CN108997172A - Antitumoral compounds - Google Patents

Antitumoral compounds Download PDF

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Publication number
CN108997172A
CN108997172A CN201810898051.9A CN201810898051A CN108997172A CN 108997172 A CN108997172 A CN 108997172A CN 201810898051 A CN201810898051 A CN 201810898051A CN 108997172 A CN108997172 A CN 108997172A
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hydroxyl
hydrogen
acid
alkyl group
halogen
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CN108997172B (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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Chinese PLA General Hospital
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Priority to CN202010772297.9A priority Critical patent/CN111960985A/en
Priority to CN202010771763.1A priority patent/CN111892516A/en
Priority to CN201810898051.9A priority patent/CN108997172B/en
Priority to CN202010772282.2A priority patent/CN111960970B/en
Priority to CN202010772284.1A priority patent/CN111892517A/en
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    • 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 a kind of antitumoral compounds for targeting Neddylation access.The compound can be by general formula I, general formula II, general formula III, and structural formula described in general formula IV, general formula V or general formula VI indicates.The compound of the present invention has good anti-tumor activity, and multiple compounds can be used as good antitumoral compounds close to positive control drug MLN4924.The compound of the present invention and composition can be used together to provide combined therapy with other drugs, and other drugs can form a part of same combination, or are administered at the same time or when different as individual component.

Description

Antitumoral compounds
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of antitumoral compounds for targeting Neddylation access.
Background technique
Neddylation access is responsible for for ubiquitin-like molecule NEDD8 being covalently bound on protein molecular, regulates and controls the albumen Activity.The access can extensively in regulating cell a variety of important albumen degradation and function, for being responsible for the albumen of signal transduction It is extremely important.Neddylation access is carried out by a series of enzymatics: firstly, NEDD8 is activated by kinase E1, it is rear to turn Desmoenzyme E2 is moved to, and NEDD8 molecule covalent is integrated to substrate protein by E2 joint ligase E3, adjusts its function. Cullin class molecule is exactly one of the substrate of NEDD8 modification.Cullin class molecule is CRLs (cullin-RING ubiquitin Ligases) the scaffold molecule of ubiquitin-like ligase.It is CRLs ubiquitin-like ligase tool in NEDD8 modification to Cullin class molecule Active premise.The degradable a variety of substrates of CRLs ubiquitin-like ligase, a variety of important molecules, controllable including P21, P27 etc. The significant process such as period, apoptosis, the aging of cell, there are substantial connections with neurodegenerative disease and tumour.Neddylation It is multiple to can achieve treatment by inhibiting the function of the access for access overexpression and overacfivity in many tumours The purpose of the kinds of tumors such as myeloma.
In recent years, the key molecule for targeting Neddylation access screens inhibitor, becomes discovery new type antineoplastic medicine A key areas.Currently, foreign study mechanism and drugmaker target Neddylation access key molecule (such as UBA3 Deng) a variety of compounds with anti-tumor activity of acquisition are screened, part high-activity compound comes into I phase clinical stage.
Summary of the invention
The purpose of the present invention is to provide a kind of antitumoral compounds for targeting Neddylation access.
