CN106632322B - Pyrazole indolizine compounds and preparation method thereof and purposes - Google Patents
Pyrazole indolizine compounds and preparation method thereof and purposes Download PDFInfo
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- CN106632322B CN106632322B CN201611189752.2A CN201611189752A CN106632322B CN 106632322 B CN106632322 B CN 106632322B CN 201611189752 A CN201611189752 A CN 201611189752A CN 106632322 B CN106632322 B CN 106632322B
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- 0 CC(C=C(C([n]1nc(*)cc1*)=O)N1C(*)=C(*)C(*)=C(*)C1)C#N Chemical compound CC(C=C(C([n]1nc(*)cc1*)=O)N1C(*)=C(*)C(*)=C(*)C1)C#N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to a kind of pyrazoles indolizine compounds with anti-inflammatory activity and preparation method thereof and the purposes as anti-inflammatory drug.The invention further relates to the Pharmaceutical compositions containing the pyrazoles indolizine compounds.It is experimentally confirmed that the compound of formula I of the present invention has significant anti-inflammatory activity, can be further used in the research and development of anti-inflammatory drug.
Description
Technical field
The present invention relates to a kind of pyrazoles indolizine compounds with anti-inflammatory activity and preparation method thereof with as anti-inflammatory agent
The purposes of object.The invention further relates to the Pharmaceutical compositions containing the pyrazoles indolizine compounds.
Background technology
In recent years, indolizine compound has a wide range of applications in field of medicaments, such as (matrix is at fiber as FGF
Porcine HGF) the strong antagonist, xanthine oxidase inhibitor, the CRTH2 antagonists that are combined with receptor；It is twisted for treating the heart
Bitterly, the illnesss such as arrhythmia cordis, hyperuricemia.
Patent WO03/084956 discloses a kind of 3 introducing benzoyls in indolizine, and obtaining one kind can inhibit
The derivative of FGF can inhibit Tumor Angiongesis, for treating all kinds of tumours, cancer.
Patent EP0235111, EP0097636, US4378362, EP0382628, which disclose some and can be used in treating the heart, to be twisted
The Indoli zine derivatives of pain and arrhythmia cordis, some of which compound also have the bioactivity for inhibiting calcium transport.
Patent CN101243086, WO2008/074966, CN101605789 are disclosed in 3 introducing thiophenyls of indolizine,
Obtain a kind of Indoli zine derivatives as CRTH2 antagonists；Patent WO2007031747 is then disclosed in 1 introducing of indolizine
Thiophenyl, obtained derivative equally also have CRTH2 antagonisms, can be used for treating the exploitation of medicament for treating respiratory system object.
Japanese Kissei Pharmaceutical Co., Ltd. discloses a kind of with xanthine oxidation in patent WO2012043638
Enzyme inhibition activity simultaneously can be used for preventing or treat (azepine) Indoli zine derivatives with the extremely relevant disease of serum uric acid level.
Present inventor discloses a kind of two pyrazoles carbonyls of 1,3 introducings in Acta Cryst. (2013) .E69, o450
The synthesis of the Indoli zine derivatives of base and its crystal structure.
Since indolizine compound has good medical usage, study such compound to drug development very
Significant, present inventor has designed and synthesized a kind of novel pyrazoles Indoli zine derivatives, is measured through biological activity test,
Being proved such compound has significant anti-inflammatory activity, can be used for anti-inflammatory drug research.
Invention content
The present invention provides the following compound of formula I or its pharmaceutically acceptable salt with anti-inflammatory activity：
Wherein：
A is oxygen or sulphur atom；
R1-R4Independently selected from：Hydrogen, alkyl, alkoxy, naphthenic base；
R5It is selected from：-CN；
R6Independently selected from：Hydrogen, alkyl；
As preferred embodiments of the present invention, A is selected from oxygen atom.
As another preferred embodiment of the present invention, R1-R4Optimizing alkyl, alkoxy.
Presently preferred scheme, R6Independently selected from alkyl.
The preferred following formula I-1 compounds represented of compound of formula I of the present invention
Wherein,
R1And R3Independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy；
R2And R4Independently selected from C1-6Alkyl, C1-6Alkoxy；
R6Independently selected from：C1-6Alkyl.
The invention further relates to the purposes that compound of formula I or its pharmaceutically acceptable salt are used to prepare to drug, the present invention
Compound there is anti-inflammatory effect, can be used for preparing and treat all kinds of inflammation related diseases.
The invention further relates to a kind of Pharmaceutical compositions, and it includes compound of formula I or its pharmaceutically acceptable salt as activity
Ingredient can further comprise pharmaceutically acceptable carrier, excipient.
