CN105315225A - Acotiamide acid addition salts and preparation methods thereof - Google Patents
Acotiamide acid addition salts and preparation methods thereof Download PDFInfo
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- CN105315225A CN105315225A CN201410319582.XA CN201410319582A CN105315225A CN 105315225 A CN105315225 A CN 105315225A CN 201410319582 A CN201410319582 A CN 201410319582A CN 105315225 A CN105315225 A CN 105315225A
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Abstract
The invention relates to acotiamide acid addition salts and preparation methods thereof. The various acotiamide acid addition salts are acotiamide hydrobromide, acotiamide citrate, acotiamide oxalate, acotiamide benzoate, acotiamide acetate, acotiamide mesylate and acotiamide tartrate, and the key absorption peaks of different acotiamide acid addition salts are determined through X-powder diffraction characterization. The acotiamide acid addition salts can be used to treat functional dyspepsia.
Description
Technical field
The invention belongs to the field of chemical synthesis, specifically, the present invention relates to the acid salt and preparation method thereof of Ah examining for amine.
Background technology
Ah examining is first the functional dyspepsia medicine for treatment in the whole world for amine (shown in formula I compound), is developed by Japanese Ze Li new drug Co., Ltd., and goes on the market in February, 2013 in Japan's approval.Be applicable to feeling of repletion after the meal, functional dyspepsia, epigastrium is glutted, early full treatment.
But, prepare the method for Ah examining for amine salt at present, still have much room for improvement.
Summary of the invention
The present invention one of is intended to solve the problems of the technologies described above at least to a certain extent or at least provides a kind of useful business to select.For this reason, one object of the present invention is that Ah the examining that propose to be suitable for suitability for industrialized production is for the acid salt of amine be used for the treatment of functional dyspepsia and for improving gastric motility disorder, delayed gastric emptying, thus improves FD symptom, comprises post-prandial fullness, big belly, the purposes such as morning is full.
In first of the present invention, comprise (to illustrate and unrestriced mode) for the medicinal acid of the acid salt of amine for the formation of Ah examining: Hydrogen bromide, phenylformic acid, acetic acid, hexanodioic acid, alginic acid, 4-ASA, xitix, aspartic acid, Gelucystine, L-glutamic acid, Pyrrolidonecarboxylic acid, butyric acid, dextrocamphoric acid, camphorsulfonic acid, carbonic acid, styracin, citric acid, toxilic acid, glucuronic acid, lactic acid, oxysuccinic acid, propanedioic acid, oxalic acid, formic acid, methylsulfonic acid, phenyl methanesulfonamide acid, tartrate, lauric acid, amygdalic acid, nicotinic acid, propionic acid, vitamin B13, picric acid, PIVALIC ACID CRUDE (25), SA, stearic acid, phosphoric acid, Whitfield's ointment, urobenzoic acid and 3-phenylpropionic acid etc.
In acid salt of the present invention, this acid and Ah examining can be the stoichiometric ratio of 1:n (n=1,2 or 3) for amine free cpds.
According to embodiments of the invention, contriver for Ah examining for amine hydrobromate, Ah examining for amine Citrate trianion, Ah examining for amine oxalate, Ah examining for amine benzoate, Ah examining for amine acetate, Ah examining for amine mesylate, Ah examining for amine tartrate, have studied its preparation method, physico-chemical property and its crystal formation.
To shine PhilipsAPD3720 type powder diffractometer record powder X-ray (XRD) of detector with being equipped with 3KWX-ray generator (CuK α 1 radiates) and NaI (Ti) especially, measuring from 3 ~ 45 ° (2 θ).
Ah examining has crucial absorption peak for amine hydrobromate at about 6.26 ± 0.2 °, 9.64 ± 0.2 °, 10.94 ± 0.2 °, 12.51 ± 0.2 °, 14.22 ± 0.2 °, 15.05 ± 0.2 °, 16.36 ± 0.2 °, 16.77 ± 0.2 °, 17.84 ± 0.2 °, 19.30 ± 0.2 °, 20.33 ± 0.2 °, 20.60 ± 0.2 °, 22.91 ± 0.2 °, 23.75 ± 0.2 °, 24.46 ± 0.2 ° and 26.08 ± 0.2 ° of (2 θ) places.
Ah examining has crucial absorption peak for amine Citrate trianion at about 8.21 ± 0.2 °, 8.77 ± 0.2 °, 13.86 ± 0.2 °, 14.71 ± 0.2 °, 16.31 ± 0.2 °, 18.02 ± 0.2 °, 23.15 ± 0.2 °, 24.92 ± 0.2 °, 26.06 ± 0.2 °, 27.05 ± 0.2 ° (2 θ) places.
