WO2011085701A1 - Stable protein kinase activators, preparation methods and uses thereof - Google Patents
Stable protein kinase activators, preparation methods and uses thereof Download PDFInfo
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- WO2011085701A1 WO2011085701A1 PCT/CN2011/070355 CN2011070355W WO2011085701A1 WO 2011085701 A1 WO2011085701 A1 WO 2011085701A1 CN 2011070355 W CN2011070355 W CN 2011070355W WO 2011085701 A1 WO2011085701 A1 WO 2011085701A1
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 ⁇ )
- 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
- 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
- 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.
- 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.
- Arginine salt anhydrate of cyclic adenosine 3.45
- 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:
- 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. .
- Magnesium ions inhibit the central nervous system, neuromuscular and myocardium.
- Mg 2+ is synergistic with Ca 2+ and is antagonistic to the myocardium.
- Magnesium is a major cofactor in DNA-related enzymes and an intracellular regulator that determines cell cycle and apoptosis.
- 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 ⁇ ions.
- the main role or mechanism is:
- Calcium ion is a blood coagulation factor involved in the blood coagulation process.
- 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 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.
- 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.
- the incidence of myocardial infarction is obvious.
- 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.
- LDL low-density lipoprotein
- 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.
- 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.
- 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.
- a lower ketone of C3-C7 such as acetone
- 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.
- 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;
- 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.
- the inlet air temperature can be between 100 and 140 ° C
- the outlet air temperature can be between 70 and 100 ° C.
- 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 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
- 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.
- 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.
- 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.
- pharmaceutically acceptable pH adjuster 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, mal
- 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
- 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.
- 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.
- 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 ⁇ once to six times a day.
- 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.
- FIG. 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.
- thermal analysis test conditions are: Setaram Setsys 16,
- PE-6300TGDTA sample volume about 5mg
- ⁇ 2 speed 50ml / min
- the X-ray diffraction pattern was measured by a D/ ⁇ - ⁇ X-ray diffractometer at a material testing center of Wuhan University of Technology, with a diffraction angle of 2 ⁇ and a scanning range of 3-60°, and the powder X-ray diffraction pattern of the hydrate of the present invention was measured.
- the magnesium salt 8-hydrate of the cyclic adenosine of the present invention may have a position including a value of 2 ⁇ in the measurement range of the diffraction angle 2 ⁇ (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.
- the cyclic adenosine glucosamine 1 hydrate of the present invention may have a position including a value of 2 ⁇ in the measurement range of the diffraction angle 2 ⁇ (3-60.) as measured by a powder X-ray diffraction method.
- Corresponding eigenvalues approximately 6.3, 15.0, 17.9, 20.8, 22.5
- the cyclic adenosine L-arginine monohydrate of the present invention may be included in the measurement range of diffraction angle 2 ⁇ (3-60.) by powder X-ray diffractometry.
- the position has corresponding eigenvalues: approximately 3.5, 17.6, 20.8, 30.2, 34.5
- the cyclic adenosine L-lysine monohydrate of the present invention may be included in the measurement range of diffraction angle 2 ⁇ (3-60.) by powder X-ray diffractometry.
- the position has corresponding eigenvalues: approximately 14.2, 15.8, 17.6, 20.7, 27.0
- 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.
- 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. .
- 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
- the present invention will be further described in detail below with reference to specific embodiments.
- 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.
- 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
- Cyclophosphamide adenosine L-arginine monohydrate or cyclic adenosine L-lysine monohydrate or ring
- 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)
- 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.
- 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.
- Example 6 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.
- 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.
- 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.
- Example 17 Preparation of a calcium adenosine monophosphate 8 hydrate or cyclic adenosine L-arginine 1 hydrate tablet (250 mg/tablet, based on cyclophosphazepam)
- 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)
- 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.
- 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)
- 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)
- 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.
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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
稳定的蛋白激酶激活剂及其制备方法和用途 Stable protein kinase activator, preparation method and use thereof
本申请要求于 2010 年 1 月 18 日提交中国专利局、 申请号为 201010029032.6、 发明名称为"稳定的蛋白激酶激活剂及其制备方法和用途"的 中国专利申请的优先权, 其全部内容通过引用结合在本申请中。 技术领域 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
本发明涉及医药技术领域,具体涉及一种稳定的蛋白激酶激活剂一环磷腺 苷盐的水合物及其制备和用途。 背景技术 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
环磷腺苷为蛋白激酶致活剂,是核苷酸的衍生物。 它是在人体内广泛存在 的一种具有生理活性的重要物质, 由三磷酸腺苷在腺苷环化酶催化下生成, 能 调节细胞的多种功能活动。作为激素的第 2信使,在细胞内发挥激素调节生理 机能和物质代谢作用, 能改变细胞膜的功能,促使肌浆质内的钙离子进入肌纤 维, 从而增强心肌收缩, 并可促进呼吸链氧化酶的活性, 改善心肌缺氧, 緩解 冠心病症状及改善心电图。 此外, 对糖、 脂肪代谢、 核酸、 蛋白质的合成调节 等起着重要的作用。 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.
目前公开的文献仅报道了环磷腺苷某些盐及用途,如用于治疗心绞痛、 心 力衰竭、 心肌梗死、 心肌炎、 心律失常及心源性休克, 改善风湿性心脏病的心 悸、 气急、 胸闷等症状、 急性白血病、 神经系统疾病、 呼吸系统疾病、 肝炎和 银屑病等。 [参考文献: 环磷腺苷治疗慢性充血性心力衰竭急性加重期的临床 疗效研究, 河北医学, 2004,10 ( 7 ): p627; 环磷腺苷对二尖瓣替换术后心肌 酶语的影响,中国新药杂志 2002,10(7):p559-561 ;环磷腺苷注射液治疗充血性心 力衰竭, 开封医专学报 2OO0,19(3):pl3; 多巴酚丁胺联合环磷腺苷治疗心力 衰竭的临床观察, 中国现代药物应用, 2010,16:pl32-133 ; 心先安的药理作用及 临床应用, 中国药业, 1999,8 ( 5 ) : p31 ; 中国药学杂志, 1992,27(6):p371 ; 葡 曱胺环腺苷酸的抗心律失常作用 , 中 国 药 理学与毒理学杂 志, 1989,3(4):p251-254; 中国心血管杂志, 1999, 4(5):p283; 环磷酸腺苷葡曱胺 对緩慢性心律失常并心力衰竭的疗效观察,临床内科杂志 2004, 21(8):p574; 葡
曱胺环磷腺苷治疗新生儿窒息后心肌损害疗效, 儿科药学杂志 2001 ,7(3):pl 8 ; 环磷腺苷葡胺对儿童哮喘的治疗作用及机制探讨,中国当代医药, 2010, 17(3): p49-50 ; TVI 观察环磷腺苷葡曱胺对二尖瓣环运动的影响,上海医学影像 2004, 13(4):p251-252; 环磷腺苷葡胺对慢性充血性心力衰竭患者心功能和 B型 钠尿肽的影响, 中国医学创新, 2009,34 ( 6 ) :pl3- 14]。 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].
但到目前为止,国内外尚没有公开文献报道的新颖稳定的蛋白激酶激活剂 一环磷腺苷盐的水合物及其制备方法和用途。 发明内容 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
本发明的目的之一是提供一种稳定、 不易引湿的环磷腺苷盐的水合物。 本发明提供的 3,, 5,-环磷酸腺苷盐的水合物 ( Adenosine Cyclophosphate ), 其分子式为 { [ cAMP ]mA'n¾0 , cAMP 为 C1()H12N506P或 ( 1() ^506? , m=l ~ 3 , n=0.88 ~ 8.5} , m=l或 2或 3 , n可以是 0.88、 1、 1.25、 1.5、 2、 2.5、 3.0、 3.5、 4、 5、 6、 7、 8、 8.5或其之间的数字。 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选自药学上可接受的金属离子或有机碱的一种。 其中有机碱包括三乙 胺、 二乙胺、 乙醇胺、 葡曱胺、 葡乙胺、 氨丁三醇, 哌嗪、 吗啉、 L-赖氨酸、 D-赖氨酸、 DL-赖氨酸、 L-精氨酸、 D-精氨酸、 DL-精氨酸、 组氨酸、 鸟氨酸、 瓜氨酸等中的一种, 氨基酸均包括消旋和手性的氨基酸(D或 L型氨基酸), 金属离子为锂、 钾、 钠、 钙、 镁、 辞、 铝或铋中的一种。 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.
