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EP-4734995-A1 - QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN

EP4734995A1EP 4734995 A1EP4734995 A1EP 4734995A1EP-4734995-A1

Abstract

Described herein is certain quinoline carboxamides for use in the treatment of a myeloproliferative neoplasm (MPN). The quinoline carboxamides may more specifically be used in the treatment of advanced stages of MPN, including accelerated-phase MPN and secondary acute myeloid leukemia, i.e., acute myeloid leukemia evolving from an antecedent myeloproliferative neoplasm (post-MPN AML), optionally in combination with a further compound selected from a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, and combinations thereof. Also included are pharmaceutical combinations of the quinoline carboxamides and second agents such as a BET inhibitor or a Bcl-2 inhibitor. Further included are certain quinoline carboxamides for use in combination with a BET inhibitor or a Bcl-2 inhibitor, in the treatment of a myeloproliferative neoplasm (MPN).

Inventors

  • BHALLA, KAPIL
  • ERIKSSON, Helena
  • TUVESSON, Helen

Assignees

  • Board of Regents, The University of Texas System
  • Active Biotech AB

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A pharmaceutical combination comprising: a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; and a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.
  2. 2. The pharmaceutical combination according to claim 1 , wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.
  3. 3. The pharmaceutical combination according to claim 1 or 2, wherein the further therapeutically active agent comprises a BET inhibitor.
  4. 4. The pharmaceutical combination according to claim 1 or 2, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.
  5. 5. A pharmaceutical composition comprising: a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof; and a pharmaceutically acceptable excipient.
  6. 6. The pharmaceutical composition according to claim 5, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.
  7. 7. The pharmaceutical composition according to claim 5 or 6, wherein the further therapeutically active agent comprises a BET inhibitor.
  8. 8. The pharmaceutical composition according to claim 5 or 6, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.
  9. 9. A kit comprising a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof; a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof; and a package insert with instructions for use of said kit.
  10. 10. The kit according to claim 9, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.
  11. 11. The kit according to claim 9 or 10, wherein the further therapeutically active agent comprises a BET inhibitor.
  12. 12. The kit according to claim 9 or 10, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.
  13. 13. The pharmaceutical combination according to any one of claims 1 to 4, or the pharmaceutical composition according to any one of claims 5 to 8, or the kit according to any one of claims 9 to 12, for use in the treatment of a myeloproliferative neoplasm (MPN).
  14. 14. A compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, for use in the treatment of a myeloproliferative neoplasm (MPN), wherein the treatment comprises administration of a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.
  15. 15. The compound or pharmaceutically acceptable salt thereof for use according to claim 14, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, venetoclax or a pharmaceutically acceptable salt thereof; or a combination thereof.
  16. 16. The compound or pharmaceutically acceptable salt thereof for use according to claim 14 or 15, wherein the further therapeutically active agent comprises a BET inhibitor.
  17. 17. The compound or pharmaceutically acceptable salt thereof for use according to claim 14 or 15, wherein the further therapeutically active agent comprises a Bcl-2 inhibitor.
  18. 18. Use of a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, in the manufacture of a combination medicament for the treatment of a myeloproliferative neoplasm (MPN), wherein the combination comprises a further therapeutically active agent comprising a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.
  19. 19. The use according to claim 18, wherein the further therapeutically active agent comprises the BET inhibitor pelabresib or a pharmaceutically acceptable salt thereof, or birabresib or a pharmaceutically acceptable salt thereof, or the Bcl-2 inhibitor navitoclax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof, or a combination thereof.
  20. 20. The use according to claim 18 or 19, wherein the further therapeutically active agent comprises a BET inhibitor.

