CN108997172B - Antitumor compounds - Google Patents

Antitumor compounds Download PDF

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CN108997172B
CN108997172B CN201810898051.9A CN201810898051A CN108997172B CN 108997172 B CN108997172 B CN 108997172B CN 201810898051 A CN201810898051 A CN 201810898051A CN 108997172 B CN108997172 B CN 108997172B
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CN108997172A (en
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张明华
范皎
陈香岭
刘庆艳
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Chinese PLA General Hospital
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Priority to CN202010772284.1A priority patent/CN111892517A/en
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Abstract

The invention discloses an antitumor compound targeting a Neddylation pathway. The compound can be represented by a structural formula shown in a general formula I, a general formula II, a general formula III, a general formula IV, a general formula V or a general formula VI. The compound of the invention has good anti-tumor activity, and a plurality of compounds are close to a positive control medicament MLN4924 and can be used as good anti-tumor compounds. The compounds and compositions of the present invention may be used together with other drugs to provide a combination therapy, which may form part of the same composition or be administered as separate components at the same or different times.

Description

Antitumor compounds
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an antitumor compound targeting a Neddylation pathway.
Background
The Neddylation pathway is responsible for covalently binding the ubiquitin-like molecule NEDD8 to a protein molecule, and regulating the activity of the protein. The pathway can widely regulate and control the degradation and functions of various important proteins in cells, and is very important for the proteins responsible for signal transduction. The Neddylation pathway is catalyzed by a series of enzymes: first, NEDD8 was activated by activating enzyme E1, then transferred to binding enzyme E2, and NEDD8 molecules were covalently bound to the substrate protein by E2 in combination with ligase E3, modulating its function. The Cullin-like molecule is one of the substrates modified by NEDD 8. The Cullin-like molecules are scaffold molecules for CRLs (Cullin-RING ubiquitin ligases) ubiquitin-like ligases. The modification of NEDD8 on Cullin-like molecules is a precondition that the CRLs ubiquitin-like ligase has activity. The CRLs ubiquitin-like ligase can degrade various substrates, including various important molecules such as P21, P27 and the like, can regulate important processes such as cell cycle, apoptosis, aging and the like, and has close relation with neurodegenerative diseases and tumors. The Neddylation pathway is abnormally high expressed and over-activated in a plurality of tumors, and the purpose of treating a plurality of tumors such as multiple myeloma and the like can be achieved by inhibiting the function of the pathway.
In recent years, the screening of inhibitors for key molecules targeting the Neddylation pathway becomes an important field for discovering novel antitumor drugs. At present, foreign research institutions and pharmaceutical companies screen key molecules (such as UBA3 and the like) of the Neddylation pathway to obtain a plurality of compounds with antitumor activity, and part of high-activity compounds enter the phase I clinical stage.
Disclosure of Invention
The invention aims to provide an anti-tumor compound targeting a Neddylation pathway.
An anti-neoplastic compound targeting the Neddylation pathway comprising a compound of the general structural formula:
Figure BDA0001758686320000021
in the formula, R1、R5Selected from hydrogen, halogen, hydroxy, lower alkyl; r2、R3、R4Selected from the group consisting of hydrogen, halogen, nitro, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, benzyloxy, substituted amino; r6Selected from the group consisting of hydrogen, formamidine, thiourea, amino, optionally substituted amino, nitrogen heterocycle, amide, hydroxy, lower alkyl; x is selected from methyl, ethyl, propenyl, amido, methoxy and oxo-ethyl; y is selected from sulfur atom, amino, hydrazino, epoxyalkyl and heterocyclic radical;
Figure BDA0001758686320000022
in the formula, R7、R11Selected from hydrogen, halogen, hydroxy, lower alkyl; r8、R9、R10Selected from the group consisting of hydrogen, halogen, nitro, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, benzyloxy, optionally substituted amino; r12Selected from the group consisting of hydrogen, hydroxy, amino, formamidine, thiourea, optionally substituted amino, nitrogen heterocycle, amide, lower alkyl;
