Note: Descriptions are shown in the official language in which they were submitted.
Case 4-13491/1273
Process for the manufacture of novel amidines
The invention relates to a process for the manufacture
of novel amidines, especially N,N'-bridged carboxylic acid
amidines of the general formuIa
R2
Ph - ~
R /!"N/ ( ),
in which
R~ represents phenyl optionally substituted in the
p-position by lower alkylthio having up to and
including 4 carbon atoms, by lower alkanesul~
phinyl having up to and including 4 carbon
atoms, by lower alkoxy having up to and including
4 carbon atoms or by halogen having an atomic
number of up to and including 35, thienyl, or
pyridyl optionally substituted by lower alkyl
~; '
~2~
having up to and including 4 carbon atoms,
R2 represents carboxymethyl or, secondly, lower
alkoxycarbonylmethyl having up to and including
5 carbon atoms,
Ph represents 1,2-phenylene optionally substituted
in the p-position to the nitrogen atom by lower
alkoxy having up to and including 4 carbon atom~
or by halogen having an atomic number of up to
and including 35, and
alk represents vinylene,
and of their salts, with the proviso that if Rl represents
p-methylthiophenyl and Ph represents 1,2-phenylene substituted
in the p-position to the nitrogen atom by fluorine, R2 is
other than carboxymethyl or ethoxycarbonylmethyl, and with
the further proviso that if R1 represents phenyl and Ph
represents unsubstituted 1,2-phenylene or if ~ represents
p-chlorophenyl and Ph represents 1,2-phenylene substituted
in the p-position to the nitrogen atom by methoxy, in each
case R2 is other than ethoxycarbonylmethyl
In the present description, "lower" organic radicals
and compounds are preferably to be understood as those
having up to and including 7, especially up to and including
4, carbon atoms.
The general definitions used hereinbefore and herein-
after have especially the following meanings within the
scope of the present description:
Lower alkylthio is, for example, methyl-, ethyl-, n-
propyl;, isopropyl--, n-butyl-, isobutyl-, sec.-butyl-,
tert.-butyl, n-pentyl-, n-hexyl- or n-heptyl-thio, and
lower alkanesulphinyl is, for example, methane , ethane- or
n-propane-sulphinyl.
Lower alkoxy is~ for example, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.
Halogen is, for ~xample, halogen having an atomic number
of up to and including 35, such as fluorine, chlorine or
.
bromine, and also iodine.
Lower alkyl is, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, and
also a pentyl, hexyl or heptyl radical.
Thienyl is, for example, 2- or 3-thienyl, and pyridyl
is 2-, 3- or 4-pyridyl.
Lower alkoxycarbonyl is, for example, methoxy-, ethoxy-
or n-propoxy-carbonyl, and also a butoxy-, pentyloxy-,
hexyloxy or heptyloxy-carbonyl radical.
Salts of compounds of the formula I according to the
invention are preferably pharmaceutically acceptable salts,
such as corresponding acid addition salts and/or, when
R2 is 1-carboxymethyl, internal salts or salts with bases.
Suitable acid addition salts are, for example, salts with
inorganic acids, such as mineral acids, or organic acids,
such as sulphamic acids, for example cyclohexylsulphamic
acid, optionally unsaturated dicarboxylic acids, or carboxy-
lic acids optionally additionally substituted by hydroxy or
additionally containing oxo and/or carboxy, or sulphonic
acids. Mineral acids are, for example, sulphuric acid or
hydrohalic acids, such as hydrobromic or hydrochloric acid.
There come into consideration as optionally unsaturated
dicarboxylic acids, for example, oxalic acid, malonic acid,
umaric acid or maleic acid, and there are used as
carboxylic acids optionally additionally substituted by
hydroxy or additionally containing oxo and~or carboxy, for
example, tartaric acid, malic acid, pyruvic acid or citric
acid. Sulphonic acids are, for example, benzenesulphonic,
p-toluenesulphonic or methanesulphonic acid.
Suitable salts with bases are, Eor example, metal,
such as alkali metal or alkaline earth metal, salts, for
example sodium, potassium, magnesium or calcium salts,
transition metal salts, such as zinc or copper salts, or
salts with ammonia or salts of substituted organic amines,
such as morpholine, thiomorpholine, piperidine and pyrroli-
dine, such as mono-, di- or tri-lower alkylamines or mono-,
di- or tri-hydroxy-lower alkylamines, for example mono-,
di- or tri-ethanolamine and tris(hydroxymethyl)methylc~mine
or diisopropanolamine. Mono-lower alkylamines are, for
example, ethylamine or tert.-butylamine. Di-lower alkyl-
amines are, for example, diethylamine or dipropylamine,
and there come into consideration as tri-lower alkylarnines,
for example, triethylamine, tributylamine or dimethylpropyl-
amine. Furthermore, salts can be formed with basic arnino
acids, such as lysine, arginine, histidine or ornithine,
or with amines that are derived from monosaccharides, such
as N-methyl-D-glucamine.
The compounds of the formula I have valuable pharma-
cological properties. In particular they exhibit a
pronounced antinociceptive (analgesic) activity, which may
be demonstrated, for example, by the acetic acid-writhing
syndrome in rats in a dosage range of from approxima~ely 1
to approximately 30 mg/kg p.oO and by the phenyl-p-benzo-
quinone-writhing test in mice in a dosage range of from
approximately 1 to approximately 30 mg/kg p.o..
In addition, they have a marked anti-inflammatory and
anti-arthritic activity, which may be demonstrated by
suppression of kaolin paw oedema in normal rats in a dosage
range of approximately 10 to 100 mg/kg p.o~, and which, in
addition, may be demonstrated by the suppression of
carrageenin paw oedema in rats, analogously to the method
described by Pasquale et al., Agents and Actions, 5, 256
(1976), in doses of from approximately 3 to approximately
300 mg/kg p.o..
Furthermore, in curative administration with admini-
stration, four times, of approximately 10 to 100 mg/kg p o.,
the compounds of the formula I suppress kaolin paw oedema
of rats having adjuvant-arthritis.
The compounds of the formula I are therefore
excellently suitable as medica~ents for the treatment of
inflammatory disorders, especially those in the rheumatic
and arthritic field, as antiphlogistics and/or as peripheral
analgesics.
-- 5 --
The invention relates, for exampl2, to the manu~acture
of compounds of the formula I in which R1 repesents phenyl
optionally substituted in the ~-position by lower alkylthio
having up to and including 4 carbon atoms, such as methyl-
thio, by lower alkanesulphinyl havlng up to and including
4 carbon ato~s, such as methanesulphinyl, by lower alkoxy
having up to and including 4 carbon atoms, such as methoxy,
or by halogen having an a-tomic number of up to and includ-
ing 35, such as fluorine, thienyl, such as 2-thienyl, or
pyridyl optionally substituted by lower alkyl having up
to and including 4 car~on atoms, such as methyl, such a3
2-picolinyl, R2 represents carboxymethyl or, secondly,
lower alkoxycarbonylmethyl having up to and including 5
carb~n atoms, such a~ ethoxycarbonylmethyl, Ph represents
1,2-phen~lene optionally substituted in the p-position to
the nitrogen atom by lower alXoxy having up to and includ-
ing 4 car~on atom~, such as methoxy, or by halogen having
an atomic num~er of up to and including 35, such as fluorine,
and alk represents vinylene, with the proviso that if ~
represents p-methylthiophenyl and Ph repres2nts 1,2-phenyl-
ene substituted in the p-position to the ~.itrogen atom by
fluorine, R2 is other than car~oxymethyl or ethoxycar~anyl-
methyl, and with the further proviso that if R1 represent~
phenyl and Ph represents unsubstituted 1,2-phenylene or if
R1 represents p-chlorophenyl and Ph represents 1,2-phenyl-
ene substituted in the p-position to the nitroger atom by
methoxy, in each case R2 is other than ethoxycarbonyl-
methyl.
The invention relates preferably to the manufacture
of compounds of the formula I in which Rl represents unsub-
stituted phenyl, p-methoxyphenyl or p-methanesulphinylphenyl,
R2 in each case represents ethoxycarbonylmethyl, Ph in each
case represents 1,2-phenylene substituted in the p-position
to the nitrogen atom by fluorine and alk in each case re-
presents vinylene, or in which Rl represents unsubstituted
2-thienyl, unsubstituted phenyl, p-methanesulphinyl-phenyl
or ~-methoxyphenyl, R2 in each case represents
~. ~
æ
carboxymethyl, Ph in each case represents 1,2-phenylene
substituted in the p-position to the nitrogen atom by
fluorine and alk in each case represents vinylene, or in
which R1 in each case represents unsubstituted 2-thienyl,
R2 represent3 carboxymethyl or ethoxycarbonylmethyl, Ph
in each case represent3 unsubstituted 1,2-phenylene and
alk in each case represents vinylene, or in which ~
represents unsubstituted phenyl, R2 represents carboxy-
methyl, Ph represents unsubstituted 1,2-phenylene, and
alk represents vinylene, or in which R1 represents 2-
picolinyl or p-fluorophenyl, R2 in each case represent~
carboxymethyl or ethoxycar~onylmethyl, Ph in each case
represents 1,2-phenylene substituted in the p-position t~
the nitrogen atom by methoxy and al~ in each case repre-
sent3 vinylene, and salts thereof~
The invention relates preferably to the manufacture of
compounds of the formula I in which Rl represents unsubsti-
tuted phenyl, ~-methoxyphenyl or ~-methanesulphinylphenyl, R2
in each case represents ethoxycarbonylmethyl, Ph in each case
represents 1,2-phenylene substituted in the ~-position to the
ni~rogen atom by fluorine and alk in each case represents
vinylene, or in which Rl represents unsubstituted phenyl, ~-
methanesulphinylphenyl or ~-methoxyphenyl, R2 in each case
represents carbox~methyl, Ph in each case represents 1,2-
phenylene substituted in the p-position to the nitrogen atom
by fluorine and alk in each case represents vinylene, or in
whi~h Rl in each case represents unsubstituted thienyl, R2
represents carboxymethyl or ethoxycarbonylmethyl, Ph in each
case represents unsubstituted 1,2-phenylene and alk in each
case represents vinylene, or in which Rl represents unsubsti-
tuted phenyl, R2 represents carboxymethyl, Ph represents un
substituted 1,2-phenylene and alk represents vinylene, or in
which Rl represents 2-picolinyl or ~-fluorophenyl, R2 in each
case represents carboxymethyl or ethoxycarbonylmethyl, Ph in
each case repres~nts 1,2 phenylene substituted in the
p-position to the nitrogen atom by methoxy and alk in each
i
~ , .
case represents vinylene, and salts thereof.
