CN1144092A - Non-steroid anti-inflammatory agents capable of releasing nitric oxide, their preparing method and use - Google Patents
Non-steroid anti-inflammatory agents capable of releasing nitric oxide, their preparing method and use Download PDFInfo
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- CN1144092A CN1144092A CN 95109791 CN95109791A CN1144092A CN 1144092 A CN1144092 A CN 1144092A CN 95109791 CN95109791 CN 95109791 CN 95109791 A CN95109791 A CN 95109791A CN 1144092 A CN1144092 A CN 1144092A
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Abstract
The present invention provides a group of non-steroid antiinflammatory drugs (NSAID) capable of releasing nitric oxide and its new compound, i.e. nitrate of those drugs. Those NSAID include aspirin, indomethacin, naproxen, brufen, pirprofen, phenol pirprofen, flurbiprofen, ketoprofen and diclofenac sodium, and can be extensively used for antipyretic, analgesic and anti-inflammatory, and for preventing and curing angiocardiopathy and cerebrovascular disease. The new NSAID nitrate compound can release nitric oxide in vivo, and can resist the side effect of digestive tract resulted from NSAID self-body, so that it has better safety and more extensive application.
Description
The present invention relates to one group of novel nonsteroidal and-inflammatory drug that can discharge nitric oxide (NO), their preparation method and purposes.On-steroidal AID (NSAID) has significant antiinflammatory, antipyretic analgesic and anti thrombotic action, is the most widely used drug type.Because this class medicine stops prostaglandin to generate by suppressing Cycloxygenase, generally has the gastrointestinal toxicity effect, comprises gastric mucosa infringement and gastrorrhagia etc.Reducing the digestive tract toxic and side effects is to develop the basic principle of this kind new medicine in recent years.Main means comprise the enteric coatel tablets that exploitation absorbs without stomach, original shape medicine (the activation thing behind the formation liver metabolism), drug combination (as secreting medicine or exogenous prostaglandin) with gastric acid inhibitory, yet these measures do not improve the serious side effects of NSAID significantly, as gastric perforation and hemorrhage (.Ann.Intern.Med.114:307-319 such as Soll A.H, 1991).NSAID can be discharged the noval chemical compound that nitric oxide production molecule segment connects composition with a kind of, be considered to significantly to reduce even to eliminate fully the gastrointestinal tract toxic and side effects of NSAID.This chemical compound, keep gastric mucosal blood flow by discharging NO, stop leukocyte to be attached to the stomach microcirculation, antagonism is because NSAID suppresses the synthetic gastric mucosa infringement (Wallac J.L.Can.J.Physiol.Pharmacol.71:98--102,1993) that is produced of prostaglandin.According to the current paper report, the 4-nitre oxygen Ji Dingji fat of three kinds of NSAID (BTS-18322, ketoprofen and diclofenac) is synthetic.These chemical compounds have the anti-inflammatory activity identical with parent NSAID.But, the toxic and side effects of gastric damage is starkly lower than parent NSAID (Wallace, J.L etc., Gastroenterology 80:94-98,1994; Wallace, J.L etc., Eur.JPharmacol.257:249-255,1994; Cuzzolin L etc., Pharmacol.Res.29:89-97,1994; Life sci:55:p11-p18 such as Reuter B.k, 1994).Heavy dose is repeat administration repeatedly, and NSAID causes the infringement of significant small intestinal, perforation and dead, and the NSAID nitrate of same dosage does not cause small intestinal infringement Life sci.55:p11-p18 such as (, 1994) Reuter B.K.Except antipyretic-antalgic and antiinflammatory, NSAID has anti-thrombosis function by suppressing the generation of platelet prostaglandin (mainly being thromboxane).Widely used have an aspirin.Yet, as antithrombotic, preventing the cardiovascular and cerebrovascular disease aspect at aspirin, long-term prescription causes the toxic and side effects (as hemorrhage and perforation) of stomach to become the big obstacle that aspirin uses.A kind of nitrate derivatives of aspirin may reduce the gastrointestinal toxicity (the especially patient of long-term prescription) of aspirin greatly.In addition, this nitrate derivatives discharges NO, adheres to and assembles by suppressing platelet, increases