CN103224500A - Annular secondary amino substitution cryptolepine ramification and preparation method thereof and application of annular substitution cryptolepine ramification being used as anti-cancer drug - Google Patents
Annular secondary amino substitution cryptolepine ramification and preparation method thereof and application of annular substitution cryptolepine ramification being used as anti-cancer drug Download PDFInfo
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Abstract
The invention discloses annular secondary amino substitution cryptolepine ramification and a preparation method of the annular secondary amino substitution cryptolepine ramification and application of the annular substitution cryptolepine ramification being used as an anti-cancer drug. The chemical formula of the ramification is shown as the formula (I), wherein n is 0 or 1, R1 and R2 are respectively selected from H, F, C1, and Br, R3 is alkyl group of H, OH, NH2, C1-6 or CH2(CH2)mNR4R5, R4 and R5 are respectively H, alkyl group of C1-6, naphthenic base of C3-6 or piperidyl or morpholinyl or piperazine, m is 1 or 2 or 3 or 4, and Y is NH, CH, O or S. The annular secondary amino substitution cryptolepine ramification has the obvious inbibitional effect on various cancer cells, and has low toxicity to normal cells, so that the annular secondary amino substitution cryptolepine ramification can be prepared to antineoplastic drugs, and has higher medical value and a broad market application prospect.
Description
Technical field
The present invention relates to oxadiazole derivatives as comt inhibitors, be specifically related to a kind of cyclic secondary amine base and replace cryptolepine derivative and preparation method thereof, and the application of this compounds in the preparation cancer therapy drug.
Background technology
Tumour (cancer) is one of principal disease of present serious threat human health and life security.In recent years, along with the development that molecular biology, molecular pharmacology and molecular weight tumor are learned, people have had more understanding to the essence and the pathomechanism of tumour, and the research level of cancer therapy drug obviously improves.Each key link with the tumour pathologic process is a target, and the new type anticancer medicine of seeking efficient, highly selective, low toxic side effect is the important development direction of drug development.
The alkaloid that cryptolepine (cryptolepine) is separated from the plant cryptolepis sanguinolenta (Periplocaceae) in West Africa the earliest.Have typical benzo δ-carboline structure, fewer at nature, be a kind of important indoles quinoline alkaloid.Studies show that in a large number this compound and derivative thereof have wide biological activity, as physiologically active widely such as antibiotic, antiviral, muscarine antagonist malaria, hyperglycemia, trypanosomicide, anti-inflammatory, analgesic, presynaptic α-adrenoceptor blocking-up.K.Bonjeam in 1998 etc. on Biochemistry, reported cryptolepine by disturb type suppress the B16 melanoma (Biochemistry1998,37,5136-5146).After this numerous research groups has reported the physiologically active of the cryptolepine derivative of a series of modifications in succession, but these modifications mainly concentrate on (J.Nat.Prod.1999,62,976-983 on the parent of Fourth Ring; J.Med.Chem.2001,44,949-960; J.Med.Chem.2001,44,3187-3194).Two China's patent report of 2004 and 2008 preparation and the anti-tumor activity (CN1546473A, CN101250187A) thereof of the indoles quinoline analogues that replace of a series of fat amidos.
Therefore, be that structure of modification is carried out on the basis with the parent nucleus of cryptolepine, be to find a feasible way efficient, the anticancer lead compound of low toxicity.Introducing cyclic secondary amine again 11 of parent nucleus may can improve compound activity or produce new pharmacologically active.Therefore, can predict with the cryptolepine to be that the serial new derivatives that parent nucleus designs and synthesizes may have better antitumor activity.
Summary of the invention
The purpose of this invention is to provide a kind of cyclic secondary amine base and replace the cryptolepine derivative.
Another object of the present invention provides the preparation method that above-mentioned cyclic secondary amine base replaces the cryptolepine derivative.
Another object of the present invention provides above-mentioned cyclic secondary amine base and replaces the application of cryptolepine derivative in the preparation antitumor drug.
