U.S. patent application number 10/141933 was filed with the patent office on 2003-06-05 for enantiomers of 1-[(4-chlorophenyl) phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine.
Invention is credited to Bodson, Guy, Cossement, Eric, Gobert, Jean.
Application Number | 20030105112 10/141933 |
Document ID | / |
Family ID | 10732080 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030105112 |
Kind Code |
A1 |
Cossement, Eric ; et
al. |
June 5, 2003 |
Enantiomers of 1-[(4-chlorophenyl)
phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine
Abstract
Levorotatory and dextrorotatory enantiomers of
1-[(4-chlorophenyl)phenylme-
thyl)-4-](4-methylphenyl)sulfonyl]piperazine of the formula 1 their
preparation and use for the preparation of substantially optically
pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine,
which are themselves valuable intermediate products for the
preparation of optically active therapeutic compounds having a very
high degree of optical purity.
Inventors: |
Cossement, Eric; (Bruxelles,
BE) ; Bodson, Guy; (Bellefontaine, BE) ;
Gobert, Jean; (Bruxelles, BE) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
10732080 |
Appl. No.: |
10/141933 |
Filed: |
May 10, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10141933 |
May 10, 2002 |
|
|
|
09356865 |
Jul 19, 1999 |
|
|
|
6436942 |
|
|
|
|
09356865 |
Jul 19, 1999 |
|
|
|
09087808 |
Jun 1, 1998 |
|
|
|
09087808 |
Jun 1, 1998 |
|
|
|
08947859 |
Oct 9, 1997 |
|
|
|
5792770 |
|
|
|
|
08947859 |
Oct 9, 1997 |
|
|
|
08460844 |
Jun 5, 1995 |
|
|
|
5703082 |
|
|
|
|
08460844 |
Jun 5, 1995 |
|
|
|
08207096 |
Mar 8, 1994 |
|
|
|
5478941 |
|
|
|
|
Current U.S.
Class: |
514/255.04 |
Current CPC
Class: |
A61P 37/08 20180101;
C07D 295/073 20130101; A61P 43/00 20180101; C07D 295/088 20130101;
A61P 25/22 20180101; C07D 295/26 20130101; A61P 29/00 20180101;
A61P 25/20 20180101; A61K 31/495 20130101; A61P 17/00 20180101;
A61P 11/06 20180101 |
Class at
Publication: |
514/255.04 |
International
Class: |
A61K 031/4965; A61K
031/495 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 15, 1993 |
GB |
9305282.7 |
Claims
We claim:
1. A method for inhibiting the effects of histamine in a patient
which comprises topically applying to the skin or the mucous
membrane of the patient an effective amount of substantially
optically pure dextrorotatory dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenylmethyl]- 1
-piperazinyl]ethoxy]ethanol.
Description
[0001] Enantiomers of
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)-
sulfonyl]piperazine.
[0002] The present invention relates to new compounds, the
substantially optically pure levorotatory and dextrorotatory
enantiomers of
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylpbenyl)sulfonyl]piperazine
of the formula 2
[0003] to a process for the preparation of these compounds and to
their use for the preparation of substantially optically pure
levorotatory and dextrorotatory enantiomers of
1-[(4-chlorophenyl)phenylmethyl]piperazine. The latter compounds,
are valuable intermediates for the preparation of substantially
optically pure therapeutically active compounds, in the
levorotatory and dextrorotatory forms.
[0004] These therapeutically active compounds may be used in the
treatment of asthma, allergies, inflammation and anxiety, and as
sedative or tranquilizing agents. A property frequently observed
with these compounds is their high degree of peripheral and/or
central antihistaminic activity, as the basis for their use as a
drug.
[0005] It is well known that the biological properties of many
compounds, such as for example drugs, hormones, herbicides,
insecticides or sweetening agents, are influenced by stereochemical
factors. The importance of the relationships between the optical
activity and the biological properties, has been stressed since
1926 (A. R. CUSHNY, Biological Relations of Optically Isomeric
Substances, Williams and Williams Co., Baltimore, 1926). Since that
time, many examples abound which have confirmed the now generally
accepted principle that a racemic compound and its levorotatory and
dextrorotatory enantiomers should be considered as entirely
distinct pharmacological entities. The optical activity, which is
an image of the asymmetrical structure of an organic compound is
one of the important factors which govern the pharmacological
activity of this compound and its biological response. Indeed,
according as to whether the levorotatory or dextrorotatory form of
a drug is used, considerable differences in the properties, such as
its transport, its distribution in the organism or its elimination
can appear. These properties are decisive for the concentration of
the drug in the organism or its exposure time at the site of
activity. Furthermore, the pharmacological activity of the two
isomers can differ considerably. For example, one enantiomer may be
much more active than the other or, in a border-line case, this
enantiomer could possess alone all the pharmacological activity,
the other being totally inactive and serving only as a simple
diluent. It can also occur that the pharmacological activities of
the two isomers are different, which produces consequently two
compounds having distinct therapeutic properties. Moreover, the
metabolism and the toxicity can be very different from one isomer
to another, so much so that one of the optically active isomers can
be more toxic than the other. One of the most striking examples in
this field is that of thalidomide, where the two enantiomers
possess similar hypnotic effects but only the S enantiomer has
teratogenic effects.
[0006] Finally, it has also to be added that the optical isomers
are useful as probes which are of uttermost importance in the study
of chemical interactions with physiological mechanisms (for
example, the selectivity of binding to a receptor).
[0007] That is the reason why many pharmaceutical laboratories
devote much time and efforts to isolate or synthesize the
enantiomers of pharmacologically active compounds and to study the
therapeutic properties thereof.
[0008] A process for the preparation of the enantiomers of
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic
acid dihydrochloride, known as a non-sedative antihistamine drug
under the generic name of cetirizine, is described in British
Patent No. 2,225,321. This process is based on the use of
levorotatory or dextrorotatory
1-((4-chlorophenyl)phenylmethyl]piperazine as starting material. In
that patent, the enantiomers of
1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained by chemical
resolution of the racemic form, using conventional methods, in
particular, by salt formation with a suitably selected optical
isomer of tartaric acid.
[0009] The major disadvantages of this process are, on the one
hand, that the yield of the resolution step of the racemic
1-[(4-chlorophenyl)phenyl- methyl]piperazine is extremely low (only
12.1%) and, on the other hand, that the optical purity of the
dextrorotatory and levorotatory enantiomers so obtained is
insufficient and does not allow the final product to be prepared
with an optical purity greater than 95%.
[0010] Consequently, it appears to be very desirable to provide new
routes for preparing the enantiomers of
1-[(4-chlorophenyl)phenylmethyl]piperazi- ne with improved optical
purity and in better yields and, thereby, to provide excellent
starting materials to produce optically active isomers of useful
drugs with a very high degree of optical purity.
[0011] But, to achieve this object, it is necessary to find
precursors having already the correct stereochemical configuration.
and which, on the one hand, can be themselves prepared relatively
simply and economically with satisfactory optical purity, and, on
the other hand, which can be converted easily and with high yields
into the substantially optically pure enantiomers of
1-[(4-chlorophenyl)phenylmethyl]piperazine.
[0012] We have now discovered a new compound,
1-[(4-chlorophenyl)phenylmet-
hyl]-4-[(4-methylphenyl)sulfonyl]piperazine, the levorotatory and
dextrorotatory forms of which comply perfectly with this
object.
[0013] Accordingly, the present invention provides as new
compounds, the levorotatory and dextrorotatory enantiomers of
1-[((4-chlorophenyl)phenyl-
methyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula 3
[0014] According to the present invention, the enantiomers of the
compound of formula I are advantageously in a substantially
optically pure form.
[0015] In the present specification, by "substantially optically
pure", is meant an optical purity greater than 98% and this optical
purity corresponds to the percent excess of the optically active
isomer present in major amount with respect to the optically active
isomer present in minor amount, and determined by high performance
liquid phase chromatography (HPLC) on a chiral stationary
phase.
[0016] This optical purity can be defined by the equation described
on page 107 of the book of J. MARCH, "Advanced Organic Chemistry",
John Wiley & Sons, Inc., New York, 3.sup.rd Edition, 1985: 1
Optical purity ( in % ) = [ ( + ) ] - [ ( - ) ] [ ( + ) ] + [ ( - )
] .times. 100
[0017] Where [(+)]=concentration of the dextrorotatory enantiomer;
and
[0018] [E]=concentration of the levorotatory enantiomer.
[0019] The present invention further relates to a process for
preparing the levorotatory and dextrorotatory enantiomers of
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine
of formula I, which comprises reacting an enantiomer of
(4-chlorophenyl)phenylmethylamine of the formula 4
[0020] with a N,N-diethyl-4-methylbenzenesulfonamide of the formula
5
[0021] wherein X is a chlorine, bromine or iodine atom or the
(4-methylphenyl)sulfonyloxy or methylsulfonyloxy group, in the
presence of 2.2 to 4.4 equivalents of an organic or inorganic base
per equivalent of the enantiomer of
(4-chlorophenyl)phenylmethylamine and at the boiling point of the
reaction mixture.
[0022] Bases suitable for use to prepare compounds of formula I
include organic bases such as ethyldiisopropylamine,
N-ethylmorpholine, 2,4,6-trimethylpyridine or triethylamine,
preferably ethyldiisopropylamine, and inorganic bases such as
sodium carbonate.
