CN107674110A - A kind of bit derivant of diosgenin 3 and its production and use - Google Patents

A kind of bit derivant of diosgenin 3 and its production and use Download PDF

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Publication number
CN107674110A
CN107674110A CN201710940319.6A CN201710940319A CN107674110A CN 107674110 A CN107674110 A CN 107674110A CN 201710940319 A CN201710940319 A CN 201710940319A CN 107674110 A CN107674110 A CN 107674110A
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Prior art keywords
diosgenin
acid
amino
group
bit
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黄文�
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SICHUAN JINGHUACHUANG BIOTECHNOLOGY Co Ltd
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SICHUAN JINGHUACHUANG BIOTECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a kind of bit derivant of diosgenin 3 and its production and use.The invention provides the bit derivant of diosgenin 3 shown in Formulas I, its structural formula are as follows：Wherein, R1For amino straight chain fatty acidic group or amino acid residue；R2For H orR3For H, C1‑C18Alkyl or phenyl.Derivative of the present invention, raw material sources enrich, and synthetic route is easy, and yield is high, are adapted to large-scale production；With good antitumor activity, and it is better than diosgenin.

Description

A kind of diosgenin -3- bit derivants and its production and use
The application be submit on July 30th, 2013, it is entitled " a kind of diosgenin -3- bit derivants and its The divisional application of the Chinese patent application 201310325252.7 of preparation method and purposes ".
Technical field
The present invention relates to a kind of diosgenin -3- bit derivants and its production and use.
Background technology
Diosgenin, chemical constitution is similar to steroid hormones class formation, be synthesis oral contraceptive, sex hormone and its A kind of important source material of its steroidal compounds.Diosgenin be it is a variety of in one of (into) the effective elements of the medicine, often with glucosides shape Formula is present in the natural plants such as Dioscorea, Costus L, Solanum and frenugreek spp, the content of sapogenin wherein in dioscorea zingiberensis wright Highest.
At present, more than 400 kinds of steroid drugs is there are about in the world directly or indirectly using diosgenin as raw material, passes through derivatization And it is made, such as progesterone, prednisone, cortisone medicine.In addition to for synthesizing steroid parahormone, diosgenin and its precursor Saponins compound also has other extensive purposes and higher medical value, such as anti-inflammatory, antithrombotic, reducing blood lipid, suppression Growth of tumour cell, it may also be used for treatment leukaemia, climacteric metancholia etc..
In recent years, the research of diosgenin ester also has been to be concerned by more and more people.To improve the life of diosgenin Reason activity, the present invention design and have synthesized a series of diosgenin -3- bit derivants, it is expected to filter out with higher antitumor The steroidal compounds of activity.
The content of the invention
Technical program of the present invention lies in provide a kind of diosgenin -3- bit derivants and its production and use.
The invention provides the bit derivant of diosgenin -3- shown in Formulas I, its structural formula are as follows：
Wherein, R1For amino straight chain fatty acidic group or amino acid residue；R2For H orR3For H, C1-C4Alkane Base or phenyl.
Further, the amino straight chain fatty acidic group from 4-Aminobutanoicacid, 6-aminocaprolc acid, 8- aminocaprylic acids or 12 amino dodecanoic acid；The amino acid residue is from glycine, alanine, phenylalanine, leucine, isoleucine, figured silk fabrics Propylhomoserin, methionine, proline, tryptophan, glutamine, asparagine, serine, threonine, cysteine, tyrosine, Aspartic acid, glutamic acid, lysine, arginine or histidine.
Further, R3For H, methyl, ethyl, phenyl or its acceptable salt.
Preferably, the derivative is：
Present invention also offers the preparation method of above-mentioned diosgenin -3- bit derivants, and it includes following operating procedure：
A, amino straight chain fatty acid or amino acid, add blocking group on amino；
B, protected amino straight chain fatty acid or amino acid and diosgenin, esterification, products therefrom, removing are taken Blocking group, then withReaction, produces diosgenin -3- bit derivants.
Further, the blocking group be acetyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, methyl or Ethyl.
