CN101781348A - Stable protein kinase activator, preparation method thereof and use - Google Patents

Stable protein kinase activator, preparation method thereof and use Download PDF

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CN101781348A
CN101781348A CN201010029032A CN201010029032A CN101781348A CN 101781348 A CN101781348 A CN 101781348A CN 201010029032 A CN201010029032 A CN 201010029032A CN 201010029032 A CN201010029032 A CN 201010029032A CN 101781348 A CN101781348 A CN 101781348A
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刘力
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Abstract

The invention relates to a novel stable protein kinase activator adenosine cyclophosphate salt derivate, which has high storage stability and preparation performance and can be used in the preparation of medicaments for treating or preventing the following human and animal diseases such as stenocardia, cardiac failure, myocardial infarction, myocarditis, arrhythmia, cardiogenicshock, acute leukemia, nerve system diseases, respiratory system diseases, senile chronic bronchitis, hepatitis, psoriasis and the like and relieving the symptoms, such as cardiopalmus, shortness of breath, chest distress and the like of rheumatic heart disease.

Description

Stable protein kinase activator and its production and use
Technical field
The present invention relates to medical technical field, specifically provide the protein kinase activator of new stable---hydrate and the preparation and the purposes of cAMP salt.
Background technology
Present disclosed document has only been reported some salt of cAMP, up to the present, still do not have disclosed bibliographical information to be used for stenocardia, heart failure, myocardial infarction, myocarditis, irregular pulse and cardiogenic shock both at home and abroad, improve the protein kinase activator of the new stable of the palpitaition of rheumatic heart disease, symptom, acute leukemia, nervous system disorders, respiratory system disease, hepatitis and psoriatic etc. such as out of breath, uncomfortable in chest---hydrate of cAMP salt and its production and use.
Summary of the invention
Involved in the present invention is, and report is used for stenocardia, heart failure, myocardial infarction, myocarditis, irregular pulse and cardiogenic shock, improves hydrate and the preparation and the purposes of the protein kinase activator cAMP salt of disease prevention such as the palpitaition of rheumatic heart disease, symptom, acute leukemia, nervous system disorders, respiratory system disease, hepatitis and psoriatic such as out of breath, uncomfortable in chest or treatment.Its chemical name is the hydrate (AdenosineCyclophosphate) of 3 ', 5 '-cyclic monophosphate salt, and its molecular formula is { [cAMP] mAnH 2O, cAMP are C 10H 12N 5O 6P or C 10H 11N 5O 6P, m=1～3, n=0.88～8.5}, m=1 or 2 or 3, n can be 0.88,1,1.25,1.5,2,2.5,3.0,3.5,4,5,6,7,8,8.5 or the numeral between it.
A is selected from a kind of of pharmaceutically acceptable metal ion or organic bases.Wherein organic bases comprises triethylamine, diethylamine, thanomin, meglumine, Portugal's ethamine, Trometamol, a kind of in piperazine, morpholine, L-Methionin, D-Methionin, DL-Methionin, L-arginine, D-arginine, DL-arginine, Histidine, ornithine, the citrulline etc., amino acid includes the amino acid (D or L type amino acid) of racemization and chirality, and metal ion is a kind of in lithium, potassium, sodium, calcium, magnesium, zinc, aluminium or the bismuth.
The salt of the cAMP that contains crystal water that the present invention obtains is different from the characteristic that cAMP is insoluble in water, surprisingly, the salt that does not contain the cAMP of crystal water draws moist salt far above the cAMP that contains crystal water, contain crystal water cAMP salt hydrate than do not contain crystal water more can be stable existence, be convenient to store and transportation, some of them salt at room temperature has good water-solubility, is easy to make water miscible preparation.Distinctive, the weightless as can be seen platform of the heat analysis of hydrate of the present invention (TG-DSC or TG-DTA) collection of illustrative plates has the endotherm(ic)peak of intensive correspondence, and the thermogram spectrum demonstrates cAMP L-arginine 1 hydrate (C 10H 12N 5O 6PC 6H 14N 4O 2H 2O), cAMP L-Methionin 1 hydrate (C 10H 12N 5O 6PC 6H 14N 2O 2H 2O), meglumine cyclic adenylate 1 hydrate (C 10H 12N 5O 6PC 7H 17NO 5H 2O), cAMP sodium 2 hydrate (C 10H 11N 5O 6PNa2H 2O), cAMP magnesium salts 8 hydrate [(C 10H 11N 5O 6P) 2Mg8H 2O], cAMP calcium salt 3.5 hydrate [(C 10H 11N 5O 6P) 2Ca3.5H 2O] etc., measuring its moisture with the karl Fischer method, its result is consistent with hot analytical results.
The present invention also comprises cAMP D-arginine 1 hydrate, cAMP D-Methionin 1 hydrate, cAMP DL-Methionin 1 hydrate, cAMP L-citrulline 1 hydrate, triethylamine, diethylamine etc.
The hydrate of the salt of cAMP of the present invention can stable storage.With the salt anhydride sample of the hydrate of the salt of above-mentioned cAMP and cAMP airtight respectively with cillin bottle in carry out accelerated stability test (chromatographic condition: chromatographic column: C 18(250mm * 4.6mm, 5 μ m); Moving phase: 0.05mol/L potassium dihydrogen phosphate (including the 0.01mol/L Tetrabutyl amonium bromide)-acetonitrile (85: 15); Flow velocity: lml/min; Temperature: room temperature; Detect wavelength: 259nm), unexpectedly find, the content of the hydrate of the salt of cAMP of the present invention and related substance change less, the salt anhydride accelerated test of cAMP 6 months was compared (40 ℃ with 0 month, RH75%), the multiple of related substance increase is higher than the hydrate of the salt of cAMP.Draw moist test by the Chinese Pharmacopoeia requirement: get the salt anhydride and the about 5g of hydrate of the present invention of cAMP, place the watch-glass of dry constant weight, precision is weighed.25 ℃, relative humidity are 75%, respectively at test 0h and 48h sampling, calculate the percentage that draws wet weightening finish, the result shows, anhydride draws moist more much higher than hydrate of the present invention, illustrates that the hydrate of the salt of cAMP of the present invention has better storage stability.The results are shown in Table 1～6.
In addition, the deliquescence of anhydride makes wants secluding air to prevent adhesion etc. when handling, and does not have good sliding like hydrate, improves the operability of preparation.
