CN1305997A - Diclofenac coupled derivative and its synthesizing process and inflammation relieving action - Google Patents

Diclofenac coupled derivative and its synthesizing process and inflammation relieving action Download PDF

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CN1305997A
CN1305997A CN 01108030 CN01108030A CN1305997A CN 1305997 A CN1305997 A CN 1305997A CN 01108030 CN01108030 CN 01108030 CN 01108030 A CN01108030 A CN 01108030A CN 1305997 A CN1305997 A CN 1305997A
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CN1133626C (en
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张奕华
李瑞文
季晖
于晓琳
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Chang'ao Science and Technology of Medical Industry Co., Ltd., Nanjing
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China Pharmaceutical University
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Abstract

The present invention discloses a NO donor type non-steroidal anti-inflammatory (NO-DC), which is prepared through coupling dicolfenac (DC) respectively with substituted furazan and nitroxymethyl phenol via ester bond or amide bond of linking radical. Its can release NO in human body and features its improved anti-inflammation activity and reduced by-effect to intestine and stomach, resulting in higher safety.

Description

Diclofenac coupled derivative, its synthetic method and anti-inflammatory action
The present invention relates to diclofenac (DC, down together) and furazan that replaces and link coupled compound, their synthetic method and the application aspect preparation anti-inflammatory, anodyne thereof mutually of nitre oxygen methylphenol.
NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is anti-inflammatory, the analgesic that a class is widely used clinically, but its digestive tract side effects is comparatively serious, as stomach ulcer, perforation, hemorrhage etc.Trace it to its cause mainly be NSAIDs in the inflammation-inhibiting position prostaglandin(PG) (PGs), also suppressed PGs synthetic that gi tract have the mucous membrane protection effect.Reducing gastrointestinal side effect is the basic point of departure of Recent study and development of new NSAIDs.The discovery of two kinds of subtype C OX-1 of epoxidase at the beginning of the nineties (COX) and COX-2 is the quantum jump on the NSAIDs development history, make people might study the COX-2 selective depressant of inflammation-inhibiting position PGs, whether toxigenicity must could be come to a conclusion after the long-term clinical observation but it is to kidney and central nervous system.The nineties, another major progress of NSAIDs was nitrogen protoxide (NO) donator type NSAIDs, its appearance has benefited from the further investigation of the later stage eighties to NO, its design philosophy is based on NO and PGs similarity and the complementarity in the gi tract effect, the group that will have the NO releasing properties is coupled in traditional NSAIDs molecule, this NO-NSAIDs (nitric oxide donator type NSAID (non-steroidal anti-inflammatory drug), discharge NO and former medicine NSAIDs in vivo down together), keep or the enhancing anti-inflammatory action, reduce or eliminate the gastrointestinal side effect that NSAIDs causes.
Existing in recent years several patents relate to the NO-NSAIDs of nitrate esters, mainly are preparation and the anti-inflammatory and the antithrombotic acitivity of alkyl nitrate ester selected.Britain Metgrove company has synthesized the saturated nitric ether (PCT of DC, patent No. WO94/04484), people such as Arena have synthesized the nitric acid butyl ester (PCT of arylprop acids NSAIDs, patent No. WO94/12463), Serra Masia etc. has synthesized the saturated nitre oxyalkyl ester (EP of Aceclofenac and derivative thereof, the patent No. 0738 706A1), people such as Mimoso have synthesized a series of NO-NSAIDs, wherein NSAIDs comprises the arylprop acids, the Arylacetic acids class and former times the health class, it is nitrous acid ester that NO discharges group, (PCT, patent No. US96/32946) such as sulfo-nitrous acid ester and sydnone imines, people such as Del soldato have prepared the aryl nitric ether (PCT of a series of acetylsalicylic acid compounds, the patent No. 97/16405), Zhong Guo Cai Xiong etc. has also prepared the saturated and undersaturated nitric ether (CN, publication number 1144092A) of multiple NSAIDs.These patent compounds discharge nitrogen protoxide and former medicine NSAID in vivo, have anti-inflammatory and the antithrombotic acitivity suitable with former medicine, but gastrointestinal side effect reduce obviously.Nitrofenac for example, be a known nitrate esters NO-DC (patent No. WO94/04484), its anti-inflammatory activity and DC are suitable, gastrointestinal side effect is less than DC (Wallace JL, CirinoG.A diclofenac derivative without ulcerogenic properties.Eur JPharmacol1994,257:249-255) (Elliott SN, Mcknight W, Cirino G, et al.A nitricoxide-releasing nonsteroidal anti-inflammatory drug accelerates gastriculcer healing in rats.Gastroenterology 1995,109:524-530).
