CN106265677B - A kind of pharmaceutical composition and its application preventing and treating ulcerative colitis - Google Patents
A kind of pharmaceutical composition and its application preventing and treating ulcerative colitis Download PDFInfo
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- CN106265677B CN106265677B CN201610876703.XA CN201610876703A CN106265677B CN 106265677 B CN106265677 B CN 106265677B CN 201610876703 A CN201610876703 A CN 201610876703A CN 106265677 B CN106265677 B CN 106265677B
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- ulcerative colitis
- quinoline
- hydroxyl
- benzoyl
- mesalazine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
Abstract
The invention discloses a kind of pharmaceutical compositions and its application for preventing and treating ulcerative colitis; the composition is prepared by active constituent and pharmaceutically acceptable auxiliary material; the active constituent includes 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3; 4- dihydro -1H- quinoline-2-one; it can improve microcirculation after being combined with mesalazine; inhibit inflammatory reaction; repairing ulcer; to achieve the effect that prevent and treat ulcerative colitis; and it is safe and reliable; it has no toxic side effect, is more suitable for the maintenance therapy of ulcerative colitis.
Description
Technical field
The invention belongs to pharmaceutical technology fields, in particular to a kind of pharmaceutical composition for preventing and treating ulcerative colitis
And its application.
Background technique
Ulcerative colitis is a kind of colon that the cause of disease is not still fully aware of and rectum chronic nonspecific inflammation disease,
Lesion is confined to colorectal mucosa and submucosa.Lesion multidigit also may extend to colon descendens or even whole in sigmoid colon and rectum
A colon.The disease sees any age, but common with 20~45 years old.Clinical manifestation: general to rise in addition to small number of patients onset is hurried
Sick slow, the state of an illness differs in weight.Symptom is discharged the excrement containing blood, purulence and mucus, is often accompanied by paroxysmal colon based on diarrhea
Spasmic pain, and it is tenesmus, alleviation can be obtained after defecation.Light-duty patient symptom is slighter, and daily diarrhea is less than 5 times.It is heavy
Daily diarrhea is watery diarrhea or bloody stool, abdominal pain is heavier, there is heating paresthesia, and body temperature can be more than 38.5 DEG C, and pulse frequency is greater than at 5 times or more
90 beats/min；Onset is hurried, and progression of the disease is rapid, and the amount of diarrhea is big, frequent hematochezia.Body temperature is increased up to 40 DEG C, and serious person occurs complete
Body poisoning symptom；With the passing of time disease is not cured, may occur in which syntexis, anaemia, dystrophia, weak etc.；Some patientss have parenterally performance,
Such as erythema nodosum, iritis, chronic active hepatitis and small pericholangitis.
Ditto, clinically the drug for the treatment of of ulcerative colitis is broadly divided into following a few classes: glucocorticoids, amino water
Poplar acids, immunosuppressor, antibiotic and some biological agents such as infliximab, adalimumab etc., but have not
With the toxic side effect of degree, such as: glucocorticoid easily causes obesity, and TNF-a monoclonal antibody can cause patient skin to be not suitable with symptom etc.,
Drug price is high simultaneously, and patient is difficult to long term maintenance therapy.Salicylazosulfapyridine is current clinical most common Western medicine, is suitable for
Moderate, slight and Patients With Ulcerative Colitis, are decomposed into sulfapryidine and 5-aminosalicylic acid after oral, to knot in the intestine
Intestines intestinal tissue has special affinity, plays anti-inflammatory effect.However, by having 10%~40% after instructing the oral mesalazine of dosage
Patient occur nausea, indigestion, headache, leucocyte decline etc. adverse reactions, occasionally have and cause arthralgia, fash, albuminuria
And the reaction such as pancreatitis, with the extension of the course of disease and treatment time, the patient of more than half has to stop controlling because of side effect
New therapeutic agent is treated or seeks, therefore the medicine clinical application is limited.The Small side effects of mesalazine, but its curative effect one
As, it can only be as the adjuvant therapy medicaments of ulcerative colitis.Therefore, study and develop a kind of toxic side effect it is small, to exedens
Colitis has the drug of good therapeutic effect, this is with important economic significance and social effect.
