CN111253368B - Stable nitroxide radical modified naphthalimide compound and application thereof - Google Patents
Stable nitroxide radical modified naphthalimide compound and application thereof Download PDFInfo
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- CN111253368B CN111253368B CN201811451923.3A CN201811451923A CN111253368B CN 111253368 B CN111253368 B CN 111253368B CN 201811451923 A CN201811451923 A CN 201811451923A CN 111253368 B CN111253368 B CN 111253368B
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- -1 nitroxide radical modified naphthalimide compound Chemical class 0.000 title claims abstract description 52
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 208000035269 cancer or benign tumor Diseases 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 abstract description 12
- 239000012453 solvate Substances 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000004677 hydrates Chemical class 0.000 abstract description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000007429 general method Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- QIXHMCMCFSNKOG-UHFFFAOYSA-N 6492-86-0 Chemical compound O=C1OC(=O)C2=CC=CC3=C2C1=CC=C3N QIXHMCMCFSNKOG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LKOZHLXUWUBRDK-UHFFFAOYSA-N 4-nitro-1,8-naphthalic anhydride Chemical compound O=C1OC(=O)C2=CC=CC3=C2C1=CC=C3[N+](=O)[O-] LKOZHLXUWUBRDK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000004565 tumor cell growth Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DTUOTSLAFJCQHN-UHFFFAOYSA-N 4-bromo-1,8-naphthalic anhydride Chemical compound O=C1OC(=O)C2=CC=CC3=C2C1=CC=C3Br DTUOTSLAFJCQHN-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JWUXJYZVKZKLTJ-UHFFFAOYSA-N Triacetonamine Chemical compound CC1(C)CC(=O)CC(C)(C)N1 JWUXJYZVKZKLTJ-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical group NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- ZJRBTFPRHIXQKX-UHFFFAOYSA-N 1,2,3,4-tetramethyltetrazolidine Chemical compound CN1N(N(N(C1)C)C)C ZJRBTFPRHIXQKX-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LCSNESAHHGTVLP-UHFFFAOYSA-N 2-(2,2,6,6-tetramethylpiperidin-4-yl)ethanamine Chemical compound CC1(C)CC(CCN)CC(C)(C)N1 LCSNESAHHGTVLP-UHFFFAOYSA-N 0.000 description 1
- 239000012625 DNA intercalator Substances 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910020350 Na2WO4 Inorganic materials 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000003916 ethylene diamine group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000013630 prepared media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Substances [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to stable nitroxide free radical modified naphthalimide compounds and application thereof, in particular to stable nitroxide free radical modified naphthalimide compounds and application thereof in preparation of antitumor drugs. The invention introduces stable nitroxide free radicals into a naphthalimide parent structure to obtain naphthalimide compounds with general formula I or II and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein R is1，R2，R3，R4As described in the claims and specification.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to stable nitroxide free radical modified naphthalimide compounds and application thereof, in particular to stable nitroxide free radical modified naphthalimide compounds and application thereof in preparation of antitumor drugs.
Background
The naphthalimide compound is excellent in antitumor effect as a DNA intercalator. However, the development and development of the compounds also face serious challenges, and the naphthalimide compounds researched and developed at present generally face the problem of large toxic and side effects, and the medicinal effect of some compounds in human bodies is not good enough. Therefore, the development of the micromolecular naphthalimide compound with high efficiency, low toxicity and novel structure has important significance.
The invention introduces stable nitroxide free radicals into the naphthalimide parent body for the first time to obtain naphthalimide compounds with novel structures, which not only have good antitumor activity, but also show lower toxicity to normal cells, and have good application value and development prospect.
Disclosure of Invention
The invention aims to develop an antitumor naphthalimide compound with certain selectivity on tumor cells, and compared with the naphthalimide compound in the prior art, the compound can reduce the toxicity on normal cells on the basis of keeping higher antitumor activity.
