TYROSINE KINASE INHIBITORS AND PHARMACEUTICAL APPLICATION THEREOF

Abstract

The present disclosure provides a tyrosine kinase inhibitor having the general formula (I).

##STR00001## R1 is C.sub.1-C.sub.6 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, mono-substituted phenyl, poly-substituted phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, CH.sub.3O(CH.sub.2)n-,

##STR00002##

R being methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, acetyl or acryloyl, and n being an integer from 1 to 6. R2 and R3 are respectively halogen, hydrogen, amino, substituted amino, cyano, hydroxyl, sulfonic acid group, sulfonamide, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, methoxy or ethynyl. R2 and R3 are in an ortho, para or meta position. Y is NH, O, S or Z—N, where Z is methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyclopropyl. X is Cl, Br or F.

Claims

1. A tyrosine kinase inhibitor (TKI), having the following general formula (I): ##STR00008## wherein: R1 is C.sub.1-C.sub.6 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, mono-substituted phenyl, poly-substituted phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, CH.sub.3O(CH.sub.2)n-, ##STR00009## R being methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, acetyl or acryloyl, and n being an integer from 1 to 6; R2 is halogen, hydrogen, amino, substituted amino, cyano, hydroxyl, sulfonic acid group, sulfonamide, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, methoxy or ethynyl; R3 is halogen, hydrogen, amino, substituted amino, cyano, hydroxyl, sulfonic acid group, sulfonamide, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, methoxy or ethynyl; R2 and R3 are in an ortho, para or meta position; Y is NH, O, S or Z—N, wherein Z is methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyclopropyl; and X is Cl, Br or F.

2. The TKI according to claim 1, wherein R1 is methyl, R2 is F, R3 is Cl, Y is NH, X is Br, and n=0.

3. The TKI according to claim 1, wherein R1 is methyl, R2 is F, R3 is Cl, Y is NH, X is Cl, and n=0.

4. The TKI according to claim 1, wherein R1 is methyl, R2 is F, R3 is Cl, Y is NH, X is Cl, and n=2.

5. The TKI according to claim 1, wherein R1 is propargyl, R2 is F, R3 is Cl, Y is NH, X is Br, and n=0.

6. The TKI according to claim 1, wherein R1 is phenyl, R2 is F, R3 is Cl, Y is NH, X is Cl, and n=0.

7. The TKI according to claim 1, wherein R1 is methyl, R2 is H, R3 is ethynyl, Y is NH, X is Br, and n=0.

8. Application of the TKI according to claim 1 in preparation of drugs for inhibiting and treating diseases caused by overexpression of tyrosine kinase.

9. A pharmaceutical composition, including: a TKI as shown in the general formula (I) according to claim 1 as an active ingredient, and one or more pharmaceutical carriers or excipients.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The embodiments are shown and clarified with reference to the drawings. These drawings serve to clarify the basic principle, so that only aspects necessary for understanding the basic principle are shown. The drawings are not to scale. In the drawings, the same reference numerals indicate similar features.

[0013] FIG. 1 shows an H-NMR spectrum of a compound prepared according to Example 1; and

[0014] FIG. 2 shows a statistical graph of proliferation of 40 L of pretreated mesothelioma cells analyzed by plate cloning experiments.

[0015] Other features, characteristics, advantages and benefits of the present disclosure will become more apparent through the following detailed description in conjunction with the accompanying drawings.

DETAILED DESCRIPTION

[0016] In the following detailed description of the preferred embodiments, reference will be made to the accompanying drawings constituting a part of the present disclosure. The drawings show specific embodiments capable of implementing the present disclosure by way of example. The exemplary embodiments are not intended to be exhaustive of all embodiments according to the present disclosure. It can be understood that other embodiments can be utilized, and structural or logical modifications can also be made without departing from the scope of the present disclosure. Therefore, the following detailed description is not restrictive, and the scope of the present disclosure is defined by the appended claims.

[0017] The present disclosure provides a tyrosine kinase inhibitor (TKI) and applications thereof. The disclosed TKI can be a quinazoline derivative, and can irreversibly inhibit the activity of tyrosine kinase, as well as inhibit and treat diseases caused by overexpression of the tyrosine kinase.

[0018] In one example embodiment, a basic reaction process for preparing the quinazoline derivative is shown below:

##STR00005##

[0019] Concepts of the present disclosure are further explained below according to examples below.

