MXPA00009662A - Crystalline forms of 1s-[1alpha (2s*,3r*), 9alpha]-6, 10-dioxo-n- (2-ethoxy-5 -oxo-tetrahydro-3 -furanyl) -9-[[(1-isoquinolyl) carbonyl]-amino]octahydro-6h -piridazino[1, 2-a][1,2]diazepin- 1-carboxamide - Google Patents

Abstract

The invention concerns novel crystalline forms of 1S-[1alpha(2S*, 3R*),9alpha]-6, 10-dioxo-N- (2-ethoxy-5 -oxo-tetrahydro-3 -furanyl)-9-[[( 1-isoquinolyl) carbonyl]-amino]octahydro-6H -piridazino[1, 2-a][1,2]diazepin-1 -carboxamide, anhydrous (form A) and hydrated (form B), the method for preparing them, their use as medicine and the pharmaceutical compositions containing them.

Description

CRYSTALLINE SHAPES OF 1S- [1ALFA (2S *, 3R *), 9ALFA] -6, 10-DIOXO-N- (2-ETOXY-5-OXO-TETRAHYDRO-3-FURANIL) -9- [[(1- ISOQUINOLYL) CARBONIL] -AMINO] OCTAHI DRO- 6H- PIRIDAZINE [1, 2-A] [1, 2] DIAZ EPIN - 1 -CARBOXAMI DA FIELD OF THE INVENTION The present invention relates to two new crystalline forms of 1S- [lalfa (2S *, 3R *). 9alpha] -6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9- [[(1-isoquinolyl) carbonyl] amino] octahydro-6H-pyridazino [1, 2-a] [1, 2] diazepin-1-carboxamide (anhydrous or hydrated), its preparation process and the pharmaceutical compositions that contain them BACKGROUND OF THE INVENTION The patent application W09722619 describes the SS- [lalf a (2S *, 3R *). 9alpha] -6, 10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9- [ [(1-isoquinolyl) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] dia z epin-1-carboxamide REF .: 12367S as its pharmaceutically acceptable salts (product 412 f: Compound I) as inhibitors of the interleukin-beta conversion enzyme: The compound (I) as described and prepared in this application W09722619 is in an amorphous form. It mainly has the drawback of being hygroscopic. The preparation of compound (I) is carried out in the following manner: Reaction of amidification between (1S, 9S) 9- (isoquinolin-1-oylamino) -6, 10-dioxo-1, 2, 3, 4 acid, 7, 8, 9, 10-octahydro-6H-pyridazino- [1, 2-a] [1, 2] -diazepin-1-carboxylic acid and (3S, 2S) 3-allyloxycarbonylamino-2-benzyloxycarboxylic acid. -oxotetrahydrofuran in the presence of dimethylbarbium touric acid, tetrahydrofuran triazol, and 1 (3-dimethyl-t-aminopropyl) -3-ethylcarbodiimide hydrochloride in the chloride methylene, dimethylformamide or a mixture of these two solvents. The product is purified by chromatography (ethyl acetate / dichloromethane) to give the amorphous compound (I).

DESCRIPTION OF THE INVENTION The object of the invention is to find one or more new crystalline forms which do not have the disadvantages of the amorphous form. The solid forms, and especially the pharmaceuticals, may have more than one crystalline form. This is what is called the polymorphism. The polymorphic forms of the same molecule generally show the different physical properties such as solubility, hygroscopicity and stability. It should be noted that there are currently no methods to predict the existence of this or that polymorph, nor to predict its physical properties.

