CN102126973A - Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof - Google Patents
Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof Download PDFInfo
- Publication number
- CN102126973A CN102126973A CN2010105709656A CN201010570965A CN102126973A CN 102126973 A CN102126973 A CN 102126973A CN 2010105709656 A CN2010105709656 A CN 2010105709656A CN 201010570965 A CN201010570965 A CN 201010570965A CN 102126973 A CN102126973 A CN 102126973A
- Authority
- CN
- China
- Prior art keywords
- compound
- meglumine
- solvent
- hydrate
- preparation
- 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.)
- Pending
Links
- MHPXHDFRCZHXMC-UHFFFAOYSA-N CCCCCCCCOCCCOC(CN(CC(O)=O)c(cccc1)c1OCCOc(cccc1)c1N(CC(OC)OCCOCCCCCCCC)CC(O)=O)OC Chemical compound CCCCCCCCOCCCOC(CN(CC(O)=O)c(cccc1)c1OCCOc(cccc1)c1N(CC(OC)OCCOCCCCCCCC)CC(O)=O)OC MHPXHDFRCZHXMC-UHFFFAOYSA-N 0.000 description 1
- ZBFLFZPGGMPNNU-UHFFFAOYSA-N CCCCCCCCOCCOC(CN(CC(O)=O)c(cccc1)c1OCCOc(cccc1)c1N(CC1OC1OCCOCCCCCCCC)CC(O)=O)OC Chemical compound CCCCCCCCOCCOC(CN(CC(O)=O)c(cccc1)c1OCCOc(cccc1)c1N(CC1OC1OCCOCCCCCCCC)CC(O)=O)OC ZBFLFZPGGMPNNU-UHFFFAOYSA-N 0.000 description 1
Images
Abstract
The invention relates to a meglumine compound of a dibasic ester acid derivative (compound D). The meglumine compound comprises dimeglumine, meglumine and hydrates or solvates of the dimeglumine and the meglumine. The meglumine compound has high water solubility and stability and improves adverse reactions of blood vessel stimulation, muscle stimulation and the like when metal salt of the compound is injected. The invention also provides a preparation method and medicinal application of the meglumine compound.
Description
Technical field the invention belongs to the pharmaceutical technology field, relates to a kind of derivative salt compound of dibasic ester acid, and concrete is its meglumine salt compound, and preparation method thereof with they application in medicine.
Background technology DP-BAPTA-99 is new compound, is a kind of compound of dibasic ester acid structure, in present specification, is called " Compound D ", and its molecular structural formula is as follows:
Compound D is a kind of many targeted drugs that are used for the treatment of apoplexy; can treat a series of brain injurys of paralytic; current the exploitation is used to protect brain neuroblastoma cell to avoid the medicine of the damage that acute ischemic stroke causes; it belongs to film activation sequestrant; this compound unique distinction is that it is in aqueous environment; for example lack the metal ion-chelant ability in blood and the body fluid; its active performance needs the activation of dependent cells film; and it makes its cardiac toxic also very little to the selectivity of brain cell membrane; may play neuroprotective by suppressing apoptosis, the follow-up indication that is expected to develop also comprises brain injury that cardiac operation under direct vision causes and traumatic brain injury etc.
Pharmaceutically use its sodium-salt form usually, as the disodium salt of Compound D, its structural formula is as follows:
The open WO99/16741 of international application discloses the chemical structural formula of Compound D.
Compound D has been applied to clinical study as a kind of nerve protection medicine of new acute apoplexy.Yet disadvantageously, on the one hand, Compound D water-soluble very poor is insoluble in water, is unfavorable for the preparation of pharmaceutical preparation and is not easy to stripping in pharmaceutical preparation; And metal ion type salt has short Decomposition for two ester group structures in the Compound D structure, is unfavorable for stability of drug and application; In addition, when metal-salts such as the disodium salt of Compound D use in injection, tend to cause untoward reactions such as stronger vascular stimulation, muscular irritation.
Common, make target compound form salt formula compound, be the top-priority method of improving target compound.Application for pharmaceutical preparation production aspect, usually advantageously adopt the pharmaceutical active compounds of the specific salts form that contains acidic group or base, they for example have better solvability, better stripping and absorption behavior, better stability or common better properties curve, use specific salts, also can be favourable to the preparation of active compound or pharmaceutical preparation, perhaps to meet medicine regulatory authority require favourable, for example, help the clinical application of medicine, improve the compliance of patient's medication, help the result of treatment of medicine.
Summary of the invention improves the water-soluble, stable of Compound D under the prerequisite of the pharmacological action that does not change Compound D, untoward reactions such as the vascular stimulation when improving the injection use, muscular irritation are very important and significant.The contriver finds that through experiment the non-metal salt of Compound D can improve the weak point of Compound D or its metal-salt.
Contain two carboxyls in the Compound D molecular structure, the contriver finds through experiment, adopts water-soluble good alkaline matter----meglumine, with the carboxylic group coordination salify of Compound D, can significantly improve the water-soluble of Compound D.Yet, when considering to improve water-soluble, also to consider the pharmacological action that can not change and destroy Compound D, and salifiable with it alkaline coordination material not only basicity is suitable, and will be to the human body safety non-toxic, to consider that also institute's salt-forming compound should have satisfactory stability and physical appearance, is applied to pharmaceutical preparation with the derivative salt that is convenient to Compound D as active constituents of medicine.In addition, the stability for Compound D will have good promoter action; Untoward reactions such as the blood vessel pain in the time of in addition, improving its injection use, muscular irritation.
The meglumine chemical name is: 1-deoxidation-1-(methylamino-)-D-sorbyl alcohol, molecular formula C
7H
17NO
5, Portugal's first amino molecule has the base group, is a kind of free alkali compounds of safety non-toxic, and its aqueous solution is alkalescence, uses as auxiliary material in multiple drug prescription.
Based on above consideration and requirement, the inventor by experiment and the screening, finished The compounds of this invention D meglumine salt, it comprises Compound D two meglumines, Compound D one meglumine, its hydrate or its solvate.
Further, the invention provides the preparation method of Compound D meglumine salt; The present invention also provides the medicinal application of Compound D meglumine salt.
The invention provides the compound shown in the formula I, its hydrate or its solvate:
Molecular formula C
42H
64N
2O
12N (C
7H
17NO
5), n=2 or 1 wherein represents two meglumine salts, a meglumine salt of Compound D respectively, wherein:
Compound D one meglumine:
Molecular formula C
42H
64N
2O
12C
7H
17NO
5,
Compound D two meglumines:
Concrete, the salt compound of Compound D provided by the invention and meglumine, it comprises Compound D one meglumine, Compound D two meglumines, with and hydrate or its solvate.
