CN1844121A - Antipyretic analgesic and anti-arthritis nonsteroidal compound and its pharmaceutical compositions - Google Patents
Antipyretic analgesic and anti-arthritis nonsteroidal compound and its pharmaceutical compositions Download PDFInfo
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- CN1844121A CN1844121A CN 200610013211 CN200610013211A CN1844121A CN 1844121 A CN1844121 A CN 1844121A CN 200610013211 CN200610013211 CN 200610013211 CN 200610013211 A CN200610013211 A CN 200610013211A CN 1844121 A CN1844121 A CN 1844121A
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Abstract
The invention relates a group of compounds having formula (I) and their use as medicaments for non-steroidal analgesic analgesia, anti-arthritis, and protecting gastrointestinal tract mucous membrane. The invention also discloses the pharmaceutical compositions containing the compounds of formula (I), wherein R1, R2, R3 and X are defined in the specification.
Description
Technical field
The invention belongs to autoimmunization and regulate technical field of pharmaceuticals, in particular, the pharmaceutical composition and the purposes that the present invention relates to a kind of new compound and preparation method thereof and contain this compound.
Background technology
For a long time, NSAID (non-steroidal anti-inflammatory drug) such as Asprin, be widely used in treatments such as analgesic, analgesia and resisting rheumatoid disease, but because unsatisfactory curative effect and common gi tract and Toxicity of Kidney are restricted this class medicinal application, especially to such as suffering from disease such as rheumatic arthritis, the patient that need take medicine for a long time is more like this.These pharmacological actions of NSAID (non-steroidal anti-inflammatory drug) may to carry out the biosynthetic cyclooxygenase of prostaglandin(PG) relevant with blocking-up gi tract and renal tissue arachidonic acid.Suppressing cyclooxygenase is the main mechanism of most of NSAID (non-steroidal anti-inflammatory drug), is diseases such as prevention, treatment asthma and anaphylaxis and suppress the 5-lipoxygenase.Recent study shows that prostaglandin(PG) is not the factor that directly causes leucocyte chemotaxis, and belongs to the leukotriene B of arachidonic acid metabolite
4(LTB
4) be that a kind of intensive causes the material from cell chemotaxis.Arachidonic acid generates various leukotrienes under the catalysis of 5-lipoxygenase, cause acute and chronic inflammation.The cyclooxygenase-2 inhibitors class medicine that has now gone on the market does not suppress to produce the 5-lipoxygenase of various leukotrienes under effective inhibition cyclooxygenase-2 activity concentration, also can not block the generation of this metabolic pathway product.In fact because this type of medicine has suppressed arachidonic acid and also just might cause more substrate through the metabolism of cyclooxygenase approach,, cause the synthetic increase of various leukotrienes by the lipoxygenase pathway metabolism.Compound of the present invention is the common inhibitor of cyclooxygenase and 5-lipoxygenase, promptly keeps the curative effect of cyclooxygenase-2 inhibitors, has avoided again causing various untoward reactions by leukotriene.
Summary of the invention
It is the new cyclooxygenase and the common inhibitor of 5-lipoxygenase that one object of the present invention has been to provide a kind of nonsteroidal new compound.
Another object of the present invention is to provide a kind of pharmaceutical composition, and it is made up of said composition nonsteroidal new compound and one or more pharmaceutically acceptable carriers, vehicle or thinner as activeconstituents.
A further object of the present invention has been to provide the application of nonsteroidal new compound aspect preparation treatment ntipyretic analgesic medicine.
The present invention further discloses the nonsteroidal new compound and has been used for the treatment of application in the arthritis medicine in preparation.Simultaneously, the present invention also discloses the nonsteroidal new compound is used for protecting gastrointestinal tract mucous medicine in preparation application.
The present invention is achieved by the following technical programs:
A kind of compound with general formula (I) structure:
R wherein
1Be C
1-6Alkyl; For example methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, n-pentyl or the like.R
2, R
3Be C
1-4Alkyl can be identical or different; For example methyl, ethyl, propyl group, butyl; X is that halogen comprises fluorine, chlorine, bromine, iodine.Preferred R
1Be propyl group or butyl, R
2=R
3The identical methyl that is; X is the chlorine or bromine atom.
