USE OF COMPOUND IN PREVENTING OR TREATING GRAFT VERSUS HOST DISEASE

Abstract

Use of a compound in preventing or treating a graft versus host disease (GVHD), especially use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in preparing a drug for preventing or treating GVHD.

Claims

1. A method of preventing or treating a patient with graft versus host disease (GVHD), comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient, ##STR00006## wherein, R1 is halogen, R2 is halogen, R3 is selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, R4 is selected from —CN or halogen, X1 is selected from O, S, NH or CH.sub.2, X2 is selected from O, S, NH or CH.sub.2, Q1 is selected from NH, CH.sub.2, O or S, Q2 is selected from NH, CH.sub.2, O or S, Q3 is selected from NH, CH.sub.2, O or S, Q4 is selected from N—R5 or CH—R5, wherein R5 is selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, and L1 is selected from C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene.

2. The method according to claim 1, wherein R3 is C.sub.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 C.sub.1-6 alkyl, and L1 is C.sub.1-6 alkylene.

3. The method according to claim 1, wherein the compound of Formula (I) is a compound of Formula (II), ##STR00007##

4. The method according to claim 1, wherein the GVHD is an acute GVHD (aGVHD) or a chronic GVHD (cGVHD).

5. The method according to claim 1, wherein said preventing or treating comprises improving a survival rate of the patient with GVHD.

6. The method according to claim 1, wherein said preventing or treating comprises improving a weight gain of the patient with GVHD.

7. The method according to claim 1, wherein the compound of Formula (I) or the pharmaceutically acceptable salt thereof is administered with another active ingredient for preventing or treating GVHD.

8. The method according to claim 7, wherein the another active ingredient is selected from glucocorticoid, calcineurin inhibitor, mycophenolate mofetil, sirolimus, pentostatin, anti-CD25 monoclonal antibody, anti-TNFa monoclonal antibody, ciclosporin, methotrexate, thalidomide, or rapamycin.

9. The method according to claim 8, wherein the glucocorticoid is selected from prednisone or methylprednisolone.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG. 1 is a diagram showing an effect of compound CS12192 on mouse survival rate in a GVHD model; and

[0031] FIG. 2 is a diagram showing an effect of compound CS12192 on mouse body weight in a GVHD model.

DETAILED DESCRIPTION OF THE INVENTION

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. In the case of conflicting, this document including definitions is used as a standard. Preferred methods and materials are described below, but methods and materials similar or equivalent to those described herein may be used for implementing or testing the present invention. The materials, methods, and examples disclosed herein are illustrative only, and not intended to limit.

[0033] The present invention provides a drug for preventing or treating GVHD. In one aspect, the present invention provides a drug for improving a survival rate or a weight gain of a patient with GVHD. In one aspect, the drug of the present invention has the better effects and/or fewer adverse reactions than drugs known in the field.

[0034] In one aspect, a compound of Formula (I) of the present invention, especially CS12192, may effectively treat GVHD, has a satisfactory therapeutic benefit rate for a GVHD model mouse, and has the drug effective activity superior to a first-line treatment drug adrenocortical hormone.

[0035] In one aspect, the present invention relates to a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in preparing a drug for preventing or treating GVHD,

##STR00003##

[0036] wherein,

[0037] R1 is halogen,

[0038] R2 is halogen,

[0039] R3 is selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl,

[0040] R4 is selected from —CN or halogen,

[0041] X1 is selected from O, S, NH or CH.sub.2,

[0042] X2 is selected from O, S, NH or CH.sub.2,

[0043] Q1 is selected from NH, CH.sub.2, O or S,

[0044] Q2 is selected from NH, CH.sub.2, O or S,

[0045] Q3 is selected from NH, CH.sub.2, O or S,

[0046] Q4 is selected from N—R5 or CH—R5, wherein R5 is selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, and

[0047] L1 is selected from C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene.

