CN104530057A - 2,5,8,11-tetraazatraasterane compound as well as preparation method and application thereof - Google Patents
2,5,8,11-tetraazatraasterane compound as well as preparation method and application thereof Download PDFInfo
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- CN104530057A CN104530057A CN201410758272.8A CN201410758272A CN104530057A CN 104530057 A CN104530057 A CN 104530057A CN 201410758272 A CN201410758272 A CN 201410758272A CN 104530057 A CN104530057 A CN 104530057A
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- alkyl
- tetra
- stars
- azepine
- compound
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- 0 C*(c(c(*)c1)cc(C(O)=O)c1C(O)=O)=C Chemical compound C*(c(c(*)c1)cc(C(O)=O)c1C(O)=O)=C 0.000 description 1
- XGQMXSATCGEOLJ-UHFFFAOYSA-N OC1C(O)=CC=CC1 Chemical compound OC1C(O)=CC=CC1 XGQMXSATCGEOLJ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Abstract
The invention discloses a 2,5,8,11-tetraazatraasterane compound as well as a preparation method and application thereof, and belongs to the field of synthesis of a novel compound and medicine application. The structure of the compound is as follows in the specification, wherein R1 and R2 are selected from C1-C8 alkyl and aryl; R3, R4, R5, R6, R7, R8, R9 and R10 are selected from C1-C8 alkyl, C1-C8 acidic methoxycarbonyl, C1-C8 acylamino, C1-C8 carboxyl, cyano and hydrogen. Substituted 1,4-dihydropyrazine is taken as a reaction substrate and is cultured and co-crystalized with a template in a solvent to obtain an eutectic compound; the eutectic compound is allowed to have an optical cyclization reaction by the irradiation effect of a light source. The compound disclosed by the invention can be applied to preparation of a medicine for treating malignant tumors or a medicine for treating aids.
Description
Technical field
The invention belongs to new compound synthesis and medicinal application field, be specifically related to 2,5,8,11-tetra-azepine four stars alkyl compound and preparation and this compounds thereof and preparing the application in antitumor and inverase.
Background technology
Polyhedron alkane, as diamantane, cubane, homocubane and four stars alkane etc., due to structural singularity, it is caused to show the character of the physics and chemistry far different with other compound, particularly its antiviral and antineoplastic pharmacologically active, has attracted the concern of increasing pharmaceuticals researcher.Four stars alkane is as the one of polyhedron alkane, and its physiological and pharmacological showed at antiviral and anti-tumor aspect is active, causes the interest that people study its synthetic method.Four stars alkane (Tetraasterane) is as the one of polyhedron alkane, its synthesis and the active research at present of physiological and pharmacological comparatively widely compound are 3,9-diaza four stars alkane (3,9-diazatetraasterane) He 3,9-dioxa four stars alkane (3,9-dioxotetraasterane), this compounds has the activity of HIV-1 inhibit activities and inhibition tumor cell propagation, or the active substances of cross-film medicine transportation pump P-gp, can suppress the expression of P-gp to improve the multi-drug resistance phenomenon of antitumor drug.With 3,9-diaza four stars alkane and 3, based on the synthesis of 9-dioxa four stars alkane and the research of antiviral anti-tumor activity, we propose, by Isosorbide-5-Nitrae-dihydro pyrazine being the solid phase template photocyclization obtained 2 of reaction substrate, 5,8,11-tetra-azepine four stars alkyl compound, and study its application in the antitumor and inverase of preparation.
Summary of the invention
The object of this invention is to provide class 2,5,8, a 11-tetra-azepine four stars hydride compounds, and prepare method and the application of this compounds in the medicine preparing treatment tumour and acquired immune deficiency syndrome (AIDS) of this compounds simply, efficiently.
2,5,8,11-tetra-azepine four stars alkyl compounds provided by the present invention, have following general structure (I) (dotted line wherein used is in order to its structure of clear embodiment).
Wherein, R
1, R
2be selected from C
1-8alkyl, aryl; R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10be selected from C
1-8alkyl, C
1-8acid methoxycarbonyl, C
1-8amide group, C
1-8carboxyl, cyano group, hydrogen.
