CN102120740A - Imidazoline compound chirally synthesized by using thiourea catalyst derived from rosin and application thereof in anti-inflammatory and antipyretic aspects - Google Patents
Imidazoline compound chirally synthesized by using thiourea catalyst derived from rosin and application thereof in anti-inflammatory and antipyretic aspects Download PDFInfo
- Publication number
- CN102120740A CN102120740A CN 201010552078 CN201010552078A CN102120740A CN 102120740 A CN102120740 A CN 102120740A CN 201010552078 CN201010552078 CN 201010552078 CN 201010552078 A CN201010552078 A CN 201010552078A CN 102120740 A CN102120740 A CN 102120740A
- Authority
- CN
- China
- Prior art keywords
- rosin
- inflammatory
- quinoline
- thiourea catalyst
- preparation
- 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.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an imidazoline compound chirally synthesized by using a thiourea catalyst derived from rosin and application thereof in anti-inflammatory and antipyretic aspects. In the invention, a novel chiral thiourea catalyst A derived from rosin is synthesized in the whole synthesis process and can be used for successfully synthesizing the annular thiourea presented in the specification, accordingly, a type of novel imidazoline compound with the anti-inflammatory and antipyretic effects can be further chirally synthesized, and the novel imidazoline compound synthesized chirally is applied to the anti-inflammatory and antipyretic aspects.
Description
Technical field
The present invention relates to use the new imidazolinium compounds of the synthetic class of a kind of novel rosin deutero-chirality thiourea catalyst chirality and in the application of anti-inflammatory aspect analgesic.
Background technology
In organic synthesis, the organic synthesis of drug targeting, particularly synthetic quickly and efficiently high-optical-purity have medicine or bioactive organic molecule is a kind of challenging work always.Therefore, although for the synthetic field of the chirality of guiding very big innovation requirement is arranged at medicine, up to the present, effectively the development of synthetic method and the discovery that finally is applied to newtype drug remain rareness.The relevant anti-inflammatory antipyretic analgesics of neural inflammation treatment is a kind of important and expensive medicine at present clinically, and its effective use is removed to treat encephalopathy with neural inflammation as a kind of therapeutic strategy.For example: Alzheimer (P.Eikelenboom, E.van Exel, J.J.Hoozemans, R.Veerhuis, A.J.Rozemuller, W.A.van Gool, Neurodegener Dis.2010,7,38.) and the treatment of the neural inflammation that causes of multiple myelosclerosis disease.Extensive epidemiological study and clinical evidence confirm that the life-time service antiphlogiston can reduce alzheimer's disease (Alzheimer ' s disease, AD) and multiple sclerosis (Multiple Sclerosis, MS) sickness rate (K.P.Townsend, D.Pratic ò, FASEB J.2005,19,1592; P.L.McGeer, E.G.McGeer, J Neurovirol.2002,8,529).(lipopolysaccharide LPS) is injected directly into and can causes neural inflammation in the mouse brain (third ventricle) and with the generation of heating, and this is animal model (Benamar, the K. of the neural inflammation of research of generally acknowledging at present with lipopolysaccharides; Yondorf, M.; Barreto, V.T.; Geller, E.B.; Adler, M.W.J.Pharmacol.Exp.Ther.2007,323,990.).Heating is normally caused by pyrogeneous substance (bacterial exotoxin, intracellular toxin etc.).In neural inflammatory model, heating is the early stage acute symptom of inflammation (Benamar, K.; Yondorf, M.; Barreto, V.T.; Geller, E.B.; Adler, M.W.J.Pharmacol.Exp.Ther.2007,323,990.).Therefore, the heating that can the neural inflammation of antagonism causes of our synthetic analogue has just illustrated that it has possessed anti-inflammatory refrigerant drug effect.
In the chirality building-up process to imidazolines, relate to a class cyclic thiourea 1 asymmetric synthesis of (structural formula as shown in Figure 1) in the present invention.(the Li of Seidel group, L.M.Ganesh, D.Seidel, J.Am.Chem.Soc.2009,131,11648.) and Zhong group (Z.Shi, P.Yu, P.J.Chua, G.Zhong, Adv.Synth.Catal.2009,351,2797.) done above-mentioned cyclic thiourea 1 compound experiment in the mode of using organic catalysis respectively.Although above research group has successfully synthesized the chiral ring thiocarbamide, shown that in their experimental result existing thiourea catalyst is invalid substantially to the asymmetric synthesis of this compounds.Current, cheap, modify easily and prepare, and the design of thiourea catalyst efficiently is synthetic remains the target that the organic chemist makes great efforts.In the present invention, we synthesize a kind of novel rosin deutero-chirality thiourea catalyst A (structural formula as shown in Figure 1), and successfully the cyclic thiourea of foregoing description has been synthesized in the catalysis of highly-solid selectively.This also be find at present to the unique effective thiourea catalyst of this class compound experiment.The more important thing is the synthetic new imidazolinium compounds of a class of our further chirality with the effect of anti-inflammatory antipyretic analgesics.Also do not report the relevant chirality synthetic method that relates to imidazolinium compounds among the synthetic the present invention of too high enantio-selectivity up to now.