The invention relates especially to the manufacture of
compounds of the formula I in which Ph represents unsubsti-
tuted 1,2-phenylene and Rl represents phenyl and R2 rspre-
sents carboxymethyl or Rl represents 2-thienyl and R2 repre-
sents carboxy- or ethoxycarbonyl-methyl, or Ph represants
1,2-phenylene substituted in the ~-position to the nitrogen
atom by fluorine and Rl represents phenyl, ~-methanesulphinyl-
phenyl or ~-methoxyphenyl, and R2 represents carboxy- or
ethoxycarbonyl-methyl, or Ph represents 1,2-phenylene sub-
stituted in the ~-position to the nitrogen atom by methoxy
and Rl represents ~-fluorophenyl or 2-picolinyl and R2 repres-
ents carboxy- or ethoxycarbonylmethyl, alk in each case
representing vinylene, and sàlts thereo.
The invention relates especially to processes for the
manufacture of compounds of the formula I mentioned in the
Examples, and salts, especially pharmaceutically acc~ptable
salts, thereof.
The compounds of the formula I and their salts can be
manufactured according to methods known E~ se, for example
by removing H-Zl from compounds of the general formula
Ph - ~
Rl~, \ alk (II),
Zl ~
H
. ~
-- 8 --
in which Z1 represents optionally functionally modified
hydroxy or the mercapto group, or from salts thereo~,
with the introduction of an additional bond, and, if
desired, converting a compound obtainable according to
the invention into a different compound of the formula I
or converting a free compound obtainable according to the
invention into a salt, or converting a salt obtainable
according to the process into the free compound or into
a different salt.
Functionally modified hydroxy is, for example,
hydroxy etherified by a lower alkanol, such as methanol
or ethanol, or by an optionally substituted aromatic
alcohol, such as phenol, or hydroxy esterified by an
inorganic acid, such as a mineral acid, for example a
hydrohalic acid, such as hydrochloric acid, and represents,
for example, lower alkoxy, such as methoxy, or optionally
substituted aryloxy, such as phenoxy, or halogen, such as
chlorine or bromine.
H-Z1 is removed in customary manner, for example
spontaneously, by thermal means, i.e. by heating, and/or
in the presence of a catalytic agent. The thermal removal
is usually carried out in a temperature range of from
approximately 50 to approximately 200C. As catalytic
agents there are used, for example, basic or acidic
catalyst~, there being used as bases, for example, alkali
metal hydroxides, amides or hydrides, such as potassium
hydroxide, sodium amide or sodium hydride, metal oxides,
such as aluminium oxide, or, especially, organic nitrogen
bases, such as tertiary amines, for example pyridine,
quinoline or ~,N-dime-thylaniline, and as acidic catalysts,
for example, mineral acids or acidic salts or anhydrides
thereof, such as sulphuric acid or phosphoric acids,
hydrogen sulphates, such as alkali metal hydrogen sulphate~,
for example potassium hydrogen sulphate, phosphorus
pentoxide, or mineral acid halides, such as phosphorus(III)
or phosphorus(V) chloride or phosphorus oxychloride, or
sulphuric acid halides, for example sulphuryl chloride.
The operation is, if necessary, carried out in t~e presence
o~ an inert solvent or diluent, in a closed vessel and/or
under an inert gas, for example nitrogen.
Inert solvents and diluents are optionally substitute~
hydrocarbons, such as optionally halogenated aliphatic or
aromatic hydrocarbons, for example chloroform or chloro-
benzene, ethers, such as aliphatic, cycloaliphatic or
aromatic ethers, for example diethyl ether,l dioxan, tetra-
hydrofuran, diphenyl ether or anisole, ketones, such as
aliphatic ketones, for example acetone or methylethyl-
ketone, amides, such as dialkylamides, for example
dimethylformamide, or sulphoxides, such as di-lower alkyl
sulphoxides, for example dimethyl sulphoxide.
Starting materials of the formula II can be manu-
factured according to processes known Per se, preferably
in situ. It is thus possible, for example, to cyclise
compounds of the formula
Ph - '
\y (IVa~
Xl 1
or salts thereof, in which ~1 represents hydrogen and
Y1 represents a groùp of the formula -alk-NH-C~=Z1)(R1)
or X1 represents -C(=Z1)(R1) and Y1 represents a group
of the formula -alk-NH2 and Z1 represents optionally
functionally modified oxo, and, if desired, to convert
a resulting free compound of the formula II into a
different free compound or into a salt, or to convert a
salt obtainable according to the process into the free
compound or into a different salt. Thus, for example,
free hydroxy can be converted in customary manner into
halogen or, with a lower alkanecarboxylic acid, into
esterified hydroxy.
~z~
1 o
Functionally modi~ied oxo is, for example, thioxo,
ketalised or thio-ketalised oxo, esterified dioxy, or
imino. Ketalised oxo compounds are, for example, ketals
with lower alka~ols, such as methanol or ethanol, or
lower alkanediols, such as ethylene ~lycol or propylene
glycols, for example 1,3-dihydroxypropane, and thioketals
are, for example, thioketals with lower alkanethiols,
for example methanethiol or ethanethiol, or lower
alkanedithiols, such as 1,2-ethanedithiol, or propane-
dithiols, for example propane-1,3-dithiol. Imino is, for
example, imino optionally substituted by lower alkyl or
phenyl, such as N-lower alkylimino, for example N-propyl-
imino.
The cyclisation is carried out in known manner, for
example in the presence of catalysts, such as acidic
catalysts. These are, for example, mineral acids, such
as sulphuric acid or polyphosphoric acid, mineral acid
halides, such as sulphuryl chloride, or phosphorus
halides, for example phosphorus pentachloride, or organic
sulphonic acids, such as benzenesulphonic, p-toluenesul-
phonic or methanesulphonic acid. The cyclisation is, if
necessary, carried out in one of the above-mentioned
inert solvents or diluents, preferably while heating, for
example in a temperature ran~e of from approximately
20 to approximately 200C, in a c~osed vessel and/or
under an inert gas, for example nitrogen.
In an advantageous embodiment of the above-described
process, compounds of the formula IVa are used as starting
materials and the cyclisation to form compounds of the
formula II and the removal of ~-~1 from the compounds of
the formula II are carried out _ situ without isolation
of the intermediates~
An especially advantageous embodiment of the
above-described process carried out by way of the com-
pounds of the formula II consists, for example, in
quaternising, especially with benzyl bromide, compounds
of the formula
j r~
~N/ \ ~ (IVd),
H
in which Bz represents an optionally substituted a-
phenyl-lower alkyl radical, preferably benzyl, cleaving
the bond at the quaternary nitrogen atom by means of
cyanides, such as alkali metal cyanides, for example
sodium cyanide, and, in a resulting compound of the
formula IVe
Ph j/ C~
H ! (IVe),
~.~
Bz Bz
solvolysing the cyano group as desired, removing the
benzyl groups by hydrogenolysis in the presence of a
hydrogenation catalyst, for example palladium, and
reacting the then free amino compound with a compound
of the formula R1-C \ in which ~1 represents
Hal
optionally functionally modified oxo and Hal represents
halogen, and finally reacting by means of a cyclising
agent, preferably a mineral acid halide, such as
phosphorus oxychloride or phosphorus chloride, that is
to say phosphorus(III) or phosphorus(V) chloride, to
form a compound of the formula II, from which the
corresponding compound of the formula I is formed
directly under the reaction conditions with condensation.
This reaction is especially carried out in such a manner
that corresponding 3,4-dihydropyrimido[1,6-a~indoleacetic
acids or lower alkyl esters are formed. ~ccordingly,
these dihydro derivatives must be dehydrogenated in the
mannex described below to form the desired compounds of
the formula I.
The compounds of the formula I or salts thereof may
furthermore be manufactured by isomerising compounds of
the formula
Ph - i=CHR3) R2
Rl~ q~/ (V),
in which R2 represents carboxy optionally esterified as
indicated under R2, and R3 represents hydrogen, or salts
thereof, and, if desired, converting a resulting free
compound of the formula I into a different free compound
or into a salt, or converting a salt obtainable accord-
ing to the process into the free compound or into a
different salt.
The isomerisation of compounds of the formula V
to form compounds of the formula I is carried out in
customary manner, if necessary by means of acids, such
as mineral acids, for example sulphuric acid, bases, such
as alkali metal hydroxides or carbonates, for example
sodium hydroxide or potassium carbonate, or by means of
organic amines, for example tertiary amines, such as
pyridine, or by appLying energy, such as at temperatures
of above 100 C, optionally in the presence of a catalytic
agent, such as a borate or phosphate, for example an
alkali metal borate or phosphate and, if necessary, in
a solvent or diluent, in a closed vessel and/or under an
.~ 3~
inert gas, for example nitrogen.
Inert solvents and diluents are optionally substituted
hydrocarbons, such as optionally halogenated aliphatic
or aromatic hydrocarbons, for example chloroform or
chlorobenzene, ethers, such as aliphatic, cycloaliphatic
or aromatic ethers, for example diethyl ether, d~oxan,
diphenyl ether or anisole, ketones, such as aliphatic
ketones, for example acetone or methylethylketone, amides,
such as dialkylamides, for example dimethylformamide, or
sulphoxides, such as di-lower alkyl sulphoxides, for example
dimethyl sulphoxide.
