WO2011085701A1 - Stable protein kinase activators, preparation methods and uses thereof - Google Patents

Abstract

Protein kinase activators, hydrates of adenosine cyclophosphate salt, preparation methods and uses thereof are disclosed. The hydrates of adenosine cyclophosphate salt have excellent storage stability and are not liable to absorb moisture. Furthermore, the hydrates of adenosine cyclophosphate salt are useful for treating or preventing diseases such as stenocardia, cardiac failure, myocardial infarction, myocarditis, arrhythmia, cardiogenic shock, acute leukemia, nerve system diseases, respiratory system diseases, senile chronic bronchitis, hepatitis and psoriasis, and for improving symptoms of cardiopalmus, shortness of breath, chest distress and the like of rheumatic heart disease.

Description

 Stable protein kinase activator, preparation method and use thereof

 This application claims priority to Chinese Patent Application No. 201010029032.6, entitled "Stable Protein Kinase Activator and Its Preparation Method and Use", filed on January 18, 2010, the entire contents of which are hereby incorporated by reference. Combined in this application. Technical field

 The invention relates to the technical field of medicine, in particular to a stable hydrate of a protein kinase activator monocyclic adenosine salt, and preparation and use thereof. Background technique

 Cyclic adenosine is a protein kinase activator and is a derivative of nucleotides. It is a physiologically active substance widely present in the human body. It is produced by adenosine triphosphate catalyzed by adenosine cyclase and can regulate various functional activities of cells. As the second messenger of hormones, the role of hormones in regulating physiology and substance metabolism in cells can change the function of cell membranes, promote calcium ions in the sarcoplasm and enter muscle fibers, thereby enhancing myocardial contraction and promoting respiratory chain oxidase. Activity, improve myocardial hypoxia, relieve symptoms of coronary heart disease and improve electrocardiogram. In addition, it plays an important role in the regulation of sugar, fat metabolism, nucleic acid, and protein synthesis.

The current published literature only reports certain salts and uses of cyclic adenosine, such as for the treatment of angina pectoris, heart failure, myocardial infarction, myocarditis, arrhythmia and cardiogenic shock, improving heart palpitations, shortness of breath, chest tightness in rheumatic heart disease. Such symptoms, acute leukemia, nervous system diseases, respiratory diseases, hepatitis and psoriasis. [Reference: Clinical efficacy of cyclophosphamide in the treatment of acute exacerbation of chronic congestive heart failure, Hebei Medical Journal, 2004,10 (7): p627; Effect of cyclic adenosine on myocardial enzymes after mitral valve replacement] , Chinese Journal of New Drugs 2002, 10 (7): p559-561; cyclophosphamide injection in the treatment of congestive heart failure, Kaifeng Medical College 2OO0,19 (3): pl3; dobutamine combined with cyclic adenosine monophosphate Clinical observation of treatment of heart failure, Modern Chinese Medicine Application, 2010,16:pl32-133 ; Pharmacological action and clinical application of Xin Xianan, Chinese Pharmaceuticals, 1999,8 ( 5 ) : p31 ; Chinese Journal of Pharmaceutical Sciences, 1992,27 (6): p371; antiarrhythmic effects of glucosamine cyclic adenosine, Chinese Journal of Pharmacology and Toxicology, 1989, 3(4): p251-254; Chinese Journal of Cardiology, 1999, 4(5): P283; Therapeutic effect of cyclic adenosine monophosphate on bradyarrhythmia and heart failure, Journal of Clinical Internal Medicine 2004, 21(8): p574; Therapeutic effect of indole cyclic adenosine on myocardial damage in neonates with asphyxia, Journal of Pediatric Pharmacy 2001, 7(3): pl 8 ; Therapeutic effect and mechanism of cyclophosphamide on childhood asthma, China Contemporary Medicine, 2010, 17(3): p49-50 ; TVI observation of the effect of cyclic adenosine on the movement of the mitral annulus, Shanghai Medical Imaging 2004, 13(4): p251-252; Cyclic adenosine monophosphate for chronic congestion Cardiac function and the effect of B-type natriuretic peptide in patients with heart failure, Chinese Medical Innovation, 2009, 34 (6): pl3- 14].

 However, up to now, there has not been a publicly-recognized novel stable protein kinase activator, a cyclic adenosine monophosphate hydrate, and a preparation method and use thereof. Summary of the invention

One of the objects of the present invention is to provide a hydrate of a cyclic adenosine salt which is stable and difficult to wet. The present invention provides a 3,5,-adenosine Cyclophosphate having a molecular formula of { [ cAMP ] _m A'n3⁄40 and a cAMP of C ₁₍₎ H ₁₂ N ₅ 0 ₆ P or ( ₁₍₎ ^ ₅ 0 ₆ ? , m=l ~ 3 , n=0.88 ~ 8.5} , m=l 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 a number between them.

 A is selected from one of a pharmaceutically acceptable metal ion or an organic base. The organic base includes triethylamine, diethylamine, ethanolamine, glucosamine, ethamamine, tromethamine, piperazine, morpholine, L-lysine, D-lysine, DL-lysine. , one of L-arginine, D-arginine, DL-arginine, histidine, ornithine, citrulline, etc., all of which include racemic and chiral amino acids (D or L) Type of amino acid), the metal ion is one of lithium, potassium, sodium, calcium, magnesium, rhodium, aluminum or strontium.

The salt of the cyclic adenosine containing crystal water obtained by the present invention is different from the characteristic that the cyclic adenosine is hardly soluble in water. Surprisingly, the salt hygroscopicity of the cyclic adenosine containing no crystal water is much higher than that of the salt. A salt of cyclic adenosine containing crystal water, a hydrate of a salt of a cyclic adenosine containing crystal water is more stable than a water containing no crystal water, and is convenient for storage and transportation, some of which have good at room temperature. It is water-soluble and easy to prepare into a water-soluble preparation. Characteristic, the thermal analysis (TG-DSC or TG-DTA) of the hydrate of the present invention shows that the weightless platform has a strong corresponding endothermic peak, and the thermal analysis map shows the cyclic adenosine L-arginine. 1 hydrate ((^.Η ₁₂ Ν ₅ 0 ₆ Ρ·(3 ₆ Η ₁₄ Ν ₄ 0 ₂ ·Η ₂ 0 ), cyclic adenosine L-lysine 1 hydrate ((^.Η ₁₂ Ν ₅ 0 ₆ Ρ ₆ Η ₁₄ Ν ₂ 0 ₂ · Η ₂ 0 ), Cyclophosphamide DL-lysine monohydrate, Cyclophosphamide glucosamine 1 hydrate ((^.Η ₁₂ Ν ₅ 0 ₆ Ρ) ·( ₇ Η ₁₇ Ν0 ₅ ·Η ₂ 0), sodium adenosine monophosphate 2 hydrate

( doHnNsOePNa^HsO ), cyclic adenosine magnesium salt 8 hydrate [((^.^ ₅ 0 ₆ ?) ₂ '^/3⁄4'83⁄40], Cyclic adenosine calcium salt 3.5 hydrate [(doHnNsOsP) ₂ Ca'3.5H ₂ 0], etc., was measured by Karl Fischer method, and the results were in agreement with the results of thermal analysis.

 The present invention also includes cyclic adenosine D-arginine monohydrate, cyclophosphamide D-lysine monohydrate, cyclophosphamide DL-lysine monohydrate, cyclophosphamide adenosine L-melon Amino acid hydrate, cyclic adenosine triethylamine monohydrate, cyclophosphamide diethylamine monohydrate, and the like.

