CN110172058B - 7-Azaspiro[5.6]dodecane-10-one compound and its preparation method and use - Google Patents
7-Azaspiro[5.6]dodecane-10-one compound and its preparation method and use Download PDFInfo
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- CN110172058B CN110172058B CN201910525516.0A CN201910525516A CN110172058B CN 110172058 B CN110172058 B CN 110172058B CN 201910525516 A CN201910525516 A CN 201910525516A CN 110172058 B CN110172058 B CN 110172058B
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- Prior art keywords
- reaction
- benzo
- dihydrospiro
- methyl
- triazol
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- -1 7-Azaspiro[5.6]dodecane-10-one compound Chemical class 0.000 title claims description 116
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- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 201000005202 lung cancer Diseases 0.000 claims abstract description 6
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 5
- 125000005605 benzo group Chemical group 0.000 claims description 115
- 238000006243 chemical reaction Methods 0.000 claims description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 35
- 230000002829 reductive effect Effects 0.000 claims description 34
- 238000004809 thin layer chromatography Methods 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 26
- 238000001704 evaporation Methods 0.000 claims description 25
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- 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
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Abstract
本发明属于医药领域，具体涉及7‑氮杂螺[5.6]十二烷‑10‑酮类化合物及其制备方法及应用。本发明首次合成七元环结构，得到一种更具抗肿瘤效果的全新化合物，并未见过相关结构的报道，药理研究显示本发明化合物对人肺癌A549细胞、人卵巢癌OVCAR‑3细胞均有一定的抑制活性，为后续制备抗肿瘤药物提供了基础。The invention belongs to the field of medicine, and in particular relates to a 7-azaspiro[5.6]dodecane-10-ketone compound and a preparation method and application thereof. The present invention is the first to synthesize a seven-membered ring structure and obtain a brand-new compound with more anti-tumor effect. There is no report on the relevant structure. Pharmacological studies show that the compound of the present invention is effective on human lung cancer A549 cells and human ovarian cancer OVCAR-3 cells. It has certain inhibitory activity, which provides a basis for the subsequent preparation of antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a compound with a specific chemical structure and antitumor activity, in particular to a 7-azaspiro [5.6] dodecane-10-one compound, and a preparation method and application thereof.
Background
Malignant tumors, also known as cancers, are a serious global public health problem. Most cancer patients are lost due to their high mortality and relapse rates. It is characterized by uncontrolled division and spread of abnormal cells within the human body. Therefore, the synthesis of potent novel anticancer drugs is one of the most important targets of modern pharmaceutical chemistry. At present, the main clinical cancer treatment methods mostly adopt chemical drug therapy. The existing antitumor drugs have certain curative effects, but have the problems of drug resistance, poor selection effect, great toxic and side effects and the like. Therefore, many researchers at home and abroad try to search and develop effective anti-tumor new drugs from natural plants.
Based on the above, the invention designs a brand-new anti-tumor compound, and introduces a seven-membered ring structure, so as to obtain the brand-new compound with better anti-tumor effect, and reports of related structures are not found.
Disclosure of Invention
The invention aims to provide 7-azaspiro [5.6] dodecane-10-one compounds and a preparation method thereof, and the prepared compounds show good results in-vitro antitumor activity tests.
The structural general formula I of the 7-azaspiro [5.6] dodecane-10-one compound provided by the invention is as follows:
wherein:
the R group on the benzene ring is substituted by a fluorine atom, a methyl group, a chlorine atom, a methoxy group, a bromine atom, a hydroxyl group, a cyano group or a hydrogen atom which is mono-substituted at the 2-position, the 3-position or the 4-position.