本发明获得的含有结晶水的环磷腺苷的盐不同于环磷腺苷较难溶于水的 特性,令人惊奇的是, 不含结晶水的环磷腺苷的盐引湿性远高于含有结晶水的 环磷腺苷的盐,含有结晶水的环磷腺苷的盐的水合物比不含结晶水的更能稳定 的存在,便于储存和运输, 其中一些盐在室温下具有良好的水溶性, 易于制成 水溶性的制剂。特征性的,本发明的水合物的热分析 (TG-DSC 或者 TG-DTA) 图谱可以看出失重平台具有强烈的对应的吸热峰,热分析图谱显示出环磷腺苷 L-精氨酸 1水合物( (^。Η12Ν506Ρ·(36Η14Ν402·Η20 )、 环磷腺苷 L-赖氨酸 1水合 物 ( (^。Η12Ν506Ρ 6Η14Ν202·Η20 )、 环磷腺苷 DL-赖氨酸 1水合物、 环磷腺苷 葡曱胺 1水合物 ((^。Η12Ν506Ρ·( 7Η17Ν05·Η20)、 环磷腺苷钠 2水合物 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 )、 环磷腺苷镁盐 8水合物 [((^。 ^506?)2'^/¾'8¾0]、
环磷腺苷钙盐 3.5水合物 [ ( doHnNsOsP ) 2Ca'3.5H20]等, 用卡尔费休法测定 其水分, 其结果与热分析结果一致。 ( 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.
本发明还包括环磷腺苷 D-精氨酸 1水合物、环磷腺苷 D-赖氨酸 1水合物、 环磷腺苷 DL-赖氨酸 1水合物、环磷腺苷 L-瓜氨酸 1水合物、环磷腺苷三乙胺 1水合物、 环磷腺苷二乙胺 1水合物等。 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.
本发明的环磷腺苷的盐的水合物, 能稳定存储。将上述环磷腺苷的盐的水 合物和环磷腺苷的盐无水物样品分别密闭与西林瓶中进行加速稳定性试验(色 谱条件: 色谱柱: C18(250mmx4.6mm, 5 ηι); 流动相: 0.05mol/L磷酸二氢钾 溶液(内含 0.01mol/L四丁基溴化铵) -乙腈( 85: 15 ); 流速: lml/min; 温度: 室温; 检测波长: 259nm ), 出人意料地发现, 本发明的环磷腺苷的盐的水合 物的含量和有关物质变化较少,环磷腺苷的盐无水物加速试验 6个月与 0月相 比(40°C , RH75% ), 有关物质增加的倍数高于环磷腺苷的盐的水合物。 按中 国药典要求进行引湿性试验: 取环磷腺苷的盐无水物和本发明的水合物约 5g, 置于干燥恒重的表面 中, 精密称重。 25 V、 相对湿度为 75 % , 分别于试验 Oh和 48h取样, 计算引湿增重的百分率, 结果显示, 无水物引湿性比本发明 的水合物高得多, 说明本发明的环磷腺苷的盐的水合物具有更好的存储稳定 性。结果见表 1 ~ 6,表 1-6中的各环磷腺苷盐的水合物均按相应实施例方法制 备。 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.
此外, 无水物的潮解使得在处理时要隔绝空气防止粘连等, 不似水合物具 有良好的滑动性, 改善制剂的可操作性。 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.
表 1.本发明环磷腺苷 L精氨酸盐 1水合物加速稳定性试验结果 Table 1. Results of accelerated stability test of cyclic phosphatidyl adenosine L arginine salt 1 hydrate of the present invention
取样时间(月) 性状 标示含量(%) 有关物质(%) Sampling time (month) traits labeled content (%) related substances (%)
0 类白色粉末 99.3 < 1% 0 white powder 99.3 < 1%
1 类白色粉末 99.7 < 1% Class 1 white powder 99.7 < 1%
2 类白色粉末 99.4 < 1% Class 2 white powder 99.4 < 1%
3 类白色粉末 99.9 < 1% Class 3 white powder 99.9 < 1%
6 类白色粉末 99.5 < 1% 6 white powder 99.5 < 1%
表 2. 本发明环磷腺苷 L赖氨酸盐 1水合物加速稳定性试验结果 Table 2. Results of the accelerated stability test of the cyclic phosphatidyl lysine L-lysine salt 1 hydrate of the present invention
取样时间(月) 性状 标示含量 (%:) 有关物质(%)
0 类白色粉末 99.6 < 1%Sampling time (month) trait indication content (%:) related substances (%) 0 white powder 99.6 < 1%
1 类白色粉末 99.8 < 1%Class 1 white powder 99.8 < 1%
2 类白色粉末 99.6 < 1%Class 2 white powder 99.6 < 1%
3 类白色粉末 99.4 < 1%Class 3 white powder 99.4 < 1%
6 类白色粉末 99.5 < 1% 表 3. 本发明环磷腺苷葡曱胺盐 1水合物加速稳定性试验结果 取样时间(月) 性状 标示含量(%) 有关物质(%)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 类白色粉末 99.6 < 1%0 white powder 99.6 < 1%
1 类白色粉末 99.9 < 1%Class 1 white powder 99.9 < 1%
2 类白色粉末 99.7 < 1%Class 2 white powder 99.7 < 1%
3 类白色粉末 99.4 < 1%Class 3 white powder 99.4 < 1%
6 类白色粉末 99.5 < 1% 表 4. 本发明环磷腺苷钙 8水合物加速稳定性试验结果 Class 6 white powder 99.5 < 1% Table 4. Results of accelerated stability test of calcium adenosine monophosphate 8 hydrate of the present invention
取样时间(月) 性状 标示含量(%) 有关物质(%) Sampling time (month) traits labeled content (%) related substances (%)
0 类白色粉末 99.8 < 1%0 white powder 99.8 < 1%
1 类白色粉末 99.9 < 1%Class 1 white powder 99.9 < 1%
2 类白色粉末 99.6 < 1%Class 2 white powder 99.6 < 1%
3 类白色粉末 99.4 < 1%Class 3 white powder 99.4 < 1%
6 类白色粉末 99.2 < 1% 表 5. 加速稳定性试验结果 Class 6 white powder 99.2 < 1% Table 5. Accelerated stability test results
取样时间 有关物质 (0月) 有关物质 (6月) 环磷腺苷的钠盐 2水合物 0.43 0.85 环磷腺苷的钠盐无水物 0.62 1.52 环磷腺苷的精氨酸盐 1水合物 0.67 0.94 环磷腺苷的精氨酸盐无水物 0.79 1.37 环磷腺苷的赖氨酸盐 1水合物 0.56 0.91 环磷腺苷的赖氨酸盐无水物 0.79 1.49 环磷腺苷的葡曱胺盐 1水合物 0.45 0.83 环磷腺苷的葡曱胺盐无水物 0.57 1.31
表 6. 引湿试验结果 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
取样时间 (48小时) 与 0小时相比, 增重% Sampling time (48 hours) Compared with 0 hours, weight gain
环磷腺苷的钠盐 2水合物 1.25 Sodium adenosine monophosphate 2 hydrate 1.25
环磷腺苷的钙盐 3.5水合物 0.67 Calcium adenosine phosphate 3.5 hydrate 0.67
环磷腺苷的镁盐 8水合物 0.81 Magnesium salt of cyclic adenosine monophosphate 8 hydrate 0.81
环磷腺苷的精氨酸盐 1水合物 0.79 Arginine salt of cyclic adenosine monophosphate 1 hydrate 0.79
环磷腺苷的赖氨酸盐 1水合物 0.92 Lysine salt lysine salt 1 hydrate 0.92
环磷腺苷的葡曱胺盐 1水合物 0.96 Glucosamine adenosine salt 1 hydrate 0.96
环磷腺苷的钠盐无水物 9.34 Sodium adenosine sodium anhydrate 9.34
环磷腺苷的钙盐无水物 8.23 Calcium salt anhydrate of cyclic adenosine 8.23
环磷腺苷的镁盐无水物 17.86 Magnesium salt anhydrate of cyclic adenosine 17.86
环磷腺苷的精氨酸盐无水物 3.45 Arginine salt anhydrate of cyclic adenosine 3.45
环磷腺苷的赖氨酸盐无水物 3.63 Cyanoadenosine lysine salt anhydrate 3.63
环磷腺苷的葡曱胺盐无水物 3.41 Anhydrous adenosine hydrochloride anhydrous 3.41
环磷腺苷为蛋白激酶激活剂。它是在人体内广泛存在的一种具有生理活性 的重要物质, 由三磷酸腺苷在腺苷环化酶催化下生成, 能调节细胞的多种功能 活动。作为激素的第二信使,在细胞内发挥激素调节生理机能和物质代谢作用, 能改变细胞膜的功能,促使网织肌浆质内的钙离子进入肌纤维,从而增强心肌 收缩, 并可促进呼吸链氧化酶的活性, 改善心肌缺氧, 緩解冠心病症状及改善 心电图。 此外, 对糖、脂肪代谢、核酸、蛋白质的合成调节等起着重要的作用。 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.
