CN103467368A - Medical application of N-pyridine methyl/ methoxyl-2-phenoxyl amide - Google Patents
Medical application of N-pyridine methyl/ methoxyl-2-phenoxyl amide Download PDFInfo
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- CN103467368A CN103467368A CN2013104370713A CN201310437071A CN103467368A CN 103467368 A CN103467368 A CN 103467368A CN 2013104370713 A CN2013104370713 A CN 2013104370713A CN 201310437071 A CN201310437071 A CN 201310437071A CN 103467368 A CN103467368 A CN 103467368A
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- Prior art keywords
- chloropyridine
- phenoxy group
- alkyl
- propionic acid
- hydrogen
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- XIHRUFOQGSWNFW-CYBMUJFWSA-N C[C@H](C(NCc(cn1)ccc1Cl)=O)Oc(cc1)ccc1Oc1ncc(C(F)(F)F)cc1 Chemical compound C[C@H](C(NCc(cn1)ccc1Cl)=O)Oc(cc1)ccc1Oc1ncc(C(F)(F)F)cc1 XIHRUFOQGSWNFW-CYBMUJFWSA-N 0.000 description 2
- XPARFBOWIYMLMY-UHFFFAOYSA-N NCc(cc1)cnc1Cl Chemical compound NCc(cc1)cnc1Cl XPARFBOWIYMLMY-UHFFFAOYSA-N 0.000 description 2
- MPFAFDFUXJYUOH-UHFFFAOYSA-N CC(C(Cl)=O)Oc(cc1)ccc1Oc1ncc(C(F)(F)F)cc1 Chemical compound CC(C(Cl)=O)Oc(cc1)ccc1Oc1ncc(C(F)(F)F)cc1 MPFAFDFUXJYUOH-UHFFFAOYSA-N 0.000 description 1
- KBZQFXOOCIKOBQ-CQSZACIVSA-N C[C@H](C(NCc(cc1)cnc1Cl)=O)Oc(cc1)ccc1Oc(c(F)c1)ccc1C#N Chemical compound C[C@H](C(NCc(cc1)cnc1Cl)=O)Oc(cc1)ccc1Oc(c(F)c1)ccc1C#N KBZQFXOOCIKOBQ-CQSZACIVSA-N 0.000 description 1
- YUVKUEAFAVKILW-SECBINFHSA-N C[C@H](C(O)=O)Oc(cc1)ccc1Oc1ncc(C(F)(F)F)cc1 Chemical compound C[C@H](C(O)=O)Oc(cc1)ccc1Oc1ncc(C(F)(F)F)cc1 YUVKUEAFAVKILW-SECBINFHSA-N 0.000 description 1
- SKCNYHLTRZIINA-UHFFFAOYSA-N ClCc(cc1)cnc1Cl Chemical compound ClCc(cc1)cnc1Cl SKCNYHLTRZIINA-UHFFFAOYSA-N 0.000 description 1
- VJWRGOSBPDZVMI-UHFFFAOYSA-N O=C(c1c2cccc1)N(Cc(cc1)cnc1Cl)C2=O Chemical compound O=C(c1c2cccc1)N(Cc(cc1)cnc1Cl)C2=O VJWRGOSBPDZVMI-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N O=C(c1c2cccc1)NC2=O Chemical compound O=C(c1c2cccc1)NC2=O XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
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- Pyridine Compounds (AREA)
Abstract
The invention relates to N-pyridine methyl/ methoxyl-2-phenoxyl amide shown as the chemical structural formula I, and an isomer or racemate thereof. In the formula, R1, R2, R3 and R4 are selected from H, C1-C2 alkyl, C3-C4 straight chain or branched alkyl; N is selected from 0 or 1; Y is selected from CH or N; X is selected from fluorine, chlorine, bromine and iodine; X1, X2, X4 and X6 are selected from hydrogen and C1-C2 alkyl; X3 is selected from hydrogen, C1-C2 alkyl, fluorine, chlorine and bromine; and X5 is selected from trifluoromethyl, fluorine, chlorine, bromine or cyano group. An application of the N-pyridine methyl/ methoxyl-2-phenoxyl amide and the isomer or racemate thereof in preparation of anti-cancer drugs is also disclosed.
Description
Technical field
The present invention relates to a compounds and new purposes, specifically the N-picolyl/methoxyl group-application of 2-phenoxy group acid amides in preparing cancer therapy drug.
