Irrepairzepine and its derivatives, methods for synthesizing said compounds, as Anti-malignant glioblastoma agents

Abstract

The present invention relates to a compound of the formula (I) wherein the substituents R1, R2, R3 and R4 are as defined in the disclosure of this invention. Said compounds are for treating brain cancer, wherein brain cancer is glioblastoma and such glioblastoma is Phosphatase and Tensin Homolog deleted on Chromosome 10 or PTEN.

Description

[0001] IRREPAIRZEPINE AND ITS DERIVATIVES, THE METHODS FOR SYNTHESIZING SAID COMPOUNDS, AS AN ANTI-MALIGNANT GLIOBLASTOMA AGENT

[0002] FIELD OF INVENTION

[0003] This invention relates to irrepairzepine and its derivatives, the method for synthesizing said compounds, as an anti -malignant glioblastoma agent.

[0004] BACKGROUND ART

[0005] Neoplasms in the central nervous system (CNS) arise from various types of cancer cells accounting for about 2% of all cancer cases worldwide. Most CNS malignancies occur in the brain, by 75% of them arising from glial cells or gliomas. Glioblastoma multiforme (GBM), a highly aggressive brain cancer accounting for more than 50% of all gliomas, is linked to Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) gene mutations and dysregulation of its related signaling pathways. Despite advancements in cancer treatment, GBM poses persistent challenges as the survival rate for GBM patients has been extremely low. The current standard treatment procedure, e.g., surgery, radiotherapy, and the treatment with temozolomide (TMZ). Although TMZ has resulted in an improved overall survival rate, the majority of patients still develop recurrence in less than a year after treatment due to GBM resistance evolution against TMZ. Therefore, novel chemotherapeutic agents that are more effective than the standard of treatment TMZ are urgently needed.

[0006] In 2020, irrepairzepine was isolated from the endophytic fungus Ceratorhiza hydrophila cultured from the medicinal plant Pista stratiotes. This compound has the potential to be further developed to more effective treatments for GBM. Intriguingly, irrepairzepine demonstrated a strong anti-GBM activity by inducing synthetic lethality in PTEN-deficient malignant glioblastoma cells by inhibiting double fractures repair, which is the pathway that specifically targets cancer cells, particularly GBM. At this position, irrepairzepine is a potential anticancer agent for treating PTEN-deficient GBM. Irrepairzepine exhibits efficiency in killing PTEN- deficient glioma cells and sensitizes these cells to DNA damage induced by ionizing radiation. The inventors found that structurally diverse irrepairzepine derivatives, e.g., with different functional groups show more potent anti-GBM efficacy or result than that of TMZ. SUMMARY OF THE INVENTION

[0007] The present invention relates to a compound of the formula (I) wherein the substituents R1, R2, R3and R4are as defined in the disclosure of this invention.

[0008] Said compounds are for treating brain cancer, wherein brain cancer is glioblastoma and such glioblastoma is Phosphatase and Tensin Homolog deleted on Chromosome 10 or PTEN.

[0009] DETAILED DESCRIPTION

[0010] The present invention relates to a compound of the formula (I) wherein:

[0011] R1, R2, R3and R4may be identical or different and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl, aryl group and C1-C6 alkyl group.

[0012] Said compound can be compounds having the following structures:

[0013]

[0014] Moreover, the present invention relates to pharmaceutical compositions comprising the above-mentioned compound and pharmaceutically acceptable carriers.

[0015] The present invention also relates to formulations which comprise as an active ingredient said pharmaceutical compositions, wherein optionally said formulations are in the form of tablets, granules, capsules, injections, sprays, patches, powders, or contain in any one of devices such as rollers etc. or are optionally used in foods, cosmetics, dietary supplements or pharmaceutical products.

[0016] In addition, this invention relates to a method for synthesizing compounds of formula (I) as stated above, which comprises the following steps: i) Reducing and brominating the benzaldehyde derivative to form a benzyl halide derivative; ii) Performing nucleophilic substitution on the benzyl halide derivative of step i) to obtain a benzyl azide derivative; iii) Reacting to the benzyl azide derivative of step ii) with an appropriate reagent to form a dihydroquinoline intermediate; iv) Deprotecting and oxidizing the intermediate of step iii) to obtain a quinoline derivative; v) Reducing the quinoline derivative of step iv) to form an aniline intermediate; vi) Performing lactamization of the aniline intermediate of step v) under acidic or basic conditions to obtain the compound of structure (I).