The invention relates to a compound, an isomer and a pharmaceutically acceptable salt, hydrate or prodrug thereof, which are shown in the general formula I: the following compounds are particularly preferred, but these are not meant to limit the invention in any way:
3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (a 1);
2- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 2);
2- ((1- (2-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 3);
2- ((1- (3-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 4);
2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 5);
2- ((1- (2-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 6);
2- ((1- (3-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 7);
2- ((1- (4-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A8);
2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 9);
2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 10);
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 11);
2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 12);
2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 13);
2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 14);
2- ((1- (2-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (a 15);
2- ((1- (3-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (a 16);
2- ((1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (a 17);
2- ((1- (2-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 18);
2- ((1- (3-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 19);
2- ((1- (4-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 20);
2- ((1- (2-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 21);
2- ((1- (3-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 22);
2- ((1- (4-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A23).
In order to achieve the above object, the present invention also provides a process for preparing the 7-azaspiro [5.6] dodecane-10-one compound, comprising the following steps.
Step 1, bromobenzene is used as an initial raw material, ether is used as a solvent, and an important intermediate 1-phenylcyclohexanol is prepared through a classical Grignard reaction.
And 2, taking 1-phenylcyclohexanol as a raw material and dichloromethane as a solvent, and carrying out a displacement reaction and a reduction reaction to obtain an important intermediate 1-amino-1-phenylcyclohexane.
And 3, taking 1-amino 1-phenylcyclohexane as a raw material, and carrying out Michael addition reaction, hydrolysis reaction and Friedel-crafts acylation reaction to obtain a target product 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone (A1).
And 4, taking 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone (A1) as a raw material, and carrying out alkylation reaction and click chemical reaction to obtain a target product A2-A23.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The invention can contain 7-azaspiro [5.6] dodecane-10-one compounds of general formula I and pharmaceutically acceptable salts and solvates thereof as active ingredients, and the compounds are mixed with pharmaceutically acceptable carriers or excipients to prepare a pharmaceutical composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The compounds of the present invention and their derivatives may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc.
The invention comprises the application of any 7-azaspiro [5.6] dodecane-10-one compound, isomer, pharmaceutically acceptable salt, hydrate and pharmaceutical composition in preparing antitumor drugs; the pharmaceutical composition comprises any one of the 7-azaspiro [5.6] dodecane-10-one compounds, pharmaceutically acceptable salts, hydrates or solvates thereof and a pharmaceutically acceptable carrier.
The cancer cell line provided by the invention is a human lung cancer A549 cell line and a human ovarian cancer OVCAR-3 cell line.
The invention has the beneficial effects that: (1) in the design process, a novel 7-azaspiro [5.6] dodecane-10-one anti-tumor compound is designed and synthesized, the anti-tumor effect is greatly improved, and the anti-tumor compound has excellent anti-proliferation capacity on human lung cancer A549 cells; (2) the compound has obvious effect in-vitro antitumor activity test; and (3) in the synthesis process, the synthesis steps are optimized, and the possibility is provided for future industrial production.
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be illustrative only and not to limit the scope of the invention.
In order to achieve the above object, the present invention also provides a preparation method of the 7-azaspiro [5.6] dodecane-10-one compound, which specifically comprises the following steps.
Step 1, adding 1 time (molar amount) of bromobenzene and 0.5 time of magnesium strip into a reaction bottle, dissolving the bromobenzene and the magnesium strip into a proper amount of ether, initiating the reaction at 35 ℃, and monitoring the reaction process by thin-layer chromatography. After the reaction, 1.1 times of cyclohexanone is added to react for 5 hours at the temperature of 35 ℃. After the reaction is finished, adding the reaction solution into an ammonium chloride aqueous solution, extracting with diethyl ether, drying the extract, and evaporating under reduced pressure to obtain the 1-phenylcyclohexanol.
And 2, adding 1 time of 1-phenylcyclohexanol, a proper amount of dichloromethane serving as a solvent, 2 times of sodium azide and 3 times of trifluoroacetic acid into a reaction bottle, reacting for 15 hours at normal temperature, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, adding a sodium carbonate aqueous solution into the reaction solution, extracting with dichloromethane, drying the extract, and evaporating under reduced pressure to obtain the 1-azido 1-phenylcyclohexane.
