CN101885725A - Pyrro-quinoline quinine sodium salt derivative and preparation method thereof - Google Patents
Pyrro-quinoline quinine sodium salt derivative and preparation method thereof Download PDFInfo
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- CN101885725A CN101885725A CN2009100510728A CN200910051072A CN101885725A CN 101885725 A CN101885725 A CN 101885725A CN 2009100510728 A CN2009100510728 A CN 2009100510728A CN 200910051072 A CN200910051072 A CN 200910051072A CN 101885725 A CN101885725 A CN 101885725A
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Abstract
The invention relates to a pyrro-quinoline quinine (PQQ) sodium salt derivative and a preparation method thereof, belonging to the field of pharmacy. In the preparation method, PQQ is used as a raw material, and an acid-base neutralization reaction with PQQ is carried out in a basic solvent of sodium hydroxide to prepare the PQQ sodium salt derivative represented in the structural formula (I), wherein R1, R2 and R3 can be identical or different and respectively represents H, ammonium ion (NH3), potassium ion, sodium ion, magnesium ion, calcium ion or zinc ion, and at least one of R1, R2 and R3 is sodium ion. The invention has mild reaction conditions, easy product refining and purification, simple preparation steps and high yield more than 80%. The PQQ sodium salt derivative has the functions of inhibiting GSK-3 activity, reducing senile pigment formation in a transgenic mouse brain, reducing tau protein phosphorylation and the like. Thus, the PQQ sodium salt derivative can be medically used for treating senile dementia and other diseases.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to Pyrro-quinoline quinine sodium salt derivative and preparation method thereof.
Background technology
Prior art discloses pyrroloquinoline quinone, and (pyrroloquinoline quinone PQQ) is a kind of new vitamin B group, and (Nature 2003 in the metabolism of Methionin in the participation organism; 422:832).Its molecular weight of pyrroloquinoline quinone is 330, is found from microorganism the earliest, studies show that, also has PQQ to exist in the higher eucaryote body, and its crystalline structure and chemosynthesis are as shown below.
Pyrroloquinoline quinone is the prothetic group of multiple important enzyme, and can influence respiratory chain function and interior free yl level.Find the mouse poor growth that PQQ lacks in the research, reproductive performance is poor, is easy to generate arthritis, thereby thinks that PQQ is essential VITAMIN and a nutrient substance in the body.The function that known PQQ is relevant with neural system has following four kinds: (1) is anti-oxidant, removes free radical; (2) influence the respiratory chain function, safeguard the plastosome energy metabolism; (3) the excite nerve secretion of somatomedin is repaired and is promoted nerve growth; (4) delay the proteic deposition of α-synuclein, prevent the neurocyte fibrosis.Thereby, about the researchist thinks that PQQ has the potential therapeutic value to multiple neurodegenerative diseases such as Parkinson's disease and senile dementias.
But research practice shows that PQQ both had been insoluble in water, also has been insoluble in ordinary organic solvents, brings difficulty for pharmacy preparation etc., so that has influenced promoting the use of of PQQ.
Summary of the invention
The objective of the invention is for overcoming the deficiencies in the prior art, a kind of pyrroloquinoline quinone (PQQ) sodium salt derivative is provided.
The present invention adopts PQQ to carry out derivative reaction, introduces sodium ion in its molecule, is prepared into the PQQ sodium salt derivative.
Above-mentioned PQQ is after acid-base neutralisation reaction, deriving to Pyrro-quinoline quinine sodium salt, and it is water-soluble bigger improvement.Further, the PQQ sodium salt derivative can prepare the medicine of preventing and treating alzheimer's disease, has application value widely.
Another object of the present invention provides the method for preparing Pyrro-quinoline quinine sodium salt derivative.
The present invention utilizes the acid-base neutralisation prepared in reaction to become the PQQ sodium salt derivative on PQQ molecule carboxyl.Adopting the PQQ of structural formula (II) is raw material, in sodium hydroxide alkalescence solvent, carries out the acid-base neutralisation reaction, is prepared into the PQQ sodium salt derivative of structural formula (I), and wherein having one among R1, R2, the R3 at least is sodium ion.
Reaction formula is expressed as follows:
In the reaction formula of the present invention, R
1, R
2,R
3Can be identical or inequality, each represents hydrogen, ammonium ion (NH3), potassium ion, sodium ion, magnesium ion, calcium ion, zine ion, wherein R
1, R
2,R
3In have at least one to be sodium ion.
In the reaction method of the present invention, can not add acid or alkali as a catalyst, the alkalescence of reactant hydrogen sodium oxide itself and different concns thereof has been controlled the pH value of acid-base neutralisation reaction.The big I of the concentration of reactant hydrogen sodium oxide own influences the yield of structural formula (I).
