CN102850337A - Multi-azole linked spirorenone compound and preparation method and application thereof - Google Patents
Multi-azole linked spirorenone compound and preparation method and application thereof Download PDFInfo
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- CN102850337A CN102850337A CN2011101807917A CN201110180791A CN102850337A CN 102850337 A CN102850337 A CN 102850337A CN 2011101807917 A CN2011101807917 A CN 2011101807917A CN 201110180791 A CN201110180791 A CN 201110180791A CN 102850337 A CN102850337 A CN 102850337A
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- 0 CCC(C(C)(C(*)=C(*C)C1=O)C(I)=C1N)*(CC)=C Chemical compound CCC(C(C)(C(*)=C(*C)C1=O)C(I)=C1N)*(CC)=C 0.000 description 2
- OYNZRVZOSPRPKK-UHFFFAOYSA-N CC[n]1nc(N(C(C=C2)(C=CC2=O)OC2)C2=O)nc1-c1ccccc1 Chemical compound CC[n]1nc(N(C(C=C2)(C=CC2=O)OC2)C2=O)nc1-c1ccccc1 OYNZRVZOSPRPKK-UHFFFAOYSA-N 0.000 description 1
- RRYXAOUBDBUWFP-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1-c(nc1N(C(C=C2)(C=CC2=O)OC2)C2=O)n[n]1-c1ccccc1)=O Chemical compound [O-][N+](c(cc1)ccc1-c(nc1N(C(C=C2)(C=CC2=O)OC2)C2=O)n[n]1-c1ccccc1)=O RRYXAOUBDBUWFP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a multi-azole linked spirorenone compound and preparation method and application thereof. The multi-azole linked spirorenone compound has a structure shown in formula (I), wherein each substituent R can be hydrogen, alkyl, oxyl, halogen, etc. simultaneously or respectively, Y is -O-, -S- or -NH-, and n is 1 or 2. Experiments show that the multi-azole linked spirorenone compound has a significant antitumor activity, and has application value for serving as an antitumor drug.
Description
Technical field
The application relates to a kind of many nitrogen azoles connection helicene ketones derivant and preparation method thereof and as the application of antitumor drug.
Background technology
Antitumor drug is one of Field of Drug Discovery ten large medicines of greatest concern at present.Especially how the research of antitumor drug obtain the research based on the drug-fast new type antineoplastic medicine of not tool of different structure activity relationships, different action target spots, is significant.
Research finds, many nitrogen azole compounds is often to have a multiple bioactive structural unit, at the aspect such as medicine, agricultural chemicals even often become crucial active structure unit in its molecule, and particularly 1,2, the 4-triazole class compounds is again a wherein important class formation.Such as in the structure of the medicines such as some antibacteriums, antimycotic, antiviral, tuberculosis, anticancer, antidepressant, anticonvulsion, anti-inflammatory, analgesia, 1,2,4-triazole has quite widely biological activity.Many 1,2, the 4-triazole derivative in the medicines structures such as antitumour drug vorozole (Vorozole), letrozole (Letrozole), arna department azoles (Anastrozole), all has 1,2,4-triazole structure unit as clinical medicine.
Existing 3-phenylquinazoline ketone, benzoxazole [2.3-b] quinazolinone, benzimidazole thiophanate nitrogen azoles [2.3-b] quinazolinone, benzo [b] naphtho-[2.3-d] furans-6 of studies show that, 11-diketone, 5H-benzo [b] naphtho-[2.3-d] pyrroles-6, the screening of the compound external activities such as 11-diketone shows to have good anti-tumor activity.And the common feature of these compounds is all to comprise quinonoid structure unit, nitrogen-atoms and tricyclic structure.
Summary of the invention
For above-mentioned situation, the present invention at first provides a kind of new many nitrogen azoles connection helicene ketone heterogeneous ring compound, and its preparation method further is provided, and this compound is in the application of anti-tumor aspect.
