EA040599B1 - APPLICATION OF 1-((4-(4-FLUORO-2-METHYL-1H-INDOL-5-ILOXY)-6-METHOXYQUINOLINE-7-ILOXY)METHYL)CYCLOPROPANAMINE OR ITS SALT IN COMBINATION THERAPY FOR CANCER TREATMENT - Google Patents

Description

The present application claims priority from U.S. Provisional Applications No. 62/156734 filed May 4, 2015 and No. 62/205272 filed August 14, 2015.

Technical field

The present invention relates to a new method for the synthesis of 1-((4-(4-fluoro-2-methyl-1H-indol-5yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818).

A stable crystalline form of AL3818 was obtained. Salts of AL3818 and their crystalline forms have also been obtained. The anti-cancer and optometric activity of the compound AL3818 and its salts were also investigated.

State of the art

The structure of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818) as an angiogenesis inhibitor and a number of methods for its preparation are described in the document WO2008112407.

Brief description of the invention

Abbreviations and definitions

For ease of use, the following abbreviations are used with the meanings given below.

EtOH: ethanol, MeOH: methanol, IPA: isopropanol, EtOAc: ethyl acetate, RT: room temperature, DIPEA: diisopropylethylamine, DCM: dichloromethane, DMF: NN-dimethylformamide, DMAP: 4-N,N-dimethylaminopyridine, MsCl: methanesulfonylchloride, THF : tetrahydrofuran, TFA: trifluoroacetic acid, TEA: triethylamine, Pd/C: palladium on activated carbon, eq: equivalent, g: gram, mg: milligram, ml: milliliter, min: minutes, bis=di: two or double.

DSC (DSC): differential scanning calorimetry, TGA (TGA): thermogravimetric analysis, XRPD: X-ray powder diffraction, Exo: exotherm, Endo: endotherm.

ALL: acute lymphocytic or lymphoblastic leukemia, CLL: chronic lymphocytic or lymphoblastic leukemia, AML: acute myelocytic or myeloblastic leukemia, CML: chronic myelocytic or myeloblastic leukemia.

The term C ₁ -C ₆ -alkyl in the context of the present description, unless otherwise indicated, includes from 1 to 6 monovalent saturated hydrocarbon radicals having straight or branched fragments, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The term C ₁ -C ₆ -alkoxy in the context of the present description, unless otherwise indicated, includes groups -OC ₁ -C ₆ -alkyl, and C ₁ -C ₆ -alkyl in accordance with the above definition is methoxy or ethoxy.

Scope of claims according to the invention

The present invention relates to the use of 1-((4-(4-fluoro-2-methyl1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine crystalline form or 1-((4- (4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, where the specified salt is selected from bis-hydrochloride salt, bis-hydrochloride salt monohydrate, bismaleic salt and succinic acid salt, for the treatment of ovarian, cervical and endometrial cancer in combination therapy with paclitaxel or carboplatin/paclitaxel, where:

said crystalline form of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7yloxy)methyl)cyclopropanamine has at least one of the following characteristics:

melting point 208°C-210°C;

melting temperature range according to DSC (endo): 207-220°C with a peak at 216°C, the curve is shown in Fig. 1;

thermogram TGA, according to which there is no significant weight loss up to a temperature of 205-215°C, the curve is shown in Fig. 2;

the XRPD powder diffraction pattern shown in FIG. 3, containing 10 characteristic peaks with an intensity greater than 10%, expressed by the following values of d and angles:

Corner d value Corner d value 13.344 6.62986 20.650 4.29771 15.858 5.58405 21.633 4.10463 16.799 5.27326 23.087 3.84934 17.640 5.02377 25.128 3.54112 18,770 4.72373 26.607 3.34755

said crystalline form of 1-((4-(4-fluoro-2-methyl-1H-indol-5yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine bis-hydrochloride salt has the XRPD powder diffraction pattern shown in FIG. 6 containing 21 characteristic peaks with an intensity in % greater than 10%, or 27 peaks with an intensity in % expressed by the following values of d and angles:

- 1 040599

No. Corner d value Intensity, % No. Corner d value Intensity, % 1 7,640 11.56173 19.5 14 22.814 3.89483 AND 2 2 8.642 10.22328 20 15 23.398 3.79886 I,6 3 9.361 9.43969 13.3 16 24.455 3.63702 76.6 4 10.091 8.75881 100.0 17 25.524 3.48708 34.6 5 13,740 6.43957 26.4 18 26.703 3.33576 21.7 6 14.479 6.11252 54.7 19 27.337 3.25978 18.4 7 15.186 5.82962 Yu,1 20 28.061 3.17732 18.5 8 15.766 5.61643 20.3 21 28.801 3.09732 6.3 9 17.206 5.14957 7.4 22 29.845 2.99133 13.8 10 18.569 4.77448 18.6 23 31.331 2.85271 7.1 AND 19.271 4.60215 and about 24 31.621 2.82721 9.5 12 20.041 4.42696 49.5 25 32.840 2.72504 10.5 13 22.211 3.99909 58.4 26 33.714 2.65632 3.8 27 38.348 2.34534 9.6

said crystalline form of 1-((4-(4-fluoro-2-methyl1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine bis hydrochloride salt monohydrate has the XRPD powder diffraction pattern shown in FIG. . 9, containing 9 characteristic peaks with an intensity in % of more than 10%, or 12 peaks with an intensity in %, expressed by the following values of d and angles: _____________________________________________________

No. Corner d value Intensity, % 1 5.506 16.03679 28.0 2 6.817 12.95694 100 3 8.087 10.92445 29.9 4 9.766 9.04936 20.6 5 13.318 6.64283 22.3 6 14.332 6.17523 7.0 7 16.159 5.48067 15.7 8 19.474 4.55451 8.8 9 20.920 4.24296 6.5 10 20.920 3.87321 28.2 AND 25.087 3.54678 20.2 12 25.874 3.44064 22.7

said crystalline form of the bis-maleic salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine has the XRPD powder diffraction pattern shown in FIG. . 12 containing 22 characteristic peaks with an intensity greater than 10% or 35 peaks with an intensity in % expressed by the following values of d and angles:

