CN102627614A - Diquinazoline diselenide compound as well as preparation method and bioactivity thereof - Google Patents
Diquinazoline diselenide compound as well as preparation method and bioactivity thereof Download PDFInfo
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Abstract
The invention discloses an anti-tumor drug-diquinazoline diselenide compound as well as a preparation method and bioactivity thereof, which are the compound represented by the following general formula and the preparation method thereof. In the general formula, R1, R2, R3, R4 and R5 are as defined in the specification. The invention introduces the anti-tumor drug-diquinazoline diselenide compound prepared by the steps of with 4-chlorinated quinazoline and sodium diselenide or potassium diselenide or lithium diselenide as raw materials and water, ethanol, isopropanol, absolute ethanol, N,N-dimethyl formamide, dioxane, dimethyl sulfoxide or a mixture thereof as a solvent, reacting and synthesizing. The compounds a, h have proliferation inhibition effects on breast cancer cells MDA-MB-435 and have good anti-cancer activity.
Description
Technical field
The invention belongs to organoselenium nitrogen heterocyclic ring quinazoline ditosylate salt medicine, is antitumor drug two quinazoline diselenide compounds and preparation method thereof and biological activity specifically.
Background technology
A large amount of in recent years research datas show that quinazoline compounds shows good biological activity, and are particularly particularly outstanding aspect inhibition EGF acceptor and Tyrosylprotein kinase phosphorylation thereof.Reports such as a large amount of documents, patent, paper are arranged every year.Aspect medical, like commercial Iressa (ZD1839), Tarceva (OSI-774), PD153035, PD169414 etc. EGFR is produced restraining effect, and then show antitumour activity, also have antimalarial, antitumor and HIV-resistant activity.The quinazoline ditosylate salt micromolecular compound can combine with EGFR by highly selective, and is strong tyrosine kinase inhibitor of imitating, and this type of clinical studies show medicine can make cell rest on G
1Phase.Agricultural chemicals aspect, particularly quinazoline oximinoether have the activity of resisting tobacco mosaic virus (TMV), cucumber mosaic virus (CMV) and other phytopathogen.Quinazoline compounds has wide biological activity like this, has caused the very big interest of medical research personnel and chemist.In order to seek the action site of quinazoline compounds, (Lim, J. K. such as Lim; Negash, K.; Hanraham, S. M.; VanBrocklin, H. F. Journal of Labeled Compounds and Radiopharmaceuticals, 2000,43, be lead compound 1183-1191) with PD 153035, synthesized two band [I with two kinds of diverse ways
125] radiolabeled quinazoline compound, its purity of HPLC mensuration with band spectrophotometer detector records the IC of target compound to EGFR-TK
50Be respectively 0.025 and 0.006 nmol/L, its activity that suppresses EGFR is superior to PD 153035; And measured its radioactivity, through the radioactivity tracking and measuring, found action site.(Lee, J. Y. such as Lee in 2002; Park, Y. K.; Seo, S. H.; Yang, B. S.; Park, H.; Lee; Y. S. Arch. Pharm. Pharm.Med. Chem. 2002,335 (10), 487-494.) reported one type of EGF receptor tyrosine kinase acceptor suppressor factor---7-replaces-[1; 4] dioxane [2; 3-g] quinazoline compounds, show that through bioassay its activity is superior to or near the activity of PD 153035 to A431 cell, HCT116 cell, SUN638 cell EGF receptor tyrosine kinase.(Ballard P such as Ballard in 2006; Bradbury R H, Harris C S, et al. Bioorg. Med. Chem. Lett.; 2006; 16 (6), 1633 – 1637) design has been synthesized one type the EGFR tool has been suppressed active novel 4-aryl amine quinazoline compound, the IC of part target compound
50Below 2 nmol/L.(Wissner A such as Wissner in 2007; Fraser H L, Ingalls C L, et al. Bioorg. Med. Chem.; 2007; 15 (11), 3635 – 3648) reported that one type of novel 4-quinone amine quinazoline compound shows good inhibition effect to EGFR, the IC of part target compound
50Can reach 2.6 nmol/L.(Gong G, Xie Y, Liu Y such as Gong; Et al. Bioorg. Med. Chem. Lett.; 2009,19 (4), 1191 – 1194) reported one type of 2-thiophene replacement-4-diazanyl substituted quinazoline compounds; Active different with the quinazoline compounds ability block N F-κ B conduction of finding in the past, this compounds can promote that the conduction of NF-κ B is active.
