CN117777047B - N-substituted azaspiro-decone compounds, preparation method and application thereof - Google Patents
N-substituted azaspiro-decone compounds, preparation method and application thereof Download PDFInfo
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- CN117777047B CN117777047B CN202410208065.9A CN202410208065A CN117777047B CN 117777047 B CN117777047 B CN 117777047B CN 202410208065 A CN202410208065 A CN 202410208065A CN 117777047 B CN117777047 B CN 117777047B
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- compound
- azaspiro
- intermediate compound
- substituted
- decarenone
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- 150000003852 triazoles Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides an N-substituted aza-spiro-decone compound, a preparation method and application thereof, and belongs to the technical field of spiro-decone compounds. The N-substituted azaspiro-decone compound has a structure shown in a formula I or a formula II; the invention realizes the efficient construction of the N-substituted azaspiro-decarenone compounds through nucleophilic addition reaction. The preparation method is simple, and the prepared compound has stable structure, small toxic and side effects, good water solubility and anti-tumor activity and can be used for preparing anti-tumor drugs.
Description
Technical Field
The invention belongs to the technical field of spirodecenone compounds, and particularly relates to an N-substituted aza-spirodecenone compound, a preparation method and application thereof.
Background
Malignant tumor is a serious disease which endangers human health and life, so the research and development of novel antitumor drugs with low toxicity and high curative effect based on different structure and effect relations and different action targets are significant. Spirodecenone is a derivative containing a fully substituted quaternary carbon center (spiro atom ) and has various biological activities such as anti-tumor, anti-inflammatory, antibacterial, antiviral and anti-degenerative diseases. Moreover, spirodecenone has a unique rigid and conformational structure, which is of great interest due to its structural specificity and versatile bioactivity.
The prior researches show that the sulfonamide has good nitrene reactivity and stability, the sulfonamide compound can be selectively enriched in tumor tissues, has the characteristics of potential of tumor targeted drug delivery carriers and the like, and the sulfonamide is adopted as a nitrogen source to design and synthesize serial sulfonamide biazaspirodecadienone H1 and H2 derivatives which have certain antitumor activity, however, the sulfonamide biazaspirodecadienone H1 and H2 derivatives can show the characteristic of enrichment at tumor sites and better antitumor activity, but have the problems of stronger toxicity, poor water solubility, low in-vitro activity and the like, and the defects limit the further application research of the sulfonamide biazaspirodecadienone H1 and H2 derivatives. The structural formula of the sulfonamide biazaspirodecadienone H1 and H2 derivatives is shown as follows:
。
disclosure of Invention
The invention aims to solve the problems that: provides N-substituted aza-spiro-decylenone compounds, and a preparation method and application thereof, so as to solve the problems of strong toxicity, poor water solubility and low in-vitro activity of sulfonamide biazaspiro-decylenone derivatives.
The technical scheme adopted for solving the technical problems is as follows: provided are N-substituted azaspiro-decarenones having a structure as shown in formula I or formula II:
；
Wherein:
r is H, C 1-20 straight or branched chain alkyl, halogen, alicyclic, aromatic ring, carboxyl, hydroxyl, amino, sulfhydryl, carbo-acylated derivative, phosphoryl derivative, phosphitylated derivative or sulfurylated derivative;
R 2 is an aromatic sulfonyl or substituted aromatic sulfonyl, aromatic carbonyl or substituted aromatic carbonyl, aromatic phosphoryl or substituted aromatic phosphoryl, aromatic ring or substituted aromatic ring, aliphatic ring or substituted aliphatic ring, heterocycle or substituted heterocycle, benzyl or substituted benzyl;
R 3 is C 1-20 straight or branched alkyl, halogen, alicyclic, aromatic ring, heterocyclic ring, carboxyl, hydroxyl, amino, mercapto, carbo-acylated derivative, phosphorylated derivative, phosphitylated derivative or thiolated derivative;
x is oxygen, sulfur, nitrogen or carbon element, and n is 0,1,2,3,4 or 5.
Preferably, R is H, halogen or an aromatic ring; r 2 is an aromatic sulfonyl or substituted aromatic sulfonyl, aromatic ring or substituted aromatic ring, heterocycle or substituted heterocycle, benzyl or substituted benzyl; r 3 is a heterocycle, carboxyl, mercapto or carboacylated derivative; x is oxygen; n is 1.
Preferably, the specific structural formula of the N-substituted azaspiro-decarenone compound is as follows:
。
the preparation method of the N-substituted azaspiro-decone compound comprises the following synthetic routes:
Synthesis path 1: dissolving a compound A and a compound B in an organic solvent, reacting under the action of a catalyst to obtain an intermediate compound 1, adding an oxidant to react to obtain an intermediate compound 2, and adding a nucleophile to react to obtain an N-substituted azaspiro-decamonoalkone compound shown in a formula I; the synthetic route is as follows:
；
synthesis path 2: dissolving a compound C and a compound D in an organic solvent, reacting under the action of a dehydrating agent to obtain an intermediate compound 3, adding an oxidant to react to obtain an intermediate compound 4, adding a compound B, reacting under the action of a catalyst to obtain an intermediate compound 5, and adding a nucleophile to react to obtain the N-substituted azaspiro-decone compound shown in the formula II; the synthetic route is as follows:
；
Synthesis path 3: adding a dehydrating agent into the compound E and the compound F to react to obtain an intermediate compound 6, adding an oxidant and a copper salt catalyst to react to obtain an intermediate compound 5, and adding a nucleophile to react to obtain the N-substituted azaspiro-decamonoalkenone compound shown in the formula II; the synthetic route is as follows:
。
More preferably, compound E is When the N-substituted azaspiro-decone compound is prepared, the preparation method comprises the following steps: dissolving 3-chlorobenzaldehyde, cyanamide and methanol in N-bromosuccinimide, reacting under the action of a catalyst to obtain an intermediate compound 7, adding phenylhydrazine and the catalyst to react to obtain an intermediate compound 8, adding 2- (4-methoxyphenoxy) acetic acid, carbodiimide and 1-hydroxybenzotriazole to react to obtain an intermediate compound 9, adding an oxidant and a copper salt catalyst to react to obtain an intermediate compound 10, and adding a nucleophile to react to obtain the N-substituted azaspiro-decamonoalkenone compound shown in formula II; the synthetic route is as follows:
。
The invention has the advantages that: the intermediate compound before nucleophilic reagent addition is Michael acceptor molecule, which has electrophilicity and can react with various nucleophilic bioactive molecules in vivo to express biological effect, the molecule can be covalently combined with nucleophilic amino acid residues (such as cysteine, arginine and the like) of various proteins, hydroxyl or sulfhydryl to regulate signal paths in cells such as NF-kappa B, STAT and the like, but proteins containing nucleophilic amino acid residues and the like are likely to be the acting targets of Michael acceptor molecules, so that toxic and side effects caused by off-target effects are easy to generate, and the intermediate compound and nucleophilic reagent have great potential risk in clinical application, and can reduce the in-vivo addition reaction sites of the Michael acceptor molecule, namely the finally obtained N-substituted azaspirodecanone compound can effectively reduce toxic and side effects and has better safety; meanwhile, the ternary ring, polar or hydrophilic group is introduced into the spirodecenone structure, so that the water solubility of the spirodecenone structure can be further improved, such as the multi-nitrogen heterocyclic structures of imidazole, triazole, piperazine and the like, and the bonding force of the compound and a target point can be improved, and the lipid-water distribution coefficient is improved, so that the pharmacological activity of the spirodecenone is improved.
