CN1508131A - Ferrous orotic acid, and preparing method and use thereof - Google Patents
Ferrous orotic acid, and preparing method and use thereof Download PDFInfo
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- CN1508131A CN1508131A CNA021567654A CN02156765A CN1508131A CN 1508131 A CN1508131 A CN 1508131A CN A021567654 A CNA021567654 A CN A021567654A CN 02156765 A CN02156765 A CN 02156765A CN 1508131 A CN1508131 A CN 1508131A
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- ferrous
- orotate
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Abstract
The present invention relates to an orotic acid ferrous compound or its hydrate or solvolyte, said invention also relates to a preparation process for preparing orotic acid ferrous compound, and relates to application of the medicine prepared by using said orotic acid ferrous compound for curing the diseases of iron-deficiency anemia or human body liver disease and medicine composition containing orotic acid ferrous compound. Said invented product is prepared by making orotic acid and ferrous salts implement reaction in proper solvent.
Description
The present invention relates to a kind of medical compounds, particularly, the present invention relates to ferrous orotate compound or its hydrate or solvate and its production and use.
Hypoferric anemia is that a kind of common disease and frequently-occurring disease, particularly children and pregnant woman suffer from this disease easily.Usually use ferrous sulfate treatment defective anaemia at present clinically, but, because iron ion overrich in the stomach, exist to feel sick, side effect such as vomiting when the patient takes ferrous sulfate, many patients have to discontinue medication owing to not tolerating, and have seriously influenced the disease of patient result of treatment.Therefore, people need objectively that a kind of mouthfeel is better, side effect is little and the medicine of the treatment hypoferric anemia of stable curative effect.Ferrous orotate can slowly be decomposed into ferrous ion and vitamin B13 under the interaction of intravital gastroenteric environment of people and human-body biological enzyme etc.On the one hand the slow release of ferrous ion can be avoided fully because of untoward reactions such as feeling sick of causing of the iron ion overrich in the stomach, vomitings; On the other hand, can make the absorption of iron ion more complete and thorough, make better efficacy.Moreover the vitamin B13 of generation itself belongs to the newcomer VB in the VITAMIN family
13[Beil,
25253], be a kind of good liver protecting medicine; Vitamin B13 strengthens cell viability to promoting metabolism of human cell simultaneously, prevents that aging from also having better action.Therefore, ferrous orotate not only can be used as iron-supplementing preparation and is used for the treatment of hypoferric anemia, and also effective in cure to diseases such as treatment human livers.
A kind of new ferrous orotate compound or its hydrate or solvate have been the purpose of this invention is to provide;
Another object of the present invention has provided the preparation method of preparation ferrous orotate or its hydrate or solvate;
Another object of the present invention has provided the purposes with the medicine of ferrous orotate or its hydrate or solvate preparation treatment hypoferric anemia disease;
Another object of the present invention has provided the purposes with the medicine of ferrous orotate or its hydrate or solvate preparation treatment human liver disease;
Another object of the present invention has provided the pharmaceutical composition that contains ferrous orotate compound or its hydrate or solvate.
The inventor finds, in appropriate solvent such as polar solvent, as single polar solvents such as DMSO, DMF or water, or under one or more the reaction conditionss in them with the mixed solvent of arbitrary proportion and 20-100 ℃, carboxyl in the vitamin B13 (Orotic acide) (COOH) to a certain degree disassociation takes place, the carboxylate radical with lone-pair electron of generation (COO-) can with the transition metal iron ion (Fe with sky d-track
2+) carry out the ligand complex reaction, thus the ferrous orotate coordinated metal complex generated, and this title complex can contain 0-6 crystal water, preferably contains 3 crystal water or does not contain crystal water.
Ferrous orotate structural formula of compound of the present invention is as follows:
Wherein X is the integer of 0-6, and preferred X is 0 or 3.
Reaction formula of the present invention is as follows:
Wherein, reaction product can have 0-6 crystal water, preferably has 0 or 3 crystal water.
Therefore, the inventor is by research, prepare the ferrous orotate compound, and, the inventor is surprised to find, and this compound can be used as the benefit chalybeate, can be used for the treatment of hypoferric anemia effectively, can be used to prepare the medicine of treatment hypoferric anemia disease, also can be used to prepare the medicine of treatment human liver disease.
