WO2008064615A2

WO2008064615A2 - Crystalline and amorphous forms of rimonabant and processes for obtaining them

Info

Publication number: WO2008064615A2
Application number: PCT/CZ2007/000108
Authority: WO
Inventors: Stanislav Radl; Ludek Ridvan; Josef Cerny; Petr Hruby; Hana Petrickova; Jaroslav Havlicek; Tomas Pekarek
Original assignee: Zentiva, A.S.
Priority date: 2006-12-01
Filing date: 2007-12-03
Publication date: 2008-06-05
Also published as: WO2008064615A3

Abstract

Novel crystalline polymorphic Form III of rimonabant and an amorphous form of rimonabant. Crystalline form III of rimonabant is prepared by dissolving rimonabant in an aprotic polar solvent such as acetonitrile or tetrahydrofuran, pouring the solution into water and stirring the resulting mixture. Amorphous form of rimonabant is prepared by dissolving in and alcohol of formula ROH, wherein R is an alkyl, such as methanol or isopropyl alcohol, and stirring the mixture. Rimonabant of formula (I) is obtained in such a way that an ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid of formula (III), wherein R is a Cl-C5 alkyl group, phenyl group or a substituted phenyl group, preferably methyl or ethyl, is reacted, in a solvent, preferably in a solvent from the group of diethyl ether, tetrahydrofuran, dioxan, dichloromethane, acetonitrile, toluene or their mixtures, or in an excess of N-aminopiperidine, with N-aminopiperidine with catalysis by at least one Lewis acid at a temperature from 0° C to the boiling point of the solvent or mixture of solvents used. Pharmaceutical compositions containing the above forms and use of the above forms for the manufacture of a medicament the treatment of obesity, for curing of the habit of smoking or for the treatment of Alzheimer or Parkinson diseases are also described.

Description

Crystalline and amorphous forms of rimonabant and processes for obtaining them

Technical Field

The invention relates to a new crystalline form, called Form III, and to an amorphous form of N-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) of formula I, and to processes for obtaining them.

The compound of formula I acts as a selective antagonist of cannabinoid CBl receptors and is approved as a medicament for reducing appetite in the treatment of obesity.

Background Art

Rimonabant of formula I is prepared in accordance with the basic patent (EP 0 656 354, US 5 624 941) by a sequence of reactions leading to the key intermediate, the ethyl ester of 5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid, which is then converted to rimonabant by the following procedure:

(») (I) The starting ethyl ester is first transformed, by of alkaline hydrolysis, to 5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid of formula II. This acid is then transformed, by reaction with thionyl chloride, to the corresponding chloride, which provides rimonabant of formula I in a reaction with N-aminopiperidine.

The final crystallization from methyl cyclohexane provides a substance in crystalline form, which was later called Form I (WO 03/050105 Al). Recently it has been found out that rimonabant can also exist in other polymorphic forms, differing both in spectral characteristics and in physical and chemical properties. Patent applications WO 03/040105 Al and US 2005/043356 Al) describe and characterize said Form I, and further describe a form called Form II. The latter was obtained, under various conditions, from solutions of rimonabant in various mixed solvents containing, in addition to methyl cyclohexane, various cosolvents, for example tetrahydrofuran, 4-methyl-2-pentanone, sometimes also in the presence of water, either without inoculation, or after inoculation with crystals of said Form II.

Moreover, patent application of Cadilla (WO 2006/087332 Al) discloses an amorphous form and three crystalline polymorphs of rimonabant hydrochloride.

The above mentioned method suffers from the drawbacks of using thionyl chloride for the preparation of the corresponding acid chloride as well as of the fact that the reaction does not provide a very pure product the purification of which considerably reduces the achieved yield.

Disclosure of Invention

The present invention provides a new crystalline form and an amorphous form of N- piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) and to processes for obtaining the same. For said new forms it is possible to expect, similarly as for the previously described forms, activity in reducing the appetite, in curing of the habit of smoking or in the treatment of Alzheimer of Parkinson diseases. An economical process of preparing said forms has also been found out, which can also be used in the production scale. The present invention further provides an improved method of preparing N-piperidino-5-(4- chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant), based on aminolysis of alkyl or aryl esters of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid with TV-aminopiperidine. This solution is based on the surprising finding that although the corresponding esters do not virtually react with N- aminopiperidine under acceptable conditions, if one uses at least one Lewis acid in suitable solvents or in an excess of N-aminopiperidine at a temperature of from 0 °C to the boiling point of the solvent or mixture of solvents used, aminolysis can provide excellent yields of the compound of formula I. This surprising fact is evidenced by results in Examples 17 and 18.

Detailed description of the invention

It has turned out that with the use of a suitable Lewis acid in suitable solvents or in an excess of N-aminopiperidine some esters of general formula III can be transformed to rimonabant of formula I under mild conditions. In addition, in some cases better yields and/or a higher purity of the crude product have been achieved than with the use of the original procedure.

