CN101172112A - Compound with special property, composition containing the compound, preparing method and uses of the same - Google Patents

Compound with special property, composition containing the compound, preparing method and uses of the same Download PDF

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Publication number
CN101172112A
CN101172112A CNA2007101080889A CN200710108088A CN101172112A CN 101172112 A CN101172112 A CN 101172112A CN A2007101080889 A CNA2007101080889 A CN A2007101080889A CN 200710108088 A CN200710108088 A CN 200710108088A CN 101172112 A CN101172112 A CN 101172112A
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China
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ate
anhydride
dibutyryladenosine cyclophosph
calcium dibutyryladenosine
hydrate
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刘力
陈祺
吴志刚
戴静
刘珍
李玲
杨晓燕
张力
曾繁典
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CHEN QI
Liu Li
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WUHAN ANSHI MEDICAL TECHNOLOGY Co Ltd
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Abstract

The invention relates to compound with special property and composition including the compound as well as the preparation method and the purpose thereof, and provides erdingxianhuanlinxiangangai hydrated matter with special property or anhydride, and medicine composition including the compound, as well as the preparation method and the purpose thereof. The molecular formula of the compound and the composition is C18H 23N5O8P*1/2Ca*nH2O, n is equal to 0 to 2.5, and is white to light yellow powder, which is slightly soluble in water at the room temperature, and almost insoluble in ethanol. The compound and the composition have the advantages of predominant storage stability and are protein kinase activator, the compound and the composition are mainly used for remedying the blood vessel disease and also can be used for adjusting the growth development of a mammalian animal.

Description

Have peculiar property chemical compound, contain this compound compositions and its production and use
Technical field
The present invention relates to have medicinal compound or its hydrate of peculiar property, be specifically related to Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydride, also relate to the pharmaceutical composition that contains this chemical compound, and its production and use.
Background technology
The Calcium Dibutyryladenosine Cyclophosph-ate that China national drug standard [WS-10001-(HD-0786)-2002] is legal be the hydrate of 2.3 water of crystallization of Calcium Dibutyryladenosine Cyclophosph-ate.It is easily molten in water or ethanol, and is almost insoluble in ether; The scope of loss on drying is 7.0～15.0%; Theoretical water is divided into 7.82%.The description of the product of producing according to this standard [WS-10001-(HD-0786)-2002] is reported as Calcium Dibutyryladenosine Cyclophosph-ate 2.3 hydrates, and this product meets the existing national drug standards [WS-10001-(HD～0786)-2002].
The Chinese patent publication number is the hydrate that the existence form of the Calcium Dibutyryladenosine Cyclophosph-ate described in the description of CN1554358A is 2.3 water of crystallization of Calcium Dibutyryladenosine Cyclophosph-ate; this hydrate dissolves in water or ethanol; water intaking compound 0.1g; after adding water 10ml dissolving; measure in accordance with the law; pH value is 3.0～5.0; this explanation is before the present invention finishes; for a long time, it is believed that water-soluble and ethanol, pH value 3.0～5.0, the hydrate that contains the Calcium Dibutyryladenosine Cyclophosph-ate of 2.3 water of crystallization is the form of the stable existence of Calcium Dibutyryladenosine Cyclophosph-ate.
The acidity scope that bibliographical information contains the national standard [WS-10001-(HD-0786)-2002] of the Calcium Dibutyryladenosine Cyclophosph-ate of 2.3 water of crystallization is 3.0～5.0; up to the present, still do not have disclosed bibliographical information and above-mentioned report different in kind, Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride of pH value between 5.0～7.2.
Summary of the invention
Surprisingly, we contain the Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride [C of 0～2.5 water by discovering 18H 23N 5O 8P1/2CanH 2O (n=0～2.5)] have the character with the Calcium Dibutyryladenosine Cyclophosph-ate fundamental difference that contains 2.3 water of crystallization of existing bibliographical information.The first, Calcium Dibutyryladenosine Cyclophosph-ate hydrate of the present invention and anhydride at room temperature be slightly molten or be slightly soluble in water, the second, and Calcium Dibutyryladenosine Cyclophosph-ate hydrate of the present invention and anhydride are at room temperature almost insoluble in ethanol; The 3rd, the pH value scope and the latter of Calcium Dibutyryladenosine Cyclophosph-ate hydrate of the present invention and anhydride have notable difference; The 4th, Calcium Dibutyryladenosine Cyclophosph-ate hydrate of the present invention and anhydride have better stability than Calcium Dibutyryladenosine Cyclophosph-ate 2.3 hydrates of existing bibliographical information.
Therefore, on the one hand, the invention provides Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydride with peculiar property:
Figure A20071010808800051
The present invention has the Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride of peculiar property and measures by the Ka Shi method, and its moisture is in 8.45%.
The acidity scope of the national standard of the Calcium Dibutyryladenosine Cyclophosph-ate that contains 2.3 water of crystallization that existing document is openly reported [WS～10001～(HD～0786)～2002] is 3.0～5.0; the acidity scope that has the Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride of peculiar property for the present invention; under the room temperature; getting 0.1g is dissolved in newly to boil and puts cold distilled water 20～25ml; its pH value also is different from the raw material of Calcium Dibutyryladenosine Cyclophosph-ate 2.3 hydrates of the pH value described in the Chinese patent CN1554358A description between 3.0～5.0 fully between 5.0～7.2.
Chemical compound with peculiar property is Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride C 18H 23N 5O 8P1/2CanH 2O (n=0～2.5) has the spy smelly, and hygroscopicity is arranged; Chemical compound with peculiar property is that Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride can be C 18H 23N 5O 8P1/2CanH 2O (n=0～2), the chemical compound with peculiar property can be C for the Calcium Dibutyryladenosine Cyclophosph-ate hydrate 18H 23N 5O 8P1/2Ca2.3H 2O, the chemical compound with peculiar property are that Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride can be C 18H 23N 5O 8P1/2CanH 2O (n=0～1.5), the chemical compound with peculiar property can be C for the Calcium Dibutyryladenosine Cyclophosph-ate hydrate 18H 23N 5O 8P1/2Ca1.9H 2O, the chemical compound with peculiar property are that the Calcium Dibutyryladenosine Cyclophosph-ate hydrate also can be C 18H 23N 5O 8P1/2Ca1.5H 2O, easily moisture absorption has special smelly; Chemical compound with peculiar property is that Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride also can be C 18H 23N 5O 8P1/2CanH 2O (n=0～1), the chemical compound with peculiar property can be C for the Calcium Dibutyryladenosine Cyclophosph-ate hydrate 18H 23N 5O 8P1/2CaH 2O, the easy moisture absorption of this hydrate; Chemical compound with peculiar property can be C for the Calcium Dibutyryladenosine Cyclophosph-ate hydrate 18H 23N 5O 8P1/2Ca0.5H 2O, the easy moisture absorption of this hydrate has special smelly; Chemical compound with peculiar property is Calcium Dibutyryladenosine Cyclophosph-ate anhydride C 18H 23N 5O 8P1/2Ca, this anhydride have special smelly, easily moisture absorption.
Moisture with the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property or anhydride is in 8.45%; Moisture with the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property or anhydride can be in 6.99%; Moisture with the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property or anhydride also can be in 5.0%; Further, the moisture with the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property or anhydride can be in 3.0%, and further, the moisture with the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property or anhydride can be in 2.0%.