The prepreerence compound of the present invention is R
1Be butyl, R
2And R
3Be methyl, X is the chlorine atom.Its chemical name is: 6-(4-chloro-phenyl-)-2, and 2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate nitric acid butyl ester, i.e. Xia Mian formula (II) compound:
The major technique of this compound is characterised in that:
A. infrared absorption spectrum is about 1730,1620 and 1281cm
-1Characteristic spectrum belt is arranged;
B. thermogravimetric differential thermal analysis endothermic transition is at about 105-115 ℃;
C.
1H nuclear magnetic resonance spectrum (CDCl
3Be solvent) have following characteristic peak (ppm): δ: 1.30 (6H, 2 two-CH of pyrrolizine ring
3Hydrogen), 1.76 (4H, the two-CH in nitric acid butyl ester 2 ' .3 ' position
2-hydrogen), 2.86 (2H, 1-CH of pyrrolizine ring
2-hydrogen), 3.54 (2H, 5-CH
2The hydrogen of COO-), 3.74 (2H, 3-CH of pyrrolizine ring
2-hydrogen), 4.15 (2H, 1 ' of nitric acid butyl ester-CH
2-hydrogen), 4.45 (2H, 4 ' of nitric acid butyl ester-CH
2-hydrogen), 7.04-7.26 (9H, on the phenyl ring-hydrogen of CH-).
D.
13C nuclear magnetic resonance spectrum (CDCl
3Be solvent) have a following characteristic peak (ppm): 27.97 (2 two-CH of pyrrolizine ring
3Carbon), 31.39 (on 5 on the pyrrolizine ring-CH
2The carbon of-CO-), 64.04 (1 '-OCH of nitric acid butyl ester
2-carbon), 72.43 (4 '-CH of nitric acid butyl ester
2ONO
2Carbon), 124.70-131.53 (on the phenyl ring=CH-carbon), 134.65 (carbon that connect chlorine on the phenyl ring), 170.68 (carbon of C=O).
F. powder x-ray diffraction its use the Cu-Ka radiation, about 30.78, about 29.88, about 26.66, about 25.66, about 24.54, about 22.62, about 21.40, about 20.98 about 20.68, about 18.74, about 16.74, about 13.20, about 11.78, about 9.30 and about 5.86 the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent.
G. mass spectrum: M
+496.2.
The present invention further provides the method for a kind of preparation formula (I) compound; This method comprises:
A. in the presence of dimethyl formamide, compound IV and sodium methylate react salify, and then with 1,4-dibromo alkylation reaction makes (III); Described 1,4-dibromo alkyl comprises: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, n-pentyl or the like, and preferred 1,4-dibromopropane or 1,4-dibromobutane.
B. compound (III) and Silver Nitrate are reacted (I):
R wherein
1, R
2, R
3, identical in X definition and claims.
Be the example preparation method of Ming Dynasty style (I) compound furtherly with formula (II) compound below.
The synthetic route of formula of the present invention (II) compound comprises following two kinds of methods:
Method one:
Formula (II) compound is with 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate (IV ') be raw material, with sodium methylate reaction salify, in the presence of dimethyl formamide and 1, the 4-dibromobutane react 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate bromo butyl ester (v); With compound (v) with Silver Nitrate react 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate nitric acid butyl ester (II).
Method two:
VII
The present invention also can be in the presence of sulfuric acid, nitric acid, after the 4-bromobutanol nitration reaction compound (VII), with compound IV ' reactant salt, preparation formula (II).
The present invention further provides and contained the pharmaceutical composition of formula (I) compound as activeconstituents; It comprises target compound (I) and one or more pharmaceutically acceptable carriers, vehicle or thinner as activeconstituents.
At this, contain the formed pharmaceutical composition of typical compound II effective constituent of the present invention in order to show the practicality of target compound (I), to provide below.
Preferred compound of the present invention (II) is normally taken with the form of pharmaceutical composition, can oral or non-oral administration, perhaps with the oral or non-oral administration of composition (as tablet, sustained release preparation, the capsule) safety that forms with pharmaceutically acceptable carrier, vehicle and other additive.When oral administration, composition can be mixed with tablet or capsule.For the preparation combination of oral medication can adopt lactose or starch to do carrier, gelatin, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone etc. are suitable wedding agents or become an agent.Can select starch or Microcrystalline Cellulose for use as disintegrating agent, often with talcum powder, santocedl, stearin, calcium stearate or magnesium etc. are as suitable antiadhesives and lubricant.For example, can prepare tablet by the compacting wet granular.Activeconstituents and carrier and optionally with a disintegration additive composition mixture; the aqueous solution of this mixture and tackiness agent; alcohol or aqueous alcohol solution carry out granulating in suitable device; dried particles adds other disintegrating agent subsequently, and lubricant and antisticking agent are with this mixture compressing tablet.
