CN108409654A - Tetrahydroisoquinoline -2- bases aryloxyphenoxy alkyl ketone compound with anti-tumor activity and its pharmaceutical applications - Google Patents
Tetrahydroisoquinoline -2- bases aryloxyphenoxy alkyl ketone compound with anti-tumor activity and its pharmaceutical applications Download PDFInfo
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- CN108409654A CN108409654A CN201810146086.7A CN201810146086A CN108409654A CN 108409654 A CN108409654 A CN 108409654A CN 201810146086 A CN201810146086 A CN 201810146086A CN 108409654 A CN108409654 A CN 108409654A
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- tetrahydroisoquinoline
- bases
- aryloxyphenoxy
- alkyl
- alkyl ketone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- C07D401/12—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 chain containing hetero atoms as chain links
Abstract
The invention discloses 2 base aryloxyphenoxy alkyl ketone compound of tetrahydroisoquinoline and its medical usage, chemical structural formula are shown in formula I：In formula, R1、R2、R3、R4Respectively hydrogen or C1~C3Alkyl or C1~C3Any one in halogenated alkyl；X is nitrogen or carbon；X1、X2、X3、X4Any one respectively in hydrogen or fluorine or chlorine or bromine or iodine or trifluoromethyl or cyano or nitro.The invention further relates to the composition containing above compound and 2 base aryloxyphenoxy alkyl ketone of tetrahydroisoquinoline anti-tumor aspect application.
Description
Technical field
The present invention relates to a kind of compounds, and in particular to a kind of tetrahydroisoquinoline -2- bases aryloxyphenoxy alkyl assimilation
Close object and its medical usage.
Background technology
4- aryloxyphenoxies acid derivative is with extensive bioactivity, wherein fragrant phenoxy propanoic derivatives are made
For its Typical Representative, have more than 20 a commercial varieties in agricultural herbicide.4- aryloxyphenoxy acid derivatives simultaneously
Also have in the research of anticancer drug a large amount of reports [Investigational New Drugs, 1999,16:287–296；
Investigational New Drugs, 1998,16:129–139；Acta Pharmaceutica Sinica, 2005,40 (9):814-819], wherein
XK469 (2- (4- (7- chloroquinoxalin-2-yloxies base) phenoxy group) propionic acid) is that DuPont Corporation is carrying out the clinical research of I phase
A new type antineoplastic medicine, XK469 have very wide antitumor spectra, Small side effects are effective to a variety of solid tumor models, such as colon
[JMed Chem, 2001,44 (11) such as cancer Colon38 and breast cancer:1758-76].
Invention content
The present invention provides a kind of tetrahydroisoquinoline -2- bases aryloxyphenoxy alkyl ketone compound and its isomers,
It is characterized in that, chemical structural formula is shown in formula I：
In formula, R1、R2、R3、R4Respectively hydrogen or C1~C3Alkyl or C1~C3Any one in halogenated alkyl；X be nitrogen or
Carbon；X1、X2、X3、X4Any one respectively in hydrogen or fluorine or chlorine or bromine or iodine or trifluoromethyl or cyano or nitro；
In the definition of compound I given above, no matter term used exclusive use is also used in compound word, represent such as
Lower substituent group：
Alkyl：Refer to linear or branched alkyl group；
Halogenated alkyl：Refer to linear or branched alkyl group, hydrogen moiety on these alkyl or is all replaced by halogen atom；
The compound of the present invention can exist in the form of one or more isomers.Isomers includes enantiomter, non-
Enantiomter, geometric isomer.As the present invention Formulas I compound represented, due on a carbon atom connect four differences
Substituent group and form stereoisomer (respectively with R and S to indicate different configurations), the present invention includes R types isomers and S types
The mixture of isomers and their any ratios.
In preferred scheme, the concrete structure of the tetrahydroisoquinoline -2- base aryloxyphenoxy alkyl ketone compounds
Formula is：
(R)-tetrahydroisoquinoline -2- bases -2- [4- (5- chloro-3-fluoropyridine -2- oxygroups) phenoxy group] third provided by the invention
Application of the ketone in preparing medicament for resisting cervical cancer.
Specific implementation mode
With reference to specific implementation, the present invention is furture elucidated.These embodiments are interpreted as being merely to illustrate the present invention
Rather than for limiting the scope of the invention.After having read the content of the invention recorded, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalence changes and modification are equally fallen into defined by claims of the present invention
Range.