Selenium is the necessary trace element of human body, is the constituent of plurality of enzymes, in human body, plays and resists disease, delays senility, the enhancing body immunologic function, thereby reach the effect of equilibrator internal milieu.Selenium has biological function widely; It is the important component part of red corpuscle Selenoperoxidase; Can participate in the synthetic of coenzyme A and ubiquinone; Be the protective material of opposing toxic substance in the body, can promote lymphocyte to produce antibody, still a kind of inductor can impel the early stage disorderly generegulation normalizing of canceration.Since the seventies in last century, scientist found that selenium has antitumor action; Thereafter research confirms that selenium is strong suppressor factor (Wei W Q, Abnet C C, the Qiao Y L of mammary cancer, liver cancer, skin carcinoma, colorectal carcinoma and cancer of the stomach etc.; Et al. Am. J. Clin. Nutr.; 2004,79 (1), 80-85; Kellen E, Zeegers M, Buntinx F. Int. J. Urol., 2006,13 (9), 11802-11804; Wu X-W, Yu Z-K. Tetrahedron Lett., 2010,51 (11), 1500-1503).Selenium compound produces antitumous effect through the many target spots of number of mechanisms, and organoselenium is compared with inorganic selenium, has characteristics such as bioavailability height, biological activity is strong, toxicity is low, environmental pollution is little.Synthetic organoselenium compounds in recent years, as selenizing chitosan, the small molecules that contains selenium such as seleno-protein, selenium polysaccharide, selenizing methionine(Met), selenocarrageenan, selenizing tea-polyphenol or biomacromolecule compound aspect the biological activitys such as antitumor, treatment cardiovascular disorder, anti-ageing and enhance immunity power apparently higher than respective compound without selenizing.The representative drugs of at present carrying out clinical study is as as anti-inflammatory, anti-oxidation medicine ebselen woods (Ebselen) (Schewe T. Gen. Pharmacol-Vasc. S., 1995,26 (6), 1153-1169; Azad G K, Balkrishna S J, Sathish N, et al. Biochem. Pharmacol.; 2012,83 (2), 296-303) with highly efficient anti-virus, antitumor drug Selenofurin (selenazofurin) (Franchetti P, Cappellacci L; Grifantini M, et al. Inosine Monophosphate Dehydrogenase, Chapter 11, pp 212 – 230; ACS Symposium Series, Vol. 839,2003-03-03.; Sidwell R W, Huffman J H, Call E W, et al. Anti. Res., 1986,6 (6), 343-353).Utilize selenium unique chemical and biological property to develop the concern that new medicine more and more causes scientists; The organic selenium compounds that synthesis of biologically active height and toxicity are low still is big focus (Ninomiya M, Garud D R, a Koketsu M of present drug research; Et al. Coordin. Chem. Rev.; 2011,255 (23-24), 2968-2990; Plano D, Ib á ez E, Palop J A, et al. Struct. Chem., 2011,22 (6), 1233-1240; Terazawa R, Garud D R, Hamada N, et al. Bioorg. Med. Chem., 2010,18 (19), 7001-7008; Bijian K, Zhang Z-W, Xu B, et al. Eur. J. Med. Chem., 2012,48,143-152).
In sum, along with the synthetic discovery that reaches the novel drugs action target spot of the design of organo-metallic anticancer compound, has the original new drug based theoretical of independent intellectual property right for the Pharmaceutical Chemist exploitation; Along with going deep into of the research of quinazoline compounds in recent years, designed and synthesized out a plurality of serial novel quinazoline quinoline compounds, wherein be no lack of and show good EGFR and suppress active, the value of further further investigation is arranged.Based on the polytropy of 4-bit substituent on the quinazoline ring and multimachine system, the multiple target-point anti-cancer effect of selenium-containing compound, synthesized one type of two quinazoline diselenide class new compound, the innovation cancer therapy drug that development has independent intellectual property right.
Summary of the invention
A kind of anti-tumor drug that is used for is characterized in that this medicine is two quinazoline diselenide compounds, by the compound of following general formula (I) expression:
（I）
Wherein,
R
1, R
2, R
3, R
4And R
5Each is hydrogen, halogen atom, C1-6 alkyl, C1-6 alkoxyl group naturally; But do not comprise R
1, R
2, R
3, R
4And R
5All be hydrogen.
R in the above-described a kind of anti-tumor drug that is used for, the general formula of its compound (I)
1, R
4And R
5Be hydrogen, R
2And R
3Be selected from C1-6 alkyl, C1-6 alkoxyl group.
