MXPA00003857A - Novel polymorphic forms of cipamfylline - Google Patents

Abstract

This invention relates to novel crystalline polymorphic forms, Form I, II and IV of Cipamfylline, methods of preparation, and use thereof in the treatment of PDE4 and TNF mediated diseases. Cipamfylline is 1,3-di-cyclopropylmethyl-8-amino xanthine, and represented by formula (I).

Description

NEWLY POLYMORPHIC FORMS OF CIPAMF1LINA FIELD OF THE INVENTION This invention relates to novel crystalline polymorphic forms of cipamfilin and to methods for preparing them.

BACKGROUND OF THE INVENTION The ability to exist in different crystal structures is known as polymorphism, and it is known to occur in many organic compounds. These different crystalline forms are known as "polymorphic modifications" or "polymorphs", and they occur in their crystalline state. Although the polymorphic modifications have the same chemical composition, they differ in packing, geometric arrangement and other descriptive properties of the crystalline solid state. As such, these modifications can have different physical properties in the solid state such as shape, color density, hardness, deformation capacity, stability, dissolution properties, etc. The polymorphism of an organic drug molecule and its consequences will be appreciated by the person skilled in the art. Cipamfilin, 1,3-di-cyclopropylmethyl-8-amino xanthine, has the chemical formula C? 3H17N5O2, molecular weight of 275.31, and the following structural formula: Its synthesis is described in example 9, in Maschier et al., Great Britain patent application No. 8906792.0, filed on March 23, 1989, in its corresponding EPO patent EP 389282, and corresponding US patent 5,734,051, The descriptions are incorporated herein by reference in their entirety. Cipamfilin is an inhibitor of PDE4 and is useful in the treatment, including prophylaxis, of disease states mediated by it. Cipamfilin fe also described as having TNF inhibitory activity in Esser et al., PCT / US91 / 08734 (also published as EP 558659), and is therefore useful in the treatment, including prophylaxis, of disease states mediated by TNF. . Tests, dosage forms, dosing scales, etc. Suitable for the polymorphs of this invention for use in the therapeutic treatment of diseases, can be found in the patent applications of Maschier et al. or from Esser et al., whose descriptions are incorporated herein in their entirety as a reference.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a novel crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine, referred to in the following as Form I, whose form of said compound is useful in the treatment of diseases mediated by PDE4 or FNT. This invention also relates to a novel crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine, referred to in the following as Form II, whose form of said compound is useful in the treatment of diseases mediated by PDE4 or FNT . This invention also relates to a novel crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine, referred to in the following as Form IV, whose form of said compound is useful in the treatment of diseases mediated by PDE4 or FNT.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a characteristic X-ray powder diffraction pattern for form I (vertical axis: intensity (CPS), horizontal axis: diffraction angle, in two teta (degrees)). Figure 2 is a characteristic X-ray powder diffraction pattern for form II (vertical axis: intensity (CPS); horizontal axis: diffraction angle, in two teta (degrees)).

Figure 3 is a Raman spectrum of the form I (vertical axis: intensity, lower horizontal axis: wave number (cm <-1 ->)). Figure 4 is a Raman spectrum of the form II (vertical axis: intensity, lower horizontal axis: wave number (cm <-1 ->)). Figure 5 is a Raman spectrum of the form IV (vertical axis: intensity, lower horizontal axis: wave number (cm <1 ->)). Figure 6 is a comparison of the Raman spectra of the three forms, forms I, II and IV, and the carbonyl tension region of 1750-1600 cm "1 (vertical axis: intensity; lower horizontal axis: wave number (cm <-1>)). Figure 7 is a comparison of the Raman spectra of the three forms, forms I, II and IV, and the region of 1000-800 cm "1 (vertical axis: intensity, lower horizontal axis: wave number (cm < 1 >).) Figure 8 is a comparison of the Raman spectra of the three forms, forms I, II, and IV, and the region of 400-200 cm "1 (vertical axis: intensity, lower horizontal axis: number of wave (cm <-1>)). Figure 9 shows the molecule of form I in three dimensions and with a marking scheme. Figure 10 provides a stereoscopic drawing of the form I molecule. Figure 11 is a characteristic infrared absorption spectrum of an individual crystal of form I. Figure 12 is an infrared absorption spectrum characteristic of an individual crystal of form. II. Figure 13 is a characteristic infrared absorption spectrum of an individual crystal of form IV. Figure 14 is a comparison of the infrared absorption spectra characteristic of the individual crystals of forms I, II and IV. Figure 15 is a characteristic infrared absorption spectrum in potassium bromide of the form I (vertical axis: transmission (%); lower horizontal axis: (wave number (cm <-1 ->)). is a characteristic infrared absorption spectrum in potassium bromide of form II (vertical axis: transmission (%); lower horizontal axis: (wave number (cm <-1)> Figure 17 is a spectrum of the infrared absorption characteristic of a compressed crystal of the form I. Figure 18 is a characteristic infrared absorption spectrum of a compressed crystal of the form II.Figure 19 is an infrared absorption spectrum characteristic of a compressed crystal of Figure IV is a comparison of the infrared absorption spectra of an individual and compressed crystal of form IV, Figure 21 shows the IV-shaped molecule in three dimensions and with a marking scheme. ura 22 provides a stereoscopic drawing of the molecule in form IV.

Figure 23 shows the molecule of form II in three dimensions and with a marking scheme.

DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that cipamfilin can exist as any of several novel crystalline forms, polymorphic forms, which differ from each other in their stability, physical properties, spectral data and methods of preparation. Three of these polymorphic forms are described in this application, and are referred to consecutively, respectively, as forms I, II and IV. Of the three novel polymorphs referred to above, Form I exhibits the greatest stability. Form I is characterized by a minimum of crystalline stability for 5 years. This invention also relates to a pharmaceutical composition comprising an effective amount of a polymorph of Form I, with any of the features noted herein, and a pharmaceutically acceptable carrier or diluent thereof. This invention also relates to a pharmaceutical composition comprising an effective amount of a polymorph of form II, with any of the features noted herein, and a pharmaceutically acceptable carrier or diluent thereof. This invention also relates to a pharmaceutical composition comprising an effective amount of a polymorph of Form IV, with any of the features noted herein, and a pharmaceutically acceptable carrier or diluent thereof. This invention further relates to the use of Form I, for the treatment of a disease mediated by PDE4 or TNF in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph of Form I with any of the features mentioned herein. This invention further relates to the use of the form II, for the treatment of a disease mediated by PDE or TNF in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph of form II with any of the features mentioned herein. This invention further relates to the use of form IV, for the treatment of a disease mediated by PDE4 or TNF in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a polymorph of form IV with any of the features mentioned herein. This invention results from the determination that certain batches of cipamfilin showed differences in their IR spectra. All batches were prepared by the same route with ethanol as the final recrystallization solvent. Therefore, it seemed possible that the rate of crystallization could affect the shape of the crystal. In light of this, recrystallized samples were prepared by cooling a portion of the hot liquid by collision, while the rest was allowed to stand and crystallize without assistance.

In each case, the batch size was approximately 1 g or less. The samples were dried on silica gel under vacuum at room temperature. In this recrystallization program, three polymorphic forms had been positively identified, and are described herein as forms I, II and IV. Therefore, this invention also relates to a method for preparing a polymorph of Form I with any of the above characteristics, which comprises crystallizing cipamfilin in an alcoholic solution of ethanol (s / f), propanol (s / f) , butanol (s / f), isopropanol (s / f), or an organic solvent of ethyl acetate (s / f), toluene *, or as a solvent, water *.