Summary of the invention
In view of above-mentioned, the object of the present invention is to provide new chiral imidazole quinoline compounds of a class and preparation method thereof.
Another object of the present invention aims to provide the class rosin deutero-chirality thiourea catalyst of catalytically synthesizing chiral imidazolines effectively.
Another object of the present invention provides a class chiral imidazole quinoline compounds in the application of anti-inflammatory aspect analgesic.
The object of the present invention is achieved like this:
(1) a kind of chiral imidazole quinoline compounds, its structural formula is shown in (I):
R is-Ts or be-H in (I) formula, or is-Me, or is-Et.
R
1For-Me, or be-Et, or be-H.
R
2For-Ph, or be-napathyl, or be-Cl-Ph, or be-Br-Ph, or be-F-Ph, or be-thiophenyl, or be-furanyl, or be-Me-Ph, or be-OMe-Ph, or be-Et, or be-Me.
R
3For
Or be-OH, or be-OMe, or be-OEt, or be-NH
2
(2) preparation method of chiral imidazole quinoline compounds:
With substrate N-protected group with imine moiety and consumption is that the rosin deutero-chirality thiourea catalyst of substrate N-protected group with imine moiety 3mol% is dissolved in the toluene; adding consumption under-15 ℃ of conditions carefully is 2/3 times of amount of substrate N-protected group with imine moiety isothiocyanate compound, reacts 18 hours.After reacting completely, column chromatography (H60 silica gel, sherwood oil: ethyl acetate=8: 1) obtain the product intermediate.Be that 1.2 times of amounts of above-mentioned product intermediate salt of wormwood is dissolved in the anhydrous propanone with above-mentioned product intermediate and consumption then, adding consumption under 0 ℃ of condition carefully is 1.1 times of amounts of above-mentioned product intermediate idoalkane, reacts 8 hours.After reacting completely, column chromatography (H60 silica gel, sherwood oil: methylene dichloride=5: 1) obtain final product.
The reaction of chiral imidazole quinoline compounds is as follows with chemical formulation:
(3) one class rosin deutero-chirality thiourea catalysts, its structural formula is shown in (II):
R is-OH in (II) formula, or is-OMe.
The preparation method of (4) one class rosin deutero-chirality thiourea catalysts:
The amine of chicken Jenner alkali preparation is dissolved in the anhydrous methylene chloride, under 0 ℃ of condition, is added dropwise to the dehydroabietylamine lsothiocyanates, at room temperature reacted column chromatography (H60 silica gel, ethyl acetate: obtain end product methyl alcohol=6: 1) 12 hours.
Above-mentioned reaction is as follows with chemical formulation:
(5) one class chiral imidazole quinoline compounds are in the application of anti-inflammatory aspect analgesic
Description of drawings
Fig. 1 is the structure iron of a class cyclic thiourea 1 and rosin deutero-chirality thiourea catalyst A.
Fig. 2 shows behind test group 1-5 and the test group 10 mouse third ventricles injection different pharmaceutical at 120 minutes, and 180 minutes, 240 minutes, the body temperature on 300 minutes several time points changed mean value.Data results is expressed as mean value plus-minus standard error, and (mean ± s.e.m.), statistical method is One-way ANOVA (One-way ANOVA followed by the Bonferroni ' s post-hoc test).P＜0.05 has been considered to significant difference.Compare #P＜0.05 with test group 1.
Fig. 3 shows behind test group 1 and the test group 6-10 mouse third ventricle injection different pharmaceutical at 120 minutes, and 180 minutes, 240 minutes, the body temperature on 300 minutes several time points changed mean value.Data results is expressed as mean value plus-minus standard error, and (mean ± s.e.m.), statistical method is One-way ANOVA (One-way ANOVA followed by the Bonferroni ' s post-hoc test).P＜0.05 has been considered to significant difference.Compare #P＜0.05 with test group 1.
Fig. 4 is that the body temperature on 240 minutes time points changes mean value post figure behind the test group 1-10 mouse third ventricle injection different pharmaceutical.Data results is expressed as mean value plus-minus standard error, and (mean ± s.e.m.), statistical method is One-way ANOVA (One-way ANOVA followed by the Bonferroni ' s post-hoc test).P＜0.05 has been considered to significant difference.Compare #P＜0.05 for 1 group with test group; Compare * P＜0.05 with test group 10.
In the present invention, utilize the natural organic product rosin that is easy to get to design and synthesize the new rosin deutero-chirality thiourea catalyst of a class, the more important thing is, the synthetic new imidazolines anti-inflammatory drug of a class of our further chirality.Chiral imidazole quinoline compounds is in the application of anti-inflammatory aspect analgesic.
What time following advantage applies of the present invention is:
(1). the new rosin deutero-chirality thiourea catalyst of a class that utilizes natural chiral source to synthesize to have high catalytic activity of our success.Such catalyzer is cheap, modifies easily and prepares, and handles simply, separates from product easily and reclaims reproducible utilization.Not only expand the scope of limited known thiourea catalyst, and shown the great potential that the rosin natural product is used in asymmetric catalysis field.
