CN109020890B - Preparation and application of saturated aliphatic cyclo-pyrazole derivatives - Google Patents
Preparation and application of saturated aliphatic cyclo-pyrazole derivatives Download PDFInfo
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Abstract
The invention discloses a preparation method of a novel tubulin inhibitor saturated fat cyclopyrazole derivative and application thereof in the aspect of tumor resistance. Has a structure shown in formula I:
wherein: n is selected from 1, 2 and 3; r1Selected from: -H, -OCH3；R2Selected from: -H, -Cl, -OCH3；R3Selected from: -H, -OCH3；R4Selected from: -H, -F, -OH, -CH3、‑OCH3；R5Selected from: -H, -F, -Cl, -Br, -I, -CH3、‑CF3、‑OCH3、‑COOH、‑NO2、‑OH；R6Selected from: -H, -OCH3。
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method, activity evaluation and anti-tumor application of saturated fat cyclopyrazole derivatives.
Background
Tumors are a common disease that seriously threatens human health, and malignant proliferation of cells is a main characteristic of the tumors. The search for efficient anti-tumor drugs and treatment methods to completely overcome cancer remains a worldwide problem. Chemotherapy is a common method of treating tumors, and chemotherapeutic drugs can be classified into two main groups according to different mechanisms of action: the first is a cell cycle nonspecific inhibition drug, which inhibits cells in different cell cycles, such as alkylating agent, hormone, etc.; the second type is cell cycle specific inhibiting medicine acting on cell in proliferation stage, and has tubulin and microtubule associated protein as its target, such as taxol, colchicine, vincristine, etc. as one of the hotter targets for tumor proliferation research.
Microtubules are the major components of the cytoskeleton, are composed of α -tubulin (α -tubulin) and β -tubulin (β -tubulin) heterodimers, and have various cellular functions of maintaining cell morphology, participating in cell division, signal transduction, and substance transport. By influencing and interfering the polymerization and depolymerization kinetics of the tubulin, the formation of M-phase spindle is blocked, and the aim of resisting cell malignant proliferation is fulfilled. The anti-microtubule drug is the main chemotherapy drug at present and is widely applied to the clinical treatment of various tumors. Clinically applied tubulin inhibitors can be divided into two main categories according to the action target: the first are microtubule stabilizing agents, such as paclitaxel; the second class is microtubule destabilizing agents such as colchicine, vincristine, CA-4, and the like. CA-4 is one of the most active compounds in the currently known tubulin inhibitors, has simple structure, high efficiency and low toxicity, but has poor water solubility, low bioavailability and poor structural stability, and can be easily isomerized into a trans-structure with no pharmacological activity and relative stability from a cis-stilbene active structure after administration. The maintenance of the cis configuration of two benzene rings in the CA-4 structure is the primary condition for maintaining the activity, so that researchers do a lot of work to modify the structure of the CA-4 structure, and the invention further modifies the structure of the CA-4 based on the basic skeleton of the CA-4 and the previous research.
Pyrazoles are important heterocyclic compounds and have various pharmacological activities, such as anti-inflammation, pain relief, bacteriostasis, hyperglycemia resistance, cancer resistance, anticoagulation, sedation, muscle relaxation, arrhythmia resistance, spasm resistance and the like. It can be used as an intermediate of certain medicines and pesticides, and plays an important role in research and development of medicines and pesticides. Pyrazole compounds are receiving more and more attention due to their broad spectrum of action and strong potency. In recent years, many novel pyrazole medicines are commercialized successively, and intensive research on pyrazole compounds has become one of the hot spots in the research of drug design and synthesis nowadays.
Therefore, the invention takes colchicine action site as a target spot, introduces a rigid structure of a saturated fat cyclopyrazole ring into a CA-4 structure, designs and synthesizes a series of saturated fat cyclopyrazole derivatives, and researches the application of the derivatives in the aspect of tumor resistance.
Disclosure of Invention
The invention aims to provide a saturated aliphatic cyclo-pyrazole derivative with microtubule inhibiting effect.
The second purpose of the invention is to provide a simple and efficient method for synthesizing the compound.
The third purpose of the invention is to provide the application of the compound in the aspect of tumor resistance.
