CN102250179A

CN102250179A - Stable protein kinase activator, and preparation method and purpose thereof

Info

Publication number: CN102250179A
Application number: CN2011100099297A
Authority: CN
Inventors: 刘力
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-01-18
Filing date: 2011-01-18
Publication date: 2011-11-23
Anticipated expiration: 2031-01-18
Also published as: CN102250179B; CN101781348A; WO2011085701A1

Abstract

The invention relates to a novel stable protein kinase activator adenosine cyclophosphate derivative, which has good storage stability and preparation performance and can be applied to preparations of medicaments for treating or preventing human and mammal diseases, such as angina pectoris, heart failure, myocardial infarction, myocarditis, arrhythmia, acute leukemia, neurological diseases, respiratory system disease, senile chronic bronchitis, hepatitis and psoriasis, etc, and medicaments for improving symptoms of palpitaition, dyspnea and chest distress of rheumatic heart disease.

Description

Stable protein kinase activator and its production and use

Technical field

The present invention relates to medical technical field, be specifically related to a kind of hydrate and preparation and purposes of stable protein kinase activator-cAMP salt.

Background technology

CAMP is the protein kinase activator, is the derivative of Nucleotide.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.The 2nd courier 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 sarcoplasm 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.

Present disclosed document has only been reported some salt of cAMP and purposes, as be used for the treatment of stenocardia, heart failure, myocardial infarction, myocarditis, irregular pulse and cardiogenic shock, improve 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.[reference: the clinical efficacy research of cAMP treatment chronic heart failure acute exacerbation phase, Hebei medical science, 2004,10(7): p627; CAMP to mitral valve replacement after the influence of myocardial enzymes, Chinese Journal of New Drugs 2002,10 (7): p559-561; Cyclic AMP injecta treatment congestive heart failure, Kaifeng doctor special journal 2000,19 (3): p13; Dobutamine associating cAMP treatment clinical observation in heart failure, contemporary Chinese medicinal application, 2010,16:p132-133; The pharmacological action of meglumine cyclic adenylate and clinical application, Chinese medicine company, 1999,8(5): p31; Chinese Pharmaceutical Journal, 1992,27 (6): p371; Anti-arrhythmic effects of meglumine cyclic adenylate, Chinese J Pharmacol Toxicol, 1989,3 (4): p251-254; The cardiovascular magazine of China, 1999,4 (5): p283; Meglumine Cyclic Adenylate is to bradyarrhythmia and observation of curative effect in heart failure, clinical department of internal medicine magazine 2004,21 (8): p574; Cardiac damage curative effect after the meglumine cAMP treatment asphyxia neonatorum, paediatrics pharmaceutical journal 2001,7 (3): p18; Meglumine Adenosine Cyelophosphate is inquired into the therapeutic action and the mechanism of childhood asthma, China's medicine in the present age, 2010,17 (3): p49-50; TVI observes the influence of meglumine cyclic adenylate to mitral annular motion, shanghai Medicine image 2004,13 (4): p251-252; Meglumine Adenosine Cyelophosphate is to the influence of chronic heart failure patient heart function and Type B natriuretic peptide, and Chinese medicine is innovated, and 2009,34(6): p13-14].

But the hydrate and its production and use of protein kinase activator-cAMP salt that up to the present, does not still have both at home and abroad the new stable of open source literature report.

Summary of the invention

One of purpose of the present invention provides a kind of hydrate of stablizing, being difficult for drawing wet cAMP salt.

The hydrate of 3 ', 5 '-cyclic monophosphate salt provided by the invention (Adenosine Cyclophosphate), 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), cAMP DL-Methionin 1 hydrate, 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, cAMP triethylamine 1 hydrate, cAMP diethylamine 1 hydrate 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 _L8(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, the hydrate of each the cAMP salt among the table 1-6 is all by corresponding embodiment method preparation.

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.

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 mainly acts on as follows:

1, keeps the activity of enzyme

Magnesium is cofactor or the agonist that many enzymes are, 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, keep the excitability of excitable cell

Magnesium ion 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, keep the genetic stability of cell

Magnesium is main cofactor and decision cell cycle and the interior attemperator of apoptotic cells in the DNA related enzyme systems.

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.

2, participate in muscle (comprising skeletal muscle, unstriated muscle) contraction process, impel heartbeat.

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 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.