Ah examining for amine oxalate about 6.52 ± 0.2 °, 6.64 ± 0.2 °, 13.43 ± 0.2 °, 15.56 ± 0.2 °, 21.21 ± 0.2 °, 25.05 ± 0.2 °, 26.33 ± 0.2 °, there is crucial absorption peak at (2 θ) place.
Ah examining has crucial absorption peak for amine benzoate at about 11.88 ± 0.2 °, 15.67 ± 0.2 °, 15.94 ± 0.2 °, 16.46 ± 0.2 °, 19.75 ± 0.2 °, 20.56 ± 0.2 °, 21.24 ± 0.2 °, 22.45 ± 0.2 °, 26.20 ± 0.2 °, 26.53 ± 0.2 ° (2 θ) places.
Ah examining has crucial absorption peak for amine acetate at about 12.44 ± 0.2 °, 13.94 ± 0.2 °, 15.72 ± 0.2 °, 24.10 ± 0.2 °, 25.83 ± 0.2 °, 26.16 ± 0.2 ° (2 θ) places.
Ah examining has crucial absorption peak for amine methylsulfonic acid at about 7.41 ± 0.2 °, 9.70 ± 0.2 °, 12.50 ± 0.2 °, 13.04 ± 0.2 °, 13.99 ± 0.2 °, 14.40 ± 0.2 °, 14.80 ± 0.2 °, 16.35 ± 0.2 °, 19.80 ± 0.2 °, 22.08 ± 0.2 °, 24.29 ± 0.2 °, 24.82 ± 0.2 °, 27.11 ± 0.2 ° (2 θ) places.
Ah examining has crucial absorption peak for amine tartrate at about 7.33 ± 0.2 °, 9.24 ± 0.2 °, 11.68 ± 0.2 °, 13.45 ± 0.2 °, 14.48 ± 0.2 °, 14.93 ± 0.2 °, 17.18 ± 0.2 °, 17.88 ± 0.2 °, 19.49 ± 0.2 °, 19.96 ± 0.2 °, 20.2 ° 9 ± 0.2 °, 23.69 ± 0.2 °, 24.35 ± 0.2 ° (2 θ) places.
According to a particular embodiment of the invention, above-mentioned Ah examining is hydrate forms for sour acid salt.According to a particular embodiment of the invention, described salt is monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, eight hydrates, nonahydrate or decahydrate.More particularly, the salt of hydrate forms produces with very high degree of crystallinity, and further, it shows beyond thought chemical stability, and therefore they are very useful for the stable medicinal forms of preparation.Pharmaceutical dosage form can be provided further to develop and clinical application.
According to a particular embodiment of the invention, described salt is crystallization, partial crystallization, amorphous or polymorphous form.Thus can so that Ah examining be for the purifying of amine salt.
According to a second aspect of the invention, the invention allows for foregoing Ah examining and preparing the purposes in medicine for the acid salt of amine, medicine is used for the treatment of functional dyspepsia.Utilization can utilize Ah examining to be used for the treatment of the medicine of functional dyspepsia as active fraction preparation for the tartrate etc. of amine for the mesylate of amine, Ah examining for the acetate of amine, Ah examining for the benzoate of amine, Ah examining for the oxalate of amine, Ah examining for the Citrate trianion of amine, Ah examining for the hydrobromate of amine, Ah examining.The purposes such as above-mentioned Ah examining may be used for improving gastric motility disorder, delayed gastric emptying for the acid salt of amine thus, thus improves FD symptom, comprises post-prandial fullness, big belly, and morning is full.
According to a third aspect of the invention we, the present invention proposes a kind of pharmaceutical composition, comprise: foregoing Ah examining is for the acid salt of amine; With pharmaceutically acceptable vehicle.Such as pharmaceutical composition can comprise Ah examining for the hydrobromate of amine, Ah examining for the Citrate trianion of amine, Ah examining for the oxalate of amine, Ah examining for the benzoate of amine, Ah examining for the acetate of amine, Ah examining for the mesylate of amine, Ah examining for the tartrate etc. of amine as activeconstituents.Pharmaceutical composition may be used for the disease for the treatment of functional dyspepsia aspect thus, such as, improve gastric motility disorder, delayed gastric emptying, thus improve FD symptom, comprise post-prandial fullness, big belly, early satisfies.
According to a forth aspect of the invention, the present invention relates to the preparation method of Ah examining for amine salt:
(1) Ah examining is mixed with organic solvent for amine, to obtain containing first mixture of Ah examining for amine and organic solvent;
(2) medicinal acid is added by described first mixture, to obtain containing Ah examining for amine and the second sour mixture;
(3) this salt-pepper noise is brought out;
(4) this crystalloid Ah examining is reclaimed for amine salt;
(5) adopt moisture organic solvent to carry out recrystallization, obtain highly purified Ah examining for amine salt.
