WO2021088975A1 - 一种化合物用于预防或治疗移植物抗宿主病的用途 - Google Patents
一种化合物用于预防或治疗移植物抗宿主病的用途 Download PDFInfo
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- WO2021088975A1 WO2021088975A1 PCT/CN2020/127064 CN2020127064W WO2021088975A1 WO 2021088975 A1 WO2021088975 A1 WO 2021088975A1 CN 2020127064 W CN2020127064 W CN 2020127064W WO 2021088975 A1 WO2021088975 A1 WO 2021088975A1
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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- A—HUMAN NECESSITIES
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Definitions
- the present invention relates to the use of a compound in the preparation of a medicament for the prevention or treatment of graft-versus-host disease (GVHD).
- GVHD graft-versus-host disease
- GVHD graft versus host disease
- HLA identical allogeneic hematopoietic stem cell transplantation
- GVHD is usually divided into acute GVHD (aGVHD) and chronic GVHD (cGVHD) according to the time of occurrence.
- aGVHD usually occurs within 3 months after transplantation, and within 6 months at the latest.
- the three organs involved in aGVHD are skin, gastrointestinal tract and liver; it may occur at any time period after 6 months of transplantation.
- cGVHD the barrier tissues attacked by cGVHD include the mucosal area of the eye, mouth, intestine or genitals, and the epithelial barrier involving the mucosa in bronchiolitis obliterans.
- the median time of immunosuppressive therapy for transplanted patients usually takes 2-3 years.
- the first-line treatment of aGVHD uses intravenous injection of the adrenal cortex hormone methylprednisolone, and the second-line treatment includes tacrolimus or mycophenolate mofetil or combination with methylprednisolone for patients who have failed hormone therapy.
- Ruxolitinib a small-molecule targeted drug JAK inhibitor, was recently approved for second-line treatment in the acute phase but has not yet been marketed in China. The earlier GVHD appears, the worse the prognosis, so it needs to be actively treated clinically.
- the standard first-line treatment of cGVHD is to start the combination of prednisolone and azathioprine at an early stage and gradually reduce the dose. If the patient is intolerant, prednisolone and cyclosporine can also be used.
- prednisolone and cyclosporine can also be used.
- tacrolimus or ritoximab or imatinib or pentostatin can be used. When single-agent second-line drugs are ineffective, the combination of second-line drugs is preferred. There are fewer drugs to enter the third-line treatment, and shock-dose hormone therapy or mycophenolate mofetil or methotrexate can be used.
- T lymphocytes The activation of T lymphocytes is the primary link in inducing the occurrence and development of GVHD. Receiving radiotherapy and chemotherapy before transplantation and GVHD after transplantation will cause damage to the TEC, leading to the limitation of the standard central tolerance mechanism and the inability to remove reactive T and B lymphocytes. Especially naive T lymphocytes (no antigens experienced) induce more severe GVHD.
- the occurrence of aGVHD may involve the regulation of GVHD's inflammatory mediators and T lymphocyte subsets by JAK/STAT and NK- ⁇ B pathways.
- GVHD graft-versus-host disease
- the purpose of the present invention is to provide drugs for the prevention or treatment of graft-versus-host disease (GVHD).
- Another object of the present invention is to provide drugs for improving the survival rate or weight gain of patients with graft-versus-host disease (GVHD).
- the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of graft-versus-host disease (GVHD),
- GVHD graft-versus-host disease
- R1 is halogen
- R2 is halogen
- R3 is selected from C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl,
- R4 is selected from -CN or halogen
- X1 is selected from O, S, NH or CH 2 ,
- X2 is selected from O, S, NH or CH 2 ,
- Q1 is selected from NH, CH 2 , O or S,
- Q2 is selected from NH, CH 2 , O or S,
- Q3 is selected from NH, CH 2 , O or S,
- Q4 is selected from N-R5 or CH-R5, wherein R5 is selected from C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and
- L1 is selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene.
- R3 is C 2-6 alkenyl
- R4 is -CN
- X1 is O
- X2 is O
- Q1 is NH
- Q2 is NH
- Q3 is NH
- Q4 is N-R5
- R5 is a C 1-6 alkyl group
- L1 is a C 1-6 alkylene group.
- the compound of formula (I) is compound CS12192:
- the graft-versus-host disease is acute graft-versus-host disease (aGVHD) or chronic graft-versus-host disease (cGVHD).
- aGVHD acute graft-versus-host disease
- cGVHD chronic graft-versus-host disease
- the drug is used to improve the survival rate of patients with graft-versus-host disease (GVHD).
