Note: Descriptions are shown in the official language in which they were submitted.
~ 1094097
The N-substituted cyclic amino acid derivatives accord-
ing to the present invention are compounds of the general
formula:
IR2
; Rl - N - CH2 - C - CH2 - COOR3 (I)
(CH2)n
wherein Rl is a hydrogen atom or a methyl radical, R2 is a
lower alkyl or cycloalkyl radical, or a benzyl radical, the
aromatic nucleus of which may be substituted, or a furfuryl-
or thiophene-methyl radical, R3 is a hydrogen atom or a lower
alkyl radical and n is 4,5, or 6; and the pharmacologically
compatible salts thereof.
By lower alkyl radicals, there are to be understood
straight-chained or branched alkyl radicals containing up to
8 and preferably up to 5 carbon atoms, especially the methyl,
ethyl, isopropyl, n-butyl and isopentyl radicals.
Those compounds of formula (I) are preferred in which
Rl is a hydrogen atom or a methyl radical, R2 is an alkyl
radical containing up to 5 carbon atoms or a benzyl radical
and R3 is a hydrogen atom or a methyl or ethyl radical.
The compounds encompassed by the genera1 formula (I)
exhibit hypothermal and, in some cases, narcosis-potentiating
or sedating properties. They are also characterized by an
extremely low toxicity. In animal experiments, there was,
surprisingly, also found a remarkable protective effect
against cramp induced by thiosemicarbazide. Some of the
compounds also possess a considerable protective action against
cardiazole cramp. These new compounds (I) can be used for the
therapy of certain cerebral diseases, for example, they are
-- 1 --
094097
suitable for the treatment of certain forms of epilepsy,
dizziness, of hypokinesia and cranial trauma. They also bring
about an improvement of the cerebral functions. Consequently,
they are also especially effective in the treatment of geri-
atric patients.
The novel compounds of general formula (I) according to
the present invention can be prepared by the reductive N-alkyl-
ation of compounds of the general formula:
H2N - CH2 - C - CH2 - COOR4
r ~ (II)
(CH2)n
wherein R4 is a hydrogen atom or a lower alkyl radical and n
is 4,~, or 6, followed, ;f desired, by esterification or
transesterification with an alcohol of the general formula:
H0 - R3 (III)
wherein R3 is a hydrogen atom or a lower alkyl. If desired,
the compounds thus obtained may be further converted into
their pharmacologically compatible salts by reaction with
appropriate acids or bases.
The N-alkylation according to the present invention is
carried out by known processes (see Houben-Weyl, Vol. 11/2,
p. 330) by first reacting the compounds of general formula
(II) with a carbonyl compound which contains a number of carbon
atoms corresponding to the radical Rl or R2 After the inter-
mediate compound is obtained, it is then converted into the
desired end product by means of a reducing agent.
-` 1094097
The reaction can be carried out in an inert solvent and,
as reducing agent, there can be used, for example, formic acid,
catalytically activated hydrogen, or a metal hydride, such as
sodium borohydride or sodium cyanoborohydride.
Examples of carbonyl compounds which can be used include
the aliphatic aldehydes, such as formaldehyde, acetaldehyde,
propionaldehyde, isobutyraldehyde, butyraldehyde and valer-
aldehyde, and the ketones, such as acetone, methyl ethyl ketone,
methylpropyl ketone, diethyl ketone, cyclohexanone, cyclopent-
anone and cycloheptanone.
Examples of aromatic aldehydes, which can be usedencompass benzaldehyde, halogenated aldehydes, such as
chlorobenzaldehyde or bromobenzaldehyde, tolualdehyde, mono-
and dihydroxybenzaldehyde, methoxybenzaldehyde, di- and tri-
methoxybenzaldehydes, such as veratraldehyde, piperonal and 3,
4, 5-trimethoxybenzaldehyde, and hydroxymethoxybenzaldehydes,
such as vanillin or isovanillin, as well as furfural or thio-
phene-aldehyde.