In addition, preparation method according to the above embodiment of the present invention can also have following additional technical characteristic:
According to embodiments of the invention, described organic solvent is the wherein at least one be selected from methyl alcohol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, methyl tertiary butyl ether, methyltetrahydrofuran, ethyl acetate, butylacetate, isopropyl acetate, butanone, pentanone, toluene, dimethylbenzene, dimethyl formamide, normal hexane, hexanaphthene, particular methanol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, methyl tertiary butyl ether, the wherein at least one most preferably in methyl alcohol, ethanol, Virahol.
According to embodiments of the invention, at least one in solvent selected from methanol, ethanol, Virahol, tetrahydrofuran (THF), acetone in described moisture organic solvent, particular methanol, ethanol, Virahol, tetrahydrofuran (THF), the most preferably at least one of methyl alcohol, ethanol, Virahol.Also the purity of Ah examining for amine salt can be improved further thus.
According to a particular embodiment of the invention, in described moisture organic solvent, organic solvent volume ratio is 40 ~ 95% volumes, is preferably 60 ~ 90% volumes.
According to embodiments of the invention, described one-tenth salt solvent is medicinal aqueous acid.
According to embodiments of the invention, based on the gross weight of described medicinal aqueous acid, the content of described medicinal acid is 10 ~ 40% weight, and the content of medicinal acid is preferably 30 ~ 40% weight.
According to embodiments of the invention, described salt-forming reaction temperature is 20 ~ 100 DEG C, preferably 30 ~ 80 DEG C, most preferably 40 ~ 60 DEG C.
According to embodiments of the invention, above-mentioned Ah examining for the additive salt of amine as functional dyspepsia medicine for treatment.The bioavailability of Ah examining for amine can be improved thus, increase result for the treatment of further.
Compared with prior art, the invention has the advantages that: preparing a kind ofly does not have Ah the examining of bibliographical information for amino acid additive salt.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or additional aspect of the present invention and advantage will become obvious and easy understand from accompanying drawing below combining to the description of embodiment, wherein:
Fig. 1 composes for the hydrogen of amine hydrobromate according to Ah the examining of the embodiment of the present invention;
Fig. 2 composes for the XRD of amine hydrobromate according to Ah the examining of the embodiment of the present invention;
Fig. 3 composes for the hydrogen of amine Citrate trianion according to Ah the examining of the embodiment of the present invention;
Fig. 4 composes for the XRD of amine Citrate trianion according to Ah the examining of the embodiment of the present invention;
Fig. 5 composes for the hydrogen of amine oxalate according to Ah the examining of the embodiment of the present invention;
Fig. 6 composes for the XRD of amine oxalate according to Ah the examining of the embodiment of the present invention;
Fig. 7 composes for the hydrogen of amine benzoate according to Ah the examining of the embodiment of the present invention;
Fig. 8 composes for the XRD of amine benzoate according to Ah the examining of the embodiment of the present invention;
Fig. 9 composes for the hydrogen of amine acetate according to Ah the examining of the embodiment of the present invention;
Figure 10 composes for the XRD of amine acetate according to Ah the examining of the embodiment of the present invention;
Figure 11 composes for the hydrogen of amine mesylate according to Ah the examining of the embodiment of the present invention;
Figure 12 composes for the XRD of amine mesylate according to Ah the examining of the embodiment of the present invention;
Figure 13 composes for the hydrogen of amine tartrate according to Ah the examining of the embodiment of the present invention;
Figure 14 composes for the XRD of amine tartrate according to Ah the examining of the embodiment of the present invention.
Embodiment
Be described below in detail embodiments of the invention, it should be noted that embodiment described below is exemplary, only for explaining the present invention, and can not limitation of the present invention be interpreted as.In addition, if do not clearly not stated, adopted in the following embodiments all reagent are, and market can be buied, or can according to text or the synthesis of known method, for the reaction conditions do not listed, be also that those skilled in the art easily obtain.
General method
With reference to following formula, in the examples below that, prepare Ah examining mainly to comprise the following steps for the method for amine hydrochlorate hydrate: (1) takes free state Ah examining for amine, adds into salt solvent after adding organic solvent heating for dissolving, stirring, naturally cooling;
(2) filter, filter cake organic solvent washing, dry, get A Kao is for amine additive salt;
(3) Ah examining is dissolved in moisture organic solvent for amine salt, slow cooling crystallization after heating for dissolving, stirs, filter, obtain highly purified Ah examining for amino acid salt hydrate.
