1. * GB780027 (A)
Description: GB780027 (A) ? 1957-07-31
3-piperidyl ethers and thioethers
Description of GB780027 (A)
Translate this text into Tooltip
[75][(1)__Select language]
Translate this text into
The EPO does not accept any responsibility for the accuracy of data
and information originating from other authorities than the EPO; in
particular, the EPO does not guarantee that they are complete,
up-to-date or fit for specific purposes.
PATENT SPECIFICATION
780,027 Date of Application and filing Complete Specification: Jan.
17, 1956.
" |;INo. 1586/56.
Application made in United States of America on Jan. 20, 1955.
Complete Specification Published: July 31, 1957.
Index at acceptance:-Class 2(3), C1E4K(4: 6: 8), C3A13C(4C: 6B: 10D:
10F), C5(A4: E2).
International Classification:-C07d.
COMPLETE SPECIFICATION
3-Piperidyl Ethers and Thioethers We, SCHERING CORPORATION, of 60,
Orange Street, Bloomfield, New Jersey, United States of America, a
corporation organised under the laws of the State of New Jersey,
United States of America, do hereby declare the invention, for which
we pray rthat a patent may be granted to us, and the method by which
it is to be performed, to, be particularly described in and by the
following statement:-
This invention relates to a new group of compounds which have
desirable therapeutic properties. More particularly, this invention
relates to ethers and thio-ethers of N-substituted 3-piperidinols
together with their therapeutically acceptable acid addition and
quaternary salts, and to methods for their manufacture. The compounds
2. of this invention are noted particularly for their selectivity of
action upon the in situ uterus.
The free bases of the present invention may be represented by the
following general formula:
wherein R1 is a lower alkyl or monocydic arallkyl group, R, is a
1,1-diphenyl-ethyl, benzhydryl, fluorenyl or xanthyl group, which may
be substituted by halogen, lower alkyl and lower alkoxy groups, and X
is oxygen or sulphur. Representative examples of R, are methyl, ethyl,
propyl, hexyl and benzyl while representative illustrations of R. are
benzhydryl, p-methylbenzhydryl, 9-fluorenyl, 9xanthyl and
3-chloro-9-xanthyl. By the terms "lower a'lkyl"' and "lower alkoxy" we
mean alkyl and alkoxy groups having less than seven carbon atoms.
We have found that the compounds reprdsented by the general formula
exhibit marked oxytocic activity, a property which is most striking
with 1-ethyl-3-pperidylbenzhydryl ether, for example. Furthermore, we
have found that these compounds, in their oxytocic [Peice 3s. 6d.]
action, are relatively selective in that the elevation of tonus and
increased contractions of an in situ.primed uterus easily occur with a
concomitant complete absence of side effects. For example, at a dose
normally employed for the manifestatiqon of oxytocic action, the
compounds of this invention are for the most part devoid of activity
as antihistamninics, antispasmodics or parasympathetic blocking
agemnts.
This selectivity of action upon the in situ primed uterus is
surprising since isomers of these compounds Which contain the ether
linkage at the 4-position, are nort only oxytocic but 55 also
simultaneously act upon other systems and organs of the body. For
example, the benzhydryl ether of 1-methyl-4-piperidinol, in addition
to its oxytocic action, simultaneously exhibits antihistaminic and
anticholinergic 60 properties. The side effects arising from the
latter two physiological actions such as dckowsiness, mydrissis,
xerostomia and the like, are undesirably present. Furthermore, the
additional properties together with their undesirable side effects are
also exhibited by piperidine ethers containing one or more lower alkyl
groups attached to a carbon atom of the piperidine ring, such as
1,2,6-trimethyl-3-piperidyl.
benzhydryl ether. It is therefore surprising that 70 the compounds of
our invention, unlike their Isomers and homologues, are selective in
their action upon the -primed in situ uterus and are relatively devoid
of undesirable secondary properties and side effects. 75 These new
compounds are useful in the prevention or treatment of post partum
hemorrhage, certain cases of excessive uterine bleeding, induction of
labor andc other similar instances where oxytocic action is
therapeutically indicated.
