propyl]-4-[2-thienyl-(2)-carbonyl-oxy)-phenyl]
piperazine
: : ~,co oc(~3 oco ~
~o H ~,CO~ c~z-c~-c~2-^~ N~)
C0
7 g (0.0167 mole) of (+)-1-[3-(3,4,5-trimethoxy-
phenoxy)-2-hydroxy-propyl]-4-(2-hydroxy-phenyl)piperazine are
suspended in 100 ml of dioxane and 4 ml of triethylamine, where-
upon 5 g (0.034 mole) of thiophene-2-carboxylic chloride are
added in portions at room temperature while stirring. On
completed addition stirring is continued for further six hours.
The mixture is then allowed to stand at room temperature. The
triethyl ammonium hydrochloride formed is filtered off and the
solvent is distilled off in vacuo. The remaining oil product
is taken up in 100 ml of ether and mixed with isopropanolic
- 27 -
llZ4~718
hydrochloric acid to the acid reaction, whereupon the precipi-
tated hydrochloride is filtered with suction and recrystallized
from isopropanol in order to purify it.
Yield: 61%, m.p. of the hydrochloride = 221 to 222~C.
~ 20
, ~
~ ~ .
.,
~ 28 -
