Hspc-sparing treatments for rb-positive abnormal cellular proliferation

Patent metadata

Field	Value
Publication number	US-2019070185-A1
Application number	US-201816178419-A
Country	US
Kind code	A1
Filing date	Nov 1, 2018
Priority date	Mar 15, 2013
Publication date	Mar 7, 2019
Grant date	—

Abstract

This invention is in the area of improved compounds for and methods of treating selected RB-positive cancers and other Rb-positive abnormal cellular proliferative disorders while minimizing the deleterious effects on healthy cells, for example healthy Hematopoietic Stem Cells and Progenitor Cells (HSPCs), associated with current treatment modalities. In one aspect, improved treatment of select RB-positive cancers is disclosed using specific compounds disclosed herein. In certain embodiments, the compounds described herein act as highly selective and, in certain embodiments, short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects.

First claim

We claim:

1 . A method for the treatment of cancer in a human, wherein the cancer is Retinoblastoma-positive (Rb) and selected from the group consisting of breast cancer, colon cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, and glioblastoma, comprising administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor of formula:

or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the cancer is breast cancer.

3 . The method of claim 1 , wherein the cancer is colon cancer.

4 . The method of claim 1 , wherein the cancer is ovarian cancer.

5 . The method of claim 1 , wherein the cancer is non-small cell lung cancer.

6 . The method of claim 1 , wherein the cancer is glioblastoma.

7 . The method of claim 1 , wherein the cancer is prostate cancer.

8 . The method of claim 1 , wherein the compound is administered in combination with another chemotherapeutic agent.

9 . The method of claim 8 , wherein the CDK4/6 inhibitor is administered prior to administration of the chemotherapeutic agent.

10 . The method of claim 8 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.

11 . A method for the treatment of Retinoblastoma-positive breast cancer in a human comprising administering an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor of formula

or a pharmaceutically acceptable salt thereof.

12 . The method of claim 11 , wherein the compound is administered in combination with a chemotherapeutic agent.

13 . The method of claim 12 , wherein the chemotherapeutic agent is doxorubicin.

14 . The method of claim 12 , wherein the chemotherapeutic agent is paclitaxel.

15 . The method of claim 12 , wherein the chemotherapeutic agent is carboplatin.

16 . The method of claim 12 , wherein the chemotherapeutic agent is gemcitabine.

17 . The method of claim 12 , wherein the chemotherapeutic agent is cisplatin.

18 . The method of claim 12 , wherein the CDK4/6 inhibitor is administered prior to administration of the chemotherapeutic agent.

19 . The method of claim 12 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.

20 . The method of claim 11 , wherein the breast cancer is estrogen-receptor positive.

21 . A method for the treatment of Retinoblastoma (Rb)-positive non-small cell lung cancer in a human comprising administering an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor of formula

or a pharmaceutically acceptable salt thereof.

22 . The method of claim 21 , wherein the compound is administered in combination with a chemotherapeutic agent.

23 . The method of claim 22 , wherein the chemotherapeutic agent is docetaxel.

24 . The method of claim 22 , wherein the chemotherapeutic agent is doxorubicin.

25 . The method of claim 22 , wherein the chemotherapeutic agent is paclitaxel.

26 . The method of claim 22 , wherein the chemotherapeutic agent is etoposide.

27 . The method of claim 22 , wherein the chemotherapeutic agent is vinblastine sulfate.

28 . The method of claim 22 , wherein the chemotherapeutic agent is carboplatin.

29 . The method of claim 22 , wherein the chemotherapeutic agent is gemcitabine.

30 . The method of claim 22 , wherein the chemotherapeutic agent is cisplatin.

31 . A method for the treatment of cancer in a human, wherein the cancer is Retinoblastoma-positive (Rb) and selected from the group consisting of breast cancer, colon cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, and glioblastoma, comprising:
administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor of formula:

or a pharmaceutically acceptable salt thereof; and
administering to the human a chemotherapeutic agent;
wherein the CDK4/6 inhibitor is administered to the human prior to administration of the chemotherapeutic agent.

32 . The method of claim 31 , wherein the cancer is breast cancer.

33 . The method of claim 31 , wherein the cancer is colon cancer.

34 . The method of claim 31 , wherein the cancer is ovarian cancer.

35 . The method of claim 31 , wherein the cancer is non-small cell lung cancer.

36 . The method of claim 31 , wherein the cancer is glioblastoma.

37 . The method of claim 31 , wherein the cancer is prostate cancer.

38 . The method of claim 8 , wherein the CDK4/6 inhibitor is administered 24 hours or less prior to administration of the chemotherapeutic agent.

39 . The method of claim 8 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.

40 . A method for the treatment of Retinoblastoma-positive breast cancer in a human comprising:
administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor of formula:

or a pharmaceutically acceptable salt thereof; and
administering to the human a chemotherapeutic agent;
wherein the CDK4/6 inhibitor is administered to the human prior to administration of the chemotherapeutic agent.

41 . The method of claim 40 , wherein the chemotherapeutic agent is doxorubicin.

42 . The method of claim 40 , wherein the chemotherapeutic agent is paclitaxel.

43 . The method of claim 40 , wherein the chemotherapeutic agent is carboplatin.

44 . The method of claim 40 , wherein the chemotherapeutic agent is gemcitabine.

45 . The method of claim 40 , wherein the chemotherapeutic agent is cisplatin.

46 . The method of claim 40 , wherein the CDK4/6 inhibitor is administered 24 hours or less prior to administration of the chemotherapeutic agent.

47 . The method of claim 46 , wherein the CDK4/6 inhibitor is administered 4 hours or less prior to administration of the chemotherapeutic agent.

48 . The method of claim 40 , wherein the breast cancer is estrogen-receptor positive.

49 . A method for the treatment of Retinoblastoma (Rb)-positive non-small cell lung cancer in a human comprising:
administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor of formula:

or a pharmaceutically acceptable salt thereof; and
adm

Assignees

• G1 Therapeutics Inc

Inventors

• Strum Jay Copeland
• Bisi John Emerson
• Roberts Patrick Joseph
• Tavares Francis Xavier

Classifications

• 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

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K31/527 Primary

  spiro-condensed · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title