Starting materials of the formula V or salts thereof
can be manufactured according to methods known per se,
for example by reacting compounds of the formula
Ph - -
\~/ \\ (VIa),
R / ~ /
in which X1 represents oxo or thioxo, with compounds
of the formula p(z2)3=C(R3)-R2 or X1 P~Z3)2 C ( 3) 2
respeckively, which may be in the form of phosphonium
ylides or in the form of phosphoranes, and in which X
represents oxo or thioxo, Z2 represents alkyl and/or
phenyl, Z3 represents alkyl and/or phenyl, or alkoxy
and/or phenoxy, and R3 represents hydrogen~ Skarting
materials of the formula V or salts thereof may likewise
be manufactured, for example,by reacting compounds of
the formula
_ 14 _
H X
\~ 2
Ph - '
- H
\alk (VIb),
'- ~`N/
in which X2 represents a yroup of the formula -C~R3)=X2
and X2 represents optionally functionally modified oxo,
with hydrogen cyanide or a salt, for example an alkali
metal salt, thereof. After solvolysis, which optionally
follows, a compound of the formula Z4-Z5 is removed from
resulting inkermediates of the formula
\alk (VII),
/ ~ /
Rl N
in which Z4 represents hydroxy or thio optionally
present in salt form and Z5 represents a radical of the
formula P(Z2)3 or -P(Z3)~-O , or Z4 represents hydrogen
and Z5 represents hydroxy or mercapto.
Alkoxy is, for example, lower alkoxy, such as
methoxy, ethoxy, propoxy or butoxy. Optionally function-
ally modified oxo is oxo, thioxo,or imino optionally
substituted by lower alkyl or phenyl.
In an advantageous embodiment of the above-
described process for the manufacture of compounds of
the forn~ula I, for example using compounds of the formula
VII as starting materials, the manuracture of compounds
of the formula V and the isomerisation according to the
invention can be carried out _ situ.
- 15 _
The removal of Z4-Z5 is carried Ol~t in customary
manner, for example by the application of energy, for
example a reaction temperature of from approximately
50 to approximately 200C, or in the presence of a
catalytic agent~ Such agents are, for example, hasic or
acidic catalysts, there being used as bases, for example
alkali metal hydroxides, amides, carbonates or hydrides,
such as potassium hydroxide, sodium arnide, potassium
carbonate or sodium hydride, metal oxides, such as aluminium
oxide, or organic nitrogen bases, such as tertiary amines,
for example pyridine, quinoline or N,~-dimethylaniline,
and as acidic catalysts, for example, mineral acids, such
as sulphuric acid, hydrogen sulphates, such as alkali
metal hydrogen sulphates, for example potassium hydrogen
sulphate, polxphosphoric acid, mineral acid anhydrides,
such as phosphorus pentoxide, or mineral acid halides,
such as sulphuric acid halides, for example sulphuryl
chloride.
The method for the formation of starting materials
of the formula V is, if necessary, carried out in the
presence of an inert solvent or diluent, in a closed
vessel and/or under an inert gas, for example nitrogen.
Compounds of the formulae VIa or VIb may, for
their part, be manufactured according to analogous
processes that are known per se, for example by condensing
compounds of the formula
. ~ Xl / X2
_H
~! alk N alk
/ ~ NH2 (VId) or j!~ I (VIe)
Xl 1 Xl
_ 16 --
in the presence of a condensation agent. Suitable conden
sation agents are, for example, acids, such as mineral
acids, for ex~mple sulphuric acid, polyphosphoric acid or
a hydrohalic acid, for example hydrochloric acid, or
phosphoric acid halides, such as phosphorus oxychloride
or phosphorus trichloride.
Phosphoranes of the formula P(Z2)3=C(R3)-R2 and
their phosphonium ylides can be manufactured according to
methods known ~ se, for example by reacting phosphines
of the formula P(22)3 with quat~rnary ammonium bases of
the formula R2-CH(R3)-N(alk')3B in which alk' repre-
sents an alkyl radical, such as a lower alkyl radical,
and B represents an anion, such as a halide or hydroxyl
anion, and by subsequent reaction with strong bases, such
as alkali metal organyls, for example butyllithium or
phenyllithium. The corresponding quaternary ammonium
bases are obtained likewise by reaction of phosphines
P(Z2)3 with known compounds of the formula R2-Hal in the
presence of bases, such as alkali metal hydroxides, lower
alkoxides, hydrides or amides, for example sodium hydroxide,
sodium methoxide, potassium hydride or potassium amide.
Compounds of the formula X1=P(Z3)2-CH(R3)-R2 can
be manufactured, for example, by reacting compounds of
the formula P(Z3)3 in which Z3 represents alkoxy or
phenoxy, with compounds of the formula Hal-CH(R3)-R2 in
which Hal represents halogen.
Compounds of the formula VId are obtainable by
acylation of compounds of the formula
Ph- j4~ 1
alk
NH2 (VIg)
- 17 _
with compounds of the formula R1-C~ in which X~
X~,
represents halogen or acyl.
Acyl is derived, for example, from a carboxylic acid,
such as a lower alkanecarboxylic acid, and represenk~,
for example, lower alkanoyl, such as acetyl, propionyl or
pivaloyl~
The compounds of the formula I or salts thereof can
furthermore be produced, for example, by cyclising a
compound o~ the general formula
Ph - -R2
~ alk' (VIII),
Rl-C=~EI
in which alk' represents a group of the formula -CH=CH Z6
or -CH2-CH=Z6, and Z6 represents optionally functionally
modified hydroxy or amino, and Z6 represents oxo or imino,
or a salt thereof, and, if desired, converting a resulting
free compound of the formula I into a different free
compound or into a salt, or converting a salt obtainable
according to the process into the free compound or into
a different salt~
Functionally modified hydroxy is, for example,
hydroxy etherified by lower alkanol, such as methanol or
ethanol, or by an optionally substituted aromatic alcohol,
such as phenol, or hydroxy esterified by a suitable
anhydride, such as acetic anhydride, by an organic acid,
such as a sulphonic acid, for example lower alkylsulphonic
or optionally substituted arylsulphonic acid, such as
methanesulphonic or p-toluenesulphonic acid, or by an
inorganic acid, such as a mineralacid, for example a
hydrohalic acid, such as hydrochloric acid, and represents,
- 18 -
for example, lower alkoxy, such as methoxy, or optionally
substituted aryloxy, such as phenoxy, or lower alkanoyloxy,
such as acetoxy, lower alkanesulphonyloxy or optionally
substituted arylsulphonyloxy, such as methanesulphonyloxy
or p-toluenesulphonyloxy, or halogen, such as chlorine or
bromine.
The cyclisation is carried out in a manner known
se, for example in the presence of a condensation
agent, such as an acidic condensation agent. Included
among these are, for example, acids, such as mineral acids,
for example sulphuric acid or polyphosphoric acid, and
mineral acid halides, such as phosphoric acid halides,
for example phosphorus oxychloride, phosphorus tri-
bromide or phosphorus pentachloride. The reaction is, if
necessary, carried out in a solvent or diluent, in a
temperature range of from approximately 20 to approximately
200C, in a closed vessel and/or under an inert gas, for
example nitrogen.
Inert solvents and diluents are optionally sub-
stituted hydrocarbons, such as aliphatic or aromatic
halogenated hydrocarbons, for example chloroform or
chlorobenzene, optionally mixed ethers, such as aliphatic,
cycloaliphatic or aromatic ethers, for example diethyl
ether, dioxan, diphenyl ether or anisole, ketones, such
as aliphatic ketones, such as acetone or methylethyl-
ketone, amides, such as dialkylamides, for example
dimethylformamide, or sulphoxides, such as lower alkyl
sulphoxides, for example dimethyl sulphoxide.
The starting materials of the formula VIII can be
manufactured according to methods known Per se, for example
by substituting the primary amino group in compounds of
the formula
il~ 2
alk
2 (IX)
- 19 _
by means of alkali metal nitrites in the presence of acids,
by hydroxy, optionally reactively es-terifying khis group,
acylating the indole nitrogen with a compound of the
formula R1-COOH or with a functionally modified derivative
thereof, and then forming the corresponding amidine with
ammonia.
The acylation of the indole nitrogen is carried
out according to methods known ~ se, for example by
reaction with optionally functionally modified carboxy
derivatives, such as acids, acid anhydrides or activated
esters. Anhydridised carboxy in this process is
anhydridised, for example, by inorganic acids, such as a
hydrohalic acid, by hydrazoic acid, by hydrocyanic acid
or by organic acids, such as lower alkanoic acids option-
ally substituted by halogen, for example acetic acid.
Included among these are, for example, acid halides, for
example acid chlorides, corresponding acid azides, acid
nitriles or acyloxycarbonyl.
The acylation with a compound o~ the formula ~ -COO~I
or an optionally ~unctionally modi~ied derivative thereof
is carried out in customary manner. When using an
anhydride, especially an acid halide, as starting material,
the acylation is preferably carried out in the presence
of a strong base, for example an alkali metal hydride,
for example sodium hydride, an alkali metal amide, for
example sodium amide, or an alkali metal alcoholate, for
example potassium methoxide.
The acylation, like the subse~uent reaction with
ammonia, is carried out, for example, in an inert solvent,
such as an al]cylated amide, for example N,N~dimethylform-
amide, an optiona~ly halogenated hydrocarbon, for example
chloroform or chlorobenzene, or a nitrile, for example
acetonitrile, or in a mixture thereof, if necessary at
reduced or elevated temperature and~or in an inert gas
atmosphere.
The compounds of the formula IX may, for their part,
be produced according to processes known ~ se, for
.i
~2~
- 20 -
example analogously to Fischer's indole synthesis, by
treating phenyl hydrazones or correspondlngly 1,3-sub-
stituted 4-piperidones with acids, such as with ethanolic
hydrochloric acid, or by acylation and condensation of
correspondingly subskituted ~-hydroxyketones with
optionally substituted anilines.
The compounds of the formula IX may furthermore,
in a preferred embodiment, be manufactured, for example,
by quaternising starting compounds of the formula
~ ~ B (IVd).
\~ \./j
in which Bz represents an optionally substituted a-phenyl-
lower alkyl radical, preferably benzyl, especially with
benzyl bromide, and cleaving the bond at the resulting
quaternary nitrogen by means of a nucleophile, preferably
by cyanides, and in a compound of the formula
Ph il CN
\ ~ \. (IVe)
t I i
~(BZ)2
obtainable as intermediate, solvolysing the cyano group
as desired and removing the benzyl groups, for example
by hydrogenolysis in the presence of a hydrogenation
catalyst, for example palladium.
The compounds of the general formula I or salts
thereof can furthermore be manufactured, for example, by,
- 21 -
in a compound of the formula
.