Above-mentioned C
1-8alkyl refers to the alkyl with 1-8 carbon atom straight chain or side chain.Such as: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group etc.Preferably there is the alkyl of the straight or branched of 1-4 carbon atom, particularly preferably there is the alkyl of 1-2 carbon atom, as methyl or ethyl.
C
1-8acid methoxycarbonyl refers to have 1-8 carbon atom straight chain or branched acids methoxycarbonyl.Such as: methyl acetate base, methyl propionate base, methyl-butyrate base, methyl isobutyrate base, tertiary methyl-butyrate base, secondary methyl-butyrate base, methyl valerate base, methyl pivalate base, methyl caproate base, Methylheptanoate base, methyl caprylate base.Preferably there is the sour methoxycarbonyl of the straight or branched of 1-4 carbon atom, particularly preferably there is the sour methoxycarbonyl of 1-2 carbon atom, as methyl-formiate or methyl acetate.
C
1-8amide group refers to the amide group with 1-8 carbon atom straight chain or side chain.As formamido-, acetamido, propionamido-, Isopropamide base, amide-based small, isobutyl amide, t-butyl carboxamide base, secondary amide-based small, valeryl amido, pivalyl amido, hexanoyl amido, hexanecarboxamido, decoyl amido etc.Preferably there is the amide group of the straight or branched of 1-4 carbon atom, particularly preferably there is the amide group of 1-2 carbon atom, as formamido-or acetamido.
C
1-8carboxyl refers to the carboxyl with 1-8 carbon atom straight chain or side chain.Such as: formyloxy, acetoxyl, isopropyl acidic group, butyric acid base, isobutyl acidic group, tertiary butyric acid base, Zhong Ding acidic group, valeric acid base, PIVALIC ACID CRUDE (25) base, caproyl, enanthic acid base, sad base etc.Preferably there is the carboxyl of the straight or branched of 1-4 carbon atom, particularly preferably there is the carboxyl of 1-2 carbon atom, as formyloxy or acetoxyl.
Above-mentioned aryl preferably has 1-5 substituent phenyl or without substituted-phenyl.Such as: a substituted-phenyl, di-substituted-phenyl, tri-substituted phenyl, tetra-substituted phenyl.Particularly preferably there is 1-3 substituent phenyl.
Substituting group on above-mentioned phenyl is C
1-8alkyl, the C replaced by 1-3 halogen atom
1-8alkyl, C
1-8alkoxyl group, C
1-8acid methoxycarbonyl, C
2-8amide group, halogen, hydroxyl, nitro or amino.The preferred C of substituting group on phenyl
1-4alkyl, the C replaced by 1-3 halogen atom
1-4alkyl, C
1-4alkoxyl group, C
1-4acid methoxycarbonyl or C
2-4amide group.Particularly preferably C
1-2alkoxyl group, C
1-2acid methoxycarbonyl or acetamido, most preferably methoxyl group or methyl acetate base.
Substituting group on above-mentioned phenyl is halogen.Such as: fluorine, chlorine, bromine, iodine.Preferred fluorine, chlorine or bromine.
The preparation method of 2,5,8,11-tetra-azepine four stars alkyl compounds provided by the present invention (as Suo Shi general formula (I)) has following general formula:
As for the reaction of thiocarbamide:
The method is the Isosorbide-5-Nitrae-dihydro pyrazine replaced
for reaction substrate, cultivate eutectic in a solvent with template, obtain cocrystalization compound; The cocrystalization compound of gained issues third contact of a total solar or lunar eclipse ring-closure reaction at the radiation of light source, obtains 2,5,8,11-tetra-azepine four stars alkyl compound.Above-mentioned photocyclization is [2+2] photocyclization.
Above-mentioned template is: the compound at least containing two reactive hydrogens such as O-Phenylene Diamine, pyrocatechol, Pyromellitic Acid, thiocarbamide.
Above-mentioned solvent is: the good solvents of volatility such as tetrahydrofuran (THF), benzene, methyl alcohol.