In the content of the present invention, the C1-6 alkyl can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, uncle's hexyl, new hexyl.
In the content of the present invention, the C1-6 alkoxyl group can be methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, uncle's pentyloxy, neopentyl oxygen.
R in the above-described a kind of anti-tumor drug that is used for, the general formula of its compound (I)
1, R
3And R
5Be hydrogen, R
2And R
4Be selected from halogen atom.
In the content of the present invention, halogen atom can be fluorine, chlorine, bromine, iodine atom.
R in the above-described a kind of anti-tumor drug that is used for, the general formula of its compound (I)
5Be methyl, R
1, R
2, R
3And R
4Be selected from halogen atom, C1-6 alkyl, C1-6 alkoxyl group; R particularly
1And R
4Be hydrogen, R
2And R
3Be selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, uncle's pentyloxy, neopentyl oxygen.
Above-described a kind of anti-tumor drug that is used for is characterized in that the compound of partial synthesis is following:
A. 1,2-two (6,7-dimethoxyquinazoline-4-yl) diselenide,
B. 1,2-two (6,7-diethoxy quinazoline-4-yl) diselenide,
C. 1,2-two (2-methyl-6,7-dimethoxyquinazoline-4-yl) diselenide,
D. 1,2-two (2-methyl-6,7-diethoxy quinazoline-4-yl) diselenide,
E. 1,2-two (2-chloro-6,7-dimethoxyquinazoline-4-yl) diselenide,
F. 1,2-two (2-chloro-6,7-diethoxy quinazoline-4-yl) diselenide,
G. 1,2-two (6-chloro-quinazoline-4-yl) diselenide,
H. 1,2-two (6,8-two chloro-quinazolines-4-yl) diselenide,
I. 1,2-two (2-methyl-6-chloro-quinazoline-4-yl) diselenide,
J. 1,2-two (2-methyl-6,8-two chloro-quinazolines-4-yl) diselenide,
K. 1,2-two (2-chloro-6-chloro-quinazoline-4-yl) diselenide,
L. 1,2-two (2-chloro-6,8-two chloro-quinazolines-4-yl) diselenide,
M. 1,2-two (6-bromine quinazoline-4-yl) diselenide,
N. 1,2-two (6,8-dibromo quinazoline-4-yl) diselenide,
O. 1,2-two (2-methyl-6-bromine quinazoline-4-yl) diselenide,
P. 1,2-two (2-methyl-6,8-dibromo quinazoline-4-yl) diselenide,
Q. 1,2-two (2-chloro-6-bromine quinazoline-4-yl) diselenide,
R. 1,2-two (2-chloro-6,8-dibromo quinazoline-4-yl) diselenide.
Above-described a kind of preparing anti-tumor medicine method that is used for is characterized in that with 4-chloro quinazoline, two sodium selenides or two potassium selenides or two lithium selenides be raw material, with water, ethanol, Virahol, absolute ethyl alcohol,
N, N-N, dioxane, methyl-sulphoxide or its mixture are solvent, and reaction is synthetic: in the solution of two sodium selenides that prepare or two potassium selenides or two lithium selenides, add 4-chloro quinazoline under 20-120 ℃ in batches; Back flow reaction 3-36h, cooling, suction filtration; Get the red-brown solid, use
N, N-N and water recrystallization obtain orange to the red-brown crystal, are product two quinazoline diselenide compounds.The synthetic chemistry reaction equation is following:
This step is applicable to the synthetic of all above-mentioned two quinazoline diselenide compounds.
Above-described a kind of antitumor drug that is used for; Can be a kind of pharmaceutical composition; It is characterized in that comprising formula (I) compound or its pharmacy acceptable salt of significant quantity; Its purposes is as treatment and prevents various optimum or malignant tumours that wherein said tumour comprises prostate cancer, white blood disease, skin carcinoma, cancer of the stomach, mammary cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, lymphatic cancer, large bowel cancer, nasopharyngeal carcinoma, oral cancer, wherein is meant prostate cancer and mammary cancer especially.
Said pharmaceutical composition contains the mixture as formula at least (I) compound of activeconstituents itself or itself and one or more pharmaceutically useful inert non-toxic vehicle or carrier.
Embodiment
Following exemplifying embodiment will better be explained the present invention, but it is emphasized that the present invention never only limits to the represented content of these several exemplifying embodiments.
Following examples have shown not ipsilateral of the present invention, and given data comprise concrete operations and reaction conditions and product, its structure that product purity has been passed through ir spectra, proton nmr spectra and mass spectrum confirmation.