And 3, adding 1 time of 1-azido 1-phenylcyclohexane which is suitable for tetrahydrofuran as a solvent and reducing by 1.2 times of lithium aluminum hydride, reacting for 4 hours at normal temperature, raising the temperature to 40-60 ℃ for continuous reaction, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, sequentially adding the aqueous solution and the sodium hydroxide solution into the reaction solution, carrying out suction filtration, carrying out reduced pressure evaporation on the filtrate, then adding a small amount of water, adjusting the pH value to acidity, extracting impurities with diethyl ether, adjusting the pH value to alkalinity after impurity extraction, extracting with dichloromethane, drying the extract, and carrying out reduced pressure evaporation to obtain the 1-amino-1-phenylcyclohexane.
And 4, adding 1-amino 1-phenylcyclohexane in an amount which is 1 time that of the reaction bottle, 1.1 times that of the methyl acrylate and a proper amount of DBU (dimethyl diallyl ammonium chloride) as a catalyst into the reaction bottle, reacting for 15-20 hours at 70 ℃, and monitoring the reaction process by using a reverse thin-layer chromatography. After the reaction is finished, adding a proper amount of water for dissolving, extracting by ethyl acetate, drying the extract liquid, evaporating under reduced pressure, and purifying by column chromatography to obtain the methyl 3- ((1-phenylcyclohexyl) amino) propionate.
And 5, adding 1 time of methyl 3- ((1-phenylcyclohexyl) amino) propionate, 2 times of sodium hydroxide and a proper amount of water into a reaction bottle, reacting for 1-2 hours at 50 ℃, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, extracting impurities by ethyl acetate, adjusting the pH value of a water layer to 6-7, removing the solvent by reduced pressure evaporation until solid is separated out, adding a large amount of dichloromethane for dissolution, filtering to obtain filtrate, drying the filtrate, and evaporating under reduced pressure to obtain the 3- ((1-phenylcyclohexyl) amino) propionic acid.
And step 6, adding 1 time of 3- ((1-phenylcyclohexyl) amino) propionic acid, 3 times of thionyl chloride and a proper amount of dichloromethane into a reaction bottle, reacting at 40 ℃, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, performing reduced pressure evaporation to obtain 3- ((1-phenylcyclohexyl) amino) propane acyl chloride;
and 7, adding 1 time of 3- ((1-phenylcyclohexyl) amino) propane acyl chloride and a proper amount of dichloromethane into a reaction bottle as a solvent, reacting at 70 ℃ until the materials are dissolved, reducing the temperature to 40-50 ℃, adding 3 times of aluminum trichloride, continuing the reaction, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, adding the reaction solution into a mixture of hydrochloric acid and ice water, extracting impurities by using diethyl ether, adjusting the pH value of a water layer to be alkaline, extracting by using ethyl acetate, drying an extract liquid, evaporating under reduced pressure, and purifying by using column chromatography to obtain 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone;
and step 8, adding 1 time of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone, a proper amount of acetonitrile serving as a solvent, 1.1 times of potassium carbonate and 1 time of bromopropyne into a reaction bottle, heating for refluxing, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, carrying out suction filtration, adding a proper amount of water into the filtrate for extraction, drying the extract, and carrying out reduced pressure evaporation to obtain 2- (propyl-2-alkyne-1-yl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone;
and step 9, adding 1 time of aniline substituted by R group, a proper amount of water as a solvent and 1.2 times of hydrochloric acid into a reaction bottle, stirring for 0.5 hour at normal temperature, adding 2 times of sodium nitrite, continuously stirring for 0.5 hour, adding 1.3 times of sodium azide, stirring for 2 hours, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, adding water for extraction, drying the extract liquor, and evaporating under reduced pressure to obtain the corresponding R-group substituted azidobenzene;
step 10, adding 1 time of R-substituted azidobenzene and a proper amount of DMF as a solvent into a reaction bottle, reacting 1 time of 2- (propyl-2-alkyne-1-yl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone at 30-40 ℃, and monitoring the reaction process by thin-layer chromatography. And after the reaction is finished, drying, and evaporating under reduced pressure to obtain the target compound.
Example 1.
