JPWO2021142257A5 - - Google Patents
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- JPWO2021142257A5 JPWO2021142257A5 JP2022542216A JP2022542216A JPWO2021142257A5 JP WO2021142257 A5 JPWO2021142257 A5 JP WO2021142257A5 JP 2022542216 A JP2022542216 A JP 2022542216A JP 2022542216 A JP2022542216 A JP 2022542216A JP WO2021142257 A5 JPWO2021142257 A5 JP WO2021142257A5
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- 229940124291 BTK inhibitor Drugs 0.000 claims description 20
- 210000002798 bone marrow cell Anatomy 0.000 claims description 20
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 claims description 16
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 claims description 16
- 230000003211 malignant effect Effects 0.000 claims description 16
- 206010028537 myelofibrosis Diseases 0.000 claims description 14
- 229940121730 Janus kinase 2 inhibitor Drugs 0.000 claims description 10
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 10
- 210000000952 spleen Anatomy 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 4
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 4
- 108010008212 Integrin alpha4beta1 Proteins 0.000 claims description 4
- 238000009825 accumulation Methods 0.000 claims description 4
- 230000003247 decreasing effect Effects 0.000 claims description 4
- 230000005012 migration Effects 0.000 claims description 4
- 238000013508 migration Methods 0.000 claims description 4
- 230000035772 mutation Effects 0.000 claims description 4
- 210000005259 peripheral blood Anatomy 0.000 claims description 4
- 239000011886 peripheral blood Substances 0.000 claims description 4
- 208000003476 primary myelofibrosis Diseases 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229940125814 BTK kinase inhibitor Drugs 0.000 claims description 2
- 208000032027 Essential Thrombocythemia Diseases 0.000 claims description 2
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 208000017733 acquired polycythemia vera Diseases 0.000 claims description 2
- 208000037244 polycythemia vera Diseases 0.000 claims description 2
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 claims description 2
- 229960000215 ruxolitinib Drugs 0.000 claims description 2
- 230000004936 stimulating effect Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 29
- 230000003394 haemopoietic effect Effects 0.000 claims 7
- 210000001519 tissue Anatomy 0.000 claims 7
- 239000000203 mixture Substances 0.000 claims 2