On the other hand, provide preparation the present invention to have the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property and the method for anhydride.Can prepare Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride that the present invention has peculiar property by the following method:
A, in exsiccant three-neck flask, add cAMP triethylamine salt, anhydrous pyridine, heavily steam butanoic anhydride, chloroform, 20～70 ℃ are constantly stirred, sponge are all dissolved, reaction finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, concentrating under reduced pressure pulp thing is dibutyryl cyclic adenosine monophosphate then; Get dibutyryl cyclic adenosine monophosphate slurry dissolve with ethanol, join in the ethanol or dehydrated alcohol and aqueous acetone solution of an amount of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether or acetone rinse; drain, add dehydrated alcohol or dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature; place; filter, solids absolute ether rinse is drained; in the presence of phosphorus pentoxide, 5～80 ℃ of drying under reduced pressure get off-white powder to pale yellow powder.Perhaps
B, in exsiccant three-neck flask, add cAMP triethylamine salt, anhydrous pyridine, heavily steam butanoic anhydride, chloroform, 20～70 ℃ are constantly stirred, and sponge is all dissolved, and reaction finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, extract with hexone, abandon organic layer, concentrating under reduced pressure pulp thing is used chloroform extraction then, is dibutyryl cyclic adenosine monophosphate; Get dibutyryl cyclic adenosine monophosphate slurry dissolve with ethanol, add in the ethanol or dehydrated alcohol and aqueous acetone solution of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether or purifying acetone rinse; drain; add dehydrated alcohol or dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature, place; filter; solids absolute ether rinse is drained, 5～80 ℃ of dry finished products that get.
On the one hand, the invention provides a kind of pharmaceutical composition again, it contains Calcium Dibutyryladenosine Cyclophosph-ate hydrate or the anhydride that the present invention has peculiar property, and pharmaceutically acceptable excipient or carrier.
Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride with peculiar property of the present invention is used to prepare injection freeze-dried powder, aseptic subpackaged powder injection formulation.The preparation method of freeze-dried powder is: get Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydride raw material (by anhydride); add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, add injection and blunge and make dissolving, pharmaceutically acceptable acid-alkali accommodation pH is 5.0～7.5; add activated carbon 0.01～0.5% (W/V) and stir 15～45min; filter, moisturizing is with 0.22 micron filtering with microporous membrane; by 10mg/ bottle～80mg/ bottle (in principal agent) packing; lyophilization, tamponade gets finished product.
Chemical compound Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride with peculiar property of the present invention prepares injection freeze-dried powder, aseptic subpackaged powder injection formulation; (10～80mg) are dissolved in 10～15ml water the preparation of a unit dose, and its pH value is between 5～7.5.
Have the chemical compound Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property and injection freeze-dried powder, the aseptic subpackaged powder injection formulation of anhydride preparation, its moisture is in 5.0%.
On the one hand, Calcium Dibutyryladenosine Cyclophosph-ate hydrate or the anhydride with peculiar property of the present invention can be used as protein kinase activator again; Be used for the treatment of pulmonary heart disease, heart failure, ischemic cardiomyopathy, angina pectoris, coronary heart disease, myocardial infarction, cardiogenic shock, arrhythmia; Be used for the treatment of diseases such as bradyarrhythmia, tachy-arrhythmia, heart failure, myocarditis, psoriasis, rheumatic heart disease, leukemia with bradyarrhythmia; Be used for the treatment of cerebral ischemia, cerebral infarction, cerebral thrombosis and sequela thereof; Be used to improve anestheticing period surgical patient myocardial ischemia, improve cardiac function, reduce muscle relaxant, reduce operation risk cardiovascular side effect; Be used for the reparation of senile chronic bronchitis, various hepatitis auxiliary treatment and damaging cells; And the purposes of medicine that is used for regulating the growth promoter of mammal.
The specific embodiment
Characteristic according to 2005 editions regulations of Chinese Pharmacopoeia medicine dissolution; Calcium Dibutyryladenosine Cyclophosph-ate hydrate of the present invention and anhydride at room temperature are slightly molten or are slightly soluble in water; almost insoluble in ethanol; the raw material that is different from Calcium Dibutyryladenosine Cyclophosph-ate 2.3 hydrates described in the Chinese patent CN1554358A description fully, dissolved physicochemical property in water or ethanol.
Derive from sample of the present invention, its pH value can be 5.1,5.2,5.3,5.5,5.6,5.8,5.9,6.0, also can be 6.1,6.2,6.4,6.5,6.6,6.8,7.0, and its pH value scope is between 5.0～7.2.
Raw material [C of the present invention 18H 23N 5O 8P1/2CanH 2O (n=0～2.5)] { promptly meet existing national drug standards sample [WS～10001～(HD～0786)～2002] } with the raw material water-soluble, the Calcium Dibutyryladenosine Cyclophosph-ate that contains 2.3 water of crystallization of pH value between 3.0～5.0 of bibliographical information and compare, more can stable storage.Respectively above-mentioned sample is sealed in the cillin bottle, carries out influence factor's test, the results are shown in Table 1.
Influence factor's result of the test of table 1. raw material
Figure A20071010808800081
* this sample vacuum drying to moisture is 5.81%, and it is 1.95% to moisture that * * will meet existing national drug standards sample vacuum drying, * * * with sample of the present invention spray water to moisture be 8.12%.
We carry out influence factor's test with different raw materials, detect the situation of change of related substance with HPLC method (potassium dihydrogen phosphate-acetonitrile of 0.05mol/L (75: 25) is a mobile phase, and the detection wavelength is 273nm).The result shows, of the present invention have a raw material that the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property and absolute value that anhydride purity descends are starkly lower than the national standard between pH=3.0～5.0.Therefore, illustrate that the raw material with character of the present invention has outstanding storage stability.
Raw material with character of the present invention is made freeze-dried powder by the mode of embodiment, unexpectedly finds, and the preparation of pH value between 5.0～7.5, the preparation of pH value between 3.0～5.0 than national drug standards regulation has better stability.
Chemical compound with peculiar property can be C for the Calcium Dibutyryladenosine Cyclophosph-ate hydrate 18H 23N 5O 8P1/2CaH 2O, the easy moisture absorption of this hydrate; Chemical compound with peculiar property can be C for the Calcium Dibutyryladenosine Cyclophosph-ate hydrate 18H 23N 5O 8P1/2Ca0.5H 2O, the easy moisture absorption of this hydrate has special smelly; This chemical compound is at room temperature placed 2 ~ 48h in the different air of moist degree, its hygroscopic moisture can arrive 4%, 5%, 8%, 9%, even reaches 12%.But the character of this chemical compound is at room temperature still slightly molten or be slightly soluble in water, and is almost insoluble in ethanol, and the acidity scope under the room temperature, is got 0.1g and is dissolved in newly to boil and puts cold distilled water 20～25ml, and its pH value is between 5.0～7.2.
Chemical compound with peculiar property is Calcium Dibutyryladenosine Cyclophosph-ate anhydride C 18H 23N 5O 8P1/2Ca, this anhydride can be amorphous, has the spy smelly, easily moisture absorption, according to the Chinese Pharmacopoeia regulation, the chemical compound that does not contain water of crystallization is not definitely anhydrous, and this chemical compound carries out determination of water by the Ka Shi method, and its moisture is generally in 1.5%; This chemical compound is at room temperature placed 1 ~ 48h in the different air of moist degree, its hygroscopic moisture can arrive 2%, 3%, 4%, 5%, 8%, 9%, even reach 12%, but the character of this chemical compound is at room temperature still slightly molten or be slightly soluble in water, almost insoluble in ethanol, the acidity scope is under the room temperature, get 0.1g and be dissolved in newly to boil and put cold distilled water 20～25ml, its pH value is between 5.0～7.2.