本发明环磷腺苷的衍生物中除含有蛋白激酶激活剂的环磷腺苷外,还含有 重要的碱金属和碱土金属离子或氨基酸等,这些离子或氨基酸具有多种生理功 能, 例如: 镁是人体必需的常量元素, 镁离子具有多种生物学活性, 是维持正 常神经肌肉兴奋性和组织细胞能量代谢必不可少的因子,镁离子是生物体内多 种酶系统中重要的辅助因子在人体新陈代谢过程中发挥着重要的生理功能。其 主要作用如下: 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、 维持酶的活性镁是许多酶系的辅助因子或激动剂, 可启动体内 300 多种酶, 包括己糖激酶, Na+-K+ATP酶、 羧化酶、 丙酮酸脱氢酶、 肽酶、 胆碱
酯酶等, 参与体内许多重要代谢过程, 包括蛋白质、 脂肪和碳水化合物及核酸 的代谢, 氧化磷酸化, 离子转运, 神经沖动的产生和传递, 肉收缩等, 几乎 与生命活动的各个环节有关。 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、 维持可兴奋细胞的兴奋性 2. Maintain the excitability of excitable cells
镁离子对中枢神经系统、神经肌肉和心肌等, 均起抑制作用。 对于神经肌 肉应激性, Mg2+与 Ca2+是协同的, 对于心肌又是拮抗的。 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、 维持细胞的遗传稳定性 3. Maintain the genetic stability of the cells
镁是 DNA相关酶系中的主要辅助因子和决定细胞周期和凋亡的细胞内调 节者。 Magnesium is a major cofactor in DNA-related enzymes and an intracellular regulator that determines cell cycle and apoptosis.
目前, 含镁药物在降压、 利胆、 导泻、 抗惊厥等方面具有重要作用, 在治 疗哮喘、 毛细支气管炎、 重症肺炎合并心衰、 呼衰、 脑衰及肺动脉高压等呼吸 系统疾病中发挥了解痉、 平喘、 镇静、 祛痰等多方面的综合作用, 并在动物实 验和大量的临床实践中得到了证实。 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.
钙离子是机体各项生理活动不可缺少的离子。 它对于维持细胞膜两侧的 生物电位, 维持正常的神经传导功能。 维持正常的肌肉伸缩与舒张功能以及神 经-肌肉传导功能,还有一些激素的作用机制均通过 4丐离子表现出来。主要作 用或机制为: 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、 钙离子是凝血因子, 参与凝血过程。 1. Calcium ion is a blood coagulation factor involved in the blood coagulation process.
2、 参与肌肉 (包括骨 肌、 平滑肌)收缩过程, 促使心脏跳动。 2. Participate in the contraction process of muscles (including musculoskeletal and smooth muscles), causing the heart to beat.
3、 参与神经递质合成与释放、 激素合成与分泌, 并传导神经信号。 其传 导机制为促进神经递质分泌。 当机体缺钙时, 神经递质的释放受到阻隔, 人体 的兴奋机制和抑制机制遭到破坏。如果是儿童缺钙,会夜啼、夜惊、烦躁失眠, 严重的导致大脑发育障碍, 出现反应迟钝、 多动、 学习困难等症, 影响大脑成 熟和智力。 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、 是骨骼构成的重要物质。 4. It is an important substance composed of bones.
5、 传递御敌信号。 其机制为: 当外来抗原激活 T细胞受体, 启动了钙离 子介导的信号通路, 促使免疫细胞分化和生长。 一旦钙缺乏, 就会发生免疫系 统功能下降、 紊乱, 引发疾病。 如: 自身免疫性疾病红斑狼疮、 风湿病; 皮肤 病: 皮炎、 痤疮等。 补钙, 对治疗这些病有重要作用。
精氨酸是一种条件必须氨基酸,在体内参与能量代谢中的三羧酸循环及具 有解毒作用的尿素循环, 促使机体能量平衡, 用药后可降低血氨, 促进有毒物 质排出体外, 达到消除疲劳之目的。 其药理作用广泛, 其主要作用有: 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:
精氨酸(arginine, Arg )是人体一氧化氮的来源, 一氧化氮 (NO)促使血 管舒张, 促进血液循环。 精氨酸可促进心率的恢复, 增加冠状动脉的血流量, 改善心脏功能,对心肌具有一定的保护作用,提示补充精氨酸有助于保护运动 时心脏的正常供血功能,对延緩疲劳的发生和促进恢复具有一定的作用。 心肌 缺血患者补充 L-精氨酸后的次极量运动实验的结果表明, 精氨酸补充组在运 动实验时冠状动脉血流量明显好转。 L-精氨酸补充能明显提高冠状动脉血管痉 挛性心绞痛患者的运动能力, 且具有较好的持续性, 并使血浆 NO水平显著提 高。 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.
研究表明, 精氨酸能有效的降低心肌梗塞的发生率, 同时具有舒张血管、 降血压、 促进血液循环顺畅的作用, 对于心血管疾病的预防及动脉硬化患者, 心肌梗塞的发生率具有明显的降低作用,精氨酸也具有抗氧化作用, 可以降低 低密度脂蛋白 (LDL) 氧化, 形成血管内层乳糜沉淀的作用, 因此对于心脏小 血管阻塞、 造成心几坏死的机率下降。 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.
此外,精氨酸具有特异性免疫促进作用。精氨酸及其代谢产物如一氧化氮 ( NO )等, 在免疫防御、 免疫调节、 维持和保护肠道粘膜功能以及肿瘤的特 异性免疫等方面发挥着重要作用。 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.
精氨酸可有效提高免疫力、 促进免疫系统分泌自然杀手细胞、 吞噬细胞、 白介素 1 等内生性物质, 有利于对抗癌细胞及预防病毒感染。 无论是正常饮 食还是静脉输入精氨酸, 均能特异性增强正常或创伤动物的细胞免疫功能; 在 创伤和患肿瘤动物中, 除减轻创伤导致的免疫抑制外,精氨酸还能增强淋巴细 胞功能, 并具有潜在的 IL-2免疫抗肿瘤作用, 能够促进 T细胞有丝分裂、 改 善氮平衡、 提高动物生存率、 增强对过敏的延迟反应。 另外, 精氨酸是鸟氨酸 及脯氨酸的前趋物,脯氨酸是构成胶原蛋白的重要元素, 补充精氨酸对于严重 外伤、 烧伤等需要大量组织修护的康护, 具有明显的帮助, 同时具有降低感染 及发炎的效果。 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.
赖氨酸属碱性氨基酸,是人体必须 8种氨基酸之一,赖氨酸为合成肉碱提
供结构组分, 而肉碱会促使细胞中脂肪酸的合成。 特别是在儿童发育期、 病后 恢复期、 妊娠授乳期, 对赖氨酸的需要量更高。 由于在大米、 玉米等食物中含 量较低, 容易造成人体缺乏, 被称为"第一缺乏氨基酸"。 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".
赖氨酸缺乏会引起发育不良、 食欲不振、 体重减轻、 负氮平衡、 低蛋白血 症、 贫血、 酶活性下降及其它生理机能障碍。 赖氨酸有提高智力、 促进生长、 增强体质; 增进食欲、 改善营养不良状况; 改善失眠, 提高记忆力; 帮助 产生抗体、 激素和酶, 提高免疫力、 增加血色素; 帮助钙的吸收, 治疗防 止骨质疏松症; 帮助神经组织修复, 促进神经细胞再生, 提高中枢神经组织 功能的作用。 赖氨酸能提高血脑屏障通透性, 有助于药物进入脑细胞内, 临床 用作治疗颅脑外伤、 慢性脑组织缺血、 缺氧性疾病的脑保护剂, 或对其他脑病 的辅助治疗,也可用于赖氨酸缺乏引起的小儿食欲不振、 营养不良及脑发育不 全。组氨酸的咪唑基能与 Fe2+或其他金属离子形成配位化合物,促进铁的吸收, 因而可用于防治贫血。 组氨酸能降低胃液酸度, 緩和胃肠手术的疼痛, 减轻妊 娠期呕吐及胃部灼热感,抑制由植物神经紧张而引起的消化道溃烂,对过敏性 疾病, 如哮喘等也有功效。 此外, 组氨酸可扩张血管, 降低血压, 临床上用于 心绞痛、 心功能不全等疾病的治疗。类风湿性关节炎患者血中组氨酸含量显著 减少, 使用组氨酸后发现其握力、 走路与血沉等指标均有好转。 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-瓜氨酸可提高免疫系统功能, 维护关节运动机能, 平衡正常血糖水平, 吸收有害自由基, 帮助保持胆固醇正常水平, 提高健康性功能, 维护健康的肺 功能, 提高脑力清晰度, 降低压力和克服沮丧情绪。 瓜氨酸可在人体内与氨作 用, 生成精氨酸和一氧化氮作血管舒张剂, 并用于治疗精神和体力疲劳以及性 功能障碍。 瓜氨酸属于氨基酸类药物, 可同鸟氨酸、 精氨酸等合用于治疗高氨 血症 。 瓜氨酸可以完全吸收到血液中, 产生一氧化氮, 参与多种多样的生理 过程, 如神经传递、 血管张力、 括约肌松弛、 微生物的杀灭以及阴茎勃起等, 对男性性功能有非常重要作用。一氧化氮是在氧分子和血红蛋白存在下, 由一 氧化氮合成酶 (NOS)催化 L-精氨酸胍基氧化脱氨成 L-瓜氨酸时形成的。 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).