Table 1. cAMP L of the present invention arginic acid salt 1 hydrate accelerated stability test result
Figure G2010100290326D00021
Table 2. cAMP L of the present invention lysine salt 1 hydrate accelerated stability test result
Table 3. meglumine cyclic adenylate salt 1 hydrate accelerated stability test result of the present invention
Figure G2010100290326D00023
Table 4. cAMP calcium 8 hydrate accelerated stability test results of the present invention
Figure G2010100290326D00024
Table 5. accelerated stability test result
Figure G2010100290326D00025
Figure G2010100290326D00031
Table 6. draws the wet test result
Figure G2010100290326D00032
CAMP is a protein kinase activator.It is a kind of important substance with physiologically active that extensively exists in human body, is generated under adenosine cyclase catalysis by Triphosaden, can regulate the multiple functional activity of cell.Second messenger as hormone, performance hormone regulation physiological function and substance metabolism effect in cell, can change function of plasma membrane, impel the calcium ion in the net agonistic muscle slurry matter to enter myofiber, thereby enhancing myocardial contraction, and can 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.
In the derivative of cAMP of the present invention except that the cAMP that contains protein kinase activator, also contain important basic metal and alkaline-earth metal ions or amino acid etc., these ions or amino acid have different physiological roles, for example: magnesium is the major element of needed by human, magnesium ion has the various biological activity, be to keep the normal neural muscle excitability and the requisite factor of histocyte energy metabolism, magnesium ion is that important cofactor is being brought into play important physiological function in the interior plurality of enzymes system of organism in the human body metabolic processes.It has mainly acted on as follows:
1, the activated carbon of keeping enzyme is the cofactor or the agonist of many enzymes system, can start 300 plurality of enzymes in the body, comprises hexokinase, Na +-K +ATP enzyme, carboxylase, pyruvic oxidase, peptase, Pseudocholinesterase etc., participate in many important metabolic processes in the body, comprise the metabolism of protein, fat and carbohydrate and nucleic acid, oxidative phosphorylation, ion transport, the generation of nerve impulse and transmission, Muscle contraction etc., almost relevant with each link of vital movement.
2, the excitability magnesium ion of keeping excitable cell all plays restraining effect to central nervous system, neuromuscular and cardiac muscle etc.For nervomuscular irritability, Mg 2+With Ca 2+Working in coordination with, is again antagonism for cardiac muscle.
3, the genetic stability magnesium of keeping cell is attemperator in main cofactor in the DNA related enzyme systems and decision cell cycle and the apoptotic cells.In cytoplasm, it can be kept film integrality, strengthen tolerance, adjusting cell proliferation, differentiation and apoptosis to oxidative stress; At nucleus then is the fidelity of reproduction of keeping dna structure, dna replication dna, starts the repair process of DNA, comprises that the nucleosides excision is repaired, base is excised reparation and mispairing reparation, and stimulates the microtubule assembling.
At present, contain the magnesium medicine and have vital role at step-down, cholagogic, catharsis, aspect such as anticonvulsion, merge heart failure at treatment asthma, capillary bronchitis, severe pneumonia, exhale decline, brain declines and respiratory system disease such as pulmonary hypertension in brought into play spasmolysis, relievingd asthma, calm, many-sided comprehensive action such as eliminate the phlegm, and in experimentation on animals and a large amount of clinical practice, obtained confirmation.
Calcium ion is the indispensable ion of the every physiological activity of body.It keeps normal nerve conduction function for the biopotential of keeping the cytolemma both sides.Keep normal muscle flexible and diastolic function and nerve-muscle conduction function, also have some functions of hormones mechanism all to show by calcium ion.Main effect or mechanism are:
1, calcium ion is a thrombin, participates in coagulation process; Its mechanism is: intracellular calmodulin combines with calcium ion, and a kind of mixture of formation can swash the in vivo activity of plurality of enzymes.If skin has been hurt, to have bled, calcium ion sends signal at once, activates zymoplasm step by step, starts clotting mechanism, with hemostasis.
2, participate in muscle (comprising skeletal muscle, unstriated muscle) contraction process, impel heartbeat.Its mechanism is: the calcium ion of positively charged allows the inside and outside potential difference that takes place of cell.The calcium ion of positively charged passes cytolemma, enters the myocardial cell, because of the calcium concn inside and outside the cell differs bigger, forms big potential difference, has produced the physiological effect that the irritation cell film shrinks.The myocardial cell shrinks, and again calcium ion has been pumped outside the cytolemma, forms reverse potential difference, and myocardial cell membrane begins diastole under the effect of this reverse potential difference; After the diastole, the permeability of cytolemma strengthens, and calcium ion passes cytolemma once more and enters the myocardial cell, causes myocardial contraction once more, and and so forth, heart just has rhythm and pace of moving things ground to beat.
3, participate in neurotransmitter synthetic with release, hormone is synthetic and secretion, and conduction nerve signal.Its transmission mechanism is for promoting neurotransmitter secretion.When first cell excitement, produced an electricity impulsion, at this moment, extracellular calcium ion flows in this cell, impel this emiocytosis neurotransmitter, neurotransmitter combines with protein molecular on the adjacent next stage neuron membrane, impels this one-level neurocyte to produce new electricity impulsion.By that analogy, nerve signal just hands on to the one-level one-level, thereby constitutes complicated signal scheme, and even the final Premium Features that brains such as study, memory occur.When the body calcium deficiency, the release of neurotransmitter is intercepted, and the excitation mechanism of human body and inhibition mechanism are destroyed.If children's calcium deficiency, can the morbid night crying of babies, sleep terror fright at night, irritated insomnia, the serious brain development obstacle that causes, occurs slow in reacting, move more, disease such as difficulty of learning, influence brain maturation and intelligence.
4, be the important substance that bone constitutes.The adult in 30-40 year, scleroblast and osteoclast activity are suitable, and the bone calcium level is being kept the level of high peak bone mass; After 40 years old, osteoclast activity is greater than scleroblast.But, although the life middle and later periods can not bone density improving, if the calcium intake abundance can keep existing bone density at least and increase bone mineral content.
5, transmit the signal of resisting the enemy.Its mechanism is: when exotic antigen activated T cell acceptor, started the signal path of calcium ion mediation, impelled immunocyte differentiation and growth.When exotic invasive persons such as germ, bacterium, poisonous substance invaded human body, calcium ion at first sent early warning signal; Calcium ion sends the signal what characteristic the invader has again subsequently, and immunity system is organized corresponding immunocyte thereupon, catches and engulfs the enemy.In case function of immune system decline, disorder will take place in calcium deficiency, and be diseases induced.As: autoimmune disorder lupus erythematosus, rheumatosis; Tetter: dermatitis, acne etc.Replenish the calcium, play an important role the function of the calcium of having given counterevidence to treating these diseases.