[0020] The present disclosure provides a tyrosine kinase inhibitor, which is a quinazoline derivative having the general formula (I).

##STR00006##

[0021] R1 is C.sub.1-C.sub.6 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, mono-substituted phenyl, poly-substituted phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, CH.sub.3O(CH.sub.2)n-,

##STR00007##

R being methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, acetyl or acryloyl, and n being an integer from 1 to 6. R2 and R3 are respectively halogen, hydrogen, amino, substituted amino, cyano, hydroxyl, sulfonic acid group, sulfonamide, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, methoxy or ethynyl. R2 and R3 are in an ortho, para or meta position. Y is NH, O, S or Z—N, where Z is methyl, ethyl, isopropyl, trifluoromethyl, 2,2,2-trifluoroethyl or cyclopropyl. X is Cl, Br or F.

Example 1

[0022] The disclosed tyrosine kinase inhibitor in this example is 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-((N-bromoacetyl)amino)quinazoline, which can be prepared based on the following steps. In this example, R1 is methyl, R2 is F, R3 is Cl, Y is NH, X is Br. and n=0 in formula (I).

(1) Preparation of 4-chloro-7-fluoro-6-nitroquinazoline

[0023] 4-Hydroxy-7-fluoro-6-nitroquinazoline (8.5 g) and phosphorus oxychloride (150 ml) were added to a 250 ml round-bottomed flask, and the mixture was stirring under reflux for 6 hours. Excessive phosphorus oxychloride was removed by rotary evaporation, and then the mixture was washed with 10:1 petroleum ether/ethyl acetate to obtain 4-chloro-7-fluoro-6-nitroquinazoline (8.0 g). MS (m/z): 227.78 (M+1).sup.+.

(2) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-fluoro-6-nitroquinazoline

[0024] To 4-chloro-7-fluoro-6-nitroquinazoline (2.3 g) in N,N-dimethylformamide (30 ml), were added 4-fluoro-3-chloroaniline (1.6 g) and potassium carbonate (1.7 g). The mixture was stirred at 50° C. for 10 hours. Then the solvent was distilled under reduced pressure. Ethyl acetate (100 ml) was added, the mixture was washed with water (30 ml). Ethyl acetate was separated and dried over magnesium sulfate. After the mixture was filtrated and concentrated, the residue was purified by chromatography column (dichloromethane/methanol as eluent) to obtain 3.0 g of 4-((4-fluoro-3-chlorophenyl)amino)-7-fluoro-6-nitroquinazoline, MS (m/z): 336.80 (M+1).sup.+.

(3) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-nitroquinazoline

[0025] To 4-((4-fluoro-3-chlorophenyl)amino)-7-fluoro-6-nitroquinazoline (3.3 g) in tetrahydrofuran (100 ml) was added sodium methoxide solution (25% in methanol, 5 ml). The mixture was stirred at room temperature for 8 hours, then diluted with 50 ml of water. The mixture was extracted with ethyl acetate (100 ml). The ethyl acetate was separated and dried over magnesium sulfate. After the mixture was filtrated and concentrated, the residue was purified by a chromatography column (dichloromethane/methanol as eluent) to obtain 2.5 g of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-nitroquinazoline, MS (m/z): 348.72 (M+1).sup.+.

(4) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-aminoquinazoline

[0026] To 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-nitroquinazoline (3.3 g) in ethanol (150 ml) and water (8 ml), ammonium chloride (1.6 g) andiron powder (2.8 g) were added, and then the mixture was heated under reflux with stirring for 5 hours. The mixture was filtered and concentrated, and the obtained solid was further washed with 15 ml of water. After drying in high vacuum, the product 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-aminoquinazoline (2.6 g) was obtained, MS (m/z): 318.74 (M+1).sup.+.

(5) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-(N-bromoacetyl) aminoquinazoline

[0027] To the mixture of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-aminoquinazoline (160 mg) and triethylamine (129 mg) in 50 ml of dichloromethane was added bromoacetyl bromide (120 mg) slowly at 0° C. After the mixture was stirred for 3 hours at this temperature, it was diluted with 10 ml of water. The dichloromethane was separated and dried over anhydrous magnesium sulfate. A crude product was obtained by filtering and concentration, and further purified by chromatography column to provide 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-(N-bromoacetyl) aminoquinazoline (170 mg).

[0028] The representation of the prepared compound was: MS (m/z): 438.80 (M+1).sup.+.