Under certain conditions, tetrahydrofuran (s / f) and acetone (s) may also be used. In addition to working with rapid cooling, ie, an ice water bath for use with small scale samples, the time for the reaction temperature to decrease from reflux temperature to room temperature, takes about one minute with ethanol as the solvent. In a preferred embodiment of this invention, 1-propanol is the solvent of choice for preparing polymorphic forms of form I. This invention also relates to a method for preparing a polymorph of form II with any of the above characteristics, which comprises crystallizing cipamfilin in a solution methanol alcohol (s / f), or an organic solvent of tetrahydrofuran (s) or acetone (f). Under certain conditions, chloroform * or pyridine * may be used. This invention also relates to a method for preparing a (5 polymorph of form IV with any of the above characteristics, which comprises crystallizing cipamfilin in an organic solvent of 50:50 mixture of ethanol and isopropanol. * Due to the particularly low solubility of cipamfilin in solvent marked with an asterisk (*), such as toluene or water for the form I, the recrystallization process was modified, that is, the hot solution was filtered to remove undissolved material, and the filtrate was allowed to stand and the compound was allowed to crystallize. The terms as used herein refer to slow recrystallization at room temperature. It is noted that the term "slow" cooling (and "fast" cooling) are relative terms. In this particular meaning, slow cooling may involve removal of the oil bath and cooling with air. On the sole basis of the scale (amounts of about 1 g for some experiments against a commercial batch size 20), the cooling may actually be quite fast, such as on the scale of 15 to 30 minutes. However, under controlled circumstances, slow cooling is generally defined as about 1 hour reflux temperature at room temperature. The very slow cooling will be about 4 hours of reflux temperature at room temperature. Under these conditions, form II can also be obtained from ethanol as described later in this document. However, similarly under the small batch sizes in some of the experiments used for form I, the ethanol path (slow cooling) is not necessarily a reliable solvent / temperature of choice for form I. It is also noted that With respect to the use of acetone in rapid cooling (ie the use of an ice bath), form I is also formed. Limited analysis also indicates that the use of acetone under the rapid cooling route is not necessarily a reliable solvent / temperature of choice for form II. The term (f) as used herein, refers to rapid recrystallization by collision cooling, such as by placing the flask in an ice water bath, or similar techniques for processing on a larger scale. These three novel crystalline polymorphs of cipamfilin, also referred to as BRL61063, also melt at about 305 ° C to about 313 ° C. The crystalline polymorph, form I, exhibits a characteristic X-ray powder diffraction pattern with characteristic maximum values expressed as d (A) separation at decreasing intensity, at 12,302, 7,702, 8,532, 4,289 and 2,854 as shown in Figure 1 A description of the theory of X-ray powder diffraction patterns can be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968). The crystalline polymorph, form II, exhibits a characteristic X-ray powder diffraction pattern with characteristic maximum values expressed as d (A) separation at decreasing intensity, at 12.001, 6.702, 3.687, 3.773 and 7.345 as shown in figure 2 This invention also relates to the crystalline polymorphs, forms I, II and IV, of cipamfilin that are further characterized by crystal parameters obtained from crystallographic X-ray analyzes of individual crystals as described in Tables I, II and III. next. The three-dimensional X-ray data were collected at room temperature.

TABLE I Shape crystal parameters I Shape of the crystal (mm): flat needles < _ Glass dimensions: 1.0 x 0.12 x 0.08 mm Glass color: colorless Spatial group: triclinic # 2 P1 Temperature: 295K Cell constant: a = 10,829 (2) Á 10 b = 12,636 (2) Á c = 5,105 ( 3) A alpha (a) = 99.48 (4) beta (ß) = 91.53 (4) gamma (?) = 83.84 (3) Volume: 683.0 (8) A 3 Molecules / unit cell (Z): 4 p (cale), density: 1,354 g / cm "3 μ: 7,362 cm" 1 F (000): 292 TABLE II Parameters of form II glass Crystal shape (mm): rectangular blocks Crystal color: colorless Crystal dimensions: 0.80 x 0.50 x 0.15 mm Spatial group: monoclinic # 14 P2 c Cell constants: a = 12.227 (4) A b = 7448 (2) A c = 14.946 (8) A alpha (a) = 90 (4) beta (ß) = 97.95 (4) gamma (?) = 90 (4) Volume: 1348.1 (9) A 3 Molecules / unit cell (Z): 4 p (cale), density: 1,356 g / cm "3 μ: 0.896 cm" 1 F (000): 584 TABLE III Parameters of form IV glass Shape of the crystal (mm): flat needles Color of the crystal: colorless Dimensions of the crystal: 0.60 x 0.10 x 0.05 mm Spatial group: triclinic # 2 P1 Temperature: 295K Cell constant: a = 10.210 (3) A b = 13.753 ( 2) A c = 4.942 (31) A alpha (a) = 97.94 (2) beta (ß) = 97.95 (4) gamma (?) = 83.33 (2) Volume: 677.1 (5) A 3 Molecules / unit cell ( Z): 2 p (cale), density: 1,350 g / cm "3 μ: 7.448 cm" 1 F (000): 292 The dimension of the unit cell is defined by three parameters: length of the sides of the cell, angles relative of the corresponding sides, and the volume of the cell. The lengths of the sides of the unit cells are defined by a, b and c. The relative angles of the cell angles are defined by alpha, beta and gamma. The volume of the cell is defined as V. A more detailed explanation of the unit cells can be found in chapter 3 of Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968). The crystalline state of a compound can be described unambiguously by several crystallographic parameters: dimensions of the unit cell, spatial group and atomic position of all the atoms in the compound with respect to the origin of its unit cell. These parameters are determined experimentally by X-ray analysis of individual crystals. It is possible for a compound to form more than one type of crystal. These different crystalline forms are called polymorphs. It has now been discovered that there are three polymorphic forms of cipamfilin. This discovery was confirmed by three separate X-ray analyzes of individual crystals. A comparison of the dimensions of the unit cell and the spatial groups of the three crystalline states is shown in tables I to III above. The graph of the atomic positions for the three polymorphs of the atoms derived from the X-ray analysis of individual crystals confirms that the crystals contain cipamfilin and no other molecule of crystallization or impurity. Figure 10 shows the molecule in three dimensions and with a marking scheme. Figure 11 provides a stereoscopic drawing. In general, the molecular conformation observed in Form I is identical to that of Form IV, with the exception of a clear disorder in one of the cyclopropyl groups (C12 and C13 atoms), which was represented by models with two occupation positions the same for each of these atoms. The high degree of thermal movement in the other cyclopropyl groups (C16 and C17 atoms) suggests that you may be experiencing conformational flexion. The unitary cell of the crystals of form I has the same shape as that of form III, with similar cell dimensions, a volume of 8 A3 higher and, correspondingly, a density reduced by 0.15 g cm "3. The effects are in harmony with the presence of the disorder in the channel which occupy the cyclopropyl groups.The formation of hydrogen bonds in this crystal structure, is all intermolecular in nature and is similar, in terms of specific interactions, with that observed in Form IV As in the structure of form IV, the positions of the amino hydrogens are indicated based on the Fourier electronic density difference maps.The position of H2N2 is not consistent with the participation of that hydrogen in a hydrogen bond formation interaction, however, a distance of 3.399 (3) A between the atoms of N2 and 05 in the form I, suggests the possibility of a weak interaction analogous to that observed in the structure of the form II, although the distance observed in this form is greater in 0.4 Angstroms. When a position for H (2) N (2) was calculated to meet this hydrogen bonding interaction, and attempts were made to refine it, the thermal value became irrationally large, suggesting that the data does not support this alternative position. In this way, the refinement was concluded with H2N2 in its original position, as indicated by the difference of the Fourier synthesis. The associated metric details of the other two hydrogen bonds are: Summary of the formation of hydrogen bonds of the form I With respect to the form IV, figure 26 shows the molecule in three dimensions and with a marking scheme. Figure 27 provides a stereoscopic drawing of form IV. For the data described in this section, the crystals of form IV were obtained from a 50/50 mixture of ethanol and isopropanol by slow evaporation. In addition, form II crystals were also obtained from this solvent mixture with form crystals.

II that appear to be nuclear first with IV-shaped needles that appear after the solution has evaporated for several days. In general, the molecular conformation observed in form IV is very similar to that of form II. The main differences are concentrated in the rotational orientation of the cyclopropyl groups that show an almost enantiomorphic relationship with their counterparts in the structure of form II, as summarized in table 1 of the tabulation of the torsion angles and shown in the figure 3 in the present.

TABLE 1 Tables of the torsion angle for forms II and IV Form II Form IV C7-N8-C10-C11 101.8 (3) 74.6 (3) C9-N8-C10-C11 -84.6 (3) -99.5 (3) C5-N8-C10-C11 98.7 (3) 91.7 (3 ) C7-N6-C14-C15 -80.2 (3) -85.1 (3) N8-C10-C11-C12 -77.5 (3) 80.4 (3) N8-C10-C11-C13 -146.6 (3) 149.8 (3) C10-C11-C12-C13 -104.9 (4) -107.5 (3) N6-C14-C15-C16 -88.5 (3) 89.4 (3) N6-C14-C15-C17 -158.3 (3) 158.8 (3) C14 -C15-C16-C17 -108.1 (3) -111.4 (3) The formation of hydrogen bonds in the crystal structure for form IV is all intermolecular in nature and is similar, in terms of specific interactions, to that observed in form II. One important difference involves one of the two hydrogens in N2. There is a clear indication of the position for H1 N2 in Fourier electronic density difference maps. The position is not consistent with the participation of that hydrogen in a hydrogen bond formation interaction. However, a distance of 3.273 (3) A between the atoms of N2 and O5 in the form IV, suggests the possibility of a hydrogen bond formation interaction, analogous to that observed in the structure of form II, although the The distance observed in this form is greater by 0.2 Angstroms. When a position for H1 N2 was calculated to meet this hydrogen bonding interaction, and attempts were made to refine it, the thermal value became irrationally large, suggesting that the data does not support this alternative position. In this way, the refinement was concluded with H1N2 in its original position, as indicated by the difference of the Fourier synthesis. The associated metric details of the other two hydrogen bonds are: Summary of the formation of hydrogen bonds of the form IV With respect to the form II, figure 32 shows the molecule of form II in three dimensions and with a marking scheme. The formation of hydrogen bonds for the crystal structure of the polymorph of form II is all intermolecular in nature. The associated metric details are: Summary of the formation of hydrogen bonds of the form II This structural information clearly shows that the forms I, II and IV of cipamfilin are all crystallographically different. The formation of hydrogen bonds in all forms is intermolecular in nature, and all three have hydrogen bond formation between HN (2) N (1) and HN (3) 0 (5).

