阅读说明：本技术 5-氟-4-(4-氟-2-甲氧基苯基)-n-{4-[(s-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺用于治疗弥漫性大b细胞淋巴瘤中的用途 (Use of 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulfonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine for the treatment of diffuse large B-cell lymphoma ) 是由 A·肖尔茨 于 2019-02-12 设计创作，主要内容包括：本发明涉及5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A),更特别是(+)5-氟-4-(4-氟-2-甲氧基苯基)-N-{4-[(S-甲基磺亚胺酰基)甲基]吡啶-2-基}吡啶-2-胺(化合物A’),用于治疗弥漫性大B细胞淋巴瘤(DLBCL),尤其是生发中心B细胞型弥漫性大B细胞淋巴瘤,并且尤其是其细胞具有MYC基因和/或BCL2基因的扩增或易位和/或MYC和/或BCL2的过表达的弥散性大B细胞淋巴瘤的用途。(The present invention relates to 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 the treatment of diffuse large B-cell lymphoma (DLBCL), especially of germinal center B-cell type, and in particular the use of diffuse large B-cell lymphomas whose cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or overexpression of MYC and/or BCL 2.)

1. 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulfonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine of the formula (I) or one of its physiologically acceptable salts or enantiomers,

use in the manufacture of a medicament for the treatment of cancer in a subject, wherein the medicament is prepared for the treatment of diffuse large B-cell lymphoma, in particular diffuse large B-cell lymphoma of the germinal center B-cell type.

2. Use of a compound of formula (I) according to claim 1, wherein the medicament prepared is for the treatment of diffuse large B-cell lymphoma the cells of which have an amplification or translocation of the MYC gene and/or BCL2 gene and/or overexpression of MYC and/or BCL 2.

3. Use of a compound of formula (I) according to claim 1 or 2, wherein the enantiomer (+) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulphonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine or one of its physiologically acceptable salts is used.

4. The compound 5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulfonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine (Compound A, formula (I)),

the compounds are useful for the treatment of diffuse large B-cell lymphoma, especially diffuse large B-cell lymphoma of the germinal center B-cell type.

5. The compound according to claim 4, for use in the treatment of diffuse large B-cell lymphoma whose cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or overexpression of MYC and/or BCL 2.

6. A compound according to claim 4 or 5, wherein the enantiomer (+) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulphonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine or one of its physiologically acceptable salts is used.

7. 4- (4-fluoro-2-methoxyphenyl) -N- {3- [ (S-methylsulfonimidoyl) methyl ] phenyl } -1,3, 5-triazin-2-amine of the formula I or one of its physiologically acceptable salts or enantiomers

For the treatment and/or prevention of diffuse large B-cell lymphoma, in particular of germinal center B-cell type.

8. Use of a compound of formula (I) according to claim 7 for the treatment and/or prevention of diffuse large B-cell lymphoma whose cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or overexpression of MYC and/or BCL 2.

9. Use of a compound of formula (I) according to claim 7 or 8, wherein the enantiomer (+) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulphonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine or one of its physiologically acceptable salts is used.

10. A pharmaceutical combination comprising 4- (4-fluoro-2-methoxyphenyl) -N- {3- [ (S-methylsulphonimidoyl) methyl ] phenyl } -1,3, 5-triazin-2-amine of the formula I as defined in claim 1 or one of its physiologically acceptable salts or enantiomers

And at least one or more other active ingredients for the treatment and/or prevention of diffuse large B-cell lymphoma, in particular diffuse large B-cell lymphoma of the germinal central B-cell type.

11. A pharmaceutical composition comprising 4- (4-fluoro-2-methoxyphenyl) -N- {3- [ (S-methylsulphonimidoyl) methyl ] phenyl } -1,3, 5-triazin-2-amine of the formula I as defined in claim 1 or one of its physiologically acceptable salts or enantiomers

And at least one inert, non-toxic, pharmaceutically suitable adjuvant for the treatment and/or prevention of diffuse large B-cell lymphoma, in particular of the germinal central B-cell type.

12. The drug conjugate or the pharmaceutical composition according to claim 10 or 11, for the treatment and/or prevention of diffuse large B-cell lymphoma whose cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or overexpression of MYC and/or BCL 2.

13. Pharmaceutical combination or pharmaceutical composition according to any one of claims 12 to 25, comprising the enantiomer (+) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulphonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine or one of its physiologically acceptable salts.

14. Method for the treatment and/or prophylaxis of diffuse large B-cell lymphomas, in particular of the germinal center B-cell type, using an effective amount of 4- (4-fluoro-2-methoxyphenyl) -N- {3- [ (S-methylsulphonimidoyl) methyl ] phenyl } -1,3, 5-triazin-2-amine of formula I or one of its physiologically acceptable salts or enantiomers

15. The method of treatment and/or prevention of claim 14, wherein diffuse large B-cell lymphoma whose cells have an amplification or translocation of the MYC gene and/or BCL2 gene and/or overexpression of MYC and/or BCL2 is treated.

16. A method of treatment according to claim 14 or 15, wherein the enantiomer (+) -5-fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {4- [ (S-methylsulphonimidoyl) methyl ] pyridin-2-yl } pyridin-2-amine or one of its physiologically acceptable salts is used.

Examples

1. Preparation of Compound A

Compound a' was prepared according to the method described in example 2 of WO 2014/076091.

2. In vitro experiments

2.1. Method of producing a composite material

2.1.1 cell lines

Table 1: list of DLBLC cell lines studied.

Indications of tumors	Subtype of cell	Examples of cell lines	Translocation (TL) or amplification (ampli) situations
				DLBCL	ABCa	HBL1	MYC TL
DLBCL	ABC	OCI-LY-3	MYC ampl/BCL2 ampl
				DLBCL	ABC	TMD8	MYC TL
DLBCL	GCBb	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	-

^a(ii) an activated B-cell type,^bgerminal center B cell type

2.1.2 cell proliferation assay

Proliferation of all (DLCBL) cell lines in the presence of different concentrations of compound a' or FR compound was assessed using the CellTiter Glo kit (Promega Corporation, Madison, WI) for 72 hours. All values presented are the average of triplicate experiments and IC50 was calculated according to the manufacturer's instructions using GraphPad Prism 5(GraphPad software, San Diego, CA) or MTS software.

The FR compound is example 4 of WO2012/160034 and has the structure of formula II:

2.2 in vitro results

Table 2 summarizes the results of proliferation assays performed using compound a' or FR compounds. Table 2: list of cell lines studied and results of proliferation assays using compound a' or FR compounds.