A kind of antitumoral compounds targeting Neddylation access, comprise the following structure the compound of general formula:
In formula, R1、R5Selected from hydrogen, halogen, hydroxyl, low alkyl group；R2、R3、R4Selected from hydrogen, halogen, nitro, hydroxyl, rudimentary Alkyl, lower alkoxy, low-grade halogenated alkyl, benzyloxy, substituted amido；R6Selected from hydrogen, carbonamidine, ghiourea group, amino, optionally take Amido, azacyclo-, amide groups, hydroxyl, the low alkyl group in generation；X is selected from methyl, ethyl, acrylic, amide groups, methoxyl group, oxo Ethyl；Y is selected from sulphur atom, amino, diazanyl, epoxy alkyl, heterocycle；
In formula, R7、R11Selected from hydrogen, halogen, hydroxyl, low alkyl group；R8、R9、R10Selected from hydrogen, halogen, nitro, hydroxyl, low Grade alkyl, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R12Selected from hydrogen, hydroxyl, amino, carbonamidine, Ghiourea group, the amido optionally replaced, azacyclo-, amide groups, low alkyl group；
In formula, R13、R16Selected from hydrogen, halogen, hydroxyl, low alkyl group；R14、R15Selected from hydrogen, halogen, nitro, hydroxyl, rudimentary Alkyl, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R17Selected from hydrogen, amino, carbonamidine, ghiourea group, Amido, azacyclo-, amide groups, hydroxyl, the low alkyl group optionally replaced；X1Selected from methyl, ethyl, acrylic, amide groups, methoxy Base, oxoethyl；Y1Selected from sulphur atom, amino, diazanyl, epoxy alkyl, heterocycle；
In formula, R18、R22Selected from hydrogen, halogen, hydroxyl, low alkyl group；R19、R20、R21Selected from hydrogen, halogen, nitro, hydroxyl, Low alkyl group, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R23Selected from carboxyl, hydroxyl, hydrogen, first Amidine, ghiourea group, amino, the amido optionally replaced, azacyclo-, amide groups, low alkyl group；
In formula, R24、R27Selected from hydrogen, halogen, hydroxyl, low alkyl group；R25、R26Selected from hydrogen, halogen, nitro, hydroxyl, rudimentary Alkyl, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R28Selected from hydrogen, amino, carbonamidine, ghiourea group, Amido, azacyclo-, amide groups, hydroxyl, the low alkyl group optionally replaced；X2Selected from methyl, ethyl, acrylic, amide groups, methoxy Base, oxoethyl；Y2Selected from sulphur atom, amino, diazanyl, epoxy alkyl, heterocycle；
In formula, R29、R33Selected from hydrogen, halogen, hydroxyl, low alkyl group；R30、R31、R32Selected from hydrogen, halogen, nitro, hydroxyl, Low alkyl group, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R34Selected from hydroxyl, hydrogen, carbonamidine, sulphur Urea groups, amino, the amido optionally replaced, azacyclo-, amide groups, low alkyl group ,-C (R35)2CH2OH、-CH(CH2OH)R35、- CH2CH(OH)R35；；X3Selected from methyl, ethyl, ethylamino-, acrylic, amide groups, methoxyl group, oxoethyl；Y3Selected from sulphur original Son, amino, diazanyl, isobutyl alkyl, epoxy alkyl, heterocycle.
The R35For low alkyl group.
Corresponding pharmaceutical salts are made with inorganic acid or organic acid reaction in the compound；The inorganic acid refers to hydrochloric acid, sulphur Acid, phosphoric acid, diphosphonic acid, hydrobromic acid or nitric acid；Organic acid refer to acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, P-methyl benzenesulfonic acid, salicylic acid or oxalic acid.
The compound of the present invention further includes its racemic modification, diastereomer, optical isomer, cis-trans isomerism and any group Conjunction or its pharmaceutical salts.
The compound and the pharmaceutical salts are preparing the application in anti-tumor drug or anti-inflammatory drug, tumour therein Refer to esophagus, stomach, intestines, oral cavity, pharynx, larynx, lung, mammary gland, uterus, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone, knot Form the cancer or thyroid cancer, leukaemia, suddenly king's evil, leaching that tissue, skin, eye, brain and central nervous system position occur Bar tumor, myeloma.
Beneficial effects of the present invention: the compound of the present invention has good anti-tumor activity, the close sun of multiple compounds Property comparison medicine MLN4924, can be used as good antitumoral compounds.The compound of the present invention and composition can be with other drugs one Rise usings to provide combined therapy, other drugs can form a part of same combination, or at the same time or difference when It is administered as individual component.
Specific embodiment
The present invention will be further described combined with specific embodiments below.