Embodiment 1:(R)-tetrahydroisoquinoline -2- bases -2- [4- (5- chloro-3-fluoropyridine -2- oxygroups) phenoxy group] acetone (1)
Preparation
N,N-Dimethylformamide (40mL), (R) -2- (4- hydroxy benzenes oxygen) propionic acid (0.02mol, 3.64g), potassium carbonate
(0.02mol, 2.76g) adds the potassium carbonate of equivalent at 75 DEG C after stirring 0.5h, continues to stir 0.5h.2,3- is slowly added dropwise
Difluoro-5-chloropyridine (0.02mol, 3.00g), after being added dropwise, reaction temperature maintains 75 DEG C, 12h.Stop heating, is cooled to
Room temperature pours into reaction solution in 100mL ice water, and dilute hydrochloric acid adjusts pH 4-5, and filtering is washed three times with a small amount of ice water, and vacuum is dry
It is dry, obtain (R) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionic acid white solid 3.86g, yield 62.0%.
Toluene 40mL, (R) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionic acid (3.3mmol, 1.04g), adds
Enter into the single-necked flask of 100mL, after stirring and dissolving, thionyl chloride (20mmol, 2.24g), back flow reaction 4h is added, decompression is steamed
It evaporates, obtains (R) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionyl chloride yellow oily liquid, without isolating and purifying,
It is directly used in and reacts in next step.
Dichloromethane is added into above-mentioned (R) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionyl chloride reaction bulb
Alkane (40mL), tetrahydroisoquinoline (0.44g, 3.30mmol), 4-dimethylaminopyridine (0.02g, 0.17mmol) stir under ice bath
15min.Triethylamine (1.37mL, 10mmol) is added dropwise, after being added dropwise, continues stirring 10 minutes, then removes ice bath, allow
It returns and is warmed to room temperature naturally, stops reaction after stirring 4h, reaction solution is poured into 150mL ice water, dichloromethane extracts (40mL*
3), combining extraction liquid is successively washed twice with 50mL saturated sodium bicarbonate solutions, and 100mL is washed three times, the anhydrous sulphur of gained organic phase
Sour sodium drying, removes dichloromethane, silica gel column chromatography separating purification product, eluant, eluent (V under reduced pressurePetroleum ether：VEthyl acetate=3:1) it, obtains
(R)-tetrahydroisoquinoline -2- bases -2- [4- (5- chloro-3-fluoropyridine -2- oxygroups) phenoxy group] acetone (1) yellow oily liquid
0.22g, yield 15.6%；1H NMR(CDCl3,400MHz)δ:1.67 (d, J=6.8Hz, 3H, CHCH3 ), 2.73~2.94 (m,
2H,NCH2CH 2), Ph 3.64~3.99 (m, 2H, NCH 2CH2), Ph 4.66~4.96 (m, 2H, NCH 2), Ph 5.01 (q, J=
6.8Hz,1H,CHCH3), 6.91~7.20 (m, 8H, PhH), 7.48 (dd, J=8.8Hz, 2.0Hz, 1H, Py-H), 7.85 (d, J
=2.0Hz, 1H, Py-H)；13C NMR(CDCl3,100MHz)δ:17.87,29.52,44.98,46.82,74.91,115.77,
122.39,124.82,125.00,126.51,128.38,128.96,132.72,133.73,140.13,145.63,146.93,
148.27,151.19,154.61,170.03.
Embodiment 2：(R)-tetrahydroisoquinoline -2- bases -2- [4- (3- chloro-5-trifluoromethylpyridine -2- oxygroups) phenoxy group]
The preparation of acetone (2)
(R) -2- (4- hydroxyphenoxies) propionic acid (3.00g), DMF (35ml) are slowly added to K2CO3(4.55g), is warming up to
70~80 DEG C, 1h is stirred, 2,3-, bis- chloro-5-trifluoromethylpyridines (3.56g) are added dropwise, 70~80 DEG C of stirring 8h is kept, stops
It only reacts, cooled to room temperature, pours the mixture into ice water (100mL), adjust pH 4~5 using dilute hydrochloric acid, use acetic acid
Ethyl ester extracts, and organic phase washing, dry, precipitation obtains (R) -2- [4- (5- trifluoromethyl -3- chloropyridine -2- oxygroups) phenoxy group] third
Sour brown liquid 5.03g, yield 84.4%.
(R) -2- [4- (5- trifluoromethyl -3- chloropyridine -2- oxygroups) phenoxy group] propionic acid (3.3mmol, 1.08g), is dissolved in
In toluene (35mL), SOCl is added dropwise2(20mmol, 2.24g), is heated to reflux, and reacts 4h, and precipitation obtains (R) -2- [4- (5- fluoroforms
Base -3- chloropyridine -2- oxygroups) phenoxy group] propionyl chloride be directly used in next step.