The hydrate of the salt of cyclic adenosine of the present invention can be stably stored. The above hydrated adenosine salt hydrate and cyclic adenosine salt anhydrate sample were separately sealed in a vial for accelerated stability test (chromatographic conditions: column: C ₁₈ (250 mm x 4.6 mm, 5 ηι) Mobile phase: 0.05mol/L potassium dihydrogen phosphate solution (containing 0.01mol/L tetrabutylammonium bromide) - acetonitrile (85: 15); Flow rate: lml/min; Temperature: room temperature; Detection wavelength: 259nm Surprisingly, it has been found that the content of the hydrate of the cyclic adenosine monophosphate of the present invention and the related substances are less changed, and the salt an adenosine salt anhydrate is accelerated for 6 months compared with the month of 0 (40 ° C, RH75%), the doubling of the substance is higher than the hydrate of the cyclic adenosine salt. The wettability test was carried out according to the requirements of the Chinese Pharmacopoeia: About 5 g of the salt anhydrate of the cyclic adenosine and the hydrate of the present invention were placed on a dry constant weight surface and accurately weighed. 25 V, relative humidity of 75%, samples were taken at the test Oh and 48h, respectively, and the percentage of wetting gain was calculated. The results showed that the anhydrate is more hygroscopic than the hydrate of the present invention, indicating the ring-phosphorus of the present invention. The hydrate of the salt of the glycoside has better storage stability. The results are shown in Tables 1 to 6, and the hydrates of the respective cyclic adenosine salts in Tables 1-6 were prepared according to the respective examples.

 In addition, the deliquescent of the anhydrate causes the air to be prevented from sticking during the treatment, and the hydrate does not have good slidability, and the operability of the preparation is improved.

 Table 1. Results of accelerated stability test of cyclic phosphatidyl adenosine L arginine salt 1 hydrate of the present invention

 Sampling time (month) traits labeled content (%) related substances (%)

 0 white powder 99.3 < 1%

 Class 1 white powder 99.7 < 1%

 Class 2 white powder 99.4 < 1%

 Class 3 white powder 99.9 < 1%

 6 white powder 99.5 < 1%

 Table 2. Results of the accelerated stability test of the cyclic phosphatidyl lysine L-lysine salt 1 hydrate of the present invention

Sampling time (month) trait indication content (%:) related substances (%) 0 white powder 99.6 < 1%

Class 1 white powder 99.8 < 1%

Class 2 white powder 99.6 < 1%

Class 3 white powder 99.4 < 1%

6 kinds of white powder 99.5 < 1% Table 3. The results of the accelerated stability test of the cyclic adenosine glucoside salt of the present invention 1 sampling time (month) traits labeled content (%) related substances (%)

0 white powder 99.6 < 1%

Class 1 white powder 99.9 < 1%

Class 2 white powder 99.7 < 1%

Class 3 white powder 99.4 < 1%

Class 6 white powder 99.5 < 1% Table 4. Results of accelerated stability test of calcium adenosine monophosphate 8 hydrate of the present invention

 Sampling time (month) traits labeled content (%) related substances (%)

0 white powder 99.8 < 1%

Class 1 white powder 99.9 < 1%

Class 2 white powder 99.6 < 1%

Class 3 white powder 99.4 < 1%

Class 6 white powder 99.2 < 1% Table 5. Accelerated stability test results

Sampling time related substances (0 months) Related substances (June) Cyclic adenosine sodium salt 2 hydrate 0.43 0.85 Cyclic adenosine sodium salt anhydrate 0.62 1.52 Cyclic adenosine arginine salt 1 hydrate 0.67 0.94 Cyclic adenosine arginine anhydrate 0.79 1.37 Cyclic adenosine lysine salt 1 hydrate 0.56 0.91 Cyclic adenosine lysine salt anhydrate 0.79 1.49 Cyclophosphamide adenosine Indoleamine salt 1 hydrate 0.45 0.83 Cyclophosphamide aglucosamine salt anhydrate 0.57 1.31 Table 6. Results of the wettigation test

 Sampling time (48 hours) Compared with 0 hours, weight gain

 Sodium adenosine monophosphate 2 hydrate 1.25

 Calcium adenosine phosphate 3.5 hydrate 0.67

 Magnesium salt of cyclic adenosine monophosphate 8 hydrate 0.81

 Arginine salt of cyclic adenosine monophosphate 1 hydrate 0.79

 Lysine salt lysine salt 1 hydrate 0.92

 Glucosamine adenosine salt 1 hydrate 0.96

 Sodium adenosine sodium anhydrate 9.34

 Calcium salt anhydrate of cyclic adenosine 8.23

 Magnesium salt anhydrate of cyclic adenosine 17.86

 Arginine salt anhydrate of cyclic adenosine 3.45

 Cyanoadenosine lysine salt anhydrate 3.63

 Anhydrous adenosine hydrochloride anhydrous 3.41

 Cyclic adenosine is a protein kinase activator. It is a physiologically active substance widely present in the human body. It is produced by adenosine triphosphate catalyzed by adenosine cyclase and can regulate various functional activities of cells. As the second messenger of hormones, the role of hormones in regulating physiology and substance metabolism in cells can change the function of cell membranes, promote the entry of calcium ions into the muscle fibers in the sarcoplasmic reticulum, thereby enhancing myocardial contraction and promoting respiratory chain oxidation. Enzyme activity, improve myocardial hypoxia, relieve symptoms of coronary heart disease and improve electrocardiogram. In addition, it plays an important role in the regulation of sugar, fat metabolism, nucleic acid, and protein synthesis.

 The derivative of the cyclic adenosine of the present invention contains important alkali metal and alkaline earth metal ions or amino acids in addition to the cyclic adenosine containing a protein kinase activator, and these ions or amino acids have various physiological functions, such as: magnesium It is an essential element of the human body. Magnesium ions have a variety of biological activities and are essential factors for maintaining normal neuromuscular excitability and tissue cell energy metabolism. Magnesium ions are important cofactors in various enzyme systems in vivo. The metabolism plays an important physiological role. Its main functions are as follows:

1. Maintaining the activity of enzymes Magnesium is a cofactor or agonist of many enzymes. It can activate more than 300 enzymes in the body, including hexokinase, Na ⁺ -K ⁺ ATPase, carboxylase, pyruvate dehydrogenase, peptide. Enzyme, choline Esterase, etc., participate in many important metabolic processes in the body, including metabolism of proteins, fats and carbohydrates and nucleic acids, oxidative phosphorylation, ion transport, generation and transmission of nerve impulses, meat shrinkage, etc., almost related to various aspects of life activities. .

 2. Maintain the excitability of excitable cells

Magnesium ions inhibit the central nervous system, neuromuscular and myocardium. For neuromuscular stress, Mg ²⁺ is synergistic with Ca ²⁺ and is antagonistic to the myocardium.

 3. Maintain the genetic stability of the cells

 Magnesium is a major cofactor in DNA-related enzymes and an intracellular regulator that determines cell cycle and apoptosis.

 At present, magnesium-containing drugs play an important role in the treatment of asthma, bronchiolitis, severe pneumonia, heart failure, respiratory failure, brain failure and pulmonary hypertension. To play a comprehensive role in understanding phlegm, asthma, sedation, phlegm and so on, and confirmed in animal experiments and a large number of clinical practice.

 Calcium ions are indispensable ions of various physiological activities of the body. It maintains normal nerve conduction function by maintaining biopotentials on both sides of the cell membrane. Maintaining normal muscle stretching and diastolic function as well as neuro-muscular conduction, as well as some hormones, are expressed by 4 丐 ions. The main role or mechanism is:

 1. Calcium ion is a blood coagulation factor involved in the blood coagulation process.

 2. Participate in the contraction process of muscles (including musculoskeletal and smooth muscles), causing the heart to beat.

 3. Participate in the synthesis and release of neurotransmitters, hormone synthesis and secretion, and conduct nerve signals. Its guiding mechanism is to promote neurotransmitter secretion. When the body is deficient in calcium, the release of neurotransmitters is blocked, and the excitatory mechanism and inhibition mechanism of the human body are destroyed. If the child is deficient in calcium, it will cause nightingale, night terrors, irritability and insomnia, severe brain development disorders, slow response, hyperactivity, learning difficulties, etc., affecting brain maturity and intelligence.