- 2 040599

No. Corner Meaning Intensity, No. Corner d value Intensity, d % % 1 6.716 13.14986 29.7 19 22.876 3.88434 5.8 2 8.816 10.02189 34.3 20 23.204 3.83021 19.0 3 9.743 9.07069 15.3 21 23.622 3.76332 78.4 4 10.033 8.80923 21.4 22 24.418 3.64247 6.3 5 11.777 7.50803 21.2 23 26.140 3.40621 87.0 6 13.418 6.59342 6.2 24 26.958 3.30469 26.5 7 14.816 5.97445 and about 25 27.383 3.25443 61.3 8 16.089 5.50434 9.5 26 28.154 3.16697 41.5 9 16.801 5.27279 24.5 27 29.554 3.02013 6.8 10 17.360 5.10409 87.9 28 30.611 2.91815 23.7 eleven 17.179 5.15755 70.7 29 31.373 2.84906 14.3 12 18.190 4.87308 20.2 thirty 33.457 2.67620 6.7 13 18.704 4.74028 16.7 31 34.541 2.59465 2.8 14 19.296 4.59623 5.0 32 35.137 2.55199 3.8 15 19.920 4.45371 12.6 33 35.734 2.51067 2.5 16 20.824 4.26227 65.5 34 37.129 2.41949 8.6 17 21.457 4.13785 100.0 35 39.704 2.26833 3.9 18 22.411 3.96393 4.5

said 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine succinic acid salt form has the XRPD powder diffraction pattern shown in FIG. 15 containing 11 characteristic peaks with an intensity greater than 10% or 19 peaks with an intensity in % expressed by the following values of d and angles:

No. Corner Meaning d Intensity, % No. Corner d value Intensity,% 1 5.765 15.31849 12.9 AND 23.167 3.83630 1.8 2 8.038 10.98994 7.4 12 24.085 3.69200 16.9 3 11.639 7.59700 27.7 13 24.485 3.63268 14.6 4 12,950 6 6.83065 100 14 25.737 3.45874 13.7 5 16.141 5 5.48683 18.0 15 28.621 3.11637 6.4 6 17.483 5 5.06848 18.7 16 29.255 3.05025 22.1 7 18.385 4.82175 17.8 17 31.357 2.85048 0.9 8 19.394 4.57325 1.1 18 31.967 2.79743 2.1 9 20.756 4.27609 13.4 19 35.630 2.51780 2.4 10 22.034 4.03092 2.8

Description of drawings

Fig. 1. DSC curve of the crystalline form of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 2. TGA curve of the crystalline form of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 3. XRPD diffraction pattern of the crystalline form of 1((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 4. DSC curve of the crystalline form of the bis-hydrochloride salt of 1-((4-(4-fluoro-2-methyl-1Hindol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 5. DSC curve of the crystalline form of the bis-hydrochloride salt of 1-((4-(4-fluoro-2-methyl-1Hindol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 6. XRPD diffraction pattern of the crystalline form of the bis-hydrochloride salt of 1-((4-(4-fluoro-2-methyl-1 H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine

Fig. 7. DSC curve of the crystalline form of the bis-hydrochloride hydrate salt of 1-((4-(4-fluoro-2methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

- 3 040599

Fig. 8. DSC curve of the crystalline form of the bis-hydrochloride hydrate salt of 1-((4-(4-fluoro-2methyl-1 H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 9. XRPD diffraction pattern of the crystalline form of the bis-hydrochloride hydrate salt of 1-((4-(4-fluoro-2-methyl-1 H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 10. DSC curve of the crystalline form of the bis-maleic salt of 1-((4-(4-fluoro-2-methyl-1Nindol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 11. TGA curve of the crystalline form of the bis-maleic salt of 1-((4-(4-fluoro-2-methyl-1Nindol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 12. XRPD diffraction pattern of the crystalline form of the bis-maleic salt of 1-((4-(4-fluoro-2-methyl-1 H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 13. DSC curve of the crystalline form of the succinic salt of 1-((4-(4-fluoro-2-methyl-1H-indol5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 14. TGA curve of the crystalline form of the succinic salt of 1-((4-(4-fluoro-2-methyl-III-indol5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 15. XRPD diffraction pattern of the crystalline form of the succinic acid salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

Fig. 16. Effect of AL3818 and its salts on nude mice with human endometrial cancer xenograft of the Ishikawa cell line.

Fig. 17. Effect of AL3818 salts in combination with carboplatin (CBX)/n-aclitaxel (Taxol) on nude mice with human endometrial cancer xenograft of the Ishikawa cell line.

Fig. 18. Effect of oral AL3818 on laser-induced choroidal neovascularization (laser-induced CNV).

Fig. 19. Effect of AL3818 (0.15mg/kg body weight) and intraventricular administration of an antibody against vascular endothelial growth factor (anti-VEGF antibody) on laser-induced choroidal neovascularization (laser-induced CNV).

Detailed description of the invention

The present invention relates to a new method for the synthesis of 1-((4-(4-fluoro-2-methyl-1H-indol-5yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818) by condensation of intermediate (X1) with (Y1) in a solvent in the presence of KI or NaI, or intermediate (X2) with (Y2) in a solvent to give intermediate (Z), which is deprotected to give the final compound (AL3818) in Scheme 1.

Scheme 1

While R is selected from H and C ₁ -C ₆ -alkoxy, preferably from H and -Ome.

The present invention relates to the preparation of a stable crystalline form of 1-((4-(4-fluoro2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

The present invention relates to the preparation of stable crystalline forms of 1-((4-(4fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine salts.

The present invention relates to salts of bis-hydrochloric acid, bis-hydrochloride hydrate, bis-maleic acid and succinic acid, as well as stable crystalline forms of these acids or a stable crystalline form of the free base 1-((4-(4-fluoro-2methyl-1 N-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine.

The present invention relates to the preparation of a pharmaceutical composition which comprises a stable crystalline form of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7yloxy)methyl)cyclopropanamine and a pharmaceutically acceptable carrier .

The present invention relates to the preparation of a pharmaceutical composition which comprises salts or stable crystalline forms of salts of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy- yloxy)methyl)cyclopropanamine; and a pharmaceutically acceptable carrier.

The present invention relates to a stable crystalline form or salts or stable crystalline forms of salts of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine for method of treating neoplastic disease.

The present invention relates to a stable crystalline form or salts or stable crystalline forms of salts of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine for applications for the preparation of a medicament for a method of treating neoplastic disease.

The present invention relates to a stable crystalline form or salts or stable crystalline forms of salts of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine for method of monotherapy or for combination therapy with chemotherapeutic agents selected from agents based on platinum or taxane, for the treatment of solid tumors selected from lung, kidney, colon, stomach, skin, head/neck, thyroid, pancreas, liver, prostate, bladder, brain, breast, ovary, cervix, endometrium and sarcoma; and blood cancers selected from ALL, CLL, AML, CML, and multiple myeloma.

