CN103833646A - Fatty amino substituted quinazolinone derivative and preparation method and application thereof - Google Patents
Fatty amino substituted quinazolinone derivative and preparation method and application thereof Download PDFInfo
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- CN103833646A CN103833646A CN201410072813.1A CN201410072813A CN103833646A CN 103833646 A CN103833646 A CN 103833646A CN 201410072813 A CN201410072813 A CN 201410072813A CN 103833646 A CN103833646 A CN 103833646A
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- CCUCNIFMGAJVCY-UHFFFAOYSA-N COCCOc(cc(c(N=CN1CCCC[Br]=C)c2)C1=O)c2OCCOC Chemical compound COCCOc(cc(c(N=CN1CCCC[Br]=C)c2)C1=O)c2OCCOC CCUCNIFMGAJVCY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
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- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses fatty amino substituted quinazolinone derivative and a preparation method and application thereof. A chemical structural formula of the fatty amino substituted quinazolinone derivative is shown as formula (I) (described in the specification), wherein n is equal to 1, 2, 3 or 4, R1 and R2 can be the same or different and are respectively selected from C1-6 alkyl, C3-6 naphthenic base, CH2CH3OCH3 or Bn; R3 is OH, NH2, NHR4 or NR5R6; R4 is C1-6 alkyl, C3-6 naphthenic base; R5 and R6 are C1-6 alkyl, C3-6 naphthenic base, piperidyl, morpholinyl, piperazine or pyrrl respectively. The fatty amine substituted quinazolinone derivative can obviously inhibit multiple cancer cell lines and toxicity to normal cells is low, so that the fatty amine substituted quinazolinone derivative can be prepared into antitumour drug and has high medical value and great market prospect. The formula (I) is shown in the specification.
Description
Technical field
The present invention relates to oxadiazole derivatives as comt inhibitors, be specifically related to a kind of fat amido substituted quinazoline ketone derivatives and preparation method thereof, and this compounds is in the application of preparing in antitumor drug.
Background technology
Tumour (cancer) is one of principal disease of current serious threat human health and life security.The research and development of antitumor drug are the focuses that medicine scholar pays close attention to always.The antitumor drug of finding efficient, highly selective, low toxic side effect is one of important directions of drug development research.
Quinazoline ketones alkaloid is the large class of one in alkaloid, is the primary structure fragment of the medicines such as the peaceful alkali of camel, febrifugin(e), halofuginone hydrobromide, couroupitine A.These alkaloids are the effective constituent in the Chinese medicines such as camel wormwood artemisia, Changshan, Leaf of Indigowoad, have biological activity widely.Research in recent years shows, the quianzolinones of synthetic also has important biological activity.For example antifol Raltitrexed (Raltitrexed) from 1996 after Britain listing, for the treatment (Eur.J.Cancer, 2002,38,478-486) of late period knot, the rectum cancer.And another Quinazol derivative AG337 can suppress the tumour cell of resistance effectively, enter clinical trial (Cancer Chemother.Pharmacol., 1996,37,509-517).
Therefore, carrying out structure of modification taking the parent nucleus of quinazolinone as basis, is a feasible way finding to have better anti-cancer active compound.On the N of parent nucleus lactam bond, introducing aliphatic amide chain may make compound activity produce very large change or produce new pharmacologically active.Can predict that the Novel series alkaloid designing and synthesizing taking quinazolinone structure as parent nucleus may have good anti-tumor activity.
Summary of the invention
The object of this invention is to provide a kind of fat amido substituted quinazoline ketone derivatives.
Another object of the present invention is to provide the preparation method of above-mentioned fat amido substituted quinazoline ketone derivatives.
Another object of the present invention is to provide above-mentioned fat amido substituted quinazoline ketone derivatives in the application of preparing in antitumor drug.