Ph - i1
~ \ alk (X),
Rl N
in which R2 represents a radical that can be converted
into the group R2, or in salts thereof, converting R2
into the group R2 by solvolysis or oxidation and, if
desired, converting a resulting free compound of the
formula I into a different free compound or into a salt,
or converting a salt obtainable according to the process
into the free compound or into a different salt
Thus, R2 is, for example, a group of the formula
-CH~R3)-R2 in which R3 represents hydrogen and R2
represents functionally modified carboxy other than
R2 and R2 i5 identical to the carboxy or lower alkoxy-
carbonyl moiety of R2 as hereinbefore defined,
or is a group of the formula -C~=O)-N2B , in which B
represents the anion of a mineral acid, for exarnple
chloride, bromide, or tetrafluoroborate, or represents
methyl optionally oxidised to the formyl stage.
Functionally modified carboxy radicals and function-
ally modified carboxy radicals other than R2 are, for
example, corresponding esterified or amidated carboxy,
optionally functionally modified ortho-ester groups, such
as trihalo-, halo-di-lower alkoxy- or tri-lower alkoxy-
methyl groups, anhydridised carboxy, such as cyano, a
group of the formula =C=O, cyano-, azido- or halo-carbonyl,
acyloxycarbonyl, lower alkanoylcarbonyl, such as, for
example,acetoxycarbonyl, or derivatives of carboxy of
the formul.a R1 or R2, in which oxo is optionally replaced
by thio or optionally substituted imino, such as option-
ally esterified thiocarboxy, such as lower alkylthio-
carboxy, for example ethylthiocarboxy, ami~ated thio-
carboxy, imino-eskers, such as imide or amide-halide
groupings, for example iminochlorornethyl or amino~i-
chloromethyl, imino ether groupings, such as lower
alkylimino ether or lower alkyleneimino ether groupinys,
for example methoxyiminomethylene or ethoxyiminomethylene,
or amidino groups, such as amidino or lower alkylamidino,
for example me-thylamidino.
Esterified carboxy R2 is, for example, lower alkoxy-
carbonyl which may be mono-substituted by optionally
substituted aryl, such as phenyl or pyridyl, or mono-
or poly-substituted by hydroxy, halogen or lower alkoxy:
such as lower alkoxycarbonyl substituted by hydroxy,
lower alkoxy and/or halogen, for example mono- or di-
hydroxy-lower alkoxy-, halo- or lower alkoxy-lower alkoxy-
carbonyl, or phenyl-lower alkoxycarbonyl substituted by
lower alkyl, lower alkoxy and/or halogen.
~ midated carkoxy R2 is, for example, carbamoyl which
may be mono-substituted by hydro~y or amino, mono- or di-
substituted by lower alkyl or hydroxy-lower alkyl or
phenyl-lower alkyl, or di-substituted by 4- to 7-membered
lower alkylene or 3-oxa-, 3-thia- or 3-aza-lower alkylene.
Examples that may be mentioned are: carbamoyl, N-hydroxy-,
N-amino-, N-mono- or N,N-di-lower alkyl- or N-mono- or
N,N-di-hydroxy-lower alkyl-carbamoyl. Carbamoyl N-di-
substituted by 4- to 7-memhered lower alkyle~e is, for
example, pyrrolidin-1-yl- or piperidino-carbonyl or
morpholino-, thiomorpholino-, piperazin-1-yl- or N-lower
alkyl-, such as ~-methyl-piperazin-l-yl-carbonyl.
Methyl oxidised to the formyl stage, or functionally
modified groups thereof are, for example, optionally
reactively esterified or etherified hydroxymethyl or
optionally functionally modified formylj such as hydroxy-
methyl, mono- or di-halomethyl, lower alkoxymethyl,
formyl or formimino.
Functionally modified carboxy compounds, such as
esterified or amidated carboxy, optionally functionally
modified ortho-esters, anhydridised carboxy or acy1Oxy-
carbonyl, can be solvolysed directly or in several
sclvolysis steps to form free or esterified carboxy R2.
Esterified carboxy other than ~2 can be converted inko
esterified carboxy R2 by customary transesterification~
The solvolysis of R2 is effected in known manner, for
example by hydrolysis with water or by alcoholysis, for
example o-E cyano or optionally substituted carbamoyl, to
form esterified carboxy R2 with a corresponding alcohol.
The transesterification is also effected by alcoholysis
with the desired alcohol. In each case the operation is
carried out, if necessary, in the presence of a catalyst,
in a solvent or diluent, in a closed vessel, in a
temperature range of from approximately 0 to approximately
150C, and/or under an inert gas, for example nitrogen.
Catalysts are, for example, basic condensation
agents, such as alkali metal or alkaline earth metal
hydroxides, for example sodium, potassium or calcium
hydroxide, or tertiary organic amines, such as pyridine
or trialkyl~mines, for example triethylamine, or acidic
hydrolysing agents, such as mineral acids, for example
hydrohalic acids, such as hydrochloric acid, or organic
carboxylic or sulphonic acids, such as lower alkanecarboxy-
lic acids or optionally substituted ben2enesulphonic acids,
for example acetic acid or p-toluenesulphonic acid.
Methyl optionally oxidised to the formyl stage,
such as methyl, hydroxymethyl or formyl, or functionally
modified derivatives thereof, such as halomethyl, for
example chloromethyl, mercaptomethyl, thioformyl or
optionally substituted formimino, may be oxidised
directly or by way of several oxidation steps, optionally
by way of hydroxymethyl or formyl, to form carboxy.
Etherified hydroxymethyl, preferably lower alkoxymethyl,
for example ethoxymethyl, is oxidised, in the presence
of an oxidising agent, to form lower alkoxycarbonyl. The
~, . .~7
i8~
- 24 -
reaction of formyl to form carbamoyl is carried out,
for example, by means of an amino compound in -the presence
of an oxidising agent, such as a transition metal oxide,
for example manganese dioxide, and, if necessary, in the
presence of a nucleophile, especially a cyanide.
Oxidation of ~2 is carried out in customary manner,
for example using customary oxidising agents. These are,
for example, optionally catalytically activated oxygen,
alkali metal salts o~ chromates or manganates, such as
sodium chromate or potassium permanganate, or transition
metal oxides, such as manganese dioxide or chromium
trioxide. The oxidation is carried out, if necessary,
in an inert solvent, in a closed vessel and~or while
cooling or heating, for example at approximately 0 to
approximately 150C.
The starting materials of the formula X can be
manufactured according to analogous processes, for example
by reacting compounds of the formula
Ph ~ ~
I alk (VIa),
,'\~ /
R1 N
in which X1 represents oxo or thioxo, with compounds of
the formula P(Z2)3-R2, which may be in the form either of
phosphonium ylides or of phosphoranes, or X1=PtZ3)2-R2,
in which Z2 represents alkyl and/or phenyl and Z3 repre-
sents alkyl and/or phenyl, or alkoxy, such as lower alkoxy,
and/or phenoxy, and R2 represents functionally modified
carboxy other than R2, a group of the formula -Ct-O)N2B
or methyl optionally oxidised to the formyl stage,
removing from intermediates of the formula
f~
- 25 -
Il l4
Ph - ~ - C -R2
\N/ \ 3
I alk (VIh),
/ \~N/
which may be obtained in this manner, in which X1 repre-
(~) (~)
sents -0 or -S and Z4 represents a radical of the
( 2)3 or -P(~1)(Z3)2~ respectively~ a compOund
of the formula x1=P(Z2)3 or X1=P(X1)(Z3)2~ re p Y
and isomerising a compound obtained in this manner to
form a compound of the formula X.
The reaction is usually carried out in an inert
solvent, fox example an optionally halogenated hydrocarbon,
such as an aromatic compound, for example benzene or
toluene, an ether, such as tetrahydrofuran or dioxan, or
an amide, for ex~mple dimethylformamide, in a temperature
range of from approximately 20 to approximately 150C
and/or optionally in the presence of a catalyst, such as
a base, for example an alkali metal alcoholate, such as
potassium text.-butoxide.
Especially, the starting materials of the formula
in which R2 i 5 a radical that can be converted by
solvolysis or oxidation into R2 are obtained, and starting,
for example, from compounds of the formula
Ph - jl \ N-Bz
N~ IVd)
H
.,: .
- 26 -
in which Bz represents an optionally substituted a-phenyl-
lower alkyl radical, preferably benz,yl, the tertiary
nitrogen atom is quaternised, especial]y with benzyl
chloride, the bond at the quaternary nitrogen atom is
cleaved by means of a strong base, such as by a cyanide,
for example sodium cyanide, and in a resulting compound
of the formula
Ph ~ CN
N ~. (IVe)
H ,!
~N
Bz Bz -
the cyano group is converted into R~, for example by
solvolysis to carboxy or lower alkoxycarbonyl and then
reduction to hydroxymethyl or lower alkoxymethyl,
respectively, and the Bz groups are removed by hydro-
genolysis in the presence of a hydrogenation catalyst.
The compound obtained in this manner is then reacted
with a compound of the formula
~ Z1
R1-C ~ H l ~ in which Z1 represents optionally
functionally modified oxo and Hal represents halogen,
and cyclisation to form corresponding compounds of the
formula X is carried out in the presence of a customary
cyclising agent, such as a minera~ acid halide, for
example phosphorus o~ychloride.
In a preferred embodiment of this process variant,
using corresponding starting materials of the formulae
IVd, IVe and R,l-C(-Z1)-Hal, there are formed first of all,
without isolation of the intermediates, those compounds
of the formula X in which 21]c represents 1,2-ethylene and
R1, R2 and Ph have the meanings indicated.
:~ .
~ 27.-
Especiall~, corresponding compounds of the formula Xin which a~k represents 1,2_ethylene and R~ represents
cyanomethyl or opkionally substi-tuted carbamoylmethyl
formed therefrom, are first dehydrogenated analogously
to the dehydrogenation described hereinafter and then
solvolysed ag desired to form the desired compounds of
the formula I.
Accordingly, using suitable starting materials of
the formulae IVd, IVe and R1-C(=Z1~-Hal, there are formed,
with isolation of the intermediate~, those 3,4-dihydro
compounds o~ the formula X in wllich R2 represents lower
al~oxycarbonylmethyl and alk represents 1,2-ethylene.