(III) (D

The procedure according to the invention can be preferably carried out as follows: During an otherwise usual procedure a suitable Lewis acid is added or two Lewis acids are gradually added to a mixture of the starting ester of formula III and a suitable solvent or a mixture of solvents and the mixture is stirred at a temperature from 0 °C to 40 °C for 5 minutes to 1 hour. The starting esters can be alkyl esters of formula III, wherein R is an unbranched or branched C1-C5 alkyl, preferably methyl, ethyl, /-propyl, or /-butyl, or aryl esters of formula III, wherein R is a phenyl or substituted phenyl. Suitable solvents include ethers, e.g. methyl-J- butyl ether, tetrahydrofuran or dioxan, chlorinated solvents, e.g. dichloromethane, chloroform or tetrachloromethane, aromatic hydrocarbons as e.g. benzene, toluene or xylene, non-polar aprotic solvents, e.g. acetonitrile, dimethylformamide, N-methylpyrrolidone or dimethylsulphoxide. Although in some cases slightly better yields are achieved with the use of anhydrous solvents, the reaction is not generally very sensitive to the humidity of the used solvents and all the results mentioned as examples have been achieved with the use of commercial solvents with technical purity. In general, a conclusion can be drawn that the solvents may contain water in a quantity of up to several percent without any significant impact of the yield. An excess of N-aminopiperidine is a preferable solvent, which can be subsequently easily recovered by mere distillation from the reaction mixture under atmospheric or preferably reduced pressure. Suitable Lewis acids include e.g. aluminum chloride, ferric chloride, boron trichloride, boron trifluoride etherate, tin chloride, tin trifluoromethanesulphonate, tin tetrachloride, zinc chloride, zinc bromide, zinc iodide, magnesium chloride, magnesium bromide, cerium trichloride, titanium tetrachloride, or titanium tetraisopropoxide, preferably aluminum chloride, zinc chloride or bromide, magnesium chloride or bromide or titanium tetrachloride. In some cases gradual addition of two Lewis acids have proved to be successful, e.g. aluminum chloride and boron trifluoride etherate or magnesium chloride and magnesium bromide.

Then, TV-aminopiperidine is added to the stirred mixture (1.0 to 50 equivalents, preferably 1.1 to 5 equivalents) and the mixture is stirred at a temperature from 0 °C to the boiling point of the solvent or the mixture of solvents used, preferably at a temperature from 25 °C to 80 ⁰C. This mixture can be either a homogeneous solution or suspension. After the reaction is complete, the mixture is cooled down and further processed. One of the possible ways of processing comprises evaporation of the respective solvent, preferably under a reduced pressure, addition of water and sucking off the insoluble fraction. In some cases successful processing consisted in pouring the crude reaction mixture into water or onto a mixture of ice and water and subsequent sucking off the crude product. One can proceed similarly also in the case of using water-insoluble solvents; in this case after the pouring of the crude reaction mixture into water or onto the water-ice mixture the aqueous and non-aqueous layers are separated and extracted with a suitable solvent.

N-Aminopiperidine can be used in the reaction as a base or this base may be released from a suitable inorganic salt, e.g. hydrochloride, hydro bromide, hydrogensulphate, sulphate or a salt with organic acids, e.g. benzoate, oxalate, hydrogen oxalate, maleate, tosylate, fumarate, etc. by the action of a suitable base, e.g. an alkali hydrogen carbonate, carbonate, acetate, t- butanolate, etc. or calcium oxide, magnesium oxide, etc. as well as with the use of suitable amines, e.g. pyridine, ethyl diisopropyl amine, triethylamine, or DBU. The advantages of using amines include a minimum increase of the thickness of the reaction mixture which is hence easy to stir.

The starting esters of formula III can be obtained from the acid of formula II by standard procedures used for esterification of carboxylic acids. For example, the methyl ester (III, R = methyl) can be easily obtained by the reaction of the acid of formula II with a methanolic hydrogen chloride solution. The ethyl ester of the acid (III, R = ethyl) is an intermediate of the synthesis of the acid of formula II and hence its use is especially preferable. The t-butyl ester (III, R = t-butyl) can be obtained by acid catalyzed reaction of 2-methylprop-l-ene with the acid of formula II or by other standard processes of synthesis of t-butyl esters. Aryl esters (III, R = phenyl, substituted phenyl) can be prepared by reaction of a chloride or mixed anhydride of the acid of formula III with the corresponding phenol or phenolate or by direct reaction of the acid with phenol in the presence of suitable reagents, e.g. phosphorus pentachloride.

Compared to the procedure of the basic patent the procedure according to the invention has the advantages of a high yield of the reaction, favourable reaction times and other reaction conditions as well as the avoidance of using thionyl chloride, which causes release of poisonous and acidic gases.

Development of a medicament should provide a product which is stable in physical and chemical terms and which has also optimal bioavailability. For practical reasons it is also necessary that the selected polymorph has appropriate physical properties in terms of handling and processing capability. Another requirement includes sufficient robustness of its production process. In case of polymorphic drugs, usually the thermodynamically most stable polymorph is preferred, which usually ensures reproducible bioavailability for the whole shelf life of the drug in various conditions of storage, encountered in practice. Another non-negligible advantage resides in the fact that production of such polymorph is usually more easily controllable also in larger production scales. In some case, however, a meta-stable or amorphous form is preferred for medical reasons. This is mainly the case when a higher concentration of the active substance in the system or more rapid dissolution with poorly soluble substances is required. For finding the optimal form for practical use in a pharmaceutical formulation it is therefore advantageous, in case of polymorphic drugs, to have several polymorphic forms of the drug as well as its amorphous form.

