CN102093234B - Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof - Google Patents
Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof Download PDFInfo
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Abstract
The invention relates to a tromethamine salt compound of a derivative (compound D) of dibasic ester acid, which comprises diamido-butantriol, monoamino-butantriol, a hydrate or a solvate of the tromethamine salt compound. The tromethamine salt compound has good water solubility and stability and improves untoward effects such as muscular stimulation, muscle stimulation, and the like of the metal salt of the compound while injection. The invention also provides a preparation method and medicinal application of the tromethamine salt compound.
Description
Technical field the invention belongs to pharmaceutical technology field, relates to a kind of derivative salt compound of dibasic ester acid, and concrete is its Trometamol salt compound, and preparation method thereof the application in medicine with them.
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:
The open WO99/16741 of international application discloses the chemical structural formula of Compound D.
Compound D, as a kind of nerve protection medicine of new acute apoplexy, has been applied to clinical study.But 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; On the other hand, metal ion type salt has short Decomposition for two ester group structures in Compound D structure, is unfavorable for stability and the application of medicine; Again on the one hand, the metal-salts such as the disodium salt of Compound D, in the time that injection is used, tend to cause the stronger untoward reaction such as vascular stimulation, muscular irritation.
Common, make target compound form salt formula compound, be the top-priority method of improving target compound.For the application of 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, or to meet medicine regulatory authority require favourable, for example, be conducive to the clinical application of medicine, improve the compliance of patient's medication, be conducive to the result for the treatment of of medicine.
Summary of the invention, under the prerequisite of pharmacological action that does not change Compound D, improves water-soluble, the stability of Compound D, and the untoward reaction such as vascular stimulation, muscular irritation while improving injection use, is very important and significant.Contriver is through experiment discovery, and the non-metal salt of Compound D can improve the weak point of Compound D or its metal-salt.
In Compound D molecular structure, contain two carboxyls, contriver finds through experiment, adopts water-soluble good alkaline matter----Trometamol, with the carboxylic group coordination salify of Compound D, can significantly improve the water-soluble of Compound D.But, in the time considering to improve water-soluble, also to consider the pharmacological action that can not change and destroy Compound D, and with it the alkaline coordination material of salify not only basicity is suitable, and nontoxic to human-body safety, also to consider that institute's salt-forming compound should have satisfactory stability and physical appearance, is applied to pharmaceutical preparation using the derivative salt that is convenient to Compound D as active constituents of medicine.Further, to there is good promoter action for the stability of Compound D; In addition, the untoward reaction such as blood vessel pain, muscular irritation can improve its injection use time.
Trometamol, has another name called three (methylol) aminomethane, and chemistry is by name: TRIS, molecular formula C
4h
11nO
3, Trometamol belongs to alkaline matter, and good stability is nonhygroscopic, high to human safety, and injection or oral equal safety non-toxic use as auxiliary material in multi-medicament prescription.
Based on above consideration and requirement, the inventor by experiment and screening, completed the compounds of this invention D tromethamine salt, it comprises Compound D two Trometamols, Compound D one Trometamol, its hydrate or its solvate.
Further, the invention provides the preparation method of Compound D tromethamine salt; The present invention also provides the medicinal application of Compound D tromethamine salt.
The invention provides the compound shown in formula I, its hydrate or its solvate:
Compound D one Trometamol:
Compound D two Trometamols:
Concrete, the salt compound of Compound D provided by the invention and Trometamol, it comprises Compound D one Trometamol, Compound D two Trometamols, with and hydrate or its solvate.
Should illustrate, and those skilled in the art should be familiar with and understand, due to the external neutral of compound of institute of the present invention salify or electrically not aobvious, therefore, the compound of institute of the present invention salify 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, in compound due to institute of the present invention salify, with the molecule number of the Trometamol of a part Compound D coordination salify be 1 or 2, in the expression of molecular structure, by the molecular digital of Trometamol be marked on Trometamol molecular formula above with the suffix that is marked on Trometamol molecular formula, be all the same, for example, the compound of institute of the present invention salify can also represent by the chemical structure of following general formula I I-2 or general formula III-2:
Molecular formula C
42h
64n
2o
12.C
4h
11nO
3,
Molecular formula C
42h
64n
2o
12. (C
4h
11nO
3)
2.