Obtaining the new polymorphic forms of molecules that have a therapeutic activity presents a great interest for the pharmaceutical industry mainly from the point of view of its preparation on an industrial scale, its implementation within the pharmaceutical compositions, the search for a better stability and better bioavailability. (Byrn, SR, Solid-State Chemistry of Drugs, New York, Academ. Press (1982), Kuhner T-Br and S tatt er, M, Thermomi cr os copy In the Analysis of Pharmaceuticals, New York, Pergamon Press (1971) J. Halebian et al., J. Pharm. Science (1969) - vol 58 (8) 911; 'J. Halebian et al., J. Pharm. Science (1975) vol 64 (8) 1269-1288). Polymorphic form is understood to mean all the asolvated forms of a crystallized molecule and pseudopoly or any solvated forms. The methods of analysis of the crystalline forms are the following: Thermal behavior: it is determined by DSC (difer ential scanning calorimetry) (differential calorimetric analysis): 2 to 5 mg of substance to be studied are weighed in a sealed aluminum capsule not hermetically . The analysis is carried out, under nitrogen sweep, from 25 to 350 ° C at a temperature rise rate of 20 ° C / min. IR (Infrared): The substance to be studied is dispersed in liquid paraffin oil. The analysis is carried out on an infrared to Fourier transform spectrophotometer (FTIR) of 4000 to 600 cm-1. RX (diffraction of X-rays on powder): The substance to be studied is distributed in the alveolus of a glass sample holder. The analysis is carried out by scanning from 2 ° to 38 ° (2 teta) with a step of 0.02 ° and 1 second of counting per step. The X-ray source is a Copper tube (45kV, 30mA). The applicant has revealed two new crystalline forms (form A and form B). Form A which is anhydrous and Form B which is hydrated. The crystalline form A presents, in addition to the advantages mentioned above, an absence of hygroscopic property (see test below). The invention thus mainly has as object, a new crystalline form of the SS- [lalfa (2S *, 3R *). 9alpha] 6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl). ) -9- [[(1-isoquinolyl) carbonyl] amino] octahydro-6H-pyridazino [1, 2-a] [1,2] diazepin-1-carboxamide anhydrous which is called form A. This form A has the characteristics following: Crystal system: triclinic to (A): 8.02; b (Á): 9.21; c (A) 17.70; alpha (grade): 91.38; beta (grade): 93.62; gamma (degree): 90.43; group of space P 1; Z 2. The invention also relates to a new crystalline form of 1S- [lalfa (2S *, 3R *) .9alf a] 6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3) -furanyl) -9 [[(1-isoquinolyl) carbonyl] amino] octahydro-6H-pyridazino [1, 2-a] [1, 2] diazepin-1-carboxamide hydrate which is called form B.

Form A has the following characteristics: The compound of the formula (I) anhydrous, as prepared by one of the methods indicated below, has a particular crystalline form (form A). The physical characteristics are described in Figures 1A (DSC) 2A (IR) and 3A (RX). DSC: Fusion endotherm from 168 ° C. IR (nujol.c "1): 3253; 1789; 1702; 1681; 1644 RX (d, Á): 17.73; 8.87; 8.11; 7.50; 7.17; 6.31; 6. 09; 5.81.

Form B has the following characteristics: The compound of the formula (I) hydrated, as prepared by one of the methods indicated below, has a particular crystalline form (form B). The physical characteristics are described in figures IB (DSC) 2B (IR) and 3B (RX). DSC: Dehydration endotherm between 50 and 110 ° C and between 110 and 130 ° C. A melting endotherm is observed from 162 ° C. IR (nujol, cm "1): 3569; 3447; 3322; 1778; 1682; 1660 RX (d, Á): 11.34; 10.80; 10.06; 7.59; 7.16; 6.71; 6. 41; 6.11; 5.44.

The subject of the invention is the form A as defined above having at least one of the following characteristics and preferably all the following characteristics: a) Fusion endotherm from 168 ° C, b) Infrared spectrum presenting the absorptions characteristic to approximately (nujol, cm "1): 3253; 1789; 1702; 1681; 1644, c) DX diffraction diagram that presents int e ticular characteristics equal to (d, Á): 17.73, 8.87, 8.11; 7.50; 7.17; 6.31; 6.09; 5.81 More particularly, the invention relates to form A as defined above having an infrared spectrum substantially identical to that of Figure 2A and a substantially identical diffraction pattern RX. to that of Figure 3A The invention also relates to form B as defined above having at least one of the following characteristics and preferably all of these characteristics. the following: a) Dehydration endotherm between 50 and 110 ° C and between 110 and 130 ° C and fusion endotherm from 162 ° C, b) Infrared spectrum of form B which has absorption characteristics of approximately (nujol, c "1): 3569; 3447; 3322; 1778; 1682; 1660, c) DX diffraction diagram of the form B that presents in t ere ti culare characteristics equal to (d, Á): 11.34; 10.80; 10.06; 7.59; 7.16; 6.71; 6.41; 6.11; 5.44 More particularly, the invention also relates to form B as defined above having an infrared spectrum substantially identical to that of Figure 2B and a X-ray diffraction diagram substantially identical to that of Figure 3B The present invention also has as its object a method of preparing form A or B, characterized in that the amorphous compound (I) obtained according to the defined method is dissolved further in an organic solvent or a mixture of these solvents, and mainly at room temperature, and after the crystallization is obtained the expected form A or B. The obtaining of the form A is preferably carried out by crystallization in an alcohol or an ether and mainly isopropyl ether, butanol or isopropanol. Form A is also obtained by crystallization in a mixture of these solvents, mainly in the ethanol / isopropyl ether mixture. The preparation of form B is carried out in particular by crystallization in toluene. The obtaining of the expected forms A or B can be, if necessary, initiated by a seeding of the solution with any crystals correspondingly of form A or B. The isolation of the forms A or B is carried out according to the methods known per se. the expert in the art. The crystalline forms A or B of the compound of the formula (I) have the same therapeutic activities as those described for the amorphous compound (I) in the application W097 / 22169 and WO95 / 35308.