The specific embodiment of patent of the present invention is as follows:
Embodiment 1 Ah examining is for the preparation of amine hydrobromate
Get 3.0g free state Ah examining for amine, add 30ml Virahol, be heated to 80 DEG C of dissolvings, then add 4g40%HBr (3eq) in a heated condition, heating 0.5h, reaction system is clarified, and naturally cools to normal temperature, and a large amount of solid is separated out.Stir 2h, filter, filter cake washed with isopropyl alcohol.Dry, gained crude product 2.63g, adds 25ml80% isopropanol water solution (v/v) wherein, is heated to 80 DEG C, stirs 2h, naturally cools to room temperature, filters, filter cake washed with isopropyl alcohol.Finally obtain 2.0g white solid.
Target product
1h-NMR (400MHz, DMSO-d6): δ 1.30-1.33 (d, 12H), 3.20-3.25 (m, 2H), 3.56-3.61 (m, 2H), 3.67-3.70 (t, 2H), 3.77-3.84 (ss, 6H), 6.69-6.70 (s, 1H), 7.51-7.52 (s, 1H), 7.91-7.95 (s, 1H), 8.63-8.68 (m, 2H), 11.68-11.69 (s, 1H), (11.74-11.76 s, 1H).
Through XRD analysis, it has crucial absorption peak at about 6.26 ± 0.2 °, 9.64 ± 0.2 °, 10.94 ± 0.2 °, 12.51 ± 0.2 °, 14.22 ± 0.2 °, 15.05 ± 0.2 °, 16.36 ± 0.2 °, 16.77 ± 0.2 °, 17.84 ± 0.2 °, 19.30 ± 0.2 °, 20.33 ± 0.2 °, 20.60 ± 0.2 °, 22.91 ± 0.2 °, 23.75 ± 0.2 °, 24.46 ± 0.2 ° and 26.08 ± 0.2 ° of (2 θ) places.
Embodiment 2 Ah examining is for the preparation of amine Citrate trianion
Get 200mg free state Ah examining for amine, add 4ml Virahol, be heated to 80 DEG C of dissolvings, then add 83.9mg citric acid (1.0eq) in a heated condition, heating 4h, reaction system is clarified, and naturally cools to normal temperature, and a large amount of solid is separated out, stir 2h, filter, filter cake washed with isopropyl alcohol.Dry, finally obtain 150mg white solid.Add 5ml Virahol wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washed with isopropyl alcohol.Finally obtain 120mg white solid.
Target product
1h-NMR (400MHz, CD3OD): δ 1.41-1.43 (d, 12H), (2.80-2.92 m, 4H), 3.32-3.38 (m, 2H), 3.75-3.90 (m, 10H), 6.55 (s, 1H), 7.54 (s, 1H), 7.85 (s, 1H).
Through XRD analysis, it has crucial absorption peak at about 8.21 ± 0.2 °, 8.77 ± 0.2 °, 13.86 ± 0.2 °, 14.71 ± 0.2 °, 16.31 ± 0.2 °, 18.02 ± 0.2 °, 23.15 ± 0.2 °, 24.92 ± 0.2 °, 26.06 ± 0.2 °, 27.05 ± 0.2 ° (2 θ) places.
Embodiment 3 Ah examining is for the preparation of amine Citrate trianion
Get 1g free state Ah examining for amine, add 10ml ethanol, be heated to 70 DEG C do not dissolve completely, then add 466.78mg citric acid (1.0eq) in a heated condition, reaction system is clarified, 40 DEG C of heating 4h, naturally cool to normal temperature, a large amount of solid is separated out, and stirs 2h, filter, filter cake washed with isopropyl alcohol.Dry, finally obtain 500mg white solid, add 20ml ethanol wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washing with alcohol.Finally obtain 450mg white solid.
Embodiment 4 Ah examining is for the preparation of amine oxalate
Get 1g free state Ah examining for amine, add 10ml ethanol and 280mg oxalic acid (1.0eq), be heated to 40 DEG C of dissolvings, heating 2h, has solid to separate out, naturally cools to normal temperature, stirs 2h, filters, filter cake washing with alcohol.Dry, finally obtain 800mg white solid.Add 20ml80% aqueous ethanolic solution (V/V) wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washing with alcohol.Finally obtain 700mg white solid.
Target product
1h-NMR (400MHz, DMSO-d6): δ 1.04-1.26 (d, 12H), 3.11-3.42 (m, 2H), 3.47-3.60 (m, 5H), 3.74-3.83 (m, 8H), 6.67 (s, 1H), 7.44 (s, 1H), 7.75 (s, 1H), 8.56-8.57 (d, 1H).
Through XRD analysis, its about 6.52 ± 0.2 °, 6.64 ± 0.2 °, 13.43 ± 0.2 °, 15.56 ± 0.2 °, 21.21 ± 0.2 °, 25.05 ± 0.2 °, 26.33 ± 0.2 °, there is crucial absorption peak at (2 θ) place.