[0048] In one aspect, the halogen is, for example, fluorine, chlorine, bromine or iodine.

[0049] In one aspect, the alkyl is, for example, C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, or C.sub.6 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0050] In one aspect, the alkenyl is, for example, C.sub.2, C.sub.3, C.sub.4, C.sub.5, or C.sub.6 alkenyl, such as vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0051] In one aspect, the alkynyl is, for example, C.sub.2, C.sub.3, C.sub.4, C.sub.5, or C.sub.6 alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0052] In one aspect, while a chemical bond of a substituent in Formula (I) is intersected with a chemical bond between two adjacent ring atoms of a cyclic moiety, it means that the substituent may be linked to any possible linkage positions of the cyclic moiety.

[0053] For example, in Formula (I),

##STR00004##

[0054] R1 may be linked with a position 1 or 2, preferably linked with the position 1; R2 may be linked with a position 3, 4, 5 or 6, preferably linked with the position 5; and R4 may be linked with a position 7, 8, 9, 10 or 11, preferably linked with the position 9.

[0055] In one aspect, in Formula (I), R3 is C.sub.2-6 alkenyl, preferably a vinyl, R4 is —CN, X1 is O, X2 is O, Q1 is NH, Q2 is NH, Q3 is NH, and Q4 is N—R5, R5 is C.sub.1-6 alkyl, preferably a methyl, and L1 is C.sub.1-6 alkylene, preferably a propylidene.

[0056] In one aspect, the compound of Formula (I) is a compound CS12192:

##STR00005##

[0057] The chemical name of the compound CS12192 is N-(3-((5-chloro-2-((4-fluoro-3-(N-methacrylamido)phenyl)amino)pyrimidin-4-yl)amino) propyl)-4-nitrilebenzamide.

[0058] Embodiment 7 of Chinese patent CN105399685B discloses compound CS12192 and a preparation method thereof.

[0059] In one aspect, the GVHD is aGVHD or cGVHD.

[0060] In one aspect, the drug is used to improve survival rate of a patient with GVHD.

[0061] In one aspect, the drug is used to improve weight gain of a patient with GVHD.

[0062] In one aspect, the drug further includes another active ingredient for preventing or treating GVHD. Preferably, the another active ingredient is selected from glucocorticoid, calcineurin inhibitor, mycophenolate mofetil, sirolimus, pentostatin, anti-CD25 monoclonal antibody, anti-TNFa monoclonal antibody, ciclosporin, methotrexate, thalidomide, or rapamycin. Preferably, the glucocorticoid is selected from prednisone or methylprednisolone.

[0063] In one aspect, the present invention relates to a method for preventing or treating GVHD, including administering a compound of Formula (I) to a subject in need thereof.

[0064] In one aspect, the subject is a mammal, such as a human.

[0065] In one aspect, the drug of the present invention may be an injection, a tablet, a pill, a lozenge, a soft capsule, a hard capsule, a granule, a powder, a solution, a suspension, a syrup, and any other suitable dosage forms. In one aspect, the drug of the present invention may be administered orally. In one aspect, the drug of the present invention may be administered parenterally, for example, by intraperitoneal, intramuscular, intraarterial, intravenous, subcutaneous, intradermal and other routes.

[0066] In one aspect, in addition to the active ingredient, the drug of the present invention further includes a pharmaceutically acceptable adjuvant. As the pharmaceutically acceptable adjuvant, it may be listed as, for example, a lubricant, a binder, a filler, a preservative, a surfactant, a colorant, a flavoring agent, an emulsifier, a suspending agent, a diluent, a gelling agent, a disintegrant, a pH adjuster, and a solubilizer. Those skilled in the art know that these adjuvants may be appropriately selected according to the appropriate dosage form, and the content thereof may be changed according to specific needs.

Embodiment

[0067] The following embodiments show the use of the compound of Formula (I), CS12192, in prevention and treatment of GVHD.

