CN101723894B - N-quinoline amide derivatives and preparation method and application thereof - Google Patents
N-quinoline amide derivatives and preparation method and application thereof Download PDFInfo
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- CN101723894B CN101723894B CN2009102321985A CN200910232198A CN101723894B CN 101723894 B CN101723894 B CN 101723894B CN 2009102321985 A CN2009102321985 A CN 2009102321985A CN 200910232198 A CN200910232198 A CN 200910232198A CN 101723894 B CN101723894 B CN 101723894B
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- 0 CC(NC(c1cccc(C)c1O)=O)=C1N=CC=CC1=* Chemical compound CC(NC(c1cccc(C)c1O)=O)=C1N=CC=CC1=* 0.000 description 1
- VQGPXZMYXXKECU-UHFFFAOYSA-N COC(c(ccc(OC)n1)c1[BrH]I)Nc1c2ncccc2ccc1 Chemical compound COC(c(ccc(OC)n1)c1[BrH]I)Nc1c2ncccc2ccc1 VQGPXZMYXXKECU-UHFFFAOYSA-N 0.000 description 1
- JMYBJCKNXAOOEP-UHFFFAOYSA-N Cc1ccc(C(Nc2cccc3c2nccc3)=O)c(Br)n1 Chemical compound Cc1ccc(C(Nc2cccc3c2nccc3)=O)c(Br)n1 JMYBJCKNXAOOEP-UHFFFAOYSA-N 0.000 description 1
- ZIAPZGPAZUMZBU-UHFFFAOYSA-N Oc(c(Br)ccc1)c1C(Nc1c2ncccc2ccc1)=O Chemical compound Oc(c(Br)ccc1)c1C(Nc1c2ncccc2ccc1)=O ZIAPZGPAZUMZBU-UHFFFAOYSA-N 0.000 description 1
- SNRCUUQWTRCNEH-UHFFFAOYSA-N Oc1cc(I)ccc1C(Nc1c2ncccc2ccc1)=O Chemical compound Oc1cc(I)ccc1C(Nc1c2ncccc2ccc1)=O SNRCUUQWTRCNEH-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses quinoline amide derivatives which are characterized by comprising the following general formula. in the general formula, when X is equal to C and R1 is equal to OH, R2 is equal to CH3, C1, BR and F or I and R3, R4, R5 and H are equal; or R3 is equal to Br, F or I, and R2, R4, R5 and H are equal; or R4 is equal to Br, F or I and R2, R3, R5 and H are equal; or R5 is equal toCl, Br, F or I and R2, R3, R4 and H are equal; when X is equal to N, R4 is equal to CH3, R1 is equal to Cl, Br, F or I, R2, R3 and H are equal and R5 is not included; and or R1 is equal to Cl, Br, For I, R4 is equal to OH or H, R3 is equal to H and R5 is not included. Founded by the research, the quinoline amide derivatives have strong specific bonding ability with VEGFR and the bonding of vascular endothelial growth factors in tumor cells and the VEGFR is blocked off by the bonding of the quinoline amide derivatives and the VEGFR, thereby fundamentally inhibiting the vasculogenesis and signal transduction of cancer cells and inhibiting the proliferation of the cancer cells, therefore, the quinoline amide derivatives can be applied to preparing an anti-tumor medicament. The invention also discloses the preparation method of the quinoline amide derivatives.
Description
Technical field
The present invention relates to quinoline amide derivatives and preparation method thereof and purposes.
Background technology
Nearly ten years, owing to found the effect of angiogenesis factor to vasculogenesis, and vasculogenesis to tumor growth and invade to shift, especially to the early stage material impact that takes place of tumour, vasculogenesis becomes one of focus of tumor research in recent years, for a new thinking has been opened up in oncotherapy.The immunocyte of matter between tumour cell or its host, (vumor angiogenesis factor, TAF), wherein the effect of vascular endothelial growth factor (VEGF) is the most important to produce the kinds of tumors angiogenesis factor as scavenger cell and inoblast.VEGF is that known intensive directly activates angiogenin protein, is soluble vascular endothelial mitogenic element and angiogenesis factor, and can increases vascular permeability.It combines and works with tyrosine kinase receptor Flt and KDR on the tapetum cell.Tumour source property VEGF plays an important role in the paracrine of vasculogenesis stimulates, and also tumour source property VEGF is played an important role in the paracrine of vasculogenesis stimulates.Also the autocrine stimulation to tumour cell works, and especially anoxic is reacted.Anoxic stimulates vasculogenesis by the thin receptor KDR of endothelium that raises VEGF.The expression of VEGF is subjected to ras gene and p53 generegulation, and the ras gene raises the expression of VEGF, and the wild type p53 gene then reduces the expression of VEGF.Excessive vegf expression sharply increases vasculogenesis, causes the tumour expansion, and it has important oncobiology meaning.
Quinoline amide derivatives is the broad-spectrum compound of a class, and it is parent with the quinolyl amine, combines by amido linkage with the Whitfield's ointment and the nicotinic acid derivates that replace.The derivative that with the quinoline is parent has multiple biological activity, comprises effects such as antimalarial disease, anti-diabetic and anti-HIV.Moreover, this compounds shows great potential in cancer therapy drug research.Play a role mainly as receptor tyrosine kinase inhibitors, comprise transforming growth factor receptor (TGFR), fibroblast growth factor acceptor (FGFR), platelet derived growth factor receptor (PDGFR), vascular endothelial growth factor (VEGFR).The quinolyl amine derivative is owing to contain the different amido linkages that replace in the structure, and asymmetric unit is the common constitutional features of many enzyme inhibitorss and biosimulation peptide, so most biologically active.Therefore, the quinoline amides compounds is with a wide range of applications.This patent discovers that quinoline amide derivatives can combine with the ATP-binding site of VEGFR competitively, thereby suppresses combining of cancer cell medium vessels somatomedin and its acceptor, reaches the purpose that suppresses the cancer cell growth and spread.