[0017] The present invention further relates to irrepairzepine derivatives obtained from the above method, wherein said irrepairzepine derivatives have an anti-brain cancer activity, optionally brain cancer is glioblastoma.

[0018] Furthermore, at least one of said irrepairzepine derivatives has an IC50 value of less than 10 pM as compared with U-251 glioblastoma cells or at least one of said irrepairzepine derivatives has structure: which has an anti -cancer activity.

[0019] This invention also relates to a method of treating brain cancer comprising administering to a patient in need thereof a therapeutically effective amount of the above compounds of formula (I), pharmaceutical compositions, formulations, or irrepairzepine derivatives, wherein brain cancer is glioblastoma, wherein glioblastoma is PTEN-deficient (Phosphatase and Tensin Homolog deleted on Chromosome 10, PTEN), wherein the above compounds of formula (I), pharmaceutical compositions, formulations, or irrepairzepine derivatives are administered in combination with ionizing radiation.

[0020] Additionally, the present invention relates to the use of the above compounds of formula (I), pharmaceutical compositions, formulations, or irrepairzepine derivatives for the manufacture of a medicament for treating brain cancer patients, wherein brain cancer is glioblastoma, wherein glioblastoma is PTEN-deficient, wherein the use of the above compounds of formula (I), pharmaceutical compositions, formulations, or irrepairzepine derivatives are used in combination with ionizing radiation. Synthesis of Irrepairzepine derivatives

[0021] Irrepairzepine derivatives were synthesized using the chemical reaction of azide compound, as illustrated in Scheme 1. The process commenced with the preparation of benzyl azides 3, derived from benzaldehyde derivatives 1. The aldehyde group of compound 1 was subjected to reduction and bromination to give benzyl bromide, followed by substitutions by sodium azide which is nuclophile to provide the corresponding product 3. The construction of the quinoline core structure 5 was then accomplished by the reaction of a mixture of compounds 3 and 4 in the presence of TfOH. This process yielded the crude product of dihydroquinoline, with subsequent deprotection of the benzyl group from the phenolic moiety.

[0022] Subsequently, the crude product was further oxidized using molecular iodine, to provide quinoline 5 as a corresponding product. Following that, the nitro group of compound 5 was subjected to reduction using Pd / C and H2, resulting in the formation of aniline intermediates 6. This intermediate was used without further purification for the subsequent lactamization reaction. The lactamization reaction was performed under two different conditions, i.e., acidic and basic conditions. Under acidic conditions, acidic MsOH was used, the reaction yielded irrepairzepine products. In addition, when the reaction was carried out under basic conditions using K2CO3 in MeCN, the irrepairzepine products were also obtained.

[0023] Scheme 1 The total synthesis of irrepairzepine

[0024] Furthermore, the inventors expanded their study by creating irrepairzepine derivatives using their established protocol (Scheme 1). The derivatives of compounds 4 and 3 played a crucial role as key precursors in this formation. The formation of quinoline derivatives was initiated by reacting compound 4 with various substituents of compound 3 under optimal conditions to form quinoline derivatives.

[0025] In this series, eight quinoline core structures were successfully synthesized, as detailed in Table 1. Especially, the reaction between compounds 4a and 3a yielded the corresponding product 5a in only 25% yield (entry 1). The reduced ability of benzyl azide to rearrangement due to the presence of a strong electron-withdrawing group (methyl ester) resulted in low product yield. Specifically, when using compound 3b containing an electronically neutral group, the reaction produced the desired product 5b in a 25% yield (entry 2).

[0026] The use of precersurs as substrates 3c and 3d (entries 3 and 4) containing a fluorine substituent at different positions also yielded the corresponding product in comparable yields. Moreover, the further introduction of electron-donating groups on the aromatic ring in the substrates 3e, 3f, and 3g (entries 5, 6, and 7) did not improve the yields of the corresponding products.

[0027] Similarly, substrate 3h, containing a chlorine substituent, showed no improvement in yield (entry 8). These results indicate that the electronic effect on ort / zo-nitrophenyl acetylene had minimal impact on the yields of the desired products. Furthermore, the phenylacetylene derivative containing an ortho-nitro group exhibited limited reactivity, resulting in a low yield of product formation.

[0028] Additionally, the inventors also synthesized compound 4b, which lacked an ortho- substituent of the ester group, aiming to create irrepairzepine without the ort / zo-hydroxyl group. Unfortunately, when compound 4b was reacted with compound 3g, only 9% of the desired product 5i was obtained. In contrast, the reactions of compound 4b with compounds 3h and 3a produced the corresponding products in 28% and 23% yield, respectively. Table 1. The synthesis of quinoline substrates 5.

