CN101781227B - 2-N-[(1R, 2R)-1, 3-dihydroxy-1-phenylpropyl]-fatty amide compound, preparation and application thereof - Google Patents
2-N-[(1R, 2R)-1, 3-dihydroxy-1-phenylpropyl]-fatty amide compound, preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a 2-N-[(1R, 2R)-1, 3-dihydroxy-1-phenylpropyl]-fatty amide compound, preparation and application thereof. The compound is a small molecule nerve growth factor ceramide analogue which is prepared by reforming the structure of (1R, 2R)-2-amido-1, 3-benzene propylene glycol used as a raw material. The structural formula is shown in the specification of the invention, wherein R=amyl, heptyl, nonyl, undecyl, tridecyl, pentadecyl or heptadecyl. The preparation method comprises the steps of: adding quantitative different p-nitrophenyl fatty acid ester to an anhydrous THF solution of the (1R, 2R)-2-amido-1, 3-benzene propylene glycol; stirring at room temperature; reacting for 48 hours; finishing a TLC track detection reaction; evaporating reaction mixtures under a decompression condition; and taking solution of chloroform and acetone which are mixed in the proportion of 85: 15 to 80: 20 to separate and purify residues by silica gel chromatographic columns to obtain the 2-N-[(1R, 2R)-1, 3-dihydroxy-1-phenylpropyl]-fatty amide compound. The compound can be used as a nerve growth factor and a regulating agent in immune reactions.
Description
Technical field
The present invention relates to a kind of compound, the similar thing 2-N-of particularly a kind of small molecules NGFF ceramide [(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide compound and preparation and application.
Background technology
Senile dementia (AD) is the disease that a kind of carrying out property is cognitive and memory function is lost; Along with the acceleration of social astogeny, the ratio of patients of senile dementia in population increases gradually, and its sickness rate increases with age growth; 65 years old sickness rate is about more than 0.5%, 85 years old and reaches 8% approximately.Because senile dementia brings very big burden for family and society, its hazardness is only second to cancer, heart disease and stroke.Therefore, WHO has been decided to be senile dementia one of five big principal diseases of 21 century threat human health.Seek the active drug of treatment senile dementia, become one of research focus of world medical circle.The medicine of treatment senile dementia all is the final stage that is used to control morbidity at present, and effect mainly is the memory that improves the patient, because interpretation of the cause, onset and process of an illness cause of disease complicacy is unclear, control medicine effect is general.In addition, but at present there are many spinoffs in the Western medicine of suiting the medicine to the illness.Only develop the medicine that really can effect a permanent cure and come, and spinoff is low, senile dementia just can really be cured.
NGFF (NGF) is a kind of natural protein; In the process of neuronic survival, growth, growth, differentiation, injury repairing, neurotization, cynapse formation and synaptic plasticity and nerve degenerative diseases, play important effect, be one of focus in the present neuroscience field.NGF has prevention and treats some function like disease of brain such as presenile dementia and Parkinsonism.In addition, NGF also has the genetic expression of the PC12 of promotion cell family increases calcium current, as the regulator in inflammation and the immunoreation.NGFF is a kind of natural protein, is difficult for through hemato encephalic barrier, and bioavailability is low, is easy to degraded, adds to be difficult to from animal body such as snake venom, obtain enough amounts, thereby has limited its application clinically.Therefore, excavating the micromolecular compound with nerve growth factor subfunction then is very important.
Summary of the invention
Be difficult for through hemato encephalic barrier to the macromole NGFF, bioavailability is low, is easy to degraded; Limited its application clinically, the objective of the invention is, the similar thing 2-N-of a kind of NGFF micromolecular ceramide is provided [(1R; 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-the fatty amide compound, 2-N-[(1R of the present invention; 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-the fatty amide compound be with (1R, 2R)-2-amino-1; 3-phenylpropyl alcohol glycol be raw material in addition structure of modification process, can be used in the application of regulator in neurotrophy regenerator and the immunoreation of neurotrophic factor with it.
