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 PDF

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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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host disease
versus
gvhd
graft
compound
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山松
余金迪
潘德思
辛利军
王世刚
张钰
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Shenzhen Chipscreen Biosciences Co Ltd
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Shenzhen Chipscreen Biosciences Co Ltd
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Priority to JP2022526301A priority Critical patent/JP2023500352A/ja
Priority to BR112022008831A priority patent/BR112022008831A2/pt
Priority to AU2020381064A priority patent/AU2020381064A1/en
Priority to EP20883709.6A priority patent/EP4056181A4/en
Priority to US17/774,989 priority patent/US20220387430A1/en
Priority to CA3157631A priority patent/CA3157631A1/en
Priority to KR1020227018879A priority patent/KR20220121793A/ko
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
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    • 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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    • 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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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

一种化合物用于预防或治疗移植物抗宿主病的用途，特别是式(I)的化合物或其药学上可接受的盐在制备用于预防或治疗移植物抗宿主病(GVHD)的药物中的用途。

Description

一种化合物用于预防或治疗移植物抗宿主病的用途 技术领域
本发明涉及一种化合物在制备用于预防或治疗移植物抗宿主病(GVHD)的药物中的用途。
背景技术
移植物抗宿主病(GVHD)是同种异体造血干细胞移植(HSCT)后最常见的并发症。尽管有强力的免疫抑制预防，甚至当供体是完全匹配的(HLA相同的)兄弟姐妹时，也可以发生GVHD。这是受体的抗原呈递细胞和供体的成熟细胞之间相互作用的结果。移植物中的免疫细胞也会对宿主组织造成免疫损害，并引起非疾病复发性的死亡。GVHD在接受移植并长期生存的患者中的发生率在20-80％之间，是临床移植手术需要关注的常见问题。根据中华医学会血液学分会的数据，中国每年接受异基因骨髓移植的患者超过5000例，所有患者都需要接受GVHD的预防和治疗。
GVHD按照发生时间通常分为急性GVHD(aGVHD)和慢性GVHD(cGVHD)。aGVHD通常发生在移植后3个月内，最迟6个月内发生，aGVHD主要涉及的三种器官是皮肤、胃肠道和肝；而在移植6个月以后的任何时间段都有可能发生cGVHD，cGVHD攻击的屏障组织包括眼、口、肠或生殖器粘膜区以及闭塞性细支气管炎中涉及粘膜的上皮屏障。接受移植的患者采用免疫抑制治疗的中位时间通常需要2-3年。
aGVHD的一线治疗采用肾上腺皮质激素甲基强的松龙静脉注射，激素治疗无效的患者采用二线治疗包括他克莫司或麦考酚酸酯或与甲基强的松龙联用。小分子靶向药物JAK抑制剂Ruxolitinib最近获批用 于急性期的二线治疗但是在国内还没有上市。GVHD出现越早，预后越差，因此临床需要积极处理。
cGVHD治疗的标准一线方案为早期开始给予强的松龙和硫唑嘌呤联用，并逐渐减量，如患者不耐受，也可采用强的松龙联合环孢素。二线治疗则可以选用他克莫司或利托昔单抗或伊马替尼或喷司他汀等，二线药物单药无效时优先考虑二线药物之间的联合。进入三线治疗选择的药物更少，可以采用冲击剂量的激素治疗或麦考酚酸酯或甲氨喋呤等。
T淋巴细胞活化是诱导GVHD发生、发展的首要环节，移植前接受放化疗及移植后的GVHD均会造成TEC的损伤导致标准的中心耐受机制受限，无法去除反应性T、B淋巴细胞，尤其幼稚T淋巴细胞(未经历抗原)诱导更严重的GVHD。aGVHD的发生可能涉及JAK/STAT及NK-κB通路对GVHD的炎症介质和T淋巴细胞亚群的调节。
仍需要用于预防或治疗移植物抗宿主病(GVHD)的药物，尤其是用于改善移植物抗宿主病(GVHD)患者的存活率或体重的增长的药物。
发明内容
本发明的目的是提供用于预防或治疗移植物抗宿主病(GVHD)的药物。本发明的另一个目的是提供用于改善移植物抗宿主病(GVHD)患者的存活率或体重的增长的药物。
在一个方面，本发明涉及式(I)的化合物或其药学上可接受的盐在制备用于预防或治疗移植物抗宿主病(GVHD)的药物中的用途，
Figure PCTCN2020127064-appb-000001
其中，
R1为卤素，
R2为卤素，
R3选自C 1-6烷基、C 2-6烯基或C 2-6炔基，
R4选自-CN或卤素，
X1选自O、S、NH或CH 2，
X2选自O、S、NH或CH 2，
Q1选自NH、CH 2、O或S，
Q2选自NH、CH 2、O或S，
Q3选自NH、CH 2、O或S，
Q4选自N-R5或CH-R5，其中R5选自C 1-6烷基、C 2-6烯基或C 2-6炔基，且
L1选自C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基。
在一个方面，式(I)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。
在一个方面，所述式(I)的化合物为化合物CS12192：
Figure PCTCN2020127064-appb-000002
在一个方面，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)。
在一个方面，所述药物用于改善移植物抗宿主病(GVHD)患者的存活率。
在一个方面，所述药物用于改善移植物抗宿主病(GVHD)患者的 体重的增长。
在一个方面，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。优选地，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。优选地，所述糖皮质激素选自泼尼松或甲基泼尼松龙。
在一个方面，本发明涉及用于预防或治疗移植物抗宿主病(GVHD)的方法，包括向有此需要的对象给予式(I)的化合物。优选地，式(I)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。更优选地，所述式(I)的化合物为化合物CS12192。优选地，所述方法可以例如改善移植物抗宿主病(GVHD)患者的存活率或改善移植物抗宿主病(GVHD)患者的体重的增长。优选地，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)。