Further, in esterification, with 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride EDC-HCl For condensing agent, DMAP DMAP is catalyst.
Present invention also offers purposes of the above-mentioned diosgenin -3- bit derivants in anti-tumor drug is prepared.
Further, the medicine is inhibitor against colon carcinoma cells, liver cancer, the medicine of breast cancer.
Present invention also offers a kind of antitumor medicine composition, it containing described compound is active component system that it, which is, The standby preparation formed.
Wherein, described preparation is injection or oral formulations.
Derivative of the present invention, raw material sources enrich, and synthetic route is easy, and yield is high, are adapted to large-scale production；With good Antitumor activity, and be better than diosgenin.
Embodiment
The preparation (compound 5) of embodiment 1N- acetyl group 6-aminocaprolc acid diosgenin esters
A, N- tertbutyloxycarbonyls -6-aminocaprolc acid
Compound 1 (13.0g), di-tert-butyl dicarbonate (25ml) and appropriate triethylamine, acetone-water (v are added in flask:v 1:1) solvent is made, at room temperature until reaction is complete.Watery hydrochloric acid adjusts pH ethyl acetate extraction, to merge organic phase, through saturation to acidity Sodium chloride solution washing, anhydrous sodium sulfate drying, vacuum drying, obtain white solid 2N- tertbutyloxycarbonyls -6-aminocaprolc acid (22.6g, 98%).1H NMR(400MHz,CDCl3) δ 4.61 (s, 1H), 3.12 (d, J=5.9Hz, 2H), 2.35 (t, J= 7.4Hz,2H),1.72-1.57(m,2H),1.56-1.41(m,12H),1.41-1.29(m,2H)。
B, N- tertbutyloxycarbonyls -6-aminocaprolc acid diosgenin ester
The DMAP of diosgenin (12.5g), compound 2 (7.0g) and catalytic amount is in anhydrous methylene chloride, at room temperature Add appropriate EDC reactions 6h.Filtrate is done through dilute sodium chloride solution, saturated sodium bicarbonate solution, water washing, anhydrous sodium sulfate successively It is dry, silica gel post separation (petrol ether/ethyl acetate 12:1) compound as white solid 3N- tertbutyloxycarbonyls -6-aminocaprolc acid potato, is obtained Chinese yam sapogenin ester (15.2g, 80%).1H NMR(400MHz,CDCl3) δ 5.37 (d, J=4.3Hz, 1H), 4.67-4.50 (m, 2H), 4.41 (dd, J=15.0,7.4Hz, 1H), 3.67 (s, 1H), 3.53-3.43 (m, 1H), 3.37 (t, J=10.9Hz, 1H), 3.11 (d, J=6.3Hz, 2H), 2.38-2.21 (m, 4H), 2.08-1.91 (m, 2H), 1.04 (s, 3H), 0.97 (d, J= 6.9Hz, 3H), 0.79 (d, J=3.5Hz, 6H).
C, 6-aminocaprolc acid diosgenin ester
Compound 3 (15.0g) is dissolved in dichloromethane, and trifluoroacetic acid solution (37.5ml) is slowly added dropwise at room temperature.Reaction After substantially completely, triethylamine adjusts pH to alkalescent.Reaction solution is done through water, saturated sodium bicarbonate, water washing, anhydrous sodium sulfate successively It is dry, silica gel column separating purification, obtain the 6-aminocaprolc acid diosgenin ester (11.7g, 81%) of faint yellow solid compound 4.1H NMR(400MHz,CDCl3) δ 5.56 (s, 1H), 5.37 (d, J=3.5Hz, 1H), 4.65-4.49 (m, 1H), 4.41 (dd, J= 14.8,7.3Hz, 1H), 3.55 (q, J=7.2Hz, 2H), 3.51-3.43 (m, 1H), 3.37 (t, J=10.9Hz, 1H), 3.07- 2.89 (m, 2H), 2.29 (t, J=7.8Hz, 4H), 2.07-1.93 (m, 2H), 1.02 (d, J=9.4Hz, 3H), 0.97 (d, J= 6.7Hz,3H),0.79(s,6H)。
D, N- acetyl -6-aminocaprolc acid diosgenin ester
Compound 4 (10.56g) is dissolved in anhydrous methylene chloride (100ml) solution, adds appropriate triethylamine, under ice-water bath Chloroacetic chloride (2.8ml) is added dropwise, maintenance reaction is after alkaline environment, TLC monitoring question responses, and reaction solution is successively through unsaturated carbonate Hydrogen sodium solution, dilute sodium chloride solution washing, anhydrous sodium sulfate drying, silica gel column separating purification, obtain compound as white solid 5N- second Acyl group 6-aminocaprolc acid diosgenin ester (9.03g, yield 80%).1H NMR(400MHz,CDCl3)δ6.26(s,1H), 5.59 (s, 1H), 4.81 (s, 1H), 4.64 (d, J=6.3Hz, 1H), 3.74-3.54 (m, 2H), 3.46 (s, 2H), 2.96 (s, 1H),2.59-2.42(m,4H),1.02(s,5H)。
The preparation (compound 10) of embodiment 2N- α-acetyllysine diosgenin ester
With reference to the method for embodiment 1, reaction amino acid starting material, prepare compound 9 are changed.1H NMR(400MHz,MeOD)δ 5.33 (d, J=5.0Hz, 1H), 4.67-4.49 (m, 1H), 4.30 (dd, J=14.6,7.6Hz, 1H), 3.85 (t, J= 6.4Hz,1H),3.39-3.30(m,1H),2.93-2.76(m,2H),2.41-2.20(m,2H)。
Compound 9 is taken with after acyl chloride reaction, producing compound 10, target compound faint yellow solid.1H NMR (400MHz,CDCl3) δ 6.37 (d, J=7.9Hz, 1H), 5.99 (t, J=5.3Hz, 1H), 5.31 (d, J=4.8Hz, 1H), 4.65-4.50 (m, 1H), 4.49-4.40 (m, 1H), 4.34 (dd, J=15.0,7.4Hz, 1H), 3.40 (dd, J=10.4, 3.2Hz, 1H), 3.30 (t, J=10.9Hz, 1H), 3.23-3.08 (m, 2H), 2.32-2.19 (m, 2H), 2.15 (s, 1H), 0.72 (t, J=3.1Hz, 6H).