When using the carbonyl compound formaldehyde, the
corresponding N-methyl or N,N-dimethyl compounds are obtained,
whereas the other aldehydes yield only the N-monosubstituted
compounds. The N,N-mixed substituted compounds are, therefore,
prepared by first carrying out a reductive alkylation with a -
carbonyl compound which possess a number of carbon atoms cor-
responding to the radical R2 and then introducing the methyl
radical Rl by means of formaldehyde.
Compounds of general formula (I) in which Rl is a
hydrogen atom and R2 is a methyl radical can be prepared by
reductively N-methylating the N-benzyl compound by means of
formaldehyde and subsequently splitting off the benzyl radical
hydrogenolytically in the presence of a catalyst such as pal-
ladium charcoal or platinum oxide.
-- 3
~09409'7
For the preparation of the compounds of general formula
(I), the compounds of formula (II) are reacted with equivalent
or excess amounts of a carbonyl compound in an inert solvent.
The carbonyl compound may also serve as the solvent. The
intermediate is then hydrogenated in the presence of a catalyst,
such as palladium-charcoal or platinum oxide, at ambient or a
moderately elevated temperature, preferably at 20 to 50C. The
hydrogenation can be carried out at a hydrogen pressure of about
1 to 5 atmospheres. The reductive alkylation, especially the
10 methylation or benzylation, may be carried out in such a manner
that the intermediate formed by the reaction with a compound
of general formula (II) is reduced with sodium borohydride
(see Helv. Chim. Acta., 46 327/1963) or sodium cyanoborohydride
(see J. Org. Chem., 37, 1673/1972); the reaction is preferably
carried out at a temperature of from O to 25C. and in a polar
solvent such as water, methanol, ethanol, dioxan, tetrahydro-
furan, acetonitrile or aqueous mixtures of these solvents.
N-methylation can also be accomplished by reductive
alkylation of the monosubstituted amine with a carbonyl com-
20 pound, such as formaldehyde, and formic acid or formamides asreducing agents. (See Houben-Weyl, vol. 11/2, p. 331).
When R3 is to be an alkyl radical, the carboxyl group
of the amino acid obtained is esterified. The reaction is,
most simply, carried out by dissolving the free amino acid of
formula (I~ or a salt thereof in an excess of the esterifying
alcohol and saturating the solution with hydrogen chloride.
The amino acid ester hydrochloride is thus directly obtained.
The compounds of general formula (II) used as starting
materials can be prepared by one of the following methods:
1094097
(a) converting a compound of the general formula:
HOOC - CH2 ~ C - CH2 - COOR5
~ (IV),
(CH2)n
wherein R5 is an alkyl radical containing up to 8 carbon atoms
and n is 4,5, or 6, via a reactive acid derivative, into an
azide and then subjecting this to the Curtius rearrangement; or
~b) subjecting a compound of the general formula:
H2N - OC - CH2 - C - CH2 - COOH
(V)
(CH2)n
in which n is 4,5 or 6 to the Hofmann rearrangement, or
(c) subjecting a compound of the general formula:
> N - CO - CH2 - C j CH2 - COOH
HO ~ (VI)
(CH2)n
wherein n is 4, 5, or 6, or a compound of the general formula:
CO - CH2
HO - N \ \ C /'~~~(CH2)n (VIa)
CO - CH2
wherein n is 4, 5 or 6, to the Lossen rearrangement.
When a free amino acid is obtained, it may be ester-
ified to give a corresponding lower alkyl ester and/or the
product obtained may be converted into a pharmaceutically com-
patible salt by reaction with an acid or a base.
1094097
The reaction of the compounds of general formula (IV)
takes place according to the well-known Curtius rearrangement.
The free carboxyl group is first activated by conversion into
a reactive derivative, for example an acid halide or a mixed
anhydride, and subsequently reacted with an appropriate azide,
for example, sodium azide. The acid azide thus obtained is
then subjected to thermal decomposition in an organic solvent,
for example, benzene, toluene or an alcohol, such as ethanol,
during which nitrogen is split off and an introamolecular
rearrangement to an isocyanate or, in the presence of an alco-
hol, to a urethane takes place. The isocyanates and theureth-
anes can easily be converted into the desired primary amines
by basic or acidic hydrolysis.