本发明化合物中含有药学上可接受的金属离子或有机碱,金属离子包括碱 金属离子或碱土金属离子等,有机碱包括氨基酸、三乙胺、二乙胺、 乙醇胺等, 其中氨基酸均包括消旋和手性的氨基酸( D或 L型氨基酸), 并形成稳定的化
合物,使得其在不同疾病的预防或治疗中比单一的环磷腺苷更具有优势, 或者 使得在制备环磷腺苷其它的衍生物时更方便。 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.
本发明还提供所述环磷腺苷盐的水合物的制备方法及用于心绞痛、心力衰 竭、 心肌梗死、 心肌炎、 心律失常及心源性休克, 改善风湿性心脏病的心悸、 气急、 胸闷等症状、 急性白血病、 神经系统疾病、 呼吸系统疾病、 肝炎和银屑 病等疾病预防或治疗的用途。 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.
环磷腺苷的盐的水合物制备方法包括: A method for preparing a hydrate of a cyclic adenosine salt comprises:
方法 A.在反应容器中, 加水和环磷腺苷, 搅拌, 按反应的摩尔比加药学 上可接受的有机碱或金属的氧化物或氢氧化物或其金属盐或其溶液,搅拌,待 反应完毕, 过滤, 緩慢加入 C3-C7的低级酮, 如丙酮, 或 C1-C6的低分子醇, 如曱醇、 乙醇、 异丙醇, C2-C8的低级醚中的一种或几种, 冷却, 过滤, 固体 物用有机溶剂 C1-C6的低分子醇, 如曱醇、 乙醇、 异丙醇、 C3-C7的低级酮, 如丙酮、 C2-C6的低级醚如乙醚、 或水中一种或几种润洗, 抽干, 干燥, 得到 环磷腺苷盐的水合物; 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;
或者方法 B. 将金属的氧化物或氢氧化物或其金属盐或有机碱的溶液按反 应的摩尔比投入到含有环磷腺苷和水的反应容器中, 搅拌, 控制温度 0 ~ 50°C 之间, 搅拌, 待反应完毕, 活性炭脱色, 一次或多次过滤, 将其冷冻到 - 70 ~ -30°C , 升温, 真空干燥, 得有环磷腺苷盐的水合物; 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;
或者方法 C. 将分别将金属的氧化物或氢氧化物或其金属盐或药学上可接 受的有机碱的一种或其溶液按反应的摩尔比加入含有环磷腺苷和水的反应容 器中, 搅拌, 控制温度 -5 ~ 40°C之间, 反应 0.5 ~ 24h, 待反应完毕, 活性炭脱 色, 一次或多次过滤, 喷雾干燥, 得环磷腺苷盐的水合物。 喷雾干燥中, 进风 温度可在 100~140°C之间, 出风温度可在 70~100°C之间, 喷压可在 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/cm2。 1.0~2.0kg/cm 2 .
将环磷腺苷的盐的水合物在 60 ~ 120°C之内, 一般在 90 ~ 120°C之内,五氧 化二磷为干燥剂, 高真空干燥 8小时至数日以上, 得环磷腺苷的盐无水物。 并 可将所得的产物用于引湿性试验或加速稳定性试验的比较。 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.
本发明中的低级酮或低分子酮定义为 C3-C7, 如丙酮, 丁酮等; 低级醇或 低分子醇定义为 C1-C6, 如曱醇、 乙醇、 异丙醇, 低级醚或低分子醚定义为
C2-C8, 如乙醚、 丁醚等。 所提到金属的氧化物或氢氧化物或其金属盐, 分别 可为: 氧化钙、 氢氧化钙、 氧化镁、 碱式碳酸镁、 氢氧化钠、 碳酸钠、 碳酸氢 钠、 氧化辞、 三氧化二铝、 氢氧化钾、 碳酸钾、 硝酸铋, 其金属盐包括碳酸盐 或碳酸氢盐或碱式碳酸盐。 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.
本发明的环磷腺苷的盐的水合物用途:本发明的环磷腺苷的盐的水合物用 于制备注射用冻干粉针制剂、 或者大输液制剂、 或者小水针注射剂, 无菌分装 的粉针, 固体制剂, 包括片剂、 胶嚢、 颗粒剂, 经皮肤外用制剂包括软膏、 凝 胶剂等。 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.
用于制备固体制剂的片剂、胶嚢或颗粒剂, 这些制剂中可含有药学上可接 受的填充剂, 如淀粉、 变性淀粉、 乳糖、 微晶纤维素、 环糊精、 山梨醇、 甘露 醇、 磷酸 4弓、 氨基酸等; 药学上可接受的崩解剂, 如淀粉、 变性淀粉、 微晶纤 维素、 羧曱基淀粉钠、 交联聚乙烯吡咯烷酮、 低取代羟丙基纤维素、 表面活性 剂; 药学上可接受的润湿剂和粘合剂, 如胶化淀粉、 曱基纤维素、 羧曱基紆维 素钠、 乙基纤维素、 聚乙烯吡咯烷酮、 海藻酸及其盐; 药学上可接受的润滑剂 和助流剂, 如硬脂酸、 硬脂酸镁、 聚乙二醇 4000 - 8000、 滑石粉、 微粉硅胶、 十二烷基硫酸镁等; 药学上可接受的甜味剂和香精, 如阿斯巴甜、 甜蜜素、 糖 精钠、 三氯蔗糖、 食用香精等。 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.
本发明的结晶水合物不同于无水物的潮解使得在处理时要隔绝空气防止 粘连等, 而结晶水合物具有良好的滑动性, 从而改善制剂的可操作性; 并使制 备的固体制剂具有良好的溶出性能,使得其容易被吸收进入血液循环, 改善生 物利用度, 并有利于快速发挥其作用。 从另一个方面, 使得其防止出现在进行 无菌分装时不易因为吸潮而导致分装时产生堵塞使得装量发生差异导致剂量 不足,从而带来产品的不合格, 或因为不合格的产品没有被抽检到形成实际上 的漏检, 进而流入市场, 在临床治疗中对患者的治疗代理负面的效果, 或者因 剂量不足危及病人的生命。或者在分装时, 因为吸潮而导致整个生产线被迫暂 停, 严重降低设备的生产能力, 大大增加工时费用等的隐患。 本发明的环磷腺 合物,对于治疗心脑血管疾病的静脉给药的制剂来说,将大大有利于提高临床 给药的安全性。
由于环磷腺苷微溶解于水, 一般情况下需要加油溶性的辅料, 易于污染, 而且较难清洗,本发明的环磷腺苷的盐的水合物的存储稳定性和一般易溶解于 水的特性,使得在制备凝胶剂方面更具有制剂的易操作性, 其所制备的凝胶剂 具有良好的释放性能, 使得其容易被吸收进入血液循环, 提高生物利用度, 并 有利于快速发挥其作用。 无需加油溶性的辅料, 不易污染, 而且较易清洗。 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.
环磷腺苷盐的水合物的凝胶制备: 将环磷腺苷盐水合物与 50 ~ 95 %基质 混匀, 基质可以是乙醇、 甘油、 三乙醇胺、 甘油明胶、 聚乙二醇 200 ~ 8000、 泊洛沙姆、 聚乙烯吡咯烷酮、 半合成硬脂肪酸脂、 水溶性单甘酯、 卡波姆系列 ( 931、 934、 940、 974、 AA-1、 1342等)、 吐温 60 - 80。 凝胶中可含有药学 上可接收的防腐剂和稳定剂, 制备时可分别将卡波姆用水分散, 加入甘油、 聚 乙二醇 200 ~ 8000、 加热, 搅拌混合, 加处方量的环磷腺苷盐水合物、 搅拌、 用药学上可接收的无机碱或者有机碱调节 pH = 5.0 ~ 8.5左右, 加水至全量、 搅拌至勾、 分装, 即得。 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.
环磷腺苷的盐的水合物针剂, 其制备方法为: a hydrate injection of a salt of cyclic adenosine, which is prepared by:
环磷腺苷的盐的水合物无菌分装粉针制剂可按照常规方法制备。 The hydrated aseptic powdered needle preparation of the salt of cyclic adenosine can be prepared according to a conventional method.