The object of the present invention is to provide a kind of than the better novel NO-NSAID of existing medicine, they discharge NO and DC in vivo, the performance anti-inflammatory action, also reduce or eliminate simultaneously the gi tract toxic side effect of DC, can be used as anti-inflammation analgesia medicine, be used for the treatment of diseases such as rheumatic, rheumatoid arthritis, osteoarthritis.
But the present invention also aims to provide the preparation method of the suitability for industrialized production of a kind of novel NO-NSAID.
Technical scheme of the present invention is as follows:
Generalformula: Wherein: R 1Represent O, NH; R 2Representative-(CH 2) n-, n=3-5; CH 2C ≡ CCH 2CH 2CH (CH 3) CH 2CH 2CH 2CH 2OCH 2CH 2-PhCH 2-(m, p).General formula II compound:
Figure A0110803000062
Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).General formula III compound: Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).General formula IV compound:
Figure A0110803000071
The generalformula preparation method, it is characterized in that: after the reaction of diclofenac sodium (DC-Na) and halohydrin again with the furazan oxynitride condensation that replaces, perhaps DC and hydroxyl or amino furazan oxynitride (I p) condensation in the presence of dicyclohexyl carbimide (DCC)
Wherein: R 1Represent OH, NH 2R 2Representative-(CH 2) n-, n=3-5; CH 2C ≡ CCH 2CH 2CH (CH 3) CH 2CH 2CH 2CH 2OCH 2CH 2-PhCH 2-(m, p).
Concrete reactions steps is:
Wherein: X represents Br, Cl; N=3-5; Perhaps:
Figure A0110803000074
General formula II compounds process for production thereof is characterized in that: furazan oxynitride (II p) condensation in the presence of DCC of DC and hydroxyl,
Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).Concrete reactions steps is:
General formula III compounds process for production thereof is characterized in that: furazan oxynitride (III p) condensation in the presence of DCC of DC and hydroxyl, Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).
Concrete reactions steps is:
Figure A0110803000084
General formula IV compounds process for production thereof is characterized in that: DC and nitre oxygen sylvan (IV p) condensation in the presence of DCC.
Concrete reactions steps is:
Formula I, II, III, IV compound are used to prepare anti-inflammatory, anodyne.
The pharmacological evaluation of formula I, II, III, IV compound is as follows.1. anti-inflammatory activity 1.1 p-Xylol cause the influence of mice ear
Experimental technique is seen: Xu Shuyun, Bian Rulian, Chen Xiu chief editor, " pharmacological experimental methodology " second edition, Beijing people's health press, version in 1991.
DC-Na is available from Yicheng, Hubei 5-linked pharmaceutical factory, and specification is medicinal, down together.
Nitrofenac is synthetic by patent (EP, the patent No. 738706) method, and its structure is proved conclusively through wave spectrum.Nitrofenac is known nitrate esters NO-DC (WO94/04484), and bibliographical information is arranged, and its anti-inflammatory activity and DC are suitable, and gastrointestinal side effect is less than DC, thus with it as the reference medicine, down with.
All medicines all use 0.5% Xylo-Mucine (CMC-Na) to be made into 1.57 * 10 -3The suspension of mol/L is with volumetric molar concentrations such as DC-Na.Oily matter then adds the dimethyl sulfoxide (DMSO) of soup cumulative volume 5% earlier, adds the 0.5%CMC-Na of cumulative volume 95% again, fully mixing.The DC-Na dosage is set at 20mg/kg, and this dosage is converted by human dosage.
The mouse fasting is 12 hours before the experiment, but can't help water.To the mouse stomach administration, the administration volume is 0.4ml/10g.Administration evenly is coated with dimethylbenzene 20 μ l with the wide both sides of mouse right ear with microsyringe after 1 hour and causes inflammation, and left auricle compares.After causing scorching 30 minutes mouse is taken off cervical vertebra and put to death, take off two ears, respectively get an auricle in same position with punch tool (diameter is 7mm) and weigh along the auricle baseline.Causing the inflammation sheet weight of picking up the ears deducts
Control sides auricle weight is the swelling degree.Each group data is carried out t check, the significance of comparative group differences.
Table 1. compound p-Xylol causes influence (n=10, the x ± s) of mice ear
Compound swelling degree (1mg) compound swelling degree (mg)
CMC-Na 11.31±3.23# Ⅰ 4 9.97±2.39
DC-Na 7.30±2.10* Ⅰ 5 7.32±2.30 *
Nitrofenac?8.67±3.56 Ⅱ 1 10.64±1.65 #
Ⅰ 1 8.74±1.20 Ⅱ 2 7.25?±?1.86 **
Ⅰ 2 9.91±2.87 Ⅱ 3 9.55±0.74 *
Ⅰ 3 9.00±3.61 Ⅳ 1 6.31±1.45 *
Compare with CMC-Na, *P＜0.05, #P＜0.01
Compare with DC-Na, #P＜0.05
By table 1 as seen, compound N itrofenac, I 1, I 2, I 3, I 4, I 5, II 2, II 3And IV 1Anti-inflammatory activity and DC-Na are suitable, there was no significant difference (P＞0.05).1.2 on Carrageenan causes the influence of rat paw edema
Experimental technique is seen: Cirino G, Peers SH, Flower RJ, et al.Human recombinantlipocortin 1 has acute local anti-inflammatory properties in the rat pawedema test.Proc Natl Acad Sci USA, 1989,86:3428.
