CN110172058A - 7- azaspiro [5.6] dodecane -10- ketone compounds and preparation method thereof and purposes - Google Patents
7- azaspiro [5.6] dodecane -10- ketone compounds and preparation method thereof and purposes Download PDFInfo
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- CN110172058A CN110172058A CN201910525516.0A CN201910525516A CN110172058A CN 110172058 A CN110172058 A CN 110172058A CN 201910525516 A CN201910525516 A CN 201910525516A CN 110172058 A CN110172058 A CN 110172058A
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- A61P35/00—Antineoplastic agents
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention belongs to field of medicaments, and in particular to 7- azaspiro [5.6] dodecane -10- ketone compounds and preparation method and application.The present invention synthesizes seven-members ring structure for the first time, obtain a kind of novel compounds of more antitumous effect, the report of dependency structure was not met, pharmacological research shows that the compounds of this invention has certain inhibitory activity to typeⅡ pneumocyte, human ovarian cancer OVCAR-3 cell, provides the foundation for the subsequent anti-tumor drug for preparing.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to the compound of a kind of specified chemical structure with anti-tumor activity,
Specially 7- azaspiro [5.6] dodecane -10- ketone compounds and the preparation method and application thereof.
Background technique
Malignant tumour, also known as cancer are a serious global public health problems.Most of cancer patients are due to its height
The death rate and recurrence rate and die.It is characterized in that in human body abnormal cell uncontrolled division and diffusion.Therefore, effectively
The synthesis of new anticancer drug be one of most important target of Modern Pharmaceutical Chemistry.At this stage, the master of clinical treatment cancer
Mode is wanted to mostly use chemotherapy.At present although anti-tumor drug has certain curative effect, but there is also drug resistances, selection
Act on the problems such as poor, toxic side effect is big.Therefore, lot of domestic and foreign researcher, which attempts to find from natural plants, develops effectively anti-swell
The new drug of tumor.
Based on this, the present invention designs completely new antitumoral compounds, introduces seven-members ring structure, is desirably to obtain a kind of more anti-
The novel compounds of tumor effect, and have not seen the report of dependency structure.
Summary of the invention
The purpose of the present invention is to provide a kind of 7- azaspiro [5.6] dodecane -10- ketone compounds and its preparation sides
Method, prepared compound in vitro anti-tumor activity test in shown good result.
The general structure I of 7- azaspiro [5.6] dodecane -10- ketone compounds provided by the invention is specific as follows:
Wherein:
R group on phenyl ring is substituted by 2,3 or 4 mono-substituted fluorine atoms, methyl, chlorine atom, methoxyl group, bromines
Atom, hydroxyl, cyano or hydrogen atom.
Compound, isomers and its pharmaceutically acceptable salt described in general formula I of the present invention, hydrate or prodrug: especially
It is preferred that following compound, but these compounds are not meant to any limitation of the invention:
3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one (A1)；
2- ((1- phenyl -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- ring
Hexane] -5 (2H) -one (A2)；
2- ((1- (2- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A3)；
2- ((1- (3- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A4)；
2- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A5)；
2- ((1- (2- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A6)；
2- ((1- (3- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A7)；
2- ((1- (4- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A8)；
2- ((1- (2- chlorphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A9)；
2- ((1- (3- chlorphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A10)；
2- ((1- (4- chlorphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A11)；
2- ((1- (2- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A12)；
2- ((1- (3- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A13)；
2- ((1- (4- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A14)；
2- ((1- (2- bromophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A15)；
2- ((1- (3- bromophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A16)；
2- ((1- (4- bromophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A17)；
2- ((1- (2- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A18)；
2- ((1- (3- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A19)；
2- ((1- (4- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A20)；
2- ((1- (2- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A21)；
2- ((1- (3- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A22)；
2- ((1- (4- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A23).
To achieve the goals above, the present invention also provides 7- azaspiro [5.6] dodecane -10- ketone compounds
Preparation method, include the following steps.
Step 1, using bromobenzene as starting material, ether is solvent, and important intermediate 1- is made by classical grignard reaction
Phenylcyclohexanol.
Step 2, using 1- phenylcyclohexanol as raw material, methylene chloride is solvent, is reacted by displacement, and weight is made in reduction reaction
Want intermediate 1- amino 1- cyclohexylbenzene.
Step 3, using 1- amino 1- cyclohexylbenzene as raw material, by Michael addition reaction, hydrolysis and Fu Ke acyl
Target product 3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one (A1) can be obtained in glycosylation reaction.
Step 4, with 3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one (A1) for raw material, warp
It crosses alkylation reaction and target product A2-A23 can be obtained in click chemistry reaction.
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of general formula I
Object, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as pass through
Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
The present invention can 7- azaspiro [5.6] dodecane -10- ketone compounds containing general formula I, and its can pharmaceutically connect
The salt received, solvate are prepared by mixing into pharmaceutical composition with pharmaceutically acceptable carrier or excipients as active ingredient,
And it is prepared into clinically acceptable dosage form, above-mentioned pharmaceutically acceptable excipients, which refer to, any can be used for the dilute of pharmaceutical field
Release agent, adjuvant and/or carrier.The compound of the present invention and its derivative can be applied in combination with other active ingredients, as long as
They do not generate other unfavorable effects, such as allergic reaction.
Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some common figurations in drug field
Agent.Several dosage form as described above can be using injection, tablet, capsule, aerosol, suppository, film, pill, outer
With drug forms such as liniment, ointments.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: adhesive, profit
Lubrication prescription, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, non-pigment, corrigent, preservative, solubilizer and matrix etc..
The present invention includes any described 7- azaspiro [5.6] dodecane -10- ketone compounds, isomers, pharmaceutically may be used
Application of the salt, hydrate, pharmaceutical composition of receiving in preparation treatment anti-tumor drug；The pharmaceutical composition includes appointing
7- azaspiro [5.6] dodecane -10- ketone compounds, its pharmaceutically acceptable salt, hydrate or solvate described in one
And pharmaceutically acceptable carrier.
Cancerous cell line of the present invention is typeⅡ pneumocyte system and human ovarian cancer OVCAR-3 cell line.