冻干粉针制剂的制备方法为: 取环磷腺苷的盐的水合物, 可以加药学上可 接受的冻干支持剂或辅形剂, 加注射用水搅拌使溶解, 若需要, 可用药学上可 接受的酸碱调节 pH为 4.0 ~ 8.5 ,加活性碳 0.005 ~ 0.5%( W/V )搅拌 15 ~ 45min, 过滤, 补水, 无菌过滤, 按 20 ~ 200mg /瓶(以环磷腺苷计)分装, 冷冻干燥, 压塞, 得成品。 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.
环磷腺苷的盐的水合物小容量注射液及其制备工艺:环磷腺苷的盐的水合 物加注射用水和药学上可接受的附加剂, 例如: 药学上可接受的 pH调节剂、 药学上可接受的抗氧剂、 惰性气体, 过滤、 除菌制成灭菌小容量注射液, 其 pH值在 4.0 ~ 8.5之间。 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.
其药学上可接受的 pH调节剂可以是药学上可接受的无机酸或有机酸、 无 机碱或有机碱, 也可以是广义的路易斯酸或碱, 可以含有一种或者几种, 可以 是盐酸、 磷酸、 丙酸、 醋酸及醋酸盐、 如醋酸钠等, 乳酸以及乳酸药用盐、 枸 橼酸药用盐、 碳酸钠、 碳酸氢钠、 碳酸氢钾、 氢氧化钠、 氢氧化钾、 磷酸盐、 酒石酸及其药用盐、 硼砂、 硼酸、 丁二酸、 己酸、 己二酸、 反丁烯二酸、 顺丁
烯二酸、 三羟基氨基曱烷、 二乙醇胺、 乙醇胺、 异丙醇胺、 二异丙醇胺、 2- 氨基 -2- (羟曱基) 1 , 3-丙二醇胺、 1 , 2-己二胺、 N-曱基葡萄胺、 二异丙胺以 及它们的盐, 多羟基羧酸及药用盐, 如葡萄糖醛酸、 葡萄糖酸、 乳糖酸、 苹果 酸、 苏糖酸、 葡庚糖酸、 氨基酸及氨基酸盐等中的一种或者几种。 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.
其药学上可接受的抗氧剂和稳定剂可以是亚硫酸、亚硫酸盐、亚硫酸氢盐、 焦亚直酸盐、 连二亚直酸盐、 直代直酸盐, 有机直化合物直脲、 谷胱甘肽、 二 巯基丙醇、 巯基乙酸及盐、 硫代乳酸及盐、 硫代二丙酸及盐、 苯酚类化合物, 如没食子酸及盐、 咖啡酸、 咖啡酸盐、 阿魏酸、 阿魏酸盐、 二叔丁基对苯酚、 2, 5-二羟基苯曱酸、 2, 5-二羟基苯曱酸盐、 水杨酸或其盐; 氨基酸以及其盐; 抗坏血酸及抗坏血酸盐、 异抗坏血酸及异抗坏血酸盐、 烟酰胺、 酒石酸、 硝酸 盐、 磷酸盐、 醋酸药用盐、 柠檬酸盐、 EDTA及 EDTA盐、 如 EDTA二钠、 EDTA四钠等中的一种或者几种。 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.
其药学上可接受的等渗调节剂可以是葡萄糖、 果糖、 木糖醇、 山梨醇、 甘 露醇、 转化糖、 麦芽糖、 右旋糖酐、 氯化钠、 氯化钾、 乳酸钠等中的一种或几 种。 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. .
去热源和除菌方式可以是加入配液量 0.005 ~ 3 %的活性炭去热源, 微孔 滤膜除菌和热压灭菌, 也可以采用超滤除菌、 去热源。 超滤方法中, 超滤器可 选用平板式、 卷式、 管式、 中空纤维式或圓盒式等, 优选卷式和中空纤维式超 滤器, 采用截留相对分子质量为 5万至 30万的滤膜除去大部分发热性物质和 细菌后,再采用截留相对分子质量 3000 ~ 30000的超滤膜除去剩余热源,优选 相对分子质量 6000 ~ 20000的超滤膜。 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.
本发明的环磷腺苷的盐的水合物,适用于制备下列对所引起的人和动物感 染的治疗或预防的药物中的应用: 在制备用于心绞痛、 心力衰竭、 心月几梗死、 心肌炎、 心律失常及心源性休克, 改善风湿性心脏病的心悸、 气急、 胸闷等症 状、 急性白血病、 神经系统疾病、 呼吸系统疾病、 老年慢性支气管炎、 肝炎和 银屑病等治疗或预防的药物中的应用。 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 .
用量用法: 一般情况下, 于成人, 取本发明药物 0.020 ~ 0.2g于 0.9%氯化 钠或者 5 ~ 10%葡萄糖 20 ~ 500亳升中, 作静脉推注或滴注, 每日 1 ~ 2次; 取 本发明药物 0.020 ~ 0.2g溶于注射用水中, 肌内注射, 每日 1 ~ 2次; 儿童减半
量以上使用。 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.
经胃肠道给药用量用法: 10 ~ 70 kg体重的人或动物 '般情况下 40 600mg/天, 分 2-3次给药; 儿童减半量以上使用。 外用给 直接凃于麾 每天一次到六次。 附图说明 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
图 1为环磷腺苷的镁盐 8水合物的热分析图谱。 Figure 1 is a thermogram of magnesium salt 8 hydrate of cyclic adenosine.
图 2为环磷腺苷葡曱胺盐 1水合物的热分析图谱。 Figure 2 is a thermogram of cyclic adenosine glucoside salt 1 hydrate.
图 3为环磷腺苷 L-精氨酸盐 1水合物的热分析图谱。 Figure 3 is a thermogram of cyclic adenosine L-arginine salt 1 hydrate.
图 4为环磷腺苷 L-赖氨酸盐 1水合物的热分析图谱。 Figure 4 is a thermogram of cyclic adenosine L-lysine salt 1 hydrate.
图 5为环磷腺苷钠盐 2水合物的热分析图谱。 Figure 5 is a thermogram of cyclic adenosine sodium salt 2 hydrate.
图 6为环磷腺苷的镁盐 8水合物的 X射线衍射图谱。 具体实施方式 Figure 6 is an X-ray diffraction pattern of the magnesium salt 8 hydrate of cyclic adenosine. detailed description
本发明公开了一种环磷腺苷盐的水合物及其制备和用途,本领域技术人员 可以借鉴本文内容, 适当改进工艺参数实现。 特别需要指出的是, 所有类似的 替换和改动对本领域技术人员来说是显而易见的, 它们都被视为包括在本发 明。 本发明的产品、 方法及应用已经通过较佳实施例进行了描述, 相关人员明 显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或 适当变更与组合, 来实现和应用本发明技术。 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.
在具体实施例中, 热分析测试条件均为: Setaram公司 Setsys 16, In a specific embodiment, the thermal analysis test conditions are: Setaram Setsys 16,
PE-6300TGDTA,样品量约 5mg, 升温速度: ΙΟΚ/min, Ν2 速: 50ml/min, 室温〜 400°C。 PE-6300TGDTA, sample volume about 5mg, heating rate: ΙΟΚ / min, Ν 2 speed: 50ml / min, room temperature ~ 400 ° C.
X射线衍射图是在武汉理工大学材料测试中心利用 D/ΜΧ-ΠΙΑ X射线衍 射仪,衍射角 2Θ,扫描范围 3-60°,测定了本发明水合物的粉末 X射线衍射图。 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.
在一个实施方案中, 利用粉末 X射线衍射法测量, 在衍射角 2Θ ( 3-60。) 测量范围内, 本发明的环磷腺苷的镁盐 8水合物可以在包括如下 2Θ值的位置 具有相应的特征值: 约 4.3 , 5.9, 11.0, 13.0, 16.9, 17.9, 20.0, 21.6, 24.3 , 26.0, 31.3 , 33.9。
在一个实施方案中, 利用粉末 X射线衍射法测量, 在衍射角 2Θ ( 3-60。) 测量范围内, 本发明的环磷腺苷葡曱胺 1水合物可以在包括如下 2Θ值的位置 具有相应的特征值: 约 6.3 , 15.0, 17.9 , 20.8, 22.5 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
在一个实施方案中, 利用粉末 X射线衍射法测量, 在衍射角 2Θ ( 3-60。) 测量范围内, 本发明的环磷腺苷 L-精氨酸 1水合物可以在包括如下 2Θ值的位 置具有相应的特征值: 约 3.5 , 17.6, 20.8, 30.2, 34.5 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
在一个实施方案中, 利用粉末 X射线衍射法测量, 在衍射角 2Θ ( 3-60。) 测量范围内, 本发明的环磷腺苷 L-赖氨酸 1水合物可以在包括如下 2Θ值的位 置具有相应的特征值: 约 14.2, 15.8, 17.6, 20.7, 27.0 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
在具体实施方案中,对本发明所述环磷腺苷盐水合物进行检测分析, 其中 环磷腺苷的含量测定参照中国国家药品标准进行。 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.