The saturated fat cyclopyrazole derivative has a structure shown in a formula I:
wherein: n is selected from 1, 2 and 3; r1Selected from: -H, -OCH3；R2Selected from: -H, -Cl, -OCH3；R3Selected from: -H, -OCH3；R4Selected from: -H, -F, -OH, -CH3、-OCH3；R5Selected from: -H, -F, -Cl, -Br, -I, -CH3、-CF3、-OCH3、-COOH、-NO2、-OH；R6Selected from: -H, -OCH3。
The invention relates to a saturated fat cyclopyrazole derivative, which comprises the following steps:
step a: dissolving saturated aliphatic cyclic ketone (10mmol) in tetrahydrofuran (30mL) at room temperature, stirring, slowly dropwise adding 1M LiHMDS (10mL) solution, adding the solution within 30min, continuing stirring for 15min, adding mono-substituted or multi-substituted benzoyl chloride (20mmol), continuously stirring at room temperature for reacting overnight, after the TCL detection reaction is finished, carrying out vacuum spin drying on a reaction solvent, adding excessive saturated saline solution into a reaction bottle, extracting with ethyl acetate (3 × 100mL), collecting an organic layer, drying with anhydrous sodium sulfate, carrying out reduced pressure evaporation to obtain a crude product of a corresponding compound of a general formula (2a-k), and purifying by silica gel column chromatography (eluent petroleum ether: ethyl acetate is 10: 1) to obtain a pure product of the corresponding compound of the general formula (2 a-k).
Step b: mixing N, N-dimethylformamide and tetrahydrofuran in a volume ratio of 3: 1, taking a mixed solution as a reaction solvent, dissolving a compound corresponding to a general formula (2a-k) and mono-substituted or multi-substituted phenylhydrazine hydrochloride or sulfate in the solvent, reacting at 120 ℃ for 3h, after TCL detection reaction is finished, evaporating the tetrahydrofuran solution under reduced pressure, adding excess saturated saline solution into a reaction bottle, extracting with ethyl acetate (3x 30mL), collecting an organic layer, drying with anhydrous sodium sulfate, evaporating under reduced pressure to obtain a crude compound corresponding to the general formula (3a-x), and purifying by silica gel column chromatography (eluent petroleum ether and ethyl acetate are 4: 1) to obtain a pure compound corresponding to the general formula (3 a-x).
The saturated fat cyclopyrazole derivatives have an inhibiting effect on malignant proliferation of human cervical cancer cells (HeLa), human liver cancer cells (HepG2) and human lung cancer cells (A549), wherein the anti-tumor effect of the compound 3f is superior to that of Colchicine. The saturated aliphatic cyclo-pyrazole derivatives have the potential of being used as antitumor drugs.
Detailed Description
The first embodiment is as follows:
preparation of 3- (4-chlorophenyl) -2-phenyl-2, 4, 5, 6-tetrahydrocyclopenta [ c ] pyrazole (3a)
At room temperature, dissolving cyclopentanone (10mmol) in tetrahydrofuran (30mL), stirring, slowly dropwise adding a 1M LiHMDS (10mL) solution, adding the solution within 30min, continuing to stir for 15min, adding p-chlorobenzoyl chloride (20mmol), continuously stirring at room temperature for reacting overnight, after the detection reaction of TCL, carrying out vacuum spin-drying on a reaction solvent, adding excess saturated saline solution into a reaction bottle, extracting with ethyl acetate (3X 100mL), collecting an organic layer, drying with anhydrous sodium sulfate, carrying out reduced pressure evaporation to obtain a crude compound 2a, and purifying by silica gel column chromatography (eluent petroleum ether: ethyl acetate is 10: 1) to obtain a pure compound 2 a. Adding compound 2a (2mmol) and phenylhydrazine hydrochloride (6mmol) into a mixed solvent of N, N-Dimethylformamide (DMF) and Tetrahydrofuran (THF) in a volume ratio of 3: 1, reacting at 120 ℃ for 3h, after the reaction of TCL detection, evaporating the tetrahydrofuran solution under reduced pressure, adding excess saturated saline into a reaction bottle, extracting with ethyl acetate (3X 30mL), collecting an organic layer, drying with anhydrous sodium sulfate, evaporating under reduced pressure to obtain a crude compound 3a, and purifying by silica gel column chromatography (eluent petroleum ether: ethyl acetate is 4: 1) to obtain the compound 3 a. A yellow powder was obtained, yield: 40.1 percent and m.p.103.5-105 ℃.1H NMR(600MHz，DMSO-d6)δ7.42-7.38(m，4H)，7.34-7.31(m，1H)，7.24-7.22(m，2H)，7.19-7.16(m，2H)，2.74-2.71(m，4H)，2.45-2.40(m，2H).
