CN105384651B - Aromatic ring contained amine chemical compound and preparation method and application thereof - Google Patents

Aromatic ring contained amine chemical compound and preparation method and application thereof Download PDF

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CN105384651B
CN105384651B CN201510696243.8A CN201510696243A CN105384651B CN 105384651 B CN105384651 B CN 105384651B CN 201510696243 A CN201510696243 A CN 201510696243A CN 105384651 B CN105384651 B CN 105384651B
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compound
cell
chemical compound
tumor
aromatic ring
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CN105384651A (en
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李维莉
马银海
鞠海东
黄文忠
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Kunming University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention discloses a class of an aromatic ring contained amine chemical compound and pharmaceutically acceptable salts thereof. Such chemical compound is good to inhibit tumorigenesis and metastasis activity, especially has significant inhibitory effects on prostate cancer cells and breast cancer cells, is an excellent anti-cancer lead compound, can be further developed as anti-tumor drugs for treating tumor metastasis lesions, advanced tumors, non-solid tumors and other tumors, and has potential and broad application prospects in the field of tumor therapy. The chemical compound is prepared by alkylation reaction of amines in DMSO-class solvent using halogenated parts and primary amine parts. The preparation method is simple and suitable for industrialized production.

Description

Aminated compoundss containing aromatic ring and its preparation method and application
The application is Application No. " 201410362592.1 ", entitled " aminated compoundss containing aromatic ring and its system The divisional application of the application for a patent for invention of Preparation Method and application ".
Technical field
The present invention relates to contain the aminated compoundss of aromatic ring.
Background technology
Malignant tumor is the principal disease for affecting health of people.Count according to WHO, the morbidity 1100 every year of whole world malignant tumor Many ten thousand people, die of illness ten thousand people more than 800, and developed country's tumor annual morbidity is higher than 3,00/,100,000.According to statistics, China city over the past two years Malignant Tumors among Residents account for the 1st of the cause of death, and ten thousand people of newly-increased patient about 160-170 every year, account for fatal disease 25.47%.WHO is newest to be delivered《World's cancer report》Say, to the year two thousand twenty, global cancer morbidity may be than growth now More than 50%, newly-increased tumor patient will be up to 20,000,000 people.The treatment of malignant tumor is with chemotherapy as Main Means, but chemotherapy institute at present The drug on tumor that uses, the killing activity of cancer cell be not high, the property selected is not strong, and needs strong dose thing, so as to right Human body generates very big toxic and side effects, therefore the new antitumor drug of exploitation is current urgent problem.
Cancer metastasiss are the dead main reasons of tumor patient：50% tumour patient is there are about clinically when making a definite diagnosis It was found that transfer, the ratio shifted in 3 months after clinical treatment (operation, chemicotherapy) is more up to 69%, and recurs in 1 year More than the 90% of the almost whole transfer case of the ratio of transfer.Its result be the final cause of death of 90% tumour patient all It is recurrence, invasion and attack and the transfer due to tumor.The invasion and attack of anti-curing oncoma, transfer be reduce tumor mortality rate effective way it One, it is that antineoplastic is crucial.
Carcinoma of prostate refers to the epithelial malignancy occurred in prostate.China's tumour registration area prostate in 2012 Cancer morbidity be 9.92/10 ten thousand, the 6th of row male malignancy sickness rate.The Symptoms of carcinoma of prostate are pressure symptom And metastasis symptom.The prostate gland urethra that pressure symptom shows as gradually increasing can cause progressive dysuria, table Now for urine line it is thin, range is short, bradyuria, uroflow interrupt, urine after the sound of rain pattering, urination not to the utmost, trouble urinating, additionally, also frequent micturition, Urgent micturition, nocturia increase, even urinary incontinence.Oncothlipsiss rectum can cause dyschesia or intestinal obstruction, can also oppress deferent duct and draw Absence of ejaculation is played, pressuring nerve causes perineal position pain, and can radiate to sciatic nerve.Metastasis symptom shows as to invade and wing Guang, seminal vesicle, nervus vasculairs beam, cause hematuria, hemospermia, sexual impotence.Lymph node transfers prognosi can cause double lower limb edema.Carcinoma of prostate Often easily there is Bone tumour, cause osteodynia or pathologisch Bruch, paraplegia.Carcinoma of prostate can also be invaded and bone marrow cause anemia or whole blood as Reduce.