According to the present invention, pharmaceutically acceptable excipient can be dextran, mannitol, glucose, sorbitol, sucrose, lactose, lactose monohydrate, lactose, trehalose, maltose, xylose, xylitol, glucide, magnesium chloride, sodium chloride, sodium sulfate, sodium succinate, sodium hydrogen phosphate, sodium dihydrogen phosphate, gluconic acid and salt, glucuronic acid and salt, Lactobionate, polyvinylpyrrolidone, cetomacrogol 1000-4000, nicotiamide, glycine, lysine, arginine, methionine, glutamic acid, histidine, histidine etc. and salt thereof, cholate, glycyrrhizic acid, glycyrrhetate, meglumine or its salt, water for injection, gelatin hydrolysate, soluble starch, soluble cellulose class material, cyclodextrin or cyclodextrin derivative can contain wherein one or more.
One or more in the preferred mannitol of excipient, xylitol, sorbitol, meglumine, lysine hydrochloride, hydrochloric acid L-arginine, the water for injection etc. wherein.
Its pharmaceutically acceptable pH regulator agent can be pharmaceutically acceptable mineral acid or organic acid, inorganic base or organic base, also can be generalized lewis acid or alkali, can contain one or several, can be hydrochloric acid, sulphuric acid, acetic acid and acetate, lactic acid, the lactic acid pharmaceutical salts, sodium lactate, citric acid, citrate, sodium citrate, sodium carbonate, sodium bicarbonate, sodium hydroxide, succinic acid, the trihydroxy aminomethane, triethanolamine, N-methyl Fructus Vitis viniferae amine, and their salt, multi-hydroxy carboxy acid and salt, glucuronic acid, gluconic acid, glycine, lysine, arginine, methionine waits in aminoacid and the amino acid salts etc. one or several.
When preparation injection freeze-dried powder, can add pharmaceutically acceptable antioxidant and stabilizing agent can be sulfurous acid, sulphite, bisulfites, pyrosulfite, dithionite, thiosulfate, organosulfur compound thiourea, glutathion, TGA and salt, phenol compound, as gallic acid and salt, glycine, cysteine, methionine, aminoacid with and salt, one or several in citrate, EDTA and EDTA disodium, EDTA four sodium, the calcium disodium edetate etc.
Because Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride (DBCAC) with peculiar property of the present invention is the derivant of human body " second message,second messenger " adenosine cyclophosphate; be hydrolyzed into adenosine cyclophosphate cAMP by the phosphodiesterase in the cell in the cell; simultaneously activated protein kinase A and Protein kinase C; protein kinase is a kind of allosteric enzyme; be made up of two catalytic subunits and two adjusting subunits, catalytic subunit has the phosphorylation of catalytic proteins (or enzyme).Adenosine cyclophosphate is a protein kinase activator, is a kind of important substance with physiologically active that extensively exists in human body, can regulate the multiple functional activity of cell.The 2nd courier as hormone, performance hormonal regulation physiological function and substance metabolism effect in cell, can change function of plasma membrane, impel the calcium ion in the net agonistic muscle slurry matter to enter muscle fiber, thereby enhancing myocardial contraction, and can promote the oxidasic activity of respiratory chain, and change myocardial ischemia, alleviate coronary heart disease symptom and improve electrocardiogram.
Calcium Dibutyryladenosine Cyclophosph-ate is by biochemical metabolism phosphorylation reaction and tricarboxylic acid cycle the most basic in the catalysis human body; it is active that most protein and enzyme are produced; the various reactions of human activin; produce a large amount of ATP simultaneously; improve cellular metabolism and energy metabolism; suppress free-radical generating; reduce biologically active pdgf; reduce thrombosis; microcirculation improvement, the blood vessel dilating smooth muscle reduces the heart contraction afterload; coronary artery dilating improves the myocardial cell of myocardial cell metabolism and protection ischemia; improve heart sinuatrial node P cell function arrhythmia, increase myocardial contraction, improve cardiac output; reduce particularly filling pressure of ventricular chamber, reduce coronary heart disease patients with heart failure blood plasma brain natriuretic peptide concentration.In addition, sugar, lipid metabolism, nucleic acid, proteinic synthetic adjusting etc. are played an important role.Partial action is measured as follows:
1, the Calcium Dibutyryladenosine Cyclophosph-ate with peculiar property is measured the influence of ischemical reperfusion injury myocardial cell vigor
After the separation and purification of newborn SD rats neonatal rat myocardial cell, be culture medium reference literature (Journal of physiology 1995,47:357 with DMEM; J Mol Cell Cardiol, 1995; 27:453-8) carry out cell culture; and the Calcium Dibutyryladenosine Cyclophosph-ate anhydride carried out pretreatment with the positive contrast of diltiazem (DIL) to myocardial cell, repel test by trypan blue and carry out DBCAC the influence of ischemical reperfusion injury myocardial cell vigor is measured.The results are shown in Table 2.
Table 2 DBCAC repels test to the trypan blue of cardiac muscle cells effect of vigor
Figure A20071010808800101
The result shows; after anoxia 60min, 120min reach oxygen supply 30min, 60min again; the model group cell survival rate; be starkly lower than the preceding normal cell of anoxia; the cell survival rate of each administration group is significantly higher than model group; the cell survival rate of high dose DBCAC group is significantly higher than the DIL group, shows that the protective effect to myocardial cell has concentration dependent.
2, to the effect of rabbit sinus bradycardia
20 of rabbit, male and female are regardless of, and body weight 2.09 ± 0.32kg is divided into 2 groups at random, and intravenous injection gives normal saline 1mlkg respectively -1, with Calcium Dibutyryladenosine Cyclophosph-ate (DBCAC) the anhydride 2.2mgkg of physiological saline solution -13% pentobarbital sodium 40mgkg -1After the anesthesia, dorsal position is fixed on the operating-table.The auricular vein drug administration by injection, about 7min after, constant speed intravenous injection 0.25% verapamil, 1mgmin -1(0.4mlmin -1), the atrioventricular block of II degree appears in record, the time (min) of III degree atrioventricular block, calculates corresponding dosage (mgkg -1).
Table 3 Calcium Dibutyryladenosine Cyclophosph-ate (DBCAC) anhydride is to the effect of rabbit sinus bradycardia
Figure A20071010808800111
The result shows that DBCAC of the present invention can obviously prolong II, III degree atrioventricular block time, its residence time and retardance dosage and normal saline group evident difference, and two groups are compared P＜0.01.
3, calcium chloride is brought out the effect of rat ventricular
30 of SD rats, male and female are regardless of, and body weight 215 ± 18g is divided into 3 groups at random, and intravenous injection gives normal saline, Calcium Dibutyryladenosine Cyclophosph-ate (DBCAC) anhydride (physiological saline solution) 12.4mgkg respectively -13% pentobarbital sodium 40mgkg -1After the anesthesia, dorsal position is fixed on the operating-table.The sublingual vein drug administration by injection, about 6min after, quick intravenous injection (having pushed away in the 5s) 2.5% calcium chloride 100mgkg -1(0.4ml/100g), quiver (VF) and dead (CA) number of animals in the record chamber of appearance.