- OXOXFDSEGFLWLU-UHFFFAOYSA-N 1-[4-[[[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino]methyl]-4-fluoropiperidin-1-yl]prop-2-en-1-one Chemical group C=1C=C(OC=2C=CC=CC=2)C=CC=1C=1C(N)=NC=NC=1NCC1(F)CCN(C(=O)C=C)CC1 OXOXFDSEGFLWLU-UHFFFAOYSA-N 0.000 claims 1
- 210000001185 bone marrow Anatomy 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 238000000034 method Methods 0.000 description 32
- 150000001875 compounds Chemical class 0.000 description 3
- 230000016396 cytokine production Effects 0.000 description 3
- 206010041660 Splenomegaly Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000014564 chemokine production Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
Description
実施例７：サイトカイン産生
[00212]化合物Ｎｏ．１２８への曝露後のインビトロでのサイトカイン産生に対する影響を、２４時間のインキュベーション後の刺激された全血において査定した。図４に示されるように、化合物Ｎｏ．１２８は、細胞刺激があり次第のサイトカイン及びケモカイン産生を減少させた。
さらなる実施形態は以下のとおりである。
［実施形態１］
ヒト対象にブルトン型チロシンキナーゼ（ＢＴＫ）阻害剤を投与するステップを含む、治療を必要とするヒト対象における脾腫を治療する方法。
［実施形態２］
前記ヒト対象が、彼らの脾臓において悪性ＣＤ３４＋骨髄細胞の蓄積を有する、実施形態１に記載の方法。
［実施形態３］
前記悪性ＣＤ３４＋骨髄細胞が、正常な骨髄細胞と比べて、ＣＸＣＲ４の発現の減少を有する、実施形態２に記載の方法。
［実施形態４］
前記ＢＴＫ阻害剤が、前記ヒト対象の末梢血への前記悪性ＣＤ３４＋骨髄細胞の遊走を刺激するのに十分な量で投与される、実施形態２に記載の方法。
［実施形態５］
前記ＢＴＫ阻害剤が、前記悪性ＣＤ３４＋骨髄細胞におけるＶＬＡ－４の活性を減少させるのに十分な量で投与される、実施形態２に記載の方法。
［実施形態６］
前記ＢＴＫ阻害剤が、前記悪性ＣＤ３４＋骨髄細胞におけるＶＬＡ－４の発現を減少させるのに十分な量で投与される、実施形態２に記載の方法。
［実施形態７］
前記ヒト対象が骨髄線維症に罹患している、実施形態１～６のいずれか１つに記載の方法。
［実施形態８］
ヒト対象にＢＴＫ阻害剤を投与するステップを含む、脾腫に罹患しているヒト対象における脾臓から末梢血への悪性ＣＤ３４＋骨髄細胞の遊走を刺激する方法。
［実施形態９］
前記ヒト対象が、脾臓において悪性ＣＤ３４＋骨髄細胞の蓄積を有する、実施形態８に記載の方法。
［実施形態１０］
前記悪性ＣＤ３４＋骨髄細胞が、正常な骨髄細胞と比べて、ＣＸＣＲ４の発現の減少を有する、実施形態８に記載の方法。
［実施形態１１］
前記ヒト対象が骨髄線維症に罹患している、実施形態８に記載の方法。
［実施形態１２］
前記骨髄線維症が、原発性骨髄線維症（ＰＭＦ）、真性赤血球増加症後骨髄線維症（ｐｏｓｔ ＰＶ－ＭＦ）、及び本態性血小板血症後骨髄線維症（ｐｏｓｔ ＥＴ－ＭＦ）からなる群から選択される、実施形態７又は１１に記載の方法。
［実施形態１３］
前記ヒト対象がルキソリチニブ療法に応答しなかった、実施形態１～１２のいずれか１つに記載の方法。
［実施形態１４］
前記ヒト対象がＪＡＫ２Ｖ６１７Ｆ変異を有する、実施形態１～１３のいずれか１つに記載の方法。
［実施形態１５］
前記ヒト対象が、骨髄増殖性新生物（ＭＰＮ）に続発する急性骨髄性白血病（ＡＭＬ）を有する、実施形態１４に記載の方法。
［実施形態１６］
前記ヒト対象がＪＡＫ２Ｖ６１７Ｆ変異を有しない、実施形態１～１３のいずれか１つに記載の方法。
［実施形態１７］
前記ヒト対象が、骨髄増殖性新生物に続発する急性骨髄性白血病を有する、実施形態１６に記載の方法。
［実施形態１８］
前記ヒト対象がＪＡＫ２阻害剤を用いて治療されたことがない、実施形態１～１７のいずれか１つに記載の方法。
［実施形態１９］
前記ヒト対象がＪＡＫ２阻害剤に不耐性である、実施形態１～１８のいずれか１つに記載の方法。
［実施形態２０］
前記ヒト対象がＪＡＫ２阻害剤を用いた治療に不適格である、実施形態１～１９のいずれか１つに記載の方法。
［実施形態２１］
前記ヒト対象が、ＪＡＫ２阻害剤治療後に再発する、又はＪＡＫ２阻害剤治療に対して難治性である、実施形態１～２０のいずれか１つに記載の方法。
［実施形態２２］
前記ＢＴＫ阻害剤が、１５ｍｇ、２５ｍｇ、３０ｍｇ、５０ｍｇ、６０ｍｇ、７５ｍｇ、９０ｍｇ、１００ｍｇ、１２０ｍｇ、１５０ｍｇ、１７５ｍｇ、１８０ｍｇ、２００ｍｇ、２２５ｍｇ、２４０ｍｇ、２５０ｍｇ、２７５ｍｇ、３００ｍｇ、３２５ｍｇ、３５０ｍｇ、３６０ｍｇ、３７５ｍｇ、４８０ｍｇ、及び５６０ｍｇからなる群から選択される用量で１日に１回投与される、実施形態１～２１のいずれか１つに記載の方法。
［実施形態２３］