Breast carcinoma is that the malignant tumor in mammary gland glandular epithelium tissue occurs, and is to threaten the able-bodied kinds of tumor of women. 8, U.S. women just has 1 people in life and suffers from breast cancer.According to Cancer in China center and Ministry of Public Health prevention and control of diseases office 2012 The pathogenesis of breast carcinoma data in 2009 announced show：National tumour registration area breast cancer incidence occupies female malignant 1st, female mammary gland cancer morbidity (rough and careless) whole nation adds up to 42.55/10 ten thousand, and city is 51.91/10 ten thousand, and rural area is 23.12/10 ten thousand.As breast cancer cell loses the characteristic of normal cell, connect loose between cell, easily come off.Cancer is thin Born of the same parents once come off, and free cancerous cell can send out whole body with blood or lymph fluid, form transfer, threat to life.
The content of the invention
It is an object of the present invention to provide aminated compoundss of the class containing aromatic ring.
It is a further object of the present invention to provide aminated compoundss pharmaceutically acceptable salt of the class containing aromatic ring.
A further object of the present invention is to provide the aminated compoundss of a class containing aromatic ring and its pharmaceutically acceptable salt Preparation method.
Another object of the present invention is to provide aminated compoundss of the class containing aromatic ring and is preparing prevention or treating antineoplastic agent Application in thing.
The purpose of the present invention is achieved by the following technical solution：
I-V structures of the present invention are as follows：
The above-mentioned aminated compoundss containing aromatic ring, its pharmaceutically acceptable salt can be hydrochlorate, hydrobromate, Fluohydric acid. Salt, sulfate, nitrate or phosphate；Alternatively formates, propionate, oxalates, malonate, succinate, fumaric acid Salt, maleate, malate, tartrate, citrate, picrate, mesylate or esilate；Can also be and acid The acid-addition salts of acidic amino acid and the salt formed with basic amino acid.
The preferred day east propylhomoserin of above-mentioned acidic amino acid or glutamic acid.
The preferred lysine of above-mentioned basic amino acid, arginine or ornithine.
The preparation method of the above-mentioned aminated compoundss containing aromatic ring and its pharmaceutically acceptable salt, comprises the following steps：
Wherein：I-IV structures have aforementioned given justice.
Further, the mol ratio of the VI-a and VII-a-c is 1：2.
Further, the mol ratio of the VI-b and VII-e is 2：1.
Further, the coupling reaction solvent dimethyl sulfoxide (DMSO), or tetrahydrofuran (THF) in carry out.
Further, the coupling reaction of the VI-b and VII-c use acylating reagent for thionyl chloride or Phosphorous chloride. or Phosphorus tribromide.
The above-mentioned aminated compoundss containing aromatic ring and its pharmaceutically acceptable salt are preparing the application in antitumor drug：Especially Which is the application in terms of carcinoma of prostate, breast carcinoma.
The beneficial effects of the present invention is：
The invention provides aminated compoundss of the class containing aromatic ring, as VGSCs parts, after testing with preferably suppression The activity that tumor occurs and shifts, especially has obvious inhibiting effect to prostate gland cancer cell and breast cancer cell, is excellent Antitumor lead compound, antitumor drug can be developed further into, for neoplasm metastasis, late tumor, non-physical The cancers such as tumor, have potential, wide application prospect in therapeutic field of tumor.Compound of the present invention adopts halogeno part The alkylation reaction that amine is carried out in DMSO class solvents with primary amine moiety is prepared, and method is simple, is adapted to industrialized production.
The suppression activity of tumor cells of the aminated compoundss containing aromatic ring of the present invention and its salt is determined as follows：
Extracorporeal anti-tumor cytoactive and antitumor cell transfer activity：
Experiment cell strain：Human prostate cancer cells strain DU145, PC3, mankind mastopathy cell strain MCF-7.Cell strain It is purchased from American type culture collection (American Type Culture Collection, ATCC).
Detection compound：5 kinds of compound DMSO are configured to the storing solution of 50mmol/L, store in -20 DEG C.