Many nitrogen azoles connection helicene ketone compounds of the present invention, structure is suc as formula shown in (I):
R in the formula (I)
1, R
2, R
3And R
4Can be H at the same time or separately, C
1-3-alkyl, C
1-3--oxyl or halogen element; R
5, R
6Can be H at the same time or separately, C
1-3-alkyl, halogen element, phenyl or by methyl, methoxyl group, Cl, Br, amino, nitro is with 2-, 3-, the single of 4-position replaces, or such as 2-, the 4-position, 2-, the 5-position, 3-, the 5-position, 2-, dibasic phenyl of the non-ortho position forms such as 6-position, naphthyl or by methyl, methoxyl group, halogen element, amino, the α of nitro-, β-list replaces or dibasic naphthyl, thiophene 2-base, quinoline 6-base, or by methyl, methoxyl group, halogen element, amino, nitro is with 3-, 4-, the mono-substituted thiophene 2-base in 5-position, or by methyl, methoxyl group, halogen element, amino, nitro is with 2-, 3-, 4-, 5-, 7-, 8-is mono-substituted quinoline 6-base; R
7Can be H or C
1-3-alkyl, and because the triazole ring at its place can have different isomeric forms because of two key transpositions, so R
6And R
7In each isomer of triazole ring, be not simultaneous; Y can for-O-,-S-,-NH-; N=1 or 2.
In above-mentioned formula (I) compound structure, said halogen element in each substituting group, all with the most frequently used and stable high Cl or Br as preferred.
In addition, in above-mentioned formula (I) compound structure, R
5, R
6Be preferably and be at the same time or separately H, C
1-3-alkyl, Cl, Br, phenyl, thiophene 2-base or quinoline 6-base.
The basic preparation method of many nitrogen of above-mentioned formula (I) azoles connection helicene ketone compounds can be undertaken by following mode.R in the reaction formula
1, R
2, R
3, R
4, R
5, R
6, R
7, Y and n be identical with each corresponding substituting group in above-mentioned formula (I) compound:
1 ': 5-amino-triazole ring derivative raw material (II) and halogen acyl halide are reacted in the organic basic environment, obtain corresponding intermediate (III);
2 ': with the intermediate (III) in upper step and the reaction of formula (V) compound, obtain corresponding intermediate (IV), wherein, the YA in formula (V) compound is-ONa ,-SNa or-NH
2
3 ': intermediate (IV) after cyclization under oxygenant and the catalyzer, is obtained corresponding target product (I).Said oxygenant comprises iodobenzene acetic ester, trifluoroacetyl iodobenzene, iodosobenzene, lead tetra-acetate or Manganse Dioxide; Said catalyzer comprises at least a in cupric chloride, cuprous iodide, cupric bromide, trifluoromethayl sulfonic acid copper or the acetic acid rhodium.Reaction medium can select to comprise chloroform, DMF (DMF), tetrahydrofuran (THF) (THF), 1, at least a in the multi-solvents such as 2-ethylene dichloride, toluene, acetone or methylene dichloride.Experiment shows that this step reaction can be carried out and be finished smoothly under-15 ℃～100 ℃ wide temperature condition.Such as needs, after this step, reaction was finished, can also further reaction soln be carried out separation and purification with common methods such as polymeric amide or silica gel, can obtain formula (I) the structure product of purifying.
The reaction that above-mentioned the 1st ' step prepares corresponding intermediate (III) by 5-amino-triazole ring derivative raw material (II) and halogen acyl halide, generally comprising methylene dichloride, chloroform, 1, all allow in the mediums such as 2-ethylene dichloride, tetracol phenixin, DMF (DMF) or toluene.Said organic basic environment, can select normally used such as quadrol, N, formed alkaline condition under at least a existence in N-dimethyl-ethylenediamine, 1.8-diazabicylo [5.4.0] 11 rare-7 (DBU), NaH, potassium tert.-butoxide or the triethylamine.Said halogen acyl halide can be selected any as in chloroacetyl chloride, bromoacetyl chloride, chlorpromazine chloride, the bromo propionyl chloro etc.
Further concrete preparation method and process to above-mentioned intermediate (III), can be with reference to such as Banks, M.B.et.:Enantiospecific preparation of[(2,6)-endo]-5-aza-1,10,10-trimethyl-3-oxatricyclo[5.2.1.02,6] decan-4-one by a nitrene-mediated route from[(1)-endo]-(Tetrahedron 1992 for (-)-borneol and its utility as a chiralauxiliary in some asymmetric transformations, 48, (37), 7979-8006) etc. the mode of existing bibliographical information is carried out.