(2) although. other research group has also successfully synthesized the chiral ring thiocarbamide that the present invention relates to before this, has shown that in their research existing thiourea catalyst is invalid substantially to the asymmetric synthesis of this compounds.At present, the synthetic target that remains organic chemist's effort of the design of new and effective thiourea catalyst.In the present invention, we synthesize a kind of novel rosin deutero-chirality thiourea catalyst A, and successfully the cyclic thiourea of foregoing description has been synthesized in the catalysis of highly-solid selectively.This also be find at present this class is reacted unique effective thiourea catalyst.
The synthetic new imidazolines of a class of further again thus chirality with the effect of anti-inflammatory antipyretic analgesics.Also do not report the relevant chirality synthetic method that relates to imidazolines among the synthetic the present invention of too high enantio-selectivity up to now.
(3). among the present invention, we provide a class the new effective preparation method of imidazolines with the effect of anti-inflammatory antipyretic analgesics.Present method is simple to operate, does not use metal reagent, and is low in the pollution of the environment, environmentally friendly; The reaction conditions gentleness needn't be carried out under anhydrous, the oxygen free condition of harshness, can react in air.
(4). among the present invention, by to chirality imidazolines anti-neuritis disease febrifugal activity research, we have found that it has good anti-neuritis disease antipyretic effect.Further for it in neural inflammation or the application in the disease of its neural inflammation of following made initiative work.
Embodiment
The present invention will be illustrated by the following examples, but not limit by this.
Chirality thiourea catalyst and imidazolinium compounds are through mass spectrum, nuclear-magnetism, infrared identification, and high performance liquid phase (HPLC) is measured enantioselectivity.
Embodiment 1: rosin deutero-chirality thiourea catalyst (is called for short: (A), [English full name 1-(((1R, 4aS, 10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a, 9,10,10a-octahydrophenanthren-1-yl) methyl)-and 3-((1R)-(6-methoxyquinolin-4-yl) (8-vinylquinuclidin-2-yl) methyl) thiourea] structural formula is as follows:
Rosin deutero-chirality thiourea catalyst preparation method:
The amine of 3.23g (10mmol) quinine chicken Jenner alkali preparation is dissolved in the anhydrous 40ml methylene dichloride, under 0 ℃ of condition, be added dropwise to 3.27g (10mmol) dehydroabietylamine lsothiocyanates, at room temperature reacted 12 hours, column chromatography (H60 silica gel, ethyl acetate: obtain white solid end product 5.7g (amounting to 89% productive rate) methyl alcohol=6: 1).
[α]
20 D=-70 (c=1.0, CHCl
3); Fusing point: 163 ℃.
Nmr analysis:
1H?NMR(300MHz，[D
6]DMSO)：δ8.67(s，1H)，7.89-7.92(m，2H)，7.37-7.44(m，2H)，7.10-7.13(d，J＝8.1Hz，1H)，6.83-6.95(m，2H)，5.72-5.83(m，2H)，4.87-4.98(m，2H)，3.90(s，3H)，3.55-3.58(d，J＝10.5Hz，1H)，3.04-3.14(m，4H)，2.75-2.80(m，3H)，2.51-2.58(m，2H)，2.22(m，2H)，1.81(br，1H)，1.38-1.54(m，7H)，1.15-1.18(m，11H)，1.09(m，3H)，0.78(m，4H)；
13C?NMR(75MHz，[D
6]DMSO)：δ157.9，148.5，148.1，145.9，145.2，142.9，135.7，132.2，128.9，127.4，125.0，124.5，122.2，115.2，104.2，56.6，56.3，45.1，41.8，38.9，38.4，37.9，36.8，33.9，30.5，28.4，28.1，26.6，26.1，25.1，24.9，21.8，19.8，19.6，19.2.
Infrared spectroscopy: IR:3271,3069,2931,2866,2212,1915,1735,1622,1539,1472,1363,1292,1234,11362,1032,911,824,732cm
-1.
High resolution mass spectrum is analyzed:
HRMS-ESI(m/z)：calcd?for?C
41H
54N
4OS+H
+：651.4091；found：651.4079，1.8ppm.