Detection method：
MTT analysis methods are used for detecting tumor cell survival
MTT working solutions (5mg/ml) are prepared with sterile PBS buffer.Cell is inoculated in 96 orifice plates, individual per hole 3000-5000 Cell culture after overnight incubation (10-12 hours), adds each compound in 100 μ l culture medium, concentration for the treatment of is 0.5,1.0, 2.5th, 5.0,10.0,25.0,50.0,100.0 μm of ol/L, each concentration set three parallel control holes.Each group DMSO final concentration is equal For 1/1000, while setting up 1/1000DMSO matched groups and medium controls.After test-compound is acted on 72 hours, remove Culture medium, adds the 100 μ l of fresh culture containing 10 μ l MTT solution per hole cell, makes MTT concentration be 0.5mg/ml.Cell after Continuous culture 3-5 hours, remove the culture medium containing MTT, add 100 μ lDMSO, jog culture plate to dissolve purple crystal per hole Afterwards, detected at 570nm wavelength with microplate reader (TECAN magellan Infinite 200, TECAN, Switzerland) and inhaled Luminosity, calculates survival rate of the cell relative to normal group cell by calculating each group relative to the absorbance of DMSO solvent controls.
Transwell methods are used for detecting the invasion and attack of tumor cell
According to 8：1 ratio is mixed on ice bath by serum-free medium and with Matrigel Matrix (U.S. company BD), The upper room of each Transwell cultures cell (Corning companies of the U.S.) adds the 50ul mixed liquors, in 37 DEG C of CO2 incubators Middle overnight incubation (less than 24h).Digest cultured PC3 cells into cell suspension count, each Transwell cell it is upper Room adds 100ul cell suspension (1 × 105 cell), overnight makes cell attachment in CO2 incubators, and on next day, room is changed to depletion of blood Clear culture medium simultaneously adds variable concentrations drug treating, with 1/1000DMSO as solvent control；600ul serum-free bars are added in lower room Part culture medium；48h is incubated in 37 DEG C of incubators；Take out Transwell cells PBS to wash 2 times, upper surface is wiped with cotton balls thin Born of the same parents, 10% poly dialdehyde fix cell film, add 0.1% violet staining, and after room temperature 0.5h, PBS is washed 2 times, carefully goes lower film, In basis of microscopic observation.
Data analysiss：
The IC50 that each compound kills various tumor cells is calculated, 1 is shown in Table.
1 each compound on prostate cancerous cell DU145, PC3 of table and breast cancer cell MCF-7, MDA-MB231's is direct Fragmentation effect (IC50/ μM)
Conclusion：Experiment shows that these compound on prostate cancerous cell and breast cancer cell have good inhibiting effect, makees There is very big DEVELOPMENT PROSPECT for new antitumor drug.
Impact of Transwell methods detection compound I-V to the invasive ability of prostate gland cancer cell PC3, referring to explanation Book accompanying drawing 1-6 (consumption of compound I-V is 10 μm of ol/L).
In various prostate cancer cell lines, the transfer ability of PC3 is most strong.Fig. 1 results show, 1/1000DMSO matched groups It was observed that a large amount of cells pass through transwell cells, the lower room side of cell film is come across；Equally, 10 μm of ol/L IV process PC3 After cell, a large amount of cells pass through transwell cells；And very small amount cell is seen in room side under the cell of 10 μm of ol/L II and V process Through transwell cells；And room side has no any cell under the cell of 10 μm of ol/L I and III process, show the concentration I-III and V can suppress the invasion and attack of high metastatic potential cell PC3 cells, so as to suppress the invasion and attack and transfer of tumor.
Description of the drawings
Fig. 1 is observation invasive ability of the 1/1000DMSO matched groups to prostate gland cancer cell PC3.
Fig. 2 is observation invasive abilities of the compound I to prostate gland cancer cell PC3.
Fig. 3 is observation invasive abilities of the compound II to prostate gland cancer cell PC3.
Fig. 4 is observation invasive abilities of the compound III to prostate gland cancer cell PC3.
Fig. 5 is observation invasive abilities of the compound IV to prostate gland cancer cell PC3.
Fig. 6 is observation invasive abilities of the compound V to prostate gland cancer cell PC3.
Specific embodiment
In order that the object, technical solutions and advantages of the present invention are clearer, below the preferred embodiments of the present invention are entered The detailed description of row.
Main agents and raw material：Primary amine and halogenating agent (Sigma-Aldrich Co.)；Nuclear magnetic resonance analyser (AV400, Bruker, TMS are internal standard)；Mass spectrograph (LC-MSD-1100 types, Aglent).Agents useful for same of the present invention is commercially available prod.