Should illustrate, and those skilled in the art should be familiar with and understand, because the present invention institute external neutral of salifiable compound or do not show electrically, therefore, the present invention salifiable compound can also represent by the chemical structure of following general formula I I-1 or general formula III-1:
Should illustrate, and those skilled in the art should be familiar with and understand, because in the present invention's salifiable compound, with the molecule number of the salifiable meglumine of a part Compound D coordination be 1 or 2, in the expression of molecular structure, the molecular digital of meglumine is marked on the front and the suffix that is marked on the meglumine molecular formula of meglumine molecular formula, all be the same, for example, the present invention salifiable compound can also represent by the chemical structure of following general formula I I-2 or general formula III-2:
(II-2), molecular formula C
42H
64N
2O
12C
7H
17NO
5,
What formula II-1, formula II-2 and formula II represented is with a kind of compound, i.e. Compound D one meglumine;
What formula III-1, formula III-2 and formula III were represented is with a kind of compound, i.e. Compound D two meglumines.
The meglumine salt compound of The compounds of this invention D is a kind of solid chemical compound, has good physical appearance, in preparation process, for keeping peculiar structural form, may contain a certain amount of water molecules or solvent molecule, therefore, the present invention also comprises the hydrate or the solvate of above-claimed cpd D meglumine.
For example, the semihydrate of Compound D two meglumines of the present invention, monohydrate, sesqui hydrate, dihydrate, two sesquialter hydrates, trihydrate, three sesquialter hydrates, tetrahydrate, four sesquialter hydrates, pentahydrate, five sesquialter hydrates, hexahydrate, six sesquialter hydrates, heptahydrate, seven sesquialter hydrates, eight hydrates, octuple semihydrate, nonahydrate, nine sesquialter hydrate or decahydrates, or the like;
For example, the semihydrate of Compound D one meglumine of the present invention, monohydrate, sesqui hydrate, dihydrate, two sesquialter hydrates, trihydrate, three sesquialter hydrates, tetrahydrate, four sesquialter hydrates, pentahydrate, five sesquialter hydrates, hexahydrate, six sesquialter hydrates, heptahydrate, seven sesquialter hydrates, eight hydrates, octuple semihydrate, nonahydrate, nine sesquialter hydrate or decahydrates, or the like.
Again for example, Compound D two meglumines of the present invention contain the solvent molecule of half point, 1 molecule, 1.5 molecules, 2 molecules, 2.5 molecules, 3 molecules, 3.5 molecules, 4 molecules, 4.5 molecules, 5 molecules, 5.5 molecules, 6 molecules, 6.5 molecules, 7 molecules, 7.5 molecules, 8 molecules, 8.5 molecules, 9 molecules, 9.5 molecules or 10 molecules, or the like;
Again for example, Compound D one meglumine of the present invention contains the solvent molecule of half point, 1 molecule, 1.5 molecules, 2 molecules, 2.5 molecules, 3 molecules, 3.5 molecules, 4 molecules, 4.5 molecules, 5 molecules, 5.5 molecules, 6 molecules, 6.5 molecules, 7 molecules, 7.5 molecules, 8 molecules, 8.5 molecules, 9 molecules, 9.5 molecules or 10 molecules, or the like.
Should illustrate; above-mentioned many The compounds of this invention D two meglumines enumerated or the hydrate or the solvate of Compound D one meglumine; it is The compounds of this invention D meglumine contingent situation in crystallization or purge process; any hydrate or solvate in them; it only is the existence form of The compounds of this invention D derivative material; normally may command or the removal of crystal water that is contained or recrystallisation solvent; for example crystal water or recrystallisation solvent are removed by adding thermal burn or changeing crystalline substance; therefore, the hydrate of above-mentioned many Compound D derivatives of enumerating or solvate still belong to the content of technical scheme content of the present invention and scope of patent protection.
The present invention also provides the preparation method of Compound D meglumine, its hydrate or its solvate, it is included in the solvent Compound D is contacted with meglumine, the reaction salify, described solvent is selected from the mixing of one or more solvents in ethanol, methyl alcohol, Virahol, acetone, acetonitrile, ethyl acetate, water, N,N-DIMETHYLACETAMIDE, the dimethyl formamide; Described temperature of reaction be in room temperature to the reflux temperature condition of solvent, make Compound D and meglumine the reaction salify.
In the embodiments of the invention scheme, described Compound D meglumine, its hydrate or solvate are as described in the unrestricted embodiment of compound of the present invention, in information as herein described, by with all similar methods as described, in containing the solution of Compound D, add meglumine, perhaps in containing the solution of meglumine, add Compound D, perhaps the solution that contains Compound D is mixed with the solution that contains meglumine, to reach Compound D is contacted with meglumine, react salifiable purpose.
For the preparation of Compound D one meglumine, its hydrate or solvate, concrete,
In room temperature to the reflux temperature condition of solvent, with mol ratio is 1: the Compound D of (1～1.1) contacts in solvent with meglumine, the reaction salify, and under room temperature or subambient condition, make institute's salify crystallization, filter, drain after the washing, dry, promptly get Compound D one meglumine, or its hydrate, solvate, wherein said solvent is selected from ethanol, methyl alcohol, Virahol, acetone, acetonitrile, ethyl acetate, water, N,N-DIMETHYLACETAMIDE, the mixing of one or more solvents in the dimethyl formamide optionally can be by reducing Tc or/and steam except that the formation of partial solvent with accelerate crystallisation; Perhaps,
Being 1: 1 Compound D and meglumine with mol ratio makes them dissolve fully in suitable quantity of water in 5～80 ℃, stirs, and lyophilize promptly gets Compound D one meglumine or its hydrate.
For the preparation of Compound D two meglumines, its hydrate or solvate, concrete,
In room temperature to the reflux temperature condition of solvent, with mol ratio is 1: the Compound D of (2～2.2) contacts in solvent with meglumine, the reaction salify, and under room temperature or subambient condition, make institute's salify crystallization, filter, drain after the washing, dry, promptly get Compound D two meglumines, or its hydrate, solvate, wherein said solvent is selected from ethanol, methyl alcohol, Virahol, acetone, acetonitrile, ethyl acetate, water, N,N-DIMETHYLACETAMIDE, the mixing of one or more solvents in the dimethyl formamide optionally can be by reducing Tc or/and steam except that the formation of partial solvent with accelerate crystallisation; Perhaps,
Being 1: 2 Compound D and meglumine with mol ratio makes them dissolve fully in suitable quantity of water in 5～80 ℃, stirs, and lyophilize promptly gets Compound D two meglumines or its hydrate.
