CN104402894B - 3-(1-alkoxyl oxygen alkyl ethyl) metal complex and its preparation method and application of chlorin e 6 analog - Google Patents
3-(1-alkoxyl oxygen alkyl ethyl) metal complex and its preparation method and application of chlorin e 6 analog Download PDFInfo
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Abstract
The invention discloses the preparation method of the metal complex of a series of 3 (1 alkoxyl oxygen alkyl ethyl) chlorin e 6 analog and in anti-gastric-ulcer and the application of anti-anemia action field of medicaments.This compound structure formula is as shown in following formula I: the compound structure of the present invention is stable, and activity substantially, can make further research and develop into anti-gastric-ulcer and resistance to iron deficiency anaemia new drug.The raw material of the present invention is cheap and easy to get, and synthetic method is simple, is swift in response, and is suitable for industrialized production.
Description
Technical field
The invention belongs to chlorin compounds field, particularly to 3-(1-alkoxyl oxygen alkyl ethyl) chlorin e 6 analog
Metal complex and preparation method thereof and application in field of medicaments.
Background technology
Chlorophyll is magnesium porphyrin complex, and under the effects such as light, heat, acid, alkali, enzyme, magnesium ion is easily de-from porphyrin ring
Fall formation pheophytin and make chlorophyll fade or variable color.Under certain condition, some metal ions can enter into de-
Magnesium pheophytin porphyrin ring center, replaces magnesium ion and forms Metal-Substituted Chlorophyll Derivatives, be allowed to recover color, and stability carries significantly
Height, but also have promotion hematopoiesis, protect the liver, the special physiological function such as anti-sudden change, be widely used in the necks such as food, medical treatment, health care
Territory.
It has been proved that chlorophyll degradation product and derivative thereof have sterilization, anti-mutagenesis, promotion healing up of traumatic tissues, resist
Ulcer, protect the liver, promote many biologically actives such as hematopoiesis function and optical dynamic therapy.Therefore, chlorophyllous deep exploitation is expected to
Become a brand-new medicine and health products extended familys.But, up to now, domestic and international biological medicine scientific and technological circle particularly pharmacy
This is not yet formed and payes attention to by boundary, and chlorophyll is still blank out in current pharmaceutical chemistry research.
Development antiulcer medicine is mainly by controlling gastric acid secretion, killing helicobacter pylori and protection
3 kinds of approach of stomach lining realize, if the drug main of existing control hydrochloric acid in gastric juice and protection stomach lining is cured the symptoms, not the disease, and China's mesh
Preclinical therapy Gastric Ulcer Treatment major part is that the gastric ulcer seldom having the innovation of independent research is new from external import or Counterfeit Item
Medicine.
Worldwide hypoferric anemia is extremely serious, mends iron pharmaceutical requirements amount huge.According to investigations, China's iron deficiency patient is high
Reaching 200,000,000, hypoferric anemia incidence reaches 20%, especially higher the women of child-bearing age and infant incidence, current domestic listing
Mostly there is the weak points such as absorption rate is low, mouthfeel is poor in iron supplementary, therefore, improves absorptivity and reduce toxicity, overcome evil
The novel iron supplementary of the bad reaction such as the heart, diarrhoea becomes the focus of current anti-anemia action drug research.
Summary of the invention
Technical barrier to be solved by this invention provide a kind of structure clearly, activity is notable, prepare simple dihydro porphin
The metal complex synthesis preparation method of fen e6 analog and in the application of field of medicaments.A series of chlorins of the present invention
E6 analog metal complex has good prevention or result for the treatment of to experimental gastric ulcer model and hypoferric anemia.Can
For researching and developing into anti-gastric-ulcer and the potential drug for the treatment of anaemia.
The 3-(1-alkoxyl oxygen alkyl ethyl of the present invention) the chemical constitution such as formula of metal complex of chlorin e 6 analogInstitute
Show:
Wherein, M is Cu2+、Zn2+、Fe2+、Mn2+、Ni2+、Co2+、Pd2+Or other common bivalent metal ions；
Described R1、 R2CH can be all3、CH2CH3、CH2CH2CH3、n-C4H9 Or other are common substituted or unsubstituted
C1-6Straight or branched alkyl, the most unsubstituted C1-4Straight chained alkyl；
As described R1During for H, R2Can be CH3、CH2CH3、CH2CH2CH3、n-C4H9 Or other common replacements or do not take
The C in generation1-6Straight or branched alkyl, the most unsubstituted C1-4Straight chained alkyl；
Described R3Can be CH3、CH2CH3、CH2CH2CH3、n-C4H9 Or other common C1-6Straight or branched alkyl,
The most unsubstituted C1-4Straight chained alkyl.