The well-known Hofmann rearrangement of compounds of
general formula (V) also takes place via isocyanates. In this
case, the acid amides are reacted with alkali metal hypohalites.
Upon hydrolysis of the isocyanate formed by anionotropic re-
arrangement, the desired amine is formed, together with carbon
dioxide.
The Lossen rearrangement of the hydroxamic acids of
general formula (VI) also takes a similar course. In this
case, water is split off, the corresponding isocyanate first
eing formed, hydrolysis of which gives the desired amine.
Usually the hydroxamic acids are reacted with bases
via their 0-acyl derivatives as, for example, the 0-acetyl-,
0-benzoyl- and preferably 0-sulfonyl- derivatives.
The compounds of general formula (Vla) can be prepared
10!~4097
by reacting a hemiester of the general formula:
/ CH2 - COOH
(CH2)n C (VIb)
CH2 - COOR3
wherein R3 is an alkyl radical containing up to 5 carbon atoms
and n is 4,5 or 6, with hydroxylamine at an elevated temper-
ature, preferably of from 50 to 100C. (See ~.C.S., 1929, 713).
Since amino acids are amphoteric, pharmacologically
compatible salts when R3 is a hydrogen atom, can be salts of
appropriate inorganic or organic acids, for example, hydro-
chloric acid, sulphuric acid, phosphoric acid, acetic acid,
oxalic acid, latic acid, citric acid, malic acid, salicylic
acid, malonic acid, maleic acid, succinic acid or ascorbic
acid, but also, starting from the correspond;ng hydroxides
or carbonates~ salts with alkali metals or alkaline earth
metals, for example, sodium, potassium, magnesium or calcium.
Salts with quaternary ammonium ions can also be prepared with,
for example, the tetramethyl-ammonium ion. Of course, when R3
is a lower alkyl radical, it is only possible to form salts
with acids.
The compounds of general formula (IV) used as starting
materials can be prepared by reacting an acid anhydride of the
general formula:
C - CH2
ICl CH2 (VI I )
'-` 1094097
wherein n is 4, 5, or 6, either with water, or with one mole
of an alcohol of the general formula:
~0 - R5 (VIII),
wherein R~ has the same meaning as above.
The compounds of general formula (VII) are known (see
J.C.S., 115, 686/1919; Soc., 99, 446; J.C.S., 117, 639/1920.
Some of the compounds of general formula (V), as well
as processes for the preparation thereof, are known (see Austral
J.C., 13, 127/1960). They can also be prepared, for example,
by reacting compounds of general formula (VII) with ammonia.
In this case it is advantageous to operate at the lowest
possible temperature. However, it is also possible, as des-
cribed above, to prepare a hemiester and to react the free
carboxyl group with, for example, ethyl chloroformate and
subsequently with ammonia.
The hydroxamic acids of general formula (VI) can be
obtained analogously by reaction of the anhydride (VII) with
hydroxylamine.
Because of their low toxicity, the compounds of
general formula (I) according to the present invention can be
administered enterally or parenterally within wide dosage
limits in solid or liquid form. As injection solution, water
which contains the additives usual in the case of injection
solutions, such as stabilizing agents, solubilizing agents or
buffers is preferably employed.
Additives of this type include, for example, tartrate
and citrate buffers, ethanol, complex-forming agents such as
ethylenediamine-tetraacetic acid and the non-toxic salts there-
of, as well as high molecular weight polymers such as liquid
polyethylene oxide for viscosity regulation. Sold carrier
-- 8 --
1094097
materials include, for example, starch, lactose, mannitol,
methyl cellulose, talc, highly dispersed silicic acids, high
molecular weight fatty acids such as stearic acid, gelatine,
agar-agar, calcium phosphate, magnesium stearate, animal and
vegetable fats and solid high molecular weight polymers such
as polyethylene glycol. Compositions which are suitable for
oral administration can, if desired, also contain flavoring
and/or sweetening agents.
The individual dosage for the compounds according to
the present invention are preferably 5 - 50 mg. parenterally
and 20 - 200 mg. enterally.
