CN104341591A - Anthracycline coupled non-linear multi-block copolymers, and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a type of novel anthracycline antibiotic compound coupled non-linear multi-block copolymers, and a preparation method and an application thereof. Compared with medicines or agents with other forms, the anthracycline antibiotic coupled non-linear multi-block copolymers provide better effects in treating ulcerative colitis disease.
Description
Technical field
The invention discloses the non-linear segmented copolymer of anthracycline antibiotics compound coupling that a class is new, with and its production and use.
Background technology
Ulcerative colitis is a kind of agnogenic enteropathy mainly occurring in colon mucosa, based on curing ulcer erosion, mainly involves rectum, sigmoid colon mucosa, and upwards expansion can to a left side half, right hemicolon, even total colectomy and terminal ileum.This disease is more common in the young and the middle aged, and its main clinical manifestation has courageous and upright Mucous Stool, stomachache, diarrhoea, tenesmus etc., and serious complication can occur this disease.At present along with the development of society and the raising of people's living standard, people's rhythm of life is also constantly accelerated, also can cause the irregular of life, dysfunction of spleen and stomach, suffers from diarrhoea with persistence or repeatability mucosanguineous feces, stomachache and constitutional symptom in various degree simultaneously.Therefore a kind of medicine efficiently of research, just seems extremely important.
The present inventor is surprised to find that some new compounds containing anthracycline antibiotics medicines structure have an unexpected effect on the medicine of preparation treatment ulcerative colitis, there is no report at present for this compounds for treating ulcerative colitis.
Summary of the invention
Content of the present invention is as follows:
The invention discloses the non-linear segmented copolymer of the anthracycline antibiotics coupling shown in following formula I, its structure is as follows:
Wherein R1, R2, R3, R4, R5 are independently H, OH, CH separately
3, CH
2oH or OCH
3, R6 is H, OH, CH
3, CH
2oH, OCH
3,cOCH
3or COCH
2oH, R7, R8 are independently H, OH, CH separately
3, OCH
3, COCH
3or the integer between OR9, n=1-20, preferred n=1-10; Wherein R9 is pyridyl, furyl, pyrryl, thienyl or pyranyl.Preferably wherein R1, R2, R3, R4 are independently H, OH or OCH separately
3, R5 is OH, R6 is H, OH, COCH
3or COCH
2oH, R7, R8 are independently OH, CH separately
3, OCH
3, COCH
3, the integer between n=1-20.More preferably wherein R1 is H or OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
3or COCH
2oH, R7, R8 are independently OH, CH separately
3or the integer (preferred n=1-100) between OR9, n=1-200; Wherein R9 is pyranyl.Integer wherein between W=1-500, preferred 1-300.
Described polymkeric substance is respectively:
1) R1 is OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
2oH, R7 are CH
3,r8 is the integer (preferred n=1-100) between OH, n=1-200;
2) R1 is OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
2oH, R7 are CH
3,r8 is OR9, R9 is pyranyl, the integer (preferred n=1-100) between n=1-200;
3) R1 is OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
3, R7 is CH
3,r8 is the integer (preferred n=1-100) between OH, n=1-200;
4) R1, R2 are H, R3, R4 and R5 be OH, and R6 is COCH
3, R7 is CH
3,r8 is the integer (preferred n=1-100) between OH, n=1-200.
Most preferred configuration is as follows:
The preparation method of multipolymer of the present invention, is characterized in that:
1) compd A is obtained by reacting with compound first (being purchased) and compound second (being purchased);
2) compd A and acetylizad 1,6-two (to carboxyphenoxy) hexane are obtained by reacting polymer B, the wherein integer of n=1-200, preferred 1-100; W is 1-500, preferred 1-300
3) polymer B and anthracycline antibiotics C(are purchased) be obtained by reacting final product;
Compound first
Compound second
Wherein compound first also can be selected from:
Wherein compound second also can be selected from:
compd A;
Polymer B;
Anthracycline antibiotic C.
Preferably, wherein anthracycline antibiotics C is selected from Dx, Zorubicin, pidorubicin, pirarubicin, daunorubicin, daunoblastin, idarubicin, aclarubicin, zhengdingmeisu, aclacinomycin or carminomycin.Wherein optionally use solvent in chemical reaction step, described in step 1, solvent is selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dicyclohexylcarbodiimide; Step 2 optionally uses solvent, one or more in described solvent selected from methanol, ethanol, methylene dichloride, chloroform, tetracol phenixin, dimethyl sulfoxide (DMSO), DMF, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dicyclohexylcarbodiimide; Step 3 optionally uses solvent, one or more in described solvent selected from methanol, ethanol, methylene dichloride, chloroform, tetracol phenixin, dimethyl sulfoxide (DMSO), DMF.