3. The compounds of our invention are preferably administered orally in,
the form of tablets, capsules, elixinrsi and the like, mand generally
in conjunction with a therapeutically 85 accepta!Ae carrier or
vehicle. Where parenteral adinistration is indicated, solutions of the
salts are easily prepared in water or other nontoxic therapeutically
acceptable vehicles.
The compounds of this invention may generally be prepared by reacting
a 1-alkyl-3piperidinol with, an aralkyl halide, such as benzhydryl
bromide, in the presence of a basic agent, and, if desired, an inert
solvent such as toluene or xylene. Specifically, when benzhydryl
bromide is refluxed with 1-ethyl-3piperidinol and anhydrous xylene in
the presence of anhydrous potassium carbonate, there is obtained the
benzhydryl ether of 1ethyl-3-piperidineol.
In certain cases the ethers may be prepared by the interaction of a
1-alkyl-3-halogenopiperidine with an aralkyl alcohol; e.g. by heating
1-ethyl-3-chloropiperidine with benzhydrol there is obtained the
benzhydryl ether of 1-ethyl-3-piperidinol.
Although the compounds of our invention may be prepared by simply
heating the desired reactants together until the desired ether is
obtained, we prefer to perform the reactions in the presence of some
inert solvent such as an aliphatic or aromatic hydrocarbon or
highboiling ether. The particular solvent is not critical since its
primary purpose is to permit more efficient interaction of the
reactants.
Thus, any unreactive solvent having a boiling point above about 80 C.
may be employed.
In this reaction, a mole of hydrohalic acid is liberated and since it
may precipitate the ether, or even some unreacted amino-alcohol, wve
prefer to employ an acid acceptor such as pyridine, dialkylanlines,
or, as shown above, inorganic bases such as sodium or potassium
carbonate. Alternatively, an excess of basic alcohol may be used to
neutralize the hydrogen halide released. In those cases wherein the
basic alcohol is liquid at the reaction temperature, it may be
employed as solvent.
The reaction is preferably carried out more or less under anhydrous
conditions in order to realize more favorable yields; therefore, if is
preferable to, employ only substantially anhydrous reactants and
solvents.
In addition to the foregoing, the appropriate piperidinol may be
alkylated. with a benzhydryl halide in liquid ammonia solvent using an
alkali metal amide as catalyst. For example, reacting benzhydryl
bromide with 1-isopropyl3-piperidinol in liquid ammonia in the
presence of sedamide, yields 1-isopropyl-3-piperidyl benzhydryl ether.
Moreover, the free bases of the general formula, may be prepared by
4. reacting the sodium salts of the amino alcohol with the appropriate
halide, preferably in. an inert solvent. Conversely, the sodium salt
of an appropriate alcohol may be reacted with a 1alkyl-piperidine
containing a halogen atom in the 3-position. For- example, reacting
the sodium salt of 1-ethyl-3-piperidinol with xanthydryl bromide in
refluxing toluene yields the xanthydryl ether of 1-ethyl-3-piperidinoL
Similarly', reacting the sodium salt of xanthydrol with
1-ethyI-3-chloropiperidine in. refluxing toluene, yields the same
product.
To prepare compounds wherein X is sulphur, the corresponding
thiopiperidines may be employed. The intermediate thiopiperidines are
preferably obtained from the reaction of a piperidinol with phosphorus
pentasulfide. For example, heating an intimate mixture of
1methyl-3-piperidinol and phosphorus pentasulfide followed by
distillation after the excess sulfurizing agent is destroyed, affords
the corresponding 1-methyl-3-thiopiperidine. The
1alkyl-3-thiepiperidines are converted into the thio-esters of the
invention by reaction with an aralkyl halide RHal (R, being as
hereinbefore defined) by procedures similar to those above described
for the production of the ethers.