[0029] Additionally, derivatives of compound 5 underwent hydrogenation, followed by lactamization reaction to produce irrepairzepine derivatives. The reaction of compound 5a converted to irrepairzepine 7a in a good yield (63%) while a compound having a methyl substituent, 5b, provided the desired product in a slightly lower yield (52%).

[0030] Next, irrepairzepine derivatives containing a fluorine substituent were prepared. When quinoline with R1= F (5c) was used, the corresponding product 7c was obtained in a 64% yield which is higher than the substrate 5d containing R2= F (40% yield of 7d). This suggests that substrate comprising para-fluoroaniline could facilitate lactamization due to the resonance effect of para-fluoroaniline, while meta-fluoroaniline reduced the nucleophilicity of aniline in the lactamization step, leading to the formation of the product in a lower yield.

[0031] Indeed, it is noted that the substrate containing an ortho-methoxy group on nitrobenzene 5e converted to the corresponding product 7e with a good yield of 56%. On the other hand, the substracte containing a methoxy group at the para position of the nitro group, 5f, yielded the desired product 7f with a comparatively lower yield of 47%.

[0032] For substrate 5h which contains meto-methoxynitrobenzene and meto-chloronitrobenzene moi eties, the lactamization product 7h was obtained in only 13% yield in both cases.

[0033] Furthermore, the inventors also synthesized irrepairzepine derivatives that do not contain the ortho-hydroxyl group, specifically compounds 7i, 7j, and 7k.

[0034] The results showed that the lactamization reaction proceeded more smoothly to obtain the corresponding products yield in the range of 37-53%. In addition, methylation of hydroxyl group and N-amide was conducted to give compounds 71 and 7m in 48% and 70% yields, respectively. The products of hydrogenation reaction, followed by lactamination reaction, of the substrate 5 to the product 7 are summarized in Figure 1.

[0035] Anticancer activities assay of irrepairzepine and its derivatives in human malignant glioblastoma U-251 cells

[0036] A previous report by Crawford et al. demonstrated that irrepairzepine induced lethality in glioblastoma multiform (GBM) U-251 cells with PTEN deficiency, which is a common characteristic in malignant cancers including GBM.

[0037] In the present study, the same GBM in vitro model as that of the study of Crawford et al. has been used, the inventors synthesized irrepairzepine and its 12 derivatives with diverse structures for anti -GBM activity assay. The potencies of the test compounds were compared to those of the first chemotherapy agent (Temozolomide (TMZ)) which is clinically used to treat brain cancer and GBM. As shown in Figure 1 and Table 2, irrepairzepine (7a) stimulated moderate anti-cancer activity (24 hr, IC50 = 29.4 pM; 48 hr, IC50 = 28.8 pM) as compared with other irrepairzepine derivatives.

[0038] Surprisingly, two irrepairzepine derivatives 7c and 7g showed the most prominent anticancer activity against GBM U-251 cells with the 24 hr. IC50; and 48 hr. IC50 values of 8.64 pM, 6.5 pM; and 10.1 pM, 6.9 pM, respectively.

[0039] Irrepairzepine (7a) was about 4.1 to 4.4 folds less effective in inducing GBM U-251 cytotoxicity than its analogs 7c and 7g.

[0040] It is noted that TMZ had an exceptionally high 24 hr. IC50 and 48 hr. IC50 values of 278.1 pM and 80 pM, respectively, indicating that TMZ had low anti-cancer activity against GBM U- 251 cells.

[0041] When comparing the 48 hr. IC50 value of 7c and 7g with TMZ, the efficiency of 7c and 7g in suppressing GBM cell viability was much superior to that of TMZ by 12.3 and 11.6 folds, respectively, indicating the efficacy for use irrepairzepine derivatives as anti-cancer and anti- GBM therapeutic agents (Table 2).

[0042] Table 2. The 50% relative cytotoxic concentration (RIC50) of irrepairzepine and its derivatives treated for 24 and 48 hr in the U-251 malignant glioblastoma cell line.

