1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)pyrimidin-2-yl)-1H-pyrazol-4-ol and use thereof in the treatment of cancer
This invention relates to an active metabolite of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimindin-4-amine that modulates the activity of adenosine A2a receptor. In particular, the present invention relates to pharmaceutical compositions comprising 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, as well as processes for its preparation and its use in the treatment of cancer alone of in combination with one or more immunotherapeutic agents.
1. A metabolite of 5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimindin-4-amine, which is compound:
or a pharmaceutically acceptable salt thereof.
2. The compound 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, in an isolated form.
3. A pharmaceutical composition comprising, 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for simultaneous, concurrent, or sequential use.
4. A combination, comprising a therapeutically effective amount of 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol, or a pharmaceutically acceptable salt thereof and one or more immunotherapeutic agents.
5. A method of treating cancer, in a subject in need of such treatment, the method comprising: administering to a subject in need thereof, a therapeutically effective amount of 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol , or a pharmaceutically acceptable salt thereof; alone or in combination with one or more immunotherapeutic agents wherein the cancer is selected from a lung cancer, a melanoma, a renal cancer, a liver cancer, a myeloma, a prostate cancer, a breast cancer, a colorectal cancer, a pancreatic cancer, a head and neck cancer, anal cancer, gastro-esophageal cancer, thyroid cancer, cervical cancer, a lymphoproliferative disease or a hematological cancer, T-cell lymphoma, B-cell lymphoma, a non-Hogdkin lymphoma, or a leukemia.
6. A method of inhibiting adenosine A2a receptor in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the 1-(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol according to claim 1 ; or administering a pharmaceutical composition according to claim 3 to a subject.
7. The method of claim 5 , wherein the cancer is lung cancer.
8. The method of claim 5 , wherein one or more immunotherapeutic agents are selected from the group consisting of anti-CTLA4 antibodies, anti-PD-1 antibodies and anti-PD-L1 antibodies.
9. The method of claim 5 , wherein the immunotherapeutic agent is selected from the group consisting of: Ipilimumab, Tremelimumab, Nivolumab, Pembrolizumab, Pidilizumab (CT-011), AMP-224, AMP-514 (MEDI0680), MPDL3280A, MEDI4736, MSB0010718C, YW243.55.S70 and MDX-1105.
10. The method of claim 5 , wherein the immunotherapeutic agents is an anti-PD-1 antibody.
11. The method, the use or the combination for use according to claim 10 , wherein the anti-PD-1 antibody comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 41, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15; or
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 41; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12.
12. The method, according to claim 10 , wherein the anti-PD-1 comprises a VH comprising the amino acid sequence of SEQ ID NO: 6 and a VL comprising the amino acid sequence of SEQ ID NO: 20.
13. The method, according to embodiment 10 , wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 8 and a light chain comprising the amino acid sequence of SEQ ID NO: 22.
14. The method, according to embodiment 10 , wherein the anti-PD-1 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 6 and a VL comprising the amino acid sequence of SEQ ID NO: 16.
15. The method, according to embodiment 10 , wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 8 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.
16. The method, according to claim 10 , wherein the anti-PD-1 antibody molecule is administered at a dose of about 300 mg once every three weeks.
17. The method, according to claim 10 , wherein the anti-PD-1 antibody molecule is administered at a dose of about 400 mg once every four weeks.
18. The method of claim 5 , wherein the immunotherapeutic agents is an anti-PD-L1 antibody.
19. The method, according to claim 18 , wherein the anti PD-L1 antibody molecule comprises:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 47, a VHCDR2 amino acid sequence of SEQ ID NO: 48, and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 52, a VLCDR2 amino acid sequence of SEQ ID NO: 53, and a VLCDR3 amino acid sequence of SEQ ID NO: 54;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 44; a VHCDR2 amino acid sequence of SEQ ID NO: 45; and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 49, a VLCDR2 amino acid sequence of SEQ ID NO: 50, and a VLCDR3 amino acid sequence of SEQ ID NO: 51;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 63, a VHCDR2 amino acid sequence of SEQ ID NO: 48, and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 52, a VLCDR2 amino acid sequence of SEQ ID NO: 53, and a VLCDR3 amino acid sequence of SEQ ID NO: 54; or
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 63; a VHCDR2 amino acid sequence of SEQ ID NO: 45; and a VHCDR3 amino acid sequence of SEQ ID NO: 46; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 49, a VLCDR2 amino acid sequence of SEQ ID NO: 50, and a VLCDR3 amino acid sequence of SEQ ID NO: 51.
20. The method, according to claim 18 , wherein the anti PD-L1 antibody molecule comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 55 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 58.
21. The method, according to claim 8 , wherein immunotherapeutic agent is administered together in a single composition or administered separately in two or more different compositions forms.
22. The method, according to claim 8 , wherein the immunotherapeutic agent is administered concurrently with, prior to, or subsequent to, the compound: -(4-amino-5-bromo-6-(1H-pyrazol-1-yl)-pyrimidin-2-yl)-1H-pyrazol-4-ol.
23. The method according to claim 7 , wherein the lung cancer is non-small cell lung cancer.