Background technology
4-aryloxy phenoxy group acid derivative has biological activity widely, and wherein fragrant phenoxy propanoic derivatives, as its Typical Representative, has more than 20 commercialization kind in agricultural herbicide.4-aryloxy phenoxy group acid derivative also has a large amount of reports [Investigational New Drugs, 1999,16:287 – 296 in the research of cancer therapy drug simultaneously; Investigational New Drugs, 1998,16:129 – 139; Acta Pharmaceutica Sinica, 2005,40 (9): 814-819], XK469(2-(4-(7-chloroquinoxalin-2-yloxy base) phenoxy group) propionic acid wherein) be the new type antineoplastic medicine that du pont company is carrying out the clinical study of I phase, XK469 has very wide antitumor spectra, and side effect is little, effective to multiple solid tumor models, as [J Med Chem, 2001,44 (11): 1758-76] such as colorectal carcinoma Colon38 and mammary cancer.The Chinese invention patent of 2-phenoxy group alkane acid amides application is in Table 1.
The application patent of table 1 2-phenoxy group alkane acid amides
The antitumour activity of N-picolyl/methoxyl group-2-phenoxy group acid amides is not is not researched and developed report.
Summary of the invention
The invention provides the N-picolyl/methoxyl group shown in formula I-2-phenoxy group acid amides and isomer or racemic modification:
R in formula
1, R
2, R
3, R
4be selected from: H, C
1～C
2alkyl, C
3~ C
4the straight or branched alkyl; N is selected from: 0 or 1; Y is selected from: CH or N; X is selected from: fluorine, chlorine, bromine, iodine; X
1be selected from: hydrogen, C
1~ C
2alkyl; X
2be selected from: hydrogen, C
1~ C
2alkyl; X
3be selected from: hydrogen, C
1~ C
2alkyl, fluorine, chlorine, bromine; X
4be selected from: hydrogen, C
1~ C
2alkyl; X
5be selected from: trifluoromethyl, fluorine, chlorine, bromine or cyano group; X
6be selected from: hydrogen, C
1~ C
2alkyl.
The preparation method of N-picolyl/methoxyl group-2-phenoxy group acid amides is shown in embodiment.
N-picolyl/methoxyl group provided by the invention-2-phenoxy group acid amides and isomer thereof or racemic modification have antitumour activity, the application in preparing cancer therapy drug:
R in formula
1, R
2, R
3, R
4be selected from: H, C
1～C
2alkyl, C
3~ C
4the straight or branched alkyl; N is selected from: 0 or 1; Y is selected from: CH or N; X is selected from: fluorine, chlorine, bromine, iodine; X
1be selected from: hydrogen, C
1~ C
2alkyl; X
2be selected from: hydrogen, C
1~ C
2alkyl; X
3be selected from: hydrogen, C
1~ C
2alkyl, fluorine, chlorine, bromine; X
4be selected from: hydrogen, C
1~ C
2alkyl; X
5be selected from: trifluoromethyl, fluorine, chlorine, bromine or cyano group; X
6be selected from: hydrogen, C
1~ C
2alkyl.
(R)-N-provided by the invention (2-chloropyridine-5-ylmethoxy)-2-(4-(the fluoro-5-chloropyridine of the 3--2-base oxygen base) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
(R)-N-provided by the invention (2-chloropyridine-5-ylmethyl)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
(R)-N-provided by the invention (2-chloropyridine-5-ylmethyl)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
(R)-N-provided by the invention (2-chloropyridine-5-ylmethoxy)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
。
(R)-N-provided by the invention (2-chloropyridine-5-ylmethyl)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) application of propionic acid amide in preparing medicament for resisting cervical cancer:
Embodiment
Following examples are intended to illustrate the present invention rather than limitation of the invention further.
Embodiment 1
(R) preparation of-N-(2-chloropyridine-5-ylmethyl)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid amide
(1) preparation of (R)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid
DMF (DMF, 40 mL), (R)-2-(4-hydroxybenzene oxygen) propionic acid (3.64 g, 0.02 mol), after stirring and dissolving, add salt of wormwood (5.52 g in batches, 0.04 mol), 70 ~ 80 ℃ are stirred 1 h, drip 2,3-difluoro-5-chloropyridine (2.99 g, 0.02 mol), continue to stir 7 ~ 8 h, be cooled to room temperature, pour in frozen water (250 mL), slowly add dilute hydrochloric acid, regulate pH4 ~ 5, filter, washing, dry (R)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid 5.92 g that obtain white solid, productive rate 95%.