Embodiment 5 Ah examining is for the preparation of amine oxalate
Get 100mg free state Ah examining for amine, add 10ml Virahol and 28mg oxalic acid (1.0eq), reaction system is clarification, and stirring at normal temperature is spent the night, and has solid to separate out.Stir 2h, filter, filter cake washed with isopropyl alcohol.Dry, finally obtain 750mg white solid.Add 20ml80% isopropanol water solution (V/V) wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washed with isopropyl alcohol.Finally obtain 600mg white solid.
Embodiment 6 Ah examining is for the preparation of amine benzoate
Get 1g free state Ah examining for amine, add 20ml ethanol and 271.3mg phenylformic acid, normal-temperature dissolution, stir 2h, adularescent solid is separated out, and be heated to 70 DEG C, all dissolve, then Temperature fall is to room temperature.Solid is had to separate out.Stir 2h, filter, filter cake washing with alcohol.Dry, finally obtain 700mg white solid.Add 20ml80% aqueous ethanolic solution (V/V) wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washing with alcohol.Finally obtain 623mg white solid.
Target product
1h-NMR (400MHz, DMSO-d6): δ 1.08-1.18 (d, 12H), 2.98 (s, 2H), 3.42-3.47 (m, 4H), 3.71-3.76 (d, 6H), 4.38 (s, 1H), 6.43 (s, 1H), 7.40 (s, 1H), 7.59 (s, 1H), 8.39 (s, 1H).
Through XRD analysis, it has crucial absorption peak at about 11.88 ± 0.2 °, 15.67 ± 0.2 °, 15.94 ± 0.2 °, 16.46 ± 0.2 °, 19.75 ± 0.2 °, 20.56 ± 0.2 °, 21.24 ± 0.2 °, 22.45 ± 0.2 °, 26.20 ± 0.2 °, 26.53 ± 0.2 ° (2 θ) places.
Embodiment 7 Ah examining is for the preparation of amine acetate
Get 0.5g free state Ah examining for amine, add 20ml ethanol and 66.7mg acetic acid, normal-temperature dissolution, stir 2h, adularescent solid is separated out, and be heated to 70 DEG C, all dissolve, then Temperature fall is to room temperature.Solid is had to separate out.Stir 2h, filter, filter cake washing with alcohol.Dry, finally obtain 360mg white solid.Add 5ml80% aqueous ethanolic solution (V/V) wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washing with alcohol.Finally obtain 280mg white solid.
Target product
1h-NMR (400MHz, CDCl3): δ 1.24-1.32 (d, 12H), 1.35-1.42 (m, 2H), 2.71-3.00 (s, 2H), 3.28-3.37 (m, 2H), 3.60-3.61 (s, 2H), 3.71-3.85 (m, 1H), 3.85-4.06 (d, 6H), 6.28 (s, 1H), 7.65 (m, 1H), 7.75 (s, 1H), 7.95 (s, 1H).
Through XRD analysis, it has crucial absorption peak at about 12.44 ± 0.2 °, 13.94 ± 0.2 °, 15.72 ± 0.2 °, 24.10 ± 0.2 °, 25.83 ± 0.2 °, 26.16 ± 0.2 ° (2 θ) places.
Embodiment 8 Ah examining is for the preparation of amine mesylate
Get 1g free state Ah examining for amine, add 10ml ethanol and 213.5mg methylsulfonic acid, normal-temperature dissolution, be heated to 40 DEG C, reaction 4h, solid does not dissolve, and be heated to 70 DEG C, solid does not still dissolve, and then Temperature fall is to room temperature.Stir 2h, filter, filter cake washing with alcohol.Dry, finally obtain 750mg white solid.Add 20ml80% aqueous ethanolic solution (V/V) wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washing with alcohol.Finally obtain 600mg white solid.
Target product
1h-NMR (400MHz, DMSO-d6): δ 1.29-1.31 (d, 12H), 2.37 (s, 3H), 3.20 (s, 2H), 3.37-3.45 (m, 2H), 3.54-3.59 (m, 2H), 3.66-3.84 (d, 6H), 6.71 (s, 1H), 7.50 (s, 1H), 7.91 (s, 1H), 8.56 (s, 1H), 8.66 (s, 1H), (11.75-11.76 d, 2H).
Through XRD analysis, it has crucial absorption peak at about 7.41 ± 0.2 °, 9.70 ± 0.2 °, 12.50 ± 0.2 °, 13.04 ± 0.2 °, 13.99 ± 0.2 °, 14.40 ± 0.2 °, 14.80 ± 0.2 °, 16.35 ± 0.2 °, 19.80 ± 0.2 °, 22.08 ± 0.2 °, 24.29 ± 0.2 °, 24.82 ± 0.2 °, 27.11 ± 0.2 ° (2 θ) places.