[0029] The H NMR spectrum is as shown in FIG. 1.

[0030] H NMR (CD.sub.3OD/DMSO-D.sub.6): δ=8.92 (s, 1H), 8.55 (s, 1H), 8.12 (m, 1H), 7.79 (m, 1H), 7.38 (m, 1H), 7.30 (s, 1H), 4.28 (s, 2H), 4.06 (s, 3H).

[0031] In addition, in FIG. 1, δ=4.04 is a peak of H.sub.2O, 3.13 is a peak of MeOH, and 2.60 is a peak of DMSO.

Example 2

[0032] The disclosed tyrosine kinase inhibitor in this example is 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-(N-chloracetyl) aminoquinazoline, which can be prepared based on the following steps. In this example, R1 is methyl, R2 is F, R3 is Cl, Y is NH, X is Cl, and n=0 in formula (I).

[0033] The mixture of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-aminoquinazoline (160 mg) (e.g., as prepared in step (4) of Example 1) and triethylamine (120 mg) in dichloromethane (50 ml) was cooled to 0° C. Then chloroacetyl chloride (68 mg) was added dropwise. After the reaction mixture was stirred for 5 hours, diluted with water (10 ml). The dichloromethane was separated and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated, the residue was further purified by column to obtain the product 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-(N-chloracetyl) aminoquinazoline (160 mg), MS (m/z): 394.68 (M+1).

Example 3

[0034] The disclosed tyrosine kinase inhibitor in this example is 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-(N-3-chloropropanoyl)aminoquinazoline, which can be prepared based on the following steps. In this example, R1 is methyl, R2 is F, R3 is Cl, Y is NH, X is Cl, and n=2 in formula (I).

[0035] To the mixture of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-aminoquinazoline (160 mg)(e.g., as prepared in step (4) of Example 1) and of 4-dimethylaminopyridine (60 mg) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg), 3-chloropropionic acid (70 mg) and N,N-diisopropylethylamine (129 mg). The mixture was stirred at rt for 15 hours, then diluted with water (20 ml). The mixture was extracted with ethyl acetate (100 ml), the ethyl acetate was separated and dried over magnesium sulfate. The mixture was filtrated and concentrated, and the residue was purified by chromatography column (dichloromethane/methanol as eluent) to obtain 55 mg of 4-((4-fluoro-3-chlorophenyl)amino)-7-methoxy-6-(N-3-chloropropanoyl)aminoquinazoline, MS (m/z): 408.68 (M+1).sup.+.

Example 4

[0036] The disclosed tyrosine kinase inhibitor in this example is 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-(N-bromoacetyl)aminoquinazoline, which can be prepared based on the following steps. In this example, R1 is propargyl, R2 is F, R3 is Cl, Y is NH, X is Br, and n=0 in formula (I).

(1) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-nitroquinazoline

[0037] To propargyl alcohol (6.0 g) in tetrahydrofuranm (300 ml), 4.3 g of sodium hydride was added portionwise, and the mixture was stirred at room temperature for 1 hour. Then 4-((4-fluoro-3-chlorophenyl)amino)-7-fluoro-6-nitroquinazoline (13.0 g) (e.g., as prepared in step (2) of Example 1) was added, and the mixture was stirred continuously at room temperature for 5 hours. Diluted with water (100 ml), then extracted with ethyl acetate (300 ml). The ethyl acetate was separated and dried over magnesium sulfate. The mixture was filtered and concentrated, 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-nitroquinazoline (2.5 g) was obtained, MS (m/z): 372.75 (M+1).sup.+.

(2) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-aminoquinazoline

[0038] To 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-nitroquinazoline (10.0 g) in ethanol (250 ml) and water (18 ml), ammonium chloride (4.5 g) and iron powder (7.0 g) were added. Then the mixture was heated under reflux for 15 hours. The mixture was filtered and concentrated, and the obtained solid was further purified by chromatography column to obtain 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-aminoquinazoline (7.6 g), MS (m/z): 342.76 (M+1).sup.+.

(3) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-(N-bromoacetyl) aminoquinazoline

[0039] The mixture of 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-aminoquinazoline (343 mg) and triethylamine (258 mug) in dichloromethane (100 ml) was cooled to 0° C. Bromoacetyl bromide (220 mg) was added dropwise, and the mixture was stirred for 3 hours. Diluted with water (20 ml), and the dichloromethane was separated and dried over anhydrous magnesium sulfate. After filtering and concentration, the residue was further purified by chromatography column to obtain 4-((4-fluoro-3-chlorophenyl)amino)-7-propargyloxy-6-(N-bromoacetyl) aminoquinazoline (300 mg), MS (m/z): 462.69 (M+1).sup.+.