The beneficial effects of the present invention are: (1) in of the invention design process, design and synthesize 7- azaspiro [5.6]
The antitumor novel compounds of dodecane -10- ketone, greatly improve antitumous effect, and it was found that thin to human lung cancer A549
Born of the same parents have more outstanding anti-proliferative capacity；(2) the compound of the present invention has remarkable result in anti-tumor activity test in vitro；
(3) in the synthesis process, synthesis step is optimized, producing offer to futurity industry may.
Specific embodiment
The present invention is described further combined with specific embodiments below, these embodiments are merely illustrative, unlimited
The scope of the invention processed.
To achieve the goals above, the present invention also provides 7- azaspiro [5.6] dodecane -10- ketone compounds systems
Preparation Method specifically includes following steps.
1 times of amount (mole dosage) bromobenzene and 0.5 times of amount magnesium rod are added in reaction flask and is dissolved in suitable ether for step 1
In, cause under the conditions of 35 DEG C, thin-layer chromatography monitors reaction process.The cyclohexanone of 1.1 times of amounts is added after having reacted, in 35 DEG C
Under the conditions of react 5 hours.After completion of the reaction, reaction solution is added in aqueous ammonium chloride solution, is extracted with ether, extract liquor is through dry
Dry, reduction vaporization obtains 1- phenylcyclohexanol.
Step 2, the 1- phenylcyclohexanol that 1 times of amount is added in reaction flask, q. s. methylene chloride make solvent, 2 times of amounts it is folded
Sodium nitride, the trifluoroacetic acids of 3 times of amounts reacts 15 hours under room temperature, thin-layer chromatography monitoring reaction process.After completion of the reaction, by carbon
Acid sodium aqueous solution is added in reaction solution, is extracted with dichloromethane, and extract liquor obtains 1- azido 1- benzene through drying, reduction vaporization
Butylcyclohexane.
Step 3, the 1- azido 1- cyclohexylbenzene that 1 times of amount is added in reaction flask, make solvent suitable for tetrahydrofuran,
The lithium aluminium hydride reductions of 1.2 times of amounts, after reacting 4 hours under normal temperature condition, increasing the temperature to 40-60 DEG C, the reaction was continued, thin layer color
Spectrum monitoring reaction process.After completion of the reaction, successively aqueous solution, sodium hydroxide solution are added in reaction solution, are filtered, filtrate subtracts
Then pressure evaporation is added a small amount of water and adjusts pH value to acidity, ether extracting impurities, extract it is miscellaneous after adjust pH value to alkalinity, two
Chloromethanes extraction, extract liquor obtain 1- amino 1- cyclohexylbenzene through drying, reduction vaporization.
Step 4, the 1- amino 1- cyclohexylbenzene that 1 times of amount is added in reaction flask, 1.1 times of amount methyl acrylates, in right amount
DBU make catalyst, 70 DEG C reaction 15-20 hours, anti-thin-layer chromatography monitors reaction process.After answering, suitable water is added
Dissolution, ethyl acetate extraction, extract liquor obtain 3- ((1- phenylcyclohexyl) ammonia by column chromatographic purifying through drying, reduction vaporization
Base) methyl propionate.
Step 5,3- ((1- phenylcyclohexyl) amino) methyl propionate that 1 times of amount is added in reaction flask, the hydrogen of 2 times of amounts
Sodium oxide molybdena, suitable water as solvent, 50 DEG C reaction 1-2 hours, thin-layer chromatography monitor reaction process.After completion of the reaction, acetic acid second
Ester extracting impurities, water layer adjust pH value to 6-7, and a large amount of methylene chloride is added to there is solid precipitation in solvent removed by evaporation at reduced pressure
Dissolution, filters to obtain filtrate, and filtrate obtains 3- ((1- phenylcyclohexyl) amino) propionic acid after drying, reduction vaporization.
Step 6,3- ((1- phenylcyclohexyl) amino) propionic acid that 1 times of amount is added in reaction flask, the dichloro of 3 times of amounts are sub-
Sulfone, suitable methylene chloride make solvent, 40 DEG C of reactions, and thin-layer chromatography monitors reaction process.After completion of the reaction, after reduction vaporization
3- ((1- phenylcyclohexyl) amino) propane acyl chlorides；
Step 7,3- ((1- phenylcyclohexyl) amino) propane acyl chlorides that 1 times of amount is added in reaction flask, suitable dichloro
Methane makees solvent, and 70 DEG C of reactions reduce the temperature to 40-50 DEG C after dissolution, and the alchlor that 3 times are measured is added, and the reaction was continued,
Thin-layer chromatography monitors reaction process.After completion of the reaction, reaction solution is added in the mixture of hydrochloric acid and ice water, ether extraction is miscellaneous
Matter, water intaking layer adjust pH value to alkalinity, and ethyl acetate extracts, and extract liquor obtains 3 by column chromatographic purifying through drying, reduction vaporization,
4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one；
Step 8, the 3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 that 1 times of amount is added in reaction flask
(2H) -one, suitable acetonitrile as solvents, the potassium carbonate of 1.1 times of amounts, the propargyl bromide of 1 times of amount are heated to reflux, thin-layer chromatography monitoring
Reaction process.After completion of the reaction, it filters, filtrate adds suitable water to extract, and extract liquor obtains 2- (propyl-through drying, reduction vaporization
2- alkynes -1- base) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one；
Step 9, the aniline that 1 times of amount R base substitution is added in reaction flask, suitable water as solvent, the hydrochloric acid of 1.2 times of amounts,
After stirring at normal temperature 0.5 hour, after adding the sodium nitrite of 2 times of amounts to continue stirring 0.5 hour, the sodium azide that 1.3 times of amounts are added is stirred
It mixes 2 hours, thin-layer chromatography monitors reaction process.After completion of the reaction, water is added to extract, extract liquor obtains accordingly through drying, reduction vaporization
The phenylazide that R base replaces；
The phenylazide that 1 times of amount R base replaces is added in step 10 in reaction flask, and suitable DMF makees solvent, the 2- of 1 times of amount
(propyl -2- alkynes -1- base) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, it is anti-at 30-40 DEG C
It answers, thin-layer chromatography monitors reaction process.After completion of the reaction, dry, reduction vaporization, obtains target compound.
Embodiment 1.
The preparation of 3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one (A1).
A.1- the preparation of phenylcyclohexanol.