Embodiment 2:(4S, 5R)-the English full name 4 of methimazole quinoline-1[, 4-dimethyl-3-((4S, 5R)-2-(methylthio)-5-phenyl-1-tosyl-4,5-dihydro-1H-imidazole-4-carbonyl) oxazolidin-2-one] structural formula is as follows:
Rosin deutero-chirality thiourea catalyst A preparation (4S, 5R)-method of methimazole quinoline-1:
77.7mg (0.3mmol) substrate N-Tos phenyl imine and 6.6mg (0.009mmol) rosin deutero-chirality thiourea catalyst A are dissolved in the 1.5ml toluene, under-15 ℃ of conditions, add 42.8mg (0.2mmol) 4 carefully, 4 dimethyl oxazoline quinoline ketone lsothiocyanates reacted 18 hours.After reacting completely, column chromatography (H60 silica gel, sherwood oil: ethyl acetate=8: 1) obtain product intermediate 91.7mg (97% productive rate).Be that above-mentioned product intermediate 1.2 times of amounts salt of wormwood (32.1mg) is dissolved in the 2.5ml anhydrous propanone with above-mentioned product intermediate and consumption then, adding consumption under 0 ℃ of condition carefully is the methyl iodide (30.3mg) of 1.1 times of amounts of above-mentioned product intermediate, reacts 8 hours.After reacting completely, column chromatography (H60 silica gel, sherwood oil: methylene dichloride=5: 1) obtain the final white solid (4S, 5R)-methimazole quinoline-1:87.8mg (93% productive rate).
[α]
20 D＝-17(c＝1.0，CHCl
3)。
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel AD-H, Virahol/normal hexane=30/70,1.0mL/min, uv-absorbing 245nm.) t
Minor=13.74min, t
Major=19.27min, enantio-selectivity reaches 97%.
Nmr analysis:
1H NMR (300MHz, CDCl
3): δ 7.69-7.67 (d, J=8.4Hz, 2H), 7.29-7.23 (m, 5H), and 7.22-7.19 (d, J=8.4Hz, 2H), 5.64-5.62 (d, J=4.2Hz, 1H), 5.56-5.55 (d, J=4.2Hz, 1H), 3.99 (s, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 1.47 (s, 3H, 1.36 (s, 3H);
13CNMR (75MHz, CDCl
3): δ 169.7,160.6, and 153.2,144.4,139.8,135.4,129.4,128.7,128.3,128.0,126.9,75.8,75.3,66.7,60.6,24.8,24.0,21.6,15.5. Infrared spectroscopy: IR:3394,2972,2930,2256,1779,1706,1571,1363,1306,1162,1093,672cm
-1.
High resolution mass spectrum is analyzed:
HRMS-ESI(m/z)：calcd?for?C
23H
25N
3O
5S
2+H
+：488.1308；found：488.1305，0.6ppm.
Embodiment 3:(4S, 5R)-the English full name 3-of methimazole quinoline-2[((4S, 5R)-and 5-(2-fluorophenyl)-2-(methylthio)-1-tosyl-4,5-dihydro-1H-imidazole-4-carbonyl)-4,4-dimethyloxazolidin-2-one] structural formula is as follows:
The required N-protected imines of its preparation process is 2-fluorophenyl N-Tos imines 83.1mg (0.3mmol), and other processes are identical with embodiment 2.(4S, 5R)-methimazole quinoline-2 has 95% productive rate.[α]
20 D＝-50(c＝1.0，CHCl
3)。
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel AD-H, Virahol/normal hexane=30/70,1.0mL/min, uv-absorbing 245nm.) t
Minor=9.89min, t
Major=12.56min, enantio-selectivity reaches 95%.
Nmr analysis:
1H?NMR(300MHz，CDCl
3)：δ7.83-7.80(d，J＝8.4Hz，2H)，7.40-7.30(m，4H)，7.16-7.11(m，1H)，7.03-6.97(m，1H)，5.75-5.74(d，J＝4.5Hz，1H)，5.69-5.67(d，J＝4.5Hz，1H)，3.99(s，2H)，2.50(s，3H)，2.42(s，3H)，1.45(s，3H，1.35(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ169.6，160.6，158.0，153.2，144.7，134.6，129.9，129.8，129.6，128.1，127.6，127.4，124.6，124.6，115.6，115.3，75.3，74.8，60.9，60.6，24.6，24.0，21.6，15.5.
Infrared spectroscopy: IR:3396,2972,2931,2957,1779,1708,1574,1366,1306,1176,1093,671cm
-1.
High resolution mass spectrum is analyzed:
HRMS-ESI(m/z)：calcd?for?C
23H
24FN
3O
5S
2+H
+：506.1214；found：506.1209，1.0ppm.
Embodiment 4:(4S, 5R)-the English full name 3-of methimazole quinoline-3[((4S, 5R)-and 5-(2-chlorophenyl)-2-(methylthio)-1-tosyl-4,5-dihydro-1H-imidazole-4-carbonyl)-4,4-dimethyloxazolidin-2-one] structural formula is as follows:
The required N-protected imines of its preparation process is 2-chloro-phenyl-N-Tos imines 87.9mg (0.3mmol), and other processes are identical with embodiment 2.(4S, 5R)-methimazole quinoline-3 has 91% productive rate.[α]
20 D＝-90(c＝1.0，CHCl
3)。
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel AD-H, Virahol/normal hexane=30/70,1.0mL/min, uv-absorbing 245nm.) t
Minor=11.24min, t
Major=14.39min, enantio-selectivity reaches 97%.