CN105237474A discloses 6- hydroxyl -7- sweet-smelling formacyl quinolinones compound and its application, such compound
It can be used to treat or prevent various diseases relevant to estrogen function, such as: osteoporosis, cancer, especially breast cancer, ovary
Cancer, osteosarcoma and carcinoma of endometrium.Currently, in terms of still there is prevention and treatment ulcerative colitis without this kind of compound of document report
Bioactivity.
Summary of the invention
In view of the deficiencies in the prior art, that it is an object of the invention to a kind of toxic side effects is small, cheap, to exedens knot
Enteritis has the pharmaceutical composition and its application of good therapeutic effect.
In order to achieve the object of the present invention, inventor is finally obtained as follows by a large number of experiments research and unremitting effort
Technical solution:
A kind of pharmaceutical composition preventing and treating ulcerative colitis, by active constituent and the preparation of pharmaceutically acceptable auxiliary material
At the active constituent includes 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline -
2- ketone.
Active compound component 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3 according to the present invention,
4- dihydro -1H- quinoline-2-one, pharmaceutically acceptable salt class include the conventional non-toxic salts formed by inorganic or organic acid.Often
The nontoxic salts of rule include being originated from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, the salt of nitric acid etc., Yi Jiyou
Organic acids such as acetic acid, propionic acid, succinic acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,
Pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2- acetyl oxygen
Base-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, the preparation such as trifluoracetic acid
Salt.
Preferably, the pharmaceutical composition of prevention and treatment ulcerative colitis, active constituent therein include (1) 6- hydroxyl as described above
Base -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one, and (2) mesalazine.
It is further preferred that preventing and treating the pharmaceutical composition of ulcerative colitis as described above, active constituent therein is by (1)
6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one, and (2) mesalazine group
At.
Still further preferably, the pharmaceutical composition of ulcerative colitis is prevented and treated as described above, wherein 6- hydroxyl -7- [2-
(4- morpholine base oxethyl) benzoyl] weight ratio of -3,4- dihydro -1H- quinoline-2-one and mesalazine is (3~20): 1.
Still further preferably, the pharmaceutical composition of ulcerative colitis is prevented and treated as described above, wherein 6- hydroxyl -7- [2-
(4- morpholine base oxethyl) benzoyl] weight ratio of -3,4- dihydro -1H- quinoline-2-one and mesalazine is (5~10): 1.
In highly preferred embodiment of the invention, the pharmaceutical composition of ulcerative colitis is prevented and treated as described above, wherein 6-
The weight ratio of hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one and mesalazine is
5∶1。
The pharmaceutical composition of prevention and treatment ulcerative colitis of the present invention, wherein 6- hydroxyl -7- [2- (4- morpholinyl ethoxy
Base) benzoyl] -3,4- dihydro -1H- quinoline-2-one as active constituent carried out relevant animal test in a manner of stomach-filling, it ties
Fruit drug is significant through gastrointestinal absorption, therefore the pharmaceutical composition can be oral preparation.The wherein oral preparation packet
Include tablet, capsule, granule.It should be noted that according to the common process of formulation art, those skilled in the art holds very much
Easily 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one can be connect in pharmacy
The auxiliary material received is prepared into common oral preparation, such as granule, tablet, capsule.Wherein, acceptable accessory package in pharmacy
Include filler, disintegrating agent, adhesive, corrigent, lubricant etc..The filler is selected from the following one or more: pre-
Gelling starch, lactose, mannitol and microcrystalline cellulose；The disintegrating agent is selected from the following one or more: carboxymethyl starch
Sodium, crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose；The adhesive selected from the following one
Kind is a variety of: starch slurry, hydroxypropyl cellulose solution, povidone solution；Lubricant one or two selected from the following:
Magnesium stearate, talcum powder.