They exhibit an inhibitory activity of ICE (interleukin-lbeta conversion enzyme) and are particularly useful in the treatment of inflammatory, autoimmune and neurodegenerative diseases. The subject of the invention is the crystalline forms A or B, as described above as a medicine. The crystalline forms A or B of the compound of the formula (I) can be used orally, parenterally, topically by inhalation, or via implants. They can be prescribed in the form of simple tablets or in the form of dragees, capsules, granules, suppositories, ovules, injectable preparations, ointments, creams, gels, microspheres, implants, patches. , which are prepared according to the usual methods. The crystalline forms A or B of the compound of the formula (I) can be mixed with the excipients, diluents and any vehicles known to the person skilled in the art for the manufacture of the pharmaceutical compositions. As an example of an excipient commonly used in these pharmaceutical compositions, mention may be made of talc, ointment, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of origin animal or vegetable, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives. The invention is thus understood for pharmaceutical compositions which include as active ingredient at least one of the crystalline forms A or B of the compound of the formula (I) as defined above and one or more excipients, diluents or pharmaceutically acceptable carriers. The subject of the invention is also the application of the crystalline forms A or B of the compound of the formula (I) as defined above for the preparation of a medicament intended to inhibit the ICE activity (conversion enzyme of the in ter 1 eucine - lbe ta). The following examples illustrate the invention without in any way limiting it.

EXAMPLE Ob t tion of Form A by crystallization in n-butanol To 300 mg of the amorphous compound I (obtained according to the method described in the application W09722619) is added 1.5 ml of n-butanol and stirred at room temperature for 2 hours 15. The crystallization of the product that dries and dries is observed at 20 ° C under 4mbar. 160 mg of the compound of the formula (I) anhydrous are obtained (form A).

EXAMPLE Obtaining form A by crystallization in isopropanol To 300 mg of the amorphous compound I (obtained according to the method described in the application W09722619) is added 1.5 ml of isopropanol and stirred at room temperature for 16 hours. The crystallization of the product that drained off and dried at 20 ° C under 4mbar is observed. 166 mg of the compound of the formula (I) anhydrous are obtained (form A).

EXAMPLE 3: Obtaining form B by crystallization in toluene To 300 mg of the amorphous compound I (obtained according to the method described in the application W09722619) is added 1.5 ml of toluene and stirred at room temperature for 16 hours. The crystallization of the product that drained off and dried at 20 ° C under 4mbar is observed. The compound of the formula (I) hydrated (form B) is obtained.

EXAMPLE 4: Obtaining form A by crystallization in a mixture of isopropyl ether / ethanol.

To 11.9 g of the amorphous compound (I), 23.8 ml of absolute ethanol are added under nitrogen and stirring and the suspension is heated at 60 ° + 2 ° C to obtain a solution. It is cooled to 40 ° + 2 ° C, crystallization starts and it is kept at this temperature for 1 hour. Then, 119 ml of isopropyl ether are added in 15 minutes at 40 ° + 2 ° C and maintained 15 minutes at this temperature. It cools 1 at -20X2 ° C in 15 minutes, it is kept for 1 hour in these conditions, then it is cooled again to 0 °, + 5 ° C in 15 minutes and stays 2 hours. It is drained, washed with isopropyl ether, dried under reduced pressure at 20 ° C for 12 hours and 11.3 g of the compound of the formula (I) anhydrous are obtained (form A).

Hygroscopicity curve (or water sorption isotherm) The sorption isotherms of the water have been obtained with the help of a Dynamic Vapor Sorption DVS 1 (Surface Measurements System Ltd) at a constant temperature and under a more or less hydrated nitrogen atmosphere. The relative humidity (RH) of the atmosphere has been modified by degrees. The passage from one grade or level to the next is carried out when the weight of the sample to be analyzed has reached a constant value.