Above-mentioned technical purpose of the present invention is achieved by following scheme:
A kind of fat amido substituted quinazoline ketone derivatives provided by the invention, has following chemical structure of general formula (I):
R in formula
1, R
2can be identical, also can be different, be selected from respectively C
1-6alkyl, C
3-6cycloalkyl, CH
2cH
3oCH
3or Bn; R
3oH, NH
2, NHR
4or NR
5r
6; R
4for C
1-6alkyl, C
3-6cycloalkyl; R
5, R
6be respectively C
1-6alkyl, C
3-6cycloalkyl, piperidyl, morpholinyl, piperazinyl or pyrryl; N=1,2,3 or 4.
The present invention also provides a kind of preparation method of fat amido substituted quinazoline ketone derivatives,
Reaction expression is:
R in reaction expression
1, R
2, R
3and n is as shown in claim 1;
This preparation method comprises the steps:
By above-mentioned Quinazol derivative
mix with reaction solvent acetonitrile, add salt of wormwood as catalyzer, add above-mentioned aliphatic amide chain, stir 10 hours at 80 DEG C, cooling rear suction filtration, by the concentrated filtrate solid of collecting, with purification by silica gel column chromatography, obtains fat amido substituted quinazoline ketone derivatives.
The mol ratio of above-mentioned Quinazol derivative and aliphatic amide chain is 1:1.2.
Reaction solvent acetonitrile adds in right amount.
Catalyzer carbonic acid potassium is excess molar ratio.
Fat amido substituted quinazoline ketone derivatives of the present invention 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. fat amido substituted quinazoline ketone derivatives of the present invention has significant restraining effect to multiple JEG-3;
2. fat amido substituted quinazoline ketone derivatives of the present invention is less to normal cytotoxicity, safe in the application of preparing antitumor drug;
3. fat amido substituted quinazoline ketone derivatives of the present invention can be made the antitumor drug of various formulations, has very high medical value and wide market outlook.
Embodiment
Embodiment 1
14 (n-butyl bromide-bis--methyl ethyl ether-quinazolinones)
Get salt of wormwood 0.235g and be dissolved in 30ml acetonitrile, heat 80 DEG C and stir 20Min, add 0.5g
keep 80 DEG C to stir 1h, add 0.44g1,4-dibromobutane, keeps 80 DEG C to stir 10h, and cooling rear suction filtration, by the concentrated filtrate solid of collecting, with purification by silica gel column chromatography, obtains white powder compound (title), and its chemical structural formula is as shown in formula II:
Productive rate: 87%; M.P.:169-171 DEG C;
1hNMR (400Hz.DMSO-d
6) 8.28 (1H, s), 7.5 (1H, s), 7.2 (1H, s), 4.27 (2H, d, J=8.0Hz), 4.26 (2H, t, J=8.0Hz), 3.99 (2H, s, J=8.0Hz), 3.73 (4H, t, J=8.0Hz), 3.57 (2H, t, J=8.0Hz), 3.33 (m, 4H), 2.50 (2H, d, J=8.0Hz), 1.82 (s, 4H) ESI-MSm/z450.91[M-I]
+; Ultimate analysis C
18h
25brN
2o
5, theoretical value C, 58.42; H, 3.79; N, 6.19. measured value C, 50.12; H, 4.01; N, 5.93.