前記ＢＴＫ阻害剤が、１５ｍｇ、２５ｍｇ、３０ｍｇ、５０ｍｇ、６０ｍｇ、７５ｍｇ、９０ｍｇ、１００ｍｇ、１２０ｍｇ、１５０ｍｇ、１７５ｍｇ、１８０ｍｇ、２００ｍｇ、２２５ｍｇ、２４０ｍｇ、２５０ｍｇ、２７５ｍｇ、３００ｍｇ、３２５ｍｇ、３５０ｍｇ、３６０ｍｇ、３７５ｍｇ、４８０ｍｇ、及び５６０ｍｇからなる群から選択される用量で１日に２回投与される、実施形態１～２２のいずれか１つに記載の方法。
［実施形態２４］
前記ＢＴＫ阻害剤が経口投与される、実施形態１～２３のいずれか１つに記載の方法。
［実施形態２５］
前記ＢＴＫ阻害剤が共有結合性ＢＴＫ阻害剤である、実施形態１～２４のいずれか１つに記載の方法。
［実施形態２６］
前記ＢＴＫ阻害剤が非共有結合性ＢＴＫ阻害剤である、実施形態１～２５のいずれか１つに記載の方法。
［実施形態２７］
前記ＢＴＫ阻害剤が、表１から選択される化合物又はその薬学的に許容できる塩である、実施形態１～２６のいずれか１つに記載の方法。
Example 7: Cytokine production
[00212] Compound No. The effects on in vitro cytokine production following exposure to 128 were assessed in stimulated whole blood after 24 hours of incubation. As shown in FIG. 4, compound no. 128 reduced cytokine and chemokine production upon cell stimulation.
Further embodiments are as follows.
[Embodiment 1]
A method of treating splenomegaly in a human subject in need thereof, the method comprising administering to the human subject a Bruton's tyrosine kinase (BTK) inhibitor.
[Embodiment 2]
The method of embodiment 1, wherein the human subject has an accumulation of malignant CD34+ bone marrow cells in their spleen.
[Embodiment 3]
3. The method of embodiment 2, wherein the malignant CD34+ bone marrow cells have decreased expression of CXCR4 compared to normal bone marrow cells.
[Embodiment 4]
3. The method of embodiment 2, wherein the BTK inhibitor is administered in an amount sufficient to stimulate migration of the malignant CD34+ bone marrow cells into the peripheral blood of the human subject.
[Embodiment 5]
3. The method of embodiment 2, wherein the BTK inhibitor is administered in an amount sufficient to reduce the activity of VLA-4 in the malignant CD34+ bone marrow cells.
[Embodiment 6]
3. The method of embodiment 2, wherein the BTK inhibitor is administered in an amount sufficient to reduce expression of VLA-4 in the malignant CD34+ bone marrow cells.
[Embodiment 7]
The method according to any one of embodiments 1-6, wherein said human subject is suffering from myelofibrosis.
[Embodiment 8]
A method of stimulating the migration of malignant CD34+ bone marrow cells from the spleen to peripheral blood in a human subject suffering from splenomegaly, the method comprising administering to the human subject a BTK inhibitor.
[Embodiment 9]
9. The method of embodiment 8, wherein the human subject has an accumulation of malignant CD34+ bone marrow cells in the spleen.
[Embodiment 10]
9. The method of embodiment 8, wherein the malignant CD34+ bone marrow cells have decreased expression of CXCR4 compared to normal bone marrow cells.