[0023] The levorotatory and dextrorotatory enantiomers of
(4-chlorophenyl)phenylmethylamine of formula II, used as starting
materials are known compounds; they can be prepared by chemical
resolution of racemic (4-chlorophenyl)phenylmethylamine by known
methods using tartaric acid. These enantiomers can be prepared with
an optical purity of at least 98%.
[0024] The compounds of formula III used as starting materials are
also known products which can be easily obtained starting from
bis(2-hydroxyethyl)amine and using known methods.
[0025] The present invention further relates to the use of the new
levorotatory and dextrorotatory enantiomers of
1-[(4-chlorophenyl)phenylm- ethyl]-4-8
(4-methylphenyl)sulfonyl]piperazine of formula I, for the
preparation of the substantially optically pure enantiomers of
1-[(4-chlorophenyl)phenylmethyl]piperazine of the formula 6
[0026] According to the present invention, the levorotatory and
dextrorotatory enantiomers of the compound of formula IV are
prepared by a process, which comprises subjecting an enantiomer of
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine
of formula I to hydrolysis with hydrobromic acid, in acetic acid
medium and in the presence of a phenolic compound, preferably
4-hydroxybenzoic acid.
[0027] This hydrolysis is generally carried out at a temperature of
between 18 and 100.degree. C., preferably at a temperature of about
25.degree. C.
[0028] The advantages resulting from the use of
1-[((4-chlorophenyl)phenyl-
methyl]-4-[((4-methylphenyl)sulfonyl]piperazine of formula I, in
the form of its levorotatory or dextrorotatory enantiomers;
according to the invention, are numerous.
[0029] These advantages appear not only at the level of the route
which leads to the enantiomers of the compound of formula I but
also at the level of the conversion step of these enantiomers to
prepare the substantially optically pure enantiomers of
1-[(4-chlorophenyl)phenylmeth- yl]piperazine of formula IV.
[0030] First of all, we have found that the enantiomers of the
compound of formula I, with a 4-methylphenylsulfonyl group on the
amine function, were practically the sole capable of being
synthesized in a wholly satisfactory manner. Indeed, if, in the
preparation of these compounds, it is attempted to replace the
N,N-diethyl-4-methylbenzenesulfonamide of formula III by a
corresponding compound, in which the 4-methylphenylsulfonyl group
has been replaced by hydrogen or by another protecting group of the
amine function such as for example a carbonyl, alkyl or
triphenylmethyl group, an important racemization of the Starting
compound of formula II and or of the compound of formula I, or the
production of many undesirable by-products, is observed during the
formation of the enantiomer of the compound of formula I.
[0031] Moreover, the starting materials of formula III, wherein the
4-methylphenylsulfonyl group would have been replaced by hydrogen,
are known to be extremely toxic due to the presence of a free-amine
group (nitrogen mustards).
[0032] However, all of these significant disadvantages can be
avoided by using the N,N-diethyl-4-methylbenzenesulfonamide of
formula III, as starting material. Indeed, the enantiomers of
1-[(4-chlorophenyl)phenylme-
thyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I,
according to the invention, are prepared by a process which does
not cause racemization and provides a high yield, which can reach
89%, and these enantiomers are obtained with an optical purity
greater than 98% which, in many cases, approaches 100%, using
sulfonated raw materials of relatively low toxicity and much less
hazardous to manipulate. This last point means also a considerable
advantage as regards the industrial application of the process
according to the invention.
[0033] Moreover, the use of the enantiomers of the compound of
formula I is particularly advantageous for the preparation of the
enantiomers of 1-[((4-chlorophenyl)phenylmethyl]piperazine of
formula IV. Indeed,
[0034] on the one hand, the enantiomers of
1-[(4-chlorophenyl)phenylmethyl- ]piperazine of formula IV are
obtained with a yield much greater than 80%. This yield is
considerably higher than that achievable using the process
described in British patent No. 2,225,321;
[0035] on the other hand, since the hydrolysis reaction, leading to
the formation of the enantiomers of the compound of formula IV, is
non-racemizing, these enantiomers are obtained with an optical
purity which is much greater than 95%, even approaching 100%.
[0036] The enantiomers of
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphe-
nyl)sulfonyl]piperazine of formula I, according to the invention,
thus, open up a highly favorable preparative route to the
enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazines of the
formula IV.
[0037] The substantially optically pure levorotatory and
dextrorotatory enantiomers of
1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV, so
prepared, are of interest mainly as precursors in the preparation
of substantially optically pure therapeutically active levorotatory
and dextrorotatory forms of
1-[(.sup.4-chlorophenyl)phenylmethyl]piperazines of the formula
7
[0038] wherein R is a methyl, (3-methylphenyl)methyl,
(4-tert-butylphenyl)methyl, 2-(2-hydroxyethorxy)ethyl,
2-[(2-(2-hydroxyethoxy]ethoxy]ethyl, 2-(carbamoylmethoxy)ethyl,
2-(methoxycarbonylmethoxy)ethyl or 2-(carboxymethoxy)ethyl
radical.
[0039] These compounds, which are already known in the racemic
form, possess valuable pharmacological properties and may be used
for the treatment of asthma, allergies and inflammation or as
sedative, tranquilizing or anxiolytic agents.
[0040] The preferred compounds of formula V are the levorotatory
and dextrorotatory enantiomers of
1-[(4-chlorophenyl)phenylmethyl]-4-methylpi- perazine, of
1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]pi-
perazine, of
1-[(4-tert-butylphenyl)methyl)-4-[(4-chlorophenyl)phenylmethy-
l]piperazine, of
2-[(2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl)
ethoxy]ethanol, of
2-[2-[2-[4-((4-chlorophenyl)phenylmethyl]-1-piperaziny-
l]ethoxy)ethoxy]ethanol, of
2-[(2-[(4-[(4-chlorophenyl)phenylmethyl]-1-pip-
erazinyl]ethoxy]acetamide, of methyl
2-[(2-[(4-[(4-chlorophenyl)phenylmeth-
yl]-1piperazinyl]ethoxy]acetate and of
2-[2-4-[(4-chlorophenyl)phenylmethy- l)-1-piperazinyl]ethoxy]
acetic acid and the pharmaceutically acceptable salts of these
enantiomers.
[0041] The preparation of these substantially optically pure
enantiomers can be carried out by means of known methods which
comprise reacting an enantiomer of the compound of formula IV,
while hot, with a halide of the formula RX wherein R has the
meaning given above and X represents a halogen atom. The
enantiomers of formula V are new compounds, with the exception of
the compounds where R is a 2-(carboxymethoxy)ethyl radical, and
possess valuable antihistaminic properties; in particular, they
exhibit a very distinct difference in behavior as regards the
inhibition of the histamine Hi receptor, one of the enantiomers
being a competitive inhibitor and the other a non-competitive
inhibitor.
[0042] The pharmacological tests described below demonstrate these
properties.
[0043] The following Examples illustrate the invention without,
however, limiting it. In these Examples, the melting points are
determined by differential scanning calorimetry (D.S.C.) with a
temperature gradient of 20.degree. C./min. The optical purity as
defined hereinbefore was determined by high performance liquid
phase chromatography, on a chiral stationary phase (CHIRALPAK AD
column, 250.times.4.6 mm; eluent: 50:50:0.1 (v/v/v) mixture of
hexane-ethanol-diethylamine; pressure 104 bar; temperature
25.degree. C.; flow rate 1 ml/min).
EXAMPLE 1
Preparation of the Levorotatory and Dextrorotatory Enantiomers of
(4-chlorophenyl)phenylmethylamine of Formula II
[0044] 1. Levorotatory (-)-(4-chlorophenyl)phenylmethylamine
[0045] This compound is prepared by resolution of racemic
(4-chlorophenyl)phenylmethylamine by means of (+)-tartaric acid
according to the method described by R. CLEMO et al. (J. Chem.
soc., (1939), p. 1958-1960).
[0046] 2. Dextrorotatory (+)-(4-chlorophenyl)phenylmethylamine
[0047] This compound is prepared by resolution of racemic
(4-chlorophenyl)phenylmethylamine by means of (-)-tartaric acid
according to the method described by R.CLEMO et al. (loc.cit.).
[0048] 3. Recovery of the Unrequired Enantiomer of
(4-chlorophenyl)phenylm- ethylamine
[0049] With the aim of recovering and recycling the unrequired
enatiomer of (4-chlorophenyl)phenylmethylamine, the compound is
subjected to a racemization reaction and the resulting racemic
(4-chlorophenyl)phenylmet- hylamine is then subjected to a new step
of resolution by means of an isomer of tartaric acid according to
the method described at point 1 or 2 above.
[0050] 4.35 g (0.02 mole) of dextrorotatory
(+)-(4-chlorophenyl)phenylmeth- ylamine, 244 mg (0.002 mole) of
2-hydroxybenzaldehyde and 1.1 g (0.02 mole) of sodium methoxide are
suspended in 21.8 ml of methanol. The mixture is heated under
reflux for five and a half hours, then allowed to return to ambient
temperature and 6.7 ml of concentrated hydrochloric acid are added
dropwise to the mixture. The methanol is evaporated, the residue
taken up in 50 ml of water, and a further 25 ml of concentrated
hydrochloric acid are added thereto. After 1 hour, the white
precipitate which forms is filtered off, washed with water and
dried under vacuum at 40.degree. C. 3.7 g of racemic
(4-chlorophenyl)phenylmethylamine are obtained. Yield: 73%.