Example 5

[0040] The disclosed tyrosine kinase inhibitor in this example is 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-(N-chloracetyl)aminoquinazoline, which can be prepared based on the following steps. In this example, R1 is phenyl, R2 is F. R3 is Cl, Y is NH, X is Cl, and n=0 in formula (I).

(1) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-nitroquinazoline

[0041] To 4-((4-fluoro-3-chlorophenyl)amino)-7-fluoro-6-nitroquinazoline (2.0 g) (e.g., as prepared in step (2) of Example 1) in tetrahydrofuran (100 ml) was added sodium phenoxide (2.2 g), and the mixture was stirred at room temperature for 2 hours. Diluted with water (50 ml), then extracted with ethyl acetate (100 ml). The ethyl acetate was separated and dried over magnesium sulfate. The mixture was filtrated and concentrated, and the residues were purified by chromatographic column (dichloromethane/methanol as eluent) to obtain 1.5 g of 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-nitroquinazoline, MS (m/z): 410.79 (M+1).sup.+.

(2) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-aminoquinazoline

[0042] To 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-nitroquinazoline (1.5 g) in ethanol (100 ml) and water (6 ml), ammonium chloride (2.0 g) and iron powder (2.8 g) were added, and then the mixture was heated under reflux with stirring for 5 hours. The mixture was filtered and concentrated, and the obtained solid was further washed with water (15 ml) and ether (20 ml), dried in high vacuum to obtain 1.0 g of 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-aminoquinazoline, MS (m/z): 380.81 (M+1).sup.+.

(3) Preparation of 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-(N-chloracetyl) aminoquinazoline

[0043] To 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-aminoquinazoline (160 mg) and triethylamine (129 mg) in dichloromethane (50 ml) was added chloroacetyl chloride (80 mg) dropwise at 0° C., and the mixture was stirred for 3 hours. Diluted with water (10 nil), and the dichloromethane was separated and dried over anhydrous magnesium sulfate. After filtering and concentration, the residue was further purified by column to obtain 150 mg of 4-((4-fluoro-3-chlorophenyl)amino)-7-phenylol-6-(N-chloracetyl) aminoquinazoline, MS (m/z): 456.74 (M+1).sup.+.

Example 6

[0044] The disclosed tyrosine kinase inhibitor in this example is 4-((3-ethynylphenyl)amino)-7-methoxy-6-(N-bromoacetyl)aminoquinazoline, which can be prepared based on the following steps. In this example, R1 is methyl, R2 is H, R3 is ethynyl, Y is NH, X is Br, and n=0 in formula (I).

(1) Preparation of 4-((3-ethynylphenyl)amino)-7-fluoro-6-nitroquinazoline

[0045] 4-Chloro-7-fluoro-6-nitroquinazoline (2.3 g) (e.g., as prepared in step (1) of Example 1), 3-ethynylaniline (1.3 g) and potassium carbonate (1.7 g) were added to N,N-dimethylformamide (30 ml). The mixture was stirred at 50° C. for 10 hours. Then the solvent was distilled under reduced pressure. Ethyl acetate (100 ml) was added, the mixture was washed with 30 ml of water. Ethyl acetate was separated and dried over magnesium sulfate. After the mixture was filtrated and concentrated, the residue was purified by chromatography column (dichloromethane/methanol as eluent) to obtain 2.1 g of 4-((3-ethynylphenyl)amino)-7-fluoro-6-nitroquinazoline, MS (m/z): 308.68 (M+1)+.

(2) Preparation of 4-((3-ethynylphenyl)amino)-7-methoxy-6-nitroquinazoline

[0046] To 4-((3-ethynylphenyl)amino)-7-fluoro-6-nitroquinazoline (1.3 g) in tetrahydrofuran (100 ml) was added sodium methoxide solution (25% in methanol, 5 nil), and the mixture was stirred at room temperature for 8 hours. Diluted with water (50 ml), and extracted with ethyl acetate (100 ml). The ethyl acetate was separated and dried over magnesium sulfate. The mixture was filtrated and concentrated, and the residue were purified by chromatography column (dichloromethane/methanol as eluent) to obtain 0.8 g of 4-((3-ethynylphenyl)amino)-7-methoxy-6-nitroquinazoline, MS (m/z): 320.70 (M+1).sup.+.