The present invention relates to bis-hydrochloride, bis-hydrochloride hydrate, bismaleic, succinic acid salts and stable crystalline forms of these acids or a stable crystalline form of the free base 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy )-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine for a method of monotherapy or combination therapy together with chemotherapeutic agents selected from platinum or taxane based agents for the treatment of solid tumors selected from lung, kidney, colon, stomach cancer, melanoma, head/neck cancer, thyroid, pancreas, liver, prostate, bladder, brain, breast, ovary, cervix, endometrium and sarcoma; and blood cancers selected from ALL, CLL, AML, CML, and multiple myeloma.

The present invention relates to bis-hydrochloride, bis-hydrochloride hydrate, bismaleic and succinic acid salts, and stable crystalline forms of these acids or a stable crystalline form of the free base 1-((4-(4-fluoro-2-methyl-1H-indole-5- yloxy)-6methoxyquinolin-7-yloxy)methyl)cyclopropanamine for a method of monotherapy or combination therapy together with chemotherapeutic agents selected from agents based on platinum or taxane, for the treatment of cancer of the lung, colon, stomach, thyroid, pancreas, liver, prostate, breast, ovary, cervix and endometrium.

The present invention relates to bis-hydrochloride, bis-hydrochloride hydrate, bismaleic, succinic acid salts and stable crystalline forms of these acids or a stable crystalline form of the free base 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy )-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine for combination therapy together with immunotherapeutic agents selected from PD-1 or PD-L1, SLAM7, agents for oncolytic virus therapy, bispecific T-cell recruiting activators (BiTE) and agents chimeric antigen receptor (CAR) T cells such as nivolumab, pembrolizumab, ipilimumab, blinatumomab, elotuzumab, daratumumab, talimogen laherparepvec for the treatment of solid tumors selected from lung, kidney, colon, stomach, melanoma, head cancer/ neck, thyroid, pancreas, liver, prostate, bladder, brain, breast, ovary, cervix, endometrium and sarcoma; and blood cancers selected from ALL, CLL, AML, CML, and multiple myeloma.

The present invention relates to a new method for the synthesis of 1-((4-(4-fluoro-2-methyl-1H-indol-5yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818) by condensation of intermediate (X1) c (Y1) in solvent in the presence of KI or NaI or intermediate (X2) c (Y2) in solvent to form intermediate (Z), which is deprotected to give final compound (AL3818) according to method A.

Method A

R is selected from H and C ₁ -C ₆ alkoxy.

The final compound (AL3818) was obtained according to method A1, where R represents

- 5 040599 a H, by deprotecting intermediate (Z-1) with HCOONH4 (ammonium formate) and Pd/C in an alcoholic solvent such as MeOH at 25-80°C for 0.1-4 h .

Compound (Z-1) was prepared by reacting intermediate (X1) with (Y1-1) in the presence of KI or NaI with K2CO; in a solvent, such as acetone or dimethyl fumarate, at a temperature of 60-160 ° C for 2-24 hours.

Method A1 (R=H)

The final compound (AL3818) was prepared according to method A2, where R is 4-OMe, by deprotecting intermediate (Z-2) with trifluoroacetic acid in dichloromethane at 0-30°C for 1-24 hours. (Z-2) obtained by reacting intermediate (X1) with (Y1-2) in the presence of KI or NaI with K ₂ CO ₃ in a solvent such as acetone or dimethyl fumarate at a temperature of 60-160°C for 2-24 h .

Method A2 (R=4-OMe)

The present invention relates to a novel method for the synthesis of 1-((4-(4-fluoro-2-methyl-1H-indol-5yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818) by reaction of intermediate (X2) c (Y2) in a solvent to form an intermediate (Z), which is deprotected to give the final compound (AL3818) according to method B.

Method B

R is selected from H and C ₁ -C ₆ alkoxy.

The final compound (AL3818) was prepared according to method B1 where R is H by deprotecting intermediate (Z-1) with HCOONH4 (ammonium formate) and Pd/C in an alcoholic solvent such as MeOH at 25 -80°C for 0.1-4 hours (Z-1) is obtained by reacting an intermediate (X2-1) with (Y2) in a solvent such as pyridine or lutidine at a temperature of 60-160°C for 1-12 noon

Method B1 (R=H)

The final compound (AL3818) was obtained according to method B2, where R is

- 6 040599 a 4-Ome, upon deprotection of intermediate (Z-2) with trifluoroacetic acid in dichloromethane at 0-30°C for 1-24 hours. (Z-2) was obtained by reacting intermediate (X2 -2) with (Y2) in a solvent, such as pyridine or lutidine, at a temperature

60-160°C for 1-12 hours

Method B2 (R=4-OMe)

The following examples illustrate the present invention and should not be construed as limiting the scope of the present invention.

Example 1

Description of method A,

Method A1. Process for the preparation of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3 818).

Diisopropylethylamine (39 g) was added to a stirred mixture of benzyl-1-(hydroxymethyl)cyclopropylcarbamate (50 g) and dichloromethane (200 ml). The resulting solution was cooled to 0-5°C with ice/water and further stirred at this temperature for 15 min. Methansulfonyl chloride (MsCl) (30 g) was added using an addition funnel, keeping the temperature below 5°C for 1.5 h. After adding MsCl, the resulting mixture was stirred at 0-5°C for 30 min and quenched with saturated NaHCO ₃ (150 ml). The solution was extracted by adding 150 ml of dichloromethane twice. The dichloromethane mixed layer was washed with 0.1 N HCl (400 ml) then brine. Dry with Na ₂ SO ₄ and concentrate to 60 g of off-white solid (1-(benzyloxycarbonylamino)cyclopropyl)methyl methanesulfonate (Y1-1), MS: (M+1) 300.

To a stirred mixture of (Y1-1) (16 g), X1 [(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7hydroxyquinoline, 12 g], K2CO3 (21 g ) and KI (21 g) were added dimethyl fumarate (100 ml), the reaction suspension was heated at 80°C for 10 h, (Y1-1) (10 g) was added and continued to be heated at 80°C for 10 h. the mixture was poured into water (150 ml), extracted twice with 150 ml dichloromethane The resulting dichloromethane layer was washed with 2 N NaOH (100 ml) then with water and brine, dried with Na ₂ SO ₄ and concentrated, then recrystallized from EtOH to give a yellow solid substance, which is benzyl 1-((4-(4-fluoro-2-methyl-1H-indol-5yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate (Z-1) 9.5 g. MS: (M+1) 542.

