CN104163818A - 2-amino oxazole compound and preparation method and application thereof - Google Patents
2-amino oxazole compound and preparation method and application thereof Download PDFInfo
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- CN104163818A CN104163818A CN201410335767.XA CN201410335767A CN104163818A CN 104163818 A CN104163818 A CN 104163818A CN 201410335767 A CN201410335767 A CN 201410335767A CN 104163818 A CN104163818 A CN 104163818A
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- methylamino
- piperazine
- hydroxyethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the field of pharmaceutical compounds synthesis, and relates to a Src / Abl kinase dual inhibitor drug 2-amino oxazole compound and a preparation method and application thereof. The invention provides a new drug with a broad market prospect.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of Src/Abl kinases double inhibitors medicine and synthesize.
Background technology
Chronic myelogenous leukemia (CML) is the first malignant tumour that is found to have fixed cell genetic alteration, and global annual morbidity is 1.6～2,/10 ten thousand people, its Etiological be due to
9number and
22after number chromosome reciprocal translocation, oncogene Abl transfers to long-armed breaking point region and forms Bcr-Abl fusion gene, and one of its product is a kind of abnormal Tyrosylprotein kinase (tyrosine protein kinase, TPK) receptor protein
p210 bcr-Abl, this albumen does not need to get final product autophosphorylation with corresponding ligand binding, and causes many important substrate protein phosphorylations simultaneously, thereby activates many barss (comprising Src family member) transduction pathway, make cell proliferation excessively, prosoplasia and apoptosis be obstructed.Current research unanimously thinks, the TPK activity that Bcr-Abl abnormal protein increases is the major cause that causes CML to occur.
Summary of the invention
The object of the present invention is to provide a kind of Src/Abl kinases double inhibitors medicine 2-An Ji oxazole compounds and preparation method thereof and purposes.
This 2-An Ji oxazole compounds structural formula is:
，
R=H wherein, C
1-5alkyl, halogen; R
1=H, C
1-5alkyl, halogen, CN; X=N, CH, R
3=H, CH
3, halogen, CN, NO
2; R
4=H, CH
3, halogen, CN, NO
2;
R
2for hydroxyethyl piperazine, hydroxyethyl piperidine, piperazine ethylamino-, morpholine ethylamino-, piperidine-1-ethanamine base
Piperazine methylamino, morpholine methylamino, piperidines methylamino, hydroxyethyl piperazine methylamino, hydroxyethyl piperidine methylamino, C
1-5alkylamino radical.
The present invention also provides the preparation method of aforementioned 2-An Ji oxazole compounds, and Technology Roadmap is as Fig. 1:
Comprise the steps:
Substituted aromatic amines obtains E-N-aryl-3-ethoxy propylene acid amides with E-3-ethoxy propylene acyl chloride reaction in pyridine and tetrahydrofuran (THF); E-N-aryl-3-ethoxy propylene acid amides and NBS occur after addition reaction, close ring immediately with urea condensation, obtain compound formula (4
a-c)
; Compound formula (4
a-c) by more respectively with dichloro pyrimidine or dichloropyridine, and hydroxyethyl piperazine respectively anti-raw nucleophilic substitution obtain ultimate aim product; Or compound formula (4
a-c) by reacting with aroyl chloride or alkyl acyl chloride, obtain ultimate aim product.
The invention has the beneficial effects as follows: a kind of novel Src/Abl kinases double inhibitors and preparation method thereof is provided, and it is high, effective that it suppresses K562 cytoactive inhibiting rate.
Accompanying drawing explanation
Fig. 1 2-An of the present invention Ji oxazole compounds synthetic route chart.
Embodiment
According to the synthetic route chart of Fig. 1, the present invention is described further below.
embodiment 1 2-An Ji oxazole compounds preparation
e-N-p-methylphenyl-3-ethoxy propylene acid amides (3a):get para-totuidine (3.0g, 28mmol), pyridine (3.2mL, 40mmol) and tetrahydrofuran (THF) (40mL) add in reaction flask, ice bath, slowly drip wherein E-3-ethoxy propylene acyl chlorides (
2) (3.6mL, 30mmol), drip off room temperature reaction 2h;
At 0-5 ℃ of HCl(7.0mL that adds 1mol/L), then add wherein 40mL water, concentrating under reduced pressure adds 30mL toluene in concentrated solution, and ice bath stirs 10min, filters, filter residue 20mL water washing, vacuum-drying obtains pale product 5.0g, productive rate 87.0%,
1h-NMR (600 MHz, DMSO-d6) δ: 1.27 (t, 3H, J=7.0Hz), 2.16 (s, 3H), 3.94 (q, 2H, J=7.0 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.18-7.23 (m, 2H, J=7.5Hz), 7.32 (d, 1H, J=7.5 Hz), 7.46 (d, 1H, J=12.4 Hz), 9.29 (s, 1H).