the aspirin anti-platelet activity.Also direct coronary artery dilating of NO and cerebrovascular.Therefore, this aspirin nitrate derivatives has the prospect of using widely to the aspect that prevents and treats of cardiovascular and cerebrovascular disease.To the gastrointestinal protective effect, contain NO molecule segment according to NO with connecting one on the NSAID molecule.This new type NS AID nitrate enters release NO in back in the body, can resist the gastrointestinal tract toxic and side effects that is caused by NSAID itself.Britain Metgrove company once applied for world patent (PCT, patent No. WO94/04484) to the saturated nitrate of diclofenac.Wallace etc. close nitrate pharmaceutical research (Wallace.J.L etc., Currentawareness, Tips-Novenber 1994 Vol:15 405-406) were also arranged BTS-18322 and ketoprofen are full.The nitrate compound of other NSAID is not seen reported in literature so far.The invention provides the various nitrate compounds of aspirin, indometacin, naproxen, ibuprofen, phenol pyrroles sweet smell and pyrroles's sweet smell.The present invention also comprises the unsaturated nitrate compound of diclofenac, BTS-18322 and ketoprofen.The present invention also comprises the preparation method of unsaturated nitrate of the various nitrates of aspirin, indometacin, naproxen, ibuprofen, phenol pyrroles sweet smell and pyrroles's sweet smell and diclofenac, BTS-18322 and ketoprofen and their purposes.The one group of new NSAID nitrate compound that the object of the present invention is to provide the molecule segment that can discharge nitric oxide (NO) and NSAID structure to be connected to form.NO can discharge and resist the gastrointestinal toxicity that corresponding NSAID medicine produces in vivo.This group new type NS AID nitrate compound is expected to replace substance medicine NSAID, be used for antiinflammatory, analgesic, ease pain and prevent and treat cardiovascular and cerebrovascular vessel and peripheral blood vessel.The preparation method of new type NS AID nitrate compound of the present invention comprises: will contain the alcohol reaction of the NSAID of carboxyl and unit that one has halogen (Br, cl or I) and generate halogen-containing carboxylate, and then halogen will be converted into nitro ester; The nitrate compound that maybe will contain the NSAID of carboxyl and the unit alcohol reaction generation NSAID that contains nitro.Synthetic route is as follows: synthetic method one:
Synthetic method two:
Below be the embodiment of preparation The compounds of this invention, these embodiment also do not mean that limitation of the present invention.Synthetic (chemical compound 1) 1 of method one: embodiment 1,2-acetoxy-benzoic acid-3-nitre oxygen base propyl diester (nitrate), at aspirin (2.0g; 11.10mmol) benzole soln (40ml) in, add the 3-bromopropyl alcohol (1.85g, 13.31mmol) and concentrated sulphuric acid (43.5mg, 0.44mmol).This reactant liquor refluxes, and removes moisture content, adds 10%K after 1 hour
2CO
3(20ml), with ethyl acetate extraction (50ml * 3), acetic acid ethyl acetate extract is used 10%K after merging
2CO
3Wash (10ml * 1), washing (10ml * 1) and saturated NaCL aqueous solution are washed (10ml * 1).Acetic acid ethyl acetate extract anhydrous magnesium sulfate drying after washing filters, and is evaporated to driedly, and residue silica gel column chromatography, 9: 1 normal hexane-ethyl acetate mixed liquor eluting get that the 2-acetoxy-benzoic acid-3-bromopropyl ester (101) (0.98g)
1HNMR (300MH
2) (CDCL3): 2.30 (m, 2H); 2.36 (s, 3H); 3.52 (t, 2H); 4.43 (t, 2H); 7.10 (d, 1H); 7.32 (t, 1h); 7.58 (t, 1h); 8.01 (d, 1h) IR (cm
-1): 2963; 1769; 1723; 1607; 1452; 1254; 1194; 1082.2, in flask at the bottom of the garden, put into above-mentioned gained 2-acetoxy-benzoic acid-3-bromopropyl ester (101) (140mg; 0.46mmol) second eyeball solution (1ml).Drip AgNO then
3Solution (85mg, 0.50mmol are dissolved in 1.5ml second fine in).85 ℃ of heated and stirred reactions of above-mentioned reactant liquor 2 hours have yellow-green precipitate to produce in the reaction, remove by filter precipitation, and filtrate is concentrated into dried.Residue separates with silica gel column chromatography, gets 2-acetoxy-benzoic acid propyl diester (aspirin nitrate) (chemical compound 1 with 4: 1 normal hexane-ethyl acetate mixed liquor eluting; 128mg).