More preferably, the catalysts are triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene or potassium tert-butoxide.
More preferably, the oxidizing agents are iodobenzene trifluoroacetate or diacetoxyiodobenzene; the copper salt catalyst is tetraacetonitrile copper perchlorate.
More preferably, the dehydrating agent in synthetic pathway 2 is 1, 3-dicyclohexylcarbodiimide; the dehydrating agent in synthetic pathway 3 is a mixture of carbodiimide and 1-hydroxybenzotriazole.
More preferably, the nucleophiles are all ethanethiol, dimethyl malonate, 2H-1,2, 3-triazole, imidazole or 1-methylpiperazine.
More preferably, the organic solvents are all dichloromethane, acetonitrile, methanol, ethanol, diethyl ether, 1, 2-dichloroethane, chloroform, toluene or xylene.
The invention also provides application of the N-substituted azaspiro-decone compounds in preparing antitumor drugs.
The invention has the following beneficial effects:
(1) The method for preparing the N-substituted azaspiro-decarenone compound provided by the invention has moderate reaction, and the prepared N-substituted azaspiro-decarenone compound is not easy to open the ring and has better biological activity.
(2) The N-substituted azaspiro-decarenone compound provided by the invention has good anti-tumor activity, low toxicity, good water solubility and high purity, and the structure is a novel compound.
(3) The N-substituted azaspiro-decarenone compound provided by the invention is simple in synthesis, easy in raw material acquisition and capable of being generated in a large scale.
Detailed Description
The examples given below are only intended to illustrate the invention and are not intended to limit the scope thereof. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The ratios of millimoles (mmol) of the charges in examples 1 to 12 were uniform.
Example 1
10- (Ethylsulfanyl) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dode-6-en-8-one (I-6) having the structure shown in the following formula:
。
The preparation of 10- (ethylsulfanyl) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dode-6-en-8-one in this example was as follows:
s1, dissolving 2-phenoxyethylamine (1.2 mmol) in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2, sequentially dissolving triethylamine (1.5 mmol) and p-toluenesulfonyl chloride (1 mmol) in a 2-phenoxyethylamine solution under ice bath, stirring at room temperature for reaction 8 and h, washing the reacted reaction solution with saturated saline, and then separating and purifying with polyamide to obtain an intermediate compound 1;
s3, mixing and adding an intermediate compound 1 (0.4 mmol), iodobenzene trifluoroacetate (1 mmol), rhodium diacetate dimer (0.04 mmol) and calcium oxide (4 mmol) into methylene dichloride of 25mL, stirring at 50 ℃ to react for 6h, and separating and purifying a reaction solution after the reaction by polyamide to obtain an intermediate compound 2;
S4, dissolving the intermediate compound 2 (0.1 mmol) in an ethanol solution with the volume fraction of 50%, adding ethanethiol (0.2 mmol), stirring at room temperature for reaction 10 h, and separating and purifying by using polyamide after the reaction to obtain 10- (ethylthio) -4-toluenesulfonyl-1-oxygen-4-azaspiro [4.5] dodecan-6-en-8-one (yield 39%).
The nuclear magnetic data of 10- (ethylthio) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dode-6-en-8-one are specifically as follows:
1H NMR (400MHz, CDCl3)δ(ppm)：7.79 (d,J= 8.3 Hz, 2H), 7.36 (d,J= 8.3 Hz, 2H), 6.65 (d,J= 10.1 Hz, 1H), 6.05 (d,J= 10.1 Hz, 1H), 4.38 – 4.27 (m, 1H), 4.13 – 4.00 (m, 2H), 3.81 – 3.61 (m, 2H), 2.92 – 2.85 (m, 2H), 2.78 – 2.53 (m, 2H), 2.46 (s, 3H), 1.24 (t,J= 7.4 Hz, 3H);
13C-NMR (400MHz, CDCl3)δ(ppm)：196.9, 146.5, 144.3, 136.7, 130.3, 129.9, 127.5, 94.2, 66.4, 49.5, 47.9, 43.9, 25.9, 21.6, 14.9;
HRMS (ESI)m/z(%) forC17H21NNaO4S2(M+Na)：Calcd. 390.0810Found. 390.0811.
