Note: Descriptions are shown in the official language in which they were submitted.
The invention reLates to ~ T!ethyl-~-
-piperidylidene)~4,9-dihydrothieno(2,3-c)-2-benzo-
thiepin oE formul~ :[
~ 6~ S ~
~l) (I)
N
CH3
and its hydrogen(-~)tartrate.
The present invention, in particular, provides
a process ~or the preparation of 4-(1-methyl-4-
-piperidylidene~-4,9-dihydrothieno(2,3-c)-2~benzo-
thiep:in of ormula I
~o
~ l (I)
N
I
CH3
and its hydrogen(+)tartrate by the reaction of thieno
(2,3-c)-2-benzo~hiepin-4(9H)-one with 1-methyl-4-
-piperidylmagnesium chloride in tetrahydrofuran and
subsequent acid catalyzed dehydration of the resulting
., . -- 1 --
~-ll metllyl-4-piperidy:L)~,9-dihyclrothieno(2,3-c)
-2-benzothiepin-4-ol oE formula II
[~,~ III)
N'
CH3
characterized in that said crude alcohol of formula II
is purlfied by separating thereErom simultaneously
formed 7-(l--methyl~4-piperidy:L)thienol2,3 c)-2-
-henzothiepin-4(911~-one of :Eormula III
CH3N ~
o
by extraction with ethanol, -the purifled alcohol of
formula II is separated as the insoluble material and
subjected to said dehydration, and the obtained crude
base of formula I is purified by crystallization from
-- 2 --
3~
ethano:L to separate thereErorn res:LcluaL lcetone of
Eormula I:[l, whereupon the obta:Lned pur:Lfied base
oE formula I, if desired, is converted to said salt
by neutrallzation with (-I-)-tartaric acid in aqueous
ethanol.
The present invention, in accordance with
another aspect, provides a pharmaceutical composi-
tion comprising 4-(1-methyl-4~piperidylidene)-4,9-
-dihydrothieno(2,3-c)-2-benzothiepin of formula I
~ (I)
N
C~'3
2n
or its hydrogen(~)tartrate, and a pharmaceuticalLy
acceptable carrier.
The compound of -the formula (I) (pipethiadene~
and its hydrogen (~)tartra-te have high ~egree oE anti-
histamine, antiserotin, antireserpine and anti-
cataleptic activity and~ due to their comparatively
low toxicity, are expected to find use in the therapy
of migraine.
This compound I was pharmacologically tested in the
Eorm of its hydrogen(~)tartrate; the salt was administered
oral].y and :Lntr~peri~oneally. The doses glven are
calculatecl for -the base. Its efEect in a number o:E pharma-
cological tests are similar to those of tricyclic anti
clepressants oE the imi.pramine group: the compound ac-ts
ant~.gonistically towards ~eserpine in mice (it antagonizes
significantly the reserpine hypothermia in a dose of
2 mg/kg i.p.) and in rats (starting with a subcutaneous
dose of 20 mg/k~, it s-tatistically significantly suppresses
the ulcerogenic effect of reserpine)~ has a markedly
pronounced anticataleptic effect i.n rats (its medium
protective dose PD50 in the test of perphenazine catalepsy
is 7.0 mg/kg s.c.), and also antagonizes the oxotremorine
tremor in mice (the threshold dose which signi:Eicantly
inhibits the tremor is 1.0 mg/kg i.p.). In addition to
this, compound I has a pronounced central antiserotonin
activity; this property is shown by influerlcing the
behavioral manifestations induced by the administration
of 5-hydroxytryptophan in rats, by inEluencing the
- quipazine hyperthermia in ra~bit.s and, to a certain extent,
by -the interaction with tryp-tamine :in rats. The intensity
of the central antiserotonin effect of compound I on the
behavioral syndrome after the administration of 5-hydroxy-
tryptophan in rats is expressed by the medium protective
doses ~PD50 on subcutaneous administration) against tremor
(2.9 mg/kg) and against vertical motions of the forepaw
("tapping') ~2.6 mg/~g). The effect of compound I in this
test is similar to that of cyproheptadine and substantially
stronger than the effect of amitriptyline.