IR(KBrcm-1):?3257，1662，1622，1508，1292，1161；
2-amino-N-p-methylphenyl-5-oxazole methane amide (5a):in 150mL there-necked flask, add 40mL water, 40mL dioxane and E-N-p-methylphenyl-3-ethoxy propylene acid amides (
3a) (5.0g, 25mmol), ice bath adds NBS(4.4g, 25mmol in reaction flask), this temperature is lower keeps 1h, then room temperature reaction 2h;
In reaction flask, add urea (1.7g, 29mmol), room temperature reaction 0.5h, then 60 ℃ of reaction 3h, 80 ℃ of reaction 1h, be cooled to room temperature, add strong aqua to adjust PH 8～9, concentrated, filter filter cake washing, vacuum-drying, obtains yellow product 2.5g, productive rate 45.7%, m.p.271-272 ° of C.
1H-NMR?(600?MHz,?DMSO-d6?)?δ:?2.26(s,?3H?)、7.12(?d,?2H,?J=?8.4?Hz)、7.30(?s,?2H)、7.53?(?d,?2H,?J=8.4?H?z)、7.61(s,?1H?)、9.70?(s,?1H?)，
13C-NMR?(DMSO-d6,?400?MHz)?δ(ppm):?20.97,?42.11,?120.76,?120.76,?127.41,?128.50,?128.96,?128.96,?129.59,?129.59,?129.80,?129.80,?133.22,?135.14,?136.59,?140.73,?159.74,?161.43,?170.28;
Mass?Spectra?(
m/z)?[M?+?H]
?+?：217.49;?
IR(KBrcm-1):?3304，3103，1663，1633，1607，1574，1529，1286，1173；
n-p-methylphenyl-2-benzamide-5-oxazole methane amide (6d):get phenylformic acid and 5mL methylene dichloride and be placed in 50mL single port bottle, ice bath, drips (0.5mL, 6.95mmol) thionyl chloride wherein, is slowly warming up to afterwards 75 ℃, and to overflowing without gas, decompression extracts solvent and excessive thionyl chloride.Add wherein 5mL tetrahydrofuran (THF), be transferred in dropping funnel;
In 50mL single port bottle, add 2-amino-N-p-methylphenyl-5-thiazole carboxamides (
4a) (0.5g, 2.15mmol), 5mL tetrahydrofuran (THF) and (0.7mL, 4.99mmol) triethylamine, ice bath, slowly drips the Benzoyl chloride of preparing above, drips off, and continues reaction 1h, then room temperature reaction 2h.Remove solvent under reduced pressure, add wherein 5mL methylene dichloride and 20mL water, stir 5min, suction filtration, 1mL methylene dichloride and 5mL water washing for filter residue, acetone recrystallization, obtains white solid 0.62g, productive rate 86.1%,
1h-NMR (600 MHz, DMSO-d6) δ: 2.29 (s, 3H), 7.17 (d, 2H, J=8.4H z), 7.57 (t, 2H, J=7.8H z), 7.61 (d, 2H, J=8.4H z), 7.67 (t, 1H, J=7.2H z), 8.13 (d, 2H, J=7.2H z), 8.40 (s, 1H), 10.17 (s, 1H), 12.93 (s, 1H)
13c-NMR (DMSO-d6,400 MHz) δ (ppm): 20.97,42.11,120.76; 120.76,127.41,128.50,128.96; 128.96,129.59,129.59; 129.80,129.80,133.22; 135.14,136.59,140.73; 159.74,161.43,170.28; Mass Spectra (
m/z) [M+H]
+337.87, [M+Na]
+359.9; IR (KBrcm-1): 3454,3136,1676,1634,1514,1298,1182.
Embodiment 2
4a-cthe preparation of compounds as described in Example 1;
synthesizing of 2-(6-chloro-2-methyl pyrimidine-4-is amino)-N-substituted-phenyl-5-oxazole methane amide
Compound
4a-c(41 mmol), chloro-2-picoline (8.0 g of 4,6-bis-, 41mmol) with THF(105 ml) add in 250 mL three-necked bottles, cryosel is bathed be cooled to-10-~ 5 ℃, adds sodium tert-butoxide (25.8 g of fresh preparation, 250 mmol) ,-10 ℃ of stirring reaction 1.5 h.Add the hydrochloric acid of 2 mol/L to be adjusted to neutrality, 0 ℃ is stirred 1.5h, filter, and a small amount of water washing of filter cake, dry, obtain faint yellow solid
6(15g, 88%) mp>300 ℃;
4 N-substituted-phenyl-2-[6-[4-(3-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl-amino]-5-oxazole methane amide synthetic
Above-claimed cpd (8.16 mmol) is dissolved in 30 mL DMFs, adds 1-(2-hydroxyethyl) piperazine (3.2 g, 21 mmol) and triethylamine (1.6 g, 16 mmol), be heated to 80 ℃, stir 4 h.Be cooled to room temperature, it is slowly poured in 100 m L water, stir 10 m in, suction filtration, filter cake is added in the aqueous ethanolic solution that 20 mL volume fractions are 80%, be heated to 80 ℃, stir 5min, more slowly drip 5mL water, be cooled to room temperature, suction filtration, is dried to obtain white solid 3.5 g, yield 85%.