Example two:
preparation of 2- (4-methoxyphenyl) -3- (3, 4, 5-trimethoxyphenyl) -2, 4, 5, 6-tetrahydrocyclopenta [ c ] pyrazole (3b)
The preparation method refers to the first embodiment. A dark yellow powder was obtained, yield: 46.0 percent and m.p.103.4-104.6 ℃.1H NMR(600MHz，DMSO-d6)δ7.20-7.18(m，2H)，6.99-6.96(m，2H)，6.40(s，2H)，3.77(s，3H)，3.64(s，3H)，3.57(s，6H)，2.78(t，J＝7.10Hz，2H)，2.70(t，J＝7.14Hz，2H)，2.44-2.40(m，2H).
Example three:
preparation of 3-phenyl-2- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-indole (3c)
The preparation method refers to the first embodiment. A dark yellow powder is obtained, yield 35.6%, m.p.135.3-136.9 ℃.1H NMR(600MHz，DMSO-d6)δ7.41-7.39(m，2H)，7.36-7.34(m，1H)，7.22(d，J＝1.38，1H)，7.21(s，1H)，6.44(s，1H)，3.63(s，3H)，3.53(s，6H)，2.67(t，J＝6.30Hz，2H)，2.49(s，1H)，1.83-1.79(m，2H)，1.73-1.70(m.2H).
Example four:
preparation of 2-phenyl-3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-indazole (3d)
The preparation method refers to the first embodiment. A yellow powder is obtained, yield 40%, m.p.169.2-170.4 ℃.1H NMR(600MHz，DMSO-d6)δ7.37(t，J＝7.56，2H)，7.29(t，J＝7.38，1H)，7.22(d，J＝1.14，1H)，7.21(s，1H)，6.41(s，2H)，3.66(s，3H)，3.57(s，6H)，2.66(t，J＝6.24Hz，2H)，2.59(t，J＝6.18Hz，2H)，1.83-1.80(m，2H)，1.75-1.72(m.2H).
Example five:
preparation of 3- (3, 4-dimethoxyphenyl) -2-phenyl-4, 5, 6, 7-tetrahydro-2H-indazole (3e)
The preparation method refers to the first embodiment. Get lightYellow powder, yield 40%, m.p.106.5-107.7 ℃.1H NMR(600MHz，DMSO-d6)δ7.37(t，J＝7.56，2H)，7.29(t，J＝7.38，1H)，7.22(d，J＝1.14，1H)，7.21(s，1H)，6.41(s，2H)，3.66(s，3H)，3.57(s，6H)，2.66(t，J＝6.24Hz，2H)，2.59(t，J＝6.18Hz，2H)，1.83-1.80(m，2H)，1.75-1.72(m.2H).
Example six:
preparation of 2- (4-methoxyphenyl) -3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-indazole (3f)
The preparation method refers to the first embodiment. A yellow powder is obtained, yield 42.9%, m.p.118.5-119.5 ℃.1H NMR(600MHz，DMSO-d6)δ7.16-7.13(m，2H)，6.94-6.91(m，2H)，6.41(s，2H)，3.75(s，3H)，3.65(s，3H)，3.59(s，6H)，2.64(t，J＝6.18Hz，2H)，2.58(t，J＝6.18Hz，2H)，1.83-1.79(m，2H)，1.74-1.71(m.2H).
Example seven:
preparation of 2- (4-chlorophenyl) -3- (3, 4, 5-trimethoxy) -4, 5, 6, 7-tetrahydro-2H-indazole (3g)
The preparation method refers to the first embodiment. A pale yellow powder is obtained, yield 33.3%, m.p.137.9-139.8 ℃.1H NMR(600MHz，DMSO-d6)δ7.43(d，J＝8.82，2H)，7.3(d，J＝8.82，2H)，6.44(s，2H)，3.67(s，3H)，3.61(s，6H)，2.66(t，J＝6.24Hz，2H)，2.57(t，J＝6.18Hz，2H)，1.83-1.79(m，2H)，1.74-1.71(m.2H).
