CN103333084B - 3,3'-azobis[6-(butanoyloxy)benzoic acid] and preparation method and application thereof - Google Patents
3,3'-azobis[6-(butanoyloxy)benzoic acid] and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses 3,3'-azobis[6-(butanoyloxy)benzoic acid] and a preparation method and application thereof. The method comprises the following steps of: synthesizing a symmetric compound 1,3-dibutanoyloxy-2-carbonyl propane by taking 1,3-dihydroxy acetone as a synthesis raw material, and reducing the 1,3-dibutanoyloxy-2-carbonyl propane into dibutyrate 1,3-dibutanoyloxy-2-carbonyl propane; and carrying out an ester condensation reaction between dibutyrate 1,3-dibutanoyloxy-2-carbonyl propane and 1,3-dibutanoyloxy-2-carbonyl propane in the presence of EDCI serving as a dehydrating agent and DMAP serving as a catalyst to generate the target compound 3,3'-azobis[6-(butanoyloxy)benzoic acid]. After being orally taken into colon, 3,3'-azobis[6-(butanoyloxy)benzoic acid] is decomposed to release 5-aminosalicylic acid which acts together with butyric acid on the colon focus to realize a treatment effect.
Description
Technical field
The invention belongs to medicament for resisting ulcerative colitis technical field, relate to 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] and its preparation method and application.
Background technology
Ulcerative colitis (ulcerative colitis, UC) is a kind of chronic nonspecific inflammation of mainly involving rectum, mucous membrane of colon, and clinical manifestation is mainly diarrhoea, stomachache, mucosanguineous feces etc.; Its pathological change is the tissue reaction of filling the air, and comprises the non-opposite sex of holding such as ulceration, crypt abscess, thin vessels inflammation, goblet cell minimizing and all kinds cell infiltration and shows.Can occur, as erythema nodosum, sacroiliitis, ankylosing spondylitis, sclerosing cholangitis, autoimmune hemolytic anemia etc. with various autoimmune disease.Course of disease protracted course of disease reaches the more than ten years, even decades have the possibility of canceration.Its sickness rate is about 3 ~ 14.3/10 ten thousand in American-European countries, China over nearly 10 years case more than 20,000.Epidemiologic data is pointed out, and the sickness rate of UC has the trend increased year by year at home and abroad.This sick cause and onset of disease mechanism is still not very clear; Be difficult to cure, very easily recur; The course of disease is tediously long, has a strong impact on patient body Health and Living quality, is classified as one of modern difficult treatment by the World Health Organization.
Summary of the invention
The problem that the present invention solves is to provide a kind of 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] and preparation method thereof and with for the preparation of the pharmaceutical use for the treatment of ulcerative colitis.
The present invention is achieved through the following technical solutions:
A kind of compound, this compound is 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid], and its structural formula is:
Compound 3, the preparation method of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid], comprises following operation:
By butyryl oxide and 3,3 '-azo two (6-hydroxy-benzoic acid) uses base catalysis esterification, generates 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid];
Or by butyryl oxide and 3, two (6-hydroxy-benzoic acid) heating reflux reaction of 3 '-azo, generates 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid].
Described base catalysis esterification comprises the following steps:
3,3 '-azo two (6-hydroxy-benzoic acid) is dissolved in anhydrous propanone, adds the butyryl oxide being dissolved in anhydrous propanone, then adds triethylamine, stirring at room temperature, fully after reaction, and vacuum concentration solvent; With water and extraction into ethyl acetate residue, get organic layer, use HCl, NaHCO respectively
3washing, regulates pH to neutral, concentrates with anhydrous sodium sulfate drying; Residue dissolved and is splined on silicagel column, carrying out wash-out using the mixed solution of sherwood oil and ethyl acetate as elutriant, collecting product, steaming after desolventizing, obtain 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid].
Described sherwood oil and ethyl acetate are mixed to get elutriant according to the volume ratio of 10:1 ~ 5.
Described heating reflux reaction comprises the following steps:
3,3 '-azo two (6-hydroxy-benzoic acid) is dissolved in butyryl oxide, is heated to 81 ~ 82 DEG C of back flow reaction, fully after reaction, by petroleum ether, filter, obtain 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid].
3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] is preparing the application in medicament for resisting ulcerative colitis.
Described medicament for resisting ulcerative colitis is the medicine lowering mucosa injury exponential sum disease activity index.
Described medicament for resisting ulcerative colitis is the medicine reducing intestinal tissue MPO level.