The scheme adopted by the invention for solving the technical problems is as follows: naphthalimide compounds of general formula I or II obtained by introducing stable nitroxide free radicals into a naphthalimide parent structure, and pharmaceutically acceptable salts, solvates and hydrates thereof:
wherein,
in the general formula I, the compound is shown in the specification,
R1is H, C1-C4Alkyl radical, C1-C4An alkoxy group;
R2is composed of
May be mono-substituted at the 5-or 6-position, and di-substituted at the 5-and 8-or 6-and 7-positions of the naphthalimide;
R3is a stable nitroxide radical; including, but not limited to, 2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
n is an integer of 1 to 4;
in the general formula II, the compound of formula II,
R3examples of stable nitroxide radicals include, but are not limited to, 2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
R4can be independently selected from nitro, amino and substituted amino, and the substituent is C1-C5Alkyl radical, C6-C10Aryl, hydroxy (C)1-C4) Alkyl, aryl, heteroaryl, and heteroaryl,C3-C6Cycloalkyl, 5-to 10-membered heterocyclic group,
Can be singly substituted at 5 or 6 positions of naphthalimide and can be doubly substituted at 5 and 8 positions or 6 and 7 positions
R1Is H, C1-C4Alkyl radical, C1-C4An alkoxy group;
n is an integer of 1 to 4;
the invention preferably selects the naphthalimide compound with the general formula I or II and the pharmaceutically acceptable salt, solvate and hydrate thereof:
wherein,
in the general formula I, the compound is shown in the specification,
R1is H, C1-C4Alkyl radical, C1-C4An alkoxy group;
R2is composed of
R3Examples of stable nitroxide radicals include, but are not limited to, 2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
n is an integer of 1 to 4;
in the general formula II, the compound of formula II,
R3examples of stable nitroxide radicals include, but are not limited to, 2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
R4can be independently selected from nitro, amino and substituted amino, and the substituent is C1-C5Alkyl radical, C6-C10Aryl, hydroxy (C)1-C4) Alkyl radical, C3-C6Cycloalkyl, 5-to 10-membered heterocyclic group,
R1Is H, C1-C4Alkyl radical, C1-C4An alkoxy group;
n is an integer of 1 to 4;
the invention preferably selects the naphthalimide compound with the general formula I or II and the pharmaceutically acceptable salt, solvate and hydrate thereof:
wherein,
in the general formula I, the compound is shown in the specification,
R1is C1-C4An alkyl group;
R2is composed of
R3Examples of stable nitroxide radicals include, but are not limited to, 2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
n is an integer of 1 to 4;
in the general formula II, the compound of formula II,
R3examples of stable nitroxide radicals include, but are not limited to, 2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
R4can be independently selected from nitro, amino and substituted amino, and the substituent is C1-C5Alkyl radical, C6-C10Aryl, hydroxy (C)1-C4) Alkyl radical, C3-C6Cycloalkyl, 5-to 10-membered heterocyclic group,
R1Is C1-C4An alkyl group;
n is an integer of 1 to 4;
the invention preferably selects the naphthalimide compound with the general formula I or II and the pharmaceutically acceptable salt, solvate and hydrate thereof:
wherein,
in the general formula I, the compound is shown in the specification,
R1is methyl or ethyl;
R2is composed of
R3Is 2,2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole;
n is an integer of 1 to 4;
in the general formula II, the compound of formula II,
R3is 2,2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole;
R4can be independently selected from nitro, amino and substituted amino, and the substituent is C1-C5Alkyl radical, C6-C10Aryl, hydroxy (C)1-C4) Alkyl radical, C3-C6Cycloalkyl, 5-to 10-membered heterocyclic group,
R1Is methyl or ethyl;
n is an integer of 1 to 4.
The invention also provides a pharmaceutical composition, which comprises the naphthalimide compound shown in the general formula I or II, and pharmaceutically acceptable salts, solvates and hydrates thereof, and a pharmaceutically acceptable carrier.