Example 2
Dimethyl 2- (8-oxo-4-tosyl-1-oxo-4-azaspiro [4.5] dec-9-en-6-yl) malonate (I-7) having the structure shown in the following formula:
。
In this example dimethyl 2- (8-oxo-4-tosyl-1-oxo-4-azaspiro [4.5] dec-9-en-6-yl) malonate was prepared as follows:
S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution under ice bath, stirring at room temperature for reaction 8h, washing the reacted reaction solution with saturated saline solution, and separating and purifying with silica gel to obtain an intermediate compound 1;
s3, mixing the intermediate compound 1, iodobenzene trifluoroacetate, rhodium diacetate dimer and calcium oxide, adding the mixture into methylene dichloride, stirring the mixture at 50 ℃ for reaction 8 h, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 2;
S4, dissolving the intermediate compound 2 in acetonitrile, adding 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), adding dimethyl malonate, stirring at room temperature for reaction 7h, and separating and purifying by using silica gel after the reaction to obtain dimethyl 2- (8-oxo-4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dec-9-en-6-yl) malonate (yield 67%).
The nuclear magnetic data of dimethyl 2- (8-oxo-4-tosyl-1-oxo-4-azaspiro [4.5] dec-9-en-6-yl) malonate are specifically as follows:
1H NMR (400MHz, CDCl3)δ(ppm)：7.74 (d,J= 8.3 Hz, 2H), 7.33 (d,J= 8.3 Hz, 2H), 6.62 (d,J= 10.2 Hz, 1H), 6.03 (d,J= 10.2 Hz, 1H), 4.06 – 3.91 (m, 2H), 3.80 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.63 (m, 1H), 3.51 (d,J= 3.6 Hz, 1H), 3.02 (m, 1H), 2.82 (m, 1H), 2.45 (s, 3H);
13C NMR (400MHz, CDCl3)δ(ppm)：197.2, 168.4, 167.9, 145.3, 144.5, 136.6, 130.5, 130.0, 127.4, 94.1, 64.9, 52.8, 52.3, 49.9, 47.3, 42.3, 37.9, 21.6;
HRMS (ESI)m/z(%) forC20H24NO8S (M+H)：Calcd. 438.1223Found. 438.1214。
Example 3
4-Tosyl-10- (2H-1, 2, 3-triazol-2-yl) -1-oxo-4-azaspiro [4.5] dec-6-en-8-one (I-5) having the structure shown in the following formula:
。
The preparation of 4-toluenesulfonyl-10- (2H-1, 2, 3-triazol-2-yl) -1-oxo-4-azaspiro [4.5] dec-6-en-8-one in this example was as follows:
S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution under ice bath, stirring at room temperature for reaction 8h, washing the reacted reaction solution with saturated saline solution, and then separating and purifying with polyamide to obtain an intermediate compound 1;
S3, mixing the intermediate compound 1, iodobenzene trifluoroacetate, rhodium diacetate dimer and calcium oxide, adding the mixture into methylene dichloride, stirring the mixture at 50 ℃ for reaction 8h, and separating and purifying the reacted reaction solution by polyamide to obtain an intermediate compound 2;
S4, dissolving the intermediate compound 2 in acetonitrile, adding DBU, adding 2H-1,2, 3-triazole, stirring at room temperature for reaction 8H, and separating and purifying by polyamide after the reaction to obtain 4-toluenesulfonyl-10- (2H-1, 2, 3-triazole-2-yl) -1-oxo-4-azaspiro [4.5] dec-6-en-8-one (yield 47%).
The nuclear magnetic data of 4-toluenesulfonyl-10- (2H-1, 2, 3-triazol-2-yl) -1-oxo-4-azaspiro [4.5] dec-6-en-8-one are specifically as follows:
1H NMR (400MHz, CDCl3)δ(ppm)：7.98 (d,J= 8.4 Hz, 2H), 7.67 (s, 2H), 7.36 (d,J= 8.4 Hz, 2H), 6.82 (d,J= 10.2 Hz, 1H), 6.27 (dd,J= 10.2, 1.1 Hz, 1H), 6.03 (m, 1H), 3.93 – 3.86 (m, 1H), 3.71 (dd,J= 16.7, 12.6 Hz, 1H), 3.47 – 3.39 (m, 1H), 3.06 (m, 1H), 2.96 – 2.87 (m, 2H), 2.46 (s, 3H);
13C NMR (400MHz, CDCl3)δ(ppm)：195.2, 144.7, 144.1, 135.9, 134.6, 131.3, 129.7, 128.4, 92.7, 65.7, 63.7, 46.6, 40.5, 21.7;
HRMS (ESI)m/z(%) forC17H19N4O4S（M+H）：Calcd. 375.1127Found. 375.1119。
Example 4
10- (1H-imidazol-1-yl) -4-tosyl-1-oxo-4-azaspiro [4.5] dod-6-en-8-one (I-3) having a structure represented by the following formula:
。
The procedure for the preparation of 10- (1H-imidazol-1-yl) -4-tosyl-1-oxo-4-azaspiro [4.5] dode-6-en-8-one in this example was as follows:
S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution under ice bath, stirring at room temperature for reaction 8h, washing the reacted reaction solution with saturated saline solution, and separating and purifying with silica gel to obtain an intermediate compound 1;
s3, mixing the intermediate compound 1, iodobenzene trifluoroacetate, rhodium diacetate dimer and calcium oxide, adding the mixture into methylene dichloride, stirring the mixture at 50 ℃ for reaction 8 h, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 2;
S4, dissolving the intermediate compound 2 in acetonitrile, adding DBU, adding imidazole, stirring at room temperature for reaction 8H, and separating and purifying by silica gel after the reaction to obtain 10- (1H-imidazole-1-yl) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dodeca-6-en-8-one (yield 61%).