In the next rea~tion step the lower alkoxycarbonyl group
is reduced to form 2-hydroxyethyl R2, for example using
complex hydrides, such as lithium aluminium hydride, and
the hydroxy group is et~lerified with a desired lower
alkanol. The compound6 that are obtainable in corres~
pondlng manner are then dehydrogenated in the manner
descr.ibed hereinafter. 2-Lower alkoxyethyl ~2~ 2-hydroxy~
ethyl formed there~rom and formylmethyl R2 are finally
oxidised in the desired manner to form R2, as indicated
above.
The compounds of the formula I are manuractured
pre~errably by dehydrogenating corresponding compounds
of the formula
~2
Ph -l;
\ N/ \
~! /alkll ~XI) ,
in which alkllrepresents ethylene, with the removal of
hydrogen and the simultaneous formation of an additional
bond, and, if desired, convertin~ a compound obtainable
according to the invention into a different compound of the
formula I or converting a free compound of the formula I obtain-
able according to the invention into a saltor a salt ohtainable
according to the process into the free compound of the formula I
or into a different salt.
- 28 -
The dehydrogenation is carried out in a manner known
per se, especially at elevated temperature, for example
in a temperature range of ~rom room temperature to
approximately 300C, especially from approximately 100
to approximatel~ 300 C, and using a dehydrogenating
agent~ As such agents there come into consideration, for
example, dehydrogenation catalysts, for example sub-group
elements, preferably of the sub-group VIII, such as
palladium or platinum, or salts thereof, such as ruthenium-
triphenyl-phosphide-chloride, the catalysts optionally
being supported on a suitable carrier, such as carbon,
aluminium oxide or silicorl dioxide. Other dehydrogenating
agents are, for example, quinones, such as p-benzoquinones,
for example tetrachloro-p-benzoquinone or 2,3-dichloro-
5,6-dicyano-p-benzoquinone, or anthraquinones, for example
phenanthrene-9,10-~uinone. Preferred dehydrogenation
catalysts are suitable selenium derivatives, especially
selenium dioxide or diphenylselenium bis(acetate), and
also diphenylselenium oxide. In an advantageous embodi-
ment of the dehydrogenation described above, this process
is carried out at elevated temperature when using
selenium dioxide as catalyst, and when using diphenyl-
selenium bis(trifluoroacetate) the dehydrogenation is
effected at room temperature.
The reaction is carried out in an inert, optionally
high-boiling, solvent, such as an ether, for example
diphenyl ether, if necessary under pressure, in a closed
vessel and/or under an inert gas, for example nitrogen.
The starting materials of ~he formula XI in which alk"
represents l,2-ethylene are manufactured analogously to the
procedure described at the beginning s-carting from correspond-
ing compounds of formulae II, V, VIII or X wherein alk is
ethylene and alk' is 2-Z6-ethyl. For example, compounds of
the formula IVd are alkylated exhaustively, for example
with benzyl halides, and the bond at the quaternary nitrogen
- 29 -
atom i~ cleaved with alkali me-tal cyanicles.In the resul-tin~
compounds of the formula IVe, the cyano group can be
solvolysed as desired in customary manner, conversion
into lower alkoxycarbonyl being preferred. After removing
the benzyl groups by hydrogenolysis, reaction is effected
with compo~nds of the formula R1-C(-Z1)-Hal, there being
formed under the reaction conditions, with the aid of
cyclising agents, such as phosphorus oxychloride, corres-
ponding compounds of the formula II which lead directly
to corresponding compounds of the formula XI in which alk"
represents 1,2-ethylene and R2 preferably represents
lower alkoxycarbonylmethyl.
If it is desired to manufacture free acid derivatives
after the subsequent dehydrogenation, resulting lower
alkyl esters are advantageously hydrolysed.
A compound of the formula I obtainable according to
the invention can be converted into a different compound
of the formula I in a manner known per se.
If the group R2 contains free carboxy, this can be
converted according to esterification methods known
se into correspondingly esterified carboxy, for
example by reactin~ optionally reactive modified carboxy
or a salt thereof by alcoholysis with a desired alcohol,
for example a reactive derivative thereof or an olefin
derived therefrom, or by aLkylation with diazo-lower
alkane.
Suitable reactive functional carboxy derivatives
are, for example, anhydrides, there being used as
anhydrides especially mixed anhydrides, for example those
with inorganic acids, such as hydrohalic acids, for
example hydrochloric acid, or hydrazoic or hydrocyanic
acids, or with organic carboxylic acids, such as lower
alkanoic acids, for example acetic acid.
Reactive derivatives of an alcohol are, for example,
carboxylic, phosphorous, sulphurous or carbonic acid
- 30 -
esters, for example lower alkanecarboxylic acid esters,
tri-lower alkylphosphite, di-lower alkylsulphite or
pyrocarbonate, or mineral or sulphonic acid eskers, for
example chloride, bromide or sulphuric acid esters,
benzenesulphonic, toluenesulphonic or methanesulphonic
acid esters, of the alcohol concerned.
The esterification of free carboxy is carried out
in the presence of a condensation agent. There come into
consideration as agents that split off water by catalysis
in the esterlfication with alcohols, for example, acids,
for example protonic acids, such as hydrochloric, hydro-
bromic, sulphuric, phosphoric, boric, benzenesulphonic
and/or toluenesulphonic acid, or Lewis acids, such as
boron trifluoride etherate. Customary water-binding
condensation agents are, for example, carbodiimides sub-
stituted by hydrocarbon radicals, for example ~,NI-diethyl-
carbodiimide, ~ dicyclohexylcarbodiimide or N-ethyl-~'-
(3-dimethylaminopropyl)-carbodiimide. Condensation agents
for the esterification with reactive esters are, for
example, basic condensation agents, such as inorganic
bases, for example alkali metal or alkaline earth metal
hydroxides or carbonates, such as sodium, potassium or
calcium hydroxide or carbonate, or organic nitrogen bases,
for example tertiary organic amines, such as triethyl-
amine or pyridine. The esterification is advantageously
carried out in an excess of the alcohol used. It is
preerably carried out in an anhydrous medium, if
necessary in the presence of an inert solvent, such as
in halogenated hydrocarbons, for example chloroform or
chloroben~ene, ox in ethers, for example tetrahy~rofuran
or dioxan.
The reaction with an olefin can be carried out,
for example, in the presence of an acidic catalyst, for
example a Lewis acid, for example boron trifluoride, a
sulphonic acid, for example p-toluenesulphonic aci~, or,
especially, a basic catalyst, for example sodium or
potassium hydroxide, advantageously in an inert solvent,
- 31 -
such as an ether, for example diethyl et~er or tetra-
hydrofuran.
Furthermore, free carboxy or reactive functiona]
carboxy derivatives can be converted into a desired
amidated form by solvolysis with ammonia or a primary or
secondary amine, it being possible also for hydroxyl-
amines or hydrazines to be used, the solvolysis being
carried out in customary manner with dehydration, option-
ally in the presence of a condensation agent. T~ere are
used as condensation agents preferably bases, for example
inorganic bases, such as alkali metal hydroxides, for
example sodium or potassium hydroxide, organic nitrogen
bases, such as tert.-amines, for example pyridine,
tributylamine or N-dimethylaniline, or tetrahalosilanes,
such as tetrachlorosilane.
Further, compounds of the formula I obtainable accord-
ing to the invention in which R2 contains esterified
carboxy as substituent, can be transesterified in custom-
ary manner, for example by reaction with a corresponding
alcohol or a metal salt thereof, such as an alkali metal
salt, for example the sodium or potassium salt, if
necessary in the presence of a catalyst, for example a
stron~ base, such as an alkali metal hydroxide, amide
or alcoholate, for example potassium hydroxide, sodium
amide or sodium methoxide, or a strong acid, such as a
mineral acid, for example sulphuric acid, phosphoric acid
or hydrochloric acid, or an organic sulphonic acid, for
example an aromatic sulphonic acid, such as p-toluenesul-
phonic acid.
Esterified carboxy can furthermore be converted into
the free carboxy group according to known processes, for
example by hydrolysis in the presence of a catalyst.
There come into consideration as catalysts preferably
bases, for example alkali metal hydroxides, such as
sodium or potassium hydroxide. Esterified carboxy may
furthermore be converted into carboxy in customary manner,
for example by solvolysis, optionally in the presence of
- 32 -
a catalyst, for example an acidic or basic ayent, or
into amidated carboxy by ammonolysis or ~rninolysis with
ammonia or with a primary or secondary amine. There
are used as bases, for example, alkali metal hy~roxides,
such as sodium or potassium hydroxides, and as acids,
for example, mineral acids, sueh as sulphuric acid,
phosphoric acid or hydrochloric acid. Likewise, in
compounds of the formula I obtainable according to the
invention in which the group R2 contains an amidated
carboxy substituent, it is possible according to methods
known ~ se to cleave the amide bond and thus convert
the carbamoyl into free carboxy. This operation is
earried out in the presence of a catalyst, for example
a base, such as an alkali metal or alkaline earth metal
hydroxide or carbonate, for example sodium, potassium
or calcium hydroxide or carbonate, or an acid, such as
a mineral acid, for example hydrochloric acid, sulphurie
acid or phosphoric acid.
If the group R2 of the formula I contains an
esterified carboxy group, this ean be converted into an
amidated carboxy group, for example by customary solvoly-
sis, advantageously by an excess of ammonia or an amine
containing at least one hydrogen atom, optionally in the
presence of a catalyst. There are used as catalysts,
for example, acids, such as mineral acids, for example
hydrochloric; sulphuric or phosphoric acid, or bases,
such as alkali metal hydroxides, for example sodium
or potassium hydroxide.
If the group R2 of the formula I contains as sub-
stituent amidated carboxy, this can be converted into
esterified carboxy, for example by customary solvolysis
with an alcohol in the presence of a eatalyst. The
catalysts used are, for example, acidie catalysts, such
as mineral acids, for example phosphoric acid, hydro-
chloric acid or sulphurie aeid.
If the substituent R1 of the formula I is sub-
stituted by lower alkylthio, this can be oxidised in
- 33 -
customary manner to ~orm corresponding lower alkane-
sulphinyl or lower alkanesulphonyl. There come into
consideration as suitable oxidising agents for the
oxidation to the sulphoxide stage, for example, inorganic
peracids, such as peracids of mineral acids, for example
periodic acid or persulphuric acid, organic peracids,
such as suitable percarboxylic or persulphonic acids,
for example performic, peracetic, trifluoroperacetic,
perbenzoic or p-toluenepersulphonic acid, or mixtures of
hydrogen peroxide and acids, for example a mixture of
hydrogen peroxide with acetic acid.