Bromobenzene (50g, 0.31mol) is added in 1000mL three-necked bottle, magnesium rod (8.13g, 0.33mol) is simultaneously dissolved in suitable
In the ether of amount, cause under the conditions of 35 DEG C.Cyclohexanone (34.38g, 0.35mol) is added after having reacted, under the conditions of 35 DEG C
Reaction 5 hours, thin-layer chromatography monitor reaction process.After completion of the reaction, reaction solution is added in saturated aqueous ammonium chloride, uses second
Ether extraction, extract liquor obtain product through drying, reduction vaporization, yield: 95.5%.
B.1- the preparation of azido 1- cyclohexylbenzene.
1- phenylcyclohexanol (20.00g, 0.11mol) is added in 1000mL reaction flask, methylene chloride 500mL, Azide
Sodium (8.11g, 0.12mol), trifluoroacetic acid (25.88 g, 0.23mol) react 15 hours under room temperature, thin-layer chromatography monitoring reaction
Process.After completion of the reaction, saturated aqueous sodium carbonate is added in reaction solution, is extracted with dichloromethane, extract liquor through drying,
Reduction vaporization obtains product, yield: 97.2%.
C.1- the preparation of amino 1- cyclohexylbenzene.
1- azido 1- cyclohexylbenzene (13g, 0.064 mol) is added in 1000mL reaction flask, tetrahydrofuran
500mL, lithium aluminium hydride reduction (4.77g, 0.13mol), after reacting 4 hours under normal temperature condition, increase the temperature to 40-60 DEG C continue it is anti-
It answers, thin-layer chromatography monitors reaction process.After completion of the reaction, successively aqueous solution, sodium hydroxide solution are added in reaction solution, are taken out
Then filter, filtrate decompression evaporation are added a small amount of water and adjust pH value to acidity, ether extracting impurities extract miscellaneous rear adjusting pH value
To alkalinity, methylene chloride extraction, extract liquor obtains product through drying, reduction vaporization, yield: 89.43%.
D.3- the preparation of ((1- phenylcyclohexyl) amino) methyl propionate.
1- amino 1- cyclohexylbenzene (20.00g, 0.11 mol) is added in 500mL reaction flask, methyl acrylate
(10.81g, 0.13mol), DBU (8.69g, 0.057mol), 70 DEG C are reacted 17 hours, and thin-layer chromatography monitors reaction process.Instead
After answering, suitable water dissolution, ethyl acetate extraction is added, extract liquor is obtained through drying, reduction vaporization by column chromatographic purifying
To product, yield: 79.5%.
E.3- the preparation of ((1- phenylcyclohexyl) amino) propionic acid.
3- ((1- phenylcyclohexyl) amino) methyl propionate (15.00g, 0.057mol) is added in 500mL reaction flask,
Sodium hydroxide (4.59g, 0.115mol), water 300mL, 50 DEG C are reacted 1.5 hours, and thin-layer chromatography monitors reaction process.It has reacted
Bi Hou, ethyl acetate extracting impurities, water layer adjust pH value to 7, and solvent removed by evaporation at reduced pressure is added a large amount of to there is solid precipitation
Methylene chloride dissolution, filters to obtain filtrate, filtrate obtains product after drying, reduction vaporization, yield: 97.15%.
F.3- the preparation of ((1- phenylcyclohexyl) amino) propane acyl chlorides.
3- ((1- phenylcyclohexyl) amino) propionic acid (20.00 g, 0.081mol), dichloro are added in 500mL reaction flask
Sulfoxide (19.24g, 0.162mol), methylene chloride 300mL, 40 DEG C of reactions, thin-layer chromatography monitor reaction process.End of reaction
Afterwards, product is obtained after reduction vaporization, yield: 100%.
G.3,4- the preparation (A1) of dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one.
3- ((1- phenylcyclohexyl) amino) propane acyl chlorides (9g, 0.034mol), dichloromethane are added in 500mL reaction flask
Alkane 200mL, 70 DEG C of reactions reduce the temperature to 45 DEG C after dissolution, and alchlor (12.94g, 0.097mol) is added and continues instead
It answers, thin-layer chromatography monitors reaction process.After completion of the reaction, reaction solution is added in the mixture of hydrochloric acid and ice water, ether extraction
Impurity, water intaking layer adjust pH value to alkalinity, and ethyl acetate extracts, and extract liquor is obtained through drying, reduction vaporization by column chromatographic purifying
To product, yield: 35.2%.1HNMR(600MHz,DMSO-d6) δ 7.50 (s, 1H), 7.41 (s, 1H), 7.22 (d, J=
8.0Hz,2H),3.02(s,2H),2.71(s,2H),1.60(m,10H)；MS(ESI,m /z):230.1550[M+H]+。
Embodiment 2.
2- ((1- phenyl -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- ring
Hexane] -5 (2H) -one (A2) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one.
A.2- (propyl -2- alkynes -1- base) -3,4- dihydro loop coil [benzo [c] azepine -1,1'-
Hexamethylene] -5 (2H) -one preparation.
3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one are added in 100mL reaction flask
(1.00g, 0.004mol), acetonitrile 50mL, potassium carbonate (1.21 g, 0.009mol), propargyl bromide (0.57g, 0.005mol), 85 DEG C
It is heated to reflux, thin-layer chromatography monitors reaction process.After completion of the reaction, it filters, filtrate adds suitable water to extract, and extract liquor is through dry
Dry, reduction vaporization, obtains 2- (propyl -2- alkynes -1- base) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -
Ketone.
B.1- azido-benzene preparation.
Aniline (2.00g, 0.021mol) is added in 100mL reaction flask, water 50mL, hydrochloric acid (2.68g, 0.028mol),
After stirring at normal temperature 0.5 hour, after adding sodium nitrite (1.63 g, 0.024mol) to continue stirring 0.5 hour, sodium azide is added
(1.54g, 0.024 mol) is stirred 2 hours, and thin-layer chromatography monitors reaction process.After completion of the reaction, water is added to extract, extract liquor warp
Dry, reduction vaporization, obtains 1- azido-benzene.
C.2- ((1- phenyl -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'-
Hexamethylene] -5 (2H) -one preparation.