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.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 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.Arginine 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 arginine 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-arginine shows that arginine supplementation group coronary artery blood flow when exercise testing is clearly better.The L-arginine 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 arginine, all can specificity strengthen the cellular immune function of normal or wound animal; In wound and tumor-bearing animal, except that alleviating the immunosuppression that wound causes, arginine 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.

Methionin belongs to basic aminoacids, 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, 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 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 present invention also provide described cAMP salt hydrate the preparation method and be used for stenocardia, heart failure, myocardial infarction, myocarditis, irregular pulse and cardiogenic shock, improve the purposes of the palpitaition of rheumatic heart disease, disease prevention such as symptom, acute leukemia, nervous system disorders, respiratory system disease, hepatitis and psoriatic such as out of breath, uncomfortable in chest or treatment.

The hydrate preparation method of the salt of cAMP comprises:

Method A. is in reaction vessel, add water and cAMP, stir, add oxide compound or oxyhydroxide or its metal-salt or its solution of pharmaceutically acceptable organic bases or metal by the mol ratio of reaction, stir, question response finishes, and filters, and slowly adds the lower ketones of C3-C7, as acetone, or the low mass molecule alcohol of C1-C6, as methyl alcohol, ethanol, Virahol, one or more in the rudimentary ether of C2-C8, cooling, filter, solids is with the low mass molecule alcohol of organic solvent C1-C6, as methyl alcohol, ethanol, Virahol, the lower ketones of C3-C7, as acetone, rudimentary ether such as the ether of C2-C6, or one or more rinses in the water, drain, drying obtains the hydrate of cAMP 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 8 hours is to more than a few days, 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, solid 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 are as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; 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.The hydrate of cAMP salt of the present invention with respect to anhydride between the shelf lives related substance be that the content increasing degree of impurity is lower than hydrate, preparation for the intravenously administrable for the treatment of cardiovascular and cerebrovascular diseases will help improving the security of clinical administration 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 ethanol, glycerine, trolamine, glycogelatin, Macrogol 200～8000, poloxamer, polyvinylpyrrolidone, 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=5.0～8.5, 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 4.0～8.5, 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 4.0～8.5.

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, 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 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 0.9% sodium-chlor or 5～10% glucose, 20～500 milliliters, 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 10～70 kg 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 Tu is in the affected part, once a day to six times.

Description of drawings

Fig. 1 is the thermogram spectrum of magnesium salts 8 hydrates of 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.

Fig. 6 is the X ray diffracting spectrum of magnesium salts 8 hydrates of cAMP.

Embodiment

The invention discloses a kind of hydrate and preparation and purposes of cAMP salt, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as being included in the present invention.Product of the present invention, method and application are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.

In specific embodiment, hot analytical test condition is: the Setsys of Setaram company 16, PE-6300TGDTA, the about 5mg of sample size, heat-up rate: 10K/min, N ₂Flow velocity: 50ml/min, room temperature～400 ℃.

X-ray diffractogram is to utilize D/MX-III A X-ray diffractometer at Wuhan University of Technology testing of materials center, and diffraction angle 2 θ, have measured the x-ray diffractogram of powder of hydrate of the present invention by sweep limit 3-60 °.

In one embodiment, utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, magnesium salts 8 hydrates of cAMP of the present invention can have corresponding eigenwert in the position that comprises following 2 θ values: about 4.3,5.9,11.0,13.0,16.9,17.9,20.0,21.6,24.3,26.0,31.3,33.9.

In one embodiment, utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, meglumine cyclic adenylate 1 hydrate of the present invention can have corresponding eigenwert in the position that comprises following 2 θ values: about 6.3,15.0,17.9,20.8,22.5.

In one embodiment, utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, cAMP L-arginine 1 hydrate of the present invention can have corresponding eigenwert in the position that comprises following 2 θ values: about 3.5,17.6,20.8,30.2,34.5.

In one embodiment, utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, cAMP L-Methionin 1 hydrate of the present invention can have corresponding eigenwert in the position that comprises following 2 θ values: about 14.2,15.8,17.6,20.7,27.0.

In specific embodiments, cAMP salt hydrate of the present invention is carried out check and analysis, wherein the assay of cAMP carries out with reference to the China national drug standard.

In one embodiment, cAMP salt hydrate of the present invention is carried out check and analysis, 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.

In one embodiment, cAMP salt hydrate of the present invention carrying out check and analysis, wherein the mensuration reference literature of Methionin: agricultural brightness etc. lysine hydrochloride and Injection by HPLC thereof are measured, chemical industry technology and exploitation, 2003,32 (2): 33.