Preparation method of the present invention is specific as follows:
1) two for 1,6-(to carboxyphenoxy) hexane is refluxed in diacetyl oxide, form acetylizad 1,6-two (to carboxyphenoxy) hexane (also can be purchased);
2) compound first is dissolved with compound second and is mixed in a solvent, and at room temperature reaction is spent the night, and drying obtains compd A;
3) acetylizad 1,6-two (to carboxyphenoxy) hexane is mixed with compd A, react at 100-200 DEG C, reaction times 20min to 2h; After the cooling of question response mixture, washing, drying obtains polymer B;
4) by anthracycline antibiotics C and polymer B as 3-48 hour in solvent, in 0-is subzero 30 DEG C after ultrasonic reaction 1-20 minute, then homogenizer high-speed stirring 1-10 minute, rotate volatilization and obtain crude product, rear centrifugal frozen dried obtains the suitable formulations of finished product formula I polymkeric substance.
Its reaction equation is as follows:
+
↓
+
；
This final product compound has beyond thought outstanding effect when treating ulcerative colitis.
accompanying drawing illustrates:
fig. 1the nuclear magnetic resonance map of the end product of embodiment 1.
Embodiment
Specific embodiment is described in further detail the present invention below, but the present invention not only limits to following examples.
Preparation embodiment is as follows:
embodiment 1
1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 25g in 500ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;
2) compound first 3g, compound second 51mg, dicyclohexylcarbodiimide 165mg and pyridine 8mg mix, and at room temperature stir and spend the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;
3) by the 1st) step and the 2nd) step Product mix puts into flask, decompression melting polyreaction 1 hour at 180 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
4) polymkeric substance of Dx and step 3 is put into 20ml dimethyl sulphoxide solution 48 hours; Then to insert in baking oven 3 hours; In subzero 10-20 degree, ultrasonic 15 minutes; Homogenizer high-speed stirring 1 minute, the cholic acid solution 400 turns then putting into 5% stirs 2 hours; Freeze-drying after collected by centrifugation, obtains end product.
embodiment 2
1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 30g in 300ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;
2) compound first 2.7g, compound second 29mg, dicyclohexylcarbodiimide 130mg and pyridine 5mg mix, and at room temperature stir and spend the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;
3) by the 1st) step and the 2nd) step Product mix puts into flask, decompression melting polyreaction 1 hour at 150 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
4) pirarubicin and this polymkeric substance are put into the solution mixed by 5ml ethanol and 5ml methylene dichloride; Then to insert in baking oven 24 hours; In subzero 10-20 degree, ultrasonic 2 minutes; Then homogenizer high-speed stirring 2 minutes, product put into 3% cholic acid solution 400 turns stir 2 hours; Freeze-drying after collected by centrifugation, obtains end product.
embodiment 3
1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 17g in 500ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;
2) compound first 1.8g, compound second 26mg, dicyclohexylcarbodiimide 90mg and pyridine 4mg mixing add 10ml chloroform, at room temperature stir and spend the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;
3) by the 1st) step and the 2nd) step Product mix puts into flask, decompression melting polyreaction 1 hour at 170 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
4) polymkeric substance of aclarubicin and step 3 is put into the solution mixed by 10ml methylene dichloride and 6ml dimethyl sulfoxide (DMSO); Then dry 1 hour is inserted in baking oven; In subzero 20-30 degree, ultrasonic 1 minute, then homogenizer high-speed stirring 5 minutes, product put into 2% cholic acid solution 400 turns stir 4 hours; Freeze-drying after collected by centrifugation, obtains end product.
embodiment 4
1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 30g in 350ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;
2) compound first 3g, compound second 47mg, dicyclohexylcarbodiimide 160mg, 4mg pyridine mixes, and adds 20ml methylene dichloride, at room temperature stirs and spends the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;
3) by the 1st) step and the 2nd) step Product mix puts into flask, decompression melting polyreaction 1 hour at 180 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;
4) polymkeric substance of daunorubicin and step 3) is put into the solution mixed by 10ml methylene dichloride and 10mlDMF; Then to insert in baking oven 48 hours; In 0-subzero 10 degree, ultrasonic 10 minutes; Then homogenizer high-speed stirring 10 minutes, product put into 2% cholic acid solution 800 turns stir 2.5 hours; Freeze-drying after collected by centrifugation, obtains end product.