Compound of the present invention (II) is effective in quite wide dosage range.For example the dosage of taking every day can be in the scope of the about 0.5mg-10mg of per kilogram of body weight.In adult's treatment, dosage range once or is several times taken preferably 100mg-500mg/d/ people.The dosage of the actual compound of taking should be decided according to relevant situation by the doctor, these situations comprise by curer's physical state, the person's of choosing route of administration, age, body weight, patient are to the individual reaction of medicine, severity of patient's symptom or the like, therefore above-mentioned dosage range is not to limit the scope of the invention by any way.
The present invention further provides and contained the application that formula (I) compound is used to prepare non-steroidal antipyretic-antalgic and arthritis, the gastrointestinal tract mucous medicine of protection aspect.
The inventor discovers; compound of the present invention not only can antipyretic-antalgic and arthritis; but also have the gastrointestinal tract mucous and toxic characteristics of reduction of protection; at this in order to show the practicality of target compound (I); provide the pharmacological experimental data of typical compound of the present invention (II) below, and concrete pharmacodynamics and toxicity test result be summarized as follows:
One, pharmacodynamics test:
1, compound on Carrageenan of the present invention causes the swollen restraining effect (arthritis test) of rat foot:
Compound on Carrageenan of the present invention cause rat foot swollen restraining effect arranged, test-results shows, compound of the present invention is 25,50 and during 100mg/kg in dosage, respectively at swollen the rising of rat foot all being had obvious restraining effect (P＜0.01) in 0.5,1,2,3 and 4 hour after the administration, positive control drug nimesulide (50mg/kg) has identical restraining effect (P＜0.01).
2, compound of the present invention is to the analgesic activity (acetic acid twisting test) of mouse:
Test-results shows, the oral compound of the present invention of mouse, at dosage is 25,50 and during 100mg/kg, the mouse pain that Dichlorodiphenyl Acetate causes all has restraining effect in various degree, compare (P＜0.05,0.05 and 0.01) with model group, suitable with contrast medicine nimesulide (50mg/kg) effect.
3, compound of the present invention is to the refrigeration function (endotoxin pyrogenic) of rabbit:
Test-results shows that rabbit filling stomach gives compound 50 of the present invention and 100mg/kg, all can suppress rabbit and raise (P＜0.05), and restraining effect continues 1～2 hour, with suitable with contrast medicine nimesulide (50mg/kg) effect.
4. compound of the present invention is to the influence of rat stomach intestinal mucosa:
Test-results shows, the oral compound of the present invention of rat is 100,300 and during 1000mg/kg at dosage, and the table mucous membrane is not seen ecchymosis, erosion and ulcer in stomach, the intestines, with blank group indifference.
Two, toxicity test:
Mouse with peak concentration, oral administration gavage of maximum administration volume compound 2g/kg of the present invention after, the mental status is good, autonomic activities is normal, breathes, heart rate is normal, observes a week continuously, body weight gain is normal, does not see any toxic reaction, the no phenomena of mortality.Therefore, the medium lethal dose LD of compound gastric infusion of the present invention
50＞2g/kg.
Figure of description
Fig. 1 is compound of the present invention (I) structural formula;
Fig. 2 is compound of the present invention (II) infrared absorpting light spectra;
Fig. 3 is compound of the present invention (II) thermogravimetric differential thermal analysis endothermic transition figure;
Fig. 4 is compound of the present invention (II)
13The C nmr spectrum;
Fig. 5 is compound of the present invention (II) powder x-ray diffraction figure;
Fig. 6 is compound of the present invention (II) nmr spectrum;
Fig. 7 is compound of the present invention (II) mass spectrum.
Embodiment
Further specify the preparation of formula of the present invention (I) compound below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Wherein compound (IV), (VI) preparation method are with reference to Tetrahedron 1999.5145-5156.(VII) preparation method is with reference to Chem.Pharm.Bull 41 (6) 1049-1054.Except as otherwise noted, in this article, temperature be meant centigradetemperature (℃), room temperature is meant about 18-23 ℃.