Embodiment 9 Ah examining is for the tartaric preparation of amine
Get 1g free state Ah examining for amine, add 10ml ethanol, be heated to 70 DEG C, all do not dissolve, then add 333.33mg tartrate, rapid solution, then separate out white solid fast, be cooled to 40 DEG C, stir 4h, then Temperature fall is to room temperature.Stir 2h, filter, filter cake washing with alcohol.Dry, finally obtain 760mg white solid.Add 20ml90% aqueous ethanolic solution (V/V) wherein, be heated to 80 DEG C, stir 2h, naturally cool to room temperature, filter, filter cake washing with alcohol.Finally obtain 600mg white solid.
Target product
1h-NMR (400MHz, DMSO-d6): δ 1.20-1.22 (d, 12H), 2.98-3.01 (s, 2H), 3.42-3.47 (m, 4H), (3.72-3.76 d, 6H), 4.20 (s, 1H), 6.50 (s, 1H), (7.41 s, 1H), 7.63 (s, 1H), 8.46 (s, 1H).
Through XRD analysis, it has crucial absorption peak at about 7.33 ± 0.2 °, 9.24 ± 0.2 °, 11.68 ± 0.2 °, 13.45 ± 0.2 °, 14.48 ± 0.2 °, 14.93 ± 0.2 °, 17.18 ± 0.2 °, 17.88 ± 0.2 °, 19.49 ± 0.2 °, 19.96 ± 0.2 °, 20.2 ° 9 ± 0.2 °, 23.69 ± 0.2 °, 24.35 ± 0.2 ° (2 θ) places.
Embodiment 10 Ah examining is for the physical properties of the various medicinal acid addition salt of amine
Table 1 Ah examining is for the physico-chemical property of amino acid additive salt
| Medicinal acid | Fusing point (being measured by WRR melting point apparatus) | Water-soluble |
| Ah examining is for amine Hydrogen bromide | 182.6-186.6℃ | Insoluble |
| Ah examining is for amine Citrate trianion | 171.8-174.3℃ | Yi Rong |
| Ah examining is for amine oxalate | 150-174℃ | Yi Rong |
| Ah examining is for amine benzoate | 124.4-126.3℃ | Insoluble |
| Ah examining is for amine acetate | 124.5-126.9℃ | Yi Rong |
| Ah examining is for amine mesylate | 251.4-254.3℃ | Insoluble |
| Ah examining is for amine tartrate | 209.7-212.9℃ | Insoluble |
Embodiment 11 Oral Administration in Rats Ah examining is for the pharmacokinetics of the various salt of amine
Candidate drug
Adopt respectively Ah the examining that prepare of above-described embodiment for amine Citrate trianion, Ah examining for amine oxalate, Ah examining for amine benzoate, Ah examining for amine acetate, Ah examining for amine mesylate, Ah examining for amine tartrate and commercially available acotiamide hydrochloride trihydrate.
Grouping administration
Select Wistar rat 70, be divided into 7 groups at random, often organize 10, male and female dual-purpose, fasting 16h, wherein 1-6 group is experimental group, and oral administration gavage Ah examining examines for amine tartrate for amine mesylate, Ah for amine acetate, Ah examining for amine benzoate, Ah examining for amine oxalate, Ah examining for amine Citrate trianion, Ah examining respectively.7th group is control group, and oral administration gavage acotiamide hydrochloride trihydrate, dosage is 20mg/kg.Respectively, respectively after administration 0.5,1,2,4,6,8,12,18,24,36,48,60h eye frame gets blood, separation of serum ,-20 DEG C of preservations are to be measured.
Chromatographic condition
Stationary phase: DiamonsilTMC18 post, 10 μm, 250 × 4.6mm (I.D.), column temperature 30 DEG C.
Moving phase: methyl alcohol: water=70: 30, flow velocity: 1ml/min.
Determined wavelength: 215nm, sensitivity: 0.005AUFS.
Sample size: 20 μ l.
Blood sample treatments
Get rat blood serum 200 μ l, add interior mark (Ah examining is for amine 200 μ g/ml) 10 μ l, after mixing, add DMF (N, dinethylformamide) 200 μ l, vibration 10min, place 30 minutes, with the centrifugation 10min of 10000 turns/min, get supernatant liquor 20 μ l sample introduction.
Determination of plasma concentration
After bioassay standard curve, draw linear regression equation (y=ax+b).After the administration of mensuration rat, the ratio of blood sample gained peak area, calculates Plasma Concentration according to linear regression equation, and calculates medicine for parameter through 3P97 medicine for computation program.
Instrument
HPLC test macro: Shimadzu SPD-10AUv detector, Hi-TechP4000 high-pressure pump, LabAlliance-AS1000 automatic sampler, ANASTAR chromatographic working station.
HT-230A column oven: Tianjin Hengao Technology Development Co., Ltd. produces.
