Application of imidazolinone derivatives in combination with doxorubicin in the treatment of tumors

Abstract

This invention provides the use of the compound represented by general formula (I) in combination with doxorubicin in the preparation of anticancer drugs.

Description

Technical Field

[0001] The present invention relates to the use of an imidazolinone derivative combined with doxorubicin in treating tumors. Prior Art

[0002] Doxorubicin is a broadly effective anti-tumor drug. One of its primary mechanisms of cancer treatment is to directly damage cancer cell DNA, causing extensive DNA damage and ultimately killing the cells. The DNA damage response (DDR) is a self-protection mechanism activated by cells when they encounter DNA damage. It can cause cell cycle arrest and repair of damaged DNA, thereby reducing cancer cell sensitivity to doxorubicin. Clinically, this results in a reduced therapeutic effect of doxorubicin.

[0003] DNA double-strand breaks (DSBs) are a highly detrimental form of DNA damage within cells. Unrepaired DSBs are closely associated with cell carcinogenesis. Non-homologous end-joining (NHEJ) is one of the major DSB repair mechanisms within cells. In NHEJ, the DSB ends are first recognized and bound by Ku70 / 80, which then associates with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-dependent protein kinase (DNAPK), the NHEJ initiation complex (DNAPK). Subsequently, the two DNAPKs bind the broken DNA ends and recruit subsequent NHEJ repair factors (XRCC4 and XLF) and DNA ligase IV (LigIV) to repair the broken DNA.

[0004] WO2021209055 describes the use of an imidazolidinone derivative in the preparation of a drug for treating cancer, wherein the compound described in the specification has high selectivity and significant inhibitory activity against DNAPK. Summary of the Invention

[0005] The purpose of the present invention is to provide an application of an imidazolinone derivative combined with doxorubicin in tumor treatment, so as to overcome the shortcomings of the existing technology.

[0006] One or more embodiments of the present application provide a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof as an active ingredient in combination with doxorubicin for treating tumors: (I) in: for 、 or ; is a single bond or a double bond; A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R 0 is H, C 1-6 alkyl or cyclopropyl, the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium; R1 is 、 、 、 、 、 、 、 、 、 、 、 Or pyridyl, and R 1 is optionally further substituted by 1 or 2 substituents selected from D, halogen, cyano, hydroxy, C 1-6 alkyl and C 1-6 alkoxy; R 1a is H or C 1-6 alkyl; R 1b is H, OH, cyano or C 1-6 alkyl substituted by hydroxy; R 2 is H, cyano, = O, carboxyl, -C (= O) NR 2aR 2b, C 1-6 alkoxy, C 1-6 alkyl, halogen, -S (= O) 2R 2a or -C (= O) OC 1-6 alkyl; the C 1-6 alkyl, -C (= O) OC 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one or more substituents selected from halogen and deuterium; R 2a and R 2b are each independently H, C 1-6 alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH, D, halogen, C 1-6 alkyl and C 1-6 alkoxy; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted with 1 or more substituents selected from C 1-6 alkyl, OH and halogen; R 3 is halogen or C 1-6 alkyl, the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2 or 3; The condition is, when When R 0, R 2, and R 3 satisfy the following conditions at the same time, R 1 is not 、 or : for , n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2Me, and R 3 is methyl.

[0007] In one or more embodiments of the present application, R 1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or ; R 1a is H or C 1-6 alkyl; R 2 is H, cyano, -C(=O)NR 2aR 2b, C 1-6 alkoxy, halogen, -S(=O) 2R 2a or -C(=O)OC 1-6 alkyl; the -C(=O)OC 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one or more substituents selected from halogen and deuterium; R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH, D or halogen; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen; R 3 is halogen or C 1-6 alkyl, the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; The condition is, when When R 0, R 2, and R 3 satisfy the following conditions at the same time, R 1 is not 、 or : for , n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2Me, and R 3 is methyl.

[0008] In one or more embodiments of the present application, wherein: for or ; R 0 is H, C 1-4 alkyl or cyclopropyl, the C 1-4 alkyl is optionally further substituted by one or more substituents selected from halogen and D; R1 is 、 、 、 、 、 、 、 、 、 、 or ; R 1a is H, C 1-6 alkyl or -C(=O)C 1-6 alkyl; R 2 is H, cyano, -C(=O)NR 2aR 2b, C 1-6 alkoxy, halogen, -S(=O) 2R 2a or -C(=O)OC 1-6 alkyl; the -C(=O)O alkyl or C 1-6 alkoxy is optionally substituted by one or more substituents selected from halogen and deuterium; R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH, D and halogen; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen; R 3 is halogen or C 1-6 alkyl, the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; The condition is, when When R 0, R 2, and R 3 satisfy the following conditions at the same time, R 1 is not 、 or : when for , n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2Me, and R 3 is methyl.