What formula II-1, formula II-2 and formula II represented is same compound, i.e. Compound D one Trometamol;
What formula III-1, formula III-2 and formula III represented is same compound, i.e. Compound D two Trometamols.
The Trometamol salt compound of the compounds of this invention D is a kind of solid chemical compound, there is 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 hydrate or the solvate of above-claimed cpd D Trometamol.
For example, the semihydrate of Compound D two Trometamols of the present invention, monohydrate, sesqui hydrate, dihydrate, two times of semihydrates, trihydrate, three times of semihydrates, tetrahydrate, four times of semihydrates, pentahydrate, five times of semihydrates, hexahydrate, six times of semihydrates, heptahydrate, seven times of semihydrates, eight hydrates, octuple semihydrate, nonahydrate, nine times of semihydrates or decahydrate, etc.;
For example, the semihydrate of Compound D one Trometamol of the present invention, monohydrate, sesqui hydrate, dihydrate, two times of semihydrates, trihydrate, three times of semihydrates, tetrahydrate, four times of semihydrates, pentahydrate, five times of semihydrates, hexahydrate, six times of semihydrates, heptahydrate, seven times of semihydrates, eight hydrates, octuple semihydrate, nonahydrate, nine times of semihydrates or decahydrate, etc.
Again for example, the solvent molecule that Compound D two Trometamols of the present invention contain half molecule, 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, etc.;
Again for example, the solvent molecule that Compound D one Trometamol of the present invention contains half molecule, 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, etc.
Should illustrate, above-mentioned many compounds of this invention D bis-Trometamols of enumerating or hydrate or the solvate of Compound D one Trometamol, just the compounds of this invention D Trometamol contingent situation in crystallization or purge process, any hydrate or solvate in them, it is only the existence form of the compounds of this invention D derivative material, contained crystal water or recrystallisation solvent normally can be controlled or remove, for example by adding thermal burn or turning crystalline substance, crystal water or recrystallisation solvent are removed, 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 Trometamol, its hydrate or its solvate, it is included in solvent Compound D is contacted with Trometamol, 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, dimethyl formamide; Described temperature of reaction be in room temperature to the reflux temperature condition of solvent, make Compound D react salify with Trometamol.
In embodiments of the invention scheme, described Compound D Trometamol, its hydrate or solvate is as described in the unrestricted embodiment of compound of the present invention, in information as herein described, by with such as described similar method, in the solution that contains Compound D, add Trometamol, or add Compound D in the solution that contains Trometamol, or the solution that contains Compound D is mixed with the solution that contains Trometamol, to reach, Compound D is contacted to the object of reaction salify with Trometamol.
For the preparation of Compound D one Trometamol, its hydrate or solvate, concrete,
In room temperature to the reflux temperature condition of solvent, be 1 by mol ratio: the Compound D of (1～1.1) contacts in solvent with Trometamol, reaction salify, and under room temperature or the condition lower than room temperature, make institute's salify crystallization, filter, after washing, drain, dry, obtain Compound D one Trometamol, 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 dimethyl formamide, optionally can be by reducing Tc or/and steam except partial solvent is to accelerate the formation of crystallization, or,
The Compound D that is 1: 1 by mol ratio and Trometamol make them dissolve completely in 5～80 DEG C in suitable quantity of water, stir, and lyophilize, obtains Compound D one Trometamol or its hydrate.
For the preparation of Compound D two Trometamols, its hydrate or solvate, concrete,
In room temperature to the reflux temperature condition of solvent, be 1 by mol ratio: the Compound D of (2～2.2) contacts in solvent with Trometamol, reaction salify, and under room temperature or the condition lower than room temperature, make institute's salify crystallization, filter, after washing, drain, dry, obtain Compound D two Trometamols, 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 dimethyl formamide, optionally can be by reducing Tc or/and steam except partial solvent is to accelerate the formation of crystallization, or,
The Compound D that is 1: 2 by mol ratio and Trometamol make them dissolve completely in 5～80 DEG C in suitable quantity of water, stir, and lyophilize, obtains Compound D two Trometamols or its hydrate.
For Compound D, can be synthetic according to following operational path, be mainly calcium sequestrant BAPTA (two (adjacent amino-benzene) ethane-N of chemical name: 1,2-, N, N ', N '-tetra-acetyl acid) and bromooctane with raw material:
For Trometamol, conventionally can commercially obtain.
