CN105769859B - It is a kind of to treat the pharmaceutical composition of skin injury and its application after radiotherapy patients with cervix carcinoma - Google Patents
It is a kind of to treat the pharmaceutical composition of skin injury and its application after radiotherapy patients with cervix carcinoma Download PDFInfo
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- CN105769859B CN105769859B CN201610130909.8A CN201610130909A CN105769859B CN 105769859 B CN105769859 B CN 105769859B CN 201610130909 A CN201610130909 A CN 201610130909A CN 105769859 B CN105769859 B CN 105769859B
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- pharmaceutical composition
- skin injury
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- radiotherapy
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The pharmaceutical composition of skin injury and its application after radiotherapy patients with cervix carcinoma are treated the invention discloses a kind of, the pharmaceutical composition is prepared by active constituent and auxiliary material, and the active constituent includes 5 (2 phenylethylcarbamates of N) 2 (4 methoxyphenyl) 2H benzotriazole.The present invention can improve neutrophil phagocytosis and Chemotaxis Function, significant in efficacy and easy to operate by skin injury after external application for curing irradiation for cervical cancer, easy to use, not occur adverse events, securely and reliably.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of drug for treating skin injury after radiotherapy patients with cervix carcinoma
Composition and its application.
Background technology
Cervical carcinoma is to be primary in the malignant tumour of uterine cervix, is ranked first in female sex organ malignant tumour, operation
It is the main method for treating cervical carcinoma, but is only used for early stage (0 phase or Ia phases), therefore radiotherapy is the important of cervical carcinoma again
One for the treatment of means.For the radiotherapy of cervical carcinoma generally after radical-ability dosage 1/3 is irradiated, skin can occur in irradiation area
Erythema, sepage and breakage, due to the unique anatomical structure of perineum, perineal skin humidity, thin tender, more gauffer, in addition size
Just and the friction of clothing easily causes infection.With the increase of intergal dose, above-mentioned position reaction aggravates then occur serious
Moist reaction forms ulceration, if preventing not in time and handling, ulcer and infection once being formed in early days, can influence entirely to radiate and control
Treatment process or even interruption treatment, late period there is also the prolonged ulcer of irradiation area skin and be not cured, and very big pain will be caused to patient
It is bitter.
CN105218532A discloses a kind of benzotriazole micromolecular compound or its pharmaceutically acceptable acid adds
Into salt, also disclose the benzotriazole micromolecular compound or its pharmaceutically acceptable acid-addition salts prepare treatment by
Medical usage in the disease medicaments such as various malignant growths, transfer and recurrence caused by RAS gene mutations, however it does not have
Have disclose such compound after radiotherapy patients with cervix carcinoma is treated skin injury or treat diabetic complication in terms of bioactivity.
Invention content
In view of the deficiencies in the prior art, the purpose of the present invention is to provide a kind of skin damages after treating radiotherapy patients with cervix carcinoma
The pharmaceutical composition of wound and its application.
The object of the present invention is achieved like this：
A kind of pharmaceutical composition for treating skin injury after radiotherapy patients with cervix carcinoma, prepared by active constituent and auxiliary material and
Into the active constituent includes 5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzotriazole.
Preferably, as described above treatment radiotherapy patients with cervix carcinoma after skin injury pharmaceutical composition, wherein the work
Property ingredient is made of 5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzotriazole.
Compound 5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzos three according to the present invention
Azoles, hydrogen modal data are：1HNMR (DMSO, 300MHz)：δ 8.13 (d, J=9.0Hz, 2H), 7.69 (d, J=9.0Hz, 1H),
7.32 (s, 3H), 7.23-7.22 (m, 1H), 7.13 (m, 2H), 7.03 (dd, J=0.3,0.3Hz, 1H), 6.61 (s, 1H),
6.33-6.32 (m, 1H), 3.83 (s, 3H), 3.62-3.36 (m, 2H), 2.96-2.92 (m, 2H).
It is further preferred that the pharmaceutical composition of skin injury after radiotherapy patients with cervix carcinoma, wherein institute are treated as described above
The therapeutic combination stated is topical administration formulations, and the topical administration formulations are selected from gelling agent, ointment, liniment and lotion
It is a kind of.
Still further preferably, the pharmaceutical composition of skin injury is wiping after treatment radiotherapy patients with cervix carcinoma as described above
Agent, and drug concentration is 5~50mg/mL, further preferred drug concentration is 10~30mg/mL.