Frequently, the oxidation is carried out in the
presence o~ suitable catalysts, and there should be
mentioned as catalysts suitable acids, such as optionally
substituted carboxylic acids, for example acetic or tri-
fluoroacetic acid, or transition metal oxides, such as
oxides of elements of sub-group ~II, for example vanadium,
molybdenum or tungsten oxide. The oxidation is carried
out under mild conditions, for example at temperatures of
approximately -50 to approximately +100C.
The oxidation to the sulphone stage can also be
carried out in corresponding manner, using dinitrogen
tetroxide as catalyst in the presence of o~ygen at low
temperatures, as can also the direct oxidation of the
lower alkylthio to lower alkanesulphonyl, except that
usually the oxidising agent is used in excess~
Compounds of the formula I in which R1 represents
an aromatic r2dical substituted by lower alkylsulphinyl
or lower alkylsulphonyl can be reduced according to
methods known E~ se to the corresponding lower alkylthio
compounds, and, starting from lower alkanesulphonyl
derivatives, also to 1ower alkanesulphinyl. A suitable
reducing agent is, for example, catalytically activated
hydrogen, there being used noble metals or oxides, such
as palladium, platinum or rhodium or their oxides,
optionally supported on a suitable carrier, such as
active carbon or barium sulphate. There also come into
~Z~ L~
34 -
consideration reducing metal cations, such as ti~(II),
lead(II), copper(I), manganese(II), titanium(II),
vanadium(II), molybdenum(III) or tungsten(III) compounds,
hydrogen halides, such as hydxogell chloride, hydrogen
bromide or hydrogen iodide, hydr.ides, such as complex
metal hydrides, for example li.thium aluminium hydride,
sodium borohydride and tributyltin hydride, phosphorus
compounds, such as phosphorus halides, for example
phosphorus trichloride, phosphorus tribromide, phosphorus
pentachloride or phosphorus oxychloride, phosphines,
such as triphenylphosphine, or phosphorus pentasulphide-
pyridine, or sulphur compounds, such as mercaptans, thio
acids, such as thiophosphoric acids or dithiocarboxylic
acids, dithionite or sulphur/o~ygen complexes, such as
an iodine/pyridine/sulphur dioxide complex.
Resulting salts can be converted into the free
compounds in a manner known per se, for example by
treatment with an acidic reagent, such as a mineral acid,
or a base, for example an alkali hydroxide solution.
Depending upon the starting materials and methods
chosen, the novel compounds may be in the form of one
of the possible isomers or mixtures thereof, for example,
depending on the number of asymmetrical carbon atoms,
in the form of pure optical isomers, such as antipodes,
or in the form of mixtures of isomers, such as racemates,
mixtures of diastereoisomers or mixtures of racemates.
Resulting mixtures of diastereoisomers and mixtures
of racemates can be separated on the basis of the physico-
chemical differences between the constituents, in known
manner, into the pure isomers, diastereoisomers or
racemates, for example by chromatography and~or fractional
crystallisation.
Resulting racemates can furthermore be resolved into
the optical antipodes by known methods, for example by
recrystallisation from an optically ac-tive solvent, with
the aid of micro-organisms or by reacting an acidic end
r ~
-- 35 --
product with an optically active base that forms salts
with the racemic acid, and separating the salts obtained
in this manner, for example on the basis of their different
solubilities, into the diastereoisomers, from which the
antipodes can be freed by the action of suitable agents.
Advantageously, the mo.re active of the two antipodes is
isolated.
The compounds, including their salts, can also be
obtained in the form of their hydrates, or include other
solvents used for the crystallisation.
As a result of the close relationship between the
novel compounds in free form and in the form of their
salts, hereinbefore and hereinafter the free compounds
or their salts shall be understood to mean optionally
also the corresponding salts or free compounds, respect-
ively, where appropriate with regard to meaning and
purpose.
The invention relates also to those embodiments of
the process according to which compounds obtainable as
intermediates at any stage of the process are used as
starting materials and the remaining steps are carried
out or a starting material is used in the form of a
salt or, especially, is formed under the reaction
conditions.
In the process of the present invention it is
preferable to use those starting materials which result
in the compounds described at the beginning as being
especially valuable. The present invention relates also
to novel starting materials and to processes for their
manufacture.
The pharmaceutical preparations according to the
invention, which contain compounds of the formula I or
pharmaceutically acceptable salts thereof, are for
enteral, such as oral or rectal, and parenteral admini-
stration and also for toplcal application to (a) warm
hlooded animal(s) and contain the pharmacological active
ingredient alone or together with a pharmaceutically
- 36 -
acceptable carrier. The dosage o~ the active ingredient
depends on the species of warm-blooded animal, a~e and
individual condition, and on the method of administrakion.
In normal cases, the estimated approximate daily dose
in the case of oral administration to a warm-blooded
animal weighing approximately 75 kg is about 30 - 300 mg,
advantageously divided into several equal partial doses.
The novel pharmaceutical preparations contain, for
example, from approximately 10 % to approximately 80 %,
pre~erably from approximately 20 % to approximately 60 %,
o~ active ingredient. Pharmaceutical preparations
according to the invention for enteral or parenteral
administration are, for example, those in dosage unit forms,
such as dragees, tablets, capsules or suppositories, and
also ampoules. These are manufactured in a manner known
per se, for example by means of conventional mixing,
granulating, con~ectioning, dissolving or lyophilising
processes. For example, pharmaceutical preparations for
oral use can be obtained by combining the active ingred-
ient with solid carriers, optionall~ granulating a
resulting mixture and processing the mixture or granulate,
if desired or necessary after the addition of suitable
adjuncts, to form tablets or dragée cores.
Suitable carriers are especially fillers, such as
sugar, for example lactose, saccharose, mannitol or
sorbitol, cellulose preparations and/or calcium phos-
phates, for example tricalcium phosphate or calcium
biphosphate, also binders, such as starch pastes using,
for example, maize, wheat, rice or potato starch, gelatine,
tragacanth, methylcellulose and/or polyvinylpyrrolidone,
and/or, if desired, disintegrators, such as the above-
mentioned starches, also carboxymethyl starch, cross-
linked polyvinylpyrrolidone, agar, alginic acid or a
salt thereof, such as sodium alginate. Adjuncts are
especially flow-regulating agents and lubricants, for
example silica, talc, stearic acid or salts thereof, such
as magnesium stearate or calcium stearate, and/or poly-
- 37 -
ethylene glycol. Drayée cores are provided wlth sui-table
coatings that are optionally resistant to gastric juices,
there being used, inter alia, concentrated sugar solutions
which may contain gum arabic, talc~ polyvinylpyrrolidone,
polyethylene glycol and/or titanium dioxide, lacquer
solutions in suitable organic solvents or solvenl mixtures
or, for the production of coatings that are resistant to
gastric juices, solutions of suitable cellulose prepara-
tions, such as acetylcellulose phthalate or hydroxypropyl-
methylcellulose phthalate. Dyes or pigments can be added
to the tablets or dragée coatings, for example for
identification purposes or to indicate different doses
of active ingredient.
Further pharmaceutical preparations for oral
administration are dry-filled capsules consisting of
gelatine and also soft, sealed cap~ules consisting of
gelatine and a plasticiser, such as glycerine or sorbitol.
The dry-filled capsules may contain the active ingredient
in the form of a granulate, for example in admixture with
fillers, such as lactose, binders, such as starches,
and/or glidants, such as talc or magnesium stearate, and
optionally stabilisers. In soft capsules, the active
ingredient is preferably dissolved or suspended in
suitable liquids, such as fatty oils, paraffin oil or
liquid polyethylene glycols~ it being possible also to
add stabilisers.
~ s rectally administrable pharmaceutical pr~parations
there come into consideration, for example, suppositories
which consist of a combination of the active ingredient
with a suppository base. Suitable suppository bases are,
for example, natural or synthetic triylycerides, paraffin
hydrocarbons, polyethylene glycols and higher alkanols.
It is also possible to use yelatine rectal capsules which
contain a combination of the active ingredient with a
base material, as base materials there come into con-
sideration, for example, liquid triglycerides, poly-
ethylene glycols and paraffin hydrocarbons.
~2~
- 38 -
Especially suitable for parenteral administration are
aqueous solutions of an active in~redient in water soluble
form, for example a water-soluble salt, also suspensions of
the active ingredient, such as corresponding oily injection
su.spensions, there bein~ used suitable lipophilic solvents
or vehicles, such as fatty oils, for example sesame oil, or
synthetic fatty acid esters, for example ethyl oleate or
tri~lycerides, or aqueous injection suspensions that contain
substances which increase the viscosity, for example sodium
carboxymethylcellulose, sorbitol and/or dextran, and,
optionally, also stabilisers.
There come into consideration as pharmaceutical
preparations for topical use especially creams, ointments,
pastes, foams, tinctures and solutions that contain from
approximately 0.5 % to approximately 20 % of active
ingredient.
Creams are oil-in-water emulsions that contain^more
than 50 % of water. As oily base there are used especially
fatty alcohols, for example lauryl, cetyl or stearyl
alcohol, fatty acids, for example palmitic or stearic acid,
liquid to solid waxes, for example isopropyl myristate,
wool wax or beeswax, and/or hydrocarbons, for example
petroleum jelly (petrolatum) or paraffin oil. As
emulsifiers there come into consideration surface-active
substances having predominantly hydrophilic properties,
such as corresponding non-ionic emulsifiers, for example
fatty acid esters of polyalcohols, or ethylene oxlde
adducts thereof, such as polyglycerine fatty acid esters
or polyoxyethylene sorbitan fatty acid esters (Tweens),
also polyoxyethylene fatty alcohol ethers or polyoxy-
ethylene fatty acid esters, or corresponding ionic
emulsifiers, such as alkali metal salts of fatty alcohol
sulphates, for example sodium lauryl sulphate, sodium
cetyl sulphate or sodium stearyl sulphate, which are
customarily used in the presence of fatty alcohols, for
example cetyl alcohol or stearyl alcohol. Additives to
the aqueous phase are, inter alia, agents that reduce the
.~2~
- 39 -
drying out of the creams, for example polyalcohols,
such as glycerine, sorbitol, propylene glycol and/Qr
polyethylene glycols, also preservatives, perfumes etc.~
Ointments are water-in-oil emulsions that contain up
to 70 %, but preferably from approximately 20 % to
approximately 50 %, of water or aqueous phases. ~s fatt~
phase there come into consideration especially hydro-
carbons, for example petroleum jelly, paraffin oil and/or
hard paraffins, which, in order to improve the water-
binding capacity, preferably contain suitable hydroxy
compounds, such as fatty alcohols or esters thereof,
for example cetyl alcohol or wool wax alcohols, or wool
wax. Emulsifiers are corresponding lipophilic substances,
such as sorbitan fatty acid esters ~Spans), for example
sorbitan oleate and/or sorbitan isostearate. Additives
to the aqueous phase are, inter alia, humectants, such
as polyalcohols, for example glycerine, propylene glycol,
sorbitol and/or polyethylene glycol, and also preservatives,
perfumes etc..