Embodiment 1：The preparation of compound I：
By 4,4- double (4- difluorophenyls) -1-chlorobutanes (compound VI-a, 0.56g, 2.0mmol) and L-phenylalanine first Ester (VII-a, 0.72g, 4.0mmol) is added in the DMSO in stand up reaction bottle of the 25mL with magnetic agitation (10mL), at 80 DEG C Stirring 10 hours.Reactant is transferred in the separatory funnel of 250mL, adds 150mL diluted ethyl acetates, then with 50mL's 5% Na2CO3 aqueous solutions are washed twice, twice, are finally washed once with the NaCl aqueous solutions of saturation 60mL with the washing of 60mL. Then organic layer anhydrous sodium sulfate drying, filters, concentration, column chromatography purification, obtain compound I (0.97g, 88%).1H-NMR (CDCl3,400MHz):7.32～7.23 (m, 5H), 7.20-7.10 (m, 4H), 7.01-6.95 (m, 4H), 4.08 (t, J= 7.7Hz,1H),3.64(s,3H),3.48(m,1H),2.94(m,2H),2.63-2.46(m,2H),2.03-1.96(m,3H), 1.41-1.36(m,2H).13C-NMR(CD3OD,100MHz):(d, J=240Hz), 178.3,162.4 147.9,141.8 (d, J =3Hz), 128.2 (d, J=8Hz), 129.1,126.1,125.7,116.4 (d, J=21Hz), 64.9,51.8,50.2, 49.8,48.6,32.6,27.6。MS(ES)m/z 424(M+1)。
Embodiment 2：The preparation of compound II：
By 4,4- double (4- difluorophenyls) -1-chlorobutanes (compound VI-a, 0.84g, 3.0mmol) and L-Leu methyl ester (VII-b, 0.87g, 6.0mmol) is added in the DMSO in stand up reaction bottle of the 50mL with magnetic agitation (20mL), is stirred at 80 DEG C Mix 16 hours.Reactant is transferred in the separatory funnel of 300mL, adds 200mL diluted ethyl acetates, then with the 5% of 80mL Na2CO3 aqueous solutions wash twice, twice, finally washed once with the NaCl aqueous solutions of saturation 80mL with the washing of 80mL.Then Organic layer anhydrous sodium sulfate drying, filter, concentration, column chromatography purification, obtain compound II (0.95g, 81%).1H-NMR (CDCl3,400MHz):7.16-7.12 (m, 4H), 6.98-6.92 (m, 4H), 3.85 (t, J=7.8Hz, 1H), 3.69 (s, 3H), 3.22 (t, J=6.9Hz, 1H), 2.56 (m, 1H), 2.24 (m, 1H), 2.03-1.98 (m, 2H), 1.67 (m, 1H), 1.46-1.41 (m, 5H), 0.91 (d, J=6.6Hz, 3H), 0.88 (d, J=6.6Hz, 3H).13C-NMR(CD3OD, 100MHz):(d, J=244Hz), 173.3,161.2 142.7 (d, J=3Hz), 129.3 (d, J=8Hz), 116.5 (d, J= 21Hz),61.5,52.9,50.9,47.8,40.5,36.2,29.6,24.6,23.1,23.0。MS(ES)m/z 290(M+1)。
Embodiment 3：The preparation of compound III：
By 4,4- double (4- difluorophenyls) -1-chlorobutanes (compound VI-a, 0.28g, 1.0mmol) and compound VII-c (0.22g, 2.0mmol) is added in the DMSO in stand up reaction bottle of the 15mL with magnetic agitation (5mL), little in 80 DEG C of stirrings 12 When.Reactant is transferred in the separatory funnel of 100mL, add 50mL diluted ethyl acetates, then with the 5% of 20mL Na2CO3 Aqueous solution is washed twice, twice, is finally washed once with the NaCl aqueous solutions of saturation 20mL with the washing of 20mL.Then organic layer is used Anhydrous sodium sulfate drying, filter, concentration, column chromatography purification, obtain compound III (0.27g, 76%).1H-NMR(CDCl3, 400MHz):7.76 (d, J=7.3Hz, 1H), 7.21-7.11 (m, 4H), 7.07-6.98 (m, 4H), 6.50 (m, 1H), 6.28 (d, J=7.2Hz, 1H), 4.11 (t, J=7.6Hz, 1H), 3.71 (s, 2H), 2.98 (d, J=7.3Hz, 2H), 2.61 (s, 3H),2.53-2.48(m,2H),2.07-1.99(m,2H),1.48-1.37(m,2H)。13C-NMR(CD3OD,100MHz): 163.1 (d, J=241Hz), 149.2,143.9,141.2 (d, J=3Hz), 129.1 (d, J=8Hz), 116.4 (d, J= 21Hz),111.2,110.6,60.1,57.8,51.1,43.6,33.5,26.5。MS(ES)m/z 356(M+1)。
Embodiment 4：The preparation of compound IV：