The Pharmaceutical composition is prepared into the form of medication such as oral, subcutaneous, intramuscular, intravenous, transdermal.
Preferably, Pharmaceutical composition of the invention can prepare piece agent, capsule, pulvis, granule, oral solution, suspension
Liquid or injection.
Term
" alkyl " refers to the alkyl of the linear chain or branched chain with 1-10 carbon atom, preferably C1-6Alkyl, more preferable C1-3
Alkyl, suitable alkyl is such as：Methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl etc..
" alkoxy " refers to-O- alkyl.
" naphthenic base " refers to the cyclic alkyl of saturation, including 3-6 atom, preferably cyclopropyl, cyclobutyl, cyclopenta, ring
Hexyl.
" pharmaceutically acceptable salt ", including base addition salts and acid-addition salts, base addition salts preferably with NaOH, KOH,
Na2CO3、K2CO3、NaHCO3、KHCO3Formed salt, acid-addition salts preferably with hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, amber
Amber acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, benzene sulfonic acid, acetic acid,
Salt formed by mandelic acid.
The present invention also provides the synthetic methods of indolizine analog derivative shown in Formulas I：
It include mainly following synthesis step：
1) Formula VII compound is stirred to react production V compounds in organic solvent with VI compounds；
2) Formula V compound is in alkali and CrO3In the presence of with acrylonitrile formula IV compound is obtained by the reaction in DMF or DMA；
3) formula IV compound hydrazinolysis obtains formula III compound；
4) formula III compound and Formula II compound condensation it is cyclic -1 compound of Formulas I；
Or, further including that -1 compound of Formulas I 5) is further converted to -2 compound of Formulas I；
Or optionally convert Formulas I -1 and I-2 compounds to its pharmaceutically acceptable salt；Formulas I -1 is collectively constituted with Formulas I -2
The compound of formula I of the application.
Wherein, X Cl, Br；RbFor C1-6Alkyl；R1-R6, A have definition identical with compound of formula I.
As the preferred embodiment of the present invention, in step 1), the organic solvent be selected from ethyl acetate, dichloromethane, chloroform,
Tetrahydrofuran, acetone, acetonitrile.
As another preferred embodiment of the present invention, in step 1), the molar ratio of Formula VII and Formula IV compound is 1-2:1.
In an embodiment of invention, in step 2), the alkali is selected from NaOH, KOH, Na2CO3、K2CO3、NaHCO3、
KHCO3, triethylamine, pyridine etc., preferably triethylamine.
In the another embodiment of invention, the hydrazinolysis of step 3) is under the conditions of ethanol as solvent, with 80% hydration
What hydrazine reaction was implemented.
Further, step 4) is reacted in the case where aliphatic acid makees solvent condition, the preferred formic acid of the aliphatic acid, second
Acid, propionic acid.
Further, step 5) the further conversion is to convert 3 carbonyls to thiocarbonyl group with lawesson reagent.
Wherein, lawesson reagent of the present invention is that a kind of oxygen sulphur well-known to those skilled in the art exchanges reagent, can
Convert carbonyls to thiocarbonyls.
Description of the drawings
Fig. 1：Compound 41H-NMR spectrum；
Fig. 2：Cytotoxicity test result of the compound 4 to mouse primary peritoneal macrophage；
Fig. 3：The anti-inflammatory activity test result of compound 4
Specific embodiment
In the compounds of this invention Structural Identification：Fusing point test laboratory apparatus is X-4 micro melting point apparatus；1H-NMR is used
Bruker companies ACF-400 type Nuclear Magnetic Resonance, DMSO-d6For solvent, TMS is internal standard.
Embodiment 1
The synthesis of step 1) pyridinium compound 1
By 120mmol 2,4- lutidines and 60mmol bromoacetates are dissolved in 200mL ethyl acetate, stirring 20
Hour, it filters.After filter cake is washed with 50ml ethyl acetate, drying at room temperature, it is white powder, yield 75% to obtain product 1.
The synthesis of step 2) compound 2
By 30mmol compounds 1,180mmol triethylamines, 120mmol acrylonitrile and 120mmol chromium trioxides are added to
It is heated to 90 DEG C in 180ml DMF (n,N-Dimethylformamide), is kept for 2 hours.After cooling, reaction mixture pours into 500ml
It in 5% hydrochloric acid, stands, filters, after filtration cakes torrefaction, with petroleum ether (bp 60-90 DEG C)-ethyl acetate (volume ratio 4:1) column layer
Analysis, obtains yellow powder compound 2, yield 40%.