In order to make those skilled in the art understand technical scheme of the present invention better, the present invention is described in further detail below in conjunction with specific embodiment.

The preparation of magnesium salts 8 hydrates of embodiment 1 cAMP

In the 250ml three-necked flask, add cAMP 0.1mol, water 100ml, stir, the magnesium oxide that adds 0.05mol, 20～60 ℃ were stirred about 50 minutes down, made dissolving, filtered, the acetone that adds 5 times of amounts is separated out solid, be cooled to about-10 ℃, placed 24 hours, filter, about 50 ℃ dryings of solids got off-white color solid 23.6g in 4 hours, fusing point: 227 ℃ of decomposition (not proofreading and correct), HPLC: cAMP content 39.86%, it is 17.57% that the Ka Shi method is measured moisture, heat is analyzed: the weightless about 17.16%(of platform sees accompanying drawing 1), this and sample contain result's (theoretical value 17.48%) of 8 crystal water in limit of error; Infrared spectra: ν ^KBr _MaxCm ^-13437,3210,2913,2428,1659,1606,1581,1488,1425,1384,1343,1290,1237,1136,1095,1053,1022,952,869,843,724,640,545; 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

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 about 60 minutes down, make dissolving, filter, add the dehydrated alcohol and the Virahol (1:1) of 5 times of amounts, be cooled to-10～5 ℃, placed 24 hours, 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; ESI:m/z:328; Infrared spectra: ν ^KBr _MaxCm ^-13436,3209,2913,2428,1658,1606,1581,1488,1425,1384,1343,1290,1237,1136,1094,1053,1022,951,869,843,724,640,545; 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, use 0.22 micron filtering with microporous membrane again, it is freezing to-60～-40 ℃, keeps about 4 hours, is warming up to then about-16 ℃, between the vacuum tightness 5-12Pa, about vacuum-drying 20 hours, again at 20～30 ℃, between the vacuum tightness 5-12Pa, vacuum-drying is about 4 hours, get the off-white color solid, this solid is 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:523,328,19,6,195; 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; Infrared spectra: ν ^KBr _MaxCm ^-13404,3210,2918,2766,2427,1648,1605,1571,1478,1422,1384,1332,1299,1233,1134,1083,1018,945,839,765,724,644,540; 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, and uses 0.22 micron filtering with microporous membrane again, and it is freezing to-60～-40 ℃, kept about 4 hours, be warming up to then about-16 ℃, under the vacuum tightness 0.5-15Pa, vacuum-drying is about 20 hours, again at 20～30 ℃, between the vacuum tightness 0.5-15Pa, about vacuum-drying 4-8 hour, get off-white color solid 10.1g, this solid is soluble in water, fusing point: 189～195 ℃ of (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), HPLC: cAMP content is 63.07%, arginine 33.31%; ESI:m/z:502,328,175,158; It is 3.82% that the Ka Shi method is measured moisture, and heat is analyzed: the weightless about 3.61%(of platform sees accompanying drawing 4), this and sample contain result's (theoretical value 3.46%) of 1 crystal water in limit of error; Infrared spectra: ν ^KBr _MaxCm ^-13422,3210,2928,2765,2426,2071,1641,1476,1384,1331,1238,1134,1083,1018,839,796,765,72,3,643,540; 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, stirring reaction 30min, the centesimal gac that adds the solution total amount stirs half an hour and filters, use 0.22 micron filtering with microporous membrane again, it is freezing to-60～-40 ℃, keeps about 4 hours, is warming up to then about-20 ℃, under vacuum tightness 0.8-15Pa, about vacuum-drying 20 hours, again at 20～30 ℃, under the vacuum tightness 0.8-15Pa, vacuum-drying is about 4 hours, get off-white color solid 11.6g, this solid is soluble in water, fusing point: 195～201 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS does not proofread and correct); HPLC: cAMP content is 66.65%, Methionin 29.46%; ESI:m/z:474,328,147,130; Moisture (Ka Shi method): 3.96%, heat is analyzed: the weightless about 4.01%(of platform sees accompanying drawing 5), this and sample contain result's (theoretical value 3.65%) of 1 crystal water in limit of error; Infrared spectra: ν ^KBr _MaxCm ^-13424,3198,2933,2766,2427,1642,1599,1509,1477,1384,1332,1237,1134,1083,1018,839,796,7,59,724,644,542.