Compared with prior art, the present invention has following useful technique effect:
Provided by the invention 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA), that the collaborative prodrug of 5-aminosalicylic acid and butyric acid is to treat UC, when it is oral enter colon after, be decomposed into 5-aminosalicylic acid and butyric acid, then the two acting in conjunction plays therapeutic action in colon lesions position.
Provided by the invention 3, the preparation method of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid], by 1,3-otan becomes Lipase absobed compound 1 with butyryl oxide, 3-bis-butyryl acyloxy-2-carbonyl propane, then reduced generation 1,3-bis-butyryl acyloxy-2-hydroxy propane; Adopt EDCI as dewatering agent, DMAP as catalyzer, by dibutyrate 1,3-bis-butyryl acyloxy-2-hydroxy propane and 1,3-bis-butyryl acyloxy-2-hydroxy propane generation ester condensation reaction, synthesising target compound.Its synthetic route is simple, and productive rate is high.
Provided by the invention 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid], in the preparation of medicament for resisting ulcerative colitis, effectively should can lower mouse mucosa injury exponential sum and improve DAI degree, reduces intestinal tissue MPO level.Compare with Sodium propanecarboxylate mixture control group with use 5-aminosalicylic acid, be all better than 5-aminosalicylic acid and Sodium propanecarboxylate mixture control group at multiple Testing index and DAI index.
Accompanying drawing explanation
Fig. 1 is 3, the effect diagram that 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) changes Mouse Weight;
Fig. 2 is 3, and 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) is to the effect diagram of mouse DAI index variation;
Fig. 3 is 3, and 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) is to the effect diagram of mouse weight index of the colon;
Fig. 4 is 3, and 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) is to the effect diagram of mouse Colon mucosa injury index;
Fig. 5 is 3, and 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) organizes the effect diagram of MPO activity to mouse Colon.
Embodiment
The invention provides 5-aminosalicylic acid and butyric acid works in coordination with prodrug 3, the effect of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) and preparation and resistive connection enteritis.Below in conjunction with specific embodiment, the present invention is described in further detail, and the explanation of the invention is not limited.
Adopt 3,3 '-azo two (6-hydroxy-benzoic acid) is carrier, is combined with ester bond with butyric acid, builds collaborative prodrug treatment UC, to realizing Synergistic treatment UC.Adopt two kinds of synthesis technique synthesising target compounds 3 respectively, 3 '-azo two [6-(butyryl acyloxy) phenylformic acid].After synthesising target compound, by Fourier's infrared analysis, nucleus magnetic hydrogen spectrum analysis and mass spectrum determination target compound structure; Investigate the effect of OLZ-BA anti-mouse experimental colitis on this basis.
1,3, the synthesis of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA)
3, two [6-(butyryl acyloxy) phenylformic acid] synthetic route of 3 '-azo:
Synthetic route one:
Synthetic route two:
1.13, the synthesis (route one) of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid]:
1g(0.0033mol) 3,3 '-azo two (6-hydroxy-benzoic acid) is dissolved in 20mL anhydrous propanone, the 1.44g(0.0099mol being dissolved in 10mL anhydrous propanone is added in this heterogeneous solution) butyryl oxide, be added dropwise to 2.0mL triethylamine, stirring at room temperature.Detection reaction progress, until 3,3 '-azo two (6-hydroxy-benzoic acid) reacts completely, vacuum concentration solvent.With water and extraction into ethyl acetate residue, get organic layer, use 1mol/LHCl, 1mol/LNaHCO respectively
3washing, regulates pH to neutral, concentrates, obtain colorless oil with anhydrous sodium sulfate drying.Residue is dissolved and is splined on silicagel column, sherwood oil: ethyl acetate (10:1) is as eluent, and ethyl acetate ratio increases progressively.Collect product, solvent evaporated under reduced pressure, obtains 3, and two [6-(butyryl acyloxy) phenylformic acid] 0.8g of 3 '-azo is safran pulverulent solids; Productive rate is 54.4%.Its fusing point is 216.0 DEG C.
1.23, the synthesis (route two) of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid]:
7.0g(23mmol) 3,3 '-azo two (6-hydroxy-benzoic acid) is dissolved in 36.4g(0.23mol) butyryl oxide 81-82 DEG C backflow.Monitoring extent of reaction, until 3,3 '-azo two (6-hydroxy-benzoic acid) reacts completely, and by petroleum ether, filters, obtains 3, and two [6-(butyryl acyloxy) phenylformic acid] 9.0g of 3 '-azo is safran pulverulent solids; Productive rate is 95.7%.Its fusing point is 216.0 DEG C.