 4. It is an important substance composed of bones.

5. Pass the enemy signal. The mechanism is: When a foreign antigen activates a T cell receptor, it initiates a calcium-mediated signaling pathway that promotes differentiation and growth of immune cells. Once calcium is deficient, immune system function declines, disorders, and disease. Such as: autoimmune disease lupus erythematosus, rheumatism; skin diseases: dermatitis, hemorrhoids and so on. Calcium supplementation plays an important role in the treatment of these diseases. Arginine is a conditionally essential amino acid, which participates in the tricarboxylic acid cycle in energy metabolism and the urea cycle with detoxification in the body, which promotes the energy balance of the body. After treatment, it can reduce blood ammonia and promote the excretion of toxic substances to eliminate fatigue. The purpose. Its pharmacological effects are extensive, and its main functions are:

 Arginine (Arg) is a source of nitric oxide in the human body. Nitric oxide (NO) promotes blood vessel relaxation and promotes blood circulation. Arginine can promote the recovery of heart rate, increase the blood flow of coronary arteries, improve cardiac function, and have a certain protective effect on the myocardium, suggesting that arginine supplementation can help protect the normal blood supply function of the heart during exercise and delay the occurrence of fatigue. And promote recovery has a certain role. The results of submaximal exercise experiments after supplementation with L-arginine in patients with myocardial ischemia showed that the coronary blood flow was significantly improved in the arginine supplementation group during the exercise experiment. L-arginine supplementation can significantly improve the exercise capacity of patients with coronary vasospasm and angina pectoris, and has a good persistence, and significantly increase plasma NO levels.

 Studies have shown that arginine can effectively reduce the incidence of myocardial infarction, and at the same time have the effect of relaxing blood vessels, lowering blood pressure, and promoting smooth blood circulation. For patients with cardiovascular disease prevention and arteriosclerosis, the incidence of myocardial infarction is obvious. In order to reduce the effect, arginine also has an anti-oxidation effect, which can reduce the oxidation of low-density lipoprotein (LDL) and form an intravascular chylomicron. Therefore, the chance of occlusion of the small blood vessels of the heart and causing a few necrosis of the heart is reduced.

 In addition, arginine has a specific immune promoting effect. Arginine and its metabolites, such as nitric oxide (NO), play an important role in immune defense, immune regulation, maintenance and protection of intestinal mucosal function, and specific immunity of tumors.

 Arginine can effectively improve immunity and promote the secretion of endogenous substances such as natural killer cells, phagocytic cells and interleukin-1 by the immune system, which is beneficial to fight cancer cells and prevent viral infection. Whether it is a normal diet or intravenous arginine, it can specifically enhance the cellular immune function of normal or traumatic animals; in trauma and tumor-bearing animals, in addition to reducing the immunosuppression caused by trauma, arginine can also enhance lymphocytes It has the potential of IL-2 immune anti-tumor effect, can promote T cell mitosis, improve nitrogen balance, improve animal survival rate, and enhance delayed response to allergies. In addition, arginine is a precursor of ornithine and proline. Proline is an important element of collagen. Supplementation of arginine is essential for severe trauma, burns, etc., which require extensive tissue repair. Help, while reducing the effects of infection and inflammation.

Lysine is a basic amino acid, which is one of the eight amino acids required by the human body. Lysine is a synthetic carnitine. For structural components, carnitine promotes the synthesis of fatty acids in cells. Especially in children's developmental period, post-recovery period, and pregnancy lactation, the demand for lysine is higher. Due to the low content of rice, corn and other foods, it is easy to cause human body deficiency, which is called "the first lack of amino acids".

Lysine deficiency can cause dysplasia, loss of appetite, weight loss, negative nitrogen balance, hypoproteinemia, anemia, decreased enzyme activity, and other physiological dysfunctions. Lysine enhances intelligence, promotes growth, enhances physical fitness; increases appetite, improves malnutrition; improves insomnia, improves memory; helps produce antibodies, hormones and enzymes, improves immunity, increases hemoglobin; helps calcium absorption, treatment prevents bone Osteoporosis; Helps nerve tissue repair, promotes nerve cell regeneration, and enhances central nervous system function. Lysine can improve blood-brain barrier permeability, help drugs enter brain cells, and be used as a brain protector for treating craniocerebral trauma, chronic brain tissue ischemia, hypoxic diseases, or assisting other encephalopathy. Treatment can also be used for children with loss of appetite, malnutrition and brain hypoplasia caused by lysine deficiency. The imidazolyl group of histidine can form a coordination compound with Fe ²⁺ or other metal ions to promote the absorption of iron, and thus can be used for preventing anemia. Histidine can reduce the acidity of gastric juice, alleviate the pain of gastrointestinal surgery, reduce the vomiting and stomach burning sensation during pregnancy, inhibit the gastrointestinal ulcer caused by autonomic nervous tension, and also have effects on allergic diseases such as asthma. In addition, histidine can dilate blood vessels, lower blood pressure, and is clinically used for the treatment of diseases such as angina pectoris and cardiac insufficiency. The histidine content in the blood of patients with rheumatoid arthritis was significantly reduced. After using histidine, the indicators such as grip strength, walking and erythrocyte sedimentation rate were improved.

 L-citrulline can improve immune system function, maintain joint movement function, balance normal blood sugar level, absorb harmful free radicals, help maintain normal cholesterol level, improve healthy sexual function, maintain healthy lung function, improve mental clarity, reduce stress And overcome the frustration. Citrulline works with ammonia in the human body to produce arginine and nitric oxide as vasodilators and is used to treat mental and physical fatigue as well as sexual dysfunction. Citrulline is an amino acid drug that can be used in combination with ornithine and arginine to treat hyperammonemia. Citrulline can be completely absorbed into the blood, produce nitric oxide, and participate in a variety of physiological processes, such as nerve transmission, vascular tone, sphincter relaxation, microbial killing, and penile erection. It plays a very important role in male sexual function. . Nitric oxide is formed by the oxidative deamination of L-arginine sulfhydryl to L-citrulline in the presence of oxygen molecules and hemoglobin by nitric oxide synthase (NOS).

The compound of the present invention contains a pharmaceutically acceptable metal ion or an organic base, the metal ion includes an alkali metal ion or an alkaline earth metal ion, and the like, and the organic base includes an amino acid, triethylamine, diethylamine, ethanolamine, etc., wherein the amino acid includes racemization. And chiral amino acids (D or L-form amino acids), and form a stable The composition makes it more advantageous than the single cyclic adenosine in the prevention or treatment of different diseases, or makes it more convenient in the preparation of other derivatives of cyclic adenosine.

 The present invention also provides a method for preparing the hydrate of the cyclic adenosine salt and for angina pectoris, heart failure, myocardial infarction, myocarditis, arrhythmia and cardiogenic shock, improving heart palpitations, shortness of breath, chest tightness, etc. of rheumatic heart disease Use for the prevention or treatment of symptoms, acute leukemia, neurological diseases, respiratory diseases, hepatitis and psoriasis.