The synthesis of 1 compound 2 of embodiment
(E) -2- ((E) -3- (3- nitrobenzophenone) allylidene) diazanyl -1- carbonamidine, Chemdiv ID0589-0011, Chemical structural formula is as follows:
Preparation method
3- (3- nitro) -1- propyl alcohol (54.36mg, 0.3mmol), DMSO 0.6mL, acetonitrile 0.9mL, diiodo- formic acid (210mg, 0.75mmol), catalyst (0.12mg, 0.06mmol) react 8h at room temperature, and rotary evaporation removes volatile solvent, Crude product is obtained, with cyclohexane/ethyl acetate (70:1) for mobile phase, silica gel post separation is crossed, obtains compound 1 (42.3mg, yield 80%).
Compound 1 (177.16mg, 1mmol), aminoguanidinium salts hydrochlorate (110mg, 1mmol) dehydrated alcohol (6mL) and dense salt Sour (0.2mL), for 24 hours, rotary evaporation removes solvent to back flow reaction, and crude product with water is washed 3 times, then washes 3 times with dehydrated alcohol, finally Using acetone/dehydrated alcohol/methanol mixed liquor as mobile phase, compound 2 (157.21mg, the yield purified with column chromatography 64.5%).
1H-NMRδ(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).
The synthesis of 2 compound 12 of embodiment
4- methoxyl group -3- bromobenzyl isothiourea, Chemdiv ID 4298-0374, chemical structural formula are as follows:
Preparation method:
3- (3- nitro) -1- propyl alcohol (54.36mg, 0.3mmol), DMSO 0.6mL, acetonitrile 0.9mL, diiodo- formic acid (210mg, 0.75mmol), catalyst (0.12mg, 0.06mmol) react 8h at room temperature, and rotary evaporation removes volatile solvent, Crude product is obtained, with cyclohexane/ethyl acetate (70:1) for mobile phase, silica gel post separation is crossed, obtains compound 1 (42.3mg, yield 80%).
Compound 1 (177.16mg, 1mmol), aminoguanidinium salts hydrochlorate (110mg, 1mmol) dehydrated alcohol (6mL) and dense salt Sour (0.2mL), for 24 hours, rotary evaporation removes solvent to back flow reaction, and crude product with water is washed 3 times, then washes 3 times with dehydrated alcohol, finally Using acetone/dehydrated alcohol/methanol mixed liquor as mobile phase, compound 2 (157.21mg, the yield purified with column chromatography 64.5%).
1H-NMRδ(400MHz,DMSO+CCl4):3.85(s,3H),4.93(s,2H),6.97(d,1H),7.42(d,1H), 7.60(s,1H).
The synthesis of 3 compound 90 of embodiment
(R) -4- (4- luorobenzyl) -1- oxa- -9- azaspiro [5.5] hendecane, Chemdiv ID T500-0182, chemistry Structural formula is as follows:
Preparation method
0.5mol compound 1 is dissolved in 10mL ethyl acetate, and appropriate husky Rett reagent is added, reacts 8h at room temperature, filtering is received Collect filtrate, rotary evaporation removes ethyl acetate, and obtained solid is obtained by column chromatographic purifying (petrol ether/ethyl acetate=20:1) Compound 2.0.5mol compound 3 is dissolved in after 10mL acetonitrile, triphenylphosphine is added, react 10h at room temperature, 0.6molization is added Close object 2 and equimolar C4H9Li, subzero 20 DEG C of reactions 14h, after concentration cross column chromatographic purifying (petrol ether/ethyl acetate=10: 1) compound 5 purified.0.2mol compound 5 is dissolved in 5mL acetonitrile, equimolar AlCl is added350 DEG C of reaction 8h, add Column chromatographic purifying (petrol ether/ethyl acetate=8:1) purifying, the compound 90 after chiral fractionation are crossed in Pb/C reduction after concentration.
1H-NMRδ(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).
The synthesis of 4 compound 10 of embodiment
6- hydroxyl -2- ((2- (4- methoxyphenyl) -2- oxoethyl) sulfenyl) pyrimidine -4 (3H) -one, Chemdiv ID4112-3276, chemical structural formula are as follows:
Preparation method:
Compound 1 is purchased from 3B Scientific (Wuhan) Product List, China.
Compound 2 is purchased from AbovChem Product List, United States.