Example eight:
preparation of 2- (4-fluorophenyl) -3- (3, 4, 5-trimethoxy) -4, 5, 6, 7-tetrahydro-2H-indazole (3H)
The preparation method refers to the first embodiment. White powder is obtained with a yield of 48.2%, m.p.143.6-145.0 ℃.1H NMR(600MHz，DMSO-d6)δ7.27-7.21(m，4H)，6.43(s，2H)，3.66(s，3H)，3.60(s，6H)，2.65(t，J＝6.24Hz，2H)，2.58(t，J＝6.18Hz，2H)，1.83-1.79(m，2H)，1.74-1.72(m.2H)..
Example nine:
preparation of 2- (4-bromophenyl) -3- (3, 4, 5-trimethoxy) -4, 5, 6, 7-tetrahydro-2H-indazole (3i)
The preparation method refers to the first embodiment. A yellow powder is obtained, yield 46.6%, m.p.126.1-126.8 ℃.1H NMR(600MHz，DMSO-d6)δ7.58-7.55(m，2H)，7.18-7.15(m，2H)，6.44(s，2H)，3.68(s，3H)，3.61(s，6H)，2.66(t，J＝6.24Hz，2H)，2.56(t，J＝6.18Hz，2H)，1.83-1.79(m，2H)，1.74-1.71(m.2H).
Example ten:
preparation of 2- (p-tolyl) -3- (3, 4, 5-trimethoxy) -4, 5, 6, 7-tetrahydro-2H-indazole (3j)
The preparation method refers to the first embodiment. White powder is obtained with a yield of 49.0%, m.p.102.4-104.1 ℃.1H NMR(600MHz，DMSO-d6)δ7.17(d，J＝8.16，2H)，7.09(d，J＝8.34，2H)，6.41(s，2H)，3.66(s，3H)，3.58(s，6H)，2.65(t，J＝6.24Hz，2H)，2.57(t，J＝6.12Hz，2H)，2.30(s，3H)，1.83-1.79(m，2H)，1.74-1.71(m.2H).
Example eleven:
preparation of 2- (4-trifluoromethylphenyl) -3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3k)
The preparation method refers to the first embodiment. White powder was obtained, yield 46.2%, m.p.106.7-108.5 ℃.1H NMR(600MHz，DMSO-d6)δ7.74(d，J＝8.52，2H)，7.42(d，J＝8.40，2H)，6.47(s，2H)，3.68(s，3H)，3.60(s，6H)，2.69(t，J＝6.24Hz，2H)，2.58(t，J＝6.18Hz，2H)，1.84-1.80(m，2H)，1.75-1.72(m.2H).
Example twelve:
preparation of 4- (3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-indazol-2-yl) benzoic acid (3l)
The preparation method refers to the first embodiment. Light yellow was obtained, yield 37.7%, m.p.192.1-193.3 ℃.1H NMR(600MHz，DMSO-d6)δ13.03(s，1H)，7.90(d，J＝8.70，2H)，7.32(d，J＝8.64，2H)，6.45(s，2H)，3.68(s，3H)，3.60(s，6H)，2.68(t，J＝6.18Hz，2H)，2.58(t，J＝6.18Hz，2H)，1.83-1.80(m，2H)，1.74-1.72(m.2H).
Example thirteen:
preparation of 2- (4-nitrophenyl) -3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3m)
The preparation method refers to the first embodiment. A dark yellow powder is obtained, yield 38.0%, m.p.179.7-181.4 ℃.1H NMR(600MHz，DMSO-d6)δ8.22(d，J＝9.06，2H)，7.46(d，J＝9.06，2H)，6.52(s，2H)，3.70(s，3H)，3.63(s，6H)，2.70(t，J＝6.24Hz，2H)，2.56(t，J＝6.18Hz，2H)，1.83-1.81(m，2H)，1.74-1.72(m.2H).
Example fourteen:
preparation of 3- (3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-indazol-2-yl) phenol (3n)
The preparation method refers to the first embodiment. A pale yellow powder is obtained, yield 35.0%, m.p.194.6-195.1 ℃.1H NMR(600MHz，DMSO-d6)δ9.63(s，1H)，7.13(t，J＝8.04，1H)，6.69-6.67(m，1H)，6.65(t，J＝2.64，1H)，6.61-6.60(m，1H)，6.43(s，2H)，3.66(s，3H)，3.60(s，6H)，2.65(t，J＝6.18Hz，2H)，2.57(t，J＝6.12Hz，2H)，1.82-1.79(m，2H)，1.74-1.71(m.2H).