Embodiment 2
Compound 6, two (2-methoxy ethoxy)-3 – butyl pyrrolidine-quinazolinones of 7-synthetic
Get salt of wormwood 0.235g and be dissolved in 30ml acetonitrile, heat 80 DEG C and stir 20Min, add 0.5g6, two (2-methoxy ethoxy) quinazolinones of 7-, keep 80 DEG C to stir 1h, add 0.44g4-brombutyl tetramethyleneimine, keep 80 DEG C to stir 10h, cooling rear suction filtration, by the concentrated filtrate solid of collecting, with purification by silica gel column chromatography, obtain white powder compound 6, two (2-methoxy ethoxy)-3 – butyl pyrrolidine-quinazolinones of 7-, its structural formula is as shown in formula III:
Productive rate: 88%; M.P.:169-171 DEG C;
1hNMR (400Hz, DMSO-d
6) 8.28 (1H, s), 7.48 (1H, s), 7.16 (1H, s), 4.26 (2H, t, J=4.0Hz), 4.22 (2H, t, J=4.0Hz), 3.94 (2H, t, J=6.0Hz), 3.73 (4H, m), 3.41 (6H, s), 2.38 (6H, m), 1.72 (2H, t, J=7.2Hz), 1.64 (4H, m), 1.43 (2H, m) ESI-MSm/z420.09[M-I]
+; Ultimate analysis C
22h
33n
3o
5, theoretical value C, 58.42; H, 3.79; N, 6.19. measured value C, 56.22; H, 4.01; N, 5.50.
Embodiment 3
Compound 6, two (2-methoxy ethoxy)-3 – (the 4-propyl group morpholine) quinazolinones of 7-synthetic
The preparation method of the present embodiment is except replacing 4-brombutyl tetramethyleneimine with 3-bromopropyl morpholino, all the other are with embodiment 1, finally obtain white powder compound 6, two (2-methoxy ethoxy)-3 – (the 4-propyl group morpholine) quinazolinones of 7-, its structural formula is as shown in formula IV:
Productive rate: 87%; M.P.:169-171 DEG C;
1hNMR (400Hz.DMSO-d
6) 8.26 (1H, s), 7.48 (1H, s), 7.15 (1H, s), 4.27 (2H, t, J=4.0Hz), 4.20 (2H, t, J=4.0Hz), 3.99 (2H, t, J=4.0Hz), 3.72 (4H, m), 3.49 (4H, m), 3.36 (6H, m), 2.31 (6H, m), 1.86 (2H, m) ESI-MSm/z421.22[M-I]
+; Ultimate analysis C
21h
31n
3o
6, theoretical value C, 58.42; H, 3.79; N, 6.19. measured value C, 49.22; H, 4.01; N, 5.50.
Embodiment 4
Two (2-the methoxy ethoxy)-3-(4-piperidyl methyl tert-butyl acrylates of 6,7-) quinazolinone synthetic
The preparation method of the present embodiment is except replacing 4-brombutyl tetramethyleneimine with 4-bromine piperidyl methyl tert-butyl acrylate, all the other are with embodiment 1, finally white powder compound 6, two (2-the methoxy ethoxy)-3-(4-bromine piperidyl methyl tert-butyl acrylates of 7-) its structural formula of quinazolinone is suc as formula shown in (V):
Productive rate: 87%; M.P.:169-171 DEG C;
1hNMR (400Hz.DMSO-d
6) 8.24 (1H, s), 7.49 (1H, s), 7.17 (1H, s), 4.26 (2H, t, J=8.0Hz), 4.21 (2H, t, J=4HZ), (3.95 2H, m), 3.86 (2H, t, J=4.0Hz), 3.72 (4H, m), 3.36 (8H, m), (1.98 1H, m), 1.53 (2H, m), 1.39 (9H, m), 1.12 (2H, m) ESI-MSm/z429.21[M-I]
+; Ultimate analysis C
21h
28n
3o
6, theoretical value C, 58.42; H, 3.79; N, 6.19. measured value C, 49.22; H, 4.01; N, 5.50.