Further, the invention provides the pharmaceutical composition that contains Compound D two Trometamols, Compound D one Trometamol, its hydrate or its solvate and pharmaceutically acceptable carrier.
Can pass through the administration Compound D tromethamine salt of the present invention of any appropriate, but conventionally by parenterai administration or oral administration, be preferably injection system.In order to carry out this class application, generally use the salt of Compound D of the present invention with the pharmaceutical compositions that contains pharmaceutically acceptable carrier, but, the exact form of said composition depends on form of medication naturally.
Concrete, the present invention also provides one to contain Compound D two Trometamols of the present invention, Compound D one Trometamol, the pharmaceutical composition of its hydrate or its solvate, and contain one or more pharmaceutically acceptable carrier, wherein Compound D two Trometamols, Compound D one Trometamol, 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.
Taking the compounds of this invention D bis-Trometamols, Compound D one Trometamol, its hydrate or its solvate as active ingredient, and contain one or more pharmaceutically acceptable pharmaceutical carriers, be mixed with the form through any suitable administration, can prepare any pharmaceutical dosage form of acceptable in pharmaceutics, comprise injection formulations, oral preparations, parenteral liquid preparation, etc., as injection, comprise powder ampoule agent for injection and injection liquid, etc.; And for example oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent etc.; For another example the emulsion of parenteral eye drop, nasal drops, [Dan, Transdermal absorption, etc.Also can be the formulations such as the 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, etc.Especially, by 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 in 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 meet the various needs in 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, conventionally select or be used in combination according to different medicaments, optionally comprise vehicle or thinner, for example, 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, cyclodextrin derivative one or more, etc.; Also can comprise tackiness agent, for example, in polyvidone (polyvinylpyrrolidone), methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, guar gum, xanthan gum one or more, etc.; Also comprise lubricant, for example, in Magnesium Stearate, stearic acid, talcum powder, stearyl fumarate, Sodium Lauryl Sulphate BP/USP one or more, etc.; Also can comprise disintegrating agent, for example, in sodium starch glycolate, low-substituted hydroxypropyl cellulose, Xylo-Mucine, cross-linked polyvinylpyrrolidone, croscarmellose sodium, crosslinked carboxymethyl fecula sodium, pregelatinized Starch one or more, etc.; Also comprise tensio-active agent, for example, in sodium lauryl sulphate, Tween-80 one or more, etc.; Also can comprise pH value conditioning agent or buffer reagent, one or more of for example phosphate buffered saline buffer, citric acid, Trisodium Citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, etc.; Also can comprise sanitas, for example, in Sodium Benzoate, potassium sorbate, methyl p-hydroxybenzoate, propylparaben one or more, etc.; Also can comprise stablizer and oxidation inhibitor, for example, in Calcium Disodium Edetate, S-WAT, vitamins C one or more, etc.; Also can comprise taste conditioning agent, for example, in maltose alcohol, fructose, sucrose, soluble saccharin, flavoring orange essence, strawberry flavour one or more, etc.; Also can comprise in addition additive other routine, appropriate.
Should be appreciated that above-mentioned " optionally comprising " both referred to also can not use optionally choice for use.
It is also understood that when agent type is tablet or capsule, can be film dressing.For the material of film dressing, comprise applicable Drug coating, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, etc.; Also can comprise softening agent, for example polyoxyethylene glycol, triethyl citrate, etc.; Also comprise suitable solubilizing agent, as Polyoxyethylene Sorbitan Monooleate; Also can comprise suitable pigment, as titanium dioxide, various ferric oxide, pink pigment, etc.
Pharmaceutical composition as above, contain one or more pharmaceutically acceptable pharmaceutical carriers, be mixed with the form through any suitable administration, can prepare any pharmaceutical dosage form of acceptable in pharmaceutics, Compound D two Trometamols, Compound D one Trometamol, its hydrate or its solvate are active substances wherein, in pharmaceutical composition, can also comprise other and have the material of pharmaceutical active, form a kind of pharmaceutical composition of compound, carry out combination therapy.
Further, the preparation method of pharmaceutical composition of the present invention, the method comprises Compound D two Trometamols, Compound D one Trometamol, its hydrate or its solvate and pharmaceutically acceptable carrier are fully mixed and made into acceptable any pharmaceutical dosage form in 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 etc.