In studying the polymorphism of N-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (rimonabant) it has turned out that when solutions of this substance are poured into water under various conditions (the concentration of rimonabant, the ratio of the solution used and the temperature), in some cases formation of a new crystalline form occurs, which will be called Form III, or of an amorphous form of rimonabant. We have surprisingly found out that formation of crystalline Form III occurs not only in using rimonabant in said solvents but also in processing the reaction mixture containing a rimonabant solution by pouring the crude reaction mixture into water or onto an ice-water mixture. This process significantly simplifies the isolation of the product, which is very well filterable.

The crystalline Form III of N-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (rimonabant) according to this invention can be especially advantageously prepared if acetonitrile or tetrahydrofuran is used as the solvent, by pouring thus obtained solution into water, followed by stirring the resulting mixture. Form III can preferably be obtained by pouring a solution of rimonabant with a temperature of from 25 °C to the boiling point into water or into a mixture of ice and water. A usual concentration of the rimonabant solution is 5 - 30 % w/w and the ratio of solvent with water is usually 1/2 to 1/10. The reason is good reproducibility of the process both for small and large batches and, moreover, the process leads exclusively to a defined crystalline modification (¹³C CP-MAS NMR and XRPD); besides the process is characterized by high yields, which are obtained in a reproducible manner. The described process repeatedly provides crystalline Form III in the yields of 95 to 97 %. The enumerated properties of the crystalline Form III are very advantageous for its manufacture and pharmaceutical use.

The amorphous form of N-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (rimonabant) can be prepared in accordance with the present invention by dissolving rimonabant in an alcohol of general formula ROH, wherein R is an alkyl, such as methanol or isopropyl alcohol. Preferably it can be prepared if methanol is used as the solvent. Amorphous rimonabant can be obtained by pouring a solution of rimonabant with a temperature of from 25 °C to the boiling point into water or into a mixture of ice and water. A usual concentration of the rimonabant solution is 5 - 30 % w/w and the ratio of solvent with water is usually 1/2 to 1/10. The described process repeatedly provides the amorphous form according to the invention in the yields of 92 to 97 %.

Selection of a suitable analytical methodology, which is capable of unambiguously characterizing, distinguishing and determining all the solid forms of the compound studied, is also an important aspect of the polymorphism of pharmaceutical substances. This is necessary not only for determination of phase purity of the form chosen for the manufacture (amorphous, polymorphic, solvato-morphic), but also in patent disputes. Both the crystalline structure of the crystalline Form III and the amorphous form of 7V-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) have been unambiguously characterized by the results of the following analytical methods: X-ray powder diffraction (XRPD), melting point, ¹³C CP-MAS NMR, IR spectroscopy. The results are presented in the Examples and in the annexed Figures.

Crystalline Form III prepared by the method of the invention displays, as measured by the method of X-ray diffraction by the radiation of CuKa (λ = 1.542 A), reflections at diffraction angles 9.26; 10.47; 13.49; 17.07 and 17.76 °2Θ, ascertained with accuracy of ±0.2 °2Θ. In a preferable embodiment said crystalline form is characterized by additional reflections at diffraction angles 15.23; 16.30; 20.77 and 22.88 °2Θ under the same conditions.

The crystalline Form III has proved sufficiently stable in the stability studies carried out under standard conditions. During these studies no remarkable decomposition or transformation of the crystalline form has occurred. In comparable conditions, the amorphous form according to the invention was stable for 6 months.

Advantages of the new crystalline Form III as well as of the amorphous form of iV-piperidino- 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) include also easy performance of their manufacturing process and easy performance of said process in the industrial scale. Both the new crystalline Form III and the amorphous form of N-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) have proved suitable for development of novel formulations, which is another advantage.

The present invention also extends to pharmaceutical compositions, containing any of the above-described crystalline or amorphous forms, in combination with pharmaceutically acceptable excipients. It also covers medicinal formulations comprising said compositions.

The invention also relates to use of the above-described crystalline and amorphous forms for the manufacture of medicaments for the treatment of obesity, for curing of the habit of smoking or for the treatment of Alzheimer or Parkinson diseases.

The invention is described in more detail in the following Examples. These Examples, which illustrate the improvement of the method of preparing rimonabant, only have an illustrative character and do not limit the scope of the invention in any respect.

Brief Description of Drawings

Fig. 1 depicts a ¹³C CP-MAS NMR spectrum of crystalline Form I of rimonabant prepared according to Example 26.

Fig. 2 depicts a ¹³C CP-MAS NMR spectrum of crystalline Form II of rimonabant prepared according to Example 27.