Figure BDA0001758686320000031
in the formula, R13、R16Selected from hydrogen, halogen, hydroxy, lower alkyl; r14、R15Selected from the group consisting of hydrogen, halogen, nitro, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, benzyloxy, optionally substituted amino; r17Selected from the group consisting of hydrogen, amino, formamidine, thiourea, optionally substituted amino, nitrogen heterocycle, amide, hydroxy, lower alkyl; x1Selected from methyl, ethyl, propenyl, amido, methoxy, oxoethyl; y is1Selected from sulfur atom, amino, hydrazino, epoxyalkyl and heterocyclic radical;
Figure BDA0001758686320000032
in the formula, R18、R22Selected from hydrogen, halogen, hydroxy, lower alkyl; r19、R20、R21Selected from the group consisting of hydrogen, halogen, nitro, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, benzyloxy, optionally substituted amino; r23Selected from the group consisting of carboxyl, hydroxyl, hydrogen, formamidine, thioureido, amino, optionally substituted amino, nitrogen heterocycle, amide, lower alkyl;
Figure BDA0001758686320000041
in the formula, R24、R27Selected from hydrogen, halogen, hydroxy, lower alkyl; r25、R26Selected from the group consisting of hydrogen, halogen, nitro, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, benzyloxy, optionally substituted amino; r28Selected from the group consisting of hydrogen, amino, formamidine, thiourea, optionally substituted amino, nitrogen heterocycle, amide, hydroxy, lower alkyl; x2Selected from methyl, ethyl, propenyl, amido, methoxy, oxoethyl; y is2Selected from sulfur atom, amino, hydrazino, epoxyalkyl and heterocyclic radical;
Figure BDA0001758686320000042
in the formula, R29、R33Selected from hydrogen, halogen, hydroxy, lower alkyl; r30、R31、R32Selected from the group consisting of hydrogen, halogen, nitro, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, benzyloxy, optionally substituted amino; r34Selected from the group consisting of hydroxy, hydrogen, formamidine, thiourea, amino, optionally substituted amino, nitrogen heterocycle, amide, lower alkyl, -C (R)35)2CH2OH、-CH(CH2OH)R35、-CH2CH(OH)R35；；X3Selected from methyl, ethyl, ethylamino, propenyl, amido, methoxy, oxoethyl; y is3Selected from sulfur atom, amino group, hydrazino group, isobutyl group, epoxyalkyl group and heterocyclic group.
The R is35Is a lower alkyl group.
The compound reacts with inorganic acid or organic acid to prepare corresponding medicinal salt; the inorganic acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid; the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid or oxalic acid.
The compound also comprises racemes, diastereomers, optical isomers, cis-trans isomers, any combination thereof or medicinal salts thereof.
The compound and the medicinal salt thereof can be applied to the preparation of antitumor drugs or anti-inflammatory drugs, wherein tumors refer to cancers of esophagus, stomach, intestine, oral cavity, pharynx, larynx, lung, breast, uterus, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system, or thyroid cancer, leukemia, Hodgkin's disease, lymphoma and myeloma.
The invention has the beneficial effects that: the compound of the invention has good anti-tumor activity, and a plurality of compounds are close to a positive control medicament MLN4924 and can be used as good anti-tumor compounds. The compounds and compositions of the present invention may be used together with other drugs to provide a combination therapy, which may form part of the same composition or be administered as separate components at the same or different times.
Detailed Description
The present invention is further illustrated by the following specific examples.
EXAMPLE 1 Synthesis of Compound 2
(E) -2- ((E) -3- (3-nitrophenyl) 2-propenyl) hydrazino-1-carboxamidine, Chemdiv ID0589-0011, chemical structure formula:
Figure BDA0001758686320000061
preparation method
Figure BDA0001758686320000062
3- (3-Nitro) -1-propanol (54.36mg, 0.3mmol), DMSO 0.6mL, acetonitrile 0.9mL, diiodoformic acid (210mg, 0.75mmol), catalyst (0.12mg, 0.06mmol), reacted at room temperature for 8h, rotary evaporated to remove volatile solvent to give crude product, which was separated on silica gel column with cyclohexane/ethyl acetate (70:1) as mobile phase to give compound 1(42.3mg, 80% yield).
Compound 1(177.16mg, 1mmol), aminoguanidine hydrochloride (110mg, 1mmol), absolute ethanol (6mL) and concentrated hydrochloric acid (0.2mL) were refluxed for 24h, the solvent was removed by rotary evaporation, the crude product was washed with water 3 times, then with absolute ethanol 3 times, and finally, compound 2(157.21mg, 64.5% yield) was purified by column chromatography using acetone/absolute ethanol/methanol mixture as the mobile phase.