The result shows that the DBCAC group can obviously suppress calcium chloride and bring out rat VF (p＜0.05), and DBCAC group and quinidine group can obviously suppress the rat ventricular death that calcium chloride causes.DBCAC group the prevention rat because severe arrhythmia and effect in the death has the trend that is better than the quinidine group due to the calcium chloride.See Table 4.
Table 4 Calcium Dibutyryladenosine Cyclophosph-ate (DBCAC) anhydride brings out the ARR effect of rat to calcium chloride
4, aconitine is brought out the effect of rat ventricular
20 of SD rats, male and female are regardless of, and body weight 179 ± 17g is divided into 2 groups at random, and intravenous injection gives normal saline, DBCAC (physiological saline solution) 12.4mgkg respectively -13% pentobarbital sodium 40mgkg -1After the anesthesia, dorsal position is fixed on the operating-table.The sublingual vein drug administration by injection, behind the 6min, constant speed intravenous injection 0.0025% aconitine, 2 μ gmin -1(0.08mlmin -1), the record chamber of appearance early (VP), chamber speed (VT), quiver (VF) in the chamber and the time of dead (CA), calculates corresponding dosage.
The result shows that the DBCAC group can significantly increase the consumption that aconitine causes rat VP, VT, VF and CA.See Table 5.
Table 5 Calcium Dibutyryladenosine Cyclophosph-ate (DBCAC) anhydride to aconitine bring out the ARR effect of rat ( N=10)
Figure A20071010808800122
The DBCAC group is compared (t check) with the normal saline group: p＜0.05
The clinical practice of object of the present invention
Chronic pulmonary heart disease: the Calcium Dibutyryladenosine Cyclophosph-ate with peculiar property of the present invention can promote the survival of myocardial cell; strengthen the anti-damage of myocardial cell, ischemia resisting and anoxia ability; strengthen phosphorylation; promote an excited contraction coupling; improve myocardial contraction, and expansible peripheral blood vessel, the cardiac ejection impedance reduced; load before and after alleviating heart, increase cardiac output.Simultaneously, bronchial smooth muscle also there is stronger dilating effect, pulmonary hypertension patient under the anaerobic condition is then shown lung blood vessel selectivity dilating effect, can increase the oxygen conveying capacity, help to improve blood oxygen concentration.
For 20 routine chronic pulmonary heart disease patients, on the conventional therapy basis, add with Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride 40～160mg/d intravenous drip, 7～14d is a course of treatment.90% patient cough, breathe heavily suppress, tachypnea, symptoms such as cyanosis, hepatomegaly, lower limbs edema obviously alleviate, pulmonary rale disappears or significantly reduces.Mean pulmonary arterial pressure obviously descends.
Chronic heart failure: Calcium Dibutyryladenosine Cyclophosph-ate is hydrolyzed into adenosine cyclophosphate cAMP by the phosphodiesterase in the cell in cell; adenosine cyclophosphate can be expanded peripheral blood vessel; reduce the cardiac ejection impedance; load before and after alleviating heart, increase the heart blood discharge amount, reduce myocardial oxygen consumption; the protection cardiac muscle; reduce coronary resistance, improve coronary circulation, increase oxygen-supplying amount.For 12 routine patients, add with the Calcium Dibutyryladenosine Cyclophosph-ate hydrate with peculiar property of the present invention and anhydride 40-80mg/ days intravenous drip, 14 days courses of treatment on the conventional therapy basis.The result: clinical symptom remissions such as patient's precordialgia of 95%, paroxysm at night dyspnea, electrocardio diagram ST-T ischemia type changes to be eliminated or significantly improvement, LVED (Left Ventricular End Systolic Dimension), left ventricular ejection mark and cardiothoracic ratio all obviously improve.
The dilated cardiomyopathy heart failure: because cardiac damage is serious, the patient is insensitive to Radix Rehmanniae class medicine usually.
For 12 routine patients, add with the Calcium Dibutyryladenosine Cyclophosph-ate hydrate with peculiar property of the present invention and anhydride 40-80mg/ days intravenous drip, 7～14 days courses of treatment on the conventional therapy basis.The result: the patient's of treatment back 90% symptom, sign, cardiac function and LAD, LVSD, LVDD, LVEF all have clear improvement.
Of the present invention have the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property and a treatment that anhydride can be used for rheumatic heart disease, angina pectoris, myocardial infarction, arrhythmia, myocarditis, cardiogenic shock etc.: Calcium Dibutyryladenosine Cyclophosph-ate is hydrolyzed into adenosine cyclophosphate by the phosphodiesterase in the cell in cell; cAMP can make the ATP-Ca on the cell membrane as the second message,second messenger 2+Ca in the complex 2+Discharge, the oxidasic activation of the respiratory chain of promotion is arranged, improve the effect of myocardial ischemia, so can be used for coronary heart disease, myocarditis, rheumatic heart disease, arrhythmia patient's treatment.To the angina pectoris that coronary heart disease causes, symptom such as uncomfortable in chest has the effect of alleviation.Trypan blue repels test and shows that the Calcium Dibutyryladenosine Cyclophosph-ate anhydride with peculiar property of the present invention has protective effect to the ischemical reperfusion injury myocardial cell, can be used for the treatment of coronary heart disease, angina pectoris etc.During intravenous injection, can be used for the rescue of acute myocardial infarction, not only can help it to leave on pass rapidly, and can shorten the period of convalescence, make the state of an illness stable early.The blood vessel dilating of its effect basis and cAMP, particularly the coronary artery dilator effect is relevant.
Reduce the anestheticing period operation risk: Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride with peculiar property of the present invention is hydrolyzed into adenosine cyclophosphate by the phosphodiesterase in the cell in cell; cAMP can improve anestheticing period surgical patient myocardial ischemia; improve cardiac function; simultaneously can reduce muscle relaxant to cardiovascular side effect; reduce operation risk, help patient's postoperative body recovery.
Oncotherapy: Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride with peculiar property of the present invention is hydrolyzed into adenosine cyclophosphate by the phosphodiesterase in the cell in cell; adenosine cyclophosphate has the effect of obvious body leukocyte increasing, can be used for the treatment of acute leukemia and can resist the leukopenia that radiotherapy causes.Can improve curative effect to acute leukemia in conjunction with chemotherapy, also can be used for the inducer remission of acute leukemia.Because of the cAMP in the tumor tissues all lacks than normal structure, behind the application Calcium Dibutyryladenosine Cyclophosph-ate cAMP is increased, thereby suppress to worsen cell proliferation, tumor cell is transformed to normal aspect.In addition, the hepatic and renal function damage that chemicotherapy is caused can give nutritional support.
Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride with peculiar property of the present invention can be used for cerebral ischemia, cerebral infarction, cerebral thrombosis and sequela thereof: Calcium Dibutyryladenosine Cyclophosph-ate hydrate and the anhydride with peculiar property of the present invention is hydrolyzed into adenosine cyclophosphate by the phosphodiesterase in the cell in cell; adenosine cyclophosphate is by the effect of blood vessel dilating; blood circulation promoting; reduce thrombosis; suppress free-radical generating; prevent reperfusion injury, cerebral ischemia, cerebral infarction, cerebral thrombosis and sequela thereof are all had better curative effect.CAMP can also promote phosphide in the neurocyte simultaneously, nucleic acid and proteinic anabolism, regulate the biomembranous synthetic and reconstruction of neurocyte, and play trophic nerve, the activation neurocyte, promote the reparation and the regeneration of neurocyte, disturbance of consciousness, stupor, neural cell injury that cerebrovascular accident and cerebral trauma are caused have and promote restitution preferably.