Embodiment 1,1, and (compound number is a) for 2-two (6,7-dimethoxyquinazoline-4-yl) diselenide synthetic.
, 150 mL there-necked flasks of reflux condensing tube add 0.3 g (3.8 mmol) selenium, 0.1 g (2.6mmol) Peng Qinghuana, 15 mL absolute ethyl alcohols in being housed successively; The control of ice-water bath temperature is below 3 ℃; Solution becomes brown by black; Solution becomes reddish-brown behind about 10min, removes ice bath, and intensification stirring and refluxing 1.5 h solution become dark-brown.Add 2.5 mmol 6 in batches, 7-dimethoxy-4 '-chloro-quinazoline, about 1 h adds, and solution becomes latericeous, and back flow reaction 24 h are chilled to room temperature, and with Glacial acetic acid min. 99.5 conditioned reaction system pH=5-6, the decompression precipitation gets the khaki color solid, with DMF and water recrystallization (V
DMF/H2O=5:1), get the orange crystal, be product 1,2-two (6,7-dimethoxyquinazoline-4-yl) diselenide, productive rate 53.8%, Rong Dian>300 ℃.IR?(KBr)?v:?3039.6?(v
Ar-H),?2945.3?(v
asCH3
),?2845.0?(v
sCH3
),?1602.9-1467.8?(quinazoline?skeleton?vibration),?1246.0?(v
asAr-O-C
),?1136.1?(v
sAr-O-C
),?786.9?(δ
Ar-H)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.93?(s,?2H,?quinazoline?H-2),?7.60?(s,?2H,?quinazoline?H-8),?7.29?(s,?2H,?quinazoline?H-5),?4.06,?4.01?(2s,?12H,?4OCH
3).?EIMS:?m/z?538?(M
+·,?17.2)。
Embodiment 2,1, synthetic (compound number is b) of 2-two (6,7-diethoxy quinazoline-4-yl) diselenide.
Method and condition like embodiment 1 are synthetic, and only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 6,7-diethoxy-4-chloro-quinazoline; Obtain product 1,2-two (6,7-diethoxy quinazoline-4-yl) diselenide; Orange crystal, productive rate 52.6%, fusing point>300 ℃.IR?(KBr)?v:?3036.9?(v
Ar-H),?2946.7?(v
asCH3
),?2935.8?(v
asCH2
),?2847.4?(v
sCH3
),?2836.4?(v
sCH2
),?1608.2-1464.6?(quinazoline?skeleton?vibration),?1242.6?(v
asAr-O-C
),?1134.8?(v
sAr-O-C
),?787.6?(δ
Ar-H)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.95?(s,?2H,?quinazoline?H-2),?7.64?(s,?2H,?quinazoline?H-8),?7.31?(s,?2H,?quinazoline?H-5),?4.09,?4.06?(2s,?8H,?4OCH
2),?1.34,?1.31?(2s,?12H,?4CH
3).?EIMS:?m/z?594?(M
+·,?18.6)。
Embodiment 3,1, synthetic (compound number is c) of 2-two (2-methyl-6,7-dimethoxyquinazoline-4-yl) diselenide.
Method and condition like embodiment 1 are synthetic, and only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 2-methyl-6,7-dimethoxy-4 '-chloro-quinazoline; Obtain product 1,2-two (2-methyl-6,7-dimethoxyquinazoline-4-yl) diselenide; Orange-yellow crystal, productive rate 48.2%, fusing point>300 ℃.IR?(KBr)?v:?3030.2?(v
Ar-H),?2954.2?(v
asCH3
),?2865.9?(v
sCH3
),?1614.8-1458.2?(quinazoline?skeleton?vibration),?1248.3?(v
asAr-O-C
),?1139.4?(v
sAr-O-C
),?779.8?(δ
Ar-H)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?7.63?(s,?2H,?quinazoline?H-8),?7.39?(s,?2H,?quinazoline?H-5),?3.90,?3.85?(2s,?12H,?4OCH
3),?2.46,?2.42?(2s,?6H,?2CH
3).?EIMS:?m/z?566?(M
+·,?15.2)。
Embodiment 4,1, synthetic (compound number is d) of 2-two (2-methyl-6,7-diethoxy quinazoline-4-yl) diselenide.