In addition, by a large amount of animal experiments show compound of the present invention individually or combination mesalazine stomach-filling after,
It can make the bright significant decrease of colonic mucosa general form Injury score of ulcerative colitis mouse and rat.Therefore, of the invention
Another be designed to provide a kind of pharmaceutical applications, it may be assumed that 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,
Application of the 4- dihydro -1H- quinoline-2-one in the drug of preparation prevention and treatment ulcerative colitis.6- hydroxyl -7- [2- (4- morpholinyl
Ethyoxyl) benzoyl] active ingredient compositions of -3,4- dihydro -1H- quinoline-2-one and mesalazine burst in preparation prevention and treatment
Application in the drug of ulcer colitis.
Compared with prior art, 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline
Quinoline -2- ketone prevents and treats the significant in efficacy of ulcerative colitis, especially can be obviously improved the general feelings of rat with after mesalazine combination
Condition increases rat weight, improves microcirculation, inhibits inflammatory reaction, repairing ulcer, to reach prevention and treatment ulcerative colitis
Effect, and it is safe and reliable, it has no toxic side effect, is more suitable for the maintenance therapy of ulcerative colitis.
Detailed description of the invention
Fig. 1 is the DAI appraisal results on the 6th of 1 each group mouse of embodiment, wherein series 1 is Normal group, series 2 is mould
Type control group, series 3 are compound low dose group, and series 4 is compound high dose group.
Specific embodiment
Following embodiment further describes effete test embodiment and preparation embodiment, embodiment of the invention and is only used for illustration
Purpose does not limit the scope of the invention, while the obvious change that those of ordinary skill in the art are made according to the present invention
It is also contained within the scope of the invention.
Embodiment 1:6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one pair
The influence of Mouse Ulcerative Colitis Model is tested
Healthy adult KM mouse 32, male, 22 ± 2g of weight are randomly divided into following four groups: Normal group, model
Control group, compound low dose group, drug high dose group.Normal group freely drinks distilled water, remaining each group is freely drunk
5% dextran sulfate sodium aqueous solution 6d manufactures mouse colitis model.During modeling, Normal group and model control group are every
Day stomach-filling physiological saline；Compound is low, the daily stomach-filling 30 of high dose group, 60mg/kg/d 6- hydroxyl -7- [2- (4- morpholinyl second
Oxygroup) benzoyl] -3,4- dihydro -1H- quinoline-2-one, it is each primary in the morning, afternoon and evening.
During test, the performance such as the daily state of mind, mobility, hair for observing mouse weighs mouse weight, acquisition
Stool, judges stool, detects stool blood using Ortho-tolidine method.Disease activity index is carried out by the standard of table 1 to comment
Point, to assess disease activity situation.Disease activity index (DAI)=(weight mitigation rate score+fecal character score+is occulted blood
Degree score)/3.
Table 1: disease activity index (DAI) standards of grading
The judgment criteria for shape of defecating: 1. normal: shaped particles sample is just；2. half loose stools: paste or half form do not attach to
Anus；3. loose stools: dilute watery stool of anus can be attached to.Each group mouse DAI appraisal result is shown in Fig. 1.Normal group mouse is living
Sprinkle that active, hair is glossy, stool is normal, weight slowly increases；Other each group mouse gradually appear weight decline,
Loose stools, bloody stool, few dynamic, apathetic, symptoms such as hair is at random, model control group is the most significant, and symptom appearance is more early.This hair
The stool situation of bright compound treatment group mouse is relieved, and weight loss degree is obviously light.Compared with model control group, respectively give
The scoring of medicine group is substantially reduced, and closer to Normal group.
Embodiment 2:6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one connection
Influence test with mesalazine to Ulcerative Colitis Model rat
60 Wistar rats are randomly divided into five groups: Normal group, model control group, compound group, mesalazine
Group and drug combination group, every group rat 12.Whole Rat Fasts (can't help water) for 24 hours after, using etherization, Normal group
Not bowel lavage, the silicone tube that diameter 2mm is respectively adopted in model control group, compound group and mesalazine group are inserted into away from rat anus about
8cm colon, with the 30% ethyl alcohol bowel lavage of 0.5mL of the trinitrobenzene sulfonic acid containing 20mg, after, so that rat is lain low, retains
15min, naturally awake, free diet.Rats in normal control group expression is easy, and activity is quick, and coat gloss, dietary amount is larger,
Posture is normal, graininess of defecating, and crissum is clean；Model control group, compound group and mesalazine group rat are after modeling 2d
There is diarrhea, crissum is filthy, and times of defecation increases, soft stool or loose stools, and there is the performance such as mucus or pus point in stool end, prompts modeling
Success.