1H-NMR(300MHz DMSO):5.24(s,1H),6.81(s,2H),7.10(d,1H),7.33(d,1H),7.69(t,1H),8.00(m,2H),8.14(d,1H),8.31(s,1H),9.36(s,2H).
EXAMPLE 2 Synthesis of Compound 12
4-methoxy-3-bromobenzylisothiourea, Chemdiv ID 4298-0374, the chemical structural formula is as follows:
Figure BDA0001758686320000063
the preparation method comprises the following steps:
Figure BDA0001758686320000071
3- (3-Nitro) -1-propanol (54.36mg, 0.3mmol), DMSO 0.6mL, acetonitrile 0.9mL, diiodoformic acid (210mg, 0.75mmol), catalyst (0.12mg, 0.06mmol), reacted at room temperature for 8h, rotary evaporated to remove volatile solvent to give crude product, which was separated on silica gel column with cyclohexane/ethyl acetate (70:1) as mobile phase to give compound 1(42.3mg, 80% yield).
Compound 1(177.16mg, 1mmol), aminoguanidine hydrochloride (110mg, 1mmol), absolute ethanol (6mL) and concentrated hydrochloric acid (0.2mL) were refluxed for 24h, the solvent was removed by rotary evaporation, the crude product was washed with water 3 times, then with absolute ethanol 3 times, and finally, compound 2(157.21mg, 64.5% yield) was purified by column chromatography using acetone/absolute ethanol/methanol mixture as the mobile phase.
1H-NMR(400MHz,DMSO+CCl4):3.85(s,3H),4.93(s,2H),6.97(d,1H),7.42(d,1H),7.60(s,1H).
EXAMPLE 3 Synthesis of Compound 90
(R) -4- (4-fluorobenzyl) -1-oxa-9-azaspiro [5.5] undecane, Chemdiv ID T500-0182, of the formula:
Figure BDA0001758686320000072
preparation method
Figure BDA0001758686320000081
0.5mol of the compound 1 is dissolved in 10mL of ethyl acetate, an appropriate amount of sarrette reagent is added, the reaction is carried out for 8h at room temperature, the filtrate is collected by filtration, ethyl acetate is removed by rotary evaporation, and the obtained solid is purified by column chromatography (petroleum ether/ethyl acetate 20:1) to obtain a compound 2. Dissolving 0.5mol of compound 3 in 10mL of acetonitrile, adding triphenylphosphine, reacting at room temperature for 10h, adding 0.6mol of compound 2 and equimolar C4H9Li, reaction at-20 ℃ for 14h, concentration and column chromatography purification (petroleum ether/ethyl acetate 10:1) of purified compound 5. 0.2mol of Compound 5 dissolved in 5mL of acetonitrile is added with equimolar amounts of AlCl3Reacting at 50 ℃ for 8h, adding Pb/C for reduction, concentrating, purifying by column chromatography (petroleum ether/ethyl acetate: 8:1), and carrying out chiral resolution to obtain the compound 90.
1H-NMR(400MHz,DMSO):1.05(m,2H),1.50(dd,4H),1.75(m,1H),1.85(brs,1H),2.30(t,1H),2.50(m,5H),2.80(m,1H),3.00(s,3H),3.3(m,4H),3.6(d,1H),7.15(dq,4H),8.85(brs,2H).
EXAMPLE 4 Synthesis of Compound 10
6-hydroxy-2- ((2- (4-methoxyphenyl) -2-oxoethyl) thio) pyrimidin-4 (3H) -one, Chemdiv ID4112-3276, chemical structure formula as follows:
Figure BDA0001758686320000082
the preparation method comprises the following steps:
Figure BDA0001758686320000091
compound 1 was purchased from 3B Scientific (Wuhan) Product List, China.
Compound 2 was purchased from above Product List, United States.
NaOH (80mg, 2mmol) was dissolved in 6ml H2O, Compound 2(144mg, 1mmol) was added thereto, and 2mL of ethanol containing Compound 1(228mg, 1mmol) was added dropwise to the above system with stirring, reacted at room temperature for 2 hours, the pH of the reacted solution was adjusted to 7.0 with 0.1mol/L hydrochloric acid, and the product was precipitated, filtered, washed with deionized water, and dried under vacuum to give white Compound 10(142mg, 49% yield).