NaOH (80mg, 2mmol) is dissolved in 6ml H2O adds compound 2 (144mg, 1mmol), by 2mL under stirring Ethyl alcohol containing compound 1 (228mg, 1mmol) is added drop-wise in above-mentioned system, reacts 2h at room temperature, with the hydrochloric acid of 0.1mol/L The pH to 7.0 of solution after adjusting reaction, product filter after being precipitated, are dried in vacuo after being washed with deionized, obtain white chemical combination Object 10 (142mg, yield 49%).
1H-NMRδ(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).
The synthesis of 5 compound 13 of embodiment
2- (5- (benzyloxy) -1H- indol-3-yl) ethyl -1- amine, Chemdiv ID 4513-1373, chemical structural formula It is as follows:
5- benzyloxy indole -3- formaldehyde (251.3mg, 1mmol) and ammonium acetate (231mg, 3mmol) are dissolved in 5mL nitro Methane, back flow reaction 2h, vacuum distillation remove nitromethane, and product filters after being washed with water, and vacuum drying obtains product 1, do not have to Product 1 (294mg, 1mmol) is dissolved in and is added dropwise to 10mL after 10mL tetrahydrofuran and contains LiAlH by purifying4(228mg, 6mmol) Tetrahydrofuran in, 0 DEG C starts to react, and is gradually heated to 25 DEG C, the reaction was continued 36h, water is added dropwise into reaction system, until without gas Until bubble generates.Suitable Rochelle salt saturated solution and suitable ether are added into reaction system, are stirred at room temperature for 24 hours Afterwards, ether layer is collected in liquid separation, is washed ether layer extraction 3 times with the hydrochloric acid solution of 1mol/L, water phase is collected, with the hydroxide of 3mol/L Potassium solution neutralizes, and is finally extracted with ether, and rotary evaporation arrives compound 13 after anhydrous sodium sulfate is dry.
1H-NMRδ(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).
The synthesis of 6 compound 16 of embodiment
2- (5- methoxyl group -1H- indol-3-yl) Ethyl isothiuronium, Chemdiv ID 5911-0003, chemical structural formula is such as Under:
Preparation method
3- (the bromo- ethyl of 2-) -5- methoxyl group -1H- indoles is bought from Apichemical (Shanghai) Product List。
By thiocarbamide (150m g, 1.97mmol) and 3- (the bromo- ethyl of 2-) -5- methoxyl group -1H- indoles (581.66mg, 2.29m mol) it is dissolved in 20mL dehydrated alcohol, 60 DEG C of reaction 3h.Rotary evaporation removes ethyl alcohol after reaction, and obtained oily produces Object is transferred in the beaker of 500mL and stands still for crystals, and vacuum drying obtains product 16 after filtering.
1H-NMRδ(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).
The synthesis of 7 compound 17 of embodiment
(R) -2- (2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxin -2- base) methyl isothiourea, Chemdiv ID5914- 0610, chemical structural formula is as follows:
Preparation method
The purchase of 2- bromomethyl -1,4- benzdioxan likes (Shanghai) chemical conversion industry Development Co., Ltd from ladder is uncommon.
Thiocarbamide (150g, 1.97mmol) and 2- bromomethyl-Isosorbide-5-Nitrae-benzdioxan (524.41g, 2.29mol) are dissolved in 200mL dehydrated alcohol, 60 DEG C of reaction 3h.Rotary evaporation removes ethyl alcohol after reaction, and obtained oil product is transferred to 500mL's It is stood still for crystals in beaker, vacuum drying obtains product 17 after filtering.
1H-NMRδ(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).
The synthesis of 8 compound 20 of embodiment
2- ((3- (4- benzyl chloride oxygroup) benzyl) amino) -2- methyl-1 propyl alcohol, Chemdiv ID 6408-0439, chemistry knot Structure formula is as follows:
Preparation method
3- (4- chlorobenzyl) oxygroup benzaldehyde and 2-amino-2-methyl-1-propanol are purchased from lark prestige science and technology.