Arginine is the necessary amino acid of a kind of condition, participates in the tricarboxylic acid cycle in the energy metabolism in vivo and has the ornithine cycle of detoxification, impels the human body energy balance, can reduce blood ammonia after the medication, promotes that toxic substance excretes, and reaches the purpose of Ginseng Extract.Its pharmacological action is extensive, and it has mainly acted on:
(arginine Arg) is the nitric oxide production source of human body to arginine, and nitrogen protoxide (NO) impels vasorelaxation, stimulates circulation.Arg can promote the recovery of heart rate; increase volume of blood flow coronarius, improve heart function, cardiac muscle is had the certain protection effect; the normal blood supply function of heart when prompting replenishes Arg and helps to protect motion is to the generation of delay fatigue with promote to recover tool and have certain effect.The inferior maximal exercise result of experiment that the myocardial ischemia patient replenishes behind the L-Arg shows that Arg supplementation group coronary artery blood flow when exercise testing is clearly better.L-Arg replenishes can obviously improve the motor capacity of the spastic patient with angina pectoris of coronary artery, and has persistence preferably, and plasma nitric oxide levels is significantly improved.
Studies show that, arginine can effectively reduce the incidence of myocardial infarction, have vasodilator, hypotensive, the effect of stimulating circulation smoothly simultaneously, prevention and arteriosclerotic for cardiovascular disorder, the incidence of myocardial infarction has tangible reduction effect, and arginine also has antioxygenation, can reduce low-density lipoprotein (LDL) oxidation, form the sedimentary effect of blood vessel inner layer chyle, therefore for the little angiemphraxis of heart, cause the probability of myocardial necrosis to descend.
In addition, arginine has the specific immunity promoter action.Arginine and meta-bolites thereof such as nitrogen protoxide (NO) etc. are in immune defense, immunomodulatory, keep and protect the aspects such as specific immunity of intestinal mucosa function and tumour bringing into play important effect.
Arginine can effectively improve immunizing power, promote endogenous materials such as immunity system secretion natural killer cell, phagocytic cell, interleukin-11, help resisting cancer cells and prophylaxis of viral infections.No matter be normal diet or vein input Arg, all can specificity strengthen the cellular immune function (increase thymic weight, cell count, strengthen its conversion reaction ability etc.) of normal or wound animal; In wound and tumor-bearing animal, except that alleviating the immunosuppression that wound causes, Arg can also strengthen lymphocyte function, and has potential IL-2 immunity antitumor action, can promote the T cell mitogen, improves nitrogen equilibrium, improves the animal survival rate, strengthen time-delay reaction hypersensitive.In addition, arginine is the precursors of ornithine and proline(Pro), and proline(Pro) is the important element that constitutes collagen protein, replenishes arginine and need organize the health of maintenance to protect in a large number for severe trauma, burn etc., have tangible help, have the effect that reduces infection and inflammation simultaneously.Wherein, arginic assay (HPLC method) and discriminating can be with reference to Chinese Pharmacopoeia versions in 2005, and the method for P588 arginine hydrochloride sheet is carried out.
Methionin belongs to basic aminoacids, contains two amino in the molecule, is that human body one of must 8 seed amino acids, and Methionin provides structural constituent for synthetic carnitine, and carnitine can impel the synthetic of lipid acid in the cell.Particularly, higher to the requirement of Methionin in childhood development phase, decubation, pregnant lactication phase after being ill.Because content is lower in foods such as rice, corn, cause human body to lack easily, be called as " first lack amino acid ".
The Methionin shortage can cause dysplasia, loses the appetite, loses weight, negative nitrogen balance, hypoproteinemia, hypoplasia of tooth, anaemia, enzymic activity descend and other physiological function obstacle.Methionin has the intelligence of raising, promotes growth, builds up health; Improve a poor appetite, improve malnutritive situation; Improve insomnia, memory; Help to produce antibody, hormone and enzyme, improve immunizing power, increase hemochrome; Help the absorption of calcium, treatment prevents osteoporosis; The help nervous tissue is repaired, and promotes nervous cell regenerating, improves the effect of central nervous tissue function.Methionin can improve blood-brain barrier permeability; help medicine to enter in the brain cell; clinical cerebral protective agent as treatment craniocerebral trauma, chronic brain tissue ischemia, anoxic disease; or, also can be used for Methionin and lack children's's poor appetite, malnutrition and the cerebral dysgenesis that causes the assisting therapy of other encephalopathics.The mensuration reference literature of Methionin wherein: agricultural brightness etc. lysine hydrochloride and Injection by HPLC thereof are measured, chemical industry technology and exploitation, 2003,32 (2): 33.
The imidazolyl energy and the Fe of Histidine 2+Or other metal ions formation coordination compoundes, promote the absorption of iron, thereby can be used for preventing and treating anaemia.Histidine can reduce gastric acidity, relaxes the pain of gastro-intestinal surgery, alleviates Gestation period vomiting and stomach burning sensation, suppresses nervous by vegetative nerve and digestive tube that cause festers, and is to anaphylactic disease, also powerful as asthma etc.In addition, the expansible blood vessel of Histidine brings high blood pressure down, and is used for treatment of diseases such as stenocardia, cardiac insufficiency clinically.Histidine content significantly reduces in the patient with rheumatoid arthritis blood, uses and to find its grip behind the Histidine, walks and index such as erythrocyte sedimentation rate all take a favorable turn.
The L-citrulline can improve function of immune system, safeguards the joint motion function, balance euglycemia level, absorb harmful free radical, help to keep the cholesterol normal level, improve the health function, the pulmonary function of maintaining healthy improves mental sharpness, reduces pressure and overcomes dejected mood.Citrulline can be in human body and the ammonia effect, generates arginine and nitrogen protoxide and makes vasodilator, and be used for the treatment of spirit and physical fatigue and sexual dysfunction.Citrulline belongs to amino acid drug, can same ornithine, arginine etc. share in the treatment hyperammonemia.Citrulline can absorb in the blood fully, produces nitrogen protoxide, participates in diversified physiological process, as killing and erection etc. of neurotransmission, antiotasis, sphincter dilatation, microorganism, male's sexual is had extremely important effect.Nitrogen protoxide is in the presence of oxygen molecule and oxyphorase, forms when becoming the L-citrulline by nitric oxide synthetase (NOS) catalysis L-arginine guanidine radicals oxidative deamination.
Contain pharmaceutically acceptable metal ion or organic bases in the The compounds of this invention, metal ion comprises alkalimetal ion or alkaline-earth metal ions etc., organic bases comprises amino acid, triethylamine, diethylamine, thanomin etc., wherein amino acid includes the amino acid (D or L type amino acid) of racemization and chirality, and form stable compound, make it in the prevention of various disease or treatment, have more advantage, perhaps make when other derivative of preparation cAMP more convenient than single cAMP.