Nmr analysis:
1H NMR (300MHz, CDCl
3): δ 7.91-7.89 (d, J=8.4Hz, 2H), 7.46-7.27 (m, 4H), 7.26-7.23 (m, 2H), 5.93-5.92 (d, J=3.9Hz, 1H), 5.66-5.64 (d, J=3.9Hz, 1H), 3.98 (s, 2H), 2.48 (s, 3H), 2.44 (s, 3H), 1.46 (s, 3H, 1.33 (s, 3H);
13C NMR (75MHz, CDCl
3): δ 169.5,160.6, and 153.1,144.8,134.6,131.5,129.6,129.6,129.3,128.3,127.5,75.2,65.8,63.8,60.6,24.6,24.1,21.6,15.5. Infrared spectroscopy: IR:3398,2971,2932,2256,1779,1707,1574,1365,1305,1163,1092,670cm
-1.
High resolution mass spectrum is analyzed:
HRMS-ESI(m/z)：calcd?for?C
23H
24ClN
3O
5S
2+H
+：522.0919；found：522.0929，1.9ppm.
Embodiment 5:(4S, 5R)-the English full name 4 of methimazole quinoline-4[, 4-dimethyl-3-((4S, 5R)-2-(methylthio)-5-o-tolyl-1-tosyl-4,5-dihydro-1H-imidazole-4-carbonyl) oxazolidin-2-one] structural formula is as follows:
The required N-protected imines of its preparation process is 2-tolyl N-Tos imines 81.9mg (0.3mmol), and other processes are identical with embodiment 2.(4S, 5R)-methimazole quinoline-4 has 87% productive rate.[α]
20 D＝-23(c＝1.0，CHCl
3)。
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel AD-H, Virahol/normal hexane=30/70,1.0mL/min, uv-absorbing 245nm.) t
Minor=9.37min, t
Major=14.62min, enantio-selectivity reaches 99%.
Nmr analysis:
1H?NMR(300MHz，CDCl
3)：δ7.69-7.66(d，J＝8.1Hz，2H)，7.23-7.20(d，J＝8.4Hz，2H)，7.16-7.09(m，4H)，5.95-5.94(d，J＝4.2Hz，1H)，5.57-5.55(d，J＝4.5Hz，1H)，4.00(s，2H)，2.51(s，3H)，2.40(s，3H)，2.32(s，3H)，1.50(s，3H，1.36(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ169.7，160.2，153.1，144.4，138.1，135.4，134.8，130.6，129.4，128.0，128.0，126.7，75.9，75.3，65.9，60.6，24.8，23.8，21.6，19.3，15.5.
Infrared spectroscopy: IR:3393,2968,2929,2256,1780,1706,1571,1365,1305,1166,1092,673cm
-1.
High resolution mass spectrum is analyzed:
HRMS-ESI(m/z)：calcd?for?C
24H
27N
3O
5S
2+H
+：502.1465；found：502.1461，0.8ppm.
Embodiment 6:(4S, 5R)-the English full name 4 of methimazole quinoline-5[, 4-dimethyl-3-((4S, 5R)-2-(methylthio)-5-m-tolyl-1-tosyl-4,5-dihydro-1H-imidazole-4-carbonyl) oxazolidin-2-one] structural formula is as follows:
The required N-protected imines of its preparation process is 3-tolyl N-Tos imines 81.9mg (0.3mmol), and other processes are identical with embodiment 2.(4S, 5R)-methimazole quinoline-5 has 89% productive rate.[α]
20 D＝-15(c＝1.0，CHCl
3)。
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel AD-H, Virahol/normal hexane=30/70,1.0mL/min, uv-absorbing 245nm.) t
Minor=12.41min, t
Major=13.25, min, enantio-selectivity reaches 99%.
Nmr analysis:
1H?NMR(300MHz，CDCl
3)：δ7.67-7.64(d，J＝8.1Hz，2H)，7.21-7.18(d，J＝8.1Hz，2H)，7.17-7.03(m，3H)，6.97(s，1H)，5.62-5.60(d，J＝4.5Hz，1H)，5.56-5.55(d，J＝4.2Hz，1H)，4.00(s，2H)，2.52(s，3H)，2.39(s，3H)，2.26(s，3H)，1.49(s，3H)，1.38(s，3H)；
13C?NMR(75MHz，CDCl
3)：δ169.6，160.3，153.2，144.3，139.4，138.4，135.5，129.7，129.3，129.2，128.6，128.0，127.4，126.5，124.2，75.7，75.3，66.7，60.7，24.7，24.0，21.6，21.3，15.6.
Infrared spectroscopy: IR:3384,2971,2928,2252,1779,1706,1570,1362,1306,1165,1092,672cm
-1.
High resolution mass spectrum is analyzed:
HRMS-ESI(m/z)：calcd?for?C
24H
27N
3O
5S
2+H
+：502.1465；found：502.1470，1.0ppm.
