CRYSTALLINE(R)-(-)-2-CYCLOHEPTYL-N-METHYLSULFONYL- [4-(2-QUINOLINYL-METHOXY)-PHENYL]-ACETAMIDE

(R)-(-)-2-CYCLOHEPTYL-N-METHYLSULFONYL- [4-(2-QUINOLINYL-METHOXY)-PHENYL]-ACETAMIDE CRISTALLIN

English Abstract

A b s t r a c t
(R)-(-)-2-cycloheptyl-N-methylsulfonyl- [4-(2-quinolinyl-
methoxy)-phenyl]-acetamide, which is an inhibitor of
leukotriene synthesis, is prepared in crystalline form by
suspending the active compound in non-crystalline form in
inert organic solvents, optionally in the presence of
water, and, at elevated temperature, converting it by
stirring into the crystalline modification. The crystal-
line active compound is suitable, in particular, for
preparing medicaments having increased storage stability
and temperature resistance.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. (R)-(-)-2-Cycloheptyl-N-methylsulfonyl-[4-(2-quinoo-
linylmethoxy)-phenyl]-acetamide of the formula
<IMG>
in crystalline form.
2. Crystalline active compound according to claim 1 for
therapeutic use.
3. A process for preparing the compound in crystalline
form, which process comprises suspending non-crystalline
(R)-(-)-2-cycloheptyl-N-methylsulfonyl-[4-(2-quinolinylmethoxy)-
phenyl]-acetamide in an inert organic solvent at elevated
temperature until conversion to the crystalline form of the
compound has occurred.
4. A process according to claim 3 wherein water is also
present in the solvent.
5. A process according to claim 4 wherein the solvent is
a mixture of water and one or more lower alcohols having up to
6 carbon atoms.
- 7 -

6. A process according to claim 4 wherein the solvent is
a mixture of ethanol and water.
7. A process according to claim 4 wherein the solvent is
a mixture of isopropanol and water.
8. A process according to any one of claims 5 to 7
wherein one part of alcohol and up to 20 parts of water are
employed.
9. A process according to any one of claims 3 to 7
wherein the compound is suspended at a temperature in the range
of +40 to +70°C.
10. Process for preparing the crystalline active compound
according to claim 1, characterised in that non-crystalline
(R)-(-)-2-cycloheptyl-N-methylsulfonyl-[4-(2-quinolinylmethoxy)-
phenyl]-acetamide is suspended in inert organic solvents,
optionally in the presence of water, and treated at elevated
temperatures until it is quantitatively converted into the
crystalline modification, and the resulting crystals of the
crystalline modification are then separated off by customary
methods and, to remove any solvent residues which may be present,
dried to constant weight at temperatures of +20 to +70°C.
11. Process according to claim 10, characterised in that
mixtures of lower alcohols having up to 6 carbon atoms and water
are employed.
- 8 -

12. Process according to claim 10, characterised in that
ethanol/water mixtures or isopropanol/water mixtures are
employed.
13. Process according to claim 10, characterised in that
alcohol/water mixtures in the ratio of one part of alcohol to
20 parts of water are employed.
14. Use of the crystalline active compound according to
claim 1 for preparing medicaments.
15. Use according to claim 14 for preparing solid
medicaments.
16. Medicaments containing the crystalline active compound
according to claim 1, together with a suitable diluent or
carrier.
17. Process for preparing medicaments according to claim
16, characterised in that the crystalline active compound,
optionally with the aid of customary auxiliaries and vehicles,
is converted into an appropriate form for administration.
- 9 -

Description

21(38~86
The invention relates to a crystalline form of the
(R)-(-)-2-cycloheptyl-N-methylsulfonyl- [4-(2-quinol inyl -
methoxy)-phenyl]-acetamide, a process for its preparation
and its use in medicaments.
(R)-(-)-2-Cycloheptyl-N-methylsulfo n y 1 - t 4-(2-qui no 1 i ny 1 -
methoxy)-phenyl]-acetamide of the formula (I),
~ N ~
o,~o
CO-NH-SO2-CH3
which is an inhibitor of leukotriene synthesis, its
preparation and its use in medicaments, is already
described in EP 344 519.
According to the preparation process described therein,
the compound of the formula (I) is obtained in the form
of a non-crystalline powder. A solvate-free, crystalline
modification is hitherto unknown.
However, it has become evident that the non-crystalline
form of the compound (I) has crucial disadvantages, in
particular in the preparation of solid medicaments. Thus,
medicaments which contain the compound of the formula (I)
Le A 29 305 - 1 -

