CN102875550B - 1,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives and preparation method - Google Patents

1,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives and preparation method Download PDF

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CN102875550B
CN102875550B CN201110193554.4A CN201110193554A CN102875550B CN 102875550 B CN102875550 B CN 102875550B CN 201110193554 A CN201110193554 A CN 201110193554A CN 102875550 B CN102875550 B CN 102875550B
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nonane
diazabicyclo
benzyl
carbobenzoxy
cbz
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CN102875550A (en
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何亮
彭宣嘉
叶俊涛
汪秀
蔡兰兰
沈余红
董径超
吴颢
马汝建
陈曙辉
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CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD.
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Changzhou Hequan Pharmaceutical Co Ltd
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Abstract

The present invention relates to 1,3,7-tri-replaces-3,7-diazabicyclo [3,3,1] nonane substitutive derivative and preparation method, mainly solve current 3, the endocyclic compound of 7-diazabicyclo [3,3,1] nonane structure is restricted in space structure extension the technical problem being unfavorable for rapid screening compound activity and carrying out SAR analysis.Chemical structural formula is as follows: , wherein R 1for replacing the protecting group of functional group or amino, be selected from H or benzyl; R 2for replacing the protecting group of functional group or amino, be selected from H or carbobenzoxy-(Cbz); G is the one of methylol, carboxyl, ester group, formamido-.

Description

1,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives and preparation method
Technical field
The present invention relates to 1,3,7-tri-and replace-3,7-diazabicyclo [3,3,1] nonane derivatives and preparation method, particularly 1-replaces-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane analog derivative and 1-ethoxycarbonyl-3,7-bis-replaces-3,7-diazabicyclo [3,3,1] nonane analog derivative and preparation method thereof.
Background technology
Bridged ring compounds is the more special molecule of a class formation, the pharmacophore unit of key effectively can be connected is incorporated in its rigid structure, form the molecule with special space configuration/conformation, thus the space structure of different biomacromolecule in organism can be mated, produce corresponding biological activity or effectiveness, a lot of endocyclic compound all has different biological activity, so have wide using value, particularly in drug research process as template compound.Molecule containing two piperidines twin nuclei is distributed in feather fan bucket Alkaloid widely and some have in bioactive molecule, and is confirmed in experiment with various biological activity.Be below disclosed in partial monopoly and document and examples more closely-related with the technology of the present invention.
Document J.Med.Chem.:EN:46:2003:1456-1464 reports the compound of a series of 3-azabicyclo [3.2.1] octane fragment 1, this compound is a kind of effectively Dopamine uptake inhibitor, has good biological activity as lead compound, and what can be developed as ***es drugs gives up medicine.
Document Bioorg.Med.Chem.Lett.:EN:20:2010:6452-6458 reports a series of compounds of a series of 3,7-diazabicyclos [3,3,1] nonane fragment 2,3there is good anti-microbial activity.This compounds uses comparatively low dosage, all has very high activity to Gram-negative and Gram-positive.
Document Bioorg.Med.Chem.Lett.:EN:20:2010:6637-6643 also reports some compounds of a series of 3-azabicyclo [3,3,1] nonane fragment, wherein compound 4there is very high antibacterial and microorganism active.
The compound of patent US6468998 report 5to serum plain-2 acceptor, there is antagonistic action, can hematoblastic congregation, peripheral circulation and lacrimation be improved simultaneously.Therefore, this compound is expected to become one and offsets removing thrombus embolism, the medicine that alleviation and treatment dry eyes etc. are useful.
Patent US2002137766 reports compound 6there is antiarrhythmic effect, be the effective especially lead compound of prevention and therapy heart disorder, and the ionic current of sodium and calcium is not affected substantially.
Although we can see that azabicyclo structure finds in a large amount of active compounds from example above, but, current caged scaffold mostly depends on the group that nitrogen-atoms goes to carry out modifying or connecting other on space structure extends, thus space extension is restricted, and cannot meet the various enzyme of organism, acceptor diversity structurally.Also be unfavorable for rapid screening compound activity and carry out SAR analysis.Therefore, we need to expand its structural modification space to improve its quasi-medicated property matter further.