For Compound D, can be synthetic according to following operational path, be calcium sequestrant BAPTA (chemical name: 1,2-couple of (adjacent amino-benzene) ethane-N, N, N ', N '-four acetyl acid) and bromooctane with raw material mainly:
For meglumine, can commercially obtain usually.
Further, the invention provides the pharmaceutical composition that contains Compound D two meglumines, Compound D one meglumine, its hydrate or its solvate and pharmaceutically acceptable carrier.
Can pass through the administration Compound D meglumine salt of the present invention of any appropriate, but, be preferably injection system usually by parenterai administration or oral administration.Use in order to carry out this class, generally use the salt of Compound D of the present invention with the pharmaceutical compositions that contains pharmaceutically acceptable carrier, but, the definite form of said composition depends on form of medication naturally.
Concrete, the present invention also provides a kind of Compound D two meglumines of the present invention that contain, Compound D one meglumine, the pharmaceutical composition of its hydrate or its solvate, and contain one or more pharmaceutically acceptable carrier, Compound D two meglumines wherein, Compound D one meglumine, the content of its hydrate or its solvate is 0.1～500mg, for example 0.1mg, 0.2mg, 0.5mg, 0.7mg, 1mg, 2mg, 3mg, 4mg, 5mg, 7mg, 10mg, 15mg, 20mg, 25mg, 30mg, 40mg, 41mg, 42mg, 43mg, 45mg, 47mg, 48.5mg, 50mg, 60mg, 62mg, 70mg, 80mg, 82mg, 83mg, 85mg, 88mg, 90mg, 92mg, 95mg, 98mg, 100mg, 110mg, 116mg, 120mg, 125mg, 130mg, 132mg, 135mg, 140mg, 150mg, 166mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg.
With The compounds of this invention D two meglumines, Compound D one meglumine, its hydrate or its solvate is active ingredient, and contain one or more pharmaceutically acceptable pharmaceutical carriers, be mixed with form through any suitable administration, can prepare any pharmaceutical dosage form of acceptable on the pharmaceutics, comprise injection formulations, oral preparations, non-oral liquid preparation, or the like, as injection, comprise powder ampoule agent for injection and injection liquid, or the like; And for example oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent or the like; The emulsion of non-for another example oral eye drop, nasal drops, [, Transdermal absorption, or the like.Also can be the formulation such as quick-release, slowly-releasing, controlled release of above various formulations, for example oral dispersible tablet, slow releasing tablet, chewable tablet, slow releasing capsule, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets, effervescent granule, or the like.Especially, by the means known in the art preparation, be preferred for preparing the tablet (comprising dispersible tablet, slow releasing tablet, chewable tablet, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets) that uses on the pharmaceutics, capsule (comprise that stomach is molten, enteric, slow releasing capsule), granule, oral solution, injection (comprising powder ampoule agent for injection and injection liquid) etc., to satisfy the various needs in the clinical use.
Be to be understood that, according to method well known in the art, pharmaceutical carrier is matrix or the auxiliary material that keeps pharmaceutical dosage form, usually select for use or be used in combination according to different medicaments, optionally comprise vehicle or thinner, one or more in Microcrystalline Cellulose, lactose, pregelatinized Starch, starch, dextrin, calcium phosphate, sucrose, dextran, N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin, the cyclodextrin derivative for example, or the like; Also can comprise tackiness agent, one or more in polyvidone (polyvinylpyrrolidone), methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, guar gum, the xanthan gum for example, or the like; Also comprise lubricant, one or more in Magnesium Stearate, stearic acid, talcum powder, stearyl fumarate, the Sodium Lauryl Sulphate BP/USP for example, or the like; Also can comprise disintegrating agent, one or more in sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, croscarmellose sodium, crosslinked carboxymethyl fecula sodium, the pregelatinized Starch for example, or the like; Also comprise tensio-active agent, one or more in sodium lauryl sulphate, the Tween-80 for example, or the like; Also can comprise pH value conditioning agent or buffer reagent, one or more of phosphate buffered saline buffer, citric acid, Trisodium Citrate, acetate buffer, dilute hydrochloric acid, yellow soda ash, sodium hydroxide for example, or the like; Also can comprise sanitas, one or more in Sodium Benzoate, potassium sorbate, methyl p-hydroxybenzoate, the propylparaben for example, or the like; Also can comprise stablizer and oxidation inhibitor, one or more in Calcium Disodium Edetate, S-WAT, the vitamins C for example, or the like; Also can comprise the taste conditioning agent, one or more in maltose alcohol, fructose, sucrose, soluble saccharin, flavoring orange essence, the strawberry flavour for example, or the like; Also can comprise additive other routine, appropriate in addition.
Should be appreciated that above-mentioned " optionally comprising " is meant both can optionally select to use, and also can not use.
It is also understood that when the agent type is tablet or capsule, can be the film dressing.The material that is used for the film dressing comprises suitable Drug coating, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, or the like; Also can comprise softening agent, for example polyoxyethylene glycol, triethyl citrate, or the like; Also comprise suitable solubilizing agent, as Polyoxyethylene Sorbitan Monooleate; Also can comprise suitable pigment, as titanium dioxide, various ferric oxide, pink pigment, or the like.
Aforesaid pharmaceutical composition, contain one or more pharmaceutically acceptable pharmaceutical carriers, be mixed with form through any suitable administration, can prepare any pharmaceutical dosage form of acceptable on the pharmaceutics, Compound D two meglumines, Compound D one meglumine, its hydrate or its solvate are active substances wherein, can also comprise the material that other has pharmaceutical active in the pharmaceutical composition, form a kind of pharmaceutical composition of compound, come combination therapy.
Further, preparation of drug combination method of the present invention, this method comprises makes acceptable any pharmaceutical dosage form on the pharmaceutics with Compound D two meglumines, Compound D one meglumine, its hydrate or its solvate and pharmaceutically acceptable carrier thorough mixing, and preferred pharmaceutical dosage form is injection (comprising powder ampoule agent for injection and injection liquid), tablet (comprising dispersible tablet, slow releasing tablet, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets etc.), capsule (comprise that stomach is molten, enteric, slow releasing capsule), granule, oral solution etc.