In order to realize above-mentioned task, the present invention is achieved through following technical scheme:
A kind of compound 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide, it is characterized in that its general structure is:
In the formula, R=amyl group, heptyl, nonyl, undecyl, tridecyl, pentadecyl or heptadecyl.
The present invention gives the preparation method of above-claimed cpd 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide; It is characterized in that, quantitative different lipid acid p-nitrophenyl esters are added (1R, 2R)-2-amino-1; In the anhydrous THF solution of 3-phenylpropyl alcohol glycol, stirring at room is followed the tracks of after detection reaction accomplishes with TLC behind the reaction 48h; Make the reaction mixture evaporation under reduced pressure, its resistates is eluent with chloroform and acetone with 85: 15～80: 20 mixing solutions, through the silica gel chromatography column separating purification; Obtain compound 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide.
Prove after deliberation, compound 2-N-of the present invention [(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide, can be used in preparation and have the compsn of NGFF effect, or be used in preparation neurotrophic agents and the application for preparing in the immunomodulator.
Embodiment
According to technical scheme of the present invention, compound 2-N-of the present invention [(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide, it is characterized in that its general structure is:
In the formula, R=amyl group, heptyl, nonyl, undecyl, tridecyl, pentadecyl or heptadecyl.
Its preparation method be quantitative different lipid acid p-nitrophenyl esters are added (1R, 2R)-2-is amino-1, in the anhydrous THF solution of 3-phenylpropyl alcohol glycol; Stirring at room is reflected at behind the 48h with TLC and follows the tracks of after detection reaction accomplishes, and makes the reaction mixture evaporation under reduced pressure; Its resistates is with chloroform: and acetone (85: 15,80: 20, v/v) be eluent; Through the silica gel chromatography column separating purification, obtain general formula (I) compound.
Above-mentioned different lipid acid p-nitrophenyl ester is n-caproic acid p-nitrophenyl ester, n-caprylic acid p-nitrophenyl ester, positive ten sour p-nitrophenyl esters, positive laurostearic acid p-nitrophenyl ester, positive TETRADECONIC ACID p-nitrophenyl ester, positive palmitic acid p-nitrophenyl ester or n-octadecanoic acid p-nitrophenyl ester.
Below be the embodiment that the contriver provides, need to prove that these embodiment are the preferable examples of the present invention, the invention is not restricted to these embodiment.
Embodiment 1:
2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-hexanamide (L-2-6) synthetic
The new steaming dichloromethane solution 30ml that in the 100ml round-bottomed flask, adds p-NP 584mg (4.2mmol); Triethylamine 465mg (4.6mmol); Under the ice bath agitation condition, drip the dichloromethane solution 10ml of positive caproyl chloride 565mg (4.2mmol); Finish reaction behind the room temperature reaction 1h, reaction solution is used the HCl solution of 1M, saturated NaHCO respectively
3, saturated common salt washing, anhydrous sodium sulfate drying.Revolve after desolvating light yellow liquid 906mg, be the n-caproic acid p-nitrophenyl ester;
In the 25ml round-bottomed flask, add the n-caproic acid p-nitrophenyl ester 474mg (2mmol) that makes, (1R, 2R)-2-amino-1,3-phenylpropyl alcohol glycol 167mg (1mmol), anhydrous THF 10ml, stopped reaction behind the stirring at room reaction 48h.Column chromatography purification (CHCl
3/ acetone, 4/1) must white solid 234.