The reaction that above-mentioned the 2nd ' step prepares intermediate (IV) by said intermediate (III) and formula (V) compound, usually can be chosen in the multiple reaction medium that comprises dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF), acetone, chloroform, methylene dichloride or DMF (DMF) etc. and carry out.This step reaction for example under the condition of room temperature～100 ℃, can successfully be carried out and be finished in very wide temperature range.Such as needs, after reaction is finished, can also be further reaction soln be washed with water, after the ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, can obtain intermediate (IV) product of purifying.This step preparation intermediate (IV) more specifically operates, all right reference is such as Palazzo, G.et.:Synthesis and Pharmacological Properties of 1-Substituted 3-Dimethylaminoalkoxy-1H-indazoles (Journal Of Medicinal Chemistry 1966,9, (1), the content of bibliographical information such as 38-41).
In this step reaction said for the YA of formula (V) compound structure of intermediate (III) reaction, can for-ONa ,-SNa, when being corresponding phenol sodium or thiophenol sodium structure, its preparation can be adopted the method for knowing, corresponding p-phenol derivatives or p-thiophenol derivative are dissolved in tetrahydrofuran (THF) (THF), N, in dinethylformamide (DMF), toluene, ethyl acetate, methylene dichloride or the chloroform, with NaH, LiAlH
4, NaBH
4, NaOH or KOH prepare.
In above-mentioned preparation method, said 5-amino-triazole ring derivative raw material (II) prepares by following mode:
1 ': formaldehyde derivatives and cyanamide are added in the methyl alcohol, slowly add successively the reaction of sodium tert-butoxide and N-bromo-succinimide and obtain corresponding cyanogen imines ester intermediate.Concrete preparation process can be with reference to such as Yin, and (OrganicLetters 2009,11, (23), the content of bibliographical information such as 5482-5485) for P.et.:Highly efficientcyanoimidation of aldehydes.
2 ': with cyanogen imines ester intermediate and the hydrazine in upper step, fully reaction namely obtains said 5-amino-triazole derivative raw material (II) in methyl alcohol, ethanol, DMF, toluene or DMSO reaction medium.Concrete preparation method can be with reference to comprising such as Barluenga, J.et.:Developments in Pd Catalysis:Synthesis of 1H-1,2,3-Triazoles from SodiumAzide and Alkenyl Bromides (Angewandte Chemie International Edition 2006,45, (41), 6893-6896), Lipshutz, B.H.et.:Heterogeneous Copper-in-Charcoal-Catalyzed Click Chemistry (Angewandte Chemie International Edition 2006,45, (48), 8235-8238), and Zarguil, A.et.:Easy access to triazoles, triazolopyrimidines, benzimidazoles and imidazoles from imidates (Tetrahedron Letters 2008,49, (41), the content of each bibliographical information such as 5883-5886).
The present invention can form triazole connection helicene ketone derivatives in high regioselectivity ground, and preparation process is simple by the shift reaction of above-mentioned transition metal-catalyzed nitrene, and reaction conditions is gentle, and adaptability is wide.
Experimental result shows that many nitrogen azoles connection helicene ketone compounds of the above-mentioned formula of the present invention (I) structure all demonstrates significant anti-tumor activity to multiple cancer cells, has the using value that can be used as antitumor drug.
Embodiment by the following examples is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away from the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment
Embodiment 1
4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-dione compounds (LHDYX-1)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, phenylhydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying, namely obtain corresponding 1,3-phenylbenzene-5-amino-triazole.Yield 65-85%.
3) with 1,3-phenylbenzene-5-amino-triazole adds new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) ethanamide.Yield 70-85%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 80-95%.
5) (IV), iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtains product 4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-and 1-oxygen-4-nitrogen spiral shell [4.5] suffering-6,9-diene-3,8-diketone.Yield 85-99%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
4.56(s，2H)，6.14(d，J＝10.0Hz，2H)，6.56(d，J＝10.0Hz，2H)，7.42-7.45(m，3H)，7.50-7.56(m，5H)，8.05-8.07(m，2H)
13C-NMR(CDCl
3，100MHz)δ(ppm)：
66.0，88.1，124.8，126.4，128.6，129.6，129.8，129.9，129.9，131.1，136.3，141.7，142.2，161.8，170.3，183.5
HRMS(ESI)m/z(％)for C
22H
17N
4O
3(M+H)：
Calcd.385.1301Found.385.1293。The structure of product is:
Embodiment 2
4-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone (LHDYX-2)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, methyl hydrazine are added in the methyl alcohol, 20 ℃～50 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-methyl-3-phenyl-5-amino-triazole.Yield 50-65%.