Summary of the invention
The object of the invention is to be to provide a kind of 1,3,7-tri-to replace-3,7-diazabicyclos [3,3,1] nonane derivatives and preparation method.The endocyclic compound mainly solving current azabicyclo [3,3,1] nonane structure is restricted in space structure extension the technical problem being unfavorable for rapid screening compound activity and carrying out SAR analysis.Change polarity or the biological metabolism performance of existing azabicyclo [3,3,1] nonane derivatives, and organism, various enzyme, acceptor diversity structurally can be better met.
Technical scheme is: a kind of 1,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives, it is characterized in that: general structure is shown in following formula:
Wherein R 1for replacing the protecting group of functional group or amino, be selected from H or benzyl; R 2for replacing the protecting group of functional group or amino, be selected from H or carbobenzoxy-(Cbz); G is the one of methylol, carboxyl, ester group, formamido-.
According to the present invention, 1,3,7-tri-replaces the preferred compound of-3,7-diazabicyclos [3,3,1] nonane derivatives and is: work as R 1for benzyl, R 2during for carbobenzoxy-(Cbz), for the 1-shown in formula I replaces-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane derivatives:
Wherein G is the one in methylol, carboxyl, ester group, formamyl or amido formacyl;
On this basis, the further preferred compound of the present invention includes but not limited to:
I-a:1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane;
I-b:1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane;
I-c:1-methylol-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane
I-d:1-formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane;
I-e:1-(N-methyl) formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane;
I-f:1-(N, N-dimethyl) formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane.
According to the present invention, 1,3,7-tri-replaces-3, the preferred compound of 7-azabicyclo [3,3,1] nonane derivatives is: when G is ethoxycarbonyl, replaces-3 for the 1-ethoxycarbonyl-3-shown in formula II replaces-7-, 7-diazabicyclo [3,3,1] nonane derivatives:
R 1for H or benzyl; R 2for H or carbobenzoxy-(Cbz).
On this basis, the further preferred compound of the present invention includes but not limited to:
II-a:1-ethoxycarbonyl-3,7-diazabicyclo [3,3,1] nonane;
II-b:1-ethoxycarbonyl-3-benzyl-3,7-diazabicyclo [3,3,1] nonane.
The above-mentioned structural formula of compound mentioned is as follows:
Above-claimed cpd is the endocyclic compound of a class formation novelty, at present without its structure of any bibliographical information and synthetic method.
Replace the method for-3,7-diazabicyclos [3,3,1] nonane derivatives such as formula 1,3,7-described in I tri-, it is characterized in that: in formula 1, work as R 1for benzyl, R 2for carbobenzoxy-(Cbz), it is that 1-replaces-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane, preparation process: adopt the compound reported that 1-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives 1for raw material, through twice Mannich reaction, obtain 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-carbonyl-3,7-diazabicyclo [3,3,1] nonane 2, compound 2with to Methyl benzenesulfonyl hydrazine reaction, obtain compound 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-Tosylhydrazone-3,7-diazabicyclo [3,3,1] nonane 3; Compound 3compound 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is generated under sodium cyanoborohydride and hydrochloric acid effect i-a; Then i-arespectively through hydrolysis, reduction obtains compound 1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane i-bwith compound 1-methylol-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane i-c; Compound i-bobtain 1-from different ammonia (amine) base reagent reacts and replace-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane i-d ~ f, reaction formula is as follows:
Substituent R, R 1all be selected from H or methyl.
Described 1,3,7-tri-replaces-3, the method of 7-diazabicyclo [3,3,1] nonane derivatives, it is characterized in that: in formula 1, G is ethoxycarbonyl, 1,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives is that 1-ethoxycarbonyl-3,7-bis-replaces-3,7-azabicyclos [3,3,1] nonane, preparation process: adopt compound i-afor raw material, (room temperature or 0 degree Celsius, room temperature is 20-30 degree Celsius) obtains through catalytic hydrogenation selectivity at different temperatures iI-awith iI-breaction formula is as follows:
Beneficial effect of the present invention :we are at 3,7-diazabicyclo [3,3,1] 1 carbonylate class functional group of nonane compound, not only improves the polarity of template, and we are based on 3-carbobenzoxy-(Cbz)-7-benzyl compounds simultaneously, by hydrolysis reaction, acid amide condensation reaction introduces other group at 1; Based on 1-ethoxycarbonyl compound, 3,7 change the substituting groups in atom N, the while of greatly increasing substrate molecule multifarious, the growth of the compounds of this invention to human lung cancer cell A549's cell has certain restraining effect, lays a good foundation for preparation has bioactive medicine.