Thus, the present invention also provides pharmaceutical
compositions containing at least one compound of general
formula (I) and/or at least one pharmaceutically compatible
salt thereof in admixture with a solid or liquid pharmaceutical
diluent or carrier.
The following Examples are given for the purpose of
illustrating the present invention:
EXAMPLE 1
l-(n,N-Dimethylaminomethyl)-cyclohexane-acetic acid.
4.5 9. l-aminomethylcyclohexane-acetic acid are dis-
solved in 150 ml. water and mixed with 8.5 ml. 37% aqueous
formaldehyde solution. The reaction mixture is hydrogenated
in the presence of palladium-charcoal (10%) at ambient temper-
ature and atmospheric pressure. The calculated amount of
hydrogen is taken up after 3 hours. The reaction mixture is
filtered and the filtrate acidified to pH 2 with dilute hydro-
chloric acid and then concentrated in a vacuum. By crystal-
lisation of the residue from acetone/diethyl ether, there are
obtained 4.9 9. (79% of theory) l-(N,N-dimethylaminoethyl)-
cyclohexane-acetic acid in the form of its hydrochloride; m.p.
140 - 142C.
g
' 1094097
Analysis:
CllH21N02.HCl.l/4H20
calc. : C 54.99%; H 9.44%; N 5.83~; CI 14.76%
found : 54.90%; 9.36X; 6.22%; 15.05%
The l-aminomethylcyclohexane-acetic acid used as
starting material is prepared as follows:
5.6 ml. triethylamine in 16 ml. anhydrous acetone is
added dropwise, with stirring and cooling to 0C., to a
solution of 7.28 9. l,l-cyclohexane-diacetic acid monomethyl
ester in 60 ml. anhydrous acetone, followed by a solution of
3.6 ml. ethyl chloroformate in 16 ml. anhydrous acetone.
Stirring is continued for 30 minutes at 0C. and then a
solution of 3.4 9. sodium azide in 12 ml. water is added there-
to dropwise. The reaction mixture is further stirred for
1 hour at 0C., then poured into ice-water and extracted three
times with 50 ml. amounts of ice-cold toluene. The combined
extracts are dried at 0C. over anhydrous sodium sulphate and
subsequently dropped into a flask pre-heated to 100C. The
mixture is further heated under reflux for 1 hour and then
~0 evaporated in a vacuum. The crude methyl l-isocyanatomethyl-l-
cyclohexane-acetate remaining behind is heated under reflux
for 3 hours in 50 ml. 20% hydrochloric acid. After cooling
the solution, the l-aminomethyl-l-cyclohexane-acetic acid
lactam formed as a by-product is removed by extracting three
times with 100 ml. amounts of chloroform, whereafter the
aqueous hydrochloric acid solution is evaporated in a vacuum.
The l-aminomethyl-l-cyclohexane-acetic acid crystallises out
as the hydrochloride; m.p. 123 - 132C., after recrystal-
lisation from acetone/methanol/diethyl ether.
- 10 -
-` 1094097
EXAMPLE 2
l-(N,N-Dimethylaminomethyl)-cycloheptane-acetic acid
In a manner analogous to that described in Example 1,
by the catalytic hydrogenation of a solution of 5.5 9. 1-
aminomethyl-cycloheptane-acetic acid and 9.6 ml. 37~ aqueous
formaldehyde solution in 180 ml. water in the presence of 5.5
9. palladium-charcoal (10%) and corresponding working up,
there are obtained 4.97 9. (67% of theory) l-(N,N-dimethyl-
aminomethyl)-cycloheptane-acetic acid in the form of its hydro-
chloride; m.p. 185 - 188C.