Qualitative identification: at sherwood oil: ethyl acetate: under the development system of triethylamine=2mL: 1mL: 1 droplet, silica GF254 fluorescent plate under 253.7nm ultraviolet wavelength on a display spot, and have fluorescence, Rf value is 0.67.
The comparison of two kinds of synthetic methods:
Synthetic route one: adopt base catalysis esterification, react and carry out at normal temperature, condition is easy to control.But product is more difficult, need pickling, alkali cleaning, and need column chromatography for separation to purify, reduce productive rate.
Synthetic route two: adopt heating in water bath for reaction raw material to 81-82 DEG C, stir 2h; More for convenience, purify without the need to column chromatography for separation, productive rate is higher in aftertreatment.
1.33, the structure elucidation of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid]:
1) 3, two [6-(butyryl acyloxy) phenylformic acid] FTIR spectrum of 3 '-azo
At 2974.03cm
-1, 2665.44cm
-1, 2352.99cm
-1for ν CH on butyryl radicals
3-, ν-CH
2-, ν-CH
2-absorption peak; At 3458.13cm
-1, 1755.10cm
-1for the absorption peak of ester bond C=O key; At 1143.71cm
-1the asymmetrical stretching vibration peak of ester bond C-O-C, therefore prove have ester bond to generate; At 1294.15cm
-1, 1228.57cm
-1for the charateristic avsorption band of phenyl ring.
2) 3, two [6-(butyryl acyloxy) phenylformic acid] proton nmr spectra of 3 '-azo
Proton nmr spectra (DMSO) ownership is as follows:
δ 0.8828 (t, 3H) is three hydrogen on butyryl radicals α C; 1.0026 (t, 3H) are two hydrogen on another butyryl radicals α C; δ 1.5287 (m, 2H) is two hydrogen on butyryl radicals β C; δ 1.6844 (m, 2H) is two hydrogen on another butyryl radicals β C; δ 2.1590 (t, 2H) is two hydrogen on butyryl radicals γ C; δ 2.6027 (t, 2H) is two hydrogen on another butyryl radicals γ C; δ 7.4672 (d, 2H), δ 8.2097 (d, 2H), δ 8.4267 (s, 2H) is benzene ring hydrogen.
3) 3, two [6-(butyryl acyloxy) phenylformic acid] mass spectrum of 3 '-azo
m/z443.1
In sum, gained compound is 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid].
Said synthesis route is simple, and productive rate is high.
Below, select the mouse TNBS colitis model similar to acute human and active ulcerativ e colitis, further illustrate 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) is for the therapeutic action of ulcerative colitis.
2,3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) is to the therapeutic action of mouse TNBS colitis
The foundation of 2.1 mouse TNBS colitis model
Mouse experiment room routine is raised, and 48 mouse are divided into 4 groups immediately, often organizes 12.With picric acid by each group of mouse label respectively, weigh and record successively.Before modeling, fasting 12h, freely drinks water.By the slight micro-anesthesia of ether of the mouse of fasting 12h, insert in mouse Colon with blunt nosed gastric perfusion needle per anum, head end is about about 4cm apart from anus, slow injected slurry volume mark is the 50% ethanolic soln 0.1ml of the TNBS of 2.5%, after keeping mouse to be inverted the downward posture 30s of head, put back to normal in cage raising; Normal group mouse gives normal saline enema.Administration is started after modeling 24h.
2.2 experiment grouping and observation index
Normal group, model control group, 5-aminosalicylic acid and Sodium propanecarboxylate mixture (5-ASA+BA) control group and 3 are established in experiment, two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) group of 3 '-azo, gastric infusion, every day is administered once, successive administration 5 days.Normal and model control group all gives the CMC-Na aqueous solution of 0.5% of equivalent.5-aminosalicylic acid and Sodium propanecarboxylate mixture (5-ASA+BA) control group dosage are [100mg (5-ASA)+40mg (Sodium propanecarboxylate)] kg
-1; 3, two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) dosage 240mgkg of 3 '-azo
-1.After modeling the 6th day, put to death by the mouse anesthesia of fasting 12h, back of the body position is fixed.Mouse cuts belly open, takes out total colectomy.Longitudinally cut off colon along mesentery, rinse out intestinal contents with cold saline, the situation of visual inspection colonic mucosal injury.