The synthesis of step 3) hydrazide compound 3
20mmol compounds 2 and 10ml ethyl alcohol are flowed back 8 hours after the mixing of 80% hydrazine hydrates of 30ml.It is cooling, it filters,
Obtain white powder compound 3, yield 74%.
The synthesis of step 4) 5,7- dimethyl -1- cyano -3- (3,5- dimethyl pyrazole oxazolyls carbonyl) indolizine
10mmol compounds 3 are dissolved in 20ml acetic acid, 40mmol acetylacetone,2,4-pentanediones are then added dropwise.After stirring 2 hours, take out
It filters, after filtration cakes torrefaction, with petroleum ether (bp 60-90 DEG C)-ethyl acetate (volume ratio 4:1) column chromatography obtains white powder final product
4, yield 70%.After measured：Fusing point is 184-185 DEG C；1H-NMR(CD3SOCD3,400MHz):2.17(s,3H,–CH3),
2.40 (s, 3H ,-CH3), 2.46 (s, 3H ,-CH3), 2.55 (s, 3H ,-CH3), 6.31 (s, 1H, pyrazole=CH), 7.04
(s, 1H, ArH), 7.62 (s, 1H, ArH), 7.82 (s, 1H, ArH) are shown in Fig. 1.
Biological activity determination：
(1) 4 cytotoxicity of compound detects
We have carried out cytotoxicity detection to compound 4.It is that detection is thin to choose mouse primary peritoneal macrophage first
Born of the same parents, the inoculating cell suspension (10 in 96 porocyte culture plates4The μ l cell suspensions of a cell/100,100 μ l cell suspensions/hole),
By culture plate in cell incubator preculture 12 hours (at 37 DEG C, 5%CO2Under conditions of), then it is added in culture plate
The compound 4 of various concentration (5 μ g/ml, 10 μ g/ml, 20 μ g/ml) continues culture plate being placed on incubator incubation 24 hours, to
10 μ l CCK-8 solution (being careful not to generate bubble in hole, they can influence O.D. values reading) are added per hole, it then will be thin
Born of the same parents' culture plate, which is placed in incubator, is protected from light incubation 1 hour, and the absorbance at 450nm is finally measured with microplate reader.
Cell survival rate computational methods：Cell survival rate=[(As-Ab)/(Ac-Ab)] * 100%
As:Experimental port (culture medium containing cell, CCK-8 solution, compound 4)
Ac:Control wells (culture medium containing cell, CCK-8 solution, without compound 4)
Ab:Blank well (is free of the culture medium of cell and compound 4, CCK-8 solution)
In cytotoxicity test experience, our every group of Duplicate Samples are arranged 5, and experiment repeats to do 3 times, to ensure data
It is credible.Data are shown by the form of mean+/-standard error (means ± SEM).It is different dense through statistical analysis
The compound 4 of degree does not have overt toxicity to mouse primary peritoneal macrophage (referring to Fig. 2).
(2) the anti-inflammatory performance of compound 4 is probed into the inflammatory environment simulated in vitro
We have carried out anti-inflammatory performance detection to compound 4.It is that detection is thin to choose mouse primary peritoneal macrophage first
Born of the same parents, the inoculating cell suspension (10 in 24 porocyte culture plates5The μ l cell suspensions of a cell/500,500 μ l cell suspensions/hole),
Then by culture plate incubator preculture 12 hours (at 37 DEG C, 5%CO2Under conditions of), then it is added not in culture plate
The compound 4 of same concentration (5 μ g/ml, 10 μ g/ml, 20 μ g/ml) after culture plate is placed on incubator incubation 1 hour, is added thin
Culture plate, is then placed on by bacterium lipopolysaccharides (Lipopolysaccharides, LPS) (the final concentration of 1 μ g/ml of each hole LPS)
Incubator is incubated 24 hours, and cell conditioned medium, 1000rpm is taken to centrifuge 10min.With reference on ELISA kit specification detection cell
The content of inflammatory factor-tumor necrosis factor-alpha in clear.
In inflammatory factor test experience, our every group of Duplicate Samples are arranged 3, and experiment repeats to do 3 times, to ensure data
It is credible.Data are shown by the form of mean+/-standard error (means ± SEM).Through statistical analysis, 10 μ g/
The compound 4 of ml and 20 μ g/ml concentration has significant antiphlogistic effects (* p<0.05 indicates statistically difference, * * p<0.01 table
It is shown with statistically significantly sex differernce) (referring to Fig. 3).
As it can be seen that there is the compound of formula I of the present invention significant anti-inflammatory activity, the research that can be further used for anti-inflammatory drug to open
In hair.