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (A1).
a.1-phenylcyclohexanol preparation.
Bromobenzene (50g,0.31mol), magnesium strip (8.13g, 0.33mol) was added to a 1000mL three-necked flask and dissolved in the appropriate amount of ether and initiated at 35 ℃. After completion of the reaction, cyclohexanone (34.38g,0.35mol) was added and reacted at 35 ℃ for 5 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding the reaction solution into saturated ammonium chloride aqueous solution, extracting with diethyl ether, drying the extract, and evaporating under reduced pressure to obtain a product with the yield: 95.5 percent.
b.preparation of 1-azido-1-phenylcyclohexane.
A1000 mL reaction flask was charged with 1-phenylcyclohexanol (20.00g,0.11mol), dichloromethane 500mL, sodium azide (8.11g,0.12mol), trifluoroacetic acid (25.88 g,0.23mol), reacted at room temperature for 15 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding a saturated sodium carbonate aqueous solution into the reaction solution, extracting with dichloromethane, drying the extract, and evaporating under reduced pressure to obtain a product with the yield: 97.2 percent.
c, preparing 1-amino-1-phenylcyclohexane.
1-azido 1-phenylcyclohexane (13g,0.064 mol), tetrahydrofuran (500 mL) and lithium aluminum hydride (4.77g,0.13mol) are added into a 1000mL reaction flask, and after reacting for 4 hours under normal temperature conditions, the temperature is raised to 40-60 ℃ to continue the reaction, and the reaction progress is monitored by thin layer chromatography. After the reaction is finished, sequentially adding the aqueous solution and the sodium hydroxide solution into the reaction solution, performing suction filtration, performing reduced pressure evaporation on the filtrate, then adding a small amount of water, adjusting the pH value to acidity, extracting impurities with diethyl ether, adjusting the pH value to alkalinity after impurity extraction, performing dichloromethane extraction, drying and reduced pressure evaporation on the extract liquor to obtain a product, wherein the yield is as follows: 89.43 percent.
Preparation of methyl 3- ((1-phenylcyclohexyl) amino) propionate.
A500 mL reaction flask was charged with 1-amino 1-phenylcyclohexane (20.00g,0.11mol), methyl acrylate (10.81g,0.13mol), DBU (8.69g,0.057mol), reacted at 70 ℃ for 17 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding a proper amount of water for dissolving, extracting by ethyl acetate, drying and decompressing the extract, and purifying by column chromatography to obtain a product with the yield: 79.5 percent.
Preparation of 3- ((1-phenylcyclohexyl) amino) propionic acid.
A500 mL reaction flask was charged with methyl 3- ((1-phenylcyclohexyl) amino) propionate (15.00g,0.057mol), sodium hydroxide (4.59g,0.115mol), and water (300 mL) at 50 ℃ for 1.5 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, extracting impurities by ethyl acetate, adjusting the pH value of a water layer to 7, removing the solvent by reduced pressure evaporation until solid is separated out, adding a large amount of dichloromethane for dissolution, performing suction filtration to obtain filtrate, drying and performing reduced pressure evaporation on the filtrate to obtain a product, wherein the yield is as follows: 97.15 percent.
f.3 preparation of- ((1-phenylcyclohexyl) amino) propanecarbonyl chloride.
A500 mL reaction flask was charged with 3- ((1-phenylcyclohexyl) amino) propanoic acid (20.00g, 0.081mol), thionyl chloride (19.24g,0.162mol), and dichloromethane (300 mL) and reacted at 40 ℃ with monitoring of the progress of the reaction by thin layer chromatography. After the reaction is finished, the product is obtained after reduced pressure evaporation, and the yield is as follows: 100 percent.
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A1).