To a stirred mixture of (Z-1) (9.5 g), HCOONH4 (4.7 g) and Pd/C (10%, 50% moisture, 4.7 g) was added MeOH, the reaction mixture was heated at 45°C for 1.5 hours Cooled and filtered through celite, then evaporated. 2N HCl (200 ml) was added and extracted twice with dichloromethane/MeOH (10/1, 100 ml). The aqueous layer was adjusted with 3N NaOH to pH 11-12 to obtain a solid precipitate. The solid precipitate was filtered and washed with water until neutral and then dried in vacuo. The solid was dissolved in dichloromethane/MeOH (250 ml, 10/1), washed with water and brine. Dry over MgSO ₄ and filter, then evaporate to give 5.5 g of a pale yellow crude solid. Further purification was carried out by dissolving the crude material in dichloromethane/MeOH (40 ml, 10/1) and pulverizing in petroleum ether (40 ml) over 2 hours with slow stirring. The precipitate was filtered and dried in an oven to obtain 4.4 g of the final crystalline product (melting point: 203208°C), which can be further purified by recrystallization from EtOH to obtain a purer final substance in the same crystalline form. MS: (M+1) 408; 1H NMR (DMSO-d ₆ ) δ 0.60-0.63 (d, 4H), 2.41 (s, 1H), 2.42-2.51 (t, 2H), 3.31 (s, 2H), 3.96 (s, 3H), 4.04 (s, 2H), 6.27 (s, 1H), 6.31-6.32 (m, 1H), 6.97-7.02 (t, 1H), 7.20-7.22 (d, 1H), 7.36 (s, 1H), 7.60 (s, 1H), 8.40-8.42 (d, 1H), 11.41 (s, 1H). MP: 208-210°C; DSC melting range (endo): 207-220°C with a peak at 216°C. TGA showed unsolvated material with weight loss at about 210°C (between 205-215°C).

The XRPD diffraction pattern contains 10 characteristic peaks with an intensity of more than 10%, expressed by the following values of d and angles:

- 7 040599

Corner d value Corner d value 13.344 6.62986 20.650 4.29771 15.858 5.58405 21.633 4.10463 16.799 5.27326 23.087 3.84934 17.640 5.02377 25.128 3.54112 18,770 4.72373 26.607 3.34755

The XRPD diffraction pattern contains 26 characteristic peaks with a total intensity in % expressed by the following values of d and angles:

No. Corner d value Intensity (%) No. Corner d value Intensity (%) 1 10.892 8.11623 2.1 14 25.128 3.54112 14.6 2 11.589 7.62991 6.1 15 25.669 3.46768 3.8 3 12.195 7.25174 5.9 16 26.607 3.34755 18.0 4 13.344 6.62986 36.2 17 26.607 3.34755 3.1 5 15.858 5.58405 31.5 18 29.050 3.07132 5.7 6 16.799 5.27326 77.9 19 29.797 2.99602 1.5 7 17.640 5.02377 18.8 20 30.681 2.91167 4.3 8 18,770 4.72373 I,9 21 31.853 2.80718 1.2 9 19.987 4.43884 7.2 22 33.524 2.67095 2.8 10 20.650 4.29771 42.0 23 34.789 2.57667 2.6 eleven 21.633 4.10463 15.3 24 35.873 2.50131 2.2 12 23.087 3.84934 100.0 25 37.391 2.40313 3.9 13 24.356 3.65157 3.5 26 38.637 2.32846 1.4

DSC, TGA and XRPD curves are shown in Fig. 1, fig. 2 and FIG. 3 respectively.

Example 2

Description of Method A.

Method A2. Process for the preparation of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7yloxy)methyl)cyclopropanamine (AL3818).

The specified compound was obtained similarly to the production process (Z-1) described in example 1, using 4-methoxybenzyl 1-(hydroxymethyl)cyclopropylcarbamate first to obtain (1((4-methoxybenzyloxy)carbonylamino)cyclopropyl)methyl methanesulfonate (Y1-2) , then to obtain 4-methoxybenzyl 1 -((4-(4-fluoro-2-methyl-1 H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate (Z-2), MS : (M+1) 572.

To a stirred mixture of (Z-2) (1.5 g) in dichloromethane (15 ml) at 0°C was added trifluoroacetic acid (1.5 ml) over 30 min and warmed to room temperature. The resulting reaction mixture was stirred at room temperature for 2 h and added to water (30 ml). Extract the aqueous layer with dichloromethane twice (100 ml x 2) then adjust with 2N NaOH to pH 11-12. The mixture was extracted with dichloromethane (100 ml x 3), then washed with brine (100 ml). Dried over MgSO ₄ and filtered. The solution was evaporated to obtain 1.05 g of the crude final substance. It was then purified by dissolving the crude material in dichloromethane/MeOH, pulverized in petroleum ether and oven dried to give 0.8 g of pure final material in the same crystalline form.

Example 3

Description of Method A.

Method B1.

Process for the preparation of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinoline-7-uloksi)methyl)cyclopropanamine (AL3818).

To a mixture of benzyl-1-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)cyclopropyl-carbamate (X2-1) (5 g), 4-fluoro-2-methyl-1H-indol-5-ol (Y2) (5 g) and dimethylaminopyridine (4 g) were added 1,6-lutidine (15 ml). Shake the resulting reaction mixture and heat at 135°C for 5 h, cool, then add isopropyl alcohol, slowly stir for 2 h at room temperature. The solid precipitate was filtered, washed with isopropyl alcohol, dried to obtain 5.2 g of solid (Z-1). Then, by analogy with the deprotection procedures described in Example 1 for (Z-1), the final compound AL3818 was obtained in the same crystalline form.

Example 4

Description of Method A.

Process B2. Process for preparing 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine (AL3818).

(Z-2) was prepared in analogy to the procedures described in Example 3 using 4-methoxybenzyl 1-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate (X2-2) and (Y2). Then, by analogy with the deprotection procedures with (Z-2) described in example 2, received the final compound AL3818 in the same crystalline form.

Example 5

Preparation of bis-hydrochloride acid salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine and its crystalline form.

To a 25 ml flask was added 250 mg of free base (AL3818), 4N HCl in dioxane 0.625 ml (2.5 mmol, 4 eq.) in 10 ml of EtOH, the reaction mixture was heated at 75°C for 30 min, cooled to room temperature and stirred overnight. The solid precipitate was filtered and washed twice in acetone. Dry in an oven at 50°C for 4 hours to give 126 mg of a white solid, which is the bis-hydrochloride salt in crystalline form, which was then recrystallized from EtOH to give a purer substance in the same crystalline form. 1H NMR(DMSO-d ₆ ) δ 1.09-1.24 (m, 4H), 2.43 (s, 3H), 4.08 (s, 3H), 4.40 (s, 2H), 6 .32 (s, 1H), 6.76 (s, 1H), 7.05-7.11 (t, 1H), 7.27-7.30 (d, 1H), 7.65 (s, 1H ), 7.82 (s, 1H), 8.64 (s, 2H), 8.70-8.73 (m, 1H), 11.51 (s, 1H).