The nuclear magnetic data of 10- (1H-imidazol-1-yl) -4-tosyl-1-oxo-4-azaspiro [4.5] dod-6-en-8-one are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.73 (d,J= 8.1 Hz, 2H), 7.69 (s, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.13 (d,J= 25.3 Hz, 2H), 6.54 (d,J= 10.2 Hz, 1H), 6.18 (d,J= 10.2 Hz, 1H), 5.50 (dd,J= 13.6, 4.4 Hz, 1H), 3.88 (td,J= 7.2, 4.2 Hz, 1H), 3.42 – 3.32 (m, 1H), 3.32 – 3.19 (m, 2H), 3.13 (ddd,J= 8.5, 5.9, 4.2 Hz, 1H), 2.98 – 2.89 (m, 1H), 2.47 (s, 3H);
13C NMR (101 MHz, Chloroform-d)δ194.69, 145.07, 144.07, 137.40, 135.91, 131.21, 130.17, 129.10, 127.58, 119.27, 92.51, 65.82, 57.47, 47.00, 41.46, 21.65
HRMS(ESI)m/z: calculated for C18H19N3O4S [M+H]+374.1173, found 374.1173.
example 5
10- (4-Methylpiperazin-1-yl) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dod-6-en-8-one (I-4) having the structure shown in the following formula:
。
The procedure for the preparation of 10- (4-methylpiperazin-1-yl) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dod-6-en-8-one in this example is as follows:
S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2, sequentially dissolving triethylamine and p-toluenesulfonyl chloride in a 2-phenoxyethylamine solution under ice bath, stirring at room temperature for reaction 8h, washing the reacted reaction solution with saturated saline solution, and then separating and purifying with polyamide to obtain an intermediate compound 1;
S3, mixing the intermediate compound 1, iodobenzene trifluoroacetate, rhodium diacetate dimer and calcium oxide, adding the mixture into methylene dichloride, stirring the mixture at 50 ℃ for reaction 8h, and separating and purifying the reacted reaction solution by polyamide to obtain an intermediate compound 2;
S4, dissolving the intermediate compound 2 in acetonitrile, adding DBU, adding 1-methylpiperazine, reacting at room temperature for 8 h, and separating and purifying by polyamide after the reaction to obtain 10- (4-methylpiperazin-1-yl) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dodeca-6-en-8-one (yield 36%).
The nuclear magnetic data of 10- (4-methylpiperazin-1-yl) -4-toluenesulfonyl-1-oxo-4-azaspiro [4.5] dod-6-en-8-one are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.90 – 7.70 (m, 2H), 7.34 (d,J= 8.1 Hz, 2H), 6.64 (d,J= 10.2 Hz, 1H), 6.04 (dd,J= 10.2, 1.3 Hz, 1H), 4.20 – 4.11 (m, 1H), 4.02 (q,J= 7.1 Hz, 1H), 3.90 – 3.81 (m, 1H), 3.75 (dd,J= 13.0, 4.2 Hz, 1H), 3.66 (ddd,J= 8.1, 6.6, 4.6 Hz, 1H), 3.00 – 2.63 (m, 4H), 2.59 – 1.76 (m, 12H);
13C NMR (101 MHz, Chloroform-d)δ198.67, 146.88, 144.03, 137.43, 130.35, 129.83, 127.32, 95.68, 65.80, 63.58, 55.87, 48.06, 45.83, 36.89, 21.56;
HRMS(ESI)m/z: calculated for C20H27N3O4S [M+H]+406.1788, found 406.1788.
example 6
4- ((4-Fluorophenyl) sulfonyl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-en-8-one (I-2) having the structure shown below:
。
the procedure for the preparation of 4- ((4-fluorophenyl) sulfonyl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-en-8-one in this example was as follows:
S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2, sequentially dissolving triethylamine and p-fluorobenzenesulfonyl chloride in a 2-phenoxyethylamine solution under ice bath, stirring at room temperature for reaction 8 h, washing the reacted reaction solution with saturated saline solution, and separating and purifying with silica gel to obtain an intermediate compound 1;
S3, mixing the intermediate compound 1, iodobenzene trifluoroacetate, rhodium diacetate dimer and calcium oxide, adding the mixture into methylene dichloride, stirring the mixture at 50 ℃ for reaction 8h, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 2; the nuclear magnetic data of intermediate compound 2 are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.83 (dd,J= 8.6, 5.0 Hz, 2H), 7.22 (t,J= 8.4 Hz, 2H), 6.50 (d,J= 9.8 Hz, 2H), 6.22 (d,J= 9.8 Hz, 2H), 4.19 (t,J= 6.1 Hz, 2H), 3.73 (t,J= 6.1 Hz, 2H);
13C NMR (101 MHz, Chloroform-d)δ184.63, 165.46, 143.03, 135.04, 130.50, 129.68, 116.48, 86.29, 65.56, 47.05;
HRMS(ESI)m/z: calculated for C14H12FNO4S [M+H]+310.0545, found 310.0545;
S4, dissolving the intermediate compound 2 in acetonitrile, adding DBU, adding imidazole, stirring at room temperature for reaction 8H, and separating and purifying by silica gel after the reaction to obtain 4- ((4-fluorophenyl) sulfonyl) -10- (1H-imidazole-1-yl) -1-oxo-4-azaspiro [4.5] dodeca-6-en-8-one (yield 55%).
The nuclear magnetic data of 4- ((4-fluorophenyl) sulfonyl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-en-8-one are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.95 – 7.80 (m, 2H), 7.73 (s, 1H), 7.34 – 7.22 (m, 2H), 7.15 (d,J= 19.7 Hz, 2H), 6.52 (d,J= 10.2 Hz, 1H), 6.20 (dd,J= 10.2, 1.1 Hz, 1H), 5.51 (dd,J= 13.6, 4.4 Hz, 1H), 3.91 (ddd,J= 8.0, 6.5, 4.4 Hz, 1H), 3.43 – 3.21 (m, 3H), 3.19 – 3.08 (m, 1H), 2.95 (ddd,J= 15.8, 4.4, 1.2 Hz, 1H);
13C NMR (101 MHz, Chloroform-d)δ194.43, 165.73, 143.63, 137.31, 134.92, 131.52, 130.39, 129.07, 119.26, 116.96, 92.75, 65.81, 57.50, 47.03, 41.50;
HRMS(ESI)m/z: calculated for C17H16FN3O4S [M+H]+378.0916, found 378.0916.