Concrete, aforesaid preparation of drug combination method, this method comprises Compound D two meglumines, Compound D one meglumine, its hydrate or its solvate and pharmaceutically acceptable pharmaceutical carrier thorough mixing are made acceptable any pharmaceutical dosage form on the pharmaceutics, preferred pharmaceutical dosage form is injection (comprising powder ampoule agent for injection and injection liquid), tablet (comprises dispersible tablet, slow releasing tablet, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets etc.), capsule (comprises that stomach is molten, enteric, slow releasing capsule), granule, oral solution, non-oral liquid preparation, for example non-oral eye drop, nasal drops, [, the emulsion of Transdermal absorption, cutaneous permeable agent (the emulsifiable paste that comprises Transdermal absorption, gel, emulsion, emulsion agent, patch etc.), etc.
In addition, the pharmaceutical composition of salt of the present invention can form pharmaceutical composition by mixing cpd, and particularly, composition of the present invention can comprise the Compound D and the meglumine of following structural formula by mixing:
Be to be understood that, mixing cpd D and meglumine, can be in solvent, to carry out, for example in being arranged, the environment of water carries out, as: preferably in purified water (as deionized water or distilled water) or/and mix in the ethanol, dissolving, further adopt oven dry, Rotary Evaporators drying, drying under reduced pressure or vacuum-drying, cryodesiccated method to obtain pharmaceutical composition; The pressed powder that also can be the pressed powder of Compound D and meglumine mixes, and the preparation method who for example adopts solid dispersion mixes and obtains pharmaceutical composition.
The invention still further relates to Compound D two meglumines, Compound D one meglumine, its hydrate or the application in the following areas of its solvate:
Application in preparation treatment acute ischemic cerebral apoplexy medicine;
Application in the medicine of brain injury that preparation treatment cardiac operation under direct vision causes and traumatic brain injury;
Application in the medicine of preparation treatment DPN disease;
Application in the medicine of preparation treatment Parkinson's disease and alzheimer's disease.
Description of drawings: relevant accompanying drawing provided by the invention is as follows:
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of Compound D
1H NMR (DMSO-d
6);
Fig. 2 is the carbon-13 nmr spectra figure of Compound D
13C NMR (DMSO-d
6).
The advantage of The compounds of this invention D derivative salt:
1. The compounds of this invention D two meglumines, Compound D one meglumine, its hydrate or its solvate, its alkaline ligand is safe and reliable, human body there is not extra side effect, and the stable in properties of The compounds of this invention D two meglumines, Compound D one meglumine, its hydrate or its solvate, be difficult for decomposing, be easy to preserve and use as bulk drug.
Stability test:
Compound D at high temperature can be decomposed usually, generates its monoesters analog and other impurity, is referred to as total related substance, under the hot conditions, measures the wherein content of total related substance, analyzes its stability.
Get respectively an amount of Compound D two meglumines, Compound D one meglumine, Compound D disodium, put and be positioned in the measuring cup in 50 ℃ of baking ovens, respectively at sampling in the 5th, 10 day, measure total related substance wherein.
Adopt high-efficient liquid phase chromatogram technique analysis, result of the test sees Table 1.
Table 1
Measurement result shows, 50 ℃ of Compound D two meglumines, Compound D one meglumine, Compound D disodium high temperature were placed 10 days, total its related substances increases to some extent, total its related substances of Compound D disodium is far longer than the content of total related substance of Compound D two meglumines, Compound D one meglumine, total related substance percentage composition net added value in the time of the 10th day, the Compound D disodium is more than 1.6 times of Compound D one meglumine, is that Compound D two meglumines are more than 1.9 times. Can find out that the stability of Compound D two meglumines, Compound D one meglumine significantly improves than Compound D disodium.
2. The compounds of this invention D two meglumines, Compound D one meglumine, its hydrate or its solvate is water-soluble good, has improved the water-soluble of Compound D.
Through the Preliminary Determination comparison, Compound D two meglumines, Compound D one meglumine, the water-soluble solution characteristic of Compound D (normal temperature and pressure) are compared as follows table 2.
Table 2
As can be seen from Table 1, The compounds of this invention D two meglumines, the water-soluble Compound D that is far longer than of Compound D one meglumine show the water-soluble of its excellence.
The compounds of this invention D two meglumines, Compound D one meglumine, its hydrate or its solvate excellence water-soluble stripping in preparation has good facilitation for Compound D. Especially for oral formulations, significant.
Be to be understood that oral medicament need to just can enter blood of human body reaching therapeutic action through GI absorption, the quality of oral absorption directly affects the result for the treatment of of medicine. According to the concept of pharmacy, bioavilability (Bioavailability) refers to that medicine is absorbed to enter and sanguimotorly utilizes degree and utilize speed. Compare Compound D, The compounds of this invention D meglumine salt has excellent water-soluble, enters aspect sanguimotor degree and the speed in absorption for the oral drug preparation take it as active ingredient, has important facilitation and meaning. Medicament enters the absorption process behind the stomach and intestine, divide two stages, it is two stages of disintegration dispersion and Gastrointestinal Wall Absorption, at first need in gastric juice or intestinal juice, disintegration scatter, and then contact and be attached to gastrointestinal wall and absorb and enter blood, this two stages all can affect the performance with drug effect of absorbing of medicine, Compound D is prepared as water-soluble good derivative form, drug-eluting speed is significantly accelerated, degree and the rate of dispersion of its disintegration dispersion in gastric juice or intestinal juice have greatly been improved, then medicament active composition is more abundant with contacting of gastrointestinal wall, be attached to Gastrointestinal Wall Absorption and to enter the active ingredient of blood also more abundant, this raising for the bioavilability of efficacy component Compound D meglumine salt is significant.
4. The compounds of this invention D two meglumines, Compound D one meglumine, its hydrate or its solvate have improved the bad reactions such as vascular stimulation, muscular irritation when injection is used, and significantly are better than Compound D disodium, sylvite.