 A method for preparing a hydrate of a cyclic adenosine salt comprises:

 Method A. In a reaction vessel, adding water and cyclic adenosine, stirring, adding a pharmaceutically acceptable organic base or metal oxide or hydroxide or a metal salt thereof or a solution thereof in a molar ratio of the reaction, stirring, and waiting After completion of the reaction, filtration, slowly add a lower ketone of C3-C7, such as acetone, or a low molecular weight alcohol of C1-C6, such as one or more of the lower ethers of decyl alcohol, ethanol, isopropanol, and C2-C8. Cooling, filtration, solid organic solvent C1-C6 low molecular alcohol, such as decyl alcohol, ethanol, isopropanol, C3-C7 lower ketone, such as acetone, C2-C6 lower ether such as ether, or water Or several kinds of rinses, drained, and dried to obtain a hydrate of cyclic adenosine;

 Or method B. A solution of a metal oxide or hydroxide or a metal salt or an organic base thereof is added to a reaction vessel containing cyclic adenosine and water at a molar ratio of the reaction, and stirred to control the temperature of 0 to 50 ° C. Between, stirring, to be completed, decolorization of activated carbon, one or more filtration, freezing it to -70 ~ -30 ° C, heating, vacuum drying, to obtain a hydrate of cyclic adenosine;

 Or method C. respectively adding a metal oxide or hydroxide or a metal salt thereof or a pharmaceutically acceptable organic base or a solution thereof to the reaction vessel containing cyclophosphamide and water in a molar ratio of the reaction Stirring, control temperature between -5 ~ 40 °C, reaction 0.5 ~ 24h, after the reaction is completed, decolorization of activated carbon, one or more filtration, spray drying, to obtain a hydrate of cyclic adenosine salt. In spray drying, the inlet air temperature can be between 100 and 140 ° C, and the outlet air temperature can be between 70 and 100 ° C.

1.0~2.0kg/cm ² .

 The hydrate of the cyclic adenosine salt is within 60 ~ 120 ° C, generally within 90 ~ 120 ° C, phosphorus pentoxide is a desiccant, high vacuum drying for 8 hours to several days, to obtain cyclophosphine An adenosine salt anhydrate. The resulting product can be used for comparison of the wettability test or the accelerated stability test.

The lower ketone or low molecular ketone in the present invention is defined as C3-C7, such as acetone, butanone, etc.; lower alcohol or low molecular alcohol is defined as C1-C6, such as decyl alcohol, ethanol, isopropanol, lower ether or low molecular weight. Ether is defined as C2-C8, such as diethyl ether, dibutyl ether, and the like. The oxide or hydroxide of the metal or the metal salt thereof may be: calcium oxide, calcium hydroxide, magnesium oxide, basic magnesium carbonate, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, oxidation, three Aluminium oxide, potassium hydroxide, potassium carbonate, cerium nitrate, the metal salt thereof includes a carbonate or a hydrogencarbonate or a basic carbonate.

 Hydrate use of the salt of cyclic adenosine of the present invention: the hydrate of the salt of cyclic adenosine of the present invention is used for preparing a lyophilized powder preparation for injection, or a large infusion preparation, or a small water injection, sterile Dispensed powder needles, solid preparations, including tablets, capsules, granules, external preparations for skin including ointments, gels and the like.

 A tablet, capsule or granule for the preparation of a solid preparation, which may contain a pharmaceutically acceptable filler such as starch, modified starch, lactose, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol , phosphoric acid 4 bow, amino acid, etc.; pharmaceutically acceptable disintegrating agents, such as starch, modified starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substituted hydroxypropyl cellulose, surface active a pharmaceutically acceptable wetting agent and binder, such as gelatinized starch, thioglycolic acid, sodium carboxymethyl sulphate, ethyl cellulose, polyvinylpyrrolidone, alginic acid and salts thereof; Acceptable lubricants and glidants, such as stearic acid, magnesium stearate, polyethylene glycol 4000-8000, talc, micronized silica gel, magnesium lauryl sulfate, etc.; pharmaceutically acceptable sweeteners And flavors, such as aspartame, cyclamate, sodium saccharin, sucralose, food flavors, etc.

The crystal hydrate of the present invention is different from the deliquescent of the anhydrate in that it is isolated from air to prevent blocking or the like during the treatment, and the crystalline hydrate has good slidability, thereby improving the operability of the preparation; and making the prepared solid preparation have good Its dissolution properties make it easy to be absorbed into the blood circulation, improve bioavailability, and facilitate its rapid function. On the other hand, it prevents it from appearing in the aseptic dispensing process, which is not easy to cause clogging during dispensing due to moisture absorption, resulting in a difference in the amount of the load, resulting in insufficient dosage, resulting in product failure, or because of unqualified products. It has not been sampled to form an actual missed test, and then flows into the market, causing a negative effect on the patient's therapeutic agent in clinical treatment, or jeopardizing the patient's life due to insufficient dose. Or in the case of sub-assembly, the entire production line is forced to suspend due to moisture absorption, which seriously reduces the production capacity of the equipment and greatly increases the hidden troubles such as working hours. The cyclophosphorus admixture of the present invention will greatly contribute to the safety of clinical administration for the preparation of intravenous administration for the treatment of cardiovascular and cerebrovascular diseases. Since cyclophosphamide is slightly soluble in water, it is generally required to add an oil-soluble auxiliary material, which is easy to be contaminated, and is difficult to clean. The storage stability of the hydrate of the cyclic adenosine salt of the present invention is generally easy to be dissolved in water. The characteristics make the preparation of the gelling agent more operability, and the prepared gelling agent has good release property, so that it is easily absorbed into the blood circulation, improves bioavailability, and is beneficial to quickly exert its performance. effect. No need to add oil-soluble auxiliary materials, it is not easy to be contaminated, and it is easy to clean.

 Gel preparation of hydrated adenosine salt hydrate: Mix the cyclic adenosine salt hydrate with 50 ~ 95% matrix, the matrix can be ethanol, glycerol, triethanolamine, glycerin gelatin, polyethylene glycol 200 ~ 8000 , poloxamer, polyvinylpyrrolidone, semi-synthetic hard fatty acid ester, water-soluble monoglyceride, carbomer series (931, 934, 940, 974, AA-1, 1342, etc.), Tween 60-80. The gel may contain a pharmaceutically acceptable preservative and a stabilizer. The carbomer may be separately dispersed in water during preparation, added with glycerin, polyethylene glycol 200 ~ 8000, heated, stirred and mixed, and a prescribed amount of cyclophosphamide is added. Glycoside hydrate, stirring, pharmaceutically acceptable inorganic base or organic base to adjust pH = 5.0 ~ 8.5, add water to the full amount, stir to the hook, sub-package, that is.

 a hydrate injection of a salt of cyclic adenosine, which is prepared by:

 The hydrated aseptic powdered needle preparation of the salt of cyclic adenosine can be prepared according to a conventional method.

 The preparation method of the lyophilized powder preparation is as follows: taking a hydrate of a salt of cyclic adenosine, a pharmaceutically acceptable lyophilized support agent or a co-agent may be added, and the water is stirred and dissolved to dissolve, if necessary, pharmaceutically Acceptable pH adjustment of pH 4.0 ~ 8.5, addition of activated carbon 0.005 ~ 0.5% (W / V), stirring for 15 ~ 45min, filtration, hydration, sterile filtration, according to 20 ~ 200mg / bottle (based on cyclophosphamide ) Packing, freeze-drying, tamping, and finished products.

 Hydrate small volume injection of cyclic adenosine salt and preparation process thereof: hydrate of cyclic adenosine salt plus water for injection and pharmaceutically acceptable additive, for example: pharmaceutically acceptable pH adjuster, A pharmaceutically acceptable antioxidant, an inert gas, filtered, and sterilized to form a sterile small volume injection having a pH between 4.0 and 8.5.

The pharmaceutically acceptable pH adjusting agent may be a pharmaceutically acceptable inorganic or organic acid, an inorganic base or an organic base, or a Lewis acid or a base in a broad sense, and may contain one or more kinds, and may be hydrochloric acid. Phosphoric acid, propionic acid, acetic acid and acetate, such as sodium acetate, lactic acid and lactic acid pharmaceutically acceptable salts, citric acid pharmaceutically acceptable salts, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, phosphoric acid Salt, tartaric acid and its pharmaceutically acceptable salts, borax, boric acid, succinic acid, caproic acid, adipic acid, fumaric acid, cisplatin Aenedioic acid, trihydroxyaminodecane, diethanolamine, ethanolamine, isopropanolamine, diisopropanolamine, 2-amino-2-(hydroxyindenyl) 1, 3-propanediolamine, 1 , 2-hexane Amine, N-mercaptoglucosamine, diisopropylamine and their salts, polyhydroxycarboxylic acids and pharmaceutically acceptable salts, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic acid, amino acids And one or more of amino acid salts and the like.