Embodiment 6 is with the preparation of cAMP sodium 2 hydrates

10g places reaction flask with cAMP, 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 30min, the gac that adds solution gross weight 0.2% stirs half an hour and filters, and uses 0.22 micron filtering with microporous membrane again, it is freezing to-70～-40 ℃, be warming up to then about-16 ℃, between the vacuum tightness 0.5-10Pa, vacuum-drying is about 20 hours, again at 20～30 ℃, between the vacuum tightness 2-12Pa, about vacuum-drying 6 hours, get off-white color solid 10.6g, this solid is soluble in water, fusing point: 227 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS does not proofread and correct); Assay: HPLC method: cAMP content is 84.82%; Moisture (Ka Shi method): 9.47%, heat is analyzed: the weightless about 9.03%(of platform sees accompanying drawing 6), 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%.

The preparation of embodiment 7 cAMP DL-Methionins 1 hydrate

With the cAMP 10g after pure and and equimolar DL-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 ℃, keeps about 24 hours, is warming up to then about-16 ℃, under the vacuum tightness 2-10Pa, about vacuum-drying 20 hours, again at 20～30 ℃, between the vacuum tightness 2-10Pa, vacuum-drying is about 6 hours, get off-white color solid 12.2g, this solid is soluble in water, fusing point: 194～199 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS does not proofread and correct); HPLC: cAMP content is 66.52%, Methionin 29.34%; ESI:m/z:474,330,328,147,130; Moisture (Ka Shi method): 4.02%, heat is analyzed: platform is weightless about 3.83%, and this and sample contain result's (theoretical value 3.65%) of 1 crystal water in limit of error; Infrared spectra: ν ^KBr _MaxCm ^-13424,3198,2933,2766,2427,1642,1599,1509,1477,1384,1332,1237,1134,1083,1018,839,796,7,59,724,644,542.

The preparation of embodiment 8 cAMP D-arginine 1 hydrate

With the cAMP 10g after pure and and equimolar D-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, and uses 0.22 micron filtering with microporous membrane again, and it is freezing to-70～-40 ℃, kept about 5 hours, be warming up to then about-16 ℃, under the vacuum tightness 3-15Pa, vacuum-drying is about 20 hours, again at 20～30 ℃, between the vacuum tightness 3-15Pa, about vacuum-drying 6 hours, get off-white color solid 11.5g, soluble in water, fusing point: 190～194 ℃ of (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), HPLC: cAMP content is 63.01%, arginine 33.35%; It is 3.78% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 3.57%, and this and sample contain result's (theoretical value 3.46%) of 1 crystal water in limit of error.

The preparation of embodiment 9 cAMP triethylamines 1 hydrate

With reference to the method for embodiment 3, be prepared into cAMP triethylamine 1 hydrate of off-white color.

CAMP L-arginine 1 hydrate or cAMP L-Methionin 1 hydrate or cAMP DL-Methionin 1 hydrate or meglumine cyclic adenylate 1 hydrate 200g are got in the preparation (each hydrate of cAMP prepares by corresponding embodiment method) of embodiment 10 cAMP L-arginine 1 hydrates or cAMP L-Methionin 1 hydrate or cAMP DL-Methionin 1 hydrate or meglumine cyclic adenylate 1 hydrate freeze-dried preparation, 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.

CAMP L-arginine 1 hydrate (by the preparation of embodiment 4 methods) is got in the preparation of embodiment 11 freeze-dried preparation or meglumine cyclic adenylate 1 hydrate 10g(prepares by embodiment 3 methods) (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 12 gets the hydrate 20Kg(of salt of aseptic cAMP in cAMP) (each hydrate of cAMP is by corresponding embodiment method preparation), 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.

Preparation cAMP sodium 2 hydrates of the small-volume injection of the hydrate of the salt of embodiment 13 cAMPs (by the preparation of embodiment 6 methods) or cAMP L-arginine 1 hydrate (by the preparation of embodiment 4 methods) or meglumine cyclic adenylate 1 hydrate (by the preparation of embodiment 3 methods) (by cAMP) 10 g, 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) stirring 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 2～10ml/ bottle, sterilize finished product.

The freeze-dried preparation preparation of embodiment 14 cAMP sodium 2 hydrates is got cAMP sodium 2 hydrate 10g(by the preparation of embodiment 4 methods), adding injection blunges and makes dissolving, add activated carbon 0.3%(W/V) stirring 15～45min, filter, moisturizing is to 2000ml, with 0.22 micron filtering with microporous membrane, by the packing of 2～5ml/ bottle, lyophilize, tamponade gets finished product.