Summary of the invention
The object of the present invention is to provide a class novel quinoline amide derivatives and their preparation method and purposes.
Technical scheme of the present invention is as follows:
One class quinoline amide derivatives is characterized in that it has following general formula:
In the formula: work as X=C, R
1During=OH, R
2=CH
3, Cl, Br, F or I, R
3=R
4=R
5=H; Perhaps R
3=Br, F or I, R
2=R
4=R
5=H; Perhaps R
4=Br, F or I, R
2=R
3=R
5=H; Perhaps R
5=Cl, Br, F or I, then R
2=R
3=R
4=H;
When X=N, R
4=CH
3, R
1=Cl, Br, F or I, R
2=R
3=H, no R
5Perhaps R
1=Cl, Br, F or I, R
4=OH or H, R
3=H, no R
5
A kind of method for preparing above-mentioned N-quinoline amide derivatives, it is made up of the following step:
Step 1. is dissolved in anhydrous CH with the corresponding substituted benzoic acid or the nicotinic acid of 8-quinolylamine with the amount of substance such as grade
2Cl
2In, and 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) that adds catalytic amount is as catalyzer, and heating is stirred, and in 40 ℃ of following back flow reaction 8h, obtains clarifying reaction liquid;
Step 2. adds 200-300 purpose column chromatography silica gel in reaction solution, stir underpressure distillation down, removing unnecessary solvent and to make it abundant mixing, the silica gel Urea post of gained is carried out column chromatography, with ethyl acetate: the mixed solvent of sherwood oil=1: 2 is isolated target product as elutriant;
Step 3. is removed the elutriant underpressure distillation that obtains and is desolvated, and purifying promptly obtains N-quinoline amide derivatives of the present invention.
The method for making of above-mentioned N-quinoline amide derivatives, the described anhydrous CH of step 1
2Cl
2Consumption can be every mmole substd quinolines amine solubilizing agent 5ml.
The method for making of above-mentioned N-quinoline amide derivatives, the consumption of the described 1-of step 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride can be that every mmole substd quinolines amine adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 200mg.
The method for making of above-mentioned N-quinoline amide derivatives, the consumption of the described column chromatography silica gel of step 2 can be every mmole substd quinolines amine silica gel 40ml.
Discover quinoline amide derivatives of the present invention, with VEGFR very strong specific binding capacity is arranged, by with the combining of VEGFR, blood vessel endothelium growth factor in the blocking-up tumour cell combines with VEGFR's, thereby the fundamentally vasculogenesis of anticancer and signal transduction, the propagation of anticancer.Therefore N-quinoline amide derivatives of the present invention can be applied to prepare antitumor drug.
Embodiment
Embodiment one: the preparation of 2-hydroxyl-6-methyl-N-(quinoline-8-yl) benzamide (compound 1)
Add 1mmol 6-cresotinic acid and 1mmol 8-quinolylamine in the 50ml single necked round bottom flask, the 1-of 200mg (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) is as catalyzer, and the anhydrous CH of adding 5ml
2Cl
2As reaction solvent.Use magnetic stirrer, and in oil bath pan with 40 ℃ of reflux, react after 8 hours, obtain clarifying reaction liquid.40ml 200-300 purpose column chromatography silica gel is joined in the reaction solution, with Rotary Evaporators decompression rotation, to remove unnecessary solvent and to make it abundant mixing.With column chromatography separate targets product, with ethyl acetate: the mixed solvent of sherwood oil=1: 2 carries out wash-out.The elutriant that obtains is used the Rotary Evaporators underpressure distillation once more, remove and desolvate, promptly obtain the white powder target compound.Productive rate 77%, mp:163-165 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 2.42 (s, 1H); 6.95 (d, J=8.4Hz, 1H); 7.27 (d, J=8.4Hz, 1H); 7.50 (dd, J=8.4,4.2Hz, 1H); 7.57 (d, J=3.3Hz, 3H), 8.20 (dd, J=8.2,1.7Hz, 1H); 8.82 (t, J=7.8,1.9Hz, 1H); 8.90 (dd, J=4.5,1.6Hz, 1H); 10.90 (s, 1H); 12.09 (s, 1H); MS (ESI): 279.11 (C
17H
15N
2O
2 +, [M+H]
+) .Anal.Calcd for C
17H
14N
2O
2: C, 73.37; H, 5.07; N, 10.07; O, 11.50; Found:C, 73.32; H, 5.08; N, 10.01; O, 11.43.
Embodiment two: the preparation of 2-fluoro-6-hydroxy-n-(quinoline-8-yl) benzamide (compound 2)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 6-fluorosalicylic acid, obtain yellow powder shape target compound.Productive rate 78%, mp:178-179 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.10 (d, J=8.4Hz, 1H); 7.41 (dd, J=8.8,2.2Hz, 1H); 7.51-7.54 (m, 1H); 7.58 (d, J=3.6Hz, 2H); 7.77 (d, J=2.7Hz, 1H); 8.12 (dd, J=8.0,1.6Hz, 1H); 8.78 (t, J=4.7Hz, 1H); 8.88 (dd, J=4.2,1.5Hz, 1H); 10.93 (s, 1H); 12.13 (s, 1H); MS (ESI): 283.08 (C
16H
12FN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11FN
2O
2: C, 68.08; H, 3.03; F, 6.73; N, 9.92; O, 11.34; Found:C, 68.16; H, 3.08; F, 6.81; N, 9.87; O, 11.26.
