[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN102153548B - Analogue nucleoside derivative containing thiazolidone (thiazinidone) ring, preparation method and application thereof to medicinal preparations - Google Patents

Analogue nucleoside derivative containing thiazolidone (thiazinidone) ring, preparation method and application thereof to medicinal preparations Download PDF

Info

Publication number
CN102153548B
CN102153548B CN2011100445410A CN201110044541A CN102153548B CN 102153548 B CN102153548 B CN 102153548B CN 2011100445410 A CN2011100445410 A CN 2011100445410A CN 201110044541 A CN201110044541 A CN 201110044541A CN 102153548 B CN102153548 B CN 102153548B
Authority
CN
China
Prior art keywords
compound
preparation
methylol
ring
stirring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN2011100445410A
Other languages
Chinese (zh)
Other versions
CN102153548A (en
Inventor
李小六
陈华
孟明
焦玲玲
殷庆梅
张平竹
张金超
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hebei University
Original Assignee
Hebei University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hebei University filed Critical Hebei University
Priority to CN2011100445410A priority Critical patent/CN102153548B/en
Publication of CN102153548A publication Critical patent/CN102153548A/en
Application granted granted Critical
Publication of CN102153548B publication Critical patent/CN102153548B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses an analogue nucleoside derivative containing a thiazolidone (thiazinidone) ring, a preparation method and application thereof to medicinal preparations. The preparation method comprises the following steps of: a, dissolving fatty amine or aromatic amine (1) and furfural (2) which serve as initial raw materials in absolute methanol solvent with stirring according to a molar ratio of 1.2:1; and b, performing microwave radiation or stirring at the room temperature, adding mercaptoacetic acid or mercaptopropionic acid according to a molar ratio of 1:2 and reacting, and regulating the pH value to be between 6.5 and 7.5 to obtain a compound shown as a chemical general formula (I).