The antihistamine and antiserotonin effects of
compound I are the most intensive among its peripheral
effects. On oral administration to guinea-pigs, the
antihistamine effect in the histamine aerosol test as
expressed as the medium protective dose P.D50 is 0.046 mg/kg.
In the -tests of histamine detoxication and histamine
bronchoconstriction, compound I belongs to the most potent
4 --
antihistaminics known. The an~isero-tonin efEect in the
tes-t oE rat paw oedema after 5-hydroxytryptamine is
s-tatistically significan-t aEter an oral dose oE 0.3 ~ng/kg.
Compound I has also mild peripheral anticholinergic
effects: it acts mydriatically in mice and blocks the
lethal action of acetylcholine in guinea-pigs.
As compared with -the known an-timigraine agent
pizotifen (Dixon et al., Arzneim.-Forsch. 27, 1968, 1977?,
compound I has a distinct advantage in its lower anti-
depressant activity. On oral administration, compound Iinhibits the exploratory activity of mice in the observa-
tion test according to Boissier and Simon three times less
intensively than pizotifen (D50 of compound I is 23 mg/kg
and D50 of pizotifen is 7 mg/kg). In the -test oE
spontaneous locomotor activlty in mice with the use of the
photo-cell method by Dews~ the inhibitory activity of
compound I is even seven times lower than the effect oE
pizotifen (D50 of compound I is 2402 mg/kg, D50 of
pi.zo-tifen is 3.~ mg/kg). In a less specif:ic test of
thiopental sleep poten-tiation in mice, the threshold
dose of compound I corresponds to 10% of its oral I.D50
whereas the threshold dose of pizotifen is onl~ 2.5% of
its oral LD50 (the oral toxicities of the two compounds
in mice are similar). Compound I has a distinct tendency
to behavioral stimulation in rats: in observlng i-ts
effect on the -total activity of -the animals with the use of
the Animex instrument, the oral doses of 10 ancl 30 mg/kg
of compound I have a mild stimulatory effect tthe animal
activity increase to a value of 125 to 131% of the control
group), while oral doses of 3 to 30 mg/kg of pizotifen
elicit a statistically significant suppression of the
total activity of the animals (to a value of 57 to 64% as
compared with the control group).
The oral toxicity of compound I in rats is
surprisingly low- af-ter administration of a dose of
5 --
3~
1 g/kcJ p.o. not a single an:Lrllal out of a ten-member test
cJroup died within 7 days. Only mild depression was
observed in -the interval of 30 minutes af-ter the adlrlinis-
tration. In mice the oral LD50 i5 129 mg/kg. A single
administration of compound I in doses oE 50 and 100 mg/kg
p.o. to dogs does not induce any behavioral ehanges,
toxlc manifes-tations or animal death.
The compound of formula I was described in the
litera-ture (~ajsner M., Metys J. and Protiva M., Collect.
Czech.Chem.Commun. 32, 2854, 1967; Czechoslov.patent NoO
_
115 241). It was prepared by the reaction of thieno(2,3-c)-
-2-benzothiepin-4(9H)-one with l-methyl-4-piperidylmagnesium
chloride in tetrahydrofuran and subsequent acid-eatalyzed
dehydration of the formed 4-(1-methyl~4-piperidyl)-4,9-
-dihydrothieno(2,3-c) 2~benzothiepin-4-ol of formula II.
~ S \/ S ~
~011
,1~
(II)
N
CEI3
At that time it was overseen that compound II,
which resulted from the Grignard reaetion allegedly in a
yield of 74%, was not homogeneous but considerably
contaminated wi-th another compound which remained unchanged
during the subsequent acid-cataly~ed dehydration (heating
with diluted sulphuric acid) and so contaminated the final
product, i.e., compound I. The dehydration yield of 95% as
reported in the mentioned paper related to an evaporation
residue, i.e., to the crude compound I, which contained
undefined amount oE the above impurity. The presence of
that impurity in the obtained product can also accoun-t for
the low melting points as reported for compound II (125C
Erom benzene petroleum ether and even llg to 120C from
acetone). Those low-melting products were considered to be
solvates; in fact, however, they were mixtures of compound
II with the above men-tioned impurlty.