Embodiment
32-An Ji oxazole compounds of the present invention is tested people CML cell K562 cell inhibitory activity
Method is described below: make 2-An Ji oxazole compounds of the present invention in K562 cell, in different time, with mtt assay, measure and to make 50% non-infected cells that cytopathic concentration IC occur
50;
Materials and methods: the drug-induced cytopathic restraining effect efficiency of inhibition K562 cytoactive of each compound is monitored;
Concrete operations are as follows: at CO
2incubator, cell is subculture in the substratum of the RPMI1640 of the calf serum containing 10% deactivation.To after the cell centrifugation of logarithmic phase, be made into 1*10
5suspension, be inoculated in containing in the RPMI-1640 of 10% new-born calf serum, by 10000/hole, be inoculated in 96 orifice plates, every hole adds 100ul containing the medicine of different concns and the fresh culture of coordinative solvent, add 0.4% Trypan blue, with blood counting chamber, count respectively 4 large grid cell survivals, death toll, calculate survival rate;
It is emphasized that when compound water soluble poor, need to be with DMSO could dissolve time, DMSO ultimate density in MT-4 cell culture medium is less than 2%.Because it is active that DMSO can affect the anti-cell of test compounds, to containing the active contrast of same concentrations DMSO solution anti-cell blank assay, also should parallelly carry out.The present invention adopts clinical application Dasatinib to compare product, and part target compound the results are shown in Table 1 to the inhibition activity of K562 cell:
Table 1. compound suppresses K562 cytoactive
Experimental result shows, the compound comprising in chemical structure of general formula generally has stronger inhibition K562 cytoactive, wherein compound
4bwith
6cquite active with Dasatinib.
Claims (3)
1.2-An Ji oxazole compounds, its structural formula is:
, wherein
R=H, C
1-5alkyl, halogen; R
1=H, C
1-5alkyl, halogen, CN;
X=N，CH；
R
3=H, CH
3, halogen, CN, NO
2;
R
4=H, CH
3, halogen, CN, NO
2;
R
2for hydroxyethyl piperazine, hydroxyethyl piperidine, piperazine ethylamino-, morpholine ethylamino-, piperidine-1-ethanamine base,
Piperazine methylamino, morpholine methylamino, piperidines methylamino, hydroxyethyl piperazine methylamino, hydroxyethyl piperidine methylamino, or C
1-5alkylamino radical.
2. the preparation method of 2-An Ji oxazole compounds described in claim 1, is characterized in that comprising the steps: substituted aromatic amines, in pyridine and tetrahydrofuran (THF), obtains E-N-aryl-3-ethoxy propylene acid amides with E-3-ethoxy propylene acyl chloride reaction; E-N-aryl-3-ethoxy propylene acid amides and NBS occur after addition reaction, close ring immediately with urea condensation, obtain formula (4
a-c) compound
; Formula (4
a-c) compound by more respectively with dichloro pyrimidine or dichloropyridine, and hydroxyethyl piperazine respectively anti-raw nucleophilic substitution obtain ultimate aim product; Or formula (4
a-c) compound is by reacting with aroyl chloride or alkyl acyl chloride, obtains ultimate aim product.
3. described in claim 1,2-An Ji oxazole compounds suppresses the application in K562 cytoactive medicine in preparation.
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| CN201410335767.XA CN104163818A (en) | 2014-07-15 | 2014-07-15 | 2-amino oxazole compound and preparation method and application thereof |
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|---|---|---|---|
| CN201410335767.XA CN104163818A (en) | 2014-07-15 | 2014-07-15 | 2-amino oxazole compound and preparation method and application thereof |
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Family
ID=51907820
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| WO2010054107A2 (en) * | 2008-11-05 | 2010-05-14 | Principia Biopharma Inc. | Kinase knockdown via electrophilically enhanced inhibitors |
| CN102573485A (en) * | 2009-06-08 | 2012-07-11 | 加利福尼亚资本权益有限责任公司 | Triazine derivatives and their therapeutical applications |
-
2014
- 2014-07-15 CN CN201410335767.XA patent/CN104163818A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1764454A (en) * | 2003-03-24 | 2006-04-26 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| WO2010054107A2 (en) * | 2008-11-05 | 2010-05-14 | Principia Biopharma Inc. | Kinase knockdown via electrophilically enhanced inhibitors |
| CN102573485A (en) * | 2009-06-08 | 2012-07-11 | 加利福尼亚资本权益有限责任公司 | Triazine derivatives and their therapeutical applications |
Non-Patent Citations (1)
| Title |
|---|
| HU LI，等: "Synthesis and cytotoxicity of novel 2-amino-5-thiazolecarboxamide derivatives", 《JOURNAL OF CHEMICAL RESEARCH》 * |
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Application publication date: 20141126 |