[.alpha.].sub.D.sup.25:0.degree.(c=1, methanol).
EXAMPLE 2
Preparation of N,N-diethyl-4-methylbenzenesulfonamides of Formula
III
[0051] 1.
4-methyl-N,N-bis[2-[(4-methylphenyl)sulfonyloxy]ethyl]benzenesul-
fonamide (formula III, X=(4-methylphenyl)sulfonyloxy)
[0052] This compound is prepared from N,
N-bis(2-hydroxyethyl)-4-methylben- zenesulfonamide according to the
method described by D. H. PEACOCK and U. C. DUTTA (J. Chem. Soc.,
(1934) p. 1303-1305).
[0053] M.P.: 75.9.degree. C. Yield 79.7%.
[0054] 2.
4-methyl-N,N-bis(2-(methylsulfonyloxy)ethyl]benzenesulfonamide.
(formula III, X=methylsulfonyloxy)
[0055] A solution of 11.4 g (0.1 mole) of methanesulfonyl chloride
in 17.1 ml of dichloromethane is cooled to 5.degree. C. A solution
of 13 g (0.05 mole) of
N,N-bis(2-hydroxyethyl)-4-methylbenzenesulfonamide and 10.1 g (0.1
mole) of triethylamine in 52 ml of dichloromethane is then added
dropwise with stirring. The resulting mixture is allowed to return
to ambient temperature and stirred for a further 3 hours. The
reaction mixture is then extracted three times with 40 ml water.
The organic phase is dried over sodium sulfate, filtered and
concentrated in a rotating evaporator. The resulting oil is then
crystallized from ethanol. 17.8 g of
4-methyl-N,N-bis(2-methylsulfonyloxy)ethyl]benzenesulfonamide are
obtained. ;
[0056] M.P.: 64.6GC. Yield: 85.7 %.
[0057] 3. N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide.
(formula III, X=C1)
[0058] This compound is prepared using the method described by K.
A. AL-RASHOOD et al. (Arzneim.-Forsch./Drug Res. 40(II) (1990),
p.1242-1245).
[0059] M.P.: 45.8.degree. C. Yield: 69.0 %.
[0060] 4. N, N-bis(2-iodoethyl)-4-methylbenzenesulfonamide.
(formula III, X=I)
[0061] 5.7 g (0.01 mole) of 4-methyl-N,N-bis[2-[(4-methylphenyl)
sulfonyloxy]ethyl]benzenesulfonamide (prepared as indicated in 1
above) are dissolved in 57 ml of acetone and 4.5 g (0.03 mole) of
sodium iodide are added thereto. The resulting mixture is heated
under reflux for 22 hours. It is then allowed to cool and the
acetone is evaporated off. The solid residue is taken up in a
mixture of 10 ml of water and 25 ml of dichloromethane and the two
phases are separated. The aqueous phase is extracted with 25 ml of
dichloromethane and the organic phases are combined. The combined
organic phase is washed successively with 10 ml of a 10% aqueous
solution of sodium thiosulfate and then with 10 ml of water. The
organic phase is then dried over sodium sulfate, filtered and
evaporated. The white solid obtained is dried under vacuum at
25.degree. C. 4.7 g of N,
N-bis(2-iodoethyl)-4-methylbenzenesulfonamide are obtained.
[0062] M.P. 93.8.degree. C. Yield: 98%.
[0063] 5. N,N-bis(2-bromoethyl)-4-methylbenzenesulfonamide.
(formula III, X=Br)
[0064] This compound is prepared using the method described at
point 4 above, except that sodium bromide is used in place of
sodium iodide and the reaction mixture is heated in acetone under
reflux for 16 days.
[0065] M.P.: 69.2.degree. C. Yield 98.7%.
EXAMPLE 3
Preparation of Enantiomers of
1-[(4-Chlorophenyl)Phenylmethyl)-4-[(4-Methy-
lphenyl)Sulfonyl]Piperazine of Formula I
[0066] A1. Levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl)-4-[(4-methylp-
henyl)sulfonyl]piperazine
[0067] 3.4 g (0.0156 mole) of levorotatory
(-)-(4-chlorophenyl)phenylmethy- lamine (prepared in Example 1.1)
and 5.1 g (0.0172 mole) of
N,N-biss(2-chloroethyl)-4-methylbenzenesulfonamide (prepared in
Example 2.3) in 6 ml (4.4 g or 0.0343 mole) of
ethyldiisopropylamine are mixed in a 25 ml round-bottomed flask.
The mixture is heated under reflux (127.degree. C.) for 4 hours and
then cooled, with stirring, to 86.degree. C. and 13.8 ml of
methanol are added at once. The mixture is then cooled in an ice
bath and still stirred for 1 hour. The precipitate which forms is
filtered off, washed with 10 ml of methanol and dried under vacuum
at 40.degree. C. The product is recrystallized from a 3:1(v/v)
mixture of methanol and acetone. 6 g of levorotatory
(-)-1-((4-chlorophenyl)phenylmethyl]-4-1(4-methylphenyl)sulfonyl]piperazi-
ne are obtained.
[0068] M.P. 171.1.degree. C. Yield: 87.2%.
[0069] [.alpha.].sub.D.sup.25:-40.680(c=1, toluene)
[0070] Optical purity: 100%
[0071] Analysis for C.sub.24H.sub.25ClN.sub.2O.sub.2S in %:
1 Calc.: C 65.37 H 5.71 N 6.35 Cl 8.04 S 7.27 Found: .sup. 65.95
5.80 6.60 .sup. 8.12.sup. 7.33
[0072] A2 to A5. Influence of the Nature of the Base
[0073] Levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylpheny-
l)sulfonyl]piperazine is also prepared from
N,N-bis(2-chloroethyl)-4-methy- lbenzenesulfonamide using the
method described at point A1 above, but with various other bases in
place of ethyldiisopropylamine.
[0074] The results obtained are set out in Table I, wherein the
first column indicates the number of the Example, the second
column, the base used, the third column, the amount of base used,
expressed in equivalents per equivalent of
(-)-(4-chlorophenyl)phenylmethylamine, the fourth column, the time
(in hours) during which the reaction mixture is kept under reflux,
the fifth column, the yield of levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazi-
ne obtained and the sixth column, the optical purity of the product
obtained, expressed in percent.
2TABLE I Amount Optical of base Time Yield Purity Example 3 Base
(eq.) (hours) (%) (%) A1 ethyldiisopropylamine 2.2 4 87.2
.apprxeq.100 A2 2,4,6-trimethylpyridine 3.0 1.5 64.2 .apprxeq.100
A3 N-ethylmorpholine 2.2 4 61.2 .apprxeq.98.4 A4 triethylamine 3.0
48 59.7 .apprxeq.100 A5 Na.sub.2CO.sub.3/xylene(*) 3.0 28 56.7
.apprxeq.100 (*)Auxiliary solvent for reaction
[0075] From this Table, it can be seen that the nature of the base
has only a small influence on the optical purity of the product
obtained. However, it appears that ethyldiisopropylamine is much
more advantageous as regards the yield of the reaction.
[0076] A6 to A9. Influence of the Nature of the
N,N-diethyl-4-methylbenzen- esulfonamide of Formula III
[0077] Levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylpheny-
l)sulfonyl]piperazine is also prepared using the method described
at point A1 above, but the
N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide of formula III
(X=Cl) used as starting material is replaced by the corresponding
brominated (X=Br), iodinated (X=I), tosylated
(X=(4-methylphenyl)sulfonyloxy) or mesylated (X=methylsulfonyloxy)
derivative, prepared respectively in Examples 2.5, 2.4, 2.1 and
2.2.
[0078] In Table II, the first column gives the number of the
Example, the second column, the nature of the substituent X in the
starting material of formula III, the third column, the amount of
the compound of formula III used, expressed in equivalents per
equivalent of (-)-(4-chlorophenyl)phenylmethylamine, the fourth
column, the time, expressed in hours during which the reaction
mixture is kept under reflux, the fifth column, the yield of
levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazi-
ne obtained and the sixth column, the optical purity of the product
expressed in percent.
3TABLE II Compound of Amount Optical formula III of III Time Yield
Purity Example 3 Substituent X (eq.) (hours) (%) (%) A1 Cl 1.1 4
87.2 .apprxeq.100 A6 Br 1 1 88.9 .apprxeq.100 A7 methylsulfonyloxy
1 2 84.6 .apprxeq.100 A8 I 1 1 84.1 .apprxeq.99.4 A9
(4-methylphenyl) 1 1 83.8 .apprxeq.100 sulfonyloxy
[0079] From this Table, it can be seen that the nature of the
compound of formula III has only a small influence on the optical
purity of the product obtained. Moreover, the compound of formula
III has only a very small influence on the yield of the reaction,
although the best yield is obtained using the bromine
derivative.
[0080] B. Dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl)-4-[(4-methyl-
phenyl)sulfonyl]piperazine
[0081] 57 g (0.2618 mole) of dextrorotatory
(+)-(4-chlorophenyl)phenylmeth- ylamine (prepared in Example 1.2)
and 86.4 g (0.2917 mole) of
N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (prepared in
Example 2,3) are added to 200 ml (1.15 mole) of
ethyldiisopropylamine in a 500 ml three-necked round-bottomed
flask. The mixture is heated under reflux for 3 hours, then poured
in 400 ml of methanol and the mixture is cooled, in an ice bath,
and stirred for 1 hour. The precipitate which forms is filtered
off, washed with methanol and dried under vacuum at 50.degree. C.