 The pharmaceutically acceptable antioxidants and stabilizers thereof may be sulfurous acid, sulfite, bisulfite, pyro-cateride, di-di-ortho-acid salt, cis-acid salt, organic straight compound straight urea , glutathione, dimercaptopropanol, thioglycolic acid and salt, thiolactic acid and salt, thiodipropionic acid and salt, phenolic compounds, such as gallic acid and salt, caffeic acid, caffeate, ferulic acid , ferulic acid salt, di-tert-butyl-p-phenol, 2, 5-dihydroxybenzoic acid, 2, 5-dihydroxybenzoate, salicylic acid or a salt thereof; amino acid and a salt thereof; ascorbic acid and ascorbate One or more of isoascorbic acid and isoascorbate, nicotinamide, tartaric acid, nitrate, phosphate, pharmaceutically acceptable salt, citrate, EDTA and EDTA salts, such as disodium EDTA, tetrasodium EDTA, and the like.

 The pharmaceutically acceptable isotonicity adjusting agent may be one or more of glucose, fructose, xylitol, sorbitol, mannitol, invert sugar, maltose, dextran, sodium chloride, potassium chloride, sodium lactate, and the like. .

 The heat removal source and the sterilization method may be an activated carbon dehydration source with a 0.0030 to 3 % dosing amount, a microporous membrane sterilization and hot pressing sterilization, or an ultrafiltration sterilization or deheating source. In the ultrafiltration method, the ultrafilter may be a flat plate type, a coil type, a tube type, a hollow fiber type or a round box type, etc., preferably a roll type and a hollow fiber type ultrafilter, and the molecular weight of the interception is 50,000 to 300,000. After removing most of the febrile substances and bacteria, the filter removes the remaining heat source by using an ultrafiltration membrane with a molecular weight of 3,000 to 30,000, preferably an ultrafiltration membrane with a molecular weight of 6000 to 20000.

 The hydrate of the salt of cyclic adenosine of the present invention is suitable for use in the preparation of the following drugs for the treatment or prevention of infections caused by humans and animals: in the preparation for angina pectoris, heart failure, heart and infarction, myocarditis , arrhythmia and cardiogenic shock, improve the symptoms of rheumatic heart disease, palpitations, shortness of breath, chest tightness, acute leukemia, nervous system diseases, respiratory diseases, chronic bronchitis, hepatitis and psoriasis Application in .

Dosage Usage: Under normal circumstances, in adults, take the drug of the invention 0.020 ~ 0.2g in 0.9% sodium chloride or 5 ~ 10% glucose 20 ~ 500 liters, for intravenous bolus or infusion, daily 1 ~ 2 Second; take the drug of the invention 0.020 ~ 0.2g dissolved in water for injection, intramuscular injection, 1 ~ 2 times a day; children halved Use more than the amount.

 Dosage for parenteral administration: 10 ~ 70 kg body weight of human or animal '40 600 mg / day in the general case, divided into 2-3 times; children more than half of the use. For external use, apply directly to 麾 once to six times a day. DRAWINGS

 Figure 1 is a thermogram of magnesium salt 8 hydrate of cyclic adenosine.

 Figure 2 is a thermogram of cyclic adenosine glucoside salt 1 hydrate.

 Figure 3 is a thermogram of cyclic adenosine L-arginine salt 1 hydrate.

 Figure 4 is a thermogram of cyclic adenosine L-lysine salt 1 hydrate.

 Figure 5 is a thermogram of cyclic adenosine sodium salt 2 hydrate.

 Figure 6 is an X-ray diffraction pattern of the magnesium salt 8 hydrate of cyclic adenosine. detailed description

 The invention discloses a hydrate of a cyclic adenosine salt and its preparation and use, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The products, methods and applications of the present invention have been described by the preferred embodiments, and it is obvious that those skilled in the art can change or modify and combine the methods and applications described herein without departing from the spirit and scope of the invention. The techniques of the present invention are implemented and applied.

 In a specific embodiment, the thermal analysis test conditions are: Setaram Setsys 16,

PE-6300TGDTA, sample volume about 5mg, heating rate: ΙΟΚ / min, Ν ₂ speed: 50ml / min, room temperature ~ 400 ° C.

 The X-ray diffraction pattern was measured by a D/ΜΧ-ΠΙΑ X-ray diffractometer at a material testing center of Wuhan University of Technology, with a diffraction angle of 2 Θ and a scanning range of 3-60°, and the powder X-ray diffraction pattern of the hydrate of the present invention was measured.

In one embodiment, the magnesium salt 8-hydrate of the cyclic adenosine of the present invention may have a position including a value of 2 如下 in the measurement range of the diffraction angle 2Θ (3-60.) as measured by powder X-ray diffraction. Corresponding eigenvalues: approximately 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, the cyclic adenosine glucosamine 1 hydrate of the present invention may have a position including a value of 2 如下 in the measurement range of the diffraction angle 2Θ (3-60.) as measured by a powder X-ray diffraction method. Corresponding eigenvalues: approximately 6.3, 15.0, 17.9, 20.8, 22.5

 In one embodiment, the cyclic adenosine L-arginine monohydrate of the present invention may be included in the measurement range of diffraction angle 2Θ (3-60.) by powder X-ray diffractometry. The position has corresponding eigenvalues: approximately 3.5, 17.6, 20.8, 30.2, 34.5

 In one embodiment, the cyclic adenosine L-lysine monohydrate of the present invention may be included in the measurement range of diffraction angle 2Θ (3-60.) by powder X-ray diffractometry. The position has corresponding eigenvalues: approximately 14.2, 15.8, 17.6, 20.7, 27.0

 In a specific embodiment, the cyclic adenosine hydrate salt of the present invention is tested and analyzed, wherein the content of cyclic adenosine is determined in accordance with the Chinese National Drug Standard.

 In one embodiment, the cyclophosphamide salt hydrate of the present invention is detected and analyzed, wherein the determination of arginine content (HPLC method) and identification can be carried out by referring to the Chinese Pharmacopoeia 2005 edition, P588 hydrochloride arginine tablet method. .

 In one embodiment, the cyclophosphamide salt hydrate of the present invention is detected and analyzed, wherein the determination of lysine is referred to as: Nong Hui et al. HPLC determination of lysine hydrochloride and its injection, chemical technology and development 2003, 32(2): 33 In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below with reference to specific embodiments. Example 1 Preparation of Magnesium Salt of Cyclic Adenosine 8 Hydrate Preparation

In a 250 ml three-necked flask, add cyclophosphamide O.lmol, water 100 ml, stir, add 0.05 mol of magnesium oxide, stir at 20 ~ 60 °C for about 50 minutes, dissolve, filter, add 5 times the amount of acetone The solid was precipitated, cooled to about -10 ° C, left for 24 hours, filtered, and dried at 50 ° C for 4 hours to obtain a white solid 23.6 g, melting point: 227 ° C. Decomposition (uncorrected), HPLC: Cyclophosphamide The content of glycosides was 39.86%, the moisture content was 17.57% by Cartesian method, and the thermal analysis: the platform weight loss was about 17.16% (see Figure 1), which is within the error range of the sample containing 8 crystal waters (theoretical value 17.48%); Infrared spectrum: V cm- ¹ 3437, 3210, 2913, 2428, 1659, 1606, 1581, 1488, 1425, 1384, 1343, 1290, 1237, 1136, 1095, 1053, 1022, 952, 869, 843, 724, 640, 545; Theoretical analysis of elemental analysis: C 29.12%, H4.64%, N16.98% P7.51%, Mg2.95%; Found: C 29.33%, H4.52%, N17.11% Ρ7·67%, Mg 3·23%. Example 2 Preparation of Cyclic Adenosine Calcium Salt 3.5 Hydrate

