CN102796156A - Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof - Google Patents
Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof Download PDFInfo
- Publication number
- CN102796156A CN102796156A CN2012103142132A CN201210314213A CN102796156A CN 102796156 A CN102796156 A CN 102796156A CN 2012103142132 A CN2012103142132 A CN 2012103142132A CN 201210314213 A CN201210314213 A CN 201210314213A CN 102796156 A CN102796156 A CN 102796156A
- Authority
- CN
- China
- Prior art keywords
- camp
- meglumine
- compound
- preparation
- molecule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 verivate of Nucleotide.It is a kind of important substance with physiologically active that in human body, extensively exists, and is generated under adenosine cyclase catalysis by Triphosaden, can regulate the multiple functional activity of cell.Second messenger as hormone; The effect of performance hormone regulation physiological function and substance metabolism in cell changes function of plasma membrane, impels the calcium ion in the sarcoplasm matter to get into 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, sugar, metabolism of fat, nucleic acid, proteinic synthetic adjusting etc. are played an important role.
Meglumine, molecular weight is 195, and is soluble in water; Have suitable alkalescence and certain reductibility, and safe, nontoxic, with the compound combination that contains phenolic hydroxyl group; Behind the salify to skin, mucous membrane, organize nonirritant, so be suitable as very much the solubility promoter of medicine, improve the water-soluble of principal constituent.
CAMP is slightly soluble in water, and in cAMP, adding meglumine can increase its solvability.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, the U.S. happy heart) injection liquid; Be a kind of cardiac drug, be used for treatment 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 when standing storage, and also it is water-soluble not enough, can not be used for oral prepns etc.Therefore this area also needs a kind of stable cAMP medicine, can be used for the illness that cAMP is suitable for, stable simultaneously, safety, effective, good water solubility.
Summary of the invention
The objective 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, effectively, has better water-solubility simultaneously.
Another object of the present invention provides the preparation method of said compound.
The present invention also provides a kind of pharmaceutical composition, and it comprises said compound and pharmaceutically acceptable carrier.
Another object of the present invention provides the application of said 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 used for injection.Yet in Meglumine Adenosine Cyelophosphate solution; Along with the prolongation of shelf time, cAMP can be separated out gradually, and it is rotten, muddy that soup is taken place; Changing the small quilt that then is difficult for like it is discovered; If delivering medicine to patient then serious adverse effects can occur, thereby influence the curative effect of medicine, influence the security of medication simultaneously.Meglumine cyclic adenosine injection is in solution state preservation process; Being prone to meet light changes; Make drug degradation, because of its clinical anaphylaxis increase, curative effect descend, and Meglumine Adenosine Cyelophosphate solution is subject to Effect of Environmental oxidation, polymerization and medicines structure is changed.
The inventor finds under 60-70 ℃ of heating 0.5-2 hour through concentrating on studies, and can the meglumine of 1 molecule cAMP and 2 molecules be synthesized a compound.Find through analyzing; Under heating condition; Meglumine not only with the phosphatase reaction of cAMP, and can with embody weakly acidic phenolic group reaction, so just formed cAMP two meglumine compounds; Formed compound stability and water-soluble better is better cAMP medicinal forms.And temperature controlling is critical, and temperature is low excessively, then can not form said compound, only possibly form 1: 1 compound; Temperature is too high, stable influential to cAMP and meglumine self then, and impurity is too much.Based on above-mentioned discovery, accomplished the present invention.
Said compound structure is following:
The preparation method of compound of the present invention, technology is easy, and it comprises:
With meglumine and N, dinethylformamide joins in the cAMP suspension and stirs, and under 60-70 ℃, is heated to clarification then, directly obtains said compound after the lyophilize.
Wherein, said cAMP suspension joins cAMP in water, methyl alcohol or the 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 said 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 prepns, for example tablet, capsule, granule, oral liquid, powder agent, pill, sublingual administration agent etc.; Non-oral eye drop, nasal drops, [etc. also can be the controlled release agent types of above various formulations.