Of the present invention have the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property and a reparation that anhydride can be used for damaging cells: Calcium Dibutyryladenosine Cyclophosph-ate is hydrolyzed into adenosine cyclophosphate by the phosphodiesterase in the cell in cell; adenosine cyclophosphate can promote the reparation of damaging cells, promotes wound healing.Major surgery patients such as various bone surgeries, craniocerebral operations, organ transplantation, adenosine cyclophosphate has obvious help rehabilitative action.And adenosine cyclophosphate has regeneration that effect is arranged to sensory nerve and nervus motorius, can apply to replantation of severed extremity.
Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride with peculiar property of the present invention can be used for treating psoriasis: Calcium Dibutyryladenosine Cyclophosph-ate is hydrolyzed into adenosine cyclophosphate by the phosphodiesterase in the cell in cell; increase the endogenous adenosine cyclophosphate effect that suppresses epidermis cell division and propagation is arranged; so Calcium Dibutyryladenosine Cyclophosph-ate can make patient's pruritus obviously alleviate or disappear; squama reduces or disappears, and the skin lesion attenuation flattens or recovers normal.
Calcium Dibutyryladenosine Cyclophosph-ate hydrate and anhydride with peculiar property of the present invention is hydrolyzed into adenosine cyclophosphate by the phosphodiesterase in the cell in cell; adenosine cyclophosphate energy diastole bronchial smooth muscle; stablize mast cell membrane, can treat various asthmas such as chronic bronchitis.
To hepatitis and patient with liver cirrhosis, can improve liver function by influencing the human body metabolism, and reduce hepatocyte injury, promote hepatocyte to repair.
Its indication has: be used for treatment of diseases such as pulmonary heart disease, chronic heart failure, ischemic cardiomyopathy, dilated cardiomyopathy heart failure, angina pectoris, coronary heart disease, myocardial infarction, myocarditis, cardiogenic shock, arrhythmia, psoriasis, rheumatic heart disease, leukemia, also be used for cerebral ischemia, cerebral infarction, cerebral thrombosis and sequela treatment thereof; Can be used for improving anestheticing period surgical patient myocardial ischemia, improve cardiac function, reduce muscle relaxant, reduce operation risk, and can be used for the reparation of senile chronic bronchitis, various hepatitis auxiliary treatment and damaging cells cardiovascular side effect.
The treatment of bradyarrhythmia is many at present with atropine or isoproterenol, perhaps pacing therapy.The former curative effect is relatively poor, and untoward reaction is more, and latter's price is more expensive.
Surprisingly, we find to have Calcium Dibutyryladenosine Cyclophosph-ate hydrate and antiarrhythmic drug with biphasic effect of anhydride of peculiar property, not only but also can treat bradyarrhythmia, again tachy-arrhythmia are had therapeutical effect.And atlansil, procaine hydrochloride, lidocaine hydrochloride, propafenone hydrochloride, mexiletine hydrochloride, beta-Blocking agent, calcium antagonist (as verapamil, diltiazem) etc. only have the effect of treatment tachy-arrhythmia, in fact, Folium Digitalis Purpureae, beta-Blocking agent, calcium antagonist (as verapamil, diltiazem), atlansil, I class antiarrhythmic drug can cause and increase the weight of bradyarrhythmia on the contrary as quinidine, procainamide, norpace (disopyramide), flecainide, encainide etc.
Heart failure (CHF) finally can take place in various organic heart diseasies, and heart failure is in case the application of just too busy to get away cardiac tonic takes place.For a long time, in most cases also relying on digitalis preparation, and digitalis preparation has negative chronotropic action, heart rate can make heart failure further increase the weight of too slowly.So to congestive heart failure companion bradycardia person, the application of digitalis preparation is subjected to certain restriction, the present invention provides new Therapeutic Method for the heart failure scorpion with the disease of bradyarrhythmia.
Its consumption usage: generally speaking, 10～160mg Calcium Dibutyryladenosine Cyclophosph-ate dissolves in the normal saline, does intramuscular injection, every day secondary; Or get preparation 10～160mg of the present invention (in Calcium Dibutyryladenosine Cyclophosph-ate) in 50～1000 milliliters of 5% glucose or normal saline, do intravenous drip, every day 1-2 time.
Of the present invention have the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property and an adjusting that anhydride also can be used for the growth promoter of mammal.Adenosine cyclophosphate is the second message,second messenger of multiple hormonal action, has Nutrition and Metabolism regulating action widely, is the important regulatory factor of growth of animal.External source cAMP has obvious facilitation to growth of animal, is a kind of regulant for animal's growth that the applications well prospect is arranged.Yet,, limited its application at the animal production field because cAMP can only use with injection.Calcium Dibutyryladenosine Cyclophosph-ate is the derivant of cAMP, has similar physiological function and mechanism of action to cAMP.Because it has lipotropy, can in cell, play a role by cell membrane, thereby can add by feedstuff and use, overcome the defective in the cAMP use.Calcium Dibutyryladenosine Cyclophosph-ate can significantly improve the grow-finish daily gain in pigs, and the material anharmonic ratio obviously reduces, and promotes protein synthesis, improves the speed of growth, promotes steatolysis, reduces the trunk lipidosis, improves trunk and forms.Dosage is that subcutaneous injection 1.0mg/kg and feedstuff add 20mg/kg preferably.
Embodiment 1 Calcium Dibutyryladenosine Cyclophosph-ate anhydride: in exsiccant three-neck flask, add adenosine cyclophosphate triethylamine salt 6.5g, anhydrous pyridine 8.5ml, heavily steam butanoic anhydride 33ml, chloroform 200ml, 20-70 ℃ is constantly stirred, sponge is all dissolved, reaction finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, concentrating under reduced pressure pulp thing is dibutyryl cyclic adenosine monophosphate then; Get dibutyryl cyclic adenosine monophosphate slurry dissolve with ethanol, join in the ethanol and aqueous acetone solution of an amount of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether and acetone rinse; drain, add dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature; place; filter, solids absolute ether rinse is drained; in the presence of phosphorus pentoxide, 50～80 ℃ of drying under reduced pressure got off-white powder in 72 hours.Have special smelly, slightly molten or be slightly soluble in water, almost insoluble in ethanol, fusing point: 291.5 ℃ (proofreading and correct), moisture (Ka Shi method): 0.79%, HPLC analyzes: the sample main peak is consistent with the retention time of the main peak of dibutyryl adenosine cyclophosphate sodium.Get 0.1g and be dissolved in distilled water 25ml, its pH value is 5.3.