1- azido-benzene (0.50g, 0.004mol), DMF50mL, 2- (propyl -2- alkynes-are added in 100mL reaction flask
1- yl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one (1g, 0.004mol), it is anti-at 30 DEG C
It answers, thin-layer chromatography monitors reaction process.After completion of the reaction, dry, reduction vaporization, obtains 2- ((1- phenyl -1H-1,2,3- triazoles -
4- yl) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one (A2), white solid, yield:
70.6%.
1H NMR(600MHz,DMSO-d6) δ 8.67 (s, 1H), 7.89 (d, J=8.0 Hz, 2H), 7.58 (t, J=
7.9Hz,2H),7.49–7.42(m,3H),7.34–7.30 (m,1H),7.26–7.22(m,1H),3.68(s,2H),3.30(s,
2H), 2.93 (s, 2H), 2.25 (d, J=12.2Hz, 2H), 1.79-1.69 (m, 2H), 1.59 (m, 3H), 1.49-1.40 (m,
2H),1.27–1.14(m,1H)；MS(ESI, m/z):387.2179.
Embodiment 3.
2- ((1- (2- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A3) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 2- fluorine
Aniline is raw material, and 1- azido -2- fluorobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(2- fluorophenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A3), brown solid, yield: 62.1%.
1H NMR(600MHz,DMSO-d6)δ8.42(s,1H),7.76(m,1H),7.67 (m,1H),7.60(m,2H),
7.49–7.43(m,2H),7.36–7.30(m,1H), 7.27–7.23(m,1H),3.71(s,2H),2.92(s,2H),2.26
(d, J=12.2Hz, 2H), 1.99 (s, 1H), 1.79-1.70 (m, 2H), 1.60 (m, 3H), 1.48-1.41 (m, 2H),
1.26–1.12(m,2H)；MS(ESI,m/z):405.2076 [M+H]+。
Embodiment 4.
2- ((1- (3- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A4) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 3- fluorine
Aniline is raw material, and 1- azido -3- fluorobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(3- fluorophenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A4), brown solid, yield: 62.5%.
1H NMR(600MHz,DMSO-d6)δ8.74(s,1H),7.84(m,1H),7.79 (m,1H),7.62(m,1H),
7.47-7.42 (m, 2H), 7.32 (m, 2H), 7.26-7.23 (m, 1H), 3.67 (s, 2H), 2.90 (m, 2H), 2.24 (d, J=
12.4Hz,2H),1.79–1.69(m,2H),1.64–1.54(m,3H), 1.47–1.41(m,2H),1.26–1.12(m,3H)；
MS(ESI,m/z):405.2090 [M+H]+。
Embodiment 5.
2- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A5) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 4- fluorine
Aniline is raw material, and 1- azido -4- fluorobenzene is made according to embodiment 2b step, and 3- ((1- is made according to embodiment 2a, 2c step
(4- fluorophenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A5), brown solid, yield: 63.1%.
1H NMR(600MHz,DMSO-d6)δ8.65(s,1H),7.97–7.89(m, 3H),7.46–7.40(m,4H),
7.25 (td, J=7.8,2.6Hz, 1H), 3.66 (s, 2H), 2.89 (s, 2H), 2.24 (d, J=12.1Hz, 2H), 2.09-
1.88 (m,1H),1.81–1.68(m,2H),1.59(m,3H),1.50–1.37(m,2H), 1.27–1.11(m,2H)；MS
(ESI,m/z):405.2075[M+H]+。
Embodiment 6.
2- ((1- (2- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A6) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 2- first
Base aniline is raw material, and 1- azido -2- methylbenzene is made according to embodiment 2b step, and 3- is made according to embodiment 2a, 2c step
((1- (2- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A6), off-white powder, yield: 53.2%.
1H NMR(600MHz,DMSO-d6)δ8.32(s,1H),7.49–7.44(m, 5H),7.42–7.39(m,2H),
7.26-7.23 (m, 1H), 3.70 (s, 2H), 2.92 (s, 2H), 2.26 (d, J=12.1Hz, 2H), 2.13 (s, 3H), 1.98
(s,1H), 1.78–1.69(m,2H),1.64–1.55(m,3H),1.45(m,2H), 1.25–1.19(m,2H)；MS(ESI,m/
z):401.2342[M+H]+。
Embodiment 7.
2- ((1- (3- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A7) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 3- first
Base aniline is raw material, and 1- azido -3- methylbenzene is made according to embodiment 2b step, and 3- is made according to embodiment 2a, 2c step
((1- (3- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A7), off-white powder, yield: 54.3%.
1H NMR(600MHz,DMSO-d6) δ 8.64 (s, 1H), 7.73 (s, 1H), 7.68 (d, J=7.9Hz, 1H), 7.44
(m,3H),7.34–7.30(m,1H),7.28–7.23 (m,2H),3.67(s,2H),2.91(s,2H),2.40(s,3H),2.24
(d, J=12.2Hz, 2H), 1.97 (d, J=5.5Hz, 1H), 1.78-1.69 (m, 2H), 1.63-1.55 (m, 3H), 1.47-
1.40(m,2H),1.25–1.14(m, 2H)；MS(ESI,m/z):401.2339[M+H]+。
Embodiment 8.
2- ((1- (4- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A8) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 4- first
Base aniline is raw material, and 1- azido -4- methylbenzene is made according to embodiment 2b step, and 2- is made according to embodiment 2a, 2c step
((1- (4- benzyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A8), off-white powder, yield: 52.6%.
1H NMR(600MHz,DMSO-d6) δ 8.62 (s, 1H), 7.78 (t, J=6.6 Hz, 2H), 7.49-7.43 (m,
2H), 7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.25 (d, J=7.3Hz, 1H), 3.67 (s, 2H), 2.91 (s, 2H),
2.38 (s, 3H), 2.26 (d, J=12.7Hz, 2H), 2.00-1.95 (m, 1H), 1.80-1.69 (m, 2H), 1.60 (m, 3H),
1.46(m,2H),1.27–1.15(m,2H)；MS(ESI, m/z):401.2335[M+H]+。
Embodiment 9.
2- ((1- (2- chlorphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A9) preparation
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 2- chlorine
Aniline is raw material, and 1- azido -2- chlorobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(2- chlorphenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A9), yellow solid, yield: 51.2%.