Whole rats (14d) after modeling success 2 weeks start gastric infusion.Compound group gives 6- hydroxyl -7- [2- (4-
Quinoline base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one 30mg/kg/d stomach-filling；Mesalazine group gives mesalazine
150mg/kg/d stomach-filling；Drug combination group gives 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H-
Quinoline-2-one 15mg/kg/d and mesalazine 75mg/kg/d stomach-filling；Normal group and model control group give isometric(al)
Distilled water stomach-filling.Each group is each primary in the morning, afternoon and evening daily；The free diet of rat, continuous gavage 2 weeks.Daily observation each group rat
Situations such as state of mind, feed, activity, defecation and weight, and keep a record.Each group rat before administration and is administered 1,2 week
Afterwards, after with 2% yellow Jackets (3ml/kg) anesthesia, dead 4 of every component other places, and colon sample is left and taken, using formalin
The fixed rat gut mucosa layer of solution is laid on hardboard upwards, is fixed with pin, and be maintained at 0.9% sodium chloride injection
In, mucosa injury degree is observed, and scored Colonic Mucosa damage that (standards of grading are referring to cell immune response
The foundation of inflammatory bowel disease animal model, Zhu Feng etc., Chinese Academy of Medical Sciences's journal, 08 month 1998).
Table 2: each group rat administration front and back changes of body mass compares (g)
Model control group compared with Normal group,#P < 0.05,##P < 0.01；
Administration group compared with model control group,*P < 0.05,**P < 0.01.
Each group rat administration front and back changes of body mass is relatively shown in Table 2.As can be seen from Table 2, model control group rat weight with
Normal group same period comparing difference is statistically significant (P < 0.01)；After being administered 1 week, mesalazine group rat weight
It is not statistically significant (P > 0.05) with model control group same period comparing difference, and compound group and drug combination group rat body
Quality and model control group same period comparing difference are statistically significant (P < 0.05 or P < 0.01).
Table 3: each group Colonic Mucosa general form Injury score compares and (divides)
Model control group compared with Normal group,#P < 0.05；Administration group compared with model control group,*P < 0.05.
Each group Colonic Mucosa general form Injury score is relatively shown in Table 3.Seen from table 3, model control group rat
Colonic mucosa general form Injury score and Normal group same period comparing difference are statistically significant (P < 0.05)；It gives
After medicine 1 week, compound group and mesalazine group Colonic Mucosa general form Injury score and model control group same period ratio
(P > 0.05) not statistically significant compared with difference, and drug combination group Colonic Mucosa general form Injury score and mould
Type control group same period comparing difference is statistically significant (P < 0.05)；After being administered 2 weeks, compound rats colonic mucosa is big
Volume morphing Injury score and model control group same period comparing difference are statistically significant (P < 0.05).