在一个实施方案中,对本发明所述环磷腺苷盐水合物进行检测分析, 其中 精氨酸的含量测定( HPLC法)及鉴别可参照中国药典 2005年版, P588盐酸 精氨酸片的方法进行。 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. .
在一个实施方案中, 对本发明所述环磷腺苷盐水合物进行检测分析, 其 中赖氨酸的测定参照文献: 农辉等. 盐酸赖氨酸及其注射液的 HPLC测定, 化 工技术与开发, 2003 , 32(2):33 为了使本领域的技术人员更好地理解本发明的技术方案, 下面结合具体 实施例对本发明作进一步的详细说明。 实施例 1 环磷腺苷的镁盐 8水合物的制备 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
在 250ml三颈烧瓶中, 加环磷腺苷 O.lmol, 水 100ml、 搅拌, 加入 0.05mol 的氧化镁, 20 ~ 60 °C下搅拌 50分钟左右, 使溶解, 过滤, 加 5倍量的丙酮使固 体析出, 冷却到 -10°C左右, 放置 24小时, 过滤, 固体物 50°C左右干燥 4小时得 类白色固体 23.6g,熔点: 227°C 分解(未校正), HPLC: 环磷腺苷含量 39.86%, 卡氏法测定水分为 17.57 % ,热分析:平台失重约 17.16 % (见附图 1 ) , 这与样品 含有 8个结晶水的结果(理论值 17.48 % )在误差范围内; 红外光谱: 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; 元素分 析 理论值: C 29.12%, H4.64%, N16.98% P7.51%, Mg2.95%; 实测值: C 29.33%, H4.52%, N17.11% Ρ7·67%, Mg 3·23%。 实施例 2 环磷腺苷钙盐 3.5水合物的制备 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
在 250ml三颈烧瓶中, 加折纯后的环磷腺苷 0.1 mol, 水 100ml、 搅拌, 加入 0.05mol的氢氧化钙或氧化钙, 20 ~ 60 °C下搅拌 60分钟左右, 使溶解, 过滤, 加 5倍量的无水乙醇和异丙醇( 1: 1) , 冷却到 -10~5°C, 放置 24小时, 待固 体析出,过滤, 50°C左右干燥 4~6小时干燥,得类白色固体 19.2克,熔点: 223 °C 分解( ELECTROTHERMAL MELTING POINT APPARATUS,未校正;), 红外光 谱: 卡氏法测定水分为 8.52%, 热分析:平台失重约 8.4%, 这与样品含有 3.5个 结晶水的结果(理论值 8.30% )在误差范围内; ESI: m/z: 328; 红外光谱: KBr max cm_13436, 3209, 2913,2428, 1658, 1606, 1581, 1488, 1425, 1384, 1343,1290, 1237, 1136, 1094, 1053, 1022, 951, 869, 843, 724, 640, 545; 元素分析 理论值: C 31.63%, H3.85%, N18.44% P8.16%, Ca5.28%; 实测值: C 31.57%, H3.94%, N18.36% Ρ8·07%, Ca 5·35%。 实施例 3 环磷腺苷葡曱胺 1水合物的制备 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
将折纯后的环磷腺苷 10g和以及等摩尔的葡曱胺投入反应瓶中, 加水 200ml, 搅拌, 控制温度 10 ~ 60 °C之间, 反应 10~120min, 加溶液总量的百分 之一的活性炭搅拌半小时过滤, 再用 0.22微米微孔滤膜过滤, 其冷冻到 -60 ~ -40 °C, 保持 4小时左右, 然后升温至 -16°C左右, 真空度 5-12Pa之间, 真空干燥 20小时左右, 再在 20~30°C、 真空度 5-12Pa之间, 真空干燥 4小时左右, 得类 白色固体, 该固体易溶于水, 熔点: 67~71.°C ( ELECTROTHERMAL MELTING POINT APPARATUS,未校正); HPLC: 环磷腺苷含量为 60.79%, ESI: m/z:523,328, 19,6, 195; 水分(卡氏法): 3.51%, 热分析: 平台失重 约 3.31%, 这与样品含有 1个结晶水的结果(理论值 3.32% )在误差范围内 (见 附图 3); 红外光谱: ffir max cm_13404, 3210, 2918, 2766, 2427, 1648, 1605, 1571, 1478, 1422, 1384, 1332, 1299, 1233, 1134, 1083, 1018, 945, 839,
765, 724, 644, 540;元素分析 理论值: C 37.64%, H5.76%, N15.49% P5.71%; 实测值: C 37.52%, Η5.87%, Ν15.37% Ρ5·56%。 实施例 4 环磷腺苷 L-精氨酸 1水合物的制备 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
将折纯后的环磷腺苷 10g和以及等摩尔的 L-精氨酸投入反应瓶中, 加水 Put the purified cyclic adenosine 10g and the equimolar L-arginine into the reaction bottle, add water
200ml, 搅拌, 控制温度 10~60°C之间, 反应 10 - 120min, 加溶液总量的百分 之一的活性炭搅拌半小时过滤,再用 0.22微米微孔滤膜过滤,其冷冻到 -60 ~ -40 °C, 保持 4小时左右, 然后升温至 -16°C左右, 真空度 0.5-15Pa下, 真空干 燥 20小时左右, 再在 20~30°C、 真空度 0.5-15Pa之间, 真空干燥 4-8小时 左右, 得类白色固体 lO.lg, 该固体易溶于水, 熔点: 189~ 195°C 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,未校正), HPLC: 环 磷腺苷含量为 63.07%, 精氨酸 33.31%; ESI: m/z:502,328, 175,158; 卡氏法 测定水分为 3.82% , 热分析: 平台失重约 3.61 % (见附图 4), 这与样品含有 1 个结晶水的结果(理论值 3.46% )在误差范围内; 红外光谱:
, 3210, 2928, 2765, 2426, 2071, 1641, 1476, 1384, 1331, 1238, 1134, 1083, 1018, 839, 796, 765, 72, 3, 643, 540; 元素分析 理论值: C 36.86%, H5.41%, N24.18%, P5.94%; 实测值: C 37.08%, H5.20%, N24.36%, P5.75%。 实施例 5 环磷腺苷 L-赖氨酸 1水合物的制备 (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
将折纯后的环磷腺苷 10g和以及等摩尔的 L-赖氨酸投入反应瓶中, 加水 Put the purified cyclic adenosine 10g and the equimolar L-lysine into the reaction bottle, add water
220ml, 搅拌, 控制温度 10~60°C之间, 搅拌反应 30min, 加溶液总量的百分之 一的活性炭搅拌半小时过滤, 再用 0.22微米微孔滤膜过滤, 其冷冻到 -60 ~ -40 °C, 保持 4小时左右, 然后升温至 -20°C左右, 真空度 0.8-15Pa下, 真空干燥 20小时左右, 再在 20~30°C、 真空度 0.8-15Pa下, 真空干燥 4小时左右, 得类 白色固体 11.6g,该固体易溶于水,熔点: 195 ~ 201°C分解(ELECTROTHERMAL MELTING POINT APPARATUS,未校正); HPLC: 环磷腺苷含量为 66.65%, 赖 氨酸 29.46%; ESI: m/z:474,328, 147, 130; 水分(卡氏法): 3.96%, 热分 析:平台失重约 4.01% (见附图 5 ),这与样品含有 1个结晶水的结果(理论值 3.65 % )在误差范围内;红外光谱: vKBr maxCm-13424, 3198, 2933,2766, 2427, 1642,
1599, 1509, 1477, 1384, 1332, 1237, 1134, 1083 , 1018, 839, 796, 7,59, 724, 644, 542. 实施例 6 将环磷腺苷钠 2水合物的制备 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