Description

A kind of class nucleoside derivates that contains thiazole (piperazine) alkane ketone ring and preparation method thereof and its application in pharmaceutical prepn
Technical field
Type of the present invention relates to nucleoside derivates and compound method thereof and its application in pharmaceutical prepn specifically relate to contain class nucleoside derivates and compound method and its application in pharmaceutical prepn of thiazole (piperazine) alkane ketone ring.
Background technology
Immunity is the crucial physiological function of body.Normal immunologic function is the assurance of body health, in case immune dysfunction will cause the reaction of disease and immunopathogenesis.The generation of many clinical diseases such as malignant tumour, virus disease and autoimmune disease etc., development all have close getting in touch with the functional disorder and the immunodeficiency of body immune system.Immunomodulator through and the various lymphocytes of immunity system between interaction or immune molecule intrinsic network activation, the adjustment body's immunity, correct immunologic derangement, be the medicine that one type of ability strengthens non-specificly or suppress body's immunity.At present; Clinical widely used immunomodulator is mainly biological products and part microbial metabolism class medicine; Like Zadaxin, Interferon, rabbit, interleukin, BCG-CWS, ciclosporin A, mycophenlate mofetil, rapamycin etc.; Because these medicines exist toxic side effect big, water-soluble and poor stability, purity and the shortcoming such as low of tiring, and therefore, demand developing the novel immunomodulator of high-efficiency low-toxicity urgently.
Chemosynthesis small molecules immunomodulator; Because the needs of its good chemistry and zymetology stability, the multiple formulation of adaptation and route of administration; And cost is lower, purity is high, when raising is tired, can reduce toxic side effect; Avoid the untoward reaction of hormone medicine and biogenetic derivation immunomodulator, caused that people pay close attention to widely.At present more existing small molecules immunomodulators are applied to clinical, like pidotimod, CGP52608 and Nucleotide, glucosides (peptide) analogue etc.Yet characteristics such as that immunomodulatory has is various, complicated and target spot is uncertain, therefore, existing small molecules immunomodulator can not satisfy clinical immunoregulatory research and application far away.
Summary of the invention
The object of the invention is exactly that a kind of new small molecules immunomodulator will be provided; Be a kind of class nucleoside derivates that contains thiazole (piperazine) alkane ketone ring, a kind of compound method and the application of this compounds in preparation immunoregulation druge preparation of this compounds are provided simultaneously.
The objective of the invention is to realize like this:
The invention provides a kind of class nucleoside derivates that contains thiazole (piperazine) alkane ketone ring,
Its chemical general formula is shown in (I):
Figure BDA0000047792080000021
Wherein k is 1 or 2; M is 0 or 1; X is Sauerstoffatom or amino, R 1For Wasserstoffatoms or hydroxyl or contain C 1-C 6The alkoxyl group of straight or branched; R 2For containing C 1-C 18Alkyl, the aryl of straight or branched.
Above-mentioned aryl can be selected phenyl for use; Benzyl; The 4-p-methoxy-phenyl; The 4-aminomethyl phenyl; The 4-chloro-phenyl-; The 4-bromophenyl; The 4-iodophenyl; The 4-hydroxy phenyl; The 2-p-methoxy-phenyl; The 2-aminomethyl phenyl; The 2-chloro-phenyl-; The 2-bromophenyl; The 2-iodophenyl; The 2-hydroxy phenyl; The 3-p-methoxy-phenyl; The 3-aminomethyl phenyl; The 3-chloro-phenyl-; The 3-bromophenyl; The 3-iodophenyl; The 3-hydroxy phenyl; The 1-naphthyl; The 2-naphthyl; The 2-furyl; The 3-pyridyl; The 2-pyridyl; In the 4-pyridyl any one.
Being defined as of aryl among the present invention:
Figure BDA0000047792080000022
Figure BDA0000047792080000031
