CN106632059A - N-naphthylalkyl-substituted N-containing heterocyclic derivatives, preparation method and anti-tumor application thereof - Google Patents
N-naphthylalkyl-substituted N-containing heterocyclic derivatives, preparation method and anti-tumor application thereof Download PDFInfo
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Abstract
The invention discloses N-naphthylalkyl-substituted N-containing heterocyclic derivatives, a preparation method and anti-tumor application thereof, in particular to compounds as shown in a general formula I or nitrogen oxides, and pharmaceutically-acceptable salts or solvates thereof, a preparation method thereof and application in pharmaceuticals, especially in tumor resisting. Pharmacodynamic experiment results indicate that the compounds of the general formula I in the invention can decrease the level of a tumor promoting factor Mdm2 in tumor cells and produce significant anti-tumor effects. Therefore, the compounds in the invention can be used to prepare pharmaceuticals for preventing or treating tumor-related diseases. The general formula I is shown in the description.
Description
Technical field
The present invention relates to pharmaceutical field, and in particular to the alkyl-substituted nitogen-contained heterocycle derivant of N- naphthalenes, its preparation
Method and its application in prevention or treatment tumor disease medicine.
Background technology
Cancer is the public health problem of whole world serious concerns, is also the maximum prestige of the human health not yet captured
One of side of body.Tumour is to exchange the signals such as ganglion cell's growth, differentiation, function and apoptosis with cell itself
What wrong responses were characterized.At present, the antineoplastic for clinically using includes cytotoxic drug, kinases
Inhibitor, proteasome inhibitor, hdac inhibitor and hedgehog inhibitor etc..
Mdm2 is a ubiquitin ligase, and its vital function is that poly ubiquitination is carried out to p53, is promoted
Enter it and enter proteasome degraded.P53 is referred to as " the gene bodyguard " of cell, p53 genes in normal cell
Stable low transcriptional level is maintained, and concentration is low to being almost difficult to detect in cell, its main cause is Mdm2
To the ubiquitination degradation and functional transcription inhibitory action of p53 (Cell Death Differ.2010,
17(1)：86-92).Cell is activated by DNA damage, the former cancer factor, the stimulating of active oxygen, poor nutritional
Deng Pressure stimulation when, p53 will be activated, and p53 that is stable and activating can just recruit some Cotranscription factors knots
The expression of transcriptional control downstream gene in the specific region of DNA is closed, a series of biological effect is produced,
The growth of regulating cell, aging, apoptosis and metabolism.Research shows that Mdm2 crosses table in many tumor tissues
Reach, so that the functional transcription and level of p53 albumen have and significantly decline in tumour cell, and then
Weaken inhibitory action (Curr.Cancer Drug Targets 2005,5,3-8) of the p53 to tumour cell.Additionally,
Mdm2 also produces carcinogenesis (Trends in Biochemical Sciences by the approach that non-p53 is relied on
2009,34 (6)：279-286), for example, Mdm2 can cause cancer suppressorfactor Rb albumen to drop by poly ubiquitination
Solution (Nature 1995,375,694-698；EMBO J.2005,24,160-169)；Mdm2 is by activating E2F1
Functional transcription so that promote cell cycle progression (Nature 1995,375,691-694)；Mdm2 can promote
Proteasome degraded (EMBO J.2003,22,6365-6377) of cancer suppressorfactor p21 etc..In a word, Mdm2
Key effect is played in regulating cell apoptosis and cell cycle progression, is the carcinogen of a confirmation.Therefore,
The function of suppressing Mdm2 is expected to become the new way of oncotherapy.
At present, Mdm2-p53 protein-protein phase interactions are mainly developed in the anti-cancer agent research based on Mdm2
With inhibitor (Curr.Med.Chem.2014；21(5)：553-74), and existing some Mdm2-p53 albumen-eggs
White interaction inhibitor is (such as：AMG232, DS-3032b, MI-77301 etc.) enter clinical investigation phase.
Although Mdm2-p53 protein-protein interaction inhibitor shows certain antitumor work in clinical testing
With, but such inhibitor has the related limitation of obvious mechanism of action, and for example, the curative effect of such medicine is high
Degree relies on the state of p53, thus (p53 is to be mutated or lack in the tumour more than 50% to p53 mutated tumors
Lose) offer limited effectiveness (Cell Cycle 2011,10,1590-1598).Additionally, Mdm2-p53 protein-protein phases
Interaction inhibitor is remarkably improved the expression of Mdm2 in cell, and (Mdm2 is the target gene of p53, p53 water
Flat rising can promote on the contrary the expression of Mdm2), and increased by suppressing the degraded of itself ubiquitination of Mdm2
Plus the stability of Mdm2, its result be negative-feedback enhance the carcinogenic effect of Mdm2, and therefore and can
Drug resistance (Cell Cycle 2011,10,1590-1598) can be produced.
In recent years, deubiquitinating enzymes USP7 is of concern as antineoplastic new target.It is right that USP7 can pass through
Mdm2 deubiquitinations and suppress the ubiquitination of Mdm2 to degrade, so as to improve its stability (Mol Cell.2004,
26；13(6)：879-86).Research shows, USP7 overexpression in the tumour such as prostate cancer and Huppert's disease
(Nature 2008,455,813-818；Cancer Cell 2012,22,345-358).USP7 inhibitor can have
Effect reduces the content of Mdm2 in cell, and the approach relied on by p53 dependences and non-p53 is played and suppresses to swell
Effect (the Cancer Cell 2012,22,345-358 of knurl；Cell Death and Disease 2013,4, e867；Nat
Cell Biol.2006,8 (10)：1064-73；Nature 2008,455,813-818).Suppress in the USP7 for grinding at present
Agent species is less, and selective poor (Chinese pharmaceutical chemistry magazine 2013,23,486-492).Additionally, existing
There is USP7 inhibitor also unclear with the binding site of USP7 and the mode of action.Representational USP7 suppresses
Agent include P5091, its Huppert's disease is had significant inhibitory action (Cancer Cell 2012,22,
345-358)。
In sum, compared with Mdm2-p53 protein-protein interaction inhibitor, Mdm2 can be reduced
Stability further reduces the medicine of its content and advantage is had more in terms of antitumor curative effect.
The content of the invention
The present inventor based on USP7 Binding Capacities domain-Mdm2 peptides albumen eutectic structure (PLoSBiol2006,4 (2)：
E27), using fragment method of formation, series of new compound has been designed and synthesized, by anti-tumor biological
Evaluate and study on mechanism, it was found that a class has the active compound for anti tumor of brand new.Such chemical combination
Thing can significantly reduce the content of Mdm2 in tumour cell, and with dose dependent.The invention discloses such as
Compound or its pharmaceutically acceptable salt or solvate shown in following formula I：
Wherein, K, M are independently chosen from CH, N or CR4；
L is CH, N or CR5；
R1For H, NO2, halogen, CN, trifluoromethyl, Y-R8、COR9、COOR10、CONR11R12、SO2NR11R12、
Or the aryl or heteroaryl of non-substituted or one or more replacements；
R2For H, NO2, halogen, CN, trifluoromethyl, formoxyl, CH (R6)XR7、COR9、COOR10、
CONR11R12, the alkyl of 1～12 carbon, alkyl, non-substituted or one or more aryl for replacing for replacing
Or heteroaryl
R3、R6Be independently chosen from H, the alkyl of 1～12 carbon, the alkyl for replacing, it is non-substituted or one or more
Substituted aryl or heteroaryl；
N is 0～2；
R7For H, the alkyl of 1～12 carbon, the alkyl for replacing, substituted or non-substituted benzyl, it is non-substituted or
One or more aryl for replacing or heteroaryl；
R4、R5It is independently chosen from H, halogen, formoxyl, COR9、COOR10、CONR11R12, 1～12 carbon
Alkyl, replace alkyl, substituted or non-substituted benzyl, it is non-substituted or one or more replace aryl or
Heteroaryl；Or R5And R64～8 yuan of rings are formed together with other atoms；
R8For H, COR9、SO2R13, the alkyl of 1～12 carbon, the alkyl, the substituted or non-substituted benzyl that replace
Base, the aryl or heteroaryl, substituted or non-substituted hetervaromatic methyl of non-substituted or one or more replacements；
R9、R10、R11、R12、R13Be independently chosen from H, the alkyl of 1～12 carbon, the alkyl for replacing, replace or
Non-substituted benzyl, the aryl or heteroaryl of non-substituted or one or more replacements；
X is NR14Or O；
Y is O, NR14, S, SO or SO2；
R14It is independently chosen from H, the alkyl of 1～12 carbon, the alkyl for replacing, non-substituted or one or more replacements
Aryl or heteroaryl.
In the present invention, K preferred CH or CR4；
M preferred N or CH；
L preferred CH or CR5；
R1It is preferred that Y-R8、COR9、COOR10、CONR11R12、SO2NR11R12It is non-substituted or one or
Multiple substituted aryl or heteroaryl；
R2It is preferred that CH (R6)XR7, 1～12 carbon alkyl, replace alkyl, it is non-substituted or one or more take
The aryl or heteroaryl in generation
R3、R6Preferably be selected from H, the alkyl of 1～12 carbon, the alkyl for replacing, it is non-substituted or one or more take
The aryl or heteroaryl in generation；
N preferably 0 or 1；
R7It is preferred that the alkyl of H, 1～12 carbon, the alkyl for replacing, substituted or non-substituted benzyl, non-substituted
Or the aryl or heteroaryl of one or more replacements；
R4、R5It is preferred that H, halogen, formoxyl, COR9、COOR10、CONR11R12, 1～12 carbon alkyl,
Substituted alkyl, substituted or non-substituted benzyl, the aryl or heteroaryl of non-substituted or one or more replacements；
Or R5And R64～8 yuan of rings are formed together with other atoms；
R8It is preferred that the alkyl of H, 1～12 carbon, the alkyl for replacing, substituted or non-substituted benzyl, non-substituted
Or the aryl or heteroaryl, substituted or non-substituted hetervaromatic methyl of one or more replacements；
R9、R10、R11、R12、R13It is preferred that the alkyl of 1～12 carbon, the alkyl, substituted or non-substituted for replacing
Benzyl, the aryl or heteroaryl of non-substituted or one or more replacements；
The preferred NR of X14Or O；
Y preferred O, NR14, S, SO or SO2；
R14It is preferred that the alkyl of H, 1～12 carbon, the alkyl for replacing, non-substituted or one or more virtues for replacing
Base or heteroaryl.