将环磷腺苷 10g置于反应瓶中, 加水 200ml, 搅拌, 緩慢向反应瓶中加入 与环磷腺苷等摩尔的碳酸氢钠, 搅拌, 控制温度 10 ~ 60°C之间, 反应 30min, 加溶液总重量 0.2%的活性炭搅拌半小时过滤, 再用 0.22微米微孔滤膜过滤, 其 冷冻到 - 70 ~ -40°C , 然后升温至 -16°C左右, 真空度 0.5-10Pa之间, 真空干燥 20小时左右, 再在 20 ~ 30°C、 真空度 2-12Pa之间, 真空干燥 6小时左右, 得类 白色固体 10.6g, 该固体易溶于水, 熔点: 227 °C分解(ELECTROTHERMAL MELTING POINT APPARATUS,未校正); 含量测定: HPLC法: 环磷腺苷含量 为 84.82%; 水分(卡氏法): 9.47%, 热分析: 平台失重约 9.03% (见附图 6 ), 这与样品含有 2个结晶水的结果(理论值 9.31 % )在误差范围内; ESI: m/z:350; 元素分析 理论值: C 31.02%, H3.90%, N18.09%, P8.00%, Na5.94%; 实测值: C 30.88%, Η4.03%, Ν18·19%, Ρ8·12%, Na5.83%。 实施例 7 环磷腺苷 DL-赖氨酸 1水合物的制备 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
将折纯后的环磷腺苷 10g和以及等摩尔的 DL-赖氨酸投入反应瓶中, 加水 220ml, 搅拌, 控制温度 10 ~ 60 °C之间, 反应 10 ~ 120min, 加溶液总量的百分 之一的活性炭搅拌半小时过滤, 再用 0.22微米微孔滤膜过滤或者采用截留相对 分子质量 6000 ~ 30000的超滤膜过滤,其冷冻到 - 70 ~ -30 °C ,保持 24小时左右, 然后升温至 -16°C左右, 真空度 2-10Pa下, 真空干燥 20小时左右, 再在 20 ~ 30 °C、 真空度 2-10Pa之间, 真空干燥 6小时左右, 得类白色固体 12.2g, 该固体易 溶于水, 熔点: 194 ~ 199 °C分解( ELECTROTHERMAL MELTING POINT APPARATUS,未校正); HPLC: 环磷腺苷含量为 66.52%,赖氨酸 29.34%; ESI: m/z:474,330, 328, 147,130;水分(卡氏法): 4.02%,热分析:平台失重约 3.83%, 这与样品含有 1个结晶水的结果(理论值 3.65 % )在误差范围内; 红外光谱: V KBr max cm-13424, 3198, 2933, 2766, 2427, 1642, 1599, 1509, 1477, 1384, 1332, 1237, 1134, 1083 , 1018, 839, 796, 7,59, 724, 644, 542。
实施例 8 环磷腺苷 D-精氨酸 1水合物的制备 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
将折纯后的环磷腺苷 10g和以及等摩尔的 D-精氨酸投入反应瓶中, 加水 200ml, 搅拌, 控制温度 10 ~ 60°C之间, 反应 10 - 120min, 加溶液总量的百分 之一的活性炭搅拌半小时过滤,再用 0.22微米微孔滤膜过滤,其冷冻到 - 70 ~ -40 °C , 保持 5小时左右, 然后升温至 -16°C左右, 真空度 3-15Pa下, 真空干燥 20小时左右, 再在 20 ~ 30°C、 真空度 3-15Pa之间, 真空干燥 6小时左右, 得类白色固体 11.5g, 易溶于水, 熔点: 190 ~ 194°C ( ELECTROTHERMAL MELTING POINT APPARATUS,未校正), HPLC: 环磷腺苷含量为 63.01%, 精 氨酸 33.35%; 卡氏法测定水分为 3.78 % , 热分析: 平台失重约 3.57 % , 这与 样品含有 1个结晶水的结果(理论值 3.46 % )在误差范围内。 实施例 9 环磷腺苷三乙胺 1水合物的制备 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
参照实施例 3的方法, 制备得类白色的环磷腺苷三乙胺 1水合物。 实施例 10 环磷腺苷 L-精氨酸 1水合物或环磷腺苷 L-赖氨酸 1水合物或环磷 腺苷 DL-赖氨酸 1水合物或环磷腺苷葡曱胺 1水合物冻干制剂的制备(环磷腺苷 各水合物按相应实施例方法制备 ) 取环磷腺苷 L-精氨酸 1水合物或环磷腺苷 L-赖氨酸 1水合物或环磷腺苷 DL-赖氨酸 1水合物或环磷腺苷葡曱胺 1水合物 200g,加葡萄糖或甘露醇或木糖醇 2.0 ~ 5g加新鲜的注射用水 10 ~ 20L搅拌使溶 解, 用 2M盐酸或 2M氢氧化钠适量, 调节 pH为 5.0 - 8.5 , 加活性碳 0.01 ~ 0.5% ( W/V )搅拌 15 ~ 45min, 过滤, 用 0.22微米微孔滤膜过滤或者采用截留相对 分子质量 6000 ~ 20000的超滤膜过滤, 按 20mg、 30mg/瓶或 40mg或 50mg/瓶或 60mg/瓶或 lOOmg/瓶或 120mg/瓶分装(以环磷腺苷计)分装, 冷冻干燥, 压塞, 得成品。 实施例 11 冻干制剂的制备取环磷腺苷 L-精氨酸 1水合物(按实施例 4方法 制备 )或环磷腺苷葡曱胺 1水合物 10g (按实施例 3方法制备 ) (以环磷腺苷计 ), 加甘露醇 40g, 加 40 ~ 60°C注射用水 1460 ~ 1850ml搅拌使溶解, 用 1M的枸橼酸
或氢氧化钠调节 pH为 5.0 ~ 8.0, 加活性碳 0.01 ~ 0.5% ( W/V )搅拌 15 ~ 45min, 过滤, 补水至 2000ml, 用 0.22微米微孔滤膜过滤或者采用截留相对分子质量 6000 ~ 20000的超滤膜过滤,按 20、 30mg/瓶或 60mg/瓶或 lOOmg/或 12011¾/瓶(按 环磷腺苷计)分装, 冷冻干燥, 压塞, 得成品。 实施例 12取无菌的环磷腺苷的盐的水合物 20Kg (以环磷腺苷计)(环磷 腺苷各水合物按相应实施例方法制备 ),以无菌分装工艺按 20、30mg/瓶或 50mg/ 瓶、 或 60mg/瓶或 lOOmg/瓶分装, 加塞、 压塞, 轧铝盖得成品。 实施例 13 环磷腺苷的盐的水合物的小容量注射剂的制备环磷腺苷钠 2 水合物 (按实施例 6方法制备)或环磷腺苷 L-精氨酸 1水合物 (按实施例 4方法 制备 )或环磷腺苷葡曱胺 1水合物(按实施例 3方法制备)(按环磷腺苷计 ) 10 g, 加盐酸半胱氨酸 0.8g, EDTA二钠 O.lg, 加注射用水搅拌使溶解, 2M乳酸和乳 酸钠调节 pH为 5.0 ~ 7.8, 加活性碳 0.5% ( W/V )搅拌 15 ~ 45min,过滤, 补水至 1000ml, 用 0.22微米微孔滤膜过滤或者采用截留相对分子质量 6000 ~ 20000的 超滤膜过滤, 按 2 ~ 10ml/瓶分装, 灭菌得成品。 实施例 14 环磷腺苷钠 2水合物的冻干制剂制备取环磷腺苷钠 2水合物 10g (按实施例 4方法制备), 加注射用水搅拌使溶解, 加活性碳 0.3% ( W/V ) 搅拌 15 ~ 45min,过滤, 补水至 2000ml, 用 0.22微米微孔滤膜过滤, 按 2 ~ 5ml/ 瓶分装, 冷冻干燥, 压塞, 得成品。 实施例 15 环磷腺苷钠 2水合物或环磷腺苷 L-精氨酸 1水合物或环磷腺苷 葡曱胺 1水合物大容量注射液的制备(各环磷腺苷盐的水合物按相应实施例方 法制备 ) 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)
称取葡萄糖 500g加入注射用水中, 搅拌使溶解完全, 加入配液量 0.05 % 的活性炭, 加热 10 ~ 30 分钟左右, 放冷, 过滤脱炭; 将环磷腺苷的盐的水合 物 (以环磷腺苷计) 4.01g用新鲜的注射用水溶解完全后, 与上述滤液混合均 匀, 加盐酸 L-半胱氨酸 lg, EDTA二钠 0.2g, 用 1M乳酸溶液调节 pH值在 5.2 ~
7.5的范围内, 加注射用水至 10000ml, 加配液量 0.01 ~ 0.5% ( W/V )的活性炭, 加热搅拌 10 ~ 30 分钟左右, 过滤脱炭,再经 0.22um微孔滤膜精滤或者采用截 留相对分子质量 6000 ~ 20000的超滤膜过滤, 经半成品化验, 待其含量、 pH值 和澄明度合格后, 灌封于 50ml或 100ml或 200ml的玻璃瓶中, 灭菌, 成品检查, 包装即得。 实施例 16 环磷腺苷的盐的水合物氯化钠输液的制备 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
将环磷腺苷的盐的水合物(以环磷腺苷计)(各环磷腺苷盐的水合物按相 应实施例方法制备) 4g、 氯化钠 85g、 焦亚疏酸钠 l.lg、 EDTA二钠 0.2g, 加入 注射用水中, 搅拌使溶解完全, 用 1M的枸橼酸和枸橼酸钠溶液调节 pH值在 4.0 ~ 7.5的范围内, 加注射用水至 10000ml, 加配液量 0.05 %的活性炭, 加热搅 拌 10 ~ 30 分钟左右, 过滤脱炭, 再经 0.22um微孔滤膜精滤或者采用截留相 对分子质量 6000 ~ 20000的超滤膜过滤, 经半成品化验, 待其含量、 pH值和澄 明度合格后, 灌封于 50ml或 100ml或 200ml 的玻璃瓶中, 灭菌, 成品检查, 包 装即得。 实施例 17. 环磷腺苷镁 8水合物或环磷腺苷 L-精氨酸 1水合物片剂的制 备( 250mg/片, 以环磷腺苷计) 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)
处方: 环磷腺苷镁 8水合物或环磷腺苷 L-精氨酸 1水合物 250g (以环 磷腺苷计 ) Prescription: Magnesium adenosine adenosine 8 hydrate or cyclic adenosine monophosphate L-arginine 1 hydrate 250g (based on cyclic adenosine)