Above-mentioned technical purpose of the present invention is achieved by following scheme:
A kind of cyclic secondary amine base replaces the cryptolepine derivative, has following chemical structure of general formula suc as formula (I):
N is 0 or 1 in the formula; R
1, R
2Be selected from H, F, Cl or Br respectively; R
3Be H, OH, NH
2, C
1-6Alkyl or CH
2(CH
2)
mNR
4R
5R
4, R
5Be respectively H, C
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl or piperazinyl; M is 1,2,3 or 4; Y is NH, CH, O or S.
The present invention also provides a kind of cyclic secondary amine base to replace the preparation method of cryptolepine derivative, and reaction expression is:
R in the reaction expression
1, R
2, R
3, Y and n be as shown in claim 1;
This preparation method comprises the steps:
With above-mentioned 11-iodo cryptolepine derivative
Mix with the reaction solvent ethylene glycol ethyl ether, add above-mentioned cyclic secondary amine analogue
, stirred 0.5 hour at 120 ° of C, the cooling precipitation, solid collected by filtration promptly gets the cyclic secondary amine base with ether-alcohol mixeding liquid recrystallization and replaces the cryptolepine derivative.
The mol ratio of above-mentioned 11-iodo cryptolepine derivative and cyclic secondary amine analogue is 1:1.5.
Cyclic secondary amine base of the present invention replaces the cryptolepine derivative multiple JEG-3 is had significant inhibitory effect, therefore can be used for preparing cancer therapy drug.
Cyclic secondary amine base of the present invention replaces the cryptolepine derivative and can mix with pharmaceutically acceptable auxiliary, prepares the antitumor drug of various formulations, as tablet, pill, capsule, injection, suspension agent or emulsion etc.
Compared with prior art, the present invention has following beneficial effect:
1. cyclic secondary amine base of the present invention replaces the cryptolepine derivative multiple JEG-3 is had significant inhibitory effect;
2. it is less to normal cytotoxicity that cyclic secondary amine base of the present invention replaces the cryptolepine derivative, safe in the application of preparation antitumor drug;
3. cyclic secondary amine base of the present invention replaces the cancer therapy drug that the cryptolepine derivative can be made various formulations, has very high medical value and vast market prospect.
Embodiment
Synthesizing of embodiment 1 compound pyrrolidyl substituent methyl cumarone quinoline
With 0.1mol exsiccant 10-hydrogen-11-iodo-methyl cumarone [3,2-b] ethylene glycol ethyl ether of quinoline and 60ml mixes, add the 0.15mol tetramethyleneimine, stirred 0.5 hour at 120 ℃, the cooling precipitated solid, obtain khaki color powder compounds pyrrolidyl substituent methyl cumarone [3,2-b] quinoline with ether-alcohol mixeding liquid recrystallization, its chemical structural formula is shown in formula II:
Productive rate: 88%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.70 (1H, d, J=8.4Hz), 8.62 (1H, d, J=8.4Hz), 8.31 (1H, d, J=8.4Hz), 8.06 (1H, t, J=8.8Hz), 7.99 (1H, d, J=8.4Hz), 7.91 (1H, t, J=7.6Hz), 7.66 (2H, m), 4.55 (3H, s), 4.43 (4H, m), 2.09 (4H, m); ESI-MSm/z302.93[M-I]
+Ultimate analysis C
20H
19IN
2O, theoretical value C, 55.83; H, 4.45; N, 6.51; Measured value C, 55.73; H, 4.64; N, 6.42.
Synthesizing of embodiment 2 compound morphine quinoline base substituent methyl cumarone quinoline
The preparation method of present embodiment is except replacing the tetramethyleneimine with the morphine quinoline, and all the other are with embodiment 1, at last golden yellow solid morphine quinoline base substituent methyl cumarone quinoline, its structural formula is shown in formula III:
Productive rate: 86%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.73 (1H, d, J=8.0Hz), 8.51 (1H, d, J=8.2Hz), 8.40 (1H, d, J=8.0Hz), 8.14 (1H, dd, J=7.6,1.2Hz), 8.04 (1H, d, J=8.4Hz), 7.99 (1H, t, J=8.0Hz), 7.82 (1H, t, J=7.6Hz), 7.71 (1H, t, J=8.0Hz), 4.70 (3H, s), 4.14 (4H, t, J=4.4Hz), 3.98 (4H, t, J=4.4Hz); ESI-MSm/z318.89[M-I]
+Ultimate analysis C
20H
19IN
2O
2, theoretical value C, 53.83; H, 4.29; N, 6.28; Measured value C, 53.71; H, 4.52; N, 6.17.