Experimental Details Form I: Flat needles were obtained by slow evaporation from a mixture of ethyl acetate and butanol. The parameters of the crystal lattice structure were determined from the angles of adjustment of well-distributed reflections in reciprocal space measured in an Enraf Nonius CAD-4 diffractometer, and are also described in the following table IV. A full sphere of intensity data was also collected on the diffractometer using monochrome copper radiation in graphite from a rotating anode source and a variable speed scrutinizing technique? -2 ?. The intensities of three reflections in monitor measured at the beginning, final and every two hours of exposure time, changed as much as +/- 0.1%. Three orientation controls were also monitored to evaluate any movement of the crystals during the experiment. The data was corrected for Lorentz and polarization effects, and using the DIFABS algorithm, for the effects of absorption. Redundant observations were averaged to obtain the final series of data. The structure was solved by direct methods using the series of SHELXS programs. The atomic positions were initially refined with temperature isotropic factors and subsequently with anisotropic parameters of displacement. The function reduced to the minimum was? W (| Fo | - | Fc |) 2. The weights, w, were finally assigned to the data as w = 1 / s2 (fo) =. { s2 (lc) + (0.04l) 2]. The positions for hydrogen atoms bound to nitrogens were discovered on subsequent Fourier maps of electron density differences. The positions for the (< 5 hydrogen atoms bonded to carbons based on geometrical considerations, and kept fixed in the final refining stages together with the isotropic temperature factors assigned as 1.3 (Beq) of the attached atom. hydrogen in the cyclopropyl groups, all the other positions of the hydrogens were refined together with the isotropic temperature factors. The least squares refinement of the complete matrix converged (? / S maximum = 0.05) with maximum values of the conventional crystallographic residues R = 0.056, wR = 0.092. A final Fourier map of electronic density difference lacked characteristic features with maximum density of +/- 0.285 eÁ "3. values of the dispersion factors of neutral atoms were taken from the international tables for X-ray crystallography.

TABLE IV Data of intensity measurement for form I Diffractometer: Enraf Nonius CAD4 Radiation: CuKa? = 1.5406 A Monochromator: Individual graphite crystal Scrying technique: Scanning? -2? Scanning speed: Variable, 1.50 to 6.7 degrees min'1 in? Background measurements: Moving glass - mobile counter at each end of the scanning scale; scrutiny time / background time = 2.0 Data scale: 2 ° < 2T < 60 ° -12 < h < 12-14 < k < 14 -5 < 1 < 5 Standard reflections: Three standards measured every three hours of exposure time to X-rays Total number of reflections: 2320; 2032 unique R. nt .: 1.2% Number of observed data: 1749 l > 3 s (l) Number of variables: 199 p: 0.04 R: 0.056% Rw: 0.092% Goodness of fit: 3.311 Correction for absorption: 0.868 minimum; 1,254 maximum; 0.991 on average The complete experimental X-ray data of individual crystals used to produce the structure shown in Figure 9 for Form I are included in Tables 2 to 5. The parameters presented in the tables are measured in units commonly used by the experts in The technique. A more detailed description of the units for measuring such parameters can be found in International Tables for X-ray Crystallography, Vol. IV, pp. 55, 99, 149 Birmingham: Kynoch Press, 1974, and G. M. Sheldrick, SHELXTL. User Manual, Nicolet Instrument Co., 1981.

TABLE 2 Link distance chart in Angstroms Atom 1 Atom 2 Distance Atom 1 Atom 2 Distance 05 C5 1,237 (2) C10 C11 1,493 (3) 07 C7 1,211 (2) C11 C12B 1,155 (5) N1 C2 1,344 (2) C11 C12A 1,481 (8) N1 C9 1,367 ( 2) C11 C13B 1.366 (9) N2 C2 1.355 (2) C11 C13A 1.292 (5) N3 C2 1.343 (2) C12B C12A 1.287 (9) ro N3 C4 1.397 (2) C12B C13B 1.50 (1)) N6 C5 1.399 (2) C12B C13B 1.597 (8) N6 C7 1.402 (2) C12A C13B 0.55 (2) N6 C14 1.476 (2) C12A C13A 1.55 (1) N8 C7 1.388 (2) C13B C13A 1.16 (1) N8 C9 1,365 (2) C14 C15 1,492 (3) N8 C10 1,461 (2) C15 C16 1,453 (3) C4 C5 1,407 (2) C15 C17 1.490 (3) C4 C9 1.362 (2) C16 C17 1.501 (4) The numbers in parentheses they are standard deviations calculated in the least significant digits.

TABLE 3 Table of angles of link in degrees Momo 1 Atom 2 Atom 3 Angle Atom 1 Atom 2 Atom 3 Angle C2 N1 C9 102.5 (1) C10 C11 C12A 124.9 (4) C2 N3 C4 105.6 (1) C10 C11 C13B 121.6 (5 ) C5 N6 C7 126.1 (1) C10 C11 C13A 132.1 (5) C5 N6 C14 119.0 (1) C12B C11 C12A 56.9 (4) C7 N6 C14 114.8 (1) C12B C11 C13B 72.5 (5) C7 N8 C9 119.4 (1) C12B C11 C13A 81.3 (4) C7 N8 C10 119.4 (1) C12A C11 C13B 21.6 (7) C9 N8 C10 121.2 (1) C12A C11 C13A 67.8 (6) N1 C2 N2 122.8 (1) C13B C11 C13A 51.6 (6) N1 C2 N3 114.1 (1) C11 C12B C12A 74.5 (5) N2 C2 N3 123.0 (1) C11 C12B C13B 60.3 (4) N3 C4 C5 131.5 (1) C11 C12B C13A 53.1 (3) NJ N3 04 09 105.1 (1) C12A C12B C13B 20.9 (7) C5 C4 C9 123.3 (1) C12A C12B C13A 64.1 (6) 05 C5 N6 120.7 (1) C13B C12B C13A 43.8 (5) 05 C5 C4 126.9 (1) C11 C12A C12B 48.7 (4) N6 C5 C4 112.4 (1) C11 C12A C13B 67 (1) 07 C7 N6 121.5 (2) C11 C12A C13A 50.3 (4) 07 C7 N8 121.6 (1) C12B C12A C13B 102 (2) N6 C7 N8 116.8 (2) C12B C12A C13A 67.7 (5) N1 C9 N8 125.4 (1) C13B C12A C13A 36 (2) N1 C9 C4 112.7 (2) C11 C13B C12B 47.2 (4) N8 C9 C4 112.9 (1) C11 C13B C12A 91 (2) N8 C10 C11 113.6 (2) C11 C13B C13A 60.9 (6) C10 C11 C12B 146.4 (4) C12B C13B C12A 57 (1) C12B C13B C13A 72.5 (9) C12A C13A C13B 16.2 ( 7) C12A C13B C13A 127 (2) N6 C14 C15 111.7 (2) C11 C13A C12B 45.6 (3) C14 C15 C16 122.2 (2) C11 C13A C12A 61.9 (4) C14 C15 C17 119.2 (2) C11 C13A C13B 67.5 (5) ) C16 C15 C17 61.3 (2) C12B C13A C12A 48.2 (4) C15 C16 C17 60.6 (2) C12B C13A C13B 63.6 (6) C15 C17 C16 58.1 (1) The numbers between aréntesis are standard deviations calculated in the least significant dates.