3) 1-methyl-3-phenyl-5-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 70-85%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-methyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 80-95%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
3.88(s，3H)，4.64(s，2H)，6.35(d，J＝10.0Hz，2H)，6.90(d，J＝10.0Hz，2H)，7.39(br，3H)，7.90-7.91(m，2H)
13C-NMR(CDCl
3，100MHz)δ(ppm)：
36.1，65.8，88.0，125.9，128.5，139.5，130.1，131.4，141.7，143.0，160.6，168.9，183.6HRMS(ESI)m/z(％)for C
17H
14N
4O
3Na(M+Na)：
Calcd.345.0964Found.345.0988。The structure of product is:
Embodiment 3
4-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone (LHDYX-3)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, methyl hydrazine are added in the methyl alcohol, 50 ℃～90 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-methyl-5-phenyl-3-amino-triazole.Yield 35-50%.
3) 1-methyl-5-phenyl-3-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl) 2-(4-anisole oxygen) ethanamide.Yield 75-85%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-methyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 70-80%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
3.96(s，3H)，4.61(s，2H)，6.31(d，J＝10.0Hz，2H)，6.90(d，J＝10.0Hz，2H)，7.49-7.50(m，3H)，7.57-7.59(m，2H)
HRMS(ESI)m/z(％)for C
17H
14N
4O
3Na(M+Na)：
Calcd.345.0964.Found.345.0965。The structure of product is:
Embodiment 4
4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-6-methoxyl group-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone (LHDYX-4)
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 65-85%.
2) cyanogen imines ester, phenylhydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying, namely obtain corresponding 1,3-phenylbenzene-5-amino-triazole.Yield 65-80%.
3) with 1,3-phenylbenzene-5-amino-triazole adds new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-75%.
4) hydroxyanisole is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 75-85%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtains product 4-(1,3-phenylbenzene-1H-1,2,4-triazole-5-yl)-and 6-methoxyl group-1-oxygen-4-nitrogen spiral shell [4.5] suffering-6,9-diene-3,8-diketone.Yield 80-95%.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
3.69(s，3H)，4.51(d，J＝14.4Hz，1H)，4.70(d，J＝14.4Hz，1H)，5.47(d，J＝1.6Hz，1H)，
6.10(dd，J＝10.0Hz，1.6Hz，1H)，6.30(d，J＝10Hz，1H)，7.41-7.44(m，3H)，
7.51-7.55(m，5H)，8.02-8.05(m，2H)。The structure of product is:
Embodiment 5
4-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively paranitrobenzaldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.
2) cyanogen imines ester, phenylhydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-amine.
3) with 3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-amine adds new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours are carried out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carry out separation and purification with methods such as polymeric amide or silica gel again, namely obtain product N-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(3-(4-nitrophenyl)-1-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Detected result:
1H-NMR(CDCl
3，400MHz)δ(ppm)：
4.58(s，2H)，6.16(d，J＝10.0Hz，2H)，6.57(d，J＝10.0Hz，2H)，7.51-7.52(m，2H)，
7.57-7.59(m，3H)，8.24(d，J＝8.8Hz，2H)，8.30(d，J＝8.8Hz，2H)。The structure of product is:
Embodiment 6
4-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-80%.
2) cyanogen imines ester, ethyl hydrazine are added in the methyl alcohol, 50 ℃～90 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-ethyl-5-phenyl-3-amino-triazole.Yield 35-45%.
3) 1-ethyl-5-phenyl-3-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl) 2-(4-anisole oxygen) ethanamide.Yield 70-80%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-ethyl-5-phenyl-1H-1,2,4-triazole-3-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 65-75%.The structure of product is:
Embodiment 7
4-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, ethyl hydrazine are added in the methyl alcohol, 20 ℃～50 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-ethyl-3-phenyl-5-amino-triazole.Yield 50-65%.
3) 1-ethyl-3-phenyl-5-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-75%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) formula structural compounds and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carries out separation and purification with methods such as polymeric amide or silica gel again, namely obtains product N-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 70-80%.
5) (IV) formula structural compounds, iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-ethyl-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 80-95%.The structure of product is:
Embodiment 8
4-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) with cyanogen imines ester, the methoxyl group phenylhydrazine is added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-(4-p-methoxy-phenyl)-3-phenyl-5-amino-triazole.Yield 65-75%.