Vascular stimulation tests:
Get 32 of rabbit, weight 1.8～2.2kg, male and female half and half, be divided at random four groups, it is Compound D one meglumine injection group (physiological saline solution, phosphate is transferred PH=7 ± 0.5,1mg/ml), (physiological saline solution, phosphate are transferred PH=7 ± 0.5 to Compound D two meglumine injection groups, 1mg/ml), Compound D two sodium injection group (physiological saline solutions, phosphate is transferred PH=7 ± 0.5,1mg/ml) with the normal saline solution group, 8 every group, shave off the rabbit hair that covers auricular vein with stainless steel blade, the left ear of alcohol disinfecting rabbit
The 1st group of auricular vein injection Compound D one meglumine injection 1.2mg/kg, 1 time/d;
The 2nd group of auricular vein injection Compound D two meglumine injection 1.4mg/kg, 1 time/d;
The 3rd group of auricular vein injection Compound D two sodium injection 1.0mg/kg, 1 time/d;
The 4th group of auricular vein injecting normal saline parenteral solution 1.0ml/kg, 1 time/d;
Injection speed is 2.0ml/min, injects continuously 14d, and all inject at same position every day, observes animal general reaction and injection site every day and has or not the congestion of blood vessel and oedema reaction, puts to death in the 14th day, draws materials and does the pathology inspection.
Inflammatory reaction deciding degree vein inflammatory extent of reaction criterion: be divided into 4 grades according to the inflammatory reaction degree under the light microscopic,
NIP reaction (-): connective tissue congestion and edema around rarely seen vein;
Mild inflammation (+): connective tissue is seen lymphocyte, plasmocyte infiltrating around the blood vessel, and vascular wall and lumen of vessels have no inflammatory cell;
Moderate inflammation (++): connective tissue and each layer of vascular wall have lymphocyte, thick liquid cell and a little neutrophil infiltration around the blood vessel;
Hyperphlogosis (+++): connective tissue, each layer of vascular wall and the visible diffusivity lymphocyte of lumen of vessels, neutrophil infiltration around the blood vessel, the visible more exudate of Endovascular and downright bad cell fragment.
Each is organized rabbit inflammatory reaction situation and the results are shown in Table 3.
Table 3
The result as seen, the normal saline solution group does not have injury of vein substantially, Compound D two meglumine injection groups have the slight injury of vein of 2 examples, Compound D one meglumine injection group has the slight injury of vein of 3 examples, do not have moderate to hyperphlogosis, and Compound D two sodium injection group injury of vein are serious, only 1 routine mild inflammation, all the other are moderate to hyperphlogosis, show that Compound D meglumine salt parenteral solution group and Compound D two sodium injection group comparing differences have statistical significance (P＜0.01).
Embodiment is in implementation process of the present invention, various embodiments that those of ordinary skills produce on the basis that does not depart from the scope of the present invention with spirit and modify conspicuous and be to carry out easily, the invention is not restricted to the scope of specific embodiment as herein described, really, various modification of the present invention is except those that narrated are to be understood by those skilled in the art from the narration of front.Come derivative salt compound by the following examples to The compounds of this invention D, and preparation method thereof specify with its should be used as further in medicine, but do not represent the embodiment limitation of the present invention.
In the embodiments of the invention scheme, the derivative salt compound of following Compound D is as described in the unrestricted embodiment of compound of the present invention, in information as herein described, by with following described similar method, in Compound D, add the meglumine that needs, perhaps in containing the solution of meglumine, add the Compound D of needs, perhaps the solution that contains Compound D is mixed with the solution that contains meglumine, to reach Compound D is contacted with meglumine, react salifiable purpose.
At first, for Compound D, can be synthetic according to operational path of the present invention, the proton nmr spectra of Compound D and carbon-13 nmr spectra data are as follows:
1HNMR(DMSO-d
6)δ(ppm)：0.834～0.860(6H，t)，1.231(20H，d)，1.420～1.444(4H，m)，3.294～3.411(8H，m)，3.988～4.205(16H，m)，6.724～6.955(8H，m)。
13CNMR(DMSO-d
6)δ(ppm)：13.965，22.086，25.581，28.679，28.832，29.107，31.259，53.068，53.251，63.263，67.093，67.643，70.222，113.901，118.159，121.135，139.068，149.614，170.935，172.171。
Among mass spectroscopy: the ESI-MS (m/z), quasi-molecular ion peak [M+1] is 790.4, with C in its molecular formula
42H
64N
2O
12Conform to.
Embodiment 1. Compound D, two meglumines and preparation thereof
Get 1g (1.267mmol) Compound D and add in the 55ml ethanol, stir and heat to make fully and dissolve, add the solution of 0.49g (2.53mmol) meglumine in 40ml ethanol, slowly add and stirring, finish more than the insulated and stirred 30min of back, reduce to room temperature, optionally available Rotary Evaporators steams and removes partial solvent, put the refrigerator internal cooling, make its sufficient crystallising, suction filtration, filter cake cold ethanol of 5ml or washing with acetone, vacuum-drying promptly gets Compound D two meglumines to constant weight.
1HNMR(DMSO-d
6)δ(ppm)：0.816～0.855(6H，t)，1.226～1.270(21H，m)，1.420～1.430(4H，m)，2.414(6H，s)，2.808～2.843(2H，m)，2.911～2.932(2H，m)，3.292～3.322(4H，m)，3.385～3.427(8H，m)，3.466～3.494(2H，m)，3.566～3.589(2H，m)，3.640～3.654(6H，m)，3.835～3.854(2H，m)，3.938～3.954(4H，m)，4.144(2H，s)，4.175(2H，s)，6.758～6.806(6H，m)，6.880(2H，d)。
13CNMR(DMSO-d
6)δ(ppm)：13.967，22.117，25.597，28.710，28.863，29.137，31.289，33.289，51.435，53.465，55.494，63.110，63.461，66.956，67.719，68.864，70.283，70.558，71.306，113.474，118.098，120.296，121.044，?140.304，149.446，171.652，174.598。
Get 1g (1.267mmol) Compound D and add in the 85ml Virahol, stir and heat to make fully and dissolve, add the solution of 0.49g (2.53mmol) meglumine in the 70ml Virahol, slowly add and stirring, finish more than the insulated and stirred 30min of back, reduce to room temperature, optionally available Rotary Evaporators steams and removes partial solvent, put the refrigerator internal cooling, make its sufficient crystallising, suction filtration, filter cake washs with the 6ml cold isopropanol, vacuum-drying promptly gets Compound D two meglumines to constant weight.
Compound D two meglumines of above-mentioned preparation or its hydrate all are consistent with embodiment 1 through proton nmr spectra, carbon spectrum analysis.
