Use of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine for treating diffuse large B-cell lymphoma

Abstract

The present invention relates to the use of 5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine (compound A), more particularly (+)5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine (compound A′), for treating diffuse large B-cell lymphoma (DLBCL), especially in germinal-centre B-cell type of diffuse large B-cell lymphoma and especially in diffuse large B-cell lymphoma which cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or an overexpression of MYC and/or BCL2.

Claims

1. A method of treatment and/or prophylaxis of diffuse large B-cell lymphoma, comprising administering an effective amount of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of formula I or a physiologically acceptable salt or enantiomer thereof to a patient in need thereof ##STR00009## wherein the diffuse large B-cell lymphoma is a diffuse large B-cell lymphoma which cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or an overexpression of the BCL2 protein.

2. The method according to claim 1, wherein the enantiomer (+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin- 2-yl}pyridin-2-amine or a physiologically acceptable salt thereof is used.

3. The method according to claim 1, wherein the diffuse large B-cell lymphoma is a germinal-centre B-cell type of diffuse large B-cell lymphoma.

4. A method of treatment and/or prophylaxis of diffuse large B-cell lymphoma, comprising administering a pharmaceutical combination comprising an effective amount of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of formula I or a physiologically acceptable salt or enantiomer thereof ##STR00010## and at least one or more further active ingredients to a patient in need thereof; wherein the diffuse large B-cell lymphoma is a diffuse large B-cell lymphoma which cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or an overexpression of the BCL2 protein.

5. The method according to claim 4, wherein the enantiomer (+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine or a physiologically acceptable salt thereof is used.

6. The method according to claim 4, wherein the diffuse large B-cell lymphoma is a germinal-centre B-cell type of diffuse large B-cell lymphoma.

7. A method of treatment and/or prophylaxis of diffuse large B-cell lymphoma, comprising administering a pharmaceutical composition comprising an effective amount of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine of formula I or a physiologically acceptable salt or enantiomer thereof ##STR00011## and at least one inert, nontoxic, pharmaceutically suitable adjuvant to a patient in need thereof; wherein the diffuse large B-cell lymphoma is a diffuse large B-cell lymphoma which cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or an overexpression of the BCL2 protein.

8. The method according to claim 7, wherein the enantiomer (+)-5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine or a physiologically acceptable salt thereof is used.

9. The method according to claim 7, wherein the diffuse large B-cell lymphoma is a germinal-centre B-cell type of diffuse large B-cell lymphoma.

Description

EXAMPLES 1. Preparation of Compound A′

(1) Compound A′ was prepared according to the procedure described in example 2 of WO2014/076091.

(2) 2. In-vitro Experiments

(3) 2.1. Methods

(4) 2.1.1 Cell Lines

(5) TABLE-US-00001 TABLE 1 List of the DLBLC cell lines investigated. Translocation (TL) or Tumour indication Subtype Example cell line amplification (ampl) status DLBCL ABC.sup.a HBL1 MYC TL DLBCL ABC OCI-LY-3 MYC ampl/BCL2 ampl DLBCL ABC TMD8 MYC TL DLBCL GCB.sup.b DB BCL2 TL DLBCL GCB SU-DHL-6  MYC TL DLBCL GCB HT — DLBCL GCB OCI-LY-19 MYC TL DLBCL GCB SU-DHL-8  MYC TL/BCL2 TL DLBCL GCB SU-DHL-10 MYC TL/BCL2 TL DLBCL GCB SU-DHL-4  MYC ampl/BCL2 TL DLBCL GCB SU-DHL-5  — .sup.aactivated B-cell type, .sup.bgerminal-centre B-cell type

(6) 2.1.2 Cell Proliferation Assay

(7) The proliferation of all (DLCBL) cell lines in the presence of different concentrations of Compound A′ or FR compound for 72 h was assessed using CellTiter Glo kits (Promega Corporation, Madison, Wis.). All expressed values were averages of triplicate experiments, and IC.sub.50 was calculated using GraphPad Prism 5 (GraphPad Software, San Diego, Calif.) according to the manufacturer's instructions or the MTS software.

(8) The FR compound is example 4 of WO2012/160034 and has a structure according to formula II:

(9) ##STR00008##

(10) 2.2 In-Vitro Results

(11) Table 2 summarizes the results in the proliferation assays with compound A′ or FR compound.