Analysis:
C12H23N02.HCl
calc. : C 57.70%; H 9.68%; N 5.61%; Cl 14.19%
found : 57.75%; 9.60% 5.51%; 14.23%
The l-aminomethyl-cycloheptane-acetic acid used as
starting material is prepared as follows:
13.7 9. l,l-cycloheptane-diacetic anhydride are mixed
with 2.36 9. anhydrous methanol in 10 ml. benzene and the
mixture boiled under reflux for 2 hours. After evaporating
20 the reaction mixture in a vacuum, there are obtained 15.~ 9.
l,l-cycloheptane-diacetic acid monomethyl ester. This is
dissolved in 100 ml. anhydrous acetone and, in a manner anal-
ogous to that described in Example 1, first mixed with 8.1 9.
triethylamine in 30 ml. acetone and thereafter with 9.8 9.
ethyl chloroformate in 30 ml. anhydrous acetone and finally
with 6.5 9. sodium azide in 20 ml. water. After the reaction
has taken place, the reaction mixture is extracted in the
manner described in Example 1 and the solution obtained of
l,1-cycloheptane-diacetic acid monomethyl ester azide in
30 toluene is rearranged to give the corresponding isocyanate.
The l-isocyanatomethyl-l-cycloheptane-acetic acid methyl
ester obtained is then boiled under reflux for 3 hours with
1 1
~094097
20% hydrochloric acid. Upon concentrating the reaction
mixture in a vacuum, l-aminomethyl-l-cycloheptane-acetic acid
separates out in the form of its hydrochloride, which is re-
crystallised from methanol/acetone/ethyl acetate; m.p. 69 -
72C.
EXAMPLE 3
l-(N-Isopropylaminomethyl)-cyclohexane-acetic acid
5 9. l-aminomethylcyclohexaneacetic acid hydrochloride
are hydrogenated at ambient temperature in a mixture of 60 ml.
water and 30 ml. acetone in the presence of 0.5 9. platinum
oxide. The calculated amount of hydrogen is taken up after
5 hours. The catalyst is filtered off and the filtrate is
evaporated in a vacuum. Crystallisation of the residue for
isopropanol/acetone gives 5.2 g. (88% of theory) l-(N-iso-
propylaminomethyl)-cyclohexaneacetic acid in the form of its
hydrochloride; m.p. 175 - 180C.
Analysis:
C12H23N02.HCl
calc. : C 57.70%; H 9.68%; H 5.61%; Cl 14.19%
found : 57.76%; 9.74%; 5.94%; 14.12%
EXAMPLE 4
l-(N-Isopropylaminomethyl)-cycloheptane-acetic acid
In a manner analogous to that described in Example 3,
1.11 9. l-aminomethylcycloheptane-acetic acid hydrochloride
is hydrogenated in a solution of 10 ml. water and 10 ml. ace-
tone in the presence of 0.1 9. platinum oxide. After appropri-
ate working up and crystallisation from isopropanol/acetone,
there is obtained l-(N-isopropylaminomethyl~-cycloheptane-
acetic acid in the form of its hydrochloride; m.p. 193 - 194C.
30 (sublimes ~150C.).
- 1094097
EXAMPLE 5
l-(N-n-Propylaminomethyl)-cyclohexane-acetic acid
A solution of 0.86 g. l-aminomethylcyclohexane-acetic
acid in 1.16 9. propionaldehyde in 100 ml. 95% ethanol is
hydrogenated at ambient temperature in the presence of 0.85 9.
palladium-charcoal (10%). After 1 hour, the calculated amount
of hydrogen is taken up. The catalyst is filtered off, the
filtrate is acidified with dilute hydrochloric acid and then
evaporated in a vacuum. Crystallisation from acetone/diethyl
ether gives l-(N-n-propylaminomethyl)-cyclohexane-acetic acid
in the form of its hydrochloride; m.p. 148 - 152C.
EXAMPLE 6
l-(N-n-Propylaminomethyl)-cycloheptane-acetic acid
In a manner analogous to that described in Example 5,
by the catalytic hydrogenation of 1.1 9. l-aminomethyl-cyclo-
heptane-acetic acid and 1.16 9. propionaldehyde in 100 ml.
ethanol in the presence of 1.16 9. palladium-charcoal ~10~)
at ambient temperature and appropriate working up, there is
obtained l-(N-n-propylaminomethyl)-cycloheptane-acetic acid;
m.p. 182 - 183C.