The reac-tion oE -thieno (2,3-c)-2--benzothiepin-4~9H)-
-one with l-methyl-4-piperidylmagnesium chloride in tetra-
hydrofuran has recently been subjected to a more detailed
study, and the crude product obtained was separated by a
combination of crystallization and chromatographic methods.
With the use of thin-layer chromatography on silica gel, the
material obtained was shown to be rather inhomogeneous and
to contain, in addition to the amino alcohol II, also
substantial amoun-t of a less polar component. The pure
amino alcohol II can be obtained from the crude product by
extraction with ethanol; -the desired compound II remains
undissolved while the less polar substance passes in-to the
solution. The latter substance can be isolated from -the
mother liquor by column chromatography on silLca gel and
purified by crystallization. It is most surprising that
both the pure amino alcohol II and the pure less polar
componen-t melt exactly at the same temperature of 21~ to
213C. Their mixture, however, melts with a deep depression,
and these are the melting points oE the "solvates" as
reported in the above-mentioned previous paper.
While the elemental analysis of the less po]ar
component showed a composition which was quite similar to
that of the amino alcohol II, the mass spectrum proved its
exact composition C17H16NOS2, which corresponds to a
compound containing two hydorgen atoms less than the amino
alcohol II. The ultra-violet spectrum of the new compound
indicated a high degree of conjugation, which corresponds
to a structure of a diaryl ketone. The infrared spectrum
confirmed the diaxyl ketone structure by a band at 1611 cm 1.
Both the infrared and H NMR spectra proved the absence of
the hydroxyl group~ The difference in the lE~ NMR spectra of
-- 7 --
compound II and the less polar suhs-tance was especially
signi:Eican-t i.n the reg:iorl o:E siqnals o.E aromatic protons.
While the spectrum of compourld II indicates -the presence of
six aromatic pro-tons, out of whlch the signals of five are
merged to an unresolved multiplet and only the signal of
the proton in the position 5 of the skeleton is clearly
separated, the lH NMR spectrum of -the less polar compound
evidences the presence of only five aromatic pro-tons, the
signals of which are all clearly differentiated and can be
localized into the individual positions of the skeleton,
the proton in the position 7 being absent. Further
evidence of the structural difference between compound II
and the less polar component is given by the mass spectra
in the region corresponding to the fragments. While this
main fragment of compound II has an m/z of 98, which
corresponds to the a~monium ion with a preserved l-methyl-
piperidine structure, the main fragrnent of the less polar
i.mpurity has an m/z of 70; -this corresponds to a fragment
of me-thylpiperi.dine with only ~ carbon atoms. The first
case is typical Eor a methylpiperidyl radical attached to
an aliphatic carbon, the second case corresponds to the
behavior of a methylpiperidyl group bound to an aromatic
carbon atom~ All these spec-tral Ei.ndings indicate for the
less polar compound the structure of 7~ methyl-~-piperi-
dyl)thieno(2,3-c)-2-benzothiePin-4(9H)-one of formula III
CH3N ~
~ LII)
The formation of compound III can be explained
by a l,~-addition of the Grignard reagent to a system of
three double bonds in the molecule of the starting ketone
~ 3
(inclucl:lng also the double bond of the keto c3roupe C - 0) or
-to a dlpole Eormed by -the Eorced enolization oE the starting
ketone under -the reaction conditions used (cf. Gaertner R.,
Cllcm.Revs. ~ 93, 19~9). Suctl an addltion and subse~uent
hydrolysis had to be followed by elimination oE two hydrogen
atoms, i.e., by oxidation, probable under the action of the
air oxygen. This was the case of a rather rarely observed
reactlon sequence which had previously been studied in
reactions of s-terically st-rongly hindered aromatic ketones,
-Eor example 2~3,5,6-tetramethyl and 2,3,5,6-tetramethyl-2'
-methoxybenzophenone, with Grignard reagents (Fuson RoC~ et
al., J.Amer.ChemOSoc. 65, 60, 1943; 71, 25~13, 1949;
J.Org.Chem. 13, ~96, 1948).