The inventor finds that also ferrous orotate of the present invention can combine with pharmaceutically acceptable carrier, makes multiple forms of pharmaceutical compositions, as tablet, capsule, oral liquid, granule, pill, soft capsule, injection etc.
Particularly, the present invention includes following content and step:
The preparation of ferrous orotate: with protection of inert gas and deoxygenation; under agitation; vitamin B13 is added in the appropriate solvent; solvent is the mixture of deionized water or water-soluble polar organic solvent or deionized water and water-soluble polar organic solvent; after the heating for dissolving; add ferrous salt and carry out the ligand complex reaction, the ferrous crude product of obtain whey acid.Wherein the mol ratio of ferrous salt and vitamin B13 is 0.5-2: 1, and preferably 0.6: 1, temperature of reaction was 20-100 ℃, preferred 50-95 ℃, more preferably 65-85 ℃, reaction needs 2～10 hours approximately, after the reaction after filtration, the washing, then at 50～80 ℃ of following vacuum-dryings, yield 80～95%.
Protection of inert gas gas among the present invention can be selected from one or more in nitrogen, argon gas, the helium; water-miscible organic solvent can be selected from dimethyl sulfoxide (DMSO), N, dinethylformamide; tetrahydrofuran (THF); ethylene glycol, glycerine, 1; the 2-propylene glycol; 1, one or more in the ammediol, ferrous salt can be selected from one or more in iron protochloride, ferrous sulfate, ferrous ammonium sulphate or the ferrous acetate.
The purifying of ferrous orotate: solvent is a dimethyl sulfoxide (DMSO).The ferrous orotate crude product that the makes ratio by weight 1: 0.5～5 is added solvent, and under protection of inert gas, low-grade fever stirred 10～60 minutes, and temperature is controlled at below 80 ℃, filtered then, washing, vacuum-drying get product, yield 80～96%.
The sign of ferrous orotate: the ferrous orotate behind the purifying is carried out infrared spectra (IR) analysis respectively see accompanying drawing 1.The difference that the infrared spectra of raw material vitamin B13 and product ferrous orotate is very big: 1. the raw material vitamin B13 is at 3438.796cm
-1The weak absorption at place has become the 3345.00cm in the product
-1Near strong absorption peak in; 2. 1700cm
-1Near two carbonyl absorption peaks violet shift (moving to high wave number direction) and two peaks have taken place gets more and open; 3. 1416 and 1380cm
-1The intensity at two peaks obviously increases, especially latter's intensity even surpassed 1440cm
-1Absorption peak; 4. be positioned at 1264-1341cm in the raw material
-1Between several absorption peaks disappear and become 1299cm
-1A weak absorption peak; 5. fingerprint region (＜1000cm
-1) increased many absorption peaks; The infrared spectra of raw material vitamin B13 is seen Fig. 2.The result shows: product is pure ferrous orotate, and purity is more than 98%.
Solvent recovery cycle: the mother liquor that will prepare after ferrous orotate product and purifying products filter merges, and adjusts the pH value of solution value earlier to neutral, and moisture is removed in evaporation on Rotary Evaporators; Then, be transferred to vacuum distillation apparatus, under suitable vacuum tightness, carry out underpressure distillation, reclaim reaction solvent, recycle.
Contain ferrous orotate composition medicaments preparation:, ferrous orotate compound of the present invention or its hydrate or solvate and pharmaceutically acceptable carrier compatibility can be made various formulations according to the field of pharmaceutical preparations known method.Ferrous orotate of the present invention and pharmaceutically acceptable carrier can be mixed by a certain percentage, compressing tablet is made tablet on the medicine tabletting machine then.Wherein the weight content of ferrous orotate in pharmaceutical composition can be between 0.1-80%.
The animal experiment of ferrous orotate treatment hypoferric anemia disease: with the anaemia rat is subjects, and ferrous orotate is pressed 2mg/g-0.02mg/g respectively with high, medium and low different dosed administration, and contrasts with commercially available benefit chalybeate.
