Note: Descriptions are shown in the official language in which they were submitted.
107121~
The invention relates to new piperidines of the
formula
~2 / alkl ~6- C ~~~ C~ n
2 C~2 ~ ~ CH - N \Ph
O
wherein Rl denotes an optionally substituted aryl radical,
alkl and alk2 independently of one another are lower alkyl--
ene radicals which each separate the nitrogen atom bonded
to them, and the methine group bonded to them, by 2 carbon
atoms, P~2 denotes an optionally acylated hydroxYl group, Ph
denotes an optionally substituted o-p'nenylene radical, n is
O or 1, R3 denotes a hydrogen atom, a lower alkyl radical or
the hydroxyl group and R5 denotes a lower alkyl radical or
a hydrogen atom or R3 and R5 together represent a second
bond and R4 and R6 each denote a hydrogen atom, or R4 to-
gether with R3 represents an oxo group, R5 denotes a lower
alkyl radical or a hydrogen atom and R6 denotes a hydrogen
atom, or R6 together with R5 represents an oxo group, R3
denotes a hydrogen atom, a lower alkyl radical or the hy-
droxyl group and R4 represents a hydrogen atom, and their
_ 2
.
'
. ,: . '. ' ' . .'- ',,' :
- : . - ' ' .
. . -: ' - ' ~ ~
1~7~Zl~
salts, as ~el.l as processes for the manufacture of these
compounds and pharmaceutical preparations in whicn these
compounds are present.
If n is 1, the invention relates to compounds of
ormula
R6 R5 R4 R3
12 alkl C / - C
Rl - - CH2 - CH - CH2 N ~ alk ~ C ''
O
and, if n is 0, the invention relates to compounds of formula
Rl - O - CH2 - CH - CH2 - n~ ~CH - N / Ph (I)
wherein in the above formulae Rl, R2, R3, R4, R5, R6, Ph,
fllkl and alk2 have the above defined meanings.
An optionally substituted aryl radical Rl is for
example phenyl, lndenyl or naphthyl substituted by one, two
-- 3 --
-- - , ,
\
1071Zll
or more substituents and also, for example, optionally sub-
stituted 2,3-dihydro-5- or -6-indenyl or 5,6,7,8-tetrahydro-
-1- or -2-naphthyl. A monosubstituted or disubstituted
phenyl or naphthyl radical is preferred, and a monosubstit-
uted phenyl radical is preferred very particularly.
The aryl radical Rl is, for example, substituted by
aliphatic or cycloaliphatic hydrocarbon radicals,especia~y
by lower aliphatic hydrocarbon radicals which can also be
substituted. Examples of such optionally substituted lower
aliphatic and cycloaliphatic hydrocarbon radicals are lower
alkyl, lower alkenyl or lower alkinyl groups; 5 to 7 ring-
membered cycloalkyl groups: lower alXoxy-lower alkyl, lower
alkylthio-lower alkyl, hydroxy-lower alkyl, halogeno-lower
alkyl, carbamoyl-lower alkyl, lower alkoxycarbonylamino-
-lower alkyl and acylamino-ethenyl groups.
A substltuent of an aryl radical ~1 can also be
hydroxyl which is optionally etherified by an aliphatic
hydrocarbon radical, especially by a lower aliphatlc hydro-
carbon radical, which can be substituted yet further.
Examples of such radlcals are lower alkoxy groups, lower
alkenyloxy groups, lower alkinyloxy groups, hydroxy-lower
alkoxy groups, lower alkoxy-lower alkoxy groups, lower
alkylthio-lower alkoxy groups, aryl-lower alkoxy groups,
such as phenyl-lower alkoxy groups, and hydroxyl groups.
' . . .
. . ' . '
.
-- . . -- . --
10~2~1
.
The aryl radical Rl can also be substituted by the
following substituents: lower alkanoyl groups, lower alka-
noyloxy groups, lower alkylmercapto groups, acylamino
groups, halogen atoms or nitrile, amino and nitro groups.
Further possible substituents of the aryl radical R
are optionally substituted carbamoyl groups, such as, for
example, N-mono-lower alkylcarbamoyl groups, N,N-di-lower
alkylcarbamoyl groups or N,N-lower alkylenecarbamoyl groups.
Further possible substituents of the aryl radical R
are optionally substituted ureido groups.
Substltuents of the aryl radical which should be
singled out particularly are optionally lower-alkylated
carbamoyl radicals, acylaminoethenyl radicals, such as, for
example lower alkanoylaminoethenyl radicals and lower
alkoxycarbonylamlno-lower alkyl radicals (which are prefer-
ably in the para-position on the phenyl radical), as well
as nitrile groups (which are preferably in the ortho-pos-
ltlon on the phenyl radical) and lower alkanoyl radicals
(whlch are preferably in the ortho- or para-position on the
phenyl radical). However, particularly preferred subs-
tituents of the aryl radical are halogen atoms (which are
preferably in the o-position on the phenyl radical), and
hydroxyl groups (which are preferably in the para-position
on the phenyl radical) and above all lower alkoxy-lower
alkyl groups and acylamlno groups (which are preferably in
_ 5 _
~071Zll
the para-position on the phenyl), as well as lower alkyl
radicals, lower alkenyl radicals, 5 to 7 ring-membered
cycloalkyl, lower alkoxy groups, lower alkenyloxy and
alkinyloxy groups (which are preferably in the ortho-
-position on the phenyl).
Examples of lower alkylene radicals alkl and alk2
are 2,3-butylene radicals, 1,2-butylene, 1,1-dimethyl-1,2-
ethylene radicals or preferably 1,2-propylene radicals or
especially 1,2-ethylene radicals.
The o-phenylene radical Ph can carry one, two or
more substituents; however, it preferably does not contain
more than two substituents. Possible substituents of the
o-phenylene radical are, in particular: lower alkyl rad-
lcals, lower alkoxy groups, halogen atoms, trifluoromethyl
groups, hydroxyl groups and, as a second cholce, also acyl-
amino groups, nitro groups and amino groups.
An optionally acylated hydroxyl group ~2 is, for
example, a lowèr alkanoyloxy group, such as, for example,
an acetoxy, propionyloxy or butyryloxy group or preferably
the pivaloyloxy group, or above all a free hydroxyl group.
Where not stated otherwise, lower radicals are those
radicals which contain not more than 7 carbon atoms and
preferably up to 4 carbon atoms.
Examples of lower alkyl radicals are methyl, ethyl,
n-propyl or isopropyl radicals, or straight-chain or
. ' : - "~ '
.
.
71Zll
branched butyl, pentyl or hexyl radicals which can be
bonded in any desired position.
Lower alkenyl radicals are, in particular, allyl or
methallyl radicals and a possible lower alkinyl radical is
above all the propargyl radical. Of the 5 to 7 ring-mem- :
bered cycloalkyl groups cyclohexyl is preferred.
~ ower alkoxy-lower alkyl radicals are, for example,
those composed of the lower alkyl radicals mentioned, for
example methoxymethyl, ethoxymethyl, n-propoxymethyl,
n-butoxymethyl, 2-(n-butoxy)-ethyl, 3-(n-propoxy)-propyl
or especially 2-methoxyethyl.
Lower alkylthio-lower alkyl groups are, for example,
those composed of the lower alkyl radicals mentioned and
are thus, for example, methylthiomethyl, 2-ethylthioethyl,
3-methylthlo-n-propyl and especially 2-methylthioethyl.
Hydroxy-lower alkyl groups are above all those in
whlch the lower alkyl parts has the above meaning, such
as, for example, 2-hydroxyethyl, 3-hydroxy-n-propyl and
especially hydroxymethyl.
Posslble halogeno-lower alkyl radicals are especlal-
ly those which are derived from the alkyl radicals men-
tioned and ln which the halogen atom is a bromine atom or
especially a chlorine atom or fluorine atom, such as, for
example, chloromethyl, 2-chloroethyl, dichloromethyl and
especially trifluoromethyl.
1071Z~l
Lower alkoxycarbonylamino-lower alkyl groups are
understood, for example, as those radicals of which the
lower alkyl parts are derived from the lower alkyl groups
mentioned. Such groups are, for example, methoxycarbonyl-
aminomethyl, ethoxycarbonylaminomethyl, 4-methoxycarbonyl-
amino-n-butyl, 2-ethoxycarbonylaminoethyl, 3-ethoxycar-
bonylamino-n-propyl and especially 2-methoxycarbonylamino-
ethyl and 3-methoxycarbonylamino-n-propyl, carbamoylmethyl
or 2-carbamoylethyl.
Acylamino-ethenyl groups are in particular radicals
of the formula
18 ~ 1lO
R7 - ~ - N - C = C -
whereln R7 is a lower alkyl or lower alkkoxy group, for
example one of those mentloned above or below, or an amino
group, that ls to say a primary, secondary or tertiary
amlno group, prefera~ly a mono- or di-lower alkylamino
group, wherein possible lower alkyl radicals are those
mentloned~ R8 is hydrogen or a lower alkyl group, for
example one of those mentioned; Rg is hydrogen, a lower
alkyl group, for example one of those mentioned, carboxyl
or lower alkoxycarbonyl, wherein the lower alkoxy part is
derived, for example, from the lower alkyl radicals
mentloned; Rlo ls hydrogen or a lower alkyl group, for
-- 8 --
: - - . - . .: -
:. ' : - ~ -. .
107~Z~l
example one of those mentioned.
Lower alkoxy radicals are especially those radicals
which are derived from the lower alkyl radicals mentioned.
Examples of such lower alkoxy radicals are methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy and n-amyloxy. Two lower
alkoxy radicals, especially two adjacent lower alkoxy
radicals, ¢an also be linked, as in the case of lower
alkylenedioxy, for example methylenedioxy.
Examples of lower alkenyloxy radicals are allyloxy
or methallyloxy radicals.
Lower alkinyloxy radicals are in particular propar-
gyloxy radicals.
Hydroxy-lower alkoxy radicals are especially those
derlved from the hydroxy-lower alkyl groups mentioned but
wherein preferably the two oxygen atoms are separated by
at least 2 carbon atoms.
Lower alkoxy-lower alkoxy radicals are, for example,
those derived from the lower alkoxy radicals mentioned.