TABLE 4 Table of torsion angles in degrees TABLE 4 (continued) TABLE 4 (continued) TABLE 4 (continued) TABLE 5 Position parameters and their standard derivations calculated Atom XYZB (A2) 05 1.5599 (1) 1.8918 (1) 1.1475 (3) 4.88 (4 07 1.3047 (2) 1.7197 (1) | 0.5279 (3) 5.25 (4 N1 1.1341 (2) 1.9527 (1) I 1.2713 ( 4) 3.77 (4 N2 1.1397 (2) 2.0771 (2) I 1.6721 (4) 4.71 (4 N3 1.3206 (2) 1.9967 (1) 1.4356 (4) 3.89 (4 N6 1.4311 (2) 1.8063 (21.). 0.8378 (4) 4.13 (4 N8 1.2113 (2) 1.8305 (1,> 0.8786 (4) 3.90 (4 C2 1.1968 (2) 2.0099 (2)) 1.4663 (4) 3.70 (4 C4 1.3420 (2) 1.9242 (2) ) 1.1994 (4) 3.83 (4 C5 1.4528 (2) 1.8769 (2]) 1.0720 (5) 3.94 (5 C7 1.3146 (2) 1.7809 (2) I 0.7346 (5) 4.11 (5 C9 1.2273 (2) 1.9003 (2 ] I 1.1082 (4) 3.57 (4 C10 1.0876 (2) 1.8054 (2) I 0.7843 (5) 4.60 (5 C11 1.0417 (3) 1.7161 (3) 0.9008 (9) 8.42 (9 C12B 1.0527 (8) 1.6649 (6 ] 1,069 (2) 10.7 (2 C12A 1.1006 (7) 1.6034 (5] 0.863 (2) 9.9 (2) C13B 1.066 (1) 1.6107 (5] 0.786 (2) 1 1.4 (3 C13A 0.9638 (6) 1.6475 (8 ] 0.814 (2) 12.2 (3 C14 1.5381 (2) 1.7453 (2] 0.6891 (5) 5.12 (6 C15 1.5630 (3) 1.6339 (9] 0.7530 (7) 7.89 (9 C16 1.6823 (4) 1.5701 (4) 0.7024 (9) 11.2 (1 C17 1.6453 (4) 1.6152 (4) 0.9832 (9) 10.9 (1 The anisotropically refined atoms are given in the form of the equivalent sotropic displacement parameter defined as: (4/3) * [a2 * B (1, 1) + b2 * B (2,2) + c2 * B (2.2 ) + c2 * B (3,3) + ab (gamma cos) * B (1, 2) + ac (beta cos) * B (1, 3) + bc (cos alpha) + B (2,3)] .

Form II: Rectangular plates were obtained by slow evaporation from a solution prepared in methanol / 2-butanone. The crystal lattice structure parameters were determined from the adjustment angles of well-distributed reflections in reciprocal space measured in an Enraf Nonius CAD-4 diffractometer, and are also described in Table V. The intensity data were also collected in the diffractometer using monochrome molybdenum radiation in graphite and a variable velocity scrutineering technique? -2 ?. A correction was applied to the data for a 4.8% decrease in the intensities of three monitor reflections measured at the beginning, end and every two hours of exposure time. Three orientation controls were also monitored to evaluate any movement of the crystals during the experiment. The data were corrected for Lorentz and polarization effects and using the DIFABS algorithm for absorption effects. The symmetry equivalents and zonal reflections were averaged to obtain the final series of data. The structure was solved by direct methods using the MULTAN 80 series of programs. The atomic positions were initially refined with temperature isotropic factors and subsequently with anisotropic parameters of displacement. The function reduced to the minimum was Sw (| Fo | - | Fc |) 2. The weights, w, were finally assigned to the data as w = 1 / s2 (fo) = (s2 (lc) + (0.04l) 2] The positions for the hydrogen atoms were discovered in subsequent Fourier maps of difference Electronic density was allowed to refine the isotropic temperature factors for the amino hydrogen atoms and the methine hydrogens on the cyclopropyl rings The positions for the other hydrogen atoms were calculated based on geometrical considerations, and were kept fixed in the final refining stages together with the isotropic temperature factors assigned as 1.3 (Beq) of the bound atom. least squares refinement of the entire matrix converged (? / s maximum = 0.005) with values of conventional crystallographic residues (• R = 0.044, wR = 0.054.) A final Fourier map of electronic density difference lacked characteristic features with maximum density of +/- 0.196 y "3. The values of neutral atom scattering factors were taken from the international tables for X-ray crystallography. The complete experimental data of crystal X-rays Individuals for producing the structure formed in Figure 23 for Form II are included in Tables 10 to 13. The parameters presented in the tables are measured in units commonly used by those skilled in the art.

TABLE 10 Table of link distances in Angstroms P Atom 1 Atom 2 Atom Distance 1 Atom 2 Distance 05 C5 1,251 (3) N8 C10 1,485 (3) 07 C7 1,216 (3) C4 C5 1,386 (3) N1 C2 1,352 (3) C4 C9 1,368 (3) N1 C9 1,351 (3) C10 C11 1,494 (4) 20 N2 C2 1,344 (3) C11 C12 1,493 (4) N3 C2 1,340 (3) C11 C13 1,509 (4) N3 C4 1,394 (3) C12 C13 1,513 (5) N6 C5 1,402 ( 3) C14 C15 1,496 (4) N6 C7 1,403 (3) C15 C16 1,498 (4) N6 C14 1,474 (3) C15 C17 1,491 (4) N8 C7 1,375 (3) C16 C17 1,497 (4) N8 C9 1,375 (3) The numbers in parentheses are standard deviations calculated in the least significant digits.

TABLE 11 Link angle chart in degrees Atom 1 Atom 2 Atom 2 Atomulus Atom 1 Atom 2 Atom 2 Anchor C2 N1 C9 102.9 (2) 07 C7 N8 122.2 (2) C2 N3 C4 106.5 (2) N6 C7 N8 117.1 (2) C5 N6 C7 125.4 (2) N1 C9 N8 125.6 (2) C5 N6 C14 119.4 (2) N1 C9 C4 113.2 (2) C7 N6 C14 115.3 (2) N8 C9 C4 121.2 (2) C7 N8 C9 119.7 (2) N8 C10 C11 113.2 (2) C7 N8 C10 119.0 (2) C10 C11 C12 118.9 (3) C9 N8 C10 121.0 (2) C10 C11 C13 115.7 (3) N1 C2 N2 122.6 (2) C12 C11 C13 60.5 (2) N1 C2 N3 113.2 (2) C11 C12 C13 60.3 (2) N2 C2 N3 124.2 (2) C11 C13 C12 59.2 (2) N3 C4 C5 132.3 (2) N6 C14 C15 111.5 (2) N3 C4 C9 104.3 (2) C14 C15 C16 119.3 (2) C5 C4 C9 123.4 (2) C14 C15 C17 118.6 (3) 05 C5 N6 120.1 (2) C16 C15 C17 60.1 (2) 05 C5 C4 126.7 (2) C15 C16 C17 59.7 (2) N6 C5 C4 113.2 (2) C15 C17 C16 60.2 (2) 07 C7 N6 120.7 (2) The numbers in parentheses are standard deviations calculated in the least significant digits.