2-amino-2-methyl-1-propanol (0.97g, 10.89mmol) and 3- (4- chlorobenzyl) oxygroup benzaldehyde (2.819g, 11.44mmol) is dissolved in 25mL toluene, is cooled to room temperature after back flow reaction 4h, and rotary evaporation removes toluene, is added It is cooled to 0 DEG C after 25mL ethyl alcohol and NaBH is added4The hydrochloric acid and dioxane of 4.0mol/L is added dropwise in (1.03g, 27.2mmol) Mixed liquor adjusts the pH to 2.0 of solution, is at room temperature stirred overnight above-mentioned mixed liquor.It will be added after mixed liquor concentration after stirring The hydrochloric acid and methylene chloride (20mL) of isometric 1.0mol/L, after layering, collects water phase respectively, by the suitable dichloro of water phase Methane extracts 3 times, after organic phase discards, then water phase is adjusted to 8.0 with the NaOH of 10mol/L, and be extracted with dichloromethane Machine phase 3 times, collect organic phase and with anhydrous MgSO4It dries, filters, rotary evaporation removes methylene chloride and obtains product 20.
1H-NMRδ(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).
The synthesis of 9 compound 25 of embodiment
(2R, 4S) -2- (2,3- dihydroxy phenyl) thiazolidine -4- formic acid, Chemdiv ID 8010-6264, chemical structure Formula is as follows:
Preparation method:
By L-cysteine (0.175g, 1.1mmol), NaHCO3(0.084g, 1mmol) and 2,3- 4-dihydroxy benzaldehyde (0.124g, 0.9mmol) is dissolved in the DMSO aqueous solution of 10mL10%, reacts at room temperature, and TLC is detected after reaction, will react Liquid precipitates in ice-water bath, obtains white solid, obtains product 20 by liquid phase chiral separation method after drying.
1H-NMRδ(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: Cytostatic to tumor cell experiment
Cytostatic to tumor cell experiment is carried out to part of compounds of the invention, method uses CCK8 method (Japanese colleague Chemistry).
Cell strain using Human colorectal cancer cells strain HCT116+ /+, human large cell lung cancer cell strain H460, human lung adenocarcinoma H1299 cell, human breast cancer cell MCF7.Culture solution is DMEM (Hyclone)+10%FBS (Hyclone)+dual anti-.
Sample preparation: being dissolved as 10mM solution with DMSO (sigma), with it is preceding using cell culture medium to required dense Degree.Compound MLN4924 is configured to positive control solution with similarity condition.
CCK8 detection method: it is 5-6 × 10 that concentration, which is added, in the every hole of 96 orifice plates4The cell suspension 100ul of a/ml, in cell (37 DEG C, 5% carbon dioxide) of incubator cultures.After 24 hours, culture medium is discarded, the culture medium containing compound sample is added 300ul, if duplicate hole, 37 DEG C, 5% carbon dioxide continues culture 48 hours.Culture medium solution is discarded, addition contains 10% Serum-free DMEM (Hyclone) culture medium of CCK8 solution after continuing culture 2 hours, is detected using Tecan F50 microplate reader 450nm OD value.Calculate cell half-inhibitory concentration IC50.It the results are shown in Table 1 and table 2.
Table 1
Table 2
The experimental results showed that, most compounds of the invention have good anti-tumor activity, multiple compounds above Close to positive control drug MLN4924, it can be used as good antitumoral compounds.
Above description and show basic principles and main features of the invention.One of skill in the art is it should be appreciated that originally Invention is not restricted to the described embodiments, and above-described embodiment and description only illustrate basic principle of the invention, is not departing from this Under the premise of spirit and range, various changes and improvements may be made to the invention, these changes and improvements both fall within requirement and protect In the scope of the invention of shield.The claimed scope of the invention is defined by affiliated claim and its equivalent.