Fig. 3 depicts a ¹³C CP-MAS NMR spectrum of crystalline Form III of rimonabant prepared according to Examples 19, 20, 21, 22 and 23.

Fig. 4 depicts a ¹³C CP-MAS NMR spectrum of the amorphous form of rimonabant prepared according to Examples 24 and 25.

Fig. 5 depicts an IR spectrum of crystalline Form I of rimonabant prepared according to Example 26. Fig. 6 depicts an IR spectrum of crystalline Form II of rimonabant prepared according to Example 27.

Fig. 7 depicts an IR spectrum of crystalline Form IIII of rimonabant prepared according to Examples 19, 20, 21 , 22 and 23.

Fig. 8 depicts an IR spectrum of the amorphous form of rimonabant prepared according to Examples 24 and 25.

Fig. 9 depicts an XRPD pattern of the amorphous form of rimonabant prepared according to Examples 24 and 25.

Fig. 10 depicts an XRPD pattern of crystalline Form III of rimonabant prepared according to Examples 19, 20, 21, 22 and 23.

Fig. 11 depicts a comparison of XRPD patterns of crystalline Forms I, II and III of rimonabant prepared according to Examples 19, 20, 21, 22, 23, 26 and 27.

Examples

Example 1

7V-Piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamidε (I)

A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carrboxylate (III, R = Et) (0.5 g), acetonitrile (10 ml) and MgCl₂ (0.58 g) was stirred at the room temperature for 10 minutes. Then, N-aminopiperidine was added in a single dose (0.49 g) and the mixture was refluxed in an inert atmosphere for 2 hours. After adding water (50 ml) the formed precipitate was sucked off, washed with water and dried; 0.57 g of the crude substance was obtained whose crystallization from cyclohexane provided 0.47 g (83%) of the product (I) with the purity of 99.7 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105). Example 2

N-Piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I)

Using the procedure described in Example 1, wherein MgBr₂ (0.7 g) was used as the Lewis acid, 0.45 g (81 %) of the product of formula I was obtained with the purity of 99.6 %; m.p. 156-158 ⁰C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 3

iV-Piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I)

Using the procedure described in Example 1, wherein tetrahydrofuran (10 ml) was used as the solvent, 0.55 g of the crude substance was obtained with the purity of 93.5%. Crystallization from cyclohexane yielded 0.44 g (77 %) of the product of formula I with the purity of 99.5 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 4

Λ^LPiperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I)

Using the procedure described in Example 1, wherein tetrahydrofuran (10 ml) was used as the solvent and MgBr₂ (1.1 g) was used as the Lewis acid, 0.54 g of the crude substance was obtained with the purity of 97.5 %. Crystallization from cyclohexane provided 0.46 g (81 %) of the product of formula I with the purity of 99.6 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 5

Using the procedure described in Example 1, wherein AlCl₃ (0.7 g) was used as the Lewis acid, 0.54 g of the crude substance was obtained with the purity of 96.8 %. Crystallization from cyclohexane provided 0.43 g (75 %) of the product of formula I with the purity of 99.4 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 6

A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyύ)-4-methyl-lH-pyrazol-3- carboxylate (III, R = Et) (0.5 g), toluene (10 ml) and MgCl₂ (0.58 g) was stirred at the room temperature for 10 minutes. Then, N-aminopiperidine (0.49 g) was added in a single dose and the mixture was refluxed for 3 hours. After cooling the reaction mixture was washed with a 1% solution of acetic acid and saline. After MgSO₄ drying and evaporating in a vacuum evaporator 0.5 g of the crude substance was obtained with the purity of 97.2 %. Crystallization from cyclohexane provided 0.43 g (75 %) of the product of formula I with the purity of 99.7 %, m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 7

N-Piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I)

Using the procedure described in Example 1, wherein MgBr₂ (1.1 g) was used as the Lewis acid, 0.51 g of the product of formula I was obtained with the purity of 96.9 %. Crystallization from cyclohexane provided 0.45 g (79%) of the product of formula I with the purity of 99.6%; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 8

A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- cyrboxylate (III, R = Et) (5 g) and MgBr₂ (6.74 g) in iV-aminopiperidine (25 ml) was stirred at the temperature of 80 °C for 4 hours. Then, a part of N-aminopiperidine (15 ml) was removed by distillation under the atmospheric pressure and 200 ml of water were added to the reaction mixture. The formed precipitate was sucked off, washed with water and dried. 5.5 g of the crude substance was obtained with the purity of 97.8%. Crystallization from cyclohexane provided 4.5 g (79 %) of the product of formula I with the purity of 99.5 %, m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 9

Using the procedure described in Example 1 with the use of methyl 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-l//-pyrazole-3-carboxylate (III, R = Me), 0.44 g (80 %) of the product of formula I was obtained with the purity of 99.7 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 10

Using the procedure described in Example 9, wherein tetrahydrofuran (10 ml) was used as the solvent, 0.53 g of the crude substance was obtained with the purity of 94.1 %. Crystallization from cyclohexane yielded 0.47 g (82 %) of the product of formula I with the purity of 99.6 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 11

jV-Piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I)