Example 7
4- ((4-Chlorophenyl) sulfonyl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-en-8-one (I-1) having the structure shown below:
。
In this example 4- ((4-chlorophenyl) sulfonyl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-en-8-one was prepared as follows:
S1, dissolving 2-phenoxyethylamine in dichloromethane to obtain a 2-phenoxyethylamine solution;
S2, sequentially dissolving triethylamine and p-chlorobenzenesulfonyl chloride in a 2-phenoxyethylamine solution under ice bath, stirring at room temperature for reaction 8h, washing the reacted reaction solution with saturated saline solution, and then separating and purifying with polyamide to obtain an intermediate compound 1;
S3, mixing the intermediate compound 1, iodobenzene trifluoroacetate, rhodium diacetate dimer and calcium oxide, adding the mixture into methylene dichloride, stirring the mixture at 50 ℃ for reaction 8 h, and separating and purifying the reacted reaction solution by polyamide to obtain an intermediate compound 2; the nuclear magnetic data of intermediate compound 2 are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.80 – 7.66 (m, 2H), 7.57 – 7.43 (m, 2H), 6.57 – 6.40 (m, 2H), 6.29 – 6.14 (m, 2H), 4.19 (t,J= 6.1 Hz, 2H), 3.73 (t,J= 6.1 Hz, 2H);
13C NMR (101 MHz, Chloroform-d)δ184.60, 142.91, 140.06, 137.44, 129.75, 129.51, 129.11, 86.36, 65.56, 47.08;
HRMS(ESI)m/z: calculated for C14H12ClNO4S [M+H]+326.0246, found 326.0246;
S4, dissolving the intermediate compound 2 in acetonitrile, adding DBU, adding imidazole, stirring at room temperature for reaction 8H, and separating and purifying by using polyamide after the reaction to obtain 4- ((4-chlorophenyl) sulfonyl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dodeca-6-en-8-one (yield 47%).
The nuclear magnetic data of 4- ((4-chlorophenyl) sulfonyl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-en-8-one are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.79 (d,J= 8.2 Hz, 2H), 7.73 (s, 1H), 7.57 (d,J= 8.2 Hz, 2H), 7.15 (d,J= 19.7 Hz, 2H), 6.50 (d,J= 10.2 Hz, 1H), 6.20 (d,J= 10.2 Hz, 1H), 5.50 (dd,J= 13.6, 4.4 Hz, 1H), 3.91 (dt,J= 11.9, 5.4 Hz, 1H), 3.45 – 3.04 (m, 4H), 2.95 (dd,J= 15.8, 4.4 Hz, 1H);
13C NMR (151 MHz, Chloroform-d)δ194.38, 143.50, 140.65, 137.28, 137.24, 131.54, 129.90, 129.07, 128.91, 119.23, 92.73, 65.78, 57.50, 47.01, 41.44;
HRMS(ESI)m/z: calculated for C17H16ClN3O4S [M+H]+394.0626, found 394.0626.
Example 8
Dimethyl-2- (4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -3, 8-dioxo-1-oxo-4-azaspiro [4.5] dod-9-en-6-yl) malonic acid dimethyl ester (II-3), having a structure represented by the following formula:
。
In this example dimethyl-2- (4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -3, 8-dioxo-1-oxo-4-azaspiro [4.5] dode-9-en-6-yl) malonate was prepared as follows:
S1, adding 3-chlorobenzaldehyde, cyanamide, methanol, potassium tert-butoxide and N-bromosuccinimide into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by polyamide to obtain an intermediate compound 7;
s2, adding the intermediate compound 7, phenylhydrazine and triethylamine into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by using polyamide to obtain an intermediate compound 8;
S3, adding the intermediate compound 8, 2- (4-methoxyphenoxy) acetic acid, carbodiimide and 1-hydroxybenzotriazole into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by polyamide to obtain an intermediate compound 9;
s4, adding the intermediate compound 9, iodobenzene trifluoroacetate and copper tetraacetonitrile perchlorate into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by polyamide to obtain an intermediate compound 10;
s5, dissolving the intermediate compound 10 in acetonitrile, adding DBU, adding dimethyl malonate, stirring at 30 ℃ for reaction 8H, and separating and purifying by polyamide after the reaction to obtain dimethyl-2- (4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazole-5-yl) -3, 8-dioxo-1-oxo-4-azaspiro [4.5] dodeca-9-en-6-yl) malonate (yield: 59.6%).
The nuclear magnetic data of dimethyl-2- (4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -3, 8-dioxo-1-oxo-4-azaspiro [4.5] dod-9-en-6-yl) malonate are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ8.05 (d,J= 1.7 Hz, 1H), 7.95 (dt,J= 7.0, 1.6 Hz, 1H), 7.63–7.51 (m, 5H), 7.44–7.33 (m, 2H), 6.52 (d,J= 10.2 Hz, 1H), 6.00 (d,J= 9.5 Hz, 1H), 4.49–4.36 (m, 2H), 3.78 (d,J= 2.7 Hz, 1H), 3.74 (s, 3H), 3.74 (s, 3H), 3.24–3.13 (m, 1H), 3.03 (dd,J= 16.7, 12.8 Hz, 1H), 2.77 (dd,J= 16.4, 4.4 Hz, 1H);
13C NMR (100 MHz, Chloroform-d)δ196.1, 171.1, 168.1, 167.5, 160.8, 143.7, 142.8, 135.9, 134.7, 132.1, 131.6, 130.4, 123.0, 129.7, 126.6, 125.0, 124.4, 95.0, 66.3, 53.1, 52.5, 49.1, 41.3,36.3;
HRMS(ESI-TOF) m/z: [M+H]+calcd for C27H24ClN4O7, 551.1328; found, 551.1324.
example 9
4- (3- (3-Chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dode-6-ene-3, 8-dione (II-2) has a structure represented by the following formula:
。
The preparation of 4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-en-3, 8-dione in this example was as follows:
S1, adding 3-chlorobenzaldehyde, cyanamide, methanol, potassium tert-butoxide and N-bromosuccinimide into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 7;
S2, adding the intermediate compound 7, phenylhydrazine and triethylamine into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 8;
S3, adding the intermediate compound 8, 2- (4-methoxyphenoxy) acetic acid, carbodiimide and 1-hydroxybenzotriazole into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 9;
S4, adding the intermediate compound 9, iodobenzene trifluoroacetate and copper tetraacetonitrile perchlorate into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 10;
s5, dissolving the intermediate compound 10 in acetonitrile, adding DBU, adding imidazole, stirring at 30 ℃ for reaction 8H, and separating and purifying by silica gel after the reaction to obtain 4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazole-5-yl) -10- (1H-imidazole-1-yl) -1-oxo-4-azaspiro [4.5] dodeca-6-ene-3, 8-dione (yield: 46.6%).