[0043] In basic conditions: Methyl 6-hydroxy-4-(2-nitrophenyl)quinoline-5-carboxylate (5a) (96.1 mg, 1.0 equiv, 0.2963 mmol) was dissolved in 5 mL of EtOAc. In a round-bottom flask, the solution was added 10 mol% Pd / C, followed by surrounding with hydrogen for 2 hr at room temperature. After completion, the reaction mixture was filtered with celite. The filtrate was concentrated under reduced pressure to obtain methyl 4-(2-aminophenyl)-6-hydroxyquinoline-5- carboxylate. The aminoquinoline derivative was then dissolved in 5 mL of MeCN and added K2CO3(81.9 mg, 2.0 equiv, 0.5926 mmol) and stirred at 100 °C for 2 hr. After completion, the reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (1% MeOH / DCM) to obtain 6-hydroxybenzo[6,7]azepino[5,4,3-de ]quinolin-7(8H)-one (7a) in 18.1 mg (23% yield).

[0044] In acidic conditions: Methyl 6-hydroxy-4-(2-nitrophenyl)quinoline-5-carboxylate (5a) (44.8 mg, 1.0 equiv, 0.1382 mmol) was dissolved in 5 mL of EtOAc. In round-bottom flask, the solution was added 10 mol% Pd / C, followed by surrounding with hydrogen for 2 hr at room temperature. After completion, the reaction mixture was filtered with celite. The filtrate was concentrated under reduced pressure to obtain methyl 4-(2-aminophenyl)-6-hydroxyquinoline-5- carboxylate. The aminoquinoline derivative was then dissolved in 5 mL of MeCN and added MsOH (18 pL, 2.0 equiv, 0.2764 mmol) and stirred at 100 °C for 2 h. After completion, the reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (1% MeOH / DCM) to obtain 6-hydroxybenzo[6,7]azepino[5,4,3-6fe]quinolin-7(8J7)-one (7a) in 22.8 mg (63% yield) as a pale brown amorphous solid; mp 266.0-268.2 °C; Rf= 0.3 (80% EtOAc / Hexane); IR (neat) vmax:: 3195, 2919, 1651, 1408, 755 cm'1;1H NMR (300 MHz, DMSO- d6) 5 14.50 (br s, 1H), 10.49 (br s, 1H), 8.73 (d, 1H, J= 4.7 Hz), 8.10 (d, 1H, J= 9.2 Hz), 7.66 (d, 1H, J= 4.7 Hz), 7.48-7.41 (m, 3H), 7.33-7.22 (m, 2H);13C{1H} NMR (75 MHz, DMSO-d6) 5 175.7, 166.2, 148.4, 143.4, 142.1, 137.9, 137.7, 132.6, 131.2, 128.8, 128.0, 126.2, 124.3, 122.9, 121.3, 106.4; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C16H11O2N2 263.0815; found 263.0815.

[0045] 6-hydroxy-10-methylbenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7b). Yield 47.9 mg (52%, pale brown amorphous solid); mp 151.3-153.1 °C; Rf= 0.6 (80% EtOAc / Hexane); IR (neat) vmax: 3213, 2920, 2850, 1654, 1263, 822 cm'1;1H NMR (300 MHz, DMSO-d6) δ 14.53 (br s, 1H), 10.40 (br s, 1H), 8.70 (d, 1H, J= 4.7 Hz), 8.08 (d, 1H, J= 9.2 Hz), 7.61 (d, 1H, J= 4.7 Hz), 7.40 (d, 1H, .7= 9.2 Hz), 7.31 (d, 1H, J = 7.9 Hz), 7.11-7.04 (m, 2H), 2.31 (s, 3H);13C{1H} NMR (75 MHz, CDCL) δ 175.6, 166.2, 148.4, 143.4, 142.1, 141.2, 137.9, 137.4, 132.6, 128.7, 127.2, 125.2, 124.2, 122.5, 121.5, 106.4, 21.1; HRMS (ESI-Orbitrap) m / z: [M + H]+cal cd for C17H13O2N2277.0972; found 277.0972.

[0046] 11-fhioro-6-hydroxybenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7c). Yield 52.3 mg (64%, pale brown amorphous solid); mp 217.4-218.7 °C; Rf= 0.4 (80% EtOAc / Hexane); IR (neat) vmax; 3206, 2926, 1657, 1508, 1282, 831 cm'1;1H NMR (300 MHz, DMSO-d6) δ 10.49 (br s, 1H), 8.73 (d, 1H, J= 4.7 Hz), 8.09 (d, 1H, J= 9.3 Hz), 7.70 (d, 1H, J = 4.7), 7.42 (d, 1H, J= 92 Hz), 7.36-7.27 (m, 3H);13C{1H} NMR (75 MHz, DMSO-d6) δ 175.5, 166.4, 160.2 (d, JCF = 240 Hz),

[0047] 148.4, 143.4, 140.7 (d, JCF = 2 Hz), 137.9, 134.2 (d, JCF = 2 Hz), 130.0 (d, JCF = 8 Hz), 128.6,

[0048] 124.4, 123.3 (d, JCF = 8 Hz), 123.2, 118.4 (d, JcF= 19 Hz), 118.1 (d, JcF= 17 Hz), 106.4;19F NMR (282 MHz, DMSO-d6) δ -118.5 (S); HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C16H10O2N2F 281.0721; found 281.0724.