This compound is 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-hexanamide (L-2-6), and its structure and structured data are:
Yield 90%; 64～65 ℃ of mp; [α]
20 D=-48 ° of (c 0.36mg/ml, CHCl
3); TLC R
f=0.58 (CHCl
3: MeOH=9: 1, v/v); IR (KBr) ν: 3320,2954,1621,1566,1456,1382,1273,1057,998,764,700cm
-1 1H?NMR(500MHz，CDCl
3)δ：7.27-7.36(m，5H)，6.20(d，J＝7.5Hz，1H)，5.05(d，J＝4.0Hz，1H)，4.08-4.12(m，1H)，3.76-3.83(m，2H)，2.08-2.17(m，2H)，1.48-1.54(m，2H)，1.13-1.28(m，4H)，0.86(t，J＝7.3Hz，3H)。MS(ESI-Trap)m/z?266.0(M+H)
+。
Embodiment 2:
2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-decoylamide (L-2-8) synthetic
The new steaming dichloromethane solution 30ml that in the 100ml round-bottomed flask, adds p-NP 528mg (3.8mmol); Triethylamine 455mg (4.5mmol); Under the ice bath agitation condition, drip the dichloromethane solution 10ml of positive capryl(yl)chloride 528mg (3.8mmol); Finish reaction behind the room temperature reaction 1h, reaction solution is used the HCl solution of 1M, saturated NaHCO respectively
3, saturated common salt washing, anhydrous sodium sulfate drying.Revolve after desolvating light yellow liquid 928mg, be the n-caprylic acid p-nitrophenyl ester.
In the 25ml round-bottomed flask, add the n-caprylic acid p-nitrophenyl ester 477mg (1.8mmol) that makes, (1R, 2R)-2-amino-1,3-phenylpropyl alcohol glycol 150mg (0.90mmol), anhydrous THF 10ml, stopped reaction behind the stirring at room reaction 48h.Column chromatography (CHCl
3/ acetone, 4/1) must white solid 220mg.
This compound is 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-decoylamide (L-2-8), and its structure and structured data are:
Yield 83%, 75～76 ℃ of mp; [α]
20 D=-57 ° of (c 0.32mg/ml, CHCl
3); TLC R
f=0.58 (CHCl
3/ MeOH, 9/1); IR (KBr) ν: 3303,2930,1642,1615,1547,1467,1366,1053,760,697cm
-1 1H NMR (500MHz, CDCl
3) δ 7.27-7.36 (m, 5H), 6.17 (d, J=7.5Hz, 1H), 5.05 (d, J=4.0Hz; 1H), and 4.08-4.12 (m, 1H), 3.78-3.84 (m, 2H), 2.09-2.17 (m, 2H); 1.48-1.54 (m, 2H), 1.16-1.29 (m, 8H), 0.88 (t, J=7.1Hz, 3H).MS(ESI-Trap)m/z?294.1(M+H)
+。
Embodiment 3:
2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-ten acid amides (L-2-10) synthetic
The new steaming dichloromethane solution 50ml that in the 100ml round-bottomed flask, adds p-NP 1.74g (12.5mmol); Triethylamine 1.32g (13mmol); Under the ice bath agitation condition, drip the dichloromethane solution 10ml of positive ten acyl chlorides 2.38g (12.5mmol); Finish reaction behind the room temperature reaction 1h, reaction solution is used the HCl solution of 1M, saturated NaHCO respectively
3, saturated common salt washing, anhydrous sodium sulfate drying.Revolve after desolvating white solid 3.30g, be positive ten sour p-nitrophenyl esters.
In the 25ml round-bottomed flask, add the positive ten sour p-nitrophenyl ester 493mg (1.68mmol) that make, (1R, 2R)-2-amino-1,3-phenylpropyl alcohol glycol 140mg (0.84mmol), anhydrous THF 10ml, stopped reaction behind the stirring at room reaction 48h.Column chromatography (CHCl
3/ Acetone, 4/1) must white solid 244mg.