Shown in (I) in the compound, preferred compound has following several kinds of compounds at above-mentioned chemical general formula:
Wherein k is 1; M is 0; X is a Sauerstoffatom, R 1Be methylol; R 2Be methyl;
Wherein k is 1; M is 0; X is a Sauerstoffatom, R 1Be methylol; R 2Be butyl;
Wherein k is 1; M is 0; X is a Sauerstoffatom, R 1Be methylol; R 2Be octyl group;
Wherein k is 1; M is 0; X is a Sauerstoffatom, R 1Be methylol; R 2Be octadecyl;
Wherein k is 1; M is 0; X is a Sauerstoffatom, R 1Be methylol; R 2Be phenyl.
Above-claimed cpd can be a pair of diastereomer (concrete structure is shown in (4), (5)) of following form.
Figure BDA0000047792080000032
Compound according to the invention shows through pharmacological evaluation; It has the effect of good promotion T cell-proliferation activity; Thereby be active substance with compound according to the invention; With the carrier uniform mixing that allows on the pharmacology to use, can be prepared into the immunomodulator of various formulations according to the formulation method of routine.
As being active ingredient with the The compounds of this invention, be prepared into oral liquid with combination of components such as water, sucrose, Sionit, fructose; Be prepared into tablet or capsule with vehicle (lactose, glucose, sucrose, N.F,USP MANNITOL sugar), disintegrating agent (starch), lubricant (Triple Pressed Stearic Acid, talcum powder), tackiness agent combination of components such as (gelatin, Z 150PH).
The compounds of this invention also can be prepared into injection liquid with the mixed carrier that saline water, glucose solution or salt solution and glucose are formed as active ingredient.
The present invention be used for when clinical can reference effective dose be 10～20mg/ people/day, every day 2～3 times.The doctor also can draft taking dose according to the patient individual difference.
Thus, the applicant has accomplished the purposes invention that this compound is used to prepare immunomodulator.
The preparation method who contains the class nucleoside derivates of thiazole (piperazine) alkane ketone ring provided by the present invention may further comprise the steps:
A, be starting raw material with aliphatic amide or aromatic amine (1), alditol (2), in the anhydrous methanol solvent, according to mol ratio 1.2: 1, stirring and dissolving;
B, microwave radiation or stirring at room according to mol ratio 1: 2, add the reaction of Thiovanic acid or thiohydracrylic acid (3), transfer pH6.5-7.5, obtain chemical general formula compound shown in (I);
Figure BDA0000047792080000041
Wherein k is 1 or 2; M is 0 or 1; X is Sauerstoffatom or amino, R 1For Wasserstoffatoms or hydroxyl or contain C 1-C 6The alkoxyl group of straight or branched; R 2For containing C 1-C 18Alkyl, the aryl of straight or branched.
Reaction expression in the inventive method is following:
Figure BDA0000047792080000042
Description of drawings
Fig. 1 is the influence chart of The compounds of this invention to mouse T lymphocyte (ConA stimulation) propagation.
Wherein ordinate zou is represented T cell appreciation rate (%); X-coordinate is a test compounds; A is untreated splenocyte; B is the splenocyte that ConA stimulates;
Figure BDA0000047792080000043
The representation compound consumption is 100 μ m; The representation compound consumption is 25 μ m; # represents P＜0.01, compares with A (untreated splenocyte); *P＜0.05, *P＜0.01, * *Compare with B (splenocyte that ConA stimulates) P＜0.001.
Embodiment
To help understanding of the present invention through following embodiment, but not limit content of the present invention in any form.
Embodiment 1
Synthetic compound (S)-2-((2S, 3S, 4S; 5R)-tetrahydrochysene-3; 4-dihydroxyl-5-(methylol) furans-2-yl)-3-methylthiazol alkane-4-ketone and compound (being called for short compound 4a) and (R)-2-((2S, 3S, 4S; 5R)-and tetrahydrochysene-3,4-dihydroxyl-5-(methylol) furans-2-yl)-3-methylthiazol alkane-4-ketone (being called for short compound 5a).
Its chemical reaction flow process is following:
Figure BDA0000047792080000051