During the sorption cycle form A is not hygroscopic (<0.2%). Non-hygroscopicity has been confirmed by leaving a sample for 7 days in a chamber at 96% relative humidity (at 32 ° C). An absorption of water of approximately 0.15% has been observed. The hydrate form (form B) is more hygroscopic (7% water) under the same conditions. It is the same when it comes to the amorphous form.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (16)

1. Crystalline form of IS '[lalfa (2S *, 3R *). 9alpha] 6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9- [[(1-isoquinolyl ) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] diazepin-1-carboxamide anhydrous (form A).

2. Crystalline form of 1S- [lalfa (2S *, 3R *) .9alpha] 6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9- [[(1-isoquinolyl ) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] diazepin-1-carboxamide anhydrous (form A) according to claim 1 having at least one of the following characteristics: a) fusion endotherm from 168 ° C,) infrared spectrum that has characteristic absorptions of approximately (nujol, c "1): 3253; 1789; 1702; 1681; 1644, c) diffraction diagram RX that presents int icul ares characteristics equal to (d, Á): 17.73; 11 7.50 7.17; 6.31; 6.09; 5.81.

3. Crystalline form of 1S- [lalfa (2S *, 3R *). 9alpha] -6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9- [[(1- isoquinolyl) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] diazepin-1 -carboxamide anhydrous (form A) according to claim 2, characterized in that it has characteristics a, b and c.

4. Crystalline form of 1S- [lalfa (2S *, 3R *) .9alpha] -6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9 [[(1-isoquinolyl ) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] tl / 2] diazepin-1-carboxamide anhydrous (form A) according to the rei indication 2 or 3, characterized in that it has an infrared spectrum substantially identical to that of Figure 2A and a diffraction diagram RX substantially identical to that of Figure 3A. characteristics equal to (d, Á): 11.34; 10.80; 10.06; 7.59; 7.16; 6.71; 6.41; 6.11; 5.44.

7. Crystalline form of 1S- [lalfa (2S *, 3R *), 9alpha] -6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9 [[(1-isoquinolyl ) car onyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] di az-epin-1-carboxylated hydrate (form B) according to claim 5, characterized in that it has the characteristics a, by c.

8. Crystalline form of 1S- [lalfa (2S *, 3R *), 9alpha] -6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9 [[(1-i soquinoli 1) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] diazepin-1-carbohydrate hydrate (form B) according to claim 6 6 7, characterized in that it has an infrared spectrum substantially identical to that of Figure 2B and a diagram of 1 characteristics equal to (d, A): 11.34; 10.80; 10.06; 7.59; 7.16; 6.71; 6.41; 6.11; 5.44.

7. Crystalline form of 1S- [lalfa (2S *, 3R *), 9alpha] -6,10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9 [[(1-isoquinolyl carbonyl] amino] octahydro-6H-pyridazino [1, 2-a] [1,2] diazepin-1-carboxamide hydrate (form B) according to claim 5, characterized in that it has characteristics a, b and c.

8. Crystalline form of 1S- [lalfa (2S *, 3R *), 9alpha] -6, 10-dioxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9 [[(1-isoquinolyl ) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] diazepin-1-carboxamide hydrate (form B) according to claim 6 or 7, characterized in that it has an infrared spectrum substantially identical to that of Figure 2B and a diagram of 2 RX diffraction substantially identical to that of Figure 3B.

9. A process for preparing form A or B according to any of claims 1 to 8, characterized in that the IS is mixed- [1 to fa (2 S *, 3R *), 9 to fa] 6, 10-di oxo-N- (2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9 [[(1-isoquinolyl) carbonyl] amino] octahydro-6H-pyridazino [1,2-a] [1,2] diazepin Amorphous-1-carboxamide in an appropriate organic solvent or a mixture of these solvents, mainly at room temperature, and after the crystallization the expected form A or B is obtained.

10. The preparation process of Form A, according to claim 9, characterized in that the solvent is an ether and mainly isopropyl ether.

11. The method of preparing form A, according to claim 9, characterized in that the solvent is an alcohol and especially n-butanol or isopropanol.

12. The process for the preparation of Form A, in accordance with the rei indication 9, characterized in that the crystallization takes place in a mixture of alcohol and ether and mainly in the mixture ethanol / isopropyl ether.

13. The preparation process of Form B, in accordance with the rei indication 9, characterized in that the solvent is toluene.

14. As the medicament, the crystalline forms A or B according to claims 1 to 8.

15. Pharmaceutical compositions characterized in that they include at least one medicament in accordance with rei indication 13 and one or more pharmaceutically acceptable excipients, diluents or carriers.

16. The application of the crystalline forms according to any of claims 1 to 8, for the preparation of a medicament intended to inhibit ICE activity (enzyme of conversion of the intercellulite).