In a 250 ml three-necked flask, add 0.1 mol of cyclophosphamide, 100 ml of water, stir, add 0.05 mol of calcium hydroxide or calcium oxide, and stir at 20 to 60 ° C for 60 minutes to dissolve and filter. Add 5 times the amount of absolute ethanol and isopropanol (1:1), cool to -10~5 °C, leave for 24 hours, wait for the solid to precipitate, filter, dry at 50 °C for 4-6 hours to obtain White solid 19.2 g, melting point: 223 °C decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected;), infrared spectrum: Karlsfeld method for moisture determination 8.52%, thermal analysis: platform weight loss of about 8.4%, which contains 3.5 samples The result of crystallization water (theoretical 8.30%) is within the error range; ESI: m/z: 328; infrared spectrum: K ^Br _max cm ^_1 3436, 3209, 2913,2428, 1658, 1606, 1581, 1488, 1425, 1384 , 1343, 1290, 1237, 1136, 1094, 1053, 1022, 951, 869, 843, 724, 640, 545; theoretical value of elemental analysis: C 31.63%, H3.85%, N18.44% P8.16%, Ca5.28%; Found: C 31.57%, H3.94%, N 18.36% Ρ8·07%, Ca 5.35%. Example 3 Preparation of Cyclophosphamide Glucosamine 1 Hydrate

Put the purified cyclophosphamide 10g and the equimolar glucosamine into the reaction bottle, add 200ml of water, stir, control the temperature between 10 ~ 60 °C, the reaction is 10~120min, the percentage of the total solution is added. One of the activated carbon is stirred for half an hour, and then filtered with a 0.22 micron microporous membrane. It is frozen to -60 ~ -40 °C for about 4 hours, then heated to about -16 °C, and the vacuum is 5-12 Pa. Between, vacuum drying for about 20 hours, then at 20 ~ 30 ° C, vacuum between 5-12Pa, vacuum drying for about 4 hours, to obtain a white solid, the solid is easily soluble in water, melting point: 67 ~ 71. ° C (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected); HPLC: cyclic adenosine content 60.79%, ESI: m/z: 523,328, 19,6, 195; moisture (Card's method): 3.51%, thermal analysis: platform weight loss About 3.31%, which is within the error range of the sample containing one crystal water (theoretical value 3.32%) (see Figure 3); infrared spectrum: ^ffir _max cm ^_1 3404, 3210, 2918, 2766, 2427, 1648, 1605, 1571, 1478, 1422, 1384, 1332, 1299, 1233, 1134, 1083, 1018, 945, 839, 765, 724, 644, 540; theoretical value of elemental analysis: C 37.64%, H5.76%, N15.49% P5.71%; Found: C 37.52%, Η5.87%, Ν15.37% Ρ5·56 %. Example 4 Preparation of Cyclic Adenosine L-Arginine 1 Hydrate

 Put the purified cyclic adenosine 10g and the equimolar L-arginine into the reaction bottle, add water

200ml, stirring, control temperature between 10~60 °C, reaction 10 - 120min, add one percent of the total solution of activated carbon for half an hour to filter, then filter with 0.22 micron microporous membrane, which is frozen to -60 ~ -40 °C, hold for about 4 hours, then heat up to -16 °C, vacuum 0.5-15Pa, vacuum dry for about 20 hours, then at 20~30 °C, vacuum between 0.5-15Pa, vacuum Dry for 4-8 hours, get white solid lO.lg, the solid is easily soluble in water, melting point: 189~ 195 °C

(ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), HPLC: cyclic adenosine content 63.07%, arginine 33.31%; ESI: m/z: 502,328, 175,158; Karlscher's method for moisture 3.82%, thermal analysis: platform The weight loss is about 3.61% (see Figure 4), which is within the error range of the sample containing 1 crystal water (theoretical value 3.46%); infrared spectrum:

, 3210, 2928, 2765, 2426, 2071, 1641, 1476, 1384, 1331, 1238, 1134, 1083, 1018, 839, 796, 765, 72, 3, 643, 540; Elemental analysis theoretical value: C 36.86%, H5.41%, N24.18%, P5.94%; Found: C 37.08%, H5.20%, N24.36%, P5.75%. Example 5 Preparation of Cyclic Adenosine L-Lysine 1 Hydrate

 Put the purified cyclic adenosine 10g and the equimolar L-lysine into the reaction bottle, add water

220ml, stirring, control temperature between 10~60 °C, stir the reaction for 30min, add one percent of the total amount of the solution to the activated carbon and stir for half an hour, then filter with 0.22 micron microporous membrane, which is frozen to -60 ~ -40 °C, hold for about 4 hours, then heat up to -20 °C, vacuum 0.8-15Pa, vacuum dry for about 20 hours, then at 20~30 °C, vacuum 0.8-15Pa, vacuum drying 4 After about one hour, 11.6g of white solid was obtained. The solid was easily soluble in water. Melting point: 195 ~ 201 °C decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected); HPLC: cyclic adenosine content 66.65%, lysine 29.46 %; ESI: m/z: 474, 328, 147, 130; Moisture (Card's method): 3.96%, Thermal analysis: platform weight loss of about 4.01% (see Figure 5), which is the result of the sample containing 1 crystal water ( The theoretical value is 3.65 %) within the error range; infrared spectrum: v ^KBr _maxCm - ¹ 3424, 3198, 2933, 2766, 2427, 1642, 1599, 1509, 1477, 1384, 1332, 1237, 1134, 1083, 1018, 839, 796, 7,59, 724, 644, 542. Example 6 Preparation of sodium cyclic adenosine dihydrate

 Put 10 g of cyclic adenosine in a reaction flask, add 200 ml of water, stir, slowly add an equimolar amount of sodium bicarbonate with cyclophosphamide to the reaction flask, stir, control the temperature between 10 ~ 60 ° C, and react for 30 min. Add 0.2% of the total weight of the solution to the activated carbon for half an hour of filtration, then filter with a 0.22 micron microporous membrane, freeze to -70 ~ -40 ° C, then raise the temperature to about -16 ° C, vacuum between 0.5-10 Pa , vacuum drying for about 20 hours, then at 20 ~ 30 ° C, vacuum between 2-12Pa, vacuum drying for about 6 hours, to obtain a white solid 10.6g, the solid is easily soluble in water, melting point: 227 ° C decomposition ( ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected); Determination of content: HPLC method: cyclic adenosine content of 84.82%; water (Card's method): 9.47%, thermal analysis: platform weight loss of about 9.03% (see Figure 6), The result of the sample containing 2 crystal water (theoretical value 9.31%) is within the error range; ESI: m/z: 350; Elemental analysis theoretical value: C 31.02%, H3.90%, N18.09%, P8.00 %, Na5.94%; Found: C 30.88%, Η 4.03%, Ν18.19%, Ρ8·12%, Na5.83%. Example 7 Preparation of Cyclic Adenosine DL-Lysine 1 Hydrate