3) 1-(4-p-methoxy-phenyl)-3-phenyl-5-amino-triazole is added new the steaming in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-80%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carry out separation and purification with methods such as polymeric amide or silica gel again, namely obtain product N-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 80-90%.
5) (IV), iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtain product 4-(1-(4-p-methoxy-phenyl)-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] hot-6,9-diene-3, the 8-diketone.Yield 70-85%.The structure of product is:
Embodiment 9
4-(1-(2,4 dichloro benzene base)-3-phenyl-1H-1,2,4-triazole-5-yl)-1-oxygen-4-nitrogen spiral shell [4.5] last of the ten Heavenly stems-6,9-diene-3, the preparation of 8-diketone
1) successively phenyl aldehyde, cyanamide are added in the methyl alcohol, under ice-water bath, slowly add successively again potassium tert.-butoxide, N-bromo-succinimide, in 20 ℃～70 ℃ lower stirrings 3～24 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain corresponding cyanogen imines ester products.Yield 70-85%.
2) cyanogen imines ester, 2,4 dichloro benzene hydrazine are added in the methyl alcohol, 20 ℃～70 ℃ lower stirrings 3～24 hours, reaction soln is put into the refrigerator cooling, suction filtration, vacuum-drying namely obtains corresponding 1-(4-p-methoxy-phenyl)-3-phenyl-5-amino-triazole.Yield 60-75%.
3) with 1-(2, the 4-dichlorophenyl)-3-phenyl-5-amino-triazole adding is new steams in the methylene dichloride, again to be added dropwise to successively triethylamine, chloroacetyl chloride,-15 ℃～100 ℃ lower stirrings 3～48 hours, carry out separation and purification with methods such as polymeric amide or silica gel after the reaction, namely obtain product 2-chloro-N-(1-(2,4 dichloro benzene base)-3-phenyl-1H-1,2,4-triazole-5-yl) ethanamide.Yield 65-75%.
4) p methoxy phenol is dissolved in the THF solution that heavily steamed, adds NaH, room temperature～100 ℃ stirring 1～6 hour is spin-dried for THF, adds (III) and solvent DMF, and mixture stirred 2～6 hours in 30 ℃～140 ℃.Reacted reaction soln washes with water, ethyl acetate extraction, carry out separation and purification with methods such as polymeric amide or silica gel again, namely obtain product N-(1-(2,4 dichloro benzene base)-3-phenyl-1H-1,2,4-triazole-5-yl) 2-(4-anisole oxygen) ethanamide.Yield 80-90%.
5) (IV), iodobenzene acetic ester, cupric chloride are added in the reaction flask, add methylene dichloride, mixture stirred 4～48 hours in-15 ℃～100 ℃, reacted reaction soln carries out separation and purification with methods such as polymeric amide or silica gel, obtains product 4-(1-(2,4 dichloro benzene base) 3-phenyl-1H-1,2,4-triazole-5-yl)-and 1-oxygen-4-nitrogen spiral shell [4.5] suffering-6,9-diene-3,8-diketone.Yield 65-80%.The structure of product is:
Embodiment 10
The CCK-8 method is measured tumor cell in vitro and is suppressed experiment
1. experiment material
BALB/c nu/nu nude mouse [animal conformity certification SCXK (river) 09-2006] is provided by West China Center of Medical Sciences of Sichuan University animal center, and is male, SPF level, 6～8 ages in week.
2. experimental technique
1) cancer cells is cultivated
Cancer cells X1 and X2 grow in the RPMI-1640 substratum that contains 10% deactivation calf serum, in 37 ℃, 5%CO
2, cultivate under the saturated humidity condition.Went down to posterity with 0.25% trysinization in every 2-3 days.
2) CCK-8 experiment
Skin carcinoma A431 cell, colorectal carcinoma HCT116 cell, cancer of the stomach MKN45 cell, ovarian cancer SKOV-3 cell that the phase of taking the logarithm grows, be inoculated in 96 well culture plates by 5 * 104/mL, 200 μ L are inoculated in every hole, behind the DMEM high glycoform nutrient solution cultivation 24h that contains 10% calf serum, change nutrient solution, give respectively following processing to above-mentioned cell: 1) control group: every hole adds DMEM high glycoform nutrient solution 200 μ L, establishes altogether 6 multiple holes; 2) administration group: the experimental concentration scope is 50 μ M, 5 μ M, 2.5 μ M, 0.5 μ M, 0.05 μ M and 0.005 μ M, each concentration is established 6 multiple holes, the every hole of 24h, 48h and 72h adds 20 μ L CCK-8 solution (being purchased from green skies biotechnology research institute) after the administration, and 37 ℃ are continued to cultivate 3h.On microplate reader, choose the 450nm wavelength and measure every hole light absorption value.Each time point and each concentration all repeat to test three times.