(2) preparation of 2-chloropyridine-5-base methylamine
DMF (DMF) (40 mL), phthalic imidine (7.35 g, 0.05 mol) and potassium hydroxide (2.8 g, 0.05 mol), stirring and dissolving, drip CCMP (8.10 g, 0.05 mol), stirring is spent the night.Reactant is poured in frozen water (250 mL), filters, and washes to obtain white solid.Solid adds in the there-necked flask of 250 mL, adds ethanol (150 mL).After heating for dissolving, drip hydrazine hydrate (18 g, 80%), stirring and refluxing 4 h, cooling, filter, get filtrate, precipitation obtains yellow oily matter, pour in saturated nacl aqueous solution, the ethyl acetate extraction, drying, precipitation obtains faint yellow 2-chloropyridine-5-base methylamine 2.96 g.
(3) preparation of (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid amide
Toluene (40 mL), (R)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid (1.04 g, 3.3 mmol) and thionyl chloride (1.18 g, 10 mmol), slough solvent toluene after backflow 3 ~ 5 h and obtain (R)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionyl chloride, add methylene dichloride (40 mL), 2-chloropyridine-5-base methylamine (0.44 g, 3.3 mmol) and the 4-dimethylaminopyridine (DMAP) of catalytic amount, stir 10 min under ice bath, dropwise splash into triethylamine (1.0 g, 10 mmol), reactant continues to stir 2 ~ 3 h, pour into again in 100 ~ 200 mL frozen water, dichloromethane extraction, organic phase washes (100 mL * 2) with water, anhydrous sodium sulfate drying, precipitation, reduced pressure chromatography obtains white solid (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid amide.134.4 ~ 135.4 ℃ of fusing points,
1h NMR (300MHz, CDCl
3) δ: 1.61 (d, J=6.9 Hz, 3H, CH
3), 4.49 (d, J=6.6 Hz, 2H, CH
2), 4.74 (q, J=6.9 Hz, 1H, CH), 6.88 ~ 6.94 (m, 3H, C
6h
4, NH), 7.08 ~ 7.13 (m, 2H, C
6h
4), 7.29 (d, J=8.1 Hz, 1H, Py H), 7.49 ~ 7.53 (m, 2H, Py H), 7.87 (d, J=2.1 Hz, 1H, Py H), 8.30 (d, J=2.4 Hz, 1H, Py H); LC-MS (Positive ion) m/z:436.0[M+H]
+.
Embodiment 2
(R) preparation of-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid amide
(1) preparation of 2-chloropyridine-5-ylmethyl azanol
N, dinethylformamide (DMF) (40 mL), HP (8.15 g, 0.05 mol) and sodium hydroxide (3.0 g, 0.075 mol), stirring at room is dissolved, drip CCMP (8.10 g, 0.05 mol), stirred overnight at room temperature, pour in frozen water (250 mL), filter, wash to obtain white solid, add ethanol (150 mL), after heating for dissolving, drip hydrazine hydrate (18 g, 80%), mechanical stirring back flow reaction 4 h, cooling, filter, get filtrate, precipitation obtains yellow oily matter, pour in saturated nacl aqueous solution, extracted with diethyl ether, dry, precipitation obtains faint yellow 2-chloropyridine-5-ylmethyl azanol 2.80 g, productive rate 35.3%.
