WO2015149727A1

WO2015149727A1 - Novel solid phases of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1 -piperazinyl)propoxy]-3-quinolinecarbonitrile

Info

Publication number: WO2015149727A1
Application number: PCT/CZ2014/000033
Authority: WO
Inventors: Violetta Kiss; Ondrej Dammer; Ludek Ridvan
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2014-04-02
Filing date: 2014-04-02
Publication date: 2015-10-08
Anticipated expiration: 2016-10-02

Abstract

Crystal modifications 1, 2, 3, 4, 5, and 6 and amorphous form of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile. (Formula (I))

Description

NOVEL SOLID PHASES OF

-[(2,4-DICHLORO-5-METHOXYPHENYL)AMINO]-6-METHOXY-7-[3-(4-METHYL- 1 -PIPERAZINYL)PROPOXY]-3-QUINOLINECARBONITRILE

Background of the invention

Field of the invention

The present invention relates to a novel modifications of 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile of Formula I

(I)

in crystalline or amorphous phase and the processes for the preparation thereof.

Background information

4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3- quinolinecarbonitrile compound which is also known as bosutinib (CAS no.: 380843-75-) has an tyrosine kinase inhibitor activity which is indicated for the treatment of chronic, accelerated or blast phase Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML) for adult patients that have resistance or intolerance to prior therapy.

The enzyme tyrosine kinase is a subclass of protein kinase and it plays an important role in the phosphate group transfer in form adenosine triphosphate (ATP) to a protein in the cell. The phosphate group is attached to the appropriate amino acid, tyrosine on the protein. Tyrosine kinases act as an "on" and "off' switch, however, can be easily go under mutation by sticking in the "on" position resulting in uncontrolled growth of the cell that leads to the development of cancer. Consequently, tyrosine kinase inhibitors are often used as effective agents for cancer treatments.

WO03093241 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases. One example of the compounds disclosed is 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile; preparation of the base is described.

Crystalline forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile and various hydrated and solvated modifications thereof are disclosed in patent WO 2007005462.

Organic Process Research and Development 2013; 17; pages 500-504 describes systematic investigation that lead to the process for the preparation of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (bosutinib) monohydrate with excellent purity. Many pharmaceutical solid compounds can exist in various crystalline forms regarded as polymorphs and hydrates/solvates. Organic compound, like 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile may exist in various crystal modifications having different crystal units and hence different physico-chemical properties including melting point, solubility, dissolution rate and finally, bioavailability. In order to distinguish the distinct solid phases of a compound several solid state analytical techniques can be used, e.g. X- Ray Powder Diffraction, Raman spectroscopy and thermoanalytical methods.

Discovery of new solid phases (polymorphs, solvates, hydrates and amorphous phase) of an active pharmaceutical compound offers the opportunity to select the appropriate modification having desirable physico-chemical properties and processability and improve the characteristics of the pharmaceutical product. For this reason there is an explicit need for new solid forms (polymorphs, solvates, hydrates) of 4-[(2,4-dichIoro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile.

Summary of the invention

The object of the present invention is to provide novel modifications of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile suitable for oral administration which meet the pharmaceutical requirements.

It has now surprisingly been found that the compound of formula I can be prepared in 6 different crystal modifications as well as in amorphous phase. These 7 solid phase modifications, referred to herein as Crystal modification 1, Crystal modification 2, Crystal modification 3, Crystal modification 4, Crystal modification 5, Crystal modification 6 and amorphous phase, have different physico-chemical properties. Each solid phases were identified by characteristic X-Ray Powder diffractograms and Raman spectra; furthermore the melting process is described, too.

Brief description of the figures

Figure 1 is an XRPD pattern of the Crystal modification 1 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 1;

Figure 2 is a Raman spectra of the Crystal modification 1 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 1;

Figure 3 is an XRPD pattern of the Crystal modification 2 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 2;

Figure 4 is a Raman spectra of the Crystal modification 2 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 2;

Figure 5 is an XRPD pattern of the Crystal modification 3 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 6;

Figure 6 is a Raman spectra of the Crystal modification 3 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 6; Figure 7 is an XRPD pattern of the Crystal modification 4 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 9;

Figure 8 is a Raman spectra of the Crystal modification 4 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 9;

Figure 9 is an XRPD pattern of the Crystal modification 5 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 11;

Figure 10 is a Raman spectra of the Crystal modification 5 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 11;

Figure 11 is an XRPD pattern of the Crystal modification 6 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 12;

Figure 12 is a Raman spectra of the Crystal modification 6 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 12;

Figure 13 is an XRPD pattern of the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 14;

Figure 14 is a Raman spectra of the amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]- 6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile prepared according to Example 14.