Embodiment 3:6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one
Preparation
By 3.26g (0.02mol) 6- copper 8hydroxyquinolate, 150mL methylene chloride, 2.24g (0.024mol) triethylamine is added
In 250mL round-bottomed flask, stir evenly at room temperature.Stirring is lower to be added dropwise the dichloromethane solution containing anisoyl chloride
(anisoyl chloride 3.74g, 0.022mol；Methylene chloride 40mL), at the uniform velocity in instillation reaction solution, dripped in 20min
Finish.5h is stirred at room temperature, TLC is monitored to fully reacting, reaction solution is poured slowly into the hydrochloric acid of 50mL1mol/L, is filtered, water
30mL is washed filter cake 3 times, dry.Filtrate is transferred in separatory funnel, separates organic layer, water 100mL is washed 2 times, anhydrous
MgSO4Removing desiccant is dried, filtered, filtrate decompression boils off organic solvent, obtains white solid, yield 5.86g, yield
98.7%.m.p.257-259℃；ESI-MS:m/z297.1 ([M+H]+)。
In 100mL round-bottomed flask, 6- (4- methoxybenzoyl oxygroup) -3,4- dihydro -1H- quinoline-2-one is added
2.98g (0.012mol), aluminum trichloride (anhydrous) (4.4g, 0.034mol) install air set pipe, and anhydrous CaCl is housed2Ball
6h is reacted in shape drying tube, 180 DEG C of oil baths, and TLC is monitored to fully reacting, is cooled to room temperature.Appropriate ice water and 1mol/L is added
Hydrochloric acid solution adjusts pH to 2~3, soaked overnight, and mashing filters and washes product to neutrality, obtains faint yellow solid 6- hydroxyl -7-
(4- hydroxy benzoyl) -3,4- dihydro -1H- quinoline-2-one, yield 2.91g, yield 97.7%.m.p.281-283℃；1H-
NMR (600MHz, DMSO-d6) δ (ppm) 10.38 (s, 1H), 10.15 (s, 1H), 9.90 (s, 1H), 7.61 (d, J=6.0Hz,
2H), 6.87-6.79 (m, 4H), 2.88 (t, J=12.0Hz, 2H), 2.43 (t, J=12.0Hz, 2H)；ESI-MS:m/z283.1
([M+H]+)。
By 6- hydroxyl -7- (4- hydroxy benzoyl) -3,4- dihydro -1H- quinoline-2-one (3mmol), 4- (2- chloroethyl)
Morpholine hydrochloride (3.5mmol), potassium carbonate (6.2g, 45mmol) and potassium iodide (0.1g, 0.6mmol) and 30mL acetone are added on circle
In the flask of bottom, after being heated to reflux 12h, TLC is monitored to end of reaction.It filters, through column chromatography [V (petroleum ether): V (ethyl acetate)
=1: 3] isolated bright yellow solid 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline
Quinoline -2- ketone 0.31g, yield 25.60%.1H-NMR (600MHz, DMSO-d6) δ (ppm) 10.12 (s, 1H), 9.91 (s, 1H),
7.68 (d, J=9.0Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 6.86 (s, 1H), 6.80 (s, 1H), 4.19 (s, 2H), 3.58
(t, J=8.4Hz, 4H), 2.88 (t, J=15Hz, 2H), 2.72 (s, 2H), 2.48-2.42 (m, 5H), 2.19 (s, 1H)；MS
(m/z): 397.2 ([M+H]+).
Claims (5)
1. a kind of pharmaceutical composition for preventing and treating ulcerative colitis, by active constituent and the preparation of pharmaceutically acceptable auxiliary material
At, it is characterised in that: the active constituent is by (1) 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- bis-
Hydrogen -1H- quinoline-2-one, and (2) mesalazine composition, 6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4-
The weight ratio of dihydro -1H- quinoline-2-one and mesalazine is (3~20): 1.
2. preventing and treating the pharmaceutical composition of ulcerative colitis according to claim 1, it is characterised in that: 6- hydroxyl -7- [2-
(4- morpholine base oxethyl) benzoyl] weight ratio of -3,4- dihydro -1H- quinoline-2-one and mesalazine is (5~10): 1.
3. preventing and treating the pharmaceutical composition of ulcerative colitis according to claim 2, it is characterised in that: 6- hydroxyl -7- [2-
(4- morpholine base oxethyl) benzoyl] weight ratio of -3,4- dihydro -1H- quinoline-2-one and mesalazine is 5:1.
4. preventing and treating the pharmaceutical composition of ulcerative colitis according to claim 1, it is characterised in that: the pharmaceutical composition
Object is oral preparation, and the oral preparation is selected from oral solution, dripping pill, tablet, capsule, granule.
5.6- hydroxyl -7- [2- (4- morpholine base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-one is pressed with mesalazine
Weight ratio is (3~20): application of the active ingredient compositions of 1 composition in the drug of preparation prevention and treatment ulcerative colitis.
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