CN102796156B - Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof - Google Patents
Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof Download PDFInfo
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- CN102796156B CN102796156B CN201210314213.2A CN201210314213A CN102796156B CN 102796156 B CN102796156 B CN 102796156B CN 201210314213 A CN201210314213 A CN 201210314213A CN 102796156 B CN102796156 B CN 102796156B
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 238000012859 sterile filling Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Abstract
The invention relates to an adenosine cyclophosphate double-molecule meglumine compound and a preparation method thereof, and provides a compound formed by 1 molecule of adenosine cyclophosphate and 2 molecules of meglumine, a preparation method thereof and a medicinal composition comprising the denosine cyclophosphate double-molecule meglumine compound. The water solubility and the stability of the compound are more excellent than those of the conventional compounds.
Description
Technical field
The present invention relates to a kind of cAMP two meglumine compounds and preparation method thereof, belong to the synthetic field of pharmaceutical chemistry.
Background technology
CAMP is a kind of protein kinase activator, belongs to the derivative of Nucleotide.It is a kind of important substance with physiologically active extensively existing in human body, is generated under adenosine cyclase catalysis by Triphosaden, can regulate the several functions activity of cell.As the second messenger of hormone, in cell, bring into play the effect of hormone regulation physiological function and substance metabolism, change the function of cytolemma, impel the calcium ion in sarcoplasm matter to enter myofiber, thereby enhancing myocardial contraction, and promote the oxidasic activity of respiratory chain, and improve myocardial anoxia, alleviate coronary heart disease symptom and improve electrocardiogram(ECG.In addition, synthetic adjusting to sugar, metabolism of fat, nucleic acid, protein etc. plays an important role.
Meglumine, molecular weight is 195, soluble in water, there is suitable alkalescence and certain reductibility, and safe, nontoxic, with the compound combination that contains phenolic hydroxyl group, after salify to skin, mucous membrane, organize nonirritant, therefore be suitable as very much the solubility promoter of medicine, improve the water-soluble of principal constituent.
CAMP is slightly soluble in water, adds meglumine can increase its solvability in cAMP.Meglumine Adenosine Cyelophosphate (1: 1 compound of cAMP and meglumine, chemical name: meglumine cyclic adenylate, be called for short MCA, trade(brand)name, meglumine cyclic adenylate, MCA) injection liquid, be a kind of cardiac drug, be used for the treatment of heart failure, myocarditis, sick sinus syndrome, coronary heart disease, myocarditis, and ARR assisting therapy.Because of its determined curative effect, effect is unique in recent years, and security is good, is widely used in clinical.But it is water-soluble, stability is still not enough, impurity showed increased in the time of standing storage, and also it is water-soluble not, can not be used for oral preparations etc.Therefore this area also needs a kind of stable cAMP medicine, can be for the applicable illness of cAMP, and Simultaneous Stabilization, safety, effective, good water solubility.
Summary of the invention
The object of the invention is to address the above problem, the compound of a kind of cAMP and meglumine is provided, i.e. cAMP two meglumine compounds, this compound is safer, stable, effective, has better water-soluble simultaneously.
Another object of the present invention is to provide the preparation method of described compound.
The present invention also provides a kind of pharmaceutical composition, and it comprises described compound and pharmaceutically acceptable carrier.
Another object of the present invention is to provide the application of described compound in preparation treatment heart failure, myocarditis, sick sinus syndrome, coronary heart disease, myocarditis and antiarrhythmic medicament.
As previously mentioned, it is known in the art that cAMP and meglumine share, and their 1: 1 salifies are for injection.But in Meglumine Adenosine Cyelophosphate solution, along with the prolongation of shelf time, cAMP can be separated out gradually, liquid is occurred rotten, muddy, as changing small being difficult for, it is discovered, there will be serious untoward reaction if deliver medicine to patient, thereby affect the curative effect of medicine, affect the security of medication simultaneously.Meglumine cyclic adenosine injection is in solution state preservation process, easily meeting light changes, make drug degradation, because its clinical anaphylaxis increase, curative effect decline, and Meglumine Adenosine Cyelophosphate solution is subject to the affecting oxidation, polymerization of environmental factors and medicines structure is changed.
The inventor, through concentrating on studies, finds, under 60-70 DEG C of heating 0.5-2 hour, the meglumine of 1 molecule cAMP and 2 molecules to be synthesized to a compound.Find by analysis, under heating condition, meglumine not only with the phosphatase reaction of cAMP, and can react with the weakly acidic phenolic group of embodiment, cAMP two meglumine compounds are so just formed, the compound stability forming and water-soluble better is better cAMP medicinal forms.And the control of temperature is critical, temperature is too low, can not form described compound, only may form 1: 1 compound; Excess Temperature, has impact to the stability of cAMP and meglumine self, and impurity is too much.Based on above-mentioned discovery, complete the present invention.