Put the purified cyclic adenosine 10g and the equimolar DL-lysine into the reaction bottle, add 220ml of water, stir, control the temperature between 10 ~ 60 °C, the reaction is 10 ~ 120min, add the total amount of the solution One percent of activated carbon is stirred for half an hour, filtered through a 0.22 micron microfiltration membrane or filtered through an ultrafiltration membrane with a molecular weight of 6000 to 30000. It is frozen to -70 ~ -30 °C for about 24 hours. Then, the temperature is raised to about -16 ° C, the vacuum is 2-10 Pa, vacuum dried for about 20 hours, then at 20 ~ 30 ° C, vacuum between 2-10 Pa, vacuum drying for about 6 hours, to obtain a white solid 12.2 g, the solid is readily soluble in water, melting point: 194 ~ 199 °C decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected); HPLC: cyclic adenosine content 66.52%, lysine 29.34%; ESI: m/z: 474,330, 328, 147,130; Moisture (Card's method): 4.02%, thermal analysis: platform weight loss is about 3.83%, which is within the error range of the sample containing 1 crystal water (theoretical value 3.65 %); Infrared spectrum: V ^KBr max cm- ¹ 3424, 3198, 2933, 2766, 2427, 1642, 1599, 1509, 1477, 1384, 1332, 1237, 1134, 1083, 1018, 839, 796, 7, 59, 724, 644, 542. Example 8 Preparation of Cyclic Adenosine D-Arginine 1 Hydrate

 Put the purified cyclophosphamide 10g and the equimolar D-arginine into the reaction bottle, add 200ml of water, stir, control the temperature between 10 ~ 60 °C, the reaction is 10 - 120min, add the total amount of the solution One percent of the activated carbon is stirred for half an hour, filtered through a 0.22 micron microfiltration membrane, and frozen to -70 ~ -40 °C for about 5 hours, then heated to about -16 °C, vacuum 3- Under 15Pa, vacuum drying for about 20 hours, then at 20 ~ 30 ° C, vacuum between 3-15Pa, vacuum drying for about 6 hours, to obtain a white solid 11.5g, soluble in water, melting point: 190 ~ 194 °C (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), HPLC: cyclic adenosine content 63.01%, arginine 33.35%; Karlsfeld method for moisture 3.78%, thermal analysis: platform weight loss about 3.57 %, which contains 1 sample The result of a crystal water (theoretical value of 3.46 %) is within the error range. Example 9 Preparation of Cyclic Adenosine Triethylamine 1 Hydrate

The white-like cyclic adenosine triethylamine 1 hydrate was prepared by the method of Example 3. Example 10 Cyclic adenosine L-arginine monohydrate or cyclophosphamide L-lysine monohydrate or cyclophosphamide DL-lysine monohydrate or cyclophosphamide aglycone 1 Preparation of hydrate lyophilized preparation (cyclophosphamide hydrates prepared according to the corresponding examples) Cyclophosphamide adenosine L-arginine monohydrate or cyclic adenosine L-lysine monohydrate or ring Phosphoadenosine DL-lysine monohydrate or cyclophosphamide aglycone 1 hydrate 200g, add glucose or mannitol or xylitol 2.0 ~ 5g plus fresh water for injection 10 ~ 20L stir to dissolve, use 2M Hydrochloric acid or 2M sodium hydroxide, adjust the pH to 5.0 - 8.5, add activated carbon 0.01 ~ 0.5% (W / V) and stir for 15 ~ 45min, filter, filter with 0.22 micron microporous membrane or use the molecular weight of interception 6000 ~ Ultrafiltration membrane filtration of 20000, divided into 20mg, 30mg/bottle or 40mg or 50mg/bottle or 60mg/bottle or 100mg/bottle or 120mg/bottle (as cyclophosphamide), freeze-dried, tampon, Get the finished product. Example 11 Preparation of lyophilized preparation Cyclophosphamide adenosine L-arginine monohydrate (prepared according to the method of Example 4) or cyclic adenosine glucosamine 1 hydrate 10 g (prepared according to the method of Example 3) In terms of cyclophosphamide, 40 g of mannitol was added, and 40-60 ° C of water for injection was immersed in 1460 ~ 1850 ml to dissolve, using 1 M citric acid. Or sodium hydroxide to adjust the pH to 5.0 ~ 8.0, add activated carbon 0.01 ~ 0.5% (W / V), stir for 15 ~ 45min, filter, hydrate to 2000ml, filter with 0.22 micron microporous membrane or use the molecular weight of interception 6000 ~ The ultrafiltration membrane of 20000 is filtered and packed in 20, 30 mg/bottle or 60 mg/bottle or 100 mg/or 120113⁄4/bottle (as cyclophosphamide), freeze-dried, and tamponed to obtain a finished product. Example 12 Take a hydrate of a salt of sterile cyclic adenosine 20Kg (based on cyclophosphamide) (the cyclic adenosine monohydrate is prepared according to the method of the corresponding embodiment), and the aseptic packaging process is 20, 30mg/bottle or 50mg/bottle, or 60mg/bottle or lOOmg/bottle, add stopper, press plug, and roll the aluminum cover to get the finished product. Example 13 Preparation of a small volume injection of a hydrate of a cyclic adenosine salt. Sodium adenosine monophosphate 2 hydrate (prepared according to the method of Example 6) or cyclic adenosine L-arginine monohydrate (according to the implementation) Example 4 method preparation) or cyclic adenosine monoglucosamine 1 hydrate (prepared according to the method of Example 3) (as cyclophosphamide) 10 g, plus cysteine hydrochloride 0.8 g, EDTA disodium O. lg Add water for injection to dissolve, 2M lactic acid and sodium lactate to adjust pH to 5.0 ~ 7.8, add activated carbon 0.5% (W / V) and stir for 15 ~ 45min, filter, hydrate to 1000ml, filter with 0.22 micron microporous membrane or use The ultrafiltration membrane with a molecular weight of 6000 ~ 20000 is intercepted and filtered, and the product is sterilized by 2 ~ 10ml / bottle. Example 14 Preparation of lyophilized preparation of sodium adenosine monophosphate 2 hydrate 10 g of sodium adenosine monophosphate 2 hydrate (prepared according to the method of Example 4), dissolved by stirring with water for injection, and activated carbon 0.3% (W/ V) Stir for 15 ~ 45min, filter, hydrate to 2000ml, filter with 0.22 micron microporous membrane, dispense in 2 ~ 5ml / bottle, freeze-dry, tampon, to get the finished product. Example 15 Preparation of a large volume injection of sodium cyclic adenosine monophosphate or cyclic adenosine monophosphate L-arginine monohydrate or cyclic adenosine monoglucoside 1 hydrate (hydration of each cyclic adenosine salt) Prepared according to the method of the corresponding examples)

Weigh 500g of glucose into the water for injection, stir to dissolve completely, add activated carbon with 0.05% of the solution, heat for 10 ~ 30 minutes, let cool, filter and decarbonize; hydrate the salt of cyclic adenosine (with ring After the dissolution of 4.01g with fresh water for injection, it was mixed well with the above filtrate, and added L-cysteine lg, EDTA disodium 0.2g, and the pH value was adjusted to 5.2~ with 1M lactic acid solution. Within the range of 7.5, add water for injection to 10000ml, add activated carbon with a liquid content of 0.01 ~ 0.5% (w / v), stir for about 10 ~ 30 minutes, filter for decarbonization, and then finely filter through 0.22um microporous membrane or use The ultrafiltration membrane with a relative molecular mass of 6000 ~ 20000 is intercepted and filtered. After the semi-finished product is tested, after the content, pH value and clarity are qualified, it is potted in 50ml or 100ml or 200ml glass bottles, sterilized, finished product inspection, packaging is Got it. Example 16 Preparation of hydrate hydrate sodium chloride infusion of cyclic adenosine salt