1H NMR(600MHz,DMSO-d6)δ8.41(s,1H),7.75(m,1H),7.67 (m,1H),7.59(m,2H),
7.47-7.43 (m, 2H), 7.33 (m, 1H), 7.26-7.23 (m, 1H), 3.70 (s, 2H), 2.92 (s, 2H), 2.25 (d, J=
12.3Hz,2H),1.98(s,1H),1.76–1.71(m,2H),1.59(m,2H), 1.47–1.42(m,2H),1.25–1.13
(m,3H)；MS(ESI,m/z):421.1789[M +H]+。
Embodiment 10.
2- ((1- (3- chlorphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A10) preparation.
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 3- chlorine
Aniline is raw material, and 1- azido -3- chlorobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(3- chlorphenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A10), yellow solid, yield: 50.7%.
1H NMR(600MHz,DMSO-d6) δ 8.76 (d, J=4.6Hz, 1H), 8.04 (m, 1H), 7.94-7.89 (m,
1H),7.61(m,1H),7.56–7.50(m,1H), 7.46–7.41(m,2H),7.32(m,1H),7.25–7.22(m,1H),
3.67 (s, 2H), 2.92 (s, 2H), 2.24 (d, J=12.2Hz, 2H), 1.97 (d, J=5.5 Hz, 1H), 1.79-1.68 (m,
2H),1.59(m,3H),1.48–1.39(m,2H), 1.26–1.12(m,2H)；MS(ESI,m/z):421.1837[M+H]+。
Embodiment 11.
2- ((1- (4- chlorphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A11).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 4- chlorine
Aniline is raw material, and 1- azido -4- chlorobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(4- chlorphenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A11), yellow solid, yield: 51.5%.
1H NMR(600MHz,DMSO-d6)δ8.71(s,1H),7.96–7.94(m, 2H),7.67–7.63(m,2H),
7.45 (m, 2H), 7.33 (m, 1H), 7.26-7.23 (m, 1H), 3.68 (s, 2H), 2.92 (s, 2H), 2.25 (d, J=
12.4Hz,2H), 1.98(s,1H),1.79–1.70(m,2H),1.60(m,3H),1.50–1.42(m, 2H),1.27–1.14
(m,2H)；MS(ESI,m/z):421.1805[M+H]+。
Embodiment 12.
2- ((1- (2- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A12).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 2- first
Oxygroup aniline is raw material, 1- azido -2- methoxybenzene is made according to embodiment 2b step, according to embodiment 2a, 2c step system
2- ((1- (2- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A12), off-white powder, yield: 65.7%.
1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),7.61(m,1H), 7.53–7.49(m,1H),7.48–
7.43(m,2H),7.35–7.30(m,2H), 7.27–7.24(m,1H),7.14(m,1H),3.84(s,3H),3.66(s,2H),
2.95 (s, 2H), 2.26 (d, J=12.1Hz, 2H), 1.99 (s, 1H), 1.79-1.68 (m, 2H), 1.65-1.56 (m, 3H),
1.50–1.42(m,2H),1.28–1.14(m, 2H)；MS(ESI,m/z):417.2290[M+H]+。
Embodiment 13.
2- ((1- (3- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A13).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 3- first
Oxygroup aniline is raw material, 1- azido -3- methoxybenzene is made according to embodiment 2b step, according to embodiment 2a, 2c step system
2- ((1- (3- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A13), off-white powder, yield: 66.2%
1H NMR(600MHz,DMSO-d6)δ8.69(s,1H),7.50–7.40(m, 5H),7.35–7.29(m,1H),
7.25 (d, J=7.4Hz, 1H), 7.05-6.99 (m, 1H), 3.84 (s, 3H), 3.65 (s, 2H), 2.92 (s, 2H), 2.24 (d,
J=12.0Hz, 2H), 1.98 (s, 1H), 1.73 (m, 2H), 1.58 (m, 3H), 1.43 (m, 2H), 1.25-1.12 (m, 2H)；
MS(ESI,m/z):417.2290[M+H]+。
Embodiment 14.
2- ((1- (4- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A14).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 4- first
Oxygroup aniline is raw material, 1- azido -4- methoxybenzene is made according to embodiment 2b step, according to embodiment 2a, 2c step system
2- ((1- (4- methoxyphenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,
1'- hexamethylene] -5 (2H) -one (A14), off-white powder, yield: 65.9%
1H NMR(600MHz,DMSO-d6) δ 8.54 (s, 1H), 7.78 (d, J=8.9 Hz, 2H), 7.43 (d, J=
5.0Hz, 2H), 7.32-7.29 (m, 1H), 7.24 (d, J=7.3Hz, 1H), 7.10 (d, J=8.9Hz, 2H), 3.81 (s,
3H), 3.66 (s, 2H), 3.29 (s, 2H), 2.23 (d, J=12.1Hz, 2H), 1.97 (s, 1H), 1.73 (m, 2H), 1.57
(m,3H),1.42(m,2H),1.17(m,2H)；MS(ESI, m/z):417.2297[M+H]+。
Embodiment 15.
2- ((1- (2- bromophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A15).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 2- bromine
Aniline is raw material, and 1- azido -2- bromobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(2- bromophenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A15), gray solid, yield: 62.9%.
1H NMR(600MHz,DMSO-d6)δ7.64–7.59(m,3H),7.57–7.52 (m,2H),7.50–7.42(m,
2H),7.36–7.30(m,1H),7.25(m,1H), 3.71(s,2H),3.32(s,2H),2.30–2.22(m,2H),1.76(d,
J=11.9Hz, 2H), 1.67-1.55 (m, 4H), 1.48-1.41 (m, 2H), 1.17 (t, J=7.1Hz, 2H)；MS(ESI,m/
z):465.1271[M+H]+。
Embodiment 16.
2- ((1- (3- bromophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A16).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 3- bromine
Aniline is raw material, and 1- azido -3- bromobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(3- bromophenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A16), gray solid, yield: 64.0%.
1H NMR(600MHz,DMSO-d6)δ8.18(m,2H),7.97(m,2H), 7.75–7.64(m,2H),7.55(m,
2H), 7.46 (d, J=5.3Hz, 1H), 3.69 (s, 2H), 3.32 (s, 2H), 2.26 (d, J=13.7Hz, 2H), 1.81-1.41
(m,5H),1.20(m,5H)；MS(ESI,m/z):465.1276[M+H]+。
Embodiment 17.