Embodiment 7:
Experimental technique and result
(lipopolysaccharide LPS) buys (St.Louis, MO) company, and being dissolved in the no pyrogen physiological saline in Sigma-Aldrich to lipopolysaccharides.All medicines all will be dissolved in no pyrogen physiological saline and be kept in-20 ℃ of environment.Male kunming mouse is adopted in experiment, and portfolio acquisition is in Lanzhou University's Experimental Animal Center (GLP laboratory).Whole experiment requires at 10:00 to carrying out between the 17:00, and envrionment temperature is at 22 ± 0.5C, and relative humidity remains on 52 ± 2%.Before the experiment beginning, get 80 kunming mouses, male, body weight is divided into 10 groups at random between 22-25g, 8 every group.Every group of medicine that injection is different, grouping sees Table 1.When beginning experiment is fixed in mousetail (Rosow, C.E. on the special device of people's design such as Rosow gently; Miller, J.M.; Pelikan, E.W.; Cochin, J.J Pharmacol Exp Ther 1980,213,273), the mouse feed of can freely intaking.To connect and insert mouse rectum (degree of depth 2.5cm) with the temperature transducer CW100 type of BL-420E+ biological function experimental system (Chengdu TME Technology Co., Ltd.) (Beijing newly navigate industrial scientific ﹠ trading Co., Ltd.) and carry out rectal temperature and measure.Measure the basal body temperature of mouse before the administration earlier, obtain the basal body temperature mean value of every group of mouse, see table 1 for details.Each group is given different medicines immediately after having surveyed basal body temperature, sees Table 1.Administering mode is taked injection in the third ventricle, quotes people's method (Frances, B. such as Franc é s; Lahlou, H.; Zajac, J.M.Regul Pept 2001,98,13).After the administration the 120th minute, 180 minutes, 240 minutes, respectively surveyed one time body temperature in 300 minutes.The body temperature numerical value of different time points after the administration is deducted the body temperature that the basal body temperature numerical value before the administration obtains on each time point change numerical value, obtain mean value, see Fig. 2-Fig. 4.(lipopolysaccharide LPS) is meant the main component of gram-negative bacterial cell wall to lipopolysaccharides.(lipopolysaccharide LPS) is injected directly into and can causes neural inflammation in the mouse brain (third ventricle) and with the generation of heating, and this is the animal model of the neural inflammation of research of generally acknowledging at present with lipopolysaccharides.(lipopolysaccharide LPS) causes fervescence to injection 100ng lipopolysaccharides, reaches the highest at 240 minutes, sees Fig. 2, Fig. 3 in the third ventricle.Changing numerical value by analyze different dosing group mouse after administration 240 minutes body temperature studies lipopolysaccharides (lipopolysaccharide, whether the heating that LPS) causes can be suppressed by our synthetic chiral imidazole quinoline compound.The basal body temperature mean value of mouse does not have difference before the test group 1-10 administration about 37 ℃ as can be seen from Table 1.Different dosing group body temperature mean value of 240 minutes after administration has nothing in common with each other.
Table 1: 240 minutes body temperature mean value contrast after mouse test group basal body temperature mean value and the administration, data
The result is expressed as mean value plus-minus standard error (mean ± s.e.m.)
As can be seen from Table 1: after the administration, (lipopolysaccharide LPS) causes fervescence to injection 100ng lipopolysaccharides, and mouse temperature was 38.06 ± 0.1 ℃ at 240 minutes in test group 1 third ventricle; Injection 100ng lipopolysaccharides in test group 2 third ventricles (lipopolysaccharide, LPS)+2nmol (4S, 5R)-methimazole quinoline-1, mouse temperature was 37.81 ± 0.1 ℃ at 240 minutes; Injection 100ng lipopolysaccharides in test group 3 third ventricles (lipopolysaccharide, LPS)+10nmol (4S, 5R)-methimazole quinoline-1, mouse temperature was 37.60 ± 0.1 ℃ at 240 minutes; Injection 100ng lipopolysaccharides in test group 4 third ventricles (lipopolysaccharide, LPS)+20nmol (4S, 5R)-methimazole quinoline-1, mouse temperature was 36.98 ± 0.1 ℃ at 240 minutes; Independent injection 20nmol in test group 5 third ventricles (4S, 5R)-methimazole quinoline-1, mouse temperature was 36.99 ± 0.1 ℃ at 240 minutes; Can learn from test group 1-5: (lipopolysaccharide LPS) can cause that mouse temperature raises to the inflammation-causing substance lipopolysaccharides of 100ng; Lipopolysaccharides (lipopolysaccharide, LPS) and (4S, 5R)-methimazole quinoline-1 Combined Preparation after, the body temperature of rising along with (4S, 5R)-concentration of methimazole quinoline-1 increases gradually, mouse temperature is on a declining curve; Compare with physiological saline, high density (4S, 5R)-methimazole quinoline-1 self can not cause the variation of body temperature, but energy antagonism lipopolysaccharides (lipopolysaccharide, the intensification that LPS) causes.
In like manner, (4S, 5R)-methimazole quinoline-2 also have with (4S, 5R)-the similar anti-inflammatory refrigeration function of methimazole quinoline-1.Difference be (4S, 5R)-structure of methimazole quinoline-2 be (4S, 5R)-the structure phenyl ring ortho position of methimazole quinoline-1 is replaced by fluorine.