effect experimental is as follows:
Medicine is to the therapeutic action of mouse ulcerative colitis
Modeling and administration: Wistar rat 110, body weight about 200 grams, animal rearing is in the diel rhythm Animal House of 12/12 hour, and envrionment temperature controls at 22 ± 2 DEG C, humidity 55-60%, rat ad lib and drinking-water.After Animal House adapts to 3 days, rat is divided into 11 groups at random, blank group (not modeling), model group (modeling but do not treat); Positive control drug medication group (existing clinical application, sulfasalazine, every 0.5/(kg.d) administration); Each group of embodiment medicine and the agent of anthracycline normal injection are respectively organized all by muscle injection mode administration, and dosage 5mg lyophilized injection/kg is administered once for one week, start administration after all animal model successes, and the observation 2 weeks that continues medication.
Except blank group, rat odd-numbered day fasting 12 hours, and give 4 DEG C of frozen water gavages 1 time (2ml/ is only), and give lard gavage 1 time (4ml/ is only), make daytime every day rat stand in the dark water of 2cm, control 8 hours lengths of one's sleep, continuous 20 days.Within 21st day, start fasting and can't help water 24 hours, by the chloral hydrate anesthesia of 10%, rat anus epimere about 8cm is inserted by polypropylene tube, the mixture that the trinitro-benzene-sulfonic acid injecting 5% mixes with ethanol is about 1ml, then rat tails is mentioned, continue to be inverted into enteron aisle, within 3 days subsequently, model is successfully prepared and weigh (ensure that often group has 10 mouse, inadequate modeling is again filled).Start administration after modeling success, continue two weeks.
After treatment in 2 weeks, weigh mouse body weight, and get mouse intestinal tissue observation scoring, standards of grading: 0 point of not damaged; , there is not ulcer in 1 point of mucous membrane hyperemia, oedema; 2 points of mucous membrane hyperemia, oedema, slightly rotten to the corn, without ulcer; 3 points of mucous membrane hyperemia, oedema, moderate are rotten to the corn, have single ulcer; 4 points of mucous membrane hyperemia, oedema, severe are rotten to the corn, have many places ulcer; 5 points of mucous membrane hyperemia, oedema, severe are rotten to the corn, have and are greater than 1cm
2ulcer.Experimental result is in table 1 and table 2.
Table 1 embodiment compound is to the treatment result (n=10) of ulcerative colitis in rats
| Group | Scoring after 2 weeks |
| Blank group | 0.52±0.32** |
| Model group | 3.99±0.98 |
| Positive drug control group | 2.89±0.99* |
| Embodiment 1 | 1.06±0.43** |
| Embodiment 2 | 1.04±0.49** |
| Embodiment 3 | 1.05±0.39** |
| Embodiment 4 | 1.03±0.42** |
| How soft mycin ordinary preparation group | 3.90±0.88 |
| Pirarubicin ordinary preparation group | 3.69±0.85 |
| Aclarubicin ordinary preparation group | 3.59±0.98 |
| Daunorubicin ordinary preparation group | 3.87±0.97 |
* P<0.05**P<0.01 is compared with model group
Table 2 embodiment compound is on the impact (n=10) of body weight during ulcerative colitis in rats
| Group | Ill initial stage body weight | Body weight after treatment after 2 weeks |
| Blank group | 200.2±9.5 | 221.2±13.4** |
| Model group | 201.1±9.2 | 167.2±16.0 |
| Positive drug control group | 197.2±10.6 | 193.6±14.5* |
| Embodiment 1 | 198.2±10.2 | 217.2±10.3** |
| Embodiment 2 | 197.7±12.7 | 219.8±11.4** |
| Embodiment 3 | 196.7±10.1 | 222.4±11.6** |
| Embodiment 4 | 199.9±8.7 | 220.5±11.8** |
| How soft mycin ordinary preparation group | 203.5±12.1 | 171.7±13.9 |
| Pirarubicin ordinary preparation group | 200.2±11.2 | 172.5±14.5 |
| Aclarubicin ordinary preparation group | 201.3±11.7 | 173.2±12.2 |
| Daunorubicin ordinary preparation group | 203.0±12.6 | 170.1±15.0 |
* P<0.05**P<0.01 is compared with model group.