Detailed description of the invention

The aim of the present invention is to provide novel modifications of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile (bosutinib) of formula I with advantageous properties for pharmaceutical use regarding the physico- chemical properties and which can be produced in a reproducible manner even in industrial scale.

(I)

The invention relates to novel crystalline and amorphous modifications of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, which have not been described in the literature and no solid state analytical data (X-Ray Powder Diffraction patterns, Single-Crystal X-Ray Diffraction data etc.) serving to characterize the novel solid phases have been provided.

The Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile has the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7- [3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 1, below:

Table 1

The Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation. Figure 2 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2939, 2820, 2214, 1622, 1594, 1508, 1464, 1428, 1328 and 703 cm ¹ wavenumbers.

The Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera). The crystalline Modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 90°C- 99°C.

The Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) suspending 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in water;

b) stirring the suspension of the step a) for 10-15 min at a temperature of 95°C-100°C;

c) cooling the suspension of the step b) to a temperature of 20°C-25°C;

d) keeping the suspension of the step c) at a temperature of 20°C-25°C for 12-16 hours;

e) isolating the 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in Crystal modification 1.

The Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 3. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The Crystal modification 2 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 2, below:

Table 2

The Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation. Figure 4 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3014, 2944, 2828, 2208, 1620, 1594, 1461, 1403, 1326 and 736 cm ¹ wavenumbers. The Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera). The crystalline Modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process with recrystallization phenomena between 100°C-110°C and final melting between 115^oC-120°C.

The Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in methanol at 60°C-65°C;

b) cooling the solution of the step a) to room temperature at laboratory condition;

c) keeping the suspension of the step b) at a temperature of 20°C-25°C for 12-16 hours;

d) isolating the Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile.

Another process of preparation of the Crystal modification 2 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile comprises the steps of:

a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in methanol at 60°C-65°C;

b) cooling the solution of the step a) to 0°C-5°C by placing the vial containing the solution of 60°C-65°C into ice;

c) keeping the suspension of the step b) at a temperature of 0°C-5°C for 12-16 hours;

b) evaporating the solvent at laboratory conditions.

b) evaporating the solvent in vacuum oven applying a temperature of 60°C and atmospheric pressure.

The Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 5. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 3 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoli exhibits the following diffraction peaks in XRPD pattern, see Table 3, below:

Table 3

The Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation. Figure 6 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3017, 2939, 2833, 2209, 1595, 1407, 1463, 1404, 1328 and 738 cm ¹ wavenumbers.

The Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera). The crystalline Modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 89°- 95°C.

The Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrilecan be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in ethanol at 73°C-78°C;

c) keeping the suspension of the step b) at a temperature of 20°C-25°C for 12-16 hours; d) isolating the Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile.

Another process of preparation of the Crystal modification 3 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile comprises the steps of:

a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in ethanol at 73°C-78°C;

b) cooling the solution of the step a) to 0°C-5°C by placing the vial containing the solution of 73°C-78°C into ice;

d) isolating the Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile.

a) dissolving 4-[(2 4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in methanol at 73°C-78°C;

b) evaporating the solvent at laboratory conditions.

The Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 7. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The Crystal modification 4 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 4, below:

Pos. [^e2Th.] d-spacing [A] Rel. Int. [%]

8.31 10.628 31.6

10.12 8.734 19.9

10.99 8.047 26.8

11.47 7.710 34.0

13.08 6.763 14.4

14.21 6.229 25.1

14.60 6.062 37.5

15.22 5.817 25.1

15.75 5.620 4.5

16.66 5.318 26.1

17.36 5.103 40.7

20.08 4.419 48.9

21.34 4.161 27.0

22.13 4.014 8.5

23.15 3.839 21.6

23.85 3.728 100.0

24.54 3.624 26.0 25.14 3.539 9.0

28.63 3.116 6.5

29.35 3.041 5.2

32.44 2.758 5.6

33.83 2.647 5.2

Table 4

The Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation. Figure 8 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3075, 2942, 2976, 2215, 1620, 1590, 1466, 1404, 1381 and 740 cm^"1 wavenumbers.

The Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera). The crystalline Modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process with a recrystallization phenomena between 98°C-103°C and final melting between 143°C-153°C.

The Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrilecan be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in 4-methyl-2-pentanone at 110°C-115°C;

Another process of preparation of the Crystal modification 4 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile comprises the steps of:

a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in ethyl acetate at 72°C-77°C;

The Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 9. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The Crystal modification 5 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table 5, below:

Pos. [°2Th.] d-spacing [A] Rel. Int. [%]

4.18 21.128 36.1

6.19 14.266 23.4

7.27 12.142 40.1

7.66 11.533 44.8

8.35 10.577 8.1

12.39 7.136 100.0 12.85 6.883 51.1

13.30 6.653 31.4

13.68 6.468 55.2

14.26 6.207 8.3

14.56 6.080 5.9

15.35 5.769 11.1

17.16 5.164 20.8

17.55 5.050 6.3

18.13 4.888 13.4

18.64 4.757 8.5

19.31 4.592 6.4

20.02 4.431 44.2

21.41 4.147 15.0

22.20 4.001 10.5

23.80 3.736 6.4

24.91 3.572 9.3

25.23 3.527 5.4

25.87 3.441 4.8

26.44 3.369 3.7

27.56 3.233 4.6

28.82 3.095 4.2

30.67 2.913 9.4

31.81 2.811 4.5

33.16 2.700 3.7

34.83 2.574 3.4

Table 5

The Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation. Figure 10 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3073, 3035, 2929, 2830, 2219, 1595, 1461, 1386, 1313 and 721 cm ¹ wavenumbers.

The Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera). The crystalline Modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 136°C-145°C.

The Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrilecan be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in butyl acetate at 120°C-125°C;

b) evaporating the solvent in vacuum oven applying a temperature of 60°C and atmospheric pressure. The Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 11. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The Crystal modification 6 of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile exhibits the following diffraction peaks in XRPD pattern, see Table6, below:

Table 6

The Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy. Figure 12 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks 3041, 2945, 2792, 2214, 1623, 1596, 1405, 1329, 1248 and 741 cm ¹ wavenumbers.

The Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrilecan be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in dichloromethane at 35°C-40°C;

b) cooling the solution of the step a) to 0°C-5°C by placing the vial containing the solution of 35°C-40°C into ice;

c) keeping the suspension of the step b) at a temperature of 0°C-5°C for 12-16 hours; d) isolating the Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile.

The Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination (Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera). The crystalline Modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a recrystallization phenomena between 85°C-88°c and final melting between 90°C-100°C.

The amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile according to the invention has the characteristic XRPD pattern as shown in Figure 13. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).

The amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be characterized by Raman spectroscopy investigation. Figure 14 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2944, 2215, 1619, 1593, 1502, 1464, 1402, 1327, 1219 and 738 cm^"1 wavenumbers.

The amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile can be further described by melting process determination Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProRes CT3 camera). The amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile gives a melting process between 108°C - 118°C.

The amorphous 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrilecan be prepared by a process comprising the steps of: a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in dichloromethane at 35°C-40°C;

Another process of preparation of the amorphous phase of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile comprises the steps of:

a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in 2-propanol at 78⁰C-83°C;

a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in tetrahydrofuran at 60^oC-65°C;

b) evaporating the solvent in vacuum oven applying a temperature of 60°C and atmospheric pressure. Another process of preparation of the amorphous phase of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile comprises the steps of:

a) dissolving 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile in toluene at 105°C-110°C;

Analysis -XRPD (X-Ray Powder Diffractometry)

Diffractograms were obtained with laboratory X'PERT PRO MPD PANalytical diffractometer, used radiation CuKoc (λ = 1.542A).

Generator settings:

excitation voltage 45 kV

anodic current 40 mA.

Scan description:

scan type - gonio

measurement range 2 - 40⁹ 2Θ

- step size O.Ol⁹ 2Θ

time per step: 50 s.

Samples were measured as received on Si plate (zero background holder).

Incident beam optics: programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/4⁹ anti-scatter fixed slit, 0.02 rad Soller slits.

Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122⁹. 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.

Analysis - Raman spectroscopy

FTIR spectra were recorded by FT-Raman Bruker RFS 100/S Spectrometer.

General settings:

Excitation source: Nd-YAG laser (1064 nm)

Applied spectral domain: 3600-200 cm^"1

Applied laser power: 250 mW

Detector: liquid nitrogen cooled Ge-diode detector (D418-T)

Resolution: 4 cm^"1

Number of accumulations: 128

Scattering geometry: 180° (back scattering)

Aperture: 3.5 mm Analysis - Melting process determination

Melting process was determined by Nikon Eclipse Ni microscope equipped with LINKAM hotstage and Jenoptik ProgRes CT3 camera collecting the data by NIS-Elements AR software.

General settings:

Magnification: 40x

Applied temperature range: 25°C - 250°C

Heating rates: 5°C / min to 100 °C

4°C / min to 250°c

Data acquisition: 1/ 5 sec to 100°C

1 / 1 sec to 250°C

Examples

Example 1

Preparation of Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

60 mg (0.070 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 12 mL of water at 95^oC-100°C. The slurry was cooled back to room temperature and left overnight standing. The resulting suspension was filtered off and dried at laboratory condition.

