Treatment method by combined use of MDM2 inhibitor and BTK inhibitor

Patent metadata

Field	Value
Publication number	US-10485794-B2
Application number	US-201615566336-A
Country	US
Kind code	B2
Filing date	Apr 12, 2016
Priority date	Apr 13, 2015
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

Abstract

It is intended to provide a medicament and a method for treating cancer comprising a compound having MDM2 inhibiting activity and a compound having BTK inhibiting activity in combination. The present invention provides a medicament comprising (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a pharmaceutically acceptable salt thereof and ibrutinib or a pharmaceutically acceptable salt thereof in combination, and a treatment method using these compounds or salts in combination.

First claim

The invention claimed is:

1. A medicament for cancer treatment comprising (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a pharmaceutically acceptable salt thereof and ibrutinib or a pharmaceutically acceptable salt thereof.

2. The medicament of claim 1 , wherein the (3′R,4'S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or the pharmaceutically acceptable salt thereof and ibrutinib or the pharmaceutically acceptable salt thereof are separately contained in different formulations.

3. The medicament of claim 1 , wherein the (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or the pharmaceutically acceptable salt thereof and ibrutinib or the pharmaceutically acceptable salt thereof are contained in a single formulation.

4. A kit comprising the medicament of claim 1 .

5. A method of treating a hematological malignancy comprising administering (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a pharmaceutically acceptable salt thereof and ibrutinib or a pharmaceutically acceptable salt thereof in combination.

6. The medicament of claim 1 , wherein the salt of (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide is p-toluenesulfonate.

7. The method of claim 5 , wherein the salt of (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide is p-toluenesulfonate.

8. The method of claim 5 , wherein the hematological malignancy is chronic lymphatic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma (MM), marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt high-grade B cell lymphoma, extranodal marginal zone B cell lymphoma, acute or chronic myelogenous (myelocytic) leukemia, myelodysplastic syndrome or acute lymphoblastic leukemia.

9. The method of claim 5 , wherein the hematological malignancy is a hematological malignancy confirmed to be MDM2 inhibitor-sensitive using a gene signature.

10. The method of claim 5 , wherein the (3′R,4'S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or the pharmaceutically acceptable salt thereof and the ibrutinib or the pharmaceutically acceptable salt thereof are administered in combination.

11. The method of claim 5 , wherein the (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or the pharmaceutically acceptable salt thereof and the ibrutinib or the pharmaceutically acceptable salt thereof are administered at the same time or different times.

12. A method of treating cancer comprising administering (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or a pharmaceutically acceptable salt thereof and ibrutinib or a pharmaceutically acceptable salt thereof in combination, wherein the cancer is characterized by BTK activation.

13. The method of claim 12 , wherein the cancer is a B cell tumor, mantle cell lymphoma (MCL), chronic lymphatic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), or multiple myeloma (MM).

14. The method of claim 12 , wherein the cancer is cancer confirmed to be MDM2 inhibitor-sensitive using a gene signature.

15. The method of claim 12 , wherein the salt of (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide is p-toluenesulfonate.

16. The method of claim 12 , wherein the (3′R,4′S,5′R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or the pharmaceutically acceptable salt thereof and the ibrutinib or the pharmaceutically acceptable salt thereof are administered in combination.

17. The method of claim 12 , wherein the (3′R,4′S,5R)—N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxamide or the pharmaceutically acceptable salt thereof and the ibrutinib or the pharmaceutically acceptable salt thereof are administered at the same time or different times.

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Seki Takahiko

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• Y02A50/385

  Cross-Sectional Technologies · mapped topic