Description of drawings
Accompanying drawing 1: the infrared spectrogram of ferrous orotate (pressing potassium bromide troche)
Accompanying drawing 2: the infrared spectrogram of vitamin B13 (pressing potassium bromide troche)
Embodiment
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment 1: preparation ferrous orotate compound
In the 1000ml four neck round-bottomed flasks that electric mixer, condenser, porous gas sparger, thermometer and constant pressure funnel are housed, the mixing solutions that adds 600ml dimethyl sulfoxide (DMSO) and 200ml deionized water, feed the nitrogen deoxygenation, start stirring, vitamin B13 52.0 grams that slowly add accurate weighing, control reaction temperature stirs adding iron vitriol solid 60.0 grams down at 80 ℃.Finish continuing stirring reaction under 80 ℃ the temperature after 2 hours, be warming up to 85 ℃, reacted 6 hours, check that with thin-layer chromatography vitamin B13 reacts completely.Then, leave standstill the cooling layering, with deionized water wash to sulfate radical-free (SO
4 -), with B suction filtration under water jet pump, continue to use the deionized water wash filter cake.Then, in 60 ℃ vacuum drying oven dry 8 hours.It is fine ground that taking-up is ground alms bowl with agate.Get ferrous orotate 55g, yield 88%.
Under nitrogen protection, the ferrous orotate product that obtains is joined in the dimethyl sulfoxide (DMSO) of 250ml, under 50 ℃ temperature, stirred 30 minutes, filtered while hot, washing, vacuum-drying get ferrous orotate product 53g, yield 96% then.
Mother liquor after preparation ferrous orotate product and the purifying products filtration is merged, use sodium bicarbonate NaHCO
3Regulator solution pH value to neutral back vacuum distillation recovered solvent recycles.
The ferrous orotate product of gained is done analyses such as impurity content mensuration such as infrared spectra, ultimate analysis, total iron and heavy metal.
The ultimate analysis of ferrous orotate compound:
| N％ | C％ | H％ | Fe％ | |
| Measured value: | 13.20 | 29.43 | 3.05 | 13.43 |
| Calculated value: | 13.38 | 29.74 | 2.98 | 13.39 |
The ferrous orotate infrared spectra:
Characteristic peak (cm
-1): 3345,1616,1416,1380,1299,807.
Impurity content measurement results such as iron total amount and heavy metal
| Molecular formula C 10H 6FeN 4O 8·3H 2O | Molecular weight 420 |
| Content＞98% | Total iron content 13.43% |
| Nitrogen (N): 13.20% | Hydrogen (H): 3.05% |
| Chlorine (Cl -)：0.002％ | Manganese (Mn): 0.05% |
| Arsenic (As): 0.0002% | Zinc (Zn): 0.005% |
| Plumbous (Pb): 0.002% | Copper (Cu): 0.002% |
Embodiment 2: preparation ferrous orotate compound
Other just changes into N with solvent dimethyl sulfoxide (DMSO) (DMSO) with embodiment 1, dinethylformamide (DMF), the mixing solutions that consists of 600ml DMF and 100ml deionized water of solvent.Get ferrous orotate product 52g, yield 83% by the step identical with embodiment 1.
Embodiment 3: the ferrous orotate compound is used for the treatment of the test of the hypoferric anemia disease of rat
Experimental technique:
1. prepare the low about 10-20 kilogram of feed of iron-holder;
2. give the young rat of firm wean and feed low iron feed; Quicken anaemia every putting about 10 of tail blood day;
3. put tail blood weekly and survey oxyphorase, red corpuscle is weighed;
4. treat red corpuscle,, oxyphorase begin when reducing to the tool statistical significance experiment;
5. the anaemia rat is divided 6 groups at random: be divided into the normal control group, negative control group, commercially available chalybeate control group, the high, medium and low dosage group of ferrous orotate;
6. at least ten every group female, great and mighty or powerful mouse;
7. low ferrous orotate dosage: 2mg/Kg, 0.2mg/Kg, 0.02mg/Kg, be administered once every day, and the oral dosage of commercially available chalybeate control group is undertaken by this medicine specification sheets;
8. administration cycle: surveyed a Hb in per 5 days, RBC, about 2 week the back finish.