Embodiment 3. Compound D, two meglumines or its hydrate and preparation thereof
Get the stirring of 1g (1.267mmol) Compound D adding 25ml distilled water and obtain suspension, stir the solution of meglumine in 7ml distilled water that adds 2.534mmo1 down, slowly add and stirs, finish more than 30～45 ℃ of stirrings of back insulation 10min, make and form clear and bright solution, reduce to room temperature, by cryodesiccated common process, send into that to carry out freeze-drying in the disinfectant freeze drying box dry, pre-freeze 5 hours, temperature drops to-35 ℃, distils 8 hours for the first time, and temperature rises to-5 ℃; Distilled 7 hours for the second time, temperature rises to 25 ℃, and vacuum-drying promptly, through proton nmr spectra, carbon-13 nmr spectra, differential thermal analysis TG-DTA collection of illustrative plates, shows that products therefrom is Compound D two meglumines and hydrate thereof to constant weight.
Optionally, with purifying, the solvent of recrystallization can be selected Virahol-water mixed solution, acetone-water mixing solutions, alcohol-water mixing solutions, methanol-water mixing solutions or ether-water mixed solution for use with above-mentioned Compound D two meglumines and the further recrystallization of hydrate thereof.
Compound D two meglumines of above-mentioned preparation or its hydrate all are consistent with embodiment 1 through proton nmr spectra, carbon spectrum analysis.
Embodiment 4. Compound D, one meglumine and preparation thereof
Get 1g (1.267mmol) Compound D and add in the 55ml methyl alcohol, stir and be heated to 50 ℃ and make dissolving fully, add the solution of 0.25g (1.267mmol) meglumine in 22ml methyl alcohol, slowly add and stirring, finish more than the insulated and stirred 30min of back, reduce to room temperature, optionally available Rotary Evaporators steams and removes partial solvent, put the refrigerator internal cooling, make its sufficient crystallising, suction filtration, filter cake washs with the 8ml cold methanol, vacuum-drying promptly gets Compound D one meglumine salt to constant weight.
1HNMR(DMSO-d
6)δ(ppm)：0.834～0.860(6H，t)，1.041(4H，d)，1.230～1.273(20H，m)，1.425～1.436(4H，m)，2.416(6H，s)，2.802～2.837(2H，m)，2.910～2.936(2H，m)，3.301～3.323(4H，t)，3.383～3.424(8H，m)，3.462～3.477(2H，m)，3.566～3.589(2H，m)，3.634(2H，d)，3.737(3H，s)，3.817～3.845(2H，m)，3.894(1H，s)，3.967～3.982(2H，t)，4.129(3H，s)，4.206(2H，s)，6.780～6.808(4H，m)，6.881～6.912(2H，m)。
13CNMR(DMSO-d
6)(ppm)：13.952，22.071，25.566，28.664，28.817，29.107，31.243，33.334，51.343，53.404，55.098，62.011，63.141，63.415，66.926，67.704，68.849，70.329，71.290，113.428，118.312，120.571，120.968，139.938，149.599，171.423，173.911，175.025。
Embodiment 5. Compound D, one meglumine or its hydrate and preparation thereof
Get the stirring of 1g (1.267mmol) Compound D adding 22ml distilled water and obtain suspension, stir the solution of meglumine in 5ml distilled water that adds 1.267mmol down, slowly add and stirs, finish more than 30～45 ℃ of stirrings of back insulation 10min, make and form clear and bright solution, reduce to room temperature, by cryodesiccated common process, send into that to carry out freeze-drying in the disinfectant freeze drying box dry, pre-freeze 5 hours, temperature drops to-35 ℃, distils 8 hours for the first time, and temperature rises to-5 ℃; Distilled 7 hours for the second time, temperature rises to 25 ℃, and vacuum-drying promptly, through proton nmr spectra, carbon-13 nmr spectra, differential thermal analysis TG-DTA collection of illustrative plates, shows that products therefrom is Compound D one meglumine and hydrate thereof to constant weight.
Optionally, with purifying, the solvent of recrystallization can be selected acetone-water mixing solutions, alcohol-water mixing solutions, methanol-water mixing solutions or ether-water mixed solution for use with above-mentioned Compound D one meglumine and the further recrystallization of hydrate thereof.
Compound D one meglumine of above-mentioned preparation or its hydrate all are consistent with embodiment 4 through proton nmr spectra, carbon spectrum analysis.
The lyophilized injectable powder of embodiment 6. Compound D two meglumines
Compound D two meglumine 30g (during Compound D two meglumine hydrates in Compound D two meglumines)
N.F,USP MANNITOL 120g
The pH buffer reagent is an amount of
Water for injection adds to 2500ml
Compound D two meglumines, the N.F,USP MANNITOL of getting recipe quantity add the dissolving of 2300ml water for injection, regulating pH is 7～8, adds the injection water to 2500ml, with the filtering with microporous membrane degerming, under hundred grades of conditions, carry out in sterile filling to 1000 cillin bottle, add plug after checking loading amount, box out, the glass bottle is sent into to carry out freeze-drying in the disinfectant freeze drying box dry, pre-freeze 5 hours, temperature drops to-35 ℃, distils 8 hours for the first time, and temperature rises to-5 ℃; Distilled 7 hours for the second time, temperature rises to 25 ℃, takes out behind vacuum gland or the inflated with nitrogen gland, and jewelling lid labeling gets product, and every bottle of freeze-dried powder contains Compound D two meglumine 30mg.
The lyophilized injectable powder of embodiment 7. Compound D two meglumines
Compound D two meglumine 25g (during Compound D two meglumine hydrates in Compound D two meglumines)
Sodium-chlor 18g
Glucose 30g
Calcium Disodium Edetate 0.15g
The pH regulator agent is an amount of
Water for injection adds to 2000ml
Compound D two meglumines, sodium-chlor, the glucose of getting recipe quantity adds and adds the Calcium Disodium Edetate dissolving after 1800ml water for injection dissolves, regulating pH is 8～9, add the injection water to 2000ml, stir with 0.3% (w/v) needle-use activated carbon, stirred 30 minutes down in 45 ℃, take off charcoal with 0.6 μ m filter membrane through sterilization, after 0.22 μ m membrane filtration degerming, surveying and transferring pH is 8～9, the filtrate can is sent into the freeze drier freeze-drying in 1000 control cillin bottles, add a cover or inflated with nitrogen after add a cover taking-up, label promptly, wherein freeze-drying curve is as follows:
| ? | Operation | Temperature rise rate | Temperature (℃) |
| 1 | Pre-freeze | ? | Be refrigerated to-40 ℃ by |
| 2 | Insulation | ? | -35℃ |
| 3 | Vacuumize | ? | -35℃ |
| 4 | Heat up | 6 ℃/hour | Be warming up to-5 ℃ |
| 5 | Heat up | ? | -5 ℃ are warming up to 0 ℃ |
| 6 | Heat up | ? | 0 ℃ is warming up to 10 ℃ |
| 7 | Heat up | ? | 10 ℃ are warming up to 25 ℃ |
| 8 | Insulation | ? | 25℃ |
The above-mentioned freeze-dried powder that makes, every bottle contains Compound D two meglumines is 25mg.