The therapeutically acceptable acid addition salts of the basic ethers
and thioethers of the general formula are prepared by reacting the
basic ether or thioether directly with an acid in the usual manner,
preferably in the presence of an inert solvent. For example;-. by
passing anhydrous hydrogen chloride through an ether solution of the
benzhydryl ether of 1-ether-3piperidinol, there precipitates the
corresponding hydrochloride which may be recrystallized from
alcohol-ether. Similarly, by heating the aforementioned base with an
equivalent of maleic acid in isopropyl acetate, the corresponding
maleic acid salt is obtained upon coolIng. Examples of therapeutically
acceptable anions which may be employed are chloride, bromide,
maleate, tartrate and citrate.
The quaternary salts of the free bases of this invention may be
prepared by reacting the base with an alkyl halide or sulfate such as
methyl bromide, optionally in the presence of an inert solvent.
Alternatively, quaternary chlorides and bromides may be Drepared from
corresponding iodides by heating an--alcoholic solution of the iodide
in the presence of a silver chloride or bromide, whereupon halogen
exchange is effected.
The following examples, in which all the temperatures are Centigrade,
illustrate the preparation of the compounds of this invention, but do
not limit invention, except as defined in the appended claims:
EXAMPLE 1 115
1-Methyl-3-pipewidyl benzhydryl ether A mixture of 14.5 g. of
5. 1-methyl-3-piperidinol, 11 g. of anhydrous potassium carbonate and 200
ml. of xylene is heated to -reflux.
While stirring the mixture, 30 g. of benzhydryl bromide is added
dropwise and the resultant mixture stirred and refluxed overnight.
After cooling, the mixture is poured into water and extracted with
ether. The ether solution is extracted with dilute aqueous 125
hydrochloric acid and the acid solution, after treatment with dilute
sodium hydroxide solution, is extracted with ether. The ether extracts
are washed with water, dried over anhydrous potassium carbonate,
concentrated in vacuo 130 780,027 there is obtained the
above-identified ether, b.p. 180-185 /2 nmm EXAMPLE 8
1-Ethyl-2-piperidyl p,pl-dimethylbenzhydryl 65 ether From the reaction
of ppL-dimethylbenzhydryl bromide and 1-ethyl piperidinol, according
to the procedure of example 1, there Is obtained the compound of this
example, b.p. 70 200-202 /0.5 mi.
EXAMPLE 9
1-Ethyl-3-piperidyl p-methoxy-benzhydryl ether By substituting
p-methoxy benzhydryl bromide in the procedure described in example 2,
there is obtained the ether of this example, b.p. 205 /1 mm.
EXAMPLE 10
1-Ethyl-3-piperidyl benzhydryl thiioether 80 The requisite
intermediate, 1-ethyl-3-thiopiperidine is prepared as follows:
An intimate mixture of equal molar quantities of 1-ethyl-3-piperidinol
and phosphorus pentasulfide is heated at 150-200 for several 85 hours.
After cooling, the mixture is decomposed with dilute hydrochloric acid
and then made alkaline with sodium hydroxide solution. The alkaline
mixture is extracted with ether, which is dried and distilled in vacio
90 yielding 1-ethyl-3-4thiopiperidine.
By reacting the thiopiperidine obtained above with benzhydryl bromide,
according to the procedure of example 1, there is obtained
1-ethyl-3-piperidyl.benzhydryl thioether, b.p. 95 175-180 /1 mm.
EXAMPLE 11
1-Methyl-3-piperidyl benwhydryl ether methyl iodide A mixture of 10 mL
of methyl iodide and 100 2 g. of the ether obtained in example 1, in
mil. of anhydrous ethyl ether is refluxed for several hours. After
filtration, the solids are recrystallized from methanol ether yielding
the quatmrnary salt of this example, m.p. 167.5168 .