Also can find out from Fig. 2-Fig. 4: in the time of 240 minutes, the intensification that LPS causes by energy (4S, 5R)-methimazole quinoline-1 (20nmol) and (4S, 5R)-methimazole quinoline-2 (20nmol) obviously (P＜0.05) reduce.Simultaneously, compare with physiological saline, (4S, 5R)-methimazole quinoline-1 (20nmol) and (4S, 5R)-methimazole quinoline-2 (20nmol) is expelled to the obvious change that third ventricle can not cause body temperature separately.(4S, 5R)-methimazole quinoline-1 (2,10nmol) and (4S, 5R)-methimazole quinoline-2 (2,10nmol) can partly reduce the intensification that LPS causes, but difference is not obvious.This can illustrate (4S, 5R)-methimazole quinoline-1 and (4S, 5R)-intensification that methimazole quinoline-2 can dose-dependent reduction LPS causes.In brief, (4S, 5R)-methimazole quinoline-1 and (4S, 5R)-methimazole quinoline-2 self can not change body temperature, but they can antagonism LPS (lipopolysaccharides, the main component of gram-negative bacterial cell wall) heating of causing, illustrate that they bring into play refrigeration function by anti-inflammatory.Can reach a conclusion thus: (4S, 5R)-methimazole quinoline-1 has the anti-inflammatory refrigeration function.
Claims (5)
1. chiral imidazole quinoline compounds, its structural formula is shown in (I):
R is-Ts in (I) formula, or is-Boc, or is-Cbz, or is-Ac, or is-H, or is-Me, or is-Et;
R
1For-Me, or be-Et, or be-H;
R
2For-Ph, or be-napathyl, or be-Cl-Ph, or be-Br-Ph, or be-F-Ph, or be-thiophenyl, or be-furanyl, or be-Me-Ph, or be-OMe-Ph, or be-Et, or be-Me;
R
3For
Or be-OH, or be-OMe, or be-OEt, or be-NH
2
2. the preparation method of a kind of chiral imidazole quinoline compounds as claimed in claim 1 the steps include:
With substrate N-protected group with imine moiety and consumption is that the rosin deutero-chirality thiourea catalyst of substrate N-protected group with imine moiety 3mol% is dissolved in the toluene, adding consumption under-15 ℃ of conditions carefully is 2/3 times of amount of substrate N-protected group with imine moiety isothiocyanate compound, reacts 18 hours; After reacting completely, column chromatography (H60 silica gel, sherwood oil: ethyl acetate=8: 1) obtain the product intermediate, be that 1.2 times of amounts of above-mentioned product intermediate salt of wormwood is dissolved in the anhydrous propanone with above-mentioned product intermediate and consumption then, adding consumption under 0 ℃ of condition carefully is 1.1 times of amounts of above-mentioned product intermediate idoalkane, reacts 8 hours, after reacting completely, column chromatography (H60 silica gel, sherwood oil: methylene dichloride=5: 1) obtain final product, above-mentioned reaction is as follows with chemical formulation:
3. the preparation method of a kind of chiral imidazole quinoline compounds as claimed in claim 2 is characterized in that: a described class rosin deutero-chirality thiourea catalyst, and its structural formula is shown in (II):
R is-OH in (II) formula, or is-OMe.
4. the preparation method of a class rosin deutero-chirality thiourea catalyst as claimed in claim 3 the steps include:
The amine of chicken Jenner alkali preparation is dissolved in the anhydrous methylene chloride, under 0 ℃ of condition, is added dropwise to the dehydroabietylamine lsothiocyanates, at room temperature reacted 12 hours, column chromatography (H60 silica gel, ethyl acetate: obtain end product methyl alcohol=6: 1),
Above-mentioned reaction is as follows with chemical formulation:
5. a class chiral imidazole quinoline compounds is in the application of anti-inflammatory aspect analgesic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010552078 CN102120740B (en) | 2010-11-17 | 2010-11-17 | Imidazoline compound chirally synthesized by using thiourea catalyst derived from rosin and application thereof in anti-inflammatory and antipyretic aspects |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010552078 CN102120740B (en) | 2010-11-17 | 2010-11-17 | Imidazoline compound chirally synthesized by using thiourea catalyst derived from rosin and application thereof in anti-inflammatory and antipyretic aspects |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102120740A true CN102120740A (en) | 2011-07-13 |
| CN102120740B CN102120740B (en) | 2013-04-17 |
Family
ID=44249426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010552078 Active CN102120740B (en) | 2010-11-17 | 2010-11-17 | Imidazoline compound chirally synthesized by using thiourea catalyst derived from rosin and application thereof in anti-inflammatory and antipyretic aspects |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102120740B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391204A (en) * | 2011-09-22 | 2012-03-28 | 兰州大学 | Chiral 2,4-disubstituted-thaizolidinone compounds and preparation method and application thereof in preparation of anticancer medicaments |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101318146A (en) * | 2008-06-21 | 2008-12-10 | 兰州大学 | Application of dehydroabietylamine thiourea catalyst in synthesizing chiral compound with high-antipodism both-hand control |