Any one that heretofore described chlorin e 6 analog metal complex is the most as described below
Compound:
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy
Acyl ethyl-17,18-chlorin zinc complex；
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13 carboxyl-15-methoxy acyl methyl-17-methoxy acyl
Ethyl-17,18-chlorin copper complex；
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy
Acyl ethyl-17,18-chlorin ferrous complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13 carboxyl-15-ethoxy acyl methyl-17-ethoxy acyl
Ethyl-17,18-chlorin zinc complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl-15-ethoxy acyl methyl-17-ethoxy
Acyl ethyl 17,18-chlorin copper complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl 15-ethoxy acyl methyl-17-ethoxy acyl
Ethyl-17,18-chlorin ferrous complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13 carboxyl-15-the third oxygen acyl methyl-17 the-the third oxygen acyl
Ethyl-17,18-chlorin zinc complex；
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl 15-fourth oxygen acyl methyl-17-fourth oxygen acyl
Ethyl-17,18-chlorin copper complex.
Present invention also offers described such as formulaThe preparation method of shown compound, including esterification, addition, replacement and
Complexation approach, wherein:
A () is esterified: extract from silkworm excrement the chlorin e 6 (chlorin e6) of isolated purified after, at the concentrated sulfuric acid
Carrying out esterification with alcohol under catalytic action, obtain 2,7,12,18-tetramethyl-3-vinyl-8-ethyl-13-carboxyl-15-take
For ethyl-17-substituted propyl-17,18-chlorin (compound), the definition of the most each substituent is all with claim 1
Described；It is for the C of liquid under normal temperature with the alcohol of chlorin e 6 esterification1-6Lower alcohol, preferably methyl alcohol, ethanol, propyl alcohol
Or butanol；
(b) addition: compoundPurified after with the acetic acid solution generation addition reaction of halogenated acid, generation 2,7,12,18-
Tetramethyl-3-(1 halogenated ethyl)-8-ethyl-13-carboxyl-15-replacement ethyl-17-substituted propyl-17,18-chlorin (change
Compound )；With compoundThe halogenated acid of addition reaction is bromo-acid or chloroacid, preferably bromo-acid；
C () replaces: compound Again from different alcohol generation substitution reactions, generate 2,7,12,18-tetramethyl-3-(1-
Alkoxyl oxygen alkyl ethyl)-8-ethyl-13-carboxyl-15-replaces ethyl-17-substituted propyl-17,18-chlorin (compound)；With
Compound The alcohol of substitution reaction is the C under normal temperature for liquid1-6Lower alcohol, preferably methyl alcohol, ethanol, propyl alcohol or butanol；
D () is complexed: compoundIn a solvent, then with slaine at N2Under protection, stirring reaction generation 2,7,12,18-tetra-
Methyl-3-(1-alkoxyl oxygen alkyl ethyl)-8-ethyl-13-carboxyl-15-replaces ethyl-17-substituted propyl-17,18-chlorin metal
Complex compound (compound).
Preparing compoundMethod in, described solvent i.e. dissolved compoundIt is normal with the organic solvent of slaine
See low boiling single organic solvent or mixed solvent, preferably methyl alcohol, ethanol, acetone and/or dichloromethane, more preferably dichloromethane
Mixed solvent with methyl alcohol；Described solvent and compoundVolume mass than preferably 10 ~ 200ml/g, further preferred 50-
100ml/g；When described solvent uses the mixed solvent of dichloromethane and methyl alcohol, both preferred 1:1 ~ 20 of volume ratio, further
Preferably 1:2 ~ 10.Described slaine is that conventional divalent metal salt is for zinc agent, for copper agent or for ferrous agent；Preferably zinc acetate, nitre
Acid zinc or zinc chloride are for for zinc agent, more preferably zinc acetate；Preferably copper acetate, copper sulphate or copper chloride are for for copper agent, more preferably second
Acid copper；Preferably frerrous chloride, ferrous sulfate, ferrous phosphate are for for ferrous agent, more preferably frerrous chloride；Described compoundWith
Preferred 1:1 ~ 6 of mol ratio of slaine, further preferred 1:2 ~ 4.
Preparing compoundMethod in, the temperature of described reaction can be at the boiling point from the freezing point of solvent to solvent
The temperature of change, preferably 0～80 ° C, further preferred 20～60 ° of C in temperature range.
Preparing compoundMethod in, the process of described reaction can use traditional test methods in this area (as
Nuclear magnetic resonance, infrared spectrum, spectrophotometric or mass spectral analysis, HPLC or TLC) determine, with compoundDisappearing is reaction end,
Preferably reaction time 0.5～16h, further preferred 1～10h.