(1) is alditol in the above-mentioned reaction formula, (2a) is methylamine hydrochloride, and (3) are Thiovanic acid;
Concrete grammar is:
((2S, 3S, 4S, 5R)-3,4-dihydroxyl-5-(methylol) furans-2-formaldehyde) and methylamine hydrochloride (1.2equiv) are dissolved in the 3mL anhydrous methanol, and the room temperature nitrogen protection was stirred 60 minutes down to take by weighing 200mg (1.23mmol) alditol; Add Thiovanic acid (2.0equiv) subsequently, continued stirring at room 30 minutes, finish reaction, add Anhydrous potassium carbonate powder neutralization reaction liquid to pH=7, (methyl alcohol: column chromatography water=70: 30) obtains isomer 4a and 5a to the reverse phase silica gel post of last C18.
Compound 4a: yellow syrup, yield 21.6%. δ H(600MHz, CD 3OD): 3.09 (3H, s, CH 3), 3.52 (1H, d, J=15.6Hz, H-3), 3.66 (1H, dd, J=12.0Hz, 4.8Hz; H-5 '), 3.72-3.76 (2H, m, H-5, H-5 '), 3.98-4.00 (1H, m, H-4 '), 4.04 (1H; T, J=6.0Hz, H-1 '), 4.15 (1H, t, J=4.8Hz, H-2 '), 4.19 (1H; T, J=4.8Hz, H-3 '), 4.96 (1H, dd, J=6.6Hz, 2.4Hz, H-2); δ C(125MHz, CD 3OD): 31.0,31.3,61.7 (C-2), 64.6,77.3,78.4,84.8,85.7,172.4; HRMS (ESI): Calcd for C 9H 15NO 5SNa (M+Na) +, 272.0568, Found:272.0563.
Compound 5a: white solid, yield 20.4%. δ H(600MHz, CD 3OD): 2.99 (3H, s, CH 3), 3.40 (1H, d, J=15.0Hz, H-5), 3.62 (1H, dd, J=12.6Hz, 4.8Hz; H-5 '), 3.74 (1H, d, J=14.4Hz, H-5 '), 3.78 (1H, dd, J=12.6Hz; 4.8Hz, H-5), 3.91-3.94 (1H, m, H-4 '), 4.07-4.10 (2H, m, H-2 '; H-1 '), 4.22 (1H, d, J=6.6Hz, H-3 '), 4.87 (1H, s, H-2); δ C(125MHz, CD 3OD): 29.2,32.0,61.4 (C-2), 66.2,76.1,77.8,80.3,83.8,172.9 (C-4); HRMS (ESI): Calcd for C 9H 15NO 5SNa (M+Na) +, 272.0568, Found:272.0559.
Starting raw material alditol in the present embodiment ((2S, 3S, 4S, 5R)-3, and 4-dihydroxyl-5-(methylol) furans-2-formaldehyde) can be synthetic according to following method:
Its chemical reaction flow process is following:
Figure BDA0000047792080000061
Concrete compound method may further comprise the steps:
D-glucosamine hydrochloride 6 (commercially available) 10.8g (50mmol) is used the 100ml water dissolution, in cryosel is bathed, add NaNO in batches 26.9g (100mmol), add H+ ion exchange resin 70g again, vigorous stirring is simultaneously kept 0～5 ℃ of the temperature of reaction system in batches; Reinforced finishing removes cryosel and bathes, vigorous stirring 1h under the room temperature (TLC monitoring reaction), and reaction finishes; The elimination resin, filtrating is neutralized to neutrality with resin anion(R.A), elimination resin, concentrated filtrate; Have in a large number to salt out, use the anhydrous methanol lysate, filtering salt, concentrated filtrate; (second second: methyl alcohol=7: 1) get 6.5g yellow solid 1, yield is 85%, and fusing point is 31-32 ℃, [α] with the silicagel column separation and purification 25 D+ 31.7 (c 1.0, CH 3OH) (literature value: fusing point is 33 ℃, [α] 25 D+ 31.8 ° (c 1.0, CH 3OH), reference: Samantha, C., et al., Carbohydra.Res.1999,315,339-344.).
Embodiment 2
Synthetic compound (S)-2-((2S, 3S, 4S; 5R)-tetrahydrochysene-3; 4-dihydroxyl-5-(methylol) furans-2-yl)-3-butyl thiazolidin-4-one (be called for short compound 4b) and (R)-2-((2S, 3S, 4S; 5R)-and tetrahydrochysene-3,4-dihydroxyl-5-(methylol) furans-2-yl)-3-butyl thiazolidin-4-one (being called for short compound 5b).
Its chemical reaction flow process is following:
Figure BDA0000047792080000062
(1) is alditol in the above-mentioned reaction formula, and (2b) n-Butyl Amine 99 is for (3) are Thiovanic acid;
Concrete grammar is:
((2S, 3S, 4S, 5R)-3,4-dihydroxyl-5-(methylol) furans-2-formaldehyde) and n-Butyl Amine 99 (1.2equiv) are dissolved in the 3mL anhydrous methanol, and the room temperature nitrogen protection was stirred 60 minutes down to take by weighing 200mg (1.23mmol) alditol; Add Thiovanic acid (2.0equiv) subsequently, continued stirring at room 30 minutes, finish reaction, add Anhydrous potassium carbonate powder neutralization reaction liquid to pH=7, (methyl alcohol: column chromatography water=72: 28) obtains isomer 4b and 5b to the reverse phase silica gel post of last C18.