(2) preparation of (R)-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid amide
(the R)-2-made by embodiment 1 method (4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionyl chloride, methylene dichloride (40 mL), 2-chloropyridine-5-ylmethyl azanol (0.53 g, 3.3 mmol) and the 4-dimethylaminopyridine (DMAP) of catalytic amount, stir 10 min under ice bath, dropwise splash into triethylamine (1.0 g, 10 mmol), reactant continues to stir 2 ~ 3 h, pour into again in 100 ~ 200 mL frozen water, dichloromethane extraction, organic phase washes (100 mL * 2) with water, anhydrous sodium sulfate drying, precipitation, reduced pressure chromatography [thin-layer chromatography silica gel, V (sherwood oil): V (ethyl acetate)=3:1] obtain (R)-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(the fluoro-5-chloropyridine of 3--2-base oxygen base) phenoxy group) propionic acid amide 0.93 g, yield 61.8%, white solid, m.p. 108.0 ~ 109.1 ℃,
1h NMR (CDCl
3, 300 MHz) and δ: 1.60 (d, J=6.6 Hz, 3H, CH
3), 4.74 (q, J=6.6 Hz, 1H, CH), 4.90 (dd, J
1=11.7 Hz, J
2=18.1 Hz, CH
2), 6.90 (d, J=9.0 Hz, 2H, Ph H), 7.09 (d, J=9.0 Hz, 2H, Ph H), 7.35 (d, J=9.0 Hz, 1H, Py H), 7.50 (dd, J
1=9.0 Hz, J
2=2.4 Hz, 1H, Py H), 7.67 (dd, J
1=8.4 Hz, J
2=2.4 Hz, 1H, Py H), 7.85 (d, J=2.4 Hz, 1H, Py H), 8.36 (d, J=2.4 Hz, 1H, Py H), 9.05 (br, 1H, NH),
13c NMR (CDCl
3, 75 MHz) and δ: 18.66,74.70,75.11,116.26,122.54,124.26,124.88,125.13,129.45,139.94,145.10,147.45,148.62,150.04,150.98,151.80,153.76,169.54, LC-MS (Positive ion) m/z:451.8[M+H]
+.
Embodiment 3
(R) preparation of-N-(2-chloropyridine-5-ylmethyl)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) propionic acid amide
(1) preparation of (R)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) propionic acid
N, dinethylformamide (DMF) (40 mL), (R)-2-(4-hydroxybenzene oxygen) propionic acid (3.64 g, 0.02 mol), add salt of wormwood (5.52 g 0.04 mol) in batches, stir 1 h under 70 ~ 80 ℃, dropwise add 2,3-bis-chloro-5-trifluoromethylpyridines (4.32 g, 0.02 mol), continue to stir 7 ~ 8 h.Reactant is cooled to room temperature, pour in frozen water (250 mL), slowly add dilute hydrochloric acid, regulate pH4 ~ 5, the ethyl acetate extracting twice, the organic phase drying, precipitation obtains (R)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) propionic acid 7.02 g of brown mucus, productive rate 97%.
(2) preparation of (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) propionic acid amide
Make (the R)-N-(2-chloropyridine-5-ylmethyl) of white solid-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) propionic acid amide by embodiment 1 method.113.2 ~ 114.7 ℃ of fusing points,
1h NMR (300MHz, CDCl
3) δ: 1.62 (d, J=6.6 Hz, 3H, CH
3), 4.49 (d, J=6.0 Hz, 2H, CH
2), 4.73 (q, J=6.6 Hz, 1H, CH), 6.92 ~ 6.97 (m, 3H, C
6h
4, NH), 7.09 (d, J=9.0 Hz, 2H, C
6h
4), 7.27 (d, J=8.1 Hz, 1H, Py H), 7.50 (dd, J
1=8.1 Hz, J
2=2.4 Hz, 1H, Py H), 7.99 (d, J=2.4 Hz, 1H, Py H), 8.27 ~ 8.28 (m, 2H, Py H); LC-MS (Positive ion) m/z:486.0[M+H]
+.
Embodiment 4
(R) preparation of-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) propionic acid amide
Make (R)-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) propionic acid amide by embodiment 2 methods, yield 45.5%, white solid, 136.8 ~ 137.8 ℃ of m.p.,
1h NMR (CDCl
3, 300 MHz) and δ: 1.62 (d, J=6.9 Hz, 3H, CH
3), 4.76 (q, J=6.9 Hz, 1H, CH), 4.93 (dd, J
1=11.4 Hz, J
2=17.1 Hz, 2H, CH
2), 6.95 (d, J=9.0 Hz, 2H, Ph H), (7.14 d, J=9.0 Hz, 2H, Ph H), 7.36 (d, J=8.1 Hz, 1H, Py H), 7.69 (d, J=8.1 Hz, 1H, Py H), 7.99 (s, 1H, Py H), (8.26 s, 1H, Py H), 8.38 (s, 1H, Py H), 8.97 (br, 1H, NH);
13c NMR (CDCl
3, 75 MHz) and δ: 18.72,74.86,75.23,116.14,116.35,119.22,122.63,123.01,124.35,129.42,136.34,139.89,142.50,147.35,150.13,151.99,154.11,161.20,169.57; LC-MS (Positive ion) m/z:502.0[M+H]
+.