2- ((1- (4- bromophenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -
1,1'- hexamethylene] -5 (2H) -one (A17).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 4- bromine
Aniline is raw material, and 1- azido -4- bromobenzene is made according to embodiment 2b step, and 2- ((1- is made according to embodiment 2a, 2c step
(4- bromophenyl) -1H- 1,2,3-triazoles -4- base) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5
(2H) -one (A17), gray solid, yield: 63.6%.
1H NMR(600MHz,DMSO-d6)δ7.88(m,3H),7.84–7.75(m, 2H),7.48–7.42(m,2H),
7.35-7.28 (m, 1H), 7.24 (d, J=7.0 Hz, 1H), 3.67 (s, 2H), 3.31 (s, 2H), 2.21-2.19 (m, 2H),
1.79–1.66(m,2H),1.60(m,3H),1.44(m,2H),1.18(m,3H)； MS(ESI,m/z):465.1266[M+H]+。
Embodiment 18.
2- ((1- (2- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A18).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 2- hydroxyl
Base aniline is raw material, and 1- azido -2- hydroxy benzenes is made according to embodiment 2b step, and 2- is made according to embodiment 2a, 2c step
((1- (2- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A18), white solid, yield: 66.6%.
1H NMR(600MHz,DMSO-d6)δ7.60(m,2H),7.47–7.40(m, 2H),7.27–7.22(m,1H),
7.11 (m, 2H), 6.97 (m, 2H), 3.68 (s, 2H), 2.91 (s, 2H), 2.26 (d, J=12.8Hz, 2H), 1.72 (m, 2H),
1.60 (m,2H),1.45(m,2H),1.19(m,4H)；MS(ESI,m/z):403.2122[M +H]+。
Embodiment 19.
2- ((1- (3- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A19).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 3- hydroxyl
Base aniline is raw material, and 1- azido -3- hydroxy benzenes is made according to embodiment 2b step, and 2- is made according to embodiment 2a, 2c step
((1- (3- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A19), white solid, yield: 64.8%.
1H NMR(600MHz,DMSO-d6)δ7.50–7.42(m,2H),7.40–7.23 (m,6H),6.86(m,1H),
3.66 (s, 2H), 2.91 (m, 2H), 2.25 (d, J=12.9Hz, 2H), 1.82-1.68 (m, 2H), 1.61 (m, 3H), 1.45
(m,2H), 1.29–1.12(m,3H)；MS(ESI,m/z):403.2056[M+H]+。
Embodiment 20.
2- ((1- (4- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A20).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 4- hydroxyl
Base aniline is raw material, and 1- azido -4- hydroxy benzenes is made according to embodiment 2b step, and 2- is made according to embodiment 2a, 2c step
((1- (4- hydroxy phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A20), white solid, yield: 63.1%.
1H NMR(600MHz,DMSO-d6)δ7.69–7.60(m,3H),7.49–7.42 (m,2H),7.36–7.30(m,
1H), 7.25 (d, J=7.3Hz, 1H), 6.95-6.90 (m, 2H), 3.65 (s, 2H), 2.90 (m, 2H), 2.25 (d, J=
12.5Hz,2H), 1.75(m,2H),1.65–1.57(m,2H),1.45(m,2H),1.26–1.14(m, 4H)；MS(ESI,m/
z):403.2134[M+H]+。
Embodiment 21.
2- ((1- (2- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A21).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 2- cyanogen
Base aniline is raw material, and 1- azido -2- cyano benzene is made according to embodiment 2b step, and 2- is made according to embodiment 2a, 2c step
((1- (2- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A21), off-white powder, yield: 61.9%.
1H NMR(600MHz,DMSO-d6) δ 8.13 (t, J=9.7Hz, 2H), 7.99-7.87 (m, 5H), 7.82-7.72
(m, 2H), 3.64 (m, 2H), 2.88 (s, 2H), 2.26 (d, J=12.9Hz, 2H), 1.76 (m, 2H), 1.61 (m, 3H), 1.46
(m,2H),1.27–1.13(m,3H)；MS(ESI,m/z):412.2145[M+H]+。
Embodiment 22.
2- ((1- (3- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A22).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 3- cyanogen
Base aniline is raw material, and 1- azido -3- cyano benzene is made according to embodiment 2b step, and 2- is made according to embodiment 2a, 2c step
((1- (3- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A22), off-white powder, yield: 64.2%.
1H NMR(600MHz,DMSO-d6)δ8.29(m,2H),8.00–7.91(m, 2H),7.80(m,2H),7.48–
7.41 (m, 2H), 7.32 (m, 1H), 3.67 (m, 2H), 2.90 (m, 2H), 2.24 (d, J=13.1Hz, 2H), 1.75 (m, 2H),
1.61 (m,3H),1.51–1.40(m,2H),1.28–1.12(m,3H)；MS(ESI, m/z):412.2148[M+H]+。
Embodiment 23.
2- ((1- (4- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] nitrogen
Miscellaneous -1,1'- hexamethylene] -5 (2H) -one (A23).
The preparation such as embodiment 1 of 3,4- dihydro loop coils [benzo [c] azepine -1,1'- hexamethylene] -5 (2H) -one, with 4- cyanogen
Base aniline is raw material, and 1- azido -4- cyano benzene is made according to embodiment 2b step, and 2- is made according to embodiment 2a, 2c step
((1- (4- cyano-phenyl) -1H-1,2,3- triazole-4-yls) methyl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene
Alkane] -5 (2H) -one (A23), off-white powder, yield: 63.7%.
1H NMR(600MHz,DMSO-d6) δ 8.19-8.06 (m, 5H), 7.48-7.21 (m, 4H), 3.63 (t, J=
2.4Hz, 2H), 3.31 (s, 2H), 2.24 (d, J=13.3Hz, 2H), 1.78-1.68 (m, 2H), 1.62 (m, 3H), 1.17 (m,
5H)；MS(ESI,m/z):412.2134[M+H]+。
Inhibit tumor cell proliferation experiment.
Cytostatic to tumor cell experiment is carried out to the compound of the present invention, test method is using conventional mtt assay.
The culture of tumour cell: cell strain select A549 (human lung carcinoma cell), human ovarian cancer (OVCAR3 cell) with
The culture solution culture of RPMI1640+10%FBS+ dual anti-(100 units of penicillin/ml, 100 μ g/ml of streptomysin).