- GVHD graft-versus-host disease
- the drug is used to improve the weight gain of patients with graft versus host disease (GVHD).
- GVHD graft versus host disease
- the medicament also includes other active ingredients for the prevention or treatment of graft-versus-host disease (GVHD).
- the other active ingredients are selected from the group consisting of glucocorticoids, calcineurin inhibitors, mycophenolate mofetil, sirolimus, pentostatin, anti-CD25 monoclonal antibodies, anti-TNFa monoclonal antibodies, cyclic Spores, methotrexate, thalidomide, or rapamycin.
- the glucocorticoid is selected from prednisone or methylprednisolone.
- the present invention relates to a method for preventing or treating graft-versus-host disease (GVHD), comprising administering a compound of formula (I) to a subject in need thereof.
- GVHD graft-versus-host disease
- R3 is C 2-6 alkenyl
- R4 is -CN
- X1 is O
- X2 is O
- Q1 is NH
- Q2 is NH
- Q3 is NH
- Q4 is N-R5, R5 Is a C 1-6 alkyl group
- L1 is a C 1-6 alkylene group.
- the compound of formula (I) is compound CS12192.
- the method can, for example, improve the survival rate of patients with graft-versus-host disease (GVHD) or improve the weight gain of patients with graft-versus-host disease (GVHD).
- GVHD graft-versus-host disease
- aGVHD acute graft-versus-host disease
- cGVHD chronic graft-versus-host disease
- the method further comprises administering to the subject other active ingredients for the prevention or treatment of graft-versus-host disease (GVHD).
- the other active ingredients are selected from the group consisting of glucocorticoids, calcineurin inhibitors, mycophenolate mofetil, sirolimus, pentostatin, anti-CD25 monoclonal antibodies, anti-TNFa monoclonal antibodies, cyclic Spores, methotrexate, thalidomide, or rapamycin.
- the glucocorticoid is selected from prednisone or methylprednisolone.
- the medicament of the present invention can be used to prevent or treat graft-versus-host disease (GVHD), for example, to improve the survival rate or weight of patients with graft-versus-host disease (GVHD).
- GVHD graft-versus-host disease
- Figure 1 is a graph showing the effect of compound CS12192 on the survival rate of mice in a GVHD model
- Figure 2 is a graph showing the effect of compound CS12192 on the body weight of mice in a GVHD model.
- the present invention provides drugs for preventing or treating graft-versus-host disease (GVHD).
- the present invention provides drugs for improving the survival rate or weight gain of patients with graft-versus-host disease (GVHD).
- the drugs of the present invention have better effects and/or fewer adverse reactions than drugs known in the art.
- the compound of formula (I) of the present invention can effectively treat GVHD, has a satisfactory therapeutic benefit rate for GVHD model mice, and is superior to the first-line treatment drug adrenocortical hormone. Effective activity.
- the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of graft-versus-host disease (GVHD),
- GVHD graft-versus-host disease
- R1 is halogen
- R2 is halogen
- R3 is selected from C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl,
- R4 is selected from -CN or halogen
- X1 is selected from O, S, NH or CH 2 ,
- X2 is selected from O, S, NH or CH 2 ,
- Q1 is selected from NH, CH 2 , O or S,
- Q2 is selected from NH, CH 2 , O or S,
- Q3 is selected from NH, CH 2 , O or S,
- Q4 is selected from N-R5 or CH-R5, wherein R5 is selected from C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, and
- L1 is selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene.
- the halogen is, for example, fluorine, chlorine, bromine or iodine.
- the alkyl group is, for example, C 1 , C 2 , C 3 , C 4 , C 5 or C 6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Tert-butyl, pentyl, hexyl.
- the alkenyl group is, for example, a C 2 , C 3 , C 4 , C 5 or C 6 alkenyl group, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl.
- the alkynyl group is, for example, C 2 , C 3 , C 4 , C 5 or C 6 alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl.
- R1 can be connected to position 1 or 2, preferably to position 1;
- R2 can be connected to position 3, 4, 5 or 6, preferably to position 5;
- R4 can be connected to position 7, 8, 9, 10 or 11, preferably Connected to position 9.
- R3 is C 2-6 alkenyl, preferably vinyl
- R4 is -CN
- X1 is O
- X2 is O
- Q1 is NH
- Q2 is NH
- Q3 is NH
- Q4 It is N-R5, R5 is a C 1-6 alkyl group, preferably a methyl group, and L1 is a C 1-6 alkylene group, preferably a propylene group.
- the compound of formula (I) is compound CS12192:
- compound CS12192 is N-(3-((5-chloro-2-((4-fluoro-3-(N-methacrylamido)phenyl)amino)pyrimidin-4-yl)amino)propyl Yl)-4-cyanobenzamide.