TGL-16G table model high speed centrifuge: Anting Scientific Instrument Factory, Shanghai manufactures.
The miniature vortex mixed instrument of WX-80A: Shanghai Hu Xi analytical instrument factory produces.
Result of study
Note: in table, data are mean number ± standard deviation (n=6).
Conclusion: Oral Administration in Rats Ah examining shows for the pharmacokinetic of the salt of amine, the salt examined for amine of Oral Administration in Rats gavage 20mg/kg, from medicine for parameter, between parameters, there is some difference, but substantially all within the scope of the same order of magnitude, may be used for being developed to new medicine, and this Stability Analysis of Structures, absorption in animal body, eliminate basically identical.
Ah examining of the present invention shows higher biological activity, for Subsequent pharmacological exploitation provides broad space for the salt of amine in preparation treatment functional dyspepsia medicine.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (14)
1. Ah examining is for the acid salt of amine, has following shown chemical structure:
It is characterized in that, n is 1, 2 or 3, A is medicinal acid, described medicinal acid is selected from Hydrogen bromide, phenylformic acid, acetic acid, hexanodioic acid, alginic acid, 4-ASA, xitix, aspartic acid, Gelucystine, L-glutamic acid, Pyrrolidonecarboxylic acid, butyric acid, dextrocamphoric acid, camphorsulfonic acid, carbonic acid, styracin, citric acid, toxilic acid, glucuronic acid, lactic acid, oxysuccinic acid, propanedioic acid, oxalic acid, formic acid, methylsulfonic acid, phenyl methanesulfonamide acid, tartrate, lauric acid, amygdalic acid, nicotinic acid, propionic acid, vitamin B13, picric acid, PIVALIC ACID CRUDE (25), SA, stearic acid, phosphoric acid, Whitfield's ointment, urobenzoic acid or 3-phenylpropionic acid.
2. Ah examining according to claim 1 is for the acid salt of amine, it is characterized in that, described Ah examining is the hydrobromate of Ah examining for amine for the acid salt of amine, described Ah examining for the X-ray powder diffraction figure of the hydrobromate of amine at 6.26 ± 0.2 °, 9.64 ± 0.2 °, 10.94 ± 0.2 °, 12.51 ± 0.2 °, 14.22 ± 0.2 °, 15.05 ± 0.2 °, 16.36 ± 0.2 °, 16.77 ± 0.2 °, 17.84 ± 0.2 °, 19.30 ± 0.2 °, 20.33 ± 0.2 °, 20.60 ± 0.2 °, 22.91 ± 0.2 °, 23.75 ± 0.2 °, there is X-ray diffraction peak in 24.46 ± 0.2 ° and 26.08 ± 0.2 ° (2 θ).
3. Ah examining according to claim 1 is for the acid salt of amine, it is characterized in that, described Ah examining is the Citrate trianion of Ah examining for amine for the acid salt of amine, and described Ah examining occurs X-ray diffraction peak for the X-ray powder diffraction figure of the Citrate trianion of amine at 8.21 ± 0.2 °, 8.77 ± 0.2 °, 13.86 ± 0.2 °, 14.71 ± 0.2 °, 16.31 ± 0.2 °, 18.02 ± 0.2 °, 23.15 ± 0.2 °, 24.92 ± 0.2 °, 26.06 ± 0.2 °, 27.05 ± 0.2 ° (2 θ).
4. Ah examining according to claim 1 is for the acid salt of amine, it is characterized in that, described Ah examining is the oxalate of Ah examining for amine for the acid salt of amine, and described Ah examining occurs X-ray diffraction peak for the X-ray powder diffraction figure of the oxalate of amine at 6.52 ± 0.2 °, 6.64 ± 0.2 °, 13.43 ± 0.2 °, 15.56 ± 0.2 °, 21.21 ± 0.2 °, 25.05 ± 0.2 °, 26.33 ± 0.2 ° (2 θ).
5. Ah examining according to claim 1 is for the acid salt of amine, it is characterized in that, described Ah examining is the benzoate of Ah examining for amine for the acid salt of amine, and described Ah examining occurs X-ray diffraction peak for the X-ray powder diffraction figure of the benzoate of amine at 11.88 ± 0.2 °, 15.67 ± 0.2 °, 15.94 ± 0.2 °, 16.46 ± 0.2 °, 19.75 ± 0.2 °, 20.56 ± 0.2 °, 21.24 ± 0.2 °, 22.45 ± 0.2 °, 26.20 ± 0.2 °, 26.53 ± 0.2 ° (2 θ).
6. Ah examining according to claim 1 is for the acid salt of amine, it is characterized in that, described Ah examining is the acetate of Ah examining for amine for the acid salt of amine, and described Ah examining occurs X-ray diffraction peak for the X-ray powder diffraction figure of the acetate of amine at 12.44 ± 0.2 °, 13.94 ± 0.2 °, 15.72 ± 0.2 °, 24.10 ± 0.2 °, 25.83 ± 0.2 °, 26.16 ± 0.2 ° (2 θ).