88.6 g of dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-me-
thylphenyl)sulfonyl]piperazine are obtained.
[0082] M.P. 173.3.degree. C. Yield: 76.7%.
[0083] [.alpha.].sub.D.sup.25:+43.2.degree. (c=0.5, toluene).
[0084] Optical purity: 98.35%.
[0085] Analysis for C.sub.24H.sub.25ClN.sub.2O.sub.2S in %
4 Calc.: C 65.38 H 5.71 N 6.35 C 8.04 S 7.27 Found: .sup. 64.98
5.70 6.40 .sup. 7.96 7.35
EXAMPLE 4
Preparation Of Levorotatory And Dextrorotatory Enantiomers of
1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV
[0086] 1. Levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine
[0087] 370 g (0.839 mole) of levorotatory
(-)-1-[(4-chlorophenyl)phenylmet-
hyl]-4-[(4-methylphenyl)sulfonyl]piperazine (prepared in Example
3.A1) and 405 g of 4-hydroxybenzoic acid are added to 1 liter of a
30% solution of hydrobromic acid in acetic acid. The suspension is
stirred for 17 hours at 25.degree. C. 2 liters of water are then
added thereto and the suspension is cooled in an ice bath. The
precipitate which forms is filtered and washed with 750 ml of
water. 2 liters of toluene and 0.9 liters of a 50% aqueous solution
of sodium hydroxide are then added to the filtrate. The organic
phase is decanted off and washed with 100 ml of water and then once
again with 1 liter of a saturated aqueous solution of sodium
chloride. The organic phase is dried over sodium sulfate, filtered
and the solvent evaporated off under reduced pressure. The residue
is recrystallized from 600 ml of boiling hexane. The solution is
filtered while hot, so as to remove any slightly insoluble material
and the filtrate is then allowed to crystallize, first at ambient
temperature, and then for 24 hours in an ice bath. The crystals are
filtered off, washed with hexane and dried under vacuum at
40.degree. C. 204.15 g of levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained.
[0088] M.P.: 90.5.degree. C. Yield: 84.8%.
[0089] [.alpha.].sub.D.sup.25:14.25.degree. (c=1, methanol).
[0090] Optical purity: .gtoreq.99.8 %.
[0091] Analysis for C.sub.17H.sub.19CIN.sub.2 in %:
5 Calc.: C 71.19 H 6.68 N 9.77 Cl 12.36 Found: .sup. 71.19 6.84
9.55 .sup. 11.48.sup.
[0092] 2. Dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine
[0093] Dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine is prepared using
the method described at point 1 above, but the starting
levorotatory enantiomer of
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylp-
henyl)sulfonyl]piperazine is replaced by the dextrorotatory
enantiomer (prepared in Example 3.B).
[0094] M.P.: 91.5.degree. C. Yield: 97.9%.
[0095] [.alpha.]:+14.94.degree. (c=1, methanol).
[0096] Optical purity: 100%.
[0097] Analysis for C.sub.17 H.sub.19 ClN.sub.2 in %:
6 Calc.: C 71.19 H 6.68 N 9.77 Cl 12.36 Found: .sup. 70.90 6.74
9.72 .sup. 12.23.sup.
EXAMPLE 5
Use Of The Enantiomers of
1-[(4-chlorophenyl)phenylmethyl]Piperazine in the Preparation of
Therapeutically Active Compounds of Formula V
[0098] 1. Levorotatory Dihydrochloride of
1-[(4-chlorophenyl)phenylmethyl]-
-4-[(3-methylphenyl)methyl]Piperazine
[0099] A solution containing 10 g (0.0348 mole) of dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example
4.2) in 100 ml of n-butanol is heated at 50.degree. C. 5.5 ml
(0.0417 mole) of 1-chloromethyl-3-methylbenzene, 8.9 g (0.0836
mole) of sodium carbonate and 0.5 g (0.0030 mole) of potassium
iodide are added thereto and the mixture is heated at reflux
temperature for 3 hours. The mixture is then cooled and the solid
residues removed by filtration and washed with 200 ml of toluene.
The organic phases are combined and the solvents evaporated until a
residual oil is obtained. The oil is redissolved in 500 ml of
ethanol to which 15 ml of concentrated hydrochloric acid, dissolved
in 35 ml of ethanol, are added. This solution is cooled in an ice
bath, the resulting precipitate filtered off and the filtrate
evaporated. The residue obtained after evaporation and the
precipitate are combined and suspended in 100 ml of isopropyl
alcohol. The suspension is filtered and the solids are washed with
a small amount of isopropyl alcohol and dried under vacuum at
50.degree. C. 12.7 g of the levorotatory dihydrochloride of
1-[(4-chlorophenyl)phenylmethyl]-4-[(3-me-
thylphenyl)methyl]piperazine are obtained.
[0100] M.P.: 252.3.degree. C. Yield: 78.6%.
[0101] [.alpha.].sub.365.sup.25:-27.960(c=1, methanol).
[0102] Optical purity: 100%.
[0103] Analysis for C.sub.25H.sub.27ClN.sub.2.2HCl in %:
7 Calc.: C 64.73 H 6.30 N 6.04 Cl.sup.- 15.29 Found: .sup. 64.45
6.42 5.93 .sup. 15.18
[0104] 2. Dextrorotatory Dihydrochloride of
1-[(4-chlorophenyl)phenylmethy-
l]-4-[(3-methylphenyl)methyl]piperazine
[0105] The procedure described at point 1 above is followed using
the levorotatory 1-[(4-chlorophenyl)phenylmethyl]piperazine
(prepared in Example 4.1) in place of the dextrorotatory enantiomer
and using the same quantities of reagents. 13 g of the
dextrorotatory dihydrochloride of
1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine
are obtained.
[0106] M.P.: 252.9.degree. C. Yield: 80.4%.
[0107] [.alpha.].sub.365.sup.25:+27.5.degree. (c=1, methanol).
[0108] Optical purity: 100%.
[0109] Analysis for C.sub.25H.sub.27ClN.sub.2.2 HCl in %
8 Calc.: C 64.73 H 6.30 N 6.04 Cl.sup.- 15.29 Found: .sup. 64.47
6.32 5.88 .sup. 15.18
[0110] 3. Levorotatory Dihydrochloride of
1-[(4-tert-butylphenyl)methyl]-4-
-[(4-chlorophenyl)phenylmethyl]piperazine
[0111] A solution containing 10 g (0.0348 mole) of dextrorotatory
(+)-1-[4-chlorophenyl)phenylmethyl]piperazine (prepared in Example
4.2) in 100 ml of n-butanol is heated to 50.degree. C. 7.6 ml
(0.0418 mole) of 1-chloromethyl-4-tert-butylbenzene, 8.9 g (0.0836
mole) of sodium carbonate and 0.5 g (0.0030 mole) of potassium
iodide are added thereto and the mixture is heated at reflux
temperature for 1 hour. It is then cooled and the solids are
removed by filtration and washed with 200 ml of toluene. The
organic phases are combined and the solvents evaporated until a
residual oil is obtained. This oil is redissolved in 300 ml of
acetone, and 15 ml of concentrated hydrochloric acid, dissolved in
35 ml of acetone, are added thereto, followed by a further 200 ml
of acetone. The mixture is cooled in an ice bath and the
precipitate which forms is filtered off and dried under vacuum at
50.degree. C. 14.68 g of the levorotatory dihydrochloride of
1-[(4-tert-butylphenyl)methyl]-4-[(4-chlo-
rophenyl)phenylmethyl]piperazine are obtained.
[0112] M.P.: 257.7.degree. C. Yield: 83.3%.
[0113] [.alpha.].sub.365.sup.25: -13.26.degree.. (c=0.2,
methanol).
[0114] Optical purity: .apprxeq.100%.
[0115] Analysis for C.sub.28H.sub.33 ClN.sub.2.2HCl in %:
9 Calc.: C 66.47 H 6.97 N 5.54 Cl.sup.- 14.01 Found: .sup. 66.35
7.39 5.45 .sup. 13.85
[0116] 4 . Dextrorotatory dihydrochloride of
1-[(4-tert-butylphenyl)methyl-
)-4-[(4-chlorophenyl)phenylmethyl]Piperazine
[0117] This compound is prepared by using the method described at
point 3 above, but starting with 4 g of levorotatory
(-)-1-[(4-chlorophenyl)pheny- lmethyl]piperazine (prepared in
Example 4.1). 4.75 g of the dextrorotatory dihydrochloride of
1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phen-
ylmethyl]piperazine are obtained.
[0118] M.P.: 273.9.degree. C. Yield: 67.4%.
[0119] [.alpha.].sub.365.sup.25: +11.33.degree. (c=0.2,
methanol).
[0120] Optical purity: .apprxeq.100%.