Embodiment three: the preparation of 2-chloro-6-hydroxy-n-(quinoline-8-yl) benzamide (compound 3)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 6-chloro-salicylic acid, obtain the white powder target compound.Productive rate 88%, mp:165-166 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.03 (d, J=8.9Hz, 1H); 7.41 (dd, J=8.8,2.4Hz, 1H); 7.50-7.55 (m, 1H); 7.63 (d, J=3.7Hz, 2H); 7.81 (d, J=2.4Hz, 1H); 8.21 (dd, J=8.2,1.5Hz, 1H); 8.83 (t, J=4.4Hz, 1H); 8.91 (dd, J=4.1,1.6Hz, 1H); 10.90 (s, 1H); 12.25 (s, 1H); MS (ESI): 299.05 (C
16H
12ClN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11ClN
2O
2: C, 64.33; H, 3.71; Cl, 11.87; N, 9.38; O, 10.71; Found:C, 64.26; H, 3.68; Cl, 11.80; N, 9.33; O, 10.68.
Embodiment four: the preparation of 2-bromo-6-hydroxy-n-(quinoline-8-yl) benzamide (compound 4)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 6-bromo ortho-oxybenzoic acid, obtain brown powder shape target compound.Productive rate 75%, mp:189-190 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.00 (d, J=8.9Hz, 1H); 7.41 (dd, J=8.9,2.4Hz, 1H); 7.50-7.54 (m, 1H); 7.60 (d, J=3.9Hz, 2H); 7.80 (d, J=2.4Hz, 1H); 8.22 (dd, J=8.2,1.5Hz, 1H); 8.80 (t, J=4.5Hz, 1H); 8.92 (dd, J=4.2,1.7Hz, 1H); 10.90 (s, 1H); 12.23 (s, 1H); MS (ESI): 343.00 (C
16H
12BrN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11BrN
2O
2: C, 56.00; H, 3.23; Br, 23.28; N, 8.16; O, 9.32; Found:C, 56.07; H, 3.21; Br, 23.19; N, 8.12; O, 9.26.
Embodiment five: the preparation of 2-hydroxyl-6-iodo-N-(quinoline-8-yl) benzamide (compound 5)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 6-iodo-salicylic acid, obtain yellow powder shape target compound.Productive rate 78%, mp:203-204 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.12 (d, J=8.6Hz, 1H); 7.38 (dd, J=8.5,2.3Hz, 1H); 7.49-7.55 (m, 1H); 7.67 (d, J=3.7Hz, 2H); 7.87 (d, J=2.5Hz, 1H); 8.32 (dd, J=8.2,1.7Hz, 1H); 8.70 (t, J=4.3Hz, 1H); 8.88 (dd, J=4.0,1.7Hz, 1H); 10.94 (s, 1H); 12.26 (s, 1H); MS (ESI): 390.99 (C
16H
12IN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11IN
2O
2: C, 49.25; H, 2.84; I, 32.52; N, 7.18; O, 8.20; Found:C, 49.18; H, 2.81; I, 32.46; N, 7.12; O, 8.23.
Embodiment six: the preparation of 5-fluoro-2-hydroxy-n-(quinoline-8-yl) benzamide (compound 6)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 5-fluorosalicylic acid, obtain pale powder shape target compound.Productive rate 71%, mp:178-179 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.15 (d, J=8.4Hz, 1H); 7.41 (dd, J=8.8,2.2Hz, 1H); 7.49-7.53 (m, 1H); 7.65 (d, J=3.6Hz, 2H); 7.73 (d, J=2.7Hz, 1H); 8.12 (dd, J=8.0,1.6Hz, 1H); 8.78 (t, J=4.7Hz, 1H); 8.87 (dd, J=4.2,1.5Hz, 1H); 10.93 (s, 1H); 12.13 (s, 1H); MS (ESI): 283.08 (C
16H
12FN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11FN
2O
2: C, 68.08; H, 3.03; F, 6.73; N, 9.92; O, 11.34; Found:C, 68.14; H, 3.01; F, 6.80; N, 9.89; O, 11.29.
Embodiment seven: the preparation of 5-bromo-2-hydroxy-n-(quinoline-8-yl) benzamide (compound 7)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 5 bromosalicylic acid, obtain pale yellow powder shape target compound.Productive rate 80%, mp:187-188 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 6.95 (d, J=8.8Hz, 1H); 7.48-7.55 (m, 1H); 7.60 (d, J=3.9Hz, 2H); 7.93 (d, J=2.3Hz, 1H); 8.25 (dd, J=9.6,2.6Hz, 1H); 8.80 (t, J=4.5Hz, 1H); 8.92 (dd, J=4.4,1.7Hz, 1H); 10.66 (s, 1H); 12.26 (s, 1H); MS (ESI): 343.00 (C
16H
12BrN
2O
2 +, [M+H]
+) .Anal.Calcd for C
13H
17FN
2O
2: C, 56.00; H, 3.23; Br, 23.28; N, 8.16; O, 9.32; Found:C, 56.07; H, 3.20; Br, 23.24; N, 8.14; O, 9.29.
Embodiment eight: the preparation of 2-hydroxyl-5-iodo-N-(quinoline-8-yl) benzamide (compound 8)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 5-iodo-salicylic acid, obtain pale powder shape target compound.Productive rate 82%, mp:173-175 ℃.
