CN104961789A - Cholic acid-modified glucosamine derivative and preparation method and application thereof - Google Patents

Cholic acid-modified glucosamine derivative and preparation method and application thereof Download PDF

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CN104961789A
CN104961789A CN201510253403.1A CN201510253403A CN104961789A CN 104961789 A CN104961789 A CN 104961789A CN 201510253403 A CN201510253403 A CN 201510253403A CN 104961789 A CN104961789 A CN 104961789A
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cholic acid
preparation
derivative
glucosamine
active ester
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任力
侯思润
刘卅
姚航
薛婧晨
王迎军
王琳
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South China University of Technology SCUT
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Priority to PCT/CN2015/098527 priority patent/WO2016184103A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Steroid Compounds (AREA)

Abstract

The present invention relates to a cholic acid-modified glucosamine derivative and a preparation method and application thereof, the derivative is shown as the formula (I), wherein R1 is H or OH, R2 is H or OH, and R3 is H, CH2 = CHCO-or CH2 = C (CH3) CO-. In the presence of a carbodiimide condensing agent, cholic acid is reacted with an excess amount of N-hydroxysuccinimide or 1-hydroxybenzotriazole to produce cholic acid active ester, the cholic acid active ester is then reacted with D-glucosamine to produce a derivative with no polymeric group; or the cholic acid active ester is first reacted with vinyl-containing acyl chloride, and then reacted with D-glucosamine to produce a derivative with a polymeric group; the derivative has good biocompatibility, the derivative with no polymeric group can be used as a drug for treatment of osteoarthritis, the derivative with the polymeric group can be used as a cartilage repair material organic matrix, or used for building in-situ formed glucosamine function hydrogel.