Although present invention has been a degree of descriptions, it will be apparent that, do not departing from the spirit and scope of the present invention
Under the conditions of, can suitably it be changed.It is appreciated that the present invention is not limited to the embodiments, and it is attributed to the scope of the claims,
It includes the equivalent replacement of each factor.
Claims (8)
1. compound shown in Formulas I -1 or its pharmaceutically-acceptable salts,
Wherein：
R1And R3Independently selected from hydrogen, C1-6Alkyl, C1-6Alkoxy；
R2And R4Independently selected from C1-6Alkyl, C1-6Alkoxy；
R6Independently selected from：Hydrogen, C1-6Alkyl.
2. -1 compound of Formulas I according to claim 1, it is characterised in that R1And R3Independently selected from hydrogen；R2And R4Independently selected from
C1-6Alkyl, C1-6Alkoxy；R6Independently selected from C1-6Alkyl.
3. according to -1 compound of Formulas I of any one of claim 1-2, it is characterised in that R1And R3Independently selected from hydrogen；R2、R4And R6
Independently selected from methyl, ethyl, propyl, isopropyl.
4. according to -1 compound of Formulas I of any one of claim 1-2, it is characterised in that compound chosen from the followings：
5. the preparation method of -1 compound of Formulas I of any one of claim 1-4, it is characterised in that include the following steps：
1) Formula VII compound is stirred to react production V compounds in organic solvent with Formula IV compound；
2) Formula V compound is in alkali and CrO3In the presence of with acrylonitrile formula IV compound is obtained by the reaction in DMF or DMA；
3) formula IV compound hydrazinolysis obtains formula III compound；
4) formula III compound and Formula II compound condensation it is cyclic -1 compound of Formulas I；
Or optionally convert -1 compound of Formulas I to its pharmaceutically acceptable salt；
Wherein, X Cl, Br；RbFor C1-6Alkyl；R1-R6With identical fixed with any one of claim 1-4-1 compound of Formulas I
Justice.
6. preparation method according to claim 5, which is characterized in that in step 1), the organic solvent is selected from acetic acid second
Ester, dichloromethane, chloroform, tetrahydrofuran, acetone, acetonitrile；In step 2), the alkali is selected from NaOH, KOH, Na2CO3、K2CO3、
NaHCO3、KHCO3, triethylamine, pyridine；The hydrazinolysis of step 3) is carried out with 80% hydrazine hydrate anti-under the conditions of ethanol as solvent
It answers；Step 4) is to make to be reacted under solvent condition in one or more in formic acid, acetic acid, propionic acid.
7. pharmaceutical composition, it is characterised in that can be connect comprising -1 compound of claim 1-4 any one of them Formulas I or its pharmacy
The salt received is as active constituent and pharmaceutically acceptable carrier or excipient.
8. -1 compound of claim 1-4 any one of them Formulas I or its pharmaceutically acceptable salt are preparing treatment anti-inflammatory drug
In purposes.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6576654B1 (en) * | 1998-09-23 | 2003-06-10 | Eli Lilly And Company | Method for the treatment of cystic fibrosis |
| US20030119793A1 (en) * | 2001-06-06 | 2003-06-26 | Brian Ledford | CAK inhibitors and uses thereof |
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2016
- 2016-12-20 CN CN201611189752.2A patent/CN106632322B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6576654B1 (en) * | 1998-09-23 | 2003-06-10 | Eli Lilly And Company | Method for the treatment of cystic fibrosis |
| US20030119793A1 (en) * | 2001-06-06 | 2003-06-26 | Brian Ledford | CAK inhibitors and uses thereof |
Non-Patent Citations (5)
| Title |
|---|
| Facile approach to diverse 3-acylated indolizines via a sequential Sonogashira coupling iodocyclization process;Youngeun Jung et al.;《Tetrahedron》;20120731;第68卷;图1及第8198页 * |
| Synthesis, Anticonvulsant, and Anti-inflammatory Activities of Some New Benzofuran-Based Heterocycles;Kamal M.Dawood等;《Arch.Pharm.Chem.Life Sci》;20061231;第339卷;第133-140页 * |
| Synthesis, molecular docking and biological evaluation of novel bis-pyrazole derivatives for analgesic, anti-inflammatory and antimicrobial activities;Prakash S.Nayak等;《Med Chem Res》;20150911;第24卷;第4191-4206页 * |
| 中氮茚及其衍生物的合成方法学研究;章敏;《安徽师范大学硕士学位论文》;20101231;全文 * |
| 中氮茚衍生物的新合成方法及其荧光属性研究;李国栋;《东北师范大学硕士学位论文》;20150215;全文 * |
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