Pharmaceutical carrier can comprise vehicle or thinner, for example one or more in Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, Expex, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, Ucar 35, glycerine, Schardinger dextrins, the cyclodextrin derivative; Tackiness agent, for example one or more in Vinylpyrrolidone polymer, methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, X 5363, the XG 550; Lubricant, for example one or more in Magnesium Stearate, Triple Pressed Stearic Acid, talcum powder, stearyl fumarate, the Sodium Lauryl Sulphate BP/USP; Disintegrating agent, for example one or more in sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, crosslinked carboxymethyl fecula sodium, the pregelatinized Starch; Tensio-active agent, for example one or more in sodium lauryl sulphate, the Tween-80; PH regulator agent or buffer reagent, for example one or more of phosphate buffered saline buffer, Hydrocerol A, Trisodium Citrate, acetate buffer, Hydrogen chloride, yellow soda ash, sodium hydroxide; Sanitas, for example one or more in Sodium Benzoate, POTASSIUM SORBATE GRANULAR WHITE, methyl paraben, the propylben; Stablizer and oxidation inhibitor, for example one or more in Calcium Disodium Edetate, S-WAT, the vitamins C; Seasonings, for example one or more in maltose alcohol, fructose, sucrose, soluble saccharin, flavoring orange essence, the strawberry flavour; And other auxiliary material.
It is also understood that when formulation is tablet or capsule, can be the film dressing.The material that is used for the film dressing comprises suitable seed dressing agent, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate; Softening agent, for example polyoxyethylene glycol, triethyl citrate; Solubilizing agent is like Polyoxyethylene Sorbitan Monooleate; Pigment, like titanium oxide, various red stone, pink pigment, or the like.
Aforesaid pharmaceutical composition can also comprise other material with pharmaceutical active, for example is used for the medicine of disease as stated, and the pharmaceutical composition that forms a kind of compound comes combination therapy.
The advantage of compound of the present invention is that it is water-soluble, stability better, has also kept the activity of cAMP self simultaneously, and this is it with respect to the outstanding feature of cAMP and cAMP one meglumine salt.This is useful especially for preparation and storage pharmaceutical prepn.
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; With said salt and cAMP and cAMP one comparing property of meglumine salt test; Find that they have suitable basically effectiveness, 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 the preparation method is easy, is fit to scale operation, is suitable for preparing various types of pharmaceutical dosage forms, for effective application of cAMP provides better selection.
Embodiment
Further explain through embodiment below, but the present invention is not limited in these embodiment.
Embodiment 1. cAMPs, two meglumines and preparation thereof
Getting 0.30g (0.911mmol) cAMP adds in the 20ml ethanol; Stir and heating makes dissolving fully,, slowly add and stir to wherein adding 0.49g (2.53mmol) meglumine; Heated 1.8 hours down at 65 ℃ after accomplishing; To solution clarification, lyophilize, promptly get 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. cAMPs, two meglumines and preparation thereof
Getting 0.50g (1.519mmol) cAMP adds in the 35ml water; Stir and heating makes dissolving fully,, slowly add and stir to wherein adding 1.20g (6.148mmol) meglumine; Heated 0.8 hour down at 70 ℃ after accomplishing; To solution clarification, lyophilize, promptly get the cAMP two meglumine 0.987g (yields: 90.8%) of white powder.
CAMP two meglumines of above-mentioned preparation or its hydrate all are consistent with embodiment 1 through proton nmr spectra, carbon spectrum analysis.
Embodiment 3. stable accelerated tests
CAMP at high temperature can decompose usually, produces impurity impurity, is referred to as total related substance, under the hot conditions, measures the wherein content of total related substance, analyzes its stability.
Get in 50 ℃ of baking ovens of an amount of cAMP two meglumines,, measure total related substance wherein respectively at sampling in the 5th, 10 day.
Adopt high-efficient liquid phase chromatogram technique analysis, test-results is seen table 1.
Table 1
Mensuration result shows, cAMP two meglumine high temperature were placed 10 days for 50 ℃, and total its related substances increases to some extent, but that the overwhelming majority still keeps is stable, and is more more stable than cAMP one meglumine.
Embodiment 4. soluble tests
Through the rough determination comparison, cAMP two meglumines and cAMP water-soluble (normal temperature and pressure) are relatively like following table 2.
Table 2
| Compound | Water-soluble (mg/ml water) |
| CAMP two meglumines | Less than 1 |
| CAMP one meglumine | Greater than 8 |
| CAMP | Greater than 20 |
Can find out that by table 2 the water-soluble cAMP that is far longer than of cAMP two meglumines of the present invention also greater than cAMP one meglumine, shows the water-soluble of excellence.