Further, preferred compounds of the invention is as follows：
It is a further object of the present invention to provide the synthetic method of such compound.
Specifically include following steps：
(1) by compound I and R5There is in the basic conditions nucleophilic substitution and compound II-a be obtained in-X, adopt
Alkaline reagent is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, preferred potassium carbonate；Using solvent
Selected from DMF, acetone, acetonitrile, preferred DMF；The reaction time for adopting is 1-24 hours；Adopt temperature for
Subzero 20 DEG C to 120 DEG C, preferably 60 DEG C to 100 DEG C.
(2) there is reduction reaction prepared compound III or III-3, the go back original reagent choosing of employing in compound II or II-a
From sodium borohydride, potassium borohydride, Lithium Aluminium Hydride, preferred sodium borohydride；Using solvent selected from methanol, ethanol,
Tetrahydrofuran, preferred methyl alcohol；The reaction time for adopting is 0.5-10 hours；Temperature is adopted for subzero 20 DEG C extremely
100 DEG C, preferably 0 DEG C to 30 DEG C.
(3) with halide reagent there is substitution reaction generation compound IV or IV-a in compound III or III-3, adopt
Halide reagent be selected from phosphorus tribromide, bromine, carbon tetrabromide, protochloride maple, preferred phosphorus tribromide；Using
Solvent is selected from dichloromethane, acetonitrile, ether, preferred dichloromethane；The reaction time for adopting is 1-24 hours；
Temperature is adopted for subzero 20 DEG C to 60 DEG C, preferably 0 DEG C to 25 DEG C.
(4) with the heterocycle containing NH or heteroaromatic there is in the basic conditions nucleophilic displacement of fluorine in compound IV or IV-a
Reaction is obtained compound V or V-a.Using alkaline reagent be selected from potassium carbonate, sodium carbonate, cesium carbonate, preferably
Potassium carbonate；The solvent for adopting is DMF, acetone, acetonitrile, preferred DMF；The reaction time for adopting is for 1-24
Hour；Temperature is adopted for subzero 20 DEG C to 120 DEG C, preferably 60 DEG C to 120 DEG C.
(5) there is the prepared compound VI-1a of reduction reaction in compound VI-1, and the go back original reagent of employing is selected from boron hydrogen
Change sodium, potassium borohydride, Lithium Aluminium Hydride, preferred sodium borohydride；Using solvent selected from methanol, ethanol, tetrahydrochysene
Furans, preferred methyl alcohol；The reaction time for adopting is 0.5-10 hours；Temperature is adopted for subzero 20 DEG C to 100 DEG C,
It is preferred that 0 DEG C to 30 DEG C.
(7) compound VI-2 occur reductive amination process be obtained VI-2a, the go back original reagent for adopting for sodium borohydride,
Sodium cyanoborohydride, sodium triacetoxy borohydride, preferred itrile group sodium borohydride；The solvent for adopting for methyl alcohol,
Ethanol, dichloromethane, tetrahydrofuran, preferred methyl alcohol；The reaction time for adopting is 1-24 hours；Using temperature
Spend for subzero 20 DEG C to 100 DEG C, preferably 25 DEG C to 50 DEG C.
(8) there is in the basic conditions the prepared VI-3a of alkylated reaction, the alkaline reagent of employing in compound VI-3
Selected from sodium methoxide, caustic alcohol, potassium tert-butoxide；The solvent for adopting is methyl alcohol, ethanol, acetonitrile, preferred methyl alcohol；
The reaction time for adopting is 1-24 hours；Temperature is adopted for subzero 20 DEG C to 120 DEG C, preferably 20 DEG C to 80 DEG C.
Specific compounds process for production thereof is with reference to embodiment.
It is yet another object of the invention to provide compound or pharmaceutically acceptable salt or solvate prepare it is pre-
Purposes in medicine that is anti-and treating tumour.Pharmacodynamic experiment result shows that compound has notable in the present invention
Anti-tumour cell proliferative effect.
The part pharmacological evaluation and result of the compound of the present invention is presented herein below.
【1】Cell in vitro activity pharmacological evaluation
1. experiment purpose：It is external to human colon cancer cell HCT116 using each compound of CCK-8 Determination Stainings
The impact of proliferation activity, and calculate respective half-inhibition concentration IC50。
2. experiment material：The compounds of this invention is configured to mother liquor with DMSO dissolvings, is trained completely using front employing
Foster base is diluted to debita spissitudo；Reagent：CCK-8 kits build up bio tech ltd purchased from Nanjing；Training
Foster base：Modified form RMPI-1640 culture mediums：Purchased from Hyclone companies；Class hyclone：Purchased from Hyclone
Company；96 porocyte culture plates are purchased from Costar companies.
3. experimental technique：The cell that live cell fraction is taken up to more than 90% is tested.Cell inhibitory effect is tested
Using EnoGeneCellTMCounting Kit-8 (CCK-8) cell viability detection kit.Cell dissociation,
Count, make concentration for 3 × 104The cell suspension of individual/ml, every hole adds 100 μ l cell suspensions in 96 orifice plates
(per hole 3 × 103Individual cell)；96 orifice plates are placed in 37 DEG C, 5%CO2Cultivate 24 hours in incubator；With complete
Culture medium dilutes medicine to desired concn, the culture medium of the corresponding drug containing of 100 μ L is added per hole, while setting up
Negative control group, vehicle control group.Per group of 5 multiple holes；96 orifice plates are placed in 37 DEG C, 5%CO2In incubator
Culture 72 hours；10 μ L CCK-8 solution are added per hole, culture plate are incubated 3.5 hours in incubator,
The OD values at 450nm are determined with ELIASA, the cell inhibitory rate under variable concentrations state is calculated and is calculated
IC50Value.
4. experimental result：Suppression of the compounds of this invention to human colon cancer cell HCT116 cell line in-vitro multiplications
Activity (IC50) see the table below.
| Compound | IC50(μM) | Compound | IC50(μM) | Compound | IC50(μM) | Compound | IC50(μM) |
| I-1 | 9.906 | I-14 | ＞ 100 | I-30 | ＞ 100 | I-45 | 18.85 |
| I-2 | 10.08 | I-15 | 30～100 | I-31 | 30～100 | I-46 | ＞ 100 |
| I-3 | 11.26 | I-16 | 30～100 | I-32 | 30～100 | I-47 | 8.495 |
| I-4 | 9.077 | I-17 | ＞ 100 | I-33 | ＞ 100 | P5091 | 12.21 |
| I-5 | 9.875 | I-18 | ＞ 100 | I-35 | 5.060 | ||
| I-6 | 11.57 | I-19 | ＞ 100 | I-37 | ＞ 100 | ||
| I-7 | 5.055 | I-20 | ＞ 100 | I-38 | ＞ 100 | ||
| I-8 | 11.03 | I-21 | ＞ 100 | I-39 | ＞ 100 | ||
| I-9 | 4.68 | I-22 | ＞ 100 | I-40 | 30～100 | ||
| I-10 | ＞ 100 | I-23 | ＞ 100 | I-41 | 7.782 | ||
| I-11 | 14.55 | I-24 | ＞ 100 | I-42 | 4.177 | ||
| I-12 | 11.25 | I-25 | 29.27 | I-43 | 28.55 | ||
| I-13 | 13.1 | I-27 | 7.799 | I-44 | 30～100 |
Above-mentioned test result shows that growth of the compounds of this invention to colon cancer cell has different degrees of suppression
Effect.Part of compounds shows the antitumor activity more higher than positive drug P5091.The result prompting present invention
Compound can be used for preparing antineoplastic.
【2】Normal cell toxicity pharmacological evaluation
With similar to the similar method of inhibiting tumour cells activity, carried out from representation compound I-1 normal thin
The pharmacological evaluation detection of cellular toxicity, experimental result is as follows：
As a result show, representation compound I-1 has the selectivity to tumour cell and normal cell, while it is anti-
Tumor promotion has certain P53 dependences.
【3】External molecular level pharmacological evaluation --- the horizontal checkout (Western blot) of tumour cell Mdm2
1. experiment purpose：Compound is determined in human colon cancer cell HCT116 using Western blot methods
The impact of Mdm2 contents
2. experiment material：The compounds of this invention is configured to mother liquor with DMSO dissolvings, is cultivated completely using front employing
Base is diluted to debita spissitudo；Reagent is purchased from Sheng Xing biotech firms；Culture medium：Modified form RMPI-1640 culture mediums：
Purchased from Hyclone companies；Class hyclone：Purchased from Hyclone companies；96 porocyte culture plates are purchased from Costar
Company.
3. experimental technique：The cell that live cell fraction is taken up to more than 90% is tested.Cell dissociation, counting,
The cell suspension that concentration is 100000/ml is made, adds 1000 μ l cell suspensions (every per hole in 12 orifice plates
Hole 2 × 105Individual cell)；12 orifice plates are placed in 37 DEG C, 5%CO2In incubator cultivate 24 hours it is adherent, suck
Layer culture medium；Medicine is diluted to desired concn, the corresponding drug containing of 1000 μ L is added per hole with complete medium
Culture medium, while set up negative control group, vehicle control group.Per group of 3 multiple holes；12 orifice plates are placed in 37 DEG C,
5%CO2Cultivate 7 hours in incubator, remove upper strata culture medium；With after PBS cell use cell lysis
Liquid cell lysis, extract albumen；
HCT-116 cells positive drug and compound I-1 are acted on, concentration selects 0 μM, 15 μM, 30 μM
With 50 μM, cell lysis after the corresponding time, with 10% separate gel electrophoresis.As a result show：With positive drug or change
The rising of compound I-1 concentration, the cellular level of Mdm2 significantly reduce (Fig. 1,2).