The invention further provides the naphthalimide compound with the general formula I or II and the application of the pharmaceutically acceptable salt, solvate and hydrate thereof in preparing antitumor drugs.
The invention also provides application of a pharmaceutical composition containing the naphthalimide compound shown in the general formula I or II and pharmaceutically acceptable salts, solvates and hydrates thereof in preparing antitumor drugs.
The tumor is cervical cancer, lung cancer, breast cancer, liver cancer and the like.
The synthetic route of the naphthalimide compound containing the stable nitroxide radical is as follows:
r is C1-C5Alkyl radical, C6-C10Aryl, hydroxy (C)1-C4) Alkyl radical, C3-C6Cycloalkyl, 5-to 10-membered heterocyclic group,
R1、R3N are as described in the claims and specification.
Detailed Description
The present invention is described in detail by the following examples. It should be understood, however, that the present invention is not limited to the following examples which are specifically set forth.
Synthesis of 4-amino-1, 8-naphthalic anhydride
2.00g of the compound 4-nitro-1, 8-naphthalic anhydride is placed in a 100mL eggplant-shaped bottle, 100mL of THF is added, after stirring and dissolving, 0.20g of 5% Pd-C is added, and catalytic hydrogenation reaction is carried out for one day at normal temperature and pressure. Pd-C is recovered by suction filtration, and the filtrate is decompressed and evaporated to remove the solvent, so as to obtain 1.50g of orange solid with the yield of 83.4 percent. m.p.:>300℃；MS(ESI)m/z:214.1[M+H]+。
synthesis of 2,2,6, 6-tetramethyl-1-oxo-4-piperidone
10.50g (68mmol)2,2,6, 6-tetramethyl-4-piperidone, 0.15g (0.4mmol) Na2WO4And 0.15g (0.5mmol) of EDTA in a 250mL round-bottom flask, 150mL of anhydrous methanol was added, and 16.5mLH was slowly added dropwise with stirring2O2The solution was added and reacted at room temperature for 24 h. The methanol was evaporated under reduced pressure and extracted 3 times with ether. Mixing the extractive solutions, and adding anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating by column chromatography [ v (petroleum ether): v (ethyl acetate): 8:1]7.39g of yellow needle-shaped solid is obtained, the yield is 64.3 percent, and m.p. is 32-34℃。
Synthesis of 2,2,6, 6-tetramethyl-4- (2-aminoethylamino) -1-oxypiperidine
General synthesis method 1: a100 mL round-bottom flask was charged with 3.40g (20.0mmol) of the compound 2,2,6, 6-tetramethyl-1-oxo-4-piperidone nitroxide radical, 30mL of anhydrous methanol, and 6.01g (10.0mmol) of ethylenediamine, and the pH was adjusted to 6 with 10% hydrochloric acid. 0.84g (13.4mmol) NaBH was added with stirring3CN, nitrogen protection and reaction for 48h at room temperature. The solvent was evaporated under reduced pressure and the pH adjusted to 11, CH with solid NaOH2Cl2Extracting, and using anhydrous Na for an organic layer2SO4And (5) drying. Separating by column chromatography [ V (chloroform): V (methanol) ═ 20: 1%]1.80g of red oil was obtained, and the yield was 42.0%. EPR, G is 2.00524, Δ H is 28.49G; HRMS m/z calcd for [ C ]11H25N3O]+([M+H]+)215.2006,found:215.1998；MS(ESI)m/z:215.1[M+H]+。
Synthesis of 2,2,6, 6-tetramethyl-4- (3-aminopropylamino) -1-oxopiperidine
Synthesized according to general method 1, ethylenediamine was replaced with 1, 3-propanediamine to give a red oil with a yield of 40.0%. EPR, g is 2.00525, Δ H is 28.54; HRMS m/z calcd for [ C ]12H27N3O]+([M+H]+):229.2161,found:229.2154；MS(ESI)m/z:229.1[M+H]+。