The lyophilized injectable powder of embodiment 4. cAMPs two meglumines
CAMP two meglumines, the N.F,USP MANNITOL of getting recipe quantity add the dissolving of 2300ml water for injection, and regulating pH is 5～6, add the injection water to 2500ml; With the filtering with microporous membrane degerming, under hundred grades of conditions, carry out in sterile filling to 1000 cillin bottle, add plug after the inspection loading amount; Box out, the glass bottle is sent into to carry out freeze-drying in the disinfectant freeze drying box dry, pre-freeze 5 hours; Temperature drops to-35 ℃, distils 8 hours for the first time, and temperature rises to-5 ℃; Distilled 7 hours for the second time, temperature rises to 25 ℃, takes out behind vacuum gland or the inflated with nitrogen gland, and jewelling lid labeling gets product, and every bottle of freeze-dried powder contains cAMP two meglumine 30mg.
Embodiment 5. cAMPs two meglumine injections
Described meglumine cyclic adenylate salt of 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, every bottle of freeze-dried powder injection or injection liquid contain the meglumine cyclic adenylate salt of 0.1～500mg.
Embodiment 6. cAMPs two meglumine tablet/capsules
Described meglumine cyclic adenylate salt of embodiment 1-2 and conventional pharmaceutical excipient are mixed, and the preparation method who presses tablet or capsule is prepared into tablet or capsule, and every tablet or capsule contain the meglumine cyclic adenylate salt of 0.1～500mg.
Claims (7)
1. the cAMP that is 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 comprises: meglumine is joined in the cAMP suspension stir, under 60-70 ℃, be heated to clarification then, directly obtain said compound after the lyophilize.
3. the preparation method of claim 2, wherein said cAMP suspension joins cAMP in water, methyl alcohol or the ethanol and is prepared from.
4. the preparation method of claim 2-3, wherein the mol ratio of meglumine and cAMP is 2-10: 1.
5. the preparation method of claim 2-4, wherein be 0.5-3 hour heat-up time.
6. pharmaceutical composition comprises the compound and the pharmaceutically acceptable carrier of claim 1.
7. the application of the compound of claim 1 in treatment heart failure, myocarditis, sick sinus syndrome, coronary heart disease, myocarditis and irregular pulse.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210314213.2A CN102796156B (en) | 2012-08-24 | 2012-08-24 | Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210314213.2A CN102796156B (en) | 2012-08-24 | 2012-08-24 | Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102796156A true CN102796156A (en) | 2012-11-28 |
| CN102796156B CN102796156B (en) | 2014-07-30 |
Family
ID=47195487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210314213.2A Active CN102796156B (en) | 2012-08-24 | 2012-08-24 | Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102796156B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613626A (en) * | 2013-11-29 | 2014-03-05 | 湖北美林药业有限公司 | Adenosine cyclophosphate compound and meglumine adenosine cyclophosphate medicine composition thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS49116096A (en) * | 1972-07-25 | 1974-11-06 | ||
| US3872082A (en) * | 1971-05-19 | 1975-03-18 | Boehringer Mannheim Gmbh | Substituted purineribofuranoside-3,5-cyclophosphate compounds and process for their preparation |
| CN1459288A (en) * | 2003-06-18 | 2003-12-03 | 赵琛 | Cyclophosphadenosine glucosamine infusion prepn., and its prepn. process, and method for testing contents thereof |
| CN1579413A (en) * | 2004-02-11 | 2005-02-16 | 江卫世 | Meglumine adenosine cyclophosphate for injection and its preparing method |
| CN1923180A (en) * | 2006-09-22 | 2007-03-07 | 江苏万邦生化医药股份有限公司 | Meglumine cyclic adenosine for injecta and its preparing process |
| CN101455631A (en) * | 2009-01-06 | 2009-06-17 | 湖北德康药业有限公司 | Meglumine cyclic adenosine injection and preparation technique thereof |
| CN102258531A (en) * | 2011-04-12 | 2011-11-30 | 宁辉 | Medicinal composition containing adenosine cyclophosphate and meglumine and preparation method thereof |
| CN102488650A (en) * | 2011-12-19 | 2012-06-13 | 王保明 | Adenosine cyclophosphate pharmaceutical composition and preparation method thereof |
-
2012
- 2012-08-24 CN CN201210314213.2A patent/CN102796156B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3872082A (en) * | 1971-05-19 | 1975-03-18 | Boehringer Mannheim Gmbh | Substituted purineribofuranoside-3,5-cyclophosphate compounds and process for their preparation |