Using the procedure described in Example 9, wherein tetrahydrofuran (10 ml) was used aδ the solvent and MgBr₂ (1.1 g) was used as the Lewis acid, 0.57 g of the crude substance was obtained with the purity of 94.8 %. Crystallization from cyclohexane provided 0.45 g (79%) of the product of formula I with the purity of 99.5 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105). Example 12

7V-Piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I)

A mixture of phenyl 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3- carboxylate (III, R = Ph) (0.5 g), acetonitrile (15 ml) and MgCl₂ (0.52 g) was stirred at the room temperature for 10 minutes. Then, iV-aminopiperidine (0.55 g) was added in a single dose and the mixture was reflux ed for 2 hours. After adding of water (75 ml) the reaction mixture was extracted with dichloromethane (30 ml); the combined extracts were washed with saline and dried with MgSO₄. After evaporation 0.5 g of the crude product was obtained with the purity of 98.1 %. Crystallization from cyclohexane provided 0.44 g (77 %) of the product of formula I with the purity of 99.6 %. M.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 13

A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- . carboxylate (III, R = Et) (0.5 g), tetrahydrofuran (15 ml) and MgCl₂ (0.52 g) was stirred at the room temperature for 10 minutes. Then, N-aminopiperidine (0.5 g) was added in a single dose and the mixture was stirred at the room temperature for 24 hours. After that, MgBr₂ (0.5 g) and tetrahydrofuran (10 ml) were added and the mixture was stirred at the room temperature for 12 hours. After adding of water (75 ml) the reaction mixture was extracted with dichloromethane (30 ml); the combined extracts were washed with saline and dried with MgSO₄. After evaporation 0.5 g of the crude product was obtained with the purity of 94.8 %. Crystallization from cyclohexane provided 0.43 g (75 %) of the product of formula I with the purity of 99.6 %. M.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105). Example 14

A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (0.5 g), acetonitrile (10 ml) and MgCl₂ (0.58 g) was stirred at the room temperature for 10 minutes. Then, triethylamine (0.68 ml) and N-aminopiperidine hydrochloride (0.67 g) were added at once and the mixture was refluxed in an inert atmosphere for 4 hours. After addition of water (50 ml) the formed precipitate was sucked off, washed with water and dried; 0.47 g of the crude substance with the purity of 99.0% was obtained. Crystallization from cyclohexane provided 0.44 g (77 %) of the product of formula I with the purity of 99.6 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 15

N-Aminopiperidine hydrochloride (0.67 g) and t-BuOK (0.55 g) were stirred in acetonitrile (10 ml) at the room temperature for 30 min. Then, ethyl 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylate (III, R = Et) (0.5 g) and MgCl₂ (0.58 g) were added and the mixture was refluxed in an inert atmosphere for 4 hours. After adding of water (50 ml the formed precipitate was sucked off, washed with water and dried; 0.50 g of the crude substance was obtained with the purity of 90.0 %. Crystallization from cyclohexane provided 0.35 g (61%) of the product of formula I with the purity of 99.2 %; m.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

Example 16

Using the procedure described in Example 14, wherein N-aminopiperidine hydrogen sulphate was used as the salt instead of the hydrochloride and triethylamine was used as the base, 0.54 g of the crude substance was obtained with the purity of 97.2 %. Crystallization from cyclohexane provided 0.44 g (77 %) of the product of formula I with the purity of 99.3 %. M.p. 156-158 °C. An XRPD analysis confirmed the crystalline form I (WO 03/040105).

5 Example 17

Comparison of the reactivity of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-cyrboxylate (III, R = Et) with N-aminopiperidine without and in the presence of MgCl₂

10

A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (1 g, 2.5 mmol), dry MgCl₂ (1.16 g) and the corresponding solvent (20 ml) was stirred (700-900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Dry tetrahydrofuran (Experiment 1), dried over sodium (water content 0.07 %), dry

15 acetonitrile Aldrich (cat. no. 271004, water content < 0.005 %) (Experiment 3) and N- aminopiperidine Aldrich (cat. no. A75900) (Experiment 5) were used as the solvents. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 4

20 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ΗPLC analysis was performed. Table 1 summarizes the results of these experiments.

25 Table 1 - ΗPLC evaluation of reaction mixtures after 2 and 4 hours

Example 18

5 Comparison of the reactivity of esters of 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid (III, R = Me, Et, Ph) with s jV-aminopiperidine without and in the presence OfMgCl₂

A mixture of the respective ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-

10 pyrazole-3-carboxylic acid of formula III (2.5 mmol), dry MgCl₂ (1.16 g) and acetonitrile (20 ml; acetonitrile Aldrich, cat. no. 271004, water content < 0.005 % of weight) was stirred (700- 900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without

15 the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 4 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ΗPLC analysis was performed. Table 2 summarizes the results of these experiments.