[0049] 10-fhioro-6-hydroxybenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7d). Yield 29.5 mg (40%, pale brown amorphous solid); mp 272.6-273.7 °C; Rf= 0.4 (80% EtOAc / Hexane); IR (neat) vmax: 3200, 2920, 2850, 1615, 1252 cm'1;1H NMR (300 MHz, DMSO-d6) δ 14.35 (br s, 1H), 14.35 (br s, 1H), 10.54 (br s, 1H), 8.72 (d, 1H, J = 4.7 Hz), 8.11 (d, 1H, J = 9.2 Hz), 7.63 (d, 1H, J= 4.7 Hz), 7.52-7.45 (m, 1H), 7.43 (d, 1H, J= 9.3 Hz), 7.16-7.08 (m, 2H);13C{1H} NMR (75 MHz, DMSO-d6) δ 175.5, 166.3, 163.7 (d, JCF = 246 Hz), 148.3, 143.4, 141.1, 139.5 (d, JcF= 11 Hz), 138.1, 135.0 (d, JcF= 10 Hz), 128.4, 124.5 (d, JCF = 3 Hz), 124.3, 122.9, 113.1 (d, JCF = 21 Hz), 107.7 (d, JCF = 25 Hz), 106.2;19F NMR (282 MHz, DMSO-d6) δ -111.8 (S); HRMS (ESI- Orbitrap) m / z: [M + H]+calcd for C16H10O2N2F 281.0721; found 281.0719.

[0050] 6-hydroxy-9-methoxybenzo[6, 7]azepino [5,4, 3-de] quinolin-7(8H)-one (7e). Yield 46.6 mg (56%, pale brown amorphous solid); mp 219.6-221.4 °C; Rf= 0.4 (50% EtOAc / Hexane); IR (neat) vmax: 3356, 2961, 1640, 1511, 1265 cm'1;1H NMR (300 MHz, CDCh) δ 14.35 (br s, 1H), 8.71 (d, 1H, J= 4.7 Hz), 8.14-8.08 (m, 2H), 7.48 (d, 1H, J= 4.7), 7.39 (d, 1H, J= 9.3 Hz), 7.16 (t, 1H, J = 8.1 Hz), 6.98-6.92 (m, 2H), 3.98 (s, 3H);13C{ 1H} NMR (75 MHz, CDCh) δ 176.0, 167.0, 148.3,

[0051] 147.4, 143.5, 142.3, 137.9, 128.8, 128.5, 126.6, 125.4, 124.1, 123.4, 122.4, 111.1, 105.9, 56.3; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C17H13O3N2 293.0921; found 293.0920.

[0052] 6-hydroxy-l 1 -methoxybenzo [6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7f). Yield 44.9 mg (47%, pale brown amorphous solid); mp 272.6-273.7 °C; Rf= 0.4 (80% EtOAc / Hexane); IR (neat) vmax: 3195, 2851, 1650, 1505, 1295, 821 cm'1;1HNMR (300 MHz, DMSO-d6) δ 14.54 (br s, 1H), 10.39 (br s, 1H), 8.73 (d, 1H, J= 4.7 Hz), 8.09 (d, 1H, J= 9.2 Hz), 7.74 (d, 1H, J= 4.7 Hz), 7.41 (d, 1H, J= 9.2 Hz), 7.23 (d, 1H, J= 8.8 Hz), 7.06 (dd, 1H, J= 8.8, 2.8 Hz), 6.92 (d, 1H, .7= 2.8 Hz), 3.79 (s, 3H);13C{1H} NMR (75 MHz, DMSO-d6) δ 175.4, 166.1, 157.5, 148.4, 143.4, 141.9, 137.7, 130.8, 129.2, 128.8, 124.2, 122.82, 122.75, 117.4, 116.3, 106.5, 56.0; HRMS (ESI-Orbitrap) m / z: [M + H]+cal cd for C17H13O3N2 293.0921; found 293.0918.