Compound 4b: yellow syrup, yield 16.5%. δ H(600MHz, CD 3OD): 0.91 (3H, s, J=7.2Hz, CH 3), 1.24-1.31 (2H, m, CH 2), 1.52-1.60 (2H, m, CH 2), 3.28-3.32 (1H, m, CH), 3.42 (1H, d, J=15.6Hz, H-5), 3.58 (1H, dd, J=14.0Hz, 5.4Hz; H-5), 3.65 (1H, t, J=5.4Hz, H-1 '), 3.76 (1H, dd, J=7.8Hz, 3.6Hz, CH), 3.71-3.76 (1H; M, H-5 '), 3.89-3.91 (1H, m, H-4 '), 3.95 (1H, t, J=5.4Hz, H-5 '), 4.05 (1H, t; J=4.8Hz, H-2 '), 4.08 (1H, t, J=4.2Hz, H-3 '), 4.94 (1H, dd, J=6.6Hz, 1.8Hz, H-2); δ C(125MHz, CD 3OD): 12.7,19.6,28.6,31.3,44.0,61.7 (C-2), 62.1,77.4,78.7,85.1,86.3,172.6 (C-4); HRMS (ESI): Calcd for C 12H 21NO 5SNa (M+Na) +, 314.1038, Found:.314.1033.
Compound 5b: yellow syrup, yield 24.5%. δ H(600MHz, CD 3OD): 0.98 (3H, J=7.2Hz, CH 3), 1.31-1.41 (2H, m, CH 2), 1.56-1.67 (2H, m, CH 2), 3.08-3.12 (1H, m, CH), 3.37 (1H, d, J=15.6Hz, H-5); 3.60 (1H, dd, J=12.0Hz, 4.8Hz, H-5), 3.72-3.77 (3H, m, CH; H-1 ', H-5 '), 3.89-3.93 (1H, m, H-4 '), 4.04-4.08 (2H, m, H-5 '; H-2 '), 4.17 (1H, d, J=6.6Hz, H-3 '), 4.91 (1H, s, H-2); δ C(125MHz, CD 3OD): 12.7,19.6,28.8,32.5,42.2,61.4 (C-2), 64.1,76.0,77.9,80.6,83.8,172.9 (C-4); HRMS (ESI): Calcd for C 12H 21NO 5SNa (M+Na) +, 314.1038, Found:314.1035
With reference to embodiment 1 and 2 said methods, be raw material with NSC 9824 (2c) and stearylamine (2d) respectively, can obtain the compound of following different optical isomer:
Compound 4c i.e. (S)-2-((2S, 3S, 4S, 5R)-tetrahydrochysene-3,4-dihydroxyl-5-(methylol) furans-2-yl)-3-octyl group thiazolidin-4-one;
Compound 5c i.e. (R)-2-((2S, 3S, 4S, 5R)-tetrahydrochysene-3,4-dihydroxyl-5-(methylol) furans-2-yl)-3-octyl group thiazolidin-4-one;
Compound 4d i.e. (S)-2-((2S, 3S, 4S, 5R)-tetrahydrochysene-3,4-dihydroxyl-5-(methylol) furans-2-yl)-3-octadecyl thiazolidin-4-one;
Compound 5d i.e. (R)-2-((2S, 3S, 4S, 5R)-tetrahydrochysene-3,4-dihydroxyl-5-(methylol) furans-2-yl)-3-octadecyl thiazolidin-4-one;
The particular chemical formula is following:
Figure BDA0000047792080000071
Compound 4c: colourless syrup, yield 24.0%. δ H(600MHz, CD 3OD): 0.94 (3H, t, J=6.6Hz, CH 3), 1.33-1.36 (10H, m, 5CH 2), 1.61-1.69 (2H, m, CH 2), 3.34-3.35 (1H, m, CH); 3.49 (1H, d, J=15.6Hz, H-5), 3.65 (1H, dd, J=13.2Hz, 7.2Hz, H-5 '); 3.72-3.75 (2H, m, CH, H-5), 3.78-3.83 (1H, m, H-4 '), 3.98 (1H; Q, J=5.4Hz, H-1 '), 4.03 (1H, t, J=4.8Hz, H-2 '), 4.15 (1H; Q, J=4.8Hz, H-3 '), 5.01 (1H, dd, J=7.2Hz, 4.8Hz, H-2); δ C(125MHz, CD 3OD); 13.2,22.4,26.5,29.0,29.1,31.4,31.7,44.3,61.9 (C-2), 62.2,77.5,78.9,85.4,86.6,172.6 (C-4); HRMS (ESI): Calcd for C 16H 29NO 5SNa (M+Na) +, 370.1664, Found:370.1657.
Compound 5c: colourless syrup, yield 15.0%. δ H(600MHz, CD 3OD): 0.92 (3H, t, J=6.6Hz, CH 3), 1.32-1.35 (10H, m, 5CH 2), 1.56-1.69 (2H, m, CH 2), 3.07-3.11 (1H, m, CH), 3.37 (1H, d, J=15.6Hz, H-5); (3.65 1H, dd, J=12.0Hz, 4.8Hz, H-5 '), 3.67-3.77 (3H, m, CH; H-5, H-5 '), 3.89-3.92 (1H, m, H-4 '), 4.03-4.08 (2H, m, H-2 '; H-1 '), 4.16 (1H, d, J=6.6Hz, H-3 '), 4.90 (1H, s, H-2); δ C(125MHz, CD 3OD): 13.0,22.3,26.4,26.6,28.9,28.9,31.5,32.4,42.45,61.5 (C-2), 64.1,76.1,77.8,80.6,83.8,172.9 (C-4); HRMS (ESI): Calcd for C 16H 29NO 5SNa (M+Na) +, 370.1664, Found:370.1665.
Compound 4d: yellow solid, yield 13.8%. δ H(600MHz, CD 3OD): 0.92 (3H, t, J=7.2Hz, CH 3), 1.31-1.37 (30H, m, 15CH 2), 1.61-1.70 (2H, m, CH 2), 3.34-3.39 (1H, m, CH), 3.47 (1H, d, J=15.6Hz, H-5), 3.64 (1H, dd, J=12.0Hz; 5.4Hz, H-5), 3.65-3.71 (1H, m, H-1 '), 3.73 (1H, t, J=3.6Hz, H-5 '), 3.77-3.82 (1H, m; CH), 3.96-3.98 (1H, m, H-4 '), 4.02 (1H, t, J=5.4Hz, H-5 '), 4.11 (1H, t, J=4.2Hz; H-2 '), 4.14 (1H, t, J=4.8Hz, H-3 '), 5.00 (1H, dd, J=7.2Hz, 1.8Hz, H-2); δ C(125MHz, CD 3OD): 13.1,22.3,26.4,28.9,29.1,29.3,29.4,29.4,31.3,31.7,44.3,61.7 (C-2), 62.0,77.4,78.7,85.2,86.5,172.5 (C-4); HRMS (ESI): Calcd for C 26H 49NO 5SNa (M+Na) +, 510.3229, Found:510.3232.
Compound 5d: white solid, yield 22.2%. δ H(600MHz, CD 3OD): 0.93 (3H, t, J=6.6Hz, CH 3), 1.32-1.36 (30H, m, 15CH 2), 1.58-1.68 (2H, m, CH 2, H-5), 3.31-3.38 (2H, m, H-1 ', H-5), 3.59-3.82 (3H, m, CH, H-5 ', H-1), and 3.86-3.94 (1H, m, H-4 '), 4.06-4.09 (1H, m, H-2 '), 4.17-4.19 (1H, m, H-3 '), 4.91 (1H, s, H-2); δ C(125MHz, CD 3OD): 13.1,22.2,26.6,28.9,29.1,29.4,29.7,31.3,32.5,42.3,61.5 (C-2), 64.1,76.0,78.8,83.6,84.5,172.5 (C-4); HRMS (ESI): Calcd for C 26H 49NO 5SNa (M+Na) +, 510.3229, Found:510.3225.