Gained acyl chlorides is dissolved in dichloromethane (35mL), and 1,2,3,4- tetrahydroisoquinoline (0.44g) of intermediate is added and urges
The DMAP of change amount is slowly dropped into triethylamine (1.37mL, 10mmol), is stirred to react 5h with stirring.Reaction is completed, by mixture
It to pouring into ice water (100mL), is extracted with dichloromethane (80mL*2), organic phase washing, dry, precipitation.It is pure through column chromatography
Change to obtain white solid (R)-tetrahydroisoquinoline -2- bases -2- [4- (3- chloro-5-trifluoromethylpyridine -2- oxygroups) phenoxy group] acetone
(2) 0.66g, m.p.47~48 DEG C, yield 41.90%.1H NMR:δ 1.67 (d, J=6.8Hz, 3H, CHCH3 ),2.73-2.94
(m,2H,CH2CH2 ),3.64-4.01(m,2H,CH2),4.66-4.97(m,2H,CH2), 5.03 (q, J=6.8Hz, 1H,
CHCH3),6.94-7.21(m,8H,Ph-H),7.96(s,1H,Py-H),8.24(s,1H,Py-H)；13C NMR:δ17.89,
29.56,45.02,46.86,75.07,115.85,115.96,119.18,122.64,122.76,126.39,126.55,
126.66,127.04,128.39,132.75,136.19,142.53,146.80,155.01,161.32,170.00.
Embodiment 3：(R) system of-tetrahydroisoquinoline -2- bases -2- [4- (4 cyano -2- fluorophenoxies) phenoxy group] acetone (3)
It is standby
In n,N-Dimethylformamide (DMF, 40mL), addition (R) -2- (4- hydroxy benzenes oxygen) propionic acid (3.03g,
0.02mol), potassium carbonate (5.52g, 0.04mol) is added portionwise, is warming up at 70 DEG C~80 DEG C, persistently stirs 1h, is added by amount
(2.38g, the 0.02mol) of 3,4- difluorobenzonilyiles, continues to be stirred to react 6~7h.It is cooled to room temperature, pours into ice water (250mL),
Be slowly added to dilute hydrochloric acid, be adjusted to pH 4~5, filter, washing, vacuum dried case it is dry (R) -2- [4- (4- cyano -2-
Fluorophenoxy) phenoxy group] propionic acid gray solid (R) -2- [4- (4- cyano -2- fluorophenoxies) phenoxy group] propionic acid 3.26g, production
Rate 65.7%.
(R) -2- [4- (4- cyano -2- fluorophenoxies) phenoxy group] propionic acid (1.00g, 3.3mmol) is dissolved in toluene
In (40ml), it is slowly added to SOCl2(1.18g, 10mmol), back flow reaction 5h after sloughing solvent with Rotary Evaporators, are obtained (R)-
2- [4- (4- cyano -2- fluorophenoxies) phenoxy group] propionyl chloride directly carries out next step reaction.
Gained acyl chlorides is dissolved in dichloromethane (40ml), 1,2,3,4- tetrahydroisoquinolines (0.44g, 3.3mmol) are added
With the 4-dimethylaminopyridine (DMAP) of catalytic amount, 10min is stirred under ice bath, and triethylamine (1g, 10mmol) is added dropwise dropwise.After
Continuous stirring 3h to 10h.It after the completion of reaction, pours into 100ml ice water, is extracted with dichloromethane, collect organic phase, and be washed with water
(100ml × 2), gained crude product are dried with anhydrous sodium sulfate, after precipitation through silica gel chromatographic column purify yellow mucus (R)-
Tetrahydroisoquinoline -2- bases -2- [4- (4 cyano -2- fluorophenoxies) phenoxy group] acetone (3) 1.08g, yield 78.9%.1H NMR:
δ 1.68 (d, J=6.8Hz, 3H, CHCH 3), 2.75~2.90 (m, 2H, Ph-CH 2), 3.78~4.02 (m, 2H, N-CH2),4.68
~4.89 (m, 2H, Ph-CH2- N), 5.05 (q, J=6.8Hz, 1H, CHCH3), 6.74~6.85 (m, 1H, PhH), 6.88~
7.00 (m, 4H, PhH), 7.07~7.23 (m, 4H, PhH), 7.29~7.33 (m, 1H, PhH), 7.44 (dd, J=10.0Hz,
2.0Hz,1H,PhH)；13C NMR:δ17.98,29.56,45.02,46.88,75.00,106.09,116.47,118.63,
120.46,120.67,121.17,125.93,126.68,127.06,128.39,128.98,129.32,132.73,148.58,
150.47,153.63,154.80,169.93.
Embodiment 4：Antitumor activity is tested
1. Cell culture invitro
By Caski cell culture in containing 10% newborn calf serum, 105The RPMI- of U/L penicillin, 100mg/L streptomysins
In 1640 culture mediums, it is placed in 37 DEG C, CO2It is cultivated under the conditions of the saturated humidity that volume fraction is 5%, waits for cell adherent growth, take
Exponential phase cell is for testing.