TABLE 12 Box of torsion angles in degrees TABLE 12 (continued) TABLE 12 (continued) TABLE 12 (continued) TABLE 13 Position parameters and their standard deviations calculated ATOMUM X AND Z B ((A2) O5 0.9075 (2]) -0.3990 (2) 0.8878 (1) 3.22 (4) O7 0.7135 (2)) 0.1280 (3) .08696 (1) 3.93 (5) N1 0.9202 (2) I -0.0215 (3) 1.1348 (1) 2.60 (5) N2 1.0398 (2) -0.1997 (3) 1.2364 (2) 3.35 (5) N3 0.9771 (2) -0.2857 (3) 1.0851 (1) 2.85 (5) N6 0.8070 (2) -0.1371 (3) 0.8743 (1) 2.61 (5) N8 0.8128 (2) 0.0729 (3) 0.9941 (2) 2.61 (5) C2 0.9803 (2) -0.1720 (4) 1.1549 (2,) 2.58 (5) C4 0.9096 (2] -0.2061 (3) 1.0131 (2)) 2.44 (5) C5 0.8785 (2) -0.2590 (4) 0.9243 (2)) 2.53 (5) C7 0.7738 (2) 0.0287 (4) 0.9061 (2)) 2.86 (6) C9 0.8781 (2) -0.0468 (3) 1.0473 (2) I 2.33 (5) C10 0.7932 (2) 0.2569 (4) 1.0268 (2) 3.20 (6) C11 0.7010 (3) 0.2660 (5) 1.0827 (2) 4.22 (7) C12 0.5848 (3) 0.2621 (6) 1.0363 (3) 6.2 (1) C13 0.6342 (3) 0.4370 (5) 1.0743 (3) 7.0 (1) C14 0.7592 (2) -0.1827 (4) 0.7812 (2) 3.04 (6) C15 0.6443 (2) -0.2544 (4) 0.7773 (2) 3.73 (7) C16 0.6275 (3) -0.4518 (5) 0.7891 (3) 5.49 (9) C17 0.5985 (3) 0.3664 (5) 0.6983 (3) 5.36 (9) Anisotropically refined atoms are given in the form of equivalent isotropic displacement parameter defined as: (4/3) * [a2 * B (1, 1) + b2 * B (2,2) + c2 * B (3,3) + ab (gamma cos) * B (1, 2) + ac (beta cos) * B (1, 3) + bc (alpha cos) * B (2,3)]. € • TABLE V Data of intensity measurement for form II Diffractometer: Enraf Nonius CAD4 Radiation: MoKa? = 0.71073 A Monochromator: Individual graphite crystal 10 Scrutiny technique: Scrutiny? -2? Scanning speed: Variable, 2.50 to 6.7 degrees min "1 in? Bottom measurements: Moving glass - mobile counter at each end of the scanning scale, scan time / background time = 2.0 Data scale: 2 ° < 2T <60 ° 0 < h < 14 0 < k < 8 -17 < 1 < 17 standard: Three standards measured every three hours of Reflections X-ray exposure time Total number of reflections: 2469 2353 unique R. nt .: 3.4% Number of observed data: 1417 I > 3 t (l) Number of variables: 202 p: 0.04 R: 0.044% Rw: 0.054% Goodness of fit: 1.403 20 Extinction coefficient: 7.869 (1) x 10"7 Correction for disintegration: 0.9769 minimum; 1.1374 maximum Form IV: Flat needles were obtained by slow evaporation from a 50/50 mixture of ethanol and isopropanol. The parameters of the crystal lattice structure were determined from the angles of adjustment of well-distributed reflections in reciprocal space measured in an Enraf Nonius CAD-4 diffractometer, and are further described in Table VI below. A full sphere of intensity data was also collected on the diffractometer using monochrome copper radiation in graphite from a rotating anode source and a variable speed scrutinizing technique? -2 ?. The intensities of three reflections in monitor measured at the beginning, end and every two hours of exposure time, changed at most in +/- 1.1%. Three orientation controls were also monitored to evaluate any movement of the crystals during the experiment. The data was corrected for Lorentz and polarization effects, and using the DIFABS algorithm, for the effects of absorption. The symmetry equivalents and the related Friedel pairs were averaged to obtain the final series of data. The structure was solved by direct methods using the series of SHELXS programs. The atomic positions were initially refined with temperature isotropic factors and subsequently with anisotropic parameters of displacement. The function reduced to the minimum was Sw (| Fo | - | Fc |) 2. The weights, w, were finally assigned to the data as w = 1 / s2 (fo) =. { s2 (lc) + (0.04l) 2]. The positions for hydrogen atoms bound to nitrogens were discovered on subsequent Fourier maps of electron density difference. The positions for the hydrogen atoms bound to the methylene carbons of the cyclopropyl groups were calculated based on geometrical considerations, and they were fixed in the final refining stages together with the isotropic factors of (• 5 temperature assigned as 1.3 (Beq) of the bound atom.All other positions of the hydrogens were refined together with the temperature sotropic factors.The least squares refinement of the complete matrix converged (? / S maximum = 0.01) with values the conventional crystallographic residues R = 0.049, wR = 0.071 A final Fourier map of electronic density difference lacked characteristic features with maximum density of +/- 0.515 eA "3. The values of the dispersion factors of atoms neutrals were taken from the international tables for X-ray crystallography.

TABLE VI Data of intensity measurement for form IV Diffractometer: Enraf Nonius CAD4 Radiation: CuK? = 1.5406 Á (t> Monochromator: Individual graphite crystal Scanning technique: Scanning? -2? Scanning speed: Variable, 2.50 to 6.7 degrees min. "1 in? Bottom measurements: Mobile crystal - mobile counter at each end of the scrutiny scale, scrutiny time / background time = 2.0 Data scale: 2 ° <2T <60 ° -11 <h <11 -15 <k < 15 -5 <1 &5 Standard reflections: Three standards measured every three hours time of exposure to X-rays Total number of reflections: 3998 2017 only R. nt .: 2.5% Number of observed data: 1662 I > 3 s (l) Number of variables: 202 P: 0.04 R: 0.049% Rw: 0.071% Goodness of fit: 2.095 15 Extinction coefficient: 1.411 (1) x 10"6 Correction for absorption: 0.911 minimum, 1.088 maximum, 0.997 on average The complete experimental data of crystal X-rays individual to produce the structure shown in figures 21 and 22 for the form IV, are included in tables 6 to 9. The parameters presented in the tables are measured in units commonly used by experts in the technique TABLE 6 Link distance chart in Angstroms Atom 1 Atom 2 Distance Atom 1 Atom 2 Distance Atom 1 Atom 2 Distance 05 C5 1.243 (2) N6 C7 1.396 (2) C11 C12 1.480 (4) 07 C7 1,214 (2) N6 C14 1.477 (2) C11 C13 1.468 (3) N1 C2 1.335 (2) N8 C7 1.390 (2) C12 C13 1.457 (3) N1 C9 1.367 (2) N8 C9 1.362 (2) C14 C15 1.494 (3) N2 C2 1.351 (2) N8 C10 1.475 (2) C15 C16 1.478 (4) N3 C2 1.345 (2) C4 C5 1.412 (2) C15 C17 1.487 (3) N3 C4 1.391 (2) C4 C9 1.358 (2) C16 C17 1.467 (3) *.

N6 C5 1,398 (2) C IO C 1,494 (3) The numbers in parentheses are standard deviations calculated in the least significant digits.

TABLE 7 Frame of angles of link in gradt DS Atom 1 Atom 2 Atom 3 Angle Atom 1 Atom 2 Atom 3 Angle Atom 1 Atom 2 Atom 3 Angle C2 N1 C9 103.0 (1) N3 C4 C9 105.3 (1) C10 C11 C12 118.9 (2) C2 N3 C4 105.8 (1) C5 C4 C9 123.2 (2) C10 C11 C13 120.6 (2) C5 N6 C7 126.3 (1) 05 C5 N6 121.2 (1) C12 C11 C13 59.2 (2) C5 N6 C14 117.7 (1) 05 C5 C4 126.5 (2) C11 C12 C13 60.0 (2) C7 N6 C14 115.9 (1) N6 C5 C4 112.2 (1) C11 C13 C12 60.8 (2) C7 N8 C9 119.7 (1 I O7 C7 N6 122.4 (2) N6 C14 C15 112.3 (2) C7 N8 C10 117.6 (1 O7 C7 N8 121.0 (2, C14 C15 C16 121.2 (2) C9 N8 C10 122.4 (1) N6 C7 N8 116.6 (1) C14 C15 C17 118.3 (2)? N1 C2 N2 124.2 (2) N1 C9 N8 125.9 (1) C16 C15 C17 59.3 (2) N1 C2 N3 113.7 (1) N1 C9 C4 112.3 (1) C15 C16 C17 60.6 (2) N2 C2 N3 122.1 (2) N8 C9 C4 121.8 (1) C15 C17 C16 60.0 (2) The numbers in parentheses are standard deviations calculated in the least significant digits.

