Polymorphic form of rimonabant method for preparing it and pharmaceutical compositions containing it

1 . Crystalline polymorph of rimonabant (form II), characterized by the infrared spectrum absorption bands described below:

λ (cm −1 )

λ (cm −1 )

3311.30

1484.80

2787.23

986.57

1683.48

922.58

1526.55

781.02

2 . Crystalline polymorph of rimonabant, characterized by the X-ray powder diffractogram lines described below:

Peak

Angle

ångstroms

2-Theta°

d = 17.41664

5.070

d = 8.70963

10.148

d = 8.19062

10.793

d = 5.82785

15.191

d = 4.63425

19.136

d = 3.49212

25.486

3 . Crystalline polymorph of rimonabant, characterized by a melting peak at 157±2° C. with ΔH=66±2 J/g.

4 . Method for preparing the compound according to any one of claims 1 to 3 wherein:

a) rimonabant is dissolved in the hot state in a solvent chosen from:

methylcyclohexane in the pure state or containing 1 to 10% of water by volume,

acetonitrile

4-methyl-2-pentanone,

acetone,

or a mixture of these solvents;

b) where appropriate, the medium is cooled to a temperature of between 5° C. and 25° C.,

c) the crystals formed are filtered at a temperature of between 5° C. and 25° C.

5 . Method according to claim 4 wherein after step a), the medium is inoculated with rimonabant, crystalline form II.

6 . Method according to claim 4 wherein

a) rimonabant is dissolved at the concentration of 150 to 220 g/l by heating to the reflux temperature of a solvent consisting of methylcyclohexane containing 1 to 10% of water, and then either steps b), c) and d) below are carried out, or steps c) and d) are carried out directly;

b) the medium is cooled to a temperature of between 40° C. and 50° C., and then the medium is heated to a temperature of between 60° C. and 75° C. and maintained for 2 hours;

c) the temperature is reduced with a cooling step of −15° C. to −20° C. per hour up to a temperature of between 5° C. and 20° C.;

d) the crystals formed are filtered at a temperature of between 5° C. and 20° C.

7 . Method according to claim 6 wherein

in step a), the compound is dissolved at the concentration of 200 g/l in a solvent consisting of methylcyclohexane containing 1 to 5% of water, by heating to the reflux temperature of the solvent;

in step b), the medium is cooled to 45° C. over 30 minutes, and then the medium is heated to 70° C.±2° C. and the temperature is maintained for 2 hours;

in step c), the temperature is reduced with a step of −15° C. to −20° C. per hour up to a temperature of between 15° C. and 20° C.

8 . Method according to claim 4 wherein

a) rimonabant is dissolved at the concentration of 50 to 250 g/l in a solvent consisting of methylcyclohexane in the pure state or containing 1 to 10% of water;

b) the medium is cooled to a temperature of between 65° C. and 75° C. and allowed to stand for 2 hours at this temperature;

c) the medium is inoculated by addition of 1% to 5% by weight of rimonabant, crystalline form II;

d) the temperature is reduced with a cooling step of −15° C. to −20° C. per hour up to a temperature of between 10° C. and 20° C.;

e) the crystals formed are filtered at a temperature of between 10° C. and 20° C.

9 . Method according to claim 8 wherein

in step a), rimonabant is at the concentration of 120 to 150 μl;

in step b), the mixture is cooled to 70° C.;

in step c), the crystallization is initiated with 2% by weight of rimonabant in crystalline form II.

10 . Method according to claim 4 wherein

a) rimonabant is dissolved at the concentration of 200 to 250 g/l while heating to the temperature of the solvent consisting either of methylcyclohexane, or of methyl isobutyl ketone, or of acetone, or of the mixture of these solvents;

b) the temperature is reduced with a cooling step of −10° C. to −20° C. per hour until the nucleation begins, optionally the nucleating temperature is maintained for 1 hour;

c) the temperature is again reduced with a cooling step of —I 0° C. to −20° C. per hour until a temperature of between 10° C. and 20° C. is obtained;

d) the crystals are filtered at a temperature of between 10° C. and 20° C.

11 . Method according to claim 4 wherein

a) rimonabant is dissolved at the concentration of 120 to 250 g/l by heating at the reflux temperature of the solvent which is methylcyclohexane;

b) the mixture is cooled to a temperature of between 80° C. and 90° C.;

c) the medium is inoculated by adding 1% to 5% by weight of rimonabant in crystalline form II in suspension in methylcyclohexane and the temperature is maintained for one hour between 80° C. and 90° C.;

d) the temperature is reduced with a cooling step of −15° C. to −20° C. per hour up to a temperature of between 10° C. and 20° C.;

e) the crystals formed are filtered at a temperature of between 10° C. and 20° C.

12 . Method according to claim 11 wherein

in step a), rimonabant is dissolved at the concentration of 200 g/l in the solvent;

in step b), the mixture is cooled to 85° C.±2° C.;

in step c), the mixture is inoculated with 2% by weight of rimonabant form II, and then the temperature of the medium is maintained for one hour at 85° C.±2° C.

13 . Method according to claim 4 wherein

a) rimonabant is dissolved at room temperature in acetonitrile, to saturation;

b) the mixture is left to evaporate at room temperature;

c) the crystals formed are recovered.

14 . Method for prepareng the compound according to any one of claims 1 to 3 wherein

a) rimonabant at the concentration of 150 g/l to 300 g/l in methylcyclohexane is heated to a temperature of between 85° C. and 95° C.;

b) the medium is inoculated with 1% to 5% by weight of rimonabant in crystalline form II and the temperature is maintained between 85° C. and 95° C. for several hours until form I disappears;

c) the temperature is reduced with a cooling step of −15° C. to −20° C. per hour up to a temperature of between 10° C. and 20° C.;

d) the crystals formed are filtered at a temperature of between 10° C. and 20° C.

15 . Method according to claim 14 wherein in step a), rimonabant is prepared at the concentration of 150 μl to 300 μl in methylcyclohexane by treating 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid chloride in methylcyclohexane with 1-aminopiperidine in a mixture of methylcyclohexane and tetrahydrofuran in the presence of triethylamine.

16 . Pharmaceutical composition containing, as active ingredient, the crystalline polymorph of rimonabant (form II) according to claim 1 in combination with at least one pharmaceutical excipient.

17 . A method for treating diseases in which an antagonist of the CB 1 cannabinoid receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 1 .

18 . A method for treating diseases in which an antagonist of the CB 1 cannabinoid receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 2 .

19 . A method for treating diseases in which an antagonist of the CB 1 cannabinoid receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 3 .

20 . Pharmaceutical composition containing, as active ingredient, the crystalline polymorph of rimonabant (form II) according to claim 2 in combination with at least one pharmaceutical excipient.

21 . Pharmaceutical composition containing, as active ingredient, the crystalline polymorph of rimonabant (form II) according to claim 3 in combination with at least one pharmaceutical excipient.