Description

A kind of cholic acid modified amido glucose derivative and preparation method and application
Technical field
The present invention relates to cholic acid modified amido glucose derivative and preparation method thereof.Cholic acid modified amido glucose derivative in the present invention can be used for treating the medicine of osteoarthritis, the organic substrate of cartilage repair material, and can be used for building formed in situ modified amido glucose functionalization hydrogel soft bone renovating material.
Background technology
D-glucosamine, as the final degraded product of chitin, has the synthesis for the treatment of of arthritis, anti-inflammatory, stimulatory protein(SP) polysaccharide, immunoregulation effect, and participates in structure tissue and cytolemma, is the intermediate material of protein-polysaccharide macromole synthesis.Because this compounds has physiologically active, therefore in medicine, biological field application comparatively extensively, the research of association area is also more and more paid attention to.Cholic acid derives from the amphiphilic species with special biological activity and good biocompatibility in humans and animals body, the cyclopentanoperhydro-phenanthrene of its molecule there are carboxyl and hydroxyl, be easy to carry out chemically modified, therefore, with cholic acid, chemical modification is carried out to glucosamine and can prepare derivative without polymerizable groups, as the medicine for the treatment of osteoarthritis; Or preparation has the derivative of polymerizable functional group further, as having the application of bioactive bio-medical material.There is many problem demanding prompt solutions in existing cartilage repair material, as biological activity, biocompatibility, degraded product whether safety non-toxic, mechanics of materials intensity, implants rejection etc.
In the synthesis of aminoglucose sugar derivatives, the existing report of document.According to the difference of functional group; be divided into N-bit derivant (acylated derivatives, alkyl derivative, amino acid derivative etc.), O-bit derivant (Carboxylation derivative, phosphatide derivative, alkene derivatives, fragrance derivatives etc.) and metal complexes etc.And less with the modification report of steroid compound to glucosamine, also do not report about the monomer of the cholic acid modified amido glucose with polymerizable functional group at present.
Summary of the invention
The present invention proposes the method adopting cholic acid modified amido glucose, solves the medicine of existing treatment osteoarthritis, and the problem existing for cartilage repair material.
Object of the present invention is achieved through the following technical solutions:
A kind of cholic acid modified amido glucose derivative, concrete structure is such as formula (I):
Wherein, R 1for H or OH, R 2for H or OH, R 3for H, CH 2=CHCO-or CH 2=C (CH 3) CO-.
The preparation method of above-mentioned cholic acid modified amido glucose derivative, comprises the steps:
1) by cholic acid and excessive N-hydroxy-succinamide or I-hydroxybenzotriazole, make catalyzer at carbon imide, tetrahydrofuran (THF) is the obtained cholic acid active ester of reaction under solvent system condition;
2) under room temperature, cholic acid active ester and D-glucosamine react 6-12 hour under trimethylamine makes the condition of catalyzer, the obtained derivative without polymerizable groups; Or at-20 DEG C to-15 DEG C, cholic acid active ester first with containing after acyl chloride reaction 110-130 minute of vinyl, be returned to room temperature reaction and spend the night, and then at room temperature, 6-12 hour is reacted, the obtained derivative having polymerizable groups under making the condition of catalyzer at trimethylamine with D-glucosamine.
Described carbon imide is one or more in N, N'-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N, N'-DIC.
Described D-glucosamine is D-Glucosamine Hydrochloride.
The described acyl chlorides containing vinyl is acrylate chloride or methacrylic chloride.
Described trimethylamine is DIPEA or triethylamine.
Described N-hydroxy-succinamide or I-hydroxybenzotriazole are excessive, and the ratio of the amount of substance of cholic acid and N-hydroxy-succinamide or I-hydroxybenzotriazole is 1:1 ~ 1:1.5.
Described carbon imide is excessive, and cholic acid is 1:1.5 ~ 1:2 with the ratio of the amount of substance of carbon imide.
Described trimethylamine is excessive, and cholic acid active ester is 1:1 ~ 1:1.5 with the ratio of the amount of substance of trimethylamine; Acyl chlorides containing vinyl is excessive, and cholic acid active ester is 1:2 ~ 1:2.5 with the ratio of the amount of substance of the acyl chlorides containing vinyl; D-glucosamine is excessive, and cholic acid active ester is 1:1 ~ 1:1.5 with the ratio of the amount of substance of D-glucosamine.
The application of above-mentioned obtained cholic acid modified amido glucose derivative in the medicine of preparation treatment osteoarthritis, or the application in cartilage repair material, or the application in the glucosamine functionalization hydrogel building formed in situ.
Compared with prior art, tool of the present invention has the following advantages:
(1) preparation of the present invention above-mentioned cholic acid modified amido glucose derivative has route briefly, easy to operate, and purify easily, yield is advantages of higher comparatively.
(2) derivative without polymerizable groups prepared by the present invention, can be used for the medicine as treatment osteoarthritis.
(3) derivative having polymerizable groups prepared by the present invention, there is unique biological activity, good biocompatibility, can be used for the organic substrate of cartilage repair material, and can be used for building formed in situ modified amido glucose functionalization hydrogel soft bone renovating material.
Accompanying drawing explanation
Fig. 1 is the structural formula of the cholic acid modified amido glucose derivative without polymerizable groups prepared by embodiment 1,2;
Fig. 2 is the proton nmr spectra of the cholic acid modified amido glucose derivative without polymerizable groups prepared by embodiment 1;
Fig. 3 is the cell proliferation toxicity test result figure of the cholic acid modified amido glucose derivative without polymerizable groups prepared by embodiment 1;
Fig. 4 is the cell colored graph anyway of the cholic acid modified amido glucose derivative without polymerizable groups prepared by embodiment 1;
Fig. 5 is the structural formula having the cholic acid modified amido glucose derivative of polymerizable groups prepared by embodiment 3;
Fig. 6 is the proton nmr spectra having the cholic acid modified amido glucose derivative of polymerizable groups prepared by embodiment 3.
Fig. 7 is the cell proliferation toxicity test result figure of the cholic acid modified amido glucose derivative without polymerizable groups prepared by embodiment 3;
Fig. 8 is the cell colored graph anyway of the cholic acid modified amido glucose derivative without polymerizable groups prepared by embodiment 1;
Fig. 9 is the structural formula having the cholic acid modified amido glucose derivative of polymerizable groups prepared by embodiment 4.
Embodiment
Below in conjunction with specific embodiment, the present invention is more specifically described in detail, but embodiments of the present invention are not limited thereto, for the processing parameter do not indicated especially, can refer to routine techniques and carry out.
Embodiment 1
Prepare the derivative without polymerizable groups: cholic acid modified amido glucose derivative, comprises the steps:
4.0858g (0.01mol) cholic acid, 1.1509g (0.01mol) N-hydroxy-succinamide adds 150ml three-necked bottle, stirring and dissolving, in 30ml tetrahydrofuran (THF), at 0 DEG C, slowly drips containing 3.0949g (0.015mol) N, the 10ml tetrahydrofuran solution of N'-dicyclohexylcarbodiimide, after insulation 2h, get back to room temperature, stopped reaction after continuation reaction 18h, suction filtration gets filtrate, and rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is petrol ether/ethyl acetate (1/4), obtains cholic acid active ester A4.258g, and productive rate is 84.21%.
The glucosamine of 2.1563g (0.01mol) adds in the mono-neck bottle of 100ml, add the N of 30ml, dinethylformamide/deionized water (2/1), instill the triethylamine of 1.0119g (0.01mol) again, stir 10min, after add the cholic acid active ester A of 5.057g (0.01mol), stopped reaction after reaction 6h, rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is methylene chloride/methanol (8/1), obtains product 4.134g, and productive rate is 72.65%.
The structural formula of the cholic acid modified amido glucose derivative of above-mentioned synthesis as shown in Figure 1.
As shown in Figure 2 1h-NMR (DMSO-d6,400MHz) analyzes confirmation: 0.57 (s, 3H), 0.80 (s, 3H), 0.92 (d, 3H), 1.20 ~ 2.25 (m, 24H), 3.15 ~ 4.90 (m, 16H), 6.35 (d, 1H), 7.48 (d, 1H).
Fig. 3 be embodiment 1 synthesize cholic acid modified amido glucose derivative different concns be dissolved in substratum on cell proliferation (L929 Apoptosis, this cell be GB GB/T 16886.5-2003 vitro cytotoxicity experiment designated cell) affect situation.Control group is normal incubation medium, and result shows just to occur slight cytotoxic when concentration reaches 1mM concentration, and overt toxicity appears in 1.5mM, this modification ammonia sugar is described at below 1mM to cell safety.
Fig. 4 be synthesis cholic acid modified amido glucose derivative different concns be dissolved in the life or death cell dyeing result figure (scale be 50 μm) of substratum to cell survival (L929 cell), result and quantitative result basically identical, cell 1mM modification ammonia sugar concentration cultures in still can large number of viable.
Embodiment 2
Prepare the derivative without polymerizable groups: cholic acid modified amido glucose derivative, comprises the steps:
4.0858g (0.01mol) cholic acid, 2.0269g (0.015mol) I-hydroxybenzotriazole adds 150ml three-necked bottle, stirring and dissolving is in 30ml tetrahydrofuran (THF), at 0 DEG C, slowly drip the 10ml tetrahydrofuran solution of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride containing 3.8340g (0.02mol), after insulation 2h, get back to room temperature, stopped reaction after continuation reaction 24h, suction filtration gets filtrate, and rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is petrol ether/ethyl acetate (1/4), obtains cholic acid active ester B3.833g, and productive rate is 75.79%.