TABLE 8 Table of torsion angles in degrees Atom 1 Atom 2 Atom 3 Atom 4 Angle Atom 1 Atom 2 Atom 3 Atom 4 Angle C9 N1 C2 N2 179.22 (0.22) N3 C4 C9 N18 -178.86 (0.19) C9 N1 C2 N3 0.77 (0.25) C5 C4 C9 N1 176.60 (0.20) C2 N1 C9 N8 178.50 (0.21) C5 C4 C9 N8 -2.61 (0.34) C2 N1 C9 C4 -0.68 (0.24) N8 C10 C11 C12 80.44 (0.32) H1N2 N2 C2 N1 167.56 (2.15) N8 C10 C11 C13 149.79 (0.27) H1N2 N2 C2 N3 -14.11 (2.17) N8 C10 C11 HC11 4.32 (2.94) H2N2 N2 C2 N1 11.84 (1.96) H1C10 C10 C11 C12 -159.31 (2.98) H2N2 N2 C2 N3 -169.83 (1.93) H1C10 C10 C11 C13 -89.96 (2.98) C4 N3 C2 N1 -0.59 (0.26) H1C10 C10 C11 HC11 124.57 (4.16) C4 N3 C2 N2 -179.07 (0.21) C10 C11 C12 C13 110.38 (0.32) HN3 N3 C2 N1 -177.62 (1.77) C10 C11 C12 HC11 -147.35 (1.63) 4- » HN3 N3 C2 N2 3.89 (1.79) C10 C11 C12 H1C13 -1.59 (0.50) C2 N3 C4 C5-175.70 (0.23) C13 C11 C12 HC11 102.26 (1.61) C2 N3 C4 C9 0.13 (0.23) C13 C11 C12 H1C13 -111.98 (0.40) HN3 N3 C4 C5 0.78 (2.14) HC11 C11 C12 C13 -102.26 (1.61) HN3 N3 C4 C9 176.60 (2.11) HC11 C11 C12 H1C13 145.76 (1.64) C7 N6 C5 05 178.11 (0.21) C10 C11 C13 C12 -107.50 (0.33) C7 N6 C5 C4 -1.77 (0.31) C10 C11 C13 H1C12 141.23 (0.31) C14 N6 C5 05 1.69 (0.31) C12 C11 C13 H1C12 -111.28 (0.38) C14 N6 C5 C4 -178.19 (0.19) HC11 C11 C13 C12 56.85 (1.39) C5 N6 C7 07 179.80 (0.22) HC1 C11 C13 H1C12 -54.43 (1.41) C5 N6 C7 N8 -0.20 (0.32) C10 C11 HC11 C12 92.91 (2.68) TABLE 8 (continued) Atom 1 Atom 2 Atom 3 Atom 4 Angle Atom 1 Atom 2 Atom 3 Atom 4 Angle C14 N6 C7 07 -3.72 (0.32) C13 C11 HC11 C12 -57.68 (0.80) C14 N6 C7 N8 176.29 (0.19) C11 C12 C13 H1C12 109.36 (0.36) C5 N6 C14 C15 91.67 (0.25) HC11 C12 C13 C11 -45.77 (1.19) C5 N6 C14 C1C14 -150.04 (2.73) HC11 C12 C13 H1C12 63.59 (1.22) C7 N6 C14 C15 -85.13 (0.26) H1C13 C12 C13 C11 108.50 (0.41) C7 N6 C14 H1C14 '33.16 (2.74) H1C13 C12 C13 HC12-142.15 (0.36) C9 N8 C7 07-178.99 (0.21) C13 C12 HC11 C11 60.10 (1.04) C9 N8 C7 N6 1.01 (0.30) H1C13 C12 HC11 C11 -73.54 (2.58) C10 N8 C7 07 6.73 (0.32) N6 C14 C15 C16 89.36 (0.32) C10 N8 C7 N6 -173.28 (0.19) N6 C14 C15 C17 158.79 (0.25) 4-.

C7 N8 C9 N1 -178.77 (0.21) N6 C14 C15 HC15 -53.54 (2.68) C7 N8 C9 C4 0.33 (0.32) H1C14 C14 C15 C16 -26.61 (2.79) C10 N8 C9 N1 -4.78 (0.34) H1C14 C14 C15 C17 42.82 (2.78) C10 N8 C9 C4 174.32 (0.21) H1C14 C14 C15 HC15 -169.51 (3.84) C7 N8 C10 C11 74.61 (0.27) C14 C15 C16 C17 106.62 (0.32) C7 N8 C10 H1C10 -50.49 (2.79) HC15 C15 C16 C17 -104.94 (2.34) C9 N8 C10 C11 -99.51 (0.26) C14 C15 C17 C16 -111.35 (0.32) C9 N8 C10 H1C10 135.39 (2.79) C14 C15 C17 H1C16 139.79 (0.30) N3 C4 C5 05 -1.55 (0.40) C16 C15 C17 H1C16 -108.85 (0.37) N3 C4 C5 N6 178.32 (0.21) HC15 C15 C17 C16 97.10 (2.41) C9 C4 C5 05 -176.73 (0.22) HC15 C15 C17 H1C16 -11.75 (2.43) C9 C4 C5 N6 3.14 (0.31) C15 C16 C17 H1C16 110.17 (0.40) N3 C4 C9 N1 0.35 (0.25) TABLE 9 Position parameters and their standard deviations calculated ÁTOMO XYB (A2) 05 0.1193 (2) 0.8847 (1) 0.7643 (3) 4.17 (4) 07 -0.0432 (2]) 0.7070 (1) -0.0448 (3) 4.94 (4) N1 -0.3270 (2) I 0.9413 (1) 0.4337 (4) 3.61 (4) N2 -0.3813 (2) I 1.0649 (2,) 0.7969 (5) 5.08 (5) N3 0.1646 (2) 0.9868 (1]) 0.7668 (4) 3.62 (4) N6 0.0374 (2) 0.7967 (1]) 0.3570 (4) 3.69 (4) N8 0.1894 (2) 0.8182 (1]) 0.1688 (4) 3.63 (4) C2 0.2944 (2) 0.9987 (2) I 0.6689 (5) 3.68 (5) C4 0.1072 (2) 0.9147 (2)) 0.5811 (5) 3.48 (5) C5 0.0236 (2) 0.8679 (2) 0.5850 (5) 3.42 (5) C7 0.0633 (2) 0.7697 (2] 0.1476 (5 ) 3.83 (5) C9 0.2085 (2) 0.8891 (2) 0.3845 (5) 3.33 (4) C10 0.3002 (2) 0.7832 (2) I -0.0323 (5) 4.21 (5) C11 -0.3407 (3] 0.6883 (2) ] 0.0279 (7) 5.89 (7) C12 -0.4282 (4] 0.6908 (3] 0.2439 (8) 7.09 (9) C13 -0.4789 (3) 0.6647 (2] -0.0445 (7) 6.82 (8) C14 0.1687 (2 ) 0.7401 (2) 0.3404 (5) 4.33 (5) C15 0.1807 (3) 0.6467 (2) 0.4687 (6) 5.81 (7) C16 0.1415 (3) 0.5538 (2) 0.3060 (9) 7.6 (1) C17 0.2830 ( 3) 0.5663 (2) 0.3858 (8) 6.86 (9) The anisotropically refined atoms are given in the form of the isotropic displacement parameter ecuivalent defined as: (4/3) * [a2 * B (1, 1) + b2 * B (2,2) + c2 * B (3,3) + ab (gamma cos) * B (1, 2) + ac (beta cos) * B (1, 3) + bc (cos alpha) * B (2,3)]. The results of an X-ray analysis of individual crystals are limited to, as the name implies, the only crystal placed in the X-ray beam. Crystallographic data on a large group of crystals provide X-ray powder diffraction. If the powder is a pure crystalline compound, a simple powder diagram is obtained. To compare the results of the analysis of an individual crystal and the analysis of X-ray powder, a simple calculation can be made by converting the individual crystal data into an X-ray powder diagram, SHELXTL Plus computer program (registered trademark), reference manual by Siemens Analytical X-ray Instrument, chapter 10, p. 179-181, 1990. This conversion is possible because the experiment with individual crystals usually allows to determine the dimensions of the unit cell, spatial group and atomic positions. These parameters provide a basis for calculating a perfect powder pattern. The comparison of this calculated powder pattern and the experimentally obtained powder pattern of a large group of crystals will confirm whether the results of the two techniques are equal.

Diffraction of X-ray powder (XRD) X-ray powder diffraction showed differences between the three forms of polymorphs. The analysis of 4 x samples of Form I and samples of 4 x of Form II, showed that consistent patterns of diffraction by equalization were obtained for each series. These data are presented in figures 1 and 2 herein.

Infrared spectroscopy (IR) The absorption spectra of the infrared have positively identified the existence of forms I, II and IV. These data are shown in figures 11 to 20 for the compound, the individual crystal and compressed crystals of the different polymorphic forms. In a compression and grinding study, it was shown that Form I is stable to compression and grinding, while it was shown that Form II is stable to compression, but not to severe grinding. The comparison of the IR spectra of forms I and IV show remarkable differences. The prominent band in a putative region of methylene deformation at 1430cm "1 (with a shoulder at 1442 cm" 1) for form I, is separated into form IV to give a band at 1424 cm "1 (with a shoulder at 1434 cm "1) and a band at 1455 cm" 1 (with a shoulder at 1466 cm '1) The carbonyl tension bands in the form I occur at 1648 (with a shoulder at 1656 cm "1) and 1682 cm "1, while in the IV form occur at 1656 cm" 1 and 1694 cm "1. The weak characteristics in the spectra of form IV at approximately 2000 and 2300 cm'1 are absent in form I, but these can represent Overextends of the carbonyl region These spectra were recorded using a Spectra-Tech Plan II microscope coupled to a PE 1760 FTIR spectrometer (64-256 scrutinies, ratio mode, MCT detector, resolution of 4 cm "1, dry air flea ). The spectra of samples without sample preparation were obtained by mounting crystals on a diamond window. Compressed crystals were prepared using a plane for Spectra-Tech microsamples (a compression cell) adapted with diamond windows. A stereoscopic microscope was used to observe the behavior of the crystals during compression. After compression, the diamond windows were separated, and a spectrum of the material adhering to one of the windows was recorded. The IR spectra of individual crystals of forms I, II and IV show numerous differences, and are also easily distinguishable. There are significant differences in the relative band intensities between the IR spectra of individual crystals of forms I and II, and the corresponding spectra obtained from potassium bromide disks; these differences occur in all spectra, but are more obvious below 1700 cm. "1 In particular, note the difference in the relative intensities of the bands near 1530, 1440, 1260 and 800 cm" 1 in the spectra of the form I, and the bands close to 1540, 1420, 1260 and 1060 cm "1 in the spectra of form II.The spectra of the compressed crystals are very similar to the corresponding spectra of the KBr disc.This is not surprising, since Compressed crystals and KBr disks represent molecular orientations In many cases, adequate IR transmission through crystalline samples can only be achieved by compression There is reduced correspondence between spectra of individual crystals and compressed crystals of form IV, the most notable difference occurring in the regions of 1660-1620, 1260-1180, 1000-920 and 800-750 cm "1. However, the spectra of the compressed crystals of form IV are very similar to the spectra of the compressed crystals of form I.