Compound of the present invention and combinations thereof can be used to prepare antineoplastic.The tumour include but not
Be limited to it is following these：
Osteocarcinoma, including (such as)：Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma cell
Knurl, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), Huppert's disease, evil
Property giant-cell tumor chordoma, osteochondroma (turn round and look at hose epostoma), benign chondromas, chondroblast
Knurl, cartilage and knurl sample fibroma, osteoidosteoma and giant-cell tumor.
Hematology's cancer, including (such as)：Hematologic cancers, such as acute myelogenous leukemia, chronic myelognous
It is leukaemia, acute lymphoblastic system leukaemia, chronic lymphocytic system leukaemia, myeloproliferative disease, many
Send out property myeloma and myelodysplastic syndrome, hodgkin's lymphomas (malignant lymphoma) and Walden this
Special human relations macroglobulinemia.
Nervous system cancer, including (such as)：Skull cancer, such as osteocarcinoma, hemangioma, granulation knurl, vitiligoidea and
Osteitis deformans；Meninx cancer, such as meningioma, meningosarcoma and glioma；The cancer of the brain, such as astrocytoma,
Medulloblastoma, glioma, ependymoma, gonioma (pinealoma), polymorphy into
Spongiocytoma, Oligodendroglioma, neurinoma, retinoblastoma and congenital tumor；
And spinal cord knurl, such as fibroneuroma, meningioma, glioma and sarcoma.
Stomach enteroncus, including (such as)：Esophagus cancer, such as squamous cell carcinoma, gland cancer, leiomyosarcoma and pouring
Bar knurl；Cancer of the stomach, such as tumour, lymthoma and leiomyosarcoma；Cancer of pancreas, such as duct adenocarcinoma, insulinoma, pancreas
Glucagonoma, gastrinoma, carcinoid tumor and vasoactive intestinal peptide tumor；Carcinoma of small intestine, such as gland cancer, lymthoma,
Carcinoid tumor, Kaposi's sarcoma, liomyoma, hemangioma, lipoma, fibroneuroma and fibroma；Greatly
Intestinal cancer, such as gland cancer, tubule gland cancer, villous adenoma, hamartoma and liomyoma.
Urinary system cancer, including (such as)：Kidney, such as gland cancer, wilms' tumor (nephroblastoma),
Lymthoma and leukaemia；Bladder and carcinoma of urethra, such as squamous cell carcinoma, transitional cell carcinoma and gland cancer；Prostate cancer,
Such as gland cancer and sarcoma；Carcinoma of testis, such as seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma,
Sarcoma, interstitial cell cancer, fibroma, adenofibroma, adenomatoid tumor and lipoma.
Lung cancer, including (such as)：It is bronchiolar carcinoma, such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated big
Cell cancer and gland cancer；Bronchioalveolar carcinoma；Bronchial adenoma；Sarcoma；Lymthoma；Chondroma of lung paramnesia
Knurl and celiothelioma.
Liver cancer, including (such as)：Hepatocellular carcinoma, such as hepatocellular carcinoma；Cholangiocarcinoma；Hepatoblastoma；Blood vessel
Sarcoma；Adenoma and hemangioma.
Cutaneum carcinoma, including (such as)：Chromoma, basal-cell carcinoma, squamous cell carcinoma, card ripple Ji Shi
Sarcoma, dysplasia mole, lipoma, hemangioma, histiocytoma, cheloid, psoriasis.
Present invention also offers a kind of pharmaceutical composition of prevention and treatment tumour, wherein containing therapeutically effective amount
The compound or its pharmaceutically acceptable salt or solvate are used as active ingredient and pharmaceutically acceptable load
Body.Described pharmaceutical composition can be conventional tablet or capsule, sustained-release tablet or capsule, Dospan or capsule,
Conventional dosage form on the galenic pharmacies such as granule, powder, syrup, oral liquid, injection.
In pharmaceutical composition of the present invention the dosage of the compound or its pharmaceutically acceptable salt or solvate with
Symptom and age etc. are different and different.Difference and formulation also dependent on disease degree different and deviate this dosage
Scope.
When applying compound of the present invention and being treated or prevented, also can be with the method (example of existing treating cancer
Such as, by chemotherapy, radiotherapy or operation) it is administered in combination.Therefore present invention also offers a kind of side for the treatment of cancer
Method, including to patient using therapeutically effective amount according to the same of the compound or its pharmaceutically useful salt form or preparation
When to one or more of patient therapeuticallv's effective dose other cancer chemotherapeutic agent.For any specific patient,
Depending on specific pharmaceutical combination and specific treatment effective dose level need to be according to multiple factors, the factor
Including the tumor type, feature and its grade malignancy treated；The activity of the particular compound for being adopted；Patient
Age, body weight, general health, sex and diet；The administration time of the particular compound for being adopted,
Method of administration and excretion rate；Treatment duration and similar factor known to medical field.
The example of suitable chemotherapeutics including but not limited to it is following these：
Alkylating agent：Nitrogen mustards, endoxan, ifosfamide, melphalan, Chlorambucil, bendamustine
Spit of fland, Estramustine；Ethylenimines, Tespamin, quinone imine；Sulphonic acid ester and polyalcohols, busulfan, two
Bromine mannitol；Nitrosoureas, hexamethylene nitrous, carmustine, nimustine, CH3-CCNU；Triazenes
Imidazoles, dacarbazine；Hydrazine, procarbazine.
Antimetabolite：Pyrimidine antagonists, fluorouracil, cytarabine, FT, Tegadifur；
Purine antagonist, mercaptopurine, Sulfomercaprine Sodium, imuran, thioguanine；Antifol, first ammonia butterfly
Purine, aminopterin.
Antitumor antibiotics：Mitomycin C, bleomycin, actinomycin D, mithramycin, daunorubicin,
Adriamycin, chromomycin A3, enramycin, Neocarzinostatin, sarkomycin, M3.
Plant kind anti-cancer drugs：Vincristine, colchicin, camptothecine, HCPT, cantharidin, indigo are beautiful
It is red.
Hormone：Adrenocorticotropic hormone, metacortandracin, prednisolone, hydrocortisone, dexamethasone；
Estrogen, diethylstilbestrol, hexoestrol dibromoacetate；Androgen and anabolic hormone, testosterone propionate, methyltestosterone,
Nandrolone Phenylpropionate, NSC-70735, TAM.
Other types：Neoplatin, interferon, L-asparaginase, hydroxycarbamide, tetrahydroform, methyl GAG,
Haematoporphyrin；Immune formulation.
Description of the drawings
When Fig. 1 shows that positive drug p5091 acts on HCT-116 cells, intracellular Mdm2 levels are reduced with medicine
Thing concentration increases and reduces；
When Fig. 2 shows that compound I-1 acts on HCT-116 cells, intracellular Mdm2 levels are reduced with medicine
Concentration increases and reduces；
Fig. 3 is the nucleus magnetic hydrogen spectrum of compound I-1；
Fig. 4 is the nuclear-magnetism carbon spectrum of compound I-1.
Specific embodiment
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below is
It is not for limiting the scope of the present invention to preferably illustrate the present invention.
Embodiment 1
The preparation of 6- benzyloxies-naphthalene -2- aldehyde (II)
6- hydroxyls-beta naphthal (150mg, 0.87mmol), potassium carbonate (361mg, 2.61mmol) are added dry
In DMF (3ml), stir 30 minutes under room temperature.Be added dropwise in reactant liquor the chloro- bromobenzyls of 2- (223mg, 155 μ l,
After 1.31mmol), 80 DEG C of oil baths are placed in, stir complete to reaction.Add water and reaction is quenched, use ethyl acetate
Extraction, merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains mesh
Mark compound (200mg, yield 87.5%).1H NMR (300MHz, DMSO) δ 10.06 (s, 1H), 8.48
(s, 1H), 8.07 (d, J=9.0Hz, 1H), 7.92 (d, J=8.6Hz, 1H), 7.83 (d, J=8.5Hz, 1H),
7.55 (s, 1H), 7.50 (d, J=6.7Hz, 2H), 7.45-7.21 (m, 4H), 5.25 (s, 2H).
Embodiment 2
The preparation of (6- benzyloxies-naphthalene -2- bases)-methyl alcohol (III)
6- benzyloxies-naphthalene -2- aldehyde (II) (200mg, 0.76mmol) is dissolved in and is dried in methyl alcohol (5ml), added
Sodium borohydride (43mg, 1.14mmol) is dried, 2h is stirred under room temperature complete to reaction.Solvent is evaporated, is used
Ethyl acetate is extracted, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silicagel column
Target compound III crude products are chromatographed to obtain, the next step is direct plungeed into.(190mg, crude yield 94.3%)
Embodiment 3
The preparation of 2- benzyloxies -6- bromomethyls-naphthalene (IV)
(6- benzyloxies-naphthalene -2- bases)-methyl alcohol (III) (150mg, 0.57mmol) is dissolved in dichloromethane (5ml),
The dichloromethane solution (384mg, 135 μ l, 1.42mmol/1ml) of phosphorus tribromide is added dropwise under 0 DEG C of ice bath, is risen naturally
Warm to room temperature stirring 4h.Add water and be quenched, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate is done
It is dry.It is evaporated rear silica gel column chromatography and obtains target compound V crude products, direct plunges into the next step.(110mg, slightly
Product yield 59.2%)
Embodiment 4
The preparation of 1- [(6- benzyloxies-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (1)
By 2- benzyloxies -6- bromomethyls-naphthalene (100mg, 0.31mmol), potassium carbonate (93mg, 0.67mmol), 2-
Formaldehyde-imidazoles (48mg, 0.50mmol) is dissolved in DMF, stirs complete to reaction at 80 DEG C, is warmed to room temperature, and adds water
It is quenched, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography to obtain
The crude product of target compound 1, direct plunges into the next step.(110mg, crude yield 94.35%)
Embodiment 5
The preparation of 1- { 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-1)
1- [(6- benzyloxies-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (100mg, 0.29mmol) is dissolved in into drying
Methyl alcohol, adds methylamine alcohol solution (0.5ml), adds excessive drying anhydrous sodium sulfate as attached water agent, and room temperature is stirred
Mix overnight；Solid sodium sulfate is filtered off, is added in reactant liquor and is dried sodium borohydride solids (17mg, 0.44mmol),
It is stirred at room temperature complete to reaction.Solvent is evaporated, is extracted with ethyl acetate, merge organic layer, saturated aqueous common salt
Washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains target compound I-1 (90mg, yield 86.2%)1H
NMR (300MHz, DMSO) δ 7.70 (d, J=8.9Hz, 2H), 7.56-7.18 (m, 9H), 7.03 (s,
1H), 6.91 (s, 1H), 5.36 (s, 2H), 5.19 (s, 2H), 3.85 (s, 2H), 2.47 (s, 3H).13C NMR(75
MHz, CDCl3) δ 157.14,148.90,145.67,136.69,134.04,131.67,129.35,128.82,
128.61,128.05,127.72,127.51,125.66,125.26,120.82,119.72,107.14,70.07,49.71,
47.36.35.81.