The glucosamine of 3.23445g (0.015mol) adds in the mono-neck bottle of 100ml, add the N of 30ml, dinethylformamide/deionized water (2/1), instill the N of 1.9386g (0.015mol) again, N-diisopropylethylamine, stirs 10min, after add the cholic acid active ester B of 5.2571g (0.01mol), stopped reaction after reaction 12h, rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is methylene chloride/methanol (8/1), obtains product 4.134g, and productive rate is 72.65%.
Synthetic product structural formula as shown in Figure 1.
Embodiment 3
Preparation has the derivative of polymerizable groups: acryloyl cholic acid modified amido glucose derivative, comprises the steps:
4.0858g (0.01mol) cholic acid, 1.1509g (0.01mol) N-hydroxy-succinamide adds 150ml three-necked bottle, stirring and dissolving, in 30ml tetrahydrofuran (THF), at 0 DEG C, slowly drips containing 1.8915g (0.015mol) N, the 10ml tetrahydrofuran solution of N'-DIC, after insulation 2h, get back to room temperature, stopped reaction after continuation reaction 18h, suction filtration gets filtrate, and rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is petrol ether/ethyl acetate (1/4), obtains cholic acid active ester A, quality 4.258g, and productive rate is 84.21%.
The cholic acid active ester A of 2.5283g (0.005mol), the triethylamine (dewatering) of 1.012g (0.01mol) adds in the mono-neck bottle of 100ml, at 0 DEG C, add the tetrahydrofuran (THF) (dewatering) of 30ml, dry ice is cooled to-15 DEG C, and instillation 0.905g (0.01mol) acrylate chloride, is incubated and is returned to room temperature after two hours, continue reaction to spend the night, rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is methylene chloride/methanol (100/1).Obtain acryloyl cholic acid active ester A, quality 0.8221g, productive rate 29.38%.
The glucosamine of 2.1563g (0.01mol) adds in the mono-neck bottle of 100ml, adds the dmf/H of 30ml 2o (2/1), then instill 1.0119g (0.01mol) triethylamine, stirs 10min, after add the acryloyl cholic acid active ester A of 5.597g (0.01mol), stopped reaction after reaction 6h, rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is methylene chloride/methanol (8/1).Obtain product 3.803g, productive rate 61.04%.
The structural formula of the cholic acid modified amido glucose derivative that embodiment 3 is synthesized as shown in Figure 5.
As shown in Figure 6, 1h-NMR (DMSO-d 6, 400MHz) and analyze confirmation: 0.58 (s, 3H), 0.84 (s, 3H), 0.92 (d, 3H), 0.96 ~ 2.46 (m, 24H), 3.03 ~ 4.90 (m, 15H), 5.88 (d, J=10Hz, 1H), 6.12 (dd, J 1,2=10Hz, 17.2Hz, 1H), 6.28 (d, J=17.2Hz, 1H), 6.35 (d, 1H), 7.48 (d, 1H).
Fig. 7 is that embodiment 3 is synthesized cholic acid modified amido glucose derivative cell culture medium vat liquor and (had and be insoluble to substratum with this modification ammonia sugar, according to GB GB/T 16886.5-2003 vitro cytotoxicity experiment vat liquor standard system for vat liquor) toxic effect result is bred to cell (L929), use different vat liquor concentration for reference (saturation extract is 1 times), control group is that all vat liquor concentration of normal incubation medium all can not make a difference to the propagation toxicity of cell.
Fig. 8 is that embodiment 3 synthesizes the life or death cell dyeing picture (scale be 50 μm) of cholic acid modified amido glucose derivative cell culture medium vat liquor to cell survival, result is consistent with quantitative result, and the vat liquor of this modification ammonia sugar different concns can not make a difference to the survival of cell.
Embodiment 4
Preparation has the derivative of polymerizable groups: methacryloyl cholic acid modified amido glucose derivative, comprises the following steps:
4.0858g (0.01mol) cholic acid, 2.0269g (0.015mol) I-hydroxybenzotriazole adds 150ml three-necked bottle, stirring and dissolving is in 30ml tetrahydrofuran (THF), at 0 DEG C, slowly drip the 10ml tetrahydrofuran solution of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride containing 3.8340g (0.02mol), after insulation 2h, get back to room temperature, stopped reaction after continuation reaction 24h, suction filtration gets filtrate, and rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is petrol ether/ethyl acetate (1/4), obtains cholic acid active ester B, quality 3.833g, and productive rate is 75.79%.
The cholic acid active ester B of 2.6286g (0.005mol), the triethylamine (dewatering) of 1.012g (0.01mol) adds in the mono-neck bottle of 100ml, at 0 DEG C, add the tetrahydrofuran (THF) (dewatering) of 30ml, dry ice is cooled to-20 DEG C, and instillation 1.0453 (0.01mol) methacrylic chloride, is incubated and is returned to room temperature after two hours, continue reaction to spend the night, rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is methylene chloride/methanol (100/1).Obtain methacryloyl cholic acid active ester 0.812g, productive rate 27.38%
The GA of 2.1563g (0.01mol) adds in the mono-neck bottle of 100ml, add the dmf/H2O (2/1) of 30ml, instill 1.0119g (0.01mol) triethylamine again, stir 10min, after add the methacryloyl cholic acid active ester of 5.9374g (0.01mol), stopped reaction after reaction 12h, rotary evaporation is except desolventizing.Purify with silica gel column chromatography, eluent is methylene chloride/methanol (8/1).Obtain product 3.8519g, productive rate 60.47%.
Embodiment 4 synthesizes cholic acid modified amido glucose derivant structure formula as shown in Figure 9.