Select the active compound I 1, I 2, I 3, I 4, I 5, II 2, IV 1Conduct is tried thing with Nitrofenac, and all is made into 3.14 * l0 with 0.5% CMC-Na -3The suspension of mol/L is with volumetric molar concentrations such as DC-Na.Oily matter then adds the dimethyl sulfoxide (DMSO) of soup cumulative volume 5% earlier, adds 0.5% CMC-Na of cumulative volume 95% again, abundant mixing, and the DC-Na dosage is set at 10mg/kg, and this dosage is converted by human dosage.Every group of 10 rats, preceding fasting 18-22 hour of experiment, but can't help water.To the rat oral gavage administration, the administration volume is 1ml/100g.After the administration 30 minutes, inject 1% carrageenin (sterile saline preparation) 0.1ml down to the right back sufficient plantar aponeurosis of rat, mensuration causes before the inflammation and causes scorching back 1,2,3,4,5 hours right back sufficient sole of the foot volumes of rat, with its sufficient sole of the foot volume difference that causes scorching front and back is the swelling degree, carries out the t check, the significance of comparative group differences.
The injection carrageenin causes that the right back sufficient sole of the foot volume of rat obviously increases in after the inflammation 5 hours.Give DC-Na in advance, can significantly reduce sufficient sole of the foot volumetrical increasing amount.Compare IV with the CMC-Na group 1Paw swelling (2 hours some P＜0.001 have obviously been alleviated at 2 hours, 3 hours and 4 hours points; 3,4 hours some P＜0.05), especially in 2 little time points, IV 1Anti-inflammatory action be better than DC-Na (P＜0.01).Compare with CMC-Na group, there were significant differences (P＜0.05) at 3 little time points (P＜0.01) and 4,5 little time points for Nitrofenac; I 4There were significant differences (P＜0.05) at 3,4 little time points; I 5There were significant differences (P＜0.01) at 4 little time points.Nitrofenac and I 4, I 5Anti-inflammatory activity and DC-Na suitable.II 2Anti-inflammatory action at 5 little time points obviously is better than DC-Na (P＜0.05).2. to the influence of rat gastrointestinal tract
Experimental technique is with reference to Xu Shuyun, Bian Rulian, " pharmacological experimental methodology " second edition of Chen Xiu chief editor, Beijing people's health press, 1991.
Select chemical compounds I 4, I 5, II 2, IV 1Conduct is tried thing with Nitrofenac.Dosage and medicine preparation are with 1.2.Every group of 8 rats (DC-Na organizes 11), gastric infusion is 7 days continuously, measures before the administration and the variation of administration body weight in latter stage, and observation and comparative drug are to the influence of rat gastrointestinal tract after the last administration.
All rat fasting are after 12 hours, pluck eyeball and get hematometry hematological indices (red blood cell count(RBC), content of hemoglobin), put to death rat with the cervical vertebra dislocation method, open the abdominal cavity immediately, collect ight soil from rectum and carry out occult blood test by the test kit method, and the taking-up gi tract, vertically cut open and carry out visual inspection, the hemorrhage situation of comprehensive evaluation animal gastrointestinal tract.2.1 influence to rat body weight
Table 2. compound is to the influence of rat body weight
Compound initial stage body weight (g) body weight in latter stage (g)
CMC-Na 203.88±16.62 227.57±24.60
DC-Na 201.67±19.99 191.00±17.49* Nitrofenac 208.63±14.72 211.14±10.30
Ⅰ 4 196.57±?9.76 210.12±15.20
Ⅰ 5 200.88±17.98 217.00±25.33
Ⅱ 2 197.12±19.00 210.00±23.92
Ⅳ 1 201.50±14.74 213.12±15.66
Compare with CMC-Na, *P＜0.05
By table 2 as seen, DC-Na group rat obviously reduces (P＜0.05) in administration body weight in latter stage, does not all have significant difference (P＞0.05) and compare before the body weight of other all compound group rats and the administration.2.2 the Anatomical Observation of rat gastrointestinal tract
Table 3. compound is to the influence of rat gastrointestinal tract
Animals survived animal gastrointestinal tract during the compound administration
The mortality ratio opinion rating
CMC-Na 0/8 0
DC-Na 5/11 3 Nitrofenac 1/8 2
Ⅰ 4 0/8 1
Ⅰ 5 0/8 1
Ⅱ 2 0/8 0
Ⅳ 1 0/8 0
0 grade: no ulcer
1 grade: the mucomembranous surface erosion
2 grades: deep ulcer or chamber face diffuse necrosis
3 grades: perforated ulcer
By table 3 as seen, the DC-Na group has 5 rats deaths, and Nitrofenac organizes 1 rats death, and other groups there is no the phenomena of mortality.By the gi tract score value as can be known, I 4, I 5, II 2, IV 1The gastrointestinal side effect of group rat is all less than DC-Na group and Nitrofenac group.2.3 occult blood test
Experiment adopts the Pyramidon filter paper method of improvement to carry out.