20

Table 2 - ΗPLC evaluation of the reaction mixtures after 2 and 4 hours

Description of the analytic method - HPLC analysis

Device: HP 1050 (Agilent Technologies), autosampler 1100, ChemStation

(Agilent)

Column: Phenomenex Luna Ci₈ 5μ (250 x 4.60 mm)

Flow rate: 1 ml / min

Column temp. _: 25 °C

Detection: UV 225 nm

Eluent A: acetonitrile (25) : H₂O (1000) : H₃PO₄ (1)

Eluent B: acetonitrile (1000) : H₂O (25) : H₃PO₄ (1)

Gradient elution:

Time A% B%

3 100 0

23 0 100

40 0 100

42 100 0

45 100 0

Example 19

A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carrboxylate (30 g), acetonitrile (350 ml) and MgCl₂ (34.86 g) was stirred at the room temperature for 10 minutes. Then, N-aminopiperidine was added in a single dose (29.34 g) and the mixture was refluxed in an inert atmosphere for 2 hours. After adding water (1250 ml) the formed precipitate was sucked off, washed with water and dried; 33.5 g of the crude product (I) with the purity of 99.1 %; m.p. 100.4 °C. XRPD analysis, ¹³C CP-MAS NMR and IR spectroscopy confirmed Form III. Example 20

7V-Piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I), Form III

N-Piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (5 g) was dissolved in acetonitrile (35 ml) at the boil and poured when boiling into a mixture of ice and water (120 g) under vigorous stirring. After 30 min the crystals were filtered, washed with water and dried in a vacuum dryer at 30 °C. 4.77 g of Form III were obtained.

Example 21

N-Piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I), Form III

N-Piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (5 g) was dissolved in acetonitrile (35 ml) at the boil and, after cooling down to the room temperature, poured into water (120 ml) under vigorous stirring. After 30 min the crystals were filtered, washed with water and dried in a vacuum dryer at 30 ⁰C. 4.73 g of Form III were obtained.

Example 22

Following the procedure described in Example 20, using tetrahydrofuran (35 ml) as the solvent, 4.58 g of Form III were obtained. Example 23

Λ^LPiperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I), Form III

Following the procedure described in Example 21, using tetrahydrofuran (35 ml) as the solvent, 4.61 g of Form III were obtained.

Example 24

N-Piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I), amorphous form

Following the procedure described in Example 20, using methanol (35 ml) as the solvent, 4.62 g of an amorphous form were obtained; m.p. 157±2 °C. the amorphous form was confirmed by XRPD analysis, ¹³C CP-MAS NMR and IR spectroscopy.

Example 25

Following the procedure described in Example 21, using methanol (35 ml) as the solvent, 4.64 g of the amorphous form were obtained.

Example 26

N-Piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I), Form I

Following the procedure described in EP 0 656 354, Form I was prepared; m.p. 157±2 ⁰C. Form I was confirmed by XRPD analysis, ¹³C CP-MAS NMR and IR spectroscopy. Example 27

τV-Piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (I), Form II

Following the procedure described in US 2005/0043356 Al, Form II, was prepared; m.p. 157±2 °C. Form II was confirmed by XRPD analysis, ¹³C CP-MAS NMR and IR spectroscopy.

ANALYTICAL DATA (A-D): The following analytical data unambiguously characterize the crystalline Form III and amorphous form of N-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant).

A X-Ray Powder Diffraction

The XRPD patterns of crystalline Form III of iV-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant), which were prepared according to Examples 19, 20, 21, 22 and 23, are shown in Fig. 10.

The XRPD pattern of the amorphous form of N-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant), which was prepared according to Examples 24 and 25, is shown in Fig. 9.

Fig. 11 shows a comparison of crystalline Forms I, II and III.

The values of the characteristic diffraction angles of crystalline Form III of N-piperidino-5-(4- chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) are given in Table 1.

Experimental conditions: The diffraction patterns were obtained by measuring in the X'PERT PRE MPD PANalytical laboratory X-ray diffractometer in the reflection mode θ - θ with the CuKa (λ=1.542 A, 45 kV/40 mA) copper lamp, a graphite monochromator, in the range of 2 - 40 °2Θ with a the step of 0.01 °2Θ on a flat sample with area/thickness 10/0.5 mm. The characteristic diffraction patterns, corresponding to forms A and B are in Figs. 1 and 2.

Table 1. Values of characteristic diffraction 2Θ angles and interplanar distances d of crystalline Form III of 7V-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (rimonabant).

B IR Spectroscopy

The spectra were measured in the Perkin Elmer Spectrum BX apparatus by the diffusion reflectance method. The ER spectra of crystalline Form I of N-piperidino-5-(4-chlorophenyl)- l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant), which was prepared according to Example 26, are shown in Fig. 5.

The IR spectra of crystalline Form II of N-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant), which was prepared according to Example 27, are shown in Fig. 6.

The ER spectra of crystalline Form III of N-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant), which were prepared according to Examples 19, 20, 21, 22 and 23, are shown in Fig. 7.

The ER spectra of the amorphous form of N-piperidino-5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant), which were prepared according to Examples 24 and 25, are shown in Fig. 8.

The values of the characteristic absorption bands of crystalline Form I of 7V-piperidino-5-(4- chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) are given in Table 2.

The values of the characteristic absorption bands of crystalline Form II of N-piperidino-5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) are given in Table 2.

