CN101239980B - Immune receptor regulator couplet precursor, couplet and application thereof - Google Patents
Immune receptor regulator couplet precursor, couplet and application thereof Download PDFInfo
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- CN101239980B CN101239980B CN2008100142473A CN200810014247A CN101239980B CN 101239980 B CN101239980 B CN 101239980B CN 2008100142473 A CN2008100142473 A CN 2008100142473A CN 200810014247 A CN200810014247 A CN 200810014247A CN 101239980 B CN101239980 B CN 101239980B
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- 239000002243 precursor Substances 0.000 title claims abstract description 16
- 102000027596 immune receptors Human genes 0.000 title abstract 3
- 108091008915 immune receptors Proteins 0.000 title abstract 3
- 239000000126 substance Substances 0.000 claims abstract description 5
- 244000005700 microbiome Species 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 230000007365 immunoregulation Effects 0.000 claims abstract 2
- 230000036039 immunity Effects 0.000 claims description 13
- 108091006073 receptor regulators Proteins 0.000 claims description 11
- 125000003636 chemical group Chemical group 0.000 claims description 6
- 230000009849 deactivation Effects 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- -1 sulfonyloxy Chemical group 0.000 claims description 3
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- 230000000840 anti-viral effect Effects 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
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- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 1
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- 230000000694 effects Effects 0.000 abstract description 3
- 241000700605 Viruses Species 0.000 abstract description 2
- 230000001154 acute effect Effects 0.000 abstract description 2
- 206010064097 avian influenza Diseases 0.000 abstract description 2
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a couplet precursor and a couplet of an immunoreceptor regulator, and a preparation method and application thereof in immunoregulation. The chemical structural formula is [ I]：
Hair brushThe beneficial effects are as follows: the immune receptor regulator precursor and the immune receptor regulator conjugate are used for immune regulation of virus resistance, influenza resistance, avian influenza resistance, various acute and chronic viral diseases and other diseases such as microorganism resistance, tumor resistance and the like, and have better effect.
Description
Technical field
The present invention relates to a kind of immunity receptor regulator couplet precursor and couplet, and preparation method thereof and the application in immunomodulatory.
Background technology
Immunity agonist and immunizing antigen are (as vaccine, immune peptide, immune protein, immune polysaccharide, immunity polymerized nucleoside and acid, the cell of deactivation and the microorganism of deactivation etc.) combined utilization or coupling, immunological effect (World Chin J Digestol 2005 September 15 that often produce to improve; 13 (17): 2078-2081 ﹠amp; Vaccine, Volume 23, Issue45,1 November 2005, Pages 5263-5270). the present invention has synthesized a series of immunity receptor regulator couplet precursors, and the couplet of they and immunizing antigen.
Summary of the invention
The object of the present invention is to provide a series of immunity receptor regulator couplet precursors and couplet, to improve their immunological effect.
Another object of the present invention is to provide above-mentioned immunity receptor regulator couplet precursor and the application of couplet on medicine.
The present invention is relevant a series of immunity receptor regulator couplet precursors and couplet thereof, and its chemical structure of general formula is [I]:
In the general formula [I]:
X
1Represent O, S, Se or NRR
R represents hydrogen, alkyl various straight chains or side chain, haloalkyl, alkoxyalkyl. cycloalkyl, Heterocyclylalkyl, acyloxy alkyl, aryl or heteroaryl.
R
1Represent hydrogen, various straight chains or side chain, replacement and unsubstituted alkyl, alkoxyalkyl, the carbonyl of various replacements (comprising aldehyde radical, ester group, amide group etc.), nitro, itrile group, halogen;
Work as R
2Represent under the various bio-ligands situation of (comprising vaccine, immune peptide, immune protein, immune polysaccharide, immune polymerized nucleoside and acid, the cell of deactivation and the microorganism of deactivation etc.),
X
2Represent chemical group as follows:
Work as R
2Represent the H atomic time, X
2Represent chemical group as follows:
The structural formula representative of proteic couplet 25,26,27,28 that with OVA is example is as follows:
In general formula [I], work as X
2When representing singly-bound, R
2Represent hydrogen atom. perhaps work as X
2Represent methyne (CH
2-) time, R
2Represent following chemical group:
N=0----10 wherein; R
3Represent halogen or sulfonyloxy and various acyloxy; Representative compounds 19,20,21,23 structural formula is as follows:
With coupling precursor compound 5,8,11 is that the synthetic route (Scheme 1) of example is as follows:
With coupling precursor compound 13 and 17 is that the synthetic route (Scheme 2) of example is as follows:
With chemical combination 19,20,21,23,24 is that the synthetic route (Scheme 3) of example is as follows:
Beneficial effect of the present invention is: by immunity receptor regulator couplet precursor and couplet thereof, it is antiviral that it is used for, anti influenza and bird flu and various acute and chronic virus disease and other disease such as antimicrobial and antitumor etc. immunomodulatory have effect preferably.