Embodiment 5
7-(benzyloxy)-6-methoxyl group-3-(3-propyl group morpholine) quinazolinone synthetic
The preparation method embodiment 1 of this present embodiment, difference is to use 7-(benzyloxy)-6-(methoxyl group) quinazolinone alternative 6, two (2-methoxy ethoxy) quinazolinones of 7-, with the alternative 4-brombutyl tetramethyleneimine of 3-bromopropyl morpholine, obtain white powder compound 7-(benzyloxy)-6-methoxyl group-3-(3-morpholino propyl group) quinazolinone, its structural formula is as shown in formula VI:
Productive rate: 82%; M.P.:169-171 DEG C;
1hNMR (400Hz.DMSO-d
6) 8.27 (1H, s), 7.50 (3H, m), 7.44 (2H, d, J=8HZ), 7.36 (1H, m), 7.23 (1H, s), 5.26 (2H, s), 4.01 (2H, t, J=8.0Hz), 3.88 (3H, s), 3.50 (4H, m), 2,31(6H, m), 1.86 (2H, m) ESI-MSm/z409.20[M-I]
+; Ultimate analysis C
23h
27n
3o
4, theoretical value C, 58.42; H, 3.79; N, 6.19. measured value C, 54,79; H, 4.01; N, 5.92.
Embodiment 6
7-(benzyloxy)-6-methoxyl group-3-(4-piperidyl methyl tert-butyl acrylate) quinazolinone synthetic
The preparation method embodiment 1 of the present embodiment, difference is to use 7-(benzyloxy)-6-(methoxyl group) quinazolinone alternative 6, two (2-methoxy ethoxy) quinazolinones of 7-, with the alternative 4-brombutyl tetramethyleneimine of 4-bromine piperidyl methyl tert-butyl acrylate, finally obtain white powder compound 7-(benzyloxy)-6-methoxyl group-3-(3-morpholino propyl group) quinazolinone, its structural formula is suc as formula shown in (VII):
Productive rate: 87%; M.P.:169-171 DEG C;
1hNMR (400Hz.DMSO-d
6) 8.24 (1H, s), 7.49 (3H, m), 7.43 (2H, d, J=4HZ), 7.35 (1H, m), (7.24 1H, s), 5.27 (2H, s), 3.89 (3H, m),, 2.67 (2H, d, J=8.0Hz), 2.51 (4H, m), (1.98 1H, s), 1.52 (2H, d, J=12.0Hz), 1.39 (9H, m), 1.1 (2H, m) ESI-MSm/z417.27[M-I]
+; Ultimate analysis C
23h
27n
3o
4, theoretical value C, 58.42; H, 3.79; N, 6.19. measured value C, 54,21; H, 4.01; N, 5.80.
Embodiment 7
7-(benzyloxy)-6-(methoxyl group)-3-(4-methyl piperidine) quinazolinone synthetic
The preparation method embodiment 1 of the present embodiment, difference is to use 7-(benzyloxy)-6-(methoxyl group) quinazolinone alternative 6, two (2-methoxy ethoxy) quinazolinones of 7-, with the alternative 4-brombutyl tetramethyleneimine of 4 – brooethyl piperidines, finally obtain white powder compound 7-(benzyloxy)-6-(methoxyl group)-3-(4-methyl piperidine) quinazolinone, its structural formula is suc as formula shown in (VII):
Productive rate: 82%; M.P.:169-171 DEG C;
1hNMR (400Hz.DMSO-d
6) 8.23 (1H, s), 7.49 (3H, m), 7.42 (2H, t, J=8Hz), 7.41 (1H, s), (5.27 2H, s), 3.89 (3H, s), 3.83 (2H, d, J=4.0Hz), 2.89 (1H, s), (2.51 4H, m), 2.36 (1H, m), 1.85 (1H, m), 1.43 (2H, d, J=12.0Hz), 1.07 (2H, m) .ESI-MSm/z417.27[M-I]
+; Ultimate analysis C
22h
5n
3o
3, theoretical value C, 58.42; H, 3.79; N, 6.19. measured value C, 56.34; H, 4.01; N, 5.50.