1HNMR (300MH
2) (CDCL
3): 2.20 (m, 2H); 2.35 (S, 3H); 4.40 (t, 2H); 4.61 (t, 2H); 7.12 (d, 1H); 7.33 (t, 1H); 7.60 (t, 1H); 8.01 (d, 1H) .IR (cm
-1): 2969; 2901; 1767; 1723; 1628; 1194; 1080; 860. synthetic (chemical compound 2) 1 of embodiment 2, Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid-3-nitre oxygen base propyl diester (ibuprofen nitrate), at Alpha-Methyl-4-(2-methyl-propyl) sodium phenylacetate (ibuprofen sodium salt) (2.0g, 8.76mmol) the benzene suspension in (40ml) add concentrated sulphuric acid (894mg, 9.11mmol), transfer pure clear solution to after this suspension stirred for several minute, in this solution, add 3-bromopropyl alcohol (1.46g:10.50mmol).This reaction mixture refluxed is removed moisture content, adds 10%K after 1 hour
2CO
3(20ml), with ethyl acetate extraction (50ml * 3), acetic acid ethyl acetate extract is used 10%K after merging
2CO
3Wash (10ml * 1); Washing (10ml * 1) and saturated NaCL aqueous solution are washed (10ml * 1).Ethyl acetate layer anhydrous magnesium sulfate drying after washing filters, be evaporated to dried, the residue silica gel column chromatography, 95: 5 normal hexane-ethyl acetate mixed liquor eluting get Alpha-Methyl-4-(2-methyl-propyl), and phenylacetic acid-3-bromopropyl ester (102) (2.01g)
1HNMR (300MH
2) (CDCL
3): 0.90 (d, 6H); 1.50 (d, 3H); 1.84 (m, 1H); 2.10 (m, 2H); 2.45 (d, 2H); 3.28 (t, 2H); 3.70 (g, 1H); 4.20 (m, 2H); 7.10 (d, 2H); 7.20 (d, 2H) .IR (cm
-1): 2957; 2868; 1738; 1512; 1464; 1215; 1163; 1094; 1022; 848.2, (2.01g drips AgNO in the fine solution of second 6.13mmol) (7ml) at Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid-3-bromopropyl ester (102)
3Solution (1.2g, 7.06mmol be dissolved in the 11ml acetonitrile), above-mentioned reactant liquor was in 85 ℃ of heated and stirred reactions 2 hours, remove by filter the yellow-green precipitate of generation, filtrate is concentrated into dried, residue separates with silica gel column chromatography, gets Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid-3-nitre oxygen base propyl diester " ibuprofen nitrate (chemical compound 2,1.81g) " with 9: 1 normal hexane-ethyl acetate mixed liquor eluting
1HNMR (300MH
2) (CDCL
3): 0.90 (d, 6H); 1.50 (d, 3H); 1.85 (m, 1H); 2.00 (m, 2H); 2.45 (d, 2H); 3.70 (g, 1H); 4.17 (m, 2H); 4.35 (t, 2H); 7.10 (d, 1H); 7.02 (d, 1H); 7.20 (d, 1H) .IR (cm
-1): 2957; 2870; 1738; 1632; 1281; 1165; Synthetic (chemical compound 3) 1 of 858. method two: embodiment 3: Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid-4-nitre oxygen base-butine (2) ester (the unsaturated nitrate of ibuprofen)), 1,4-crotonylene glycol (4g, 46.45mmol) be dissolved in (100ml) in the methane dioxide, in this solution, add t butyldimethylsilyl chloride (7.68g, 51.13mmol) and imidazoles (3.48g, 51.13mmol), this reactant mixture is removed precipitation at four hours after-filtration of stirring at room reaction, filtrate decompression is concentrated into dried, its residue separates with silica gel column chromatography, gets from 4: 1 n-hexane-ethyl acetate mixed liquor eluting that 1-tertiary butyl dimethyl Si base butine (2)-4-alcohol (103) (4.2g)