Experimental result: show that the ferrous orotate compound can treat the hypoferric anemia disease of rat effectively.
Claims (14)
1. the ferrous orotate compound of a following formula or its hydrate or solvate:
Wherein X is the integer of 0-6.
2. according to ferrous orotate compound or its hydrate or the solvate of claim 1, wherein X is 0.
3. according to ferrous orotate compound or its hydrate or the solvate of claim 1, wherein X is 3.
4. a method for preparing ferrous orotate compound or its hydrate or the solvate of one of claim 1-3 is characterized in that: in appropriate solvent vitamin B13 and ferrous salt are reacted.
5. according to the method for claim 4, it is characterized in that reaction is protection gas with the rare gas element, solvent is the mixture of deionized water or water-soluble polar organic solvent or deionized water and water-soluble polar organic solvent.
6. according to the method for claim 5; it is characterized in that: described protection gas is selected from one or more in nitrogen, argon gas, the helium, and water-miscible organic solvent is selected from dimethyl sulfoxide (DMSO), N; dinethylformamide; tetrahydrofuran (THF), ethylene glycol, glycerine; 1; the 2-propylene glycol, 1, one or more in the ammediol.
7. according to the method for claim 6, it is characterized in that: described ferrous salt is selected from one or more in iron protochloride, ferrous sulfate, ferrous ammonium sulphate or the ferrous acetate.
8. according to the method for one of claim 4-7, it is characterized in that: described temperature of reaction is 20～100 ℃, and the molar ratio scope of described ferrous salt and vitamin B13 is 0.5～2: 1.
9. method according to Claim 8, it is characterized in that: described temperature of reaction is 50～95 ℃, the molar ratio scope of described ferrous salt and vitamin B13 is 0.6: 1.
10. the method according to claim 9 is characterized in that: described temperature of reaction is 65～85 ℃.
11. the ferrous orotate of one of claim 1-3 or its hydrate or solvate are used to prepare the purposes of treatment hypoferric anemia disease medicament.
12. the ferrous orotate of one of claim 1-3 or its hydrate or solvate are used to prepare the purposes of treatment human liver disease medicament.
13. a pharmaceutical composition for the treatment of hypoferric anemia disease or diseases such as treatment human liver etc. is characterized in that containing ferrous orotate or its hydrate or solvate and pharmaceutically acceptable carrier of one of claim 1-3.
14., it is characterized in that it to be tablet, capsule, oral liquid, granule, pill, soft capsule, injection according to the pharmaceutical composition of claim 12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021567654A CN1508131A (en) | 2002-12-18 | 2002-12-18 | Ferrous orotic acid, and preparing method and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021567654A CN1508131A (en) | 2002-12-18 | 2002-12-18 | Ferrous orotic acid, and preparing method and use thereof |
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|---|---|
| CN1508131A true CN1508131A (en) | 2004-06-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA021567654A Pending CN1508131A (en) | 2002-12-18 | 2002-12-18 | Ferrous orotic acid, and preparing method and use thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100344326C (en) * | 2005-09-30 | 2007-10-24 | 北京康比特威创体育新技术发展有限公司 | Iron-supplementing preparation |
| WO2018148922A1 (en) * | 2017-02-17 | 2018-08-23 | 普惠德生技股份有限公司 | Use of composition containing ferrous amino acid chelate for manufacturing medicament for treating dysfunction of liver |
-
2002
- 2002-12-18 CN CNA021567654A patent/CN1508131A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100344326C (en) * | 2005-09-30 | 2007-10-24 | 北京康比特威创体育新技术发展有限公司 | Iron-supplementing preparation |
| WO2018148922A1 (en) * | 2017-02-17 | 2018-08-23 | 普惠德生技股份有限公司 | Use of composition containing ferrous amino acid chelate for manufacturing medicament for treating dysfunction of liver |
| CN110198709A (en) * | 2017-02-17 | 2019-09-03 | 普惠德生技股份有限公司 | Composition containing Ferrous amino acid chelates is used to manufacture the purposes of the pharmaceuticals for the treatment of dysfunction of liver |
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