Preparation method of the present invention, it is simple to have technology, the advantage that product yield is high.
Description of drawings:
Fig. 1 conjugate 25 and non-conjugate 6 IFN-γ induce contrast
The IL-12 of Fig. 2 conjugate 25 and non-conjugate 6 induces contrast
Embodiment:
Synthesizing of compound 3:
With compound 1 (403mg, 1mmol) and in the 10mL DMF solution of 300mL TEA, the Vinyl chloroformate that adds 110mg. mixture stirring reaction 3 hours, DMF is removed in vacuum distilling, add the 100mL ethyl acetate in the resistates, wash with water once, organic layer of salt washing is isolated, anhydrous sodium sulfate drying. ethyl acetate is removed in underpressure distillation, compound 2, can be directly used in the synthetic of compound 3. the compound 2 that obtains is dissolved in the dehydrated alcohol of 100mL, adds 1 milliliter active nickel (R-Ni), feed hydrogen to 40psi (about 2.8 normal atmosphere), sealing hydrogenation 12 hours. remove by filter catalyzer, filtrate decompression concentrates, silica gel column chromatography separating purification (elutriant: methylene chloride-methanol 10: 1), get compound 3 (311mg, 65%) .ESIMS:m/z 480.3 (MH
+).
Synthesizing of compound 5:
With compound 3 (100mg, 0.21mmol) and TEA100 μ L be dissolved among the DMF of 10mL, add compound 4 (59mg, 0.22mmol). stirring at room 12 hours. DMF is removed in vacuum distilling, add the 100mL ethyl acetate in the resistates, wash with water once, organic layer of salt washing is isolated, anhydrous sodium sulfate drying. ethyl acetate is removed in underpressure distillation, resistates silica gel column chromatography separating purification (elutriant: methylene chloride-methanol 20: 1), get compound 5 (101mg, 76%) .ESIMS:m/z 631.5 (MH
+).
Synthesizing of compound 8:
With compound 6 (100mg, 0.24mmol) be dissolved among the DMF of 10mL, add Succinic anhydried (25mg, 0.24mmol), in stirring at room 3 hours. add N-maloyl imines (28mg again, 0.24mmol). in addition with DCC (54mg 0.25mmol) is dissolved in the anhydrous tetrahydro furan of 2mL, is added drop-wise in the above-mentioned DMF solution in 0 ℃. mixture stirs and spends the night, filter, the filtrate decompression distillation removes desolvates, and remaining and 20 milliliters of ethyl acetate are mixed stirring 1 hour, refilter, filtrate is concentrated into smaller size smaller, with silica gel column chromatography separating purification (elutriant: methylene dichloride), get compound 8 (96mg, 65%) .ESIMS:m/z 614.4 (MH
+).
Synthesizing of compound 11:
(120mg 0.25mmol) is mixed in the glycol dimethyl ether of 20mL with compound 10 (56mg.0.25mmo1), adds the Glacial acetic acid of 0.2mL with compound 9, mixture room temperature reaction 24 hours. separate out solid, filter dry product 11 (146mg, the 85%) .ESIMS:m/z 686.6 (MH that get
+).
Synthesizing of compound 13:
With compound 9 (120mg, 0.25mmol) and compound 12 (101mg.0.25mmol) be mixed in the anhydrous glycol dimethyl ether of 20mL, underpressure distillation gets solid to doing (less than 60 ℃), gets compound 13 (98.8mg, 48%) .ESIMS:m/z 824.6 (MH with re-crystallizing in ethyl acetate
+).
Synthesizing of compound 15:
With compound 3 (100mg, 0.21mmol) and 14 (23mg, 0.11mmol) mixed dissolution is in 20 milliliters dry DMF, under 0 ℃, slowly add DCC (45.5mg, 0.22mmol) 1mL THF solution, after adding, in room temperature reaction 24 hours, evaporated under reduced pressure solvent, remnants are dissolved in 50 milliliters of ethyl acetate and stirred 2 hours, filter, filtrate concentrates, resistates silica gel column chromatography separating purification (elutriant: methylene dichloride: methyl alcohol=20: 1), get compound 15 (84mg, 67%) .ESIMS:m/z 1134.2 (MH
+).