Fatty ointments are anhydrous and contain as base
especially hydrocarbons, for example paraffin, petroleum
jelly and/or li~uid paraffins, and also natural or
partially synthetic fats, for example coconut fatty acid
triglyceride, or preferably hardened oils, for example
hydrogenated ground nut oil or castor oil, and also
fatty acid partial esters of glycerine, for example
glycerine mono- and di-stearate, and also, for example,
the fatty alcohols, which increase the water-absorbing
capacity, emulsifiers and/or additives mentioned in
connection with the ointments.
Pastes are creams and ointments containing powder
ingredients that absorb secretions, such as metal oxides,
for example titanium oxide or zinc oxide, also talc and/or
aluminium silicates, the purpose of which is to bind any
moisture or secretions present.
Foams are administered from pressurised containers
and are liquid oil~in-water emulsions in aerosol form,
:~p~ J
- 40 ~
halogenated hydrocarbons, such as chlorofluoro-lower
alkanes, for example dichlorodifluoromethane and dichloro-
tetrafluoroethane, being used as pxopellants. For the
oily phase there are used, inter alia, hydrocarbons, for
example paraffin oil, fatty alcohols, for example cet~l
alcohol, fatty acid esters, for example isopropyl
myristate, and/or other waxes. As emulsifiers there
are used, ,inter alia, mixtures of those emulsifiers
having predominantly hydrophilic properties, such as
polyoxyethylene sorbitan fatty acid esters (Tweens),
and those having predominantly lipophilic properties,
such as sorbitan fatty acid esters (Spans). In addition,
there may be used customary additives, such as preserva-
tives etc..
Tinctures and solutions generally have an aqueous
ethanolic base to which there are added, inter alia,
polyalcohols, for example glycerine, glycols, and/or
polyethylene glycol, as humectants for reducing
evaporation, and fat-restori~g substances, such as fatty
acid esters with lower polyethylene glycols, that is to
say lipophilic substances that are soluble in the
aqueous mixture,to replace the fatty substances that are
taken from the skin by the ethanol, and, if necessary,
other adjunct~ and additives.
The pharmaceutical preparations for topical applica-
tion are manufactured in a manner known per se, for
example by dissolving or suspending the active ingredient
in the base or, if necessary, in a part thereof. ~en
processing the active ingredient in the form of a
solution, it is usually dissolved in one of the two
phases before emulsification; when processing the active
ingredient in the form of a suspension, it is mixed with
a part of the base after emulsification and then added
to the remainder of the formulation.
The present invention relates also to the use of
compounds of the formula I and salts of such compounds
~z~
- 41 -
having salt-forming properties, preferably for the
treatment of inflammation, especially inflam-
matory disorders of the rheumatic type, especially
chronic arthritis.
The following Examples illustrate the invention
descrihed above but are not intended to limit the scope
of the invention in any way. Temperatures are given in
degrees Centigrade.
There is no consistent characterisation in the
literature of the linking points in the pyrimido-indole
ring system,
j8 ll9alO
~ 6/ \~
forming the basis of the compounds of the formula I.
Thus, the older literature sources characterise
the linking points in the ring system by ~3,4-a],
whereas recently the characterisation ~1,6-a] has been
used.
From considerations of principle, the following
nomenclature is used hereinafter for the above ring
structure: pyrimidoC1!6-a~indole.
- ~12 -
Example 1
While stirring, 38 g of 7-fluoro-1-phenyl-3~4-dihydro~
pyrimido~1,6-a]indole-5-acetic acid ethyl ester in 200 ml
of diphenyl ether are heated at ~60 for 50 minutes in
the presence of 10 g of palladium-carbon (10 %). The
diphenyl ether is removed under reduced pressure and the
residue obtained after concentration by evaporation
is taken up in diethyl ether, filtered off from the
catalyst and concentrated until crystallisation begins.
The crystals are stirred with hexane and a small quantity
of diethyl ether and filtered with suction. 7-fluoro-1-
phenylpyrimidoC1,6-a]indole-S-acetic acid ethyl ester
having a melting point of 91 - 93 is obtained.
The starting material can be prepared, for example,
as follows:
a) 131 g (0.45 mol) of 3-benzyl-6-fluorotetrahydro-~-
carboline are dissolved, while stirring, in 1300 ml of
acetonitrile at 40, and 94 g l0.55 mol) of benzyl bromide
are added over a period of 10 minutes. After a short time
the benzylammonium derivative begins to crystallise out.
Stirring is continued at room temperature for approximately
15 hours followed by cooling in an ice bath and the
crystallisate is filtered with suction.
b) 464 g (1 mol) of the N,N-dibenzyl-6-fluorotetrahydro-
~-carbolinium bromide so obtained are dissolved in 4250 ml
of methanol while heating at 65 and, while stirring, a
solution of ~96 g (4 mol) of sodium cyanide in 500 ml of
water is added over a period of 5 minutes. The solution
is boiled under reflux for 3 hours. On cooling and after
inoculation, 2-(dibenzylaminoethyl)-3-cyanomethyl-5-
fluoroindole crystallises to form colourless crystals.
c) 220 g (0~537 mol) of the nitrile prepared as
described in b) are dissolved in 300 ml of absolute
ethanol and, at -5, the solution is saturated with dry
~Z~
_ 43 -
hydrogen chloride. The solution is then stirred at 20
for 5~ days. The precipitated cr~stals are allowed to
settle and the superna-tant liquid is decanted off, the
sediment is dissolvecl in 2000 ml o-f ice water and the
solution ls stirred at 20 for approximately 3 hours.
While cooling with ice, the solution is then rendered
alkaline with concentrated a~monia solution and extracted
by stirring with 1500 ml of toluene ice water. The
separated toluene phase is washed with water, dried over
sodium sulphate and filtered through 1000 g of aluminium
oxide (actO stage 3) and then washed with toluene. ~fter
distilling off the toluene there remains a light brown
oil which is subjected to hydrogenation as described in
d) without further purification.
d~ 181.3 g of the 2-dibenzylamino-5-fluoroindole-3-
acetic acid ethyl ester obtained as described in c) are
dissolved in 1500 ml of absolute alcohol and are hydro-
genated at normal pressure at 20 - 35 with the addition
of 18 g of Pd/C (5 %~. ~fter 12500 ml of H2 have been
absorbed, a urther 18 g of catalyst are added and
hydrogenation is continued until the absorption of H2,
totalling 17300 ml, has ceased. After filtering off
from the catalyst and subse~uently washing with methylene
chloride, the solution is concentrated to dryness by
evaporation and the residue is dissolved in 250 ml o~
ether. After inoculation, the 2-aminoethyl-5-fluoro-
indole-3-acetic acid ethyl ester crystallises in the
form of colourless crystals.
e) 61.7 g (0.223 mol) of the 2-aminoethyl-5-fluoro-
indole-3-acetic acid ethyl ester prepared as described
in d) are dissolved in 600 ml of methylene chloride and
the solution is covered with a layer of 150 ml of 2N
sodium hydroxide solution. h7hile stirring vigorously
at 0 - 5, a solution of 43 g (0.245 mol) of benzoyl
chloride is added over a period of 2~ hours and then
. ~
~2~
- ~4 -
extracted by stirring for a further 1 hour~ The methylene
chloride phase is then separated off, washed with water,
dried over MgS04 and concentrated to dryness by evaporation.
The residue crystallises when taken up in ether. 2-(2-
benzoylaminoethyl)-S-fluoroindole-3-acetic acid ethyl
ester is obtained.
f) 37 g (0.15~ mol) of 2-~2-benzoylaminoethyl)-5-fluoro-
indole-3-acetic acid ethyl ester in 160 ml of phosphorus
oxychloride are boiled under reflux for 3 hours. The
excess phosphorus oxychloride is distilled off ln vacuo
at 60 and the residue is stirred with 650 ml of ice
water. The aqueous solution is cleared by filtering
through diatomaceous earth, rendered alkaline with
concentrated ammonia solution and extracted with 400 ml
of ether. The ether phase is dried over sodium sulphate
and concentrated to dryness~ The residue is dissolved
in ?50 ml of acetone and 16 ml of an approximately 4~
solution of hydrogen chloride in ether are added. After
inoculation, the hydrochloride of 7-fluoro-1-phenyl-3,4-
dihydropyrimidoC1,6-a]indole-S-acetic acid ethyl ester
crystallises to form yellowish crystals which can be
recrystallised from 2N hydrochloric acid. After
recrystallisation from ether, the base freed from the
salt melts at 56 - 58.
Example 2
In a manner analogous to that described in Example 1
there is obtained using 2-aminoethyl-5-fluoroindole-3-
acetic acid ethyl ester and ~-methanesulphinylbenzoyl
chloride as starting materials and via 7-fluoro-1-(p-
methane~ulphinylphenyl)-3,4-dihydropyrimido~1,6-a]indole-
S-acetic acid ethyl ester (melting point of the hydro~
chloride = 208 - 210), 7-fluoro-1 (p-methanesulphinyl-
phenyl)-pyrimido~1,6-a]indole-5-acetic acid ethyl ester
having a melting point of 133 - 135 .