- Example 7 of Chinese Patent CN105399685B discloses compound CS12192 and its preparation method.
- the graft-versus-host disease is acute graft-versus-host disease (aGVHD) or chronic graft-versus-host disease (cGVHD).
- aGVHD acute graft-versus-host disease
- cGVHD chronic graft-versus-host disease
- the drug is used to improve the survival rate of patients with graft-versus-host disease (GVHD).
- GVHD graft-versus-host disease
- the drug is used to improve the weight gain of patients with graft versus host disease (GVHD).
- GVHD graft versus host disease
- the medicament also includes other active ingredients for the prevention or treatment of graft-versus-host disease (GVHD).
- the other active ingredients are selected from the group consisting of glucocorticoids, calcineurin inhibitors, mycophenolate mofetil, sirolimus, pentostatin, anti-CD25 monoclonal antibodies, anti-TNFa monoclonal antibodies, cyclic Spores, methotrexate, thalidomide, or rapamycin.
- the glucocorticoid is selected from prednisone or methylprednisolone.
- the present invention relates to a method for preventing or treating graft-versus-host disease (GVHD), comprising administering a compound of formula (I) to a subject in need thereof.
- GVHD graft-versus-host disease
- the subject is a mammal, such as a human.
- the medicament of the present invention can be injection, tablet, pill, lozenge, soft capsule, hard capsule, granule, powder, solution, suspension, syrup, and any other suitable dosage forms.
- the medicament of the invention can be administered orally.
- the medicament of the present invention can be administered parenterally, for example, via intraperitoneal, intramuscular, intraarterial, intravenous, subcutaneous, intradermal and other routes.
- the medicament of the present invention also contains pharmaceutically acceptable excipients.
- pharmaceutically acceptable auxiliary materials for example, lubricants, binders, fillers, preservatives, surfactants, coloring agents, flavoring agents, emulsifiers, suspending agents, diluents, gelling agents, Disintegrant, pH adjuster, solubilizer, etc.
- lubricants for example, lubricants, binders, fillers, preservatives, surfactants, coloring agents, flavoring agents, emulsifiers, suspending agents, diluents, gelling agents, Disintegrant, pH adjuster, solubilizer, etc.
- lubricants for example, lubricants, binders, fillers, preservatives, surfactants, coloring agents, flavoring agents, emulsifiers, suspending agents, diluents, gelling agents, Disintegrant, pH adjuster, solubilizer, etc.
- these excipients can be appropriately selected according to
- the embodiment of the present invention discloses the application of the compound CS12192 of formula (I) in the prevention and treatment of GVHD disease.
- Example 1 The pharmacodynamic evaluation of CS12192 on the graft-versus-host disease model induced by allogeneic bone marrow transplantation in mice
- mice C57BL/6 (H-2b) and BALB/c (H-2d) male mice aged 6-8 weeks were used as donor and recipient animals, respectively. Among them, C57BL/6 mice are donor mice, and BALB/c mice are recipient mice.
- Recipient mice were sent to the irradiation center to receive 8.5Gry systemic irradiation one day before transplantation. After the irradiation, they were randomly divided into groups according to their body weight. On day 0, the donor mice were sacrificed after pre-anaesthesia with 3-5% isoflurane, and the spleens were removed in a sterile environment, and after grinding, they were filtered with a sterile filter. Then the red blood cells were digested with ammonium chloride buffer, and the lymphocytes were washed twice with RPMI 1640 medium, and finally resuspended in RPMI 1640 medium containing 10% fetal bovine serum to make a lymphocyte suspension.
- mice were divided into 6 groups, each with 10 mice.
- the first group of mice in the same strain control group was injected with the same amount of BALB/c(H-2d) mouse cells through the tail vein; groups 2-5 were allogeneic bone marrow transplantation, including the vehicle group, the positive drug group and the CS12192 high,
- each BALB/c(H-2d) recipient mouse was injected with 0.5ml of RPMI 1640 culture medium through the tail vein, which contained allogeneic C57BL/6(H-2b) donor mice 10 ⁇ 10 6 bone marrow cells and 6.25 ⁇ 10 6 spleen cells; the irradiated control group will not undergo any cell transplantation.
- Table 1 Each component group and administration situation are shown in Table 1.
- the 61-day survival rate was 89% and 100% respectively (relative to the vehicle control, p ⁇ 0.0005 and p ⁇ 0.0001); meanwhile, the weight gain of mice in the two dose groups of CS12192 was also significantly better than that of the positive drug prednisolone group, which had a statistical advantage over the solvent control group ( Figure 2).