Synthesizing of compound 16:
(113.3mg 0.1mmol) is dissolved among the dehydrated alcohol 20mL, adds NaBH with compound 15
4(23mg, 0.6mmol), mixture stirring at room 12 hours, decompression is down in being concentrated into smaller size smaller less than 30 ℃, mixture in 0 ℃ of 1N HCl solution that adds down 50mL, with ethyl acetate extraction (2 * 50mL), washing, the salt washing, anhydrous sodium sulfate drying, underpressure distillation is done, and is remaining with silica gel column chromatography separating purification (elutriant: methylene dichloride: methyl alcohol=10: 1), get compound 16 (92mg, 81%) .ESIMS:m/z 568.5 (MH
+).
Synthesizing of compound 17:
With compound 16 (113.5mg, 0.2mmol) be dissolved in the methylene dichloride of 10mL, in addition with 2,2 '-two pyridine persulfides (176.2mg, 0.8mmol) dichloromethane solution that is dissolved in 15mL slowly is added drop-wise in 16 the dichloromethane solution, and mixture was in stirring at room 18 hours, concentrating under reduced pressure, resistates silica gel column chromatography separating purification (elutriant: methylene dichloride: methyl alcohol=10: 1), get compound 17 (88mg, 65%) .ESIMS:m/z 677.6 (MH
+).
Synthesizing of compound 23:
With compound 6 (100mg, 0.24mmol) be dissolved in 10 milliliters the anhydrous pyridine, add DMAP (30mg again, 0,24mmol), be cooled to 0 ℃, slowly drip compound 22 (63mg, anhydrous tetrahydrofuran solution 0.24mmol). continue at 10 ℃ after adding and stirred 2 hours. reaction mixture is poured in 50 milliliters of frozen water, with dichloromethane extraction (3 * 50mL), united extraction liquid, salt water washing once, anhydrous sodium sulfate drying. filter, filtrate decompression concentrates, resistates silica gel column chromatography separating purification (elutriant: methylene dichloride), get compound 23 (126mg, 82%) .ESIMS:m/z 641.5 (MH
+).
Same quadrat method with synthetic compound 23 gets 19,20,21.
Synthesizing of compound 24:
Compound 23 is mixed with concentrated hydrochloric acid, and with stirring at room 12 hours, decompression (less than 40 ℃) was concentrated into dried, compound 24 (100%) .ESIMS:m/z 568.5 (MH
+)
The conjugate 25 of compound 8 and OVA protein is synthetic:
OVA (ovalbumin with 100mg, chicken ovalbumin, molecular-weight average 45000) is dissolved in the distilled water of 2mL, mix with the DMSO solution of the 20mL of 50mg compound 8. in stirred overnight at room temperature. add 2 milliliters of saturated solution of sodium bicarbonate in the mixture liquid, evenly stirred 30 minutes, separate (Amershamdisposable PD-1 desalting column) with the PD-10 desalting column, the effluent liquid (absorbing ripple with 280nM detects) that will contain product OVA binding substances merges, lyophilize. determine that with mass spectrum molecular-weight average is the corresponding monomer that 47492. definite products 25 have comprised 5 compounds 8. use the same method and synthesized 26,27,28.
The biological activity test method:
Method: ELISA
Reagent and condition:
The human peripheral blood monocyte obtains with the settling methods centrifugation.Whizzer be Ficoll-Hypaque. with isolated cell suspension in the RPMI1640 media, add 10% FBS, L-L-glutamic acid, (RP1O Invitrogen), plants in the test plate (panel) of 96 wells penicillin/streptomycin.With the compound 25---28 among the present invention, at concentration 0.1--10 μ M activated cell, in 37 ℃, 5% CO
2Under the environment, cultivated 24 hours.With Luminex instrument (Austin, TX) level of measurement alpha-interferon and interleukin.Result shown among Fig. 1 and Fig. 2 is a mean value.
Fig. 1 and Fig. 2 are the immune stirring effect contrast of conjugate 25 and non-conjugate 6: Fig. 1 compound 25 and 6 IFN-γ induce contrast; Fig. 2 compound 25 and 6 IL-12 induce contrast.As can be seen from Figure, the immune effect of conjugate is greatly improved.