Examples of such radicals are methoxymethoxy, ethoxymethoxy,
l-methoxyethoxy, 4-methoxy-n-butoxy, 3-methoxy-n-butoxy
and especlally 3-methoxy-n-propoxy, 2-methoxyethoxy and
2-ethoxyethoxy.
Lower alkylthio-lower alkoxy groups are, for example,
those groups which are derived from the lower alkyl radic-
als mentioned. Examples of such groups are methylthio-
~07~
methoxy, 2-ethylthioethoxy, 3-methylthio-n-propoxy and
especially 2-methylthioethoxy.
Phenyl-lower alkoxy radicals are especially a-phenyl-
-lower alkoxy radicals, such as benzyloxy radicals, but
can also be other radicals of this type which are derived
from the lower alkyl radicals mentioned, such as, for
example, the phenethoxy radical.
Lower alkanoyl radicals to be mentioned are above
all pivaloyl, propionyl or butyryl radicals, but above all
the acetyl radical; examples of alkanoyloxy radicals are
those in which the alkanoyl part has the above meaning.
Examples of lower alkylmercapto groups are those
groups derived from the lower alkyl radicals mentioned.
Examples of such groups are ethylmercapto, isopropyl-
mercapto, n-butylmercapto and especially methylmercapto.
Acylamino groups are especially those which contain
cycloaliphatic, aromatic, araliphatic and above all
aliphatic acyl radicals as the acyl radicals.
Aliphatic acyl radicals of the formula R-CO- are
especially those in which R is a lower alkyl radical, for
example one of those mentioned.
Cycloaliphatic acyl radicals of the formula R'-CO~
are especially those in which R' denotes an optionally
lower alkylated lower cycloalkyl radical, above all with
3-7, especially 5-7, ring members, such as, for example,
-- 10 --
~' ,, ' ~ ' ~ '
.
1071Zl'l
the cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl
radical.
Examples of aromatic or araliphatic acyl radicals
which may be mentioned are benzoyl and naphthoyl radicals
and phenyl-lower alkanoyl radicals, such as phenylac~tyl
and ~- and ~-phenylpropionyl radicals.
The acyl radicals mentioned can be substituted yet
further.
The following may be mentioned as substituents of
the aromatic and araliphatic acyl radicals, the substituents
preferably being present in the rings: lower alkyl or
alkoxy radicals, such as those mentioned above, halogen
atoms, such as those mentioned below, or the pseudohalogen
trlfluoromethyl. The radicals can be monosubstituted, di-
substituted or polysubstituted.
Preferred acyl radicals are benzoyl and particularly
lower alkanoyl, such as acetyl.
Possible halogen atoms are especially fluorine or
bromlne atoms, but particularly chlorine atoms.
The N-mono-lower alkylcarbamoyl and N,N-di-lower
alkylcarbamoyl groups for example contain, as the lower
alkyl part, the above mentioned lower alkyl radicals. The
N,N-lower alkylenecarbamoyl radicals contain, as lower
alkylene radicals, especially butylene-1,4 or pentylene-
-1,5 radicals. Examples of such radicals are N-methyl-
-- 11 --
1071Z~l
carbamoyl, N,N-dimethylcarbamoyl, pyrrolidino-carbocarbonyl
and piperidino-carbonyl radicals.
An optionally substituted ureido group is, for
example, a ureido group in which the free amino group can
optionally be substituted by lower alkyl groups, for
example those mentioned, such as, for example, a N',N'-
-dimethylureido group or N',N'-diethylureido group. If the
ureido group is substituted by divalent radicals, then
these are radicals which can optionally be interrupted by
hetero-atoms and/or be substituted, preferably lower
alkylene radicals, which can be straightchain or ~ranched
and above all have 4-6 chain carbon atoms if the carbon
chaln ls unlnterrupted or 4 or 5 carbon atoms if the
carbon chain is interrupted by hetero-atoms. Possible
hetero-atoms are, ln particular, oxygen, sulphur and
nitrogen. Examples of such radicals are butylene-(1,4),
pentylene-(1,5), hexylene-(1,5), hexylene-(2,5), hexylene-
-(1,6), heptylene-(1,6), 3-oxapentylene-(1,5), 3-oxahexyl-
ene-(1,6), 3-thia-pentylene-(1,5), 2,4-dimethyl-3-thia-
-pentylene-(1,5) and 3-lower alkyl-3-aza-pentylene-(1,5)
radicals, such as 3-methyl-3-aza-pentylene-(1,5) or 3-aza-
-hexylene-(1,6) radicals.
The new compounds possess valuable pharmacolo~ical
properties. Thus,they show a blood pressure-lowering action,
as can be demonstrated in animal experlments, for example
- 12 -
107~Z~l
on intravenous administration of doses of about 0.01-1 mg
kg to narcotised cats. Furthermore, the new compounds
cause an inhibition of tachycardia, as can also be shown
in animal experiments, for example in in vitro experiments
at concentrations of 0.3-3 y/ml on an isolated guineapig
heart by the Langendorff method (resolution of the tachy-
cardia by isoproterenol [5 x 10 9 y/ml] or histamine
[3 x 10 7 y/ml]). Furthermore, the new compounds cause a
vasodllatation which can be demonstrated on animals, for
example on narcotised dogs, by measuring the haemodynamics
on intraduodenal administration in a dose of about 10 mg/kg.
The new compounds further possess a noradrenolytic
action which can be demonstrated in vitro, for exa~ple in
experlments on isolated perfused mesenteric arteries of
rats at concentrations of 0.001-0.01 y/ml.
The new compounds further show an anti-arrythmic
and positlvely lnotropic effect.
Accordingly, the new compounds can in particular be
used as anti-hypertensive agents and as vasodilatant agents.
Further, the new compounds can serve as startlng materials
or intermediate products for the manufacture of other
compounds, especially pharmaceutlcally active compounds.
Compounds to be mentioned particularly are those of
the formula
C~71Z~l
:
R' loRl2 R6 -~ C ~ R"'
~ 2 CH - CH2 - N ~ C~ - N (Ia)
Rn
; wherein R' denotes a hydrogen atom, a p-alkanoylaminoethen-
yl radical, an optionally lower alkylated p-carbamoyl
radical, an o- or p-lower alkanoyl radical, an o-nitrile
group, a p-lower alkoxycarbonylamino-lower alkyl radical,
an o-halogen atom or a p-hydroxyl group or above all a
p-lower alkanoylamlno radical, a p-[2(lower alkoxy)ethyl]
radical, a lower o-alkyl or o-al~oxy radical, or an o-al-
kenyl or o-alkenyloxy radical, R" denotes a lower alkyl
radical, a lower alkoxy radical, a lower alkenyl radical,
a lower alkenyloxy radical or above all a hydrogen atom,
R2 denotes a lower alkanoyl radical, such as, in particular,
the acetyl, propionyl or pivalyl radical, or above all a
hydrogen atom, R3 denotes a hydrogen atom or the hydroxyl
group and R5 denotes a hydrogen atom, or R3 and R5 together
represent a second bond and R4 and R6 each denote a
hydrogen atom, or R4 together with R3 represents an oxo
group and R5 and R6 each denote a hydrogen atom, or R6
together wlth R5 represents an oxo group and R3 and R4 each
denote a hydrogen atom and R"' denotes a lower alkanoyl-
amino radical, the amino group, the nltro group or, above
all, a lower alkyl radical, a lower alkoxy group, a halogen
- 14 -
10712~
atom, the trifluoromethyl radical or the hydroxyl group,
and their salts.
Compounds to be mentioned especially are in partic-
ular those of the formula Ia, wherein R' denotes a p-lower
alkanoylamino radical, for example p-acetylamino, a
p-[2-(lower alkoxy)-ethyl] radical, for example 2-methoxy-
ethyl, or especially a lower o-alkenyl or o-alkenyloxy
radical, for example o-allyl or o-allyloxy, or above all
a lower o-alkyl or o-alkoxy radical, such as the o-methyl
or o-methoxy radical, R" represents hydrogen, R2 denotes
the acetyl, propionyl or, in particular, pivalyl radical,
or above all a hydrogen atom, R3 denotes a hydrogen atom
or the hydroxyl group and R5 denotes a hydrogen atom or
R3 and R5 together represent a second bond and R4 and R6
each denote a hydrogen atom, or R4 together with R3
represents an oxo group and R5 and R6 each denote a
hydrogen atom, or R6 together with R5 represents an oxo
group and R3 and R4 each denote a hydrogen atom, but in
which above all R4 and R6 each represent hydrogen and R3
and R5 elther represent a second bond or each denote a
a hydrogen atom, and R"' denotes a lower alkyl radical,
for example methyl, a lower alkoxy radical, for example
methoxy, a halogen atom, for example chlorine, the tri-
fluoromethyl radtcal or, in particular, a hydrogen atom,
and their salts.
1~371;~1
Compounds to be mentioned specifically are
2-~1-[3-(o-allyloxy-phenoxy)-2-hydroxypropyl]-4-piperidyl~-
-3,4-dihydro-1(2H)-isoquinolinone, 2-~1-[3-(o-chloro-
phenoxy)-2-hydroxypropyl]-4-piperidyl}-3,4-dihydro-1(2H)-
-isoquinolinone, 2-~1-[3-(o-methoxyphenoxy)-2-pivaloyloxy-
propyl]-4-piperidyl}-3,4-dihydro-1(2H)-isoquinolinone,
2-~1-[3-(o-tolyloxy)-2-hydroxypropyl]-4-piperidyl~-3,4-di-
hydro-1(2H)-isoquinolinone, and above al~ 2- ~-~3-(o-
-methoxyphenoxy)-2-hydroxypropyl]-4-piperidyl~-3,4-dihydro-
-1(2H)-isoquinolinone which, for example, when administered
lntravenously, in a dose of about 0.01 mg/kg, to narcotised
cats, causes a distinct lowering of the blood pressure.