[Embodiment 11]
9. The method of embodiment 8, wherein the human subject is suffering from myelofibrosis.
[Embodiment 12]
The myelofibrosis is from the group consisting of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post PV-MF), and post-essential thrombocythemia myelofibrosis (post ET-MF). The method of embodiment 7 or 11, wherein the method is selected.
[Embodiment 13]
13. The method of any one of embodiments 1-12, wherein said human subject did not respond to ruxolitinib therapy.
[Embodiment 14]
The method according to any one of embodiments 1-13, wherein said human subject has the JAK2V617F mutation.
[Embodiment 15]
15. The method of embodiment 14, wherein the human subject has acute myeloid leukemia (AML) secondary to myeloproliferative neoplasm (MPN).
[Embodiment 16]
The method of any one of embodiments 1-13, wherein said human subject does not have the JAK2V617F mutation.
[Embodiment 17]
17. The method of embodiment 16, wherein the human subject has acute myeloid leukemia secondary to a myeloproliferative neoplasm.
[Embodiment 18]
18. The method of any one of embodiments 1-17, wherein said human subject has not been treated with a JAK2 inhibitor.
[Embodiment 19]
19. The method of any one of embodiments 1-18, wherein said human subject is intolerant to a JAK2 inhibitor.
[Embodiment 20]
20. The method of any one of embodiments 1-19, wherein the human subject is ineligible for treatment with a JAK2 inhibitor.
[Embodiment 21]
21. The method of any one of embodiments 1-20, wherein the human subject relapses after JAK2 inhibitor treatment or is refractory to JAK2 inhibitor treatment.
[Embodiment 22]
The BTK inhibitor is 15mg, 25mg, 30mg, 50mg, 60mg, 75mg, 90mg, 100mg, 120mg, 150mg, 175mg, 180mg, 200mg, 225mg, 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 36 0mg, 375mg, 22. The method of any one of embodiments 1-21, wherein the method is administered once a day at a dose selected from the group consisting of 480 mg, and 560 mg.
[Embodiment 23]
The BTK inhibitor is 15mg, 25mg, 30mg, 50mg, 60mg, 75mg, 90mg, 100mg, 120mg, 150mg, 175mg, 180mg, 200mg, 225mg, 240mg, 250mg, 275mg, 300mg, 325mg, 350mg, 36 0mg, 375mg, 23. The method according to any one of embodiments 1-22, wherein the method is administered twice a day at a dose selected from the group consisting of 480 mg, and 560 mg.
[Embodiment 24]
24. The method according to any one of embodiments 1-23, wherein said BTK inhibitor is administered orally.
[Embodiment 25]
25. The method of any one of embodiments 1-24, wherein the BTK inhibitor is a covalent BTK inhibitor.
[Embodiment 26]
26. The method of any one of embodiments 1-25, wherein the BTK inhibitor is a non-covalent BTK inhibitor.
[Embodiment 27]
27. The method according to any one of embodiments 1-26, wherein the BTK inhibitor is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.
Claims (27)
前記ＢＴＫ阻害剤が、１－（４－（（（６－アミノ－５－（４－フェノキシフェニル）ピリミジン－４－イル）アミノ）メチル）－４－フルオロピペリジン－１－イル）プロパ－２－エン－１－オン又はその薬学的に許容できる塩であり、
前記ヒト対象が、その造血組織において悪性ＣＤ３４＋骨髄細胞の蓄積を有する、医薬組成物。 A pharmaceutical composition for treating myeloproliferative neoplasm (MPN) in a human subject in need of treatment, comprising a Bruton 's tyrosine kinase (BTK) inhibitor , the composition comprising:
The BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2- En-1-one or a pharmaceutically acceptable salt thereof,
A pharmaceutical composition, wherein said human subject has an accumulation of malignant CD34+ bone marrow cells in its hematopoietic tissue .