Product: 55 mg; yield: 92%, Crystal modification 1 Example 2

Preparation of Crystal modification 2 of 4-[{2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 775 μΙ_ of methanol at 60°C-65°C. The hot solution left to cool down to room temperature and kept at room temperature overnight. The precipitated solid was filtered off and dried at laboratory condition.

Product: 11 mg; yield: 55%, Crystal modification 2

Example 3

Preparation of Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 775 μΐ of methanol at 60°C-65°C. The hot solution left to 0°C-5°C by placing the vial into ice and left at 0°C-5°C overnight. The precipitated solid was filtered off and dried at laboratory condition.

Product: 12 mg; yield: 60%, Crystal modification 2 Example 4

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 775 μΐ of methanol at 60°C-65°C. The solvent was completely evaporated at laboratory condition.

Product: 16 mg; yield: 80%, Crystal modification 2

Example 5

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 775 μΐ of methanol at 60°C-65°C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 12 mg; yield: 60%, Crystal modification 2

Example 6

Preparation of Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 125 μί of ethanol at 73°C-78°C. The hot solution left to cool down to room temperature and kept at room temperature overnight. The precipitated solid was filtered off and dried at laboratory condition.

Product: 10 mg; yield: 50%, Crystal modification 3

Example 7

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 125 μί of ethanol at 73°C-78°C. The hot solution left to 0°C-5°C by placing the vial into ice and left at 0°C-5°C overnight. The precipitated solid was filtered off and dried at laboratory condition.

Product: 11 mg; yield: 55%, Crystal modification 3

Example 8

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 125 μί of ethanol at 73°C-78°C. The solvent was completely evaporated at laboratory condition.

Product: 13 mg; yield: 65%, Crystal modification 3 Example 9

Preparation of Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 275 μΐ of 4-methyl-2-pentanone at 110^oC-115°C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 12 mg; yield: 60%, Crystal modification 4 Example 10

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 1.25 mL of ethyl acetate at 72°C-75⁰C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 13 mg; yield: 65%, Crystal modification 4 Example 11

Preparation of Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 225 μί of butyl acetate at 120°C-125°C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 13 mg; yield: 65%, Crystal modification 5 Example 12

Preparation of Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3- (4-methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 300 μΐ of dichloromethane at 35°C- 40°C. The hot solution left to 0°C-5°C by placing the vial into ice and left at 0°C-5°C overnight. The precipitated solid was filtered off and dried at laboratory condition.

Product: 12 mg; yield: 60%, Crystal modification 6 Example 13

Preparation of amorphous phase of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 300 μί. of dichloromethane at 35°C- 40°C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 9 mg; yield: 45%, amorphous phase Example 14

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 175 μί of 2-propanol at 78°C-83°C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 18 mg; yield: 90%, amorphous phase Example 15

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 125 μί of tetrahydrofurane at 60°C- 65°C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 9 mg; yield: 45%, amorphous phase Example 16

20 mg (0.038 mmol) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-3-quinolinecarbonitrile was dissolved in 625 μί. of toluene at 105°C-110°C. The solvent was completely evaporated in vacuum oven at 60°C applying atmospheric pressure.

Product: 17 mg; yield: 85%, amorphous phase

Claims

Claims:

1. Crystal modification 1 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, characterised by a XRPD pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 5.7; 12.7; 17.2; 25.8 and 28.7°.

2. Crystal modification 2 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, characterised by a XRPD pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 5.6; 12.6; 16.8; 23.2; 25.4 and 28.2°.

3. Crystal modification 3 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, characterised by a XRPD pattern having the characteristic diffraction peaks at reflection angle 2Θ (+ 0.2° 2Θ) of 5.6; 8.5; 11.9; 16.9; 19.6; 23.9 and 27.1°.

4. Crystal modification 4 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, characterised by a XRPD pattern having the characteristic diffraction peaks at reflection angle 2Θ (+ 0.2° 2Θ) of 8.3; 11.5; 14.6; 17.4; 20.1 and 23.8°.

5. Crystal modification 5 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, characterised by a XRPD pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 4.2; 7.7; 12.4; 13.7; 17.2 and 20.0°.

6. Crystal modification 6 of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4- methyl-l-piperazinyl)propoxy]-3-quinolinecarbonitrile, characterised by a XRPD pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 6.0; 9.7; 12.6; 15.4; 19.9 and 25.0°.

7. Amorphous 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyi-l- piperazinyl)propoxy]-3-quinolinecarbonitrile.