Above-mentioned light source is selected from sunlight or other have the light source in near-ultraviolet light district, as: mercury lamp or ultraviolet lamp.
CCK-8 method of cell apoptosis is adopted to measure 2,5,8,11-tetra-azepine four stars alkyl compound to the restraining effect of tumour cell.Experiment employing 96 orifice plate, adherent or suspension cell 100 μ L/ hole volume of culture (>5000 cells/well) in 96 well culture plates.Experiment is to comprising MCF-7, and the kinds of tumor cells such as EC9706, HN-6, Hela, HepG2 have carried out anti-tumor activity detection.2,5,8,11-tetra-azepine four stars alkyl compound is configured to the solution of gradient concentration with DMEM serum-free medium, every hole adds 10 μ L.Every concentration establishes 4 multiple holes, separately establishes blanc cell control wells.37 DEG C, 5%CO
2hatch 24h, add 10 μ LCCK-8 solution (note not generating bubble in hole, they can affect the reading of OD value) to every hole.After culture plate is continued to hatch 1h in incubator, be determined at the absorbancy at 450nm place by microplate reader.
Experiment proves: compound of the present invention all demonstrates excellent anti-tumor activity to kinds of tumor cells in vitro, can be used for the medicine preparing treatment malignant tumour.
The method of p24 Detection of antigen is adopted to measure the restraining effect of 2,5,8,11-tetra-azepine four stars alkyl compound HIV-1.Experiment employing 96 orifice plate, by 2,5,8,11-tetra-azepine four stars alkyl compound is configured to the solution of 100 μm of ol/L with RPMI-1640 serum-free medium, and does 2 times of serial dilutions, every hole 100 μ L, every concentration establishes 4 multiple holes, separately establishes virus control, cytotoxic control and cell control well.Separately join 500,000 cells (containing 1000TCID
50virus liquid), be added with in the hole of liquid in above-mentioned 96 orifice plates, every hole adds 10 μ L.37 DEG C, 5%CO
2hatch 1.5h, discard free virus, continue cultivation 5 days, wherein changed liquid at the 3rd day.Within 5th day, get every hole supernatant, by p24 kit measurement p24 antigen amount to represent that 2,5,8,11-tetra-azepine four stars alkyl compound is to the restraining effect of virus.
Experiment proves: it is active that compound of the present invention demonstrates excellent AIDS virus resisting (HIV-1) in vitro, can be used for the medicine preparing treatment acquired immune deficiency syndrome (AIDS).
Isosorbide-5-Nitrae-dihydro the pyrazine of the replacement that the present invention is used can be synthesized by direct or indirect method according to prior art.
Embodiment
Below in conjunction with the invention will be further described, but the present invention is not limited to following examples.
Reaction involved in the embodiment of the present invention has following general formula (thiocarbamide template can be replaced O-Phenylene Diamine, pyrocatechol, Pyromellitic Acid):
Embodiment 1
Take N, N-diacetyl-Isosorbide-5-Nitrae-dihydro pyrazine 1.66g and thiocarbamide 0.76g, is dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treats 2/3 of its volume of solvent evaporates, and adularescent needle-like crystal is separated out, and filters, dry, obtains crystal 2.1g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-acetylated-2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 1.95 (q, 12H), 4.89-4.97 (m, 4H), 5.27-5.42 (m, 4H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 20.9,21.0,21.2,46.7,46.9,47.3,47.4,47.9,52.3,53.0,53.2,79.1,79.4,79.8,169.3,169.5,169.8; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 333.15628, detected value 333.15442.The activity of its AIDS virus resisting (HIV-1) is in table 1, and anti-tumor activity is in table 2.
Embodiment 2
Take N, N-bis-couples chlorobenzene formacyl-Isosorbide-5-Nitrae-dihydro pyrazine 3.58g and thiocarbamide 0.76g, is dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treats 2/3 of its volume of solvent evaporates, and adularescent needle-like crystal is separated out, and filters, dry, obtains crystal 3.8g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-pairs of chlorobenzene formacyls-2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 4.70-4.77 (m, 4H), 5.17-5.22 (m, 4H), 7.45-7.55 (m, 8H), 7.80-7.90 (m, 8H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 59.3,135.3,133.3,128.6,129.8,171.7; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 716.05517, detected value 716.05522.The activity of its AIDS virus resisting (HIV-1) is in table 1, and anti-tumor activity is in table 2.