Example fifteen:
preparation of 2- (m-tolyl) -3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3o)
The preparation method refers to the first embodiment. A pale yellow powder is obtained, yield 47.4%, m.p.94.0-95.1 ℃.1H NMR(600MHz，DMSO-d6)δ7.21(t，J＝7.74，1H)，7.15(s，1H)，7.11(d，J＝7.62，1H)，6.90(d，J＝8.04，1H)，6.42(s，2H)，3.66(s，3H)，3.58(s，6H)，2.65(t，J＝6.18Hz，2H)，2.58(t，J＝6.18Hz，2H)，2.27(s，3H)，1.83-1.79(m，2H)，1.75-1.72(m.2H).
Example sixteen:
preparation of 2- (3-methoxyphenyl) -3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3p)
The preparation method refers to the first embodiment. So as to obtain the white powder,yield 45.6%, m.p.71.8-73.0 ℃.1H NMR(600MHz，DMSO-d6)δ7.24(t，J＝8.1，1H)，6.87-6.85(m，1H)，6.81(t，J＝1.98，1H)，6.75(d，J＝7.86，1H)，6.45(s，2H)，3.66(s，6H)，3.60(s，6H)，2.66(t，J＝6.18Hz，2H)，2.57(t，J＝6.18Hz，2H)，1.82-1.80(m，2H)，1.73-1.72(m.2H).
Example seventeen:
preparation of 2- (3-fluorophenyl) -3- (3, 4, 5-trimethoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3q)
The preparation method refers to the first embodiment. A yellow powder is obtained, yield 39.0%, m.p.134.3-135.5 ℃.1H NMR(600MHz，DMSO-d6)δ7.40-7.37(m，1H)，7.16-7.09(m，2H)，7.00-6.99(m，1H)，6.46(s，2H)，3.67(s，3H)，3.61(s，6H)，2.67(t，J＝6.24Hz，2H)，2.57(t，J＝6.18Hz，2H)，1.83-1.79(m，2H)，1.74-1.72(m.2H).
Example eighteen:
preparation of 3- (3, 4-dimethoxyphenyl) -2- (p-tolyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3r)
The preparation method refers to the first embodiment. A yellow powder is obtained, yield 50.0%, m.p.110.5-111.7 ℃.1H NMR(600MHz，DMSO-d6)δ7.14(d，J＝8.22，2H)，7.07(d，J＝8.32，2H)，6.93(d，J＝8.10，1H)，6.70-6.68(m，2H)，3.74(s，3H)，3.55(s，3H)，2.64(t，J＝6.24Hz，2H)，2.52(t，J＝6.18Hz，2H)，2.29(s，3H)，1.82-1.78(m，2H)，1.73-1.70(m.2H).
Example nineteenth:
preparation of 3- (3, 4-dimethoxyphenyl) -2- (4-methoxyphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3s)
The preparation method refers to the first embodiment. White powder was obtained, yield 46.5%, m.p.88.0-89.4 ℃.1H NMR(600MHz，DMSO-d6)δ7.13-7.10(m，2H)，6.93-6.90(m，3H)，6.70(dd，J＝8.22，J＝1.86，1H)，6.66-(d，J＝1.80，1H)，3.74(s，6H)，3.55(s，3H)，2.64(t，J＝6.36Hz，2H)，2.52(t，J＝6.24Hz，2H)，1.81-1.79(m，2H)，1.72-1.70(m.2H).
Example twenty:
preparation of 3- (3, 4-dimethoxyphenyl) -2- (3, 4-dimethylphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3t)
The preparation method refers to the first embodiment. White powder was obtained, yield 47.0%, m.p.76.3-77.0 ℃.1H NMR(600MHz，DMSO-d6)δ7.12(d，J＝1.68，1H)，7.04(d，J＝8.10，1H)，6.92(d，J＝8.28，1H)，6.77(dd，J＝7.98，J＝1.98，1H)，6.70(d，J＝1.86，1H)，6.77(dd，J＝8.22，J＝1.92，1H)，3.74(s，3H)，3.56(s，3H)，2.64(t，J＝6.24Hz，2H)，2.52(t，J＝6.18Hz，2H)，2.19(s，3H)，2.17(s，3H)，1.81-1.78(m，2H)，1.72-1.70(m.2H).