Elementary analysis measured value: C 44.23%, H4.82%, N14.30%, P 6.3 1%, Ca4.06%;
Theoretical value: C 44.26%, H4.75%, N14.34%, P 6.34%, Ca4.10%;
IR(KBr)：3417cm -1v N-H，2965cm -1v C-H，，1749cm -1v C＝0，1705cm -1v C＝0，1610cm -1v C＝N，1588cm -1v C＝N，1464cm -1δ C-H，1252cm -1v P＝0，1024cm -1v P-O-C。
1H?NMR(D 2O，DMSO)：0.91δ(3H，t，C 1)，0.95δ(3H，t，C 18)，1.58δ(1H，m，C 2)，1.64δ(1H，m，C 17)，2.41δ(1H，m，C 3)，2.57δ(3H，t，C 16)，4.02δ(1H，m，C 13)，4.24δ(2H，C 14)，5.13δ(1H，s，C 12)，5.78δ(1H，d，C 11)，6.28δ(1H，s，C 10)，8.72δ(1H，s，C 6)，8.76δ(1H，s，C 9)，10.78δ(1H，s，HN-)。DEPT composes demonstration :-CH 3, 2;-CH 2, 5;-CH, 6. 1C?NMR(DMSO)14.02δ(-CH 3，C 1)，14.22δ(-CH 3，C 18)，18.43δ(-CH 2，C 2)，18.8δ(C 17)，35.73δ(C 3)，38.69δ(-CH 2，C 16)，66.30δ(C 14)，73.35δ(C 13)，73.δ5δ(C 11)，75.88δ(C 12)，89.40δ(C 10)，124.18δ(C 8)，144.03δ(C 9)，150.51δ(C 5)，151.88δ(C 7)，152.78δ(C 6)，172.26δ(C 15)，172.69δ(C 4)。
Embodiment 2 Calcium Dibutyryladenosine Cyclophosph-ates 1 hydrate: in exsiccant three-neck flask, add adenosine cyclophosphate triethylamine salt 6.5g, anhydrous pyridine 8.5ml, heavily steam butanoic anhydride 33ml, chloroform 220ml, 28-55 ℃ is constantly stirred, sponge is all dissolved, reaction finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, concentrating under reduced pressure pulp thing is dibutyryl cyclic adenosine monophosphate acid then; Get dibutyryl cyclic adenosine monophosphate slurry dissolve with ethanol, join in the ethanol and aqueous acetone solution of an amount of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether and acetone rinse; drain; add dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature, place; filter; solids absolute ether rinse is drained, and drying under reduced pressure got off-white powder in 30 hours.Fusing point: do not proofread and correct moisture (Ka Shi method) for 289.5 ℃: 3.93%, HPLC analyzes: purity 97.3%, the sample main peak is consistent with the retention time of the main peak of dibutyryl adenosine cyclophosphate sodium.Weightlessness was 3.88% before heat analysis TG-DTA showed 210 ℃, got 0.1g and was dissolved in distilled water 22ml, and its pH value is 5.28.
Elementary analysis measured value: C42.61%, H5.05%, N13.88%, P6.06%, Ca3.88%;
Theoretical value: C42.69%, H4.98%, N13.93%, P6.12%, Ca3.96%.
IR(KBr)：3417cm -1v N-H，2965cm -1v C-H，，1749cm -1v C＝0，1705cm -1v C＝0，1610cm -1v C＝N，1588cm -1v C＝N，1464cm -1δ C-H，1252cm -1v P＝0，1024cm -1v P-O-C。
1H?NMR(D 2O，DMSO)：0.91δ(3H，t，C 1)，0.95δ(3H，t，C 18)，1.58δ(1H，m，C 2)，1.64δ(1H，m，C 17)，2.41δ(1H，m，C 3)，2.57δ(3H，t，C 16)，3.43δ(H 2O，s)，4.02δ(1H，m，C 13)，4.24δ(2H，C 14)，5.13δ(1H，s，C 12)，5.78δ(1H，d，C 11)，6.28δ(1H，s，C 10)，8.72δ(1H，s，C 6)，8.76δ(1H，s，C 9)，10.78δ(1H，s，NH-)。DEPT composes demonstration :-CH 3, 2;-CH 2, 5;-CH, 6. 1C?NMR(DMSO)14.02δ(-CH 3，C 1)，14.22δ(-CH 3，C 18)，18.43δ(-CH 2，C 2)，18.8δ(C 17)，35.73δ(C 3)，38.69δ(-CH 2，C 16)，66.30δ(C 14)，73.35δ(C 13)，73.65δ(C 11)，75.88δ(C 12)，89.40δ(C 10)，124.18δ(C 8)，144.03δ(C 9)，150.51δ(C 5)，151.88δ(C 7)，152.78δ(C 6)，172.26δ(C 15)，172.69δ(C 4)。
Embodiment 3 Calcium Dibutyryladenosine Cyclophosph-ates 1.5 hydrates: in exsiccant three-neck flask, add adenosine cyclophosphate triethylamine salt 6.5g, anhydrous pyridine 8.6ml, heavily steam butanoic anhydride 35ml, chloroform 200ml, 20-70 ℃ is constantly stirred, sponge is all dissolved, reaction finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, concentrating under reduced pressure pulp thing is dibutyryl cyclic adenosine monophosphate then; Get dibutyryl cyclic adenosine monophosphate slurry dissolve with ethanol, join in the ethanol and aqueous acetone solution of an amount of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether and acetone rinse; drain; add dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature, place; filter; solids absolute ether rinse is drained, and drying under reduced pressure got pale yellow powder in 12 hours.Slightly molten or be slightly soluble in water, almost insoluble in ethanol, fusing point: do not proofread and correct moisture (Ka Shi method) for 286.5 ℃: 5.58%, MS:[M-Ca] -M/e 468.5, and HPLC analyzes: the sample main peak is consistent with the retention time of the main peak of dibutyryl adenosine cyclophosphate sodium.Weightlessness was 5.76% before heat analysis TG-DTA showed 210 ℃, got 0.1g and was dissolved in distilled water 20ml, and its pH value is 5.25.
Elementary analysis measured value: C41.84%, H5.13%, N13.51%, P5.92%, Ca3.82%;
Theoretical value: C41.94%, H5.08%, N13.59%, P6.01%, Ca3.89%.
IR(KBr)：3417cm -1v N-H，2965cm -1v C-H，，1749cm -1v C＝0，1705cm -1v C＝0，1610cm -1v C＝N，1588cm -1v C＝N，1464cm -1δ C-H，1252cm -1v P＝0，1024cm -1v P-O-C。
1H?NMR(D 2O，DMSO)：0.91δ(3H，t，C 1)，0.95δ(3H，t，C 18)，1.58δ(1H，m，C 2)，1.64δ(1H，m，C 17)，2.41δ(1H，m，C 3)，2.57δ(3H，t，C 16)，3.43δ(H 2O，s)，4.02δ(1H，m，C 13)，4.24δ(2H，C 14)，5.13δ(1H，s，C 12)，5.78δ(1H，d，C 11)，6.28δ(1H，s，C 10)，8.72δ(1H，s，C 6)，8.76δ(1H，s，C 9)，10.78δ(1H，s，NH-)。DEPT composes demonstration :-CH 3, 2;-CH 2, 5;-CH, δ. 1C?NMR(DMSO)14.02δ(-CH 3，C 1)，14.22δ(-CH 3，C 18)，18.43δ(-CH 2，C 2)，18.8δ(C 17)，35.73δ(C 3)，38.69δ(-CH 2，C 16)，66.30δ(C 14)，73.35δ(C 13)，73.65δ(C 11)，75.88δ(C 12)，89.40δ(C 10)，124.18δ(C 8)，144.03δ(C 9)，150.51δ(C 5)，151.88δ(C 7)，152.78δ(C 6)，172.26δ(C 15)，172.69δ(C 4)。
Embodiment 4 is in exsiccant three-neck flask, add adenosine cyclophosphate triethylamine salt 6.5g, anhydrous pyridine 9ml, heavily steam butanoic anhydride 35ml, chloroform 220ml, 25-65 ℃ is constantly stirred, sponge is all dissolved, reaction finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, concentrating under reduced pressure pulp thing is dibutyryl cyclic adenosine monophosphate then; Get dibutyryl cyclic adenosine monophosphate slurry dissolve with ethanol, join in the ethanol and aqueous acetone solution of an amount of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether and acetone rinse; drain; add dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature, place; filter; solids absolute ether rinse is drained, and drying under reduced pressure 5-8 hour must pale yellow powder.Slightly molten or be slightly soluble in water, have special smellyly, almost insoluble in ethanol, fusing point: 285.6C does not proofread and correct, moisture (Ka Shi method): 7.96%, MS:[M-Ca] -M/e 468.5, and HPLC analyzes: the sample main peak is consistent with the retention time of the main peak of dibutyryl adenosine cyclophosphate sodium.Get 0.1g and be dissolved in distilled water 25ml, its pH value is 5.26.
