Note: Descriptions are shown in the official language in which they were submitted.
The present invention relates to a novel basic esters
of benzoic acids and of 2-thiophencarboxylic acids, their
pharmaceutically acceptable salts with acids, to processes for
their preparatlon and to a pharmaceutical composition, containing
these novel esters.
Thus, the present invention provides novel compounds
which e.g. may be used as agents in local anaesthesia, and which
show a lower toxicity and an improved effectiveness over conven-
tional compounds.
The present invention also provid~s processes for
preparing the novel compounds which are easy to carry out and
which are economical.
According to the present invention there are provided
novel basic esters having the formula I
~ ,Il 2--CI~ 2 3
wherein R is a group of the formulae
1~l
~$
~
1 11
l~l s ~
wherein Rl is hydrogen or Cl-C4 alkyl, and R2 is Cl-C4 alkyl,
halogen, a C1-C4 alkoxy, Cl-C4 alkylthio, nitro, amino or a Cl-C4
alkylamino, Rl and R2 being the same or different, and R3 is a
~.
basic group selected from di(Cl-C4) alkylamino or a 6-membered
nitrogen containlng aromatic heterocyclic group which may contain
a further oxygen atom, and their pharmacologlcally useful salts
with acids.
~2~
The first process of this invention for preparing the
ncvel basic esters of formula I
R-~-O-CH2-CH2-R3 (I)
wherein R and R3 are defined above, and their pharmacologically
useful salts, is characterized in that benzoic acids or
thiophencarboxylic acids or their acid halides of the formulae
1 . Rl
~ - COR' alld ~ COR'
- J~2
wherein R' is a hydroxyl group or halogen, and Rl and R2 are
defined above, are reacted with an alcohol of formula II
Hoo-cH2-cH2-R3 (II)
wherein R3 is defined above, and that the obtained compounds
occasionally are transformed into their pharmacologically useful
salts.
The second process of this inventi.on for preparing the
novel basic esters of formula I
o
R-~-o-c~2-cH2-R3 (I)
wherein R and R3 are defined above, and their pharmacologically
useful salts, is characterized ln that salts of benzoi.c acids or
thiophencarboxylic acids of the formulae
~1
- COOI~I and l ~ i
~ ' COO;~I
~2
wherein M is a metal salt, and Rl and R2 are defined above, are
reacted with a halide of formula III
Hal-cH2-c~2-R3 ~III)
wherein ~Ial is a halogen atom, and R3 is defined above, and that
the obtained compounds occasionally are transformed into their
pharmacologically useful salts.
The compounds of the general formula I, wherein R2 is
amino, may be prepared by reducing the nitro compounds.
Both processes of this invention may also be realized
in the presence of at least ona solvent. Occasionally also cata-
lysts may be used. Somebody skilled in the art may easily deter-
mine the suitable reactlon temperatures and reaction times. Usu-
ally one works at standard pressure, whereby also excess pressure
and underpressure ~vacuum) are not excluded.
The administration of the novel compounds of formula I
according to this invention is realized in an usual way, as this
is known in the art for the known compounds,
The preferred embodimen-ts are illustrated in the set of
Examples, wherein also some novel starting materials and interme-
diates are described.
A. Exam~les for benzoic acid esters
Example 1
To a solution of sodium me-thylate, prepared of 2.34 g
(o.l mol) sodiurn in 100 ml absolute ethanol, are added 13.6 g
(o.l mol) 2-methylbenzoic acid and then 15 g (O.ll mol) N-(2-
chloroethyl)-piperidine are added slowly drop by drop. The mix-
ture ~as stirred and heated for 5 hours. After cooling, the pre-
cipitated sodium chloride was filtered with suction and then
washed with ethanol. The filtrate was evaporated in the vacuum
of a water jet pump, the residue was diluted with water and
extracted with ether. The base was extracted with diluted
hydrochloric acid. The acidic solution was made alkaline and was
extracted with ether. After the evaporation of the ether the
base was reacted with etheric hydrochloric acid lnto the
hydrochloride of the 2-methyl-benzoic acid-2-piperidino ethyl
ester. Mp. 164-165C.
ExamPle 2
In the same way as described in Example 1 the
hydrochloride of 2,6-dlmethylbenzoic acid-2-piperidino-ethyl
ester having an mp. 211-213C was obtained, when 26,-dimethyl-
benzoic acid is used instead of 2-methyl-benzoic acid.