-- ~5 --
Example 3
In a manner analogous to that described in Example 1
there is obtained using 2-aminoethylindole-3-acetic acid
ethyl ester and 2-thenoyl chloride as starting materials
and via 1-(2-thienyl)-3,4-dih~dropyrimido[1 ,6-a]indole-5-
acetic acid ethyl ester (melting point of the hydrochloride
= 153 - 157), 1-(2-thienyl)-pyrimidoC1,6-a]indole-5-
acetic acid ethyl ester having a melting point of 94 - 95.
Example 4
In a manner analogous to that described in Example 1,
there is obtained using 2-aminoethyl-5-methoxyindole-3-
acetic acid ethyl ester and 2-picolyl chloride as starting
materials and via 7-methoxy-1-(2-picolinyl~-3,4-dihydro-
pyrimido~1,6-a]indole-5-acetic acid ethyl ester, 7-
methoxy-1-(2-picolinyl)-pyrimido['l,6-a~indole-5-acetic
acid ethyl ester having a melting point of 103 - 104.
Example 5
.
12.2 g of 1-phenylpyrimido[1,6-a]indole-5-acetic acid
ethyl ester (melting point 59 - 62), manufactured from
2-aminoethylindole-3-acetic acid ethyl ester and benzoyl
chloride via 1-phenyl-3,4-dihydropyrimido[1,6-a~indole-
5-acetic acid ethyl ester (melting point 83 - 84 ), are
stirred at room temperature for 3 hours with 30 ml of
ethanol and 40 ml of 2N sodium hydroxide solution. The
mixture is acidified to pH 3 with concentrated h~dro-
chloric acid and, while stirring, 30 ml of propylene
oxide are added. After a short time 1-phenylpyrimido-
[1,6-a~indole-5-acetic acid crystallises c>ut. This is
filtered off and recrystallised ~rom 90 % ethanol.
Melting point 198 - 204 (decomposition).
~ ~ .
:~2~
- 46 -
Example 6
In a man~er analogous to that described in Example 5
there i5 obtained, using 7-fluoro-1-(p-methanesulphinyl-
phenyl)-pyrimido[1,6-a]indole-5-acetic acid ethyl ester
as starting material, 7-fluoro-tp-methanesulphinylphenyl)-
pyrimido~1,6-a]indole-S-acetic acid having a melting
point of 218 224 (decomposition).
Example 7
In a manner analogous to that described in Example 5
there is obtained using 7-fluoro-1 phenylpyrimido[1,6-a]-
indole-5-acetic acid ethyl es-ter as starting material,
7-fluoro-1-phenylpyrimidv~,6-a]indole-5-2cetic acid
hav ~g a melting point of 217 - 220 .
Exa~ple 8
In a manner analogous to that described in Example 5
there is obtained using 1-(2-thienyl)-pyrimido[1,6-a]-
lndole-5-acetic acid ethyl ester as starting material,
1-t2-thienyl~-pyrimido[1,6-a~indole-5-acetic acid having
a melting point of 196 - 200 (decomposition).
Example g
. . . . _,
In a manner analogous to that described in Example 5
there is obtained using 7-methoxy-1-(2-picolinyl~-pyrimido-
~1,6-a]indole-S-acetic acid ethyl ester as starting material,
7-methoxy~1-(2-picolinyl~-pyrimido[1,6 a]indole-5-acetic
acid having a melting point of 201 - 206.
~.'. "~
~ 47 -
Example 10
In a manner analogou3 to that described in Examples 1
and 5 there are also obtained:
7-fluoro-1-(p-methoxyphenyl)-pyrimido~1,6-a]indole-5-
acetic acid having a melting point o~ 220 - 225 and the
ethyl ester thereof,
7-methoxy 1-~p-fluorophenyl3-pyrlmidoL1,6-a]indole-5-
acetic acid and the ethyl ester thereof, and
7-fluoro-1-(2-thienyl)-pyrimido[1,6-a]indole-5-acetic
acid having a melting point of 233 - 236.
Example 11
~ ile stirring, 3 g of 7-fluoro-1-phenyl-3,4-dihydro-
pyrimido[1,6-a]indole-5-acetic acid ethyl
ester a-e boiled for 1O5 hours with 1 g of selenium
dioxide in 50 ml of chlorobenzene and 5 ml of glacial
acetic acid. The mixtu~e is concentrated to dryness by
evaporation and the residue is ta~en up in 20 ml o~
et'nyl acetate, filtered off frcm the selenium and the
solution is washed neutral with sodium bicarbonate solution
and concentrated to drynes~ by evaporation. The residue
is taken up in ether and chromatograohed over 80 g of
silica gel. The 7-fluoro-1-phenylpyrimidoL1,6-a]indole-
5-acetic acid ethyl ester is eluted with hexane/ethyl
acetate (4 1) and crystallises from etherJhexane.
~!elting point 91 _ 93~,
~Z~iB9~
- 48 -
Example l2
A solution of 0.01 mol of diphenylselenium bis(tri-
fluoroacetate) [manufactured according to J. Amer. Chem.
Soc,, 1_, 4642 (1981 ) ], is added dropwise over a period
of 0.5 hours to a solution of 3.38 g of 1-(2-thienyl)-
3,4-dihydropyrimido[1,6-a]indole-5-acetic acid ethyl
ester in Z0 ml of dimethoxyethane. The mixture is left to
stand at room temperature for a further 3 hours, concen-
trated to dryness by evaporation and the residue is taken
up in ether, washed with sodium bicarbonate solution and
chromatographed over 80 g of silica gel. 1-(2-thienyl~-
pyrimido~1,6-a]indole-S-acetic acid ethyl ester i3
eluted with hexane/ethyl acetate (4:1) and crystallises
from ether/hexane to form yellow crystals. Melting
point 94 - 95
Exam~ e 13
;
Tablets containing 25 mg of the active ingredient, for
example l-t2-thienyl)-3,4-dihydropyrimido~1,6-aJindole-5-
acetic acid or a salt, for example the hydrochloride, thereof,
can be manufactured as follows:
Constituent~ ~for 1000 tablets)
.
active ingredient 25.0 g
lactose 100 7 g
wheat starch 7.5 g
poly~thylene glycol ~0005.0 g
talc 5.0 g
magnesium stearate 1.8 g
demineralised water q.s.
~23L~
- 49 -
Preparation
All the solid ingredients are first forced through
a sieve having a mesh width of 0.6 mm. Then the active
ingredient, the lactose, the talc, the magnesi~m stearate
and half the starch are mixed together. The other half
of the starch is suspended in 40 ml of water and this
suspension is added to a ~oiling solution of the poly-
ethylene glycol in 100 ml of water. The resulting starch
paste is added to the main quantity and the mixture is
granulated, if necessary with the addition of water. The
granulate is dried overnight at 35, forced through a
sieve having a mesh width of 1.2 mm and pressed to form
tablets of approximately 6 mm diameter th~t are concave
on both sides.
In analogous manner it is possible to manufacture
tablets each containing 25 mg of a different compound
of the formula I selected from those mentioned in
Exa~ples 1 to 12, it being possible for the compounds
also to be in the fonm of acid addition salts, such as
hydrochlorides, and in the case of compounds in which
R2 is 1-carboxy~ethyl to be also in the form of salts
with basea, such as sodium, potassium or zinc salts.
Example 14
Chewable tablets containing 30 mg of active ingredient,
for example l-(2-thienyl)-3,4-dihydropyrimido~l,6-a]indole-
5-acetic acid or a salt, for example the hydrochloride,
thereof, can be manufactured, for example, as follows:
Lf~ P3
-- 50 --
Com~osition (for 1000 tablets~
actîve in~redient 30.0 g
mannitol 267.0 g
lactose 17g.5 g
talc 20.0 g
glycine 12.5 g
stearic acid 10.0 g
saccharin~ 1.0 g
S ~ gel~tine solution q.s.
Manufactu~e
. _ .
All the solid ingredient~ are first forced through
a sieve having a mesh width of 0. 25 mm~ The mannitol
and the lactose are mixed, granulated with the addition
of gelatine solution, forced through a sieve having a
mesh width of 2 mm, dried at 50 and again forced
through a sieve having a mesh width of 1 . 7 mm. The
active ing edient, the glycine and the saccharin a-e
carefully mixed tosether, the mannitol, the lactose
granulate, the stearic acid and the talc are added
and the whole is mixed thoroughly and pressed to form
tablets of appro.Yima`ely 10 mm diameter that are concave
on ~oth sides and have a breaking groove on the upper
side. ~n analosous manner it is also possible to manu-
facture chewable tablets each containing 30 mg of a
di ~erent compound of the formula I selected from those
mer.tioned in Exæ~.oles 1 to 12, it being possible for the
cc..~o~nds to be also in the form of acid addition salts,
s~ch as hydro_hloride~, and in the case of compo~nds
in wnich R2 is 1-carboxy~ethyl ~o be also in the form of
salts with bases, such as sodium, potas=ium and zinc
salts.
, ~,
- 51 -
Example 15
Tablets containing lO0 mg of active ingredient, for
example l-(2-thienyl)-3,4-dihydropyrimido[1,6-a]indole-S-
acetic acld, can be manufactured in the following manner:
Composition (for 1000 tablets)
active ingredient 100.0 g
lactose 248.5 g
maize starch 17.5 g
polyethylene glycol 6000 5.0 g
talc 1S,o g
magnesium stearate 4.0 g
demineralised water q.s.
Manufacture
The solid ingredients are first forced through a
sieve having a mesh width of 0.6 mm. Then the active
in~redient, lactose, talc, magnesi~m stearate and half
the starch are intimately mixed. The other half of the
starch is suspended in 65 ml of water and this sUcpension
is added to a boiling solution of the polyethylene glycol
in 260 ml of water, The resulti~g paste is added to the
pulverulent substances and the wnole i3 ml~ed and
granulated, if necessary with the addition of water.
The granulate is dried overnight at 35, forced through
a sieve having a mesh width of 1.2 m~m 2nd p~essed to
form tablets of approximately 10 r~ diameter that are
concave on both sides and have a breaking notch on the
upper side.
In analogous manner it is possible to manufacture
tablets containing 100 ~g of a different compound of
the formula I according to Example~ lto 12, it being
~6~ J
- 52 -
possible for compounds to be also in the form of acid
addition salts, such as hydrochlorides, and in the case
of compounds in which R2 is 1-carboxymethyl to be also
in the form of salts with bases, such as sodlum, potassium
or zinc salts.