1H NMR (300MHz, d
6-DMSO): 6.95 (d, J=8.8Hz, 1H); 7.48-7.55 (m, 1H); 7.60 (d, J=3.9Hz, 2H); 7.93 (d, J=2.3Hz, 1H); 8.25 (dd, J=9.6,2.6Hz, 1H); 8.80 (t, J=4.5Hz, 1H); 8.92 (dd, J=4.4,1.7Hz, 1H); 10.66 (s, 1H); 12.26 (s, 1H); MS (ESI): 390.99 (C
16H
12IN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11IN
2O
2: C, 49.25; H, 2.84; I, 32.52; N, 7.18; O, 8.20; Found:C, 49.18; H, 2.81; I, 32.46; N, 7.12; O, 8.23.
Embodiment nine: the preparation of 4-fluoro-2-hydroxy-n-(quinoline-8-yl) benzamide (compound 9)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 4-fluorosalicylic acid, obtain light grey Powdered target compound.Productive rate 85%, mp:194-195 ℃.
1H NMR (500MHz, CDCl
3, δ, ppm): 7.14 (d, J=8.4Hz, 1H); 7.40 (dd, J=8.6,2.0Hz, 1H); 7.48-7.53 (m, 1H); 7.64 (d, J=3.9Hz, 2H); 7.73 (d, J=2.7Hz, 1H); 8.12 (dd, J=8.0,1.6Hz, 1H); 8.78 (t, J=4.7Hz, 1H); 8.89 (dd, J=4.2,1.5Hz, 1H); 10.93 (s, 1H); 12.13 (s, 1H); MS (ESI): 283.08 (C
16H
12FN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11FN
2O
2: C, 68.08; H, 3.03; F, 6.73; N, 9.92; O, 11.34; Found:C, 68.12; H, 3.00; F, 6.85; N, 9.86; O, 11.29.
Embodiment ten: the preparation of benzamide (compound 10) 2-hydroxyl-4-iodo-N-quinoline-8-yl)
The preparation method is with embodiment one.The 4-iodo-salicylic acid replaces the 6-cresotinic acid, obtains yellow powder shape target compound.Productive rate 80%, mp:187-188 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 6.92 (d, J=8.8Hz, 1H); 7.48-7.55 (m, 1H); 7.60 (d, J=3.8Hz, 2H); 7.94 (d, J=2.4Hz, 1H); 8.28 (dd, J=9.6,2.6Hz, 1H); 8.80 (t, J=4.5Hz, 1H); 8.90 (dd, J=4.3,1.7Hz, 1H); 10.63 (s, 1H); 12.32 (s, 1H) .MS (ESI): 390.99 (C
16H
12IN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11IN
2O
2: C, 49.25; H, 2.84; I, 32.52; N, 7.18; O, 8.20; Found:C, 49.19; H, 2.79; I, 32.49; N, 7.10; O, 8.25.
Embodiment 11: the preparation of 4-bromo-2-hydroxy-n-(quinoline-8-yl) benzamide (compound 11)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 4-bromo ortho-oxybenzoic acid, obtain the white powder target compound.Productive rate 81%, mp:177-178 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 6.92 (d, J=8.8Hz, 1H); 7.48-7.55 (m, 1H); 7.60 (d, J=3.8Hz, 2H); 7.94 (d, J=2.4Hz, 1H); 8.28 (dd, J=9.6,2.6Hz, 1H); 8.80 (t, J=4.5Hz, 1H); 8.90 (dd, J=4.3,1.7Hz, 1H); 10.63 (s, 1H); 12.32 (s, 1H); MS (ESI): 343.00 (C
16H
12BrN
2O
2 +, [M+H]
+) .Anal.Calcd for C
13H
17BrN
2O
2: C, 56.00; H, 3.23; Br, 23.28; N, 8.16; O, 9.32; Found:C, 56.07; H, 3.20; Br, 23.24; N, 8.14; O, 9.29.
Embodiment 12: the preparation of 3-chloro-2-hydroxy-n-(quinoline-8-yl) benzamide (compound 12)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 3-chloro-salicylic acid, obtain the white powder target compound.Productive rate 75%, mp:198-199 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 6.98 (d, J=8.9Hz, 1H); 7.49-7.54 (m, 1H); 7.64 (d, J=3.8Hz, 2H); 7.90 (d, J=2.2Hz, 1H); 8.18 (dd, J=9.6,2.6Hz, 1H); 8.80 (t, J=4.5Hz, 1H); 8.94 (dd, J=4.3,1.7Hz, 1H); 10.63 (s, 1H); 12.22 (s, 1H) .MS (ESI): 299.05 (C
16H
12ClN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11ClN
2O
2: C, 64.33; H, 3.71; Cl, 11.87; N, 9.38; O, 10.71; Found:C, 64.23; H, 3.68; Cl, 11.80; N, 9.32; O, 10.67.
Embodiment 13: the preparation of 3-bromo-2-hydroxy-n-(quinoline-8-yl) benzamide (compound 13)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 3-bromo ortho-oxybenzoic acid, obtain brown ceramic powder shape target compound.Productive rate 80%, mp:182-183 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 6.95 (d, J=8.8Hz, 1H); 7.48-7.55 (m, 1H); 7.60 (d, J=3.9Hz, 2H); 7.93 (d, J=2.3Hz, 1H); 8.25 (dd, J=9.6,2.6Hz, 1H); 8.80 (t, J=4.5Hz, 1H); 8.92 (dd, J=4.4,1.7Hz, 1H); 10.66 (s, 1H); 12.26 (s, 1H); MS (ESI): 343.00 (C
16H
12BrN
2O
2 +, [M+H]
+) .Anal.Calcd for C
13H
17BrN
2O
2: C, 56.00; H, 3.23; Br, 23.28; N, 8.16; O, 9.32; Found:C, 56.08; H, 3.21; Br, 23.26; N, 8.14; O, 9.28.