(12) TABLE-US-00002 TABLE 2 List of the cell lines investigated and results of the proliferation assay performed with compound A′ or the FR compound. Tumour Example Compound A′ FR compound indication Subtype Cell line IC.sub.50 [nmol/l] IC.sub.50 [nmol/l] DLBCL ABC HBL1 196 540 DLBCL ABC OCI-LY-3 83 340 DLBCL ABC TMD8 100 n/a DLBCL GCB DB 88 570 DLBCL GCB SU-DHL-6  37 360 DLBCL GCB HT 81 710 DLBCL GCB OCI-LY-19 39 480 DLBCL GCB SU-DHL-8  93 610 DLBCL GCB SU-DHL-10 129 600 DLBCL GCB SU-DHL-4  90 170 DLBCL GCB SU-DHL-5  105 n/a

(13) These in vitro data indicate an efficient inhibition of the proliferation of both ABC (Activated B-cell type) and GCB (Germinal-centre B-cell type) subtypes of diffuse large B-cell lymphoma (DLBCL) by Compound A′. These data recommend Compound A′ for the treatment of patients with DLBCL.

(14) 3. In-Vivo Experiment using OCL-LY-3 Diffuse Large B-Cell Lymphoma (DLBCL) Xenograft Model in Mice

(15) The aim of the present experiments was to assess the in vivo efficacy and tolerability of Compound A′ in monotherapy in the DLBCL OCI-LY-3 tumour model subcutaneously implanted in SCID mice. In vivo efficacy was determined in female SCID mice bearing subcutaneous DLBCL OCI-LY-3 xenografts. Compound A′ was assessed at one dose level in monotherapy. Anti-tumour activity and tolerability of the treated group was assessed using the vehicle control group as a reference.

(16) For this purpose, OCI-LY-3 cells were subcutaneously injected (4×106 cells in 0.1 ml 100% Matrigel) in the right flank of female SCID mice (Charles River) Animals and tumour implants were monitored daily until the maximum number of implants showed clear signs of beginning solid tumour growth. At randomisation, the area of growing tumours was initially determined Animals bearing one tumour of an area of 25-35 mm2 were distributed in experimental groups according to the study protocol. The day of randomisation is designated as day 0 of an experiment Animals either received Compound A′ (formulated in 30% PEG400/10% Ethanol/60%water), at a dose of 10 mg/kg q7d intravenously or vehicle control (qd po) for a period of 14 days.

(17) Fatal toxicities did not occur and the maximum body weight loss was −6% in Compound A′ group compared to −4% in the vehicle group indicating good tolerability of Compound A′ at a dose of 10 mg/kg q7d iv.

(18) At the end of the experiment Treatment to Control ratios (T/C) were calculated based on the mean tumor area and the mean tumor weight in the Compound A′ treatment group and in the vehicle control group. The mean tumor weights and mean tumor areas were statistically significantly different, respectively. Compound A′ reached a T/C by area of 0.29 and a T/C by weight of 0.24 demonstrating moderate in vivo activity of Compound A′ in this model.

(19) 4. In-Vivo Experiment using SU-DHL-10 Diffuse Large B-Cell Lymphoma (DLBCL) Xenograft Model in Mice

(20) The aim of the present experiments was to assess the in vivo efficacy and tolerability of Compound A′ in monotherapy in the DLBCL SU-DHL-10 tumour model subcutaneously implanted in SCID mice. In vivo efficacy was determined in female SCID mice bearing subcutaneous DLBCL SU-DHL-10 xenografts. Compound A′ was assessed at one dose level in monotherapy. Anti-tumour activity and tolerability of the treated group was assessed using the vehicle control group as a reference. For this purpose, SU-DHL-10 cells were subcutaneously injected (10×106 cells in 0.2 ml 50% Matrigel) in the right flank of female SCID mice (Taconic M&B A/S, Denmark) Animals and tumour implants were monitored daily until the maximum number of implants showed clear signs of beginning solid tumour growth. At randomisation, the area of growing tumours was initially determined Animals bearing one tumour of an area of 25-35 mm2 were distributed in experimental groups according to the study protocol. The day of randomisation is designated as day 0 of an experiment Animals either received Compound A′ (formulated in 30% PEG400/10% Ethanol/60%water), at a dose of 15 mg/kg q7d intravenously or vehicle control (q7d iv) for a period of 16 days.

(21) The maximum body weight loss was −9% in Compound A′ group compared to −4% in the vehicle group indicating moderate tolerability of Compound A′ at a dose of 15 mg/kg q7d iv. At the end of the experiment the Treatment to Control ratios (T/C) was calculated based on the mean tumor area in the Compound A′ treatment group and in the vehicle control group. The mean tumor areas were statistically significantly different. Compound A′ reached a T/C by area of 0.02 demonstrating very high in vivo activity of Compound A′ in this model corresponding to complete remissions.

4.5. SUMMARY AND CONCLUSION

(22) These data indicate a significant and meaningful anti-tumour activity of Compound A′ in patients with diffuse large B-cell lymphoma (DLBCL).