Inhibiting rate=(1-administration group light absorption value/control group light absorption value) * 100%.
Experimental result is as shown in table 1.
Table 1LHDYX-1 cell experiment result (IC
50)
Table 1 result shows, the compound L HDYX-1 of the embodiment of the invention 1 has inhibition in various degree active to cancer cells, and the restraining effect of cancer cells is higher than has been widely used antitumor drug Zorubicin (Doxorubicin) at present clinical.
Embodiment 11
The CCK-8 method is measured tumor cell in vitro and is suppressed experiment
Experiment material and method
Take human breast carcinoma MDA-MB-231 cell as experimental cell.Compound D YX-2, DYX-5, DYX-6, DYX-7 is mixed with 5mM solution after dissolving with analytical pure dimethyl sulfoxide (DMSO) (DMSO), add the DMEM high glycoform substratum that contains 10% calf serum and be diluted to 500 μ M, filtration sterilization, redilution becomes the serial solution of six concentration.Get 96 well culture plates, every hole is inoculated 200 μ L and is contained 10000 cells.Continue to cultivate 24 hours, suck old substratum, dosing, Experimental agents is respectively LHDYX-1, LHDYX-2, LHDYX-3, LHDYX-4.Every kind of medicine is established 6 parallel holes, and the blank group does not add medicine, also establishes 6 parallel holes.Final administration concentration is 50 μ M, 5 μ M, 2.5 μ M, 0.5 μ M, 0.05 μ M, 0.005 μ M.Continue to cultivate after 24 hours, 48 hours, 72 hours, every hole adds 20 μ LCCK-8 solution, continues to cultivate after 3.5 hours again, and with the absorbance (OD value) of microplate reader measurement enchylema, the measurement wavelength is 450nM, calculates inhibitory rate of cell growth.Every group of experiment triplicate.The inhibiting rate calculation formula:
Inhibiting rate %=(1-administration group OD value/cell control group OD value) * 100%
Whether experimental result is shown in table 2～table 4.
Table 2LHDYX-1, LHDYX-3 is to the IC50 value of human breast carcinoma MDA-MB-231 cell
| 24h | 48h | 72h | |
| LHDYX-1 | 26.03uM | 2.88uM | 0.34uM |
| LHDYX-3 | 2.96uM | 1.46uM |
Table 3LHDYX-2 is to the inhibiting rate of human breast carcinoma MDA-MB-231 cell
| 50μM | 5μM | 0.5μM | 0.05μM | |
| 24h | 100％ | 39.92％ | 17.12％ | 19.11％ |
| 48h | 93.49％ | 94.70％ | 76.38％ | 19.02％ |
| 72h | 96.39％ | 96.25％ | 95.27％ | 39.44％ |
Table 4LHDYX-4 is to the inhibiting rate of human breast carcinoma MDA-MB-231 cell
| 50μM | 5μM | |
| 24h | 42.02％ | - |
| 48h | 98.39％ | 4.30％ |
| 72h | 100％ | 17.23％ |
Annotate: "-" expression unrestraint effect.
The experimental result of table 2～table 4 shows that compound of the present invention is active to the inhibition that human breast carcinoma MDA-MB-231 cell all has in various degree.Wherein compound L HDYX-1 reaches 0.34uM in 72 hours IC50 values to the MDA-MB-231 cell; Compound L HDYX-2 concentration 5 μ M, inhibiting rate reached 96.25% in 72 hours; Compound L HDYX-4 concentration 50 μ M, inhibiting rate reached 100% in 72 hours.
