[go: up one dir, main page]

WO2011085701A1 - Activateurs stables de protéine kinases, leurs procédés de préparation et utilisations - Google Patents

Activateurs stables de protéine kinases, leurs procédés de préparation et utilisations Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
cyclic adenosine
hydrate
salt
adenosine
protein kinase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2011/070355
Other languages
English (en)
Chinese (zh)
Inventor
刘力
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UnitedHealth Beijing Pharmaceutical Technology Co Ltd
Original Assignee
UnitedHealth Beijing Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by UnitedHealth Beijing Pharmaceutical Technology Co Ltd filed Critical UnitedHealth Beijing Pharmaceutical Technology Co Ltd
Publication of WO2011085701A1 publication Critical patent/WO2011085701A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • 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
    • 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
    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des activateurs de protéine kinases, des hydrates de sel cyclophosphate d'adénosine, leurs procédés de préparation et utilisations. Les hydrates de sel cyclophosphate d'adénosine ont une excellente stabilité au stockage et ne sont pas susceptibles d'absorber l'humidité. En outre, les hydrates de sel cyclophosphate d'adénosine sont utiles pour traiter ou prévenir des maladies telles que la sténocardie, l'insuffisance cardiaque, l'infarctus du myocarde, la myocardite, l'arythmie, le choc cardiogène, la leucémie aiguë, les maladies du système nerveux, les maladies du système respiratoire, la bronchite chronique sénile, l'hépatite et le psoriasis, et pour améliorer les symptômes de la cardiopalmie, de la dyspnée, de la détresse pulmonaire et des maladies du type cardiopathie rhumatismale.
PCT/CN2011/070355 2010-01-18 2011-01-18 Activateurs stables de protéine kinases, leurs procédés de préparation et utilisations Ceased WO2011085701A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010029032.6 2010-01-18
CN201010029032A CN101781348A (zh) 2010-01-18 2010-01-18 稳定的蛋白激酶激活剂及其制备方法和用途

Publications (1)

Publication Number Publication Date
WO2011085701A1 true WO2011085701A1 (fr) 2011-07-21

Family

ID=42521510

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2011/070355 Ceased WO2011085701A1 (fr) 2010-01-18 2011-01-18 Activateurs stables de protéine kinases, leurs procédés de préparation et utilisations

Country Status (2)

Country Link
CN (2) CN101781348A (fr)
WO (1) WO2011085701A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101781348A (zh) * 2010-01-18 2010-07-21 刘力 稳定的蛋白激酶激活剂及其制备方法和用途
CN102989034B (zh) * 2011-09-10 2016-01-20 温州医学院 一种应用于神经吻合术的水凝胶及其制备方法
CN105147569B (zh) * 2015-10-16 2018-01-19 广州丽彦妆生物科技有限公司 一种用于化妆品的抗氧化组合物及温敏型凝胶
CN106565796A (zh) * 2016-11-04 2017-04-19 南京工业大学 一种环磷酸腺苷钠盐溶剂化物的晶体及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1579413A (zh) * 2004-02-11 2005-02-16 江卫世 注射用环磷腺苷葡胺及其制备工艺
CN1931180A (zh) * 2006-05-25 2007-03-21 武汉安士医药科技有限公司 具有不同性状的药物及其制备和用途
CN101172112A (zh) * 2007-05-25 2008-05-07 武汉安士医药科技有限公司 具有独特性质的化合物、含有该化合物的组合物及其制备方法和用途
CN101781348A (zh) * 2010-01-18 2010-07-21 刘力 稳定的蛋白激酶激活剂及其制备方法和用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2236442A1 (de) * 1972-07-25 1974-02-14 Max Planck Gesellschaft Neue substituierte adenosincyclophosphate
JPH09116096A (ja) * 1995-10-16 1997-05-02 Rohm Co Ltd 半導体集積回路
CN100425620C (zh) * 2006-11-09 2008-10-15 常月梅 一种从枣中提取环磷酸腺苷的工艺

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1579413A (zh) * 2004-02-11 2005-02-16 江卫世 注射用环磷腺苷葡胺及其制备工艺
CN1931180A (zh) * 2006-05-25 2007-03-21 武汉安士医药科技有限公司 具有不同性状的药物及其制备和用途
CN101172112A (zh) * 2007-05-25 2008-05-07 武汉安士医药科技有限公司 具有独特性质的化合物、含有该化合物的组合物及其制备方法和用途
CN101781348A (zh) * 2010-01-18 2010-07-21 刘力 稳定的蛋白激酶激活剂及其制备方法和用途

Also Published As

Publication number Publication date
CN102250179B (zh) 2014-10-01
CN102250179A (zh) 2011-11-23
CN101781348A (zh) 2010-07-21

Similar Documents

Publication Publication Date Title
ES2908332T3 (es) Forma cristalina de cloruro de ribosilnicotinamida
ES2791524T3 (es) Fenilacetato de L-ornitina y métodos de elaboración del mismo
ES3015371T3 (en) Solid forms and combination compositions comprising a beta-lactamase inhibitor and uses thereof
JPS5838421B2 (ja) 分岐鎖状ケト酸のオルニチン及びアルギニン塩並びに肝臓及び腎臓障害の治療への使用
KR101626506B1 (ko) 에리트로마이신염의 수화물, 그의 제조방법 및 용도
US20090281047A1 (en) Compositions And Methods For Immunotherapy
WO2009021404A1 (fr) Hydrates d'acide (1s, 2s, 3s, 4r)-3-[(1s)-1-acétylamino-2-éthylbutyl]-4-guanidino-2-hydroxylcyclopentyl-1-carboxylique et leurs utilisations pharmaceutiques
EP2995308B1 (fr) Composition pharmaceutique antihypoxique et son application
CN106659711A (zh) 呈现长期稳定性的褪黑素注射剂的持久制剂
US20230321127A1 (en) Sperm motility improving agent and sperm motility improving method
WO2011085701A1 (fr) Activateurs stables de protéine kinases, leurs procédés de préparation et utilisations
JP2008523090A (ja) 新生児肺高血圧症の治療のための方法および組成物
CN101347412B (zh) 三水合氨磷汀结晶冻干制剂及其制备方法
PT96447B (pt) Processo para a preparacao de um hemi-hidrato de um derivado de tetra-hidroimidazo-piridina
WO2007143895A1 (fr) Solution supersaturée de chlorhydrate de gemcitabine et son procédé de préparation
CN106032377A (zh) 四氮唑类urat1抑制剂、制备方法及其在高尿酸血症和痛风治疗上的用途
WO2019144484A1 (fr) Forme cristalline d'un monohydrate de s-nitrosocaptopril et son procédé de préparation
CN106806382B (zh) 抗癌组合物
ES2786774B2 (es) Composición para compuesto de coenzima NADH, preparación y aplicación del mismo.
US20160113955A1 (en) Compositions And Methods For Immunotherapy
CN102442918B (zh) 稳定的左卡尼汀化合物
JP2016520538A (ja) 鉄欠乏症および鉄欠乏性貧血の治療および予防のためのＦｅ（ＩＩＩ）錯体
US7572832B2 (en) Non-hygroscopic L-carnitine salts
CN103012421B (zh) 异喹啉类药物及其制备和用途
JP2020147507A (ja) シトリン欠損症治療剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11732691

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11732691

Country of ref document: EP

Kind code of ref document: A1