A500 mL reaction flask was charged with 3- ((1-phenylcyclohexyl) amino) propanecarbonyl chloride (9g,0.034mol), dichloromethane (200 mL), and 70 ℃ for reaction until dissolved, the temperature was lowered to 45 ℃ and aluminum trichloride (12.94g,0.097mol) was added to continue the reaction, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding the reaction solution into a mixture of hydrochloric acid and ice water, extracting impurities by using diethyl ether, adjusting the pH value of a water layer to be alkaline, extracting by using ethyl acetate, drying and evaporating an extract liquor under reduced pressure, and then purifying by using column chromatography to obtain a product, wherein the yield is as follows: 35.2 percent.1HNMR(600MHz,DMSO-d6)δ7.50(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]+。
Example 2.
Preparation of 2- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A2).
3, 4-Dihydropirocyclo [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one was prepared as in example 1.
a.2- (propyl-2-yn-1-yl) -3, 4-dihydrospiro [ benzo [ c ] azepine-1, 1-
Preparation of cyclohexane-5 (2H) -one.
A100 mL reaction flask was charged with 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan ] -5(2H) -one (1.00g,0.004mol), acetonitrile 50mL, potassium carbonate (1.21 g,0.009mol), bromopropyne (0.57g,0.005mol), heated to reflux at 85 deg.C, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, filtering, adding a proper amount of water into the filtrate for extraction, drying the extract, and evaporating under reduced pressure to obtain the 2- (propyl-2-alkyne-1-yl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone.
b.1-azido-benzene preparation.
A100 mL reaction flask was charged with aniline (2.00g,0.021mol), water (50 mL), hydrochloric acid (2.68g,0.028mol), stirred at room temperature for 0.5 hour, then stirred with sodium nitrite (1.63 g,0.024mol) for 0.5 hour, stirred with sodium azide (1.54g,0.024 mol) for 2 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, water is added for extraction, and the extract liquid is dried and evaporated under reduced pressure to obtain the 1-azido-benzene.
Preparation of 2- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one.
1-azido-benzene (0.50g,0.004mol), DMF50mL, 2- (propyl-2-yn-1-yl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (1g,0.004mol) were added to a 100mL reaction flask, reacted at 30 ℃ and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, drying and evaporating under reduced pressure to obtain 2- ((1-phenyl-1H-1, 2, 3-triazole-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -ketone (A2) as a white solid with the yield: 70.6 percent.
1H NMR(600MHz,DMSO-d6)δ8.67(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。
Example 3.
Preparation of 2- ((1- (2-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A3).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 2-fluoroaniline, 1-azido-2-fluorobenzene was obtained according to the procedure of example 2b and 2- ((1- (2-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a3), brown solid, yield: 62.1 percent.
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]+。
Example 4.
Preparation of 2- ((1- (3-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A4).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 3-fluoroaniline, 1-azido-3-fluorobenzene was obtained according to the procedure of example 2b and 2- ((1- (3-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a4), brown solid, yield as described in example 1: 62.5 percent.
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]+。
Example 5.
Preparation of 2- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A5).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 4-fluoroaniline, 1-azido-4-fluorobenzene was obtained according to the procedure of example 2b and 3- ((1- (4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a5), brown solid, yield as described in example 1: 63.1 percent.
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]+。
Example 6.
Preparation of 2- ((1- (2-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A6).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one as in example 1, starting from 2-methylaniline, 1-azido-2-methylbenzene was prepared according to the procedure of example 2b, 3- ((1- (2-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a6) was prepared according to the procedures of examples 2a, 2c, as an off-white solid in yield: 53.2 percent.
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]+。
Example 7.
Preparation of 2- ((1- (3-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A7).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one as in example 1, starting from 3-methylaniline, 1-azido-3-methylbenzene was prepared according to the procedure of example 2b, 3- ((1- (3-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a7) was prepared according to the procedures of examples 2a, 2c, as an off-white solid in yield: 54.3 percent.
1H NMR(600MHz,DMSO-d6)δ8.64(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]+。
Example 8.
Preparation of 2- ((1- (4-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A8).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one as in example 1, starting from 4-methylaniline, 1-azido-4-methylbenzene was prepared according to the procedure of example 2b, 2- ((1- (4-benzyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A8) was prepared according to the procedures of examples 2a, 2c, an off-white solid, yield: 52.6 percent.