Claims (10)
1. many nitrogen azoles connection helicene ketone compounds, structure be suc as formula shown in (I),
In the formula: R
1, R
2, R
3And R
4Be H at the same time or separately, C
1-3-alkyl, C
1-3--oxyl or halogen element; R
5, R
6Be H at the same time or separately, C
1-3-alkyl, halogen element, phenyl or replaced or the dibasic phenyl in non-ortho position by methyl, methoxyl group, halogen element, amino, nitro list, naphthyl or replace or dibasic naphthyl by α, the β of methyl, methoxyl group, halogen element, amino, nitro are single, thiophene 2-base, quinoline 6-base, or by methyl, methoxyl group, halogen element, amino, the mono-substituted thiophene 2-base of nitro, or by methyl, methoxyl group, halogen element, amino, the mono-substituted quinoline 6-base of nitro; R
7Be H or C
1-3-alkyl, and R
6And R
7Do not exist simultaneously; Y is-O-,-S-,-NH-; N=1 or 2.
2. compound as claimed in claim 1 is characterized in that the R in the said formula (I)
1, R
2, R
3And R
4In halogen element be Cl or Br; R
5, R
6Be H at the same time or separately, C
1-3-alkyl, Cl, Br, phenyl, thiophene 2-base or quinoline 6-base.
3. prepare the method for claim 1 or 2 described many nitrogen azoles connection helicene ketone compounds, it is characterized in that carrying out in the steps below the R in the reaction formula
1, R
2, R
3, R
4, R
5, R
6, R
7, Y is identical with claim 1 with n:
1 ': 5-amino-triazole ring derivative raw material (II) and halogen acyl halide are reacted in the organic basic environment, obtain corresponding intermediate (III);
2 ': with the intermediate (III) in upper step and the reaction of formula (V) compound, obtain corresponding intermediate (IV), wherein, the YA in formula (V) compound is-ONa ,-SNa or-NH
2
3 ': with intermediate (IV) after cyclization under oxygenant and the catalyzer, obtain corresponding target product (I), said oxygenant comprises iodobenzene acetic ester, trifluoroacetyl iodobenzene, iodosobenzene, lead tetra-acetate or Manganse Dioxide, said catalyzer comprises at least a in cupric chloride, cuprous iodide, cupric bromide, trifluoromethayl sulfonic acid copper or the acetic acid rhodium, reaction solvent is chloroform, dimethyl formamide, tetrahydrofuran (THF), 1, at least a in 2-ethylene dichloride, toluene, acetone or the methylene dichloride.
4. preparation method as claimed in claim 3 is characterized in that said the 1st ' step reaction with methylene dichloride, chloroform, 1, and 2-ethylene dichloride, tetracol phenixin, DMF or toluene are that the reaction environment of medium carries out.
5. preparation method as claimed in claim 3, the organic basic environment that it is characterized in that said the 1st ' step is at quadrol, N, N-dimethyl-ethylenediamine, 1,8-diazabicylo [5.4.0] 11 is rare-7, the reaction medium environment under at least a existence in NaH, potassium tert.-butoxide or the triethylamine.
6. preparation method as claimed in claim 3 is characterized in that said halogen acyl halide composition in said the 1st ' step reaction comprises a kind of in chloroacetyl chloride, bromoacetyl chloride, chlorpromazine chloride, the bromo propionyl chloro.
7. preparation method as claimed in claim 3 is characterized in that said the 2nd ' step reaction is to carry out in the reaction medium at dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetone, chloroform, methylene dichloride or dimethyl formamide.
8. such as the preparation method of one of claim 3 to 7, it is characterized in that said 5-amino-triazole ring derivative raw material (II) prepares by following mode:
1 ': formaldehyde derivatives and cyanamide are added in the methyl alcohol, add successively the reaction of sodium tert-butoxide and N-bromo-succinimide and obtain corresponding cyanogen imines ester intermediate;
2 ': the fully reaction in methyl alcohol, ethanol, dimethyl formamide, toluene or dimethyl sulfoxide (DMSO) reaction medium with cyanogen imines ester intermediate and hydrazine derivative obtains said 5-amino-triazole derivative raw material (II).
9. such as the preparation method of one of claim 3 to 7, it is characterized in that said formula (V) compound is for to be dissolved in tetrahydrofuran (THF), N with p-anisole amphyl or p-methoxybenzenethiol derivative, in dinethylformamide, toluene, ethyl acetate, methylene dichloride or the chloroform, with NaH, LiAlH
4, NaBH
4, NaOH or KOH prepare the compound of corresponding p-methoxyphenol sodium or p-methoxybenzenethiol sodium class.
10. the many nitrogen azoles with claim 1 or 2 joins the helicene ketone compounds as the application of antitumor drug.
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