Embodiment 3
Take N, N-di-p-methoxy benzoyl-Isosorbide-5-Nitrae-dihydro pyrazine 3.50g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out; filter, dry, obtain crystal 3.6g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-pairs of methoxybenzoyl bases-2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 3.81 (s, 12H) 4.90-4.98 (m, 4H), 5.20-5.24 (m, 4H), 7.08-7.12 (m, 8H), 7.87-7.97 (m, 8H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 60.1,116.3,128.3,127.8,171.7; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 700.25331, detected value 700.25322.The activity of its AIDS virus resisting (HIV-1) is in table 1, and anti-tumor activity is in table 2.
Embodiment 4
Take N, N-bis-(3,4-difluoro benzoyl)-Isosorbide-5-Nitrae-dihydro pyrazine 3.58g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out; filter, dry, obtain crystal 3.8g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(3,4-difluoro benzoyl)-2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 4.70-4.77 (m, 4H), 5.17-5.22 (m, 4H), 7.45-7.55 (m, 6H), 7.80-7.90 (m, 6H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 59.3,135.3,133.3,128.6,129.8,171.7; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 724.13568, detected value 724.13570.Its anti-tumor activity is in table 2.
Embodiment 5
Take N, N-bis-(3,4-dimethylbenzoyl)-Isosorbide-5-Nitrae-dihydro pyrazine 3.50g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out; filter, dry, obtain crystal 3.6g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(3,4-dimethylbenzoyl)-2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 1.89 (q, 24H) 4.90-4.98 (m, 4H), 5.20-5.24 (m, 4H), 7.08-7.12 (m, 6H), 7.87-7.97 (m, 6H);
13cNMR (100MHz, DMSO-d
6) δ
c(ppm) 60.1,116.3,128.3,127.8,171.7; HRMS (ESI+) m/z [M+H]
+c
16h
21n
4o
4calculated value 700.25331, detected value 700.25322.The activity of its AIDS virus resisting (HIV-1) is in table 1.
Embodiment 6
Take N; N-bis-(3; 4,5-trimethoxybenzoy)-Isosorbide-5-Nitrae-dihydro pyrazine 3.50g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol; treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out, and filters; drying, obtains crystal 3.6g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(3,4,5-trimethoxybenzoy)-2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 3.81 (m, 36H) 4.90-4.98 (m, 4H), 5.20-5.24 (m, 4H), 7.08-7.12 (m, 4H), 7.87-7.97 (m, 4H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 60.1,116.3,128.3,127.8,171.7; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 940.33783, detected value 940.33790.Its anti-tumor activity is in table 2.
Embodiment 7
Take N, N-bis-(2,3-dimethyl) ethanoyl-Isosorbide-5-Nitrae-dihydro pyrazine 1.94g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out; filter, dry, obtain crystal 1.5g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(2,3-dimethyl) ethanoyl 2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 1.90 (m, 12H) 2.06-2.25 (m, 12H), 4.90-4.98 (m, 2H), 5.20-5.24 (m, 2H), 7.08-7.12 (m, 4H), 7.87-7.97 (m, 4H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 60.1,116.3,128.3,127.8,171.7; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 388.21103, detected value 388.21121.The activity of its AIDS virus resisting (HIV-1) is in table 1, and anti-tumor activity is in table 2.
Embodiment 8
Take N, N-bis-(2,6-dicyano) ethanoyl-Isosorbide-5-Nitrae-dihydro pyrazine 2.16g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out; filter, dry, obtain crystal 3.0g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(2,6-dicyano) acyl group 2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 1.95 (q, 12H), 4.89-4.97 (m, 2H), 5.27-5.42 (m, 2H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 13.9,21.7,39.3,72.2,76.3,82.4,155.9,166.1,168.3,197.0; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 448.1608, detected value 448.1610.The activity of its AIDS virus resisting (HIV-1) is in table 1.