Furthermore compounds to be mentioned particularly
are those o~ formula
~ C~2 ~ C~ ~ C~2 ~ ~ /C~
R' O
- 16 -
~071Zll
R' is hydrogen, lower alkyl, lower alkenyl, lower alkinyl,
5 to 7 ring-membered cycloalkyl, carbamoyl-lower alkyl, hy-
droxy, lower alkoxy, lower alkenyloxy, lower alkinyloxy, ha-
logeno, trifluoromethyl or cyano, each of R " and R " ' is
hydrogen, lower alkyl, hydroxy, lower alkoxy, halogeno, tri-
fluoromethyl, nitro, amino or lower alkanoylamino, R2 is hy
drogen or lower alkanoyl, particularly acetyl 9 propionyl
or pivaloyl, each of R5 and R6 denote a hydrogen a~om, or
R5 together with R6 represents oxo, and their therapeutically
useful acid addition salts. In said compounds R' preferably
is in one of the ortho-positions, R " is one of the meta-
positions or the para-position and R " ' is preferably meta
to carbonyl and para to methylene.
Compounds to be mentioned especially are in parti-
cular those of Formula Ib, R' is methyl, allyl, cyclohexyl,
carbamoylmethyl, methoxy, allyloxy, propargyloxy, chloro,
bromo, tri~luoromethyl or cyano, R " ' is hydrogen, methyl,
methoxy or acetylamino, R2 is hydrogen, acetyl, propionyl or
pivaloyl, and each o~ R5 and R6 is hydrogen, and salts there-
of. Of said compounds, R' is preferably o-methyl, o-allyl,
o-cyclohexyl, p-carbamoylmethyl, o-methoxy, o-allyloxy, o-
propargylo.~y, o- or p-chloro, -bromo or -trifluoromethyl or
o-cyano, R " is preferably hydro~en, m-methyl, m-methoxy or
1071Zll
m-acetylami.no, R2 is hydrogen, acetyl, propionyl or pivaloyl,
and each of R " ', R5 and R6 is hydrogen, and their thera-
peutically useful acid addition salts.
Compounds to be mentioned specifically are 1-[3-(o- .
methoxy-phenoxy)-2-hydroxypropyl3-4-(1-oxo-isoindolino)-pi-
peridine and the 1-[3-(o-cyanophenoxy)~2~hydroxypropyl]-4-
(l-oxo-isoindolino)-piperidine and their therapeutically
useful acid addition salts, which, or example, when admini-
stered intravenously, in a dose of about 0.01 mg/kg, to
narcotised cats, cause a distinct lowering of the blood pres-
sure.
The new compounds are obtained according to methods
which are in themselves known.
For example, a compound o~ the formula
Rl - O - Yi (II)
can be reacted with a compo~md of the formula
R~ R~ R3
alkl R C ( C)n (III)
\ alk2/ ~ / Ph
18
~71Z~l
wherein R , alkl, alk2, Ph, n, R3, R4, R5 6
indicated meanings, one of the radicals Yl and Y2
represents hydrogen and the other denotes a radical of the
formula
- CH2 - CH - CH - z
X
and X represents the group R2, wherein R2 has the indicated
meaning, and Z denotes a reactively esterified hydroxyl
group, or X and Z together form an epoxy group.
Thus, for example, a possible procedure is to react
a compound of the formula
, .
1 CH2 - CH - CH2 - z (IIa)
wlth a compound of the formula
/alkl \ R5 R~ R3
\ alk2 ~ Ph (IIIa)
o
wherein alkl, alk2, Ph, n, R3, R4, R5 6
above meanings and either X represents the group R2, wherein
R2 has the indicated meanings, and Z represents a reactive
esterified hydroxyl group,or X and Z together form an
epoxy group.
-- 19 --
1071Z~l
A reactive esterified hydroxyl group is, in partic-
ular, a hydroxyl group esterified by a strong inorganic
or organic acid, above all a hydrogen halide acid, such as
hydrochloric acid, hydrobromic acid, hydriodic acid or
sulphuric acid, or an organic sulphonic acid, for example
benzenesulphonic acid, p-bromobenzenesulphonic acid or
p-toluenesulphonic acid. Thus, Z in particular represents
chlorine, bromlne or iodine.
This reaction is carried out in the usual manner.
~7hen a reactive ester is used as the starting material,
the reaction ls preferably carried out in the presence of
a baslc condensation agent and/or with an excess of the
compound of the formula IIIa.
Further, a compound of the formula
Rl - OH (IIb)
wherein Rl has the above meanings, can be reacted wlth a
compound of the formula
R5 ~ /
X /alkl\ R6 ~C ( C~n
Z - CH - CH - CH - N CH - N C / ~h (IIIb)
o
wherein X, Z, alkl, alk2, Ph, n, R3, 4, 5 6
the above meanlngs.
- 20 -
, ' ': ' :
- ~,
10~2~1
This reaction is carried out in the usual manner.
If reactive esters are used as the starting material, the
compound of the formula IIb can preferably be used in the
form of its metal phenolate, such as alkali metalphenolate,
for example sodium phenolate, or the reaction is carried
out in the presence of an acid-binding agent, especially
of a condensation agent, which can form a salt with the
compound of the formula IIb, such as an alkali metal
aicoholate.
The new compounds in which R3 is hydroxyl can
furthermore be manufactured by reducing the oxo group of
the propyl chain to a hydroxyl group in a compound of the
formula
al~2 / ~ IIV)
o
wherein Rl, alkl, alk2, Ph, n, R3, R4, R5 6
above meanings.
This reduction is carried out in the usual manner,
ln particular using a di-light metal hydride, such as
sodium borohydride. However, the reduction can also be
carried out with nascent hydrogen. Nascent hydrogen can be
obtained for this purpose by reaction of metals or metal
. .
.
.
`: ^
10712
alloys on agents which provide hydrogen, such as carboxylic
acid, alcohols or water, and in particular zinc or zinc
alloys together with acetic acid, or alkali metals and
alcohol, such as sodium and ethanol, can be used.
The reduction can furthermore be carried out by
catalytic hydrogenation, such as with hydrogen in the
presence of a hydrogenation catalyst, for example heavy
metals such as palladium, platinum or Raney nickel. Care
must be taken that other reducible groups are not attacked
during the reduction.
The new compounds can also be obtained when the
pyridinium ring is reduced to the piperidine ring in a
compound of the formula
~2 ~ ~ R6 - C ~ ~ 3
Rl-O-CH -CH-CH - N~ ~ C ~ h
(P~y~s O
1~ 2~ R3t R4, R5, R6, Ph and n have the above
meanings, Rx and Ry independently of one another denote
lower alkyl radicals or hydrogen atoms and r and s repres-
ent 1 or 2, and A ~ is an anion.
The reduction can be carried out in the usual
manner, preferably by catalytic hydrogenation, such as
- 22 -
.
.
107~Zll
with hydrogen in the presence of a hydrogenation catalyst,
for example heavy metals, such as palladium, platinum or
Raney nickel, or with nascent hydrogen, such as, for
example, is produced by sodium and an alcohol, such as a
lower alkanol, for example ethanol.
Care must be taken that other reducible groups are
not attacked in the reduction.
The new compounds can also be obtained bY intra-
molecular Icondensation of a compound of the formula
-- R6~ ~ 5
X'-- C 1 4
lR2 /alkl C~--~.3
Rl-o-CH2-CH CH2 ~ ~ ~ ~ Ph
alk2 C (Y~ )
whereln Rl, R2, alkl, alk2, Ph, n, R3, R4, R5 and R6 have
the indicated meanings and X' denotes a reactive esterified
hydroxyl group.
A reactive esterified hydroxyl group is in partic-
ular one of those mentloned above.
The cyclisatlon (intramolecular condensation) can
be carried out in the usual manner, preferably in the
presence of a solvent, such as an inert polar solvent,
- 2~ -
107~2~1
such as an alcohol, for example ethanol or isopropanol, or
dimethylformamide, and advantageously in the presence of
a condensation agent, particularly of a basic condensation
agent. The cyclisation is preferably carried out in the
presence of an alkali metal hydroxide, carbonate or bi- -
carbonate or alkaline earth metal hydroxide, carbonate or
bicarbonate, for example sodium hydroxide, potassium
hydroxide, calcium hydroxide, sodium carbonate, potassium
carbonate, calcium carbonate, sodium bicarbonate or
potassium blcarbonate, or of an alkali metal acetate, such
as sodium acetate, or of an alkali metal alcoholate, such
as sodium methylate, or of organic tertiary nitrogen bases,
such as trialkylamines, for example trimethylamine or
triethylamine, or pyridine.
The new compounds in which R3 and R5 together
represent a second bond, wherein n is 1, can also be ob-
tained when a compound of the formula
12 / alkl
Rl ~ ~ CH2 - CH - CH2 - N / CH - NH2 (VII)
is reacted with a compound of the formula
- 24 -
1071Z~l
R~ / ~4
C, - C
. ¦ (VIII)
C
o
1' 2' R4, R6, alkl, alk2 and Ph have the
indicated meanings.
The reaction can be carried out in a manner which
is ln itself known. It is advantageously carried out in
the presence of an organic base, such as a tertiary amine,
above all pyridine, and this base can also simultaneously
serve as the solvent. However, the reaction can also be
carrled out in the presence of further solvents.
The new compounds can also be obtained by intramole-
cular condensation of a compound of the formula
12 alkl / C --~~C~- R3
Rl_o_cH2_cH_cH2 _ ~ CH ~ N Ph (IX)
whereln R , R2, alkl, alk2, R~, R~, R5, 6
the indlcated meanings, and Y3 denotes a free carboxyl
.. ~ ,
- ,: -
' ~:
. : . . : .. . .
1071Z~l
group or preferably a functionally modified carboxyl group
which contains an oxo group.
A functionally modified carboxyl group which con-
tains an oxo group is, for example, an esterified carboxyl
group such as, in particular, a carboxyl group esterified
with a lower alkanol or aralkanol, such as methanol, phenol,
p-nitrophenol or benzyl alcohol, or an activated esterified
carboxyl group, such as a carboxyl group esterified with
cyanomethanol, or an acid halide grouping, such as, in
particular, an acid chloride grouping, or an acid azide,
acid amide or acid anhydride grouping. Possible acid an-
hydride groupings are especially those of mixed anhydrides,
especially of mixed anhydrides with carbonic acid monoalkyl
esters, such as carbonic acid monoethyl ester or carbonlc
acid monolsobutyl ester.
The reaction can be carried out in the usual manner.
Preferably, elevated temperatures are used. The reaction ls
advantageously carried out in a solvent, such as an inert
solvent, for example a hydrocarbon, such as benzene or
toluene, or in a high-boiling inert solvent such as, for
example, diphenyl ether.