1H-NMR(300MHz,DMSO):3.81(s,3H),4.84(s,2H),7.08(d,2H),7.48(s,1H),7.96(d,2H),12.02(s,1H).
EXAMPLE 5 Synthesis of Compound 13
2- (5- (benzyloxy) -1H-indol-3-yl) ethyl-1-amine, Chemdiv ID 4513-one 1373, having the following chemical formula:
Figure BDA0001758686320000092
dissolving 5-benzyloxy indole-3-formaldehyde (251.3mg, 1mmol) and ammonium acetate (231mg, 3mmol) in 5mL nitromethane, refluxing for 2h, distilling under reduced pressure to remove nitromethane, washing the product with water, filtering, vacuum drying to obtain product 1, dissolving product 1(294mg, 1mmol) in 10mL tetrahydrofuran, and adding dropwise to 10mL LiAlH-containing solution without purification4(228mg, 6mmol) of tetrahydrofuran, the reaction was started at 0 ℃ and gradually increased to 25 ℃ to continue the reaction for 36 hours, and water was added dropwise to the reaction system until no bubbles were formed. Adding a proper amount of saturated Rochelle salt solution and a proper amount of ether into the reaction system, stirring for 24 hours at room temperature, separating liquid, collecting an ether layer, washing the ether layer for 3 times by using 1mol/L hydrochloric acid solution, collecting a water phase, neutralizing by using 3mol/L potassium hydroxide solution, extracting by using ether, drying by using anhydrous sodium sulfate, and performing rotary evaporation to obtain the compound 13.
1H-NMR(400MHz,DMSO):2.50(d,4H),2.95(dd,1H),3.30(s,1H),5.10(s,1H),6.80(d,1H),7.35(m,8H),7.95(s,3H),10.85(s,1H).
EXAMPLE 6 Synthesis of Compound 16
2- (5-methoxy-1H-indol-3-yl) ethylisothiourea, Chemdiv ID 5911-:
Figure BDA0001758686320000101
preparation method
Figure BDA0001758686320000111
3- (2-bromo-ethyl) -5-methoxy-1H-indole was purchased from Apichemical (Shanghai) Product List.
Thiourea (150m g, 1.97mmol) and 3- (2-bromo-ethyl) -5-methoxy-1H-indole (581.66mg, 2.29m mol) were dissolved in 20mL of absolute ethanol and reacted at 60 ℃ for 3H. After the reaction is finished, the ethanol is removed by rotary evaporation, the obtained oily product is transferred into a 500mL beaker for standing and crystallization, and the product 16 is obtained after filtration and vacuum drying.
1H-NMR(400MHz,DMSO):3.05(m,2H),3.40(m,2H),3.75(s,3H),6.65(d,1H),6.93(s,1H),7.15(m,2H),9.60(brs,2H),10.65(s,1H).
EXAMPLE 7 Synthesis of Compound 17
(R) -2- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-2-yl) methylisothiourea, Chemdiv ID5914-0610, chemical structural formula as follows:
Figure BDA0001758686320000112
preparation method
Figure BDA0001758686320000121
2-bromomethyl-1, 4-benzodioxane was purchased from Chishiei (Shanghai) chemical industries development Co., Ltd.
Thiourea (150g, 1.97mmol) and 2-bromomethyl-1, 4-benzodioxane (524.41g, 2.29mol) were dissolved in 200mL of absolute ethanol and reacted at 60 ℃ for 3 h. After the reaction is finished, the ethanol is removed by rotary evaporation, the obtained oily product is transferred into a 500mL beaker for standing and crystallization, and the product 17 is obtained after filtration and vacuum drying.
1H-NMR(400MHz,DMSO-d6+CCl4):3.50(dd,1H),3.75(d,1H),4.05(dd,1H),4.40(d,2H),6.80(m,4H),9.20(d,4H).
EXAMPLE 8 Synthesis of Compound 20
2- ((3- (4-chlorobenzyloxy) benzyl) amino) -2-methyl-1 propanol, Chemdiv ID 6408-:
Figure BDA0001758686320000122
preparation method
Figure BDA0001758686320000123
3- (4-chlorobenzyl) oxybenzaldehyde and 2-amino-2-methyl-1-propanol were purchased from carbofuran technology.