The hydrate preparation method of the salt of cAMP comprises:
Method A. is in reaction vessel, add water and cAMP, stir, the oxide compound or oxyhydroxide or its metal-salt or its solution that add pharmaceutically acceptable organic bases or metal by the mol ratio of reaction, stir, question response finishes, filter, slowly add the lower ketones of C3-C7, as acetone, or low mass molecule alcohol C1-C6 such as methyl alcohol, ethanol, Virahol, one or more of the rudimentary ether of C2-C8, cooling is filtered, the solids low mass molecule alcohol of organic solvent C1-C6, as methyl alcohol, ethanol, Virahol, the lower ketones of C3-C7 is as acetone, rudimentary ether such as the ether of C2-C6, or one or more rinses in the water, drain, drying obtains the metal-salt of cAMP or the hydrate of its organic alkali salt;
Perhaps method B. puts into the oxide compound of metal or the solution of oxyhydroxide or its metal-salt or organic bases in the reaction vessel that contains cAMP and water by the mol ratio of reaction, stir, between 0～50 ℃ of the controlled temperature, stir, question response finishes, activated carbon decolorizing, one or many filters, and it is freezing to-70～-30 ℃, heats up, vacuum-drying must have the hydrate of cAMP salt;
Perhaps method C. will contain the oxide compound of metal or a kind of or its solution of oxyhydroxide or its metal-salt or pharmaceutically acceptable organic bases in the reaction vessel of cAMP and water by the mol ratio adding of reacting respectively, stir, between the controlled temperature-5～40 ℃, reaction 0.5～24h, question response finishes, activated carbon decolorizing, and one or many filters, spraying drying, the hydrate of cAMP salt.In the spraying drying, inlet temperature can be between 100～140 ℃, and air outlet temperature can be between 70～100 ℃, and spray is pressed can be at 1.0～2.0kg/cm 2
Within 60～120 ℃, generally within 90～120 ℃, Vanadium Pentoxide in FLAKES is a siccative with the hydrate of the salt of cAMP, and high vacuum dry is more than 8 hours, the salt anhydride of cAMP.And the comparison that the product of gained can be used to draw moist test or accelerated stability test.
Lower ketones among the present invention or low molecule ketone are defined as C3-C7, as acetone, and butanone etc.; Lower alcohol or low mass molecule alcohol are defined as C1-C6, and as methyl alcohol, ethanol, Virahol, rudimentary ether or low molecule ether are defined as C2-C8, as ether, butyl ether etc.The oxide compound of the metal of mentioning or oxyhydroxide or its metal-salt, can be respectively: calcium oxide, calcium hydroxide, magnesium oxide, magnesium basic carbonate, sodium hydroxide, yellow soda ash, sodium bicarbonate, zinc oxide, aluminium sesquioxide, potassium hydroxide, salt of wormwood, Bismuth trinitrate, its metal-salt comprise carbonate or supercarbonate or subcarbonate.
The hydrate purposes of the salt of cAMP of the present invention: the hydrate of the salt of cAMP of the present invention is used to prepare injection freeze-dried powder or great transfusion preparation or little water needle injection, aseptic subpackaged powder pin, through the enterally administering preparation, comprise tablet, capsule, granule, comprise ointment, gelifying agent etc. through preparation for external application to skin.
Be used to prepare tablet, capsule or the granule of solid preparation, can contain pharmaceutically acceptable weighting agent in these preparations, as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, amino acid etc.; Pharmaceutically acceptable disintegrating agent is as starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, tensio-active agent; Pharmaceutically acceptable wetting agent and tackiness agent adjoin pyrrolidone, Lalgine and salt thereof as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyethylene; Pharmaceutically acceptable lubricant and glidant are as stearic acid, Magnesium Stearate, Macrogol 4000-8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence are as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.
The deliquescence that crystalline hydrate of the present invention is different from anhydride makes wants secluding air to prevent adhesion etc. when handling, and crystalline hydrate has good sliding, thereby improves the operability of preparation; And the solid preparation that makes preparation has good dissolving out capability, makes it be absorbed easily and enters blood circulation, improves bioavailability, and helps bringing into play fast its effect.From another aspect, making it prevent produces obstruction and makes loading amount generation difference cause underdosage when carrying out being difficult for when aseptic subpackaged to cause packing because of the moisture absorption, thereby bring the defective of product, or because underproof product is not inspected by random samples the actual omission of formation, and then come into the market, in clinical treatment,, perhaps jeopardize patient's life because of underdosage to patient's the negative effect of treatment agency.Perhaps when packing, cause whole production line to be forced to suspend because of the moisture absorption, seriously reduce the throughput of equipment, increase the hidden danger of work time cost etc. greatly.
Because the cAMP micro dissolution is in water, need to add the auxiliary material of oil soluble generally speaking, be easy to pollute, and difficult the cleaning, the storage stability of the hydrate of the salt of cAMP of the present invention and the general easy characteristic that is dissolved in water make in the ease for operation that has more preparation aspect the preparation gelifying agent, its prepared gelifying agent has good release performance, make it be absorbed easily and enter blood circulation, improve bioavailability, and help bringing into play fast its effect.Need not to add the auxiliary material of oil soluble, be difficult for polluting, and than easy cleaning.
The preparing gel of the hydrate of cAMP salt: with cAMP salt hydrate and 50～95% matrix mixings, matrix can be that ethanol, glycerine, trolamine, glycogelatin, Macrogol 200～8000, poloxamer, polyethylene adjoin pyrrolidone, semi-synthetic hard fatty acids fat, water-soluble mono-glycerides, carbomer series (931,934,940,974, AA-1,1342 etc.), polysorbate60-80.Can contain pharmaceutically receivable sanitas and stablizer in the gel, can be during preparation respectively with the carbomer water-dispersion, add glycerine, Macrogol 200～8000, heating, mix, add the cAMP salt hydrate, stirring of recipe quantity, with pharmaceutically receivable mineral alkali or organic bases are regulated about pH=5.0～7.8, add water to full dose, be stirred to even, packing, promptly.
The hydrate injection of the salt of cAMP, its preparation method is:
The aseptic subpackaged powder injection of the hydrate of the salt of cAMP can prepare according to ordinary method.
The preparation method of freeze-dried powder is: get the hydrate of the salt of cAMP, can add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, add injection and blunge and make dissolving, if need, available pharmaceutically acceptable acid-alkali accommodation pH is 4.0～7.5, adds activated carbon 0.005～0.5% (W/V) and stirs 15～45min, filters, moisturizing, sterile filtration is by 20～200mg/ bottle (in cAMP) packing, lyophilize, tamponade gets finished product.