Embodiment
Enumerate embodiment to be described in detail the present invention, but the present invention is not limited to these embodiments.
embodiment 1: the preparation of 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-oxo-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-carbobenzoxy-(Cbz)-3-ethyl formate-4-piperidone 1(5.0 gram is added in the there-necked flask of 1 liter; 16 mmoles); N; N-diethoxy methyl-benzyl amine (7.3 grams; 32 mmoles) and anhydrous acetonitrile (30 milliliters); trichloromethyl silane (4.9 grams, 32 mmoles) is dripped, stirring at room temperature 20 hours under nitrogen protection under zero degrees celsius.Reaction solution regulates pH to 7 with saturated sodium bicarbonate solution under zero degrees celsius, extraction into ethyl acetate, and after organic phase is concentrated, petrol ether/ethyl acetate (6/1) elutriant is crossed post and obtained product 3.2 grams, yield 45%.
HNMR(CDCl 3)d:7.18-7.14（m，5H），7.13-7.10（m，5H），5.15-5.11（m，1H），5.02-4.97（m，1H），4.64-4.51（m，1H），4.42-4.34（m，1H），4.07-4.02（m，2H），3.64-3.51（m，1H），,3.35-2.92（m，6H），,2.60-2.52（m，1H），,2.38-2.31（m，1H），1.10（t， J=8.0Hz,3H）。
embodiment 2: the preparation of 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-Tosylhydrazone-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-oxo-3,7-diazabicyclo [3,3,1] nonane is added in the there-necked flask of 100 milliliters 2(1.6 grams, 3.7 mmoles) and anhydrous methanol (25 milliliters), drip the methanol solution of p-toluene sulfonyl hydrazide (1.7 grams, 9.2 mmoles), under nitrogen protection stirring at room temperature 36 hours under zero degrees celsius.Reaction solution directly concentrates under 50 degree celsius temperature at 40 degrees Celsius, cross column purification with petrol ether/ethyl acetate (6/1) elutriant, obtain 0.8 gram of 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-Tosylhydrazone-3,7-diazabicyclo [3,3,1] nonane 5, be directly used in next step reaction, yield 36%.
HNMR(CDCl 3)d:7.80-7.71（m，2H），7.34-7.30（m，6H）,7.25-7.19（m，6H）,5.27-5.20（m，1H）,5.10-5.07（m，1H）,4.60-4.48（m，1H）,4.45-4.34（m，1H）,4.31-4.08（m，2H）,3.66-3.53（m，1H）,3.40-3.36（m，1H）,3.30-3.27（m，5H）,2.85-2.79（m，1H）,2.44-2.30（m，4H）,1.21（t， J=8.0Hz，3H）。
embodiment 3: the preparation of 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-Tosylhydrazone-3,7-diazabicyclo [3,3,1] nonane is added in the there-necked flask of 100 milliliters 3(0.8 gram; 1.32 mmoles), methyl alcohol (10 milliliters) and tetrahydrofuran (THF) (10 milliliters), add sodium cyanoborohydride (57 milligrams, 0.9 mmole) under zero degrees celsius; with 1 mole often liter dilute hydrochloric acid regulate the pH value about 4 of reaction system, stirring at room temperature 2 hours under nitrogen protection.Reaction solution is used water quenched dilution, ethyl acetate (3 × 20 milliliters) extracts, and organic phase is concentrated is dissolved in ethanol (30 milliliters), adds a hydrated sodium acetate (4.94 grams, 49.3 mmoles).Under nitrogen protection, continue 75 degrees Celsius of lower stirring reactions 2 hours.Reaction terminates rear cool to room temperature, dilute with water, ethyl acetate (3 × 25 milliliters) extracts, organic phase concentrates, cross column purification with petrol ether/ethyl acetate (8/1) elutriant, obtain 200 milligrams of 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclos [3,3,1] nonane i-a, yield 35.8%.