Embodiment 6
The preparation of 1- { 1- { [6- (2- benzyl chloride epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-2)
Reactions steps obtain target compound I-2 (65mg, yield 62.50%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.64-7.59 (m, 1H), 7.46 (s, 1H), 7.42 (s,
1H), 7.29 (s, 3H), 7.22 (m, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 5.34 (s, 2H), 5.29 (s, 2H),
3.82 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ 156.81,146.32,134.00,
131.95,129.42,129.06,128.96,128.81,127.76,127.49,126.97,126.91,125.61,
125.34,120.66,119.51,107.31,67.18,49.62,47.79,36.10.
Embodiment 7
The preparation of 1- { 1- { [6- (3- methoxybenzyl epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-3)
Reactions steps obtain target compound I-3 (85mg, yield 81.70%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 7.36-7.25 (m, 2H), 7.21 (s,
2H), 7.04 (m, 3H), 6.96 (s, H), 6.84 (s, H), 5.33 (s, 2H), 5.15 (s, 2H), 3.80 (s, 3H)
3.11 (s, 2H), 2.44 (s, 3H).13C NMR (75MHz, CDCl3) δ 159.88,157.08,146.32,138.32,
134.02,131.84,129.66,129.34,128.86,127.70,127.48,125.63,125.29,120.66,
119.66,113.51,113.01,107.22,69.94,55.22,49.62,47.77,36.09.
Embodiment 8
The preparation of 1- { 1- { [6- (3- benzyl chloride epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-4)
Reactions steps obtain target compound I-4 (63mg, yield 43.27%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.69 (d, J=8.6Hz, 2H), 7.47 (d, J=8.8Hz, 2H), 7.40-7.06 (m, 6H),
7.01 (s, 1H), 6.89 (s, 1H), 5.33 (s, 2H), 5.14 (s, 2H), 3.80 (s, 2H), 2.43 (s, 3H).13C
NMR (75MHz, CDCl3) δ 157.22,146.69,139.23,134.98,134.38,132.43,130.29,
129.89,129.38,128.57,128.12,127.95,127.84,126.06,125.80,125.77,121.09,
119.94,107.65,69.61,50.03,48.20,36.50.
Embodiment 9
The preparation of 1- { 1- { [6- (4- fluorine benzyloxies) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-5)
Reactions steps obtain target compound I-5 (90mg, yield 43.27%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.70 (d, J=8.3Hz, 2H), 7.45 (s, 2H), 7.42 (s.1H), 7.26-7.16 (m,
3H), 7.08 (m, 2H), 7.02 (s, 1H), 6.89 (s, 1H), 5.33 (s, 2H), 5.12 (s, 2H), 3.81 (s, 2H),
2.44 (s, 3H).13C NMR (75MHz, CDCl3) δ 164.17,160.90,156.95,146.35,133.99,
131.95,129.41,129.29,127.68,127.48,125.64,125.36,120.65,119.60,115.64,
115.36,107.20,69.39,49.60,47.79,36.10.
Embodiment 10
The preparation of 1- { 1- { [6- (4- methylbenzyloxies) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-6)
Reactions steps obtain target compound I-6 (67mg, yield 58.44%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.68 (dd, J=8.4,4.6Hz, 2H), 7.45 (s, 1H), 7.37 (d, J=7.8Hz, 2H),
7.23 (m, 5H), 7.01 (s, 1H), 6.89 (s, 1H), 5.32 (s, 2H), 5.13 (s, 2H), 3.80 (s, 2H), 2.44
(s, 3H), 2.37 (s, 3H).13C NMR (75MHz, CDCl3) δ 157.63,146.76,143.78,138.26,
134.47,134.10,132.18,129.71,129.23,128.10,128.06,127.90,126.05,125.67,
121.07,120.18,107.58,70.45,50.06,48.21,36.52,21.57.
Embodiment 11
The preparation of 1- { 1- { [6- (4- benzyl chloride epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-7)
Reactions steps obtain target compound I-7 (220mg, yield 75.55%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.70 (d, J=8.3Hz, 2H), 7.46 (s, 1H), 7.39 (m, 4H), 7.21 (m, 3H),
7.02 (s, 1H), 6.90 (s, 1H), 5.35 (s, 2H), 5.15 (s, 2H), 3.82 (s, 2H), 2.45 (s, 3H).13C
NMR (75MHz, CDCl3) δ 156.85,146.23,135.23,133.96,133.85,131.96,129.44,
128.92,128.77,128.65,127.69,127.52,125.64,125.37,120.68,119.55,107.23,
69.28,49.62,47.74,36.06.
Embodiment 12
The preparation of 1- { 1- { [6- (4- nitro benzyloxies) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-8)
Reactions steps obtain target compound I-8 (60mg, yield 55.81%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 8.28 (d, J=8.5Hz, 2H), 7.70 (dd, J=19.8,8.8Hz, 4H), 7.32-7.11
(m, 4H), 7.03 (s, 1H), 6.91 (s, 1H), 5.36 (s, 2H), 5.30 (s, 2H), 3.83 (s, 2H), 2.45 (s,
3H).13C NMR (75MHz, CDCl3) δ 148.64,146.74,136.48,134.76,132.28,130.34,
130.21,130.06,129.80,128.27,128.10,126.45,123.32,122.65,121.94,117.18,
109.91,71.32,52.24,50.13,38.57.
Embodiment 13
The preparation of 1- { 1- { [6- (4- bromo-benzyloxys) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-9)
Reactions steps obtain target compound I-9 (105mg, yield 53.14%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.68 (d, J=8.6Hz, 2H), 7.52 (d, J=8.1Hz, 2H), 7.45 (s, 1H), 7.34
(d, J=8.1Hz, 2H), 7.28-7.18 (m, 2H), 7.17 (s, 1H), 7.01 (s, 1H), 6.85 (d, J=17.8
Hz, 1H), 5.33 (s, 2H), 5.22-5.02 (m, 2H), 3.75 (d, J=33.2Hz, 2H), 2.43 (s, 3H).13C
NMR (75MHz, CDCl3) δ 157.25,146.71,136.18,134.37,132.43,132.15,129.87,
129.48,129.35,128.10,127.96,126.06,125.80,122.37,121.08,119.96,107.67,
69.72,50.03,48.22,36.50.
Embodiment 14
The preparation of 1- { 1- { [6- (naphthalene -2- bases) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-10)
Reactions steps obtain target compound I-10 (50mg, yield 65.57%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.95 (s, 1H), 7.87 (m, 3H), 7.72 (d, J=8.6Hz, 2H), 7.60 (d, J=8.5
Hz, 1H), 7.56-7.48 (m, 2H), 7.47 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 5.36 (s, 2H),
5.34 (s, 2H), 3.82 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ 157.16,146.28,
134.20,134.04,133.32,133.12,131.82,129.39,128.89,128.43,127.93,127.73,
127.65,127.47,126.37,126.27,126.11,125.65,125.30,125.24,120.67,119.71,
107.32,61.62,49.64,47.70,36.06.
Embodiment 15
The preparation of 1- { 1- [(6- isobutyl group epoxide naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-11)
Reactions steps obtain target compound I-11 (66mg, yield 56.90%) with reference to embodiment 1-5.1H NMR(300
MHz, CDCl3) δ 7.69 (t, J=8.2Hz, 2H), 7.47 (d, J=11.2Hz, 1H), 7.27-7.08 (m,
2H), 7.02 (s, 1H), 6.90 (s, 1H), 5.33 (s, 2H), 3.85 (d, J=6.5Hz, 2H), 3.81 (s, 2H),
2.44 (s, 3H), 2.20 (dd, J=15.8,9.2Hz, 1H), 2.12 (s, 1H), 1.08 (d, J=6.7Hz, 6H).13C
NMR (75MHz, CDCl3) δ 157.62,146.42,134.14,131.51,129.16,128.61,127.56,
127.47,125.62,125.19,120.66,119.71,106.52,77.45,77.03,76.61,74.48,49.64,
47.86,36.16,28.24,19.29.
Embodiment 16
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- propyl group -1H- imidazoles (I-12)
Reactions steps obtain target compound I-12 (60mg, yield 53.47%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.70 (dd, J=8.6,5.1Hz, 2H), 7.52-7.13 (m, 9H), 7.01 (d, J=1.2
Hz, 1H), 6.85 (d, J=1.3Hz, 1H), 5.18 (s, 4H), 2.67-2.59 (m, 2H), 1.82-1.69 (m,
2H), 0.95 (t, J=7.4Hz, 3H).13C NMR (75MHz, CDCl3) δ 157.14,148.62,136.71,
134.02,131.77,130.93,129.36,128.86,128.65,128.09,127.74,127.55,127.30,
125.38,125.02,119.76,107.14,70.09,49.53,28.84,21.31,13.95.
Embodiment 17
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- isopropyls -1H- imidazoles (I-13)
Reactions steps obtain target compound I-13 (50mg, yield 65.57%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.69 (dd, J=8.2,6.2Hz, 2H), 7.50-7.10 (m, 9H), 7.03-6.77 (m,
2H), 5.20 (s, 2H), 5.17 (s, 2H), 3.02 (tt, J=13.5,6.9Hz, 1H), 1.28 (d, J=6.8Hz,
6H).13C NMR (75MHz, CDCl3) δ 136.65,133.95,131.85,129.26,128.54,127.98,
127.64,127.43,127.26,127.14,125.80,125.24,124.85,119.67,119.49,115.46,
107.13,70.02,49.21,25.96,21.73.