For these IR spectra, the crystals of form IV were obtained in the presence of those of form II, by slow evaporation from a 50:50 mixture of ethanol: isopropanol and manually separated. The conversion of form IV to form I may not be surprising; the 3-dimensional X-ray diffraction data fc 5 indicates that the molecular conformation (in addition to the orientation in the cyclopropyl groups) and the formation of hydrogen bonds (in terms of specific interactions), are similar in forms I and IV. In forms I and IV, only one of the amino hydrogens is involved in the formation of hydrogen bonds (this contrasts with the form II, in which it was found that all hydrogen donors intervene). These findings relate well to the conclusions obtained from the infrared spectra of individual crystals of the three forms, where the regions of N-H tension of forms I and IV are similar, and different from form II. Forms I and IV have a band near 3455 cm "1, which is assigned to a non-associated NH function In form II, this band is missing, and it is clear that all hydrogen donors are involved in the formation of hydrogen bonds. IR of individual crystals of form IV in different instruments and are similar, except in the region of 1280-1260 cm "1 This can be explained by orientation effects A definitive spectrum of form IV is presented here as figure 13.

RAMAN Spectra Raman Spectra for Forms I, II and IV, are also shown in the present as Figures 3 to 8. As can be clearly seen, there are significant differences between the spectra of the three forms, which allows them to be easily distinguishable. It has been shown that, under some circumstances, the IV form under pressure becomes the I form; therefore, conventional sampling techniques, such as alkali haiogenide discs, or Nujol muslin, may not be the best way to obtain infrared spectra for this polymorph, since it takes a long time to select crystals of appropriate size and to obtain spectra of good quality. Raman spectroscopy provides a quick method to distinguish forms I, II and IV from another without the need to prepare the sample. Spectra were recorded using a 200 FT-Raman spectrometer from Perkin-Elmer equipped with a Nd: YAG NIR laser (1064 μm). The scrutiny conditions were 64 to 256 scrutinies, quartz beam separator, resolution of 4 cm "1 and laser energy of 1 W. The spectra of form IV (figure 5) show a significant amount of Raman thickness of the This is observed as an underlying curve with a broad maximum close to 400 cm-1. Glass makes only a minor contribution to the relatively intense spectra of forms I and II (figures 3 and 4).

The Raman spectra of forms I, II and IV show numerous differences, and are easily distinguishable. The carbonyl tension region, 1750-1600 cm-1 (Figure 6) shows the most notable difference between the forms (as was found in the case with IR spectra recorded at (• 5 from individual crystals (shown here as Figures 11 to 13) There are significant differences between the three forms on the scale of 1000-800 cm-1 (Figure 7) The region of 400-200 cm-1 (inaccessible when recording spectra using an infrared microscope) also shows significant differences (figure 8), although the sensitivity in this region is relatively poor due to the detector response.

Solution heat solution heats were determined using acetone and methanol as suitable solvents. The endothermic values are given in table VII next. Different polymorphic forms give rise to different heats of solution. This is demonstrated by the data obtained here. The value of HT, the heat of transition, is equal to the difference in the energy of the crystal lattice structure of the two forms, and is the same in both solvents. This can be predicted since the individual enthalpies are dependent on the solvent, but not the differences. From these results, it is suggested that the dissolution of form II is more endothermic in both solvents, and therefore the more stable form. The heats of solution for form IV are in progress.

TABLE VII (• Thermal analysis Differential scanning calorimetry (DSC) did not differentiate the three forms of cipamfilin. In each case, thermograms showed fusion only with similar start and maximum temperatures, typically Te 312, Tp 314 ° C. However, when the heating rate was sufficiently reduced, the fusion endotherm appeared as a fused fused material, i.e., two components melting. This behavior was common for forms I and II. Thermomicroscopic observations showed that all three forms sublimate. The start of sublimation was different for each shape, and continued on a wide temperature scale (130-290 ° C on an uncalibrated instrument). This is not evident in DSC thermograms. The fusion occurred on a scale (130-290 ° C in an uncalibrated instrument) for all three forms. The possibility of two components melting consecutively could not be distinguished. Sublimated material was collected for all three forms, and analyzed by IR and NMR. This showed that Form I had occurred. Forms I and II were annealed, and found to have been converted to Form I by IR. The annealing procedure consisted of heating at 10 ° C / min from room temperature to about 250 ° C, and continuing at this point for V -1 hour, then allowing the sample to cool slowly to room temperature. ("The previous thermal experiments seem to indicate that form I is the most stable form." This could explain the similarity in the melting points of the three forms.

Synthetic methods of recrystallization Several lots of cipamfilin were prepared by the same route, and the final recrystallization solvent and the rate of cooling were varied as shown in Table VIII below.

TABLE VIII 15 * In the case of THF (rapid cooling rate), it appears that the form I produced is contaminated with another form, form III. All the data indicate that the lll form could be a polymorph, but it has not been characterized since it always seems to be produced in the mixtures.

Slow cooling in this solvent produced form I.

Recrystallization of Form II Another experimental procedure used to recrystallize form II from a methanol / 2-butanone solvent mixture is as follows: Solid material from a cipamfilin sample was added to an aliquot of 2-butanone in a glass jar, and moderately heated on a hot plate with stirring. Methanol was added dropwise to the hot solution under stirring until it appeared that all the solid material had dissolved. Small holes were made in the cap of the plastic bottle, and the clear colorless solution was allowed to slowly evaporate in a cover at room temperature. Regular crystals of Form II appeared within 11 days. - In yet another study, cipamfilin (1 g) was dissolved in EtOH (55 volumes), and the solutions were cooled to 20-25 ° C for 1 hour and 4 hours, respectively. The results are shown in the following table IX.

TABLE IX Recrystallization of cipamfilin from EtOH Notes: a) Time to cool reflux temperature (~ 78 ° C) to approximately 20-25 ° C. b) Determined by IR spectroscopy. In both cases, cooling for a prolonged period (> 1 h) gave cipamfilin in the polymorphic form II.

Recrystallization of Form IV The other experimental procedure for recrystallization of Form IV, solid material from a sample of cipamfilin was added to an aliquot of isopropanol in a glass flask, and moderately heated on a hot plate with stirring. An equal volume of ethanol was added, and the stirring was continued until it appeared that all the solid material had dissolved. Small holes were made in the lid of the plastic bottle, and the clear solution was allowed to slowly evaporate in a cover at room temperature. In a short time, rectangular crystals of form II appeared, followed by several days of needles, one of which was used for the determination of the structure of form IV.

Recrystallization of form I In another experimental procedure for the purification of cipamfilin, they were dissolved (15.5 g) in n-propanol (300 ml) at reflux. Cooling to room temperature led to the precipitation of the purified product of Form I, which was isolated by filtration and dried at 70 ° C overnight. Recovered weight of cipamfilin = 11.96 g; yield = 63%. Alternative solvents such as n-propanol / water, 3: 1, also resulted in similar yields and results. As described above, 1-propanol is a preferred solvent for preparing cipamfilin in polymorphic form I. The recrystallization procedure with 1-propanol has been carried out on a larger scale, a scale of approximately 2 kg, with repeated success. Cooling times of 97 ° C at room temperature were varied from about 70 minutes to overnight (about 8 to 12 hours). Form I has been formed in reproducible form. This procedure can be summarized as follows: BRL-61063 crude (2.06 kg) was dissolved in 1-propanol (40 I) at about 97 ° C. The reaction was then cooled to about 18 ° C for about 70 minutes. The resulting suspension was filtered, the solid was washed with precooled 1-propanol (3 x 0.6 I), and dried in air at about 50 ° C overnight to yield the form I of cipamfilin (1.85 kg, 90%). In another recrystallization study, similar to that shown previously in Table VIII, using again MeOH, THF and acetone, the results shown in Table X below were obtained.