The values of the characteristic absorption bands of crystalline Form III of 7V-piperidino-5-(4- chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) are given in Table 2. The values of the characteristic absorption bands of the amorphous form of 7V-piperidino-5-(4- chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) are given in Table 2.

Table 2. Values of characteristic absorption bands of crystalline Forms I, II and III and of the amorphous form of jV-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (rimonabant) in IR spectra.

Melting Point

The melting points of crystalline Forms I, II and III and of the amorphous form of TV- piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) were measured in the Kofler block with the sample heating rate of 10 °C (up to 150 °C) and 4 ⁰C (above 150 °C) per minute. The measured values of the melting points are found in the temperature range from 80 to 160 ⁰C. The typical values of the melting points are given in the Examples.

D Solid State Carbon NMR Spectra (13C CP-MAS NMR)

The NMR spectra of crystalline Form III and of the amorphous form of iV-piperidino-5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant) for the ¹³C carbon isotope were measured in the Avance 500 Bruker spectrometer with the measuring frequency 125.76 MHz by the CP/MAS technique with 15 kHz rotation of the sample. The obtained spectra are shown in Figs. 1-4.

Claims

C L A I M S

1. Crystalline form III of N-piperidino-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide (rimonabant) of formula I

characterized by an X-ray diffraction pattern, displaying reflections at the diffraction angles 9.26; 10.47; 13.49; 17.07 and 17.76 °2Θ, determined with accuracy to ±0.2 °2Θ.

2. Crystalline form according to claim 1, characterized by further reflections at the diffraction angles 15.23; 16.30; 20.77 and 22.88 °2Θ.

3. Crystalline form III of rimonabant, characterized by the X-ray diffraction depicted in

Fig. 10.

4. Crystalline form III of rimonabant, characterized by the following chemical shifts in tthhee ¹¹³³CC CCPP--MMAASS NNMMRR ssppeeccttrruumm:: 116611..7733;; 115599..7788;; 11-45.19; 143.42; 135.17; 130.86; 128.26; 120.18; 118.90; 56.80; 27.34; 22.63; 11.09.

5. Crystalline form III of rimonabant, characterized by the ¹³C CP-MAS NMR spectrum depicted in Fig. 3.

6. Crystalline form III of rimonabant, characterized by the following values of characteristic absorption bands in the IR spectrum: 2942 (C-H str.); 1686 (C=O str.); 1526 (N-H def); 1494 (C=C str.); 1093 (Ar); 833 (Ar).

7. Crystalline form III of rimonabant, characterized by the ER spectrum depicted in Fig. 7.

8. Amorphous form of rimonabant, characterized by X-ray diffraction with two broad bands in the range of angles 4 to 12 °and 12 to 30 °.

9. Amorphous form of rimonabant, characterized by the X-ray diffraction depicted in Fig. 9.

10. Amorphous form of rimonabant, characterized by the following chemical shifts in the 1³C CP-MAS NMR spectrum: 161.65; 159.73; 143.47; 135.49; 130.57; 128.54; 118.79; 56.82; 27.34; 22.68; 11.10.

11. Amorphous form of rimonabant, characterized by the ¹³C CP-MAS NMR spectrum substantially as depicted in Fig. 4.

12. Amorphous form of rimonabant, characterized by the following values of characteristic absorption bands in the IR spectrum: 2935 (C-H str.); 1682 (C=O str.); 1527 (N-H def); 1494 (C=C str.); 1097 (Ar); 833 (Ar).

13. Amorphous form of rimonabant, characterized by the IR spectrum depicted in Fig. 8.

14. A process for the preparation of crystalline form III according to claim 1, characterized in that rimonabant is dissolved in an aprotic polar solvent such as acetonitrile or tetrahydrofuran, thus obtained solution is poured into water and the resulting mixture is subsequently stirred.

15. The process according to claim 14, characterized in that the temperature of the solution of rimonabant is from 10 ⁰C to the boiling point of the solvent used, preferably between 20 and 50 ⁰C.

16. The process according to claim 14, characterized in that the temperature of the water used is from 0 °C to the boiling point of the solvent used, preferably between 20 and

50 °C.

17. The process according to claim 14, characterized in that the concentration of the solution of rimonabant is from 1 to 50 %, preferably between 10 and 20 %.

18. The process according to claim 14, characterized in that the volume ratio of the solution used to the water used is from 1 : 1 to 1 : 10, preferably between 1: 2.5 and 1 :

5.

19. The process according to claim 14, characterized in that the resulting mixture is stirred at a temperature from 0 to 40 °C for 0 to 2 hours, preferably for 0.5 hours.

20. The process according to claim 14, characterized in that rimonabant is prepared by reacting an ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole- 3-carboxylic acid of formula III

wherein R is a C1-C5 alkyl group, phenyl group or a substituted phenyl group, preferably methyl or ethyl, with TV-aminopiperidine in a solvent, preferably in a solvent from the group consisting of diethyl ether, tetrahydrofuran, dioxan, dichloromethane, acetonitrile, toluene or their mixtures, or in an excess of N-aminopiperidine, with catalysis by at least one Lewis acid at a temperature from 0 °C to the boiling point of the solvent or mixture of solvents used.