Synthesizing of embodiment 3 compound piperazinyl substituent methyl cumarone quinoline
The preparation method of present embodiment is except replacing with piperazine the tetramethyleneimine, and all the other are with embodiment 1, at last brown solid piperazinyl substituent methyl cumarone quinoline, its structural formula is suc as formula shown in (IV):
Productive rate: 89%; M.P.:256-262 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.72 (1H, d, J=8.4Hz), 8.51 (1H, d, J=8.8Hz), 8.41 (1H, d, J=8.4Hz), 8.12 (1H, t, J=8.4Hz), 8.06 (1H, d, J=8.4Hz), 8.00 (1H, t, J=8.4Hz), 7.82 (1H, t, J=7.6Hz), 7.73 (1H, t, J=7.2Hz), 4.68 (3H, s), 3.11 (4H, m), 2.90 (2H, m); ESI-MSm/z318.09[M-I]
+Ultimate analysis C
20H
19IN
2O
2, theoretical value C, 53.94; H, 4.53; N, 9.44; Measured value C, 53.71; H, 4.72; N, 8.17.
Synthesizing of embodiment 4 compounds 4 '-methylpiperazine base substituent methyl cumarone quinoline
The preparation method of present embodiment is except replacing the tetramethyleneimine with the 4-methylpiperazine, and all the other are with embodiment 1, at last orange red look solid 4 '-methylpiperazine base substituent methyl cumarone quinoline, its structural formula is shown in formula V:
Productive rate: 84%; M.P.:290-292 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.72 (1H, d, J=8.4Hz), 8.52 (1H, d, J=8.8Hz), 8.41 (1H, d, J=8.4Hz), 8.13 (1H, t, J=7.2Hz), 8.06 (1H, d, J=8.4Hz), 7.98 (1H, t, J=8.0Hz), 7.82 (1H, t, J=7.6Hz), 7.71 (1H, t, J=8.0Hz), 4.64 (3H, s), 4.09 (4H, m), 2.67 (4H, m), 2.28 (3H, s); ESI-MSm/z332.2[M-I]
+Ultimate analysis C
21H
22IN
3O, theoretical value C, 54.91; H, 4.83; N, 9.15; Measured value C, 54.81; H, 5.04; N, 9.04.
Synthesizing of embodiment 5 compounds 4 '-methyl piperidine base substituent methyl cumarone quinoline
The preparation method of present embodiment replaces the tetramethyleneimine except using the 4-methyl piperidine, and all the other get yellow solid 4 '-methyl piperidine base substituent methyl cumarone quinoline at last with embodiment 1, and its structural formula is suc as formula shown in (VI):
Productive rate: 87%; M.P.:239-240 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.70 (1H, d, J=8.0Hz), 8.49 (1H, d, J=9.2Hz), 8.37 (1H, d, J=8.4Hz), 8.11 (1H, t, J=8.4Hz), 8.04 (1H, d, J=8.4Hz), 7.98 (1H, d, J=7.6Hz), 7.79 (1H, t, J=7.6Hz), 7.69 (1H, t, J=8.0Hz), 4.66 (3H, s), and 4.41-4.34 (2H, m), 3.83-3.78 (2H, m), 1.95-1.92 (3H, m), 1.57-1.54 (2H, m), 1.04 (3H, d, J=6.4); ESI-MSm/z330.99[M-I]
+Ultimate analysis C
22H
23IN
2O, theoretical value C, 57.65; H, 5.06; N, 6.11; Measured value C, 57.54; H, 5.29; N, 5.99.