Preparing compoundMethod in, described raw material i.e. chlorophyll degradation product chlorin e 6 and compound
I.e. 2,7,12,18-tetramethyl-3-vinyl-8-ethyl-13-carboxyl-15-replaces ethyl-17-substituted propyl-17,18-dihydro
The purifying of porphine metal complex compound all uses silica gel column chromatography to separate, and solvent is Conventional solvents, preferably dichloromethane, three chloromethanes
In alkane, carbon tetrachloride, methyl alcohol, ethanol, ethyl acetate, acetone and petroleum ether (60-90) one or more and wherein containing overall
The formic acid of long-pending 2% ~ 0.5%, preferably 1.2% ~ 0.8% formic acid.
Preparing compoundMethod in, described compoundPreparation method can be with further reference to the present inventor's
Another patent (patent publication No. CN 103833762 A).
Room temperature in the present invention refers to that environment temperature is 10～30 ° of C.
Present invention also offers described such as formulaThe metal complex of shown chlorin e 6 analog is preparing anti-stomach
Application in ulcer and resistance to iron deficiency anaemia medicine.
The synthesis preparation method of the present invention is simple, is swift in response, and is suitable for large-scale industrial production.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention to described reality
Execute among example scope.
Embodiment 1:2,7,12,18-tetramethyl-3-vinyl-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-first
The preparation of oxygen acyl ethyl-17,18-chlorin
By chlorin e6(6g, 10mmol) joins in methyl alcohol (120ml), and the concentrated sulfuric acid (6 of dropping 98% is stirred at room temperature
Ml), 5 h are reacted in 55 DEG C under nitrogen protection.Reactant liquor cools down, and after dichloromethane (360ml) dilution, pours frozen water (600 ml) into
Middle extraction, stratification, organic phase concentrated by rotary evaporation, to dry, washes suction filtration, and after filter cake vacuum drying, to obtain 4.5g black for silica gel column chromatography
Look fine grained product, yield: 75%.LC-MS (ESI): [M+H]+= 625。
Embodiment 2:2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-
The preparation of 17-methoxy acyl ethyl-17,18-chlorin
Step 1: preparation 2,7,12,18-tetramethyl-3-(1-bromoethyl)-8-ethyl-13-carboxyl-15-methoxy acyl first
Base-17-methoxy acyl ethyl-17,18-chlorin
By 2,7,12,18-tetramethyl-3-vinyl-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl second
Base-17,18-chlorin (1.0g, 1.6mmol) adds in saturated hydrogen bromide acetic acid solution (15 ml), 12 hs is stirred at room temperature,
100 DEG C of concentrated by rotary evaporations remove hydrogen bromide and acetic acid, then vacuumize dry 6 h in the drier containing sodium acid carbonate, obtain atropurpureus
Powder 0.98g, yield 98%, stand-by.
Step 2: preparation 2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl first
Base-17-methoxy acyl ethyl-17,18-chlorin
Atropurpureus powder in above-mentioned steps 1 is added absolute ethyl alcohol (100ml), and room temperature continues stirring reaction 6h.Reaction knot
Bundle, after dichloromethane (200ml) dilution, pours extraction in frozen water (600ml), stratification into, and organic phase concentrated by rotary evaporation is the most dry, water
Washing suction filtration, after filter cake is vacuum dried, silica gel column chromatography obtains bright purple powder 0.65g, yield: 65%.Spectral data is as follows: LC-
MS (ESI): [M+H]+= 671。1H-NMR, DMSO-d6,500MHz) δ ppm:3.46 (3H, s, 21H), 6.05-6.11 (1H,
M, 31H), 1.67 (3H, d, 32H), 2.59-2.67 (2H, m, 33H), 1.95 (3H, t, 34H), 9.67 (1H, s, 5H), 3.25
(3H, s, 71H), 3.75 (2H, m, 81H), 1.65 (3H, t, 82H), 9.82 (1H, s, 10H), 3.61 (3H, s, 121H), 5.42
(2H, s, 151H), 3.67 (3H, s, 153H), 4.33 (1H, q, 17H), 1.78-2.51 (2H, m, 171H), 2.16-2.21 (2H,