Synthesis of 2,2,6, 6-tetramethyl-4- (4-aminobutylamino) -1-oxopiperidine
Synthesized according to general method 1, ethylenediamine was changed to 1, 4-butanediamine to obtain red oil with a yield of 40.0%. EPR, G is 2.00524, Delta H is 28.57G; HRMS m/z calcd for [ C ]13H29N3O]+([M+H]+)243.2317,found:243.2311；MS(ESI)m/z:243.2[M+H]+。
Synthesis of 2- (N, N-dimethylethylamino) -6-bromo-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione
5.54g (20mmol) of 4-bromo-1, 8-naphthalic anhydride, 2mL (21mmol) of N, N-dimethylethylenediamine and 30mL of anhydrous ethanol are sequentially added into a 100mL round-bottom flask, heated and refluxed for 2h, TLC is used for tracking till the reaction is complete, the mixture is poured into water after the reaction is cooled, filtered by suction, dried,6.30g of pale yellow solid is obtained with a yield of 91.9%. m.p.:>300℃；1H-NMR(400MHz,d6-DMSO):8.57(t,J＝8.3Hz,2H),8.35(d,J＝7.9Hz,1H),8.23(d,J＝7.8Hz,1H),8.01(t,J＝7.8Hz,1H),4.15(t,J＝6.6Hz,2H),3.32(s,2H),2.21(s,6H)；MS(ESI)m/z:347.9[M+H]+。
synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminoethyl) -6-bromo-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione
General synthesis method 2: placing 0.55g (2mmol) of 4-bromo-1, 8-naphthalic anhydride into a 50mL round-bottom flask, adding 0.64g (3mmol) of compound 2,2,6, 6-tetramethyl-4-aminoethyl piperidine nitroxide radical, adding 30mL of anhydrous methanol, heating and refluxing for 2h, tracking by TLC until the reaction is complete, evaporating the solvent under reduced pressure, and separating by column chromatography [ v (ethyl acetate): v (petroleum ether): 1]Obtaining light yellow solid 0.75g with 79.4% yield, m.p.: 126-. EPR, G is 2.00524, Δ H is 10.94G; HRMS m/z calcd for [ C ]23H28BrN3O3]+([M+H]+)473.1350,found:475.1330；MS(ESI)m/z:473.0[M+H]+。
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminopropyl) -6-bromo-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione
Synthesized according to the general method 2 to obtain a light yellow solid with the yield of 79.8 percent, m.p. of 148-149 ℃. EPR, G is 2.00524, Delta H is 8.85G; HRMS m/z calcd for [ C ]24H30BrN3O3]+([M+H]+)487.1532,found:489.1518；MS(ESI)m/z:487.0[M+H]+。
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminobutyl) -6-bromo-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione
Synthesized according to the general method 2 to obtain a light yellow solid with the yield of 80.5 percent, m.p. 171-172 ℃. EPR, G is 2.00524, Δ H is 10.91G; HRMS m/z calcd for [ C ]25H32BrN3O3]+([M+H]+)501.1628，found:503.1615；MS(ESI)m/z:501.1[M+H]+。
Example 1
Synthesis of 2- (N, N-dimethylaminoethyl) -6- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminoethylamino) -1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (I-a)
General synthesis method 3: 0.73g (2mmol) of the compound 2- (N, N-dimethylethylamino) -6-bromo-1H-benzo [ de ]]Isoquinoline-1, 3-dihydrodione was put in a 50mL eggplant type bottle, and 0.43g (2mmol) of 2,2,6, 6-tetramethyl-4- (2-aminoethylamino) -1-oxopiperidine and 0.28g of potassium carbonate (2mmol) were added thereto, followed by addition of 10mL of N, N-dimethylformamide and reaction at 120 ℃ for 7 hours. After most of the solvent was distilled off under reduced pressure, 100mL of water was added and extracted with dichloromethane until colorless. Drying, concentrating, and separating by column chromatography [ v (chloroform): v (methanol): 20:1]0.75g of red oil was obtained, and the yield was 78.3%. EPR, G is 2.00524, Δ H is 21.86G; HRMS m/z calcd for [ C ]27H38N5O3]+480.2991,found:480.2975；MS(ESI)m/z:481.3[M+H]+。