Chloride ion chromatography showed 2 molecular ratios of ions (16.1%). Melting point range according to DSC (exo): 249-280°C with a peak at 268°C. The TGA curve showed unsolvated material with weight loss at about 230°C (between 225-235°C).

The XRPD diffraction pattern contains 21 characteristic peaks with an intensity greater than 10% or 27 peaks with an intensity in % expressed by the following values of d and angles:

- 9 040599

No. Corner d value Intensity, % No. Corner d value Intensity, % 1 7,640 11.56173 19.5 14 22.81 4 3.89483 AND 2 2 8.642 10.22328 20 15 23.39 8 3.79886 11.6 3 9.361 9.43969 13.3 16 24.45 5 3.63702 76.6 4 10.091 8.75881 100.0 17 25.52 4 3.48708 34.6 5 13,740 6.43957 26.4 18 26.70 3 3.33576 21.7 6 14.479 6.11252 54.7 19 27.33 7 3.25978 18.4 7 15.186 5.82962 10.1 20 28.06 1 3.17732 18.5 8 15.766 5.61643 20.3 21 28.80 1 3.09732 6.3 9 17.206 5.14957 7.4 22 29.84 5 2.99133 13.8 1 0 18.569 4.77448 18.6 23 31.33 1 2.85271 7.1 1 1 19.271 4.60215 11.0 24 31.62 1 2.82721 9.5 1 2 20.041 4.42696 49.5 25 32.84 0 2.72504 10.5 1 3 22.211 3.99909 58.4 26 33.71 4 2.65632 3.8 27 38.34 8 2.34534 9.6

DSC, TGA and XRPD curves are shown in Fig. 4, fig. 5 and FIG. 6, respectively.

Example 6

Obtaining bis-hydrochloride salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine and its crystalline form.

140 mg of the 3818-2HCl salt prepared according to Example 4 above and 0.7 ml (x5 with salt volume) of 80% MeOH in H ₂ O were placed in a 10 ml flask. The resulting suspension was heated to 70°C until a solution formed, cooled to room temperature and stirred overnight. The solid precipitate was filtered and washed with acetone twice. Dry in an oven at 50° C. for 4 hours to obtain 110 mg of an off-white solid in crystalline form, which is the bis-hydrochloride hydrate salt. ¹ H NMR (DMSO-d ₆ ) δ 1.09 (s, 2H), 1.22 (s, 2H), 2.44 (s, 1H), 2.52 (s, 2H), 4.09 ( s, 3H), 4.44 (s, 2H), 6.32 (s, 1H), 6.81-6.82 (d, 1H), 7.08-7.14 (t, 1H), 7 .29-7.32(d, 1H), 7.79(s, 1H), 7.85(s, 1H), 8.75-8.78(d, 1H), 8.85(s, 2H ), 11.66 (s. 1H). Chloride ion chromatography showed 2 molecular ratios of ions (17.8%). Melting point range according to DSC (exo): 207-260°C with a peak at 226°C. TGA showed a weight loss of 2.68% (-3%, 1 water) up to 120°C (between 115-125°C) and further weight loss at about 170°C (between 165-175°C). The diffraction pattern obtained by XRPD contains 9 characteristic peaks with an intensity of more than 10%, or 12 peaks with an intensity in %, expressed by the following values of d and angles:

- 10 040599

No. Corner d value Intensity, % 1 5.506 16.03679 28.0 2 6.817 12.95694 100 3 8.087 10.92445 29.9 4 9.766 9.04936 20.6 5 13.318 6.64283 22.3 6 14.332 6.17523 7.0 7 16.159 5.48067 15.7 8 19.474 4.55451 8.8 9 20.920 4.24296 6.5 10 20.920 3.87321 28.2 eleven 25.087 3.54678 20.2 12 25.874 3.44064 22.7

DSC, TGA and XRPD curves are shown in Fig. 7, fig. 8 and FIG. 9, respectively.

Example 7

Obtaining a salt of bis-maleic salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine and its crystalline form.

In a 25 ml flask was added 50 mg of free base (AL3818) in 1.5 ml of EHN, the reaction mixture was heated to 70°C with stirring. To the resulting solution was added 36 mg (2.5 eq.) of maleic acid and stirred at 70°C for 0.5 h. Cooled to room temperature and stirred overnight. The solid was filtered and washed twice with acetone, then dried in an oven at 50°C for 4 h to obtain 68 mg of a crystalline solid, which was then recrystallized from EHN to obtain a more pure substance of the same crystalline form, which is two (bis)maleic salt. Ή NMR (DMSO-d ₆ ) δ 0.73 (s, 2H), 0.88 (s, 2H), 3.43 (s, 2H), 3.53 (s, 2H), 3.59 (s , 2H), 3.86 (s, 4H), 3.97 (s, 3H), 4.41 (s, 1H), 6.07 (s, 2H), 7.26 (s, 1H), 7 .44-7.50 (t, 1H), 7.76-7.79 (d, 1H), 7.88 (s, 1H), 8.10-8.12 (d, 1H), 8.55 (s, 1H), 9.54 (s. 1H).

Ion chromatography showed 2 molecular ratios of ions (37.1%). Melting point range according to DSC (endo): 165-202°C with a peak at 183°C. The TGA curve showed unsolvated material with weight loss at about 160°C (between 155-165°C). The diffraction pattern obtained by XRPD contains 22 characteristic peaks with an intensity greater than 10%, or 35 peaks with an intensity in %, expressed by the following values of d and angles. ___________

No. Corner d value Intensity, % No. Corner d value Intensity, % 1 6.716 13.14986 29.7 19 22.876 3.88434 5.8 2 8.816 10.02189 34.3 20 23.204 3.83021 19.0 3 9.743 9.07069 15.3 21 23.622 3.76332 78.4 4 10.033 8.80923 21.4 22 24.418 3.64247 6.3 5 11.777 7.50803 21.2 23 26.140 3.40621 87.0 6 13.418 6.59342 6.2 24 26.958 3.30469 26.5 7 14.816 5.97445 11.0 25 27.383 3.25443 61.3 8 16.089 5.50434 9.5 26 28.154 3.16697 41.5 9 16.801 5.27279 24.5 27 29.554 3.02013 6.8 10 17.360 5.10409 87.9 28 30.611 2.91815 23.7 AND 17.179 5.15755 70.7 29 31.373 2.84906 14.3 12 18.190 4.87308 20.2 thirty 33.457 2.67620 6.7 13 18.704 4.74028 16.7 31 34.541 2.59465 2.8 14 19.296 4.59623 5.0 32 35.137 2.55199 3.8 15 19.920 4.45371 12.6 33 35.734 2.51067 2.5 16 20.824 4.26227 65.5 34 37.129 2.41949 8.6 17 21.457 4.13785 100.0 35 39.704 2.26833 3.9 18 22.411 3.96393 4.5

-11040599

The DSC, TGA and XRPD curves are shown in Fig. 10, fig. 11 and FIG. 12, respectively.