-
2010
- 2010-11-17 CN CN 201010552078 patent/CN102120740B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101318146A (en) * | 2008-06-21 | 2008-12-10 | 兰州大学 | Application of dehydroabietylamine thiourea catalyst in synthesizing chiral compound with high-antipodism both-hand control |
Non-Patent Citations (2)
| Title |
|---|
| 《ORGANIC LETTERS 》 20041027 J M.Concello´n， et al. Synthesis of Enantiopure Imidazolines through a Ritter Reaction of 2-(1-Aminoalkyl)aziridines with Nitriles 第4499-4501页 1 第6卷, 第24期 * |
| 《中国临床神经科学》 20080520 钱掩映等 咪唑克生对脂多糖诱导的皮质星形胶质细胞相关炎症细胞因子的影响 第225页-230页 5 第16卷, 第3期 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391204A (en) * | 2011-09-22 | 2012-03-28 | 兰州大学 | Chiral 2,4-disubstituted-thaizolidinone compounds and preparation method and application thereof in preparation of anticancer medicaments |
| CN102391204B (en) * | 2011-09-22 | 2014-01-15 | 兰州大学 | Chiral 2,4-disubstituted-thaizolidinone compounds and preparation method and application thereof in preparation of anticancer medicaments |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102120740B (en) | 2013-04-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Manfredini et al. | Design, synthesis and activity of ascorbic acid prodrugs of nipecotic, kynurenic and diclophenamic acids, liable to increase neurotropic activity | |
| Sodeoka et al. | Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR and cdc25B inhibition | |
| Liu et al. | Core scaffold-inspired stereoselective synthesis of spiropyrazolones via an organocatalytic Michael/cyclization sequence | |
| Naas et al. | Palladium-catalyzed oxidative direct C3-and C7-alkenylations of indazoles: Application to the synthesis of Gamendazole | |
| Nicolaou et al. | Total synthesis of epicoccin G | |
| Aursnes et al. | Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions | |
| Numajiri et al. | Enantioselective synthesis of dialkylated N-heterocycles by palladium-catalyzed allylic alkylation | |
| Shang et al. | Synthesis and biological activities of novel pleuromutilin derivatives with a substituted thiadiazole moiety as potent drug-resistant bacteria inhibitors | |
| Wang et al. | Iron-catalyzed aminolysis of β-carbonyl 1, 3-dithianes: Synthesis of stereodefined β-enaminones and 3, 4-disubstituted pyrazoles | |
| Song et al. | TMSCl-Mediated Synthesis of α, β-Unsaturated Amides via C–C Bond Cleavage and C–N Bond Formation of Propargyl Alcohols with Trimethylsilyl Azide | |
| Xiao et al. | γ-Carbon activation through n-heterocyclic carbene/brønsted acids cooperative catalysis: a highly enantioselective route to δ-lactams | |
| Duthion et al. | Enantioselective Synthesis of β-Fluoroamines from β-Amino Alcohols: Application to the Synthesis of LY503430 | |
| Kotani et al. | Highly selective aldose reductase inhibitors. 3. Structural diversity of 3-(arylmethyl)-2, 4, 5-trioxoimidazolidine-1-acetic acids | |
| Ahari et al. | A direct stereoselective approach to trans-2, 3-disubstituted piperidines: application in the synthesis of 2-Epi-CP-99,994 and (+)-epilupinine | |
| Kwon et al. | Synthesis of bicyclic guanidines via cascade hydroamination/Michael additions of mono-N-acryloylpropargylguanidines | |
| Ma et al. | Total synthesis of kaitocephalin, the first naturally occurring AMPA/KA receptor antagonist | |
| Li et al. | N-phenoxyamides as multitasking reagents: base-controlled selective construction of benzofurans or dihydrobenzofuro [2, 3-d] oxazoles | |
| Li et al. | Praseodymium (III)-catalyzed regioselective synthesis of C3-N-substituted coumarins with coumarins and azides | |
| Terasaka et al. | Structure-based design, synthesis, and structure− activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors | |
| Nagao et al. | Enantioselective synthesis of nelfinavir via asymmetric bromocyclization of bisallylic amide | |
| Sharma et al. | Sensitization of cancer cells to DNA damaging agents by imidazolines | |
| Cheng et al. | An unexpected bromolactamization of olefinic amides using a three-component Co-catalyst system | |
| Bell et al. | (S)-N-{3-[1-Cyclopropyl-1-(2, 4-difluoro-phenyl)-ethyl]-1 H-indol-7-yl}-methanesulfonamide: A Potent, Nonsteroidal, Functional Antagonist of the Mineralocorticoid Receptor | |
| AU2016248886B2 (en) | Pyridopyrimidinones and their use as NMDA receptor modulators | |
| CN102120740B (en) | Imidazoline compound chirally synthesized by using thiourea catalyst derived from rosin and application thereof in anti-inflammatory and antipyretic aspects |
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 |