Colonic mucosal injury index score standard: 0 point: not damaged; 1 point: without ulcer, contrafluxion; 2 points: have ulcer; 3 points: only a position exists ulcer and inflammation; There is ulcer and inflammation in 4 points: two multiple positions; 5 points: ulcer is more than 2cm.
Measure total colectomy length and weigh, calculating weight index of the colon (total colectomy weight/total colectomy length).Get colonic pathological change site tissue one piece ,-20 DEG C of preservations, measure MPO, SOD and GSH-PX activity and MDA and GSH content, measure and all undertaken by testing cassete method.
Other observation index: 1) add up each group of dead mouse situation; 2) Mouse Weight change is observed; 3) observe mouse disease activity index (Disease activity index, DAI), DAI standards of grading are in table 1; Wherein stool in mice is occulted blood to measure and is adopted o tolidine, and criterion is in table 2.
Table 1 mouse DAI standards of grading
Table 2 o tolidine measures fecal occult blood result of determination
| Result | Phenomenon |
| Normally | Still do not develop the color after adding reagent 2min |
| Occult blood+ | After adding reagent 10s, just aobvious light blue, become blue gradually |
| Occult blood ++ | After adding reagent, just aobvious light blue, turn blue brown gradually |
| Occult blood +++ | Blue brown is shown immediately after adding reagent |
? mPO determination of activity: adopt dianisidine method.Get mouse Colon tissue to weigh, add the pH7.0PBS of 9 times of volumes, the centrifugal 30min of 4 DEG C of homogenate 30s, 12000rpm, abandons supernatant liquor, takes off the HTAB solution that layer tissue 50mg adds 0.5%, 4 DEG C of homogenate 30s, 12000rpm pelleted by centrifugation 15min.Get supernatant liquor 0.1m, add ODD solution 2.9ml, mix fast, in 460nm METHOD FOR CONTINUOUS DETERMINATION 3min, calculate per minute absorbancy changing value.Being defined in the amount that per minute under 25 DEG C of conditions decomposes 1 micromole's superoxide is a unit of enzyme activity.
The enzymic activity of 100 μ l sample tissue units is:
Note: 1molL
-1h
2o
2absorbancy change be 1.13 × 10
4, so according to definition, 1 unit MPO is 1 μm of olL
-1h
2o
2absorbance, be 1.13 × 10
-2.
2.3 statistical analysis
Experimental data is with means standard deviation
represent, statistical method adopts t check analysis.P<0.05 is that difference has statistical significance.
2.4 experimental result
1) on the impact of mouse survival situation: Normal group 12, TNBS group 7,5-aminosalicylic acid and Sodium propanecarboxylate mixture (5-ASA+BA) control group 6,3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) organizes 8.
2) on the impact of Mouse Weight change: each group Mouse Weight result of variations as described in Figure 1.After modeling, Mouse Weight declines, and after pharmacological agent, body weight is gone up gradually.3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) is organized Mouse Weight and is recovered the most obvious.
3) on the impact of mouse DAI index: after TNBS modeling, mouse all there will be bloody stool, just rare, movable, feed minimizing after 24h, the situations such as weight loss.The DAI index variation of each group of mouse as shown in Figure 2, TNBS group mouse DAI index obviously raises, modeling is basicly stable after 3 days, after drug treatment, DAI index significantly reduces, 3, two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) impact on DAI index of 3 '-azo is better than 5-aminosalicylic acid and Sodium propanecarboxylate mixture (5-ASA+BA) control group.
4) on the impact of mouse weight index of the colon and colonic mucosal injury index
Mucous hyperemia oedema is there is in mouse Colon after the process of TNBS bowel lavage, intestines wall thickening, there are necrosis and ulceration in surface, and compared with normal group, the mucosa injury index of TNBS group significantly increases (P < 0.01) and shows that Mouse Ulcerative Colitis Model is set up good; Compared with TNBS group, 3, the mucosa injury index that 3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) is organized significantly declines (P < 0.01).Some animals occurs that the damage of colon transmural is downright bad, and enteron aisle exists hardening, distortion or narrow in various degree.Colon lengths shortens, and its weight index of the colon significantly increases (P < 0.01), and compared with TNBS group, the mouse weight index of the colon of administration group declines (P < 0.01) all to some extent.Experimental result as shown in Figure 3, Figure 4.