Method and condition like embodiment 1 are synthetic, and only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 2-methyl-6,7-diethoxy-4-chloro-quinazoline; Obtain product 1,2-two (2-methyl-6,7-diethoxy quinazoline-4-yl) diselenide; Orange-yellow crystal, productive rate 45.6%, fusing point>300 ℃.IR?(KBr)?v:?3033.0?(v
Ar-H),?2956.3?(v
asCH3
),?2948.5?(v
asCH2
),?2869.7?(v
sCH3
),?2838.6?(v
sCH2
),?1618.8-1451.7?(quinazoline?skeleton?vibration),?1247.8?(v
asAr-O-C
),?1132.4?(v
sAr-O-C
),?781.7?(δ
Ar-H)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?7.65?(s,?2H,?quinazoline?H-8),?7.41?(s,?2H,?quinazoline?H-5),?4.05,?4.02?(2s,?8H,?4OCH
2),?2.47,?2.45?(2s,?6H,?2CH
3),?1.36,?1.33?(2s,?12H,?4CH
3).?EIMS:?m/z?622?(M
+·,?13.7)。
Embodiment 5,1, synthetic (compound number is e) of 2-two (2-chloro-6,7-dimethoxyquinazoline-4-yl) diselenide.
Method and condition like embodiment 1 are synthetic, and only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 6,7-dimethoxy-2; 4-two chloro-quinazolines obtain product 1,2-two (2-chloro-6,7-dimethoxyquinazoline-4-yl) diselenide; Orange red crystal, productive rate 53.8%, fusing point>300 ℃.IR?(KBr)?v:?3032.1?(v
Ar-H),?2958.1?(v
asCH3
),?2868.5?(v
sCH3
),?1618.2-1460.8?(quinazoline?skeleton?vibration),?1250.4?(v
asAr-O-C
),?1140.6?(v
sAr-O-C
),?787.1?(δ
Ar-H)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?7.67?(s,?2H,?quinazoline?H-8),?7.43?(s,?2H,?quinazoline?H-5),?3.99,?3.89?(2s,?12H,?4OCH
3).?EIMS:?m/z?606?(M
+·,?28.5)。
Embodiment 6,1, synthetic (compound number is g) of 2-two (6-chloro-quinazoline-4-yl) diselenide.
Synthetic like the method for embodiment 1 and condition, only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 4, and 6-two chloro-quinazolines obtain product 1,2-two (6-chloro-quinazoline-4-yl) diselenide, orange-yellow crystal, productive rate 50.3%, fusing point>300 ℃.IR?(KBr)?v:?3039.9?(v
Ar-H),?1496.4-1570.1?(quinazoline?skeleton?vibration)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.75?(s,?2H,?quinazoline?H-2),?8.31?(s,?2H,?quinazoline?H-5),?7.86?(d,?
J?=?8.8?Hz,?2H,?quinazoline?H-8),?7.73?(d,?
J?=?8.8?Hz,?2H,?quinazoline?H-7).?EIMS:?m/z?484?(M
+·,?20.8)。
Embodiment 7,1, synthetic (compound number is h) of 2-two (6,8-two chloro-quinazolines-4-yl) diselenide.
Synthetic like the method for embodiment 1 and condition, only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 4,6, and 8-three chloro-quinazolines obtain product 1,2-two (6,8-two chloro-quinazolines-4-yl) diselenide, orange-yellow crystal, productive rate 47.8%, fusing point>300 ℃.IR?(KBr)?v:?3036.4?(v
Ar-H),?1477.5-1566.2?(quinazoline?skeleton?vibration)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.76?(s,?2H,?quinazoline?H-2),?8.63?(d,?
J?=?2.0?Hz,?2H,?quinazoline?H-7),?8.20?(d,?
J?=?2.0?Hz,?2H,?quinazoline?H-5).?EIMS:?m/z?554?(M
+·,?24.5)。
Embodiment 8,1, synthetic (compound number is i) of 2-two (2-methyl-6-chloro-quinazoline-4-yl) diselenide.
Synthetic like the method for embodiment 1 and condition, only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 2-methyl-4, and 6-two chloro-quinazolines obtain product 1,2-two (2-methyl-6-chloro-quinazoline-4-yl) diselenide, orange red crystal, productive rate 43.1%, fusing point>300 ℃.IR?(KBr)?v:?3032.0?(v
Ar-H),?2974.4?(v
asCH3
),?2868.2?(v
sCH3
),?1490.6-1582.0?(quinazoline?skeleton?vibration)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.77?(s,?2H,?quinazoline?H-2),?8.33?(s,?2H,?quinazoline?H-5),?7.88?(d,?
J?=?8.8?Hz,?2H,?quinazoline?H-8),?7.75?(d,?