In the method involved in the present invention, temperature of reaction can be carried out in 0 ℃～100 ℃ scopes, among the present invention, and preferred 15-20 ℃; Reaction times is different because of preparing different PQQ sodium salt derivatives, and among the present invention, the reaction times is 15 minutes to 72 hours.
Reaction conditions gentleness of the present invention, product is single, easily refining purifying, preparation process is simple, is beneficial to industrial production.
The salifiable routinely method of structural formula of the present invention (I) is prepared into the sodium salt of structural formula (I) in basic solvent.
The present invention has carried out the experimental study of control alzheimer's disease to the PQQ sodium salt derivative that makes, the result shows, described PQQ sodium salt derivative has effect such as senile plaque formation and Protein tau phosphorylation in the Transgenic Mice Brain of minimizing, can be used for treating diseases such as senile dementia in medical treatment.
Embodiment
The following example explanation the present invention.But the present invention is not limited by embodiment.
Test described temperature with degree centigrade (℃) expression.
Embodiment 1
4,5-dicarbapentaborane-1 hydrogen-pyrroles [2,3-f] quinoline-2,7,9-tricarboxylic acid trisodium salt (PQQ3Na) synthetic:
In the reactor of 1L, add 15.0 gram raw material and 450 milliliters of tetrahydrofuran (THF)s, stir down, the mixed solution of Dropwise 5 .8 gram sodium hydroxide and 150 ml waters, stirred 24 hours down at 15-20 ℃, hydrochloric acid neutralization reaction liquid, get reddish-brown precipitation, filter, obtain 16.2 gram reddish-brown powder solid product P QQ3Na (90.0%).
Embodiment 2
4,5-dicarbapentaborane-1 hydrogen-pyrroles [2,3-f] quinoline-2,7,9-tricarboxylic acid disodium salt (PQQ2Na) synthetic:
Add 15.0 gram raw material and 450 milliliters of tetrahydrofuran (THF)s in the reactor of 1L, stir down, drip the mixed solution of 3.87 gram sodium hydroxide and 150 ml waters, stirred 24 hours down at 15-20 ℃, hydrochloric acid neutralization reaction liquid obtains reddish-brown precipitation.Filter, obtain 14.4 gram reddish-brown powder solid product P QQ2Na (84.7%).
Embodiment 3
4,5-dicarbapentaborane-1 hydrogen-pyrroles [2,3-f] quinoline-2,7,9-tricarboxylic acid one sodium salt (PQQNa) synthetic:
In the reactor of 1L, add 15.0 gram raw material and 450 milliliters of tetrahydrofuran (THF)s.Under agitation, drip the mixed solution of 1.94 gram sodium hydroxide and 150 ml waters.Stirred 24 hours down at 15-20 ℃, hydrochloric acid neutralization reaction liquid obtains reddish-brown precipitation.Filter, obtain 8.1 gram reddish-brown powder solid product P QQNa (80.1%).
Embodiment 4 prevents and treats the experimental study of senile dementia:
1) Pyrro-quinoline quinine sodium salt of preparation different dosage form:
According to a conventional method, prepare Pyrro-quinoline quinine sodium salt tablet, pulvis, powder injection, rectal suppository, skin patch (transdermal administration), aqueous injection or sprays respectively;
2) clinical application of different dosage form Pyrro-quinoline quinine sodium salt experiment:
Adopt the Pyrro-quinoline quinine sodium salt of different dosage form, the different approaches of through port (containing) clothes, intramuscular injection, abdominal injection, intravenous injection, spray delivery, rectal administration or transdermal administration is used and is prevented or treat alzheimer's disease or old and feeble experiment 0.1 milligram-1000 milligrams of every days;
3) experimentation on animals curative effect observation:
By oral or intraperitoneal injection mode, give Kunming kind naturally-aged mouse, transgenosis Alzheimer disease model mouse was taken prepared Pyrro-quinoline quinine sodium salt 2 months continuously, by 1 milligram of administration of per kg body weight per day, with non-treatment group is control group, the result shows that Pyrro-quinoline quinine sodium salt treatment group has remarkable improvement and treats the cognitive function of animal, prolongs its average expected life-span effect.The result shows that Pyrro-quinoline quinine sodium salt of the present invention has prevention and treatment alzheimer's disease and old and feeble effect;
Continuous or branch different time sections administration reaches 2 months, every day, dosage was 0.1 milligram to 1000 milligrams, wherein, adopt Pyrro-quinoline quinine sodium salt and add benfotiamine or add benfotiamine and Coenzyme Q10 99.0, wherein, Pyrro-quinoline quinine sodium salt dosage is 0.1 milligram to 1000 milligrams of every day, and benfotiamine or Coenzyme Q10 99.0 dosage every day are respectively 1 milligram to 1000 milligrams.