Synthesizing of embodiment 6 compounds 4 '-hydroxy piperidine base substituent methyl cumarone quinoline
The preparation method of present embodiment is except replacing the tetramethyleneimine with the 4-hydroxy piperidine, and all the other are with embodiment 1, at last golden yellow solid 4 '-hydroxy piperidine base substituent methyl cumarone quinoline, its structural formula is suc as formula shown in (VII):
Productive rate: 87%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.71 (1H, d, J=8.0Hz), 8.51 (1H, d, J=8.8Hz), 8.40 (1H, d, J=8.4Hz), 8.12 (1H, dd, J=8.4,1.6Hz), 8.05 (1H, d, J=8.4Hz), 7.98 (1H, t, J=8.4Hz), 7.80 (1H, t, J=7.6Hz), 7.70 (1H, t, J=8.4Hz), 5.01 (1H, s), 4.67 (3H, s), 4.33-4.28 (2H, m), 3.97-3.92 (3H, m), 2.10 (2H, m), 1.80 (2H, dd, J=8.0,3.6Hz); ESI-MSm/z332.97[M-I]
+Ultimate analysis C
21H
21IN
2O
2, theoretical value C, 54.79; H, 4.60; N, 6.09; Measured value C, 54.69; H, 4.79; N, 6.00.
Synthesizing of embodiment 7 compounds 4 '-(2-hydroxyethyl) piperazinyl substituent methyl cumarone quinoline
The preparation method of present embodiment is except using the 4-(2-hydroxyethyl) piperazine replaces the tetramethyleneimine, all the other are with embodiment 1, at last khaki color solid 4 '-(2-hydroxyethyl) piperazinyl substituent methyl cumarone quinoline, its structural formula is suc as formula shown in (VIII):
Productive rate: 83%; M.P.:281-282 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.71 (1H, d, J=8.0Hz), 8.50 (1H, d, J=8.8Hz), 8.39 (1H, d, J=8.4Hz), 8.12 (1H, dd, J=8.4,7.2Hz), 8.05 (1H, d, J=8.4Hz), 7.98 (1H, t, J=8.0Hz), 7.80 (1H, t, J=7.6Hz), 7.70 (1H, t, J=7.6Hz), 4.67 (3H, s), 4.13 (4H, m), 3.60 (2H, d, J=5.6Hz), 3.17 (2H, d, J=5.2Hz), 2.81 (4H, m); ESI-MSm/z362.01[M-I]
+Ultimate analysis C
22H
24IN
3O
2, theoretical value C, 54.00; H, 4.94; N, 8.59; Measured value C, 53.90; H, 5.05; N, 8.48.
Synthesizing of embodiment 8 compounds 4 '-ethyl piperazidine base substituent methyl cumarone quinoline
The preparation method of present embodiment replaces the tetramethyleneimine except using the 4-ethyl piperazidine, and all the other get reddish-brown solid 4 '-ethyl piperazidine base substituent methyl cumarone quinoline at last with embodiment 1, and its structural formula is suc as formula shown in (IX):
Productive rate: 81%; M.P.:249-250 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.72 (1H, d, J=8.4Hz), 8.52 (1H, d, J=9.2Hz), 8.41 (1H, d, J=8.4Hz), 8.13 (1H, t, J=8.0Hz), 8.05 (1H, d, J=8.4Hz), 7.98 (1H, t, J=8.4Hz), 7.81 (1H, t, J=7.6Hz), 7.71 (1H, t, J=7.6Hz), 4.67 (3H, s), 4.14 (4H, m), 2.75 (4H, m), 2.48 (2H, q, J=7.2,7.2Hz), 1.10 (3H, t, J=7.0Hz); ESI-MSm/z346.01[M-I]
+Ultimate analysis C
22H
24IN
3O, theoretical value C, 55.82; H, 5.11; N, 8.88; Measured value C, 54.68; H, 5.19; N, 9.08.
Synthesizing of embodiment 9 compound pyrrolidyl substituent methyl indoles quinoline
With 0.1mol compound 10-hydrogen-11-iodo-skatole [3,2-b] ethylene glycol ethyl ether of quinoline and 60ml mixes, add the 0.15mol tetramethyleneimine, stirred 0.5 hour at 120 ℃, the cooling precipitated solid, obtain yellow powder compound pyrrolidyl substituent methyl indoles quinoline with ether-alcohol mixeding liquid recrystallization, its chemical structural formula is suc as formula shown in (X):
Productive rate: 89%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 11.76 (1H, s), 8.52 (2H, d, J=8.4Hz), 8.22 (1H, d, J=8.8Hz), 7.95 (1H, t, J=7.6Hz), 7.82 (1H, d, J=8.4Hz), 7.70 (1H, t, J=8.0Hz), 7.54 (1H, t, J=7.6Hz), 7.37 (1H, t, J=7.6Hz), 4.55 (3H, s), 4.32 (4H, m), 2.05 (4H, m); ESI-MSm/z301.96[M-I]
+Ultimate analysis C
20H
20IN
3, theoretical value C, 55.96; H, 4.70; N, 9.79; Measured value C, 55.86; H, 4.89; N, 9.69.