 A hydrate of a salt of cyclic adenosine monophosphate (based on cyclophosphamide) (hydrated by cyclic adenosine salt according to the corresponding example method) 4 g, sodium chloride 85 g, sodium pyrosulfate l. lg , EDTA disodium 0.2g, added to the water for injection, stirred to dissolve completely, with 1M citric acid and sodium citrate solution to adjust the pH value of 4.0 ~ 7.5, add water for injection to 10000ml, add 0.05 % of activated carbon, heated and stirred for 10 ~ 30 minutes, filtered and decarbonized, then filtered through 0.22um microporous membrane or filtered with ultrafiltration membrane with molecular weight of 6000 ~ 20000. After semi-finished test, its content and pH After passing the value and clarity, enclose it in a 50ml or 100ml or 200ml glass bottle, sterilize, check the finished product, and pack it. Example 17. Preparation of a calcium adenosine monophosphate 8 hydrate or cyclic adenosine L-arginine 1 hydrate tablet (250 mg/tablet, based on cyclophosphazepam)

 Prescription: Magnesium adenosine adenosine 8 hydrate or cyclic adenosine monophosphate L-arginine 1 hydrate 250g (based on cyclic adenosine)

Microcrystalline cellulose 200g Carboxymethyl starch sodium 20g Aspartame 2g Polyvinylpyrrolidone 5% Appropriate amount of magnesium stearate 2g Cyclophosphamide adenosine 8 hydrate or cyclic adenosine L-arginine monohydrate, Microcrystalline cellulose, sodium carboxymethyl starch, aspartame over 100 mesh sieve, soft material with 5% polyvinylpyrrolidone, sieved through 18 - 24 mesh, dried, sieved through 14 - 20 mesh After the granules, add micro-powder silica gel and magnesium stearate to mix and compress. Example 18 Preparation of hydrated adenine of cyclic adenosine monophosphate (100 mg/particle, based on cyclic adenosine) Prescription: 100 g of hydrated adenosine monophosphate (based on cyclophosphamide)

 Microcrystalline cellulose 100g

 Lactose 20g

 Gelatinized starch 10%

 Magnesium stearate 2g

 The hydrate of the cyclic adenosine salt of the present invention (the hydrate of each cyclic adenosine salt is prepared according to the method of the corresponding examples), the microcrystalline cellulose, the lactose through a 100 mesh sieve, and the amount of 10% gelatinized starch is used. Soft material, granulated with 18 - 24 mesh sieve, dried, sieved through 14 - 20 mesh sieve, mixed with magnesium stearate, filled with plastic bottles. Example 19 Preparation of hydrated particles of cyclic adenosine monophosphate includes sodium cyclophosphate adenosine 2 hydrate or calcium adenosine monophosphate 8 hydrate or cyclic adenosine monogluconate 1 hydrate or cyclic adenosine L- Granules such as arginine 1 hydrate or cyclic adenosine L-lysine monohydrate (50 mg/bag, based on cyclic adenosine)

 Prescription: hydrate of cyclic adenosine monophosphate 50g (based on cyclic adenosine)

 Mannitol 180g

 Sucrose 20g

 Sodium cyclamate 2g

 Solid food flavor lg

 Polyvinylpyrrolidone 5 %

 The hydrate of the cyclic adenosine salt (hydrated by the cyclic adenosine salt according to the method of the corresponding examples), mannitol, sucrose, cyclamate, food flavor passed through a 100 mesh sieve, and the amount of 5% polyvinylpyrrolidone was used. Soft material, granulated by 18 - 24 mesh, dried below 60 °C, sieved through 14 - 20 mesh, and packaged. Example 20 Gel of hydrate of cyclic adenosine of the present invention (hydrate of cyclic adenosine salt prepared according to the method of the corresponding example)

 Prescription: hydrate of cyclic adenosine salt 25g (based on cyclic adenosine, feed)

 Polyethylene glycol 6000 50g

Polyethylene glycol 400 10g Glycerin 5 ml

 Carbomer 934 8g

 Carbomer 1342 2g

 Water 400-500ml

 The carbomer 1342 and carbomer 934 will be dispersed with water, glycerin, polyethylene glycol 6000, polyethylene glycol 400, stirred and mixed, and the hydrate of the cyclic adenosine salt will be added, heated and stirred until homogeneous. The disodium hydrogen phosphate and sodium dihydrogen phosphate solution are adjusted to pH = 5.0 ~ 7.0, and are obtained separately. It is to be understood that many variations of the details are possible, and thus do not limit the scope and spirit of the invention, and the invention is not limited to the embodiments described above.

Claims

Rights request

A protein kinase activator characterized by having the formula [cAMP ] _m A.nH ₂ 0, cAMP being C ₁₀ H ₁₂ N ₅ O ₆ P or C ₁₀ H _u N ₅ O ₆ P, m=l Or 2 or 3, n = 0.88 to 8.5, and A is selected from one of a pharmaceutically acceptable metal ion or an organic base.

 The protein kinase activator according to claim 1, wherein the organic base is selected from the group consisting of triethylamine, diethylamine, ethanolamine, glucosamine, ethamine, tromethamine, piperazine, Morpholine, L-lysine, D-lysine, DL-lysine, L-arginine, D-arginine, DL-arginine, histidine, ornithine, citrulline One of them.

 The protein kinase activator according to claim 1, wherein the metal ion is one selected from the group consisting of lithium, potassium, sodium, calcium, magnesium, sulphur, aluminum or cerium.

 The protein kinase activator according to claim 1, which is a cyclic adenosine L-arginine monohydrate or a cyclic adenosine D-arginine monohydrate.

 The protein kinase activator according to claim 1, which is a cyclic adenosine L-lysine monohydrate or a cyclic adenosine DL-lysine monohydrate.

 The protein kinase activator according to claim 1, which is a cyclic adenosine glucosamine 1 hydrate.

 The stable protein kinase activator according to claim 1, which is sodium adenosine monophosphate 2 or calcium adenosine phosphate 3.5 hydrate or magnesium adenosine adenosine 8 hydrate.

 8. The method for preparing a protein kinase activator according to claim 1, which is characterized by the following method:

 Method A. Mixing water with cyclic adenosine, adding a pharmaceutically acceptable organic base or metal oxide or hydroxide or a metal salt thereof or a solution thereof in a molar ratio of the reaction, stirring, reacting, filtering, Slowly add C3-C6 ketone, or C1-C6 molecular alcohol, one or more of C2-C6's ether, cool, filter, solid solvent C1-C6 low molecular alcohol, C3 - a lower ketone of C6, a lower ether of C2-C6, or one or more rinses in water, filtered, dried to obtain a hydrate of cyclic adenosine;

Or method B. A solution of a metal oxide or hydroxide or a metal salt or an organic base thereof is added to a reaction vessel containing cyclic adenosine and water at a molar ratio of the reaction, and stirred to control the temperature of 0 to 50 ° C. Between, stir, to be reacted, decolorization of activated carbon, one or more filtration, freeze it to - 70 ~ -30 ° C, vacuum drying, to obtain a hydrate of cyclic adenosine;

 Or method C. respectively, a metal oxide or hydroxide or a metal salt or an organic base thereof or a solution thereof is added to a reaction vessel containing cyclic adenosine and water in a molar ratio of the reaction, and stirred to control the temperature. Between -5 ~ 40 °C, the reaction is 0.5 ~ 24h, after the reaction is completed, the activated carbon is decolorized, filtered one or more times, and spray-dried to obtain a hydrate of cyclic adenosine salt.

 9. A lyophilized powder preparation for injection according to claim 1, wherein the lyophilized powder preparation for injection, or a sterile powder injection preparation, or a small water injection preparation, or a large infusion preparation, a solid preparation, including a tablet , capsules, granules, external preparations for skin including ointments, gels.

 10. The protein kinase activator of claim 1 for use in preparing a heart palpitus suitable for causing human and mammalian diseases including angina pectoris, heart failure, myocardial infarction, myocarditis, arrhythmia and cardiogenic shock, and improving rheumatic heart disease. The use of drugs for the treatment or prevention of symptoms such as acute urgency, chest tightness, acute leukemia, nervous system diseases, respiratory diseases, chronic bronchitis, hepatitis and psoriasis.