The nuclear magnetic data of 4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-ene-3, 8-dione are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ8.13 (s, 1H), 8.03 (d,J= 8.9 Hz, 2H), 7.58–7.51 (m, 3H), 7.50–7.42 (m, 4H), 7.20 (s, 1H), 6.38 (d,J= 10.2 Hz, 1H), 6.25 (d,J= 10.2 Hz, 1H), 5.72 (dd,J= 13.8, 4.3 Hz, 1H), 4.25–4.06 (m, 2H), 3.50–3.38 (m, 2H), 3.06 (dd,J= 15.8, 3.8 Hz, 1H);
HRMS (ESI-TOF) m/z: [M+H]+calcd for C25H20ClN6O3, 487.1280; found, 487.1281.
Example 10
4- (3- (3-Chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -10- (ethylsulfanyl) -1-oxo-4-azaspiro [4.5] dode-6-ene-3, 8-dione (II-5) having a structure represented by the following formula:
。
the preparation of 4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -10- (ethylsulfanyl) -1-oxo-4-azaspiro [4.5] dode-6-ene-3, 8-dione in this example was as follows:
S1, adding 3-chlorobenzaldehyde, cyanamide, methanol, potassium tert-butoxide and N-bromosuccinimide into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 7;
S2, adding the intermediate compound 7, phenylhydrazine and triethylamine into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 8;
S3, adding the intermediate compound 8, 2- (4-methoxyphenoxy) acetic acid, carbodiimide and 1-hydroxybenzotriazole into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 9;
S4, adding the intermediate compound 9, iodobenzene trifluoroacetate and copper tetraacetonitrile perchlorate into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 10;
S5, dissolving the intermediate compound 10 in acetonitrile, adding DBU, adding ethanethiol, stirring at 30 ℃ for reaction for 8H, and separating and purifying by silica gel after the reaction to obtain 4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazole-5-yl) -10- (ethylthio) -1-oxo-4-azaspiro [4.5] dodeca-6-alkene-3, 8-dione (yield: 42.3%).
The nuclear magnetic data of 4- (3- (3-chlorophenyl) -1-phenyl-1H-1, 2, 4-triazol-5-yl) -10- (ethylsulfanyl) -1-oxo-4-azaspiro [4.5] dod-6-ene-3, 8-dione are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ8.06 (d,J= 1.8 Hz, 1H), 7.95 (td,J= 6.8, 1.7 Hz, 1H), 7.65 (dd,J= 8.2, 1.5 Hz, 2H), 7.59–7.55 (m, 1H), 7.55–7.49 (m, 2H), 7.42–7.35 (m, 2H), 6.56 (d,J= 10.1 Hz, 1H), 6.12 (dd,J= 10.1, 1.0 Hz, 1H), 4.75 (d,J= 14.4 Hz, 1H), 4.37 (d,J= 14.4 Hz, 1H), 4.23 (dd,J= 13.0, 5.0 Hz, 1H), 3.12–2.87 (m, 3H), 2.69 (dd,J= 12.5, 7.5 Hz, 1H), 1.33–1.28 (m, 3H);
13C NMR (100 MHz, Chloroform-d)δ196.1, 169.7, 160.1, 144.4, 143.3, 137.0, 134.8, 133.4, 131.7, 130.0, 130.0, 129.7, 129.7, 126.4, 124.3, 124.3, 94.9, 68.0, 49.1, 43.1, 26.2, 15.1.
Example 11
4- (2, 6-Dichlorobenzene) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dode-6-ene-3, 8-dione
(II-7) having a structure represented by the following formula:
。
The preparation of 4- (2, 6-dichlorobenzene) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-ene-3, 8-dione in this example was as follows:
s1, adding para-aminophenol, glycollic acid and dimethyl dicyandiamide into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 3;
S2, adding the intermediate compound 3, diacetoxyiodobenzene, tetraacetonitrile copper perchlorate and methylene dichloride into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 4;
S3, adding the intermediate compound 4, DBU, tetrahydrofuran and 2, 6-dichlorobenzyl chloride into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 5;
S4, dissolving the intermediate compound 5 in acetonitrile, adding DBU, adding imidazole, stirring at 30 ℃ for reaction 8H, and separating and purifying by silica gel after the reaction to obtain 4- (2, 6-dichlorobenzene) -10- (1H-imidazole-1-yl) -1-oxygen-4-azaspiro [4.5] dodeca-6-alkene-3, 8-dione (yield: 53.3%).
The nuclear magnetic data of 4- (2, 6-dichlorobenzene) -10- (1H-imidazol-1-yl) -1-oxo-4-azaspiro [4.5] dod-6-ene-3, 8-dione are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.53 (s, 1H), 7.41–7.36 (m, 2H), 7.31 (dd,J= 9.1, 6.8 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 6.06 (d,J= 10.2 Hz, 1H), 5.79 (d,J= 10.2 Hz, 1H), 5.36 (d,J= 15.2 Hz, 1H), 5.22 (dd,J= 13.4, 4.3 Hz, 1H), 4.59 (d,J= 15.2 Hz, 1H), 4.26 (d,J= 13.8 Hz, 1H), 3.70 (d,J= 13.8 Hz, 1H), 3.34 (dd,J= 15.6, 13.5 Hz, 1H), 2.91 (dd,J= 15.6, 4.3 Hz, 1H);
13C NMR (100 MHz, Chloroform-d)δ193.9, 168.3, 144.4, 136.8, 136.5, 131.2, 131.1, 130.3, 130.1, 129.1, 118.3, 92.2, 66.4, 54.8, 40.5, 39.2;
HRMS(ESI-TOF) m/z: [M+H]+calcd for C18H16N3O3Cl2, 392.0563, found, 392.0577.