Example 3
To a solution of 805 mg (0.035 mol~ sodium in 40 rnl
absolute ethanol are added 5.4 g ~0.035 mol) 2-fluoro-6-methyl-
benzoic acid, and then 6.1 g (0.045 mol) 2-diethyl-amino-
ethylchloride are added drop by drop, and this mixture is
reacted, as described in Example 1, to yield the hydrochloride of
2-fluoro-6-methyl-benzoic acid-2-diethyl-aminoethyl ester having
an mp. of 136.7.
- 5 -
`'.~
The starting material was obtained as follows:
18.75 g (0.1 mol) of 2-amino-6-methyl-benzoic acid-
hydrochloride are diazotized in 55 ml water and 9 ml concentrated
hydrochloric acid with sodium nitrite, and at a temperature of
-5C 50 ml hexafluorophosphoric acid are added. The precipitated
salt was filtered with suction and decomposed in xylene at a tem-
perature of 125C. After cooling, the acid is extracted in a
sodium carbonate solution, acidified and extracted in ether.
After dryiny and evaporating the e-ther, the substance contains as
a by-product 2-hydroxy-6-methyl-benzoic acid. After the esteri-
fication to the ethyl ester, the 2-hydroxy-6-methyl-benzoic acid
ester is extracted in sodium carhonate solution, the 2-fluoro-6-
methyl-benzoic acid-ethyl ester is distilled and saponified with
alcoholic potassium hydroxide. Mp. 124.6~.
Exam~le 4
As described in Example 3, the hydrochloride of 2-
bromo-6-methyl-benzoic acid-2-diethylamino-ethyl ester is pre-
pared from 2-bromo-6-methyl-benzoic acid. Mp. 183.5-18~.5.
Example_5
AS described in Example 3, the hydrochloride of 2-iodo-
6-methyl-benzoic acid-2-diethylamino-ethyl ester is prepared from
the sodium salt of 2-iodo-6-methyl-benzoic acid and 2-diethy-
lamino-ethylchloride and etheric hydrochloric acid. Mp. 192.8.
Exam~le 6
As described in Example 1, the hydrochloride of 2-
ethoxy-6-methyl-benzoic acid-2-diethylamino-ethyl ester is pre-
pared from 2-ethoxy-6-methyl-benzoic acid and 2-diethylamino-
ethylchloride. Mp. 125-127.
~2~
Example 7
When using N--(2-chloroethyl)-piperidine instead of 2-
diethylamino-ethylchloride, then, as described in Example 6, the
hydrochloride of 2-ethoxy-6-methyl-benzoic acid-2-piperidino-
ethyl ester is obtained. Mp. 154.6.
The 2-ethoxy-6-methyl-benzoic acid is synthesized in a
two-step synthesis of 2-chloro-6-methyl-1-benzonitrile.
2-ethoxy-6-methyl-benzonitri]e:
To a sodium methylate solution, prepared of 5.3 g
sodium in 75 ml absolute ethanol, are added 20 g (0.132 mol) 2-
chloro-6-methyl-benzonitrile and this mixture is heated in an
autoclave having a glass insertion for 40 hours at a temperature
of 130. After cooling the precipitated sodium salt is flltered
with suction, the filtrate is evaporated in the vacuum of the
water ~et pump, and the residue is dilute with ether. After
washi.ng, drying and evaporating the ether, a produce having an
mp. of 36-37.5 is obt,ained.
2-ethoxy-6-methyl-benzoic acid:
The nitrile is saponified either in ethanolic potassium
hydroxide under pressure or in glycerine at a temperature of
210C. Mp. 86-38.
_xamPle 8
When 2-ethyl-thio-6-methyl-benzoic acid is used instead
of 2-ethoxy-6-methyl-benzoic acid, then, as in Example 7, the
hydrochloride of 2-ethylthio-6-methyl-benzoic acid-2-diethy-
lamino-ethyl ester is obtained. Mp. 104.3.
Example 8a
When 2.3 g ~0.02 mol) fumaric acid in ethanol are added
to 6 g (0.02 mol~ base of 2-ethylthio-5-methyl-benzoic acid-2-
diethylamino-ethyl ester in ether, then the fumarate crystal-
lizes. Mp. 116.4.
Ex amPl e 9
As in Example 1, the hydrochloride of 2-methyl-6-nitro-
benzoic acid-2-diethylamino-ethyl ester is prepared from the
sodium salt of 2-methyl-6-nitro-benzoic acid, 2-diethylamino-
ethylchloride and etheric hydrochloric acid. Mp. 159-160.5.