Example 2
Synthesis of 2- (N, N-dimethylaminoethyl) -6- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminopropylamino) -1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (I-b)
The red oil was obtained in 77.4% yield according to general method 3. EPR, G is 2.00472, Δ H is 6.14G, An is 14.79G; HRMS m/z calcd for [ C ]28H40N5O3]+494.3115,found:494.3131；MS(ESI)m/z:495.3[M+H]+。
Example 3
Synthesis of 2- (N, N-dimethylaminoethyl) -6- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminobutylamino) -1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (I-c)
The red oil was obtained in 79.8% yield according to general method 3. EPR, G is 2.00487, Δ H is 6.75G, An is 14.52G; HRMS m/z calcd for [ C ]29H43N5O3]+([M+H]+)found:509.3400；MS(ESI)m/z:509.3[M+H]+。
Example 4
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminoethyl) -6- (N, N-dimethylaminoethylamino) -1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-a)
General synthesis method 4: 0.47g (1mmol) of 2- (2,2,6, 6-tetramethyl-1-oxopiperidin-4-aminoethyl) -6-bromo-1H-benzo [ de ]]Isoquinoline-1, 3-dihydrodione was placed in a 50mL round-bottomed flask, and 0.44g (5mmol) of N, N-dimethylethylenediamine and 0.14g of potassium carbonate (1mmol) were added thereto, followed by addition of 10mL of N, N-dimethylformamide and reaction at 120 ℃ for 7 hours. After most of the solvent was distilled off under reduced pressure, 100mL of water was added and extracted with dichloromethane until colorless. Separating by column chromatography [ v (ethyl acetate): v (methanol) ═ 5:1]0.24g of red oil was obtained, and the yield was 50.2%. EPR, G is 2.00457, Δ H is 6.43G, An is 14.62G; HRMS m/z calcd for [ C ]27H38N5O3]+480.2982,found:480.2875；MS(ESI)m/z:481.3[M+H]+。
Example 5
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminopropyl) -6- (N, N-dimethylaminoethylamino) -1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-b)
Synthesized according to general method 4 to obtain a red oil with a yield of 49.8%. EPR, G is 2.00451, Delta H is 5.63G, An is 15.62G; HRMS m/z calcd for [ C ]28H40N5O3]+494.3145,found:494.3131；MS(ESI)m/z:495.3[M+H]+。
Example 6
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminobutyl) -6- (N, N-dimethylaminoethylamino) -1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-c)
Synthesized according to general method 4 to obtain a red oil with a yield of 51.3%. EPR, G is 2.00456, Delta H is 4.88G, An is 15.80G; HRMS m/z calcd for [ C ]29H43N5O3]+([M+H]+)found:509.3438；MS(ESI)m/z:509.3[M+H]+。
Example 7
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminoethyl) -5-nitro-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-d)
General synthesis method 5: taking 0.12g (0.5mmol) of the compound 3-nitro-1, 8-naphthalic anhydride and 0.16g (0.75mmol) of the compound 2,2,6, 6-tetramethyl-4-aminoethyl piperidine nitroxideThe mixture was placed in a 50mL eggplant-shaped flask, 20mL of absolute ethanol was added thereto, and the mixture was refluxed for 2 hours, and then the solvent was distilled off under pressure. Separating by column chromatography to obtain [ v (ethyl acetate): v (petroleum ether): 2:1]0.18g of brown yellow solid is obtained, the yield is 83.0 percent, and m.p. is 140-141 ℃. EPR, G is 2.00638, Delta H is 8.22G; HRMS m/z [ C23H28N4O5]+([M+H]+)found:440.2069；MS(ESI)m/z:440.0[M+H]+。