(3) Preparation of 4-((3-ethynylphenyl)amino)-7-methoxy-6-aminoquinazoline

[0047] To 4-((3-ethynylphenyl)amino)-7-methoxy-6-nitroquinazoline (0.8 g) in ethanol (50 ml) and water (5 ml) were added ammonium chloride (0.6 g) and iron powder (1.1 g), and then the mixture was heated under reflux with stirring for 5 hours. The mixture was filtered and concentrated, the obtained solid was washed with water (10 ml) and dried in high vacuum to obtain 0.5 g of 4-((3-ethynylphenyl)amino)-7-methoxy-6-aminoquinazoline, MS (m/z): 290.80 (M+1)+.

(4) Preparation of 4-((3-ethynylphenyl)amino)-7-methoxy-6-(N-bromoacetyl) aminoquinazoline

[0048] The reaction mixture of 4-((3-ethynylphenyl)amino)-7-methoxy-6-aminoquinazoline (145 mg) and triethylamine (129 mg) in dichloromethane (50 ml) was cooled to 0° C. 120 mg of bromoacetyl bromide was added dropwise. The mixture was stirred for 3 hours, then diluted with water (10 ml). The dichloromethane was separated and dried over anhydrous magnesium sulfate. A crude product was obtained by filtering and concentration, and further purified by chromatography column to obtain 105 mg of 4-((3-ethynylphenyl)amino)-7-methoxy-6-(N-bromoacetyl)aminoquinazoline, MS (m/z): 410.84 (M+1).sup.+.

Experiment 1

[0049] Effects of the compound prepared in Example 1 and gefitinib were tested and compared. Experiment 1 included cell plate cloning experiments to detect cell proliferation.

[0050] 1. Experimental Steps:

[0051] (1) 30 μM of gefitinib was used to pretreat one group of 40 L of mesothelioma cell lines, 30 μM of the compound prepared in Example 1 were used to pretreat another group of 40 L of mesothelioma cell lines, and phosphate-buffered saline (PBS) was used as a blank control group;

[0052] (2) The 40 L of cell lines in different treatment groups were collected; the cells were counted under a microscope, the cells were inoculated in a six-well plate by adjusting the number of cells to 200 cells/well (2 mL) with corresponding complete medium, and the cells were cultured in an incubator containing 5% CO2 at 37° C.;

[0053] (3) Fresh complete medium was changed every 3 days;

[0054] (4) After about 7-10 days of continuous culture, the culture medium was discarded, the cells were carefully washed with 1×PBS 3 times, and 1 mL of 4% paraformaldehyde was added to each culture dish to fix the cells for 30 minutes. The paraformaldehyde was discarded, and the cells were washed again with 1×PBS 3 times. The cells were stained with crystal violet at room temperature for 10 min, the staining solution was discarded, and the cells were washed with 1×PBS 3 times; and

[0055] (5) the cells were pictured with a camera and counted for statistical analysis.

[0056] 2. Experimental Results

[0057] The effects of different compounds on the proliferation ability of the 40 L of cells were analyzed by plate cloning experiments. The experimental results after 10 days are shown in FIG. 2. As shown in FIG. 2, ** denotes P<0.01, and **** denotes P<0.0001. The results demonstrates that the compound prepared in Example 1 has a significantly better ability in inhibiting the proliferation of tumor cells than gefitinib.

[0058] Those skilled in the art should understand that the modifications and variations of the various embodiments disclosed above can be made without departing from the essence of the invention. Therefore, the protection scope of the present disclosure should be defined by the appended claims.

[0059] Although different exemplary embodiments of the present disclosure have been described, it is obvious to those skilled in the art that various changes and modifications can be made, which can achieve some of the advantages of the present disclosure without departing from the spirit and scope of the present disclosure. For those who are quite skilled in the art, other components performing the same function can be replaced as appropriate. It should be mentioned that the features explained here with reference to particular figures can be combined with features of other figures, even in those cases where this is not explicitly mentioned. In addition, the method of the present disclosure can be implemented either in all software implementations using appropriate processor instructions or in a hybrid implementation using a combination of hardware logic and software logic to achieve the same result. Such modifications to the solution according to the invention are intended to be covered by the appended claims.