Occult blood test kit Fecal OB-II available from Baso Diagnostic Inc.
Table 4 occult blood test result
CMC-Na Nitrofenac Ⅰ 4 Ⅰ 5 Ⅱ 2 Ⅳ 1
Average mark 8 14.00 11.25 11.38 11.75 9.88
Gradit 1.0 2.1667 1.7083 1.7292?1.7917 1.4792
Ridit 0.5 1.0833 0.8542 0.8646 0.8958 0.7396 test of significance 1.0 2.78 *1.55 1.61 1.79 0.90 compare with CMC-Na, *P＜0.01
By table 4 as seen, except that Nitrofenac group, difference (P＞0.05) that all test-compound groups compare with the CMC-Na group that there are no significant.2.4 hematological indices
Table 5. compound is learned the influence of index to rat blood
Compound of red cell counting (* 10 12/ L) content of hemoglobin (g/L)
CMC-Na 7.77±0.706 # 131.33±9.83 ## Nitrofenac 6.93±0.538 * 113.71±6.52 **
Ⅰ 4 7.44±0.840 129.38±9.13 ##
Ⅰ 5 7.85±1.047 130.62±11.88 ##
Ⅱ 2 9.00±0.837 ### 144.20±6.18 ###
Ⅳ 1 8.46±0.864 ## 142.86±8.40 ###
Compare with CMC-Na, *P＜0.05, *P＜0.01,
Compare with Nitrofenac, #P＜0.05, ##P＜0.01, ###P＜0.001
By table 5 as seen, test-compound I 4, I 5, II 2And IV 1Content of hemoglobin and the II of group rat 2And IV 1The red blood cell count(RBC) of group rat is pointed out I than the Nitrofenac height 4, I 5, II 2And IV 1The situation of losing blood of group rat is lighter.3.NO releasing research in the body
Experiment is undertaken by kit method-nitrate reductase method.
The NO test kit is available from the poly-Lik-Sang thing engineering in medicine institute in Nanjing.
Select chemical compounds I 4, I 5, II 2, IV 1Conduct is tried thing with Nitrofenac.Its dosage, mode and soup preparation are measured the content of NO in the rat blood serum with 1.2.
NO content in table 6. rat blood serum (μ mol/L) measurement result (n=6, x ± s)
Compound 1 hour 3 hours
CMC-Na 18.63±8.07 ### 15.93±5.80 ###Nitrofenac 54.08±6.05 *** 49.77±9.91 ***
Ⅰ 4 25.94±6.52 ### 28.72±9.75 *##
Ⅰ 5 29.62±11.74 ## 28.89±7.08 **##
Ⅱ 2 27.24±8.21 ### 27.78±2.75 **###
Ⅳ 1 28.87±8.75 ### 51.77±23.25 **
Compare with CMC-Na, *P＜0.01, * *P＜0.001
Compare with Nitrofenac, #P＜0.05, ##P＜0.01, ###P＜0.001
By table 6 as seen, compare with CMC-Na, Nitrofenac obviously increases (P＜0.001), chemical compounds I 1 hour and 3 hours NO burst sizes 4, I 5, II 2Obviously increase 3 hours some NO burst sizes.IV 1At the NO of 3 little time points burst size and Nitrofenac suitable (P＞0.05).
Below be the embodiment of The compounds of this invention, these embodiment also do not mean that limitation of the present invention.
