CN111892517A - Antitumor compounds - Google Patents

Antitumor compounds Download PDF

Info

Publication number
CN111892517A
CN111892517A CN202010772284.1A CN202010772284A CN111892517A CN 111892517 A CN111892517 A CN 111892517A CN 202010772284 A CN202010772284 A CN 202010772284A CN 111892517 A CN111892517 A CN 111892517A
Authority
CN
China
Prior art keywords
acid
compound
hydrogen
lower alkyl
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010772284.1A
Other languages
Chinese (zh)
Inventor
张明华
范皎
陈香岭
刘庆艳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chinese PLA General Hospital
Original Assignee
Chinese PLA General Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chinese PLA General Hospital filed Critical Chinese PLA General Hospital
Priority to CN202010772284.1A priority Critical patent/CN111892517A/en
Publication of CN111892517A publication Critical patent/CN111892517A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
    • C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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 IV. 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
Original application No.: 2018108980519
Application date of the original case: 20180808
The original case applicant: general hospital for Chinese people liberation army
The original application name: 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 BDA0002617097840000021
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 BDA0002617097840000022
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 BDA0002617097840000031
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 BDA0002617097840000032
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 BDA0002617097840000041
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 BDA0002617097840000042
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 ID 0589-:
Figure BDA0002617097840000061
preparation method
Figure BDA0002617097840000062
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 BDA0002617097840000071
the preparation method comprises the following steps:
Figure BDA0002617097840000072
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 BDA0002617097840000081
preparation method
Figure BDA0002617097840000082
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 14hAnd after concentration, the purified compound 5 was purified by column chromatography (petroleum ether/ethyl acetate 10: 1). 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, ChemdivID4112-3276, chemical structure formula as follows:
Figure BDA0002617097840000091
the preparation method comprises the following steps:
Figure BDA0002617097840000092
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 BDA0002617097840000101
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 BDA0002617097840000111
preparation method
Figure BDA0002617097840000112
3- (2-bromo-ethyl) -5-methoxy-1H-indole was purchased from Apichemical (Shanghai) ProductList.
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 ID 5914-:
Figure BDA0002617097840000121
preparation method
Figure BDA0002617097840000122
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 BDA0002617097840000123
preparation method
Figure BDA0002617097840000131
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 BDA0002617097840000141
the preparation method comprises the following steps:
Figure BDA0002617097840000142
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 plate4Each cell suspension (100. mu.l/ml) was cultured in a cell culture chamber (37 ℃ C., 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 BDA0002617097840000151
TABLE 2
Figure BDA0002617097840000161
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 (3)

1. An anti-neoplastic compound targeting the Neddylation pathway comprising a compound of the general structural formula:
Figure FDA0002617097830000011
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.
2. The pharmaceutically acceptable salt of the compound of claim 1, wherein the compound is reacted with an inorganic or organic acid to form the corresponding pharmaceutically acceptable 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.
3. Use of a compound according to claim 1 and a pharmaceutically acceptable salt according to claim 2 in the preparation of an anti-tumor or anti-inflammatory agent, wherein the tumor is cancer of the esophagus, stomach, intestine, mouth, pharynx, larynx, lung, breast, uterus, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain, and central nervous system, or thyroid, leukemia, hodgkin's disease, lymphoma, myeloma.
CN202010772284.1A 2018-08-08 2018-08-08 Antitumor compounds Pending CN111892517A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010772284.1A CN111892517A (en) 2018-08-08 2018-08-08 Antitumor compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810898051.9A CN108997172B (en) 2018-08-08 2018-08-08 Antitumor compounds
CN202010772284.1A CN111892517A (en) 2018-08-08 2018-08-08 Antitumor compounds

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201810898051.9A Division CN108997172B (en) 2018-08-08 2018-08-08 Antitumor compounds

Publications (1)

Publication Number Publication Date
CN111892517A true CN111892517A (en) 2020-11-06

Family

ID=64595584

Family Applications (5)

Application Number Title Priority Date Filing Date
CN202010772297.9A Pending CN111960985A (en) 2018-08-08 2018-08-08 Antitumor compounds
CN202010771763.1A Pending CN111892516A (en) 2018-08-08 2018-08-08 Antitumor compounds
CN201810898051.9A Active CN108997172B (en) 2018-08-08 2018-08-08 Antitumor compounds
CN202010772284.1A Pending CN111892517A (en) 2018-08-08 2018-08-08 Antitumor compounds
CN202010772282.2A Active CN111960970B (en) 2018-08-08 2018-08-08 Antitumor compounds

Family Applications Before (3)

Application Number Title Priority Date Filing Date
CN202010772297.9A Pending CN111960985A (en) 2018-08-08 2018-08-08 Antitumor compounds
CN202010771763.1A Pending CN111892516A (en) 2018-08-08 2018-08-08 Antitumor compounds
CN201810898051.9A Active CN108997172B (en) 2018-08-08 2018-08-08 Antitumor compounds

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN202010772282.2A Active CN111960970B (en) 2018-08-08 2018-08-08 Antitumor compounds

Country Status (1)

Country Link
CN (5) CN111960985A (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3785696A1 (en) * 2019-08-28 2021-03-03 B.R.A.I.N. Biotechnology Research And Information Network AG Cosmetic use of aromatic formamidine derivatives