HNMR(CD 3OD)d:7.33-7.26（m，5H），7.24-7.14（m，5H）,5.20-5.10（m，2H）,4.37-4.07（m，4H）,3.34-3.19（m，4H）,3.12-3.01（m，4H）,2.24-2.16（m，1H）,1.99-1.83（m，2H）,1.19（t， J=8.0Hz，3H）。
embodiment 4: the preparation of 1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is added in the single port flask of one 50 milliliters i-a(100 milligrams, 0.24 mmole), lithium hydroxide (29 milligrams, 1.2 mmoles), methanol/water (3/1) (4 milliliters) mixed solvent, this reaction mixture under nitrogen protection 40 degrees Celsius stir 1.5 hours.Reaction terminates the dilution of rear use 10 ml water, regulates pH to 4 under zero degrees celsius with the dilute hydrochloric acid of 1 mole often liter, concentrated, crude product is separated through preparative high-performance liquid chromatographic and obtains 89 milligrams of 1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyls-3,7-diazabicyclo [3,3,1] nonane i-b, yield 96%.
HNMR(CD 3OD)d:7.51-7.49（m，5H），7.41-7.34（m，5H）,5.17（s,2H）,4.37-4.29（m，2H）,4.23-4.19（m，1H）,4.10-4.06（m，1H）,3.69-3.46（m，3H）,3.29-3.25（m，2H）,3.13-3.09（m，1H）,2.41（s,1H）,2.05（s,2H）。
embodiment 5: the preparation of 1-methylol-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is added in the single port flask of 50 milliliters i-a(40 milligrams, 0.22 mmole), DCM methylene dichloride (2 milliliters); drip diisobutyl aluminium hydride (250 milliliters, 0.5 mmole) under zero degrees celsius, stirring at room temperature is after 2 hours under nitrogen protection; add a small amount of water to stir until do not have bubble to occur; add after anhydrous magnesium sulfate stirs 10 minutes, solids removed by filtration, filtrate concentrates; thick product is separated through silica-gel plate and obtains 36 milligrams of 1-methylol-3-carbobenzoxy-(Cbz)-7-benzyls-3; 7-diazabicyclo [3,3,1] nonane i-c, yield 84%.
HNMR(CD 3OD)d:7.50-7.44（m，5H），7.40-7.32（m，5H）,5.16（s，2H），4.29（s，2H），4.08-4.05（m，2H）,3.54-3.48（m，2H）,3.33-3.30（m，2H）,3.20-3.17（m，1H）,3.11-3.04（m，2H）,2.87-2.83（m，1H）2.35（s，1H），1.68-1.54（m，2H）。
embodiment 6: the preparation of 1-formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is placed in the single port flasks of 10 milliliters i-b(30 milligrams; 0.07 mmole); HATU2-(7-azo benzotriazole)-N; N; N', N'-tetramethyl-urea phosphofluoric acid ester (32 milligrams, 0.08 mmole); triethylamine (16 milligrams; 0.15 mmole), ammonium chloride (4.5 milligrams, 0.08 mmole); anhydrous acetonitrile (2 milliliters) stirred overnight at room temperature under nitrogen protection; after reaction terminates, after removing acetonitrile, obtain product 1-formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3 through preparative high-performance liquid chromatographic separation and purification; 3,1] nonane i-d(20 milligrams), yield 69%.
HNMR(CD 3OD)d:7.51-7.45（m，5H），7.39-7.31（m，5H），5.18（s，2H），4.30（s，2H），4.21-4.05（m，2H），3.69-3.46（m，2H），3.24-3.09（m，4H），2.41（s，1H），2.09-1.90（m，2H）。
embodiment 7: the preparation of 1-(N-methyl) formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is placed in the single port flasks of 10 milliliters i-b(30 milligrams, 0.07 mmole), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (32 milligrams, 0.08 mmole), triethylamine (16 milligrams, 0.15 mmole), methylamine hydrochloride (5.6 milligrams, 0.08 mmole), anhydrous acetonitrile (2 milliliters) at N 2the lower stirred overnight at room temperature of protection, after reaction terminates, obtains product 1-(N-methyl through preparative high-performance liquid chromatographic separation and purification after removing acetonitrile) formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane i-e(24 milligrams), yield 77%.