Example 12
4- (4-Chlorophenyl) -10- (ethylsulfanyl) -1-oxo-4-azaspiro [4.5] dod-6-en-3, 8-dione (II-8) has a structure represented by the following formula:
。
The preparation of 4- (4-chlorophenyl) -10- (ethylsulfanyl) -1-oxo-4-azaspiro [4.5] dode-6-ene-3, 8-dione in this example was as follows:
s1, adding para-aminophenol, glycollic acid and dimethyl dicyandiamide into a reaction bottle, uniformly stirring, reacting for 8 hours at room temperature, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 3;
S2, adding the intermediate compound 3, diacetoxyiodobenzene, tetraacetonitrile copper perchlorate and methylene dichloride into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 4;
S3, adding the intermediate compound 4, DBU, tetrahydrofuran and 2, 6-dichlorobenzyl chloride into a reaction bottle, uniformly stirring, reacting at room temperature for 8 hours, and separating and purifying the reacted reaction solution by using silica gel to obtain an intermediate compound 5;
S4, dissolving the intermediate compound 5 in acetonitrile, adding DBU, adding ethanethiol, stirring at 30 ℃ for reaction for 8 h, and separating and purifying by silica gel after the reaction to obtain 4- (4-chlorobenzene) -10- (ethylthio) -1-oxo-4-azaspiro [4.5] dodeca-6-alkene-3, 8-dione (yield: 41.1%).
The nuclear magnetic data of 4- (4-chlorobenzene) -10- (ethylthio) -1-oxo-4-azaspiro [4.5] dod-6-en-3, 8-dione are specifically as follows:
1H NMR (400 MHz, Chloroform-d)δ7.33–7.27 (m, 4H), 6.38 (d,J= 10.1 Hz, 1H), 6.06 (dd,J= 10.1, 1.1 Hz, 1H), 4.57 (d,J= 13.5 Hz, 1H), 4.48–4.37 (m, 3H), 3.19 (dd,J= 13.0, 4.4 Hz, 1H), 3.01 (dd,J= 16.2, 13.0 Hz, 1H), 2.81 (td,J= 16.2, 4.4, 1.1 Hz, 1H), 2.34 (td,J= 11.8, 7.4 Hz, 1H), 2.11 (dd,J= 11.8, 7.4 Hz, 1H), 1.13 (t,J= 7.4 Hz, 3H);
13C NMR (100 MHz, Chloroform-d)δ196.3, 170.7, 146.1, 134.4, 134.3, 132.5, 130.2, 129.0, 93.8, 68.0, 48.8, 43.3, 42.4, 25.2, 14.6;
HRMS(ESI-TOF) m/z: [M+H]+calcd for C17H19NO3SCl, 352.0769, found, 352.0785.
Example 13 determination of antitumor Activity
Proliferation of adherent cells was detected using the Sulfonyl Rhodamine B (SRB) method. The positive control drugs were bendamustine and vorinostat. Human breast cancer cells MDA-MB-231 in the logarithmic growth phase are inoculated into a 96-well plate (200 mu L/well), and are cultured at 37 ℃ and 5% carbon dioxide concentration for 24h to adhere. Then, the sample was treated with different concentrations of the test compound, 3 duplicate wells were set for each concentration, and corresponding blank and zeroed wells were set. After 72 h incubations, 1h was fixed with 10% trichloroacetic acid (TCA) at 4 ℃, the fixed solution was poured, washed 5 times with distilled water, and naturally air-dried. Cells after completion of fixation were stained with 0.4% (w/v) SRB at room temperature for 20 min times, the solution was poured, washed with 1% glacial acetic acid for 5 times, excess unbound SRB dye was removed, and air dried. SRB-binding proteins were solubilized with 10mM Tris (hydroxymethyl amino) methane (Tris), shaking 20 in horizontal shaker min, and equivalent amounts of DMSO as vehicle controls, bendamustine (Bendamustiune, bifunctional alkylating agent) and vorinostat (SAHA, HDAC inhibitor) as positive controls. The cell number was counted using a cell viability analyzer (Beckman-Coulter). Viability is the ratio of the number of compound-treated cells to the number of vector-treated cells, and IC 50 values were obtained from the dose-response curves for each compound. Experiments were performed in triplicate and data are presented as average values.
In vitro antitumor activity experiments were performed on the compounds of examples 1-12, and the in vitro cell growth inhibition ability of the target compounds on human breast cancer cells MDA-MB-231 was tested using bendamustine (Bendamustiune, bifunctional alkylating agent) and vorinostat (SAHA, HDAC inhibitor) as positive drug controls, and the results are shown in Table 1. As can be seen from Table 1, after the nucleophilic site in intermediate compound 2 is added, the activity of the prepared N-substituted azaspiro-decarenone compound is significantly improved compared with that before the nucleophilic site is added except for examples 4 and 5; meanwhile, the N-substituted azaspiro-decarenone compounds prepared in examples 1-12 also show certain proliferation inhibition activity (IC 50 0.13-4.66 mu M) on lung cancer cell line A549 and cervical cancer cell line Hela cells.
TABLE 1
Example 14 acute toxicity assay and analysis of Compound dissolution behavior
Acute toxicity tests were conducted on the intermediate compound 2 and the N-substituted azaspiro-decone compounds prepared in examples 1 to 7, SPF-grade Km mice were divided into two groups, and the two groups of mice were respectively administered with different doses of the intermediate compound 2 and the N-substituted azaspiro-decone compounds, the administration doses were 120 to 1000mg/kg, and 14 days of observation was conducted on the mice after administration. The results show that the mice in the group of the intermediate compound 2 die, and the mice in the group of the N-substituted azaspiro-decamonooleone compound do not die, and the mice have no obvious change in behavior, normal diet, no abnormal secretion and continuous increase of body weight; the intermediate compound 2 is shown to be more toxic than the N-substituted azaspiro-decone compounds, i.e. the toxicity can be reduced after the nucleophilic site in the intermediate compound 2 is added. Meanwhile, the in-vivo and in-vitro activity research results show that the activity of certain compounds (I-2) in the N-substituted azaspiro-decarenone compounds synthesized by eliminating the single-side alpha, beta-unsaturated ketone structure or modifying other types of the intermediate compounds 2 can be raised to the nanomolar level, and the toxicity is greatly reduced; animal toxicity experiments show that the LD 50 of the intermediate compound 2 is 66.1-80 mg/kg, the intermediate compound belongs to a medium toxicity range, and the half-lethal dose of the N-substituted azaspiro-decone compounds on Km mice is more than 120-1000 mg/kg.