Example 8

Obtaining succinic salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7yloxy)methyl)cyclopropanamine and its crystalline form.

In a 50 ml flask was added 100 mg of free base (AL3818) in 4 ml of EtOH, the reaction mixture was heated to 75°C with stirring. To the resulting solution was added succinic acid as a solid in an amount of 36 mg (0.308 mmol, 1.25 eq.) and stirred at 75° C. for 0.5 h. Cooled to room temperature and stirred overnight. The solid was filtered and washed twice with acetone, then dried in an oven at 50°C for 4 h to obtain 84 mg of a crystalline solid, which was then recrystallized from EtOH to obtain a purer substance of the same crystalline form. 1H NMR(DMSO-d ₆ ) δ 0.72 (s, 4H), 2.37-2.42 (m, 7H), 3.99 (s, 3H), 4.10 (s, 2H), 6 .27 (s, 1H), 6.32-6.33 (d, 1H), 6.97-7.02 (t, 1H), 7.20-7.23 (d, 1H), 7.39 (s, 1H), 7.61 (s, 1H), 8.42 (s, 2H), 11.41 (s, 1H). Ion chromatography showed 1 molecular ratio of ions (23.2%). Melting point range according to DSC (endo): 176-202°C with a peak at 198°C. TGA showed unsolvated material with weight loss at about 180°C (between 175-185°C). The diffraction pattern obtained by XRPD contains 11 characteristic peaks with an intensity greater than 10% or 19 characteristic peaks with an intensity in % expressed in the following values of d and angles:

No. Corner d value Intensity, % No. Corner d value Intensity, O/ /O 1 5.765 15.31849 12.9 eleven 23.167 3.83630 1.8 2 8.038 10.98994 7.4 12 24.085 3.69200 16.9 3 11.639 7.59700 27.7 13 24.485 3.63268 14.6 4 12,950 6 6.83065 100 14 25.737 3.45874 13.7 5 16.141 5 5.48683 18.0 15 28.621 3.11637 6.4 6 17.483 5 5.06848 18.7 16 29.255 3.05025 22.1 7 18.385 4.82175 17.8 17 31.357 2.85048 0.9 8 19.394 4.57325 1.1 18 31.967 2.79743 2.1 9 20.756 4.27609 13.4 19 35.630 2.51780 2.4 10 22.034 4.03092 2.8

DSC, TGA and XRPD curves are shown in Fig. 13, fig. 14 and FIG. 15, respectively.

Example 9

An in vitro MTT (proliferation) test was performed on the compounds from the above examples, which showed the following inhibition results:

- 12 040599

Sample name AL3818-H1 (2HC1) AL3818-H2 (2NS1.NS1) AL3818-S (amber) AL3818-M (bis maleic) AL3818-F (loose base) Cancer cell lines IC50 (µM) IC50 (µM) IC50 (µM) IC50 (µM) IC50 (µM) PANC-1 (pancreas) 1.58 1.55 1.24 1.15 1.34 NC1-H157 (light) 7.18 2.29 2.28 2.02 1.83 MDA-MB-231 (breast) 10.25 5.71 6.1 5.37 5.56 Hela (cervix) 3.7 4.07 4.66 3.94 3.23 PC-3 (prostate) 5.53 3.88 4.41 3.62 5,I BEL7404 (liver) 2.75 1.74 1.43 1.15 0.93 MKN45 (stomach) 1.77 3.9 4.16 2.65 h,i Ishikawa (endometrium) 5.67 1.56 1.32 1.34 1.04 Saos-2 (sarcoma) 4.68 4.98 5.68 5.49 5.13 SKOV3 (ovaries) 5.34 5.7 7.6 6.56 5.97 SW579 (thyroid gland) 2.33 1.29 2.61 1.15 1 NST116 (colon) 3.45 3.34 3.94 4.62 3.25

Example 10

Based on the studies carried out by the inventors using AL3818 free base, its 2HCl salts, its bis-maleic acid salt and succinic acid salt, the following tumor inhibition results are expected in the MTT assay according to Example 9.

Expected 2-10 µM ± 1.7 µM activity against solid tumor inhibition of various cell lines such as colorectal, head/neck, bladder, brain, melanoma as well as blood cancers such as ALL, CLL, AML , CML and multiple myeloma.

Example 11

An in vivo animal test for antitumor activity on the Ishikawa endometrial cell line (xenograft) was performed as follows.

Rapidly growing Ishikawa endometrial cancer tumor tissue was cut into 3 mm pieces. In each nude mouse, one such piece of tissue was inoculated subcutaneously in the right armpit. Animals were divided into groups and observed as follows:

1) AL3818-H1 (bis hydrochloride salt, 2HCl), MW: 480, 3.54 mg/kg

2) AL3818-H2 (bis hydrochloride hydrate salt, 2HCl.H2O), MW: 598, 3.67 mg/kg

3) AL3818-S (succinic salt), MW: 525, 3.87 mg/kg

4) AL3818-M (bis-maleic salt), MW: 639, 4.71 mg/kg

5) AL3818-F (free base), MW: 407.3mg/kg

6) Control group

Treatment was initiated when the size of the tumors exceeded 100 mm ³ after 13 days. Depending on tumor size, animals with too large or too small tumors were excluded.

- 13 040599 from the test, and animals with approximately the same size of tumors remained in the test. The animals were then orally administered 0.5 ml/20 g of the substance according to the above groups for 14 days. Large diameter a (mm) and small diameter b (mm) were measured with calipers twice a week for 13 days after inoculation. Tumor volume was calculated using the formula: TV = ab ² /2. Relative tumor volume was calculated as: RTV = Vt/Vo where Vo is the tumor volume on the first day of treatment; Vt is the volume of the tumor on each of the days of measurement. Animals were sacrificed and tumors were removed using dissection 30 days after inoculation (D18). Then, individual body weight and tumor weight were measured and calculated by the following formula. Tumor inhibiting actions were observed in 50-95% of cases. The results are shown in FIG. 16.