EXAMPLE 12
1-Methyl-3-piperidyl benzhydryl ether methyl bromide To a stirred
suspension of freshly prepared 110 silver bromide, in 300 ml. of
anhydrous methanol is added a solution of the quaternary iodide
obtained in the preceding example. The mixture is stirred and refluxed
overnight whereupon, after cooling, the suspended salts 115 are
removed by filtration. Evaporation of the methanolic solution,
6. followed by recrystallizadtion of the residue from methanol ether,
yields the quaternary bromide of this example.
and distilled to yield 1-methyl-3-piperidyl benzhydryl ether, b.p.
152-154 /1 man.
EXAMPLE 2
1-Ethyl-3-piperidyl benzhydryl ether From the reaction of 22 g. of
1-ethyl-3piperidinol, 12.5 g. of potassium carbonate, 250 ml. of
xylene and 42 g. of benzhydryl bromide, according to the procedure of
example 1, there is obtained 1-ethyl-3-piperi!0 dyl benzhydryl ether,
b.p. 170 /1 m EXAMPLE 3
1-Isopropyl-3-piperidyl benzhydryl ether The intermediate amino
alcohol, 1-isopropyl-3-piperidinol, is prepared accqrding to described
procedures for the lower alkyl homologues, b.p. 95-102 /13-15 mm.
To a solution of 23 g. of 1-isopropyl-3piperidinol in 250 cc. of
xylene is added 20 g.
of potassium carbonate, followed by 35 g. of benzhydryl bromide
according to, the procedure of example 1. Upon distillation, there ts
obtained 1-isopropyl-3-piperidyl benzhydryl ether, h.p. 190--195'/2
mmn.
EXAMPLE 4
1-Hexyl-3-piperidyl benzhydryl ether From the reaction of
1-hexyl-3-piperidinol and benzhydryl bromide, according to the
procedure of example 1, there is obtained the ether of this example,
b.p. 215-220 /1 minl.
EXAMPLE 5
1-Ethyl-3-piperidyl p-chlorobenzhydryl ether A mixture of 20 g. of
1-ethyl-3-piperidinol and 9.8 g. of anhydrous potassium carbonate is
heated for two hourms at 120--130 . To the hot mixture, while
stirring, is slowly added 29 g. of p-chlorobenzyl bromide. The
rearction mixture is stirred andc heated for 8 hours at 130 and, upon
cooling, is poured into water and extracted with chloroform.
The chloroform layer is extracted with dilute hydrochloric acid
solution which, in, turn, is rendered alkaline and then extracted with
chloroform. The chloroform extracts are dried over anhydrous,
potassium carbonate, concentrated in vacuo and distilled to yield the
chlorinated ether of this example, b.p. 186188 /2 min.
EXAMPLE 6
I-Ethyl-3-piperidyl benzhydryl ether hydrochloride A solution of 5 g.
of the aimmino ether obtained in example 2 is treated with anhydrous
HC1, whereupon a gummy precipitate forms.
The solvent is removed by decantation and the residue is
recrystallized from alcohol-ether, m.p. 137-139 .
EXAMPLE 7
1-Methyl-3-piperidyl p-methylbenzhydryl ether By substituting
7. p-methylbenzhydryl bromide in the procedure described in example 1,
EXAMPLE 13 i-Isopropyl-3,piperidyl benzhydryl ether methiodide A
solution of 6 g. of 1-isopropyl-3-piperidyl benzhydryl ether, 10 ml.
of methiodide and ml. of anhydrous benzene is refluxed for 780,027
several hours. After cooling, the solvent is removed by decantation
and the oily residue is recrystallized from isopropyl acetate,
yielding the quaternary iodide of this example, mp.
170-171 .
In all of the foregoing examples, the benzhydryl ethers were prepared
by the reaction of a benzhydryl halide with a piperidinol or a
piperidine thiol in the presence of an alkali metal carbonate
condensing agent. Other types of acid acceptors, such as potassium
hydroxide and sodium hydroxide may be used. In addition to the
foregoing, the following examples show alternative methods of
preparing compounds of this irnvention.