Described compound structure is as follows:
The preparation method of compound of the present invention, simple process, it comprises:
Meglumine and DMF are joined in cAMP suspension and stirred, then at 60-70 DEG C, be heated to clarification, the direct described compound of acquisition after lyophilize.
Wherein, described cAMP suspension joins cAMP in water, methyl alcohol or ethanol and is prepared from, and the mol ratio of meglumine and cAMP is 2-10: 1.Usually, be 0.5-2 hour heat-up time.
The present invention also provides a kind of pharmaceutical composition, and it comprises described compound and pharmaceutically acceptable carrier, can be mixed with the form through any suitable administration, can prepare pharmaceutically acceptable any pharmaceutical dosage form, comprises injection, for example powder pin, injection liquid; Oral preparations, such as tablet, capsule, granule, oral liquid, powder agent, pill, sublingual administration agent etc.; Parenteral eye drop, nasal drops, [Dan etc. can be also the controlled release agent types of above various formulations.
Pharmaceutical carrier can comprise vehicle or thinner, for example, in Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin, cyclodextrin derivative one or more; Tackiness agent, for example, in polyvinylpyrrolidone, methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, guar gum, xanthan gum one or more; Lubricant, for example, in Magnesium Stearate, stearic acid, talcum powder, stearyl fumarate, Sodium Lauryl Sulphate BP/USP one or more; Disintegrating agent, for example, in sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, croscarmellose sodium, crosslinked carboxymethyl fecula sodium, pregelatinized Starch one or more; Tensio-active agent, for example, in sodium lauryl sulphate, Tween-80 one or more; PH adjusting agent or buffer reagent, one or more of for example phosphate buffered saline buffer, citric acid, Trisodium Citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide; Sanitas, for example, in Sodium Benzoate, potassium sorbate, methyl p-hydroxybenzoate, propylparaben one or more; Stablizer and oxidation inhibitor, for example, in Calcium Disodium Edetate, S-WAT, vitamins C one or more; Seasonings, for example, in maltose alcohol, fructose, sucrose, soluble saccharin, flavoring orange essence, strawberry flavour one or more; And other auxiliary material.
It is also understood that in the time that formulation is tablet or capsule, can be film dressing.For the material of film dressing, comprise applicable Drug coating, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate; Softening agent, for example polyoxyethylene glycol, triethyl citrate; Solubilizing agent, as Polyoxyethylene Sorbitan Monooleate; Pigment, as titanium dioxide, various ferric oxide, pink pigment, etc.
Pharmaceutical composition as above can also comprise other and have the material of pharmaceutical active, and for example, for the medicine of disease as mentioned above, the pharmaceutical composition that forms a kind of compound carrys out combination therapy.
The advantage of compound of the present invention is that it is water-soluble, stability is better, has also kept the activity of cAMP self simultaneously, and this is that it is with respect to cAMP and the outstanding feature of cAMP one meglumine salt.This is useful especially for preparation and storage pharmaceutical preparation.
Compound of the present invention has the pharmacological action identical with cAMP.In heart failure, myocarditis, sick sinus syndrome, coronary heart disease, myocarditis and ARR correlation model, by described salt and cAMP and cAMP one comparing property of meglumine salt test, find that they have substantially suitable effect, do not exist notable difference.This shows, is consistent with the knowledge of this area, and salify can't change the activity of medicine.
Compound water soluble of the present invention, stability are better, and preparation method is easy, are applicable to scale operation, are suitable for preparing various types of pharmaceutical dosage forms, for effective application of cAMP provides better selection.
Embodiment
Be further detailed below by embodiment, but the present invention is not limited in these embodiment.
Embodiment 1. cAMP two meglumines and preparations thereof
Getting 0.30g (0.911mmol) cAMP adds in 20ml ethanol, stir and heat and make to dissolve completely, add wherein 0.49g (2.53mmol) meglumine, slowly add and stir, after completing, at 65 DEG C, heat 1.8 hours, to solution clarification, lyophilize, obtain the cAMP two meglumine 0.607g (yields: 93.5%) of white powder.