Embodiment 1a) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-2-hydroxy methacrylate (I p 1) (0.63g, 2mmol), (0.34g, 4mmol), (0.68ml, 0.8g 10mmol) are dissolved in 10ml N with a small amount of potassiumiodide to ethylene chlorhydrin to sodium bicarbonate, in the dinethylformamide (DMF), are heated to 80 ℃, and reaction solution is a reddish-brown with DC-Na.After the cooling, in reaction solution impouring 60ml water, with ethyl acetate (3 * 20ml) extractions.Merge organic layer, with 5: 2 ethyl acetate: sherwood oil (60-90 ℃) recrystallization, must orange powder shape solid 0.65g, yield 91%, mp60-62 ℃.IR (KBr, cm -1): 3276,1720 1H NMR (CDCl 3), δ (ppm): 3.85-3.88 (m, 4H), 4.28-4.31 (t, 2H), 6.55-6.58 (d, 1H), 6.94-7.02 (m, 2H), 7.11-7.17 (m, 1H), 7.23-7.25 (dd, 1H), 7.26-7.36 (d, 2H) .ESI-MS:340.1 (M+H) +B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-4-(3-benzenesulfonyl-1,2,2-ethoxyethyl acetate (I of 5-oxadiazole-2-oxide compound-4-) 1) with 3,4-two benzenesulfonyls-1,2, (0.37g is 1mmol) with I p for 5-oxadiazole-2-oxide compound 1(0.34g 1.2mmol) is dissolved in the 10ml tetrahydrofuran (THF) (THF), and (0.08ml 1.2mmol), gradually has muddy the generation to splash into 25% aqueous sodium hydroxide solution.Reaction solution is poured in the 100ml water, added 6N hydrochloric acid and transfer pH=7.(3 * 20ml) extractions add the saturated common salt washing, anhydrous magnesium sulfate drying after organic layer merges with ethyl acetate.After the filtration filtrate decompression is concentrated, the residue silica gel column chromatography, ethyl acetate-sherwood oil (60-90 ℃) mixed solution wash-out got white powder solid 0.51g, yield 76%, mp124-125 ℃ in 1: 6.IR(KBr,cm -1):3333,1724 1H?NMR(CDCl 3),δ(ppm):3.87(s,2H),4.40-4.90(m,4H),6.40-8.10(m,13H)ESI-MS:564.3(M+H) +
Embodiment 2a) preparation 4-(3-benzenesulfonyl-1,2, oxygen butanols (the I p of 5-oxadiazole-2-oxide compound-4-) 2) with 1, and the 4-butyleneglycol (0.9ml, 10mmol) with 3,4-two benzenesulfonyls-1,2, (0.73g 2mmol) is dissolved among the 15ml THF 5-oxadiazole-2-oxide compound, and (0.36ml 3mmol), gradually has muddy the generation to splash into 25% aqueous sodium hydroxide solution.React after 1 hour solid filtering.Concentrated filtrate adds 50ml water in resistates, (3 * 20ml) extracting twice add the saturated common salt washing once after organic layer merges, use anhydrous magnesium sulfate drying with ethyl acetate.After the filtration filtrate decompression is concentrated, the residue silica gel column chromatography, ethyl acetate-sherwood oil (60-90 ℃) mixed solution wash-out got white powder solid 0.48g, yield 76%, mp70-72 ℃ in 1: 4.IR (KBr, cm -1): 3353 1H NMR (CDCl 3), δ (ppm): 1.74-1.79 (m, 2H), 1.98-2.03 (m, 2H), 2.06 (s, 1H), and 3.76-3.78 (t, 2H), 4.47-4.79 (t, 2H), 7.61-7.64 (t, 2H), and 7.76-7.79 (t, 1H), 8.05-8.07 (d, 2H) .ESI-MS:315.2 (M+H) +B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-4-(3-benzenesulfonyl-1,2, oxygen butyl ester (I of 5-oxadiazole-2-oxide compound-4-) 2) with I p 2Be dissolved in the 15ml anhydrous methylene chloride, and adding DC (0.53g, 1.8mmol), the dicyclohexyl carbimide (DCC, 0.37g, 1.8mol), 4-N, several of N-Dimethylamino pyridines (DMAP).Stirring at room 2 hours, the adularescent precipitation generates.Filter, filtrate is concentrated, the residue silica gel column chromatography, ethyl acetate-sherwood oil (60-90 ℃) mixed solution wash-out got yellow oil 0.73g, yield 82% in 1: 9.IR (film, cm -1): 3320,1722 1H NMR (CDCl 3), δ (ppm): 1.82-1.88 (m, 2H), 1.90-1.95 (m, 2H), 3.83 (s, 2H), 4.23-4.25 (t, 2H), 4.41-4.43 (t, 2H), 6.54-6.58 (d, 1H), 6.87 (s, 1H), 6.93-7.00 (m, 2H), 7.12-7.14 (t, 1H), 7.22 (d, 1H), and 7.33-7.34 (m, 2H), 7.57-7.60 (t, 2H), 7.71-7.74 (t, 1H), 8.03-8.05 (d, 2H) .ESI-MS:614.0 (M+Na) +Embodiment 3a) preparation (3-benzenesulfonyl-1,2, oxygen-3-butanols (the I p of 5-oxadiazole-2-oxide compound-4-) 4) with reference to I p 2The preparation method make by 1,3 butylene glycol.Get white cotton-shaped solid, yield 77%, mp101-103 ℃ with 1: 1 ethyl acetate-sherwood oil (60-90 ℃) recrystallization.IR (KBr, cm -1): 3437 1H NMR (CDCl 3), δ (ppm): 1.30-1.32 (d, 3H), 1.67 (s, 1H), 1.92-2.08 (m, 2H), and 4.07-4.13 (m, 1H), 4.51-4.69 (m, 2H), 7.59-7.65 (t, 2H), and 7.73-7.79 (t, 1H), 8.04-8.07 (dd, 2H) .ESI-MS:315.1 (M+H) +B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-(3-benzenesulfonyl-1,2, oxygen-3-butyl ester (I of 5-oxadiazole-2-oxide compound-4-) 4) with reference to I 2The preparation method by I p 4Make.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got colorless oil, yield 82% in 1: 8.IR (film, cm -1): 3327,1722 1H NMR (CDCl 3), δ (ppm): 1.35-1.37 (d, 3H), 2.12-2.18 (m, 2H), 3.80 (s, 2H), 4.36-4.44 (m, 2H), 5.15-5.21 (m, 1H), 6.53-7.34 (m, 8H), 7.55-7.85 (m, 5H) .ESI-MS:614.0 (M+Na) +Embodiment 4a) preparation 2-[2-(3-benzenesulfonyl-1,2, the oxygen ethyl oxygen of 5-oxadiazole-2-oxide compound-4-)] ethanol (I p5) is with reference to I p 2The preparation method make by glycol ether.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got faint yellow oily thing, yield 80% in 1: 3.IR (film, cm -1): 3419 1H NMR (CDCl 3), δ (ppm): 2.19 (s, 1H), 3.50-3.80 (m, 4H), 3.80-4.00 (m, 2H), 4.50-4.70 (m, 2H), 7.61-8.13 (m, 5H) .ESI-MS:353.0 (M+Na) +B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-2-[2-(3-benzenesulfonyl-1,2, the oxygen ethyl of 5-oxadiazole-2-oxide compound-4-)] 2-ethoxyethyl acetate (I 5) with reference to I 2The preparation method by I p 5Make.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 83%, mp93-96 ℃ in 1: 3.IR(KBr,cm -1):3367,1740 1H?NMR(CDCl 3),δ(ppm):3.80-3.82(t,2H),3.85-3.86(m,4H),4.34-4.36(t,2H),4.50-4.52(t,2H),6.53-7.34(m,8H),7.58-8.07(m,5H).ESI-MS:630.0(M+Na) +
Embodiment 5a) preparation 3-(3-benzenesulfonyl-1,2, oxygen propylamine (the I p of 5-oxadiazole-2-oxide compound-4-) 8) with reference to I p 2The preparation method make by n-propyl alcohol amine.Methyl alcohol-chloroform column chromatography got faint yellow oily thing, yield 43% in 1: 20.IR (film, cm -1): 3410 1H NMR (CDCl 3), δ (ppm): 2.03-2.12 (m, 2H), 2.86 (s, 2H), 2.98-3.03 (t, 2H), 4.51-4.55 (t, 2H), 7.58-8.06 (m, 5H) .ESI-MS:300.0 (M+H) +B) preparation N-[3-(3-benzenesulfonyl-1,2, the oxygen propyl group of 5-oxadiazole-2-oxide compound-4-)]-2-(2,6-dichlorobenzene amido) phenylacetamide (I 8) with reference to I 2The preparation method by I p 8Make.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got the white powder solid in 3: 7, yield 83%, mp165-168 ℃ (dec), yield 71%.IR (KBr, cm -1): 3417,3296,1648 1H NMR (CDCl 3), δ (ppm): 2.10-2.27 (m, 2H), 3.45 (s, 1H), 3.56-3.59 (t, 2H), 3.78 (s, 2H), 4.52-4.54 (t, 2H), 6.50-7.34 (m, 8H), 7.63-8.09 (m, 5H) .ESI-MS:599.0 (M+Na) +Embodiment 6a) preparation 3-(4-phenyl-1,2, the anisole methyl alcohol (II p1) of 5-oxadiazole-2-oxide compound-3-) is with 3-methylol-4-phenyl-1,2,5-oxadiazole-2-oxide compound (0.25g, 1.3mmol) be dissolved in the 10ml methylene dichloride, add anhydrous pyridine (0.24ml, 3.4mmol) after, splash into thionyl chloride (0.25ml, 3.4mmol), reaction solution is yellow clear solution, stirred overnight at room temperature.Reaction solution is washed one time with the 40ml frozen water, and it is neutral being washed till water layer with saturated sodium bicarbonate aqueous solution, again with saturated common salt washing, dry organic layer.Filtering and concentrating gets orange-yellow oily thing.This product is dissolved among the 15ml DMF, and (0.2g, 1.6mmol), (1g, 7.2mmol) with a small amount of potassiumiodide, reaction is 3 hours under the room temperature for Anhydrous potassium carbonate for salicylic alcohol between adding.In reaction solution impouring