Embodiment 14: the preparation of 3-fluoro-2-hydroxy-n-(quinoline-8-yl) benzamide (compound 14)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 3-fluorosalicylic acid, obtain light grey Powdered target compound.Productive rate 80%, mp:163-165 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.07 (d, J=8.8Hz, 1H); 7.49-7.53 (m, 1H); 7.65 (d, J=3.7Hz, 2H); 7.94 (d, J=2.4Hz, 1H); 8.29 (dd, J=9.6,2.6Hz, 1H); 8.85 (t, J=4.7Hz, 1H); 8.96 (dd, J=4.2,1.7Hz, 1H); 10.62 (s, 1H); 12.28 (s, 1H) .MS (ESI): 283.08 (C
16H
12FN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11FN
2O
2: C, 68.08; H, 3.03; F, 6.73; N, 9.92; O, 11.34; Found:C, 68.13; H, 3.01; F, 6.80; N, 9.85; O, 11.29.
Embodiment 15: the preparation of 2-hydroxyl-3-iodo-N-(quinoline-8-yl) benzamide (compound 15)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 3-iodo-salicylic acid, obtain the white powder target compound.Productive rate 79%, mp:241-243 ℃.
1H NMR (300MHz, d
6-DMSO): 6.96 (d, J=8.8Hz, 2H); 7.18 (d, J=8.2Hz, 2H); 7.58 (dd, J
1=2.2,8.8Hz, 3H); 8.10 (d, J=2.4Hz, 2H); 10.34 (s, 1H); 11.95 (s, 1H) .MS (ESI): 390.99 (C
16H
12IN
2O
2 +, [M+H]
+) .Anal.Calcd for C
16H
11IN
2O
2: C, 49.25; H, 2.84; I, 32.52; N, 7.18; O, 8.20; Found:C, 49.19; H, 2.79; I, 32.49; N, 7.10; O, 8.25.
Embodiment 16: the preparation of 2-chloro-6-methyl-N-(quinoline-8-yl) niacinamide (compound 16)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-chloro-6-methylnicotinic acid, obtain light grey Powdered target compound.Productive rate 83%, mp:123-124 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 2.56 (s, 3H); 7.45 (d, J=4.7Hz, 1H); 7.64-7.68 (m, 2H); 7.77 (dd, J=4.6,0.8Hz, 1H); 8.11 (d, J=4.8Hz, 1H); 8.45 (dd, J=4.9,0.9Hz, 1H); 8.72 (d, J=4.8Hz, 1H); 8.92 (d, J=1.2Hz, 1H); 10.70 (s, 1H); MS (ESI): 298.07 (C
16H
13ClN
3O
+, [M+H]
+) .Anal.Calcd for C
16H
12ClN
3O:C, 64.54; H, 4.06; Cl, 11.91; N, 14.11; O, 5.37; Found:C, 64.50; H, 4.04; Cl, 11.84; N, 14.05; O, 5.33.
Embodiment 17: the preparation of 2-fluoro-6-methyl-N-(quinoline-8-yl) niacinamide (compound 17)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-fluoro-6-methylnicotinic acid, obtain brown ceramic powder shape target compound.Productive rate 85%, mp:137-139 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 2.53 (s, 3H); 7.42 (d, J=4.8Hz, 1H); 7.62-7.65 (m, 2H); 7.75 (dd, J=4.8,0.8Hz, 1H); 8.10 (d, J=4.6Hz, 1H); 8.39 (dd, J=4.7,0.9Hz, 1H); 8.70 (d, J=4.7Hz, 1H); 8.89 (d, J=1.2Hz, 1H); 10.74 (s, 1H); MS (ESI): 282.10 (C
16H
13FN
3O
+, [M+H]
+) .Anal.Calcd for C
16H
12FN
3O:C, 68.32; H, 4.30; F, 6.75; N, 14.94; O, 5.69; Found:C, 68.32; H, 4.30; F, 6.75; N, 14.94; O, 5.69.
Embodiment 18: the preparation of 2-bromo-6-methyl-N-(quinoline-8-yl) niacinamide (compound 18)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-bromo-6-methylnicotinic acid, obtain brown ceramic powder shape target compound.Productive rate 79%, mp:145-146 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 2.56 (s, 3H); 7.45 (d, J=4.7Hz, 1H); 7.66-7.68 (m, 2H); 7.76 (dd, J=4.6,0.8Hz, 1H); 8.01 (d, J=4.8Hz, 1H); 8.47 (dd, J=4.5,0.9Hz, 1H); 8.70 (d, J=4.8Hz, 1H); 8.92 (d, J=1.1Hz, 1H); 10.70 (s, 1H); MS (ESI): 342.02 (C
16H
13BrN
3O
+, [M+H]
+) .Anal.Calcd for C
16H
12BrN
3O:C, 56.16; H, 3.53; Br, 23.35; N, 12.28; O, 4.68; Found:C, 56.13; H, 3.51; Br, 23.30; N, 12.23; O, 4.66.
Embodiment 19: the preparation of 2-iodo-6-methyl-N-(quinoline-8-yl) niacinamide (compound 19)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-iodo-6-methylnicotinic acid, obtain brown ceramic powder shape target compound.Productive rate 75%, mp:178-179 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 2.56 (s, 3H); 7.45 (d, J=4.7Hz, 1H); 7.64-7.68 (m, 2H); 7.77 (dd, J=4.6,0.8Hz, 1H); 8.11 (d, J=4.8Hz, 1H); 8.45 (dd, J=4.9,0.9Hz, 1H); 8.72 (d, J=4.8Hz, 1H); 8.92 (d, J=1.2Hz, 1H); 10.70 (s, 1H); MS (ESI): 390.00 (C
16H
13IN
3O
+, [M+H]
+) .Anal.Calcd for C
16H
12IN
3O:C, 49.38; H, 3.11; I, 32.61; N, 10.80; O, 4.11; Found:C, 49.33; H, 3.09; I, 32.65; N, 10.83; O, 4.08.