J?=?8.8?Hz,?2H,?quinazoline?H-7),?2.49,?2.47?(2s,?6H,?2CH
3).?EIMS:?m/z?512?(M
+·,?18.3)。
Embodiment 9,1, synthetic (compound number is j) of 2-two (2-methyl-6,8-two chloro-quinazolines-4-yl) diselenide.
Method and condition like embodiment 1 are synthetic, and only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 2-methyl-4,6; 8-three chloro-quinazolines obtain product 1,2-two (2-methyl-6,8-two chloro-quinazolines-4-yl) diselenide; Orange red crystal, productive rate 40.1%, fusing point>300 ℃.IR?(KBr)?v:?3036.0?(v
Ar-H),?2971.1?(v
asCH3
),?2866.7?(v
sCH3
),?1465.7-1502.6?(quinazoline?skeleton?vibration)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.79?(s,?2H,?quinazoline?H-2),?8.76?(d,?
J?=?2.0?Hz,?2H,?quinazoline?H-7),?8.23?(d,?
J?=?2.0?Hz,?2H,?quinazoline?H-5),?2.44,?2.42?(2s,?6H,?2CH
3).?EIMS:?m/z?582?(M
+·,?15.4)。
Embodiment 10,1, synthetic (compound number is m) of 2-two (6-bromine quinazoline-4-yl) diselenide.
Synthetic like the method for embodiment 1 and condition, only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 6-bromo-4-chloro-quinazoline, obtains product 1,2-two (6-bromine quinazoline-4-yl) diselenide, orange red crystal, productive rate 47.5%, fusing point>300 ℃.IR?(KBr)?v:?3030.8?(v
Ar-H),?1458.6-1599.1?(quinazoline?skeleton?vibration)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.81?(s,?2H,?quinazoline?H-2),?8.46?(s,?2H,?quinazoline?H-5),?7.92?(d,?
J?=?8.8?Hz,?2H,?quinazoline?H-8),?7.84?(d,?
J?=?8.8?Hz,?2H,?quinazoline?H-7).?EIMS:?m/z?576?(M
+·,?21.6)。
Embodiment 11,1, synthetic (compound number is n) of 2-two (6,8-dibromo quinazoline-4-yl) diselenide.
Synthetic like the method for embodiment 1 and condition, only 6,7-dimethoxy-4 '-chloro-quinazoline is changed to 6, and 8-two bromo-4-chloro-quinazolines obtain product 1,2-two (6,8-dibromo quinazoline-4-yl) diselenide, orange red crystal, productive rate 40.7%, fusing point>300 ℃.IR?(KBr)?v:?3030.7?(v
Ar-H),?1457.7?-1652.6?(quinazoline?skeleton?vibration)?cm
-1.?
1H?NMR?(DMSO-
d 6 ,?600?MHz)?δ:?8.85?(s,?2H,?quinazoline?H-2),?8.71?(d,?
J?=?2.0?Hz,?2H,?quinazoline?H-7),?8.38?(d,?
J?=?2.0?Hz,?2H,?quinazoline?H-5).?EIMS:?m/z?732?(M
+·,?19.2)。
Embodiment 12,1, and (compound number is a) for 2-two (6,7-dimethoxyquinazoline-4-yl) diselenide synthetic.
Synthetic like the method for embodiment 1 and condition, only be changed to the solvent absolute ethyl alcohol 50% aqueous ethanolic solution, obtain product 1,2-two (6,7-dimethoxyquinazoline-4-yl) diselenide, orange crystal, productive rate 38.6%, fusing point>300 ℃.
Embodiment 13,1, and (compound number is a) for 2-two (6,7-dimethoxyquinazoline-4-yl) diselenide synthetic.
Method and condition like embodiment 1 are synthetic, only are changed to the solvent absolute ethyl alcohol
N, N-N, maintain is carried out in 80 ℃ of water-baths, obtains product 1,2-two (6,7-dimethoxyquinazoline-4-yl) diselenide, orange crystal, productive rate 56.1%, Rong Dian>300 ℃.
Embodiment 14,1, and (compound number is a) for 2-two (6,7-dimethoxyquinazoline-4-yl) diselenide synthetic.
Method and condition like embodiment 1 are synthetic, only are changed to methyl-sulphoxide to the solvent absolute ethyl alcohol, and maintain is carried out in 80 ℃ of water-baths; Obtain product 1,2-two (6,7-dimethoxyquinazoline-4-yl) diselenide; Orange crystal, productive rate 53.7%, fusing point>300 ℃.
