Note: Descriptions are shown in the official language in which they were submitted.
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SALTS OF AROMATIC SULPHONIC ACIDS
The invention pertains to a salt of the compound trans-5-chloro-2,3,3a,12b-
tetrahydro-2-
methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole and a salt forming agent.
Such salts are known. Thus, e.g., the maleate of the above compound (Org
5222), as well
as the preparation thereof, has been described in US 4,145,434, the disclosure
of which is
incorporated herein by reference.
The compound is described as having CNS-depressant activity and antihistamine
and
antiserotonin activities.
IS The pharmacological profile of trans-5-chloro-2,3,3a,12b-tetrahydro-2-
methyl-1H-
dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, its kinetics and metabolism, as well as
the first
safety and efficacy studies in human volunteers and in schizophrenic patients
were
reviewed by De Boer et al. (Drugs of the Future 1993, 18(12), 1117-1123). It
has been
established that Org 5222, which is traps-5-chloro-2,3,3a, l2b-tetrahydro-2-
methyl-1H-
dibenz[2,3:6,7]oxepino[4,5-c]pyrrole(Z)-2-butenedio.ae (1:1), is a very potent
dopamine
and serotonin antagonist and antihistaminic with potential antipsychotic
activity.
In view of the compound's utility, it is desired for it to be incorporated
into
pharmaceutical compositions of all kind and, notably, those that are
advantageous with
regard to administering to patients suffering from mental disorders. Due to
the vary nature
of their disease, these patients frequently refuse to take their medicine or
simply forget to
take it, e.g. as a result of apathy. In view hereof, it is highly desired for
compounds such
as the above, to be administered in the form of a depot preparation, i.e. a
pharmaceutical
composition containing a dose of the medicine sufficient for a prolonged time,
e.g. several
;0 weeks, and which by means of sustained release will perform its desired
function to the
central nervous system.
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The known compounds, however, are not very well suitable for use in such depot
preparations. The main requirements for such a use are that the compound is
crystalline
(otherwise the compound will be metastable, due to which it cannot be
predicted what, at
a certain point in time, the amount of biologically desired compound is) and
that it has a
low solubility in water. The latter is important for attaining the required
sustained release.
E.g. the maleate, (the (Z}-2-butenedioate Org 5222), which is crystalline, has
a solubility
of 3 mg/ml (21°C) which means that also higher doses, intended for
controlled sustained
release, will be taken up in the patient's blood immediately. The free base
(Org 33254) has
a relatively low solubility of Less then 0.1 mg/ml, but is instable. The
pamoate (Org 33388)
is amorphous, the hemipamoate (Org 39058) is a mixture of amorphous and
crystalline
material. Further, it is desired that the melting point is not too low
(preferably above
80°C), as this may lead to temperature-induced problems when making
tablets or granules.
For long it has been recognized in the art that there is no reliable way of
predicting the
influence of a particular salt species on the behaviour of the parent
compound, see e.g.
J.Pharm.Sci. 66, 1-19, 1977. Salt-forming agents are therefore generally
chosen
empirically, and also in later literature, e.g. International Journal of
Pharmaceutics, 33
(1986) 201-217, it has been recognized that, notably for properties such as
hygroscopicity,
stability and solubility, it is difficult to select the salt fornung agent
beforehand.
The same holds for the present compounds, all the more since also
crystallinity is required.
Hence it is an object of the present invention to select a salt-forming agent
for the above
compound which leads to this pharmacon being substantially water-insoluble,
and
crystalline.
According to the invention the salt-forming agent selected is an aromatic
sulphonic acid.
Although in principle any pharmaceutically acceptable aromatic sulphonic acid
is suitable,
some aromatic moieties are clearly preferred. Thus the aromatic moiety may
advantageously be of the type having a single phenyl ring. Preferred acids of
this type
being benzene sulphonic acid and toluene sulphonic acid, the preferred salts
of the
invention are the besylate and the tosylate. In the alternative, it may be
advantageous for
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3
the aromatic moiety to be unsubstituted (apart from the sulphonic acid group
of course).
In this respect not only the besylate is the preferred salt of the invention,
but naphthalene
sulphonic acid is also a suitable candidate for the acid, resulting in the
corresponding
napsylate. However, the most preferred salt of the invention is the besylate.
The salts of the present invention can be prepared analogously to those
described in US
4,145,434. For the preparation of the compound trans-S-chloro-2,3,3a,12b-
tetrahydro-2-
methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole reference is made to said
document. In
order to obtain the desired salt, said compound can be dissolved in a suitable
solvent, such
as ethanol and then be mixed with a solution of the appropriate aromatic
sulphonic acid,
preferably in the same solvent or in a solvent miscible with the solvent for
said compound.