Embodiment 9
Take N, N-bis-(2,6-diethylamide) acyl group-Isosorbide-5-Nitrae-dihydro pyrazine 2.52g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out; filter, dry, obtain crystal 3.2g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(2,6-diethylamide) acyl group 2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 1.90 (m, 12H) 4.90-4.98 (m, 2H), 5.20-5.24 (m, 2H), 7.08-7.12 (m, 8H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 20.9,21.7,60.9,70.6,166.1,168.3,181.7; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 504.1717, detected value 504.1719.The activity of its AIDS virus resisting (HIV-1) is in table 1.
Embodiment 10
Take N, N-bis-(2,6-dicarboxyl) ethanoyl-Isosorbide-5-Nitrae-dihydro pyrazine 3.46g and thiocarbamide 0.76g; be dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treat 2/3 of its volume of solvent evaporates, adularescent needle-like crystal is separated out; filter, dry, obtain crystal 3.2g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(2,6-dicarboxyl) acyl group 2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 1.90 (m, 12H) 4.90-4.98 (m, 2H), 5.20-5.24 (m, 2H), 12.20-12.22 (m, 4H);
13c NMR (100MHz, DMSO-d
6) δ
c(ppm) 21.7,60.5,70.7,166.1,168.3,178.6; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 508.1078, detected value 508.1079.Its anti-tumor activity is in table 2.
Embodiment 11
Take N; N-bis-(2; 6-methyl acetate) propionyl-1; 4-dihydro pyrazine 2.82g and O-Phenylene Diamine 1.08g, is dissolved in the mixed solvent (V:V=2:1) of benzene and methyl alcohol, treats 2/3 of its volume of solvent evaporates; adularescent needle-like crystal is separated out; filter, dry, obtain crystal 3.0g.
Be applied on the inwall of photoreactor by above-mentioned gained crystal, make coating uniform, use 500W high voltage mercury lamp radiation, light source is apart from reactant 5cm.TLC follows the tracks of reaction.After 30h, react completely.Elute after reactant 20mL methylene dichloride is dissolved, filter, concentrated, anhydrous methanol and methylene dichloride recrystallization, obtain target product 2,5,8,11-tetra-(2,6-methyl acetate) propionyl 2,5,8,11-tetra-azepine four stars alkane.
1h NMR (400MHz, DMSO-d
6): δ
h(ppm) 1.90 (m, 12H) 2.06-2.25 (m, 8H), 3.20-3.23 (m, 12H), 4.90-4.98 (m, 2H), 5.20-5.24 (m, 2H;
13cNMR (100MHz, DMSO-d
6) δ
c(ppm) 10.3,26.9,27.2,52.2,59.6,61.7,62.6,68.5,69.1,70.5,170.8,171.1,171.8; HRMS (ESI
+) m/z [M+H]
+c
16h
21n
4o
4calculated value 606.2537, detected value 606.2538.The activity of its AIDS virus resisting (HIV-1) is in table 1, and anti-tumor activity is in table 2.
CCK-8 method of cell apoptosis is adopted to measure 2,5,8,11-tetra-azepine four stars hydride compounds to the restraining effect of tumour cell.Adopt the method for p24 Detection of antigen to measure the restraining effect of 2,5,8,11-tetra-azepine four stars alkyl compound HIV-1, experiment is listed in table 1 and table 2.
Table 1:2,5,8,11-tetra-azepine four stars alkyl compound to the restraining effect of kinds of tumor cells
Table 2:2,5,8,11-tetra-azepine four stars alkyl compound HIV-1 is infected to the restraining effect of MT4 cell
| Compound | Test concentrations (μm ol/L) | P24 antigen inhibiting rate (%) |
| Embodiment 1 | 30 | 95.56 |
| Embodiment 2 | 50 | 90.41 |
| Embodiment 3 | 50 | 88.65 |
| Embodiment 5 | 25 | 94.76 |
| Embodiment 7 | 25 | 97.86 |
| Embodiment 8 | 50 | 90.47 |
| Embodiment 9 | 50 | 84.24 |
| Embodiment 11 | 25 | 96.67 |
Claims (10)
1.2,5,8,11-tetra-azepine four stars alkyl compound, is characterized in that having following general structure
Wherein, R
1, R
2be selected from C
1-8alkyl, aryl; R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10be selected from C
1-8alkyl, C
1-8acid methoxycarbonyl, C
1-8amide group, C
1-8carboxyl, cyano group, hydrogen.