M, 172H), 3.52 (3H, s, 174H), 4.45 (H, q, 18H), 1.71 (3H, d, 181H) ,-1.62 (s, 1H) ,-1.87 (s,
1H)。
Embodiment 3:2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-
The preparation of 17-methoxy acyl ethyl-17,18-chlorin zinc complex
By 2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-first
Oxygen acyl ethyl-17,18-chlorin drying sample (1.0g, 1.5mmol) is finely ground, is dissolved in dichloromethane (100ml), acetic acid
Zinc (0.5g, 2.3mmol) is dissolved completely in methyl alcohol (20ml), and the two is at N2Mix under protection, stirring reaction under room temperature
1h.Reaction solution, by yellowish-brown discoloration blue-green, after reactant liquor is with 2 times of volumes methylene chloride extractions, adds 5 times of volume frozen water slow
Stir to organic phase precipitation solid.Quiet be washed to filtrate clear to organic phase suction filtration after separatory, after filtration cakes torrefaction black
Fine particulate compound 0.07g, yield 70%.Spectral data is as follows: LC-MS (ESI): [M+H]+=735,1H-NMR, DMSO-
D6,500MHz) δ ppm:3.46 (3H, s, 21H), 6.05-6.11 (1H, m, 31H), 1.67 (3H, d, 32H), 2.59-2.67
(2H, m, 33H), 1.95 (3H, t, 34H), 9.67 (1H, s, 5H), 3.25 (3H, s, 71H), 3.75 (2H, m, 81H), 1.65
(3H, t, 82H), 9.82 (1H, s, 10H), 3.61 (3H, s, 121H), 5.42 (2H, s, 151H), 3.67 (3H, s, 153H),
4.33 (1H, q, 17H), 1.78-2.51 (2H, m, 171H), 2.16-2.21 (2H, m, 172H), 3.52 (3H, s, 174H), 4.45
(H, q, 18H), 1.71 (3H, d, 181H)。
Embodiment 4:2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-
The 17-methoxy acyl ethyl copper complex formazan preparation of-17,18-chlorin
By 2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-first
Oxygen acyl ethyl-17,18-chlorin (1.0g, 1.6mmol) is finely ground, is dissolved in 100ml dichloromethane, (0.4g, 2.0mmol)
Copper acetate is dissolved in 50 ml methyl alcohol, and the two is at N2Mix under protection, be stirred at room temperature reaction 0.5h.Reaction solution by
Yellowish-brown brightens green, after reactant liquor is with 2 times of volumes methylene chloride extractions, adds 5 times of volumes of deionized water and is slowly stirred and washes away
Free copper ion.After standing separatory, lower floor's organic phase concentrated by rotary evaporation is to dry, and after soaking, stirring washing repeatedly, is clarified to filtrate
Transparent, suction filtration, obtain black fine particulate compound 0.98g, yield 98% after filtration cakes torrefaction, spectral data is as follows: LC-MS (ESI):
[M+H]+=734,1H-NMR, DMSO, 500MHz) δ ppm:3.47 (3H, s, 21H), 6.05-6.11 (1H, m, 31H), 1.66
(3H, d, 32H), 2.59-2.68 (2H, m, 33H), 1.95 (3H, t, 34H), 9.66 (1H, s, 5H), 3.27 (3H, s, 71H),
3.73 (2H, m, 81H), 1.65 (3H, t, 82H), 9.82 (1H, s, 10H), 3.60 (3H, s, 121H), 5.42 (2H, s, 151H),
3.67 (3H, s, 153H), 4.33 (1H, q, 17H), 1.78-2.51 (2H, m, 171H), 2.16-2.21 (2H, m, 172H), 3.51
(3H, s, 174H), 4.46 (H, q, 18H), 1.73 (3H, d, 181H)。
Embodiment 5:2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-
The preparation of 17-methoxy acyl ethyl-17,18-chlorin ferrous complex
By 2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-first
Oxygen acyl ethyl-17,18-chlorin (1.0g, 1.6mmol), finely ground, it is dissolved in 100ml dichloromethane, (0.8g, 4.0mmol)
Frerrous chloride is dissolved in 20ml methyl alcohol, and the two is at N2Mix rapidly under protection, be stirred at reflux anti-under 45 DEG C of heating water baths
Answer 5h.Reaction solution is by the dimmed green of yellowish-brown, and after reactant liquor amasss dchloromethane with dliploid, deionized water washes away free
Iron ion.After standing separatory, organic phase concentrated by rotary evaporation, to dry, be washed to filtrate clear, suction filtration, obtain black after filtration cakes torrefaction