The new compounds in which R2 represents hydrogen,
can also be obtained when, in a compound of the formula
- 26 -
.
~D71Z~l
OR2 ~ alkl R6 ¦ 5 R4 R
Rl O CH2 C~ CH2 ~ / CH - N ~ Ph
(X)
wherein Rl, alkl, alk2, Ph, n, R3, R4, R5 and R6 have the
indicated meanings and R2 denotes a radical which can be
split off by hydrogenolysis, R2 is split off by hydrogen-
olysis.
A radical which can be split off by hydrogenolysis
is above all an ~-aralkyl radical, such as the benzyl
radical, or an a-aralkoxycarbonyl radica7, such as the
carbobenzoxy radical. The hydrogenolysis can be carried
out in the usual manner, preferably by means of hydrogen
ln the presence of a hydrogenation catalyst, such as a
nickel, palladium, platinum or ruthenium catalyst.
The new compounds of the formula I, wherein R6
together with R5 forms an oxo group, can also be obtained
when a compound of the formula
12
Rl - O - CH2 - CH - C~l2 ~ N~ lk ~ 2 (VII)
` - 27 -
,
. - -: . .
-: - -
~0~7~Zll
wherein Rl, R2, alkl and alk2 have the above meanings, isreacted with a compound of the formula
~ R3
Y3 - (C) n (XI)
~ Ph
wherein R3, R4, n and Ph have the above meanings and the
substituents Y3 independently of one another represent a
free carboxyl group or preferably a functionally modified
carboxyl group which contains an oxo group, or together
represent the grouping
O z C
~C~
A functlonally modified carboxyl group which con-
talns an oxo group is, for example, an esterified carboxyl
group such as, in partlcular, a carboxyl group esterified
with a lower alkanol or aralkanol, such as methanol, phenol,
p-nitrophenol or benzyl alcohol, or an activated esterified
carboxyl group, such as a carboxyl group esterified with
~O~lZll
~hd~ cyanomethanol, or an acid halide grouping, such as,
in particular, an acid chloride grouping, or an acid azideJ
acid amide or acid anhydride grouping. Possible acid an-
hydride groupings are in particular those of mixed anhydrides,
especially of mixed anhydrides with carbonic acid monoalkyl
esters, such as carbonic acid monoethyl ester or carbonic
acid monoisobutyl ester.
The reaction can be carried out in the usual manner.
Preferably, elevated temperatures are used. The reaction
is advantageously carried out in a solvent, such as an
inert solvent, for example a hydrocarbon, such as benzene
or toluene, or in a high-boiling inert solvent such as,
for example, diphenyl ether.
In resulting compounds, substituents can be split
off, introduced or converted, within the scope of the end
products.
Thus, for example, in compounds of the formula I,
wherein Rl denotes an aryl radical which is substituted by
a ratical Z" which can be converted into an optionally
substituted carbamoyl group, Z" can be converted into an
optionally substituted carbamoyl group.
A radical Z" is in this case above all an optionally
functionally modified carboxyl group containing an oxo
group.
A functionally modified carboxyl group which con-
- 29 -
.
~7~Zll
tains an oxo group is, for example, an esterified carboxyl
group, such as, in particular, a carboxyl group esterified
with a lower alkanol or aralkanol, such as methanol,phenol,
p-nitrophenol or benzyl alcohol, or an activitated ester-
ified carboxyl group, such as a carboxyl group esteri~ied
with cyanomethanol, or an acid halide grouping, such as,
in particular, an acid chloride grouping, or an acid azide
grouping or acid anhydride grouping.Possible acid anhyd-
ride groupings are in particular those of mixed anhydrides,
especially of mixed anhydrides with carbonic acid mono-
alkyl esters, such as carbonic acid monoethyl ester or
carbonic acid monolsobutyl ester.
The conversion of the group Z" is effected, for
example, by reaction with ammonia or with a corresponding
amlne possesslng at least 1 hydrogen atom.
The reaction is carried out in the usual manner, in
partlcular at elevated temperature, if necessary at dras-
tically elevated temperature, such as at a temperature
whlch may even be above 200C, if desired under pressure
and lf desired with an excess of the particular amine. If
the reaction is carried out at room temperature or only
moderately elevated temperature, it is preferably carried
out in an inert solvent using a longer reaction time.
Examples of inert solvents are alcohols, such as methanol
and ethanol, ethers, such as diethyl ether or dloxane,
benzene and the like.
- 30 -
1071211
Furthermore, for example, in compounds of the
formula I, wherein Rl denotes an aryl radical substituted
by a radical Z"' which can be converted into an optionally
substituted ureido group, Z"' can be converted into an op-
tionally substituted ureido group.
Z"' is here in particular a reactively modified
carboxyamino radical, such as a carboxyamino radical
esterified by a lower alkanol or phenol, or a corresponding
halogenocarbonylamino radical, such as, in particular, a
chlorocarbonylamino radical.
The conversion to the ureido group is carried out,
for example, by reactlon with ammonia or a corresponding
amlne possessing at least 1 hydrogen atom.
This reactlon can be carried out in the usual manner,
especially using an excess of ammonia or amine and option-
ally ln a solvent and preferably at elevated temperature.
Furthermore, resulting compounds in which Rl denotes
an aryl radical substituted by a hydroxyalkyl, hydroxy-
alkoxy, mercaptoalkyl or mercaptoalkoxy radical, can be
alkylated, for example by reaction with a reactive ester
of a correspondlng alkanol. Reactive esters are here above
all esters with strong inorganic or organlc acids, prefer-
ably with hydrogen halide acids, such as hydrochloric acid,
hydrobromic acid or hydriodic acid, with sulphur acid or
with arylsulphonlc acids, such as benzenesulphonic acid,
,:
: ~ . ; '
.
.
`
1071211
p-bromobenzenesulphonic acid or p-toluenesulphonic acid.
The reaction can be carried out in the usual manner,
advantageously in the presence of solvents and, for example,
in the presence of condensation agents, such as basic con-
densation agents, at lowered, ordinary or elevated temper-
ature.
Furthermore, in compounds of the formula I, wherein
Rl denotes an aryl radical substituted by a Z2-alkyl or
Z2-alkoxy radical and Z2 represents a reactively esterified
hydroxyl group, Rl can be converted into alkoxy- or alkyl-
mercapto-alkyl or -alkoxy radicals by reaction with
alkanols or alkylmercaptans.
Reactively esterified hydroxyl groups are here in
particular hydroxyl groups esterified with the strong acids
mentioned.
The reaction can be carried out in the usual manner,
advantageously in the presence of solvents and, for example,
in the presence of condensation agents, such as basic con-
densatlon agents, at lowered, ordinary or elevated tem-
perature.
Furthermore, in comp~unds of the formula I wherein
R1 denotes an aryl radical substituted by a hydroxyl group,
the hydroxyl group can be converted into a group of the
formula RxO-, wherein Rx denotes an alkyl radical, an
alkenyl radical, an alkinyl radical, an alkoxyalkyl radical
- 32 -
1071Z~l
or an alkylmercaptoalkyl radical. This conversion can be
effected in the usual manner, for example by reaction with
a reactive ester of an alcohol of the formula RxOH or a
diazoalkane, such as diazomethane. Furthermore, hydroxyl
groups in the radical Ph can be alkylated, for example by
reaction with a reactive ester of a lower alkanol or a
diazoalkane, such as diazomethane.
Reactive esters are above all esters with strong
inorganic or organic acids, preferably with hydrogenhalide
acids, such as hydrochloric acid, hydrobromic acid or
hydriodic acid, with sulphuric acid or with arylsulphonic
acids, such as benzenesulphonic acid, p-bromobenzenesul-
phonic acid or p-toluenesulphonic acid.
The reaction can be carried out in the usual manner,
advantageously in the presence of solvents. When using the
reactive esters, the reaction is preferably carried out in
the presence of condensation agents, such as basic conden-
sation agents, or the phenolic hydroxy compound is employed
in the form of a salt, for example a metal salt, such as
an alkali metal salt, for example the sodium salt or potas-
sium salt. The reaction can be carried out at lowered,
ordlnary or elevated temperature.
Furthermore it ls possible, in compounds of the
formula I, wherein Rl denotes an aryl radical substituted
by an amino group or by a substituent containing an amino
- 33 -
' ,~
.. . " ..
10712~1
group, and/or Ph denotes an o-phenylene radical containing
an amino group, to acylate the said amino group or groups,
such as, for example, by reaction with an acylating agent.
Possible acylating agents are carboxylic acids, for
example aliphatic, araliphatic or cycloaliphatic carboxylic
acids, preferably in the form of their functional deriv-
atives, such as halides, especially chlorides, or anhyd-
rides, for example pure of mixed anhydrides, or inner an-
hydrides, such as ketenes.
Furthermore, in compounds of the formula I which
contain hydroxyl groups, these groups can be acylated
(esterified). The acylation is carried out in the usual
manner, for example by reaction with carboxylic acids,
advantageously in the form of their reactive furnctional
derivatives, such as acid halides, for example chlorides,
esters, especlally esters wlth lower alkanols, such as
methanol and ethanol, or activated esters such as cyano-
methyl esters, or pure or mixed anhydrides, for example
mixed anhydrides with carbonic acid monoalkyl esters such
as carbonic acid monoethyl ester and monoisobutyl ester.
In compounds of the formula I which contain an acyl-
ated hydroxyl or amino group, this group can be split in
the usual manner to give the free hydroxyl or amino group
respectively, and can in partlcular by splithydrolytically,
with acid or basic catalysts as appropriate, for example
- 34 -
10712~1
with inorganic acids or alkali metal hydroxide solutions
(bases), for example, with hydrochloric acid or withsodium
hydroxide solution. If such splitting should already occur
in the course of one of the above methods of manufacture,
a resulting free hydroxyl or amino group can optionally be
acylated as described above.
In compounds of the formula I which contain a
halogen atom, for example chlorine or bromine, on an arom-
atic ring, for example on Rl or Ph, this halogen atom can
be replaced by hydrogen. This is done in the usual manner,
for example by dehalogenating hydrogenation, such as
hydrogenation in the presence of nickel or palladium
catalysts. Compounds which contain an unsubstituted aryl
radlcal or an aryl radlcal which is partly substituted by
other groups, can be halogenated at the aryl radical. This
can be done in the usual manner, for example with halogen,
especlally at non-elevated temperatures or with cooling,
and in the presence of a catalyst, such as iron, iodine,
iron-III chloride or aluminium chloride or the correspon-
ding bromldes.