Concrete, the preparation method of pharmaceutical composition as above, the method comprises Compound D two Trometamols, Compound D one Trometamol, its hydrate or its solvate and pharmaceutically acceptable pharmaceutical carrier are fully mixed and made into acceptable any pharmaceutical dosage form in 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, parenteral liquid preparation, for example parenteral eye drop, nasal drops, [Dan, the emulsion of Transdermal absorption, cutaneous permeable agent (comprises the emulsifiable paste of Transdermal absorption, gel, emulsion, emulsion agent, patch etc.), Deng.
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 Compound D and the Trometamol of structural formula below by mixing:
Be to be understood that, mixing cpd D and Trometamol, can be to carry out in solvent, for example in the environment that has water, carry out, as: preferably in purified water (as deionized water or distilled water) or/and mix in ethanol, dissolve, further adopt dry, Rotary Evaporators is dry, drying under reduced pressure or vacuum-drying, cryodesiccated method obtain pharmaceutical composition; Also can be that the pressed powder of Compound D and the pressed powder of Trometamol mix, for example, adopt the preparation method of solid dispersion to be obtained by mixing pharmaceutical composition.
The invention still further relates to Compound D two Trometamols, Compound D one Trometamol, its hydrate or the application in the following areas of its solvate:
Application in preparation treatment Acute ischemic stroke medicine;
Application in the brain injury causing in preparation treatment cardiac operation under direct vision and the medicine of 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.
Brief description of the 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 bis-Trometamols, Compound D one Trometamol, its hydrate or its solvate, its alkaline ligand is safe and reliable, human body is not had to extra side effect, and the stable in properties of the compounds of this invention D bis-Trometamols, Compound D one Trometamol, 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 conventionally, generates its monoesters analogue and other impurity, is referred to as total related substance, under hot conditions, measures the wherein content of total related substance, analyzes its stability.
Get respectively appropriate Compound D two Trometamols, Compound D one Trometamol, Compound D disodium, put in weighing bottle and be positioned in 50 DEG C of baking ovens, respectively at sampling in the 5th, 10 days, measure total related substance wherein.
Adopt high-efficient liquid phase chromatogram technique analysis, test-results is in table 1.
Table 1
Measurement result shows, 50 DEG C of Compound D two Trometamols, Compound D one Trometamol, Compound D disodium high temperature are 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 Trometamols, Compound D one Trometamol, total related substance percentage composition net added value the 10th day time, Compound D disodium is the more than 1.5 times of Compound D one Trometamol, is that Compound D two Trometamols are more than 1.9 times.Can find out, the stability of Compound D two Trometamols, Compound D one Trometamol significantly improves than Compound D disodium.
2. the compounds of this invention D bis-Trometamols, Compound D one Trometamol, its hydrate or its solvate is water-soluble good, has improved the water-soluble of Compound D.
Through rough determination comparison, Compound D two Trometamols, Compound D one Trometamol, Compound D water dissolution characteristic (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 bis-Trometamols, the water-soluble Compound D that is far longer than of Compound D one Trometamol, show the water-soluble of its excellence.
The compounds of this invention D bis-Trometamols, Compound D one Trometamol, its hydrate or its solvate excellence water-soluble for Compound D, the stripping in preparation has good promoter action.Especially for oral preparations, significant.
Be to be understood that, oral medicament need to just can enter blood of human body to reach therapeutic action through GI absorption, and the quality of oral absorption directly affects the result for the treatment of of medicine.According to the concept of pharmaceutics, bioavailability (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 tromethamine salt has excellent water-soluble, enters aspect sanguimotor degree and speed in absorption for the oral drug preparation taking it as active ingredient, has important promoter action and meaning.Medicament enters the absorption process after stomach and intestine, divide two stages, it is two stages of disintegration dispersion and Gastrointestinal Wall Absorption, 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 absorbing and the performance of drug effect of medicine, Compound D is prepared as to 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 are greatly improved, 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 bioavailability of efficacy component Compound D tromethamine salt is significant.