[0121] Analysis for C.sub.28H.sub.33ClN.sub.2%
10 Calc.: C 66.47 H 6.97 N 5.54 Cl.sup.- 14.01 Found: .sup. 66.37
7.16 5.27 .sup. 13.85
[0122] 5. Levorotatory Dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenylm-
ethyl]-1-piperazinyl]ethoxy]ethanol
[0123] A solution containing 10 g (0.0348 mole) of dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example
4.2) in 100 ml of n-butanol is heated to 50.degree. C. 5 ml (0.0464
mole) of 2-(2-chloroethoxy)ethanol, 8.9 g (0.0836 mole) of sodium
carbonate and 0.5 g (0.0030 mole) of potassium iodide are added
thereto and the mixture is heated at reflux temperature for 16
hours. A further 2 ml of 2-(2-chloroethoxy)ethanol are added and
refluxing is continued for a further 4 hours. The mixture is cooled
and filtered and the precipitate washed with 200 ml of toluene. The
organic phases are evaporated until an oil is obtained and this is
dissolved in 100 ml of ethanol. 12 ml of concentrated hydrochloric
acid, dissolved in 38 ml of ethanol, are added thereto. The solvent
is evaporated and the residue recrystallized from ethanol. The
precipitate is filtered off and washed with a small amount of
isopropyl alcohol (first crop). The filtrate is evaporated and the
solid residue washed with a small amount of isopropyl alcohol
(second crop). The two crops are recrystallized together from a
30:1(v/v) mixture of isopropyl alcohol and methanol. 10.57 g of the
levorotatory dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]e-
thoxy]ethanol are obtained.
[0124] M.P.: 229.8.degree. C. Yield: 67.8%.
[0125] [.alpha.].sub.365.sup.25: -6.07.degree.(c1, water).
[0126] Optical purity: .apprxeq.100%.
[0127] Analysis for C.sub.21H.sub.27ClN.sub.2O.sub.2.2HCl in %
11 Calc.: C 56.32 H 6.53 N 6.26 Cl.sup.- 15.83 Found: .sup. 56.32
6.79 6.08 .sup. 15.63
[0128] 6. Dextrorotatory Dihydrochloride of
2-[2-[4-[(4-chlorophenyl)pheny-
lmethyl]-1-piperazinyl]ethoxy]Ethanol
[0129] Using the same amounts of reagents as used in the method
described at point 5 above, the dextrorotatory enantiomer is
prepared in the same way, but starting with levorotatory
(-)-1-((4-chlorophenyl)phenylmethyl]p- iperazine (prepared in
Example 4.1). 11.7 g of the dextrorotatory dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl)e-
thoxy]ethanol are obtained.
[0130] M.P.: 231.3.degree. C. Yield: 70.5%.
[0131] [.alpha.].sub.365.sup.25: .apprxeq.5.16.degree. (c1,
water).
[0132] Optical purity: .apprxeq.100%.
[0133] Analysis for C.sub.21H.sub.27CIN.sub.2O.sub.2.2HCl in %
12 Calc.: C 56.32 H 6.52 N 6.25 Cl.sup.- 15.83 Found: .sup. 55.75
6.54 6.10 .sup. 15.81
[0134] 7. Levorotatory Dihydrochloride of
2-[2-[2-[4-[(4-chloropbenyl)phen-
ylmethyl]-1-piperazinyl)ethoxy]ethoxy]ethanol
[0135] A solution containing 10 g (0.0348 mole) of dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example
4.2) in 100 ml. of n-butanol is heated to 40.degree. C. 6.1 ml
(0.0419 mole) of 2-[2-(2-chloroethoxy)ethoxy]ethanol, 8.9 g (0.0836
mole) of sodium carbonate and 0.5 . g (0.0030 mole) of potassium
iodide are added thereto. The mixture is heated at reflux
temperature for six hours. It is then cooled and the solids are
removed by filtration and washed with a small amount of toluene.
The filtrate and the washing solvent are combined and the solvents
evaporated. The residue is taken up in 50 ml of toluene which is
then evaporated. The residue obtained is taken up again in 100 ml
of toluene, washed with a 100 ml of water and the organic phase
evaporated. The oil obtained after evaporation is dissolved in 100
ml of isopropyl alcohol. A solution containing 12 ml of
concentrated hydrochloric acid in 38 ml of isopropyl alcohol is
added thereto and the solvent evaporated. The solid residue is
taken up in 150 ml of hot isopropyl alcohol, 100 ml of hexane are
added and the solution heated under reflux. The solution is then
cooled in an ice bath, filtered and the precipitate is washed with
50 ml of a 1:1(v/v) mixture of isopropyl alcohol and hexane and
then with 50 ml of hexane. The resulting solid product is dried
under vacuum at 50.degree. C. 12.2 g of the levorotatory
dihydrochloride of
2-[2-(2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperaziny-
l]ethoxy]ethoxy]ethanol are obtained.
[0136] M.P.: 198.degree. C. Yield: 71.13%.
[0137] [.alpha.].sub.365.sup.25 : -10.7.degree. (c=1,
methanol).
[0138] Optical purity: .apprxeq.100%.
[0139] Analysis for C.sub.23H.sub.31ClN.sub.2O.sub.3.2HCl in %:
13 Calc.: C 56.16 H 6.76 N 5.69 Cl.sub.tot 21.62 Found: .sup. 56.34
7.00 5.67 21.76
[0140] 8. Dextrorotatory Dihydrochloride of
2-[2-[2-[4-((4-chlorophenyl)ph-
enylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol
[0141] Using the same method as described at point 7 above, the
dextrorotatory enantiomer is prepared starting from levorotatory
(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example
4.1).
[0142] M.P.: 196.1.degree. C. Yield 73.8%.
[0143] [.alpha.].sub.365.sup.25:+8.94.degree. (c=1, methanol).
[0144] Optical purity: .apprxeq.100%.
[0145] Analysis for C.sub.23H.sub.31ClN.sub.2O.sub.3.2 HCl. in
%:
14 Calc.: C 56.16 H 6.76 N 5.69 Cl.sub.tot 21.62 Found: .sup. 56.48
6.96 5.65 22.1
[0146] 9. Levorotatory
(-)-2-[2-[4-((4-chlorophenyl)phenylmethyl]-1-pipera-
zinyl]ethoxy]acetamide
[0147] 77 g (0.2685 mole) of levorotatory
(-)-1-[(4-chlorophenyl)phenylmet- hyl]piperazine (prepared in
Example 4.1), 40.5 g (0.2932 mole) of 2-(2-chloroethoxy)acetamide,
62.8 g (0.591 mole) of sodium carbonate and 2 g (0.0120 mole) of
potassium iodide are added to 700 ml of toluene. The mixture is
heated at reflux temperature for 24 hours. 10 g of Norit are then
added and the mixture is filtered while hot through Dicalite. The
filtrate is washed with 500 ml of water and then with 500 ml of a
saturated aqueous solution of sodium chloride. The organic phase is
separated and dried over 250 g of sodium sulfate. It is then
filtered and the solvent is evaporated. The residual oil is taken
up in 1500 ml of hot diisopropyl oxide. The solution is heated
under reflux and allowed to crystallize by cooling in an ice bath.
The crystals are filtered, washed with a small amount of
diisopropyl oxide and dried under vacuum at 40.degree. C. 82.91 g
of levorotatory (-)-2-[2-[4-[(4-chlorophenyl)phenyl-
methyl]-1-piperazinyl]ethoxylacetamide are obtained.
[0148] M.P.: 94.3.degree. C. Yield: 79.6%.
[0149] [.alpha.].sub.365.sup.25:-23.5.degree. (c=1, methanol).
[0150] Optical purity: .apprxeq.100%.
[0151] Analysis for C.sub.21H.sub.26ClN.sub.3O.sub.2in %:
15 Calc.: C 65.02 H 6.76 N 10.83. Cl 9.14 Found: .sup. 65.39 6.70
.sup. 10.99 .sup. 9.23.sup.
[0152] 10. Dextrorotatory
(+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-pip-
erazinyl]ethoxy]acetamide 15 g (0.0523 mole) of dextrorotatory
(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example
4.2), 8.3 g (0.0601 mole) of 2-(2-chloroethoxy)acetamide, 12.8 g
(0.1203 mole) of sodium carbonate and 0.5 g (0.0030 mole) of
potassium iodide are added to a mixture of 100 ml of p-xylene and
150 ml of toluene. The mixture is heated at reflux temperature for
17 hours. A small amount of Norit is added and the mixture is
filtered while hot through Dicalite. The residue on the filter is
washed with a small amount of toluene and the filtrate and washing
solution are combined. The solvents are evaporated and the residue
is taken up in 100 ml of toluene. The organic phase is washed
successively with 100 ml of water and twice with 100 ml of a
saturated aqueous solution of sodium chloride. he organic phase is
separated off and the solvent evaporated. At this point, the crude
residue obtained could be purified in a manner similar to that
described at point 9 above, in order to obtain dextrorotatory
(+)-2-[2-[(4-[(4-chlorophenyl)phenylmet-
hyl]-1-piperazinyl]ethoxy)acetamide in the form of the free base.
However, if desired, the crude residue may also be converted to the
corresponding dihydrochloride in the following manner : the crude
residue obtained is taken up in 100 ml of acetone, cooled in an ice
bath and 15 ml of concentrated hydrochloric acid are added dropwise
thereto. A further 200 ml of acetone are added and the mixture is
cooled and stirred on an ice bath for 1 hour. The precipitate is
filtered off and dried under vacuum at 50.degree. C. 19 g of the
levorotatory dihydrochloride of
2-[2-[4-((4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide
are obtained.