1HNMR (300MH
2) (CDCL
3): 0.10 (S, 6H); 0.90 (S, 9H); 4.30 (S, 2H); 4.35 (S, 2H) .2), the mid-acetic anhydride (9.13ml of flask at the bottom of a garden, 89.50mmol) and cool off with ice-water bath, in this cold acetic anhydride, drip colourless concentrated nitric acid (2.37ml, 51.35mmol), dripping the back reacted 15 minutes in ice-water bath, then this mixed liquor is added to 1-tertiary butyl dimethyl Si base butine (2)-4 alcohol (4.2g under the ice-water bath cooling, 22.34mmol) in, this reactant mixture reacts in ice-water bath and adds a small amount of ice after one hour, use dichloromethane extraction then three times (30ml * 3), extracting solution 10%NaHCO
3Aqueous solution is washed secondary (5ml * 2), water Xian is (5ml) once, saturated NaCL aqueous solution is (5ml) once, the dichloromethane extract anhydrous magnesium sulfate drying, remove by filter magnesium sulfate, filtrate is concentrated into dried, and residue separates with silica gel column chromatography, and 4: 1 normal hexane-eluent ethyl acetates get that 1-tertiary butyl dimethyl Si base-4-nitre oxygen base crotonylene (104) (3.1g)
1HNMR (300MH
2) (CDCL
3): 0.12 (S, 6H); 0.92 (S, 9H); 4.38 (S, 2H); 5.04 (S, 2H) .3), 1-tertiary butyl dimethyl Si base-4-nitre oxygen base crotonylene (the 104) (3.1g under the ice-water bath cooling, 12.65mmol) add in oxolane (30ml) solution and fluoridize tetra-n-butyl ammonium (9.8g, 37.72mmol), reactant mixture at room temperature reacted two hours then, reactant liquor is evaporated to dried, and its residue separates with silica gel column chromatography, gets with 2: 1 normal hexane-ethyl acetate mixed liquor eluting that 1-nitre oxygen base butine (2)-4-alcohol (105) is (1.1g).
1HNMR (300MH
2) (CDCL
3): 4.32 (S, 2H); 5.05 (S, 2H) .4). at Alpha-Methyl-4-(2-methyl-propyl) sodium phenylacetate (100mg, 0.44mmol) the benzene suspension in (20ml) add concentrated sulphuric acid (43.1mg, 0.44mmol), transfer pure clear solution to after this suspension stirred for several minute, in this solution, add 1-nitre oxygen base butine (2)-4-alcohol (105) (86.1g, 0.66mmol), this reactant refluxes, and removes moisture content, adds 10%K after 1 hour
2CO
3(10ml), use ethyl acetate extraction (20ml * 3) then, ethyl acetate is mixed and reuse 10%K
2CO
3Wash (5ml * 1) washing (5ml * 1) and saturated NaCl aqueous solution and wash (5ml * 1).The ethyl acetate layer anhydrous magnesium sulfate drying, remove by filter magnesium sulfate, filtrate decompression is concentrated into dried, and residue separates with silica gel column chromatography, gets Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid 2-nitre oxygen base-butine (2) ester (chemical compound 3) (88mg) with 9: 1 n-hexane-eluent ethyl acetates.