微晶纤维素 200g 羧曱基淀粉钠 20g 阿斯巴甜 2g 聚乙烯吡咯烷酮 5 % 适量 硬脂酸镁 2g 将环磷腺苷镁 8水合物或环磷腺苷 L-精氨酸 1水合物、 微晶纤维素、 羧 曱基淀粉钠、 阿斯巴甜过 100目筛, 用 5 %的聚乙烯吡咯烷酮适量制软材, 过 18 - 24目筛制粒, 干燥, 过 14 - 20目筛整粒后, 加微粉硅胶、硬脂酸镁混合, 压片。
实施例 18 环磷腺苷盐的水合物胶嚢的制备 ( lOOmg/粒, 以环磷腺苷计) 处方: 环磷腺苷的盐水合物 100g (以环磷腺苷计 ) 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)
微晶纤维素 100g Microcrystalline cellulose 100g
乳糖 20g Lactose 20g
胶化淀粉 10 % 适量 Gelatinized starch 10%
硬脂酸镁 2g Magnesium stearate 2g
将本发明的环磷腺苷盐的水合物(各环磷腺苷盐的水合物按相应实施例方 法制备)、 微晶纤维素、 乳糖过 100目筛, 用 10 %的胶化淀粉适量制软材, 过 18 - 24目筛制粒, 干燥, 过 14 - 20目筛整粒后, 加硬脂酸镁混合, 灌装胶嚢。 实施例 19 环磷腺苷盐的水合物颗粒的制备 包括环磷腺苷钠 2水合物 或环磷腺苷镁 8水合物或环磷腺苷葡曱胺 1水合物或环磷腺苷 L-精氨酸 1水 合物或环磷腺苷 L-赖氨酸 1水合物等颗粒( 50mg/包, 以环磷腺苷计) 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)
处方: 环磷腺苷盐的水合物 50g (以环磷腺苷计) Prescription: hydrate of cyclic adenosine monophosphate 50g (based on cyclic adenosine)
甘露醇 180g Mannitol 180g
蔗糖 20g Sucrose 20g
甜蜜素 2g Sodium cyclamate 2g
固体食用香精 lg Solid food flavor lg
聚乙烯吡咯烷酮 5 % 适量 Polyvinylpyrrolidone 5 %
将环磷腺苷盐的水合物 (环磷腺苷盐的水合物按相应实施例方法制备)、 甘露醇、 蔗糖、 甜蜜素、 食用香精过 100目筛, 用 5 %的聚乙烯吡咯烷酮适量 制软材,过 18 - 24目筛制粒, 60 °C以下干燥,过 14 - 20目筛整粒后,分包装。 实施例 20 本发明的环磷腺苷 的水合物的凝胶(环磷腺苷盐的水合物 按相应实施例方法制备 ) 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)
处方: 环磷腺苷盐的水合物 25g (以环磷腺苷计, 投料) Prescription: hydrate of cyclic adenosine salt 25g (based on cyclic adenosine, feed)
聚乙二醇 6000 50g Polyethylene glycol 6000 50g
聚乙二醇 400 10g
甘油 5 ml Polyethylene glycol 400 10g Glycerin 5 ml
卡波姆 934 8g Carbomer 934 8g
卡波姆 1342 2g Carbomer 1342 2g
水 400-500ml Water 400-500ml
将分别将卡波姆 1342和卡波姆 934用水分散,加入甘油、聚乙二醇 6000、 聚乙二醇 400、 搅拌混合, 加环磷腺苷盐的水合物, 加热、 搅拌至匀、 用磷酸 氢二钠和磷酸二氢钠溶液调节 pH = 5.0 ~ 7.0左右, 分装即得。 可以理解, 很多细节的变化是可能的, 这并不因此限制本发明范围和精 神, 本发明并不限于上述实施例。
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
1、一种蛋白激酶激活剂,其特征在于,分子式为 [ cAMP ]mA.nH20, cAMP 为 C10H12N5O6P或 C10HuN5O6P, m=l或 2或 3 , n=0.88 ~ 8.5, A选自药学上 可接受的金属离子或有机碱的一种。 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.
2、 根据权利要求 1所述的蛋白激酶激活剂, 其特征在于: 所述有机碱选 自三乙胺、 二乙胺、 乙醇胺、 葡曱胺、 葡乙胺、 氨丁三醇, 哌嗪、 吗啉、 L- 赖氨酸、 D-赖氨酸、 DL-赖氨酸、 L-精氨酸、 D-精氨酸、 DL-精氨酸、 组氨酸、 鸟氨酸、 瓜氨酸中的一种。 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.
3、 根据权利要求 1所述的蛋白激酶激活剂, 其特征在于: 所述金属离子 选自锂、 钾、 钠、 钙、 镁、 辞、 铝或铋中的一种。 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.
4、 根据权利要求 1所述的蛋白激酶激活剂, 其特征在于, 其为环磷腺苷 L-精氨酸 1水合物或环磷腺苷 D-精氨酸 1水合物。 The protein kinase activator according to claim 1, which is a cyclic adenosine L-arginine monohydrate or a cyclic adenosine D-arginine monohydrate.
5、 根据权利要求 1所述的蛋白激酶激活剂, 其特征在于: 其为环磷腺苷 L-赖氨酸 1水合物或环磷腺苷 DL-赖氨酸 1水合物。 The protein kinase activator according to claim 1, which is a cyclic adenosine L-lysine monohydrate or a cyclic adenosine DL-lysine monohydrate.
6、 根据权利要求 1所述的蛋白激酶激活剂, 其特征在于: 其为环磷腺苷 葡曱胺 1水合物。 The protein kinase activator according to claim 1, which is a cyclic adenosine glucosamine 1 hydrate.
7、 根据权利要求 1所述的稳定的蛋白激酶激活剂, 其特征在于: 其为环 磷腺苷钠 2水合物或环磷腺苷钙 3.5水合物或环磷腺苷镁 8水合物。 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、 权利要求 1所述蛋白激酶激活剂的制备方法, 其特征在于: 选自如下 方法: 8. The method for preparing a protein kinase activator according to claim 1, which is characterized by the following method:
方法 A. 将水和环磷腺苷混合, 按反应的摩尔比加药学上可接受的有机碱 或金属的氧化物或氢氧化物或其金属盐或其溶液, 搅拌, 待反应完毕, 过滤, 緩慢加入 C3-C6的氏级酮, 或 C1-C6 氏分子醇, C2-C6的氏级醚的一种或几 种, 冷却, 过滤, 固体物用有机溶剂 C1-C6的低分子醇, C3-C6的低级酮, C2-C6的低级醚、 或水中一种或几种润洗, 过滤, 干燥, 得到环磷腺苷盐的水 合物; 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;
或者方法 B. 将金属的氧化物或氢氧化物或其金属盐或有机碱的溶液按反 应的摩尔比投入到含有环磷腺苷和水的反应容器中, 搅拌, 控制温度 0 ~ 50°C 之间, 搅拌, 待反应完毕, 活性炭脱色, 一次或多次过滤, 将其冷冻到 - 70 ~ -30 °C , 真空干燥, 得有环磷腺苷盐的水合物; 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;
或者方法 C. 将分别将金属的氧化物或氢氧化物或其金属盐或有机碱的一 种或其溶液按反应的摩尔比加入含有环磷腺苷和水的反应容器中,搅拌,控制 温度 -5 ~ 40°C之间, 反应 0.5 ~ 24h, 待反应完毕, 活性炭脱色, 一次或多次过 滤, 喷雾干燥, 得环磷腺苷盐的水合物。 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、以权利要求 1所述蛋白激酶激活剂为活性成分的注射用冻干粉针制剂、 或者无菌分装粉针制剂、 或者小水针注射剂、 或者大输液制剂、 固体制剂, 包 括片剂、 胶嚢、 颗粒剂, 经皮肤外用制剂包括软膏、 凝胶剂。 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、权利要求 1所述的蛋白激酶激活剂在制备适用于下列引起人和哺乳动 物疾病, 包括心绞痛、 心力衰竭、 心肌梗死、 心肌炎、 心律失常及心源性休克, 改善风湿性心脏病的心悸、 气急、 胸闷等症状、 急性白血病、 神经系统疾病、 呼吸系统疾病、老年慢性支气管炎、肝炎和银屑病等的治疗或预防的药物中的 应用。 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.
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