The hydrate injection with small volume and the preparation technology thereof of the salt of cAMP: the hydrate of the salt of cAMP adds injection water and pharmaceutically acceptable additives, for example: pharmaceutically acceptable pH regulator agent, pharmaceutically acceptable oxidation inhibitor, rare gas element, the sterilization injection with small volume is made in filtration, degerming, and its pH value is between 4.0～7.5.
Its pharmaceutically acceptable pH regulator agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases, also can be generalized Lewis acid or alkali, can contain one or several, can be hydrochloric acid, phosphoric acid, propionic acid, acetic acid and acetate, as sodium-acetate etc., lactic acid and lactic acid pharmaceutical salts, the Citric Acid pharmaceutical salts, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, phosphoric acid salt, tartrate and pharmaceutical salts thereof, borax, boric acid, Succinic Acid, caproic acid, hexanodioic acid, FUMARIC ACID TECH GRADE, maleic acid, the trihydroxy-aminomethane, diethanolamine, thanomin, Yi Bingchunan, diisopropanolamine (DIPA), 2-amino-2-(methylol) 1, ammediol amine, 1, the 2-hexanediamine, N-methyl grape amine, Diisopropylamine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts are as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, glucoheptonic acid, in amino acid and the amino acid salts etc. one or several.
Its pharmaceutically acceptable oxidation inhibitor and stablizer can be sulfurous acid, sulphite, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate, organosulfur compound thiocarbamide, gsh, dimercaprol dimercaptopropanol, Thiovanic acid and salt, thiolactic acid and salt, thio-2 acid and salt, phenol compound, as gallic acid and salt, coffic acid, caffeiate, forulic acid, ferulate, di-t-butyl Pyrogentisinic Acid, 2,5-resorcylic acid, 2,5-resorcylic acid salt, phenol or derivatives thereof, Whitfield's ointment or its salt; Amino acid with and salt; Xitix and ascorbate salt, saccharosonic acid and erythorbate, niacinamide, tartrate, nitrate, phosphoric acid salt, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, as in EDTA disodium, EDTA four sodium, N-two (2-hydroxyethyl) glycine etc. one or several.
Its pharmaceutically acceptable isotonic regulator can be one or more in glucose, fructose, Xylitol, sorbyl alcohol, N.F,USP MANNITOL, Nulomoline, maltose, dextran, sodium-chlor, Repone K, the Sodium.alpha.-hydroxypropionate etc.
Source and the degerming mode of reducing phlegm and internal heat can be the gac that adds dosing amount 0.005～3% source of reducing phlegm and internal heat, and millipore filtration degerming and pressure sterilizing also can adopt heat sterilization, the source of reducing phlegm and internal heat.In the hyperfiltration process, that ultra-fine filter can be selected for use is flat, rolling, tubular type, tubular fibre formula or circle boxlike etc., preferred rolling and tubular fibre formula ultra-fine filter, it is after 50,000 to 300,000 filter membrane is removed most of heat generation material and bacterium that relative molecular mass is held back in employing, adopt the ultra-filtration membrane of holding back relative molecular mass 3000～30000 to remove the residue thermal source, the ultra-filtration membrane of preferred relative molecular mass 6000～20000 again.
The hydrate of the salt of cAMP of the present invention, be applicable to the application in the medicine of following treatment that caused humans and animals is infected of preparation or prevention: be used for stenocardia, heart failure, myocardial infarction, myocarditis, irregular pulse and cardiogenic shock in preparation, improve the application in the medicine of treatment such as the palpitaition of rheumatic heart disease, symptom, acute leukemia, nervous system disorders, respiratory system disease, senile chronic bronchitis, hepatitis and psoriatic such as out of breath, uncomfortable in chest or prevention.
Consumption usage: generally speaking,, get medicine 0.020～0.2g of the present invention in 20～500 milliliters of 0.9% sodium-chlor or 5～10% glucose, do intravenous injection or instillation, every day 1～2 time in the adult; Get medicine 0.020～0.2g of the present invention and be dissolved in the water for injection, intramuscularly, every day 1～2 time; Children's amount of reducing by half is above to be used.
Through gastrointestinal administration consumption usage: the human or animal of 10～70kg body weight, 40～600mg/ days generally speaking, divide 2-3 administration; Children's amount of reducing by half is above to be used.Topical administration directly is applied to the affected part, once a day to six times.
Description of drawings
The thermogram spectrum of magnesium salts 8 hydrates of Fig. 1 cAMP.
Fig. 2 is the thermogram spectrum of meglumine cyclic adenylate salt 1 hydrate.
Fig. 3 is the thermogram spectrum of cAMP L-arginic acid salt 1 hydrate.
Fig. 4 is the thermogram spectrum of cAMP L-lysine salt 1 hydrate.
Fig. 5 is the thermogram spectrum of cAMP sodium salt 2 hydrates.
Test condition: the Setsys of Setaram company 16, PE6300TGDTA, the about 5mg of sample size, heat-up rate: 10K/min, N 2Flow velocity: 50ml/min, room temperature～400 ℃.
Embodiment
The preparation of magnesium salts 8 hydrates of embodiment 1 cAMP adds cAMP 0.1mol, water 100ml, stirring in the 250ml three-necked flask, the magnesium oxide that adds 0.05mol, 20～60 ℃ were stirred 30～90 minutes down, made dissolving, filtered, the acetone that adds 1～5 times of amount is separated out solid, be cooled to-10～15 ℃, placed 1～24 hour, filter, about 50 ℃ dryings of solids got off-white color crystalline powder 23.6g, fusing point in 2～4 hours; 227 ℃ of decomposition (not proofreading and correct), HPLC: cAMP content 39.86%, it is 17.57% that the Ka Shi method is measured moisture, and heat is analyzed: weightless about 17.16% (the seeing accompanying drawing 1) of platform, this and sample contain result's (theoretical value 17.48%) of 8 crystal water in limit of error.Ultimate analysis theoretical value: C 29.12%, H4.64%, N16.98%P7.51%, Mg 2.95%; Measured value: C 29.33%, H4.52%, N17.11%P7.67%, Mg 3.23%.