[0053] 6-hydroxy-10-methoxybenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7g). Yield 10.8 mg (13%, pale yellow amorphous solid); mp 195.4-195.6 °C; Rf= 0.2 (50% EtOAc / Hexane); IR (neat) vmax: 3202, 2922, 2851, 1730, 1654, 1444, 1258 cm'1;1H NMR (300 MHz, DMSO-d6) 5 14.53 (br s, 1H), 10.40 (br s, 1H), 8.68 (d, 1H, J= 4.7 Hz), 8.07 (d, 1H, J= 9.2 Hz), 7.58 (d, 1H, J= 4.7 Hz), 7.44-7.36 (m, 2H), 6.92-6.82 (m, 2H), 3.80 (s, 3H);13C{1H} NMR (75 MHz, DMSO-d6) δ 175.0, 165.7, 161.2, 147.9, 143.0, 141.6, 138.4, 137.6, 133.6, 127.9, 123.7, 121.7, 119.8, 111.9, 105.9, 105.7, 55.0; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C17H13O3N2 293.0921; found 293.0911.

[0054] 10-chloro-6-hydroxybenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7h). Yield 10.7 mg (13%, pale brown amorphous solid); mp 190.0-191.0 °C; Rf= 0.4 (50% EtOAc / Hexane); IR (neat) vmax: 3392, 3201, 2919, 2850, 1725, 1647, 1471 cm'1;1H NMR (300 MHz, DMSO-d6) δ 14.35 (br s, 1H), 10.50 (br s, 1H), 8.73 (d, 1H, J= 4.7 Hz), 8.10 (d, 1H, J= 9.2 Hz), 7.64 (d, 1H, J= 4.7 Hz), 7.44 (d, 1H, J= 8.6 Hz), 7.42 (d, 1H, J= 9.2 Hz), 7.36 (d, 1H, J= 2.1 Hz), 7.29 (dd, 1H, J= 8.5, 2.1 Hz);13C{ 1H} NMR (75 MHz, DMSO-d6) δ 175.2, 165.9, 148.1, 143.0, 140.6, 138.6, 137.7,

[0055] 135.2, 134.0, 128.0, 126.5, 125.5, 124.0, 122.6, 120.2, 105.9; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C16H10O2N2CI (Cl-35) 297.0425; found 297.0422.

[0056] 10-methoxybenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7i). Yield 12.9 mg (37%, pale yellow amorphous solid); mp 271.5-271.7 °C; Rf= 0.3 (50% EtOAc / Hexane); IR (neat) vmax: 2958, 2925, 2853, 1673, 1591, 1507 cm'1;1H NMR (400 MHz, CDCh) δ 8.92 (d, 1H, J = 4.7 Hz), 8.69 (dd, 1H, J= 7.4, 1.2 Hz), 8.32 (dd, 1H, J= 8.3, 1.3 Hz), 8.0 (br s, 1H), 7.82 (t, 1H, J= 7.8 Hz), 7.62 (d, 1H, J= 4.7 Hz), 7.45 (d, 1H, J= 8.9 Hz), 6.83 (dd, 1H, J= 8.8, 2.5 Hz), 6.57 (d, 1H, J= 2.5 Hz), 3.89 (s, 3H);13C{ 1H} NMR (100 MHz, CDCh) δ 168.3, 161.8, 150.1,

[0057] 148.2, 143.1, 137.2, 135.6, 133.8, 133.2, 128.4, 127.7, 127.4, 120.2, 120.1, 111.7, 105.2, 55.6; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C17H13O2N2 277.0972; found 277.0971. 10-chlorobenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7 / ). Yield 33.6 mg (41%, pale yellow amorphous solid); mp 266.0-267.2 °C; Rf= 0.3 (50% EtOAc / Hexane); IR (neat) vmax: 2956, 2923, 1741, 1595, 1464 cm'1;1H NMR (400 MHz, DMSO-d6) δ 10.71 (br s, 1H), 8.97 (d, 1H, J= 4.6 Hz), 8.54 (dd, 1H, J= 7.4, 1.4 Hz), 8.29 (dd, 1H, J= 8.2, 1.4 Hz), 7.95-7.85 (m, 2H), 7.61 (d, 1H, J= 8.6 Hz), 7.43 (d, 1H, J= 2.2 Hz), 7.31 (dd, 1H, J = 8.6, 2.2 Hz);13C{1H} NMR (100 MHz, DMSO-d6) δ 168.3, 151.8, 148.7, 142.6, 139.2, 136.6, 136.0, 135.4, 134.0, 130.1,