Embodiment 18
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- methylols -1H- imidazoles (I-14)
1- [(6- benzyloxies-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (100mg, 0.29mmol) is dissolved in into drying
Methyl alcohol (5ml), addition is dried sodium borohydride solids (17mg, 0.44mmol), is stirred at room temperature complete to reaction.
Solvent is evaporated, is extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.
The next step (160mg, crude yield 113.62%), silica gel can be direct plungeed into after being evaporated as I-14 crude products
Column chromatography is obtained target compound sterling.1H NMR (300MHz, DMSO) δ 7.78 (dd, J=8.7,2.8Hz,
1H), 7.67 (s, 1H), 7.50 (d, J=6.9Hz, 1H), 7.46-7.29 (m, 2H), 7.24 (dd, J=9.0,2.4Hz,
0H), 7.16 (s, 0H), 6.85 (s, 0H), 5.74 (s, 1H), 5.37 (s, 2H), 5.21 (s, 2H), 4.51 (s, 2H).13C
NMR (75MHz, DMSO) δ 156.88,147.59,137.31,134.03,133.11,129.71,128.83,
128.74,128.27,128.17,127.62,126.91,126.49,126.35,121.47,119.60,107.64,
69.74,56.09,49.19.
Embodiment 19
The preparation of 1- [(6- methoxyl groups-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (V-a)
Reference implementation row four, by 6- methoxyl groups -2- bromomethyls-naphthalene, 2- formaldehyde imidazoles, potassium carbonate is added and is dried DMF
In, stir complete to reaction at 80 DEG C.Add water and reaction is quenched, be extracted with ethyl acetate, merge organic layer, satisfy
And brine It, anhydrous sodium sulfate drying.Rear silica gel column chromatography is evaporated by target compound crude product V-a
(500mg, crude yield 32.58%).
Embodiment 20
The preparation of N- benzyl -1- { 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-15)
1- [(6- methoxyl groups-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (100mg, 0.38mmol) is dissolved in and is dried methyl alcohol,
Benzylamine (44.26mg) is added dropwise, adds excessive drying anhydrous sodium sulfate as attached water agent, be stirred overnight at room temperature；Filter
Solid sodium sulfate is removed, is added in reactant liquor and is dried sodium borohydride solids (7.1mg), be stirred at room temperature complete to reaction.
Solvent is evaporated, is extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.
It is evaporated rear silica gel column chromatography and obtains target compound 16 (120mg, yield 89.40%)1H NMR (300MHz,
CDCl3) δ 7.66 (dd, J=14.4,8.7Hz, 2H), 7.39 (s, 1H), 7.35-7.05 (m, 8H), 7.01 (s,
1H), 6.90 (s, 1H), 5.29 (s, 2H), 3.91 (s, 3H), 3.84 (s, 2H), 3.79 (s, 2H), 3.46 (m,
1H).13C NMR (75MHz, CDCl3) δ 157.97,146.46,139.83,134.07,131.72,129.28,
128.70,128.55,128.36,128.22,127.58,127.44,127.11,127.01,125.71,125.35,
120.72,119.32,105.72,55.31,53.45,49.65,45.31.
Embodiment 21
The preparation of N- methyl isophthalic acids-{ 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-16)
Reactions steps obtain target compound 17 (80mg, yield 75.72%) with reference to embodiment 20.1H NMR
(300MHz, CDCl3) δ 7.69 (dd, J=12.6,8.7Hz, 2H), 7.44 (s, 1H), 7.20 (dd, J=8.5,
1.3Hz, 1H), 7.16 (dd, J=8.9,2.4Hz, 1H), 7.12 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H),
5.33 (s, 2H), 3.91 (s, 3H), 3.80 (s, 2H), 2.43 (s, 3H).13C NMR (75MHz, CDCl3)δ
157.99,145.83,134.09,131.60,129.26,128.70,127.64,127.53,125.66,125.28,
120.80,119.37,105.71,55.30,49.68,47.48,35.86.
Embodiment 22
The preparation of N- ethyl -1- { 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-17)
Reactions steps obtain target compound I-17 (100mg, yield 90.15%) with reference to embodiment 20.1H NMR
(300MHz, CDCl3) δ 7.69 (dd, J=13.5,8.7Hz, 2H), 7.46 (s, 1H), 7.29-7.10 (m, 3H),
7.01 (s, 1H), 6.90 (s, 1H), 5.34 (s, 2H), 3.92 (s, 3H), 3.84 (s, 2H), 2.66 (q, J=7.1Hz, 2H),
1.08 (t, J=7.1Hz, 3H).13C NMR (75MHz, CDCl3) δ 157.96,146.74,134.06,131.77,
129.25,128.71,127.59,127.45,125.62,125.30,120.57,119.35,105.70,55.29,49.60,
45.86,43.84,15.11.
Embodiment 23
The preparation of N- isobutyl group -1- { 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-18)
Reactions steps obtain target compound I-18 (86mg, yield 70.81%) with reference to embodiment 20.1H NMR
(300MHz, CDCl3) δ 7.68 (dd, J=12.7,8.8Hz, 2H), 7.45 (s, 1H), 7.29-7.07 (m,
3H), 6.99 (s, 1H), 6.88 (s, 1H), 5.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 2H), 3.45 (s, 1H),
2.42 (d, J=6.7Hz, 2H), 1.70 (dt, J=13.2,6.6Hz, 1H), 0.87 (d, J=6.6Hz, 6H).13C
NMR (75MHz, CDCl3) δ 157.96,146.50,134.07,131.75,129.24,128.71,127.59,
127.35,125.68,125.36,120.70,119.33,105.71,77.45,77.03,76.60,57.62,55.29,
49.66,46.22,28.26,20.58.
Embodiment 24
The preparation of 6- { [2- (Methyaminomethyl) -1H- imidazoles -1- bases] methyl } Betanaphthol (I-19)
Compound I-16 (35mg) is dissolved in 2ml DCM, in -20 degree phosphorus tribromide (4M, 2ml) is added,
After the completion of be slowly increased to room temperature, 3.5h is stirred at room temperature, reactant liquor is poured into frozen water, be neutralized to sodium acid carbonate
Neutrality, EA: THF=1: 1 extraction, anhydrous sodium sulfate drying, the target compound I-19 of silica gel column chromatography purifying
(32mg, yield 91.4%).1H NMR (300MHz, CDCl3) δ 7.69 (dd, J=12.6,8.7Hz,
1H), 7.44 (s, 0H), 7.20 (dd, J=8.5,1.3Hz, 1H), 7.16 (dd, J=8.9,2.4Hz, 0H), 7.12
(s, 0H), 7.00 (s, 1H), 6.89 (s, 0H), 5.33 (s, 1H), 3.91 (s, 2H), 3.80 (s, 1H), 2.43 (s,
2H).
Embodiment 25
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -3- (2- thienyls) -1H- pyrazole-5-ethyl formates (I-20)
Reactions steps obtain target compound I-20 (20mg, yield 27.9%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.79-7.17 (m, 14H), 7.08 (s, 1H), 5.92 (s, 2H), 5.17 (s, 2H), 4.33
(dd, J=13.9,6.9Hz, 2H), 1.36 (t, J=6.9Hz, 3H) .13C NMR (75MHz, CDCl3) δ
159.41,156.88,145.64,136.83,135.72,133.96,133.35,132.34,129.53,128.82,
128.57,127.97,127.50,127.12,126.35,126.06,124.89,124.07,119.24,108.43,
107.08,77.41,76.99,76.56,70.01,61.13,55.14,14.15.
Embodiment 26
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2,4,5- tri- bromo- 1H- imidazoles (I-21)
Reactions steps obtain target compound I-21 (35mg, yield 41.56%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.73 (d, J=8.6Hz, 2H), 7.57-7.17 (m, 9H), 5.34 (s, 2H), 5.20 (s,
2H).13C NMR (75MHz, CDCl3) δ 157.31,136.63,134.18,129.44,129.19,128.69,
128.60,128.05,127.80,127.48,125.92,124.78,119.89,118.70,117.12,107.12,
105.67,70.07,51.42.
Embodiment 27
1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- isobutyl group -1H-1, the preparation of 2,4- triazoles -2- methyl formates (I-22)
Reactions steps obtain target compound I-22 (18mg, yield 31.55%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 8.10 (s, 1H), 7.77 (s, 1H), 7.73 (d, J=4.1Hz, 2H), 7.53-7.29 (m, 7H),
7.28 (s, 1H), 7.24 (s, 1H), 5.55 (s, 2H), 5.20 (s, 2H), 4.02 (s, 3H).13C NMR (75MHz,
CDCl3) δ 157.57,144.36,136.57,134.55,130.85,129.50,128.80,128.75,128.62,
128.48,128.15,128.09,127.75,127.50,125.92,120.07,107.14,70.10,54.75,52.72.
Embodiment 28
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -3,4,5- tri- bromo- 1H- pyrazoles (I-23)
Reactions steps obtain target compound I-23 (47mg, yield 55.82%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.83-7.64 (m, 3H), 7.56-7.31 (m, 6H), 7.28-7.20 (m, 2H), 5.49 (s,
2H), 5.19 (s, 2H).13C NMR (75MHz, CDCl3) δ 157.26,136.69,134.28,130.86,129.93,
129.52,128.72,128.60,128.29,128.04,127.64,127.50,126.92,125.72,119.71,
116.26,107.12,70.06,56.08.
Embodiment 29
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -3- (4- chlorphenyls) -1H- pyrazoles (I-24)
Reactions steps obtain target compound I-24 (15mg, yield 23.1%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.75 (m, 4H), 7.67 (s, 1H), 7.50 (d, J=7.2Hz, 2H), 7.41 (m, 7H), 7.26
(m, 3H), 6.56 (d, J=2.2Hz, 1H), 5.48 (s, 2H), 5.20 (s, 2H).13CNMR (75MHz, CDCl3) δ
157.15,151.23,150.44,136.74,134.17,131.51,130.70,129.44,128.85,128.71,
128.61,128.04,127.60,127.52,126.97,126.87,126.76,126.11,119.59,107.15,
103.28,70.07,56.33.