Example twenty one:
preparation of 3- (3, 4-dimethoxyphenyl) -2- (4-trifluoromethylphenyl) -4, 5, 6, 7-tetrahydro-2H-pyrazole (3u)
The preparation method refers to the first embodiment. Light yellow powder is obtained with a yield of 48.0%, m.p.137.3-138.2 ℃.1H NMR(600MHz，DMSO-d6)δ7.72(d，J＝8.68，2H)，7.41(d，J＝8.46，2H)，6.98(d，J＝8.64，1H)，6.75-6.73(m，2H)，3.77(s，3H)，3.58(s，3H)，2.68(t，J＝6.30Hz，2H)，2.53(t，J＝6.24Hz，2H)，1.82-1.79(m，2H)，1.74-1.71(m.2H).
Example twenty two:
preparation of 2, 3-diphenyl-2, 4, 5, 6, 7, 8-hexahydrocyclohepta [ c ] pyrazole (3v)
The preparation method refers to the first embodiment. Milky white powder was obtained with a yield of 33.6%, m.p.74.5-75.6 ℃.1H NMR(600MHz，DMSO-d6)δ7.40-7.36(m，3H)，7.28(t，J＝7.50，2H)，7.21(t，J＝7.32，1H)，7.15-7.11(m，4H)，2.77(t，J＝6.72Hz，2H)，2.45(t，J＝5.58Hz，2H)，1.83-1.82(m，2H)，1.69-1.67(m，2H)，1.59-1.58(m.2H).
Example twenty three:
preparation of 2-phenyl-3- (3, 4, 5-trimethoxyphenyl) -2, 4, 5, 6, 7, 8-hexahydrocyclohepta [ c ] pyrazole (3w)
The preparation method refers to the first embodiment. Yellow powder is obtained, yield 40.8%, m.p.137.2-137.5 ℃.1H NMR(600MHz，DMSO-d6)δ7.23(t，J＝7.74，2H)，7.5(t，J＝7.14，1H)，7.16(d，J＝8.04，2H)，6.39(s，2H)，3.67(s，3H)，3.59(s，6H)，2.76(t，J＝5.34Hz，2H)，2.53(t，J＝5.16Hz，2H)，1.83-1.83(m，2H)，1.68-1.67(m，2H)，1.61-1.60(m，2H).
Example twenty-four:
2- (4-methoxyphenyl) -3- (3, 4, 5-trimethoxyphenyl) -2, 4, 5, 6, 7, 8-hexahydrocyclohepta [ c ] pyrazole (3x)
The preparation method refers to the first embodiment. White powder is obtained, yield 46.5%, m.p.129.7-130.8 ℃.1H NMR(600MHz，DMSO-d6)δ7.37-7.36(m，2H)，7.07-7.06(m，2H)，6.75(s，2H)，3.82(s，3H)，3.80(s，6H)，3.69(s，3H)，2.73-2.70(m，4H)，1.82-1.81(m，2H)，1.66-1.65(m，4H).
Example twenty-five:
the compounds of the above examples were tested for antitumor activity.
MTT [3- (4, 5) -dimethyl-2-thiazole- (2, 5) -phenyl tetrazolium bromide ] method is adopted to determine the drug concentration (IC50) when the inhibition rate of a saturated aliphatic cyclo-pyrazole derivative on human cervical cancer cells (HeLa), human hepatoma cells (HepG2) and human lung cancer cells (A549) reaches 50%.
Three cells were selected and placed at 37 ℃ in 5% CO2Culturing in incubator until the cells can be plated, digesting, counting, and making into concentration of 0.5-1.0 × 105Mixing the cell suspension/mL, adding into 96-well culture plate (100 μ L/well), setting blank group and negative control group at 37 deg.C, and adding 5% CO2Culturing for 12h in an incubator; preparing a compound to be detected and a positive control drug by using a 2% culture solution to a required concentration gradient, wherein each compound has five concentration gradients, each concentration is provided with three parallel holes, and 100 mu L of corresponding drug-containing culture solution is added into each hole; after administration 96-well plates were placed at 37 ℃ in 5% CO2Culturing for 48h in an incubator; to a 96-well plate, 5. mu.L/well of MTT (5mg/mL) was added, and the mixture was placed at 37 ℃ in 5% CO2Removing supernatant in incubator for 4h, adding DMSO 150 μ L/well, shaking until formazan crystal is completely dissolved, detecting optical density (OD value) of each well at 570nm wavelength with automatic microplate reader, and calculating IC50The value is obtained. The results are shown in Table 1:
table 1: IC of saturated fat ring pyrazole derivative to tumor cell50Value of
The saturated fat cyclopyrazole derivatives have an inhibiting effect on malignant proliferation of human cervical cancer cells (HeLa), human liver cancer cells (HepG2) and human lung cancer cells (A549), wherein the anti-tumor effect of the compound 3f is superior to that of Colchicine. The saturated aliphatic cyclo-pyrazole derivatives have the potential of being used as antitumor drugs.