The mixture then can be allowed to stand for sufficient time to let the
corresponding salt
according to the invention crystallize (which occurs spontaneously). If
desired the
obtained crystals can further undergo conventional washing and drying and/or
purifying
steps, e.g. simple recrystallization followed by drying.
Just as the known maleates, the compositions of the invention are useful in
treating
mammals, including humans, suf~'ering from all diseases susceptible to
treatment by trans-
5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7)oxepino[4,5-
c]pyrrole. These
diseases include mental disorders, such as tension, excitation, anxiety,
psychosis, and
schizophrenia. The compositions may also be used for antidopamine,
antihistamine and for
antiserotonin related diseases.
Hence, the salts of the present invention have a utility as a medicine per se,
and they may
be administered in any form, although, as described in WO 95/23600, peroral
administration may lead to cardiotoxic side-effects. Thus other forms of
administration are
preferred, e.g. subcutaneous administration, injection, or by means of
sublingual or buccal
pharmaceutical composition as described in WO 95/23600.
All of these single dosage forms of pharmaceutical compositions containing the
salt of the
present invention comprise one dosage unit of trans-5-chloro-2,3,3a,12b-
tetrahydro-2-
methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole as an active ingredient. A
dosage unit
may contain between 0.005 mg and I S mg of the active ingredient. Preferably
the dosage
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unit contains of from about 0.03 to 0.50 mg of trans-5-chloro-2,3,3a,12b-
tetrahydro-2-
methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole. Any suitable, pharmaceutically
acceptable carrier material may be applied, and pharmaceutically acceptable
auxiliaries be
added. All of these pharmaceutically acceptable excipients such as carriers
and auxiliaries
are known to the person skilled in the art and do not require elucidation
here.
It is preferred, and only possible as a result of the present invention, that
the salt be
administered by means of a depot injection, i.e. at a dose higher than that in
a single
dosage form. Typical doses for such preparations comprise 10 to 40 mg of the
active
ingredient. The depot preparations of the present invention in its simplest
form may
comprise water as a carrier, the low aqueous solubility of the salt of course
making it
preferable for it to be dispersed rather than dissolved. To facilitate making
a stable
dispersion, conventional adjuvants may be used, e.g. Tween (surfactant),
propylene glycol,
lecithin, etc. Other pharmaceutically acceptable carriers are also suitable,
e.g. carboxy
methyl cellulose, gelatin, poly(vinyi pyrrolidone), or other well-known
excipients. For
background knowledge of depot preparations reference is made to Leiberman,
Rieger,
Bunker, Pharmaceutical Dosage Forms: Disperse System Volume 2.
The invention is further illustrated with reference to the following examples.
EXAMPLE I
A solution of 940 mg of benzene sulphonic acid in 15 ml of ethanol was added
to a
solution of 1.7 g of trans-S-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-
dibenz[2,3:6,7]-
oxepino[4,5-c]pyrrole. Crystallization occurred, and the crystals obtained
were collected
and recrystallized from 75 ml of boiling ethanol. After cooling to 20°C
the crystals were
collected and dried in vacuo over calcium chloride and potassium hydroxide.
Yield: 1.9 g
(72%) of trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-
dibenz[2,3:6,7)oxepino[4,5-
c]pyrrole benzene sulphonate (besylate). This salt was found to have a melting
point of
227.8°C and a solubility in water measured at 20°C of « 1 mg/ml.
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COMPARATIVE EXAMPLE
The procedure of Example 1 was repeated, employing a great many different
acids, all
known for their suitability as a salt-forming agent for a pharmacon. The
results attained
5 are given in the following table:
TABLE
Salt Form Melting Solubility
in water
point (C) (mg/ml)
maieate crystalline 141-145 3
fumarate crystalline 185.5-187 1
1-hydroxy no crystallization- -
naphthoate
palmitate no crystallization- -
pamoate amorphous 23 0-240 <0.3 5
hemipamoate amorphous /crystalline167-168 <0.25
benzoate no crystallization- -
2-hydroxy no crystallization- -
benzoate
4-acetyl aminono crystallization- -
benzoate
3-hydroxy-2- no crystallization- -
naphthoate
2-methoxy no crystallization- -
phenyl
acetate
Clearly, the aromatic sulphonates of the invention form an exception in
combining the
desired properties of being crystalline, having a high melting point and
displaying such a
low solubility in water as to be held water-insoluble.
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EXAMPLE II
The procedure of Example I was repeated, substituting toluene-4-sulphonic acid
for
benzene sulphonic acid. Thus the corresponding toluene sulphonate (tosylate)
was
obtained.
EXAMPLE III
The procedure of Example I was repeated, substituting naphthalene-I-sulphonic
acid and
naphthalene-2-sulphonic acid for benzene sulphonic acid. Thus the
corresponding
naphthalene sulphonates (napsylates) were obtained.
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