[0058] 129.6, 127.8, 127.0, 125.9, 122.7, 121.5; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C16H10ON2CI (Cl-35) 281.0476; found 281.0485. benzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7k). Yield 39.3 mg (53%, pale yellow amorphous solid); mp 160.0-161.0 °C; Rf= 0.3 (50% EtOAc / Hexane); IR (neat) vmax: 3189, 3112, 3056, 2984, 2925, 1591, 1515 cm'1;1HNMR (300 MHz, CDCh) δ 8.97 (d, 1H, , J = 4.6), 8.7 (dd, 1H, J= 7.4, 1.4 Hz), 8.34 (dd, 1H, J= 8.3, 1.3 Hz), 8.04 (br s,lH), 7.84 (t, 1H, J= 7.7 Hz), 7.7 (d, 1H, J= 4.7 Hz), 7.54-7.41 (m, 2H), 7.29 (d, 1H, J= 1.2 Hz), 7.08 (d, 1H, J= 7.9 Hz);13C{ 1H} NMR (75 MHz, CDCh) δ 168.4, 150.1, 148.1, 143.1, 136.0, 135.5, 133.4, 132.4,

[0059] 130.9, 128.6, 127.8, 127.7, 127.5, 125.4, 121.0, 120.6; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C16H11ON2 247.0866; found 247.0864.

[0060] 6-methoxy-8-methylbenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (71). Yield 9.90 mg (48%, green amorphous solid); mp 159.1-159.5 °C; Rf= 0.1 (50% EtOAc / Hexane); IR (neat) vmax: 2955, 2923, 2853, 1749, 1464 cm'1;1H NMR (300 MHz, CDCh) δ 8.84 (d, 1H, J= 4.5 Hz), 8.12 (d, 1H, J= 9.3 Hz), 7.63-7.36 (m, 4H, J= 4.7 Hz), 7.25 (d, 1H, J= 6.9 Hz), 7.17 (dd, 1H, J=

[0061] 7.9, 1.4 Hz), 4.10 (s, 3H), 3.59 (s, 3H);13C{ 1H} NMR (75 MHz, CDCh) δ 166.7, 163.3, 148.3, 142.3, 142.1, 141.1, 134.3, 133.8, 132.3, 130.9, 129.8, 125.8, 123.5, 119.9, 119.5, 115.6, 58.6, 38.2; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C18H15O2N2291.1128; found 291.1133.

[0062] 8-methylbenzo[6, 7]azepino[5,4,3-de]quinolin-7(8H)-one (7m). Yield 8.3 mg (70%, pale yellow amorphous solid); mp 161-162 °C; Rf= 0.3 (50% EtOAc / Hexane); IR (neat) vmax: 3058, 3024, 2914, 2860, 1631, 1590 cm'1;1H NMR (300 MHz, CDCh) δ 8.97 (d, 1H, J= 4.6 Hz), 8.57 (dd, 1H, J= 7.3, 1.2 Hz), 8.24 (dd, 1H, J= 8.3, 1.2 Hz), 7.79 (dd, 1H, J= 8.2, 7.44 Hz), 7.66 (d, 1H, J= 4.6 Hz), 7.53-7.45 (m, 1H), 7.4 (d, 1H, J= 7.9 Hz), 7.32-7.23 (m, 2H), 3.58 (s, 3H);13C{ 1H} NMR (75 MHz, CDCh) δ 168.7, 150.0, 147.0, 143.5, 140.8, 134.0, 133.5, 132.6, 131.6, 130.1,

[0063] 129.7, 128.7, 128.5, 125.8, 122.2, 119.9, 38.8; HRMS (ESI-Orbitrap) m / z: [M + H]+calcd for C17H13ON2 261.1022; found 261.1015. BRIEF DESCRIPTION OF DRAWINGS

[0064] Figure 1 shows irrepairzepine derivatives 7 which is for anti-cancer activity testing in human malignant glioblastoma U-251 cells.

Claims

CLAIMS1. A compound of formula (I):Formula (I) whereinR1, R2, R3and R4may be identical or different and are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methoxyl, aryl group and Cl- C6 alkyl group.