By 4,4- double (4- difluorophenyls) -1-chlorobutanes (compound VI-a, 1.12g, 4.0mmol) and compound VII-d (0.69g, 8.0mmol) is added in the DMSO in stand up reaction bottle of the 50mL with magnetic agitation (20mL), little in 80 DEG C of stirrings 11 When.Reactant is transferred in the separatory funnel of 300mL, adds 200mL diluted ethyl acetates, then with the 5% of 100mL Na2CO3 aqueous solutions are washed twice, twice, are finally washed once with the NaCl aqueous solutions of saturation 100mL with the washing of 100mL.Then Organic layer anhydrous sodium sulfate drying, filter, concentration, column chromatography purification, obtain compound IV (1.22g, 92%).1H-NMR (CDCl3,400MHz):7.15 (m, 4H), 6.96 (m, 4H), 3.86 (t, J=7.8Hz, 1H), 3.68 (t, J=4.6Hz, 4H), 2.36-2.31(m,6H),2.01(m,2H),1.43(m,2H).13C-NMR(CD3OD,100MHz):161.4 (d, J= 243Hz), 140.6 (d, J=3Hz), 129.1 (d, J=8Hz), 115.3 (d, J=21Hz), 67.1,59.0,53.9,49.8, 33.8,25.1。MS(ES)m/z 332(M+1)。
Embodiment 5：The preparation of compound V：
2- indolecarboxylic acids (compound VI-b, 2.1g, 12mol) and thionyl chloride (SOCl2,20mL) are added to into 50mL band magnetic In the stand up reaction bottle of power stirring, 3 hours are refluxed.Then decompression removes excessive thionyl chloride, is subsequently adding 15mL's Tetrahydrofuran solution and 4- (N, the N- dimethyl) pyridine (DMAP, 2.5g, 20mmol) of benzylamine (VII-c, 1.1g, 10mmol), Reactant liquor is stirred at room temperature 11 hours.Reactant is transferred in the separatory funnel of 100mL, 40mL diluted ethyl acetates is added, so Washed twice with the 5% of 40mL Na2CO3 aqueous solutions afterwards, with the washing of 20mL, twice, the NaCl finally with saturation 20mL is water-soluble Liquid is washed once.Then organic layer anhydrous sodium sulfate drying, filters, concentration, column chromatography purification, obtain compound VIII (2.1g, 78% yield).
By the compound VIII (0.38g, 1.0mmol) and Lithium Aluminium Hydride (LiAlH4,0.12g, 3.1mmol) of above-mentioned gained It is added in the tetrahydrofuran (5mL) in twoport reaction bulbs of the 25mL with magnetic agitation and reflux and nitrogen, is stirred at reflux 6 After hour, excessive Lithium Aluminium Hydride is destroyed with ethyl acetate.Reactant liquor is transferred in the separatory funnel of 50mL, 20mL second is added Acetoacetic ester dilutes, and with the washing of 10mL twice, is finally washed once with the NaCl aqueous solutions of saturation 10mL.Then organic layer is with anhydrous Sodium sulfate be dried, filter, concentration, column chromatography purification, obtain compound V (0.18g, 71%).1H-NMR(CDCl3,400MHz): 7.65 (d, J=7.9Hz, 1H), 7.43-7.21 (m, 7H), 7.18 (m, 1H), 6.22 (s, 1H), 3.89 (s, 2H), 3.82 (s, 2H),3.71(s,3H),2.069s,1H)；MS(ES)m/z 351(M+1).

Claims (2)

1. the preparation method of Formula I, it is characterised in that：The structure of Formula I is
It is obtained using following route：
2. compound I obtained in claim 1 is preparing answering in preventing or treating carcinoma of prostate invasion and attack or/and diversion medicaments With.
CN201510696243.8A 2014-07-28 2014-07-28 Aromatic ring contained amine chemical compound and preparation method and application thereof Expired - Fee Related CN105384651B (en)

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CN101230037A (en) * 2008-01-22 2008-07-30 张南 Anti-cancer drug compounds and method for synthesizing same
CN102701992A (en) * 2012-07-03 2012-10-03 重庆医科大学 Anti-tumour compound, pharmaceutically accepted salts as well as preparation method and application thereof

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