2108~86
in the dmorphous form exhibit very unsatisfactory storage
stability for example Thi s phy5 i cal instability
which preferentially arises when the preparations are
stored over a relatively long period of time at tempera-
tures above 30C, impairs the absorption efficacy and, inparticular, the safety of these preparations. It is
therefore of qreat importance to make available a stable
form of the compound of the formula (I), which does not
possess the abovementioned disadvantages, for preparing
medicaments.
A novel crystalline form of the compound (R)-(-)-2-cyclo-
heptyl-N-methylsulfonyl- [4-(2-quinolinylmethoxy)-
phenyl]-acetamide has now been found which is distin-
guished, in comparison with the known non-crystalline
form, by increased physical stability and reduced sensi-
tivity to pressure, and is therefore considerably more
suitable for the preparation of various medicament forms
than is the non-crystalline form.
The preparation of the novel crystalline form of the
compound of the formula (I) according to the invention is
effected, e.g., by the compound of the formula (I) in
non-crystalline form being suspended in inert organic
solvents, optionally in the presence of water, and being
treated at elevated temperatures until it is quantita-
tively converted into the crystalline modification, andthe resulting crystals of the crystalline modification
then being separated off by customary methods and, to
remove any solvent residues which may be present, dried
Le A 29 305 - 2 -

210848~
to constant weight at temperatures of +20C to +70C.
The duration of the conversion depends on the nature of
the solvent and the temperature selected. As a rule, it
amounts to several days to weeks.
Lower alcohols having 1 to 6 carbon atoms are preferably
employed as solvents; ethanol or isopropanol is pre-
ferably used. In this context, mixtures of the alcohols
with water in the ratio of one part of alcohol to 20
parts of water, preferably of one part of alcohol to 10
parts of water, are very particularly preferred. The use
of ethanol or isopropanolJwater mixtures in the ratio 1:8
is very particularly preferred.
The conversion of the non-crystalline form into the
crystalline form of the compound of the formula (I) is
usually effected by stirring or shaking the suspension at
elevated temperatures.
The separation of the crystals from the water/solvent
mixture takes place according to customary methods, such
as, for example, by filtration, decanting off, centri-
fugation or the like. Subsequently, the crystals aredried to constant mass at an elevated temperature, for
example at +50C or in vacuo.
The complete conversion of the non-crystalline form into
the crystalline modification is determined by DSC (dif-
ferential scanning calorimetry), spectroscopic or
Le A 29 305 - 3 -

- 2~0~86
crystallographic methods.
A more rapid process, which is particularly suitable for
preparing relatively large quantities of crystalline
active compound, is achieved with the aid of seed crys-
tals, by, for example, the non-crystalline active com-
pound being suspended in a mixture of water and ethanol
in the ratio 8:1, the suspension being heated to +70C,
some seeds of the crystalline active compound being
added, and the mixture being stirred for about 4 h until
the non-crystalline active compound has been quantita
tively converted into the crystalline active compound.
However~ if the time of stirring is extended, the com-
plete conversion can also be effected at an elevated
temperature below +70C, for example in a temperature
range of ~40~ to +60C, or in other solvent mixtures,
such as, for example, water and isopropanol, or in
solvent mixtures with other mixture ratios, such as, for
example, in mixtures of water and alcohol in the ratio of
15:1 to 25:1.
The crystalline modification of the (R)-(-)-2-cyclo-
heptyl-N-methylsulfony1- [4-(2-quinolinylmethoxy)-
phenyl]-acetamide according to the invention possesses a
characteristic IR spectrum.
The thermogram of the crystalline modification according
to the invention, recorded by means of DSC (differential
scanning calorLmetry) under atmospheric pressure, shows
an endothermic melting peak at 124-127C and thus differs
Le A 29 305 - 4 -

2108~6
unan~iguously from the thermograms of other forms of the
active compound.
soth the X-ray diffractograms and the 13C solid NMR
spectra are characteristic of the crystalline modifica-
tion according to the invention. The density of the
crystalline (R)-(~)-2-cycloheptyl-N-methylsulfonyl- t4-
(2-quino 1 inyl methoxy)-phenyl]-acetamide is 1.30 g/cm3.
The present invention also includes pharmaceutical
preparations which, besides inert non-toxic pharmaceuti-
cally suitable auxiliaries and vehicles, contain thecrystalline form of the compound of the formula (I)
according to the invention, or which comprise the crys-
talline modification of the compound of the formula (I),
as well as processes for producing these preparations. In
this context, solid drug forms and suspensions are to be
mentioned as being preferred. The crystalline active
compound is particularly suitable for preparing solid
medicament~, e.g. in the form of tablets, pill8, coated
tablets or capsules.
In these preparations, the novel crystalline modification
of the compound of the formula (I) should be present in
a concentration of 0.1 to 99.5~ by weight, preferably of
0.5 to 95~ by weight, of the total mixture.
As well as the crystalline modification of the compound
of the formula (I), the pharmaceutical preparations may
also contain other pharmaceutical active compounds.
Le A 29 305 - 5 _

21~84~6
The abovementioned pharmaceutical preparations can be
prepared in a customary manner by known methods, for
example with one or more auxiliaries or vehicles.
Preparation examples
Example 1
Preparation of seed crystals
1 g of non-crystalline active compound is suspended in a
water/isopropanol mixture (8 ml:1 ml), and stirred at
+50C for 14 days. The suspension is subsequently fil-
tered and dried in vacuo to constant mass.
Example 2
Crystallisation by seeding
1 g of non-crystalline active compound is suspended in a
water/ethanol mixture (8 ml:l ml), seeded with a few seed
crystals and stirred at +70C for 4 hours. The suspension
is subsequently filtered and dried to constant mass.
Le A 29 305 - 6 -

Representative Drawing