Embodiment 3
Synthetic compound (S)-2-((2S, 3S, 4S; 5R)-tetrahydrochysene-3; 4-dihydroxyl-5-(methylol) furans-2-yl)-3-phenyl thiazole alkane-4-ketone (be called for short compound 4e) and (R)-2-((2S, 3S, 4S; 5R)-and tetrahydrochysene-3,4-dihydroxyl-5-(methylol) furans-2-yl)-3-phenyl thiazole alkane-4-ketone (being called for short compound 5e).
Its chemical reaction flow process is following:
Figure BDA0000047792080000081
Concrete grammar is:
((2S, 3S, 4S, 5R)-3,4-dihydroxyl-5-(methylol) furans-2-formaldehyde) and aniline 2e (1.2equiv) are dissolved in the 3mL anhydrous methanol, and the room temperature nitrogen protection was stirred 60 minutes down to take by weighing 200mg (1.23mmol) alditol 1; Add Thiovanic acid (2.0equiv) subsequently, continued stirring at room 30 minutes, finish reaction, add Anhydrous potassium carbonate powder neutralization reaction liquid to pH=7, (methyl alcohol: column chromatography water=70: 30) obtains isomer 4e and 5e to the reverse phase silica gel post of last C18.
Compound 4e: white solid, yield 14.3%. δ H(600MHz, CD 3OD): 3.51 (1H, dd, J=12.0Hz, 4.8Hz, H-5), 3.62 (1H, dd, J=12.0Hz, 3.6Hz, H-5 '), 3.66 (1H; D, J=15.6Hz, H-5), 3.74-3.77 (1H, m, H-4 '), 3.95-3.99 (2H, m, H-1 ', H-5 '); (4.05 1H, dd, J=7.8Hz, 4.2Hz, H-2 '), 4.30 (1H, t, J=6.6Hz, H-3 '), 5.55 (1H; Dd, J=4.8Hz, 1.8Hz, H-2), 7.33-7.36 (1H, m, CH), 7.44-7.48 (4H, m, 4CH); δ C(125MHz, CD 3OD): 32.0,61.7 (C-2), 65.3,77.1,77.5,, 82.8,83.6,126.4,127.3,128.8,138.2,172.1 (C-4); HRMS (ESI): Calcd for C 14H 18NO 5S (M+H) +, 312.0905, Found:312.0908.
Compound 5e: white solid, yield 28.7%. δ H(600MHz, CD 3OD): 3.59 (1H, d, J=15.6Hz, H-5), 3.63 (1H, dd, J=12.0Hz, 5.4Hz, H-5 '); 3.64 (1H, dd, J=12.6Hz, 2.4Hz, H-5), 3.96-4.02 (4H, m, H-5 ', H-4 '; H-1 ', H-2 '), 4.10 (1H, t, J=7.8Hz, H-3 '), 5.34 (1H, s; H-2), 7.40-7.46 (3H, m, 3CH), 7.51 (2H, t, J=8.4Hz, 2CH); δ C(125MHz, CD 3OD): 32.8,61.4 (C-2), 67.3,76.3,77.7,80.8,83.9,126.9,127.8,129.2,137.2,172.6 (C-4); HRMS (ESI): Calcd for C 14H 18NO 5S (M+H) +, 312.0905, Found:312.0910.
Embodiment 4
Compound is to mouse T lymphocyte proliferation activity testing method: get the BALb/C mouse boosting cell, be made into 4.5 * 10 with the RPMI1640 substratum that contains 5%FCS 5/ well, 90uL.The every kind of compound sample (4a, 5a, 4b, 4e, 5e) that adds ConA (being concanavalin A) (10 μ g/mL) and two kinds of final concentrations of 100,25 μ M, 37 ℃, 5%CO 2Hatched under the condition 72 hours, and establish the splenocyte group that do not add sample compound splenocyte and only add ConA and be contrast, all tests all repeat 3 times at least, establish 4 multiple holes at every turn.Measure the absorbancy (A) of cell with mtt assay, calculate proliferation rate (%)=(A at the 570nm place The administration group-A Control group)/A Control group* 100%.The result sees Fig. 1.
Visible by Fig. 1, chemical general formula of the present invention compound 4a, 5a, 4b, 4e, 5e shown in (I) have obvious promoter action to the lymphocytic propagation of T, and wherein compound 4e (25 μ M) effect is the most remarkable.
Embodiment 5
Get the compound 4a 5mg of embodiment 1 preparation, lactose 60mg, potato powder 30mg, Z 150PH 2mg, Magnesium Stearate 1mg is prepared into oral tablet.
Listed examples 1-5 of the present invention is intended to illustrate chemical structure, preparation method and this compounds of one type of class nucleoside derivates that contains thiazole (piperazine) alkane ketone ring to immune lymphocyte proliferation activity; Embodiment singly is not the compound method and the immunoregulatory activity of the described concrete compound of explanation itself; Also can be used for simultaneously explaining kind and the quantity that changes raw material; Synthetic its homologue and analogue, and scope of the present invention is not constituted any restriction.