Embodiment 30
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- dodecyls -1H- imidazoles (I-25)
Reactions steps obtain target compound I-25 (30mg, yield 41.9%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.71 (dd, J=8.5,5.2Hz, 2H), 7.53-7.31 (m, 7H), 7.20 (dd, J=19.7,5.9
Hz, 2H), 7.03 (s, 1H), 6.87 (s, 1H), 5.19 (s, 4H), 2.73-2.61 (t, 2H), 1.72 (m, J=7.6Hz,
2H), 1.29-1.20 (m, 16H), 0.90 (t, J=6.3Hz, 3H).13C NMR (75MHz, CDCl3) δ 157.14,
148.78,136.70,134.00,132.13,131.74,130.86,129.31,128.81,128.60,128.04,
127.70,127.49,127.24,125.38,124.99,119.72,107.13,77.40,76.98,76.56,70.07,
49.54,31.86,29.56,29.44,29.39,29.29,27.91,26.90,22.64,14.06.
Embodiment 31
1- { the preparations of 1- [(6- benzyloxy naphthalene -2- bases) methyl] the chloro- 1H- imidazoles (I-26) of -2- butyl -4- formoxyl -5-
Reactions steps obtain target compound I-26 (yield 41.9%) with reference to embodiment 1-4.1HNMR (300MHz,
CDCl3) δ 9.78 (s, 1H), 7.68 (dd, J=8.6,3.6Hz, 2H), 7.39 (dq, J=19.1,7.1Hz, 6H), 7.19
(dd, J=12.0,7.1Hz, 3H), 5.67 (s, 2H), 5.17 (s, 2H), 2.73-2.57 (m, 2H), 1.67 (dt, J=15.4,
7.6Hz, 2H), 1.33 (tt, J=11.4,5.7Hz, 2H), 0.86 (t, J=7.3Hz, 3H) .13C NMR (75MHz,
CDCl3) δ 177.98,157.15,154.66,136.69,134.03,130.80,129.33,128.78,128.60,
128.04,127.76,127.50,125.08,124.76,124.35,119.75,114.59,107.12,70.07,48.30,
29.18,26.56,22.36,13.58.
Embodiment 32
1- { the preparations of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- propyl group -4- methyl isophthalic acids H- imidazoles (I-27)
Reactions steps obtain target compound I-27 (yield 48%) with reference to embodiment 1-4.1H NMR (300MHz, CDCl3)
δ 7.71 (d, J=8.5Hz, 2H), 7.50 (d, J=7.2Hz, 2H), 7.41 (dd, J=13.0,5.5Hz, 4H), 7.26 (d,
J=11.0Hz, 2H), 7.18 (d, J=8.4Hz, 1H), 6.56 (s, 1H), 5.19 (s, 2H), 5.11 (s, 2H), 2.73-
2.61 (m, 2H), 2.23 (s, 3H), 1.30 (d, J=7.5Hz, 3H).13C NMR (75MHz, CDCl3) δ 157.06,
148.94,136.70,136.07,133.95,131.94,129.32,128.83,128.61,128.04,127.63,
127.51,125.31,125.06,119.68,116.11,107.09,70.04,49.27,20.19,13.52,12.38.
Embodiment 33
1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- propyl group -1H- imidazoles -4, the preparation of 5- dicarboxylates (I-28)
Reactions steps obtain target compound I-28 (23mg, yield 30%) with reference to embodiment 1-4.1H NMR (300MHz,
CDCl3) δ 7.68 (dd, J=8.6,4.0Hz, 2H), 7.40 (ddd, J=19.4,16.6,7.2Hz, 6H), 7.24 (dd, J
=8.9,2.4Hz, 1H), 7.21 (s, 1H), 7.14 (dd, J=8.5,1.6Hz, 1H), 5.53 (s, 2H), 5.18 (s, 2H),
4.44-4.35 (m, 2H), 4.22 (q, J=7.1Hz, 2H), 2.74-2.64 (m, 2H), 1.74 (dd, J=15.3,
7.6Hz, 2H), 1.40 (t, J=7.1Hz, 3H), 1.18 (t, J=7.1Hz, 3H), 0.93 (t, J=7.4Hz, 3H).13C
NMR (75MHz, CDCl3) δ 163.04,160.60,157.11,151.82,136.69,133.96,130.98,
129.34,128.77,128.59,128.03,127.69,127.50,124.82,124.53,119.71,107.10,
70.05,61.20,48.32,29.12,21.24,14.25,13.83.
Embodiment 34
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -4- methyl -5- formoxyls -1H- imidazoles (I-29)
Reactions steps obtain target compound I-29 (yield 42%) with reference to embodiment 1-4.1H NM R (300MHz, CDCl3)
δ 9.86 (s, 1H), 7.72 (dd, J=8.6,4.0Hz, 2H), 7.61 (d, J=4.7Hz, 2H), 7.49 (d, J=7.0Hz,
2H), 7.46-7.28 (m, 4H), 7.27-7.18 (m, 2H), 5.60 (s, 2H), 5.19 (s, 2H), 2.53 (s, 3H).13C
NMR (75MHz, CDCl3) δ 178.68,157.19,153.61,144.13,143.22,142.10,142.05,
136.67,134.17,130.94,129.46,128.79,128.61,128.04,127.66,127.51,126.69,
125.81,119.70,107.06,70.03,50.45,13.34.
Embodiment 35
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- imidazoles -4- Ethyl formates (I-30)
Reactions steps obtain target compound I-30 (40mg, yield 67.74%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.82 (s, 1H), 7.76-7.66 (m, 3H), 7.53-7.19 (m, 8H), 5.65 (s, 2H), 5.19
(s, 2H), 4.29 (dd, J=14.1,7.1Hz, 2H), 1.37-1.30 (m, 3H).13C NMR (75MHz, CDCl3) δ
160.27,157.15,142.13,137.92,136.71,134.10,131.39,129.42,128.83,128.59,
128.01,127.61,127.48,126.27,125.61,122.75,119.64,107.12,70.05,60.46,50.15,
14.20.
Embodiment 36
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2,3- dicyanos -1H- imidazoles (I-31)
Reactions steps obtain target compound I-31 (17mg, yield 30.53%) with reference to embodiment 1-4.1H NMR(300
MHz, DMSO) δ 8.55 (s, 1H), 7.89-7.77 (m, 3H), 7.53-7.25 (m, 8H), 5.60 (s, 2H), 5.23
(s, 2H).13C NMR (75MHz, DMSO) δ 157.32,144.06,137.25,134.49,131.93,130.01,
129.94,129.09,128.89,128.61,128.34,128.23,128.14,127.48,126.30,119.97,
112.82,108.92,107.76,69.81,51.28.
Embodiment 37
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- phenyl -1H- imidazoles (I-32)
Reactions steps obtain target compound I-32 (10mg, yield 16.8%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.71 (t, J=8.7Hz, 2H), 7.60 (dd, J=6.3,2.7Hz, 2H), 7.55-7.28 (m,
10H), 7.21 (m, 3H), 7.02 (s, 1H), 5.35 (s, 2H), 5.20 (s, 2H).13C NMR (75MHz, CDCl3) δ
157.15,148.27,136.71,133.99,132.17,131.92,130.57,129.38,128.97,128.89,
128.81,128.62,128.55,128.05,127.75,127.50,125.34,124.92,121.30,119.73,
107.16,70.08,50.47.
Embodiment 38
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- nitros -1H- imidazoles (I-33)
Reactions steps obtain target compound I-33 (20mg, yield 36.42%) with reference to embodiment 1-4.1H NMR(300
MHz, CDCl3) δ 7.74 (dd, J=8.6,3.2Hz, 2H), 7.62 (s, 1H), 7.57-7.32 (m, 5H), 7.29 (dd,
J=8.6,2.2Hz, 2H), 7.23 (d, J=2.0Hz, 1H), 7.18 (s, 1H), 7.09 (s, 1H), 5.72 (s, 2H), 5.20
(s, 2H).13C NMR (75MHz, CDCl3) δ 157.50,136.58,134.43,130.86,129.49,129.22,
128.75,128.62,128.41,128.07,127.50,127.13,125.73,125.60,120.03,114.57,
107.13,70.09,53.55.
Embodiment 39
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- formoxyls -1H- pyrroles (I-34)
Reactions steps obtain target compound I-34 (yield 52.3%) with reference to embodiment 1-4.1H NMR (300MHz,
CDCl3) δ 9.59 (d, J=0.8Hz, 1H), 7.73-7.64 (m, 2H), 7.57-7.46 (m, 3H), 7.46-7.28
(m, 4H), 7.25-7.17 (m, 2H), 7.04-6.95 (m, 2H), 6.32-6.23 (m, 1H), 5.70 (s, 2H),
5.18 (s, 2H).13C NMR (75MHz, DMSO) δ 179.95,156.79,137.34,134.11,133.94,
132.77,131.52,130.07,129.71,128.86,128.72,128.64,128.30,128.21,127.50,
126.17,125.82,124.83,119.56,110.43,107.66,69.75,51.31.
Embodiment 40
The preparation of 1- { 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- pyrroles's -2- bases }-N- methyl methylamines (I-35)
Reactions steps obtain target compound I-35 (yield 74%) with reference to embodiment 5.1H NMR (300MHz, CDCl3)
δ 7.67 (d, J=8.5Hz, 2H), 7.49 (d, J=7.1Hz, 1H), 7.40 (dd, J=18.2,8.4Hz, 4H), 7.19
(dd, J=18.5,9.5Hz, 3H), 6.73 (s, 1H), 6.27 (s, 1H), 6.15 (s, 1H), 5.37 (s, 2H), 5.18 (s,
2H), 4.40-4.25 (m, 1H), 3.76 (s, 2H), 2.40 (s, 3H).13C NMR (75MHz, CDCl3) δ 156.91,
136.76,133.84,133.39,129.33,128.90,128.57,127.98,127.49,126.66,125.10,
125.02,123.36,119.46,110.99,107.46,107.10,70.02,50.77,45.59,33.74.