Claims (10)

1. a cholic acid modified amido glucose derivative, is characterized in that, concrete structure is such as formula (I):
Wherein, R 1for H or OH, R 2for H or OH, R 3for H, CH 2=CHCO-or CH 2=C (CH 3) CO-.
2. the preparation method of cholic acid modified amido glucose derivative according to claim 1, is characterized in that, comprise the steps:
1) by cholic acid and excessive N-hydroxy-succinamide or I-hydroxybenzotriazole, make catalyzer at carbon imide, tetrahydrofuran (THF) is the obtained cholic acid active ester of reaction under the condition of solvent;
2) under room temperature, cholic acid active ester and D-glucosamine react 6-12 hour under trimethylamine makes the condition of catalyzer, the obtained derivative without polymerizable groups; Or at-20 DEG C to-15 DEG C, cholic acid active ester first with containing after acyl chloride reaction 110-130 minute of vinyl, be returned to room temperature reaction and spend the night, and then at room temperature, 6-12 hour is reacted, the obtained derivative having polymerizable groups under making the condition of catalyzer at trimethylamine with D-glucosamine.
3. preparation method according to claim 2, it is characterized in that, described carbon imide is one or more in N, N'-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and N, N'-DIC.
4. preparation method according to claim 2, is characterized in that, described D-glucosamine is D-Glucosamine Hydrochloride.
5. preparation method according to claim 2, is characterized in that, the described acyl chlorides containing vinyl is acrylate chloride or methacrylic chloride.
6. preparation method according to claim 2, is characterized in that, described trimethylamine is DIPEA or triethylamine.
7. the preparation method according to any one of claim 2 ~ 6, is characterized in that, the ratio of the amount of substance of described cholic acid and N-hydroxy-succinamide or I-hydroxybenzotriazole is 1:1 ~ 1:1.5.
8. the preparation method according to any one of claim 2 ~ 6, is characterized in that, described cholic acid is 1:1.5 ~ 1:2 with the ratio of the amount of substance of carbon imide.
9. the preparation method according to any one of claim 2 ~ 6, is characterized in that, described cholic acid active ester is 1:1 ~ 1:1.5 with the ratio of the amount of substance of trimethylamine; Cholic acid active ester is 1:2 ~ 1:2.5 with the ratio of the amount of substance of the acyl chlorides containing vinyl; Cholic acid active ester is 1:1 ~ 1:1.5 with the ratio of the amount of substance of D-glucosamine.
10. the application of cholic acid modified amido glucose derivative according to claim 1 in the medicine of preparation treatment osteoarthritis, or the application in cartilage repair material, or the application in the glucosamine functionalization hydrogel building formed in situ.
CN201510253403.1A 2015-05-18 2015-05-18 Cholic acid-modified glucosamine derivative and preparation method and application thereof Pending CN104961789A (en)

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CN108504342A (en) * 2018-04-09 2018-09-07 王建东 A kind of preparation method of water shutoff agent

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WO2016184103A1 (en) * 2015-05-18 2016-11-24 华南理工大学 Cholic acid modified glucosamine derivative and preparation method and use
CN108504342A (en) * 2018-04-09 2018-09-07 王建东 A kind of preparation method of water shutoff agent

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