1HNMR (300MH
2) (CDCL
3): 0.90 (d, 6H); 1.50 (d, 3H); 1.86 (M, 1H); 2.46 (d, 2H); 3.74 (g, 1H); 4.70 (g, 2H); 5.00 (S, 2H); 7.10 (d, 2H); 7.20 (d, 2H). synthetic (chemical compound 4) 1-(4-chlorobenzoyl)-5-methoxyl group-2-methyl-indole-3-acetic acid (indometacin) (300mg of embodiment 4:1-(4-chlorobenzoyl)-5-methoxyl group-2-methyl-indole-3-acetic acid-4-nitre oxygen base butine (2) ester (the unsaturated nitrate of indometacin), 0.84mmol, 1-nitre oxygen base butine (2)-4-alcohol (105) (91.6mg, 0.70mmol), (28.1mg 0.23mmol) is dissolved in 5ml CH with 4-dimethylamino pyridine (DMAP)
2CL
2.1,3-dicyclohexylcarbodiimide (DCC) (172.7mg, 0.84mmol) join in the above-mentioned reactant liquor, this reactant liquor was room temperature reaction six hours, reactant mixture removes by filter precipitate, filtrate is concentrated into dried, and the residue silica gel column chromatography separates, and gets with 2: 1 normal hexane-ethyl acetate mixed liquor eluting that 1-(4-chlorobenzoyl)-5-methoxyl group-2-methyl-indole-3-acetic acid-4-nitre oxygen base-butine (2) ester (the unsaturated nitrate of indometacin) (chemical compound 4) (210mg)
1HNMR (300MH
2) (CDCL
3): 2.40 (S, 3H); 3.72 (S, 2H); 3.85 (S, 3H); 4.76 (S, 2H); 5.02 (S, 2H); 6.07 (M, 1H); 6.88 (D, 1H); 6.97 (d, 1H); 7.50 (d, 2H); 7.70 (d, 2H). embodiment 5:(S)-synthetic (chemical compound 5) of 6-methoxyl group-alpha-methyl-2-naphthalene acetic acid-4-nitre oxygen base-butine (2) ester (the unsaturated nitrate of naproxen).(S)-6-methoxyl group-alpha-methyl-2-naphthalene acetic acid (naproxen) (200mg, 0.87mmol), 1-nitre oxygen base-butine (2)-4-alcohol (105) (94.9mg, 0.72mmol) and 4-dimethylamino pyridine (DMAP) (29.1mg.0.23mmol) be dissolved in 5mlCH
2CL
2.1,3-dicyclohexylcarbodiimide (DCC) (178.9mg, 0.87mmol) join in the above-mentioned reactant liquor, this reactant liquor was room temperature reaction six hours, reactant mixture cool to room temperature after-filtration disgorging, filtrate is concentrated into dried, and the residue silica gel column chromatography separates, and gets with 3: 1 n-hexane-ethyl acetate mixed liquor eluting that (S)-6-methoxyl group-alpha-methyl-2-naphthalene acetic acid-4-nitre oxygen base-butine (2) ester (the unsaturated nitrate of naproxen) (chemical compound 5) (178mg)
1HNMR (300MH
2) (CDCL
3): 1.60 (d, 3H); 3.89 (M, 1H); 3.90 (S, 3H); 4.70 (M, 2H); 5.00 (S, 2H); 7.15 (d, 2H); 7.40 (d, 1H); 7.70 (t, 3H). parent NSAID medicine is except that comprising above-mentioned aspirin, ibuprofen, indometacin, naproxen in above-mentioned two methods, saturated and the unsaturated straight chain and side chain and the diclofenac that also comprise phenol pyrroles sweet smell and Pirprofen, the undersaturated straight chain of BTS-18322 and ketoprofen and side chain nitrate.The pure and mild double base alcohol in unit comprises the pure HORX of following structure, HOROH wherein: R=1-10 carbon saturated and unsaturated, the alkyl of straight chain and side chain; X=CL, Br, the oral back of I new type NS AID nitrate of the present invention activity in vivo is measured: 65 female CD-1 mices (body weight 21-26 gram) are divided into 13 groups (5 every group) at random.Be respectively the solvent control group; Indometacin and indometacin-4-nitro butine ester administration group (1.0mg/kg and 0.1mg/kg); Naproxen and naproxen-4-nitro butine