EXAMPLE 14
1-Ethy34-3-piperidyl m-bromobenzhydryl ether To a suspension of 0.1
mole of sodamide in 500 ml. of anhydrous toluene is added a solution
of 0.1 mole of m-bromobenzhydrol in toluene. The mixture is refluxed
for several hours, after which time, a solution of 0.1 mole of
1-ethyl-3-chloropiperidine (prepared according to the procedure of
Fuson and Zirkle, J.A.C.S. 70, 2760 (1948)), is slowly added.
The reaction mixture is refluxed for an additional 4 hours and, after
cooling, is poured into ice-water and extracted with ether. Following
the isolation procedure of example 1, there is obtained the
bnomobenzhydryl ether of this example, b.p. 185-190 /1 mn.
Alternatively, the compound of this example is prepared from
m-bromobenzhydryl bromide and 1-ethyl-3-piperidinol according to the
procedure described in example 1.
EXAMPLE 15
1-Methyl-3-piperidyl,p-tolyl -phenyl ethyl ether To a suspension of
0.1 atom of powdered sodium in 100 nil. of anhydrous tpluene is slowly
added a solution of 0.1 mole of 1methyl-3-piperidinol in -100 ml. of
anhydrous toluene. The mixture is stirred and refiuxed for several
hours until amino alcohol is completely converted to its sodium salt.
To the stirred suspension of the sodium derivative, there is slowly
added a solution of 0.1 mole of o,,pitolyl -phenyl ethyl bromide. The
resulting mixture is refluxed for several hours and, after cooling, is
poured into ice-water and extracted with ether. The ether solution is
extracted with dilute aqueous hydrochloric acid and the acid solution
is then rendered alkaline. The aqueous alkaline mixture is extracted
with ether which, 55.after drying with anhydrous potassium carbonate,
is concentrated in vacuo and distilled to yield the compound of this
example, b.p.
8. 180 /1 mamn.
EXAMPLE 16
1-Ethyl-3-piperidyl 91-fluorenyl ether From the reaction of
l-ethyl-3-piperidinol, potassium carbonate and 9-bromofluorene in
xylene, according to the procedure of Example 1, the ether of this
example is obtained, b.p.
175-180 /1 mm.
EXAMPLE 17
1-Methyl-3-piperidyl 91-xanthyl ether A mixture of 0.13 mole of
1-methyl-3piperidinol and 0.06 mole of anhydrous potassium carbonate
is heated, while stirring, to 120--130 . To the hot mixture is added
0.1 mole of xanthydryl bromide and the resultant mixture is stirred
and heated at 130 for 8 hours. After cooling, the mixture is diluted
with water and extracted with ether. The ether solution is extracted
with dilute hydrochloric acid which is then made strongly alkaline
with sodium hydroxide solution. The alkaline mixture is extracted with
ether which, after drying with anhydrous potassium carbonate, is
concentrated and distilled to yield the xanthydryl ether of this
example, b.p. 190-195 /1 m.
EXAMPLE 18
1-Ethyl-3-piperidyl benzhydryl ether maleate A solution of 0.1 mole of
1-ethyl-3-piperidyl benzhydryl ether (obtained in Examkle 2) in mi. of
isopropyl acetate is added to a solution of 0.1 mole of maleic acid in
50 ml. of isopropyl acetate. The resulting mixture is warmed on a
steam bath and, upon cooling, crystallization of the salt occurs.
After removal by filtration, the salt is purified by recrystallization
from isopropyl acetate.
EXAMPLE 19
1-Benzyl-3-piperidyl benzhydryl ether From the reaction of
1-benzyl-3-piperidinol and benzhydryl bromide, according to the
procedure described in example 1, the 1-benzyl piperidyl ether of this
example is obtained, b.p. 180--185 /0.5-1 mnn.
* Sitemap
* Accessibility
* Legal notice
* Terms of use
* Last updated: 08.04.2015
* Worldwide Database
* 5.8.23.4; 93p