Claims (4)

1. a kind of antitumoral compounds for targeting Neddylation access, which is characterized in that comprise the following structure the chemical combination of general formula Object:
In formula, R1、R5Selected from hydrogen, halogen, hydroxyl, low alkyl group；R2、R3、R4Selected from hydrogen, halogen, nitro, hydroxyl, low alkyl group, Lower alkoxy, low-grade halogenated alkyl, benzyloxy, substituted amido；R6Selected from hydrogen, carbonamidine, ghiourea group, amino, optionally replace Amido, azacyclo-, amide groups, hydroxyl, low alkyl group；X is selected from methyl, ethyl, acrylic, amide groups, methoxyl group, oxo second Base；Y is selected from sulphur atom, amino, diazanyl, epoxy alkyl, heterocycle；
In formula, R7、R11Selected from hydrogen, halogen, hydroxyl, low alkyl group；R8、R9、R10Selected from hydrogen, halogen, nitro, hydroxyl, lower alkyl Base, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R12Selected from hydrogen, hydroxyl, amino, carbonamidine, thiocarbamide Base, the amido optionally replaced, azacyclo-, amide groups, low alkyl group；
In formula, R13、R16Selected from hydrogen, halogen, hydroxyl, low alkyl group；R14、R15Selected from hydrogen, halogen, nitro, hydroxyl, low alkyl group, Lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R17Selected from hydrogen, amino, carbonamidine, ghiourea group, optionally Substituted amido, azacyclo-, amide groups, hydroxyl, low alkyl group；X1Selected from methyl, ethyl, acrylic, amide groups, methoxyl group, Oxoethyl；Y1Selected from sulphur atom, amino, diazanyl, epoxy alkyl, heterocycle；
In formula, R18、R22Selected from hydrogen, halogen, hydroxyl, low alkyl group；R19、R20、R21Selected from hydrogen, halogen, nitro, hydroxyl, lower alkyl Base, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R23Selected from carboxyl, hydroxyl, hydrogen, carbonamidine, thiocarbamide Base, amino, the amido optionally replaced, azacyclo-, amide groups, low alkyl group；
In formula, R24、R27Selected from hydrogen, halogen, hydroxyl, low alkyl group；R25、R26Selected from hydrogen, halogen, nitro, hydroxyl, low alkyl group, Lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R28Selected from hydrogen, amino, carbonamidine, ghiourea group, optionally Substituted amido, azacyclo-, amide groups, hydroxyl, low alkyl group；X2Selected from methyl, ethyl, acrylic, amide groups, methoxyl group, Oxoethyl；Y2Selected from sulphur atom, amino, diazanyl, epoxy alkyl, heterocycle；
In formula, R29、R33Selected from hydrogen, halogen, hydroxyl, low alkyl group；R30、R31、R32Selected from hydrogen, halogen, nitro, hydroxyl, lower alkyl Base, lower alkoxy, low-grade halogenated alkyl, benzyloxy, the amido optionally replaced；R34Selected from hydroxyl, hydrogen, carbonamidine, ghiourea group, ammonia Base, the amido optionally replaced, azacyclo-, amide groups, low alkyl group ,-C (R35)2CH2OH、-CH(CH2OH)R35、-CH2CH(OH) R35；；X3Selected from methyl, ethyl, ethylamino-, acrylic, amide groups, methoxyl group, oxoethyl；Y3Selected from sulphur atom, amino, hydrazine Base, isobutyl alkyl, epoxy alkyl, heterocycle.
2. targeting the antitumoral compounds of Neddylation access according to claim 1, which is characterized in that the R35For Low alkyl group.
3. the pharmaceutical salts of compound described in claim 1, which is characterized in that the compound and inorganic acid or organic acid reaction Corresponding pharmaceutical salts are made；The inorganic acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, diphosphonic acid, hydrobromic acid or nitric acid；Organic acid refers to Acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-methyl benzenesulfonic acid, salicylic acid or oxalic acid.
4. pharmaceutical salts described in compound described in claim 1 and claim 3 are in preparing anti-tumor drug or anti-inflammatory drug Application, which is characterized in that tumour therein refers to esophagus, stomach, intestines, oral cavity, pharynx, larynx, lung, mammary gland, uterus, ovary, forefront The cancer that gland, testis, bladder, kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system position occur, Or thyroid cancer, leukaemia, suddenly king's evil, lymthoma, myeloma.
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