Fine particulate compound 0.86g yield 86%, spectral data is as follows: LC-MS (ESI): [M+H]+=726,1H-NMR (DMSO,
500MHz) δ ppm:3.42 (3H, s, 21H), 6.05-6.13 (1H, m, 31H), 1.65 (3H, d, 32H), 2.59-2.62
(2H, m, 33H), 1.95 (3H, t, 34H), 9.67 (1H, s, 5H), 3.27 (3H, s, 71H), 3.77 (2H, m, 81H), 1.65
(3H, t, 82H), 9.82 (1H, s, 10H), 3.62 (3H, s, 121H), 5.42 (2H, s, 151H), 3.69 (3H, s, 153H),
4.35 (1H, q, 17H), 1.77-2.52 (2H, m, 171H), 2.15-2.21 (2H, m, 172H), 3.51 (3H, s, 174H), 4.42
(H, q, 18H), 1.70 (3H, d, 181H)。
Embodiment 6:2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl 15-ethoxy acyl methyl-
The preparation of 17-ethoxy acyl ethyl-17,18-chlorin
First according to embodiment 1 same procedure, replace methyl alcohol with ethanol, be esterified generation 2,7,12,18-tetramethyl-3-ethene
Base-8-ethyl-13-carboxyl 15-ethoxy acyl methyl-17-ethoxy acyl ethyl-17,18-chlorin, the most again by embodiment 2
Method, replaces ethanol to prepare with methyl alcohol.LC-MS (ESI): [M+H]+=685；1H-NMR (DMSO-d6,500MHz): δ
Ppm:3.49 (3H, s, 21H), 6.00-6.02 (1H, m, 31H), 2.05 (3H, d, 32H), 3.52 (3H, s, 33H), 9.67
(1H, s, 5H), 3.25 (3H, s, 71H), 3.75 (2H, m, 81H), 1.65 (3H, t, 82H), 9.82 (1H, s, 10H), 3.63
(3H, s, 121H), 5.42 (2H, s, 151H), 3.67 (3H, s, 153H), 4.32 (1H, q, 17H), 1.78-2.45 (2H, m,
171H), 1.98 (2H, m, 172H), 3.82 (2H, m, 174H), 1.08 (3H, t, 175H), 4.43 (1H, q, 18H), 1.63 (3H,
D, 181H) ,-1.63 (s, 1H) ,-1.88 (s, 1H).
Embodiment 7:2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl 15-ethoxy acyl methyl-
The preparation of 17-ethoxy acyl ethyl-17,18-chlorin zinc complex
According to embodiment 3 same procedure, with 2,7,12,18-tetramethyl-3-(1-methoxyethyls)-8-ethyl-13-carboxyl
15-ethoxy acyl methyl-17-ethoxy acyl ethyl-17,18-chlorin replaces 2,7,12,18-tetramethyl-3-(1-ethyoxyl second
Base)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl ethyl-17,18-chlorin prepares.Wave spectrum number
According to as follows: LC-MS (ESI): [M+H]+=748,1H-NMR (DMSO-d6,500MHz), δ ppm:3.46 (3H, s, 21H),
6.00-6.02 (1H, m, 31H), 2.05 (3H, d, 32H), 3.53 (3H, s, 33H), 9.67 (1H, s, 5H), 3.25 (3H, s,
71H), 3.75 (2H, m, 81H), 1.65 (3H, t, 82H), 9.82 (1H, s, 10H), 3.61 (3H, s, 121H), 5.42 (2H, s,
151H), 3.67 (3H, s, 153H), 4.32 (1H, q, 17H), 1.78-2.45 (2H, m, 171H), 1.98 (2H, m, 172H), 3.81
(2H, m, 174H), 1.08 (3H, t, 175H), 4.43 (1H, q, 18H), 1.63 (3H, d, 181H)。
Embodiment 8:2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl 15-ethoxy acyl methyl-
17-ethoxy acyl ethyl-17,18-chlorin copper complex
According to embodiment 4 same procedure, with 2,7,12,18-tetramethyl-3-(1-methoxyethyls)-8-ethyl-13-carboxyl
15-ethoxy acyl methyl-17-ethoxy acyl ethyl-17,18-chlorin replaces 2,7,12,18-tetramethyl-3-(1-ethoxy second
Base)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl ethyl-17,18-chlorin prepares.Wave spectrum number
According to as follows: LC-MS (ESI): [M+H]+=749,1H-NMR, (DMSO-d6,500MHz) δ ppm:3.49 (3H, s, 21H),
6.01-6.05 (1H, m, 31H), 2.06 (3H, d, 32H), 3.51 (3H, s, 33H), 9.67 (1H, s, 5H), 3.25 (3H, s,
71H), 3.77 (2H, m, 81H), 1.67 (3H, t, 82H), 9.83 (1H, s, 10H), 3.63 (3H, s, 121H), 5.42 (2H, s,
151H), 3.67 (3H, s, 153H), 4.32 (1H, q, 17H), 1.78-2.46 (2H, m, 171H), 1.99 (2H, m, 172H), 3.82
(2H, m, 174H), 1.09 (3H, t, 175H), 4.45 (1H, q, 18H), 1.65 (3H, d, 181H)。
Embodiment 9:2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl 15-ethoxy acyl methyl-
The preparation of 17-ethoxy acyl ethyl-17,18-chlorin ferrous complex
According to embodiment 5 same procedure, with 2,7,12,18-tetramethyl-3-(1-methoxyethyls)-8-ethyl-13-carboxyl
15-ethoxy acyl methyl-17-ethoxy acyl ethyl-17,18-chlorin replaces 2,7,12,18-tetramethyl-3-(1 ethoxyethyl)-
8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl ethyl-17,18-chlorin prepares.Spectral data is such as