Embodiment 20: the preparation of 2-chloro-6-hydroxy-n-(quinoline-8-yl) niacinamide (compound 20)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-chloro-6-hydroxy niacin, obtain brown powder shape target compound.Productive rate 71%, mp:186-187 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.43 (d, J=4.7Hz, 1H); 7.64-7.68 (m, 2H); 7.79 (dd, J=4.6,0.8Hz, 1H); 8.15 (d, J=4.6Hz, 1H); 8.54 (m, 1H); 8.72 (d, J=4.8Hz, 1H); 8.92 (d, J=1.2Hz, 1H); 10.70 (s, 1H); 13.05 (s, 1H); MS (ESI): 300.05 (C
15H
11ClN
3O
2 +, [M+H]
+) .Anal.Calcd for C
15H
10ClN
3O
2: C, 60.11; H, 3.36; Cl, 11.83; N, 14.02; O, 10.68; Found:C, 60.01; H, 3.33; Cl, 11.80; N, 14.00; O, 10.61.
Embodiment 21: the preparation of 2-fluoro-6-hydroxy-n-(quinoline-8-yl) niacinamide (compound 21)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-fluoro-6-hydroxy niacin, obtain yellow powder shape target compound.Productive rate 73%, mp:165-166 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.43 (d, J=4.7Hz, 1H); 7.65-7.68 (m, 2H); 7.80 (dd, J=4.9,0.8Hz, 1H); 8.16 (d, J=4.7Hz, 1H); 8.54 (m, 1H); 8.71 (d, J=4.8Hz, 1H); 8.90 (d, J=1.2Hz, 1H); 10.73 (s, 1H); 13.00 (s, 1H); MS (ESI): 284.08 (C
15H
11FN
3O
2 +, [M+H]
+) .Anal.Calcd for C
15H
10FN
3O
2: C, 63.60; H, 3.56; F, 6.71; N, 14.83; O, 11.30; Found:C, 63.63; H, 3.52; F, 6.70; N, 14.81; O, 11.34.
Embodiment 22: the preparation of 2-bromo-6-hydroxy-n-(quinoline-8-yl) niacinamide (compound 22)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-bromo-6-hydroxy niacin, obtain the white powder target compound.Productive rate 73%, mp:186-187 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.45 (d, J=4.7Hz, 1H); 7.68-7.71 (m, 2H); 7.83 (dd, J=4.3,0.8Hz, 1H); 8.14 (d, J=4.6Hz, 1H); 8.53 (m, 1H); 8.72 (d, J=4.6Hz, 1H); 8.90 (d, J=1.2Hz, 1H); 10.70 (s, 1H); 13.10 (s, 1H); MS (ESI): 344.00 (C
15H
11BrN
3O
2 +, [M+H]
+) .Anal.Calcd for C
15H
10BrN
3O
2: C, 52.35; H, 2.93; Br, 23.22; N, 12.21; O, 9.30; Found:C, 52.31; H, 2.91; Br, 23.20; N, 12.18; O, 9.34.
Embodiment 23: the preparation of 2-iodo-6-hydroxy-n-(quinoline-8-yl) niacinamide (compound 23)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-iodo-6-hydroxy niacin, obtain brown ceramic powder shape target compound.Productive rate 79%, mp:184-185 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.37 (d, J=4.5Hz, 1H); 7.54-7.58 (m, 2H); 7.73 (dd, J=4.5,0.9Hz, 1H); 8.13 (d, J=4.4Hz, 1H); 8.52 (m, 1H); 8.70 (d, J=4.9Hz, 1H); 8.92 (d, J=1.2Hz, 1H); 10.76 (s, 1H); 13.02 (s, 1H); MS (ESI): 391.98 (C
15H
11IN
3O
2 +, [M+H]
+) .Anal.Calcd for C
15H
10IN
3O
2: C, 46.06; H, 2.58; I, 32.44; N, 10.74; O, 8.18; Found:C, 46.02; H, 2.53; I, 32.34; N, 10.67; O, 8.09.
Embodiment 24: the preparation of 2-chloro-N-(quinoline-8-yl) niacinamide (compound 24)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 2-chlorine apellagrin, obtain brown ceramic powder shape target compound.Productive rate 67%, mp:145-146 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.63-7.69 (m, 2H); 7.76 (dd, J=3.0,1.2Hz, 1H); 7.79 (d, J=1.3Hz, 1H); 8.41-8.47 (m, 2H); 8.62 (dd, J=7.5,1.3Hz, 1H); 8.97 (dd, J=4.2,1.6Hz, 1H); 9.03 (t, J=1.8Hz, 1H); 10.74 (s, 1H); MS (ESI): 284.05 (C
15H
11ClN
3O
+, [M+H]
+) .Anal.Calcd for C
15H
10ClN
3O:C, 63.50; H, 3.55; Cl, 12.50; N, 14.81; O, 5.64; Found:C, 63.45; H, 3.53; Cl, 12.46; N, 14.78; O, 5.60.
Embodiment 25: the preparation of 2-fluoro-N-(quinoline-8-yl) niacinamide (compound 25)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with the 2-fluorine nicotinic acid, obtain the white powder target compound.Productive rate 77%, mp:148-149 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.70-7.74 (m, 2H); 7.79 (dd, J=3.0,1.1Hz, 1H); 7.85 (d, J=1.2Hz, 1H); 8.40-8.45 (m, 2H); 8.68 (dd, J=7.5,1.3Hz, 1H); 8.92 (dd, J=4.1,1.6Hz, 1H); 9.13 (t, J=1.8Hz, 1H); 10.68 (s, 1H); MS (ESI): 268.08 (C
15H
11FN
3O
+, [M+H]
+) .Anal.Calcd for C
15H
10FN
3O:C, 67.40; H, 3.77; F, 7.11; N, 15.72; O, 5.99; Found:C, 67.28; H, 3.75; F, 7.06; N, 15.76; O, 5.96.