在一个方面，所述方法还包括向所述对象给予用于预防或治疗移植物抗宿主病(GVHD)的其它活性成分。优选地，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。优选地，所述糖皮质激素选自泼尼松或甲基泼尼松龙。
本发明所述药物可用于预防或治疗移植物抗宿主病(GVHD)，例如，改善移植物抗宿主病(GVHD)患者的存活率或体重。
附图说明
图1是显示化合物CS12192对于GVHD模型中小鼠存活率影响的图；
图2是显示化合物CS12192对于GVHD模型中小鼠体重影响的图。
具体实施方式
除非另外定义，本文所用的所有技术和科学术语具有本领域技术人员通常理解的相同含义。在冲突的情况下，以包括定义在内的本文件为准。下面描述优选的方法和材料，但是与本文所述那些类似或等同的方法和材料可用于实施或测试本发明。本文公开的材料、方法和实例仅是说明性的，而非旨在限制。
本发明提供了用于预防或治疗移植物抗宿主病(GVHD)的药物。在一个方面，本发明提供了用于改善移植物抗宿主病(GVHD)患者的存活率或体重的增长的药物。在一个方面，本发明的药物与本领域已知的药物相比具有更好的效果和/或更少的不良反应。
在一个方面，本发明所述式(I)化合物，特别是CS12192，可以有效治疗GVHD，对于GVHD模型小鼠有着令人满意的治疗获益率，且具有优于一线治疗药物肾上腺皮质激素的药效活性。
在一个方面，本发明涉及式(I)的化合物或其药学上可接受的盐在制备用于预防或治疗移植物抗宿主病(GVHD)的药物中的用途，
Figure PCTCN2020127064-appb-000003
其中，
R1为卤素，
R2为卤素，
R3选自C 1-6烷基、C 2-6烯基或C 2-6炔基，
R4选自-CN或卤素，
X1选自O、S、NH或CH 2，
X2选自O、S、NH或CH 2，
Q1选自NH、CH 2、O或S，
Q2选自NH、CH 2、O或S，
Q3选自NH、CH 2、O或S，
Q4选自N-R5或CH-R5，其中R5选自C 1-6烷基、C 2-6烯基或C 2-6炔基，且
L1选自C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基。
在一个方面，所述卤素为例如氟、氯、溴或碘。
在一个方面，所述烷基为例如C 1、C 2、C 3、C 4、C 5或C 6烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基。
在一个方面，所述烯基为例如C 2、C 3、C 4、C 5或C 6烯基，例如乙烯基、丙烯基、丁烯基、戊烯基、己烯基。
在一个方面，所述炔基为例如C 2、C 3、C 4、C 5或C 6炔基，例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基。
在一个方面，当式(I)中取代基的化学键与环状部分相邻两个环原子之间的化学键相交时，表示该取代基可以与该环状部分任何可能连接的位置连接。
例如，在式(I)中，
Figure PCTCN2020127064-appb-000004
R1可以和位置1或2连接，优选和位置1连接；R2可以和位置3、4、5或6连接，优选和位置5连接；R4可以和位置7、8、9、10或11连接，优选和位置9连接。
在一个方面，式(I)中，R3为C 2-6烯基，优选为乙烯基，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，优选为甲基，且L1为C 1-6亚烷基，优选为亚丙基。
在一个方面，所述式(I)的化合物为化合物CS12192：
Figure PCTCN2020127064-appb-000005
化合物CS12192的化学名为N-(3-((5-氯-2-((4-氟-3-(N-甲基丙烯酰胺基)苯基)氨基)嘧啶-4-基)氨基)丙基)-4-腈基苯甲酰胺。
中国专利CN105399685B的实施例7公开了化合物CS12192及其制备方法。
在一个方面，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)。
在一个方面，所述药物用于改善移植物抗宿主病(GVHD)患者的存活率。
在一个方面，所述药物用于改善移植物抗宿主病(GVHD)患者的体重的增长。
在一个方面，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。优选地，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。优选地，所述糖皮质激素选自泼尼松或甲基泼尼松龙。
在一个方面，本发明涉及用于预防或治疗移植物抗宿主病(GVHD)的方法，包括向有此需要的对象给予式(I)的化合物。
在一个方面，所述对象为哺乳动物，例如人。
在一个方面，本发明的药物可以为注射剂、片剂、丸剂、锭剂、 软胶囊剂、硬胶囊剂、颗粒剂、散剂、溶液剂、混悬剂、糖浆剂以及任何其他合适的剂型。在一个方面，本发明的药物可口服施用。在一个方面，本发明的药物可肠胃外施用，例如经腹膜内、肌内、动脉内、静脉内、皮下、皮内等途径。
在一个方面，除了活性成份之外，本发明的药物还包含药学上可接受的辅料。作为药学上可接受的辅料，例如可举出润滑剂、粘合剂、填充剂、防腐剂、表面活性剂、着色剂、矫味剂、乳化剂、助悬剂、稀释剂、胶凝剂、崩解剂、pH调节剂、增溶剂等。本领域技术人员知晓，这些辅料可根据合适的剂型适当选择，并视具体需要改变其含量。
实施例
以下实施例显示了式(I)化合物CS12192在GVHD疾病预防和治疗中的应用。
本发明实施例公开了式(I)化合物CS12192在GVHD疾病预防和治疗中的应用。
下面结合具体的实施例，并参照数据进一步详细描述本发明。应理解，这些实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。在以下的实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1.CS12192对小鼠异基因骨髓移植诱导的移植物抗宿主疾病模型的药效学评价
本研究评价测试药CS12192在小鼠异基因骨髓移植诱导的GVHD模型中的药效学作用。在GVHD模型中，用6-8周龄的C57BL/6(H-2b)和BALB/c(H-2d)两种雄性小鼠分别作为供体和受体动物。其中，C57BL/6小鼠为供体小鼠，BALB/c小鼠为受体小鼠。
受体小鼠在移植前一天送到辐照中心接受8.5Gry全身性辐照，辐照结束后，根据小鼠的体重随机分组。在第0天，3-5％异氟烷预 麻醉后脱颈椎处死供体小鼠，在无菌环境下摘取脾脏，磨碎后，用无菌滤网过滤。然后用氯化铵缓冲液消化红细胞，再用RPMI 1640培养液洗涤两次淋巴细胞，最后重悬在含10％胎牛血清的RPMI 1640培养液中，制成淋巴细胞悬液。
将受体小鼠分为6组，每组10只。其中第一组同系对照组小鼠尾静脉注射相同数量的BALB/c(H-2d)小鼠细胞；2-5组为同种异系骨髓移植，包括溶媒组、阳性药组和CS12192高、低两个剂量给药组，每只BALB/c(H-2d)受体小鼠尾静脉注射0.5ml的RPMI 1640培养液，其中含同种异系C57BL/6(H-2b)供体鼠的10×10 6骨髓细胞和6.25×10 6脾细胞；辐照对照组将不进行任何细胞移植。各组分组及给药情况见表1所示。
表1-给药组及给药方案
Figure PCTCN2020127064-appb-000006
CS12192针对小鼠GVHD模型的试验结果显示(图1)，小鼠进行同种异系骨髓移植后饲养61天，同种异系骨髓移植对照组的存活率为0，阳性药物泼尼松龙组的存活率为67％(相对溶媒对照p＜0.01)，CS12192以40和80mg/kg两个剂量，一天两次给药，61天的存活率分别为89％、100％(相对溶媒对照分别p＜0.0005和p＜0.0001)；同时，CS12192两个剂量组小鼠的体重增长也明显优于阳性药物泼尼松龙组，相对溶剂对照组有统计学的增长优势(图2)。上述试验结果表明CS12192可以使GVHD模型小鼠大幅提高存活率，获得综合治 疗获益，提示GVHD是CS12192的有效适应症。
虽然本发明某些特征已经在本文中阐释和描述，但本领域技术人员将想到许多修改、替代、变更和等同。因此，应理解的是，所附权利要求书意在涵盖落入本发明真实精神范围之内的所有此类修改、替代、变更和等同。