Synthesizing of embodiment 10 compound morphine quinoline base substituent methyl indoles quinoline
The preparation method of present embodiment is except replacing the tetramethyleneimine with the morphine quinoline, and all the other are with embodiment 9, at last golden yellow solid morphine quinoline base substituent methyl indoles quinoline, its structural formula is suc as formula shown in (XI):
Productive rate: 89%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 11.80 (1H, s), 8.69 (1H, d, J=8.4Hz), 8.58 (1H, d, J=8.8Hz), 8.44 (1H, d, J=8.4Hz), 8.10 (1H, t, J=8.0Hz), 7.92 (1H, d, J=8.0Hz), 7.87-7.79 (2H, m), 7.48 (1H, t, J=8.0Hz), 4.81 (3H, s), 4.04 (4H, d, J=4.4Hz), 3.95 (4H, d, J=4.4Hz); ESI-MSm/z317.96[M-I]
+Ultimate analysis C
20H
20IN
3O, theoretical value C, 53.94; H, 4.53; N, 9.44; Measured value C, 53.83; H, 4.73; N, 9.35.
Synthesizing of embodiment 11 compound piperazinyl substituent methyl indoles quinoline
The preparation method of present embodiment is except replacing with piperazine the tetramethyleneimine, and all the other are with embodiment 9, at last yellow solid piperazinyl substituent methyl indoles quinoline, its structural formula is suc as formula shown in (XII):
Productive rate: 85%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.65 (1H, d, J=8.4Hz), 8.53 (1H, d, J=8.8Hz), 8.39 (1H, d, J=8.4Hz), 8.06 (1H, t, J=8.4Hz), 7.90 (1H, d, J=8.4Hz), 7.814-7.762 (2H, m), 7.42 (1H, t, J=7.6Hz), 4.77 (3H, s), 3.90 (4H, m), 3.18 (4H, m); ESI-MSm/z316.99[M-I]
+Ultimate analysis C
20H
21IN
4, theoretical value C, 54.06; H, 4.76; N, 12.61; Measured value C, 53.97; H, 4.87; N, 12.49.
Synthesizing of embodiment 12 compounds 4 '-methylpiperazine base substituent methyl indoles quinoline
The preparation method of present embodiment replaces the tetramethyleneimine except using the 4-methylpiperazine, and all the other get yellow-green colour solid 4 '-methylpiperazine base substituent methyl indoles quinoline at last with embodiment 9, and its chemical structural formula is suc as formula shown in (XIII):
Productive rate: 82%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.66 (1H, d, J=8.4Hz), 8.54 (1H, d, J=8.4Hz), 8.38 (1H, d, J=8.4Hz), 8.07 (1H, t, J=8.4Hz), 7.90 (1H, d, J=8.4Hz), 7.83-7.77 (2H, m), 7.43 (1H, t, J=7.6Hz), 4.78 (3H, s), 3.94 (4Hm), 2.75 (4H, m), 2.38 (3H, s); ESI-MSm/z331.02[M-I]
+Ultimate analysis C
21H
23IN
4, theoretical value C, 55.03; H, 5.06; N, 12.22; Measured value C, 54.91; H, 5.26; N, 12.14.