| JPS49116096A (en) * | 1972-07-25 | 1974-11-06 | ||
| CN1459288A (en) * | 2003-06-18 | 2003-12-03 | 赵琛 | Cyclophosphadenosine glucosamine infusion prepn., and its prepn. process, and method for testing contents thereof |
| CN1579413A (en) * | 2004-02-11 | 2005-02-16 | 江卫世 | Meglumine adenosine cyclophosphate for injection and its preparing method |
| CN1923180A (en) * | 2006-09-22 | 2007-03-07 | 江苏万邦生化医药股份有限公司 | Meglumine cyclic adenosine for injecta and its preparing process |
| CN101455631A (en) * | 2009-01-06 | 2009-06-17 | 湖北德康药业有限公司 | Meglumine cyclic adenosine injection and preparation technique thereof |
| CN102258531A (en) * | 2011-04-12 | 2011-11-30 | 宁辉 | Medicinal composition containing adenosine cyclophosphate and meglumine and preparation method thereof |
| CN102488650A (en) * | 2011-12-19 | 2012-06-13 | 王保明 | Adenosine cyclophosphate pharmaceutical composition and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613626A (en) * | 2013-11-29 | 2014-03-05 | 湖北美林药业有限公司 | Adenosine cyclophosphate compound and meglumine adenosine cyclophosphate medicine composition thereof |
| CN103613626B (en) * | 2013-11-29 | 2015-10-14 | 湖北美林药业有限公司 | A kind of adenosine cyclophosphate compound and meglumine adenosine cyclophosphate medicine composition thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102796156B (en) | 2014-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3889481B2 (en) | Pharmaceutical composition | |
| JP2002531508A5 (en) | ||
| CN102391250A (en) | Dabigatran compound and preparation method and medicinal composition thereof | |
| WO2013023102A1 (en) | Inhibiting transient receptor potential ion channel trpa1 | |
| US20190247342A1 (en) | Alpha-Ketobutyrate, 2-Hydroxybutyrate, and Alpha-Ketoglutarate for Stimulating Hair Growth | |
| TW200820995A (en) | Rapidly disintegrating lyophilized oral formulations of a thrombin receptor antagonist | |
| JPH07330584A (en) | Fatigue improver | |
| CN100584835C (en) | Novel medicinal salt for cinepazide and preparation method thereof | |
| CN102481287B (en) | Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof | |
| US6509035B1 (en) | Oral preparation of coenzyme a useful for lowering blood lipid and a method producing for same | |
| CN102796156B (en) | Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof | |
| CN112402392A (en) | Dabigatran etexilate mesylate sustained release preparation and preparation method thereof | |
| CN103183722A (en) | Glyoxalase I inhibitor, preparation method and medical application thereof | |
| CN102079717B (en) | Arginine salt compound of dibasic ester acids and preparation method and medicinal application thereof | |
| CN101514189B (en) | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof | |
| CN100488514C (en) | Slowly released solid ivermectin microballoon preparation | |
| CN1729988A (en) | Composite medicine of creatine phosphate sodium and magnesium salt | |
| CN112294777B (en) | Ivabradine hydrochloride sustained-release preparation and preparation method and application thereof | |
| RU2092161C1 (en) | Agent exhibiting the regulated pentoxyphylline release | |
| CN113491668B (en) | Pharmaceutical composition preparation for injection and preparation method and application thereof | |
| CN114028334B (en) | Preparation method of immunosuppressant for pulmonary administration | |
| CN103570679A (en) | Dabigatran etexilate gluconate, preparation method and application thereof | |
| JPH0687750A (en) | Medicine composition | |
| CN102304088A (en) | Ivabradine compound, preparation method and pharmaceutical composition thereof | |
| CN107982259A (en) | A kind of Febustat preparation and its application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20121128 Assignee: SHANDONG LUYE PHARMACEUTICAL Co.,Ltd. Assignor: Ning Hui Contract record no.: 2014370000117 Denomination of invention: Adenosine cyclophosphate double-molecule meglumine compound and preparation method thereof License type: Common License Record date: 20140711 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240418 Address after: Room 202, East Building C, Headquarters Center, No. 23 Guangfu East Street, Houtang Community, Jiangbei Street, Dongyang City, Jinhua City, Zhejiang Province, 322100 Patentee after: Zhejiang Zhongyan Pharmaceutical Technology Co.,Ltd. Country or region after: China Address before: Room 202, Study Abroad Building, No. 129 Fuzhou North Road, Shibei District, Qingdao City, Shandong Province, 266034 Patentee before: Ning Hui Country or region before: China |