The preparation of embodiment 2 cAMP calcium salts 3.5 hydrates is in the 250ml three-necked flask, add the cAMP 0.1mol after pure, water 100ml, stir, the calcium hydroxide or the calcium oxide that add 0.05mol, 20～60 ℃ were stirred 30～90 minutes down, make dissolving, filter, add the dehydrated alcohol and the Virahol (1: 1) of 1～5 times of amount, be cooled to-10～15 ℃, placed 1～24 hour, treat that solid separates out, filter, dry 4～6 hours dryings about 50 ℃, get off-white color solid 19.2 grams, fusing point: 223 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS does not proofread and correct), infrared spectra: it is 8.52% that the Ka Shi method is measured moisture, heat is analyzed: platform is weightless about 8.4%, and this and sample contain result's (theoretical value 8.30%) of 3.5 crystal water in limit of error; Ultimate analysis theoretical value: C 31.63%, H3.85%, N18.44%P8.16%, Ca 5.28%; Measured value: C 31.57%, H3.94%, N18.36%P8.07%, Ca 5.35%.
The preparation of embodiment 3 meglumine cyclic adenylates 1 hydrate with the cAMP 10g after pure and and equimolar meglumine drop in the reaction flask, add water 200ml, stir, between 10～60 ℃ of the controlled temperature, reaction 10～120min, the centesimal gac that adds the solution total amount stirs half an hour and filters, hold back the ultrafiltration membrance filter of relative molecular mass 6000～30000 again with 0.22 micron filtering with microporous membrane or employing, it is freezing to-70～-30 ℃, kept about 24 hours, be warming up to～about 20 ℃, vacuum-drying, 20～30 ℃ of dryings are about 3～6 hours again, get the off-white color crystalline powder, soluble in water, fusing point: 67～71. ℃ (ELECTROTHERMAL MELTING POINT APPARATUS does not proofread and correct); HPLC: cAMP content is 60.79%, ESI:m/z:523; Moisture (Ka Shi method): 3.51%, heat is analyzed: platform is weightless about 3.31%, and result's (theoretical value 3.32%) that this and sample contain 1 crystal water (sees accompanying drawing 3) in limit of error; Ultimate analysis theoretical value: C 37.64%, H5.76%, N15.49%P5.71%; Measured value: C 37.52%, H5.87%, N15.37%P5.56%.
The preparation of embodiment 4 cAMP L-arginine 1 hydrate with the cAMP 10g after pure and and equimolar L-arginine drop in the reaction flask, add water 200ml, stir, between 10～60 ℃ of the controlled temperature, reaction 10～120min, the centesimal gac that adds the solution total amount stirs half an hour and filters, hold back the ultrafiltration membrance filter of relative molecular mass 6000～30000 again with 0.22 micron filtering with microporous membrane or employing, it is freezing to-70～-30 ℃, keeps about 24 hours, is warming up to about-20 ℃, vacuum-drying, 20～30 ℃ of dryings got the off-white color crystalline powder about 2～8 hours again, and are soluble in water, fusing point: 189～195 ℃ of (ELECTROTHERMAL MELTING POINTAPPARATUS, do not proofread and correct), HPLC: cAMP content is 63.07%, arginine 33.31%; ESI:m/z:502; It is 3.82% that the Ka Shi method is measured moisture, and heat is analyzed: weightless about 3.61% (the seeing accompanying drawing 4) of platform, this and sample contain result's (theoretical value 3.46%) of 1 crystal water in limit of error.
Ultimate analysis theoretical value: C 36.86%, H5.41%, N24.18%, P5.94%; Measured value: C 37.08%, H5.20%, N24.36%, P5.75%.
The preparation of embodiment 5 cAMP L-Methionins 1 hydrate with the cAMP 10g after pure and and equimolar L-Methionin drop in the reaction flask, add water 220ml, stir, between 10～60 ℃ of the controlled temperature, reaction 10～120min, the centesimal gac that adds the solution total amount stirs half an hour and filters, hold back the ultrafiltration membrance filter of relative molecular mass 6000～30000 again with 0.22 micron filtering with microporous membrane or employing, it is freezing to-70～-30 ℃, kept about 24 hours, be warming up to～about 20 ℃, vacuum-drying, 20～30 ℃ of dryings are about 3～6 hours again, get the off-white color crystalline powder, soluble in water, fusing point: 195～201 ℃ of decomposition (ELECTROTHERMAL MELTING POINTAPPARATUS does not proofread and correct); HPLC: cAMP content is 66.65%, Methionin 29.46%; ESI:m/z:474; Moisture (Ka Shi method): 3.96%, heat is analyzed: weightless about 4.01% (the seeing accompanying drawing 5) of platform, this and sample contain result's (theoretical value 3.65%) of 1 crystal water in limit of error;
Embodiment 6 places reaction flask with the preparation of cAMP sodium 2 hydrates with cAMP 10g, add water 200ml, stir, slowly in reaction flask, add and the equimolar sodium bicarbonate of cAMP, stir, between 10～60 ℃ of the controlled temperature, reaction 10～120min, the gac that adds solution gross weight 0.2% stirs half an hour and filters, and holds back the ultrafiltration membrance filter of relative molecular mass 6000～20000 again with 0.22 micron filtering with microporous membrane or employing, and it is freezing to-70～-30 ℃, kept about 24 hours, be warming up to about-20 ℃, vacuum-drying, 20～30 ℃ of dryings are about 3～6 hours again, get the off-white color crystalline powder, soluble in water, fusing point: 227 ℃ of decomposition (ELECTROTHERMAL MELTINGPOINT APPARATUS does not proofread and correct); Assay: HPLC method: cAMP content is 84.82%; Moisture (Ka Shi method): 9.47%, heat is analyzed: weightless about 9.03% (the seeing accompanying drawing 6) of platform, this and sample contain result's (theoretical value 9.31%) of 2 crystal water in limit of error; ESI:m/z:350; Ultimate analysis theoretical value: C 31.02%, H3.90%, N18.09%, P8.00%, Na5.94%; Measured value: C 30.88%, H4.03%, N18.19%, P8.12%, Na5.83%.
Embodiment 7 gets cAMP L-arginine 1 hydrate or meglumine cyclic adenylate 1 hydrate 200g, adding glucose or N.F,USP MANNITOL or Xylitol 2.0～5g adds fresh water for injection 10～20L and stirs and make dissolving, an amount of with 2M hydrochloric acid or 2M sodium hydroxide, regulating pH is 5.0～8.5, add activated carbon 0.01～0.5% (W/V) and stir 15～45min, filter, hold back the ultrafiltration membrance filter of relative molecular mass 6000～20000 with 0.22 micron filtering with microporous membrane or employing, press 20mg, 30mg/ bottle or 40mg or 50mg/ bottle or 60mg/ bottle or 100mg/ bottle or 120mg/ bottle packing (in cAMP) packing, lyophilize, tamponade gets finished product.