Embodiment 5 gets Calcium Dibutyryladenosine Cyclophosph-ate monohydrate raw material 2.0g (by anhydride); add injection water 380～450ml stirring with mannitol 2.0～6.0g and make dissolving; regulating pH is 5.0～7.5, adds activated carbon 0.01～0.5% (W/V) and stirs 15～45min, filters; moisturizing to 420～520ml; with 0.22 micron filtering with microporous membrane, by 20mg/ bottle or 40mg/ bottle (in principal agent) packing, lyophilization; tamponade gets 100～200 bottles of finished products.
Embodiment 6 gets Calcium Dibutyryladenosine Cyclophosph-ate anhydride 2.0g; add injection water 380～450ml stirring with mannitol 2.0～6.0g and make dissolving, regulating pH is 5.0～6.0, adds activated carbon 0.01～0.5% (W/V) and stirs 15～45min; filter; moisturizing to 420～520ml is with 0.22 micron filtering with microporous membrane, by 20mg/ bottle or 40mg/ bottle (in principal agent) packing; lyophilization; tamponade gets 100～200 bottles of finished products, and it is 1.83% that the Ka Shi method is surveyed its moisture.
Embodiment 7 gets Calcium Dibutyryladenosine Cyclophosph-ate hydrate feed 2.0g (in anhydride); add xylitol 2.0～6.0g and add injection water 190～350ml and stir and make dissolving, regulating pH is 5.0～6.5, adds activated carbon 0.01～0.5% (W/V) and stirs 15～45min; filter; moisturizing to 220～380ml is with 0.22 micron filtering with microporous membrane, by 20mg/ bottle or 40mg/ bottle (in principal agent) packing; lyophilization; tamponade gets 100～200 bottles of finished products, and it is 4.03% that the Ka Shi method is surveyed its moisture.
Embodiment 8 gets Calcium Dibutyryladenosine Cyclophosph-ate anhydride 2.0g; add xylitol 2.0～6.0g, macrodex 100～400mg adds injection water 190～350ml stirring makes dissolving, and regulating pH is 5.0～7.1; add activated carbon 0.01～0.5% (W/V) and stir 15～45min; filter, moisturizing to 220～380ml is with 0.22 micron filtering with microporous membrane; by 20mg/ bottle or 40mg/ bottle (in principal agent) packing; lyophilization, tamponade gets 100～200 bottles of finished products.
Embodiment 9 gets Calcium Dibutyryladenosine Cyclophosph-ate anhydride 1.0g; add xylitol 1.0g; macrodex 100～400mg adds injection water 200ml stirring makes dissolving; regulating pH is 5.0～7.5, adds activated carbon 0.01～0.5% (W/V) and stirs 15～45min, filters; moisturizing is to 250ml; with 0.22 micron filtering with microporous membrane, press the packing of 5ml/ bottle, get 50 bottles of finished products.
Raw material with character of the present invention, make powder pin or freeze-dried powder by the mode of embodiment, unexpectedly find, the preparation of a unit dose (general every bottle of packing dosage 10-80mg), in being dissolved in 10-15ml water, its pH value is between 5.0～7.5, than the preparation of pH value between 3.0～5.0 of national drug standards regulation, have better storage stability, the results are shown in Table 6.
Influence factor's result of the test of the different preparations of table 6.
Figure A20071010808800171
Lyophilized formulations can be the preparation that the method by embodiment 5-embodiment 9 obtains
The present invention is not limited to the foregoing description.

Claims (18)

1. the Calcium Dibutyryladenosine Cyclophosph-ate hydrate or the anhydride C that have peculiar property 18H 23N 5O 8P1/2CanH 2O, n=0～2.5 wherein, it is the molten or slightly soluble in the water part omitted at room temperature, and is almost insoluble in ethanol, and when 0.1g was dissolved in distilled water 20～25ml, pH value was 5.0～7.2.
2. according to described Calcium Dibutyryladenosine Cyclophosph-ate hydrate or the anhydride of claim 1, it is characterized in that wherein n=0～2 with peculiar property.
3. according to claim 1 or 2 described Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydrides, it is characterized in that wherein n=0～1.5 with peculiar property.
4. according to claim 1 or 3 described Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydrides, it is characterized in that wherein n=0～1 with peculiar property.
5. according to claim 1 or 4 described Calcium Dibutyryladenosine Cyclophosph-ate anhydrides with peculiar property, it is characterized in that this anhydride have draw moist, easily moisture absorption.
6. according to claim 1 or 4 described Calcium Dibutyryladenosine Cyclophosph-ate hydrates with peculiar property, it is characterized in that the Calcium Dibutyryladenosine Cyclophosph-ate hydrate be off-white color to pale yellow powder, under the room temperature in the water part omitted molten or slightly soluble, almost insoluble in ethanol.
7. according to claim 1 or 4 described Calcium Dibutyryladenosine Cyclophosph-ate hydrates with peculiar property, it is characterized in that getting under the room temperature Calcium Dibutyryladenosine Cyclophosph-ate hydrate 0.1g and be dissolved in distilled water 20～25ml, its pH value is between 5.0～7.2.
8. according to claim 1 or 5 described Calcium Dibutyryladenosine Cyclophosph-ate anhydrides with peculiar property, it is characterized in that this Calcium Dibutyryladenosine Cyclophosph-ate anhydride be off-white color to pale yellow powder, under the room temperature in the water part omitted molten or slightly soluble, almost insoluble in ethanol.
9. according to claim 1 or 5 described Calcium Dibutyryladenosine Cyclophosph-ate anhydrides, it is characterized in that under the room temperature that get Calcium Dibutyryladenosine Cyclophosph-ate anhydride 0.1g and be dissolved in distilled water 20～25ml, its pH value is between 5.0～7.2 with peculiar property.
10. have the Calcium Dibutyryladenosine Cyclophosph-ate hydrate or the anhydride of peculiar property according to claim 1 or 5, the moisture that it is characterized in that this hydrate or anhydride is in 8.45%.
11. according to claim 1 or 5 described Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydrides with peculiar property, the moisture that it is characterized in that this hydrate or anhydride is in 6.99%.
12. preparation has the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property or the method for anhydride, it comprises the steps:
Make adenosine cyclophosphate triethylamine salt, anhydrous pyridine, butanoic anhydride, chloroform all dissolves and reacts at 20～70 ℃ and finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, concentrating under reduced pressure pulp thing obtains dibutyryl cyclic adenosine monophosphate acid then; Get dibutyryl cyclic adenosine monophosphate acid slurry dissolve with ethanol, join in the ethanol or dehydrated alcohol and aqueous acetone solution of an amount of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether or acetone rinse; drain, add dehydrated alcohol or dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature; place; filter, solids absolute ether rinse is drained; can be in the presence of phosphorus pentoxide, drying under reduced pressure gets finished product.