Sample preparation: after DMSO (Merck) dissolution, the solution or uniform that culture medium (-) is made into 1000 μ g/ml is added
Suspension, then with containing DMSO culture medium (-) dilution.Ultimate density be respectively as follows: 50 μM, 25 μM, 12.5mM, 6.25 μM,
3.125μM.Using Etoposide (Etoposide) as control.
The test method of cell inhibitory effect: it is 4~5 × 10 that concentration, which is added, in the every hole of 96 orifice plates4The cell suspension of a/ml
100 μ l, set 37 DEG C, 5%CO2In incubator.After 24 hours, it is separately added into sample liquid and reference substance liquid, 10 holes μ l/, if double multiple
Hole, 37 DEG C, 5%CO2Effect 24 hours.MTT (3- (4,5- dimethylthiazole -2- base) -2,5- bis- of 5mg/ml is added in every hole
Phenyltetrazole father-in-law bromine) compound) 20 μ l of solution, lysate DMSO is added after effect 4 hours, 150 holes μ l/ are set in incubator, are dissolved
570nm OD value is surveyed with the full-automatic microplate reader of MK-2 afterwards, calculates this number inhibition concentration IC50。
Experimental result is shown in Table 1.
In-vitro multiplication inhibitory activity IC of 1 sample of table to human body tumour cell50Value
The above experimental data shows that the compound in the present invention is most of all with preferable anti tumor activity in vitro, more
There is further investigation and develop the value of new anti-tumor drug, openr thinking is also provided for new drug development.
7- azaspiro [5.6] dodecane -10- ketone compounds of the present invention and preparation method thereof, belong to pharmaceutical technology field,
In particular to the compound of a kind of specified chemical structure with anti-tumor activity；The compound formula is pharmaceutically acceptable
Salt, hydrate or solvate.The present invention is to test (human lung carcinoma cell, Proliferation of Human Ovarian Cell) according to kinds of tumor cells system,
Prove that the compound has the function of inhibiting tumor promotion.Raw materials of compound provided by the invention is easy to get, experiments have shown that its have it is good
Good anticancer effect has good application prospect in anti-tumor drug design research and development field.
Claims (8)
1. a kind of 7- azaspiro [5.6] dodecane -10- ketone compounds, general structure I are as follows:
,
R group is substituted by 2,3 or 4 mono-substituted fluorine atoms, methyl, chlorine atom, methoxyl group, bromine atom, hydroxyl, cyano
Or hydrogen atom.
2. 7- azaspiro [5.6] dodecane -10- ketone compounds according to claim 1, which is characterized in that described logical
The compound of formula I or its pharmaceutically acceptable salt, hydrate or solvate, structure be selected from it is following any one:
3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5(2H) -one (A1)；
2-((1-phenyl-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,1'- hexamethylenes
Alkane] -5(2H) -one (A2)；
2-((1-(2- fluorophenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coils [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A3)；
2-((1-(3- fluorophenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A4)；
2-((1-(4- fluorophenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A5)；
2-((1-(2- benzyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A6)；
2-((1-(3- benzyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A7)；
2-((1-(4- benzyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A8)；
2-((1-(2- chlorphenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A9)；
2-((1-(3- chlorphenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A10)；
2-((1-(4- chlorphenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A11)；
2-((1-(2- methoxyphenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-
1,1'- hexamethylene] -5(2H) -one (A12)；
2-((1-(3- methoxyphenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-
1,1'- hexamethylene] -5(2H) -one (A13)；
2-((1-(4- methoxyphenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-
1,1'- hexamethylene] -5(2H) -one (A14)；
2-((1-(2- bromophenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A15)；
2-((1-(3- bromophenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A16)；
2-((1-(4- bromophenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A17)；
2-((1-(2- hydroxy phenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A18)；
2-((1-(3- hydroxy phenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A19)；
2-((1-(4- hydroxy phenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A20)；
2-((1-(2- cyano-phenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A21)；
2-((1-(3- cyano-phenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A22)；
2-((1-(4- cyano-phenyl)-1H- 1,2,3-triazoles-4- base) methyl)-3,4- dihydro loop coil [benzo [c] azepine-1,
1'- hexamethylene] -5(2H) -one (A23).
3. the preparation method of -2 described in any item 7- azaspiro [5.6] dodecane -10- ketone compounds according to claim 1,
Characterized by comprising the following steps:
Step 1, using bromobenzene as starting material, ether is solvent, and intermediate 1- phenylcyclohexanol is made through grignard reaction；
Step 2, using 1- phenylcyclohexanol as raw material, methylene chloride is solvent, through displacement reaction, reduction reaction be made intermediate 1-
Amino 1- cyclohexylbenzene；
Step 3, using 1- amino 1- cyclohexylbenzene as raw material, by Michael addition reaction, hydrolysis and friedel-crafts acylation
3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5(2H can be obtained in reaction) -one (A1)；
Step 4, with 3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5(2H) -one (A1) be raw material, by hydrocarbon
Change reaction and 7- azaspiro [5.6] dodecane -10- ketone compounds can be obtained in click chemistry reaction.