The result shows, Pyrro-quinoline quinine sodium salt and and benfotiamine and/or the prevention of Coenzyme Q10 99.0 combined utilization and treatment alzheimer's disease or aging have above-mentioned effect same.
Embodiment 5: prevent and treat Parkinsonian experimental study experiment
1) Pyrro-quinoline quinine sodium salt of preparation different dosage form:
According to a conventional method, prepare Pyrro-quinoline quinine sodium salt tablet, pulvis, powder injection, rectal suppository, skin patch (transdermal administration), aqueous injection, sprays etc. respectively;
2) clinical application of different dosage form Pyrro-quinoline quinine sodium salt experiment:
Use the Pyrro-quinoline quinine sodium salt of different dosage form, the different approaches of through port (containing) clothes, intramuscular injection, abdominal injection, intravenous injection, spray delivery, rectal administration or transdermal administration is used 0.1 milligram-1000 milligrams preventions every day or treatment alzheimer's disease or aging;
3) experimentation on animals curative effect observation:
By oral or intraperitoneal injection mode, give 6-hydroxyl DOPA inductive Parkinson disease model rat and took Pyrro-quinoline quinine sodium salt continuously 2 months, by 1 milligram of administration of per kg body weight per day, with non-treatment group is control group, the result shows that Pyrro-quinoline quinine sodium salt treatment group has the remarkable motor function of improving animal pattern.The result shows that Pyrro-quinoline quinine sodium salt has prevention and treats Parkinsonian effect;
Continuously or the administration of branchs different time sections reach 2 months, every day, dosage was 0.1 milligram to 1000 milligrams, wherein, employing Pyrro-quinoline quinine sodium salt and add benfotiamine or add benfotiamine and Coenzyme Q10 99.0.Wherein, Pyrro-quinoline quinine sodium salt dosage is 0.1 milligram to 1000 milligrams of every day, and benfotiamine or Coenzyme Q10 99.0 dosage every day are respectively 1 milligram to 1000 milligrams.
The result shows, pyrroloquinoline quinone and and benfotiamine and/or the prevention of Coenzyme Q10 99.0 combined utilization and treatment Parkinson's disease have above-mentioned effect same.
Claims (8)
1. Pyrro-quinoline quinine sodium salt derivative, it is characterized in that the having formula structure of (I)
R wherein
1, R
2, R
3Identical or inequality, each represents hydrogen, ammonium ion (NH3), potassium ion, sodium ion, magnesium ion, calcium ion, zine ion, wherein R
1, R
2,R
3In have at least one to be sodium ion.
2. by the preparation method of the described Pyrro-quinoline quinine sodium salt derivative of claim 1, the compound that it is characterized in that employing formula (II) is a raw material, in basic solvent, carries out the acid-base neutralisation reaction, is prepared into the PQQ sodium salt derivative of structural formula (I),
3. by the described preparation method of claim 2, wherein said basic solvent is the sodium hydroxide solvent.
4. by the described preparation method of claim 2, in the wherein said reaction method, can not add acid or alkali as a catalyst.
5. by the described preparation method of claim 2, in the wherein said reaction method, temperature of reaction is 0 ℃～100 ℃.
6. by the described preparation method of claim 2, in the wherein said reaction method, temperature of reaction is 15-20 ℃.
7. by the described preparation method of claim 2, in the wherein said reaction method, the reaction times is 15 minutes to 72 hours.
8. the Pyrro-quinoline quinine sodium salt derivative of claim 1 is prevented and treated application in senile dementia, aging or the Parkinson's disease medicine in preparation.
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| CN102471336A (en) * | 2009-07-16 | 2012-05-23 | 三菱瓦斯化学株式会社 | Crystals of pyrroloquinolinequinone sodium salts |
| CN103351387A (en) * | 2013-07-01 | 2013-10-16 | 上海日馨生物科技有限公司 | Preparation method of pyrroloquinolinequinone lithium salt crystal and applications thereof |
| WO2014071772A1 (en) * | 2012-11-09 | 2014-05-15 | 诸城市浩天药业有限公司 | Pyrroloquinoline quinine disodium salt crystal |
| CN106255691A (en) * | 2014-04-16 | 2016-12-21 | 安瑟生物科技私人有限公司 | 4,5 dihydro 1H pyrrolo-[2,3 F] quinoline 2,7,9 tricarboxylic acids and the polymorphic forms of disodium salt, Preparation Method And The Uses |
| WO2017050171A1 (en) * | 2015-09-25 | 2017-03-30 | 浙江海正药业股份有限公司 | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof |
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2009
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