Embodiment 8. presses the method for embodiment 6 or embodiment 7, adjust the recipe quantity of Compound D two meglumines and/or pharmaceutical carrier (or auxiliary material), being prepared into every bottle, to contain Compound D two meglumines be the lyophilized injectable powder of 5～100mg, and for example being prepared into every bottle, to contain Compound D two meglumines be the lyophilized injectable powder of 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg or 100mg.
The injection of embodiment 9. Compound D two meglumines, Compound D one meglumine, its hydrate or its solvate
With any described Compound D meglumine salt, its hydrate or its solvate among the embodiment 1～5, select conventional pharmaceutical excipient for use, mix with pharmaceutical excipient, press the preparation method of injection, be prepared into freeze-dried powder injection or injection liquid, every bottle of freeze-dried powder injection or injection liquid contain the Compound D meglumine salt of 0.1～500mg.
The tablets/capsules agent of embodiment 10. Compound D two meglumines, Compound D one meglumine, its hydrate or its solvate
With any described Compound D meglumine salt, its hydrate or its solvate among the embodiment 1～5, select conventional pharmaceutical excipient for use, mix with pharmaceutical excipient, press the preparation method of tablet or capsule, be prepared into tablet or capsule, every tablet or capsule contain the Compound D meglumine salt of 0.1～500mg.
Embodiment 11. mixes the meglumine of 0.1mol Compound D and 0.2mol in 1 liter of deionized water, obtain settled solution, filters the back and is spin-dried for Rotary Evaporators, promptly obtains containing Compound D and meglumine pharmaceutical composition.
Embodiment 13. sour reversible reduction experiments
Get Compound D two meglumines, Compound D one meglumine, its hydrate or each about 0.1g of its solvate of the foregoing description preparation respectively, be dissolved in the 20ml distilled water, it is about 1 that dripping hydrochloric acid is transferred pH, all have precipitation and separate out, collect, analyze, consistent with the spectrogram of Compound D, confirm as Compound D, illustrate that the meglumine salt of The compounds of this invention D has only changed the pharmaceutical property of Compound D, rather than change its pharmacological action.
Compound D meglumine salt and preparation thereof that embodiment 1 to embodiment 10 is prepared, application in the following areas:
Application in preparation treatment acute ischemic cerebral apoplexy medicine;
Application in the medicine of brain injury that preparation treatment cardiac operation under direct vision causes and traumatic brain injury;
Application in the medicine of preparation treatment DPN disease;
Application in the medicine of preparation treatment Parkinson's disease and alzheimer's disease.
Claims (10)
1. the compound shown in the formula I, its hydrate or its solvate:
N=2 or 1 wherein.
2. compound according to claim 1, its hydrate or its solvate, it comprises:
3. the preparation method of claim 1 or 2 described compounds, its hydrate or its solvate, it is included in the solvent Compound D is contacted with meglumine, choose wantonly, in containing the solution of Compound D, add meglumine, perhaps in containing the solution of meglumine, add Compound D, perhaps the solution that contains Compound D is mixed with the solution that contains meglumine, the reaction salify, described solvent is selected from the mixing of one or more solvents in ethanol, methyl alcohol, Virahol, acetone, acetonitrile, ethyl acetate, water, N,N-DIMETHYLACETAMIDE, the dimethyl formamide; Described temperature of reaction be in room temperature to the reflux temperature condition of solvent.
4. claim 1 or 2 described compounds, the preparation method of its hydrate or its solvate, it is included in room temperature to the reflux temperature condition of solvent, with mol ratio is 1: the Compound D of (1～1.1) contacts in solvent with meglumine, the reaction salify, and under room temperature or subambient condition, make institute's salify crystallization, filter, dry, promptly, wherein said solvent is selected from ethanol, methyl alcohol, Virahol, acetone, acetonitrile, ethyl acetate, water, N,N-DIMETHYLACETAMIDE, the mixing of one or more solvents in the dimethyl formamide optionally can be by reducing Tc or/and steam except that the formation of partial solvent with accelerate crystallisation; Perhaps,
Being 1: 1 Compound D and meglumine with mol ratio makes them dissolve fully in suitable quantity of water in 5～80 ℃, stir, and lyophilize, promptly.
5. claim 1 or 2 described compounds, the preparation method of its hydrate or its solvate, it is included in room temperature to the reflux temperature condition of solvent, with mol ratio is 1: the Compound D of (2～2.2) contacts in solvent with meglumine, the reaction salify, and under room temperature or subambient condition, make institute's salify crystallization, filter, dry, promptly, wherein said solvent is selected from ethanol, methyl alcohol, Virahol, acetone, acetonitrile, ethyl acetate, water, N,N-DIMETHYLACETAMIDE, the mixing of one or more solvents in the dimethyl formamide optionally can be by reducing Tc or/and steam except that the formation of partial solvent with accelerate crystallisation; Perhaps,
Being 1: 2 Compound D and meglumine with mol ratio makes them dissolve fully in suitable quantity of water in 5～80 ℃, stir, and lyophilize, promptly.
6. a pharmaceutical composition contains claim 1 or 2 described any compound and pharmaceutically acceptable carrier.
7. a pharmaceutical composition contains claim 1 or 2 described any compound and pharmaceutically acceptable carrier, and wherein the content of claim 1 or 2 described any compounds is 0.1～500mg.
8. claim 6 or 7 described preparation of drug combination methods comprise Compound D one meglumine, Compound D two meglumines, its hydrate or its solvate and pharmaceutically acceptable carrier thorough mixing are made acceptable any pharmaceutical dosage form on the pharmaceutics.