Description

QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN CROSS-REFERENCE TO RELATED APPLICATIONS [0001 ] The present application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63/510,726, filed 28 June 2023 and titled QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN, U.S. Provisional Patent Application No. 63/514,844, filed 21 July 2023 and titled QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN, and U.S. Provisional Patent Application No. 63/594,235, filed 30 October 2023 and titled QUINOLINE CARBOXAMIDES FOR USE IN THE TREATMENT OF MPN, each of which is incorporated by reference herein in its entirety for all purposes. FIELD OF THE INVENTION [0002] The present invention relates to the treatment of a myeloproliferative neoplasm (MPN) with certain quinoline carboxamides. The quinoline carboxamides may more specifically be used in the treatment of advanced stages of MPN, including accelerated-phase MPN and secondary acute myeloid leukemia, i.e., acute myeloid leukemia evolving from an antecedent myeloproliferative neoplasm (post-MPN AML), optionally in combination with a further compound selected from a JAK (Janus kinase) inhibitor, a BET (Bromodomain and Extra-Terminal motif protein) inhibitor, a Bcl-2 (B-cell lymphoma 2) inhibitor, and combinations thereof. Also included are pharmaceutical combinations of the quinoline carboxamides and second agents such as a BET inhibitor or a Bcl-2 inhibitor. The invention further relates to certain quinoline carboxamides for use in combination with at least one of a BET inhibitor and a Bcl-2 inhibitor, in the treatment of a myeloproliferative neoplasm (MPN). BACKGROUND [0003] Tasquinimod and a method for its preparation were described in WO 99/55678 and WO 00/03991, which publications also disclosed the utility of tasquinimod and other quinoline carboxamides for the treatment of diseases resulting from autoimmunity, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis and, furthermore, diseases where pathologic inflammation plays a major role, such as asthma, atherosclerosis, stroke, and Alzheimer’s disease. [0004] Processes for preparing tasquinimod also have been described in WO 03/106424 and in WO 2012/004338. A deuterated form of tasquinimod was described in WO 2012/175541. WO 2022/248401 discloses particles of tasquinimod in free base form or as a pharmaceutically acceptable salt, and the use of such particles, said particles having a D(v,0.9) of at most 30 pm and a D(v,0.5) of at most 15 pm. In WO/2023/275248, degradation products of tasquinimod in a pharmaceutical formulation are identified and used in methods for assessing the suitability for use of such a formulation. [0005] The use of various quinoline carboxamides for the treatment of cancer, more particularly solid cancers, such as prostate cancer and breast cancer, was disclosed in WO 01/30758. It has been found that these compounds bind to and inhibit the interactions of an immunomodulatory protein (S 100A9), which protein promotes tumor development, influences suppressive and pro-angiogenic cells in the tumor microenvironment and participates in the establishment of pre- metastatic niches. [0006] WO 2016/078921 discloses tasquinimod for use in the treatment of leukemia including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. WO 2016/042112 discloses tasquinimod for use in the treatment of multiple myeloma. WO 2022/018240 discloses tasquinimod for use in the prevention or treatment of a myeloproliferative neoplasm associated with a fibrotic phase, such as primary myelofibrosis, essential thrombocythemia or polycythemia vera. WO2022/152902 discloses tasquinimod or a pharmaceutically acceptable salt thereof for use in the treatment of myelodysplastic syndrome. [0007] WO 2016/146329 discloses tasquinimod for use in combination with a PD-1 and/or PD-L1 inhibitor in the treatment of cancer, in particular bladder cancer. WO 2021/175924 discloses tasquinimod for use in combination with and at least one further compound selected from a proteasome inhibitor, an immunomodulatory imide, and an antibody for use in the treatment of multiple myeloma. [0008] What is needed are novel uses and methods of treatment including tasquinimod. SUMMARY OF THE INVENTION [0009] A first aspect relates to a pharmaceutical combination comprising a compound of formula (I) wherein R is selected from hydrogen and methyl, or a pharmaceutically acceptable salt thereof, and a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof. [0010] A further aspect relates to a pharmaceutical combination comprising a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and a BET inhibitor, a Bcl-2 inhibitor, or a combination th