Furthermore, in compounds of the formula I which
contain substituents with a C-C double bond or C-C triple
bond, the C-C double bond or C-C triple bond can be conver-
ted into a C-C single bond by catalytic hydrogenation, such
- 35 -
1071;2~1
as by hydrogen in the presence of a hydrogenation catalyst,
for example nickel, platinum or palladium, such as Raney
nickel, platinum black or palladium on active charcoal.
Care must be taken at the same time that other reducible
groups are not attacked.
In compounds of the formula I, which contain sub-
stituents with a C-C triple bond, this bond can further-
more be reduced merely to a C-C double bond and can, if
deslred, be reduced stereospecifically to a C-C-cis- or
C-C-trans-double bond. The reduction of a C-C triple bond
to a C-C double bond can be carried out, for example, by
hydrogenation with 1 mol of hydrogen in the presence of a
less active hydrogenation catalyst, such as iron or pal-
ladlum, for example Raney iron or paladium on barium sul-
phate, especially at elevated temperature. The reduction
to a C-C-cis double bond can be effected, for example, by
means of 1 mol of hydrogen in the presence of a deactiv-
ating catalyst, such as palladium on animal charcoal in
the presence of quinoline, palladium on calcium carbonate
ln the presence of lead salts, or Raney nickel. The reduc-
tion to a C-C-trans-double bond can be effected, for exam-
ple, by means of sodium in liquid ammonia, in which case,
especially taking into accountan urea group, short reac-
tion times and no excess reducing agent are employed and,
if appropriate, an ammonium halide, such as ammonium
1~17~Z~l
chloride, is added as the catalyst.
In resulting compounds of the formula I which con-
tain an a-aralkylamino or ~-aralkoxycarbonylamino group or
an a-aralkoxy or ~-aralkoxycarbonyloxy group, these radic-
als can be split to give free amino or hydroxyl groups
respectively. a-Aralkyl is in such cases especially benzyl.
The splitting off can be effected in the usual manner, es-
pecially by means of hydrogen in the presence of a hydrog-
enation catalyst, such as a palladium, platinum or nickel
catalyst.
In resulting compounds of the formula I which pos-
sess nitro groups on an aromatic nucleus, these groups can
be reduced to amino groups.
The reduction can be carried out in the usual man-
ner, for example by nascent hydrogen Ifor example with
iron and hydrochloric acid or with aluminium amalgam) cr
with catalytically activated hydrogen, such as hydrogen in
the presence of platinum, nickel or palladium catalysts.
It is also possible to reduce compounds of the
formula I, in which R3 and R4 together represent an oxo
group, to compounds wherein R3 represents hydroxyl and R4
represents hydrogen.
The reduction of the oxo group ls carried out in
the usual manner, for example by metallic reduction, such
as by treatment with sodlum in alcohol, or with complex
1~7121~
metal hydrides, such as sodium borohydride, or by means of
catalytically activated hydrogen, for example hydrogen in
the presence of a platinum, palladium, nickel or copper
catalyst, such as platinum oxide, palladium on charcoal,
Raney nickel or copper chromite. The reaction is preferably
carried out in the presence of diluents and/or solvents,
at low, ordinary or elevated temperature, in an open vessel
or in a closed vessel, under pressure.
The reduction of the oxo group can also be carried
out in accordance with the Meerwein-Ponndorf-Verley method.
Thus, for example, the oxo compound can be treated in the
usual manner with a lower alkanol, such as isopropanol, in
the presence of a corresponding alXanolate, such as alum-
lnium lsopropylate.
It ls also possible to split off the hydroxyl group
ln compounds of the formula I, wherein R3 represents
hydroxyl. This gives compounds in which R3 and R5 represent
a second bond.
The splitting off can be effected ln the usual
manner, for example by treatment with strong acids, such
as sulphuric acid, p-toluenesulphonic acid, concentrated
hydrochloric acld, oxalic acid or other dehydrating agents,
such as phosphorus pentoxide, zlnc chloride or boron
trioxide. If appropriate, the water ls removed by means of
a water separator. For example, the reaction can becarried
- 38 -
' - ~
1~71Zll
out in a boiling hydrocarbon, such as benzene or toluene.
Furthermore, it is possible to replace the hydroxyl
group by hydrogen in compounds of the formula I, wherein
R3 represents hydroxyl. This can be done, for example, by
catalytic hydrogenation.
Furthermore, compounds of the formula I, wherein R3
and R5 represent a second bond, can be hydrogenated to
compounds in which R3 and R5 represent hydrogen atoms.
This can be done, in particular, by catalytic hydrogenation.
The catalytic hydrogenation can be carried out in
the usual manner, in particular by means of hydrogen in
the presence of a hydrogenation catalyst, such as a pal-
ladium, platinum or nickel catalyst.
The reactions mentioned can optionally be carried
out simultaneously or successively, and in optional
sequence.
The reactions mentioned can be carried out in the
usual manner in the presence or absence of solvents or
diluents, acid or basic condensation agents and/or catal-
ysts, at lowered, ordinary or elevated temperature and if
appropriate in a closed vessel under elevated pressure
and/or under an inert gas atmosphere.
Depending on the process conditions and starting
materials, the end products are obtained in the free form
or in the form of their acid addition salts, which are also
- 39 -
107~Z~
encompassed by the invention. Thus, for example, basic,
neutral or mixed salts and at times also hemihydrates,
monohydrates, sesquihydrates or polyhydrates thereof, can
be obtained. The acid addition salts of the new compounds
can be converted into the free compound in a manner which
s is in itself known, for example by means of basic agents,
such as alkalis or ion exchangers. On the other hand, the
resulting free bases can form salts with organic or in-
organic acids. Acids used for the preparation of acid ad-
; dition salts are especially those which are suitable for
forming therapeutically usable salts. As examples of such
acids there may be mentioned: hydrogen halide acids, for
example hydrochloric acid, sulphuric acids, ~or example
sulphuric acld, phosphoric acids, nitric acid, perchloric
acid, aliphatic, alicyclic, aromatic or heterocyclic car-
boxylic aclds or sulphonic acids, such as formic acid,
acetic acid, propionic acid, succinic acid, glycollic acid,
lactic acid, malic acid, tartaric acid, citric acid, as-
corbic acid, malelc acld, hydroxymaleic acid or pyruvic
acid, fumarlc acid, benzoic acid, p-aminobenzoic acid,
anthranilic acid, p-hydroxybenzoic acid, salicylic acid or
p-aminosalicyllc acid, embonic acid, methanesulphonic acid,
ethanesulphonlc acld, hydroxyethanesulphonic acid, ethyl-
enesulphonic acld; halogenobenzenesulphonic acid, toluene-
sulphonic acid, naphthalenesulphonic acid or sulphanilic
- 40 -
1071Zll
acid; methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds, such as,
for example, the picrates, can also serve for the purifi-
cation of the resulting free bases by converting the free
bases into salts, isolating these and again liberating the
bases from the salts. Because of the close relationships be-
tween the new co~pounds in the free form and in the form of
their salts, the free compounds are, in the preceding and
following text, where appropriate also to be understood as
the corresponding salts, with regard to general sense and
intended use.
The invention also relates to those embodiments of
the process, according to which a compound obtainable as an
intermediate product at any stage of the process is used as
the starting ~aterial and the missing process steps are
carried out, or the process is discontinued at any stage,
or in which a starting material is formed under the reac-
tion conditions or in which a reactant is present, if ap-
propriate, in the form of an optical antipode and/or of a
salt,
Thus, for example, the new piperidines can be ob-
tained if a compound of the formula
12 alkl
Rl - 0 - ~H2 ~ CH - CH2 - N CH - NH2 '
alk2
- 41 -
lC~71Zll
wherein Rl, R2, alkl and alk2 have the indicated meanings,
is reacted with a compound of the formula
R~ R5
X' - C 14
IJn 3
Ph
Y3
wherein n, R3, R4, R5 and R6 have the indicated meanings,
and X' and Y3 have the meanings indicated for formula VI
or IX. Here, a product of the formula VI is produced as an
intermediate and then reacts further, in accordance with
the invention, to give a compound of the formula I. The
reactlon can be carried out in the usual manner, for exam-
ple as descrlbed above for the intramolecular condensations.
The new compounds can, depending on the choice of
the starting materials and procedures, be in the form of
optical antipodes or racemates or, if they contain at least
two asymmetrical carbon atoms, also in the form of racemate
mlxtures and/or pure geometrical isomers or mixtures there-
of ~isomer mixtures).
Resulting isomer mixtures can be separated into the
two pure geometrical isomers on the basls of the physico-
chemical differences of the constituents in a known manner,
~07~Z~l
for example by chromatography on a suitable stationary
phase, such as silica gel, or aluminium oxide, which has
been pretreated with a complex-forming heavy metal com-
pound, for example with a silver compound, or by forming
a heavy metal addition compound, for example the silver
nitrate complex, separating this into the addition com-
pounds of the pure isomers, for example by fractional crys-
tallisation, and subsequently liberating the pure isomers.
Resulting pure isomers, for example tranc-isomer
can be converted in the usual manner, for example photo-
chemlcally, for example by irradation with light of a
suitable wavelength, advantageously in a suitable solvent,
~uch as an aliphatic hydrocarbon, or in the presence of a
sultable catalyst, into the isomers of opposite configur-
ation, for example into the cis-isomers.
Racemate mixtures can be separated into the two
stereoisomeric ~diastereomeric) pure racemates on the basis
of the physico-chemical differences of the constituents in
a known manner, for example by chromatography and/or frac-
tlonal crystallisation.
Resultlng racemates can be resolved according to
known methods, for example by recrystalllsation from an
optically active solvent, with the ald of micro-organisms
or by reaction with an optically active acid which forms
- g3 -
'
. , . , .............................................. - . .
.,, '' - .
.. . . ~ . . . . .