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB841524A (en) * 1955-11-18 1960-07-20 May & Baker Ltd Improvements in or relating to indole derivatives
US2945046A (en) * 1956-02-21 1960-07-12 Francesco Vismara Societa Per Process for preparing 5 hydroxy-tryptamine through new intermediates
FR2182915A1 (en) * 1972-03-30 1973-12-14 Nelson Res & Dev Substd indoles, benzimidazoles - as anti-immune agents , antitumour agents, serotonin inhibitors, hypnotics
US5206377A (en) * 1991-12-05 1993-04-27 Whitby Research, Inc. Compounds useful as antiproliferative agents
EP0639573A1 (en) * 1993-08-03 1995-02-22 Hoechst Aktiengesellschaft Benzocondensed five membered heterocycles, process of their preparation, their use as drug, as diagnostic means and pharmaceuticals containing it
FR2763335B1 (en) * 1997-05-16 2000-11-24 Adir NOVEL SUBSTITUTED HETEROCYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JP2006028104A (en) * 2004-07-16 2006-02-02 Kyowa Hakko Kogyo Co Ltd Histone deacetylase inhibitor
WO2009086303A2 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
EP3632426A1 (en) * 2013-02-01 2020-04-08 Wellstat Therapeutics Corporation Amine compounds having anti-inflammatory, antifungal, antiparasitic and anticancer activity
MX2015012760A (en) * 2013-03-15 2016-06-17 Als Mountain Llc Pharmaceutical composition comprising an ampk activator and a serotonergic agent and methods of use thereof.
MX2016002544A (en) * 2013-09-04 2016-06-17 Squibb Bristol Myers Co Compounds useful as immunomodulators.
WO2015143072A1 (en) * 2014-03-18 2015-09-24 Whitehead Institute For Biomedical Research Methods for inhibiting proliferation of cancer cells and uses thereof
JP6635949B2 (en) * 2014-06-04 2020-01-29 トーマス・ヘレデイズ・スティフテルス・フォー・メディシンスク・フォルスクニング MTH1 inhibitors for the treatment of inflammatory and autoimmune diseases
US9981920B2 (en) * 2014-06-26 2018-05-29 Rodin Therapeutics, Inc. Inhibitors of histone deacetylase
GB2533925A (en) * 2014-12-31 2016-07-13 Univ Bath Antimicrobial compounds, compositions and methods
CA2986083A1 (en) * 2015-06-11 2016-12-15 Basilea Pharmaceutica International AG Efflux-pump inhibitors and therapeutic uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ROHIDAS M. JAGTAP ET AL.: "Crystal structure, computational studies, and stereoselectivity in the synthesis of 2-aryl-thiazolidine-4-carboxylic acids via in situ imine intermediate", 《JOURNAL OF SULFUR CHEMISTRY》 *
VEERESA GUDUDURU ET AL.: "Discovery of 2-Arylthiazolidine-4-carboxylic Acid Amides as a New Class of Cytotoxic Agents for Prostate Cancer", 《JOURNAL OF THE MEDICINAL CHEMISTRY》 *
刘纪云等: "噻唑烷酸类化合物的合成及其抗肿瘤的研究", 《医药工业》 *

Also Published As

Publication number Publication date
CN108997172B (en) 2020-12-15
CN111960970B (en) 2021-08-20
CN111960985A (en) 2020-11-20
CN108997172A (en) 2018-12-14
CN111960970A (en) 2020-11-20
CN111892516A (en) 2020-11-06

Similar Documents

Publication Publication Date Title
JP7095945B2 (en) Polycyclic pyridone derivatives and their prodrugs
JP6697209B2 (en) Substituted polycyclic pyridone derivative and its prodrug
EP3325477B1 (en) Novel tricyclic 4-pyridone-3-carboxylic acid derivatives for the treatment and prophylaxis of hepatitis b virus infection
AU2018365174B2 (en) Processes for the resolution of benzodiazepin-2-one and benzoazepin-2-one derivatives
EP3495354A1 (en) Ido1 inhibitor and preparation method and application thereof
JP5971830B1 (en) Substituted polycyclic pyridone derivatives and prodrugs thereof
WO2015048567A1 (en) Spirocyclic ebi2 modulators
US11731954B2 (en) Histone demethylase inhibitors
CN112300153B (en) Heterocyclic compound, pharmaceutical composition and application
CN111315744B (en) Heteroaryl tetrahydropyridine compound, preparation method, pharmaceutical composition and application thereof
CN114539223B (en) Aryl-containing aza-seven-membered ring compound and preparation method and application thereof
EP3929185A1 (en) Nitrogen-containing fused cyclic compound, preparation method therefor and use thereof
CN115353508B (en) 5-pyridine-1H-indazole compound, pharmaceutical composition and application
CN111960970B (en) Antitumor compounds
CN108947912B (en) Neddylation pathway targeted anti-tumor compound
US20190055212A1 (en) Histone demethylase inhibitors
US10329279B2 (en) Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use
CN115340502B (en) BCL-XL inhibitor and preparation method and application thereof
CN115340499B (en) BCL-XL inhibitors and uses thereof
EP3677581A1 (en) Deuterated indoleamine 2,3-dioxygenase inhibitor and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20201106