2. The compound according to claim 1, wherein R1, R2, R3or R4is fluorine.

3. The compound according to claim 1, wherein R1, R2, R3or R4is chlorine.

4. The compound according to claim 1, wherein R1, R2, R3or R4is bromine.

5. The compound according to claim 1, wherein R1, R2, R3or R4is iodine.

6. The compound according to claim 1, wherein R1, R2, R3or R4is hydroxyl.

7. The compound according to claim 1, wherein R1, R2, R3or R4is methoxyl.

8. The compound according to claim 1, wherein R1, R2, R3or R4is aryl group.

9. The compound according to claim 1, wherein R1, R2, R3or R4is C1-C6 alkyl group.

10. The compound according to claim 1, which is a compound having a structure:

11. The compound according to claim 1, which is a compound having a structure:

12. The compound according to claim 1, which is a compound having a structure:

13. The compound according to claim 1, which is a compound having a structure:

14. The compound according to claim 1, which is a compound having a structure:

15. The compound according to claim 1, which is a compound having a structure:

16. The compound according to claim 1, which is a compound having a structure:

17. The compound according to claim 1, which is a compound having a structure:

18. The compound according to claim 1, which is a compound having a structure:

19. The compound according to claim 1, which is a compound having a structure:

20. The compound according to claim 1, which is a compound having a structure:

21. The compound according to claim 1, which is a compound having a structure:

22. The compound according to claim 1, which is a compound having a structure:

23. A pharmaceutical composition comprising the compound according to any one of claim 1 to 22 and a pharmaceutically acceptable carrier.

24. A formulation comprising the pharmaceutical composition according to claim 23 as an active ingredient.

25. The formulation according to claim 24, which is optionally selected to be in the form of tablets, granules, capsules, injections, sprays, patches, powders, or contained in any one of device e.g. roller.

26. The formulation according to claim 24, which is for use in foods, cosmetics, supplements, or medicaments.

27. A method for synthesizing the compound of formula (I) according to any one of claims 1 to 22, which comprises: i) Reducing and brominating the benzaldehyde derivative to form a benzyl halide derivative; ii) Performing nucleophilic substitution on the benzyl halide derivative of step i) to obtain a benzyl azide derivative; iii) Reacting the benzyl azide derivative of step ii) with an appropriate reagent to form a dihydroquinoline intermediate; iv) Deprotecting and oxidizing the intermediate of step iii) to obtain a quinoline derivative; v) Reducing the quinoline derivative of step iv) to form an aniline intermediate; vi) Performing lactamization of the aniline intermediate of step v) under acidic or basic conditions to obtain the compound of structure (I).

28. The method according to claim 27, wherein the lactamization of step vi) is performed under the acidic condition.

29. The method according to claim 27, wherein the lactamization of step vi) is performed under the basic condition.

30. The irrepairzepine derivatives obtained from the method according to any one of claims27 to 29.

31. The irrepairzepine derivatives according to claim 30, which has anti-brain cancer activity.

32. The irrepairzepine derivatives according to claim 30, wherein brain cancer is glioblastoma.

33. The irrepairzepine derivatives according to any one of claims 30 to 32, wherein at least one of irrepairzepine derivatives has an IC50 value of less than 10 pM as compared with U-251 glioblastoma cells.

34. The irrepairzepine derivatives according to any one of claims 30 to 33, wherein at least one of irrepairzepine derivatives has structure:which has anti -cancer activity.

35. A method for treating brain cancer, which comprises administration of a therapeutical effective amount of the compound according to any one of claims 1 to 22, the pharmaceutical composition according to claim 23, the formulation according to any one of claim 24 to 26, or the irrepairzepine derivatives according to any one of claims 30 to 34 to a patient in need thereof.

36. The method according to claim 35, wherein the brain cancer is glioblastoma.

37. The method according to claim 36, wherein the glioblastoma is PTEN-deficient (Phosphatase and Tensin Homolog deleted on Chromosome 10).

38. The method according to any one of claims 35 to 37, wherein the compound according to any one of claims 1 to 22, the pharmaceutical composition according to claim 23, the formulation according to any one of claim 24 to 26, or the irrepairzepine derivatives according to any one of claims 30 to 34 is administered in combination with ionizing radiation.

39. The use of the compound of any one of claims 1 to 22, the pharmaceutical composition according to claim 23, or the irrepairzepine derivatives according to any one of claims 30 to 34 for the manufacture of a medicament for the treatment of brain cancer patients.

40. The use according to claim 39, wherein brain cancer is glioblastoma.

41. The use according to claim 40, wherein the glioblastoma is PTEN-deficient.

42. The use according to any one of claims 39 to 41, which is used in combination with ionizing radiation.

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