Claims (3)

  1. One kind contain the thiazolidone ring the class nucleoside derivates, its chemical general formula is shown in (I):
    Figure 10549DEST_PATH_IMAGE001
    ；
    Wherein k is 1; M is 0; X is a Sauerstoffatom, R 1Be methylol; R 2Be methyl, butyl, phenyl, octyl group or octadecyl.
  2. 2. the described compound method that contains the class nucleoside derivates of thiazolidone ring of a claim 1 is characterized in that it may further comprise the steps:
    A, be starting raw material with aromatic amine or aliphatic amide, alditol, in the anhydrous methanol solvent, according to mol ratio 1.2:1, stirring and dissolving; The chemical general formula of alditol wherein is:
    ；
    B, microwave radiation or stirring at room according to alditol and Thiovanic acid mol ratio 1:2, add the Thiovanic acid reaction, transfer pH6.5-7.5, and extraction obtains chemical general formula compound shown in (I);
    Figure 282447DEST_PATH_IMAGE003
    ；
    Wherein k is 1; M is 0; X is a Sauerstoffatom, R 1Be methylol; R 2Be methyl, butyl, phenyl, octyl group or octadecyl.
  3. 3. the described application of class nucleoside derivates in preparation immunomodulator pharmaceutical prepn that contains the thiazolidone ring of claim 1.
CN2011100445410A 2011-02-24 2011-02-24 Analogue nucleoside derivative containing thiazolidone (thiazinidone) ring, preparation method and application thereof to medicinal preparations Expired - Fee Related CN102153548B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2011100445410A CN102153548B (en) 2011-02-24 2011-02-24 Analogue nucleoside derivative containing thiazolidone (thiazinidone) ring, preparation method and application thereof to medicinal preparations