EXAMPLE 7
l-(N-Ethylaminomethyl)-cyclohexane-acetic acid
In a manner analogous to that described in Example 5,
by the catalytic hydrogenation of a solution of 0~86 9.
l-aminomethylcyclohexane-acetic acid and 2.2 9. acetaldehyde
in 100 ml. methanol in the presence of 0.85 9. palladium-
charcoal and appropriate working up, there is obtained
l-(N-ethylaminomethyl)-cyclohexane-acetic acid; m.p. 172 -
173C., after recrystallisation from isopropanol/diethyl
ether.
- 13 -
1094097
EXAMPLE 8
l-(N-Ethylaminomethyl`)-cycloheptane-acetic acid
In a manner analogous to that described in Example 5,
by the catalytic hydrogenation of 1.85 9. l-aminomethyl-
cycloheptane-acetic acid and 2.2 9. acetaldehyde in 100 ml.
ethanol in the presence of 1.85 9. palladium-charcoal and
appropriate working up, there is obtained l-(N-ethylamino-
methyl)-cycloheptane-acetic acid in the form of its hydro-
chloride; m.p. 168 - 170C.
EXAMPLE 9
l-(N-n-Butylaminomethyl)-cyclohexane-acetic acid
In a manner analogous to that described in Example 5,
by the catalytic hydrogenation of a mixture of 0.86 9.
l-aminomethylcyclohexane-acetic acid and 1.44 9. n-butyr-
aldehyde in 50 ml. 95% ethanol in the presence of 0.8 9.
palladium-charcoal, there is obtained l-(N-n-butylaminomethyl)
-cyclohexane-acetic acid; m.p. 142 - 154C.
EXAMPLE 10
l-(N-n-Butylaminomethyl)-cycloheptane-acetic acid
In a manner analogous to that described in Example 5,
0.93 9. l-aminomethylcycloheptane-acetic acid are hydrogen-
ated with 1.44 9. n-butyraldehyde in 50 ml. ethanol in the
presencepresence of 0.9 9. palladium-charcoal. After appropri-
ate working up and crystallisation from acetone/diethyl ether,
there is obtained l-N-n-butylaminomethyl)-cycloheptane-
acetic acid in the form of its hydrochloride; m.p. 158 - 165C.
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10'34097
EXAMPLE 11
l-(N-Benzylaminome`thyl)-cyclohexane-acetic acid
Variant A.
0.86 9. l-aminomethylcyclohexane-acetic acid are
hydrogenated in 50 ml. 95% ethanol with 0.65 9. benzaldehyde
in the presence of 0.1 q. platinum oxide. The reaction
mixture is work up in the manner described in Example 5. After
crystallisation from acetone/diethyl ether, there is obtained
- l-N-benzylaminomethyl)-cyclohexane-acetic acid in the form of
its hydrochloride; m.p. 125 - 135 C.
Variant B.
386 g. sodium l-aminomethylcyclohexane-acetate in 2 ml.
water, prepared from the free amino acid by the addition of
an equivalent amount of sodium hydroxide in water, are mixed
with 0.21 ml. benzaldehyde. The reaction mixture is stirred
at ambient temperature until the solution is homogeneous.
Subsequently, 75 mg. sodium cyanoborohydride are introduced
portionwise, while stirring. After stirring for one hour, the
reaction mixture is acidified with dilute hydrochloric acid
20 and evaporated in a vacuum. After crystallisation of the
residue from acetone/diethyl ether, there is obtained l-(N-
benzylaminomethyl)-cyclohexane-acetic acid, the hydrochloride
of which melts at 125 - 135C.
EXAMPLE 12
l-(N-Benzyl-N-methylaminomethyl)-cyclohexane-acetic acid
500 mg. l-(N-Benzylaminomethyl)-cyclohexane-acetic
acid hydrochloride (cf. Example 11) are dissolved in 10 ml.
water and mixed with 1.68 ml. lN aqueous sodium hydroxide
solution. This solution is introduced into a prehydroqenated
-- 15
` 1094097
solution of 500 mg. platinum dioxide in 10 ml. water. After
the addition of 1 ml. 37% aqueous formaldehyde solution,
hydrogenation is carried out at ambient temperature and
atmostpheric pressure. After about 2 hours, the take up of
hydrogen ceases. The catalyst is filtered off and the fil-
trate, after acidification with dilute hydrochloric acid, is
evaporated in a vacuum. Excess formaldehyde is removed by
repeated evaporation with water. Crystallisation of the
residue from acetone/diethyl ether gives l-(N-benzyl-N-meth-
ylaminomethyl)-cyclohexane-acetic acid hydrochloride; m.p.