Example 8
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxopiperidin-4-aminopropyl) -5-nitro-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-e)
According to the general method 5, a brown yellow solid is obtained, the yield is 84.5%, and the m.p. is 162-. EPR, G is 2.00637, Delta H is 15.06G; HRMS m/z calcd for [ C ]24H29N4O5]+453.2145,found:453.2138；MS(ESI)m/z:454.1[M+H]+。
Example 9
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminobutyl) -5-nitro-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-f)
The brown yellow solid was obtained according to general method 5 with a yield of 86.7%, m.p. 184-. EPR, G is 2.00638, Delta H is 15.52G; HRMS m/z calcd for [ C ]25H31N4O5]+467.2288,found:467.2294；MS(ESI)m/z＝468.2[M+H]+。
Example 10
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminoethyl) -6-nitro-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-g)
The raw material is changed into 4-nitro-1, 8-naphthalic anhydride, and orange yellow solid is obtained according to the general method 5, the yield is 74.3 percent, and the m.p. is 155-.
EPR:g＝2.00638,ΔH＝13.45G；HRMS m/z:[C23H28N4O5]+([M+H]+)found:440.2055；MS(ESI)m/z:440.2[M+H]+。
Example 11
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxopiperidin-4-aminopropyl) -6-nitro-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-H)
The raw material is changed into 4-nitro-1, 8-naphthalic anhydride, and orange yellow solid is obtained according to the general method 5, the yield is 76.7 percent, and the m.p. is 177-.
EPR:g＝2.00638,ΔH＝15.77G；HRMS m/z:[C24H30N4O5]+([M+H]+)found:454.2228；MS(ESI)m/z:454.2[M+H]+。
Example 12
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminobutyl) -6-nitro-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-i)
The raw material is changed into 4-nitro-1, 8-naphthalic anhydride, and orange yellow solid is obtained according to the general method 5, the yield is 78.5 percent, and the m.p. is 201-.
EPR:g＝2.00637,ΔH＝11.85G；HRMS m/z:[C25H32N4O5]+([M+H]+)found:468.2654；MS(ESI)m/z:468.2[M+H]+。
Example 13
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminoethyl) -6-amino-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-j)
The raw material is changed into 4-amino-1, 8-naphthalic anhydride, and orange yellow solid is obtained according to the general method 5, the yield is 70.3 percent, and the m.p. is 186-.
EPR:g＝2.00624,ΔH＝22.85G；HRMS m/z:[C23H30N4O3]+([M+H]+)found:410.2329；MS(ESI)m/z:410.2[M+H]+。
Example 14
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxopiperidin-4-aminopropyl) -6-amino-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-k)
The raw material is changed into 4-amino-1, 8-naphthalic anhydride, and orange yellow solid is obtained according to the general method 5, the yield is 72.7 percent, and the m.p. is 209-.
EPR:g＝2.00638,ΔH＝13.21G；HRMS m/z:[C24H32N4O3]+([M+H]+)found:424.2492；MS(ESI)m/z:424.2[M+H]+。
Example 15
Synthesis of 2- (2,2,6, 6-tetramethyl-1-oxypiperidine-4-aminobutyl) -6-amino-1H-benzo [ de ] isoquinoline-1, 3-dihydrodione (II-l)
The raw material is changed into 4-amino-1, 8-naphthalic anhydride, and orange yellow solid is obtained according to the general method 5, the yield is 74.1 percent, and the m.p. is 231 ℃ and 232 ℃.