2.MTT methods detect inhibitory rate of cell growth
It is 1 × 10 to take the cervical carcinoma CAKSI cells that logarithmic phase is grown to be configured to cell density5The cell of a/mL is outstanding
Supernatant liquid is inoculated in 96 orifice plates, per hole 100 μ L, 5%CO2, 37 DEG C be incubated, after cell is adherent, replace culture solution, experimental group
It is divided into the red Bo alcohol extract group in south of various concentration, sequentially adds the tetrahydroisoquinoline -2- base virtues of different quality concentration from low to high
100 μ L of oxygroup phenoxyalkyl ketone compound (6.25,12.5,25.0,50.0,100 μ g/mL), every group sets 4 multiple holes.It will training
It supports plate and moves into CO2Continue to cultivate in incubator, respectively at taking out culture plate afterwards for 24 hours, the 5mg/mL MTT liquid newly prepared is added every time
20 μ L, 37 DEG C are protected from light incubation 4h, terminate culture.Supernatant is sucked, 150 μ L of DMSO are added per hole, set low-speed oscillation on shaking table
After 10min, the absorbance value (OD in each hole is measured at 490nm with microplate reader490Nm) according to formula：Cell inhibitory rate=(1- gives
Medicine group OD values/blank control group OD values) × 100%.IC50Value calculates：Sample solution concentration logarithm and cell inhibitory rate linear regression,
Half-inhibition concentration IC of the sample to cell is calculated using software50Value.
Active testing is the results show that (R)-tetrahydroisoquinoline -2- bases -2- [4- (5- chloro-3-fluoropyridine -2- oxygroups) benzene oxygen
Base] acetone at 25.0 μ g/mL to the IC of cervical cancer cell CAKSI50Value is 77.23 μm of ol/L.Other are in mass concentration
Detection data is as follows under 25.0 μ g/mL：
Claims (5)
1. a kind of tetrahydroisoquinoline -2- bases aryloxyphenoxy alkyl ketone compound, which is characterized in that its chemical structural formula such as formula
Shown in I：
In formula, R1、R2、R3、R4Respectively hydrogen or C1~C3Alkyl or C1~C3Any one in halogenated alkyl；X is nitrogen or carbon；
X1、X2、X3、X4Any one respectively in hydrogen or fluorine or chlorine or bromine or iodine or trifluoromethyl or cyano or nitro.
2. tetrahydroisoquinoline -2- bases aryloxyphenoxy alkyl ketone compound described in claim 1, it is characterised in that：It is described
The concrete structure formulas of tetrahydroisoquinoline -2- base aryloxyphenoxy alkyl ketone compounds be：
3. tetrahydroisoquinoline -2- bases aryloxyphenoxy alkyl ketone compound as claimed in claim 1 or 2 includes R type isomers
Or S types isomers and R types isomers and S types isomers are with the mixture of arbitrary proportion.
4. (R)-tetrahydroisoquinoline -2- bases -2- [4- (5- chloro-3-fluoropyridine -2- oxygroups) benzene oxygen as claimed in claim 1 or 2
Base] application of the acetone in terms of preparing antitumor drug.
5. the application described in claim 4, which is characterized in that (R)-tetrahydroisoquinoline -2- bases -2- [4- (chloro- 3- of 5-
Fluorine pyridine -2- oxygroups) phenoxy group] application of the acetone on the drug of cervical carcinoma.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1243582A1 (en) * | 1999-12-24 | 2002-09-25 | Kirin Beer Kabushiki Kaisha | Quinoline and quinazoline derivatives and drugs containing the same |
| CN101351467A (en) * | 2005-11-30 | 2009-01-21 | 诺瓦提斯公司 | 3-(substituted amino)-pyrazolo[3,4-d]pyrimidines as EphB and VEGFR2 kinase inhibitors |
| CN106632258A (en) * | 2016-12-15 | 2017-05-10 | 三峡大学 | Tetrahydroisoquinoline-2-aryloxyphenoxyalkyl ketone compound and application thereof |
-
2018
- 2018-02-12 CN CN201810146086.7A patent/CN108409654B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1243582A1 (en) * | 1999-12-24 | 2002-09-25 | Kirin Beer Kabushiki Kaisha | Quinoline and quinazoline derivatives and drugs containing the same |
| CN101351467A (en) * | 2005-11-30 | 2009-01-21 | 诺瓦提斯公司 | 3-(substituted amino)-pyrazolo[3,4-d]pyrimidines as EphB and VEGFR2 kinase inhibitors |
| CN106632258A (en) * | 2016-12-15 | 2017-05-10 | 三峡大学 | Tetrahydroisoquinoline-2-aryloxyphenoxyalkyl ketone compound and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 刘祈星等: ""N-吡啶基-2-4-芳氧苯氧基_丙酰胺的合成及抗肿瘤活性"", 《精细化工》 * |
| 刘祈星等: ""N-氮杂环甲基芳氧苯氧丙酰胺衍生物的抗肿瘤活性"", 《三峡大学学报》 * |
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