13. preparation has the Calcium Dibutyryladenosine Cyclophosph-ate hydrate of peculiar property or the method for anhydride, it comprises the steps:
Make adenosine cyclophosphate triethylamine salt, anhydrous pyridine, butanoic anhydride, chloroform all dissolves and reacts at 20～70 ℃ and finishes, behind the pressure reducing and steaming solvent, slowly add distilled water, make at low temperatures to react completely, extract, abandon organic layer with hexone, concentrating under reduced pressure pulp thing obtains two butyryl cycli phosphate gland acid then; Get dibutyryl cyclic adenosine monophosphate acid slurry dissolve with ethanol, add in the ethanol or dehydrated alcohol and aqueous acetone solution of calcium chloride, stir; fully mix decompressing and extracting solvent, absolute ether or purifying acetone rinse; drain; add dehydrated alcohol or dehydrated alcohol and purifying acetone mixing again, add absolute ether under the low temperature, place; filter; solids absolute ether rinse is drained, the dry finished product that gets.
14. a pharmaceutical composition, it contains each described Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydride with peculiar property of claim 1 to 11, and pharmaceutically acceptable excipient or carrier.
15. pharmaceutical composition according to claim 13, it is characterized in that this pharmaceutical composition is injection freeze-dried powder or aseptic subpackaged powder injection formulation form, the pharmaceutical composition of a unit dose is dissolved in 10 to the 15ml water, and its pH value is between 5.0 to 7.5.
16. according to the pharmaceutical composition of claim 13, it is characterized in that this pharmaceutical composition is injection freeze-dried powder or aseptic subpackaged powder injection formulation form, water content is in 5%.
17. each described Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydride with peculiar property of claim 1 to 11 is used as protein kinase activator in preparation; Be used for the treatment of pulmonary heart disease, heart failure, ischemic cardiomyopathy, angina pectoris, coronary heart disease, myocardial infarction, cardiogenic shock, arrhythmia; Be used for the treatment of diseases such as bradyarrhythmia, tachy-arrhythmia, heart failure, myocarditis, psoriasis, rheumatic heart disease, leukemia with bradyarrhythmia; Be used for the treatment of cerebral ischemia, cerebral infarction, cerebral thrombosis and sequela thereof; Be used to improve anestheticing period surgical patient myocardial ischemia, improve cardiac function, reduce muscle relaxant, reduce operation risk cardiovascular side effect; Be used for the reparation of senile chronic bronchitis, various hepatitis auxiliary treatment and damaging cells; And the purposes of medicine that is used for regulating the growth promoter of mammal.
18. each described Calcium Dibutyryladenosine Cyclophosph-ate hydrate or anhydride with peculiar property of claim 1 to 11 is used for the treatment of pulmonary heart disease, heart failure, ischemic cardiomyopathy, angina pectoris, coronary heart disease, myocardial infarction, cardiogenic shock, arrhythmia; Be used for the treatment of diseases such as bradyarrhythmia, tachy-arrhythmia, heart failure, myocarditis, psoriasis, rheumatic heart disease, leukemia with bradyarrhythmia; Be used for the treatment of cerebral ischemia, cerebral infarction, cerebral thrombosis and sequela thereof; Be used to improve anestheticing period surgical patient myocardial ischemia, improve cardiac function, reduce muscle relaxant, reduce operation risk cardiovascular side effect; Be used for the reparation of senile chronic bronchitis, various hepatitis auxiliary treatment and damaging cells; And the method that is used to regulate the growth promoter of mammal.
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CN103242403A (en) * 2012-06-21 2013-08-14 辽宁亿灵科创生物医药科技有限公司 High-purity dibutyryladenosine cyclophosphate calcium and preparation method thereof
CN103417474A (en) * 2012-05-15 2013-12-04 袁璐 Calcium dibutyacyladenosine cyclophosphate-containing composition for injection
CN104478979A (en) * 2014-12-24 2015-04-01 上海第一生化药业有限公司 Crystal water-free calcium dibutyryladenosine cyclophosphate crystal form, as well as preparation method and application thereof
CN104490798A (en) * 2014-12-24 2015-04-08 上海第一生化药业有限公司 Crystal water-free calcium dibutyryladenosine cyclophosphate crystal form freeze-dried powder injection and preparation method thereof
CN105566424A (en) * 2014-10-17 2016-05-11 上海紫源制药有限公司 Method for preparing calcium dibutyryladenosine cyclophosphate
CN106361762A (en) * 2015-07-22 2017-02-01 上海上药第生化药业有限公司 Applications of dibutyryl adenosine cyclophosphate calcium in preparation of brain injury treatment drugs
CN108997430A (en) * 2018-07-16 2018-12-14 南京工业大学 Crystal of calcium dibutyryladenosine cyclophosphate

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WO2011085701A1 (en) * 2010-01-18 2011-07-21 联合康兴（北京）医药科技有限公司 Stable protein kinase activators, preparation methods and uses thereof
CN103417474A (en) * 2012-05-15 2013-12-04 袁璐 Calcium dibutyacyladenosine cyclophosphate-containing composition for injection
CN103417474B (en) * 2012-05-15 2014-09-03 袁璐 Calcium dibutyacyladenosine cyclophosphate-containing composition for injection
CN103242403B (en) * 2012-06-21 2016-01-20 北京赛盟医药科技发展有限公司 High-purity dibutyryladenosine cyclophosphate calcium and preparation method thereof
CN103242403A (en) * 2012-06-21 2013-08-14 辽宁亿灵科创生物医药科技有限公司 High-purity dibutyryladenosine cyclophosphate calcium and preparation method thereof
CN102846557A (en) * 2012-09-20 2013-01-02 浙江亚太药业股份有限公司 Adenosine cyclophosphate freeze-drying preparation and preparation method thereof
CN105566424A (en) * 2014-10-17 2016-05-11 上海紫源制药有限公司 Method for preparing calcium dibutyryladenosine cyclophosphate
CN104490798A (en) * 2014-12-24 2015-04-08 上海第一生化药业有限公司 Crystal water-free calcium dibutyryladenosine cyclophosphate crystal form freeze-dried powder injection and preparation method thereof
CN104478979A (en) * 2014-12-24 2015-04-01 上海第一生化药业有限公司 Crystal water-free calcium dibutyryladenosine cyclophosphate crystal form, as well as preparation method and application thereof
WO2016101412A1 (en) * 2014-12-24 2016-06-30 上海上药第一生化药业有限公司 Crystallization water-free calcium dibutyryladenosine cyclophosphate crystal form, and preparation method and use thereof
CN104490798B (en) * 2014-12-24 2018-05-11 上海第一生化药业有限公司 Nodeless mesh water Calcium Dibutyryladenosine Cyclophosph-ate crystal form freeze-dried powder and preparation method thereof
US10420787B2 (en) 2014-12-24 2019-09-24 Sph No.1 Biochemical & Pharmaceutical Co., Ltd. Crystal-water-free calcium dibutyryladenosine cyclophosphate crystal form and preparation method and application thereof
CN106361762A (en) * 2015-07-22 2017-02-01 上海上药第生化药业有限公司 Applications of dibutyryl adenosine cyclophosphate calcium in preparation of brain injury treatment drugs
CN108997430A (en) * 2018-07-16 2018-12-14 南京工业大学 Crystal of calcium dibutyryladenosine cyclophosphate
WO2020015763A1 (en) * 2018-07-16 2020-01-23 南京工业大学 Calcium dibutyacyladenosine cyclophosphate salt crystal

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