ester administration group (10mg/kg and 1mg/kg); Ibuprofen and ibuprofen-4-nitro butine ester administration group (10mg/kg and 1mg/kg).Ibuprofen, indometacin, three kinds of original shape medicines of naproxen are bought from sigma company.The animal fasting is 15 hours before the experiment.10%PEG200 is as solvent, and various medicines are dissolved in earlier among the PEG200, add aquae destillata in the 10%PEG200 ratio under ultrasonic state then, make oral liquid.Each animal is irritated stomach respectively and gives control solvent or experiment medicine (1ml/kg body weight).After the administration 1 hour, broken end was got blood.Add 100 units heparin anticoagulants with every ml blood.Get the 0.3ml whole blood and add 2mM Ca
+ 2Iontophoresis agent A23187 3 μ l, after cultivating 30 minutes under 37 ℃ of temperature, centrifugal preparation blood plasma.Adopt U.S. Cayman company thromboxance B then
2(T * B
2) EIA measures medicine box and detect T * B in the plasma sample
2Content.Blood T * B
2Level reflection complete blood cell medium ring oxidase active.With Cayman T * B
2The EIA medicine contains measures whole blood T * B
2Content is not having to be 7.2ng/ml under the A23187 incentive condition.T * B after adding A23187
2Blood concentration is increased to 502.8 ± 83ng (x ± SE)/ml.Various medicines are to A23187 stimulation of whole T * B
2The inhibition activity that generates sees Table 1:
The result shows, more than the nitro butine ester of three kinds of NSAID after oral absorption, all have remarkable inhibition Cycloxygenase and produce the effect of prostaglandin metabolism product.And compare its inhibitory action with the prototype compound in various degree raising is all arranged.
| The experiment medicine | Dosage (mg/kg) | T×B 2Generate and suppress (%) |
| Indometacin | 1.0 | 94.3 |
| 0.1 | 54.6 | |
| Indometacin-4-nitro butine ester (chemical compound 4) | 1.0 | 37.9 |
| 0.1 | 16.8 | |
| Naproxen | 10.0 | 72.2 |
| 1.0 | 50.6 | |
| Naproxen-4-nitro butine ester (chemical compound 5) | 10.0 | 51.8 |
| 1.0 | 20.9 |
| Ibuprofen | 10.0 | ?75.4 |
| 1.0 | ?62.2 | |
| Ibuprofen-4-nitro butine ester (chemical compound 3) | 10.0 | ?64.1 |
| 1.0 | ?4.4 |
Claims (10)
1, one group of nitrate that can discharge the carboxylic nonsteroid anti-inflammatory drugs (NSAID) of nitric oxide molecule has following molecular structure:
Y-COO-R-ONO
2Wherein Y-COO-is carboxyl NSAID, R is the saturated or unsaturated straight or branched alkyl of 1-10 carbon, when Y-COO-is aspirin, indometacin, naproxen, ibuprofen, phenol pyrroles sweet smell and Pirprofen, R is the alkyl of the saturated or unsaturated straight or branched of 1～10 carbon, when Y-COO-was diclofenac, BTS-18322 and ketoprofen, R was the alkyl of the unsaturated straight or branched of 1～10 carbon.
2, that the NSAID nitrate of claim 1 is used for is analgesic, analgesia, antiinflammatory and control ischemic cardio cerebrovascular diseases.
3, the method for new type NS AID nitrate of preparation claim 1, the carboxyl that it is characterized by among the NSAID reacts with alcohol halogen-containing or that contain nitre oxygen base.
4,, it is characterized in that described halogen is Br, CL, I according to the preparation method of claim 3; Its reaction that changes into nitre oxygen base is to react with silver nitrate in acetonitrile solvent.