TABLE X Recrystallization of cipamfilin from various solvents3 Notes: a) General method: x g of BRL-61063 was suspended in and ml of the appropriate solvent, and heated to reflux, after which dissolution occurred. The solution was then cooled for an appropriate time, and the product was isolated by filtration. b) Time to cool reflux temperature to 20-25 ° C. c) Determined by IR spectroscopy. d) Predominantly form II, a certain amount of form I. e) Cooling of the solution by collision with a water bath. These data (Table X) show that the slow crystallization of BRL-61063 from MeOH (step 1), provided the product in polymorphic form II. Polymorphic form II was the predominant form obtained from the slow cooling of a solution of BRL-61063 in acetone (step 2). Cooling by collision of an identical solution (step 3), gave BRL-61063 in Form I exclusively. The rapid cooling experiment was repeated, and gave the form I (step 4), confirming the original observation. BRL-61063 was dissolved in THF, and rapid cooling led to the isolation of the material that exists in the polymorphic forms I and III (step 5). Form I was obtained exclusively from slow cooling (step (• 5 6). These experiments therefore provide another aspect of the present invention, which is a process for producing Form I, which process comprises placing raw cipamfilin in an organic solvent, dissolving the crude product by heating to approximately reflux temperature, and then cooling to crystallize the desired shape. For Form I, the preferred solvent is 1-propanol, acetone or THF, more preferably 1-propanol. For Form I, the cooling time of the reaction is determined by the minimum time to cool from reflux temperature, or from the temperature at which The dissolution of the crude product occurred in a solvent, that is, from a minimum time until collision cooling a solution, which on a commercial scale is about 15 minutes. Preferably, the cooling time P minimum is a real period of approximately 50 to 70 minutes until what is desired, such as during the night (ie from 8 to 12 hours). From Preferably, the cooling time is about 60 to 70 minutes, with a scale of about 120 minutes until overnight, if desired. The cooling temperature is preferably from about 0 ° C to about 25 ° C, preferably from about 15 ° C to about 25 ° C, more preferably from about 18 ° C to about 25 ° C. Likewise, ethanol is an alternative solvent, but only if collision cooling is used. For form II, ethanol or methanol is used, and a long cooling time is used (see tables VIII to X). If THF is used as a solvent to produce Form I, then slow cooling is necessary, and if acetone is used, then rapid cooling is also necessary. It is recognized that other combinations of solvents can be used herein under suitable conditions, and these combinations could include mixing with water or with other organic solvents such as DMF, heptanes, MeCN, n-butanol, isopropanol, ethyl acetate, TBME, toluene, decalin, etc. All these combinations are included within the meaning of modifications or improvements of the modalities specifically exemplified herein. It is recognized that this is within the knowledge of one skilled in the art to produce the optimum solvent that will be used to carry out recrystallization on a commercial and laboratory scale using the descriptions herein. All publications including, but not limited to, patents and patent applications cited in this specification, are incorporated herein by reference as if each individual publication was specifically and individually indicated to be incorporated herein by reference. The above description fully describes the invention, including the preferred modalities thereof. Modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. Therefore, the examples herein should be considered solely as illustrative and in no way as a limitation on the scope of the present invention. The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows:

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine which exhibits an X-ray powder diffraction pattern having characteristic maximum values expressed in separation d (A) at decreasing intensity at approximately 12302, 7.702, 8.532, 4.289 and 2.854 and as expressed in figure 1. 2.- A crystalline polymorph of 1,3-di-cyclopropylmethanol-8-amino xanthine that exhibits an infrared absorption spectrum in potassium bromide that it has characteristic absorption bands expressed in reciprocal centimeters as described in Figure 15. 3.- A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits an X-ray crystallographic analysis of individual crystals with (a ) crystal parameters that are approximately equal to the following: crystal shape (mm): flat needles; Glass dimensions: 1.0 x 0.12 x 0.08 mm; color of the crystal: colorless; space group: triclinic # 2 P1; Temperature: 295K; constants of the cell: a = 10.829 (2) A, b = 12.636 (2) A, c = 5.105 (3) A, alpha (a) = 99.48 (4), beta (ß) = 91.53 (4), gamma (?) = 83.84 (3); volume: 683.0 (8) A 3; molecules / unit cell (Z): 4; density p (cale): 1354 g / cm "3; μ: 7,362 cm" 1; F (000): 292; where the atomic positions of all the atoms with respect to the origin of the unit cell are represented in tables 2 to 5. 4.- A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a pattern of Raman spectroscopy as expressed in figure 3. 5.- A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine which exhibits a powder diffraction pattern of X-rays having characteristic maximum values expressed in the separation (A) at decreasing intensity at approximately 12.001, 6.702, 3.687, 3.773 and 7.345 and as expressed in figure

2. 6.- A crystalline polymorph of 1,3-di- cyclopropylmethyl-8-amino-xanthine which exhibits an infrared absorption spectrum in potassium bromide having characteristic absorption bands expressed in reciprocal centimeters as described in Figure 16. 7.- A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine which exhibits a crystallographic analysis d X rays of individual crystals with crystal parameters that are approximately equal to the following: shape of the crystal (mm): rectangular blocks; space group: monoclinic # 14 P2 1 c; constants of the cell: a = 12.227 (4) A, b = 7448 (2) A, c = 14.946 (8) A, beta (ß) = 97.95 (4); volume: 1348.1 (9) A 3; molecules / unit cell (Z): 4; density p (cale): 1356 g / cm "3; μ: 0.896 cm" 1; F (000): 584. 8.- A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine which exhibits a Raman spectroscopy pattern as expressed in figure 4. 9.- A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine which exhibits an infrared absorption spectrum of a crystal having characteristic absorption bands expressed in reciprocal centimeters as described in figures 13, 19 or 20. 10. A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine exhibiting an X-ray crystallographic analysis of individual crystals with crystal parameters that are approximately equal to the following: shape of the crystal (mm): flat needles; space group: triclinic # 2 10 P1; constants of the cell: a = 10.210 (3) A, b = 13.753 (2) A, c = 4.942 (31) A, alpha (a) = 97.94 (2), beta (ß) = 97.95 (4), gamma (?) = 83.33 (2); volume: 677.1 (5) A 3; molecules / unit cell (Z): 2; density p (cale): 1350 g / cm "

3. 11.- A crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino xanthine that exhibits a Raman spectroscopy pattern as expressed in Figure 5. 12. - A pharmaceutical composition comprising an amount of a polymorph according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier or diluent 13. A pharmaceutical composition comprising an amount of a polymorph in accordance with any of claims 5 to 8, and a pharmaceutically acceptable carrier or diluent. 1

4. A pharmaceutical composition comprising an amount of a polymorph according to any of claims 9 to 11, and a pharmaceutically acceptable carrier or diluent. 1

5. The use of a polymorph according to any of claims 1 to 4, in the manufacture of a medicament for treating a disease mediated by PDE4 in a mammal. 1

6. The use of a polymorph according to any of claims 5 to 8, in the manufacture of a medicament for treating a disease mediated by PDE4 in a mammal. 1

7. The use of a polymorph according to any of claims 9 to 11, in the manufacture of a medicament for treating a disease mediated by PDE in a mammal. 1

8. The use of a polymorph according to any of claims 1 to 4, in the manufacture of a medicament for treating a disease mediated by TNF in a mammal. 1

9. The use of a polymorph according to any of claims 5 to 8, in the manufacture of a medicament for treating an illness mediated by TNF in a mammal. 20. The use of a polymorph according to any of claims 9 to 11, in the manufacture of a medicament for treating a disease mediated by TNF in a mammal. 21. A process for producing a crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino-xanthine, form I, which process comprises: a) dissolving 1,3-di- c-chloropropylmethyl-8-amino xanthine in 1-propanol; and b) cooling the solution to crystallize therefrom the desired polymorphic form I. 22. The process according to claim 21, further characterized in that 1-propanol is mixed with water. 23. The method according to claim 21, further characterized in that the cooling temperature is from about 0 to about 25 ° C. 24. The method according to claim 23, further characterized in that the crystallization time is from about 15 to about 120 minutes. 25. The process according to claim 21, further characterized in that the xanthine is dissolved by heating the 1-propanol to reflux conditions. 26.- A procedure to produce a crystalline polymorph of 1,3-di-cyclopropylmethyl-8-amino-xanthine, form I, which process comprises: a) dissolving 1,3-di-cyclopropylmethyl-8-amino-xanthine in tetrahydrofuran or acetone; and b) cooling the solution to crystallize therefrom the desired polymorphic form I.