Example 12

Based on the studies carried out by the inventors using AL3818 free base, its HCl salts (mono or bis), its bis-maleic salt and succinic salt, the following in vivo tumor inhibition results (xenograft) are expected according to example 11.

Expected in vivo 50%-100% inhibitory activity in solid tumors of various cell lines such as lung, rectal, colon, stomach, head/neck, melanoma, thyroid, pancreas, liver, prostate, bladder, brain, breast, ovary, cervix, endometrium, sarcoma and blood cancer - ALL, CLL, AML, CML and multiple myeloma.

Example 13

The bis-HCl salt and bis-maleic salt of AL3818 have also been tested in combination with chemotherapy using platinum-based drugs, taxane-based drugs, or both; such as cisplatin, carboplatin, paclitaxel or in combination cisplatin/paclitaxel, carboplatin/paclitaxel. An experiment on the carboplatin/paclitaxel combination was carried out by analogy with the description of example 11. The inhibitory effect on tumors is estimated as from 50 to >100%. The results are shown in FIG. 17.

Example 14

Based on the studies carried out by the inventors using AL3818 free base, its HCl salts (mono or bis), its bis-maleic salt and succinic salt, the following results are expected in vivo tumor inhibition (xenografts) in combination with chemotherapy (standard of care, such as chemotherapy based on platinum, taxane or both) according to example 13, especially in combination with cisplatin, carboplatin, paclitaxel or simultaneously cisplatin/paclitaxel, carboplatin/paclitaxel.

Tumor regression of 50% to >100% in vivo is expected with drugs to inhibit solid tumors of various cell lines, such as cancer of the lung, rectum, colon, stomach, head/neck, skin, thyroid, pancreas, liver, prostate, bladder, brain, breast, ovary, cervix, endometrium, sarcoma and blood cancers such as ALL, CLL, AML, CML and multiple myeloma.

Example 15

Based on the studies conducted by the inventors using the free base of AL3818, its HCl salts (mono or bis), its bis-maleic salt and succinic salt, the following combined action in vivo is expected together with immunotherapeutic agents selected from PD-1 or PD- L1, SLAM7, agents for oncolytic viral therapy, bispecific activator (BiTE) T cell recruiting agents, and chimeric antigen receptor (CAR) T cell therapy, including but not limited to nivolumab, pembrolizumab, ipilimumab, blinatumomab, elotuzamab, daratumumab, talimogen laherparepvec , for the treatment of solid tumors selected from cancers of the lung, rectum, colon, stomach, head/neck, melanoma, thyroid, pancreas, liver, prostate, bladder, brain, breast, ovary, cervix, endometrium , sarcoma and blood cancer selected from ALL, CLL, AML, CML and multiple myeloma.

Tumor regression of 50% to >100% is expected in vivo with inhibitory effects on solid tumors of various cell lines such as lung, rectal, colon, stomach, head/neck, melanoma, thyroid, pancreas, liver, prostate, bladder, brain, breast, ovary, cervix, endometrium, sarcoma and blood cancers such as ALL, CLL, AML, CML and multiple myeloma.

Example 16

Mouse Model of Laser-Induced Choroidal Neovascularization (CNV) (1) Experiments were performed on C57BL/6 mice aged 10 to 12 weeks. CNV was induced with a 532 nm diode laser mounted on a slit lamp using a spot size of 50 μm, a duration of 100 ms, and a laser energy of 100 mW. 4 laser flashes were made in each eye. The stock solution of AL3818-H1 was prepared by dissolving the compound in water at a concentration of 25 mg/mL, and then diluted to obtain a working solution in water at either 250 or 25 mg/mL. Mice were administered the drug orally at a dosage of 2.5 or 0.25 mg/kg of body weight, in a volume of 200 μl per 20 g of body weight, once a day from the first day of laser use and for 10 days

-

Claims (5)