HNMR(CD 3OD)d:7.49-7.44（m，5H），7.40-7.32（m，5H），5.18（s，2H），4.29（s，2H），4.22-4.05（m，2H），3.76-3.46（m，2H），3.21-3.05（m，4H），2.70(s,3H),2.41（s，1H），2.02-1.87（m，2H）。
embodiment 8: the preparation of 1-(N, N-dimethyl) formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is placed in the single port flasks of 10 milliliters i-b(30 milligrams; 0.07 mmole); 2-(7-azo benzotriazole)-N; N, N', N'-tetramethyl-urea phosphofluoric acid ester (32 milligrams; 0.08 mmole); triethylamine (16 milligrams, 0.15 mmole), dimethylamine hydrochloride (6.8 milligrams; 0.08 mmole); anhydrous acetonitrile (2 milliliters) stirred overnight at room temperature under nitrogen protection, after reaction terminates, obtain product 1-(N through preparative high-performance liquid chromatographic separation and purification after removing acetonitrile; N-dimethyl) formamido--3-carbobenzoxy-(Cbz)-7-benzyl-3; 7-diazabicyclo [3,3,1] nonane i-f(21 milligrams), yield 66%.
HNMR(CD 3OD)d:7.49-7.44（m，5H），7.40-7.32（m，5H）,5.18（s，2H），4.31（s，2H），4.22-4.05（m，2H）,3.99-3.95（m，2H）,3.21-3.05（m，4H）,2.99(s,6H),2.41（s，1H），2.17-2.12（m，2H）。
embodiment 9: the preparation of 1-ethoxycarbonyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is placed respectively in 10 milliliters of single port flasks i-a(50 milligrams, 0.1 mmole), wet palladium carbon (5 milligrams, mass percent 10%), methyl alcohol (5 milliliters), under a normal atmosphere hydrogen, stirring at room temperature is after 30 minutes, solids removed by filtration, after filtrate is concentrated, crude product is separated through preparative high-performance liquid chromatographic and obtains 1-ethoxycarbonyl-3,7-diazabicyclo [3,3,1] nonane iI-a(10 milligrams), yield 43%.
HNMR(CD 3OD)d:4.19-4.14（m，2H），3.54-3.51（m，2H）,3.40-3.36（m，4H）,3.20-3.16（m，2H），2.26（s，1H），2.10（s，2H），1.21（t， J=8.0Hz，3H）。
embodiment 10: the preparation of 1-ethoxycarbonyl-3-benzyl-3,7-diazabicyclo [3,3,1] nonane
Operation steps:
1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is placed respectively in 10 milliliters of single necked round bottom flask i-a(50 milligrams, 0.1 mmole), wet palladium carbon (5 milligrams, mass percent 10%), methyl alcohol (5 milliliters), after under a normal atmosphere hydrogen, zero degrees celsius stirs 30 minutes, solids removed by filtration, after filtrate is concentrated, crude product is separated through preparative high-performance liquid chromatographic and obtains 1-ethoxycarbonyl-7-benzyl-3,7-diazabicyclo [3,3,1] nonane iI-b(12 milligrams), yield 35%.
HNMR(CD 3OD)d:7.35-7.27（m，5H）,4.16-4.10（m，2H），3.59-3.55（m，3H）,3.46-3.32（m，2H），3.22-3.09（m，3H），2.54-2.51（m，1H），2.43-2.40（m，1H），2.21（s，1H），2.06-1.94（m，2H），1.22（t， J=8.0Hz，3H）。
In order to understand essence of the present invention better, here is compound i-ato the inhibiting the pharmacological results that tumor cell line A549 grows, its novelty teabag in pharmacy field is described.
embodiment 11:compound i-ato the cytotoxic activity of A549 cell
A549 cell RPMI1640 culture medium culturing, containing the foetal calf serum of 10% in substratum, the Streptomycin sulphate of 100U/ ml penicillin and 100U/ milliliter.Cell joins in 96 orifice plates with 2500, every hole cell, cultivates 24 hours in 37 degrees Celsius of incubators containing the damp atmosphere of volume percent 5% carbonic acid gas.