Carrying out an animal level antitumor activity experiment, randomly dividing 24 BALB/c tumor-bearing mice into 4 groups, wherein each group comprises 6 mice, namely a blank control group, a positive drug control-bendamustine control group, namely 10 mg/kg, a low-dose N-substituted azaspiro-decarenone compound group, namely 10 mg/kg, and a high-dose N-substituted azaspiro-decarenone compound group, namely 20 mg/kg; four groups of mice were dosed once every two days, 7 times consecutively, and mice signs were observed over 14 days. The result shows that the tumor inhibition rate of the N-substituted azaspiro-decarenone compound on the BALB/c breast cancer model mice reaches 61%; the results of histopathological section and staining show that the compounds do not cause obvious lesions of normal tissues. Namely, the N-substituted aza-spiro-decone ketone compound reduces the protein toxicity site on the parent nucleus on the premise of retaining the basic structure of the spiro-decone, thereby reducing the toxicity of the compound in vivo.
Meanwhile, as nucleophilic site addition reaction is carried out under the condition of ethanol/water or acetonitrile/organic alkali, residual transition metal salt is dissolved in the system, and the final product is further purified after the process, so that the purity of the prepared N-substituted azaspiro-decarenone compound is improved.
In addition, the lipid partition coefficient is an important index, and determines the distribution of the compound in the body. Suitable water solubility aids in dissolving the drug in the body fluid to achieve an effective concentration at the site of action, thereby producing a therapeutic effect. For the antitumor drugs, the better water solubility not only facilitates absorption and distribution, but also enables the drugs to be discharged rapidly, and reduces accumulation and toxic and side effects on kidneys. The incorporation of one or more heteroatoms in the N-substituted azaspiro-decarenone compound increases the likelihood of hydrogen bonding with water, which improves the dissolution behavior compared to intermediate 2, as is evident from the observed complete dissolution of 2 mg N-substituted azaspiro-decarenone compound in 200 μl DMSO and 1.8 mL olive oil solution, while intermediate 2 of 1 mg remains a suspension in 200 μl DMSO and 1.8 mL olive oil solution, when animal level antitumor activity studies are performed. Thus being more beneficial to improving the binding force of the compound and the target spot and improving the lipid-water distribution coefficient so as to improve the pharmacological activity of the compound.
While the invention has been described in terms of the foregoing embodiments, it will be understood that the embodiments are not intended to limit the invention in any way, but are intended to cover modifications of the invention using equivalent alternatives or modifications.
Claims (8)
- An n-substituted azaspiro-decarenone compound characterized by the specific structural formula:。
- 2. The process for the preparation of an N-substituted azaspiro-decarenone compound of claim 1, selected from the following synthetic routes:Synthesis path 1: dissolving a compound A and a compound B in an organic solvent, reacting under the action of a catalyst to obtain an intermediate compound 1, adding an oxidant to react to obtain an intermediate compound 2, and adding a nucleophile to react to obtain an N-substituted azaspiro-decamonoalkone compound shown in a formula I; the synthetic route is as follows:；synthesis path 2: dissolving a compound C and a compound D in an organic solvent, reacting under the action of a dehydrating agent to obtain an intermediate compound 3, adding an oxidant to react to obtain an intermediate compound 4, adding a compound B, reacting under the action of a catalyst to obtain an intermediate compound 5, and adding a nucleophile to react to obtain the N-substituted azaspiro-decone compound shown in the formula II; the synthetic route is as follows:；Synthesis path 3: adding a dehydrating agent into the compound E and the compound F to react to obtain an intermediate compound 6, adding an oxidant and a copper salt catalyst to react to obtain an intermediate compound 5, and adding a nucleophile to react to obtain the N-substituted azaspiro-decamonoalkenone compound shown in the formula II; the synthetic route is as follows:；R, R 2、R3, X and N in the synthetic routes 1-3 are corresponding and consistent with the structures of the N-substituted azaspiro-decarenone compounds I-1-II-12 in claim 1.
- 3. The process for the preparation of N-substituted azaspiro-decone compounds as claimed in claim 2, wherein the catalysts are selected from triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene or potassium tert-butoxide.
- 4. The method of preparing an N-substituted azaspiro-decarenone compound of claim 2, wherein the oxidizing agents are each selected from iodobenzene trifluoroacetate or diacetoxyiodobenzene; the copper salt catalyst is tetraacetonitrile copper perchlorate.
- 5. The method for preparing an N-substituted azaspiro-decarenone compound according to claim 2, wherein the dehydrating agent in the synthetic pathway 2 is 1, 3-dicyclohexylcarbodiimide; the dehydrating agent in the synthetic route 3 is a mixture of carbodiimide and 1-hydroxybenzotriazole.
- 6. The method for preparing an N-substituted azaspiro-decarenone compound according to claim 2, wherein the nucleophiles are each selected from the group consisting of ethanethiol, dimethyl malonate, 2H-1,2, 3-triazole, imidazole, and 1-methylpiperazine.
- 7. The method for preparing an N-substituted azaspiro-decarenone compound according to claim 2, wherein the organic solvents are selected from dichloromethane, acetonitrile, methanol, ethanol, diethyl ether, 1, 2-dichloroethane, chloroform, toluene, and xylene.
- 8. The use of an N-substituted azaspiro-decarenone compound of claim 1 for the preparation of an antitumor drug.
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| CA3017020C (en) * | 2016-03-07 | 2024-01-16 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
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