21. A process for the preparation of the amorphous form according to claim 8, characterized in that rimonabant is dissolved in an alcohol of general formula ROH, wherein R is an alkyl, such as methanol or isopropyl alcohol, and thus obtained solution is poured into water and the resulting mixture is subsequently stirred.

22. The process according to claim 21, characterized in that the temperature of the solution of rimonabant is from 10 ⁰C to the boiling point of the solvent used, preferably between 20 and 50 °C.

23. The process according to claim 21, characterized in that the temperature of the water used is from 0 ⁰C to the boiling point of the solvent used, preferably between 20 and 50 °C.

24. The process according to claim 21, characterized in that the concentration of the solution of rimonabant is from 1 to 40 %, preferably between 10 and 20 %.

25. The process according to claim 21, characterized in that the volume ratio of the solution used to the water used is from 1 : 1 to 1 : 10, preferably between 1 : 2.5 and 1 : 5.

26. The process according to claim 21, characterized in that the resulting mixture is stirred at a temperature from 0 to 40 °C for 0 to 2 hours, preferably for 0.5 hours.

27. The process according to claim 21, characterized in that rimonabant is prepared by reacting an ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole- 3-carboxylic acid of formula III

wherein R is a C1-C5 alkyl group, phenyl group or a substituted phenyl group, preferably methyl or ethyl, with N-aminopiperidine in a solvent, preferably in a solvent from the group consisting of diethyl ether, tetrahydrofuran, dioxan, dichloromethane, acetonitrile, toluene or their mixtures, or in an excess of TV-aminopiperidine, with catalysis by at least one Lewis acid at a temperature from 0 °C to the boiling point of the solvent or mixture of solvents used.

28. A method of preparing rimonabant of formula I

(I)

characterized in that an ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid of formula III, wherein R is a C1-C5 alkyl group, phenyl group or a substituted phenyl group, preferably methyl or ethyl,

is reacted, in a solvent, preferably in a solvent from the group consisting of diethyl ether, tetrahydrofuran, dioxan, dichloromethane, acetonitrile, toluene or their mixtures, or in an excess of TV-aminopiperidine, with N-aminopiperidine with catalysis by at least one Lewis acid at a temperature from 0 ⁰C to the boiling point of the solvent or mixture of solvents used.

29. The method according to claim 28, characterized in that a solvent with a water content up to 5 % by weight is used.

30. The method according to claim 28, characterized in that a solvent with a water content up to 1% by weight is used.

31. The method according to claim 28, characterized in fact that a solvent with a water content up to 0.1 % by weight is used.

32. The method according to claim 28, characterized in fact that the methyl ester (III, R = methyl) is used as the ester.

33. The method according to claim 28, characterized in fact that the ethyl ester (III, R = ethyl) is used as the ester.

34. The method according to claim 28, characterized in fact that the phenyl ester (III, R = phenyl) is used as the ester.

35. The method according to claim 28, characterized in that tetrahydrofuran is used as the solvent.

36. The method according to claim 28, characterized in that acetonitrile is used as the solvent.

37. The method according to claim 28, characterized in that toluene is used as the solvent.

38. The method according to claim 28, characterized in that an excess of N- aminopiperidine is used as the solvent.

39. The method according to claim 28, characterized in that magnesium chloride is used as the Lewis acid.

40. The method according to claim 28, characterized in that magnesium bromide is used as the Lewis acid.

41. The method according to claim 28, characterized in that aluminum chloride is used as the Lewis acid.

42. The method according to claim 28, characterized in that a mixture of magnesium chloride and magnesium bromide is used as the Lewis acid.

43. The method according to claims 28-42, characterized in that iV-aminopiperidine is released directly in the reaction mixture by the action of a base upon a salt of TV- aminopiperidine.

44. The method according to claim 43, characterized in that iV-aminopiperidine hydrochloride is used as the salt.

45. The method according to claim 43, characterized in that N-aminopiperidine hydrogensulphate is used as the salt.

46. The method according to claims 43-45, characterized in that sodium bicarbonate is used as the base.

47. The method according to claims 43-45, characterized in that pyridine is used as the base.

48. The method according to claims 43-45, characterized in that triethylamine is used as the base.

49. A pharmaceutical composition, characterized in that it contains the crystalline Form III of rimonabant according to any of claims 1-7 or the amorphous form according to any of claims 8-13 or a mixture thereof in combination with at least one suitable pharmaceutically acceptable excipient.

50. A pharmaceutical formulation, characterized in that it comprises a pharmaceutical composition containing the crystalline Form III of rimonabant according to any of claims 1-7 or the amorphous form according to any of claims 8-13 or mixtures thereof.

51. Use of the crystalline Form III of rimonabant according to any of claims 1-7 or of the amorphous form according to any of claims 8-13 for the manufacture of a medicament for the treatment of obesity, for curing of the habit of smoking or for the treatment of Alzheimer or Parkinson diseases.