7. Ah examining according to claim 1 is for the acid salt of amine, it is characterized in that, described Ah examining is the mesylate of Ah examining for amine for the acid salt of amine, and described Ah examining occurs X-ray diffraction peak for the X-ray powder diffraction figure of the mesylate of amine at 7.41 ± 0.2 °, 9.70 ± 0.2 °, 12.50 ± 0.2 °, 13.04 ± 0.2 °, 13.99 ± 0.2 °, 14.40 ± 0.2 °, 14.80 ± 0.2 °, 16.35 ± 0.2 °, 19.80 ± 0.2 °, 22.08 ± 0.2 °, 24.29 ± 0.2 °, 24.82 ± 0.2 °, 27.11 ± 0.2 ° (2 θ).
8. Ah examining according to claim 1 is for the acid salt of amine, it is characterized in that, described Ah examining is the tartrate of Ah examining for amine for the acid salt of amine, and described Ah examining occurs X-ray diffraction peak for the X-ray powder diffraction figure of the tartrate of amine at 7.33 ± 0.2 °, 9.24 ± 0.2 °, 11.68 ± 0.2 °, 13.45 ± 0.2 °, 14.48 ± 0.2 °, 14.93 ± 0.2 °, 17.18 ± 0.2 °, 17.88 ± 0.2 °, 19.49 ± 0.2 °, 19.96 ± 0.2 °, 20.2 ° 9 ± 0.2 °, 23.69 ± 0.2 °, 24.35 ± 0.2 ° (2 θ).
9. Ah the examining according to any one of claim 1-8, for the acid salt of amine, is characterized in that, described Ah examining is the form of hydrate for the acid salt of amine;
Optionally, described salt is monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, eight hydrates, nonahydrate or decahydrate;
Optionally, described salt is crystallization, partial crystallization, amorphous or polymorphous form.
10. Ah the examining described in any one of claim 1-9 is preparing the purposes in medicine for the acid salt of amine, and described medicine is used for the treatment of functional dyspepsia.
11. 1 kinds of pharmaceutical compositions, is characterized in that, comprise:
Ah examining described in any one of claim 1-9 is for the acid salt of amine;
Pharmaceutically acceptable vehicle.
Ah examining described in 12. any one of preparation claim 1-9, for the method for amino acid additive salt, is characterized in that, comprising:
(1) Ah examining is mixed with organic solvent for amine, to obtain containing first mixture of Ah examining for amine and organic solvent;
(2) described medicinal acid is added by described first mixture, to obtain containing Ah examining for amine and the second sour mixture;
(3) this salt-pepper noise is brought out;
(4) this crystalloid Ah examining is reclaimed for amine salt;
(5) adopt moisture organic solvent to carry out recrystallization, obtain highly purified Ah examining for amine salt.
13. methods according to claim 12, it is characterized in that, described organic solvent is the wherein at least one be selected from methyl alcohol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, methyl tertiary butyl ether, methyltetrahydrofuran, ethyl acetate, butylacetate, isopropyl acetate, butanone, pentanone, toluene, dimethylbenzene, dimethyl formamide, normal hexane, hexanaphthene, particular methanol, ethanol, Virahol, ethyl acetate, tetrahydrofuran (THF), acetone, methyl tertiary butyl ether, the wherein at least one most preferably in methyl alcohol, ethanol, Virahol.
14. methods according to claim 12, it is characterized in that, in described moisture organic solvent, organic solvent is selected from least one in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone, particular methanol, ethanol, Virahol, tetrahydrofuran (THF), the most preferably at least one of methyl alcohol, ethanol, Virahol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646123A (en) * | 2002-04-08 | 2005-07-27 | 泽里新药工业株式会社 | Therapeutic agent for food competence disorder in stomach |
| CN101006040A (en) * | 2004-08-23 | 2007-07-25 | 泽里新药工业株式会社 | Method for producing aminothiazole derivative and production intermediate |
| CN103896873A (en) * | 2013-10-23 | 2014-07-02 | 山东诚创医药技术开发有限公司 | Refining method for hydrochloride acid acotiamide |
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2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646123A (en) * | 2002-04-08 | 2005-07-27 | 泽里新药工业株式会社 | Therapeutic agent for food competence disorder in stomach |
| CN101006040A (en) * | 2004-08-23 | 2007-07-25 | 泽里新药工业株式会社 | Method for producing aminothiazole derivative and production intermediate |
| CN103896873A (en) * | 2013-10-23 | 2014-07-02 | 山东诚创医药技术开发有限公司 | Refining method for hydrochloride acid acotiamide |
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