Embodiment 8 gets cAMP L-arginine 1 hydrate or meglumine cyclic adenylate 1 hydrate 10g (in cAMP), with N.F,USP MANNITOL 40g, add 40～60 ℃ of water for injection 1460～1850ml stirrings and make dissolving, Citric Acid or sodium hydroxide adjusting pH with 1M are 5.0～8.0, add activated carbon 0.01～0.5% (W/V) and stir 15～45min, filter, moisturizing is to 2000ml, hold back the ultrafiltration membrance filter of relative molecular mass 6000～20000 with 0.22 micron filtering with microporous membrane or employing, by 20,30mg/ bottle or 60mg/ bottle or 100mg/ or 120mg/ bottle (by cAMP) packing, lyophilize, tamponade gets finished product.
Embodiment 9 gets the hydrate 20Kg (in cAMP) of the salt of aseptic cAMP, with aseptic subpackaged technology by 20,30mg/ bottle or 50mg/ bottle or 60mg/ bottle or the packing of 100mg/ bottle, jump a queue, tamponade, roll aluminium lid and get finished product.
Embodiment 10 cAMP sodium, 2 hydrates or cAMP L-arginine 1 hydrate or meglumine cyclic adenylate 1 hydrate (by cAMP) 10g, add cysteine hydrochloride 0.8g, EDTA disodium 0.1g, adding injection blunges and makes dissolving, it is 5.0～7.8 that 2M lactic acid and Sodium.alpha.-hydroxypropionate are regulated pH, add activated carbon 0.5% (W/V) and stir 15～45min, filter, moisturizing is to 1000ml, hold back the ultrafiltration membrance filter of relative molecular mass 6000～20000 with 0.22 micron filtering with microporous membrane or employing, by the packing of 2～10m1/ bottle, sterilize finished product.
Embodiment 11 cAMP sodium 2 hydrate 10g, adding injection blunges and makes dissolving, add activated carbon 0.3% (W/V) and stir 15～45min, filter, moisturizing is held back the ultrafiltration membrance filter of relative molecular mass 6000～20000 to 2000ml with 0.22 micron filtering with microporous membrane or employing, by the packing of 2～5ml/ bottle, lyophilize, tamponade gets finished product.
The preparation of embodiment 12 cAMP sodium, 2 hydrates or cAMP L-arginine 1 hydrate or meglumine cyclic adenylate 1 hydrate high-capacity injection takes by weighing glucose 500g and adds in the water for injection, stirring makes dissolving fully, the gac that adds dosing amount 0.05%, heated about 10～30 minutes, put cold, filtering decarbonization; With hydrate (in the cAMP) 4.01g of the salt of cAMP with fresh water for injection dissolving fully after, mix with above-mentioned filtrate, add hydrochloric acid L-halfcystine 1g, EDTA disodium 0.2g, regulate the pH value in 5.2～7.5 scope with the 1M lactic acid solution, add the injection water to 10000ml, the gac that adds dosing amount 0.01～0.5% (W/V), about heated and stirred 10～30 minutes, filtering decarbonization, filter or adopt the ultrafiltration membrance filter of holding back relative molecular mass 6000～20000 through 0.22um millipore filtration essence again,, treat its content through the work in-process chemical examination, after pH value and clarity are qualified, embedding is in the vial of 50ml or 100ml or 200ml, sterilization, finished product inspection, packing is promptly.
The preparation of the hydrate sodium-chlor of the salt of embodiment 13 cAMPs transfusion: with hydrate (in the cAMP) 4g of the salt of cAMP, sodium-chlor 85g, Sodium Pyrosulfite 1.1g, EDTA disodium 0.2g, add in the water for injection, stirring makes dissolving fully, Citric Acid and liquor sodii citratis with 1M are regulated the pH value in 4.0～7.5 scope, add the injection water to 10000ml, the gac that adds dosing amount 0.05%, about heated and stirred 10～30 minutes, filtering decarbonization, filter or adopt the ultrafiltration membrance filter of holding back relative molecular mass 6000～20000 through 0.22um millipore filtration essence again, chemically examine through work in-process, treat its content, after pH value and clarity were qualified, embedding was sterilized in the vial of 50ml or 100ml or 200ml, finished product inspection, packing promptly.
Embodiment 13. cAMP magnesium, 8 hydrates or cAMP L-arginine 1 hydrate tablet (the 250mg/ sheet is in cAMP)
Prescription: cAMP magnesium 8 hydrates or cAMP L-arginine 1 hydrate 250g (in cAMP)
Microcrystalline Cellulose 200g
Sodium starch glycolate 20g
Aspartame 2g
Polyvinylpyrrolidone 5% is an amount of
Magnesium Stearate 2g
CAMP magnesium 8 hydrates or cAMP L-arginine 1 hydrate, Microcrystalline Cellulose, sodium starch glycolate, aspartame are crossed 100 mesh sieves, polyvinylpyrrolidone with 5% is made softwood in right amount, crossing the 18-24 mesh sieve granulates, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel, Magnesium Stearate mixing, compressing tablet.
The salt hydrate capsule of embodiment 14 cAMPs (the 100mg/ grain is in cAMP)
Prescription: the salt hydrate 100g of cAMP (in cAMP)
Microcrystalline Cellulose 100g
Lactose 20g
Gelling starch 10% is an amount of
Magnesium Stearate 2g
Salt hydrate, Microcrystalline Cellulose, the lactose of cAMP of the present invention are crossed 100 mesh sieves, and the gelling starch with 10% is made softwood in right amount, cross the 18-24 mesh sieve and granulate, drying, cross the whole grain of 14-20 mesh sieve after, add Magnesium Stearate and mix the can capsule.
The salt hydrate particle of embodiment 15 cAMPs comprises cAMP sodium 2 hydrates or cAMP magnesium 8 hydrates or meglumine cyclic adenylate 1 hydrate or particles such as cAMP L-arginine 1 hydrate or cAMP L-Methionin 1 hydrate (the 50mg/ bag is in cAMP)
Prescription: the salt hydrate 50g of cAMP (in cAMP)
N.F,USP MANNITOL 180g
Sucrose 20g
Sodium Cyclamate 2g
Solid food flavour 1g
Polyvinylpyrrolidone 5% is an amount of
Salt hydrate, N.F,USP MANNITOL, sucrose, Sodium Cyclamate, the food flavour of cAMP are crossed 100 mesh sieves, and the polyethylene with 5% adjoins pyrrolidone and makes softwood in right amount, crosses the 18-24 mesh sieve and granulates, and is dry below 60 ℃, cross the whole grain of 14-20 mesh sieve after, divide packing.