Embodiment 5
(R) preparation of-N-(2-chloropyridine-5-ylmethyl)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) propionic acid amide
(1) preparation of (R)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) propionic acid
N, dinethylformamide (DMF) (40 mL), (R)-2-(4-hydroxybenzene oxygen) propionic acid (3.64 g, 0.02 mol), add salt of wormwood (5.41 g 0.04 mol) in batches, stir 1 h under 70～80 ℃, dropwise add 2-chloro-5-trifluoromethylpyridine (3.63 g, 0.02 mol), continue to stir 5 ~ 6 h.Be cooled to room temperature, pour in frozen water (250 mL), slowly add dilute hydrochloric acid, regulate pH4 ~ 5, ethyl acetate extraction, organic phase drying, precipitation obtains brown mucus (R)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) propionic acid 6.30 g, productive rate 96.3%.
(2) preparation of (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) propionic acid amide
Make (the R)-N-(2-chloropyridine-5-ylmethyl) of faint yellow solid-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) propionic acid amide by embodiment 1 method.78.8 ~ 80.1 ℃ of fusing points,
1h NMR (300MHz, CDCl
3) δ: 1.62 (d, J=6.9 Hz, 3H, CH
3), 4.49 (d, J=6.6 Hz, 2H, CH
2), 4.75 (q, J=6.7 Hz, 1H, CH), 6.88 ~ 7.12 (m, 6H, C
6h
4, NH, Py H), 7.30 (d, J=8.4 Hz, 1H, Py H), 7.50 (dd, J
1=8.4 Hz, J
2=2.4 Hz, 1H, Py H), 7.90 (dd, J
1=8.7 Hz, J
2=2.4 Hz, 1H, Py H), 8.27 (d, J=2.4 Hz, 1H, Py H), 8.43 (m, 1H, Py H); LC-MS (Positive ion) m/z:451.9[M+H]
+.
Embodiment 6
(R) preparation of-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) propionic acid amide
Make (R)-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) propionic acid amide by embodiment 2 methods, yield 57.9%, white solid, 123.4 ~ 124.8 ℃ of m.p.,
1h NMR (CDCl
3, 300 MHz) and δ: 1.61 (d, J=6.9 Hz, 3H, CH
3), 4.72 (q, J=6.9 Hz, 1H, CH), 4.93 (dd, J
1=11.4 Hz, J
2=16.5 Hz, 2H, CH
2), 6.90 (d, J=9.0 Hz, 2H, Ph H), 6.98 (d, J=8.7 Hz, 1H, Py H), 7.11 (d, J=9.0 Hz, 2H, Ph H), 7.36 (d, J=8.1 Hz, 1H, Py H), 7.69 (d, J=8.7 Hz, 1H, Py H), (7.90 d, J=8.1 Hz, 1H, Py H), 8.36 (s, 1H, Py H), 8.41 (s, 1H, Py H); LC-MS (Positive ion) m/z:468.0[M+H]
+.
Embodiment 7
(R) preparation of-N-(2-chloropyridine-5-ylmethyl)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid amide
(1) preparation of (R)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid
N, dinethylformamide (DMF) (40 mL), (R)-2-(4-hydroxybenzene oxygen) propionic acid (3.64 g, 0.02 mol) adds salt of wormwood (5.41 g in batches, 0.04 mol), stir 1 h under 70 ~ 80 ℃, dropwise add DMF solution (2.78 g of 3,4-difluorobenzonilyile, 0.02 mol), continue stirring reaction 5 ~ 6 h.Be cooled to room temperature, pour in frozen water (250 mL), slowly add dilute hydrochloric acid, be adjusted to pH4 ~ 5, filter, washing, dry (R)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid 5.20 g that obtain gray solid, productive rate 86.4%.
(2) preparation of (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid amide
Make (the R)-N-(2-chloropyridine-5-ylmethyl) of white solid-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid amide by embodiment 1 method.130.7 ~ 131.3 ℃ of fusing points,
1h NMR (300MHz, CDCl
3) δ: 1.60 (d, J=6.9 Hz, 3H, CH
3), 4.40 ~ 4.58 (m, 2H, CH
2), 4.74 (q, J=6.9 Hz, 1H, CH), 6.87 ~ 7.01 (m, 5H, C
6h
4, NH), 7.04 (d, J=6.6 Hz, 1H, Py H), 7.27 (d, J=6.6 Hz, 1H, Py H), 7.37 ~ 7.56 (m, 3H, C
6h
4), 8.22 (d, J=1.8 Hz, 1H, Py H); LC-MS (Positive ion) m/z:426.1[M+H]
+.