Synthesizing of embodiment 13 compounds 4 '-methyl piperidine base substituent methyl indoles quinoline
The preparation method of present embodiment replaces the tetramethyleneimine except using the 4-methyl piperidine, and all the other get yellow solid 4 '-methyl piperidine base substituent methyl indoles quinoline at last with embodiment 9, and its chemical structural formula is suc as formula shown in (XIV):
Productive rate: 85%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 11.73 (1H, s), 8.66 (1H, d, J=8.8Hz), 8.52 (1H, d, J=9.2Hz), 8.34 (1H, d, J=8.4Hz), 8.06 (1H, t, J=8.8Hz), 7.91 (1H, d, J=8.4Hz), 7.83-7.76 (2H, m), 7.43 (1H, t, J=7.6Hz), 4.77 (3H, s), 4.09 (2H, dd, J=6.0,5.2Hz), 3.75 (2H, dd, J=12.0,11.2Hz), 1.97 (2H, d, J=12.4Hz), 1.86-1.83 (1H, m), 1.64-1.61 (2H, m), 1.11 (3H, d, J=5.6Hz); ESI-MSm/z330.00[M-I]
+Ultimate analysis C
22H
24IN
3, theoretical value C, 57.78; H, 5.29; N, 9.19; Measured value C, 57.66; H, 5.40; N, 9.10.
Synthesizing of embodiment 14 compounds 4 '-hydroxy piperidine base substituent methyl indoles quinoline
The preparation method of present embodiment is except replacing the tetramethyleneimine with the 4-hydroxy piperidine, and all the other are with embodiment 9, at last golden yellow solid 4 '-hydroxy piperidine base substituent methyl indoles quinoline, its chemical structural formula is suc as formula shown in (XV):
Productive rate: 84%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.64 (1H, d, J=8.0Hz), 8.52 (1H, d, J=8.8Hz), 8.34 (1H, d, J=8.4Hz), 8.06 (1H, t, J=8.0Hz), 7.89 (1H, d, J=8.4Hz), 7.81-7.77 (2H, m), 7.42 (1H, t, J=7.6Hz), 5.04 (1H, s), 4.76 (3H, s), 4.09-4.07 (3H, m), 3.81-3.79 (2H, m), and 2.14-2.13 (2H, m), 1.86-1.84 (2H, m); ESI-MSm/z331.98[M-I]
+Ultimate analysis C
21H
22IN
3O, theoretical value C, 54.91; H, 4.83; N, 9.15; Measured value C, 54.79; H, 5.03; N, 9.07.
Synthesizing of embodiment 15 compounds 4 '-(2-aminoethyl) piperazinyl replacement-7-chloro-skatole [3,2-b] quinoline
With 0.1mol compound 7-chloro-11-iodo-skatole [3,2-b] ethylene glycol ethyl ether of quinoline and 60ml mixes, add the 0.15mol4-(2-aminoethyl) piperazine, stirred 0.5 hour at 120 ℃, the cooling precipitated solid is filtered and is collected the sorrel solid, obtains yellow powder 4 '-(2-aminoethyl) piperazinyl replacement-7-chloro-skatole [3 with ether-alcohol mixeding liquid recrystallization, 2-b] quinoline, its chemical structural formula is suc as formula shown in (XVI):
Productive rate: 85%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.60 (1H, d, J=8.4Hz), 8.44 (1H, s), 8.27 (1H, d, J=8.8Hz), 7.92 (1H, dd, J=8.4,7.2Hz), 7.72 (1H, d, J=8.8Hz), 7.80 (1H, t, J=7.6Hz), 7.48 (1H, d, J=8.4Hz), 4.55 (3H, s), 2.85 (8H, m), 2.65 (4H, m); ESI-MSm/z394.02[M-I]
+Ultimate analysis C
22H
25ClIN
5, theoretical value C, 50.64; H, 4.83; N, 13.42; Measured value C, 50.53; H, 5.05; N, 13.31.