water, and the usefulness ether (3 * 20ml) extractions, ether layer 20ml aqueous sodium hydroxide washes washes with water to neutrality again, after the saturated common salt washing, dry organic layer.Filter, filtrate is concentrated back column chromatography [3: 7 ethyl acetate-sherwood oils (60-90 ℃)] get orange red oily matter, get yellow solid 0.24g, yield 62%, mp66-68 ℃ after the vacuum-drying.IR (KBr, cm -1): 3460 1H NMR (CDCl 3), δ (ppm): 1.07 (s, 1H), 4.70 (s, 2H), 5.11 (s, 2H), 6.90-7.33 (m, 4H), 7.50-7.87 (m, 5H) .ESI-MS:321.2 (M+Na) +B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-3-(4-phenyl-1,2, anisole methyl esters (II of 5-oxadiazole-2-oxide compound-3-) 1) with reference to I 2The preparation method by II p 1Make.Methylene dichloride-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 75%, mp116-118 ℃ in 1: 2.IR (KBr, cm -1): 3417,3296,1648 1H NMR (CDCl 3), δ (ppm): 3.88 (s, 2H), 4.97 (s, 2H), 5.17 (s, 2H), 6.47-7.32 (m, 12H), 7.49-7.82 (m, 5H) .ESI-MS:576.3 (M+Na) +Embodiment 7a) preparation 4-(4-phenyl-1,2, anisole methyl alcohol (the II p of 5-oxadiazole-2-oxide compound-3-) 2) with reference to II p 1The preparation method make by salicylic alcohol.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got white solid, yield 69%, mp64-66 ℃ in 1: 4.IR (KBr, cm -1): 3353 1H NMR (CDCl 3), δ (ppm): 2.08 (s, 1H), 4.65 (s, 2H), 5.11 (s, 2H), 6.98-7.34 (q, 4H), 7.51-7.86 (m, 5H) .ESI-MS:321.2 (M+Na) +B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-4-(4-phenyl-1,2, anisole methyl esters (II of 5-oxadiazole-2-oxide compound-3-) 2) with reference to I 2The preparation method by II p 2Make.Methylene dichloride-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 71%, mp91-94 ℃ in 1: 2.IR (KBr, cm -1): 3448,1715 1H NMR (CDCl 3), δ (ppm): 3.86 (s, 2H), 5.12 (s, 2H), 5.14 (s, 2H), 6.55-7.35 (m, 12H), 7.54-7.88 (m, 5H) .FAB-MS:575.8 (M+1) *Embodiment 8a) preparation 2-(4-phenyl-1,2, anisole methyl alcohol (the II p of 5-oxadiazole-2-oxide compound-3-) 3) with reference to II p 1The preparation method make by neighbour-salicylic alcohol.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got white solid, yield 71%, mp82-86 ℃ in 1: 4.IR (KBr, cm -1): 3509 1H NMR (CDCl 3), δ (ppm): 2.28 (s, 1H), 4.56 (s, 2H), 5.19 (s, 2H), 6.96-7.35 (m, 4H), 7.53-7.81 (m, 5H) .ESI-MS:321.2 (M+Na) +B) (4-phenyl-1,2, the anisole methyl esters (II 3) of 5-oxadiazole-2-oxide compound-3-) is with reference to I for preparation 2-(2,6-dichlorobenzene amido) toluylic acid-2- 2The preparation method by II p 3Make.Methylene dichloride-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 65%, mp98-100 ℃ in 1: 2.IR (KBr, cm -1): 3357,1741 1H NMR (CDCl 3), δ (ppm): 3.78 (s, 2H), 5.09 (s, 2H), 5.10 (s, 2H), 6.50-7.34 (m, 12H), 7.48-7.82 (m, 5H) .ESI-MS:598.1 (M+Na) +Embodiment 9a) preparation 3-(3-phenyl-1,2, anisole methyl alcohol (the III p of 5-oxadiazole-2-oxide compound-4-) 1) with 3-methylol-4-phenyl-1,2, (1.0g 5.2mmol) is dissolved in the 30ml toluene 5-oxadiazole-2-oxide compound, refluxes 3 days.The pressure reducing and steaming solvent, resistates column chromatography [1: 15 ethyl acetate-sherwood oil (60-90 ℃)] yellow oil, after freezing faint yellow solid (3-phenyl-4-methylol-1,2,5-oxadiazole-2-oxide compound), refer again to II p 1The preparation method, ethyl acetate-sherwood oil (60-90 ℃) column chromatography got yellow oil, yield 60% in 1: 4.IR (film, cm -1): 3380 1H NMR (CDCl 3), δ (ppm): 1.59 (s, 1H), 4.70 (s, 2H), 5.23 (s, 2H), 6.92-7.35 (m, 4H), 7.48-7.93 (m, 5H) .ESI-MS:321.1 (M+Na) +B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-3-(3-phenyl-1,2, anisole methyl esters (III of 5-oxadiazole-2-oxide compound-4-) 1) with reference to I 2The preparation method by III p 1Make.Methylene dichloride-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 74%, mp132-135 ℃ in 1: 2.IR (KBr, cm -1): 