Under: LC-MS (ESI): [M+H]+=657,1H-NMR, (DMSO-d6,500MHz) δ ppm:3.45 (3H, s, 21H), 6.01-
6.03 (1H, m, 31H), 2.08 (3H, d, 32H), 3.56 (3H, s, 33H), 9.67 (1H, s, 5H), 3.25 (3H, s, 71H),
3.73 (2H, m, 81H), 1.62 (3H, t, 82H), 9.82 (1H, s, 10H), 3.61 (3H, s, 121H), 5.40 (2H, s, 151H),
3.62 (3H, s, 153H), 4.31 (1H, q, 17H), 1.78-2.40 (2H, m, 171H), 1.96 (2H, m, 172H), 3.81 (2H, m,
174H), 1.08 (3H, t, 175H), 4.40 (1H, q, 18H), 1.67 (3H, d, 181H)。
Effect example: large and small mouse Experimental Gastric Ucler and the biological of hypoferric anemia are lived by part of compounds of the present invention
Journal of Sex Research.
Effect example 1:2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl
Methyl-17-methoxy acyl ethyl-17,18-chlorin zinc complex inhibitory activity to large and small mouse Experimental Gastric Ucler
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy
Acyl ethyl-17,18-chlorin zinc complex (embodiment 3 compound) weighs and is dissolved in ethanol on a small quantity, then with water for injection
Being diluted to certain volume stand-by, the modeling the most in conventional manner of healthy large and small mouse becomes various gastric ulcer model, during normal raising one section
After between, after test group and other each control groups gastric infusion respectively, then carry out ulcer experimental result statistics by correlation method, draw
Result is as shown in the table.
The effect to rat chronic acetic acid type ulcer of the table 1. embodiment 3 compound gavage
*P<0.05; **P<0.01
As seen from Table 1, giving substantially shallow compared with control group with the rat gastric ulcer of embodiment 3 compound, part ulcer area contracts
Little, and there is obvious dose-effect relationship, show that this compound can promote the healing of experimental chronic gastric ulcer.
The effect to rat indocin type gastric ulcer of table 2. embodiment 3 gavage
*P<0.05; **P<0.01
Table 2 shows, intraperitoneal administration embodiment 3 compound 100 mg/kg, 300 mg/kg and 600 mg/kg can significantly subtract
The light mucosal lesion caused by indocin, and there is obvious dose-effect pass.Experiment is it is also shown that under same dose, be better than leaf
Green element copper sodium control group.
The effect to rat Pylorus Ligated Gastric Ulcer of table 3. embodiment 3 compound
X=SD n=7~11 *P<0.05 **P<0.01
The impact on pylorus-ligated rats gastric acid secretion of table 4. embodiment 3 compound
P<0.05
The feature of Pylorus Ligated Gastric Ulcer is that front stomach (film) has point-like hemorrhagic ulcer.Test result indicate that, implement
Example 3 compound can alleviate the stomach lining oedema of this type of gastric ulcer, reduces ulcer rates and reduce ulcer number (table 3), but right
Gastric acidity impact is little (table 4).
Table 5. embodiment 3 compound is to the protective effect of acute gastric mucosal injury caused by 50% ethanol
| Group | Number of animals | UI (mm2) | Ulcer number |
| Chlorophyll copper sodium group | 18 | 44.33±32.41 | 15.36±8.76 |
| Embodiment 10 | 18 | 24.08±16.97* | 12.38±10.40 |
X=SD P<0.02
The protective effect of the chmice acute gastric mucosa damage that ethanol is caused by table 6. embodiment 3 compound
| Group | Number of animals | UI (mm2) | Ulcer number |
| Chlorophyll copper sodium group | 22 | 20.45±17.81 | 8.77±6.25 |
| Embodiment 3 | 19 | 10.26±9.91* | 3.78±4.13** |
X=SD *P<0.02 **P<0.01
The big mouse acute gastric mucosal injury that 50% ethanol gavage is caused by embodiment 3 compound has significant protective effect
(table 5,6).50% ethanol is substantially suitable with the alcohol content of commercially available high spirit, and this compound can substantially reduce drinks to stomach
The damage that mucous membrane causes.