Synthesizing of embodiment 16 compounds 4 '-(2-dimethyl aminoethyl) piperazinyl replacement-7-chloro-skatole [3,2-b] quinoline
The preparation method of present embodiment is except using the 4-(2-dimethyl aminoethyl) piperazine replaces the 4-(2-amino-ethyl) the piperazine, all the other are with embodiment 15, get orange/yellow solid 4 '-(2-dimethyl aminoethyl) piperazinyl replacement-7-chloro-skatole [3 at last, 2-b] quinoline, its chemical structural formula is suc as formula shown in (XVII):
Productive rate: 84%; M.P.:〉300 ° of C;
1HNMR (400Hz.DMSO-d
6) δ 8.72 (1H, s), 8.57 (1H, d, J=9.2Hz), 8.38 (1H, d, J=8.4Hz), 8.09 (1H, t, J=8.4Hz), 7.96 (1H, d, J=8.4Hz), 7.85-7.77 (2H, m), 4.77 (3H, s), 4.01 (4H, m), 3.11 (4H, m), 2.90 (4H, m), 2.80 (6H, s); ESI-MSm/z422.05[M-I]
+Ultimate analysis C
24H
29ClIN
5, theoretical value C, 52.42; H, 5.32; N, 12.74; Measured value C, 43.42; H, 5.52; N, 12.63.
Embodiment 17 cyclic secondary amine bases replace the restraining effect of cryptolepine derivative to growth of tumour cell
Select the representative compound of part, with the strain of three kinds of tumor cell line PC-3(prostate cancer cells), HepG-2 (human hepatoma cell strain), GLC-82(human lung adenocarcinoma cell line), adopt mtt assay to carry out the cell in vitro poison and measure.The cyclic secondary amine base that the logarithmic phase cell adds different concns replaces the cryptolepine derivative, acts on after 48 hours, measures its absorbancy.Calculate the compound concentration that cell growth inhibiting reaches at 50% o'clock respectively, with IC
50Value representation, the result is as shown in table 1.The result shows that formula I compound all has stronger restraining effect external to these three kinds of tumor cell lines.Cyclic secondary amine base therefore of the present invention replaces the cryptolepine derivative and can be used for preparing anticancer medicine.
Table 1 cyclic secondary amine base of the present invention replaces the restraining effect (IC of cryptolepine derivative to the tumor cell line growth
50/ μ M)
Embodiment 18 cyclic secondary amine bases replace the acute toxicity test of cryptolepine derivative
Select the representative compound (is example with morphine quinoline base substituent methyl indoles quinoline) of part, carry out acute toxicity test.Get 18-22 gram mouse and divide six groups at random, every group of 10 mouse, use physiological saline respectively, DMSO2.5ml/kg, compound morphine quinoline base substituent methyl indoles quinoline 600mg/kg, compound morphine quinoline base substituent methyl indoles quinoline 350mg/kg, compound morphine quinoline base substituent methyl indoles quinoline 200mg/kg, compound morphine quinoline base substituent methyl indoles quinoline 100mg/kg, compound morphine quinoline base substituent methyl indoles quinoline 50mg/kg handles, observed 14 days, 45% death of the visible 600mg/kg group of result mouse, promptly compound morphine quinoline base substituent methyl indoles quinoline is approximately 600mg/kg to the acute toxicity LD50 value of mouse.Therefore the acute toxicity of morphine quinoline base substituent methyl indoles quinoline of the present invention is less, can be used for preparing cancer therapy drug.
Claims (5)
1. a cyclic secondary amine base replaces the cryptolepine derivative, its chemical structural formula suc as formula
IShown in:
N is 0 or 1 in the formula;
R
1, R
2Be selected from H, F, Cl or Br respectively;
R
3Be H, OH, NH
2, C
1-6Alkyl or CH
2(CH
2)
mNR
4R
5
R
4, R
5Be respectively H, C
1-6Alkyl, C
3-6Cycloalkyl, piperidyl, morpholinyl or piperazinyl;
M is 1,2,3 or 4;
Y is NH, CH, O or S.
2. the described cyclic secondary amine base of claim 1 replaces the preparation method of cryptolepine derivative, it is characterized in that:
Reaction expression is:
R in the reaction expression
1, R
2, R
3, Y and n be as shown in claim 1;
This preparation method comprises the steps:
With above-mentioned 11-iodo cryptolepine derivative
Mix with the reaction solvent ethylene glycol ethyl ether, add above-mentioned cyclic secondary amine analogue
, 120
oC stirred 0.5 hour, the cooling precipitation, and solid collected by filtration promptly gets the cyclic secondary amine base with ether-alcohol mixeding liquid recrystallization and replaces the cryptolepine derivative.
3. preparation method according to claim 2 is characterized in that: the mol ratio of above-mentioned 11-iodo cryptolepine derivative and cyclic secondary amine analogue is 1:1.5.