2-amino-2-methyl-1-propanol (0.97g,10.89mmol) and 3- (4-chlorobenzyl) oxybenzaldehyde (2.819g,11.44mmol) were dissolved in 25mL of toluene, refluxed for 4h and cooled to room temperature, toluene was removed by rotary evaporation, 25mL of ethanol was added, cooled to 0 deg.C and NaBH was added4(1.03g,27.2mmol), 4.0mol/L of a mixture of hydrochloric acid and dioxane was added dropwise to adjust the pH of the solution to 2.0, and the mixture was stirred at room temperature overnight. Concentrating the stirred mixture, adding 1.0mol/L hydrochloric acid and dichloromethane (20mL) with equal volume, demixing, collecting water phase, extracting the water phase with appropriate amount of dichloromethane for 3 times, discarding the organic phase, adjusting the water phase to 8.0 with 10mol/L NaOH, extracting the organic phase with dichloromethane for 3 times, collecting the organic phase, and extracting with anhydrous MgSO4Drying, filtering and rotary evaporating to remove dichloromethane to obtain the product 20.
1H-NMR(300MHz,DMSO-d6):1.30(s,6H),4.00(s,2H),4.15(s,2H),4.26(s,1H),5.15(s,2H),6.85(d,3H),7.25(m,5H),7.40(d,2H).
EXAMPLE 9 Synthesis of Compound 25
(2R,4S) -2- (2, 3-dihydroxyphenyl) thiazolidine-4-carboxylic acid, Chemdiv ID 8010-:
Figure BDA0001758686320000131
the preparation method comprises the following steps:
Figure BDA0001758686320000141
mixing L-cysteine (0.175g, 1.1mmol) and NaHCO3(0.084g, 1mmol) and 2, 3-dihydroxybenzaldehyde (0.124g, 0.9mmol) are dissolved in 10mL of 10% DMSO aqueous solution, the reaction is carried out at room temperature, after the TLC detection reaction is finished, the reaction solution is precipitated in an ice-water bath to obtain a white solid, and the white solid is dried and then the product 20 is obtained by a liquid phase chiral separation method.
1H-NMR(300MHz,DMSO-d6):2.85(dq,2H),3.76(t,1H),6.35(s,1H),6.70(m,2H),6.85(d,1H),7.90(s,1H),9.48(s,1H),9.58(s,1H).
Test example: tumor cell proliferation inhibition assay
Tumor cell proliferation inhibition experiments were performed on a fraction of the compounds of the present invention using the CCK8 method (Japan Homophilus chemical).
The cell strain adopts human colorectal cancer cell strain HCT116+/+, human large cell lung cancer cell strain H460, human lung adenocarcinoma H1299 cell and human breast cancer cell MCF 7. The culture medium was dmem (hyclone) + 10% fbs (hyclone) + diabody.
Sample preparation: dissolved in DMSO (sigma) to a 10mM solution and diluted to the desired concentration using cell culture medium before use. Compound MLN4924 was formulated into a positive control solution under the same conditions.
CCK8 detection method: the concentration of the added solution is 5-6 multiplied by 10 per hole of a 96-hole plate4Cell suspension of cell/ml100ul, cultured in a cell culture chamber (37 ℃, 5% carbon dioxide). After 24 hours, the medium was discarded, 300ul of the medium containing the compound sample was added, and the culture was continued for 48 hours at 37 ℃ with double wells and 5% carbon dioxide. The medium solution was discarded, and serum-free DMEM (Hyclone) medium containing 10% CCK8 solution was added thereto, and after further culturing for 2 hours, OD 450nm was measured using a Tecan F50 microplate reader. Calculation of half inhibitory concentration of cells IC50. The results are shown in tables 1 and 2.
TABLE 1
Figure BDA0001758686320000151
TABLE 2
Figure BDA0001758686320000152
Figure BDA0001758686320000161
The experimental results show that most of the compounds have good anti-tumor activity, and a plurality of the compounds are close to the positive control medicament MLN4924 and can be used as good anti-tumor compounds.
The foregoing describes and illustrates the general principles and features of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (1)

1. The application of a compound in preparing an anti-tumor medicine is characterized in that the structural formula of the compound is as follows:
Figure FDA0002681004540000011
the tumor is human colorectal cancer or human lung cancer.
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