Claims (4)
1. immunity receptor regulator couplet precursor and couplet, its chemical structure of general formula is [I]:
X
1Represent 0, S, Se;
R represents alkyl, haloalkyl, alkoxyalkyl;
R
1Represent hydrogen;
(1) works as R
2Represent under the situation of bio-ligand, described bio-ligand is the cell of immune peptide, immune protein, deactivation or the microorganism of deactivation, X
2Represent any of chemical group as follows:
(2) work as R
2Represent the H atomic time, X
2Represent any of chemical group as follows:
(3) work as X
2Represent methylene radical (CH
2-) time, R
2Represent any of following chemical group:
N=0--10 wherein; R
3Represent halogen, sulfonyloxy.
2. immunity receptor regulator couplet precursor according to claim 1 and couplet thereof are any of following structural formula:
3. immunity receptor regulator couplet precursor or its couplet have following structure:
4. claim 1 described immunity receptor regulator couplet precursor and couplet thereof the application on the antiviral immunoregulation druge of preparation.
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| TW200831105A (en) | 2006-12-14 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
| ATE530549T1 (en) | 2007-03-19 | 2011-11-15 | Astrazeneca Ab | 9-SUBSTITUTED 8-OXOADENINE COMPOUNDS AS MODULATORS OF THE TOLL-LIKE RECEPTOR (TLR7) |
| EP2132209B8 (en) | 2007-03-19 | 2014-04-16 | AstraZeneca AB | 9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7 ) modulators |
| JPWO2008114819A1 (en) | 2007-03-20 | 2010-07-08 | 大日本住友製薬株式会社 | New adenine compounds |
| JP5400763B2 (en) | 2007-05-08 | 2014-01-29 | アストラゼネカ・アクチエボラーグ | Imidazoquinolines with immunomodulatory properties |
| PE20091156A1 (en) | 2007-12-17 | 2009-09-03 | Astrazeneca Ab | SALTS OF (3 - {[[3- (6-AMINO-2-BUTOXY-8-OXO-7,8-DIHIDRO-9H-PURIN-9-IL) PROPYL] (3-MORFOLIN-4-ILPROPIL) AMINO] METHYL} PHENYL) METHYL ACETATE |
| WO2010088924A1 (en) | 2009-02-06 | 2010-08-12 | Telormedix Sa | Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration |
| US9050319B2 (en) | 2010-04-30 | 2015-06-09 | Telormedix, Sa | Phospholipid drug analogs |
| WO2011134668A1 (en) | 2010-04-30 | 2011-11-03 | Telormedix Sa | Phospholipid drug analogs |
| EP2651937B8 (en) | 2010-12-16 | 2016-07-13 | Sumitomo Dainippon Pharma Co., Ltd. | Imidazo[4,5-c]quinolin-1-yl derivative useful in therapy |
| JP5978226B2 (en) | 2010-12-17 | 2016-08-24 | 大日本住友製薬株式会社 | Purine derivatives |
| CN103254304A (en) * | 2012-05-30 | 2013-08-21 | 深圳大学 | Immune stimulant couplet, preparation method thereof and antineoplastic application of the immune stimulant couplet |
| CN105061567B (en) * | 2012-10-10 | 2021-07-20 | 深圳大学 | Immune receptor regulator couplet, preparation method and application thereof, coupled precursor for preparing immune receptor regulator couplet and compound for synthesizing coupled precursor |
| CA2982704C (en) | 2015-05-08 | 2023-10-24 | F. Hoffmann-La Roche Ag | Sulfonimidoylpurinone compounds and derivatives for the treatment and prophylaxis of virus infection |
| CN106267188A (en) * | 2016-08-15 | 2017-01-04 | 深圳大学 | The novel antibodies of small molecule immune agonist coupling PD 1 antibody and the application in antitumor thereof |
| WO2018041763A1 (en) | 2016-08-29 | 2018-03-08 | F. Hoffmann-La Roche Ag | 7-substituted sulfonimidoylpurinone compounds for the treatment and prophylaxis of virus infection |
| BR112019004560A2 (en) | 2016-09-13 | 2019-07-02 | Hoffmann La Roche | combination treatment with tlr7 agonist and a hbv capsid formation inhibitor |
| JP7328977B2 (en) | 2018-02-12 | 2023-08-17 | エフ． ホフマン－ラ ロシュ アーゲー | Novel sulfone compounds and derivatives for the treatment and prevention of viral infections |
| CN108379591B (en) * | 2018-04-03 | 2022-03-29 | 深圳大学 | Synthesis of immune agonist targeting compound and application thereof |
| WO2021226261A1 (en) | 2020-05-06 | 2021-11-11 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| TW202241889A (en) | 2020-12-23 | 2022-11-01 | 美商雅捷可斯治療公司 | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| CA3234638A1 (en) | 2021-11-09 | 2023-05-19 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
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