1H NMR(600MHz,DMSO-d6)δ8.62(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]+。
Example 9.
Preparation of 2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A9)
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 2-chloroaniline, 1-azido-2-chlorobenzene was prepared according to the procedure of example 2b and 2- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a9) was prepared according to the procedures of examples 2a, 2c in example 1 as a yellow solid in yield: 51.2 percent.
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]+。
Example 10.
Preparation of 2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A10).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 3-chloroaniline, 1-azido-3-chlorobenzene was prepared according to the procedure of example 2b and 2- ((1- (3-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a10) was prepared according to the procedures of examples 2a, 2c in example 1 as a yellow solid in yield: 50.7 percent.
1H NMR(600MHz,DMSO-d6)δ8.76(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]+。
Example 11.
2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A11).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 4-chloroaniline, 1-azido-4-chlorobenzene was prepared according to the procedure of example 2b and 2- ((1- (4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a11) was prepared according to the procedures of examples 2a, 2c in example 1 as a yellow solid in yield: 51.5 percent.
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]+。
Example 12.
2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 12).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one as in example 1, starting from 2-methoxyaniline, 1-azido-2-methoxybenzene was prepared according to the procedure of example 2b, 2- ((1- (2-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a12) was prepared according to the procedures of examples 2a, 2c, an off-white solid, yield: 65.7 percent.
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]+。
Example 13.
2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 13).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 3-methoxyaniline according to example 1, 1-azido-3-methoxybenzene was prepared according to the procedure of example 2b, 2- ((1- (3-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a13) was prepared according to the procedures of examples 2a, 2c, an off-white solid, yield: 66.2 percent
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]+。
Example 14.
2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a 14).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 4-methoxyaniline according to example 1, 1-azido-4-methoxybenzene was prepared according to the procedure of example 2b, 2- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a14) was prepared according to the procedures of examples 2a, 2c, an off-white solid, yield: 65.9 percent
1H NMR(600MHz,DMSO-d6)δ8.54(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]+。
Example 15.
2- ((1- (2-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (A15).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 2-bromoaniline, 1-azido-2-bromobenzene was prepared according to the procedure of example 2b and 2- ((1- (2-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a15) was prepared according to the procedures of examples 2a, 2c in example 1, yield as a grey solid: 62.9 percent.
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]+。
Example 16.
2- ((1- (3-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (A16).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 3-bromoaniline, 1-azido-3-bromobenzene was prepared according to the procedure of example 2b and 2- ((1- (3-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a16) was prepared according to the procedures of examples 2a, 2c, as a grey solid in yield: 64.0 percent.
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]+。
Example 17.
2- ((1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexane ] -5(2H) -one (A17).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 4-bromoaniline, 1-azido-4-bromobenzene was prepared according to the procedure of example 2b and 2- ((1- (4-bromophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a17) was prepared according to the procedures of examples 2a, 2c, as a grey solid in yield: and (3.6).
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]+。
Example 18.
2- ((1- (2-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A18).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 2-hydroxyaniline, 1-azido-2-hydroxybenzene was prepared according to the procedure of example 2b and 2- ((1- (2-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a18) was prepared according to the procedures of examples 2a, 2c, in the same manner as in example 1, and as a white solid, yield: 66.6 percent.
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]+。
Example 19.
2- ((1- (3-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A19).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 3-hydroxyaniline, 1-azido-3-hydroxybenzene was prepared according to the procedure of example 2b and 2- ((1- (3-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a19) was prepared according to the procedures of examples 2a, 2c, as a white solid in yield: 64.8 percent.
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]+。
Example 20.
2- ((1- (4-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A20).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 4-hydroxyaniline, 1-azido-4-hydroxybenzene was prepared according to the procedure of example 2b and 2- ((1- (4-hydroxyphenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a20) was prepared according to the procedures of examples 2a, 2c, in the same manner as in example 1, and as a white solid, yield: 63.1 percent.
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]+。
Example 21.