Embodiment 41
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -4- formoxyls -1H- imidazoles (I-36)
Reactions steps obtain target compound I-36 (yield 30%) with reference to embodiment 1-4.1H NMR (300MHz,
CDCl3) δ 9.87 (s, 1H), 7.77-7.68 (m, 2H), 7.68-7.57 (m, 3H), 7.48 (d, J=7.1Hz, 2H),
7.45-7.31 (m, 3H), 7.29 (d, J=2.4Hz, 1H), 7.23 (dd, J=5.7,2.1Hz, 2H), 5.27 (s, 2H),
5.18 (s, 2H).13C NMR (75MHz, CDCl3) δ 186.17,157.52,138.82,136.54,134.43,
130.89,129.53,129.42,129.42,128.81,128.64,128.64,128.22,128.22,128.11,
128.11,127.53,127.53,126.96,125.45,124.60,120.13,107.12,70.09,51.68.
Embodiment 42
The preparation of 1- { 1- [(1- naphthalene bromide -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-37)
Reactions steps are with reference to embodiment 2-5.Obtain target compound I-37 (yield 85.90%).1H NMR (300MHz,
CDCl3) δ 8.34 (d, J=8.4Hz, 1H), 7.77 (2H), 7.59 (2H), 7.04 (s, 1H), 6.89 (s, 1H), 6.80
(d, J=8.4Hz, 1H), 5.53 (s, 2H), 3.79 (s, 2H), 2.43 (s, 3H).13C NMR (75MHz, CDCl3) δ
146.73,133.96,133.91,132.18,128.43,128.18,127.92,127.86,127.13,126.93,
124.70,122.64,120.67,50.49,47.88,36.20.
Embodiment 43
The preparation of 1- (6- methoxynaphthalene -2- bases) -2- (2- isopropyl -1H- imidazoles -1- bases)-ethanol (I-38)
A. reactions steps are with reference to embodiment 4.Obtain compound 2- (2- isopropyl -1H- imidazoles -1- bases) -1- (6- methoxynaphthalenes
Phenol -2- bases)-ethyl ketone (yield 47.07%).
B. by 2- (2- isopropyl -1H- imidazoles -1- bases) -1- (6- methoxynaphthol -2- bases)-ethyl ketone (20mg, 0.065mmol)
It is dissolved in and is dried methyl alcohol (5ml), addition is dried sodium borohydride solids (5mg, 0.13mmol), is stirred at room temperature to reaction
Completely.Solvent is evaporated, is extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous slufuric acid
Sodium is dried.It is evaporated rear silica gel column chromatography and obtains target compound I-38 (20mg, yield 99.35%).1H NMR(300
MHz, CDCl3) δ 7.78-7.66 (m, 3H), 7.34 (d, 1H), 7.21-7.10 (m, 2H), 7.01 (s, 1H), 6.92
(5,1H), 5.33 (s, 1H), 5.10 (s, 2H), 4.19 (s, 2H), 2.97-2.88 (m, 1H), 1.25 (d, 6H).
Embodiment 44
The preparation of 1- [1- (naphthalene -1- ylmethyls) 1H- imidazoles -2- bases]-N- methyl methylamines (I-39)
Reactions steps are with reference to embodiment 2-5.Obtain target compound I-39 (yield 50.14%).1H NMR (300MHz,
CDCl3) δ 7.94 (s, 2H), 7.83 (d, J=8.4Hz, 1H), 7.55 (d, J=9.2Hz, 2H), 7.40 (t, J=7.6Hz,
1H), 6.99 (s, 1H), 6.90 (d, J=7.1Hz, 1H), 6.78 (s, 1H), 5.70 (s, 2H), 3.83 (s, 2H), 2.45 (s,
3H).13C NMR (75MHz, CDCl3) δ 146.51,133.61,132.00,130.58,128.90,128.68,
127.45,126.74,126.13,125.47,124.77,122.51,120.64.47.94,47.36,36.22.
Embodiment 45
The preparation of 1- { 1- { [6- (pyridin-4-yl methoxyl group) naphthalene -2- bases] methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-40)
Reactions steps are with reference to embodiment 1-5.Obtain target compound I-40 (yield 25.89%).1H NMR (300MHz,
CDCl3) δ 8.62 (d, J=6.0Hz, 2H), 7.69 (t, J=9.1Hz, 2H), 7.44 (s, 1H), 7.39 (d, 2H), 7.26
- 7.17 (m, 2H), 7.13 (d, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 5.34 (s, 2H), 5.19 (s, 2H), 3.80 (s,
2H), 2.43 (s, 3H).13C NMR (75MHz, CDCl3) δ 150.02,146.11,145.88,133.86,132.16,
129.62,129.03,127.70,127.56,127.53,125.62,125.46,121.46,120.72,119.33,
107.24,68.17,49.60,47.66,36.02.
Embodiment 46
The system of 1- { 1- { [6- (1,1- diphenylmethyl epoxide) naphthalene -2- bases] methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-41)
It is standby
Reactions steps are with reference to embodiment 1-5.Obtain target compound I-41 (yield 82.05%).1H NMR (300MHz,
CDCl3) δ 7.66 (d, J=9.0Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 7.47 (d, J=7.1Hz, 3H), 7.41
(s, 1H), 7.31 (dddd, J=9.7,7.3,5.6,1.6Hz, 7H), 7.20 (d, J=2.2Hz, 1H), 7.14 (dd, J=
6.7,1.8Hz, 2H), 7.00 (s, 1H), 6.86 (s, 1H), 6.36 (s, 1H), 5.30 (s, 2H), 3.79 (s, 2H), 2.43
(s, 3H), 2.19 (s, 2H).13C NMR (75MHz, CDCl3) δ 156.30,146.08,140.98,133.85,
131.80,129.26,128.79,128.63,128.41,128.10,127.81,127.76,127.67,127.49,
126.85,125.89,125.52,125.12,120.67,120.08,109.40,81.86,49.61,47.65,36.00.
Embodiment 47
(E) preparation of -1- { 1- { [6- (Chinese cassia tree epoxide) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-42)
Reactions steps are with reference to embodiment 1-5.Obtain target compound I-42 (yield 48.04%).1H NMR (300MHz,
CDCl3) δ 7.71 (dd, J=8.6,5.2Hz, 2H), 7.45 (d, J=11.1Hz, 3H), 7.38-7.21 (m, 5H),
7.03 (s, 1H), 6.91 (s, 1H), 6.80 (d, J=16.0Hz, 1H), 6.48 (dt, J=16.0,5.7Hz, 1H), 5.30
(s, 2H), 4.82 (d, J=5.7Hz, 2H), 3.82 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ
134.02,133.22,131.79,129.34,128.80,128.57,127.93,127.66,126.55,125.62,
125.28,124.11,120.67,119.62,107.05,68.67,49.62,47.79,36.09,29.65.
Embodiment 48
The preparation of 1- { 1- [(6- phenylsulfonyloxy naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-43)
Reactions steps are with reference to embodiment 1-5.Obtain target compound I-43 (yield 63.20%).1H NMR (300MHz,
CDCl3) δ 7.76 (d, J=7.5Hz, 2H), 7.65-7.55 (m, 3H), 7.43 (t, J=7.7Hz, 2H), 7.36 (s,
2H), 7.19 (d, J=5.8Hz, 1H), 7.00 (dd, J=8.9,2.2Hz, 1H), 6.93 (s, 1H), 6.80 (s, 1H),
5.30 (s, 2H), 3.70 (s, 2H), 2.34 (s, 3H).13C NMR (75MHz, CDCl3) δ 147.39,146.24,
135.40,134.96,134.27,132.87,131.77,129.67,129.16,128.74,128.47,127.73,
125.78,125.41,121.78,120.67,119.85,49.46,47.82,36.08.
Embodiment 49
The system of 1- { 1- { [6- (1- benzoyls) methoxynaphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-44)
It is standby
A. 6- hydroxyls-naphthalene -2- aldehyde (I) (200mg, 1.16mmol) is dissolved in and is dried in methyl alcohol (5ml), add drying
Sodium borohydride (89mg, 2.32mmol), stirs 2h complete to reaction under room temperature.Solvent is evaporated, acetic acid is used
Ethyl ester is extracted, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography
6- methylols-beta naphthal crude product is obtained, the next step is direct plungeed into.(200mg, crude yield 98.84%)
B. by 6- methylols-beta naphthal crude product (200mg, 1.15mmol), potassium carbonate (317mg, 2.3mmol), 1- bromobenzenes
Ethyl ketone (343mg, 1.72mmol) is dissolved in and is dried DMF, stirs complete to reaction at 80 DEG C, is warmed to room temperature, plus
Water quenching is gone out, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography
2- [(6- methylol naphthols -2- bases) epoxide] -1- phenyl-ethyl group ketone crude products are obtained, the next step is direct plungeed into.(304mg,
Crude yield 90.58%)
C. by 2- [(6- methylol naphthols -2- bases) epoxide] -1- phenyl-ethyl group ketone (300mg, 1.03mmol), triphenylphosphine
During (808mg, 3.08mmol) is dissolved in dry methylene chloride, under 0 DEG C of ice bath be added dropwise carbon tetrabromide (1.02g,
Dichloromethane solution 3.08mmol), warms naturally to that 2h is stirred at room temperature.Add water and be quenched, dichloromethane extraction,
Saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains 2- [(6- bromomethyl naphthols -2- bases)
Epoxide] -1- phenyl-ethyl group ketone crude products, direct plunge into the next step.(142mg, crude yield 42.24%)
D. reactions steps are with reference to embodiment 4-5.Obtain target compound I-44 (yield 48.04%).1H NMR (300MHz,
CDCl3) δ 8.03 (d, J=7.4Hz, 2H), 7.72-7.59 (m, 3H), 7.51 (t, J=7.6Hz, 2H), 7.38 (s,
1H), 7.27 (dd, J=8.9,2.3Hz, 1H), 7.12 (dd, J=14.0,5.3Hz, 2H), 7.02 (s, 1H), 6.81 (s,
1H), 5.38 (s, 2H), 5.20 (s, 2H), 3.01 (dq, J=20.5,6.9Hz, 1H), 1.26 (d, J=6.8Hz,
6H).13C NMR (75MHz, DMSO) δ 156.50,152.59,134.86,134.24,133.89,133.05,
129.69,129.28,128.80,128.34,127.75,126.00,125.88,125.27,120.85,119.44,
114.56,107.80,70.71,49.11,25.50,22.11.