前記ＢＴＫ阻害剤が、１－（４－（（（６－アミノ－５－（４－フェノキシフェニル）ピリミジン－４－イル）アミノ）メチル）－４－フルオロピペリジン－１－イル）プロパ－２－エン－１－オン又はその薬学的に許容できる塩である、医薬組成物。 A pharmaceutical composition for stimulating the migration of malignant CD34+ bone marrow cells from hematopoietic tissue to peripheral blood in a human subject suffering from a myeloproliferative neoplasm (MPN), comprising a B TK inhibitor, the composition comprising:
The BTK inhibitor is 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2- A pharmaceutical composition which is en-1-one or a pharmaceutically acceptable salt thereof .
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202062958632P | 2020-01-08 | 2020-01-08 | |
| US62/958,632 | 2020-01-08 | ||
| PCT/US2021/012696 WO2021142257A1 (en) | 2020-01-08 | 2021-01-08 | Methods of treating splenomegaly |
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| JP2023509968A JP2023509968A (en) | 2023-03-10 |
| JPWO2021142257A5 true JPWO2021142257A5 (en) | 2024-01-17 |
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| EP (2) | EP3980069A4 (en) |
| JP (1) | JP2023509968A (en) |
| KR (1) | KR20220130151A (en) |
| CN (1) | CN114423457A (en) |
| AU (1) | AU2021205484A1 (en) |
| BR (1) | BR112022013646A2 (en) |
| CA (1) | CA3164063A1 (en) |
| CO (1) | CO2022010592A2 (en) |
| CR (1) | CR20220374A (en) |
| IL (1) | IL294582A (en) |
| JO (1) | JOP20220168A1 (en) |
| MA (1) | MA57226B1 (en) |
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| US20240024314A1 (en) | 2020-01-08 | 2024-01-25 | Telios Pharma, Inc. | Methods of Treating Splenomegaly |
| JOP20220168A1 (en) * | 2020-01-08 | 2023-01-30 | Telios Pharma Inc | Methods of treating splenomegaly |
| WO2023071973A1 (en) * | 2021-10-26 | 2023-05-04 | Shenzhen Targetrx, Inc. | Fused bicyclic compound for inhibiting activity of tyrosine kinase |
| WO2024041614A1 (en) * | 2022-08-25 | 2024-02-29 | Beigene Switzerland Gmbh | Solid forms comprising (s) -7- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrimidine-3-carboxamide, and oxalic acid, compositions and methods of use thereof |
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| WO2015057992A1 (en) * | 2013-10-16 | 2015-04-23 | Izumi Raquel | Btk inhibitors for hematopoietic mobilization |
| HUE056329T2 (en) * | 2014-08-11 | 2022-02-28 | Acerta Pharma Bv | Therapeutic combinations of a btk inhibitor and a bcl-2 inhibitor |
| WO2016054491A1 (en) * | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| JP2021527685A (en) * | 2018-06-19 | 2021-10-14 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ | A novel crystal form of 1-(4-{[6-amino-5- (4-phenoxy-phenyl) -pyrimidine-4-ylamino] -methyl} -4-fluoro-piperidine-1-yl) -propenone, which Salt form, and process for obtaining |
| TW202128156A (en) * | 2019-11-14 | 2021-08-01 | 美商夸格智財控股有限公司 | Combination of a btk inhibitor and an mdm2 inhibitor for cancer treatment |
| JOP20220168A1 (en) * | 2020-01-08 | 2023-01-30 | Telios Pharma Inc | Methods of treating splenomegaly |
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- 2021-01-08 IL IL294582A patent/IL294582A/en unknown
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- 2021-01-08 AU AU2021205484A patent/AU2021205484A1/en active Pending
- 2021-01-08 WO PCT/US2021/012696 patent/WO2021142257A1/en active Application Filing
- 2021-01-08 CR CR20220374A patent/CR20220374A/en unknown
-
2022
- 2022-07-28 CO CONC2022/0010592A patent/CO2022010592A2/en unknown
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