Claims (9)

  1. 式(I)的化合物或其药学上可接受的盐在制备用于预防或治疗移植物抗宿主病(GVHD)的药物中的用途，
    Figure PCTCN2020127064-appb-100001
    其中，
    R1为卤素，
    R2为卤素，
    R3选自C 1-6烷基、C 2-6烯基或C 2-6炔基，
    R4选自-CN或卤素，
    X1选自O、S、NH或CH 2，
    X2选自O、S、NH或CH 2，
    Q1选自NH、CH 2、O或S，
    Q2选自NH、CH 2、O或S，
    Q3选自NH、CH 2、O或S，
    Q4选自N-R5或CH-R5，其中R5选自C 1-6烷基、C 2-6烯基或C 2-6炔基，且
    L1选自C 1-6亚烷基、C 2-6亚烯基或C 2-6亚炔基。
  2. 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。
  3. 根据权利要求1所述的用途，其中，所述式(I)的化合物为化合物CS12192：
    Figure PCTCN2020127064-appb-100002
  4. 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)。
  5. 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。
  6. 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。
  7. 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。
  8. 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。
  9. 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。
PCT/CN2020/127064 2019-11-08 2020-11-06 一种化合物用于预防或治疗移植物抗宿主病的用途 Ceased WO2021088975A1 (zh)

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