Effect example 2:2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl
Methyl-17-methoxy acyl ethyl-17,18-chlorin ferrous complex biologically active to rat hypoferric anemia
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy
Acyl ethyl-17,18-chlorin ferrous complex (embodiment 5 compound) weighs and mixes with low iron feed by a certain percentage in right amount
It is stand-by that chalybeate (in this experiment, chalybeate refers to embodiment 5 compound) feed uniformly made by sample, and healthy rat divides 3 groups at random, normally
Group is given and is fed with equivalent low iron formula feed with, iron deficiency group normal diet iron deficiency group, and experimental group is fed containing above-mentioned chalybeate feed with equivalent
Supporting, the most from the 3rd week, iron deficiency group and experimental group are aided with the most a small amount of tail venesection and set up iron-deficiency anemia model, weekly
Taking blood 1-1.5mL uses HemoCue to measure HC, and red blood cell number uses red blood cell count(RBC) plate to be shown by low
Micro mirror counts, and whole blood levels of iron index uses aas determination.Experimental result counting statistics, every finger is carried out after testing one month
Mark is as shown in table 7 below, table 8.
The impact (g/d) on rat feed intake of table 7 embodiment 5 compound
| Group | Number of animals | 1st week | 2nd week | 3rd week | 4th week |
| Normal group | 12 | 25.95± 1.78 | 25.45±1.57 | 26.77±0.25 | 26.95±0.79 |
| Iron deficiency group | 10 | 25.51± 1.16 | 22.26±1.91* | 21.78±0.43** | 18.63±1.18 |
| Embodiment 5 | 10 | 25.66± 1.25 | 25.62±1.82 | 26.53± 17.8 | 25.77±1.09 |
±S *P<0.02 **P<0.01
Group rat absorption 1st Wednesday forage volume no significant difference, starts iron deficiency group rat feed amount on the 2nd week significantly lower than just
Often group, simultaneously also below test group (iron deficiency forage feed supplements chalybeate group) simultaneously, iron deficiency group rat body weight is also significantly lower than real
Test group and normal group.
Testing the 3rd week Induced By Iron Deficiency Anemia In Rats model substantially to set up, HC is 90.82g/L, and normal group pair
It is 150.91g/L according to rat hemoglobin concentration, experimental group (with the addition of the low iron forage feed of iron supplementary) HC
Close with normal group is 151.21, and after testing one month, hypoferric anemia group rat hemoglobin (Hb) drops to 80.21g/L,
Its red blood cell (RBC) and full iron blood index also have significantly decline.Result is as shown in table 8.
Table 8. rat hemoglobin, red blood cell and whole blood levels of iron index determining result
±S *P<0.01
Above-mentioned experimental data shows, embodiment 5 compound (2,7,12,18-tetramethyl-3-(1-ethoxyethyl group)-8-second
Base-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl ethyl-17,18-chlorin ferrous complex) there is obvious resisting
Rat hypoferric anemia activity, developmental research can become resistance to iron deficiency anaemia medicine further.
Claims (16)
1. a 3-(1-alkoxyl oxygen alkyl ethyl) metal complex of chlorin e 6 analog, it is characterised in that chemical constitution such as formula I
Shown in:
Ⅰ
Wherein, M is bivalent metal ion Cu2+、Zn2+、Fe2+、Mn2+、Ni2+、Co2+Or Pd2+；
Described R1For H or unsubstituted C1-6Straight or branched alkyl；
Described R2、R3For unsubstituted C1-6Straight or branched alkyl.
2. 3-(1-alkoxyl oxygen alkyl ethyl as claimed in claim 1) metal complex of chlorin e 6 analog, it is characterised in that
Described C1-6Straight or branched alkyl is C1-4Straight chained alkyl.
3. 3-(1-alkoxyl oxygen alkyl ethyl as claimed in claim 1) metal complex of chlorin e 6 analog includes following appointing
What a kind of compound:
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl second
Base-17,18-chlorin zinc complex；
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl second
Base-17,18-chlorin copper complex；
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-methoxy acyl methyl-17-methoxy acyl second
Base-17,18-chlorin ferrous complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl-15-ethoxy acyl methyl-17-ethoxy acyl second
Base-17,18-chlorin zinc complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl-15-ethoxy acyl methyl-17-ethoxy acyl second
Base-17,18-chlorin copper complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl-15-ethoxy acyl methyl-17-ethoxy acyl second
Base-17,18-chlorin ferrous complex；
2,7,12,18-tetramethyl-3-(1-methoxyethyl)-8-ethyl-13-carboxyl-15-the third oxygen acyl methyl-17 the-the third oxygen acyl second
Base-17,18-chlorin zinc complex；
2,7,12,18-tetramethyl-3-(1-ethoxyethyl)-8-ethyl-13-carboxyl-15-fourth oxygen acyl methyl-17-fourth oxygen acyl second
Base-17,18-chlorin copper complex.