107~Zll
salts with the racemic compound and separation of the salts
obtained in this manner, for example on the basis of their
different solubilities, into the diastereomers, from which
the antipodes can be liberated by treatment with suitable
agents. Particularly customary optically active acids are,
for example, the D- and L-forms of tartaric acid, di-o-
-toluyltartaric acid, malic acid, mandelic acid, camphor-
sulphonic acid or quinic acid. Advantageously, the more
active L-antipode is isolated.
Suitably, those starting materials are used for
carrying out the reactions according to the invention
which lead to the initially particularly mentioned groups
of end products and particularly to the end products which
have been specifically described or singled out.
The starting materials are known or can, if they
are new, be obtained according to methods which are in
themselves known.
The compounds of the formula
alkl /C ~C~;
alk2~ C ~ (IIIa)
U
used as preferred starting materials, can be obtained, for
.
;~
- 44 -
-
': ~ . -` - `:
,. , ., , . , . : .
, , -
.
.~ . .
: . - . :
.
1071Zll
example, if a compound of the formula
~alkl
1 1 ~ CH -- NH2
alk2
wherein alkl and alk2 have the indicated meanings and R
denotes an a-aralkyl radical, such as benzyl radical, is
reacted with a compound of the formula
R ~ 15
C ~ R3
I n
Ph
Y3
wherein n, R3, R4, R5 and R6 have the indicated meanings
and X' and Y3 have the meanings indicated for formulae VI
or IX, and in the resulting compound of the formula
Rll- N \ CH - N/
- 45 -
. .. : . . : ~ .
, . . . - :
.. . .. . ...... . .
-
~07~Z~l
the a-aralkyl radical Rll is replaced by hydrogen, for
example by catalytic hydrogenation as described above.
The new compounds can be used as medicaments, for
example in the form of pharmaceutical preparations in
which they or their salts are present in a mixture with a
pharmaceutical, organic or inorganic, solid or liquid
excipient which is suitable, for example, for enteral, for
example,oral, or.parenteral administration. Suitable
materials for forming the excipient are those which do not
react with the néw compounds such as, for example, water,
gelatine, lactose, starch, magnesium stearate, talc,
vegetable oils, benzyl alcohols, gum, polyalkylene glycols,
white petroleum jelly, cholesterol or other known medicinal
excipients. The pharmaceutical preparations can be, for
example, in the form of tablets, dragees, capsules, sup-
positories, ointments or creams or in a liquld form, as
solutlons (for example as an elixir or syrup), suspensions
or emulsions. They are optionally sterilised and/or con-
tain auxiliaries, such as preservatives, stabllisers,
wetting agents or emulsifiers, salts for regulating the
osmotlc pressure or buffers. They can also contain yet
other therapeutically valuable materials. The preparations,
which can also be used in veterinary medicine, are for-
mulated according to customary methods.
- 46 -
., :
.
.
.
:
' ~ . - . :
1071Zli
The dosage of the new compounds depends on the
nature of the conditions to be treated and on the indiv-
idual requirements. For example, the new compounds can be
administered to a warm-blooded animal of about 75 kg body
weight in a daily dose of about 5-100 mg, especially
about 5 to 60 mg.
The new compounds can also be used advantageously
in pharmaceutical preparations in combination with other
anti-hyper~tensive agents and/or diuretics.
Compounds, having an anti-hypertensive action,
which can be used are in particular those of the type of
a-amino-~-hydroxyphenyl-propionic zcid and ~-amino-~-al-
koxyphenyl-propionic acid and especially of the hydrazin-
opyrldazines and of the sympathicolytics.
Sultable diuretics are materials which increase the
diuresls both through renal and through extrarenal action
on the tlssues. For this purpose, substances with an in-
hlbitlng action on the back-resorptlon ln the tubulus,
such as, for example, ln partlcular saluretlcs as well as
ethacrlnlc acid and its analogues, can be used.
Partlcularly suitable compounds are benzothiadiazine
derlvatlves, such as thlazides and hydrothlazides, benzene-
sulphonamldes, phenoxyacetic acids, benzofurane-2-carbox-
ylic acids and benzofurane-2,3-dihydroxy-2-carboxylic acids.
The examples which follow illustrate the invention
wlthout however restricting it.
- 47 -
: ' : . '.
-
:' ' ~
.:
1071Zl~
Example 1
A mixture of 30.2 g of 1-(o-methoxyphenoxy)-2,3-
epoxypropane and 38.7 g of 2-(4-piperidyl)-3,4-dihydro-
1(2H)-iso~uinolinone in 50 ml of absolute ethanol is boiled
for 6 hours under reflux and is then evaporated in vacuo.
The residue is acidified with ethanolic hydrochloric acid;
on adding ether, 2-{1-~3-~o-methoxyphenoxy)-2-hydroxy-
propyl]-4-piperidyl}-3,4-dihydro-1 ~2H~-isoquinolinone
hydrochloride precipitates and after recrystallisation
from ethanol/ether melts at 174-176&.
2-(4-Piperidyl)-3,4-dihydro-1 (2H)-isoquinolinone,
used as the starting material, is prepared as follows:
A solution of 40 g of 2-(2-chloroethyl)-benzoyl
chloride in 100 ml of acetone is added dropwise to a mix-
ture of 53 g of potassium hydroxide and 30 g of 4-amino-1-
benzyl-piperidine in 600 ml of acetone at room temperature.
After completion of the addition, the reaction mixture is
heated for 4 hours to the reflux temperature and is then
evaporated to dryness. The residue is taken up in water
and extracted with methylene chloride. The organic layer
is dried over sodium sulphate and evaporated. The oily
residue is taken up in a little ethanol and acidified with
ethanolic hydrochloric acid. The hydrochloride of 2-(1-
ben~yl-4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone is ob-
tained in a crystalline form and melts at 276-278C (with
decomposition),
- 48 -
.
.
:. ' : ,, .. ' - '.
- : - . : ' ' . . .' :
1071~1~
13.6 g of 2-(1-benzyl-4-piperidyl)-3,4-dihydro-
1(2H)-isoquinolinone hydrochloride are hydrogenated
together with 1.5 g of 10% strength palladium on charcoal
at room temperature and atmospheric pressure. The reaction
mixture is freed from the catalyst by filtration and the
residue ls well washed with water. The filtrate is evap-
orated to dryness, the residue is dissolved in as little
ethanol as possible and the hydrochloride of 2-(4-piper-
idyl)-3,4-dihydro-1(2H)-isoquinolinone is precipitated
wlth ether. It melts, after recrystallisation from ethanol,
at 318-320C (decomposition).
The base is liberated with 10 N sodium hydroxide
solutlon and extracted with methylene chloride. Drying,
and evaporation of the solvent, gives the base an oil.
Example 2
A solutlon of 9.9 g (0.06 mol) of l-(o-tolyloxy)-
2,3-epoxy-propane, 15.9 g (0.06 mol) of 2-~4-plperldyl)-
3,4-dlhydro-l~2H)-isoquinolinone hydrochloride and 24 ml
of trlethyla~ine in 240 ml of isopropanol is heated to the
reflux temperature for 6 hours and then evaporated ln vacuo.
The resldue is crytalllsed from ethanol-water. After
recrys~alllsatlon from ethanol-water, 2-~1-[3~(o-tolyloxy)-
2-hydroxypropyl]-4-plperidyl~-3,4-dihydro-1(2~)-iso~uinol-
lnone melts at 104-105C.
- 49 -
" ' ' ' -
,. ~
. ' . . ~ .: , - ' ' .
.
. . ~
1071Zll
The maleic acid salt of this compound melts, after
recrystallisation from ethanol-ether, at 165-166C (with
decomposition).
Example 3
A solution of 8.1 g of 2-~l-[3-(o-methoxy-phenoxy)-
2-hydroxy-1-propyl]-piperidyl-(4)~-3,4-dihydro-1(2H)-iso-
quinolinone hydrochloride and 5 g of pivaloyl chloride in
50 ml of pyridine is warmed to 100C over the course of
1/2 hour and is then evaporated in vacuo. The residue is
a~idified with alcoholic hydrochlorlc acid and again evap-
orated. After recrystallisation from isopropanol, 2-~1-[3-
-(o-methoxy-phenoxy)-2-pivaloyloxy-1-propyl]-piperidyl-
~4)}-3,4-dihydro-1~2H)-isoquinolinone hydrochloride of
meltlng polnt 232-234C ls obtained.
Example 4
A mixture of 5.5 g of 1-(o-chlorophenoxy)-2,3-epoxy-
propane and 7 g of 2-(4-plperldyl)-3,4-dlhydro-1(2H)-lso-
qulnollnone in 100 ml o~ isopropanol is boiled for 5 hours
under reflux and then evaporated in vacuo. The oily residue
is dissolved in absolute ethanol and the equivalent amount
of malelc acld 19 added. After addition of ether, 2-~ 3-
~o-chlorophenoxy)-2-hydroxy-propyl~-piperidyl-(4)~-3,4-di-
hydro-1(2H)-isoqulnolinone maleate precipitates and melts,
after recryqtallisatlon from ethanol/ether at 139-140C.
-- 50 --
' . ' -
''' ,, '' - -
-. - - ~ , .
.. - :
.. . .
1~71Zll
Example 5
- A solution of 6.2 g of l-Ip-(2-m2thoxy-ethyl)-
phenoxyl-2,3-epoxy-propane and 7.0 g of 2-(4-piperidylj-
3,4-dihydro-1(2H)-isoquinolinone in 80 ml of isopropanol
is refluxed for 5 hours. The reaction mixture is
concentrated by evaporation to dryness with the resulting
precipitation of 2-~ 3-C~p-~2-methoxy-2thyl)-phenoxy ~ -2-
hydroxypropyl]-4-piperidyl~-3~4-dihydro-1(2H)--isoquirlolinone.
The product melts at 116-117 after recrystallisation from
an ethanol/ether mixture. The maleic acid salt crystallises
from a mi.~ture of ethanol/ether and melts at 138-139.
Example 6
6.~ ~ o~ 1-(o-allyloxyphenoxy)-2,3-epoxy-propane and
7.0 g of 2-(4-piperidyl)-3,4 dihydro-1(2H)-isoquinoline
are dissolved in 100 ml of isopropanol. The solution is
re~luxed ~or 5 hours and then concentrated in vacuo. The
oily residue is converted with 3.1 g of fumaric acid in~o the
crystalline 2~ [3-(o-allyloxyphenoxy)-2-hydroxypropyl]-
4-piperi.dyl}-3,4-dihydro-1(2H)-isoquinolinone^fumarate.