The preparation (compound 14) of the 8- aminocaprylic acid diosgenin esters of embodiment 3
A, N- tertbutyloxycarbonyls -8- aminocaprylic acids
Compound 11 (3.18g), di-tert-butyl dicarbonate ((Boc) are added in flask2O, 5.06ml) and appropriate triethylamine (Et3N), acetone-water (v:v 1:1) solvent is made, at room temperature until reaction is complete.Part organic solvent is rotated, raffinate is with dilute Hydrochloric acid adjusts pH to acidity, ethyl acetate extraction, merges organic phase, is washed through saturated nacl aqueous solution, be anhydrous sodium sulfate drying, true Sky revolving removes solvent, is placed in 5 DEG C of refrigerator overnights, obtains white solid 12N- tertbutyloxycarbonyl -8- aminocaprylic acids.
B, N- tertbutyloxycarbonyls -6- aminocaprylic acids diosgenin ester
Diosgenin dios (4.14g), compound 12 (2.59g), DMAP (244mg) are in anhydrous methylene chloride, room Temperature is lower plus DCC (2.48g) reactions are stayed overnight, filtering.Filtrate successively through dilute sodium chloride solution, saturated sodium bicarbonate solution, water washing, Anhydrous sodium sulfate drying, silica gel post separation (petrol ether/ethyl acetate 10:1) compound as white solid 13N- tertiary butyloxycarbonyls, are obtained Base -8- aminocaprylic acid diosgenin esters.1H NMR(400MHz,CDCl3) δ 5.30 (d, J=5.0Hz, 1H), 4.60-4.46 (m, 1H), 4.34 (dd, J=14.9,7.5Hz, 1H), 3.44-3.36 (m, 1H), 3.30 (t, J=10.9Hz, 1H), 3.02 (t, J=7.0Hz, 2H), 2.30-2.14 (m, 4H), 1.98-1.86 (m, 2H), 0.72 (t, J=3.1Hz, 6H).
C, 8- aminocaprylic acids diosgenin ester
Compound 13 (5.25g) is dissolved in dichloromethane, and trifluoroacetic acid solution (6.0ml) is slowly added dropwise at room temperature.Reaction After substantially completely, triethylamine is added dropwise thereto and adjusts to alkalescent.Reaction solution is successively through water, saturated sodium bicarbonate, water washing, nothing Aqueous sodium persulfate is dried, and silica gel column separating purification, obtains faint yellow solid compound 14.1H NMR(400MHz,CDCl3)δ8.17(s, 1H), 5.30 (d, J=4.8Hz, 1H), 4.52 (tdd, J=10.9,6.9,4.2Hz, 1H), 4.34 (dd, J=15.0,7.5Hz, 1H), 3.45-3.37 (m, 1H), 3.30 (t, J=10.9Hz, 1H), 3.08 (q, J=7.3Hz, 2H), 2.96-2.84 (m, 2H), 2.27-2.15 (m, 4H), 0.72 (t, J=3.1Hz, 6H).
The preparation (compound 18) of the 12 amino dodecanoic acid diosgenin ester of embodiment 4
A, N- tertbutyloxycarbonyls -12 amino dodecanoic acid
Preparation method adds compound 15 (3.23g), di-tert-butyl dicarbonate ((Boc) with reference to embodiment 3a in flask2O, 4.14ml), obtain white solid 13N- tertbutyloxycarbonyls -12 amino dodecanoic acid.
B, N- tertbutyloxycarbonyls -12 amino dodecanoic acid diosgenin ester
Preparation method takes diosgenin (4.14g) and compound 16 (3.15g) to make in DCC/DMAP with reference to embodiment 3b Compound as white solid 17N- tertbutyloxycarbonyls -12 amino dodecanoic acid diosgenin ester is obtained with lower.1H NMR(400MHz, CDCl3) δ 5.30 (d, J=4.9Hz, 1H), 4.62-4.23 (m, 3H), 3.40 (dd, J=10.1,3.4Hz, 1H), 3.30 (t, J =10.9Hz, 1H), 3.02 (t, J=7.1Hz, 2H), 2.32-2.10 (m, 4H), 1.99-1.86 (m, 2H), 0.72 (t, J= 3.1Hz,6H)。
C, 12 amino dodecanoic acid diosgenin ester
Preparation method obtains faint yellow solid chemical combination with reference to embodiment 3c, compound 17 (5.70g) under trifluoroacetic acid effect The 12 amino dodecanoic acid diosgenin ester of thing 18.1H NMR(400MHz,CDCl3) δ 7.99 (s, 1H), 5.30 (d, J= 4.8Hz, 1H), 4.60-4.45 (m, 1H), 4.34 (dd, J=15.0,7.5Hz, 1H), 3.40 (dd, J=10.2,3.4Hz, 1H), 3.30 (t, J=10.9Hz, 1H), 3.11-3.01 (m, 7H), 2.85 (s, 2H), 2.29-2.13 (m, 4H), 0.72 (t, J =3.1Hz, 6H).
Beneficial effects of the present invention are illustrated below by way of test example.
The pharmacological evaluation of test example 1
The human breast cancer cell MDA-MB-231 used in experiment, mouse colonic cell C26, human liver cancer cell Hep G2 There is provided by Sichuan University's nano biological medical technology and membrane biology research institute.Tumor cell culture condition is according to American Type Culture Collection (ATCC) requirements are cultivated.
According to document report, diosgenin -3- 4,5,9,10,14,18 pairs of people's mammary gland of bit derivant are detected using mtt assay Cancer cell MDA-MB-231, tri- kinds of mouse colonic cell C26, human liver cancer cell Hep G2 tumor cell culture 48h growth Inhibitory activity.
MTT experiment IC of the diosgenin derivative of table 1 to tumour cell50(μM)
It can be seen from Table 1 that compound 4,5,9,10,14,18 has obvious active anticancer, wherein, compound 9 Activity is substantially better than compound 4.