After total body radiation damage, contraction of wounds slows down, and the average healing extends, and wound stretching intensity significantly reduces.This
Invention drug has effects that promote new granulation tissue's growth, the repairing ulcer surface of a wound, to promote contraction of wounds, shortens average be cured
The time is closed, increases surface of a wound tensile strength.In addition, Changes of Radiation Damaged Skin is necessarily occurred in Patients During Radiotherapy in Patients During Radiotherapy
Complication has become restriction patient and has smoothly completed one of principal element of radiotherapy.Drug of the present invention can improve neutrophil leucocyte
Phagocytosis and Chemotaxis Function, it is significant in efficacy and easy to operate by skin injury after external application for curing irradiation for cervical cancer, it is easy to use,
Do not occur adverse events, securely and reliably.Therefore, the present invention also provides a kind of pharmaceutical applications, i.e.,：5- (N-2- phenylethyl ammonia
Base) application of -2- (4- the methoxyphenyls) -2H- benzotriazole after treating cancer radiotherapy is prepared in the drug of skin injury.It is excellent
Selection of land, the cancer are cervical carcinoma.
Specific embodiment
The following is specific embodiments of the present invention, and technical scheme of the present invention is done and is further described, but of the invention
Protection domain be not limited to these embodiments.It is every to be included in this hair without departing substantially from the change of present inventive concept or equivalent substitute
Within bright protection domain.
Embodiment 1：The preparation of 5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzotriazole
(1) P-nethoxyaniline (2.48g, 20.14mmol) is dissolved in the aqueous hydrochloric acid solution (4M) of 48ml, in ice bath
Under the conditions of add in sodium nitrite (1.67g, 24.17mmol), react half an hour after, by Amcide Ammate (3.16g) at 0 DEG C delay
In slow addition system and continue to stir half an hour.The pH of solution is adjusted to 5-6 with sodium acetate, by adjacent benzene two under condition of ice bath
Amine hydrochlorate (3.33g, 18.42mmol) is added in reaction system, is stirred overnight.TLC is detected after the reaction was complete, uses hydrogen
Sodium hydroxide solution, which is adjusted to pH, is more than 14, is extracted with ethyl acetate and water, merges organic phase, and vacuum distillation obtains drying
Crude product azo-compound.The pyridinium dissolution of azo-compound 40ml, by 10g anhydrous cupric sulfates be added to 60ml concentrated ammonia liquors/
In water (v/v=1/1) mixed solution, mixture flows back under oil bath, until the reaction is complete.
(2) reaction solution of cooling is added in excessive water, is extracted with ethyl acetate and water, merges organic phase, decompression
Distillation, obtained crude product benzotriazole amine detached through column chromatography, obtain pure 2- (4- methoxyphenyls) -5- amino -
2H- benzotriazole 2.52g.
(3) by 2- (4- methoxyphenyls) -5- amino -2H- benzotriazole (0.42g, 1.74mmol), phenylacetic acid
(0.24g, 1.74mmol), HOBt (0.26g, 1.92mmol) and EDC.HCl (0.43g, 2.24mmol) are dissolved in DMF (10ml)
In, it is stirred under 50-60 DEG C of oil bath, is detected with TLC, until the reaction is complete.Excessive water is added in, uses ethyl acetate
It is extracted with water, merges organic phase, vacuum distillation obtains crude product, detached with column chromatography, obtains pure N- (2- (4- first
Phenyl) -2H- benzotriazole -5- amino) -2- phenyl-acetamides 0.57g, yield 91%.Then by N- (2- (4- methoxyl groups
Phenyl) -2H- benzotriazole -5- amino) -2- phenyl-acetamides (0.57g, 1.59mmol) under condition of ice bath under be dissolved in THF
In (10ml), lithium aluminium hydride reduction (0.60g, 15mmol) is added portionwise, until when no bubble generates, removes ice bath, it is enterprising in oil bath
Row reflux, TLC are detected until the reaction is complete.Excessive ethyl acetate is added in, is extracted with ethyl acetate and water, is merged
Organic phase, vacuum distillation, obtains crude product, is detached with column chromatography, obtain pure 5- (N-2- phenylethylcarbamates) -2- (4-
Methoxyphenyl) -2H- benzotriazole 0.32g, yield 59%.1HNMR (DMSO, 300MHz)：δ 8.13 (d, J=9.0Hz,
2H), 7.69 (d, J=9.0Hz, 1H), 7.32 (s, 3H), 7.23-7.22 (m, 1H), 7.13 (m, 2H), 7.03 (dd, J=0.3,
0.3Hz, 1H), 6.61 (s, 1H), 6.33-6.32 (m, 1H), 3.83 (s, 3H), 3.62-3.36 (m, 2H), 2.96-2.92 (m,
2H)。
Embodiment 2：- 2H- benzotriazole is (hereinafter referred to as by 5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls)
RS042) the preparation of liquid
Preparation method：At normal temperatures and pressures, propylene glycol 10g is weighed, is dissolved in suitable distilled water, according still further to each in prescription
The proportioning of component is separately added into RS042 1.5g, and sodium benzoate 0.01g is stirred to dissolve, and finally plus distilled water is to 100ml, fills
Divide stirring, mixing, while adjust pH to 7.0, canned, finished product is examined to obtain in sealing.