The salt mei~s at 145-146 after recrystallisation from
ethanol/ether, with decomposition.
- 51 -
,
:
- - .
', '' ~ '.'"''~ ` ' , ,, ' ' ''~ '. ' ' '
1071Zll
Example 7
The mixture of 3.8 g of 1-(o-methoxyphenoxy)-2,3-
epoxypropane, 4.32 g of 4-(1-oxoisoindolino)-piperidine and
35 ml of isopropanol is refluxed for 4 hours while stirring.
After cooling to room temperature it is acidified with sa-
turated hydrogen chloride in ethyl acetate to reach the pH=l,
and more cooled with an ice bath. It is filtered, the re-
sidue washed with ice-cold isopropanol and diethyl ether
and recrystallized from 100 ml of isopropanol, to yield the
1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(1-oxoisoindolino)-
piperidine hydrochloride melting at 172-174,
The starting material is prepared as follows: The
mixture of 150 g of 2-formylbenzoic acid, 85.2 g of 4-amino-
pyridine and ~,8 lt of toluene is refluxed on a water-se-
parator for 2.5 hours while stirring and stirring is con-
tinued at room temperature over night. It is filtered and
the residue washed with toluene, to yield the 1-(4-pyridyl-
amino)-3-oxophthalan melting at 215-220~ lAnalogously the
1-(3-pyridylamino)-3-oxophthalan is obtained from 3-amino-
pyridlne; m.p. 150-1553,
To the suspension of 278 g thereof in 4.7 lt of an-
hydrous ethanol, 96 g of sodium borohydride are added por-
tionwise during 105 minutes while stirring 3t 18~ Stirripg
. . ` .
.
.
, . -
.
' ' " ' . ' ' '
,
1071Z~l
is continued at room temperature over night, the mixture is
filtered, the filtrate concentrated to a volume of 1.2 lt.
cooled and the precipitate formed collected, to yield the
2-(4-pyridylaminomethyl)-benzoic acid melting above 250.
180.6 g thereof are added to 1.4 lt of concentrated
sulfuric acid during 40 minutes while stirring and allowing
the temperature to rise to about 67. The mixture is stirred
for 1 hour at about 95, cooled to 25G, and slowly poured
onto 4 Icg ice. The mixture is neutralized with about 4.5 lt
of aqueous ammonia, the precipitate formed filtered off and
taken up in 2.3 ~t of isopropanol and 600 ml of chloroform.
The mixture is refluxed for 30 minutes, filtered hot, the
filtrate cooled and the precipitate formed collected, to
yield the 4~ oxoisoindolino)-py,idine
The mixture of 30 g thereof, 400 ml of glacial ace-
tic acid and 30 g of 10% palladium on charcoal is hydrogena-
ted at about 65 and 3 atm until the theoretical amount of
hydrogen has been absorbed. It is cooled to room temperature,
filtered and evaporated The residue is taken up in 6 N
aqueous hydroxide, the mixture extracted with chloroform,
the extract washed with saturated aqueous sodium chloride,
dried and evaporated, to yield the 4-(1-oxoisoindolino)-pi-
perld~ne melting at 144-146
- 53 -
.. . ~
.
.
107~211
Example 8
In the exact analogous manner, illustrated by
Example 7 following compounds as listed have been obtained:
a) l-[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]-4-
(l-oxo-isoindolino)-piperidine-hydrochloride, melting
point 206-208,
b) l-[3-(o-allylphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoin-
dolino)-piperidine-hydrochloride, melting point 205-207;
c) l-[3-(2-allyl-3-acetylaminophenoxy)-2-hydroxypropyl]-4-
(l-oxo-isoindolino)-piperidine-hydrochloride, melting point
177-180;
d) l-[3-(2-cyclohexylphenoxy)-2-hydroxypropyl]-4-(1-oxo-
isoindolino)-piperidine-hydrochloride, melting point 214-
216;
e) l-[3-(p-carbamoylmethylphenoxy)-2-hydroxypropyl]-4-(1-
oxo-isoindolino)-piperidine-hydrochloride, melting point
266-270;
f) l-[3-(2-methoxy-3-methoxyphenoxy)-2-hydroxypropyl]-4-
(l-oxo-isoindolino)-piperidine-hydrochloride, melting point
161-163;
g) l-[3-(o-allyloxyphenoxy)-2-hydroxypropyl]-4-(1-oxo-iso-
indolino)-piperidine-hydrochloride, melting point 185-186;
h) l-l-3-(o-propargyloxyphenoxy)-2-hydroxypropyl]-4-(1-oxo-
- 54 -
-
:' -
. . . .
.
" ' ' '' ' ' ~ - ', ',
1~ 7 1 2
isoindolino)-piperidine-hydrochloride, melting point 173-
175;
i) l-[3~(p-bromophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoin-
dolino)-piperidine-hydrochloride, melting point 253-257;
j~ l-[3-(o-cyanophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoin-
dolino)-piperidine-hydrochloride, mèlting point 203-205;
k) l-~3-(5-indanyloxy)-2-hydroxypropyl]-4-(1-oxo-isoin-
dolino)-piperidine-hydrochloride, melting point 270-272
Example 9
To the solution of 3.96 g of 1-[3-(o-methoxyphenoxy)-
2-hydroxypropyl)-4-(1-oxoisoindolino)-piperidine (prepared
from the hydrochloride of Example 1 and 2N aqueous sodium
hydroxide, extracting the mixture with ethyl acetate and
evaporating the dryed extract) and 2 ml of pyridine in 50 ml
of methylene chloride, 1 32 g o~ pivaloyl chloride in 10 ml
of methylene chloride are added dropwise during 20 minutes,
while stirring and cooling with ice. Stirring is continued
for 48 hours at room temperature, 48 hours while refluxing
and again 48 hours at room temperature The mixture is
washed with cold 10% aqueous sodium carbonate and water,
dried, filtered and evaporated. The residue is dissolved
in 20 ml of ethanol, the solution acidified with saturated
- 55 -
~07~21~
hydrogen chloride in ethyl acetate ~nd the precipitate
formed collected. It is dissolved in 50 ml of hot ethanol,
50 ml of ethyl acetate are added, the mixture cooled with
ice and the precipitate formed collected, to yield the 1-
[3-(o-methoxyphenoxy)-2-pivaloyloxypropyl)-4-(1-ox~isoin-
dolino)-piperidine hydrochloride melting at 206-212.
Example 10
A mixture of 28 g of 1~ naphthoxy)-2,3-epoxy-propane
and 18.8 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-iso--
quinolinone in 40 ml of isopropanol is refluxed for 4
hours. After completion of the reaction, the precipitated
crystals are filtered off and washed with ether. There is
thus obtained 2-{1-[3-(~-naphthoxy)-2-hydroxy-1-propyl]-
piperidyl-(4)~-3,4-dihydro-1(2H)-isoquinolinone, which
melts at 181-183 after recrystallisation from chloroform/
ethanol.
24 g of the above base is dissolved in 250 ml of hot
chloroform, and 30 ml of 2N ethanolic hydrochloric acid
is added to ~he solution. There precipitates the hydro-
chlor~de of 2-~1-[3-(~-naphthoxy~-2-hydroxy-1-propyl]-
piperidyl-(4)}-3,4-dihydro-1(2H)-isoquinolinone, which
melts at 269-271.
.
, -
: - .
~, ' . . '.:
-
. , - .- ~ ~ .
~07~ 2
Example 11
A mixture of 26.9 g of 1-(2-methoxy-4-chlorophenoxy)-
2,3-epoxy-propane and 25.8 g of 2-(4-piperidyl)-3,4-
dihydro-1(2H)-isoquinolinone in 30 ml of isopropanol is
refluxed for 4 hours. After completed reaction, trituration
with ether is performed, whereupon 2-~ 3-(2-methoxy-4-
chlorophenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-3,4-
dihydro-1(2H)-isoquinolinone precipitates, which melts at
108-110 after recrystallisation from isopropanol.
22.8 g of the above base is dissolved in 60 ml of hot
isopropanol, and to this solution there is added 10 ml
of 8.7N ethanolic hydrochloric acid. ~fter trituration
with ether there precipita~es the hydrochloride of
2-~ 3-(2-methoxy-4-chlorophenoxy)-2-hydroxy)-1-
propyl]-piperidyl-(4)} -3,4-dihydro-1(2H)-isoquinolinone,
which melts at 210-212.
Example 12
A mixtu~e of 11.55 g of 1-(o-cyanophenoxyj-2,3-epoxy-
propane and 14.95 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-
isoquinolinone in 30 ml of isopropanol is refluxed for
- 57 -
.
', :
- : :
1~:)71Zl~
6 hours. After completion of the reaction, the reaction
solution is diluted with 150 ml of isopropanol, heated to
boiling and filtered hot. On cooling and with trituration
with ether there precipitates 2-~1-[3-(o-cyanophenoxy)-2-
hydroxy-l-propyl3-piperidyl-(4))-3,4-dihydro-1(2H)-iso- -
quinolinone, which melts at 138-140.
16.5 g of the above base is dissolved in 100 ml of hot
ethanol, and ~ g of maleic acid is added. On cooling of
the solution there precipitates the maleate of 2-{l-~3-(o-
cyanophenoxy)-2-hydroxy-l-propyll-piperidyl-(4)~-3,4-dihydro-
1(2H)-isoquinolinone, which melts at 183-184.
Example 13
A mixture of 18 g of 1-(o-methoxyphenoxy)-2,3-epoxy-
propane, 27 g of 4-phthalimidopiperidine-hydroclloride,
60 ml of triethylamine and 300 ml of isopropanol is refluxed
for 4 hours. The reaction mixture is concentrated by
evaporation to dryness, and the residue is suspended in
2N sodium hydroxide solution. The aqueous suspension is
extracted with methylene chloride, the organic phase is
dried with sodium sulphate and freed from the solvent in
vacuo. 11.6 g of maleic acid is added to the residue. The
- 58 -
,,
- . .