Claims (10)

1. the bit derivant of diosgenin -3- shown in Formulas I, its structural formula are as follows：
Wherein, R1For amino straight chain fatty acidic group or amino acid residue；R2For H orR3For H, C1-C18Alkyl, Phenyl or its acceptable salt.
2. diosgenin -3- bit derivants according to claim 1, it is characterised in that：The amino straight chain fatty acid Base derives from 4-Aminobutanoicacid, 6-aminocaprolc acid, 8- aminocaprylic acids or 12 amino dodecanoic acid；The amino acid residue source In glycine, alanine, phenylalanine, leucine, isoleucine, valine, methionine, proline, tryptophan, glutamy Amine, asparagine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid, lysine, arginine or group ammonia Acid.
3. diosgenin -3- bit derivants according to claim 1, it is characterised in that：R3For H, methyl, ethyl, phenyl Or its acceptable salt.
4. diosgenin -3- bit derivants according to claim 1, it is characterised in that：The derivative is：
5. the preparation method of diosgenin -3- bit derivants described in claim 1, it is characterised in that：It includes following operation Step：
A, amino straight chain fatty acid or amino acid, blocking group is added on amino or carboxyl；
B, protected amino straight chain fatty acid or amino acid and diosgenin, esterification, products therefrom, deprotection are taken Group, then withReaction, produces diosgenin -3- bit derivants.
6. preparation method according to claim 5, it is characterised in that：The blocking group be acetyl group, tertbutyloxycarbonyl, Benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl, methyl or ethyl.
7. preparation method according to claim 5, it is characterised in that：In esterification, with 1- ethyls-(3- dimethylaminos Base propyl group) carbodiimide hydrochloride EDC-HCl is condensing agent, DMAP DMAP is catalyst.
8. purposes of the diosgenin -3- bit derivants in anti-tumor drug is prepared described in claim 1-4 any one.
9. purposes according to claim 8, it is characterised in that：The medicine is inhibitor against colon carcinoma cells, liver cancer, the medicine of breast cancer Thing.
10. a kind of antitumor medicine composition, it be containing the compound described in claim 1-4 any one for activity into Divide the preparation being prepared.
CN201710940319.6A 2013-07-24 2013-07-30 A kind of bit derivant of diosgenin 3 and its production and use Pending CN107674110A (en)

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