[0009] One or more embodiments of the present application provide a compound of formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof as an active ingredient for use in combination with doxorubicin in treating tumors: (II) in: R 0 is H, C 1-6 alkyl or cyclopropyl, the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium; R1 is 、 、 、 、 、 、 、 、 、 、 、 Or pyridyl, and R 1 is optionally further substituted by 1 to 2 substituents selected from D, halogen, cyano, hydroxy, C 1-6 alkyl and C 1-6 alkoxy; R 1a is H or C 1-6 alkyl; R 1b is H, OH, cyano or C 1-6 alkyl substituted by hydroxy; R 2c is H, cyano, halogen or C 1-6 alkoxy; R 2d is H, cyano, carboxyl, -C(=O)NR 2aR 2b, C 1-6 alkyl, halogen, -S(=O) 2R 2a or -C(=O)OC 1-6 alkyl; said C 1-6 alkyl, -C(=O)OC 1-6 alkyl is optionally substituted by one or more substituents selected from halogen and deuterium; R 2a, R 2b are H, C 1-6 alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from OH, D, halogen, C 1-6 alkyl and C 1-6 alkoxy; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from C 1-6 alkyl, OH and halogen; R 3 is halogen or C 1-6 alkyl, the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2 or 3; The condition is, when When R 0, R 2, and R 3 satisfy the following conditions at the same time, R 1 is not 、 or : Selected from , n is 1, R 0 is H or methyl, R 2 is methoxy or -S(=O) 2Me, and R 3 is methyl.

[0010] One or more embodiments of the present application provide a compound of formula (III), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof as an active ingredient for use in combination with doxorubicin in treating tumors: (III) in, R 0 is H, C 1-6 alkyl or cyclopropyl, the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium; R1 is 、 、 、 、 、 、 、 、 、 、 、 Or pyridyl, and R 1 is optionally further substituted by 1 to 2 substituents selected from D, halogen, cyano, hydroxy, C 1-6 alkyl and C 1-6 alkoxy; R 1b is H, OH, cyano or C 1-6 alkyl substituted by hydroxy; R 2a and R 2b are each independently H, C 1-6 alkyl or 3 to 5-membered cycloalkyl, wherein the C 1-6 alkyl is optionally further substituted by one or more substituents selected from D or halogen; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from C 1-6 alkyl, OH and halogen; R 2c is H, cyano, halogen or C 1-6 alkoxy, wherein the C 1-6 alkoxy is optionally substituted by one or more deuteriums; R 3 is halogen or C 1-6 alkyl, the C 1-6 alkyl is optionally further substituted by 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2 or 3.

[0011] One or more embodiments of the present application provide a compound of formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof as an active ingredient for use in combination with doxorubicin in treating tumors: (IV) in: R 0 is H, C 1-6 alkyl or cyclopropyl, the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium; R1 is -(CH)m-4 to 7-membered carbocyclyl, -(CH)m-4 to 7-membered heterocyclyl, -(CH)m-8 to 12-membered bridged ring, or -(CH)m-7 to 12-membered spirocyclic ring, and the -(CH)m-4 to 7-membered carbocyclyl, -(CH)m-4 to 7-membered heterocyclyl, -(CH)m-8 to 12-membered bridged ring, or -(CH)m-7 to 12-membered spirocyclic ring is optionally further substituted by one or more substituents selected from hydroxyl, cyano, halogen, =0, C1-6 alkyl, C1-6 alkoxy, and C1-6 alkyl substituted by hydroxyl.

[0012] In one or more embodiments of the present application, wherein: R 0 is H, C 1-6 alkyl or cyclopropyl, the C 1-6 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium; R1 is 、 、 、 、 、 、 、 、 、 、 、 Or pyridyl, and R 1 is optionally further substituted by 1 to 2 substituents selected from D, halogen, cyano, hydroxy, C 1-6 alkyl and C 1-6 alkoxy; R 1a is H or C 1-6 alkyl; R 1b is H, OH, cyano or C 1-6 alkyl substituted by hydroxy; m is 0 or 1; x and y are each independently 1, 2 or 3.