As indicated above, the present invention provides
for a process for the preparation of compound I including
such measures that allow to remove -the compound III rom
~he amino alcohol II, which is then used in an almost pure
state for the dehydration, and also measures by which even
the last residues oE compound III are eliminated Erorn the
desired final product. These important additional operations
make use of a better solubility o compound III in ethanol.
The crude produc-t of the first reaction step, i.e., of the
Grignard reaction, is suspended in ethanol, the suspension
is heated to the boiling point and after cooling the almost
pure amino alcohol II is filtered by suction. This
substance is obtained in a yield of approx. 50%; the mother
liquors that contain rather considerable amount of compound
III do not allow to recover economically further crops of
the desired amino alcohol intermediate II. The last
residues of compound III are eliminated from the final
product I b-y crystallization -from ethanol; this impurity
remains in the mother solution. Finally, an integral part
of the present invention is the process for the prepara-tion
o~ a new hydrogen(~tartrate of compound I by its
neutra:Llzatiorl wLt~ )tartaric acLd ln aqueous ethanoL.
The hyclrogen(-~)tartrate readlly crystal]izes, :Is
modera-tely soluble :in water and much more suitable for the
preparation o~ Einal dosage forms than other acid addl-tion
sal-ts (s~lccinate, fumarate and hydrogen maleate), whlch
were previously described (cf. Rajsner M. et al., l.c.).
The process for the preparation of compound TII in pure
s-tate is not described herein below, because it is not
included in the present invention.
In accordance with this invention, compound I can
be prepared advantageously by the procedure of the following
example, which however does not limit the scope of the
invention.
Fifty ml of dry tetrahydroEuran are added to 24 g
of maynesium, and approx. 25~ of a solution of 134 g of
~-chloro-l-me-thylpiperidine (Adlerova et al., Cesk farm. 12,
122, 1963) in 300 ml of dry tetrahydrofuran (dried over the
molecular sieve Potasit 4 A) is let in and the mixture is
warmed in an oil bath preheated to a temperature of 50 to
55~C. Iodine (0.5 g) and 1 rlll of 1,2-dlbromoethane are
added and the mixture is allowed to stand from approx. 10 to
30 minu-tes until the reaction starts. When the mlxture
begins to reflux vividly, the oil bath is removed and the
remaining portion of the 4-chloro-1-methylpiperidine solu-
tion is dropped in at such a rate that the reactlon mixture
continues to reflux vividly. When the reaction begins to
run full rate, stirring is started. After approx. 40 -
50 minutes, when most of the solution was dropped in, the
reaction mixture is warmed moderately. The refluxing is
continued under stirring for another 1.5 hour. The
mixture is then cooled with ice-cold water to lO~C and
treated, within one hour, under constant stirring and ice-
water cooling, with a solutlon of 155 g of thieno(2,3-c)
-2-benzothiepin-4-(9H)-one (Protiva M., Rajsner M. et al.,
-- 10 --
Coll~ct.Czech.Ch~rn.Commlln. 29, 216.L, _964; 32, 2B5~, 19f,7;
39, 1366, 197~) in 325 ml. of dry tetrahydroEuran. The
re~c-tion mlxture ls ma:Lntained at a temperature of 10 to
15C. Wh~n the solution was clropped :Ln completely, the
cooling is d:iscon-tinued and the mixture is stirrecl fo:r
approx. 30 minutes unti] it warms spontaneously -to room
temperature. The resulting dark solution is treated, under
vigorous s-tirrlng, with a solution of 225 g of (~)tartaric
acid in 2 litres of water at such a rate that the tempera~
ture of the mixture does not exceed 20C (intensive external
cooling is at first necessary). After that, sno ml of
toluene is added and the mixture is stirred vigorously for
10 minutes. ~he toluene layer containing neutral
substances is then separated, the aqueous por-tion is washed
with 200 ml of toluene, 1600 ml of chloroform are added and
the mixture is made alkaline, under intensive stirring and
cooling, with 300 ml of concentra-ted aqueous ammonia. The
cllloroEorm layer is separatecl, the aqueous portion is
extracted with 200 ml of chloroform, and the combined
chloroform sol.utions are washed with 300 ml of water and
al.lowed to stand Eor 12 hours over 30 g of anhydrous
potassium carbonate and 10 g of active carbon. The solids
are then Eiltered off and washed with 50 ml of chloroform.