[0153] M.P.: 237.4.degree. C. Yield 78.8%.
[0154] [.alpha.].sub.365.sup.25: -19.64.degree. (c1, methanol).
[0155] Optical purity: .apprxeq.100%.
[0156] Analysis for C.sub.21H.sub.26ClN.sub.3O.sub.2.2 HCl in
%:
16 Calc.: C 54.73 H 6.12 N 9.12 Cl.sub.tot 23.08 Cl.sup.- 15.38
Found: .sup. 53.70 6.20 8.91 23.08 .sup. 15.61
[0157] 11. Levorotatory dimaleate of methyl
2-[2-(4-[(4-chlorophenyl)pheny-
lmethyl]-1-piperazinyl]ethoxy]acetate
[0158] 46 g (0.16 mole) of levorotatory
(-)-1-[(4-chlorophenyl)phenylmethy- l]piperazine (prepared in
Example 4.1), 36.6 g (0.24 mole) of methyl (2-chloroethoxy)acetate,
37.3 g (0.35 mole) of anhydrous sodium carbonate and 1.05 g (0.0064
mole) of potassium iodide are suspended in 46 ml of toluene. The
suspension is heated with stirring for 18 hours at reflux
temperature, then cooled to ambient temperature and filtered. The
solids are washed with 100 ml of toluene and the filtrate and the
washing solvent are combined. The toluene is evaporated at
50.degree. C. under reduced pressure in a rotating evaporator. 76 g
of a brown oil are obtained and are taken up in 80 ml of
dichloromethane. The solution is purified by chromatography (silica
column (15 to 40 .mu.m) 1 kg; eluent: pure dichloromethane
gradually diluted with methanol up to a maximum of 2% of methanol
(v/v)). 43.5 g of methyl 2-[2-[4-[(4-chlorophenyl)phenylme-
thyl]-1-piperazinyl]ethoxy]acetate in the form of an oil are thus
obtained. Yield 67.5%.
[0159] This compound can be converted to the corresponding
dimaleate in the following manner: 15 g (0.037 mole) of methyl
2-[2-[4-[(4-chloropheny-
l)phenylmethyl]-1-piperazinyl]ethoxy]acetate prepared above are
dissolved in 45 ml of methanol at reflux temperature and 9, 1 g
(0.078 mole) of maleic acid are then added at once thereto. The
mixture is maintained at reflux temperature until the maleic acid
is completely dissolved, then the solution is allowed to return to
ambient temperature, always with stirring. The crystals which form
are filtered off and suspended in 15 ml of methanol. The suspension
is stirred for an hour and a half at ambient temperature and then
again for an hour and a half at 0.degree. C. The crystals are
filtered off, washed with 15 ml of methanol at 0.degree. C. and
dried to constant weight. 19.5 g of the levorotatory dimaleate of
methyl
2-[2-(4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetat-
e are obtained.
[0160] M.P. 143.5.degree. C. Yield: 56%.
[0161] [.alpha.].sub.365.sup.25: -10.09.degree. (c=1,
methanol).
[0162] Optical purity: .apprxeq.100%.
[0163] Analysis for
C.sub.22H.sub.27ClN.sub.2O.sub.3.2C.sub.4H.sub.4O.sub.- 4in %:
17 Calc.: C 56.79 H 5.56 N 4.41 Found: .sup. 56.81 5.68 4.12
[0164] 12. Dextrorotatory Dimaleate of Methyl
2-[2-[4-[(4-chlorophenyl)phe-
nylmethyl]-1-piperazinyl]ethoxy)acetate
[0165] 14.3 g (0.05 mole) of dextrorotatory
(+)-1-[(4-chlorophenyl)phenylm- ethyl]piperazine (prepared in
Example 4.2), 8.4 g (0.055 mole) of methyl (2-chloroethoxy)acetate,
11.7 g (0.11 mole) of anhydrous sodium carbonate and 0.332 g (0.002
mole) of potassium iodide are suspended in 14.3 ml of toluene. The
suspension is heated with stirring for 17 hours at reflux
temperature. A further 1.52 g (0.01 mole) of methyl
(2-chloroethoxy)acetate are added and the suspension is further
heated with stirring for 3 hours at reflux temperature, then cooled
to ambient temperature and filtered. The solids are washed with 50
ml of toluene and the filtrate and the washing solvent are
combined. The toluene is evaporated at 50.degree. C. under reduced
pressure in a rotating evaporator. 22.8 g of a brown oil are
obtained and are taken up in 45 ml of dichloromethane. The solution
is purified by chromatography (silica column (15 to 40 .mu.m) 1 kg;
eluent: pure dichloromethane gradually diluted with methanol up to
a maximum of 2% of methanol (v/v)). 11.1 g of methyl
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinylethoxy]acetate
in the form of an oil are obtained.
[0166] Yield: 55.1%.
[0167] This compound can be converted to the corresponding
dimaleate in the following manner: 8 g (0.0198 mole) of methyl
2-[2-[4-[(4-chloropheny-
l)phenylmethyl)-1-piperazinyl]ethoxy]acetate prepared above are
dissolved in 16 ml of methanol at reflux temperature and 4.85 g
(0.0417 mole) of maleic acid are then added at once thereto. The
mixture is maintained at reflux temperature until the maleic acid
is completely dissolved, then the solution is allowed to return to
ambient temperature, always with stirring. The crystals which form
are filtered off and suspended in 16 ml of methanol. The suspension
is stirred for two hours at ambient temperature.. The crystals are
filtered off, washed with 10 ml of methanol and dried to constant
weight. 7.3 g of the dextrorotatory dimaleate of methyl
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-
ethoxy]acetate are obtained.
[0168] M.P. 143.2.degree. C. Yield: 32%.
[0169] [.alpha.].sub.365.sup.25: +9.8.degree. (c=1, methanol).
[0170] Optical purity: .apprxeq.100%.
[0171] Analysis for
C.sub.22H.sub.27ClN.sub.2O.sub.3.2C.sub.4H.sub.4O.sub.- 4in %:
18 Calc.: C 56.79 H 5.56 N 4.41 Found: .sup. 56.71 5.58 4.17
[0172] 13. Levorotatory Dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenyl-
methyl]-1-piperazinyl)ethoxy]acetic acid
[0173] 26 ml of concentrated hydrochloric acid are added dropwise
to a suspension of 25.2 g (0.065 mole) of dextrorotatory
(+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide
(prepared at point 10 above) in 70 ml of water, causing the
temperature of the mixture to rise to 38.degree. C. The mixture is
then heated at 50.degree. C. for 17 hours. The reaction mixture is
then cooled in an ice bath and the pH brought to a value of between
4 and 5 by addition of a 4 N aqueous solution of sodium hydroxide.
The resulting solution is extracted successively with 100 ml, then
twice with 50 ml of dichloromethane. The organic phases are
combined and dried over magnesium sulfate. They are filtered and
the solvent is evaporated. The residual oil is dissolved in 243 ml
of acetone and the solution is treated with 3.5 g of Norit and
filtered through Celite, which is then washed with 35 ml of
acetone. The solution is heated at reflux temperature and 198 ml
(0.13 mole) of concentrated hydrochloric acid are added dropwise
thereto. The mixture is cooled in an ice bath and allowed to stand
for one hour. The precipitate which forms is filtered off, washed
with 100 ml of acetone and dried under vacuum at 50.degree. C. 24.1
g of the levorotatory dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1--
piperazinyl]ethoxy]acetic acid are obtained.
[0174] M.P.: 229.3.degree. C. Yield: 80.3%.
[0175] [.alpha.].sub.D.sup.25: -12.79.degree. (c=1, water).
[0176] Optical purity: .apprxeq.100%.
[0177] Analysis for C.sub.21H.sub.25CiN.sub.2O.sub.3.2HCl in %
19 Calc.: C 54.61 H 5.90 N 6.07 Cl.sup.- 15.35 Cl.sub.tot 23.03
Found: .sup. 54.67 5.91 6.03 .sup. 15.34 23.28
[0178] 14. Dextrorotatory Dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phen-
ylmethyl]-1-piperazinyl]ethoxy]acetic acid
[0179] The dextrorotatory dihydrochloride of
2-[2-[4-((4-chlorophenyl)phen-
ylmethyl]-1-piperazinyl]ethoxy]acetic acid is prepared according to
the method described at point 13 above, starting with 25.2 g (0.065
mole) of levorotatory
(-)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]eth-
oxy]acetamide (prepared at point 9 above). 25.6 g of the desired
product are thus obtained.
[0180] M.P.: 227.9.degree.. Yield: 85.3%.
[0181] [.alpha.].sub.365.sup.25 : +12.87.degree. (c=1, water).
[0182] Optical purity: 99.87%.
[0183] Analysis for C.sub.21H.sub.25ClN.sub.2O.sub.3HCl %:
20 Calc.: C 54.61 H 5.90 N 6.07 Cl.sup.- 15.35 Cl.sub.tot 23.03
Found: .sup. 54.71 5.92 6.04 .sup. 15.34 23.19
[0184] 15. Dextrorotatory Dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phen-
ylmethyl)-1-piperazinyl]ethoxy]acetic acid
[0185] 13.75 g (0.00216 mole) of the levorotatory dimaleate of
methyl
2-[2-[4-([4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate
(prepared at point 11 above) are added with stirring and at ambient
temperature to 54 ml of a 2N aqueous solution of sodium hydroxide.