In Fig. 3, ##P < 0.01 compared with Normal group; * * P < 0.01 compared with modeling group; Δ P < 0.05 compared with 5-ASA and BA mixing group;
In Fig. 4, ##P < 0.01 compared with Normal group; * * P < 0.01 compared with modeling group; Δ P < 0.05 compared with 5-ASA and BA mixing group;
5) on the impact of MPO activity in mouse Colon tissue
Mouse Colon, after the process of TNBS bowel lavage, obviously raises because MPO in the colons such as inflammation, oedema, ulceration is active.Compared with normal group, in TNBS group mouse Colon tissue, MPO is active significantly increases (P < 0.01); Compared with TNBS group, 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) organizes the active significantly decline (P < 0.01) of MPO in mouse Colon tissue.Experimental result as shown in Figure 5.
In Fig. 5, ##P < 0.01 compared with Normal group; * * P < 0.01 compared with modeling group; Δ Δ P < 0.01 compared with 5-ASA and BA mixing group.
To sum up, experimental result shows, and provide 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] (OLZ-BA) effectively can lower Rat mucosal damage index and improve DAI degree, reduces colon MPO level.
Claims (6)
1. a compound, is characterized in that, this compound is 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid], and its structural formula is:
2. compound 3, the preparation method of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid], is characterized in that, comprise following operation:
By butyryl oxide and 3,3 '-azo two (6-hydroxy-benzoic acid) uses base catalysis esterification, generates 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid];
Described base catalysis esterification comprises the following steps:
3,3 '-azo two (6-hydroxy-benzoic acid) is dissolved in anhydrous propanone, adds the butyryl oxide being dissolved in anhydrous propanone, then adds triethylamine, stirring at room temperature, fully after reaction, and vacuum concentration solvent; With water and extraction into ethyl acetate residue, get organic layer, use HCl, NaHCO respectively
3washing, regulates pH to neutral, concentrates with anhydrous sodium sulfate drying; Residue dissolved and is splined on silicagel column, carrying out wash-out using the mixed solution of sherwood oil and ethyl acetate as elutriant, collecting product, steaming after desolventizing, obtain 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid];
Or by butyryl oxide and 3, two (6-hydroxy-benzoic acid) heating reflux reaction of 3 '-azo, generates 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid]
Described heating reflux reaction comprises the following steps:
3,3 '-azo two (6-hydroxy-benzoic acid) is dissolved in butyryl oxide, is heated to 81 ~ 82 DEG C of back flow reaction, fully after reaction, by petroleum ether, filter, obtain 3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid].
3. compound 3 as claimed in claim 2, the preparation method of 3 '-azo two [6-(butyryl acyloxy) phenylformic acid], it is characterized in that, described sherwood oil and ethyl acetate are mixed to get elutriant according to the volume ratio of 10:1 ~ 5.
4.3,3 '-azo two [6-(butyryl acyloxy) phenylformic acid] is preparing the application in medicament for resisting ulcerative colitis.
5. apply as claimed in claim 4, it is characterized in that, described medicament for resisting ulcerative colitis is the medicine lowering mucosa injury exponential sum disease activity index.
6. apply as claimed in claim 4, it is characterized in that, described medicament for resisting ulcerative colitis is the medicine reducing intestinal tissue MPO level.
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| CN101610670A (en) * | 2006-11-03 | 2009-12-23 | 萨利克斯药品公司 | The preparation and the purposes of 2-hydroxyl-5-phenylazobenzoic acid derivatives |
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Non-Patent Citations (2)
| Title |
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| Bacterial Reduction as Means for Colonic Drug Delivery: Can Other Chemical Groups Provide an Alternative to the Azo Bond?;Sigal Saphier, et al.;《J. Med. Chem.》;20121119;第55卷;10781-10785 * |
| 赖俊英.偶氮类结肠靶向高分子药物的合成、生物降解和释药性能的研究.《中国优秀博硕士学位论文全文数据库(博士) 工程科技I辑》.2006,(第07期),B016-20. * |
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Effective date of registration: 20200910 Address after: Room 10101, unit 1, building 3, No. 69, Keji 2nd Road, hi tech Zone, Xi'an City, Shaanxi Province Patentee after: MEDICINE Research Institute OF SHAANXI PHARMACEUTICAL HOLDING COOPERATION Address before: 710075 No. two, No. 69, hi tech Zone, Shaanxi, Xi'an Patentee before: Shaanxi pharmaceutical holding group new drug technology development Co.,Ltd. |
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