2., according to 2,5,8,11-tetra-azepine four stars alkyl compounds of claim 1, it is characterized in that, C
1-8alkyl refers to the alkyl with 1-8 carbon atom straight chain or side chain; C
1-8acid methoxycarbonyl refers to have 1-8 carbon atom straight chain or branched acids methoxycarbonyl; C
1-8amide group refers to the amide group with 1-8 carbon atom straight chain or side chain; C
1-8carboxyl refers to the carboxyl with 1-8 carbon atom straight chain or side chain.
3., according to 2,5,8,11-tetra-azepine four stars alkyl compounds of claim 2, it is characterized in that, C
1-8alkyl is the alkyl of the straight or branched with 1-4 carbon atom; C
1-8acid methoxycarbonyl is the sour methoxycarbonyl of the straight or branched with 1-4 carbon atom; C
1-8amide group is the amide group of the straight or branched with 1-4 carbon atom; C
1-8carboxyl has the carboxyl of the straight or branched of 1-4 carbon atom.
4. according to 2,5,8,11-tetra-azepine four stars alkyl compounds of claim 1, it is characterized in that, aryl is for having 1-5 substituent phenyl or without substituted-phenyl.
5., according to 2,5,8,11-tetra-azepine four stars alkyl compounds of claim 4, it is characterized in that, the substituting group on phenyl is C
1-8alkyl, the C replaced by 1-3 halogen atom
1-8alkyl, C
1-8alkoxyl group, C
1-8acid methoxycarbonyl, C
2-8amide group, halogen, hydroxyl, nitro or amino.
6., according to 2,5,8,11-tetra-azepine four stars alkyl compounds of claim 5, it is characterized in that, the preferred C of the substituting group on phenyl
1-4alkyl, the C replaced by 1-3 halogen atom
1-4alkyl, C
1-4alkoxyl group, C
1-4acid methoxycarbonyl or C
2-4amide group.
7. prepare the method for 2,5,8,11-tetra-azepine four stars alkyl compounds of claim 1, it is characterized in that, with the Isosorbide-5-Nitrae replaced-dihydro pyrazine
for reaction substrate, cultivate eutectic in a solvent with template, obtain cocrystalization compound; The cocrystalization compound of gained issues third contact of a total solar or lunar eclipse ring-closure reaction at the radiation of light source, and obtain 2,5,8,11-tetra-azepine four stars alkyl compound, template is: the compound at least containing two reactive hydrogens, R
1, R
2be selected from C
1-8alkyl, aryl; R
3, R
4, R
5, R
6be selected from C
1-8alkyl, C
1-8acid methoxycarbonyl, C
1-8amide group, C
1-8carboxyl, cyano group, hydrogen.
8. according to the method for claim 7, it is characterized in that, template is O-Phenylene Diamine, pyrocatechol, Pyromellitic Acid or thiocarbamide.
9. according to the method for claim 7, it is characterized in that, solvent is tetrahydrofuran (THF), benzene or methyl alcohol; Light source is selected from sunlight or other have the light source in near-ultraviolet light district.
10. the application of 2,5,8,11-tetra-azepine four stars alkyl compounds in the medicine of preparation treatment malignant tumour or the medicine of preparation treatment acquired immune deficiency syndrome (AIDS) of claim 1.
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| CN111362941A (en) * | 2020-04-22 | 2020-07-03 | 北京工业大学 | Visible light preparation method of aza-tetraacetalkane compounds |
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| CN111362941A (en) * | 2020-04-22 | 2020-07-03 | 北京工业大学 | Visible light preparation method of aza-tetraacetalkane compounds |
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