The reaction mixture is extracted successively with 100 ml and 75
ml of diethylether and the organic phases are combined. This
organic phase is dried over anhydrous sodium sulfate, filtered and
the filtration residue is washed with 50 ml of diethylether. The
organic phases are combined and the diethylether is evaporated. The
oil thus obtained (8.4 g) is taken up in 50 ml of ethanol and 1.3 g
(0.0229) of solid potassium hydroxide are added thereto. The
mixture is heated for one hour at reflux temperature and then
allowed to return to ambient temperature, then filtered and the
filtrate is evaporated. The residue is taken up in 50 ml of water
and concentrated in a rotating evaporator to remove residual
ethanol. 10 ml of water are added to the partially concentrated
solution and the pH of the solution is brought to a value of
between 4 and 5 by addition of a 10% aqueous solution of
hydrochloric acid. The resulting solution is extracted with 50 ml
of dichloromethane, the pH of the solution is again brought to a
value of between 4 and 5 by addition of a 10% aqueous solution of
hydrochloric acid and the solution is once again extracted with 50
ml of dichloromethane. The organic phases are combined and dried
over anhydrous magnesium sulfate, filtered and the dichloromethane
is evaporated. The viscous oil thus obtained (9.8 g) is dissolved
in 68.6 ml of acetone and the slightly cloudy solution is treated
with 1 g of activated charcoal and filtered while hot through
diatomaceous earth. 3.6 ml (0.043 mole) of concentrated
hydrochloric acid are added to the hot clear yellow solution thus
obtained. The suspension is allowed to cool to ambient temperature
with stirring and stirring of the suspension is continued for one
hour at 0.degree. C. The precipitate which forms is-filtered off,
washed with 50 ml of acetone and dried under vacuum at 40.degree.
C. 6.8 g of the dextrorotatory dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl)ethoxy]acetic
acid are thus obtained.
[0186] M.P.: 227.8.degree. C. Yield: 70.8%.
[0187] [.alpha.].sub.365.sup.25: +13.70(c=1, water).
[0188] Optical purity: 100%.
[0189] Analysis for C.sub.21H.sub.25ClN.sub.2 O.sub.3.2 HCl in
%:
21 Calc.: C 54.61 H 5.90 N 6.07 Found: .sup. 54.18 6.02 5.68
[0190] The following compounds have been subjected to
pharmacological tests, the results of which are given
hereinafter.
[0191] (-)-1-[(4-chlorophenyl)phenylmethyl]piperazine (compound A,
prepared in Example 4.1);
[0192] (+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (compound B,;
prepared in Example 4.2);
[0193] levorotatory dihydrochloride of
1-[(4-chlorophenyl)phenylmethyl]-4--
[(3-methylphenyl)methyl]piperazine (compound C, prepared in Example
5.1);
[0194] dextrorotatory dihydrochloride of
1-[(4-chlorophenyl)phenylmethyl]--
4-[(3-methylphenyl)methyl]piperazine (compound D, prepared in
Example 5.2);
[0195] levorotatory dihydrochloride of
1-[(4-tert-butylphenyl)methyl]-4-[(-
4-chlorophenyl)phenylmethyl]piperazine (compound E, prepared in
Example 5.3);
[0196] dextrorotatory dihydrochloride of
1-[(4-tert-butylphenyl)methyl-4-[-
(4-chlorophenyl)phenylmethyl]piperazine (compound F, prepared in
Example 5.4);
[0197] levorotatory dihydrochloride of
2-(2-[4-[(4-chlorophenyl)phenylmeth-
yl-1-piperazinyl]ethoxy]ethanol (compound G, prepared in Example
5.5);
[0198] dextrorotatory dihydrochloride of
2-[2-[4-[(4-chlorophenyl)phenylme-
thyl-1-piperazinyl]ethoxy]ethanol (compound H, prepared in Example
5.6);
[0199] levorotatory dihydrochloride of
2-[2-[2-[4-[(4-chlorophenyl)phenylm-
ethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol (compound I, prepared in
Example 5.7);
[0200] dextrorotatory dihydrochloride of
2-[2-[2-[4-[(4chlorophenyl)phenyl-
methyl]-1-piperazinyl]ethoxy]ethoxy]ethanol (compound J, prepared
in Example 5.8);
[0201]
(-)-2-[2-(4-[(4-chlorophenyl]phenylmethyl]-1piperazinyl]ethoxy]acet-
amide (compound K, prepared in Example 5.9);
[0202]
(+)-2-[2-[(-[(4-chlorophenyl]phenylmethyl]-1-piperazinyl]ethoxy]ace-
tamide (compound L, prepared in Example 5.10);
[0203] levorotatory dimaleate of methyl
2-[2-[4-[(4-chlorophenyl]phenylmet-
hyl]-1-piperazinyl]ethoxy]acetate (compound M, prepared in Example
5.11);
[0204] dextrorotatory dimaleate of methyl
2-[2-[4-((4-chlorophenyl]phenylm-
ethyl]-1-piperazinyl]ethoxy]acetate (compound N, prepared in
Example 5.12);
[0205] levorotatory dihydrochloride of
2-[2-[4-((4-chlorophenyl]phenylmeth-
yl]-1-piperazinyl]ethoxy]acetic acid (compound 0, prepared in
Example 5.13) and
[0206] dextrorotatory dihydrochloride of
2-[2-[4-[(4-chlorophenyl]phenylme-
thyl]-1-piperazinyl]ethoxy]acetic acid (compound P, prepared in
Example 5.14).
[0207] 1. Affinity Towards the Histamine H.sub.1 Receptor
[0208] The affinity of these compounds towards the rat cortex
histamine H.sub.1 receptor has been determined using the method
described by M. M. BILLAH et al., J. Pharmacol. Exp. Ther., 252(3),
(1990), 1090-1096.
[0209] These conventional assays involve the competitive binding to
the histamine H.sub.1 receptor of, on the one hand, the compound to
be tested and, on the other hand, a radioligand, which in the
particular case of the histamine H.sub.1 receptor is
[.sup.3H]mepyramine, known to be a selective antagonist of this
receptor.
[0210] Displacement curves of the binding of [.sup.3H]mepyramine
are plotted for various concentrations of the compounds to be
tested ranging from 10-10 to 10.sup.4 mole/1, and for a
concentration of 4.5.times.10.sup.-9 mole/1 of (.sup.3H)mepyramine
(24.8 Ci/mmole, provided by New England Nuclear, Belgium).
[0211] Cerebral cortexes from male Sprague-Dawley rats are
homogenized in 2 ml per cortex of a 20 mM Tris-HCl buffer (pH 7.4)
containing 250 mM sucrose. The homogenates are centrifuged at
30,000 g for 30 minutes at 4.degree. C. and the centrifugation
pellets are resuspended in the same fresh buffer and preserved in
liquid nitrogen.
[0212] In order to determine the binding to the H.sub.1 receptor,
the samples containing 0.5 mg of cortex membrane protein, in 0.5 ml
of 50 mM Tris-HCl buffer (pH 7.4) containing 2 mM magnesium
chloride, are incubated with [.sup.13H ]mepyramine and the compound
to be tested, at 25.degree. C. for 60 minutes. The bound [.sup.3
H]mepyramine is separated from the free radioligand by rapid
filtration of the sample through a Whatman GF/C filter, previously
impregnated for at least 2 hours with a 0.1% solution of
polyethyleneimine, in order to reduce the possibility of
non-specific binding of the radioligand with other proteins. The
residue from the filtration is then washed four times with 2 ml of
50 mM Tris-HCl buffer (pH 7.4) and cooled in an ice bath. The
radioactivity thereof is then measured using a .beta.particle
Tri-carb 1090 scintillation counter (Camberra-Packard, Belgium).
Non-specific binding has been estimated in the presence of a 10 W
aqueous solution of cetirizine and represents 30% of the total
binding. The IC.sub.50 values of the compounds to be tested
(concentrations in mole/l necessary to inhibit binding of the
radioligand to the H.sub.1 receptor by 50%) are determined by
analysis of the competitive binding curves (A. DE LEAN et al., Mol.
Pharmacol., 21(1982), 5-16) and their inhibition constants
(K.sub.i) are calculated by means of the CHENG and PRUSOFF equation
(Y.C.CHENG and W.H.PRUSOFF, Biochem. Pharmacol., 22(1973),
3099-3108).
[0213] Table III below gives the values of pK.sub.i(cologarithm of
K.sub.i) calculated from K.sub.i(mean value .+-.deviation with
respect to the mean (n=2)), for the compounds tested.
22 TABLE III Compound pKi C 6.2 .+-. 0.1 D 7.2 .+-. 0.2 E 5.9 .+-.
0.2 F 6.2 .+-. 0.0 G 7.6 .+-. 0.1 H 8.7 .+-. 0.0 I 7.1 .+-. 0.0 J
8.6 .+-. 0.0 K 8.6 .+-. 0.1 L 6.8 .+-. 0.1 M 7.1 .+-. 0.1 N 8.5
.+-. 0.1 O 7.4 .+-. 0.0 P 8.2 .+-. 0.0
[0214] From this Table, it can be seen that the compounds of
formula V have good antihistaminic activity. These results also
show. that there is a difference, between the pK.sub.i values for
the two enantiomers of one compound, which corresponds to a
difference in relative affinity (thus in K.sub.i) of a factor of
between about 2 and 64 towards the rat cortex H.sub.1 receptor.
