N-(phenylsulfonyl)benzamides and related compounds as Bcl-2 inhibitors

Patent metadata

Field	Value
Publication number	US-12343352-B2
Application number	US-202017287661-A
Country	US
Kind code	B2
Filing date	Dec 3, 2020
Priority date	Dec 3, 2019
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

Described herein are methods of treating a hematologic malignancy in a patient in need thereof, comprising administering to the patient a Bcl-2 inhibitor in a step-wise dosing regimen.

First claim

What is claimed is:

1. A method of treating a hematologic malignancy in a patient in need thereof, comprising:
administering a daily step-wise dosing regimen of a compound(S)-N-((4-(((1,4-dioxan-2-yl) methyl) amino)-3-nitrophenyl) sulfonyl)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl) oxy)-4-(4-((6-(4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) benzamide or a pharmaceutically acceptable salt thereof;

wherein administering the daily step-wise dosing regimen comprises:
administering a first dose of 20 mg of the compound to the patient for one day;
administering a second dose of 50 mg of the compound to the patient for one day, on the day after the first dose, and
administering a third dose of 100 mg of the compound to the patient for one day, on the day after the second dose

wherein the patient has a reduced risk of tumor lysis syndrome during administration of the daily step-wise dosing regimen.

2. The method of claim 1 , further comprising administering to the patient a fourth dose of 200 mg of the compound daily for 1 to 5 days or more.

3. The method of claim 2 , wherein the daily step-wise regimen further comprises administering to the patient a fifth dose of 400 mg after the fourth dose is administered.

4. The method of claim 3 , further comprising administering to the patient a daily dose of 400 mg, 600 mg, 800 mg, or 1000 mg of the compound for 1 week or more, or 1 month or more, after administering the daily step-wise dosing regimen.

5. The method of claim 1 , wherein the hematologic malignancy is selected from the group consisting of chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, lymphoplasmacytic lymphoma, non-Hodgkin's lymphoma, small lymphocytic leukemia, Waldenström Macroglobulinemia, and Immunoglobulin Light Chain Amyloidosis.

6. The method of claim 1 , further comprising administering to the patient a member of the group consisting of: rituximab, azacytidine, decitabine, low-dose cytarabine, a BTK inhibitor, topetecan, an MDM2 inhibitor, a CD20 inhibitor, a CDK9i inhibitor, or Homoharringtonine (HTT) inhibitor before, during or after the daily step-wise dosing regimen.

7. A method of treating a hematologic malignancy in a patient in need thereof, comprising:
administering a daily step-wise dosing regimen of a compound(S)-N-((4-(((1,4-dioxan-2-yl) methyl) amino)-3-nitrophenyl) sulfonyl)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl) oxy)-4-(4-((6-(4-chlorophenyl) spiro [3.5] non-6-en-7-yl) methyl) piperazin-1-yl) benzamide or a pharmaceutically acceptable salt thereof;

wherein administering the daily step-wise dosing regimen comprises
administering a first dose of 20 mg to 100 mg of the compound to the patient for one day;
administering a second dose of 50 mg to 200 mg of the compound to the patient for one day, on the day after the first dose

wherein the patient, during or after administration of the daily step-wise dosing regimen, has a reduced risk of tumor lysis syndrome.

8. The method of claim 7 , wherein the daily step-wise dosing regimen further comprises administering a third dose of 100 to 400 mg of the compound to the patient for one day, on the day after the second dose.

9. The method of claim 8 , wherein the daily step-wise dosing regimen further comprises administering a fourth dose of 200 mg to 800 mg of the compound to the patient for one to seven days after the third dose.

10. The method of claim 9 , further comprising administering to the patient, after the daily step-wise dosing regimen, about 400 mg to 1000 mg of the compound daily for 1 week or more.

11. The method of claim 7 , wherein the hematologic malignancy is selected from the group consisting of chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, lymphoplasmacytic lymphoma, non-Hodgkin's lymphoma, small lymphocytic leukemia, Waldenström Macroglobulinemia, and Immunoglobulin Light Chain Amyloidosis.

12. The method of claim 7 , further comprising administering to the patient a member of the group consisting of rituximab, azacytidine, decitabine, low-dose cytarabine, a BTK inhibitor, topetecan, an MDM2 inhibitor, a CD20 inhibitor, a CDK9i inhibitor, and Homoharringtonine (HTT) inhibitor, before, during or after the daily step-wise dosing regimen.

Assignees

• Ascentage Pharma Suzhou Co Ltd
• Ascentage Pharma Group Corp Ltd

Inventors

• Zhai Yifan
• Yang Dajun
• Chen Zi

Classifications

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/519

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