Embodiment 15, compound a suppress to measure to the propagation of breast cancer cell MDA-MB-435.
TP: medicine is mixed with each concentration, every concentration triplicate with the DMSO dissolving; With processing suspension-s 4 * 10 behind the MDA-MB-435 cell dissociation
4Individual/ml, get 10ml and add in the big petridish, treat that 24hr is adherent after, dosing is handled; Get 2 wares behind the 24hr at random and take pictures, the record cell state; The former substratum of sucking-off changes pastille substratum (10%FBS 1640) and handles 72hr; Add the 1.5ml pancreatin, add former pastille substratum behind the digestion 4min and stop digestion, beat and spare, the counting cells number is averaged, and calculates inhibiting rate.
Test-results: through test, compound
aWhen drug concentration is 10mmol/L the MDA-MB-435 cell proliferation inhibition rate is reached 99.69 ± 0.18%, more much better than positive control medicine oxaliplatin effect, show high antitumour activity.
Embodiment 16, compound h suppress to measure to the propagation of breast cancer cell MDA-MB-435.
TP is with embodiment 15.
Test-results: through test, compound
hWhen drug concentration is 10mmol/L the MDA-MB-435 cell proliferation inhibition rate is reached 59.07 ± 3.95%, more effective than positive control medicine oxaliplatin, show higher anti-cancer activity.
Claims (10)
1. one kind is used for anti-tumor drug, it is characterized in that this medicine is two quinazoline diselenide compounds, by the compound of following general formula (I) expression:
（I）
Wherein,
R
1, R
2, R
3, R
4And R
5Each is hydrogen, halogen atom, C1-6 alkyl, C1-6 alkoxyl group naturally; But do not comprise R
1, R
2, R
3, R
4And R
5All be hydrogen.
2. R in a kind of anti-tumor drug that is used for according to claim 1, the general formula of its compound (I)
1, R
4And R
5Be hydrogen, R
2And R
3Be selected from C1-6 alkyl, C1-6 alkoxyl group.
3. R in a kind of anti-tumor drug that is used for according to claim 1, the general formula of its compound (I)
1, R
3And R
5Be hydrogen, R
2And R
4Be selected from halogen atom.
4. R in a kind of anti-tumor drug that is used for according to claim 1, the general formula of its compound (I)
5Be methyl, R
1, R
2, R
3And R
4Be selected from halogen atom, C1-6 alkyl, C1-6 alkoxyl group.
5. R in a kind of anti-tumor drug that is used for according to claim 2, the general formula of its compound (I)
2And R
3Be selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, uncle's pentyloxy, neopentyl oxygen.
6. R in a kind of anti-tumor drug that is used for according to claim 3, the general formula of its compound (I)
2And R
4Be selected from fluorine, chlorine, bromine, iodine atom.
7. R in a kind of anti-tumor drug that is used for according to claim 4, the general formula of its compound (I)
1And R
4Be hydrogen, R
2And R
3Be selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, uncle's pentyloxy, neopentyl oxygen.
8. a kind of anti-tumor drug that is used for according to claim 1 is characterized in that the compound of partial synthesis is following:
A. 1,2-two (6,7-dimethoxyquinazoline-4-yl) diselenide,
B. 1,2-two (6,7-diethoxy quinazoline-4-yl) diselenide,
C. 1,2-two (2-methyl-6,7-dimethoxyquinazoline-4-yl) diselenide,
D. 1,2-two (2-methyl-6,7-diethoxy quinazoline-4-yl) diselenide,
E. 1,2-two (2-chloro-6,7-dimethoxyquinazoline-4-yl) diselenide,
F. 1,2-two (2-chloro-6,7-diethoxy quinazoline-4-yl) diselenide,
G. 1,2-two (6-chloro-quinazoline-4-yl) diselenide,
H. 1,2-two (6,8-two chloro-quinazolines-4-yl) diselenide,
I. 1,2-two (2-methyl-6-chloro-quinazoline-4-yl) diselenide,
J. 1,2-two (2-methyl-6,8-two chloro-quinazolines-4-yl) diselenide,
K. 1,2-two (2-chloro-6-chloro-quinazoline-4-yl) diselenide,
L. 1,2-two (2-chloro-6,8-two chloro-quinazolines-4-yl) diselenide,
M. 1,2-two (6-bromine quinazoline-4-yl) diselenide,
N. 1,2-two (6,8-dibromo quinazoline-4-yl) diselenide,
O. 1,2-two (2-methyl-6-bromine quinazoline-4-yl) diselenide,
P. 1,2-two (2-methyl-6,8-dibromo quinazoline-4-yl) diselenide,
Q. 1,2-two (2-chloro-6-bromine quinazoline-4-yl) diselenide,
R. 1,2-two (2-chloro-6,8-dibromo quinazoline-4-yl) diselenide.
9. a kind of preparing anti-tumor medicine method that is used for according to claim 1 is characterized in that with 4-chloro quinazoline, two sodium selenides or two potassium selenides or two lithium selenides be raw material, with water, ethanol, Virahol, absolute ethyl alcohol,
N, N-N, dioxane, methyl-sulphoxide or its mixture are solvent, and reaction is synthetic: in the solution of two sodium selenides that prepare or two potassium selenides or two lithium selenides, add 4-chloro quinazoline under 20-120 ℃ in batches; Back flow reaction 3-36h, cooling, suction filtration; Get the red-brown solid, use
N, N-N and water recrystallization obtain orange to the red-brown crystal, are product two quinazoline diselenide compounds.
10. a kind of antitumor drug that is used for according to claim 1 can be a kind of pharmaceutical composition, it is characterized in that comprising formula (I) compound or its pharmacy acceptable salt of significant quantity, and its purposes is as treatment and prevents various optimum or malignant tumours.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191121A (en) * | 2013-04-22 | 2013-07-10 | 鲁东大学 | Anti-cancer biological activity of di(quinazoline-4-group)diselenide compound |
| CN104798808A (en) * | 2015-05-06 | 2015-07-29 | 鲁东大学 | Application of 2-quinazoline diselenide derivatives in preparing phytopathogen resisting medicine |
| CN104000828B (en) * | 2014-06-16 | 2016-07-06 | 鲁东大学 | Quinazoline two selenium salt compounds and preparation method and biologically active |
| CN111454240A (en) * | 2020-04-30 | 2020-07-28 | 上海爱启医药技术有限公司 | Process for preparing diselenide compounds |
| CN113004210A (en) * | 2021-03-29 | 2021-06-22 | 鲁东大学 | Quinazoline-4-selenium salt compound, preparation method and biological activity |
| CN113135861A (en) * | 2021-04-30 | 2021-07-20 | 重庆理工大学 | Ligustrazine derivative and preparation method and application thereof |
-
2012
- 2012-03-29 CN CN201210086997.8A patent/CN102627614B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| HARJIT SINGH ET AL.: "Synthesis of Functionalised Heterocyclic Selenoamide Derivatives & Their Reactions", 《INDIAN JOURNAL OF CHEMISTRY》 * |
| PFEIFFER, W.-D.: "Product class 23: annulated selenazole compounds", 《SCIENCE OF SYNTHESIS》 * |
| 刘刚等: "4-硫醚基喹唑啉类化合物的合成及抑菌活性研究", 《有机化学》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191121A (en) * | 2013-04-22 | 2013-07-10 | 鲁东大学 | Anti-cancer biological activity of di(quinazoline-4-group)diselenide compound |
| CN103191121B (en) * | 2013-04-22 | 2015-09-23 | 鲁东大学 | Two (quinazoline-4-base) diselenide compound is preparing the purposes in cancer therapy drug |
| CN104000828B (en) * | 2014-06-16 | 2016-07-06 | 鲁东大学 | Quinazoline two selenium salt compounds and preparation method and biologically active |
| CN104798808A (en) * | 2015-05-06 | 2015-07-29 | 鲁东大学 | Application of 2-quinazoline diselenide derivatives in preparing phytopathogen resisting medicine |
| CN104798808B (en) * | 2015-05-06 | 2017-05-10 | 鲁东大学 | Application of 2-quinazoline diselenide derivatives in preparing phytopathogen resisting medicine |
| CN111454240A (en) * | 2020-04-30 | 2020-07-28 | 上海爱启医药技术有限公司 | Process for preparing diselenide compounds |
| CN111454240B (en) * | 2020-04-30 | 2023-05-16 | 上海爱启医药技术有限公司 | Process for preparing diselenide compounds |
| CN113004210A (en) * | 2021-03-29 | 2021-06-22 | 鲁东大学 | Quinazoline-4-selenium salt compound, preparation method and biological activity |
| CN113135861A (en) * | 2021-04-30 | 2021-07-20 | 重庆理工大学 | Ligustrazine derivative and preparation method and application thereof |
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|---|---|
| CN102627614B (en) | 2014-06-25 |
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