[0013] In one or more embodiments of the present application, wherein: R 0 is C 1-4 alkyl, said C 1-4 alkyl is optionally further substituted by one or more substituents selected from halogen and deuterium; R1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0014] In one or more embodiments of the present application, the active ingredient is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

[0015] In one or more embodiments of the present application, the active ingredient has a significant synergistic therapeutic effect when used in combination with doxorubicin.

[0016] In one or more embodiments of the present application, the tumor is selected from solid tumors.

[0017] In one or more embodiments of the present application, the daily dose of the active ingredient is 25 mg to 500 mg, preferably 50 mg to 400 mg, more preferably 100 mg to 300 mg, and the dosage of doxorubicin or a pharmaceutically acceptable salt thereof is 0.02 mg / kg to 10 mg / kg.

[0018] In one or more embodiments of the present application, the dosage of doxorubicin or a pharmaceutically acceptable salt thereof does not exceed 50 mg / m2 of the subject's body surface area. Simple diagram

[0019] Figure 1 shows compound A; Figure 2 is a graph showing the tumor volume trend in the H1299 mouse tumor-bearing model; Figure 3 is a trend chart of the weight change rate of nude mice bearing H1299 tumor model. Implementation Method

[0020] DETAILED DESCRIPTION

[0021] The following describes in detail the implementation process of the present invention and the beneficial effects produced through specific examples, which is intended to help readers better understand the essence and characteristics of the present invention and is not intended to limit the scope of implementation of this case.

[0022] The present invention is described in further detail below in conjunction with the accompanying drawings:

[0023] Compound A in the embodiment is shown in Figure 1, which is compound 62 of WO2021209055. Compound A was prepared according to the preparation method described in the patent.

[0024] [H1299] [Drug efficacy test in mouse tumor-bearing model]

[0025] [1] [、Experimental steps:]

[0026] 1.1 Cell culture

[0027] Human lung cancer H1299 cells were purchased from ATCC. H1299 cells were cultured adherently in 15 cm culture dishes in DMEM supplemented with 10% fetal bovine serum, penicillin, and streptomycin at 37°C in an incubator containing 5% CO₂. When the cells reached the exponential growth phase, they were dissociated with trypsin, harvested, counted, and plated.

[0028] 1.2 Grouping and Dosing

[0029] After BALB / c-nude mice were acclimated to the laboratory environment, H1299 cell suspension was inoculated subcutaneously in the right flank of the nude mice at a dose of 7.6×10⁶ cells / mouse in a 0.2 mL inoculation volume (pre-inoculated with BD Matrigel, mixed with the cell suspension at a 1:1 ratio). Prior to tumor cell inoculation, the nude mice were immobilized, the skin on the right buttocks was wiped with 75% alcohol, and 5×10⁶ cells / mouse (100 μL cell suspension + 100 μL Matrigel) were injected subcutaneously. The needle was withdrawn with gentle rotation to prevent cell spillage. When tumors grew to approximately 120 mm³, 24 animals were screened for enrollment. The animals were then divided into three groups of 8 mice each using a S-shaped grouping method based on tumor size. Grouping was designated experimental day 1 (PG-D1), and drug administration began on day 1. The grouping and dosing schedule is detailed in Table 1.

[0030] Table 1 Dosage regimen Group number Group Dosage animal quantity 1 Blank (vehicle) - 8 2 Liposomal doxorubicin 5 mg / kg IV every 4 weeks 8 3 Compound A + doxorubicin liposomes Compound A: 20 mg / kg, BID, ig+ Doxorubicin: 5 mg / kg, QW, IV 8 Note: ig refers to oral administration; iv refers to tail vein administration; BID: twice daily; QW: once weekly. The vehicle was a 30% w / v aqueous solution of 2-hydroxypropyl-β-cyclodextrin. This vehicle was also used as a solvent for Compound A.

[0031] [2] [, Measurement method]

[0032] 2.1 Tumor volume: During the drug treatment cycle, the long diameter (a) and short diameter (b) of the tumor tissue were measured twice a week with a vernier caliper, and the tumor volume was calculated (tumor volume = 0.5 × a × b²).

[0033] 2.2 Mouse body weight: During the drug treatment period, weigh the mice at least twice a week.