This compound is 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-ten acid amides (L-2-10), and its structure and structured data are:
Yield 84%; 64～65 ℃ of mp; TLC R
f=0.60 (CHCl
3/ MeOH, 9/1).IR(KBr)ν：3307，2923，1623，1572，1457，1379，1269，1058，994，764，699cm
-1；
1H?NMR(500MHz，CDCl
3)δ：7.27-7.36(m，5H)，6.17(d，J＝7.6Hz，1H)，5.05(d，J＝4.1Hz，1H)，4.08-4.12(m，1H)，3.78-3.84(m，2H)，2.09-2.18(m，2H)，1.48-1.54(m，2H)，1.18-1.31(m，12H)，0.88(t，J＝7.2Hz，3H)。MS(ESI-Trap)m/z322.2(M+H)
+。
Embodiment 4:
2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-lauramide (L-2-12) synthetic
The new steaming dichloromethane solution 30ml that in the 100ml round-bottomed flask, adds p-NP 417mg (3.0mmol); Triethylamine 354mg (3.5mmol); Under the ice bath agitation condition, drip the dichloromethane solution 10ml of positive lauroyl chloride 656mg (3.0mmol); Finish reaction behind the room temperature reaction 1h, reaction solution is used the HCl solution of 1M, saturated NaHCO respectively
3, saturated common salt washing, anhydrous sodium sulfate drying.Revolve after desolvating white solid 937mg, be positive laurostearic acid p-nitrophenyl ester.
In the 25ml round-bottomed flask, add the positive laurostearic acid p-nitrophenyl ester 501.4mg (1.56mmol) that makes, (1R, 2R)-2-amino-1,3-phenylpropyl alcohol glycol 130mg (0.78mmol), anhydrous THF 10ml, stopped reaction behind the stirring at room reaction 48h.Column chromatography (CHCl
3/ acetone, 85/15) must white solid 179mg.
This compound is 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-lauramide (L-2-12), and its structure and structured data are:
Yield 65%; 62～64 ℃ of mp; [α]
20 D=-41 ° of (c 0.35mg/ml, CHCl
3); TLC R
f=0.58 (CHCl
3/ MeOH, 9/1); IR (KBr) 3398,3333,2919,1641,1546,1466,1379,1278,1182,1071,992,760,696cm
-1 1H NMR (500MHz, CDCl
3) δ 7.27-7.36 (m, 5H), 6.18 (d, J=7.6Hz, 1H), 5.04 (d, J=4.0Hz; 1H), and 4.07-4.12 (m, 1H), 3.77-3.83 (m, 2H), 2.08-2.18 (m, 2H); 1.47-1.53 (m, 2H), 1.18-1.32 (m, 16H), 0.88 (t, J=7.1Hz, 3H).MS(ESI-Trap)m/z?350.2(M+H)
+；HR-MS(ESI)m/z?calcd?for?C
21H
35NO
3，349.2617(Δ＝3.7ppm)。
Embodiment 5:
2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-myristamide (L-2-14) synthetic
The new steaming dichloromethane solution 30ml that in the 100ml round-bottomed flask, adds p-NP 403.4mg (2.9mmol); Triethylamine 344mg (3.4mmol); Under the ice bath agitation condition, drip the dichloromethane solution 10ml of positive myristyl chloride 705.9mg (2.86mmol); Finish reaction behind the room temperature reaction 1h, reaction solution is used the HCl solution of 1M, saturated NaHCO respectively
3, saturated common salt washing, anhydrous sodium sulfate drying.Revolve after desolvating white solid 946.8mg, be positive TETRADECONIC ACID p-nitrophenyl ester.
In the 25ml round-bottomed flask, add the positive TETRADECONIC ACID p-nitrophenyl ester 503mg (1.44mmol) that makes, (1R, 2R)-2-amino-1,3-phenylpropyl alcohol glycol 120mg (0.72mmol), anhydrous THF 10ml, stopped reaction behind the stirring at room reaction 48h.Column chromatography (CHCl
3/ acetone, 85/15) must white solid 222mg.