after. A control group of mice received water via gavage, which was used to dissolve the compound. At the end of the experiment, mice underwent fluorescein angiography to rule out hemorrhagic spots and other mechanical damage caused by the procedure. Mice were sacrificed and CNV size measured by immunostaining RPE/horizontal section of choroid stained with FITC-conjugated isolectin B4 and anti-ICAM2 antibody. In the control groups receiving 0.25 mg/kg and 2.5 mg/kg of the drug, 43, 44 and 49 eyes were examined in the region of RPE/horizontal section of the choroid. After immunostaining, images were taken using a Zeiss fluorescence microscope. CNV size was measured using Image J software. The results (Figure 18) show that mice treated with AL3818 at 0.25 or 2.5 mg/kg bw experienced a reduction in mean laser-induced CNV size of approximately 70 %. 1 5.765 15.31849 12.9 eleven 23.167 3.83630 1.8 1 6.716 13.14986 29.7 19 22.876 3.88434 5.8 1 5.506 16.03679 28.0 1 7,640 11.56173 19.5 14 22.814 3.89483 11.2 1. Use of 1-((4-(4-fluoro-2-methyl-1H-undole-5-yloxy)-6methoxyquinolin-7-yloxy)methyl)cyclopropanamine crystalline form or 1-((4-(4 -fluoro-2methyl-N-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine, wherein said salt is selected from bis-hydrochloride salt, bis-hydrochloride salt monohydrate, bis-maleic salt and succinic acid salt, for the treatment of ovarian, cervical and endometrial cancer in combination therapy with paclitaxel or carboplatin/paclitaxel, where: said crystalline form of 1-((4-(4-fluoro-2-methyl-1H-indole-5-noxy)-6-methoxyquinolin-7yloxy)methyl)cyclopropanamine has at least one of the following characteristics: melting point 208°C-210°C; melting temperature range according to DSC (endo): 207-220°C with a peak at 216°C, the curve is shown in Fig. 1; thermogram TGA, according to which there is no significant weight loss up to a temperature of 205-215°C, the curve is shown in Fig. 2; the XRPD powder diffraction pattern shown in FIG. 3, containing 10 characteristic peaks with an intensity greater than 10%, expressed by the following values of d and angles: - 15 040599 Corner d value Corner d value 13.344 6.62986 20.650 4.29771 15.858 5.58405 21.633 4.10463 16.799 5.27326 23.087 3.84934 17.640 5.02377 25.128 3.54112 18,770 4.72373 26.607 3.34755 said crystalline form of the bis-hydrochloride salt of 1-((4-(4-fluoro-2-methyl-N-indol-5yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine has an XRPD X-ray powder diffraction pattern represented by in fig. 6 containing 21 characteristic peaks with an intensity in % of more than 10%, or 27 peaks with an intensity in % expressed by the following values of d and angles: No. Corner d value Intensity, % No. Corner d value Intensity, % 2. Use according to claim 1, characterized in that the crystalline form is selected from the bis-hydrochloride salt crystal form, the bis-hydrochloride salt monohydrate crystal form, the bis-maleic salt crystal form and the succinic acid salt crystal form. 2 8.038 10.98994 7.4 12 24.085 3.69200 16.9 2 8.816 10.02189 34.3 20 23.204 3.83021 19.0 2 6.817 12.95694 100 2 8.642 10.22328 20 15 23.398 3.79886 11.6 (2) Possible synergistic and additive actions between AL3818-M and anti-VEGF antibodies were also investigated. Immediately after laser exposure, mice were treated with an anti-VEGF monoclonal antibody from R&D Systems (mAb AF564) at a dosage of 1 μg by intravitreal injection. There were 4 experimental groups: control (treated with water), AL3818-M, anti-VEGF and AL3818-M+anti-VEGF. A total of 75 laser spots were analyzed. Mice in the control group or mice in the AL3818-M-only group received an intravitreal injection of saline in a volume of 2 μl. The results (Fig. 19) showed that eyes treated with 0.15 mg/kg AL3818 and 1 μg anti-VEGF antibody experienced a reduction in the size of laser-induced CNV of about 30% compared with the control group (P<0.01, univariate analysis of variance, Dunnett's posterior test). Example 17 Based on studies conducted by the inventors using the free base of AL3818, its HCl salts (mono or bis), bis-maleic salt and succinic salt, according to example 16 in an in vivo animal model, efficacy in CNV associated with effective treatment is expected. optometric diseases, including, but not limited to, AMD (age-related macular degeneration); or in combination of these compounds with an anti-VEGF antibody or a VEGF trap, including but not limited to ranibizumab or aflibercep, to create a synergistic effect of treatment, the efficacy according to example 16 is also expected. Example 18 A standard water solubility test was carried out, which showed the following results: Sample Name AL3818-H1 (2HC1) AL3818-H2 (2HC1.H ₂ O) AL3818-S (Amber) AL3818-M (2Maleic) AL3818-F (Free Base) (mg/ml) (mg/ml) (mg/ml) ml) (mg/ml) (mg/ml) Solubility in water 6 7 OD 0.5 0.02 CLAIM 3. Use according to claim 2, characterized in that the crystalline form is the bis-hydrochloride salt crystalline form. 3 11.639 7.59700 27.7 13 24.485 3.63268 14.6 3 9.743 9.07069 15.3 21 23.622 3.76332 78.4 3 8.087 10.92445 29.9 3 9.361 9.43969 13.3 16 24.455 3.63702 76.6 4. Use according to claim 2, characterized in that the crystalline form is the bis-hydrochloride salt monohydrate crystalline form. 4 12,950 6 6.83065 100 14 25.737 3.45874 13.7 5 16.141 5 5.48683 18.0 15 28.621 3.11637 6.4 6 17.483 5 5.06848 18.7 16 29.255 3.05025 22.1 7 18.385 4.82175 17.8 17 31.357 2.85048 0.9 8 19.394 4.57325 1.1 18 31.967 2.79743 2.1 9 20.756 4.27609 13.4 19 35.630 2.51780 2.4 10 22.034 4.03092 2.8 4 10.033 8.80923 21.4 22 24.418 3.64247 6.3 5 11.777 7.50803 21.2 23 26.140 3.40621 87.0 6 13.418 6.59342 6.2 24 26.958 3.30469 26.5 7 14.816 5.97445 11.0 25 27.383 3.25443 61.3 8 16.089 5.50434 9.5 26 28.154 3.16697 41.5 9 16.801 5.27279 24.5 27 29.554 3.02013 6.8 10 17.360 5.10409 87.9 28 30.611 2.91815 23.7 eleven 17.179 5.15755 70.7 29 31.373 2.84906 14.3 12 18.190 4.87308 20.2 thirty 33.457 2.67620 6.7 13 18.704 4.74028 16.7 31 34.541 2.59465 2.8 14 19.296 4.59623 5.0 32 35.137 2.55199 3.8 15 19.920 4.45371 12.6 33 35.734 2.51067 2.5 16 20.824 4.26227 65.5 34 37.129 2.41949 8.6 17 21.457 4.13785 100.0 35 39.704 2.26833 3.9 18 22.411 3.96393 4,5 This crystalline form of the succinic salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine has an XRPD powder diffraction pattern shown in fig. 15 containing 11 characteristic peaks with an intensity greater than 10%, or 19 peaks with an intensity in % expressed by the following values of d and angles: No. Corner Meaning d Intensity, % No. Corner Meaning d Intensity, % 4 9.766 9.04936 20.6 5 13.318 6.64283 22.3 6 14.332 6.17523 7.0 7 16.159 5.48067 15.7 8 19.474 4.55451 8.8 9 20.920 4.24296 6.5 10 20.920 3.87321 28.2 eleven 25.087 3.54678 20.2 12 25.874 3.44064 22.7 said crystalline form of bis-maleic salt of 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine has an XRPD X-ray powder diffraction pattern, shown in FIG. 12 containing 22 characteristic peaks with an intensity greater than 10% or 35 peaks with an intensity in % expressed by the following values of d and angles: - 16 040599 No. Corner d value Intensity, % No. Corner d value Intensity, % 4 10.091 8.75881 100.0 17 25.524 3.48708 34.6 5 13,740 6.43957 26.4 18 26.703 3.33576 21.7 6 14.479 6.11252 54.7 19 27.337 3.25978 18.4 7 15.186 5.82962 10.1 20 28.061 3.17732 18.5 8 15.766 5.61643 20.3 21 28.801 3.09732 6.3 9 17.206 5.14957 7.4 22 29.845 2.99133 13.8 10 18.569 4.77448 18.6 23 31.331 2.85271 7.1 eleven 19.271 4.60215 11.0 24 31.621 2.82721 9.5 12 20.041 4.42696 49.5 25 32.840 2.72504 10.5 13 22.211 3.99909 58.4 26 33.714 2.65632 3.8 27 38.348 2.34534 9,6 said 1-((4-(4-fluoro-2-methyl1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanamine bis hydrochloride salt monohydrate crystal form has an XRPD X-ray powder diffraction pattern, shown in FIG. 9, containing 9 characteristic peaks with an intensity in % of more than 10%, or 12 peaks with an intensity in %, expressed by the following values of d and angles: ______________________________________________________________ No. Corner d value Intensity, % 5. Use according to claim 2, characterized in that the crystalline form is the bis-maleic salt crystalline form. -