Claims (4)
1. A saturated aliphatic cyclo-pyrazole derivative is characterized by having a structure shown in a general formula I:
wherein: n is selected from 1, 2 and 3; r1、R2、R3is-OCH3；R4Selected from: -H, -F, -OH, -CH3、-OCH3；R5Selected from: -H, -F, -Cl, -Br, -CH3、-CF3、-OCH3、-COOH、-NO2；R6is-H.
2. The method for preparing saturated aliphatic cyclic pyrazole derivatives according to claim 1, comprising the following steps:
(1) a process for the preparation of corresponding compounds of the general formula (I): dissolving saturated alicyclic ketone in tetrahydrofuran solvent at room temperature, slowly dropwise adding 1M LiHMDS solution within 30min, continuing to react for 15min, adding mono-substituted or multi-substituted benzoyl chloride, and reacting overnight to generate a compound corresponding to the general formula (I);
(2) a process for the preparation of corresponding compounds of the general formula (II): taking mixed liquid of N, N-dimethylformamide and tetrahydrofuran in a volume ratio of 3: 1 as a solvent, and reacting the compound corresponding to the general formula (I) with mono-substituted or multi-substituted phenylhydrazine hydrochloride or sulfate at 120 ℃ for 3 hours to generate the compound corresponding to the general formula (II).
3. The use of the saturated aliphatic cyclic pyrazole derivatives according to claim 1 for preparing anti-tumor drugs.
4. An antitumor tubulin inhibitory drug comprising the saturated aliphatic cyclic pyrazole derivative according to claim 1 and a pharmaceutically acceptable carrier.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6083969A (en) * | 1999-10-20 | 2000-07-04 | Ortho-Mcneil Pharaceutical, Inc. | 1,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles as selective inhibitors of cyclooxygenase-2 and antiinflammatory agents |
| CN102459240A (en) * | 2009-04-22 | 2012-05-16 | 詹森药业有限公司 | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
| CN108409663A (en) * | 2018-05-10 | 2018-08-17 | 四川大学 | Microtubule inhibitors and its preparation method and application |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6083969A (en) * | 1999-10-20 | 2000-07-04 | Ortho-Mcneil Pharaceutical, Inc. | 1,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles as selective inhibitors of cyclooxygenase-2 and antiinflammatory agents |
| CN102459240A (en) * | 2009-04-22 | 2012-05-16 | 詹森药业有限公司 | Azetidinyl diamides as monoacylglycerol lipase inhibitors |
| CN108409663A (en) * | 2018-05-10 | 2018-08-17 | 四川大学 | Microtubule inhibitors and its preparation method and application |
Non-Patent Citations (6)
| Title |
|---|
| Differential estrogen receptor subtype modulators: Assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles;Xanthippi Alexi，等;《Journal of Steroid Biochemistry & Molecular Biology》;20091231;159-167，fig.1和2 * |
| Facile synthesis of 2H-indazole derivatives starting from the Baylis–Hillman adducts of 2-cyclohexen-1-one;Ka Young Lee,等;《Tetrahedron Letters》;20051231;5387-5391，table1 * |
| Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from Baylis–Hillman adducts;Ka Young Lee，等;《Tetrahedron Letters》;20031231;6937-6740，table1 * |
| Synthesis of hydrogenated indazole derivatives starting with α,β-unsaturated ketones and hydrazine derivatives;Azadeh Nakhai,等;《Tetrahedron》;20090115;2298-2306，scheme5 * |
| Synthesis, docking studies and anti-inflammatory activity of 4,5,6,7-tetrahydro-2H-indazole derivatives;Ornelio Rosati，等;《Bioorganic & Medicinal Chemistry》;20170306;3463-3473，table1化合物13 * |
| Synthesis, Mechanism of Action, and QSAR of Herbicidal 3-Substituted-2-aryl-4,5,6,7-tetrahydroindazoles;John W. Lyga，等;《Prstic. Sci.》;19941231;29-36，fig.7 * |
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