This compound is 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-myristamide (L-2-14), and its structure and structured data are:
Yield 83%; Mp78～79 ℃; [α]
20 D(39 °) (c 0.37mg/ml, CHCl
3); TLC R
f=0.58 (CHCl
3/ MeOH, 9/1); IR (KBr) ν: 3399,3333,2919,2849,1641,1545,1462,1379,1181,1071,1050,992,761,696cm
-1 1H NMR (500MHz, CDCl
3) δ 7.27-7.36 (m, 5H), 6.16 (d, J=7.6Hz, 1H), 5.04 (d, J=4.1Hz; 1H), and 4.08-4.12 (m, 1H), 3.78-3.84 (m, 2H), 2.10-2.18 (m, 2H); 1.48-1.54 (m, 2H), 1.18-1.32 (m, 20H), 0.88 (t, J=7.1Hz, 3H).MS(ESI-Trap)m/z?378.3(M+H)
+。
Embodiment 6:
2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-palmitamide (L-2-16) synthetic
The new steaming dichloromethane solution 30ml that in the 100ml round-bottomed flask, adds p-NP 361mg (2.6mmol); Triethylamine 314mg (3.1mmol); Under the ice bath agitation condition, drip the dichloromethane solution 10ml of positive hexadecanoyl chloride 715mg (2.6mmol); Finish reaction behind the room temperature reaction 1h, reaction solution is used the HCl solution of 1M, saturated NaHCO respectively
3, saturated common salt washing, anhydrous sodium sulfate drying.Revolve after desolvating white solid 942.7mg, be positive palmitic acid p-nitrophenyl ester.
In the 25ml round-bottomed flask, add the positive palmitic acid p-nitrophenyl ester 528mg (1.4mmol) that makes, (1R, 2R)-2-amino-1,3-phenylpropyl alcohol glycol 115mg (0.69mmol), anhydrous THF 10ml, stopped reaction behind the stirring at room reaction 48h.Column chromatography (CHCl
3/ acetone, 85/15) must white solid 217mg.
This compound is 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-palmitamide (L-2-16), and its structure and structured data are:
Yield 77%; Mp82～84 ℃; [α]
20 D=-44 ° of (c 0.33mg/ml, CHCl
3); TLC R
f=0.59 (CHCl
3/ MeOH, 9/1); IR (KBr) ν: 3404,3333,2920,2848,1641,1545,1461,1181,1072,991,761,696cm
-1 1H NMR (500MHz, CDCl
3) δ: 7.27-7.36 (m, 5H), 6.16 (d, J=7.6Hz, 1H), 5.05 (d, J=4.0Hz; 1H), and 4.07-4.12 (m, 1H), 3.78-3.84 (m, 2H), 2.10-2.18 (m, 2H); 1.48-1.53 (m, 2H), 1.18-1.31 (m, 24H), 0.88 (t, J=7.0Hz, 3H).MS(ESI-Trap)m/z?406.3(M+H)
+。
Embodiment 7:
2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-stearylamide (L-2-18) synthetic
The new steaming dichloromethane solution 30ml that in the 100ml round-bottomed flask, adds p-NP 348mg (2.5mmol); Triethylamine 303mg (3.0mmol); Under the ice bath agitation condition, drip the dichloromethane solution 10ml of n-octadecanoyl chloride 757mg (2.5mmol); Finish reaction behind the room temperature reaction 1h, reaction solution is used the HCl solution of 1M, saturated NaHCO respectively
3, saturated common salt washing, anhydrous sodium sulfate drying.Revolve after desolvating white solid 869mg, be the n-octadecanoic acid p-nitrophenyl ester.
In the 25ml round-bottomed flask, add the n-octadecanoic acid p-nitrophenyl ester 535mg (1.32mmol) that makes, (1R, 2R)-2-amino-1,3-phenylpropyl alcohol glycol 110mg (0.66mmol), anhydrous THF 10ml, stopped reaction behind the stirring at room reaction 48h.Column chromatography (CHCl
3/ acetone, 85/15) must white solid 227mg.