The mensuration MTS method of cell survival rate.Cell after 24 hours hatch, by the compound of newly joining i-adimethyl sulfoxide solution join in hole, concentration from 10 micromoles per liter, with the extent of dilution of three times be diluted to respectively 1.5 nmoles/liter, 9 concentration altogether.Cultivate 72 hours in 37 degree of incubators containing the damp atmosphere of volume percent 5% carbonic acid gas after, add 20 microlitre list solution 96 porocytes propagation detection kit (CellTiter96AquenousOneSolutionReagent), after continuing to cultivate 4 hours at 37 degrees Celsius again, formazan (formazan) surveying biochemistry light instrument (SpectraMax) colorimetric under 590 nmole wavelength formed, cell survival rate is by the ratio calculation of sample relative to reference substance.
Compound i-abe 1643 nmoles to 50% inhibition concentration of A549 cell.
Experiment conclusion: this experiment shows that the growth of this compounds to human lung cancer cell A549's cell has certain restraining effect, likely develops into the new medicine with antitumor action.

Claims (6)

1. one kind 1,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives, it is characterized in that: general structure is shown in following formula:
Formula 1
Wherein R 1be selected from H or benzyl; R 2be selected from H or carbobenzoxy-(Cbz); G is the one in ethoxycarbonyl, methylol or carboxyl.
2. according to claim 11,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives, is characterized in that: when G is ethoxycarbonyl, replaces-3 for the 1-ethoxycarbonyl-3-shown in formula II replaces-7-, 7-diazabicyclo [3,3,1] nonane derivatives:
R 1for H or benzyl; R 2for H or carbobenzoxy-(Cbz).
3. according to claim 11,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives, it is characterized in that, works as R 1for benzyl, R 2during for carbobenzoxy-(Cbz), described 1-replaces-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane derivatives and is:
I-a:1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane;
I-b:1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane;
I-c:1-methylol-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane.
4. according to claim 11,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives, is characterized in that, when G is ethoxycarbonyl, and described 1-ethoxycarbonyl-3,7-bis-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives:
II-a:1-ethoxycarbonyl-3,7-diazabicyclo [3,3,1] nonane;
II-b:1-ethoxycarbonyl-3-benzyl-3,7-diazabicyclo [3,3,1] nonane.
5. prepare the method that according to claim 11,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives for one kind, it is characterized in that: in formula 1, work as R 1for benzyl, R 2for carbobenzoxy-(Cbz), it is that 1-replaces-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane, preparation process: adopt compound that 1-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives 1for raw material, through twice Mannich reaction, obtain 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-carbonyl-3,7-diazabicyclo [3,3,1] nonane 2, compound 2with to Methyl benzenesulfonyl hydrazine reaction, obtain compound 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-9-Tosylhydrazone-3,7-diazabicyclo [3,3,1] nonane 3; Compound 3compound 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is generated under sodium cyanoborohydride and hydrochloric acid effect i-a; Then i-acompound 1-formic acid-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane is obtained respectively through hydrolysis and reduction i-bwith compound 1-methylol-3-carbobenzoxy-(Cbz)-7-benzyl-3,7-diazabicyclo [3,3,1] nonane i-c; Reaction formula is as follows:
。
6. prepare according to claim 11,3,7-tri-and replace-3 for one kind, the method of 7-diazabicyclo [3,3,1] nonane derivatives, it is characterized in that: in formula 1, G is ethoxycarbonyl, 1,3,7-tri-replaces-3,7-diazabicyclos [3,3,1] nonane derivatives is that 1-ethoxycarbonyl-3,7-bis-replaces-3,7-diazabicyclos [3,3,1] nonane, preparation process: adopt compound i-afor raw material, at room temperature obtain through catalytic hydrogenation iI-a,or obtain through catalytic hydrogenation under 0 degree Celsius iI-b;reaction formula is as follows:
。
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