4. the compounds of this invention D bis-Trometamols, Compound D one Trometamol, its hydrate or its solvate, in the time that injection is used, have improved the untoward reaction such as vascular stimulation, muscular irritation, are significantly 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 Trometamol injection liquid group (physiological saline solution, phosphoric acid salt is adjusted PH=7 ± 0.5, 1mg/ml), Compound D two Trometamol injection liquid group (physiological saline solutions, phosphoric acid salt is adjusted PH=7 ± 0.5, 1mg/ml), Compound D two sodium injection group (physiological saline solutions, phosphoric acid salt is adjusted PH=7 ± 0.5, 1mg/ml) with normal saline solution group, every group 8, 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 Trometamol injection liquid 1.1mg/kg, 1 time/d;
The 2nd group of auricular vein injection Compound D two Trometamol injection liquid 1.24mg/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 injection liquid 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 systemic 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 makes pathologic finding.
Inflammatory response deciding degree vein inflammatory level of response judging criterion: under light microscopic, be divided into 4 grades according to Inflammatory response degree,
NIP reaction (-): rarely seen vein is reticular tissue congestion and edema around;
Mild inflammation (+): blood vessel around reticular tissue is shown in lymphocyte, plasmocyte infiltrating, and vessel wall and lumen of vessels have no inflammatory cell;
Moderate inflammation (++): blood vessel around each layer of reticular tissue and vessel wall has lymphocyte, plasmocyte and a little neutrophil infiltration;
Hyperphlogosis (+++): blood vessel is reticular tissue, each layer of vessel wall and the visible diffusivity lymphocyte of lumen of vessels, neutrophil infiltration around, the visible more exudate of Endovascular and downright bad cell debris.
Each group rabbit Inflammatory response situation the results are shown in Table 3.
Table 3
Result is visible, normal saline solution group does not have venous injury substantially, Compound D two Trometamol injection liquid groups have the slight venous injury of 3 example, Compound D one Trometamol injection liquid group has the slight venous injury of 4 example, there is no moderate to hyperphlogosis, and Compound D two sodium injection group venous injury are serious, only 1 routine mild inflammation, all the other are moderate to hyperphlogosis, show that Compound D Trometamol saline injection 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, those of ordinary skill in the art do not depart from the scope of the present invention with the basis of spirit on the various embodiments that produce and modify apparent and be easily to carry out, the invention is not restricted to the scope of specific embodiment as herein described, really, various modification of the present invention, except those that narrated are to be understood by those skilled in the art from narration above.Carry out the derivative salt compound to the compounds of this invention D by the following examples, and preparation method thereof should be used as further in medicine illustrates with it, but do not represent embodiment limitation of the present invention.
In 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 described similar method below, in Compound D, add the Trometamol of needs, or in the solution that contains Trometamol, add the Compound D of needs, or the solution that contains Compound D is mixed with the solution that contains Trometamol, to reach, Compound D is contacted to the object of reaction salify with Trometamol.
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。
In mass spectroscopy: 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 Trometamols and preparations thereof
Getting 1g (1.267mmol) Compound D adds in 90ml Virahol, stir and heat and make to dissolve completely, add the solution of 0.31g (2.54mmol) Trometamol in 190ml Virahol, slowly add and stir, more than finishing rear insulated and stirred 30min, be down to room temperature, optionally can be with steaming at 35 DEG C of Rotary Evaporators except partial solvent, put in refrigerator cooling, make its sufficient crystallising, suction filtration, 6ml cold isopropanol washing for filter cake, vacuum-drying, to constant weight powder, obtains Compound D two Trometamols.
1HNMR(DMSO-d
6)δ(ppm)：0.833～0.855(6H，t)，1.227(23H，s)，1.431(4H，s)，3.302(4H，m)，3.418(4H，d)，3.630(4H，s)，3.912(4H，s)，4.168(8H，d)，5.801(10H，broad s)，6.785(6H，s)，6.887(2H，d)。
13CNMR(DMSO-d
6)δ(ppm)：13.982，22.147，25.627，28.756，28.908，29.168，31.320，53.495，55.556，60.104，60.271，63.141，66.926，67.719，70.314，113.383，118.190，120.266，121.029，140.442，149.431，171.789，174.888。
Embodiment 2. Compound D two Trometamols and preparations thereof
Get 1g (1.267mmol) Compound D and add in 55ml ethanol, stir and heat and make to dissolve completely, add the solution of 0.31g (2.54mmol) Trometamol in 60ml ethanol, slowly add and stir, more than finishing rear insulated and stirred 30min, be down to room temperature, optionally can steam except partial solvent with Rotary Evaporators, put in refrigerator cooling, make its sufficient crystallising, suction filtration, the cold ethanol of 5ml or washing with acetone for filter cake, vacuum-drying, to constant weight, obtains Compound D two Trometamols.