Embodiment 1:
6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate bromo butyl ester (preparation v):
50 milliliters of analytical pure methyl alcohol are put in 250 milliliter of four neck reaction flask, under the stirring and refluxing, added 1.5 gram sodium Metal 99.5s, back flow reaction 10 minutes is reduced to room temperature; Add 7.5 gram (0.02mol) 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate (IV) reacted 30 minutes; 50-60 ℃ of underpressure distillation be to doing, and adds that 50 milliliters of dimethyl formamides and 12.9 grams (0.06mol) heavily steam 1, the 4-dibromobutane, and room temperature reaction is after 24 hours, and 100 ℃ of underpressure distillation get oily to doing.Adopting 200 order silicagel columns to analyse method, is developping agent with normal hexane and 1: 1 ratio of ether, gets 7-8 gram light yellow solid (v), yield 60-70%, fusing point 89-92 ℃.
HNMR (CDCl
3) δ: 1.29 (6H, 2 two-CH of pyrrolizine ring
3Hydrogen), 1.77-1.94 (4H, two-CH in the middle of the butyl
2-hydrogen), 2.85 (2H, 1-CH of pyrrolizine ring
2-hydrogen), 3.41 (2H, connect bromine-CH
2-hydrogen), 3.54 (2H, 5-CH of pyrrolizine ring
2The hydrogen of COO-), 3.74 (2H, connect nitrogen-CH
2-hydrogen), 4.15 (2H, become ester-COOCH
2-hydrogen), 7.04-7.26 (9H, on the phenyl ring-hydrogen of CH-).
Embodiment 2:
6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2, the preparation of 3-dihydro-pyrrolizine-5-acetate nitric acid butyl ester (II):
In 250 milliliter of four neck reaction, add 50 milliliters of tetrahydrofuran (THF)s and 8 gram (0.015mol) (v), stirring and dissolving under the room temperature.Restrain (0.023mol) Silver Nitrates with 4 and be dissolved in 30 milliliters of acetonitriles, add in 250 milliliter of four neck reaction flask, reaction is after 24 hours under the room temperature, and adding 1 restrains (0.006mol) Silver Nitrate and continues to react 24 hours under the room temperature, and 50-60 ℃ of underpressure distillation gets oily to dried.Adopting 200 order silicagel columns to analyse method, is developping agent with normal hexane and 7: 3 ratio of ether, gets 4 grams (II), yield 40%, fusing point 105-107 ℃.
HNMR (CDCl
3) δ: 1.30 (6H, 2 two-CH of pyrrolizine ring
3Hydrogen), 1.76 (4H, the two-CH in nitric acid butyl ester 2 ' .3 ' position
2-hydrogen), 2.86 (2H, 1-CH of pyrrolizine ring
2-hydrogen), 3.54 (2H, 5-CH
2The hydrogen of COO-), 3.74 (2H, 3-CH of pyrrolizine ring
2-hydrogen), 4.15 (2H, 1 ' of nitric acid butyl ester-CH
2-hydrogen), 4.45 (2H, 4 ' of nitric acid butyl ester-CH
2-hydrogen), 7.04-7.26 (9H, on the phenyl ring-hydrogen of CH-).Infrared absorption spectrum is about 1730,1620 and 1281cm
-1Characteristic spectrum belt is arranged.
Embodiment 3:
6-(4-bromophenyl)-2,2-dimethyl-7-phenyl-2, the preparation of 3-dihydro-pyrrolizine-5-acetate bromo propyl ester (III):
50 milliliters of analytical pure methyl alcohol are put in 250 milliliter of four neck reaction flask, under the stirring and refluxing, added 1.5 gram sodium Metal 99.5s, back flow reaction 10 minutes is reduced to room temperature; Add 8.5 gram (0.02mol) 6-(4-bromophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate (VI) reacted 30 minutes; 50-60 ℃ of underpressure distillation be to doing, and adds that 50 milliliters of dimethyl formamides and 12 grams (0.06mol) heavily steam 1, the 4-dibromopropane, and room temperature reaction is after 24 hours, and 100 ℃ of underpressure distillation get oily to doing.Adopting 200 order silicagel columns to analyse method, is developping agent with normal hexane and 1: 1 ratio of ether, gets 6 gram light yellow solids, and yield 70%, crude product do not need purifying, directly drop into the next step.