The chloroform is distilled off under moderately reduced
pressure (10 to 20 kPa), the residue is diluted.with 200 ml
o~ ethanol, and the mixture is shortly refluxed and cool.ed
to 5C. The precipitated crystalline 4~ methyl-4-
piperidyl)-4,9-dihydrothieno(2,3-c)-2-benzothiepin-4-ol (II)
is filtered with suction, washed successively with 100 ml o~
ethanol and 100 ml of petroleum ether, and dried at room
temperature under reduced pressure. The yield is 113 g
(51%) and the product melts at 209 - 211C. The obtained
ma-terial is almost pure and quite suitable for further
treatment. Crystallization of a sample from ethanol affords
-- 11 --
a completcly pure substancc havLncJ a m~p. of 212 - 213C.
A solution of 2q0 g oE su]phurlc acid in 1170 ml of
wa-ter is treated at ~0 to 50C with 166 ~ of the Eoregoing
amino alcohol II and the mixture is reEluxed Eor 15 minutes
with stirring. ~f-ter cooling, the mixture is diluted with
200 ml of water, 400 ml oE chloroform are added, and the
stirred mixture is made a]kaline with 220 g of concen-trated
aqueous ammonia, added dropwise. The -temperature of the
mixture is maintained at 20 to 30C. The chloroform layer
is separated and the aqueous portion is extracted with 2 X
100 ml of chloroform. The combined chloroform solutions are
washed with 150 ml of water, dried over 20 g of potassium
carbonate, and after standing overnight -the drying agent is
filtered off. The filtrate is evaporated under moderately
reduced pressure (10 to 20 kPa), the crystalline residue is
treated with 900 ml of ethanol and dissolved under stirring
by heating -to the boiling temperature. The solution is
decolorized while hot by Eiltration with 10 g o charcoal
and the filtrate is allowed to crystalli~e at 5C. AE-ter
~o 12 hours of standing, the crystallized base of 4~ methyl~
-~-piperidylidene) 4,9-dihydrothieno(2,3-c)-2-benzothiepin
~I) is collected by suc-tion and washed successively with
50 ml of ethanol and 100 ml of petroleum ether. On drying
at room -temperature, a yield of 124 g of the product is
obtained. Evaporation of the mother li~uor to a volume of
200 ml and standing at 5C affords the second crop of 14 g
of the product of a satisfactory puri-ty; the overall yield
is then 138 g (88%), m.p. 160 - 161C. The entire amount of
the material is suitable for the subsequent conversion to
the salt. Another crystallization of a sample yields the
completely pure base I melting at 162 - 164C.
Base I (g4 g) is dissolved in 650 ml of boiling
ethanol. After dissolution, heating is discontinued and a
hot solution of 47 g of (+) -tar-taric acid in 8S ml of water
- 12 -
3~
is adcled s:Low:Ly. T~-le solution formed :l5 then cooled to 10C
under stirring to lncluce crystalliza-tion. ~fter 12 hours of
cooling, the crystals are co:l:lected by suction and washed
with 2 x 50 ml of ethanol. The wet procluct is dissolved by
warming to the boiling -temperature in a mixture of 1250 ml
of ethanol and lO00 ml of wa-ter, -the solution is filtered
while hot and the filtrate is allowed for 4 hours under
stirring and cooling in an ice bath to crystall.ize. The
product is then washed with 2 x 30 ml ethanol and dried in
air at room temperature. The mother liquor is evaporated
under reduced pressure ~3 to 5 kPa) to approx. a half of the
initial volume and cooled to 5C to give the second crop of
the product. The total yield is 125 g (90~) of the hydrogen
(~)tartrate of the base I; -the salt melts (with decomposi-
tion) at 228 - 231C.
~ 13 -