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2011100445410A CN102153548B (en) 2011-02-24 2011-02-24 Analogue nucleoside derivative containing thiazolidone (thiazinidone) ring, preparation method and application thereof to medicinal preparations

Publications (2)

Publication Number Publication Date
CN102153548A CN102153548A (en) 2011-08-17
CN102153548B true CN102153548B (en) 2012-11-28

Family

ID=44435259

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2011100445410A Expired - Fee Related CN102153548B (en) 2011-02-24 2011-02-24 Analogue nucleoside derivative containing thiazolidone (thiazinidone) ring, preparation method and application thereof to medicinal preparations

Country Status (1)

Country Link
CN (1) CN102153548B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111205240A (en) * 2020-03-06 2020-05-29 魏彬 Immunity regulator containing thiazolidine-4-ketone and its application

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE238328T1 (en) * 1996-10-16 2003-05-15 Ribapharm Inc MONOCYCLIC L-NUCLEOSIDES, ANALOGAS AND THEIR APPLICATIONS
WO2003045968A1 (en) * 2001-11-27 2003-06-05 Anadys Pharmaceuticals, Inc. 3-β-D-RIBOFURANOSYLTHIAZOLO[4,5-d]PYRIDIMINE NUCLEOSIDES AND USES THEREOF
MXPA06014182A (en) * 2004-06-07 2007-06-25 Anadys Pharmaceuticals Inc 3-beta-D-RIBOFURANOSYLTHIAZOLO[4,5-d]PYRIDIMINE NUCLEOSIDES AND USES THEREOF.

Also Published As

Publication number Publication date
CN102153548A (en) 2011-08-17

Similar Documents

Publication Publication Date Title
AU2018217236B2 (en) Synthesis of polycyclic-carbamoylpyridone compounds
AU2012204336B2 (en) Methods for preparation of glycosphingolipids and uses thereof
Tanino et al. Total synthesis of (−)-muraymycin D2 and its epimer
Zhang et al. Polyoxins and nikkomycins: progress in synthetic and biological studies
US10233202B2 (en) Tenofovir monobenzyl ester phosphamide prodrug, preparation method and use thereof
CN108473477A (en) The pyrimidine of aryl substitution for being used in influenza infection
JP6917527B2 (en) SGLT inhibitors and their applications
US7521569B2 (en) Process to obtain dibenzylbutyrolactonic lignans, process to obtain synthetic derivatives from lignans bearing anti-Chagas chemoprophylactic and therapeutical activities
CN102153548B (en) Analogue nucleoside derivative containing thiazolidone (thiazinidone) ring, preparation method and application thereof to medicinal preparations
JPS5953499A (en) Desoxyuridine derivative, manufacture and medicine
Vale et al. Primaquine dipeptide derivatives bearing an imidazolidin-4-one moiety at the N-terminus as potential antimalarial prodrugs
CN103059074B (en) Glucosamine peptidomimetic compound as well as preparation method and application thereof
JP4233262B2 (en) Carbasugar amine derivatives and glycosidase inhibitors using the same
CN106905193B (en) Aroyl guanidine radicals Oseltamivir carboxylic acid derivates and its preparation method and application
CN109678815A (en) N- benzyl benzamide derivatives and preparation method thereof and pharmaceutical applications
Steiner et al. 1-Deoxygalactonojirimycin-lysine hybrids as potent D-galactosidase inhibitors
NO177589B (en) Polyhydroksycyklopentanderivat
CN101829598B (en) Preparation method of acetylated glycosyl thiourea derivative and application thereof in isoquinoline acid synthesis
US8349834B2 (en) Dioxolane derivates for the treatment of cancer
CN104854124A (en) Macrocyclic ketoamide immunoproteasome inhibitors
CN102417528A (en) Thiazole (-zin) alkane ketone ring conjoined disaccharide compound, its preparation method and application in pharmaceutical preparation
Fernández et al. Polyhydroxylated cyclopentane β-amino acids derived from D-mannose and D-galactose: synthesis and protocol for incorporation into peptides
CN105001197A (en) Alogliptin derivative I, preparation method and application thereof
JP4248052B2 (en) Novel anhydrodeoxyinositol and glycosidase inhibitors
JPH0560474B2 (en)

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20121128

Termination date: 20170224

CF01 Termination of patent right due to non-payment of annual fee