Compound D two Trometamols of above-mentioned preparation or its hydrate, through proton nmr spectra, carbon spectrum analysis, are all consistent with embodiment 1.
Embodiment 3. Compound D two Trometamols or its hydrate and preparations thereof
Getting 1g (1.267mmol) Compound D adds the stirring of 20ml distilled water to obtain suspension, the solution of the Trometamol that adds 2.534mmol under stirring in 8ml distilled water, slowly adds and stirs, and finishes more than 30～45 DEG C of rear insulations stir 10min, make to form clear and bright solution, be down to room temperature, by cryodesiccated common process, send into that in the freeze drying box of having sterilized, to carry out freeze-drying dry, pre-freeze 5 hours, temperature drops to-35 DEG C, distils for the first time 8 hours, and temperature rise is to-5 DEG C; Distil for the second time 7 hours, temperature rise to 25 DEG C, vacuum-drying, to constant weight, to obtain final product, and 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 Trometamols and hydrate thereof.
Optionally, by above-mentioned Compound D two Trometamols and the further recrystallization of hydrate thereof, 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.
Compound D two Trometamols of above-mentioned preparation or its hydrate, through proton nmr spectra, carbon spectrum analysis, are all consistent with embodiment 1.
Embodiment 4. Compound D one Trometamol and preparations thereof
Getting 1g (1.267mmol) Compound D adds in 60ml methyl alcohol, stir and be heated to 50 DEG C and make to dissolve completely, add the solution of 0.153g (1.267mmol) Trometamol in 25ml methyl alcohol, slowly add and stir, more than finishing rear insulated and stirred 30min, be down to room temperature, optionally can steam except partial solvent with Rotary Evaporators, put in refrigerator cooling, make its sufficient crystallising, suction filtration, 4ml cold methanol washing for filter cake, vacuum-drying, to constant weight, obtains Compound D one tromethamine salt.
1HNMR(DMSO-d
6)δ(ppm)：0.833～0.856(6H，t)，1.226～1.271(22H，m)，1.418～1.440(4H，m)，3.293～3.305(4H，m)，3.365～3.402(2H，m)，3.641(4H，s)，3.993(8H，d)，4.132(4H，s)，4.201(2H，s)，5.813(7H，broad s)，6.720～6.734(6H，m)，6.813～6.843(4H，m)，6.934～6.950(2H，m)。
13CNMR(DMSO-d
6)δ(ppm)：13.952，22.139，25.630，28.761，28.898，29.172，31.331，39.637，53.513，55.564，60.088，60.293，63.148，67.011，67.722，70.350，113.401，118.121，120.358，121.156，140.389，149.437，171.793，172.251，175.103。
Embodiment 5. Compound D one Trometamol or its hydrate and preparations thereof
Getting 1g (1.267mmol) Compound D adds the stirring of 20ml distilled water to obtain suspension, the Trometamol aqueous solution that adds 1.267mmol under stirring, slowly adds and stirs, more than finishing 30～45 DEG C of stirring 10min of rear insulation, make to form clear and bright solution, be down to room temperature, by cryodesiccated common process, send into that in the freeze drying box of having sterilized, to carry out freeze-drying dry, pre-freeze 5 hours, temperature drops to-35 DEG C, distils for the first time 8 hours, and temperature rise is to-5 DEG C; Distil for the second time 7 hours, temperature rise to 25 DEG C, vacuum-drying, to constant weight, to obtain final product, and 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 Trometamol and hydrate thereof.
Optionally, by above-mentioned Compound D one Trometamol and the further recrystallization of hydrate thereof, with purifying, the solvent of recrystallization can be selected isopropanol-water mixing solutions, acetone-water mixing solutions, alcohol-water mixing solutions, methanol-water mixing solutions or ether-water mixed solution.
Compound D one Trometamol of above-mentioned preparation or its hydrate, through proton nmr spectra, carbon spectrum analysis, are all consistent with embodiment 4.