Exam~le 10
~ s in Example 1, the hydrochloride of 2-methyl-6-nitro-
benzoic acid-2-piperidino-ethyl ester is prepared from 2-methyl-
6-nitro-benzoic acid. Mp. 181.6.
Example 11
As in Example 10, the hydrochloride of 2-methyl-6-
nitro-benzoic acid-2-morpholino-ethyl ester is prepared when 4-
(2-chloroethyl)-morpholine is used instead of N-(2-chloroethyl)-
piperidine. ~p. 186.9.
Example 12
.
As described in Example 1, the dihydrochloride of 2-
ethylamino-6-methyl-benzoic acid-2-diethylaminoethyl ester is
prepared from 2-ethylamino-6-methyl-benzoic acid, 2-diethylamino-
ethylchloride and etheric hydrochloric acid. Mp. 129.2.
Example 13
AS described ln Example 1, 2-butylamino-6-methyl-ben-
zoic acid and 2-diethyl-amino-ethylchloride are reacted to the
base (2-butylamino-6-methyl-benzoic acid-2-diethylamino-ethyl
ester). When an eg~limolar amount fumaric acid, as described in
Example 8a, is added to the base, then the fumarate having an mp.
of 99.7 is obtained.
The starting materials are prepared as follows:
The mixture of 10.5 g (0.058 mol) 2-amino-6-methyl-ben-
zoic acid-ethyl ester in 87 ml benzene and 14.5 ml acetic acid
and 1~.5 g zinc powder are heated to reflux temperature. Then
6.6 g acetaldehyde in 14.5 ml benzene are added slowly drop by
drop, and the mixture is heated for 2.5 hours under reflux.
After cooling, the mixture is filtered with suction, washed with
benzene, and the filtrate is made alkaline. The benzene layer is
separated, the al~aline aqueous solution is extracted with ben-
zene, the combined benzene layers are washed and dried, and after
the evaporation of the benzene the 2-ethylamino-6-methyl-benzoic
acid-ethyl ester is distilled. Bp. 136-139/min.
~.1 g (0.02 mol) of the ethyl ester in 50 ml ethanol
are saponified with 3.25 g potassium hydroxide in 21.5 ml water
by refluxing for 8 hours. The ethanol is evaporated, to the
residue water is added, the neutral compounds, which may be pre-
sen-t, are extracted with ether, the aqueous solution is acidified
to a pH of 6.5 and extracted with ether. After washing, drying
and evaporating the ether, 2-ethylamino-6-methyl-benzoic acid is
obtained. Mp. 97 . 6.
When butyraldehyde is used instead of acetaldehyde,
then as described above, 2-butylamino-6-methyl-benzoic acid-ethyl
ester is obtained. Bp. 156-158/0.65 mm.
~S
After saponification, 2-butylamino-6-methyl-benzoic
acid is obtained. Mp. 87.9.
Example 14
To 25.5 g (0.92 mol) 2-methyl-6-nitro-benzoic acid-2-
diethylamino-ethyl ester in 500 ml concentrated hydrochloric acid
are added during one hour 100 g tin (II)-chloride, and then the
mixture is heated for one hour on the boiling water bath. After
cooling, the mixture is made alkaline with 35 percent sodium
hydroxide and extracted with ether. After washing the etherical
solution, drying and evaporating the ether, the base is reacted
with etheric hydrogen chloride in the dihydrochloride of 2-amino-
6-methyl-benzoic acid-2-diethylamino-ethyl-ester. Mp. 186-188.
Example 15
~ s described in Example 14, the dihydrochloride of 2-
amino-6-methyl-benzoic acid-N-(2-piperidino)-ethyl ester is pre-
pared, when 2-methyl-6-nitro-benzoic acid-N-(2-piperidino)-ethyl
ester ls used. Mp. 199.8.
B. Examples for 2-thiophencarboxvlic acid esters
Example 1
In the same way as with the benzoic acid esters the
hydrochloride of 3-methylthiophen-2-carboxylic acid-2-diethy-
lamino-ethyl ester is prepared from the sodium sal-t of 3-
methylthiophen-2-carboxylic acid, 2-diethylaminoethylchloride and
etheric hydrochloric acid. Mp. 145.7.
-- 10 --
Example 2
~s described in Example 1, the hydrochloride of 5-
methylthiophen-2-carboxylic acid-2-diethylamino-ethyl ester is
prepared, Mp. 145.7, when 5-methylthiophen-2-carboxylic acid is
used.
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