Embodiment 26: the preparation of 2-iodo-N-(quinoline-8-yl) niacinamide (compound 26)
The preparation method is with embodiment one.Replace the 6-cresotinic acid with 2-iodine nicotinic acid, obtain pale yellow powder shape target compound.Productive rate 65%, mp:179-180 ℃,
1H NMR (500MHz, CDCl
3, δ, ppm): 7.66-7.69 (m, 2H); 7.78 (dd, J=3.3,1.3Hz, 1H); 7.83 (d, J=1.4Hz, 1H); 8.40-8.45 (m, 2H); 8.60 (dd, J=7.2,1.6Hz, 1H); 8.89 (dd, J=4.1,1.7Hz, 1H); 9.01 (t, J=1.9Hz, 1H); 10.69 (s, 1H); MS (ESI): 375.99 (C
15H
11IN
3O
+, [M+H]
+) .Anal.Calcd for C
15H
10IN
3O:C, 48.20; H, 2.69; I, 33.83; N, 11.20; O, 4.26; Found:C, 48.25; H, 2.62; I, 33.76; N, 11.25; O, 4.22.
Embodiment 27: the external anti-Human umbilical vein endothelial cells proliferation activity research of quinoline amide derivatives
Adopt the method for 5-bromo-2 '-pancreatic desoxyribonuclease (BrdU) mark to measure quinoline amide derivatives to Human umbilical vein endothelial cells inhibition of proliferation activity, by half-inhibition concentration (IC
50, be defined as the drug level when inhibiting rate is 50%) and estimate active height.The human umbilical vein cell in 5% calf serum substratum, hatch spend the night after, add the testing sample of different concns gradient, behind the reaction 30min, add VEGF or bFGF and induce.Add 5-bromo-2 '-pancreatic desoxyribonuclease after cultivating 48h, continue to cultivate after the 18-24h, utilize its OD value of ELISA enzyme-linked immunosorbent assay, the data that obtain can obtain IC with following equation
50Value.Y=Vmax (1-(x/ (K+x))), wherein the K value is IC
50Value.
(1) preparation of nutrient solution (every liter): RPMI-1640 cultivates one bag in powder (10.4g), NaHCO
32.00g, HEPES2.38g, new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, add tri-distilled water dissolving after, the NaHCO with 5.6%
3Solution transfers pH value to 7.2-7.4, is settled to 1000ml at last.Filtration sterilization.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na
2HPO
412H
2O 0.06g, KH
2PO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of VEGF and bFGF: utilize the D-Hanks damping fluid to be made into concentration and be VEGF (10ng/mL) and bFGF (0.3ng/mL), filtration sterilization.
(4) preparation of trypsin solution: utilizing the D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(5) preparation of experiment soup: specimen is made into storing solution with a spot of tri-distilled water dissolving, general 10 times of preparation storing solutions by the experiment maximum concentration.According to the compound dissolution difference, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, adds the tri-distilled water dissolving again.The concentration of DMSO in nutrient solution is unsuitable excessive, and the final concentration of DMSO generally is no more than 0.05%-0.1% in the every porocyte suspension after the dosing.Storing solution is stored in-20 ℃ of refrigerators standby.
(6) cultivation of Human umbilical vein endothelial cells: be the adherent growth cell, routine is incubated in the RPMI-1640 nutrient solution (containing 10% calf serum, 100U/ml Streptomycin sulphate), puts 37 ℃, 5%CO
2Cultivate in the incubator, went down to posterity once every 3-4 days.Discard original fluid when going down to posterity earlier, again with the washing of D-Hanks damping fluid; Use 0.5% tryptic digestion about 30 seconds then, add a small amount of fresh medium and stop digestion; Piping and druming makes attached cell split away off from the culturing bottle wall; Pipette in right amount to the fresh culture bottle, the restock fresh medium is to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(7) cell is hatched: the Human umbilical vein endothelial cells in the vegetative period of taking the logarithm, the accent concentration of cell suspension is 1-1.5 * 10
5Individual ml
-1Every hole adds cell suspension 100 μ l in 96 well culture plates, puts 37 ℃, 5%CO
2Cultivate 24h in the incubator.After cultivating 24h, add soup by design respectively.
(8) dosing and inducing: will test soup and join respectively in each hole according to the concentration gradient of ultimate density, each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds different concns respectively), control group (only add nutrient solution and cell, do not add the test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after the dosing are placed 37 ℃, 5%CO
2Cultivate 48h in the incubator.The activity of positive control medicine is measured according to the method for specimen.Behind the dosing 30min, add VEGF (10ng/mL) respectively and bFGF (0.3ng/mL) induces.
(9) ELISA measures: in having cultivated 96 orifice plates behind the 48h, add 5-bromo-2 '-pancreatic desoxyribonuclease, continue to cultivate after the 18-24h, utilize ELISA enzyme-linked immunosorbent assay 5-bromo-2 '-pancreatic desoxyribonuclease coupling situation.At last, utilize automatic microplate reader to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
IC
50The calculating of value can be calculated according to following formula:
Y=Vmax (1-(x/ (K+x))), wherein the K value is IC
50Value.