9. the pharmaceutical composition that forms of mixing cpd comprises compound and meglumine with following structural formula:
10. claim 1 or 2 described compounds, its hydrate or the application in the following areas of its solvate:
Application in preparation treatment acute ischemic cerebral apoplexy medicine;
Application in the medicine of brain injury that preparation treatment cardiac operation under direct vision causes and traumatic brain injury;
Application in the medicine of preparation treatment DPN disease;
Application in the medicine of preparation treatment Parkinson's disease and alzheimer's disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105709656A CN102126973A (en) | 2009-11-26 | 2010-11-24 | Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910224894.1 | 2009-11-26 | ||
| CN200910224894 | 2009-11-26 | ||
| CN2010105709656A CN102126973A (en) | 2009-11-26 | 2010-11-24 | Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102126973A true CN102126973A (en) | 2011-07-20 |
Family
ID=44085940
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010570080.6A Expired - Fee Related CN102079715B (en) | 2009-11-26 | 2010-11-24 | Lysine salt compound of binary ester acid, preparation method and medicinal application |
| CN201010571076.1A Expired - Fee Related CN102079717B (en) | 2009-11-26 | 2010-11-24 | Arginine salt compound of dibasic ester acids and preparation method and medicinal application thereof |
| CN2010105709656A Pending CN102126973A (en) | 2009-11-26 | 2010-11-24 | Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof |
| CN201010571246.6A Expired - Fee Related CN102093234B (en) | 2009-11-26 | 2010-11-24 | Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010570080.6A Expired - Fee Related CN102079715B (en) | 2009-11-26 | 2010-11-24 | Lysine salt compound of binary ester acid, preparation method and medicinal application |
| CN201010571076.1A Expired - Fee Related CN102079717B (en) | 2009-11-26 | 2010-11-24 | Arginine salt compound of dibasic ester acids and preparation method and medicinal application thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010571246.6A Expired - Fee Related CN102093234B (en) | 2009-11-26 | 2010-11-24 | Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (4) | CN102079715B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373957A (en) * | 2012-04-12 | 2013-10-30 | 成都苑东药业有限公司 | Chelate with functions of protecting nerve cells |
| KR102200892B1 (en) * | 2019-05-13 | 2021-01-12 | 대원제약주식회사 | Novel salts of pelubiprofen, preparation method thereof and pharmaceutical compositions comprising thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999016741A2 (en) * | 1997-09-28 | 1999-04-08 | D-Pharm Limited | Lipophilic diesters of chelating agents |
| CN1899275A (en) * | 2005-07-11 | 2007-01-24 | 江苏联创医药技术有限公司 | Composition of rheinic acid or rheinic acid compounds, its preparing method and its use in preparing medicine for treating osteoarthritis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923798A (en) * | 2005-08-30 | 2007-03-07 | 陈亦林 | Preparation method of dexibuprofen amino acid salt and application |
| CN1944378A (en) * | 2006-10-23 | 2007-04-11 | 广东中科药物研究有限公司 | Biphenyl ammonia acetate butantriol salt and its preparing method |
| CN101514189B (en) * | 2008-02-18 | 2012-07-04 | 杨喜鸿 | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof |
| CN101486644B (en) * | 2009-02-24 | 2012-07-25 | 合肥工业大学 | Preparation of arginine acetylsalicylate |
-
2010
- 2010-11-24 CN CN201010570080.6A patent/CN102079715B/en not_active Expired - Fee Related
- 2010-11-24 CN CN201010571076.1A patent/CN102079717B/en not_active Expired - Fee Related
- 2010-11-24 CN CN2010105709656A patent/CN102126973A/en active Pending
- 2010-11-24 CN CN201010571246.6A patent/CN102093234B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999016741A2 (en) * | 1997-09-28 | 1999-04-08 | D-Pharm Limited | Lipophilic diesters of chelating agents |
| CN1899275A (en) * | 2005-07-11 | 2007-01-24 | 江苏联创医药技术有限公司 | Composition of rheinic acid or rheinic acid compounds, its preparing method and its use in preparing medicine for treating osteoarthritis |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102093234A (en) | 2011-06-15 |
| CN102093234B (en) | 2014-06-18 |
| CN102079717A (en) | 2011-06-01 |
| CN102079717B (en) | 2014-01-22 |
| CN102079715B (en) | 2014-07-23 |
| CN102079715A (en) | 2011-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5671560B2 (en) | Tetracycline metal complexes in solid dosage forms. | |
| CN101633662A (en) | Prasugrel pharmaceutical acid addition salt as well as preparation method and pharmaceutical application thereof | |
| MXPA05008784A (en) | Ferric organic compounds, uses thereof and methods of making same. | |
| CN101412690A (en) | Medicinal acid addition salt of silodosin, and preparation and medicament use thereof | |
| CN108938626B (en) | Carbazochrome sodium sulfonate pharmaceutical composition with good stability and high safety as well as preparation method and application thereof | |
| US10428086B2 (en) | Solvated crystal form of rifaximin, production, compositions and uses thereof | |
| CN103087042B (en) | Salts of sitafloxacin and pharmaceutical purposes thereof | |
| CN100584835C (en) | Novel medicinal salt for cinepazide and preparation method thereof | |
| CN101597271A (en) | The derivative of Ailamode, its preparation method and medicinal application | |
| CN111825547B (en) | Salt of aryl propionic acid compound and pharmaceutical application thereof | |
| CN102093234B (en) | Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof | |
| JP2013184902A (en) | Rifaximin containing crystal | |
| CN115124420B (en) | Rhein and matrine eutectic hydrate, preparation method, composition and application thereof | |
| CN103214459B (en) | Pantoprazole sodium crystalline compound, pharmaceutical composition and preparation method thereof | |
| CN102351881B (en) | Stable levofloxacin hydrochloride compound | |
| CN102442942A (en) | Polymorphic substances of 4-aminopyridine, and preparation and application thereof | |
| CN101514189B (en) | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof | |
| CN115124419B (en) | Rhein and cytisine eutectic crystal, preparation method, composition and application thereof | |
| CN115120588A (en) | Eutectic crystal of rhein and sophocarpine, preparation method, composition and application thereof | |
| JP3281872B2 (en) | Salts of 7-isoindoline-3-quinolinecarboxylic acid, hydrates thereof and compositions containing them as active ingredients | |
| JPS58966A (en) | Salts of antibacterial naphthyridine and quinoline compound | |
| CN111100122A (en) | Novel levo-tetrahydropalmatine compound | |
| CN108148097A (en) | Benzimidazoles compound cobalt complex and its application containing pyridine | |
| CN101205205A (en) | Alanine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20110720 |