The preparation of embodiment 15 cAMP sodium, 2 hydrates or cAMP L-arginine 1 hydrate or meglumine cyclic adenylate 1 hydrate high-capacity injection (hydrate of each cAMP salt is by corresponding embodiment method preparation)

Take by weighing glucose 500g and add in the water for injection, stir and make dissolving fully, add the gac of 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 transfusion of the salt of embodiment 16 cAMPs

Hydrate (in cAMP) (hydrate of each cAMP salt is by corresponding embodiment method preparation) 4g with 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.

The preparation (the 250mg/ sheet is in cAMP) of embodiment 17. cAMP magnesium, 8 hydrates or cAMP L-arginine 1 hydrate tablet

Prescription: cAMP magnesium 8 hydrates or cAMP L-arginine 1 hydrate 250g(are 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 capsular preparation of hydrate (the 100mg/ grain is in cAMP) of embodiment 18 cAMP salt

Prescription: the salt hydrate 100g(of cAMP is in cAMP)

Microcrystalline Cellulose 100g

Lactose 20g

Gelling starch 10% is an amount of

Magnesium Stearate 2g

Hydrate (hydrate of each cAMP salt prepares by corresponding embodiment method), Microcrystalline Cellulose, the lactose of cAMP salt of the present invention are crossed 100 mesh sieves, gelling starch with 10% 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 Magnesium Stearate and mix the can capsule.

The preparation of the hydrate particle of embodiment 19 cAMP salt 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 hydrate 50g(of cAMP salt is in cAMP)

N.F,USP MANNITOL 180g

Sucrose 20g

Sodium Cyclamate 2g

Solid food flavour 1g

Polyvinylpyrrolidone 5% is an amount of

Hydrate (hydrate of cAMP salt prepares by corresponding embodiment method), N.F,USP MANNITOL, sucrose, Sodium Cyclamate, the food flavour of cAMP salt are crossed 100 mesh sieves, polyvinylpyrrolidone with 5% is made softwood in right amount, crossing the 18-24 mesh sieve granulates, dry below 60 ℃, after crossing the whole grain of 14-20 mesh sieve, divide packing.

The gel of the hydrate of embodiment 20 cAMP salt of the present invention (hydrate of cAMP salt is by corresponding embodiment method preparation)

Prescription: the hydrate 25g(of cAMP salt feeds intake 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 hydrate that adds cAMP salt, 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

1. a protein kinase activator is characterized in that, molecular formula is [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 is selected from a kind of of pharmaceutically acceptable metal ion or organic bases.

2. protein kinase activator according to claim 1, it is characterized in that: described organic bases is selected from 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. protein kinase activator according to claim 1 is characterized in that: described metal ion is selected from a kind of in lithium, potassium, sodium, calcium, magnesium, zinc, aluminium or the bismuth.

4. protein kinase activator according to claim 1 is characterized in that, it is cAMP L-arginine 1 hydrate or cAMP D-arginine 1 hydrate.

5. protein kinase activator according to claim 1 is characterized in that: it is cAMP L-Methionin 1 hydrate or cAMP DL-Methionin 1 hydrate.

6. protein kinase activator according to claim 1 is characterized in that: it is meglumine cyclic adenylate 1 hydrate.

7. stable protein kinase activator according to claim 1 is characterized in that: it is cAMP sodium 2 hydrates or cAMP calcium 3.5 hydrates or cAMP magnesium 8 hydrates.

8. protein kinase activator according to claim 1 is characterized in that: its preparation method is selected from following method:

Method A. mixes water and cAMP, 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, the lower ketones that slowly adds C3-C6, or C1-C6 low mass molecule alcohol, one or more of the rudimentary ether of C2-C6, cooling, filter the solids low mass molecule alcohol of organic solvent C1-C6, the lower ketones of C3-C6, one or more rinses in the rudimentary ether of C2-C6 or the water, filter, drying obtains the hydrate of cAMP 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, it is freezing to-70～-30 ℃, and 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. be the injection freeze-dried powder of activeconstituents or aseptic subpackaged powder injection or little water needle injection or great transfusion preparation, solid preparation with the described protein kinase activator of claim 1, comprise tablet, capsule, granule, comprise ointment, gelifying agent through preparation for external application to skin.

10. the described protein kinase activator of claim 1 is applicable to following people of causing and mammalian diseases in preparation, 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.