Claims (9)
1. the non-linear segmented copolymer of the anthracycline antibiotics coupling be shown below, its structure is as follows:
Wherein R1, R2, R3, R4, R5 are independently H, OH, CH separately
3, CH
2oH or OCH
3, R6 is H, OH, CH
3, CH
2oH, OCH
3,cOCH
3or COCH
2oH, R7, R8 are independently H, OH, CH separately
3, OCH
3, COCH
3or the integer between OR9, n=1-200; Wherein R9 is pyridyl, furyl, pyrryl, thienyl or pyranyl, the integer wherein between W=1-500.
2. the multipolymer of claim 1, wherein R1, R2, R3, R4 are independently H, OH or OCH separately
3, R5 is OH, R6 is H, OH, COCH
3or COCH
2oH, R7, R8 are independently OH, CH separately
3, OCH
3, COCH
3, the integer between n=1-200; Preferred n=1-100, the integer wherein between W=1-500, preferred 1-300.
3. the multipolymer of claim 1, wherein R1 is H or OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
3or COCH
2oH, R7, R8 are independently OH, CH separately
3or the integer (preferred n=1-100) between OR9, n=1-200; Wherein R9 is pyranyl.
4. the multipolymer of claim 1, it is respectively:
1) R1 is OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
2oH, R7 are CH
3,r8 is the integer (preferred n=1-100) between OH, n=1-200;
2) R1 is OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
2oH, R7 are CH
3,r8 is OR9, R9 is pyranyl, the integer (preferred n=1-100) between n=1-200;
3) R1 is OCH
3, R2 is H, R3, R4 and R5 is OH, and R6 is COCH
3, R7 is CH
3,r8 is the integer (preferred n=1-100) between OH, n=1-200;
4) R1, R2 are H, R3, R4 and R5 be OH, and R6 is COCH
3, R7 is CH
3,r8 is the integer (preferred n=1-100) between OH, n=1-200.
5. the multipolymer of claim 1, its structure is as follows:
That is:
。
6. the preparation method of multipolymer any one of claim 1-5, is characterized in that:
1) compd A is obtained by reacting with compound first and compound second;
2) compd A and acetylating 1,6-two (to carboxyphenoxy) hexane are obtained by reacting polymer B, the wherein integer of n=1-200, preferred 1-100;
3) polymer B and anthracycline antibiotics C are obtained by reacting final product;
Compound first
Compound second
Wherein compound first also can be selected from:
，
Wherein compound second also can be selected from:
，
compd A;
Polymer B;
Anthracycline antibiotic C.
7. preparation method according to claim 6, wherein anthracycline antibiotics C is selected from Dx, Zorubicin, pidorubicin, pirarubicin, daunorubicin, daunoblastin, idarubicin, aclarubicin, zhengdingmeisu, aclacinomycin or carminomycin.
8. the method for claim 6 or 7, wherein optionally use solvent in chemical reaction step, described in step 1, solvent is selected from: one or more in benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dicyclohexylcarbodiimide; Step 2 optionally uses solvent, one or more in described solvent selected from methanol, ethanol, methylene dichloride, chloroform, tetracol phenixin, dimethyl sulfoxide (DMSO), DMF, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dicyclohexylcarbodiimide; Step 3 optionally uses solvent, one or more in described solvent selected from methanol, ethanol, methylene dichloride, chloroform, tetracol phenixin, dimethyl sulfoxide (DMSO), DMF.
9. the purposes of any one of claim 1-5 polymkeric substance, purposes is the medicine of preparation treatment ulcerative colitis disease.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103083341A (en) * | 2011-10-31 | 2013-05-08 | 张雅珍 | Use of anthracycline antibiotics in preparation of medicines for treating age-related macular degeneration |
| CN103169720A (en) * | 2011-12-21 | 2013-06-26 | 张雅珍 | Application of anthracene nucleus antibiotic and its pharmaceutical salt for treating retinal vein occlusion |
| CN103910875A (en) * | 2012-12-31 | 2014-07-09 | 张雅珍 | Anthracycline antibiotic coupled nonlinear multi-block copolymer, and preparation method and application thereof |
-
2013
- 2013-08-03 CN CN201310333775.6A patent/CN104341591A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103083341A (en) * | 2011-10-31 | 2013-05-08 | 张雅珍 | Use of anthracycline antibiotics in preparation of medicines for treating age-related macular degeneration |
| CN103169720A (en) * | 2011-12-21 | 2013-06-26 | 张雅珍 | Application of anthracene nucleus antibiotic and its pharmaceutical salt for treating retinal vein occlusion |
| CN103910875A (en) * | 2012-12-31 | 2014-07-09 | 张雅珍 | Anthracycline antibiotic coupled nonlinear multi-block copolymer, and preparation method and application thereof |
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