This compound is 2-N-[(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-stearylamide (L-2-18), and its structure and structured data are:
Yield 79%; 88～90 ℃ of mp; TLC R
f=0.58 (CHCl
3/ MeOH, 9/1); IR (KBr) ν: 3402,3332,2919,2848,1641,1546,1462,1379,1181,1050,991,761,696cm
-1 1H?NMR(500MHz，CDCl
3)δ：7.27-7.36(m，5H)，6.16(d，J＝7.6Hz，1H)，5.05(d，J＝4.0Hz，1H)，4.07-4.12(m，1H)，3.78-3.84(m，2H)，2.10-2.18(m，2H)，1.48-1.53(m，2H)，1.18-1.31(m，28H)，0.88(t，J＝7.0Hz，3H)。MS(ESI-Trap)m/z?434.4(M+H)
+。
The compound 2-N-of above-mentioned preparation [(1R, 2R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide, the influence that external PC12 cell is grown is to be confirmed through following experiment:
Experimental technique: the cultivation of PC12 cell: place RPMI 1640 cell culture fluids (including 10% horse serum and 5% foetal calf serum) to cultivate in the PC12 cell.Add 10% hot deactivation horse serum and 5% foetal calf serum in the nutrient solution.At 37 ℃, 5%CO
2, cultivate under the saturated humidity condition.
Separate cell with mechanical dispersion method, in 24 well culture plate inoculation culture, 24 well culture plates cover with osso-albumin type I (from the mouse tail, proposing) in advance.After cultivating 24h, change nutrient solution in 24 orifice plates with the lower concentration RPMI RPMI-1640 that contains 2ng/mL NGF.To prepare the compound solution of concentration (50 μ M) then and contrast in liquid (DMSO+2ng/mL NGF) the adding culture plate and cultivate.Repeat 3 times.
The result: when compound concentration is 20-50 μ M, and when 2ng/ml NGF existed, all compounds can significantly increase PC12 cell axon (rope) growth, differentiation and the PC12 cell number of NGFF NGF mediation, and the result sees the following form 1.
Table 1: compound is to the influence (contrast: DMSO+2ng/mL NGF) of PC12 cell growth
Claims (5)
1. compound 2-
N-[(1
R, 2
R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide, it is characterized in that its general structure is:
In the formula, R=amyl group, heptyl, undecyl, tridecyl, pentadecyl or heptadecyl.
2. the described compound 2-of claim 1
N-[(1
R, 2
R)-1,3-dihydroxyl-1-hydrocinnamyl]-preparation method of fatty amide, it is characterized in that, quantitative different lipid acid p-nitrophenyl esters are added (1
R, 2
R)-2-amino-1; In the anhydrous THF solution of 3-phenylpropyl alcohol glycol, stirring at room is followed the tracks of after detection reaction accomplishes with TLC behind the reaction 48h; Make the reaction mixture evaporation under reduced pressure; Its resistates is an eluent with chloroform and 85: 15～80: 20 mixing solutions of acetone volume ratio, through the silica gel chromatography column separating purification, obtains compound 2-
N-[(1
R, 2
R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide.
3. the described compound 2-N-[(1 of claim 1
R, 2
R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide is used to prepare the application of the compsn with NGFF effect.
4. the described compound 2-N-[(1 of claim 1
R, 2
R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide is used for the application at the preparation neurotrophic agents.
5. the described compound 2-N-[(1 of claim 1
R, 2
R)-1,3-dihydroxyl-1-hydrocinnamyl]-fatty amide is used for the application at the preparation immunomodulator.
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Non-Patent Citations (1)
| Title |
|---|
| K. R. WARREN et al..GLYCOSYLTRANSFERASES OF RAT BRAIN THAT MAKE CEREBROSIDES: SUBSTRATE SPECIFICITY,INHIBITORS, AND ABNORMAL PRODUCTS.《Journal of Neurochemistry》.1976,第26卷1063-1072. * |
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