The gel of embodiment 16 cAMP salt hydrate of the present invention
Prescription: salt hydrate 2 5g (, feeding intake) of cAMP in cAMP
Polyethylene glycol 6000 50g
Poly(oxyethylene glycol) 400 10g
Glycerine 5ml
Carbomer 934 8g
Carbomer 1342 2g
Water 400-500ml
Will be respectively with carbomer 1342 and carbomer 934 water-dispersion, add glycerine, polyethylene glycol 6000, poly(oxyethylene glycol) 400, mix, the salt hydrate that adds cAMP, heating, be stirred to even, regulate about pH=5.0～7.0 with Sodium phosphate dibasic and sodium dihydrogen phosphate, packing is promptly.
The variation that is appreciated that a lot of details is possible, and therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to the foregoing description.

Claims (10)

1. the hydrate of the salt of stable protein kinase activator---cAMP is characterized in that: the hydrate of the salt of cAMP, molecular formula are { [cAMP] mAnH 2O, cAMP are C 10H 12N 5O 6P or C 10H 11N 5O 6P, m=1 or 2 or 3, n=0.88～8.5}, A are selected from a kind of of pharmaceutically acceptable metal ion or organic bases.
2. stable protein kinase activator according to claim 1 is characterized in that; Organic bases is triethylamine, diethylamine, thanomin, meglumine, Portugal's ethamine, Trometamol, a kind of in piperazine, morpholine, L-Methionin, D-Methionin, DL-Methionin, L-arginine, D-arginine, DL-arginine, Histidine, ornithine, the citrulline.
3. stable protein kinase activator according to claim 1 is characterized in that: metal ion is a kind of in lithium, potassium, sodium, calcium, magnesium, zinc, aluminium or the bismuth.
4. stable protein kinase activator according to claim 1 is characterized in that: the hydrate of cAMP salt is cAMP L-arginine 1 hydrate.
5. stable protein kinase activator according to claim 1 is characterized in that: the hydrate of cAMP salt is cAMP L-Methionin 1 hydrate.
6. stable protein kinase activator according to claim 1 is characterized in that: the hydrate of cAMP salt is meglumine cyclic adenylate 1 hydrate.
7. stable protein kinase activator according to claim 1 is characterized in that: the hydrate of cAMP salt is cAMP sodium 2 hydrates or cAMP calcium 3.5 hydrates or cAMP magnesium 8 hydrates.
8. the preparation method of stable protein kinase activator is characterized in that: its preparation method is selected from following method:
Method A. is in reaction vessel, add water and cAMP, stir, the oxide compound or oxyhydroxide or its metal-salt or its solution that add pharmaceutically acceptable organic bases or metal by the mol ratio of reaction, stir, question response finishes, filter, slowly add the lower ketones of C3-C6, as acetone, or low mass molecule alcohol C1-C6 such as methyl alcohol, ethanol, Virahol, one or more of the rudimentary ether of C2-C6, cooling is filtered, the solids low mass molecule alcohol of organic solvent C1-C6, as methyl alcohol, ethanol, Virahol, the lower ketones of C3-C6 is as acetone, rudimentary ether such as the ether of C2-C6, or one or more rinses in the water, drain, drying obtains the metal-salt of cAMP or the hydrate of its organic alkali salt;
Perhaps method B. puts into the oxide compound of metal or the solution of oxyhydroxide or its metal-salt or organic bases in the reaction vessel that contains cAMP and water by the mol ratio of reaction, stir, between 0～50 ℃ of the controlled temperature, stir, question response finishes, activated carbon decolorizing, one or many filters, and it is freezing to-70～-30 ℃, heats up, vacuum-drying must have the hydrate of cAMP salt;
Perhaps method C. will contain the oxide compound of metal or a kind of or its solution of oxyhydroxide or its metal-salt or organic bases in the reaction vessel of cAMP and water by the mol ratio adding of reacting respectively, stir, between the controlled temperature-5～40 ℃, reaction 0.5～24h, question response finishes, activated carbon decolorizing, and one or many filters, spraying drying, the hydrate of cAMP salt.
9. the purposes of stable protein kinase activator, it is characterized in that: preparing injection freeze-dried powder or aseptic subpackaged powder injection or little water needle injection or great transfusion preparation, solid preparation, comprise tablet, capsule, granule, comprise application on ointment, the gelifying agent through preparation for external application to skin.
10. the purposes of stable protein kinase activator, it is characterized in that: preparation is applicable to following people of causing and mammalian diseases, comprise stenocardia, heart failure, myocardial infarction, myocarditis, irregular pulse and cardiogenic shock, improve the application in the medicine of the treatment of the palpitaition of rheumatic heart disease, symptom, acute leukemia, nervous system disorders, respiratory system disease, senile chronic bronchitis, hepatitis and psoriatic etc. such as out of breath, uncomfortable in chest or prevention.
CN201010029032A 2010-01-18 2010-01-18 Stable protein kinase activator, preparation method thereof and use Pending CN101781348A (en)

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WO2011085701A1 (en) * 2010-01-18 2011-07-21 联合康兴（北京）医药科技有限公司 Stable protein kinase activators, preparation methods and uses thereof
CN102989034A (en) * 2011-09-10 2013-03-27 温州医学院 Hydrogel applicable to neuroanastomosis and preparation method thereof
CN105147569A (en) * 2015-10-16 2015-12-16 孟红琳 Antioxidation composition for cosmetics and temperature-sensitive gel
CN106565796A (en) * 2016-11-04 2017-04-19 南京工业大学 Cyclic adenosine phosphate sodium salt solvate crystal and preparation method thereof

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CN101781348A (en) * 2010-01-18 2010-07-21 刘力 Stable protein kinase activator, preparation method thereof and use

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Publication number Priority date Publication date Assignee Title
WO2011085701A1 (en) * 2010-01-18 2011-07-21 联合康兴（北京）医药科技有限公司 Stable protein kinase activators, preparation methods and uses thereof
CN102989034A (en) * 2011-09-10 2013-03-27 温州医学院 Hydrogel applicable to neuroanastomosis and preparation method thereof
CN102989034B (en) * 2011-09-10 2016-01-20 温州医学院 A kind of hydrogel being applied to nerve anastomosis and preparation method thereof
CN105147569A (en) * 2015-10-16 2015-12-16 孟红琳 Antioxidation composition for cosmetics and temperature-sensitive gel
CN105147569B (en) * 2015-10-16 2018-01-19 广州丽彦妆生物科技有限公司 A kind of antioxidant composition and temperature sensitive hydrogel for cosmetics
CN106565796A (en) * 2016-11-04 2017-04-19 南京工业大学 Cyclic adenosine phosphate sodium salt solvate crystal and preparation method thereof

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