The listed N-quinoline amides of table 1 the present invention compounds is to HUVEC cell inhibiting IC
50Value (nM)
| Compound | HUVEC b (VEGF) | HUVEC b (bFGF) |
| 1 | 72.4 | 160 |
| 2 | 46.7 | 450 |
| 3 | 15.2 | 220 |
| 4 | 122.7 | 1150 |
| 5 | 5.8 | 210 |
| 6 | 5.5 | 110 |
| 7 | 9.8 | 45 |
| 8 | ND | 1140 |
| 9 | 9.9 | 560 |
| 10 | 13.6 | 1150 |
| 11 | 140.8 | 560 |
| 12 | 10.7 | 346 |
| 13 | 78.9 | 68 |
| 14 | 11.6 | 660 |
| 15 | 76.3 | 560 |
| 16 | 8.9 | 240 |
| 17 | 9.8 | 45 |
| 18 | ND | 1240 |
| 19 | 8.9 | 1560 |
| 20 | 13.6 | 1250 |
| 21 | 10.8 | 560 |
| 22 | 20.7 | 1346 |
| 23 | 78.9 | 680 |
| 24 | 11.6 | 1660 |
| 25 | 76.3 | 560 |
| 26 | 18.9 | 1240 |
| Positive control AMG706 | 4.5 | 1980 |
Attached: AMG706 is a kind of VEGFR inhibitor that uses clinically
Embodiment 28: N-quinoline amide derivatives vitro inhibition vascular endothelial growth factor receptor VEGFR activity research
(St.Louis, Mo USA), prepare the testing compound of various concentration with the mixed solvent of DMSO and water (v/v, 1: 1) available from Sigma-Aldrich company to suppress vascular endothelial growth factor receptor (VEGFR) activity experiment: VEGFR., will contain VEGFR (25 μ L, 10kUL
-1) and the mixing solutions of the testing compound (25 μ L) of various concentration be placed in the assay plate (96-well) 37 ℃ of pre-down 1h that cultivate.Add ATP (11.8 μ M) again, and at room temperature cultivate 60min.Under 665nm fluorescence, use the anti-tyrosine phosphorylation antibody of europium mark to detect then.
The IC that records
50Be shown in Table 2:
The listed N-quinoline amides of table 2 the present invention compounds is to the inhibition IC of VEGFR
50Value (nM)
Claims (6)
1. a class N-quinoline amide derivatives is characterized in that it has following general formula:
In the formula: work as X=C, R
1During=OH, R
2=CH
3, Cl, Br, F or I, R
3=R
4=R
5=H; Perhaps R
3=Br, F or I, R
2=R
4=R
5=H; Perhaps R
4=Br, F or I, R
2=R
3=R
5=H; Perhaps R
5=Cl, Br, F or I, then R
2=R
3=R
4=H;
When X=N, R
4=CH
3, R
1=Cl, Br, F or I, R
2=R
3=H, no R
5Perhaps R
1=Cl, Br, F or I, R
4=OH, R
2=R
3=H, no R
5Perhaps R
1=Cl, F or I, R
4=H, R
2=R
3=H, no R
5
2. method for preparing the described N-quinoline amide derivatives of claim 1 is characterized in that it is made up of the following step:
Step 1. with corresponding substituted salicylic acid or nicotinic acid and etc. the corresponding quinolyl amine of amount of substance, be dissolved in anhydrous CH
2Cl
2In, and 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride that adds catalytic amount is as catalyzer, and heating is stirred, and in 40 ℃ of following back flow reaction 8h, obtains clarifying reaction liquid;
Step 2. adds 200-300 purpose column chromatography silica gel in the reaction solution that step 1 obtains, stir underpressure distillation down, to remove unnecessary solvent and to make it abundant mixing, the silica gel of gained dress post is carried out column chromatography, and with ethyl acetate: the mixed solvent of sherwood oil=1: 2 is isolated target product as elutriant;
The elutriant underpressure distillation that step 3. obtains step 2 removes desolvates, and purifying promptly obtains the N-quinoline amide derivatives.
3. the method for making of N-quinoline amide derivatives according to claim 2 is characterized in that: the described anhydrous CH of step 1
2Cl
2Consumption be every mmole quinolyl amine solubilizing agent 5ml.
4. the method for making of N-quinoline amide derivatives according to claim 2 is characterized in that: the consumption of the described 1-of step 1 (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is that every mmole quinolyl amine adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 200mg.
5. the method for making of N-quinoline amide derivatives according to claim 2 is characterized in that: the consumption of the described column chromatography silica gel of step 2 is every mmole quinolyl amine silica gel 40ml.
6. the application of the described quinoline amide derivatives of claim 1 in the preparation cancer therapy drug.
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| CN1446212A (en) * | 2000-08-09 | 2003-10-01 | 阿斯特拉曾尼卡有限公司 | Quinoline derivatives having VEGF inhibiting activity |
| CN101316590A (en) * | 2005-11-07 | 2008-12-03 | 卫材R&D管理有限公司 | Use of combination of anti-angiogenic substance and c-kit kinase inhibitor |
| WO2009134973A1 (en) * | 2008-05-01 | 2009-11-05 | Sirtris Pharmaceuticals, Inc. | Quenolines and related analogs as sirtuin modulators |
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| CN1446212A (en) * | 2000-08-09 | 2003-10-01 | 阿斯特拉曾尼卡有限公司 | Quinoline derivatives having VEGF inhibiting activity |
| CN101316590A (en) * | 2005-11-07 | 2008-12-03 | 卫材R&D管理有限公司 | Use of combination of anti-angiogenic substance and c-kit kinase inhibitor |
| WO2009134973A1 (en) * | 2008-05-01 | 2009-11-05 | Sirtris Pharmaceuticals, Inc. | Quenolines and related analogs as sirtuin modulators |
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