4. the described cyclic secondary amine base of claim 1 replaces the application of cryptolepine derivative in the preparation cancer therapy drug.
5. the formulation of cancer therapy drug according to claim 4 is tablet, pill, capsule, injection, suspension agent or emulsion.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103666452A (en) * | 2013-09-23 | 2014-03-26 | 中山大学 | Methylbenzofuran quinoline type biological probe, and preparation method and application thereof |
| CN111153916A (en) * | 2020-01-17 | 2020-05-15 | 玉林师范学院 | White leaf vine zinc (II) complex and synthesis method and application thereof |
| CN111205311A (en) * | 2020-01-17 | 2020-05-29 | 玉林师范学院 | Novel high-antitumor-activity white leaf vine zinc (II) complex and synthesis method and application thereof |
| CN111253418A (en) * | 2020-01-17 | 2020-06-09 | 玉林师范学院 | Novel white leaf vine zinc (II) complex and synthesis method and application thereof |
| CN115160310A (en) * | 2022-05-10 | 2022-10-11 | 中国人民解放军北部战区总医院 | Sinomenine derivatives as CDK2/Topo I inhibitor, and preparation method and anti-tumor application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5763453A (en) * | 1995-08-08 | 1998-06-09 | Taiho Pharmaceutical Co., Ltd. | Condensed indan derivatives and salts thereof |
| CN101250187A (en) * | 2008-03-28 | 2008-08-27 | 中山大学 | Fatty amido substituted methylindole quinoline derivatives as well as preparation method and use thereof as anti-tumour drugs |
| CN102633719A (en) * | 2012-04-19 | 2012-08-15 | 广东工业大学 | Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof |
-
2013
- 2013-03-26 CN CN2013101002902A patent/CN103224500A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5763453A (en) * | 1995-08-08 | 1998-06-09 | Taiho Pharmaceutical Co., Ltd. | Condensed indan derivatives and salts thereof |
| CN101250187A (en) * | 2008-03-28 | 2008-08-27 | 中山大学 | Fatty amido substituted methylindole quinoline derivatives as well as preparation method and use thereof as anti-tumour drugs |
| CN102633719A (en) * | 2012-04-19 | 2012-08-15 | 广东工业大学 | Anilino-substituted-methylbenzofuryl quinoline derivatives, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| N. Z. TUGUSHEVA，等: "SYNTHESIS OF 2,10,11-TRISUBSTITUTED INDOLO[3,2-b]QUINOLINES", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》, vol. 38, no. 12, 30 June 2002 (2002-06-30), XP002325161, DOI: doi:10.1023/A:1022653813802 * |
| PEDA V. L. BODDUPALLY，等: "Anticancer Activity and Cellular Repression of c-MYC by the G-Quadruplex-Stabilizing 11-Piperazinylquindoline Is Not Dependent on Direct Targeting of the G-Quadruplex in the c-MYC Promoter", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 55, no. 13, 12 June 2012 (2012-06-12), pages 6080 - 2 * |
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| CN103666452A (en) * | 2013-09-23 | 2014-03-26 | 中山大学 | Methylbenzofuran quinoline type biological probe, and preparation method and application thereof |
| CN103666452B (en) * | 2013-09-23 | 2016-06-29 | 中山大学 | A kind of bioprobe of methyl benzofuran quinolines and its preparation method and application |
| CN111153916A (en) * | 2020-01-17 | 2020-05-15 | 玉林师范学院 | White leaf vine zinc (II) complex and synthesis method and application thereof |
| CN111205311A (en) * | 2020-01-17 | 2020-05-29 | 玉林师范学院 | Novel high-antitumor-activity white leaf vine zinc (II) complex and synthesis method and application thereof |
| CN111253418A (en) * | 2020-01-17 | 2020-06-09 | 玉林师范学院 | Novel white leaf vine zinc (II) complex and synthesis method and application thereof |
| CN115160310A (en) * | 2022-05-10 | 2022-10-11 | 中国人民解放军北部战区总医院 | Sinomenine derivatives as CDK2/Topo I inhibitor, and preparation method and anti-tumor application thereof |
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