Embodiment 4:
6-(4-bromophenyl)-2,2-dimethyl-7-phenyl-2, the preparation of 3-dihydro-pyrrolizine-5-acetate propyl nitrate (I):
In 250 milliliter of four neck reaction, add 50 milliliters of tetrahydrofuran (THF)s and 6 gram (0.015mol) 6-(4-bromophenyl)-2 under the room temperature, 2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate bromo propyl ester, stirring and dissolving.Restrain (0.023mol) Silver Nitrates with 4 and be dissolved in 30 milliliters of acetonitriles, add in 250 milliliter of four neck reaction flask, reaction is after 24 hours under the room temperature, and adding 1 restrains (0.006mol) Silver Nitrate and continues to react 24 hours under the room temperature, and 50-60 ℃ of underpressure distillation gets oily to dried.Adopting 200 order silicagel columns to analyse method, is developping agent with normal hexane and 7: 3 ratio of ether, gets 3.5 grams (I), yield 44%, fusing point 102-105 ℃.
Embodiment 5:4-bromine nitric acid butyl ester (VII) preparation:
In the reaction of 250 milliliter of four neck, add 28 gram nitric acid (90%, 0.4mol), be cooled to 0 ℃, add 43.59 gram sulfuric acid (98%, 0.4mol), react after 1 hour, add 30.6 and restrain 4-bromobutanols (0.2mol), reacted 3 hours, ice is separated, ether extraction, dry, reclaim ether, get 31.2 gram 4-bromine nitric acid butyl ester oil, yield 84%, crude product does not need purifying, directly drops into the next step.
Embodiment 6:
6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2, the preparation of 3-dihydro-pyrrolizine-5-acetate nitric acid butyl ester (II):
50 milliliters of analytical pure methyl alcohol are put in 250 milliliter of four neck reaction flask, under the stirring and refluxing, added 1.5 gram sodium Metal 99.5s, back flow reaction 10 minutes is reduced to room temperature; Add 7.5 gram (0.02mol) 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate (IV '), reacted 30 minutes; 50-60 ℃ of underpressure distillation dissolved with 50 milliliters of dimethyl formamides to doing, and adds 7.9 grams (0.04mol) (VII), and room temperature reaction is after 24 hours, and 100 ℃ of underpressure distillation get oily to doing.Adopting 200 order silicagel columns to analyse method, is developping agent with normal hexane and 1: 1 ratio of ether, gets 4 grams (II), yield 40%, fusing point 105-107 ℃.
In order to explain enforcement of the present invention more fully, provide following example of formulations.These embodiment explain rather than limit the scope of the invention.Preparation can adopt the activeconstituents of any one compound among the present invention.
Every tablet preparation that contains the 100mg activeconstituents is as follows:
Consumption/1000 weight concentration (%)
Compound (II) 100g 40.0
Microcrystalline Cellulose 35mg 25.0
Starch 45mg 28.0
Polyvinylpyrrolidone 7.5g 3.0
Sodium starch glycolate 5g 2.0
Magnesium Stearate 1.25mg 0.5
Talcum powder 3.75g 1.5
Amount to 250g 100.0
Activeconstituents and carboxymethyl starch sodium salt, starch and Mierocrystalline cellulose thorough mixing are sieved, polyvinylpyrrolidonesolution solution is mixed with above-mentioned powder, sieve, make wet granular, add Magnesium Stearate and talcum powder, mixing, compressing tablet then in 50-60 ℃ of drying.
Every capsule contains the capsular of 100mg activeconstituents and is prepared as follows:
Consumption/1000 capsules weight concentration (%)
Compound (II) 100g 40.0
Microcrystalline Cellulose 35mg 25.0
Starch 45mg 28.0
Polyvinylpyrrolidone 7.5g 3.0
Carboxymethyl starch sodium salt 5g 2.0
Magnesium Stearate 1.25mg 0.5
Talcum powder 3.75g 1.5
Amount to 250g 100.0
Activeconstituents and carboxymethyl starch sodium salt, starch and Mierocrystalline cellulose thorough mixing are sieved, polyvinylpyrrolidonesolution solution is mixed with above-mentioned powder, sieve, make wet granular, add Magnesium Stearate and talcum powder, mixing, the snap fit capsule of packing in 50-60 ℃ of drying.