5, be converted in the method for nitrate (nitre oxygen base) according to the wherein pure hydroxyl of the method for claim 3 or 4, agents useful for same is the mixture of acetic anhydride and concentrated nitric acid.
6, the NSAID medicine in the claim 1 is meant aspirin, indometacin, naproxen, ibuprofen, phenol pyrroles sweet smell, Pirprofen, diclofenac, BTS-18322 and ketoprofen.
7, the method alcohol wherein according to claim 3 is following structure: HORX, HCROH. wherein: R=1-10 carbon saturated or unsaturated, the alkyl of straight or branched; X=CL, Br, I
8, with one preparation aspirin nitrate (2-acetoxy-benzoic acid-3-nitre oxygen base propyl diester) and the ibuprofen nitrate (Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid-3-nitre oxygen base propyl diester) of method in the description.
9, prepare the unsaturated nitrate of ibuprofen (Alpha-Methyl-4 (2-methyl-propyl) phenylacetic acid-4-nitre oxygen base-butine (2) ester) with method two in the description, the unsaturated nitrate of indometacin (1-(4-chlorobenzoyl)-5-methoxyl group-2-methyl-indole-3-acetic acid-4-nitre oxygen base-butine (2) ester and the unsaturated nitrate of naproxen ((S)-6-methoxyl group-alpha-methyl-2-naphthalene acetic acid-4-nitre oxygen base-butine (2) ester.
10, prepare aspirin nitrate (the basic ester of 2-acetoxy-benzoic acid nitre oxygen base alkane (alkene, alkynes)) with method in the description one or method two, naproxen nitrate ((the S)-6-methoxyl group-alpha-methyl-2-naphthalene acetic acid-basic ester of nitre oxygen base alkane (alkene, alkynes)), ibuprofen nitrate (the basic ester of Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid nitre oxygen base alkane (alkene, alkynes)), indometacin nitrate (1-(4-the chlorobenzoyl)-5-methoxyl group-2-methyl-indole-3-acetic acid-basic ester of 4-nitre oxygen base alkane (alkene, alkynes); Fragrant nitrate (the Alpha-Methyl-3-phenolic group-basic the ester of phenylacetic acid nitre oxygen base alkane (alkene, alkynes) of phenol pyrroles; Pirprofen nitrate (the basic ester of 3-chloro-4-(3-pyrrolin-1-yl) hydratropic acid nitre oxygen base alkane (alkene, alkynes)); The basic ester of diclofenac nitre oxygen base (alkene, alkynes); Flurbiprofen nitrate (Alpha-Methyl-3 fluoro-4-phenyl-basic ester of phenylacetic acid nitre oxygen base alkene (alkynes)); With ketoprofen nitrate (Alpha-Methyl-3-benzophenone base-basic ester of phenylacetic acid nitre oxygen base alkene (alkynes)).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95109791 CN1144092A (en) | 1995-08-25 | 1995-08-25 | Non-steroid anti-inflammatory agents capable of releasing nitric oxide, their preparing method and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95109791 CN1144092A (en) | 1995-08-25 | 1995-08-25 | Non-steroid anti-inflammatory agents capable of releasing nitric oxide, their preparing method and use |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011042690A (en) * | 1999-08-04 | 2011-03-03 | Nicox Sa | Naproxen nitroxyalkyl ester |
| CN107137387A (en) * | 2017-07-07 | 2017-09-08 | 中国科学技术大学 | A kind of synthetic method of aryl propionic non-steroid antiphlogistic |
-
1995
- 1995-08-25 CN CN 95109791 patent/CN1144092A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011042690A (en) * | 1999-08-04 | 2011-03-03 | Nicox Sa | Naproxen nitroxyalkyl ester |
| CN107137387A (en) * | 2017-07-07 | 2017-09-08 | 中国科学技术大学 | A kind of synthetic method of aryl propionic non-steroid antiphlogistic |
| CN107137387B (en) * | 2017-07-07 | 2020-05-12 | 中国科学技术大学 | Synthetic method of aryl propionic acid non-steroidal anti-inflammatory drug |
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