150 - 157C.
EXAMPLE 13
l-(N-Methylaminomethyl)-cyclohexane-acetic acid
178 mg. l-(N-benzyl-N-methylaminomethyl)-cyclohexane-
acetic acid hydrochloride are hydrogenated in 25 ml. ethanol
in the presence of 0.2 9. palladium-charcoal at ambient
temperature and atmospheric pressure. After 1 hour, the cata-
lyst is filtered off and the filtrate evaporated ;n a vacuum
at 20C. Crystallisation of the residue from acetone/diethyl
ether gives l-(N-methylaminomethyl)-cyclohexane-acetic acid
in the form of its hydrochloride; m.p. 160 - 162C.
EXAMPLE 14
l-(N-Ethyl-N-methylaminomethyl)-cycloheptane-acetic acid
1 9. l-(N-ethylaminomethyl)-cycloheptane-acetic acid
hydrochloride (cf. Example 8) is dissolved in 60 ml. water
and mixed with 4 ml. lN aqueous sodium hydroxide solution.
After the addition of 2 ml. 37% aqueous formaldehyde solution,
the reaction mixture is hydrogenated in the presence of 1 9.
palladium-charcoal at ambient temperature and atmospheric
pressure. After about 2 hours, the calculated amount of
- 16 -
~0~34097
hydrogen is taken up. The reaction mixture is then worked up
in the manner described in Example 12 and, after recrystal-
lisation from acetone/diethyl ether, there is obtained
l-(N-ethyl-N-methylaminomethyl)-cycloheptane-acetic acid in
the form of its hydrochloride; m.p. 148 - 153C.
EXAMPLE 15
l-(N-Cyclohexylaminomethyl)-cycloheptane-acetic acid
A solution of 925 mg. l-aminomethylcycloheptane-
acetic acid and 982 mg. cyclohexanone in 50 ml. 90% aqueous
methanol is hydrogenated in the presence of 0.8 9. palladium-
charcoal at ambient temperature and atmospheric pressure.
After working up the reaction mixture in the manner described
in Example 5 and crystallising from aqueous methanol, there
is obtained l-(N-cyclohexylaminomethyl)-cycloheptane-acetic
acid hydrochloride; m.p. 198 - 204C.
EXAMPLE 16
Ethyl l-(N-ethylaminomethyl)-cycloheptane-acetate
166 mg. l-(N-ethylaminomethyl)-cycloheptane-acetic
acid hydrochloride (cf. Example 8) are dissolved in 5 ml.
absolute ethanol. Gaseous hydrogen chloride is passed in
and the solution is left to stand overnight at ambient temper-
ature. After evaporation in a vacuum and crystallisation of
the residue from ethyl acetate/diethyl ether/hexane, there is
obtained ethyl l-(N-ethylaminomethyl)-cycloheptane-acetate
in the form of its hydrochloride; m.p. 110 - 118C.
109~097
EXAMPLE 17
l-(N-benzylaminomethyl~-cycloheptaneOacetic acid
A solution of 3 9. l-aminomethylcycloheptane-acetic
acid hydrochloride and 13.86 ml. lM aqueous sodium hydroxide
solution in 150 ml. ethanol is mixed with 3 g. freshly dis-
tilled benzaldehyde and hydrogenated in the presence of 2.3 9.
platinum dioxide at ambient temperature and atmospheric pres-
sure. After working up the reaction mixture as described in
Example 5 and crystallisation from aqueous ethanol, there is
obtained l-(N-benzylaminomethyl)-cycloheptane-acetic acid
hydrochloride; m.p. 145 - 157C.
- 18 -