4. a 3-(1-alkoxyl oxygen alkyl ethyl as claimed in claim 1) the preparation side of metal complex of chlorin e 6 analog
Method, extracts the chlorin e 6 of isolated as raw material, including esterification, addition, replacement and complexation approach, wherein in silkworm excrement:
A () is esterified: silkworm excrement extracts the chlorin e 6 of isolated purified after, carry out with alcohol under sulphuric acid catalysis effect
Esterification, obtains compounds Ⅳ, and chemical constitution is as follows:
Ⅳ
The definition of the most each substituent is all with described in claim 1；It is for liquid under normal temperature with the alcohol of chlorin e 6 esterification
The C of state1-6Lower alcohol；
(b) addition: purified rear and halogenated acid the acetic acid solution of compounds Ⅳ carries out addition reaction, generates compound III, chemistry
Structure is as follows:
Ⅲ
Wherein X is halogen；It is bromo-acid or chloroacid with the halogenated acid of compounds Ⅳ addition reaction；
C () replaces: compound III carries out substitution reaction again from different alcohol, generates compound ii, and chemical constitution is as follows:
Ⅱ
It is for the C of liquid under normal temperature with the alcohol of compound III substitution reaction1-6Lower alcohol；
It is characterized in that, (d) is complexed: compound ii in a solvent, then with slaine at N2Under protection, stirring reaction generates chemical combination
Thing I, chemical constitution is as follows:
Ⅰ
The definition of the most each substituent is all with described in claim 1.
5. preparation method as claimed in claim 4, it is characterised in that described C1-6Lower alcohol be methyl alcohol, ethanol, propyl alcohol or
Butanol.
6. preparation method as claimed in claim 4, it is characterised in that described halogenated acid is bromo-acid.
7. preparation method as claimed in claim 4, it is characterised in that described solvent is dissolved compound II and slaine
Organic solvent；Described organic solvent is methyl alcohol, ethanol, acetone and/or dichloromethane.
8. preparation method as claimed in claim 7, described organic solvent is the mixed solvent of dichloromethane and methyl alcohol, both
Volume ratio is 1:1 ~ 20.
9. preparation method as claimed in claim 8, in described mixed solvent, dichloromethane is 1:2 ~ 10 with the volume ratio of methyl alcohol.
10. preparation method as claimed in claim 4, it is characterised in that be routine two with the slaine of compound ii complex reaction
Valency slaine is for zinc agent, for copper agent or for ferrous agent；Described is zinc acetate, zinc nitrate or zinc chloride for zinc agent, described for copper agent
For copper acetate, copper sulphate or copper chloride, described is frerrous chloride, ferrous sulfate or ferrous phosphate for ferrous agent.
11. preparation methods as claimed in claim 10, it is characterised in that described is zinc acetate for zinc agent, described is second for copper agent
Acid copper, described is frerrous chloride for ferrous agent.
12. preparation methods as claimed in claim 4, it is characterised in that solvent described in described complexation approach and compound ii
Volume mass ratio is 10 ~ 200ml/g, and compound ii is 1:1 ~ 6 with the mol ratio of slaine, and the stirring reaction time is 0.5 ~ 16h,
Reaction temperature is 0 ~ 80 DEG C.
13. preparation methods as claimed in claim 4, it is characterised in that solvent described in described complexation approach and compound ii
Volume mass ratio is 50 ~ 100ml/g, and compound ii is 1:2 ~ 4 with the mol ratio of slaine, and the stirring reaction time is 1 ~ 10h, instead
Answering temperature is 20～60 DEG C.
14. preparation methods as claimed in claim 4, it is characterised in that extract the two of isolated in described raw material i.e. silkworm excrement
Hydrogen porphines e6 all uses silica gel column chromatography to separate with the purifying of compounds Ⅳ, and solvent is dichloromethane, chloroform, four chlorinations
In carbon, methyl alcohol, ethanol, ethyl acetate, acetone and petroleum ether one or more and wherein containing the formic acid of cumulative volume 2% ~ 0.5%.
15. preparation methods as claimed in claim 14, it is characterised in that the first Han cumulative volume 1.2% ~ 0.8% in described solvent
Acid.
16. 3-(1-alkoxyl oxygen alkyl ethyls as claimed in claim 1) metal complex of chlorin e 6 analog preparing anti-stomach
Application in ulcer and resistance to iron deficiency anaemia medicine.
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