1HNMR(DMSO-d
6)δ(ppm)：0.767～0.785(4H，t)，1.134～1.160(21H，m)，1.450～1.466(4H，m)，2.514(4H，s)，2.815～2.843(2H，m)，2.946～2.997(2H，m)，3.312～3.319(4H，m)，3.385～3.427(8H，m)，3.640～3.654(6H，m)，3.835～3.844(2H，m)，3.931～3.952(4H，m)，4.154(2H，s)，4.371(2H，s)，6.658～6.616(6H，m)，7.082(2H，d)。
13CNMR(DMSO-d
6)δ(ppm)：13.967，22.117，25.597，29.137，31.289，33.289，51.435，53.465，63.461，66.956，67.719，68.864，70.283，113.474，121.044，130.304，141.446。
Embodiment 2. cAMP two meglumines and preparations thereof
Getting 0.50g (1.519mmol) cAMP adds in 35ml water, stir and heat and make to dissolve completely, add wherein 1.20g (6.148mmol) meglumine, slowly add and stir, after completing, at 70 DEG C, heat 0.8 hour, to solution clarification, lyophilize, obtain the cAMP two meglumine 0.987g (yields: 90.8%) of white powder.
CAMP two meglumines of above-mentioned preparation or its hydrate, through proton nmr spectra, carbon spectrum analysis, are all consistent with embodiment 1.
Embodiment 3. Accelerated stability tests
CAMP at high temperature can decompose conventionally, produces impurity impurity, is referred to as total related substance, under hot conditions, measures the wherein content of total related substance, analyzes its stability.
Get in 50 DEG C of baking ovens of appropriate cAMP two meglumine, respectively at sampling in the 5th, 10 days, measure total related substance wherein.
Adopt high-efficient liquid phase chromatogram technique analysis, test-results is in table 1.
Table 1
Measurement result shows, 50 DEG C of cAMP two meglumine high temperature are placed 10 days, and total its related substances increases to some extent, but that the overwhelming majority still keeps is stable, more more stable than cAMP one meglumine.
Embodiment 4. soluble tests
Through rough determination comparison, cAMP two meglumines and cAMP water-soluble (normal temperature and pressure) are compared as follows table 2.
Table 2
| Compound | Water-soluble (mg/ml water) |
| CAMP two meglumines | Be less than 1 |
| CAMP one meglumine | Be greater than 8 |
| CAMP | Be greater than 20 |
As can be seen from Table 2, the water-soluble cAMP that is far longer than of cAMP two meglumines of the present invention, is also greater than cAMP one meglumine, shows the water-soluble of excellence.
The lyophilized injectable powder of embodiment 4. cAMP two meglumines
| CAMP two meglumines | 30g |
| N.F,USP MANNITOL | 120g |
| Buffer reagent | In right amount |
| Water for injection | Add to 2500ml |
CAMP two meglumines, the N.F,USP MANNITOL of getting recipe quantity add 2300ml water for injection and dissolve, regulating pH is 5～6, injects water to 2500ml, with filtering with microporous membrane degerming, under hundred grades of conditions, carry out in sterile filling to 1000 cillin bottle, check after loading amount and add plug, box out, glass bottle is sent into in the freeze drying box of having sterilized, to carry out freeze-drying dry, pre-freeze 5 hours, temperature drops to-35 DEG C, distils for the first time 8 hours, and temperature rise is to-5 DEG C; Distil for the second time 7 hours, temperature rise to 25 DEG C, takes out after vacuum gland or inflated with nitrogen gland, and jewelling lid labeling gets product, and every bottle of freeze-dried powder is containing cAMP two meglumine 30mg.
Embodiment 5. cAMP two meglumine injections
Meglumine cyclic adenylate salt described in embodiment 1-2 and conventional pharmaceutical excipient are mixed, press the preparation method of injection, be prepared into freeze-dried powder injection or injection liquid, the meglumine cyclic adenylate salt that every bottle of freeze-dried powder injection or injection liquid contain 0.1～500mg.
Embodiment 6. cAMP two meglumine tablet/capsules
Meglumine cyclic adenylate salt described in embodiment 1-2 and conventional pharmaceutical excipient are mixed, by the preparation method of tablet or capsule, be prepared into tablet or capsule, the meglumine cyclic adenylate salt that every tablet or capsule contain 0.1～500mg.
Claims (6)
1. the cAMP being shown below and the compound of meglumine, its meglumine by 1 molecule cAMP and 2 molecules forms
。
2. the preparation method of the compound of claim 1, comprising: meglumine is joined in cAMP suspension and stirred, then at 60-70 DEG C, be heated to clarification, directly obtain described compound after lyophilize; Wherein the mol ratio of meglumine and cAMP is 2-10: 1.
3. the preparation method of claim 2, wherein said cAMP suspension joins cAMP in water, methyl alcohol or ethanol and is prepared from.
4. the arbitrary preparation method of claim 2-3, be wherein 0.5-3 hour heat-up time.
5. a pharmaceutical composition, the compound that comprises claim 1 and pharmaceutically acceptable carrier.
6. the application of the compound of claim 1 in preparation treatment heart failure, sick sinus syndrome, coronary heart disease, myocarditis and ARR medicine.
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