4. the preparation method of -2 described in any item 7- azaspiro [5.6] dodecane -10- ketone compounds according to claim 1,
It is characterized in that, specifically includes the following steps:
1 times of amount (mole dosage) bromobenzene and 0.5 times of amount magnesium rod are added in reaction flask and is dissolved in suitable ether for step 1, in
Cause under the conditions of 35 DEG C, thin-layer chromatography monitors reaction process；The cyclohexanone of 1.1 times of amounts is added after having reacted, in 35 DEG C of conditions
Lower reaction 5 hours；After completion of the reaction, by reaction solution be added aqueous ammonium chloride solution in, extracted with ether, extract liquor through drying, subtract
Pressure evaporation obtains 1- phenylcyclohexanol；
Step 2, the 1- phenylcyclohexanol that 1 times of amount is added in reaction flask, q. s. methylene chloride make solvent, the Azide of 2 times of amounts
Sodium, the trifluoroacetic acids of 3 times of amounts reacts 15 hours under room temperature, thin-layer chromatography monitoring reaction process；After completion of the reaction, by sodium carbonate
Aqueous solution is added in reaction solution, is extracted with dichloromethane, and extract liquor obtains 1- azido 1- benzyl ring through drying, reduction vaporization
Hexane；
Step 3, the 1- azido 1- cyclohexylbenzene that 1 times of amount is added in reaction flask make solvent suitable for tetrahydrofuran, and 1.2 times
The lithium aluminium hydride reduction of amount, after reacting 4 hours under normal temperature condition, increasing the temperature to 40-60 DEG C, the reaction was continued, thin-layer chromatography monitoring
Reaction process；After completion of the reaction, successively aqueous solution, sodium hydroxide solution are added in reaction solution, are filtered, filtrate decompression is steamed
Then hair is added a small amount of water and adjusts pH value to acidity, ether extracting impurities extract the miscellaneous rear pH value that adjusts to alkalinity, dichloromethane
Alkane extraction, extract liquor obtain 1- amino 1- cyclohexylbenzene through drying, reduction vaporization；
Step 4, the 1- amino 1- cyclohexylbenzene that 1 times of amount is added in reaction flask, 1.1 times of amount methyl acrylates, suitable DBU
Make catalyst, 70 DEG C reaction 15-20 hours, anti-thin-layer chromatography monitors reaction process；After answering, suitable water dissolution is added,
Ethyl acetate extraction, extract liquor obtain 3-((1- phenylcyclohexyl) amino) third by column chromatographic purifying through drying, reduction vaporization
Sour methyl esters；
Step 5,3-((1- phenylcyclohexyl) amino) methyl propionates that 1 times of amount is added in reaction flask, the hydroxide of 2 times of amounts
Sodium, suitable water as solvent, 50 DEG C reaction 1-2 hours, thin-layer chromatography monitor reaction process；After completion of the reaction, ethyl acetate extracts
Impurity is taken, water layer adjusts pH value to 6-7, and a large amount of methylene chloride dissolution is added to there is solid precipitation in solvent removed by evaporation at reduced pressure,
Filtrate is filtered to obtain, filtrate obtains 3-((1- phenylcyclohexyl after drying, reduction vaporization) amino) propionic acid；
Step 6,3-((1- phenylcyclohexyl) amino) propionic acid that 1 times of amount is added in reaction flask, the thionyl chloride of 3 times of amounts are fitted
The methylene chloride of amount makees solvent, 40 DEG C of reactions, and thin-layer chromatography monitors reaction process；After completion of the reaction, 3- is obtained after reduction vaporization
((1- phenylcyclohexyl) amino) propane acyl chlorides;
Step 7, the 3-((1- phenylcyclohexyl that 1 times of amount is added in reaction flask) amino) propane acyl chlorides, suitable methylene chloride
Make solvent, 70 DEG C of reactions reduce the temperature to 40-50 DEG C after dissolution, and the alchlor that 3 times are measured is added, and the reaction was continued, thin layer
Chromatography monitors reaction process；After completion of the reaction, reaction solution is added in the mixture of hydrochloric acid and ice water, ether extracting impurities take
Water layer adjusts pH value to alkalinity, and ethyl acetate extracts, and extract liquor obtains 3,4- bis- by column chromatographic purifying through drying, reduction vaporization
Hydrogen loop coil [benzo [c] azepine -1,1'- hexamethylene] -5(2H) -one;
Step 8,3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5(2H that 1 times of amount is added in reaction flask) -
Ketone, suitable acetonitrile as solvents, 1.1 times amount potassium carbonate, 1 times amount propargyl bromide, be heated to reflux, thin-layer chromatography monitoring react into
Journey；After completion of the reaction, it filters, filtrate adds suitable water to extract, and extract liquor obtains 2-(propyl-2- alkynes-through drying, reduction vaporization
1- yl) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5(2H) -one;
The aniline that 1 times of amount R base replaces, suitable water as solvent, the hydrochloric acid of 1.2 times of amounts, room temperature is added in step 9 in reaction flask
After stirring 0.5 hour, after adding the sodium nitrite of 2 times of amounts to continue stirring 0.5 hour, the sodium azide stirring 2 that 1.3 times of amounts are added is small
When, thin-layer chromatography monitors reaction process；After completion of the reaction, water is added to extract, extract liquor obtains corresponding R base and take through drying, reduction vaporization
The phenylazide in generation;
The phenylazide that 1 times of amount R base replaces is added in step 10 in reaction flask, and suitable DMF makees solvent, and the 2-(third of 1 times of amount
Base -2- alkynes -1- base) -3,4- dihydro loop coil [benzo [c] azepine -1,1'- hexamethylene] -5(2H) -one, it reacts at 30-40 DEG C,
Thin-layer chromatography monitors reaction process, and after completion of the reaction, dry, reduction vaporization obtains 7- azaspiro [5.6] dodecane -10- ketone
Compound.
5. according to claim 1-2 described in any item 7- azaspiro [5.6] dodecane-10- ketone compounds and its isomers,
The application of pharmaceutically acceptable salt, hydrate, pharmaceutical composition in preparation treatment anti-tumor drug.
6. a kind of anti-tumor drug, which is characterized in that 7- azaspiro [5.6] dodecane -10- ketone compounds including general formula I,
Pharmaceutically acceptable salt, solvate are standby at clinically as active ingredient and pharmaceutically acceptable carrier or excipients
Acceptable dosage form.
7. anti-tumor drug according to claim 6, which is characterized in that the clinically acceptable dosage form includes injection
Agent, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
8. according to any anti-tumor drug of claim 6-7, which is characterized in that the tumour is human lung cancer A549, people
Oophoroma OVCAR-3.
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Non-Patent Citations (2)
| Title |
|---|
| GUO-QINGLU ET AL.: "Design,synthesis and biological evaluation of novel uracil derivatives bearing 1,2,3-triazole moiety as thymidylatesynthase(TS)inhibitors and as potential antitumor drugs", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| XIN HE ET AL.: "Design,synthesis and anticancer activities evaluation of novel 5H-dibenzo[b,e]azepine-6,11-dione derivatives containing 1,3,4-oxadiazole units", 《BIOORGANIC&MEDICINAL CHEMISTRY LETTERS》 * |
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| CN111116551B (en) * | 2020-01-03 | 2022-05-20 | 中国医科大学 | 1-azaspiro [5.5] undecane-3-ones and 1-azaspiro [5.5] undecane-3-ols |
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