- the above test results show that CS12192 can greatly increase the survival rate of GVHD model mice and obtain comprehensive treatment benefits, suggesting that GVHD is an effective indication for CS12192.
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Abstract
Description
Claims (9)
- 根据权利要求1所述的用途,其中,R3为C 2-6烯基,R4为-CN,X1为O,X2为O,Q1为NH,Q2为NH,Q3为NH,Q4为N-R5,R5为C 1-6烷基,且L1为C 1-6亚烷基。
- 根据权利要求1所述的用途,其中,所述移植物抗宿主病为急性移植物抗宿主病(aGVHD)或慢性移植物抗宿主病(cGVHD)。
- 根据权利要求1所述的用途,其中,所述药物用于改善移植物抗宿主病(GVHD)患者的存活率。
- 根据权利要求1所述的用途,其中,所述药物用于改善移植物抗宿主病(GVHD)患者的体重的增长。
- 根据权利要求1所述的用途,其中,所述药物还包括用于预防或治疗移植物抗宿主病(GVHD)的其它活性成分。
- 根据权利要求7所述的用途,其中,所述其它活性成分选自糖皮质激素、钙调神经磷酸酶抑制剂、霉酚酸酯、西罗莫司、喷司他丁、抗CD25单克隆抗体、抗TNFa单克隆抗体、环孢素、甲氨喋呤、沙利度胺或雷帕霉素。
- 根据权利要求8所述的用途,其中,所述糖皮质激素选自泼尼松或甲基泼尼松龙。
Priority Applications (7)
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EP20883709.6A EP4056181A4 (en) | 2019-11-08 | 2020-11-06 | USE OF A COMPOUND TO PREVENT OR TREAT GRAFT VERSUS HOST DISEASE |
CA3157631A CA3157631A1 (en) | 2019-11-08 | 2020-11-06 | Use of compound in preventing or treating graft versus host disease |
BR112022008831A BR112022008831A2 (pt) | 2019-11-08 | 2020-11-06 | Uso de composto na prevenção ou tratamento de doença de enxerto versus hospedeiro |
AU2020381064A AU2020381064A1 (en) | 2019-11-08 | 2020-11-06 | Use of compound in preventing or treating graft versus host disease |
KR1020227018879A KR20220121793A (ko) | 2019-11-08 | 2020-11-06 | 이식편대숙주 질환의 예방 또는 치료에 있어서의 화합물의 용도 |
US17/774,989 US20220387430A1 (en) | 2019-11-08 | 2020-11-06 | Use of compound in preventing or treating graft versus host disease |
JP2022526301A JP2023500352A (ja) | 2019-11-08 | 2020-11-06 | 移植片対宿主病を予防又は治療するための化合物 |
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US (1) | US20220387430A1 (zh) |
EP (1) | EP4056181A4 (zh) |
JP (1) | JP2023500352A (zh) |
KR (1) | KR20220121793A (zh) |
CN (1) | CN112773802B (zh) |
AU (1) | AU2020381064A1 (zh) |
BR (1) | BR112022008831A2 (zh) |
CA (1) | CA3157631A1 (zh) |
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WO (1) | WO2021088975A1 (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102740847A (zh) * | 2009-12-29 | 2012-10-17 | 阿维拉制药公司 | 杂芳基化合物和其用途 |
CN105399685A (zh) | 2014-09-16 | 2016-03-16 | 深圳微芯生物科技有限责任公司 | 作为选择性jak3和/或jak1激酶抑制剂的芳杂环化合物的制备方法及其应用 |
CN105399686A (zh) * | 2014-09-16 | 2016-03-16 | 深圳微芯生物科技有限责任公司 | 嘧啶衍生物、其制备方法及其应用 |
CN105481778A (zh) * | 2014-09-16 | 2016-04-13 | 深圳微芯生物科技有限责任公司 | 嘧啶衍生物、其制备方法及其应用 |
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Also Published As
Publication number | Publication date |
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EP4056181A4 (en) | 2023-12-20 |
CA3157631A1 (en) | 2021-05-14 |
JP2023500352A (ja) | 2023-01-05 |
US20220387430A1 (en) | 2022-12-08 |
CN112773802A (zh) | 2021-05-11 |
BR112022008831A2 (pt) | 2022-08-16 |
EP4056181A1 (en) | 2022-09-14 |
CN112773802B (zh) | 2023-11-21 |
KR20220121793A (ko) | 2022-09-01 |
AU2020381064A1 (en) | 2022-06-23 |
TW202120092A (zh) | 2021-06-01 |
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