- . : - -
:
1071;21~
maleic acid salt of l-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-
4-phthalimidopiperidine is crystallised from ethanol/ether
and melts at 201-202 with decomposition,
Exam ~
Tablets containing 2-~ 3-(o-methoxyphenoxy)-2-
hydroxypropyl]-4-piperidyl3-3,4-dihydro-1-(2H)-isoquinolone,
Composition
2-¦1-[3-(o-Methoxyphenoxy)-2-hydroxypropyl]-4-piperidyl -
3,4-dihydro-1-(2H)-isoquinolone
Crystalline lactose
Wheat starch
Aerosil 200
Talc
Magnesium stearate
Manufactur_
The active compound is mixed with a part of the
wheat starch, with lactose and with Aerosil 200 and the
mixture is forced through a sieve, A further part of the
wheat 8tarch is worked into a paste with a 5-fold amount
of water on a waterbath and the powder mixture is kneaded
with this paste until a slightly plastic mass has been pro-
duced, The plastic mass is pressed through a sieve of approx,
- 59 -
lZ~l
3 mm mesh width and dried, and the dried granules are again
forced through a sieve. Thereafter, the remaining wheat
starch, talc and magnesium stearate are mixed in and the
resulting mixture is pressed to give tablets having a cross-
shaped notch
' ' .
Example ~r
Preparation of 10,000 tablets each containing 2~.0 mg -~
of the active ingredient:
Formula:
1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-
4-(1-oxoisoindolino)-piperidine hydrochloride250.00 g
Lactose 1,956.00 g
Corn starch 90 00 g
Polyethylene glycol 6,000 90.00 g
Talcum powder 90 00 g
Magnesium stearate 24.00 g
Purified water q.s.
Procedure:
All the powders are passed through a screen with
openings of 0.6 mm. Then the drug substance, lactose, talc-
cum, magnesium stearate and half of the starch is suspended
- 60 -
- , -
.: . . . , -
1071Z~
in 45 ml of water and the suspension added to the boiling
solution of the polyethylene glycol in 180 ml of water.
The paste formed is added to the powders which are granula-
ted, if necessary, with an additional amount of water. The
granulate is dried overnight at 35, broken on a screen
with 1.2 mm openings and compressed into tablets using con-
cave punches with 7.1 mm diameter, uppers bisected.
~xample ~
~i .
Preparation of 10,000 capsules each containing 50 mg
of the active ingredient:
F mula:
1-[3-(o-cyanophenoxy)-2-hydroxypropyl]-
3-(1-oxoisoindolino)-piperidine cyclamate500.0 g
Lactose 2,350.0 g
Talcum powder 150.0 g
Procedure-
All the powders are passed through a screen with
openings of 0.6 mm. Then the drug substance is placed in a
suitable mixer and mixed first with the taleum, then with
the lactose until homogenous. No. 2 capsules are filled with
300 mg, using a capsule filling machine.
- 61 -
~071Zll
Example 14
10.8 g of o-cresol is dissolved in 250 ml of dimethyl-
formamide and, with stirring, the solution is added
dropwise to a solution of 5.0 g of sodium hydride in
250 ml of dimethylformamide, and the temperature is then
held at 50 for 30 minutes. There is subsequently added
28.6 g of 2-ll-(2,3-epoxypropyl)-4-piperidyl]-3,4-dihydro-1-
(2H)-isoquinolinone in 300 ml of dimethylformamide, and
the temperature i8 maintained for a further 3 hours at 50.
Decomposition i8 effected with cooling with a large amount
of ice and water, and extraction is performed by shaking
with ether. The ethereal solution is extracted twice with
2 N sodium hydroxide solution, dried and the ether is
subsequently evaporated off. Concentration by evaporation
yields 2-{1-t3-(o-tolyoxy)-2-hjdroxypropyll-4-piperidyl~-
3,4-dihydro-1(2H)-isoquinolinone in the form of a crystal-
line product, which melts at 104-105. The maleic acid
salt obtained therefrom melts at 165-166.
Example 15
a) 4.6 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-iso-
quinolinone i8 added to 1.85 g of epichlorohydrin in
35 ml of benzene, and stirring is maintained for 15 hours
at room temperature. The solvent is then evaporated off
at 40 in vacuo, and the residue is subsequently repeatedly
- 62 -
, .
. . i . . ;
. . - , :
- .
- . . - ~
. ' ' - '~ . ,: - - ' . .
107~Zll
extracted with benzene, in the course of which the
product crystallises. The crystals are stirred with
acetonitrile and filtered off under suction. The
resulting 2-[1-(2,3-epoxypropane)-4-piperidyl]-3,4-
dihydro-1(2H)-isoquinolinone hydrochloride melts
at 173-174.
b) 1.08 g of o-cresol, 2.9 g of the 2-11-(2,3-epoxy-
propane)-4-piperidyl]-3,4-dihydro-1(2H)-isoquinolinone
obtained above and 2.8 g of potassium carbonate in 20 ml
of acetonitrile are refluxed for 15 hours. The potassium
carbonate i~ then filtered off, and the filtrate is
concentrated in vacuo. The residue is crystalliQed from
ethanol/water. After recrystallisation from ethanol/water,
the resulting 2-{1-l3-(o-tolyoxy)-2-hydroxypropyl]-4-
piperidyl~-3,4-dihydro-1(2H)-isoquinolinone melts at
104-105. The maleic acid salt of this compound melts
at 165-166 (decomposition) after recrystallisation from
ethanol/ether.
Example 16
5.2 g of 1-(o-methoxyphenoxy)-2-hydroxy-3-bromo-
propane, 4.6 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-
isoquinolinone and 2.6 g of N-ethyldiisopropylamine in
80 ml of dimethylformamide are heated at 80 for 12 hours.
The dimethylformamide and the amine are then distilled off
in vacuo. The residue is taken up in water, rendered
63
107121~
alkaline with 2 N ~odium hydroxide solution, and extracted
with chloroform. The organic phase is dried, and concen-
trated by evap~ration, and the hydrochloride is produced
with ethanolic hydrochloric acid Crystallisation from
ethanol/ether yields the 2-~1-[3-(o-methoxyphenoxy)-2-
hydroxypropyll-4-piperidyl}-3,4-dihydro-1(2H)-isoquinolinone
hydrochloride, which melts at 174-176.
Example 17
a) 10 g of 1-l3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-
(3,4-dihydro-1(2H)-isoquinolinon-2-yl)-pyridinium bromide
in 100 ml of ethanol is hydrogenated, in the presence of
concentrated hydrochloric acid, at room temperaturP with
platinum oxide. The reaction mixture obtained is made
alkaline with 2 N sodium hydroxite solution; it is then
extracted with chloroform, dried, and concentrated by
evaporation. The catalyst is filtered off; the filtrate
i8 concentrated by evaporation and the residue is taken
up in water. The hydrochloride is produced with etha~olic
hydrochloric acid. The resulting 2-{1-l3-(o-methoxyphenoxy)-
2-hydroxypropyll-4-piperidyl}-3,4-dihydro-1(2H)-iso-
quinolinone hydrochloride is recrystallised from ethanol/
ether, and has a melting point of 174-176.
b) The above-mentioned quaternary salt is produced from
l-(o-methoxyphenoxy)-2-hydroxy-3-bromopropane and 2-(4-
pyridyl)-3,4-dihydro-1(2H)-isoquinolinone in dimethyl-
- 64 -
,, ' ~ ' ' . '. '~
- :
., : - - .
~ -. - '' ., ,' ' ' ''
.
1071Zl~ -
formamide at 80 with the addition of N-ethyldiisopropyl-
amine, and in the unpurified state further processed
as described under a).
Example 18
A solution of 2.6 g of 2-(2-chloroethyl)-benzoyl
chloride in 50 ml of acetone is added dropwise to 4.1 g
of l-(3-o-methoxyphenoxy)-2-hydroxy-(propyl)-4-æmino- -
piperidine and 3 g of potassium hydroxide in 50 ml of
acetone, and the reaction mixture obtained is refluxed
for 9 hours. The precipitated material is filtered off,
ànd the filtrate is evaporated to dryness. To the oil
obtained is added 2 N hydrochloric acid, and extraction
is performed by shaking with methylene chloride, The
comblned extracts are dried and concentrated by evaporation.
The re~idue is recrystalli~ed from methylene chloride/
ethyl acetate to thus obtain 2-{1-(3-(o-methoxyphenoxy)-2-
hydroxypropyl]-4-piperidy~-3,4-dihydro-1(2H)-isoquinolinone
hydrochloride, which has a melting point of 174-176.
Example 19
1.5 g of isocoumarin and 2.8 g of 1-l(3-o-methoxy-
phenoxy-2-hydroxy)-propyl]-4-aminopiperidine in 30 ml of
ethanol are refluxed for 3 hours. 0.5 g of palladium/
charcoal is added to the reaction mixture, and the mixture
i8 hydrogenated until the theoretical amount of hydrogen
has been absorbed. The catalyst is then filtered off, and
~ - 65 -
~07~;211 ~
the filtrate is evaporated to dryness. Ethanolic
hydrochloric acid is added to the residue, and the
resulting 2-¦1-l3-(o-methoxyphenoxy-2-hydroxy)-propyl]-4-
piperidyl]-3,4-dihydro-1(2H)-isoquinoline hydrochloride
is recrystallised by trituration with ether. The product
melts at 173-175 after recrystallisation from ethanol/ether.
Example 20
a) 9.1 g of N-~1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-
piperidyl}-2-aminoethyl-benzoic acid ethyl ester in 100 ml
of ethanol and 2.6 g of N-ethyldiisopropylamine are
refluxed for 6 hours. The amine and the alcohol are then
removed in vacuo, and the oil xemaining behind is converted
with ethanolic hydrochloric acid into the hydrochloride.
Recrystallisation from ethanoltether yields 2-ll-[3-(o-methoxy-
phenoxy)-2-hydroxypropyl]-4-piperidyl~-3,4-dihydro-1(2H)-
isoquinolinone hydrochloride, which melts at 174-176,
b) The ester mentioned above is obtained by reductive
amination of l-[3-(o-methoxyphenoxy)-2-hy~ro~ypro~yl]-4-
piperidone with 2-aminoethyl-benzoic acid ethyl ester with
platinum/charcoal catalysis in methanol, and can be
further processed in the unpurified state as given under a).
, - 66 -
~...1
'
.
.. . . . ..
