mTOR/JAK inhibitor combination therapy

Patent metadata

Field	Value
Publication number	US-9993480-B2
Application number	US-201213399274-A
Country	US
Kind code	B2
Filing date	Feb 17, 2012
Priority date	Feb 18, 2011
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

Provided herein is a combination therapy comprising an mTOR inhibitor and a JAK inhibitor. The combination therapy is useful for the treatment of a variety of cancers, including myeloproliferative neoplasms. The combination therapy is also useful for the treatment of any number of JAK-associated diseases.

First claim

The invention claimed is:

1. A method of treating a myeloproliferative neoplasm in a subject in need thereof, comprising administering to the subject synergistically effective amounts of an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, wherein the mTOR inhibitor is everolimus or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol.

2. The method of claim 1 , wherein the mTOR inhibitor is everolimus.

3. The method of claim 1 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are in a single formulation or unit dosage form.

4. The method of claim 3 , further comprising a pharmaceutically acceptable carrier.

5. The method of claim 1 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are administered separately.

6. The method of claim 1 , wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary or idiopathic myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, and atypical chronic myelogenous leukemia.

7. The method of claim 1 , wherein the myeloproliferative neoplasm is primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.

8. The method of claim 5 , wherein the subject is human.

9. The method of claim 5 , wherein the treatment comprises administering the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, at substantially the same time.

10. The method of claim 5 , wherein the treatment comprises administering the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, at different times.

11. The method of claim 10 , wherein the mTOR inhibitor is administered to the subject, followed by administration of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

12. The method of claim 10 , wherein (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, is administered to the subject, followed by administration of the mTOR inhibitor.

13. The method of claim 5 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are in separate formulations or unit dosage forms.

14. The method of claim 5 , wherein the mTOR inhibitor and/or (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are administered at dosages that would not be effective when one or both of the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are administered alone, but which amounts are effective in combination.

15. A method of inhibiting STAT5 phosphorylation, comprising administering synergistically effective amounts of an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, wherein the mTOR inhibitor is everolimus or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol.

16. The method of claim 15 , wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof are administered to a subject in need thereof.

17. The method of claim 16 , wherein the administration of the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof treats a myeloproliferative neoplasm in the subject.

18. The method of claim 17 , wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary or idiopathic myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, and atypical chronic myelogenous leukemia.

19. The method of claim 17 , wherein the myeloproliferative neoplasm is primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.

20. A composition comprising an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof in synergistically effective amounts, wherein the mTOR inhibitor is everolimus or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol.

21. The composition of claim 20 , further comprising a pharmaceutically acceptable carrier.

22. A method of treating a myeloproliferative neoplasm in a subject in need thereof, comprising administering to the subject an effective amount of the composition of claim 20 .

23. A method of treating a myeloproliferative neoplasm in a subject in need thereof, comprising administering to the subject synergistically effective amounts of an mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, wherein the mTOR inhibitor is everolimus.

Assignees

• Vannucchi Alessandro M
• Bogani Costanza
• Guglielmelli Paola
• Novartis Pharma Ag
• Incyte Corp

Inventors

• Vannucchi Alessandro M
• Bogani Costanza
• Guglielmelli Paola

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title