[0068] The embodiments of the present invention disclose the use of compound of Formula (I), CS12192, in prevention and treatment of GVHD.

[0069] The present invention is further described in detail below in combination with the specific embodiments and with reference to data. It should be understood that these embodiments are intended to describe the present invention only, and not to limit a scope of the present invention in any way. It should be particularly pointed out that all similar replacements and modifications are apparent to those skilled in the art, and they are regarded to be included in the present invention. In the following embodiments, various processes and methods which are not described in detail are conventional methods well-known in the art.

Embodiment 1. Pharmacodynamic Evaluation of CS12192 on GVHD Model Induced by Mouse Allogeneic Bone Marrow Transplantation

[0070] This study evaluates a pharmacodynamics effect of a test drug CS12192 in a GVHD model induced by mouse allogeneic bone marrow transplantation. In the GVHD model, 6-8 week old of two types of C57BL/6 (H-2b) and BALB/c (H-2d) male mice are used as donor and receptor animals respectively. Wherein, C57BL/6 mice are the donor mice, and BALB/c mice are the receptor mice.

[0071] The receptor mice are sent to an irradiation center to receive 8.5 Gry systemic irradiation on the day before transplantation, and after the irradiation, the mice are randomly divided into groups according to the body weights of the mice. On day 0, after 3-5% isoflurane pre-anesthesia, the donor mice are killed by cervical dislocation, and spleens are excised in a sterile environment, ground, and filtered by a sterile filter. Then red blood cells are digested with ammonium chloride buffer solution, lymphocytes are washed twice with RPMI 1640 culture solution, and finally resuspended in RPMI 1640 culture solution containing 10% fetal bovine serum, to prepare a lymphocyte suspension.

[0072] The receptor mice are divided into 6 groups, and each group includes 10 mice. Wherein the same number of BALB/c(H-2d) mouse cells are injected into tail veins of syngeneic control mice of the first group; groups 2-5 are allogeneic bone marrow transplantation, including a vehicle group, a positive drug group and CS12192 high and low two-dose administration groups, each BALB/c(H-2d) receptor mouse is injected with 0.5 ml of the RPMI 1640 culture solution by the tail vein, wherein 10×10.sup.6 bone marrow cells and 6.25×10.sup.6 splenocytes of allogeneic C57BL/6(H-2b) donor mice are contained; and an irradiation control group does not undergo any cell transplantation. The grouping and dosing situations of each group are shown in Table 1.

TABLE-US-00001 TABLE 1 Dosing group and dosing regimen Group Test drug Dose (mg/kg) Dosing regimen Syngeneic bone marrow transplantation Vehicle — Twice a day Allogeneic bone marrow transplantation Vehicle — Twice a day Positive drug Prednisolone 20 Once a day Low dose group CS12192 40 Twice a day High dose group CS12192 80 Twice a day Irradiation group Vehicle — Twice a day

[0073] Experimental results of CS12192 against the mouse GVHD model (FIG. 1) show that the mice are reared for 61 days after allogeneic bone marrow transplantation, the survival rate of the allogeneic bone marrow transplantation control group is 0, and the survival rate of the positive drug prednisolone group is 67% (p<0.01 relative to the vehicle control), and CS12192 is administered at two doses of 40 and 80 mg/kg twice a day, the survival rates at 61 days are 89% and 100% respectively (p<0.0005 and p<0.0001 relative to the vehicle control respectively); and at the same time, the weight gains of the mice of CS12192 two-dose groups are also significantly better than that of the positive drug prednisolone group, and it has a statistical increase advantage relative to the solvent control group (FIG. 2). The above experimental results show that CS12192 may significantly improve the survival rate of the GVHD model mice and obtain the comprehensive treatment benefits, it is indicated that GVHD is an effective indication for CS12192.

[0074] Although certain features of the present invention are already illustrated and described herein, many modifications, replacements, changes and equivalents may occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications, replacements, changes and equivalents falling within the true spirit of the present invention.