Embodiment 8
(R) preparation of-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid amide
Make (R)-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid amide by embodiment 2 methods, yield 44.9%, white solid, 161.3 ~ 164.0 ℃ of m.p.,
1h NMR (CDCl
3, 300 MHz) and δ: 1.61 (d, J=6.6 Hz, 3H, CH
3), 4.73 (q, J=6.6 Hz, 1H, CH), 4.93 (s, 2H, CH
2), 6.87 ~ 7.04 (m, 5H, Ph H), 7.04 ~ 7.49 (m, 3H, 2Ph H+PyH), 7.73 (d, J=6.6 Hz, 1H, Py H), 8.31 (s, 1H, Py H), 8.92 (br, 1H, NH); LC-MS (Positive ion) m/z:441.9[M+H]
+.
Embodiment 9
The anti-tumor activity of N-picolyl/methoxyl group-2-phenoxy group acid amides
1. anti-tumor activity principle
The mtt assay biological activity test claims again the MTT colorimetry, is a kind of method that detects cell survival and growth.The MTT analytical method is with viable cell metabolite reductive agent tetrazolium bromide [3-(4,5-dimethyl-2-thiazole)-2,5-phenylbenzene bromination tetrazole; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT] be basis.MTT is a kind of dyestuff that can accept hydrogen atom.Desaturase relevant to NADP in the viable cell plastosome can change into yellow MTT insoluble hepatic first a ceremonial jade-ladle, used in libation (formazon) in cell, and dead cell is without this function.After dissolving formazon with DMSO, under certain wavelength, by microplate reader, measure optical density value, both can quantitatively measure the survival rate of cell.Observe the restraining effect of sample to tumour cell according to the variation of optical density value.
2. anti-tumor activity experiment
Sample: N-picolyl/methoxyl group-2-phenoxy group acid amides (I) and isomer or racemic modification:
R in formula
1, R
2, R
3, R
4be selected from: H, C
1～C
2alkyl, C
3~ C
4the straight or branched alkyl; N is selected from: 0 or 1; Y is selected from: CH or N; X is selected from: fluorine, chlorine, bromine, iodine; X
1be selected from: hydrogen, C
1~ C
2alkyl; X
2be selected from: hydrogen, C
1~ C
2alkyl; X
3be selected from: hydrogen, C
1~ C
2alkyl, fluorine, chlorine, bromine; X
4be selected from: hydrogen, C
1~ C
2alkyl; X
5be selected from: trifluoromethyl, fluorine, chlorine, bromine or cyano group; X
6be selected from: hydrogen, C
1~ C
2alkyl.
Clone: cervical cancer tumer line Hela and lung adenocarcinoma cell line A549 (the Xiangya Medical College, Zhongnan Univ cell bank provides).
Reagent: tetrazolium bromide (MTT), RPMI RPMI-1640, new-born calf serum, microbiotic (U.S. hero Life Technologies, Inc.); Pancreatin (U.S. AMRESCO company); 96 well culture plates (U.S. hero Life Technologies, Inc.); Dimethyl sulfoxide (DMSO) (U.S. Sigma company).
Instrument: HFsafe-1500 type Bechtop, HF151UV type CO
2incubator (Shanghai Lishen Scientific Equipment Co., Ltd.); XSP-15C type inverted microscope (Shanghai rectangular opticinstrument company limited); Multiskan MK3 type microplate reader (U.S. Thermo company); Ultrapure water preparing instrument (U.S. Milli-Q company).
Experimental implementation: sample is for the test of cancer cells.In an experimentation, per sample (p.s.) arranges 5 concentration gradients (1.000 μ mol/mL, 0.300 μ mol/mL, 0.100 μ mol/mL, 0.030 μ mol/mL and 0.010 μ mol/mL), four parallel samples of each concentration, test parallel 3 times for every group, and reach a conclusion by the contrast of blank group.Microplate reader detects each hole OD value, detects wavelength 570 nm.