Embodiment 3：RS042 liquids after irradiation for cervical cancer the effect of skin injury patient to studying
Cervical cancer patient 52, wherein squamous carcinoma 23, gland cancer 29.Observation group 26 is randomly divided into, control group 26 is seen
Examine group age 25 years old~59 years old, average (44.2 ± 9.6) year, 24 years old~60 years old control group age, average (45.7 ± 8.5) year.
Two groups of ages compare, pathological comparing difference is without conspicuousness, are comparable.All patients use linear accelerator x-ray
External exposure, B points DT40Gy~50Gy/20~25 time/4~5 week；Intracavitary afterloading therapy, using 198Ir afterloading unit intracavitary radiotherapies, A
Point DT4 dosage 30~36Gy/5~6 time.Every group of case does introduction on discharge：Perineum cleaning is kept, it is dry, forbid embrocating stimulation
Property and oiliness drug, treatment dermoreaction appearance after start, control group use 0.1% bromogeramine or normal saline flushing
Perineum 3 times/d, continues to radiotherapy to terminate.Observation group is to be applied with RS042 liquids, 3 times/d, operating procedure：Sterile treatment bowl is taken to fall
Enter RS042 liquids and 10~20mL (is prepared) by the formulation and technology of embodiment 2, perineal region is covered in after sterile gauze is impregnated with solution
On skin, surrounding can prevent drug volatilization to be dried, and can prevent more than ulceration 1~2cm of range, then one layer of sterile gauze fixation of lid
Only liquid stains clothing, retains 15~20min/ times, 3 times/d, continues to radiotherapy to terminate.Observation part is paid attention to during medication daily
Skin conditions, pain relief situation, ulceration healing and patient have no adverse reaction.
After two groups for the treatment of ends, judged according to cancer radiation therapy association skin acute radiation injury by RTOG grade scales
It is as follows：
It is effective：7d inner skins ulcer heals completely after treatment, and engorgement pain disappears substantially；
Effectively：7d inner skins ulcer is obviously reduced after treatment, and engorgement pain disappears substantially；
Minor effect：7d inner skins ulcer area, hyperemia, pain are not improved after treatment；14d inner skins ulcer area is filled
Blood, pain have improvement；
In vain：14d inner skins ulcer area, hyperemia, pain are not improved after treatment.
General curative effect comparison result is referring to table 1.It is the results show that total effective after observation group's skin acute radiation injury treatment
Rate (effective+effectively) and it is 96.2%, control group 61.5%.The effect of observation group, is significantly better than control group.
1 two groups of general curative effects of table compare
Claims (2)
1.5- (N-2- phenylethylcarbamates) -2- (4- methoxyphenyls) -2H- benzotriazole skin after treating cancer radiotherapy is prepared
Application in the drug of skin damage.
2. application according to claim 1, it is characterised in that：The cancer is cervical carcinoma.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610130909.8A CN105769859B (en) | 2016-03-09 | 2016-03-09 | It is a kind of to treat the pharmaceutical composition of skin injury and its application after radiotherapy patients with cervix carcinoma |
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|---|---|---|---|
| CN201610130909.8A CN105769859B (en) | 2016-03-09 | 2016-03-09 | It is a kind of to treat the pharmaceutical composition of skin injury and its application after radiotherapy patients with cervix carcinoma |
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| CN105769859A CN105769859A (en) | 2016-07-20 |
| CN105769859B true CN105769859B (en) | 2018-06-26 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105218532A (en) * | 2015-10-16 | 2016-01-06 | 华东师范大学 | Benzotriazole compounds, preparation method and its medicinal use |
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| JP5937968B2 (en) * | 2010-01-29 | 2016-06-22 | ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド | Small molecules that modulate MCL-1 and methods for modulating cell death, cell division, cell differentiation, and methods of treating diseases. |
| ES2763527T3 (en) * | 2014-04-04 | 2020-05-29 | Univ Michigan Regents | Mcl-1 small molecule inhibitors and uses thereof |
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| CN105218532A (en) * | 2015-10-16 | 2016-01-06 | 华东师范大学 | Benzotriazole compounds, preparation method and its medicinal use |
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