EPR:g＝2.00637,ΔH＝16.85G；HRMS m/z:[C25H34N4O3]+([M+H]+)found:438.2663；MS(ESI)m/z:438.3[M+H]+。
Table 1 list of compounds of the examples
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Example 16
In vitro tumor cell growth inhibition activity assay
The in vitro tumor cell growth inhibition activity assay is carried out on human cervical cancer cells HeLa, human lung cancer cells A549 and human breast cancer cells MCF-7 by using a tetramethyltetrazole (MTT) reduction method.
The method comprises the following specific operation steps: selecting A549, MCF-7 and HeLa cells in logarithmic growth phase, digesting with pancreatin, and preparing into 8 × 10 with culture medium containing 10% calf serum4The cell suspension/mL, seeded in 96-well plates at 100. mu.L/well, 37 ℃ 5% CO2And culturing for 24 h. The experimental group was added with 10. mu.L of culture medium containing samples to be tested at different concentrations, the control group was added with culture medium of equal volume of solvent, each group was provided with 3 parallel wells, 37 ℃, 5% CO2And culturing for 24 h. The supernatant was discarded, carefully washed 2 times with PBS, 100. mu.L of freshly prepared medium containing 0.5mg/mL MTT was added to each well, and incubation continued for 3-4h at 37 ℃. The supernatant was carefully discarded, 150. mu.L of DMSO was added, and after mixing for 10min with a micro-shaker, the optical density was measured at 492nm using a microplate reader.
The inhibition rate of the drug on the growth of tumor cells was calculated according to the following formula:
tumor cell growth inhibition (%) was [ a492 (negative control) -a 492 (plus drug group) ]/[ a492 (negative control) -a 492 (plate bottom) ] × 100%
From this, the half Inhibitory Concentration (IC) of the sample was determined50)。
TABLE 2 IC of Compounds on tumor cells50Value of
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Claims (8)
1. Naphthalimides of the general formula I or II:
wherein,
in the general formula I, the compound is shown in the specification,
R1is H, C1-C4An alkyl group;
R2is-NH-R3Or
R3Is 2,2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
n is an integer of 1 to 4;
in the general formula II, the compound of formula II,
R3is 2,2,6, 6-tetramethyl-1-oxypiperidine, 2,5, 5-tetramethyl-1-oxytetrahydropyrrole, 2,5, 5-tetramethyl-1-oxy-2, 5-dihydropyrrole;
R4can be independently selected from nitro, amino and substituted amino, and the substituent is C1-C5Alkyl, hydroxy (C)1-C4) Alkyl, aryl, heteroaryl, and heteroaryl,
R1Is H, C1-C4An alkyl group;
n is an integer of 1 to 4.
2. The naphthalimide compound of the general formula I or II according to claim 1, wherein,
R2is composed of
Mono-substituted in the 5-or 6-position of the naphthalimide.
3. The naphthalimide compound of the general formula I or II and the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein,
R4mono-substituted in the 5-or 6-position of the naphthalimide.
4. The naphthalimide compound and the pharmaceutically acceptable salt thereof,
5. a pharmaceutical composition comprising a naphthalimide compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts thereof.
6. A process for the preparation of the naphthalimide compounds of general formula I or II and the pharmaceutically acceptable salts thereof according to claim 1,
wherein R is1，R3N is as defined in claim 1, R is
7. Use of the naphthalimide compound and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 for the preparation of an antitumor medicament.
8. The use of claim 7, wherein the neoplasm is cervical cancer, lung cancer, breast cancer.
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| CN101479247A (en) * | 2006-05-05 | 2009-07-08 | 尤尼拜欧斯克林股份公司 | 5-urea substituted naphthalimide derivatives, methods of production and pharmaceutical compositions for treating cancer |
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| CN101479247A (en) * | 2006-05-05 | 2009-07-08 | 尤尼拜欧斯克林股份公司 | 5-urea substituted naphthalimide derivatives, methods of production and pharmaceutical compositions for treating cancer |
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