Embodiment 8
The restraining effect of fat amido substituted quinazoline ketone derivatives to growth of tumour cell
Select the compound of embodiment 4～6 preparation, with three kinds of tumor cell line MCF-7 (human breast cancer cell strain), GLC-82(human lung adenocarcinoma cell line), PC-3(human prostate cancer cell line), adopt mtt assay to carry out cell in vitro poison and measure.Logarithmic phase cell adds the fat amido substituted quinazoline ketone derivatives of different concns, acts on after 48 hours, measures its absorbancy.Compound concentration when calculating respectively cell growth inhibiting and reaching 50%, with IC
50value representation, result is as shown in table 2.Result shows, fat amido substituted quinazoline ketone derivatives of the present invention all has stronger restraining effect to these three kinds of tumor cell lines in vitro.Therefore fat amido substituted quinazoline ketone derivatives of the present invention can be used for preparing anticancer medicine.
Restraining effect (the IC of table 1 fat amido substituted quinazoline of the present invention ketone derivatives to tumor cell line growth
50/ μ M)
Embodiment 9 fat amido substituted quinazoline ketone derivatives acute toxicity tests
The compound (with compound 6, two (2-methoxy ethoxy)-3 – (the 4-propyl group morpholine) quinazolinones of 7-are example) of selecting part of representative, carries out acute toxicity test.Get 18-22 gram of mouse and divide six groups at random, every group of 10 mouse, use respectively physiological saline, DMSO2.5ml/kg, compound 6, two (2-methoxy ethoxy)-3 – (4-propyl group morpholine) the quinazolinone 800mg/kg of 7-, compound 6, two (2-methoxy ethoxy)-3 – (4-propyl group morpholine) the quinazolinone 500mg/kg of 7-, compound 6, two (2-methoxy ethoxy)-3 – (4-propyl group morpholine) the quinazolinone 250mg/kg of 7-, compound 6, two (2-methoxy ethoxy)-3 – (4-propyl group morpholine) the quinazolinone 100mg/kg of 7-, compound 6, two (2-methoxy ethoxy)-3 – (4-propyl group morpholine) the quinazolinone 50mg/kg of 7-process, observe 14 days, 46% death of the visible 800mg/kg group of result mouse, it is compound 6, two (2-methoxy ethoxy)-3 – (the 4-propyl group morpholine) quinazolinones of 7-are approximately 500mg/kg to the acute toxicity LD50 value of mouse.Therefore of the present invention 6, the acute toxicity of two (2-methoxy ethoxy)-3 – (the 4-propyl group morpholine) quinazolinones of 7-is less, can be used for preparing cancer therapy drug.
Claims (5)
1. a fat amido substituted quinazoline ketone derivatives, is characterized in that chemical structural formula is suc as formula shown in I:
In formula, n=1,2,3 or 4;
R
1, R
2can be identical, also can be different, be selected from respectively C
1-6alkyl, C
3-6cycloalkyl, CH
2cH
3oCH
3or Bn;
R
3for OH, NH
2, NHR
4or NR
5r
6;
R
4for C
1-6alkyl, C
3-6cycloalkyl;
R
5, R
6be respectively C
1-6alkyl, C
3-6cycloalkyl, piperidyl, morpholinyl, piperazinyl or pyrryl.
2. a preparation method for fat amido substituted quinazoline ketone derivatives claimed in claim 1, is characterized in that:
Reaction expression is:
R in reaction expression
1, R
2, R
3and n is as shown in claim 1;
This preparation method comprises the steps:
By above-mentioned Quinazol derivative
mix with reaction solvent acetonitrile, add salt of wormwood as catalyzer, add above-mentioned aliphatic amide chain, stir 10 hours at 80 DEG C, cooling rear suction filtration, by the concentrated filtrate solid of collecting, with purification by silica gel column chromatography, obtains fat amido substituted quinazoline ketone derivatives.
3. preparation method according to claim 2, is characterized in that: the mol ratio of above-mentioned Quinazol derivative and aliphatic amide chain is 1:1.2.
4. a fat amido substituted quinazoline ketone derivatives claimed in claim 1 is in the application of preparing in antitumor drug.
5. application according to claim 4, is characterized in that: the formulation of described antitumor drug is tablet, pill, capsule, injection, suspension agent or emulsion.
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