3. anti-tumor activity evaluation
1) cell inhibitory rate calculates:
2) IC
50value is calculated
Sample solution concentration logarithmic value and cell inhibitory rate linear regression, utilize the half-inhibition concentration IC of computed in software sample to cell
50value.The IC of N-picolyl/methoxyl group-2-phenoxy group acid amides to lung adenocarcinoma cell A549
50in Table 2.
The inhibition activity of table 2 N-picolyl/methoxyl group-2-phenoxy group acid amides to lung adenocarcinoma cell A549
(R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) propionic acid amide is for the active IC of the inhibition of cervical cancer cell Hela
50be 0.023 μ mol/mL.
The demonstration of active testing result, N-picolyl/methoxyl group-2-phenoxy group acid amides has good inhibition activity to cancer cells, can be used for preparing cancer therapy drug.
Claims (7)
1. N-picolyl/methoxyl group shown in the chemical structural formula I-2-phenoxy group acid amides and isomer or racemic modification:
R in formula
1, R
2, R
3, R
4be selected from: H, C
1～C
2alkyl, C
3~ C
4the straight or branched alkyl; N is selected from: 0 or 1; Y is selected from: CH or N; X is selected from: fluorine, chlorine, bromine, iodine; X
1be selected from: hydrogen, C
1~ C
2alkyl; X
2be selected from: hydrogen, C
1~ C
2alkyl; X
3be selected from: hydrogen, C
1~ C
2alkyl, fluorine, chlorine, bromine; X
4be selected from: hydrogen, C
1~ C
2alkyl; X
5be selected from: trifluoromethyl, fluorine, chlorine, bromine or cyano group; X
6be selected from: hydrogen, C
1~ C
2alkyl.
2. N-picolyl/methoxyl group claimed in claim 1-2-phenoxy group acid amides and isomer thereof or the application of racemic modification in preparing cancer therapy drug:
R in formula
1, R
2, R
3, R
4, n, Y, X, X
1, X
2, X
3, X
4, X
5, X
6definition as claimed in claim 1.
3. (R)-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(the fluoro-5-chloropyridine of the 3--2-base oxygen base) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
4. (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(3-chloro-5-trifluoromethylpyridine-2-base oxygen base) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
5. (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(5-5-flumethiazine-2-base oxygen base) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
6. (R)-N-(2-chloropyridine-5-ylmethoxy)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) application of propionic acid amide in preparing Antilung gland cancer medicine:
7. (R)-N-(2-chloropyridine-5-ylmethyl)-2-(4-(4-cyano group-2-fluorophenoxy) phenoxy group) application of propionic acid amide in preparing medicament for resisting cervical cancer:
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Cited By (3)
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| WO2015000392A1 (en) * | 2013-07-02 | 2015-01-08 | 湖南化工研究院有限公司 | N-(aryl alkyl) aryloxy phenoxy carboxylic acid amide compound and preparation method and application thereof |
| CN105085386A (en) * | 2014-05-16 | 2015-11-25 | 湖南大学 | Medical application of 2-(4-phenoxyphenoxy)fatty acyl pyridylamine |
| CN105085385A (en) * | 2014-05-16 | 2015-11-25 | 湖南大学 | Medical application of 2-[4-(pyridine-2-oxyl)phenoxyl]fatty acyl pyridylamine |
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| CN103086985A (en) * | 2013-02-01 | 2013-05-08 | 湖南大学 | 2-[4-(quinoxaline-2-oxygroup) phenoxy] alkylamide and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015000392A1 (en) * | 2013-07-02 | 2015-01-08 | 湖南化工研究院有限公司 | N-(aryl alkyl) aryloxy phenoxy carboxylic acid amide compound and preparation method and application thereof |
| CN105085386A (en) * | 2014-05-16 | 2015-11-25 | 湖南大学 | Medical application of 2-(4-phenoxyphenoxy)fatty acyl pyridylamine |
| CN105085385A (en) * | 2014-05-16 | 2015-11-25 | 湖南大学 | Medical application of 2-[4-(pyridine-2-oxyl)phenoxyl]fatty acyl pyridylamine |
| CN105085385B (en) * | 2014-05-16 | 2017-10-31 | 湖南大学 | The medical usage of 2 [4 (epoxide of pyridine 2) phenoxy group] fatty acyl pyridine amine |
| CN105085386B (en) * | 2014-05-16 | 2017-10-31 | 湖南大学 | The medical usage of 2 (4 phenoxy-phenoxy) fatty acyl pyridine amine |
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| CN103467368B (en) | 2014-10-22 |
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