The lyophilized injectable powder of embodiment 6. Compound D two Trometamols
Compound D two Trometamol 30g (when Compound D two Trometamol hydrate in Compound D two Trometamols)
N.F,USP MANNITOL 120g
PH buffer reagent is appropriate
Water for injection adds to 2500ml
Compound D two Trometamols, the N.F,USP MANNITOL of getting recipe quantity add 2300ml water for injection and dissolve, regulating pH is 7～8, injects water to 2500ml, with filtering with microporous membrane degerming, under hundred grades of conditions, carry out in sterile filling to 1000 cillin bottle, check after loading amount and add plug, box out, glass bottle is sent into in the freeze drying box of having sterilized, to carry out freeze-drying dry, pre-freeze 5 hours, temperature drops to-35 DEG C, distils for the first time 8 hours, and temperature rise is to-5 DEG C; Distil for the second time 7 hours, temperature rise to 25 DEG C, takes out after vacuum gland or inflated with nitrogen gland, and jewelling lid labeling gets product, and every bottle of freeze-dried powder is containing Compound D two Trometamol 30mg.
The lyophilized injectable powder of embodiment 7. Compound D two Trometamols
Compound D two Trometamol 25g (when Compound D two Trometamol hydrate in Compound D two Trometamols)
Sodium-chlor 18g
Glucose 30g
Calcium Disodium Edetate 0.15g
PH adjusting agent is appropriate
Water for injection adds to 2000ml
Compound D two Trometamols, sodium-chlor, the glucose of getting recipe quantity adds after 1800ml water for injection dissolves and adds Calcium Disodium Edetate dissolving, regulating pH is 8～9, inject water to 2000ml, stir with 0.3% (w/v) needle-use activated carbon, at 45 DEG C, stir 30 minutes, with the de-charcoal of the 0.6 μ m filter membrane through sterilizing, after 0.22 μ m membrane filtration degerming, surveying and adjusting pH is 8～9, filtrate is filling sends into freeze drier freeze-drying in 1000 control cillin bottles, add a cover or inflated with nitrogen after add a cover taking-up, label and get final product, wherein freeze-drying curve is as follows:
| Operation | Temperature rise rate | Temperature (DEG C) | |
| 1 | Pre-freeze | Be refrigerated to-40 DEG C by room temperature | |
| 2 | Insulation | -35℃ | |
| 3 | Vacuumize | -35℃ | |
| 4 | Heat up | 6 DEG C/h | Be warming up to-5 DEG C |
| 5 | Heat up | -5 DEG C are warming up to 0 DEG C | |
| 6 | Heat up | 0 DEG C is warming up to 10 DEG C | |
| 7 | Heat up | 10 DEG C are warming up to 25 DEG C | |
| 8 | Insulation | 25℃ |
The above-mentioned freeze-dried powder making, every bottle is 25mg containing Compound D two Trometamols.
Embodiment 8. presses the method for embodiment 6 or embodiment 7, adjust the recipe quantity of Compound D two Trometamols and/or pharmaceutical carrier (or auxiliary material), be prepared into the lyophilized injectable powder that every bottle is 5～100mg containing Compound D two Trometamols, being for example prepared into every bottle is 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 containing Compound D two Trometamols.
The injection of embodiment 9. Compound D two Trometamols, Compound D one Trometamol, its hydrate or its solvate
By the Compound D tromethamine salt described in any one in embodiment 1～5, its hydrate or its solvate, select conventional pharmaceutical excipient, mix with pharmaceutical excipient, press the preparation method of injection, be prepared into freeze-dried powder injection or injection liquid, the Compound D tromethamine salt that every bottle of freeze-dried powder injection or injection liquid contain 0.1～500mg.
The tablets/capsules agent of embodiment 10. Compound D two Trometamols, Compound D one Trometamol, its hydrate or its solvate
By the Compound D tromethamine salt described in any one in embodiment 1～5, its hydrate or its solvate, select conventional pharmaceutical excipient, mix with pharmaceutical excipient, press the preparation method of tablet or capsule, be prepared into tablet or capsule, the Compound D tromethamine salt that every tablet or capsule contain 0.1～500mg.
Embodiment 11., in 1 liter of deionized water, mixes the Trometamol of 0.1mol Compound D and 0.2mol, obtains settled solution, after filtration, is spin-dried for Rotary Evaporators, obtains containing Compound D and Trometamol pharmaceutical composition.