3366,1739 1H NMR (CDCl 3), δ (ppm): 3.87 (s, 2H), 5.07 (s, 2H), 5.18 (s, 2H), 6.47-7.32 (m, 12H), 7.46-7.89 (m, 5H) .ESI-MS:598.2 (M+Na) +Embodiment 10 preparation 2-(2,6-dichlorobenzene amido) toluylic acid-(3-nitre oxygen methyl) phenyl ester (IV 1) will between the hydroxyl bromobenzyl (0.5g 2.67mmol) is dissolved in the 10ml acetonitrile, and (0.54g, acetonitrile solution 3.20mmol) have faint yellow muddy the generation to add the 5ml Silver Nitrate.Stirring reaction 48 hours, the elimination precipitation concentrates filtrate, adds the dissolving of 10ml methylene dichloride, the elimination insolubles, filtrate concentrates, and gets faint yellow oily thing 0.43g.It is dissolved in the 15ml anhydrous methylene chloride, add DC (0.9g, 3.04mmol), DCC (0.63g, 3.04mmol), DMAP number.Stirred overnight at room temperature, the adularescent precipitation generates.Filter, filtrate is concentrated, ethyl acetate-sherwood oil (60-90 ℃) column chromatography got yellow granular crystal 0.89g, yield 81%, mp85-88 ℃ in 1: 15.IR(KBr,cm -1):3372,3340,1737 1H?NMR(CDCl 3),δ(ppm):4.09(s,2H),5.40(s,2H),6.63-6.64(d,1H),6.77(s,1H),6.98-7.02(t,H),7.03-7.06(t,1H),7.13-7.22(m,3H),7.27-7.28(d,1H),7.35-7.38(m,3H),7.40-7.43(t,1H)ESI-MS:470.0(M+Na) +

Claims (9)

1. generalformula:
Figure A0110803000021
Wherein: R 1Represent O, NH; R 2Representative-(CH 2) n-, n=3-5; CH 2C ≡ CCH 2CH 2CH (CH 3) CH 2CH 2CH 2CH 2OCH 2CH 2-PhCH 2-(m, p).
2. general formula II compound
Figure A0110803000022
Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).
3. general formula III compound:
Figure A0110803000023
Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).
4. general formula IV compound:
5. the generalformula preparation method of claim 1, it is characterized in that: after the reaction of diclofenac sodium (DC-Na) and halohydrin again with the furazan oxynitride condensation that replaces, perhaps diclofenac (DC) and hydroxyl or amino furazan oxynitride (I p) condensation in the presence of dicyclohexyl carbimide (DCC)
Figure A0110803000032
Wherein: R 1Represent OH, NH 2R 2Representative-(CH 2) n-, n=3-5; CH 2C-≡ CCH 2CH 2CH (CH 3) CH 2CH 2CH 2CH 2OCH 2CH 2-PhCH 2-(m, p).
6. the general formula II compounds process for production thereof of claim 2 is characterized in that: furazan oxynitride (II p) condensation in the presence of DCC of DC and hydroxyl,
Figure A0110803000033
Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).
7. the general formula III compounds process for production thereof of claim 3 is characterized in that: furazan oxynitride (III p) condensation in the presence of DCC of DC and hydroxyl, Wherein: R 3Representative-PhCH 2-(o, m, p);-Ph-(m, p).
8. the general formula IV compounds process for production thereof of claim 4 is characterized in that: DC and nitre oxygen sylvan (IV p) condensation in the presence of DCC,
9. the formula I among the claim 1-4, II, III, IV compound are used to prepare anti-inflammatory, anodyne.
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US7883714B2 (en) 2002-07-03 2011-02-08 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
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US8304409B2 (en) 2002-07-03 2012-11-06 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
WO2006042387A1 (en) * 2004-10-21 2006-04-27 Cmax Otimizacão De Resultados S C Ltda Drugs derived from diclofenac containing no-donor heterocycles, composition and method of inflammation treatment
ITMI20132056A1 (en) * 2013-12-10 2015-06-11 Pharmaday Srl COMPOSITIONS FOR AFTE AND AFTOSE STOMATITIS TREATMENT
CN105367511A (en) * 2015-12-08 2016-03-02 辛衍雪 Pharmaceutical composition used for treating bone diseases
CN111606852A (en) * 2020-05-12 2020-09-01 中国药科大学 Nitric oxide donor type Netarsudil derivative and preparation method and application thereof
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