Claims (10)
1, a kind of compound with general formula (I) structure:
R wherein
1Be C
1-6Alkyl;
R
2, R
3Be identical or different C
1-4Alkyl;
X is a halogen.
2, compound as claimed in claim 1, wherein R
1Be propyl group or butyl, R
2=R
3Be methyl, X is the chlorine or bromine atom.
3, compound as claimed in claim 1 or 2, wherein this compound is 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate nitric acid butyl ester.
4, compound as claimed in claim 3, wherein, the constitutional features of this compound is:
A. infrared absorption spectrum is about 1730,1620 and 1281cm
-1Characteristic spectrum belt is arranged;
B. thermogravimetric differential thermal analysis endothermic transition is at about 105-115 ℃;
C. nuclear magnetic resonance spectrum (CDCl
3Be solvent) have following characteristic peak (ppm) a: δ: 1.30,1.76,2.86,3.54,3.74,4.15,4.45,7.04-7.26; The 1H nuclear magnetic resonance spectrum;
D.
13C nuclear magnetic resonance spectrum (CDCl
3Be solvent) have a following characteristic peak (ppm): 27.97,31.39,64.04,72.43,124.70-131.53,134.65,170.68;
E. powder x-ray diffraction its use the Cu-Ka radiation, about 30.78, about 29.88, about 26.66, about 25.66, about 24.54, about 22.62, about 21.40, about 20.98 about 20.68, about 18.74, about 16.74, about 13.20, about 11.78, about 9.30 and about 5.86 the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent;
F. mass spectrum: M
+496.2.
5, a kind of method that is used to prepare the described compound of claim 1-3, this method comprises:
A. in the presence of dimethyl formamide, compound IV and sodium methylate react salify, and then with 1,4-dibromo alkylation reaction makes (III);
B. compound (III) and Silver Nitrate are reacted (I):
6, a kind of pharmaceutical composition, it contains as defined any one compound of the claim 1-3 of activeconstituents and one or more pharmaceutical excipients.
7, composition as claimed in claim 6, wherein said compound are 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate nitric acid butyl ester.
8, any defined non-steroid compound is used for the treatment of the application of antipyretic-antalgic, anti-arthritic object space face among the claim 1-3 in preparation.
9, any defined compound is used for protecting the application of gastrointestinal tract mucous medicine among the claim 1-3 in preparation.
10, use as claimed in claim 8 or 9, compound wherein is 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate nitric acid butyl ester.
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| CN102464660A (en) * | 2010-11-05 | 2012-05-23 | 天津药物研究院 | 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate-butyl nitrate crystal, and preparation method and application thereof |
| CN102464660B (en) * | 2010-11-05 | 2013-12-11 | 天津药物研究院 | 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-pyrrolizine-5-acetate-butyl nitrate crystal, and preparation method and application thereof |
| CN102464659B (en) * | 2010-11-05 | 2014-01-15 | 天津药物研究院 | Licopyrinobuter compound crystal forms, preparation method, and use thereof |
| CN103172634A (en) * | 2011-12-21 | 2013-06-26 | 天津药物研究院 | Method for preparing 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizinone-5-acetic acid-4'-bromo-butyl ester |
| CN103172634B (en) * | 2011-12-21 | 2015-09-30 | 天津药物研究院 | 6-(4-chloro-phenyl-)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrroles mile piperazine-5-acetic acid-4 ' preparation method of-bromine butyl ester |
| CN103709168A (en) * | 2012-10-09 | 2014-04-09 | 天津药物研究院 | Crystallization morphology of 6-(4-chlorophenyl)-2, 2-dimethyl-7-phenyl-2, 3-dihydro-pyrrolizinone-5-acetate nitric acid butyl ester |
| CN105250221A (en) * | 2014-07-14 | 2016-01-20 | 天津药物研究院 | Licopyrinobuter dry emulsion and preparation method thereof |
| CN105250221B (en) * | 2014-07-14 | 2018-06-19 | 天津药物研究院 | A kind of Licopyrinobuter dried emulsifier and preparation method thereof |
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| CN100545162C (en) | 2009-09-30 |
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