Embodiment 50
The preparation of 1- { 1- [(6- benzylthio naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-45)
A.6- bromo- 2- naphthoic acids (500mg, 1.99mmol) are dissolved in 20ml and are dried in methyl alcohol, the dropwise addition 1ml concentrated sulfuric acids, 80 DEG C
Under be heated to reflux 2h to reacting complete.Solvent is evaporated, saturation NaHCO3After neutralization, extracted with ethyl acetate
Take, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains 6-
Bromo- 2- naphthoic acids methyl esters crude product, direct plunges into the next step.(520mg, crude yield 98.50%)
B. by the bromo- 2- naphthoic acids methyl esters (265mg, 1mmol) of 6-, diisopropyl ethyl amine (259mg, 350 μ l, 2mmol) is dissolved in
5ml anhydrous dioxanes, after benzenethiol (248mg, 235 μ l, 2mmol) is added dropwise, addition Pd2 (dba) 3 (46mg, 5%),
(5%) 58mg, under argon gas protection, is heated to reflux 16h complete to reaction to Xantphos at 105 DEG C.By solvent
It is evaporated, is extracted with ethyl acetate, merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated
Afterwards silica gel column chromatography obtains 6- benzylthio -2- naphthoic acid methyl esters crude products, direct plunges into the next step.(300mg, crude product is received
Rate 97.32%)
C. 6- benzylthios -2- naphthoic acid methyl esters (600mg, 1.95mmol) is dissolved in 8ml dry tetrahydrofurans, 0 DEG C of ice
Bath is lower to add Lithium Aluminium Hydride solid (148mg, 3.89mmol), warms naturally to that 2h is stirred at room temperature.Add water and be quenched,
Dichloromethane is extracted, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains (6- benzyls
Sulfenyl naphthalene -2- bases) methyl alcohol crude product, direct plunge into the next step.(337mg, crude yield 61.78%)
D. by (6- benzylthio naphthalene -2- bases) methyl alcohol (337mg, 1.2mmol), triphenylphosphine (946mg, 3.61mmol) is dissolved in dry
In dry dichloromethane, the dichloromethane solution of carbon tetrabromide (1.20g, 3.61mmol) is added dropwise under 0 DEG C of ice bath, it is natural
It is warming up to and 2h is stirred at room temperature.Add water and be quenched, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate
It is dried.It is evaporated rear silica gel column chromatography and obtains benzyl [(6- bromomethyls) naphthalene 2- yls] thioether crude product, direct plunges into lower step
Reaction.(270mg, crude yield 65.44%)
E. reactions steps are with reference to embodiment 3-5.Obtain target compound I-45 (yield 71.98%).1H NMR (300MHz,
CDCl3) δ 7.62-7.54 (m, 3H), 7.32 (m, 2H), 7.26-7.10 (m, 6H), 6.94 (s, 1H), 6.82 (s,
1H), 5.27 (s, 2H), 4.13 (s, 2H), 3.72 (s, 2H), 2.35 (s, 3H).13C NMR (75MHz, CDCl3) δ
146.30,134.71,133.95,133.14,131.67,128.79,128.52,128.35,128.24,128.15,
128.02,127.62,127.26,127.17,125.48,125.32,120.72,49.60,47.81,38.73,36.10.
Embodiment 51
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- pyrroles's -2- methyl formates (I-46)
Reactions steps are with reference to embodiment 1-4.Obtain target compound I-46 (yield 38.9%).1H NMR (300MHz,
CDCl3) δ 7.80-7.66 (m, 3H), 7.50-7.23 (m, 9H), 7.04 (dd, J=3.8,1.6Hz, 1H), 6.93 (s,
1H), 5.69 (s, 2H), 5.18 (s, 2H), 3.78 (s, 3H).
Embodiment 52
3 '-((6- (benzyloxy) naphthalene -2- bases) methyl) -1,7 '-dimethyl -2 '-propyl group -1H, 3 ' H-2,5 '-and phenylpropyl alcohol [d] imidazoles (I-47)
Preparation
Reactions steps are with reference to embodiment 1-4.Obtain target compound I-47 (yield 47.0%).1H NMR (300MHz,
CDCl3) δ 7.83-7.72 (m, 1H), 7.70-7.59 (m, 2H), 7.52-7.10 (m, 14H), 5.50 (s, 2H),
5.14 (s, 2H), 3.65 (s, 3H), 3.00-2.87 (m, 2H), 2.78 (s, 3H), 1.85 (dt, J=14.9,7.5Hz,
2H), 1.03 (t, J=7.3Hz, 3H).
Embodiment 53
The preparation of Pharmaceutical composition：Tablet
Compound I-1 (1g) is mixed with lactose (23g) and microcrystalline cellulose (5.7g) with mixer.Compressed with roller bearing
Machine is compressing by gained mixture, is worth flake sheeted product.The flake is pressed with beater grinder
Material processed is pulverized, and makes gained granular material pass through 20 mesh sieves.By a light silicon dioxide (0.3g)
It is added in screened material with magnesium stearate (0.3g), and mixes.Gained mix products pelleter compressing tablet,
Prepare tablet.
Embodiment 54
The preparation of Pharmaceutical composition：Gelatine capsule agent
By compound I-1 (1g) and microcrystalline cellulose (0.35g) and lactose (0.15g) water granulation, then should
Grain mixes with hinge sodium carboxymethylcellulose (0.04g) and magnesium stearate (0.01g).Gained mix products filling is bright
Glue capsule, prepares gelatine capsule agent.
Claims (6)
1. the compound or pharmaceutically acceptable salt or solvate shown in formula I：
Wherein, K, M are independently chosen from CH, N or CR4；
L is CH, N or CR5；
R1For H, NO2, halogen, CN, trifluoromethyl, Y-R8、COR9、COOR10、CONR11R12、SO2NR11R12、
Or the aryl or heteroaryl of non-substituted or one or more replacements；
R2For H, NO2, halogen, CN, trifluoromethyl, formoxyl, CH (R6)XR7、COR9、COOR10、CONR11R12、
The alkyl of 1～12 carbon, the alkyl for replacing, the aryl or heteroaryl of non-substituted or one or more replacements
R3、R6It is independently chosen from H, the alkyl of 1～12 carbon, the alkyl for replacing, non-substituted or one or more aryl for replacing
Or heteroaryl；
N is 0～2；
R7For H, the alkyl of 1～12 carbon, the alkyl for replacing, substituted or non-substituted benzyl, it is non-substituted or one or more
Substituted aryl or heteroaryl；
R4、R5It is independently chosen from H, halogen, formoxyl, COR9、COOR10、CONR11R12, 1～12 carbon alkyl, take
The alkyl in generation, substituted or non-substituted benzyl, the aryl or heteroaryl of non-substituted or one or more replacements；Or R5And R6With
Other atoms form together 4～8 yuan of rings；
R8For H, COR9、SO2R13, the alkyl of 1～12 carbon, the alkyl, substituted or non-substituted benzyl, non-substituted that replaces
Or one or more replace aryl or heteroaryl, substituted or non-substituted hetervaromatic methyl；
R9、R10、R11、R12、R13Alkyl, the substituted or non-substituted benzyl for be independently chosen from H, the alkyl of 1～12 carbon, replacing
Base, the aryl or heteroaryl of non-substituted or one or more replacements；
X is NR14Or O；
Y is O, NR14, S, SO or SO2；
R14It is independently chosen from H, the alkyl of 1～12 carbon, the alkyl for replacing, non-substituted or one or more aryl or miscellaneous for replacing
Aryl.
2. compound as claimed in claim 1, it is characterised in that in the compound of formula I：
K is CH or CR4；
M is N or CH；
L is CH or CR5；
R1For Y-R8、COR9、COOR10、CONR11R12、SO2NR11R12Or it is non-substituted or one or more replacements
Aryl or heteroaryl；
R2For CH (R6)XR7, 1～12 carbon alkyl, replace alkyl, non-substituted or one or more aryl for replacing or
Heteroaryl
R3、R6For H, the alkyl of 1～12 carbon, the alkyl for replacing, non-substituted or one or more aryl for replacing or heteroaryl
Base；
N is 0 or 1；
R7For H, the alkyl of 1～12 carbon, the alkyl for replacing, substituted or non-substituted benzyl, it is non-substituted or one or more
Substituted aryl or heteroaryl；
R4、R5It is alone H, halogen, formoxyl, COR9、COOR10、CONR11R12, 1～12 carbon alkyl, replace
Alkyl, substituted or non-substituted benzyl, it is non-substituted or one or more replace aryl or heteroaryl；Or R5And R6With it
His atom forms together 4～8 yuan of rings；
R8For H, the alkyl of 1～12 carbon, the alkyl for replacing, substituted or non-substituted benzyl, it is non-substituted or one or more
Substituted aryl or heteroaryl, substituted or non-substituted hetervaromatic methyl；
R9、R10、R11、R12、R13Be alone the alkyl of 1～12 carbon, it is the alkyl for replacing, substituted or non-substituted benzyl, non-
Aryl or heteroaryl replace or one or more replacements；
X is NR14Or O；
Y is O, NR14, S, SO or SO2；
R14For H, the alkyl of 1～12 carbon, the alkyl for replacing, non-substituted or one or more aryl for replacing or heteroaryl.
3. compound as claimed in claim 1, it is characterised in that the compound of formula I includes following compound：
4. the compound of formula I of claim 1 or its pharmaceutically acceptable salt or solvate are preparing prevention or are treating tumor disease medicine
Application in thing.
5. it is a kind of prevention or treat tumor disease pharmaceutical composition, it is characterised in that contain therapeutically effective amount in described pharmaceutical composition
Compound of formula I or its pharmaceutically acceptable salt or solvate as active ingredient and pharmaceutically acceptable carrier.
6. pharmaceutical composition according to claim 5, it is characterised in that described pharmaceutical composition can be conventional tablet or capsule,
Sustained-release tablet or capsule, Dospan or capsule, granule, powder, syrup, oral liquid or injection.
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Application publication date: 20170510 |
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| WD01 | Invention patent application deemed withdrawn after publication |