Embodiment 12., in 1 liter of deionized water, mixes the Trometamol of 0.1mol Compound D and 0.1mol, obtains settled solution, after filtration, is spin-dried for Rotary Evaporators, obtains containing Compound D and Trometamol pharmaceutical composition.
The sour reversible reduction experiment of embodiment 13.
Get respectively Compound D two Trometamols, Compound D one Trometamol, its hydrate or the each about 0.1g of its solvate prepared by above-described embodiment, be dissolved in 25ml distilled water, dripping hydrochloric acid tune pH is 1 left and right, all have Precipitation, collect, analyze, consistent with the spectrogram of Compound D, confirm as Compound D, illustrate that the tromethamine salt of the compounds of this invention D has only changed the pharmaceutical property of Compound D, instead of change its pharmacological action.
Embodiment 14.
Compound D tromethamine salt and preparation thereof that embodiment 1 to embodiment 10 is prepared, application in the following areas:
Application in preparation treatment Acute ischemic stroke medicine;
Application in the brain injury causing in preparation treatment cardiac operation under direct vision and the medicine of 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 (7)
1. the compound shown in formula I:
Wherein n=2 or 1.
2. the preparation method of compound claimed in claim 1, it is included in room temperature to the reflux temperature condition of solvent, be that 1: 1～1.1 Compound D contacts in solvent with Trometamol by mol ratio, reaction salify, and under room temperature or the condition lower than room temperature, make institute's salify crystallization, filter, dry, obtain, 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 dimethyl formamide, optionally can be by reducing Tc or/and steam except partial solvent is to accelerate the formation of crystallization, or the Compound D that is 1: 1 by mol ratio and Trometamol make them dissolve completely in 5～80 DEG C in suitable quantity of water, to stir, lyophilize, to obtain final product,
Wherein, the structural formula of described Compound D is as follows:
3. the preparation method of compound claimed in claim 1, it is included in room temperature to the reflux temperature condition of solvent, be that 1: 2～2.2 Compound D contacts in solvent with Trometamol by mol ratio, reaction salify, and under room temperature or the condition lower than room temperature, make institute's salify crystallization, filter, dry, obtain, 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 dimethyl formamide, optionally can be by reducing Tc or/and steam except partial solvent is to accelerate the formation of crystallization, or the Compound D that is 1: 2 by mol ratio and Trometamol make them dissolve completely in 5～80 DEG C in suitable quantity of water, to stir, lyophilize, to obtain final product,
Wherein, the structural formula of described Compound D is as follows:
4. a pharmaceutical composition, contains any compound claimed in claim 1 and pharmaceutically acceptable carrier.
5. a pharmaceutical composition, contains any compound claimed in claim 1 and pharmaceutically acceptable carrier, and wherein the content of any compound claimed in claim 1 is 0.1～500mg.
6. the preparation method of the pharmaceutical composition described in claim 4 or 5, comprises Compound D one Trometamol, Compound D two Trometamols and pharmaceutically acceptable carrier is fully mixed and made into acceptable any pharmaceutical dosage form in pharmaceutics,
Wherein, the structural formula of described Compound D is as follows:
7. compound claimed in claim 1 application in the following areas: the application in preparation treatment Acute ischemic stroke medicine; Application in the brain injury causing in preparation treatment cardiac operation under direct vision and the medicine of 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.
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| WO1999016741A2 (en) * | 1997-09-28 | 1999-04-08 | D-Pharm Limited | Lipophilic diesters of chelating agents |
| 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 |
| CN101514189A (en) * | 2008-02-18 | 2009-08-26 | 杨喜鸿 | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof |
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| CN1923798A (en) * | 2005-08-30 | 2007-03-07 | 陈亦林 | Preparation method of dexibuprofen amino acid salt and application |
| CN101486644B (en) * | 2009-02-24 | 2012-07-25 | 合肥工业大学 | Preparation of arginine acetylsalicylate |
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| WO1999016741A2 (en) * | 1997-09-28 | 1999-04-08 | D-Pharm Limited | Lipophilic diesters of chelating agents |
| 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 |
| CN101514189A (en) * | 2008-02-18 | 2009-08-26 | 杨喜鸿 | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof |
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| CN102126973A (en) | 2011-07-20 |
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