Such a difference indicates that the enantiomer, which has the
greatest affinity for this type of receptor (for example compound J
compared with the other enantiomer I), is to be used specifically
as an anxiolytic or tranquilizing agent for the treatment of
diseases which are caused by an excitation of the central nervous
system.
[0215] 2. Peripheral Antihistaminic Properties
[0216] The peripheral antihistaminic properties of the compounds
are determined by measuring the inhibition of the contraction of
the isolated guinea pig trachea, caused by histamine, using the
method described by M. H. AMIRI and G.GABELLA (Anat. Embryol.,
178(1988), 389-397).
[0217] Tracheas of Dunkin-Hartley guinea pigs of both sexes
(weight: 250 -500 g) are excised and cut into four fragments of
three segments of cartilage each. These fragments are immersed in a
Krebs-Heinseleit solution at 37.degree. C. containing 10.sup.-7
mole/1 of atropine and 10.sup.-5 mole/1 of indomethacin and are
stretched with a weight of 1 g. The solution is aerated with a
current of oxygen containing 5% carbon dioxide. Each change in
tension is recorded with an isometric force indicator K 30(from
Hugo Sachs Elektronik) coupled to an amplifier and a Sanborn 7700
recorder (from Hewlett Packard). The preparation (i.e. trachea
fragment) so obtained is allowed to stabilize for one hour during
which the base line for the tension is readjusted if necessary.
[0218] Each preparation is precontracted by the addition of
10.sup.-4 mole/1 of histamine to the medium; the observed
contraction is taken as a reference (100%). After washing and
stabilization, a cumulative curve showing the effects of histamine,
as a function of its concentration (10.sup.-6, 10.sup.-5 and
10.sup.-4 mole/1) is plotted as a control.
[0219] For the same preparation, four further cumulative curves
showing the effects of histamine as a function of its concentration
are then recorded at four increasing concentrations of each
compound to be tested.
[0220] The compounds to be tested are incorporated in the medium
five minutes before the histamine. Between each measurement, the
preparations are washed at least four times with an interval of
five minutes between each washing. Each compound is tested on at
least 6 trachea fragments. When the last curve is plotted,
additional concentrations of 3.2.times.10.sup.-4 and 10.sup.-3
mole/1 of histamine are added in order to determine whether the
antagonism is competitive or not.
[0221] When non-competitive inhibition is observed, pD.sub.2, is
calculated, i.e. the cologarithm of the concentration of the
compound tested which causes a 50% inhibition of the maximum
recorded contraction (J.M.VAN ROSSUM, Arch. Int. Pharmacodyn.,
143(1963), 299-330). When competitive inhibition is observed,
pA.sub.2 is calculated, i.e. the cologarithm of the concentration
of the compound tested which requires the histamine dose to be
doubled in order to obtain the same contraction effect.
[0222] Table IV below gives the pA.sub.2 or pD.sub.2, calculated
for the compounds tested (mean value .+-.standard deviation).
23TABLE IV Compound pA.sub.2 pD.sub.2 A 5.7 .+-. 0.4 -- B 5.0 .+-.
0.1 -- G 6.5 .+-. 0.3 -- H -- 6.7 .+-. 0.1 I 6.5 .+-. 0.4 -- J --
6.0 .+-. 0.3 K -- 6.3 .+-. 0.2 L 6.4 .+-. 0.2 -- O 6.6 .+-. 0.3 --
P -- 6.3 .+-. 0.2
[0223] This test reveals a surprising characteristic for the tested
levorotatory and dextrorotatory enantiomer pairs. With the
exception of the pair of enantiomers A and B, it is found for all
the other pairs, that one enantiomer is a competitive inhibitor,
whilst the other is a non-competitive inhibitor. This clearly
demonstrates the advantage of preparing optically pure derivatives
of 1-[(4-chlorophenyl)phenylmethyl]p- iperazine.
[0224] The advantage of the competitive inhibitors stems from the
fact that they have generally a lower affinity towards the rat
cortex H.sub.1 histamine receptor, which predicts that the
anti-allergic properties of these compounds are associated, very
little or not at all, to undesirable effects on the central nervous
system, such as for example sedation or drowsiness. Non-competitive
inhibitors have the advantage of being able to inhibit the effects
of histamine, even when the latter is present in high local
concentrations. They, thus, are better indicated for the topical
treatment of diseases of the skin or the mucous membranes.
[0225] 3. Inhibition of the Cutaneous Reaction Induced by Histamine
in Dogs
[0226] The dog is considered, among the animal species, to be the
species having a sensitivity to histamine relatively close to that
of man. Thus, it is considered that the antihistaminic activity of
a compound, observed in the dog, is predictive of the activity
which would be observed in man.
[0227] In this test, nine Beagle dogs are used, having an average
weight of 12.6 kg and of about two years of age and of which the
abdomens have been locally shaved. 50 .mu.l of a 0.9% aqueous
solution of sodium chloride, containing 10 .mu.g/ml of histamine,
is injected intradermally into the shaved area. Simultaneously, a
solution of Evans blue dye (60 mg/ml in a 0.9% aqueous solution of
sodium chloride), is administered by intravenous injection to each
dog at a dose of 0.1 ml/kg. An allergic reaction develops at the
intradermal injection site and there appears a wheal, the area of
which is measured exactly 30 minutes after the two injections. This
area is taken as the reference area (100%)
[0228] The compound to be tested is then administered orally, at a
dose of 0.15 mg/kg (0.32.times.10.sup.-6 mole/kg). 0.5, 1.5, 3, 6,
9, 12, 24 and 32 hours after administration of the compound to be
tested, new wheals are induced at different abdominal locations by
injecting histamine. Each time, the area of the induced wheal is
measured 30 minutes after the injection of histamine.
[0229] The antihistaminic activity of a compound on the cutaneous
allergic reaction is determined by measuring the reduction in the
area of the induced wheals, following administration of the
compound, with respect to the area of the reference wheal, and then
expressed in percent.
[0230] Table V below, gives the antihistaminic activity obtained
for compound P. In this table, the first column indicates the time,
expressed in hours elapsed since administration of the tested
compound; the second column, the area, expressed in mm.sup.2, of
the wheals induced by histamine (mean observed for nine dogs t
standard deviation); the third column, the reduction (in percent)
in the area of the wheals observed with time, with respect to the
reference area and; the fourth column, the statistical significance
of the effect observed with time, evaluated by means of the
Wilcoxon test.
24 TABLE V Time Area of wheals Reduction in area Statistical
(hours) (mm.sup.2) (%) value 0 76 .+-. 8 100 0.5 65 .+-. 10 85
p.ltoreq.0.01 1.5 44 .+-. 12 58 p.ltoreq.0.001 3 33 .+-. 10 43
p.ltoreq.0.001 6 41 .+-. 13 54 p.ltoreq.0.001 9 41 .+-. 10 54
p.ltoreq.0.001 12 41 .+-. 10 54 p.ltoreq.0.001 24 45 .+-. 5 59
p.ltoreq.0.001 32 51 .+-. 5 67 p.ltoreq.0.01
[0231] It can be seen that the reduction in the area of the wheals,
observed 30 minutes after administration of compound P, is 15%.
Maximum inhibition is observed after three hours and reaches 57%.
After 32 hours, a statistically significant inhibition of 33% is
still observed.
[0232] 4. Toxicity.
[0233] The compounds of formula V have low toxicity. The lethal
dose (causing death in 2 out of 3 mice following intraperitoneal
injection of the compounds) is appreciably higher than the dose
required to inhibit the cutaneous reaction induced by histamine in
the dog. Table VI gives the the lethal doses (in mice) for the
compounds of formula V.
25 TABLE VI Compound Lethal dose (mole/kg) C >1 .times.
10.sup.-3 D >1 .times. 10.sup.-3 E 1 .times. 10.sup.-3 F >1
.times. 10.sup.-3 G 6 .times. 10.sup.-4 H 6 .times. 10.sup.-4 I 1
.times. 10.sup.-4 J 1 .times. 10.sup.-4 K 3 .times. 10.sup.-4 L 1
.times. 10.sup.-3 O 3 .times. 10.sup.-4 P 3 .times. 10.sup.-4
[0234] 5. Posology and Administration
[0235] The compounds of formula V have, in particular, antiallergic
and antihistaminic activity as well as tranquilizing and anxiolytic
activity. Pharmaceutical compositions containing these compounds
may be administered orally, parenterally or rectally. They may also
be administered in a nasal spray or instillations (aerosols) or in
the form of a cream or ointment.
[0236] For oral administration, solid or liquid forms are used such
as tablets, gelatine capsules, sugar-coated pills, granulated
materials, solutions, syrups, etc.
[0237] For parenteral administration, aqueous or oily solutions,
suspensions or emulsions can be suitable.
[0238] For rectal administration, suppositories are used.
[0239] The pharmaceutical forms listed above are prepared using
methods currently used by pharmacists and can contain traditional
excipients in pharmaceutically non-toxic amounts, such as
dispersants, stabilizers, preservative agents, sweeteners, coloring
agents and the like.
[0240] The percentage of active compound can vary within wide
limits, depending upon the mode of administration and in particular
the frequency of administration. As regards the daily dosage, this
can vary within a wide range of from 0.5 to 100 mg, preferably
between 2 and 20 mg of active compound per day.
* * * * *