2- ((1- (2-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A21).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 2-cyanoaniline according to example 1, 1-azido-2-cyanobenzene was prepared according to the procedure of example 2b and 2- ((1- (2-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a21) was prepared according to the procedures of examples 2a, 2 c) as an off-white solid in yield: 61.9 percent.
1H NMR(600MHz,DMSO-d6)δ8.13(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]+。
Example 22.
2- ((1- (3-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A22).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 3-cyanoaniline according to example 1, 1-azido-3-cyanobenzene was prepared according to the procedure of example 2b and 2- ((1- (3-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a22) was prepared according to the procedures of examples 2a, 2 c) as an off-white solid in yield: 64.2 percent.
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]+。
Example 23.
2- ((1- (4-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (A23).
Preparation of 3, 4-dihydrospiro [ benzo [ c ] aza-1, 1 '-cyclohexan-5 (2H) -one starting from 4-cyanoaniline, 1-azido-4-cyanobenzene was prepared according to the procedure of example 2b and 2- ((1- (4-cyanophenyl) -1H-1,2, 3-triazol-4-yl) methyl) -3, 4-dihydrospiro [ benzo [ c ] aza-1, 1' -cyclohexan-5 (2H) -one (a23) was prepared according to the procedures of examples 2a, 2c in the same manner as in example 1, and as a white solid, yield: and (3.7).
1H NMR(600MHz,DMSO-d6)δ8.19–8.06(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]+。
Experiment for inhibiting tumor cell proliferation.
The compound of the invention is subjected to tumor cell proliferation inhibition experiments, and the test method adopts a conventional MTT method.
Culturing of tumor cells: the cell strain is cultured in culture medium of A549 (human lung cancer cell) and human ovarian cancer (OVCAR3 cell) in RPMI1640+ 10% FBS + double antibody (penicillin 100 unit/ml, streptomycin 100 μ g/ml).
Sample preparation: after dissolution in DMSO (Merck), media (-) is added to make a 1000. mu.g/ml solution or homogeneous suspension, which is then diluted with DMSO-containing media (-). The final concentrations were: 50. mu.M, 25. mu.M, 12.5mM, 6.25. mu.M, 3.125. mu.M. Etoposide (Etoposide) was used as a control.
Test methods for inhibition of cell proliferation: the adding concentration of each hole of the 96-hole plate is 4-5 multiplied by 104Mu.l of cell suspension/ml, placed at 37 ℃ in 5% CO2In the incubator. After 24 hours, the sample solution and the control solution were added to each well at 10. mu.l/well in duplicate, 37 ℃ with 5% CO2The reaction was carried out for 24 hours. Adding 20 μ l of 5mg/ml MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) solution into each well, reacting for 4 hr, adding DMSO solution into each well, placing in incubator at 150 μ l/well, dissolving, measuring 570nm OD value with MK-2 full-automatic enzyme standard instrument, and calculating inhibitory concentration IC50。
The results are shown in Table 1.
TABLE 1 in vitro proliferation inhibitory Activity of samples on human tumor cells IC50Value of
The experimental data show that most of the compounds in the invention have better in-vitro anti-tumor activity, have more value in further research and development of new anti-tumor drugs, and provide a wider idea for research and development of new drugs.
The invention relates to a 7-azaspiro [5.6] dodecane-10-one compound and a preparation method thereof, belonging to the technical field of medicines, in particular to a compound with a specific chemical structure and antitumor activity; the general formula of the compound is pharmaceutically acceptable salt, hydrate or solvate. The invention proves that the compound has the function of inhibiting the tumor activity according to the tests of various tumor cell lines (human lung cancer cells and human ovarian cancer cells). The compound provided by the invention has easily available raw materials, and experiments prove that the compound has good anticancer effect and good application prospect in the field of design and research of antitumor drugs.
Claims (8)
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| Design,synthesis and biological evaluation of novel uracil derivatives bearing 1,2,3-triazole moiety as thymidylatesynthase(TS)inhibitors and as potential antitumor drugs;Guo-qingLu et al.;《European Journal of Medicinal Chemistry》;20190324;第171卷;第282-296页 * |
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