[0034] [3] Data Analysis

[0035] All data were statistically analyzed using SPSS 16.0 software, and data were compared using one-way analysis of variance (ANOVA). P < 0.05 was considered to indicate a statistically significant difference.

[0036] [4] Experimental results

[0037] 4.1 Tumor volume results

[0038] Table 2-1. Average tumor volume statistics of tumor-bearing nude mice (mm 3) Group PG-D0 PG-D4 PG-D8 PG-D11 PG-D15 Blank (vehicle) 124±12 244±35 585±70 889±82 1443±139 Liposomal doxorubicin 124±12 230±34 474±54 677±67 850±105 Compound A + doxorubicin liposomes 123±11 221±18 251±21*** # 281±29*** ## 262±36** ##

[0039] Table 2-2. Average tumor volume statistics of tumor-bearing nude mice (mm3) Group PG-D18 PG-D22 PG-D25 PG-D29 Blank (vehicle) 1924±172 2802±250 3525±303 4573±286 Liposomal doxorubicin 1022±174* 1177±234** 1294±297** 1421±361*** Compound A + doxorubicin liposomes 253±50*** ## 207±61*** ## 161±54*** # 142±54*** ## Note: PG-D1 is the first administration time; P values ​​refer to the comparison with Vehicle: *P < 0.05, **P < 0.01, ***P < 0.001; P values ​​refer to the comparison between Compound A + liposome doxorubicin and liposome doxorubicin: #P < 0.05, ##P < 0.01.

[0040] As shown in Table 2-1, Table 2-2 and Figure 2, at the end of dosing (PG-D29), the tumor volume of the compound A and doxorubicin liposome combination group was significantly lower than that of the blank and doxorubicin liposome groups (P<0.01), indicating that compound A can significantly enhance the anti-tumor effect of doxorubicin liposomes.

[0041] 4.2 Weight results

[0042] Table 3-1. Body weight of tumor-bearing nude mice (g) Group PG-D0 PG-D4 PG-D8 PG-D11 PG-D15 Blank (vehicle) 18.16±0.16 18.41±0.24 18.40±0.32 19.70±0.34 20.50±0.41 Liposomal doxorubicin 18.63±0.38 18.36±0.35 18.33±0.47 18.83±0.53 19.35±0.58 Compound A + doxorubicin liposomes 18.58±0.29 18.19±0.32 17.24±0.24 17.18±0.37 17.38±0.45

[0043] Table 3-2. Body weight of tumor-bearing nude mice (g) Group PG-D18 PG-D22 PG-D25 PG-D29 Blank (vehicle) 21.30±0.44 22.13±0.45 22.36±0.61 23.06±0.38 Liposomal doxorubicin 19.54±0.51 19.95±0.53 20.40±0.58 20.98±0.50 Compound A + doxorubicin liposomes 17.25±0.38 17.10±0.49 16.74±0.49 17.24±0.44

[0044] As shown in Table 3-1, Table 3-2, and Figure 3, by the end of dosing (PG-D29), the body weight of the compound A and doxorubicin liposome group was only slightly lower than their initial body weight, and the overall tolerance was good.

[0045] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is illustrative and cannot be understood as limiting the present invention. Those skilled in the art will recognize that, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the patent application of the present invention.

[0046] none

[0047] none

Claims

1. Use of a compound A, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient for the preparation of an antitumor drug for use in combination with doxorubicin, wherein the tumor is a solid tumor of lung cancer, (compound A).

2. As claimed in claim 1, wherein the daily dose of the active ingredient is from 25 mg to 500 mg, and the dose of doxorubicin or a pharmaceutically acceptable salt thereof is from 0.02 mg / kg to 10 mg / kg.

3. As claimed in claim 2, wherein the daily dose of the active ingredient is from 50 mg to 400 mg.

4. As claimed in claim 2, wherein the daily dose of the active ingredient is 100 mg to 300 mg.

5. As claimed in claim 2, wherein the dose of doxorubicin or a pharmaceutically acceptable salt thereof administered does not exceed 50 mg / m² of the body surface area of ​​the subject.

6. As claimed in claim 1, wherein the daily dose of the active ingredient is from 25 mg to 500 mg.

7. As claimed in claim 1, wherein the dose of doxorubicin or a pharmaceutically acceptable salt thereof is 0.02 mg / kg to 10 mg / kg.

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